ORCID Profile
0000-0003-2343-8534
Current Organisation
University of Birmingham
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Publisher: Springer Science and Business Media LLC
Date: 17-07-2019
Publisher: Springer Science and Business Media LLC
Date: 18-01-2023
DOI: 10.1038/S41467-022-35716-1
Abstract: The glucagon-like peptide-1 receptor (GLP1R) is a class B G protein-coupled receptor (GPCR) involved in glucose homeostasis and food intake. GLP1R agonists (GLP1RA) are widely used in the treatment of diabetes and obesity, yet visualizing the endogenous localization, organization and dynamics of a GPCR has so far remained out of reach. In the present study, we generate mice harboring an enzyme self-label genome-edited into the endogenous Glp1r locus. We also rationally design and test various fluorescent dyes, spanning cyan to far-red wavelengths, for labeling performance in tissue. By combining these technologies, we show that endogenous GLP1R can be specifically and sensitively detected in primary tissue using multiple colors. Longitudinal analysis of GLP1R dynamics reveals heterogeneous recruitment of neighboring cell subpopulations into signaling and trafficking, with differences observed between GLP1RA classes and dual agonists. At the nanoscopic level, GLP1Rs are found to possess higher organization, undergoing GLP1RA-dependent membrane diffusion. Together, these results show the utility of enzyme self-labels for visualization and interrogation of endogenous proteins, and provide insight into the biology of a class B GPCR in primary cells and tissue.
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.JINF.2021.10.014
Abstract: Rates of acute rheumatic fever, a sequelae of group A Streptococcal (GAS) infection, remain unacceptably high in Indigenous Māori and Pacific children in New Zealand. This prospective study aimed to describe GAS antibody titres in healthy children (5-14 years) by ethnicity, and to determine how paired titres vary with GAS culture positive and negative pharyngitis, and GAS skin infections. Analysis included 887 children (32% Māori, 36% Pacific, 33% European/Other) from Auckland, New Zealand. Cases comprise 772 children who had a sore throat or skin infection, which resulted in a swab taken for culture. Healthy controls were asymptomatic (N = 154) and matched by age, ethnicity and region. All participants had a serum s le, with a second s le collected from cases only. Sera were analysed for anti-streptolysin O (ASO) and anti-DNase-B (ADB) antibodies. Healthy Māori and Pacific children had higher GAS antibody titres than healthy European/Other children. Children with GAS-positive sore throat had the highest mean ASO titres and children with GAS-positive skin infection had the highest mean ADB titres. When a two-fold increase or an upper limit of normal cut-off (ASO 450 IU/ml, ADB 400 U/ml) was applied to titres from children with GAS-positive sore throat, 62.1% were classified as having serologically confirmed GAS pharyngitis and 37.9% had GAS detected without serological response. Elevated ASO titres were associated with GAS pharyngitis and elevated ADB titres were associated with GAS skin infections in New Zealand children. Higher ASO/ADB titres in healthy Māori and Pacific children could indicate a greater prior exposure to GAS infections.
Publisher: BMJ
Date: 09-2021
DOI: 10.1136/BMJOPEN-2021-053720
Abstract: The absence of a diagnostic test for acute rheumatic fever (ARF) is a major impediment in managing this serious childhood condition. ARF is an autoimmune condition triggered by infection with group A Streptococcus . It is the precursor to rheumatic heart disease (RHD), a leading cause of health inequity and premature mortality for Indigenous peoples of Australia, New Zealand and internationally. ‘Searching for a Technology-Driven Acute Rheumatic Fever Test’ (START) is a biomarker discovery study that aims to detect and test a biomarker signature that distinguishes ARF cases from non-ARF, and use systems biology and serology to better understand ARF pathogenesis. Eligible participants with ARF diagnosed by an expert clinical panel according to the 2015 Revised Jones Criteria, aged 5–30 years, will be recruited from three hospitals in Australia and New Zealand. Age, sex and ethnicity-matched in iduals who are healthy or have non-ARF acute diagnoses or RHD, will be recruited as controls. In the discovery cohort, blood s les collected at baseline, and during convalescence in a subset, will be interrogated by comprehensive profiling to generate possible diagnostic biomarker signatures. A biomarker validation cohort will subsequently be used to test promising combinations of biomarkers. By defining the first biomarker signatures able to discriminate between ARF and other clinical conditions, the START study has the potential to transform the approach to ARF diagnosis and RHD prevention. The study has approval from the Northern Territory Department of Health and Menzies School of Health Research ethics committee and the New Zealand Health and Disability Ethics Committee. It will be conducted according to ethical standards for research involving Indigenous Australians and New Zealand Māori and Pacific Peoples. Indigenous investigators and governance groups will provide oversight of study processes and advise on cultural matters.
Publisher: Elsevier BV
Date: 02-2021
Publisher: AMPCo
Date: 24-06-2021
DOI: 10.5694/MJA2.51149
Publisher: Elsevier BV
Date: 09-2022
Publisher: Elsevier BV
Date: 09-2022
Publisher: Wiley
Date: 22-03-2020
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Nicholas Fine.