Semantic Web Technologies for Managing EHR-related Clinical Knowledge

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PI3Kα inhibition reduces obesity in mice

Partial inhibition of PI3K is one of the best-validated and evolutionary conserved manipulations to extend longevity. The best known health beneficial effects of reduced PI3K are related to metabolism and include increased energy expenditure, reduced nutrient storage, and protection from obesity. We have previously shown that a dual chemical inhibitor of the alpha and delta PI3K isoforms (CNIO-PI3Ki) reduces obesity in mice and monkeys, without evident toxic effects after long-term treatment. Here, we dissect the role of the alpha and delta PI3K isoforms by making use of selective inhibitors against PI3Kα (BYL-719 also known as alpelisib) or PI3Kδ (GS-9820 also known as acalisib). Treatment of mice with the above mentioned inhibitors indicated that BYL-719 increases energy expenditure in normal mice and efficiently reduces body weight in obese (ob/ob) mice, whereas these effects were not observed with GS-9820. Of note, the dose of BYL-719 required to reduce obesity was 10x higher than the equivalent dose of CNIO-PI3Ki, which could suggest that simultaneous inhibition of PI3K alpha and delta is more beneficial than single inhibition of the alpha isoform. In summary, we conclude that inhibition of PI3Kα is sufficient to increase energy expenditure and reduce obesity, and suggest that concomitant PI3Kα inhibition could play an auxiliary role

Deciphering the biotic and climatic factors that influence floral scents : a systematic review of floral volatile emissions

Altres ajuts: Catalan Government grant FI-2013Currently, a global analysis of the information available on the relative composition of the floral scents of a very diverse variety of plant species is missing. Such analysis may reveal general patterns on the distribution and dominance of the volatile compounds that form these mixtures, and may also allow measuring the effects of factors such as the phylogeny, pollination vectors, and climatic conditions on the floral scents of the species. To fill this gap, we compiled published data on the relative compositions and emission rates of volatile organic compounds (VOCs) in the floral scents of 305 plant species from 66 families. We also gathered information on the groups of pollinators that visited the flowers and the climatic conditions in the areas of distribution of these species. This information allowed us to characterize the occurrence and relative abundances of individual volatiles in floral scents and the effects of biotic and climatic factors on floral scent. The monoterpenes trans-β-ocimene and linalool and the benzenoid benzaldehyde were the most abundant floral VOCs, in both ubiquity and predominance in the floral blends. Floral VOC richness and relative composition were moderately preserved traits across the phylogeny. The reliance on different pollinator groups and the climate also had important effects on floral VOC richness, composition, and emission rates of the species. Our results support the hypothesis that key compounds or compounds originating from specific biosynthetic pathways mediate the attraction of the main pollinators. Our results also indicate a prevalence of monoterpenes in the floral blends of plants that grow in drier conditions, which could link with the fact that monoterpene emissions protect plants against oxidative stresses throughout drought periods and their emissions are enhanced under moderate drought stress. Sesquiterpenes, in turn, were positively correlated with mean annual temperature, supporting that sesquiterpene emissions are dominated mainly by ambient temperature. This study is the first to quantitatively summarise data on floral-scent emissions and provides new insights into the biotic and climatic factors that influence floral scents

A Chemical Screen Identifies Compounds Capable of Selecting for Haploidy in Mammalian Cells

The recent availability of somatic haploid cell lines has provided a unique tool for genetic studies in mammals. However, the percentage of haploid cells rapidly decreases in these cell lines, which we recently showed is due to their overgrowth by diploid cells present in the cultures. Based on this property, we have now performed a phenotypic chemical screen in human haploid HAP1 cells aiming to identify compounds that facilitate the maintenance of haploid cells. Our top hit was 10-Deacetyl-baccatin-III (DAB), a chemical precursor in the synthesis of Taxol, which selects for haploid cells in HAP1 and mouse haploid embryonic stem cultures. Interestingly, DAB also enriches for diploid cells in mixed cultures of diploid and tetraploid cells, including in the colon cancer cell line DLD-1, revealing a general strategy for selecting cells with lower ploidy in mixed populations of mammalian cells.We would like to thank the members of the O.F.-C. laboratory and MonicaAlvarez-Fernandez for insightful comments and the Transgenic Mice, FlowCytometry, and Confocal Microscopy Units from the CNIO for their technicalhelp. T.O. was funded by a PhD fellowship from Boehringer IngelheimFonds. Research was funded by Fundacion Botı n, Banco Santander throughits Santander Universities Global Division, and by grants from MINECO(SAF2014-57791-REDC and SAF2014-59498-R to O.F.-C., SAF-2013-44866-R to S.O., and SAF2013-49147-P and SAF2016-80874-P to S.R.; pro-jects that were co-financed with ERDF-EU funds) and the EuropeanResearch Council (ERC-617840). Research at the G.d.C. laboratory is fundedby the AECC Scientific Foundation (LABAE16017DECA).S

Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality

Replicative stress during embryonic development influences ageing and predisposition to disease in adults. A protective mechanism against replicative stress is provided by the licensing of thousands of origins in G1 that are not necessarily activated in the subsequent S-phase. These `dormant' origins provide a backup in the presence of stalled forks and may confer flexibility to the replication program in specific cell types during differentiation, a role that has remained unexplored. Here we show, using a mouse strain with hypomorphic expression of the origin licensing factor mini-chromosome maintenance (MCM)3 that limiting origin licensing in vivo affects the functionality of hematopoietic stem cells and the differentiation of rapidly-dividing erythrocyte precursors. Mcm3-deficient erythroblasts display aberrant DNA replication patterns and fail to complete maturation, causing lethal anemia. Our results indicate that hematopoietic progenitors are particularly sensitive to replication stress, and full origin licensing ensures their correct differentiation and functionality.We thank members of our laboratories for helpful discussions, Marcos Malumbres (CNIO) for advice on the design of the Mcm3-Lox allele, Isabel Blanco for her administrative help with mouse work and Soraya Ruiz for excellent handling of the mouse colony in J.M.'s group. Research was supported by the Spanish Ministry of Economy and Competitiveness (grants BFU2013-49153-P and Consolider-Ingenio CSD2007-00015 to J.M., SAF2011-23753 to O.F.-C., BFU2012-35892 to J.I.) and RO1 HL092471 to E.P., S.A. was the recipient of an EMBO short-term fellowship to visit E.P.'s laboratory at UCSF. We are grateful to Manuel Serrano (CNIO), Almudena Ramiro (CNIC) and Arkaitz Ibarra (The Salk Institute, USA) for useful comments on the manuscript.S

miRNA profiling during antigen-dependent T cell activation: A role for miR-132-3p

microRNAs (miRNAs) are tightly regulated during T lymphocyte activation to enable the establishment of precise immune responses. Here, we analyzed the changes of the miRNA profiles of T cells in response to activation by cognate interaction with dendritic cells. We also studied mRNA targets common to miRNAs regulated in T cell activation. pik3r1 gene, which encodes the regulatory subunits of PI3K p50, p55 and p85, was identified as target of miRNAs upregulated after T cell activation. Using 3'UTR luciferase reporter-based and biochemical assays, we showed the inhibitory relationship between miR-132-3p upregulation and expression of the pik3r1 gene. Our results indicate that specific miRNAs whose expression is modulated during T cell activation might regulate PI3K signaling in T cells.We thank Miguel Vicente-Manzanares for help with English editing and Almudena R. Ramiro for helpful discussions. We appreciate help from Gloria Martinez del Hoyo on DCs experiments set up. We also thank the CNIC Genomics, Bioinformatics and Cellomics Units for technical support. This work was supported by grants SAF2014-55579R from Ministerio de Economia y Competitividad-Spain, ERC-2011-AdG 294340-GENTRIS, CIBER CARDIOVASCULAR (FEDER and Instituto de Salud Carlos III), PIE-13-00041 and INDISNET S2011-BMD-2332 (F.S.M.). The Centro Nacional de Investigaciones Cardiovasculares (CNIC, Spain) is supported by the Ministerio de Economia y Competitividad-Spain and the Pro-CNIC Foundation.S

A MODIS Photochemical Reflectance Index (PRI) as an Estimator of Isoprene Emissions in a Temperate Deciduous Forest

The quantification of isoprene and monoterpene emissions at the ecosystem level with available models and field measurements is not entirely satisfactory. Remote-sensing techniques can extend the spatial and temporal assessment of isoprenoid fluxes. Detecting the exchange of biogenic volatile organic compounds (BVOCs) using these techniques is, however, a very challenging goal. Recent evidence suggests that a simple remotely sensed index, the photochemical reflectance index (PRI), which is indicative of light-use efficiency, relative pigment levels and excess reducing power, is a good indirect estimator of foliar isoprenoid emissions. We tested the ability of PRI to assess isoprenoid fluxes in a temperate deciduous forest in central USA throughout the entire growing season and under moderate and extreme drought conditions. We compared PRI time series calculated with MODIS bands to isoprene emissions measured with eddy covariance. MODIS PRI was correlated with isoprene emissions for most of the season, until emissions peaked. MODIS PRI was also able to detect the timing of the annual peak of emissions, even when it was advanced in response to drought conditions. PRI is thus a promising index to estimate isoprene emissions when it is complemented by information on potential emission. It may also be used to further improve models of isoprene emission under drought and other stress conditions. Direct estimation of isoprene emission by PRI is, however, limited, because PRI estimates LUE, and the relationship between LUE and isoprene emissions can be modified by severe stress conditions

A MODIS Photochemical Reflectance Index (PRI) as an Estimator of Isoprene Emissions in a Temperate Deciduous Forest

The quantification of isoprene and monoterpene emissions at the ecosystem level with available models and field measurements is not entirely satisfactory. Remote-sensing techniques can extend the spatial and temporal assessment of isoprenoid fluxes. Detecting the exchange of biogenic volatile organic compounds (BVOCs) using these techniques is, however, a very challenging goal. Recent evidence suggests that a simple remotely sensed index, the photochemical reflectance index (PRI), which is indicative of light-use efficiency, relative pigment levels and excess reducing power, is a good indirect estimator of foliar isoprenoid emissions. We tested the ability of PRI to assess isoprenoid fluxes in a temperate deciduous forest in central USA throughout the entire growing season and under moderate and extreme drought conditions. We compared PRI time series calculated with MODIS bands to isoprene emissions measured with eddy covariance. MODIS PRI was correlated with isoprene emissions for most of the season, until emissions peaked. MODIS PRI was also able to detect the timing of the annual peak of emissions, even when it was advanced in response to drought conditions. PRI is thus a promising index to estimate isoprene emissions when it is complemented by information on potential emission. It may also be used to further improve models of isoprene emission under drought and other stress conditions. Direct estimation of isoprene emission by PRI is, however, limited, because PRI estimates LUE, and the relationship between LUE and isoprene emissions can be modified by severe stress conditions

A MODIS Photochemical Reflectance Index (PRI) as an Estimator of Isoprene Emissions in a Temperate Deciduous Forest

The quantification of isoprene and monoterpene emissions at the ecosystem level with available models and field measurements is not entirely satisfactory. Remote-sensing techniques can extend the spatial and temporal assessment of isoprenoid fluxes. Detecting the exchange of biogenic volatile organic compounds (BVOCs) using these techniques is, however, a very challenging goal. Recent evidence suggests that a simple remotely sensed index, the photochemical reflectance index (PRI), which is indicative of light-use efficiency, relative pigment levels and excess reducing power, is a good indirect estimator of foliar isoprenoid emissions. We tested the ability of PRI to assess isoprenoid fluxes in a temperate deciduous forest in central USA throughout the entire growing season and under moderate and extreme drought conditions. We compared PRI time series calculated with MODIS bands to isoprene emissions measured with eddy covariance. MODIS PRI was correlated with isoprene emissions for most of the season, until emissions peaked. MODIS PRI was also able to detect the timing of the annual peak of emissions, even when it was advanced in response to drought conditions. PRI is thus a promising index to estimate isoprene emissions when it is complemented by information on potential emission. It may also be used to further improve models of isoprene emission under drought and other stress conditions. Direct estimation of isoprene emission by PRI is, however, limited, because PRI estimates LUE, and the relationship between LUE and isoprene emissions can be modified by severe stress conditions