Endoplasmic reticulum-mitochondria crosstalk and beta-cell destruction in type 1 diabetes

Beta-cell destruction in type 1 diabetes (T1D) results from the combined effect of inflammation and recurrent autoimmunity. In response to inflammatory signals, beta-cells engage adaptive mechanisms where the endoplasmic reticulum (ER) and mitochondria act in concert to restore cellular homeostasis. In the recent years it has become clear that this adaptive phase may trigger the development of autoimmunity by the generation of autoantigens recognized by autoreactive CD8 T cells. The participation of the ER stress and the unfolded protein response to the increased visibility of beta-cells to the immune system has been largely described. However, the role of the other cellular organelles, and in particular the mitochondria that are central mediator for beta-cell survival and function, remains poorly investigated. In this review we will dissect the crosstalk between the ER and mitochondria in the context of T1D, highlighting the key role played by this interaction in beta-cell dysfunctions and immune activation, especially through regulation of calcium homeostasis, oxidative stress and generation of mitochondrial-derived factors.Therapeutic cell differentiatio

Subpopulations and accuracy of prediction in pig carcass classification

Classification of pig carcasses in the European Community (EC) is based on the lean meat percentage of the carcasses. The lean meat percentage is predicted from instrumental carcass measurements, such as fat and muscle depth measurements, obtained in the slaughterline. The prediction formula for an instrument is derived from the data of a dissection experiment. When the relationship between percentage lean and instrumental carcass measurements differs between subpopulations, such as sexes or breeds, accuracy of prediction may differ between these subpopulations. In particular for some subpopulations predicted lean meat percentages may be systematically too low and for other subpopulations systematically too high. Producers or buyers that largely specialize in subpopulations where the percentage lean is underestimated, are put at a financial disadvantage. The aim of this paper is to gain insight, on the basis of real data, into the effects of differences between subpopulations on the accuracy of the predicted percentage lean meat of pig carcasses. A simulation study was performed based on data from dissection trials in The Netherlands, comprising gilts and castrated males, and trials in Spain, comprising different genetic types. The possible gain in accuracy, i.e. reduction of prediction bias and mean squared prediction error, by the use of separate prediction formulae for (some of) the subpopulations was determined. We concluded that marked bias in the predicted percentage lean meat may occur between subpopulations when a single overall prediction formula is employed. Systematic differences in predicted percentage lean between subpopulations that are overestimated and underestimated may exceed 4% and for selected values of instrumental measurements may run up to 6%. Bias between subpopulations may be eliminated, and prediction accuracy may be markedly improved, when separate prediction formulae are used. With the use of separate formulae the root mean squared prediction error may be reduced by 13 to 26% of the expected value when a single prediction formula is used for all pig carcasses. These are substantial reductions on a national scale. This suggests that there will be a commercial interest in the use of separate prediction formulae for different subpopulations. In the near future, when the use of implants becomes more reliable, subpopulations will be recognized automatically in the slaughterline and use of different prediction formulae will become practically feasible. Some possible consequences for the EC regulations and national safeguards for quality of prediction formulae are discussed

Estimating Visual Comfort in Stereoscopic Displays Using Electroencephalography: A Proof-of-Concept

International audienceWith stereoscopic displays, a depth sensation that is too strong could impede visual comfort and result in fatigue or pain. Electroencephalography (EEG) is a technology which records brain activity. We used it to develop a novel brain-computer interface that monitors users' states in order to reduce visual strain. We present the first proof-of-concept system that discriminates comfortable conditions from uncomfortable ones during stereoscopic vision using EEG. It reacts within 1s to depth variations, achieving 63% accuracy on average and 74% when 7 consecutive variations are measured. This study could lead to adaptive systems that automatically suit stereoscopic displays to users and viewing conditions

Injecteerbare transponders

Uit de resultaten van de veldtest met injecteerbare transponders op proefbedrijven blijkt dat er nog problemen bestaan ten aanzien van verlies van transponders (technisch defect en/of verdwijnen uit het dier), optreden van infecties en nauwkeurigheid van injecteren van transponders

Willingness to participate in a lifestyle intervention program of patients with type 2 diabetes mellitus: a conjoint analysis

Background: Several studies suggest that lifestyle interventions can be effective for people with, or at risk for, diabetes. The participation in lifestyle interventions is generally low. Financial incentives may encourage participation in lifestyle intervention programs. Objetive: The main aim of this exploratory analysis is to study empirically potential effects of financial incentives on diabetes patients' willingness to participate in lifestyle interventions. One financial incentive is negative ("copayment") and the other incentive is positive ("bonus"). The key part of this research is to contrast both incentives. The second aim is to investigate the factors that influence participation in a lifestyle intervention program. Methods: Conjoint analysis techniques were used to empirically identify factors that influence willingness to participate in a lifestyle intervention. For this purpose diabetic patients received a questionnaire with descriptions of various forms of hypothetical lifestyle interventions. They were asked if they would be willing to participate in these hypothetical programs. Results: In total, 174 observations were rated by 46 respondents. Analysis showed that money was an important factor independently associated with respondents' willingness to participate. Receiving a bonus seemed to be associated with a higher willingness to participate, but having to pay was negatively associated with participation in the lifestyle intervention. Conclusion: Conjoint analysis results suggest that financial considerations may influence willingness to participate in lifestyle intervention programs. Financial disincentives in the form of copayments might discourage participation. Although the positive impact of bonuses is smaller than the negative impact of copayments, bonuses could still be used to encourage willingness to participate

Early but not late exercise training in mice exacerbates hepatic inflammation in developing nonalcoholic fatty liver disease

Host-parasite interactio

Direct AMPK activation corrects NASH in rodents through metabolic effects and direct action on inflammation and fibrogenesis

No approved therapies are available for nonalcoholic steatohepatitis (NASH). Adenosine monophosphate–activated protein kinase (AMPK) is a central regulator of cell metabolism; its activation has been suggested as a therapeutic approach to NASH. Here we aimed to fully characterize the potential for direct AMPK activation in preclinical models and to determine mechanisms that could contribute to efficacy for this disease. A novel small-molecule direct AMPK activator, PXL770, was used. Enzyme activity was measured with recombinant complexes. De novo lipogenesis (DNL) was quantitated in vivo and in mouse and human primary hepatocytes. Metabolic efficacy was assessed in ob/ob and high-fat diet–fed mice. Liver histology, biochemical measures, and immune cell profiling were assessed in diet-induced NASH mice. Direct effects on inflammation and fibrogenesis were assessed using primary mouse and human hepatic stellate cells, mouse adipose tissue explants, and human immune cells. PXL770 directly activated AMPK in vitro and reduced DNL in primary hepatocytes. In rodent models with metabolic syndrome, PXL770 improved glycemia, dyslipidemia, and insulin resistance. In mice with NASH, PXL770 reduced hepatic steatosis, ballooning, inflammation, and fibrogenesis. PXL770 exhibited direct inhibitory effects on pro-inflammatory cytokine production and activation of primary hepatic stellate cells. Conclusion: In rodent models, direct activation of AMPK is sufficient to produce improvements in all core components of NASH and to ameliorate related hyperglycemia, dyslipidemia, and systemic inflammation. Novel properties of direct AMPK activation were also unveiled: improved insulin resistance and direct suppression of inflammation and fibrogenesis. Given effects also documented in human cells (reduced DNL, suppression of inflammation and stellate cell activation), these studies support the potential for direct AMPK activation to effectively treat patients with NASH