Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design.

Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves the -terminal amino acids of peptides, which can then bind onto major histocompatibility class I (MHC-I) molecules for presentation onto the cell surface, driving the activation of adaptive immune responses. In cancer, overtrimming of mature antigenic peptides can reduce cytotoxic T-cell responses, and ERAP1 can generate self-antigenic peptides which contribute to autoimmune cellular responses. Therefore, modulation of ERAP1 activity has potential therapeutic indications for cancer immunotherapy and in autoimmune disease.

Pharmacological and structural understanding of the Trypanosoma cruzi proteasome provides key insights for developing site-specific inhibitors.

The proteasome is considered an excellent drug target for many infectious diseases as well as cancer. Challenges with robust and safe supply of proteasomes from infectious agents, lack of structural information, and complex pharmacology due to multiple active sites have hampered progress in the infectious disease space. We recombinantly expressed the proteasome of the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease, and demonstrate pharmacological equivalence to the native T.

Implications for fall efficacy strategies on center of pressure and center of gravity sway distances in adults with chronic low back pain.

Background: Although chronic low back pain (LBP) is a complex condition often associated with altered motor control and compensatory postural adjustments, existing literature provides inconsistent reports on the underlying control mechanisms for maintaining balance.

Purpose: This study aimed to compare differences in sway distances between the center of pressure (COP) and the center of gravity (COG), while considering limb dominance, in adults with and without LBP.

Methods: There were 26 subjects with LBP and 39 control subjects who performed three repeated unilateral standing tasks on a force platform.

Professionalism lapses in health professions training: Navigating the 'Yellow Card' moments for transformative learning.

Introduction: Health professions training programmes face increasing reports of professionalism lapses, which can delay, or end, trainee progression. How programmes respond to professionalism lapses to facilitate professional identity development has not been clarified. The objective of this study is to identify factors that facilitate and impair transformations around professionalism lapses in health professions training programmes.