GPC3-Unc5 receptor complex structure and role in cell migration.

Neural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these mechanisms to disseminate. Here, we reveal crystal structures of Uncoordinated-5 receptor D (Unc5D) in complex with morphogen receptor glypican-3 (GPC3), forming an octameric glycoprotein complex. In the complex, four Unc5D molecules pack into an antiparallel bundle, flanked by four GPC3 molecules. Central glycan-glycan interactions are formed by N-linked glycans emanating from GPC3 (N241 in human) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. MD simulations, mass spectrometry and structure-based mutants validate the crystallographic data. Anti-GPC3 nanobodies enhance or weaken Unc5-GPC3 binding and, together with mutant proteins, show that Unc5/GPC3 guide migrating pyramidal neurons in the mouse cortex, and cancer cells in an embryonic xenograft neuroblastoma model. The results demonstrate a conserved structural mechanism of cell guidance, where finely balanced Unc5-GPC3 interactions regulate cell migration.

Fifty years of longitudinal continuity in general practice: a retrospective observational study.

BACKGROUND: Continuity of care has been defined as relational continuity between patient and doctor and longitudinal continuity describing the duration of the relationship. Measurement of longitudinal continuity alone is associated with outcomes including patient satisfaction, medical costs, hospital admissions and mortality. METHODS: In one UK general practice, records were searched for patients with continuous registration for 50 or more years. Characteristics of these patients were analysed for age, gender, social deprivation, partner registration and length of registration. Trends in numbers and proportions of this group over the previous 14 years were determined. A comparison group of patients, aged 50 or more, and registered in the same practice within the last 2-4 years, was identified. RESULTS: Patients registered for 50 years or more with a median registration of 56.2 years numbered 190 out of a population of 8420 (2.3%). These patients increased in number by 35.3% (1.7-2.3%) over 14 consecutive years. There were no differences between groups for GP consultation rate, number of repeat medications and hospital use, despite the significantly higher prevalence of multi-morbidity, depression and diabetes in patients with high continuity. CONCLUSIONS: This is the first report of 50-year continuity in general practice. Numbers of such patients and proportions are increasing. Longitudinal continuity is easily measured in general practice and associated with important clinical outcomes.