ORCID Profile
0000-0003-1380-6655
Current Organisation
University of Oxford
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Oxford University Press (OUP)
Date: 29-09-2011
DOI: 10.1093/BRAIN/AWR237
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-04-2022
Abstract: Biomolecule environments can enhance chemistries with the potential to mediate and modulate self-modification (e.g., self-cleavage). While these enhanced modes are found in certain biomolecules (e.g., RNA ribozymes), it is more rare in proteins. Targeted proteolytic cleavage is vital to physiology, biotechnology, and even emerging therapy. Yet, purely chemically induced methods for the site-selective cleavage of proteins remain scarce. Here, as a proof of principle, we designed and tested a system intended to combine protein-enhanced chemistry with tag modification to enable synthetic reductive protein chemistries promoted by diboron. This reductively driven, single-electron chemistry now enables an operationally simple, site-selective cleavage protocol for proteins directed to readily accessible dehydroalanine (Dha) residues as tags under aqueous conditions and in cell lysates. In this way, a mild, efficient, enzyme-free method now allows not only precise chemical proteolysis but also simultaneous use in the removal of affinity tags and/or protein-terminus editing to create altered N- and C-termini such as protein amidation (─CONH 2 ).
Publisher: Springer Science and Business Media LLC
Date: 06-01-2021
DOI: 10.1186/S12974-020-02050-6
Abstract: The acute phase response (APR) to CNS insults contributes to the overall magnitude and nature of the systemic inflammatory response. Aspects of this response are thought to drive secondary inflammatory pathology at the lesion site, and suppression of the APR can therefore afford some neuroprotection. In this study, we examined the APR in a mouse model of traumatic spinal cord injury (SCI), along with its relationship to neutrophil recruitment during the immediate aftermath of the insult. We specifically investigated the effect of IL-1 receptor antagonist (IL-1RA) administration on the APR and leukocyte recruitment to the injured spinal cord. Adult female C57BL/6 mice underwent either a 70kD contusive SCI, or sham surgery, and tissue was collected at 2, 6, 12, and 24 hours post-operation. For IL-1RA experiments, SCI mice received two intraperitoneal injections of human IL-1RA (100mg/kg), or saline as control, immediately following, and 5 hours after impact, and animals were sacrificed 6 hours later. Blood, spleen, liver and spinal cord were collected to study markers of central and peripheral inflammation by flow cytometry, immunohistochemistry and qPCR. Results were analysed by two-way ANOVA or student’s t-test, as appropriate. SCI induced a robust APR, hallmarked by elevated hepatic expression of pro-inflammatory marker genes and a significantly increased neutrophil presence in the blood, liver and spleen of these animals, as early as 2 hours after injury. This peripheral response preceded significant neutrophil infiltration of the spinal cord, which peaked 24 hours post-SCI. Although expression of IL-1RA was also induced in the liver following SCI, its response was delayed compared to IL-1β. Exogenous administration of IL-1RA during this putative therapeutic window was able to suppress the hepatic APR, as evidenced by a reduction in CXCL1 and SAA-2 expression as well as a significant decrease in neutrophil infiltration in both the liver and the injured spinal cord itself. Our data indicate that peripheral administration of IL-1RA can attenuate the APR which in turn reduces immune cell infiltration at the spinal cord lesion site. We propose IL-1RA treatment as a viable therapeutic strategy to minimise the harmful effects of SCI-induced inflammation.
Publisher: Oxford University Press (OUP)
Date: 04-02-2022
DOI: 10.1093/CVR/CVAC012
Abstract: Acute myocardial infarction rapidly increases blood neutrophils (& h). Release from bone marrow, in response to chemokine elevation, has been considered their source, but chemokine levels peak up to 24 h after injury, and after neutrophil elevation. This suggests that additional non-chemokine-dependent processes may be involved. Endothelial cell (EC) activation promotes the rapid (& min) release of extracellular vesicles (EVs), which have emerged as an important means of cell–cell signalling and are thus a potential mechanism for communicating with remote tissues. Here, we show that injury to the myocardium rapidly mobilizes neutrophils from the spleen to peripheral blood and induces their transcriptional activation prior to arrival at the injured tissue. Time course analysis of plasma-EV composition revealed a rapid and selective increase in EVs bearing VCAM-1. These EVs, which were also enriched for miRNA-126, accumulated preferentially in the spleen where they induced local inflammatory gene and chemokine protein expression, and mobilized splenic-neutrophils to peripheral blood. Using CRISPR/Cas9 genome editing, we generated VCAM-1-deficient EC-EVs and showed that its deletion removed the ability of EC-EVs to provoke the mobilization of neutrophils. Furthermore, inhibition of miRNA-126 in vivo reduced myocardial infarction size in a mouse model. Our findings show a novel EV-dependent mechanism for the rapid mobilization of neutrophils to peripheral blood from a splenic reserve and establish a proof of concept for functional manipulation of EV-communications through genetic alteration of parent cells.
Publisher: American Society for Clinical Investigation
Date: 02-2008
DOI: 10.1172/JCI33314
Publisher: Springer Science and Business Media LLC
Date: 13-06-2014
Publisher: MDPI AG
Date: 24-11-2021
DOI: 10.3390/BIOM11121759
Abstract: A deficiency in GM3-derived gangliosides, resulting from a lack of lactosylceramide-alpha-2,3-sialyltransferase (ST3GAL5), leads to severe neuropathology, including epilepsy and metabolic abnormalities. Disruption of ganglioside production by this enzyme may also have a role in the development of neuropsychiatric disorders. ST3Gal5 knock-out (St3gal5−/−) mice lack a-, b-, and c-series gangliosides, but exhibit no overt neuropathology, possibly owing to the production of compensatory 0-series glycosphingolipids. Here, we sought to investigate the possibility that St3gal5−/− mice might exhibit attention-deficit/hyperactivity disorder (ADHD)-like behaviours. In addition, we evaluated potential metabolic and electroencephalogram (EEG) abnormalities. St3gal5−/− mice were subjected to behavioural testing, glucose tolerance tests, and the levels of expression of brain and peripheral A and B isoforms of the insulin receptor (IR) were measured. We found that St3gal5−/− mice exhibit locomotor hyperactivity, impulsivity, neophobia, and anxiety-like behavior. The genotype also altered blood glucose levels and glucose tolerance. A sex bias was consistently found in relation to body mass and peripheral IR expression. Analysis of the EEG revealed an increase in litude in St3gal5−/− mice. Together, St3gal5−/− mice exhibit ADHD-like behaviours, altered metabolic and EEG measures providing a useful platform for better understanding of the contribution of brain gangliosides to ADHD and associated comorbidities.
Publisher: SAGE Publications
Date: 05-02-2014
Abstract: Neuroinflammation has been identified as a potential therapeutic target in amyotrophic lateral sclerosis (ALS), but relevant biomarkers are needed. The superoxide dismutase (SOD1) G93A transgenic mouse model of ALS offers a unique opportunity to study and potentially manipulate presymptomatic pathology. While T 2 -weighted magnetic resonance imaging (MRI) has been shown to be sensitive to pathologic changes at symptom onset, no earlier biomarkers were previously identified and the underlying histopathologic correlates remain uncertain. To address these issues, we used a multimodal MRI approach targeting structural ( T 2 , T 2 , apparent diffusion coefficient (ADC), magnetization transfer ratio (MTR)), vascular (gadolinium diethylene triamine pentaacetic acid), and endothelial (vascular cell adhesion molecule-microparticles of iron oxide) changes, together with histopathologic analysis from presymptomatic to symptomatic stages of disease. Presymptomatic changes in brainstem nuclei were evident on T 2 -weighted images from as early as 60 days ( P .05). Histologic indices of vacuolation, astro- and microglial activation all correlated with T 2 -weighted changes. Significant reductions in ADC ( P .01) and MTR ( P .05) were found at 120 days in the same brainstem nuclei. No changes in T 1 relaxation, vascular permeability, or endothelial activation were found at any stage of disease. These findings suggest that T 2 -weighted MRI offers the strongest biomarker potential in this model, and that MRI has unique potential for noninvasive and longitudinal assessment of presymptomatically applied therapeutic and neuroprotective agents.
Publisher: Mary Ann Liebert Inc
Date: 15-02-2018
Abstract: Inflammatory lesions in the brain activate a systemic acute-phase response (APR), which is dependent on the release of extracellular vesicles (EVs) into the circulation. The resulting APR is responsible for regulating leukocyte mobilization and subsequent recruitment to the brain. Factors that either exacerbate or inhibit the APR will also exacerbate or inhibit central nervous system (CNS) inflammation as a consequence and have the potential to influence ongoing secondary damage. Here, we were interested to discover how the circulating EV population changes after traumatic brain injury (TBI) and how manipulation of the circulating EV pool impacts on the outcome of TBI. We found the number of circulating EVs increased rapidly post-TBI, and this was accompanied by an increase in CNS and hepatic leukocyte recruitment. In an adoptive transfer study, we then evaluated the outcomes of TBI after administering EVs derived from either in vitro macrophage or endothelial cell lines stimulated with lipopolysaccharide (LPS), or from murine plasma from an LPS challenge using the air-pouch model. By manipulating the circulating EV population, we were able to demonstrate that each population of transferred EVs increased the APR. However, the characteristics of the response were dependent on the nature of the EVs specifically, it was significantly increased when animals were challenged with macrophage-derived EVs, suggesting that the cellular origins of EVs may determine their function. Selectively targeting EVs from macrophage/monocyte populations is likely to be of value in reducing the impact of the systemic inflammatory response on the outcome of traumatic CNS injury.
Publisher: Wiley
Date: 21-02-2022
DOI: 10.1111/LIV.15192
Abstract: Primary sclerosing cholangitis (PSC) and IgG4‐related sclerosing cholangitis (IgG4‐SC) are chronic fibro‐inflammatory immune‐mediated hepatobiliary conditions that are challenging to distinguish in a clinical setting. Accurate non‐invasive biomarkers for discriminating PSC and IgG4‐SC are important to ensure a correct diagnosis, prompt therapy and adequate cancer surveillance. We performed nuclear magnetic resonance (NMR)‐based metabolomic profiling using serum s les collected prospectively from patients with PSC ( n = 100), IgG4‐SC ( n = 23) and healthy controls (HC n = 16). Multivariate analysis of the serum metabolome discriminated PSC from IgG4‐SC with greater accuracy (AUC 0.95 [95%CI 0.90–0.98]) than IgG4 titre (AUC 0.87 [95%CI 0.79–0.94]). When inflammatory bowel disease (IBD) was excluded as a comorbid condition (IgG4‐SC n = 20, PSC n = 22), the diagnostic AUC increased to 1.0, suggesting that the metabolome differences identified are not a result of the increased prevalence of IBD in PSC relative to IgG4‐SC patients. Serum lactate ( p .0001), glucose ( p .01) and glutamine ( p .01) metabolites were increased in IgG4‐related disease (IgG4‐RD) and IgG4‐SC in iduals compared to PSC, whereas mobile choline ( p .05), 3‐hydroxybutyric acid ( p .01) and ‐CH 3 lipoprotein resonances ( p .01) were decreased. Taken together, serum metabolomic profiling has the potential to be incorporated as a diagnostic criterion, independent of IgG4 titre, to improve the diagnosis of IgG4‐RD and help distinguish IgG4‐SC from PSC.
Publisher: Elsevier BV
Date: 03-2020
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Daniel Anthony.