Endosomal MR1 Trafficking Plays a Key Role in Presentation of Mycobacterium tuberculosis Ligands to MAIT Cells

Mucosal-Associated Invariant T (MAIT) cells, present in high frequency in airway and other mucosal tissues, have Th1 effector capacity positioning them to play a critical role in the early immune response to intracellular pathogens, including Mycobacterium tuberculosis (Mtb). MR1 is a highly conserved Class I-like molecule that presents vitamin B metabolites to MAIT cells. The mechanisms for loading these ubiquitous small molecules are likely to be tightly regulated to prevent inappropriate MAIT cell activation. To define the intracellular localization of MR1, we analyzed the distribution of an MR1-GFP fusion protein in antigen presenting cells. We found that MR1 localized to endosomes and was translocated to the cell surface upon addition of 6-formyl pterin (6-FP). To understand the mechanisms by which MR1 antigens are presented, we used a lentiviral shRNA screen to identify trafficking molecules that are required for the presentation of Mtb antigen to HLA-diverse T cells. We identified Stx18, VAMP4, and Rab6 as trafficking molecules regulating MR1-dependent MAIT cell recognition of Mtb-infected cells. Stx18 but not VAMP4 or Rab6 knockdown also resulted in decreased 6-FP-dependent surface translocation of MR1 suggesting distinct pathways for loading of exogenous ligands and intracellular mycobacterially-derived ligands. We postulate that endosome-mediated trafficking of MR1 allows for selective sampling of the intracellular environment.Career Development Award: (#IK2 CX000538); U.S. Department of Veterans Affairs Clinical Sciences Research and Development Program (MJH); U.S.Department of Veterans Affairs Biomedical Laboratory Research and Development Program (DML) Merit Award: (#I01 BX000533); American Lung Association: (RT-350058)

The inclusive teacher educator: spaces for civic engagement

This paper is concerned with the teacher educator who is aspiring to be inclusive. It considers the obligations which arise within Higher Education Institutions and the extent to which these contribute to a loss of civic engagement and a lack of capacity to pursue inclusion, social justice and equity. The paper argues that this need not be the case and a reorientation for teacher educators is offered which affords teacher educators opportunities to, in Bourdieu’s (1998) terms, ‘play seriously’. This reorientation is in relation to three significant spaces – the ontological, the aesthetic and the epiphanic – and it is argued that operating within these spaces could enable new practices of inclusive teacher education to emerge

The Dementias Platform UK (DPUK) Data Portal

Abstract: The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure ‘lab’ using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee

The evolving self : finding meaning in near-death experiences using interpretative phenomenological analysis.

Objectives: A variety of anomalous experiences have been reported in the research literature as enhancing, rather than indicating poor mental health. The out-of-body experience (OBE), where the person’s self and body are phenomenologically separate, is a relatively common anomalous experience. The aim of this study was to investigate the experience of an OBE and its resultant after-effects. Design: An idiographic, phenomenological, qualitative approach was adopted. Methods: Three participants took part in recorded face-to-face, semi-structured interviews. Data were analysed using Interpretative Phenomenological Analysis. Results: IPA found experients perceived their OBEs as occurring at times of personal significance. They were inextricably linked with participants’ lives beyond their point of occurrence and played an adaptive role in response to difficult life events. The process of integration was helped or hindered by the varying reactions from others to the disclosure of the OBE. Conclusions: The idiographic nature of this study was instrumental in highlighting the subtle personal and social factors that influenced how the OBE was managed and integrated