β-cell dysfunctional ERAD/ubiquitin/proteasome system in type 2 diabetes mediated by islet amyloid polypeptide-induced UCH-L1 deficiency.

ObjectiveThe islet in type 2 diabetes is characterized by β-cell apoptosis, β-cell endoplasmic reticulum stress, and islet amyloid deposits derived from islet amyloid polypeptide (IAPP). Toxic oligomers of IAPP form intracellularly in β-cells in humans with type 2 diabetes, suggesting impaired clearance of misfolded proteins. In this study, we investigated whether human-IAPP (h-IAPP) disrupts the endoplasmic reticulum-associated degradation/ubiquitin/proteasome system.Research design and methodsWe used pancreatic tissue from humans with and without type 2 diabetes, isolated islets from h-IAPP transgenic rats, isolated human islets, and INS 832/13 cells transduced with adenoviruses expressing either h-IAPP or a comparable expression of rodent-IAPP. Immunofluorescence and Western blotting were used to detect polyubiquitinated proteins and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) protein levels. Proteasome activity was measured in isolated rat and human islets. UCH-L1 was knocked down by small-interfering RNA in INS 832/13 cells and apoptosis was evaluated.ResultsWe report accumulation of polyubiquinated proteins and UCH-L1 deficiency in β-cells of humans with type 2 diabetes. These findings were reproduced by expression of oligomeric h-IAPP but not soluble rat-IAPP. Downregulation of UCH-L1 expression and activity to reproduce that caused by h-IAPP in β-cells induced endoplasmic reticulum stress leading to apoptosis.ConclusionsOur results indicate that defective protein degradation in β-cells in type 2 diabetes can, at least in part, be attributed to misfolded h-IAPP leading to UCH-L1 deficiency, which in turn further compromises β-cell viability

(η5-Cyclo­penta­dien­yl){[3-(2,2-dicyano­ethen­yl)bicyclo­[2.2.1]hepta-2,5-dien-2-yl]ethyn­yl}(triphenyl­phosphine)nickel(II)

The title compound, [Ni(C5H5)(C13H7N2)(C18H15P)] or (η5-C5H5)(PPh3)Ni—C C—C7H6—C(H)=C(CN)2, contains an unusual disubstituted norbornadienyl (NBD) ligand containing ethynyl (–C C–) and dicyano­vinyl [–C(H)=C(CN)2] groups. Disorder is present in the NBD group with site occupancies of 0.636 (10) and 0.364 (10) for two distinct orientations. There are no strong hydrogen bonds and the primary inter­actions are weak C—H⋯π(arene) inter­actions

Role of angiopoietin-like protein 3 in sugar-induced dyslipidemia in rhesus macaques: suppression by fish oil or RNAi.

Angiopoietin-like protein 3 (ANGPTL3) inhibits lipid clearance and is a promising target for managing cardiovascular disease. Here we investigated the effects of a high-sugar (high-fructose) diet on circulating ANGPTL3 concentrations in rhesus macaques. Plasma ANGPTL3 concentrations increased ∼30% to 40% after 1 and 3 months of a high-fructose diet (both P < 0.001 vs. baseline). During fructose-induced metabolic dysregulation, plasma ANGPTL3 concentrations were positively correlated with circulating indices of insulin resistance [assessed with fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR)], hypertriglyceridemia, adiposity (assessed as leptin), and systemic inflammation [C-reactive peptide (CRP)] and negatively correlated with plasma levels of the insulin-sensitizing hormone adropin. Multiple regression analyses identified a strong association between circulating APOC3 and ANGPTL3 concentrations. Higher baseline plasma levels of both ANGPTL3 and APOC3 were associated with an increased risk for fructose-induced insulin resistance. Fish oil previously shown to prevent insulin resistance and hypertriglyceridemia in this model prevented increases of ANGPTL3 without affecting systemic inflammation (increased plasma CRP and interleukin-6 concentrations). ANGPTL3 RNAi lowered plasma concentrations of ANGPTL3, triglycerides (TGs), VLDL-C, APOC3, and APOE. These decreases were consistent with a reduced risk of atherosclerosis. In summary, dietary sugar-induced increases of circulating ANGPTL3 concentrations after metabolic dysregulation correlated positively with leptin levels, HOMA-IR, and dyslipidemia. Targeting ANGPTL3 expression with RNAi inhibited dyslipidemia by lowering plasma TGs, VLDL-C, APOC3, and APOE levels in rhesus macaques

The virtual pedagogy initiative

Contemporary Higher Education Institutions must adapt to address government funded calls for expansion and widened participation. The adoption of e-learning strategies, such as the use of the podcasts, can facilitate flexible learning around the needs and expectations of students. In this article we outline a number of e-learning developments at Aston University collectively referred to as the Virtual Pedagogy Initiative. Each of the strands, podcasts, vodcasts, mobile telephony and the campus wide remote broadcasts, are described pedagogically as well as technically. Where possible data highlighting the student response and experience are included. The article begins with the contention that contemporary undergraduates may be qualitatively different and can considered „digital natives?

Physiological Response to Feeding in Little Penguins

© 2006 by The University of Chicago.Specific dynamic action (SDA), the increase in metabolic rate above resting levels that accompanies the processes of digestion and assimilation of food, can form a substantial part of the daily energy budget of free-ranging animals. We measured heart rate (fH) and rate of oxygen consumption ( ) in 12 little penguins while they digested a meal of sardines in order to determine whether they show specific dynamic action. In contrast to some studies of other penguin species, little penguins showed a substantial SDA, the magnitude of which was proportional to the size of the meal. The energy utilized in SDA was equivalent to 13.4% of the available energy content of the fish. Furthermore, animals such as penguins that forage in a cold environment will probably expend further energy in heating their food to body temperature to facilitate efficient digestion. It is estimated that this additional energy expenditure was equivalent to 1.6%-2.3% of the available energy content of the fish, depending on the time of year and therefore the temperature of the water. Changes in fH during digestion were qualitatively similar to those in , implying that there were no substantial circulatory adjustments during digestion and that the relationship between fH and in penguins is unaffected by digestive state

Relationship between pancreatic vesicular monoamine transporter 2 (VMAT2) and insulin expression in human pancreas

Vesicular monoamine transporter 2 (VMAT2) is expressed in pancreatic beta cells and has recently been proposed as a target for measurement of beta cell mass in vivo. We questioned, (1) What proportion of beta cells express VMAT2? (2) Is VMAT2 expressed by other pancreatic endocrine or non-endocrine cells? (3) Is the relationship between VMAT2 and insulin expression disturbed in type 1 (T1DM) or type 2 diabetes (T2DM)? Human pancreas (7 non-diabetics, 5 T2DM, 10 T1DM) was immunostained for insulin, VMAT2 and other pancreatic hormones. Most beta cells expressed VMAT2. VMAT2 expression was not changed by the presence of diabetes. In tail of pancreas VMAT2 immunostaining closely correlated with insulin staining. However, VMAT2 was also expressed in some pancreatic polypeptide (PP) cells. Although VMAT2 was not excluded as a target for beta cell mass measurement, expression of VMAT2 in PP cells predicts residual VMAT2 expression in human pancreas even in the absence of beta cells

Two Jovian-Mass Planets in Earthlike Orbits

We report the discovery of two new planets: a 1.94 M_Jup planet in a 1.8-year orbit of HD 5319, and a 2.51 M_Jup planet in a 1.1-year orbit of HD 75898. The measured eccentricities are 0.12 for HD 5319 b and 0.10 for HD 75898 b, and Markov Chain Monte Carlo simulations based on derived orbital parameters indicate that the radial velocities of both stars are consistent with circular planet orbits. With low eccentricity and 1 < a < 2 AU, our new planets have orbits similar to terrestrial planets in the solar system. The radial velocity residuals of both stars have significant trends, likely arising from substellar or low-mass stellar companions.Comment: 32 pages, including 11 figures and 5 tables. Accepted by Ap

Enhanced effects of combined cognitive bias modification and computerised cognitive behaviour therapy on social anxiety

This study examines whether combined cognitive bias modification for interpretative biases (CBM-I) and computerised cognitive behaviour therapy (C-CBT) can produce enhanced positive effects on interpretation biases and social anxiety. Forty socially anxious students were randomly assigned into two conditions, an intervention group (positive CBM-I + C-CBT) or an active control (neutral CBM-I + C-CBT). At pre-test, participants completed measures of social anxiety, interpretative bias, cognitive distortions, and social and work adjustment. They were exposed to 6 × 30 min sessions of web-based interventions including three sessions of either positive or neutral CBM-I and three sessions of C-CBT, one session per day. At post-test and two-week follow-up, participants completed the baseline measures. A combined positive CBM-I + C-CBT produced less negative interpretations of ambiguous situations than neutral CBM-I + C-CBT. The results also showed that both positive CBM-I + C-CBT and neutral CBM-I + C-CBT reduced social anxiety and cognitive distortions as well as improving work and social adjustment. However, greater effect sizes were observed in the positive CBM-I + C-CBT condition than the control. This indicates that adding positive CBM-I to C-CBT enhanced the training effects on social anxiety, cognitive distortions, and social and work adjustment compared to the neutral CBM-I + C-CBT condition