High-field vortices in Josephson junctions with alternating critical current density

We study long Josephson junctions with the critical current density alternating along the junction. New equilibrium states, which we call the field synchronized or FS states, are shown to exist if the applied field is from narrow intervals centered around equidistant series of resonant fields, $H_m$. The values of $H_m$ are much higher than the flux penetration field, $H_s$. The flux per period of the alternating critical current density, $\phi_i$, is fixed for each of the FS states. In the $m$-th FS state the value of $\phi_i$ is equal to an integer amount of flux quanta, $\phi_i =m\phi_0$. Two types of single Josephson vortices carrying fluxes $\phi_0$ or/and $\phi_0/2$ can exist in the FS states. Specific stepwise resonances in the current-voltage characteristics are caused by periodic motion of these vortices between the edges of the junction.Comment: 4 pages, 5 figure

Maximum supercurrent in Josephson junctions with alternating critical current density

We consider theoretically and numerically magnetic field dependencies of the maximum supercurrent across Josephson tunnel junctions with spatially alternating critical current density. We find that two flux-penetration fields and one-splinter-vortex equilibrium state exist in long junctions.Comment: 11 pages, 8 figure

CYP-450 Epoxygenase Derived Epoxyeicosatrienoic Acid Contribute To Reversal of Heart Failure in Obesity-Induced Diabetic Cardiomyopathy via PGC-1 alpha Activation

We have previously shown that an Epoxyeicosatrienoic Acid (EET) -agonist has pleiotropic effects and reverses cardiomyopathy by decreasing inflammatory molecules and increasing antioxidant signaling. We hypothesized that administration of an EET agonist would increase Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha), which controls mitochondrial function and induction of HO-1 and negatively regulates the expression of the proinflammatory adipokines CCN3/NOV in cardiac and pericardial tissues. This pathway would be expected to further improve left ventricular (LV) systolic function as well as increase insulin receptor phosphorylation. Measurement of the effect of an EET agonist on oxygen consumption, fractional shortening, blood glucose levels, thermogenic and mitochondrial signaling proteins was performed. Control obese mice developed signs of metabolic syndrome including insulin resistance, hypertension, inflammation, LV dysfunction, and increased NOV expression in pericardial adipose tissue. EET agonist intervention decreased pericardial adipose tissue expression of NOV, while normalized FS, increased PGC-1alpha, HO-1 levels, insulin receptor phosphorylation and improved mitochondrial function, theses beneficial effect were reversed by deletion of PGC-1alpha. These studies demonstrate that an EET agonist increases insulin receptor phosphorylation, mitochondrial and thermogenic gene expression, decreased cardiac and pericardial tissue NOV levels, and ameliorates cardiomyopathy in an obese mouse model of the metabolic syndrome

Regulation of Diabetic Cardiomyopathy by Caloric Restriction is Mediated by Intracellular Signaling Pathways Involving \u27SIRT1 and PGC-1alpha\u27

BACKGROUND: Metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus (DM2) are all linked to diabetic cardiomyopathy that lead to heart failure. Cardiomyopathy is initially characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and fibrosis, both of which are aggravated by angiotensin. Caloric restriction (CR) is cardioprotective in animal models of heart disease through its catabolic activity and activation of the expression of adaptive genes. We hypothesized that in the diabetic heart; this effect involves antioxidant defenses and is mediated by SIRT1 and the transcriptional coactivator PGC-1alpha (Peroxisome proliferator-activated receptor-gamma coactivator). METHODS: Obese Leptin resistant (db/db) mice characterized by DM2 were treated with angiotensin II (AT) for 4 weeks to enhance the development of cardiomyopathy. Mice were concomitantly either on a CR diet or fed ad libitum. Cardiomyocytes were exposed to high levels of glucose and were treated with EX-527 (SIRT1 inhibitor). Cardiac structure and function, gene and protein expression and oxidative stress parameters were analyzed. RESULTS: AT treated db/db mice developed cardiomyopathy manifested by elevated levels of serum glucose, cholesterol and cardiac hypertrophy. Leukocyte infiltration, fibrosis and an increase in an inflammatory marker (TNFalpha) and natriuretic peptides (ANP, BNP) gene expression were also observed. Oxidative stress was manifested by low SOD and PGC-1alpha levels and an increase in ROS and MDA. DM2 resulted in ERK1/2 activation. CR attenuated all these deleterious perturbations and prevented the development of cardiomyopathy. ERK1/2 phosphorylation was reduced in CR mice (p = 0.008). Concomitantly CR prevented the reduction in SIRT activity and PGC-1alpha (p \u3c 0.04). Inhibition of SIRT1 activity in cardiomyocytes led to a marked reduction in both SIRT1 and PGC-1alpha. ROS levels were significantly (p \u3c 0.03) increased by glucose and SIRT1 inhibition. CONCLUSION: In the current study we present evidence of the cardioprotective effects of CR operating through SIRT1 and PGC-1 alpha, thereby decreasing oxidative stress, fibrosis and inflammation. Our results suggest that increasing SIRT1 and PGC-1alpha levels offer new therapeutic approaches for the protection of the diabetic heart

Monoamines, BDNF, Dehydroepiandrosterone, DHEA-Sulfate, and Childhood Depression—An Animal Model Study

Basal levels of monoamines and DHEA in four main limbic brain regions were measured in prepubertal Wistar Kyoto (WKY) rats (a putative animal model of childhood depression). Basal levels of “Brain-Derived Neurotrophic Factor (BDNF)” were also determined in two regions in the hippocampus, compared with Wistar strain controls. In the second phase, we examined the responsiveness of prepubertal WKY rats to different types of chronic antidepressant treatments: Fluoxetine, Desipramine, and dehydroepiandrosterone sulfate (DHEAS). WKY prepubertal rats exhibited different monoamine levels in the limbic system, reduced DHEA levels in the VTA and lower levels of BDNF in the hippocampus CA3 region compared to controls. In prepubertal WKY rats, only treatment with DHEAS produced a statistically significant decrease in immobility, compared to saline-administered controls in the forced swim test. Wistar controls were not affected by any antidepressant. The results imply that DHEA(S) and BDNF may be involved in the pathophysiology and pharmacotherapy of childhood depression

Epoxyeicosatrienoic acids regulate adipocyte differentiation of mouse 3T3 cells, via PGC-1α activation, which is required for HO-1 expression and increased mitochondrial function

Epoxyeicosatrienoic acid (EET) contributes to browning of white adipose stem cells to ameliorate obesity/diabetes and insulin resistance. In the current study, we show that EET altered preadipocyte function, enhanced peroxisome proliferation-activated receptor γ coactivator α (PGC-1α) expression, and increased mitochondrial function in the 3T3-L1 preadipocyte subjected to adipogenesis. Cells treated with EET resulted in an increase, P \u3c 0.05, in PGC-1α and a decrease in mitochondria-derived ROS (MitoSox), P \u3c 0.05. The EET increase in heme oxygenase-1 (HO-1) levels is dependent on activation of PGC-1α as cells deficient in PGC-1α (PGC-1α knockout adipocyte cell) have an impaired ability to express HO-1, P \u3c 0.02. Additionally, adipocytes treated with EET exhibited an increase in mitochondrial superoxide dismutase (SOD) in a PGC-1α-dependent manner, P \u3c 0.05. The increase in PGC-1α was associated with an increase in β-catenin, P \u3c 0.05, adiponectin expression, P \u3c 0.05, and lipid accumulation, P \u3c 0.02. EET decreased heme levels and mitochondria-derived ROS (MitoSox), P \u3c 0.05, compared to adipocytes that were untreated. EET also decreased mesoderm-specific transcript (MEST) mRNA and protein levels (P \u3c 0.05). Adipocyte secretion of EET act in an autocrine/paracrine manner to increase PGC-1α is required for activation of HO-1 expression. This is the first study to dissect the mechanism by which the antiadipogenic and anti-inflammatory lipid, EET, induces the PGC-1α signaling cascade and reprograms the adipocyte phenotype by regulating mitochondrial function and HO-1 expression, leading to an increase in healthy, that is, small, adipocytes and a decrease in adipocyte enlargement and terminal differentiation. This is manifested by an increase in mitochondrial function and an increase in the canonical Wnt signaling cascade during adipocyte proliferation and terminal differentiation