Cryo-EM structure of metazoan TRAPPIII, the multi-subunit complex that activates the GTPase Rab1.

The TRAPP complexes are nucleotide exchange factors that play essential roles in membrane traffic and autophagy. TRAPPII activates Rab11, and TRAPPIII activates Rab1, with the two complexes sharing a core of small subunits that affect nucleotide exchange but being distinguished by specific large subunits that are essential for activity in vivo. Crystal structures of core subunits have revealed the mechanism of Rab activation, but how the core and the large subunits assemble to form the complexes is unknown. We report a cryo-EM structure of the entire Drosophila TRAPPIII complex. The TRAPPIII-specific subunits TRAPPC8 and TRAPPC11 hold the catalytic core like a pair of tongs, with TRAPPC12 and TRAPPC13 positioned at the joint between them. TRAPPC2 and TRAPPC2L link the core to the two large arms, with the interfaces containing residues affected by disease-causing mutations. The TRAPPC8 arm is positioned such that it would contact Rab1 that is bound to the core, indicating how the arm could determine the specificity of the complex. A lower resolution structure of TRAPPII shows a similar architecture and suggests that the TRAPP complexes evolved from a single ur-TRAPP

Hif-1α knockdown reduces glycolytic metabolism and induces cell death of human synovial fibroblasts under normoxic conditions

[Abstract] Increased glycolysis and HIF-1α activity are characteristics of cells under hypoxic or inflammatory conditions. Besides, in normal O2 environments, elevated rates of glycolysis support critical cellular mechanisms such as cell survival. The purpose of this study was to analyze the contribution of HIF-1α to the energy metabolism and survival of human synovial fibroblasts (SF) under normoxic conditions. HIF-1α was silenced using lentiviral vectors or small-interfering RNA (siRNA) duplexes. Expression analysis by qRT-PCR and western blot of known HIF-1α target genes in hypoxia demonstrated the presence of functional HIF-1α in normoxic SF and confirmed the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a HIF-1α target even in normoxia. HIF-1α silencing induced apoptotic cell death in cultured SF and, similarly, treatment with glycolytic, but not with OXPHOS inhibitors, induced SF death. Finally, in vivo HIF-1α targeting by siRNA showed a significant reduction in the viability of human SF engrafted into a murine air pouch. Our results demonstrate that SF are highly dependent on glycolytic metabolism and that HIF-1α plays a regulatory role in glycolysis even under aerobic conditions. Local targeting of HIF-1α provides a feasible strategy to reduce SF hyperplasia in chronic arthritic diseases.Instituto de Salud Carlos III; FIS 12/439Instituto de Salud Carlos III; RETICS RD12/009Instituto de Salud Carlos III; CP13/00014Comunidad de Madrid; RAPHYME-CM S2010/BMD235

Combinación de estrategias de innovación docente para la enseñanza de asignaturas de Ciencias de la Tierra: aprendizaje colaborativo y basado en proyectos como fuente de material para el aula invertida

Se han combinado diferentes estrategias de innovación docente para la creación de material de uso en el aula invertida. Grupos de alumnos han realizado micro-videotutoriales para la resolución de problemas básicos de cortes geológicos, realizando ellos mismos desde el guion hasta la edición, pasando por la grabación. Mediante esta actividad han tenido que desarrollar un proyecto y trabajar de forma colaborativa. El resultado de este trabajo ha sido una colección de microvideos que están siendo empleados en la formación de otros alumnos mediante el aula invertida en varias asignaturas de Ciencias de la Tierra. Los videos se han puesto a disposición de los alumnos a través de la plataforma Moodle de la UPM para que puedan aprender y repasar las técnicas de resolución de problemas de forma autónoma

Wage inequality, segregation by skill and the price of capital in an assignment model

Some pieces of empirical evidence suggest that in the U.S., over the last few decades, (i) wage inequality between-plants has risen much more than wage inequality within-plants and (ii) there has been an increase in the segregation of workers by skill into separate plants. This paper presents a frictionless assignment model in which these two features can be explained simultaneously as the result of the decline in the relative price of capital. Additional implications of the model regarding the skill premium and the dispersion in labor productivity across plants are also consistent with the empirical evidence. [resumen de autor

abd-A Regulation by the iab-8 Noncoding RNA

The homeotic genes in Drosophila melanogaster are aligned on the chromosome in the order of the body segments that they affect. The genes affecting the more posterior segments repress the more anterior genes. This posterior dominance rule must be qualified in the case of abdominal-A (abd-A) repression by Abdominal-B (Abd-B). Animals lacking Abd-B show ectopic expression of abd-A in the epidermis of the eighth abdominal segment, but not in the central nervous system. Repression in these neuronal cells is accomplished by a 92 kb noncoding RNA. This “iab-8 RNA” produces a micro RNA to repress abd-A, but also has a second, redundant repression mechanism that acts only “in cis.” Transcriptional interference with the abd-A promoter is the most likely mechanism

IVRIPARC project: a method for assessing the impact of global change on geoheritage of the Canary Islands national parks (Spain)

El patrimonio geológico y la geodiversidad de los parques nacionales contribuyen, junto con la biodiversidad, para que sean espacios naturales protegidos únicos en el país, pero también únicos a nivel mundial. El patrimonio geológico es de carácter no renovable, de tal forma que, si se pierden o degradan, lo hacen para siempre. Ante el escenario del cambio global, el patrimonio geológico de los parques nacionales canarios es muy vulnerable a los impactos rovocados por los cambios en la temperatura, avenidas torrenciales, tormentas extremas, sequías, desertificación y ascenso del nivel del mar, fundamentalmente, y a los impactos derivados de la actividad humana. Estos fenómenos provocan la activación de procesos geológicos que afectan directamente a su conservación, de tal forma que es necesario identificar los Lugares de Interés Geológico más amenazados, evaluar su incidencia y establecer los indicadores a escala de cada parque nacional para realizar su seguimiento. Conocer el estado de conservación actual, su vulnerabilidad y sus amenazas directas contribuirá a la gestión de los parques para el proceso de adaptación y mitigación del cambio global.The geoheritage and geodiversity of the national parks contribute, together with biodiversity, to make them protected natural areas that are unique in Spain, but also unique worldwide. Geoheritage is non-renewable and if it is lost or degraded it does so forever. Under the Global Change and Climate Change scenario, the geoheritage of the Canary national parks is highly vulnerable to the impacts caused by changes in temperature, flash floods, extreme storms, droughts, desertification, fires and sea level rise, fundamentally and to the impacts directly derived from human activity. These phenomena trigger the activation of geological processes that directly affect their conservation, in such a way that it is necessary to identify the geosites most threatened, to evaluate their impact and to establish the indicators at the scale of each national park for monitoring them. The knowledge of the current conservation status of geoheritage, its vulnerability and its direct threats will contribute to the management of the national parks for the process of adaptation and mitigation of Global Change.Depto. de Geodinámica, Estratigrafía y PaleontologíaDepto. de Mineralogía y PetrologíaFac. de Ciencias GeológicasTRUEOrganismo Autónomo de Parques Nacionalespu

New high-sensitivity searches for neutrons converting into antineutrons and/or sterile neutrons at the HIBEAM/NNBAR experiment at the European Spallation Source

The violation of baryon number, B, is an essential ingredient for the preferential creation of matter over antimatter needed to account for the observed baryon asymmetry in the Universe. However, such a process has yet to be experimentally observed. The HIBEAM/NNBAR program is a proposed two-stage experiment at the European Spallation Source to search for baryon number violation. The program will include high-sensitivity searches for processes that violate baryon number by one or two units: free neutron-antineutron oscillation (n -> (n) over bar) via mixing, neutron-antineutron oscillation via regeneration from a sterile neutron state (n -> [n',(n) over bar'] -> (n) over bar), and neutron disappearance (n -> n'); the effective Delta B = 0 process of neutron regeneration (n ->[n',(n) over bar'] -> n) is also possible. The program can be used to discover and characterize mixing in the neutron, antineutron and sterile neutron sectors. The experiment addresses topical open questions such as the origins of baryogenesis and the nature of dark matter, and is sensitive to scales of new physics substantially in excess of those available at colliders. A goal of the program is to open a discovery window to neutron conversion probabilities (sensitivities) by up to three orders of magnitude compared with previous searches. The opportunity to make such a leap in sensitivity tests should not be squandered. The experiment pulls together a diverse international team of physicists from the particle (collider and low energy) and nuclear physics communities, while also including specialists in neutronics and magnetics.Peer reviewe