Alternative splicing regulates adaptor protein binding, trafficking, and activity of the Vps10p domain receptor SorCS2 in neuronal development.

The Vps10p domain receptor SorCS2 is crucial for the development and function of the nervous system and essential for brain-derived neurotrophic factor (BDNF)-induced changes in neuronal morphology and plasticity. SorCS2 regulates the subcellular trafficking of the BDNF signaling receptor TrkB as well as selected neurotransmitter receptors in a manner that is dependent on the SorCS2 intracellular domain (ICD). However, the cellular machinery and adaptor protein (AP) interactions that regulate receptor trafficking via the SorCS2 ICD are unknown. We here identify four splice variants of human SorCS2 differing in the insertion of an acidic cluster motif and/or a serine residue within the ICD. We show that each variant undergoes posttranslational proteolytic processing into a one- or two-chain receptor, giving rise to eight protein isoforms, the expression of which differs between neuronal and nonneuronal tissues and is affected by cellular stressors. We found that the only variants without the serine were able to rescue BDNF-induced branching of SorCS2 knockout hippocampal neurons, while variants without the acidic cluster showed increased interactions with clathrin-associated APs AP-1, AP-2, and AP-3. Using yeast two-hybrid screens, we further discovered that all variants bound dynein light chain Tctex-type 3; however, only variants with an acidic cluster motif bound kinesin light chain 1. Accordingly, splice variants showed markedly different trafficking properties and localized to different subcellular compartments. Taken together, our findings demonstrate the existence of eight functional SorCS2 isoforms with differential capacity for interactions with cytosolic ligands dynein light chain Tctex-type 3 and kinesin light chain 1, which potentially allows cell-type specific SorCS2 trafficking and BDNF signaling.

CED-6/GULP and components of the clathrin-mediated endocytosis machinery act redundantly to correctly display CED-1 on the cell membrane in Caenorhabditis elegans.

CED-1 (cell death abnormal) is a transmembrane receptor involved in the recognition of "eat-me" signals displayed on the surface of apoptotic cells and thus central for the subsequent engulfment of the cell corpse in Caenorhabditis elegans. The roles of CED-1 in engulfment are well established, as are its downstream effectors. The latter include the adapter protein CED-6/GULP and the ATP-binding cassette family homolog CED-7. However, how CED-1 is maintained on the plasma membrane in the absence of engulfment is currently unknown. Here, we show that CED-6 and CED-7 have a novel role in maintaining CED-1 correctly on the plasma membrane. We propose that the underlying mechanism is via endocytosis as CED-6 and CED-7 act redundantly with clathrin and its adaptor, the Adaptor protein 2 complex, in ensuring correct CED-1 localization. In conclusion, CED-6 and CED-7 impact other cellular processes than engulfment of apoptotic cells.

Factors affecting patients' ratings of health-care satisfaction.

INTRODUCTION: Surveys that include rating scales are commonly used to collect data about patients' experiences. We studied how patients associated their ratings with their experiences of care. METHODS: A survey and a qualitative study were conducted at a Danish hospital. Initially, 19 female patients completed a questionnaire using the response categories from very good to very bad; and subsequently they participated in a semi-structured interview held within two days after they completed the questionnaire. Additionally, 44 female patients participated in an interview within six weeks of completing a questionnaire. A phenomenological-hermeneutical approach was used in the analysis and interpretation. RESULTS: Two major themes emerged: experienced versus expected clinical quality and health-care professional attitude. Patients responded to each question by combining their experiences of both themes, e.g. a "very good" experience required that clinical service was provided at the expected level, at the very least, and that it was provided with recognition and respect. CONCLUSIONS: The female patients associated their experiences with their ratings, and two types of relation seemed to be at play: a care relation and a human relation. This finding can inform health-care practice, but department-specific examples may be needed to initiate improvements. FUNDING: The study received funding from the Centre for Patient Experience and Evaluation, Copenhagen, Denmark. The Danish Scientific Ethical Committees deemed it unnecessary to be involved in this project. TRIAL REGISTRATION: The Danish Data Protection Agency number of this study is 2008-58-0035.

[The National Danish Survey of Patient Experiences has a small positive bias]. / LUP giver et lidt for positivt billede af patientoplevelser.

The response rate in The National Danish Survey of Patient Experiences in 2009 was 54%. In order to evaluate bias due to non-responders, The Unit of Patient-perceived Quality merged survey data and data on patient background from Statistics Denmark. The relationships between the responding patients' background and their answers to six questions in the survey questionnaire are estimated with logistic regression analysis and subsequently used for predicting the answers of the non-responders. Results indicate a small positive bias in four of the questions and no bias in the remaining two.