Discovery and Characterization of Novel CNS-Penetrant GPR55 Agonists.

From our NETSseq-derived human brain transcriptomics data, we identified GPR55 as a potential molecular target for the treatment of motor symptoms in patients with Parkinson's disease. From a high-throughput screen, we identified and optimized agonists with nanomolar potency against both human and rat GPR55. We discovered compounds with either strong or limited β-arrestin signaling and receptor desensitization, indicating biased signaling.

The amyloid precursor protein: a converging point in Alzheimer's disease.

The decades of evidence that showcase the role of amyloid precursor protein (APP), and its fragment amyloidβ (Aβ), in Alzheimer's disease (AD) pathogenesis are irrefutable. However, the absolute focus on the single APP metabolite Aβ as the cause for AD has resulted in APP and its other fragments that possess toxic propensity, to be overlooked as targets for treatment. The complexity of its processing and its association with systematic metabolism suggests that, if misregulated, APP has the potential to provoke an array of metabolic dysfunctions.

A superior loading control for the cellular thermal shift assay.

The cellular thermal shift assay (CETSA), as a method to determine protein-ligand interaction and cellular protein modification, has rapidly become routine laboratory practice. However, current options to determine that (1) sample was loaded in each lane of the analysed western blot and (2) the amount loaded was equal, are suboptimal. Here, we report that the αC-terminal fragment of the amyloid precursor protein (APP-αCTF), detected in several wild-type mammalian cell lines, is a highly stable, soluble protein equally present from 4 to 95 °C.

Synthesis and SAR of novel GPR39 agonists and positive allosteric modulators.

We report a significant decrease in transcription of the G protein-coupled receptor GPR39 in striatal neurons of Parkinson's disease patients compared to healthy controls, suggesting that a positive modulator of GPR39 may beneficially impact neuroprotection. To test this notion, we developed various structurally diverse tool molecules. While we elaborated on previously reported starting points, we also performed an in silico screen which led to completely novel pharmacophores.

"You Do It Through the Grapevine": A Bourdieusian Analysis of Under-Age Access to Tobacco Among Adolescents From Seven European Cities.

Despite efforts to reduce adolescent smoking via minimum age-of-sale legislation, many young people continue to access tobacco through a mix of social and commercial sources. Little is known about the roles of habitus, capital, and social topographies in shaping under-age access to tobacco. This article draws on Bourdieu's theory of practice and data generated from 56 focus groups with 14- to 19-year-olds across seven European cities to answer the question "via what sources and by what means do adolescents obtain tobacco?" We find that adolescents use a range of personal capitals (social, cultural, and economic) to access tobacco, with the specific constitution and deployment of these capitals varying according to the regularities of different fields.