Geometric-Phase-Effect Tunnel-Splitting Oscillations in Single-Molecule Magnets with Fourth-Order Anisotropy Induced by Orthorhombic Distortion

We analyze the interference between tunneling paths that occurs for a spin system with both fourth-order and second-order transverse anisotropy. Using an instanton approach, we find that as the strength of the second-order transverse anisotropy is increased, the tunnel splitting is modulated, with zeros occurring periodically. This effect results from the interference of four tunneling paths connecting easy-axis spin orientations and occurs in the absence of any magnetic field.Comment: 6 pages, 5 eps figures. Version published in EPL. Expanded from v1: Appendix added, references added, 1 figure added, others modified cosmeticall

Epigenome-Guided Analysis of the Transcriptome of Plaque Macrophages during Atherosclerosis Regression Reveals Activation of the Wnt Signaling Pathway

We report the first systems biology investigation of regulators controlling arterial plaque macrophage transcriptional changes in response to lipid lowering in vivo in two distinct mouse models of atherosclerosis regression. Transcriptome measurements from plaque macrophages from the Reversa mouse were integrated with measurements from an aortic transplant-based mouse model of plaque regression. Functional relevance of the genes detected as differentially expressed in plaque macrophages in response to lipid lowering in vivo was assessed through analysis of gene functional annotations, overlap with in vitro foam cell studies, and overlap of associated eQTLs with human atherosclerosis/CAD risk SNPs. To identify transcription factors that control plaque macrophage responses to lipid lowering in vivo, we used an integrative strategy – leveraging macrophage epigenomic measurements – to detect enrichment of transcription factor binding sites upstream of genes that are differentially expressed in plaque macrophages during regression. The integrated analysis uncovered eight transcription factor binding site elements that were statistically overrepresented within the 5′ regulatory regions of genes that were upregulated in plaque macrophages in the Reversa model under maximal regression conditions and within the 5′ regulatory regions of genes that were upregulated in the aortic transplant model during regression. Of these, the TCF/LEF binding site was present in promoters of upregulated genes related to cell motility, suggesting that the canonical Wnt signaling pathway may be activated in plaque macrophages during regression. We validated this network-based prediction by demonstrating that β-catenin expression is higher in regressing (vs. control group) plaques in both regression models, and we further demonstrated that stimulation of canonical Wnt signaling increases macrophage migration in vitro. These results suggest involvement of canonical Wnt signaling in macrophage emigration from the plaque during lipid lowering-induced regression, and they illustrate the discovery potential of an epigenome-guided, systems approach to understanding atherosclerosis regression

Short-term pacing in the mouse alters cardiac expression of connexin43

Background: Cardiac insults such as ischemia, infarction, hypertrophy and dilatation are often accompanied by altered abundance and/or localization of the connexin43 gap junction protein, which may predispose towards arrhythmic complications. Models of chronic dyssynchronous cardiac activation have also been shown to result in redistribution of connexin43 in cardiomyocytes. We hypothesized that alterations in connexin43 expression and localization in the mouse heart might be induced by ventricular pacing over a short period of time. Results: The subdiaphragmatic approach was used to pace a series of wild type mice for six hours before the hearts were removed for analysis. Mice were paced at 10–15% above their average anesthetized sinus rate and monitored to ensure 1:1 capture. Short-term pacing resulted in a significant reduction in connexin43 mRNA abundance, a partial redistribution of connexin43 from the sarcolemma to a non-sarcolemmal fraction, and accumulation of ubiquitinated connexin43 without a significant change in overall connexin43 protein levels. These early pacing-induced changes in connexin43 expression were not accompanied by decreased cardiac function, prolonged refractoriness or increased inducibility into sustained arrhythmias. Conclusion: Our data suggest that short-term pacing is associated with incipient changes in the expression of the connexin43 gap junction, possibly including decreased production and a slowed rate of degradation. This murine model may facilitate the study of early molecular changes induced by pacing and may ultimately assist in the development of strategies to prevent gap junction remodeling and the associated arrhythmic complications of cardiac disease

Statins promote the regression of atherosclerosis via activation of the CCR7-dependent emigration pathway in macrophages.

HMG-CoA reductase inhibitors (statins) decrease atherosclerosis by lowering low-density-lipoprotein cholesterol. Statins are also thought to have additional anti-atherogenic properties, yet defining these non-conventional modes of statin action remains incomplete. We have previously developed a novel mouse transplant model of atherosclerosis regression in which aortic segments from diseased donors are placed into normolipidemic recipients. With this model, we demonstrated the rapid loss of CD68+ cells (mainly macrophages) in plaques through the induction of a chemokine receptor CCR7-dependent emigration process. Because the human and mouse CCR7 promoter contain Sterol Response Elements (SREs), we hypothesized that Sterol Regulatory Element Binding Proteins (SREBPs) are involved in increasing CCR7 expression and through this mechanism, statins would promote CD68+ cell emigration from plaques. We examined whether statin activation of the SREBP pathway in vivo would induce CCR7 expression and promote macrophage emigration from plaques. We found that western diet-fed apoE(-/-) mice treated with either atorvastatin or rosuvastatin led to a substantial reduction in the CD68+ cell content in the plaques despite continued hyperlipidemia. We also observed a significant increase in CCR7 mRNA in CD68+ cells from both the atorvastatin and rosuvastatin treated mice associated with emigration of CD68+ cells from plaques. Importantly, CCR7(-/-)/apoE(-/-) double knockout mice failed to display a reduction in CD68+ cell content upon statin treatment. Statins also affected the recruitment of transcriptional regulatory proteins and the organization of the chromatin at the CCR7 promoter to increase the transcriptional activity. Statins promote the beneficial remodeling of plaques in diseased mouse arteries through the stimulation of the CCR7 emigration pathway in macrophages. Therefore, statins may exhibit some of their clinical benefits by not only retarding the progression of atherosclerosis, but also accelerating its regression

Changing glucocorticoid action:11β-hydroxysteroid dehydrogenase type 1 in acute and chronic inflammation

AbstractSince the discovery of cortisone in the 1940s and its early success in treatment of rheumatoid arthritis, glucocorticoids have remained the mainstay of anti-inflammatory therapies. However, cortisone itself is intrinsically inert. To be effective, it requires conversion to cortisol, the active glucocorticoid, by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Despite the identification of 11β-HSD in liver in 1953 (which we now know to be 11β-HSD1), its physiological role has been little explored until recently. Over the past decade, however, it has become apparent that 11β-HSD1 plays an important role in shaping endogenous glucocorticoid action. Acute inflammation is more severe with 11β-HSD1-deficiency or inhibition, yet in some inflammatory settings such as obesity or diabetes, 11β-HSD1-deficiency/inhibition is beneficial, reducing inflammation. Current evidence suggests both beneficial and detrimental effects may result from 11β-HSD1 inhibition in chronic inflammatory disease. Here we review recent evidence pertaining to the role of 11β-HSD1 in inflammation.This article is part of a Special Issue entitled ‘CSR 2013’

Macrophages, Dendritic Cells, and Regression of Atherosclerosis

Atherosclerosis is the number one cause of death in the Western world. It results from the interaction between modified lipoproteins and monocyte-derived cells such as macrophages, dendritic cells, T cells, and other cellular elements of the arterial wall. This inflammatory process can ultimately lead to the development of complex lesions, or plaques, that protrude into the arterial lumen. Ultimately, plaque rupture and thrombosis can occur leading to the clinical complications of myocardial infarction or stroke. Although each of the cell types plays roles in the pathogenesis of atherosclerosis, in this review, the focus will be primarily on the monocyte derived cells- macrophages and dendritic cells. The roles of these cell types in atherogenesis will be highlighted. Finally, the mechanisms of atherosclerosis regression as it relates to these cells will be discussed

Effect of water on tholeiitic basalt phase equilibria: An experimental study under oxidizing conditions

To investigate the effect of water on phase relations and compositions in a basaltic system, we performed crystallization experiments at pressures of 100, 200 and 500 MPa in a temperature range of 940 to 1,220°C using four different water contents. Depending on the water activity, the oxygen fugacity varied between 1 and 4 log units above the quartz-magnetite-fayalite buffer. Addition of water to the dry system shifts the solidus \u3e 250°C to lower temperatures and increases the amount of melt drastically. For instance, at 1,100°C and 200 MPa, the melt fraction increases from 12.5 wt% at a water content of 1.6 wt% to 96.3% at a water content of 5 wt% in the melt. The compositions of the experimental phases also show a strong effect of water. Plagioclase is shifted to higher anorthite contents by the addition of water. Olivine and clinopyroxene show generally higher MgO/ FeO ratios with added water, which could also be related to the increasing oxygen fugacity with water. Moreover, water affects the partitioning of certain elements between minerals and melts, e.g., the Ca partitioning between olivine and melt. Plagioclase shows a characteristic change in the order of crystallization with water that may help to explain the formation of wehrlites intruding the lower oceanic crust (e.g., in Oman, Macquarie Island). At 100 MPa, plagioclase crystallizes before clinopyroxene at all water contents. At pressures \u3e 100 MPa, plagioclase crystallizes before clinopyroxene at low water contents (e.g. \u3c 3 wt%), but after clinopyroxene at H2O in the melt \u3e 3 wt%. This change in crystallization order indicates that a paragenesis typical for wehrlites (olivine-clinopyroxene-without plagioclase) is stabilized at low pressures typical of the oceanic crust only at high water contents. This opens the possibility that typical wehrlites in the oceanic crust can be formed by the fractionation and accumulation of olivine and clinopyroxene at 1,060°C and \u3e 100 MPa in a primitive tholeiitic basaltic system containing more than 3 wt% water. The comparison of the experimental results with evolution trends calculated by the thermodynamic models MELTS and Comagmat shows that neither model predicts the experimental phase relations with sufficient accuracy. © Springer-Verlag 2006

Effect of oxygen fugacity and water on phase equilibria of a hydrous tholeiitic basalt

The influence of oxygen fugacity and water on phase equilibria and the link between redox conditions and water activity were investigated experimentally using a primitive tholeiitic basalt composition relevant to the ocean crust. The crystallization experiments were performed in internally heated pressure vessels at 200 MPa in the temperature range 940-1,220°C. The oxygen fugacity was measured using the H2-membrane technique. To study the effect of oxygen fugacity, three sets of experiments with different hydrogen fugacities were performed, showing systematic effects on the phase relations and compositions. In each experimental series, the water content of the system was varied from nominally dry to water-saturated conditions, causing a range of oxygen fugacities varying by ~3 log units per series. The range in oxygen fugacity investigated spans ~7 log units. Systematic effects of oxygen fugacity on the stability and composition of the mafic silicate phases, Cr-spinel and Fe-Ti oxides, under varying water contents were recorded. The Mg# of the melt, and therefore also the Mg# of olivine and clinopyroxene, changed systematically as a function of oxygen fugacity. An example of the link between oxygen fugacity and water activity under hydrogen-buffered conditions is the change in the crystallization sequence (olivine and Cr-spinel) due to a change in the oxygen fugacity caused by an increase in the water activity. The stability of magnetite is restricted to highly oxidizing conditions. The absence of magnetite in most of the experiments allows the determination of differentiation trends as a function of oxygen fugacity and water content, demonstrating that in an oxide-free crystallization sequence, water systematically affects the differentiation trend, while oxygen fugacity seems to have a negligible effect. © 2010 Springer-Verlag

Partial melting experiments on oceanic cumulated gabbros

We performed hydrous partial melting experiments at shallow pressures (0.2 GPa) under slightly oxidizing conditions (NNO oxygen buffer) on oceanic cumulate gabbros drilled by ODP (Ocean Drilling Program) cruises to evaluate whether the partial melting of oceanic gabbro can generate SiO2-rich melts with compositions typical of oceanic plagiogranites. The experimental melts of the low-temperature runs broadly overlap those of natural plagiogranites. At 940 °C, the normalized SiO2 contents of the experimental melts of all systems range between 60 and 61 wt%, and at 900 °C between 63 and 68 wt%. These liquids are characterized by low TiO2 and FeOtot contents, similar to those of natural plagiogranites from the plutonic section of the oceanic crust, but in contrast to Fe and Ti-rich low-temperature experimental melts obtained in MORB systems at ~950 °C. The ~1,500-m-long drilled gabbroic section of ODP Hole 735B (Legs 118 and 176) at the Southwest Indian Ridge contains numerous small plagiogranitic veins often associated with zones which are characterized by high-temperature shearing. The compositions of the experimental melts obtained at low temperatures match those of the natural plagiogranitic veins, while the compositions of the crystals of low-temperature runs correspond to those of minerals from high-temperature microscopic veins occurring in the gabbroic section of the Hole 735B. This suggests that the observed plagiogranitic veins are products of a partial melting process triggered by a water-rich fluid phase. If the temperature estimations for hightemperature shear zones are correct (up to 1,000 °C), and a water-rich fluid phase is present, the formation of plagiogranites by partial melting of gabbros is probably a widespread phenomenon in the genesis of the ocean crust