Following homozygosity mapping in a single kindred, we identified nonsense and missense mutations in MYO5B, encoding type Vb myosin motor protein, in individuals with microvillus inclusion disease (MVID). MVID is characterized by lack of microvilli on the surface of enterocytes and occurrence of intracellular vacuolar structures containing microvilli. In addition, mislocalization of transferrin receptor in MVID enterocytes suggests that MYO5B deficiency causes defective trafficking of apical and basolateral proteins in MVID.

Autosomal recessive microvillus inclusion disease (MVID) is characterized by an intractable diarrhea starting within the first few weeks of life. The hallmarks of MVID are a lack of microvilli on the surface of villous enterocytes, occurrence of intracellular vacuoles lined by microvilli (microvillus inclusions), and the cytoplasmic accumulation of periodic acid-Schiff (PAS)-positive vesicles in enterocytes. Recently, we identified mutations in MYO5B, encoding the unconventional type Vb myosin motor protein, in a first cohort of nine MVID patients. In this study, we identified 15 novel nonsense and missense mutations in MYO5B in 11 unrelated MVID patients. Fluorescence microscopy, Western blotting, and electron microscopy were applied to analyze the effects of MYO5B siRNA knockdown in polarized, brush border possessing CaCo-2 cells. Loss of surface microvilli, increased formation of microvillus inclusions, and subapical enrichment of PAS-positive endomembrane compartments were induced in polarized, filter-grown CaCo-2 cells, following MYO5B knock-down. Our data indicate that MYO5B mutations are a major cause of microvillus inclusion disease and that MYO5B knockdown recapitulates most of the cellular phenotype in vitro, thus independently showing loss of MYO5B function as the cause of microvillus inclusion disease.

Late endosomes locally regulate cell migration by transporting the p14–MP1 scaffold complex to the vicinity of focal adhesions.

Mitogen-activated protein kinase (MAPK) signaling is regulated by assembling distinct scaffold complexes at the plasma membrane and on endosomes. Thus, spatial resolution might be critical to determine signaling specificity. Therefore, we investigated whether epidermal growth factor receptor (EGFR) traffic through the endosomal system provides spatial information for MAPK signaling. To mislocalize late endosomes to the cell periphery we used the dynein subunit p50 dynamitin. The peripheral translocation of late endosomes resulted in a prolonged EGFR activation on late endosomes and a slow down in EGFR degradation. Continuous EGFR signaling from late endosomes caused sustained extracellular signal-regulated kinase and p38 signaling and resulted in hyperactivation of nuclear targets, such as Elk-1. In contrast, clustering late endosomes in the perinuclear region by expression of dominant active Rab7 delayed the entry of the EGFR into late endosomes, which caused a delay in EGFR degradation and a sustained MAPK signaling. Surprisingly, the activation of nuclear targets was reduced. Thus, we conclude that appropriate trafficking of the activated EGFR through endosomes controls the spatial and temporal regulation of MAPK signaling.

PurposeResearch in the area of technology‐enhanced learning (TEL) throughout the last decade has largely focused on sharing and reusing educational resources and data. This effort has led to a fragmented landscape of competing metadata schemas, or interface mechanisms. More recently, semantic technologies were taken into account to improve interoperability. The linked data approach has emerged as the de facto standard for sharing data on the web. To this end, it is obvious that the application of linked data principles offers a large potential to solve interoperability issues in the field of TEL. This paper aims to address this issue.Design/methodology/approachIn this paper, approaches are surveyed that are aimed towards a vision of linked education, i.e. education which exploits educational web data. It particularly considers the exploitation of the wealth of already existing TEL data on the web by allowing its exposure as linked data and by taking into account automated enrichment and interlinking techniques to provide rich and well‐interlinked data for the educational domain.FindingsSo far web‐scale integration of educational resources is not facilitated, mainly due to the lack of take‐up of shared principles, datasets and schemas. However, linked data principles increasingly are recognized by the TEL community. The paper provides a structured assessment and classification of existing challenges and approaches, serving as potential guideline for researchers and practitioners in the field.Originality/valueBeing one of the first comprehensive surveys on the topic of linked data for education, the paper has the potential to become a widely recognized reference publication in the area.