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Mechanisms coordinating pancreatic β cell metabolism with insulin secretion are essential for glucose homeostasis. One key mechanism of β cell nutrient sensing uses the mitochondrial GTP (mtGTP) cycle. In this cycle, mtGTP synthesized by succinyl-CoA synthetase (SCS) is hydrolyzed via mitochondrial PEPCK (PEPCK-M) to make phosphoenolpyruvate, a high-energy metabolite that integrates TCA cycling and anaplerosis with glucose-stimulated insulin secretion (GSIS). Several strategies, including xenotopic overexpression of yeast mitochondrial GTP/GDP exchanger (GGC1) and human ATP and GTP-specific SCS isoforms, demonstrated the importance of the mtGTP cycle. These studies confirmed that mtGTP triggers and amplifies normal GSIS and rescues defects in GSIS both in vitro and in vivo. Increased mtGTP synthesis enhanced calcium oscillations during GSIS. mtGTP also augmented mitochondrial mass, increased insulin granule number, and membrane proximity without triggering de-differentiation or metabolic fragility. These data highlight the importance of the mtGTP signal in nutrient sensing, insulin secretion, mitochondrial maintenance, and β cell health.

Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes.sup.1-3, the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation--all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment--reversing hepatic steatosis and glucose intolerance--were abrogated in Insp3r1 (also known as Itpr1)-knockout mice. These results provide insights into glucagon biology and suggest that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type-2 diabetes. A role and mechanism of action are identified for INSP3R1 in the stimulation of hepatic gluconeogenesis and mitochondrial oxidation by glucagon, suggesting that INSP3R1 may be a target for ameliorating dysregulation of hepatic glucose metabolism., Author(s): Rachel J. Perry [sup.1] [sup.2] , Dongyan Zhang [sup.1] , Mateus T. Guerra [sup.1] , Allison L. Brill [sup.2] , Leigh Goedeke [sup.1] , Ali R. Nasiri [sup.1] , [...]

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D), but whether NAFLD plays a causal role in the pathogenesis of T2D is uncertain. One proposed mechanism linking NAFLD to hepatic insulin resistance involves diacylglycerol-mediated (DAG-mediated) activation of protein kinase C-ζ (PKCζ) and the consequent inhibition of insulin receptor (INSR) kinase activity. However, the molecular mechanism underlying PKCζinhibition of INSR kinase activity is unknown. Here, we used mass spectrometry to identify the phosphorylation site [Thr.sup.1160] as a PKCζ substrate in the functionally critical INSR kinase activation loop. We hypothesized that [Thr.sup.1160] phosphorylation impairs INSR kinase activity by destabilizing the active configuration of the INSR kinase, and our results confirmed this prediction by demonstrating severely impaired INSR kinase activity in phosphomimetic T1160E mutants. Conversely, the INSR T1160A mutant was not inhibited by PKCζ in vitro. Furthermore, mice with a threonine-to-alanine mutation at the homologous residue [Thr.sup.1150] ([Insr.sup.T1150A] mice) were protected from high fat diet-induced hepatic insulin resistance. InsrTm0A mice also displayed increased insulin signaling, suppression of hepatic glucose production, and increased hepatic glycogen synthesis compared with WT controls during hyperinsulinemic clamp studies. These data reveal a critical pathophysiological role for INSR [Thr.sup.1160] phosphorylation and provide further mechanistic links between PKCζ and INSR in mediating NAFLD-induced hepatic insulin resistance., Introduction Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized nations (1). NAFLD is observed in nearly 100% of obese people with type 2 diabetes (T2D) [...]

Due to the lack of magnets and suitable final price, Synchronous Reluctance Motors (SynRMs) are potential candidates for household electric appliances and so on. However, in general, they have a major drawback, i.e., high torque ripple. The optimized design of a synchronous reluctance rotor structure is presented for two different types of barrier shape with the aim of reducing the torque ripple and increasing the average torque. In this paper, optimization of rotor geometries with a fixed machine size for two types of C-shaped and circular barriers is investigated. Most of the rotor parameters such as the width of the iron parts as well as the width of the barriers along d and q axes are optimized by a new method using the Particle Swarm Optimization (PSO) algorithm. In addition, the angle of the end points for each barrier with constant rib and insulation factor are considered in the optimization process. Minimizing the torque ripple without losing or even increasing the average torque is the most critical optimization achievement. Two prototypes of the optimized rotor with the C-shaped and circular barriers were fabricated and experimentally compared. The results obtained from the 2D finite element simulation of the recommended machine conformed well to the experimental result. [ABSTRACT FROM AUTHOR]

"nBackground: Acute pyelonephritis may lead to permanent renal scarring. The standard recommendation for treatment of febrile children with urinary tract infection (UTI) is hospitalization for intravenous antibiotics. The purpose of this study was to compare the efficacy of outpatient intravenous ceftriaxone and cefixime versus inpatient of the same regimen for children with febrile UTI. "nMethods: In a randomized clinical trial, we compared the efficacy of administration two days intravenous ceftriaxone followed by an oral cefixime for eight days (as outpatient group) versus four days intravenous ceftriaxone followed by an oral cefixime for six days (as inpatient group), in 203 children (99 cases in outpatient group and 104 cases in inpatient group) 3 months to 15 years of age with febrile UTI, in terms of short-term clinical outcomes (sterilization of the urine and defeverescence) and long-term morbidity (incidence of reinfection and renal scarring documented by DMSA scintigraphy. "nResults: Repeat urine cultures were sterile within 48 hours in all children, mean time to defeverescence was 27.58 (SD=±12.62) and 31.44 (SD=±17.06) hours for children in outpatient and inpatient groups, respectively (P=0.067). Reinfection occurred in 9.1% of outpatient and 13.4% of inpatient group (P=0.326). Renal scarring developed in 11% of children of outpatient and 7.6% of children of inpatient group (P=0.884). There was no significant difference between the two groups in respect of renal scarring. "nConclusions: Outpatient ceftriaxone for two days followed by cefixime to complete a 10 days course can be recommended as a safe and effective treatment for children with febrile UTI.

This study proposes a special topology of transvers flux permanent magnet generator, which benefits from low Permanent Magnet (PM) costs due to use of cheap Ferrite PMs. In this structure, only one PM per phase is used to ensure easy manufacturing. Despite the above-mentioned advantages of the topology, it is subject to some disadvantages such as unbalanced voltage, high demagnetization risk of the PM, and high cogging torque. Aiming to solve these problems and maintaining the advantages of the topology, a new structure is proposed. The stator of this structure contains two series connected coils that eliminate all the even-order harmonics and balance the voltage waveform. This trick reduces the armature reaction as well as demagnetization of the PMs significantly. Moreover, the rotor teeth of the proposed structure are skewed, causing a significant reduction in cogging torque. The output results of the proposed structure are compared with those of the original one in terms of harmonic components, cogging torque profile, and PM demagnetisation. [ABSTRACT FROM AUTHOR]

High temperature is one of the main environmental factors causing economic losses to the poultry industry, as it reduces growth and production performance of chickens. The heat shock proteins (HSPs) play a key role in cellular defense mechanisms during exposure in a hot environment. The aim of this study was to evaluate the expression level of the candidate genes in the liver of Khorasan native chickens under acute heat stress. Sixteen 42 days old chickens were divided into two groups; the control (25 °C and 50% humidity) and heat-treated (42 °C and 50% humidity), and then the liver was sampled. The level of gene expression of HSPB1, HSPB9, SERPINH1, HSPA2 and HSP110 were evaluated using the reverse transcriptionquantitative polymerase chain reaction (RT-qPCR) method. The results of the analysis of variance revealed that the expression of HSPA2 and HSP110 was significantly increased. In the biological processes of gene ontology, three processes had FDR < 0.01. HSPA2 and HSPB1 involved in the processes that stimulated cells against increasing temperature. The results indicated that Khorasan native chickens have suitable resistance to acute heat stress. Furthermore, HSPA2 has the ability to express under high ambient temperature in order to protect the structure of cellular proteins. [ABSTRACT FROM AUTHOR]

The purification, reconstitution into proteoliposomes and functional characterization of the diheme-containing succinate:menaquinone reductase from the Gram-positive bacterium Bacillus licheniformis is described. The design, synthesis and characterization of quinones with finely tuned oxidation/reduction potentials have provided evidence for [DELTA]p (transmembrane electrochemical proton potential)-dependent catalysis of succinate oxidation by quinone as well as for [DELTA]p generation upon catalysis of fumarate reduction by quinol.