Nitric oxide-dependent vasodilation is compromised in isolated pulmonary arteries from COX knockout mice

Cyclooxygenase (COX) has two isoforms and is essential for prostanoid synthesis. COX-1 is constitutive whilst COX-2 is induced in inflammation. Two COX products, prostacyclin (PGI2) and thromboxane (TxA2), regulate vessel tone; PGI2 mediates vasodilation and platelet inhibition, and TxA2 opposes this. PGI2 therapies are used in pulmonary arterial hypertension (PAH). Endogenous TxA2/PGI2 has been linked to PAH in animal models, but the mechanism and isoform involved is debated. We hypothesized that pulmonary artery (PA) from COX-1–/– and COX-2–/– mice would have altered vasodilatory function compared with wild-type (WT; C57Bl6) mice. Vasomotor responses to contractile and relaxant agents were measured by myography. PA from all mice responded similarly to contraction by high potassium or the TxA2 mimetic, U46619. Relaxation to PGI2 receptor or PPARβ/ agonists was also similar in all PAs. However, COX-1–/– and, to a lesser extent, COX-2–/– PA had impaired vasodilation to acetylcholine (ACh), which stimulates endothelial nitric oxide (NO) release, and COX-1–/– PA also dilated less to sodium nitroprusside (SNP); an NO donor that works on smooth muscle (Fig 1). These data indicate an interaction between COX and NO sensing pathways in pulmonary vessels, and have implications for our understanding of PAH.Non peer reviewedFinal Accepted Versio

Role of the endothelium and COX-1 in prostacyclin generation by whole vessels stimulated with different agonists

Prostacyclin is an important cardioprotective hormone produced by the vascular wall, whose synthesis is dependent on cyclo-oxygenase (COX) enzymes. In healthy vessels the endothelium is thought to be the main site of prostacyclin release (Moncada et al 1977). Two isoforms of COX exist, and we have recently published data demonstrating that it is COX-1 rather than COX-2 that drives the production of prostacyclin in mouse aorta (Kirkby et al 2012). In this study we aimed to extend these observations by investigating what proportion of the COX-1 driven aortic prostacyclin production that comes from the endothelium versus the rest of the vessel wall (smooth muscle layers and adventitia). To do this, we explored how removal of the endothelium would influence the ability of aortic tissue to release prostacyclin in response to a range of agonists that are known to activate the endothelium and the vessel wallNon peer reviewe

Pharmacological assessment of ibuprofen arginate on platelet aggregation and colon cancer cell killing

This work was funded in part by grants from the Wellcome Trust (0852551Z108/Z, to J.A.M.) and British Heart Foundation (FS/16/1/31699, to NSK). SM is a recipient of a PhD award from the King of Saud University, AT is a recipient of a MRC PhD studentship

Phenomenology of the Deuteron Electromagnetic Form Factors

A rigorous extraction of the deuteron charge form factors from tensor polarization data in elastic electron-deuteron scattering, at given values of the 4-momentum transfer, is presented. Then the world data for elastic electron-deuteron scattering is used to parameterize, in three different ways, the three electromagnetic form factors of the deuteron in the 4-momentum transfer range 0-7 fm^-1. This procedure is made possible with the advent of recent polarization measurements. The parameterizations allow a phenomenological characterization of the deuteron electromagnetic structure. They can be used to remove ambiguities in the form factors extraction from future polarization data.Comment: 18 pages (LaTeX), 2 figures Feb. 25: minor changes of content and in Table

Recoil Polarization for Delta Excitation in Pion Electroproduction

We measured angular distributions of recoil-polarization response functions for neutral pion electroproduction for W=1.23 GeV at Q^2=1.0 (GeV/c)^2, obtaining 14 separated response functions plus 2 Rosenbluth combinations; of these, 12 have been observed for the first time. Dynamical models do not describe quantities governed by imaginary parts of interference products well, indicating the need for adjusting magnitudes and phases for nonresonant amplitudes. We performed a nearly model-independent multipole analysis and obtained values for Re(S1+/M1+)=-(6.84+/-0.15)% and Re(E1+/M1+)=-(2.91+/-0.19)% that are distinctly different from those from the traditional Legendre analysis based upon M1+ dominance and sp truncation.Comment: 5 pages, 2 figures, for PR

Coherent π0 photoproduction on the deuteron up to 4 GeV

The differential cross section for 2H(γ,d)π0 has been measured at deuteron center-of-mass angles of 90° and 136°. This work reports the first data for this reaction above a photon energy of 1 GeV, and permits a test of the apparent constituent counting rule and reduced nuclear amplitude behavior as observed in elastic ed scattering. Measurements were performed up to a photon energy of 4.0 GeV, and are in good agreement with previous lower energy measurements. Overall, the data are inconsistent with both constituent-counting rule and reduced nuclear amplitude predictions

Serum magnesium and calcium levels in relation to ischemic stroke : Mendelian randomization study

ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 7 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 7 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype

Semantic Types and Approximation for Featherweight Java

We consider semantics for the class-based object-oriented calculus Featherweight Java (without casts) based upon approximation. We also define an intersection type assignment system for this calculus and show that it satisfies subject reduction and expansion, i.e. types are preserved under reduction and its converse. We establish a link between type assignment and the approximation semantics by showing an approximation result, which leads to a sufficient condition for the characterisation of head-normalisation and termination. We show the expressivity of both our calculus and our type system by defining an encoding of Combinatory Logic into our calculus and showing that this encoding preserves typeability. We also show that our system characterises the normalising and strongly normalising terms for this encoding. We thus demonstrate that the great analytic capabilities of intersection types can be applied to the context of class-based object orientation