ORCID Profile
0000-0002-8257-626X
Current Organisations
University of Oxford
,
University of Southern California
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Publisher: eLife Sciences Publications, Ltd
Date: 22-08-2019
DOI: 10.7554/ELIFE.46840
Abstract: The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation. Loss of G6b-B results in severe macrothrombocytopenia, myelofibrosis and aberrant platelet function in mice and humans. Using a combination of immunohistochemistry, affinity chromatography and proteomics, we identified the extracellular matrix heparan sulfate (HS) proteoglycan perlecan as a G6b-B binding partner. Subsequent in vitro biochemical studies and a cell-based genetic screen demonstrated that the interaction is specifically mediated by the HS chains of perlecan. Biophysical analysis revealed that heparin forms a high-affinity complex with G6b-B and mediates dimerization. Using platelets from humans and genetically modified mice, we demonstrate that binding of G6b-B to HS and multivalent heparin inhibits platelet and megakaryocyte function by inducing downstream signaling via the tyrosine phosphatases Shp1 and Shp2. Our findings provide novel insights into how G6b-B is regulated and contribute to our understanding of the interaction of megakaryocytes and platelets with glycans.
Publisher: Wiley
Date: 13-11-2022
Publisher: Elsevier BV
Date: 08-2018
Publisher: American Geophysical Union (AGU)
Date: 09-2018
DOI: 10.1029/2017GB005839
Publisher: Elsevier BV
Date: 12-2015
Publisher: Springer Science and Business Media LLC
Date: 17-10-2022
Publisher: Copernicus GmbH
Date: 16-06-2022
Abstract: Abstract. Spatially distant sources of neodymium (Nd) to the ocean that carry different isotopic signatures (εNd) have been shown to trace out major water masses and have thus been extensively used to study large-scale features of the ocean circulation both past and current. While the global marine Nd cycle is qualitatively well understood, a complete quantitative determination of all its components and mechanisms, such as the magnitude of its sources and the paradoxical conservative behavior of εNd, remains elusive. To make sense of the increasing collection of observational Nd and εNd data, in this model description paper we present and describe the Global Neodymium Ocean Model (GNOM) v1.0, the first inverse model of the global marine biogeochemical cycle of Nd. The GNOM is embedded in a data-constrained steady-state circulation that affords spectacular computational efficiency, which we leverage to perform systematic objective optimization, allowing us to make preliminary estimates of biogeochemical parameters. Owing to its matrix representation, the GNOM model is additionally amenable to novel diagnostics that allow us to investigate open questions about the Nd cycle with unprecedented accuracy. This model is open-source and freely accessible, is written in Julia, and its code is easily understandable and modifiable for further community developments, refinements, and experiments.
Publisher: The Open Journal
Date: 05-01-2022
DOI: 10.21105/JOSS.03814
Publisher: eLife Sciences Publications, Ltd
Date: 30-07-2019
Publisher: Wiley
Date: 09-2012
Publisher: Elsevier BV
Date: 12-2021
Location: United Kingdom of Great Britain and Northern Ireland
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 Seth John.