Substance P Induces Rapid and Transient Membrane Blebbing in U373MG Cells in a p21-Activated Kinase-Dependent Manner

U373MG astrocytoma cells endogenously express the full-length neurokinin 1 receptor (NK1R). Substance P (SP), the natural ligand for NK1R, triggers rapid and transient membrane blebbing and we report that these morphological changes have different dynamics and intracellular signaling as compared to the changes that we have previously described in HEK293-NK1R cells. In both cell lines, the SP-induced morphological changes are Gq-independent, and they require the Rho, Rho-associated coiled-coil kinase (ROCK) signaling pathway. Using confocal microscopy we have demonstrated that tubulin is phosphorylated subsequent to cell stimulation with SP and that tubulin accumulates inside the blebs. Colchicine, a tubulin polymerization inhibitor, blocked SP-induced blebbing in U373MG but not in HEK293-NK1R cells. Although p21-activated kinase (PAK) is expressed in both cell lines, SP induced rapid phosphorylation of PAK in U373MG, but failed to phosphorylate PAK in HEK293-NK1R cells. The cell-permeable Rho inhibitor C3 transferase inhibited SP-induced PAK phosphorylation, but the ROCK inhibitor Y27632 had no effect on PAK phosphorylation, suggesting that Rho activates PAK in a ROCK-independent manner. Our study demonstrates that SP triggers rapid changes in cell morphology mediated by distinct intracellular signaling mechanisms in U373MG versus HEK293-NK1R cells

Measuring disparities in police use of force and injury among persons with serious mental illness

Abstract Objectives To measure disparities in experience of police use of force and injury among persons with serious mental illnesses. Methods We gathered novel police use of force and suspect injury data from 2011 to 2017 from a nonrandom sample of nine police departments in the United States and used synthetic methods to estimate the share of the local population with serious mental illness. We estimate disparities using multi-level models estimated in a Bayesian framework. Results Persons with serious mental illness constitute 17.0% of use of force cases (SD = 5.8) and 20.2% of suspects injured in police interaction (SD = 9.0) in sample cities. The risk that persons with serious mental illness will experience police use of force is 11.6 times higher (95% CI, 10.7–12.6) than persons without serious mental illness. Persons with serious mental illness are also at a higher risk of experiencing injury, 10.7 times (95% CI, 9.6–11.8), relative to persons without serious mental illness. These relative risk ratios are several times larger than racial and ethnic disparities estimated in the same cities. Conclusion Persons with serious mental are at a significantly elevated risk of experiencing police use of force and injury in police encounters than the general public. The disparities we estimate are several times higher than racial/ethnic disparities in force and injury. Efforts to reform police practices and reimagine public safety in the United States should address significant disparities in police use of force against those with serious mental illness