New mediators of p38alpha MAPK actions on cell survival and migration-invasion : cross-talk with C3G

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular II, leída el 12-12-2014Sección Deptal. de Bioquímica y Biología Molecular (Farmacia)Fac. de FarmaciaTRUEunpu

Estructura en estado sólido y propiedades térmicas de poli N-(5-n-alquiloxicarbonil-n-pentil) y N-(n-alquiloxicarbonil-metil) maleimidas

Eine nützliche bibliographische Übersicht zu Europa bietet: http://www.libraria.fr/fr/publications-scientifiques/acc%C3%A9der-au-livre-et-au-texte-au-moyen-%C3%A2ge-petite-bibliographie-de-base Siehe auch http://archiv.twoday.net/stories/28582508

Estructura en estado sólido y propiedades térmicas de poli N-(5-n-alquiloxicarbonil-n-pentil) y N-(n-alquiloxicarbonil-metil) maleimidas

Tit. tomado de la cub. Tesis-Universidad Complutense de Madrid, 1981.Fac. de Ciencias QuímicasTRUEProQuestpu

Limnological description of the Tarelo lagoon (SW Spain)

The lagoon of Tarelo (SW, Spain) is a permanent aquatic system located near the estuary of the Guadalquivir River. The water quality of this lagoon was poor during the study period (January 2001-August 2002): the high water turbidity hindered the growth of submersed aquatic macrophytes and the bottom water was depleted of dissolved oxygen in spring-summer despite the mixing created by the wind. The concentration of planktonic chlorophyll a ranged from 74.2 to 330.7 μg l-1 in the surface water and from 34.8 to 256.2 μg l-1 in the bottom water. The blooms of cyanobacteria (>106 cells ml-1) were frequent and contributed to the generation of episodic anoxia in the water column. Consequently, the number of both planktonic and benthonic taxa were very low. Two taxa of cyanobacteria, Aphanocapsa holsatica and Microcystis sp., occurred with an average relative abundance >30%. The most commonly found taxa were Oscillatoria sp., Oocystis sp., Oscillatoria limnetica, Chroococcus sp. and Monoraphidium circinalle. Population explosions (>2000 ind l-1) were common in rotifers such as Brachionus plicatilis and Keratella tropica. The density of Chironomus plumosus in the sediment surface declined abruptly when oxygen was scarce. The temporal variability of nutrient concentrations ranged from event-scale pulses to seasonal time scales. Nitrogen followed a seasonal pattern of loading in winter and depletion in summer, whereas the availability of o-P in the water oscillated in pulses. The concentration of o-P in the interstitial water of the sediment peaked intermittently during the study period and it was positively correlated with the concentration of o-P in the bottom-water (r=0.698, P106 cells ml-1) y contribuyeron a la aparición de episodios de anoxia en la columna de agua. En consecuencia, el número de taxa tanto en el plancton como en el bentos fue muy bajo. Dos cianobacterias, Aphanocapsa holsatica y Microcystis sp., alcanzaron una abundancia relativa promedio >30%. Los taxa más comunes en el fitoplancton fueron: Oscillatoria sp., Oocystis sp., Oscillatoria limnetica, Chroococcus sp. y Monoraphidium circinalle. Las poblaciones de rotíferos como Brachionus plicatilis y Keratella tropica experimentaron explosiones de más de 2000 ind l-1. La densidad de Chironomus plumosus en la superficie del sedimento disminuyó drásticamente a bajas concentraciones de oxígeno. La concentración de nutrientes mostró una amplia variabilidad temporal: desde patrones estacionales hasta pulsos intermitentes. El N siguió un patrón estacional de enriquecimiento en invierno y desaparición en verano, mientras que la disponibilidad de o-P osciló en pulsos. La concentración de o-P en el agua intersticial del sedimento, que siguió una evolución de picos y valles a lo largo del período de estudio, se correlacionó con la concentración de o-P en el agua del fondo (r=0.698, P<0.05). Las concentraciones promedio de materia orgánica y Tot-P en el sedimento fueron relativamente bajas (7 % y 456 μg gDW-1, respectivamente) y, ambas variables se correlacionaron fuertemente (r=0.853, P<0.01). La mayor parte del P sedimentario era de composición orgánica, lo que indica la importancia de la producción autóctona en la carga de nutrientes del sedimento. Es esperable que la carga interna de P aumente en el tiempo elevando el nivel trofico de este sistema

Papel de SLU7 en la diferenciación hepática y en la protección del hígado frente al daño: regulación de HNF4A

El hígado es un órgano con un papel central en el organismo puesto que realiza numerosas funciones esenciales para mantener la homeostasis sistémica. A nivel histológico, el hígado presenta una arquitectura compleja y muy organizada, formada por diferentes poblaciones celulares que desarrollan funciones concretas y, en conjunto, permiten el correcto funcionamiento del órgano. Así, el hígado está formado por las células parenquimales que incluyen a los hepatocitos y a los colangiocitos, y las células no parenquimales, que engloban a las células estrelladas hepáticas (HSC, hepatic stellate cells), las células de Kupffer o las células endoteliales sinusoidales. La población celular más abundante son los hepatocitos, que constituyen alrededor de un 80 % de la masa hepática total, y son los que más contribuyen al desarrollo de la función hepática. Se trata de unas células epiteliales polarizadas, muy diferenciadas y quiescentes, aunque presentan una gran capacidad de regeneración en respuesta a estímulos nocivos 1–4 . Las células hepáticas se organizan en el hígado alrededor de una estructura anatómica peculiar y compleja, determinada por el patrón del flujo sanguíneo, y que es esencial para que se puedan llevar a cabo las funciones hepáticas. Brevemente, el hígado recibe sangre de la vena porta rica en nutrientes y productos de deshecho, y sangre de la arteria hepática rica en oxígeno, que fluye a través de una red de capilares sinusoidales entre las células hepáticas, hasta drenar en las venas centrales. Junto a las venas porta y las arterias hepáticas se encuentran los conductos biliares que conducen la bilis hasta la vesícula biliar y el intestino, y los tres conductos juntos forman la triada portal. La unidad funcional del hígado son los lobulillos hepáticos, que consisten en fragmentos poligonales de células hepáticas dispuestas en torno a una vena central y rodeadas de triadas portales. Los capilares sinusoidales conectan la vena central con los espacios porta y, en paralelo a ellos, se organizan los hepatocitos formando cordones gruesos unicelulares (Figura 1A). Tanto la vena porta como la arteria hepática suministran la sangre a los hepatocitos conforme fluye a través de la red de sinusoides hasta drenar en las venas centrales. En función de si los hepatocitos se localizan más cerca de la región periportal o más cerca de la región pericentral, presentan diferencias fenotípicas en cuanto a la expresión de enzimas metabólicas, por lo que realizan funciones metabólicas diferentes. Esta distribución diferencial de las funciones metabólicas y secretoras del hígado a lo largo del eje porto-central se conoce como zonación, y constituye un marcador clave de la maduración hepática (Figura 1B) 1–5

Met signaling in cardiomyocytes is required for normal cardiac function in adult mice

et al.Hepatocyte growth factor (HGF) and its receptor, Met, are key determinants of distinct developmental processes. Although HGF exerts cardio-protective effects in a number of cardiac pathologies, it remains unknown whether HGF/Met signaling is essential for myocardial development and/or physiological function in adulthood. We therefore investigated the requirement of HGF/Met signaling in cardiomyocyte for embryonic and postnatal heart development and function by conditional inactivation of the Met receptor in cardiomyocytes using the Cre-α-MHC mouse line (referred to as α-MHCMet-KO). Although α-MHCMet-KO mice showed normal heart development and were viable and fertile, by 6. months of age, males developed cardiomyocyte hypertrophy, associated with interstitial fibrosis. A significant upregulation in markers of myocardial damage, such as β-MHC and ANF, was also observed. By the age of 9. months, α-MHCMet-KO males displayed systolic cardiac dysfunction. Mechanistically, we provide evidence of a severe imbalance in the antioxidant defenses in α-MHCMet-KO hearts involving a reduced expression and activity of catalase and superoxide dismutase, with consequent reactive oxygen species accumulation. Similar anomalies were observed in females, although with a slower kinetics. We also found that Met signaling down-regulation leads to an increase in TGF-β production and a decrease in p38MAPK activation, which may contribute to phenotypic alterations displayed in α-MHCMet-KO mice. Consistently, we show that HGF acts through p38α to upregulate antioxidant enzymes in cardiomyocytes. Our results highlight that HGF/Met signaling in cardiomyocytes plays a physiological cardio-protective role in adult mice by acting as an endogenous regulator of heart function through oxidative stress control.This work was supported by grants: (AFM)-13683 from Association Française contre les myopathies, France, FIS-PI07/0071 and SAF-2010-20198-C02-01 from Ministry of Science and Innovation, Spain, and grants from Comunidad de Madrid/Universidad Complutense de Madrid: CAM/UCM 920384 and UCM-BSCH 920384, Spain to A.P.; BFU2011-25304 from Ministry of Science and Innovation, Spain, RD12/0019/0022 (TerCel network, ISCIII), P11-CTS-7564 (Junta de Andalucía) to R. M.-Ch.; FRM (Fondation pour la Recherche Médicale), Fondation Bettencourt-Schueller, and Association Française contre les myopathies (AFM) to F.M.; SAF2010-15881 from Ministry of Science and Innovation, Spain, and RD012/0021 (RedinRen network, ISCIII), and GR100 (Junta de Castilla y León) to J.M. L.-N. The cardiovascular phenotyping unit of the University of Salamanca, including the telemetry equipment, has been acquired with the support of the European Regional Development Funds (FEDER).Peer Reviewe

Phytoplankton from NE Doñana marshland (“El Cangrejo Grande”, Doñana Natural Park, Spain)

The study area (“El Cangrejo Grande”, Doñana Natural Park) is located at the final section of the Guadiamar River channel and it is a part of the NE Do˜nana marshland. The hydrological characteristics of the area are complex and dynamic due to the different origin of its water input: the Guadiamar River basin, the Guadalquivir River estuary, and rice paddies outlets. This area is included in the hydrologic regeneration plan for the Doñana marshland (“Doñana 2005”), though the present study was finished before any modification took place. Phytoplankton richness was high since a total of 224 phytoplankton taxa were registered. Diatoms and Clorophytes were the groups that had the highest richness, Nitzschia palea, Cyclotella atomus and Monoraphidium contortum being the most widely distributed and abundant species. Phytoplankton exhibited a strong seasonal variation, in both composition and biomass, segregated in two periods (flood and desiccation) as suggested by the results of the PCA. On the other hand, the spatial differences were less evident according to a multidimensional scaling analysis (MDS). This seasonal pattern was stronger in the ordination of physico-chemical variables (conductivity, nutrient concentration and suspended matter).We conclude that this system is an ecotone zone with a high hydrologic complexity due to a variety of water inputs with a strong seasonality. These hydrologic features would be the determining factor in phytoplankton composition and high taxon richness.El Lucio de “El Cangrejo Grande” (Parque Natural de Doñana) est´a situado en el tramo final del encauzamiento del río Guadiamar y forma parte de la marisma NE de Doñana. Las características hidrológicas de la zona son complejas y dinámicas debido a los diferentes aportes que recibe de la cuenca del Guadiamar, del estuario del Guadalquivir y del desagúe de los arrozales. Esta zona está incluida dentro del Plan de Regeneración Hídrica (“Doñana 2005”) aunque el presente trabajo finalizó antes de que se llevaran a cabo las actuaciones previstas. La riqueza del fitoplancton fue elevada ya que se registró un total de 224 taxa. Las Diatomeas y las Clorofitas fueron los grupos que reunieron mayor riqueza, siendo Nitzschia palea, Cyclotella atomus y Monoraphidium contortum las especies m´as representativas, en abundancia y distribución. El fitoplancton presentó una fuerte variación estacional, en composici´on y biomasa, identific´andose claramente una dinámica temporal repartida en dos períodos (inundación y estiaje) como sugieren los resultados del análisis de componentes principales. En cambio, las diferencias espaciales fueron menos evidentes como demostró el análisis de ordenación multidimensional no jerárquico (MDS). El patrón estacional fue a´un más marcado en el análisis de las principales variables físico-químicas (conductividad, concentración de nutrientes y materia en suspensión). Se concluye que este sistema corresponde a una zona de ecotono de gran complejidad hidrológica debido a la existencia de una variedad de aportes hídricos sujetos a variaciones estacionales; esta complejidad sería el factor determinante de la composición y elevada riqueza del fitoplancton

C3G is upregulated in hepatocarcinoma, contributing to tumor growth and progression and to HGF/MET pathway activation

[EN]The complexity of hepatocellular carcinoma (HCC) challenges the identification of disease-relevant signals. C3G, a guanine nucleotide exchange factor for Rap and other Ras proteins, plays a dual role in cancer acting as either a tumor suppressor or promoter depending on tumor type and stage. The potential relevance of C3G upregulation in HCC patients suggested by database analysis remains unknown. We have explored C3G function in HCC and the underlying mechanisms using public patient data and in vitro and in vivo human and mouse HCC models. We found that C3G is highly expressed in progenitor cells and neonatal hepatocytes, whilst being down-regulated in adult hepatocytes and re-expressed in human HCC patients, mouse HCC models and HCC cell lines. Moreover, high C3G mRNA levels correlate with tumor progression and a lower patient survival rate. C3G expression appears to be tightly modulated within the HCC program, influencing distinct cell biological properties. Hence, high C3G expression levels are necessary for cell tumorigenic properties, as illustrated by reduced colony formation in anchorage-dependent and -independent growth assays induced by permanent C3G silencing using shRNAs. Additionally, we demonstrate that C3G down-regulation interferes with primary HCC tumor formation in xenograft assays, increasing apoptosis and decreasing proliferation. In vitro assays also revealed that C3G down-regulation enhances the pro-migratory, invasive and metastatic properties of HCC cells through an epithelial-mesenchymal switch that favors the acquisition of a more mesenchymal phenotype. Consistently, a low C3G expression in HCC cells correlates with lung metastasis formation in mice. However, the subsequent restoration of C3G levels is associated with metastatic growth. Mechanistically, C3G down-regulation severely impairs HGF/MET signaling activation in HCC cells. Collectively, our results indicate that C3G is a key player in HCC. C3G promotes tumor growth and progression, and the modulation of its levels is essential to ensure distinct biological features of HCC cells throughout the oncogenic program. Furthermore, C3G requirement for HGF/MET signaling full activation provides mechanistic data on how it works, pointing out the relevance of assessing whether high C3G levels could identify HCC responders to MET inhibitors

Met signaling in cardiomyocytes is required for normal cardiac function in adult mice.

Hepatocyte growth factor (HGF) and its receptor, Met, are key determinants of distinct developmental processes. Although HGF exerts cardio-protective effects in a number of cardiac pathologies, it remains unknown whether HGF/Met signaling is essential for myocardial development and/or physiological function in adulthood. We therefore investigated the requirement of HGF/Met signaling in cardiomyocyte for embryonic and postnatal heart development and function by conditional inactivation of the Met receptor in cardiomyocytes using the Cre-α-MHC mouse line (referred to as α-MHCMet-KO). Although α-MHCMet-KO mice showed normal heart development and were viable and fertile, by 6 months of age, males developed cardiomyocyte hypertrophy, associated with interstitial fibrosis. A significant upregulation in markers of myocardial damage, such as β-MHC and ANF, was also observed. By the age of 9 months, α-MHCMet-KO males displayed systolic cardiac dysfunction. Mechanistically, we provide evidence of a severe imbalance in the antioxidant defenses in α-MHCMet-KO hearts involving a reduced expression and activity of catalase and superoxide dismutase, with consequent reactive oxygen species accumulation. Similar anomalies were observed in females, although with a slower kinetics. We also found that Met signaling down-regulation leads to an increase in TGF-β production and a decrease in p38MAPK activation, which may contribute to phenotypic alterations displayed in α-MHCMet-KO mice. Consistently, we show that HGF acts through p38α to upregulate antioxidant enzymes in cardiomyocytes. Our results highlight that HGF/Met signaling in cardiomyocytes plays a physiological cardio-protective role in adult mice by acting as an endogenous regulator of heart function through oxidative stress control.Comunidad de Madrid/Universidad Complutense de Madrid; Association Française contre les Myopathies; Seventh Framework Programme; Fondation pour la Recherche Médicale; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación; Fondation Bettencourt Schueller; European Regional Development Fund; Junta de Andalucía; Junta de Castilla y Leó

Caspase-2 in liver disease and hepatocellular carcinoma

Caspases are key factors in the regulation of the apoptotic and/or inflammatory responses, both crucial in the pathogenesis of diverse diseases. Caspase-2 is the most evolutionary conserved albeit functionally poorly defined member of the caspase family. The precise role of caspase-2 as an initiator or effector caspase is still unknown, but it has been involved in a wide variety of functions, from apoptosis to genomic stability, oxidative stress, metabolism, and cancer. However, many conflicting results render the exact function of this protease still unresolved. Although caspase-2 has several hundred substrates, the activation, processing, and activity on specific substrates remain poorly described. Recent evidence indicates that caspase-2 has a role in metabolic homeostasis and is required for lipotoxicity-induced apoptosis in hepatocytes, contributing to non-alcoholic steatohepatitis (NASH) progression towards hepatocellular carcinoma (HCC). Caspase-2 protein expression strongly localizes to injured/ballooned hepatocytes, correlating with NASH severity. Also, mice lacking caspase-2 showed protection from western diet-induced obesity, dyslipidemia, and insulin resistance. Although there are no effective therapies for NASH and HCC, the evaluation of a pan-caspase inhibitor has reached a phase I/II in clinical trials for advanced liver disease. Nevertheless, a better understanding of caspase functions with the identification of specific proteolytic substrates is essential for future therapeutic developments. Bearing in mind the pressing need to identify new targets for NASH-HCC and its metabolic-related comorbidities, and the favorable effect of caspase-2 genetic inhibition in animal models, pharmacological caspase-2 inhibition arises as a promising strategy that should be further investigated