13 research outputs found

    Notch Signaling Mediates Differentiation in Barrett\u27s Esophagus and Promotes Progression to Adenocarcinoma

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    © 2020 AGA Institute Background & Aims: Studies are needed to determine the mechanism by which Barrett\u27s esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis. Methods: We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5+ (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB. Results: Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5+ cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5+ cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5+ cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation. Conclusions: Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE

    Efficacy, Toxicity, and Immunogenicity of Adenoviral Vectors

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    Maximum rooting depth of vegetation types at the global scale

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    The depth at which plants are able to grow roots has important implications for the whole ecosystem hydrological balance, as well as for carbon and nutrient cycling. Here we summarize maximum rooting depth of species belonging to the major terrestrial biomes. We found 290 observations of maximum rooting depth in the literature which covered 255 woody and herbaceous species. Maximum rooting depth ranged from 0.3 m for some tundra species to 68 m for Boscia albitrunca in the central Kalahari; 196 species had roots at least 2 m deep, 50 species had roots at a depth of 5 m or more, and 22 species had roots as deep as 10 m or more. The average for the globe was 4.6 +0.5 m. Maximum root depth by biome was 2.0 m for boreal forest, 2.1 m for cropland, 9.5 m for desert, 5.2 m for sclerophyllous shrubland and forest, 3.9 m for temperate coniferous forest, 2.9 m for temperate deciduous forest, 2.6 m for temperate grassland, 3.7 m for tropical deciduous forest, 7.3 m for tropical evergreen forest, 15.0 m for tropical grassland/savanna, and 0.5 m for tundra. Grouping all species across biomes (except croplands) by three basic functional groups (trees, shrubs, and herbaceous plants), the average maximum rooting depth was 7.0 m for trees, 5.1 m for shrubs, and 2.6 m for herbaceous plants

    Economie sociale et solidaire et territoires : un couple allant de soi ?

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    L’ancrage territorial constitue, avec le fonctionnement démocratique et la solidarité économique, l’une des caractéristiques majeures de l’économie sociale et solidaire (ESS). Loin de postuler une territorialité spontanée de l’ESS, nous proposons de réintégrer l’observation des dynamiques d’ESS dans les jeux de complémentarité, coopération ou concurrence propres aux processus de constructions territoriales. Le statut de l’ESS dans les transformations globales des modes de coordination des systèmes productifs territoriaux est d’abord analysé. Deux pistes de recherche concernant l’ESS et la gouvernance territoriale sont ensuite déclinées. La première concerne l’institutionnalisation de l’ESS en tant que secteur de l’action publique territoriale. La deuxième interroge le postulat d’une congruence parfaite entre le tournant horizontal et territorial de l’action publique et les objectifs affichés de l’ESS.Like democratic management and economic solidarity, local embeddedness is one of the main features of the social and solidarity economy. Far from arguing that the social and solidarity economy is naturally embedded in the community, we propose to bring the observed dynamics of the social and solidarity economy back into the complementarity, cooperation or competition specific to the processes of territorial constructions. The role of the social and solidarity economy in the global transformation of the coordination of territorial productive systems is then examined. Two lines of research concerning the social and solidarity economy and territorial governance are presented. The first concerns the institutionalisation of the social and solidarity economy as a sector of local community action. The second questions the premise that the horizontal and territorial transformation of local community action and the declared objectives of the social and solidarity economy are perfectly compatible

    Search for third-generation scalar leptoquarks and heavy right-handed neutrinos in final states with two tau leptons and two jets in proton-proton collisions at sqrt(s)=13 TeV

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    A search is performed for third-generation scalar leptoquarks and heavy right-handed neutrinos in events containing one electron or muon, one hadronically decaying τ lepton, and at least two jets, using a s=13 TeV pp collision data sample corresponding to an integrated luminosity of 12.9 fb-1collected with the CMS detector at the LHC in 2016. The number of observed events is found to be in agreement with the standard model prediction. A limit is set at 95% confidence level on the product of the leptoquark pair production cross section and β2, where β is the branching fraction of leptoquark decay to a τ lepton and a bottom quark. Assuming β = 1, third-generation leptoquarks with masses below 850 GeV are excluded at 95% confidence level. An additional search based on the same event topology involves heavy right-handed neutrinos, NR, and right-handed W bosons, WR, arising in a left-right symmetric extension of the standard model. In this search, WRbosons are assumed to decay to a tau lepton and NRfollowed by the decay of the NRto a tau lepton and an off-shell WRboson. Assuming the mass of the right-handed neutrino to be half of the mass of the right-handed W boson, WRboson masses below 2.9 TeV are excluded at 95% confidence level. These results improve on the limits from previous searches for third-generation leptoquarks and heavy right-handed neutrinos with τ leptons in the final state.[Figure not available: see fulltext.]
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