Selective COX-2 inhibitors and risk of myocardial infarction

Selective inhibitors of cyclooxygenase- 2 ( COX- 2, ` coxibs') are highly effective anti-inflammatory and analgesic drugs that exert their action by preventing the formation of prostanoids. Recently some coxibs, which were designed to exploit the advantageous effects of non- steroidal anti-inflammatory drugs while evading their side effects, have been reported to increase the risk of myocardial infarction and atherothrombotic events. This has led to the withdrawal of rofecoxib from global markets, and warnings have been issued by drug authorities about similar events during the use of celecoxib or valdecoxib/ parecoxib, bringing about questions of an inherent atherothrombotic risk of all coxibs and consequences that should be drawn by health care professionals. These questions need to be addressed in light of the known effects of selective inhibition of COX- 2 on the cardiovascular system. Although COX- 2, in contrast to the cyclooxygenase-1 ( COX- 1) isoform, is regarded as an inducible enzyme that only has a role in pathophysiological processes like pain and inflammation, experimental and clinical studies have shown that COX- 2 is constitutively expressed in tissues like the kidney or vascular endothelium, where it executes important physiological functions. COX- 2- dependent formation of prostanoids not only results in the mediation of pain or inflammatory signals but also in the maintenance of vascular integrity. Especially prostacyclin ( PGI(2)), which exerts vasodilatory and antiplatelet properties, is formed to a significant extent by COX- 2, and its levels are reduced to less than half of normal when COX- 2 is inhibited. This review outlines the rationale for the development of selective COX- 2 inhibitors and the pathophysiological consequences of selective inhibition of COX- 2 with special regard to vasoactive prostaglandins. It describes coxibs that are currently available, evaluates the current knowledge on the risk of atherothrombotic events associated with their intake and critically discusses the consequences that should be drawn from these insights. Copyright (C) 2005 S. Karger AG, Basel

DMRG evaluation of the Kubo formula -- Conductance of strongly interacting quantum systems

In this paper we present a novel approach combining linear response theory (Kubo) for the conductance and the Density Matrix Renormalization Group (DMRG). The system considered is one-dimensional and consists of non-interacting tight binding leads coupled to an interacting nanostructure via weak links. Electrons are treated as spinless fermions and two different correlation functions are used to evaluate the conductance. Exact diagonalization calculations in the non-interacting limit serve as a benchmark for our combined Kubo and DMRG approach in this limit. Including both weak and strong interaction we present DMRG results for an extended nanostructure consisting of seven sites. For the strongly interacting structure a simple explanation of the position of the resonances is given in terms of hard-core particles moving freely on a lattice of reduced size.Comment: 7 pages, 2 figures. Minor typos correcte

OMP Peptides Modulate the Activity of DegS Protease by Differential Binding to Active and Inactive Conformations

Upon sensing misfolded outer-membrane porins (OMPs) in the periplasm, the E. coli DegS protease cleaves RseA, a transmembrane regulator, transmitting a signal to activate cytoplasmic gene expression. Misfolding is detected by binding of normally inaccessible OMP sequences to the DegS-PDZ domain, which relieves allosteric inhibition and activates proteolysis. Here we show that DegS stimulation can be regulated by OMP peptide affinity for the active and for the inactive protease conformations, as well as by preferential substrate binding to active DegS. Based on the effects of mutations in the peptide-binding pocket of the PDZ domain and elsewhere, we suggest an allosteric pathway that links peptide binding to DegS activation. These results explain fast responses to envelope stress; demonstrate that the protein-unfolding response, even under catastrophic conditions, can be tailored by the peptide sequences that become accessible to DegS; and suggest strategies for control of related PDZ proteases by allosteric effectors.National Institutes of Health (U.S.) (NIH grant AI-16892)National Institutes of Health (U.S.) (NIH postdoctoral fellowship (AI-074245-01A1)

The M31 Velocity Vector. III. Future Milky Way-M31-M33 Orbital Evolution, Merging, and Fate of the Sun

We study the future orbital evolution and merging of the MW-M31-M33 system, using a combination of collisionless N-body simulations and semi-analytic orbit integrations. Monte-Carlo simulations are used to explore the consequences of varying the initial phase-space and mass parameters within their observational uncertainties. The observed M31 transverse velocity implies that the MW and M31 will merge t = 5.86 (+1.61-0.72) Gyr from now, after a first pericenter at t = 3.87 (+0.42-0.32) Gyr. M31 may (probability p=41%) make a direct hit with the MW (defined here as a first-pericenter distance less than 25 kpc). Most likely, the MW and M31 will merge first, with M33 settling onto an orbit around them. Alternatively, M33 may make a direct hit with the MW first (p=9%), or M33 may get ejected from the Local Group (p=7%). The MW-M31 merger remnant will resemble an elliptical galaxy. The Sun will most likely (p=85%) end up at larger radius from the center of the MW-M31 merger remnant than its current distance from the MW center, possibly further than 50 kpc (p=10%). The Sun may (p=20%) at some time in the next 10 Gyr find itself moving through M33 (within 10 kpc), but while dynamically still bound to the MW-M31 merger remnant. The arrival and possible collision of M31 (and possibly M33) with the MW is the next major cosmic event affecting the environment of our Sun and solar system that can be predicted with some certainty. (Abridged)Comment: 58 pages, 16 figures, to be published in ApJ. Version with high resolution figures and N-body movies available at http://www.stsci.edu/~marel/M31 . Press materials, graphics, and visualizations available at http://hubblesite.org/newscenter/archive/releases/2012/2

UV Properties of Galactic Globular Clusters with GALEX II. Integrated colors

We present ultraviolet (UV) integrated colors of 44 Galactic globular clusters (GGCs) observed with the Galaxy Evolution Explorer (GALEX) in both FUV and NUV bands. This data-base is the largest homogeneous catalog of UV colors ever published for stellar systems in our Galaxy. The proximity of GGCs makes it possible to resolve many individual stars even with the somewhat low spatial resolution of GALEX. This allows us to determine how the integrated UV colors are driven by hot stellar populations, primarily horizontal branch stars and their progeny. The UV colors are found to be correlated with various parameters commonly used to define the horizontal branch morphology. We also investigate how the UV colors vary with parameters like metallicity, age, helium abundance and concentration. We find for the first time that GCs associated with the Sagittarius dwarf galaxy have (FUV-V) colors systematically redder than GGCs with the same metallicity. Finally, we speculate about the presence of an interesting trend, suggesting that the UV color of GCs may be correlated with the mass of the host galaxy, in the sense that more massive galaxies possess bluer clusters.Comment: Accepted for publication by The Astronomical Journal. 36 pages, 9 figures, 1 tabl

Danish values, the foundation of the Folkeskole

We have imaged with Hubble Space Telescope WFC3/UVIS the central 2′7 × 2′7 region of the giant elliptical galaxy M87, using the ultraviolet filter F275W. In combination with archival ACS/WFC data taken through the F606W and F814W filters, covering the same field, we have constructed integrated-light UV-optical colors and magnitudes for 1460 objects, most of which are believed to be globular clusters (GCs) belonging to M87. The purpose was to ascertain whether the multiple-populations syndrome, ubiquitous among Galactic GCs, also exists among the M87 family of clusters. To achieve this goal, we sought those GCs with exceptionally blue UV-to-optical colors because helium-enriched sub-populations produce a horizontal-branch morphology that is well populated at high effective temperature. For comparison, integrated, synthetic UV-optical and purely optical colors and magnitudes have been constructed for 45 Galactic GCs, starting from individual-star photometry obtained with the same instruments and the same filters. We identify a small group of M87 clusters exhibiting a radial UV-optical color gradient, representing our best candidate GCs hosting multiple populations with extreme helium content. We also find that the central spatial distribution of the bluer GCs is flattened in a direction parallel to the jet, while the distribution of redder GCs is more spherical. We release to the astronomical community our photometric catalog in F275W, F606W, and F814W bands and the high-quality image stacks in the same bands