23 research outputs found
Generation and characterisation of Friedreich ataxia YG8R mouse fibroblast and neural stem cell models
This article has been made available through the Brunel Open Access Publishing Fund.Background: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by GAA repeat expansion in the first intron of the FXN gene, which encodes frataxin, an essential mitochondrial protein. To further characterise the molecular abnormalities associated with FRDA pathogenesis and to hasten drug screening, the development and use of animal and cellular models is considered essential. Studies of lower organisms have already contributed to understanding FRDA disease pathology, but mammalian cells are more related to FRDA patient cells in physiological terms. Methodology/Principal Findings: We have generated fibroblast cells and neural stem cells (NSCs) from control Y47R mice (9 GAA repeats) and GAA repeat expansion YG8R mice (190+120 GAA repeats). We then differentiated the NSCs in to neurons, oligodendrocytes and astrocytes as confirmed by immunocytochemical analysis of cell specific markers. The three YG8R mouse cell types (fibroblasts, NSCs and differentiated NSCs) exhibit GAA repeat stability, together with reduced expression of frataxin and reduced aconitase activity compared to control Y47R cells. Furthermore, YG8R cells also show increased sensitivity to oxidative stress and downregulation of Pgc-1α and antioxidant gene expression levels, especially Sod2. We also analysed various DNA mismatch repair (MMR) gene expression levels and found that YG8R cells displayed significant reduction in expression of several MMR genes, which may contribute to the GAA repeat stability. Conclusions/Significance: We describe the first fibroblast and NSC models from YG8R FRDA mice and we confirm that the NSCs can be differentiated into neurons and glia. These novel FRDA mouse cell models, which exhibit a FRDA-like cellular and molecular phenotype, will be valuable resources to further study FRDA molecular pathogenesis. They will also provide very useful tools for preclinical testing of frataxin-increasing compounds for FRDA drug therapy, for gene therapy, and as a source of cells for cell therapy testing in FRDA mice. © 2014 Sandi et al
German Monetary Unification and European Monetary Union: Theoretical Issues and Strategic Policy Problems
Boards of directors in international organizations: A framework for understanding the dilemmas of institutional design
Boards of directors, Executive boards, Institutional design, Governance, Accountability, Democratic deficit, F33, F53, F55, F59,
Arbeitsmarktpolitik: zum Verhältnis von Marktsteuerung und staatlicher Beschäftigungssicherung
Der Verfasser skizziert einleitend Elemente einer über ökonomische Kategorien hinausgehenden Sicht von Arbeitslosigkeit. Der Kern der aktuellen wirtschaftspolitischen Problematik wird in mangelnder Nachfrage aufgrund gebremster Innovations- und Investitionstätigkeit gesehen. Vor diesem Hintergrund setzt sich der Verfasser kritisch mit fünf Aspekten des neoklassischen Arguments inflexibler Lohn- und Vertragsstrukturen auseinander: (1) staatliche Regulierung der Lohnnebenkosten; (2) lohnpolitische Kartellierung des Arbeitsmarkts; (3) Nivellierung der Löhne; (4) Starrheit der Lohnstrukturen; (5) arbeitsrechtliche Schutzvorschriften. Die Vorstellung einer "Wohlstandsarbeitslosigkeit" wird auf der Basis von Untersuchungen über finanzielle, gesundheitliche und psychische Folgen von Arbeitslosigkeit zurückgewiesen. Abschließend werden acht Facetten einer aktiven Arbeitsmarktpolitik diskutiert: (1) Schaffung von Arbeitsplätzen; (2) Abbau von Subventionen, Erhöhung der Mobilität; (3) Finanzierung von Arbeit statt Finanzierung von Arbeitslosigkeit; (4) Reduzierung der fixen Lohnnebenkosten; (5) Flexibilisierung der Lohnersatzleistungen; (6) Modernisierung der Arbeitsverwaltung; (7) Bildung und Pflege von Netzwerken; (8) Recht auf Arbeit für Langzeitarbeitslose. (ICE