Activation of the integrated stress response by inhibitors of its kinases.

Phosphorylation of the translation initiation factor eIF2α to initiate the integrated stress response (ISR) is a vital signalling event. Protein kinases activating the ISR, including PERK and GCN2, have attracted considerable attention for drug development. Here we find that the widely used ATP-competitive inhibitors of PERK, GSK2656157, GSK2606414 and AMG44, inhibit PERK in the nanomolar range, but surprisingly activate the ISR via GCN2 at micromolar concentrations.

Variations in medial and lateral slope and medial proximal tibial angle.

Purpose: The primary objective of this study was to quantify the variations of the medial posterior tibial slope (MPTS) and the lateral posterior tibial slope (LPTS), as well as of the medial proximal tibial angle (MPTA), and to determine the fraction of patients for which standard techniques including different alignment techniques would result in alteration of the patient's individual posterior tibial slope (PTS) and MPTA. Furthermore, it was of interest if a positive correlation between PTS and MPTA or between medial and lateral slope exists.

Methods: A retrospective study was performed on CT-scans of 234 consecutively selected European patients undergoing individual total knee replacement.