0000000000056627
AUTHOR
Daniel Merk
Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma
Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mu…
White Etching Crack Root Cause Investigations
White etching crack (WEC) failure is distinct to classical fatigue and driven by the composition of lubricants under special loading conditions; for example, slippage and electricity. The white etching area (WEA) within WEC contains carbon supersaturated ferrite (bcc-iron) and carbides, with a size of a few nanometers. This article presents investigations supporting the hypothesis that WEC processes start within a failure-free period by successive accumulation of a structural distortion. This can be measured by acoustic emission. Failure statistics show a steep ascent in the Weibull diagram (s values beyond 1) leading to the assumption that WEC processes start unsuspicious, as one would see…
Nonacidic Farnesoid X Receptor Modulators.
As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. Clinical results have validated FXR as therapeutic target in hepatic and metabolic diseases. To date, potent FXR agonists share a negatively ionizable function that might compromise their pharmacokinetic distribution and behavior. Here we report the development and characterization of a high-affinity FXR modulator not comprising an acidic residue.