Exacerbated inflammatory arthritis in response to hyperactive gp130 signalling is independent of IL-17A

Objective Interleukin (IL)-17A producing CD4 T-cells (TH-17 cells) are implicated in rheumatoid arthritis (RA). IL-6/STAT3 signalling drives TH-17 cell differentiation, and hyperactive gp130/STAT3 signalling in the gp130F/F mouse promotes exacerbated pathology. Conversely, STAT1-activating cytokines (eg, IL-27, IFN-γ) inhibit TH-17 commitment. Here, we evaluate the impact of STAT1 ablation on TH-17 cells during experimental arthritis and relate this to IL-17A-associated pathology. Methods Antigen-induced arthritis (AIA) was established in wild type (WT), gp130F/F mice displaying hyperactive gp130-mediated STAT signalling and the compound mutants gp130F/F:Stat1−/− and gp130F/F: Il17a−/− mice. Joint pathology and associated peripheral TH-17 responses were compared. Results Augmented gp130/STAT3 signalling enhanced TH-17 commitment in vitro and exacerbated joint pathology. Ablation of STAT1 in gp130F/F mice (gp130F/F: Stat1−/− ) promoted the hyperexpansion of TH-17 cells in vitro and in vivo during AIA. Despite this heightened peripheral TH-17 cell response, disease severity and the number of joint-infiltrating T-cells were comparable with that of WT mice. Thus, gp130-mediated STAT1 activity within the inflamed synovium controls T-cell trafficking and retention. To determine the contribution of IL-17A, we generated gp130F/F:IL-17a−/− mice. Here, loss of IL-17A had no impact on arthritis severity. Conclusions Exacerbated gp130/STAT-driven disease in AIA is associated with an increase in joint infiltrating T-cells but synovial pathology is IL-17A independent

The discovery and dynamical evolution of an object at the outer edge of Saturn's A ring

This work was supported by the Science and Technology Facilities Council (Grant No. ST/F007566/1) and we are grateful to them for financial assistance. C.D.M. is also grateful to the Leverhulme Trust for the award of a Research Fellowshippublisher PDF not permitted, withdraw

Fibre-based fluorescence-lifetime imaging microscopy:a real-time biopsy guidance tool for suspected lung cancer

Lung cancer is the most common cause of cancer-related deaths worldwide. Early detection improves outcomes, however, existing sampling techniques are associated with suboptimal diagnostic yield and procedure-related complications. Autofluorescence-based fluorescence-lifetime imaging microscopy (FLIM), a technique which measures endogenous fluorophore decay rates, may aid identification of optimal biopsy sites in suspected lung cancer. Our fibre-based fluorescence-lifetime imaging system, utilising 488 nm excitation, which is deliverable via existing diagnostic platforms, enables real-time visualisation and lifetime analysis of distal alveolar lung structure. We evaluated the diagnostic accuracy of the fibre-based fluorescence-lifetime imaging system to detect changes in fluorescence lifetime in freshly resected ex vivo lung cancer and adjacent healthy tissue as a first step towards future translation. The study compares paired non-small cell lung cancer (NSCLC) and non-cancerous tissues with gold standard diagnostic pathology to assess the performance of the technique. Paired NSCLC and non-cancerous lung tissues were obtained from thoracic resection patients (N=21). A clinically compatible 488 nm fluorescence-lifetime endomicroscopy platform was used to acquire simultaneous fluorescence intensity and lifetime images. Fluorescence lifetimes were calculated using a computationally-lightweight, rapid lifetime determination method. Fluorescence lifetime was significantly reduced in ex vivo lung cancer, compared with non-cancerous lung tissue [mean ± standard deviation (SD), 1.79±0.40 vs. 2.15±0.26 ns, P&lt;0.0001], and fluorescence intensity images demonstrated distortion of alveolar elastin autofluorescence structure. Fibre-based fluorescence-lifetime imaging demonstrated good performance characteristics for distinguishing lung cancer, from adjacent non-cancerous tissue, with 81.0% sensitivity and 71.4% specificity. Our novel fibre-based fluorescence-lifetime imaging system, which enables label-free imaging and quantitative lifetime analysis, discriminates ex vivo lung cancer from adjacent healthy tissue. This minimally invasive technique has potential to be translated as a real-time biopsy guidance tool, capable of optimising diagnostic accuracy in lung cancer. </p

Spectrofluorimetry with attomole sensitivity in photonic crystal fibres

We report the use of photonic crystal fibres (PCF) as spectrofluorimetric systems in which sample solutions are excited within the microstructure of the fibre. The use of intra-fibre excitation has several advantages that combine to enable highly sensitive measurements of fluorescence spectra and lifetimes: long path-lengths are achieved by the efficient guidance of the fundamental mode; sample volumes contained within the micron-scale structure are very small, only a few nanolitres per cm of path; collection and guidance of the emitted fluorescence is efficient and the fluorescence lifetime is unperturbed. Fluorophores in bulk solution can be studied in hollow core PCF, whereas the use of PCF with a suspended, solid core enables selective excitation of molecules in close proximity to the silica surface, through interaction with the evanescent field. We demonstrate the measurement of fluorescence spectra and fluorescence lifetimes in each of these excitation regimes and report the detection of attomole quantities of fluorescein

The iron law of democratic socialism: British and Austrian influences on the young Karl Polanyi

This article has been made available through the Brunel Open Access Publishing Fund.A central thesis of Karl Polanyi's The great transformation concerns the tensions between capitalism and democracy: the former embodies the principle of inequality, while democracy represents that of equality. This paper explores the intellectual heritage of this thesis, in the ‘functional theory’ of G.D.H. Cole and Otto Bauer and in the writings of Eduard Bernstein. It scrutinizes Polanyi's relationship with Bernstein's ‘evolutionary socialism’ and charts his ‘double movement’ vis-à-vis Marxist philosophy: in the 1910s he reacted sharply against Marxism's deterministic excesses, but he then, in the 1920s, engaged in sympathetic dialogue with Austro-Marxist thinkers. The latter, like Bernstein, disavowed economic determinism and insisted upon the importance and autonomy of ethics. Yet they simultaneously predicted a law-like expansion of democracy from the political to the economic arena. Analysis of this contradiction provides the basis for a concluding discussion that reconsiders the deterministic threads in Polanyi's oeuvre. Whereas for some Polanyi scholars these attest to his residual attraction to Marxism, I argue that matters are more complex. While Polanyi did repudiate the more rigidly deterministic of currents in Marxist philosophy, those to which he was attracted, notably Bernstein's ‘revision’ and Austro-Marxism, incorporated a deterministic fatalism of their own, in respect of democratization. Herein lies a more convincing explanation of Polanyi's incomplete escape from a deterministic philosophy of history, as exemplified in his masterwork, The great transformation

Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study.

The ability to investigate therapeutic interventions in animal models of neurodegenerative diseases depends on extensive characterization of the model(s) being used. There are numerous models that have been generated to study Alzheimer\u27s disease (AD) and the underlying pathogenesis of the disease. While transgenic models have been instrumental in understanding AD mechanisms and risk factors, they are limited in the degree of characteristics displayed in comparison with AD in humans, and the full spectrum of AD effects has yet to be recapitulated in a single mouse model. The Model Organism Development and Evaluation for Late-Onset Alzheimer\u27s Disease (MODEL-AD) consortium was assembled by the National Institute on Aging (NIA) to develop more robust animal models of AD with increased relevance to human disease, standardize the characterization of AD mouse models, improve preclinical testing in animals, and establish clinically relevant AD biomarkers, among other aims toward enhancing the translational value of AD models in clinical drug design and treatment development. Here we have conducted a detailed characterization of the 5XFAD mouse, including transcriptomics, electroencephalogram