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

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

Improved Quality of Life Following Addiction Treatment Is Associated with Reductions in Substance Use

People seeking treatment for substance use disorders (SUD) ultimately aspire to improve their quality of life (QOL) through reducing or ceasing their substance use, however the association between these treatment outcomes has received scant research attention. In a prospective, multi-site treatment outcome study (‘Patient Pathways’), we recruited 796 clients within one month of intake from 21 publicly funded addiction treatment services in two Australian states, 555 (70%) of whom were followed-up 12 months later. We measured QOL at baseline and follow-up using the WHOQOL-BREF (physical, psychological, social and environmental domains) and determined rates of “SUD treatment success” (past-month abstinence or a statistically reliable reduction in substance use) at follow-up. Mixed effects linear regression analyses indicated that people who achieved SUD treatment success also achieved significantly greater improvements in QOL, relative to treatment non-responders (all four domains p 0.001). Paired t-tests indicated that non-responders significantly improved their social (p = 0.007) and environmental (p = 0.033) QOL; however, their psychological (p = 0.088) and physical (p = 0.841) QOL did not significantly improve. The findings indicate that following treatment, QOL improved in at least some domains, but that reduced substance use was associated with both stronger and broader improvements in QOL. Addressing physical and psychological co-morbidities during treatment may facilitate reductions in substance use

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

Designing and Implementing Future Aerial Communication Networks

Providing "connectivity from the sky" is the new innovative trend in wireless communications. High and low altitude platforms, drones, aircrafts and airships are being considered as the candidates for deploying wireless communications complementing the terrestrial communication infrastructure. In this article, we report the detailed account of the design and implementation challenges of an aerial network consisting of LTE Advanced (LTE-A) base stations. In particular, we review achievements and innovations harnessed by an aerial network composed of Helikite platforms. Helikites can be raised in the sky to bring Internet access during special events and in the aftermath of an emergency. The trial phase of the system mounting LTE-A technology onboard Helikites to serve users on the ground showed not only to be very encouraging but that such a system could offer even a longer lasting solution provided that inefficiency in powering the radio frequency equipment in the Helikite can be overcome.Comment: IEEE Communications Magazine 201

The development of peptide-based inhibitors for Tau aggregation as a potential therapeutic for Alzheimer’s disease

There are currently approximately 50 million individuals worldwide with dementia resulting in predicted global societal costs of up to US $1 trillion. Approximately 60-70% of these individuals have Alzheimer’s disease, which results in a chronic and insidious decline in memory. One of the main proteins that misfolds in this disease is Tau protein, which aggregates into toxic oligomers and neurofibrillary tangles. It is these aggregates, which cause damage to the brain resulting in dementia. As a result, it is imperative to be able to prevent or suppress the pathogenic aggregation of this protein, so the onset of dementia is halted or delayed, improving quality of life. Certain amino acid sequences in Tau such as VQIINK and VQIVYK play important roles in aggregation. Targeting these sequences can potentially prevent aggregation. This project aims to produce effective peptide inhibitors based on the human Tau peptide sequences VQIINK and VQIVYK, to specifically target pathogenic Tau aggregation. Using molecular docking softrware ‘ICM-Pro’ the potential binding locations of a variety of peptide candidates were computationally investigated to determine which will be most successful in a laboratory setting. Recombinant TauΔ1-250 was incubated in the prescense of heparin and subsequently aggregated to display highly ordered parallel, in-register β-strand structures; including fibrils and paired helical filaments presenting the characteristic twist under transmission electron microscope. This aggregation was achieved using of 20μM Tau at pH 7.4 in the presence of 20mM Tris buffer, 1mM DTT, 5μM Heparin, and 15uM ThT and incubated at 37 °C for 48 hours. The first generation of peptides AG01, AG02, AG02, AG02R4, AG02R5, AGR502, AG02PR5, AG02R6, AG02R9, AG02TAT, AG02ΔI, AG02ΔV inhibited approximately 50% of Tau aggregation determined by Thioflavin-T (ThT) fluorescence assay. The next generation, AG03 was slightly more effective, however when retroinverted (RI-AG03) inhibited over 90% of Tau aggregation, confirmed by Thioflavin-T fluorescence assay, transmission electron microscopy, circular dichroism and Congo red birefringence. RI-AG03 was determined to be stable in cells at therapeutic concentrations. After determining stability of RI-AG03 using SDS-PAGE, thermal circular dichroism and mass spectrometry, it was tested in vivo in rough eye Drosophila model. Results suggested that RI-AG03 partially rescued the rough eye phenotype in this model. This research demonstrates that retro-inverted peptide RI-AG03 is a potent inhibitor of Tau aggregation and can be further developed as a novel therapeutic for Tauopathies like Alzhimer’s Disease