The study sought to test whether high-dose statin treatment would result in greater reductions in plaque inflammation than low-dose statins, using fluorodeoxyglucose-positron emission ...tomography/computed tomographic imaging (FDG-PET/CT).
Intensification of statin therapy reduces major cardiovascular events.
Adults with risk factors or with established atherosclerosis, who were not taking high-dose statins (n = 83), were randomized to atorvastatin 10 versus 80 mg in a double-blind, multicenter trial. FDG-PET/CT imaging of the ascending thoracic aorta and carotid arteries was performed at baseline, 4, and 12 weeks after randomization and target-to-background ratio (TBR) of FDG uptake within the artery wall was assessed while blinded to time points and treatment.
Sixty-seven subjects completed the study, providing imaging data for analysis. At 12 weeks, inflammation (TBR) in the index vessel was significantly reduced from baseline with atorvastatin 80 mg (% reduction 95% confidence interval: 14.42% 8.7% to 19.8%; p < 0.001), but not atorvastatin 10 mg (% reduction: 4.2% -2.3% to 10.4%; p > 0.1). Atorvastatin 80 mg resulted in significant additional relative reductions in TBR versus atorvastatin 10 mg (10.6% 2.2% to 18.3%; p = 0.01) at week 12. Reductions from baseline in TBR were seen as early as 4 weeks after randomization with atorvastatin 10 mg (6.4% reduction, p < 0.05) and 80 mg (12.5% reduction, p < 0.001). Changes in TBR did not correlate with lipid profile changes.
Statin therapy produced significant rapid dose-dependent reductions in FDG uptake that may represent changes in atherosclerotic plaque inflammation. FDG-PET imaging may be useful in detecting early treatment effects in patients at risk or with established atherosclerosis.
The angiotensin II receptors AT
R and AT
R serve as key components of the renin-angiotensin-aldosterone system. AT
R has a central role in the regulation of blood pressure, but the function of AT
R ...is unclear and it has a variety of reported effects. To identify the mechanisms that underlie the differences in function and ligand selectivity between these receptors, here we report crystal structures of human AT
R bound to an AT
R-selective ligand and to an AT
R/AT
R dual ligand, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G proteins or β-arrestins, in agreement with the lack of signalling responses in standard cellular assays. Structure-activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity. Our results thus provide insights into the structural basis of the distinct functions of the angiotensin receptors, and may guide the design of new selective ligands.
Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain's ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest ...effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OX
R) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OX
R agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OX
R bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OX
R to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OX
R suggests a molecular mechanism that rationalizes both receptor activation and inhibition. Our results enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders.
The demand for new chemicals spanning the fields of health care to materials science combined with the pressure to produce these substances in an environmentally benign fashion pose great challenges ...to the synthetic chemical community. The maximization of synthetic efficiency by the conversion of simple building blocks into complex targets remains a fundamental goal. In this context, ruthenium complexes catalyze a number of non‐metathesis conversions and allow the rapid assembly of complex molecules with high selectivity and atom economy. These complexes often exhibit unusual reactivity. Careful consideration of the mechanistic underpinnings of the transformations can lead to the design of new reactions and the discovery of new reactivity.
Ru complexes emerged from obscurity to become accepted as ideal catalysts for diverse CC bond‐forming reactions beyond the more‐well‐known redox and metathesis processes. These reactions are highly selective and atom‐economic processes for the synthesis of complex molecules (see scheme). Mechanistic principles provide the basis for the semirational design of new reactions, notably for CC coupling.
Anthropogenic releases of mercury (Hg)
are a human health issue
because the potent toxicant methylmercury (MeHg), formed primarily by microbial methylation of inorganic Hg in aquatic ecosystems, ...bioaccumulates to high concentrations in fish consumed by humans
. Predicting the efficacy of Hg pollution controls on fish MeHg concentrations is complex because many factors influence the production and bioaccumulation of MeHg
. Here we conducted a 15-year whole-ecosystem, single-factor experiment to determine the magnitude and timing of reductions in fish MeHg concentrations following reductions in Hg additions to a boreal lake and its watershed. During the seven-year addition phase, we applied enriched Hg isotopes to increase local Hg wet deposition rates fivefold. The Hg isotopes became increasingly incorporated into the food web as MeHg, predominantly from additions to the lake because most of those in the watershed remained there. Thereafter, isotopic additions were stopped, resulting in an approximately 100% reduction in Hg loading to the lake. The concentration of labelled MeHg quickly decreased by up to 91% in lower trophic level organisms, initiating rapid decreases of 38-76% of MeHg concentration in large-bodied fish populations in eight years. Although Hg loading from watersheds may not decline in step with lowering deposition rates, this experiment clearly demonstrates that any reduction in Hg loadings to lakes, whether from direct deposition or runoff, will have immediate benefits to fish consumers.
Globally, calls for the improvement of science education are frequent and fervent. In parallel, the phenomenon of having Science Faculty with Education Specialties (SFES) within science departments ...appears to have grown in recent decades. In the context of an interview study of a randomized, stratified sample of SFES from across the United States, we discovered that most SFES interviewed (82%) perceived having professional impacts in the realm of improving undergraduate science education, more so than in research in science education or K-12 science education. While SFES reported a rich variety of efforts towards improving undergraduate science education, the most prevalent reported impact by far was influencing the teaching practices of their departmental colleagues. Since college and university science faculty continue to be hired with little to no training in effective science teaching, the seeding of science departments with science education specialists holds promise for fostering change in science education from within biology, chemistry, geoscience, and physics departments.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Methylmercury contamination of fisheries from centuries of industrial atmospheric emissions negatively impacts humans and wildlife worldwide. The response of fish methylmercury concentrations to ...changes in mercury deposition has been difficult to establish because sediments/soils contain large pools of historical contamination, and many factors in addition to deposition affect fish mercury. To test directly the response of fish contamination to changing mercury deposition, we conducted a whole-ecosystem experiment, increasing the mercury load to a lake and its watershed by the addition of enriched stable mercury isotopes. The isotopes allowed us to distinguish between experimentally applied mercury and mercury already present in the ecosystem and to examine bioaccumulation of mercury deposited to different parts of the watershed. Fish methylmercury concentrations responded rapidly to changes in mercury deposition over the first 3 years of study. Essentially all of the increase in fish methylmercury concentrations came from mercury deposited directly to the lake surface. In contrast, <1% of the mercury isotope deposited to the watershed was exported to the lake. Steady state was not reached within 3 years. Lake mercury isotope concentrations were still rising in lake biota, and watershed mercury isotope exports to the lake were increasing slowly. Therefore, we predict that mercury emissions reductions will yield rapid (years) reductions in fish methylmercury concentrations and will yield concomitant reductions in risk. However, a full response will be delayed by the gradual export of mercury stored in watersheds. The rate of response will vary among lakes depending on the relative surface areas of water and watershed.
A wide variety of diynols containing tertiary, secondary, and primary propargylic alcohols undergo a cycloisomerization reaction to form dienones and dienals in the presence of a catalytic amount of ...CpRu(CH3CN)3PF6. The formation of five- and six-membered rings is possible using this methodology. Secondary diynols react to form single geometrical isomeric dienones and -als. Primary diynols undergo a cycloisomerization as well as a hydrative cyclization process. The utility of primary diynol cycloisomerization is demonstrated in a synthesis of (+)-α-kainic acid.
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