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.

Systems Analysis to Increase HIV Testing Delivery and HIV Diagnosis in Primary Care Clinics in South Africa.

BACKGROUND: Provider-initiated testing and counseling remains highly underused in many South African health facilities. We implemented a systems analysis to investigate whether simple adjustments to HIV testing services (HTS) delivery can increase HTS provision. SETTING: Ten primary care facilities in the Ekurhuleni District in South Africa. METHODS: Following a baseline HTS assessment that showed limited offering of HTS by clinicians, clinic staff had the option to adopt several change approaches to increase HTS delivery using existing human resources. Approaches included adjusting HTS timing, strengthening HTS promotion, counsellor management, and implementing reward systems. Evaluation was conducted identically to the baseline study using patient exit interviews to quantify HTS engagement and value stream mapping to map patient flow through the clinic. RESULTS: We conducted 2163 exit interviews and followed 352 patients for value stream mapping. After change implementation, a significantly higher proportion of patients reported being offered HTS (742/2163, 34.3% vs. 231/2206, 10.5% during the baseline period; χ2P < 0.001) and having undertaken testing (527/2163, 24.4% vs. 197/2206, 8.9% during the baseline period; χ2P < 0.001) with only a 3-percentage point decrease in HIV-positive yield (14.0% vs. 17.1% during the baseline period). The median time to HTS offer decreased from 77 minutes to 3 minutes after clinic arrival during the intervention (χ2P = 0.001). CONCLUSIONS: A systems approach can be an effective and appropriate implementation strategy to augment HTS delivery and increase HIV diagnoses. This low-cost approach may be extended to optimize other aspects of clinic service delivery.