Fatigue failure load indicator

An indicator for recording the load at which a fatigue specimen breaks during the last cycle of a fatigue test is described. A load cell is attached to the specimen which is alternately subjected to tension and compression loads. The output of the load cell which is proportional to the load on the specimen is applied to the input of a peak detector. Each time the specimen is subjected to a compression load, means are provided for applying a positive voltage to the rest of the peak detector to reset it. During the last cycle of the tension load the peak detector measures the maximum load on the specimen. Means are provided for disconnecting the load cell from the peak detector when there is a failure in the specimen

Novel Omega-3 Fatty Acid Epoxygenase Metabolite Reduces Kidney Fibrosis.

Cytochrome P450 (CYP) monooxygenases epoxidize the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid into novel epoxydocosapentaenoic acids (EDPs) that have multiple biological actions. The present study determined the ability of the most abundant EDP regioisomer, 19,20-EDP to reduce kidney injury in an experimental unilateral ureteral obstruction (UUO) renal fibrosis mouse model. Mice with UUO developed kidney tubular injury and interstitial fibrosis. UUO mice had elevated kidney hydroxyproline content and five-times greater collagen positive fibrotic area than sham control mice. 19,20-EDP treatment to UUO mice for 10 days reduced renal fibrosis with a 40%-50% reduction in collagen positive area and hydroxyproline content. There was a six-fold increase in kidney α-smooth muscle actin (α-SMA) positive area in UUO mice compared to sham control mice, and 19,20-EDP treatment to UUO mice decreased α-SMA immunopositive area by 60%. UUO mice demonstrated renal epithelial-to-mesenchymal transition (EMT) with reduced expression of the epithelial marker E-cadherin and elevated expression of multiple mesenchymal markers (FSP-1, α-SMA, and desmin). Interestingly, 19,20-EDP treatment reduced renal EMT in UUO by decreasing mesenchymal and increasing epithelial marker expression. Overall, we demonstrate that a novel omega-3 fatty acid metabolite 19,20-EDP, prevents UUO-induced renal fibrosis in mice by reducing renal EMT

The reaction 2H(p,pp)n in three kinematical configurations at E_p = 16 MeV

We measured the cross sections of the $^2$H(p,pp)n breakup reaction at E$_p$=16 MeV in three kinematical configurations: the np final-state interaction (FSI), the co-planar star (CST), and an intermediate-star (IST) geometry. The cross sections are compared with theoretical predictions based on the CD Bonn potential alone and combined with the updated 2$\pi$-exchange Tucson-Melbourne three-nucleon force (TM99'), calculated without inclusion of the Coulomb interaction. The resulting excellent agreement between data and pure CD Bonn predictions in the FSI testifies to the smallness of three-nucleon force (3NF) effects as well as the insignificance of the Coulomb force for this particular configuration and energy. The CST also agrees well whereas the IST results show small deviations between measurements and theory seen before in the pd breakup space-star geometries which point to possible Coulomb effects. An additional comparison with EFT predictions (without 3NF) up to order N$^3$LO shows excellent agreement in the FSI case and a rather similar agreement as for CD Bonn in the CST and IST situations.Comment: 20 pages, 11 figure

Cytochrome P450 Epoxygenase-Derived Epoxyeicosatrienoic Acids Contribute to Insulin Sensitivity in Mice and in Humans

Aims/hypothesis: Insulin resistance is frequently associated with hypertension and type 2 diabetes. The P450 arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure and may also improve glucose homeostasis. However, the direct contribution of endogenous EET production on insulin sensitivity has not been previously investigated. In this study we tested the hypothesis that endogenous CYP2C-derived EETs alter insulin sensitivity by analyzing mice lacking Cyp2c44, amajor EET producing enzyme, and by testing the association of plasma EETs with insulin sensitivity in humans.Methods: We assessed insulin sensitivity in wild-type (WT) and Cyp2c44(-/-) mice using hyperinsulinaemic-euglycaemic clamps and isolated skeletal muscles. Insulin secretory function was assessed using hyperglycaemic clamps and isolated islets. Vascular function was tested in isolated-perfused mesenteric vessels. Insulin sensitivity and secretion were assessed in humans using frequently sampled intravenous glucose tolerance tests and plasma EETs were measured by mass spectrometry.Results: Cyp2c44(-/-) mice showed decreased insulin sensitivity compared to WT controls. Although glucose uptake was diminished in Cyp2c44(-/-) mice in vivo, insulin-stimulated glucose uptake was unchanged ex vivo in isolated skeletal muscle. Capillary density was similar but vascular KATP-induced relaxation was impaired in isolated Cyp2c44(-/-) vessels, suggesting that impaired vascular reactivity produces impaired insulin sensitivity in vivo. Similarly, plasma EETs positively correlated with insulin sensitivity in human subjects. Conclusions/Interpretation: CYP2C-derived EETs contribute to insulin sensitivity in mice and in humans. Interventions to increase circulating EETs in humans could provide a novel approach to improve insulin sensitivity and treat hypertension

Regulation of ENaC-Mediated Sodium Reabsorption by Peroxisome Proliferator-Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are members of a steroid hormone receptor superfamily that responds to changes in lipid and glucose homeostasis. Peroxisomal proliferator-activated receptor subtype γ (PPARγ) has received much attention as the target for antidiabetic drugs, as well as its role in responding to endogenous compounds such as prostaglandin J2. However, thiazolidinediones (TZDs), the synthetic agonists of the PPARγ are tightly associated with fluid retention and edema, as potentially serious side effects. The epithelial sodium channel (ENaC) represents the rate limiting step for sodium absorption in the renal collecting duct. Consequently, ENaC is a central effector impacting systemic blood volume and pressure. The role of PPARγ agonists on ENaC activity remains controversial. While PPARγ agonists were shown to stimulate ENaC-mediated renal salt absorption, probably via Serum- and Glucocorticoid-Regulated Kinase 1 (SGK1), other studies reported that PPARγ agonist-induced fluid retention is independent of ENaC activity. The current paper provides new insights into the control and function of ENaC and ENaC-mediated sodium transport as well as several other epithelial channels/transporters by PPARs and particularly PPARγ. The potential contribution of arachidonic acid (AA) metabolites in PPAR-dependent mechanisms is also discussed

Peroxisome proliferator-activated receptors, farnesoid X receptor, and dual modulating drugs in hypertension

Hypertension characterized by an elevated blood pressure is a cardiovascular disease that afflicts greater than one in every three adults worldwide. Nuclear receptors are large superfamily of DNA-binding transcription factors that target genes to regulate metabolic and cardiovascular function. Drugs have been developed for nuclear receptors such as peroxisome proliferator-activated receptors (PPARα and PPARγ) and farnesoid X receptor (FXR). PPARα, PPARγ, and FXR agonists are used clinically to treat lipid disorders and metabolic diseases. Evidence from clinical studies and animal hypertension models have demonstrated that PPARα, PPARγ, and FXR agonism can lower blood pressure and decrease end organ damage which could be useful for the treatment of hypertension in patients with metabolic diseases. Unfortunately, PPAR and FXR agonists have unwanted clinical side effects. There have been recent developments to limit side effects for PPAR and FXR agonists. Combining PPAR and FXR agonism with soluble epoxide hydrolase (sEH) inhibition or Takeda G protein receptor 5 (TGR5) agonism has been demonstrated in preclinical studies to have actions that would decrease clinical side effects. In addition, these dual modulating drugs have been demonstrated in preclinical studies to have blood pressure lowering, anti-fibrotic, and anti-inflammatory actions. There is now an opportunity to thoroughly test these novel dual modulators in animal models of hypertension associated with metabolic diseases. In particular, these newly developed dual modulating PPAR and FXR drugs could be beneficial for the treatment of metabolic diseases, organ fibrosis, and hypertension

"Women's rights, the European Court and Supranational Constitutionalism"

This analysis examines supranational constitutionalism in the European Union. In particular, the study focuses on the role of the European Court of Justice in the creation of women’s rights. I examine the interaction between the Court and member state governments in legal integration, and also the integral role that women’s advocates – both individual activists and groups – have played in the development of EU social provisions. The findings suggest that this litigation dynamic can have the effect of fueling the integration process by creating new rights that may empower social actors and EU organizations, with the ultimate effect of diminishing member state government control over the scope and direction of EU law. This study focuses specifically on gender equality law, yet provides a general framework for examining the case law in subsequent legal domains, with the purpose of providing a more nuanced understanding of supranational governance and constitutionalism

In vivo imaging of systemic transport and elimination of xenobiotics and endogenous molecules in mice

We describe a two-photon microscopy-based method to evaluate the in vivo systemic transport of compounds. This method comprises imaging of the intact liver, kidney and intestine, the main organs responsible for uptake and elimination of xenobiotics and endogenous molecules. The image quality of the acquired movies was sufficient to distinguish subcellular structures like organelles and vesicles. Quantification of the movement of fluorescent dextran and fluorescent cholic acid derivatives in different organs and their sub-compartments over time revealed significant dynamic differences. Calculated half-lives were similar in the capillaries of all investigated organs but differed in the specific sub-compartments, such as parenchymal cells and bile canaliculi of the liver, glomeruli, proximal and distal tubules of the kidney and lymph vessels (lacteals) of the small intestine. Moreover, tools to image immune cells, which can influence transport processes in inflamed tissues, are described. This powerful approach provides new possibilities for the analysis of compound transport in multiple organs and can support physiologically based pharmacokinetic modeling, in order to obtain more precise predictions at the whole body scale

A dual COX-2/sEH inhibitor improves the metabolic profile and reduces kidney injury in Zucker diabetic fatty rat

Cyclooxygenase (COX) and soluble epoxide hydrolase (sEH) inhibitors have therapeutic potential. The present study investigated efficacy of a novel dual acting COX-2/sEH inhibitor, PTUPB in type 2 diabetic Zucker Diabetic Fatty (ZDF) rats. Male ZDF rats were treated with vehicle or PTUPB (10mg/kg/d, i.p.) for 8 weeks. At the end of the 8-week experimental period, ZDF rats were diabetic (fasting blood glucose, 287±45mg/dL) compared to Zucker Diabetic Lean rats (ZDL, 99±6mg/dL), and PTUPB treatment improved glycemic status in ZDF rats (146±6mg/dL). Kidney injury was evident in ZDF compared to ZDL rats with elevated albuminurea (44±4 vs 4±2mg/d) and nephrinurea (496±127 vs 16±4μg/d). Marked renal fibrosis, tubular cast formation and glomerular injury were also present in ZDF compared to ZDL rats. In ZDF rats, PTUPB treatment reduced kidney injury parameters by 30-80% compared to vehicle. The ZDF rats also demonstrated increased inflammation and oxidative stress with elevated levels of urinary monocyte chemoattractant protein-1 excretion (862±300 vs 319±75ng/d), renal macrophage infiltration (53±2 vs 37±4/mm(2)) and kidney malondialdehyde/protein ratio (10±1 vs 5±1μmol/mg). PTUPB treatment decreased these inflammatory and oxidative stress markers in the kidney of ZDF rats by 25-57%. These data demonstrate protective actions of a novel dual acting COX-2/sEH inhibitor on the metabolic abnormalities and kidney function in ZDF rat model of type 2 diabetes