Cardiac-specific Conditional Knockout of the 18-kDa Mitochondrial Translocator Protein Protects from Pressure Overload Induced Heart Failure.

Heart failure (HF) is characterized by abnormal mitochondrial calcium (Ca2+) handling, energy failure and impaired mitophagy resulting in contractile dysfunction and myocyte death. We have previously shown that the 18-kDa mitochondrial translocator protein of the outer mitochondrial membrane (TSPO) can modulate mitochondrial Ca2+ uptake. Experiments were designed to test the role of the TSPO in a murine pressure-overload model of HF induced by transverse aortic constriction (TAC). Conditional, cardiac-specific TSPO knockout (KO) mice were generated using the Cre-loxP system. TSPO-KO and wild-type (WT) mice underwent TAC for 8 weeks. TAC-induced HF significantly increased TSPO expression in WT mice, associated with a marked reduction in systolic function, mitochondrial Ca2+ uptake, complex I activity and energetics. In contrast, TSPO-KO mice undergoing TAC had preserved ejection fraction, and exhibited fewer clinical signs of HF and fibrosis. Mitochondrial Ca2+ uptake and energetics were restored in TSPO KO mice, associated with decreased ROS, improved complex I activity and preserved mitophagy. Thus, HF increases TSPO expression, while preventing this increase limits the progression of HF, preserves ATP production and decreases oxidative stress, thereby preventing metabolic failure. These findings suggest that pharmacological interventions directed at TSPO may provide novel therapeutics to prevent or treat HF

Efficacy and Safety of Ertugliflozin in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular Disease Treated With Metformin and Sulfonylurea

Abstract Introduction: Ertugliflozin (ERTU), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is approved as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM). Aim: As a pre-specified sub-study of the Phase 3 VERTIS CV trial (NCT01986881), the efficacy and safety of ERTU were assessed in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) inadequately controlled with metformin and sulfonylurea (SU). Methods: Patients with T2DM, established ASCVD, and HbA1c 7.0–10.5% on stable metformin (≥1500 mg/day) and SU doses as defined per protocol were randomized to once-daily ERTU (5 mg or 15 mg) or placebo. The primary sub-study objectives were to assess the effect of ERTU on HbA1c compared with placebo and to evaluate safety and tolerability during 18-week follow-up. Key secondary endpoints included proportion of patients achieving HbA1c <7%, fasting plasma glucose (FPG), body weight, and systolic blood pressure. Changes from baseline at Week 18 for continuous efficacy endpoints were assessed using a constrained longitudinal data analysis model. Results: Of the 8246 patients enrolled in the VERTIS CV trial, 330 patients were eligible for this sub-study (ERTU 5 mg, n=100; ERTU 15 mg, n=113; placebo, n=117). Patients had a mean (SD) age of 63.2 (8.4) years, T2DM duration 11.4 (7.4) years, estimated glomerular filtration rate 83.5 (17.8) mL/min/1.73 m2, and HbA1c 8.3% (1.0) (67.4 [10.6] mmol/mol). At Week 18, ERTU 5 mg and 15 mg were each associated with a significantly greater least squares mean (95% CI) HbA1c reduction from baseline versus placebo; the placebo-adjusted differences for ERTU 5 mg and 15 mg were –0.7% (–0.9, –0.4) and –0.8% (–1.0, –0.5), respectively (P<0.001). A higher proportion of patients in each ERTU group achieved HbA1c <7% relative to placebo (P<0.001). ERTU significantly reduced FPG and body weight (P<0.001, for each dose versus placebo), but not systolic blood pressure. Adverse events were reported in 48.0%, 54.9%, and 47.0% of patients in the ERTU 5 mg, 15 mg, and placebo groups, respectively. Genital mycotic infections were experienced by significantly higher proportions of male patients who received ERTU 5 mg and 15 mg (4.2% and 4.8%, respectively) versus placebo (0.0%; P≤0.05) and by a numerically, but not significantly, higher proportion of female patients who received ERTU 15 mg (10.3%) compared with placebo (3.8%) (P=0.36). The incidences of symptomatic hypoglycemia were 11.0% (5 mg), 12.4% (15 mg), and 7.7% (placebo), and of severe hypoglycemia 2.0% (5 mg), 1.8% (15 mg), and 0.9% (placebo). Conclusion: Among patients with T2DM and ASCVD, ERTU (5 mg and 15 mg) added to metformin and SU for 18 weeks improved glycemic control (HbA1c and FPG) and reduced body weight, and was generally well tolerated with a safety profile consistent with the SGLT2 inhibitor class

Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice

Obesity is closely associated with the metabolic syndrome, a combination of disorders including insulin resistance, diabetes, dyslipidemia, and hypertension. A role for local glucocorticoid reamplification in obesity and the metabolic syndrome has been suggested. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active cortisol from inactive 11-keto forms, and aP2-HSD1 mice with relative transgenic overexpression of this enzyme in fat cells develop visceral obesity with insulin resistance and dyslipidemia. Here we report that aP2-HSD1 mice also have high arterial blood pressure (BP). The mice have increased sensitivity to dietary salt and increased plasma levels of angiotensinogen, angiotensin II, and aldosterone. This hypertension is abolished by selective angiotensin II receptor AT-1 antagonist at a low dose that does not affect BP in non-Tg littermates. These findings suggest that activation of the circulating renin-angiotensin system (RAS) develops in aP2-HSD1 mice. The long-term hypertension is further reflected by an appreciable hypertrophy and hyperplasia of the distal tubule epithelium of the nephron, resembling salt-sensitive or angiotensin II–mediated hypertension. Taken together, our findings suggest that overexpression of 11β-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS. The potential role of adipose 11β-HSD1 in mediating critical features of the metabolic syndrome extends beyond obesity and metabolic complications to include the most central cardiovascular feature of this disorder

Egg development, hatching rhythm and moult patterns in Paralomos spinosissima (Decapoda: Anomura: Paguroidea: Lithodidae) from South Georgia waters (Southern Ocean)

Larval release, hatching rhythms and moult patterns were examined in a captive population of the subantarctic lithodid, Paralomis spinosissima from the South Georgia and Shag Rocks region. Larvae hatched throughout the year with the majority of females starting to release larvae at the end of the austral summer and beginning of autumn. Larval release continued over a period of up to 9 weeks with high variability in the numbers that hatched each day. A similar seasonal pattern to hatching was evident in the moulting of females. Intermoult period for two adult females (CL = 63 and 85 mm) ranged from 894 to 1,120 days while an intermoult period for males was estimated to be in excess of 832 days. The results are consistent with other species of Paralomis and are discussed in relation to physiological and environmental adaptations to the cold-water conditions south of the Antarctic Convergence

Who Invited You? The Complex Story Of Aquatic Invasive Species

Invasive species represent a global threat to ecosystems, human health, and the economy. A basic knowledge of invasive species biology is crucial to understand current and future impacts and implications. The purpose of this book is to provide a broad background on invasive species, and also details on specific examples through case studies. The students in the course Aquatic Invasive Species (MAR 442) at the University of New England in Biddeford, Maine, have researched and reviewed scientific literature to educate readers about these issues. The class, comprised of fifteen junior and senior Marine Science, Marine Affairs, Animal Behavior, and Environmental Sciences students, selected the different topics, presented the material, wrote the chapters, and assembled the final versions into this book. This book cannot be all inclusive, but we think this book will provide an excellent broad overview of the most important aspects of Invasive Species Biology and might stimulate the reader to dive deeper into the material.https://dune.une.edu/marinesci_studproj/1003/thumbnail.jp

Forced Convection Heat Transfer from a Finite-Height Cylinder

[EN] This paper presents a large eddy simulation of forced convection heat transfer in the flow around a surface-mounted finite-height circular cylinder. The study was carried out for a cylinder with height-to-diameter ratio of 2.5, a Reynolds number based on the cylinder diameter of 44 000 and a Prandtl number of 1. Only the surface of the cylinder is heated while the bottom wall and the inflow are kept at a lower fixed temperature. The approach flow boundary layer had a thickness of about 10% of the cylinder height. Local and averaged heat transfer coefficients are presented. The heat transfer coefficient is strongly affected by the free-end of the cylinder. As a result of the flow over the top being downwashed behind the cylinder, a vortex-shedding process does not occur in the upper part, leading to a lower value of the local heat transfer coefficient in that region. In the lower region, vortex-shedding takes place leading to higher values of the local heat transfer coefficient. The circumferentially averaged heat transfer coefficient is 20 % higher near the ground than near the top of the cylinder. The spreading and dilution of the mean temperature field in the wake of the cylinder are also discussed.The simulation was carried out using the supercomputing facilities of the Steinbuch Centre for Computing (SCC) of the Karlsruhe Institute of Technology. MGV has been partially supported by grant TRA2012-37714 of the Spanish Ministry of Economy and Competitiveness.García Villalba, M.; Palau-Salvador, G.; Rodi, W. (2014). Forced Convection Heat Transfer from a Finite-Height Cylinder. Flow, Turbulence and Combustion. 93(1):171-187. https://doi.org/10.1007/s10494-014-9543-7S171187931Ames, F., Dvorak, L.: Turbulent transport in pin fin arrays: experimental data and predictions. J. Turbomach. 128(1), 71–81 (2006)Armstrong, J., Winstanley, D.: A review of staggered array pin fin heat transfer for turbine cooling applications. J. 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Mammalian Comparative Sequence Analysis of the Agrp Locus

Agouti-related protein encodes a neuropeptide that stimulates food intake. Agrp expression in the brain is restricted to neurons in the arcuate nucleus of the hypothalamus and is elevated by states of negative energy balance. The molecular mechanisms underlying Agrp regulation, however, remain poorly defined. Using a combination of transgenic and comparative sequence analysis, we have previously identified a 760 bp conserved region upstream of Agrp which contains STAT binding elements that participate in Agrp transcriptional regulation. In this study, we attempt to improve the specificity for detecting conserved elements in this region by comparing genomic sequences from 10 mammalian species. Our analysis reveals a symmetrical organization of conserved sequences upstream of Agrp, which cluster into two inverted repeat elements. Conserved sequences within these elements suggest a role for homeodomain proteins in the regulation of Agrp and provide additional targets for functional evaluation