36 research outputs found
Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418
Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC50 = 104 ± 27 nM), in an ATP-competitive manner (K i = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 ÎŒM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3ÎČ protein and provide a description of the interactions within the ATP pocket, as well as an understanding of the structural basis for the selectivity of AR-A014418. AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein. AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. Furthermore, AR-A014418 inhibits neurodegeneration mediated by ÎČ-amyloid peptide in hippocampal slices. AR-A014418 may thus have important applications as a tool to elucidate the role of GSK3 in cellular signaling and possibly in Alzheimer's disease. AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5.Supported by grants from the Comunidad de Madrid, the Fundacion âLa Caixa,â the Lilly Foundation, the Spanish Comision Interministerial de Ciencia y Tecnologia, and an institutional grant from the Fundacion Ramon Areces.Peer reviewe
Vilken pÄverkan har Skolverkets utbildningsinspektion pÄ lÀrarprofessionen? : - En studie pÄ tre skolor i SödertÀlje
Det hÀr arbetet syftar till att ge en ökad förstÄelse för hur Skolverkets utbildningsinspektion, som startade 2003, har pÄverkat lÀrarna i deras professionella roll. Dessutom har ocksÄ lÀrarnas Äsikter om hur inspektionen kan utvecklas och förbÀttras förts fram. Insamlingen av information har frÀmst skett genom intervjuer med lÀrare och rektorer pÄ tre grundskolor i SödertÀlje kommun. Olika teorier och studier kring professioner, lÀrarprofessionen samt utvecklingen av den svenska skolan har anvÀnts som teoretisk grund i arbetet. Det har visat sig att lÀrarna sjÀlva inte i nÄgon större omfattning har reflekterat över hur inspektionen pÄverkar deras profession. DÀremot har lÀrarna mycket Äsikter kring inspektionen och dess utformning. LÀrarna anser bland annat att inspektionen skulle kunna förbÀttras genom mer Äterkoppling frÄn Skolverket efter genomförd skolinspektion, för att fÄ en bÀttre dialog mellan skolan och Skolverket. Vidare betonades vikten av att de som granskar skolan har pedagogisk bakgrund. Dessutom framkom att lÀrarna anser att inspektionen ocksÄ, i större utstrÀckning, borde se till elevernas sociala förhÄllanden dÄ de pÄverkar arbetet i skolan
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Analysis of molecular determinants of affinity and relative efficacy of a series of R- and S-2-(dipropylamino)tetralins at the 5-HT1A serotonin receptor
1 Factors influencing agonist affinity and relative efficacy have been studied for the 5-HT1A serotonin receptor using membranes of CHO cells expressing the human form of the receptor and a series of R-and S-2-(dipropylamino)tetralins (nonhydroxylated and monohydroxylated (5-OH, 6-OH, 7-OH, 8-OH) species). 2 Ligand binding studies were used to determine dissociation constants for agonist binding to the 5HT(1A) receptor: (a) K-i values for agonists were determined in competition versus the binding of the agonist [H-3]-8-OH DPAT. Competition data were all fitted best by a one-binding site model. (b) K-i values for agonists were also determined in competition versus the binding of the antagonist [H-3]-NAD-199. Competition data were all fitted best by a two-binding site model, and agonist affinities for the higher (K-h) and lower affinity (K-1) sites were determined. 3 The ability of the agonists to activate the 5-HT1A receptor was determined using stimulation of [S-35]-GTPgammaS binding. Maximal effects of agonists (E-max) and their potencies (EC50) were determined from concentration/response curves for stimulation of [S-35]-GTPgammaS binding. 4 K-1/K-h determined from ligand binding assays correlated with the relative efficacy (relative Em) of agonists determined in [S-35]-GTPgammaS binding assays. There was also a correlation between K-1/K-h and K-1/EC50 for agonists determined from ligand binding and [S-35]-GTPgammaS binding assays. 5 Simulations of agonist binding and effect data were performed using the Ternary Complex Model in order to assess the use of K-1/K-h for predicting the relative efficacy of agonists. British Journal of Pharmacology (2003) 138, 1129-1139. doi: 10. 1038/sj.bjp.705085