Splicing Factor SLU7 Prevents Oxidative Stress-Mediated Hepatocyte Nuclear Factor 4α Degradation, Preserving Hepatic Differentiation and Protecting From Liver Damage

Background and Aims: Hepatocellular dedifferentiation is emerging as an important determinant in liver disease progression. Preservation of mature hepatocyte identity relies on a set of key genes, predominantly the transcription factor hepatocyte nuclear factor 4α (HNF4α) but also splicing factors like SLU7. How these factors interact and become dysregulated and the impact of their impairment in driving liver disease are not fully understood. Approach and Results: Expression of SLU7 and that of the adult and oncofetal isoforms of HNF4α, driven by its promoter 1 (P1) and P2, respectively, was studied in diseased human and mouse livers. Hepatic function and damage response were analyzed in wild-type and Slu7-haploinsufficient/heterozygous (Slu7) mice undergoing chronic (CCl) and acute (acetaminophen) injury. SLU7 expression was restored in CCl-injured mice using SLU7-expressing adeno-associated viruses (AAV-SLU7). The hepatocellular SLU7 interactome was characterized by mass spectrometry. Reduced SLU7 expression in human and mouse diseased livers correlated with a switch in HNF4α P1 to P2 usage. This response was reproduced in Slu7 mice, which displayed increased sensitivity to chronic and acute liver injury, enhanced oxidative stress, and marked impairment of hepatic functions. AAV-SLU7 infection prevented liver injury and hepatocellular dedifferentiation. Mechanistically we demonstrate a unique role for SLU7 in the preservation of HNF4α1 protein stability through its capacity to protect the liver against oxidative stress. SLU7 is herein identified as a key component of the stress granule proteome, an essential part of the cell’s antioxidant machinery. Conclusions: Our results place SLU7 at the highest level of hepatocellular identity control, identifying SLU7 as a link between stress-protective mechanisms and liver differentiation. These findings emphasize the importance of the preservation of hepatic functions in the protection from liver injury.Supported by MINECO/AEI/FEDER (UE SAF2016-75972-R, PID2019-104265RB-I00/AEI/10.13039/501100011033, and PID2019-104878RB-100/AEI/10.13039/501100011033), CIBERehd, Fundación La Caixa (HEPACARE), an AECC postdoctoral fellowship (POSTD18014AREC, to M.A.), a Ministerio de Educación FPU fellowship (FPU18/01461, to M.G.R.), a Ministerio de Educación FPI fellowship (BES-2017-079883, to M.R.); a Ramón y Cajal Program contract (RYC2018-024475-1, to M.G.F.B.), the Fundación Eugenio Rodríguez Pascual, the Fundación Mario Losantos, the Fundación M. Torres, and a generous donation from Mr. Eduardo Avila

Splicing factor SLU7 prevents oxidative stress-mediated hepatocyte nuclear factor 4α degradation, preserving hepatic differentiation and protecting from liver damage

Background and Aims: Hepatocellular dedifferentiation is emerging as an important determinant in liver disease progression. Preservation of mature hepatocyte identity relies on a set of key genes, predominantly the transcription factor hepatocyte nuclear factor 4α (HNF4α) but also splicing factors like SLU7. How these factors interact and become dysregulated and the impact of their impairment in driving liver disease are not fully understood. Approach and Results: Expression of SLU7 and that of the adult and oncofetal isoforms of HNF4α, driven by its promoter 1 (P1) and P2, respectively, was studied in diseased human and mouse livers. Hepatic function and damage response were analyzed in wild-type and Slu7-haploinsufficient/heterozygous (Slu7+/−) mice undergoing chronic (CCl4) and acute (acetaminophen) injury. SLU7 expression was restored in CCl4-injured mice using SLU7-expressing adeno-associated viruses (AAV-SLU7). The hepatocellular SLU7 interactome was characterized by mass spectrometry. Reduced SLU7 expression in human and mouse diseased livers correlated with a switch in HNF4α P1 to P2 usage. This response was reproduced in Slu7+/− mice, which displayed increased sensitivity to chronic and acute liver injury, enhanced oxidative stress, and marked impairment of hepatic functions. AAV-SLU7 infection prevented liver injury and hepatocellular dedifferentiation. Mechanistically we demonstrate a unique role for SLU7 in the preservation of HNF4α1 protein stability through its capacity to protect the liver against oxidative stress. SLU7 is herein identified as a key component of the stress granule proteome, an essential part of the cell’s antioxidant machinery. Conclusions: Our results place SLU7 at the highest level of hepatocellular identity control, identifying SLU7 as a link between stress-protective mechanisms and liver differentiation. These findings emphasize the importance of the preservation of hepatic functions in the protection from liver injury.Supported by MINECO/AEI/FEDER (UE SAF2016‐75972‐R, PID2019‐104265RB‐I00/AEI/10.13039/501100011033, and PID2019‐104878RB‐100/AEI/10.13039/501100011033), CIBERehd, Fundación La Caixa (HEPACARE), an AECC postdoctoral fellowship (POSTD18014AREC, to M.A.), a Ministerio de Educación FPU fellowship (FPU18/01461, to M.G.R.), a Ministerio de Educación FPI fellowship (BES‐2017‐079883, to M.R.); a Ramón y Cajal Program contract (RYC2018‐024475‐1, to M.G.F.B.), the Fundación Eugenio Rodríguez Pascual, the Fundación Mario Losantos, the Fundación M. Torres, and a generous donation from Mr. Eduardo Avila

Determinantes socioeconómicos de la salud en Andalucía: estudio comparado del impacto de la crisis económica en la salud de los andaluces (Proyecto IMPACT-A)

Los estudios sobre determinantes socioeconómicos de la salud se han centrado fundamentalmente en el análisis de los factores de carácter económico, es decir, en las diferencias de salud generadas por los ingresos. Sin embargo, la relación entre los ingresos y las desigualdades de salud parece ser algo más compleja. Como se ha puesto de manifiesto en recientes estudios, la inclusión de los ingresos como factor explicativo de las desigualdades de salud, aunque resulta necesaria, no es suficiente para entender la diversidad y la complejidad de otras dimensiones sociales como la educación o la clase social, que resultan igualmente relevantes en la explicación de estas desigualdades. En línea con este conjunto de consideraciones, el objetivo del presente trabajo se dirige a comparar el impacto de diferentes medidas del estatus socioeconómico (educación, clase social, ocupación e ingresos) sobre la salud auto-percibida (self-rated health - SRH) en las diferentes Comunidades Autónomas españolas, a partir de datos de los Barómetros Sanitarios del Centro de Investigaciones Sociológicas. Adicionalmente, se estudia el efecto contextual de indicadores macroeconómicos, de servicios sanitarios, y calidad de vida mediante el diseño de diferentes modelos de regresión logística ordinal multinivel. Los datos del presente trabajo revelan que, a pesar de que España es un país que goza de una auto-percepción de la salud positiva, se observan desigualdades en la salud a nivel interregional. Si bien en nuestro país no existen grandes diferencias en la salud, los datos ponen de manifiesto que factores socioeconómicos como los ingresos, clase social, la ocupación o la educación pueden tener un importante impacto sobre la salud de los grupos en riesgo de exclusión social. En el nivel contextual, el riesgo de pobreza y el desempleo se encuentran negativamente relacionados con la auto-percepción de la salud de los españoles. Unos resultados que tienen implicaciones muy claras en el reciente contexto de crisis económica. El presente análisis aporta claros indicios de la importancia de tener unas condiciones vitales dignas para poder mantener la salud. Sin lugar a dudas vivir en la pobreza o en una condición de riesgo de caer en un estado de privación material, aumenta la probabilidad de tener una mala salud, y esta misma relación se aplica a la falta de trabajo. En este sentido, es necesario considerar el impacto socioeconómico de la actual crisis económica y los actuales recortes del gasto público en la salud de los grupos más desfavorecidos de nuestra sociedad

Splicing regulator SLU7 is essential for maintaining liver homeostasis

A precise equilibrium between cellular differentiation and proliferation is fundamental for tissue homeostasis. Maintaining this balance is particularly important for the liver, a highly differentiated organ with systemic metabolic functions that is endowed with unparalleled regenerative potential. Carcinogenesis in the liver develops as the result of hepatocellular de-differentiation and uncontrolled proliferation. Here, we identified SLU7, which encodes a pre-mRNA splicing regulator that is inhibited in hepatocarcinoma, as a pivotal gene for hepatocellular homeostasis. SLU7 knockdown in human liver cells and mouse liver resulted in profound changes in pre-mRNA splicing and gene expression, leading to impaired glucose and lipid metabolism, refractoriness to key metabolic hormones, and reversion to a fetal-like gene expression pattern. Additionally, loss of SLU7 also increased hepatocellular proliferation and induced a switch to a tumor-like glycolytic phenotype. Slu7 governed the splicing and/or expression of multiple genes essential for hepatocellular differentiation, including serine/arginine-rich splicing factor 3 (Srsf3) and hepatocyte nuclear factor 4α (Hnf4α), and was critical for cAMP-regulated gene transcription. Together, out data indicate that SLU7 is central regulator of hepatocyte identity and quiescence

Tarbiya : revista de investigación e innovación educativa

Cuando se habla de calidad, es necesario definirla bien y poner sobre la mesa los criterios que están involucrados en la propia definición. Se ofrecen una serie de elementos que, entrelazados, hacen que un centro de Educación Infantil sea considerado de calidad. A partir de cinco experiencias se proponen criterios concretos para hablar de contextos de calidad. Con este documento se pretende definir más claramente el camino de la mejora de las escuelas infantiles. El fin es lograr una escuela realmente de calidad y de excelencia, entendida esta como el modo sobresaliente de gestionar la organización en los ocho conceptos fundamentales de la excelencia que, según el criterio del modelo de calidad europeo, son: orientación hacia los resultados; orientación al cliente; liderazgo y coherencia; gestión por procesos y hechos; desarrollo e implicación de las personas; proceso continuo de aprendizaje; innovación y mejora y responsabilidad social de la organización. Este documento es un instrumento orientativo para la autoevaluación de cada escuela y se reflexiona sobre una serie de criterios de evaluación que crean la calidad educativa.MadridCRIF Las Acacias. Dirección General de Mejora de la Calidad de la Enseñanza. Comunidad de Madrid; Calle General Ricardos, 179; 28025 Madrid; Tel. +34915250893; Fax +34915255888; [email protected]

Hiriko gune berdeak eta osasuna

Nowadays, living in a world more focused on citizenship, specialists are concerned on the impact produced by cities in the health of our society. This impact, which can be either positive or negative, has been profoundly researched lastly. However, it is important to mention the existence of positive exposures to overcome negative impact. These positive exposures are named green and blue areas, and have the aim of helping society maintain a healthier lifestyle. Recently, more and more research is made concerning green and blue areas; focusing on their positive impact in mental, physical and social health. The aim of this article is to present a compilation of information on green and blue areas in latest investigations, explaining different methodologies used for research and showing the diverse impact these areas might produce in human health; Azken urte luzeetan hiritarragoa den mundu batean, hiri guneek sortutako esposizio positibo zein negatiboek osasunean duten eraginak geroz eta gehiago kezkatzen gaitu. Osasunean eragin negatiboa duten esposizioak ikertu dira gehien, baina hauei aurre egiteko esposizio positiboak ere badaude, bizimodu osasuntsuago batera bultzatzen gaituztenak, eta hortaz, osasun maila hobe bat izatera. Esposizio positibo hauek gune berde eta urdinak dira. Geroz eta ikerketa gehiagotan aurki daitezke eta osasun mental, fisiko eta sozialean duten eragin positiboa hainbat ikerketetan aurki daiteke. Artikulu honen helburua gune berde eta urdinak aztertzen dituzten ikerketek diotena aztertzea, esposizio hauek neurtzeko metodologia ezberdinak azaltzea eta osasunean dituzten eragin ezberdinak ikustea da

Efecto de la marea negra del Prestige sobre el halcón peregrino en el País Vasco

Informe original disponible en la web de Icarus, Estudios Medioambientales, S.L., que ha participado en su elaboración: http://www.icarus.es/La afección de la marea negra del petrolero Prestige sobre el Halcón Peregrino durante el primer año ha sido patente. Se ha comprobado que se da una afección directa, aunque evidentemente, de menor magnitud que la esperada en aves relacionadas directamente con el medio marino. Las probabilidades de alimentarse sobre presas contaminadas son evidentes y aumentarán conforme pase el tiempo y siga existiendo fuel. Además, la contaminación de las cadenas tróficas intermedias produce un efecto de bioacumulación añadido en las presas del halcón. Por lo que las concentraciones de elementos perniciosos pueden incrementarse de una forma lenta pero continua. Este es el verdadero problema de la marea negra sobre el halcón, que provoca problemas en la fase de la reproducción, bien por malfuncionamiento de las gónadas, bien por efectos letales en los embriones de los huevos, o bien por afecciones a largo plazo en los pollos. Además de provocar la muerte a corto-medio plazo de los ejemplares adultos.Por lo tanto, en este primer informe se van a exponer los resultados obtenidos durante el seguimiento de las poblaciones de Halcón Peregrino en Bizkaia, comparándolos con seis años de estudios previos. Los resultados permitirán valorar el grado y la magnitud de la afección en su primer episodio (periodo de reproducción de 2003).Peer reviewe

DNA Methylation Regulates a Set of Long Non-Coding RNAs Compromising Hepatic Identity during Hepatocarcinogenesis

Background: Long noncoding RNAs (lncRNAs) are emerging as key players in cancer, including hepatocellular carcinoma (HCC). Here we identify the mechanism implicated in the HCC inhibition of a set of lncRNAs, and their contribution to the process of hepatocarcinogenesis. Methods and Results: The top-ranked 35 lncRNAs downregulated in HCC (Top35 LNDH) were validated in several human HCC cohorts. We demonstrate that their inhibition is associated with promoter hypermethylation in HCC compared to control tissue, and in HCC human cell lines compared to primary hepatocytes. Moreover, demethylating treatment of HCC human cell lines induced the expression of these lncRNAs. The Top35 LNDH were preferentially expressed in the adult healthy liver compared to other tissues and fetal liver and were induced in well-differentiated HepaRG cells. Remarkably, their knockdown compromised the expression of other hepato-specific genes. Finally, the expression of the Top35 LNDH positively correlates with the grade of tumor differentiation and, more importantly, with a better patient prognosis. Conclusions: Our results demonstrate that the selected Top35 LNDH are not only part of the genes that compose the hepatic differentiated signature but participate in its establishment. Moreover, their downregulation through DNA methylation occurs during the process of hepatocarcinogenesis compromising hepatocellular differentiation and HCC patients’ prognosis

Short-term effects of the prestige oil spill on the peregrine falcon (Falco peregrinus)

6 pages.-- Original working paper (extended-version in Spanish) available at Digital.CSIC: http://digital.csic.es/handle/10261/6808.-- Final full-text version of the paper available at: http://dx.doi.org/10.1016/j.marpolbul.2006.02.016.We have monitored the distribution, population status, breeding success, turnover rate and diet of a Peregrine Falcon population in Bizkaia (North of Spain) since 1997. On the 13th November 2002, the tanker Prestige sunk off La Coruña (NW Spain) causing an oil spill that affected the whole of the Cantabrian Coast and the Southwest of France. The total number of birds affected by the Prestige oil spill was expected to be between 115,000 and 230,000, some of them raptors. The loss of clutches during the incubation period increased significantly and was correlated with the loss of females. Moreover, the turnover rate of the population increased from 21% to 30%. The polycyclic aromatic hydrocarbon concentrations in the eggs, collected from five nests after they were deserted, ranged from 21.20 ng/g to 461.08 ng/g, values which are high enough to cause the death of the embryos and poisoning of adult birds. The effects of pollution reached inland since some inland-breeding falcons prey on shorebirds that use rivers during their migratory flights. As the Prestige oil spill has clearly resulted in increased rates of adult mortality and reduced fertility, we suggest that the environmental authorities urgently undertake measures aimed at protecting the Peregrine Falcon in Bizkaia.The Biodiversity Department of Basque Government partially supported this study. The Dpto Agricultura, Diputación Foral de Bizkaia, provided the licences to work with Peregrine Falcons and the San Sebastian Ringing Scheme contributed with the material for ringing.Peer reviewe