The role of hybrid ubiquitin chains in the MyD88 and other innate immune signalling pathways

The adaptor protein MyD88 is required for signal transmission by Toll-like Receptors (TLRs) and receptors of the interleukin 1 (IL-1) family of cytokines. MyD88 signalling triggers the formation of Lys63-linked and Met1-linked ubiquitin (K63-Ub, M1-Ub) chains within minutes. The K63-Ub chains, which are formed by the E3 ubiquitin ligases TRAF6, Pellino1 and Pellino2, activate TAK1, the master kinase that switches on mitogen-activated protein (MAP) kinase cascades and initiates activation of the canonical IκB kinase (IKK) complex. The M1-Ub chains, which are formed by the Linear Ubiquitin chain Assembly Complex (LUBAC), bind to the NEMO component of the IKK complex and are required for TAK1 to activate IKKs, but not MAP kinases. An essential E3 ligase-independent role of TRAF6 is to recruit LUBAC into the MyD88 signalling complex, where it recognises preformed K63-Ub chains attached to protein components of these complexes, such as IRAK1, producing ubiquitin chains containing both types of linkage, termed K63/M1-Ub hybrids. The formation of K63/M1-Ub hybrids, which is a feature of several innate immune signalling pathways, permits the co-recruitment of proteins that interact with either K63-Ub or M1-Ub chains. Two likely roles for K63/M1- Ub hybrids are to facilitate the TAK1-dependent activation of the IKK complex and to prevent the hyper-activation of these kinases by recruiting A20 and A20-binding inhibitor of NF-κB1 (ABIN1). These proteins restrict activation of the TAK1 and IKK complexes, probably by competing with them for binding to K63/M1-Ub hybrids. The formation of K63/M1-Ub hybrids may also regulate the rate at which the ubiquitin linkages in these chains are hydrolysed. The IKK-catalysed phosphorylation of some of its substrates permits their recognition by the E3 ligase SCFβ TRCP, leading to their Lys48-linked ubiquitylation and proteasomal degradation. Innate immune signalling is therefore controlled by the formation and destruction of three different types of ubiquitin linkage

Proposal, project, practice, pause: developing a framework for evaluating smart domestic product engagement

Smart homes are fast becoming a reality, with smart TVs, smart meters and other such “smart” devices/systems already representing a substantial household presence. These, which we collectively term “smart domestic products” (SDPs), will need to be promoted, adopted, and normalized into daily routines. Despite this, the marketing canon lacks a substantive discourse on pertinent research. We look to help correct this by melding ideas from organizational sociology, innovation diffusion and appropriation studies, and service dominant logic. Consequently, we suggest a framework for research that responds directly to the specific characteristics of SDPs. Using the SDP eco-system as a context, our framework emphasizes the interplay of embeddedness, practice, value and engagement. It comprises a four-stage horizontal/ longitudinal axis we describe as proposal, project, practice and pause. Cross-sectionally we focus on value, and combine aspects of existing thought to suggest how this impacts each stage of our engagement continuum. We subsequently identify perceived personal advantage as the resultant of these two axes and propose this as the key for understanding consumer and SDP sociomaterial engagement. This article also advances a definition of SDPs and ends with an agenda for further research

Epidemiology of Acute Myocarditis/Pericarditis in Hong Kong Adolescents Following Comirnaty Vaccination

BACKGROUND: Age-specific incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination in Asia is lacking. This study aimed to study the clinical characteristics and incidence of acute myocarditis/pericarditis among Hong Kong adolescents following Comirnaty vaccination. METHODS: This is a population cohort study in Hong Kong that monitored adverse events following immunization through a pharmacovigilance system for COVID-19 vaccines. All adolescents aged between 12 and 17 years following Comirnaty vaccination were monitored under the COVID-19 vaccine Adverse Event Response and Evaluation Programme. The clinical characteristics and overall incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination were analysed. RESULTS: Between 14 June 2021 and 4 September 2021, 33 Chinese adolescents who developed acute myocarditis/pericarditis following Comirnaty vaccination were identified. 29 (87.88%) were males and 4 (12.12%) were females, with a median age of 15.25 years. 27 (81.82%) and 6 (18.18%) cases developed acute myocarditis/pericarditis after receiving the second and first dose, respectively. All cases are mild and required only conservative management.The overall incidence of acute myocarditis/pericarditis was 18.52 (95% Confidence Interval [CI], 11.67-29.01) per 100,000 persons vaccinated. The incidence after the first and second doses were 3.37 (95%CI 1.12-9.51) and 21.22 (95%CI 13.78-32.28 per 100,000 persons vaccinated, respectively. Among male adolescents, the incidence after the first and second doses were 5.57 (95% CI 2.38-12.53) and 37.32 (95% CI 26.98-51.25) per 100,000 persons vaccinated. CONCLUSIONS: There is a significant increase in the risk of acute myocarditis/pericarditis following Comirnaty vaccination among Chinese male adolescents, especially after the second dose

Powder bed generation in integrated modelling of additive layer manufacturing of orthopaedic implants

This paper presents an original model of powder bed generation developed within the frame of an integrated modelling approach for studying the interaction of physical mechanisms in additive layer manufacturing (ALM) of orthopaedic implants. The model is based on cellular automata (CA) approach and describes the relationship between moving particles of different sizes during deposition on a surface in three dimensions. The surface is defined by the horizontal two-dimensional CA on which particles fall and irreversibly stick to a growing deposit. The model allows for consideration of different restructuring cases when particles are allowed to rotate as often as necessary until achievement of a local minimum position. Changes in the packing density of the powder bed have been investigated numerically depending on technological parameters, such as particle size distribution, deposition rate and sequence of powder deposition. The model has been developed with the aim of merging to the finite element (FE)-based integrated model and is applicable to a different ranges of materials including metals and also non-metals

The health promoting hospital movement in Taiwan: recent development and gaps in workplace

Objective To examine the development in healthcare workplace health promotion (WHP) in Taiwan through the Health Promoting Hospital (HPH) initiative. Methods A cross-sectional survey was conducted with a self-administered questionnaire, involving all 55 hospitals committed to the HPH approach (HP hospitals) as of the end of 2009; 52 completed the questionnaire. Results Fifty of 52 hospitals perceived a change in organizational capacity which mainly occurred in the areas of re-aligning strategies (96 %) and more resources (71 %). Regarding re-aligning strategies, 85 % of the hospitals engaged in increased staff participation, 66 % in staff-oriented health services. Conclusions The HPH initiative has led to new developments in capacity building of WHP among HP hospitals in Taiwan, and this study has mapped a pattern of such developments.No Full Tex