Subjective and Objective Indicators of Recovery in Severe Mental Illness: a Cross-Sectional Study

Background: This study aimed to determine whether subjective dimensions of recovery such as empowerment are associated with self-report of more objective indicators such as level of participation in the community and income from employment. A secondary aim was to investigate the extent to which diagnosis or other consumer characteristics mediated any relationship between these variables. Methods: The Community Integration Measure, the Empowerment Scale, the Recovery Assessment Scale, and the Camberwell Assessment of Needs Short Appraisal Schedule were administered to a convenience sample of 161 consumers with severe mental illness. Results: The majority of participants had a primary diagnosis of schizophreniform, anxiety/depression or bipolar affective disorder. The Empowerment Scale was quite strongly correlated with the Recovery Assessment Scale and the Community Integration Measure. Participants with a diagnosis of bipolar affective disorder had signifi cantly higher recovery and empowerment scores than participants with schizophrenia or depression. Both empowerment and recovery scores were significantly higher for people engaged in paid employment than for those receiving social security benefits. Conclusions: The measurement of subjective dimensions of recovery such as empowerment has validity in evaluation of global recovery for people with severe mental illness. A diagnosis of bipolar disorder is associated with higher scores on subjective and objective indicators of recovery.

Preliminary study on bridge health prediction using Dynamic Objective Oriented Bayesian Network (DOOBN)

The availability of bridges is crucial to people’s daily life and national economy. Bridge health prediction plays an important role in bridge management because maintenance optimization is implemented based on prediction results of bridge deterioration. Conventional bridge deterioration models can be categorised into two groups, namely condition states models and structural reliability models. Optimal maintenance strategy should be carried out based on both condition states and structural reliability of a bridge. However, none of existing deterioration models considers both condition states and structural reliability. This study thus proposes a Dynamic Objective Oriented Bayesian Network (DOOBN) based method to overcome the limitations of the existing methods. This methodology has the ability to act upon as a flexible unifying tool, which can integrate a variety of approaches and information for better bridge deterioration prediction. Two demonstrative case studies are conducted to preliminarily justify the feasibility of the methodology

Rational design of serine protease inhibitors

Proteases regulate a spectrum of diverse physiological processes, and dysregulation of proteolytic activity drives a plethora of pathological conditions. Understanding protease function is essential to appreciating many aspects of normal physiology and progression of disease. Consequently, development of potent and specific inhibitors of proteolytic enzymes is vital to provide tools for the dissection of protease function in biological systems and for the treatment of diseases linked to aberrant proteolytic activity. The studies in this thesis describe the rational design of potent inhibitors of three proteases that are implicated in disease development. Additionally, key features of the interaction of proteases and their cognate inhibitors or substrates are analysed and a series of rational inhibitor design principles are expounded and tested. Rational design of protease inhibitors relies on a comprehensive understanding of protease structure and biochemistry. Analysis of known protease cleavage sites in proteins and peptides is a commonly used source of such information. However, model peptide substrate and protein sequences have widely differing levels of backbone constraint and hence can adopt highly divergent structures when binding to a protease’s active site. This may result in identical sequences in peptides and proteins having different conformations and diverse spatial distribution of amino acid functionalities. Regardless of this, protein and peptide cleavage sites are often regarded as being equivalent. One of the key findings in the following studies is a definitive demonstration of the lack of equivalence between these two classes of substrate and invalidation of the common practice of using the sequences of model peptide substrates to predict cleavage of proteins in vivo. Another important feature for protease substrate recognition is subsite cooperativity. This type of cooperativity is commonly referred to as protease or substrate binding subsite cooperativity and is distinct from allosteric cooperativity, where binding of a molecule distant from the protease active site affects the binding affinity of a substrate. Subsite cooperativity may be intramolecular where neighbouring residues in substrates are interacting, affecting the scissile bond’s susceptibility to protease cleavage. Subsite cooperativity can also be intermolecular where a particular residue’s contribution to binding affinity changes depending on the identity of neighbouring amino acids. Although numerous studies have identified subsite cooperativity effects, these findings are frequently ignored in investigations probing subsite selectivity by screening against diverse combinatorial libraries of peptides (positional scanning synthetic combinatorial library; PS-SCL). This strategy for determining cleavage specificity relies on the averaged rates of hydrolysis for an uncharacterised ensemble of peptide sequences, as opposed to the defined rate of hydrolysis of a known specific substrate. Further, since PS-SCL screens probe the preference of the various protease subsites independently, this method is inherently unable to detect subsite cooperativity. However, mean hydrolysis rates from PS-SCL screens are often interpreted as being comparable to those produced by single peptide cleavages. Before this study no large systematic evaluation had been made to determine the level of correlation between protease selectivity as predicted by screening against a library of combinatorial peptides and cleavage of individual peptides. This subject is specifically explored in the studies described here. In order to establish whether PS-SCL screens could accurately determine the substrate preferences of proteases, a systematic comparison of data from PS-SCLs with libraries containing individually synthesised peptides (sparse matrix library; SML) was carried out. These SML libraries were designed to include all possible sequence combinations of the residues that were suggested to be preferred by a protease using the PS-SCL method. SML screening against the three serine proteases kallikrein 4 (KLK4), kallikrein 14 (KLK14) and plasmin revealed highly preferred peptide substrates that could not have been deduced by PS-SCL screening alone. Comparing protease subsite preference profiles from screens of the two types of peptide libraries showed that the most preferred substrates were not detected by PS SCL screening as a consequence of intermolecular cooperativity being negated by the very nature of PS SCL screening. Sequences that are highly favoured as result of intermolecular cooperativity achieve optimal protease subsite occupancy, and thereby interact with very specific determinants of the protease. Identifying these substrate sequences is important since they may be used to produce potent and selective inhibitors of protolytic enzymes. This study found that highly favoured substrate sequences that relied on intermolecular cooperativity allowed for the production of potent inhibitors of KLK4, KLK14 and plasmin. Peptide aldehydes based on preferred plasmin sequences produced high affinity transition state analogue inhibitors for this protease. The most potent of these maintained specificity over plasma kallikrein (known to have a very similar substrate preference to plasmin). Furthermore, the efficiency of this inhibitor in blocking fibrinolysis in vitro was comparable to aprotinin, which previously saw clinical use to reduce perioperative bleeding. One substrate sequence particularly favoured by KLK4 was substituted into the 14 amino acid, circular sunflower trypsin inhibitor (SFTI). This resulted in a highly potent and selective inhibitor (SFTI-FCQR) which attenuated protease activated receptor signalling by KLK4 in vitro. Moreover, SFTI-FCQR and paclitaxel synergistically reduced growth of ovarian cancer cells in vitro, making this inhibitor a lead compound for further therapeutic development. Similar incorporation of a preferred KLK14 amino acid sequence into the SFTI scaffold produced a potent inhibitor for this protease. However, the conformationally constrained SFTI backbone enforced a different intramolecular cooperativity, which masked a KLK14 specific determinant. As a consequence, the level of selectivity achievable was lower than that found for the KLK4 inhibitor. Standard mechanism inhibitors such as SFTI rely on a stable acyl-enzyme intermediate for high affinity binding. This is achieved by a conformationally constrained canonical binding loop that allows for reformation of the scissile peptide bond after cleavage. Amino acid substitutions within the inhibitor to target a particular protease may compromise structural determinants that support the rigidity of the binding loop and thereby prevent the engineered inhibitor reaching its full potential. An in silico analysis was carried out to examine the potential for further improvements to the potency and selectivity of the SFTI-based KLK4 and KLK14 inhibitors. Molecular dynamics simulations suggested that the substitutions within SFTI required to target KLK4 and KLK14 had compromised the intramolecular hydrogen bond network of the inhibitor and caused a concomitant loss of binding loop stability. Furthermore in silico amino acid substitution revealed a consistent correlation between a higher frequency of formation and the number of internal hydrogen bonds of SFTI-variants and lower inhibition constants. These predictions allowed for the production of second generation inhibitors with enhanced binding affinity toward both targets and highlight the importance of considering intramolecular cooperativity effects when engineering proteins or circular peptides to target proteases. The findings from this study show that although PS-SCLs are a useful tool for high throughput screening of approximate protease preference, later refinement by SML screening is needed to reveal optimal subsite occupancy due to cooperativity in substrate recognition. This investigation has also demonstrated the importance of maintaining structural determinants of backbone constraint and conformation when engineering standard mechanism inhibitors for new targets. Combined these results show that backbone conformation and amino acid cooperativity have more prominent roles than previously appreciated in determining substrate/inhibitor specificity and binding affinity. The three key inhibitors designed during this investigation are now being developed as lead compounds for cancer chemotherapy, control of fibrinolysis and cosmeceutical applications. These compounds form the basis of a portfolio of intellectual property which will be further developed in the coming years.

The development of a conceptual framework for a district 4-Year Pavement Management Plan, implementation of network-level project screening process

The Texas Department of Transportation (TxDOT) is concerned about the widening gap between preservation needs and available funding. Funding levels are not adequate to meet the preservation needs of the roadway network; therefore projects listed in the 4-Year Pavement Management Plan must be ranked to determine which projects should be funded now and which can be postponed until a later year. Currently, each district uses locally developed methods to prioritize projects. These ranking methods have relied on less formal qualitative assessments based on engineers’ subjective judgment. It is important for TxDOT to have a 4-Year Pavement Management Plan that uses a transparent, rational project ranking process. The objective of this study is to develop a conceptual framework that describes the development of the 4-Year Pavement Management Plan. It can be largely divided into three Steps; 1) Network-Level project screening process, 2) Project-Level project ranking process, and 3) Economic Analysis. A rational pavement management procedure and a project ranking method accepted by districts and the TxDOT administration will maximize efficiency in budget allocations and will potentially help improve pavement condition. As a part of the implementation of the 4-Year Pavement Management Plan, the Network-Level Project Screening (NLPS) tool including the candidate project identification algorithm and the preliminary project ranking matrix was developed. The NLPS has been used by the Austin District Pavement Engineer (DPE) to evaluate PMIS (Pavement Management Information System) data and to prepare a preliminary list of candidate projects for further evaluation.

Rational avoidance of accountability

Anthony Downs public choice theory proposes that every rational person would try to meet their own desires in preference to those of others, and that such rational persons would attempt to obtain these desires in the most efficient manner possible. This paper will demonstrate that the application of this theory would mean that public servants and politicians would perform acts of corruption and maladministration in order to efficiently meet their desires. As such action is unavoidable, political parties must appear to meet the public demand for accountability systems, but must not make these systems viable lest they expose the corruption and maladministration that would threaten the government’s chance or re-election. It is therefore logical for governments to display a commitment for accountability whilst simultaneously ensuring the systems would not be able to interfere with government control or expose its flaws.

Multi-objective design optimization of morphing UAV aerofoil/wing using hybridised MOGA

The paper investigates two advanced Computational Intelligence Systems (CIS) for a morphing Unmanned Aerial Vehicle (UAV) aerofoil/wing shape design optimisation. The first CIS uses Genetic Algorithm (GA) and the second CIS uses Hybridized GA (HGA) with the concept of Nash-Equilibrium to speed up the optimisation process. During the optimisation, Nash-Game will act as a pre-conditioner. Both CISs; GA and HGA, are based on Pareto optimality and they are coupled to Euler based Computational Fluid Dynamic (CFD) analyser and one type of Computer Aided Design (CAD) system during the optimisation.

Bi-objective bundle adjustment: towards large-scale visual sea-floor mapping with a minimal sensor suite

Visual sea-floor mapping is a rapidly growing application for Autonomous Underwater Vehicles (AUVs). AUVs are well-suited to the task as they remove humans from a potentially dangerous environment, can reach depths human divers cannot, and are capable of long-term operation in adverse conditions. The output of sea-floor maps generated by AUVs has a number of applications in scientific monitoring: from classifying coral in high biological value sites to surveying sea sponges to evaluate marine environment health.

Roll the dice, rational agent : should extra-curial punishment mitigate an offender's sentence?

It was rugby league State of Origin night 2008 and a group of adults had descended upon a house in Eagleby, Brisbane to have some drinks and to celebrate the game. At 11pm that evening, Shane Thomas Davidson entered the bedroom of the homeowner’s 10-year-old son, TC. Davidson approached the bed and began to massage the boy’s penis under his clothing, which caused TC to wake. Davidson stated, ‘Show me how big your willy is and I’ll show you how big mine is’. TC refused the request and after a small period of time, left the bedroom and told his father what had happened...

Cross layer optimization of VANET routing with multi-objective decision making

Vehicular Ad-hoc Networks (VANET) have different characteristics compared to other mobile ad-hoc networks. The dynamic nature of the vehicles which act as routers and clients are connected with unreliable radio links and Routing becomes a complex problem. First we propose CO-GPSR (Cooperative GPSR), an extension of the traditional GPSR (Greedy Perimeter Stateless Routing) which uses relay nodes which exploit radio path diversity in a vehicular network to increase routing performance. Next we formulate a Multi-objective decision making problem to select optimum packet relaying nodes to increase the routing performance further. We use cross layer information for the optimization process. We evaluate the routing performance more comprehensively using realistic vehicular traces and a Nakagami fading propagation model optimized for highway scenarios in VANETs. Our results show that when Multi-objective decision making is used for cross layer optimization of routing a 70% performance increment can be obtained for low vehicle densities on average, which is a two fold increase compared to the single criteria maximization approach.

Visual sea-floor mapping from low overlap imagery using bi-objective bundle adjustment and constrained motion

In most visual mapping applications suited to Autonomous Underwater Vehicles (AUVs), stereo visual odometry (VO) is rarely utilised as a pose estimator as imagery is typically of very low framerate due to energy conservation and data storage requirements. This adversely affects the robustness of a vision-based pose estimator and its ability to generate a smooth trajectory. This paper presents a novel VO pipeline for low-overlap imagery from an AUV that utilises constrained motion and integrates magnetometer data in a bi-objective bundle adjustment stage to achieve low-drift pose estimates over large trajectories. We analyse the performance of a standard stereo VO algorithm and compare the results to the modified vo algorithm. Results are demonstrated in a virtual environment in addition to low-overlap imagery gathered from an AUV. The modified VO algorithm shows significantly improved pose accuracy and performance over trajectories of more than 300m. In addition, dense 3D meshes generated from the visual odometry pipeline are presented as a qualitative output of the solution.

Smart demand side management of low-voltage distribution networks using multi-objective decision making

A novel intelligent online demand side management system is proposed for peak load management in low-voltage distribution networks. This method uses low-cost controllers with low-bandwidth two-way communication installed in custumers’ premises and at distribution transformers to manage the peak load while maximising customer satisfaction. A multi-objective decision making process is proposed to select the load(s) to be delayed or controlled. The efficacy of the proposed control system is verified by simulation of three different feeder types.

Data requirements and graph data structures for a multi-modal, multi-objective trip planner

Traffic congestion has a significant impact on the economy and environment. Encouraging the use of multimodal transport (public transport, bicycle, park’n’ride, etc.) has been identified by traffic operators as a good strategy to tackle congestion issues and its detrimental environmental impacts. A multi-modal and multi-objective trip planner provides users with various multi-modal options optimised on objectives that they prefer (cheapest, fastest, safest, etc) and has a potential to reduce congestion on both a temporal and spatial scale. The computation of multi-modal and multi-objective trips is a complicated mathematical problem, as it must integrate and utilize a diverse range of large data sets, including both road network information and public transport schedules, as well as optimising for a number of competing objectives, where fully optimising for one objective, such as travel time, can adversely affect other objectives, such as cost. The relationship between these objectives can also be quite subjective, as their priorities will vary from user to user. This paper will first outline the various data requirements and formats that are needed for the multi-modal multi-objective trip planner to operate, including static information about the physical infrastructure within Brisbane as well as real-time and historical data to predict traffic flow on the road network and the status of public transport. It will then present information on the graph data structures representing the road and public transport networks within Brisbane that are used in the trip planner to calculate optimal routes. This will allow for an investigation into the various shortest path algorithms that have been researched over the last few decades, and provide a foundation for the construction of the Multi-modal Multi-objective Trip Planner by the development of innovative new algorithms that can operate the large diverse data sets and competing objectives.

Multi-objective design optimisation of GFRP sandwich beams

A novel Glass Fibre Reinforced Polymer (GFRP) sandwich panel was developed by an Australian manufacturer for civil engineering applications. This research is motivated by the new applications of GFRP sandwich structures in civil engineering such as slab, beam, girder and sleeper. An optimisation methodology is developed in this work to enhance the design of GFRP sandwich beams. The design of single and glue laminated GFRP sandwich beam were conducted by using numerical optimisation. The numerical multi-objective optimisation considered a design two objectives simultaneously. These objectives are cost and mass. The numerical optimisation uses the Adaptive Range Multi-objective Genetic Algorithm (ARMOGA) and Finite Element (FE) method. Trade-offs between objectives was found during the optimisation process. Multi-objective optimisation shows a core to skin mass ratio equal to 3.68 for the single sandwich beam cross section optimisation and it showed that the optimum core to skin thickness ratio is 11.0.