ABSTRACT
BACKGROUND: In response to the COVID-19 pandemic, internal medicine residencies have had to develop new teaching strategies and attend to wellness concerns. Providing front-line care for patients in a time of widespread crisis while maintaining attention to training has created unprecedented challenges. OBJECTIVE: Our large community hospital based internal medicine residency sought to develop and evaluate a crisis response to the demands of the COVID-19 pandemic to meet our residents' educational and wellness needs. METHODS: In March 2020, our residency developed a crisis plan for functioning during the COVID-19 pandemic. A brief survey was sent via email to our 149 residents to obtain their evaluation of how well their needs were being met by this response. RESULTS: 92 (62%) residents completed the survey. 88% indicated their well-being needs were well met. Other components were also rated as successful: effective communication (86%), scheduling/staffing (78%), preparing residents for clinical service (77%), and educational needs (76%). CONCLUSIONS: Our residency crisis response to the COVID-19 pandemic was favorably evaluated by our residents in meeting their training and well-being needs. In future work we plan to seek longer-term and more objective measures to assess how residents fare during these challenging times, and to use lessons learned to prepare for future crisis situations.
ABSTRACT
Recently, we identified extracellular ubiquitin as an endogenous CXC chemokine receptor (CXCR) 4 agonist. However, the receptor selectivity and molecular basis of the CXCR4 agonist activity of ubiquitin are unknown, and functional consequences of CXCR4 activation with ubiquitin are poorly defined. Here, we provide evidence that ubiquitin and the cognate CXCR4 ligand stromal cell-derived factor (SDF)-1α do not share CXCR7 as a receptor. We further demonstrate that ubiquitin does not utilize the typical two-site binding mechanism of chemokine-receptor interactions, in which the receptor N terminus is important for ligand binding. CXCR4 activation with ubiquitin and SDF-1α lead to similar Gα(i)-responses and to a comparable magnitude of phosphorylation of ERK-1/2, p90 ribosomal S6 kinase-l and Akt, although phosphorylations occur more transiently after activation with ubiquitin. Despite the similarity of signal transduction events after activation of CXCR4 with both ligands, ubiquitin possesses weaker chemotactic activity than SDF-lα in cell migration assays and does not interfere with productive entry of HIV-1 into P4.R5 multinuclear activation of galactosidase indicator cells. Unlike SDF-1α, ubiquitin lacks interactions with an N-terminal CXCR4 peptide in NMR spectroscopy experiments. Binding and signaling studies in the presence of antibodies against the N terminus and extracellular loops 2/3 of CXCR4 confirm that the ubiquitin CXCR4 interaction is independent of the N-terminal receptor domain, whereas blockade of extracellular loops 2/3 prevents receptor binding and activation. Our findings define ubiquitin as a CXCR4 agonist, which does not interfere with productive cellular entry of HIV-1, and provide new mechanistic insights into interactions between CXCR4 and its natural ligands.
