Production in Au-Au Collisions

This thesis presents the first J/ Ψ production analysis of Au+Au reactions at forward rapidity at p √sNN = 200 GeV. In the second year of RHIC running, design energy was achieved in the collisions of both Au+Au ions and proton+proton reactions. The production of the J/Ψ is measured by the PHENIX experiment in Au+Au collisions as well as in proton-proton collisions. The scientific goal is to investigate the nature of hot, dense nuclear matter capitalizing on the unique properties of the J/ Ψ as a probe of this matter. Recent experimental results by the NA50 collaboration at CERN strongly deviate from the conventional picture that successfully describes data at lower energies. The importance of such a measurement is demonstrated by the wide spectrum of theoretical explanations concerning the existing data. The merits of these models will be explored in a systematic and comprehensive study of the J/ Ψ and open charm in collisions of a variety of species and energy. A survey of the theoretical models is presented and the relevant open charm and J/ Ψ PHENIX measurements are compared

cAMP-induced actin cytoskeleton remodelling inhibits MKL1-dependent expression of the chemotactic and pro-proliferative factor, CCN1

AbstractElevation of intracellular cAMP concentration has numerous vascular protective effects that are in part mediated via actin cytoskeleton-remodelling and subsequent regulation of gene expression. However, the mechanisms are incompletely understood. Here we investigated whether cAMP-induced actin-cytoskeleton remodelling modulates VSMC behaviour by inhibiting expression of CCN1. In cultured rat VSMC, CCN1-silencing significantly inhibited BrdU incorporation and migration in a wound healing assay. Recombinant CCN1 enhanced chemotaxis in a Boyden chamber. Adding db-cAMP, or elevating cAMP using forskolin, significantly inhibited CCN1 mRNA and protein expression in vitro; transcriptional regulation was demonstrated by measuring pre-spliced CCN1 mRNA and CCN1-promoter activity. Forskolin also inhibited CCN1 expression in balloon injured rat carotid arteries in vivo. Inhibiting RhoA activity, which regulates actin-polymerisation, by cAMP-elevation or pharmacologically with C3-transferase, or inhibiting its downstream kinase, ROCK, with Y27632, significantly inhibited CCN1 expression. Conversely, expression of constitutively active RhoA reversed the inhibitory effects of forskolin on CCN1 mRNA. Furthermore, CCN1 mRNA levels were significantly decreased by inhibiting actin-polymerisation with latrunculin B or increased by stimulating actin-polymerisation with Jasplakinolide. We next tested the role of the actin-dependent SRF co-factor, MKL1, in CCN1 expression. Forskolin inhibited nuclear translocation of MKL1 and binding of MKL1 to the CCN1 promoter. Constitutively-active MKL1 enhanced basal promoter activity of wild-type but not SRE-mutated CCN1; and prevented forskolin inhibition. Furthermore, pharmacological MKL-inhibition with CCG-1423 significantly inhibited CCN1 promoter activity as well as mRNA and protein expression. Our data demonstrates that cAMP-induced actin-cytoskeleton remodelling regulates expression of CCN1 through MKL1: it highlights a novel cAMP-dependent mechanism controlling VSMC behaviour

Differential effects of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 on atherosclerosis and monocyte/macrophage invasion

AIMS: MMPs contribute to atherosclerotic plaque progression and instability, but the relative potency of their endogenous tissue inhibitors of metalloproteinases (TIMPs) as protective factors has not been defined. We therefore investigated the impact of TIMP-1 and TIMP-2 knockout on atherosclerotic plaque burden and composition in apolipoprotein E-knockout (Apoe(−/−)) mice and studied the underlying effects on monocyte/macrophage behaviour. METHODS AND RESULTS: Analysis of brachiocephalic artery plaques revealed comparable atherosclerotic lesion areas between TIMP-1(−/−) Apoe(−/−) or TIMP-2(−/−) Apoe(−/−) double deficient mice and relevant age-matched, strain-matched Apoe(−/−) controls after 8 weeks of high-fat feeding. However, lesions from TIMP-2(−/−) Apoe(−/−) mice had higher levels of markers associated with plaque vulnerability, including increased macrophage: vascular smooth muscle cell ratios, larger necrotic core areas, reduced collagen contents, increased macrophage proliferation, and apoptosis frequencies, compared with TIMP-1(−/−)Apoe(−/−) and controls. In contrast, TIMP-1(−/−) Apoe(−/−) animals only had a significant reduction in vascular smooth muscle cell content compared with Apoe(−/−) controls. In vitro and in vivo findings implicated heightened monocyte/macrophage invasion in the detrimental effects observed on atherosclerotic plaque composition in TIMP-2(−/−) Apoe(−/−) mice. Moreover, TIMP-2 specifically decreased MMP-14-dependent monocyte/macrophage infiltration into sites of experimentally induced inflammation and established atherosclerotic lesions. CONCLUSION: Our data demonstrate that TIMP-2 plays a greater protective role than TIMP-1 during the pathogenesis of atherosclerosis, in part by suppressing MMP-14-dependent monocyte/macrophage accumulation into plaques

Noninvasive Molecular Imaging of Disease Activity in Atherosclerosis.

Major focus has been placed on the identification of vulnerable plaques as a means of improving the prediction of myocardial infarction. However, this strategy has recently been questioned on the basis that the majority of these individual coronary lesions do not in fact go on to cause clinical events. Attention is, therefore, shifting to alternative imaging modalities that might provide a more complete pan-coronary assessment of the atherosclerotic disease process. These include markers of disease activity with the potential to discriminate between patients with stable burnt-out disease that is no longer metabolically active and those with active atheroma, faster disease progression, and increased risk of infarction. This review will examine how novel molecular imaging approaches can provide such assessments, focusing on inflammation and microcalcification activity, the importance of these processes to coronary atherosclerosis, and the advantages and challenges posed by these techniques.M.R.D and D.E.N are supported by the British Heart Foundation (CH/09/002 to D.E.N., FS/14/78/31020 to M.R.D). M.R.D is the recipient of the Sir Jules Thorn Biomedical Research Award 2015 (M.R.D.) E.A. research is supported by R01HL 114805 and R01HL 109506.This is the final version of the article. It first appeared from Lippincott, Williams & Wilkins via http://dx.doi.org/10.1161/CIRCRESAHA.116.30797

68Ga-DOTATATE PET Identifies Residual Myocardial Inflammation and Bone Marrow Activation After Myocardial Infarction.

Myocardial infarction (MI) healing occurs in two phases: first an inflammatory phase, where clearance of necrotic debris occurs, followed by a reparative phase characterized by angiogenesis, granulation tissue formation and attempts to repair the extracellular matrix. While efficient healing relies on co-ordinated mobilization of monocytes to the damaged myocardium, with resolution of the acute inflammatory response by ~10-14 days, excessive inflammation impairs myocardial salvage and promotes adverse cardiac remodelling

Relationship of MMP-14 and TIMP-3 Expression with Macrophage Activation and Human Atherosclerotic Plaque Vulnerability

Matrix metalloproteinase-14 (MMP-14) promotes vulnerable plaque morphology in mice, whereas tissue inhibitor of metalloproteinases-3 (TIMP-3) overexpression is protective. MMP-14hi  TIMP-3lo rabbit foam cells are more invasive and more prone to apoptosis than MMP-14lo  TIMP-3hi cells. We investigated the implications of these findings for human atherosclerosis. In vitro generated macrophages and foam-cell macrophages, together with atherosclerotic plaques characterised as unstable or stable, were examined for expression of MMP-14, TIMP-3, and inflammatory markers. Proinflammatory stimuli increased MMP-14 and decreased TIMP-3 mRNA and protein expression in human macrophages. However, conversion to foam-cells with oxidized LDL increased MMP-14 and decreased TIMP-3 protein, independently of inflammatory mediators and partly through posttranscriptional mechanisms. Within atherosclerotic plaques, MMP-14 was prominent in foam-cells with either pro- or anti-inflammatory macrophage markers, whereas TIMP-3 was present in less foamy macrophages and colocalised with CD206. MMP-14 positive macrophages were more abundant whereas TIMP-3 positive macrophages were less abundant in plaques histologically designated as rupture prone. We conclude that foam-cells characterised by high MMP-14 and low TIMP-3 expression are prevalent in rupture-prone atherosclerotic plaques, independent of pro- or anti-inflammatory activation. Therefore reducing MMP-14 activity and increasing that of TIMP-3 could be valid therapeutic approaches to reduce plaque rupture and myocardial infarction