Untargeted Metabolomic Analysis of Human Plasma Indicates Differentially Affected Polyamine and L-Arginine Metabolism in Mild Cognitive Impairment Subjects Converting to Alzheimer’s Disease

This study combined high resolution mass spectrometry (HRMS), advanced chemometrics and pathway enrichment analysis to analyse the blood metabolome of patients attending the memory clinic: cases of mild cognitive impairment (MCI; n = 16), cases of MCI who upon subsequent follow-up developed Alzheimer's disease (MCI_AD; n = 19), and healthy age-matched controls (Ctrl; n = 37). Plasma was extracted in acetonitrile and applied to an Acquity UPLC HILIC (1.7μm x 2.1 x 100 mm) column coupled to a Xevo G2 QTof mass spectrometer using a previously optimised method. Data comprising 6751 spectral features were used to build an OPLS-DA statistical model capable of accurately distinguishing Ctrl, MCI and MCI_AD. The model accurately distinguished (R2 = 99.1%; Q2 = 97%) those MCI patients who later went on to develop AD. S-plots were used to shortlist ions of interest which were responsible for explaining the maximum amount of variation between patient groups. Metabolite database searching and pathway enrichment analysis indicated disturbances in 22 biochemical pathways, and excitingly it discovered two interlinked areas of metabolism (polyamine metabolism and L-Arginine metabolism) were differentially disrupted in this well-defined clinical cohort. The optimised untargeted HRMS methods described herein not only demonstrate that it is possible to distinguish these pathologies in human blood but also that MCI patients 'at risk' from AD could be predicted up to 2 years earlier than conventional clinical diagnosis. Blood-based metabolite profiling of plasma from memory clinic patients is a novel and feasible approach in improving MCI and AD diagnosis and, refining clinical trials through better patient stratification.

Plasma Clusterin Levels and the rs11136000 Genotype in Individuals with Mild Cognitive Impairment and Alzheimer's Disease

Aim: Substantial evidence links atherosclerosis and Alzheimer's disease (AD). Apolipoproteins, such as apolipoprotein E, have a causal relationship with both diseases. The rs11136000 SNP within the CLU gene, which encodes clusterin (apolipoprotein J), is also associated with increased AD risk. The aim of this study was to investigate the relationship between plasma clusterin and the rs11136000 genotype in mild cognitive impairment (MCI) and AD.

Methods: Plasma and DNA samples were collected from control, MCI and AD subjects (n=142, 111, 154, respectively). Plasma clusterin was determined by ELISA and DNA samples were genotyped for rs11136000 by TaqMan assay.

Results: Plasma clusterin levels were higher in MCI and AD subjects vs. controls (222.3 +/- 61.3 and 193.6 +/- 58.2 vs. 178.6 +/- 52.3 mu g/ml, respectively; p

Conclusion: This study examined control, MCI and AD subjects, identifying for the first time that plasma clusterin levels were influenced, not only by the presence of AD, but also the transitional stage of MCI, while rs11136000 genotype only influenced plasma clusterin levels in the control group. The increase in plasma clusterin in MCI and AD subjects may occur in response to the disease process and would be predicted to increase binding capacity for amyloid-beta peptides in plasma, enhancing their removal from the brain.

Cockney, pseudo-slang et argot de série noire : San-Antonio et le moment Peter Cheyney du roman noir français

This article examines how in post-war France slang became a byword for the noir genre. It considers the mechanisms, models, networks and translators' practices which set the tone for the "Série Noire”, whose influence, both written and on the screen, had, within a decade, become, a "mythology" studied by Roland Barthes. It argues that this use of slang is redolent of the inauthenticity which characterises this stage in the reception of the Noir genre in France. It is certain that this artificial French slang is far from devoid of charm, or even mystery. But it tends to depreciate and deform the translated works and seems to be the hallmark of an era that might have defined and acclimatised Noir fiction in France, yet remains one which has not fully understood the gravity of its purpose. While such translations seem outdated nowadays (if not quite incomprehensible ), original works written at the time in French by writers inspired by the model of " pseudo- slang" and the fashionability of American popular culture have benefited from them. In this very inauthenticity, derivative novels have found a licence for invention and freedom, with authors such as Cocteau hailing it as a revival of the French written language. We see here how the adventures of Commissaire San Antonio, by Frédéric Dard constitute the best examples of this new creativity in French and draw upon a template set for the reception of American literature

Northern Ireland, America and the Emerging Church Movement: Exploring the Significance of Peter Rollins andthe Ikon Collective

The Emerging Church Movement (ECM) is a primarily Western religious phenomenon, identifiable by its critical ‘deconstruction’ of ‘modern’ religion. While most prominent in North America, especially the United States, some of the most significant contributors to the ECM ‘conversation’ have been the Belfast-based Ikon Collective and one of its founders, philosopher Peter Rollins. Their rootedness in the unique religious, political and social landscape of Northern Ireland in part explains their position on the ‘margins’ of the ECM, and provides many of the resources for their contributions. Ikon’s development of ‘transformance art’ and its ‘leaderless’ structure raise questions about the institutional viability of the wider ECM. Rollins’ ‘Pyrotheology’ project, grounded in his reading of post-modern philosophy, introduces more radical ideas to the ECM conversation. Northern Ireland’s ‘Troubles’ and ‘marginal’ location provides the ground from which Rollins and Ikon have been able to expose the boundaries of the ECM and raise questions about just how far the ECM may go in its efforts to transform Western Christianity.

Combining multi-band and frequency-filtering techniques for speech recognition in noisy environments

While current speech recognisers give acceptable performance in carefully controlled environments, their performance degrades rapidly when they are applied in more realistic situations. Generally, the environmental noise may be classified into two classes: the wide-band noise and narrow band noise. While the multi-band model has been shown to be capable of dealing with speech corrupted by narrow-band noise, it is ineffective for wide-band noise. In this paper, we suggest a combination of the frequency-filtering technique with the probabilistic union model in the multi-band approach. The new system has been tested on the TIDIGITS database, corrupted by white noise, noise collected from a railway station, and narrow-band noise, respectively. The results have shown that this approach is capable of dealing with noise of narrow-band or wide-band characteristics, assuming no knowledge about the noisy environment.

Research in Progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK)

The UK Refractory Asthma Stratification Programme(RASP-UK) will explore novel biomarker stratificationstrategies in severe asthma to improve clinicalmanagement and accelerate development of newtherapies. Prior asthma mechanistic studies have notstratified on inflammatory phenotype and theunderstanding of pathophysiological mechanisms inasthma without Type 2 cytokine inflammation is limited.RASP-UK will objectively assess adherence tocorticosteroids (CS) and examine a novel compositebiomarker strategy to optimise CS dose; this will alsoaddress what proportion of patients with severe asthmahave persistent symptoms without eosinophilic airwaysinflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies.