Mutations in LRRK2 impair NF-κB pathway in iPSC-derived neurons

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both familial and idiopathic forms of Parkinson's disease (PD). Neuroinflammation is a key event in neurodegeneration and aging, and there is mounting evidence of LRRK2 involvement in inflammatory pathways. In a previous study, we described an alteration of the inflammatory response in dermal fibroblasts from PD patients expressing the G2019S and R1441G mutations in LRRK2. Methods: Taking advantage of cellular reprogramming, we generated induced pluripotent stem cell (iPSC) lines and neurons thereafter, harboring LRRK2G2019S and LRRK2R1441G mutations. We used gene silencing and functional reporter assays to characterize the effect of the mutations. We examined the temporal profile of TNF alpha-induced changes in proteins of the NF-kappa B pathway and optimized western blot analysis to capture alpha-synuclein dynamics. The effects of the mutations and interventions were analyzed by two-way ANOVA tests with respect to corresponding controls. Results: LRRK2 silencing decreased alpha-synuclein protein levels in mutated neurons and modified NF-kappa B transcriptional targets, such as PTGS2 (COX-2) and TNFAIP3 (A20). We next tested whether NF-kappa B and alpha-synuclein pathways converged and found that TNF alpha modulated alpha-synuclein levels, although we could not detect an effect of LRRK2 mutations, partly because of the individual variability. Nevertheless, we confirmed NF-kappa B dysregulation in mutated neurons, as shown by a protracted recovery of I kappa B alpha and a clear impairment in p65 nuclear translocation in the LRRK2 mutants. Conclusions: Altogether, our results show that LRRK2 mutations affect alpha-synuclein regulation and impair NF-kappa B canonical signaling in iPSC-derived neurons. TNFa modulated alpha-synuclein proteostasis but was not modified by the LRRK2 mutations in this paradigm. These results strengthen the link between LRRK2 and the innate immunity system underscoring the involvement of inflammatory pathways in the neurodegenerative process in PDThis study is funded by grants from the Spanish Ministry of Economy and Competitiveness (MINECO), Fondo de Investigaciones Sanitarias PI15/00486, the European Commission FP7 Health -278871, and the Joint Program in Neurodegenerative Diseases AC 14/0041 (DAMNDPATHS) to RSP

The relationship between coping style and psychological distress in people with head and neck cancer: a systematic review

Objective Individuals diagnosed with head and neck cancer (HNC) are at an elevated risk of experiencing psychological distress and a reduced quality of life. The aim of this review was to systematically examine and assess the quality of empirical evidence on the associations between coping mechanisms and psychological distress among people with HNC. Methods CINAHL, MEDLINE, PsycINFO, EMBASE and Web of Science were accessed to conduct this review. Studies were included if they used reliable and valid measures to investigate the relationship between coping style and psychological distress. Study quality was assessed and rated according to pre-set criteria, and showed variability in relation to selection methods. Results 12 studies (nine cross-sectional and three prospective designs) involving 1281 patients were reviewed. There was considerable heterogeneity in study samples and coping measures. Moderate to large associations between disengagement coping mechanisms (e.g. avoidance) and psychological distress were observed. Engagement coping strategies (e.g. direct action) were not consistently associated with psychological distress across studies. Conclusions Several studies observed a significant relationship between coping styles aimed at disengaging and distancing from cancer and increased psychological distress. To understand directionality of these associations and further develop an understanding of temporal features of the relationship between coping styles and distress, longitudinal designs could be used in future research

Additional file 5: of Mutations in LRRK2 impair NF-κB pathway in iPSC-derived neurons

Uncropped blots related to Fig. 6

La medicina y los seguros en el abordaje del problema de los inválidos del trabajo en España en la primera mitad del siglo XX Medicine, social security, and occupational disabilities in Spain in the first half of the twentieth century

En el presente trabajo, utilizando fuentes legislativas, médicas, de algunas instituciones (CRS, IRS, INP, Irpit y Clínica del Trabajo), prensa general y obrera, se estudia el abordaje del problema de los inválidos del trabajo durante la primera mitad del siglo XX. Se trata de poner de relieve cómo junto a medidas de protección social se fue generando y articulando una atención médica especializada del accidentado que tendría como objetivo final la reintegración del inválido del trabajo a la sociedad.<br>Relying on legislative, medical, institutional, media, and labor sources, the article examines how the issue of worker disabilities was addressed during the first half of the twentieth century. It shows how specialized medical care developed and evolved, along with a social safety network, with the ultimate aim of integrating those with occupational disabilities back into work and society

Modelos de administración y gestión, políticas y metodologías, en materia de e-learning para la enseñanza en la universidad pública española

Proyecto elaborado en el ámbito de la 'III convocatoria de ayudas a la innovación educativa: convocatoria para el desarrollo y participación en proyectos de innovación educativa y mejora de la calidad docente, curso 2007-2008'No existe un modelo estándar, ni aproximaciones pedagógicas, tecnológicas u organizativas únicas al e-learning. Por ello es necesario determinar cuáles son los elementos que definen la elección de un modelo u otro para su aplicación al ámbito de la educación superior. En este sentido se ofrece una aproximación a los distintos modelos existentes de e-learning para, a continuación, realizar un estudio sobre el aprendizaje derivado del uso de estos modelos: aprendizaje significativo, aprendizaje basado en problemas, aprendizaje basado en proyectos, y aprendizaje basado en casos. Por último, se ofrece un apartado en el que se describe la situación del e-learning en la Universidad pública española, se proponen modelos de evaluación del e-learning y se dan herramientas para la acción docente y para la gestión de modelos en el ámbito universitario.MadridBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín 5 -3 Planta; 28014 Madrid; Tel. +34917748000; [email protected]