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.

Flexible high voltage pulsed power supply for plasma applications

Demands for delivering high instantaneous power in a compressed form (pulse shape) have widely increased during recent decades. The flexible shapes with variable pulse specifications offered by pulsed power have made it a practical and effective supply method for an extensive range of applications. In particular, the release of basic subatomic particles (i.e. electron, proton and neutron) in an atom (ionization process) and the synthesizing of molecules to form ions or other molecules are among those reactions that necessitate large amount of instantaneous power. In addition to the decomposition process, there have recently been requests for pulsed power in other areas such as in the combination of molecules (i.e. fusion, material joining), gessoes radiations (i.e. electron beams, laser, and radar), explosions (i.e. concrete recycling), wastewater, exhausted gas, and material surface treatments. These pulses are widely employed in the silent discharge process in all types of materials (including gas, fluid and solid); in some cases, to form the plasma and consequently accelerate the associated process. Due to this fast growing demand for pulsed power in industrial and environmental applications, the exigency of having more efficient and flexible pulse modulators is now receiving greater consideration. Sensitive applications, such as plasma fusion and laser guns also require more precisely produced repetitive pulses with a higher quality. Many research studies are being conducted in different areas that need a flexible pulse modulator to vary pulse features to investigate the influence of these variations on the application. In addition, there is the need to prevent the waste of a considerable amount of energy caused by the arc phenomena that frequently occur after the plasma process. The control over power flow during the supply process is a critical skill that enables the pulse supply to halt the supply process at any stage. Different pulse modulators which utilise different accumulation techniques including Marx Generators (MG), Magnetic Pulse Compressors (MPC), Pulse Forming Networks (PFN) and Multistage Blumlein Lines (MBL) are currently employed to supply a wide range of applications. Gas/Magnetic switching technologies (such as spark gap and hydrogen thyratron) have conventionally been used as switching devices in pulse modulator structures because of their high voltage ratings and considerably low rising times. However, they also suffer from serious drawbacks such as, their low efficiency, reliability and repetition rate, and also their short life span. Being bulky, heavy and expensive are the other disadvantages associated with these devices. Recently developed solid-state switching technology is an appropriate substitution for these switching devices due to the benefits they bring to the pulse supplies. Besides being compact, efficient, reasonable and reliable, and having a long life span, their high frequency switching skill allows repetitive operation of pulsed power supply. The main concerns in using solid-state transistors are the voltage rating and the rising time of available switches that, in some cases, cannot satisfy the application’s requirements. However, there are several power electronics configurations and techniques that make solid-state utilisation feasible for high voltage pulse generation. Therefore, the design and development of novel methods and topologies with higher efficiency and flexibility for pulsed power generators have been considered as the main scope of this research work. This aim is pursued through several innovative proposals that can be classified under the following two principal objectives. • To innovate and develop novel solid-state based topologies for pulsed power generation • To improve available technologies that have the potential to accommodate solid-state technology by revising, reconfiguring and adjusting their structure and control algorithms. The quest to distinguish novel topologies for a proper pulsed power production was begun with a deep and through review of conventional pulse generators and useful power electronics topologies. As a result of this study, it appears that efficiency and flexibility are the most significant demands of plasma applications that have not been met by state-of-the-art methods. Many solid-state based configurations were considered and simulated in order to evaluate their potential to be utilised in the pulsed power area. Parts of this literature review are documented in Chapter 1 of this thesis. Current source topologies demonstrate valuable advantages in supplying the loads with capacitive characteristics such as plasma applications. To investigate the influence of switching transients associated with solid-state devices on rise time of pulses, simulation based studies have been undertaken. A variable current source is considered to pump different current levels to a capacitive load, and it was evident that dissimilar dv/dts are produced at the output. Thereby, transient effects on pulse rising time are denied regarding the evidence acquired from this examination. A detailed report of this study is given in Chapter 6 of this thesis. This study inspired the design of a solid-state based topology that take advantage of both current and voltage sources. A series of switch-resistor-capacitor units at the output splits the produced voltage to lower levels, so it can be shared by the switches. A smart but complicated switching strategy is also designed to discharge the residual energy after each supply cycle. To prevent reverse power flow and to reduce the complexity of the control algorithm in this system, the resistors in common paths of units are substituted with diode rectifiers (switch-diode-capacitor). This modification not only gives the feasibility of stopping the load supply process to the supplier at any stage (and consequently saving energy), but also enables the converter to operate in a two-stroke mode with asymmetrical capacitors. The components’ determination and exchanging energy calculations are accomplished with respect to application specifications and demands. Both topologies were simply modelled and simulation studies have been carried out with the simplified models. Experimental assessments were also executed on implemented hardware and the approaches verified the initial analysis. Reports on details of both converters are thoroughly discussed in Chapters 2 and 3 of the thesis. Conventional MGs have been recently modified to use solid-state transistors (i.e. Insulated gate bipolar transistors) instead of magnetic/gas switching devices. Resistive insulators previously used in their structures are substituted by diode rectifiers to adjust MGs for a proper voltage sharing. However, despite utilizing solid-state technology in MGs configurations, further design and control amendments can still be made to achieve an improved performance with fewer components. Considering a number of charging techniques, resonant phenomenon is adopted in a proposal to charge the capacitors. In addition to charging the capacitors at twice the input voltage, triggering switches at the moment at which the conducted current through switches is zero significantly reduces the switching losses. Another configuration is also introduced in this research for Marx topology based on commutation circuits that use a current source to charge the capacitors. According to this design, diode-capacitor units, each including two Marx stages, are connected in cascade through solid-state devices and aggregate the voltages across the capacitors to produce a high voltage pulse. The polarity of voltage across one capacitor in each unit is reversed in an intermediate mode by connecting the commutation circuit to the capacitor. The insulation of input side from load side is provided in this topology by disconnecting the load from the current source during the supply process. Furthermore, the number of required fast switching devices in both designs is reduced to half of the number used in a conventional MG; they are replaced with slower switches (such as Thyristors) that need simpler driving modules. In addition, the contributing switches in discharging paths are decreased to half; this decrease leads to a reduction in conduction losses. Associated models are simulated, and hardware tests are performed to verify the validity of proposed topologies. Chapters 4, 5 and 7 of the thesis present all relevant analysis and approaches according to these topologies.

The role of near adaptation in myopia development

Prolonged near work is associated with myopia development in children and young adults but the reason underlying this association is unknown. Two potentially important factors are the near work induced ocular adaptations of contrast and accommodative adaptation. This study measured the degrees of contrast and accommodative adaptation during and following reading in myopic and emmetropic children and young adults in Singapore, where myopia is highly prevalent. Reading caused significantly greater contrast and accommodative adaptations in myopic children and myopic young adults compared to that measured in emmetropes of comparable ages. The adaptations were greater in magnitude in children than young adults, suggesting that children are more susceptible to ocular changes induced by reading and thus are potentially at greater risk of adverse refractive outcomes from these adaptations. In addition to the magnitude of the adaptations the regression time of these adaptations, (i.e. their durations) are also important. Longer accommodative adaptation regression times were measured for myopic children than for emmetropic children. Although the regression of contrast adaptation was not measured, its duration may likewise be important. The refractive effects of both of these adaptations are likely to be cumulative across the day and this could promote myopia in susceptible individuals performing considerable amounts of near work. Whether the type of text read affected the magnitude of the adaptations was also explored. Given the high prevalence of myopia in Chinese children and the fact that Chinese text is more complicated to write than English text, it was hypothesized that Chinese text would induce greater adaptation. However, both Chinese and English text produced similar amounts of accommodative and contrast adaptation in young adult subjects. We propose that children who spend prolonged periods reading at a young age are most vulnerable to near work induced adaptations and hence near work induced myopia. Both Chinese and English texts produce these effects and we propose that these adaptations are likely to occur for all types of common reading texts.

Influence of rainfall and catchment characteristics on urban stormwater quality

This thesis presents the outcomes of a comprehensive research study undertaken to investigate the influence of rainfall and catchment characteristics on urban stormwater quality. The knowledge created is expected to contribute to a greater understanding of urban stormwater quality and thereby enhance the design of stormwater quality treatment systems. The research study was undertaken based on selected urban catchments in Gold Coast, Australia. The research methodology included field investigations, laboratory testing, computer modelling and data analysis. Both univariate and multivariate data analysis techniques were used to investigate the influence of rainfall and catchment characteristics on urban stormwater quality. The rainfall characteristics investigated included average rainfall intensity and rainfall duration whilst catchment characteristics included land use, impervious area percentage, urban form and pervious area location. The catchment scale data for the analysis was obtained from four residential catchments, including rainfall-runoff records, drainage network data, stormwater quality data and land use and land cover data. Pollutants build-up samples were collected from twelve road surfaces in residential, commercial and industrial land use areas. The relationships between rainfall characteristics, catchment characteristics and urban stormwater quality were investigated based on residential catchments and then extended to other land uses. Based on the influence rainfall characteristics exert on urban stormwater quality, rainfall events can be classified into three different types, namely, high average intensity-short duration (Type 1), high average intensity-long duration (Type 2) and low average intensity-long duration (Type 3). This provides an innovative approach to conventional modelling which does not commonly relate stormwater quality to rainfall characteristics. Additionally, it was found that the threshold intensity for pollutant wash-off from urban catchments is much less than for rural catchments. High average intensity-short duration rainfall events are cumulatively responsible for the generation of a major fraction of the annual pollutants load compared to the other rainfall event types. Additionally, rainfall events less than 1 year ARI such as 6- month ARI should be considered for treatment design as they generate a significant fraction of the annual runoff volume and by implication a significant fraction of the pollutants load. This implies that stormwater treatment designs based on larger rainfall events would not be feasible in the context of cost-effectiveness, efficiency in treatment performance and possible savings in land area needed. This also suggests that the simulation of long-term continuous rainfall events for stormwater treatment design may not be needed and that event based simulations would be adequate. The investigations into the relationship between catchment characteristics and urban stormwater quality found that other than conventional catchment characteristics such as land use and impervious area percentage, other catchment characteristics such as urban form and pervious area location also play important roles in influencing urban stormwater quality. These outcomes point to the fact that the conventional modelling approach in the design of stormwater quality treatment systems which is commonly based on land use and impervious area percentage would be inadequate. It was also noted that the small uniformly urbanised areas within a larger mixed catchment produce relatively lower variations in stormwater quality and as expected lower runoff volume with the opposite being the case for large mixed use urbanised catchments. Therefore, a decentralised approach to water quality treatment would be more effective rather than an "end-of-pipe" approach. The investigation of pollutants build-up on different land uses showed that pollutant build-up characteristics vary even within the same land use. Therefore, the conventional approach in stormwater quality modelling, which is based solely on land use, may prove to be inappropriate. Industrial land use has relatively higher variability in maximum pollutant build-up, build-up rate and particle size distribution than the other two land uses. However, commercial and residential land uses had relatively higher variations of nutrients and organic carbon build-up. Additionally, it was found that particle size distribution had a relatively higher variability for all three land uses compared to the other build-up parameters. The high variability in particle size distribution for all land uses illustrate the dissimilarities associated with the fine and coarse particle size fractions even within the same land use and hence the variations in stormwater quality in relation to pollutants adsorbing to different sizes of particles.

Athletes series

The researcher was invited to photograph athletes in the lead-up to the 2006 Commonwealth Games held in Melbourne. She photographed four indigenous athletes, to produce a series of four large-scale cotton rag prints, 1 meter x 1 meter, printed onto photorag paper from digital files. “My photographic practice can be described as both political and spiritual, in the sense that as an Aboriginal Indigenous artist I take stock of the rationalising effect of the technologies I use, and create work that evokes nature and spirit. My methods often involve re-photographing or digitally re-working landscape photographs and adding historical or cultural icons of significance. Working with Indigenous athletes has been an honour and a pleasure. I admire the athletes’ passion and dedication to their chosen sport, and above all their humility, which seems a trait somewhat in contrast to what it takes to attain the highest levels of achievement. Indigenous athletes are wonderful role models for all Australians, and in making creative work that places their luminary presence with the land, I am aligning sportspeople with a deep sense of nature and spirit.” – Leah King-Smith. These works were commissioned by the National Portrait Gallery for the exhibition FLASH: Australian Athletes in Focus. The exhibition was a significant element in Melbourne2006 Festival, the cultural festival of the Commonwealth Games. The exhibition was prominently reviewed in Portrait: Magazine of Australian and International Portraiture and was subsequently remounted at Old Parliament House, Canberra (15 July to 12 November, 2006). One image was used for the front cover of Art Monthly, (March 2006).

Dancelines series

Dancelines was a body of work commissioned by Bangarra Dance Company and The Arts Centre, Melbourne. The artist was invited to produce a body of work that responded to the dance company's production of 'Boomerang'. The result was a body of photographs that applied the artist's interest in layering as a photographic technique and her interest in indigenous subjectivity and sprituality. The works drew correspondences between Rheannan Port, the subject's, own biography and character and the artist's voluminous archive of iamges of the natural world. The result complemented and formalised the collaborative processes that the artist had previously only explored in the video medium. The work was shown at the George Adams Gallery of the Arts Centre as part of Melbourne 2006 Commonwealth Games Arts Festival. 'Rheannan Port, #1' was selected for the 2006 Archibald Photographic Portrait Prize, at the Art Gallery of New South Wales. The work was reviewed in The Age newspaper.

Entertainment industries : entertainment as a cultural system

Entertainment Industries is the first book to map entertainment as a cultural system. Including work from world-renowned analysts such as Henry Jenkins and Jonathan Gray, this innovative collection explains what entertainment is and how it works. Entertainment is audience-centred culture. The Entertainment Industries are a uniquely interdisciplinary collection of evolving businesses that openly monitor evolving cultural trends and work within them. The producers of entertainment – central to that practice– are the new artists. They understand audiences and combine creative, business and legal skills in order to produce cultural products that cater to them. Entertainment Industries describes the characteristics of entertainment, the systems that produce it, and the role of producers and audiences in its development, as well as explaining the importance of this area of study, and how it might be better integrated into Universities.

Understanding user experience of mobile video : framework, measurement, and optimization

Since users have become the focus of product/service design in last decade, the term User eXperience (UX) has been frequently used in the field of Human-Computer-Interaction (HCI). Research on UX facilitates a better understanding of the various aspects of the user’s interaction with the product or service. Mobile video, as a new and promising service and research field, has attracted great attention. Due to the significance of UX in the success of mobile video (Jordan, 2002), many researchers have centered on this area, examining users’ expectations, motivations, requirements, and usage context. As a result, many influencing factors have been explored (Buchinger, Kriglstein, Brandt & Hlavacs, 2011; Buchinger, Kriglstein & Hlavacs, 2009). However, a general framework for specific mobile video service is lacking for structuring such a great number of factors. To measure user experience of multimedia services such as mobile video, quality of experience (QoE) has recently become a prominent concept. In contrast to the traditionally used concept quality of service (QoS), QoE not only involves objectively measuring the delivered service but also takes into account user’s needs and desires when using the service, emphasizing the user’s overall acceptability on the service. Many QoE metrics are able to estimate the user perceived quality or acceptability of mobile video, but may be not enough accurate for the overall UX prediction due to the complexity of UX. Only a few frameworks of QoE have addressed more aspects of UX for mobile multimedia applications but need be transformed into practical measures. The challenge of optimizing UX remains adaptations to the resource constrains (e.g., network conditions, mobile device capabilities, and heterogeneous usage contexts) as well as meeting complicated user requirements (e.g., usage purposes and personal preferences). In this chapter, we investigate the existing important UX frameworks, compare their similarities and discuss some important features that fit in the mobile video service. Based on the previous research, we propose a simple UX framework for mobile video application by mapping a variety of influencing factors of UX upon a typical mobile video delivery system. Each component and its factors are explored with comprehensive literature reviews. The proposed framework may benefit in user-centred design of mobile video through taking a complete consideration of UX influences and in improvement of mobile videoservice quality by adjusting the values of certain factors to produce a positive user experience. It may also facilitate relative research in the way of locating important issues to study, clarifying research scopes, and setting up proper study procedures. We then review a great deal of research on UX measurement, including QoE metrics and QoE frameworks of mobile multimedia. Finally, we discuss how to achieve an optimal quality of user experience by focusing on the issues of various aspects of UX of mobile video. In the conclusion, we suggest some open issues for future study.

Enhancing Chinese TEFL academics' research performance : necessity and urgency

China’s increasing participation in world affairs and the growing popularity of English as a lingua franca have made significant impact on Chinese society, culture and education. As such, considerable research topics in relation to English require TEFL researchers’ attentions. Additionally, higher education reform in China has created higher demand on academics by stressing research as an important element in academics’ assessment. Recurrent rhetoric in the field of TEFL also calls on practitioners to theorise their practice. All these practical needs and theoretical arguments point to the necessity and significance of TEFL academics’ engagement in research. To find out whether Chinese TEFL academics’ research meet the new demand on them, a survey of TEFL academics at three Chinese higher institutions was conducted. One hundred eighty two of them provided valid responses which were analysed using SPSS. It was found that TEFL academics’ research productivity in each category of research products was quite low. Large percentages of them did not produce any item in the investigated categories of research. They were least productive in conference papers and research products at the national level. However for these least productive categories, there were highly-productive TEFL academics. The categories of research where the TEFL academics were found relatively productive were non-core journal articles and provincial projects. The findings suggest that it is necessary and urgent for Chinese TEFL academics to enhance their research productivity to be able to meet the demand that new era has rendered.

Planning most-likely paths from overhead imagery

This paper is about planning paths from overhead imagery, the novelty of which is taking explicit account of uncertainty in terrain classification and spatial variation in terrain cost. The image is first classified using a multi-class Gaussian Process Classifier which provides probabilities of class membership at each location in the image. The probability of class membership at a particular grid location is then combined with a terrain cost evaluated at that location using a spatial Gaussian process. The resulting cost function is, in turn, passed to a planner. This allows both the uncertainty in terrain classification and spatial variations in terrain costs to be incorporated into the planned path. Because the cost of traversing a grid cell is now a probability density rather than a single scalar value, we can produce not only the most-likely shortest path between points on the map, but also sample from the cost map to produce a distribution of paths between the points. Results are shown in the form of planned paths over aerial maps, these paths are shown to vary in response to local variations in terrain cost.

Classifying external causes of injury : history, current approaches, and future directions

The International Classification of Diseases (ICD) is used to categorise diseases, injuries and external causes, and is a key epidemiological tool enabling the storage and retrieval of data from health and vital records to produce core international mortality and morbidity statistics. The ICD is updated periodically to ensure the classification remains current and work is now underway to develop the next revision, ICD-11. There have been almost 20 years since the last ICD edition was published and over 60 years since the last substantial structural revision of the external causes chapter. Revision of such a critical tool requires transparency and documentation to ensure that changes made to the classification system are recorded comprehensively for future reference. In this paper, the authors provide a history of external causes classification development and outline the external cause structure. Approaches to manage ICD-10 deficiencies are discussed and the ICD-11 revision approach regarding the development of, rationale for and implications of proposed changes to the chapter are outlined. Through improved capture of external cause concepts in ICD-11, a stronger evidence base will be available to inform injury prevention, treatment, rehabilitation and policy initiatives to ultimately contribute to a reduction in injury morbidity and mortality.

Laughing & disability : comedy, collaborative authorship and Down Under Mystery Tour

This thesis is an exploration of representation, authorship and creative collaboration in disability comedy, the centre piece of which is a feature-length film starring, co-created and co-written by three intellectually-disabled people. The film, entitled Down Under Mystery Tour, aims to entertain, and be accessible to, a mainstream audience, one that would not normally care about disability or listen to disabled voices. In the past, the failure of these voices to reach audiences has been blamed on poor training, marginal timeslots and indifferent audiences. But this project seeks an alternative approach, building collaboration between disabled and non-disabled people to express voice, conceive, construct and produce a filmed narrative, and engage willing audiences who want to listen.

Physical effect in patent law

This thesis addresses one of the fundamental issues that remains unresolved in patent law today. It is a question that strikes at the heart of what a patent is and what it is supposed to protect. That question is whether an invention must produce a physical effect or cause a physical transformation of matter to be patentable, or whether it is sufficient that an invention involves a specific practical application of an idea or principle to achieve a useful result. In short, the question is whether patent law contains a physicality requirement. Resolving this issue will determine whether only traditional mechanical, industrial and manufacturing processes are patent eligible, or whether patent eligibility extends to include purely intangible, or non-physical, products and processes. To this end, this thesis seeks to identify where the dividing line lies between patentable subject matter and the recognised categories of excluded matter, namely, fundamental principles of nature, physical phenomena, and abstract ideas. It involves determining which technological advances are worth the inconvenience monopoly protection causes the public at large, and which should remain free for all to use without restriction. This is an issue that has important ramifications for innovation in the ‘knowledge economy’ of the Information Age. Determining whether patent law contains a physicality requirement is integral to deciding whether much of the valuable innovation we are likely to witness, in what are likely to be the emerging areas of technology in the near future, will receive the same encouragement as industrial and manufacturing advances of previous times.

Algebraic analysis of the SSS stream cipher

Both the SSS and SOBER-t32 stream cipher designs use a single word-based shift register and a nonlinear filter function to produce keystream. In this paper we show that the algebraic attack method previously applied to SOBER-t32 is prevented from succeeding on SSS by the use of the key dependent substitution box (SBox) in the nonlinear filter of SSS. Additional assumptions and modifications to the SSS cipher in an attempt to enable algebraic analysis result in other difficulties that also render the algebraic attack infeasible. Based on these results, we conclude that a well chosen key-dependent substitution box used in the nonlinear filter of the stream cipher provides resistance against such algebraic attacks.

Mathematical modelling of tumour-induced angiogenesis

The growth of solid tumours beyond a critical size is dependent upon angiogenesis, the formation of new blood vessels from an existing vasculature. Tumours may remain dormant at microscopic sizes for some years before switching to a mode in which growth of a supportive vasculature is initiated. The new blood vessels supply nutrients, oxygen, and access to routes by which tumour cells may travel to other sites within the host (metastasize). In recent decades an abundance of biological research has focused on tumour-induced angiogenesis in the hope that treatments targeted at the vasculature may result in a stabilisation or regression of the disease: a tantalizing prospect. The complex and fascinating process of angiogenesis has also attracted the interest of researchers in the field of mathematical biology, a discipline that is, for mathematics, relatively new. The challenge in mathematical biology is to produce a model that captures the essential elements and critical dependencies of a biological system. Such a model may ultimately be used as a predictive tool. In this thesis we examine a number of aspects of tumour-induced angiogenesis, focusing on growth of the neovasculature external to the tumour. Firstly we present a one-dimensional continuum model of tumour-induced angiogenesis in which elements of the immune system or other tumour-cytotoxins are delivered via the newly formed vessels. This model, based on observations from experiments by Judah Folkman et al., is able to show regression of the tumour for some parameter regimes. The modelling highlights a number of interesting aspects of the process that may be characterised further in the laboratory. The next model we present examines the initiation positions of blood vessel sprouts on an existing vessel, in a two-dimensional domain. This model hypothesises that a simple feedback inhibition mechanism may be used to describe the spacing of these sprouts with the inhibitor being produced by breakdown of the existing vessel's basement membrane. Finally, we have developed a stochastic model of blood vessel growth and anastomosis in three dimensions. The model has been implemented in C++, includes an openGL interface, and uses a novel algorithm for calculating proximity of the line segments representing a growing vessel. This choice of programming language and graphics interface allows for near-simultaneous calculation and visualisation of blood vessel networks using a contemporary personal computer. In addition the visualised results may be transformed interactively, and drop-down menus facilitate changes in the parameter values. Visualisation of results is of vital importance in the communication of mathematical information to a wide audience, and we aim to incorporate this philosophy in the thesis. As biological research further uncovers the intriguing processes involved in tumourinduced angiogenesis, we conclude with a comment from mathematical biologist Jim Murray, Mathematical biology is : : : the most exciting modern application of mathematics.