110 research outputs found
EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription
Caveolae are small invaginated pits that function as dynamic mechanosensors to buffer tension variations at the plasma membrane. Here we show that under mechanical stress, the EHD2 ATPase is rapidly released from caveolae, SUMOylated, and translocated to the nucleus, where it regulates the transcription of several genes including those coding for caveolae constituents. We also found that EHD2 is required to maintain the caveolae reservoir at the plasma membrane during the variations of membrane tension induced by mechanical stress. Metal-replica electron microscopy of breast cancer cells lacking EHD2 revealed a complete absence of caveolae and a lack of gene regulation under mechanical stress. Expressing EHD2 was sufficient to restore both functions in these cells. Our findings therefore define EHD2 as a central player in mechanotransduction connecting the disassembly of the caveolae reservoir with the regulation of gene transcription under mechanical stress
EMT Inducers Catalyze Malignant Transformation of Mammary Epithelial Cells and Drive Tumorigenesis towards Claudin-Low Tumors in Transgenic Mice
The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMTâinducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cellâlike characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation
Expert range maps of global mammal distributions harmonised to three taxonomic authorities
Aim: Comprehensive, global information on species' occurrences is an essential biodiversity variable and central to a range of applications in ecology, evolution, biogeography and conservation. Expert range maps often represent a species' only available distributional information and play an increasing role in conservation assessments and macroecology. We provide global range maps for the native ranges of all extant mammal species harmonised to the taxonomy of the Mammal Diversity Database (MDD) mobilised from two sources, the Handbook of the Mammals of the World (HMW) and the Illustrated Checklist of the Mammals of the World (CMW). Location: Global. Taxon: All extant mammal species. Methods: Range maps were digitally interpreted, georeferenced, error-checked and subsequently taxonomically aligned between the HMW (6253 species), the CMW (6431 species) and the MDD taxonomies (6362 species). Results: Range maps can be evaluated and visualised in an online map browser at Map of Life (mol.org) and accessed for individual or batch download for non-commercial use. Main conclusion: Expert maps of species' global distributions are limited in their spatial detail and temporal specificity, but form a useful basis for broad-scale characterizations and model-based integration with other data. We provide georeferenced range maps for the native ranges of all extant mammal species as shapefiles, with species-level metadata and source information packaged together in geodatabase format. Across the three taxonomic sources our maps entail, there are 1784 taxonomic name differences compared to the maps currently available on the IUCN Red List website. The expert maps provided here are harmonised to the MDD taxonomic authority and linked to a community of online tools that will enable transparent future updates and version control.Fil: Marsh, Charles J.. Yale University; Estados UnidosFil: Sica, Yanina. Yale University; Estados UnidosFil: Burguin, Connor. University of New Mexico; Estados UnidosFil: Dorman, Wendy A.. University of Yale; Estados UnidosFil: Anderson, Robert C.. University of Yale; Estados UnidosFil: del Toro Mijares, Isabel. University of Yale; Estados UnidosFil: Vigneron, Jessica G.. University of Yale; Estados UnidosFil: Barve, Vijay. University Of Florida. Florida Museum Of History; Estados UnidosFil: Dombrowik, Victoria L.. University of Yale; Estados UnidosFil: Duong, Michelle. University of Yale; Estados UnidosFil: Guralnick, Robert. University Of Florida. Florida Museum Of History; Estados UnidosFil: Hart, Julie A.. University of Yale; Estados UnidosFil: Maypole, J. Krish. University of Yale; Estados UnidosFil: McCall, Kira. University of Yale; Estados UnidosFil: Ranipeta, Ajay. University of Yale; Estados UnidosFil: Schuerkmann, Anna. University of Yale; Estados UnidosFil: Torselli, Michael A.. University of Yale; Estados UnidosFil: Lacher, Thomas. Texas A&M University; Estados UnidosFil: Wilson, Don E.. National Museum of Natural History; Estados UnidosFil: Abba, Agustin Manuel. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - La Plata. Centro de Estudios ParasitolĂłgicos y de Vectores. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Centro de Estudios ParasitolĂłgicos y de Vectores; ArgentinaFil: Aguirre, Luis F.. Universidad Mayor de San SimĂłn; BoliviaFil: Arroyo Cabrales, JoaquĂn. Instituto Nacional de AntropologĂa E Historia, Mexico; MĂ©xicoFil: AstĂșa, Diego. Universidade Federal de Pernambuco; BrasilFil: Baker, Andrew M.. Queensland University of Technology; Australia. Queensland Museum; AustraliaFil: Braulik, Gill. University of St. Andrews; Reino UnidoFil: Braun, Janet K.. Oklahoma State University; Estados UnidosFil: Brito, Jorge. Instituto Nacional de Biodiversidad; EcuadorFil: Busher, Peter E.. Boston University; Estados UnidosFil: Burneo, Santiago F.. Pontificia Universidad CatĂłlica del Ecuador; EcuadorFil: Camacho, M. Alejandra. Pontificia Universidad CatĂłlica del Ecuador; EcuadorFil: de Almeida Chiquito, Elisandra. Universidade Federal do EspĂrito Santo; BrasilFil: Cook, Joseph A.. University of New Mexico; Estados UnidosFil: CuĂ©llar Soto, Erika. Sultan Qaboos University; OmĂĄnFil: Davenport, Tim R. B.. Wildlife Conservation Society; TanzaniaFil: Denys, Christiane. MusĂ©um National d'Histoire Naturelle; FranciaFil: Dickman, Christopher R.. The University Of Sydney; AustraliaFil: Eldridge, Mark D. B.. Australian Museum; AustraliaFil: Fernandez Duque, Eduardo. University of Yale; Estados UnidosFil: Francis, Charles M.. Environment And Climate Change Canada; CanadĂĄFil: Frankham, Greta. Australian Museum; AustraliaFil: Freitas, Thales. Universidade Federal do Rio Grande do Sul; BrasilFil: Friend, J. Anthony. Conservation And Attractions; AustraliaFil: Giannini, Norberto Pedro. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico - TucumĂĄn. Unidad Ejecutora Lillo; ArgentinaFil: Gursky-Doyen, Sharon. Texas A&M University; Estados UnidosFil: HacklĂ€nder, Klaus. Universitat Fur Bodenkultur Wien; AustriaFil: Hawkins, Melissa. National Museum of Natural History; Estados UnidosFil: Helgen, Kristofer M.. Australian Museum; AustraliaFil: Heritage, Steven. University of Duke; Estados UnidosFil: Hinckley, Arlo. Consejo Superior de Investigaciones CientĂficas. EstaciĂłn BiolĂłgica de Doñana; EspañaFil: Holden, Mary. American Museum of Natural History; Estados UnidosFil: Holekamp, Kay E.. Michigan State University; Estados UnidosFil: Humle, Tatyana. University Of Kent; Reino UnidoFil: Ibåñez Ulargui, Carlos. Consejo Superior de Investigaciones CientĂficas. EstaciĂłn BiolĂłgica de Doñana; EspañaFil: Jackson, Stephen M.. Australian Museum; AustraliaFil: Janecka, Mary. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Jenkins, Paula. Natural History Museum; Reino UnidoFil: Juste, Javier. Consejo Superior de Investigaciones CientĂficas. EstaciĂłn BiolĂłgica de Doñana; EspañaFil: Leite, Yuri L. R.. Universidade Federal do EspĂrito Santo; BrasilFil: Novaes, Roberto Leonan M.. Universidade Federal do Rio de Janeiro; BrasilFil: Lim, Burton K.. Royal Ontario Museum; CanadĂĄFil: Maisels, Fiona G.. Wildlife Conservation Society; Estados UnidosFil: Mares, Michael A.. Oklahoma State University; Estados UnidosFil: Marsh, Helene. James Cook University; AustraliaFil: Mattioli, Stefano. UniversitĂ degli Studi di Siena; ItaliaFil: Morton, F. Blake. University of Hull; Reino UnidoFil: Ojeda, Agustina Alejandra. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mendoza. Instituto Argentino de Investigaciones de las Zonas Ăridas. Provincia de Mendoza. Instituto Argentino de Investigaciones de las Zonas Ăridas. Universidad Nacional de Cuyo. Instituto Argentino de Investigaciones de las Zonas Ăridas; ArgentinaFil: Ordóñez Garza, NictĂ©. Instituto Nacional de Biodiversidad; EcuadorFil: Pardiñas, Ulises Francisco J.. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Centro Nacional PatagĂłnico. Instituto de Diversidad y EvoluciĂłn Austral; ArgentinaFil: Pavan, Mariana. Universidade de Sao Paulo; BrasilFil: Riley, Erin P.. San Diego State University; Estados UnidosFil: Rubenstein, Daniel I.. University of Princeton; Estados UnidosFil: Ruelas, Dennisse. Museo de Historia Natural, Lima; PerĂșFil: Schai-Braun, StĂ©phanie. Universitat Fur Bodenkultur Wien; AustriaFil: Schank, Cody J.. University of Texas at Austin; Estados UnidosFil: Shenbrot, Georgy. Ben Gurion University of the Negev; IsraelFil: Solari, Sergio. Universidad de Antioquia; ColombiaFil: Superina, Mariella. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mendoza. Instituto de Medicina y BiologĂa Experimental de Cuyo; ArgentinaFil: Tsang, Susan. American Museum of Natural History; Estados UnidosFil: Van Cakenberghe, Victor. Universiteit Antwerp; BĂ©lgicaFil: Veron, Geraldine. UniversitĂ© Pierre et Marie Curie; FranciaFil: Wallis, Janette. Kasokwa-kityedo Forest Project; UgandaFil: Whittaker, Danielle. Michigan State University; Estados UnidosFil: Wells, Rod. Flinders University.; AustraliaFil: Wittemyer, George. State University of Colorado - Fort Collins; Estados UnidosFil: Woinarski, John. Charles Darwin University; AustraliaFil: Upham, Nathan S.. University of Yale; Estados UnidosFil: Jetz, Walter. University of Yale; Estados Unido
Genetic Variants For Head Size Share Genes and Pathways With Cancer
The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer
Expert range maps of global mammal distributions harmonised to three taxonomic authorities
AimComprehensive, global information on species' occurrences is an essential biodiversity variable and central to a range of applications in ecology, evolution, biogeography and conservation. Expert range maps often represent a species' only available distributional information and play an increasing role in conservation assessments and macroecology. We provide global range maps for the native ranges of all extant mammal species harmonised to the taxonomy of the Mammal Diversity Database (MDD) mobilised from two sources, the Handbook of the Mammals of the World (HMW) and the Illustrated Checklist of the Mammals of the World (CMW).LocationGlobal.TaxonAll extant mammal species.MethodsRange maps were digitally interpreted, georeferenced, error-checked and subsequently taxonomically aligned between the HMW (6253 species), the CMW (6431 species) and the MDD taxonomies (6362 species).ResultsRange maps can be evaluated and visualised in an online map browser at Map of Life (mol.org) and accessed for individual or batch download for non-commercial use.Main conclusionExpert maps of species' global distributions are limited in their spatial detail and temporal specificity, but form a useful basis for broad-scale characterizations and model-based integration with other data. We provide georeferenced range maps for the native ranges of all extant mammal species as shapefiles, with species-level metadata and source information packaged together in geodatabase format. Across the three taxonomic sources our maps entail, there are 1784 taxonomic name differences compared to the maps currently available on the IUCN Red List website. The expert maps provided here are harmonised to the MDD taxonomic authority and linked to a community of online tools that will enable transparent future updates and version control
Overview of the current use of levosimendan in France: a prospective observational cohort study
Abstract Background Following the results of randomized controlled trials on levosimendan, French health authorities requested an update of the current use and side-effects of this medication on a national scale. Method The France-LEVO registry was a prospective observational cohort study reflecting the indications, dosing regimens, and side-effects of levosimendan, as well as patient outcomes over a year. Results The patients included ( n =â602) represented 29.6% of the national yearly use of levosimendan in France. They were treated for cardiogenic shock ( n =â250, 41.5%), decompensated heart failure ( n =â127, 21.1%), cardiac surgery-related low cardiac output prophylaxis and/or treatment ( n =â86, 14.3%), and weaning from veno-arterial extracorporeal membrane oxygenation ( n =â82, 13.6%). They received 0.18â±â0.07 ”g/kg/min levosimendan over 26â±â8 h. An initial bolus was administered in 45 patients (7.5%), 103 (17.1%) received repeated infusions, and 461 (76.6%) received inotropes and or vasoactive agents concomitantly. Hypotension was reported in 218 patients (36.2%), atrial fibrillation in 85 (14.1%), and serious adverse events in 17 (2.8%). 136 patients (22.6%) died in hospital, and 26 (4.3%) during the 90-day follow-up. Conclusions We observed that levosimendan was used in accordance with recent recommendations by French physicians. Hypotension and atrial fibrillation remained the most frequent side-effects, while serious adverse event potentially attributable to levosimendan were infrequent. The results suggest that this medication was safe and potentially associated with some benefit in the population studied
Multiancestry analysis of the HLA locus in Alzheimerâs and Parkinsonâs diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinsonâs disease (PD) and Alzheimerâs disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased AÎČ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues
Preoperative physical frailty assessment among octogenarians undergoing cardiac surgery : upgrading the "eyeball" test
Titre de l'Ă©cran-titre (visionnĂ© le 1er mai 2023)Introduction: La fragilitĂ© a un impact rĂ©el sur le risque de mortalitĂ©, de morbiditĂ©s majeures ainsi que sur la qualitĂ© de vie en postopĂ©ratoire chez les personnes ĂągĂ©es qui subissent une chirurgie cardiaque par sternotomie. Cependant, il n'y a aucun consensus sur le dĂ©pistage de ce syndrome. Ce mĂ©moire a pour but de prĂ©senter notre projet de recherche qui porte sur l'identification d'un test physique pour le dĂ©pistage du syndrome de fragilitĂ©. MĂ©thodes: Entre 2016 et 2019, 200 octogĂ©naires de plus de 80 ans, en attente de chirurgie cardiaque Ă©lective, Ă©taient recrutĂ©s dans notre Ă©tude prospective et observationnelle. Tous les participants ont passĂ© 4 tests physiques la veille de leur chirurgie cardiaque: le test de vitesse de marche sur 5 mĂštres (5MWT), le test de rĂ©pĂ©titions assis-debout 5 fois (5STS), le test chronomĂ©trĂ© du lever de chaise (TUG) et le test de force de prĂ©hension de la main dominante (HGS). L'issue primaire Ă©tait composĂ©e de mortalitĂ© intra-hospitaliĂšre et/ou de morbiditĂ©(s) majeure(s). RĂ©sultats: La mortalitĂ© Ă©tait de 1.5% mais l'issue primaire a touchĂ© 26% de la cohorte entiĂšre. Seule la vitesse de marche lente (durĂ©e de marche â„ 6.4 seconds sur une distance de 5 mĂštres) avait une association avec l'issue primaire (RC ajustĂ© : 2.70 ; IC Ă 95% : 1.34-5.45; p=0.006). Au suivi d'un an, les patients ayant une vitesse de marche lente avaient une survie significativement diminuĂ©e (survie 1 an 91.5% vs 98.7%, log-rank p=0.03). Le score moyen des domaines physiques et mental du questionnaire SF-12 Ă©taient de 47.2±8.3 et 53.6±5.9 respectivement. Ces scores sont comparables Ă ceux d'une population ĂągĂ©e de plus de 75 ans. Conclusion: Le test de vitesse de marche sur 5 mĂštres s'est avĂ©rĂ© prĂ©dicteur indĂ©pendant de l'issue primaire composĂ©e de mortalitĂ© hospitaliĂšre et/ou morbiditĂ©s majeures. Ce test simple est un bon complĂ©ment au « Eyeball Test » dans une routine prĂ©opĂ©ratoire chez les octogĂ©naires en attente d'une chirurgie cardiaque par sternotomie.Objectives: There are many well-described, but as yet unproven, physical ability tools to assess frailty. Methods: Between 2016-2019, 200 patients â„80 years undergoing elective cardiac surgery were prospectively recruited. Four physical tests were performed preoperatively: the 5-meter walk test (5MWT), the timed up-and-go test (TUG), the 5-time sit-to-stand test (5STS), and the handgrip strength test (HGS). The primary endpoint was a composite of in-hospital mortality, neurologic, and pulmonary complications; multivariate analysis was performed. Results: In-hospital mortality was 1.5%. Slow performance on the 5MWT (timeâ„ 6.4 seconds) was the only independent predictor of the composite endpoint among the tests evaluated (OR 2.70; 95% CI 1.34-5.45; p=0.006). At follow-up, patients with a slow 5MWT had a significantly lower mid-term survival compared to patients with a normal test (1-year survival 91.5% vs. 98.7%, log-rank p=0.03). Mean physical and mental component scores of the SF-12 were 47.2±8.3 and 53.6±5.9 respectively, which are comparable to those of a general population>75 years old. Conclusion: The 5-meter walk time test is an independent predictor of a composite of in-hospital mortality and major morbidity, as well as mid-term survival. This test could be used as a simple adjunctive preoperative tool for octogenarians undergoing cardiac surgery
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