A systematic re-examination of processing of MHCI-bound antigenic peptide precursors by ER aminopeptidase 1

Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims antigenic peptide precursors to generate mature antigenic peptides for presentation by major histocompatibility complex class I (MHCI) molecules and regulates adaptive immune responses. ERAP1 has been proposed to trim peptide precursors both in solution and in pre-formed MHCI-peptide complexes, but which mode is more relevant to its biological function remains controversial. Here, we compared ERAP1-mediated trimming of antigenic peptide precursors in solution or when bound to three MHCI alleles, HLA-B*58, HLA-B*08 and HLA-A*02. For all MHCI-peptide combinations, peptide binding onto MHCI protected against ERAP1-mediated trimming. In only a single MHCI-peptide combination, trimming of an HLA-B*08-bound 12mer progressed at a considerable rate, albeit still slower than in solution. Results from thermodynamic, kinetic and computational analyses suggested that this 12mer is highly labile and that apparent on-MHC trimming rates are always slower than that of MHCI-peptide dissociation. Both ERAP2 and leucine aminopeptidase, an enzyme unrelated to antigen processing, could trim this labile peptide from pre-formed MHCI complexes as efficiently as ERAP1. A pseudopeptide analogue with high affinity for both HLA-B*08 and the ERAP1 active site could not promote the formation of a ternary ERAP1-MHCI-peptide complex. Similarly, no interactions between ERAP1 and purified peptide loading complex (PLC) were detected in the absence or presence of a pseudopeptide trap. We conclude that MHCI binding protects peptides from ERAP1 degradation and that trimming in solution, along with the dynamic nature of peptide binding to MHCI, are sufficient to explain ERAP1 processing of antigenic peptide precursors

Assessing health-related quality of life in patients with inflammatory bowel disease, in Crete, Greece

BACKGROUND: Health Related Quality of Life (HRQoL) is an important outcome measure in Inflammatory Bowel Disease (IBD). The aim of our study was to assess HRQoL in a population of 135 Greek patients with IBD. METHODS: A cohort of 135 patients with IBD, 81 with ulcerative colitis (UC) and 54 with Crohn's disease (CD) were enrolled in our study. Demographic and disease-related data were recorded. HRQoL was assessed by a disease-specific and a generic questionnaire, IBDQ and SF-36, respectively. Disease activity was assessed by Harvey-Bradshaw Index and the Colitis Activity Index for CD and UC patients, respectively. RESULTS: Among all variables recorded in our study, only disease activity had a significant effect on HRQoL. Patients with active disease scored significantly lower on both IBDQ and SF-36 when compared to those in remission. Only two among the four IBDQ dimensions, bowel and systemic, had significant ability in distinguishing best patients in remission from those with active disease. CONCLUSIONS: IBD has a negative impact on HRQoL. Patients with active disease are more impaired than patients in remission. In our population of patients bowel and systemic dimensions had a predominant value in patients' perception of quality of life. Patients in our study using the same instrument scored higher than previously reported

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements