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A plethora of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic tests are available, each with different performance specifications, detection methods, and targets. This narrative review aims to summarize the diagnostic technologies available and how they are best selected to tackle SARS-CoV-2 infection as the pandemic evolves. Seven key settings have been identified where diagnostic tests are being deployed: symptomatic individuals presenting for diagnostic testing and/or treatment of COVID-19 symptoms; asymptomatic individuals accessing healthcare for planned non-COVID-19-related reasons; patients needing to access emergency care (symptom status unknown); patients being discharged from healthcare following hospitalization for COVID-19; healthy individuals in both single event settings (e.g. airports, restaurants, hotels, concerts, and sporting events) and repeat access settings (e.g. workplaces, schools, and universities); and vaccinated individuals. While molecular diagnostics remain central to SARS-CoV-2 testing strategies, we have offered some discussion on the considerations for when other tools and technologies may be useful, when centralized/point-of-care testing is appropriate, and how the various additional diagnostics can be deployed in differently resourced settings. As the pandemic evolves, molecular testing remains important for definitive diagnosis, but increasingly widespread point-of-care testing is essential to the re-opening of society.

<title>Abstract</title> Altered metabolism and defective innate immune responses are hallmarks of tumor cells, creating a niche that can be exploited by viruses with oncolytic properties. However, heterogeneity in responses to oncolytic virotherapy is a barrier to clinical effectiveness. Resistance to oncolytic virotherapy exists and occurs via inhibition of viral spread within the tumor that may result in treatment failures. Here we show that the Krebs cycle-derived metabolite itaconate and its chemical derivatives or natural isomers enhance oncolytic virotherapy with VSVΔ51M in various models including resistant cancer cell lines, murine tumor biopsies, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. The strongest sensitizing effect to VSVΔ51M infection within the itaconate family is elucidated by 4-octyl itaconate (4-OI), a known activator of nuclear factor erythroid 2-related factor 2 (NRF2). Importantly, the sensitization to VSVΔ51M with 4-OI is not observed in non-cancer primary human cells, healthy mouse-derived tissues, and normal human colon organoids. Additionally, 4-OI improves the virus spread within a resistant mouse colon tumor model <italic>in vivo</italic>. Mechanistically, we found that the effect of 4-OI is not mediated by NRF2 or KEAP1. Instead, we show that 4-OI targets multiple pathways including the RIG-MAVS, the IKKβ-NF-κB and the JAK1-STAT1 pathways through the modification of cysteine residues in MAVS, IKKβ and JAK1, respectively. Here, we propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.

Conference Article| February 01 1996 Differential stimulation of IL-6 secretion following apical and basolateral presentation of IL-1 on epithelial cell lines Catherina O'Shaughnessy; Catherina O'Shaughnessy 1Elan Corporation Research Institute, Trinity College, Dublin 2, Ireland Search for other works by this author on: This Site PubMed Google Scholar Ena Prosser; Ena Prosser 1Elan Corporation Research Institute, Trinity College, Dublin 2, Ireland Search for other works by this author on: This Site PubMed Google Scholar Tracy Keane; Tracy Keane 1Elan Corporation Research Institute, Trinity College, Dublin 2, Ireland Search for other works by this author on: This Site PubMed Google Scholar Luke O'Neill Luke O'Neill ∗Biochemistry Department, Trinity College, Dublin 2, Ireland Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1996) 24 (1): 83S. https://doi.org/10.1042/bst024083s Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation Catherina O'Shaughnessy, Ena Prosser, Tracy Keane, Luke O'Neill; Differential stimulation of IL-6 secretion following apical and basolateral presentation of IL-1 on epithelial cell lines. Biochem Soc Trans 1 February 1996; 24 (1): 83S. doi: https://doi.org/10.1042/bst024083s Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 1996 Biochemical Society1996 Article PDF first page preview Close Modal You do not currently have access to this content.

Type 2 diabetes (T2D) is associated with chronic, low grade inflammation. Activation of the NLRP3 inflammasome and secretion of its target interleukin-1β (IL-1β) have been implicated in pancreatic β cell failure in T2D. Specific targeting of the NLRP3 inflammasome to prevent pancreatic β cell death could allow for selective T2D treatment without compromising all IL-1β-associated immune responses. We hypothesized that treating a mouse model of T2D with MCC950, a compound that specifically inhibits NLRP3, would prevent pancreatic β cell death, thereby preventing the onset of T2D. Diabetic db/db mice were treated with MCC950 via drinking water for 8 weeks from 6 to 14 weeks of age, a period over which they developed pancreatic β cell failure. We assessed metabolic parameters such as body composition, glucose tolerance, or insulin secretion over the course of the intervention. MCC950 was a potent inhibitor of NLRP3-induced IL-1β in vitro and was detected at high levels in the plasma of treated db/db mice. Treatment of pre-diabetic db/db mice with MCC950, however, did not prevent pancreatic dysfunction and full onset of the T2D pathology. When examining the NLRP3 pathway in the pancreas of db/db mice, we could not detect an activation of this pathway nor increased levels of its target IL-1β. NLRP3 driven-pancreatic IL-1β inflammation does not play a key role in the pathogenesis of the db/db murine model of T2D.

No abstract is provided for this article.

No abstract is provided for this article.

Schlafen-1 (Slfn-1), the prototypic member of the Schlafen family of proteins, was described as an inducer of growth arrest in T-lymphocytes and causes a cell cycle arrest in NIH3T3 fibroblasts prior to the G1/S transition. How Slfn-1 exerts its effects on the cell cycle is not currently known. We report that synchronized murine fibroblasts expressing Slfn-1 do not exit G1 when stimulated with fetal calf serum, platelet-derived growth factor BB (PDGF-BB) or epidermal growth factor (EGF). The induction of cyclin D1 by these stimuli was blocked in the presence of Slfn-1 as were all downstream cell cycle processes. Overexpression of cyclin D1 in growth-arrested, Slfn-1-expressing cells induced an increase in cell growth consistent with this protein being the biological target of Slfn-1. Activation of the mitogen-activated protein kinase pathway by EGF or phorbol 12-myristate 13-acetate was unaffected by Slfn-1 expression. PDGF signaling was, however, almost completely blocked. This was due to a lack of PDGF receptor expression in Slfn-1-expressing cells consistent with Slfn-1 blocking the cell cycle in G1 where PDGF receptor expression is normally down-regulated. Finally, overexpression of Slfn-1 inhibited the activation of the cyclin D1 promoter. Slfn-1 therefore causes a cell cycle arrest during G1 by inhibiting induction of cyclin D1 by mitogens.

Macrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the “classically activated” M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis . By contrast, “alternatively activated” M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection.