Nonlinear network model analysis of vibrational energy transfer and localisation in the Fenna-Matthews-Olson complex

Collective protein modes are expected to be important for facilitating energy transfer in the Fenna-Matthews-Olson (FMO) complex of photosynthetic green sulphur bacteria, however to date little work has focussed on the microscopic details of these vibrations. The nonlinear network model (NNM) provides a computationally inexpensive approach to studying vibrational modes at the microscopic level in large protein structures, whilst incorporating anharmonicity in the inter-residue interactions which can influence protein dynamics. We apply the NNM to the entire trimeric FMO complex and find evidence for the existence of nonlinear discrete breather modes. These modes tend to transfer energy to the highly connected core pigments, potentially opening up alternative excitation energy transfer routes through their influence on pigment properties. Incorporating localised modes based on these discrete breathers in the optical spectra calculations for FMO using ab initio site energies and excitonic couplings can substantially improve their agreement with experimental results.A.W.C. and S.E.M. acknowledge support from the Winton Programme for the Physics of Sustainability. S.E.M. is also supported by an EPSRC doctoral training award. D.J.C. is supported by a Marie Curie International Outgoing Fellowship within the seventh European Community Framework Programme

Curry-assisted diagnosis in the rheumatology clinic.

We report five cases of glucocorticoid-responsive mouth symptoms in polymyalgia rheumatica/giant cell arteritis (GCA); three cases of tongue pain exacerbated by hot/spicy food, a case of scalp pain made worse by eating hot/spicy food and a case of sore tongue as a presenting feature of GCA. These cases emphasize the importance of asking about mouth symptoms and changes in taste when evaluating patients with suspected GCA

The effects of attachment style on coping with visible skin conditions and responsiveness to a compassion based self-help intervention

No abstract available

Achieving consensus on minimum data items (including core outcome domains) for a longitudinal observational cohort study in rheumatoid arthritis

Objectives: To obtain consensus on minimum data items for an observational cohort study in rheumatoid arthritis (RA) in the UK and to make available the process for similar studies and other rheumatic conditions. Methods: Individuals with a diverse range of expertise and backgrounds were invited to participate in a process to propose a minimal core dataset (MCD) for research studies, commissioned by Arthritis Research UK as part of the larger INBANK project. The group included patients and representatives from clinical and academic rheumatology, outcomes science, stratified medicine, health economics, national professional and academic bodies/ committees. A process was devised based on Outcome Measures in Rheumatology Clinical Trials (OMERACT) principles to review aims/objectives, definition of scope, identification of important research questions, and selection of key domains. Results: Following the initial multi-stakeholder meeting, subsequent teleconferences and email communications, consensus was obtained on: 1. Most important and relevant research questions; 2. Agreement on how the OMERACT Core Areas (life impact, pathophysiological manifestations, resource use and death) could form the basis of a MCD; 3. Consensus on 22 items for inclusion into a MCD. Workshops were undertaken for two essential items which required further exploration: work/social participation and co-morbidity. Conclusions: Consensus for proposed minimal data items for long-term observational cohort studies of RA in the UK posed novel challenges and opportunities, and was largely successful. Further work is needed to select instruments for two important items and to achieve compatibility with other UK national initiatives, and more widely across Europe

Adenosine metabolic signature in circulating CD4+ T cells predicts remission in rheumatoid arthritis

\ua9 Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Objectives Long-term outcomes in rheumatoid arthritis (RA) depend on early and effective disease control. Methotrexate (MTX) remains the first-line disease modifying therapy, however there are no biomarkers with which to identify those most likely to achieve remission. To address this unmet need we explored metabolic pathways involved in MTX mechanism of action within circulating CD4+T cells in a cohort of treatment naive patients with early RA. Methods Purified CD4+T cells were isolated from peripheral blood of 68 patients with early RA commencing MTX. The expression of a range of putative MTX metabolism and mechanism of action targets were explored by flow-cytometry and transcriptional analysis. From these data significant predictors of Disease Activity Score 28-C reactive protein (DAS28-CRP) remission (<2.4 at 6 months) were determined by logistic regression (clinical; flow-cytometry data) and linear modelling (gene expression data). Results Low baseline DAS28-CRP was associated with remission at 6 months (p=0.02). Expression of the ectonucleotidase CD39, involved in ATP-ADP conversion during adenosine synthesis, was higher on CD4+CD25 High regulatory T cells at baseline in those achieving remission (molecules of equivalent fluorescence 1264 vs 847; p=0.007). Expression of other adenosine signalling elements in CD4+T cells were also upregulated at baseline in patients achieving remission: AMPD1 (p<0.001), ADORA2b (p=0.039) and ADORA3 (p=0.047). When combined into a single predictive metric, a combination of these variables outperformed baseline DAS28-CRP in prediction of early remission (area under the curve 0.92 vs 0.67, p=0.001) Conclusions Adenosine signalling is important in the achievement of early remission with MTX in RA and biomarkers of adenosine activity may hold utility for the stratification of therapy in early disease

Detection of anti-drug antibodies using a bridging ELISA compared with radioimmunoassay in adalimumab-treated rheumatoid arthritis patients with random drug levels

Objective: To determine the concordance between RIA and bridging ELISA at detecting anti-drug antibodies (ADAbs) in the context of random adalimumab levels and investigate the additional clinical utility of detecting ADAbs in RA patients who test ADAb positive by RIA and negative by ELISA. Methods: ADAb levels were determined using RIA and bridging ELISA in 63 adalimumab treated RA patients (159 samples). Immunogenicity concordance was determined using receiver-operating characteristic (ROC) curves. To determine the additional clinical value provided by a positive RIA in the presence of negative ELISA, association between treatment response (ΔDAS28), adalimumab drug levels and ADAbs was evaluated longitudinally using generalised estimating equation. Results: Of the 60 RIA+ samples (n=31 patients), 19 (n=10 patients) were also ELISA+, corresponding to 31.7% of samples. Area under the curve (AUC) for detecting ADAbs using ELISA (compared with RIA) using ROC curves was 0.65 (95% CI: 0.59-0.71); this increased to 0.91 (95% CI: 0.81-0.99) if ADAbs were ≥100 AU/ml using RIA. In RIA+/ELISA- patients, adalimumab levels were associated with ΔDAS28 over 12 months [regression coefficient: 0.098 (0.043-0.15), p<0.0001] and whilst ADAbs were significantly associated with drug level, they were not directly associated with ΔDAS28 over 12 months [β coefficient: 0.00083 (-0.0038 to 0.0054), p=0.72]. Conclusion: ADAbs were detected using ELISA more frequently when present in high titres as measured by RIA. In RIA+/ELISA- patients, only drug levels were significantly associated with treatment response. Although ADAbs were not independently associated with treatment response, they may be helpful in determining the aetiology of low drug levels

Dose-dependent oral glucocorticoid cardiovascular risks in people with immune-mediated inflammatory diseases: A population-based cohort study

Background Glucocorticoids are widely used to reduce disease activity and inflammation in patients with a range of immune-mediated inflammatory diseases. It is uncertain whether or not low to moderate glucocorticoid dose increases cardiovascular risk. We aimed to quantify glucocorticoid dose-dependent cardiovascular risk in people with 6 immune-mediated inflammatory diseases. Methods and findings We conducted a population-based cohort analysis of medical records from 389 primary care practices contributing data to the United Kingdom Clinical Practice Research Datalink (CPRD), linked to hospital admissions and deaths in 1998–2017. We estimated time-variant daily and cumulative glucocorticoid prednisolone-equivalent dose-related risks and hazard ratios (HRs) of first all-cause and type-specific cardiovascular diseases (CVDs). There were 87,794 patients with giant cell arteritis and/or polymyalgia rheumatica (n = 25,581), inflammatory bowel disease (n = 27,739), rheumatoid arthritis (n = 25,324), systemic lupus erythematosus (n = 3,951), and/or vasculitis (n = 5,199), and no prior CVD. Mean age was 56 years and 34.1% were men. The median follow-up time was 5.0 years, and the proportions of person–years spent at each level of glucocorticoid daily exposure were 80% for non-use, 6.0% for <5 mg, 11.2% for 5.0–14.9 mg, 1.6% for 15.0–24.9 mg, and 1.2% for ≥25.0 mg. Incident CVD occurred in 13,426 (15.3%) people, including 6,013 atrial fibrillation, 7,727 heart failure, and 2,809 acute myocardial infarction events. One-year cumulative risks of all-cause CVD increased from 1.4% in periods of non-use to 8.9% for a daily prednisolone-equivalent dose of ≥25.0 mg. Five-year cumulative risks increased from 7.1% to 28.0%, respectively. Compared to periods of non-glucocorticoid use, those with <5.0 mg daily prednisolone-equivalent dose had increased all-cause CVD risk (HR = 1.74; 95% confidence interval [CI] 1.64–1.84; range 1.52 for polymyalgia rheumatica and/or giant cell arteritis to 2.82 for systemic lupus erythematosus). Increased dose-dependent risk ratios were found regardless of disease activity level and for all type-specific CVDs. HRs for type-specific CVDs and <5.0-mg daily dose use were: 1.69 (95% CI 1.54–1.85) for atrial fibrillation, 1.75 (95% CI 1.56–1.97) for heart failure, 1.76 (95% CI 1.51–2.05) for acute myocardial infarction, 1.78 (95% CI 1.53–2.07) for peripheral arterial disease, 1.32 (95% CI 1.15–1.50) for cerebrovascular disease, and 1.93 (95% CI 1.47–2.53) for abdominal aortic aneurysm. The lack of hospital medication records and drug adherence data might have led to underestimation of the dose prescribed when specialists provided care and overestimation of the dose taken during periods of low disease activity. The resulting dose misclassification in some patients is likely to have reduced the size of dose–response estimates. Conclusions In this study, we observed an increased risk of CVDs associated with glucocorticoid dose intake even at lower doses (<5 mg) in 6 immune-mediated diseases. These results highlight the importance of prompt and regular monitoring of cardiovascular risk and use of primary prevention treatment at all glucocorticoid doses

A proteomics study of rheumatoid arthritis patients on etanercept identifies putative biomarkers associated with clinical outcome measures

\ua9 The Author(s) 2023. Objectives: Biologic DMARDs (bDMARDs) are widely used in patients with RA, but response to bDMARDs is heterogeneous. The objective of this work was to identify pretreatment proteomic biomarkers associated with RA clinical outcome measures in patients starting bDMARDs. Methods: Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) was used to generate spectral maps of sera from patients with RA before and after 3 months of treatment with the bDMARD etanercept. Protein levels were regressed against RA clinical outcome measures, i.e. 28-joint DAS (DAS28) and its subcomponents and DAS28 &lt;2.6 (i.e. remission). The proteins with the strongest evidence for association were analysed in an independent, replication dataset. Finally, subnetwork analysis was carried out using the Disease Module Detection algorithm and biological plausibility of identified proteins was assessed by enrichment analysis. Results: A total of 180 patients with RA were included in the discovery dataset and 58 in the validation dataset from a UK-based prospective multicentre study. Ten individual proteins were found to be significantly associated with RA clinical outcome measures. The association of T-complex protein 1 subunit g with DAS28 remission was replicated in an independent cohort. Subnetwork analysis of the 10 proteins from the regression analysis identified the ontological theme, with the strongest associations being with acute phase and acute inflammatory responses. Conclusion: This longitudinal study of 180 patients with RA commencing etanercept has identified several putative protein biomarkers of treatment response to this drug, one of which was replicated in an independent cohort