The Multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous structural work. We identify four distinct homodimerization interfaces on the GR-LBD surface, which can associate into 20 topologically different homodimers. Biologically relevant homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution, quantitative fluorescence microscopy in living cells, and transcriptomic analyses. Our results highlight the relevance of non-canonical dimerization modes for GR, especially of contacts made by loop L1-3 residues such as Tyr545. Our work illustrates the unique flexibility of GR's LBD and suggests different dimeric conformations within cells. In addition, we unveil pathophysiologically relevant quaternary assemblies of the receptor with important implications for glucocorticoid action and drug design

The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities

20 páginas, 7 figurasThe glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous structural work. We identify four distinct homodimerization interfaces on the GR-LBD surface, which can associate into 20 topologically different homodimers. Biologically relevant homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution, quantitative fluorescence microscopy in living cells, and transcriptomic analyses. Our results highlight the relevance of non-canonical dimerization modes for GR, especially of contacts made by loop L1-3 residues such as Tyr545. Our work illustrates the unique flexibility of GR's LBD and suggests different dimeric conformations within cells. In addition, we unveil pathophysiologically relevant quaternary assemblies of the receptor with important implications for glucocorticoid action and drug designE.E.-P. thanks the generosity of the Gemma E. Carretero Fund; MINECO [BFU2017-86906-R, SAF2017-71878-REDT, SAF2015-71878-REDT to E.E.-P., RTI2018-101500-B-I00 to P.F.-P., RTI2018-096735-B-100 to A.R.M., PID2019-110167RB-I00 to J.F.-R., SAF2017-89510-R to A.V.F. and C.C.]; G.L.H thanks the NIH Intramural Research Program; D.M.P was supported by CONICET. Funding for open access charge: Spanish Ministry of Science (MINECO).Peer reviewe

Registro Español de Trasplante Cardiaco. XXXI Informe Oficial de la Asociación de Insuficiencia Cardiaca de la Sociedad Española de Cardiología

Introducción y objetivos Se presentan las características clínicas y los resultados de los trasplantes cardiacos realizados en España con la actualización correspondiente a 2019. Métodos Se describen las características clínicas y los resultados de los trasplantes cardiacos realizados en 2019, así como las tendencias de estos en el periodo 2010-2018. Resultados En 2019 se realizaron 300 trasplantes (8.794 desde 1984; 2.745 entre 2010 y 2019). Respecto a años previos, los cambios más llamativos son el descenso hasta el 38% de los trasplantes realizados en código urgente, y la consolidación en el cambio de asistencia circulatoria pretrasplante, con la práctica desaparición del balón de contrapulsación (0, 7%), la estabilización del uso del oxigenador extracorpóreo de membrana (9, 6%) y el aumento de los dispositivos de asistencia ventricular (29%). La supervivencia en el trienio 2016-2018 es similar a la del trienio 2013-2015 (p = 0, 34), y ambas mejores que la del trienio 2010-2012 (p = 0, 002 y p = 0, 01 respectivamente). Conclusiones Se mantienen estables tanto la actividad del trasplante cardiaco en España como los resultados en supervivencia en los últimos 2 trienios. Hay una tendencia a realizar menos trasplantes urgentes, la mayoría con dispositivos de asistencia ventricular. Introduction and objectives: The present report describes the clinical characteristics and outcomes of heart transplants in Spain and updates the data to 2019. Methods: We describe the clinical characteristics and outcomes of heart transplants performed in Spain in 2019, as well as trends in this procedure from 2010 to 2018. Results: In 2019, 300 transplants were performed (8794 since 1984; 2745 between 2010 and 2019). Compared with previous years, the most notable findings were the decreasing rate of urgent transplants (38%), and the consolidation of the type of circulatory support prior to transplant, with an almost complete disappearance of counterpulsation balloon (0.7%), stabilization in the use of extracorporeal membrane oxygenation (9.6%), and an increase in the use of ventricular assist devices (29.0%). Survival from 2016 to 2018 was similar to that from 2013 to 2015 (P = .34). Survival in both these periods was better than that from 2010 to 2012 (P = .002 and P = .01, respectively). Conclusions: Heart transplant activity has remained stable during the last few years, as have outcomes (in terms of survival). There has been a trend to a lower rate of urgent transplants and to a higher use of ventricular assist devices prior to transplant

Tracing the origin of the panda's thumb

© 2015, Springer-Verlag Berlin Heidelberg. We investigate the relative development of the carnivoran radial sesamoids to untangle the evolution of this iconic structure. In the pandas (both giant and red), this `false thumb¿ is known to perform a grasping role during bamboo feeding in both the red and giant pandas. An original locomotor role has been inferred for ailurids, but this remains to be ascertained for ursids. A large sample of radial sesamoids of Indarctos arctoides from the Miocene of Batallones-3 (Spain) indicates that this early ailuropodine bear displayed a relatively hypertrophied radial sesamoid, with a configuration more similar to that of the red panda and other carnivorans than to that of giant pandas. This false thumb is the first evidence of this feature in the Ursidae, which can be linked to a more herbivorous diet. Moreover, in the two extant pandas, the false thumb should not be interpreted as an anatomical convergence, but as an exaptive convergence regarding its use during the bamboo feeding, which changes the evolutionary view of this singular structure.This study was supported by the Spanish Ministerio de Economía y Competitividad (CGL2011-25754, CGL2011-28681 and RYC–2009–04533 to D.M.A.). A.V. is a researcher in formation in the CSIC program JAE-PRE_CP2011 (CSIC program‘ Junta para la ampliación de estudios’), co-funded by the European Social Fund and has received funding from the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 226506 (SYNTHESYS; SE-TAF-3637),Peer Reviewe

El sistema de yacimientos de mamíferos miocenos del Cerro de los Batallones, Cuenca de Madrid: estado actual y perspectivas

77 págs, 24 láms.The Cerro de los Batallones (Los Batallones Butte) is located in the central-northern area of the Madrid Basin, central Spain. Nine vertebrates localities containing a large variety of mammals of Upper Vallesian Age (Late Miocene) have been found associated with the sediments forming the butte. From bottom to top, these sediments consist of magnesian lutite beds (Unit I), paleosols formed of sepiolite and opal (Unit II), and siliclastic, marlstone and carbonate beds (Unit III). The set of ERT profiles developed in Los Batallones Butte have demonstrate that electrical imaging techniques are an estimable tool for the characterization and prospecting of fossil sites developed in fine-grained siliciclastic sequences. These localities contain an exceptionally rich, varied and well-preserved vertebrate fauna together with invertebrate and plant fossils. Carnivore species are strikingly well represented at Batallones 1 and 3, and large herbivore species, such as mastodons, rhinoceros and giraffes, at Batallones 2, 4, 5 and 10. The taphonomical studies, together with the morphological features shown by the sedimentary fills of the mammal localities, permit an overall interpretation of these deposits as vertebrate traps. The study of these localities should offer a significant contribution to our understanding of the formation pattern of trap-like paleontological sites - which so far have been typically reported in karstic-type systems -, as well as an important source of paleobiological information about numerous vertebrate groups.Nuestro sincero agradecimiento a la Comunidad de Madrid (Dirección General de Patrimonio Histórico Artístico) por su apoyo a lo largo de todos estos años. A la empresa TOLSA, SA por su inapreciable ayuda en todas las circunstancias. National Geographic Society financió la campaña de Batallones-1 del año 2001. Son muchos los compañeros y amigos que han participado en las excavaciones, y en los diferentes proyectos de investigación de estos yacimientos, a todos ellos nuestro más sincero agradecimiento y nuestros mejores deseos, con la esperanza de seguir contando con su valiosa colaboración. Este trabajo se ha realizado en el marco de los proyectos de investigación MEC 2005-03900/BTE y CGL2006-01773/BTE, y del Grupo de Investigación CAM-UCM 910607.Peer reviewe

El sistema de yacimientos de mamíferos miocenos del Cerro de los Batallones, Cuenca de Madrid: estado actual y perspectivas.

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