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Sample records for og dyrking av

  1. Environmental enrichment rescues DYRK1A activity and hippocampal adult neurogenesis in TgDyrk1A.

    PubMed

    Pons-Espinal, Meritxell; Martinez de Lagran, Maria; Dierssen, Mara

    2013-12-01

    Hippocampal adult neurogenesis disruptions have been suggested as one of the neuronal plasticity mechanisms underlying learning and memory impairment in Down syndrome (DS). However, it remains unknown whether specific candidate genes are implicated in these phenotypes in the multifactorial context of DS. Here we report that transgenic mice (TgDyrk1A) with overdosage of Dyrk1A, a DS candidate gene, show important alterations in adult neurogenesis including reduced cell proliferation rate, altered cell cycle progression and reduced cell cycle exit leading to premature migration, differentiation and reduced survival of newly born cells. In addition, less proportion of newborn hippocampal TgDyrk1A neurons are activated upon learning, suggesting reduced integration in learning circuits. Some of these alterations were DYRK1A kinase-dependent since we could rescue those using a DYRK1A inhibitor, epigallocatechin-3-gallate. Environmental enrichment also normalized DYRK1A kinase overdosage in the hippocampus, and rescued adult neurogenesis alterations in TgDyrk1A mice. We conclude that Dyrk1A is a good candidate to explain neuronal plasticity deficits in DS and that normalizing the excess of DYRK1A kinase activity either pharmacologically or using environmental stimulation can correct adult neurogenesis defects in DS.

  2. Environmental enrichment rescues DYRK1A activity and hippocampal adult neurogenesis in TgDyrk1A.

    PubMed

    Pons-Espinal, Meritxell; Martinez de Lagran, Maria; Dierssen, Mara

    2013-12-01

    Hippocampal adult neurogenesis disruptions have been suggested as one of the neuronal plasticity mechanisms underlying learning and memory impairment in Down syndrome (DS). However, it remains unknown whether specific candidate genes are implicated in these phenotypes in the multifactorial context of DS. Here we report that transgenic mice (TgDyrk1A) with overdosage of Dyrk1A, a DS candidate gene, show important alterations in adult neurogenesis including reduced cell proliferation rate, altered cell cycle progression and reduced cell cycle exit leading to premature migration, differentiation and reduced survival of newly born cells. In addition, less proportion of newborn hippocampal TgDyrk1A neurons are activated upon learning, suggesting reduced integration in learning circuits. Some of these alterations were DYRK1A kinase-dependent since we could rescue those using a DYRK1A inhibitor, epigallocatechin-3-gallate. Environmental enrichment also normalized DYRK1A kinase overdosage in the hippocampus, and rescued adult neurogenesis alterations in TgDyrk1A mice. We conclude that Dyrk1A is a good candidate to explain neuronal plasticity deficits in DS and that normalizing the excess of DYRK1A kinase activity either pharmacologically or using environmental stimulation can correct adult neurogenesis defects in DS. PMID:23969234

  3. Drosophila Dyrk2 plays a role in the development of the visual system.

    PubMed

    Luebbering, Nathan; Charlton-Perkins, Mark; Kumar, Justin P; Lochead, Pamela A; Rollmann, Stephanie M; Cook, Tiffany; Cleghon, Vaughn

    2013-01-01

    The DYRKs (dual-specificity tyrosine phosphorylation-regulated kinases) are a conserved family of protein kinases that are associated with a number of neurological disorders, but whose biological targets are poorly understood. Drosophila encodes three Dyrks: minibrain/Dyrk1A, DmDyrk2, and DmDyrk3. Here we describe the creation and characterization of a DmDyrk2 null allele, DmDyrk2(1w17) . We provide evidence that the smell impaired allele smi35A(1) , is likely to encode DmDyrk2. We also demonstrate that DmDyrk2 is expressed late in the developing third antennal segment, an anatomical structure associated with smell. In addition, we find that DmDyrk2 is expressed in the morphogenetic furrow of the developing eye, that loss of DmDyrk2 in the eye produced a subtle but measurable defect, and that ectopic DmDyrk2 expression in the eye produced a strong rough eye phenotype characterized by increased secondary, tertiary and bristle interommatidial cells. This phenotype was dependent on DmDyrk2 kinase activity and was only manifest when expressed in post-mitotic non-neuronal progenitors. Together, these data indicate that DmDyrk2 is expressed in developing sensory systems, that it is required for the development of the visual system, and that the eye is a good model to identify DmDyrk2 targets. PMID:24146926

  4. DYRK1A kinase inhibitors with emphasis on cancer.

    PubMed

    Ionescu, A; Dufrasne, F; Gelbcke, M; Jabin, I; Kiss, R; Lamoral-Theys, D

    2012-11-01

    Various types of cancers (including gliomas, melanomas, and esophageal, pancreas and non-small-cell lung cancers) display intrinsic resistance to pro-apoptotic stimuli, such as conventional chemotherapy and radiotherapy, and/or the activation of a multidrug resistance phenotype, which are major barriers to effective treatment and lead to poor patient prognosis. The DYRK1A kinase is directly implicated in the resistance of cancer cells to pro-apoptotic stimuli and drives several pathways that enhance proliferation, migration, and the reduction of cell death, leading to very aggressive biological behavior in cancer cell populations. The DYRK1A kinase is also implicated in neurological diseases and in neoangiogenic processes. Thus, the DYRK1A kinase is of great interest for both cancer and neuroscience research. During the last decade, numerous compounds that inhibit DYRK1A have been synthesized. The present review discusses the available molecules known to interfere with DYRK1A activity and the implications of DYRK1A in cancer and other diseases and serves as a rational analysis for researchers who aim to improve the anti-DYRK1A activity of currently available compounds. PMID:23016545

  5. Mechanism of dual specificity kinase activity of DYRK1A.

    PubMed

    Walte, Agnes; Rüben, Katharina; Birner-Gruenberger, Ruth; Preisinger, Christian; Bamberg-Lemper, Simone; Hilz, Nikolaus; Bracher, Franz; Becker, Walter

    2013-09-01

    The function of many protein kinases is controlled by the phosphorylation of a critical tyrosine residue in the activation loop. Dual specificity tyrosine-phosphorylation-regulated kinases (DYRKs) autophosphorylate on this tyrosine residue but phosphorylate substrates on aliphatic amino acids. This study addresses the mechanism of dual specificity kinase activity in DYRK1A and related kinases. Tyrosine autophosphorylation of DYRK1A occurred rapidly during in vitro translation and did not depend on the non-catalytic domains or other proteins. Expression in bacteria as well as in mammalian cells revealed that tyrosine kinase activity of DYRK1A is not restricted to the co-translational autophosphorylation in the activation loop. Moreover, mature DYRK1A was still capable of tyrosine autophosphorylation. Point mutants of DYRK1A and DYRK2 lacking the activation loop tyrosine showed enhanced tyrosine kinase activity. A series of structurally diverse DYRK1A inhibitors was used to pharmacologically distinguish different conformational states of the catalytic domain that are hypothesized to account for the dual specificity kinase activity. All tested compounds inhibited substrate phosphorylation with higher potency than autophosphorylation but none of the tested inhibitors differentially inhibited threonine and tyrosine kinase activity. Finally, the related cyclin-dependent kinase-like kinases (CLKs), which lack the activation loop tyrosine, autophosphorylated on tyrosine both in vitro and in living cells. We propose a model of DYRK autoactivation in which tyrosine autophosphorylation in the activation loop stabilizes a conformation of the catalytic domain with enhanced serine/threonine kinase activity without disabling tyrosine phosphorylation. The mechanism of dual specificity kinase activity probably applies to related serine/threonine kinases that depend on tyrosine autophosphorylation for maturation. PMID:23809146

  6. Impact of Dyrk1A level on alcohol metabolism.

    PubMed

    Renon, Marjorie; Legrand, Béatrice; Blanc, Etienne; Daubigney, Fabrice; Bokobza, Cindy; Mortreux, Marie; Paul, Jean-Louis; Delabar, Jean-Maurice; Rouach, Hélène; Andreau, Karine; Janel, Nathalie

    2016-09-01

    Alcoholic liver diseases arise from complex phenotypes involving many genetic factors. It is quite common to find hyperhomocysteinemia in chronic alcoholic liver diseases, mainly due to deregulation of hepatic homocysteine metabolism. Dyrk1A, involved in homocysteine metabolism at different crossroads, is decreased in liver of hyperhomocysteinemic mice. Here, we hypothesized that Dyrk1A contributes to alcohol-induced hepatic impairment in mice. Control, hyperhomocysteinemic and mice overexpressing Dyrk1A were fed using a Lieber-DeCarli liquid diet with or without ethanol (5% v/v ethanol) for one month, and liver histological examination and liver biochemical function tests were performed. Plasma alanine aminotransferase and homocysteine levels were significantly decreased in mice overexpressing Dyrk1A compared to control mice with or without alcohol administration. On the contrary, the mean plasma alanine aminotransferase and homocysteine levels were significantly higher in hyperhomocysteinemic mice than that of control mice after alcohol administration. Paraoxonase 1 and CYP2E1, two phase I xenobiotic metabolizing enzymes, were found increased in the three groups of mice after alcohol administration. However, NQO1, a phase II enzyme, was only found increased in hyperhomocysteinemic mice after alcohol exposure, suggesting a greater effect of alcohol in liver of hyperhomocysteinemic mice. We observed positive correlations between hepatic alcohol dehydrogenase activity, Dyrk1A and ADH4 protein levels. Importantly, a deleterious effect of alcohol consumption on hepatic Dyrk1A protein level was found. Our study reveals on the one hand a role of Dyrk1A in ethanol metabolism and on the other hand a deleterious effect of alcohol administration on hepatic Dyrk1A level.

  7. Impact of Dyrk1A level on alcohol metabolism.

    PubMed

    Renon, Marjorie; Legrand, Béatrice; Blanc, Etienne; Daubigney, Fabrice; Bokobza, Cindy; Mortreux, Marie; Paul, Jean-Louis; Delabar, Jean-Maurice; Rouach, Hélène; Andreau, Karine; Janel, Nathalie

    2016-09-01

    Alcoholic liver diseases arise from complex phenotypes involving many genetic factors. It is quite common to find hyperhomocysteinemia in chronic alcoholic liver diseases, mainly due to deregulation of hepatic homocysteine metabolism. Dyrk1A, involved in homocysteine metabolism at different crossroads, is decreased in liver of hyperhomocysteinemic mice. Here, we hypothesized that Dyrk1A contributes to alcohol-induced hepatic impairment in mice. Control, hyperhomocysteinemic and mice overexpressing Dyrk1A were fed using a Lieber-DeCarli liquid diet with or without ethanol (5% v/v ethanol) for one month, and liver histological examination and liver biochemical function tests were performed. Plasma alanine aminotransferase and homocysteine levels were significantly decreased in mice overexpressing Dyrk1A compared to control mice with or without alcohol administration. On the contrary, the mean plasma alanine aminotransferase and homocysteine levels were significantly higher in hyperhomocysteinemic mice than that of control mice after alcohol administration. Paraoxonase 1 and CYP2E1, two phase I xenobiotic metabolizing enzymes, were found increased in the three groups of mice after alcohol administration. However, NQO1, a phase II enzyme, was only found increased in hyperhomocysteinemic mice after alcohol exposure, suggesting a greater effect of alcohol in liver of hyperhomocysteinemic mice. We observed positive correlations between hepatic alcohol dehydrogenase activity, Dyrk1A and ADH4 protein levels. Importantly, a deleterious effect of alcohol consumption on hepatic Dyrk1A protein level was found. Our study reveals on the one hand a role of Dyrk1A in ethanol metabolism and on the other hand a deleterious effect of alcohol administration on hepatic Dyrk1A level. PMID:27216978

  8. Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage.

    PubMed

    Souchet, Benoit; Guedj, Fayçal; Sahún, Ignasi; Duchon, Arnaud; Daubigney, Fabrice; Badel, Anne; Yanagawa, Yuchio; Barallobre, Maria Jose; Dierssen, Mara; Yu, Eugene; Herault, Yann; Arbones, Mariona; Janel, Nathalie; Créau, Nicole; Delabar, Jean Maurice

    2014-09-01

    Cognitive deficits in Down syndrome (DS) have been linked to increased synaptic inhibition, leading to an imbalance of excitation/inhibition (E/I). Various mouse models and studies from human brains have implicated an HSA21 gene, the serine/threonine kinase DYRK1A, as a candidate for inducing cognitive dysfunction. Here, consequences of alterations in Dyrk1a dosage were assessed in mouse models with varying copy numbers of Dyrk1a: mBACtgDyrk1a, Ts65Dn and Dp(16)1Yey (with 3 gene copies) and Dyrk1a(+/-) (one functional copy). Molecular (i.e. immunoblotting/immunohistochemistry) and behavioral analyses (e.g., rotarod, Morris water maze, Y-maze) were performed in mBACtgDyrk1a mice. Increased expression of DYRK1A in mBACtgDyrk1a induced molecular alterations in synaptic plasticity pathways, particularly expression changes in GABAergic and glutaminergic related proteins. Similar alterations were observed in models with partial trisomy of MMU16, Ts65Dn and Dp(16)1Yey, and were reversed in the Dyrk1a(+/-) model. Dyrk1a overexpression produced an increased number and signal intensity of GAD67 positive neurons, indicating enhanced inhibition pathways in three different models: mBACtgDyrk1a, hYACtgDyrk1a and Dp(16)1Yey. Functionally, Dyrk1a overexpression protected mice from PTZ-induced seizures related to GABAergic neuron plasticity. Our study shows that DYRK1A overexpression affects pathways involved in synaptogenesis and synaptic plasticity and influences E/I balance toward inhibition. Inhibition of DYRK1A activity offers a therapeutic target for DS, but its inhibition/activation may also be relevant for other psychiatric diseases with E/I balance alterations.

  9. Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage.

    PubMed

    Souchet, Benoit; Guedj, Fayçal; Sahún, Ignasi; Duchon, Arnaud; Daubigney, Fabrice; Badel, Anne; Yanagawa, Yuchio; Barallobre, Maria Jose; Dierssen, Mara; Yu, Eugene; Herault, Yann; Arbones, Mariona; Janel, Nathalie; Créau, Nicole; Delabar, Jean Maurice

    2014-09-01

    Cognitive deficits in Down syndrome (DS) have been linked to increased synaptic inhibition, leading to an imbalance of excitation/inhibition (E/I). Various mouse models and studies from human brains have implicated an HSA21 gene, the serine/threonine kinase DYRK1A, as a candidate for inducing cognitive dysfunction. Here, consequences of alterations in Dyrk1a dosage were assessed in mouse models with varying copy numbers of Dyrk1a: mBACtgDyrk1a, Ts65Dn and Dp(16)1Yey (with 3 gene copies) and Dyrk1a(+/-) (one functional copy). Molecular (i.e. immunoblotting/immunohistochemistry) and behavioral analyses (e.g., rotarod, Morris water maze, Y-maze) were performed in mBACtgDyrk1a mice. Increased expression of DYRK1A in mBACtgDyrk1a induced molecular alterations in synaptic plasticity pathways, particularly expression changes in GABAergic and glutaminergic related proteins. Similar alterations were observed in models with partial trisomy of MMU16, Ts65Dn and Dp(16)1Yey, and were reversed in the Dyrk1a(+/-) model. Dyrk1a overexpression produced an increased number and signal intensity of GAD67 positive neurons, indicating enhanced inhibition pathways in three different models: mBACtgDyrk1a, hYACtgDyrk1a and Dp(16)1Yey. Functionally, Dyrk1a overexpression protected mice from PTZ-induced seizures related to GABAergic neuron plasticity. Our study shows that DYRK1A overexpression affects pathways involved in synaptogenesis and synaptic plasticity and influences E/I balance toward inhibition. Inhibition of DYRK1A activity offers a therapeutic target for DS, but its inhibition/activation may also be relevant for other psychiatric diseases with E/I balance alterations. PMID:24801365

  10. Dyrk1A induces pancreatic β cell mass expansion and improves glucose tolerance.

    PubMed

    Rachdi, Latif; Kariyawasam, Dulanjalee; Aïello, Virginie; Herault, Yann; Janel, Nathalie; Delabar, Jean-Maurice; Polak, Michel; Scharfmann, Raphaël

    2014-01-01

    Type 2 diabetes is caused by a limited capacity of insulin-producing pancreatic β cells to increase their mass and function in response to insulin resistance. The signaling pathways that positively regulate functional β cell mass have not been fully elucidated. DYRK1A (also called minibrain/MNB) is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. A significant amount of data implicates DYRK1A in brain growth and Down syndrome, and recent data indicate that Dyrk1A haploinsufficient mice have a low functional β cell mass. Here we ask whether Dyrk1A upregulation could be a way to increase functional β cell mass. We used mice overexpressing Dyrk1A under the control of its own regulatory sequences (mBACTgDyrk1A). These mice exhibit decreased glucose levels and hyperinsulinemia in the fasting state. Improved glucose tolerance is observed in these mice as early as 4 weeks of age. Upregulation of Dyrk1A in β cells induces expansion of β cell mass through increased proliferation and cell size. Importantly, mBACTgDyrk1A mice are protected against high-fat-diet-induced β cell failure through increase in β cell mass and insulin sensitivity. These studies show the crucial role of the DYRK1A pathway in the regulation of β cell mass and carbohydrate metabolism in vivo. Activating the DYRK1A pathway could thus represent an innovative way to increase functional β cell mass. PMID:24870561

  11. Acridone alkaloids from Glycosmis chlorosperma as DYRK1A inhibitors.

    PubMed

    Beniddir, Mehdi A; Le Borgne, Erell; Iorga, Bogdan I; Loaëc, Nadège; Lozach, Olivier; Meijer, Laurent; Awang, Khalijah; Litaudon, Marc

    2014-05-23

    Two new acridone alkaloids, chlorospermines A and B (1 and 2), were isolated from the stem bark of Glycosmis chlorosperma, together with the known atalaphyllidine (3) and acrifoline (4), by means of bioguided isolation using an in vitro enzyme assay against DYRK1A. Acrifoline (4) and to a lesser extent chlorospermine B (2) and atalaphyllidine (3) showed significant inhibiting activity on DYRK1A with IC50's of 0.075, 5.7, and 2.2 μM, respectively. Their selectivity profile was evaluated against a panel of various kinases, and molecular docking calculations provided structural details for the interaction between these compounds and DYRK1A. PMID:24798019

  12. Pyrido[2,3-d]pyrimidines: discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors.

    PubMed

    Anderson, Kevin; Chen, Yi; Chen, Zhi; Dominique, Romyr; Glenn, Kelli; He, Yang; Janson, Cheryl; Luk, Kin-Chun; Lukacs, Christine; Polonskaia, Ann; Qiao, Qi; Railkar, Aruna; Rossman, Pamela; Sun, Hongmao; Xiang, Qing; Vilenchik, Masha; Wovkulich, Peter; Zhang, Xiaolei

    2013-12-15

    DYRK1B is a kinase over-expressed in certain cancer cells (including colon, ovarian, pancreatic, etc.). Recent publications have demonstrated inhibition of DYRK1B could be an attractive target for cancer therapy. From a data-mining effort, the team has discovered analogues of pyrido[2,3-d]pyrimidines as potent enantio-selective inhibitors of DYRK1B. Cells treated with a tool compound from this series showed the same cellular effects as down regulation of DYRK1B with siRNA. Such effects are consistent with the proposed mechanism of action. Progress of the SAR study is presented.

  13. Pyrido[2,3-d]pyrimidines: discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors.

    PubMed

    Anderson, Kevin; Chen, Yi; Chen, Zhi; Dominique, Romyr; Glenn, Kelli; He, Yang; Janson, Cheryl; Luk, Kin-Chun; Lukacs, Christine; Polonskaia, Ann; Qiao, Qi; Railkar, Aruna; Rossman, Pamela; Sun, Hongmao; Xiang, Qing; Vilenchik, Masha; Wovkulich, Peter; Zhang, Xiaolei

    2013-12-15

    DYRK1B is a kinase over-expressed in certain cancer cells (including colon, ovarian, pancreatic, etc.). Recent publications have demonstrated inhibition of DYRK1B could be an attractive target for cancer therapy. From a data-mining effort, the team has discovered analogues of pyrido[2,3-d]pyrimidines as potent enantio-selective inhibitors of DYRK1B. Cells treated with a tool compound from this series showed the same cellular effects as down regulation of DYRK1B with siRNA. Such effects are consistent with the proposed mechanism of action. Progress of the SAR study is presented. PMID:24239188

  14. Meridianin derivatives as potent Dyrk1A inhibitors and neuroprotective agents.

    PubMed

    Yadav, Rammohan R; Sharma, Sadhana; Joshi, Prashant; Wani, Abubakar; Vishwakarma, Ram A; Kumar, Ajay; Bharate, Sandip B

    2015-08-01

    Meridianins are a group of marine-derived indole alkaloids which are reported to possess kinase inhibitory activities. In the present Letter, we report synthesis of N1-substituted and C-ring modified meridianin derivatives and their evaluation as Dyrk1A inhibitors and neuroprotective agents. Among the library of 52 compounds screened, morpholinoyl linked derivative 26b and 2-nitro-4-trifluoromethyl phenyl sulfonyl derivative 29v displayed potent inhibition of Dyrk1A with IC50 values of 0.5 and 0.53 μM, respectively. The derivative 26b also inhibited Dyrk2 and Dyrk3 with IC50 values of 1.4 and 2.2 μM, respectively showing 2.2 and 4.4 fold selectivity for Dyrk1A with respect to Dyrk2 and Dyrk3. The compound 26b was not cytotoxic to human neuroblastoma SH-SY5Y cells (IC50>100 μM) and it displayed significant neuroprotection against glutamate-induced neurotoxicity in these cells at 10 μM. Molecular modelling studies of compound 26b led to identification of key interactions in the binding site of Dyrk1A and the possible reasons for observed Dyrk1A selectivity over Dyrk2. PMID:26048785

  15. Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition.

    PubMed

    Soundararajan, Meera; Roos, Annette K; Savitsky, Pavel; Filippakopoulos, Panagis; Kettenbach, Arminja N; Olsen, Jesper V; Gerber, Scott A; Eswaran, Jeyanthy; Knapp, Stefan; Elkins, Jonathan M

    2013-06-01

    Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinases (DYRKs) play key roles in brain development, regulation of splicing, and apoptosis, and are potential drug targets for neurodegenerative diseases and cancer. We present crystal structures of one representative member of each DYRK subfamily: DYRK1A with an ATP-mimetic inhibitor and consensus peptide, and DYRK2 including NAPA and DH (DYRK homology) box regions. The current activation model suggests that DYRKs are Ser/Thr kinases that only autophosphorylate the second tyrosine of the activation loop YxY motif during protein translation. The structures explain the roles of this tyrosine and of the DH box in DYRK activation and provide a structural model for DYRK substrate recognition. Phosphorylation of a library of naturally occurring peptides identified substrate motifs that lack proline in the P+1 position, suggesting that DYRK1A is not a strictly proline-directed kinase. Our data also show that DYRK1A wild-type and Y321F mutant retain tyrosine autophosphorylation activity. PMID:23665168

  16. Structures of Down Syndrome Kinases, DYRKs, Reveal Mechanisms of Kinase Activation and Substrate Recognition

    PubMed Central

    Soundararajan, Meera; Roos, Annette K.; Savitsky, Pavel; Filippakopoulos, Panagis; Kettenbach, Arminja N.; Olsen, Jesper V.; Gerber, Scott A.; Eswaran, Jeyanthy; Knapp, Stefan; Elkins, Jonathan M.

    2013-01-01

    Summary Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinases (DYRKs) play key roles in brain development, regulation of splicing, and apoptosis, and are potential drug targets for neurodegenerative diseases and cancer. We present crystal structures of one representative member of each DYRK subfamily: DYRK1A with an ATP-mimetic inhibitor and consensus peptide, and DYRK2 including NAPA and DH (DYRK homology) box regions. The current activation model suggests that DYRKs are Ser/Thr kinases that only autophosphorylate the second tyrosine of the activation loop YxY motif during protein translation. The structures explain the roles of this tyrosine and of the DH box in DYRK activation and provide a structural model for DYRK substrate recognition. Phosphorylation of a library of naturally occurring peptides identified substrate motifs that lack proline in the P+1 position, suggesting that DYRK1A is not a strictly proline-directed kinase. Our data also show that DYRK1A wild-type and Y321F mutant retain tyrosine autophosphorylation activity. PMID:23665168

  17. Plasma DYRK1A as a novel risk factor for Alzheimer's disease.

    PubMed

    Janel, N; Sarazin, M; Corlier, F; Corne, H; de Souza, L C; Hamelin, L; Aka, A; Lagarde, J; Blehaut, H; Hindié, V; Rain, J-C; Arbones, M L; Dubois, B; Potier, M C; Bottlaender, M; Delabar, J M

    2014-01-01

    To determine whether apparent involvement of DYRK1A in Alzheimer's disease (AD) pathology makes it a candidate plasma biomarker for diagnosis, we developed a method to quantify plasma DYRK1A by immunoblot in transgenic mouse models having different gene dosages of Dyrk1a, and, consequently, different relative protein expression. Then, we measured plasma DYRK1A levels in 26 patients with biologically confirmed AD and 25 controls (negative amyloid imaging available on 13). DYRK1A was detected in transgenic mouse brain and plasma samples, and relative levels of DYRK1A correlated with the gene copy number. In plasma from AD patients, DYRK1A levels were significantly lower compared with controls (P<0.0001). Results were similar when we compared AD patients with the subgroup of controls confirmed by negative amyloid imaging. In a subgroup of patients with early AD (CDR=0.5), lower DYRK1A expression was confirmed. In contrast, no difference was found in levels of DYRK1B, the closest relative of DYRK1A, between AD patients and controls. Further, AD patients exhibited a positive correlation between plasma DYRK1A levels and cerebrospinal fluid tau and phosphorylated-tau proteins, but no correlation with amyloid-β42 levels and Pittsburgh compound B cortical binding. DYRK1A levels detected in lymphoblastoid cell lines from AD patients were also lower when compared with cells from age-matched controls. These findings suggest that reduced DYRK1A expression might be a novel plasma risk factor for AD. PMID:25116835

  18. DYRK1A mutations in two unrelated patients.

    PubMed

    Ruaud, Lyse; Mignot, Cyril; Guët, Agnès; Ohl, Christelle; Nava, Caroline; Héron, Delphine; Keren, Boris; Depienne, Christel; Benoit, Valérie; Maystadt, Isabelle; Lederer, Damien; Amsallem, Daniel; Piard, Juliette

    2015-03-01

    The Dual-specify tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene has been extensively studied for its role in the pathophysiology of intellectual disability (ID) in Down syndrome. The rise of next generation sequencing (NGS) and array-CGH (aCGH) in diagnostic settings for the evaluation of patients with ID allowed the identification of 17 patients carrying heterozygous genetic aberrations involving DYRK1A to date. The rate of DYRK1A mutations in this population reaches >1% in published NGS studies. The current report aims at further defining the phenotype of this encephalopathy with the detailed report of two unrelated patients. Both patients were boys with developmental delay, febrile seizures, facial dysmorphism and brain atrophy on MRI. Patient #1 had autistic behaviors and micropenis and Patient #2 had stereotypies and microcephaly. NGS analyses identified heterozygous de novo variants in DYRK1A: the c.613C >T (p.Arg205*) nonsense mutation in Patient #1 and the c.932C >T (p.Ser311Phe) missense mutation in Patient #2. Together with previously reported cases, patients with DYRK1A mutations share many clinical features and may have a recognizable phenotype that includes, by decreasing order of frequency: developmental delay or ID with behaviors suggesting autism spectrum disorder, microcephaly, epileptic seizures, facial dysmorphism including ear anomalies (large ears, hypoplastic lobes), thin lips, short philtrum and frontal bossing. Delineation of the phenotype/genotype correlation is not feasible at the moment and will be a challenge for the coming years. PMID:25641759

  19. Prefrontal deficits in a murine model overexpressing the down syndrome candidate gene dyrk1a.

    PubMed

    Thomazeau, Aurore; Lassalle, Olivier; Iafrati, Jillian; Souchet, Benoit; Guedj, Fayçal; Janel, Nathalie; Chavis, Pascale; Delabar, Jean; Manzoni, Olivier J

    2014-01-22

    The gene Dyrk1a is the mammalian ortholog of Drosophila minibrain. Dyrk1a localizes in the Down syndrome (DS) critical region of chromosome 21q22.2 and is a major candidate for the behavioral and neuronal abnormalities associated with DS. PFC malfunctions are a common denominator in several neuropsychiatric diseases, including DS, but the contribution of DYRK1A in PFC dysfunctions, in particular the synaptic basis for impairments of executive functions reported in DS patients, remains obscure. We quantified synaptic plasticity, biochemical synaptic markers, and dendritic morphology of deep layer pyramidal PFC neurons in adult mBACtgDyrk1a transgenic mice that overexpress Dyrk1a under the control of its own regulatory sequences. We found that overexpression of Dyrk1a largely increased the number of spines on oblique dendrites of pyramidal neurons, as evidenced by augmented spine density, higher PSD95 protein levels, and larger miniature EPSCs. The dendritic alterations were associated with anomalous NMDAR-mediated long-term potentiation and accompanied by a marked reduction in the pCaMKII/CaMKII ratio in mBACtgDyrk1a mice. Retrograde endocannabinoid-mediated long-term depression (eCB-LTD) was ablated in mBACtgDyrk1a mice. Administration of green tea extracts containing epigallocatechin 3-gallate, a potent DYRK1A inhibitor, to adult mBACtgDyrk1a mice normalized long-term potentiation and spine anomalies but not eCB-LTD. However, inhibition of the eCB deactivating enzyme monoacylglycerol lipase normalized eCB-LTD in mBACtgDyrk1a mice. These data shed light on previously undisclosed participation of DYRK1A in adult PFC dendritic structures and synaptic plasticity. Furthermore, they suggest its involvement in DS-related endophenotypes and identify new potential therapeutic strategies. PMID:24453307

  20. Understanding the Multifaceted Role of Human Down Syndrome Kinase DYRK1A.

    PubMed

    Kay, L J; Smulders-Srinivasan, T K; Soundararajan, M

    2016-01-01

    The dual-specificity tyrosine (Y) phosphorylation-regulated kinase DYRK1A, also known as Down syndrome (DS) kinase, is a dosage-dependent signaling kinase that was originally shown to be highly expressed in DS patients as a consequence of trisomy 21. Although this was evident some time ago, it is only in recent investigations that the molecular roles of DYRK1A in a wide range of cellular processes are becoming increasingly apparent. Since initial knowledge on DYRK1A became evident through minibrain mnb, the Drosophila homolog of DYRK1A, this review will first summarize the scientific reports on minibrain and further expand on the well-established neuronal functions of mammalian and human DYRK1A. Recent investigations across the current decade have provided rather interesting and compelling evidence in establishing nonneuronal functions for DYRK1A, including its role in infection, immunity, cardiomyocyte biology, cancer, and cell cycle control. The latter part of this review will therefore focus in detail on the emerging nonneuronal functions of DYRK1A and summarize the regulatory role of DYRK1A in controlling Tau and α-synuclein. Finally, the emerging role of DYRK1A in Parkinson's disease will be outlined. PMID:27567487

  1. DYRK1A in neurodegeneration and cancer: Molecular basis and clinical implications.

    PubMed

    Abbassi, Ramzi; Johns, Terrance G; Kassiou, Michael; Munoz, Lenka

    2015-07-01

    Protein kinases are one of the most studied drug targets in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. Dual-specificity Tyrosine phosphorylation-Regulated Kinase 1A (DYRK1A) has been much less studied compared to many other kinases. DYRK1A primary function occurs during early development, where this protein regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells. Although most extensively characterised for its role in brain development, DYRK1A is over-expressed in a variety of diseases including a number of human malignancies, such as haematological and brain cancers. Here we review the accumulating molecular studies that support our understanding of how DYRK1A signalling could underlie these pathological functions. The relevance of DYRK1A in a number of diseases is also substantiated with intensive drug discovery efforts to develop potent and selective inhibitors of DYRK1A. Several classes of DYRK1A inhibitors have recently been disclosed and some molecules are promising leads to develop DYRK1A inhibitors as drugs for DYRK1A-dependent diseases. PMID:25795597

  2. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) enhances tau expression.

    PubMed

    Qian, Wei; Jin, Nana; Shi, Jianhua; Yin, Xiaomin; Jin, Xiaoxia; Wang, Shibao; Cao, Maohong; Iqbal, Khalid; Gong, Cheng-Xin; Liu, Fei

    2013-01-01

    Microtubule-associated protein tau is found to be accumulated and aggregated in the brains of individuals with Alzheimer's disease and related tauopathies. Dual-specificity tyrosine-phosphorylation regulated kinase 1A (Dyrk1A) is overexpressed in Down syndrome and may play a critical role in the early onset of tau pathology in this disease. To investigate the effect of Dyrk1A on tau expression, we co-expressed different isoforms of tau with Dyrk1A in HEK-293FT cells and measured the mRNA and protein levels of tau using RT-PCR and Western blots, respectively. We further investigated the mechanism of regulation of tau expression by Dyrk1A. We found that Dyrk1A enhanced tau expression in a dose-dependent manner. The enhancement did not require the kinase activity of Dyrk1A. Dyrk1A increased the expression of tau isoforms containing exon 10 to a larger extent than isoforms lacking exon 10. The expression of endogenous tau in neuronal cells was also regulated by Dyrk1A, and increased tau levels were found in the brains of Ts65Dn mice that overexpress Dyrk1A due to partial trisomy of chromosome 16. Dyrk1A did not enhance tau gene transcription, but increased tau mRNA stability. These results suggest that Dyrk1A enhances tau expression by stabilizing its mRNA and provides a novel insight into the regulation of tau expression and a molecular mechanism of tauopathies. PMID:23948904

  3. DYRK1A inhibition as potential treatment for Alzheimer's disease.

    PubMed

    Stotani, Silvia; Giordanetto, Fabrizio; Medda, Federico

    2016-04-01

    In total, 47,500,000 people worldwide are affected by dementia and this number is estimated to double by 2030 and triple within 2050 resulting in a huge burden on public health. Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia, accounting for 60-70% of all the cases. The cause of AD is still poorly understood but several brain abnormalities (e.g., loss of neuronal connections and neuronal death) have been identified in affected patients. In addition to the accumulation of β-amyloid plaques in the brain tissue, aberrant phosphorylation of tau proteins has proved to increase neuronal death. DYRK1A phosphorylates tau on 11 different Ser/Thr residues, resulting in the formation of aggregates called 'neurofibrillary tangles' which, together with amyloid plaques, could be responsible for dementia, neuronal degeneration and cell death. Small molecule inhibition of DYRK1A could thus represent an interesting approach toward the treatment of Alzheimer's and other neurodegenerative diseases. Herein we review the current progress in the identification and development of DYRK1A inhibitors. PMID:27073990

  4. DYRK1A Is a Novel Negative Regulator of Cardiomyocyte Hypertrophy*

    PubMed Central

    Kuhn, Christian; Frank, Derk; Will, Rainer; Jaschinski, Christoph; Frauen, Robert; Katus, Hugo A.; Frey, Norbert

    2009-01-01

    Activation of the phosphatase calcineurin and its downstream targets, transcription factors of the NFAT family, results in cardiomyocyte hypertrophy. Recently, it has been shown that the dual specificity tyrosine (Y) phosphorylation-regulated kinase 1A (DYRK1A) is able to antagonize calcineurin signaling by directly phosphorylating NFATs. We thus hypothesized that DYRK1A might modulate the hypertrophic response of cardiomyocytes. In a model of phenylephrine-induced hypertrophy, adenovirus-mediated overexpression of DYKR1A completely abrogated the hypertrophic response and significantly reduced the expression of the natriuretic peptides ANF and BNP. Furthermore, DYRK1A blunted cardiomyocyte hypertrophy induced by overexpression of constitutively active calcineurin and attenuated the induction of the hypertrophic gene program. Conversely, knockdown of DYRK1A, utilizing adenoviruses encoding for a specific synthetic miRNA, resulted in an increase in cell surface area accompanied by up-regulation of ANF- mRNA. Similarly, treatment of cardiomyocytes with harmine, a specific inhibitor of DYRK1A, revealed cardiomyocyte hypertrophy on morphological and molecular level. Moreover, constitutively active calcineurin led to robust induction of an NFAT-dependent luciferase reporter, whereas DYRK1A attenuated calcineurin-induced reporter activation in cardiomyocytes. Conversely, both knockdown and pharmacological inhibition of DYRK1A significantly augmented the effect of calcineurin in this assay. In summary, we identified DYRK1A as a novel negative regulator of cardiomyocyte hypertrophy. Mechanistically, this effect appears to be mediated via inhibition of NFAT transcription factors. PMID:19372220

  5. DYRK1A Controls HIV-1 Replication at a Transcriptional Level in an NFAT Dependent Manner

    PubMed Central

    Booiman, Thijs; Loukachov, Vladimir V.; van Dort, Karel A.; van ’t Wout, Angélique B.; Kootstra, Neeltje A.

    2015-01-01

    Background Transcription of the HIV-1 provirus is regulated by both viral and host proteins and is very important in the context of viral latency. In latently infected cells, viral gene expression is inhibited as a result of the sequestration of host transcription factors and epigenetic modifications. Results In our present study we analyzed the effect of host factor dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) on HIV-1 replication. We show that DYRK1A controls HIV-1 replication by regulating provirus transcription. Downregulation or inhibition of DYRK1A increased LTR-driven transcription and viral replication in cell lines and primary PBMC. Furthermore, inhibition of DYRK1A resulted in reactivation of latent HIV-1 provirus to a similar extent as two commonly used broad-spectrum HDAC inhibitors. We observed that DYRK1A regulates HIV-1 transcription via the Nuclear Factor of Activated T-cells (NFAT) by promoting its translocation from the nucleus to the cytoplasm. Therefore, inhibition of DYRK1A results in increased nuclear levels of NFAT and increased NFAT binding to the viral LTR and thus increasing viral transcription. Conclusions Our data indicate that host factor DYRK1A plays a role in the regulation of viral transcription and latency. Therefore, DYRK1A might be an attractive candidate for therapeutic strategies targeting the viral reservoir. PMID:26641855

  6. AVS on satellite

    NASA Astrophysics Data System (ADS)

    Zhao, Haiwu; Wang, Guozhong; Hou, Gang

    2005-07-01

    AVS is a new digital audio-video coding standard established by China. AVS will be used in digital TV broadcasting and next general optical disk. AVS adopted many digital audio-video coding techniques developed by Chinese company and universities in recent years, it has very low complexity compared to H.264, and AVS will charge very low royalty fee through one-step license including all AVS tools. So AVS is a good and competitive candidate for Chinese DTV and next generation optical disk. In addition, Chinese government has published a plan for satellite TV signal directly to home(DTH) and a telecommunication satellite named as SINO 2 will be launched in 2006. AVS will be also one of the best hopeful candidates of audio-video coding standard on satellite signal transmission.

  7. Computational & experimental evaluation of the structure/activity relationship of β-carbolines as DYRK1A inhibitors.

    PubMed

    Drung, Binia; Scholz, Christoph; Barbosa, Valéria A; Nazari, Azadeh; Sarragiotto, Maria H; Schmidt, Boris

    2014-10-15

    DYRK1A has been associated with Down's syndrome and neurodegenerative diseases, therefore it is an important target for novel pharmacological interventions. We combined a ligand-based pharmacophore design with a structure-based protein/ligand docking using the software MOE in order to evaluate the underlying structure/activity relationship. Based on this knowledge we synthesized several novel β-carboline derivatives to validate the theoretical model. Furthermore we identified a modified lead structure as a potent DYRK1A inhibitor (IC50=130 nM) with significant selectivity against MAO-A, DYRK2, DYRK3, DYRK4 & CLK2. PMID:25240617

  8. DYRK1A overexpression enhances STAT activity and astrogliogenesis in a Down syndrome mouse model.

    PubMed

    Kurabayashi, Nobuhiro; Nguyen, Minh Dang; Sanada, Kamon

    2015-11-01

    Down syndrome (DS) arises from triplication of genes on human chromosome 21 and is associated with anomalies in brain development such as reduced production of neurons and increased generation of astrocytes. Here, we show that differentiation of cortical progenitor cells into astrocytes is promoted by DYRK1A, a Ser/Thr kinase encoded on human chromosome 21. In the Ts1Cje mouse model of DS, increased dosage of DYRK1A augments the propensity of progenitors to differentiate into astrocytes. This tendency is associated with enhanced astrogliogenesis in the developing neocortex. We also find that overexpression of DYRK1A upregulates the activity of the astrogliogenic transcription factor STAT in wild-type progenitors. Ts1Cje progenitors exhibit elevated STAT activity, and depletion of DYRK1A in these cells reverses the deregulation of STAT. In sum, our findings indicate that potentiation of the DYRK1A-STAT pathway in progenitors contributes to aberrant astrogliogenesis in DS. PMID:26373433

  9. DYRK1A overexpression enhances STAT activity and astrogliogenesis in a Down syndrome mouse model.

    PubMed

    Kurabayashi, Nobuhiro; Nguyen, Minh Dang; Sanada, Kamon

    2015-11-01

    Down syndrome (DS) arises from triplication of genes on human chromosome 21 and is associated with anomalies in brain development such as reduced production of neurons and increased generation of astrocytes. Here, we show that differentiation of cortical progenitor cells into astrocytes is promoted by DYRK1A, a Ser/Thr kinase encoded on human chromosome 21. In the Ts1Cje mouse model of DS, increased dosage of DYRK1A augments the propensity of progenitors to differentiate into astrocytes. This tendency is associated with enhanced astrogliogenesis in the developing neocortex. We also find that overexpression of DYRK1A upregulates the activity of the astrogliogenic transcription factor STAT in wild-type progenitors. Ts1Cje progenitors exhibit elevated STAT activity, and depletion of DYRK1A in these cells reverses the deregulation of STAT. In sum, our findings indicate that potentiation of the DYRK1A-STAT pathway in progenitors contributes to aberrant astrogliogenesis in DS.

  10. Tumor suppressor DYRK1A effects on proliferation and chemoresistance of AML cells by downregulating c-Myc.

    PubMed

    Liu, Qiang; Liu, Na; Zang, Shaolei; Liu, Heng; Wang, Pin; Ji, Chunyan; Sun, Xiulian

    2014-01-01

    Acute myeloid leukemia (AML), caused by abnormal proliferation and accumulation of hematopoietic progenitor cells, is one of the most common malignancies in adults. We reported here DYRK1A expression level was reduced in the bone marrow of adult AML patients, comparing to normal controls. Overexpression of DYRK1A inhibited the proliferation of AML cell lines by increasing the proportion of cells undergoing G0/G1 phase. We reasoned that the proliferative inhibition was due to downregulation of c-Myc by DYRK1A, through mediating its degradation. Moreover, overexpression of c-Myc markedly reversed AML cell growth inhibition induced by DYRK1A. DYRK1A also had significantly lower expression in relapsed/refractory AML patients, comparing to newly-diagnosed AML patients, which indicated the role of DYRK1A in chemoresistance of AML. Our study provided functional evidences for DYRK1A as a potential tumor suppressor in AML. PMID:24901999

  11. DYRK1A BAC transgenic mouse: a new model of thyroid dysgenesis in Down syndrome.

    PubMed

    Kariyawasam, Dulanjalee; Rachdi, Latif; Carré, Aurore; Martin, Mercè; Houlier, Marine; Janel, Nathalie; Delabar, Jean-Maurice; Scharfmann, Raphaël; Polak, Michel

    2015-03-01

    The most common thyroid abnormality among Down syndrome (DS) children corresponds to a mildly elevated TSH, with T4 decreased or in the normal range and thyroid hypoplasia, from the neonatal period onward, which aggravate their mental impairment. Transgenic Dyrk1A mice, obtained by bacterial artificial chromosome engineering (mBACTgDyrk1A), have 3 copies of the Dyrk1A gene. The objective is to determine whether this transgenic Dyrk1A (Dyrk1A(+/++)) mouse is an adequate murine model for the study of thyroid dysgenesis in DS. Embryonic thyroid development from embryonic day 13.5 (E13.5) to E17.5 was analyzed in wild-type (WT) and Dyrk1A(+/++) mice by immunofluorescence with anti-Nkx2-1, anti-thyroglobulin, and anti-T4 antibodies, markers of early thyroid development, hormonogenesis, and final differentiation, respectively. The expression of transcription factors Nkx2-1, Pax8, and Foxe1 involved in thyroidogenesis were studied by quantitative RT-PCR at the same embryonic stages. We then compared the adult phenotype at 8 to 12 weeks in Dyrk1A(+/++) and WT mice for T4 and TSH levels, thyroidal weight, and histological analysis. Regarding thyroidal development, at E15.5, Dyrk1A(+/++) thyroid lobes are double the size of WT thyroids (P = .01), but the thyroglobulin stained surface in Dyrk1A(+/++) thyroids is less than a third as large at E17.5 (P = .04) and their differentiated follicular surface half the size (P = .004). We also observed a significant increase in Nkx2-1, Foxe1, and Pax8 RNA levels in E13.5 and E17.5 Dyrk1A(+/++) embryonic thyroids. Dyrk1A(+/++) young adult mice have significantly lower plasma T4 (2.4 ng/mL versus WT, 3.7 ng/mL; P = 0.019) and nonsignificantly higher plasma TSH (114 mUI/L versus WT, 73mUI/L; P = .09). In addition, their thyroids are significantly heavier (P = .04) and exhibit large disorganized regions. Dyrk1A overexpression directly leads to thyroidal embryogenetic, functional and morphological impairment. The young adult thyroid

  12. The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells.

    PubMed

    Khor, Bernard; Gagnon, John D; Goel, Gautam; Roche, Marly I; Conway, Kara L; Tran, Khoa; Aldrich, Leslie N; Sundberg, Thomas B; Paterson, Alison M; Mordecai, Scott; Dombkowski, David; Schirmer, Melanie; Tan, Pauline H; Bhan, Atul K; Roychoudhuri, Rahul; Restifo, Nicholas P; O'Shea, John J; Medoff, Benjamin D; Shamji, Alykhan F; Schreiber, Stuart L; Sharpe, Arlene H; Shaw, Stanley Y; Xavier, Ramnik J

    2015-01-01

    The balance between Th17 and T regulatory (Treg) cells critically modulates immune homeostasis, with an inadequate Treg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances Treg differentiation and impairs Th17 differentiation without affecting known pathways of Treg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of Treg cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity. PMID:25998054

  13. DYRK1A: a potential drug target for multiple Down syndrome neuropathologies.

    PubMed

    Becker, Walter; Soppa, Ulf; Tejedor, Francisco J

    2014-02-01

    Down syndrome (DS), the most common genetic cause of intellectual disability, is caused by the trisomy of chromosome 21. MNB/DYRK1A (Minibrain/dual specificity tyrosine phosphorylation-regulated kinase 1A) has possibly been the most extensively studied chromosome 21 gene during the last decade due to the remarkable correlation of its functions in the brain with important DS neuropathologies, such as neuronal deficits, dendrite atrophy, spine dysgenesis, precocious Alzheimer's-like neurodegeneration, and cognitive deficits. MNB/DYRK1A has become an attractive drug target because increasing evidence suggests that its overexpression may induce DS-like neurobiological alterations, and several small-molecule inhibitors of its protein kinase activity are available. Here, we summarize the functional complexity of MNB/DYRK1A from a DS-research perspective, paying particular attention to the capacity of different MNB/DYRK1A inhibitors to reverse the neurobiological alterations caused by the increased activity of MNB/DYRK1A in experimental models. Finally, we discuss the advantages and drawbacks of possible MNB/DYRK1A-based therapeutic strategies that result from the functional, molecular, and pharmacological complexity of MNB/DYRK1A. PMID:24152332

  14. The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells

    PubMed Central

    Khor, Bernard; Gagnon, John D; Goel, Gautam; Roche, Marly I; Conway, Kara L; Tran, Khoa; Aldrich, Leslie N; Sundberg, Thomas B; Paterson, Alison M; Mordecai, Scott; Dombkowski, David; Schirmer, Melanie; Tan, Pauline H; Bhan, Atul K; Roychoudhuri, Rahul; Restifo, Nicholas P; O'Shea, John J; Medoff, Benjamin D; Shamji, Alykhan F; Schreiber, Stuart L; Sharpe, Arlene H; Shaw, Stanley Y; Xavier, Ramnik J

    2015-01-01

    The balance between Th17 and T regulatory (Treg) cells critically modulates immune homeostasis, with an inadequate Treg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances Treg differentiation and impairs Th17 differentiation without affecting known pathways of Treg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of Treg cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity. DOI: http://dx.doi.org/10.7554/eLife.05920.001 PMID:25998054

  15. Low Expression of DYRK2 (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 2) Correlates with Poor Prognosis in Colorectal Cancer.

    PubMed

    Yan, Haiyan; Hu, Kaishun; Wu, Wenjing; Li, Yu; Tian, Huan; Chu, Zhonghua; Koeffler, H Phillip; Yin, Dong

    2016-01-01

    Dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) is a member of dual-specificity kinase family, which could phosphorylate both Ser/Thr and Tyr substrates. The role of DYRK2 in human cancer remains controversial. For example, overexpression of DYRK2 predicts a better survival in human non-small cell lung cancer. In contrast, amplification of DYRK2 gene occurs in esophageal/lung adenocarcinoma, implying the role of DYRK2 as a potential oncogene. However, its clinical role in colorectal cancer (CRC) has not been explored. In this study, we analyzed the expression of DYRK2 from Oncomine database and found that DYRK2 level is lower in primary or metastatic CRC compared to adjacent normal colon tissue or non-metastatic CRC, respectively, in 6 colorectal carcinoma data sets. The correlation between DYRK2 expression and clinical outcome in 181 CRC patients was also investigated by real-time PCR and IHC. DYRK2 expression was significantly down-regulated in colorectal cancer tissues compared with adjacent non-tumorous tissues. Functional studies confirmed that DYRK2 inhibited cell invasion and migration in both HCT116 and SW480 cells and functioned as a tumor suppressor in CRC cells. Furthermore, the lower DYRK2 levels were correlated with tumor sites (P = 0.023), advanced clinical stages (P = 0.006) and shorter survival in the advanced clinical stages. Univariate and multivariate analyses indicated that DYRK2 expression was an independent prognostic factor (P < 0.001). Taking all, we concluded that DYRK2 a novel prognostic biomarker of human colorectal cancer. PMID:27532268

  16. Intracellular distribution of differentially phosphorylated dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A).

    PubMed

    Kaczmarski, Wojciech; Barua, Madhabi; Mazur-Kolecka, Bozena; Frackowiak, Janusz; Dowjat, Wieslaw; Mehta, Pankaj; Bolton, David; Hwang, Yu-Wen; Rabe, Ausma; Albertini, Giorgio; Wegiel, Jerzy

    2014-02-01

    The gene encoding dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is located within the Down syndrome (DS) critical region of chromosome 21. DYRK1A interacts with a plethora of substrates in the cytosol, cytoskeleton, and nucleus. Its overexpression is a contributing factor to the developmental alterations and age-associated pathology observed in DS. We hypothesized that the intracellular distribution of DYRK1A and cell-compartment-specific functions are associated with DYRK1A posttranslational modifications. Fractionation showed that, in both human and mouse brain, almost 80% of DYRK1A was associated with the cytoskeleton, and the remaining DYRK1A was present in the cytosolic and nuclear fractions. Coimmunoprecipitation revealed that DYRK1A in the brain cytoskeleton fraction forms complexes with filamentous actin, neurofilaments, and tubulin. Two-dimensional gel analysis of the fractions revealed DYRK1A with distinct isoelectric points: 5.5-6.5 in the nucleus, 7.2-8.2 in the cytoskeleton, and 8.7 in the cytosol. Phosphate-affinity gel electrophoresis demonstrated several bands of DYRK1A with different mobility shifts for nuclear, cytoskeletal, and cytosolic DYRK1A, indicating modification by phosphorylation. Mass spectrometry analysis disclosed one phosphorylated site in the cytosolic DYRK1A and multiple phosphorylated residues in the cytoskeletal DYRK1A, including two not previously described. This study supports the hypothesis that intracellular distribution and compartment-specific functions of DYRK1A may depend on its phosphorylation pattern. PMID:24327345

  17. Low Expression of DYRK2 (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 2) Correlates with Poor Prognosis in Colorectal Cancer

    PubMed Central

    Wu, Wenjing; Li, Yu; Tian, Huan; Chu, Zhonghua; Koeffler, H. Phillip; Yin, Dong

    2016-01-01

    Dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) is a member of dual-specificity kinase family, which could phosphorylate both Ser/Thr and Tyr substrates. The role of DYRK2 in human cancer remains controversial. For example, overexpression of DYRK2 predicts a better survival in human non-small cell lung cancer. In contrast, amplification of DYRK2 gene occurs in esophageal/lung adenocarcinoma, implying the role of DYRK2 as a potential oncogene. However, its clinical role in colorectal cancer (CRC) has not been explored. In this study, we analyzed the expression of DYRK2 from Oncomine database and found that DYRK2 level is lower in primary or metastatic CRC compared to adjacent normal colon tissue or non-metastatic CRC, respectively, in 6 colorectal carcinoma data sets. The correlation between DYRK2 expression and clinical outcome in 181 CRC patients was also investigated by real-time PCR and IHC. DYRK2 expression was significantly down-regulated in colorectal cancer tissues compared with adjacent non-tumorous tissues. Functional studies confirmed that DYRK2 inhibited cell invasion and migration in both HCT116 and SW480 cells and functioned as a tumor suppressor in CRC cells. Furthermore, the lower DYRK2 levels were correlated with tumor sites (P = 0.023), advanced clinical stages (P = 0.006) and shorter survival in the advanced clinical stages. Univariate and multivariate analyses indicated that DYRK2 expression was an independent prognostic factor (P < 0.001). Taking all, we concluded that DYRK2 a novel prognostic biomarker of human colorectal cancer. PMID:27532268

  18. Characterization of DYRK2 ( dual-specificity tyrosine-phosphorylation-regulated kinase 2) from Zebrafish ( Dario rerio)

    NASA Astrophysics Data System (ADS)

    Sun, Wei; Tan, Xungang; Zhang, Peijun; Zhang, Yuqing; Xu, Yongli

    2010-07-01

    Proteins of the DYRK (dual-specificity tyrosine-phosphorylation-regulated kinase) family are characterized by the presence of a conserved kinase domain and N-terminal DH box. DYRK2 is involved in regulating key developmental and cellular processes, such as neurogenesis, cell proliferation, cytokinesis, and cellular differentiation. Herein, we report that the ortholog of DYRK2 found in zebrafish shares about 70% identity with that of human, mouse, and chick. RT-PCR showed that DYRK2 is expressed maternally and zygotically. In-situ hybridization results show that DYRK2 is expressed in somite cells that will develop into muscles. Our results provide preliminary evidence for investigating the in-vivo function of DYRK2 in zebrafish muscle development.

  19. Haploinsufficiency of Dyrk1A in mice leads to specific alterations in the development and regulation of motor activity.

    PubMed

    Fotaki, V; Martínez De Lagrán, M; Estivill, X; Arbonés, M; Dierssen, M

    2004-08-01

    DYRK1A is a protein kinase proposed to be involved in neurogenesis. Gene-targeting disruption of Dyrk1A in mice leads to decreased body and brain size, with no severe disturbance of behavior. In this study, the authors focused on the motor profile of Dyrk1A(+/-) mice. These mice presented impairment of neuromotor development with decreased activity, suggesting a physiological role of Dyrk1A in the maturation of the neuromotor system. In the adult, a marked hypoactivity and alteration of specific motor parameters were detected. These results are in agreement with the significant expression of Dyrk1A in structures related to motor function and support a role of Dyrk1A in the control of motor function.

  20. DYRK1A: the double-edged kinase as a protagonist in cell growth and tumorigenesis

    PubMed Central

    Fernández-Martínez, P; Zahonero, C; Sánchez-Gómez, P

    2015-01-01

    DYRK1A (dual-specificity tyrosine-regulated kinase 1A) is a kinase with multiple implications for embryonic development, especially in the nervous system where it regulates the balance between proliferation and differentiation of neural progenitors. The DYRK1A gene is located in the Down syndrome critical region and may play a significant role in the developmental brain defects, early neurodegeneration, and cancer susceptibility of individuals with this syndrome. DYRK1A is also expressed in adults, where it might participate in the regulation of cell cycle, survival, and tumorigenesis, thus representing a potential therapeutic target for certain types of cancer. However, the final readout of DYRK1A overexpression or inhibition depends strongly on the cellular context, as it has both tumor suppressor and oncogenic activities. Here, we will discuss the functions and substrates of DYRK1A associated with the control of cell growth and tumorigenesis with a focus on the potential use of DYRK1A inhibitors in cancer therapy. PMID:27308401

  1. Selective inhibition of the kinase DYRK1A by targeting its folding process.

    PubMed

    Kii, Isao; Sumida, Yuto; Goto, Toshiyasu; Sonamoto, Rie; Okuno, Yukiko; Yoshida, Suguru; Kato-Sumida, Tomoe; Koike, Yuka; Abe, Minako; Nonaka, Yosuke; Ikura, Teikichi; Ito, Nobutoshi; Shibuya, Hiroshi; Hosoya, Takamitsu; Hagiwara, Masatoshi

    2016-01-01

    Autophosphorylation of amino-acid residues is part of the folding process of various protein kinases. Conventional chemical screening of mature kinases has missed inhibitors that selectively interfere with the folding process. Here we report a cell-based assay that evaluates inhibition of a kinase at a transitional state during the folding process and identify a folding intermediate-selective inhibitor of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), which we refer to as FINDY. FINDY suppresses intramolecular autophosphorylation of Ser97 in DYRK1A in cultured cells, leading to its degradation, but does not inhibit substrate phosphorylation catalysed by the mature kinase. FINDY also suppresses Ser97 autophosphorylation of recombinant DYRK1A, suggesting direct inhibition, and shows high selectivity for DYRK1A over other DYRK family members. In addition, FINDY rescues DYRK1A-induced developmental malformations in Xenopus laevis embryos. Our study demonstrates that transitional folding intermediates of protein kinases can be targeted by small molecules, and paves the way for developing novel types of kinase inhibitors. PMID:27102360

  2. DYRK1A: the double-edged kinase as a protagonist in cell growth and tumorigenesis.

    PubMed

    Fernández-Martínez, P; Zahonero, C; Sánchez-Gómez, P

    2015-01-01

    DYRK1A (dual-specificity tyrosine-regulated kinase 1A) is a kinase with multiple implications for embryonic development, especially in the nervous system where it regulates the balance between proliferation and differentiation of neural progenitors. The DYRK1A gene is located in the Down syndrome critical region and may play a significant role in the developmental brain defects, early neurodegeneration, and cancer susceptibility of individuals with this syndrome. DYRK1A is also expressed in adults, where it might participate in the regulation of cell cycle, survival, and tumorigenesis, thus representing a potential therapeutic target for certain types of cancer. However, the final readout of DYRK1A overexpression or inhibition depends strongly on the cellular context, as it has both tumor suppressor and oncogenic activities. Here, we will discuss the functions and substrates of DYRK1A associated with the control of cell growth and tumorigenesis with a focus on the potential use of DYRK1A inhibitors in cancer therapy. PMID:27308401

  3. Selective inhibition of the kinase DYRK1A by targeting its folding process

    PubMed Central

    Kii, Isao; Sumida, Yuto; Goto, Toshiyasu; Sonamoto, Rie; Okuno, Yukiko; Yoshida, Suguru; Kato-Sumida, Tomoe; Koike, Yuka; Abe, Minako; Nonaka, Yosuke; Ikura, Teikichi; Ito, Nobutoshi; Shibuya, Hiroshi; Hosoya, Takamitsu; Hagiwara, Masatoshi

    2016-01-01

    Autophosphorylation of amino-acid residues is part of the folding process of various protein kinases. Conventional chemical screening of mature kinases has missed inhibitors that selectively interfere with the folding process. Here we report a cell-based assay that evaluates inhibition of a kinase at a transitional state during the folding process and identify a folding intermediate-selective inhibitor of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), which we refer to as FINDY. FINDY suppresses intramolecular autophosphorylation of Ser97 in DYRK1A in cultured cells, leading to its degradation, but does not inhibit substrate phosphorylation catalysed by the mature kinase. FINDY also suppresses Ser97 autophosphorylation of recombinant DYRK1A, suggesting direct inhibition, and shows high selectivity for DYRK1A over other DYRK family members. In addition, FINDY rescues DYRK1A-induced developmental malformations in Xenopus laevis embryos. Our study demonstrates that transitional folding intermediates of protein kinases can be targeted by small molecules, and paves the way for developing novel types of kinase inhibitors. PMID:27102360

  4. Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A.

    PubMed

    Guedj, Fayçal; Sébrié, Catherine; Rivals, Isabelle; Ledru, Aurelie; Paly, Evelyne; Bizot, Jean C; Smith, Desmond; Rubin, Edward; Gillet, Brigitte; Arbones, Mariona; Delabar, Jean M

    2009-01-01

    Individuals with partial HSA21 trisomies and mice with partial MMU16 trisomies containing an extra copy of the DYRK1A gene present various alterations in brain morphogenesis. They present also learning impairments modeling those encountered in Down syndrome. Previous MRI and histological analyses of a transgenic mice generated using a human YAC construct that contains five genes including DYRK1A reveal that DYRK1A is involved, during development, in the control of brain volume and cell density of specific brain regions. Gene dosage correction induces a rescue of the brain volume alterations. DYRK1A is also involved in the control of synaptic plasticity and memory consolidation. Increased gene dosage results in brain morphogenesis defects, low BDNF levels and mnemonic deficits in these mice. Epigallocatechin gallate (EGCG) - a member of a natural polyphenols family, found in great amount in green tea leaves - is a specific and safe DYRK1A inhibitor. We maintained control and transgenic mice overexpressing DYRK1A on two different polyphenol-based diets, from gestation to adulthood. The major features of the transgenic phenotype were rescued in these mice. PMID:19242551

  5. A chemical with proven clinical safety rescues Down-syndrome-related phenotypes in through DYRK1A inhibition

    PubMed Central

    Kim, Hyeongki; Lee, Kyu-Sun; Kim, Ae-Kyeong; Choi, Miri; Choi, Kwangman; Kang, Mingu; Chi, Seung-Wook; Lee, Min-Sung; Lee, Jeong-Soo; Lee, So-Young; Song, Woo-Joo; Yu, Kweon

    2016-01-01

    ABSTRACT DYRK1A is important in neuronal development and function, and its excessive activity is considered a significant pathogenic factor in Down syndrome and Alzheimer's disease. Thus, inhibition of DYRK1A has been suggested to be a new strategy to modify the disease. Very few compounds, however, have been reported to act as inhibitors, and their potential clinical uses require further evaluation. Here, we newly identify CX-4945, the safety of which has been already proven in the clinical setting, as a potent inhibitor of DYRK1A that acts in an ATP-competitive manner. The inhibitory potency of CX-4945 on DYRK1A (IC50=6.8 nM) in vitro was higher than that of harmine, INDY or proINDY, which are well-known potent inhibitors of DYRK1A. CX-4945 effectively reverses the aberrant phosphorylation of Tau, amyloid precursor protein (APP) and presenilin 1 (PS1) in mammalian cells. To our surprise, feeding with CX-4945 significantly restored the neurological and phenotypic defects induced by the overexpression of minibrain, an ortholog of human DYRK1A, in the Drosophila model. Moreover, oral administration of CX-4945 acutely suppressed Tau hyperphosphorylation in the hippocampus of DYRK1A-overexpressing mice. Our research results demonstrate that CX-4945 is a potent DYRK1A inhibitor and also suggest that it has therapeutic potential for DYRK1A-associated diseases. PMID:27483355

  6. A chemical with proven clinical safety rescues Down-syndrome-related phenotypes in through DYRK1A inhibition.

    PubMed

    Kim, Hyeongki; Lee, Kyu-Sun; Kim, Ae-Kyeong; Choi, Miri; Choi, Kwangman; Kang, Mingu; Chi, Seung-Wook; Lee, Min-Sung; Lee, Jeong-Soo; Lee, So-Young; Song, Woo-Joo; Yu, Kweon; Cho, Sungchan

    2016-08-01

    DYRK1A is important in neuronal development and function, and its excessive activity is considered a significant pathogenic factor in Down syndrome and Alzheimer's disease. Thus, inhibition of DYRK1A has been suggested to be a new strategy to modify the disease. Very few compounds, however, have been reported to act as inhibitors, and their potential clinical uses require further evaluation. Here, we newly identify CX-4945, the safety of which has been already proven in the clinical setting, as a potent inhibitor of DYRK1A that acts in an ATP-competitive manner. The inhibitory potency of CX-4945 on DYRK1A (IC50=6.8 nM) in vitro was higher than that of harmine, INDY or proINDY, which are well-known potent inhibitors of DYRK1A. CX-4945 effectively reverses the aberrant phosphorylation of Tau, amyloid precursor protein (APP) and presenilin 1 (PS1) in mammalian cells. To our surprise, feeding with CX-4945 significantly restored the neurological and phenotypic defects induced by the overexpression of minibrain, an ortholog of human DYRK1A, in the Drosophila model. Moreover, oral administration of CX-4945 acutely suppressed Tau hyperphosphorylation in the hippocampus of DYRK1A-overexpressing mice. Our research results demonstrate that CX-4945 is a potent DYRK1A inhibitor and also suggest that it has therapeutic potential for DYRK1A-associated diseases. PMID:27483355

  7. A high-performance liquid chromatography assay for Dyrk1a, a Down syndrome-associated kinase.

    PubMed

    Bui, Linh C; Tabouy, Laure; Busi, Florent; Dupret, Jean-Marie; Janel, Nathalie; Planque, Chris; Delabar, Jean-Maurice; Rodrigues-Lima, Fernando; Dairou, Julien

    2014-03-15

    Down syndrome is the most common aneuploidy. It is caused by the presence of an extra copy of chromosome 21. Several studies indicate that aberrant expression of the kinase Dyrk1a (dual-specificity tyrosine phosphorylation-regulated kinase 1a) is implicated in Down syndrome, in particular in the onset of mental retardation. Moreover, elevated Dyrk1a activity may also be a risk factor for other neurodegenerative disorders such as Alzheimer's disease. Over the past years, Dyrk1a has appeared as a potential drug target. Availability of sensitive and quantitative enzyme assays is of prime importance to understand the role of Dyrk1a and to develop specific inhibitors. Here, we describe a new method to measure Dyrk1a activity based on the separation and quantification of specific fluorescent peptides (substrate and phosphorylated product) by high-performance liquid chromatography (HPLC). Kinetic and mechanistic analyses using well-known inhibitors of Dyrk1a confirmed the reliability of this approach. In addition, this assay was further validated using brain extracts of mice models expressing different copies of the Dyrk1a gene. Our results indicate that this novel Dyrk1a assay is simple, sensitive, and specific. It avoids the use of radioactivity-based approaches that, until now, have been widely employed to measure Dyrk1a activity. PMID:24374000

  8. Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.

    PubMed

    Bronicki, Lucas M; Redin, Claire; Drunat, Severine; Piton, Amélie; Lyons, Michael; Passemard, Sandrine; Baumann, Clarisse; Faivre, Laurence; Thevenon, Julien; Rivière, Jean-Baptiste; Isidor, Bertrand; Gan, Grace; Francannet, Christine; Willems, Marjolaine; Gunel, Murat; Jones, Julie R; Gleeson, Joseph G; Mandel, Jean-Louis; Stevenson, Roger E; Friez, Michael J; Aylsworth, Arthur S

    2015-11-01

    The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.

  9. Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.

    PubMed

    Bronicki, Lucas M; Redin, Claire; Drunat, Severine; Piton, Amélie; Lyons, Michael; Passemard, Sandrine; Baumann, Clarisse; Faivre, Laurence; Thevenon, Julien; Rivière, Jean-Baptiste; Isidor, Bertrand; Gan, Grace; Francannet, Christine; Willems, Marjolaine; Gunel, Murat; Jones, Julie R; Gleeson, Joseph G; Mandel, Jean-Louis; Stevenson, Roger E; Friez, Michael J; Aylsworth, Arthur S

    2015-11-01

    The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures. PMID:25920557

  10. Design and synthesis of a potent inhibitor of class 1 DYRK kinases as a suppressor of adipogenesis.

    PubMed

    Masaki, So; Kii, Isao; Sumida, Yuto; Kato-Sumida, Tomoe; Ogawa, Yasushi; Ito, Nobutoshi; Nakamura, Mitsuhiro; Sonamoto, Rie; Kataoka, Naoyuki; Hosoya, Takamitsu; Hagiwara, Masatoshi

    2015-08-01

    Dysregulation of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) has been demonstrated in several pathological conditions, including Alzheimer's disease and cancer progression. It has been recently reported that a gain of function-mutation in the human DYRK1B gene exacerbates metabolic syndrome by enhancing obesity. In the previous study, we developed an inhibitor of DYRK family kinases (INDY) and demonstrated that INDY suppresses the pathological phenotypes induced by overexpression of DYRK1A or DYRK1B in cellular and animal models. In this study, we designed and synthesized a novel inhibitor of DYRK family kinases based on the crystal structure of the DYRK1A/INDY complex by replacing the phenol group of INDY with dibenzofuran to produce a derivative, named BINDY. This compound exhibited potent and selective inhibitory activity toward DYRK family kinases in an in vitro assay. Furthermore, treatment of 3T3-L1 pre-adipocytes with BINDY hampered adipogenesis by suppressing gene expression of the critical transcription factors PPARγ and C/EBPα. This study indicates the possibility of BINDY as a potential drug for metabolic syndrome. PMID:26145823

  11. Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

    PubMed Central

    Bronicki, Lucas M; Redin, Claire; Drunat, Severine; Piton, Amélie; Lyons, Michael; Passemard, Sandrine; Baumann, Clarisse; Faivre, Laurence; Thevenon, Julien; Rivière, Jean-Baptiste; Isidor, Bertrand; Gan, Grace; Francannet, Christine; Willems, Marjolaine; Gunel, Murat; Jones, Julie R; Gleeson, Joseph G; Mandel, Jean-Louis; Stevenson, Roger E; Friez, Michael J; Aylsworth, Arthur S

    2015-01-01

    The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures. PMID:25920557

  12. Mutual regulation between SIAH2 and DYRK2 controls hypoxic and genotoxic signaling pathways.

    PubMed

    Pérez, Moisés; García-Limones, Carmen; Zapico, Inés; Marina, Anabel; Schmitz, M Lienhard; Muñoz, Eduardo; Calzado, Marco A

    2012-10-01

    The ubiquitin E3 ligase SIAH2 is an important regulator of the hypoxic response as it leads to the ubiquitin/proteasomal degradation of prolyl hydroxylases such as PHD3, which in turn increases the stability of hypoxia-inducible factor (HIF)-1α. In the present study, we identify the serine/threonine kinase DYRK2 as SIAH2 interaction partner that phosphorylates SIAH2 at five residues (Ser16, Thr26, Ser28, Ser68, and Thr119). Phosphomimetic and phospho-mutant forms of SIAH2 exhibit different subcellular localizations and consequently change in PHD3 degrading activity. Accordingly, phosphorylated SIAH2 is more active than the wild-type E3 ligase and shows an increased ability to trigger the HIF-1α-mediated transcriptional response and angiogenesis. We also found that SIAH2 knockdown increases DYRK2 stability, whereas SIAH2 expression facilitates DYRK2 polyubiquitination and degradation. Hypoxic conditions cause a SIAH2-dependent DYRK2 polyubiquitination and degradation which ultimately also results in an impaired SIAH2 phosphorylation. Similarly, DYRK2-mediated phosphorylation of p53 at Ser46 is impaired under hypoxic conditions, suggesting a molecular mechanism underlying chemotherapy resistance in solid tumors. PMID:22878263

  13. Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth.

    PubMed

    Pozo, Natividad; Zahonero, Cristina; Fernández, Paloma; Liñares, Jose M; Ayuso, Angel; Hagiwara, Masatoshi; Pérez, Angel; Ricoy, Jose R; Hernández-Laín, Aurelio; Sepúlveda, Juan M; Sánchez-Gómez, Pilar

    2013-06-01

    Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo- and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the subpopulation of GBM tumor-initiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation-regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs. PMID:23635774

  14. Mutual regulation between SIAH2 and DYRK2 controls hypoxic and genotoxic signaling pathways.

    PubMed

    Pérez, Moisés; García-Limones, Carmen; Zapico, Inés; Marina, Anabel; Schmitz, M Lienhard; Muñoz, Eduardo; Calzado, Marco A

    2012-10-01

    The ubiquitin E3 ligase SIAH2 is an important regulator of the hypoxic response as it leads to the ubiquitin/proteasomal degradation of prolyl hydroxylases such as PHD3, which in turn increases the stability of hypoxia-inducible factor (HIF)-1α. In the present study, we identify the serine/threonine kinase DYRK2 as SIAH2 interaction partner that phosphorylates SIAH2 at five residues (Ser16, Thr26, Ser28, Ser68, and Thr119). Phosphomimetic and phospho-mutant forms of SIAH2 exhibit different subcellular localizations and consequently change in PHD3 degrading activity. Accordingly, phosphorylated SIAH2 is more active than the wild-type E3 ligase and shows an increased ability to trigger the HIF-1α-mediated transcriptional response and angiogenesis. We also found that SIAH2 knockdown increases DYRK2 stability, whereas SIAH2 expression facilitates DYRK2 polyubiquitination and degradation. Hypoxic conditions cause a SIAH2-dependent DYRK2 polyubiquitination and degradation which ultimately also results in an impaired SIAH2 phosphorylation. Similarly, DYRK2-mediated phosphorylation of p53 at Ser46 is impaired under hypoxic conditions, suggesting a molecular mechanism underlying chemotherapy resistance in solid tumors.

  15. Selectivity Profiling and Biological Activity of Novel β-Carbolines as Potent and Selective DYRK1 Kinase Inhibitors

    PubMed Central

    Rüben, Katharina; Wurzlbauer, Anne; Walte, Agnes; Sippl, Wolfgang; Bracher, Franz; Becker, Walter

    2015-01-01

    DYRK1A is a pleiotropic protein kinase with diverse functions in cellular regulation, including cell cycle control, neuronal differentiation, and synaptic transmission. Enhanced activity and overexpression of DYRK1A have been linked to altered brain development and function in Down syndrome and neurodegenerative diseases such as Alzheimer’s disease. The β-carboline alkaloid harmine is a high affinity inhibitor of DYRK1A but suffers from the drawback of inhibiting monoamine oxidase A (MAO-A) with even higher potency. Here we characterized a series of novel harmine analogs with minimal or absent MAO-A inhibitory activity. We identified several inhibitors with submicromolar potencies for DYRK1A and selectivity for DYRK1A and DYRK1B over the related kinases DYRK2 and HIPK2. An optimized inhibitor, AnnH75, inhibited CLK1, CLK4, and haspin/GSG2 as the only off-targets in a panel of 300 protein kinases. In cellular assays, AnnH75 dose-dependently reduced the phosphorylation of three known DYRK1A substrates (SF3B1, SEPT4, and tau) without negative effects on cell viability. AnnH75 inhibited the cotranslational tyrosine autophosphorylation of DYRK1A and threonine phosphorylation of an exogenous substrate protein with similar potency. In conclusion, we have characterized an optimized β-carboline inhibitor as a highly selective chemical probe that complies with desirable properties of drug-like molecules and is suitable to interrogate the function of DYRK1A in biological studies. PMID:26192590

  16. Selectivity Profiling and Biological Activity of Novel β-Carbolines as Potent and Selective DYRK1 Kinase Inhibitors.

    PubMed

    Rüben, Katharina; Wurzlbauer, Anne; Walte, Agnes; Sippl, Wolfgang; Bracher, Franz; Becker, Walter

    2015-01-01

    DYRK1A is a pleiotropic protein kinase with diverse functions in cellular regulation, including cell cycle control, neuronal differentiation, and synaptic transmission. Enhanced activity and overexpression of DYRK1A have been linked to altered brain development and function in Down syndrome and neurodegenerative diseases such as Alzheimer's disease. The β-carboline alkaloid harmine is a high affinity inhibitor of DYRK1A but suffers from the drawback of inhibiting monoamine oxidase A (MAO-A) with even higher potency. Here we characterized a series of novel harmine analogs with minimal or absent MAO-A inhibitory activity. We identified several inhibitors with submicromolar potencies for DYRK1A and selectivity for DYRK1A and DYRK1B over the related kinases DYRK2 and HIPK2. An optimized inhibitor, AnnH75, inhibited CLK1, CLK4, and haspin/GSG2 as the only off-targets in a panel of 300 protein kinases. In cellular assays, AnnH75 dose-dependently reduced the phosphorylation of three known DYRK1A substrates (SF3B1, SEPT4, and tau) without negative effects on cell viability. AnnH75 inhibited the cotranslational tyrosine autophosphorylation of DYRK1A and threonine phosphorylation of an exogenous substrate protein with similar potency. In conclusion, we have characterized an optimized β-carboline inhibitor as a highly selective chemical probe that complies with desirable properties of drug-like molecules and is suitable to interrogate the function of DYRK1A in biological studies. PMID:26192590

  17. Design and synthesis of a library of lead-like 2,4-bisheterocyclic substituted thiophenes as selective Dyrk/Clk inhibitors.

    PubMed

    Schmitt, Christian; Kail, Dagmar; Mariano, Marica; Empting, Martin; Weber, Nadja; Paul, Tamara; Hartmann, Rolf W; Engel, Matthias

    2014-01-01

    The Dyrk family of protein kinases is implicated in the pathogenesis of several diseases, including cancer and neurodegeneration. Pharmacological inhibitors were mainly described for Dyrk1A so far, but in fewer cases for Dyrk1B, Dyrk2 or other isoforms. Herein, we report the development and optimization of 2,4-bisheterocyclic substituted thiophenes as a novel class of Dyrk inhibitors. The optimized hit compounds displayed favorable pharmacokinetic properties and high ligand efficiencies, and inhibited Dyrk1B in intact cells. In a larger selectivity screen, only Clk1 and Clk4 were identified as additional targets of compound 48, but no other kinases frequently reported as off-targets. Interestingly, Dyrk1A is implicated in the regulation of alternative splicing, a function shared with Clk1/Clk4; thus, some of the dual inhibitors might be useful as efficient splicing modulators. A further compound (29) inhibited Dyrk1A and 1B with an IC50 of 130 nM, showing a moderate selectivity over Dyrk2. Since penetration of the central nervous system (CNS) seems possible based on the physicochemical properties, this compound might serve as a lead for the development of potential therapeutic agents against glioblastoma. Furthermore, an inhibitor selective for Dyrk2 (24) was also identified, which might be are suitable as a pharmacological tool to dissect Dyrk2 isoform-mediated functions. PMID:24676346

  18. Design and Synthesis of a Library of Lead-Like 2,4-Bisheterocyclic Substituted Thiophenes as Selective Dyrk/Clk Inhibitors

    PubMed Central

    Schmitt, Christian; Kail, Dagmar; Mariano, Marica; Empting, Martin; Weber, Nadja; Paul, Tamara; Hartmann, Rolf W.; Engel, Matthias

    2014-01-01

    The Dyrk family of protein kinases is implicated in the pathogenesis of several diseases, including cancer and neurodegeneration. Pharmacological inhibitors were mainly described for Dyrk1A so far, but in fewer cases for Dyrk1B, Dyrk2 or other isoforms. Herein, we report the development and optimization of 2,4-bisheterocyclic substituted thiophenes as a novel class of Dyrk inhibitors. The optimized hit compounds displayed favorable pharmacokinetic properties and high ligand efficiencies, and inhibited Dyrk1B in intact cells. In a larger selectivity screen, only Clk1 and Clk4 were identified as additional targets of compound 48, but no other kinases frequently reported as off-targets. Interestingly, Dyrk1A is implicated in the regulation of alternative splicing, a function shared with Clk1/Clk4; thus, some of the dual inhibitors might be useful as efficient splicing modulators. A further compound (29) inhibited Dyrk1A and 1B with an IC50 of 130 nM, showing a moderate selectivity over Dyrk2. Since penetration of the central nervous system (CNS) seems possible based on the physicochemical properties, this compound might serve as a lead for the development of potential therapeutic agents against glioblastoma. Furthermore, an inhibitor selective for Dyrk2 (24) was also identified, which might be are suitable as a pharmacological tool to dissect Dyrk2 isoform–mediated functions. PMID:24676346

  19. Design and synthesis of a library of lead-like 2,4-bisheterocyclic substituted thiophenes as selective Dyrk/Clk inhibitors.

    PubMed

    Schmitt, Christian; Kail, Dagmar; Mariano, Marica; Empting, Martin; Weber, Nadja; Paul, Tamara; Hartmann, Rolf W; Engel, Matthias

    2014-01-01

    The Dyrk family of protein kinases is implicated in the pathogenesis of several diseases, including cancer and neurodegeneration. Pharmacological inhibitors were mainly described for Dyrk1A so far, but in fewer cases for Dyrk1B, Dyrk2 or other isoforms. Herein, we report the development and optimization of 2,4-bisheterocyclic substituted thiophenes as a novel class of Dyrk inhibitors. The optimized hit compounds displayed favorable pharmacokinetic properties and high ligand efficiencies, and inhibited Dyrk1B in intact cells. In a larger selectivity screen, only Clk1 and Clk4 were identified as additional targets of compound 48, but no other kinases frequently reported as off-targets. Interestingly, Dyrk1A is implicated in the regulation of alternative splicing, a function shared with Clk1/Clk4; thus, some of the dual inhibitors might be useful as efficient splicing modulators. A further compound (29) inhibited Dyrk1A and 1B with an IC50 of 130 nM, showing a moderate selectivity over Dyrk2. Since penetration of the central nervous system (CNS) seems possible based on the physicochemical properties, this compound might serve as a lead for the development of potential therapeutic agents against glioblastoma. Furthermore, an inhibitor selective for Dyrk2 (24) was also identified, which might be are suitable as a pharmacological tool to dissect Dyrk2 isoform-mediated functions.

  20. DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease.

    PubMed

    Barallobre, M J; Perier, C; Bové, J; Laguna, A; Delabar, J M; Vila, M; Arbonés, M L

    2014-01-01

    In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of neurons during development, and its pathological reactivation in the adult leads to neurodegeneration. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in neural proliferation and cell death, and its role during brain growth is evolutionarily conserved. Human DYRK1A lies in the Down syndrome critical region on chromosome 21, and heterozygous mutations in the gene cause microcephaly and neurological dysfunction. The mouse model for DYRK1A haploinsufficiency (the Dyrk1a(+/-) mouse) presents neuronal deficits in specific regions of the adult brain, including the substantia nigra (SN), although the mechanisms underlying these pathogenic effects remain unclear. Here we study the effect of DYRK1A copy number variation on dopaminergic cell homeostasis. We show that mesencephalic DA (mDA) neurons are generated in the embryo at normal rates in the Dyrk1a haploinsufficient model and in a model (the mBACtgDyrk1a mouse) that carries three copies of Dyrk1a. We also show that the number of mDA cells diminishes in postnatal Dyrk1a(+/-) mice and increases in mBACtgDyrk1a mice due to an abnormal activity of the mitochondrial caspase9 (Casp9)-dependent apoptotic pathway during the main wave of PCD that affects these neurons. In addition, we show that the cell death induced by 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), a toxin that activates Casp9-dependent apoptosis in mDA neurons, is attenuated in adult mBACtgDyrk1a mice, leading to an increased survival of SN DA neurons 21 days after MPTP intoxication. Finally, we present data indicating that Dyrk1a phosphorylation of Casp9 at the Thr125 residue is the mechanism by which this kinase hinders both physiological and pathological PCD in mDA neurons. These data provide new insight into the mechanisms that control cell death in brain DA neurons and they show that

  1. Natural aristolactams and aporphine alkaloids as inhibitors of CDK1/cyclin B and DYRK1A.

    PubMed

    Marti, Guillaume; Eparvier, Véronique; Morleo, Barbara; Le Ven, Jessica; Apel, Cécile; Bodo, Bernard; Amand, Séverine; Dumontet, Vincent; Lozach, Olivier; Meijer, Laurent; Guéritte, Françoise; Litaudon, Marc

    2013-01-01

    In an effort to find potent inhibitors of the protein kinases DYRK1A and CDK1/Cyclin B, a systematic in vitro evaluation of 2,500 plant extracts from New Caledonia and French Guyana was performed. Some extracts were found to strongly inhibit the activity of these kinases. Four aristolactams and one lignan were purified from the ethyl acetate extracts of Oxandra asbeckii and Goniothalamus dumontetii, and eleven aporphine alkaloids were isolated from the alkaloid extracts of Siparuna pachyantha, S. decipiens, S. guianensis and S. poeppigii. Among these compounds, velutinam, aristolactam AIIIA and medioresinol showed submicromolar IC50 values on DYRK1A. PMID:23467012

  2. DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies.

    PubMed

    Ji, Jianling; Lee, Hane; Argiropoulos, Bob; Dorrani, Naghmeh; Mann, John; Martinez-Agosto, Julian A; Gomez-Ospina, Natalia; Gallant, Natalie; Bernstein, Jonathan A; Hudgins, Louanne; Slattery, Leah; Isidor, Bertrand; Le Caignec, Cédric; David, Albert; Obersztyn, Ewa; Wiśniowiecka-Kowalnik, Barbara; Fox, Michelle; Deignan, Joshua L; Vilain, Eric; Hendricks, Emily; Horton Harr, Margaret; Noon, Sarah E; Jackson, Jessi R; Wilkens, Alisha; Mirzaa, Ghayda; Salamon, Noriko; Abramson, Jeff; Zackai, Elaine H; Krantz, Ian; Innes, A Micheil; Nelson, Stanley F; Grody, Wayne W; Quintero-Rivera, Fabiola

    2015-11-01

    Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from -2 SD to -5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs. PMID:25944381

  3. [Effect of Danshen-containing serum on expression of SuFu and DYRK2 in HSCs].

    PubMed

    Han, Shi-qing; Wang, Hai-lan; Feng, Li-li; Cao, Wen-fu

    2015-11-01

    To observe the effects of Danshen-containing serum on SuFu and DYRK2 expression in the HSCs stimulated by leptin. SD rats (n = 60) were used to make danshen-containing serum by gastric perfusion for ten days with Danshen water decoction, normal saline and colchicine. The HSCs that were cultured in vitro would be stimulated for 24 hours by leptin (100 μg x L(-1)) except blank control group, after being intervened, the drug serum in each group would be cultured at 37 degrees C in 5% incubator. The cells would be collected after 24 hours, then the effects of danshen-containing serum on the proliferation of HSCs were detected by MTT, the expression of SuFu mRNA and DYRK2 mRNA were detected by RT-PCR, the expression of SuFu and DYRK2 proteins were tested by Western blot. Compared with blank control group, the expression of DYRK2 mRNA and DYRK2 proteins were enhanced obviously after stimulated the HSCs of rats by leptin (P < 0.01), but the expression of SuFu mRNA and SuFu proteins were decreased significantly (P < 0.01). Compared with the model group, after cyclopamine group (Hh pathway inhibitor), Danshen-containing serum and colchicine were interfered, the expression of DYRK2 mRNA and DYRK2 proteins were decreased clearly (P < 0.01), but the expression of SuFu mRNA and SuFu proteins were increased significantly (P < 0.01 or P < 0.05). Compared with model group, adding purmorphamine (Hh pathway agonist) to model group and making it activate could increase the expression of DYRK2 mRNA and DYRK2 proteins, but the expression of SuFu mRNA and SuFu proteins were decreased significantly (P < 0.01). Compared with the model group, using the Danshen-containing serum to interfere the purmorphamine group could make the expression of DYRK2 mRNA and DYRK2 proteins decrease and the expression of SuFu mRNA and SuFu proteins increase significantly (P < 0.01). Danshen-containing serum would inhibition the activation and increment of HSCs by interfering the expression of SuFu and DYRK2

  4. Overexpression of Dyrk1A regulates cardiac troponin T splicing in cells and mice.

    PubMed

    Lu, Shu; Yin, Xiaomin

    2016-05-13

    The human heart expresses four isoforms of cardiac troponin T (cTnT) through alternative splicing of exons 4 and 5 of the cTnT gene. Alternative splicing of cTnT exon 5 is developmentally regulated. cTnT isoforms containing exon 5 are expressed in the fetal and neonatal heart but not in the mature heart. SRp55 is an essential splicing factor involved in cTnT exon 5 splicing and it is phosphorylated by Dyrk1A (dual specificity tyrosine phosphorylation regulated kinase 1A). In the present study, we found Dyrk1A interacted with SRp55 and enhanced its promotion of cTnT exon 5 inclusion. The shift from cTnT exon 5 inclusion to exclusion during development was delayed in the heart of Ts65Dn mice due to Dyrk1A overexpression. These results provide new insight into the role of Dyrk1A in the neonatal cardiac development. PMID:27049307

  5. Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cells.

    PubMed

    Kurabayashi, Nobuhiro; Sanada, Kamon

    2013-12-15

    Down's syndrome (DS), a major genetic cause of mental retardation, arises from triplication of genes on human chromosome 21. Here we show that DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) and DSCR1 (DS critical region 1), two genes lying within human chromosome 21 and encoding for a serine/threonine kinase and calcineurin regulator, respectively, are expressed in neural progenitors in the mouse developing neocortex. Increasing the dosage of both proteins in neural progenitors leads to a delay in neuronal differentiation, resulting ultimately in alteration of their laminar fate. This defect is mediated by the cooperative actions of DYRK1A and DSCR1 in suppressing the activity of the transcription factor NFATc. In Ts1Cje mice, a DS mouse model, dysregulation of NFATc in conjunction with increased levels of DYRK1A and DSCR1 was observed. Furthermore, counteracting the dysregulated pathway ameliorates the delayed neuronal differentiation observed in Ts1Cje mice. In sum, our findings suggest that dosage of DYRK1A and DSCR1 is critical for proper neurogenesis through NFATc and provide a potential mechanism to explain the neurodevelopmental defects in DS. PMID:24352425

  6. Triplication of DYRK1A causes retinal structural and functional alterations in Down syndrome.

    PubMed

    Laguna, Ariadna; Barallobre, María-José; Marchena, Miguel-Ángel; Mateus, Catarina; Ramírez, Erika; Martínez-Cue, Carmen; Delabar, Jean M; Castelo-Branco, Miguel; de la Villa, Pedro; Arbonés, Maria L

    2013-07-15

    Down syndrome (DS) results from the triplication of approximately 300 human chromosome 21 (Hsa21) genes and affects almost all body organs. Children with DS have defects in visual processing that may have a negative impact on their daily life and cognitive development. However, there is little known about the genes and pathogenesis underlying these defects. Here, we show morphometric in vivo data indicating that the neural retina is thicker in DS individuals than in the normal population. A similar thickening specifically affecting the inner part of the retina was also observed in a trisomic model of DS, the Ts65Dn mouse. Increased retinal size and cellularity in this model correlated with abnormal retinal function and resulted from an impaired caspase-9-mediated apoptosis during development. Moreover, we show that mice bearing only one additional copy of Dyrk1a have the same retinal phenotype as Ts65Dn mice and normalization of Dyrk1a gene copy number in Ts65Dn mice completely rescues both, morphological and functional phenotypes. Thus, triplication of Dyrk1a is necessary and sufficient to cause the retinal phenotype described in the trisomic model. Our data demonstrate for the first time the implication of DYRK1A overexpression in a developmental alteration of the central nervous system associated with DS, thereby providing insights into the aetiology of neurosensorial dysfunction in a complex disease. PMID:23512985

  7. Structure-activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors

    PubMed Central

    Cuny, Gregory D.; Robin, Maxime; Ulyanova, Natalia P.; Patnaik, Debasis; Pique, Valerie; Casano, Gilles; Liu, Ji-Feng; Lin, Xiangjie; Xian, Jun; Glicksman, Marcie A.; Stein, Ross L.; Higgins, Jonathan M.G.

    2010-01-01

    Haspin is a serine/threonine kinase required for completion of normal mitosis that is highly expressed during cell proliferation, including in a number of neoplasms. Consequently, it has emerged as a potential therapeutic target in oncology. A high throughput screen of approximately 140,000 compounds identified an acridine analog as a potent haspin kinase inhibitor. Profiling against a panel of 270 kinases revealed that the compound also exhibited potent inhibitory activity for DYRK2, another serine/threonine kinase. An optimization study of the acridine series revealed that the structure-activity relationship (SAR) of the acridine series for haspin and DYRK2 inhibition had many similarities. However, several structural differences were noted that allowed generation of a potent haspin kinase inhibitor (33, IC50 < 60 nM) with 180-fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC50 < 400 nM) with a 5.4-fold selectivity over haspin was also identified. PMID:20529681

  8. Structure–activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors

    PubMed Central

    Cuny, Gregory D.; Robin, Maxime; Ulyanova, Natalia P.; Patnaik, Debasis; Pique, Valerie; Casano, Gilles; Liu, Ji-Feng; Lin, Xiangjie; Xian, Jun; Glicksman, Marcie A.; Stein, Ross L.; Higgins, Jonathan M. G.

    2011-01-01

    Haspin is a serine/threonine kinase required for completion of normal mitosis that is highly expressed during cell proliferation, including in a number of neoplasms. Consequently, it has emerged as a potential therapeutic target in oncology. A high throughput screen of approximately 140,000 compounds identified an acridine analog as a potent haspin kinase inhibitor. Profiling against a panel of 270 kinases revealed that the compound also exhibited potent inhibitory activity for DYRK2, another serine/threonine kinase. An optimization study of the acridine series revealed that the structure–activity relationship (SAR) of the acridine series for haspin and DYRK2 inhibition had many similarities. However, several structural differences were noted that allowed generation of a potent haspin kinase inhibitor (33, IC50 <60 nM) with 180-fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC50 <400 nM) with a 5.4-fold selectivity over haspin was also identified. PMID:20836251

  9. Normalization of Dyrk1A expression by AAV2/1-shDyrk1A attenuates hippocampal-dependent defects in the Ts65Dn mouse model of Down syndrome.

    PubMed

    Altafaj, Xavier; Martín, Eduardo D; Ortiz-Abalia, Jon; Valderrama, Aitana; Lao-Peregrín, Cristina; Dierssen, Mara; Fillat, Cristina

    2013-04-01

    The cognitive dysfunctions of Down Syndrome (DS) individuals are the most disabling alterations caused by the trisomy of human chromosome 21 (HSA21). In trisomic Ts65Dn mice, a genetic model for DS, the overexpression of HSA21 homologous genes has been associated with strong visuo-spatial cognitive alterations, ascribed to hippocampal dysfunction. In the present study, we evaluated whether the normalization of the expression levels of Dyrk1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A), a candidate gene for DS, might correct hippocampal defects in Ts65Dn mice. In the hippocampus of 2 month-old Ts65Dn mice, such normalization was achieved through the stereotaxical injection of adeno-associated viruses containing a short hairpin RNA against Dyrk1A (AAV2/1-shDyrk1A) and a luciferase reporter gene. The injected hippocampi were efficiently transduced, as shown by bioluminescence in vivo imaging, luciferase activity quantification and immunohistochemical analysis. At the molecular level, viral infusion allowed the normalization of the targeted Dyrk1A expression, as well as of the key players of the MAPK/CREB pathway. The electrophysiological recordings of hippocampal slices from Ts65Dn mice injected with AAV2/1-shDyrk1A displayed attenuation of the synaptic plasticity defects of trisomic mice. In contrast, contralateral hippocampal injection with an AAV2/1 control virus containing a scrambled sequence, showed neither the normalization of Dyrk1A levels nor changes of synaptic plasticity. In the Morris water maze task, although long-term consolidation of the task was not achieved, treated Ts65Dn mice displayed initially a normalized thigmotactic behavior, similar to euploid littermates, indicating the partial improvement in their hippocampal-dependent search strategy. Taken together, these results show Dyrk1A as a critical player in the pathophysiology of DS and define Dyrk1A as a therapeutic target in adult trisomic mice. PMID:23220201

  10. Dyrk1A-mediated phosphorylation of RCAN1 promotes the formation of insoluble RCAN1 aggregates.

    PubMed

    Song, Woo-Joo; Song, Eun-Ah Christine; Choi, Sun-Hee; Baik, Hyung-Hwan; Jin, Byung Kwan; Kim, Jeong Hee; Chung, Sul-Hee

    2013-10-25

    The mechanisms underlying aggregate formation in age-related neurodegenerative diseases remain not well understood. Here we investigated whether dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) is involved in the formation of regulator of calcineurin 1 (RCAN1) aggregates. We show that RCAN1 self-associates and forms multimers, and that this process is promoted by the Dyrk1A-mediated phosphorylation of RCAN1 at the Thr(192) residue. Transgenic mice that overexpress the Dyrk1A exhibited lower levels of phospho-Thr(192)-RCAN1 in 10-month-old-group compared to littermate controls, when analyzed with soluble hippocampus lysates. These results suggest that the phosphorylation of RCAN1 by Dyrk1A stimulates the formation of insoluble aggregates upon aging. PMID:24021800

  11. Dyrk1A, a serine/threonine kinase, is involved in ERK and Akt activation in the brain of hyperhomocysteinemic mice.

    PubMed

    Abekhoukh, Sabiha; Planque, Chris; Ripoll, Clémentine; Urbaniak, Paulina; Paul, Jean-Louis; Delabar, Jean-Maurice; Janel, Nathalie

    2013-02-01

    Hyperhomocysteinemia due to cystathionine beta synthase (CBS) deficiency is associated with diverse brain disease. Whereas the biological actions linking hyperhomocysteinemia to the cognitive dysfunction are not well understood, we tried to establish relationships between hyperhomocysteinemia and alterations of signaling pathways. In the brain of CBS-deficient mice, a murine model of hyperhomocysteinemia, we previously found an activation of extracellular signal-regulated kinase (ERK) pathway and an increase of Dyrk1A, a serine/threonine kinase involved in diverse functions ranging from development and growth to apoptosis. We then investigated the relationship between Dyrk1A and the signaling pathways initiated by receptor tyrosine kinases (RTK), the ERK and PI3K/Akt pathways. We found a significant increase of phospho-ERK, phospho-MEK, and phospho-Akt in the brain of CBS-deficient and Dyrk1a-overexpressing mice. This increase was abolished when CBS-deficient and Dyrk1A-transgenic mice were treated with harmine, an inhibitor of Dyrk1A kinase activity, which emphasizes the role of Dyrk1A activity on ERK and Akt activation. Sprouty 2 protein level, a negative feedback loop modulator that limits the intensity and duration of RTK activation, is decreased in the brain of CBS-deficient mice, but not in the brain of Dyrk1A transgenic mice. Furthermore, a reduced Dyrk1A and Grb2 binding on sprouty 2 and an increased interaction of Dyrk1A with Grb2 were found in the brain of Dyrk1A transgenic mice. The consequence of Dyrk1A overexpression on RTK activation seems to be a decreased interaction of sprouty 2/Grb2. These observations demonstrate ERK and Akt activation induced by Dyrk1A in the brain of hyperhomocysteinemic mice and open new perspectives to understand the basis of the cognitive defects in hyperhomocysteinemia. PMID:22923366

  12. Gene dosage-dependent association of DYRK1A with the cytoskeleton in the brain and lymphocytes of down syndrome patients.

    PubMed

    Dowjat, Karol; Adayev, Tatyana; Kaczmarski, Wojciech; Wegiel, Jerzy; Hwang, Yu-Wen

    2012-12-01

    The triplication of the DYRK1A gene encoding proline-directed serine/threonine kinase and located in the critical region of Down syndrome (DS) has been implicated in cognitive deficits and intellectual disability of individuals with DS. We investigated the effect of abnormal levels of this kinase on the cytoskeleton in brain and peripheral tissues of DS subjects. In DS tissues, the predictable approximately equal to 1.5-fold enhancement of the levels of DYRK1A protein was demonstrated. An association of DYRK1A with all 3 major cytoskeleton networks was identified using immunoprecipitation. We concentrated on the actin cytoskeleton because its association with DYRK1A was the most affected by the enzyme levels. As measured by coimmunoprecipitation in DS tissues, but not in fragile X lymphocytes, actin association with DYRK1A was reduced. This reduced association was dependent on the state of phosphorylation of cytoskeletal proteins and was present only in cells overproducing DYRK1A kinase; therefore, the effect was attributable to the DYRK1A gene dosage. Alterations of DYRK1A-actin assemblies were detected in newborn and infant groups, thereby linking DYRK1A overexpression with abnormal brain development of DS children. The identification of the actin cytoskeleton as one of cellular targets of DYRK1A action provides new insights into a gene dosage-sensitive mechanism by which DYRK1A could contribute to the pathogenesis of DS. In addition, the presence of this DS-specific cytoskeleton anomaly in lymphocytes attests to the systemic nature of some features of DS. To our knowledge, this is the first study conducted in human tissue that shows DYRK1A association with the cytoskeleton. PMID:23147510

  13. Kinetic properties of a MNB/DYRK1A mutant suitable for the elucidation of biochemical pathways.

    PubMed

    Adayev, Tatyana; Chen-Hwang, Mo-Chou; Murakami, Noriko; Wegiel, Jerzy; Hwang, Yu-Wen

    2006-10-01

    Minibrain kinase/dual-specificity tyrosine phosphorylation regulated kinase 1A (MNB/DYRK1A) is a proline/arginine-directed serine/threonine kinase implicated in the learning deficits of Down syndrome. Epigallocatechin-3-gallate (EGCG), the major tea polyphenolic compound, is a potent MNB/DYRK1A inhibitor. In this study, we investigated the mechanism of EGCG inhibition of MNB/DYRK1A using a combination of genetic and biochemical approaches. In the testing system using MNB/DYRK1A-promoted Gli 1-dependent transcription as the readout, NIH3T3 cells expressing EGCG resistant MNB/DYRK1A mutant R21 were found to acquire EGCG resistance for a wide range of drug concentrations. Mutant R21 harbors a single K465R substitution, which produces a 3-fold gain in the EGCG resistance in vitro. However, the gain in the EGCG resistance alone cannot fully interpret the effectiveness of mutant R21 in suppressing EGCG in cultured cells. Kinetic analysis suggests that EGCG functions as a noncompetitive inhibitor against ATP. Interestingly, the K465R mutation changes the mode of EGCG inhibition on MNB/DYRK1A so that it becomes a competitive inhibitor against ATP. This competitive mode of EGCG inhibition coupled with high intracellular ATP concentrations and an elevated EGCG resistance are likely to be the basis for the resistant property of mutant R21 in cultured cells. The K465R mutation apparently transforms the intramolecular interactions required for MNB/DYRK1A catalysis. This mutant would also be valuable for the elucidation of the mechanisms of MNB/DYRK1A-catalyzed reaction. PMID:17002300

  14. A dual specificity kinase, DYRK1A, as a potential therapeutic target for head and neck squamous cell carcinoma

    PubMed Central

    Radhakrishnan, Aneesha; Nanjappa, Vishalakshi; Raja, Remya; Sathe, Gajanan; Puttamallesh, Vinuth N.; Jain, Ankit P.; Pinto, Sneha M.; Balaji, Sai A.; Chavan, Sandip; Sahasrabuddhe, Nandini A.; Mathur, Premendu P.; Kumar, Mahesh M.; Prasad, T. S. Keshava; Santosh, Vani; Sukumar, Geethanjali; Califano, Joseph A.; Rangarajan, Annapoorni; Sidransky, David; Pandey, Akhilesh; Gowda, Harsha; Chatterjee, Aditi

    2016-01-01

    Despite advances in clinical management, 5-year survival rate in patients with late-stage head and neck squamous cell carcinoma (HNSCC) has not improved significantly over the past decade. Targeted therapies have emerged as one of the most promising approaches to treat several malignancies. Though tyrosine phosphorylation accounts for a minority of total phosphorylation, it is critical for activation of signaling pathways and plays a significant role in driving cancers. To identify activated tyrosine kinase signaling pathways in HNSCC, we compared the phosphotyrosine profiles of a panel of HNSCC cell lines to a normal oral keratinocyte cell line. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) was one of the kinases hyperphosphorylated at Tyr-321 in all HNSCC cell lines. Inhibition of DYRK1A resulted in an increased apoptosis and decrease in invasion and colony formation ability of HNSCC cell lines. Further, administration of the small molecular inhibitor against DYRK1A in mice bearing HNSCC xenograft tumors induced regression of tumor growth. Immunohistochemical labeling of DYRK1A in primary tumor tissues using tissue microarrays revealed strong to moderate staining of DYRK1A in 97.5% (39/40) of HNSCC tissues analyzed. Taken together our results suggest that DYRK1A could be a novel therapeutic target in HNSCC. PMID:27796319

  15. Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: development of chemical probe ML315.

    PubMed

    Coombs, Thomas C; Tanega, Cordelle; Shen, Min; Wang, Jenna L; Auld, Douglas S; Gerritz, Samuel W; Schoenen, Frank J; Thomas, Craig J; Aubé, Jeffrey

    2013-06-15

    Substituted pyrimidine inhibitors of the Clk and Dyrk kinases have been developed, exploring structure-activity relationships around four different chemotypes. The most potent compounds have low-nanomolar inhibitory activity against Clk1, Clk2, Clk4, Dyrk1A and Dyrk1B. Kinome scans with 442 kinases using agents representing three of the chemotypes show these inhibitors to be highly selective for the Clk and Dyrk families. Further off-target pharmacological evaluation with ML315, the most selective agent, supports this conclusion. PMID:23642479

  16. Leucettine L41, a DYRK1A-preferential DYRKs/CLKs inhibitor, prevents memory impairments and neurotoxicity induced by oligomeric Aβ25-35 peptide administration in mice.

    PubMed

    Naert, Gaëlle; Ferré, Valentine; Meunier, Johann; Keller, Emeline; Malmström, Susanna; Givalois, Laurent; Carreaux, François; Bazureau, Jean-Pierre; Maurice, Tangui

    2015-11-01

    Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) are implicated in the onset and progression of Down syndrome (DS) and Alzheimer's disease (AD). DYRK1A has emerged as a possible link between amyloid-β (Aβ) and Tau, the major pathological proteins in AD. We here assessed the neuroprotective potential of a novel inhibitor of DYRKs/CLKs. The Leucettine L41, acting preferentially on DYRK1A, was tested in Aβ25-35-treated mice, a nontransgenic model of AD-like toxicity. We co-injected intracerebroventricularly oligomeric Aβ25-35 peptide and L41 in Swiss male mice. After 7 days, they were submitted to behavioral tests addressing spatial and non-spatial, short- and long-term memories. The oxidative stress, apoptotic markers, kinases involved in Tau phosphorylation, and synaptic integrity were analyzed by Western blot and ELISA in the hippocampus. L41, tested at 0.4, 1.2, 4 µg, prevented the Aβ25-35-induced memory deficits in the Y-maze, passive avoidance and water-maze tests, with the most active dose being 4 µg. The inhibitor prevented the Aβ25-35-induced oxidative stress, as revealed by measures of lipid peroxidation levels and reactive oxygen species accumulation, and abolished Aβ25-35-induced expression of pro-apoptotic markers. L41 prevented the Aβ25-35-induced decrease of AKT activation and increase of glycogen synthase kinase-3β (GSK-3β) activation, resulting in a decrease of Tau phosphorylation. Finally, L41 restored Aβ25-35-reduced levels of synaptic markers. The novel DYRK1A-preferential inhibitor L41 therefore prevented Aβ25-35-induced memory impairments and neurotoxicity in the mouse hippocampus. These in vivo data highlighted particularly DYRK1A as a major kinase involved in Aβ pathology and suggested therapeutic developments for DYRK1A inhibitors in AD.

  17. Leucettine L41, a DYRK1A-preferential DYRKs/CLKs inhibitor, prevents memory impairments and neurotoxicity induced by oligomeric Aβ25-35 peptide administration in mice.

    PubMed

    Naert, Gaëlle; Ferré, Valentine; Meunier, Johann; Keller, Emeline; Malmström, Susanna; Givalois, Laurent; Carreaux, François; Bazureau, Jean-Pierre; Maurice, Tangui

    2015-11-01

    Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) are implicated in the onset and progression of Down syndrome (DS) and Alzheimer's disease (AD). DYRK1A has emerged as a possible link between amyloid-β (Aβ) and Tau, the major pathological proteins in AD. We here assessed the neuroprotective potential of a novel inhibitor of DYRKs/CLKs. The Leucettine L41, acting preferentially on DYRK1A, was tested in Aβ25-35-treated mice, a nontransgenic model of AD-like toxicity. We co-injected intracerebroventricularly oligomeric Aβ25-35 peptide and L41 in Swiss male mice. After 7 days, they were submitted to behavioral tests addressing spatial and non-spatial, short- and long-term memories. The oxidative stress, apoptotic markers, kinases involved in Tau phosphorylation, and synaptic integrity were analyzed by Western blot and ELISA in the hippocampus. L41, tested at 0.4, 1.2, 4 µg, prevented the Aβ25-35-induced memory deficits in the Y-maze, passive avoidance and water-maze tests, with the most active dose being 4 µg. The inhibitor prevented the Aβ25-35-induced oxidative stress, as revealed by measures of lipid peroxidation levels and reactive oxygen species accumulation, and abolished Aβ25-35-induced expression of pro-apoptotic markers. L41 prevented the Aβ25-35-induced decrease of AKT activation and increase of glycogen synthase kinase-3β (GSK-3β) activation, resulting in a decrease of Tau phosphorylation. Finally, L41 restored Aβ25-35-reduced levels of synaptic markers. The novel DYRK1A-preferential inhibitor L41 therefore prevented Aβ25-35-induced memory impairments and neurotoxicity in the mouse hippocampus. These in vivo data highlighted particularly DYRK1A as a major kinase involved in Aβ pathology and suggested therapeutic developments for DYRK1A inhibitors in AD. PMID:26381812

  18. The Down syndrome-related protein kinase DYRK1A phosphorylates p27Kip1 and Cyclin D1 and induces cell cycle exit and neuronal differentiation

    PubMed Central

    Soppa, Ulf; Schumacher, Julian; Florencio Ortiz, Victoria; Pasqualon, Tobias; Tejedor, Francisco J; Becker, Walter

    2014-01-01

    A fundamental question in neurobiology is how the balance between proliferation and differentiation of neuronal precursors is maintained to ensure that the proper number of brain neurons is generated. Substantial evidence implicates DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A) as a candidate gene responsible for altered neuronal development and brain abnormalities in Down syndrome. Recent findings support the hypothesis that DYRK1A is involved in cell cycle control. Nonetheless, how DYRK1A contributes to neuronal cell cycle regulation and thereby affects neurogenesis remains poorly understood. In the present study we have investigated the mechanisms by which DYRK1A affects cell cycle regulation and neuronal differentiation in a human cell model, mouse neurons, and mouse brain. Dependent on its kinase activity and correlated with the dosage of overexpression, DYRK1A blocked proliferation of SH-SY5Y neuroblastoma cells within 24 h and arrested the cells in G1 phase. Sustained overexpression of DYRK1A induced G0 cell cycle exit and neuronal differentiation. Furthermore, we provide evidence that DYRK1A modulated protein stability of cell cycle-regulatory proteins. DYRK1A reduced cellular Cyclin D1 levels by phosphorylation on Thr286, which is known to induce proteasomal degradation. In addition, DYRK1A phosphorylated p27Kip1 on Ser10, resulting in protein stabilization. Inhibition of DYRK1A kinase activity reduced p27Kip1 Ser10 phosphorylation in cultured hippocampal neurons and in embryonic mouse brain. In aggregate, these results suggest a novel mechanism by which overexpression of DYRK1A may promote premature neuronal differentiation and contribute to altered brain development in Down syndrome. PMID:24806449

  19. The Down syndrome-related protein kinase DYRK1A phosphorylates p27(Kip1) and Cyclin D1 and induces cell cycle exit and neuronal differentiation.

    PubMed

    Soppa, Ulf; Schumacher, Julian; Florencio Ortiz, Victoria; Pasqualon, Tobias; Tejedor, Francisco J; Becker, Walter

    2014-01-01

    A fundamental question in neurobiology is how the balance between proliferation and differentiation of neuronal precursors is maintained to ensure that the proper number of brain neurons is generated. Substantial evidence implicates DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A) as a candidate gene responsible for altered neuronal development and brain abnormalities in Down syndrome. Recent findings support the hypothesis that DYRK1A is involved in cell cycle control. Nonetheless, how DYRK1A contributes to neuronal cell cycle regulation and thereby affects neurogenesis remains poorly understood. In the present study we have investigated the mechanisms by which DYRK1A affects cell cycle regulation and neuronal differentiation in a human cell model, mouse neurons, and mouse brain. Dependent on its kinase activity and correlated with the dosage of overexpression, DYRK1A blocked proliferation of SH-SY5Y neuroblastoma cells within 24 h and arrested the cells in G₁ phase. Sustained overexpression of DYRK1A induced G₀ cell cycle exit and neuronal differentiation. Furthermore, we provide evidence that DYRK1A modulated protein stability of cell cycle-regulatory proteins. DYRK1A reduced cellular Cyclin D1 levels by phosphorylation on Thr286, which is known to induce proteasomal degradation. In addition, DYRK1A phosphorylated p27(Kip1) on Ser10, resulting in protein stabilization. Inhibition of DYRK1A kinase activity reduced p27(Kip1) Ser10 phosphorylation in cultured hippocampal neurons and in embryonic mouse brain. In aggregate, these results suggest a novel mechanism by which overexpression of DYRK1A may promote premature neuronal differentiation and contribute to altered brain development in Down syndrome.

  20. The Down syndrome-related protein kinase DYRK1A phosphorylates p27(Kip1) and Cyclin D1 and induces cell cycle exit and neuronal differentiation.

    PubMed

    Soppa, Ulf; Schumacher, Julian; Florencio Ortiz, Victoria; Pasqualon, Tobias; Tejedor, Francisco J; Becker, Walter

    2014-01-01

    A fundamental question in neurobiology is how the balance between proliferation and differentiation of neuronal precursors is maintained to ensure that the proper number of brain neurons is generated. Substantial evidence implicates DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A) as a candidate gene responsible for altered neuronal development and brain abnormalities in Down syndrome. Recent findings support the hypothesis that DYRK1A is involved in cell cycle control. Nonetheless, how DYRK1A contributes to neuronal cell cycle regulation and thereby affects neurogenesis remains poorly understood. In the present study we have investigated the mechanisms by which DYRK1A affects cell cycle regulation and neuronal differentiation in a human cell model, mouse neurons, and mouse brain. Dependent on its kinase activity and correlated with the dosage of overexpression, DYRK1A blocked proliferation of SH-SY5Y neuroblastoma cells within 24 h and arrested the cells in G₁ phase. Sustained overexpression of DYRK1A induced G₀ cell cycle exit and neuronal differentiation. Furthermore, we provide evidence that DYRK1A modulated protein stability of cell cycle-regulatory proteins. DYRK1A reduced cellular Cyclin D1 levels by phosphorylation on Thr286, which is known to induce proteasomal degradation. In addition, DYRK1A phosphorylated p27(Kip1) on Ser10, resulting in protein stabilization. Inhibition of DYRK1A kinase activity reduced p27(Kip1) Ser10 phosphorylation in cultured hippocampal neurons and in embryonic mouse brain. In aggregate, these results suggest a novel mechanism by which overexpression of DYRK1A may promote premature neuronal differentiation and contribute to altered brain development in Down syndrome. PMID:24806449

  1. Inhibition of DYRK1A and GSK3B induces human β-cell proliferation.

    PubMed

    Shen, Weijun; Taylor, Brandon; Jin, Qihui; Nguyen-Tran, Van; Meeusen, Shelly; Zhang, You-Qing; Kamireddy, Anwesh; Swafford, Austin; Powers, Andrew F; Walker, John; Lamb, John; Bursalaya, Badry; DiDonato, Michael; Harb, George; Qiu, Minhua; Filippi, Christophe M; Deaton, Lisa; Turk, Carolina N; Suarez-Pinzon, Wilma L; Liu, Yahu; Hao, Xueshi; Mo, Tingting; Yan, Shanshan; Li, Jing; Herman, Ann E; Hering, Bernhard J; Wu, Tom; Martin Seidel, H; McNamara, Peter; Glynne, Richard; Laffitte, Bryan

    2015-01-01

    Insufficient pancreatic β-cell mass or function results in diabetes mellitus. While significant progress has been made in regulating insulin secretion from β-cells in diabetic patients, no pharmacological agents have been described that increase β-cell replication in humans. Here we report aminopyrazine compounds that stimulate robust β-cell proliferation in adult primary islets, most likely as a result of combined inhibition of DYRK1A and GSK3B. Aminopyrazine-treated human islets retain functionality in vitro and after transplantation into diabetic mice. Oral dosing of these compounds in diabetic mice induces β-cell proliferation, increases β-cell mass and insulin content, and improves glycaemic control. Biochemical, genetic and cell biology data point to Dyrk1a as the key molecular target. This study supports the feasibility of treating diabetes with an oral therapy to restore β-cell mass, and highlights a tractable pathway for future drug discovery efforts. PMID:26496802

  2. Overexpression of DYRK1A inhibits choline acetyltransferase induction by oleic acid in cellular models of Down syndrome.

    PubMed

    Hijazi, Maruan; Fillat, Cristina; Medina, José M; Velasco, Ana

    2013-01-01

    Histological brain studies of individuals with DS have revealed an aberrant formation of the cerebral cortex. Previous work from our laboratory has shown that oleic acid acts as a neurotrophic factor and induces neuronal differentiation. In order to characterize the effects of oleic acid in a cellular model of DS, immortalized cell lines derived from the cortex of trisomy Ts16 (CTb) and normal mice (CNh) were incubated in the absence or presence of oleic acid. Oleic acid increased choline acetyltransferase expression (ChAT), a marker of cholinergic differentiation in CNh cells. However, in trisomic cells (CTb line) oleic acid failed to increase ChAT expression. These results suggest that the overdose of specific genes in trisomic lines delays differentiation in the presence of oleic acid by inhibiting acetylcholine production mediated by ChAT. The dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1A (DYRK1A) gene is located on human chromosome 21 and encodes a proline-directed protein kinase. It has been proposed that DYRK1A plays a prominent role in several biological functions, leading to mental retardation in DS patients. Here we explored the potential role of DYRK1A in the modulation of ChAT expression in trisomic cells and in the signaling pathways of oleic acid. Down-regulation of DYRK1A by siRNA in trisomic CTb cells rescued ChAT expression up to levels similar to those of normal cells in the presence of oleic acid. In agreement with these results, oleic acid was unable to increase ChAT expression in neuronal cultures of transgenic mice overexpressing DYRK1A. In summary, our results highlight the role played by DYRK1A in brain development through the control of ChAT expression. In addition, the overexpression of DYRK1A in DS models prevented the neurotrophic effect of oleic acid, a fact that may account for mental retardation in DS patients. PMID:23124096

  3. Inhibition of DYRK1A Stimulates Human β-Cell Proliferation.

    PubMed

    Dirice, Ercument; Walpita, Deepika; Vetere, Amedeo; Meier, Bennett C; Kahraman, Sevim; Hu, Jiang; Dančík, Vlado; Burns, Sean M; Gilbert, Tamara J; Olson, David E; Clemons, Paul A; Kulkarni, Rohit N; Wagner, Bridget K

    2016-06-01

    Restoring functional β-cell mass is an important therapeutic goal for both type 1 and type 2 diabetes (1). While proliferation of existing β-cells is the primary means of β-cell replacement in rodents (2), it is unclear whether a similar principle applies to humans, as human β-cells are remarkably resistant to stimulation of division (3,4). Here, we show that 5-iodotubercidin (5-IT), an annotated adenosine kinase inhibitor previously reported to increase proliferation in rodent and porcine islets (5), strongly and selectively increases human β-cell proliferation in vitro and in vivo. Remarkably, 5-IT also increased glucose-dependent insulin secretion after prolonged treatment. Kinome profiling revealed 5-IT to be a potent and selective inhibitor of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) and cell division cycle-like kinase families. Induction of β-cell proliferation by either 5-IT or harmine, another natural product DYRK1A inhibitor, was suppressed by coincubation with the calcineurin inhibitor FK506, suggesting involvement of DYRK1A and nuclear factor of activated T cells signaling. Gene expression profiling in whole islets treated with 5-IT revealed induction of proliferation- and cell cycle-related genes, suggesting that true proliferation is induced by 5-IT. Furthermore, 5-IT promotes β-cell proliferation in human islets grafted under the kidney capsule of NOD-scid IL2Rg(null) mice. These results point to inhibition of DYRK1A as a therapeutic strategy to increase human β-cell proliferation. PMID:26953159

  4. New Perspectives of Dyrk1A Role in Neurogenesis and Neuropathologic Features of Down Syndrome.

    PubMed

    Park, Joongkyu; Chung, Kwang Chul

    2013-12-01

    Down syndrome (DS) is one of the most common genetic disorders accompanying with mental retardation, cognitive impairment, and deficits in learning and memory. The brains with DS also display many neuropathological features including alteration in neurogenesis and synaptogenesis and early onset of Alzheimer's disease (AD)-like symptoms. Triplication of all or a part of human chromosome 21, especially the 21q22.1~21q22.3 region called 'Down syndrome critical region (DSCR)', has been considered as the main cause of DS. One gene product of DSCR, dual-specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A), has been highlighted as a key contributor to the neural consequences of DS. This minireview summarizes accumulating recent reports about Dyrk1A involvement in the neuritogenesis, synaptogenesis, and AD-like neurofibrillary tangle formation, which is mainly focusing on Dyrk1A-mediated regulation of cytoskeletal proteins, such as tubulin, actin, and microtubule-associated protein tau. Understanding the molecular mechanisms of these phenomena may provide us a rational for new preventive and therapeutic treatment of DS. PMID:24465139

  5. 10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A

    PubMed Central

    2015-01-01

    The protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing to neurological alterations found in individuals with Down syndrome. For an assessment of the role of DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, the DYRK1A inhibitors described in the literature so far either are not sufficiently selective or have not been tested against closely related kinases from the DYRK and the CLK protein kinase families. The aim of this study was the identification of DYRK1A inhibitors exhibiting selectivity versus the structurally and functionally closely related DYRK and CLK isoforms. Structure modification of the screening hit 11H-indolo[3,2-c]quinoline-6-carboxylic acid revealed structure–activity relationships for kinase inhibition and enabled the design of 10-iodo-substituted derivatives as very potent DYRK1A inhibitors with considerable selectivity against CLKs. X-ray structure determination of three 11H-indolo[3,2-c]quinoline-6-carboxylic acids cocrystallized with DYRK1A confirmed the predicted binding mode within the ATP binding site. PMID:25730262

  6. 10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acids are selective inhibitors of DYRK1A.

    PubMed

    Falke, Hannes; Chaikuad, Apirat; Becker, Anja; Loaëc, Nadège; Lozach, Olivier; Abu Jhaisha, Samira; Becker, Walter; Jones, Peter G; Preu, Lutz; Baumann, Knut; Knapp, Stefan; Meijer, Laurent; Kunick, Conrad

    2015-04-01

    The protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing to neurological alterations found in individuals with Down syndrome. For an assessment of the role of DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, the DYRK1A inhibitors described in the literature so far either are not sufficiently selective or have not been tested against closely related kinases from the DYRK and the CLK protein kinase families. The aim of this study was the identification of DYRK1A inhibitors exhibiting selectivity versus the structurally and functionally closely related DYRK and CLK isoforms. Structure modification of the screening hit 11H-indolo[3,2-c]quinoline-6-carboxylic acid revealed structure-activity relationships for kinase inhibition and enabled the design of 10-iodo-substituted derivatives as very potent DYRK1A inhibitors with considerable selectivity against CLKs. X-ray structure determination of three 11H-indolo[3,2-c]quinoline-6-carboxylic acids cocrystallized with DYRK1A confirmed the predicted binding mode within the ATP binding site. PMID:25730262

  7. Chromatin-wide profiling of DYRK1A reveals a role as a gene-specific RNA polymerase II CTD kinase.

    PubMed

    Di Vona, Chiara; Bezdan, Daniela; Islam, Abul B M M K; Salichs, Eulàlia; López-Bigas, Nuria; Ossowski, Stephan; de la Luna, Susana

    2015-02-01

    DYRK1A is a dosage-sensitive protein kinase that fulfills key roles during development and in tissue homeostasis, and its dysregulation results in human pathologies. DYRK1A is present in both the nucleus and cytoplasm of mammalian cells, although its nuclear function remains unclear. Genome-wide analysis of DYRK1A-associated loci reveals that the kinase is recruited preferentially to promoters of genes actively transcribed by RNA polymerase II (RNAPII), which are functionally associated with translation, RNA processing, and cell cycle. DYRK1A-bound promoter sequences are highly enriched in a conserved palindromic motif, which is necessary to drive DYRK1A-dependent transcriptional activation. DYRK1A phosphorylates the C-terminal domain (CTD) of RNAPII at Ser2 and Ser5. Depletion of DYRK1A results in reduced association of RNAPII at the target promoters as well as hypophosphorylation of the RNAPII CTD along the target gene bodies. These results are consistent with DYRK1A being a transcriptional regulator by acting as a CTD kinase. PMID:25620562

  8. The adaptor protein DCAF7 mediates the interaction of the adenovirus E1A oncoprotein with the protein kinases DYRK1A and HIPK2

    PubMed Central

    Glenewinkel, Florian; Cohen, Michael J.; King, Cason R.; Kaspar, Sophie; Bamberg-Lemper, Simone; Mymryk, Joe S.; Becker, Walter

    2016-01-01

    DYRK1A is a constitutively active protein kinase that has a critical role in growth and development which functions by regulating cell proliferation, differentiation and survival. DCAF7 (also termed WDR68 or HAN11) is a cellular binding partner of DYRK1A and also regulates signalling by the protein kinase HIPK2. DCAF7 is an evolutionarily conserved protein with a single WD40 repeat domain and has no catalytic activity. We have defined a DCAF7 binding motif of 12 amino acids in the N-terminal domain of class 1 DYRKs that is functionally conserved in DYRK1 orthologs from Xenopus, Danio rerio and the slime mold Dictyostelium discoideum. A similar sequence was essential for DCAF7 binding to HIPK2, whereas the closely related HIPK1 family member did not bind DCAF7. Immunoprecipitation and pulldown experiments identified DCAF7 as an adaptor for the association of the adenovirus E1A protein with DYRK1A and HIPK2. Furthermore, DCAF7 was required for the hyperphosphorylation of E1A in DYRK1A or HIPK2 overexpressing cells. Our results characterize DCAF7 as a substrate recruiting subunit of DYRK1A and HIPK2 and suggest that it is required for the negative effect of DYRK1A on E1A-induced oncogenic transformation. PMID:27307198

  9. The adaptor protein DCAF7 mediates the interaction of the adenovirus E1A oncoprotein with the protein kinases DYRK1A and HIPK2.

    PubMed

    Glenewinkel, Florian; Cohen, Michael J; King, Cason R; Kaspar, Sophie; Bamberg-Lemper, Simone; Mymryk, Joe S; Becker, Walter

    2016-01-01

    DYRK1A is a constitutively active protein kinase that has a critical role in growth and development which functions by regulating cell proliferation, differentiation and survival. DCAF7 (also termed WDR68 or HAN11) is a cellular binding partner of DYRK1A and also regulates signalling by the protein kinase HIPK2. DCAF7 is an evolutionarily conserved protein with a single WD40 repeat domain and has no catalytic activity. We have defined a DCAF7 binding motif of 12 amino acids in the N-terminal domain of class 1 DYRKs that is functionally conserved in DYRK1 orthologs from Xenopus, Danio rerio and the slime mold Dictyostelium discoideum. A similar sequence was essential for DCAF7 binding to HIPK2, whereas the closely related HIPK1 family member did not bind DCAF7. Immunoprecipitation and pulldown experiments identified DCAF7 as an adaptor for the association of the adenovirus E1A protein with DYRK1A and HIPK2. Furthermore, DCAF7 was required for the hyperphosphorylation of E1A in DYRK1A or HIPK2 overexpressing cells. Our results characterize DCAF7 as a substrate recruiting subunit of DYRK1A and HIPK2 and suggest that it is required for the negative effect of DYRK1A on E1A-induced oncogenic transformation. PMID:27307198

  10. Dyrk1A phosphorylates parkin at Ser-131 and negatively regulates its ubiquitin E3 ligase activity.

    PubMed

    Im, Eunju; Chung, Kwang Chul

    2015-08-01

    Mutations of parkin are associated with the occurrence of autosomal recessive familial Parkinson's disease (PD). Parkin acts an E3 ubiquitin ligase, which ubiquitinates target proteins and subsequently regulates either their steady-state levels through the ubiquitin-proteasome system or biochemical properties. In this study, we identify a novel regulatory mechanism of parkin by searching for new regulatory factors. After screening human fetal brain using a yeast two hybrid assay, we found dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) as a novel binding partner of parkin. We also observed that parkin interacts and co-localizes with Dyrk1A in mammalian cells. In addition, Dyrk1A directly phosphorylated parkin at Ser-131, causing the inhibition of its E3 ubiquitin ligase activity. Moreover, Dyrk1A-mediated phosphorylation reduced the binding affinity of parkin to its ubiquitin-conjugating E2 enzyme and substrate, which could be the underlying inhibitory mechanism of parkin activity. Furthermore, Dyrk1A-mediated phosphorylation inhibited the neuroprotective action of parkin against 6-hydroxydopamine toxicity in dopaminergic SH-SY5Y cells. These findings suggest that Dyrk1A acts as a novel functional modulator of parkin. Parkin phosphorylation by Dyrk1A suppresses its E3 ubiquitin ligase activity potentially contributing to the pathogenesis of PD under PD-inducing pathological conditions. Mutations of parkin are linked to autosomal recessive forms of familial Parkinson's disease (PD). According to its functional relevance in abnormal protein aggregation and neuronal cell death, a number of post-translational modifications regulate the ubiquitin E3 ligase activity of parkin. Here we propose a novel inhibitory mechanism of parkin E3 ubiquitin ligase through dual-specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A)-mediated phosphorylation as well as its neuroprotective action against 6-hydroxydopamine (6-OHDA)-induced cell death

  11. Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.

    PubMed

    van Bon, B W M; Coe, B P; Bernier, R; Green, C; Gerdts, J; Witherspoon, K; Kleefstra, T; Willemsen, M H; Kumar, R; Bosco, P; Fichera, M; Li, D; Amaral, D; Cristofoli, F; Peeters, H; Haan, E; Romano, C; Mefford, H C; Scheffer, I; Gecz, J; de Vries, B B A; Eichler, E E

    2016-01-01

    Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10(-10)) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.

  12. Design and synthesis of thiazolo[5,4-f]quinazolines as DYRK1A inhibitors, part II.

    PubMed

    Foucourt, Alicia; Hédou, Damien; Dubouilh-Benard, Carole; Girard, Angélique; Taverne, Thierry; Casagrande, Anne-Sophie; Désiré, Laurent; Leblond, Bertrand; Besson, Thierry

    2014-01-01

    The convenient synthesis of a focused library (forty molecules) of novel 6,6,5-tricyclic thiazolo[5,4-f]quinazolines was realized mainly under microwave irradiation. A novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (1) was used as a versatile molecular platform for the synthesis of various derivatives. Kinase inhibition, of the obtained final compounds, was evaluated on a panel of two kinases (DYRK1A/1B) together with some known reference DYRK1A and DYRK1B inhibitors (harmine, TG003, NCGC-00189310 and leucettine L41). Compound IC50 values were obtained and compared. Five of the novel thiazolo[5,4-f]quinazoline derivatives prepared, EHT 5372 (8c), EHT 6840 (8h), EHT 1610 (8i), EHT 9851 (8k) and EHT 3356 (9b) displayed single-digit nanomolar or subnanomolar IC50 values and are among the most potent DYRK1A/1B inhibitors disclosed to date. DYRK1A/1B kinases are known to be involved in the regulation of various molecular pathways associated with oncology, neurodegenerative diseases (such as Alzheimer disease, AD, or other tauopathies), genetic diseases (such as Down Syndrome, DS), as well as diseases involved in abnormal pre-mRNA splicing. The compounds described in this communication constitute a highly potent set of novel molecular probes to evaluate the biology/pharmacology of DYR1A/1B in such diseases. PMID:25264830

  13. Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.

    PubMed

    van Bon, B W M; Coe, B P; Bernier, R; Green, C; Gerdts, J; Witherspoon, K; Kleefstra, T; Willemsen, M H; Kumar, R; Bosco, P; Fichera, M; Li, D; Amaral, D; Cristofoli, F; Peeters, H; Haan, E; Romano, C; Mefford, H C; Scheffer, I; Gecz, J; de Vries, B B A; Eichler, E E

    2016-01-01

    Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10(-10)) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models. PMID:25707398

  14. DYRK1B as therapeutic target in Hedgehog/GLI-dependent cancer cells with Smoothened inhibitor resistance

    PubMed Central

    Gruber, Wolfgang; Hutzinger, Martin; Elmer, Dominik Patrick; Parigger, Thomas; Sternberg, Christina; Cegielkowski, Lukasz; Zaja, Mirko; Leban, Johann; Michel, Susanne; Hamm, Svetlana; Vitt, Daniel; Aberger, Fritz

    2016-01-01

    A wide range of human malignancies displays aberrant activation of Hedgehog (HH)/GLI signaling, including cancers of the skin, brain, gastrointestinal tract and hematopoietic system. Targeting oncogenic HH/GLI signaling with small molecule inhibitors of the essential pathway effector Smoothened (SMO) has shown remarkable therapeutic effects in patients with advanced and metastatic basal cell carcinoma. However, acquired and de novo resistance to SMO inhibitors poses severe limitations to the use of SMO antagonists and urgently calls for the identification of novel targets and compounds. Here we report on the identification of the Dual-Specificity-Tyrosine-Phosphorylation-Regulated Kinase 1B (DYRK1B) as critical positive regulator of HH/GLI signaling downstream of SMO. Genetic and chemical inhibition of DYRK1B in human and mouse cancer cells resulted in marked repression of HH signaling and GLI1 expression, respectively. Importantly, DYRK1B inhibition profoundly impaired GLI1 expression in both SMO-inhibitor sensitive and resistant settings. We further introduce a novel small molecule DYRK1B inhibitor, DYRKi, with suitable pharmacologic properties to impair SMO-dependent and SMO-independent oncogenic GLI activity. The results support the use of DYRK1B antagonists for the treatment of HH/GLI-associated cancers where SMO inhibitors fail to demonstrate therapeutic efficacy. PMID:26784250

  15. Development of DANDYs, new 3,5-diaryl-7-azaindoles demonstrating potent DYRK1A kinase inhibitory activity.

    PubMed

    Gourdain, Stéphanie; Dairou, Julien; Denhez, Clément; Bui, Linh Chi; Rodrigues-Lima, Fernando; Janel, Nathalie; Delabar, Jean M; Cariou, Kevin; Dodd, Robert H

    2013-12-12

    A series of 3,5-diaryl-1H-pyrrolo[2,3-b]pyridines were synthesized and evaluated for inhibition of DYRKIA kinase in vitro. Derivatives having hydroxy groups on the aryl moieties (2c, 2j-l) demonstrated high inhibitory potencies with Kis in the low nanomolar range. Their methoxy analogues were up to 100 times less active. Docking studies at the ATP binding site suggested that these compounds bind tightly to this site via a network of multiple H-bonds with the peptide backbone. None of the active compounds were cytotoxic to KB cells at 10(-6) M. Kinase profiling revealed that compound 2j showed 2-fold selectivity for DYRK1A with respect to DYRK2 and DYRK3. PMID:24188002

  16. QSAR and pharmacophore study of Dyrk1A inhibitory meridianin analogs as potential agents for treatment of neurodegenerative diseases.

    PubMed

    Bharate, Sandip B; Yadav, Rammohan R; Vishwakarma, Ram A

    2013-02-01

    Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) is a protein kinase with diverse functions in neuronal development and adult brain physiology. Elevated levels of Dyrk1A are associated with the pathology of neurodegenerative diseases and have been implicated in some neurobiological alterations of Down syndrome, such as mental retardation. Meridianins are marine derived indole alkaloids exhibiting anti-proliferative activity as well as are known to inhibit panel of kinases. In the present article, a descriptor based QSAR study was carried out for a series of meridianin analogs inhibiting Dyrk1A to find out structural features which are crucial for biological activity. Developed QSAR model showed good correlation coefficient (r > 0.9), higher F value (F > 20) and excellent predictive power (r2 cv and r2 pred > 0.6). Activity of naturally occurring meridianins was also predicted using developed model. The study indicated that kier Chi4 path/cluster, total lipole, VAMP polarization ZZ component, dipole moment Z component and log P plays important role in Dyrk1A inhibition. Further analysis of pharmacophore model using PHASE module of Schrodinger revealed that two hydrogen bond acceptors (A), two hydrogen bond donors (D) and two hydrophobic aromatic rings (R) are crucial molecular features that predict binding affinity for meridianins to the Dyrk1A enzyme. These observations provide important insights to the key structural requirements of meridianins for potent Dyrk1A inhibition. Excellent statistical results of developed models strongly suggest that these models are reasonable for prediction of the activity of new inhibitors and in future drug design. PMID:22920091

  17. Phosphorylation and inactivation of glycogen synthase kinase 3β (GSK3β) by dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A).

    PubMed

    Song, Woo-Joo; Song, Eun-Ah Christine; Jung, Min-Su; Choi, Sun-Hee; Baik, Hyung-Hwan; Jin, Byung Kwan; Kim, Jeong Hee; Chung, Sul-Hee

    2015-01-23

    Glycogen synthase kinase 3β (GSK3β) participates in many cellular processes, and its dysregulation has been implicated in a wide range of diseases such as obesity, type 2 diabetes, cancer, and Alzheimer disease. Inactivation of GSK3β by phosphorylation at specific residues is a primary mechanism by which this constitutively active kinase is controlled. However, the regulatory mechanism of GSK3β is not fully understood. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) has multiple biological functions that occur as the result of phosphorylation of diverse proteins that are involved in metabolism, synaptic function, and neurodegeneration. Here we show that GSK3β directly interacts with and is phosphorylated by Dyrk1A. Dyrk1A-mediated phosphorylation at the Thr(356) residue inhibits GSK3β activity. Dyrk1A transgenic (TG) mice are lean and resistant to diet-induced obesity because of reduced fat mass, which shows an inverse correlation with the effect of GSK3β on obesity. This result suggests a potential in vivo association between GSK3β and Dyrk1A regarding the mechanism underlying obesity. The level of Thr(P)(356)-GSK3β was higher in the white adipose tissue of Dyrk1A TG mice compared with control mice. GSK3β activity was differentially regulated by phosphorylation at different sites in adipose tissue depending on the type of diet the mice were fed. Furthermore, overexpression of Dyrk1A suppressed the expression of adipogenic proteins, including peroxisome proliferator-activated receptor γ, in 3T3-L1 cells and in young Dyrk1A TG mice fed a chow diet. Taken together, these results reveal a novel regulatory mechanism for GSK3β activity and indicate that overexpression of Dyrk1A may contribute to the obesity-resistant phenotype through phosphorylation and inactivation of GSK3β. PMID:25477508

  18. DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3.

    PubMed

    Thompson, Benjamin J; Bhansali, Rahul; Diebold, Lauren; Cook, Daniel E; Stolzenburg, Lindsay; Casagrande, Anne-Sophie; Besson, Thierry; Leblond, Bertrand; Désiré, Laurent; Malinge, Sébastien; Crispino, John D

    2015-06-01

    Pre-B and pre-T lymphocytes must orchestrate a transition from a highly proliferative state to a quiescent one during development. Cyclin D3 is essential for these cells' proliferation, but little is known about its posttranslational regulation at this stage. Here, we show that the dual specificity tyrosine-regulated kinase 1A (DYRK1A) restrains Cyclin D3 protein levels by phosphorylating T283 to induce its degradation. Loss of DYRK1A activity, via genetic inactivation or pharmacologic inhibition in mice, caused accumulation of Cyclin D3 protein, incomplete repression of E2F-mediated gene transcription, and failure to properly couple cell cycle exit with differentiation. Expression of a nonphosphorylatable Cyclin D3 T283A mutant recapitulated these defects, whereas inhibition of Cyclin D:CDK4/6 mitigated the effects of DYRK1A inhibition or loss. These data uncover a previously unknown role for DYRK1A in lymphopoiesis, and demonstrate how Cyclin D3 protein stability is negatively regulated during exit from the proliferative phases of B and T cell development. PMID:26008897

  19. DYRK2 Negatively Regulates Type I Interferon Induction by Promoting TBK1 Degradation via Ser527 Phosphorylation

    PubMed Central

    An, Tai; Li, Shu; Pan, Wei; Tien, Po; Zhong, Bo; Shu, Hong-Bing; Wu, Shuwen

    2015-01-01

    Viral infection activates the transcription factors NF-κB and IRF3, which contribute to the induction of type I interferons (IFNs) and cellular antiviral responses. Protein kinases play a critical role in various signaling pathways by phosphorylating their substrates. Here, we identified dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (DYRK2) as a negative regulator of virus-triggered type I IFN induction. DYRK2 inhibited the virus-triggered induction of type I IFNs and promoted the K48-linked ubiquitination and degradation of TANK-binding kinase 1 (TBK1) in a kinase-activity-dependent manner. We further found that DYRK2 phosphorylated Ser527 of TBK1, which is essential for the recruitment of NLRP4 and for the E3 ubiquitin ligase DTX4 to degrade TBK1. These findings suggest that DYRK2 negatively regulates virus-triggered signaling by targeting TBK1 for phosphorylation and priming it for degradation, and these data provide new insights into the molecular mechanisms that dictate the cellular antiviral response. PMID:26407194

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

    PubMed

    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 values<100nM) and remarkable selectivity. TDB, unlike other dual PIM1/CK2 inhibitors described in the literature is readily cell permeable and displays a cytotoxic effect on cancer 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). PMID:23360763

  1. Hydroxybenzothiophene Ketones Are Efficient Pre-mRNA Splicing Modulators Due to Dual Inhibition of Dyrk1A and Clk1/4.

    PubMed

    Schmitt, Christian; Miralinaghi, Parisa; Mariano, Marica; Hartmann, Rolf W; Engel, Matthias

    2014-09-11

    Dysregulated usage of pre-mRNA splicing sites contributes to the progression of cancer, neurodegenerative diseases, and viral infections. Serine/arginine-rich (SR) proteins play major roles in the splice site recognition and are largely regulated by phosphorylation. This provides an option for the pharmacological correction of aberrant splicing by inhibiting the relevant kinases. Cdc2-like kinases (Clks) and dual specificity tyrosine phosphorylation-regulated kinases (Dyrks) were both reported to phosphorylate numerous SR proteins in vitro and in vivo. In this study, we describe the discovery of new selective dual Clk/Dyrk1A/1B inhibitors, which are able to modulate alternative pre-mRNA splicing of model gene transcripts in cells with submicromolar potencies. The optimization process yielded a dual Clk and Dyrk inhibitor with exceptionally high ligand efficiency. Our results suggested that dual inhibition of both Clk1 and Dyrk1A increased the efficacy of pre-mRNA splicing modulation. PMID:25221649

  2. A novel DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro.

    PubMed

    Coutadeur, Séverine; Benyamine, Hélène; Delalonde, Laurence; de Oliveira, Catherine; Leblond, Bertrand; Foucourt, Alicia; Besson, Thierry; Casagrande, Anne-Sophie; Taverne, Thierry; Girard, Angélique; Pando, Matthew P; Désiré, Laurent

    2015-05-01

    The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene is located within the Down Syndrome (DS) critical region on chromosome 21 and is implicated in the generation of Tau and amyloid pathologies that are associated with the early onset Alzheimer's Disease (AD) observed in DS. DYRK1A is also found associated with neurofibrillary tangles in sporadic AD and phosphorylates key AD players (Tau, amyloid precursor, protein, etc). Thus, DYRK1A may be an important therapeutic target to modify the course of Tau and amyloid beta (Aβ) pathologies. Here, we describe EHT 5372 (methyl 9-(2,4-dichlorophenylamino) thiazolo[5,4-f]quinazoline-2-carbimidate), a novel, highly potent (IC50 = 0.22 nM) DYRK1A inhibitor with a high degree of selectivity over 339 kinases. Models in which inhibition of DYRK1A by siRNA reduced and DYRK1A over-expression induced Tau phosphorylation or Aβ production were used. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation at multiple AD-relevant sites in biochemical and cellular assays. EHT 5372 also normalizes both Aβ-induced Tau phosphorylation and DYRK1A-stimulated Aβ production. DYRK1A is thus as a key element of Aβ-mediated Tau hyperphosphorylation, which links Tau and amyloid pathologies. EHT 5372 and other compounds in its class warrant in vivo investigation as a novel, high-potential therapy for AD and other Tau opathies. Inhibition of the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a new high-potential therapeutic approach for Alzheimer disease. Here we describe EHT 5372, a novel potent and selective DYRK1A inhibitor. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation, Aβ production and Aβ effects on phospho-Tau, including Tau aggregation. PMID:25556849

  3. Role of dual specificity tyrosine-phosphorylation-regulated kinase 1B (Dyrk1B) in S-phase entry of HPV E7 expressing cells from quiescence

    PubMed Central

    Zhou, Na; Yuan, Shoudao; Wang, Rongchun; Zhang, Weifang; Chen, Jason J.

    2015-01-01

    The high-risk human papillomavirus (HPV) is the causative agent for cervical cancer. The HPV E7 oncogene promotes S-phase entry from quiescent state in the presence of elevated cell cycle inhibitor p27Kip1, a function that may contribute to carcinogenesis. However, the mechanism by which HPV E7 induces quiescent cells to entry into S-phase is not fully understood. Interestingly, we found that Dyrk1B, a dual-specificity kinase and negative regulator of cell proliferation in quiescent cells, was upregulated in E7 expressing cells. Surprisingly and in contrast to what was previously reported, Dyrk1B played a positive role in S-phase entry of quiescent HPV E7 expressing cells. Mechanistically, Dyrk1B contributed to p27 phosphorylation (at serine 10 and threonine 198), which was important for the proliferation of HPV E7 expressing cells. Moreover, Dyrk1B up-regulated HPV E7. Taken together, our studies uncovered a novel function of Dyrk1B in high-risk HPV E7-mediated cell proliferation. Dyrk1B may serve as a target for therapy in HPV-associated cancers. PMID:26307683

  4. Abnormal mineralization of the Ts65Dn Down syndrome mouse appendicular skeleton begins during embryonic development in a Dyrk1a-independent manner.

    PubMed

    Blazek, Joshua D; Malik, Ahmed M; Tischbein, Maeve; Arbones, Maria L; Moore, Clara S; Roper, Randall J

    2015-05-01

    The relationship between gene dosage imbalance and phenotypes associated with Trisomy 21, including the etiology of abnormal bone phenotypes linked to Down syndrome (DS), is not well understood. The Ts65Dn mouse model for DS exhibits appendicular skeletal defects during adolescence and adulthood but the developmental and genetic origin of these phenotypes remains unclear. It is hypothesized that the postnatal Ts65Dn skeletal phenotype originates during embryonic development and results from an increased Dyrk1a gene copy number, a gene hypothesized to play a critical role in many DS phenotypes. Ts65Dn embryos exhibit a lower percent bone volume in the E17.5 femur when compared to euploid embryos. Concomitant with gene copy number, qPCR analysis revealed a  ~1.5 fold increase in Dyrk1a transcript levels in the Ts65Dn E17.5 embryonic femur as compared to euploid. Returning Dyrk1a copy number to euploid levels in Ts65Dn, Dyrk1a(+/-) embryos did not correct the trisomic skeletal phenotype but did return Dyrk1a gene transcript levels to normal. The size and protein expression patterns of the cartilage template during embryonic bone development appear to be unaffected at E14.5 and E17.5 in trisomic embryos. Taken together, these data suggest that the dosage imbalance of genes other than Dyrk1a is involved in the development of the prenatal bone phenotype in Ts65Dn embryos. PMID:25556111

  5. Insights into mechanism of pyrido[2,3-d]pyrimidines as DYRK1A inhibitors based on molecular dynamic simulations.

    PubMed

    Li, Jiao Jiao; Tian, Yue Li; Zhai, Hong Lin; Lv, Min; Zhang, Xiao Yun

    2016-08-01

    DYRK1A is characterized by the early development and regulation of neuronal proliferation, and its over expression gives rise to neurological abnormalities. As the promising DYRK1A inhibitors, the binding mechanism between DYRK1A and pyrido[2,3-d]pyrimidines derivatives at molecular level are still veiled. In this article, it was achieved to get the structural insights into pyrido[2,3-d]pyrimidines derivatives as DYRK1A inhibitors by means of comprehensive computational approaches involving molecular docking, molecular dynamics simulation, free energy calculation, and energy decomposition analysis. The calculated energy values were highly consistent with the experimental activities. Based on the individual energy terms analysis, the van der Waals interaction was the major leading force in the DYRK1A-ligand interaction. Lys188 was the important residue that formed the hydrogen bond, which improved the inhibitory activity. Furthermore, four novel inhibitors with higher predicted activity were designed based on the obtained findings and confirmed by molecular simulations. Our study is expected to provide significant drug design strategy for the development of more promising DYRK1A inhibitors. Proteins 2016; 84:1108-1123. © 2016 Wiley Periodicals, Inc. PMID:27119584

  6. Dyrk1A is dynamically expressed on subsets of motor neurons and in the neuromuscular junction: possible role in Down syndrome.

    PubMed

    Arque, Gloria; Casanovas, Anna; Dierssen, Mara

    2013-01-01

    Individuals with Down syndrome (DS) present important motor deficits that derive from altered motor development of infants and young children. DYRK1A, a candidate gene for DS abnormalities has been implicated in motor function due to its expression in motor nuclei in the adult brain, and its overexpression in DS mouse models leads to hyperactivity and altered motor learning. However, its precise role in the adult motor system, or its possible involvement in postnatal locomotor development has not yet been clarified. During the postnatal period we observed time-specific expression of Dyrk1A in discrete subsets of brainstem nuclei and spinal cord motor neurons. Interestingly, we describe for the first time the presence of Dyrk1A in the presynaptic terminal of the neuromuscular junctions and its axonal transport from the facial nucleus, suggesting a function for Dyrk1A in these structures. Relevant to DS, Dyrk1A overexpression in transgenic mice (TgDyrk1A) produces motor developmental alterations possibly contributing to DS motor phenotypes and modifies the numbers of motor cholinergic neurons, suggesting that the kinase may have a role in the development of the brainstem and spinal cord motor system. PMID:23342120

  7. Pharmacokinetics of avenanthramides (AV) from AV-enriched malted oats in healthy older adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Avenanthramides (AV) are a unique group of phytochemicals found in oat bran. In vitro studies show both purified AV and concentrated oat AV mixtures have anti-atherogenic and anti-inflammatory activity, suggesting they may have similar effects in vivo if they are sufficiently bioavailable. The bioav...

  8. Overexpression of Dyrk1A is implicated in several cognitive, electrophysiological and neuromorphological alterations found in a mouse model of Down syndrome.

    PubMed

    García-Cerro, Susana; Martínez, Paula; Vidal, Verónica; Corrales, Andrea; Flórez, Jesús; Vidal, Rebeca; Rueda, Noemí; Arbonés, María L; Martínez-Cué, Carmen

    2014-01-01

    Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/-) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene may

  9. Overexpression of Dyrk1A Is Implicated in Several Cognitive, Electrophysiological and Neuromorphological Alterations Found in a Mouse Model of Down Syndrome

    PubMed Central

    García-Cerro, Susana; Martínez, Paula; Vidal, Verónica; Corrales, Andrea; Flórez, Jesús; Vidal, Rebeca; Rueda, Noemí; Arbonés, María L.; Martínez-Cué, Carmen

    2014-01-01

    Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/−) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene

  10. Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome.

    PubMed

    Shi, Jianhua; Zhang, Tianyi; Zhou, Chunlei; Chohan, Muhammad Omar; Gu, Xiaosong; Wegiel, Jerzy; Zhou, Jianhua; Hwang, Yu-Wen; Iqbal, Khalid; Grundke-Iqbal, Inge; Gong, Cheng-Xin; Liu, Fei

    2008-10-17

    Two groups of tau, 3R- and 4R-tau, are generated by alternative splicing of tau exon 10. Normal adult human brain expresses equal levels of them. Disruption of the physiological balance is a common feature of several tauopathies. Very early in their life, individuals with Down syndrome (DS) develop Alzheimer-type tau pathology, the molecular basis for which is not fully understood. Here, we demonstrate that Dyrk1A, a kinase encoded by a gene in the DS critical region, phosphorylates alternative splicing factor (ASF) at Ser-227, Ser-234, and Ser-238, driving it into nuclear speckles and preventing it from facilitating tau exon 10 inclusion. The increased dosage of Dyrk1A in DS brain due to trisomy of chromosome 21 correlates to an increase in 3R-tau level, which on abnormal hyperphosphorylation and aggregation of tau results in neurofibrillary degeneration. Imbalance of 3R- and 4R-tau in DS brain by Dyrk1A-induced dysregulation of alternative splicing factor-mediated alternative splicing of tau exon 10 represents a novel mechanism of neurofibrillary degeneration and may help explain early onset tauopathy in individuals with DS.

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

    PubMed

    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. PMID:26896709

  12. Minibrain/Dyrk1a regulates food intake through the Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals.

    PubMed

    Hong, Seung-Hyun; Lee, Kyu-Sun; Kwak, Su-Jin; Kim, Ae-Kyeong; Bai, Hua; Jung, Min-Su; Kwon, O-Yu; Song, Woo-Joo; Tatar, Marc; Yu, Kweon

    2012-01-01

    Feeding behavior is one of the most essential activities in animals, which is tightly regulated by neuroendocrine factors. Drosophila melanogaster short neuropeptide F (sNPF) and the mammalian functional homolog neuropeptide Y (NPY) regulate food intake. Understanding the molecular mechanism of sNPF and NPY signaling is critical to elucidate feeding regulation. Here, we found that minibrain (mnb) and the mammalian ortholog Dyrk1a, target genes of sNPF and NPY signaling, [corrected] regulate food intake in Drosophila melanogaster and mice. In Drosophila melanogaster neuronal cells and mouse hypothalamic cells, sNPF and NPY modulated the mnb and Dyrk1a expression through the PKA-CREB pathway. Increased Dyrk1a activated Sirt1 to regulate the deacetylation of FOXO, which potentiated FOXO-induced sNPF/NPY expression and in turn promoted food intake. Conversely, AKT-mediated insulin signaling suppressed FOXO-mediated sNPF/NPY expression, which resulted in decreasing food intake. Furthermore, human Dyrk1a transgenic mice exhibited decreased FOXO acetylation and increased NPY expression in the hypothalamus, and [corrected] increased food intake. Our findings demonstrate that Mnb/Dyrk1a regulates food intake through the evolutionary conserved Sir2-FOXO-sNPF/NPY pathway in Drosophila melanogaster and mammals.

  13. Rescue of the abnormal skeletal phenotype in Ts65Dn Down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a.

    PubMed

    Blazek, Joshua D; Abeysekera, Irushi; Li, Jiliang; Roper, Randall J

    2015-10-15

    Trisomy 21 causes skeletal alterations in individuals with Down syndrome (DS), but the causative trisomic gene and a therapeutic approach to rescue these abnormalities are unknown. Individuals with DS display skeletal alterations including reduced bone mineral density, modified bone structure and distinctive facial features. Due to peripheral skeletal anomalies and extended longevity, individuals with DS are increasingly more susceptible to bone fractures. Understanding the genetic and developmental origin of DS skeletal abnormalities would facilitate the development of therapies to rescue these and other deficiencies associated with DS. DYRK1A is found in three copies in individuals with DS and Ts65Dn DS mice and has been hypothesized to be involved in many Trisomy 21 phenotypes including skeletal abnormalities. Return of Dyrk1a copy number to normal levels in Ts65Dn mice rescued the appendicular bone abnormalities, suggesting that appropriate levels of DYRK1A expression are critical for the development and maintenance of the DS appendicular skeleton. Therapy using the DYRK1A inhibitor epigallocatechin-3-gallate improved Ts65Dn skeletal phenotypes. These outcomes suggest that the osteopenic phenotype associated with DS may be rescued postnatally by targeting trisomic Dyrk1a. PMID:26206885

  14. Recent advances in the design, synthesis, and biological evaluation of selective DYRK1A inhibitors: a new avenue for a disease modifying treatment of Alzheimer's?

    PubMed

    Smith, Breland; Medda, Federico; Gokhale, Vijay; Dunckley, Travis; Hulme, Christopher

    2012-11-21

    With 24.3 million people affected in 2005 and an estimated rise to 42.3 million in 2020, dementia is currently a leading unmet medical need and costly burden on public health. Seventy percent of these cases have been attributed to Alzheimer's disease (AD), a neurodegenerative pathology whose most evident symptom is a progressive decline in cognitive functions. Dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A) is important in neuronal development and plays a variety of functional roles within the adult central nervous system. The DYRK1A gene is located within the Down syndrome critical region (DSCR) on human chromosome 21 and current research suggests that overexpression of DYRK1A may be a significant factor leading to cognitive deficits in people with Alzheimer's disease (AD) and Down syndrome (DS). Currently, treatment options for cognitive deficiencies associated with Down syndrome, as well as Alzheimer's disease, are extremely limited and represent a major unmet therapeutic need. Small molecule inhibition of DYRK1A activity in the brain may provide an avenue for pharmaceutical intervention of mental impairment associated with AD and other neurodegenerative diseases. We herein review the current state of the art in the development of DYRK1A inhibitors. PMID:23173067

  15. Minibrain/Dyrk1a regulates food intake through the Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals.

    PubMed

    Hong, Seung-Hyun; Lee, Kyu-Sun; Kwak, Su-Jin; Kim, Ae-Kyeong; Bai, Hua; Jung, Min-Su; Kwon, O-Yu; Song, Woo-Joo; Tatar, Marc; Yu, Kweon

    2012-01-01

    Feeding behavior is one of the most essential activities in animals, which is tightly regulated by neuroendocrine factors. Drosophila melanogaster short neuropeptide F (sNPF) and the mammalian functional homolog neuropeptide Y (NPY) regulate food intake. Understanding the molecular mechanism of sNPF and NPY signaling is critical to elucidate feeding regulation. Here, we found that minibrain (mnb) and the mammalian ortholog Dyrk1a, target genes of sNPF and NPY signaling, [corrected] regulate food intake in Drosophila melanogaster and mice. In Drosophila melanogaster neuronal cells and mouse hypothalamic cells, sNPF and NPY modulated the mnb and Dyrk1a expression through the PKA-CREB pathway. Increased Dyrk1a activated Sirt1 to regulate the deacetylation of FOXO, which potentiated FOXO-induced sNPF/NPY expression and in turn promoted food intake. Conversely, AKT-mediated insulin signaling suppressed FOXO-mediated sNPF/NPY expression, which resulted in decreasing food intake. Furthermore, human Dyrk1a transgenic mice exhibited decreased FOXO acetylation and increased NPY expression in the hypothalamus, and [corrected] increased food intake. Our findings demonstrate that Mnb/Dyrk1a regulates food intake through the evolutionary conserved Sir2-FOXO-sNPF/NPY pathway in Drosophila melanogaster and mammals. PMID:22876196

  16. Molecular rescue of DYRK1A overexpression in cystathionine beta synthase-deficient mouse brain by enriched environment combined with voluntary exercise.

    PubMed

    Souchet, Benoit; Latour, Alizée; Gu, Yuchen; Daubigney, Fabrice; Paul, Jean-Louis; Delabar, Jean-Maurice; Janel, Nathalie

    2015-02-01

    Hyperhomocysteinemia resulting from cystathionine beta synthase (CBS) deficiency can produce cognitive dysfunction. We recently found that CBS-deficient mice exhibit increased expression of the serine/threonine kinase dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A) in the brain. When dysregulated, DYRK1A contributes to the neurodegeneration, neuronal death, and loss of function observed in neurodegenerative diseases. However, brain plasticity can be improved by interventions like enriched environment combined with voluntary exercise (EE/VE). The present study sought to assess the effects of EE/VE on molecular mechanisms linked to DYRK1A overexpression in the brain of CBS-deficient mice. EE/VE was applied to 3-month-old female CBS-deficient mice for 1 month. Without intervention, CBS-deficient mice exhibited increased DYRK1A and decreased brain-derived neurotrophic factor (BDNF) levels in the cortex and hippocampus. However, EE/VE rescued these altered DYRK1A and BDNF levels in the hippocampus of CBS-deficient mice. We conclude that exercise combined with enriched environment can restore the altered molecular mechanisms in the brain of CBS-deficient mice. PMID:24819931

  17. Outcomes of AV Fistulas and AV Grafts after Interventional Stent-Graft Deployment in Haemodialysis Patients

    SciTech Connect

    Schmelter, Christopher Raab, Udo; Lazarus, Friedrich; Ruppert, Volker; Vorwerk, Dierk

    2015-08-15

    PurposeThe study was designed to assess outcomes of arteriovenous (AV) accesses after interventional stent-graft deployment in haemodialysis patients.Materials and Methods63 haemodialysis patients with 66 AV fistulas and AV grafts were treated by interventional stent-graft deployment from 2006 to 2012 at our hospital. Data of these patients were retrospectively analysed for location of deployed stent-grafts, occurrence and location of (re-)stenosis and (re-)thrombosis. Complex stenosis was the most frequent indication for stent-graft deployment (45.5 %), followed by complications of angioplasty with vessel rupture or dissection (31.8 %).ResultsA high rate of procedural success was achieved (98.5 %). The most frequent location of the deployed stent-graft was the draining vein (66.7 %). Stent-graft deployment was more frequent in AV grafts than in AV fistulas. Primary patency was 45.5 % at 6 month, 31.3 % at 12 month and 19.2 % at 24 month. Primary patency was significantly better for AV fistulas than for AV grafts with deployed stent-grafts. Patency of the deployed stent-graft was much better than overall AV access primary patency with deployed stent-graft. Re-stenosis with thrombosis was the most frequent indication for re-intervention. Most frequent location of re-stenosis was the draining vein (37.1 %), followed by stenosis at the AV access (29.5 %) and the deployed stent-graft (23.5 %).ConclusionRe-stenosis and re-thrombosis remain frequent in AV fistulas and AV grafts in haemodialysis patients despite stent-graft deployment. Re-stenosis of the deployed stent-graft is, only in the minority of the cases, responsible for AV access dysfunction.

  18. Identification of a DYRK1A Inhibitor that Induces Degradation of the Target Kinase using Co-chaperone CDC37 fused with Luciferase nanoKAZ.

    PubMed

    Sonamoto, Rie; Kii, Isao; Koike, Yuka; Sumida, Yuto; Kato-Sumida, Tomoe; Okuno, Yukiko; Hosoya, Takamitsu; Hagiwara, Masatoshi

    2015-01-01

    The protein kinase family includes attractive targets for drug development. Methods for screening of kinase inhibitors remain largely limited to in vitro catalytic assays. It has been shown that ATP-competitive inhibitors antagonize interaction between the target kinase and kinase-specific co-chaperone CDC37 in living cells. Here we show a cell-based method to screen kinase inhibitors using fusion protein of CDC37 with a mutated catalytic 19-kDa component of Oplophorus luciferase, nanoKAZ (CDC37-nanoKAZ). A dual-specificity kinase DYRK1A, an importance of which has been highlighted in Alzheimer's disease, was targeted in this study. We established 293T cells stably expressing CDC37-nanoKAZ, and analyzed interaction between CDC37-nanoKAZ and DYRK1A. We revealed that DYRK1A interacted with CDC37-nanoKAZ. Importantly, point mutations that affect autophosphorylation strengthened the interaction, thus improving signal/noise ratio of the interaction relative to non-specific binding of CDC37-nanoKAZ. This high signal/noise ratio enabled screening of chemical library that resulted in identification of a potent inhibitor of DYRK1A, named CaNDY. CaNDY induced selective degradation of DYRK1A, and inhibited catalytic activity of recombinant DYRK1A with IC50 value of 7.9 nM by competing with ATP. This method based on a mutant target kinase and a bioluminescence-eliciting co-chaperone CDC37 could be applicable to evaluation and development of inhibitors targeting other kinases. PMID:26234946

  19. Hepatocyte-specific Dyrk1a gene transfer rescues plasma apolipoprotein A-I levels and aortic Akt/GSK3 pathways in hyperhomocysteinemic mice.

    PubMed

    Tlili, Asma; Jacobs, Frank; de Koning, Leanne; Mohamed, Sirine; Bui, Linh-Chi; Dairou, Julien; Belin, Nicole; Ducros, Véronique; Dubois, Thierry; Paul, Jean-Louis; Delabar, Jean-Maurice; De Geest, Bart; Janel, Nathalie

    2013-06-01

    Hyperhomocysteinemia, characterized by high plasma homocysteine levels, is recognized as an independent risk factor for cardiovascular diseases. The increased synthesis of homocysteine, a product of methionine metabolism involving B vitamins, and its slower intracellular utilization cause increased flux into the blood. Plasma homocysteine level is an important reflection of hepatic methionine metabolism and the rate of processes modified by B vitamins as well as different enzyme activity. Lowering homocysteine might offer therapeutic benefits. However, approximately 50% of hyperhomocysteinemic patients due to cystathionine-beta-synthase deficiency are biochemically responsive to pharmacological doses of B vitamins. Therefore, effective treatments to reduce homocysteine levels are needed, and gene therapy could provide a novel approach. We recently showed that hepatic expression of DYRK1A, a serine/threonine kinase, is negatively correlated with plasma homocysteine levels in cystathionine-beta-synthase deficient mice, a mouse model of hyperhomocysteinemia. Therefore, Dyrk1a is a good candidate for gene therapy to normalize homocysteine levels. We then used an adenoviral construct designed to restrict expression of DYRK1A to hepatocytes, and found decreased plasma homocysteine levels after hepatocyte-specific Dyrk1a gene transfer in hyperhomocysteinemic mice. The elevation of pyridoxal phosphate was consistent with the increase in cystathionine-beta-synthase activity. Commensurate with the decreased plasma homocysteine levels, targeted hepatic expression of DYRK1A resulted in elevated plasma paraoxonase-1 activity and apolipoprotein A-I levels, and rescued the Akt/GSK3 signaling pathways in aorta of mice, which can prevent homocysteine-induced endothelial dysfunction. These results demonstrate that hepatocyte-restricted Dyrk1a gene transfer can offer a useful therapeutic targets for the development of new selective homocysteine lowering therapy. PMID:23429073

  20. Impaired Spatial Learning Strategies and Novel Object Recognition in Mice Haploinsufficient for the Dual Specificity Tyrosine-Regulated Kinase-1A (Dyrk1A)

    PubMed Central

    Fernández, David; de Lagrán, María Martínez; Arbonés, Maria L.; Dierssen, Mara

    2008-01-01

    Background Pathogenic aneuploidies involve the concept of dosage-sensitive genes leading to over- and underexpression phenotypes. Monosomy 21 in human leads to mental retardation and skeletal, immune and respiratory function disturbances. Most of the human condition corresponds to partial monosomies suggesting that critical haploinsufficient genes may be responsible for the phenotypes. The DYRK1A gene is localized on the human chromosome 21q22.2 region, and has been proposed to participate in monosomy 21 phenotypes. It encodes a dual-specificity kinase involved in neuronal development and in adult brain physiology, but its possible role as critical haploinsufficient gene in cognitive function has not been explored. Methodology/Principal Findings We used mice heterozygous for a Dyrk1A targeted mutation (Dyrk1A+/−) to investigate the implication of this gene in the cognitive phenotypes of monosomy 21. Performance of Dyrk1A+/− mice was assayed 1/ in a navigational task using the standard hippocampally related version of the Morris water maze, 2/ in a swimming test designed to reveal potential kinesthetic and stress-related behavioral differences between control and heterozygous mice under two levels of aversiveness (25°C and 17°C) and 3/ in a long-term novel object recognition task, sensitive to hippocampal damage. Dyrk1A+/− mice showed impairment in the development of spatial learning strategies in a hippocampally-dependent memory task, they were impaired in their novel object recognition ability and were more sensitive to aversive conditions in the swimming test than euploid control animals. Conclusions/Significance The present results are clear examples where removal of a single gene has a profound effect on phenotype and indicate that haploinsufficiency of DYRK1A might contribute to an impairment of cognitive functions and stress coping behavior in human monosomy 21. PMID:18648535

  1. Synthesis of new pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs as DYRK1A inhibitors.

    PubMed

    Bruel, Amélie; Bénéteau, Romain; Chabanne, Mylène; Lozach, Olivier; Le Guevel, Rémy; Ravache, Myriam; Bénédetti, Hélène; Meijer, Laurent; Logé, Cédric; Robert, Jean-Michel

    2014-11-01

    New pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs were synthesized and their inhibitory activities against DYRK1A, CDK5/p25, GSK3α/β and p110-α isoform of PI3K evaluated using harmine as reference. Both furan-2-yl 10 and pyridin-4-yl 19 from the two different series, exhibited submicromolar IC50 against DYRK1A with no activities against the three other kinases. In addition, compound 10 exhibited antiproliferative activities in the Huh-7, Caco2 and MDA-MB-231 cell lines. PMID:25248682

  2. DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome.

    PubMed

    Najas, Sònia; Arranz, Juan; Lochhead, Pamela A; Ashford, Anne L; Oxley, David; Delabar, Jean M; Cook, Simon J; Barallobre, María José; Arbonés, Maria L

    2015-01-01

    Alterations in cerebral cortex connectivity lead to intellectual disability and in Down syndrome, this is associated with a deficit in cortical neurons that arises during prenatal development. However, the pathogenic mechanisms that cause this deficit have not yet been defined. Here we show that the human DYRK1A kinase on chromosome 21 tightly regulates the nuclear levels of Cyclin D1 in embryonic cortical stem (radial glia) cells, and that a modest increase in DYRK1A protein in transgenic embryos lengthens the G1 phase in these progenitors. These alterations promote asymmetric proliferative divisions at the expense of neurogenic divisions, producing a deficit in cortical projection neurons that persists in postnatal stages. Moreover, radial glial progenitors in the Ts65Dn mouse model of Down syndrome have less Cyclin D1, and Dyrk1a is the triplicated gene that causes both early cortical neurogenic defects and decreased nuclear Cyclin D1 levels in this model. These data provide insights into the mechanisms that couple cell cycle regulation and neuron production in cortical neural stem cells, emphasizing that the deleterious effect of DYRK1A triplication in the formation of the cerebral cortex begins at the onset of neurogenesis, which is relevant to the search for early therapeutic interventions in Down syndrome. PMID:26137553

  3. HIV-1-Tat Protein Inhibits SC35-mediated Tau Exon 10 Inclusion through Up-regulation of DYRK1A Kinase.

    PubMed

    Kadri, Ferdous; Pacifici, Marco; Wilk, Anna; Parker-Struckhoff, Amanda; Del Valle, Luis; Hauser, Kurt F; Knapp, Pamela E; Parsons, Christopher; Jeansonne, Duane; Lassak, Adam; Peruzzi, Francesca

    2015-12-25

    The HIV-1 transactivator protein Tat is implicated in the neuronal damage that contributes to neurocognitive impairment affecting people living with HIV/AIDS. Aberrant splicing of TAU exon 10 results in tauopathies characterized by alterations in the proportion of TAU isoforms containing three (3R) or four (4R) microtubule-binding repeats. The splicing factor SC35/SRSF2 binds to nuclear RNA and facilitates the incorporation of exon 10 in the TAU molecule. Here, we utilized clinical samples, an animal model, and neuronal cell cultures and found that Tat promotes TAU 3R up-regulation through increased levels of phosphorylated SC35, which is retained in nuclear speckles. This mechanism involved Tat-mediated increased expression of DYRK1A and was prevented by DYRK1A silencing. In addition, we found that Tat associates with TAU RNA, further demonstrating that Tat interferes with host RNA metabolism in the absence of viral infection. Altogether, our data unravel a novel mechanism of Tat-mediated neuronal toxicity through dysregulation of the SC35-dependent alternative splicing of TAU exon 10. Furthermore, the increased immunostaining of DYRK1A in HIV+ brains without pathology points at dysregulation of DYRK1A as an early event in the neuronal complications of HIV infection. PMID:26534959

  4. DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome.

    PubMed

    Duchon, Arnaud; Herault, Yann

    2016-01-01

    Down syndrome (DS) is one of the leading causes of intellectual disability, and patients with DS face various health issues, including learning and memory deficits, congenital heart disease, Alzheimer's disease (AD), leukemia, and cancer, leading to huge medical and social costs. Remarkable advances on DS research have been made in improving cognitive function in mouse models for future therapeutic approaches in patients. Among the different approaches, DYRK1A inhibitors have emerged as promising therapeutics to reduce DS cognitive deficits. DYRK1A is a dual-specificity kinase that is overexpressed in DS and plays a key role in neurogenesis, outgrowth of axons and dendrites, neuronal trafficking and aging. Its pivotal role in the DS phenotype makes it a prime target for the development of therapeutics. Recently, disruption of DYRK1A has been found in Autosomal Dominant Mental Retardation 7 (MRD7), resulting in severe mental deficiency. Recent advances in the development of kinase inhibitors are expected, in the near future, to remove DS from the list of incurable diseases, providing certain conditions such as drug dosage and correct timing for the optimum long-term treatment. In addition the exact molecular and cellular mechanisms that are targeted by the inhibition of DYRK1A are still to be discovered. PMID:27375444

  5. Dosage of Dyrk1a shifts cells within a p21-cyclin D1 signaling map to control the decision to enter the cell cycle.

    PubMed

    Chen, Jia-Yun; Lin, Jia-Ren; Tsai, Feng-Chiao; Meyer, Tobias

    2013-10-10

    Mammalian cells have a remarkable capacity to compensate for heterozygous gene loss or extra gene copies. One exception is Down syndrome (DS), where a third copy of chromosome 21 mediates neurogenesis defects and lowers the frequency of solid tumors. Here we combine live-cell imaging and single-cell analysis to show that increased dosage of chromosome 21-localized Dyrk1a steeply increases G1 cell cycle duration through direct phosphorylation and degradation of cyclin D1 (CycD1). DS-derived fibroblasts showed analogous cell cycle changes that were reversed by Dyrk1a inhibition. Furthermore, reducing Dyrk1a activity increased CycD1 expression to force a bifurcation, with one subpopulation of cells accelerating proliferation and the other arresting proliferation by costabilizing CycD1 and the CDK inhibitor p21. Thus, dosage of Dyrk1a repositions cells within a p21-CycD1 signaling map, directing each cell to either proliferate or to follow two distinct cell cycle exit pathways characterized by high or low CycD1 and p21 levels. PMID:24119401

  6. DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome

    PubMed Central

    Duchon, Arnaud; Herault, Yann

    2016-01-01

    Down syndrome (DS) is one of the leading causes of intellectual disability, and patients with DS face various health issues, including learning and memory deficits, congenital heart disease, Alzheimer’s disease (AD), leukemia, and cancer, leading to huge medical and social costs. Remarkable advances on DS research have been made in improving cognitive function in mouse models for future therapeutic approaches in patients. Among the different approaches, DYRK1A inhibitors have emerged as promising therapeutics to reduce DS cognitive deficits. DYRK1A is a dual-specificity kinase that is overexpressed in DS and plays a key role in neurogenesis, outgrowth of axons and dendrites, neuronal trafficking and aging. Its pivotal role in the DS phenotype makes it a prime target for the development of therapeutics. Recently, disruption of DYRK1A has been found in Autosomal Dominant Mental Retardation 7 (MRD7), resulting in severe mental deficiency. Recent advances in the development of kinase inhibitors are expected, in the near future, to remove DS from the list of incurable diseases, providing certain conditions such as drug dosage and correct timing for the optimum long-term treatment. In addition the exact molecular and cellular mechanisms that are targeted by the inhibition of DYRK1A are still to be discovered. PMID:27375444

  7. Design and synthesis of thiazolo[5,4-f]quinazolines as DYRK1A inhibitors, part I.

    PubMed

    Foucourt, Alicia; Hédou, Damien; Dubouilh-Benard, Carole; Désiré, Laurent; Casagrande, Anne-Sophie; Leblond, Bertrand; Loäec, Nadège; Meijer, Laurent; Besson, Thierry

    2014-01-01

    The convenient synthesis of a library of novel 6,6,5-tricyclic thiazolo[5,4-f] quinazolines (forty molecules) was achieved mainly under microwave irradiation. Dimroth rearrangement and 4,5-dichloro-1,2,3,-dithiazolium chloride (Appel salt) chemistry were associated for the synthesis of a novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (16) a versatile molecular platform for the synthesis of various bioactive derivatives. Kinase inhibition of the final compounds was evaluated on a panel of four Ser/Thr kinases (DYRK1A, CDK5, CK1 and GSK3) chosen for their strong implications in various regulation processes, especially Alzheimer's disease (AD). In view of the results of this preliminary screening, thiazolo[5,4-f]quinazoline scaffolds constitutes a promising source of inspiration for the synthesis of novel bioactive molecules. Among the compounds of this novel chemolibrary, 7i, 8i and 9i inhibited DYRK1A with IC50 values ranging in the double-digit nanomolar range (40, 47 and 50 nM, respectively). PMID:25268714

  8. Overview of AVS-video: tools, performance and complexity

    NASA Astrophysics Data System (ADS)

    Yu, Lu; Yi, Feng; Dong, Jie; Zhang, Cixun

    2005-07-01

    Audio Video coding Standard (AVS) is established by the Working Group of China in the same name. AVS-video is an application driven coding standard. AVS Part 2 targets to high-definition digital video broadcasting and high-density storage media and AVS Part 7 targets to low complexity, low picture resolution mobility applications. Integer transform, intra and inter-picture prediction, in-loop deblocking filter and context-based two dimensional variable length coding are the major compression tools in AVS-video, which are well-tuned for target applications. It achieves similar performance to H.264/AVC with lower cost.

  9. DYRK1A-mediated phosphorylation of GluN2A at Ser(1048) regulates the surface expression and channel activity of GluN1/GluN2A receptors.

    PubMed

    Grau, Cristina; Arató, Krisztina; Fernández-Fernández, José M; Valderrama, Aitana; Sindreu, Carlos; Fillat, Cristina; Ferrer, Isidre; de la Luna, Susana; Altafaj, Xavier

    2014-01-01

    N-methyl-D-aspartate glutamate receptors (NMDARs) play a pivotal role in neural development and synaptic plasticity, as well as in neurological disease. Since NMDARs exert their function at the cell surface, their density in the plasma membrane is finely tuned by a plethora of molecules that regulate their production, trafficking, docking and internalization in response to external stimuli. In addition to transcriptional regulation, the density of NMDARs is also influenced by post-translational mechanisms like phosphorylation, a modification that also affects their biophysical properties. We previously described the increased surface expression of GluN1/GluN2A receptors in transgenic mice overexpressing the Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), suggesting that DYRK1A regulates NMDARs. Here we have further investigated whether the density and activity of NMDARs were modulated by DYRK1A phosphorylation. Accordingly, we show that endogenous DYRK1A is recruited to GluN2A-containing NMDARs in the adult mouse brain, and we identify a DYRK1A phosphorylation site at Ser(1048) of GluN2A, within its intracellular C-terminal domain. Mechanistically, the DYRK1A-dependent phosphorylation of GluN2A at Ser(1048) hinders the internalization of GluN1/GluN2A, causing an increase of surface GluN1/GluN2A in heterologous systems, as well as in primary cortical neurons. Furthermore, GluN2A phosphorylation at Ser(1048) increases the current density and potentiates the gating of GluN1/GluN2A receptors. We conclude that DYRK1A is a direct regulator of NMDA receptors and we propose a novel mechanism for the control of NMDAR activity in neurons. PMID:25368549

  10. DYRK1A-mediated phosphorylation of GluN2A at Ser1048 regulates the surface expression and channel activity of GluN1/GluN2A receptors

    PubMed Central

    Grau, Cristina; Arató, Krisztina; Fernández-Fernández, José M.; Valderrama, Aitana; Sindreu, Carlos; Fillat, Cristina; Ferrer, Isidre; de la Luna, Susana; Altafaj, Xavier

    2014-01-01

    N-methyl-D-aspartate glutamate receptors (NMDARs) play a pivotal role in neural development and synaptic plasticity, as well as in neurological disease. Since NMDARs exert their function at the cell surface, their density in the plasma membrane is finely tuned by a plethora of molecules that regulate their production, trafficking, docking and internalization in response to external stimuli. In addition to transcriptional regulation, the density of NMDARs is also influenced by post-translational mechanisms like phosphorylation, a modification that also affects their biophysical properties. We previously described the increased surface expression of GluN1/GluN2A receptors in transgenic mice overexpressing the Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), suggesting that DYRK1A regulates NMDARs. Here we have further investigated whether the density and activity of NMDARs were modulated by DYRK1A phosphorylation. Accordingly, we show that endogenous DYRK1A is recruited to GluN2A-containing NMDARs in the adult mouse brain, and we identify a DYRK1A phosphorylation site at Ser1048 of GluN2A, within its intracellular C-terminal domain. Mechanistically, the DYRK1A-dependent phosphorylation of GluN2A at Ser1048 hinders the internalization of GluN1/GluN2A, causing an increase of surface GluN1/GluN2A in heterologous systems, as well as in primary cortical neurons. Furthermore, GluN2A phosphorylation at Ser1048 increases the current density and potentiates the gating of GluN1/GluN2A receptors. We conclude that DYRK1A is a direct regulator of NMDA receptors and we propose a novel mechanism for the control of NMDAR activity in neurons. PMID:25368549

  11. Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis.

    PubMed

    Ori-McKenney, Kassandra M; McKenney, Richard J; Huang, Hector H; Li, Tun; Meltzer, Shan; Jan, Lily Yeh; Vale, Ronald D; Wiita, Arun P; Jan, Yuh Nung

    2016-05-01

    Dendritic arborization patterns are consistent anatomical correlates of genetic disorders such as Down syndrome (DS) and autism spectrum disorders (ASDs). In a screen for abnormal dendrite development, we identified Minibrain (MNB)/DYRK1a, a kinase implicated in DS and ASDs, as a regulator of the microtubule cytoskeleton. We show that MNB is necessary to establish the length and cytoskeletal composition of terminal dendrites by controlling microtubule growth. Altering MNB levels disrupts dendrite morphology and perturbs neuronal electrophysiological activity, resulting in larval mechanosensation defects. Using in vivo and in vitro approaches, we uncover a molecular pathway whereby direct phosphorylation of β-tubulin by MNB inhibits tubulin polymerization, a function that is conserved for mammalian DYRK1a. Our results demonstrate that phosphoregulation of microtubule dynamics by MNB/DYRK1a is critical for dendritic patterning and neuronal function, revealing a previously unidentified mode of posttranslational microtubule regulation in neurons and uncovering a conserved pathway for a DS- and ASD-associated kinase. PMID:27112495

  12. 45 CFR 156.135 - AV calculation for determining level of coverage.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... cumulative basis; and (5) Update the AV Calculator user interface when a change would be useful to a broad group of users of the AV Calculator, would not affect the function of the AV Calculator, and would...

  13. Pharmacophore and 3D-QSAR characterization of 6-arylquinazolin-4-amines as Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) inhibitors.

    PubMed

    Pan, Yongmei; Wang, Yanli; Bryant, Stephen H

    2013-04-22

    Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) are protein kinases that are promising targets for treatment of diseases caused by abnormal gene splicing. 6-Arylquinazolin-4-amines have been recently identified as potent Clk4 and Dyrk1A inhibitors. In order to understand the structure-activity correlation of these analogs, we have applied ligand-based pharmacophore and 3D-QSAR modeling combined with structure-based homology modeling and docking. The high R(2) and Q(2) (0.88 and 0.79 for Clk4, 0.85 and 0.82 for Dyrk1A, respectively) based on validation with training and test set compounds suggested that the generated 3D-QSAR models are reliable in predicting novel ligand activities against Clk4 and Dyrk1A. The binding mode identified through docking ligands to the ATP binding domain of Clk4 was consistent with the structural properties and energy field contour maps characterized by pharmacophore and 3D-QSAR models and gave valuable insights into the structure-activity profile of 6-arylquinazolin-4-amine analogs. The obtained 3D-QSAR and pharmacophore models in combination with the binding mode between inhibitor and residues of Clk4 will be helpful for future lead compound identification and optimization to design potent and selective Clk4 and Dyrk1A inhibitors. PMID:23496085

  14. Pollen transmission of asparagus virus 2 (AV-2) may facilitate mixed infection by two AV-2 isolates in asparagus plants.

    PubMed

    Kawamura, Ryusuke; Shimura, Hanako; Mochizuki, Tomofumi; Ohki, Satoshi T; Masuta, Chikara

    2014-09-01

    Asparagus virus 2 (AV-2) is a member of the genus Ilarvirus and thought to induce the asparagus decline syndrome. AV-2 is known to be transmitted by seed, and the possibility of pollen transmission was proposed 25 years ago but not verified. In AV-2 sequence analyses, we have unexpectedly found mixed infection by two distinct AV-2 isolates in two asparagus plants. Because mixed infections by two related viruses are normally prevented by cross protection, we suspected that pollen transmission of AV-2 is involved in mixed infection. Immunohistochemical analyses and in situ hybridization using AV-2-infected tobacco plants revealed that AV-2 was localized in the meristem and associated with pollen grains. To experimentally produce a mixed infection via pollen transmission, two Nicotiana benthamiana plants that were infected with each of two AV-2 isolates were crossed. Derived cleaved-amplified polymorphic sequence analysis identified each AV-2 isolate in the progeny seedlings, suggesting that pollen transmission could indeed result in a mixed infection, at least in N. benthamiana.

  15. AV Rising: Demand, Budgets, and Circulation Are All Up.

    ERIC Educational Resources Information Center

    Oder, Norman

    1998-01-01

    A survey of 486 public libraries found that audiovisual (AV) budgets have increased 53% in the last five years. Provides data on average size of AV collections; budget break downs; circulation; audiobook, video, and music CD purchases; popular authors and titles in abridged and unabridged audiobooks; and problems with audiobook, video, and music…

  16. Cofactor Requirement of HpyAV Restriction Endonuclease

    PubMed Central

    Chan, Siu-Hong; Opitz, Lars; Higgins, Lauren; O'loane, Diana; Xu, Shuang-yong

    2010-01-01

    Background Helicobacter pylori is the etiologic agent of common gastritis and a risk factor for gastric cancer. It is also one of the richest sources of Type II restriction-modification (R-M) systems in microorganisms. Principal Findings We have cloned, expressed and purified a new restriction endonuclease HpyAV from H. pylori strain 26695. We determined the HpyAV DNA recognition sequence and cleavage site as CCTTC 6/5. In addition, we found that HpyAV has a unique metal ion requirement: its cleavage activity is higher with transition metal ions than in Mg++. The special metal ion requirement of HpyAV can be attributed to the presence of a HNH catalytic site similar to ColE9 nuclease instead of the canonical PD-X-D/EXK catalytic site found in many other REases. Site-directed mutagenesis was carried out to verify the catalytic residues of HpyAV. Mutation of the conserved metal-binding Asn311 and His320 to alanine eliminated cleavage activity. HpyAV variant H295A displayed approximately 1% of wt activity. Conclusions/Significance Some HNH-type endonucleases have unique metal ion cofactor requirement for optimal activities. Homology modeling and site-directed mutagenesis confirmed that HpyAV is a member of the HNH nuclease family. The identification of catalytic residues in HpyAV paved the way for further engineering of the metal binding site. A survey of sequenced microbial genomes uncovered 10 putative R-M systems that show high sequence similarity to the HpyAV system, suggesting lateral transfer of a prototypic HpyAV-like R-M system among these microorganisms. PMID:20140205

  17. Molecular cloning, characterization and tissue distribution of two ostrich β-defensins: AvBD2 and AvBD7.

    PubMed

    Lu, Shun; Peng, Kemei; Gao, Qishuang; Xiang, Min; Liu, Huazhen; Song, Hui; Yang, Keli; Huang, Haibo; Xiao, Ke

    2014-11-15

    Avian β-defensins (AvBDs) are a family of small antimicrobial peptides that play important roles in the innate immunity of birds. Herein, we report on two new ostrich AvBD genes, AvBD2 and AvBD7, which were isolated from the bone marrow of ostriches (Struthio camelus). The coding regions of ostrich AvBD2 and AvBD7 comprised 195 bp and 201bp, which encoded 64 and 66 amino acids, respectively. Homology analysis showed that ostrich AvBD2 had the highest similarity (up to 86%) with the swan goose (Anser cygnoides) AvBD2, while ostrich AvBD7 shared the highest similarity (up to 81%) with chicken AvBD7. Analysis of the codon-usage bias showed that the two ostrich AvBDs had different codon-usage patterns from other AvBDs. The two synthetic AvBD peptides exhibited antibacterial activities against both Gram-positive and Gram-negative bacteria, and these activities decreased significantly in the presence of 100mM NaCl (P<0.01). Real-time reverse transcription-polymerase chain reaction analysis showed that AvBD2 and AvBD7 were widely expressed at different levels in 17 different tissues. This is the first report of the nucleotide sequences of ostrich AvBDs. Further investigations of these two AvBDs may help us to gain new insights into the immune defense system of the ostrich and to make subsequent therapeutic use of ostrich defensins. PMID:25127671

  18. AV-95 Sun Devil: High-Speed Military Rotorcraft

    NASA Technical Reports Server (NTRS)

    1996-01-01

    The AV-95 Sun Devil must combine helicopter capabilities, such as vertical takeoff and landings (VTOL) and rotor-powered flight, along with long-duration cruise and high-speed dash capabilities unobtainable by conventional helicopters. To be able to perform both tasks, and perform them well, the AV-95 Sun Devil design incorporates several unconventional devices; the AV-95 uses two convertible turbofan engines, able to provide both shaft power for the main rotor and tall fan as well as jet thrust either separately or simultaneously. Other devices used for the AV-95 include a variable diameter main rotor and a blown flap. In helicopter mode, the AV-95 Sun Devil performs like a winged helicopter. The addition of wings to an attack helicopter results in two significant advantages. First, the addition of wings makes a helicopter more maneuverable than a wingless, but otherwise similar helicopter. Second, since the wings produce lift, rotor stall and compressibility effects can be significantly delayed at high tip velocities. In fixed-wing mode, the main rotor is completely off-loaded but slightly powered, and the rotor diameter has been minimized. The AV-95 Sun Devil has many advantages over other VTOL aircraft. The conversion process is simple and fast; conversion does not make the AV-95 vulnerable to enemy attack during conversion such as a tilt-wing or a tilt-rotor. Stop-rotor aircraft and a stowed rotor aircraft require heavy breaking of the rotor for conversion; this adds time for conversion and weight to the aircraft. Because the AV-95 never stops the rotor in flight, much weight is spared, and conversion is much simpler and faster.

  19. Expression of the DYRK1A gene correlates with its 3D positioning in the interphase nucleus of Down syndrome cells.

    PubMed

    Paz, Nerea; Felipe-Blanco, Izaskun; Royo, Félix; Zabala, Amaia; Guerra-Merino, Isabel; García-Orad, África; Zugaza, José L; Parada, Luis A

    2015-06-01

    Down syndrome is a common birth defect caused by trisomy of chromosome 21. Chromosomes occupy distinct territories in interphase nuclei, and their distribution within the nuclear space is nonrandom. In humans with Down syndrome, two chromosomes 21 frequently localize proximal to one another and distant from the third chromosome. Here, we investigated the nuclear organization of DYRK1A and SOD1, two genes mapping to chromosome 21 that greatly contribute to the pathology. We found that DYRK1A conserves its central positioning between normal and trisomic cells, whereas SOD1 adopts more peripheral distribution in trisomic cells. We also found that the relative position of these genes with respect to each other varies among the different copies of chromosome territories 21 within a cell, and that this distinct distribution is associated with differences in their expression levels. All together, our results may explain, at least in part, the difference in the expression level of these two genes implicated in the pathogenesis of Down syndrome. PMID:25645734

  20. The GBA, DYRK1A and MS4A6A polymorphisms influence the age at onset of Chinese Parkinson patients.

    PubMed

    Fan, Kuan; Tang, Bei-Sha; Wang, Ya-Qin; Kang, Ji-Feng; Li, Kai; Liu, Zhen-Hua; Sun, Qi-Ying; Xu, Qian; Yan, Xin-Xiang; Guo, Ji-Feng

    2016-05-16

    Parkinson's disease (PD) is known as the most common neurodegenerative disease after Alzheimer's disease (AD). The precise pathogenic mechanism of PD remains unclear, but genetic and environmental factors are widely recognized to be associated with it. Although many associated genes have been discovered, they account for only a few PD patients. Recently, there are growing evidences indicating that patients with PD and AD share similarities in clinical features, pathology and genetic risks. However, no study has been conducted on the relations between AD associated genes and age at onset (AAO) of PD. In this study, we have detected 14 single nucleotide polymorphisms (SNPs) in 9 AD genome wide association studies top hit genes and 4 SNPs in 4 PD-cognitive impairment related genes among 297 Chinese PD patients. Through the linear regression analysis, we identified the significant associations of the GBA L444P mutation and DYRK1A rs8126696 T allele with the earlier AAO in PD patients, and the A allele at MS4A6A rs610932 with the delayed AAO of PD. This is the first report of significant associations of DYRK1A and MS4A6A SNPs and the AAO of PD. On account of their effects both in AD and PD, it is indicated that AD and PD possibly share some common pathways. PMID:27085534

  1. Enhanced A-V nodal conduction (Lown-Ganong-Levine syndrome) by congenitally hypoplastic A-V node.

    PubMed

    Ometto, R; Thiene, G; Corrado, D; Vincenzi, M; Rossi, L

    1992-11-01

    The basic anatomical substrate of enhanced A-V nodal conduction, manifesting or not as Lown-Ganong-Levine syndrome, is still a controversial issue. We describe the case of a 34-year-old man who presented episodes of ventricular fibrillation. Electrophysiological studies showed that the AH interval was 55 ms, and increased by only 20 ms at paced cycle lengths of 300 ms; atrial pacing induced atrial fibrillation, with a shortest RR interval of 240 ms. Despite verapamil therapy, this patient died suddenly at home. Histological study disclosed a severe A-V node hypoplasia that was evidently congenital in nature; the rest of the conduction system was normal, and no accessory A-V pathways were present. We suggest that enhanced A-V nodal conduction in this patient was due to the developmental defect in the A-V node; this abnormality caused a loss of specific impulse-delaying function, and thus allowed rapid, unfiltered atrial impulses to reach the lower A-V junction and ventricles.

  2. Overdrive suppression of implanted pacemakers in patients with AV block.

    PubMed Central

    Grendahl, H; Miller, M; Kjekshus, J

    1978-01-01

    Patients being permanently paced for symptomatic AV block were studied by overdrive suppression of the QRS-inhibited pacemaker, in order to observe the underlying heart rhythm. The chest wall stimulation method was used. In complete AV block the escape rhythm recovery time proved highly reproducible on repeated testing on the same day, and in many patients remained so over months or years. Occasionally, a doubling of the escape rhythm recovery time was seen, suggesting initial exit block of the escape focus. Resetting of the escape rhythm usually followed an exponential curve until stabilisation after about 3 minutes. An early escape rhythm with a recovery time of less than 4 seconds was found on every occasion in 21 of 58 patients with complete AV block, and inconstantly in 23 more; in 14 it was never observed. Accidental pacing failure was seen in 15 patients. The overdrive suppression test was helpful in selecting pacemaker dependent patients. PMID:637960

  3. DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1-mediated transcriptional repression.

    PubMed

    Jang, Suk Min; Azebi, Saliha; Soubigou, Guillaume; Muchardt, Christian

    2014-06-01

    Heterochromatin protein 1 (HP1) proteins are chromatin-bound transcriptional regulators. While their chromodomain binds histone H3 methylated on lysine 9, their chromoshadow domain associates with the H3 histone fold in a region involved in chromatin remodeling. Here, we show that phosphorylation at histone H3 threonine 45 and serine 57 within this latter region differentially affects binding of the three mammalian HP1 isoforms HP1α, HP1β and HP1γ. Both phosphorylation events are dependent on the activity of the DYRK1A kinase that antagonizes HP1-mediated transcriptional repression and participates in abnormal activation of cytokine genes in Down's syndrome-associated megakaryoblastic leukemia. PMID:24820035

  4. Assessment of the NASA AvSTAR Project Plan

    NASA Technical Reports Server (NTRS)

    Ulrey, Michael L.; Haraldsdottir, Aslaug; Berge, Matthew E.; Hopperstad, Craig A.; Schwab, Robert W.

    2004-01-01

    This report is a preliminary evaluation of NASA's proposed Aviation System Technology Advanced Research (AvSTAR) Program during the early stages of its definition, in the first half of the year 2001. This evaluation focuses on how well the program goals address the needs of the U.S. National Airspace System, the technical feasibility of the program goals, and the logistical feasibility of the program plan. This report also provides recommendations on how the AvSTAR program could be strengthened and improved. This document has two appendices.

  5. A rare case of congenital complex pulmonary AV fistula

    PubMed Central

    Pradhan, Akshyaya; Khare, Rashi; Sethi, Rishi

    2014-01-01

    A 15-year-old boy presented with central cyanosis with clubbing and dyspnoea on exertion. Cardiovascular examination did not reveal any abnormality. ECG was normal. Chest X-ray showed a normal sized heart with rounded opacities of variable size in the left upper lung field. Two-dimensional echocardiographic examination was normal. CT angiography showed a large complex lesion composed of serpiginous tubular structures involving the left upper and lingular lobe, suggestive of racemose tangle of blood vessels. A diagnosis of large complex arteriovenous (AV) fistula involving the left upper and lingular lobe was performed. This case reports a rare case of complex pulmonary AV fistula. PMID:25326563

  6. Synthesis and optimization of an original V-shaped collection of 4-7-disubstituted pyrido[3,2-d]pyrimidines as CDK5 and DYRK1A inhibitors.

    PubMed

    Dehbi, Oussama; Tikad, Abdellatif; Bourg, Stéphane; Bonnet, Pascal; Lozach, Olivier; Meijer, Laurent; Aadil, Mina; Akssira, Mohammed; Guillaumet, Gérald; Routier, Sylvain

    2014-06-10

    We here report the synthesis and biological evaluation of an original collection of 4,7-disubstituted pyrido[3,2-d]pyrimidines designed as potential kinase inhibitors. The collection was generated from a single starting material, 4,7-dichloropyrido[3,2-d]pyrimidine, which afforded the final compounds after two steps: a sequential or one-pot sequence including selective cross coupling reactions in C-4, followed by the second cross-coupling in C-7. In position C-4, a Suzuki-Miyaura type reaction led to monosubstituted derivatives whereas in position C-7, synthesis was achieved via a Suzuki or a Buchwald type reaction using commercially available or undescribed boron derivatives. The biological activity of the V-shaped family was measured in protein kinase assays. The structure activity relationship (SAR) revealed that some compounds selectively inhibited DYRK1A and CDK5 without affecting GSK3. Docking studies furnished possible explanations that correlate with the SAR data. The most active compound on the two biological targets was 27 which exhibited the following IC50: 110 nM for CDK5, 24 nM for DYRK1A and only 1.2 μM for GSK3. In the C-7 amino subfamily, the best derivative was indubitably compound 48 which led to a near selective action on DYRK1A and a remarkable IC50 of 60 nM.

  7. Synthesis and optimization of an original V-shaped collection of 4-7-disubstituted pyrido[3,2-d]pyrimidines as CDK5 and DYRK1A inhibitors.

    PubMed

    Dehbi, Oussama; Tikad, Abdellatif; Bourg, Stéphane; Bonnet, Pascal; Lozach, Olivier; Meijer, Laurent; Aadil, Mina; Akssira, Mohammed; Guillaumet, Gérald; Routier, Sylvain

    2014-06-10

    We here report the synthesis and biological evaluation of an original collection of 4,7-disubstituted pyrido[3,2-d]pyrimidines designed as potential kinase inhibitors. The collection was generated from a single starting material, 4,7-dichloropyrido[3,2-d]pyrimidine, which afforded the final compounds after two steps: a sequential or one-pot sequence including selective cross coupling reactions in C-4, followed by the second cross-coupling in C-7. In position C-4, a Suzuki-Miyaura type reaction led to monosubstituted derivatives whereas in position C-7, synthesis was achieved via a Suzuki or a Buchwald type reaction using commercially available or undescribed boron derivatives. The biological activity of the V-shaped family was measured in protein kinase assays. The structure activity relationship (SAR) revealed that some compounds selectively inhibited DYRK1A and CDK5 without affecting GSK3. Docking studies furnished possible explanations that correlate with the SAR data. The most active compound on the two biological targets was 27 which exhibited the following IC50: 110 nM for CDK5, 24 nM for DYRK1A and only 1.2 μM for GSK3. In the C-7 amino subfamily, the best derivative was indubitably compound 48 which led to a near selective action on DYRK1A and a remarkable IC50 of 60 nM. PMID:24793883

  8. TIME VARIATION OF AV AND RV FOR TYPE Ia SUPERNOVAE BEHIND INTERSTELLAR DUST

    NASA Astrophysics Data System (ADS)

    Huang, Xiaosheng; Biederman, M.; Herger, B.; Aldering, G. S.

    2014-01-01

    TIME VARIATION OF AV AND RV FOR TYPE Ia SUPERNOVAE BEHIND NON-UNIFORM INTERSTELLAR DUST ABSTRACT We investigate the time variation of the visual extinction, AV, and the total-to-selective extinction ratio, RV, resulting from interstellar dust in front of an expanding photospheric disk of a type Ia supernova (SN Ia). We simulate interstellar dust clouds according to a power law power spectrum and produce extinction maps that either follow a pseudo-Gaussian distribution or a lognormal distribution. The RV maps are produced through a correlation between AV and RV. With maps of AV and RV generated in each case (pseudo-Gaussian and lognormal), we then compute the effective AV and RV for a SN as its photospheric disk expands behind the dust screen. We find for a small percentage of SNe the AV and RV values can vary by a large factor from day to day in the first 40 days after explosion.

  9. Electrical storm after CRT implantation treated by AV delay optimization.

    PubMed

    Combes, Nicolas; Marijon, Eloi; Boveda, Serge; Albenque, Jean-Paul

    2010-02-01

    We present a case of symptomatic ischemic heart failure with an indication for cardiac resynchronization and implantable cardiac defibrillator therapy in primary prevention. After implantation, the patient developed a severe electrical storm with multiple shocks. Hemodynamic improvement based only on AV delay, guided by echocardiography and ECG, brought about a dramatic improvement in the situation. We discuss the pathophysiology of electrical storm occurring immediately after LV pacing.

  10. Toward robust AV conferencing on next-generation networks

    NASA Astrophysics Data System (ADS)

    Liu, Haining; Cheng, Liang; El Zarki, Magda

    2005-01-01

    In order to enable a truly pervasive computing environment, next generation networks (including B3G and 4G) will merge the broadband wireless and wireline networking infrastructure. However, due to the tremendous complexity in administration and the unreliability of the wireless channel, provision of hard-guarantees for services on such networks will not happen in the foreseeable future. This consequently makes it particularly challenging to offer viable AV conferencing services due to their stringent synchronization, delay and data fidelity requirements. We propose in this paper a robust application-level solution for wireless mobile AV conferencing on B3G/4G networks. Expecting no special treatment from the network, we apply a novel adaptive delay and synchronization control mechanism to maintain the synchronization and reduce the latency as much as possible. We also employ a robust video coding technique that has better error-resilience capability. We investigate the performance of the proposed solution through simulations using a three-state hidden Markov chain as the generic end-to-end transport channel model. The results show that our scheme yields tight synchronization performance, relatively low end-to-end latency and satisfactory presentation quality. The scheme successfully provides a fairly robust AV conferencing service.

  11. Toward robust AV conferencing on next-generation networks

    NASA Astrophysics Data System (ADS)

    Liu, Haining; Cheng, Liang; El Zarki, Magda

    2004-12-01

    In order to enable a truly pervasive computing environment, next generation networks (including B3G and 4G) will merge the broadband wireless and wireline networking infrastructure. However, due to the tremendous complexity in administration and the unreliability of the wireless channel, provision of hard-guarantees for services on such networks will not happen in the foreseeable future. This consequently makes it particularly challenging to offer viable AV conferencing services due to their stringent synchronization, delay and data fidelity requirements. We propose in this paper a robust application-level solution for wireless mobile AV conferencing on B3G/4G networks. Expecting no special treatment from the network, we apply a novel adaptive delay and synchronization control mechanism to maintain the synchronization and reduce the latency as much as possible. We also employ a robust video coding technique that has better error-resilience capability. We investigate the performance of the proposed solution through simulations using a three-state hidden Markov chain as the generic end-to-end transport channel model. The results show that our scheme yields tight synchronization performance, relatively low end-to-end latency and satisfactory presentation quality. The scheme successfully provides a fairly robust AV conferencing service.

  12. New apolipoprotein A-V: comparative genomics meets metabolism.

    PubMed

    Seda, O; Sedová, L

    2003-01-01

    The availability of the human genome sequence and the recently completed draft sequences of two major mammalian model species, the mouse (Mus musculus) and the rat (Rattus norvegicus), allow researchers to apply novel approaches for gene identification and characterization, using methods of comparative and functional genomics. Recently, a new gene coding for apolipoprotein A-V was identified in the vicinity of APOA-I/C-III/A-IV cluster on human chromosome 11q23 by comparative sequencing method. In a relatively short time, compelling evidence accumulated for the substantial role of APOA-V in lipid metabolism. Studies in knock-out and transgenic mice revealed that its expression pattern correlates negatively with triglyceride levels. This observation was verified in human population studies in variety of ethnic and age groups. Several single nucleotide polymorphisms were described and particular SNP alleles and haplotypes in the APO A-V gene region were shown to be associated with dyslipidemia. The discovery and characterization of the APO A-V demonstrates current possibilities of the integrative approaches in biology, boosted by the available bioinformatic tools.

  13. Development of a Serological Assay for the Sea Lion (Zalophus californianus) Anellovirus, ZcAV

    PubMed Central

    Fahsbender, Elizabeth; Rosario, Karyna; Cannon, John P.; Gulland, Frances; Dishaw, Larry J.; Breitbart, Mya

    2015-01-01

    New diseases in marine animals are emerging at an increasing rate, yet methodological limitations hinder characterization of viral infections. Viral metagenomics is an effective method for identifying novel viruses in diseased animals; however, determining virus pathogenesis remains a challenge. A novel anellovirus (Zalophus californianus anellovirus, ZcAV) was recently reported in the lungs of captive California sea lions involved in a mortality event. ZcAV was not detected by PCR in the blood of these animals, creating the inability to assess the prevalence of ZcAV in live sea lions. This study developed an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to ZcAV in sea lion serum. To assess ZcAV prevalence, paired serum and lung samples (n = 96) from wild sea lions that stranded along the California coast were tested through ELISA and PCR, respectively. Over 50% of the samples tested positive for ZcAV by ELISA (34%), PCR (29%), or both (11%) assays. ZcAV is prevalent in stranded wild sea lion populations and results suggest that PCR assays alone may grossly underestimate ZcAV exposure. This ELISA provides a tool for testing live sea lions for ZcAV exposure and is valuable for subsequent studies evaluating the potential pathogenicity of this anellovirus. PMID:25965294

  14. Development of a Serological Assay for the Sea Lion (Zalophus californianus) Anellovirus, ZcAV.

    PubMed

    Fahsbender, Elizabeth; Rosario, Karyna; Cannon, John P; Gulland, Frances; Dishaw, Larry J; Breitbart, Mya

    2015-01-01

    New diseases in marine animals are emerging at an increasing rate, yet methodological limitations hinder characterization of viral infections. Viral metagenomics is an effective method for identifying novel viruses in diseased animals; however, determining virus pathogenesis remains a challenge. A novel anellovirus (Zalophus californianus anellovirus, ZcAV) was recently reported in the lungs of captive California sea lions involved in a mortality event. ZcAV was not detected by PCR in the blood of these animals, creating the inability to assess the prevalence of ZcAV in live sea lions. This study developed an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to ZcAV in sea lion serum. To assess ZcAV prevalence, paired serum and lung samples (n = 96) from wild sea lions that stranded along the California coast were tested through ELISA and PCR, respectively. Over 50% of the samples tested positive for ZcAV by ELISA (34%), PCR (29%), or both (11%) assays. ZcAV is prevalent in stranded wild sea lion populations and results suggest that PCR assays alone may grossly underestimate ZcAV exposure. This ELISA provides a tool for testing live sea lions for ZcAV exposure and is valuable for subsequent studies evaluating the potential pathogenicity of this anellovirus.

  15. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication.

    PubMed

    Wang, Peng; Alvarez-Perez, Juan-Carlos; Felsenfeld, Dan P; Liu, Hongtao; Sivendran, Sharmila; Bender, Aaron; Kumar, Anil; Sanchez, Roberto; Scott, Donald K; Garcia-Ocaña, Adolfo; Stewart, Andrew F

    2015-04-01

    Types 1 and 2 diabetes affect some 380 million people worldwide. Both ultimately result from a deficiency of functional pancreatic insulin-producing beta cells. Beta cells proliferate in humans during a brief temporal window beginning around the time of birth, with a peak percentage (∼2%) engaged in the cell cycle in the first year of life. In embryonic life and after early childhood, beta cell replication is barely detectable. Whereas beta cell expansion seems an obvious therapeutic approach to beta cell deficiency, adult human beta cells have proven recalcitrant to such efforts. Hence, there remains an urgent need for antidiabetic therapeutic agents that can induce regeneration and expansion of adult human beta cells in vivo or ex vivo. Here, using a high-throughput small-molecule screen (HTS), we find that analogs of the small molecule harmine function as a new class of human beta cell mitogenic compounds. We also define dual-specificity tyrosine-regulated kinase-1a (DYRK1A) as the likely target of harmine and the nuclear factors of activated T cells (NFAT) family of transcription factors as likely mediators of human beta cell proliferation and differentiation. Using three different mouse and human islet in vivo-based models, we show that harmine is able to induce beta cell proliferation, increase islet mass and improve glycemic control. These observations suggest that harmine analogs may have unique therapeutic promise for human diabetes therapy. Enhancing the potency and beta cell specificity of these compounds are important future challenges. PMID:25751815

  16. An uncommon case of spontaneous conversion from AV re-entry tachycardia to AV nodal re-entry tachycardia in a patient with dual tachycardia.

    PubMed

    Zeljković, Ivan; Benko, Ivica; Manola, Šime; Radeljić, Vjekoslav; Pavlović, Nikola

    2015-01-01

    We report the case of a 46-year old patient in whom an electrophysiology study (EP) was performed due to paroxysmal supraventricular tachycardia documented in 12-lead ECG. During the EP study, supraventricular tachycardia was induced easily and it corresponded to orthodromic AV reentry tachycardia (AVRT) using a concealed left free wall accessory pathway. However, during the study AVRT spontaneously and repeatedly converted to the typical slow-fast AV node reentry tachycardia (AVNRT). Both accessory and AV nodal slow pathways were ablated, due to the finding that both AVRT and AVNRT were independently inducible during the EP study. PMID:27134441

  17. An uncommon case of spontaneous conversion from AV re-entry tachycardia to AV nodal re-entry tachycardia in a patient with dual tachycardia

    PubMed Central

    Zeljković, Ivan; Benko, Ivica; Manola, Šime; Radeljić, Vjekoslav; Pavlović, Nikola

    2016-01-01

    We report the case of a 46-year old patient in whom an electrophysiology study (EP) was performed due to paroxysmal supraventricular tachycardia documented in 12-lead ECG. During the EP study, supraventricular tachycardia was induced easily and it corresponded to orthodromic AV reentry tachycardia (AVRT) using a concealed left free wall accessory pathway. However, during the study AVRT spontaneously and repeatedly converted to the typical slow-fast AV node reentry tachycardia (AVNRT). Both accessory and AV nodal slow pathways were ablated, due to the finding that both AVRT and AVNRT were independently inducible during the EP study. PMID:27134441

  18. Catalyst-free synthesis of quinazolin-4-ones from (hetero)aryl-guanidines: application to the synthesis of pyrazolo[4,3-f]quinazolin-9-ones, a new family of DYRK1A inhibitors.

    PubMed

    Debray, Julien; Bonte, Simon; Lozach, Olivier; Meijer, Laurent; Demeunynck, Martine

    2012-11-01

    A small library of heterocycle-fused quinazolin-4-ones was prepared and evaluated as kinase inhibitors. The key step of the two-step process involves the environmental friendly thermolysis of N-ethoxycarbonyl-N'-(hetero) arylguanidines at 130 °C in water. The cyclization is fully regioselective. The most active molecules, 7-(2-hydroxyethylamino)- and 7-(3-hydroxypropylamino)-pyrazolo[4,3-f]quinazolin-9-ones, inhibit DYRK1A and CLK1 at submicromolar concentrations, indicating the potential interest of this new heterocycle in drug design. PMID:22991074

  19. Pilot Implementation and Preliminary Evaluation of START:AV Assessments in Secure Juvenile Correctional Facilities.

    PubMed

    Desmarais, Sarah L; Sellers, Brian G; Viljoen, Jodi L; Cruise, Keith R; Nicholls, Tonia L; Dvoskin, Joel A

    2012-01-01

    The Short-Term Assessment of Risk and Treatability: Adolescent Version (START:AV) is a new structured professional judgment guide for assessing short-term risks in adolescents. The scheme may be distinguished from other youth risk assessment and treatment planning instruments by its inclusion of 23 dynamic factors that are each rated for both vulnerability and strength. In addition, START:AV is also unique in that it focuses on multiple adverse outcomes-namely, violence, self-harm, suicide, unauthorized leave, substance abuse, self-neglect, victimization, and general offending-over the short-term (i.e., weeks to months) rather than long-term (i.e., years). This paper describes a pilot implementation and preliminary evaluation of START:AV in three secure juvenile correctional facilities in the southern United States. Specifically, we examined the descriptive characteristics and psychometric properties of START:AV assessments completed by 21 case managers on 291 adolescent offenders (250 boys and 41 girls) at the time of admission. Results provide preliminary support for the feasibility of completing START:AV assessments as part of routine practice. Findings also highlight differences in the characteristics of START:AV assessments for boys and girls and differential associations between the eight START:AV risk domains. Though results are promising, further research is needed to establish the reliability and validity of START:AV assessments completed in the field. PMID:23316116

  20. Artificial vision support system (AVS(2)) for improved prosthetic vision.

    PubMed

    Fink, Wolfgang; Tarbell, Mark A

    2014-11-01

    State-of-the-art and upcoming camera-driven, implanted artificial vision systems provide only tens to hundreds of electrodes, affording only limited visual perception for blind subjects. Therefore, real time image processing is crucial to enhance and optimize this limited perception. Since tens or hundreds of pixels/electrodes allow only for a very crude approximation of the typically megapixel optical resolution of the external camera image feed, the preservation and enhancement of contrast differences and transitions, such as edges, are especially important compared to picture details such as object texture. An Artificial Vision Support System (AVS(2)) is devised that displays the captured video stream in a pixelation conforming to the dimension of the epi-retinal implant electrode array. AVS(2), using efficient image processing modules, modifies the captured video stream in real time, enhancing 'present but hidden' objects to overcome inadequacies or extremes in the camera imagery. As a result, visual prosthesis carriers may now be able to discern such objects in their 'field-of-view', thus enabling mobility in environments that would otherwise be too hazardous to navigate. The image processing modules can be engaged repeatedly in a user-defined order, which is a unique capability. AVS(2) is directly applicable to any artificial vision system that is based on an imaging modality (video, infrared, sound, ultrasound, microwave, radar, etc.) as the first step in the stimulation/processing cascade, such as: retinal implants (i.e. epi-retinal, sub-retinal, suprachoroidal), optic nerve implants, cortical implants, electric tongue stimulators, or tactile stimulators.

  1. First Aviation System Technology Advanced Research (AvSTAR) Workshop

    NASA Technical Reports Server (NTRS)

    Denery, Dallas G. (Editor); Weathers, Del W. (Editor); Rosen, Robert (Technical Monitor); Edwards, Tom (Technical Monitor)

    2001-01-01

    This Conference Proceedings documents the results of a two-day NASA/FAA/Industry workshop that was held at the NASA Ames Research Center, located at Moffett Field, CA, on September 21-22, 2000. The purpose of the workshop was to bring together a representative cross section of leaders in air traffic management, from industry. FAA, and academia, to assist in defining the requirements for a new research effort, referred to as AvSTAR Aviation Systems Technology Advanced Research). The Conference Proceedings includes the individual presentation, and summarizes the workshop discussions and recommendations.

  2. [Academician O.G. Gazenko and aviation medicine].

    PubMed

    Ushakov, I B; Bednenko, V S; Khomenko, M N; Stepanov, V K

    2008-01-01

    The paper analyzes the contribution of O.G. Gazenko to the theory and practice of aviation medicine in the period of his service at the State Test and Research Institute of Aviation and Space Medicine under the USSR Ministry of Defense (1947-1969). O.G. Gazenko took the leadership and participated in personally in the broad investigations of the altitude effects on human organism, medical care of the staff of AF units and troops based in the Arctic, improvement of life and duty conditions for pilots and technicians in hot climate, ejection seat testing, development of methods modeling erroneous pilot's actions in order to understand their triggers. PMID:19238922

  3. Screening Dyrk1A inhibitors by MALDI-QqQ mass spectrometry: systematic comparison to established radiometric, luminescence, and LC-UV-MS assays.

    PubMed

    Gode, David; Schmitt, Christian; Engel, Matthias; Volmer, Dietrich A

    2014-05-01

    Enzyme-catalyzed reactions play key roles in disease pathology, thus making them relevant subjects of therapeutic inhibitor screening experiments. Matrix-assisted laser desorption/ionization (MALDI) assays have been demonstrated to be able to replace established screening approaches. They offer increased sample throughput, but care must be taken to avoid instrumental bias from differences in ionization efficiencies. We compared a MALDI-triple-quadrupole (QqQ) method for the Dyrk1A peptide substrate woodtide to LC-MS, liquid chromatography with ultraviolet detection (LC-UV), luminescence, and radiometric assays. MALDI measurements were performed on a MALDI-QqQ instrument in the multiple-reaction monitoring mode. Different MALDI conditions were investigated to address whether matrix type, sample support, and MRM- or SIM-based detection conditions can be used to accommodate the molar responses of substrate peptide and its phosphorylated form. UV detection served as a reference method. The impact of MALDI matrix on IC50 values was small, even considering that matrix preparations were used that are known to alleviate response differences. IC50 values determined by MALDI were ca. 2-fold lower than those determined by LC-UV. Although MALDI generated lower ion yields for the phosphorylated peptide than for the peptide substrate, we found that a correction of compound potencies was readily possible using correction factors based on unbiased LC-UV results. A thorough method development delivered a robust assay with excellent performance (Z' > 0.91) that was close to that seen for LC-UV. PMID:24618988

  4. Dpysl2 (CRMP2) and Dpysl3 (CRMP4) phosphorylation by Cdk5 and DYRK2 is required for proper positioning of Rohon-Beard neurons and neural crest cells during neurulation in zebrafish.

    PubMed

    Tanaka, Hideomi; Morimura, Rii; Ohshima, Toshio

    2012-10-15

    Dpysl2 (CRMP2) and Dpysl3 (CRMP4) are involved in neuronal polarity and axon elongation in cultured neurons. These proteins are expressed in various regions of the developing nervous system, but their roles in vivo are largely unknown. In dpysl2 and dpysl3 double morphants, Rohon-Beard (RB) primary sensory neurons that were originally located bilaterally along the midline shifted their position to a more medial location in the dorsal-most part of spinal cord. A similar phenotype was observed in the cdk5 and dyrk2 double morphants. Dpysl2 and Dpysl3 phosphorylation mimics recovered this phenotype. Cell transplantation analysis demonstrated that this ectopic RB cell positioning was non-cell autonomous and correlated with the abnormal position of neural crest cells (NCCs), which also occupied the dorsal-most part of the spinal cord during the neural rod formation stage. The cell position of other interneuron and motor neurons within the central nervous system was normal in these morphants. These results suggest that the phosphorylation of Dpysl2 and Dpysl3 by Cdk5 and DYRK2 is required for the proper positioning of RB neurons and NCCs during neurulation in zebrafish embryos.

  5. A 2:1 AV rhythm: an adverse effect of a long AV delay during DDI pacing and its prevention by the ventricular intrinsic preference algorithm in DDD mode.

    PubMed

    Minamiguchi, Hitoshi; Oginosawa, Yasushi; Kohno, Ritsuko; Tamura, Masahito; Takeuchi, Masaaki; Otsuji, Yutaka; Abe, Haruhiko

    2012-07-01

    A 91-year-old woman received a dual-chamber pacemaker for sick sinus syndrome and intermittently abnormal atrioventricular (AV) conduction. The pacemaker was set in DDI mode with a 350-ms AV delay to preserve intrinsic ventricular activity. She complained of palpitation during AV sequential pacing. The electrocardiogram showed a 2:1 AV rhythm from 1:1 ventriculoatrial (VA) conduction during ventricular pacing in DDI mode with a long AV interval. After reprogramming of the pacemaker in DDD mode with a 250-ms AV interval and additional 100-ms prolongation of the AV interval by the ventricular intrinsic preference function, VA conduction disappeared and the patient's symptom were alleviated without increasing unnecessary right ventricular pacing.

  6. UNIPASS for AvSP? A Broader View

    NASA Technical Reports Server (NTRS)

    Wu, N. Eva

    2001-01-01

    UNIPASS is a general-purpose probabilistic computer program consisting of three major modules, including preprocessor, solver and postprocessor. UNIPASS contains a user-friendly Graphical User Interface (GUI), numerous state-of-the-art probabilistic analysis techniques, a large library of statistical distributions and a function module with a large library of support functions that can easily define any complex limit-state function in a scripting FORTRAN-like syntax format. Its inverse probability analysis and sensitivities analysis capabilities make it a powerful design aid in any product cycle. Its precise numerical analysis engine is accurate enough to push the failure probabilities of a design to well below 10 (exp -50). UNIPASS is equipped with advanced artificial intelligence that is designed to handle systems with an essentially unlimited number of random variables with ease and efficiency. Its modular arrangement allows you to tailor an analysis to the desired level of accuracy and efficiency. The depth and comprehensiveness of UNIPASS are built upon the decades of experience and expertise of industry leaders including Boeing Aircraft, NASA and the DoD. Its rich content also makes UNIPASS a valuable instructional tool for random processes and probabilistic mechanics. The topics include: 1) Reliability in AvSP; 2) Role of UNIPASS in AvSP; and 3) Examples. This paper is in viewgraph form.

  7. Pinunuuchi Po'og'ani: Southern Ute Indian Academy.

    ERIC Educational Resources Information Center

    Oberly, Stacey Inez (Wachimamachi [Antelope Woman])

    2002-01-01

    Describes the Pinunuuchi Po'og'ani, the Southern Ute Indian Academy, providing Montessori education for Southern Ute tribal members ages 6 weeks through 10 years and reviving the use of the Southern Ute language and culture among young students and their families. Describes how the program supports families, students, and staff, and incorporates…

  8. Developing a computational model of human hand kinetics using AVS

    SciTech Connect

    Abramowitz, Mark S.

    1996-05-01

    As part of an ongoing effort to develop a finite element model of the human hand at the Institute for Scientific Computing Research (ISCR), this project extended existing computational tools for analyzing and visualizing hand kinetics. These tools employ a commercial, scientific visualization package called AVS. FORTRAN and C code, originally written by David Giurintano of the Gillis W. Long Hansen`s Disease Center, was ported to a different computing platform, debugged, and documented. Usability features were added and the code was made more modular and readable. When the code is used to visualize bone movement and tendon paths for the thumb, graphical output is consistent with expected results. However, numerical values for forces and moments at the thumb joints do not yet appear to be accurate enough to be included in ISCR`s finite element model. Future work includes debugging the parts of the code that calculate forces and moments and verifying the correctness of these values.

  9. Crystallization and preliminary structure determination of the plant food allergen Pru av 2

    SciTech Connect

    Dall’Antonia, Yuliya; Pavkov, Tea; Fuchs, Heidemarie; Breiteneder, Heimo; Keller, Walter

    2005-02-01

    Crystals of Pru av 2, the first allergenic thaumatin-like protein, have been obtained and diffracted to 1.6 Å at a synchrotron. Using an annealing protocol, the resolution limit was improved to 1.3 Å:.

  10. Get the Most out of Your AV System Dollar. Part II

    ERIC Educational Resources Information Center

    Wadsworth, Raymond H.

    1974-01-01

    Describes how to save money when designing AV facilities; excellent viewing from all seats is achieved by applying certain basic principles to the design of the room and the selection of the equipment. (Author/MLF)

  11. The molecular chaperone TRiC/CCT binds to the Trp-Asp 40 (WD40) repeat protein WDR68 and promotes its folding, protein kinase DYRK1A binding, and nuclear accumulation.

    PubMed

    Miyata, Yoshihiko; Shibata, Takeshi; Aoshima, Masato; Tsubata, Takuichi; Nishida, Eisuke

    2014-11-28

    Trp-Asp (WD) repeat protein 68 (WDR68) is an evolutionarily conserved WD40 repeat protein that binds to several proteins, including dual specificity tyrosine phosphorylation-regulated protein kinase (DYRK1A), MAPK/ERK kinase kinase 1 (MEKK1), and Cullin4-damage-specific DNA-binding protein 1 (CUL4-DDB1). WDR68 affects multiple and diverse physiological functions, such as controlling anthocyanin synthesis in plants, tissue growth in insects, and craniofacial development in vertebrates. However, the biochemical basis and the regulatory mechanism of WDR68 activity remain largely unknown. To better understand the cellular function of WDR68, here we have isolated and identified cellular WDR68 binding partners using a phosphoproteomic approach. More than 200 cellular proteins with wide varieties of biochemical functions were identified as WDR68-binding protein candidates. Eight T-complex protein 1 (TCP1) subunits comprising the molecular chaperone TCP1 ring complex/chaperonin-containing TCP1 (TRiC/CCT) were identified as major WDR68-binding proteins, and phosphorylation sites in both WDR68 and TRiC/CCT were identified. Co-immunoprecipitation experiments confirmed the binding between TRiC/CCT and WDR68. Computer-aided structural analysis suggested that WDR68 forms a seven-bladed β-propeller ring. Experiments with a series of deletion mutants in combination with the structural modeling showed that three of the seven β-propeller blades of WDR68 are essential and sufficient for TRiC/CCT binding. Knockdown of cellular TRiC/CCT by siRNA caused an abnormal WDR68 structure and led to reduction of its DYRK1A-binding activity. Concomitantly, nuclear accumulation of WDR68 was suppressed by the knockdown of TRiC/CCT, and WDR68 formed cellular aggregates when overexpressed in the TRiC/CCT-deficient cells. Altogether, our results demonstrate that the molecular chaperone TRiC/CCT is essential for correct protein folding, DYRK1A binding, and nuclear accumulation of WDR68. PMID

  12. AVS regulation of cadmium bioavailability in a life-cycle sediment toxicity test using Leptocheirus plumulosus

    SciTech Connect

    DeWitt, T.H.; Swartz, R.C.; Hansen, D.J.; McGovern, D.; Berry, W.J.

    1995-12-31

    Numerous studies have shown the utility of interstitial water concentrations of metals and simultaneously extracted metals:acid volatile sulfide ratios (SEM:AVS) in explaining the acute toxicity of sediment-associated metals to benthic organisms, but no full life-cycle chronic tests have been conducted for this purpose. In this study, cohorts of newborn amphipods, Leptocheirus plumulosus, were exposed to cadmium-spiked estuarine sediment for 28 days to determine effects on mortality, growth, and reproduction relative to interstitial water and SEM:AVS normalizations. Seven treatments of Cd were tested: control, 0.35, 0.87, 1.32, 1.53, 2.22, and 5.10 molar SEM:AVS ratios. Overlying water, interstitial water and sediment concentrations of SEM Cd and AVS were monitored periodically and by depth during the exposure. When sediments SEM:AVS ratios were < 1.53, interstitial water concentrations of Cd were less than the 10-day water-only Cd LC50, and mortality, growth and reproduction were not affected. When SEM:AVS ratios were > 2.22, interstitial water Cd concentrations were greater than 100 times the 10-day water-only Cd LC50, and all amphipods died. These results are consistent with predictions of metal bioavailability from acute tests with metals-spiked sediments, i.e. that sediments with SEM:AVS ratios less than 1.0 and less than 0.5 interstitial water toxic units are not toxic, while sediments with SEM:AVS ratios greater than 1.0 and interstitial water toxic units (IWTUS) greater than 0.5 may be toxic.

  13. Nonlinear dynamics of the heartbeat I. The AV junction: Passive conduit or active oscillator?

    NASA Astrophysics Data System (ADS)

    West, Bruce J.; Goldberger, Ary L.; Rovner, Galina; Bhargava, Valmik

    1985-10-01

    Under physiologic conditions, the AV junction is traditionally regarded as a passive conduit for the conduction of impulses from the atria to the ventricles. An alternative view, namely that subsidiary pacemakers play an active role in normal electrophysiologic dynamics during sinus rhythm, has been suggested based on nonlinear models of cardiac oscillators. A central problem has been the development of a simple but explicit mathematical model for coupled nonlinear oscillators relevant both to stable and perturbed cardiac dynamics. We use equations describing an analog electrical circuit with an external d.c. voltage source ( V0) and two nonlinear oscillators with intrinsic frequencies in the ratio of 3:2, comparable to the SA node and AV junction rates. The oscillators are coupled by means of a resistor. 1:1 (SA:AV) phase-locking of the oscillators occurs over a critical range of V0. Externally driving the SA oscillator at increasing rates results in 3:2 AV Wenckebach periodicity and a 2:1 AV block. These findings appear with no assumptions about conduction time or refractoriness. This dynamical model is consistent with the new interpretation that normal sinus rhythm may represent 1:1 coupling of two or more active nonlinear oscillators and also accounts for the appearance of an AV block with critical changes in a single parameter such as the pacing rate.

  14. Genome-Wide DNA Methylation Analysis and Epigenetic Variations Associated with Congenital Aortic Valve Stenosis (AVS)

    PubMed Central

    Radhakrishna, Uppala; Albayrak, Samet; Alpay-Savasan, Zeynep; Zeb, Amna; Turkoglu, Onur; Sobolewski, Paul; Bahado-Singh, Ray O.

    2016-01-01

    Congenital heart defect (CHD) is the most common cause of death from congenital anomaly. Among several candidate epigenetic mechanisms, DNA methylation may play an important role in the etiology of CHDs. We conducted a genome-wide DNA methylation analysis using an Illumina Infinium 450k human methylation assay in a cohort of 24 newborns who had aortic valve stenosis (AVS), with gestational-age matched controls. The study identified significantly-altered CpG methylation at 59 sites in 52 genes in AVS subjects as compared to controls (either hypermethylated or demethylated). Gene Ontology analysis identified biological processes and functions for these genes including positive regulation of receptor-mediated endocytosis. Consistent with prior clinical data, the molecular function categories as determined using DAVID identified low-density lipoprotein receptor binding, lipoprotein receptor binding and identical protein binding to be over-represented in the AVS group. A significant epigenetic change in the APOA5 and PCSK9 genes known to be involved in AVS was also observed. A large number CpG methylation sites individually demonstrated good to excellent diagnostic accuracy for the prediction of AVS status, thus raising possibility of molecular screening markers for this disorder. Using epigenetic analysis we were able to identify genes significantly involved in the pathogenesis of AVS. PMID:27152866

  15. A histone variant, H2AvD, is essential in Drosophila melanogaster.

    PubMed Central

    van Daal, A; Elgin, S C

    1992-01-01

    H2AvD, a Drosophila melanogaster histone variant of the H2A.Z class, is encoded by a single copy gene in the 97CD region of the polytene chromosomes. Northern analysis shows that the transcript is expressed in adult females and is abundant throughout the first 12 h of embryogenesis but then decreases. The H2AvD protein is present at essentially constant levels in all developmental stages. Using D. melanogaster stocks with deletions in the 97CD region, we have localized the H2AvD gene to the 97D1-9 interval. A lethal mutation in this interval, l(3)810, exhibits a 311-base pair deletion in the H2AvD gene, which removes the second exon. P-element mediated transformation using a 4.1-kilobase fragment containing the H2AvD gene rescues the lethal phenotype. H2AvD is therefore both essential and continuously present, suggesting a requirement for its utilization, either to provide an alternative capability for nucleosome assembly or to generate an alternative nucleosome structure. Images PMID:1498368

  16. Synthesis and biological evaluation of N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues as dual inhibitors of CLK1 and DYRK1A kinases.

    PubMed

    Loidreau, Yvonnick; Marchand, Pascal; Dubouilh-Benard, Carole; Nourrisson, Marie-Renée; Duflos, Muriel; Loaëc, Nadège; Meijer, Laurent; Besson, Thierry

    2013-01-01

    Novel N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines (1) and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues (2) were designed and prepared for the first time via microwave-accelerated multi-step synthesis. Various anilines were condensed with N'-(2-cyanaryl)-N,N-dimethylformimidamide intermediates obtained by reaction of 3-amino-6-methoxybenzofuran-2-carbonitrile (3) and 3-amino-6-methoxybenzothiophene-2-carbonitrile (4) precursors with dimethylformamide dimethylacetal. The inhibitory potency of the final products against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) was estimated. Compounds (2a-z) turned out to be particularly promising for the development of new pharmacological dual inhibitors of CLK1 and DYRK1A kinases. PMID:23237976

  17. Comparative study of atrial fibrillation and AV conduction in mammals.

    PubMed

    Meijler, F L; van der Tweel, I

    1987-01-01

    Atrial fibrillation is one of the most common cardiac arrhythmias in humans. It also occurs quite frequently in dogs and horses. Comparative study of this arrhythmia may contribute to better understanding of the pathophysiological mechanisms involved. In this study, we present a quantitative analysis of atrial fibrillation in humans, dogs, horses, and in a kangaroo, making use of histograms and serial autocorrelograms of the ventricular rhythm with and without digitalis medication. Increase in the size of the animal and thus in the size of the heart is accompanied by a decrease in ventricular rate. The ventricular rhythm was random in the dog, kangaroo, and man, but periodicity was present in the horse. Digitalis decreased the ventricular rate in all species studied and enforced the periodicity in the horse. The differences in the atrial excitation process, atrioventricular (AV) conduction, and ventricular behavior between the four species studied are small when compared with the differences in their heart size. We conclude that in evolution, as far as the heart is concerned, cell size and morphology probably prevail over cell-function.

  18. ADVANCED VITRIFICATION SYSTEM (RIC AVS) RESEARCH AND DEVELOPMENT PROJECT

    SciTech Connect

    J.R. Powell; M. Reich

    2003-06-30

    The objective of this AVS testing program is to use bench-scale test equipment to produce a vitrified product at maximum waste loading from the specified AZ-101 waste simulant and conduct a TTT analysis using laboratory scale melts to show compliance with the DOE Waste Acceptance Product Specifications for Vitrified High-Level Waste Forms (WAPS). The vitrified product complies with the following WAPS. A borosilicate glass with a waste loading of 60.9-wt% was produced from a slurry feed of AZ101 simulant. Glass durability testing, glass characterization testing, and testing methodology were performed in accordance with the Department of Energy approved Test Plan. The glass has two crystalline phases and good uniformity of composition. The Product Consistency Test on the 6 location-specific samples are at least 1 to 2 orders of magnitude below the mean PCT results for the EA glass. Standard deviations were less than 10% of measured values. The glass transition temperature averaged 658 {+-} 9 C. A TTT diagram was produced. There was measured cesium loss of about 2%, and compliance with the Universal Treatment Standards.

  19. Assessing the approach to a thrombosed AV graft.

    PubMed

    Ponce, Pedro; Carvalho, Telmo; Messias, Humberto; Neves, Fernando

    2014-01-01

    The patency of the vascular access (VA) is a fight for the attending nephrologist. A retrospective observational study was conducted to compare the success rate of surgical versus endovascular technique percutaneous transluminal angioplasty (PTA) for graft thrombosis treatment. Of 3008 patients, 22.1% patients were dialyzed through grafts. Forty-five percent of all prevalent patients referred due to VA malfunction had a graft. For 18 months, 336 thrombosed grafts were submitted to surgery in 228 cases and to PTA in 126. PTA for thrombolysis included the Pharmaco-Mechanical Technique and the Arrow-Trerotola Device. Procedures were performed as outpatient, with an average delay of 1 day. Immediate success was 100% for surgery and 87.3% for PTA. The unassisted patency for thrombosed grafts for surgery/PTA was 265.12 ± 15.30/230.59 ± 19.83 days respectively, favoring surgery. The primary patency for thrombosed grafts treated by surgery/PTA at 30, 90, and 180 days was, respectively, 74.1%/81%, 63.2%/67.5%, and 53.9%/55.6% all in favor of PTA. AV grafts have a much higher rate of thrombosis than fistulas. Graft thrombosis can be dealt either by surgery or PTA, with identical success.

  20. The Unusual Resistance of Avian Defensin AvBD7 to Proteolytic Enzymes Preserves Its Antibacterial Activity.

    PubMed

    Bailleul, Geoffrey; Kravtzoff, Amanda; Joulin-Giet, Alix; Lecaille, Fabien; Labas, Valérie; Meudal, Hervé; Loth, Karine; Teixeira-Gomes, Ana-Paula; Gilbert, Florence B; Coquet, Laurent; Jouenne, Thierry; Brömme, Dieter; Schouler, Catherine; Landon, Céline; Lalmanach, Gilles; Lalmanach, Anne-Christine

    2016-01-01

    Defensins are frontline peptides of mucosal immunity in the animal kingdom, including birds. Their resistance to proteolysis and their ensuing ability to maintain antimicrobial potential remains questionable and was therefore investigated. We have shown by bottom-up mass spectrometry analysis of protein extracts that both avian beta-defensins AvBD2 and AvBD7 were ubiquitously distributed along the chicken gut. Cathepsin B was found by immunoblotting in jejunum, ileum, caecum, and caecal tonsils, while cathepsins K, L, and S were merely identified in caecal tonsils. Hydrolysis product of AvBD2 and AvBD7 incubated with a panel of proteases was analysed by RP-HPLC, mass spectrometry and antimicrobial assays. AvBD2 and AvBD7 were resistant to serine proteases and to cathepsins D and H. Conversely cysteine cathepsins B, K, L, and S degraded AvBD2 and abolished its antibacterial activity. Only cathepsin K cleaved AvBD7 and released Ile4-AvBD7, a N-terminal truncated natural peptidoform of AvBD7 that displayed antibacterial activity. Besides the 3-stranded antiparallel beta-sheet typical of beta-defensins, structural analysis of AvBD7 by two-dimensional NMR spectroscopy highlighted the restricted accessibility of the C-terminus embedded by the N-terminal region and gave a formal evidence of a salt bridge (Asp9-Arg12) that could account for proteolysis resistance. The differential susceptibility of avian defensins to proteolysis opens intriguing questions about a distinctive role in the mucosal immunity against pathogen invasion. PMID:27561012

  1. The Unusual Resistance of Avian Defensin AvBD7 to Proteolytic Enzymes Preserves Its Antibacterial Activity

    PubMed Central

    Bailleul, Geoffrey; Kravtzoff, Amanda; Joulin-Giet, Alix; Lecaille, Fabien; Labas, Valérie; Meudal, Hervé; Loth, Karine; Teixeira-Gomes, Ana-Paula; Gilbert, Florence B.; Coquet, Laurent; Jouenne, Thierry; Brömme, Dieter; Schouler, Catherine; Landon, Céline; Lalmanach, Gilles; Lalmanach, Anne-Christine

    2016-01-01

    Defensins are frontline peptides of mucosal immunity in the animal kingdom, including birds. Their resistance to proteolysis and their ensuing ability to maintain antimicrobial potential remains questionable and was therefore investigated. We have shown by bottom-up mass spectrometry analysis of protein extracts that both avian beta-defensins AvBD2 and AvBD7 were ubiquitously distributed along the chicken gut. Cathepsin B was found by immunoblotting in jejunum, ileum, caecum, and caecal tonsils, while cathepsins K, L, and S were merely identified in caecal tonsils. Hydrolysis product of AvBD2 and AvBD7 incubated with a panel of proteases was analysed by RP-HPLC, mass spectrometry and antimicrobial assays. AvBD2 and AvBD7 were resistant to serine proteases and to cathepsins D and H. Conversely cysteine cathepsins B, K, L, and S degraded AvBD2 and abolished its antibacterial activity. Only cathepsin K cleaved AvBD7 and released Ile4-AvBD7, a N-terminal truncated natural peptidoform of AvBD7 that displayed antibacterial activity. Besides the 3-stranded antiparallel beta-sheet typical of beta-defensins, structural analysis of AvBD7 by two-dimensional NMR spectroscopy highlighted the restricted accessibility of the C-terminus embedded by the N-terminal region and gave a formal evidence of a salt bridge (Asp9-Arg12) that could account for proteolysis resistance. The differential susceptibility of avian defensins to proteolysis opens intriguing questions about a distinctive role in the mucosal immunity against pathogen invasion. PMID:27561012

  2. sugE: A gene involved in tributyltin (TBT) resistance of Aeromonas molluscorum Av27.

    PubMed

    Cruz, Andreia; Micaelo, Nuno; Félix, Vitor; Song, Jun-Young; Kitamura, Shin-Ichi; Suzuki, Satoru; Mendo, Sónia

    2013-01-01

    The mechanism of bacterial resistance to tributyltin (TBT) is still unclear. The results herein presented contribute to clarify that mechanism in the TBT-resistant bacterium Aeromonas molluscorum Av27. We have identified and cloned a new gene that is involved in TBT resistance in this strain. The gene is highly homologous (84%) to the Aeromonas hydrophila-sugE gene belonging to the small multidrug resistance gene family (SMR), which includes genes involved in the transport of lipophilic drugs. In Av27, expression of the Av27-sugE was observed at the early logarithmic growth phase in the presence of a high TBT concentration (500 μM), thus suggesting the contribution of this gene for TBT resistance. E. coli cells transformed with Av27-sugE become resistant to ethidium bromide (EtBr), chloramphenicol (CP) and tetracycline (TE), besides TBT. According to the Moriguchi logP (miLogP) values, EtBr, CP and TE have similar properties and are substrates for the sugE-efflux system. Despite the different miLogP of TBT, E. coli cells transformed with Av27-sugE become resistant to this compound. So it seems that TBT is also a substrate for the SugE protein. The modelling studies performed also support this hypothesis. The data herein presented clearly indicate that sugE is involved in TBT resistance of this bacterium.

  3. 77 FR 41400 - AV Solar Ranch 1, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-13

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission AV Solar Ranch 1, LLC; Supplemental Notice That Initial Market- Based Rate...-referenced proceeding of AV Solar Ranch 1, LLC's application for market-based rate authority, with...

  4. Incidence of A-V Fistulas after Renal Biopsy of Native and Transplanted Kidney - Two Centers Experience

    PubMed Central

    Lubomirova, Mila; Krasteva, Rumiana; Bogov, Boris; Paskalev, Emil

    2015-01-01

    AIM: The aim of the study is to make a retrospective analysis of the incidence of AV fistulas after renal biopsy (RB) of native and transplanted kidney. MATERIALS AND METHODS: Five hundred and sixteen (516) RB were analyzed. One hundred twenty nine (129) were native kidneys RB performed in Clinic of Nephrology (CN), 190 were performed in Clinic of Nephrology and transplantation (CNT) and 197 were transplanted kidney biopsies from the same clinic. Biopsy technique type Gun with needle 14G, 16 and 18 G was used in CN, CNT used the same technique with needles 16G. Doppler ultrasound was made for A-V fistulas diagnosis. RESULTS: The A-V fistulas incidence was 0.8%. The frequency of A-V fistulas registered in CN was significantly higher than that registered in CNT (2.3% vs. 0.5%, p < 0.01). Biopsies performed by 14 G needles provide a higher percentage of A-V fistulas compared to those done by 16 G. (3.3% vs. 2.4%, p < 0.5). The frequency of the A-V fistulas in native and transplanted kidneys in CNT was similar (0.5% vs. 0.5%, p > 0.05). CONCLUSION: The A-V fistulas incidence is very low. The needle thickness is an important factor relevant to the risk of occurrence of A-V fistulas. PMID:27275228

  5. The Helminth-Derived Immunomodulator AvCystatin Reduces Virus Enhanced Inflammation by Induction of Regulatory IL-10+ T Cells

    PubMed Central

    Schuijs, Martijn J.; Hartmann, Susanne; Selkirk, Murray E.; Roberts, Luke B.

    2016-01-01

    Respiratory Syncytial Virus (RSV) is a major pathogen causing low respiratory tract disease (bronchiolitis), primarily in infants. Helminthic infections may alter host immune responses to both helminths and to unrelated immune triggers. For example, we have previously shown that filarial cystatin (AvCystatin/Av17) ameliorates allergic airway inflammation. However, helminthic immunomodulators have so far not been tested in virus-induced disease. We now report that AvCystatin prevents Th2-based immunopathology in vaccine-enhanced RSV lung inflammation, a murine model for bronchiolitis. AvCystatin ablated eosinophil influx, reducing both weight loss and neutrophil recruitment without impairing anti-viral immune responses. AvCystatin also protected mice from excessive inflammation following primary RSV infection, significantly reducing neutrophil influx and cytokine production in the airways. Interestingly, we found that AvCystatin induced an influx of CD4+ FoxP3+ interleukin-10-producing T cells in the airway and lungs, correlating with immunoprotection, and the corresponding cells could also be induced by adoptive transfer of AvCystatin-primed F4/80+ macrophages. Thus, AvCystatin ameliorates enhanced RSV pathology without increasing susceptibility to, or persistence of, viral infection and warrants further investigation as a possible therapy for virus-induced airway disease. PMID:27560829

  6. The Helminth-Derived Immunomodulator AvCystatin Reduces Virus Enhanced Inflammation by Induction of Regulatory IL-10+ T Cells.

    PubMed

    Schuijs, Martijn J; Hartmann, Susanne; Selkirk, Murray E; Roberts, Luke B; Openshaw, Peter J M; Schnoeller, Corinna

    2016-01-01

    Respiratory Syncytial Virus (RSV) is a major pathogen causing low respiratory tract disease (bronchiolitis), primarily in infants. Helminthic infections may alter host immune responses to both helminths and to unrelated immune triggers. For example, we have previously shown that filarial cystatin (AvCystatin/Av17) ameliorates allergic airway inflammation. However, helminthic immunomodulators have so far not been tested in virus-induced disease. We now report that AvCystatin prevents Th2-based immunopathology in vaccine-enhanced RSV lung inflammation, a murine model for bronchiolitis. AvCystatin ablated eosinophil influx, reducing both weight loss and neutrophil recruitment without impairing anti-viral immune responses. AvCystatin also protected mice from excessive inflammation following primary RSV infection, significantly reducing neutrophil influx and cytokine production in the airways. Interestingly, we found that AvCystatin induced an influx of CD4+ FoxP3+ interleukin-10-producing T cells in the airway and lungs, correlating with immunoprotection, and the corresponding cells could also be induced by adoptive transfer of AvCystatin-primed F4/80+ macrophages. Thus, AvCystatin ameliorates enhanced RSV pathology without increasing susceptibility to, or persistence of, viral infection and warrants further investigation as a possible therapy for virus-induced airway disease. PMID:27560829

  7. Mobitz II AV block within the His bundle, with progression to complete heart block.

    PubMed Central

    Amuchástegui, L M; Moreyra, E; Alday, L E

    1976-01-01

    A case of a 48-year-old woman with frequent syncopal episodes is reported. The electrocardiogram showed high degree AV block with narrow QRS complexes. The His bundle electrogram displayed a split His deflection indicating impairment of conduction within the His bundle of the Mobitz II type. The AH interval was prolonged and Wenckebach phenomenon occurred at the same atrial pacing rate before and after atropine administration. During spontaneous or induced high grade AV block an escape rhythm originating in the distal His bundle was observed. A secondary study performed one year later showed progression to complete AV block. Both His potentials were present, one following the atrial and the other preceding the ventricular deflection. The H'V interval was prolonged and a further lengthening was seen after ajmaline. All these findings indicated proximal, mid, and distal disease of the His trunk. PMID:973908

  8. In vivo imaging of neuromelanin in Parkinson's disease using 18F-AV-1451 PET.

    PubMed

    Hansen, Allan K; Knudsen, Karoline; Lillethorup, Thea P; Landau, Anne M; Parbo, Peter; Fedorova, Tatyana; Audrain, Hélène; Bender, Dirk; Østergaard, Karen; Brooks, David J; Borghammer, Per

    2016-07-01

    The tau tangle ligand (18)F-AV-1451 ((18)F-T807) binds to neuromelanin in the midbrain, and may therefore be a measure of the pigmented dopaminergic neuronal count in the substantia nigra. Parkinson's disease is characterized by progressive loss of dopaminergic neurons. Extrapolation of post-mortem data predicts that a ∼30% decline of nigral dopamine neurons is necessary to cause motor symptoms in Parkinson's disease. Putamen dopamine terminal loss at disease onset most likely exceeds that of the nigral cell bodies and has been estimated to be of the order of 50-70%. We investigated the utility of (18)F-AV-1451 positron emission tomography to visualize the concentration of nigral neuromelanin in Parkinson's disease and correlated the findings to dopamine transporter density, measured by (123)I-FP-CIT single photon emission computed tomography. A total of 17 patients with idiopathic Parkinson's disease and 16 age- and sex-matched control subjects had (18)F-AV-1451 positron emission tomography using a Siemens high-resolution research tomograph. Twelve patients with Parkinson's disease also received a standardized (123)I-FP-CIT single photon emission computed tomography scan at our imaging facility. Many of the patients with Parkinson's disease displayed visually apparent decreased (18)F-AV-1451 signal in the midbrain. On quantitation, patients showed a 30% mean decrease in total nigral (18)F-AV-1451 volume of distribution compared with controls (P = 0.004), but there was an overlap of the individual ranges. We saw no significant correlation between symptom dominant side and contralateral nigral volume of distribution. There was no correlation between nigral (18)F-AV-1451 volume of distribution and age or time since diagnosis. In the subset of 12 patients, who also had a (123)I-FP-CIT scan, the mean total striatal dopamine transporter signal was decreased by 45% and the mean total (18)F-AV-1451 substantia nigra volume of distribution was decreased by 33% after

  9. In vivo imaging of neuromelanin in Parkinson's disease using 18F-AV-1451 PET.

    PubMed

    Hansen, Allan K; Knudsen, Karoline; Lillethorup, Thea P; Landau, Anne M; Parbo, Peter; Fedorova, Tatyana; Audrain, Hélène; Bender, Dirk; Østergaard, Karen; Brooks, David J; Borghammer, Per

    2016-07-01

    The tau tangle ligand (18)F-AV-1451 ((18)F-T807) binds to neuromelanin in the midbrain, and may therefore be a measure of the pigmented dopaminergic neuronal count in the substantia nigra. Parkinson's disease is characterized by progressive loss of dopaminergic neurons. Extrapolation of post-mortem data predicts that a ∼30% decline of nigral dopamine neurons is necessary to cause motor symptoms in Parkinson's disease. Putamen dopamine terminal loss at disease onset most likely exceeds that of the nigral cell bodies and has been estimated to be of the order of 50-70%. We investigated the utility of (18)F-AV-1451 positron emission tomography to visualize the concentration of nigral neuromelanin in Parkinson's disease and correlated the findings to dopamine transporter density, measured by (123)I-FP-CIT single photon emission computed tomography. A total of 17 patients with idiopathic Parkinson's disease and 16 age- and sex-matched control subjects had (18)F-AV-1451 positron emission tomography using a Siemens high-resolution research tomograph. Twelve patients with Parkinson's disease also received a standardized (123)I-FP-CIT single photon emission computed tomography scan at our imaging facility. Many of the patients with Parkinson's disease displayed visually apparent decreased (18)F-AV-1451 signal in the midbrain. On quantitation, patients showed a 30% mean decrease in total nigral (18)F-AV-1451 volume of distribution compared with controls (P = 0.004), but there was an overlap of the individual ranges. We saw no significant correlation between symptom dominant side and contralateral nigral volume of distribution. There was no correlation between nigral (18)F-AV-1451 volume of distribution and age or time since diagnosis. In the subset of 12 patients, who also had a (123)I-FP-CIT scan, the mean total striatal dopamine transporter signal was decreased by 45% and the mean total (18)F-AV-1451 substantia nigra volume of distribution was decreased by 33% after

  10. Mineralogic mapping of the Av-9 Numisia quadrangle of Vesta

    NASA Astrophysics Data System (ADS)

    Frigeri, A.; De Sanctis, M. C.; Ammannito, E.; Buczkowski, D.; Combe, J. P.; Tosi, F.; Zambon, F.; Rocchini, D.; Jaumann, R.; Raymond, C. A.; Russell, C. T.

    2015-10-01

    In this manuscript we present the mineralogic mapping of the Av-9 Numisia quadrangle of Vesta using the most up-to-date data from the NASA-Dawn mission. This quadrangle is located in Vesta's equatorial zone (22° south to 22° north, 218° to 288° east, in Claudia coordinate system) and takes its name from the impact crater Numisia. The main feature, which dominates the quadrangle, is the Vestalia Terra plateau, a topographic high about 10 km above the surrounding areas. To the south, this region fades into the Rheasilvia basin, while to the north it is bounded by the steep scarp of Postumia basin. The Visible and Infrared mapping spectrometer (VIR) onboard NASA/Dawn provided the main data source for this work, at an unprecedented level of spatial and spectral resolution. In particular we are using spectral parameters to synthesize characteristics of the whole spectra into a single value. Pyroxene-related spectral parameters allow for the detection of lower crust or mantle material (diogenites) and upper crust material (eucrites) in the study area. The combined analysis of albedo from the Framing Camera, the geologic map and the spectroscopic data offer an interesting opportunity to understand better the surface features of this region of Vesta, and their evolution. Numisia, Cornelia, Fabia, Teia and Drusilla are the main craters in the study area, rich in bright and dark material outcrops, pitted terrains and OH-rich materials. Using the spectral parameters we demonstrate that the internal composition of Vestalia Terra is mainly diogenite-rich howardite, as shown by materials excavated by Cornelia and Fabia, and the composition of the slope north of Vestalia Terra. This agrees with the strong positive Bouguer Anomaly observed in the area, indicating a higher density of these features in relation to the surrounding areas. Besides the recently published works based on gravimetric modeling and geologic interpretation, the mineralogic mapping presented herein gives

  11. Identification of the human ApoAV gene as a novel ROR{alpha} target gene

    SciTech Connect

    Lind, Ulrika; Nilsson, Tina; McPheat, Jane; Stroemstedt, Per-Erik; Bamberg, Krister; Balendran, Clare; Kang, Daiwu . E-mail: Daiwu.Kang@astrazeneca.com

    2005-04-29

    Retinoic acid receptor-related orphan receptor-{alpha} (ROR{alpha}) (NR1F1) is an orphan nuclear receptor with a potential role in metabolism. Previous studies have shown that ROR{alpha} regulates transcription of the murine Apolipoprotein AI gene and human Apolipoprotein CIII genes. In the present study, we present evidence that ROR{alpha} also induces transcription of the human Apolipoprotein AV gene, a recently identified apolipoprotein associated with triglyceride levels. Adenovirus-mediated overexpression of ROR{alpha} increased the endogenous expression of ApoAV in HepG2 cells and ROR{alpha} also enhanced the activity of an ApoAV promoter construct in transiently transfected HepG2 cells. Deletion and mutation studies identified three AGGTCA motifs in the ApoAV promoter that mediate ROR{alpha} transactivation, one of which overlaps with a previously identified binding site for PPAR{alpha}. Together, these results suggest a novel mechanism whereby ROR{alpha} modulates lipid metabolism and implies ROR{alpha} as a potential target for the treatment of dyslipidemia and atherosclerosis.

  12. Impact of e-AV Biology Website for Learning about Renewable Energy

    ERIC Educational Resources Information Center

    Nugraini, Siti Hadiati; Choo, Koo Ah; Hin, Hew Soon; Hoon, Teoh Sian

    2013-01-01

    This paper considers the design and development of a Website for Biology in senior high schools in Indonesia. The teaching media, namely e-AV Biology, was developed with the main features of video lessons and other features in supporting the students' learning process. Some video lessons describe the production process of Biofuel or Renewable…

  13. Regional trends and spatial distribution of AVS and SEM in estuaries along the southeast coast

    SciTech Connect

    Jenkins, P.; Scott, G.; Reed, L.A.; Dias, A.

    1995-12-31

    Trace metal pollution in aquatic environments is primarily associated with urbanization and industrial discharge. This is particularly true in the coastal areas of the Southeastern United States. A total of 307 sediment samples, 24 from the Ashepoo, Combahee, and Edisto Rivers (ACE Basin), 63 from the Charleston Harbor, 144 from small tidal creeks around Charleston Harbor, and 86 from the Savannah and Brunswick areas were analyzed for trace metals concentrations, Acid Volatile Sulfide (AVS) and Simultaneously Extracted Metals (SEM) as part of a study examining metal contaminants in the salt water estuaries of South Carolina and Georgia. Trace metal investigations were performed using a microwave, nitric acid, digestion technique and measurement by Induced Coupled Plasma (ICP) and Atomic Absorption (AA) Spectrophotometric instrumentation. The AVS and SEM data was generated using a procedure based on the EPA method of extraction with an AVS calorimetric detection method. The SEM was analyzed by ICP and AA methods. The SEM-to-AVS ratio was useful in explaining the potential trace metal bioavailability by the incorporation of metal speciation into the metal toxicant equation. Results will be discussed in terms of existing laboratory sediment toxicity guidelines and field ecotoxicology studies conducted at selected sites.

  14. 45 CFR 156.135 - AV calculation for determining level of coverage.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    .... Beginning in 2015, if submitted by the State and approved by HHS, a state-specific data set will be used as the standard population to calculate AV in accordance with paragraph (a) of this section. The data set... population described in paragraph (f) of this section, unless a data set in a format specified by HHS...

  15. Photometric Properties for Selected Algol-type Binaries. IV. AV Hydrae and DZ Cassiopeiae

    NASA Astrophysics Data System (ADS)

    Yang, Y.-G.; Li, L.-H.; Dai, H.-F.

    2012-08-01

    We present BVR photometric observations and several eclipsing times for AV Hya and DZ Cas from 2004 to 2011. Using the Wilson-Devinney method, the photometric solutions with hot spots were deduced from their asymmetric light curves. The results indicate that both stars are Algol-type binaries, whose mass ratio, q ph, and fill-out factor of the primary, f 1, are q ph = 0.255(± 0.002) and f 1 = 81.2(± 0.2)% for AV Hya, and q ph = 0.093(± 0.003) and f 1 = 98.7(± 0.3)% for DZ Cas. Based on all available light minimum times, it is discovered that the O - C curve of each star could be described by a light-time orbit overlying on a downward parabola. Their periods and amplitudes are P 3 = 37.2(± 0.7) yr and A = 0fd0095(±0fd0006) for AV Hya, and P 3 = 62.5(± 1.0) yr and A = 0fd0183(±0fd0007) for DZ Cas. Cyclic variations may result from the light-time effect due to the third body. The secular period decrease rates are dP/dt = -1.47(± 0.04) × 10-7 days yr-1 for AV Hya and dP/dt = -0.92(± 0.04) × 10-7 days yr-1 for DZ Cas. This may be interpreted using mass and angular momentum loss from the system. With decreasing period, the fill-out factor of the primary increases and it may finally fill its inner Roche lobe. Therefore, AV Hya and DZ Cas with a secular period decrease will evolve from semi-detached configurations into contact ones.

  16. A Heart too Drunk to Drive; AV Block following Acute Alcohol Intoxication.

    PubMed

    van Stigt, Arthur H; Overduin, Ruben J; Staats, Liza C; Loen, Vera; van der Heyden, Marcel A G

    2016-02-29

    Acute excessive alcohol consumption is associated with heart rhythm disorders like atrial fibrillation but also premature ventricular contractions, collectively known as the "holiday heart syndrome". More rarely but clinically significant are reports of atrioventricular (AV) conduction disturbances in binge drinkers with no underlying heart disease or chronic alcohol consumption. To obtain better insights into common denominators and the potential underlying mechanisms we collected and compared individual case reports of AV block following acute alcohol intoxication in otherwise healthy people. By screening PubMed, Google Scholar, Scopus and JSTOR, fifteen cases were found of which eight were sufficiently documented for full analysis. Blood alcohol levels ranged from 90 to 958 mg/dl (19 to 205 mM). Second and third degree AV block was observed most (6/8) albeit that in two of these patients a vagal stimulus led to deterioration from first into higher order AV block. In all cases, patients reverted to normal sinus rhythm upon becoming sober again. Mildly lowered body temperature (35.9 ± 0.5°C) was observed but can be excluded as a major cause of conduction blockade. We hypothesize that ethanol induced partial inhibition of calcium and potentially also sodium currents in conductive tissue structures may be one of the mechanisms of conduction slowing and block that may become exaggerated upon increased vagal tone. An impairment of gap junction function cannot be excluded as a contributing factor. In conclusion, cases of documented alcohol induced AV block are very rare but events can occur at relatively low serum alcohol levels which should prompt to awareness of this phenomenon in alcohol intoxicated patients. PMID:26875557

  17. A Heart too Drunk to Drive; AV Block following Acute Alcohol Intoxication.

    PubMed

    van Stigt, Arthur H; Overduin, Ruben J; Staats, Liza C; Loen, Vera; van der Heyden, Marcel A G

    2016-02-29

    Acute excessive alcohol consumption is associated with heart rhythm disorders like atrial fibrillation but also premature ventricular contractions, collectively known as the "holiday heart syndrome". More rarely but clinically significant are reports of atrioventricular (AV) conduction disturbances in binge drinkers with no underlying heart disease or chronic alcohol consumption. To obtain better insights into common denominators and the potential underlying mechanisms we collected and compared individual case reports of AV block following acute alcohol intoxication in otherwise healthy people. By screening PubMed, Google Scholar, Scopus and JSTOR, fifteen cases were found of which eight were sufficiently documented for full analysis. Blood alcohol levels ranged from 90 to 958 mg/dl (19 to 205 mM). Second and third degree AV block was observed most (6/8) albeit that in two of these patients a vagal stimulus led to deterioration from first into higher order AV block. In all cases, patients reverted to normal sinus rhythm upon becoming sober again. Mildly lowered body temperature (35.9 ± 0.5°C) was observed but can be excluded as a major cause of conduction blockade. We hypothesize that ethanol induced partial inhibition of calcium and potentially also sodium currents in conductive tissue structures may be one of the mechanisms of conduction slowing and block that may become exaggerated upon increased vagal tone. An impairment of gap junction function cannot be excluded as a contributing factor. In conclusion, cases of documented alcohol induced AV block are very rare but events can occur at relatively low serum alcohol levels which should prompt to awareness of this phenomenon in alcohol intoxicated patients.

  18. PHOTOMETRIC PROPERTIES FOR SELECTED ALGOL-TYPE BINARIES. IV. AV HYDRAE AND DZ CASSIOPEIAE

    SciTech Connect

    Yang, Y.-G.; Dai, H.-F.; Li, L.-H.

    2012-08-15

    We present BVR photometric observations and several eclipsing times for AV Hya and DZ Cas from 2004 to 2011. Using the Wilson-Devinney method, the photometric solutions with hot spots were deduced from their asymmetric light curves. The results indicate that both stars are Algol-type binaries, whose mass ratio, q{sub ph}, and fill-out factor of the primary, f{sub 1}, are q{sub ph} = 0.255({+-} 0.002) and f{sub 1} = 81.2({+-} 0.2)% for AV Hya, and q{sub ph} = 0.093({+-} 0.003) and f{sub 1} = 98.7({+-} 0.3)% for DZ Cas. Based on all available light minimum times, it is discovered that the O - C curve of each star could be described by a light-time orbit overlying on a downward parabola. Their periods and amplitudes are P{sub 3} = 37.2({+-} 0.7) yr and A = 0fd0095({+-}0fd0006) for AV Hya, and P{sub 3} = 62.5({+-} 1.0) yr and A = 0fd0183({+-}0fd0007) for DZ Cas. Cyclic variations may result from the light-time effect due to the third body. The secular period decrease rates are dP/dt = -1.47({+-} 0.04) Multiplication-Sign 10{sup -7} days yr{sup -1} for AV Hya and dP/dt = -0.92({+-} 0.04) Multiplication-Sign 10{sup -7} days yr{sup -1} for DZ Cas. This may be interpreted using mass and angular momentum loss from the system. With decreasing period, the fill-out factor of the primary increases and it may finally fill its inner Roche lobe. Therefore, AV Hya and DZ Cas with a secular period decrease will evolve from semi-detached configurations into contact ones.

  19. The relation between Acid Volatile Sulfides (AVS) and metal accumulation in aquatic invertebrates: implications of feeding behavior and ecology.

    PubMed

    De Jonge, Maarten; Blust, Ronny; Bervoets, Lieven

    2010-05-01

    The present study evaluates the relationship between Acid Volatile Sulfides (AVS) and metal accumulation in invertebrates with different feeding behavior and ecological preferences. Natural sediments, pore water and surface water, together with benthic and epibenthic invertebrates were sampled at 28 Flemish lowland rivers. Different metals as well as metal binding sediment characteristics including AVS were measured and multiple regression was used to study their relationship with accumulated metals in the invertebrates taxa. Bioaccumulation in the benthic taxa was primarily influenced by total metal concentrations in the sediment. Regarding the epibenthic taxa metal accumulation was mostly explained by the more bioavailable metal fractions in both the sediment and the water. AVS concentrations were generally better correlated with metal accumulation in the epibenthic invertebrates, rather than with the benthic taxa. Our results indicated that the relation between AVS and metal accumulation in aquatic invertebrates is highly dependent on feeding behavior and ecology.

  20. Performance evaluation and optimization of BM4D-AV denoising algorithm for cone-beam CT images

    NASA Astrophysics Data System (ADS)

    Huang, Kuidong; Tian, Xiaofei; Zhang, Dinghua; Zhang, Hua

    2015-12-01

    The broadening application of cone-beam Computed Tomography (CBCT) in medical diagnostics and nondestructive testing, necessitates advanced denoising algorithms for its 3D images. The block-matching and four dimensional filtering algorithm with adaptive variance (BM4D-AV) is applied to the 3D image denoising in this research. To optimize it, the key filtering parameters of the BM4D-AV algorithm are assessed firstly based on the simulated CBCT images and a table of optimized filtering parameters is obtained. Then, considering the complexity of the noise in realistic CBCT images, possible noise standard deviations in BM4D-AV are evaluated to attain the chosen principle for the realistic denoising. The results of corresponding experiments demonstrate that the BM4D-AV algorithm with optimized parameters presents excellent denosing effect on the realistic 3D CBCT images.

  1. Chronic toxicity of zinc-spiked sediments; Evaluation of the acid volatile sulfide (AVS) model using Chironomus tentans

    SciTech Connect

    Sibley, P.K.; Ankley, G.T.; Cotter, A.M.; Leonard, E.N.

    1995-12-31

    Most research supporting AVS as a normalization phase for predicting the bioavailability of cationic metals from sediments is based on short-term laboratory exposures. Evidence supporting the theory with respect to chronic exposures is lacking. The purpose of this study, therefore, was to investigate whether the AVS model could predict toxicity to Chironomus tentans in a life cycle exposure to zinc-spiked sediments. Clean sediment was spiked with Zn to obtain nominal treatments ranging from {minus}2.35 to 58.5 {micro}g/g dw with respect to the molar difference between simultaneously extracted metal and AVS. The test was initiated with newly hatched larvae and carried through one complete generation (56 d) during which survival, growth, emergence, and reproduction were monitored. When SEM-AVS was < 0, the concentration of Zn in the pore water was low and no adverse effects were observed for any of the endpoints. Conversely, when SEM-AVS exceeded 0, a dose-dependent increase in the relative concentration of pore water Zn was observed. However, the absolute concentration of pore water Zn at each treatment declined with time, corresponding to an increase in AVS and to loss of Zn due to diffusion into the overlying water (renewed twice daily). Only when SEM-AVS exceeded approximately 6.5 were significant reductions in survival, growth, emergence, and reproductive output observed. In general, the chemical and biological data of this study agree with observations made in short-term exposures and thus support the use of AVS as a normalization phase for predicting the potential for toxicity in metal-contaminated sediments.

  2. Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan-bound lipoprotein lipase.

    PubMed

    Merkel, Martin; Loeffler, Britta; Kluger, Malte; Fabig, Nathalie; Geppert, Gesa; Pennacchio, Len A; Laatsch, Alexander; Heeren, Joerg

    2005-06-01

    Apolipoprotein A5 (APOA5) is associated with differences in triglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasma triglycerides. To elucidate the mechanism by which apoAV influences plasma triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In human APOA5 transgenic mice (hAPOA5tr), catabolism of chylomicrons and very low density lipoprotein (VLDL) was accelerated due to a faster plasma hydrolysis of triglycerides by lipoprotein lipase (LPL). Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by cross-breeding a human LPL transgene with the apoa5 knock-out and the hAPOA5tr to an lpl-deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5-deficient mice; however, overexpression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr high density lipoprotein, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL-mediated hydrolysis of VLDL triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line. A direct interaction between LPL and apoAV was found by ligand blotting. It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycan-bound LPL for lipolysis.

  3. AV3V lesions attenuate the cardiovascular responses produced by blood-borne excitatory amino acid analogs

    NASA Technical Reports Server (NTRS)

    Whalen, E. J.; Beltz, T. G.; Lewis, S. J.; Johnson, A. K.

    1999-01-01

    Systemic injections of the excitatory amino acid (EAA) analogs, kainic acid (KA) and N-methyl-D-aspartate (NMDA), produce a pressor response in conscious rats that is caused by a centrally mediated activation of sympathetic drive and the release of arginine vasopressin (AVP). This study tested the hypothesis that the tissue surrounding the anteroventral part of the third ventricle (AV3V) plays a role in the expression of the pressor responses produced by systemically injected EAA analogs. Specifically, we examined whether prior electrolytic ablation of the AV3V region would affect the pressor responses to KA and NMDA (1 mg/kg iv) in conscious rats. The KA-induced pressor response was smaller in AV3V-lesioned than in sham-lesioned rats (11 +/- 2 vs. 29 +/- 2 mmHg; P < 0.05). After ganglion blockade, KA produced a pressor response in sham-lesioned but not AV3V-lesioned rats (+27 +/- 3 vs. +1 +/- 2 mmHg; P < 0.05). The KA-induced pressor response in ganglion-blocked sham-lesioned rats was abolished by a vasopressin V1-receptor antagonist. Similar results were obtained with NMDA. The pressor response to AVP (10 ng/kg iv) was slightly smaller in AV3V-lesioned than in sham-lesioned ganglion-blocked rats (45 +/- 3 vs. 57 +/- 4 mmHg; P < 0.05). This study demonstrates that the pressor responses to systemically injected EAA analogs are smaller in AV3V-lesioned rats. The EAA analogs may produce pressor responses by stimulation of EAA receptors in the AV3V region, or the AV3V region may play an important role in the expression of these responses.

  4. Apolipoprotein AV Accelerates Plasma Hydrolysis OfTriglyceride-Rich Lipoproteins By Interaction With Proteoglycan BoundLipoprotein Lipase

    SciTech Connect

    Merkel, Martin; Loeffler, Britta; Kluger, Malte; Fabig, Nathalie; Geppert, Gesa; Pennacchio, Len A.; Laatsch, Alexander; Heeren, Joerg

    2005-02-22

    Apolipoprotein A5 (APOA5) is associated with differences intriglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasmatriglycerides. To elucidate the mechanism by which apoAV influences plasma triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In hAPOA5 transgenic mice(hAPOA5tr), catabolism of chylomicrons and VLDL was accelerated due to a faster plasma hydrolysis of triglycerides by lipoprotein lipase (LPL).Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by crossbreeding a human LPL transgene with the apoa5 knockout, and the hAPOA5tr to an LPL deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5 deficient mice,however, over expression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr HDL, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL mediated hydrolysis of VLDL triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line.A direct interaction between LPL and apoAV was found by ligand blotting.It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycans bound LPL for lipolysis.

  5. Tissue and cell tropism of Indian cassava mosaic virus (ICMV) and its AV2 (precoat) gene product

    SciTech Connect

    Rothenstein, Dirk; Krenz, Bjoern; Selchow, Olaf; Jeske, Holger . E-mail: holger.jeske@bio.uni-stuttgart.de

    2007-03-01

    In order to establish defined viruses for challenging plants in resistance breeding programmes, Indian cassava mosaic virus (ICMV; family Geminiviridae) DNA clones were modified to monitor viral spread in plants by replacing the coat protein gene with the green fluorescent protein (GFP) reporter gene. Comparative in situ hybridization experiments showed that ICMV was restricted to the phloem in cassava and tobacco. GFP-tagged virus spread similarly, resulting in homogeneous fluorescence within nuclei and cytoplasm of infected cells. To analyze viral intercellular transport in further detail, GFP was fused to AV2, a protein that has been implicated in viral movement. Expressed from replicating viruses or from plasmids, AV2:GFP became associated with the cell periphery in punctate spots, formed cytoplasmic as well as nuclear inclusion bodies, the latter as conspicuous paired globules. Upon particle bombardment of expression plasmids, AV2:GFP was transported into neighboring cells of epidermal tissues showing that the intercellular transport of the AV2 protein is not restricted to the phloem. The results are consistent with a redundant function of ICMV AV2 acting as a movement protein, presumably as an evolutionary relic of a monopartite geminivirus that may still increase virus fitness but is no longer necessary in a bipartite genome. The fusion of ICMV ORF AV2 to the GFP gene is the first example of a reporter construct that follows the whole track of viral DNA from inside the nucleus to the cell periphery and to the next cell.

  6. Treatment of pyridostigmine-induced AV block with hyoscyamine in a patient with myasthenia gravis.

    PubMed

    Gehi, Anil; Benatar, Michael; Langberg, Jonathan

    2008-02-01

    Myasthenia gravis is an autoimmune disorder of the nervous system typically mediated by antibodies against the nicotinic acetylcholine receptor at the neuromuscular junction. Treatment of myasthenia gravis frequently involves the use of cholinesterase inhibitors such as pyridostigmine. Treatment with these agents has been associated with bradycardia and syncope requiring pacemaker implantation. We report a case of a 60-year-old man with a 1-year history of myasthenia gravis treated with pyridostigmine who presented with syncope due to high degree AV block. Before committing the patient to a permanent pacemaker, a trial of medical therapy with hyoscyamine was attempted. Hyoscyamine is a muscarinic antagonist commonly used to block cholinergic side effects associated with pyridostigmine without reducing its efficacy at the neuromuscular junction. Treatment with hyoscyamine resulted in complete resolution of AV block, thereby avoiding pacemaker implantation.

  7. Integrating computation and visualization for biomolecular analysis: an example using python and AVS.

    PubMed

    Sanner, M F; Duncan, B S; Carrillo, C J; Olson, A J

    1999-01-01

    One of the challenges in biocomputing is to enable the efficient use of a wide variety of fast-evolving computational methods to simulate, analyze, and understand the complex properties and interactions of molecular systems. Our laboratory investigates several areas including molecular visualization, protein-ligand docking, protein-protein docking, molecular surfaces, and the derivation of phenomenological potentials. In this paper we present an approach based on the Python programming language to achieve a high level of integration between these different computational methods and our primary visualization system AVS. This approach removes many limitations of AVS while increasing dramatically the inter-operability of our computational tools. Several examples are shown to illustrate how this approach enables a high level of integration and inter-operability between different tools, while retaining modularity and avoiding the creation of a large monolithic package that is difficult to extend and maintain.

  8. A.V. Usova's Contribution to the Field of Concept Learning in Physics Classroom

    ERIC Educational Resources Information Center

    Yavoruk, Oleg

    2015-01-01

    A.V. Usova (1921-2014) has always been one of the leading figures in Russian physics education. Her theory of physics concept formation was formulated during the 1970s and the 1980s and directly influenced the process of physics education in the 20th and the 21st century. Over the years there have been a lot of theories of concept formation. Her…

  9. Coding efficiency of AVS 2.0 for CBAC and CABAC engines

    NASA Astrophysics Data System (ADS)

    Cui, Jing; Choi, Youngkyu; Chae, Soo-Ik

    2015-12-01

    In this paper we compare the coding efficiency of AVS 2.0[1] for engines of the Context-based Binary Arithmetic Coding (CBAC)[2] in the AVS 2.0 and the Context-Adaptive Binary Arithmetic Coder (CABAC)[3] in the HEVC[4]. For fair comparison, the CABAC is embedded in the reference code RD10.1 because the CBAC is in the HEVC in our previous work[5]. The rate estimation table is employed only for RDOQ in the RD code. To reduce the computation complexity of the video encoder, therefore we modified the RD code so that the rate estimation table is employed for all RDO decision. Furthermore, we also simplify the complexity of rate estimation table by reducing the bit depth of its fractional part to 2 from 8. The simulation result shows that the CABAC has the BD-rate loss of about 0.7% compared to the CBAC. It seems that the CBAC is a little more efficient than that the CABAC in the AVS 2.0.

  10. Frequency-dependent electrophysiological remodeling of the AV node by hydroalcohol extract of Crocus sativus L. (saffron) during experimental atrial fibrillation: the role of endogenous nitric oxide.

    PubMed

    Khori, Vahid; Alizadeh, Ali Mohammad; Yazdi, Hamidreza; Rakhshan, Elnaz; Mirabbasi, Abbas; Changizi, Shima; Mazandarani, Masumeh; Nayebpour, Mohsen

    2012-06-01

    The study assessed the hydroalcohol extract effects of Crocus sativus L. (saffron) on (i) the basic and rate-dependent electrophysiological properties of the AV node, (ii) remodeling of the AV node during experimental atrial fibrillation (AF) and (iii) the role of nitric oxide (NO) in the effects of saffron on the AV node. Stimulation protocols in isolated AV node were used to quantify AV nodal recovery, facilitation and fatigue in four groups of rabbits (n = 8-16 per group). In addition, the nodal response to AF was evaluated at multiple cycle lengths and during AF. Saffron had a depressant effect on AV nodal rate-dependent properties; further, it increased Wenckebach block cycle length, functional refractory period, facilitation and fatigue (p < 0.05). A NO-synthase inhibitor (L-NAME) prevented the depressant effects of saffron on the AV node (p < 0.05). Saffron increased the zone of concealment in experimental AF (p < 0.05). The present research showed, for the first time, established electrophysiological remodeling of the AV node during AF by saffron. Saffron increased the AV nodal refractoriness and zone of concealment. These depressant effects of saffron were mediated by endogenous NO.

  11. CORONAS-F/AVS-F Observations of Terrestrial Gamma-ray Flashes

    NASA Astrophysics Data System (ADS)

    Arkhangelskaja, I.

    2005-12-01

    Terrestrial gamma ray flashes (TGFs) were first detected by BATSE experiment onboard CGRO satellite. Whole BATSE database contains 78 TGF but it is possible to define duration only for 65 ones. We have analyze all BATSE TGF temporal profile and obtain that these duration is in region from 0.01 to 20 ms. TGFs are produced in a process of bremsstrahlung of the runaway electrons in the middle atmosphere which are accelerated upward by the thundercloud electric field and collide with the material constituting the atmosphere. These electrons are very energetic (E near 1 MeV) and the gamma radiation pattern is directed along the beam. The AVS-F (amplitude-time Sun spectrometry) apparatus is intended to study characteristics of fluxes of hard X-rays, gamma-rays and neutrons from the Sun and solar flares and to detect and record events like gamma-ray bursts. The experiment is carry out at the CORONAS-F special-purpose automatic station (NORAD catalog number 26873, International Designator 2001-032A) that had been launched from Russian kosmodrom Plesetsk at 11:00 UT of 31 July 2001 into a circular orbit oriented towards the Sun with inclination 82.5 degrees and altitude near 500 km. The AVS-F apparatus uses signals produced by the SONG-D detector (based on the CsI(Tl) crystal of 20 cm and height of 10 cm, energy deposition ranges of 0.1 to 17.0 MeV and and 4.0 to 94.0 MeV by up to date calibration data), XSS-1 detector (the semiconductor detector with 3-30 keV energy deposition range) and the anticoincidence signal generated by the plastic scintillation counter of SONG-D. The basic time resolution of AVS-F apparatus is 16 sec in the bands of X-ray and low-energy gamma-emission registration and 128 sec for high- energy gamma-band. But AVS-F apparatus also allow to obtain event temporal profile with 1 ms time resolution in the low energy gamma-band. Using data of this type we have separated several short events with duration 1 to 16 ms in AVS-F database. These short events

  12. Phase 1 Trial of Subcutaneous rAvPAL-PEG in Subjects with Phenylketonuria

    PubMed Central

    Longo, Nicola; Harding, Cary O.; Burton, Barbara K.; Grange, Dorothy K.; Vockley, Jerry; Wasserstein, Melissa; Rice, Gregory M.; Musson, Donald G.; Gu, Zhonghua; Sile, Saba

    2014-01-01

    Objective Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. A phenylalanine-restricted diet initiated early in life can ameliorate the toxic effects of phenylalanine. However, the diet is onerous and compliance is extremely difficult. Phenylalanine ammonia lyase (PAL) is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. This Phase 1, multicenter clinical trial evaluated the safety, tolerability, pharmacokinetics and efficacy of rAvPAL-PEG (recombinant Anabaena variabilis PAL produced in E. coli conjugated with polyethylene glycol [PEG] to reduce immunogenicity) in reducing phenylalanine levels in subjects with phenylketonuria. Methods Single subcutaneous injections of rAvPAL-PEG in escalating doses (0·001, 0·003, 0·01, 0·03, and 0·1 mg/kg) were administered to 25 adults with phenylketonuria recruited from those attending metabolic clinics in North America whose blood phenylalanine concentrations were ≥600 μmol/L. Results The most frequently reported adverse events were injection-site reactions and dizziness. Reactions were self-limited without sequelae. During the trial, two subjects had adverse reactions to intramuscular (IM) medroxyprogesterone acetate, a drug containing polyethylene glycol as an excipient. Three subjects developed a generalized skin rash at the highest rAvPAL-PEG dose (0·1 mg/kg). Drug levels peaked ∼5 days after the injection. Treatment was effective in reducing blood phenylalanine in all five subjects receiving the highest dose (0·1 mg/kg, mean percent change of -58 from baseline), with a nadir ∼6 days after injection and inverse correlation between drug and phenylalanine concentrations in plasma. Phenylalanine concentrations returned to near-baseline levels ∼20 days after the single injection. Conclusions

  13. Preclinical Properties of 18F-AV-45: A PET Agent for Aβ Plaques in the Brain

    PubMed Central

    Choi, Seok Rye; Golding, Geoff; Zhuang, Zhiping; Zhang, Wei; Lim, Nathaniel; Hefti, Franz; Benedum, Tyler E.; Kilbourn, Michael R.; Skovronsky, Daniel; Kung, Hank F.

    2011-01-01

    β-amyloid plaques (Aβ plaques) in the brain, containing predominantly fibrillary Aβ peptide aggregates, represent a defining pathologic feature of Alzheimer disease (AD). Imaging agents targeting the Aβ plaques in the living human brain are potentially valuable as biomarkers of pathogenesis processes in AD. (E)-4-(2-(6-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine (18F-AV-45) is such as an agent currently in phase III clinical studies for PET of Aβ plaques in the brain. Methods In vitro binding of 18F-AV-45 to Aβ plaques in the postmortem AD brain tissue was evaluated by in vitro binding assay and autoradiography. In vivo biodistribution of 18F-AV-45 in mice and ex vivo autoradiography of AD transgenic mice (APPswe/PSEN1) with Aβ aggregates in the brain were performed. Small-animal PET of a monkey brain after an intravenous injection of 18F-AV-45 was evaluated. Results 18F-AV-45 displayed a high binding affinity and specificity to Aβ plaques (Kd, 3.72 ± 0.30 nM). In vitro autoradiography of postmortem human brain sections showed substantial plaque labeling in AD brains and not in the control brains. Initial high brain uptake and rapid washout from the brain of healthy mice and monkey were observed. Metabolites produced in the blood of healthy mice after an intravenous injection were identified. 18F-AV-45 displayed excellent binding affinity to Aβ plaques in the AD brain by ex vivo autoradiography in transgenic AD model mice. The results lend support that 18F-AV-45 may be a useful PET agent for detecting Aβ plaques in the living human brain. PMID:19837759

  14. Nisin-Triggered Activity of Lys44, the Secreted Endolysin from Oenococcus oeni Phage fOg44▿

    PubMed Central

    Nascimento, João Gil; Guerreiro-Pereira, Maria Carolina; Costa, Sérgio Fernandes; São-José, Carlos; Santos, Mário Almeida

    2008-01-01

    The intrinsic resistance of Oenococcus oeni cells to the secreted endolysin from oenophage fOg44 (Lys44) was investigated. Experiments with several antimicrobials support the hypothesis that the full activity of Lys44 requires sudden ion-nonspecific dissipation of the proton motive force, an event undertaken by the fOg44 holin in the phage infection context. PMID:17981964

  15. What Engages Students in MetaL-FrOG? A Triarchy Perspective on Meta-Cognitive Learning

    ERIC Educational Resources Information Center

    Fa, Ng Sen; Hussin, Firuz Hussin

    2008-01-01

    This paper presents the central ideas of a grounded theory research by the name of Triarchy Perspective on Metacognitive Learning in Free Online Groups, or "TriP on MetaL-FrOG" in short. The research setting was online learning community on the platform of Free Online Group web (FrOG) intended for post-graduate students. The research…

  16. Cardiac resynchronization therapy and AV optimization increase myocardial oxygen consumption, but increase cardiac function more than proportionally☆

    PubMed Central

    Kyriacou, Andreas; Pabari, Punam A.; Mayet, Jamil; Peters, Nicholas S.; Davies, D. Wyn; Lim, P. Boon; Lefroy, David; Hughes, Alun D.; Kanagaratnam, Prapa; Francis, Darrel P.; I.Whinnett, Zachary

    2014-01-01

    Background The mechanoenergetic effects of atrioventricular delay optimization during biventricular pacing (“cardiac resynchronization therapy”, CRT) are unknown. Methods Eleven patients with heart failure and left bundle branch block (LBBB) underwent invasive measurements of left ventricular (LV) developed pressure, aortic flow velocity-time-integral (VTI) and myocardial oxygen consumption (MVO2) at 4 pacing states: biventricular pacing (with VV 0 ms) at AVD 40 ms (AV-40), AVD 120 ms (AV-120, a common nominal AV delay), at their pre-identified individualised haemodynamic optimum (AV-Opt); and intrinsic conduction (LBBB). Results AV-120, relative to LBBB, increased LV developed pressure by a mean of 11(SEM 2)%, p = 0.001, and aortic VTI by 11(SEM 3)%, p = 0.002, but also increased MVO2 by 11(SEM 5)%, p = 0.04. AV-Opt further increased LV developed pressure by a mean of 2(SEM 1)%, p = 0.035 and aortic VTI by 4(SEM 1)%, p = 0.017. MVO2 trended further up by 7(SEM 5)%, p = 0.22. Mechanoenergetics at AV-40 were no different from LBBB. The 4 states lay on a straight line for Δexternal work (ΔLV developed pressure × Δaortic VTI) against ΔMVO2, with slope 1.80, significantly > 1 (p = 0.02). Conclusions Biventricular pacing and atrioventricular delay optimization increased external cardiac work done but also myocardial oxygen consumption. Nevertheless, the increase in cardiac work was ~ 80% greater than the increase in oxygen consumption, signifying an improvement in cardiac mechanoenergetics. Finally, the incremental effect of optimization on external work was approximately one-third beyond that of nominal AV pacing, along the same favourable efficiency trajectory, suggesting that AV delay dominates the biventricular pacing effect — which may therefore not be mainly “resynchronization”. PMID:24332598

  17. Cardiovascular responses to microinjection of L-glutamate into the NTS in AV3V-lesioned rats.

    PubMed

    Vieira, Alexandre Antonio; Colombari, Eduardo; De Luca, Laurival A; de Almeida Colombari, Débora Simões; Menani, José V

    2004-10-29

    The excitatory amino acid L-glutamate injected into the nucleus of the solitary tract (NTS) in unanesthetized rats similar to peripheral chemoreceptor activation increases mean arterial pressure (MAP) and reduces heart rate. In this study, we investigated the effects of acute (1 day) and chronic (15 days) electrolytic lesions of the preoptic-periventricular tissue surrounding the anteroventral third ventricle (AV3V region) on the pressor and bradycardic responses induced by injections of L-glutamate into the NTS or peripheral chemoreceptor activation in unanesthetized rats. Male Holtzman rats with sham or electrolytic AV3V lesions and a stainless steel cannula implanted into the NTS were used. Differently from the pressor responses (28+/-3 mm Hg) produced by injections into the NTS of sham-lesioned rats, L-glutamate (5 nmol/100 nl) injected into the NTS reduced MAP (-26+/-8 mm Hg) or produced no effect (2+/-7 mm Hg) in acute and chronic AV3V-lesioned rats, respectively. The bradycardia to l-glutamate into the NTS and the cardiovascular responses to chemoreflex activation with intravenous potassium cyanide or to baroreflex activation with intravenous phenylephrine or sodium nitroprusside were not modified by AV3V lesions. The results show that the integrity of the AV3V region is essential for the pressor responses to L-glutamate into the NTS but not for the pressor responses to chemoreflex activation, suggesting dissociation between the central mechanisms involved in these responses.

  18. 77 FR 1667 - Nelson S. Galgoul, Av. Edison Passess 909, Rio De Janeiro, R.J., Brazil 20531-070, Respondent...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ..., the most recent being that of August 12, 2011 (76 FR 50,661 (Aug. 16, 2011)), has continued the... Bureau of Industry and Security Nelson S. Galgoul, Av. Edison Passess 909, Rio De Janeiro, R.J., Brazil... a last known address of Av. Edison Passess 909, Rio De Janeiro, R.J., Brazil 20531-070, and...

  19. [A simple method for AV-delay determination in dual chamber pacemakers].

    PubMed

    Koglek, W; Kranig, W; Kowalski, M; Kronski, D; Brandl, J; Oberbichler, A; Suntinger, A; Wutte, M; Grimm, G; Grove, R; Lüdorff, G

    2000-12-01

    The individual adjustment of the AV intervals is a prerequisite for the hemodynamic advantages of dual-chamber pacing. The methods for the optimization of the AV-Delay (AVD) applied so far are time intensive. A simple and fast method is the approximate adjustment of the AVD with the surface-ECG. The aim of this work is the conception and validation of this new method. The optimal AVD is given if at the end of the atrial contraction the mitral valve is closed by the ventricular increase of pressure. In order to achieve this with pacemaker patients, the individually different atrial and ventricular conduction times must be considered. The different conduction times can be determined from the surface-ECG. Intra- and interatrial conduction times can be defined by the beginning of the atrial spike up to the end of the p-wave. The beginning of ventricular pressure increase corresponds to the peak of the stimulated QRS complex (beginning of the Iso-Volumetric Contraction time, ISVC) and depends on the interventricular conduction time.¶   In the case of 100 patients, who did not receive a cardiac pacemaker, the interval at the end of the p-wave (left atrial excitation, EP) up to the peak of the r-wave (ISVC) during rest and exercise was measured and an age referred average value of 100ms determined; this serves as standard value if no AV-conduction is available. The approximated optimized AVD is given if the interval of the end at the p-wave to the peak of the QRS-Complex amounts to 100ms. By means of a simple algorithm, the optimized AVD can, thus, be calculated:¶   After programming a long AVD, the interval at the end of the native or paced p-wave up to the peak of the stimulated QRS-Complex (EP/ISVC) is determined. This value EP/ISVC is then taken from the long AVD, the 100ms standard value is added and one receives the approximately optimized AVD.¶   In order to validate the described method, 13 consecutive patients (2 female, 11 male, average age

  20. Chemometric formulation of bacterial consortium-AVS for improved decolorization of resonance-stabilized and heteropolyaromatic dyes.

    PubMed

    Kumar, Madhava Anil; Kumar, Vaidyanathan Vinoth; Premkumar, Manickam Periyaraman; Baskaralingam, Palanichamy; Thiruvengadaravi, Kadathur Varathachary; Dhanasekaran, Anuradha; Sivanesan, Subramanian

    2012-11-01

    A bacterial consortium-AVS, consisting of Pseudomonas desmolyticum NCIM 2112, Kocuria rosea MTCC 1532 and Micrococcus glutamicus NCIM 2168 was formulated chemometrically, using the mixture design matrix based on the design of experiments methodology. The formulated consortium-AVS decolorized acid blue 15 and methylene blue with a higher average decolorization rate, which is more rapid than that of the pure cultures. The UV-vis spectrophotometric, Fourier transform infra red spectrophotometric and high performance liquid chromatographic analysis confirm that the decolorization was due to biodegradation by oxido-reductive enzymes, produced by the consortium-AVS. The toxicological assessment of plant growth parameters and the chlorophyll pigment concentrations of Phaseolus mungo and Triticum aestivum seedlings revealed the reduced toxic nature of the biodegraded products. PMID:22940340

  1. A Comparison of the AVS-9 and the Panoramic Night Vision Goggles During Rotorcraft Hover and Landing

    NASA Technical Reports Server (NTRS)

    Szoboszlay, Zoltan; Haworth, Loran; Simpson, Carol

    2000-01-01

    A flight test was conducted to assess any differences in pilot-vehicle performance and pilot opinion between the use of a current generation night vision goggle (the AVS-9) and one variant of the prototype panoramic night vision goggle (the PNVGII). The panoramic goggle has more than double the horizontal field-of-view of the AVS-9, but reduced image quality. Overall the panoramic goggles compared well to the AVS-9 goggles. However, pilot comment and data are consistent with the assertion that some of the benefits of additional field-of-view with the panoramic goggles were negated by the reduced image quality of the particular variant of the panoramic goggles tested.

  2. Chemometric formulation of bacterial consortium-AVS for improved decolorization of resonance-stabilized and heteropolyaromatic dyes.

    PubMed

    Kumar, Madhava Anil; Kumar, Vaidyanathan Vinoth; Premkumar, Manickam Periyaraman; Baskaralingam, Palanichamy; Thiruvengadaravi, Kadathur Varathachary; Dhanasekaran, Anuradha; Sivanesan, Subramanian

    2012-11-01

    A bacterial consortium-AVS, consisting of Pseudomonas desmolyticum NCIM 2112, Kocuria rosea MTCC 1532 and Micrococcus glutamicus NCIM 2168 was formulated chemometrically, using the mixture design matrix based on the design of experiments methodology. The formulated consortium-AVS decolorized acid blue 15 and methylene blue with a higher average decolorization rate, which is more rapid than that of the pure cultures. The UV-vis spectrophotometric, Fourier transform infra red spectrophotometric and high performance liquid chromatographic analysis confirm that the decolorization was due to biodegradation by oxido-reductive enzymes, produced by the consortium-AVS. The toxicological assessment of plant growth parameters and the chlorophyll pigment concentrations of Phaseolus mungo and Triticum aestivum seedlings revealed the reduced toxic nature of the biodegraded products.

  3. Left Ventricular Mechanical Property Changes During Acute AV Synchronous Right Ventricular Pacing in Children.

    PubMed

    Tejman-Yarden, Shai; Bratincsak, Andras; Bachner-Hinenzon, Noa; Khamis, Hanan; Rzasa, Callie; Adam, Dan; Printz, Beth F; Perry, James C

    2016-01-01

    Prolonged RV pacing is recognized as a cause of LV dysfunction due to dyssynchronous activation. There are no specific longitudinal parameters known to help predict RV pacing-induced LV dysfunction. The aim of the study was to assess the acute effects of AV synchronous RV pacing on LV mechanics using echocardiographic speckle tracking. Nineteen children, aged 6-23 years, underwent echocardiographic evaluation prior to and following elective electrophysiology and ablation studies. The subjects were evaluated in sinus rhythm and later with AV synchronous RV pacing at a cycle length of 550 ms with a short AV delay of 80 ms. The echocardiographic clips were analyzed using speckle tracking methods to calculate LV circumferential and longitudinal strain, rotation and twist in all conditions. Acute RV apical pacing decreased LV longitudinal strain from 16.1 ± 3.7% in sinus rhythm to 14.4 ± 3.3% (p = 0.03) and LV base rotation from -8.4° ± 3.6° to -6.4° ± 4.0° (p = 0.04). The circumferential strain, apical rotation and LV twist were not affected. Separate analysis of subjects with no prior preexcitation showed that acute RV pacing caused significant twist reduction, from 15.9° ± 7.6° to 12.1° ± 7.0° (p = 0.02), and decreased longitudinal strain and base rotation. Patients with preexcitation had abnormalities that persisted acutely after ablation. Acute RV apical pacing causes reductions in LV base rotation, longitudinal strain and twist. The recognition of abnormal LV activation patterns may provide longitudinal clues to LV dysfunction in chronically paced patients and potential novel indices of effective CRT interventions to reverse these abnormalities.

  4. Optimal pacing for symptomatic AV block: a comparison of VDD and DDD pacing.

    PubMed

    Huang, Max; Krahn, Andrew D; Yee, Raymond; Klein, George J; Skanes, Allan C

    2003-12-01

    VDD pacing provides the physiological benefits of atrioventricular synchronous pacing with the convenience of a single lead system, but is hampered by uncertainty regarding long-term atrial sensing and potential development of sinus node disease. To examine the long-term reliability and complication rates of VDD pacing, we compared the outcome of 112 consecutive patients (age 70 +/- 13 years, 59% male) with symptomatic AV block who received a single pass bipolar VDD system to 80 patients (age 63 +/- 16 years, 70% male) who received DDD pacing for the same indication. All patients were judged to have intact sinus node function based on submitted ECGs and monitoring results at the time of implant. Implant time was reduced in VDD patients compared to DDD patients (63 +/- 20 vs 97 +/- 36 minutes, P < 0.0001). Implant complications occurred in 5 (6%) DDD patients compared to 3 (3%) VDD patients (P = 0.15). The implant P wave was lower with VDD pacing compared to DDD patients (2.91 +/- 1.48 vs 4.0 +/- 1.7 mV, P < 0.0001), but remained stable during long-term follow-up in both groups. During 17.7 +/- 10.0 months of follow-up in the VDD group, only 2 VDD patients were reprogrammed to VVIR mode, compared to 3 DDD patients. Physiological atrioventricular activation was maintained in 94%-99% of beats throughout the follow-up period in the VDD group. VDD pacing is an excellent strategy for treatment of patients with symptomatic AV block. The lower cost, high reliability, and abbreviated implantation time suggest that VDD pacing is a viable alternative to DDD pacing in patients with high-degree AV block and normal sinus node function.

  5. Optimal pacing for symptomatic AV block: a comparison of VDD and DDD pacing.

    PubMed

    Huang, Max; Krahn, Andrew D; Yee, Raymond; Klein, George J; Skanes, Allan C

    2004-01-01

    VDD pacing provides the physiological benefits of atrioventricular synchronous pacing with the convenience of a single lead system, but is hampered by uncertainty regarding long term atrial sensing and potential development of sinus node disease. To examine the long-term reliability and complication rates of VDD pacing, we compared the outcome of 112 consecutive patients (age 70 +/- 13 years, 59% men) with symptomatic AV block who received a single pass bipolar VDD system, to 80 patients (age 63 +/- 16 years, 70% men) who received DDD pacing for the same indication. All patients were judged to have intact sinus node function based on submitted ECGs and monitoring results at the time of implant. Implant time was reduced in VDD patients compared to DDD patients (63 +/- 20 vs 97 +/- 36 minutes, P < 0.0001). Implant complications occurred in 5 (6%) DDD patients compared to 3 (3%) VDD patients (P = 0.15). The implant P wave was lower with VDD pacing compared to DDD patients (2.91 +/- 1.48 vs 4.0 +/- 1.7 mv, P < 0.0001), but remained stable during long-term follow-up in both groups. During 17.7 +/- 10.0 months of follow-up in the VDD group, only two VDD patients were reprogrammed to VVIR mode, compared to three DDD patients. Physiological atrioventricular activation was maintained in 94%-99% of beats throughout the follow-up period in the VDD group. VDD pacing is an excellent strategy for treatment of patients with symptomatic AV block. The lower cost, high reliability, and abbreviated implantation time suggest that VDD pacing is a viable alternative to DDD pacing in patients with high degree AV block and normal sinus node function.

  6. ND2 AV: N-dimensional data analysis and visualization analysis for the National Ignition Campaign

    DOE PAGES

    Bremer, Peer -Timo; Maljovec, Dan; Saha, Avishek; Wang, Bei; Gaffney, Jim; Spears, Brian K.; Pascucci, Valerio

    2015-07-01

    Here, one of the biggest challenges in high-energy physics is to analyze a complex mix of experimental and simulation data to gain new insights into the underlying physics. Currently, this analysis relies primarily on the intuition of trained experts often using nothing more sophisticated than default scatter plots. Many advanced analysis techniques are not easily accessible to scientists and not flexible enough to explore the potentially interesting hypotheses in an intuitive manner. Furthermore, results from individual techniques are often difficult to integrate, leading to a confusing patchwork of analysis snippets too cumbersome for data exploration. This paper presents a case study on how a combination of techniques from statistics, machine learning, topology, and visualization can have a significant impact in the field of inertial confinement fusion. We present themore » $$\\mathrm{ND}^2\\mathrm{AV}$$: N-dimensional data analysis and visualization framework, a user-friendly tool aimed at exploiting the intuition and current workflow of the target users. The system integrates traditional analysis approaches such as dimension reduction and clustering with state-of-the-art techniques such as neighborhood graphs and topological analysis, and custom capabilities such as defining combined metrics on the fly. All components are linked into an interactive environment that enables an intuitive exploration of a wide variety of hypotheses while relating the results to concepts familiar to the users, such as scatter plots. $$\\mathrm{ND}^2\\mathrm{AV}$$ uses a modular design providing easy extensibility and customization for different applications. $$\\mathrm{ND}^2\\mathrm{AV}$$ is being actively used in the National Ignition Campaign and has already led to a number of unexpected discoveries.« less

  7. Maillard reaction and enzymatic browning affect the allergenicity of Pru av 1, the major allergen from cherry (Prunus avium).

    PubMed

    Gruber, Patrick; Vieths, Stefan; Wangorsch, Andrea; Nerkamp, Jörg; Hofmann, Thomas

    2004-06-16

    The influence of thermal processing and nonenymatic as well as polyphenoloxidase-catalyzed browning reaction on the allergenicity of the major cherry allergen Pru av 1 was investigated. After thermal treatment of the recombinant protein rPru av 1 in the absence or presence of carbohydrates, SDS-PAGE, enzyme allergosorbent tests, and inhibition assays revealed that thermal treatment of rPru av 1 alone did not show any influence on the IgE-binding activity of the protein at least for 30 min, thus correlating well with the refolding of the allergen in buffer solution as demonstrated by CD spectroscopic experiments. Incubation of the protein with starch and maltose also showed no effect on IgE-binding activity, whereas reaction with glucose and ribose and, even more pronounced, with the carbohydrate breakdown products glyceraldehyde and glyoxal induced a strong decrease of the IgE-binding capacity of rPru av 1. In the second part of the study, the effect of polyphenoloxidase-catalyzed oxidation of polyphenols on food allergen activity was investigated. Incubation of rPru av 1 with epicatechin in the presence of tyrosinase led to a drastic decrease in IgE-binding activity of the protein. Variations of the phenolic compound revealed caffeic acid and epicatechin as the most active inhibitors of the IgE-binding activity of rPru av 1, followed by catechin and gallic acid, and, finally, by quercetin and rutin, showing significantly lower activity. On the basis of these data, reactive intermediates formed during thermal carbohydrate degradation as well as during enzymatic polyphenol oxidation are suggested as the active chemical species responsible for modifying nucleophilic amino acid side chains of proteins, thus inducing an irreversible change in the tertiary structure of the protein and resulting in a loss of conformational epitopes of the allergen.

  8. Anteroventral third ventricle (AV3V) lesion affects hypothalamic neuronal nitric oxide synthase (nNOS) expression following water deprivation.

    PubMed

    Aguila, Fábio Alves; Oliveira-Pelegrin, Gabriela Ravanelli; Yao, Song Tieng; Murphy, David; Rocha, Maria José Alves

    2011-10-10

    Neuronal nitric oxide synthase (nNOS) has been reported to be up-regulated in the hypothalamic supraoptic nucleus (SON) during dehydration which in turn could increase nitric oxide (NO) production and consequently affect arginine vasopressin (AVP) secretion. The anteroventral third ventricle (AV3V) region has strong afferent connections with the SON. Herein we describe our analysis of the effects of an AV3V lesion on AVP secretion, and c-fos and nNOS expression in the SON following dehydration. Male Wistar rats had their AV3V region electrolytically lesioned or were sham operated. After 21 days they were submitted to dehydration or left as controls (euhydrated). Two days later, one group was anaesthetized, perfused and the brains were processed for Fos protein and nNOS immunohistochemistry (IHC). Another group was decapitated, the blood collected for hematocrit, osmolality, serum sodium and AVP plasma level analysis. The brains were removed for measurement of neurohypophyseal AVP content, and the SON was punched out and processed for nNOS detection by western blotting. The AV3V lesion reduced AVP plasma levels and c-fos expression in the SON following dehydration (P<0.05). Western blotting revealed an up-regulation of nNOS in the SON of control animals following dehydration, whereas such up-regulation was not observed in AV3V-lesioned rats (P<0.05). We conclude that the AV3V region plays a role in regulating the expression of nNOS in the SON of rats submitted to dehydration, and thus may affect the local nitric oxide production and the secretion of vasopressin.

  9. Maillard reaction and enzymatic browning affect the allergenicity of Pru av 1, the major allergen from cherry (Prunus avium).

    PubMed

    Gruber, Patrick; Vieths, Stefan; Wangorsch, Andrea; Nerkamp, Jörg; Hofmann, Thomas

    2004-06-16

    The influence of thermal processing and nonenymatic as well as polyphenoloxidase-catalyzed browning reaction on the allergenicity of the major cherry allergen Pru av 1 was investigated. After thermal treatment of the recombinant protein rPru av 1 in the absence or presence of carbohydrates, SDS-PAGE, enzyme allergosorbent tests, and inhibition assays revealed that thermal treatment of rPru av 1 alone did not show any influence on the IgE-binding activity of the protein at least for 30 min, thus correlating well with the refolding of the allergen in buffer solution as demonstrated by CD spectroscopic experiments. Incubation of the protein with starch and maltose also showed no effect on IgE-binding activity, whereas reaction with glucose and ribose and, even more pronounced, with the carbohydrate breakdown products glyceraldehyde and glyoxal induced a strong decrease of the IgE-binding capacity of rPru av 1. In the second part of the study, the effect of polyphenoloxidase-catalyzed oxidation of polyphenols on food allergen activity was investigated. Incubation of rPru av 1 with epicatechin in the presence of tyrosinase led to a drastic decrease in IgE-binding activity of the protein. Variations of the phenolic compound revealed caffeic acid and epicatechin as the most active inhibitors of the IgE-binding activity of rPru av 1, followed by catechin and gallic acid, and, finally, by quercetin and rutin, showing significantly lower activity. On the basis of these data, reactive intermediates formed during thermal carbohydrate degradation as well as during enzymatic polyphenol oxidation are suggested as the active chemical species responsible for modifying nucleophilic amino acid side chains of proteins, thus inducing an irreversible change in the tertiary structure of the protein and resulting in a loss of conformational epitopes of the allergen. PMID:15186129

  10. Atmospheric Turbulence Measurements With the Automatic Mini UAV 'M2AV Carolo'

    NASA Astrophysics Data System (ADS)

    Bange, J.; van den Kroonenberg, A. C.; Spieß, T.; Buschmann, M.; Krüger, L.; Heindorf, A.; Vörsmann, P.

    2007-05-01

    The limitations of manned airborne meteorological measurements led to the development of an autonomously operating mini aircraft, the Meteorological Mini-UAV (M2AV), at the Institute of Aerospace Systems, Technical University of Braunschweig, Germany. The task was to develop, test and verify a meteorological sensor package as payload for an already available automatic carrier aircraft, the UAV 'Carolo T200', which operates autonomously i.e. without remote control. The M2AV is a self constructed model aircraft with two electrically powered engines and a wingspan of two meters. The maximum take-off weight is 4.5~kg (the M2AV is therefore classified as an model plane which simplifies authority issues), including 1.5~kg of payload. It is hand-launched which makes operation of the aircraft easy. With an endurance of approximately 50 minutes, the range accounts for 60 km at a cruising speed of 20~m/s. The M2AV is capable of performing turbulence measurements (wind vector, temperature and humidity) within the troposphere and offers an economic component during meteorological campaigns. The meteorological sensors are mounted on a noseboom to minimise the aircraft's influence on the measurements and to position the sensors closely to each other. Wind is measured via a small five-hole probe, an inertia measurement unit and GPS. The flight mission (waypoints, altitudes, airspeed) is planned and assigned to the aircraft before the semi- automatic launch. The flight is only controlled by the on-board autopilot system which only communicates with a ground station (laptop PC) for the exchange of measured data and command updates like new waypoints etc. The talk gives details on the technical items, calibration and first missions. Results from first field experiments like the LAUNCH-2005 campaign near Berlin are used for data quality assessment by comparison with simultaneous lidar and sodar measurements. An in situ comparison with the highly accurate helicopter-borne turbulence

  11. The Drosophila histone variant H2A.V works in concert with HP1 to promote kinetochore-driven microtubule formation

    PubMed Central

    Vernì, Fiammetta; Cenci, Giovanni

    2015-01-01

    Unlike other organisms that have evolved distinct H2A variants for different functions, Drosophila melanogaster has just one variant which is capable of filling many roles. This protein, H2A.V, combines the features of the conserved variants H2A.Z and H2A.X in transcriptional control/heterochromatin assembly and DNA damage response, respectively. Here we show that mutations in the gene encoding H2A.V affect chromatin compaction and perturb chromosome segregation in Drosophila mitotic cells. A microtubule (MT) regrowth assay after cold exposure revealed that loss of H2A.V impairs the formation of kinetochore-driven (k) fibers, which can account for defects in chromosome segregation. All defects are rescued by a transgene encoding H2A.V that lacks the H2A.X function in the DNA damage response, suggesting that the H2A.Z (but not H2A.X) functionality of H2A.V is required for chromosome segregation. We also found that loss of H2A.V weakens HP1 localization, specifically at the pericentric heterochromatin of metaphase chromosomes. Interestingly, loss of HP1 yielded not only telomeric fusions but also mitotic defects similar to those seen in H2A.V null mutants, suggesting a role for HP1 in chromosome segregation. We also show that H2A.V precipitates HP1 from larval brain extracts indicating that both proteins are part of the same complex. Moreover, we found that the overexpression of HP1 rescues chromosome missegregation and defects in the kinetochore-driven k-fiber regrowth of H2A.V mutants indicating that both phenotypes are influenced by unbalanced levels of HP1. Collectively, our results suggest that H2A.V and HP1 work in concert to ensure kinetochore-driven MT growth. PMID:25591068

  12. ogs6 - a new concept for porous-fractured media simulations

    NASA Astrophysics Data System (ADS)

    Naumov, Dmitri; Bilke, Lars; Fischer, Thomas; Rink, Karsten; Wang, Wenqing; Watanabe, Norihiro; Kolditz, Olaf

    2015-04-01

    OpenGeoSys (OGS) is a scientific open-source initiative for numerical simulation of thermo-hydro-mechanical/chemical (THMC) processes in porous and fractured media, continuously developed since the mid-eighties. The basic concept is to provide a flexible numerical framework for solving coupled multi-field problems. OGS is targeting mainly on applications in environmental geoscience, e.g. in the fields of contaminant hydrology, water resources management, waste deposits, or geothermal energy systems, but it has also been successfully applied to new topics in energy storage recently. OGS is actively participating several international benchmarking initiatives, e.g. DECOVALEX (waste management), CO2BENCH (CO2 storage and sequestration), SeSBENCH (reactive transport processes) and HM-Intercomp (coupled hydrosystems). Despite the broad applicability of OGS in geo-, hydro- and energy-sciences, several shortcomings became obvious concerning the computational efficiency as well as the code structure became too sophisticated for further efficient development. OGS-5 was designed for object-oriented FEM applications. However, in many multi-field problems a certain flexibility of tailored numerical schemes is essential. Therefore, a new concept was designed to overcome existing bottlenecks. The paradigms for ogs6 are: - Flexibility of numerical schemes (FEM#FVM#FDM), - Computational efficiency (PetaScale ready), - Developer- and user-friendly. ogs6 has a module-oriented architecture based on thematic libraries (e.g. MeshLib, NumLib) on the large scale and uses object-oriented approach for the small scale interfaces. Usage of a linear algebra library (Eigen3) for the mathematical operations together with the ISO C++11 standard increases the expressiveness of the code and makes it more developer-friendly. The new C++ standard also makes the template meta-programming technique code used for compile-time optimizations more compact. We have transitioned the main code development to

  13. The use of C(av) rather than AUC in safety assessment.

    PubMed

    Smith, D A; Morgan, P; Vogel, W M; Walker, D K

    2010-06-01

    Toxicokinetic data have traditionally been presented as maximum observed plasma concentrations (C(max)) and area under the concentration time curve (AUC) values. These values have been used to compare exposures across studies and species to provide valuable interpretation of drug safety data. Increasingly, questions are asked of toxicology studies to more accurately describe the concentration effect relationships in terms of compound affinity for target and off-target receptors. C(max) values can immediately be referenced to known pharmacological activities, particularly when the extent of plasma protein binding is taken into account. This provides a measure of the more pharmacologically relevant free drug exposure. AUC values on the other hand contain the component of time, which means that direct comparison to pharmacological activity values are not immediately possible. Conversion of AUC to average plasma concentration (C(av)) provides a simple and convenient means to allow such a comparison without losing any information imparted by AUC values. In this paper, the benefit and advantage of applying C(av) values is illustrated using examples taken from the literature.

  14. The use of C(av) rather than AUC in safety assessment.

    PubMed

    Smith, D A; Morgan, P; Vogel, W M; Walker, D K

    2010-06-01

    Toxicokinetic data have traditionally been presented as maximum observed plasma concentrations (C(max)) and area under the concentration time curve (AUC) values. These values have been used to compare exposures across studies and species to provide valuable interpretation of drug safety data. Increasingly, questions are asked of toxicology studies to more accurately describe the concentration effect relationships in terms of compound affinity for target and off-target receptors. C(max) values can immediately be referenced to known pharmacological activities, particularly when the extent of plasma protein binding is taken into account. This provides a measure of the more pharmacologically relevant free drug exposure. AUC values on the other hand contain the component of time, which means that direct comparison to pharmacological activity values are not immediately possible. Conversion of AUC to average plasma concentration (C(av)) provides a simple and convenient means to allow such a comparison without losing any information imparted by AUC values. In this paper, the benefit and advantage of applying C(av) values is illustrated using examples taken from the literature. PMID:20074607

  15. VizieR Online Data Catalog: NH and AV Towards YSOs in the ONC (Hasenberger+, 2016)

    NASA Astrophysics Data System (ADS)

    Hasenberger, B.; Forbrich, J.; Alves, J.; Wolk, S. J.; Meingast, S.; Getman, K. V.; Pillitteri, I.

    2016-07-01

    Column density (NH) and extinction (AV) values are sample of YSO sources in the ONC. Near-infrared colours based on the VISION (Meingast et al., 2016A&A...587A.153M) catalogue were employed to calculate extinction values using the NICER algorithm (Lombardi et al., 2001A&A...377.1023L) and assuming RV=3.1. Column densities were adopted from the COUP (Getman et al., 2005, Cat. J/ApJS/160/319) catalogue. In addition to NH and AV, the following quantities are provided: JHK_s magnitudes, taken from the VISION catalogue; spectral types, adopted from the catalogue by Hillenbrand et al. (2013, Cat. J/AJ/146/85); intrinsic near-infrared colours, deduced from spectral types and data by Scandariato et al. (2012A&A...545A..19S); and the YSO classification, based on the classification by Megeath et al. (2012, Cat. J/AJ/144/192). 1-Sigma error estimates are given for all quantities in the table. (1 data file).

  16. Geologic Mapping of the Av-9 Numisia Quadrangle of Asteroid 4Vesta

    NASA Astrophysics Data System (ADS)

    Buczkowski, D.; Wyrick, D.; Capaccioni, F.; Scully, J.; Williams, D.; Hiesinger, H.; Garry, W.; Yingst, R.; LeCorre, L.; Nathues, A.; Schenk, P.; Jaumann, R.; Raymond, C.; Pieters, C.; Roatsch, T.; Preusker, F.; Russell, C.

    2012-04-01

    NASA's Dawn spacecraft arrived at the asteroid 4Vesta on July 16, 2011, and is now collecting imaging, spectroscopic, and elemental abundance data during its one-year orbital mission. As part of the geological analysis of the surface, the Dawn Science Team has begun geologic map-ping of Vesta's surface at the global scale and as a series of 15 quadrangle maps that are being produced based on Framing Camera (FC) images, along with Visible & Infrared Spectrometer data (VIR) obtained during the High-Altitude Mapping Orbit (HAMO). We here concentrate on our geologic analysis and mapping of quadrangle Av-9 Numisia, located in the equatorial region of Vesta, extending from 22˚N - 22˚S and from 216° - 288° E. Clear filter (monochrome) FC HAMO images (~70 m/p) were mosaicked to make a base for this quadrangle. Topography of Av-9, is observed in a colorized Digital Terrain Model (DTM) derived from Survey orbit FC data. Variations in surface composition are revealed by VIR hyperspectral images from Survey (700 m/p) and HAMO (200 m/p) orbits and FC color ratio images (250 m/p) from Survey orbit. Av-9 Numisia is dominated by Vestalia Terra, a distinct, albedo-bright, topographically high region of Vesta bound by steep scarps and crossed by a roughly linear unit of dark material from the northwest to the southeast. This "dark ribbon" is primarily evident in FC color ratio data but is also discernable in clear filter data. The dark material appears to fill a locally low region on top of Vestalia Terra. The ribbon-like feature is cut by Numisia crater, which shows both bright and dark layers in its walls; the dark layers may thus be exposures of subsurface "dark ribbon" material. The origin of the "dark ribbon" material has yet to be determined, but possibilities include impact ejecta flow and/or volcanism. FC color ratio images using standard Clementine ratios [Red (750/430 nm); Green (750/920 nm); Blue (430/750 nm)] show that many of the impact craters in Av-9 have

  17. Assessment of the use of the AVS concept for the routine toxicity monitoring of contaminated freshwater sediments

    SciTech Connect

    Vangheluwe, M.L.; Janssen, C.R.; Goyvaerts, M.P.; Cooman, P.

    1995-12-31

    Acid volatile sulfides (AVS) have been shown to be an important factor mediating the bioavailability of heavy metals in sediments and have consequently been suggested as a possible predictive tool for toxicity assessment of these matrices. The potential use and limitations of the AVS method for predictive toxicity screening and priority setting was assessed in a large scale sediment monitoring study (Flanders, Belgium). The acute toxicity of 50 metal contaminated freshwater sediments, with varying metal concentrations and sediment characteristics, were tested using the Microtox{reg_sign} Solid Phase test and the 10 day test with Chironomus riparius and Hyalella azteca. Uni and multivariate statistical techniques were used to asses the relations between acute toxicity and SEM/AVS ratio`s and to evaluate the influence of sediment characteristics on metal bioavailability and toxicity. In general, the results of this study indicate that the AVS-toxicity relationship proposed in literature does have certain limitations. Finally, the potential use of a concentration-addition model for predicting metal-mixture toxicity in sediments will be presented and discussed.

  18. 18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers

    PubMed Central

    Puschmann, Andreas; Schöll, Michael; Ohlsson, Tomas; van Swieten, John; Honer, Michael; Englund, Elisabet

    2016-01-01

    Tau positron emission tomography ligands provide the novel possibility to image tau pathology in vivo. However, little is known about how in vivo brain uptake of tau positron emission tomography ligands relates to tau aggregates observed post-mortem. We performed tau positron emission tomography imaging with 18F-AV-1451 in three patients harbouring a p.R406W mutation in the MAPT gene, encoding tau. This mutation results in 3- and 4-repeat tau aggregates similar to those in Alzheimer’s disease, and many of the mutation carriers initially suffer from memory impairment and temporal lobe atrophy. Two patients with short disease duration and isolated memory impairment exhibited 18F-AV-1451 uptake mainly in the hippocampus and adjacent temporal lobe regions, correlating with glucose hypometabolism in corresponding regions. One patient died after 26 years of disease duration with dementia and behavioural deficits. Pre-mortem, there was 18F-AV-1451 uptake in the temporal and frontal lobes, as well as in the basal ganglia, which strongly correlated with the regional extent and amount of tau pathology in post-mortem brain sections. Amyloid-β (18F-flutemetamol) positron emission tomography scans were negative in all cases, as were stainings of brain sections for amyloid. This provides strong evidence that 18F-AV-1451 positron emission tomography can be used to accurately quantify in vivo the regional distribution of hyperphosphorylated tau protein. PMID:27357347

  19. 18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers.

    PubMed

    Smith, Ruben; Puschmann, Andreas; Schöll, Michael; Ohlsson, Tomas; van Swieten, John; Honer, Michael; Englund, Elisabet; Hansson, Oskar

    2016-09-01

    Tau positron emission tomography ligands provide the novel possibility to image tau pathology in vivo However, little is known about how in vivo brain uptake of tau positron emission tomography ligands relates to tau aggregates observed post-mortem. We performed tau positron emission tomography imaging with (18)F-AV-1451 in three patients harbouring a p.R406W mutation in the MAPT gene, encoding tau. This mutation results in 3- and 4-repeat tau aggregates similar to those in Alzheimer's disease, and many of the mutation carriers initially suffer from memory impairment and temporal lobe atrophy. Two patients with short disease duration and isolated memory impairment exhibited (18)F-AV-1451 uptake mainly in the hippocampus and adjacent temporal lobe regions, correlating with glucose hypometabolism in corresponding regions. One patient died after 26 years of disease duration with dementia and behavioural deficits. Pre-mortem, there was (18)F-AV-1451 uptake in the temporal and frontal lobes, as well as in the basal ganglia, which strongly correlated with the regional extent and amount of tau pathology in post-mortem brain sections. Amyloid-β ((18)F-flutemetamol) positron emission tomography scans were negative in all cases, as were stainings of brain sections for amyloid. This provides strong evidence that (18)F-AV-1451 positron emission tomography can be used to accurately quantify in vivo the regional distribution of hyperphosphorylated tau protein.

  20. Balloon launched decelerator test program: Post-flight test report, BLDT vehicle AV-3, Viking 1975 project

    NASA Technical Reports Server (NTRS)

    Dickinson, D.; Hicks, F.; Schlemmer, J.; Michel, F.; Moog, R. D.

    1973-01-01

    The pertinent events concerned with the launch, float, and flight of balloon launched decelerator test vehicle AV-3 are discussed. The performance of the decelerator system is analyzed. Data on the flight trajectory and decelerator test points at the time of decelerator deployment are provided. A description of the time history of vehicle events and anaomalies encounters during the mission is included.

  1. 18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers.

    PubMed

    Smith, Ruben; Puschmann, Andreas; Schöll, Michael; Ohlsson, Tomas; van Swieten, John; Honer, Michael; Englund, Elisabet; Hansson, Oskar

    2016-09-01

    Tau positron emission tomography ligands provide the novel possibility to image tau pathology in vivo However, little is known about how in vivo brain uptake of tau positron emission tomography ligands relates to tau aggregates observed post-mortem. We performed tau positron emission tomography imaging with (18)F-AV-1451 in three patients harbouring a p.R406W mutation in the MAPT gene, encoding tau. This mutation results in 3- and 4-repeat tau aggregates similar to those in Alzheimer's disease, and many of the mutation carriers initially suffer from memory impairment and temporal lobe atrophy. Two patients with short disease duration and isolated memory impairment exhibited (18)F-AV-1451 uptake mainly in the hippocampus and adjacent temporal lobe regions, correlating with glucose hypometabolism in corresponding regions. One patient died after 26 years of disease duration with dementia and behavioural deficits. Pre-mortem, there was (18)F-AV-1451 uptake in the temporal and frontal lobes, as well as in the basal ganglia, which strongly correlated with the regional extent and amount of tau pathology in post-mortem brain sections. Amyloid-β ((18)F-flutemetamol) positron emission tomography scans were negative in all cases, as were stainings of brain sections for amyloid. This provides strong evidence that (18)F-AV-1451 positron emission tomography can be used to accurately quantify in vivo the regional distribution of hyperphosphorylated tau protein. PMID:27357347

  2. Draft Genome Sequence of Bacillus alcalophilus AV1934, a Classic Alkaliphile Isolated from Human Feces in 1934.

    PubMed

    Attie, Oliver; Jayaprakash, Anitha; Shah, Hardik; Paulsen, Ian T; Morino, Masato; Takahashi, Yuka; Narumi, Issay; Sachidanandam, Ravi; Satoh, Katsuya; Ito, Masahiro; Krulwich, Terry A

    2014-01-01

    Bacillus alcalophilus AV1934, isolated from human feces, was described in 1934 before microbiome studies and recent indications of novel potassium ion coupling to motility in this extremophile. Here, we report draft sequences that will facilitate an examination of whether that coupling is part of a larger cycle of potassium ion-coupled transporters. PMID:25395643

  3. 76 FR 42031 - Airworthiness Directives; 328 Support Services GmbH (Type Certificate Previously Held by AvCraft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-18

    ... (76 FR 19721). That NPRM proposed to correct an unsafe condition for the specified products. The MCAI... Regulatory Policies and Procedures (44 FR 11034, February 26, 1979); and 3. Will not have a significant... Services GmbH (Type Certificate Previously Held by AvCraft Aerospace GmbH; Fairchild Dornier GmbH;...

  4. 76 FR 19721 - Airworthiness Directives; 328 Support Services GmbH (Type Certificate Previously Held by AvCraft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-08

    ... rule'' under the DOT Regulatory Policies and Procedures (44 FR 11034, February 26, 1979); and 3. Will... Services GmbH (Type Certificate Previously Held by AvCraft Aerospace GmbH; Fairchild Dornier GmbH; Dornier Luftfahrt GmbH) Model 328-100 and -300 Airplanes AGENCY: Federal Aviation Administration (FAA), DOT....

  5. A microcosm approach to evaluate the degradation of tributyltin (TBT) by Aeromonas molluscorum Av27 in estuarine sediments.

    PubMed

    Cruz, Andreia; Henriques, Isabel; Sousa, Ana C A; Baptista, Inês; Almeida, Adelaide; Takahashi, Shin; Tanabe, Shinsuke; Correia, António; Suzuki, Satoru; Anselmo, Ana Maria; Mendo, Sónia

    2014-07-01

    Tributyltin (TBT) is a biocide extremely toxic to a wide range of organisms, which has been used for decades in antifouling paints. Despite its global ban in 2008, TBT is still a problem of great concern due to the high levels trapped in sediments. Aeromonas molluscorum Av27 is a TBT degrading bacterium that was isolated from an estuarine system. We investigated the ability and the role of this bacterium on TBT degradation in this estuarine system, using a microcosm approach in order to mimic environmental conditions. The experiment was established and followed for 150 days. Simultaneously, changes in the indigenous bacterial community structure were also investigated. The results revealed a maximum TBT degradation rate of 28% accompanied by the detection of the degradation products over time. Additionally, it was observed that TBT degradation was significantly enhanced by the presence of Av27. In addition a significantly higher TBT degradation occurred when the concentration of Av27 was higher. TBT degradation affected the bacterial community composition as revealed by the changes in the prevalence of Proteobacteria subdivisions, namely the increase of Deltaproteobacteria and the onset of Epsilonproteobacteria. However, the addition of Av27 strain did not affect the dominant phylotypes. Total bacterial number, bacterial biomass productivity, 16S rRNA gene and denaturing gradient gel electrophoresis (DGGE) analyses also indicated alterations on the bacterial community structure over time, with bacteria non-tolerant to pollutants increasing their representativeness, as, for instance, the increase of the number of Alphaproteobacteria clones from 6% in the beginning to 12% at the end of the experiment. The work herein presented confirms the potential of Av27 strain to be used in the decontamination of TBT-polluted environments.

  6. The glial cell modulators, ibudilast and its amino analog, AV1013, attenuate methamphetamine locomotor activity and its sensitization in mice.

    PubMed

    Snider, Sarah E; Vunck, Sarah A; van den Oord, Edwin J C G; Adkins, Daniel E; McClay, Joseph L; Beardsley, Patrick M

    2012-03-15

    Over 800,000 Americans abuse the psychomotor stimulant, methamphetamine, yet its abuse is without an approved medication. Methamphetamine induces hypermotor activity, and sensitization to this effect is suggested to represent aspects of the addiction process. Methamphetamine's regulation of 3'-5'-cyclic adenosine monophosphate (cAMP) levels may be partially responsible for its behavioral effects, and compounds that inhibit phosphodiesterase (PDE), the enzyme that degrades cAMP, can alter methamphetamine-induced behaviors. Methamphetamine also activates glial cells and causes a subsequent increase in pro-inflammatory cytokine levels. Modulation of glial cell activation is associated with changes in behavioral responses, and substances that oppose inflammatory activity can attenuate drug-induced behaviors. Ibudilast (aka AV411; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine), inhibits both PDE and glial pro-inflammatory activity. Ibudilast's amino analog, AV1013, modulates similar glial targets but negligibly inhibits PDE. The present study determined whether ibudilast and AV1013 would attenuate methamphetamine-induced locomotor activity and its sensitization in C57BL/6J mice. Mice were treated b.i.d. with ibudilast (1.8-13 mg/kg), AV1013 (10-56 mg/kg) or their vehicles intraperitoneally for 7 days, beginning 48 h before 5 days of daily 1-h locomotor activity tests. Each test was initiated by either a methamphetamine (3 mg/kg) or a saline injection. Ibudilast significantly (P<0.05) reduced the acute, chronic, and sensitization effects of methamphetamine's locomotor activity without significantly affecting activity by itself. AV1013 had similar anti-methamphetamine effects, suggesting that glial cell activity, by itself, can modulate methamphetamine's effects and perhaps serve as a medication target for its abuse.

  7. AV Reviews.

    ERIC Educational Resources Information Center

    Hays, Rachel, Ed.

    1990-01-01

    Reviewed are four videotapes for use in biology classrooms. Included are "The Biochemical Basis of Biology. Part 2--DNA and Protein Synthesis,""The Rocky Shores,""A Visit to the Rocky Shores," and "Our Immune System." Described are the content, cost, and availability of each video. (CW)

  8. AV Review.

    ERIC Educational Resources Information Center

    Friedstein, Harriet, Ed.

    1981-01-01

    Presents a list of the producer, catalog number, format, and price of audiovisual aids for: acids, bases, and salts; atomic structure and atoms; biochemistry; bonds; water chemistry (solutions); changes of state; and electrochemistry. Includes a separate list of names and addresses of randomly selected producers of audiovisual materials. (SK)

  9. AV Reviews.

    ERIC Educational Resources Information Center

    Hays, Rachel, Ed.

    1989-01-01

    Presents teacher comments on audiovisual materials dealing with: biotechnology applications in immunology, agriculture, and cancer research; efforts to halt the eutrophication of Lake Tahoe; and banana slugs. Availability and costs of materials are included. (RT)

  10. AV Corner.

    ERIC Educational Resources Information Center

    Berry, Donna A., Ed.

    1990-01-01

    Reviews three videotapes for physics teachers: (1) "Determination of the Newtonian Constant of Gravitation" showing the Cavendish experiment; (2) "Preview Film for RAM-Tutor Media" introducing a series of seven videocassettes covering physics; and (3) "Determination of the Velocity of Light" using a rotating mirror. (YP)

  11. COORDINATED AV.

    ERIC Educational Resources Information Center

    CLEAVES, PAUL C.; AND OTHERS

    THE INSTRUCTIONAL MATERIALS CENTER IS LOCATED IN THE LOCAL HIGH SCHOOL AND SUPPLIES ALL SCHOOLS IN THE AREA. AUDIOVISUAL EQUIPMENT ORDERS, AFTER SELECTIONS ARE MADE BY THE CLASSROOM TEACHER, ARE PROCESSED BY THE CENTER, CONFIRMED AND DELIVERED BY TRUCK THREE TIMES EACH WEEK. EACH SCHOOL HAS A BUILDING COORDINATOR WHO CHECKS THE ORDERS INTO THE…

  12. AV Corner.

    ERIC Educational Resources Information Center

    Berry, Donna A., Ed.

    1990-01-01

    Reviewed are two 35MM slide sets "Halley's Comet Revealed" and "Supernova 1987A"; and a videotape entitled "Experiments; Physics Level 1. Magnetic Fields." Features, availability, strengths and weaknesses are discussed. (CW)

  13. Transient AV Block as a Hemodynamic Complication of the Influenza A Virus: A Case Report.

    PubMed

    Rivera-Guzmán, Norwin; Del Olmo-Arroyo, Francisco; Robles-Arías, Carlos M; Rodríguez-Cintrón, William

    2016-09-01

    Influenza virus causes annual epidemics of respiratory illness characterized by sudden onset of fever, malaise, myalgias, headache, cough, and other respiratory complains. Each year in the United States, it is estimated that this debilitating respiratory illness accounts for 294,000 excess hospitalizations and 36,000 attributable deaths. Epidemiological studies describe increased cardiovascular mortality during influenza seasons. Cardiovascular involvement in acute influenza infection can occur through direct effects of the virus on the myocardium or through exacerbation of existing cardiovascular disease. The purpose of this report is to document a transient atrioventricular (AV) block with hemodynamic compromise after infection with the influenza virus in a patient with underlying cardiac disease without myocarditis. PMID:27623145

  14. Introduction to COFFE: The Next-Generation HPCMP CREATE-AV CFD Solver

    NASA Technical Reports Server (NTRS)

    Glasby, Ryan S.; Erwin, J. Taylor; Stefanski, Douglas L.; Allmaras, Steven R.; Galbraith, Marshall C.; Anderson, W. Kyle; Nichols, Robert H.

    2016-01-01

    HPCMP CREATE-AV Conservative Field Finite Element (COFFE) is a modular, extensible, robust numerical solver for the Navier-Stokes equations that invokes modularity and extensibility from its first principles. COFFE implores a flexible, class-based hierarchy that provides a modular approach consisting of discretization, physics, parallelization, and linear algebra components. These components are developed with modern software engineering principles to ensure ease of uptake from a user's or developer's perspective. The Streamwise Upwind/Petrov-Galerkin (SU/PG) method is utilized to discretize the compressible Reynolds-Averaged Navier-Stokes (RANS) equations tightly coupled with a variety of turbulence models. The mathematics and the philosophy of the methodology that makes up COFFE are presented.

  15. Geologic Mapping of the Av-14 Urbinia Quadrangle of Asteroid 4 Vesta

    NASA Astrophysics Data System (ADS)

    Mest, S. C.; Yingst, R. A.; Williams, D. A.; Garry, W. B.; Pieters, C. M.; Jaumann, R.; Buczkowski, D. L.; Sykes, M. V.; Wyrick, D. Y.; Schenk, P. M.; Russell, C. T.; Raymond, C. A.; Neukum, G.; Schmedemann, N.; Roatsch, T.; Preusker, F.; Ammannito, E.

    2012-04-01

    NASA's Dawn spacecraft is providing unprecedented views of the surface of 4 Vesta since it went into orbit in July 2011. Dawn is actively gathering an abundance of image, spectral and topographic data to characterize the geology, composition, shape and internal structure of the ~560-km-diameter asteroid. Geologic mapping of Vesta's surface is being undertaken at the global and regional scales by subdividing Vesta into 15 quadrangles. Here, we report the mapping results for quadrangle Av-14, the Urbinia quadrangle of Vesta, derived from data acquired during the High Altitude Mapping Orbit (HAMO) and Survey orbit. Base materials for mapping include HAMO-derived monochrome (clear filter) Framing Camera (FC) mosaic (~70 m/pixel and a Digital Terrain Model (DTM) derived from Survey orbit FC data (450 m/pixel). We also use FC color ratio images (~250 m/pixel) from Survey orbit and Visible and InfraRed (VIR) hyperspectral images from Survey (700 m/pixel) and HAMO (200 m/pixel) orbits to provide information on surface composition and refine unit boundaries. The Av-14 Quadrangle covers the region between 21°-66°S latitude and 270°-360°E longitude. The quadrangle is named after crater Urbinia (D=24 km; 30°S, 276°E), which displays an ejecta blanket with moderate albedo and a smooth, lightly cratered surface. The map area is dominated by moderately cratered equatorial terrains and lightly cratered, but highly deformed, southern terrains. The topographic gradient of the map area is declined toward the south from the more elevated equatorial terrain to the relatively lower interior of the Rheasilivia impact basin. Av-14 contains two dominant terrains - (1) intermediately-cratered equatorial terrain bearing flat-floored, E-W-trending troughs, and (2) relatively lightly-cratered south polar terrain, which contains the Rheasilvia impact basin and related terrains. The northern part of the quadrangle is covered by the moderately cratered equatorial ridge-and-trough terrain

  16. Influence of apolipoprotein A-V on hepatocyte lipid droplet formation.

    PubMed

    Gao, Xuan; Forte, Trudy M; Ryan, Robert O

    2012-10-19

    Apolipoprotein A-V (apoA-V) is postulated to modulate intra-hepatic triglyceride (TG) trafficking. Stably transfected McA-RH7777 hepatocarcinoma cells expressing human apoA-V displayed enhanced neutral lipid staining while conditioned media from these cells had 40±8% less TG than cells transfected with a control vector. To obtain homogeneous cell lines expressing different amounts of apoA-V, a strategy of clonal selection was pursued. Immunoblot analysis of two distinct apoA-V stable cell lines yielded one that expresses low amounts of apoA-V and another that expresses higher amounts. Confocal fluorescence microscopy of control cells and cells expressing low levels of apoA-V had similar numbers of lipid droplets while cells expressing higher amounts of apoA-V had twice as many lipid droplets, on average. Thus, apoA-V expression promotes lipid droplet accumulation in these cells.

  17. The dependence of the AV prior for SN Ia on host mass and disc inclination

    NASA Astrophysics Data System (ADS)

    Holwerda, B. W.; Keel, W. C.; Kenworthy, M. A.; Mack, K. J.

    2015-08-01

    Type Ia supernovae (SNe Ia) are used as `standard candles' for cosmological distance scales. To fit their light-curve shape-absolute luminosity relation, one needs to assume an intrinsic colour and a likelihood of host galaxy extinction or a convolution of these, a colour distribution prior. The host galaxy extinction prior is typically assumed to be an exponential drop-off for the current supernova programmes (P(A_V) ∝ e^{-A_V/τ_0}). We explore the validity of this prior using the distribution of extinction values inferred when two galaxies accidentally overlap (an occulting galaxy pair). We correct the supernova luminosity distances from the SDSS-III supernova projects (SDSS-SN) by matching the host galaxies to one of three templates from occulting galaxy pairs based on the host galaxy mass and the AV-bias-prior-scale (τ0) relation from Jha et al. We find that introducing an AV prior that depends on host mass results in lowered luminosity distances for the SDSS-SN on average but it does not reduce the scatter in individual measurements. This points, in our view, to the need for many more occulting galaxy templates to match to SN Ia host galaxies to rule out this possible source of scatter in the SN Ia distance measurements. We match occulting galaxy templates based on both mass and projected radius and we find that one should match by stellar mass first with radius as a secondary consideration. We discuss the caveats of the current approach: the lack of enough radial coverage, the small sample of priors (occulting pairs with HST data), the effect of gravitationally interacting as well as occulting pairs, and whether an exponential distribution is appropriate. Our aim is to convince the reader that a library of occulting galaxy pairs observed with HST will provide sufficient priors to improve (optical) SN Ia measurements to the next required accuracy in cosmology.

  18. Independent effects of apolipoprotein AV and apolipoprotein CIII on plasma triglyceride concentrations

    SciTech Connect

    Baroukh, Nadine N.; Bauge, Eric; Akiyama, Jennifer; Chang, Jessie; Fruchart, Jean-Charles; Rubin, Edward M.; Fruchart, Jamila; Pennacchio, Len A.

    2003-08-15

    Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are negatively and positively correlated with APOA5 and APOC3 expression, respectively. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. The evolutionary relationship among these two apolipoprotein genes and their close proximity on human chromosome 11q23 have largely precluded the determination of their relative contribution to altered Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are negatively and positively correlated with APOA5 and APOC3 expression, respectively. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. The evolutionary relationship among these two apolipoprotein genes and their close proximity on human chromosome 11q23 have largely precluded the determination of their relative contribution to altered triglycerides. To overcome these confounding factors and address their relationship, we generated independent lines of mice that either over-expressed (''double transgenic'') or completely lacked (''double knockout'') both apolipoprotein genes. We report that both ''double transgenic'' and ''double knockout'' mice display intermedia tetriglyceride concentrations compared to over-expression or deletion of either gene alone. Furthermore, we find that human ApoAV plasma protein levels in the ''double transgenic'' mice are approximately 500-fold lower than human ApoCIII levels, supporting ApoAV is a potent triglyceride modulator despite its low concentration. Together, these data indicate

  19. The risk assessment of heavy metals in Futian mangrove forest sediment in Shenzhen Bay (South China) based on SEM-AVS analysis.

    PubMed

    Chai, Minwei; Shen, Xiaoxue; Li, Ruili; Qiu, Guoyu

    2015-08-15

    The risks of heavy metal in Futian mangrove forest sediment were assessed using the acid-volatile sulfide (AVS) and simultaneously extracted metals (SEM) methods. The results indicated that AVS distributions were more variable than the SEM distributions at all 16 sampling sites. The positive correlation between AVS and SEM indicated that their similar formative and existing conditions and that AVS acted as an important carrier for SEM. The major SEM component was Zn (69.7.3-94.2%), whereas the Cd contribution (the most toxic metal present) to SEM was no more than 1%. The possible adverse effects caused by heavy metals at ten sampling sites may be due to higher levels of SEMs, rather than AVSs. The total organic carbon (TOC) was an important metal-binding phase in the sediments. Taking into account the TOC concentration, there were no adverse effects due to heavy metals in any of the Futian mangrove forest sediments. PMID:26028168

  20. The risk assessment of heavy metals in Futian mangrove forest sediment in Shenzhen Bay (South China) based on SEM-AVS analysis.

    PubMed

    Chai, Minwei; Shen, Xiaoxue; Li, Ruili; Qiu, Guoyu

    2015-08-15

    The risks of heavy metal in Futian mangrove forest sediment were assessed using the acid-volatile sulfide (AVS) and simultaneously extracted metals (SEM) methods. The results indicated that AVS distributions were more variable than the SEM distributions at all 16 sampling sites. The positive correlation between AVS and SEM indicated that their similar formative and existing conditions and that AVS acted as an important carrier for SEM. The major SEM component was Zn (69.7.3-94.2%), whereas the Cd contribution (the most toxic metal present) to SEM was no more than 1%. The possible adverse effects caused by heavy metals at ten sampling sites may be due to higher levels of SEMs, rather than AVSs. The total organic carbon (TOC) was an important metal-binding phase in the sediments. Taking into account the TOC concentration, there were no adverse effects due to heavy metals in any of the Futian mangrove forest sediments.

  1. Activation of defense response pathways by OGs and Flg22 elicitors in Arabidopsis seedlings

    PubMed Central

    Denoux, Carine; Galletti, Roberta; Mammarella, Nicole; Gopalan, Suresh; Werck, Danièle; De Lorenzo, Giulia; Ferrari, Simone; Ausubel, Frederick M.; Dewdney, Julia

    2010-01-01

    We carried out transcriptional profiling analysis in 10 day-old Arabidopsis thaliana seedlings treated with oligogalacturonides (OGs), oligosaccharides derived from the plant cell wall, or the bacterial flagellin peptide Flg22, general elicitors of the basal defense response in plants. Although detected by different receptors, both OGs and Flg22 trigger a fast and transient response that is both similar and comprehensive, and characterized by activation of early stages of multiple defense signaling pathways, particularly JA-associated processes. However, the response to Flg22 is stronger in both the number of genes differentially expressed and the amplitude of change. The magnitude of induction of individual genes is in both cases dose dependent, but even at very high concentrations, OGs do not induce a response that is as comprehensive as that seen with Flg22. While high doses of either microbe-associated molecular pattern (MAMP) elicit a late response that includes activation of senescence processes, SA-dependent secretory pathway genes and PR1 expression are substantially induced only by Flg22. These results suggest a lower threshold for activation of early responses than for sustained or SA-mediated late defenses. Expression patterns of aminocyclopropane-carboxylate synthase genes also implicate ethylene biosynthesis in regulation of the late innate immune response. PMID:19825551

  2. Sediment nickel bioavailability and toxicity to estuarine crustaceans of contrasting bioturbative behaviors--an evaluation of the SEM-AVS paradigm.

    PubMed

    Chandler, G Thomas; Schlekat, Christian E; Garman, Emily R; He, Lijian; Washburn, Katherine M; Stewart, Emily R; Ferry, John L

    2014-11-01

    Robust sediment quality criteria require chemistry and toxicity data predictive of concentrations where population/community response should occur under known geochemical conditions. Understanding kinetic and geochemical effects on toxicant bioavailability is key, and these are influenced by infaunal sediment bioturbation. This study used fine-scale sediment and porewater measurement of contrasting infaunal effects on carbon-normalized SEM-AVS to evaluate safe or potentially toxic nickel concentrations in a high-binding Spartina saltmarsh sediment (4%TOC; 35-45 μmol-S2-·g(-1)). Two crustaceans producing sharply contrasting bioturbation--the copepod Amphiascus tenuiremis and amphipod Leptocheirus plumulosus--were cultured in oxic to anoxic sediments with SEM[Ni]-AVS, TOC, porewater [Ni], and porewater DOC measured weekly. From 180 to 750 μg-Ni·g(-1) sediment, amphipod bioturbation reduced [AVS] and enhanced porewater [Ni]. Significant amphipod uptake, mortality, and growth-depression occurred at the higher sediment [Ni] even when [SEM-AVS]/foc suggested acceptable risk. Less bioturbative copepods produced higher AVS and porewater DOC but exhibited net population growth despite porewater [Ni] 1.3-1.7× their aqueous [Ni] LOEC. Copepod aqueous tests with/without dissolved organic matter showed significant aqueous DOC protection, which suggests porewater DOC attenuates sediment Ni toxicity. The SEM[Ni]-AVS relationship was predictive of acceptable risk for copepods at the important population-growth level.

  3. Ectopic expression of ubiquitin-conjugating enzyme gene from wild rice, OgUBC1, confers resistance against UV-B radiation and Botrytis infection in Arabidopsis thaliana

    SciTech Connect

    Jeon, En Hee; Pak, Jung Hun; Kim, Mi Jin; Kim, Hye Jeong; Shin, Sang Hyun; Lee, Jai Heon; Kim, Doh Hoon; Oh, Ju Sung; Oh, Boung-Jun; Jung, Ho Won; Chung, Young Soo

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer We isolated a novel E2 ubiquitin-conjugating enzyme from leaves of wild rice plants. Black-Right-Pointing-Pointer The OgUBC1 was highly expressed in leaves treated with SA and UV-B radiation. Black-Right-Pointing-Pointer The recombinant OgUBC1 has an enzymatic activity of E2 in vitro. Black-Right-Pointing-Pointer The OgUBC1 could protect disruption of plant cells by UV-B radiation. Black-Right-Pointing-Pointer OgUBC1 confers disease resistance and UV-B tolerance in transgenic Arabidopsis plants. -- Abstract: A previously unidentified gene encoding ubiquitin-conjugating enzyme was isolated from leaves of wild rice plant treated with wounding and microbe-associated molecular patterns. The OgUBC1 gene was composed of 148 amino acids and contained a typical active site and 21 ubiquitin thioester intermediate interaction residues and 4 E3 interaction residues. Both exogenous application of salicylic acid and UV-B irradiation triggered expression of OgUBC1 in leaves of wild rice. Recombinant OgUBC1 proteins bound to ubiquitins in vitro, proposing that the protein might act as E2 enzyme in planta. Heterologous expression of the OgUBC1 in Arabidopsis thaliana protected plants from cellular damage caused by an excess of UV-B radiation. A stable expression of chalcone synthase gene was detected in leaves of OgUBC1-expressing Arabidopsis, resulting in producing higher amounts of anthocyanin than those in wild-type Col-0 plants. Additionally, both pathogenesis-related gene1 and 5 were transcribed in the transgenic Arabidopsis in the absence of pathogen infection. The OgUBC1-expressing plants were resistant to the infection of Botrytis cinerea. Taken together, we suggested that the OgUBC1 is involved in ubiquitination process important for cellular response against biotic and abiotic stresses in plants.

  4. Modularization and Validation of FUN3D as a CREATE-AV Helios Near-Body Solver

    NASA Technical Reports Server (NTRS)

    Jain, Rohit; Biedron, Robert T.; Jones, William T.; Lee-Rausch, Elizabeth M.

    2016-01-01

    Under a recent collaborative effort between the US Army Aeroflightdynamics Directorate (AFDD) and NASA Langley, NASA's general unstructured CFD solver, FUN3D, was modularized as a CREATE-AV Helios near-body unstructured grid solver. The strategies adopted in Helios/FUN3D integration effort are described. A validation study of the new capability is performed for rotorcraft cases spanning hover prediction, airloads prediction, coupling with computational structural dynamics, counter-rotating dual-rotor configurations, and free-flight trim. The integration of FUN3D, along with the previously integrated NASA OVERFLOW solver, lays the ground for future interaction opportunities where capabilities of one component could be leveraged with those of others in a relatively seamless fashion within CREATE-AV Helios.

  5. A Comparison of the AVS-9 and the Panoramic Night Vision Goggle During Rotorcraft Hover and Landing

    NASA Technical Reports Server (NTRS)

    Szoboszlay, Zoltan; Haworth, Loran; Simpson, Carol; Rutkowski, Michael (Technical Monitor)

    2001-01-01

    The purpose of this flight test was to measure any differences in pilot-vehicle performance and pilot opinion between the use of the current generation AVS-9 Night Vision Goggle and one variant of the prototype Panoramic Night Vision Goggle (the PNV.GII). The PNVGII has more than double the horizontal field-of-view of the AVS-9, but reduced image quality. The flight path of the AH-1S helicopter was used as a measure of pilot-vehicle performance. Also recorded were subjective measures of flying qualities, physical reserves of the pilot, situational awareness, and display usability. Pilot comment and data indicate that the benefits of additional FOV with the PNVGIIs are to some extent negated by the reduced image quality of the PNVGIIs.

  6. The GRB Detected by Avs-F Apparatus Onboard Coronas-F Satellite in 2001-2005 Years

    NASA Astrophysics Data System (ADS)

    Arkhangelskaja, Irene V.; Arkhangelskiy, Andrey I.; Glyanenko, Alexander S.; Kotov, Yuri D.; Kuznetsov, Sergey N.

    2008-09-01

    The AVS-F apparatus onboard CORONAS-F satellite operated from 31.07.2001 up to 06.12.2005. This instrument constitutes the system for data processing from two detectors: SONG-D (CsI(TI) detector Ø200 mm and 100 mm height, fully surrounded by plastic anticoincidence shield) and XSS-1 (CdTe detector 4.9 mm × 4.9 mm). Despite of this satellite was Solar-oriented, over 30 GRB during August 2001 - December 2005 period were registered in the energy band of ~0.1-20 MeV by preliminary data analysis. The characteristics of GRB detected by AVS-F device are discussed.

  7. The Dural AV-Fistula (DAVF), the Most Frequent Acquired Vascular Malformation of the Central Nervous System (CNS).

    PubMed

    Wanke, I; Rüfenacht, D A

    2015-10-01

    Acquired arteriovenous malformations, such as is the case with dural arteriovenous fistulae (DAVF), are the consequence of a pathological new arterial ingrowth into venous spaces that reaches directly the venous lumen, without interposition of a capillary network, thereby creating an AV-shunt.The following concise text will provide elements in regards to diagnosis, indication for treatment discussion and choice of endovascular treatment (EVT) method. PMID:26308245

  8. Geosciences Information for Teachers (GIFT) Workshops held in Conjunction with Alexander von Humboldt (AvH) EGU Conferences

    NASA Astrophysics Data System (ADS)

    Laj, Carlo; Cifelli, Francesca

    2015-04-01

    The Alexander von Humboldt Conference Series of the European Geosciences Union are a series of meetings held outside of Europe, in particular in South America, Africa or Asia, on selected topics of geosciences with a socio-economic impact for regions on these continents, jointly organised with the scientists and their institutes and the institutions of these regions. Given the increasing success of the GIFT workshops held in conjunction with the General Assemblies, since 2010 EGU has also developed a series of GIFT workshops held in conjunction with AvH conferences. Associated GIFT workshops were held in Merida, Yucatan, on the theme of Climate Change, Natural Hazards and Societies (March 2010), then in Penang, Malaysia (June 2011) on the theme of Ocean Acidification, in November 2012 in Cusco (Peru) on the theme of Natural Disasters, Global Change and the Preservation of World Heritage Sites, finally in Istanbul (March 2014) on "High Impact Natural Hazards Related to the Euro-Mediterranean Region. The next GIFT workshop is already planned for October 2015 in Adis Ababa (Ethiopia) on the theme "Water". In each case, the GIFT workshop was held on the last two days of the AvH conference and reunited 40-45 teachers from the nation where the AvH was held. Keynote speakers from AvH were speakers to the GIFT workshops which also included hands-on activities animated by sciences educators. These GIFT workshops represented the first workshops specifically aimed at teachers held in the country, and therefore represents a significant Earth Sciences contribution to secondary education in non European countries.

  9. Geosciences Information for Teachers (GIFT) Workshops held in Conjunction with Alexander von Humboldt (AvH) EGU Conferences.

    NASA Astrophysics Data System (ADS)

    Laj, C. E.; Cifelli, F.

    2014-12-01

    Given the increasing success of the GIFT workshops held in conjunction with the General Assemblies, since 2010 EGU has also developed a series of GIFT workshops held in conjunction with AvH conferences. The Alexander von Humboldt Conference Series of the European Geosciences Union are a series of meetings held outside of Europe, in particular in South America, Africa or Asia, on selected topics of geosciences with a socio-economic impact for regions on these continents, jointly organised with the scientists and their institutes and the institutions of these regions. Associated GIFT workshops were held in Merida, Yucatan, on the theme of Climate Change, Natural Hazards and Societies (March 2010), then in Penang, Malaysia (June 2011) on the theme of Ocean Acidification, in November 2012 in Cusco (Peru) on the theme of Natural Disasters, Global Change and the Preservation of World Heritage Sites, finally in Istanbul (March 2014) on "High Impact Natural Hazards Related to the Euro-Mediterranean Region. The next GIFT workshop is already planned for October 2015 in Adis Ababa (Ethiopia) on the theme "Water". In each case, the GIFT workshop was held on the last two days of the AvH conference and reunited 40-45 teachers from the nation where the AvH was held. Keynote speakers from AvH were speakers to the GIFT workshops which also included hands-on activities animated by sciences educators. In 3 cases of the 4 cases, these GIFT workshops represented the first workshop specifically aimed at teachers held in the country, and therefore represents a significant Earth Sciences contribution to secondary education in non European countries.

  10. Assessment of heavy metals pollution using AVS-SEM and fractionation techniques in Edku Lagoon sediments, Mediterranean Sea, Egypt.

    PubMed

    El Zokm, Gehan M; Okbah, Mohamed A; Younis, Alaa M

    2015-01-01

    A method is presented to evaluate the fractionation of metals (Fe, Zn, Cu, Pb, Cd and Ni), acid volatile sulfide (AVS) and simultaneously extracted metals (SEM) in Edku lagoon sediments. Thirteen sediment samples were collected from the study area in the period of 2010-2011 to assess the potential bioavailability and toxicity of the selected metals. According to classification of the Interim Sediment Quality Quidelines (ISQG), five stations near the drains exhibited 10% toxic probability. The high AVS and low ∑SEM ranges in Summer were identified as 6-138 and 0.86-3.3 µmol g(-1) dry wet, respectively which are referring to the low mobility of heavy metals in this season and vice versa for winter (2.5-23.9 and 1.16-3.82 µmol g(-1) dry wet, respectively). According to the evaluation of USEPA, all sediment samples showed ∑SEM/AVS < 1 and ΣSEM-AVS < 0 and this indicates that Edku lagoon sediments didn't cause any adverse effects. Meanwhile, the calculations of the global contamination factor (GCF) and the individual contamination factors (ICF) using fractionation technique gave values of 111.644 and 84.555 in El Bosily drain and station 1 near the cages of fish farm, respectively due to possible contamination. Interestingly, the collected data refer that the mobility and bioavailability of heavy metals in Edku lagoon sediments posed a low risk of adverse biological effects due to cadmium, copper, lead, nickel and zinc in all evaluated stations.

  11. The glial cell modulator and phosphodiesterase inhibitor, AV411 (ibudilast), attenuates prime- and stress-induced methamphetamine relapse

    PubMed Central

    Beardsley, Patrick M.; Shelton, Keith L.; Hendrick, Elizabeth; Johnson, Kirk W.

    2010-01-01

    Stress and renewed contact with drug (a “slip”) have been linked to persisting relapse of methamphetamine abuse. Human brain microglial activation has been linked with methamphetamine abuse, and inhibitors of glial cell activation, certain phosphodiesterase (PDE) inhibitors, and glial cell derived neurotrophic factor (GDNF) have been reported to modulate drug abuse effects. Our objective was to determine whether the glial cell attenuator, 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine (AV411, ibudilast), a non-selective PDE inhibitor and promoter of GDNF, could reduce stress- and methamphetamine prime-induced reinstatement of methamphetamine-seeking behavior. Male Long-Evans hooded rats were trained to lever press reinforced with 0.1 mg/kg i.v. methamphetamine infusion according to fixed-ratio 1 (FR1) reinforcement schedules during daily, 2-h experimental sessions. After performance had stabilized, lever pressing was extinguished for 12 consecutive sessions and doses of 0 (vehicle), 2.5 and 7.5 mg/kg AV411 were then administered intraperitoneally b.i.d. on the last two days of extinction and then once on the testday to separate groups of 12 rats. During testing, the rats were given 15 min of intermittent footshock or a 1 mg/kg i.p. methamphetamine prime followed by a 2-h reinstatement test session. AV411 significantly reduced response levels of footshock-induced (2.5 and 7.5 mg/kg) and prime-induced (7.5 mg/kg) reinstatement of extinguished methamphetamine-maintained responding. AV411 has properties consistent with the ability to attenuate relapse precipitated by stress and methamphetamine “slips” during abstinence. These results thus reinforce interest in atypical neurobiological mechanisms which could be exploited for developing novel medications for treating drug abuse disorders. PMID:20399770

  12. Axial vascularization of a large volume calcium phosphate ceramic bone substitute in the sheep AV loop model.

    PubMed

    Beier, Justus P; Horch, Raymund E; Hess, Andreas; Arkudas, Andreas; Heinrich, Johanna; Loew, Johanna; Gulle, Heinz; Polykandriotis, Elias; Bleiziffer, Oliver; Kneser, Ulrich

    2010-03-01

    Vascularization still remains an obstacle to engineering of bone tissue with clinically relevant dimensions. Our aim was to induce axial vascularization in a large volume of a clinically approved biphasic calcium phosphate ceramic by transferring the arteriovenous (AV) loop approach to a large animal model. HA/beta-TCP granula were mixed with fibrin gel for a total volume of 16 cm(3), followed by incorporation into an isolation chamber together with an AV loop. The chambers were implanted into the groins of merino sheep and the development of vascularization was monitored by sequential non-invasive magnetic resonance imaging (MRI). The chambers were explanted after 6 and 12 weeks, the pedicle was perfused with contrast agent and specimens were subjected to micro-computed tomography (micro-CT) scan and histological analysis. Sequential MRI demonstrated a significantly increased perfusion in the HA/beta-TCP matrices over time. Micro-CT scans and histology confirmed successful axial vascularization of HA/beta-TCP constructs. This study demonstrates, for the first time, successful axial vascularization of a clinically approved bone substitute with a significant volume in a large animal model by means of a microsurgically created AV loop, thus paving the way for the first microsurgical transplantation of a tissue-engineered, axially vascularized bone with clinically relevant dimensions.

  13. Effects of hypoxia and ischaemia on coronary vascular resistance, A-V node conduction and S-A node excitation.

    PubMed

    Berne, R M; Belardinelli, L

    1985-01-01

    Hypoxia and ischaemia produce relaxation of the vascular smooth muscle of the resistance vessels in the myocardium. A low pH may contribute to the arteriolar dilatation but cannot account for the major response. In all likelihood the reduced pO2 acts indirectly by release of a vasodilator mediator rather than by a direct effect on the vascular muscle. Potassium release may account for a transient component of the vasodilation, but it appears that a major factor is the release of adenosine from the ischaemic tissue. Adenosine also appears to be responsible for slowing of the sinus rate and impaired A-V conduction in myocardial ischaemia. These observations are of clinical significance because hypoxia-induced A-V block, such as may occur in inferior myocardial infarction, can be abolished by an adenosine antagonist such as aminophylline. In contrast, adenosine is also useful in the treatment of some cardiac arrhythmias. Supraventricular tachycardia, in which the A-V node is involved in the re-entrant pathway, is readily abolished in humans by the intravenous administration of small doses of adenosine.

  14. Coastal surface sediment quality assessment in Leizhou Peninsula (South China Sea) based on SEM-AVS analysis.

    PubMed

    Li, Feng; Lin, Jin-qin; Liang, Yan-yan; Gan, Hua-yang; Zeng, Xiang-yun; Duan, Zhi-peng; Liang, Kai; Liu, Xing; Huo, Zhen-hai; Wu, Chang-hua

    2014-07-15

    Surface sediments from the coastal area of the Leizhou Peninsula in the South China Sea were collected and analyzed and the potential ecological risks in the area were assessed based on acid-volatile sulfide (AVS) model. The AVS levels are between 0.109 and 55.6 μmol g(-1), with the average at 4.45 μmol g(-1). The high AVS-concentration zones include the aquaculture areas of Liusha Bay and the densely populated areas of Zhanjiang Bay. The simultaneously extracted metals (SEM) range from 0.026 μmol g(-1) to 8.61 μmol g(-1), with the average at 0.843 μmol g(-1). Most of high SEM-concentration stations were located in ports or aquaculture zones. Most of the coastal surface sediments of the Leizhou Peninsula (90%) had no adverse biological effects according to the criterion proposed by USEPA (2005); while adverse effects were uncertain in some stations (8%); even in 2 stations (2%) adverse biological effects may be expected.

  15. Videos for Science Communication and Nature Interpretation: The TIB|AV-Portal as Resource.

    NASA Astrophysics Data System (ADS)

    Marín Arraiza, Paloma; Plank, Margret; Löwe, Peter

    2016-04-01

    Scientific audiovisual media such as videos of research, interactive displays or computer animations has become an important part of scientific communication and education. Dynamic phenomena can be described better by audiovisual media than by words and pictures. For this reason, scientific videos help us to understand and discuss environmental phenomena more efficiently. Moreover, the creation of scientific videos is easier than ever, thanks to mobile devices and open source editing software. Video-clips, webinars or even the interactive part of a PICO are formats of scientific audiovisual media used in the Geosciences. This type of media translates the location-referenced Science Communication such as environmental interpretation into computed-based Science Communication. A new way of Science Communication is video abstracting. A video abstract is a three- to five-minute video statement that provides background information about a research paper. It also gives authors the opportunity to present their research activities to a wider audience. Since this kind of media have become an important part of scientific communication there is a need for reliable infrastructures which are capable of managing the digital assets researchers generate. Using the reference of the usecase of video abstracts this paper gives an overview over the activities by the German National Library of Science and Technology (TIB) regarding publishing and linking audiovisual media in a scientifically sound way. The German National Library of Science and Technology (TIB) in cooperation with the Hasso Plattner Institute (HPI) developed a web-based portal (av.tib.eu) that optimises access to scientific videos in the fields of science and technology. Videos from the realms of science and technology can easily be uploaded onto the TIB|AV Portal. Within a short period of time the videos are assigned a digital object identifier (DOI). This enables them to be referenced, cited, and linked (e.g. to the

  16. Comparative assessment of an Og4C3 ELISA and an ICT filariasis test: a study of Myanmar migrants in Thailand.

    PubMed

    Nuchprayoon, Surang; Porksakorn, Chantima; Junpee, Alisa; Sanprasert, Vivornpun; Poovorawan, Yong

    2003-12-01

    Detection of circulating filarial antigen has now emerged as an alternative method for the diagnosis of bancroftian filariasis. We compared two antigen detection assays, an Og4C3 ELISA and an ICT (immunochromatography) Filariasis test, for the diagnosis of Wuchereria bancrofti infections in migrant Myanmar workers in Tak province, Western Thailand. A total of 337 Myanmars participated in this study. The microfilarial rate was 3.3%. The Og4C3 ELISA could detect 19.1% of bancroftian filariasis while the ICT test detected 12.7%. Both antigen assays could detect all microfilaremics. The Og4C3 ELISA detected 14.8% of amicrofilaremics while the ICT test identified 8.1%. Those who were positive for the ICT test were also positive by the Og4C3 ELISA. Those Og4C3 positive cases, that were ICT negative (ICT-ve/Og4C3+ve) had statistically significant (p < 0.05, unpaired t-test) lower Og4C3 antigen levels (409.5 units, range 117-2,389) than those that were ICT positive (ICT+ve/Og4C3+ve) (5,252.0 units, range 130-28,062). Our results emphasize the problem of bancroftian filariasis in Myanmar migrants working in Thailand. Close monitoring and control of this disease in Myanmar migrants are of public health importance. Antigen detection systems are promising tools for the surveillance of bancroftian filariasis. PMID:15198343

  17. [Hemodynamic benefits of AV interval adjustment and heart rate increase during exercise in dual-chamber pacing as determined by Doppler].

    PubMed

    Sancho-Tello, M J; Salvador, A; Olagüe, J

    1990-01-01

    In order to determine the relative significance of ventricular rate increase and AV delay on exercise cardiac output, we have studied 10 patients (8 male and 2 female, 16-59 years) with complete chronic heart block treated with AV sequential pacing. Cardiac output variations (delta CO) were estimated by pulsed Doppler comparisons of the aortic flow velocity in the supine position, at rest and during bicycle exercise. The following pacing programs were tested: DDD with AV intervals of 50, 100 and 150 ms (DDD50 o DDDD100, DDD150), VVI at 70 ppm (VVI70), and VVI at the maximal available rate in this pacing mode-113 or 130 ppm depending on the PM type (VVIM). Exercise measurements in DDD mode were taken when that rate was reached. The delta CO was calculated as a percent change of the product flow velocity integral x heart rate, from that obtained with VVI70 mode at rest. At rest, the delta CO obtained with DDD pacing was 20.4 +/- 14.7% and the optimal AV delay was 50 ms in 1 patient, 100 ms in 3 patients and 150 ms in six. During exercise, the delta CO was higher in DDD and VVIM modes (82.0 +/- 30.8% and 56.2 +/- 37.6%, respectively; p less than 0.01) than in VVI70 mode (20.4 +/- 10.4%; p less than 0.005), the greatest delta CO was reached at DDD mode in 8 out of 10 patients (p less than 0.03). The optimal AV delays were 50 ms in 5 patients, 100 ms in 4 patients and 150 ms in one. Thus, DDD pacing with the optimal AV delay seems to obtain greater haemodynamic benefits during exercise than does rate-responsive pacing; the optimal exercise AV delay varies from patient to patient and is usually less than 150 ms. PMID:2236802

  18. Protective effect of AVS073, a polyherbal formula, against UVA-induced melanogenesis through a redox mechanism involving glutathione-related antioxidant defense

    PubMed Central

    2013-01-01

    Background Ayurved Siriraj Brand Wattana formula (AVS073), a Thai herbal formula, has traditionally been used for health promotion and prevention of age-related problems. Ultraviolet A (UVA) is recognized to play a vital role in stimulation of melanin synthesis responsible for abnormal skin pigmentation possibly mediated by photooxidative stress. We thus aimed to study the inhibitory effect of AVS073 extracts on UVA-induced melanogenesis via a redox mechanism involving glutathione (GSH) synthesis and glutathione S-transferase (GST) using human melanoma (G361) cell culture. Methods The standardization of AVS073 extracts was carried out by TLC and UHPLC to obtain fingerprinting profiles of the formula, which identified several phenolic compounds including gallic acid (GA) in the formula. Antimelanogenic actions of AVS073 (up to 60 μg/ml) and GA (up to 10 μg/ml) were investigated by measuring tyrosinase activity and mRNA as well as melanin level in G361 cells irradiated with UVA. Moreover, antioxidant actions of the herbal formula and GA were determined by evaluating oxidant formation and modulation of GSH-related antioxidant defenses including GSH content, GST activity and mRNA level of γ-glutamate cysteine ligase catalytic (γ-GCLC) and modifier (γ-GCLM) subunit and GST. Results AVS073 extracts and GA, used as a reference compound, suppressed UVA-augmented tyrosinase activity and mRNA and melanin formation. In addition, pretreatment with AVS073 and GA was able to inhibit cellular oxidative stress, GSH depletion, GST inactivation and downregulation of γ-GCLC, γ-GCLM and GST mRNA in G361 cells exposed to UVA radiation. Conclusions AVS073 formula exerted antimelanogenic effects possibly through improving the redox state by upregulation of GSH and GST. Moreover, pharmacological activity of the polyherbal formula would be attributed to combined action of different phenolic compounds present in the formula. PMID:23826868

  19. ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis.

    PubMed

    Schaap, Frank G; Rensen, Patrick C N; Voshol, Peter J; Vrins, Carlos; van der Vliet, Hendrik N; Chamuleau, Robert A F M; Havekes, Louis M; Groen, Albert K; van Dijk, Ko Willems

    2004-07-01

    ApoAV has been discovered recently as a novel modifier of triglyceride (TG) metabolism, but the pathways involved are currently unknown. To gain insight into the function of apoAV, adenovirus-mediated gene transfer of murine apoa5 to C57Bl/6 mice was employed. The injection of low doses of Ad-apoa5 (1-5 x 10(8) plaqueforming units/mouse) dose-dependently reduced plasma very low density lipoprotein (VLDL)-TG levels. First, we evaluated whether a reduced hepatic VLDL production contributed to the TG-lowering effect. Ad-apoa5 treatment dose-dependently diminished (29-37%) the VLDL-TG production rate without affecting VLDL particle production, suggesting that apoAV impairs the lipidation of apoB. Second, Ad-apoa5 treatment dose-dependently reduced (68-88%) the postprandial hypertriglyceridemia following an intragastric fat load, suggesting that apoAV also stimulates the lipoprotein lipase (LPL)-dependent clearance of TG-rich lipoproteins. Indeed, recombinant apoAV was found to dose-dependently stimulate LPL activity up to 2.3-fold in vitro. Accordingly, intravenously injected VLDL-like TG-rich emulsions were cleared at an accelerated rate concomitant with the increased uptake of emulsion TG-derived fatty acids by skeletal muscle and white adipose tissue in Ad-apoa5-treated mice. From these data, we conclude that apoAV is a potent stimulator of LPL activity. Thus, apoAV lowers plasma TG by both reducing the hepatic VLDL-TG production rate and by enhancing the lipolytic conversion of TG-rich lipoproteins.

  20. Unified transform architecture for AVC, AVS, VC-1 and HEVC high-performance codecs

    NASA Astrophysics Data System (ADS)

    Dias, Tiago; Roma, Nuno; Sousa, Leonel

    2014-12-01

    A unified architecture for fast and efficient computation of the set of two-dimensional (2-D) transforms adopted by the most recent state-of-the-art digital video standards is presented in this paper. Contrasting to other designs with similar functionality, the presented architecture is supported on a scalable, modular and completely configurable processing structure. This flexible structure not only allows to easily reconfigure the architecture to support different transform kernels, but it also permits its resizing to efficiently support transforms of different orders (e.g. order-4, order-8, order-16 and order-32). Consequently, not only is it highly suitable to realize high-performance multi-standard transform cores, but it also offers highly efficient implementations of specialized processing structures addressing only a reduced subset of transforms that are used by a specific video standard. The experimental results that were obtained by prototyping several configurations of this processing structure in a Xilinx Virtex-7 FPGA show the superior performance and hardware efficiency levels provided by the proposed unified architecture for the implementation of transform cores for the Advanced Video Coding (AVC), Audio Video coding Standard (AVS), VC-1 and High Efficiency Video Coding (HEVC) standards. In addition, such results also demonstrate the ability of this processing structure to realize multi-standard transform cores supporting all the standards mentioned above and that are capable of processing the 8k Ultra High Definition Television (UHDTV) video format (7,680 × 4,320 at 30 fps) in real time.

  1. Finite element model for MOI applications using A-V formulation

    NASA Astrophysics Data System (ADS)

    Xuan, L.; Shanker, B.; Udpa, L.; Shih, W.; Fitzpatrick, G.

    2001-04-01

    Magneto-optic imaging (MOI) is a relatively new sensor application of an extension of bubble memory technology to NDT and produce easy-to-interpret, real time analog images. MOI systems use a magneto-optic (MO) sensor to produce analog images of magnetic flux leakage from surface and subsurface defects. The instrument's capability in detecting the relatively weak magnetic fields associated with subsurface defects depends on the sensitivity of the magneto-optic sensor. The availability of a theoretical model that can simulate the MOI system performance is extremely important for optimization of the MOI sensor and hardware system. A nodal finite element model based on magnetic vector potential formulation has been developed for simulating MOI phenomenon. This model has been used for predicting the magnetic fields in simple test geometry with corrosion dome defects. In the case of test samples with multiple discontinuities, a more robust model using the magnetic vector potential Ā and electrical scalar potential V is required. In this paper, a finite element model based on A-V formulation is developed to model complex circumferential crack under aluminum rivets in dimpled countersink.

  2. Authentication of Angelica anomala Avé-Lall cultivars through DNA barcodes.

    PubMed

    He, Yang; Hou, Pei; Fan, Gang; Song, Zhen; Arain, Saima; Shu, Hao; Tang, Ce; Yue, Qinghong; Zhang, Yi

    2012-04-01

    Angelica anomala Avé-Lall (Chuanbaizhi in Chinese) is an important medicinal plant which can be used in traditional Chinese medicines; however, there are no authentic and universal methods to differentiate this Sichuan famous-region drug of A. anomala from a large number of non-famous-region and false drugs. It has been demonstrated that DNA barcoding is a molecular diagnostic method for species identification, which uses a single standardized DNA fragment. In this study, we tested five DNA barcoding candidates (matK, ITS, ITS2, rbcL, and psbA-trnH), and we found that ITS was the best candidate to authenticate the famous-region drug of A. anomala. Moreover, through comparative analysis of these five DNA barcodes between A. anomala and Angelica dahurica, we found that ITS had the most and ITS2 had more variable regions, but the psbA-trnH, rbcL, and matK regions were identical. Hence, we suggest ITS as the DNA barcoding to identify A. anomala and A. dahurica. Moreover, we are determined to adopt the A. anomala as the accurate Latin name of Chuanbaizhi.

  3. The apolipoprotein CIII enhancer regulates both extensive histone modification and intergenic transcription of human apolipoprotein AI/CIII/AIV genes but not apolipoprotein AV.

    PubMed

    Li, Ya-Jun; Wei, Yu-Sheng; Fu, Xiang-Hui; Hao, De-Long; Xue, Zheng; Gong, Huan; Zhang, Zhu-Qin; Liu, De-Pei; Liang, Chih-Chuan

    2008-10-17

    The apolipoprotein (apo) AI/CIII/AIV/AV cluster genes are expressed at different levels in the liver and intestine. The apoCIII enhancer, a common regulatory element, regulates the tissue-specific expression of apoAI, apoCIII, and apoAIV but not apoAV. To study this regulation at the chromatin level, the histone modifications and intergenic transcription in the human apoAI/CIII/AIV/AV cluster were investigated in HepG2 and Caco-2 cells and in the livers of transgenic mice carrying the human gene cluster constructs with or without the apoCIII enhancer. We found that both the promoters and the intergenic regions of the apoAI/CIII/AIV genes were hyperacetylated and formed an open subdomain that did not include the apoAV gene. Hepatic and intestinal intergenic transcripts were identified to transcribe bidirectionally with strand preferences along the cluster. The deletion of the apoCIII enhancer influenced both histone modification and intergenic transcription in the apoAI/CIII/AIV gene region. These results demonstrate that the apoCIII enhancer contributes to the maintenance of an active chromatin subdomain of the apoAI/CIII/AIV genes, but not apoAV.

  4. Screening Analogs of β-OG Pocket Binder as Fusion Inhibitor of Dengue Virus 2

    PubMed Central

    Tambunan, Usman SF; Zahroh, Hilyatuz; Parikesit, Arli A; Idrus, Syarifuddin; Kerami, Djati

    2015-01-01

    Dengue is an infectious disease caused by dengue virus (DENV) and transmitted between human hosts by mosquitoes. Recently, Indonesia was listed as a country with the highest cases of dengue by the Association of Southeast Asian Nations. The current treatment for dengue disease is supportive therapy; there is no antiviral drug available in the market against dengue. Therefore, a research on antiviral drug against dengue is very important, especially to prevent outbreak explosion. In this research, the development of dengue antiviral is performed through the inhibition of n-octyl-β-D-glucoside (β-OG) binding pocket on envelope protein of DENV by using analogs of β-OG pocket binder. There are 828 compounds used in this study, and all of them were screened based on the analysis of molecular docking, pharmacological character prediction of the compounds, and molecular dynamics simulation. The result of these analyses revealed that the compound that can be used as an antiviral candidate against DENV is 5-(3,4-dichlorophenyl)-N-[2-(p-tolyl) benzotriazol-5-yl]furan-2-carboxamide. PMID:26617459

  5. A dual mechanism involved in membrane and nucleic acid disruption of AvBD103b, a new avian defensin from the king penguin, against Salmonella enteritidis CVCC3377.

    PubMed

    Teng, Da; Wang, Xiumin; Xi, Di; Mao, Ruoyu; Zhang, Yong; Guan, Qingfeng; Zhang, Jun; Wang, Jianhua

    2014-10-01

    The food-borne bacterial gastrointestinal infection is a serious public health threat. Defensins are evolutionarily conserved innate immune components with broad-spectrum antibacterial activity that do not easily induce resistance. AvBD103b, an avian defensin with potent activity against Salmonella enteritidis, was isolated from the stomach contents of the king penguin (Aptenodytes patagonicus). To elucidate further the antibacterial mechanism of AvBD103b, its effect on the S. enteritidis CVCC3377 cell membrane and intracellular DNA was researched. The cell surface hydrophobicity and a N-phenyl-1-naphthylamine uptake assay demonstrated that AvBD103b treatment increased the cell surface hydrophobicity and outer membrane permeability. Atomic absorption spectrometry, ultraviolet spectrophotometry, flow cytometry, and transmission electron microscopy (TEM) indicated that AvBD103b treatment can lead to the release of the cellular contents and cell death through damage of the membrane. DNA gel retardation and circular dichroism analysis demonstrated that AvBD103b interacted with DNA and intercalated into the DNA base pairs. A cell cycle assay demonstrated that AvBD103b affected cellular functions, such as DNA synthesis. Our results confirmed that AvBD103b exerts its antibacterial activity by damaging the cell membrane and interfering with intracellular DNA, ultimately causing cell death, and suggested that AvBD103b may be a promising candidate as an alternative to antibiotics against S. enteritidis. PMID:24981062

  6. A dual mechanism involved in membrane and nucleic acid disruption of AvBD103b, a new avian defensin from the king penguin, against Salmonella enteritidis CVCC3377.

    PubMed

    Teng, Da; Wang, Xiumin; Xi, Di; Mao, Ruoyu; Zhang, Yong; Guan, Qingfeng; Zhang, Jun; Wang, Jianhua

    2014-10-01

    The food-borne bacterial gastrointestinal infection is a serious public health threat. Defensins are evolutionarily conserved innate immune components with broad-spectrum antibacterial activity that do not easily induce resistance. AvBD103b, an avian defensin with potent activity against Salmonella enteritidis, was isolated from the stomach contents of the king penguin (Aptenodytes patagonicus). To elucidate further the antibacterial mechanism of AvBD103b, its effect on the S. enteritidis CVCC3377 cell membrane and intracellular DNA was researched. The cell surface hydrophobicity and a N-phenyl-1-naphthylamine uptake assay demonstrated that AvBD103b treatment increased the cell surface hydrophobicity and outer membrane permeability. Atomic absorption spectrometry, ultraviolet spectrophotometry, flow cytometry, and transmission electron microscopy (TEM) indicated that AvBD103b treatment can lead to the release of the cellular contents and cell death through damage of the membrane. DNA gel retardation and circular dichroism analysis demonstrated that AvBD103b interacted with DNA and intercalated into the DNA base pairs. A cell cycle assay demonstrated that AvBD103b affected cellular functions, such as DNA synthesis. Our results confirmed that AvBD103b exerts its antibacterial activity by damaging the cell membrane and interfering with intracellular DNA, ultimately causing cell death, and suggested that AvBD103b may be a promising candidate as an alternative to antibiotics against S. enteritidis.

  7. Geologic Mapping of the Av-8 Marcia Quadrangle of Asteroid 4 Vesta

    NASA Astrophysics Data System (ADS)

    Williams, D. A.; Hiesinger, H.; Schenk, P. M.; Jaumann, R.; Buczkowski, D. L.; McCord, T. B.; Yingst, R. A.; Garry, W. B.; Combe, J.-Ph.; Pieters, C. M.; Nathues, A.; Le Corre, L.; Reddy, V.; Roatsch, T.; Preusker, F.; Schmedemann, N.; Neukum, G.; Raymond, C. A.; Ammannito, E.; De Sanctis, M. C.

    2012-04-01

    NASA's Dawn spacecraft is spending one year in orbit of asteroid 4Vesta to characterize its geology, chemical and mineralogical composition, topography, shape, and internal structure. The Dawn Team is conducting geological mapping of the surface in the form of 15 quadrangle maps, and here we report results from the mapping of Marcia quadrangle Av-8. Mapping is based on a Framing Camera (FC) mosaic produced from High Altitude Mapping Orbit (HAMO) data with a spatial resolution of ~70 m/pixel, supplemented by a Digital Terrain Model (DTM: lateral spacing of 450 m/pixel and vertical accuracy of ~30 meters), FC color images, and Visible and InfraRed (VIR) hyperspectral images. Av-8 Marcia Quadrangle covers 144˚-216˚E longitude and ±21˚ latitude in the equatorial region of Vesta. This quadrangle is dominated by the 'Snowman' crater region, which is a low-albedo ejecta field containing impact craters Marcia, (68 km by 58 km), Calpurnia (54 km by 52 km), and Minucia (26 km by 23 km). A hill with a dark-rayed crater, named Aricia Tholus, is 42.5 km by 28 km. This quadrangle has all three of the dominant terrains found on Vesta: A heavily-cratered northern terrain with ancient troughs and grooves, an intermediately-cratered equatorial terrain bearing prominent flat-floored, E-W-trending troughs, and the relatively lightly-cratered south polar region, containing the Rheasilvia impact basin and related terrains. The low albedo ejecta field derived from the 'Snowman' craters, which we call Dark Crater Ejecta Material, mantles underlying older terrains. It has an obvious lower abundance of impact craters, indicative of a relatively younger age. A dark-rayed crater, occurring at ~14˚N, 180˚, excavates a darker unit from underneath the brighter ejecta. Images from the Low Altitude Mapping Orbit (LAMO) show dark materials exposed in the rim of crater Marcia, suggesting basaltic flows or intrusions underlie the ejecta. Bright and Dark Lobate Materials also occur in this quad

  8. Geologic Mapping of the Av-15 Rheasilvia Quadrangle of Asteroid 4 Vesta

    NASA Astrophysics Data System (ADS)

    Yingst, R. A.; Ammannito, E.; Berman, D.; De Sanctis, M. C.; Capaccioni, F.; Frigeri, A.; Jaumann, R.; Le Corre, L.; Mest, S.; Palomba, E.; Pieters, C. M.; Preusker, F.; Reddy, V.; Roatsch, T.; Russell, C. T.; Schenk, P. M.; Schmedemann, N.; Williams, D. A.; Tosi, F.; Zambon, F.

    2012-04-01

    NASA's Dawn spacecraft is spending one year in orbit around asteroid 4 Vesta to characterize its geology, chemical and mineralogical composition, topography, shape, and internal structure. The Dawn Team is conducting geological mapping of the surface in the form of one global and 15 quadrangle maps. Here we report results from the mapping of Rheasilvia quadrangle Av-15. Mapping is based on a Framing Camera (FC) mosaic produced from High Altitude Mapping Orbit (HAMO) data with a spatial resolution of ~70 m/pixel, supplemented by a Digital Terrain Model (DTM: lateral spacing of 450 m/pixel and vertical accuracy of ~30 meters), FC color images, and Visible and InfraRed (VIR) hyperspectral images. Av-15 Rheasilvia Quadrangle covers the southern pole of Vesta and stretches north to -21°S. Vesta has three dominant terrains: A heavily-cratered northern terrain with ancient troughs and grooves, an intermediately-cratered equatorial terrain bearing prominent flat-floored, E-W-trending troughs, and the relatively lightly-cratered south polar region, containing the Rheasilvia impact basin and related terrains. This quadrangle is dominated by the central mound complex of the Rheasilvia impact basin. Primary geologic features of this region include: (1) the Rheasilvia complex, including the central mound terrain, ridge-and-groove terrain, and smoother terrain; (2) slump material; and (3) impact craters and associated material. The Rheasilvia formation encompasses the central mound complex, two trends of ridges and grooves (only 5% of the quad area is covered by this terrain), and patches of smoother, less-cratered terrain on the mound itself. The mound, which covers nearly 60% of the quadrangle area, is ~22 km high and ~180 km wide, with a discontinuous bounding scarp and low crater density. The ridge-and groove terrain consists of ridges and grooves radiating approximately 90°-270°, and ridges and troughs or ridge and groove complexes that arch or curve as they extend out

  9. Apolipoprotein A-V deficiency enhances chylomicron production in lymph fistula mice

    PubMed Central

    Xu, Min; Yang, Qing; Ryan, Robert O.; Howles, Philip; Tso, Patrick

    2015-01-01

    Apolipoprotein A-V (apoA-V), a liver-synthesized apolipoprotein discovered in 2001, strongly modulates fasting plasma triglycerides (TG). Little is reported on the effect of apoA-V on postprandial plasma TG, an independent predictor for atherosclerosis. Overexpressing apoA-V in mice suppresses postprandial TG, but mechanisms focus on increased lipolysis or clearance of remnant particles. Unknown is whether apoA-V suppresses the absorption of dietary lipids by the gut. This study examines how apoA-V deficiency affects the steady-state absorption and lymphatic transport of dietary lipids in chow-fed mice. Using apoA-V knockout (KO, n = 8) and wild-type (WT, n = 8) lymph fistula mice, we analyzed the uptake and lymphatic transport of lipids during a continuous infusion of an emulsion containing [3H]triolein and [14C]cholesterol. ApoA-V KO mice showed a twofold increase in 3H (P < 0.001) and a threefold increase in 14C (P < 0.001) transport into the lymph compared with WT. The increased lymphatic transport was accompanied by a twofold reduction (P < 0.05) in mucosal 3H, suggesting that apoA-V KO mice more rapidly secreted [3H]TG out of the mucosa into the lymph. ApoA-V KO mice also produced chylomicrons more rapidly than WT (P < 0.05), as measured by the transit time of [14C]oleic acid from the intestinal lumen to lymph. Interestingly, apoA-V KO mice produced a steadily increasing number of chylomicron particles over time, as measured by lymphatic apoB output. The data suggest that apoA-V suppresses the production of chylomicrons, playing a previously unknown role in lipid metabolism that may contribute to the postprandial hypertriglyceridemia associated with apoA-V deficiency. PMID:25617349

  10. Apolipoprotein A-V: a potential modulator of plasma triglyceride levels in Turks.

    PubMed

    Hodoglugil, Ugur; Tanyolaç, Sinan; Williamson, David W; Huang, Yadong; Mahley, Robert W

    2006-01-01

    The apolipoprotein A-V gene (APOA5) plays an important role in determining plasma triglyceride levels. We studied the effects of APOA5 polymorphisms on plasma triglyceride levels in Turks, a population with low levels of HDL cholesterol and a high prevalence of coronary artery disease. We found 15 polymorphisms, three of which were novel. Seven haplotype-tagging single nucleotide polymorphisms (SNPs) were chosen and genotyped in approximately 3,000 subjects. The rare alleles of the -1464T>C, -1131T>C, S19W, and 1259T>C SNPs were significantly associated with increased triglyceride levels (19-86 mg/dl; P < 0.05) and had clear gene-dose effects. Haplotype analysis of the nine common APOA5 haplotypes revealed significant effects on triglyceride levels (P < 0.001). Detailed analysis of haplotypes clearly showed that the -1464T>C polymorphism had no effect by itself but was a marker for the -1131T>C, S19W, and 1259T>C polymorphisms. The -1131T>C and 1259T>C polymorphisms were in a strong but incomplete linkage disequilibrium and appeared to have independent effects. Thus, the APOA5 -1131T>C, S19W, and 1259T>C rare alleles were associated with significant increases in plasma triglyceride levels. At least one of these alleles was present in approximately 40% of the Turks. Similar associations were observed for -1131T>C and S19W in white Americans living in San Francisco, California.

  11. The N-terminus of apolipoprotein A-V adopts a helix bundle molecular architecture.

    PubMed

    Wong, Kasuen; Beckstead, Jennifer A; Lee, Dustin; Weers, Paul M M; Guigard, Emmanuel; Kay, Cyril M; Ryan, Robert O

    2008-08-19

    Previous studies of recombinant full-length human apolipoprotein A-V (apoA-V) provided evidence of the presence of two independently folded structural domains. Computer-assisted sequence analysis and limited proteolysis studies identified an N-terminal fragment as a candidate for one of the domains. C-Terminal truncation variants in this size range, apoA-V(1-146) and apoA-V(1-169), were expressed in Escherichia coli and isolated. Unlike full-length apoA-V or apoA-V(1-169), apoA-V(1-146) was soluble in neutral-pH buffer in the absence of lipid. Sedimentation equilibrium analysis yielded a weight-average molecular weight of 18811, indicating apoA-V(1-146) exists as a monomer in solution. Guanidine HCl denaturation experiments at pH 3.0 yielded a one-step native to unfolded transition that corresponds directly with the more stable component of the two-stage denaturation profile exhibited by full-length apoA-V. On the other hand, denaturation experiments conducted at pH 7.0 revealed a less stable structure. In a manner similar to that of known helix bundle apolipoproteins, apoA-V(1-146) induced a relatively small enhancement in 8-anilino-1-naphthalenesulfonic acid fluorescence intensity. Quenching studies with single-Trp apoA-V(1-146) variants revealed that a unique site predicted to reside on the nonpolar face of an amphipathic alpha-helix was protected from quenching by KI. Taken together, the data suggest the 146 N-terminal residues of human apoA-V adopt a helix bundle molecular architecture in the absence of lipid and, thus, likely exist as an independently folded structural domain within the context of the intact protein.

  12. ND2 AV: N-dimensional data analysis and visualization analysis for the National Ignition Campaign

    SciTech Connect

    Bremer, Peer -Timo; Maljovec, Dan; Saha, Avishek; Wang, Bei; Gaffney, Jim; Spears, Brian K.; Pascucci, Valerio

    2015-07-01

    Here, one of the biggest challenges in high-energy physics is to analyze a complex mix of experimental and simulation data to gain new insights into the underlying physics. Currently, this analysis relies primarily on the intuition of trained experts often using nothing more sophisticated than default scatter plots. Many advanced analysis techniques are not easily accessible to scientists and not flexible enough to explore the potentially interesting hypotheses in an intuitive manner. Furthermore, results from individual techniques are often difficult to integrate, leading to a confusing patchwork of analysis snippets too cumbersome for data exploration. This paper presents a case study on how a combination of techniques from statistics, machine learning, topology, and visualization can have a significant impact in the field of inertial confinement fusion. We present the $\\mathrm{ND}^2\\mathrm{AV}$: N-dimensional data analysis and visualization framework, a user-friendly tool aimed at exploiting the intuition and current workflow of the target users. The system integrates traditional analysis approaches such as dimension reduction and clustering with state-of-the-art techniques such as neighborhood graphs and topological analysis, and custom capabilities such as defining combined metrics on the fly. All components are linked into an interactive environment that enables an intuitive exploration of a wide variety of hypotheses while relating the results to concepts familiar to the users, such as scatter plots. $\\mathrm{ND}^2\\mathrm{AV}$ uses a modular design providing easy extensibility and customization for different applications. $\\mathrm{ND}^2\\mathrm{AV}$ is being actively used in the National Ignition Campaign and has already led to a number of unexpected discoveries.

  13. Massive stars exploding in a He-rich circumstellar medium - IX. SN 2014av, and characterization of Type Ibn SNe

    NASA Astrophysics Data System (ADS)

    Pastorello, A.; Wang, X.-F.; Ciabattari, F.; Bersier, D.; Mazzali, P. A.; Gao, X.; Xu, Z.; Zhang, J.-J.; Tokuoka, S.; Benetti, S.; Cappellaro, E.; Elias-Rosa, N.; Harutyunyan, A.; Huang, F.; Miluzio, M.; Mo, J.; Ochner, P.; Tartaglia, L.; Terreran, G.; Tomasella, L.; Turatto, M.

    2016-02-01

    We present spectroscopic and photometric data of the Type Ibn supernova (SN) 2014av, discovered by the Xingming Observatory Sky Survey. Stringent pre-discovery detection limits indicate that the object was detected for the first time about 4 d after the explosion. A prompt follow-up campaign arranged by amateur astronomers allowed us to monitor the rising phase (lasting 10.6 d) and to accurately estimate the epoch of the maximum light, on 2014 April 23 (JD = 245 6771.1 ± 1.2). The absolute magnitude of the SN at the maximum light is MR = -19.76 ± 0.16. The post-peak light curve shows an initial fast decline lasting about three weeks, and is followed by a slower decline in all bands until the end of the monitoring campaign. The spectra are initially characterized by a hot continuum. Later on, the temperature declines and a number of lines become prominent mostly in emission. In particular, later spectra are dominated by strong and narrow emission features of He I typical of Type Ibn supernovae (SNe), although there is a clear signature of lines from heavier elements (in particular O I, Mg II and Ca II). A forest of relatively narrow Fe II lines is also detected showing P-Cygni profiles, with the absorption component blueshifted by about 1200 km s-1. Another spectral feature often observed in interacting SNe, a strong blue pseudo-continuum, is seen in our latest spectra of SN 2014av. We discuss in this paper the physical parameters of SN 2014av in the context of the Type Ibn SN variety.

  14. Students' Decision Steps in Meta-Cognitive Learning in Free Online Groups (MetaL-FrOG): A Case Study

    ERIC Educational Resources Information Center

    Sen Fa, Kinsley Ng; Hussin, Firuz Hussin

    2011-01-01

    What prompts the students to respond in online dialogic discussion? Why some students chose to fall out? This case study through the lens of phenomenography observation attempts to explain the five decision steps of students to respond in Meta-cognitive Learning in Free Online Groups (MetaL-FrOG) discussion. It presents a part of a research…

  15. Cerebral [18 F]T807/AV1451 retention pattern in clinically probable CTE resembles pathognomonic distribution of CTE tauopathy

    PubMed Central

    Dickstein, D L; Pullman, M Y; Fernandez, C; Short, J A; Kostakoglu, L; Knesaurek, K; Soleimani, L; Jordan, B D; Gordon, W A; Dams-O'Connor, K; Delman, B N; Wong, E; Tang, C Y; DeKosky, S T; Stone, J R; Cantu, R C; Sano, M; Hof, P R; Gandy, S

    2016-01-01

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder most commonly associated with repetitive traumatic brain injury (TBI) and characterized by the presence of neurofibrillary tangles of tau protein, known as a tauopathy. Currently, the diagnosis of CTE can only be definitively established postmortem. However, a new positron emission tomography (PET) ligand, [18F]T807/AV1451, may provide the antemortem detection of tau aggregates, and thus various tauopathies, including CTE. Our goal was to examine [18F]T807/AV1451 retention in athletes with neuropsychiatric symptoms associated with a history of multiple concussions. Here we report a 39-year-old retired National Football League player who suffered 22 concussions and manifested progressive neuropsychiatric symptoms. Emotional lability and irritability were the chief complaints. Serial neuropsychological exams revealed a decline in executive functioning, processing speed and fine motor skills. Naming was below average but other cognitive functions were preserved. Structural analysis of longitudinally acquired magenetic resonance imaging scans revealed cortical thinning in the left frontal and lateral temporal areas, as well as volume loss in the basal ganglia. PET with [18F]florbetapir was negative for amyloidosis. The [18F]T807/AV1451 PET showed multifocal areas of retention at the cortical gray matter–white matter junction, a distribution considered pathognomonic for CTE. [18F]T807/AV1451 standard uptake value (SUV) analysis showed increased uptake (SUVr⩾1.1) in bilateral cingulate, occipital, and orbitofrontal cortices, and several temporal areas. Although definitive identification of the neuropathological underpinnings basis for [18F]T807/AV1451 retention requires postmortem correlation, our data suggest that [18F]T807/AV1451 tauopathy imaging may be a promising tool to detect and diagnose CTE-related tauopathy in living subjects. PMID:27676441

  16. Single primitive ventricle with normally related great arteries and atresia of the left A-V valve.

    PubMed Central

    Coto, E O; Raggio, J M; Malo, P; Sainz, C; Aparisi, R; Gomez-Ullate, J M

    1978-01-01

    A child aged 2 years and 9 months was angiocardiographically diagnosed to have a single ventricle with normally related great arteries and atresia of the left A-V valve. A Blalock-Hanlon procedure and division of a large patent ductus arteriosus were followed by reduction in pulmonary artery pressure, but after operation the patient showed signs of left ventricular failure unresponsive to medical treatment, necessitating pulmonary artery banding. We have found only three similar published cases, and this is the only one with full angiographic documentation. Images PMID:725830

  17. Reactive transport modeling in variably saturated porous media with OGS-IPhreeqc

    NASA Astrophysics Data System (ADS)

    He, W.; Beyer, C.; Fleckenstein, J. H.; Jang, E.; Kalbacher, T.; Shao, H.; Wang, W.; Kolditz, O.

    2014-12-01

    Worldwide, sustainable water resource management becomes an increasingly challenging task due to the growth of population and extensive applications of fertilizer in agriculture. Moreover, climate change causes further stresses to both water quantity and quality. Reactive transport modeling in the coupled soil-aquifer system is a viable approach to assess the impacts of different land use and groundwater exploitation scenarios on the water resources. However, the application of this approach is usually limited in spatial scale and to simplified geochemical systems due to the huge computational expense involved. Such computational expense is not only caused by solving the high non-linearity of the initial boundary value problems of water flow in the unsaturated zone numerically with rather fine spatial and temporal discretization for the correct mass balance and numerical stability, but also by the intensive computational task of quantifying geochemical reactions. In the present study, a flexible and efficient tool for large scale reactive transport modeling in variably saturated porous media and its applications are presented. The open source scientific software OpenGeoSys (OGS) is coupled with the IPhreeqc module of the geochemical solver PHREEQC. The new coupling approach makes full use of advantages from both codes: OGS provides a flexible choice of different numerical approaches for simulation of water flow in the vadose zone such as the pressure-based or mixed forms of Richards equation; whereas the IPhreeqc module leads to a simplification of data storage and its communication with OGS, which greatly facilitates the coupling and code updating. Moreover, a parallelization scheme with MPI (Message Passing Interface) is applied, in which the computational task of water flow and mass transport is partitioned through domain decomposition, whereas the efficient parallelization of geochemical reactions is achieved by smart allocation of computational workload over

  18. Reactive transport modeling in the subsurface environment with OGS-IPhreeqc

    NASA Astrophysics Data System (ADS)

    He, Wenkui; Beyer, Christof; Fleckenstein, Jan; Jang, Eunseon; Kalbacher, Thomas; Naumov, Dimitri; Shao, Haibing; Wang, Wenqing; Kolditz, Olaf

    2015-04-01

    Worldwide, sustainable water resource management becomes an increasingly challenging task due to the growth of population and extensive applications of fertilizer in agriculture. Moreover, climate change causes further stresses to both water quantity and quality. Reactive transport modeling in the coupled soil-aquifer system is a viable approach to assess the impacts of different land use and groundwater exploitation scenarios on the water resources. However, the application of this approach is usually limited in spatial scale and to simplified geochemical systems due to the huge computational expense involved. Such computational expense is not only caused by solving the high non-linearity of the initial boundary value problems of water flow in the unsaturated zone numerically with rather fine spatial and temporal discretization for the correct mass balance and numerical stability, but also by the intensive computational task of quantifying geochemical reactions. In the present study, a flexible and efficient tool for large scale reactive transport modeling in variably saturated porous media and its applications are presented. The open source scientific software OpenGeoSys (OGS) is coupled with the IPhreeqc module of the geochemical solver PHREEQC. The new coupling approach makes full use of advantages from both codes: OGS provides a flexible choice of different numerical approaches for simulation of water flow in the vadose zone such as the pressure-based or mixed forms of Richards equation; whereas the IPhreeqc module leads to a simplification of data storage and its communication with OGS, which greatly facilitates the coupling and code updating. Moreover, a parallelization scheme with MPI (Message Passing Interface) is applied, in which the computational task of water flow and mass transport is partitioned through domain decomposition, whereas the efficient parallelization of geochemical reactions is achieved by smart allocation of computational workload over

  19. Influence of reactive sulfide (AVS) and supplementary food on Ag, Cd and Zn bioaccumulation in the marine polychaete Neanthes arenaceodentata

    USGS Publications Warehouse

    Lee, J.-S.; Lee, B.-G.; Yoo, H.; Koh, C.-H.; Luoma, S.N.

    2001-01-01

    A laboratory bioassay determined the relative contribution of various pathways of Ag, Cd and Zn bioaccumulation in the marine polychaete Neanthes arenaceodentata exposed to moderately contaminated sediments. Juvenile worms were exposed for 25 d to experimental sediments containing 5 different reactive sulfide (acid volatile sulfides, AVS) concentrations (1 to 30 ??mol g-1), but with constant Ag, Cd, and Zn concentrations of 0.1, 0.1 and 7 ??mol g-1, respectively. The sediments were supplemented with contaminated food (TetraMin??) containing 3 levels of Ag-Cd-Zn (uncontaminated, 1?? or 5??1 metal concentrations in the contaminated sediment). The results suggest that bioaccumulation of Ag, Cd and Zn in the worms occurred predominantly from ingestion of contaminated sediments and contaminated supplementary food. AVS or dissolved metals (in porewater and overlying water) had a minor effect on bioaccumulation of the 3 metals in most of the treatments. The contribution to uptake from the dissolved source was most important in the most oxic sediments, with maximum contributions of 8% for Ag, 30% for Cd and 20% for Zn bioaccumulation. Sediment bioassays where uncontaminated supplemental food is added could seriously underestimate metal exposures in an equilibrated system; N. arenaceodentata feeding on uncontaminated food would be exposed to 40-60% less metal than if the food source was equilibrated (as occurs in nature). Overall, the results show that pathways of metal exposure are dynamically linked in contaminated sediments and shift as external geochemical characteristics and internal biological attributes vary.

  20. A Cluster of Genes Involved in Polysaccharide Biosynthesis from Enterococcus faecalis OG1RF

    PubMed Central

    Xu, Yi; Murray, Barbara E.; Weinstock, George M.

    1998-01-01

    Our previous work identified a cosmid clone containing a 43-kb insert from Enterococcus faecalis OG1RF that produced a nonprotein antigen in Escherichia coli. In the present work, we studied this clone in detail. Periodate treatment of lysates of the clone confirmed that the antigen was carbohydrate in nature. Analysis of DNA sequences and transposon insertion mutants suggested that the insert contained a multicistronic gene cluster. Database comparison showed that the cluster contained genes similar to genes involved in the biosynthesis of dTDP-rhamnose, glycosyltransferases, and ABC transporters involved in the export of sugar polymers from both gram-positive and gram-negative organisms. Insertions in several genes within the cluster abolished the immunoreactivity of the clone. This is the first report on a gene cluster of E. faecalis involved in the biosynthesis of an antigenic polysaccharide. PMID:9712783

  1. Geologic Mapping of the Av-3 Caparronia Quadrangle of Asteroid 4 Vesta

    NASA Astrophysics Data System (ADS)

    Blewett, D. T.; Young, B. L.; Williams, D. A.; O'Brien, D. P.; Gaskell, R.; Yingst, R. A.; Garry, W. B.; Buczkowski, D. L.; Hiesinger, H.; McCord, T. B.; Combe, J.-Ph; Schenk, P. M.; Jaumann, R.; Pieters, C. M.; Nathues, A.; Le Corre, L.; Reddy, V.; De Sanctis, M.; Roatsch, T.; Preusker, F.

    2012-04-01

    NASA's Dawn spacecraft is spending one year in orbit around asteroid (4) Vesta to characterize its geology, chemical and mineralogical composition, topography, shape, and internal structure. The Dawn Team is conducting geological mapping of the surface in the form of 15 quadrangle maps, and here we report results from the mapping of Caparronia quadrangle Av-3. Mapping is based on a Framing Camera (FC) mosaic produced from High Altitude Mapping Orbit (HAMO) data with a spatial resolution of ~70 m/pixel, supplemented by a Digital Terrain Model (DTM: lateral spacing of 450 m/pixel and vertical accuracy of ~30 meters), FC color images, and Visible and InfraRed (VIR) hyperspectral images. The Caparronia Quadrangle extends from 90˚ to 180˚ E longitude and 21˚ to 66˚ N latitude. Vesta's rotation axis is tilted ~29˚ with respect to its orbital plane. Dawn arrived during northern winter, hence portions of Vesta north of ~45˚ N are in shadow and have not yet been imaged. Vesta has three dominant terrains: A heavily-cratered northern terrain with ancient troughs and grooves, an intermediately-cratered equatorial terrain bearing prominent flat-floored, E-W-trending troughs, and the relatively lightly-cratered south polar region, containing the Rheasilvia impact basin and related terrains. The Northern Cratered Trough terrain dominates the Caparronia quadrangle. Part of a NW-SE-trending trough enters the center of the sunlit part of the quad. Caparronia crater is centered at ~36˚ N, 167˚ E and is located near the eastern edge of the quad. The crater's elongation in the north-south direction is caused by slumping, likely as a result of the steep topography on which the crater formed. Smooth ejecta from Caparronia and two other relatively fresh craters can be mapped to a distance of roughly one crater radius from the crater rims, and to greater distances in places. In addition to morphology derived from FC clear filter images, we plan to take advantage of compositional

  2. Apolipoprotein A-V Deficiency Results in MarkedHypertriglyceridemia Attributable to Decreased Lipolysis ofTriglyceride-Rich Lipoproteins and Removal of Their Remnants

    SciTech Connect

    Grosskopf, Itamar; Baroukh, Nadine; Lee, Sung-Joon; Kamari,Yehuda; Harats, Dror; Rubin, Edward M.; Pennacchio, Len A.; Cooper, AllenD.

    2005-09-01

    Objective--ApoAV, a newly discovered apoprotein, affectsplasma triglyceride level. To determine how this occurs, we studiedtriglyceride-rich lipoprotein (TRL) metabolism in mice deficient inapoAV. Methods and Results No significant difference in triglycerideproduction rate was found between apoa5_/_ mice and controls. Thepresence or absence of apoAV affected TRL catabolism. After the injectionof 14C-palmitate and 3H-cholesterol labeled chylomicrons and 125I-labeledchylomicron remnants, the disappearance of 14C, 3H, and 125I wassignificantly slower in apoa5_/_ mice relative to controls. This wasbecause of diminished lipolysis of TRL and the reduced rate of uptake oftheir remnants in apoa5_/_ mice. Observed elevated cholesterol level wascaused by increased high-density lipoprotein (HDL) cholesterol inapoa5_/_ mice. VLDL from apoa5_/_ mice were poor substrate forlipoprotein lipase, and did not bind to the low-density lipoprotein (LDL)receptor as well as normal very-low-density lipoprotein (VLDL). LDLreceptor levels were slightly elevated in apoa5_/_ mice consistent withlower remnant uptake rates. These alterations may be the result of thelower apoE-to-apoC ratio found in VLDL isolated from apoa5_/_mice.Conclusions These results support the hypothesis that the absence ofapoAV slows lipolysis of TRL and the removal of their remnants byregulating their apoproteins content after secretion.

  3. AVS: Experimental Tests of a New Process to Inductively Vitrify HLW Inside the Final Disposal Containers at Very High Waste Loadings

    SciTech Connect

    Powell, J.; Reich, M.; Jordan, J.; Ventre, L.; Barletta, R.; Manowitz, B.; Steinberg, M.; Grossman, W.; Maise, G.; Salzano, F.; Hess, C.; Ramsey, W. G.; Plodinec, M. J.

    2002-02-26

    The design and performance capabilities of the Advanced Vitrification System (AVS) are described, together with the results of experimental tests. The AVS is an in-can melting system in which high-level waste (HLW) is vitrified directly inside the final disposal container. The AVS container, or module, consists of an outer stainless steel canister and an alumina-lined, inner graphite crucible, which is thermally insulated from the outer stainless canister. The graphite crucible is inductively heated to very high temperatures (up to 1500 C) by an external low frequency (30 Hertz) alternating current (AC) transformer coil. The actively cooled outer stainless canister remains at near ambient temperature. The HLW/frit mixture is fed into the hot graphite crucible, where it is vitrified. After cooldown, the HLW/frit feed and off-gas pipes are disconnected from the top of the module, which is then sealed and readied for shipment or storage. All radioactively contaminated melter components inside the module are disposed of along with the vitrified waste. The graphite crucible also provides a geologically stable barrier for the vitrified product. The AVS potentially can double HLW loading over that obtained from Joule melters; lower vitrification costs by about half; reduce the number of disposal canisters required by about half; handle diverse waste feeds with high concentrations of problem elements such as chromium and zirconium; and reduce the time needed to vitrify a given inventory of HLW.

  4. Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages.

    PubMed

    Schwarz, Adam J; Yu, Peng; Miller, Bradley B; Shcherbinin, Sergey; Dickson, James; Navitsky, Michael; Joshi, Abhinay D; Devous, Michael D; Mintun, Mark S

    2016-05-01

    SEE THAL AND VANDENBERGHE DOI101093/BRAIN/AWW057 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-mortem Braak staging of neurofibrillary tau tangle topographical distribution is one of the core neuropathological criteria for the diagnosis of Alzheimer's disease. The recent development of positron emission tomography tracers targeting neurofibrillary tangles has enabled the distribution of tau pathology to be imaged in living subjects. Methods for extraction of classic Braak staging from in vivo imaging of neurofibrillary tau tangles have not yet been explored. Standardized uptake value ratio images were calculated from 80-100 minute (18)F-AV-1451 (also known as T807) positron emission tomography scans obtained from n = 14 young reference subjects (age 21-39 years, Mini-Mental State Examination 29-30) and n = 173 older test subjects (age 50-95 years) comprising amyloid negative cognitively normal (n = 42), clinically-diagnosed mild cognitive impairment (amyloid positive, n = 47, and amyloid negative, n = 40) and Alzheimer's disease (amyloid positive, n = 28, and amyloid negative, n = 16). We defined seven regions of interest in anterior temporal lobe and occipital lobe sections corresponding closely to those used as decision points in Braak staging. An algorithm based on the Braak histological staging procedure was applied to estimate Braak stages directly from the region of interest profiles in each subject. Quantitative region-based analysis of (18)F-AV-1451 images yielded region of interest and voxel level profiles that mirrored key features of neuropathological tau progression including profiles consistent with Braak stages 0 through VI. A simple set of decision rules enabled plausible Braak stages corresponding to stereotypical progression patterns to be objectively estimated in 149 (86%) of test subjects. An additional 12 (7%) subjects presented with predefined variant profiles (relative sparing of the hippocampus and/or occipital lobe). The estimated Braak

  5. PET2OGS: Algorithms to link the static model of Petrel with the dynamic model of OpenGeoSys

    NASA Astrophysics Data System (ADS)

    Park, C.-H.; Shinn, Y. J.; Park, Y.-C.; Huh, D.-G.; Lee, S. K.

    2014-01-01

    A set of three algorithms named PET2OGS is developed to integrate the static model (Petrel) with the dynamic model (OpenGeoSys). PET2OGS consists of three sub-algorithms that convert finite difference methods (FDMs) grids to finite element methods (FEMs) grids. The algorithms and the workflow of the integration procedures are described in detail. After the proposed algorithms are tested on a variety of grids both in homogeneous and heterogeneous media, the integrated platform of the static and dynamic models is applied to model CO2 storage in a saline aquifer. A successful demonstration of the proposed algorithms proved a robust integration of the platform. With some minor modifications of the algorithms in the part of input and output, the proposed algorithms can be extended to integrate different combinations of FDM-based static models and FEM-based dynamic models beyond the example combination in the paper.

  6. Development of cereal-based functional food using cereal-mix substrate fermented with probiotic strain - Pichia kudriavzevii OG32.

    PubMed

    Ogunremi, Omotade R; Agrawal, Renu; Sanni, Abiodun I

    2015-11-01

    Probiotic strains contribute to the functionality of foods during fermentation. In this present work, cereal-mix was fermented with probiotic Pichia kudriavzevii OG32. Selected fermentation parameters and functional properties of the product were determined. The growth of Pichia kudriavzevii OG32 was supported by the cereal-mix containing 1% salt and 0.2% red chili powder to counts of between 7.46 and 8.22 Log10 cfu/mL within 24 h. Pichia kudriavzevii OG32 increased the viscosity of cereal-mix with the highest inoculum size (1.84x105cfu/ml) giving the highest viscosity of 1793.6 mPa.S. An inoculum size of 1.98 × 10(4) cfu/mL gave the most acceptable product based on the sensory evaluation by the panelist. Forty volatile compounds were identified in the fermented product, while acids (32.21%) and esters (32.37%) accounted for the largest proportions. The cereal-based fermented product scavenged DPPH from 200 μmol/L methanolic solution by 55.71%. Probiotic yeast improved the sensory and some functional properties of cereal-based substrate during fermentation. This is one of the first reports on the volatile composition of cereal-based functional food produced with probiotic yeast. PMID:26788290

  7. Self-inhibition of an AV sequential demand (DVI) pulse generator due to polyurethane lead insulation disruption.

    PubMed

    Sanford, C F

    1983-09-01

    Self-inhibition of bipolar DVI AV-sequential pacemakers has been attributed to electrode malposition, although the potential for self-inhibition due to current leakage has been recognized. Previous cases of current leakages due to insulation defects in bipolar VVI ventricular demand systems have usually presented as abnormal sensing or pacing function without a change to actual unipolar sensing and pacing. This article describes a case of disruption of the insulation of polyurethane bipolar atrial and ventricular leads by silk ligatures, resulting in unipolar atrial and ventricular pacing and self-inhibition of ventricular output of a DVI pulse generator. This case emphasizes the importance of avoiding any application of suture material directly to polyurethane leads. This case also emphasizes the importance of monitoring pacemaker artifact amplitude and axis in patient follow-up.

  8. Effect of the electropositive elements A = Sc, La, and Ce on the microscopic dynamics of AV2Al20.

    PubMed

    Koza, Michael Marek; Leithe-Jasper, Andreas; Sischka, Erik; Schnelle, Walter; Borrmann, Horst; Mutka, Hannu; Grin, Yuri

    2014-12-28

    We report on the inelastic response of AV2Al20 (with A = Sc, La and Ce) probed by high-resolution inelastic neutron scattering experiments. Intense signals associated with the dynamics of Sc, La and Ce are identified in the low-energy range at 6-14 meV in ScV2Al20 and at 8-16 meV in LaV2Al20 and CeV2Al20. Their response to temperature changes between 2 and 300 K reveals a very weak softening of the modes upon heating in LaV2Al20 and CeV2Al20 and a distinguished blue shift by about 2 meV in ScV2Al20. By means of density functional theory (DFT) and lattice dynamics calculations (LDC) we show that the unusual anharmonicity of the Sc-dominated modes is due to the local potential of Sc featured by a strong quartic term. The vibrational dynamics of ScV2Al20 as well as of LaV2Al20 and CeV2Al20 is reproduced by a set of eigenmodes. To screen the validity of the DFT and LDC results they are confronted with data from X-ray diffraction measurements. The effect of the strong phonon renormalization in ScV2Al20 on thermodynamic observables is computed on grounds of the LDC derived inelastic response. To set the data in a general context of AV2Al20 compounds and their physical properties we report in addition computer and experimental results of the binary V2Al20 compound.

  9. Ex vivo, microelectrode analysis of conduction through the AV node of wild-type and Nkx2-5 mutant mouse hearts as guided by a Cx40-eGFP transgenic reporter.

    PubMed

    Gazit, Avihu Z; Li, Alex; Choi, Jacob S; Miquerol, Lucile; Jay, Patrick Y

    2014-01-01

    Abstract Mutations of the cardiac transcription factor NKX2-5 cause hypoplastic development of the AV node and conduction block. How the anatomy of the mutant AV node relates to its function is unknown. We thus studied conduction through the AV nodal region in ex vivo preparations of wild-type and Nkx2-5(+/-) mouse hearts in which the central conduction system was highlighted by a transgenic Cx40-eGFP reporter. Fluorescence imaging guided electrode placement and pacing of the inferior and superior approaches to the AV node. Nkx2-5(+/-) hearts had a prolonged atrio-His interval compared to the wild type, consistent with previous in vivo observations. The conduction time to the His bundle from the Cx40(-) AV nodal region that is superior to and immediately adjacent to the Cx40(+) lower node is slightly, but not significantly greater in Nkx2-5(+/-) than wild-type hearts. A novel phenotype was also observed. Pacing the Cx40(-) inferior approach to the AV node with increasing stimulus strength led to progressive shortening of the stimulus-to-His conduction interval in wild-type but not Nkx2-5(+/-) hearts. The strength of pacing at the Cx40(-) superior approach had no effect on the conduction interval in either group. The prolonged AV delay in the Nkx2-5(+/-) heart appears to arise before the Cx40(+) lower node. Whether the pacing phenotype explains the mutant's conduction defect is uncertain, but the observation adds to a number of unique properties of the inferior approach to the AV node.

  10. Physical Characteristics of Asteroid-like Comet Nucleus C/2001 OG108 (LONEOS)

    NASA Technical Reports Server (NTRS)

    Abell, P. A.; Fernandez, Y. R.; Pravec, P.; French, L. M.; Farnham, T. L.; Gaffey, M. J.; Hardersen, P. S.; Kusnirak, P.; Sarounova, L.; Sheppard, S. S.

    2003-01-01

    For many years several investigators have suggested that some portion of the near-Earth asteroid population may actually be extinct cometary nuclei. Evidence used to support these hypotheses was based on: observations of asteroid orbits and associated meteor showers (e.g. 3200 Phaethon and the Geminid meteor shower); low activity of short period comet nuclei, which implied nonvolatile surface crusts (e.g. Neujmin 1, Arend-Rigaux); and detections of transient cometary activity in some near-Earth asteroids (e.g. 4015 Wilson-Harrington). Recent investigations have suggested that approximately 5-10% of the near- Earth asteroid population may be extinct comets. However if members of the near-Earth asteroid population are extinct cometary nuclei, then there should be some objects within this population that are near their final stages of evolution and so should demonstrate only low levels of activity. The recent detections of coma from near-Earth object 2001 OG108 have renewed interest in this possible comet-asteroid connection. This paper presents the first high quality ground-based near-infrared reflectance spectrum of a comet nucleus combined with detailed lightcurve and albedo measurements.

  11. Case report: Manual lymphatic drainage and kinesio taping in the secondary malignant breast cancer-related lymphedema in an arm with arteriovenous (A-V) fistula for hemodialysis.

    PubMed

    Chou, Ya-Hui; Li, Shu-Hua; Liao, Su-Fen; Tang, Hao-Wei

    2013-08-01

    Lymphedema is a dreaded complication of breast cancer treatment. The standard care for lymphedema is complex decongestive physiotherapy, which includes manual lymphatic drainage (MLD), short stretch bandaging, exercise, and skin care. The Kinesio Taping could help to improve lymphatic uptake. We reported a patient with unilateral secondary malignant breast cancer-related lymphedema and arteriovenous (A-V) fistula for hemodialysis happened in the same arm, and used kinesio taping, MLD, and exercise to treat this patient because no pressure could be applied to the A-V fistula. The 12-session therapy created an excellent effect. We do not think the kinesio taping could replace short stretch bandaging, but it could be another choice for contraindicating pressure therapy patients, and we should pay attention to wounds induced by kinesio tape.

  12. Application of variable structure system theory to aircraft flight control. [AV-8A and the Augmentor Wing Jet STOL Research Aircraft

    NASA Technical Reports Server (NTRS)

    Calise, A. J.; Kadushin, I.; Kramer, F.

    1981-01-01

    The current status of research on the application of variable structure system (VSS) theory to design aircraft flight control systems is summarized. Two aircraft types are currently being investigated: the Augmentor Wing Jet STOL Research Aircraft (AWJSRA), and AV-8A Harrier. The AWJSRA design considers automatic control of longitudinal dynamics during the landing phase. The main task for the AWJSRA is to design an automatic landing system that captures and tracks a localizer beam. The control task for the AV-8A is to track velocity commands in a hovering flight configuration. Much effort was devoted to developing computer programs that are needed to carry out VSS design in a multivariable frame work, and in becoming familiar with the dynamics and control problems associated with the aircraft types under investigation. Numerous VSS design schemes were explored, particularly for the AWJSRA. The approaches that appear best suited for these aircraft types are presented. Examples are given of the numerical results currently being generated.

  13. Hypertriglyceridaemia and low plasma HDL in a patient with apolipoprotein A-V deficiency due to a novel mutation in the APOA5 gene.

    PubMed

    Priore Oliva, C; Carubbi, F; Schaap, F G; Bertolini, S; Calandra, S

    2008-04-01

    APOA5 encodes a novel apolipoprotein (apo A-V) which appears to be a modulator of plasma triglyceride (TG). In apoA5 knock out mice plasma TG level increases almost fourfold, whereas in human APOA5 transgenic mice it decreases by 70%. Some SNPs in the APOA5 gene have been associated with variations in plasma TG in humans. In addition, hypertriglyceridaemic (HTG) patients have been identified who carried rare nonsense mutations in the APOA5 gene (Q139X and Q148X), predicted to result in apo A-V deficiency. In this study we report a 17-year-old male with high TG and low high density lipoprotein cholesterol (HDL-C), who at the age of two had been found to have severe HTG and eruptive xanthomas suggesting a chylomicronaemia syndrome. Plasma postheparin LPL activity, however, was normal and no mutations were found in LPL and APOC2 genes. The sequence of APOA5 gene revealed that the patient was homozygous for a point mutation (c.289 C>T) in exon 4, converting glutamine codon at position 97 into a termination codon (Q97X). Apo A-V was not detected in patient's plasma, indicating that he had complete apo A-V deficiency. The administration of a low-fat and low-oligosaccharide diet, either alone or supplemented with omega-3 fatty acids, started early in life, reduced plasma TG to a great extent but had a negligible effect on plasma HDL-C. Loss of function mutations of APOA5 gene may be the cause of severe HTG in patients without mutations in LPL and APOC2 genes. PMID:18324930

  14. Endovascular image-guided treatment of in-vivo model aneurysms with asymmetric vascular stents (AVS): evaluation with time-density curve angiographic analysis and histology

    NASA Astrophysics Data System (ADS)

    Dohatcu, A.; Ionita, C. N.; Paciorek, A.; Bednarek, D. R.; Hoffmann, K. R.; Rudin, S.

    2008-03-01

    In this study, we compare the results obtained from Time-Density Curve (TDC) analysis of angiographic imaging sequences with histological evaluation for a rabbit aneurysm model treated with standard stents and new asymmetric vascular stents (AVS) placed by image-guided endovascular deployment. AVSs are stents having a low-porosity patch region designed to cover the aneurysm neck and occlude blood flow inside. To evaluate the AVSs, rabbits with elastase-induced aneurysm models (n=20) were divided into three groups: the first (n=10) was treated with an AVS, the second (n=5) with a non-patch standard coronary stent, and third was untreated as a control (n=5). We used TDC analysis to measure how much contrast media entered the aneurysm before and after treatment. TDCs track contrast-media-density changes as a function of time over the region of interest in x-ray DSA cine-sequences. After 28 days, the animals were sacrificed and the explanted specimens were histologically evaluated. The first group showed an average reduction of contrast flow into the aneurysm of 95% after treatment with an AVS with fully developed thrombus at 28 days follow-up. The rabbits treated with standard stents showed an increase in TDC residency time after treatment and partial-thrombogenesis. The untreated control aneurysms displayed no reduction in flow and were still patent at follow-up. The quantitative TDC analysis findings were confirmed by histological evaluation suggesting that the new AVS has great potential as a definitive treatment for cerebro-vascular aneurysms and that angiographic TDC analysis can provide in-vivo verification.

  15. Randomized, double-blind, active-controlled study evaluating the safety and immunogenicity of three vaccination schedules and two dose levels of AV7909 vaccine for anthrax post-exposure prophylaxis in healthy adults.

    PubMed

    Hopkins, Robert J; Kalsi, Gurdyal; Montalvo-Lugo, Victor M; Sharma, Mona; Wu, Yukun; Muse, Derek D; Sheldon, Eric A; Hampel, Frank C; Lemiale, Laurence

    2016-04-19

    AV7909 vaccine being developed for post-exposure prophylaxis of anthrax disease may require fewer vaccinations and reduced amount of antigen to achieve an accelerated immune response over BioThrax(®) (Anthrax Vaccine Adsorbed). A phase 2, randomized, double-blind, BioThrax vacccine-controlled study was conducted to evaluate the safety and immunogenicity of three intramuscular vaccination schedules and two dose levels of AV7909 in 168 healthy adults. Subjects were randomized at a 4:3:2:4:2 ratio to 5 groups: (1) AV7909 on Days 0/14; (2) AV7909 on Days 0/28; (3) AV7909 on Days 0/14/28; (4) half dose AV7909 on Days 0/14/28; and (5) BioThrax vaccine on Days 0/14/28. Vaccinations in all groups were well tolerated. The incidences of adverse events (AEs) were 79% for AV7909 subjects and 65% for BioThrax subjects; 92% of AV7909 subjects and 87% of BioThrax subjects having AEs reported Grade 1-2 AEs. No serious AEs were assessed as potentially vaccine-related, and no AEs of potential autoimmune etiology were reported. There was no discernible pattern indicative of a safety concern across groups in the incidence or severity of reactogenicity events. Groups 2-4 achieved success for the primary endpoint, demonstrated by a lower 95% confidence limit of the percentage of subjects with protective toxin neutralizing antibody NF50 values (≥0.56) to be ≥40% at Day 63. Group 1 marginally missed the criterion (lower bound 95% confidence limit of 39.5%). Immune responses were above this threshold for Groups 1, 3 and 4 at Day 28 and all groups at Day 42. Further study of an AV7909 two-dose schedule given 2 weeks apart is warranted in light of the favorable tolerability profile and immunogenicity response relative to three doses of BioThrax vaccine, as well as preliminary data from nonclinical studies indicating similar immune responses correlate with higher survival for AV7909 than BioThrax vaccine.

  16. Vesta's north pole quadrangle Av-1 (Albana): Geologic map and the nature of the south polar basin antipodes

    NASA Astrophysics Data System (ADS)

    Blewett, David T.; Buczkowski, Debra L.; Ruesch, Ottaviano; Scully, Jennifer E.; O'Brien, David P.; Gaskell, Robert; Roatsch, Thomas; Bowling, Timothy J.; Ermakov, Anton; Hiesinger, Harald; Williams, David A.; Raymond, Carol A.; Russell, Christopher T.

    2014-12-01

    As part of systematic global mapping of Vesta using data returned by the Dawn spacecraft, we have produced a geologic map of the north pole quadrangle, Av-1 Albana. Extensive seasonal shadows were present in the north polar region at the time of the Dawn observations, limiting the ability to map morphological features and employ color or spectral data for determination of composition. The major recognizable units present include ancient cratered highlands and younger crater-related units (undivided ejecta, and mass-wasting material on crater floors). The antipode of Vesta's large southern impact basins, Rheasilvia and Veneneia, lie within or near the Av-1 quadrangle. Therefore it is of particular interest to search for evidence of features of the kind that are found at basin antipodes on other planetary bodies. Albedo markings known as lunar swirls are correlated with basin antipodes and the presence of crustal magnetic anomalies on the Moon, but lighting conditions preclude recognition of such albedo features in images of the antipode of Vesta's Rheasilvia basin. “Hilly and lineated terrain,” found at the antipodes of large basins on the Moon and Mercury, is not present at the Rheasilvia or Veneneia antipodes. We have identified small-scale linear depressions that may be related to increased fracturing in the Rheasilvia and Veneneia antipodal areas, consistent with impact-induced stresses (Buczkowski, D. et al. [2012b]. Analysis of the large scale troughs on Vesta and correlation to a model of giant impact into a differentiated asteroid. Geol. Soc. of America Annual Meeting. Abstract 152-4; Bowling, T.J. et al. [2013]. J. Geophys. Res. - Planets, 118. http://dx.doi.org/10.1002/jgre.20123). The general high elevation of much of the north polar region could, in part, be a result of uplift caused by the Rheasilvia basin-forming impact, as predicted by numerical modeling (Bowling, T.J. et al. [2013]. J. Geophys. Res. - Planets, 118. http://dx.doi.org/10.1002/jgre

  17. Enhanced early innate and T cell-mediated responses in subjects immunized with Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909).

    PubMed

    Minang, Jacob T; Inglefield, Jon R; Harris, Andrea M; Lathey, Janet L; Alleva, David G; Sweeney, Diane L; Hopkins, Robert J; Lacy, Michael J; Bernton, Edward W

    2014-11-28

    NuThrax™ (Anthrax Vaccine Adsorbed with CPG 7909 Adjuvant) (AV7909) is in development. Samples obtained in a phase Ib clinical trial were tested to confirm biomarkers of innate immunity and evaluate effects of CPG 7909 (PF-03512676) on adaptive immunity. Subjects received two intramuscular doses of commercial BioThrax(®) (Anthrax Vaccine Adsorbed, AVA), or two intramuscular doses of one of four formulations of AV7909. IP-10, IL-6, and C-reactive protein (CRP) levels were elevated 24-48 h after administration of AV7909 formulations, returning to baseline by Day 7. AVA (no CPG 7909) resulted in elevated IL-6 and CRP, but not IP-10. Another marker of CpG, transiently decreased absolute lymphocyte counts (ALCs), correlated with transiently increased IP-10. Cellular recall responses to anthrax protective antigen (PA) or PA peptides were assessed by IFN-γ ELISpot assay performed on cryopreserved PBMCs obtained from subjects prior to immunization and 7 days following the second immunization (study day 21). One-half of subjects that received AV7909 with low-dose (0.25mg/dose) CPG 7909 possessed positive Day 21 T cell responses to PA. In contrast, positive T cell responses occurred at an 11% average rate (1/9) for AVA-treated subjects. Differences in cellular responses due to dose level of CPG 7909 were not associated with differences in humoral anti-PA IgG responses, which were elevated for recipients of AV7909 compared to recipients of AVA. Serum markers at 24 or 48 h (i.e. % ALC decrease, or increase in IL-6, IP-10, or CRP) correlated with the humoral (antibody) responses 1 month later, but did not correlate with cellular ELISpot responses. In summary, biomarkers of early responses to CPG 7909 were confirmed, and adding a CpG adjuvant to a vaccine administered twice resulted in increased T cell effects relative to vaccine alone. Changes in early biomarkers correlated with subsequent adaptive humoral immunity but not cellular immunity.

  18. Enhanced early innate and T cell-mediated responses in subjects immunized with Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909).

    PubMed

    Minang, Jacob T; Inglefield, Jon R; Harris, Andrea M; Lathey, Janet L; Alleva, David G; Sweeney, Diane L; Hopkins, Robert J; Lacy, Michael J; Bernton, Edward W

    2014-11-28

    NuThrax™ (Anthrax Vaccine Adsorbed with CPG 7909 Adjuvant) (AV7909) is in development. Samples obtained in a phase Ib clinical trial were tested to confirm biomarkers of innate immunity and evaluate effects of CPG 7909 (PF-03512676) on adaptive immunity. Subjects received two intramuscular doses of commercial BioThrax(®) (Anthrax Vaccine Adsorbed, AVA), or two intramuscular doses of one of four formulations of AV7909. IP-10, IL-6, and C-reactive protein (CRP) levels were elevated 24-48 h after administration of AV7909 formulations, returning to baseline by Day 7. AVA (no CPG 7909) resulted in elevated IL-6 and CRP, but not IP-10. Another marker of CpG, transiently decreased absolute lymphocyte counts (ALCs), correlated with transiently increased IP-10. Cellular recall responses to anthrax protective antigen (PA) or PA peptides were assessed by IFN-γ ELISpot assay performed on cryopreserved PBMCs obtained from subjects prior to immunization and 7 days following the second immunization (study day 21). One-half of subjects that received AV7909 with low-dose (0.25mg/dose) CPG 7909 possessed positive Day 21 T cell responses to PA. In contrast, positive T cell responses occurred at an 11% average rate (1/9) for AVA-treated subjects. Differences in cellular responses due to dose level of CPG 7909 were not associated with differences in humoral anti-PA IgG responses, which were elevated for recipients of AV7909 compared to recipients of AVA. Serum markers at 24 or 48 h (i.e. % ALC decrease, or increase in IL-6, IP-10, or CRP) correlated with the humoral (antibody) responses 1 month later, but did not correlate with cellular ELISpot responses. In summary, biomarkers of early responses to CPG 7909 were confirmed, and adding a CpG adjuvant to a vaccine administered twice resulted in increased T cell effects relative to vaccine alone. Changes in early biomarkers correlated with subsequent adaptive humoral immunity but not cellular immunity. PMID:24530403

  19. Mutational epitope analysis of Pru av 1 and Api g 1, the major allergens of cherry (Prunus avium) and celery (Apium graveolens): correlating IgE reactivity with three-dimensional structure.

    PubMed

    Neudecker, Philipp; Lehmann, Katrin; Nerkamp, Jörg; Haase, Tanja; Wangorsch, Andrea; Fötisch, Kay; Hoffmann, Silke; Rösch, Paul; Vieths, Stefan; Scheurer, Stephan

    2003-11-15

    Birch pollinosis is often accompanied by adverse reactions to food due to pollen-allergen specific IgE cross-reacting with homologous food allergens. The tertiary structure of Pru av 1, the major cherry (Prunus avium) allergen, for example, is nearly identical with Bet v 1, the major birch (Betula verrucosa) pollen allergen. In order to define cross-reactive IgE epitopes, we generated and analysed mutants of Pru av 1 and Api g 1.0101, the major celery (Apium graveolens) allergen, by immunoblotting, EAST (enzyme allergosorbent test), CD and NMR spectroscopy. The mutation of Glu45 to Trp45 in the P-loop region, a known IgE epitope of Bet v 1, significantly reduced IgE binding to Pru av 1 in a subgroup of cherry-allergic patients. The backbone conformation of Pru av 1 wild-type is conserved in the three-dimensional structure of Pru av 1 Trp45, demonstrating that the side chain of Glu45 is involved in a cross-reactive IgE epitope. Accordingly, for a subgroup of celery-allergic patients, IgE binding to the homologous celery allergen Api g 1.0101 was enhanced by the mutation of Lys44 to Glu. The almost complete loss of IgE reactivity to the Pru av 1 Pro112 mutant is due to disruption of its tertiary structure. Neither the mutation Ala112 nor deletion of the C-terminal residues 155-159 influenced IgE binding to Pru av 1. In conclusion, the structure of the P-loop partially explains the cross-reactivity pattern, and modulation of IgE-binding by site-directed mutagenesis is a promising approach to develop hypo-allergenic variants for patient-tailored specific immunotherapy.

  20. 3DVIEWNIX-AVS: a software package for the separate visualization of arteries and veins in CE-MRA images.

    PubMed

    Lei, Tianhu; Udupa, Jayaram K; Odhner, Dewey; Nyúl, László G; Saha, Punam K

    2003-01-01

    Our earlier study developed a computerized method, based on fuzzy connected object delineation principles and algorithms, for artery and vein separation in contrast enhanced Magnetic Resonance Angiography (CE-MRA) images. This paper reports its current development-a software package-for routine clinical use. The software package, termed 3DVIEWNIX-AVS, consists of the following major operational parts: (1) converting data from DICOM3 to 3DVIEWNIX format, (2) previewing slices and creating VOI and MIP Shell, (3) segmenting vessel, (4) separating artery and vein, (5) shell rendering vascular structures and creating animations. This package has been applied to EPIX Medical Inc's CE-MRA data (AngioMark MS-325). One hundred and thirty-five original CE-MRA data sets (of 52 patients) from 6 hospitals have been processed. In all case studies, unified parameter settings produce correct artery-vein separation. The current package is running on a Pentium PC under Linux and the total computation time per study is about 3 min. The strengths of this software package are (1) minimal user interaction, (2) minimal anatomic knowledge requirements on human vascular system, (3) clinically required speed, (4) free entry to any operational stages, (5) reproducible, reliable, high quality of results, and (6) cost effective computer implementation. To date, it seems to be the only software package (using an image processing approach) available for artery and vein separation of the human vascular system for routine use in a clinical setting. PMID:12821028

  1. The carboxyl-terminal segment of apolipoprotein A-V undergoes a lipid-induced conformational change.

    PubMed

    Mauldin, Kasuen; Lee, Brian L; Oleszczuk, Marta; Sykes, Brian D; Ryan, Robert O

    2010-06-15

    Apolipoprotein (apo) A-V is a 343-residue, multidomain protein that plays an important role in regulation of plasma triglyceride homeostasis. Primary sequence analysis revealed a unique tetraproline sequence (Pro293-Pro296) near the carboxyl terminus of the protein. A peptide corresponding to the 48-residue segment beyond the tetraproline motif was generated from a recombinant apoA-V precursor wherein Pro295 was replaced by Met. Cyanogen bromide cleavage of the precursor protein, followed by negative affinity chromatography, yielded a purified peptide. Nondenaturing polyacrylamide gel electrophoresis verified that apoA-V(296-343) solubilizes phospholipid vesicles, forming a relatively heterogeneous population of reconstituted high-density lipoprotein with Stokes' diameters >17 nm. At the same time, apoA-V(296-343) failed to bind a spherical lipoprotein substrate in vitro. Far-UV circular dichroism spectroscopy revealed the peptide is unstructured in buffer yet adopts significant alpha-helical secondary structure in the presence of the lipid mimetic solvent trifluoroethanol (TFE; 50% v/v). Heteronuclear multidemensional NMR spectroscopy experiments were conducted with uniformly (15)N- and (15)N/(13)C-labeled peptide in 50% TFE. Peptide backbone assignment and secondary structure prediction using TALOS+ reveal the peptide adopts alpha-helix secondary structure from residues 309 to 334. In TFE, apoA-V(296-343) adopts an extended amphipathic alpha-helix, consistent with a role in lipoprotein binding as a component of full-length apoA-V.

  2. Magnesium, Potassium and Phosphorus in Available Forms in Luvisols in the Vicinity of Głogów Copper Smelter

    NASA Astrophysics Data System (ADS)

    Jaworska, H.; Dąbkowska-Naskręt, H.; Różański, S.

    2016-02-01

    Region near Głogów is characterized as industrial—agricultural area, intensively used. Presented study was undertaken to estimate the impact of agricultural land use and the vicinity of Głogów copper smelter on the contents of available forms of magnesium, phosphorus and potassium in selected profiles of Luvisols. The following analysis were performed: soil particle-size distribution, pH, organic carbon contents, CaCO3 contents. The contents of available forms of phosphorus and potassium were determined by Egner- Riehm method and that of magnesium using Schachtschabel's method. The results of the study showed that the contents of available P is medium (III class of abundance), very low in K (V class) and for available Mg very low (V class) to medium for surface horizons and very high (I class of abundance) in other soil horizons. The soils, in spite of the elevated copper content in humus horizons, according to IUNG, were classified as uncontaminated soils, therefore, can be used in plant production for all types of crops.

  3. DC-8-based observations of aircraft CO, CH4, N2O, and H2O(g) emission indices during SUCCESS

    NASA Astrophysics Data System (ADS)

    Vay, S. A.; Anderson, B. E.; Sachse, G. W.; Collins, J. E., Jr.; Podolske, J. R.; Twohy, C. H.; Gandrud, B.; Chan, K. R.; Baughcum, S. L.; Wallio, H. A.

    We report the first measurements of CO, CH4, N2O, CO2, and H2O(g) in the exhaust trails of T-39, B-757, and DC-8 aircraft at cruise conditions. Emission indices (EI) derived from these in-situ measurements are presented. Results are in agreement with ground-based tests indicating aircraft act as a net sink for CH4 and recent airborne in-situ measurements that N2O is not an important exhaust constituent. Condensation of H2O(g) on exhaust particles resulted in EI(H2O(g)) values less than those expected from the combustion of fuel alone. Observed apparent negative EI(H2O(g)) values suggest that aircraft aerosol emissions, under unique atmospheric conditions, seed cloud formation and lead to dehydration of the exhaust-influenced air parcel. Such conditions may induce the formation of cirrus clouds from persistent contrails. Comparisons with the Boeing EMIT Code show measurement-derived CO emission index values consistent with model evaluations.

  4. Future-saving audiovisual content for Data Science: Preservation of geoinformatics video heritage with the TIB|AV-Portal

    NASA Astrophysics Data System (ADS)

    Löwe, Peter; Plank, Margret; Ziedorn, Frauke

    2015-04-01

    In data driven research, the access to citation and preservation of the full triad consisting of journal article, research data and -software has started to become good scientific practice. To foster the adoption of this practice the significance of software tools has to be acknowledged, which enable scientists to harness auxiliary audiovisual content in their research work. The advent of ubiquitous computer-based audiovisual recording and corresponding Web 2.0 hosting platforms like Youtube, Slideshare and GitHub has created new ecosystems for contextual information related to scientific software and data, which continues to grow both in size and variety of content. The current Web 2.0 platforms lack capabilities for long term archiving and scientific citation, such as persistent identifiers allowing to reference specific intervals of the overall content. The audiovisual content currently shared by scientists ranges from commented howto-demonstrations on software handling, installation and data-processing, to aggregated visual analytics of the evolution of software projects over time. Such content are crucial additions to the scientific message, as they ensure that software-based data-processing workflows can be assessed, understood and reused in the future. In the context of data driven research, such content needs to be accessible by effective search capabilities, enabling the content to be retrieved and ensuring that the content producers receive credit for their efforts within the scientific community. Improved multimedia archiving and retrieval services for scientific audiovisual content which meet these requirements are currently implemented by the scientific library community. This paper exemplifies the existing challenges, requirements, benefits and the potential of the preservation, accessibility and citability of such audiovisual content for the Open Source communities based on the new audiovisual web service TIB|AV Portal of the German National Library

  5. Angiographic analysis of animal model aneurysms treated with novel polyurethane asymmetric vascular stent (P-AVS): feasibility study

    NASA Astrophysics Data System (ADS)

    Ionita, Ciprian N.; Dohatcu, Andreea; Sinelnikov, Andrey; Sherman, Jason; Keleshis, Christos; Paciorek, Ann M.; Hoffmann, K. R.; Bednarek, D. R.; Rudin, S.

    2009-02-01

    Image-guided endovascular intervention (EIGI), using new flow modifying endovascular devices for intracranial aneurysm treatment is an active area of stroke research. The new polyurethane-asymmetric vascular stent (P-AVS), a vascular stent partially covered with a polyurethane-based patch, is used to cover the aneurysm neck, thus occluding flow into the aneurysm. This study involves angiographic imaging of partially covered aneurysm orifices. This particular situation could occur when the vascular geometry does not allow full aneurysm coverage. Four standard in-vivo rabbit-model aneurysms were investigated; two had stent patches placed over the distal region of the aneurysm orifice while the other two had stent patches placed over the proximal region of the aneurysm orifice. Angiographic analysis was used to evaluate aneurysm blood flow before and immediately after stenting and at four-week follow-up. The treatment results were also evaluated using histology on the aneurysm dome and electron microscopy on the aneurysm neck. Post-stenting angiographic flow analysis revealed aneurysmal flow reduction in all cases with faster flow in the distally-covered case and very slow flow and prolonged pooling for proximal-coverage. At follow-up, proximally-covered aneurysms showed full dome occlusion. The electron microscopy showed a remnant neck in both distally-placed stent cases but complete coverage in the proximally-placed stent cases. Thus, direct flow (impingement jet) removal from the aneurysm dome, as indicated by angiograms in the proximally-covered case, was sufficient to cause full aneurysm healing in four weeks; however, aneurysm healing was not complete for the distally-covered case. These results support further investigations into the treatment of aneurysms by flow-modification using partial aneurysm-orifice coverage.

  6. Test Characteristics of Neck Fullness and Witnessed Neck Pulsations in the Diagnosis of Typical AV Nodal Reentrant Tachycardia

    PubMed Central

    Sakhuja, Rahul; Smith, Lisa M; Tseng, Zian H; Badhwar, Nitish; Lee, Byron K; Lee, Randall J; Scheinman, Melvin M; Olgin, Jeffrey E; Marcus, Gregory M

    2011-01-01

    Summary Background Claims in the medical literature suggest that neck fullness and witnessed neck pulsations are useful in the diagnosis of typical AV nodal reentrant tachycardia (AVNRT). Hypothesis Neck fullness and witnessed neck pulsations have a high positive predictive value in the diagnosis of typical AVNRT. Methods We performed a cross sectional study of consecutive patients with palpitations presenting to a single electrophysiology (EP) laboratory over a 1 year period. Each patient underwent a standard questionnaire regarding neck fullness and/or witnessed neck pulsations during their palpitations. The reference standard for diagnosis was determined by electrocardiogram and invasive EP studies. Results Comparing typical AVNRT to atrial fibrillation (AF) or atrial flutter (AFL) patients, the proportions with neck fullness and witnessed neck pulsations did not significantly differ: in the best case scenario (using the upper end of the 95% confidence interval [CI]), none of the positive or negative predictive values exceeded 79%. After restricting the population to those with supraventricular tachycardia other than AF or AFL (SVT), neck fullness again exhibited poor test characteristics; however, witnessed neck pulsations exhibited a specificity of 97% (95% CI 90–100%) and a positive predictive value of 83% (95% CI 52–98%). After adjustment for potential confounders, SVT patients with witnessed neck pulsations had a 7 fold greater odds of having typical AVNRT, p=0.029. Conclusions Although neither neck fullness nor witnessed neck pulsations are useful in distinguishing typical AVNRT from AF or AFL, witnessed neck pulsations are specific for the presence of typical AVNRT among those with SVT. PMID:19479968

  7. Bioavailability assessment of toxic metals using the technique "acid-volatile sulfide (AVS)-simultaneously extracted metals (SEM)" in marine sediments collected in Todos os Santos Bay, Brazil.

    PubMed

    Silva, Jucelino B; Nascimento, Rodrigo A; de Oliva, Sergio T; de Oliveira, Olívia M C; Ferreira, Sergio L C

    2015-10-01

    This paper reports the bioavailability of the metals (cadmium, copper, zinc, lead, and nickel) in sediment samples collected in seven stations from the São Paulo Estuary, Todos os Santos Bay, Brazil. The bioavailability was determined by employing the technique "acid-volatile sulfide (AVS) and simultaneously extracted metal (SEM)". The elements cadmium, copper, lead, and zinc were determined using differential pulse anodic stripping voltammetry (DPASV), while nickel was quantified utilizing electrothermal atomic absorption spectrometry (ET AAS). The accuracy of these methods was confirmed using a certified reference material of estuarine sediment (NIST 1646). The sulfide was quantified using potentiometry with selective electrode and the organic matter determination employing an indirect volumetric method using potassium dichromate and iron(II) sulfate solutions. The bioavailability of the metals was estimated by relationship between the concentration of AVS and the sum of the concentrations of the simultaneously extracted metals (ΣSEM), considering a significant toxicity when (ΣSEM)/(AVS) is higher than 1. The bioavailability values in the seven stations studied varied from 0.93 to 1.31 (June, 2014) and from 0.34 to 0.58 (September, 2014). These results demonstrated a critical condition of toxicity (bioavailability >1) in six of the seven sediment samples collected during the rainy season (June, 2014). In the other period (September, 2014), the bioavailability was always lower than 1 for all sediment samples collected in the seven stations. The individual values of the concentrations of the five metals were compared with the parameters PEL (probable effects level) and TEL (threshold effects level), which are commonly employed for characterization of ecological risk in environmental systems. This comparison revealed that all metals have concentrations lower than the PEL and only zinc and lead in some stations have contents higher than the TEL. The

  8. Bioavailability assessment of toxic metals using the technique "acid-volatile sulfide (AVS)-simultaneously extracted metals (SEM)" in marine sediments collected in Todos os Santos Bay, Brazil.

    PubMed

    Silva, Jucelino B; Nascimento, Rodrigo A; de Oliva, Sergio T; de Oliveira, Olívia M C; Ferreira, Sergio L C

    2015-10-01

    This paper reports the bioavailability of the metals (cadmium, copper, zinc, lead, and nickel) in sediment samples collected in seven stations from the São Paulo Estuary, Todos os Santos Bay, Brazil. The bioavailability was determined by employing the technique "acid-volatile sulfide (AVS) and simultaneously extracted metal (SEM)". The elements cadmium, copper, lead, and zinc were determined using differential pulse anodic stripping voltammetry (DPASV), while nickel was quantified utilizing electrothermal atomic absorption spectrometry (ET AAS). The accuracy of these methods was confirmed using a certified reference material of estuarine sediment (NIST 1646). The sulfide was quantified using potentiometry with selective electrode and the organic matter determination employing an indirect volumetric method using potassium dichromate and iron(II) sulfate solutions. The bioavailability of the metals was estimated by relationship between the concentration of AVS and the sum of the concentrations of the simultaneously extracted metals (ΣSEM), considering a significant toxicity when (ΣSEM)/(AVS) is higher than 1. The bioavailability values in the seven stations studied varied from 0.93 to 1.31 (June, 2014) and from 0.34 to 0.58 (September, 2014). These results demonstrated a critical condition of toxicity (bioavailability >1) in six of the seven sediment samples collected during the rainy season (June, 2014). In the other period (September, 2014), the bioavailability was always lower than 1 for all sediment samples collected in the seven stations. The individual values of the concentrations of the five metals were compared with the parameters PEL (probable effects level) and TEL (threshold effects level), which are commonly employed for characterization of ecological risk in environmental systems. This comparison revealed that all metals have concentrations lower than the PEL and only zinc and lead in some stations have contents higher than the TEL. The

  9. Solar flares observed by AVS-F instrument onboard CORONAS-F satellite during 2,5 year of it's operation

    NASA Astrophysics Data System (ADS)

    Arkhangelsky, Andrew; Arkhangelskaja, I. V.; Kotov, Yu. D.; Glyaneneko, A. S.; Kuznetsov, S. N.

    AVS-F instrument (Amplitude-Time Spectrometry of the Sun) is the system of an electronics engineering for onboard data gathering from two detectors: scintillation (CsI (Tl)) detector SONG-D (SOlar Neutrons and Gamma quantums) of complex of detectors SKL (in low and high gamma-band) and from semiconducting detector (X-ray semiconducting spectrometer) XSS-1 (in X-ray band). The experiment is carried out on the satellite CORONAS-F launched on July 31 2001. During more than 2,5 year of apparatus operation more than 30 of solar flares were detected. Characteristics of observed solar flares are presented in this article.

  10. Imperfection works: Survival, transmission and persistence in the system of Heliothis virescens ascovirus 3h (HvAV-3h), Microplitis similis and Spodoptera exigua

    PubMed Central

    Li, Shun-Ji; Hopkins, Richard J.; Zhao, Yi-Pei; Zhang, Yun-Xuan; Hu, Jue; Chen, Xu-Yang; Xu, Zhi; Huang, Guo-Hua

    2016-01-01

    Ascoviruses are insect-specific large DNA viruses that mainly infect noctuid larvae, and are transmitted by parasitoids in the fields. Heliothis virescens ascovirus 3h (HvAV-3h) has been recently isolated from Spodoptera exigua, without parasitoid vector identified previously. Here we report that Microplitis similis, a solitary endoparasitoid wasp, could transmit HvAV-3h between S. exigua larvae in the laboratory. When the female parasitoid wasp acquired the virus and served as a vector, the period of virion viability on the ovipositor was 4.1 ± 1.4 days. Infected host larvae were still acceptable for egg laying by parasitoids, and the parasitoids thereafter transmitted virus to healthy hosts. Virus acquisition occurred only from donor hosts between 3 and 9 days post infection. The peak of virus acquisition (80.9 ± 6.3%) was found when M. similis wasps oviposited in larvae that had been inoculated with the virus 7 days previously. When virus infection of the host took place during the life cycle of the parasitoid wasp, it caused 1- to 4-day-old immature parasitoids death in the host, whilst a small proportion of 5- to 6-day-old and the majority of 7-day-old parasitoids larvae survived from the virus-infected hosts. Viral contamination did not reduce the life span or fecundity of female M. similis. PMID:26878829

  11. Overexpression of osteopontin induces angiogenesis of endothelial progenitor cells via the avβ3/PI3K/AKT/eNOS/NO signaling pathway in glioma cells.

    PubMed

    Wang, Yingyi; Yan, Wei; Lu, Xiaoming; Qian, Chunfa; Zhang, Junxia; Li, Ping; Shi, Lei; Zhao, Peng; Fu, Zhen; Pu, Peiyu; Kang, Chunshen; Jiang, Tao; Liu, Ning; You, Yongping

    2011-08-01

    Angiogenesis, a hallmark of tumor growth, is regulated by various angiogenic factors. Recent studies have shown that osteopontin (OPN) is a secreted, integrin-binding protein that contributes to glioma progression. However, its effect on the angiogenesis of gliomas is not fully understood. To elucidate the role of OPN in the process of glioma angiogenesis, endothelial progenitor cells (EPCs) were treated with conditioned media of human glioma SHG44 cells overexpressing OPN. Here, we identified that OPN secreted by glioma cells accelerated EPCs angiogenesis in vitro, including proliferation, migration, and tube formation. OPN also induced the activation of AKT and endothelial nitric oxide synthase (eNOS) and increased NO production without affecting the expression of VEGF, VEGFR-1, or VEGFR-2. Moreover, the avβ3 antibody, the PI3-K inhibitor LY294002 and the eNOS inhibitor NMA suppressed the OPN-mediated increase in NO production and angiogenesis in EPCs. Taken together, these results demonstrate that OPN directly stimulates angiogenesis via the avβ3/PI3-K/AKT/eNOS/NO signaling pathway and may play an important role in tumorigenesis by enhancing angiogenesis in gliomas.

  12. Recommendations for a standardized avian coronavirus (AvCoV) nomenclature: outcome from discussions within the framework of the European Union COST Action FA1207: "towards control of avian coronaviruses: strategies for vaccination, diagnosis and surveillance".

    PubMed

    Ducatez, Mariette F

    2016-10-01

    Viruses within the Coronaviridae family show variations within their genome sequences, especially within the major structural protein the Spike (S) glycoprotein gene. Therefore, many different antigenic forms, serotypes or variant strains of avian coronaviruses (AvCoV) exist worldwide. Only a few of them, the so called protectotypes, cross protect against different serotypes. New serotypes arise by recombination or spontaneous mutations. From time to time, antigenic virus variants appear, which differ significantly from known serotypes. The result of this variability is an inconsistent nomenclature and classification of virus strains. Furthermore, there are currently no standard classification methods defined. Within the framework of the COST Action FA1207 "Towards control of avian coronaviruses: strategies for diagnosis, surveillance and vaccination" (working groups "Molecular virology" and "Epidemiology"), we aimed at defining and developing a unified and internationally standardized nomenclature and classification of AvCoVs. We recommend the use of "CoV Genus/AvCov/host/country/specimen id/year" to refer to AvCoV strains. PMID:27647350

  13. Chemical Soil Degradation n the Area of the Głogów Copper Smelter Protective Forest/ Degradacja Ziemi Na Terenach Byłej Strefy Ochronnej Huty Miedzi Głogów

    NASA Astrophysics Data System (ADS)

    Kostecki, Jakub; Greinert, Andrzej; Drab, Michał; Wasylewicz, Róża; Walczak, Barbara

    2015-06-01

    Earth surface is under the continous influence of the environmental factors - both natural and anthropogenic. The significant impact on the environment can be noted in areas adjacent to the metal industry plants, in a consequence of pollutants emission, especially dusts containing the heavy metals, into the atmosphere,. In the surroundings of Głogów Copper Smelter (GCS) elevated amounts of copper and lead has been noted. In the soils of the test sites were found up to 5250 mg kg-1 Cu and 1290 mg kg-1 Pb. The forest litter contained 3.3-5.1 more Cu and 3.9-8.6 Pb than the humic horizon of the soil. Analyse of the different soils covering the GCS protective forest area let specify the stabilising role of particle size distribution, TOC content and the soil reaction to Cu and Pb migration in the environment. Powierzchnia ziemi jest nieustannnie narażona na oddziaływania o charakterze naturalnym i antropogenicznym. Znaczące oddziaływanie jest łatwo zauważalne na terenach przemysłowych. Szczególnie na obszarach objętych wydobyciem i przeróbką metali. Na terenach przyległych do Huty Miedzi Głogów stwierdzono wysoką koncentrację miedzi i ołowiu sięgającą 5250 mg kg-1 Cu i 1290 mg kg-1 Pb. Poziom ściółki leśnej zawierał 3,3-5,1 raza więcej Cu i 3,9-8,6 Pb niż poziom próchniczny analizowanych gleb. Analiza różnych gleb pokrywających las ochronny HMG pozwoliła wskazać na znaczącą rolę składu granulometrycznego, zawartości węgla organicznego oraz odczynu na stabilizację migracji Cu i Pb w środowisku.

  14. Improved longitudinal [(18)F]-AV45 amyloid PET by white matter reference and VOI-based partial volume effect correction.

    PubMed

    Brendel, Matthias; Högenauer, Marcus; Delker, Andreas; Sauerbeck, Julia; Bartenstein, Peter; Seibyl, John; Rominger, Axel

    2015-03-01

    Amyloid positron-emission-tomography (PET) offers an important research and diagnostic tool for investigating Alzheimer's disease (AD). The majority of amyloid PET studies have used the cerebellum as a reference region, and clinical studies have not accounted for atrophy-based partial volume effects (PVE). Longitudinal studies using cerebellum as reference tissue have revealed only small mean increases and high inter-subject variability in amyloid binding. We aimed to test the effects of different reference regions and PVE-correction (PVEC) on the discriminatory power and longitudinal performance of amyloid PET. We analyzed [(18)F]-AV45 PET and T1-weighted MRI data of 962 subjects at baseline and two-year follow-up data of 258 subjects. Cortical composite volume-of-interest (VOI) values (COMP) for tracer uptake were generated using either full brain atlas VOIs, gray matter segmented VOIs or gray matter segmented VOIs after VOI-based PVEC. Standard-uptake-value ratios (SUVR) were calculated by scaling the COMP values to uptake in cerebellum (SUVRCBL), brainstem (SUVRBST) or white matter (SUVRWM). Mean SUV, SUVR, and changes after PVEC were compared at baseline between diagnostic groups of healthy controls (HC; N=316), mild cognitive impairment (MCI; N=483) and AD (N=163). Receiver operating characteristics (ROC) were calculated for the discriminations between HC, MCI and AD, and expressed as area under the curve (AUC). Finally, the longitudinal [(18)F]-AV45-PET data were used to analyze the impact of quantitation procedures on apparent changes in amyloid load over time. Reference region SUV was most constant between diagnosis groups for the white matter. PVEC led to decreases of COMP-SUV in HC (-18%) and MCI (-10%), but increases in AD (+7%). Highest AUCs were found when using PVEC with white matter scaling for the contrast between HC/AD (0.907) or with brainstem scaling for the contrast between HC/MCI (0.658). Longitudinal increases were greatest in all diagnosis

  15. Measuring Vertical Profiles of Wind, Temperature and Humidity within the Atmospheric Boundary Layer using the Research UAVs 'M2AV Carolo'

    NASA Astrophysics Data System (ADS)

    Bange, J.; Martin, S.

    2009-09-01

    The measurement of vertical profiles is important to characterise the vertical structure of the atmospheric boundary layer (ABL). For instance, the dependence of the potential temperature on altitude defines the thermal stratification. The mechanical shear (i.e. the variation of wind speed and direction) produces turbulence and turbulent fluxes. The top of the ABL is required for scaling approaches (e.g. Deardorff scaling in the convective boundary layer, local scaling in the stable boundary layer). The Meteorological Mini Aerial Vehicles (M²AV) are self-constructed, automatically operating research aircraft of 6 kg in weight (including 1.5 kg scientific payload) and 2 m wingspan. These systems are capable of performing turbulence measurements (wind vector, temperature and humidity) and are used as a new instrument for measuring vertical profiles of the lower troposphere. Compared to a radiosonde, the spatial resolution of the M²AV is significantly higher. Especially the wind measurement is significantly more accurate compared to radiosonde data when using an aircraft that is equipped with a proper flow sensor (mainly a five-hole probe). It is important to maintain flow angles (sideslip and angle of attack) within the calibration range (typically 10 to 20 degree). This limits the vertical speed (the rate of climb and descent) of the research aircraft. In general there are two approaches to measure vertical profiles with research aircraft. Instantaneous profiles (slant flight pattern) are suitable if only little time is available, if the ABL is very in-stationary (or the aircraft is slow), if the dependence of the profile on time is requested (repeated slant flight patterns over one location) or if the dependence of the profile on the location is requested (saw-tooth pattern). For mean profiles (horizontal straight and level flights 'legs' at several altitudes within the ABL) it is necessary to use fast sensors. If the response time is too large, the vertical

  16. Bibliography of AV Materials.

    ERIC Educational Resources Information Center

    Journal of Chemical Education, 1981

    1981-01-01

    Presented is the second part of a bibliographic listing of commercially available audiovisual materials for chemistry. Information includes producer (with addresses), catalog number, format (slides, cassettes, filmstrips, films), and price for items in these categories: matter and energy, nuclear chemistry, periodic table, solids and crystals,…

  17. The AV Consultant

    ERIC Educational Resources Information Center

    Wadsworth, Raymond H.

    1976-01-01

    An audiovisual communications consultant involved in planning a new facility is able to translate the needs of educators into integrated systems, and relate these to the architects and engineers in terms of working drawings, specifications, system descriptions, functional schematics, and block diagrams. (Author/MLF)

  18. Bibliography of AV Materials.

    ERIC Educational Resources Information Center

    Friedstein, Harriet, Ed.

    1981-01-01

    Lists commercially available audiovisual materials by subject area. Includes title, producer (addresses given), catalog number, format (film, filmstrip, cassette, slides), and prices. Subject areas include: elements; equilibrium; gases; laboratory techniques and experiments; general chemistry; introductory materials (including mathematics); and…

  19. Is it time to retire the A.V. Hill Model?: A rebuttal to the article by Professor Roy Shephard.

    PubMed

    Noakes, Timothy D

    2011-04-01

    philosophies of how science should be conducted according to either the Kuhnian or the Popperian philosophies of scientific discovery. My conclusion is that the dominance of an authoritarian Kuhnian philosophy, which refuses to admit genuine error or "the need to alter one's course of belief or action," explains why there is little appetite in the exercise sciences for the acceptance of genuinely novel ideas such as the CGM. Furthermore, to advance the case for the CGM, I now include evidence from more than 30 studies, which, in my opinion, can only be interpreted according to a model of exercise regulation where the CNS, acting in an anticipatory manner, regulates the exercise behaviour by altering skeletal muscle recruitment, specifically to ensure that homeostasis is maintained during exercise. Since few, if any, of those studies can be explained by the 'brainless' A.V. Hill Cardiovascular Model on which Professor Shephard bases his arguments, I argue that it is now the appropriate time to retire that model. Perhaps this will bring to an end the charade that holds either (i) that the brain plays no part in the regulation of exercise performance; or, conversely, (ii) that the role of the brain is already so well defined that further research by other scientists is unnecessary. However, this cannot occur in a discipline that is dominated by an authoritarian Kuhnian philosophy. PMID:21425886

  20. Navier-Stokes simulation of external/internal transonic flow on the forebody/inlet of the AV-8B Harrier II

    NASA Technical Reports Server (NTRS)

    Mysko, Stephen J.; Chyu, Wei J.; Stortz, Michael W.; Chow, Chuen-Yen

    1993-01-01

    In this work, the computation of combined external/internal transonic flow on the complex forebody/inlet configuration of the AV-8B Harrier II is performed. The actual aircraft has been measured and its surface and surrounding domain, in which the fuselage and inlet have a common wall, have been described using structured grids. The 'thin-layer' Navier-Stokes equations were used to model the flow along with the Chimera embedded multi-block technique. A fully conservative, alternating direction implicit (ADI), approximately factored, partially fluxsplit algorithm was employed to perform the computation. Comparisons to some experimental wind tunnel data yielded good agreement for flow at zero incidence and angle of attack. The aim of this paper is to provide a methodology or computational tool for the numerical solution of complex external/internal flows.

  1. Acid Volatile Sulfides (avs) and the Bioavailability of Trace Metals in the Channel of the SÃO Francisco River, Sepetiba Bay - de Janeiro-Brazil

    NASA Astrophysics Data System (ADS)

    Monte, Christiane; Rodrigues, Ana Paula; Marinho, Matheus; Quaresma, Tássia; Machado, Wilson

    2014-05-01

    Sepetiba Bay has 430 Km2 of internal and 2,500 Km2 area of the drainage basin (Lacerda et al., 2007), located 60 km west of the city of Rio de Janeiro. Sepetiba Bay has 430 Km2 of internal and 2,500 Km2 area of the drainage basin (Lacerda et al., 2007), located 60 km west of the city of Rio de Janeiro.The San Francisco channel comes from the Guandu River and empties into Sepetiba Bay and is the main contributor of freshwater to the estuarine system. The Guandu River system/channel of San Francisco receives contribution of domestic and industrial effluents, which go largely to Sepetiba Bay. This work aimed to evaluate the .This work aimed to evaluate the ratio SEM/AVS as a way of predicting bioavailability trace metals from industrial sewage, mainly, in the estuarine system of Sepetiba. This model is based on the property of some Divalent metal cations (Cd, Cu, Ni, Pb and Zn), by presenting a low solubility constant, are removed from the soluble fraction by precipitation, forming secondary metal sulfides. Were held four transects, made up of three points each, the coast line to the center of the Bay. The surface sediment was collected with a van Veen sampler type ,packed in glass jars and kept frozen until analysis.The determination of SEM/AVS followed the methodology described by Allen et al. (1991). The variation between sulfide 159.88 ± 0.05 µmol/g on 12 points. The metals that entered the sum of simultaneous extraction were: Cd, Cu, Ni, Pb and Zn ranging from: 6.47 ± 0.11 µmol/g on sum.The means (± standard deviation) ratio SEM/AVS per transect were: 1.04 ± 1.20 (transect 1); 0.48 ± 0.53 (transect 2); 1.26 ± 1.32 (transect 3) and 0.18 ± 0.14 (transect 4). Only transects 1 and 3 had higher results than 1 , meaning that there are more divalent metal sulfides in the environment. This means that only the sulfides would not be capable of complex and may reflect the potential bioavailability of these in the aquatic environment. There is no statistical

  2. Modeling the influence of the VV delay for CRT on the electrical activation patterns in absence of conduction through the AV node

    NASA Astrophysics Data System (ADS)

    Romero, D. A.; Sebastián, Rafael; Plank, Gernot; Vigmond, Edward J.; Frangi, Alejandro F.

    2008-03-01

    From epidemiological studies, it has been shown that 0.2% of men and 0.1% of women suffer from a degree of atrioventricular (AV) block. In recent years, the palliative treatment for third degree AV block has included Cardiac Resynchronization Therapy (CRT). It was found that patients show more clinical improvement in the long term with CRT compared with single chamber devices. Still, an important group of patients does not improve their hemodynamic function as much as could be expected. A better understanding of the basis for optimizing the devices settings (among which the VV delay) will help to increase the number of responders. In this work, a finite element model of the left and right ventricles was generated using an atlas-based approach for their segmentation, which includes fiber orientation. The electrical activity was simulated with the electrophysiological solver CARP, using the Ten Tusscher et al. ionic model for the myocardium, and the DiFrancesco-Noble for Purkinje fibers. The model is representative of a patient without dilated or ischemic cardiomyopathy. The simulation results were analyzed for total activation times and latest activated regions at different VV delays and pre-activations (RV pre-activated, LV pre-activated). To optimize the solution, simulations are compared against the His-Purkinje network activation (normal physiological conduction), and interventricular septum activation (as collision point for the two wave fronts). The results were analyzed using Pearson's coefficient of correlation for point to point comparisons between simulation cases. The results of this study contribute to gain insight on the VV delay and how its adjustment might influence response to CRT and how it can be used to optimize the treatment.

  3. Evidence for regulation of columnar habit in apple by a putative 2OG-Fe(II) oxygenase.

    PubMed

    Wolters, Pieter J; Schouten, Henk J; Velasco, Riccardo; Si-Ammour, Azeddine; Baldi, Paolo

    2013-12-01

    Understanding the genetic mechanisms controlling columnar-type growth in the apple mutant 'Wijcik' will provide insights on how tree architecture and growth are regulated in fruit trees. In apple, columnar-type growth is controlled by a single major gene at the Columnar (Co) locus. By comparing the genomic sequence of the Co region of 'Wijcik' with its wild-type 'McIntosh', a novel non-coding DNA element of 1956 bp specific to Pyreae was found to be inserted in an intergenic region of 'Wijcik'. Expression analysis of selected genes located in the vicinity of the insertion revealed the upregulation of the MdCo31 gene encoding a putative 2OG-Fe(II) oxygenase in axillary buds of 'Wijcik'. Constitutive expression of MdCo31 in Arabidopsis thaliana resulted in compact plants with shortened floral internodes, a phenotype reminiscent of the one observed in columnar apple trees. We conclude that MdCo31 is a strong candidate gene for the control of columnar growth in 'Wijcik'.

  4. Application of PET2OGS to CO2 storage in a saline aquifer of the CO2CRC Otway project

    NASA Astrophysics Data System (ADS)

    Park, Chan-Hee; Shinn, Young Jae

    2014-05-01

    PET2OGS, a set of algorithms that integrate the static model (Petrel) with the dynamic model (OpenGeoSys), is applied to model CO2 storage in a saline aquifer. The Otway Basin is the first demonstration site of the deep geological storage of carbon dioxide as part of carbon capture and storage (CCS) technology in Australia. During Stage 2 of the CO2CRC Otway project, CO2 was injected into a saline aquifer along the injection interval of 1435 - 1450 m in a well. Upon conversion and adaption of the geological model into the dynamic model, the simulation of CO2 injection at 159 tone/day for 5 months is carried out for a hypothetical scenario. CO2 storage in each facies are analyzed for storage capacities. The discrete nature of CO2 plume behaviors known in multiphase flow in heterogeneous media is observed in the numerical simulation of CO2 storage. Sensitivity analysis of the storage capacity with respect to facies, porosity, and permeability is provided.

  5. Spectroscopic studies of Cepheids in Circinus (AV Cir, BP Cir) and Triangulum Australe (R TrA, S TrA, U TrA, LR TrA)

    NASA Astrophysics Data System (ADS)

    Usenko, I. A.; Kniazev, A. Yu.; Berdnikov, L. N.; Kravtsov, V. V.

    2014-12-01

    Based on high-resolution spectra taken with the 1.9-m telescope of the South African Astronomical Observatory, we have determined the atmospheric parameters and chemical composition for three small-amplitude (AV Cir, BP Cir, and LR TrA), two classical (R TrA and S TrA), and one double-mode (U TrA) Cepheids. The averaged atmospheric parameters have been estimated for three Cepheids (AV Cir, BP Cir, and U TrA) observed at various pulsation phases. In all Cepheids, except U TrA, the metallicity has turned out to be higher than the solar one by 0.1-0.2 dex. The abundances of the key elements of the evolution of yellow supergiants (C, O, Na, Mg, Al) show that these objects have already passed the first dredge-up, while those of the remaining elements are nearly solar. Comparison of our results on the Cepheids from the list (except U TrA) with those of other authors shows significant differences in C and O abundance estimates for AV Cir, R TrA, S TrA, and LR TrA. For AV Cir and BP Cir, the H α line profiles are symmetric but with a slight asymmetry in the core at approximately the same phase near 0{·/ P } 7: on the "blue" side for AV Cir and on the "red" one for BP Cir. BP Cir exhibits a distinct asymmetry in the absorption lines of neutral atoms and ions at various pulsation phases, which can be explained by nonradial first-overtone pulsations. The constancy of the H α absorption line profiles with pulsation phase for AV Cir and BP Cir may suggest the presence of a hydrogen envelope around them. For the double-mode Cepheid U TrA, an asymmetry is observed in the cores of the H α line and the absorption lines of neutral atoms and ions at various pulsation phases, which can be explained by nonradial pulsations in the Cepheid's atmosphere. The absorption lines of neutral atoms and ions of metals in LR TrA closely resemble those in the well-known Cepheid BG Cru: secondary "blue" and "red" components whose line depths vary with pulsation phase are noticeable. This Cepheid

  6. SU-D-9A-01: Listmode-Driven Optimal Gating (OG) Respiratory Motion Management: Potential Impact On Quantitative PET Imaging

    SciTech Connect

    Lee, K; Hristov, D

    2014-06-01

    Purpose: To evaluate the potential impact of listmode-driven amplitude based optimal gating (OG) respiratory motion management technique on quantitative PET imaging. Methods: During the PET acquisitions, an optical camera tracked and recorded the motion of a tool placed on top of patients' torso. PET event data were utilized to detect and derive a motion signal that is directly coupled with a specific internal organ. A radioactivity-trace was generated from listmode data by accumulating all prompt counts in temporal bins matching the sampling rate of the external tracking device. Decay correction for 18F was performed. The image reconstructions using OG respiratory motion management technique that uses 35% of total radioactivity counts within limited motion amplitudes were performed with external motion and radioactivity traces separately with ordered subset expectation maximization (OSEM) with 2 iterations and 21 subsets. Standard uptake values (SUVs) in a tumor region were calculated to measure the effect of using radioactivity trace for motion compensation. Motion-blurred 3D static PET image was also reconstructed with all counts and the SUVs derived from OG images were compared with SUVs from 3D images. Results: A 5.7 % increase of the maximum SUV in the lesion was found for optimal gating image reconstruction with radioactivity trace when compared to a static 3D image. The mean and maximum SUVs on the image that was reconstructed with radioactivity trace were found comparable (0.4 % and 4.5 % increase, respectively) to the values derived from the image that was reconstructed with external trace. Conclusion: The image reconstructed using radioactivity trace showed that the blurring due to the motion was reduced with impact on derived SUVs. The resolution and contrast of the images reconstructed with radioactivity trace were comparable to the resolution and contrast of the images reconstructed with external respiratory traces. Research supported by Siemens.

  7. Cross-cultural adaptation and determination of the reliability and validity of PRTEE-S (Patientskattad Utvärdering av Tennisarmbåge), a questionnaire for patients with lateral epicondylalgia, in a Swedish population

    PubMed Central

    Nilsson, Pia; Baigi, Amir; Marklund, Bertil; Månsson, Jörgen

    2008-01-01

    Background In Sweden, as well as in Scandinavia, there is no easy way to evaluate patients' difficulties when they suffer from lateral epicondylitis/epicondylalgia. However, there is a Canadian questionnaire, in English, that could make the evaluation of a patient's pain and functional loss both quick and inexpensive. Therefore, the aim of this study was to translate and cross-culturally adapt the questionnaire "Patient-rated Tennis Elbow Evaluation" into Swedish (PRTEE-S; "Patientskattad Utvärdering av Tennisarmbåge"), and to evaluate the reliability and validity of the test. Methods The Patient-rated Tennis Elbow Evaluation was cross-culturally adapted for the Swedish language according to well-established guidelines. Fifty-four patients with unilateral epicondylitis/epicondylalgia were assessed using the PRTEE-S (Patientskattad Utvärdering av Tennisarmbåge), the Disabilities of Arm, Shoulder, and Hand questionnaire, and the Roles & Maudsley score to establish the validity and reliability of the PRTEE-S. Reliability was determined via calculation of the intra-class correlation coefficient (ICC) the internal consistency was assessed by Cronbach's alpha, and validity was calculated using Spearman's correlation coefficient. Results The test-retest reliability, using the PRTEE-S (Patientskattad Utvärdering av Tennisarmbåge) intraclass correlation coefficient, was 0.95 and the internal consistency was 0.94. The PRTEE-S correlated well with the Disabilities of the Arm, Shoulder, and Hand questionnaire (r = 0.88) and the Roles & Maudsley score (r = 0.78). Conclusion The PRTEE-S (Patientskattad Utvärdering av Tennisarmbåge) represents a reliable and valid instrument to evaluate the subjective outcome in Swedish speaking patients with lateral epicondylitis/epicondylalgia, and can be used in both research and clinical settings. PMID:18534009

  8. OGS#PETSc approach for robust and efficient simulations of strongly coupled hydrothermal processes in EGS reservoirs

    NASA Astrophysics Data System (ADS)

    Watanabe, Norihiro; Blucher, Guido; Cacace, Mauro; Kolditz, Olaf

    2016-04-01

    A robust and computationally efficient solution is important for 3D modelling of EGS reservoirs. This is particularly the case when the reservoir model includes hydraulic conduits such as induced or natural fractures, fault zones, and wellbore open-hole sections. The existence of such hydraulic conduits results in heterogeneous flow fields and in a strengthened coupling between fluid flow and heat transport processes via temperature dependent fluid properties (e.g. density and viscosity). A commonly employed partitioned solution (or operator-splitting solution) may not robustly work for such strongly coupled problems its applicability being limited by small time step sizes (e.g. 5-10 days) whereas the processes have to be simulated for 10-100 years. To overcome this limitation, an alternative approach is desired which can guarantee a robust solution of the coupled problem with minor constraints on time step sizes. In this work, we present a Newton-Raphson based monolithic coupling approach implemented in the OpenGeoSys simulator (OGS) combined with the Portable, Extensible Toolkit for Scientific Computation (PETSc) library. The PETSc library is used for both linear and nonlinear solvers as well as MPI-based parallel computations. The suggested method has been tested by application to the 3D reservoir site of Groß Schönebeck, in northern Germany. Results show that the exact Newton-Raphson approach can also be limited to small time step sizes (e.g. one day) due to slight oscillations in the temperature field. The usage of a line search technique and modification of the Jacobian matrix were necessary to achieve robust convergence of the nonlinear solution. For the studied example, the proposed monolithic approach worked even with a very large time step size of 3.5 years.

  9. Increasing the probability of long-range (1 month) SPI index forecasts based on SL-AV model for the Russian territory.

    NASA Astrophysics Data System (ADS)

    Utkuzova, Dilyara; Khan, Valentina; Donner, Reik

    2016-04-01

    taken from CPC_CAMS archive) was integrated with MSLP atmospheric pressure field (from ERA Interim achieve) to create special type of SPI combined maps. As a basic seasonal forecasting model we took the SL-AV (Semi-implicit semi-Lagrangian vorticity-divergence dynamical core) model (Tolstykh, 2010) which runs in Hydrometcentre of Russia and has ALADIN/LACE parameterization. Skill scores of SPI calculation based on SL-AV hindcasts showed that it is necessary to use statistical methodology which can increase one month SPI index predictability. Calculations showed that for a new scheme the best predictors are pressure fields on the H500 and MSLP levels. This data was taken from SL-AV model hindcasts for all North Eurasian territory. The main idea of cross-correlation analysis between SPI data and pressure was to show interconnections between precipitation and pressure in different areas and detect the informative prognostic predictors (areas) for each SPI. Then using all information which was extracted before the regression analysis was done. This analysis helped to reconstruct forecasting SPI for the territory of Russia in two ways - deterministic and probabilistic. The resulting forecasts skill scores for both types of predictions are acceptable and scheme can be used in operational precipitation forecasts with one month in advance.

  10. CSF Biomarkers and Its Associations with 18F-AV133 Cerebral VMAT2 Binding in Parkinson’s Disease—A Preliminary Report

    PubMed Central

    Gao, Rui; Zhang, Guangjian; Chen, Xueqi; Yang, Aimin; Smith, Gwenn; Wong, Dean F.; Zhou, Yun

    2016-01-01

    Objective Cerebrospinal fluid (CSF) biomarkers, such as α-synuclein (α-syn), amyloid beta peptide 1–42 (Aβ1–42), phosphorylated tau (181P) (p-tau), and total tau (t-tau), have long been associated with the development of Parkinson disease (PD) and other neurodegenerative diseases. In this investigation, we reported the assessment of CSF biomarkers and their correlations with vesicular monoamine transporter 2 (VMAT2) bindings measured with 18F-9-fluoropropyl-(+)-dihydrotetrabenazine (18F-AV133) that is being developed as a biomarker for PD. We test the hypothesis that monoaminergic degeneration was correlated with CSF biomarker levels in untreated PD patients. Methods The available online data from the Parkinson’s Progression Markers Initiative study (PPMI) project were collected and analyzed, which include demographic information, clinical evaluations, CSF biomarkers (α-syn, Aβ1–42, p-tau, and t-tau), 18F-AV133 brain PET, and T1 weighted MRIs. Region of interest (ROI) and voxel-wise Pearson correlation between standardized uptake value ratio (SUVR) and CSF biomarkers were calculated. Results Our major findings are: 1) Compared with controls, CSF α-syn and tau levels decreased significantly in PD; 2) α-syn was closely correlated with Aβ1–42 and tau in PD, especially in early-onset patients; and 3) hypothesis-driven ROI analysis found a significant negative correlation between CSF Aβ1–42 levels and VMAT2 densities in post cingulate, left caudate, left anterior putamen, and left ventral striatum in PDs. CSF t-tau and p-tau levels were significantly negatively related to VMAT2 SUVRs in substantia nigra and left ventral striatum, respectively. Voxel-wise analysis showed that left caudate, parahippocampal gyrus, insula and temporal lobe were negatively correlated with Aβ1–42. In addition, superior frontal gyrus and transverse temporal gyrus were negatively correlated with CSF p-tau levels. Conclusion These results suggest that monoaminergic

  11. Searching iron sensors in plants by exploring the link among 2′-OG-dependent dioxygenases, the iron deficiency response and metabolic adjustments occurring under iron deficiency

    PubMed Central

    Vigani, Gianpiero; Morandini, Piero; Murgia, Irene

    2013-01-01

    Knowledge accumulated on the regulation of iron (Fe) homeostasis, its intracellular trafficking and transport across various cellular compartments and organs in plants; storage proteins, transporters and transcription factors involved in Fe metabolism have been analyzed in detail in recent years. However, the key sensor(s) of cellular plant “Fe status” triggering the long-distance shoot–root signaling and leading to the root Fe deficiency responses is (are) still unknown. Local Fe sensing is also a major task for roots, for adjusting the internal Fe requirements to external Fe availability: how such sensing is achieved and how it leads to metabolic adjustments in case of nutrient shortage, is mostly unknown. Two proteins belonging to the 2′-OG-dependent dioxygenases family accumulate several folds in Fe-deficient Arabidopsis roots. Such proteins require Fe(II) as enzymatic cofactor; one of their subgroups, the HIF-P4H (hypoxia-inducible factor-prolyl 4-hydroxylase), is an effective oxygen sensor in animal cells. We envisage here the possibility that some members of the 2′-OG dioxygenase family may be involved in the Fe deficiency response and in the metabolic adjustments to Fe deficiency or even in sensing Fe, in plant cells. PMID:23755060

  12. Transcriptomes analysis of Aeromonas molluscorum Av27 cells exposed to tributyltin (TBT): Unravelling the effects from the molecular level to the organism

    PubMed Central

    Cruz, Andreia; Rodrigues, Raquel; Pinheiro, Miguel; Mendo, Sónia

    2015-01-01

    Aeromonas molluscorum Av27 cells were exposed to 0, 5 and 50 μM of TBT and the respective transcriptomes were obtained by pyrosequencing. Gene Ontology revealed that exposure to 5 μM TBT results in a higher number of repressed genes in contrast with 50 μM of TBT, where the number of over-expressed genes is greater. At both TBT concentrations, higher variations in gene expression were found in the functional categories associated with enzymatic activities, transport/binding and oxidation-reduction. A number of proteins are affected by TBT, such as the acriflavin resistance protein, several transcription-related proteins, several Hsps, ABC transporters, CorA and ZntB and other outer membrane efflux proteins, all of these involved in cellular metabolic processes, important to maintain overall cell viability. Using the STRING tool, several proteins with unknown function were related with others involved in degradation processes, such as the pyoverdine chromophore biosynthetic protein, that has been described as playing a role in the Sn–C cleavage of organotins. This approach has allowed a better understanding of the molecular effects of exposure of bacterial cells to TBT. Furthermore it contributes to the knowledge of the functional genomic aspects of bacteria exposed to this pollutant. Furthermore, the transcriptomic data gathered, and now publically available, constitute a valuable resource for comparative genome analysis. PMID:26171931

  13. Transcriptomes analysis of Aeromonas molluscorum Av27 cells exposed to tributyltin (TBT): Unravelling the effects from the molecular level to the organism.

    PubMed

    Cruz, Andreia; Rodrigues, Raquel; Pinheiro, Miguel; Mendo, Sónia

    2015-08-01

    Aeromonas molluscorum Av27 cells were exposed to 0, 5 and 50 μM of TBT and the respective transcriptomes were obtained by pyrosequencing. Gene Ontology revealed that exposure to 5 μM TBT results in a higher number of repressed genes in contrast with 50 μM of TBT, where the number of over-expressed genes is greater. At both TBT concentrations, higher variations in gene expression were found in the functional categories associated with enzymatic activities, transport/binding and oxidation-reduction. A number of proteins are affected by TBT, such as the acriflavin resistance protein, several transcription-related proteins, several Hsps, ABC transporters, CorA and ZntB and other outer membrane efflux proteins, all of these involved in cellular metabolic processes, important to maintain overall cell viability. Using the STRING tool, several proteins with unknown function were related with others involved in degradation processes, such as the pyoverdine chromophore biosynthetic protein, that has been described as playing a role in the Sn-C cleavage of organotins. This approach has allowed a better understanding of the molecular effects of exposure of bacterial cells to TBT. Furthermore it contributes to the knowledge of the functional genomic aspects of bacteria exposed to this pollutant. Furthermore, the transcriptomic data gathered, and now publically available, constitute a valuable resource for comparative genome analysis. PMID:26171931

  14. Cholera in Pregnancy: Outcomes from a Specialized Cholera Treatment Unit for Pregnant Women in Léogâne, Haiti

    PubMed Central

    Ciglenecki, Iza; Bichet, Mathieu; Tena, Javier; Mondesir, Erneau; Bastard, Mathieu; Tran, Nguyen-Toan; Antierens, Annick; Staderini, Nelly

    2013-01-01

    Background The association between cholera in pregnancy and negative fetal outcome has been described since the 19th century. However, there is limited published literature on the subject. We describe pregnancy outcomes from a specialized multidisciplinary hospital unit at the onset of a large cholera outbreak in Haiti in 2010 and 2011. Methods Pregnant women with cholera were hospitalized in a specialized unit within the MSF hospital compound in Léogâne and treated using standard cholera treatment guidelines but with earlier, more intense fluid replacement. All women had intravenous access established at admission regardless of their hydration status, and all received antibiotic treatment. Data were collected on patient demographics, pregnancy and cholera status, and pregnancy outcome. In this analysis we calculated risk ratios for fetal death and performed logistic regression analysis to control for confounding factors. Results 263 pregnant women with cholera were hospitalized between December 2010 and July 2011. None died during hospitalization, 226 (86%) were discharged with a preserved pregnancy and 16 (6%) had live fullterm singleton births, of whom 2 died within the first 5 days postpartum. The remaining 21 pregnancies (8%) resulted in intrauterine fetal death. The risk of fetal death was associated with factors reflecting severity of the cholera episode: after adjusting for confounding factors, the strongest risk factor for fetal death was severe maternal dehydration (adjusted risk ratio for severe vs. mild dehydration was 9.4, 95% CI 2.5–35.3, p = 0.005), followed by severe vomiting (adjusted risk ratio 5.1, 95% 1.1–23.8, p = 0.041). Conclusion This is the largest cohort of pregnant women with cholera described to date. The main risk factor identified for fetal death was severity of dehydration. Our experience suggests that establishing specialized multidisciplinary units which facilitate close follow-up of both pregnancy and dehydration

  15. Audiovisual heritage preservation in Earth and Space Science Informatics: Videos from Free and Open Source Software for Geospatial (FOSS4G) conferences in the TIB|AV-Portal.

    NASA Astrophysics Data System (ADS)

    Löwe, Peter; Marín Arraiza, Paloma; Plank, Margret

    2016-04-01

    continues to grow - and so does the number of topics to be addressed at conferences. Up to now, commercial Web 2.0 platforms like Youtube and Vimeo were used. However, these platforms lack capabilities for long-term archiving and scientific citation, such as persistent identifiers that permit the citation of specific intervals of the overall content. To address these issues, the scientific library community has started to implement improved multimedia archiving and retrieval services for scientific audiovisual content which fulfil these requirements. Using the reference case of the OSGeo conference video recordings, this paper gives an overview over the new and growing collection activities by the German National Library of Science and Technology for audiovisual content in Geoinformatics/ESSI in the TIB|AV Portal for audiovisual content. Following a successful start in 2014 and positive response from the OSGeo Community, the TIB acquisition strategy for OSGeo video material was extended to include German, European, North-American and global conference content. The collection grows steadily by new conference content and also by harvesting of past conference videos from commercial Web 2.0 platforms like Youtube and Vimeo. This positions the TIB|AV-Portal as a reliable and concise long-term resource for innovation mining, education and scholarly research within the ESSI context both within Academia and Industry.

  16. Correlation of amyloid PET ligand florbetapir F 18 (18F-AV-45) binding with β-amyloid aggregation and neuritic plaque deposition in postmortem brain tissue

    PubMed Central

    Choi, Seok Rye; Schneider, Julie A.; Bennett, David A.; Beach, Thomas G.; Bedell, Barry J.; Zehntner, Simone P.; Krautkramer, Michael; Kung, Hank F.; Skovronsky, Daniel M.; Hefti, Franz; Clark, Christopher M.

    2011-01-01

    Background Florbetapir F 18 (18F-AV-45) is a positron emission tomography (PET) imaging ligand for the detection of amyloid aggregation associated with Alzheimer’s disease. Earlier data showed that florbetapir F 18 binds with high affinity to β-amyloid plaques in human brain homogenates (Kd = 3.7 nM) and has favorable imaging pharmacokinetic properties, including rapid brain penetration and washout. The present study used human autopsy brain tissue to evaluate the correlation between in vitro florbetapir F 18 binding and β-amyloid density measured by established neuropathological methods. Methods The localization and density of florbetapir F 18 binding in frozen and formalin-fixed paraffin-embedded sections of postmortem brain tissue from 40 subjects with a varying degree of neurodegenerative pathology was assessed by standard florbetapir F 18 autoradiography and correlated with the localization and density of β-amyloid identified by silver staining, thioflavin S staining, and immunohistochemistry. Results There were strong quantitative correlations between florbetapir F 18 tissue binding and both β-amyloid plaques identified by light microscopy (sliver staining and thioflavin S fluorescence) and by immunohistochemical measurements of β-amyloid using three antibodies recognizing different epitopes of the β-amyloid peptide (Aβ). Florbetapir F 18 did not bind to neurofibrillary tangles. Conclusion Florbetapir F 18 selectively binds β-amyloid in human brain tissue. The binding intensity was quantitatively correlated with the density of β-amyloid plaques identified by standard neuropathological techniques and correlated with the density of Aβ measured by immunohistochemistry. Since β-amyloid plaques are a defining neuropathological feature for Alzheimer’s disease, these results support the use of florbetapir F 18 as an amyloid PET ligand to identify the presence of AD pathology in patients with signs and symptoms of progressive late-life cognitive

  17. The Acute Effects of Changes to AV Delay on Blood Pressure and Stroke Volume: Potential Implications for Design of Pacemaker Optimization Protocols

    PubMed Central

    Manisty, Charlotte H.; Al-Hussaini, Ali; Unsworth, Beth; Baruah, Resham; Pabari, Punam A.; Mayet, Jamil; Hughes, Alun D.; Whinnett, Zachary I.; Francis, Darrel P.

    2012-01-01

    Background Atrioventricular (AV) delay optimization of biventricular pacemakers (cardiac resynchronization therapy, CRT) may maximise hemodynamic benefit, but consumes specialist time to conduct echocardiographically. Non-invasive blood pressure monitoring is a potentially-automatable alternative, but it is unknown whether it gives the same information, and similar precision (signal-to-noise ratio). Moreover, the immediate blood pressure increment on optimization has been reported to decay away: it is unclear whether this is the result of an (undesirable) fall in stroke volume or a (desirable) compensatory relief of peripheral vasoconstriction. Methods and Results To discriminate between these alternative mechanisms, we measured simultaneous beat-to-beat stroke volume (flow) using Doppler echocardiography, and blood pressure (BP) using finger photoplethysmography, during and after atrioventricular delay changes from 40 to 120 ms in 19 subjects with cardiac pacemakers. BP and stroke volume both increased immediately (p<0.001, within one heartbeat). BP showed a clear decline a few seconds later (average rate −0.65mmHg/beat, r=0.95 [95% CI 0.86 to 0.98]); in contrast, stroke volume did not decline (p=0.87). The immediate BP increment correlated strongly with the stroke volume increment (r=0.74, p<0.001). Signal-to-noise ratio was threefold better for BP than stroke volume (6.8±3.5 versus 2.3±1.4, p<0.001). Conclusions Improving atrioventricular delay immediately increases blood pressure, but the effect begins to decay within a few seconds. Reassuringly this is due to compensatory vasodilatation rather than reduction in cardiac function. Pacemaker optimization will never be reliable unless there is adequate signal-to-noise ratio. Using BP rather than Doppler minimises noise. The early phase – before vascular compensation – has the richest signal lode. PMID:22095639

  18. Calcium release near L-type calcium channels promotes beat-to-beat variability in ventricular myocytes from the chronic AV block dog.

    PubMed

    Antoons, Gudrun; Johnson, Daniel M; Dries, Eef; Santiago, Demetrio J; Ozdemir, Semir; Lenaerts, Ilse; Beekman, Jet D M; Houtman, Marien J C; Sipido, Karin R; Vos, Marc A

    2015-12-01

    Beat-to-beat variability of ventricular repolarization (BVR) has been proposed as a strong predictor of Torsades de Pointes (TdP). BVR is also observed at the myocyte level, and a number of studies have shown the importance of calcium handling in influencing this parameter. The chronic AV block (CAVB) dog is a model of TdP arrhythmia in cardiac hypertrophy, and myocytes from these animals show extensive remodeling, including of Ca(2+) handling. This remodeling process also leads to increased BVR. We aimed to determine the role that (local) Ca(2+) handling plays in BVR. In isolated LV myocytes an exponential relationship was observed between BVR magnitude and action potential duration (APD) at baseline. Inhibition of Ca(2+) release from sarcoplasmic reticulum (SR) with thapsigargin resulted in a reduction of [Ca(2+)]i, and of both BVR and APD. Increasing ICaL in the presence of thapsigargin restored APD but BVR remained low. In contrast, increasing ICaL with preserved Ca(2+) release increased both APD and BVR. Inhibition of Ca(2+) release with caffeine, as with thapsigargin, reduced BVR despite maintained APD. Simultaneous inhibition of Na(+)/Ca(2+) exchange and ICaL decreased APD and BVR to similar degrees, whilst increasing diastolic Ca(2+). Buffering of Ca(2+) transients with BAPTA reduced BVR for a given APD to a greater extent than buffering with EGTA, suggesting subsarcolemmal Ca(2+) transients modulated BVR to a larger extent than the cytosolic Ca(2+) transient. In conclusion, BVR in hypertrophied dog myocytes, at any APD, is strongly dependent on SR Ca(2+) release, which may act through modulation of the l-type Ca(2+) current in a subsarcolemmal microdomain.

  19. Analysis of T cell receptor AV and BV chain gene expression by infiltrating lymphocytes in Spitz naevi and in halo naevi.

    PubMed

    Birck, A; thor Straten, P; Li, L; Hou-Jensen, K; Sugár, J; Zeuthen, J

    1997-02-01

    Spitz naevi and halo naevi are benign melanocytic lesions that share many histological features with malignant melanoma. All lesions are characterized by a brisk infiltration of lymphocytes, mainly of the T cell subtype, and halo naevi are known to undergo spontaneous regression. Since the benign nature of Spitz naevi and halo naevi might therefore be caused by specific T cell responses against tumour-associated antigens, it was found of interest to characterize this T cell response in detail. A reverse transcriptase-polymerase chain reaction (RT-PCR)-based method adapted for analysis of paraffin-embedded material combined with Southern blot analysis has been used to analyse the T cell receptor (TCR) AV and BV repertoires of infiltrating lymphocytes in 14 different melanocytic lesions. The results have shown that only a few particular TCRAV and TCRBV regions are expressed in each lesion. To evaluate the T cell response, it is of interest to know the HLA-type of the analysed lesions, since most melanoma-specific effector lymphocytes are CD8+ cytotoxic T cells and therefore HLA class I-restricted. As blood samples were not available from any of these patients, an RT-PCR method using HLA-A2-specific primers was used to analyse for the presence of this allele. The preferentially expressed TCRAV genes were sequenced, and this analysis showed that the high expression of these TCRAV genes was due to a clonal or oligocional expansion of T cells. In summary, the expression of relatively few TCR variable regions indicates a clonal expansion of T cells. PMID:9067965

  20. Effects of a 3-year dietary intervention on age-related changes in triglyceride and apolipoprotein A-V levels in patients with impaired fasting glucose or new-onset type 2 diabetes as a function of the APOA5 -1131 T > C polymorphism

    PubMed Central

    2014-01-01

    Background The purpose of this study was to estimate the effects of a 3-year dietary intervention on age-related changes in triglyceride and apolipoprotein (apo A-V) levels in patients with impaired fasting glucose (IFG) or new-onset type 2 diabetes as a function of the APOA5 -1131 T > C polymorphism. Methods We genotyped the APOA5 -1131 T > C polymorphism in 203 Korean individuals with IFG or new-onset type 2 diabetes for the TT (n = 91), TC (n = 98), and CC (n = 14) alleles. Plasma apo A-V and triglyceride levels were evaluated at baseline and after a 3-year dietary intervention. Results Our results showed that HDL, glucose, insulin, HOMA-IR index, free fatty acids, and apo A-V decreased and brachial-ankle pulse wave velocity (ba-PWV) and malondialdehyde (MDA) increased at the 3-year follow-up visit compared with baseline. Plasma apo A-V levels were reduced in subjects with the C allele (TC or CC) (P = 0.036) and triglyceride levels were reduced in subjects with the TT allele (P = 0.047). Subjects with the C allele showed lower post-treatment apo A-V and higher post-treatment fasting triglyceride levels than subjects with the TT allele. Changes in apo A-V and triglyceride levels were negatively correlated in subjects with the TT allele and positively correlated in subjects with the C allele. Conclusions This study showed that the dietary intervention prevented an age-related increase in triglyceride levels in individuals with IFG or new-onset type 2 diabetes who possess the TT allele, but not the CT or CC allele, of the APOA5 -1131 T > C polymorphism. PMID:24775272

  1. Changes in Antibody Levels during and following an Episode of Acute Adenolymphangitis (ADL) among Lymphedema Patients in Léogâne, Haiti

    PubMed Central

    Mues, Katherine E.; Lammie, Patrick J.; Klein, Mitchel; Kleinbaum, David G.; Addiss, David; Fox, LeAnne M.

    2015-01-01

    Introduction Episodes of acute adenolymphangitis (ADL) are often the first clinical sign of lymphatic filariasis (LF). They are often accompanied by swelling of the affected limb, inflammation, fever, and general malaise and lead to the progression of lymphedema. Although ADL episodes have been studied for a century or more, questions still remain as to their etiology. We quantified antibody levels to pathogens that potentially contribute to ADL episodes during and after an episode among lymphedema patients in Léogâne, Haiti. We estimated the proportion of ADL episodes hypothesized to be attributed to specific pathogens. Methods We measured antibody levels to specific pathogens during and following an ADL episode among 41 lymphedema patients enrolled in a cohort study in Léogâne, Haiti. We calculated the absolute and relative changes in antibody levels between the ADL and convalescent time points. We calculated the proportion of episodes that demonstrated a two-fold increase in antibody level for several bacterial, fungal, and filarial pathogens. Results Our results showed the greatest proportion of two-fold changes in antibody levels for the carbohydrate antigen Streptococcus group A, followed by IgG2 responses to a soluble filarial antigen (BpG2), Streptococcal Pyrogenic Exotoxin B, and an antigen for the fungal pathogen Candida. When comparing the median antibody level during the ADL episode to the median antibody level at the convalescent time point, only the antigens for Pseudomonas species (P-value = 0.0351) and Streptolysin O (P-value = 0.0074) showed a significant result. Conclusion Although our results are limited by the lack of a control group and few antibody responses, they provide some evidence for infection with Streptococcus A as a potential contributing factor to ADL episodes. Our results add to the current evidence and illustrate the importance of determining the causal role of bacterial and fungal pathogens and immunological antifilarial

  2. Adapting AV for Mainstreamed Students.

    ERIC Educational Resources Information Center

    Wood, Judy W.

    1984-01-01

    The article describes possible adaptations of standard audiovisual equipment (overhead projectors, videotapes, tape recorders, graphic materials and bulletin boards) for use in teaching mainstreamed handicapped students. (CL)

  3. Reference Readiness for AV Questions.

    ERIC Educational Resources Information Center

    Drolet, Leon L., Jr.

    1981-01-01

    Reviews 50 reference tools which librarians can use to answer almost any audiovisual question including queries on trivia, equipment selection, biographical information, and motion picture ratings. (LLS)

  4. L'Anti-Atlas occidental du Maroc: étude sédimentologique et reconstitutions paléogéographiques au Cambrien inférieur

    NASA Astrophysics Data System (ADS)

    Benssaou, M.; Hamoumi, N.

    2001-04-01

    L'étude lithostratigraphique en sédimentologique des formations du Cambrien inférieur de l'Anti-Atlas occidental (Maroc) a permis de mettre en évidence la diversité extrême des faciès allant des faciès continentaux jusqu'au faciès franchement marins. La répartition verticale de ces faciès ainsi que leurs associations ont permis de (i) proposer un nouveau découpage de la succession en formations lithostratigraphiques, (ii) reconstituer les milieux de dépôt (système fluviatile, lacs, fan-deltas, milieu littoral, plate-forme dominée par des constructions stromatolitiques et récifales et plate-forme dominée par les tempêtes) et (iii) établir des modèles paléogéographiques retraçant les différentes étapes d'évolution de ce bassin qui fait partie de la plate-forme nord-gondwanienne au Cambrien inférieur. Lithostratigraphical and sedimentological studies of the Early Cambrian formations in the western Anti-Atlas (Morocco) evidence their large diversity of facies ranging from continental to clearly marine. Vertical distribution and associations of facies afford opportunities to (i) suggest a new classification of the sedimentary sequence in terms of lithostratigraphic formations, (ii) restore the depositional environments (fluvial system, lake, delta fan, coast, stromatolite and reef-dominated platform, tempest-dominated platform), and (iii) establish palæogeographic models displaying the different evolutionary stages of this basin that constituted a part of the Lower Cambrian north-Gondwanian platform.

  5. Complex rupture source of the 12 January 2010 Léogâne, Haiti earthquake derived from geologic, geodetic, and seismologic observations

    NASA Astrophysics Data System (ADS)

    Briggs, R. W.; Hayes, G. P.; Sladen, A.; Fielding, E. J.; Prentice, C. S.; Hudnut, K. W.; Mann, P.; Taylor, F. W.; Crone, A. J.; Gold, R. D.; Ito, T.; Simons, M.; Jean, P.

    2010-12-01

    The Mw 7.0, 12 January 2010 Léogâne, Haiti earthquake initially appeared to be a straightforward accommodation of oblique relative motion between the Caribbean and North America plates along the previously recognized Enriquillo-Plantain Garden fault zone (EPGF). Our combined geologic field observations, space geodetic measurements, and seismologic data show that the rupture process of this event involved slip on multiple faults and that slip along the EPGF was minimal or absent. Instead, primary surface deformation resulted from rupture on previously unrecognized blind thrust faults with only minor, deep lateral slip along or near the main EPGF. We quantified uplift along the coast north of the EPGF using vertically displaced coral microatolls. SAR interferograms demonstrate that the observed coastal deformation reflects a broader pattern of uplift and subsidence. Seismologic observations (including body-wave first motions, high non-double couple components of moment tensor inversions, the aftershock distribution and their associated moment tensors) imply that the rupture involved multiple faults. A joint inversion of all data sets yields a preferred model of slip on three faults to explain the principal observations. Moment-release calculations show that this event only partially relieved centuries of accumulated left-lateral strain on a small part of the plate-boundary system. The lack of surface deformation along the EPGF--which shows clear field evidence for Holocene, and probably historic surface rupture--and the predominance of shallow off-fault thrusting implies that considerable shallow shear strain remains to be released in future surface-rupturing earthquakes on the EPGF, including the section adjacent to Port-au-Prince. Because the geologic signature of this earthquake involves broad warping and coastal deformation rather than surface rupture along the main fault zone, the event will not leave a distinct geologic signal that will be easily recognized

  6. LasR receptor for detection of long-chain quorum-sensing signals: identification of N-acyl-homoserine lactones encoded by the avsI locus of Agrobacterium vitis.

    PubMed

    Savka, Michael A; Le, Phuong T; Burr, Thomas J

    2011-01-01

    Bacterial biosensor strains have greatly facilitated the rapid discovery, isolation, and study of quorum-sensing systems. In this study, we determined the relative sensitivity of a LasR-based E. coli bacterial bioluminescence biosensor JM109 (pSB1075) for 13 diverse long-chain N-acyl-homoserine lactones (AHLs) including oxygen-substituted and -unsubstituted AHLs containing 14, 16, and 18 carbons and with and without double bonds. Furthermore, we show by bioassay, HPLC, and GC/MS that four long-chain AHLs of the C16-HSL family are encoded by the avsI gene of Agrobacterium vitis strain F2/5, a non-tumorigenic strain that inhibits pathogenic strains of A. vitis from causing crown gall on grape. The four C16-HSLs include: C16-HSL, N-hexadecanoyl homoserine lactone; 3-oxo-C16-HSL, N-(3-oxohexadecanoyl)homoserine lactone; C16:1-HSL, N-(cis-9-octadecenoyl)homoserine lactone; and 3-oxo-C16:1-HSL, N-(3-oxo-cis-11-hexadecenoyl)homoserine lactone. Thus, the LasR-based bioluminescent biosensor tested in this study should serve as a useful tool for the detection of various long-chain AHLs with and without double bonds as well as those oxylated at the third carbon from uninvestigated species. PMID:20514483

  7. Clinical trials update from the European Society of Cardiology Meeting 2011: ARISTOTLE, SMART-AV: QLV substudy, SHIFT: echocardiography and quality of life substudies, European CRT Survey, and Basic Science Update.

    PubMed

    Cleland, John G F; Coletta, Alison P; Cullington, Damien; Castiello, Teresa; de Boer, Rudolf A; Clark, Andrew L

    2011-12-01

    This article provides information and a commentary on key trials relevant to the pathophysiology, prevention, and treatment of heart failure presented at the European Society of Cardiology meeting held in Paris, France in August 2011. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. Results from ARISTOTLE suggest that apixaban is more effective than warfarin for the prevention of stroke in patients with atrial fibrillation. Electrical dyssynchrony, measured by the time from onset of electrical activity on the surface ECG to activation of myocardium by intrinsic conduction at the pacing site (QLV), was a strong and independent predictor of improvement in ventricular function after cardiac resynchronization therapy (CRT) in an observational analysis of a subgroup of patients from the SMART-AV study. Subgroup analyses from SHIFT suggest that heart rate reduction with ivabradine causes favourable left ventricular remodelling and improves quality of life in patients with symptomatic systolic heart failure and an increased heart rate. The European CRT Survey reported outcome data.

  8. Two-nucleon spectral function of the 16O nucleus using the lowest-order constrained variational state-dependent correlation functions of the Reid and Av18 interactions

    NASA Astrophysics Data System (ADS)

    Modarres, M.; Younesizadeh, Y.

    2012-05-01

    In this work, the two-nucleon spectral functions (TNSFs) are defined in terms of the state- and the density-dependent correlation functions in the framework of the lowest-order constrained variational (LOCV) method to calculate the TNSF of the 16O nucleus in the 16O(e,e'NN)14C reaction. The Reid soft-core (Reid68) and the Av18 potentials are used as the internucleon interactions. Since, the short-range correlation effects are imposed on the wave functions for the individual channels (e.g., the 1S0 and 3PJ channels); therefore, the defect wave functions are obtained for various channels such that the high relative momenta (p>4fm-1) are ignored. The resulting TNSFs for the 16O nucleus are compared with those of the dressed random phase approximation (DRPA) calculations of Geurts and the experimental predictions, especially those of Onderwater , (NIKHEF group), where reasonable agreement is found. It is shown that the optimized state-dependent defect wave functions have substantial effects on the TNSF and it is not justified to use the simplified parametrized two-body correlation functions in all of the channels. In agreement with the experimental data of Onderwater , the knockout of a 1S0 pair proton dominates the above reaction cross section. Finally, it is demonstrated that the 0+ and 2+ peaks, which are expected to be observed in the above reaction cross section, are moved to the lower momenta of out-going protons when the state-dependent correlation functions are imposed.

  9. Physical, Structural and Operational Vulnerability of Critical Facilities in Valle de Chalco Solidaridad, Estado de Mexico, Mexico. Case of study: Avándaro, San Isidro and El Triunfo

    NASA Astrophysics Data System (ADS)

    Garcia Payne, D. G.; Novelo-Casanova, D. A.; Ponce-Pacheco, A. B.; Espinosa-Campos, O.; Huerta-Parra, M.; Reyes-Pimentel, T.; Rodriguez, F.; Benitez-Olivares, I.

    2010-12-01

    Valle de Chalco Solidaridad is located in Mexico City Metropolitan Area in Estado de Mexico, Mexico. In this town there is a sewage canal called “La Compañía”. A wall of this canal collapsed on February 5, 2010 due to heavy rains creating the flooding of four surrounding communities. It is important to point out that this area is frequently exposed to floods. In this work, we consider a critical facility as an essential structure for performance, health care and welfare within a community or/and as a place that can be used as shelter in case of emergency or disaster. Global vulnerability (the sum of the three measured vulnerabilities) of the 25 critical facilities identified in the locations of Avándaro, San Isidro and El Triunfo was assessed using the Community Vulnerability Assessment Tool developed by the National Oceanic and Atmospheric Administration (NOAA). For each critical facility we determined its operational, structural and physical vulnerabilities. For our analysis, we considered the four main natural hazards to which Valle de Chalco is exposed: earthquakes, floods, landslides and sinking. We considered five levels of vulnerability using a scale from 1 to 5, where values range from very low to very high vulnerability, respectively. A critical facilities database was generated by collecting general information for three categories: schools, government and church. Each facility was evaluated considering its location in relation to identified high-risk areas. Our results indicate that in average, the global vulnerability of all facilities is low, however, there are particular cases in which this global vulnerability is high. The average operational vulnerability of the three communities is moderate. The global structural vulnerability (sum of the structural vulnerability for the four analyzed hazards) is moderate. In particular, the structural vulnerability to earthquakes is low, to landslides is very low, to flooding is moderate and to sinking is

  10. The N-Terminal Region of the Oenococcus oeni Bacteriophage fOg44 Lysin Behaves as a Bona Fide Signal Peptide in Escherichia coli and as a cis-Inhibitory Element, Preventing Lytic Activity on Oenococcal Cells

    PubMed Central

    São-José, Carlos; Parreira, Ricardo; Vieira, Graça; Santos, Mário A.

    2000-01-01

    The function of the N-terminal region of the Oenococcus oeni phage fOg44 lysin (Lys44) as an export signal was investigated. We observed that when induced in Escherichia coli, Lys44 was cleaved between residues 27 and 28 in a SecA-dependent manner. Lys44 processing could be blocked by a specific signal peptidase inhibitor and was severely reduced by modification of the cleavage site. The lethal effect of Lys44 expression observed in E. coli was ascribed to the presence of its N-terminal 27-residue sequence, as its deletion resulted in the production of a nontoxic, albeit active, product. We have further established that lytic activity in oenococcal cells was dependent on Lys44 processing. An active protein with the molecular mass expected for the cleaved enzyme was detected in extracts from O. oeni-infected cells. The temporal pattern of its appearance suggests that synthesis and export of Lys44 in the infected host progress along with phage maturation. Overall, these results provide, for the first time, experimental evidence for the presence of a signal peptide in a bacteriophage lysin. Database searches and alignment of protein sequences support the prediction that other known O. oeni and Lactococcus lactis phages also encode secretory lysins. The evolutionary significance of a putative phage lysis mechanism relying on secretory lytic enzymes is tentatively discussed, on the basis of host cell wall structure and autolytic capacity. PMID:11004183

  11. The A/V Club Next Generation

    ERIC Educational Resources Information Center

    Tech & Learning, 2009

    2009-01-01

    Engaging the digital natives isn't as daunting as one thinks. This article describes how three classrooms do it. One of these is in Brevard Public Schools in Viera, Florida. Pete Episcopo, the digital-media artist of the school, wanted to share his love of all things digital and teach essential 21st-century skills so students could be better…

  12. A/V Alternatives for Interesting Homework.

    ERIC Educational Resources Information Center

    Kersten, Fred

    1993-01-01

    Describes the use of audiovisual materials and equipment as part of music education homework. Recommends using audiotapes and videotapes of music accompanied by analytical questions to be completed by students. Predicts that new instructional technology will improve the effectiveness of this approach. (CFR)

  13. Deep evolutionary conservation of an intramolecular protein kinase activation mechanism.

    PubMed

    Han, Jingfen; Miranda-Saavedra, Diego; Luebbering, Nathan; Singh, Aman; Sibbet, Gary; Ferguson, Michael A J; Cleghon, Vaughn

    2012-01-01

    DYRK-family kinases employ an intramolecular mechanism to autophosphorylate a critical tyrosine residue in the activation loop. Once phosphorylated, DYRKs lose tyrosine kinase activity and function as serine/threonine kinases. DYRKs have been characterized in organisms from yeast to human; however, all entities belong to the Unikont supergroup, only one of five eukaryotic supergroups. To assess the evolutionary age and conservation of the DYRK intramolecular kinase-activation mechanism, we surveyed 21 genomes representing four of the five eukaryotic supergroups for the presence of DYRKs. We also analyzed the activation mechanism of the sole DYRK (class 2 DYRK) present in Trypanosoma brucei (TbDYRK2), a member of the excavate supergroup and separated from Drosophila by ∼850 million years. Bioinformatics showed the DYRKs clustering into five known subfamilies, class 1, class 2, Yaks, HIPKs and Prp4s. Only class 2 DYRKs were present in all four supergroups. These diverse class 2 DYRKs also exhibited conservation of N-terminal NAPA regions located outside of the kinase domain, and were shown to have an essential role in activation loop autophosphorylation of Drosophila DmDYRK2. Class 2 TbDYRK2 required the activation loop tyrosine conserved in other DYRKs, the NAPA regions were critical for this autophosphorylation event, and the NAPA-regions of Trypanosoma and human DYRK2 complemented autophosphorylation by the kinase domain of DmDYRK2 in trans. Finally, sequential deletion analysis was used to further define the minimal region required for trans-complementation. Our analysis provides strong evidence that class 2 DYRKs were present in the primordial or root eukaryote, and suggest this subgroup may be the oldest, founding member of the DYRK family. The conservation of activation loop autophosphorylation demonstrates that kinase self-activation mechanisms are also primitive.

  14. A-V INSTRUCTION, MATERIALS AND METHODS. SECOND EDITION.

    ERIC Educational Resources Information Center

    BROWN, JAMES W.; AND OTHERS

    A DISCUSSION OF LEARNING AND COMMUNICATION THEORIES AND OF TEACHER AIMS FOR ACTIVE STUDENT LEARNING INTRODUCES A COMPREHENSIVE AND ILLUSTRATED DISCUSSION OF SOURCES AND METHODS FOR THE USE OF A WIDE VARIETY OF TEACHER AIDS. INFORMATION IS DETAILED ON THE SELECTION, LOCATION, USE, AND EVALUATION OF READY-MADE MATERIALS, FREE AND INEXPENSIVE…

  15. AV Instructional Technology Manual for Independent Study. Fifth Edition.

    ERIC Educational Resources Information Center

    Brown, James W., Ed.; Lewis, Richard B., Ed.

    The classroom teacher is provided with a series of exercises to develop skills in three broad areas of audiovisual technology: (1) creating instructional materials--including exercises emphasizing lettering, display boards, chalk boards, graphs, laminating, duplicating, transparencies, audio tapes, visual literacy sequences, multimedia…

  16. The Best Science Books & A-V Materials for Children.

    ERIC Educational Resources Information Center

    O'Connell, Susan M., Ed.; And Others

    Some scientists and science educators believe that the most effective strategy for raising science literacy among future workers and voters is to focus on the youngest members of the public. The reviews in this publication were undertaken to increase public understanding and appreciation of the importance and promise of the methods of science in…

  17. Transportation System After Next & Comments on AvSTAR Planning

    NASA Technical Reports Server (NTRS)

    Pearce, Robert

    2001-01-01

    The purpose of this presentation is to define and identify: the role of transportation in supporting future US needs, trends, system after next, supporting research and education, priority investments, and barriers.

  18. Aviation System Technology Advanced Research Program - AvSTAR

    NASA Technical Reports Server (NTRS)

    Denery, Dallas G.

    2001-01-01

    The objectives of this presentation is to provide the research and development by 2007 necessary to: complete the development of technology for tomorrow (Free-Flight); provide the foundations for setting the direction for the future (Beyond Free-Flight). The goals are to establish tomorrow's as well as the future's Air transportation system.

  19. 15 CFR 740.15 - Aircraft and vessels (AVS).

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ..., provided that: (i) No sale or transfer of operational control of the aircraft to nationals of a destination...) The aircraft is not departing for the purpose of sale or transfer of operational control to nationals... approved by the Federal Aviation Administration pursuant to 14 CFR part 129 of the regulations of...

  20. Periodontal manifestations and management of a patient with AV malformation.

    PubMed

    Narang, Sumit; Gupta, Ruby; Narang, Anu; Nema, Ram Narayan

    2012-04-01

    Arterio-venous malformation (AVM) is an abnormal communication between an artery and a vein. The incidence of its occurrence in oral and maxillofacial region is rare, and if present, the most common sign is gingival bleeding. A 12-year-old female patient presented with an extra oral swelling in relation with upper lip. Intra oral examination showed non tender gingival swelling with spontaneous bleeding associated with maxillary arch. On initiation of phase I therapy using hand instruments, spontaneous brisk bleeding was encountered which was difficult to control. Because of severe nature of hemorrhage encountered, some type of vascular abnormality was suspected. Ultrasonography followed by angiography confirmed AVM in relation with upper lip. Embolization of lesion was followed by gingivectomy procedure and no recurrence was reported during one year of follow-up. Thus, proper recognition and therapeutic intervention is essential to avoid serious complications and potentially tragic outcome in such situations.

  1. Cataloging, Processing, Administering AV Materials. A Model for Wisconsin Schools.

    ERIC Educational Resources Information Center

    Little, Robert D., Ed.

    The objective of this cataloging manual is to recommend specific methods for cataloging audiovisual materials for use in individual school media centers. The following types of audiovisual aids are included: educational games, filmstrips, flat graphics, kits, models, motion pictures, realia, records, slides, sound filmstrips, tapes,…

  2. 15 CFR 740.15 - Aircraft and vessels (AVS).

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... approved by the Federal Aviation Administration pursuant to 14 CFR part 129 of the regulations of the... Statistics Regulations (15 CFR part 30), except that an SED or AES record is not required when any of the... requirements of the Foreign Trade Statistics Regulations (15 CFR part 30), except that an SED or AES record...

  3. 15 CFR 740.15 - Aircraft and vessels (AVS).

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... approved by the Federal Aviation Administration pursuant to 14 CFR part 129 of the regulations of the... Statistics Regulations (15 CFR part 30), except that an SED or AES record is not required when any of the... requirements of the Foreign Trade Statistics Regulations (15 CFR part 30), except that an SED or AES record...

  4. 15 CFR 740.15 - Aircraft and vessels (AVS).

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... approved by the Federal Aviation Administration pursuant to 14 CFR part 129 of the regulations of the... Statistics Regulations (15 CFR part 30), except that an SED or AES record is not required when any of the... requirements of the Foreign Trade Statistics Regulations (15 CFR part 30), except that an SED or AES record...

  5. 15 CFR 740.15 - Aircraft and vessels (AVS).

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... approved by the Federal Aviation Administration pursuant to 14 CFR part 129 of the regulations of the... Statistics Regulations (15 CFR part 30), except that an SED or AES record is not required when any of the... requirements of the Foreign Trade Statistics Regulations (15 CFR part 30), except that an SED or AES record...

  6. The DYRK-family kinase Pom1 phosphorylates the F-BAR protein Cdc15 to prevent division at cell poles.

    PubMed

    Ullal, Pranav; McDonald, Nathan A; Chen, Jun-Song; Lo Presti, Libera; Roberts-Galbraith, Rachel H; Gould, Kathleen L; Martin, Sophie G

    2015-11-01

    Division site positioning is critical for both symmetric and asymmetric cell divisions. In many organisms, positive and negative signals cooperate to position the contractile actin ring for cytokinesis. In rod-shaped fission yeast Schizosaccharomyces pombe cells, division at midcell is achieved through positive Mid1/anillin-dependent signaling emanating from the central nucleus and negative signals from the dual-specificity tyrosine phosphorylation-regulated kinase family kinase Pom1 at the cell poles. In this study, we show that Pom1 directly phosphorylates the F-BAR protein Cdc15, a central component of the cytokinetic ring. Pom1-dependent phosphorylation blocks Cdc15 binding to paxillin Pxl1 and C2 domain protein Fic1 and enhances Cdc15 dynamics. This promotes ring sliding from cell poles, which prevents septum assembly at the ends of cells with a displaced nucleus or lacking Mid1. Pom1 also slows down ring constriction. These results indicate that a strong negative signal from the Pom1 kinase at cell poles converts Cdc15 to its closed state, destabilizes the actomyosin ring, and thus promotes medial septation. PMID:26553932

  7. The DYRK-family kinase Pom1 phosphorylates the F-BAR protein Cdc15 to prevent division at cell poles

    PubMed Central

    Ullal, Pranav; McDonald, Nathan A.; Chen, Jun-Song; Lo Presti, Libera; Roberts-Galbraith, Rachel H.; Gould, Kathleen L.

    2015-01-01

    Division site positioning is critical for both symmetric and asymmetric cell divisions. In many organisms, positive and negative signals cooperate to position the contractile actin ring for cytokinesis. In rod-shaped fission yeast Schizosaccharomyces pombe cells, division at midcell is achieved through positive Mid1/anillin-dependent signaling emanating from the central nucleus and negative signals from the dual-specificity tyrosine phosphorylation-regulated kinase family kinase Pom1 at the cell poles. In this study, we show that Pom1 directly phosphorylates the F-BAR protein Cdc15, a central component of the cytokinetic ring. Pom1-dependent phosphorylation blocks Cdc15 binding to paxillin Pxl1 and C2 domain protein Fic1 and enhances Cdc15 dynamics. This promotes ring sliding from cell poles, which prevents septum assembly at the ends of cells with a displaced nucleus or lacking Mid1. Pom1 also slows down ring constriction. These results indicate that a strong negative signal from the Pom1 kinase at cell poles converts Cdc15 to its closed state, destabilizes the actomyosin ring, and thus promotes medial septation. PMID:26553932

  8. Nineteenth International Cosmic Ray Conference. OG Sessions, Volume 3

    NASA Technical Reports Server (NTRS)

    Jones, F. C. (Compiler)

    1985-01-01

    Papers submitted for presentation at the 19th International Cosmic Ray Conference are compiled. This volume addresses cosmic ray sources and acceleration, interstellar propagation and nuclear interactions, and detection techniques and instrumentation.

  9. Ninteenth International Cosmic Ray Conference. OG Sessions, Volume 2

    NASA Technical Reports Server (NTRS)

    Jones, F. C. (Compiler)

    1985-01-01

    Contributed papers addressing cosmic ray origin and galactic phenomena are compiled. Topic areas include the composition, spectra, and anisotropy of cosmic ray nuclei with energies and 1 TeV, isotopes, antiprotons and related subjects, and electrons, positrons, and measurements of synchrotron radiation.

  10. Information Gathering Document 0321-1437-30-R-OG

    SciTech Connect

    Hollister, R

    2009-07-15

    Fines and turnings from machining depleted uranium (Dep-U), natural uranium (Nat-U), and Thorium-232, and stainless steel and aluminum. This IGO allows only small, oxidizable pieces of Dep-U/Nat-U/Th-232, with regulated metal contaminants below regulatory limits. Fines and turnings will be in 30 gallon vented drums immersed in mineral oil. The 30 gallon drums will be overpacked in 55 gallon vented drums. The waste will be stored on site until sent for stabilization & disposal with approved TSOFs.

  11. Ninteenth International Cosmic Ray Conference. OG Sessions, Volume 1

    NASA Technical Reports Server (NTRS)

    Jones, F. C. (Compiler)

    1985-01-01

    Contributed papers addressing cosmic ray origin and galactic phenomena are compiled. The topic areas covered in this volume include gamma ray bursts, gamma rays from point sources, and diffuse gamma ray emission.

  12. The structure of a dual-specificity tyrosine phosphorylation-regulated kinase 1A-PKC412 complex reveals disulfide-bridge formation with the anomalous catalytic loop HRD(HCD) cysteine.

    PubMed

    Alexeeva, Marina; Åberg, Espen; Engh, Richard A; Rothweiler, Ulli

    2015-05-01

    Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a protein kinase associated with neuronal development and brain physiology. The DYRK kinases are very unusual with respect to the sequence of the catalytic loop, in which the otherwise highly conserved arginine of the HRD motif is replaced by a cysteine. This replacement, along with the proximity of a potential disulfide-bridge partner from the activation segment, implies a potential for redox control of DYRK family activities. Here, the crystal structure of DYRK1A bound to PKC412 is reported, showing the formation of the disulfide bridge and associated conformational changes of the activation loop. The DYRK kinases represent emerging drug targets for several neurological diseases as well as cancer. The observation of distinct activation states may impact strategies for drug targeting. In addition, the characterization of PKC412 binding offers new insights for DYRK inhibitor discovery. PMID:25945585

  13. Storage, Handling and Preservation of Audiovisual Materials. AV in Action 3.

    ERIC Educational Resources Information Center

    Thompson, Anthony Hugh

    Designed to provide the librarian with suggestions and guidelines for storing and preserving audiovisual materials, this pamphlet is divided into four major chapters: (1) Normal Use Storage Conditions; (2) Natural Lifetime, Working Lifetime and Long-Term Storage; (3) Handling; and (4) Shelving of Normal Use Materials. Topics addressed include:…

  14. Environmental Technology Verification Report: Grouts for Wastewater Collection Systems, Avanti International AV-118 Acrylic Chemical Grout

    EPA Science Inventory

    Municipalities are discovering rapid degradation of infrastructures in wastewater collection and treatment facilities due to the infiltration of water from the surrounding environments. Wastewater facilities are not only wet, but also experience hydrostatic pressure conditions un...

  15. Complete genome sequence of Archaeoglobus profundus type strain (AV18T)

    PubMed Central

    von Jan, Mathias; Lapidus, Alla; Del Rio, Tijana Glavina; Copeland, Alex; Tice, Hope; Cheng, Jan-Fang; Lucas, Susan; Chen, Feng; Nolan, Matt; Goodwin, Lynne; Han, Cliff; Pitluck, Sam; Liolios, Konstantinos; Ivanova, Natalia; Mavromatis, Konstantinos; Ovchinnikova, Galina; Chertkov, Olga; Pati, Amrita; Chen, Amy; Palaniappan, Krishna; Land, Miriam; Hauser, Loren; Chang, Yun-Juan; Jeffries, Cynthia D.; Saunders, Elizabeth; Brettin, Thomas; Detter, John C.; Chain, Patrick; Eichinger, Konrad; Huber, Harald; Spring, Stefan; Rohde, Manfred; Göker, Markus; Wirth, Reinhard; Woyke, Tanja; Bristow, Jim; Eisen, Jonathan A.; Markowitz, Victor; Hugenholtz, Philip; Kyrpides, Nikos C; Klenk, Hans-Peter

    2010-01-01

    Archaeoglobus profundus (Burggraf et al. 1990) is a hyperthermophilic archaeon in the euryarchaeal class Archaeoglobi, which is currently represented by the single family Archaeoglobaceae, containing six validly named species and two strains ascribed to the genus 'Geoglobus' which is taxonomically challenged as the corresponding type species has no validly published name. All members were isolated from marine hydrothermal habitats and are obligate anaerobes. Here we describe the features of the organism, together with the complete genome sequence and annotation. This is the second completed genome sequence of a member of the class Archaeoglobi. The 1,563,423 bp genome with its 1,858 protein-coding and 52 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID:21304717

  16. Motion Pictures and Video Cassettes 1971. AV-USA Supplement 2.

    ERIC Educational Resources Information Center

    Hope, Thomas W.

    The financial status of the motion picture and of the video cassette industry in 1970 are reviewed. Based on production rates and income of these industries, trends are discovered. Figures on local origination of television programing and commercials are also included. The section on video cassettes includes the following information: the current…

  17. Development of an 8000 bps voice codec for AvSat

    NASA Technical Reports Server (NTRS)

    Clark, Joseph F.

    1988-01-01

    Air-mobile speech communication applications share robustness and noise immunity requirements with other mobile applications. The quality requirements are stringent, especially in the cockpit where air safety is involved. Based on these considerations, a decision was made to test an intermediate data rate such as 8.0 and 9.6 kb/s as proven technologies. A number of vocoders and codec technologies were investigated at rates ranging from 2.4 kb/s up to and including 9.6 kb/s. The proven vocoders operating at 2.4 and 4.8 kb/s lacked the noise immunity or the robustness to operate reliably in a cabin noise environment. One very attractive alternative approach was Spectrally Encoded Residual Excited LPC (SE-RELP) which is used in a multi-rate voice processor (MRP) developed at the Naval Research Lab (NRL). The MRP uses SE-RELP at rates of 9.6 and 16 kb/s. The 9.6 kb/s rate can be lowered to 8.0 kb/s without loss of information by modifying the frame. An 8.0 kb/s vocoder was developed using SE-RELP as a demonstrator and testbed. This demonstrator is implemented in real time using two Compaq 2 portable computers, each equipped with an ARIEL DSP016 Data Acquisition Processor.

  18. The complete genome of hyperthermophile Methanopyrus kandleri AV19 and monophyly of archaeal methanogens

    PubMed Central

    Slesarev, Alexei I.; Mezhevaya, Katja V.; Makarova, Kira S.; Polushin, Nikolai N.; Shcherbinina, Olga V.; Shakhova, Vera V.; Belova, Galina I.; Aravind, L.; Natale, Darren A.; Rogozin, Igor B.; Tatusov, Roman L.; Wolf, Yuri I.; Stetter, Karl O.; Malykh, Andrei G.; Koonin, Eugene V.; Kozyavkin, Sergei A.

    2002-01-01

    We have determined the complete 1,694,969-nt sequence of the GC-rich genome of Methanopyrus kandleri by using a whole direct genome sequencing approach. This approach is based on unlinking of genomic DNA with the ThermoFidelase version of M. kandleri topoisomerase V and cycle sequencing directed by 2′-modified oligonucleotides (Fimers). Sequencing redundancy (3.3×) was sufficient to assemble the genome with less than one error per 40 kb. Using a combination of sequence database searches and coding potential prediction, 1,692 protein-coding genes and 39 genes for structural RNAs were identified. M. kandleri proteins show an unusually high content of negatively charged amino acids, which might be an adaptation to the high intracellular salinity. Previous phylogenetic analysis of 16S RNA suggested that M. kandleri belonged to a very deep branch, close to the root of the archaeal tree. However, genome comparisons indicate that, in both trees constructed using concatenated alignments of ribosomal proteins and trees based on gene content, M. kandleri consistently groups with other archaeal methanogens. M. kandleri shares the set of genes implicated in methanogenesis and, in part, its operon organization with Methanococcus jannaschii and Methanothermobacter thermoautotrophicum. These findings indicate that archaeal methanogens are monophyletic. A distinctive feature of M. kandleri is the paucity of proteins involved in signaling and regulation of gene expression. Also, M. kandleri appears to have fewer genes acquired via lateral transfer than other archaea. These features might reflect the extreme habitat of this organism. PMID:11930014

  19. Mapping the mineralogical composition of the Pinaria region (Av-11) of Vesta

    NASA Astrophysics Data System (ADS)

    McFadden, L.; Marchi, S.; Ammannito, E.; Nantues, A.; DeSanctis, M.; Capaccioni, F.; Palomba, E.; Tosi, F.; Zambone, F.; LeCorre, L.; Reddy, V.; Jaumann, R.; Stephan, K.; Preusker, F.; Raymond, C.; Russell, C.

    2012-04-01

    We present the mineralogical map of a quadrant of the southern hemisphere of Vesta spanning 0-90 degrees longitude, and -21 to -66 degrees latitude; a region named Pinaria. The region, named after the Roman vestal virgin (c. 600 B.C.), includes an approximately 37km diameter crater, also named Pinaria. Several additional large craters are in this region as is the western most region of the rim of Rhea Silvia, named Matronalia Rupes. Mineralogical maps are based on data acquired by the Visible and Infrared Mapping Spectrometer (VIR-MS) and the Framing Camera (FC) on the Dawn spacecraft that has been orbiting Vesta since July 2011. VIR-MS is sensitive to wavelengths from 0.25um to 5.1um with a spatial resolution that depends upon the mission phase: nominally from 2.5 up to 0.8 km/pixel during the approach, 0.8 km/pixel during survey, 0.2 km/pixel during the high altitude orbit (HAMO) and about 0.05 km/pixel during the low altitude orbit (LAMO). This spatial resolution does not include the effects of the spacecraft's nor Vesta's motion. FC data from Survey orbit with a spatial resolution of about 250 m/pixel have been mapped using filter band parameters selected to enhance the anticipated mineralogy of Vesta. Global color maps of Vesta's surface using these color differences and ratios are generated. VIR data show that Vesta's surface is dominated by pyroxenes, with no evidence for the presence of other minerals observed at the scale of the survey measurements. The spectral parameters of the two major pyroxene absorption bands including band centers, depths and band areas and their variation within the Pinaria region, suggest mineralogical variation representing different compositional and/or textural terrains. Matronalia Rupes has band parameters suggesting different composition or grain size possibly resulting from down slope motion of regolith revealing different material beneath. The authors gratefully acknowledge the support of the Dawn Instrument, Operations, and Science Teams. This work is supported by an Italian Space Agency (ASI) grant, the DLR, MPI and by NASA through the Dawn project and the Dawn at Vesta Participating Scientist grant.

  20. A report from the AVS Standards Committee - Comparison of ion gauge calibrations by several standards laboratories

    NASA Technical Reports Server (NTRS)

    Warshawsky, I.

    1982-01-01

    Calibrations by four U.S. laboratories of four hot-cathode ion gauges, in the range 0.07-13 mPa, showed systematic differences among laboratories that were much larger than the expected error of any one calibration. They also suggested that any of the four gauges tested, if properly packaged and shipped, was able to serve as a transfer standard with probable error of 2%. A second comparison was made of the calibrations by two U.S. laboratories of some other gauges that had also been calibrated by the National Physical Laboratory, England. Results did not permit conclusive determination of whether differences were due to the laboratories or to changes in the gauges.

  1. ASASSN-16av: Discovery of A Type Ia Supernova in NGC 3926 NED02

    NASA Astrophysics Data System (ADS)

    Holoien, T. W.-S.; Bersier, D.; Stanek, K. Z.; Kochanek, C. S.; Brown, J. S.; Godoy-Rivera, D.; Basu, U.; Shappee, B. J.; Prieto, J. L.; Dong, Subo; Chen, Ping; Brimacombe, J.

    2016-01-01

    During the ongoing All Sky Automated Survey for SuperNovae (ASAS-SN or "Assassin"), using data from the quadruple 14-cm "Brutus" telescope in Haleakala, Hawaii, we discovered a new type Ia supernova in the galaxy NGC 3926 NED02.

  2. Why and How We Made a Problem Oriented AV Teaching Unit for Chemistry Students.

    ERIC Educational Resources Information Center

    Mulder, T. H. M.; Verdonk, A. H.

    1984-01-01

    Describes an audiovisual teaching unit on the chemical laboratory technique of recrystallization which was developed along problem-solving lines and based on observation of student laboratory behavior. Discussion includes usual procedures for developing such units, how this unit solves problems typically associated with teaching, and its general…

  3. Single-session, transarterial complete embolization of Galenic dural AV fistula.

    PubMed

    Laviv, Yosef; Kasper, Ekkehard; Perlow, Eliyahu

    2016-02-01

    Galenic dural arteriovenous fistula (DAVF) represents a unique, hard to treat subgroup of tentorial DAVFs. We present an unusual case of hemorrhagic Galenic DAVF in a 54-year-old woman. The fistula drained directly to the vein of Galen through multiple feeders. Complete occlusion of the fistula was achieved through transarterial embolization. Deep venous drainage remained intact and the patient recovered well. To our knowledge, this is the first report on complete closure of hemorrhagic Galenic DAVF using transarterial embolization with complete obliteration of vein of Galen. The presence of nonfunctioning straight sinus may have contributed to the success of treatment and it may be considered as a predictive marker for endovascular embolization.

  4. Video in Libraries--An International Perspective. AV in Action 5.

    ERIC Educational Resources Information Center

    McNally, Paul, Ed.

    This collection of papers on the use of video in libraries is designed to show the many different ways in which video can help communication. After a general introduction by Paul McNally which discusses current trends in video developments, 11 case studies are presented: (1) "Using Video in Public Libraries--Motherwell District Libraries,…

  5. Using Asynchronous AV Communication Tools to Increase Academic Self-Efficacy

    ERIC Educational Resources Information Center

    Girasoli, Anthony J.; Hannafin, Robert D.

    2008-01-01

    Technology-enhanced learning environments (TELEs) deliver instructional content and provide an array of scaffolding features designed to support independent student learning. TELEs also support teacher efforts to guide student inquiry within these sometimes complex environments. Self-efficacy, defined by Bandura [Bandura, A. (1994). Self-efficacy.…

  6. Aetervinning av faerg och ridaevatten med ultrafiltrering (recycling of paint and water curtains with ultrafiltration)

    SciTech Connect

    Fortkamp, U.; Allard, A.S.; Ekengren, O.

    1997-12-01

    Painting in spray booths causes overspray that is collected by a water curtain. The mixture of water and paint is commonly treated by means of precipitation. By means of this method, water can be used again but a paint sludge is created. Within this project, it was investigated how the paint as well as the water can be recycled. Separation by membrane filtration was tested for different paints in laboratory scale (0.2 liter volume). It was possible to separate all tested paints from the water and to concentrate it. At large scale (15 to 75 liters volume), an emulsion paint and a dispersion paint were tested. Under the tested conditions, it was slightly easier to concentrate the emulsion paint than the dispersion paint. It was possible to concentrate the paints to the original dry substance percentage. An important aspect of membrane filtration is cleaning of the membrane when the performance decreases. It was possible to clean all the tested membranes, but in many cases it was difficult. A ceramic membrane and a membrane of polyaramide showed the best results with regard to flux and cleaning of the membrane under the tested conditions. During the performance of the project two new applications of membrane filtration of paint were found. The method can be used for waste minimization by only separating the paint in an easy way at low costs. A third application is treating cleaning water from paint manufacturing.

  7. MISR Level 1A CCD Science data, all cameras (MIL1A_V2)

    NASA Technical Reports Server (NTRS)

    Diner, David J. (Principal Investigator)

    The Level 1A data are raw MISR data that are decommutated, reformatted 12-bit Level 0 data shifted to byte boundaries, i.e., reversal of square-root encoding applied and converted to 16 bit, and annotated (e.g., with time information). These data are used by the Level 1B1 processing algorithm to generate calibrated radiances. The science data output preserves the spatial sampling rate of the Level 0 raw MISR CCD science data. CCD data are collected during routine science observations of the sunlit portion of the Earth. Each product represents one 'granule' of data. A 'granule' is defined to be the smallest unit of data required for MISR processing. Also, included in the Level 1A product are pointers to calibration coefficient files provided for Level 1B processing. [Location=GLOBAL] [Temporal_Coverage: Start_Date=2000-02-24; Stop_Date=] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180].

  8. MISR Level 1A CCD Science data, all cameras (MIL1A_V1)

    NASA Technical Reports Server (NTRS)

    Diner, David J. (Principal Investigator)

    The Level 1A data are raw MISR data that are decommutated, reformatted 12-bit Level 0 data shifted to byte boundaries, i.e., reversal of square-root encoding applied and converted to 16 bit, and annotated (e.g., with time information). These data are used by the Level 1B1 processing algorithm to generate calibrated radiances. The science data output preserves the spatial sampling rate of the Level 0 raw MISR CCD science data. CCD data are collected during routine science observations of the sunlit portion of the Earth. Each product represents one 'granule' of data. A 'granule' is defined to be the smallest unit of data required for MISR processing. Also, included in the Level 1A product are pointers to calibration coefficient files provided for Level 1B processing. [Location=GLOBAL] [Temporal_Coverage: Start_Date=2000-02-24; Stop_Date=] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180].

  9. Cataloging, Processing, Administering AV Materials. A Model for Wisconsin Schools. Revised, 1974.

    ERIC Educational Resources Information Center

    Little, Robert David, Ed.; And Others

    The Wisconsin Association of School Librarians has produced a manual for standardized processing of all nonprint media, based on two principles: (1) the media should be centralized, organized, and administered for maximum access; and (2) content is more important than form. Definitions, cataloging, processing, housing, circulation, and care are…

  10. Endovascular treatment resolves non-hemorrhagic brainstem dysfunction due to tentorial dural AV fistula.

    PubMed

    Panagiotopoulos, V; Kastrup, O; Wanke, I

    2009-02-01

    Tentorial dural arteriovenous fistulas (tDAVF) clinically present usually with subarachnoid and/or intraparenchymal hemorrhage. Reported rates range from 58% to 92% and neurological deficits occur in 79% to 92% of patients. This is due to venous congestion resulting from retrograde leptomeningeal venous drainage, which rarely, can be clinically silent. A 69-year-old woman presented with vertigo, double vision and gait instability. Cerebral digital subtraction angiography revealed a tDAVF with retrograde cerebellar venous drainage directed through the vein of Galen into the straight sinus. MRI showed extensive cerebellar edema due to venous congestion. Clinical manifestations of cerebellar and brainstem dysfunction resolved completely after transarterial embolization with N-butylcyanoacrylate.

  11. Synthesis of New N,N'-Bis(5-arylidene-4-oxo-4,5-dihydrothiazolin-2-yl)piperazine Derivatives Under Microwave Irradiation and Preliminary Biological Evaluation.

    PubMed

    Coulibaly, Wacothon Karime; Paquin, Ludovic; Bénié, Anoubilé; Bekro, Yves-Alain; Durieux, Emilie; Meijer, Laurent; Le Guével, Rémy; Corlu, Anne; Bazureau, Jean-Pierre

    2012-12-01

    New N,N'-bis(5-arylidene-4-oxo-4,5-dihydrothiazoline-2-yl)diamine derivatives 5 were prepared in two steps from rhodanine and piperazine, or 1,4-bis(3-amino-propyl)piperazine, under microwave reaction conditions with retention of configuration. Some of these compounds were tested for in vitro antiproliferative activities and for their kinase inhibitory potencies towards six kinases (CDK5/p25, GSK3α/β, DYRK1A, DYRK2, CLK1, and CLK2). The compound 5d showed nanomolar activity towards DYRK1A kinase (IC(50) = 0.041 μM). PMID:23264934

  12. Functional similarity between E6 proteins of cutaneous human papillomaviruses and the adenovirus E1A tumor-restraining module.

    PubMed

    Kuppuswamy, Mohan; Subramanian, T; Kostas-Polston, Elizabeth; Vijayalingam, S; Zhao, Ling-jun; Varvares, Mark; Chinnadurai, G

    2013-07-01

    The adenovirus E1A C-terminal region restrains oncogenic transformation through interaction with three distinct cellular protein complexes that include the DYRK1A/1B/HAN11 complex. The E6 proteins of beta-human papillomaviruses (beta-HPVs) also interact with the DYRK1/HAN11 complex. A variant of HPV5 E6 frequently found in epidermodysplasia verruciformis skin lesions interacted less efficiently with DYRK1A/HAN11. The E6 variant and E7 of HPV5 efficiently coimmortalized primary epithelial cells, suggesting that naturally arising variants may contribute potential oncogenic activities of beta-HPV E6 proteins. PMID:23637414

  13. Phenological tracking og agricultural feilds investigated by using dual polarimetry tanDEM-X images

    NASA Astrophysics Data System (ADS)

    Mirzaee, S.; Motagh, M.; Arefi, H.; Nooryazdan, A.

    2015-04-01

    Remote sensing plays a key role in monitoring and assessing environmental changes. Because of its special imaging characteristics such as high-resolution, capabilities to obtain data in all weather conditions and sensitivity to geometrical and dielectric properties of the features, Synthetic Aperture Radar (SAR) technology has become a powerful technique to detect small scale changes related to earth surface.SAR images contain the information of both phase and intensity in different modes like single, dual and full polarimetric states which are important in order to extract information about various targets. In this study we investigate phenological changes in an agricultural region using high-resolution X-band SAR data. The case study is located in Doroud region of Lorestan province, west of Iran. The purpose is to investigate the ability of copolar and interferometric coherence extracted from TanDEM-X dual polarimetry (HH/VV) in bistatic StripMap mode for tracking the phenological changes of crops during growing season. The data include 11 images acquired between 12.06.2012 and 02.11.2012 and 6 images acquired between 30.05.2013 and 04.08.2013 in the CoSSC format. Results show that copolar coherence is almost able to follow phenological changes but interferometric coherence has a near constant behaviour with fluctuations mainly related to baseline variations.

  14. A kind of integrated method discuss of fOG signal processing circuit

    NASA Astrophysics Data System (ADS)

    Lu, Jun; Pan, Xin; Ying, Jiaju; Liu, Jie

    2014-12-01

    In view of the circuit miniaturization need in project application of fiber optic gyroscope(FOG), a new integrated technical scheme adopting system in package(SIP) for signal processing circuit of FOG was put forward. At first, the principle on signal processing circuit of FOG was analyzed, and the technical scheme adopting SIP based on low-temperature co-fired substrate technology was presented according to circuit characteristic and actual condition. Secondly, under the prerequisite of the concept introduction of SIP and LTCC, the SIP prototype of signal processing circuit of FOG was trialed produced,and it passed through the debug test. This SIP modular is an overall circuit complete integrated the signal processing circuit of FOG, and only a potentiometer and EPROM do not case outside. The testing results indicate that SIP is a kind of feasible scheme that carries out miniaturization for signal processing circuit of FOG.

  15. A REAL TIME COAL CONTENT ORE GRADE (C2OG) SENSOR

    SciTech Connect

    Dr. Rand Swanson

    2002-10-24

    This fifth quarterly technical report discusses the progress made on a machine vision technique for determining coal content and ore grades. Recent work has been devoted to implementing new hardware and examining defects in titanium sponge, a new application for the machine vision system. With the improvements in hardware and software, the data collection is much improved. Early results from data taken on titanium sponge defects indicate that some defects will be relatively easy to identify, but others will be much more difficult. Consequently, additional work is required with software algorithms for target recognition. Ongoing work will be divided into several fronts, which include data collection and analysis, improving the target recognition capabilities, and improving the electronic interface.

  16. A REAL TIME COAL CONTENT ORE GRADE (C2OG) SENSOR

    SciTech Connect

    Dr. Rand Swanson

    2003-04-28

    This seventh quarterly technical report discusses the progress made on a machine vision technique for determining coal content and ore grades. Considerable progress has been made on coal analysis. Naval Research Laboratory (NRL) target recognition software has been tested and incorporated into the system. This software decreases analysis time considerably and is more intuitive to use. Work with board-level computers has proceeded well; ultimately this will make the technology more compact and fieldable. Work with talc will be delayed because the graduate student working on this project is leaving the program. Ongoing work is devoted to more detailed coal analysis, improving the software interface, and developing procedures and a users manual.

  17. A REAL TIME COAL CONTENT ORE GRADE (C2OG) SENSOR

    SciTech Connect

    Rand Swanson

    2003-04-27

    This eleventh quarterly technical report discusses the installation of a spectral machine vision system in the Stillwater mine's core room. In brief, the system has been fabricated, installed, and preliminary measurements have been made. A first round of refinements has been made, included replacing a bad bearing and applying filters to the lighting. A high-speed Spectral Angle Mapper (SAM) program was written to classify the cores in real time. This program identifies sulfides in the core sample quite well, but also produces false positives at boundaries and breaks in the core. Additionally, bright reflections from facets within the ore occasionally saturate the camera. Overall, the project is on schedule, but additional refinement in the algorithm and lighting is required to obtain more accurate results.

  18. Gocad2OGS: Workflow to Integrate Geo-structural Information into Numerical Simulation Models

    NASA Astrophysics Data System (ADS)

    Fischer, Thomas; Walther, Marc; Naumov, Dmitri; Sattler, Sabine; Kolditz, Olaf

    2015-04-01

    The investigation of fluid circulation in the Thuringian syncline is one of the INFLUINS project's targets. A 3D geo-structural model including 12 stratigraphic layers and 54 fault zones is created by geologists in the first step using the Gocad software. Within the INFLUINS project a ground-water flow simulation is used to check existing hypotheses and to gain new ideas of the underground fluid flow behaviour. We used the scientific, platform independent, open source software OpenGeoSys that implements the finite element method to solve the governing equations describing fluid flow in porous media. The geo-structural Gocad model is not suitable for the FEM numerical analysis. Therefore it is converted into an unstructured grid satisfying all mesh quality criteria required for the ground-water flow simulation. The resulting grid is stored in an open data format given by the Visualization Toolkit (vtk). In this work we present a workflow to convert geological structural models, created using the Gocad software, into a simulation model that is easy to use from numerical simulation software. We tested our workflow with the 3D geo-structural model of the Thuringian syncline and were able to setup and to evaluate a hydrogeological simulation model successfully.

  19. A REAL TIME COAL CONTENT ORE GRADE (C2OG) SENSOR

    SciTech Connect

    Dr. Rand Swanson

    2002-01-31

    The overall approach of this effort is to spectrally image ore or coal, and then use the spectral content (i.e., the particular colors of the ore or coal) to differentiate between the ore or coal grades. Currently, experts with practiced eyes do just this to identify the grade of platinum/palladium ore from the Stillwater Mine in south-central Montana. Additionally, trained eyes can identify high-sulfur and high-ash coal visually. The premise of this effort is that machine vision can accomplish this same differentiation. During the first quarter, machine vision results using a digital color camera did not correlate as well with assay results for platinum/palladium ore as would be required for a commercial device. One of the possible reasons for this is that the digital camera did not provide enough spectral information to obtain good differentiation between the sulfides associated with high-grade platinum/palladium ore and background interference, most notably yellow grease that contaminates some of the sample and green colored rock. The second quarter efforts have largely been devoted to implementing an imaging spectrometer for machine vision. In brief, modifying an imaging spectrometer that was designed for remote sensing from a Remotely Controlled (RC) airplane has done this. The imaging spectrometer provides 320 spectral channels, allowing for much better spectral resolution that can be obtained with a digital color camera, which provides 3 spectral channels. Preliminary results, as discussed below in more detail, are encouraging. The technical portion of the report below is organized into subsections as dictated by the DoE contract for this effort. These sections are: Experimental Apparatus, Experimental and Operating Data, Data Reduction, and Hypothesis and Conclusions. Partners in this effort are: Montana Tech of the University of Montana, Stillwater Mining Co., Western Syncoal, and the Montana Board of Research and Commercialization.

  20. A REAL TIME COAL CONTENT ORE GRADE (C2OG) SENSOR

    SciTech Connect

    Rand Swanson

    2004-01-23

    This tenth quarterly technical report discusses the progress made on a machine vision technique for ore grading based on hyperspectral imaging. A graduate student at Montana Tech has successfully defended her thesis related to this project. Arrangements with Stillwater Mining Company to deploy a machine vision system in their core room have been completed. Designs for they system that will be installed next quarter have been drawn and parts are being machined. Presentations on the spectral imaging system developed during this effort have been made to Stillwater Mining Company and at a remote sensing symposium at Montana State University.

  1. A REAL TIME COAL CONTENT ORE GRADE (C2OG) SENSOR

    SciTech Connect

    Dr. Rand Swanson

    2003-07-21

    This eighth quarterly technical report discusses the progress made on a machine vision technique for determining coal content and preparations for Year-3 system deployment. Classification maps for coal have been generated and shown to two coal-mining executives. An application for licensing high-speed hyperspectral data analysis software from the Naval Research Laboratory (NRL) has been made. Both Western Energy and Stillwater Mining Company have offered platforms for Year-3 deployment. Barretts Minerals has expressed renewed interest in using Resonon's machine vision system for identifying dolomite in their talc ore and have agreed to provide samples to the Montana Tech team.

  2. A REAL TIME COAL CONTENT ORE GRADE (C2OG) SENSOR

    SciTech Connect

    Dr. Rand Swanson

    2002-07-19

    This fourth quarterly technical report discusses the progress made on a machine vision technique for determining coal content and ore grades. Work done this quarter has been primarily devoted to improving the apparatus and data collection system. This includes a totally new optical setup, continued development of a new imaging spectrometer, and software improvements. Additionally, interest from other mining operations has arisen and sample of titanium and talc have now been obtained for preliminary analysis. Work is ongoing with coal samples, although it appears a more diverse sampling may be required. With the improvements now being made in the system, much faster and more user-friendly data collection and analysis will result in faster and better turn-around for sample analysis.

  3. An ID2-dependent mechanism for VHL inactivation in cancer.

    PubMed

    Lee, Sang Bae; Frattini, Veronique; Bansal, Mukesh; Castano, Angelica M; Sherman, Dan; Hutchinson, Keino; Bruce, Jeffrey N; Califano, Andrea; Liu, Guangchao; Cardozo, Timothy; Iavarone, Antonio; Lasorella, Anna

    2016-01-14

    Mechanisms that maintain cancer stem cells are crucial to tumour progression. The ID2 protein supports cancer hallmarks including the cancer stem cell state. HIFα transcription factors, most notably HIF2α (also known as EPAS1), are expressed in and required for maintenance of cancer stem cells (CSCs). However, the pathways that are engaged by ID2 or drive HIF2α accumulation in CSCs have remained unclear. Here we report that DYRK1A and DYRK1B kinases phosphorylate ID2 on threonine 27 (Thr27). Hypoxia downregulates this phosphorylation via inactivation of DYRK1A and DYRK1B. The activity of these kinases is stimulated in normoxia by the oxygen-sensing prolyl hydroxylase PHD1 (also known as EGLN2). ID2 binds to the VHL ubiquitin ligase complex, displaces VHL-associated Cullin 2, and impairs HIF2α ubiquitylation and degradation. Phosphorylation of Thr27 of ID2 by DYRK1 blocks ID2-VHL interaction and preserves HIF2α ubiquitylation. In glioblastoma, ID2 positively modulates HIF2α activity. Conversely, elevated expression of DYRK1 phosphorylates Thr27 of ID2, leading to HIF2α destabilization, loss of glioma stemness, inhibition of tumour growth, and a more favourable outcome for patients with glioblastoma. PMID:26735018

  4. Optical limiting in semiconductor-doped glasses

    NASA Astrophysics Data System (ADS)

    Bindra, K. S.; Oak, S. M.; Rustagi, K. C.

    1996-02-01

    We report optical limiting at 527 nm in two Schott semiconductor-doped glasses OG530 and OG515. These two glasses show quite contrasting nonlinear optical behaviour. The glass OG515 shows strong clamping while OG530 shows no clamping in optical limiting inspite of having much larger nonlinear refractive index. Similarly OG530 exhibits saturation of absorption while OG515 does not.

  5. Hypotension and AV block after diesel exhaust exposure in heart failure-prone rats: role of gaseous and particulate components

    EPA Science Inventory

    Acute inhalations ofdiesel engine exhaust (DE) and fine particulate matter (PM2.5) have been demonstrated to provoke adverse cardiac events in humans with preexisting heart disease. Electrophysiologic dysfunction and autonomic imbalance are among the mechanisms widely held to und...

  6. A QoS aware resource allocation strategy for 3D A/V streaming in OFDMA based wireless systems.

    PubMed

    Chung, Young-Uk; Choi, Yong-Hoon; Park, Suwon; Lee, Hyukjoon

    2014-01-01

    Three-dimensional (3D) video is expected to be a "killer app" for OFDMA-based broadband wireless systems. The main limitation of 3D video streaming over a wireless system is the shortage of radio resources due to the large size of the 3D traffic. This paper presents a novel resource allocation strategy to address this problem. In the paper, the video-plus-depth 3D traffic type is considered. The proposed resource allocation strategy focuses on the relationship between 2D video and the depth map, handling them with different priorities. It is formulated as an optimization problem and is solved using a suboptimal heuristic algorithm. Numerical results show that the proposed scheme provides a better quality of service compared to conventional schemes.

  7. 75 FR 75159 - Airworthiness Directives; 328 Support Services GmbH (Type Certificate Previously Held by AvCraft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-02

    ... proposed AD. Discussion On June 3, 2008, we issued AD 2008-10-51, Amendment 39-15535 (73 FR 30752, May 29... visual inspections (DVI) of both the left (LH) and right (RH) wing panel rear trailing edge around rib 3... both the LH and RH wing panel rear trailing edges from rib 3 to rib 9. Modification does not...

  8. 76 FR 419 - Airworthiness Directives; 328 Support Services GmbH (Type Certificate Previously Held by AvCraft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-05

    ... Register on October 1, 2010 (75 FR 60659). That NPRM proposed to correct an unsafe condition for the... Procedures (44 FR 11034, February 26, 1979); and 3. Will not have a significant economic impact, positive or negative, on a substantial number of small entities under the criteria of the Regulatory Flexibility...

  9. IFLA General Conference, 1987. Division on Bibliographic Control. Bibliography and Round Table on A/V Media Section. Papers.

    ERIC Educational Resources Information Center

    International Federation of Library Associations, The Hague (Netherlands).

    The two papers in this section focus on the bibliographic control of sound recordings, primarily phonograph records. In the first, "The National Discography for the United Kingdom," Christopher Roads discusses the problem of lack of easily accessible and up-to-date information about the growing collection of new sound recordings as they are being…

  10. GB-InSAR monitoring and observational method for landslide emergency management: the Montaguto earthflow (AV, Italy)

    NASA Astrophysics Data System (ADS)

    Ferrigno, F.; Gigli, G.; Fanti, R.; Casagli, N.

    2015-12-01

    On 10 March 2010, due to the heavy rainfall that occurred on the previous days, the Montaguto earthflow reactivated, involving the road SS 90 "Delle Puglie", as had happened previously in May 2005 and in September 2009, and reaching the Roma-Bari railway. This determined a special attention of the National Civil Protection Department and a widespread monitoring and analysis program was initiated. A monitoring activity using GB-InSAR (Ground Based Interferometric Synthetic Aperture Radar) system began, in order to investigate the landslide kinematics, to plan urgent safety measures for risk mitigation and to design long term stabilization work. In this paper the GB-InSAR monitoring system results and its applications in the Observational Method (OM) approach are presented. The paper also highlights how the OM based on the GB-InSAR technique can produce savings in cost and time on engineering projects, without compromising safety, and how it can also benefit the geotechnical community by increasing scientific knowledge. This study focuses on the very much active role played by the monitoring activities, in both the design and plan modifications; with a special consideration for the emergency phase.

  11. 76 FR 58094 - Airworthiness Directives; 328 Support Services GmbH (Type Certificate Previously Held by AvCraft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-20

    ... Support Services GmbH, Global Support Center, P.O. Box 1252, D-82231 Wessling, Federal Republic of Germany... identified in this AD, contact 328 Support Services GmbH, Global Support Center, P.O. Box 1252, D-82231... routine inspection, cracks have been found on an aeroplane at the lower wing panel rear trailing...

  12. 76 FR 54145 - Airworthiness Directives; 328 Support Services GmbH (Type Certificate Previously Held by AvCraft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-31

    ... Services GmbH, Global Support Center, P.O. Box 1252, D-82231 Wessling, Federal Republic of Germany... injury to the occupants. A modification to the power lever control box has been designed to prevent... modification of the power lever control box as a retrofit for the entire fleet of 328-100 aeroplanes....

  13. SAR Aircrew--HH-3F Avionics and HH-3F Flight Preparation. ACH3AV-0442. Second Edition, Revised.

    ERIC Educational Resources Information Center

    Coast Guard Inst., Oklahoma City, OK.

    This document contains two U.S. Coast Guard self-study pamphlets that provide training in helicopter flight preparation and avionics duties. Each pamphlet consists of a number of lessons that include objectives, information illustrated with line drawings and/or photographs, and self-quizzes with answers. The avionics course covers the following…

  14. CONCENTRATION DEPENDENT ACCUMULATION OF [3H]-DELTAMETHRIN IN SODIUM CHANNEL N AV1.2 EXPRESSING XENOPUS LAEVIS OOCYTES.

    EPA Science Inventory

    Disruption of neuronal voltage-sensitive sodium channels (VSSCs) by pyrethroid insecticides such as deltamethrin (DLT) has been widely studied using Xenopus laevis oocytes transfected with VSSC. However, the extent of pyrethroid accumulation in VSSC-expressing oocytes is unknown....

  15. 75 FR 60659 - Airworthiness Directives; 328 Support Services GmbH (Type Certificate Previously Held by AvCraft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-01

    ... Procedures (44 FR 11034, February 26, 1979); and 3. Will not have a significant economic impact, positive or... identified as stress corrosion. This condition, if not corrected, could lead to in-flight failure of the tab... was found on a trim tab fitting assembly. The cause of the cracking was identified as stress...

  16. Produce Live News Broadcasts Using Standard AV Equipment: A Success Story from the Le Center High School in Minnesota.

    ERIC Educational Resources Information Center

    Rostad, John

    1997-01-01

    Describes the production of news broadcasts on video by a high school class in Le Center, Minnesota. Topics include software for Apple computers, equipment used, student responsibilities, class curriculum, group work, communication among the production crew, administrative and staff support, and future improvements. (LRW)

  17. 76 FR 61638 - Airworthiness Directives; 328 Support Services GmbH (Type Certificate Previously Held by AvCraft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-05

    ... the basic requirements of this proposed AD. The average labor rate is $85 per work-hour. Based on... Procedures (44 FR 11034, February 26, 1979), (3) Will not have a significant economic impact, positive or....-- Task description-- Identified in-- 328-100 airplanes Task 27-10-00-09...... Visual Check of 328...

  18. A chicory cytochrome P450 mono-oxygenase CYP71AV8 for the oxidation of (+)-valencene.

    PubMed

    Cankar, Katarina; van Houwelingen, Adèle; Bosch, Dirk; Sonke, Theo; Bouwmeester, Harro; Beekwilder, Jules

    2011-01-01

    Chicory (Cichorium intybus L.), which is known to have a variety of terpene-hydroxylating activities, was screened for a P450 mono-oxygenase to convert (+)-valencene to (+)-nootkatone. A novel P450 cDNA was identified in a chicory root EST library. Co-expression of the enzyme with a valencene synthase in yeast, led to formation of trans-nootkatol, cis-nootkatol and (+)-nootkatone. The novel enzyme was also found to catalyse a three step conversion of germacrene A to germacra-1(10),4,11(13)-trien-12-oic acid, indicating its involvement in chicory sesquiterpene lactone biosynthesis. Likewise, amorpha-4,11-diene was converted to artemisinic acid. Surprisingly, the chicory P450 has a different regio-specificity on (+)-valencene compared to germacrene A and amorpha-4,11-diene. PMID:21115006

  19. 77 FR 12163 - Airworthiness Directives; 328 Support Services GmbH (Type Certificate Previously Held by AvCraft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-29

    ... Register on August 31, 2011 (76 FR 54145). That NPRM proposed to correct an unsafe condition for the... requested we revise the Cost of Compliance section of the NPRM (76 FR 54145, August 31, 2011). The commenter... a ``significant rule'' under the DOT Regulatory Policies and Procedures (44 FR 11034, February...

  20. 78 FR 52872 - Airworthiness Directives; 328 Support Services GmbH (Type Certificate Previously Held by AvCraft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-27

    ... AD. Discussion On July 17, 2008, we issued AD 2008-14-16, Amendment 39-15611 (73 FR 40955, July 17... (73 FR 40955, July 17, 2008), we received reports that certain fasteners which were installed as part... $15,191 $531,685 actions from AD 2008-14-16, hour = $3230. Amendment 39-15611 (73 FR 40955, July...

  1. Truncation and Activation of Dual Specificity Tyrosine Phosphorylation-regulated Kinase 1A by Calpain I: A MOLECULAR MECHANISM LINKED TO TAU PATHOLOGY IN ALZHEIMER DISEASE.

    PubMed

    Jin, Nana; Yin, Xiaomin; Gu, Jianlan; Zhang, Xinhua; Shi, Jianhua; Qian, Wei; Ji, Yuhua; Cao, Maohong; Gu, Xiaosong; Ding, Fei; Iqbal, Khalid; Gong, Cheng-Xin; Liu, Fei

    2015-06-12

    Hyperphosphorylation and dysregulation of exon 10 splicing of Tau are pivotally involved in pathogenesis of Alzheimer disease (AD) and/or other tauopathies. Alternative splicing of Tau exon 10, which encodes the second microtubule-binding repeat, generates Tau isoforms containing three and four microtubule-binding repeats, termed 3R-Taus and 4R-Taus, respectively. Dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) lies at the Down syndrome critical region of chromosome 21. Overexpression of this kinase may contribute to the early Tau pathology in Down syndrome via phosphorylation of Tau and dysregulation of Tau exon 10. Here, we report that Dyrk1A was truncated at the C terminus and was associated with overactivation of calpain I in AD brain. Calpain I proteolyzed Dyrk1A in vitro first at the C terminus and further at the N terminus and enhanced its kinase activity toward Tau via increased Vmax but not Km. C-terminal truncation of Dyrk1A resulted in stronger activity than its full-length protein in promotion of exon 10 exclusion and phosphorylation of Tau. Dyrk1A was truncated in kainic acid-induced excitotoxic mouse brains and coincided with an increase in 3R-Tau expression and phosphorylation of Tau via calpain activation. Moreover, truncation of Dyrk1A was correlated with an increase in the ratio of 3R-Tau/4R-Tau and Tau hyperphosphorylation in AD brain. Collectively, these findings suggest that truncation/activation of Dyrk1A by Ca(2+)/calpain I might contribute to Tau pathology via promotion of exon 10 exclusion and hyperphosphorylation of Tau in AD brain. PMID:25918155

  2. Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models.

    PubMed

    Souchet, Benoit; Guedj, Fayçal; Penke-Verdier, Zsuza; Daubigney, Fabrice; Duchon, Arnaud; Herault, Yann; Bizot, Jean-Charles; Janel, Nathalie; Créau, Nicole; Delatour, Benoit; Delabar, Jean M

    2015-01-01

    Cognitive impairment in Down syndrome (DS) has been linked to increased synaptic inhibition. The underlying mechanisms remain unknown, but memory deficits are rescued in DS mouse models by drugs targeting GABA receptors. Similarly, administration of epigallocatechin gallate (EGCG)-containing extracts rescues cognitive phenotypes in Ts65Dn mice, potentially through GABA pathway. Some developmental and cognitive alterations have been traced to increased expression of the serine-threonine kinase DYRK1A on Hsa21. To better understand excitation/inhibition balance in DS, we investigated the consequences of long-term (1-month) treatment with EGCG-containing extracts in adult mBACtgDyrk1a mice that overexpress Dyrk1a. Administration of POL60 rescued components of GABAergic and glutamatergic pathways in cortex and hippocampus but not cerebellum. An intermediate dose (60 mg/kg) of decaffeinated green tea extract (MGTE) acted on components of both GABAergic and glutamatergic pathways and rescued behavioral deficits as demonstrated on the alternating paradigm, but did not rescue protein level of GABA-synthesizing GAD67. These results indicate that excessive synaptic inhibition in people with DS may be attributable, in large part, to increased DYRK1A dosage. Thus, controlling the level of active DYRK1A is a clear issue for DS therapy. This study also defines a panel of synaptic markers for further characterization of DS treatments in murine models.

  3. Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models.

    PubMed

    Souchet, Benoit; Guedj, Fayçal; Penke-Verdier, Zsuza; Daubigney, Fabrice; Duchon, Arnaud; Herault, Yann; Bizot, Jean-Charles; Janel, Nathalie; Créau, Nicole; Delatour, Benoit; Delabar, Jean M

    2015-01-01

    Cognitive impairment in Down syndrome (DS) has been linked to increased synaptic inhibition. The underlying mechanisms remain unknown, but memory deficits are rescued in DS mouse models by drugs targeting GABA receptors. Similarly, administration of epigallocatechin gallate (EGCG)-containing extracts rescues cognitive phenotypes in Ts65Dn mice, potentially through GABA pathway. Some developmental and cognitive alterations have been traced to increased expression of the serine-threonine kinase DYRK1A on Hsa21. To better understand excitation/inhibition balance in DS, we investigated the consequences of long-term (1-month) treatment with EGCG-containing extracts in adult mBACtgDyrk1a mice that overexpress Dyrk1a. Administration of POL60 rescued components of GABAergic and glutamatergic pathways in cortex and hippocampus but not cerebellum. An intermediate dose (60 mg/kg) of decaffeinated green tea extract (MGTE) acted on components of both GABAergic and glutamatergic pathways and rescued behavioral deficits as demonstrated on the alternating paradigm, but did not rescue protein level of GABA-synthesizing GAD67. These results indicate that excessive synaptic inhibition in people with DS may be attributable, in large part, to increased DYRK1A dosage. Thus, controlling the level of active DYRK1A is a clear issue for DS therapy. This study also defines a panel of synaptic markers for further characterization of DS treatments in murine models. PMID:26539088

  4. Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models

    PubMed Central

    Souchet, Benoit; Guedj, Fayçal; Penke-Verdier, Zsuza; Daubigney, Fabrice; Duchon, Arnaud; Herault, Yann; Bizot, Jean-Charles; Janel, Nathalie; Créau, Nicole; Delatour, Benoit; Delabar, Jean M.

    2015-01-01

    Cognitive impairment in Down syndrome (DS) has been linked to increased synaptic inhibition. The underlying mechanisms remain unknown, but memory deficits are rescued in DS mouse models by drugs targeting GABA receptors. Similarly, administration of epigallocatechin gallate (EGCG)-containing extracts rescues cognitive phenotypes in Ts65Dn mice, potentially through GABA pathway. Some developmental and cognitive alterations have been traced to increased expression of the serine-threonine kinase DYRK1A on Hsa21. To better understand excitation/inhibition balance in DS, we investigated the consequences of long-term (1-month) treatment with EGCG-containing extracts in adult mBACtgDyrk1a mice that overexpress Dyrk1a. Administration of POL60 rescued components of GABAergic and glutamatergic pathways in cortex and hippocampus but not cerebellum. An intermediate dose (60 mg/kg) of decaffeinated green tea extract (MGTE) acted on components of both GABAergic and glutamatergic pathways and rescued behavioral deficits as demonstrated on the alternating paradigm, but did not rescue protein level of GABA-synthesizing GAD67. These results indicate that excessive synaptic inhibition in people with DS may be attributable, in large part, to increased DYRK1A dosage. Thus, controlling the level of active DYRK1A is a clear issue for DS therapy. This study also defines a panel of synaptic markers for further characterization of DS treatments in murine models. PMID:26539088

  5. Hip Hop Culture's OGs: A Narrative Inquiry into the Intersection of Hip Hop Culture, Black Males and Their Schooling Experiences

    ERIC Educational Resources Information Center

    Buchanan, Ian P.

    2013-01-01

    Using a critical race lens, this narrative study employs a focus group design to explore the intersections between black males, hip hop culture and schooling experiences. To provide a sociocultural grounding, this study first reviews the research literature around hip hop culture.s sociocultural development and its impact as a culture force that…

  6. The formation of pentagon-heptagon pair defect by the reconstruction og vacancy defects in carbon nanotube

    SciTech Connect

    Lee, G.D.; Wang, C.Z.; Yoon, E.; Hwang, N.M.; Ho, K.M.

    2008-01-29

    The reconstruction process of vacancy hole in carbon nanotube is investigated by tight-binding molecular dynamics simulations and by ab initio total energy calculations. In the molecular dynamics simulation, a vacancy hole is found to reconstruct into two separated pentagon-heptagon pair defects. As the result of reconstruction, the radius of the carbon nanotube is reduced and the chirality of the tube is partly changed. During the vacancy hole healing process, the formation of pentagonal and heptagonal rings is proceeded by the subsequent Stone-Wales.

  7. Algorithm Visualization: The State of the Field

    ERIC Educational Resources Information Center

    Shaffer, Clifford A.; Cooper, Matthew L.; Alon, Alexander Joel D.; Akbar, Monika; Stewart, Michael; Ponce, Sean; Edwards, Stephen H.

    2010-01-01

    We present findings regarding the state of the field of Algorithm Visualization (AV) based on our analysis of a collection of over 500 AVs. We examine how AVs are distributed among topics, who created them and when, their overall quality, and how they are disseminated. There does exist a cadre of good AVs and active developers. Unfortunately, we…

  8. Discovery of pyrido[3,4-g]quinazoline derivatives as CMGC family protein kinase inhibitors: Design, synthesis, inhibitory potency and X-ray co-crystal structure.

    PubMed

    Esvan, Yannick J; Zeinyeh, Wael; Boibessot, Thibaut; Nauton, Lionel; Théry, Vincent; Knapp, Stefan; Chaikuad, Apirat; Loaëc, Nadège; Meijer, Laurent; Anizon, Fabrice; Giraud, Francis; Moreau, Pascale

    2016-08-01

    The design and synthesis of new pyrido[3,4-g]quinazoline derivatives is described as well as their protein kinase inhibitory potencies toward five CMGC family members (CDK5, CK1, GSK3, CLK1 and DYRK1A). The interest for this original tricyclic heteroaromatic scaffold as modulators of CLK1/DYRK1A activity was validated by nanomolar potencies (compounds 12 and 13). CLK1 co-crystal structures with two inhibitors revealed the binding mode of these compounds within the ATP-binding pocket. PMID:27128181

  9. Design, synthesis, and molecular modelling of pyridazinone and phthalazinone derivatives as protein kinases inhibitors.

    PubMed

    Elagawany, Mohamed; Ibrahim, Mohamed A; Ali Ahmed, Hany Emary; El-Etrawy, A Sh; Ghiaty, Adel; Abdel-Samii, Zakaria K; El-Feky, Said A; Bajorath, Jürgen

    2013-04-01

    The design and synthesis of pyridazinone and phthalazinone derivatives are described. Newly synthesized compounds were tested on a panel of four kinases in order to evaluate their activity and potential selectivity. In addition, the promising compounds were tested on four cancer cell lines to examine cytotoxic effects. The compounds inhibited DYRK1A and GSK3 with different activity. SAR analysis and docking calculations were carried out to aid in the interpretation of the results. Taken together, our findings suggest that pyridazinone and phthalazinone scaffolds are interesting starting points for design of potent GSK3 and DYRK1A inhibitors. PMID:23453843

  10. The Future Is Now: The Era of Downloadable AV Has Dawned--Here's How It's Working in the Real Library World

    ERIC Educational Resources Information Center

    Kim, Ann

    2006-01-01

    This article discusses the possible answers to most librarians' questions and how advanced and hi-technology help them in the library world. Many of the answers to librarians' questions regarding digital media depend upon community/patron awareness and library resources. In this article, the author presents some quoted statements from electronic…

  11. Right ventricular electrical and mechanical synchronization by properly timed septal pacing in a patient with right bundle branch block and first degree AV block--a case report.

    PubMed

    Siliste, Calin; Suran, Maria-Claudia-Berenice; Margulescu, Andrei-Dumitru; Vinereanu, Dragos

    2015-03-01

    We present a case of near-normalization of the QRS by septal pacing in a patient with dual-chamber pacemaker and underlying complete right bundle branch block and first degree atrioventricular block. The right ventricular mechanical synchronization suggested by the ECG was validated as such by strain echo. To the best of our knowledge, this is the first time it has been shown that the narrowing of the QRS corresponds to mechanical synchronization in a case of this seldom-recognized phenomenon.

  12. Inter-dye distance distributions studied by a combination of single-molecule FRET-filtered lifetime measurements and a weighted accessible volume (wAV) algorithm.

    PubMed

    Höfig, Henning; Gabba, Matteo; Poblete, Simón; Kempe, Daryan; Fitter, Jörg

    2014-01-01

    Förster resonance energy transfer (FRET) is an important tool for studying the structural and dynamical properties of biomolecules. The fact that both the internal dynamics of the biomolecule and the movements of the biomolecule-attached dyes can occur on similar timescales of nanoseconds is an inherent problem in FRET studies. By performing single-molecule FRET-filtered lifetime measurements, we are able to characterize the amplitude of the motions of fluorescent probes attached to double-stranded DNA standards by means of flexible linkers. With respect to previously proposed experimental approaches, we improved the precision and the accuracy of the inter-dye distance distribution parameters by filtering out the donor-only population with pulsed interleaved excitation. A coarse-grained model is employed to reproduce the experimentally determined inter-dye distance distributions. This approach can easily be extended to intrinsically flexible proteins allowing, under certain conditions, to decouple the macromolecule amplitude of motions from the contribution of the dye linkers.

  13. [On the genesis of the first heart sound: phono-echocardiographic study in patients with A-V block (author's transl)].

    PubMed

    Cannata, D; Autore, C; Fragola, P; Pierangli, L; Maccari, A M

    1981-01-01

    A phono-echocardiographic study of acustic and morphologic events was performed in three patients with atrioventricular block in order to assess the role of the mitral valve in the changes of the amplitude of the first heart and, more generally, in the genesis of the first heart sound. Simultaneous recording of the electrocardiogram, the apical phonocardiogram and the mitral echocardiogram showed: 1) the coincidence between the C point of the echocardiogram and the onset of the earlier high frequency vibrations of the first heart sound (M1); 2) a close correlation between the intensity of the first heart sound and the position of the mitral valve at the onset of ventricular systole (P less than 0.001); 3) longer duration of the first heart sound in those beats when there was superimposition of P wave in QRS. The authors illustrate the recent reports about the genesis of the first heart sound and emphasize the main role of the mitral valve suggesting that the position of the mitral leaflets at the onset of ventricular systole influences the mechanism of acceleration and deceleration of blood and vibrations of the "cardiohemic system".

  14. Intermittent bundle-branch block in patients with accessory atrio-His or atrio-AV nodal pathways. Variants of the Lown-Ganong-Levine syndrome.

    PubMed

    Befeler, B; Castellanos, A; Aranda, J; Gutierrez, R; Lazzara, R

    1976-02-01

    Intracardiac electrophysiological studies were performed in two patients with a documented history of repetitive supraventricular tachyarrhythmias. Case 1, with short PR interval and narrow QRS complexes had a short AH interval and intermittent right bundle-branch block. Thus the short PR wide QRS syndrome is not always a result of the Wolff-Parkinson-White syndrome but can also be seen in the Lown-Ganong-Levine syndrome coexisting with bundle-branch block. Case 2, with normal PR and AH at the lower limits of normal, showed the dual pathway response to atrial pacing that can occur in patients with Lown-Ganong-Levine syndrome. He also had tachycardia-dependent right bundle-branch block and left posterior hemiblock. Therefore, neither the short PR interval nor the narrow QRS complexes characterized these forms of pre-excitation. The constant features were, from the clinical viewpoint, the occurrence of repetitive supraventricular tachyarrhythmias, and electrophysiologically the abnormal response to atrial stimulation.

  15. Identification of a novel actin-dependent signal transducing module allows for the targeted degradation of GLI1

    PubMed Central

    Schneider, Philipp; Miguel Bayo-Fina, Juan; Singh, Rajeev; Kumar Dhanyamraju, Pavan; Holz, Philipp; Baier, Aninja; Fendrich, Volker; Ramaswamy, Annette; Baumeister, Stefan; Martinez, Elisabeth D.; Lauth, Matthias

    2015-01-01

    The Down syndrome-associated DYRK1A kinase has been reported as a stimulator of the developmentally important Hedgehog (Hh) pathway, but cells from Down syndrome patients paradoxically display reduced Hh signalling activity. Here we find that DYRK1A stimulates GLI transcription factor activity through phosphorylation of general nuclear localization clusters. In contrast, in vivo and in vitro experiments reveal that DYRK1A kinase can also function as an inhibitor of endogenous Hh signalling by negatively regulating ABLIM proteins, the actin cytoskeleton and the transcriptional co-activator MKL1 (MAL). As a final effector of the DYRK1A-ABLIM-actin-MKL1 sequence, we identify the MKL1 interactor Jumonji domain demethylase 1A (JMJD1A) as a novel Hh pathway component stabilizing the GLI1 protein in a demethylase-independent manner. Furthermore, a Jumonji-specific small-molecule antagonist represents a novel and powerful inhibitor of Hh signal transduction by inducing GLI1 protein degradation in vitro and in vivo. PMID:26310823

  16. Diagnostic test for prenatal identification of Down's syndrome and mental retardation and gene therapy therefor

    DOEpatents

    Smith, Desmond J.; Rubin, Edward M.

    2000-01-01

    A a diagnostic test useful for prenatal identification of Down syndrome and mental retardation. A method for gene therapy for correction and treatment of Down syndrome. DYRK gene involved in the ability to learn. A method for diagnosing Down's syndrome and mental retardation and an assay therefor. A pharmaceutical composition for treatment of Down's syndrome mental retardation.

  17. Identification of a novel actin-dependent signal transducing module allows for the targeted degradation of GLI1.

    PubMed

    Schneider, Philipp; Bayo-Fina, Juan Miguel; Singh, Rajeev; Kumar Dhanyamraju, Pavan; Holz, Philipp; Baier, Aninja; Fendrich, Volker; Ramaswamy, Annette; Baumeister, Stefan; Martinez, Elisabeth D; Lauth, Matthias

    2015-01-01

    The Down syndrome-associated DYRK1A kinase has been reported as a stimulator of the developmentally important Hedgehog (Hh) pathway, but cells from Down syndrome patients paradoxically display reduced Hh signalling activity. Here we find that DYRK1A stimulates GLI transcription factor activity through phosphorylation of general nuclear localization clusters. In contrast, in vivo and in vitro experiments reveal that DYRK1A kinase can also function as an inhibitor of endogenous Hh signalling by negatively regulating ABLIM proteins, the actin cytoskeleton and the transcriptional co-activator MKL1 (MAL). As a final effector of the DYRK1A-ABLIM-actin-MKL1 sequence, we identify the MKL1 interactor Jumonji domain demethylase 1A (JMJD1A) as a novel Hh pathway component stabilizing the GLI1 protein in a demethylase-independent manner. Furthermore, a Jumonji-specific small-molecule antagonist represents a novel and powerful inhibitor of Hh signal transduction by inducing GLI1 protein degradation in vitro and in vivo. PMID:26310823

  18. Selectivity, cocrystal structures, and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B.

    PubMed

    Tahtouh, Tania; Elkins, Jonathan M; Filippakopoulos, Panagis; Soundararajan, Meera; Burgy, Guillaume; Durieu, Emilie; Cochet, Claude; Schmid, Ralf S; Lo, Donald C; Delhommel, Florent; Oberholzer, Anselm E; Pearl, Laurence H; Carreaux, François; Bazureau, Jean-Pierre; Knapp, Stefan; Meijer, Laurent

    2012-11-01

    DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are implicated in the onset and development of Alzheimer's disease and Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor of DYRKs/CLKs. Synthesis of analogues (leucettines) led to an optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, and GSK-3β. The selectivity of L41 was studied by activity and interaction assays of recombinant kinases and affinity chromatography and competition affinity assays. These approaches revealed unexpected potential secondary targets such as CK2, SLK, and the lipid kinase PIKfyve/Vac14/Fig4. L41 displayed neuroprotective effects on glutamate-induced HT22 cell death. L41 also reduced amyloid precursor protein-induced cell death in cultured rat brain slices. The unusual multitarget selectivity of leucettines may account for their neuroprotective effects. This family of kinase inhibitors deserves further optimization as potential therapeutics against neurodegenerative diseases such as Alzheimer's disease. PMID:22998443

  19. Genetic dissection of the Down syndrome critical region.

    PubMed

    Jiang, Xiaoling; Liu, Chunhong; Yu, Tao; Zhang, Li; Meng, Kai; Xing, Zhuo; Belichenko, Pavel V; Kleschevnikov, Alexander M; Pao, Annie; Peresie, Jennifer; Wie, Sarah; Mobley, William C; Yu, Y Eugene

    2015-11-15

    Down syndrome (DS), caused by trisomy 21, is the most common chromosomal disorder associated with developmental cognitive deficits. Despite intensive efforts, the genetic mechanisms underlying developmental cognitive deficits remain poorly understood, and no treatment has been proven effective. The previous mouse-based experiments suggest that the so-called Down syndrome critical region of human chromosome 21 is an important region for this phenotype, which is demarcated by Setd4/Cbr1 and Fam3b/Mx2. We first confirmed the importance of the Cbr1-Fam3b region using compound mutant mice, which carry a duplication spanning the entire human chromosome 21 orthologous region on mouse chromosome 16 [Dp(16)1Yey] and Ms1Rhr. By dividing the Setd4-Mx2 region into complementary Setd4-Kcnj6 and Kcnj15-Mx2 intervals, we started an unbiased dissection through generating and analyzing Dp(16)1Yey/Df(16Setd4-Kcnj6)Yey and Dp(16)1Yey/Df(16Kcnj15-Mx2)Yey mice. Surprisingly, the Dp(16)1Yey-associated cognitive phenotypes were not rescued by either deletion in the compound mutants, suggesting the possible presence of at least one causative gene in each of the two regions. The partial rescue by a Dyrk1a mutation in a compound mutant carrying Dp(16)1Yey and the Dyrk1a mutation confirmed the causative role of Dyrk1a, whereas the absence of a similar rescue by Df(16Dyrk1a-Kcnj6)Yey in Dp(16)1Yey/Df(16Dyrk1a-Kcnj6)Yey mice demonstrated the importance of Kcnj6. Our results revealed the high levels of complexities of gene actions and interactions associated with the Setd4/Cbr1-Fam3b/Mx2 region as well as their relationship with developmental cognitive deficits in DS. PMID:26374847

  20. Alzheimer's disease Advax(CpG)- adjuvanted MultiTEP-based dual and single vaccines induce high-titer antibodies against various forms of tau and Aβ pathological molecules.

    PubMed

    Davtyan, Hayk; Zagorski, Karen; Rajapaksha, Harinda; Hovakimyan, Armine; Davtyan, Arpine; Petrushina, Irina; Kazarian, Konstantin; Cribbs, David H; Petrovsky, Nikolai; Agadjanyan, Michael G; Ghochikyan, Anahit

    2016-01-01

    Although β-amyloid (Aβ) may be the primary driver of Alzheimer's disease (AD) pathology, accumulation of pathological tau correlates with dementia in AD patients. Thus, the prevention/inhibition of AD may require vaccine/s targeting Aβ and tau simultaneously or sequentially. Since high antibody titers are required for AD vaccine efficacy, we have decided to generate vaccines, targeting Aβ (AV-1959R), Tau (AV-1980R) or Aβ/tau (AV-1953R) B cell epitopes, based on immunogenic MultiTEP platform and evaluate the immunogenicity of these vaccines formulated with Advax(CpG), delta inulin, Alhydrogel(®), Montanide-ISA51, Montanide-ISA720, MPLA-SM pharmaceutical grade adjuvants. Formulation of AV-1959R in Advax(CpG) induced the highest cellular and humoral immune responses in mice. The dual-epitope vaccine, AV-1953R, or the combination of AV-1959R and AV-1980R vaccines formulated with Advax(CpG) induced robust antibody responses against various forms of both, Aβ and tau pathological molecules. While anti-Aβ antibody titers after AV-1953R immunization were similar to that in mice vaccinated with AV-1959R or AV-1959R/AV-1980R combination, anti-tau titers were significantly lower after AV-1953R injection when compared to the AV-1980R or AV-1959R/AV-1980R. In silico 3D-modeling provided insight into the differences in immunogenicity of these vaccine constructs. In sum, AV-1959R and AV-1980R formulated with Advax(CpG) adjuvant were identified as promising immunogenic vaccines for ongoing pre-clinical assessment and future human clinical trials. PMID:27363809

  1. Alzheimer’s disease AdvaxCpG- adjuvanted MultiTEP-based dual and single vaccines induce high-titer antibodies against various forms of tau and Aβ pathological molecules

    PubMed Central

    Davtyan, Hayk; Zagorski, Karen; Rajapaksha, Harinda; Hovakimyan, Armine; Davtyan, Arpine; Petrushina, Irina; Kazarian, Konstantin; Cribbs, David H.; Petrovsky, Nikolai; Agadjanyan, Michael G.; Ghochikyan, Anahit

    2016-01-01

    Although β-amyloid (Aβ) may be the primary driver of Alzheimer’s disease (AD) pathology, accumulation of pathological tau correlates with dementia in AD patients. Thus, the prevention/inhibition of AD may require vaccine/s targeting Aβ and tau simultaneously or sequentially. Since high antibody titers are required for AD vaccine efficacy, we have decided to generate vaccines, targeting Aβ (AV-1959R), Tau (AV-1980R) or Aβ/tau (AV-1953R) B cell epitopes, based on immunogenic MultiTEP platform and evaluate the immunogenicity of these vaccines formulated with AdvaxCpG, delta inulin, Alhydrogel®, Montanide-ISA51, Montanide-ISA720, MPLA-SM pharmaceutical grade adjuvants. Formulation of AV-1959R in AdvaxCpG induced the highest cellular and humoral immune responses in mice. The dual-epitope vaccine, AV-1953R, or the combination of AV-1959R and AV-1980R vaccines formulated with AdvaxCpG induced robust antibody responses against various forms of both, Aβ and tau pathological molecules. While anti-Aβ antibody titers after AV-1953R immunization were similar to that in mice vaccinated with AV-1959R or AV-1959R/AV-1980R combination, anti-tau titers were significantly lower after AV-1953R injection when compared to the AV-1980R or AV-1959R/AV-1980R. In silico 3D-modeling provided insight into the differences in immunogenicity of these vaccine constructs. In sum, AV-1959R and AV-1980R formulated with AdvaxCpG adjuvant were identified as promising immunogenic vaccines for ongoing pre-clinical assessment and future human clinical trials. PMID:27363809

  2. The results of an experimental indoor hydroponic Cannabis growing study, using the 'Screen of Green' (ScrOG) method-Yield, tetrahydrocannabinol (THC) and DNA analysis.

    PubMed

    Knight, Glenys; Hansen, Sean; Connor, Mark; Poulsen, Helen; McGovern, Catherine; Stacey, Janet

    2010-10-10

    The results of an indoor hydroponic Cannabis growth study are presented. It is intended that this work will be of assistance to those with an interest in determining an estimation of yield and value of Cannabis crops. Three cycles of six plants were grown over a period of 1 year in order to ascertain the potential yield of female flowering head material from such an operation. The cultivation methods used were selected to replicate typical indoor hydroponic Cannabis growing operations, such as are commonly encountered by the New Zealand Police. The plants were also tested to ascertain the percentage of the psychoactive chemical Δ-9 tetrahydrocannabinol (THC) present in the flowering head material, and were genetically profiled by STR analysis. Phenotypic observations are related to the data collected. The inexperience of the growers was evidenced by different problems encountered in each of the three cycles, each of which would be expected to negatively impact the yield and THC data obtained. These data are therefore considered to be conservative. The most successful cycle yielded an average of 881g (31.1oz) of dry, groomed female flowering head per plant, and over the whole study the 18 plants yielded a total of 12,360g (436.0oz), or an average of 687g (24.2oz) of dry head per plant. THC data shows significant intra-plant variation and also demonstrates inter-varietal variation. THC values for individual plants ranged from 4.3 to 25.2%. The findings of this study and a separate ESR research project illustrate that the potency of Cannabis grown in New Zealand has dramatically increased in recent years. DNA analysis distinguished distinct groups in general agreement with the phenotypic variation observed. One plant however, exhibiting a unique triallelic pattern at two of the five loci tested, while remaining phenotypically indistinguishable from three other plants within the same grow.

  3. First zoeal stage of the partner shrimp Periclimenes paivai Chace, with remarks on the genus Periclimenes O.G. Costa (Caridea, Palaemonidae.

    PubMed

    Pantaleão, João A F; Terossi, Mariana; Costa, Rogério C; Mantelatto, Fernando L

    2013-01-01

    The morphology of the first zoeal stage of Periclimenes paivai Chace is described and illustrated for the first time. Larvae were obtained from three females with embryos, caught in the type locality (Cananéia, São Paulo state, Brazil). The morphological characters are detailed and compared with all previous descriptions of larvae in the genus (P. amethysteus, P. brevicarpalis, P. diversipes, P. pandionis, P. sagittifer and P. soror). The zoeae I of Periclimenes species are very similar, but P. paivai can be separated from the other six species by means of five characteristics: 8 plumose setae on the inner margin of the antennal scale, one spine on the endopod of the maxillule, one cuspidate seta on the basal endite of the maxilulle, one plumose seta on the single coxal endite of the maxilla, and one plumose seta on the endopod of the maxilla. Remarks from a comparative analysis of available descriptions of the genus are furnished. 

  4. Samtaler i hvid kittel: En analyse af indlaeggelsessamtaler og deres institutionelle betingelser (Conversations in White Aprons: An Analysis of Hospitalization Conversations and Their Institutional Conditions). ROLIG Papir 47.

    ERIC Educational Resources Information Center

    Becker, Jytte

    This report focuses on the communication that takes place between nurses and patients in a hospital setting. Nurses have for years been accused of talking at patients rather than talking to them. They have also been accused of using a language that patients do not know. The problem is partly a result of individual roles within the medical…

  5. GO2OGS 1.0: a versatile workflow to integrate complex geological information with fault data into numerical simulation models

    NASA Astrophysics Data System (ADS)

    Fischer, T.; Naumov, D.; Sattler, S.; Kolditz, O.; Walther, M.

    2015-11-01

    We offer a versatile workflow to convert geological models built with the ParadigmTM GOCAD© (Geological Object Computer Aided Design) software into the open-source VTU (Visualization Toolkit unstructured grid) format for usage in numerical simulation models. Tackling relevant scientific questions or engineering tasks often involves multidisciplinary approaches. Conversion workflows are needed as a way of communication between the diverse tools of the various disciplines. Our approach offers an open-source, platform-independent, robust, and comprehensible method that is potentially useful for a multitude of environmental studies. With two application examples in the Thuringian Syncline, we show how a heterogeneous geological GOCAD model including multiple layers and faults can be used for numerical groundwater flow modeling, in our case employing the OpenGeoSys open-source numerical toolbox for groundwater flow simulations. The presented workflow offers the chance to incorporate increasingly detailed data, utilizing the growing availability of computational power to simulate numerical models.

  6. 78 FR 36635 - Additional Designations, Foreign Narcotics Kingpin Designation Act

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-18

    ....R.P. RICH720121MJCBRL08 (Mexico) (individual) . 12. SANCHEZ BARBA, Jose de Jesus, Av. Vallarta No.... SANCHEZ GARZA, Jose de Jesus, Av. Vallarta No. 3060, Colonia Vallarta San Jorge, Guadalajara,...

  7. Evaluation of a New Cardiac Pacemaker

    ClinicalTrials.gov

    2013-06-25

    Atrial Fibrillation With 2 or 3° AV or Bifascicular Bundle Branch (BBB) Block; Normal Sinus Rhythm With 2 or 3° AV or BBB Block; Sinus Bradycardia With Infrequent Pauses or Unexplained Syncope With EP Findings

  8. A novel smart supramolecular organic gelator exhibiting dual-channel responsive sensing behaviours towards fluoride ion via gel-gel states.

    PubMed

    Mehdi, Hassan; Pang, Hongchang; Gong, Weitao; Dhinakaran, Manivannan Kalavathi; Wajahat, Ali; Kuang, Xiaojun; Ning, Guiling

    2016-07-01

    A novel smart supramolecular organic gelator G-16 containing anion and metal-coordination ability has been designed and synthesized. It shows excellent and robust gelation capability as a strong blue fluorescent supramolecular organic gel OG in DMF. Addition of Zn(2+) produced Zn(2+)-coordinated supramolecular metallogel OG-Zn. Organic gel OG and organometallic gel OG-Zn exhibited efficient and different sensing behaviors towards fluoride ion due to the variation in self-assembling nature. Supramolecular metallogel OG-Zn displayed specific selectivity for fluoride ion and formed OG-Zn-F with dramatic color change from blue to blue green in solution and gel to gel states. Furthermore after directly addition of fluoride into OG produced fluoride containing organic gel OG-F with drastically modulation in color from blue to greenish yellow fluorescence via strong aggregation-induced emission (AIE) property. A number of experiments were conducted such as FTIR, (1)H NMR, and UV/Vis spectroscopies, XRD, SEM and rheology. These results revealed that the driving forces involved in self-assembly of OG, OG-Zn, OG-Zn-F and OG-F were hydrogen bonding, metal coordination, π-π interactions, and van der Waal forces. In contrast to the most anion responsive gels, particularly fluoride ion responsive gels showed gel-sol state transition on stimulation by anions, the gel state of OG and OG-Zn did not show any gel-to-sol transition during the whole F(-) response process.

  9. A novel smart supramolecular organic gelator exhibiting dual-channel responsive sensing behaviours towards fluoride ion via gel-gel states.

    PubMed

    Mehdi, Hassan; Pang, Hongchang; Gong, Weitao; Dhinakaran, Manivannan Kalavathi; Wajahat, Ali; Kuang, Xiaojun; Ning, Guiling

    2016-07-01

    A novel smart supramolecular organic gelator G-16 containing anion and metal-coordination ability has been designed and synthesized. It shows excellent and robust gelation capability as a strong blue fluorescent supramolecular organic gel OG in DMF. Addition of Zn(2+) produced Zn(2+)-coordinated supramolecular metallogel OG-Zn. Organic gel OG and organometallic gel OG-Zn exhibited efficient and different sensing behaviors towards fluoride ion due to the variation in self-assembling nature. Supramolecular metallogel OG-Zn displayed specific selectivity for fluoride ion and formed OG-Zn-F with dramatic color change from blue to blue green in solution and gel to gel states. Furthermore after directly addition of fluoride into OG produced fluoride containing organic gel OG-F with drastically modulation in color from blue to greenish yellow fluorescence via strong aggregation-induced emission (AIE) property. A number of experiments were conducted such as FTIR, (1)H NMR, and UV/Vis spectroscopies, XRD, SEM and rheology. These results revealed that the driving forces involved in self-assembly of OG, OG-Zn, OG-Zn-F and OG-F were hydrogen bonding, metal coordination, π-π interactions, and van der Waal forces. In contrast to the most anion responsive gels, particularly fluoride ion responsive gels showed gel-sol state transition on stimulation by anions, the gel state of OG and OG-Zn did not show any gel-to-sol transition during the whole F(-) response process. PMID:27193611

  10. cDNA cloning and functional characterization of ETHYLENE INSENSITIVE 3 orthologs from Oncidium Gower Ramsey involved in flower cutting and pollinia cap dislodgement.

    PubMed

    Chen, Shin-Yu; Tsai, Hsing-Chun; Raghu, Rajasekaran; Do, Yi-Yin; Huang, Pung-Ling

    2011-10-01

    The cDNAs encoding ETHYLENE INSENSITIVE3 (EIN3) transcription factor, OgEIL1 and OgEIL2 of Oncidium were cloned, sequenced and characterized. The deduced amino acid sequences of OgEIL1 and OgEIL2 of identified cDNA clones contain all structural features found in the Arabidopsis EIN3, such as an amino terminal acidic domain, a proline-rich region, and five basic conserved domains. Complementation test for OgEIL1 in Arabidopsis ein3 mutant indicate that function of OgEIL1 is the same as Arabidopsis EIN3. RNA gel blot analysis indicated that OgEIL1 and OgEIL2 expressed differentially in the roots, stem, leaves and flower buds of Oncidium. OgEIL1 and OgEIL2 mRNA levels in fully opened flowers increased as time progressed after cutting and reached a maximum in the fifth day and decreased on seventh day, which is consistent with the hypothesis that flowers initiated to wilt when ethylene raised abruptly. In de-capped flowers, OgEIL2 mRNA showed a decrease, while OgEIL1 mRNA exhibited an increase. Exogenous application of ethylene increased the mRNA levels of OgEIL1 and OgEIL2 in flower buds and flowers after cutting compared prior to ethylene treatment, however, in pollinia de-capped flowers, both OgEIL1 and OgEIL2 mRNA levels responded to a decline to exogenous ethylene immediately after treatment. Collectively, it is suggested that the main functions of OgEIL1 and OgEIL2 are to modulate the senescence of Oncidium flowers.

  11. 78 FR 15409 - Patient Protection and Affordable Care Act; HHS Notice of Benefit and Payment Parameters for 2014

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-11

    .../Av-csr-bulletin.pdf . \\3\\ 77 FR 18310 (March 27, 2012). Federally-facilitated Exchange user fees... parameters for these programs. \\1\\ 77 FR 17220 (March 23, 2012). Advance payments of the premium tax credit... February 24, 2012 (AV/CSR Bulletin). The AV/CSR Bulletin outlined an intended regulatory approach...

  12. Algorithm Visualization in Teaching Practice

    ERIC Educational Resources Information Center

    Törley, Gábor

    2014-01-01

    This paper presents the history of algorithm visualization (AV), highlighting teaching-methodology aspects. A combined, two-group pedagogical experiment will be presented as well, which measured the efficiency and the impact on the abstract thinking of AV. According to the results, students, who learned with AV, performed better in the experiment.

  13. Students' Mathematical Work on Absolute Value: Focusing on Conceptions, Errors and Obstacles

    ERIC Educational Resources Information Center

    Elia, Iliada; Özel, Serkan; Gagatsis, Athanasios; Panaoura, Areti; Özel, Zeynep Ebrar Yetkiner

    2016-01-01

    This study investigates students' conceptions of absolute value (AV), their performance in various items on AV, their errors in these items and the relationships between students' conceptions and their performance and errors. The Mathematical Working Space (MWS) is used as a framework for studying students' mathematical work on AV and the…

  14. Wdr68 requires nuclear access for craniofacial development.

    PubMed

    Wang, Bingyan; Doan, Diana; Roman Petersen, Yanett; Alvarado, Estibaliz; Alvarado, Gregory; Bhandari, Ajay; Mohanty, Aditya; Mohanty, Sudipta; Nissen, Robert M

    2013-01-01

    Wdr68 is a highly conserved scaffolding protein required for craniofacial development and left-right asymmetry. A Ras-Map3k-Wdr68-Dyrk1 signaling relay may mediate these and other diverse signaling events important in development and disease. While the sub-cellular localization of Wdr68 has been shown to be dependent on that of its interaction partners, it is not clear where Wdr68 activity is required during development. Here we show that while a GFP-Wdr68 fusion functionally substituted for craniofacial development in the zebrafish, that a Nuclear Export Signal (NES) fusion protein (GFPNESWdr68) failed to support craniofacial development. As control for NES activity, we show that while GFP-Wdr68 exhibited a pan-cellular distribution in C2C12 cells, the GFPNESWdr68 fusion predominantly localized to the cell cytoplasm, as expected. Interestingly, while GFP-Wdr68 and RFP-Dyrk1a co-localized to the cell nucleus as expected based on the known sub-cellular localization for Dyrk1a, we found that the GFPNESWdr68 fusion redistributed RFP-Dyrk1a to the cell cytoplasm potentially disconnecting the Ras/Dyrk1 signal relay from further downstream targets. Consistent with a nuclear role in gene regulation, we also found that while a transcriptional activation domain fusion, CebpFlagWdr68, functionally substituted for endogenous Wdr68 for craniofacial development, that a transcriptional repression domain fusion, MadFlagWdr68, failed to support craniofacial development. Dyrk1b is required for myogenin (myog) expression in differentiating mouse C2C12 cells and here we report that wdr68 is also important for myog expression in differentiating C2C12 cells. Using a C2C12 cell myog promoter-reporter system, we found that Wdr68 overexpression increased reporter activity while moderate expression levels of MadFlagWdr68 interfered with reporter activity. Taken together, these findings support a nuclear role for Wdr68-containing complexes. PMID:23349862

  15. Synthesis, biological evaluation and molecular modeling studies of imidazo[1,2-a]pyridines derivatives as protein kinase inhibitors.

    PubMed

    Lawson, Marie; Rodrigo, Jordi; Baratte, Blandine; Robert, Thomas; Delehouzé, Claire; Lozach, Olivier; Ruchaud, Sandrine; Bach, Stéphane; Brion, Jean-Daniel; Alami, Mouad; Hamze, Abdallah

    2016-11-10

    We report here the synthesis, the biological evaluation and the molecular modeling studies of new imidazo[1,2-a]pyridines derivatives designed as potent kinase inhibitors. This collection was obtained from 2-aminopyridines and 2-bromoacetophenone which afforded final compound in only one step. The bioactivity of this family of new compounds was tested using protein kinase and ATP competition assays. The structure-activity relationship (SAR) revealed that six compounds inhibit DYRK1A and CLK1 at a micromolar range. Docking studies provided possible explanations that correlate with the SAR data. The most active compound 4c inhibits CLK1 (IC50 of 0.7 μM) and DYRK1A (IC50 of 2.6 μM).

  16. Transient myeloproliferative disorder with partial trisomy 21.

    PubMed

    Takahashi, Takahide; Inoue, Akira; Yoshimoto, Junko; Kanamitsu, Kiichiro; Taki, Tomohiko; Imada, Masahide; Yamada, Mutsuko; Ninomiya, Shinsuke; Toki, Tsutomu; Terui, Kiminori; Ito, Etsuro; Shimada, Akira

    2015-11-01

    Myeloid malignancy with Down syndrome (ML-DS) is estimated to have a step-wise leukemogenesis including GATA1 mutation. Trisomy 21 is essential for ML-DS; however, we do not know exactly which gene or genes located on chromosome 21 are necessary for the ML-DS. We report a female infant with transient myeloproliferative disorder (TMD) and partial trisomy 21. SNP array analysis showed 10 Mb amplification of 21q22.12-21q22.3, which included DYRK1A, ERG, and ETS but not the RUNX1 gene. With two other reported TMD cases having partial trisomy 21, DYRK1A, ERG, and ETS were the most likely genes involved in collaboration with the GATA1 mutation. PMID:26138905

  17. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.

    PubMed

    O'Roak, Brian J; Vives, Laura; Fu, Wenqing; Egertson, Jarrett D; Stanaway, Ian B; Phelps, Ian G; Carvill, Gemma; Kumar, Akash; Lee, Choli; Ankenman, Katy; Munson, Jeff; Hiatt, Joseph B; Turner, Emily H; Levy, Roie; O'Day, Diana R; Krumm, Niklas; Coe, Bradley P; Martin, Beth K; Borenstein, Elhanan; Nickerson, Deborah A; Mefford, Heather C; Doherty, Dan; Akey, Joshua M; Bernier, Raphael; Eichler, Evan E; Shendure, Jay

    2012-12-21

    Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. We therefore developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing in very large cohorts. To demonstrate the power of this approach, we captured and sequenced 44 candidate genes in 2446 ASD probands. We discovered 27 de novo events in 16 genes, 59% of which are predicted to truncate proteins or disrupt splicing. We estimate that recurrent disruptive mutations in six genes-CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1-may contribute to 1% of sporadic ASDs. Our data support associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a β-catenin-chromatin-remodeling network to ASD etiology. PMID:23160955

  18. Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders.

    PubMed

    Okamoto, N; Miya, F; Tsunoda, T; Kato, M; Saitoh, S; Yamasaki, M; Shimizu, A; Torii, C; Kanemura, Y; Kosaki, K

    2015-09-01

    We developed a next-generation sequencing (NGS) based mutation screening strategy for neurodevelopmental diseases. Using this system, we screened 284 genes in 40 patients. Several novel mutations were discovered. Patient 1 had a novel mutation in ACTB. Her dysmorphic feature was mild for Baraitser-Winter syndrome. Patient 2 had a truncating mutation of DYRK1A. She lacked microcephaly, which was previously assumed to be a constant feature of DYRK1A loss of function. Patient 3 had a novel mutation in GABRD gene. She showed Rett syndrome like features. Patient 4 was diagnosed with Noonan syndrome with PTPN11 mutation. He showed complete agenesis of corpus callosum. We have discussed these novel findings. PMID:25156961

  19. Identification and evolution of the orphan genes in the domestic silkworm, Bombyx mori.

    PubMed

    Sun, Wei; Zhao, Xin-Wei; Zhang, Ze

    2015-09-14

    Orphan genes (OGs) which have no recognizable homology to any sequences in other species could contribute to the species specific adaptations. In this study, we identified 738 OGs in the silkworm genome. About 31% of the silkworm OGs is derived from transposable elements, and 5.1% of the silkworm OGs emerged from gene duplication followed by divergence of paralogs. Five de novo silkworm OGs originated from non-coding regions. Microarray data suggested that most of the silkworm OGs were expressed in limited tissues. RNA interference experiments suggested that five de novo OGs are not essential to the silkworm, implying that they may contribute to genetic redundancy or species-specific adaptation. Our results provide some new insights into the evolutionary significance of the silkworm OGs.

  20. Impulse formation and conduction of excitation in the atrioventricular node.

    PubMed

    Watanabe, Y; Watanabe, M

    1994-06-01

    Meijler et al. have recently challenged the classical concept of AV nodal conduction (the conduction hypothesis) and suggest that the AV node might be controlling ventricular rhythmicity through its automaticity electrotonically modulated by atrial excitation (the modulated pacemaker hypothesis). This article critically evaluates the three major arguments of Meijler: (1) the absence of convincing evidence for conduction of excitation in the AV node; (2) the prevalence of disproportionately short AV intervals in larger animals; and (3) elimination of RR intervals shorter than the cycle length of ventricular pacing during atrial fibrillation, to judge which of these two hypotheses would more satisfactorily explain various experimental and clinical findings accumulated in the past. Previous observations including microelectrode mapping of the rabbit AV junction during regular sinus rhythm as well as second-degree AV block, clinical and experimental studies on concealed conduction, and studies on the ventricular response to atrial fibrillation appear to be compatible with the conduction hypothesis, whereas clearcut evidence for automatic impulse formation in the AV node has not been presented, except in a small number of hearts showing spontaneous AV junctional rhythms. In view of these observations and theoretical considerations based on comparative anatomy of the AV node-His-Purkinje system and on the latest experimental study on the equine AV node, the authors conclude that the conduction hypothesis appears to better explain all the available data, except perhaps in a few cases with second-degree intra-AV nodal block.

  1. Using EEG and stimulus context to probe the modelling of auditory-visual speech.

    PubMed

    Paris, Tim; Kim, Jeesun; Davis, Chris

    2016-02-01

    We investigated whether internal models of the relationship between lip movements and corresponding speech sounds [Auditory-Visual (AV) speech] could be updated via experience. AV associations were indexed by early and late event related potentials (ERPs) and by oscillatory power and phase locking. Different AV experience was produced via a context manipulation. Participants were presented with valid (the conventional pairing) and invalid AV speech items in either a 'reliable' context (80% AVvalid items) or an 'unreliable' context (80% AVinvalid items). The results showed that for the reliable context, there was N1 facilitation for AV compared to auditory only speech. This N1 facilitation was not affected by AV validity. Later ERPs showed a difference in amplitude between valid and invalid AV speech and there was significant enhancement of power for valid versus invalid AV speech. These response patterns did not change over the context manipulation, suggesting that the internal models of AV speech were not updated by experience. The results also showed that the facilitation of N1 responses did not vary as a function of the salience of visual speech (as previously reported); in post-hoc analyses, it appeared instead that N1 facilitation varied according to the relative time of the acoustic onset, suggesting for AV events N1 may be more sensitive to the relationship of AV timing than form.

  2. The social dilemma of autonomous vehicles.

    PubMed

    Bonnefon, Jean-François; Shariff, Azim; Rahwan, Iyad

    2016-06-24

    Autonomous vehicles (AVs) should reduce traffic accidents, but they will sometimes have to choose between two evils, such as running over pedestrians or sacrificing themselves and their passenger to save the pedestrians. Defining the algorithms that will help AVs make these moral decisions is a formidable challenge. We found that participants in six Amazon Mechanical Turk studies approved of utilitarian AVs (that is, AVs that sacrifice their passengers for the greater good) and would like others to buy them, but they would themselves prefer to ride in AVs that protect their passengers at all costs. The study participants disapprove of enforcing utilitarian regulations for AVs and would be less willing to buy such an AV. Accordingly, regulating for utilitarian algorithms may paradoxically increase casualties by postponing the adoption of a safer technology.

  3. The social dilemma of autonomous vehicles.

    PubMed

    Bonnefon, Jean-François; Shariff, Azim; Rahwan, Iyad

    2016-06-24

    Autonomous vehicles (AVs) should reduce traffic accidents, but they will sometimes have to choose between two evils, such as running over pedestrians or sacrificing themselves and their passenger to save the pedestrians. Defining the algorithms that will help AVs make these moral decisions is a formidable challenge. We found that participants in six Amazon Mechanical Turk studies approved of utilitarian AVs (that is, AVs that sacrifice their passengers for the greater good) and would like others to buy them, but they would themselves prefer to ride in AVs that protect their passengers at all costs. The study participants disapprove of enforcing utilitarian regulations for AVs and would be less willing to buy such an AV. Accordingly, regulating for utilitarian algorithms may paradoxically increase casualties by postponing the adoption of a safer technology. PMID:27339987

  4. Seasonal bioavailability of sediment-associated heavy metals along the Mississippi river floodplain.

    PubMed

    Grabowski, L A; Houpis, J L; Woods, W I; Johnson, K A

    2001-11-01

    A value of simultaneously extracted metal to acid-volatile sulfide (SEM-AVS) can provide important information regarding metal availability in anaerobic sediment. SEM and AVS concentrations were obtained by the cold-acid purge-and-trap technique during spring and summer at six locations along the Mississippi River floodplain. SEM-AVS values and AVS concentrations did not vary significantly between locations during both seasons. AVS concentrations were significantly greater during summer than spring, resulting in significantly lower SEM-AVS values in summer. Total SEM concentrations did not significantly vary between seasons or specific locations. SEM-AVS values were greater than one at each location during both seasons. Sediment metal toxicity was predicted to be absent for benthic organisms along the river floodplain. PMID:11680760

  5. Radiotherapy as a cause of complete atrioventricular block in Hodgkin's disease: an electrophysiological-pathological correlation

    SciTech Connect

    Cohen, S.I.; Bharati, S.; Glass, J.; Lev, M.

    1981-04-01

    A 20-year-old man contracted Hodgkin's disease and was treated with mantle radiotherapy. Heart block developed 11 years later. Electrocardiograms revealed predominant atrioventricular (AV) block and occasional AV conduction. Intracardiac electrograms demonstrated that the site of AV block was above the level of the His bundle. A permanent transvenous pacemaker was implanted. Seven months later the patient died of complications from cryptococcal meningitis. Pathological study of the heart revealed marked arteriosclerosis with fibrosis of the epicardium, myocardium, and endocardium. Examination of the conduction system revealed extensive arteriolosclerosis of the sinoatrial node and its approaches. In addition, there was marked fibrosis of the approaches to the AV node, the AV bundle, and both bundle branches. There was no evidence of Hodgkin's disease. This case documents the rare occurrence of AV block due to tissue destruction by radiotherapy. There was a good correlation between block proximal to the His bundle recording site and fibrosis of the approaches to the AV node.

  6. Radiotherapy as a cause of complete atrioventricular block in Hodgkin's disease. An electrophysiological-pathological correlation

    SciTech Connect

    Cohen, S.I.; Bharati, S.; Glass, J.; Lev, M.

    1981-04-01

    A 20-year-old man contracted Hodgkin's disease and was treated with mantle radiotherapy. Heart block developed 11 years later. Electrocardiograms revealed predominant atrioventricular (AV) block and occasional AV conduction. Intracardiac electrograms demonstrated that the site of AV block was above the level of the His bundle. A permanent transvenous pacemaker was implanted. Seven months later the patient died of complications from cryptococcal meningitis. Pathological study of the heart revealed marked arteriosclerosis with fibrosis of the epicardium, myocardium, and endocardium. Examination of the conduction system revealed extensive arteriolosclerosis of the sinoatrial node and its approaches. In addition, there was marked fibrosis of the approaches to the AV node, the AV bundle, and both bundle branches. There was no evidence of Hodgkin's disease. This case documents the rare occurrence of AV block due to tissue destruction by radiotherapy. There was a good correlation between block proximal to the His bundle recording site and fibrosis of the approaches to the AV node.

  7. Synthesis and preliminary in vitro kinase inhibition evaluation of new diversely substituted pyrido[3,4-g]quinazoline derivatives.

    PubMed

    Zeinyeh, Wael; Esvan, Yannick J; Nauton, Lionel; Loaëc, Nadège; Meijer, Laurent; Théry, Vincent; Anizon, Fabrice; Giraud, Francis; Moreau, Pascale

    2016-09-01

    The synthesis of new diversely substituted pyrido[3,4-g]quinazolines is described. The inhibitory potencies of prepared compounds toward a panel of five CMGC protein kinases (CDK5, CLK1, DYRK1A, CK1, GSK3), that are known to play a potential role in Alzheimer's disease, were evaluated. The best overall kinase inhibition profile was found for nitro compound 4 bearing an ethyl group at the 5-position. PMID:27469128

  8. Synthesis and preliminary in vitro kinase inhibition evaluation of new diversely substituted pyrido[3,4-g]quinazoline derivatives.

    PubMed

    Zeinyeh, Wael; Esvan, Yannick J; Nauton, Lionel; Loaëc, Nadège; Meijer, Laurent; Théry, Vincent; Anizon, Fabrice; Giraud, Francis; Moreau, Pascale

    2016-09-01

    The synthesis of new diversely substituted pyrido[3,4-g]quinazolines is described. The inhibitory potencies of prepared compounds toward a panel of five CMGC protein kinases (CDK5, CLK1, DYRK1A, CK1, GSK3), that are known to play a potential role in Alzheimer's disease, were evaluated. The best overall kinase inhibition profile was found for nitro compound 4 bearing an ethyl group at the 5-position.

  9. Effects of liquid cooling garments on recovery and performance time in individuals performing strenuous work wearing a firefighter ensemble.

    PubMed

    Kim, Jung-Hyun; Coca, Aitor; Williams, W Jon; Roberge, Raymond J

    2011-07-01

    This study investigated the effects of body cooling using liquid cooling garments (LCG) on performance time (PT) and recovery in individuals wearing a fully equipped prototype firefighter ensemble (PFE) incorporating a self-contained breathing apparatus (SCBA). Six healthy male participants (three firefighters and three non-firefighters) completed six experimental sessions in an environmental chamber (35°C, 50% relative humidity), consisting of three stages of 15 min exercise at 75% VO2max, and 10 min rest following each exercise stage. During each session, one of the following six conditions was administered in a randomized order: control (no cooling, CON); air ventilation of exhaust SCBA gases rerouted into the PFE (AV); top cooling garment (TCG); TCG combined with AV (TCG+AV); a shortened whole body cooling garment (SCG), and SCG combined with AV (SCG+AV). Results showed that total PT completed was longer under SCG and SCG+AV compared with CON, AV, TCG, and TCG+AV (p<0.01). Magnitude of core temperature (Tc) elevation was significantly decreased when SCG was utilized (p<0.01), and heart rate recovery rate (10 min) was enhanced under SCG, SCG+AV, TCG, and TCG+AV compared with CON (p<0.05). Estimated Esw rate (kg·h(-1)) was the greatest in CON, 1.62 (0.37), and the least in SCG+AV 0.98 (0.44): (descending order: CON>AV>TCG=TCG+AV>SCG>SCG+AV) without a statistical difference between the conditions (p<0.05). Results of the present study suggest that the application of LCG underneath the PFE significantly improves the recovery during a short period of rest and prolongs performance time in subsequent bouts of exercise. LCG also appears to be an effective method for body cooling that promotes heat dissipation during uncompensable heat stress.

  10. Hologram QSAR models of a series of 6-arylquinazolin-4-amine inhibitors of a new Alzheimer's disease target: dual specificity tyrosine-phosphorylation-regulated kinase-1A enzyme.

    PubMed

    Leal, Felipe Dias; da Silva Lima, Camilo Henrique; de Alencastro, Ricardo Bicca; Castro, Helena Carla; Rodrigues, Carlos Rangel; Albuquerque, Magaly Girão

    2015-01-01

    Dual specificity tyrosine-phosphorylation-regulated kinase-1A (DYRK1A) is an enzyme directly involved in Alzheimer's disease, since its increased expression leads to β-amyloidosis, Tau protein aggregation, and subsequent formation of neurofibrillary tangles. Hologram quantitative structure-activity relationship (HQSAR, 2D fragment-based) models were developed for a series of 6-arylquinazolin-4-amine inhibitors (36 training, 10 test) of DYRK1A. The best HQSAR model (q2 = 0.757; SEcv = 0.493; R2 = 0.937; SE = 0.251; R2pred = 0.659) presents high goodness-of-fit (R2 > 0.9), as well as high internal (q2 > 0.7) and external (R2pred > 0.5) predictive power. The fragments that increase and decrease the biological activity values were addressed using the colored atomic contribution maps provided by the method. The HQSAR contribution map of the best model is an important tool to understand the activity profiles of new derivatives and may provide information for further design of novel DYRK1A inhibitors.

  11. Hologram QSAR Models of a Series of 6-Arylquinazolin-4-Amine Inhibitors of a New Alzheimer’s Disease Target: Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase-1A Enzyme

    PubMed Central

    Leal, Felipe Dias; da Silva Lima, Camilo Henrique; de Alencastro, Ricardo Bicca; Castro, Helena Carla; Rodrigues, Carlos Rangel; Albuquerque, Magaly Girão

    2015-01-01

    Dual specificity tyrosine-phosphorylation-regulated kinase-1A (DYRK1A) is an enzyme directly involved in Alzheimer’s disease, since its increased expression leads to β-amyloidosis, Tau protein aggregation, and subsequent formation of neurofibrillary tangles. Hologram quantitative structure-activity relationship (HQSAR, 2D fragment-based) models were developed for a series of 6-arylquinazolin-4-amine inhibitors (36 training, 10 test) of DYRK1A. The best HQSAR model (q2 = 0.757; SEcv = 0.493; R2 = 0.937; SE = 0.251; R2pred = 0.659) presents high goodness-of-fit (R2 > 0.9), as well as high internal (q2 > 0.7) and external (R2pred > 0.5) predictive power. The fragments that increase and decrease the biological activity values were addressed using the colored atomic contribution maps provided by the method. The HQSAR contribution map of the best model is an important tool to understand the activity profiles of new derivatives and may provide information for further design of novel DYRK1A inhibitors. PMID:25756379

  12. Low dose EGCG treatment beginning in adolescence does not improve cognitive impairment in a Down syndrome mouse model.

    PubMed

    Stringer, Megan; Abeysekera, Irushi; Dria, Karl J; Roper, Randall J; Goodlett, Charles R

    2015-11-01

    Down syndrome (DS) or Trisomy 21 causes intellectual disabilities in humans and the Ts65Dn DS mouse model is deficient in learning and memory tasks. DYRK1A is triplicated in DS and Ts65Dn mice. Ts65Dn mice were given up to ~20mg/kg/day epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, or water beginning on postnatal day 24 and continuing for three or seven weeks, and were tested on a series of behavioral and learning tasks, including a novel balance beam test. Ts65Dn as compared to control mice exhibited higher locomotor activity, impaired novel object recognition, impaired balance beam and decreased spatial learning and memory. Neither EGCG treatment improved performance of the Ts65Dn mice on these tasks. Ts65Dn mice had a non-significant increase in Dyrk1a activity in the hippocampus and cerebellum. Given the translational value of the Ts65Dn mouse model, further studies will be needed to identify the EGCG doses (and mechanisms) that may improve cognitive function.

  13. Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua.

    PubMed

    Yang, Liu; Paul, Sayantanee; Trieu, Kenneth G; Dent, Lucas G; Froldi, Francesca; Forés, Marta; Webster, Kaitlyn; Siegfried, Kellee R; Kondo, Shu; Harvey, Kieran; Cheng, Louise; Jiménez, Gerardo; Shvartsman, Stanislav Y; Veraksa, Alexey

    2016-09-20

    The transcriptional repressor Capicua (Cic) controls tissue patterning and restricts organ growth, and has been recently implicated in several cancers. Cic has emerged as a primary sensor of signaling downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway, but how Cic activity is regulated in different cellular contexts remains poorly understood. We found that the kinase Minibrain (Mnb, ortholog of mammalian DYRK1A), acting through the adaptor protein Wings apart (Wap), physically interacts with and phosphorylates the Cic protein. Mnb and Wap inhibit Cic function by limiting its transcriptional repressor activity. Down-regulation of Cic by Mnb/Wap is necessary for promoting the growth of multiple organs, including the wings, eyes, and the brain, and for proper tissue patterning in the wing. We have thus uncovered a previously unknown mechanism of down-regulation of Cic activity by Mnb and Wap, which operates independently from the ERK-mediated control of Cic. Therefore, Cic functions as an integrator of upstream signals that are essential for tissue patterning and organ growth. Finally, because DYRK1A and CIC exhibit, respectively, prooncogenic vs. tumor suppressor activities in human oligodendroglioma, our results raise the possibility that DYRK1A may also down-regulate CIC in human cells. PMID:27601662

  14. Low dose EGCG treatment beginning in adolescence does not improve cognitive impairment in a Down syndrome mouse model.

    PubMed

    Stringer, Megan; Abeysekera, Irushi; Dria, Karl J; Roper, Randall J; Goodlett, Charles R

    2015-11-01

    Down syndrome (DS) or Trisomy 21 causes intellectual disabilities in humans and the Ts65Dn DS mouse model is deficient in learning and memory tasks. DYRK1A is triplicated in DS and Ts65Dn mice. Ts65Dn mice were given up to ~20mg/kg/day epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, or water beginning on postnatal day 24 and continuing for three or seven weeks, and were tested on a series of behavioral and learning tasks, including a novel balance beam test. Ts65Dn as compared to control mice exhibited higher locomotor activity, impaired novel object recognition, impaired balance beam and decreased spatial learning and memory. Neither EGCG treatment improved performance of the Ts65Dn mice on these tasks. Ts65Dn mice had a non-significant increase in Dyrk1a activity in the hippocampus and cerebellum. Given the translational value of the Ts65Dn mouse model, further studies will be needed to identify the EGCG doses (and mechanisms) that may improve cognitive function. PMID:26363314

  15. Hologram QSAR models of a series of 6-arylquinazolin-4-amine inhibitors of a new Alzheimer's disease target: dual specificity tyrosine-phosphorylation-regulated kinase-1A enzyme.

    PubMed

    Leal, Felipe Dias; da Silva Lima, Camilo Henrique; de Alencastro, Ricardo Bicca; Castro, Helena Carla; Rodrigues, Carlos Rangel; Albuquerque, Magaly Girão

    2015-01-01

    Dual specificity tyrosine-phosphorylation-regulated kinase-1A (DYRK1A) is an enzyme directly involved in Alzheimer's disease, since its increased expression leads to β-amyloidosis, Tau protein aggregation, and subsequent formation of neurofibrillary tangles. Hologram quantitative structure-activity relationship (HQSAR, 2D fragment-based) models were developed for a series of 6-arylquinazolin-4-amine inhibitors (36 training, 10 test) of DYRK1A. The best HQSAR model (q2 = 0.757; SEcv = 0.493; R2 = 0.937; SE = 0.251; R2pred = 0.659) presents high goodness-of-fit (R2 > 0.9), as well as high internal (q2 > 0.7) and external (R2pred > 0.5) predictive power. The fragments that increase and decrease the biological activity values were addressed using the colored atomic contribution maps provided by the method. The HQSAR contribution map of the best model is an important tool to understand the activity profiles of new derivatives and may provide information for further design of novel DYRK1A inhibitors. PMID:25756379

  16. Operational Group Sandy technical progress report

    USGS Publications Warehouse

    ,

    2013-01-01

    This report documents results from the March 2013 deployment of the OGS. It includes background information on Hurricane Sandy and the federal response; the OGS methodology; scenarios for Hurricane Sandy’s impact on coastal communities and urban ecosystems; potential interventions to improve regional resilience to future major storms; a discussion of scenario results; and lessons learned about the OGS process.

  17. Work Programme, 2001.

    ERIC Educational Resources Information Center

    European Centre for the Development of Vocational Training, Thessaloniki (Greece).

    This publication presents the work program for 2001 for the European Center for the Development of Vocational Training (CEDEFOP) set in the framework of four operational guidelines (OGs). The section on each OG contains an introduction including CEDEFOP's aims, followed by descriptions of research projects relevant to the OG. Each of the 11…

  18. Two Grammatical Models of Modern English. The Old and the New from A to Z. Germanic Linguistic Series.

    ERIC Educational Resources Information Center

    Stuurman, Frits

    Case studies provide detailed comparisons, arranged alphabetically by title for ease of reference, of 26 problems in Modern English grammar, from both the old grammar (OG) and new grammar (NG) viewpoints. This A-Z approach juxtaposes contributions made by OG and NG to the description of Modern English grammar. Part I surveys large OG and NG…

  19. Design and demonstrate a low heat-high volume pump compatible with the AV-YO, Inc. , proprietary variable stroke control windmill system: Final report, June 4, 1986 through June 3, 1987

    SciTech Connect

    Avery, D.E.; Young, B.F.

    1987-10-08

    This report summarizes the accomplishments of a project to build, install, and demonstrate a variable stroke pump control and windmill system. The time period covered by this report includes the four quarters between June 4, 1986 to June 3, 1987 as well as the time period from June 3, 1987 to the present.

  20. Larande I Produktionssytem. En studie av operatorsarbete i hogautomatiserad process--och verkstadsindustri = Learning in Production Systems. A Study of Operator Work in Highly Automated Process and Manufacturing Industry. Linkoping Studies in Education and Psychology, No. 63.

    ERIC Educational Resources Information Center

    Davidson, Bo; Svedin, Per-Olof

    This study of the conditions of developmental on-the-job training and learning for operators in highly automated industries is written in Swedish but contains an English abstract and 18-page summary. The summary begins with the study objectives, which were to determine the following: (1) conditions of developmental on-the-job learning in highly…