Osmolyte-induced folding of an intrinsically disordered protein: folding mechanism in the absence of ligand.

Understanding the interconversion between thermodynamically distinguishable states present in a protein folding pathway provides not only the kinetics and energetics of protein folding but also insights into the functional roles of these states in biological systems. The protein component of the bacterial RNase P holoenzyme from Bacillus subtilis (P protein) was previously shown to be unfolded in the absence of its cognate RNA or other anionic ligands. P protein was used in this study as a model system to explore general features of intrinsically disordered protein (IDP) folding mechanisms. The use of trimethylamine N-oxide (TMAO), an osmolyte that stabilizes the unliganded folded form of the protein, enabled us to study the folding process of P protein in the absence of ligand. Transient stopped-flow kinetic traces at various final TMAO concentrations exhibited multiphasic kinetics. Equilibrium "cotitration" experiments were performed using both TMAO and urea during the titration to produce a urea-TMAO titration surface of P protein. Both kinetic and equilibrium studies show evidence of a previously undetected intermediate state in the P protein folding process. The intermediate state is significantly populated, and the folding rate constants are relatively slow compared to those of intrinsically folded proteins similar in size and topology. The experiments and analysis described serve as a useful example for mechanistic folding studies of other IDPs.

Connecting Mentally Ill Detainees in Large Urban Jails with Community Care.

Large urban jails have become a collection point for many persons with severe mental illness. Connections between jail and community mental health services are needed to assure in-jail care and to promote successful community living following release. This paper addresses this issue for 2855 individuals with severe mental illness who received community mental health services prior to jail detention in King County (Seattle), Washington over a 5-year time period using a unique linked administrative data source. Logistic regression was used to determine the probability that a detainee with severe mental illness received mental health services while in jail as a function of demographic and clinical characteristics. Overall, 70 % of persons with severe mental illness did receive in-jail mental health treatment. Small, but statistically significant sex and race differences were observed in who received treatment in the jail psychiatric unit or from the jail infirmary. Findings confirm the jail's central role in mental health treatment and emphasize the need for greater information sharing and collaboration with community mental health agencies to minimize jail use and to facilitate successful community reentry for detainees with severe mental illness.