The lacrimal gland is responsible for tear production, and a major protein found in tears is secretory component (SC), the proteolytically cleaved fragment of the extracellular domain of the polymeric Ig receptor (pIgR), which is the receptor mediating the basal-to-apical transcytosis of polymeric immunoglobulins across epithelial cells. Immunofluorescent labeling of rabbit lacrimal gland acinar cells (LGACs) revealed that the small GTPase Rab3D, a regulated secretory vesicle marker, and the pIgR are colocalized in subapical membrane vesicles. In addition, the secretion of SC from primary cultures of LGACs was stimulated by the cholinergic agonist carbachol (CCH), and its release rate was very similar to that of other regulated secretory proteins in LGACs. In pull-down assays from resting LGACs, recombinant wild-type Rab3D (Rab3DWT) or the GDP-locked mutant Rab3DT36N both pulled down pIgR, but the GTP-locked mutant Rab3DQ81L did not. When the pull-down assays were performed in the presence of guanosine-5'-(gamma-thio)-triphosphate, GTP, or guanosine-5'-O-(2-thiodiphosphate), binding of Rab3DWT to pIgR was inhibited. In blot overlays, recombinant Rab3DWT bound to immunoprecipitated pIgR, suggesting that Rab3D and pIgR may interact directly. Adenovirus-mediated overexpression of mutant Rab3DT36N in LGACs inhibited CCH-stimulated SC release, and, in CCH-stimulated LGACs, pull down of pIgR with Rab3DWT and colocalization of pIgR with endogenous Rab3D were decreased relative to resting cells, suggesting that the pIgR-Rab3D interaction may be modulated by secretagogues. These data suggest that the novel localization of pIgR to the regulated secretory pathway of LGACs and its secretion therefrom may be affected by its novel interaction with Rab3D.

Background: The institutions which comprise the Clinical and Translational Science Award consortium and the National Center for Advancing Translational Sciences continue to explore and develop community engaged research strategies and to study the role of community academic partnerships in advancing the science of community engagement. Objectives: To explore Clinical and Translational Science institutions (CTSA) in relation to an Institute of Medicine recommendation that community engagement occur in all stages of translational research and be defined and evaluated consistently. Methods: A sequential multi-methods study starting with an online pilot survey followed by survey respondents and site informant interviews. A revised survey was sent to the community engagement and evaluation leads at each CTSA institution, requesting a single institutional response about definitions, indicators and metrics of community engagement and community-engaged research. Results: A plurality of CTSA institutions selected the definition of community engagement from the Principles of Community Engagement. While claiming unique institutional priorities create barriers to developing shared metrics, responses indicate an overall lack of attention to the development and deployment of metrics to assess community engagement in and contributions to research. Conclusions: Although definitions of community engagement differ among CTSAs, there appears more similarities than differences in the indicators and measures tracked and reported on across all definitions, perhaps due to commonalities among program infrastructures and goals. Metrics will likely need to be specific to translational research stages. Assessment of community engagement within translational science will require increased institutional commitment.

SummaryThe polymeric immunoglobulin receptor (pIgR) mediates transcytosis of dimeric immunoglobulin A (dIgA) and its release into mucosal secretions. The present study reveals the complexity of the trafficking of pIgR to the apical plasma membrane in epithelial cells with exocrine secretory functions; in rabbit lacrimal gland acinar cells (LGACs), trafficking of pIgR involves both the transcytotic pathway and one arm of the regulated secretory pathway. By specifically tracking pIgR endocytosed from the basolateral membrane, we show here that the Rab11a-regulated transcytotic pathway mediates the basal-to-apical transport of pIgR, and that pIgR sorted into the transcytotic pathway does not access the regulated secretory pathway. However, previous work in LGACs expanded in the present study has shown that some pIgR is localized to Rab3D-enriched mature secretory vesicles (SVs). Myosin Vb and myosin Vc motors modulate release of proteins from the Rab11a-regulated transcytotic pathway and the Rab3D-enriched secretory pathway in LGACs, respectively. Confocal fluorescence microscopy and biochemical assays showed that inhibition of myosin Vb and myosin Vc activity by overexpression of their dominant-negative mutants each significantly but differentially impaired aspects of apically targeted pIgR trafficking and secretory component release, suggesting that these motors function to regulate pIgR trafficking in both the transcytotic and exocytotic pathways. Intriguingly, a second mature SV population enriched in Rab27b was devoid of pIgR cargo, suggesting the specialization of Rab3D-enriched mature SVs to carry a particular subset of cargo proteins from the trans-Golgi network to the apical plasma membrane.

The most common complication (8.8%) was pathological fracture. The fracture involved the shaft of the femur in 62%, occurring in this section of the bone almost seven times more frequently in the patients with Paget's disease than in the general population.Because of the large number of undiagnosed cases in the community, the true incidence of pathological fracture and of sarcoma of bone in all patients with Paget's disease is probably only 1% and 0-1% respectively.Simultaneous estimates of the serum alkaline phosphatase and ESR were made in 128 ofthe patients.It was shown that the ESR is valueless as a measure of activity or extent of the disease.In many patients the level of the serum alkaline phosphatase changed very little over periods of several years.A history of the disease in one or more close relatives was found in three families, a lower incidence than was expected from previously recorded studies. The ABO blood groups were determined in 215 of the patients; 50% were of group A compared with 46% in a control group. The difference in distribution of blood groups in the two series of subjects is small and well within chance limits. The secretor status of 138 patients was investigated; 77% were secretors. This is similar to the DroDortion in control series.

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