Lateral inhibition, mediated by Notch signaling, leads to the selection of cells that are permitted to become neurons within domains defined by proneural gene expression. Reduced lateral inhibition in zebrafish mib mutant embryos permits too many neural progenitors to differentiate as neurons. Positional cloning of mib revealed that it is a gene in the Notch pathway that encodes a RING ubiquitin ligase. Mib interacts with the intracellular domain of Delta to promote its ubiquitylation and internalization. Cell transplantation studies suggest that mib function is essential in the signaling cell for efficient activation of Notch in neighboring cells. These observations support a model for Notch activation where the Delta-Notch interaction is followed by endocytosis of Delta and transendocytosis of the Notch extracellular domain by the signaling cell. This facilitates intramembranous cleavage of the remaining Notch receptor, release of the Notch intracellular fragment, and activation of target genes in neighboring cells.

IMPORTANCE Antipsychotic medications are associated with increased mortality in older adults with dementia, yet their absolute effect on risk relative to no treatment or an alternative psychotropic is unclear.OBJECTIVE To determine the absolute mortality risk increase and number needed to harm (NNH) (ie, number of patients who receive treatment that would be associated with 1 death) of antipsychotic, valproic acid and its derivatives, and antidepressant use in patients with dementia relative to either no treatment or antidepressant treatment.

Opioid mortality rates continue to increase throughout the United States 1 ; however, growth in buprenorphine hydrochloride treatment for opioid use disorder (OUD) might be limited to communities with higher income and low percentages of racial/ethnic minorities. 2 Buprenorphine, a partial opioid agonist, is 1 of 3 evidence-based medications for treating OUD and can legally be prescribed in office-based settings. To our knowledge, no national studies have examined the differences in the receipt of buprenorphine prescription by race/ethnicity and payment in office-based settings, in which most patients with buprenorphine prescription receive care. 3 In this article, we present changes in buprenorphine treatment at office-based visits in the United States since 2004 as well as the race/ethnicity and payment characteristics currently associated with its receipt.