Isolation and characterization of cidofovir resistant vaccinia viruses

© 2008 Becker et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase

AbstractBackground: The p38 mitogen-activated protein (MAP) kinase regulates signal transduction in response to environmental stress. Pyridinylimidazole compounds are specific inhibitors of p38 MAP kinase that block the production of the cytokines interleukin-1 β and tumor necrosis factor α, and they are effective in animal models of arthritis, bone resorption and endotoxin shock. These compounds have been useful probes for studying the physiological functions of the p38-mediated MAP kinase pathway.Results: We report the crystal structure of a novel pyridinylimidazole compound complexed with p38 MAP kinase, and we demonstrate that this compound binds to the same site on the kinase as does ATP. Mutagenesis showed that a single residue difference between p38 MAP kinase and other MAP kinases is sufficient to confer selectivity among pyridinylimidazole compounds.Conclusions: Our results reveal how pyridinylimidazole compounds are potent and selective inhibitors of p38 MAP kinase but not other MAP kinases. It should now be possible to design other specific inhibitors of activated p38 MAP kinase using the structure of the nonphosphorylated enzyme

Detailed Abundances in the Ultra-faint Magellanic Satellites Carina II and III

We present the first detailed elemental abundances in the ultra-faint Magellanic satellite galaxies Carina II (Car II) and Carina III (Car III). With high-resolution Magellan/MIKE spectroscopy, we determined abundances of nine stars in Car II including the first abundances of an RR Lyrae star in an ultra-faint dwarf galaxy; and two stars in Car III. The chemical abundances demonstrate that both systems are clearly galaxies and not globular clusters. The stars in these galaxies mostly display abundance trends matching those of other similarly faint dwarf galaxies: enhanced but declining [alpha/Fe] ratios, iron-peak elements matching the stellar halo, and unusually low neutron-capture element abundances. One star displays a low outlying [Sc/Fe] = -1.0. We detect a large Ba scatter in Car II, likely due to inhomogeneous enrichment by low-mass AGB star winds. The most striking abundance trend is for [Mg/Ca] in Car II, which decreases from +0.4 to -0.4 and indicates clear variation in the initial progenitor masses of enriching core-collapse supernovae. So far, the only ultra-faint dwarf galaxies displaying a similar [Mg/Ca] trend are likely satellites of the Large Magellanic Cloud. We find two stars with [Fe/H] < -3.5, whose abundances likely trace the first generation of metal-free Population III stars and are well-fit by Population III core-collapse supernova yields. An appendix describes our new abundance uncertainty analysis that propagates line-by-line stellar parameter uncertainties.Comment: 21 pages + appendix, 9 figures, 6 tables, accepted to Ap

Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial

Objectives SENECA (StEm cell iNjECtion in cAncer survivors) is a phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and feasibility of delivering allogeneic mesenchymal stromal cells (allo-MSCs) transendocardially in subjects with anthracycline-induced cardiomyopathy (AIC). Background AIC is an incurable and often fatal syndrome, with a prognosis worse than that of ischemic or nonischemic cardiomyopathy. Recently, cell therapy with MSCs has emerged as a promising new approach to repair damaged myocardium. Methods The study population is 36 cancer survivors with a diagnosis of AIC, left ventricular (LV) ejection fraction ≤40%, and symptoms of heart failure (NYHA class II-III) on optimally-tolerated medical therapy. Subjects must be clinically free of cancer for at least two years with a ≤ 30% estimated five-year risk of recurrence. The first six subjects participated in an open-label, lead-in phase and received 100 million allo-MSCs; the remaining 30 will be randomized 1:1 to receive allo-MSCs or vehicle via 20 transendocardial injections. Efficacy measures (obtained at baseline, 6 months, and 12 months) include MRI evaluation of LV function, LV volumes, fibrosis, and scar burden; assessment of exercise tolerance (six-minute walk test) and quality of life (Minnesota Living with Heart Failure Questionnaire); clinical outcomes (MACE and cumulative days alive and out of hospital); and biomarkers of heart failure (NT-proBNP). Conclusions This is the first clinical trial using direct cardiac injection of cells for the treatment of AIC. If administration of allo-MSCs is found feasible and safe, SENECA will pave the way for larger phase II/III studies with therapeutic efficacy as the primary outcome

Sunyaev–Zel’dovich observations with AMI of the hottest galaxy clusters detected in the XMM–Newton Cluster Survey

We have obtained deep Sunyaev–Zel’dovich (SZ) observations towards 15 of the hottest XMM Cluster Survey (XCS) clusters that can be observed with the Arcminute Microkelvin Imager (AMI). We use a Bayesian analysis to quantify the significance of our SZ detections. We detect the SZ effect at high significance towards three of the clusters and at lower significance for a further two clusters. Towards the remaining 10 clusters, no clear SZ signal was measured. We derive cluster parameters using the XCS mass estimates as a prior in our Bayesian analysis. For all AMI-detected clusters, we calculate large-scale mass and temperature estimates while for all undetected clusters we determine upper limits on these parameters. We find that the large-scale mean temperatures derived from our AMI SZ measurements (and the upper limits from null detections) are substantially lower than the XCS-based core-temperature estimates. For clusters detected in the SZ, the mean temperature is, on average, a factor of 1.4 lower than temperatures from the XCS. Our upper limits on the cluster temperature of undetected systems are lower than the mean XCS derived temperature

Acute Kidney Injury Results in Long-Term Diastolic Dysfunction That Is Prevented by Histone Deacetylase Inhibition

Growing epidemiological data demonstrate that acute kidney injury (AKI) is associated with long-term cardiovascular morbidity and mortality. Here, the authors present a 1-year study of cardiorenal outcomes following bilateral ischemia-reperfusion injury in male mice. These data suggest that AKI causes long-term dysfunction in the cardiac metabolome, which is associated with diastolic dysfunction and hypertension. Mice treated with the histone deacetylase inhibitor, ITF2357, had preservation of cardiac function and remained normotensive throughout the study. ITF2357 did not protect against the development of kidney fibrosis after AKI