Control of Membrane Excitability by Potassium and Chloride Leak Conductances

The permeability of the neuronal membrane to different ions determines both resting membrane potential (RMP) and input conductance. These parameters determine the cells response to synaptic input. In this thesis I have examined how the molecular properties of potassium and chloride ion channels can influence neuronal excitability in ways that have not previously been considered. For example, two‐pore domain potassium (K2P) channels open at rest to generate a persistent potassium ion efflux. In addition to its accepted role in setting the RMP, I have tested the hypothesis that this conductance is sufficient to repolarise the membrane during an action potential (AP) in the absence of voltage‐dependent potassium channels (Kv). We tested this prediction using heterologous expression of TASK3 or TREK1 K2P channels combined with conductance injection to simulate the presence of a voltage‐gated sodium conductance. These experiments demonstrated that K2P channels are sufficient to support APs during short and prolonged depolarising current pulses. The membranes permeability to chloride ions can also be affected by extrasynaptic GABAA receptors containing the delta subunit (δ‐GABAARs) that produce a tonic conductance due to their high apparent affinity for GABA. The anaesthetics Propofol and THIP are both believed to alter neuronal excitability by enhancing this persistent chloride flux. We have examined how this anaesthetic action is affected by the steady‐state ambient GABA concentrations that are believed to exist in vivo. Surprisingly, the anaesthetic enhancement of δ‐GABAARs is lost at low ambient GABA concentrations. Therefore, I would suggest that the anaesthetic potency of these drugs is affected by the resting ambient GABA concentration in a manner that has not previously been appreciated. In the current Thesis I have examined the molecular and pharmacological properties of two very different ion channel families that both generate a leak conductance, and I will present models that link the behaviour of these ion channels to their ability to modulate neuronal excitability

Social technologies for online learning: theoretical and contextual issues

Three exemplars are presented of social technologies deployed in educational contexts: wikis; a photo-sharing environment; and a social bookmarking tool. Students were found to engage with the technologies selectively, sometimes rejecting them, in the light of their prior conceptions of education. Some students (a minority in all the studies) were unsympathetic to the educational philosophy underpinning the technology’s adoption. The paper demonstrates, through an examination of in-context use, the importance of socio-cultural factors in relation to education, and the non-deterministic nature of educational technology. The academic study of technology has increasingly called into question the deterministic views which are so pervasive in popular discourse and among policy makers. Instead, socio-cultural factors play a crucial role in shaping and defining technology and educational technology is no exception, as the examples in the paper show. The paper concludes by drawing out some implications of the examples for the use of social technologies in education

Loss of GPR75 protects against non-alcoholic fatty liver disease and body fat accumulation

Open Access via the Elsevier Agreement L.K.H. designed the experiments with input from F.M., G.S.H.Y., and J.J.R.; F.M. and J.I. created the CRISPR-Cas9-deleted Gpr75 mouse line with input from A.M.; A.L.-P., C.M., B.Y.H.L., G.K.C.D., N.S., P.B.M.d.M., R.C., K.K., E.J.G., J.R.B.P., F.G., J.R.S., and J.J.R. performed experiments and/or data analysis; D.T. provided reagents and intellectual contributions; and L.K.H. and A.L.-P. wrote the manuscript with input from all other authors.Peer reviewe

The masculine logic of DDR and SSR in the Rwanda Defence Force

Since the 1994 genocide and civil war, the Rwandan government has implemented an externally funded Demobilisation, Demilitarisation and Reintegration (DDR)/Security Sector Reform (SSR) program culminating in the consolidation of armed groups into a new, professionalised Rwanda Defence Force (RDF). Feminists argue that DDR-SSR initiatives that exclude combatant women and girls or ignore gendered security needs fail to transform the political conditions that led to conflict. Less attention has been paid to how gendered relations of power play out through gender sensitive DDR and SSR initiatives that seek to integrate women and transform hyper-masculine militarised masculinities. This article investigates how Rwanda’s DDR-SSR program is governed by an oppressive masculine logic. Drawing on critical studies on men and masculinities and feminist work on peacebuilding, myths and the politics of belonging, it is argued that Rwanda’s locally-owned DDR-SSR program places the military and militarisation at the centre of the nation-building program. Through various ‘boundary construction’ practices, the Rwandan government attempts to stabilise the post-1994 gender order and entrench the hegemony of a new militarised masculinity in Rwandan society. The case study draws on field research conducted in 2014 and 2015 and a discourse analysis of RDF historical accounts, policy documents and training materials

Removing the Threat of Diclofenac to Critically Endangered Asian Vultures

Veterinary use of the nonsteroidal anti-inflammatory (NSAID) drug diclofenac in South Asia has resulted in the collapse of populations of three vulture species of the genusGyps to the most severe category of global extinction risk. Vultures are exposed to diclofenac when scavenging on livestock treated with the drug shortly before death. Diclofenac causes kidney damage, increased serum uric acid concentrations, visceral gout, and death. Concern about this issue led the Indian Government to announce its intention to ban the veterinary use of diclofenac by September 2005. Implementation of a ban is still in progress late in 2005, and to facilitate this we sought potential alternative NSAIDs by obtaining information from captive bird collections worldwide. We found that the NSAID meloxicam had been administered to 35 captiveGyps vultures with no apparent ill effects. We then undertook a phased programme of safety testing of meloxicam on the African white-backed vultureGyps africanus, which we had previously established to be as susceptible to diclofenac poisoning as the endangered AsianGyps vultures. We estimated the likely maximum level of exposure (MLE) of wild vultures and dosed birds by gavage (oral administration) with increasing quantities of the drug until the likely MLE was exceeded in a sample of 40G. africanus. Subsequently, sixG. africanus were fed tissues from cattle which had been treated with a higher than standard veterinary course of meloxicam prior to death. In the final phase, ten Asian vultures of two of the endangered species(Gyps bengalensis,Gyps indicus) were dosed with meloxicam by gavage; five of them at more than the likely MLE dosage. All meloxicam-treated birds survived all treatments, and none suffered any obvious clinical effects. Serum uric acid concentrations remained within the normal limits throughout, and were significantly lower than those from birds treated with diclofenac in other studies. We conclude that meloxicam is of low toxicity toGyps vultures and that its use in place of diclofenac would reduce vulture mortality substantially in the Indian subcontinent. Meloxicam is already available for veterinary use in India

Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial

BACKGROUND: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. METHODS: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. RESULTS: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. CONCLUSIONS: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin