Discovery of Orally Available and Brain Penetrant AEP Inhibitors.

Alzheimer's Disease (AD) is the most widespread form of dementia, with one of the pathological hallmarks being the formation of neurofibrillary tangles (NFTs). These tangles consist of phosphorylated Tau fragments. Asparagine endopeptidase (AEP) is a key Tau cleaving enzyme that generates aggregation-prone Tau fragments.

Origin and mobility of Iron Age Gaulish groups in present-day France revealed through archaeogenomics.

The Iron Age period occupies an important place in French history because the Gauls are regularly presented as the direct ancestors of the extant French population. We documented here the genomic diversity of Iron Age communities originating from six French regions. The 49 acquired genomes permitted us to highlight an absence of discontinuity between Bronze Age and Iron Age groups in France, lending support to a cultural transition linked to progressive local economic changes rather than to a massive influx of allochthone groups.

Structural insights into the inhibition of glycine reuptake.

The human glycine transporter 1 (GlyT1) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine. Inhibition of GlyT1 prolongs neurotransmitter signalling, and has long been a key strategy in the development of therapies for a broad range of disorders of the central nervous system, including schizophrenia and cognitive impairments. Here, using a synthetic single-domain antibody (sybody) and serial synchrotron crystallography, we have determined the structure of GlyT1 in complex with a benzoylpiperazine chemotype inhibitor at 3.

Ancient genomes from present-day France unveil 7,000 years of its demographic history.

Genomic studies conducted on ancient individuals across Europe have revealed how migrations have contributed to its present genetic landscape, but the territory of present-day France has yet to be connected to the broader European picture. We generated a large dataset comprising the complete mitochondrial genomes, Y-chromosome markers, and genotypes of a number of nuclear loci of interest of 243 individuals sampled across present-day France over a period spanning 7,000 y, complemented with a partially overlapping dataset of 58 low-coverage genomes. This panel provides a high-resolution transect of the dynamics of maternal and paternal lineages in France as well as of autosomal genotypes.

Discovery of Balovaptan, a Vasopressin 1a Receptor Antagonist for the Treatment of Autism Spectrum Disorder.

We recently reported the discovery of a potent, selective, and brain-penetrant V1a receptor antagonist, which was not suitable for full development. Nevertheless, this compound was found to improve surrogates of social behavior in adults with autism spectrum disorder in an exploratory proof-of-mechanism study. Here we describe scaffold hopping that gave rise to triazolobenzodiazepines with improved pharmacokinetic properties.