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PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus

[Aims/hypothesis]: A strategy to enhance pancreatic islet functional beta cell mass (BCM) while restraining inflammation, through the manipulation of molecular and cellular targets, would provide a means to counteract the deteriorating glycaemic control associated with diabetes mellitus. The aims of the current study were to investigate the therapeutic potential of such a target, the islet-enriched and diabetes-linked transcription factor paired box 4 (PAX4), to restrain experimental autoimmune diabetes (EAD) in the RIP-B7.1 mouse model background and to characterise putative cellular mechanisms associated with preserved BCM. [Methods]: Two groups of RIP-B7.1 mice were genetically engineered to: (1) conditionally express either PAX4 (BPTL) or its diabetes-linked mutant variant R129W (mutBPTL) using doxycycline (DOX); and (2) constitutively express luciferase in beta cells through the use of RIP. Mice were treated or not with DOX, and EAD was induced by immunisation with a murine preproinsulin II cDNA expression plasmid. The development of hyperglycaemia was monitored for up to 4 weeks following immunisation and alterations in the BCM were assessed weekly by non-invasive in vivo bioluminescence intensity (BLI). In parallel, BCM, islet cell proliferation and apoptosis were evaluated by immunocytochemistry. Alterations in PAX4- and PAX4R129W-mediated islet gene expression were investigated by microarray profiling. PAX4 preservation of endoplasmic reticulum (ER) homeostasis was assessed using thapsigargin, electron microscopy and intracellular calcium measurements. [Results]: PAX4 overexpression blunted EAD, whereas the diabetes-linked mutant variant PAX4R129W did not convey protection. PAX4-expressing islets exhibited reduced insulitis and decreased beta cell apoptosis, correlating with diminished DNA damage and increased islet cell proliferation. Microarray profiling revealed that PAX4 but not PAX4R129W targeted expression of genes implicated in cell cycle and ER homeostasis. Consistent with the latter, islets overexpressing PAX4 were protected against thapsigargin-mediated ER-stress-related apoptosis. Luminal swelling associated with ER stress induced by thapsigargin was rescued in PAX4-overexpressing beta cells, correlating with preserved cytosolic calcium oscillations in response to glucose. In contrast, RNA interference mediated repression of PAX4-sensitised MIN6 cells to thapsigargin cell death. [Conclusions/interpretation]: The coordinated regulation of distinct cellular pathways particularly related to ER homeostasis by PAX4 not achieved by the mutant variant PAX4R129W alleviates beta cell degeneration and protects against diabetes mellitus. The raw data for the RNA microarray described herein are accessible in the Gene Expression Omnibus database under accession number GSE62846

Neck circumference and clustered cardiovascular risk factors in children and adolescents: Cross-sectional study

Objective Early detection of cardiovascular disease (CVD) risk factors, such as obesity, is crucial to prevent adverse long-term effects on individuals'' health. Therefore, the aims were: (1) to explore the robustness of neck circumference (NC) as a predictor of CVD and examine its association with numerous anthropometric and body composition indices and (2) to release sex and age-specific NC cut-off values to classify youths as overweight/obese. Design Cross-sectional study. Setting 23 primary schools and 17 secondary schools from Spain. Participants 2198 students (1060 girls), grades 1-4 and 7-10. Measures Pubertal development, anthropometric and body composition indices, systolic and diastolic blood pressure (SBP and DBP, respectively), cardiorespiratory fitness, blood sampling triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), glucose and inflammatory markers. Homoeostasis model assessment (HOMA-IR) and cluster of CVD risk factors were calculated. Results NC was positively correlated with all anthropometric and body composition indices. NC was negatively associated with maximum oxygen consumption (R 2 =0.231, p<0.001 for boys; R 2 =0.018, p<0.001 for girls) and positively associated with SBP, DBP, TC/HDL-c, TG, HOMA, complement factors C-3 and C-4, leptin, adiponectin and clustered CVD risk factor in both sexes (R 2 from 0.035 to 0.353, p<0.01 for boys; R 2 from 0.024 to 0.215, p<0.001 for girls). Moreover, NC was positively associated with serum C reactive protein, LDL-c and visfatin only in boys (R 2 from 0.013 to 0.107, p<0.05). Conclusion NC is a simple, low-cost and practical screening tool of excess of upper body obesity and CVD risk factors in children and adolescents. Paediatricians can easily use it as a screening tool for overweight/obesity in children and adolescents. For this purpose, sex and age-specific thresholds to classify children and adolescents as normal weight or overweight/obese are provided

Development of a High-Throughput Calcium Mobilization Assay for CCR6 Receptor Coupled to Hydrolase Activity Readout

CCR6 is a chemokine receptor highly implicated in inflammatory diseases and could be a potential therapeutic target; however, no therapeutic agents targeting CCR6 have progressed into clinical evaluation. Development of a high-throughput screening assay for CCR6 should facilitate the identification of novel compounds against CCR6. To develop a cell-based assay, RBL-2H3 cells were transfected with plasmids encoding β-hexosaminidase and CCR6. Intracellular calcium mobilization of transfected cells was measured with a fluorescent substrate using the activity of released hexosaminidase as readout of the assay. This stable, transfected cell showed a specific signal to the background ratio of 19.1 with low variability of the signal along the time. The assay was validated and optimized for high-throughput screening. The cell-based calcium mobilization assay responded to the specific CCR6 ligand, CCL20, in a dose-dependent manner with an EC50 value of 10.72 nM. Furthermore, the assay was deemed robust and reproducible with a Z’ factor of 0.63 and a signal window of 7.75. We have established a cell-based high-throughput calcium mobilization assay for CCR6 receptor. This assay monitors calcium mobilization, due to CCR6h activation by CCL20, using hexosaminidase activity as readout. This assay was proved to be robust, easy to automate and could be used as method for screening of CCR6 modulators

Resource heterogeneity leads to unjust effort distribution in climate change mitigation

Climate change mitigation is a shared global challenge that involves collective action of a set of individuals with different tendencies to cooperation. However, we lack an understanding of the effect of resource inequality when diverse actors interact together towards a common goal. Here, we report the results of a collective-risk dilemma experiment in which groups of individuals were initially given either equal or unequal endowments. We found that the effort distribution was highly inequitable, with participants with fewer resources contributing significantly more to the public goods than the richer −sometimes twice as much. An unsupervised learning algorithm classified the subjects according to their individual behavior, finding the poorest participants within two 'generous clusters' and the richest into a 'greedy cluster'. Our results suggest that policies would benefit from educating about fairness and reinforcing climate justice actions addressed to vulnerable people instead of focusing on understanding generic or global climate consequences

Wisdom of groups promotes cooperation in evolutionary social dilemmas

Whether or not to change strategy depends not only on the personal success of each individual, but also on the success of others. Using this as motivation, we study the evolution of cooperation in games that describe social dilemmas, where the propensity to adopt a different strategy depends both on individual fitness as well as on the strategies of neighbors. Regardless of whether the evolutionary process is governed by pairwise or group interactions, we show that plugging into the "wisdom of groups" strongly promotes cooperative behavior. The more the wider knowledge is taken into account the more the evolution of defectors is impaired. We explain this by revealing a dynamically decelerated invasion process, by means of which interfaces separating different domains remain smooth and defectors therefore become unable to efficiently invade cooperators. This in turn invigorates spatial reciprocity and establishes decentralized decision making as very beneficial for resolving social dilemmas.Comment: 8 two-column pages, 7 figures; accepted for publication in Scientific Report

Effects of a Mediterranean Eating Plan on the Need for Glucose-Lowering Medications in Participants With Type 2 Diabetes: A Subgroup Analysis of the PREDIMED Trial

[Objective]: To examine the effects of two Mediterranean eating plans (Med-EatPlans) versus a low-fat eating plan on the need for glucose-lowering medications. [Research design and methods]: From the Prevención con Dieta Mediterránea (PREDIMED) trial, we selected 3,230 participants with type 2 diabetes at baseline. These participants were randomly assigned to one of three eating plans: Med-EatPlan supplemented with extra-virgin olive oil (EVOO), Med-EatPlan supplemented with mixed nuts, or a low-fat eating plan (control). In a subgroup (15%), the allocation was done in small clusters instead of using individual randomization, and the clustering effect was taken into account in the statistical analysis. In multivariable time-to-event survival models, we assessed two outcomes: 1) introduction of the first glucose-lowering medication (oral or injectable) among participants on lifestyle management at enrollment and 2) insulin initiation. [Results]: After a median follow-up of 3.2 years, in multivariable analyses adjusting for baseline characteristics and propensity scores, the hazard ratios (HRs) of starting a first glucose-lowering medication were 0.78 (95% CI 0.62–0.98) for Med-EatPlan + EVOO and 0.89 (0.71–1.12) for Med-EatPlan + nuts, compared with the control eating plan. After a median follow-up of 5.1 years, the adjusted HRs of starting insulin treatment were 0.87 (0.68–1.11) for Med-EatPlan + EVOO and 0.89 (0.69–1.14) for Med-EatPlan + nuts compared with the control eating plan. [Conclusions]: Among participants with type 2 diabetes, a Med-EatPlan + EVOO may delay the introduction of new-onset glucose-lowering medications. The Med-EatPlan did not result in a significantly lower need for insulin

Quality of dietary fat intake and body weight and obesity in a Mediterranean population: Secondary analyses within the PREDIMED trial

A moderately high-fat Mediterranean diet does not promote weight gain. This study aimed to investigate the association between dietary intake of specific types of fat and obesity and body weight. A prospective cohort study was performed using data of 6942 participants in the PREDIMED trial, with yearly repeated validated food-frequency questionnaires, and anthropometric outcomes (median follow-up: 4.8 years). The effects of replacing dietary fat subtypes for one another, proteins or carbohydrates were estimated using generalized estimating equations substitution models. Replacement of 5% energy from saturated fatty acids (SFA) with monounsaturated fatty acids (MUFA) or polyunsaturated fatty acids (PUFA) resulted in weight changes of −0.38 kg (95% Confidece Iinterval (CI): −0.69, −0.07), and −0.51 kg (95% CI: −0.81, −0.20), respectively. Replacing proteins with MUFA or PUFA decreased the odds of becoming obese. Estimates for the daily substitution of one portion of red meat with white meat, oily fish or white fish showed weight changes up to −0.87 kg. Increasing the intake of unsaturated fatty acids at the expense of SFA, proteins, and carbohydrates showed beneficial effects on body weight and obesity. It may therefore be desirable to encourage high-quality fat diets like the Mediterranean diet instead of restricting total fat intake

Mediterranean Diet and Atherothrombosis Biomarkers: A Randomized Controlled Trial

Scope: To assess whether following a Mediterranean diet (MedDiet) improves atherothrombosis biomarkers in high cardiovascular risk individuals. Methods and results: In 358 random volunteers from the PREvención con DIeta MEDiterránea trial, the 1-year effects on atherothrombosis markers of an intervention with MedDiet, enriched with virgin olive oil (MedDiet-VOO; n = 120) or nuts (MedDiet-Nuts; n = 119) versus a low-fat control diet (n = 119), and whether large increments in MedDiet adherence (≥3 score points, versus compliance decreases) and intake changes in key food items are associated with 1-year differences in biomarkers. Differences are observed between 1-year changes in the MedDiet-VOO intervention and control diet on the activity of platelet activating factor acetylhydrolase in high-density lipoproteins (HDLs) (+7.5% [95% confidence interval: 0.17; 14.8]) and HDL-bound 1-antitrypsin levels (−6.1% [−11.8; −0.29]), and between the MedDiet-Nuts intervention and the control arm on non-esterified fatty acid concentrations (−9.3% [−18.1; −0.53]). Large MedDiet adherence increments are associated with less fibrinogen (−9.5% [−18.3; −0.60]) and non-esterified fatty acid concentrations (−16.7% [−31.7; −1.74]). Increases in nut, fruit, vegetable, and fatty fish consumption, and decreases in processed meat intake are linked to enhancements in biomarkers. Conclusion: MedDiet improves atherothrombosis biomarkers in high cardiovascular risk individuals

Postcranial morphology of the middle Pleistocene humans from Sima de los Huesos, Spain

Current knowledge of the evolution of the postcranial skeleton in the genus Homo is hampered by a geographically and chronologically scattered fossil record. Here we present a complete characterization of the postcranium of the middle Pleistocene paleodeme from the Sima de los Huesos (SH) and its paleobiological implications. The SH hominins show the following: (i) wide bodies, a plesiomorphic char- acter in the genus Homo inherited from their early hominin ancestors; (ii) statures that can be found in modern human middle-latitude pop- ulations that first appeared 1.6–1.5 Mya; and (iii) large femoral heads in some individuals, a trait that first appeared during the middle Pleistocene in Africa and Europe. The intrapopulational size variation in SH shows that the level of dimorphism was similar to modern humans (MH), but the SH hominins were less encephalized than Ne- andertals. SH shares many postcranial anatomical features with Ne- andertals. Although most of these features appear to be either plesiomorphic retentions or are of uncertain phylogenetic polarity, a few represent Neandertal apomorphies. Nevertheless, the full suite of Neandertal-derived features is not yet present in the SH popula- tion. The postcranial evidence is consistent with the hypothesis based on the cranial morphology that the SH hominins are a sister group to the later Neandertals. Comparison of the SH postcranial skeleton to other hominins suggests that the evolution of the postcranium oc- curred in a mosaic mode, both at a general and at a detailed level