miR-7 Modulates hESC Differentiation into Insulin-Producing Beta-like Cells and Contributes to Cell Maturation

Human pluripotent stem cells retain the extraordinary capacity to differentiate into pancreatic beta cells. For this particular lineage, more effort is still required to stress the importance of developing an efficient, reproducible, easy, and cost-effective differentiation protocol to obtain more mature, homogeneous, and functional insulin-secreting cells. In addition, microRNAs (miRNAs) have emerged as a class of small non-coding RNAs that regulate many cellular processes, including pancreatic differentiation. Some miRNAs are known to be preferentially expressed in islets. Of note, miR-375 and miR-7 are two of the most abundant pancreatic miRNAs, and they are necessary for proper pancreatic islet development. Here we provide new insight into specific miRNAs involved in pancreatic differentiation. We found that miR-7 is differentially expressed during the differentiation of human embryonic stem cells (hESCs) into a beta cell-like phenotype and that its modulation plays an important role in generating mature pancreatic beta cells. This strategy may be exploited to optimize the potential for in vitro differentiation of hESCs into insulin-producing beta-like cells for use in preclinical studies and future clinical applications as well as the prospective uses of miRNAs to improve this process.Spanish Ministry of Economy and Competitiveness BFU2016-74932-C2 BFU2013-45564-C2FEDER Funds PI-0272-2017Andalusian Regional Ministry of Health PI-0272-2017European Cooperation in Science and Technology BM1305Spanish Ministry of Economy, Industry and Competitiveness CD16/00118Spanish Institute of Health Carlos III PI16/00259 PI17/02104 RD16/0011/0034 CD16/0011

Gene-Diet Interactions in Type 2 Diabetes: The Chicken and Egg Debate

Consistent evidence from both experimental and human studies indicates that Type 2 diabetes mellitus (T2DM) is a complex disease resulting from the interaction of genetic, epigenetic, environmental, and lifestyle factors. Nutrients and dietary patterns are important environmental factors to consider in the prevention, development and treatment of this disease. Nutritional genomics focuses on the interaction between bioactive food components and the genome and includes studies of nutrigenetics, nutrigenomics and epigenetic modifications caused by nutrients. There is evidence supporting the existence of nutrient-gene and T2DM interactions coming from animal studies and family-based intervention studies. Moreover, many case-control, cohort, cross-sectional cohort studies and clinical trials have identified relationships between individual genetic load, diet and T2DM. Some of these studies were on a large scale. In addition, studies with animal models and human observational studies, in different countries over periods of time, support a causative relationship between adverse nutritional conditions during in utero development, persistent epigenetic changes and T2DM. This review provides comprehensive information on the current state of nutrient-gene interactions and their role in T2DM pathogenesis, the relationship between individual genetic load and diet, and the importance of epigenetic factors in influencing gene expression and defining the individual risk of T2DM

L-type Ca2+ channels and SK channels in mouse embryonic stem cells and their contribution to cell proliferation

Mouse embryonic stem cells (mESCs) are capable of both self-renewal and multilineage differentiation; thus, they can be expanded in vivo or in vitro and differentiated to produce different cell types. Despite their biological and medical interest, many physiological properties of undifferentiated mESCs, such as ion channel function, are not fully understood. Ion channels are thought to be involved in cell proliferation and differentiation. The aim of this study was to characterize functional ion channels in cultured undifferentiated mESCs and their role in cell proliferation. L-type voltage-activated Ca2+ channels sensitive to nifedipine and small conductance Ca2+- activated K+ (SK) channels sensitive to apamin were identified. Ca2+-activated K+ currents were blocked by millimolar concentrations of tetraethylammonium (TEA). The effects of Ca2+ channel and Ca2+-activated K+ channel blockers on the proliferation of undifferentiated mESCs were investigated by bromodeoxyuridine (BrdU) incorporation. Dihydropyridine derivatives, such as nifedipine, inhibited cell growth and BrdU incorporation into the cells, whereas apamin, which selectively blocks SK channels, had no effect on cell growth. These results demonstrate that functional voltageoperated Ca2+ channels (VOCCs) and Ca2+-activated K+ channels are present in undifferentiated mESCs. Moreover, voltage-gated L-type Ca2+ channels, but not SK channels, might be necessary for proliferation of undifferentiated mESCs.Medicin

Reassessing model uncertainty for regional projections of precipitation with an ensemble of statistical downscaling methods

This is the second in a pair of papers in which the performance of Statistical Downscaling Methods (SDMs) is critically re-assessed with respect to their robust applicability in climate change studies. Whereas Part I focused on temperatures (Gutierrez et al., 2013), the present manuscript deals with precipitation and considers an ensemble of twelve SDMs from the analog, weather typing, and regression (GLM) families. In the first part, we assess the performance of the methods with perfect (reanalysis) predictors, screening different geographical domains and predictor sets. To this aim, standard accuracy and distributional similarity scores, and a test for extrapolation capability based on dry observed historical periods are considered. As in Part I, the results are highly dependent on the predictor sets, with optimum configurations including information of middle tropospheric humidity (in particular Q850). As a result of this analysis, deficient SDMs are discarded in order to properly assess the spread (uncertainty) of future climate projections, avoiding the noise introduced by unsuitable models. In the second part, the resulting ensemble of SDMs is applied to four Global Circulation Models (GCMs) from the ENSEMBLES (CMIP3) project to obtain historical (1961-2000, 20C3M scenario) and future (2001-2100, A1B) regional projections. The obtained results are compared with those produced by an ensemble of Regional Climate Models (RCMs) driven by almost the same GCMs in the ENSEMBLES project. In general, the mean signal is similar with both methodologies (with the exception of Summer, where the RCMs project drier conditions) but the spread is larger for the SDM results. Finally, the contribution of the GCM and SDM-derived components to the total spread is assessed using a simple analysis of variance previously applied to the ENSEMBLES RCM ensemble. Results show that the main contributor to the spread is the choice of the GCM, except for the autumn results in the Atlantic sub-region of Spain and the Autumn and Summer results in the Mediterranean sub-region, where the choice of the SDM dominates the uncertainty during the second half of the 21st century due mainly to the different projections obtained from different families of SDM techniques. The most noticeable difference with the RCMs is the magnitude of the interaction terms, which is larger in all cases in the present study.This work has been funded by the strategic action for energy and climate change by the Spanish R&D 2008–2011 program ‘‘Programa coordinado para la generación de escenarios regionalizados de cambio climático: Regionalización Estadística (esTcena),’’ code 200800050084078, and the project CGL2015-66583-R (MINECO/FEDER). The RCM simulations used in this study were obtained from the European Union–funded FP6 Integrated Project ENSEMBLES (Contract 505539)

Commensurate and Incommensurate Vortex Lattice Melting in Periodic Pinning Arrays

We examine the melting of commensurate and incommensurate vortex lattices interacting with square pinning arrays through the use of numerical simulations. For weak pinning strength in the commensurate case we observe an order-order transition from a commensurate square vortex lattice to a triangular floating solid phase as a function of temperature. This floating solid phase melts into a liquid at still higher temperature. For strong pinning there is only a single transition from the square pinned lattice to the liquid state. For strong pinning in the incommensurate case, we observe a multi-stage melting in which the interstitial vortices become mobile first, followed by the melting of the entire lattice, consistent with recent imaging experiments. The initial motion of vortices in the incommensurate phase occurs by an exchange process of interstitial vortices with vortices located at the pinning sites. We have also examined the vortex melting behavior for higher matching fields and find that a coexistence of a commensurate pinned vortex lattice with an interstitial vortex liquid occurs while at higher temperatures the entire vortex lattice melts. For triangular arrays at incommensurate fields higher than the first matching field we observe that the initial vortex motion can occur through a novel correlated ring excitation where a number of vortices can rotate around a pinned vortex. We also discuss the relevance of our results to recent experiments of colloidal particles interacting with periodic trap arrays.Comment: 8 figure

Reassessing statistical downscaling techniques for their robust application under climate change conditions

The performance of statistical downscaling (SD) techniques is critically reassessed with respect to their robust applicability in climate change studies. To this end, in addition to standard accuracy measures and distributional similarity scores, the authors estimate the robustness of the methods under warming climate conditions working with anomalous warm historical periods. This validation framework is applied to intercompare the performances of 12 different SD methods (from the analog, weather typing, and regression families) for downscaling minimum and maximum temperatures in Spain. First, a calibration of these methods is performed in terms of both geographical domains and predictor sets; the results are highly dependent on the latter, with optimum predictor sets including near-surface temperature data (in particular 2-m temperature), which appropriately discriminate cold episodes related to temperature inversion in the lower troposphere. Although regression methods perform best in terms of correlation, analog and weather generator approaches are more appropriate for reproducing the observed distributions, especially in case of wintertime minimum temperature. However, the latter two families significantly underestimate the temperature anomalies of the warm periods considered in this work. This underestimation is found to be critical when considering the warming signal in the late twenty-first century as given by a global climate model [the ECHAM5-Max Planck Institute (MPI) model]. In this case, the different downscaling methods provide warming values with differences in the range of 1°C, in agreement with the robustness significance values. Therefore, the proposed test is a promising technique for detecting lack of robustness in statistical downscaling methods applied in climate change studies.Thiswork has been funded by the Spanish I1D1i 2008-11 Program: A strategic action for energy and climate change (ESTCENA, code 200800050084078) and the project CGL2010-21869 (EXTREMBLES). S.B. was supported by a JAE PREDOC grant (CSIC, Spain). The authors would like to especially thank the three anonymous reviewers who helped to considerably improve this manuscript

Consumption of cows' milk is associated with lower risk of type 2 diabetes mellitus. A cross-sectional study

The aim of this prospective, adult population-based study was to analyse the prevalence of type 2 diabetes mellitus in relation to the intake of cows' milk and the prevalence of anti-beta-lactoglobulin (anti-β-LG) antibodies. Measurements were made of weight, height, levels of anti-islet antibodies, anti-β-LG antibodies and tumour necrosis factor alpha (TNF-α) in all the participants. The likelihood of having positive anti-β-LG antibodies was higher in subjects who consumed milk more frequently. Subjects who consumed milk less than once per day were more likely to have type 2 diabetes than those who consumed milk more than once per day. The levels of TNF-α were significantly higher in individuals with positive anti-β-LG antibodies and in those who consumed milk more often. The prevalence of anti-β-LG antibodies was associated with the intake of milk and with the TNF-α levels, but not with the prevalence of type 2 diabetes. © 2012 Elsevier Ltd.This study was supported by the CIBER in Diabetes and Associated Metabolic Disorders (Instituto de Salud Carlos III); Ministerio de Ciencia e Innovación (JCI-2010-08372) and Consejería Innovación, Ciencia y Empresa (P09-CTS-5125)

FIBROMYALGIA: A SEARCH FOR MARKERS AND THEIR EVALUATION THROUGHOUT A TREATMENT

Fibromyalgia syndrome (FM) is a complex chronic pain disorder of unknown causation associated with debilitating fatigue, unrefreshing sleep, cognitive and affective symptoms. There is no biological markers to monitor FM progression and no permanent cure for FM. Our aim was to identify markers associated with FM and its progression and to evaluate the efficacy of a battery of treatments. The study is a treatment trial, open label and single centre, with 27 women (41 ± 2 years) diagnosed with FM using the Widespread Pain Index (WPI), the Symptom Severity (SS) Scale and the Fibromyalgia Impact Questionnaire (FIQ). Anthropometric parameters, plasma cytokines values and clinical progression were measured before and after two months of a multi-approach treatment. A significant improvement was observed after two months of treatment as shown by WPI, SS Scale and FIQ. No significant variations were observed, except for the intracellular body water parameters, in anthropometric and body composition characteristics. Food-induced histaminosis release was observed to cow´s milk, egg, fruit, wheat and oily fish. Interleukin-1β (IL-1β) and interleukin-6 (IL-6) plasma cytokine values were significantly higher in FM. A strong positive correlation was observed between the percentage of reduction of cytokine levels and the improvement of health status. We propose: i) the existence of different subsets of FM patients; ii) the use of intracellular body water and plasma cytokine values as positive markers for FM progression; iii) that food-sensitisation could be an important mechanism for FM pathogenesis and iv) the use of a multidisciplinary approach for FM treatment

FIBROMYALGIA: A SEARCH FOR MARKERS AND THEIR EVALUATION THROUGHOUT A TREATMENT

Fibromyalgia syndrome (FM) is a complex chronic pain disorder of unknown causation associated with debilitating fatigue, unrefreshing sleep, cognitive and affective symptoms. There is no biological markers to monitor FM progression and no permanent cure for FM. Our aim was to identify markers associated with FM and its progression and to evaluate the efficacy of a battery of treatments. The study is a treatment trial, open label and single centre, with 27 women (41 ± 2 years) diagnosed with FM using the Widespread Pain Index (WPI), the Symptom Severity (SS) Scale and the Fibromyalgia Impact Questionnaire (FIQ). Anthropometric parameters, plasma cytokines values and clinical progression were measured before and after two months of a multi-approach treatment. A significant improvement was observed after two months of treatment as shown by WPI, SS Scale and FIQ. No significant variations were observed, except for the intracellular body water parameters, in anthropometric and body composition characteristics. Food-induced histaminosis release was observed to cow´s milk, egg, fruit, wheat and oily fish. Interleukin-1β (IL-1β) and interleukin-6 (IL-6) plasma cytokine values were significantly higher in FM. A strong positive correlation was observed between the percentage of reduction of cytokine levels and the improvement of health status. We propose: i) the existence of different subsets of FM patients; ii) the use of intracellular body water and plasma cytokine values as positive markers for FM progression; iii) that food-sensitisation could be an important mechanism for FM pathogenesis and iv) the use of a multidisciplinary approach for FM treatment

Statistical downscaling in the tropics can be sensitive to reanalysis choice: A case study for precipitation in the Philippines

This work shows that local-scale climate projections obtained by means of statistical downscaling are sensitive to the choice of reanalysis used for calibration. To this aim, a generalized linear model (GLM) approach is applied to downscale daily precipitation in the Philippines. First, the GLMs are trained and tested separately with two distinct reanalyses (ERA-Interim and JRA-25) using a cross-validation scheme over the period 1981–2000. When the observed and downscaled time series are compared, the attained performance is found to be sensitive to the reanalysis considered if climate change signal–bearing variables (temperature and/or specific humidity) are included in the predictor field. Moreover, performance differences are shown to be in correspondence with the disagreement found between the raw predictors from the two reanalyses. Second, the regression coefficients calibrated either with ERA-Interim or JRA-25 are subsequently applied to the output of a global climate model (MPI-ECHAM5) in order to assess the sensitivity of local-scale climate change projections (up to 2100) to reanalysis choice. In this case, the differences detected in present climate conditions are considerably amplified, leading to “delta-change” estimates differing by up to 35% (on average for the entire country) depending on the reanalysis used for calibration. Therefore, reanalysis choice is an important contributor to the uncertainty of local-scale climate change projections and, consequently, should be treated with as much care as other better-known sources of uncertainty (e.g., the choice of the GCM and/or downscaling method). Implications of the results for the entire tropics, as well as for the model output statistics downscaling approach are also briefly discussed.The authors are grateful to the free distribution of the ECMWF ERA-Interim (http://www.ecmwf.int/en/research/climate-reanalysis/era-interim), JMA JRA-25 (http://jra.kishou.go.jp/JRA-25/index_en.html), and MPI-ECHAM5 data (http://cera-www.dkrz.de/WDCC/ui/Compact.jsp?acronym=ENSEMBLES_MPEH5_SRA1B_3_D) and acknowledge PAGASA for the observational data provided. This study was supported by the EU projects QWeCI and SPECS, funded by the European Commission through the Seventh Framework Programme for Research under Grant Agreements 243964 and 308378, respectively. RM also acknowledges the EU project EUPORIAS, funded by the European Commission through the Seventh Framework Programme for Research under Grant Agreement 308291. SB is grateful to the CSIC-JAE-Predoc Program for financial support