Recognition surfaces of MHC class I

Summary: Recent crystallographic results have provided dose to atomic resolution views of the recognition events mediated by MHC class I molecules. The specificity-conferring interaction of MHC class I/peptide with a T-cell antigen receptor (TCR) appears dependent on certain key interactions with the MHC scaffold. These interactions, in particular those of the TCR Va domain, define a standard orientation for TCR binding. Previous studies on biologically significant variations in the TCR recognition surface presented by a series of MHC/variant peptide complexes can be reassessed in the light of this TCR-building mode. The interaction of CDS with MHC class I resembles that between antibody and antigen in the use of loops from the CD8 structure. The interaction is of very low affinity and buries equivalent surface area to that between the TCR and MHC class I but while the TCR/MHC interface shows poor surface shape complementarity the match in the conservative interaction between MHC and CDS is precise.     

Hepatitis C infection among injecting drug users in general practice: a cluster randomised controlled trial of clinical guidelines'' implementation

BACKGROUND: Hepatitis C is a common infection among injecting drug users and has important implications for general practice. Although several clinical guidelines concerning the infection have been published, their effectiveness has yet to be tested. AIM: To assess the effectiveness of a general practice-based complex intervention to support the implementation of clinical guidelines for hepatitis C management among current or former drug users attending general practice. DESIGN OF STUDY: Cluster randomised controlled trial. SETTING: General practices in the Eastern Regional Health Authority area of Ireland. METHOD: Twenty-six practices were randomly allocated within strata to receive the intervention under study or to provide care as usual for a period of 6 months. There was screening for patients attending general practice for methadone maintenance treatment for hepatitis C and referral of anti-HCV antibody positive patients to a specialist hepatology department for assessment. RESULTS: At study completion, patients in the intervention group were significantly more likely to have been screened for hepatitis C than those in the control group, odds ratio adjusted for clustering 3.76 (95% confidence interval [CI] = 1.3 to 11.3) and this association remained significant after adjusting for other potentially confounding variables, using multiple logistic regression, with the odds ratio adjusted for clustering 4.53 (95% CI = 1.39 to 14.78). Although anti-HCV antibody positive patients in the intervention group were more likely to have been referred to a hepatology clinic, this was not statistically significant (P = 0.06). CONCLUSION: General practice has an important role in the care of people at risk of hepatitis C and when appropriately supported can effectively implement current best practice.     

Agonist-mediated conformational changes of β-adrenoceptors could occur independent of functional coupling to Ns

Summary Agonist and antagonist binding characteristics of -adrenoceptors in turkey erythrocyte ghosts were determined at different temperatures ranging between 7°C and 42°C. [³H]-DHA saturation binding experiments revealed that the antagonist-receptor interaction is entropy-driven with a small enthalpic contribution. Isoproterenol/[³H]-DHA competition binding followed the law of mass action at all the investigated temperatures. The agonist-receptor interaction is enthalpy driven with a small unfavorable decrease in entropy. This is consistent with the agonist's ability to favor an endoenergetic transconformation of the receptors.Only part of the agonist-bound receptors can undergo functional coupling to the stimulatory component of the adenylate cyclase system (Ns). This coupling process is associated with locking-in of the agonist and becomes persistent in the presence of the alkylating reagent N-ethylmaleimide. The number of agonist/N-ethylmaleimide-sensitive sites (i.e. coupling-prone receptors) increases with the temperature until it reaches a plateau value of 50% between 27–32°C. Qualitatively similar data were obtained for rat lung and turkey erythrocyte membranes. These observations suggest that the whole receptor population can undergo agonist-mediated conformational changes but that only part of them can couple to Ns.     

Remodeling of the ICF: A commentary

Since its publication in 2001 the International Classification of Functioning, Disability and Health (ICF) has attracted debate about the content and the model presented. After almost 20 years use, regular updating since 2008 and with the prospect of a new edition in 2020 there is increasing interest in the ICF as a tool to meet contemporary information requirements. Information on functioning is important across not only health systems, but all areas where change in functioning is important: education, employment, and social welfare for example. This commentary responds to the issues raised in a commentary by Mitra & Shakespeare in 2019 and supports review of the ICF in the current context by informing users and providers of data on human functioning how they might engage in the maintenance, updating, and modernisation of the ICF.     

Identification and Validation of Nutrient State-Dependent Serum Protein Mediators of Human CD4+ T Cell Responsiveness

Intermittent fasting and fasting mimetic diets ameliorate inflammation. Similarly, serum extracted from fasted healthy and asthmatic subjects’ blunt inflammation in vitro, implicating serum components in this immunomodulation. To identify the proteins orchestrating these effects, SOMAScan technology was employed to evaluate serum protein levels in healthy subjects following an overnight, 24-h fast and 3 h after refeeding. Partial least square discriminant analysis identified several serum proteins as potential candidates to confer feeding status immunomodulation. The characterization of recombinant IGFBP1 (elevated following 24 h of fasting) and PYY (elevated following refeeding) in primary human CD4⁺ T cells found that they blunted and induced immune activation, respectively. Furthermore, integrated univariate serum protein analysis compared to RNA-seq analysis from peripheral blood mononuclear cells identified the induction of IL1RL1 and MFGE8 levels in refeeding compared to the 24-h fasting in the same study. Subsequent quantitation of these candidate proteins in lean versus obese individuals identified an inverse regulation of serum levels in the fasted subjects compared to the obese subjects. In parallel, IL1RL1 and MFGE8 supplementation promoted increased CD4⁺ T responsiveness to T cell receptor activation. Together, these data show that caloric load-linked conditions evoke serological protein changes, which in turn confer biological effects on circulating CD4⁺ T cell immune responsiveness.     

“Putting Meat on the Bones”: Understanding the Implementation of a Community-Based Early Intervention and Prevention Programme—Contextual,Person, and Programme Influences

Prevention Science - The adoption and effective delivery of evidence-based interventions within “real-world” community-based, primary health care service settings are of crucial...     

Deciphering the molecular effects of non-ablative Er:YAG laser treatment in an in vitro model of the non-keratinized mucous membrane

Lasers in Medical Science -     

Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies

Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.