CASC3 promotes transcriptome-wide activation of nonsense-mediated decay by the exon junction complex

The exon junction complex (EJC) is an essential constituent and regulator of spliced messenger ribonucleoprotein particles (mRNPs) in metazoans. As a core component of the EJC, CASC3 was described to be pivotal for EJC-dependent nuclear and cytoplasmic processes. However, recent evidence suggests that CASC3 functions differently from other EJC core proteins. Here, we have established human CASC3 knockout cell lines to elucidate the cellular role of CASC3. In the knockout cells, overall EJC composition and EJC-dependent splicing are unchanged. A transcriptome-wide analysis reveals that hundreds of mRNA isoforms targeted by nonsense-mediated decay (NMD) are upregulated. Mechanistically, recruiting CASC3 to reporter mRNAs by direct tethering or via binding to the EJC stimulates mRNA decay and endonucleolytic cleavage at the termination codon. Building on existing EJC-NMD models, we propose that CASC3 equips the EJC with the persisting ability to communicate with the NMD machinery in the cytoplasm. Collectively, our results characterize CASC3 as a peripheral EJC protein that tailors the transcriptome by promoting the degradation of EJC-dependent NMD substrates

Electric Vehicles in Imperfect Electricity Markets: A German Case Study

We analyze the impacts of a hypothetical fleet of plug-in electric vehicles on the imperfectly competitive German electricity market with a game-theoretic model. Electric vehicles bring both additional demand and additional storage capacity to the market. We determine their effects on prices, welfare, and electricity generation for various cases with different players being in charge of vehicle operations. We find that vehicle loading increases generator profits, but decreases consumer surplus. If excess vehicle batteries can be used for storage, welfare results are reversed: generating firms suffer from the price-smoothing effect of additional storage, whereas consumers benefit despite increasing overall demand. Results however depend on the player being in charge of storage operations, and on battery degradation costs. Strategic players tend to underutilize the storage capacity of the vehicle fleet, which may have negative welfare implications. In contrast, we find a small market power mitigating effect of electric vehicle recharging on oligopolistic generators. Overall, electric vehicles are unlikely to be a relevant source of market power in Germany

Gender and hypertension interact to regulate neuropeptide Y receptor responsiveness

We have compared the interaction between gender and strain (normotensive Wistar Kyoto vs. spontaneously hypertensive rats) in the regulation of cardiovascular and renal Y1 and Y5-receptor-mediated responses to neuropeptide Y. Anaesthetized rats received intravenous infusions of 0.3-10 microg/kg per min neuropeptide Y (45 min each) or vehicle. Enhancements of mean arterial pressure, renovascular resistance, diuresis and natriuresis were measured. Parallel group comparisons were performed on male normotensive, female normotensive, male hypertensive and female hypertensive rats. Gender and strain significantly affected the cardiovascular and renal neuropeptide Y responses. While neuropeptide Y elevated mean arterial pressure and renovascular resistance in all four groups, the extent of the alterations differed up to two- to threefold between genders and/or strains. Neuropeptide Y-induced diuresis and natriuresis were similar in male and female normotensive rats, desensitized in male but augmented in female hypertensive rats. We conclude that previously reported cardiovascular and renal neuropeptide Y responses are regulated by gender and the presence of hypertension. However, at least for renal function alterations in female hypertensive vs. male normotensive rats cannot be predicted from those in male hypertensive and female normotensive rat

Di(2-ethylhexyl)phthalate alters carbohydrate enzyme activities and foci incidence in rat liver.

The effect of di(2-ethylhexyl)phthalate (DEHP) on diethylnitrosamine (DEN)-initiated preneoplastic liver lesions with expression of gamma-glutamyltranspeptidase (GGTase) and loss of adenosine triphosphatase (ATPase) as well as alterations of hepatic carbohydrate metabolism in male and female Sprague-Dawley rats have been investigated. Two treatment schedules have been compared with respect to their sensitivity by the histochemical demonstration of preneoplastic islands and by the biochemical determination of alterations in enzyme activities of liver homogenates and of serum, the last indicating hepatotoxicity. For initiation, a single dose of DEN was given, followed by treatment with various doses of DEHP given three times weekly by gavage for 7 or 11 consecutive weeks. As histochemical enzyme markers, the expression of positive GGTase as well as the deficiency in ATPase were used for identification of liver foci. The weanling female rats (protocol A) were found to be more sensitive to the carcinogenic effect of DEN in view of foci incidence than the mature male rats which underwent partial hepatectomy prior to DEN application. The administration of 200 mg DEHP/kg body wt increased the incidence of ATPase-deficient foci in both male and female rats; however, concentrations of 1000 and 2000 mg DEHP/kg decreased the incidence of liver foci. The number of foci with expression of GGTase was only slightly increased in female rats following a DEHP concentration of 50 mg/kg, and 200 mg/kg body wt. DEHP alone did not induce preneoplastic lesions that could be identified by these two markers. Biochemical investigations indicate that DEHP alters the metabolic pattern in liver. An increase of the NADP-linked enzymes glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme, extra-mitochondrial ICDH as well as an enhancement of NAD-dependent α-G3PDH and lactate dehydrogenase were found following DEHP administration. On the other hand the glycolytic enzymes pyruvate kinase (PK) and enolase as well as the gluconeogenetic enzyme fructose-1,6-bisphosphatase (FBPase) were significantly reduced. In protocol B (male rats) the reactions of PK, FBPase and malic enzyme were more altered after DEHP exposure than in protocol A, while the activity of G6PDH was more increased in protocol A. Most enzymes being involved in the carbohydrate metabolism are influenced by DEHP in a dose-dependent manner. There was no increase in serum FBPase activity in both male and female rats after DEHP treatment but a reduction of glutamate-oxalate-transaminase and glutamate-pyruvate-transaminase activities was observed. This and the fact that the control and DEHP-treated animals had similar weight gains indicate that DEHP does not exert a significant hepatotoxicity effect

Fibre supplementation for the prevention of type 2 diabetes and improvement of glucose metabolism: The randomised controlled Optimal Fibre Trial (OptiFiT).

Insoluble cereal fibres have been shown in large prospective cohort studies to be highly effective in preventing type 2 diabetes, but there is a lack of interventional data. Our 2 year randomised double-blind prospective intervention study compared the effect of an insoluble oat fibre extract with that of placebo on glucose metabolism and incidence of diabetes. METHODS: A total of 180 participants with impaired glucose tolerance underwent a modified version of the 1 year lifestyle training programme PREvention of DIAbetes Self-management (PREDIAS) and were randomised to receive a fibre supplement (n = 89; 7.5 g of insoluble fibre per serving) or placebo (n = 91; 0.8 g of insoluble fibre per serving) twice daily for 2 years. Eligible participants were men and women, were at least 18 years old and did not report corticosteroid or other intensive anti-inflammatory treatment, fibre intolerance or any of the following disorders: overt diabetes, chronic or malignant disease, or severe cardiopulmonary, endocrine, psychiatric, gastrointestinal, autoimmune or eating disorder. Participants were recruited at two clinical wards in Berlin and Nuthetal. The allocation was blinded to participants and study caregivers (physicians, dietitians, study nurses). Randomisation was conducted by non-clinical staff, providing neutrally numbered supplement tins. Both supplements were similar in their visual, olfactory and gustatory appearance. Intention-to-treat analysis was applied to all individuals. RESULTS: After 1 year, 2 h OGTT levels decreased significantly in both groups but without a significant difference between the groups (fibre -0.78 ± 1.88 mmol/l [p ≤ 0.001] vs placebo -0.46 ± 1.80 mmol/l [p = 0.020]; total difference 0.32 ± 0.29 mmol/l; not significant). The 2 year incidence of diabetes was 9/89 (fibre group) compared with 16/91 (placebo group; difference not significant). As secondary outcomes, the change in HbA1c level was significantly different between the two groups (-0.2 ± 4.6 mmol/mol [-0.0 ± 0.0%; not significant] vs +1.2 ± 5.2 mmol/mol [+0.1 ± 0.0%; not significant]; total difference 1.4 ± 0.7 mmol/mol [0.1 + 0.0%]); p = 0.018); insulin sensitivity and hepatic insulin clearance increased in both groups. After 2 years, improved insulin sensitivity was still present in both groups, although the effect size had diminished. Separate analysis of the sexes revealed a significantly greater reduction in 2 h glucose levels for women in the fibre group (-0.88 ± 1.59 mmol/l [p ≤ 0.001] vs -0.22 ± 1.52 mmol/l [p = 0.311]; total difference 0.67 ± 0.31 mmol/l; p = 0.015). Levels of fasting glucose, adipokines and inflammatory markers remained unchanged in the two groups. Significantly increased fibre intake was restricted to the fibre group, despite dietary counselling for both groups. No severe side effects occurred. CONCLUSIONS/INTERPRETATION: We cannot currently provide strong evidence for a beneficial effect of insoluble cereal fibre on glycaemic metabolism, although further studies may support minor effects of fibre supplementation in reducing glucose levels, insulin resistance and the incidence of type 2 diabetes. TRIAL REGISTRATION: clinicaltrials.gov NCT01681173 Funding: German Diabetes Foundation (grant no. 232/11/08)

Dose-dependent effects of insoluble fibre on glucose metabolism: A stratified post hoc analysis of the Optimal Fibre Trial (OptiFiT).

AIMS: As the first long-term RCT on insoluble cereal fibre, the optimal fibre trial demonstrated glycometabolic benefits, confirming cohort studies. The combined study intervention of lifestyle recommendations and supplementation with insoluble oat hulls fibre allows to clarify, which amount of fibre is required for a beneficial effect. METHODS: One hundred and eighty participants with impaired glucose tolerance underwent the one-year PREDIAS lifestyle programme and received a blinded, randomized fibre or placebo supplement for two years. We conducted a regression analyses and cut-off-based tertile comparisons in subjects with full data on dietary compliance (food records and accounted supplement; n = 120) after one year, investigating effects on fasting blood parameters, oral glucose tolerance test and anthropometry. RESULTS: We found a nonlinear inverse relation between fibre intake and change in postprandial 2-h glucose levels, showing a metabolic benefit beyond 14 g and a plateau beyond 25 g of total insoluble fibre per day. 2-h glucose levels improved significantly stronger in both upper tertiles (-0.9 [-1.6;-0.2] mmol/l, p = 0.047, and -0.6 [-1.6;0.3] mmol/l, p = 0.010) compared to the lowest tertile (0.1 [-1.2;1.1] mmol/l), also when adjusted for changes in bodyweight. Subjects with the highest fibre intake showed superior effects on fasting and postprandial insulin resistance, hepatic insulin clearance, leucocyte count and fatty liver index. CONCLUSIONS: Extending the knowledge on the benefits of insoluble oat hulls fibre, our post hoc analysis demonstrates a dose effect for glycaemia and associated metabolic markers. Further research is needed in order to replicate our findings in larger trials