Inhibition of the inositol kinase Itpkb augments calcium signaling in lymphocytes and reveals a novel strategy to treat autoimmune disease

Emerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological inhibition or genetic deletion of Itpkb results in elevated intracellular Ca2+ and induction of FasL and Bim resulting in T cell apoptosis. Deletion of Itpkb or treatment with Itpkb inhibitors blocks T-cell dependent antibody responses in vivo and prevents T cell driven arthritis in rats. These data identify Itpkb as an essential mediator of T cell activation and suggest Itpkb inhibition as a novel approach to treat autoimmune disease

A comparison of methods for temporal analysis of aoristic crime

Objectives: To test the accuracy of various methods previously proposed (and one new method) to estimate offence times where the actual time of the event is not known. Methods: For 303 thefts of pedal cycles from railway stations, the actual offence time was determined from closed-circuit television and the resulting temporal distribution compared against commonly-used estimated distributions using circular statistics and analysis of residuals. Results: Aoristic analysis and allocation of a random time to each offence allow accurate estimation of peak offence times. Commonly-used deterministic methods were found to be inaccurate and to produce misleading results. Conclusions: It is important that analysts use the most accurate methods for temporal distribution approximation to ensure any resource decisions made on the basis of peak times are reliable

Ethnography and ethics in your own workplace: Reconceptualising dialysis care from an insider nurse researcher

Alison Wood - ORCID: 0000-0002-5625-8778 http://orcid.org/0000-0002-5625-8778Item not available in this repository.This chapter presents reflections on the author’s experience in conducting ethnographic research in a setting in which they had an existing professional role as a registered and practising nurse. The position held and how this was negotiated within the research and clinical environment highlight the role ethnography can play for nurses researching in healthcare settings. In particular, this chapter highlights the positional complexities of adopting both ‘insider’ ethnographer and professional roles in a healthcare context, and the insights this generated around the partial forms of knowledge that emerge. The dual status of the researcher provided a unique position in a complex setting and shaped the generation of ethnographic findings.https://doi.org/10.1007/978-3-319-89396-9_4pubpu