A Krylov-based finite state projection algorithm for solving the chemical master equation arising in the discrete modelling of biological systems

Biochemical reactions underlying genetic regulation are often modelled as a continuous-time, discrete-state, Markov process, and the evolution of the associated probability density is described by the so-called chemical master equation (CME). However the CME is typically difficult to solve, since the state-space involved can be very large or even countably infinite. Recently a finite state projection method (FSP) that truncates the state-space was suggested and shown to be effective in an example of a model of the Pap-pili epigenetic switch. However in this example, both the model and the final time at which the solution was computed, were relatively small. Presented here is a Krylov FSP algorithm based on a combination of state-space truncation and inexact matrix-vector product routines. This allows larger-scale models to be studied and solutions for larger final times to be computed in a realistic execution time. Additionally the new method computes the solution at intermediate times at virtually no extra cost, since it is derived from Krylov-type methods for computing matrix exponentials. For the purpose of comparison the new algorithm is applied to the model of the Pap-pili epigenetic switch, where the original FSP was first demonstrated. Also the method is applied to a more sophisticated model of regulated transcription. Numerical results indicate that the new approach is significantly faster and extendable to larger biological models.

The role of institutional rural property in diversified investment portfolios in NSW, Australia

The food and fuel crisis experienced in 2006 to 2008 has highlighted the importance of agricultural commodity production throughout developing and developed economies and has placed greater awareness and importance on rural property and rural property markets. These factors have led to an increased interest from major property investment institutions and property companies in the role of rural property in a mixed asset or mixed property investment portfolio. This paper will analyse rural property sales in New South Wales for the period 1990-2008, and will compare total return performance across a number of rural property sectors based on geographic location and land use type. These results show that the inclusion of rural property in an investment portfolio has benefits in relation to return and risk.

A software tool for simulating spatial separation and kinetics in biological membranes

Self-segregation and compartimentalisation are observed experimentally to occur spontaneously on live membranes as well as reconstructed model membranes. It is believed that many of these processes are caused or supported by anomalous diffusive behaviours of biomolecules on membranes due to the complex and heterogeneous nature of these environments. These phenomena are on the one hand of great interest in biology, since they may be an important way for biological systems to selectively localize receptors, regulate signaling or modulate kinetics; and on the other, they provide an inspiration for engineering designs that mimick natural systems. We present an interactive software package we are developing for the purpose of simulating such processes numerically using a fundamental Monte Carlo approach. This program includes the ability to simulate kinetics and mass transport in the presence of either mobile or immobile obstacles and other relevant structures such as liquid-ordered lipid microdomains. We also present preliminary simulation results regarding the selective spatial localization and chemical kinetics modulating power of immobile obstacles on the membrane, obtained using the program.

Tracking the Brisbane residential property market : Post GFC

Prior to the GFC, Brisbane and Perth were experiencing the highest increases in median residential house prices, compared to the other major Australian cities, due to strong demand for both owner occupied and investment residential property. In both these cities, a major driver of this demand and subsequent increases in residential property prices was the strong resources sector. With the onset of the GFC in 2008, the resources and construction sectors in Queensland contracted significantly and this had both direct and indirect impacts on the Brisbane residential property market. However, this impact was not consistent across Brisbane residential property sectors. The affect on houses and units differed, as did the impact based on geographic location and suburb value. This paper tracks Brisbane residential property sales listings, sales and returns over the period February 2009 to July 2010 and provides an analysis of the residential market for 24 Brisbane suburbs. These suburbs cover main residential areas of Brisbane and are based on an equal number of low, medium and high socioeconomic areas of Brisbane. This assessment of socio-economic status for the suburbs is based on both median household income and median house price. The analysis will cover both free standing residential property and residential units/townhouses/villas. The results will show how each of these residential property sub markets have performed following the GFC.

Understanding the diversity of non-specialised units within Australian property degrees

Building on the recommendations of the Bradley Review (2008), the Australian Federal government intends to promote a higher level of penetration of tertiary qualification across the broader Australian community which is anticipated to result in increased levels of standardisation across university degrees. In the field of property, tertiary academic programs are very closely aligned to the needs of a range of built environment professions and there are well developed synergies between the relevant professional bodies and the educational institutions. The strong nexus between the academic and the professional content is characterised by ongoing industry accreditation which nominates a range of outcomes which the academic programs must maintain across a range of specified metrics. Commonly, the accrediting bodies focus on standard of minimum requirements especially in the area of specialised subject areas where they require property graduates to demonstrate appropriate learning and attitudes. In addition to nominated content fields, in every undergraduate degree program there are also many other subjects which provide a richer experience for the students beyond the merely professional. This study focuses on the nonspecialised knowledge field which varies across the universities offering property degree courses as every university has the freedom to pursue its own policy for these non-specialised units. With universities being sensitive to their role of in the appropriate socialisation of new entrants, first year units have been used as a vehicle to support students’ transition into university education and the final year units seek to support students’ integration into the professional world. Consequentially, many property programs have to squeeze their property-specific units to accommodate more generic units for both first year and final year units and the resulting diversity is a feature of the current range of property degrees across Australia which this research will investigate. The matrix of knowledge fields nominated by the Australian Property Institute for accreditation of degrees accepted for Certified Practising Valuer (CPV) educational requirement and the complementary requirements of the other major accrediting body (RICS) are used to classify and compare similarities and differences across property degrees in the light of the streamlining anticipated from the Bradley Review.

Assessment of damages for property damage

In Gagner Pty t/as Indochine Café v Canturi Corporation Pty Ltd (2009) 262 ALR 691, the assessment of damages awarded for the rectification work to the premises of the respondent was in issue. The appellant operated a restaurant above the respondent’s jewellery store in Sydney. When the kitchen of the restaurant flooded, water escaped causing damage to the jewellery store’s fit-out. The escape of the water was held to be due to the negligence of persons for whom the appellant was vicariously liable. The trial judge awarded damages, measured by the amount required to return the premises as close as was possible to the condition prior to the flood damage as well as an allowance for interruption to the business for 10 days. The 10 day allowance reflected the number of days the store would have been closed for if it was to be returned to its previous condition. The evidence was that the flooding has only affected approximately 10% of the floor area of the store. However, instead of having work carried out to bring the premises back to its condition as before the water damage, the respondent closed the business for 29 working days for a complete internal refurbishment – at a cost substantially more than simple rectification. On appeal it was argued that the trial judge had assessed the damages incorrectly as by undertaking a complete refurbishment had the effect that the respondent did not suffer any loss as a consequence of the negligence in relation to the fit-out. It was asserted that the claim for damages was in the circumstances a claim for betterment. It was also argued that the damages should not include a component for GST. Campbell JA gave reasons, with Macfarlan JA and Sackville AJA agreeing.

Uncetainty in claiming damages for defects in property

In Project Management Company No 2 Pty Ltd v Cushway Blackford & Associates Pty Ltd [2011] QCA 102 the appellant sought leave to join its parent company party (Project Management Company No 1) as a plaintiff to the proceedings and to amend its statement of claim. It was argued that the parent company had suffered the loss claimed in the proceedings, rather than the appellant. Rule 69(1)(b)(ii) of the Uniform Civil Procedure Rules 1999 (Qld) allows a court at any stage of the proceeding to order that ‘a person whose presence before the court would be desirable, just and convenient to enable the court to adjudicate effectually and completely on all matters in dispute connected with the proceeding’ be include as a party. To determine this issue, the Court of Appeal had to review the law relevant to the proceedings – a claim in negligence for pure economic loss, in particular, the principles espoused by the High Court in Bryan v Maloney(1995) 182 CLR 609 and Woolcock Street Investments Pty Ltd v CDG Pty Ltd (2004) 216 CLR 515.

Transfer of Title by a Non-Owner : Personal Property Securities Act 2009 (Cth) exceptions to the nemo dat quod non habet rule

The fundamental personal property rule – no one can transfer a better title to property than they had – is subject to exceptions in the Sale of Goods legislation, which aim to protect innocent buyers who are deceived by a seller’s apparent physical possession of property. These exceptions cover a limited range of transactions and are restrictive in their operation. Australia now has national legislation - the Personal Property Securities Act 2009 (Cth) - which will apply to many transactions outside the scope of the Sale of Goods Act and which includes rules for sales by non-owners which will provide exceptions to the nemo dat quod non habet rule for many common commercial transactions. This article explores the effect of the Personal Property Securities Act 2009 (Cth) on the Sale of Goods exceptions, explains that the new provisions are so wide that there is little continuing relevance for the Sale of Goods Act exceptions, and indicates where they may still apply.

The role of property law in environmental management

Market-based environmental regulation is becoming increasingly common within international and national frameworks. In order for market-based regimes to attract sufficient levels of stakeholder engagement, participants within such schemes require an incentive to participate and furthermore need to feel a sense of security about investing in such processes. A sense of security is associated with property-based interests. This article explores the property-related issues connected with the operation of environmental markets. Relevant property-related considerations include examining the significant role that market-based regulation is playing in connection with the environment; examining the links between property rights and markets; exploring the legal definition of property; analysing the rights and powers associated with environmental interests in land; advancing theory on the need for landholder responsibilities in relation to land and examining the legal mechanisms used to recognise environmental property rights, including the registration thereof.

Surviving the Personal Property Securities Act (2009) Cth

Australia has new national legislation - the Personal Property Securities Act 2009 (Cth) and the Personal Property Securities Regulations 2010 – which is expected to commence operating in February 2012. Previous personal property securities legislation was very complex, with more than seventy pieces of legislation in the states and territories, and more than forty registers. This reform package is the culmination of a process that began many years ago and various drafts have been the subject of much investigation and consultation. This legislation rationalises previous laws and bring about substantial changes to this area of law. This paper seeks to explain the principal changes and their implications.

Biological and environmental determinants

- describe the complex web of determinants as part of broad causal pathways that affect health - identify and discuss the range of physical, biological and environmental determinants that impact on health - suggest why it is important to the practice of public health that you understand how determinants contribute to health - understand the complexity of health and illness and the multifaceted role of health determinants - relate determinants of health to public health activity and realise the need for multisectoral action and multiple approaches when working to improve health

Pegasus Town : innovative marketing of a new property venture

Purpose – This paper aims to outline the challenges and tasks involved in a organising and marketing a new venture from conception to sales. It presents an interesting situation with which readers can identify and apply knowledge and skills associated with entrepreneurship and marketing and link this with the key learning objectives of a new venture marketing study unit. Design/methodology/approach – The case is constructed around key principles of marketing and entrepreneurship linked to a description of a contemporary venture written from a participant observer perspective supplemented with knowledge from interviews and archival research. Findings – The case shows how effective a diligent, creative approach to developing and selling a new venture can be. It demonstrates that effective marketing requires more than rote adoption of basic principles – it requires creative thinking and enterprising adaption of relevant principles to address the specific and well defined objectives of the venture. Research limitations/implications – The case is not intended to prescribe a particular marketing method or process; rather it is meant to stimulate creativity in the use of marketing knowledge and skills. Practical implications – The case represents an effective resource for both formal and informal teaching and learning. It demonstrates the requirement for innovative and creative adoption of marketing concepts to fit the demands of a new venture. Originality/value – The case specifically addresses an identified need for learning resources and information tailored to the area of entrepreneurial new venture marketing.

Section 64 of the Property Law Act 1974 (Qld) and the reluctant buyer

The decision of the Court of Appeal in Dunworth v Mirvac Qld Pty Ltd [2011] QCA 200 arose from unusual circumstances associated with the flood in Brisbane earlier this year. Maris Dunworth (‘the buyer’) agreed to purchase a ground floor residential apartment located beside the Brisbane River at Tennyson from Mirvac Queensland Pty Ltd (‘Mirvac’). The original date for completion was 12 May 2009. In earlier proceedings, the buyer had alleged that she had been induced to purchase the apartment by false, misleading and deceptive representations. This claim was dismissed and an order for specific performance was made with a new completion date of 8 February 2011...

Legal issues in carbon farming : biosequestration, carbon pricing, and carbon rights

This paper critically analyses the proposed Australian regulatory approach to the crediting of biological sequestration activities (biosequestration) under the Australian Carbon Farming Initiative and its interaction with State-based carbon rights, the national carbon-pricing mechanism, and the international Kyoto Protocol and carbon-trading markets. Norms and principles have been established by the Kyoto Protocol to guide the creation of additional, verifiable, and permanent credits from biosequestration activities. This paper examines the proposed arrangements under the Australian Carbon Farming Initiative and Carbon Pricing Mechanism to determine whether they are consistent with those international norms and standards. This paper identifies a number of anomalies associated with the legal treatment of additionality and permanence and issuance of carbon credits within the Australian schemes. In light of this, the paper considers the possible legal implications for the national and international transfer, surrender and use of these offset credits.

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.