Conversion of a T Cell Antagonist into an Agonist by Repairing a Defect in the TCR/Peptide/MHC Interface Implications for TCR Signaling

AbstractThe structure of the A6 αβTCR/HTLV-1 Tax-peptide/MHC I complex with proline 6 of Tax substituted with alanine (P6A), an antagonist, is nearly identical to the structure with wild-type Tax agonist. Neither the proline in the agonist nor the alanine in the antagonist is contacted by the αβTCR. Here, we demonstrate that antagonist activity of P6A is associated with low affinity of the A6 αβTCR for Tax-P6A/HLA-A2. We show that stepwise repair of a packing defect in the TCR/MHC interface using N-alkylated amino acids results in stepwise increases in TCR affinity and activity. Kinetic and thermodynamic measurements suggest that for some ligands the range of T cell outcomes does not correlate with either their αβTCR affinity or the half-life of the αβTCR/peptide/MHC complex

Comparison of assertive community treatment programs in urban Massachusetts and rural North Carolina

In this pilot study, we compared teams in rural North Carolina (NC) and urban Massachusetts (MA) to examine the how sites vary the implementation of the Assertive Community Treatment (ACT) model to respond to state and local circumstances. We analysed and compared data on: client characteristics using the NC-TOPPS and a modified survey in MA; Regional Demographics and; Team Characteristics. Issues such as driving distances, lack of qualified clinical staff, scarcity of physicians, and more limited oversight created impediments to fidelity in rural NC, despite higher per patient funding. ACT is now national, but variability in implementation of the model remains

Packages of Care for Depression in Low- and Middle-Income Countries

In the first in a series of six articles on packages of care for mental disorders in low- and middle-income countries, Neerja Chowdary and colleagues discuss the treatment of depression