Structural insights into the high basal activity and inverse agonism of the orphan receptor GPR6 implicated in Parkinson's disease.

GPR6 is an orphan G protein-coupled receptor with high constitutive activity found in D2-type dopamine receptor-expressing medium spiny neurons of the striatopallidal pathway, which is aberrantly hyperactivated in Parkinson's disease. Here, we solved crystal structures of GPR6 without the addition of a ligand (a pseudo-apo state) and in complex with two inverse agonists, including CVN424, which improved motor symptoms in patients with Parkinson's disease in clinical trials. In addition, we obtained a cryo-electron microscopy structure of the signaling complex between GPR6 and its cognate G heterotrimer.

A simple but tough-to-beat baseline for fMRI time-series classification.

Current neuroimaging studies frequently use complex machine learning models to classify human fMRI data, distinguishing healthy and disordered brains, often to validate new methods or enhance prediction accuracy. Yet, where prediction accuracy is a concern, our results suggest that precision in prediction does not always require such sophistication. When a classifier as simple as logistic regression is applied to feature-engineered fMRI data, it can match or even outperform more sophisticated recent models.

In-Depth Chemical Analysis of the Brain Extracellular Space Using Microdialysis with Liquid Chromatography-Tandem Mass Spectrometry.

Metabolomic analysis of samples acquired from the brain extracellular space by microdialysis sampling can provide insights into chemical underpinnings of a given brain state and how it changes over time. Small sample volumes and low physiological concentrations have limited the identification of compounds from this compartment, so at present, we have scant knowledge of its composition. As a result, most measurements have limited depth of analysis.

Approaching Optimal pH Enzyme Prediction with Large Language Models.

Enzymes are widely used in biotechnology due to their ability to catalyze chemical reactions: food making, laundry, pharmaceutics, textile, brewing─all these areas benefit from utilizing various enzymes. Proton concentration (pH) is one of the key factors that define the enzyme functioning and efficiency. Usually there is only a narrow range of pH values where the enzyme is active.