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  • Zebrafish earns its stripes for in vivo ASC speck dynamics.

    24 October 2018

    Assembly of the ASC speck is critical for signaling by the inflammasome. In this issue, Kuri et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201703103) use live microscopy to track fluorescently tagged endogenous ASC in the zebrafish, describing the molecular domains driving ASC speck assembly and identifying a key role for macrophages in ASC speck removal in vivo.

  • N- and C-Terminal Truncations to Enhance Protein Solubility and Crystallization: Predicting Protein Domain Boundaries with Bioinformatics Tools.

    24 October 2018

    Soluble protein expression is a key requirement for biochemical and structural biology approaches to study biological systems in vitro. Production of sufficient quantities may not always be achievable if proteins are poorly soluble which is frequently determined by physico-chemical parameters such as intrinsic disorder. It is well known that discrete protein domains often have a greater likelihood of high-level soluble expression and crystallizability. Determination of such protein domain boundaries can be challenging for novel proteins. Here, we outline the application of bioinformatics tools to facilitate the prediction of potential protein domain boundaries, which can then be used in designing expression construct boundaries for parallelized screening in a range of heterologous expression systems.

  • Metalloproteinases in Rheumatoid Arthritis: Potential Therapeutic Targets to Improve Current Therapies.

    24 October 2018

    Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by the destruction of joint tissues including cartilage and bone. Cartilage degradation is attributed to metalloproteinases (MPs) that belong to matrix metalloproteinase family and a disintegrin and metalloprotease with thrombospondin type 1 motifs produced by inflamed joint tissues. In addition, an enzyme that belongs to a disintegrin and metalloprotease family is also involved in release of inflammatory cytokines. Several highly selective inhibitors have been developed for MPs thought to play a role in RA pathogenesis and examining these inhibitors as potential drugs is becoming realistic. This chapter discusses recent reports on MPs in RA and their potential as a therapeutic target.

  • Highly sensitive and adaptable fluorescence-quenched pair discloses the substrate specificity profiles in diverse protease families.

    24 October 2018

    Internally quenched fluorescent (IQF) peptide substrates originating from FRET (Förster Resonance Energy Transfer) are powerful tool for examining the activity and specificity of proteases, and a variety of donor/acceptor pairs are extensively used to design individual substrates and combinatorial libraries. We developed a highly sensitive and adaptable donor/acceptor pair that can be used to investigate the substrate specificity of cysteine proteases, serine proteases and metalloproteinases. This novel pair comprises 7-amino-4-carbamoylmethylcoumarin (ACC) as the fluorophore and 2,4-dinitrophenyl-lysine (Lys(DNP)) as the quencher. Using caspase-3, caspase-7, caspase-8, neutrophil elastase, legumain, and two matrix metalloproteinases (MMP2 and MMP9), we demonstrated that substrates containing ACC/Lys(DNP) exhibit 7 to 10 times higher sensitivity than conventional 7-methoxy-coumarin-4-yl acetic acid (MCA)/Lys(DNP) substrates; thus, substantially lower amounts of substrate and enzyme can be used for each assay. We therefore propose that the ACC/Lys(DNP) pair can be considered a novel and sensitive scaffold for designing substrates for any group of endopeptidases. We further demonstrate that IQF substrates containing unnatural amino acids can be used to investigate protease activities/specificities for peptides containing post-translationally modified amino acids. Finally, we used IQF substrates to re-investigate the P1-Asp characteristic of caspases, thus demonstrating that some human caspases can also hydrolyze substrates after glutamic acid.

  • ACL and meniscal injuries increase the risk of primary total knee replacement for osteoarthritis: a matched case-control study using the Clinical Practice Research Datalink (CPRD).

    24 October 2018

    OBJECTIVES: The aim of this study was to investigate whether ACL injury (ACLi) or meniscal injury increases the risk of end-stage osteoarthritis (OA) resulting in total knee replacement (TKR). METHODS: A matched case-control study of all TKRs performed in the UK between January 1990 and July 2011 and recorded in the Clinical Practice Research Datalink (CPRD) was undertaken. The CPRD contains longitudinal data on approximately 3.6 million patients. Two controls were selected for each case of TKR, matched on age, sex and general practitioner location as a proxy for socioeconomic status. Individuals with inflammatory arthritis were excluded. The odds of having TKR for individuals with a CPRD-recorded ACLi were compared with those without ACLi using conditional logistic regression, after adjustment for body mass index, previous knee fracture and meniscal injury. The adjusted odds of TKR in individuals with a recorded meniscal injury compared with those without were calculated. RESULTS: After exclusion of individuals with inflammatory arthritis, there were 49 723 in the case group and 104 353 controls. 153 (0.31%) cases had a history of ACLi compared with 41 (0.04%) controls. The adjusted OR of TKR after ACLi was 6.96 (95% CI 4.73 to 10.31). 4217 (8.48%) individuals in the TKR group had a recorded meniscal injury compared with 669 (0.64%) controls. The adjusted OR of TKR after meniscal injury was 15.24 (95% CI 13.88 to 16.69). CONCLUSION: This study demonstrates that ACLi is associated with a sevenfold increased odds of TKR resulting from OA. Meniscal injury is associated with a 15-fold increase odds of TKR for OA.

  • High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.

    24 October 2018

    Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.

  • Horwood Group | Osteoimmunology

    12 June 2018

    The loss of bone is a problem in many inflammatory diseases and there are few therapeutic options to replace bone once it has been lost. Our research focuses on the causes of this bone loss and identifying potential treatment options.

  • Watt Group | Translational Research in Osteoarthritis

    12 June 2018

    Our group tests findings from the laboratory in human clinical studies, and runs experimental medicine studies and clinical trials relevant to osteoarthritis within the Arthritis Research UK Centre for Osteoarthritis Pathogenesis.

  • Midwood Group | Matrix Immunology

    27 September 2018

    Our group investigates how the extracellular matrix - the component of tissue that lies immediately outside and between cells - contributes to inflammation.

  • Powrie Group | Mucosal Immunology

    20 September 2018

    Work in the Powrie lab is focused on understanding the interaction between the intestinal microbiota and the host immune system and how this mutualistic relationship breaks down in inflammatory bowel disease and cancer.

  • Arnon Group | Humoral Immune Response

    12 June 2018

    The main focus of the lab is to understand how humoral immune responses are regulated within the spleen.

  • Wann Group | Primary Cilia in Inflammatory Signalling

    12 June 2018

    Cells use unique spaces to organise the messaging that modifies their behaviour and respond to their environment. Our research looks at how one such space - the primary cilium - affects the way cells respond to inflammation.

  • Udalova Group | Genomics of Inflammation

    5 September 2018

    Work in the Udalova is focused on understanding how the inflammatory response is controlled on the molecular level.

  • Griseri Group | Haematopoiesis and Chronic Inflammation

    12 June 2018

    Can we treat chronic inflammatory arthritis by modulating the abnormal activity of the immune system factory - the bone marrow - to weaken the excessive accumulation of tissue-destructive white blood cells in the joints?

  • Research Informatics

    23 October 2017

    We are responsible for providing the Institute with solutions to challenges associated with the wide diversity of data generated and used by our scientists.