Glycogen synthase kinase-3 (GSK-3) is a critical, negative regulator of diverse signaling pathways. Lithium is a direct inhibitor of GSK-3 and has been widely used to test the putative role of GSK-3 in multiple settings. However, lithium also inhibits other targets, including inositol monophosphatase and structurally related phosphomonoesterases, and thus additional approaches are needed to attribute a given biological effect of lithium to a specific target. For example, lithium is known to increase the inhibitory N-terminal phosphorylation of GSK-3, but the target of lithium responsible for this indirect regulation has not been identified. We have characterized a short peptide derived from the GSK-3 interaction domain of Axin that potently inhibits GSK-3 activity in vitro and in mammalian cells and robustly activates Wnt-dependent transcription, mimicking lithium action. We show here, using the GSK-3 interaction domain peptide, as well as small molecule inhibitors of GSK-3, that lithium induces GSK-3 N-terminal phosphorylation through direct inhibition of GSK-3 itself. Reduction of GSK-3 protein levels, either by RNA interference or by disruption of the mouse GSK-3␤ gene, causes increased N-terminal phosphorylation of GSK-3, confirming that GSK-3 regulates its own phosphorylation status. Finally, evidence is presented that N-terminal phosphorylation of GSK-3 can be regulated by the GSK-3-dependent protein phosphatase-1⅐inhibitor-2 complex.

Most ARDS patients did not receive LTVV despite implementation of a protocol. ARDS was also recognized in a minority of patients, suggesting an opportunity for improvement of care.

Study Objectives: Evaluate consequences of intermediate to high risk of undiagnosed obstructive sleep apnea (OSA) among individuals with chronic obstructive pulmonary disease (COPD). Methods: Using data from the Long Term Oxygen Treatment Trial (LOTT), we assessed OSA risk at study entry among patients with COPD. We compared outcomes among those at intermediate to high risk (modified STOP-BANG score ≥ 3) relative to low risk (score < 3) for OSA. We compared risk of mortality or first hospitalization with proportional hazard models, and incidence of COPD exacerbations using negative binomial regression. We adjusted analyses for demographics, body mass index, and comorbidities. Last, we compared St. George Respiratory Questionnaire and Quality of Well-Being Scale results between OSA risk groups. Results: Of the 222 participants studied, 164 (74%) were at intermediate to high risk for OSA based on the modified STOP-BANG score. Relative to the 58 low-risk individuals, the adjusted hazard ratio of mortality or first hospitalization was 1.61 (95% confidence interval 1.01-2.58) for those at intermediate to high risk of OSA. Risk for OSA was also associated with increased frequency of COPD exacerbations (adjusted incidence rate ratio: 1.78, 95% confidence interval 1.10-2.89). Respiratory symptoms by St. George Respiratory Questionnaire were 5.5 points greater (P = .05), and Quality of Well-Being Scale scores were .05 points lower (P < .01) among those at intermediate to high risk for OSA, indicating more severe respiratory symptoms and lower quality of life. Conclusions: Among individuals with COPD, greater risk for undiagnosed OSA is associated with poor outcomes. Increased recognition and management of OSA in this group could improve outcomes.