111 research outputs found
Can inflammatory markers predict response to methotrexate in JIA? Results from the CHARM study
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Negative Regulation of TLR Signaling by BCAP Requires Dimerization of Its DBB Domain.
The B cell adaptor protein (BCAP) is a multimodular regulator of inflammatory signaling in diverse immune system cells. BCAP couples TLR signaling to phosphoinositide metabolism and inhibits MyD88-directed signal transduction. BCAP is recruited to the TLR signalosome forming multitypic interactions with the MAL and MyD88 signaling adaptors. In this study, we show that indirect dimerization of BCAP TIR is required for negative regulation of TLR signaling. This regulation is mediated by a transcription factor Ig (TIG/IPT) domain, a fold found in the NF-ĪŗB family of transcription factors. We have solved the crystal structure of the BCAP TIG and find that it is most similar to that of early B cell factor 1 (EBF1). In both cases, the dimer is stabilized by a helix-loop-helix motif at the C terminus and interactions between the Ī²-sheets of the Ig domains. BCAP is exclusively localized in the cytosol and is unable to bind DNA. Thus, the TIG domain is a promiscuous dimerization module that has been appropriated for a range of regulatory functions in gene expression and signal transduction
Identification of enhanced IFN-Ī³ signaling in polyarticular juvenile idiopathic arthritis with mass cytometry
Polyarticular juvenile idiopathic arthritis (JIA) is among the most challenging of the JIA subtypes to treat. Even with current biologic therapies, the disease remains difficult to control in a substantial subset of patients, highlighting the need for new therapies. The aim of this study was to use the high dimensionality afforded by mass cytometry with phospho-specific antibodies to delineate signaling abnormalities in immune cells from treatment-naive polyarticular JIA patients. Peripheral blood mononuclear cells were isolated from 17 treatment-naive polyarticular JIA patients, 10 of the patients after achieving clinical remission, and 19 healthy controls. Samples were stimulated for 15 minutes with IL-6 or IFN-Ī³ and analyzed by mass cytometry. Following IFN-Ī³ stimulation, increased STAT1 and/or STAT3 phosphorylation was observed in subsets of CD4 T cells and classical monocytes from treatment-naive patients. The enhanced IFN-Ī³ signaling was associated with increased expression of JAK1 and SOCS1 in CD4 T cells. Furthermore, substantial heterogeneity in surface marker expression was observed among the subsets of CD4 T cells and classical monocytes with increased IFN-Ī³ responsiveness. The identification of enhanced IFN-Ī³ signaling in CD4 T cells and classical monocytes from treatment-naive polyarticular JIA patients provides mechanistic support for investigations into therapies that attenuate IFN-Ī³ signaling in this disease
Enacting the Prevent Duty in Early Childhood Education Settings
This chapter examines the implementation of the Prevent Duty in early childhood education (ECE) provision in England. Findings from a small-scale empirical study suggest that ECE practitioners simultaneously performed, resisted and embodied the requirements of the Prevent Duty in practice. ECE practitioners were performative in their response to the requirement to promote fundamental British values (FBVs) as they evidenced compliance within an environment of regulation. However, ECE practitioners simultaneously operated a pedagogy rich in values education in which children were positioned as constructors of values. The layering of counter-terrorism within safeguarding policy led to a repositioning of practices of surveillance of children and families, which resonates with some critical readings of counter-terrorism policy in ECE
On computational approaches for size-and-shape distributions from sedimentation velocity analytical ultracentrifugation
Sedimentation velocity analytical ultracentrifugation has become a very popular technique to study size distributions and interactions of macromolecules. Recently, a method termed two-dimensional spectrum analysis (2DSA) for the determination of size-and-shape distributions was described by Demeler and colleagues (Eur Biophys J 2009). It is based on novel ideas conceived for fitting the integral equations of the size-and-shape distribution to experimental data, illustrated with an example but provided without proof of the principle of the algorithm. In the present work, we examine the 2DSA algorithm by comparison with the mathematical reference frame and simple well-known numerical concepts for solving Fredholm integral equations, and test the key assumptions underlying the 2DSA method in an example application. While the 2DSA appears computationally excessively wasteful, key elements also appear to be in conflict with mathematical results. This raises doubts about the correctness of the results from 2DSA analysis
Anderson's ethical vulnerability: animating feminist responses to sexual violence
Pamela Sue Anderson argues for an ethical vulnerability which āactivates an openness to becoming changedā that ācan make possible a relational accountability to one another on ethical mattersā. In this essay I pursue Andersonās solicitation that there is a positive politics to be developed from acknowledging and affirming vulnerability. I propose that this politics is one which has a specific relevance for animating the terms of feminist responses to sexual violence, something which has proved difficult for feminist theorists and activists alike. I will demonstrate the contribution of Andersonās work to such questions by examining the way in which āethical vulnerabilityā as a framework can illuminate the intersectional feminist character of Tarana Burkeās grassroots Me Too movement when compared with the mainstream, viral version of the movement. I conclude by arguing that Andersonās āethical vulnerabilityā contains ontological insights which can allay both activist and academic concerns regarding how to respond to sexual violence
Certifications of citizenship: the history, politics and materiality of identity documents in South Asian states and diasporas
Experiences in the post-partition Indian subcontinent refute the conventional expectation that the 'possession of citizenship enables the acquisition of documents certifying it' (Jayal, 2013, 71). Instead, identity papers of various types play a vital part in certifying and authenticating claims to citizenship. This is particularly important in a context where the history of state formation, continuous migration flows and the rise of right-wing majoritarian politics has created an uncertain situation for individuals deemed to be on the āmarginsā of the state. The papers that constitute this special issue bring together a range of disciplinary perspectives in order to investigate the history, politics and materiality of identity documents, and to dismantle citizenship as an absolute and fixed notion, seeking instead to theorise the very mutable āhierarchiesā and ādegreesā of citizenship. Collectively they offer a valuable lens onto how migrants, refugees and socio-economically marginal individuals negotiate their relationship with the state, both within South Asia and in South Asian diaspora communities. This introduction examines the wider context of the complex intersections between state-issued identity documents and the nature of citizenship and draws out cross-cutting themes across the papers in this collection
Lipoprotein cholesterol fractions are related to markers of inflammation in children and adolescents with juvenile idiopathic arthritis: a cross sectional study
S100A8/A9, a potent serum and molecular imaging biomarker for synovial inflammation and joint destruction in seronegative experimental arthritis
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