Hypothesis:soluble Aβ oligomers in association with redox-active metal ions are the optimal generators of reactive oxygen species in Alzheimer's disease

Considerable evidence points to oxidative stress in the brain as an important event in the early stages of Alzheimer's disease (AD). The transition metal ions of Cu, Fe, and Zn are all enriched in the amyloid cores of senile plaques in AD. Those of Cu and Fe are redox active and bind to Aβ in vitro. When bound, they can facilitate the reduction of oxygen to hydrogen peroxide, and of the latter to the hydroxyl radical. This radical is very aggressive and can cause considerable oxidative damage. Recent research favours the involvement of small, soluble oligomers as the aggregating species responsible for Aβ neurotoxicity. We propose that the generation of reactive oxygen species (i.e., hydrogen peroxide and hydroxyl radicals) by these oligomers, in association with redox-active metal ions, is a key molecular mechanism underlying the pathogenesis of AD and some other neurodegenerative disorders

Managing the Employment Relationship

This is an Accepted Manuscript of a book chapter published by SAGE Publishing in Strategic Human Resource Management: An International Perspective, 2nd Edition on 2017, available at: https://uk.sagepub.com/en-gb/eur/strategic-human-resource-management/book249141.The chapter discusses and explores the employment relationship within a UK and international context. It looks at Government ideological perspectives, employee engagement and employee voice.Peer reviewedFinal Accepted Versio

Artificial Intelligence Techniques Applied To Draughts

This thesis documents the work done to develop a draughts playing program that learns game strategies utilising various Artificial Intelligence (AI) techniques with the goal of being able to play draughts at a reasonably high skill level as a result of having played against itself without external guidance. Context/Background: AI is a fast evolving field of study. The motivation being programming computers to learn from experience should eventually eliminate the need for this detailed, time consuming, and costly programming effort currently required to program solutions to problems. Aims: The aim is to investigate a variety of AI techniques. The program’s effectiveness will be assessed in both evaluating moves and playing a computationally intensive game. Minimax based algorithms together with a basic scoring heuristic are used to evaluate enough of the game tree to pick high utility moves. Later the scoring heuristic is augmented using artificial intelligence techniques. As a result of this training “smart scoring behaviour” the program is expected to learn how to best assign values to each of the squares on the draughts board enabling it to play at an adequately high skill level. Method: In this thesis a version of the board game Draughts is implemented in the Java programming language. Players were developed using a variety of techniques. These algorithms were tested by comparing running times, number of nodes of the game tree searched and the utility of the moves picked. In addition an algorithm is developed to assign scores to given board states using a genetic algorithm. Results: The project was a success for the most part permitting the creation of the game of draughts in the JAVA programming language. Four out of the five proposed move selection techniques were successfully tested in isolation. Finally the genetic algorithm demonstrated the ability to augment the scoring heuristic without the benefit of external guidance in the form of human experience

A Fibre Optical Strain Sensor

Strain-sensing elements, fabricated in standard communications-grade single mode optical fibre, are increasingly being considered for application in structural health monitoring. The reason for this is the numerous advantages demonstrated by these devices compared with traditional indicators. This thesis describes work carried out on optical sensors at the University of Plymouth. The aim of this work was to achieve an optical fibre strain sensing system capable of measuring absolute strain with good resolution and having wide dynamic range, without bulky optical equipment and not susceptible to misalignment due to handling. Earlier work was devoted to study on an intrinsic Fabry-Perot interferometric sensor and an optical phase-shift detection technique. The sensing element investigated relied on the end face of an optical fibre as one mirror and the second mirror being a layer of Titanium Dioxide (TO2). Although some results are included, it was soon realised that this sensor had a number of problems, particularly with fabrication. As no simple solution presented itself, consideration was given to a sensor that made use of the change in reflectance of an intra-core fibre Bragg grating when the grating was subjected to strain. The bulk of work described in this thesis is concerned with this type of sensing element. The grating structure is inherently flexible and a number of structural formats were studied and investigated. The first and simplest grating considered was two linearly chirped Bragg gratings used in a Fabry-Perot configuration (a grating resonator). The sensor was tested using the sensing detection system and although the fabrication problems were overcome absolute strain measurement was unattainable. To achieve this end, a theoretical study of a number of grating structures was carried out using the T-matrix Formalism. Confidence in using this approach was gained by comparing the spectral behaviour of a proposed grating with results, which were given by another theoretical model for the same proposed grating. The outcome of this study was that two structures in particular showed promise with regard to absolutism (the measure of true strain) and linearity. Discussions held with the department of Applied Physics at Aston University about fabrication resulted in one of the proposed designs being abandoned due to difficulties of fabrication. The second structure showed more promise and fabrication attempts were put in hand. This grating is linearly-chirped with a Top-hat function and a sinusoidal perturbation as a taper function of the refractive index modulation. Experiments were performed, data were acquired and system performance for this sensor is presented. The thesis concludes that using such a fibre Bragg grating as the sensing element of a strain sensing system enables it to measure absolute strain without using bulky optical equipment. At present, the resolution of strain is limited by the quality of the grating being fabricated (anomalies on profile), this should improve once the fabrication technique is refined.British Aerospace System and Equipment, BASE and Department of Electronic Engineering and Applied Physics, Aston Universit

A preliminary electron microscopic investigation into the interaction between Aβ1-42 peptide and a novel nanoliposome- coupled retro-inverso peptide inhibitor, developed as a potential treatment for Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative condition that results in severe cognitive and functional decline in sufferers and for which there are currently no effective treatments to halt or reverse disease progression. AD is the most common form of dementia and age is the major risk factor for this disease. With worldwide population structures changing as increasing number of individuals survive into old age, there is urgent need for novel disease modifying treatments for this condition, which has profound effects upon sufferers in addition to those around them. Some of us have previously developed a peptide inhibitor of Aβ1-42 aggregation (RI-OR2-TAT) that has been shown to reduce Aβ1-42 pathology in vivo in mouse models of AD. ~1690 copies of RI-OR2-TAT have been covalently attached to nanoliposome carrier particles forming Peptide Inhibitor NanoParticles (PINPs), and this study investigated the effect of PINPs upon Aβ1-42 aggregation at the molecular level. Our results show that PINPs are able to reduce Aβ1-42 aggregation and do so by binding early (oligomers) and late (fibrillar) stage aggregates. These results highlight the ability of PINPs to disrupt the formation of multiple Aβ1-42 aggregates capable of causing neurotoxicity and thus provide a strong case for PINPs to be carried forward into early stage clinical trials as a novel therapeutic option for the treatment of AD

The bending and temperature characteristics of long period gratings written in elliptical core step-index fibre

We describe the characterisation of long period gratings written in elliptical core fibre, which yield a discriminatory sensor for curvature and temperature with a resolution ±0.05m-1 for curvature and ±0.9 °C for temperature