A release of local subunit conformational heterogeneity underlies gating in a muscle nicotinic acetylcholine receptor.

Synaptic receptors respond to neurotransmitters by opening an ion channel across the post-synaptic membrane to elicit a cellular response. Here we use recent Torpedo acetylcholine receptor structures and functional measurements to delineate a key feature underlying allosteric communication between the agonist-binding extracellular and channel-gating transmembrane domains. Extensive mutagenesis at this inter-domain interface re-affirms a critical energetically coupled role for the principal α subunit ß1-ß2 and M2-M3 loops, with agonist binding re-positioning a key ß1-ß2 glutamate/valine to facilitate the outward motions of a conserved M2-M3 proline to open the channel gate. Notably, the analogous structures in non-α subunits adopt a locally active-like conformation in the apo state even though each L9' hydrophobic gate residue in each pore-lining M2 α-helix is closed. Agonist binding releases local conformational heterogeneity transitioning all five subunits into a conformationally symmetric open state. A release of conformational heterogeneity provides a framework for understanding allosteric communication in pentameric ligand-gated ion channels.

Incidence, factors, and disparities related to cancer among Black individuals in Canada: A scoping review.

BACKGROUND: In Canada, two of five individuals will be diagnosed with cancer in their lifetime and one in four will die from this disease. Given the disparities observed in health research among Black individuals, we conducted a scoping review to analyze the state of cancer research in Canadian Black communities regarding prevalence, incidence, screening, mortality, and related factors to observe advances and identify gaps and disparities. METHODS: A comprehensive search strategy was developed and executed in December 2021 across 10 databases (e.g., Embase). Of 3451 studies generated by the search, 19 were retained for extraction and included in this study. RESULTS: Studies were focused on a variety of cancer types among Black individuals including anal, breast, cervical, colorectal, gastric, lung, and prostate cancers. They included data on incidence, stage of cancer at diagnosis, type of care received, diagnostic interval length, and screening. A few studies also demonstrated racial disparities among Black individuals. This research reveals disparities in screening, incidence, and quality of care among Black individuals in Canada. CONCLUSIONS: Given the gaps observed in cancer studies among Black individuals, federal and provincial governments and universities should consider creating special funds to generate research on this important health issue. PLAIN LANGUAGE SUMMARY: Important gaps were observed on research on cancer among Black communities in Canada. Studies included in the scoping review highlights disparities in screening, incidence, and quality of care among Black individuals in Canada.