The USP46 deubiquitylase complex increases Wingless/Wnt signaling strength by stabilizing Arrow/LRP6.

The control of Wnt receptor abundance is critical for animal development and to prevent tumorigenesis, but the mechanisms that mediate receptor stabilization remain uncertain. We demonstrate that stabilization of the essential Wingless/Wnt receptor Arrow/LRP6 by the evolutionarily conserved Usp46-Uaf1-Wdr20 deubiquitylase complex controls signaling strength in Drosophila. By reducing Arrow ubiquitylation and turnover, the Usp46 complex increases cell surface levels of Arrow and enhances the sensitivity of target cells to stimulation by the Wingless morphogen, thereby increasing the amplitude and spatial range of signaling responses. Usp46 inactivation in Wingless-responding cells destabilizes Arrow, reduces cytoplasmic accumulation of the transcriptional coactivator Armadillo/ß-catenin, and attenuates or abolishes Wingless target gene activation, which prevents the concentration-dependent regulation of signaling strength. Consequently, Wingless-dependent developmental patterning and tissue homeostasis are disrupted. These results reveal an evolutionarily conserved mechanism that mediates Wnt/Wingless receptor stabilization and underlies the precise activation of signaling throughout the spatial range of the morphogen gradient.

Patterns and Predictors of Medication Change after Discharge from Hospital: An Observational Study in Older Adults with Neurological Disorders.

BACKGROUND: Medication is often changed after inpatient treatment, which affects the course of the disease, health behavior and adherence. Thus, it is important to understand patterns of medication changes after discharge from hospital. METHODS: Inpatients at the Department of Neurology received a comprehensive assessment during their stay, including adherence, depression, cognition, health and sociodemographic variables. A month after being discharged, patients were contacted to enquire about post-discharge medication changes. RESULTS: 910 older adults aged 70 ± 8.6 years participated, of which 204 (22.4%) reported medication changes. The majority of changes were initiated by physicians (n = 112, 56.3%) and only 25 (12.6%) patients reported adjusting medication themselves. Reasons for medication changes differed between patients and doctors (p < 0.001), with side effects or missing effects cited frequently. Sociodemographic and patient-related factors did not significantly predict medication changes. CONCLUSION: Patients reported less post-discharge medication changes than expected, and contrary to previous literature on nonadherence, only a fraction of those changes were performed by patients themselves. Socioeconomic and clinical parameters regarding personality, mood and cognition were poorly associated with post-discharge medication changes. Instead, individual health-related factors play a role, with patient factors only indirectly influencing physicians' decisions.