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Design Synthesis and Evaluation of Sialyltransferase Inhibitors as Radiosensitising Agents
No full textProteins and lipids are ubiquitously decorated with sugar chains known as glycans. Sialic acid is the sugar often found at the terminal position of cell membrane glycans, where it plays an integral role in inter- and intracellular communications and physiological function. Cancer cells often hijack these pathways, overexpressing sialic acid to promote immune evasion, invasiveness and treatment resistance. Reducing sialylation through the use of sialyltransferase inhibitors has been repeatedly demonstrated to reduce deadly metastatic spread and increase a tumour’s responsiveness to treatment with chemotherapy. However, there remains an ongoing need to improve the design of sialyltransferase inhibitors, particularly in terms of their potency, selectivity and bioavailability. Furthermore, sialyltransferase inhibitors have not been thoroughly explored as radiosensitising agents,This research project first explored the rational design of triazole-linked sialyltransferase inhibitors. These compounds were more analogous to the sialyltransferase substrate, CMP-Neu5Ac, in order to increase their potency relative to the current best-in-class sialyltransferase inhibitors. Two triazole-linked ST inhibitors were synthesised and screened. The 9ʹ-N-triazole was prepared over 11 steps and was measured to have a Ki of 7 ± 3 μM against ST6GAL1, which was a four-fold increase in potency relative to the analogous ethertriazole. The 6ʹ-N-triazole was prepared over five steps and was measured to give 54% inhibition of ST6GAL1 at 10 μM, which is comparable to the ether-triazole lead compound.Computationally aided drug design was used to investigate the design of ST6GAL1-selective inhibitors. Relative binding free energy perturbations were used to screen a library of nucleoside derivatives targeting the cytidine 4N-pocket. The synthesis and screening of selected derivatives showed these simulations to be particularly powerful when using the ST6GAL1 crystal structure, giving a coefficient of determination (R2) of 0.93. Using the AlphaFold2 model of ST3GAL1 was less accurate, with an R2 value of 0.12. These experiments led to the discovery of the 4N-hydroxy and 4N-benzyl derivatives, which showed increased potency and ST6GAL1 selectivity, relative to the uridine lead compound.Investigations into improving the bioavailability of these inhibitors examined the design of neutral phosphonate bioisosteres, nanoparticle formulations and prodrug derivatives. A neutral, benzoboroxole-functionalised analogue was synthesised over just three steps. The benzoboroxole exhibited an excellent ADME profile and was found to have comparable activity to the phosphonate, giving 41% inhibition of ST6GAL1 at 10 μM. A selection of these inhibitors were then screened in a novel radiosensitisation assay at the Australian Nuclear Science and Technology Organisation (ANSTO) radiobiology laboratories through a collaboration between the University of Wollongong (UOW) and ANSTO. The radiosensitisation effect was observed to be highly variable, ranging from a radioprotective effect of up to 28% in primary cultured mouse astrocytes to a radiosensitisation effect of up to 17% in the A375 melanoma cell line.This research demonstrates a step-wise improvement to the design of sialyltransferase inhibitors in terms of their potency, selectivity and bioavailability. Moreover, these inhibitors have been used to demonstrate, for the first time, a variable radiosensitisation effect across several different types of tumour and healthy cells. It is hoped that this work will form the foundation for the next generation of sialyltransferase inhibitors that can be used to one day improve the treatment outcomes for cancer patients.</p
Enacting urban governance innovation: beyond strategic pathways to incremental “muddling through”
No full textIn recent years, cities and city governance have been comprehensively urged to innovate to address complex societal challenges. An epistemic community–including the UN, OECD, global philanthropies, consultancies and think-tanks–has provided influential support by globally circulating examples of pathways to urban governance innovation (UGI) and codified best-practice innovation techniques. In this paper, we address how these pathways and codifications of UGI gel with actual practices of institutional change. We present a grounded theorization of UGI to enhance empirical understandings of its practice, framed through a novel combination of conceptual resources drawn from recent relational theorizations of governance innovation from scholarship on urban sustainability transitions and new municipalism. Drawing on analysis of a suite of urban-based innovation units internationally, we propose three key dimensions to a more nuanced understanding of UGI; namely that UGI is a process enacted relationally, and through navigations that are inevitably situated. We conclude by stressing the importance of understanding how UGI proceeds through more uncertain, piecemeal and incremental routes than globally-circulating pathways infer. Second, we argue that understanding the relational, navigational and situated dynamics of UGI is critical to evaluating its agendas, ambitions and (ambiguous) political possibilities.</p
Exploring the School Improvement Process in an Effective Australian School: A Case Study
No full textAustralia is increasingly concerned with the level of academic achievement of its students which has led to a heightened focus on sustaining school effectiveness. The drive to discover better ways to sustain a school’s effectiveness is mostly deeply rooted in effective school improvement planning. In response, Australian schools are mandated to develop a school improvement plan outlining their future targets. To understand how an effective school plans for school improvement within its own context., this PhD dissertation addressed the overarching research question: How does an effective school undergo the school improvement process?This dissertation presents a qualitative case study that investigates and documents the school improvement process in action in an effective school in Australia. School X, an effective and high performing school was chosen as the research case. The selection was based on multiple indicators, including strong performance on audit report of school effectiveness elements, and consistent high scores on matriculation and national examination. Data was collected through semi structured in-depth interviews, observations of senior executive leader meetings and professional development sessions, analysis of various school documents, examination of school website, tours, field notes and a researcher’s reflective journal entries. These diverse data sources were triangulated to provide comprehensive insights into the school improvement process.The study was able to describe the pivotal role of the senior executive leadership team in driving the school improvement process by integrating different leadership styles and approaches. This study also highlights the importance of understanding the role of the context of a school in determining a number of facets of school improvement planning, including leadership processes, how stakeholders are involved, which data is attended to, and the nature of the school culture. This PhD study contributes to the existing knowledge on school improvement planning and provides important insights and implications for educators, policymakers, and researchers seeking to promote school improvement and drive positive change in education.</p
Co-Creation of Societal Benefits Through Human-Centered Design and Management of Dynamic Capabilities in Oyster Farm Communities
No full textThis paper explores how business reconciles the perceived conflicting demands of social and profit logic to deliver value to shareholders and the wider community it serves. Through a human-centered design lens, the paper identifies co-creation as pivotal in the design of the business model that delivers social and economic value. Empirical data from an aquaculture SME case study was collected and analyzed to comprehend the role of social good in the development of the business model. The results demonstrate that societal improvements can be achieved when concurrently considered and designed into each stage of the business model development. The findings reveal that technology when deployed within the context of economic and societal improvements has the potential to support businesses in organizing services that deliver economic, societal, and environmental benefits. Replicating this approach requires organizations to develop a deep understanding of the social context that their customers operate within.</p
A generalized integral equation formulation for pricing American options under regime-switching model
No full textIn this paper, we present a generalized and highly efficient integral equation formulation for the price of American put options under regime-switching model with a goal of improving computational efficiency in mind, particularly when the number of regimes is large. Our achieved high efficiency is based on a newly proved theorem, which facilitates the decoupling of a system with simultaneously coupled PDEs so that they can be solved recursively at the numerical solution stage. Such a high efficiency is also fueled further by that the integral equation approach being characterized with its excellent trade off between maximizing analytical tractability and minimizing numerical discretization. Upon providing some numerical examples to demonstrate the implementation of the new approach and its efficiency, we anticipate that the very same theorem can be used to reduce the computational burden if other numerical approaches are adopted, for this highly challenging nonlinear problem.</p
Optimising workflows of intracranial stereotactic radiosurgery quality assurance including single-isocentre multiple-target
No full textThe occurrence of brain metastases is one of the most common complications after primary cancer treatment. Recently published research reports incidence rates in cancer patients to be anywhere between 10 – 50%. There is a continuing trend of growing acceptance and referrals to intracranial stereotactic radiosurgery (SRS) for treatment with some of the driving factors being a lesser impact upon quality of life compared to the more traditional whole brain radiotherapy and an increased availability due to the use of conventional medical linear accelerators to deliver SRS treatment. This growth, along with the use of complex techniques, has seen the workload of the medical physicist increase making the efficiency of procedures an important consideration.It is widely accepted that due to the ablative doses delivered in few fractions to small targets, SRS requires high precision and therefore high levels of quality assurance (QA). The use of complex techniques such as single-isocentre multiple-target (SIMT) SRS has increased the level of delivery accuracy required as targets may now be located at off-axis positions and hence be more susceptible to rotational uncertainties. It has been demonstrated previously that as departments’ confidence in accurate delivery grows through experience, the levels of QA being conducted may be reduced.The aim of this thesis is to optimise workflows for SRS QA including SIMT, in order to reduce the workload of the medical physicist. The recommendations being developed will span many aspects of SRS treatment including machine QA, treatment planning and patient-specific QA (PSQA). This thesis will: examine overlap between routine QA and PSQA; identify planning factors which result in a greater plan robustness to uncertainties, potentially increasing confidence in delivery; and investigate an alternative to measurement-based PSQA techniques.</p
Harvest Strategies and Allocation – Preliminary Paper
No full textThe Western and Central Pacific Fisheries Commission (WCPFC) is unique among tuna regionalfisheries management organisations due to the significance of catches from small islanddeveloping State exclusive economic zones, and their collective influence on conservation andmanagement negotiations. This has enabled the WCPFC to make significant progress on thedevelopment of harvest strategies in fisheries that occur largely inside their waters.In 2017, the 14th Regular Session of the Commission established target reference points (TRP)for skipjack, yellowfin and bigeye that will enable the development of long term harveststrategies. Simultaneously, the WCPFC agreed to develop a process to allocate rights for thehigh seas purse seine fisheries, and the tropical longline fisheries more generally. Althoughharvest strategies do not require explicitly allocated fishing rights, the implementation ofharvest control rules (with pre-agreed adjustments to effort or catch on the basis of changesin stock status) does necessitate that there be explicitly agreed responsibilities forimplementing adjustments to fishing effort or limits, and clarity over how these adjustmentsare implemented.While negotiating these commitments, the WCPFC is required by its founding Convention toensure that decisions do not transfer a disproportionate burden of conservation action ontodeveloping States. More broadly, the global community has recognised the importance offisheries to SIDS, and Sustainable Development Goal 14 (SDG14) has committed to increasethe economic benefits to Small Island Developing States and least developed countries fromthe sustainable use of marine resources by 2030.Looking forward, these simultaneous developments provide opportunities for the WCPFC tocarefully negotiate and create transparent and equitable rules to guide management andallocation decisions, and implement their conservation obligations consistent with the WCPFCConvention. use of marine resources by 2030.</p
Microfluidics and Deep Learning for Antimicrobial Resistance Research
No full textAntimicrobial resistance is the ability of bacteria to counteract antimicrobial stressors and is a serious and growing threat to clinical treatment of infections. Decades of research have identified several different types of resistance and the molecular mechanisms underlying them. An important aspect of these phenomena is the heterogeneity within a bacterial population, which often posts a challenge to laboratory techniques that rely on the observation of properties that are averaged over a large number of cells. Traditional culture-based techniques have been the backbone of microbiology and allow for the detection of rare resistant mutants. However, when one wants to study the evolution of such an event, the analysis of single cells becomes crucial. Advancements in single-cell fluorescence microscopy of the past decades have led to the ability to observe phenotypic differences between members of populations and even allow for the study of intracellular protein dynamics and interactions. As antimicrobial resistance research progresses, more and more details appear on the complexity and environmental sensitivities within one bacterial culture. As such, the need for in vivo single-cell data in high throughput becomes apparent.The goal of this study was to develop a high throughput, single-cell fluorescence microscopy platform, able to interrogate thousands of cells, labeled with multiple fluorescent protein probes. The objective was to design and construct such a system by combining the most successful and pragmatic concepts from the fields of microfluidics and artificial intelligence, and to apply it to further our understanding of the genomic processes underlying antimicrobial resistance.In the first part of this thesis, I review the various identified bacterial resistance phenomena, including the introduction of point mutations in which antimicrobial targets are mutated, the process of persistence in which bacteria abate specific cellular processes and go into a pseudo-dormant state, the amplification of genes in which an upregulated resistance gene renders bacteria resilient, and phase variation in which specific genes are turned on or off and allow bacteria to resist antimicrobial agents without going into a dormant state. After describing these phenomena and their mechanisms, I continue with a review of some of the most successful microfluidic concepts for bacterial research, which I then organize into building blocks for live-cell interrogation systems.Next, I describe the design and implementation of a microfluidic system to study bacterial cells. To this end, I selected the mother-machine concept for its efficiency and simplicity with which it can trap thousands of Escherichia coli cells. The method describes how to produce the microfluidic chip master mold using solely ultra-violet mask-less lithography instead of electron beam lithography, greatly reducing the complexity of the process. Devices for use in bacterial observation studies are produced from these master molds by casting of the polydimethylsiloxane chip and the assembly of the microfluidic system.This system is capable of recording thousands of E. coli cells in overnight time-lapse experiments. I explain how to set up a straightforward deep-learning image processing pipeline, to analyze the large data sets produced by these high-throughput experiments. Cell detection, segmentation and tracking are all conducted using tailored versions of some of the most successful deep-learning models of the last decade. The results are used to detect full cell cycles, and to construct cell-cycle plots in which thousands of cycles are synchronized to visualize dynamics previously hidden. These temporal diagrams reveal phenotypic properties such as intracellular protein concentrations and dynamics as a function of cell-cycle phase. Furthermore, spatiotemporal diagrams can be made which reveal the average protein location as a function of cell-cycle phase. These quantitative data are highly detailed and can also be used for automated anomaly detection for extraction of rare phenotypic events.Finally, I apply this system to a decades-old research topic: post-replicative gap repair. This gap repair occurs after the replisome encounters a lesion, leading to lesion skipping and the production of a single-stranded DNA gap. In E. coli, the gap is repaired via the RecFOR pathway, in which several proteins act in concert. The precise role of each of these is an ongoing research topic. Here, we studied the influence of RecF, RecO, RecJ and RecA on the displacement of single-stranded-binding (SSB) proteins before and after a mild ultra-violet light exposure. We used ten E. coli MG1655 strains, including wild-type and nine knock-out mutants with several combinations. The results of the RecF and RecO proteins are consistent with the current RecFOR model. Furthermore, a remarkable strong influence of the absence of the RecJ protein on the displacement of SSB proteins has been revealed. This effect seems to occur even in the absence of the RecF, RecO, and RecA protein.I conclude my thesis with a discussion and provide suggestions on how this high-throughput single-cell interrogation platform can be used to enable future research on bacterial resistance phenomena.</p
Employee Values and Value Congruence: Foundations, Nature, and Future Directions
No full textThis PhD by Compilation thesis focuses on the nature and importance of employee values and value congruence in organizational settings. It was designed and delivered as a three-study project with each study written up and submitted to peer-reviewed journals separately. The central question of this thesis is “What is the contemporary nature of value congruence and incongruence in organisations?” In order to answer this question, an integrated model of congruence/incongruence of different types of value (work values, political values, and cultural values) and possible outcomes (positive and negative) was developed. This model framed and guided the three studies and the findings of the studies supported all pieces of the model. Overall, the main contribution of these studies is to reveal unconscious role of employees’ value congruency and incongruency in the decisions related to their employment (e.g., recruitment, promotion, exit).Study one is a systematic review of the similarity-attraction hypothesis (SAH) in the workplace which has been shown to exert an influential role in guiding employees’ behaviour. The review analyses 45 empirical studies of SAH. The results showed that although SAH holds in most workplaces driving employees’ attitudes and behaviour, it is a relatively weak force that can be suppressed by economic, social, and legal forces. Also, the review revealed a very low number of longitudinal studies into SAH, which is important as the SAH theory is predictive in nature of the theory. The review also showed that empirical studies of SAH far outweigh empirical studies of the alternative dissimilarity-repulsion hypothesis (DRH). Typically, studies of SAH in the workplace only measure one type of value, although there are many competing forms of value in organizational settings such as work values, cultural values, and sociocultural values which employees carry in their personal and work life. The review also highlighted the role of demographic similarity in the primary stages of relationships to bring people together (e.g., during recruitment and selection) and psychological similarity is pivotal over more lengthy periods and therefore comes more to the fore in during long-term employment. The review also demonstrated that there is a paradox at the heart of value congruence and incongruence in workplaces. Whereas employees may have a fundamental desire to be amongst people similar to themselves, many organizations want, and have a legal requirement, to be inclusive and operate with a diverse workforce in which everyone feels comfortable.In the second study, I explored how multiple types of values interact and whether congruence and incongruence might be two separate factors influencing positive or negative outcomes. This second study is a conceptual piece that presents an integrated model of three types of values (work values, political values, and cultural values) to create a new heuristic model of values that can be used to predict organizational outcomes. It argues that value congruence is underpinned by the “similarity leads to attraction” hypothesis and value incongruence is underpinned by the “dissimilarity leads to repulsion” hypothesis. According to this conceptual model, factors producing employee value congruency relate to positive organizational outcomes and factors causing value incongruency relate to negative organizational outcomes. Also, the model argues that individuals do not evaluate value similarity and value dissimilarity unidimensionally, but these are two distinct dimensions reinforced by different theoretical hypotheses.In the third study, I focus on one element of the model developed in the second study, political value incongruency, and explore how it is manifested in neo-normative organizations (i.e., those advocated diversity and inclusivity agendas) with many employees hiding their political values and pretending to accept and follow organizational values as a strategy to survive. To illustrate the importance of this strategy, I looked at what happens when those with extreme political values that are antagonistic to those of the organization are revealed to hold these views. I studied the reactions of neo-normative organizations in the USA when their employees were revealed to be right-wing extremists by taking part in the riots at The Capital on 6th January 2021. All of these employees were summarily dismissed usually before any due process or any charges were laid against them. At the same time, the dismissal rate for employees working in non-normative organizations is less than 10%. This result suggests that in these extreme circumstances when their values are put under the spotlight, neo-normative organizations’ control of employees’ values is stretching into their personal and political lives. Not only does this demonstrate the increasing surveillance of employees by value-driven organizations, it demonstrates the importance that employees with values different to those of the organization are forced to mask them or risk dismissal. The thesis begins with an introduction on values and value congruence and ends with an exegesis that draws threads together from across the three studies.</p
CASE Framework: A new method to evaluate the technologies that assist the response to a crisis
No full textA crisis is a unique and destructive event that affects individuals, communities and organisations. The availability and the sharing of knowledge is imperative to be able to successfully respond to such events. To assist in their response, crisis information systems are created to support the management of knowledge and its successful sharing. However, it is difficult to assess the variety of technologies used and their impact on the larger crisis response. That is the focus of this thesis. The creation of a new method to assess the quality of a crisis information systems from the perspective of knowledge management, the Crisis Assistant System Evaluation (CASE) Framework.The CASE framework has been built on three mixed-method empirical studies in the context of the Australian veterinary Industry. These studies include the surveying of over 250 participants, extensive one-on-one interviewing of industry leaders, and 15 different focus groups that comprised of hundreds of participants from every facet of the industry.The first study explored the veterinary industry as a whole and uncovered the core influencing factors that affect knowledge sharing in the industry. The second study examines the 2007 Australian Equine Influenza Outbreak and its response: this is one of the few examples of the successful eradication of a virus from a continent. Finally, the third study examines the preparedness of the veterinary industry to the critical Hendra virus issue. Hendra virus is a zoonotic virus (a virus that is transferred from animals to humans) that originated in Australian bats and has now killed 7 people with a mortality rate of 57%.This research was conducted during the COVID pandemic, a zoonotic virus that has killed millions and devastated the global economy. If anything has been proven during this pandemic, it is the unpreparedness of governments to the scale and commitment needed to combat such a crisis. What this thesis has shown is how an industry functions in normal settings, how they have defeated a virus outbreak and what they are doing to combat the growing threat of a new virus. Together, these studies have provided the means to evaluate the technologies used in a crisis with the hope that the damage of future crises can be mitigated.</p