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

Recommendations for ophthalmologic practice during the easing of COVID-19 control measures

In the context of the COVID-19 pandemic, this paper provides recommendations for medical eye care during the easing of control measures after lockdown. The guidelines presented are based on a literature review and consensus among all Spanish Ophthalmology Societies regarding protection measures recommended for the ophthalmologic care of patients with or without confirmed COVID-19 in outpatient, inpatient, emergency and surgery settings. We recommend that all measures be adapted to the circumstances and availability of personal protective equipment at each centre and also highlight the need to periodically update recommendations as we may need to readopt more restrictive measures depending on the local epidemiology of the virus. These guidelines are designed to avoid the transmission of SARS-CoV-2 among both patients and healthcare staff as we gradually return to normal medical practice, to prevent postoperative complications and try to reduce possible deficiencies in the diagnosis, treatment and follow-up of the ophthalmic diseases. With this update (5th) the Spanish Society of Ophthalmology is placed as one of the major ophthalmology societies providing periodic and systematized recommendations for ophthalmic care during the COVID-19 pandemic

Next-generation sequencing of bile cell-free DNA for the early detection of patients with malignant biliary strictures

Objective: despite significant progresses in imaging and pathological evaluation, early differentiation between benign and malignant biliary strictures remains challenging. Endoscopic retrograde cholangiopancreatography (ERCP) is used to investigate biliary strictures, enabling the collection of bile. We tested the diagnostic potential of next-generation sequencing (NGS) mutational analysis of bile cell-free DNA (cfDNA). Design: a prospective cohort of patients with suspicious biliary strictures (n=68) was studied. The performance of initial pathological diagnosis was compared with that of the mutational analysis of bile cfDNA collected at the time of first ERCP using an NGS panel open to clinical laboratory implementation, the Oncomine Pan-Cancer Cell-Free assay. Results: an initial pathological diagnosis classified these strictures as of benign (n=26), indeterminate (n=9) or malignant (n=33) origin. Sensitivity and specificity of this diagnosis were 60% and 100%, respectively, as on follow-up 14 of the 26 and eight of the nine initially benign or indeterminate strictures resulted malignant. Sensitivity and specificity for malignancy of our NGS assay, herein named Bilemut, were 96.4% and 69.2%, respectively. Importantly, one of the four Bilemut false positives developed pancreatic cancer after extended follow-up. Remarkably, the sensitivity for malignancy of Bilemut was 100% in patients with an initial diagnosis of benign or indeterminate strictures. Analysis of 30 paired bile and tissue samples also demonstrated the superior performance of Bilemut. Conclusion: implementation of Bilemut at the initial diagnostic stage for biliary strictures can significantly improve detection of malignancy, reduce delays in the clinical management of patients and assist in selecting patients for targeted therapies.Funding: we thank the financial support of CIBERehd; grants PI16/01126 and PI19/00163 from Instituto de Salud Carlos III (ISCIII) cofinanced by ’Fondo Europeo de Desarrollo Regional’ (FEDER) ’Una manera de hacer Europa’; grants 58/2017 and 55/2018 from Gobierno de Navarra Salud; grant 0011-1411-2020-000010 from AGATA Strategic Project from Gobierno de Navarra; grant 2020/101 from Euroregion Nouvelle Aquitaine-Euskadi-Navarra; Fundación Eugenio Rodríguez Pascual; Fundación Mario Losantos, Fundación M Torres; grant 2018/117 from AMMF, the Cholangiocarcinoma Charity; the COST Action CA181122 Euro-cholangio-Net; POSTD18014AREC postdoctoral fellowship from AECC to MA; and Ramón y Cajal Program contracts RYC-2014-15242 and RYC-2018-024475-1 to FJC and MGFB

CiTiEs (Ciudades: Tiempo + Espacio). Implementación de itinerarios didácticos para la enseñanza virtual y presencial del Patrimonio cultural de Madrid a través del aprendizaje cooperativo

Retomando los itinerarios didácticos diseñados en un PID anterior (2019/20, nº 363), se implementarán materiales digitales para la Educación patrimonial de Madrid. Se utilizarán técnicas de aprendizaje cooperativo y recursos para la enseñanza virtual.Depto. de Didáctica de las Ciencias Experimentales , Sociales y MatemáticasFac. de EducaciónFALSEsubmitte

Coordinación y donación

La progresiva incorporación del trasplante de órganos como recurso terapéutico, provocó una adecuación organizativa y de gestión global del trasplante, de la que surgió la figura del coordinador de trasplantes a mediados de los ochenta. En España se crea la Organización Nacional de Trasplantes (ONT) implantando un sistema ¿denominado ¿modelo español¿¿ basado en una red de coordinadores a tres niveles, nacional, autonómico y hospitalario. Esta estructura organizativa es un referente a nivel mundial. El coordinador hospitalario de trasplantes tiene una entendible prevalencia con la especialidad Medicina Intensiva. Mayoritariamente los órganos proceden de pacientes en muerte encefálica a corazón latiente y ello precisa la infraestructura que prestan las unidades de cuidados intensivos. Las funciones del coordinador se resumen en garantizar una sincronía de todos los elementos y equipos que concurren en esta cadena organizativa que se ha convenido denominar ¿proceso de donación¿. De modo esquemático los puntos cruciales que el coordinador hospitalario desarrolla son: ¿ Detección del donante potencial. ¿ Mantenimiento del donante. ¿ Diagnóstico de muerte encefálica. ¿ Consentimiento familiar. ¿ Preparación de la logística hospitalaria. ¿ Atención a los familiares. ¿ Implicación directa en el Programa de Garantía de Calidad. ¿ Persona de referencia en cualquier actuación con relación al trasplante. Un logro deseable es la creación de equipos de coordinación de trasplantes, con univocidad en sus mensajes, profesionalidad y permanente inyección de ese llamado ¿factor humano¿ tan necesario y a la vez cercano al mundo del trasplante

Características de la enfermedad cerebrovascular Hospital Vicente Corral Moscoso Cuenca 1993-1994

Un evento cerebro vascular es un trastorno cerebral manifestado habitualmente con signo deficitario y de restauración generalmente aguda que resulta de la obstrucción o ruptura de un vaso sanguíneo cerebral. La enfermedad cerebro vascular un grupo de entidades nosológicas resultado final de una cadena de acontecimientos que se ponen en movimiento algunas décadas antes de que se produzcan el evento es el trastorno neurológico más frecuente y produce el, mayor porcentaje de invalidez en pacientes que sobreviven al episodio agudo además está dentro de las tres causas más importantes de muerte, en países desarrollados se ha observado una incidencia menor, la que se ha atribuido al tratamiento y prevención de algunas de los factores de riesgo más importantes. El reconocimiento control y tratamiento adecuados de los factores señalados permiten que la incidencia y prevalencia de los E.C.V. disminuyan. Las medidas profilácticas y terapéuticas para el tratamiento clínico de la E.C.V. ha empezado más recientemente, pero aún no existe la unanimidad en los criterios sobre el valor de ciertas medidas terapéuticas utilizadas en el tratamiento de la E.C.V. es por esto el objetivo principal debe ser el prevenir la aparición de los eventos cerebrovasculares principalmente a través del reconocimiento de los factores de riesgo y su tratamiento adecuadoA cerebrovascular event is a brain disorder usually manifested acute deficit and restoration generally resulting from the blockage or rupture of a cerebral blood vessel sign. Vascular brain disease a group of disease entities end result of a chain of events that few decades are set in motion before the event occurring is the most common neurological disorder and produces the greater percentage of disability in patients who survive the episode It is also acute in the three major causes of death in developed countries there has been a lower incidence, which has been attributed to the treatment and prevention of some of the most important risk factors. Control and treatment of the above factors allow recognition that the incidence and prevalence of CVD decrease. Prophylactic and therapeutic measures for the clinical treatment of CVD more recently it has begun, but there is still no unanimity in the views on the value of certain therapeutic measures used in the treatment of CVD This is why the main goal should be to prevent the occurrence of cerebrovascular events primarily through the recognition of risk factors and proper treatmentDoctor en Medicina y CirugíaCuenc