Monocyte-Mediated Thrombosis Linked to Circulating Tissue Factor and Immune Paralysis in COVID-19.

BACKGROUND: SARS-CoV-2 infections cause COVID-19 and are associated with inflammation, coagulopathy, and high incidence of thrombosis. Myeloid cells help coordinate the initial immune response in COVID-19. Although we appreciate that myeloid cells lie at the nexus of inflammation and thrombosis, the mechanisms that unite the two in COVID-19 remain largely unknown. METHODS: In this study, we used systems biology approaches including proteomics, transcriptomics, and mass cytometry to define the circulating proteome and circulating immune cell phenotypes in subjects with COVID-19. RESULTS: In a cohort of subjects with COVID-19 (n=35), circulating markers of inflammation (CCL23 [C-C motif chemokine ligand 23] and IL [interleukin]-6) and vascular dysfunction (ACE2 [angiotensin-converting enzyme 2] and TF [tissue factor]) were elevated in subjects with severe compared with mild COVID-19. Additionally, although the total white blood cell counts were similar between COVID-19 groups, CD14+ (cluster of differentiation) monocytes from subjects with severe COVID-19 expressed more TF. At baseline, transcriptomics demonstrated increased IL-6, CCL3, ACOD1 (aconitate decarboxylase 1), C5AR1 (complement component 5a receptor), C5AR2, and TF in subjects with severe COVID-19 compared with controls. Using stress transcriptomics, we found that circulating immune cells from subjects with severe COVID-19 had evidence of profound immune paralysis with greatly reduced transcriptional activation and release of inflammatory markers in response to TLR (Toll-like receptor) activation. Finally, sera from subjects with severe (but not mild) COVID-19 activated human monocytes and induced TF expression. CONCLUSIONS: Taken together, these observations further elucidate the pathological mechanisms that underlie immune dysfunction and coagulation abnormalities in COVID-19, contributing to our growing understanding of SARS-CoV-2 infections that could also be leveraged to develop novel diagnostic and therapeutic strategies.

Phosphorylation of TRIP13 at Y56 induces radiation resistance but sensitizes head and neck cancer to cetuximab.

Radiation therapy, a mainstay of treatment for head and neck cancer, is not always curative due to the development of treatment resistance; additionally, multi-institutional trials have questioned the efficacy of concurrent radiation with cetuximab, the epidermal growth factor receptor (EGFR) inhibitor. We unraveled a mechanism for radiation resistance; that is, radiation induces EGFR, which phosphorylates TRIP13 (thyroid hormone receptor interactor 13) on tyrosine 56. Phosphorylated (phospho-)TRIP13 promotes non-homologous end joining (NHEJ) repair to induce radiation resistance. NHEJ is the main repair pathway for radiation-induced DNA damage. Tumors expressing high TRIP13 do not respond to radiation but are sensitive to cetuximab or cetuximab combined with radiation. Suppression of phosphorylation of TRIP13 at Y56 abrogates these effects. These findings show that EGFR-mediated phosphorylation of TRIP13 at Y56 is a vital mechanism of radiation resistance. Notably, TRIP13-pY56 could be used to predict the response to radiation or cetuximab and could be explored as an actionable target.

Uptake of certain heavy metals from contaminated soil by mushroom--Galerina vittiformis.

Remediation of soil contaminated with heavy metals has received considerable attention in recent years. In this study, the heavy metal uptake potential of the mushroom, Galerina vittiformis, was studied in soil artificially contaminated with Cu (II), Cd (II), Cr (VI), Pb (II) and Zn (II) at concentrations of 50 and 100mg/kg. G. vittiformis was found to be effective in removing the metals from soil within 30 days. The bioaccumulation factor (BAF) for both mycelia and fruiting bodies with respect to these heavy metals at 50mg/kg concentrations were found to be greater than one, indicating hyper accumulating nature by the mushroom. The metal removal rates by G. vittiformis was analyzed using different kinetic rate constants and found to follow the second order kinetic rate equation except for Cd (II), which followed the first order rate kinetics.

The uptake mechanism of Cd(II), Cr(VI), Cu(II), Pb(II), and Zn(II) by mycelia and fruiting bodies of Galerina vittiformis.

Optimum concentrations of heavy metals like copper, cadmium, lead, chromium, and zinc in soil are essential in carrying out various cellular activities in minimum concentrations and hence help in sustaining all life forms, although higher concentration of these metals is lethal to most of the life forms. Galerina vittiformis, a macrofungus, was found to accumulate these heavy metals into its fleshy fruiting body in the order Pb(II) > Cd(II) > Cu(II) > Zn(II) > Cr(VI) from 50 mg/kg soil. It possesses various ranges of potential cellular mechanisms that may be involved in detoxification of heavy metals and thus increases its tolerance to heavy metal stress, mainly by producing organic acids and phytochelatins (PCs). These components help in repairing stress damaged proteins and compartmentalisation of metals to vacuoles. The stress tolerance mechanism can be deduced by various analytical tools like SEM-EDX, FTIR, and LC-MS. Production of two kinds of phytochelatins was observed in the organism in response to metal stress.