In the present study, we report that ubiquitin-mediated degradation of dMyc, the Drosophila homologue of the human c-myc proto-oncogene, is regulated in vitro and in vivo by members of the casein kinase 1 (CK1) family and by glycogen synthase kinase 3␤ (GSK3␤). Using Drosophila S2 cells, we demonstrate that CK1␣ promotes dMyc ubiquitination and degradation with a mechanism similar to the one mediated by GSK3␤ in vertebrates. Mutation of ck1␣ or -or sgg/gsk3␤ in Drosophila wing imaginal discs results in the accumulation of dMyc protein, suggesting a physiological role for these kinases in vivo. Analysis of the dMyc amino acid sequence reveals the presence of conserved domains containing potential phosphorylation sites for mitogen kinases, GSK3␤, and members of the CK1 family. We demonstrate that mutations of specific residues within these phosphorylation domains regulate dMyc protein stability and confer resistance to degradation by CK1␣ and GSK3␤ kinases. Expression of the dMyc mutants in the compound eye of the adult fly results in a visible defect that is attributed to the effect of dMyc on growth, cell death, and inhibition of ommatidial differentiation.

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Objectives: To characterize physicians’ practices and attitudes toward the initiation, limitation, and withdrawal of venovenous extracorporeal membrane oxygenation for severe respiratory failure and evaluate factors associated with these attitudes. Design: Electronic, cross-sectional, scenario-based survey. Setting: Extracorporeal membrane oxygenation centers affiliated with the Extracorporeal Life Support Organization and the International Extracorporeal Membrane Oxygenation Network. Subjects: Attending-level physicians with experience managing adult patients receiving venovenous extracorporeal membrane oxygenation. Interventions: None. Measurements and Main Results: Five-hundred thirty-nine physicians in 39 countries across six continents completed the survey. Factors that influenced the decision to limit extracorporeal membrane oxygenation initiation included older patient age (46.9%), additional organ failures (37.7%), and prolonged mechanical ventilation (35.1%). Patient comorbidities (70.5%), patient’s wishes (56.0%), and etiology of respiratory failure (37.7%) were factors that influenced the decision to withdraw extracorporeal membrane oxygenation. In multivariable analysis, factors associated with increased odds of withdrawing life-sustaining therapies included pulmonary fibrosis, stroke, surrogate’s desire to withdraw, lack of knowledge regarding patient’s or surrogate’s wishes in the setting of fibrosis, not initiating extracorporeal membrane oxygenation in the baseline scenario, and respondent religiosity. Factors associated with decreased odds of withdrawal included practicing in an environment where it is not legally possible to make decisions against patient or surrogate wishes. Most respondents (90.5%) involved other physicians in treatment decisions for extracorporeal membrane oxygenation patients, whereas only 53.2%, 45.3%, and 29.5% of respondents involved surrogates, awake patients, or bedside nurses, respectively. Conclusions: Patient and physician-level factors were associated with decision-making regarding extracorporeal membrane oxygenation initiation and withdrawal, including patient prognosis and knowledge of patient or surrogate wishes. Respondents reported low rates of engaging in shared decision-making when managing patients receiving extracorporeal membrane oxygenation.