140 results on '"Matheson, Nicholas J"'
Search Results
102. Cell Surface Proteomic Map of HIV Infection Reveals Antagonism of Amino Acid Metabolism by Vpu and Nef
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Matheson, Nicholas J., primary, Sumner, Jonathan, additional, Wals, Kim, additional, Rapiteanu, Radu, additional, Weekes, Michael P., additional, Vigan, Raphael, additional, Weinelt, Julia, additional, Schindler, Michael, additional, Antrobus, Robin, additional, Costa, Ana S.H., additional, Frezza, Christian, additional, Clish, Clary B., additional, Neil, Stuart J.D., additional, and Lehner, Paul J., additional
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- 2015
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103. Antibody-Free Magnetic Cell Sorting of Genetically Modified Primary Human CD4+ T Cells by One-Step Streptavidin Affinity Purification
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Matheson, Nicholas J., primary, Peden, Andrew A., additional, and Lehner, Paul J., additional
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- 2014
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104. Plasma membrane proteomics identifies Notch1 as a potential regulator of ras-induced senescence
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Hoare, Matthew, primary, Weekes, Michael P, additional, Matheson, Nicholas J, additional, Menon, Suraj, additional, Antrobus, Robin, additional, Lehner, Paul J, additional, and Narita, Masashi, additional
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- 2013
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105. Neuraminidase inhibitors for preventing and treating influenza in children
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Matheson, Nicholas J, primary, Harnden, Anthony, additional, Perera, Rafael, additional, Sheikh, Aziz, additional, and Symmonds-Abrahams, Mkael, additional
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- 2007
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106. Integrative functional genomics decodes herpes simplex virus 1
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Whisnant, Adam W., Jürges, Christopher S., Hennig, Thomas, Wyler, Emanuel, Prusty, Bhupesh, Rutkowski, Andrzej J., L’hernault, Anne, Djakovic, Lara, Göbel, Margarete, Döring, Kristina, Menegatti, Jennifer, Antrobus, Robin, Matheson, Nicholas J., Künzig, Florian W. H., Mastrobuoni, Guido, Bielow, Chris, Kempa, Stefan, Liang, Chunguang, Dandekar, Thomas, Zimmer, Ralf, Landthaler, Markus, Grässer, Friedrich, Lehner, Paul J., Friedel, Caroline C., Erhard, Florian, and Dölken, Lars
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631/326/596/1553 ,article ,49/39 ,631/114 ,3. Good health ,38/91 - Abstract
Funder: Alexander von Humboldt-Stiftung (Alexander von Humboldt Foundation); doi: https://doi.org/10.13039/100005156, The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDA-approved oncolytic virus Imlygic. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of ORFs as well as N-terminal extensions (NTEs) and truncations. We show that NTEs with non-canonical start codons govern the subcellular protein localization and packaging of key viral regulators and structural proteins. We extend the current nomenclature to include all viral gene products and provide a genome browser that visualizes all the obtained data from whole genome to single-nucleotide resolution.
107. Effective control of SARS-CoV-2 transmission between healthcare workers during a period of diminished community prevalence of COVID-19
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Jones, Nick K, Rivett, Lucy, Sparkes, Dominic, Forrest, Sally, Sridhar, Sushmita, Young, Jamie, Pereira-Dias, Joana, Cormie, Claire, Gill, Harmeet, Reynolds, Nicola, Wantoch, Michelle, Routledge, Matthew, Warne, Ben, Levy, Jack, Córdova Jiménez, William David, Samad, Fathima Nisha Begum, McNicholas, Chris, Ferris, Mark, Gray, Jane, Gill, Michael, CITIID-NIHR COVID-19 BioResource Collaboration, Curran, Martin D, Fuller, Stewart, Chaudhry, Afzal, Shaw, Ashley, Bradley, John R, Hannon, Gregory J, Goodfellow, Ian G, Dougan, Gordon, Smith, Kenneth Gc, Lehner, Paul J, Wright, Giles, Matheson, Nicholas J, Baker, Stephen, and Weekes, Michael P
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Adult ,Male ,medicine ,Infectious Disease Transmission, Patient-to-Professional ,infectious disease ,Health Personnel ,Pneumonia, Viral ,global health ,Real-Time Polymerase Chain Reaction ,Hospitals, University ,Betacoronavirus ,COVID-19 Testing ,Patient Admission ,Nasopharynx ,Disease Transmission, Infectious ,Prevalence ,Humans ,Mass Screening ,human ,Hospitals, Teaching ,Pandemics ,emerging pathogens ,Family Characteristics ,Infection Control ,SARS-CoV-2 ,Clinical Laboratory Techniques ,virus diseases ,COVID-19 ,human biology ,Middle Aged ,3. Good health ,virology ,Community-Acquired Infections ,Occupational Diseases ,England ,occupational health ,Asymptomatic Diseases ,epidemiology ,Female ,Contact Tracing ,Symptom Assessment ,Coronavirus Infections ,Hospital Units ,Program Evaluation - Abstract
Previously, we showed that 3% (31/1032)of asymptomatic healthcare workers (HCWs) from a large teaching hospital in Cambridge, UK, tested positive for SARS-CoV-2 in April 2020. About 15% (26/169) HCWs with symptoms of coronavirus disease 2019 (COVID-19) also tested positive for SARS-CoV-2 (Rivett et al., 2020). Here, we show that the proportion of both asymptomatic and symptomatic HCWs testing positive for SARS-CoV-2 rapidly declined to near-zero between 25th April and 24th May 2020, corresponding to a decline in patient admissions with COVID-19 during the ongoing UK 'lockdown'. These data demonstrate how infection prevention and control measures including staff testing may help prevent hospitals from becoming independent 'hubs' of SARS-CoV-2 transmission, and illustrate how, with appropriate precautions, organizations in other sectors may be able to resume on-site work safely.
108. Antagonism of PP2A is an independent and conserved function of HIV-1 Vif and causes cell cycle arrest
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Marelli, Sara, Williamson, James C, Protasio, Anna V, Naamati, Adi, Greenwood, Edward Jd, Deane, Janet E, Lehner, Paul J, and Matheson, Nicholas J
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Host Microbial Interactions ,viruses ,infectious disease ,microbiology ,virus diseases ,HIV ,virus ,Cell Cycle Checkpoints ,biochemical phenomena, metabolism, and nutrition ,Flow Cytometry ,Vif ,3. Good health ,PP2A ,HIV-1 ,vif Gene Products, Human Immunodeficiency Virus ,Humans ,Point Mutation ,cell cycle ,APOBEC Deaminases ,Protein Phosphatase 2 - Abstract
The seminal description of the cellular restriction factor APOBEC3G and its antagonism by HIV-1 Vif has underpinned two decades of research on the host-virus interaction. We recently reported that HIV-1 Vif is also able to degrade the PPP2R5 family of regulatory subunits of key cellular phosphatase PP2A (PPP2R5A-E; Greenwood et al., 2016; Naamati et al., 2019). We now identify amino acid polymorphisms at positions 31 and 128 of HIV-1 Vif which selectively regulate the degradation of PPP2R5 family proteins. These residues covary across HIV-1 viruses in vivo, favouring depletion of PPP2R5A-E. Through analysis of point mutants and naturally occurring Vif variants, we further show that degradation of PPP2R5 family subunits is both necessary and sufficient for Vif-dependent G2/M cell cycle arrest. Antagonism of PP2A by HIV-1 Vif is therefore independent of APOBEC3 family proteins, and regulates cell cycle progression in HIV-infected cells.
109. Comparative Cell Surface Proteomic Analysis of the Primary Human T Cell and Monocyte Responses to Type I Interferon
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Soday, Lior, Potts, Martin, Hunter, Leah M., Ravenhill, Benjamin J., Houghton, Jack W., Williamson, James C., Antrobus, Robin, Wills, Mark R., Matheson, Nicholas J., and Weekes, Michael P.
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quantitative proteomics ,cell surface ,leukocytes ,FOS: Clinical medicine ,Immunology ,antiviral restrictin ,monocyte ,T cell ,plasma membrane ,3. Good health ,type I interferon (IFN) - Abstract
The cellular response to interferon (IFN) is essential for antiviral immunity, IFN-based therapy and IFN-related disease. The plasma membrane (PM) provides a critical interface between the cell and its environment, and is the initial portal of entry for viruses. Nonetheless, the effect of IFN on PM proteins is surprisingly poorly understood, and has not been systematically investigated in primary immune cells. Here, we use multiplexed proteomics to quantify IFNα2a-stimulated PM protein changes in primary human CD14+ monocytes and CD4+ T cells from five donors, quantifying 606 and 482 PM proteins respectively. Comparison of cell surface proteomes revealed a remarkable invariance between donors in the overall composition of the cell surface from each cell type, but a marked donor-to-donor variability in the effects of IFNα2a. Furthermore, whereas only 2.7% of quantified proteins were consistently upregulated by IFNα2a at the surface of CD4+ T cells, 6.8% of proteins were consistently upregulated in primary monocytes, suggesting that the magnitude of the IFNα2a response varies according to cell type. Among these differentially regulated proteins, we found the viral target Endothelin-converting enzyme 1 (ECE1) to be an IFNα2a-stimulated protein exclusively upregulated at the surface of CD4+ T cells. We therefore provide a comprehensive map of the cell surface of IFNα2a-stimulated primary human immune cells, including previously uncharacterized interferon stimulated genes (ISGs) and candidate antiviral factors.
110. Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission
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Rivett, Lucy, Sridhar, Sushmita, Sparkes, Dominic, Routledge, Matthew, Jones, Nick K, Forrest, Sally, Young, Jamie, Pereira-Dias, Joana, Hamilton, William L, Ferris, Mark, Torok, M Estee, Meredith, Luke, CITIID-NIHR COVID-19 BioResource Collaboration, Curran, Martin D, Fuller, Stewart, Chaudhry, Afzal, Shaw, Ashley, Samworth, Richard J, Bradley, John R, Dougan, Gordon, Smith, Kenneth Gc, Lehner, Paul J, Matheson, Nicholas J, Wright, Giles, Goodfellow, Ian G, Baker, Stephen, and Weekes, Michael P
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Male ,medicine ,COVID-19 Vaccines ,infectious disease ,Health Personnel ,education ,Pneumonia, Viral ,global health ,virus ,Real-Time Polymerase Chain Reaction ,Betacoronavirus ,COVID-19 Testing ,Humans ,human ,Asymptomatic Infections ,Pandemics ,emerging pathogens ,Infection Control ,SARS-CoV-2 ,Clinical Laboratory Techniques ,virus diseases ,COVID-19 ,human biology ,United Kingdom ,3. Good health ,virology ,occupational health ,epidemiology ,Female ,Coronavirus Infections - Abstract
Significant differences exist in the availability of healthcare worker (HCW) SARS-CoV-2 testing between countries, and existing programmes focus on screening symptomatic rather than asymptomatic staff. Over a 3 week period (April 2020), 1032 asymptomatic HCWs were screened for SARS-CoV-2 in a large UK teaching hospital. Symptomatic staff and symptomatic household contacts were additionally tested. Real-time RT-PCR was used to detect viral RNA from a throat+nose self-swab. 3% of HCWs in the asymptomatic screening group tested positive for SARS-CoV-2. 17/30 (57%) were truly asymptomatic/pauci-symptomatic. 12/30 (40%) had experienced symptoms compatible with coronavirus disease 2019 (COVID-19)>7 days prior to testing, most self-isolating, returning well. Clusters of HCW infection were discovered on two independent wards. Viral genome sequencing showed that the majority of HCWs had the dominant lineage B∙1. Our data demonstrates the utility of comprehensive screening of HCWs with minimal or no symptoms. This approach will be critical for protecting patients and hospital staff.
111. Functional proteomic atlas of HIV infection in primary human CD4+ T cells
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Naamati, Adi, Williamson, James C, Greenwood, Edward Jd, Marelli, Sara, Lehner, Paul J, and Matheson, Nicholas J
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CD4-Positive T-Lymphocytes ,Proteomics ,Proteome ,infectious disease ,Green Fluorescent Proteins ,HIV Infections ,virus ,Cell Separation ,Lymphocyte Activation ,Virus Replication ,primary human CD4+ T cell ,immunology ,Fragile X Mental Retardation Protein ,Magnetics ,vif Gene Products, Human Immunodeficiency Virus ,Cluster Analysis ,Humans ,human ,magnetic cell selection ,microbiology ,Lentivirus ,HIV ,Protein Tyrosine Phosphatase, Non-Receptor Type 22 ,Methyltransferases ,Hydrogen-Ion Concentration ,3. Good health ,DNA-Binding Proteins ,Gene Expression Regulation ,inflammation ,HIV-1 ,Streptavidin ,Protein Binding - Abstract
Viruses manipulate host cells to enhance their replication, and the identification of cellular factors targeted by viruses has led to key insights into both viral pathogenesis and cell biology. In this study, we develop an HIV reporter virus (HIV-AFMACS) displaying a streptavidin-binding affinity tag at the surface of infected cells, allowing facile one-step selection with streptavidin-conjugated magnetic beads. We use this system to obtain pure populations of HIV-infected primary human CD4+ T cells for detailed proteomic analysis, and quantitate approximately 9000 proteins across multiple donors on a dynamic background of T cell activation. Amongst 650 HIV-dependent changes (q < 0.05), we describe novel Vif-dependent targets FMR1 and DPH7, and 192 proteins not identified and/or regulated in T cell lines, such as ARID5A and PTPN22. We therefore provide a high-coverage functional proteomic atlas of HIV infection, and a mechanistic account of host factors subverted by the virus in its natural target cell.
112. Antagonism of PP2A is an independent and conserved function of HIV-1 Vif and causes cell cycle arrest
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Marelli, Sara, Williamson, James C, Protasio, Anna V, Naamati, Adi, Greenwood, Edward JD, Deane, Janet E, Lehner, Paul J, and Matheson, Nicholas J
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Microbiology and Infectious Disease ,viruses ,virus diseases ,HIV ,cell cycle ,biochemical phenomena, metabolism, and nutrition ,Research Advance ,Vif ,3. Good health ,PP2A ,Virus - Abstract
The seminal description of the cellular restriction factor APOBEC3G and its antagonism by HIV-1 Vif has underpinned two decades of research on the host-virus interaction. We recently reported that HIV-1 Vif is also able to degrade the PPP2R5 family of regulatory subunits of key cellular phosphatase PP2A (PPP2R5A-E; Greenwood et al., 2016; Naamati et al., 2019). We now identify amino acid polymorphisms at positions 31 and 128 of HIV-1 Vif which selectively regulate the degradation of PPP2R5 family proteins. These residues covary across HIV-1 viruses in vivo, favouring depletion of PPP2R5A-E. Through analysis of point mutants and naturally occurring Vif variants, we further show that degradation of PPP2R5 family subunits is both necessary and sufficient for Vif-dependent G2/M cell cycle arrest. Antagonism of PP2A by HIV-1 Vif is therefore independent of APOBEC3 family proteins, and regulates cell cycle progression in HIV-infected cells.
113. Single-dose BNT162b2 vaccine protects against asymptomatic SARS-CoV-2 infection
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Jones, Nick K, Rivett, Lucy, Seaman, Shaun, Samworth, Richard J, Warne, Ben, Workman, Chris, Ferris, Mark, Wright, Jo, Quinnell, Natalie, Shaw, Ashley, Cambridge COVID-19 Collaboration, Goodfellow, Ian G, Lehner, Paul J, Howes, Rob, Wright, Giles, Matheson, Nicholas J, and Weekes, Michael P
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COVID-19 Vaccines ,SARS-CoV-2 ,infectious disease ,Health Personnel ,microbiology ,Vaccination ,Immunization, Secondary ,COVID-19 ,global health ,3. Good health ,asymptomatic ,Humans ,BNT162b2 ,Pfizer-BioNTech ,epidemiology ,human ,Asymptomatic Infections ,BNT162 Vaccine ,Immunization Schedule - Abstract
The BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech) is being utilised internationally for mass COVID-19 vaccination. Evidence of single-dose protection against symptomatic disease has encouraged some countries to opt for delayed booster doses of BNT162b2, but the effect of this strategy on rates of asymptomatic SARS-CoV-2 infection remains unknown. We previously demonstrated frequent pauci- and asymptomatic SARS-CoV-2 infection amongst healthcare workers (HCWs) during the UK's first wave of the COVID-19 pandemic, using a comprehensive PCR-based HCW screening programme (Rivett et al., 2020; Jones et al., 2020). Here, we evaluate the effect of first-dose BNT162b2 vaccination on test positivity rates and find a fourfold reduction in asymptomatic infection amongst HCWs ≥12 days post-vaccination. These data provide real-world evidence of short-term protection against asymptomatic SARS-CoV-2 infection following a single dose of BNT162b2 vaccine, suggesting that mass first-dose vaccination will reduce SARS-CoV-2 transmission, as well as the burden of COVID-19 disease.
114. Comparative Cell Surface Proteomic Analysis of the Primary Human T Cell and Monocyte Responses to Type I Interferon
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Soday, Lior, Potts, Martin, Hunter, Leah M, Ravenhill, Benjamin J, Houghton, Jack W, Williamson, James C, Antrobus, Robin, Wills, Mark R, Matheson, Nicholas J, and Weekes, Michael P
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quantitative proteomics ,CD4-Positive T-Lymphocytes ,Proteomics ,leukocytes ,antiviral restrictin ,T cell ,Interferon-alpha ,Endothelin-Converting Enzymes ,plasma membrane ,Monocytes ,3. Good health ,cell surface ,monocyte ,Humans ,type I interferon (IFN) - Abstract
The cellular response to interferon (IFN) is essential for antiviral immunity, IFN-based therapy and IFN-related disease. The plasma membrane (PM) provides a critical interface between the cell and its environment, and is the initial portal of entry for viruses. Nonetheless, the effect of IFN on PM proteins is surprisingly poorly understood, and has not been systematically investigated in primary immune cells. Here, we use multiplexed proteomics to quantify IFNα2a-stimulated PM protein changes in primary human CD14+ monocytes and CD4+ T cells from five donors, quantifying 606 and 482 PM proteins respectively. Comparison of cell surface proteomes revealed a remarkable invariance between donors in the overall composition of the cell surface from each cell type, but a marked donor-to-donor variability in the effects of IFNα2a. Furthermore, whereas only 2.7% of quantified proteins were consistently upregulated by IFNα2a at the surface of CD4+ T cells, 6.8% of proteins were consistently upregulated in primary monocytes, suggesting that the magnitude of the IFNα2a response varies according to cell type. Among these differentially regulated proteins, we found the viral target Endothelin-converting enzyme 1 (ECE1) to be an IFNα2a-stimulated protein exclusively upregulated at the surface of CD4+ T cells. We therefore provide a comprehensive map of the cell surface of IFNα2a-stimulated primary human immune cells, including previously uncharacterized interferon stimulated genes (ISGs) and candidate antiviral factors.
115. Spontaneous, persistent, T cell-dependent IFN-γ release in patients who progress to Long Covid.
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Krishna, Benjamin A., Lim, Eleanor Y., Metaxaki, Marina, Jackson, Sarah, Mactavous, Lenette, Lyons, Paul A., Doffinger, Rainer, Bradley, John R., Smith, Kenneth G. C., Sinclair, John, Matheson, Nicholas J., Lehner, Paul J., Sithole, Nyaradzai, and Wills, Mark R.
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POST-acute COVID-19 syndrome , *SARS-CoV-2 , *T cells , *MONONUCLEAR leukocytes , *PATIENT experience - Abstract
After acute infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV- 2), a proportion of patients experience persistent symptoms beyond 12 weeks, termed Long Covid. Understanding the mechanisms that cause this debilitating disease and identifying biomarkers for diagnostic, therapeutic, and monitoring purposes are urgently required. We detected persistently high levels of interferon-γ (IFN-γ) from peripheral blood mononuclear cells of patients with Long Covid using highly sensitive FluoroSpot assays. This IFN-γ release was seen in the absence of ex vivo peptide stimulation and remains persistently elevated in patients with Long Covid, unlike the resolution seen in patients recovering from acute SARS-CoV- 2 infection. The IFN-γ release was CD8+ T cell-mediated and dependent on antigen presentation by CD14+ cells. Longitudinal follow-up of our study cohort showed that symptom improvement and resolution correlated with a decrease in IFN-γ production to baseline levels. Our study highlights a potential mechanism underlying Long Covid, enabling the search for biomarkers and therapeutics in patients with Long Covid. [ABSTRACT FROM AUTHOR]
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- 2024
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116. GMC assessment of junior doctors' competency is inadequate or inconsistent.
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Matheson, Nicholas J., Burns, Alex, and Henderson, Katherine
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LETTERS to the editor , *PHYSICIANS - Abstract
Presents a letter to the editor in response to the article "Foundation programme for newly qualified doctors" in the Sept. 3, 2005 issue of "British Medical Journal."
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- 2005
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117. Evidence of inadequate intravenous fluid treatment in UK hospitals.
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Matheson, Nicholas J, Irani, Sarosh R, and Irani, Anushka
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LETTERS to the editor , *ACUTE kidney failure prevention - Abstract
A letter to the editor is presented in response to the article "Early Intervention in Acute Renal Failure," by D.N. Bennett-Jones in the August 26, 2006 issue.
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- 2006
118. Plasma membrane proteomics identifies Notch1as a potential regulator of ras-induced senescence
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Hoare, Matthew, Weekes, Michael P, Matheson, Nicholas J, Menon, Suraj, Antrobus, Robin, Lehner, Paul J, and Narita, Masashi
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BackgroundOncogene-induced senescence (OIS) is an intrinsic tumour suppressor mechanism leading to stable cell-cycle arrest in response to oncogene activation. OIS is a heterogeneous phenotype of multiple effector mechanisms; understanding of in-vivo OIS is lacking because of the difficulty in identifying senescence. We wished to establish a cell-surface phenotype of OIS.
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- 2013
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119. Neural stem cells traffic functional mitochondria via extracellular vesicles
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Erika Fernandez-Vizarra, Carlo Viscomi, Ágnes Kittel, Sisareuth Tan, Christian Frezza, Stefano Pluchino, Cristiane Benincá, Nunzio Vicario, Massimo Zeviani, Tommaso Leonardi, Ben Peacock, Paul J. Lehner, Alice Braga, Joshua D. Bernstock, Aletta Van Den Bosch, Jayden A. Smith, Karin H. Muller, Carlos Bastos, Edit I. Buzás, Luca Peruzzotti-Jametti, Giulia Manferrari, Cory M. Willis, Alain Brisson, Nunzio Iraci, Rebecca Rogall, Nuno Faria, Grzegorz Krzak, James C Williamson, Nicholas J Matheson, Iacopo Bicci, Chimie et Biologie des Membranes et des Nanoobjets (CBMN), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), European Project: 258803, Peruzzotti-Jametti, Luca [0000-0002-9396-5607], Bernstock, Joshua D [0000-0002-7814-3867], Willis, Cory M [0000-0001-7938-7276], Manferrari, Giulia [0000-0001-7062-1142], Rogall, Rebecca [0000-0003-0605-2322], Fernandez-Vizarra, Erika [0000-0002-2469-142X], Williamson, James C [0000-0002-2009-189X], Braga, Alice [0000-0003-3273-9742], van den Bosch, Aletta [0000-0001-8886-8928], Leonardi, Tommaso [0000-0002-4449-1863], Benincá, Cristiane [0000-0001-7933-860X], Vicario, Nunzio [0000-0001-5934-3962], Tan, Sisareuth [0000-0003-3633-6318], Bicci, Iacopo [0000-0001-6994-3857], Iraci, Nunzio [0000-0003-2146-9329], Smith, Jayden A [0000-0003-2307-8452], Peacock, Ben [0000-0002-7823-8719], Muller, Karin H [0000-0003-4693-8558], Brisson, Alain [0000-0003-0342-352X], Matheson, Nicholas J [0000-0002-3318-1851], Apollo - University of Cambridge Repository, Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Bernstock, Joshua D. [0000-0002-7814-3867], Willis, Cory M. [0000-0001-7938-7276], Williamson, James C. [0000-0002-2009-189X], Smith, Jayden A. [0000-0003-2307-8452], Muller, Karin H. [0000-0003-4693-8558], and Matheson, Nicholas J. [0000-0002-3318-1851]
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0301 basic medicine ,Central Nervous System ,Proteomics ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Cell Membranes ,Artificial Gene Amplification and Extension ,Mitochondrion ,Outer membrane proteins ,Inbred C57BL ,Exosomes ,Biochemistry ,Nervous System ,Transgenic ,White Blood Cells ,Database and Informatics Methods ,Mice ,0302 clinical medicine ,Neural Stem Cells ,Animal Cells ,Medicine and Health Sciences ,Computer software ,Biology (General) ,Energy-Producing Organelles ,Cells, Cultured ,Phagocytes ,Cultured ,Proteomic Databases ,General Neuroscience ,Neural stem cell ,Cell biology ,Mitochondria ,Polymerase chain reaction ,medicine.anatomical_structure ,Female ,Stem cell ,Cellular Structures and Organelles ,Cellular Types ,Anatomy ,General Agricultural and Biological Sciences ,Research Article ,QH301-705.5 ,Cells ,Immune Cells ,Central nervous system ,Immunology ,Green Fluorescent Proteins ,Mice, Transgenic ,Biology ,Bioenergetics ,Research and Analysis Methods ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Extracellular Vesicles ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Organelle ,medicine ,Animals ,Vesicles ,Molecular Biology Techniques ,Molecular Biology ,Blood Cells ,General Immunology and Microbiology ,Biology and Life Sciences ,Membrane Proteins ,Biological Transport ,Mesenchymal Stem Cells ,Cell Biology ,Microvesicles ,Transplantation ,Mice, Inbred C57BL ,030104 developmental biology ,Biological Databases ,030217 neurology & neurosurgery - Abstract
Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases., This study shows that neural stem cells are able to transfer functional mitochondria via extracellular vesicles to target cells both in vitro and in vivo, suggesting that functional mitochondrial transfer via extracellular vesicles is a signaling mechanism used by neural stem cells to modulate the physiology and metabolism of target cells.
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- 2021
120. Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report
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Matthew Buckland, Kenneth G. C. Smith, Jimstan Periselneris, Sorena Kiani-Alikhan, M. Estée Török, Luke W. Meredith, Paul A. Lyons, James Galloway, Stuart Bloor, Ane Ogbe, Nicholas J Matheson, Hossain Delowar Akther, Laura Bergamaschi, John Bradley, Erik J.M. Toonen, Lorinda Turner, Lourdes Ceron-Gutierrez, Sofia Grigoriadou, Ian Goodfellow, Lise J Estcourt, Joanne D. Stockton, Josh Quick, Carl Philipp Hackstein, Nicholas Screaton, Willem H. Ouwehand, Tiffeney Mann, Devan Vaghela, James Thaventhiran, Heli Harvala, Anna Yakovleva, Paul Klenerman, Rainer Doffinger, Ian B. Wilkinson, Nicholas J. Loman, Michael Hunter, Sara Lear, B. Paul Morgan, David J. Roberts, William L Hamilton, Peter Nelson, Paul J. Lehner, Vinicius A Vieira, Nicholas M. Provine, Caoimhe Nic Fhogartaigh, Frederica Mescia, Tanya I. Coulter, Lisa Devlin, Anna Smielewska, Wioleta M. Zelek, Buckland, Matthew S. [0000-0002-5646-4707], Ogbe, Ane [0000-0001-7774-7215], Mescia, Frederica [0000-0002-2759-4027], Toonen, Erik J. M. [0000-0001-9039-635X], Vieira, Vinicius Adriano [0000-0002-4901-0424], Kiani-Alikhan, Sorena [0000-0002-1299-4415], Ouwehand, Willem H. [0000-0002-7744-1790], Lyons, Paul A. [0000-0001-7035-8997], Lehner, Paul J. [0000-0001-9383-1054], Matheson, Nicholas J. [0000-0002-3318-1851], Thaventhiran, James E. D. [0000-0001-8616-074X], Apollo - University of Cambridge Repository, Buckland, Matthew S [0000-0002-5646-4707], Toonen, Erik JM [0000-0001-9039-635X], Ouwehand, Willem H [0000-0002-7744-1790], Lyons, Paul A [0000-0001-7035-8997], Lehner, Paul J [0000-0001-9383-1054], Matheson, Nicholas J [0000-0002-3318-1851], and Thaventhiran, James ED [0000-0001-8616-074X]
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0301 basic medicine ,Male ,692/699/249/2512 ,General Physics and Astronomy ,Drug resistance ,13/1 ,0302 clinical medicine ,Pandemic ,Medicine ,Multidisciplinary ,Alanine ,biology ,article ,Humoral ,Antivirals ,13/31 ,Treatment Outcome ,030220 oncology & carcinogenesis ,Primary immunodeficiency disorders ,631/326/596/1296 ,Antibody ,Adult ,Fever ,Science ,Antiviral Agents ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,692/699/255/2514 ,Immunity ,In vivo ,Humans ,Lymphocyte Count ,631/326/596/4130 ,Pneumonitis ,business.industry ,SARS-CoV-2 ,fungi ,COVID-19 ,General Chemistry ,medicine.disease ,Adenosine Monophosphate ,Complement system ,Immunity, Humoral ,030104 developmental biology ,Viral infection ,Humoral immunity ,Immunology ,biology.protein ,business - Abstract
The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients., Remdesivir is under evaluation for treatment of COVID-19 in clinical trials. Here, the authors report results of remdesivir treatment in a patient with COVID-19 and the genetic antibody deficiency XLA. They show a temporally correlated clinical and virological response, suggesting that remdesivir can reduce SARS-CoV-2 replication in patients.
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- 2020
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121. A protease-activatable luminescent biosensor and reporter cell line for authentic SARS-CoV-2 infection
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Pehuén Pereyra Gerber, Lidia M. Duncan, Edward JD Greenwood, Sara Marelli, Adi Naamati, Ana Teixeira-Silva, Thomas WM Crozier, Ildar Gabaev, Jun R. Zhan, Thomas E. Mulroney, Emily C. Horner, Rainer Doffinger, Anne E. Willis, James ED Thaventhiran, Anna V. Protasio, Nicholas J. Matheson, Greenwood, Edward Jd [0000-0002-5224-0263], Teixeira-Silva, Ana [0000-0002-9011-9501], Crozier, Thomas Wm [0000-0003-0951-4588], Zhan, Jun R [0000-0001-6904-7999], Horner, Emily C [0000-0003-2226-1028], Protasio, Anna V [0000-0003-1723-800X], Matheson, Nicholas J [0000-0002-3318-1851], Apollo - University of Cambridge Repository, Protasio, Anna [0000-0003-1723-800X], and Matheson, Nicholas [0000-0002-3318-1851]
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viruses ,Immunology ,FOS: Physical sciences ,Engineering and technology ,Biosensing Techniques ,Virus Replication ,Microbiology ,Cell Line ,Viral Proteins ,COVID-19 Testing ,Virology ,Genetics ,Humans ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,Medicine and health sciences ,Biology and life sciences ,SARS-CoV-2 ,COVID-19 ,FOS: Engineering and technology ,Research and analysis methods ,Physical sciences ,Luminescent Measurements ,Parasitology ,Research Article ,Peptide Hydrolases - Abstract
Funder: NIHR Cambridge BRC, Efforts to define serological correlates of protection against COVID-19 have been hampered by the lack of a simple, scalable, standardised assay for SARS-CoV-2 infection and antibody neutralisation. Plaque assays remain the gold standard, but are impractical for high-throughput screening. In this study, we show that expression of viral proteases may be used to quantitate infected cells. Our assays exploit the cleavage of specific oligopeptide linkers, leading to the activation of cell-based optical biosensors. First, we characterise these biosensors using recombinant SARS-CoV-2 proteases. Next, we confirm their ability to detect viral protease expression during replication of authentic virus. Finally, we generate reporter cells stably expressing an optimised luciferase-based biosensor, enabling viral infection to be measured within 24 h in a 96- or 384-well plate format, including variants of concern. We have therefore developed a luminescent SARS-CoV-2 reporter cell line, and demonstrated its utility for the relative quantitation of infectious virus and titration of neutralising antibodies.
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- 2022
122. Single-dose BNT162b2 vaccine protects against asymptomatic SARS-CoV-2 infection
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Jo Wright, Shaun R. Seaman, Rob Howes, Giles Wright, Mark Ferris, Paul J. Lehner, Ashley Shaw, Natalie Quinnell, Lucy Rivett, Nick K Jones, Richard J. Samworth, Michael P. Weekes, Chris Workman, Nicholas J Matheson, Ian Goodfellow, Ben Warne, Jones, Nick K [0000-0003-4475-7761], Rivett, Lucy [0000-0002-2781-9345], Goodfellow, Ian G [0000-0002-9483-510X], Lehner, Paul J [0000-0001-9383-1054], Matheson, Nicholas J [0000-0002-3318-1851], Weekes, Michael P [0000-0003-3196-5545], and Apollo - University of Cambridge Repository
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0301 basic medicine ,global health ,Disease ,0302 clinical medicine ,Pandemic ,Epidemiology ,Global health ,Medicine ,Biology (General) ,Asymptomatic Infections ,Microbiology and Infectious Disease ,Transmission (medicine) ,General Neuroscience ,Vaccination ,General Medicine ,3. Good health ,epidemiology ,medicine.symptom ,Human ,medicine.medical_specialty ,COVID-19 Vaccines ,QH301-705.5 ,Science ,infectious disease ,Health Personnel ,Immunization, Secondary ,Asymptomatic ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Internal medicine ,Humans ,asymptomatic ,Infectious disease (athletes) ,BNT162 Vaccine ,Immunization Schedule ,General Immunology and Microbiology ,SARS-CoV-2 ,business.industry ,microbiology ,COVID-19 ,Epidemiology and Global Health ,030104 developmental biology ,BNT162b2 ,Pfizer-BioNTech ,Research Advance ,business ,030217 neurology & neurosurgery - Abstract
The BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech) is being utilised internationally for mass COVID-19 vaccination. Evidence of single-dose protection against symptomatic disease has encouraged some countries to opt for delayed booster doses of BNT162b2, but the effect of this strategy on rates of asymptomatic SARS-CoV-2 infection remains unknown. We previously demonstrated frequent pauci- and asymptomatic SARS-CoV-2 infection amongst healthcare workers (HCWs) during the UK’s first wave of the COVID-19 pandemic, using a comprehensive PCR-based HCW screening programme (Rivett et al., 2020; Jones et al., 2020). Here, we evaluate the effect of first-dose BNT162b2 vaccination on test positivity rates and find a fourfold reduction in asymptomatic infection amongst HCWs ≥12 days post-vaccination. These data provide real-world evidence of short-term protection against asymptomatic SARS-CoV-2 infection following a single dose of BNT162b2 vaccine, suggesting that mass first-dose vaccination will reduce SARS-CoV-2 transmission, as well as the burden of COVID-19 disease.
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- 2021
123. Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma
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David A. Tuveson, Nicholas J Matheson, Giulia Biffi, Evan C. Lien, Alicia M. Darnell, Laura V. Danai, Tyler Jacks, Shawn M. Davidson, Matthew G. Vander Heiden, Kiera M. Sapp, Ömer H. Yilmaz, Vasilena Gocheva, Sharanya Sivanand, Anna M. Westermark, Zhaoqi Li, Christopher R. Chin, Allison N. Lau, Raphael Ferreira, Jared R. Mayers, Lau, Allison N [0000-0003-4250-7355], Ferreira, Raphael [0000-0001-9881-6232], Mayers, Jared R [0000-0002-8607-1787], Matheson, Nicholas J [0000-0002-3318-1851], Vander Heiden, Matthew G [0000-0002-6702-4192], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Male ,Cell type ,Mouse ,QH301-705.5 ,Science ,Population ,pancreatic cancer ,pyruvate carboxylase ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Pancreatic cancer ,Organoid ,medicine ,Tumor Microenvironment ,Animals ,Biology (General) ,Fibroblast ,education ,Cancer Biology ,education.field_of_study ,malic enzyme 1 ,General Immunology and Microbiology ,Chemistry ,General Neuroscience ,PDAC ,General Medicine ,metabolic heterogeneity ,medicine.disease ,Pyruvate carboxylase ,Cell biology ,Mice, Inbred C57BL ,Pancreatic Neoplasms ,030104 developmental biology ,medicine.anatomical_structure ,organoid culture ,030220 oncology & carcinogenesis ,Cancer cell ,Medicine ,Female ,Carcinoma, Pancreatic Ductal ,Research Article - Abstract
Funder: Jane Coffin Childs Memorial Fund for Medical Research; FundRef: http://dx.doi.org/10.13039/100001033, Funder: Swedish Foundation for Strategic Research; FundRef: http://dx.doi.org/10.13039/501100001729, Funder: Knut and Alice Wallenberg Foundation; FundRef: http://dx.doi.org/10.13039/501100004063, Funder: Barbro Osher Pro Suecia Foundation; FundRef: http://dx.doi.org/10.13039/100008483, Funder: Howard Hughes Medical Institute; FundRef: http://dx.doi.org/10.13039/100000011, Funder: NIHR Cambridge BRC, Funder: Lustgarten Foundation; FundRef: http://dx.doi.org/10.13039/100005979, Funder: Stand Up To Cancer; FundRef: http://dx.doi.org/10.13039/100009730, Funder: MIT Center for Precision Cancer Medicine, Funder: Ludwig Center at MIT, Funder: Emerald Foundation, Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue.
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- 2020
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124. Effective control of SARS-CoV-2 transmission between healthcare workers during a period of diminished community prevalence of COVID-19
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Jones, N. K., Rivett, L., Sparkes, D., Forrest, S., Sridhar, S., Young, J., Pereira-Dias, J., Cormie, C., Gill, H., Reynolds, N., Wantoch, M., Routledge, M., Warne, B., Levy, J., Jimenez, W. D. C., Samad, F. N. B., Mcnicholas, C., Ferris, M., Gray, J., Gill, M., Curran, M. D., Fuller, S., Chaudhry, A., Shaw, A., Bradley, J. R., Hannon, G. J., Goodfellow, I. G., Dougan, G., Smith, K. G. C., Lehner, P. J., Wright, G., Matheson, N. J., Baker, S., Weekes, M. P., Bradley, J., Goodfellow, I., Gupta, R., Lyons, P. A., Torok, M. E., Toshner, M., Kean, I., Caddy, S., Caller, L., Feltwell, T., Hall, G., Hamilton, W., Hosmillo, M., Houldcroft, C., Jahun, A., Khokhar, F., Meredith, L., Yakovleva, A., Butcher, H., Caputo, D., Clapham-Riley, D., Dolling, H., Furlong, A., Graves, B., Gresley, E. L., Kingston, N., Papadia, S., Stark, H., Stirrups, K. E., Webster, J., Calder, J., Harris, J., Hewitt, S., Kennet, J., Meadows, A., Rastall, R., Brien, C. O., Price, J., Publico, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Hannon, G., Brookes, K., Canna, L., Cruz, I., Dempsey, K., Elmer, A., Escoffery, N., Jones, H., Ribeiro, C., Saunders, C., Wright, A., Nyagumbo, R., Roberts, A., Bucke, A., Hargreaves, S., Johnson, D., Narcorda, A., Read, D., Sparke, C., Worboys, L., Lagadu, K., Mactavous, L., Gould, T., Raine, T., Mather, C., Ramenatte, N., Vallier, A. -L., Kasanicki, M., Eames, P. -J., Thake, L., Bartholomew, N., Brown, N., Curran, M., Parmar, S., Zhang, H., Bowring, A., Martell, G., Quinnell, N., Wright, J., Murphy, H., Dunmore, B. J., Legchenko, E., Graf, S., Huang, C., Hodgson, J., Hunter, K., Martin, J., Mescia, F., Odonnell, C., Pointon, L., Shih, J., Sutcliffe, R., Tilly, T., Tong, Z., Treacy, C., Wood, J., Bergamaschi, L., Betancourt, A., Bowyer, G., De Sa, A., Epping, M., Hinch, A., Huhn, O., Jarvis, I., Lewis, D., Marsden, J., Mccallum, S., Nice, F., Omarjee, O., Perera, M., Romashova, N., Strezlecki, M., Yarkoni, N. S., Turner, L., Bailey, B., Doughton, R., Workman, C., Trotter, C., David, W., Jimenez, C., Jones, Nick K [0000-0003-4475-7761], Sridhar, Sushmita [0000-0001-7453-7482], Hannon, Gregory J [0000-0003-4021-3898], Goodfellow, Ian G [0000-0002-9483-510X], Lehner, Paul J [0000-0001-9383-1054], Matheson, Nicholas J [0000-0002-3318-1851], Weekes, Michael P [0000-0003-3196-5545], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Male ,Infectious Disease Transmission ,global health ,Occupational safety and health ,Hospitals, University ,Patient-to-Professional ,0302 clinical medicine ,COVID-19 Testing ,Patient Admission ,Nasopharynx ,Pandemic ,Epidemiology ,Prevalence ,Medicine ,Infection control ,Mass Screening ,030212 general & internal medicine ,Viral ,Biology (General) ,Family Characteristics ,General Neuroscience ,Infectious ,human biology ,virus diseases ,General Medicine ,Middle Aged ,Hospitals ,3. Good health ,virology ,Community-Acquired Infections ,Occupational Diseases ,England ,epidemiology ,Female ,medicine.symptom ,Symptom Assessment ,Coronavirus Infections ,Hospital Units ,Adult ,medicine.medical_specialty ,Infectious Disease Transmission, Patient-to-Professional ,QH301-705.5 ,Health Personnel ,infectious disease ,Science ,Pneumonia, Viral ,Real-Time Polymerase Chain Reaction ,Asymptomatic ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Betacoronavirus ,Disease Transmission ,Disease Transmission, Infectious ,Humans ,human ,Human Biology and Medicine ,Hospitals, Teaching ,Pandemics ,Mass screening ,Asymptomatic Diseases ,emerging pathogens ,University ,Infection Control ,General Immunology and Microbiology ,business.industry ,Clinical Laboratory Techniques ,SARS-CoV-2 ,Teaching ,COVID-19 ,Pneumonia ,medicine ,occupational health ,Contact Tracing ,Program Evaluation ,030104 developmental biology ,Epidemiology and Global Health ,Emergency medicine ,business ,Research Advance ,Contact tracing - Abstract
Previously, we showed that 3% (31/1032)of asymptomatic healthcare workers (HCWs) from a large teaching hospital in Cambridge, UK, tested positive for SARS-CoV-2 in April 2020. About 15% (26/169) HCWs with symptoms of coronavirus disease 2019 (COVID-19) also tested positive for SARS-CoV-2 (Rivett et al., 2020). Here, we show that the proportion of both asymptomatic and symptomatic HCWs testing positive for SARS-CoV-2 rapidly declined to near-zero between 25th April and 24th May 2020, corresponding to a decline in patient admissions with COVID-19 during the ongoing UK ‘lockdown’. These data demonstrate how infection prevention and control measures including staff testing may help prevent hospitals from becoming independent ‘hubs’ of SARS-CoV-2 transmission, and illustrate how, with appropriate precautions, organizations in other sectors may be able to resume on-site work safely.
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- 2020
125. Antagonism of PP2A is an independent and conserved function of HIV-1 Vif and causes cell cycle arrest
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Paul J. Lehner, Edward J. D. Greenwood, Janet E. Deane, Sara Marelli, Anna V. Protasio, Adi Naamati, James C Williamson, Nicholas J Matheson, Greenwood, Edward Jd [0000-0002-5224-0263], Deane, Janet E [0000-0002-4863-0330], Lehner, Paul J [0000-0001-9383-1054], Matheson, Nicholas J [0000-0002-3318-1851], Apollo - University of Cambridge Repository, and Greenwood, Edward JD [0000-0002-5224-0263]
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Cell cycle checkpoint ,QH301-705.5 ,Science ,viruses ,infectious disease ,Phosphatase ,Mutant ,virus ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,vif Gene Products, Human Immunodeficiency Virus ,Humans ,Point Mutation ,APOBEC Deaminases ,Protein Phosphatase 2 ,Biology (General) ,APOBEC3G ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Microbiology and Infectious Disease ,General Immunology and Microbiology ,Host Microbial Interactions ,General Neuroscience ,030302 biochemistry & molecular biology ,microbiology ,virus diseases ,HIV ,General Medicine ,Protein phosphatase 2 ,Cell Cycle Checkpoints ,Cell cycle ,biochemical phenomena, metabolism, and nutrition ,Flow Cytometry ,Vif ,3. Good health ,Cell biology ,Amino acid ,PP2A ,chemistry ,HIV-1 ,Medicine ,cell cycle ,Antagonism ,Research Advance ,Function (biology) - Abstract
The seminal description of cellular restriction factor APOBEC3G and its antagonism by HIV-1 Vif has underpinned two decades of research on the host-virus interaction. As well as APOBEC3G and its homologues, however, we have recently discovered that Vif is also able to degrade the PPP2R5 family of regulatory subunits of key cellular phosphatase PP2A (PPP2R5A-E) (Greenwood et al., 2016; Naamati et al., 2019). We now identify amino acid polymorphisms at positions 31 and 128 of HIV-1 Vif which selectively regulate the degradation of PPP2R5 family proteins. These residues covary across HIV-1 virusesin vivo, favouring depletion of PPP2R5A-E. Through analysis of point mutants and naturally occurring Vif variants, we further show that degradation of PPP2R5 family subunits is both necessary and sufficient for Vif-dependent G2/M cell cycle arrest. Antagonism of PP2A by HIV-1 Vif is therefore independent of APOBEC3 family proteins, and regulates cell cycle progression in HIV-infected cells.
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- 2020
126. Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission
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Rivett, L., Sridhar, S., Sparkes, D., Routledge, M., Jones, N. K., Forrest, S., Young, J., Pereira-Dias, J., Hamilton, W. L., Ferris, M., Torok, M. E., Meredith, L., Curran, M. D., Fuller, S., Chaudhry, A., Shaw, A., Samworth, R. J., Bradley, J. R., Dougan, G., Smith, K. G. C., Lehner, P. J., Matheson, N. J., Wright, G., Goodfellow, I. G., Baker, S., Weekes, M. P., Lyons, P. A., Toshner, M., Warne, B., Scott, J. B., Cormie, C., Gill, H., Kean, I., Maes, M., Reynolds, N., Wantoch, M., Caddy, S., Caller, L., Feltwell, T., Hall, G., Hosmillo, M., Houldcroft, C., Jahun, A., Khokhar, F., Yakovleva, A., Butcher, H., Caputo, D., Clapham-Riley, D., Dolling, H., Furlong, A., Graves, B., Gresley, E. L., Kingston, N., Papadia, S., Stark, H., Stirrups, K. E., Webster, J., Calder, J., Harris, J., Hewitt, S., Kennet, J., Meadows, A., Rastall, R., Brien, C. O., Price, J., Publico, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Brookes, K., Canna, L., Cruz, I., Dempsey, K., Elmer, A., Escoffery, N., Jones, H., Ribeiro, C., Saunders, C., Wright, A., Nyagumbo, R., Roberts, A., Bucke, A., Hargreaves, S., Johnson, D., Narcorda, A., Read, D., Sparke, C., Warboys, L., Lagadu, K., Mactavous, L., Gould, T., Raine, T., Mather, C., Ramenatte, N., Vallier, A. -L., Kasanicki, M., Eames, P. -J., Mcnicholas, C., Thake, L., Bartholomew, N., Brown, N., Parmar, S., Zhang, H., Bowring, A., Martell, G., Quinnell, N., Wright, J., Murphy, H., Dunmore, B. J., Legchenko, E., Graf, S., Huang, C., Hodgson, J., Hunter, K., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Shih, J., Sutcliffe, R., Tilly, T., Tong, Z., Treacy, C., Wood, J., Bergamaschi, L., Betancourt, A., Bowyer, G., A. D., Sa, Epping, M., Hinch, A., Huhn, O., Jarvis, I., Lewis, D., Marsden, J., Mccallum, S., Nice, F., Rivett, Lucy [0000-0002-2781-9345], Lehner, Paul J [0000-0001-9383-1054], Matheson, Nicholas J [0000-0002-3318-1851], Goodfellow, Ian G [0000-0002-9483-510X], Weekes, Michael P [0000-0003-3196-5545], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Male ,medicine ,global health ,0302 clinical medicine ,COVID-19 Testing ,Epidemiology ,Pandemic ,Health care ,Infection control ,030212 general & internal medicine ,Viral ,Biology (General) ,Asymptomatic Infections ,Nose ,0303 health sciences ,Transmission (medicine) ,COVID-19 ,SARS-CoV-2 ,emerging pathogens ,epidemiology ,human ,human biology ,infectious disease ,occupational health ,virology ,virus ,Betacoronavirus ,COVID-19 Vaccines ,Coronavirus Infections ,Female ,Humans ,Infection Control ,Pandemics ,Pneumonia, Viral ,Real-Time Polymerase Chain Reaction ,United Kingdom ,Clinical Laboratory Techniques ,Health Personnel ,General Neuroscience ,virus diseases ,General Medicine ,3. Good health ,medicine.anatomical_structure ,medicine.symptom ,Research Article ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,QH301-705.5 ,Science ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,education ,Asymptomatic ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Internal medicine ,Throat ,Infectious disease (athletes) ,Human Biology and Medicine ,030304 developmental biology ,General Immunology and Microbiology ,business.industry ,Pneumonia ,030104 developmental biology ,Epidemiology and Global Health ,Carriage ,business - Abstract
Significant differences exist in the availability of healthcare worker (HCW) SARS-CoV-2 testing between countries, and existing programmes focus on screening symptomatic rather than asymptomatic staff. Over a 3 week period (April 2020), 1032 asymptomatic HCWs were screened for SARS-CoV-2 in a large UK teaching hospital. Symptomatic staff and symptomatic household contacts were additionally tested. Real-time RT-PCR was used to detect viral RNA from a throat+nose self-swab. 3% of HCWs in the asymptomatic screening group tested positive for SARS-CoV-2. 17/30 (57%) were truly asymptomatic/pauci-symptomatic. 12/30 (40%) had experienced symptoms compatible with coronavirus disease 2019 (COVID-19)>7 days prior to testing, most self-isolating, returning well. Clusters of HCW infection were discovered on two independent wards. Viral genome sequencing showed that the majority of HCWs had the dominant lineage B∙1. Our data demonstrates the utility of comprehensive screening of HCWs with minimal or no symptoms. This approach will be critical for protecting patients and hospital staff., eLife digest Patients admitted to NHS hospitals are now routinely screened for SARS-CoV-2 (the virus that causes COVID-19), and isolated from other patients if necessary. Yet healthcare workers, including frontline patient-facing staff such as doctors, nurses and physiotherapists, are only tested and excluded from work if they develop symptoms of the illness. However, there is emerging evidence that many people infected with SARS-CoV-2 never develop significant symptoms: these people will therefore be missed by ‘symptomatic-only’ testing. There is also important data showing that around half of all transmissions of SARS-CoV-2 happen before the infected individual even develops symptoms. This means that much broader testing programs are required to spot people when they are most infectious. Rivett, Sridhar, Sparkes, Routledge et al. set out to determine what proportion of healthcare workers was infected with SARS-CoV-2 while also feeling generally healthy at the time of testing. Over 1,000 staff members at a large UK hospital who felt they were well enough to work, and did not fit the government criteria for COVID-19 infection, were tested. Amongst these, 3% were positive for SARS-CoV-2. On closer questioning, around one in five reported no symptoms, two in five very mild symptoms that they had dismissed as inconsequential, and a further two in five reported COVID-19 symptoms that had stopped more than a week previously. In parallel, healthcare workers with symptoms of COVID-19 (and their household contacts) who were self-isolating were also tested, in order to allow those without the virus to quickly return to work and bolster a stretched workforce. Finally, the rates of infection were examined to probe how the virus could have spread through the hospital and among staff – and in particular, to understand whether rates of infection were greater among staff working in areas devoted to COVID-19 patients. Despite wearing appropriate personal protective equipment, healthcare workers in these areas were almost three times more likely to test positive than those working in areas without COVID-19 patients. However, it is not clear whether this genuinely reflects greater rates of patients passing the infection to staff. Staff may give the virus to each other, or even acquire it at home. Overall, this work implies that hospitals need to be vigilant and introduce broad screening programmes across their workforces. It will be vital to establish such approaches before ‘lockdown’ is fully lifted, so healthcare institutions are prepared for any second peak of infections.
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- 2020
127. Functional proteomic atlas of HIV-infection in primary human CD4+ T cells
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Paul J. Lehner, Sara Marelli, Adi Naamati, James C Williamson, Edward J. D. Greenwood, Nicholas J Matheson, Greenwood, Edward Jd [0000-0002-5224-0263], Lehner, Paul J [0000-0001-9383-1054], Matheson, Nicholas J [0000-0002-3318-1851], and Apollo - University of Cambridge Repository
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CD4-Positive T-Lymphocytes ,Proteomics ,Proteome ,Viral pathogenesis ,viruses ,Human immunodeficiency virus (HIV) ,Host factors ,HIV Infections ,Cell Separation ,medicine.disease_cause ,Lymphocyte Activation ,Virus Replication ,Cellular protein ,immunology ,Fragile X Mental Retardation Protein ,0302 clinical medicine ,vif Gene Products, Human Immunodeficiency Virus ,Cluster Analysis ,Biology (General) ,Cellular proteins ,0303 health sciences ,virus diseases ,Hydrogen-Ion Concentration ,3. Good health ,DNA-Binding Proteins ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Medicine ,Protein Binding ,Cell physiology ,QH301-705.5 ,Science ,T cell ,infectious disease ,Green Fluorescent Proteins ,virus ,Biology ,Virus ,primary human CD4+ T cell ,03 medical and health sciences ,Magnetics ,medicine ,Humans ,human ,030304 developmental biology ,magnetic cell selection ,microbiology ,Lentivirus ,HIV ,Protein Tyrosine Phosphatase, Non-Receptor Type 22 ,Methyltransferases ,Virology ,Gene Expression Regulation ,inflammation ,HIV-1 ,Streptavidin - Abstract
Viruses manipulate host cells to enhance their replication, and the identification of host factors targeted by viruses has led to key insights in both viral pathogenesis and cellular physiology. We previously described global changes in cellular protein levels during human immunodeficiency virus (HIV) infection using transformed CEM-T4 T cells as a model. In this study, we develop an HIV reporter virus displaying a streptavidin-binding affinity tag at the surface of infected cells, allowing facile one-step selection with streptavidin-conjugated magnetic beads. We use this system to obtain pure populations of HIV-infected primary human CD4+ T cells for detailed proteomic analysis, including quantitation of >9,000 proteins across 4 different donors, and temporal profiling during T cell activation. Remarkably, amongst 650 cellular proteins significantly perturbed during HIV infection of primary T cells (q
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- 2018
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128. Integrative functional genomics decodes herpes simplex virus 1
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Adam W. Whisnant, Christopher S. Jürges, Thomas Hennig, Emanuel Wyler, Bhupesh Prusty, Andrzej J. Rutkowski, Anne L’hernault, Lara Djakovic, Margarete Göbel, Kristina Döring, Jennifer Menegatti, Robin Antrobus, Nicholas J. Matheson, Florian W. H. Künzig, Guido Mastrobuoni, Chris Bielow, Stefan Kempa, Chunguang Liang, Thomas Dandekar, Ralf Zimmer, Markus Landthaler, Friedrich Grässer, Paul J. Lehner, Caroline C. Friedel, Florian Erhard, Lars Dölken, Whisnant, Adam W. [0000-0003-2039-2809], Jürges, Christopher S. [0000-0001-5617-6601], Wyler, Emanuel [0000-0002-9884-1806], Prusty, Bhupesh [0000-0001-7051-4670], Djakovic, Lara [0000-0002-9368-9403], Matheson, Nicholas J. [0000-0002-3318-1851], Künzig, Florian W. H. [0000-0003-3730-3905], Mastrobuoni, Guido [0000-0003-4509-1295], Bielow, Chris [0000-0001-5756-3988], Kempa, Stefan [0000-0002-0696-9299], Liang, Chunguang [0000-0002-0305-2522], Dandekar, Thomas [0000-0003-1886-7625], Landthaler, Markus [0000-0002-1075-8734], Friedel, Caroline C. [0000-0003-3569-4877], Erhard, Florian [0000-0002-3574-6983], Dölken, Lars [0000-0002-4651-3544], and Apollo - University of Cambridge Repository
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Cancer Research ,Science ,viruses ,article ,49/39 ,38/91 ,Cardiovascular and Metabolic Diseases ,631/326/596/1553 ,ddc:570 ,lcsh:Q ,ddc:610 ,631/114 ,Technology Platforms ,lcsh:Science - Abstract
The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDA-approved oncolytic virus Imlygic. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of ORFs as well as N-terminal extensions (NTEs) and truncations. We show that NTEs with non-canonical start codons govern the subcellular protein localization and packaging of key viral regulators and structural proteins. We extend the current nomenclature to include all viral gene products and provide a genome browser that visualizes all the obtained data from whole genome to single-nucleotide resolution. Here, using computational integration of multi-omics data, the authors provide a detailed transcriptome and translatome of herpes simplex virus 1 (HSV-1), including previously unidentified ORFs and N-terminal extensions. The study also provides a HSV-1 genome browser and should be a valuable resource for further research.
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129. Rapid discovery of monoclonal antibodies by microfluidics-enabled FACS of single pathogen-specific antibody-secreting cells.
- Author
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Fischer K, Lulla A, So TY, Pereyra-Gerber P, Raybould MIJ, Kohler TN, Yam-Puc JC, Kaminski TS, Hughes R, Pyeatt GL, Leiss-Maier F, Brear P, Matheson NJ, Deane CM, Hyvönen M, Thaventhiran JED, and Hollfelder F
- Abstract
Monoclonal antibodies are increasingly used to prevent and treat viral infections and are pivotal in pandemic response efforts. Antibody-secreting cells (ASCs; plasma cells and plasmablasts) are an excellent source of high-affinity antibodies with therapeutic potential. Current methods to study antigen-specific ASCs either have low throughput, require expensive and labor-intensive screening or are technically demanding and therefore not widely accessible. Here we present a straightforward technology for the rapid discovery of monoclonal antibodies from ASCs. Our approach combines microfluidic encapsulation of single cells into an antibody capture hydrogel with antigen bait sorting by conventional flow cytometry. With our technology, we screened millions of mouse and human ASCs and obtained monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 with high affinity (<1 pM) and neutralizing capacity (<100 ng ml
-1 ) in 2 weeks with a high hit rate (>85% of characterized antibodies bound the target). By facilitating access to the underexplored ASC compartment, the approach enables efficient antibody discovery and immunological studies into the generation of protective antibodies., (© 2024. The Author(s).)- Published
- 2024
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130. Stability of gut microbiome after COVID-19 vaccination in healthy and immuno-compromised individuals.
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Boston RH, Guan R, Kalmar L, Beier S, Horner EC, Beristain-Covarrubias N, Yam-Puc JC, Pereyra Gerber P, Faria L, Kuroshchenkova A, Lindell AE, Blasche S, Correa-Noguera A, Elmer A, Saunders C, Bermperi A, Jose S, Kingston N, Grigoriadou S, Staples E, Buckland MS, Lear S, Matheson NJ, Benes V, Parkinson C, Thaventhiran JE, and Patil KR
- Subjects
- Humans, COVID-19 Vaccines, Vaccination, Gastrointestinal Microbiome, COVID-19 prevention & control, Neoplasms
- Abstract
Bidirectional interactions between the immune system and the gut microbiota are key contributors to various physiological functions. Immune-associated diseases such as cancer and autoimmunity, and efficacy of immunomodulatory therapies, have been linked to microbiome variation. Although COVID-19 infection has been shown to cause microbial dysbiosis, it remains understudied whether the inflammatory response associated with vaccination also impacts the microbiota. Here, we investigate the temporal impact of COVID-19 vaccination on the gut microbiome in healthy and immuno-compromised individuals; the latter included patients with primary immunodeficiency and cancer patients on immunomodulating therapies. We find that the gut microbiome remained remarkably stable post-vaccination irrespective of diverse immune status, vaccine response, and microbial composition spanned by the cohort. The stability is evident at all evaluated levels including diversity, phylum, species, and functional capacity. Our results indicate the resilience of the gut microbiome to host immune changes triggered by COVID-19 vaccination and suggest minimal, if any, impact on microbiome-mediated processes. These findings encourage vaccine acceptance, particularly when contrasted with the significant microbiome shifts observed during COVID-19 infection., (© 2024 Boston et al.)
- Published
- 2024
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- View/download PDF
131. Screening in serum-derived medium reveals differential response to compounds targeting metabolism.
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Abbott KL, Ali A, Casalena D, Do BT, Ferreira R, Cheah JH, Soule CK, Deik A, Kunchok T, Schmidt DR, Renner S, Honeder SE, Wu M, Chan SH, Tseyang T, Greaves D, Hsu PP, Ng CW, Zhang CJ, Farsidjani A, Gramatikov IMT, Matheson NJ, Lewis CA, Clish CB, Rees MG, Roth JA, Griner LM, Muir A, Auld DS, and Heiden MGV
- Abstract
A challenge for screening new candidate drugs to treat cancer is that efficacy in cell culture models is not always predictive of efficacy in patients. One limitation of standard cell culture is a reliance on non-physiological nutrient levels to propagate cells. Which nutrients are available can influence how cancer cells use metabolism to proliferate and impact sensitivity to some drugs, but a general assessment of how physiological nutrients affect cancer cell response to small molecule therapies is lacking. To enable screening of compounds to determine how the nutrient environment impacts drug efficacy, we developed a serum-derived culture medium that supports the proliferation of diverse cancer cell lines and is amenable to high-throughput screening. We used this system to screen several small molecule libraries and found that compounds targeting metabolic enzymes were enriched as having differential efficacy in standard compared to serum-derived medium. We exploited the differences in nutrient levels between each medium to understand why medium conditions affected the response of cells to some compounds, illustrating how this approach can be used to screen potential therapeutics and understand how their efficacy is modified by available nutrients.
- Published
- 2023
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132. Attenuated humoral responses in HIV infection after SARS-CoV-2 vaccination are linked to global B cell defects and cellular immune profiles.
- Author
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Touizer E, Alrubbayi A, Ford R, Hussain N, Gerber PP, Shum HL, Rees-Spear C, Muir L, Gea-Mallorquí E, Kopycinski J, Jankovic D, Pinder C, Fox TA, Williams I, Mullender C, Maan I, Waters L, Johnson M, Madge S, Youle M, Barber T, Burns F, Kinloch S, Rowland-Jones S, Gilson R, Matheson NJ, Morris E, Peppa D, and McCoy LE
- Abstract
People living with HIV (PLWH) on suppressive antiretroviral therapy (ART) can have residual immune dysfunction and often display poorer responses to vaccination. We assessed in a cohort of PLWH (n=110) and HIV negative controls (n=64) the humoral and spike-specific B-cell responses following 1, 2 or 3 SARS-CoV-2 vaccine doses. PLWH had significantly lower neutralizing antibody (nAb) titers than HIV-negative controls at all studied timepoints. Moreover, their neutralization breadth was reduced with fewer individuals developing a neutralizing response against the Omicron variant (BA.1) relative to controls. We also observed a delayed development of neutralization in PLWH that was underpinned by a reduced frequency of spike-specific memory B cells (MBCs) and pronounced B cell dysfunction. Improved neutralization breadth was seen after the third vaccine dose in PLWH but lower nAb responses persisted and were associated with global, but not spike-specific, MBC dysfunction. In contrast to the inferior antibody responses, SARS-CoV-2 vaccination induced robust T cell responses that cross-recognized variants in PLWH. Strikingly, a subset of PLWH with low or absent neutralization had detectable functional T cell responses. These individuals had reduced numbers of circulating T follicular helper cells and an enriched population of CXCR3
+ CD127+ CD8+ T cells after two doses of SARS-CoV-2 vaccination, which may compensate for sub-optimal serological responses in the event of infection. Therefore, normalisation of B cell homeostasis could improve serological responses to vaccines in PLWH and evaluating T cell immunity could provide a more comprehensive immune status profile in these individuals and others with B cell imbalances.- Published
- 2022
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133. B cell receptor repertoire kinetics after SARS-CoV-2 infection and vaccination.
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Kotagiri P, Mescia F, Rae WM, Bergamaschi L, Tuong ZK, Turner L, Hunter K, Gerber PP, Hosmillo M, Hess C, Clatworthy MR, Goodfellow IG, Matheson NJ, McKinney EF, Wills MR, Gupta RK, Bradley JR, Bashford-Rogers RJM, Lyons PA, and Smith KGC
- Subjects
- B-Lymphocytes immunology, BNT162 Vaccine immunology, COVID-19 prevention & control, Clonal Evolution, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Heavy Chains immunology, Immunoglobulin Isotypes genetics, Immunoglobulin Isotypes immunology, Immunoglobulin Variable Region genetics, Immunoglobulin Variable Region immunology, Kinetics, Receptors, Antigen, B-Cell genetics, SARS-CoV-2 immunology, Severity of Illness Index, Somatic Hypermutation, Immunoglobulin immunology, Spike Glycoprotein, Coronavirus immunology, COVID-19 immunology, Receptors, Antigen, B-Cell immunology, Vaccination
- Abstract
B cells are important in immunity to both severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and vaccination, but B cell receptor (BCR) repertoire development in these contexts has not been compared. We analyze serial samples from 171 SARS-CoV-2-infected individuals and 63 vaccine recipients and find the global BCR repertoire differs between them. Following infection, immunoglobulin (Ig)G1/3 and IgA1 BCRs increase, somatic hypermutation (SHM) decreases, and, in severe disease, IgM and IgA clones are expanded. In contrast, after vaccination, the proportion of IgD/M BCRs increase, SHM is unchanged, and expansion of IgG clones is prominent. VH1-24, which targets the N-terminal domain (NTD) and contributes to neutralization, is expanded post infection except in the most severe disease. Infection generates a broad distribution of SARS-CoV-2-specific clones predicted to target the spike protein, while a more focused response after vaccination mainly targets the spike's receptor-binding domain. Thus, the nature of SARS-CoV-2 exposure differentially affects BCR repertoire development, potentially informing vaccine strategies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)
- Published
- 2022
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134. Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission.
- Author
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Aggarwal D, Warne B, Jahun AS, Hamilton WL, Fieldman T, du Plessis L, Hill V, Blane B, Watkins E, Wright E, Hall G, Ludden C, Myers R, Hosmillo M, Chaudhry Y, Pinckert ML, Georgana I, Izuagbe R, Leek D, Nsonwu O, Hughes GJ, Packer S, Page AJ, Metaxaki M, Fuller S, Weale G, Holgate J, Brown CA, Howes R, McFarlane D, Dougan G, Pybus OG, Angelis D, Maxwell PH, Peacock SJ, Weekes MP, Illingworth C, Harrison EM, Matheson NJ, and Goodfellow IG
- Subjects
- COVID-19 prevention & control, COVID-19 virology, Contact Tracing, Genome, Viral genetics, Genomics, Humans, Phylogeny, RNA, Viral genetics, Risk Factors, SARS-CoV-2 classification, SARS-CoV-2 isolation & purification, Students, United Kingdom epidemiology, COVID-19 epidemiology, COVID-19 transmission, SARS-CoV-2 genetics, Universities statistics & numerical data
- Abstract
Understanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics., (© 2022. The Author(s).)
- Published
- 2022
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- View/download PDF
135. Increased demand for NAD + relative to ATP drives aerobic glycolysis.
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Luengo A, Li Z, Gui DY, Sullivan LB, Zagorulya M, Do BT, Ferreira R, Naamati A, Ali A, Lewis CA, Thomas CJ, Spranger S, Matheson NJ, and Vander Heiden MG
- Subjects
- A549 Cells, Adenosine Triphosphate genetics, Aerobiosis, Glucose genetics, HeLa Cells, Humans, NAD genetics, Oxidation-Reduction, Adenosine Triphosphate metabolism, Glucose metabolism, Glycolysis, NAD metabolism
- Abstract
Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation across many organisms and conditions. To better understand that association, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the NAD
+ /NADH ratio. This change in NAD+ /NADH is caused by increased mitochondrial membrane potential that impairs mitochondrial electron transport and NAD+ regeneration. Uncoupling respiration from ATP synthesis or increasing ATP hydrolysis restores NAD+ /NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when demand for NAD+ to support oxidation reactions exceeds the rate of ATP turnover in cells, NAD+ regeneration by mitochondrial respiration becomes constrained, promoting fermentation, despite available oxygen. This argues that cells engage in aerobic glycolysis when the demand for NAD+ is in excess of the demand for ATP., Competing Interests: Declaration of interests The authors declare no competing interests; however, M.G.V.H. discloses he is on the advisory board of Molecular Cell and is a scientific advisor for Agios Pharmaceuticals, Aeglea Biotherapeutics, Auron Therapeutics, Faeth Therapeutics, and iTeos Therapeutics. S.S. is member of the scientific advisory board of Arcus Biosciences, Venn Therapeutics, Tango Therapeutics, and Replimune and serves as a scientific advisor for Dragonfly Therapeutics, Merck, Ribon, Torque, and TAKEDA. A.L. is a current employee of a Flagship Pioneering biotechnology start-up company., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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136. Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report.
- Author
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Buckland MS, Galloway JB, Fhogartaigh CN, Meredith L, Provine NM, Bloor S, Ogbe A, Zelek WM, Smielewska A, Yakovleva A, Mann T, Bergamaschi L, Turner L, Mescia F, Toonen EJM, Hackstein CP, Akther HD, Vieira VA, Ceron-Gutierrez L, Periselneris J, Kiani-Alikhan S, Grigoriadou S, Vaghela D, Lear SE, Török ME, Hamilton WL, Stockton J, Quick J, Nelson P, Hunter M, Coulter TI, Devlin L, Bradley JR, Smith KGC, Ouwehand WH, Estcourt L, Harvala H, Roberts DJ, Wilkinson IB, Screaton N, Loman N, Doffinger R, Lyons PA, Morgan BP, Goodfellow IG, Klenerman P, Lehner PJ, Matheson NJ, and Thaventhiran JED
- Subjects
- Adenosine Monophosphate therapeutic use, Adult, Alanine therapeutic use, Antiviral Agents therapeutic use, COVID-19 virology, Fever prevention & control, Humans, Immunity, Humoral immunology, Lymphocyte Count, Male, SARS-CoV-2 immunology, SARS-CoV-2 physiology, Treatment Outcome, Adenosine Monophosphate analogs & derivatives, Alanine analogs & derivatives, Immunity, Humoral drug effects, SARS-CoV-2 drug effects
- Abstract
The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients.
- Published
- 2020
- Full Text
- View/download PDF
137. Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission.
- Author
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Rivett L, Sridhar S, Sparkes D, Routledge M, Jones NK, Forrest S, Young J, Pereira-Dias J, Hamilton WL, Ferris M, Torok ME, Meredith L, Curran MD, Fuller S, Chaudhry A, Shaw A, Samworth RJ, Bradley JR, Dougan G, Smith KG, Lehner PJ, Matheson NJ, Wright G, Goodfellow IG, Baker S, and Weekes MP
- Subjects
- Betacoronavirus physiology, COVID-19, COVID-19 Testing, COVID-19 Vaccines, Coronavirus Infections diagnosis, Coronavirus Infections epidemiology, Coronavirus Infections transmission, Female, Humans, Infection Control, Male, Pandemics, Pneumonia, Viral diagnosis, Pneumonia, Viral epidemiology, Pneumonia, Viral transmission, Real-Time Polymerase Chain Reaction, SARS-CoV-2, United Kingdom epidemiology, Asymptomatic Infections, Clinical Laboratory Techniques, Health Personnel
- Abstract
Significant differences exist in the availability of healthcare worker (HCW) SARS-CoV-2 testing between countries, and existing programmes focus on screening symptomatic rather than asymptomatic staff. Over a 3 week period (April 2020), 1032 asymptomatic HCWs were screened for SARS-CoV-2 in a large UK teaching hospital. Symptomatic staff and symptomatic household contacts were additionally tested. Real-time RT-PCR was used to detect viral RNA from a throat+nose self-swab. 3% of HCWs in the asymptomatic screening group tested positive for SARS-CoV-2. 17/30 (57%) were truly asymptomatic/pauci-symptomatic. 12/30 (40%) had experienced symptoms compatible with coronavirus disease 2019 (COVID-19)>7 days prior to testing, most self-isolating, returning well. Clusters of HCW infection were discovered on two independent wards. Viral genome sequencing showed that the majority of HCWs had the dominant lineage B∙1. Our data demonstrates the utility of comprehensive screening of HCWs with minimal or no symptoms. This approach will be critical for protecting patients and hospital staff., Competing Interests: LR, SS, DS, MR, NJ, SF, JY, JP, WH, MF, LM, MC, SF, AS, JB, GW No competing interests declared, MT Reports grants from Academy of Medical Sciences and the Health Foundation, non-financial support from National Institute of Health Research, grants from Medical Research Council, grants from Global Challenges Research Fund, personal fees from Wellcome Sanger Institute, personal fees from University of Cambridge, personal fees from Oxford University Press, AC Reports grants from Cambridge Biomedical Research Centre at CUHNFT, RS Reports grants from EPSRC fellowship, GD Reports grants from NIHR, KS, MW Reports grants from Wellcome Trust, PL, IG, SB Reports grants from Wellcome Trust and Addenbrooke's Charitable Trust, NM Reports grants from MRC (UK) and NHS Blood and Transfusion, (© 2020, Rivett et al.)
- Published
- 2020
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- View/download PDF
138. Integrative functional genomics decodes herpes simplex virus 1.
- Author
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Whisnant AW, Jürges CS, Hennig T, Wyler E, Prusty B, Rutkowski AJ, L'hernault A, Djakovic L, Göbel M, Döring K, Menegatti J, Antrobus R, Matheson NJ, Künzig FWH, Mastrobuoni G, Bielow C, Kempa S, Liang C, Dandekar T, Zimmer R, Landthaler M, Grässer F, Lehner PJ, Friedel CC, Erhard F, and Dölken L
- Subjects
- Animals, Biological Products pharmacology, Chlorocebus aethiops, Computational Biology, Cricetinae, Fibroblasts metabolism, Gene Expression Regulation, Viral drug effects, Genes, Viral, Genomics, Herpesvirus 1, Human drug effects, Humans, Open Reading Frames, Protein Domains, Protein Isoforms, Ribosomes metabolism, Transcriptome, Vero Cells, Genome, Viral, Herpesvirus 1, Human genetics
- Abstract
The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDA-approved oncolytic virus Imlygic. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of ORFs as well as N-terminal extensions (NTEs) and truncations. We show that NTEs with non-canonical start codons govern the subcellular protein localization and packaging of key viral regulators and structural proteins. We extend the current nomenclature to include all viral gene products and provide a genome browser that visualizes all the obtained data from whole genome to single-nucleotide resolution.
- Published
- 2020
- Full Text
- View/download PDF
139. Covid-19: should the public wear face masks?
- Author
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Javid B, Weekes MP, and Matheson NJ
- Subjects
- Betacoronavirus, COVID-19, Humans, Pandemics, SARS-CoV-2, Coronavirus Infections, Masks, Pneumonia, Viral
- Abstract
Competing Interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare no other interests. The BMJ policy on financial interests is here: https://www.bmj.com/sites/default/files/attachments/resources/2016/03/16-current-bmj-education-coi-form.pdf.
- Published
- 2020
- Full Text
- View/download PDF
140. Guidelines on neuraminidase inhibitors in children are not supported by evidence.
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Symmonds M, Matheson NJ, and Harnden A
- Subjects
- Child, Evidence-Based Medicine, Humans, Influenza, Human drug therapy, Neuraminidase antagonists & inhibitors, Practice Guidelines as Topic standards
- Published
- 2004
- Full Text
- View/download PDF
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