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Abstract Stress hyperglycaemia is common in critical illness. We have previously observed that increasing severity of respiratory failure in patients with severe COVID-19 is associated with increased insulin demand. Given previously reported direct effects of hypoxia on insulin action, we reasoned that rapid improvements in oxygenation following prone positioning may improve insulin sensitivity and increase risk of hypoglycaemia. A retrospective multi-centre service evaluation comparing blood glucose and insulin administration in patients with COVID-19 pneumonitis receiving prone mechanical ventilation, comparing the 16 h pre-prone and 16 h post-prone time periods. 155 patients were included in this analysis. Oxygenation improved significantly following prone positioning (change in SpO2/FIO2 per hour prone: 3.01 ± 0.14, P

Abstract Extracellular vesicles (EVs) are important mediators of intercellular communication. However, EV biogenesis remains poorly understood. We previously defined a role for Arrdc4 (Arrestin domain containing protein 4), an adaptor for Nedd4 family ubiquitin ligases, in the biogenesis of EVs. Here we report that ubiquitination of Arrdc4 is critical for its role in EV secretion. We identified five potential ubiquitinated lysine residues in Arrdc4 using mass spectrometry. By analysing Arrdc4 lysine mutants we discovered that lysine 270 (K270) is critical for Arrdc4 function in EV biogenesis. Arrdc4K270R mutation caused a decrease in the number of EVs released by cells compared to Arrdc4WT, and a reduction in trafficking of divalent metal transporter (DMT1) into EVs. Furthermore, we also observed a decrease in DMT1 activity and an increase in its intracellular degradation in the presence of Arrdc4K270R. K270 was found to be ubiquitinated with K‐29 polyubiquitin chains by the ubiquitin ligase Nedd4‐2. Thus, our results uncover a novel role of K‐29 polyubiquitin chains in Arrdc4‐mediated EV biogenesis and protein trafficking.

Abstract Introduction Severe COVID‐19 has been anecdotally associated with high insulin requirements. It has been proposed that this may be driven by a direct diabetogenic effect of the virus that is unique to SARS‐CoV‐2, but evidence to support this is limited. To explore this, we compared insulin requirements in patients with severe COVID‐19 and non‐COVID‐19 viral pneumonitis. Methods This is a retrospective cohort study of patients with severe COVID‐19 admitted to our intensive care unit between March and June 2020. A historical control cohort of non‐COVID‐19 viral pneumonitis patients was identified from routinely collected audit data. Results Insulin requirements were similar in patients with COVID‐19 and non‐COVID‐19 viral pneumonitis after adjustment for pre‐existing diabetes and severity of respiratory failure. Conclusions In this single‐centre study, we could not find evidence of a unique diabetogenic effect of COVID‐19. We suggest that high insulin requirements in this disease relate to its propensity to cause severe respiratory failure in patients with pre‐existing metabolic disease.

The main aim of our study is to explore some relativistic configurations of compact object solution in the background of fR gravity, by adopting the Krori-Barua spacetime. In this regard, we establish the field equations for spherically symmetric spacetime along with charged anisotropic matter source by assuming the specific form of the metric potentials, i.e., νr=Br2+C and λr=Ar2. Further, to calculate the constant values, we consider the Bardeen model as an exterior spacetime at the surface boundary. To ensure the viability of the fR gravity model, the physical characteristics including energy density, pressure components, energy bonds, equilibrium condition, Herrera cracking concept, mass-radius relation, and adiabatic index are analyzed in detail. It is observed that all the outcomes by graphical exploration and tabular figures show that the Bardeen black hole model describes the physically realistic stellar structures.

Extracellular vesicles (EVs) are important mediators of intercellular communication. However, EV biogenesis remains poorly understood. We previously defined a role for Arrdc4 (Arrestin domain containing protein 4), an adaptor for Nedd4 family ubiquitin ligases, in the biogenesis of EVs. Here we report that ubiquitination of Arrdc4 is critical for its role in EV secretion. We identified five potential ubiquitinated lysine residues in Arrdc4 using mass spectrometry. By analysing Arrdc4 lysine mutants we discovered that lysine 270 (K270) is critical for Arrdc4 function in EV biogenesis. Arrdc4K270R mutation caused a decrease in the number of EVs released by cells compared to Arrdc4WT, and a reduction in trafficking of divalent metal transporter (DMT1) into EVs. Furthermore, we also observed a decrease in DMT1 activity and an increase in its intracellular degradation in the presence of Arrdc4K270R. K270 was found to be ubiquitinated with K‐29 polyubiquitin chains by the ubiquitin ligase Nedd4‐2. Thus, our results uncover a novel role of K‐29 polyubiquitin chains in Arrdc4‐mediated EV biogenesis and protein trafficking. [ABSTRACT FROM AUTHOR]