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  • Journal article
    Smyth E, Solomon A, Birrell MA, Smallwood MJ, Winyard PG, Tetley TD, Emerson Met al., 2017,

    Influence of inflammation and nitric oxide upon platelet aggregation following deposition of diesel exhaust particles in the airways.

    , British Journal of Pharmacology, Vol: 174, Pages: 2130-2139, ISSN: 0007-1188

    Background and Purpose: Exposure to nanoparticulate pollution has been implicated in platelet-driven thrombotic events such as myocardial infarction. Inflammation and impairment of NO bioavailability have been proposed as potential causative mechanisms. It is unclear, however, whether airways exposure to combustion-derived nanoparticles such as diesel exhaust particles (DEP) or carbon black (CB) can augment platelet aggregation in vivo and the underlying mechanisms remain undefined. We aimed to investigate the effects of acute lung exposure to DEP and CB on platelet activation and the associated role of inflammation and endothelial-derived NO.Experimental Approach: DEP and CB were intratracheally instilled into wild-type (WT) and eNOS−/− mice and platelet aggregation was assessed in vivo using an established model of radio-labelled platelet thromboembolism. The underlying mechanisms were investigated by measuring inflammatory markers, NO metabolites and light transmission aggregometry.Key Results: Platelet aggregation in vivo was significantly enhanced in WT and eNOS−/− mice following acute airways exposure to DEP but not CB. CB exposure, but not DEP, was associated with significant increases in pulmonary neutrophils and IL-6 levels in the bronchoalveolar lavage fluid and plasma of WT mice. Neither DEP nor CB affected plasma nitrate/nitrite concentration and DEP-induced human platelet aggregation was inhibited by an NO donor.Conclusions and Implications: Pulmonary exposure to DEP and subsequent platelet activation may contribute to the reports of increased cardiovascular risk, associated with exposure to airborne pollution, independent of its effects on inflammation or NO bioavailability.

  • Journal article
    Patel MS, Lee J, Baz M, Wells CE, Bloch S, Lewis A, Donaldson AV, Garfield B, Hopkinson NS, Natanek SA, Man W, Wells D, Baker EH, Polkey MI, Kemp Pet al., 2015,

    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: 2190-6009

    BackgroundLoss of muscle mass is a co-morbidity common to a range of chronic diseases including chronic obstructive pulmonary disease (COPD). Several systemic features of COPD including increased inflammatory signalling, oxidative stress, and hypoxia are known to increase the expression of growth differentiation factor-15 (GDF-15), a protein associated with muscle wasting in other diseases. We therefore hypothesized that GDF-15 may contribute to muscle wasting in COPD.MethodsWe determined the expression of GDF-15 in the serum and muscle of patients with COPD and analysed the association of GDF-15 expression with muscle mass and exercise performance. To determine whether GDF-15 had a direct effect on muscle, we also determined the effect of increased GDF-15 expression on the tibialis anterior of mice by electroporation.ResultsGrowth differentiation factor-15 was increased in the circulation and muscle of COPD patients compared with controls. Circulating GDF-15 was inversely correlated with rectus femoris cross-sectional area (P < 0.001) and exercise capacity (P < 0.001) in two separate cohorts of patients but was not associated with body mass index. GDF-15 levels were associated with 8-oxo-dG in the circulation of patients consistent with a role for oxidative stress in the production of this protein. Local over-expression of GDF-15 in mice caused wasting of the tibialis anterior muscle that expressed it but not in the contralateral muscle suggesting a direct effect of GDF-15 on muscle mass (P < 0.001).ConclusionsTogether, the data suggest that GDF-15 contributes to the loss of muscle mass in COPD.

  • Journal article
    Luther PK, Burgoyne T, Morris E, 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: 1089-8638

    The Z-band in vertebrate striated muscle crosslinks actin filaments of opposite polarity from adjoiningsarcomeres and transmits tension along myofibrils during muscular contraction. It is also the location of anumber of proteins involved in signalling and myofibrillogenesis; mutations in these proteins lead to myopathies.Understanding the high-resolution structure of the Z-band will help us understand its role in muscle contractionand the role of these proteins in the function of muscle. The appearance of the Z-band in transverse-sectionelectron micrographs typically resembles a small-square lattice or a basketweave appearance. In longitudinalsections, the Z-band width varies more with muscle type than species: slow skeletal and cardiac muscles havewider Z-bands than fast skeletal muscles. As the Z-band is periodic, Fourier methods have previously beenused for three-dimensional structural analysis. To cope with variations in the periodic structure of the Z-band, wehave used subtomogram averaging of tomograms of rat cardiac muscle in which subtomograms are extractedand compared and similar ones are averaged. We show that the Z-band comprises four to six layers of links,presumably α-actinin, linking antiparallel overlapping ends of the actin filaments from the adjoining sarcomeres.The reconstruction shows that the terminal 5–7 nm of the actin filaments within the Z-band is devoid of anyα-actinin links and is likely to be the location of capping protein CapZ.

  • Journal article
    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
  • Journal article
    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
  • Journal article
    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.

  • Journal article
    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

  • Journal article
    Smyth E, Solomon A, Vydyanath A, Luther PK, Pitchford S, Tetley TD, Emerson Met al., 2014,

    Induction and enhancement of platelet aggregation in vitro and in vivo by model polystyrene nanoparticles

    , Nanotoxicology, Vol: 9, Pages: 356-364, ISSN: 1743-5404

    Abstract Nanoparticles (NPs) may come into contact with circulating blood elements including platelets following inhalation and translocation from the airways to the bloodstream or during proposed medical applications. Studies with model polystyrene latex nanoparticles (PLNPs) have shown that NPs are able to induce platelet aggregation in vitro suggesting a poorly defined potential mechanism of increased cardiovascular risk upon NP exposure. We aimed to provide insight into the mechanisms by which NPs may increase cardiovascular risk by determining the impact of a range of concentrations of PLNPs on platelet activation in vitro and in vivo and identifying the signaling events driving NP-induced aggregation. Model PLNPs of varying nano-size (50 and 100 nm) and surface chemistry [unmodified (uPLNP), amine-modified (aPLNP) and carboxyl-modified (cPLNP)] were therefore examined using in vitro platelet aggregometry and an established mouse model of platelet thromboembolism. Most PLNPs tested induced GPIIb/IIIa-mediated platelet aggregation with potencies that varied with both surface chemistry and nano-size. Aggregation was associated with signaling events, such as granule secretion and release of secondary agonists, indicative of conventional agonist-mediated aggregation. Platelet aggregation was associated with the physical interaction of PLNPs with the platelet membrane or internalization. 50 nm aPLNPs acted through a distinct mechanism involving the physical bridging of adjacent non-activated platelets leading to enhanced agonist-induced aggregation in vitro and in vivo. Our study suggests that should they translocate the pulmonary epithelium, or be introduced into the blood, NPs may increase the risk of platelet-driven events by inducing or enhancing platelet aggregation via mechanisms that are determined by their distinct combination of nano-size and surface chemistry.

  • Journal article
    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
  • Journal article
    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: 1878-1551

    Autophagy is an evolutionarily conserved process that enables catabolic and degradative pathways. These pathways commonly depend on vesicular transport controlled by Rabs, small GTPases inactivated by TBC/RabGAPs. The Rac1 effector TBC/RabGAP Armus (TBC1D2A) is known to inhibit Rab7, a key regulator of lysosomal function. However, the precise coordination of signaling and intracellular trafficking that regulates autophagy is poorly understood. We find that overexpression of Armus induces the accumulation of enlarged autophagosomes, while Armus depletion significantly delays autophagic flux. Upon starvation-induced autophagy, Rab7 is transiently activated. This spatiotemporal regulation of Rab7 guanosine triphosphate/guanosine diphosphate cycling occurs by Armus recruitment to autophagosomes via interaction with LC3, a core autophagy regulator. Interestingly, autophagy potently inactivates Rac1. Active Rac1 competes with LC3 for interaction with Armus and thus prevents its appropriate recruitment to autophagosomes. The precise coordination between Rac1 and Rab7 activities during starvation suggests that Armus integrates autophagy with signaling and endocytic trafficking.

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

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