Complexity, evolution, and the structure of demand

This chapter argues that evolutionary economics should be founded upon complex systems theory rather than neo-Darwinian analogies concerning natural selection, which focus on supply side considerations and competition amongst firms and technologies. It suggests that conceptions such as production and consumption functions should be replaced by network representations, in which the preferences or, more correctly, the aspirations of consumers are fundamental and, as such, the primary drivers of economic growth. Technological innovation is viewed as a process that is intermediate between these aspirational networks, and the organizational networks in which goods and services are produced. Consumer knowledge becomes at least as important as producer knowledge in determining how economic value is generated. It becomes clear that the stability afforded by connective systems of rules is essential for economic flexibility to exist, but that too many rules result in inert and structurally unstable states. In contrast, too few rules result in a more stable state, but at a low level of ordered complexity. Economic evolution from this perspective is explored using random and scale free network representations of complex systems.

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.

Graph rigidity for near-coplanar structure from motion

Recent algorithms for monocular motion capture (MoCap) estimate weak-perspective camera matrices between images using a small subset of approximately-rigid points on the human body (i.e. the torso and hip). A problem with this approach, however, is that these points are often close to coplanar, causing canonical linear factorisation algorithms for rigid structure from motion (SFM) to become extremely sensitive to noise. In this paper, we propose an alternative solution to weak-perspective SFM based on a convex relaxation of graph rigidity. We demonstrate the success of our algorithm on both synthetic and real world data, allowing for much improved solutions to marker less MoCap problems on human bodies. Finally, we propose an approach to solve the two-fold ambiguity over bone direction using a k-nearest neighbour kernel density estimator.

Enriching XML documents clustering by using concise structure and content

With the growing number of XML documents on theWeb it becomes essential to effectively organise these XML documents in order to retrieve useful information from them. A possible solution is to apply clustering on the XML documents to discover knowledge that promotes effective data management, information retrieval and query processing. However, many issues arise in discovering knowledge from these types of semi-structured documents due to their heterogeneity and structural irregularity. Most of the existing research on clustering techniques focuses only on one feature of the XML documents, this being either their structure or their content due to scalability and complexity problems. The knowledge gained in the form of clusters based on the structure or the content is not suitable for reallife datasets. It therefore becomes essential to include both the structure and content of XML documents in order to improve the accuracy and meaning of the clustering solution. However, the inclusion of both these kinds of information in the clustering process results in a huge overhead for the underlying clustering algorithm because of the high dimensionality of the data. The overall objective of this thesis is to address these issues by: (1) proposing methods to utilise frequent pattern mining techniques to reduce the dimension; (2) developing models to effectively combine the structure and content of XML documents; and (3) utilising the proposed models in clustering. This research first determines the structural similarity in the form of frequent subtrees and then uses these frequent subtrees to represent the constrained content of the XML documents in order to determine the content similarity. A clustering framework with two types of models, implicit and explicit, is developed. The implicit model uses a Vector Space Model (VSM) to combine the structure and the content information. The explicit model uses a higher order model, namely a 3- order Tensor Space Model (TSM), to explicitly combine the structure and the content information. This thesis also proposes a novel incremental technique to decompose largesized tensor models to utilise the decomposed solution for clustering the XML documents. The proposed framework and its components were extensively evaluated on several real-life datasets exhibiting extreme characteristics to understand the usefulness of the proposed framework in real-life situations. Additionally, this research evaluates the outcome of the clustering process on the collection selection problem in the information retrieval on the Wikipedia dataset. The experimental results demonstrate that the proposed frequent pattern mining and clustering methods outperform the related state-of-the-art approaches. In particular, the proposed framework of utilising frequent structures for constraining the content shows an improvement in accuracy over content-only and structure-only clustering results. The scalability evaluation experiments conducted on large scaled datasets clearly show the strengths of the proposed methods over state-of-the-art methods. In particular, this thesis work contributes to effectively combining the structure and the content of XML documents for clustering, in order to improve the accuracy of the clustering solution. In addition, it also contributes by addressing the research gaps in frequent pattern mining to generate efficient and concise frequent subtrees with various node relationships that could be used in clustering.

Reduced variance in monozygous twins for multiple MR parameters : implications for disease studies and the genetic basis of brain structure

Twin studies offer the opportunity to determine the relative contribution of genes versus environment in traits of interest. Here, we investigate the extent to which variance in brain structure is reduced in monozygous twins with identical genetic make-up. We investigate whether using twins as compared to a control population reduces variability in a number of common magnetic resonance (MR) structural measures, and we investigate the location of areas under major genetic influences. This is fundamental to understanding the benefit of using twins in studies where structure is the phenotype of interest. Twenty-three pairs of healthy MZ twins were compared to matched control pairs. Volume, T2 and diffusion MR imaging were performed as well as spectroscopy (MRS). Images were compared using (i) global measures of standard deviation and effect size, (ii) voxel-based analysis of similarity and (iii) intra-pair correlation. Global measures indicated a consistent increase in structural similarity in twins. The voxel-based and correlation analyses indicated a widespread pattern of increased similarity in twin pairs, particularly in frontal and temporal regions. The areas of increased similarity were most widespread for the diffusion trace and least widespread for T2. MRS showed consistent reduction in metabolite variation that was significant in the temporal lobe N-acetylaspartate (NAA). This study has shown the distribution and magnitude of reduced variability in brain volume, diffusion, T2 and metabolites in twins. The data suggest that evaluation of twins discordant for disease is indeed a valid way to attribute genetic or environmental influences to observed abnormalities in patients since evidence is provided for the underlying assumption of decreased variability in twins.

A phenomenological model for the structure-composition relationship of the high Tc cuprates based on simple chemical principles

A simple phenomenological model for the relationship between structure and composition of the high Tc cuprates is presented. The model is based on two simple crystal chemistry principles: unit cell doping and charge balance within unit cells. These principles are inspired by key experimental observations of how the materials accommodate large deviations from stoichiometry. Consistent explanations for significant HTSC properties can be explained without any additional assumptions while retaining valuable insight for geometric interpretation. Combining these two chemical principles with a review of Crystal Field Theory (CFT) or Ligand Field Theory (LFT), it becomes clear that the two oxidation states in the conduction planes (typically d8 and d9) belong to the most strongly divergent d-levels as a function of deformation from regular octahedral coordination. This observation offers a link to a range of coupling effects relating vibrations and spin waves through application of Hund’s rules. An indication of this model’s capacity to predict physical properties for HTSC is provided and will be elaborated in subsequent publications. Simple criteria for the relationship between structure and composition in HTSC systems may guide chemical syntheses within new material systems.

Molecular structure of the phosphate mineral brazilianite NaAl3(PO4)2(OH)4 : a semi precious jewel

The phosphate mineral brazilianite NaAl3(PO4)2(OH)4 is a semi precious jewel. There are almost no minerals apart from brazilianite which are used in jewellery. Vibrational spectroscopy was used to characterize the mol. structure of brazilianite. Brazilianite is composed of chains of edge-sharing Al-O octahedra linked by P-O tetrahedra, with Na located in cavities of the framework. An intense sharp Raman band at 1019 cm-1 is attributed to the PO43- sym. stretching mode. Raman bands at 973 and 988 cm-1 are assigned to the stretching vibrations of the HOPO33- units. The IR spectra compliment the Raman spectra but show greater complexity. Multiple Raman bands are obsd. in the PO43- and HOPO33- bending region. This observation implies that both phosphate and hydrogen phosphate units are involved in the structure. Raman OH stretching vibrations are found at 3249, 3417 and 3472 cm-1. These peaks show that the OH units are not equiv. in the brazilianite structure. Vibrational spectroscopy is useful for increasing the knowledge of the mol. structure of brazilianite.

Foundations for giving : why and how Australians structure their philanthropy

Philanthropic foundations in Australia have traditionally been labelled ‘icebergs’. Much of what they do and who they are is not apparent on the surface. Many are unknown and apart from an occasional biography, almost all are sparsely documented in terms of the very personal decisions behind establishing them. Practically and academically, scant data exist on the decision journeys people make into formalised philanthropy. This study seeks to fill that gap. It is believed to be the largest such study of foundation decision-making ever undertaken in this country. It is the latest in a series of ACPNS research into types of considered (versus spontaneous) giving in Australia. This research has been supported by the Perpetual Foundation, the EF and SL Gluyas Trust and the Edward Corbould Charitable Trust under the management of Perpetual Trustee Company Ltd.

The market structure and characteristics of electronic games

A multi-billion dollar industry, electronic games have been experiencing strong and rapid growth in recent times. The world of games is not only exciting due to the magnificent growth of the industry however, but due to a host of other factors. This chapter explores electronic games, providing an analysis of the industry, key motivators for game play, the game medium and academic research concerning the effects of play. It also reviews the emerging relationship games share with sport, recognizing that they can replicate sports, facilitate sports participation and be played as a sport. These are complex relationships that have not yet been comprehensively studied. The current chapter serves to draw academic attention to the area and presents ideas for future research.

Fabrication of macro-mesoporous zirconia-alumina materials with a 1D hierarchical structure

A series of one dimensional (1D) zirconia/alumina nanocomposites were prepared by the deposition of zirconium species onto the 3D framework of boehmite nanofibres formed by dispersing boehmite nanofibres into butanol solution. The materials were calcined at 773K and characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscope (TEM), N2 adsorption/desorption, infrared emission spectroscopy (IES). The results demonstrated that when the molar percentage X=100*Zr/(Al+Zr) was > 30 %, extremely long ZrO2/Al2O3 composite nanorods with evenly distributed ZrO2 nanocrystals on the surface were formed. The stacking of such nanorods gave rise to a new kind of macroporous material without the use of any organic space filler\template or other specific technologies. The mechanism for the formation of long ZrO2/Al2O3 composite nanorods was proposed in this work.

Three-dimensional geological modelling and multivariate statistical analysis of water chemistry data to analyse and visualise aquifer structure and groundwater composition in the Wairau Plain, Marlborough District, New Zealand

Concerns regarding groundwater contamination with nitrate and the long-term sustainability of groundwater resources have prompted the development of a multi-layered three dimensional (3D) geological model to characterise the aquifer geometry of the Wairau Plain, Marlborough District, New Zealand. The 3D geological model which consists of eight litho-stratigraphic units has been subsequently used to synthesise hydrogeological and hydrogeochemical data for different aquifers in an approach that aims to demonstrate how integration of water chemistry data within the physical framework of a 3D geological model can help to better understand and conceptualise groundwater systems in complex geological settings. Multivariate statistical techniques(e.g. Principal Component Analysis and Hierarchical Cluster Analysis) were applied to groundwater chemistry data to identify hydrochemical facies which are characteristic of distinct evolutionary pathways and a common hydrologic history of groundwaters. Principal Component Analysis on hydrochemical data demonstrated that natural water-rock interactions, redox potential and human agricultural impact are the key controls of groundwater quality in the Wairau Plain. Hierarchical Cluster Analysis revealed distinct hydrochemical water quality groups in the Wairau Plain groundwater system. Visualisation of the results of the multivariate statistical analyses and distribution of groundwater nitrate concentrations in the context of aquifer lithology highlighted the link between groundwater chemistry and the lithology of host aquifers. The methodology followed in this study can be applied in a variety of hydrogeological settings to synthesise geological, hydrogeological and hydrochemical data and present them in a format readily understood by a wide range of stakeholders. This enables a more efficient communication of the results of scientific studies to the wider community.

Homo- and heteronuclear meso,meso-(E)-Ethene-1,2-diyl-Linked Diporphyrins : preparation, X-ray crystal structure, electronic absorption and emission spectra and density functional theory calculations

Homo-and heteronuclear meso,meso-(E)-ethene-1,2-diyl-linked diporphyrins have been prepared by the Suzuki coupling of porphyrinylboronates and iodovinylporphyrins. Combinations comprising 5,10,15-triphenylporphyrin (TriPP) on both ends of the ethene-1,2-diyl bridge M 210 (M 2=H 2/Ni, Ni 2, Ni/Zn, H 4, H 2Zn, Zn 2) and 5,15-bis(3,5-di-tert-butylphenyl)porphyrinato-nickel(II) on one end and H 2, Ni, and ZnTriPP on the other (M 211), enable the first studies of this class of compounds possessing intrinsic polarity. The compounds were characterized by electronic absorption and steady state emission spectra, 1H NMR spectra, and for the Ni 2 bis(TriPP) complex Ni 210, single crystal X-ray structure determination. The crystal structure shows ruffled distortions of the porphyrin rings, typical of Ni II porphyrins, and the (E)-C 2H 2 bridge makes a dihedral angle of 50° with the mean planes of the macrocycles. The result is a stepped parallel arrangement of the porphyrin rings. The dihedral angles in the solid state reflect the interplay of steric and electronic effects of the bridge on interporphyrin communication. The emission spectra in particular, suggest energy transfer across the bridge is fast in conformations in which the bridge is nearly coplanar with the rings. Comparisons of the fluorescence behaviour of H 410 and H 2Ni10 show strong quenching of the free base fluorescence when the complex is excited at the lower energy component of the Soret band, a feature associated in the literature with more planar conformations. TDDFT calculations on the gas-phase optimized geometry of Ni 210 reproduce the features of the experimental electronic absorption spectrum within 0.1 eV. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Vibrational spectroscopic study of the minerals nekoite Ca3Si6O15•7H2O and okenite Ca10Si18O46•18H2O : implications for the molecular structure

Nekoite Ca3Si6O15•7H2O and okenite Ca10Si18O46•18H2O are both hydrated calcium silicates found respectively in contact metamorphosed limestone and in association with zeolites from the alteration of basalts. The minerals form two-Dimensional infinite sheets with other than six-membered rings with 3-, 4-, or 5-membered rings and 8-membered rings. The two minerals have been characterised by Raman, near-infrared and infrared spectroscopy. The Raman spectrum of nekoite is characterised by two sharp peaks at 1061 and 1092 cm-1 with bands of lesser intensity at 974, 994, 1023 and 1132 cm-1. The Raman spectrum of okenite shows an intense single Raman band at 1090 cm-1 with a shoulder band at 1075 cm-1.These bands are assigned to the SiO stretching vibrations of Si2O5 units. Raman water stretching bands of nekoite are observed at 3071, 3380, 3502 and 3567 cm-1. Raman spectrum of okenite shows water stretching bands at 3029, 3284, 3417, 3531 and 3607 cm-1. NIR spectra of the two minerals are subtly different inferring water with different hydrogen bond strengths. By using a Libowitzky empirical formula, hydrogen bond distances based upon these OH stretching vibrations. Two types of hydrogen bonds are distinguished: strong hydrogen bonds associated with structural water and weaker hydrogen bonds assigned to space filling water molecules.