Molecular mechanisms of autophagic memory in pathogenic T cells in human arthritis

T-cell resilience is critical to the immune pathogenesis of human autoimmune arthritis. Autophagy is essential for memory T cell generation and associated with pathogenesis in rheumatoid arthritis (RA). Our aim here was to delineate the role and molecular mechanism of autophagy in resilience and persistence of pathogenic T cells from autoimmune arthritis. We demonstrated \u201cAutophagic memory\u201d as elevated autophagy levels in CD4+ memory T cells compared to CD4+ naive T cells and in Jurkat Human T cell line trained with starvation stress. We then showed increased levels of autophagy in pathogenic CD4+ T cells subsets from autoimmune arthritis patients. Using RNA-sequencing, transcription factor gene regulatory network and methylation analyses we identified MYC as a key regulator of autophagic memory. We validated MYC levels using qPCR and further demonstrated that inhibiting MYC increased autophagy. The present study proposes the novel concept of autophagic memory and suggests that autophagic memory confers metabolic advantage to pathogenic T cells from arthritis and supports its resilience and long term survival. Particularly, suppression of MYC imparted the heightened autophagy levels in pathogenic T cells. These studies have a direct translational valency as they identify autophagy and its metabolic controllers as a novel therapeutic target

IL11 is elevated in systemic sclerosis and IL11-dependent ERK signalling underlies TGF beta-mediated activation of dermal fibroblasts

Objectives Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with activation of human dermal fibroblasts (HDFs) from patients with SSc or controls. Methods We measured serum IL11 levels in volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches that we combined with molecular and cellular phenotyping. Results In patients with SSc, serum IL11 levels are elevated as compared with healthy controls. All transforming growth factor beta (TGFβ) isoforms induced IL11 secretion from HDFs, which highly express IL11 receptor α-subunit and the glycoprotein 130 (gp130) co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation and extracellular matrix secretion. The pro-fibrotic action of IL11 in HDFs appeared unrelated to STAT3 activity, independent of TGFβ upregulation and was not associated with phosphorylation of SMAD2/3. Inhibition of IL11 signalling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFβ-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacological inhibition of ERK. Conclusions These data reveal that autocrine IL11-dependent ERK activity alone or downstream of TGFβ stimulation promotes fibrosis phenotypes in dermal fibroblasts and suggest IL11 as a potential therapeutic target in SSc

Fire behavior of polyurethane foams

Combustibility of polyurethane foam is an important industry issue. Many test methods are in place to characterize foam combustion, and legislation exists to ensure that the foam complies with specified standards. This paper provides a basic understanding of foam combustibility based on the British Standard BS5852 test method. Dynamic weight loss of foams made with two types of liquid flame retardants with and without melamine is used to provide this understanding. Thermogravimetric analysis and cone calorimeter have been used to support the discussions. In melamine free foams, our study has shown that the decomposition temperature of the liquid flame retardant is a key parameter, which governs the foam combustion. In the melamine containing foams, the overall combustion behavior is independent of the type of liquid flame retardant used. However, intrinsic differences do exist, and synergy is seen between melamine and liquid flame retardant under specific conditions. Applying this basic understanding and the actual combustion standards, foam producers can attain flexibility in designing cost effective foam formulations

Finding Partial Periodic and Rare Periodic Patterns in Temporal Databases

Most of the periodic pattern mining algorithms extract fully periodic patterns by strictly monitoring the cyclic behaviour of patterns in transactional as well as temporal databases. The most recent and preferred method for discarding non-periodic uninteresting patterns is partial periodic pattern mining, which has control over the strictness measure on cyclic repetitions of patterns. Recently, a variety of industries, including fraud detection, telecommunications, retail marketing, research, and medical have found applications for rare association rule mining, which uncovers unusual or unexpected combinations. A limited amount of literature demonstrated how periodicity is essential in mining low-support rare patterns. However, time of occurrence is also a vital phrase that is ignored which further aids in significant information retrieval. With this inspiration, a novel depth-first search framework named 3P-BitVectorMiner, is proposed to extract entire partial periodic patterns from a temporal database. Experiments are carried out by varying support and periodicity thresholds for a variety of datasets. It is found that 3P-BitVectorMiner consistently displays greater performance over the state-of-the-art algorithm 3P-Growth. Further, the scalability of the 3P-BitVectorMiner algorithm is also presented to demonstrate the efficiency over the 3P-Growth algorithm on large temporal databases. In addition, two variations named RFPP-BitVectorMiner and R3P-BitVectorMiner are proposed to mine rare fully periodic patterns and rare partial periodic patterns from temporal databases respectively. Different experiments carried out show that these proposed frameworks successfully capture periodic rare patterns in temporal databases

Flame spread of flexible polyurethane foam: comprehensive study

Polyurethane foams are widely used in many industrial applications: automotive, upholstered furniture and mattresses, insulating panels for building, etc. By its chemical nature, polyurethane is very flammable and the flammability of polyurethane foams is an important industry issue. Depending on the final application, many test methods are in place to characterise foam combustion and legislation exists to ensure that foams comply with specific standards. This paper deals with the fire properties of flexible polyurethane foams. It provides basic correlations between some existing fire test methods and the data recorded under cone calorimeter conditions. The long term target of such an investigation is to predict the burning behavior of foams under specific test conditions from the data of the cone calorimeter. (C) 2003 Published by Elsevier Ltd

Functionally diverse human T cells recognize non-microbial antigens presented by MR1

10.7554/eLife.24476eLife6e2447

Thermal stability and fire properties of conventional flexible polyurethane foam formulations

Polyurethane foams are widely used in many industrial applications, including automotive, upholstered furniture and mattresses, insulating panels for building. Depending on the desired application, polyurethane foams can be produced using many different chemicals and formulations. The physical properties of flexible polyurethane foams depend on their composition. They will be closely related to the characteristics of the polyol used, to the stoichiometry (polyol/isocyanate), to the quantity of catalysts and surfactants and to the water content (and so to the density). By its chemical nature, a polyurethane is very flammable. The flammability of polyurethane foams is an important industrial issue. This paper deals with the influence of the composition of conventional flexible PU foams on their thermal stability and fire behaviour. (c) 2004 Elsevier Ltd. All rights reserved