DNA Hypomethylation in the TNF-Alpha Gene Predicts Rheumatoid Arthritis Classification in Patients with Early Inflammatory Symptoms

Biomarkers for the classification of rheumatoid arthritis (RA), and particularly for anti-citrullinated peptide antibody (ACPA)-negative patients, remain an important hurdle for the early initiation of treatment. Taking advantage of DNA-methylation patterns specific to early RA, quantitative methylation-specific qPCR (qMSP) offers a robust technology for the development of biomarkers. We developed assays and established their value as RA classification biomarkers. Methods: DNA-methylation data were screened to select candidate CpGs to design qMSP assays. Eight assays were developed and tested on two early inflammatory arthritis cohorts. Logistic regression and bootstrapping were used to demonstrate the added value of the qMSP assays. Result: Differentially methylated CpG data were screened for candidate CpG, thereby meeting the qMSP assay requirements. The top CpG candidate was in the TNF gene, for which we successfully developed a qMSP assay. Significantly lower DNA-methylation levels were observed in RA (p < 4 × 10−9), with a high predictive value (OR < 0.54/AUC < 0.198) in both cohorts (n = 127/n = 157). Regression using both datasets showed improved accuracy = 87.7% and AUC = 0.944 over the model using only clinical variables (accuracy = 85.2%, AUC = 0.917). Similar data were obtained in ACPA-negative patients (n = 167, accuracy = 82.6%, AUC = 0.930) compared to the clinical variable model (accuracy = 79.5%, AUC = 0.892). Bootstrapping using 2000 datasets confirmed that the AUCs for the clinical+TNF-qMSP model had significant added value in both analyses. Conclusion: The qMSP technology is robust and can successfully be developed with a high specificity of the TNF qMSP assay for RA in patients with early inflammatory arthritis. It should assist classification in ACPA-negative patients, providing a means of reducing time to diagnosis and treatment

The societal relevance of communities in the COVID-19 era

Non peer reviewe

Differential CpG DNA methylation in peripheral naïve CD4+ T-cells in early rheumatoid arthritis patients

Background: The genetic risk associated with rheumatoid arthritis (RA) includes genes regulating DNA methylation, one of the hallmarks of epigenetic re-programing, as well as many T-cell genes, with a strong MHC association, pointing to immunogenetic mechanisms as disease triggers leading to chronicity. The aim of our study was to explore DNA methylation in early, drug-naïve RA patients, towards a better understanding of early events in pathogenesis. Result: Monocytes, naïve and memory CD4+ T-cells were sorted from 6 healthy controls and 10 RA patients. DNA methylation was assessed using a genome-wide Illumina 450K CpG promoter array. Differential methylation was confirmed using bisulfite sequencing for a specific gene promoter, ELISA for several cytokines and flow cytometry for cell surface markers. Differentially methylated (DM) CpGs were observed in 1047 genes in naïve CD4+ T-cells, 913 in memory cells and was minimal in monocytes with only 177 genes. Naive CD4+ T-cells were further investigated as presenting differential methylation in the promoter of > 500 genes associated with several disease-relevant pathways, including many cytokines and their receptors. We confirmed hypomethylation of a region of the TNF-alpha gene in early RA and differential expression of 3 cytokines (IL21, IL34 and RANKL). Using a bioinformatics package (DMRcate) and an in-house analysis based on differences in β values, we established lists of DM genes between health and RA. Publicly available gene expression data were interrogated to confirm differential expression of over 70 DM genes. The lists of DM genes were further investigated based on a functional relationship database analysis, which pointed to an IL6/JAK1/STAT3 node, related to TNF-signalling and engagement in Th17 cell differentiation amongst many pathways. Five DM genes for cell surface markers (CD4, IL6R, IL2RA/CD25, CD62L, CXCR4) were investigated towards identifying subpopulations of CD4+ T-cells undergoing these modifications and pointed to a subset of naïve T-cells, with high levels of CD4, IL2R, and CXCR4, but reduction and loss of IL6R and CD62L, respectively. Conclusion: Our data provided novel conceptual advances in the understanding of early RA pathogenesis, with implications for early treatment and prevention

'The brede of good & strong Horsis': zooarchaeological evidence for size change in horses from early modern London

Almost 200 horse bone measurements from 38 sites excavated across the city of London, dating to the period AD 1220–1900 were analysed. Results identified three main phases of size change: a reduction in size in the mid 14th to 15th century, and size increases in the mid 15th to 16th century and the 17th century. The decline in size testifies to the disruption of horse breeding in the wake of the Black Death, whilst the increases reflect purposeful attempts to increase the size of horses in England through a combination of regulated breeding and the importation of new bloodlines

Blurring genres: An agenda for political studies’

The first step in mapping a research agenda for political science that draws on the Humanities is to describe where we are now. We describe the dominant intellectual trend affecting all British universities over the past four decades – neoliberalism in the guises of marketisation, and managerialism. Two consequences follow - the mainstreaming of research, and the search for relevance. The case for blurring genres is an opportunity to withdraw from this instrumental rationale and reclaim the intrinsic value of the Humanities and Social Sciences; to reject air of gloom and doom surrounding the Humanities; and to counter the unrelenting pressure for marketization and relevance. Shared trends in political science and the New Area Studies identify the space for working with the Humanities. There is a shared concern with interpretive approaches, and qualitative methods that focuses on the meaning of human action, fieldwork or thick descriptions, narrative analysis, historical contingency, and plausible conjectures. We suggest an ambitious mind map built on four values shared by the Humanities and the ‘soft pure’ Social Sciences; empathy, enlarged thinking, edification, and the examined life

Hit or miss: A decision support system framework for signing new musical talent

In the music industry, the process of signing new musical talent is one of the most complex decision-making problems. The decision, which is generally made by an artist and repertoire (A&R) team, involves consideration of various quantitative and qualitative criteria, and usually results in a low success rate. We conducted a series of mental model interviews with the aim of developing a decision support framework for A&R teams. This framework was validated by creating a decision support system that utilises multi-criteria decision analysis to support decision-making. Our framework and subsequent implementation of the decision support system involving decision rule and weighted sum methods show an improvement in the ability to analyse and decide on greater amounts of talent. This paper serves as a building block for developing systems to aid in this complex decision-making problem