Doctor of Philosophy

dissertationUbiquitin is a small protein which interacts with other proteins as a post-translational modification and as a binding partner for proteins which contain a ubiquitin binding domain (UBD). Proteins modified with ubiquitin are often targeted for degradation. Ubiquitin regulates both soluble and membrane-bound proteins in cells of nearly all tissues. Here we use mathematical models to study three distinct regulatory systems involving ubiquitin: regulation of the yeast uracil transporter, Fur4, protein sorting mediated by the endosomal sorting complexes required for transport (ESCRTs), and regulation of Rad18 in the DNA damage tolerance pathway. Using a differential equation model of Fur4 regulation, we demonstrate that deubiquitination and retention are essential roles of the Rsp5/Ubp2 complex localized to the endosome. We also predict a nearly constant pool of endosomal Fur4 independent of extracellular conditions. ESCRTs are responsible for sorting ubiquitinated proteins (cargo) on the endosomal membrane prior to formation of intralumenal vesicles. However, the mechanisms of sorting remain unclear. Motivated by recent experimental data, we present a cellular automata model of ESCRT sorting which demonstrates that a flexible network of ESCRTs and cargoes is sufficient for high efficiency sorting under specified rules. ESCRT-cargo networks exist on membranes while all ESCRT binding studies consider ESCRT interactions in solution. We present novel results on the dimensional dependence of dissociation constants for general protein-protein interactions using stochastic methods. We present a conversion for transforming three-dimensional dissociation constants to two-dimensional dissociation constants and demonstrate that ESCRT-cargo interactions are more stable on membranes than in solution. Using our computed two-dimensional reaction rates, we present an ODE model for the evolution of the size of ESCRT-cargo networks. Our results suggest that ESCRT-mediated sorting can be achieved on the order of seconds. Lastly, we examine ubiquitin-dependent regulation of Rad18 in the DNA damage tolerance pathway, a system of strictly soluble proteins which does not rely on ubiquitin-dependent degradation. Results of ODE models suggest that the dissociation constants for Rad18 binding events must be measured in order to better understand the mechanisms behind damage-specific responses

Tolvaptan and its potential in the treatment of hyponatremia

Tolvaptan is a selective arginine vasopressin (AVP) V2 receptor blocker used to induce free water diuresis in the treatment of euvolemic or hypervolemic hyponatremia. Currently the orally active medication is in the final stages prior to approval by the FDA for outpatient therapy. It appears to be safe and effective at promoting aquaresis and raising serum sodium levels in both short- and long-term studies. Tolvaptan is also effective for treatment of congestive heart failure (CHF) exacerbation, but whether there are long standing beneficial effects on CHF is still controversial. Prolonged use of tolvaptan leads to increased endogenous levels of AVP and perhaps over-stimulation of V1A receptors. Theoretically this activation could lead to increased afterload and cardiac myocyte fibrosis, causing progression of CHF. However, after 52 weeks of tolvaptan therapy there was no worsening of left ventricular dilatation. In addition, tolvaptan is metabolized by the CYP3A4 system; thus physicians should be aware of the potential for increased interactions with other medications. Tolvaptan is a breakthrough in the therapy of hyponatremia as it directly combats elevated AVP levels associated with the syndrome of inappropriate secretion of antidiuretic hormone, congestive heart failure, and cirrhosis of the liver

Failure to respond to food resource decline has catastrophic consequences for koalas in a high-density population in Southern Australia

Understanding the ability of koalas to respond to changes in their environment is critical for conservation of the species and their habitat. We monitored the behavioural response of koalas to declining food resources in manna gum (Eucalyptus viminalis) woodland at Cape Otway, Victoria, Australia, from September 2011 to November 2013. Over this period, koala population density increased from 10.1 to 18.4 koalas.ha-1. As a result of the high browsing pressure of this population, manna gum canopy condition declined with 71.4% manna gum being completely or highly defoliated in September 2013. Despite declining food resources, radio collared koalas (N = 30) exhibited high fidelity to small ranges (0.4-1.2 ha). When trees became severely defoliated in September 2013, koalas moved relatively short distances from their former ranges (mean predicted change in range centroid = 144 m) and remained in areas of 0.9 to 1.0 ha. This was despite the high connectivity of most manna gum woodland, and close proximity of the study site (< 3 km) to the contiguous mixed forest of the Great Otway National Park. Limited movement had catastrophic consequences for koalas with 71% (15/21) of radio collared koalas dying from starvation or being euthanased due to their poor condition between September and November 2013

Working with women with a learning disability experiencing domestic abuse:how social workers can negotiate competing definitions of risk

Women with a learning disability who experience domestic abuse receive intervention from both social services and the police. Responses from these services have increasingly become focused on notions of risk. This article uses governmentality theory to examine how risk is understood and managed by both services through a focus on policy and practice. The article examines how policy directs social workers to promote positive risk taking whilst assessing and managing risk for those deemed vulnerable or lacking mental capacity to self-protect. It is argued that, whilst social work decision making around risk has primarily been based on the judgement of individual workers, the police have increasingly adopted assessments utilising calculative measures. In addition, the article explores the extent to which these women are treated as autonomous agents responsible for managing their own risk. It is argued that social workers and the police should adopt a common screening process to highlight groups of women who may be at risk of abuse. In addition, social workers should draw on their interpersonal skills to enable women with a learning disability to recognise and make informed choices about abuse

Interventional Radiology Readiness Assessment Tool for Global Health

The Interventional Radiology Readiness Assessment Tool for Global Health is a new tool to methodically evaluate the environment of a medical institution for interventional radiology services given the existing infrastructure. Global health provides an exciting opportunity for interventional radiology to impact health outcomes in developing countries. A systematic and thoughtful approach to integrating interventional radiology services in the health care institutions of resource poor countries is needed in order to maximize global health efforts and outcomes. The IR Readiness Assessment Tool is available as on online form and in PDF format under Additional Files below

Structural Analysis and Testing of the Inflatable Re-entry Vehicle Experiment (IRVE)

The Inflatable Re-entry Vehicle Experiment (IRVE) is a 3.0 meter, 60 degree half-angle sphere cone, inflatable aeroshell experiment designed to demonstrate various aspects of inflatable technology during Earth re-entry. IRVE will be launched on a Terrier-Improved Orion sounding rocket from NASA s Wallops Flight Facility in the fall of 2006 to an altitude of approximately 164 kilometers and re-enter the Earth s atmosphere. The experiment will demonstrate exo-atmospheric inflation, inflatable structure leak performance throughout the flight regime, structural integrity under aerodynamic pressure and associated deceleration loads, thermal protection system performance, and aerodynamic stability. Structural integrity and dynamic response of the inflatable will be monitored with photogrammetric measurements of the leeward side of the aeroshell during flight. Aerodynamic stability and drag performance will be verified with on-board inertial measurements and radar tracking from multiple ground radar stations. In addition to demonstrating inflatable technology, IRVE will help validate structural, aerothermal, and trajectory modeling and analysis techniques for the inflatable aeroshell system. This paper discusses the structural analysis and testing of the IRVE inflatable structure. Equations are presented for calculating fabric loads in sphere cone aeroshells, and finite element results are presented which validate the equations. Fabric material properties and testing are discussed along with aeroshell fabrication techniques. Stiffness and dynamics tests conducted on a small-scale development unit and a full-scale prototype unit are presented along with correlated finite element models to predict the in-flight fundamental mo

Metastability, Mode Coupling and the Glass Transition

Mode coupling theory (MCT) has been successful in explaining the observed sequence of time relaxations in dense fluids. Previous expositions of this theory showing this sequence have required the existence of an ideal glass transition temperature $T_0$. Recent experiments show no evidence of $T_0$. We show here how the theory can be reformulated, in a fundamental way, such that one retains this sequence of relaxation behaviors but with a smooth temperature dependence and without any indication of $T_0$. The key ingredient in the reformulation is the inclusion of the metastable nature of the glass transition problem through a coupling of the mass density to the defect density. A main result of our theory is that the exponents governing the sequence of time relaxations are weak functions of the temperature in contrast to the results from conventional MCT.Comment: 14 pages (2 figures upon request), REVTEX

Property Law Review Issues Paper 6: Property Law Act 1974 - Sales of land and other related provisions

First issues paper reviewing the Property Law Act 1974 (Qld) dealing with provision for the sales of lan

Queensland Government Property Law Review: Issues Paper 1: Seller disclosure in Queensland

This Issues Paper considers the current seller disclosure regime in Queensland including its effectiveness for the purposes of the sale and conveyancing process and whether there is a need for reform. The paper highlights the wide ranging disclosure obligations in Queensland and the disparate sources of these requirements (common law, contract, statutory and local government laws). The paper considers the seller disclosure obligations in other jurisdictions that have enacted statutory disclosure regimes. Analysis has been undertaken of these statutory regimes and the Queensland system to provide a comparison of the key features of each relevant jurisdiction including the category of land the obligations apply to, the timing of disclosure, the form of disclosure, the content of the disclosure (what must be disclosed) and remedies available for failure to comply with the obligations. It is clear from this analysis that Queensland’s seller disclosure system is complicated, cumbersome and without any guiding principles underpinning its development