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    Patel MS, Lee J, Baz M, Wells CE, Bloch S, Lewis A, Donaldson AV, Garfield BE, Hopkinson NS, Natanek A, Man WD-C, Wells DJ, Baker EH, Polkey MI, Kemp PRet al., 2016,

    Growth differentiation factor-15 is associated with muscle mass in chronic obstructive pulmonary disease and promotes muscle wasting in vivo

    , JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, Vol: 7, Pages: 436-448, ISSN: 2190-5991
    Branch T, Girvan P, Barahona M, Ying Let al., 2015,

    Introduction of a Fluorescent Probe to Amyloid-beta to Reveal Kinetic Insights into Its Interactions with Copper(II)

    , ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 54, Pages: 1227-1230, ISSN: 1433-7851
    Burgoyne T, Morris EP, Luther PK, 2015,

    Three-Dimensional Structure of Vertebrate Muscle Z-Band: The Small-Square Lattice Z-Band in Rat Cardiac Muscle

    , JOURNAL OF MOLECULAR BIOLOGY, Vol: 427, Pages: 3527-3537, ISSN: 0022-2836
    Konitsiotis AD, Jovanovic B, Ciepla P, Spitaler M, Lanyon-Hogg T, Tate EW, Magee AIet al., 2015,

    Topological Analysis of Hedgehog Acyltransferase, a Multipalmitoylated Transmembrane Protein

    , JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 290, Pages: 3293-3307, ISSN: 0021-9258
    Apostoli GL, Solomon A, Smallwood MJ, Winyard PG, Emerson Met al., 2014,

    Role of inorganic nitrate and nitrite in driving nitric oxide-GMP-mediated inhibition of platelet aggregation in vitro and in vivo

    , Journal of Thrombosis and Haemostasis, Vol: 12, Pages: 1880-1889, ISSN: 1538-7933

    BackgroundNitric oxide (NO) is a critical negative regulator of platelets that is implicated in the pathology of thrombotic diseases. Platelets generate NO, but the presence and functional significance of NO synthase (NOS) in platelets is unclear. Inorganic nitrate/nitrite is increasingly being recognized as a source of bioactive NO, although its role in modulating platelets during health and vascular dysfunction is incompletely understood.MethodsWe investigated the functional significance and upstream sources of NO–cGMP signaling events in platelets by using established methods for assessing in vitro and in vivo platelet aggregation, and assessed the bioconversion of inorganic nitrate to nitrite during deficiency of endothelial NOS (eNOS).ResultsThe phosphodiesterase 5 (PDE5) inhibitor sildenafil inhibited human platelet aggregation in vitro. This inhibitory effect was abolished by a guanylyl cyclase inhibitor and NO scavengers, but unaffected by NOS inhibition. Inorganic nitrite drove cGMP-mediated inhibition of human platelet aggregation in vitro and nitrate inhibited platelet function in eNOS−/− mice in vivo in a model of thromboembolic radiolabeled platelet aggregation associated with an enhanced plasma nitrite concentration as compared with wild-type mice.ConclusionsPlatelets generate transient, endogenous cGMP signals downstream of NO that are primarily independent of NOS and may be enhanced by inhibition of PDE5. Furthermore, nitrite can generate transient NO–cGMP signals in platelets. The absence of eNOS leads to enhanced plasma nitrite levels following nitrate administration in vivo, which negatively impacts on platelet function. Our data suggest that inorganic nitrate exerts an antiplatelet effect during eNOS deficiency, and, potentially, that dietary nitrate may reduce platelet hyperactivity during endothelial dysfunction.

    Patel MS, Natanek SA, Stratakos G, Pascual S, Martinez-Llorens J, Disano L, Terzis G, Hopkinson NS, Gea J, Vogiatzis I, Maltais F, Polkey MIet al., 2014,

    Vastus Lateralis Fiber Shift Is an Independent Predictor of Mortality in Chronic Obstructive Pulmonary Disease

    Xu H, Abe T, Liu JKH, Zalivina I, Hohenester E, Leitinger Bet al., 2014,

    Normal Activation of Discoidin Domain Receptor 1 Mutants with Disulfide Cross-links, Insertions, or Deletions in the Extracellular Juxtamembrane Region

    , JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 289, Pages: 13565-13574, ISSN: 0021-9258
    Carroll B, Mohd-Naim N, Maximiano F, Frasa MA, McCormack J, Finelli M, Thoresen SB, Perdios L, Daigaku R, Francis RE, Futter C, Dikic I, Braga VMMet al., 2013,

    The TBC/RabGAP Armus Coordinates Rac1 and Rab7 Functions during Autophagy

    , DEVELOPMENTAL CELL, Vol: 25, Pages: 15-28, ISSN: 1534-5807
    Dodson CA, Bayliss R, 2012,

    Activation of Aurora-A kinase by protein partner binding and phosphorylation are independent and synergistic.

    , J Biol Chem, Vol: 287, Pages: 1150-1157

    Protein kinases are activated by phosphorylation and by the binding of activator proteins. The interplay of these two factors is incompletely understood. We applied energetic analysis to this question and characterized the activation process of the serine/threonine kinase Aurora-A by phosphorylation and by its protein partner, targeting protein for Xenopus kinesin-like protein 2 (TPX2). We discovered that these two activators act synergistically and without a predefined order: each can individually increase the activity of Aurora-A, and the effect of both bound together is the exact sum of their individual contributions to catalysis. Unexpectedly, the unphosphorylated enzyme has catalytic activity that is increased 15-fold by the binding of TPX2 alone. The energetic contribution of phosphorylation to catalysis is 2-fold greater than that of TPX2 binding, which is independent of the phosphorylation state of the enzyme. Based on this analysis, we propose a revised, fluid model of Aurora-A activation in which the first step is a reduction in the mobility of the activation loop by either TPX2 binding or phosphorylation. Furthermore, our results suggest that unphosphorylated Aurora-A bound to the mitotic spindle by TPX2 is catalytically active and that the phosphorylation state of Aurora-A is an inaccurate surrogate for its activity. Extending this form of analysis will allow us to compare quantitatively the effects of the whole network of kinase-activating partners. Comparison with other kinases showed that kinetic characterization detects those kinases whose activation loops undergo a rearrangement upon phosphorylation and thus whose unphosphorylated state offers a distinct target for the development of Type II inhibitors.

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