Major histocompatibility complex I‐induced endoplasmic reticulum stress mediates the secretion of pro‐inflammatory muscle‐derived cytokines

© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. This is an open access article distributed under the Creative Commons Attribution License, to view a copy of the license, see: This is an open access article under the terms of the Creative Commons Attribution License,https://creativecommons.org/licenses/by/4.0/Major histocompatibility complex (MHC) I is an important component of intracellular antigen presentation. However, improper expression of MHC I upon the cell surface has been associated with several autoimmune diseases. Myositis is a rare acquired autoimmune disease which targets skeletal muscle, and MHC I overexpression on the surface of muscle fibres and immune cell infiltration are clinical hallmarks. MHC I overexpression may have an important pathogenic role, mediated by the activation of the endoplasmic reticulum (ER) stress response. Given the evidence that muscle is a diverse source of cytokines, we aimed to investigate whether MHC I overexpression can modify the profile of muscle‐derived cytokines and what role the ER stress pathway may play. Using C2C12 myoblasts we overexpressed MHC I with a H‐2kb vector in the presence or absence of salubrinal an ER stress pathway modifying compound. MHC I overexpression induced ER stress pathway activation and elevated cytokine gene expression. MHC I overexpression caused significant release of cytokines and chemokines, which was attenuated in the presence of salubrinal. Conditioned media from MHC I overexpressing cells induced in vitro T‐cell chemotaxis, atrophy of healthy myotubes and modified mitochondrial function, features which were attenuated in the presence of salubrinal. Collectively, these data suggest that MHC I overexpression can induce pro‐inflammatory cytokine/chemokine release from C2C12 myoblasts, a process which appears to be mediated in‐part by the ER stress pathway.Peer reviewe

Intonational variation in the North-West of England:The origins of a rising contour in Liverpool

This paper investigates intonation in the urban dialect of Liverpool, Scouse. Scouse is reported to be part of a group of dialects in the north of the UK where rising contours in declaratives are a traditional aspect of the dialect. This intonation is typologically unusual and has not been the subject of detailed previous research. Here, we present such an analysis in comparison to Manchester, a city less than 40 miles from Liverpool but with a noticeably different prosody. Our analysis confirms reports that rising contours are the most common realisation in Liverpool, specifically a low rise where final high pitch is not reached until the end of the phrase. Secondly, we consider the origin of declarative rises in Scouse with reference to the literature on new dialect formation. Our demographic analysis and review of previous work on relevant dialects suggests that declarative rises were not the majority variant when Scouse was formed but may have been adopted for facilitating communication in a diverse new community. We highlight this contribution of intonational data to research on phonological aspects of new dialect formation, which have largely considered segmental phonology or timing previously

Dialect variation in formant dynamics:The acoustics of lateral and vowel sequences in Manchester and Liverpool English

This study analyses the time-varying acoustics of laterals and their adjacent vowels in Manchester and Liverpool English. We use Generalized Additive Mixed-Models (GAMMs) for quantifying time-varying formant data, which allows us to model non-linearities in acoustic time series while simultaneously modelling speaker and word level variability in the data. We compare these models to single time-point analyses of lateral and vowel targets in order to determine what analysing formant dynamics can tell us about dialect variation in speech acoustics. The results show that lateral targets exhibit robust differences between some positional contexts and also between dialects, with smaller differences present in vowel targets. The time-varying analysis shows that dialect differences frequently occur globally across the lateral and adjacent vowels. These results suggest a complex relationship between lateral and vowel targets and their coarticulatory dynamics, which problematizes straightforward claims about the realization of laterals and their adjacent vowels. We further discuss these findings in terms of hypotheses about positional and sociophonetic variation. In doing so, we demonstrate the utility of GAMMs for analysing time-varying multi-segmental acoustic signals, and highlight the significance of our results for accounts of English lateral typology

Born in Bradford Age of Wonder cohort: A protocol for qualitative longitudinal research

Born in Bradford (BiB) has followed the lives of 13,776 children born in the district between 2007 and 2011. Children in the birth cohort are now entering adolescence, and the next phase of the research - Age of Wonder (AoW) - will be a whole city cohort capturing the experiences of 30,000 adolescents progressing into young adulthood. This protocol focuses on one component of the AoW programme: qualitative longitudinal research (QLR). The study will gather in depth and detailed accounts from a sub-sample of 100 young people across four major research priorities: personal life; social and community life; growing up with difference, and growing up in Bradford. As well as using traditional qualitative methods such as interviews, focus group discussions, and ethnography, we are adopting innovative creative methods including expressions through art, activism, online and digital content, portraits, and critical events. The process of engaging in and co-producing QLR potentially provides a route to empowering young people to shape the narrative of their own lives as well as informing intervention development

Influence of socio-economic status on habitual physical activity and sedentary behavior in 8- to 11-year old children

<p>Abstract</p> <p>Background</p> <p>While socio-economic status has been shown to be an important determinant of health and physical activity in adults, results for children and adolescents are less consistent. The purpose of this study, therefore, is to examine whether physical activity and sedentary behavior differs in children by socio-economic status (SES) independent of body mass index.</p> <p>Methods</p> <p>Data were from two cohorts including 271 children (117 males; 154 females) in study 1 and 131 children in study 2 (63 males; 68 females). The average age was 9.6 and 8.8 years respectively. Height and body mass were assessed according to standard procedures and body mass index (BMI, kg/m²) was calculated. Parent-reported household income was used to determine SES. Habitual, free-living physical activity (PA) was assessed by a pedometer (steps/day) in study 1 and accelerometer (time spent in moderate-to-vigorous PA) in study 2. Self-reported time spent watching TV and on the computer was used as measure of sedentary behavior. Differences in PA and sedentary behavior by SES were initially tested using ANOVA. Further analyses used ANCOVA controlling for BMI, as well as leg length in the pedometer cohort.</p> <p>Results</p> <p>In study 1, mean daily steps differed significantly among SES groups with lower SES groups approximating 10,500 steps/day compared to about 12,000 steps/day in the higher SES groups. These differences remained significant (p < 0.05) when controlling for leg length. Lower SES children, however, had higher body mass and BMI compared to higher SES groups (p < 0.05) and PA no longer remained significant when further controlling for BMI. In study 2 results depended on the methodology used to determine time spent in moderate-to-vigorous physical activity (MVPA). Only one equation resulted in significant group differences (p = 0.015), and these differences remained after controlling for BMI. Significant differences between SES groups were shown for sedentary behavior in both cohorts (P < 0.05) with higher SES groups spending less time watching TV than low SES groups.</p> <p>Conclusions</p> <p>Children from a low SES show a trend of lower PA levels and spend more time in sedentary behavior than high SES children; however, differences in PA were influenced by BMI. The higher BMI in these children might be another factor contributing to increased health risks among low SES children compared to children from with a higher SES.</p

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

A randomized trial of intravenous iron supplementation and exercise on exercise capacity in iron-deficient non-anemic patients with chronic kidney disease

From Elsevier via Jisc Publications RouterHistory: accepted 2023-05-01, issued 2023-05-09AM replaced with VoR 2023-08-21.Introduction Patients with chronic kidney disease (CKD) are often iron deficient, even when not anemic. This trial evaluated whether iron supplementation enhances exercise capacity. Methods Prospective, multicenter double-blind randomized controlled trial of non-dialysis patients with CKD and iron deficiency but without anemia (Hemoglobin (Hb)>110 g/l). Patients assigned (1:1): intravenous (IV) iron therapy, or placebo. An 8-week exercise programme commenced at week 4. Primary outcome was mean between-group difference in six-minute walk test (6MWT) at 4 weeks. Secondary outcomes included: 6MWT at 12 weeks, Transferrin Saturation (TSAT), serum ferritin (SF), hemoglobin (Hb), renal function, muscle strength, functional capacity, quality of life and adverse events at baseline, 4, 12 weeks. Mean between-group differences were analysed using ANCOVA models. Results Among 75 randomized patients, mean (SD) age for iron therapy (n=37) vs placebo (n=38) was 54(16) vs. 61(12) yrs; eGFR [34(12) vs. 35(11)ml/min/1.73m2], TSAT [23(12) vs. 21(6)]%; SF [57(64) vs. 62(33)]μg/L; Hb [122.4 (9.2) vs. 127 (13.2)g/L]; 6MWT [384 (195) vs. 469 (142)metres] at baseline, respectively. No significant mean between-group difference was observed in 6MWT distance at 4 weeks. There were significant increases in SF and TSAT at 4 and 12 weeks (p<0.02), and Hb at 12 weeks (p=0.009). There were no between-group differences in other secondary outcomes and no adverse events attributable to iron therapy. Conclusion This trial didn’t demonstrate beneficial effects of IV iron therapy on exercise capacity at 4 weeks. A larger study is needed to confirm if IV iron is beneficial in non-dialysis patients with CKD who are iron-deficient. Trial Registration EudraCT: 2018-000144-25 Registered 28/01/2019.pubpu

An electron microscopy study of b-FeOOH (akaganeite) nanorods and nanotubes

High-resolution TEM images reveal that samples of b-FeOOH (akaganeite) prepared by quenching of a condensed ferrihydrite gel contain a mixture of rod-like particles and tubes. The tubular particles are usually about 10-15 nm in diameter with a central void that is typically 1/3 of the particle diameter. Dark-field STEM images show that the tubular particles are made up of single crystals that extend across the whole tube diameter, but only rarely extend along the whole length of the tube. Both the solid rods and the tubes appear to be based on subunits of approximately 3-4 nm in diameter, and it is proposed that formation of the akaganeite particles, both tubes and rods, results from secondary nucleation of these subunits at sites on particle edges, followed by rapid linear growth along the c-direction of the akaganeite structure