Oleate induces K_ATP channel-dependent hyperpolarisation in mouse hypothalamic glucose-excited neurones without altering cellular energy charge

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.The unsaturated fatty acid, oleate exhibits anorexigenic properties reducing food intake and hepatic glucose output. However, its mechanism of action in the hypothalamus has not been fully determined. This study investigated the effects of oleate and glucose on GT1-7 mouse hypothalamic cells (a model of glucose-excited (GE) neurons) and mouse arcuate nucleus (ARC) neurons. Whole-cell and perforated patch-clamp recordings, immunoblotting and cell energy status measures were used to investigate oleate- and glucose-sensing properties of mouse hypothalamic neurons. Oleate or lowered glucose concentration caused hyperpolarization and inhibition of firing of GT1-7 cells by the activation of ATP-sensitive K(+) channels (KATP). This effect of oleate was not dependent on fatty acid oxidation or raised AMP-activated protein kinase activity or prevented by the presence of the UCP2 inhibitor genipin. Oleate did not alter intracellular calcium, indicating that CD36/fatty acid translocase may not play a role. However, oleate activation of KATP may require ATP metabolism. The short-chain fatty acid octanoate was unable to replicate the actions of oleate on GT1-7 cells. Although oleate decreased GT1-7 cell mitochondrial membrane potential there was no change in total cellular ATP or ATP/ADP ratios. Perforated patch and whole-cell recordings from mouse hypothalamic slices demonstrated that oleate hyperpolarized a subpopulation of ARC GE neurons by KATP activation. Additionally, in a separate small population of ARC neurons, oleate application or lowered glucose concentration caused membrane depolarization. In conclusion, oleate induces KATP-dependent hyperpolarization and inhibition of firing of a subgroup of GE hypothalamic neurons without altering cellular energy charge.This work was supported by: grants from the Wellcome Trust (grant number 068692) to M.L.J. Ashford; from Juvenile Diabetes Research Foundation (JDRF) to R.J. McCrimmon and Fellowships to C. Beall (JDRF; 3-576-2010 and Diabetes UK 13/0004647

Information and digital literacies; a review of concepts

A detailed literature reviewing, analysing the multiple and confusing concepts around the ideas of information literacy and digital literacy at the start of the millennium. The article was well-received, and is my most highly-cited work, with over 1100 citations

Economic Analysis of the Impact of Cloning on Improving Dairy Herd Composition

While the potential for cloning animals has been realized for at least the last 25 years, it is only recently that sufficient advances have been made to allow the technology to advance to a stage where it is possible that widespread commercial applications of cloning may become a reality in the next few years. But much has yet to be accomplished before the farming of cloned animals and their offspring become as familiar as genetically modified plants are today

Psychometric performance of the CFQ-R-8D compared to the EQ-5D-3L and SF-6D in people with cystic fibrosis

Objective: This study aimed to compare the psychometric performance of the Cystic Fibrosis Questionnaire–Revised–8 Dimensions (CFQ-R-8D), a new, condition-specific, preference-based measure, with that of generic preference-based measures EQ-5D-3L and Short Form 6 dimensions (SF-6D). Methods: Data from three trials of participants with CF aged ≥14 years who completed the CFQ-R and EQ-5D-3L or SF-6D were used. Analyses were undertaken to evaluate convergent validity based on correlations with CFQ-R domain scores. Known-group validity was assessed based on percent predicted forced expiratory volume in one second and pulmonary exacerbations. Responsiveness was based on correlation of change and sensitivity to change based on change in symptom severity. Effect sizes and standardized response means were estimated. Results: CFQ-R-8D utilities and dimensions were strongly correlated with most of the overlapping CFQ-R domain scores (ρ>0.5); EQ-5D-3L and SF-6D utilities and dimensions had moderate (ρ>0.3) to strong correlations in dimensions capturing similar concepts. All measures showed evidence of known-group validity (P0.1) for EQ-5D-3L. The SF-6D had the largest mean change over time and effect sizes, followed by CFQ-R-8D and then EQ-5D-3L. Neither CFQ-R-8D or SF-6D utility scores had ceiling effects (<9% responses in full health) compared with those of EQ-5D-3L (61%-62%). In participants classified as being in full health by EQ-5D-3L, CFQ-R-8D captured CF-specific health problems, particularly cough, abdominal pain, and breathing difficulty. Conclusions: The CFQ-R-8D reflected known-group differences and changes over time with stronger evidence of good psychometric performance than EQ-5D-3L and similar evidence as SF-6D. Additionally, the CFQ-R-8D captured more condition-specific symptoms than EQ-5D -3L or SF-6D, which are important determinants of health-related quality of life for people with CF