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Development of a Carborane Framework for Fragment-Based Drug Discovery
No full textSince the first boron-containing drug entered the clinic, there has been an increased interest in harnessing the unusual
properties of this atypical element in drug design. Carboranes, an important class of boron cluster compounds, have
garnered particular attention for their use as a novel drug framework. Despite this interest, however, their use in this
field has remained limited in part due to an inability to access certain positions of the icosahedral cage. In this thesis,
we attempt to address this synthetic barrier and report our efforts at utilising these compounds as a structural
framework for fragment-based drug discovery (FBDD).
In Chapter Two, we describe the development of new methods for functionalising unusual positions of the carborane
cage. In so doing, an iodo protecting group for carborane B-vertices is reported for the first time. Using this protecting
group, the first syntheses of closo-1,2- and closo-1,7-carborane brominated at the B8 and B5 positions, respectively, are
reported. Progress towards the synthesis of two other novel closo-1,7-carboranes brominated at the B2 and B4
positions is also presented.
Chapter Three details the preparation of a library of low-MW carborane fragments for use in FBDD. These
compounds were subsequently tested for their ability to bind to and inhibit the function of myeloperoxidase (MPO), a
haem enzyme that is an emerging target for the treatment of a range of inflammatory disorders. Surface plasmon
resonance studies and in vitro inhibition assays identified new closo-carborane derivatives with μM potency that are
promising lead fragments for the development of a novel MPO inhibitor.
Finally, our endeavours towards increasing the potency of one of these lead fragments are presented in Chapter Four.
New synthetic methods were developed which allowed the expansion of this fragment at various structural positions.
Several key derivatives were synthesised, with a focus on producing hetero-disubstituted carboranes
Medical Image Analysis with Less and Noisy Labels
No full textDeep learning has revolutionized medical image analysis, but its success heavily relies on supervised training with large, clean-labeled datasets. Acquiring such datasets is both costly and labor-intensive, often requiring expert annotations from medical professionals. To address this challenge, Medical image analysis with Less and Noisy labels (Med-LN) has emerged as a promising solution, enabling deep learning on less or noisy labeled datasets. However, the challenges posed in the medical imaging domain remain under-explored. In this thesis, we first address the issue of less labeled datasets by leveraging both labeled and unlabeled data. Then, we explore the common issue of noisy labels in medical datasets. Specifically, we focus on three key tasks in medical image analysis under Med-LN conditions: medical image enhancement, medical image segmentation, and medical visual question answering
A comparative analysis of the drivers and outcomes of work, location and commuting choices of the office only, hybrid, and home/other location only workers
No full textHybrid work in an office and non-office locations on the same or different days, has become a mainstream work pattern in addition to only working in the office or working from home (WFH). This paper compares the three work groups within a framework covering drivers and outcomes for interconnected work patterns, location and commuting choices, using survey data of 981 randomly sampled employees in Australia. The research goes beyond the socioeconomic characteristics of employees to examine other reasons why the three groups choose the way they work and commute, and their work-related motivation, performance and wellbeing. The research reveals the following key findings: 1) Having the highest level of motivation drives hybrid workers to work hard with more working hours than other groups. The long working hours, however, have a detrimental effect on their wellbeing and job performance, despite the highest level of job satisfaction. However, they perform best in terms of contextual performance when more responsibilities and challenges are present. 2) The WFH/other only group has the healthiest wellbeing and the least counterproductive work behaviour on job performance. This suggests that work location is not the key reason for poor job performance and hence productivity. 3) The office-only workers have the best task performance as well as the second-best performance for contextual performance where more responsibilities and challenges are required. 4) A discrete choice model for the three groups suggests that commuting and work patterns for each day of the week (DoW) and time of the day (ToD), together with roles in the organisation, enable us to predict whether employees are likely to belong to one of three work-location alternatives. These findings suggest a need to shift the focus of work and transport policy from the predominate focus on location to other work-related issues, such as work-related wellbeing, and to consider ways to recognise better work arrangements as a significant contributor to improved workforce performance
Immersive Interactions: Leveraging Presence to Design Virtual Reality Experiences
No full textVirtual Reality (VR) technology offers unprecedented opportunities for immersive experiences, creating a feeling of “being there” in the virtual environment (i.e., presence). However, the design of VR applications which effectively harness the power of presence remains a significant challenge. This thesis investigates the phenomenon of presence in VR, exploring how it is constructed and how it affects user experience (UX) across various applications (including education, entertainment, and simulation). Through a series of four studies, employing a combination of research-through-design and mixed-methods quasi-experimental approaches, the impacts of different immersive design elements on presence are examined. The findings reveal complex relationships between immersion, UX design, and various packagings of presence. These relationships are documented in the User Presence in Mediated Immersive Experiences (UPMIX) framework, which this thesis proposes for designing VR experiences to facilitate and leverage presence.
The UPMIX framework provides a structured approach for analysing and prioritising presence needs, ideating immersive UX elements, and integrating them into cohesive VR applications. The framework emphasises the importance of packaging different aspects of presence and offers design considerations for taking advantage of the unique experiential qualities of VR technology. This thesis contributes to both the theoretical understanding of presence in VR and its practical application in user experience design. It offers valuable insights for VR developers and researchers, providing a toolset for creating more immersive, engaging, and effective virtual experiences across various domains, including education, entertainment, and research
Post-sentence detention and supervision in New South Wales: Constructing the subject as a high risk offender
No full textThis Thesis examines the Terrorism (High Risk Offenders) Act 2017 (NSW) (THRO Act). The THRO Act constructs a post-sentence supervision and detention regime for people who are purported to pose an unacceptable risk of committing a serious terrorism offence. The THRO Act is engaged after expiry of a person’s sentence under the criminal law. Its legislative intent is to protect the community from terrorism. Unlike other post-sentence supervision and detention regimes which link prospective risk to past offending, a person subjected to THRO orders may not have committed a terrorist offence.
The THRO Act is purported to prevent harm, but causes harm instead. While the numbers of people the THRO Act has been used against are small, its impact is profound. In this Thesis, I analyse how the THRO Act works in practice and excavate its political substrata to understand the ways in which it (re)shapes relationships between people and the State. To achieve these aims, I build on existing criminal law theory analyses with critical theory. By engaging with critical theory, I am able analyse the THRO Act on a deeper level, exposing the THRO Act’s political dimensions.
I make three main arguments. First, the THRO Act allows violence: it causes pain and harms people. Second the THRO Act engages in Othering: the State uses it to construct people as not belonging. Othering legitimises the THRO Act’s violence and is a form of violence itself. Third, the THRO Act creates a state of exception: it suspends an otherwise prevailing juridical order which allows violence to be clothed in legality
Cubane as a 3D scaffold for fragment library construction
No full textA recent initiative in the pharmaceutical sciences to examine the utility of alternative core scaffolds
has been driven by the need to diverge from planar, aromatic structures that have historically
constituted a biased proportion of chemical space in screening libraries. By focusing on more
complex, three-dimensional architectures, researchers aim to increase the accessible domain of
bioactive chemical space and address familiar challenges associated with highly aromatic
compounds.
Cubane has gained much contemporary research interest due to its remarkable stability, low toxicity
and its validation as a bioisostere of benzene. Furthermore, the intrinsic conformational restriction of
rigid hydrocarbons enables the construction of complex three-dimensional molecules with enhanced
precision, posing opportunities for the design of biologically-active structures. The incorporation of novel chemical matter in medicinal chemistry faces many challenges relating to synthetic versatility
and in vivo profile, thus, to accelerate the incorporation of the cubane scaffold into the drug discovery
pipeline, a fragment-based drug design approach was envisaged.
The synthesis of a selection of cubane derivatives has been accomplished and their synthetic routes
evaluated in accordance with fragment library design and diversity-oriented synthesis approaches.
The emergent reactivity and orthogonality constraints guiding the synthesis of cubane derivatives is
frequently unfamiliar and an examination of these problems and solutions was a critical objective.
The library of cubane derivatives was subjected to a fragment screening cascade to evaluate its
relative utility on the basis of its physicochemical properties such as fragment size, complexity, threedimensionality
and solubility. A final examination of methodology towards the synthesis of novel
polysubstituted cubane derivatives has demonstrated its potential in future fragment library
elaboration and general drug discovery efforts
Cape and Torres Health Commissioning Ltd (CaTHC) Project Final Evaluation Report
No full textIn May 2024, the Cape and Torres Health Commissioning (CaTHC) Ltd was established as a regional community-controlled commissioning entity. CaTHC is governed by a Board of Aboriginal and Torres Strait Islander Directors and is independent from government. It is planned that over a 10-year period CaTHC will develop the capabilities to receive public funding and commission health services that respond to community need. The aim is to shift the way care is planned, purchased, and delivered, to drive improved health system effectiveness, equity and whole of population health and wellbeing outcomes.
This report provides a detailed evaluation of the CaTHC project covering the period of entity establishment between August 2022 and December 2024. It focusses on project deliverables and resourcing; collaboration and governance; model design and implementation; and community and engagement. The project was formerly called the Torres and Cape Health Care Commissioning Fund (TORCH), with a name change to the CaTHC project in 2024
Resonant learning and transitional space: Enabling lasting leadership for good in a post-crisis world
No full textDeveloping graduates in pre-experience higher education programs that have the transdisciplinary capability to be leaders for good throughout their career is a complex curricular challenge. Resonant business education is predicated on learning experiences that draw in the lived experiences of students and integrates their current knowledge and skills into emerging experiential contexts, both being and yet to be experienced. The creation of pathways from experiences already gained by students in leadership, either explicitly or tacitly through following leaders or heroes of their own, into opportunities for experiential learning about leadership during their degrees represents a significant design opportunity. This study interrogates the challenges and affordances of designing a leadership education program at the University of Sydney Business S program purposefully creates sequences of challenging learning experiences in transitional spaces for students to integrate, repurpose and share their transdisciplinary knowledge, skills, and experience in resonant ways as they develop their skills to be leaders for good
A corpus-based critical discourse analysis of gender bias and evaluation in Australian Rules Football and Rugby League sports news discourse
No full textThis study explores the representation of elite female and male Australian Rules Football (AFL) and
Rugby League (NRL) athletes in Australian newspapers. Over the decades, women athletes have
faced numerous barriers to participation in sport stemming from socially constructed views of binary
gender stereotypes, which have been reflected in media coverage of sport. This research examines
how elite female athletes are represented and evaluated in the Australian sports media today,
compared to their male counterparts. This research also takes an intersectional lens, exploring how
media representations of gender intersect with sexuality and ethnicity, as well as how known issues
of homophobia and racism are addressed in the media. Employing corpus linguistics, critical
discourse analysis, and the framework of appraisal which derives from systemic functional linguistics
(Martin & White, 2005), this thesis analyses the extent to which patriarchal discourses are present in
Australian sports news coverage of AFL/NRL, and how they are realised through linguistic practices.
To undertake this research, I analysed a 5-million-word purpose-built corpus of AFL/NRL print news
coverage. A variety of corpus linguistic techniques (e.g. frequency data, keywords, semantic tags)
are used to identify language patterns, including methodological triangulation. Identified discourses are analysed using appraisal and critical discourse analysis. This thesis makes conceptual,
methodological, and theoretical contributions to linguistic research into gender and sport, providing
insights into the representation and evaluation of athletes in Australian sports news discourse, as
well as insights into combining corpus linguistics with critical discourse analysis and appraisal,
including the use of methodological triangulation in corpus linguistics
When is it convenient to split public transport lines?
No full textTo serve a public transport demand on a corridor, it is possible to have just one line serving all of it, or two of them each serving one segment - which we refer to as one divided line. In this paper, we investigate theoretically under which conditions a divided line is better than a single line, minimizing the sum of users’ and operators’ costs. Both solutions are often encountered in real-life networks, with the division typically occurring on CBDs or subcenters. Understanding which is the optimal alternative is particularly relevant in the context of public transport network design, where most heuristics do not consider splitting lines as a potential step to improve their solutions.
We formulate the problem in a generalized linear city, and optimize the frequency and vehicle size of each of the lines involved, to then compare the resulting costs of the full line versus the line divided at a given node. We prove that there are three conditions that favor the partition of a line, namely i) inducing few transfers, ii) a large difference in the maximum flows between the two segments, and iii) the segment with the lowest maximum flow being long. These conditions are synthesized into a divisibility index that can be calculated for each node, which is used to propose two algorithms to rapidly find where to split the line if convenient. The approach is tested
numerically in a linear version of the Parametric City Model, where we compare the optimal set of lines with the ones resulting after dividing the full line following our algorithms with very good results