👤 Christopher J Stubbs

Upwards of 50% of people do not respond to the primary treatment modalities for major depressive disorder (MDD), which has led to increased attention and use of alternative methods, including exercise and psychedelics. While interventions using either exercise or psychedelics have demonstrated largely positive results in isolation, their synergistic potential has yet to be explored. As such, this commentary provides an overview of exercise/psychedelics as a treatment for depression and their potential synergy and/or complementarity. From a biological perspective, psychedelics acutely enhance brain-derived neurotrophic factor (BDNF) signalling, while exercise provides sustained BDNF elevation; psychedelics enhance neuroplasticity largely in the cortex (with only modest effects in the hippocampus), while exercise boosts hippocampal neurogenesis; psychedelics increase glutamate release via stimulation of 5-HT Show less

Understanding allosteric regulation in biomolecules is of great interest to pharmaceutical research and computational methods emerged during the last decades to characterize allosteric coupling. However, the prediction of allosteric sites in a protein structure remains a challenging task. Here, we integrate local binding site information, coevolutionary information, and information on dynamic allostery into a structure-based three-parameter model to identify potentially hidden allosteric sites in ensembles of protein structures with orthosteric ligands. When tested on five allosteric proteins (LFA-1, p38-α, GR, MAT2A, and BCKDK), the model successfully ranked all known allosteric pockets in the top three positions. Finally, we identified a novel druggable site in MAT2A confirmed by X-ray crystallography and SPR and a hitherto unknown druggable allosteric site in BCKDK validated by biochemical and X-ray crystallography analyses. Our model can be applied in drug discovery to identify allosteric pockets. Show less

Ventricular noncompaction cardiomyopathy is a rare form of congenital cardiomyopathy with increasing evidence of genetic etiology, especially when presenting in childhood. Fetal presentation is rare. We describe a case of fetal hydrops, presenting at 24 weeks gestation and leading to intrapartum death at 26 weeks gestation. Autopsy examination revealed characteristic features of left ventricular noncompaction. A genetic analysis identified a constellation of variants of unknown significance in MYH6, TNNC1, and MYBPC3, genes known to be important in sarcomeric function. Additionally, the variant in MYBPC3 was homozygous. While this case did not demonstrate a conventional single-gene mutation as the cause of the ventricular noncompaction, a broader genomic investigation revealed several variants in sarcomeric genes which may act synergistically to impact cardiac function. Show less