PrimPol-mediated repriming facilitates replication traverse of DNA interstrand crosslinks

DNA interstrand crosslinks (ICLs) induced by endogenous aldehydes or chemotherapeutic agents interfere with essential processes such as replication and transcription. ICL recognition and repair by the Fanconi Anemia pathway require the formation of an X-shaped DNA structure that may arise from convergence of two replication forks at the crosslink or traversing of the lesion by a single replication fork. Here, we report that ICL traverse strictly requires DNA repriming events downstream of the lesion, which are carried out by PrimPol, the second primase-polymerase identified in mammalian cells after Polα/Primase. The recruitment of PrimPol to the vicinity of ICLs depends on its interaction with RPA, but not on FANCM translocase or the BLM/TOP3A/RMI1-2 (BTR) complex that also participate in ICL traverse. Genetic ablation of PRIMPOL makes cells more dependent on the fork convergence mechanism to initiate ICL repair, and PRIMPOL KO cells and mice display hypersensitivity to ICL-inducing drugs. These results open the possibility of targeting PrimPol activity to enhance the efficacy of chemotherapy based on DNA crosslinking agents.Spanish Ministry of Science, Innovation and Universities (grants BFU2016-80402R and BFU2019-106707-RB to JM and PGC2018.093576-B-C21 to LB, co-sponsored by EU ERDF funds), the Swiss National Science Foundation (grant 31003A_169959 to ML), and an ERC Consolidator Grant (617102 to ML

Solubility of Methane in Water: Some Useful Results for Hydrate Nucleation

In this paper, the solubility of methane in water along the 400 bar isobar is determined by computer simulations using the TIP4P/Ice force field for water and a simple LJ model for methane. In particular, the solubility of methane in water when in contact with the gas phase and the solubility of methane in water when in contact with the hydrate has been determined. The solubility of methane in a gas–liquid system decreases as temperature increases. The solubility of methane in a hydrate–liquid system increases with temperature. The two curves intersect at a certain temperature that determines the triple point T3 at a certain pressure. We also determined T3 by the three-phase direct coexistence method. The results of both methods agree, and we suggest 295(2) K as the value of T3 for this system. We also analyzed the impact of curvature on the solubility of methane in water. We found that the presence of curvature increases the solubility in both the gas–liquid and hydrate–liquid systems. The change in chemical potential for the formation of hydrate is evaluated along the isobar using two different thermodynamic routes, obtaining good agreement between them. It is shown that the driving force for hydrate nucleation under experimental conditions is higher than that for the formation of pure ice when compared at the same supercooling. We also show that supersaturation (i.e., concentrations above those of the planar interface) increases the driving force for nucleation dramatically. The effect of bubbles can be equivalent to that of an additional supercooling of about 20 K. Having highly supersaturated homogeneous solutions makes possible the spontaneous formation of the hydrate at temperatures as high as 285 K (i.e., 10K below T3). The crucial role of the concentration of methane for hydrate formation is clearly revealed. Nucleation of the hydrate can be either impossible or easy and fast depending on the concentration of methane which seems to play the leading role in the understanding of the kinetics of hydrate formation

Propuesta de diseño de una plantilla multidisciplinar para el análisis y evaluación de webs de destinos turísticos

The article presents an interdisciplinary analytical framework that combines some automated analysis with other qualitative and quantitative on web sites of tourist destinations

PrimPol-mediated repriming facilitates replication traverse of DNA interstrand crosslinks

DNA interstrand crosslinks (ICLs) induced by endogenous aldehydes or chemotherapeutic agents interfere with essential processes such as replication and transcription. ICL recognition and repair by the Fanconi Anemia pathway require the formation of an X-shaped DNA structure that may arise from convergence of two replication forks at the crosslink or traversing of the lesion by a single replication fork. Here, we report that ICL traverse strictly requires DNA repriming events downstream of the lesion, which are carried out by PrimPol, the second primase-polymerase identified in mammalian cells after Polα/Primase. The recruitment of PrimPol to the vicinity of ICLs depends on its interaction with RPA, but not on FANCM translocase or the BLM/TOP3A/RMI1-2 (BTR) complex that also participate in ICL traverse. Genetic ablation of PRIMPOL makes cells more dependent on the fork convergence mechanism to initiate ICL repair, and PRIMPOL KO cells and mice display hypersensitivity to ICL-inducing drugs. These results open the possibility of targeting PrimPol activity to enhance the efficacy of chemotherapy based on DNA crosslinking agents

Cambio institucional y fiscalidad

Esta obra aborda los procesos de cambio institucional en España e Hispanoamérica durante los años que fueron desde la guerra de los Siete Años hasta la formación de los estados nacionales. Para mantener el hilo de esta historia global, dichos procesos se analizan a través del prisma de la historia de las finanzas, examinando los problemas fiscales en su interdependencia con transformaciones económicas, sociales y culturales más amplias. Resultado de dos proyectos del programa ECOS que reunieron a especialistas argentinos, franceses y mexicanos, así como a colegas de Alemania, España e Italia invitados a distintos encuentros, el libro ha intentado situarse en diferentes escalas de observación: la de la Monarquía, que negocia y reforma los mecanismos de acceso y de circulación de recursos, transformando así sus propios equilibrios políticos; o, en el otro extremo, la de las arenas locales, donde la cooperación y el conflicto de sus actores producían reconfiguraciones institucionales y territoriales; o aun el ámbito de los dispositivos que atravesaban las diferentes escalas —los derechos de propiedad, los cuerpos y las articulaciones comunitarias, o las dimensiones fiscales de la ciudadanía— cuyas evoluciones acompasaban el tránsito del Antiguo Régimen al orden republicano.Dans ce livre l’histoire de la fiscalité est replacée dans le contexte des évolutions économiques, sociales et culturelles. Elle sert ainsi de fil conducteur à l’analyse des transformations institutionnelles et politiques qui ponctuent la complexe transition de l’empire hispanique aux nouvelles nations qui en sont issues, en Amérique latine et en Espagne. Cette analyse suit une démarche multiscalaire en s’attachant d’abord aux tentatives de réforme de la monarchie et l’émergence des libéralismes, puis aux acteurs locaux et aux conflits dans lesquels ils s’impliquent et enfin au rôle des corps et communautés, de la propriété, du financement de la guerre posant la question de la citoyenneté fiscale