SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism

Genetic mutations of SHANK3 have been reported in patients with intellectual disability, autism spectrum disorder (ASD) and schizophrenia. At the synapse, Shank3/ProSAP2 is a scaffolding protein that connects glutamate receptors to the actin cytoskeleton via a chain of intermediary elements. Although genetic studies have repeatedly confirmed the association of SHANK3 mutations with susceptibility to psychiatric disorders, very little is known about the neuronal consequences of these mutations. Here, we report the functional effects of two de novo mutations (STOP and Q321R) and two inherited variations (R12C and R300C) identified in patients with ASD. We show that Shank3 is located at the tip of actin filaments and enhances its polymerization. Shank3 also participates in growth cone motility in developing neurons. The truncating mutation (STOP) strongly affects the development and morphology of dendritic spines, reduces synaptic transmission in mature neurons and also inhibits the effect of Shank3 on growth cone motility. The de novo mutation in the ankyrin domain (Q321R) modifies the roles of Shank3 in spine induction and morphology, and actin accumulation in spines and affects growth cone motility. Finally, the two inherited mutations (R12C and R300C) have intermediate effects on spine density and synaptic transmission. Therefore, although inherited by healthy parents, the functional effects of these mutations strongly suggest that they could represent risk factors for ASD. Altogether, these data provide new insights into the synaptic alterations caused by SHANK3 mutations in humans and provide a robust cellular readout for the development of knowledge-based therapies

Evaluation des Pentaho Open Source Business Intelligence Systems anhand von Big Data- Anwendungsszenarien

Diese Ausarbeitung evaluiert das Open Source Business Intelligence System von Pentaho mittels eigens aufgestellter Big Data-Anwendungsszenarien. Neben einer Einführung der im Hintergrund stehenden Thematik, sowie näheren Erläuterung der Grundelemente dieses Systems wird auch auf die aktuelle Mitbewerbersituation eingegangen. Die anschließende Realisierung der Szenarien innerhalb der Anwendung wird abschließend ausführlich bewertet.This paper evaluates the Open Source Business Intelligence System of Pentaho by using special Big Data use cases. Apart from introducing the background of this topic and also clarifying the basic elements of this system the current competitors are also discussed. Finally the subsequent implementation of these scenarios within the application is evaluated in detail