Regulación transcripcional mediada por la DNA topoisomerasa II

La topología del DNA condiciona todos los procesos del metabolismo cromosómico y, en especial, la transcripción, ya que el avance de la RNA polimerasa II (Pol II) distorsiona la doble hélice introduciendo un alto nivel de estrés torsional en la molécula. Las DNA topoisomerasas son las enzimas capaces de relajar dicho estrés mediante la formación de roturas transitorias. Por ello, tradicionalmente, el papel en transcripción de las DNA topoisomerasas se ha centrado en su función facilitadora del proceso. Sin embargo, en los últimos años se ha propuesto que las DNA topoisomerasas tipo II (TOP2) podrían participan activamente en regulación de la transcripción, aunque su función aún no se encuentra completamente establecida. En esta tesis, hemos abordado esta cuestión mediante la inhibición de la actividad TOP2. Por medio de análisis a nivel genómico, hemos demostrado que la inactivación de TOP2A produce la liberación general de la pausa próxima al promotor de Pol II dando lugar al incremento de expresión de genes con rápidas cinéticas de inducción, como los genes de respuesta temprana (ERGs). Sorprendentemente, este efecto es independiente de la formación de roturas de doble cadena, algo que había sido propuesto previamente. Utilizando el gen FOS como modelo de ERG, hemos demostrado que TOP2A elimina el superenrollamiento negativo del promotor favoreciendo el establecimiento de la pausa próxima al promotor por impedimento topológico. En conjunto, los resultados de esta tesis muestran que el mantenimiento del estado topológico de los promotores mediante la actividad TOP2 representa un mecanismo de regulación que permite las rápidas cinéticas de inducción características de ciertos genes altamente regulados

RanBP2-Mediated SUMOylation Promotes Human DNA Polymerase Lambda Nuclear Localization and DNA Repair

Cellular DNA is under constant attack by a wide variety of agents, both endogenous and exogenous. To counteract DNA damage, human cells have a large collection of DNA repair factors. Among them, DNA polymerase lambda (Polλ) stands out for its versatility, as it participates in different DNA repair and damage tolerance pathways in which gap-filling DNA synthesis is required. In this work we show that human Polλ is conjugated with Small Ubiquitin-like MOdifier (SUMO) proteins both in vitro and in vivo, with Lys27 being the main target of this covalent modification. Polλ SUMOylation takes place in the nuclear pore complex and is mediated by the E3 ligase RanBP2. This post-translational modification promotes Polλ entry into the nucleus, which is required for its recruitment to DNA lesions and stimulated by DNA damage induction. Our work represents an advance in the knowledge of molecular pathways that regulate cellular localization of human Polλ, which are essential to be able to perform its functions during repair of nuclear DNA, and that might constitute an important point for the modulation of its activity in human cells

Regulation of human Polλ by ATM-mediated phosphorylation during Non-Homologous End Joining

DNA double strand breaks (DSBs) trigger a variety of cellular signaling processes, collectively termed the DNA-damage response (DDR), that are primarily regulated by protein kinase ataxia-telangiectasia mutated (ATM). Among DDR activated processes, the repair of DSBs by non-homologous end joining (NHEJ) is essential. The proper coordination of NHEJ factors is mainly achieved through phosphorylation by an ATM-related kinase, the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), although the molecular basis for this regulation has yet to be fully elucidated. In this study we identify the major NHEJ DNA polymerase, DNA polymerase lambda (Polλ), as a target for both ATM and DNA-PKcs in human cells. We show that Polλ is efficiently phosphorylated by DNA-PKcs in vitro and predominantly by ATM after DSB induction with ionizing radiation (IR) in vivo. We identify threonine 204 (T204) as a main target for ATM/DNA-PKcs phosphorylation on human Polλ, and establish that its phosphorylation may facilitate the repair of a subset of IR-induced DSBs and the efficient Polλ-mediated gap-filling during NHEJ. Molecular evidence suggests that Polλ phosphorylation might favor Polλ interaction with the DNA-PK complex at DSBs. Altogether, our work provides the first demonstration of how Polλ is regulated by phosphorylation to connect with the NHEJ core machinery during DSB repair in human cells.España MINECO y la Comisión Europea (European Regional Development Fund) to J.F.R. RYC-2011-08752, BFU2013-44343-P) and to F.C-L. (SAF2014-55532-R)

First modern human settlement recorded in the Iberian hinterland occurred during Heinrich Stadial 2 within harsh environmental conditions

As the south-westernmost region of Europe, the Iberian Peninsula stands as a key area for understanding the process of modern human dispersal into Eurasia. However, the precise timing, ecological setting and cultural context of this process remains controversial concerning its spatiotemporal distribution within the different regions of the peninsula. While traditional models assumed that the whole Iberian hinterland was avoided by modern humans due to ecological factors until the retreat of the Last Glacial Maximum, recent research has demonstrated that hunter-gatherers entered the Iberian interior at least during Solutrean times. We provide a multi-proxy geoarchaeological, chronometric and paleoecological study on human–environment interactions based on the key site of Peña Capón (Guadalajara, Spain). Results show (1) that this site hosts the oldest modern human presence recorded to date in central Iberia, associated to pre-Solutrean cultural traditions around 26, 000 years ago, and (2) that this presence occurred during Heinrich Stadial 2 within harsh environmental conditions. These findings demonstrate that this area of the Iberian hinterland was recurrently occupied regardless of climate and environmental variability, thus challenging the widely accepted hypothesis that ecological risk hampered the human settlement of the Iberian interior highlands since the first arrival of modern humans to Southwest Europe. © 2021, The Author(s)

First modern human settlement recorded in the Iberian hinterland occurred during Heinrich Stadial 2 within harsh environmental conditions

As the south-westernmost region of Europe, the Iberian Peninsula stands as a key area for understanding the process of modern human dispersal into Eurasia. However, the precise timing, ecological setting and cultural context of this process remains controversial concerning its spatiotemporal distribution within the different regions of the peninsula. While traditional models assumed that the whole Iberian hinterland was avoided by modern humans due to ecological factors until the retreat of the Last Glacial Maximum, recent research has demonstrated that hunter-gatherers entered the Iberian interior at least during Solutrean times. We provide a multi-proxy geoarchaeological, chronometric and paleoecological study on human?environment interactions based on the key site of Peña Capón (Guadalajara, Spain). Results show (1) that this site hosts the oldest modern human presence recorded to date in central Iberia, associated to pre-Solutrean cultural traditions around 26,000 years ago, and (2) that this presence occurred during Heinrich Stadial 2 within harsh environmental conditions. These findings demonstrate that this area of the Iberian hinterland was recurrently occupied regardless of climate and environmental variability, thus challenging the widely accepted hypothesis that ecological risk hampered the human settlement of the Iberian interior highlands since the first arrival of modern humans to Southwest Europe.Tis research was carried out in the context of the ERC MULTIPALEOIBERIA project, funded by the European Research Council (ERC-2018-STG-805478), and the PALEOINTERIOR project, funded by the Spanish Ministry of Science and Innovation (HAR2017-82483-C3-3-P)

On-Surface Driven Formal Michael Addition Produces m-Polyaniline Oligomers on Pt(111)

On-surface synthesis is emerging as a highly rational bottom-up methodology for the synthesis of molecular structures that are unattainable or complex to obtain by wet chemistry. Here, oligomers of meta-polyaniline, a known ferromagnetic polymer, were synthesized from para-aminophenol building-blocks via an unexpected and highly specific on-surface formal 1, 4 Michael-type addition at the meta position, driven by the reduction of the aminophenol molecule. We rationalize this dehydrogenation and coupling reaction mechanism with a combination of in situ scanning tunneling and non-contact atomic force microscopies, high-resolution synchrotron-based X-ray photoemission spectroscopy and first-principles calculations. This study demonstrates the capability of surfaces to selectively modify local molecular conditions to redirect well-established synthetic routes, such as Michael coupling, towards the rational synthesis of new covalent nanostructures

Do specific antimicrobial stewardship interventions have an impact on carbapenem resistance in Gram-negative bacilli? A multicentre quasi-experimental ecological study: time-trend analysis and characterization of carbapenemases

CarbaPIRASOA team.[Background] Carbapenem-resistant Gram-negative bacilli (CR-GNB) are among the most threatening microorganisms worldwide and carbapenem use facilitates their spread. Antimicrobial stewardship programmes (ASPs) can help to optimize the use of antibiotics. This study evaluates the impact of a multifaceted educational ASP on carbapenem use and on the epidemiology of CR-GNB.[Methods] We conducted a quasi-experimental, time-series study in seven hospitals, from January 2014 to September 2018. The key intervention was composed of educational interviews promoting the appropriate use of carbapenems. The primary endpoints were carbapenem consumption and incidence density (ID) of CR-GNB. All non-duplicated CR-GNB clinical isolates were tested using phenotypic assays and PCR for the presence of carbapenemases. Joinpoint regression and interrupted time-series analyses were used to determine trends.[Results] A decrease in carbapenem consumption throughout the study period [average quarterly percentage change (AQPC) −1.5%, P < 0.001] and a −8.170 (−16.064 to −0.277) level change following the intervention were observed. The ID of CR-Acinetobacter baumannii decreased (AQPC −3.5%, P = 0.02) and the overall ID of CR-GNB remained stable (AQPC −0.4%, P = 0.52). CR-GNB, CR-Pseudomonas aeruginosa and CR-A. baumannii IDs per hospital correlated with the local consumption of carbapenems. The most prevalent carbapenem resistance mechanisms were OXA-23 for CR-A. baumannii (76.1%), OXA-48 for CR-Klebsiella pneumoniae (66%) and no carbapenemases for CR-P. aeruginosa (91.7%). The epidemiology of carbapenemases was heterogeneous throughout the study, especially for carbapenemase-producing Enterobacteriaceae.[Conclusions] In conclusion, a multifaceted, educational interview-based ASP targeting carbapenem prescribing reduced carbapenem use and the ID of CR-A. baumannii.This work was funded by the Spanish Infectious Diseases and Clinical Microbiology Society (SEIMC).Peer reviewe

The CARMENES search for exoplanets around M dwarfs Guaranteed time observations Data Release 1 (2016-2020)

I. Ribas et al.[Context] The CARMENES instrument, installed at the 3.5 m telescope of the Calar Alto Observatory in Almería, Spain, was conceived to deliver high-accuracy radial velocity (RV) measurements with long-term stability to search for temperate rocky planets around a sample of nearby cool stars. Moreover, the broad wavelength coverage was designed to provide a range of stellar activity indicators to assess the nature of potential RV signals and to provide valuable spectral information to help characterise the stellar targets.[Aims] We describe the CARMENES guaranteed time observations (GTO), spanning from 2016 to 2020, during which 19 633 spectra for a sample of 362 targets were collected. We present the CARMENES Data Release 1 (DR1), which makes public all observations obtained during the GTO of the CARMENES survey.[Methods] The CARMENES survey target selection was aimed at minimising biases, and about 70% of all known M dwarfs within 10 pc and accessible from Calar Alto were included. The data were pipeline-processed, and high-level data products, including 18 642 precise RVs for 345 targets, were derived. Time series data of spectroscopic activity indicators were also obtained.[Results] We discuss the characteristics of the CARMENES data, the statistical properties of the stellar sample, and the spectroscopic measurements. We show examples of the use of CARMENES data and provide a contextual view of the exoplanet population revealed by the survey, including 33 new planets, 17 re-analysed planets, and 26 confirmed planets from transiting candidate follow-up. A subsample of 238 targets was used to derive updated planet occurrence rates, yielding an overall average of 1.44 ± 0.20 planets with 1 M⊕ < Mpl sin i < 1000 M⊕ and 1 day < Porb < 1000 days per star, and indicating that nearly every M dwarf hosts at least one planet. All the DR1 raw data, pipeline-processed data, and high-level data products are publicly available online.[Conclusions] CARMENES data have proven very useful for identifying and measuring planetary companions. They are also suitable for a variety of additional applications, such as the determination of stellar fundamental and atmospheric properties, the characterisation of stellar activity, and the study of exoplanet atmospheres.CARMENES is an instrument at the Centro Astronómico Hispano en Andalucía (CAHA) at Calar Alto (Almería, Spain), operated jointly by the Junta de Andalucía and the Instituto de Astrofísica de Andalucía (CSIC). CARMENES was funded by the Max-Planck-Gesellschaft (MPG), the Consejo Superior de Investigaciones Científicas (CSIC), the Ministerio de Economía y Competitividad (MINECO) and the European Regional Development Fund (ERDF) through projects FICTS-2011-02, ICTS-2017-07-CAHA-4, and CAHA16-CE-3978, and the members of the CARMENES Consortium (Max-Planck-Institut für Astronomie, Instituto de Astrofísica de Andalucía, Landessternwarte Königstuhl, Institut de Ciències de l’Espai, Institut für Astrophysik Göttingen, Universidad Complutense de Madrid, Thüringer Landessternwarte Tautenburg, Instituto de Astrofísica de Canarias, Hamburger Sternwarte, Centro de Astrobiología and Centro Astronómico Hispano-Alemán), with additional contributions by the MINECO, the Deutsche Forschungsgemeinschaft (DFG) through the Major Research Instrumentation Programme and Research Unit FOR2544 “Blue Planets around Red Stars”, the Klaus Tschira Stiftung, the states of Baden-Württemberg and Niedersachsen, and by the Junta de Andalucía. We acknowledge financial support from the Spanish Agencia Estatal de Investigación of the Ministerio de Ciencia e Innovación (AEI-MCIN) and the ERDF “A way of making Europe” through projects PID2020-117493GB-I00, PID2019-109522GB-C5[1:4], PID2019-110689RB-I00, PID2019-107061GB-C61, PID2019-107061GB-C64, PGC2018-098153-B-C33, PID2021-125627OB-C31/AEI/10.13039/501100011033, and the Centre of Excellence “Severo Ochoa” and “María de Maeztu” awards to the Institut de Ciències de l’Espai (CEX2020-001058-M), Instituto de Astrofísica de Canarias (CEX2019-000920-S), Instituto de Astrofísica de Andalucía (SEV-2017-0709), and Centro de Astrobiología (MDM-2017-0737). We also benefited from additional funding from: the Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya and the Agència de Gestió d’Ajuts Universitaris i de Recerca of the Generalitat de Catalunya, with additional funding from the European FEDER/ERDF funds, and from the Generalitat de Catalunya/CERCA programme; the DFG through the Major Research Instrumentation Programme and Research Unit FOR2544 “Blue Planets around Red Stars” (RE 2694/8-1); the University of La Laguna through the Margarita Salas Fellowship from the Spanish Ministerio de Universidades ref. UNI/551/2021-May-26, and under the EU Next Generation funds; the Gobierno de Canarias through projects ProID2021010128 and ProID2020010129; the Spanish MICINN under Ramón y Cajal programme RYC-2013-14875; the “Fondi di Ricerca Scientifica d’Ateneo 2021” of the University of Rome “Tor Vergata”; and the programme “Alien Earths” supported by the National Aeronautics and Space Administration (NASA) under agreement No. 80NSSC21K0593. TPeer reviewe

Can the discharge of a hyperconcentrated flow be estimated from paleoflood evidence?

Many flood events involving water and sediments have been characterized using classic hydraulics principles, assuming the existence of critical flow and many other simplifications. In this paper, hyperconcentrated flow discharge was evaluated by using paleoflood reconstructions (based on paleostage indicators [PSI]) combined with a detailed hydraulic analysis of the critical flow assumption. The exact location where this condition occurred was established by iteratively determining the corresponding cross section, so that specific energy is at a minimum. In addition, all of the factors and parameters involved in the process were assessed, especially those related to the momentum equation, existing shear stresses in the wetted perimeter, and nonhydrostatic and hydrostatic pressure distributions. The superelevation of the hyperconcentrated flow, due to the flow elevation curvature, was also estimated and calibrated with the PSI. The estimated peak discharge was established once the iterative process was unable to improve the fit between the simulated depth and the depth observed from the PSI. The methodological approach proposed here can be applied to other higher-gradient mountainous torrents with a similar geomorphic configuration to the one studied in this paper. Likewise, results have been derived with fewer uncertainties than those obtained from standard hydraulic approaches, whose simplifying assumptions have not been considered. © 2011 by the American Geophysical Union.This work was funded by the Spanish Ministry of Science and Innovation within the framework of the CICYT Dendro-Avenidas project (CGL2007-62063) and the MAS Dendro-Avenidas project (CGL2010-19274). We are especially grateful to Robert D. Jarrett, Vern Manville, and one anonymous reviewer for their comments and helpful suggestions on previous versions of this manuscript.Bodoque, J.; Eguibar Galán, MÁ.; Diez-Herrero, A.; Gutierrez-Perez, I.; Ruiz-Villanueva, V. (2011). Can the discharge of a hyperconcentrated flow be estimated from paleoflood evidence?. Water Resources Research. 47(W12535). doi:10.1029/2011WR010380S47W12535Alcoverro, J., Corominas, J., & Gómez, M. (1999). The Barranco de Arás flood of 7 August 1996 (Biescas, Central Pyrenees, Spain). Engineering Geology, 51(4), 237-255. doi:10.1016/s0013-7952(98)00076-3Alexandrov, Y., Laronne, J. B., & Reid, I. (2007). Intra-event and inter-seasonal behaviour of suspended sediment in flash floods of the semi-arid northern Negev, Israel. Geomorphology, 85(1-2), 85-97. doi:10.1016/j.geomorph.2006.03.013BAAS, J. H., & BEST, J. L. (2008). The dynamics of turbulent, transitional and laminar clay-laden flow over a fixed current ripple. Sedimentology, 55(3), 635-666. doi:10.1111/j.1365-3091.2007.00916.xBallesteros, J. A., Bodoque, J. M., Díez-Herrero, A., Sanchez-Silva, M., & Stoffel, M. (2011). Calibration of floodplain roughness and estimation of flood discharge based on tree-ring evidence and hydraulic modelling. Journal of Hydrology, 403(1-2), 103-115. doi:10.1016/j.jhydrol.2011.03.045Bathurst, J. C. (1985). Flow Resistance Estimation in Mountain Rivers. Journal of Hydraulic Engineering, 111(4), 625-643. doi:10.1061/(asce)0733-9429(1985)111:4(625)BERZI, D., & JENKINS, J. T. (2008). A theoretical analysis of free-surface flows of saturated granular–liquid mixtures. Journal of Fluid Mechanics, 608, 393-410. doi:10.1017/s0022112008002401Biron, P. M., Lane, S. N., Roy, A. G., Bradbrook, K. F., & Richards, K. S. (1998). Sensitivity of bed shear stress estimated from vertical velocity profiles: the problem of sampling resolution. Earth Surface Processes and Landforms, 23(2), 133-139. doi:10.1002/(sici)1096-9837(199802)23:23.0.co;2-nBisantino, T., Fischer, P., & Gentile, F. (2009). Rheological characteristics of debris-flow material in South-Gargano watersheds. Natural Hazards, 54(2), 209-223. doi:10.1007/s11069-009-9462-4Bousmar, D., & Zech, Y. (1999). Momentum Transfer for Practical Flow Computation in Compound Channels. Journal of Hydraulic Engineering, 125(7), 696-706. doi:10.1061/(asce)0733-9429(1999)125:7(696)Costa, J. E. (1984). Physical Geomorphology of Debris Flows. Developments and Applications of Geomorphology, 268-317. doi:10.1007/978-3-642-69759-3_9COUSSOT, P., & MEUNIER, M. (1996). Recognition, classification and mechanical description of debris flows. Earth-Science Reviews, 40(3-4), 209-227. doi:10.1016/0012-8252(95)00065-8Coussot, P., Laigle, D., Arattano, M., Deganutti, A., & Marchi, L. (1998). Direct Determination of Rheological Characteristics of Debris Flow. Journal of Hydraulic Engineering, 124(8), 865-868. doi:10.1061/(asce)0733-9429(1998)124:8(865)Desilets, S. L. E., Ferré, T. P. A., & Ekwurzel, B. (2008). Flash flood dynamics and composition in a semiarid mountain watershed. Water Resources Research, 44(12). doi:10.1029/2007wr006159Dietrich, W. E., & Whiting, P. (1989). Boundary shear stress and sediment transport in river meanders of sand and gravel. River Meandering, 1-50. doi:10.1029/wm012p0001Ervine, D. A., Willetts, B. B., Sellin, R. H. J., & Lorena, M. (1993). Factors Affecting Conveyance in Meandering Compound Flows. Journal of Hydraulic Engineering, 119(12), 1383-1399. doi:10.1061/(asce)0733-9429(1993)119:12(1383)Gaume, E., Livet, M., Desbordes, M., & Villeneuve, J.-P. (2004). Hydrological analysis of the river Aude, France, flash flood on 12 and 13 November 1999. Journal of Hydrology, 286(1-4), 135-154. doi:10.1016/j.jhydrol.2003.09.015Grant, G. E. (1997). Critical flow constrains flow hydraulics in mobile-bed streams: A new hypothesis. Water Resources Research, 33(2), 349-358. doi:10.1029/96wr03134Hessel, R. (2006). Consequences of hyperconcentrated flow for process-based soil erosion modelling on the Chinese Loess Plateau. Earth Surface Processes and Landforms, 31(9), 1100-1114. doi:10.1002/esp.1307House, P. K., & Baker, V. R. (2001). Paleohydrology of flash floods in small desert watersheds in western Arizona. Water Resources Research, 37(6), 1825-1839. doi:10.1029/2000wr900408House, P. K., & Pearthree, P. A. (1995). A geomorphologic and hydrologic evaluation of an extraordinary flood discharge estimate: Bronco Creek, Arizona. Water Resources Research, 31(12), 3059-3073. doi:10.1029/95wr02428Hungr, O. (s. f.). Classification and terminology. Springer Praxis Books, 9-23. doi:10.1007/3-540-27129-5_2Iverson, R. M. (1997). The physics of debris flows. Reviews of Geophysics, 35(3), 245-296. doi:10.1029/97rg00426Iverson , R. M. 2003 The debris-flow rheology myth, paper presented at debris-flow hazards mitigation: mechanics, prediction, and assessment 303 314 Millpress Rotterdam, Davos, SwitzerlandIverson, R. M., Logan, M., LaHusen, R. G., & Berti, M. (2010). The perfect debris flow? Aggregated results from 28 large-scale experiments. Journal of Geophysical Research, 115(F3). doi:10.1029/2009jf001514Jarrett, R. D. (1987). Closure to « Hydraulics of High‐Gradient Streams » by Robert D. Jarrett (November, 1984). Journal of Hydraulic Engineering, 113(7), 927-929. doi:10.1061/(asce)0733-9429(1987)113:7(927)Jarrett, R. D., & Tomlinson, E. M. (2000). Regional interdisciplinary paleoflood approach to assess extreme flood potential. Water Resources Research, 36(10), 2957-2984. doi:10.1029/2000wr900098Lavigne, F., & Suwa, H. (2004). Contrasts between debris flows, hyperconcentrated flows and stream flows at a channel of Mount Semeru, East Java, Indonesia. Geomorphology, 61(1-2), 41-58. doi:10.1016/j.geomorph.2003.11.005McCoy, S. W., Kean, J. W., Coe, J. A., Staley, D. M., Wasklewicz, T. A., & Tucker, G. E. (2010). Evolution of a natural debris flow: In situ measurements of flow dynamics, video imagery, and terrestrial laser scanning. Geology, 38(8), 735-738. doi:10.1130/g30928.1Pierson , T. C. 2005 Distinguishing between debris flows and floods from field evidence Small Watersheds U.S. Geological Survey 2004 3142Pierson, T. C. (s. f.). Hyperconcentrated flow — transitional process between water flow and debris flow. Springer Praxis Books, 159-202. doi:10.1007/3-540-27129-5_8Pierson, T. C., & Costa, J. E. (1987). A rheologic classification of subaerial sediment-water flows. Reviews in Engineering Geology, 1-12. doi:10.1130/reg7-p1Pierson, T. C., & Scott, K. M. (1985). Downstream Dilution of a Lahar: Transition From Debris Flow to Hyperconcentrated Streamflow. 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RESCUhE Project: Cultural Heritage vulnerability in a changing and directional climate

[EN] RESCUhE Project (Improving structural RESilience of Cultural HEritage to directional extreme hydro-meteorological events in the context of the Climate Change) is a coordinated IGME-UAM research project funded by Spanish Government (MCIN/AEI/10.13039/501100011033). The framework of this research is the predicted increase in climate change vulnerability of heritage sites and the current disconnection between both environmental research on material decay and the practical aspects of designing preventive conservation measurements.RESCUhE Project (Improving structural RESilience of Cultural HEritage to directional extreme hydro-meteorological events in the context of the Climate Change) is a coordinated IGME-UAM research project funded by Spanish Government (MCIN/AEI/10.13039/501100011033).Peer reviewe