Uso de agonistas de TLRs para mejorar la respuesta inmune en vacunas

Los receptores TLR (Toll-Like Receptor) son proteínas transmembrana presentes en células del sistema inmune innato. Su activación desencadena una respuesta inflamatoria e inmune dirigida a destruir el patógeno y es una pieza decisiva en la maduración de las células presentadoras de antígeno, sirviendo de puente entre la inmunidad innata y la adaptativa. Esta estimulación del sistema inmune supone que los ligandos de los TLRs puedan tener aplicación como adyuvantes en vacunas. En esta revisión se ha recurrido a fuentes bibliográficas para recopilar la información existente sobre su potencial uso en intervenciones inmunoprofilácticas. Se han examinado estrategias basadas en la estimulación de TLR3 y de TLR5, así como otras estrategias menos estudiadas. Los resultados observados indican que este es un campo prometedor para la investigación y el desarrollo de vacunas más seguras y eficaces

Human exceptional longevity: transcriptome from centenarians is distinct from septuagenarians and reveals a role of Bcl-xL in successful aging

24 páginas, 7 figuras. Borras C, et al. Human exceptional longevity: transcriptome from centenarians is distinct from septuagenarians and reveals a role of Bcl-xL in successful aging. Aging (Albany NY). 2016 Oct 28;8(12):3185-3208. doi: 10.18632/aging.101078.Centenarians not only enjoy an extraordinary aging, but also show a compression of morbidity. Using functional transcriptomic analysis of peripheral blood mononuclear cells (PMBC) we identified 1721 mRNAs differentially expressed by centenarians when compared with septuagenarians and young people. Sub-network analysis led us to identify Bcl-xL as an important gene up-regulated in centenarians. It is involved in the control of apoptosis, cellular damage protection and also in modulation of immune response, all associated to healthy aging. Indeed, centenarians display lower plasma cytochrome C levels, higher mitochondrial membrane potential and also less cellular damage accumulation than septuagenarians. Leukocyte chemotaxis and NK cell activity are significantly impaired in septuagenarians compared with young people whereas centenarians maintain them. To further ascertain the functional role of Bcl-xL in cellular aging, we found that lymphocytes from septuagenarians transduced with Bcl-xL display a reduction in senescent-related markers. Finally, to demonstrate the role of Bcl-xL in longevity at the organism level, C. elegans bearing a gain of function mutation in the Bcl-xL ortholog ced-9, showed a significant increase in mean and maximal life span. These results show that mRNA expression in centenarians is unique and reveals that Bcl-xL plays an important role in exceptional aging.This work was supported by grants SAF2013-44663-R, from the Spanish Ministry of Education and Science (MEC); ISCIII2012-RED-43-029 from the “Red Tematica de investigacion cooperative en envejecimiento y fragilidad” (RETICEF); PROMETEOII/2014/056 from "Conselleria d’Educació, Cultura I Esport de la Generalitat Valenciana"; and EU Funded CM1001 and FRAILOMIC-HEALTH.2012.2.1.1-2 (To J.V) APM-03/15 from Conselleria de Sanitat, AICO/2016/067 and from Conselleria d’Educació, Cultura i Esport de la Generalitat Valenciana, Intramural Grant from INCLIVA (to C.B.),VAL i+d Fellowship from Generalitat Valenciana (to C.L.-F.) and Marie Curie Career Integration Grant (to N.F). This study has been co-financed by FEDER funds from the European Union.Peer reviewe

Estudio en C. elegans del papel de los genes de la vía de apoptosis como mediadores de longevidad

[EN] Despite the importance of programmed cell death (apoptosis) as a key process in the regulation and maintenance of homeostasis, and its central role in numerous age-associated pathologies such as cancer, there are no existing results that directly associate high or low levels of apoptosis regulating genes with an increased longevity. This dissertation proposes the use of the animal model Caenorhabditis elegans for the study of the role of the genes of the apoptosis pathway in longevity in vivo. With this aim different mutants of the apoptosis pathway were raised (including a gain-of-function mutant of the Bcl-xL homologue, ced-9) and longevity curves were obtained in order to study if these mutations significantly extend the nematode’s lifespan. In addition, studies of healthy aging were carried out to test the genes’ possible implication in the process. Based on the results of the study it can be suggested that reduced levels of intrinsic apoptosis are associated with a longer lifespan, and importantly, can promote a healthier aging.[ES] A pesar de su papel central en regulación de la muerte celular programada (apoptosis), y su papel central en cáncer, no existen resultados previos que asocien directamente niveles altos o bajos de los genes que regulan apoptosis con una mayor longevidad. Resultados aún sin publicar del Dr. José Viña muestran que un grupo de centenarios analizados tienen niveles elevados de la proteína antiapoptótica Bcl-xl. La vía de la apoptosis está muy conservada en evolución y fue originariamente descrita en C.elegans. Este TFC propone el uso de este modelo animal para estudiar el papel de los genes de la vía de apoptosis en longevidad. Para ello se utilizarán distintos mutantes de la vía de la apoptosis (incluyendo un mutante de ganancia de función del homólogo de Bcl-xl, ced-9) y se realizarán curvas de longevidad para estudiar si estas mutaciones alargan significativamente la vida del nemátodo.Barettino Grediaga, A. (2015). Estudio en C. elegans del papel de los genes de la vía de apoptosis como mediadores de longevidad. http://hdl.handle.net/10251/53253.TFG

Biological Versus Chronological Aging: JACC Focus Seminar

Aging is the main risk factor for vascular disease and ensuing cardiovascular and cerebrovascular events, the leading causes of death worldwide. In a progressively aging population, it is essential to develop early-life biomarkers that efficiently identify individuals who are at high risk of developing accelerated vascular damage, with the ultimate goal of improving primary prevention and reducing the health care and socioeconomic impact of age-related cardiovascular disease. Studies in experimental models and humans have identified 9 highly interconnected hallmark processes driving mammalian aging. However, strategies to extend health span and life span require understanding of interindividual differences in age-dependent functional decline, known as biological aging. This review summarizes the current knowledge on biological age biomarkers, factors influencing biological aging, and antiaging interventions, with a focus on vascular aspects of the aging process and its cardiovascular disease related manifestations.The CNIC is supported by the MCNU, the ISCIII, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Work in Dr. Andrés’ laboratory is supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (MCNU) (SAF2016-79490-R) and the Instituto de Salud Carlos III (ISCIII) (AC16/00091, AC17/00067, and CB16/11/00405) with cofunding from the European Regional Development Fund (ERDF/FEDER, “Una manera de hacer Europa”) and the Fundació Marató TV3 (122/C/2015). Dr. Hamczyk is supported by the MCNU (post-doctoral contract FJCI-2017-33299). Ms. Nevado is supported by the Ministerio de Educación, Cultura y Deporte (pre-doctoral contract FPU16/05027). Ms. Barettino is supported by the MCNU (pre-doctoral contract BES-2017-079705).S

Retinoic-Acid-Induced Downregulation of the 67 KDa Laminin Receptor Correlates with Reduced Biological Aggressiveness of Human Neuroblastoma Cells

16 pages (217-232), 6 figuresThe authors are indebted to Dr. S. Menard (Milan, Italy) for the gift of the antibody against 37LRP. C. M. R. L. was supported by Programa de Personal Técnico de Apoyo (PTA-2003-02-00207; Ministry of Education and Science, Spain). This work was supported by grants from the Spanish former Ministry of Education and Science and Ministry of Science and Innovation (SAF2003-00311, SAF2006–00647 and SAF2007–60780) and Generalitat Valenciana (GRUPOS 03/15 and ACOMP 09/212) (to D. B.) , and Instituto de Salud Carlos III (RD20-102 to S. N.).Peer reviewe

Organic matter accumulation during the Holocene in the Guadalquivir marshlands (SW Spain)

The distribution of biomarker compounds and magnetic susceptibility observed in the sediment from a 20 m core drilled in the marshlands of the estuarine region of the Guadalquivir River (southwest coast of Spain) has allowed us to reconstruct the palaeoenvironmental evolution of this area during the Holocene. Several organic compounds (n-alkanes, ra-ketones, n-alkanols, n-alkanoic acids and organic sulphur), as well as different biomarker ratios, have been used to show changing environmental conditions through time. These geochemical proxies suggest good preservation of the organic matter, although some diagenesis has occurred to particular organic compounds, especially the n-alkanoic acids. Our data indicate a major allochthonous supply of terrestrial plants, with less influence from aquatic plants or algae through the core. There are markedly different palaeoenvironmental conditions between the uppermost 5 m (last 6ka cal. B.P.) and the rest of the core. From 5 m (ca 6ka cal. B.P.) to 19 m (ca 8ka cal. B.P.) depth the palaeoenvironmental conditions were almost constant. Based on organic sulphur content and n-alkane content logs, anoxic conditions prevailed from 8 to 6ka cal. B.P., while oxic conditions with enhanced convection of water (prevalence of fluvial input), and consequently a greater organic matter supply, predominated in the upper 5 m of the core. Similarly, little variation in the magnetic susceptibility profile below 5 m indicates stable environmental conditions, while in the upper 5 m conditions shifted to one with elevated water input and clastic sediment supply. This is linked to palaeofloral alterations in the Guadiamar/Guadalquivir drainage basins and/or anthropogenic effects. We propose that from ca 8 to 6 ka cal. B.P. a stable landscape physiognomy in the surroundings of the estuarine area of the Guadalquivir River, with a predominance of pines and grassland. However, over the last 6ka cal. B.P. a variation in the terrestrial plant biomarker compounds suggests an alternation of relatively dry and humid phases and/or the impact of human populations on altering the vegetation community have occurred

Reconstrucción paleoclimática y paleoambiental de la Península Ibérica durante el Cuaternario, aplicación de modelos geoprospectivos para la evaluación de escenarios futuros

Esta comunicación trata de resumir el trabajo realizado por el ITGE, BRGM, CCMA, IPE, ETSIMM y ENRESA en el proyecto titulado "Paleoclimatological Revision of Climate Evolution and Environment in Western Mediterranean Region. Evaluation of future evolution scenarios in the Iberian Peninsula", en el marco del Programa de la Comisión de las Comunidades Europeas sobre Gestión y Almacenamiento de Residuos Radioactivos (contrato CEC FI2WCT91- 0075)

Analysis and evaluation of groundwater protection alternatives during waste extraction operations (acid tars) in a lagoon in Arganda del Rey (Madrid)

[Resumen:] La Comunidad de Madrid está llevando a cabo la restauración integral de una antigua gravera contaminada con residuos peligrosos, mayoritariamente sulfonatos de petróleo (alquitranes ácidos), procedentes del tratamiento de aceites industriales usados. Parte de dichos vertidos, realizados en las décadas de los años 1970 y 1980, se depositaron en una laguna originada por la explotación de áridos por debajo del nivel piezométrico del acuífero, conformando una balsa con 50000 m3 de residuos peligrosos. La diversa ubicación, naturaleza y estado de los residuos requiere diferentes soluciones para su extracción y tratamiento, por lo que el proyecto de restauración consta de varias fases. Los residuos depositados producen un efecto de confinamiento en el acuífero, dado que la cota del fondo de los residuos es inferior al nivel piezométrico. Con estos condicionantes es crítico establecer un procedimiento de protección de las aguas subterráneas a la hora de acometer la próxima fase, consistente en la extracción de los residuos situados por debajo del nivel piezométrico. En este artículo se describe el proceso que se ha llevado a cabo para seleccionar la mejor alternativa desde el punto de vista hidrogeológico, considerando todos los datos disponibles obtenidos en las fases previas del proyecto. Una vez planteadas y caracterizadas todas las alternativas posibles se ha seleccionado de forma argumentada y razonada como mejor alternativa la realización de una barrera impermeabilizante perimetral a la balsa y empotrada en una capa de arcillas de 2 m de espesor situada en el subsuelo de la balsa.[Abstract:] The Community of Madrid is carrying out the integral restoration of an old gravel pit contaminated with hazardous waste, mostly petroleum sulphonates (acid tars), from the treatment of used industrial oil. Part of these discharges, from the 1970s and 1980s, were deposited in a lagoon generated by the exploitation of aggregates below the piezometric level of the aquifer, forming a raft with 50,000 m3 of hazardous waste. The different locations, nature and conditions of the waste require different solutions for its extraction and treatment, so the restoration project consists of several phases. The deposited waste produces an effect of confinement in the aquifer, since the bottom level of the waste is lower than the piezometric level. With these conditions, it is critical to establish a procedure for the protection of the groundwater when executing the next phase, consisting of the extraction of waste located below the piezometric level. This article describes the process that has been carried out to select the best alternative from a hydrogeological point of view, considering all the available data obtained in the previous phases of the project. Once all the possible alternatives had been considered and characterized in a reasoned way, we chose the construction of a perimeter barrier around the raft embedded in a clay layer of 2 m thick located in the base of the raft as the best option

Human exceptional longevity: transcriptome from centenarians is distinct from septuagenarians and reveals a role of Bcl‐xL in successful aging

Centenarians not only enjoy an extraordinary aging, but also show a compression of morbidity. Using functional transcriptomic analysis of peripheral blood mononuclear cells (PMBC) we identified 1721 mRNAs differentially expressed by centenarians when compared with septuagenarians and young people. Sub‐network analysis led us to identify Bcl ‐ xL as an important gene up‐regulated in centenarians. It is involved in the control of apoptosis, cellular damage protection and also in modulation of immune response, all associated to healthy aging. Indeed, centenarians display lower plasma cytochrome C levels, higher mitochondrial membrane potential and also less cellular damage accumulation than septuagenarians. Leukocyte chemotaxis and NK cell activity are significantly impaired in septuagenarians compared with young people whereas centenarians maintain them. To further ascertain the functional role of Bcl‐ xL in cellular aging, we found that lymphocytes from septuagenarians transduced with Bcl‐xL display a reduction in senescent‐related markers. Finally, to demonstrate the role of BcL‐xL in longevity at the organism level, C. elegans bearing a gain of function mutation in the BcL‐xL ortholog ced‐9, showed a significant increase in mean and maximal life span. These results show that mRNA expression in centenarians is unique and reveals that BcL‐ xL plays an important role in exceptional aging