In Vitro–expanded Antigen-specific Regulatory T Cells Suppress Autoimmune Diabetes

The low number of CD4+ CD25+ regulatory T cells (Tregs), their anergic phenotype, and diverse antigen specificity present major challenges to harnessing this potent tolerogenic population to treat autoimmunity and transplant rejection. In this study, we describe a robust method to expand antigen-specific Tregs from autoimmune-prone nonobese diabetic mice. Purified CD4+ CD25+ Tregs were expanded up to 200-fold in less than 2 wk in vitro using a combination of anti-CD3, anti-CD28, and interleukin 2. The expanded Tregs express a classical cell surface phenotype and function both in vitro and in vivo to suppress effector T cell functions. Most significantly, small numbers of antigen-specific Tregs can reverse diabetes after disease onset, suggesting a novel approach to cellular immunotherapy for autoimmunity

Improving the relationships between Indigenous rights holders and researchers in the Arctic: an invitation for change in funding and collaboration

Truly transdisciplinary approaches are needed to tackle the complex problems that the Arctic is facing at the moment. Collaboration between Indigenous rights holders and researchers through co-creative research approaches can result in high-quality research outcomes, but crucially also address colonial legacies and power imbalances, enhance mutual trust, and respect the rights of Indigenous Peoples. However, to be successful, collaborative research projects have specific requirements regarding research designs, timeframes, and dissemination of results, which often do not fit into the frameworks of academic calendars and funding guidelines. Funding agencies in particular play an important role in enabling (or disabling) meaningful collaboration between Indigenous rights holders and researchers. There is an urgent need to re-think existing funding-structures. This article will propose a new paradigm for the financing of Arctic research, which centres around the inclusion of Indigenous partners, researchers, and institutions from the initial planning stages of funding programmes to the final stages of research projects. These findings and recommendations have been contextualized based on critical reflections of the co-authors, a group of Indigenous and non-Indigenous partners, who have practiced their own collaborative work process, the challenges encountered, and lessons learned

The clock genes Period 2 and Cryptochrome 2 differentially balance bone formation

Background: Clock genes and their protein products regulate circadian rhythms in mammals but have also been implicated in various physiological processes, including bone formation. Osteoblasts build new mineralized bone whereas osteoclasts degrade it thereby balancing bone formation. To evaluate the contribution of clock components in this process, we investigated mice mutant in clock genes for a bone volume phenotype. Methodology/Principal Findings: We found that Per2Brdm1 mutant mice as well as mice lacking Cry2-/- displayed significantly increased bone volume at 12 weeks of age, when bone turnover is high. Per2Brdm1 mutant mice showed alterations in parameters specific for osteoblasts whereas mice lacking Cry2-/- displayed changes in osteoclast specific parameters. Interestingly, inactivation of both Per2 and Cry2 genes leads to normal bone volume as observed in wild type animals. Importantly, osteoclast parameters affected due to the lack of Cry2, remained at the level seen in the Cry2-/- mutants despite the simultaneous inactivation of Per2. Conclusions/Significance: This indicates that Cry2 and Per2 affect distinct pathways in the regulation of bone volume with Cry2 influencing mostly the osteoclastic cellular component of bone and Per2 acting on osteoblast parameters

Use of expert elicitation to assign weights to climate and hydrological models in climate impact studies

Various methods are available for assessing uncertainties in climate impact studies. Among such methods, model weighting by expert elicitation is a practical way to provide a weighted ensemble of models for specific real-world impacts. The aim is to decrease the influence of improbable models in the results and easing the decision-making process. In this study both climate and hydrological models are analysed, and the result of a research experiment is presented using model weighting with the participation of six climate model experts and six hydrological model experts. For the experiment, seven climate models are a priori selected from a larger EURO-CORDEX (Coordinated Regional Downscaling Experiment - European Domain) ensemble of climate models, and three different hydrological models are chosen for each of the three European river basins. The model weighting is based on qualitative evaluation by the experts for each of the selected models based on a training material that describes the overall model structure and literature about climate models and the performance of hydrological models for the present period. The expert elicitation process follows a three-stage approach, with two individual rounds of elicitation of probabilities and a final group consensus, where the experts are separated into two different community groups: a climate and a hydrological modeller group. The dialogue reveals that under the conditions of the study, most climate modellers prefer the equal weighting of ensemble members, whereas hydrological-impact modellers in general are more open for assigning weights to different models in a multi-model ensemble, based on model performance and model structure. Climate experts are more open to exclude models, if obviously flawed, than to put weights on selected models in a relatively small ensemble. The study shows that expert elicitation can be an efficient way to assign weights to different hydrological models and thereby reduce the uncertainty in climate impact. However, for the climate model ensemble, comprising seven models, the elicitation in the format of this study could only re-establish a uniform weight between climate models.This work was funded by the project AQUA-CLEW, which is part of ERA4CS (European Research Area for Climate Services), an ERANET (European Research Area Net-work) initiated by JPI Climate (Joint Programming Initiative) andfunded by Formas (Sweden); German Aerospace Center (DLR, Germany); Ministry of Education, Science and Research (BMBWF,Austria); Innovation Fund Denmark; Ministry of Economic Affairs and Digital Transformation (MINECO, Spain); and French National Research Agency with co-funding by the European Commission (grant no. 69046). The contribution of Philippe Lucas-Picher was supported by the French National Research Agency (future investment programme no. ANR-18-MPGA-0005). Rafael Pimentel acknowledges funding by the Modality 5.2 of the Programa Propio 2018 of the University of Córdoba and the Juan de la Cierva Incorporación programme of the Ministry of Science and Innovation (grant no. IJC2018-038093-I). Rafael Pimentel and María J. Polo are members of DAUCO (Unit of Excellence reference no. CEX2019-000968-M), with financial support from the Spanish Ministry of Science and Innovation and the Spanish State Research Agency, through the Severo Ochoa Centre of Excellence and María de Maeztu Unit of Excellence in research and development (R&D)

Lifetime and 10-year cardiovascular risk prediction in individuals with type 1 diabetes: The LIFE-T1D model

AIMS: To develop and externally validate the LIFE-T1D model for the estimation of lifetime and 10-year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes. MATERIALS AND METHODS: A sex-specific competing risk-adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non-high-density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank. RESULTS: During a median follow-up of 11.8 years (interquartile interval 6.1-17.1 years), 4608 CVD events and 1316 non-CVD deaths were observed in the NDR (n = 39 756). The internal validation c-statistic was 0.85 (95% confidence interval [CI] 0.84-0.85) and the external validation c-statistics were 0.77 (95% CI 0.74-0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70-0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts. CONCLUSIONS: The LIFE-T1D model can estimate lifetime risk of CVD and CVD-free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation

Fish Oil Supplementation During Late Pregnancy Does Not Influence Plasma Lipids or Lipoprotein Levels in Young Adult Offspring

Nutritional influences on cardiovascular disease operate throughout life. Studies in both experimental animals and humans have suggested that changes in the peri- and early post-natal nutrition can affect the development of the various components of the metabolic syndrome in adult life. This has lead to the hypothesis that n-3 fatty acid supplementation in pregnancy may have a beneficial effect on lipid profile in the offspring. The aim of the present study was to investigate the effect of supplementation with n-3 fatty acids during the third trimester of pregnancy on lipids and lipoproteins in the 19-year-old offspring. The study was based on the follow-up of a randomized controlled trial from 1990 where 533 pregnant women were randomized to fish oil (n = 266), olive oil (n = 136) or no oil (n = 131). In 2009, the offspring were invited to a physical examination including blood sampling. A total of 243 of the offspring participated. Lipid values did not differ between the fish oil and olive oil groups. The relative adjusted difference (95% confidence intervals) in lipid concentrations was −3% (−11; 7) for LDL cholesterol, 3% (−3; 10) for HDL cholesterol, −1% (−6; 5) for total cholesterol,−4% (−16; 10) for TAG concentrations, 2%(−2; 7) for apolipoprotein A1, −1% (−9; 7) for apolipoprotein B and 3% (−7; 15) in relative abundance of small dense LDL. In conclusion, there was no effect of fish oil supplementation during the third trimester of pregnancy on offspring plasma lipids and lipoproteins in adolescence

High Resolution MEMS Accelerometers to Estimate VO2 and Compare Running Mechanics between Highly Trained Inter-Collegiate and Untrained Runners

BACKGROUND: The purposes of this study were to determine the validity and reliability of high resolution accelerometers (HRA) relative to VO(2) and speed, and compare putative differences in HRA signal between trained (T) and untrained (UT) runners during treadmill locomotion. METHODOLOGY: Runners performed 2 incremental VO(2max) trials while wearing HRA. RMS of high frequency signal from three axes (VT, ML, AP) and the Euclidean resultant (RES) were compared to VO(2) to determine validity and reliability. Additionally, axial rms relative to speed, and ratio of axial accelerations to RES were compared between T and UT to determine if differences in running mechanics could be identified between the two groups. PRINCIPAL FINDINGS: Regression of RES was strongly related to VO(2), but T was different than UT (r = 0.96 vs 0.92; p<.001) for walking and running. During walking, only the ratio of ML and AP to RES were different between groups. For running, nearly all acceleration parameters were lower for T than UT, the exception being ratio of VT to RES, which was higher in T than UT. All of these differences during running were despite higher VO(2), O(2) cost, and lower RER in T vs UT, which resulted in no significant difference in energy expenditure between groups. CONCLUSIONS/SIGNFICANCE: These results indicate that HRA can accurately and reliably estimate VO(2) during treadmill locomotion, but differences exist between T and UT that should be considered when estimating energy expenditure. Differences in running mechanics between T and UT were identified, yet the importance of these differences remains to be determined