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Neutrophil-Mediated Inflammation in Response to Acute Myocardial Infarction.
No full textNeutrophils and neutrophil extracellular traps (NETs) are essential effectors of the innate immune system and are increasingly appreciated as drivers of various human pathologies. Studies suggest that neutrophil activation and NETs are implicated in the pathophysiology of coronary artery disease (CAD) and hold prognostic value in predicting recovery after acute myocardial infarction (AMI). However, our understanding of neutrophils in these – and other – contexts has been hindered by the methodological complexities of studying these cells ex vivo, and investigations have largely been confined to analysis of few surrogate markers of these neutrophil functional pathways. The advancement of spectral flow cytometry has equipped us with the ability to examine co-expression of a variety of neutrophil activation, subsetting, and functional markers to comprehensively probe the role of neutrophils in human disease. Thus, this thesis developed high parameter spectral flow cytometric methodologies to accurately identify NETs and neutrophil subsets to investigate neutrophil-mediated inflammation in AMI. Additionally, we investigated the effect of dual antiplatelet therapy (DAPT) – as the mainstay therapeutic management of AMI – on neutrophil effector functions and phenotype in a healthy cohort.Firstly, we developed a 7-marker flow cytometric methodology for the specific detection of cell-appendant NETs on neutrophils in peripheral blood. We established experimental conditions for monitoring NETosis in vitro and reported a conservative phenotyping strategy for the detection of NET-positive neutrophils. This panel utilised all surrogate markers of NETosis, and the gating strategy excluded necrotic cells to positively identify NETs over other cell death pathways. We then applied this methodology in a cohort of CAD patients and determined that cell-appendant NETs were elevated in AMI patients. The AMI cohort exhibited substantial variation in NET burden, although no clear clinical drivers for this variance were identified.To determine how best to assess neutrophil subsets and function by flow cytometry, we conducted a review of current approaches to neutrophil phenotyping by cytometry to inform the design of a panel to examine circulating neutrophils. This review highlighted that a lack of standardised nomenclature and phenotyping approaches has limited our ability to delineate bona fide subsets from highly activated neutrophil populations. We subsequently developed a 17-marker panel, which overlaid several alternative subsetting markers, to identify eight peripheral neutrophil ‘subsets’ and interrogate neutrophil function across multiple pathways.Next, we applied this panel in a CAD cohort to examine neutrophil-mediated inflammation in this context. As expected, we demonstrated that neutrophil activation was heightened in patients with AMI, compared to stable CAD. Additionally, when defined by manual gating, neutrophil maturation subsets differed between subjects with AMI and stable CAD. However, overlay of alternative markers to aid identification of these subsets was difficult due to discordant expression between these patient groups. We determined that high-dimensional analysis successfully delineated several neutrophil populations that exhibited distinct maturation and activation phenotypes. These populations could be recapitulated using a manual gating strategy for downstream applications.Finally, we examined neutrophil phenotype and effector functions in a healthy cohort before and after a DAPT regime to mirror the therapy our AMI patients were on at the time of sampling in this thesis. We implemented our manual gating strategy to recapitulate neutrophil populations identified by high-dimensional analysis, and confirmed the presence of the same neutrophil populations in this cohort. Further, we demonstrated that these subsets did not change after DAPT. However, we demonstrated that neutrophil reactive oxygen species (ROS) production was altered following short-term DAPT, and some subsetting and activation markers changed following in vitro stimulation and short- and long-term DAPT.Findings from this thesis demonstrate the complexity of examining neutrophil-mediated inflammation in healthy and disease states, such as CAD. We have demonstrated that comprehensive flow cytometric methodologies can be utilised to accurately identify circulating NETs and neutrophil subsets, and that peripheral neutrophils are phenotypically distinct in AMI compared to stable CAD. Furthermore, in vivo DAPT may alter the phenotype and function of circulating neutrophils after in vitro stimulation. This thesis provides a foundation for further investigation into neutrophil phenotyping by flow cytometry and application of these approaches in AMI will enhance our understanding of the critical role of neutrophils in this context.</p
Dismissal, Delay, and Denial: A Discourse Analysis of Women and People’s Endometriosis Healthcare Journeys
No full textIt is estimated that 190 million women and people from across the globe are diagnosed with endometriosis (World Health Organisation, 2023). Despite this staggering number, endometriosis remains an ’unknown’ disorder (Ellis et al., 2023). There remains limited research and knowledge about endometriosis, and there are clear gaps in the literature that seek to understand and challenge the discursive construction of endometriosis within a healthcare system that continues to medicalise women and people's bodies. The main objective of this qualitative study was to understand the role that discourse plays in constructing women and people’s healthcare interactions and subjectivities when seeking a diagnosis for endometriosis in Aotearoa New Zealand. To understand this, a feminist poststructuralist discourse analysis approach was utilised to analyse interviews with eight women and people located across Aotearoa New Zealand. Analysis revealed the role of dominant discourses in constructing oppressive meanings and interactions leading to participants feeling that their symptoms of pain were denied and dismissed. This in turn led to a lack of trust in and fear about the healthcare system. Despite this, participants were able to create threads of resistance through counter-discourses created and maintained through making connections with others online. These findings suggest the work needed within the healthcare system to ensure that women and people are active participants within their healthcare to order to address gendered inequities in endometriosis and broader healthcare.</p
Impedance -based Stability Analysis on IBR Integrated Power System
No full textThis thesis examines the small-signal stability of inverter-based resources (IBRs) in a power system that contains grid-forming inverters (GFMs) using impedance-based methods. With the increasing integration of power electronics in modern grids, there is a need to study dynamic stability under the influence of complicated inverter-grid interactions. While the traditional eigen value-based methods have limitations in assessing the stability in converter dominated systems, impedance-based stability analysis is a more suitable alternative. This suitability arises from its ability to analyze interactions without requiring access to the internal state variables of every component; instead, it relies on the terminal frequency response (impedance), which can be measured or scanned from detailed EMT models, thus bypassing the common barrier of proprietary converter control data.The study utilises the standard IEEE 9-bus system, where the conventional synchronous generators are gradually replaced with Virtual Synchronous Machine (VSM)-based GFM converters. Electromagnetic Transient simulations were conducted in DigSilent Powerfactory using frequency-domain perturbation methods. A customized simulation setup, based on Powerfactory’s Impedance Scan Template, created by DigSilent Powerfactory is used to extract frequency-dependent impedance characteristics from the inverter terminal. The methodology includes pre-simulation settling runs, automatic frequency scans by measuring the terminal voltage and current to calculate the complex impedance characteristics.Stability is determined by accounting for loop gain functions between the inverter and grid impedances and evaluation using Nyquist plot under the Generalized Nyquist Criterion (GNC). This was done in both single IBR and multiple IBR configurations across several operating conditions. The results showed that the inverter’s impedance is relatively insensitive to its operating point when the SCR is high and thereby produces consistent loop gains with stable Nyquist margins. Under reduced grid strength, some sensitivity and potential phase lag was observed leading to reduced phase margins and further proximity to the critical point. These results present some insights into the use of impedance-based methods to identify regions of concern in frequency space to estimate dynamic stability margins in complex converter-dominated systems. The study concludes that impedance-based analysis provides a reliable framework for investigating the stability of grid-forming inverters under different network conditions.Quantitatively, the system was found to be stable in both single and multiple IBR configurations, with the Nyquist locus not encircling the critical point (-1,0) in all cases. The analysis revealed that stability is robust in strong grid conditions, confirmed by a calculated Short-Circuit Ratio (SCR) of 8.6. Qualitatively, it was discovered that the inverter's impedance profile is highly dependent on its operating point; stressed, low-power, high reactive-power absorption scenarios produced more resonant impedance characteristics than high-power operation. Despite the presence of sharp mid-frequency grid resonances (300-800 Hz), the low-impedance nature of the GFM inverters provided effective damping. A basic time-domain validation was also conducted, which supports the frequency-domain analysis and identifies the resulting changes to the overall system behaviour when subject to small disturbances. Future work can take this framework further by employing coordinated multi-inverter controls, examining different grid-forming strategies and scaling this work to more complex, realistic transmission networks.</p
Investigating Microbial Utilisation of Seaweed Cell Wall Polysaccharides
No full textSeaweed cell wall polysaccharides are an invaluable reservoir for photosynthetically fixed carbon in the marine environment. This thesis interrogates the genomic and enzymological components that enable two recently isolated seaweed-associated bacteria, Rhizobium sp. nov. C1 (RhiC1) and Aliiglaciecola sp. nov. SL4 (GlaSL4) to access this crucial nutrient source. Heterotrophic bacteria express highly specialised microbial enzymatic cascades for utilisation of these varied and complex polysaccharides as substrate for central energy-yielding metabolism.To begin, genomes of RhiC1 and GlaSL4 were annotated for the presence of putative polysaccharide utilisation loci (PUL). These are defined and coregulated genomic regions that encode carbohydrate active enzymes (CAZymes) alongside additional polysaccharide-modifying, transcription-regulatory, and transport machinery. CAZyme classes are delineated by their specific activities towards the degradation, modification, or synthesis of polysaccharides. Classes include polysaccharide lyases (PLs), glycoside hydrolases (GHs), carbohydrate esterases (CEs), glycosyl transferases (GTs), and enzymes with auxiliary activities (AA). Annotation of these enzyme classes, their respective subfamilies, and additional protein encoding genes within the defined PUL inform the likely degradation capacity and specificity of a PUL.One bioinformatically validated enzymatic cascade was identified in both GlaSL4 and RhiC1, each containing signatures of marine polysaccharide utilisation. The predicted metabolic activity of RhiC1 against seaweed cell wall polysaccharides was restricted to a truncated PUL encoding three localised CAZymes (RhiGH28, RhiGH105, and RhiPL15) and a distal RhiPL12. Putative activities of these GH and PL families have not been reported to work in concert, revealing a seemingly novel putative enzymatic cascade. This complement of CAZyme machinery was biochemically investigated for their specificity and contribution to the metabolic profile of RhiC1. RhiGH28 was characterised as an exopolygalacturonase, contributing to the degradation of pectin species, and broadly confirming pectinolytic activity at its native locus. Putative activities of CAZymes encoded in this PUL, as well as localised transportation and transcription machinery, established a likely preference of RhiC1 for substrates sourced from the wider microbiome environment, revealing the polysaccharide utilisation capacity of a microbial genus that is presently understudied in the marine environment.By contrast, an expansive locus was annotated from the genome of GlaSL4, equipped with 19 CAZymes and eight sulfatases. The collective enzymatic potential in this PUL indicates complete degradation of the seaweed cell wall polysaccharide ulvan. This PUL presents comprehensive enzymology for the modification and degradation of ulvan, which facilitates the optimisation of ulvan’s existing bioactive properties as a sulfated, uronic acid-containing polysaccharide. Enzymes selected from this locus for biochemical investigation (GlaPL25a, GlaGH105, GlaS1_NC, and GlaS1_25) represent critical initiating steps in the cascade of ulvan degradation, the sequence of which had not been previously biochemically validated in concert. This contributes to our understanding of microbial utilisation of this complex and significant cell wall polysaccharide. Comparison between the RhiC1 pPUL and the GlaSL4 ulvan PUL (uPUL) illustrates the complexity of marine polysaccharide utilisation and differentiation in heterotrophic polysaccharide metabolism.Together, CAZymes characterised in this study enact crucial activities in seaweed cell wall polysaccharide utilisation by RhiC1 and GlaSL4. These findings contribute not only to an improved understanding of fundamental glycan utilisation and carbon flux in the marine environment, but also the development of bespoke oligosaccharides as bioactive candidates.</p
Investigating the factors and expectations that influence Chinese international students to study in New Zealand in the post-COVID-19 era
No full textThis study explored the factors influencing Chinese international master’s level students’ choice to study in New Zealand, their expectations and study experiences in the post-COVID-19 era, including the challenges and adaptations they face in New Zealand, as well as their perceptions of New Zealand international education and advice for studying abroad. This study adopted a mixed-methods explanatory sequential design. The quantitative research used a questionnaire of 395 Chinese international master’s level students to understand the influencing factors and expectations of their decision to study in New Zealand. The qualitative research phase collected data through semi structured interviews with 12 Chinese international master’s level students to further explain the influencing factors and expectations, and to describe the challenges and adaptation of studying in New Zealand, complementing and explaining the quantitative data.By applying the push-pull model, this study found that the decision-making process of Chinese international master’s level students studying in New Zealand is a dynamic process influenced by push and pull factors in different dimensions (environmental, economic, geopolitical and international relations, educational, and personal) in both the home country (China) and the destination country (New Zealand). In addition, the findings provide evidence that gender, age, programme and major were associated with variations in expectations and the importance of different push-pull factors.Using Pierre Bourdieu’s concepts of field, habitus and capital as a theoretical framework, this study found that after arriving in New Zealand, Chinese international master’s level students form new habitus in the new environment that are different from those in China in order to cope with various challenges they face during their study abroad (language barriers, cultural adaptation challenges, adapting to daily life). It is also a process of gradually achieving various expectations or goals (cultural, career development, academic, personal), as well as capital accumulation and transformation. In the process of studying abroad, Chinese international students have formed different views and advice about studying in New Zealand. This study provides a reference for New Zealand higher education institutions to explore how to provide better student services to Chinese international students and how to attract Chinese international students.</p
Improving Evolutionary Neural Architecture Search: Flexibility, Compactness, and Efficiency
No full textConvolutional neural networks (CNNs) are a superb computing paradigm in deep learning and their architectures are considered to be the key to performance. Manually designing CNNs which involve numerous ingenuity and efforts from domain experts can no longer meet the increasing demands with the expansion of deep learning technology and the difficulty of the real-world tasks. Recently, neural architecture search (NAS) has emerged as a promising means to automate the process of deep model design. Evolutionary computation (EC), a population-based heuristic search paradigm, is gaining popularity in NAS because of the merit of being gradient-free in dealing with NAS as a highly non-convex optimization problem. However, the limitations of evolutionary NAS have also been exposed along with its development. One big problem comes from the conservative search space design which reduces the flexibility of architecture search. In addition, many existing NAS algorithms lack consideration of the complexity of the searched architectures, which results in the obtained architectures being bloated thus impeding their deployment on resource-constrained devices. More seriously, NAS usually suffers from the prohibitive computational cost due to a massive number of architecture evaluations required during the search process. This thesis aims to address the above issues in terms of flexibility, compactness, and efficiency of EC-based NAS. Flexibility is achieved by developing new comprehensive search spaces, encoding schemes, and genetic operators for EC algorithms. Simultaneously, compactness is reached through the design of innovative computationally efficient modules and evolutionary multi-objective optimization methods. Meanwhile, efficiency is obtained through acceleration techniques including novel low-fidelity proxy combinations, weight inheritance mechanisms, and zero-cost proxy. This thesis proposes four novel methods with varying degrees of focus on these three aspects of NAS. Firstly, this thesis proposes a two-level variable-length particle swarm optimization (PSO, an EC algorithm) method to flexibly evolve both the micro-architecture and macro-architecture of CNNs. A compactness-aware search space with parameter-efficient blocks is designed and an acceleration scheme combining several low-fidelity proxies is proposed to speed up architecture evaluations. Experimental results on the CIFAR-10, CIFAR-100, and ImageNet datasets show the superiority of the proposed method in classification accuracy, search cost (slightly >1 GPU day), and architecture/model complexity. Next, this thesis proposes a PSO approach with a new encoding strategy to achieve a flexible search on the number of convolution filters. In addition, the evaluation time is greatly saved by a novel elite weight inheritance method based on an online updating weight pool, and a customized fitness function considering multiple objectives is developed to well control the complexity of the searched architectures. The proposed method achieves faster search speed (0.4 GPU days on CIFAR) and outperforms many advanced peer competitors at much lower architecture complexity. Furthermore, this thesis designs a computationally efficient yet powerful module, dubbed EMixConv, by leveraging multi-scale convolution with concatenation-based feature reuse. An evolutionary one-shot NAS method integrating the EMixConv module is proposed to search for good architectures. For the purpose of enhancing the robustness of weight inheritance in one-shot NAS, an effective multi-path weight sampling mechanism is developed. The effectiveness of EMixConv is examined on the same datasets, and the search method only takes 0.2 and 1.2 GPU days for a complete search on CIFAR and ImageNet, respectively. Finally, a lightweight mixed-scale convolution block, named LightMix, is proposed, for further improving the model expressivity and also compactness through channel divisions. To seek close-to-optimal architectures with promising performance and low complexity, this thesis develops an evolutionary multi-objective NAS framework integrating the LightMix block to search for lightweight architecture with high predictive performance. A zero-cost proxy is leveraged to obviate the expensive architecture training cost. The proposed method only takes 0.02 GPU days to discover architectures on CIFAR-10 and CIFAR-100. On ImageNet, the architecture search takes merely 0.3 GPU days.</p
Sick of Toxic Black Mould? Development of a Stable-Isotope Dilution Assay for the Quantification of Stachybotrys chartarum Trichothecenes in New Zealand’s Leaky Buildings
No full textLiving in damp, mouldy housing is linked to the development of respiratory disorders, and New Zealand’s leaky building crisis in the mid-1990’s was accompanied by both pervasive mould growth and many anecdotal reports of illness. The most common fungus identified in the rotting timber of these houses, Stachybotrys chartarum, has long been suspected of causing building-related illness, and can produce some of the most potent mycotoxins known — the macrocyclic trichothecenes (MCTs). A Government inquiry into the leaky building crisis recommended investigating the health impacts from exposure to S. chartarum in such buildings, and in response, a group of multi-disciplinary health researchers proposed an epidemiological study into the incidence of asthma- related symptoms in New Zealand’s leaky building occupants in relation to low-level chronic exposure to Stachybotrys trichothecenes. The present research aimed to quantify low-level trichothecenes in dust samples by developing two complementary analytical methods.The gold standard in low-level mycotoxin analysis, stable-isotope dilution assay (SIDA), has not been applied to S. chartarum. Firstly, it was proposed that a SIDA-based gas chromatography-mass spectrometry (GCMS) method be developed to quantify verrucarol, the hydrolysis product of most Stachybotrys trichothecenes, as a proxy for total trichothecene content. Secondly, the development of a high-performance liquid chromatography-mass spectrometry (HPLC-MS) method was proposed to quantify key trichothecenes (KTCs), including two of the most potent MCTs, satratoxins G and H, in samples where verrucarol was detected using the SIDA-GCMS method. To enable this method development, standards of both natural verrucarol and a tri-deuterated isotopologue required for the SIDA-GCMS analysis were to be prepared by semi-synthesis from a related trichothecene, diacetoxyscirpenol, while standards of the KTCs required for HPLC-MS analysis would be isolated from large scale rice cultures of S. chartarum.Synthesis of verrucarol and a tri-deuterated isotopologue 15-2H1-3-2H2-verrucarol was successful, allowing development of the SIDA-GCMS method. In contrast, the HPLC-MS method was not developed due to a lack of KTC recovery from fungal cultures. The cultured S. chartarum strains were therefore subject to genomic analysis which revealed only two of five strains were potential MCT producers. The desired house dust samples could not be obtained. Instead, the SIDA-GCMS method was applied to extracts from the S. chartarum rice cultures and a selection of infested building materials provided by industry partners Biodet Services Ltd. Verrucarol was quantified in 15 of 101 hydrolysed extracts of the building materials and detected in a further five. Extracts of the cultured strains identified as MCT producers by genomic analysis yielded high levels of verrucarol upon hydrolysis, with low levels detected from a third isolate. These results strongly correlated with a qualitative analysis for the presence of KTCs (from an external provider), demonstrating the validity of SIDA-GCMS method. This work thus represents the first application of SIDA to the analysis of Stachybotrys trichothecenes and should provide a powerful tool for future investigation into their effect on human health.</p
A Moderated-Expression Model of 'Successful' Psychopathy: Psychopathic Personality Traits, Psychological Flexibility, and Valued Goal Pursuit
No full textThe mechanisms underlying ‘successful’ manifestations of psychopathy remain poorly understood. This study examined the moderated-expression model of successful psychopathy, which posits that adaptive behaviours in individuals with high levels of psychopathic traits emerge through interactions between these traits and external moderating factors. Specifically, we investigated psychological flexibility (PF) and Self-Centred Impulsivity (SCI) as potential moderators influencing the relationship between Fearless Dominance (FD) and valued goal pursuit. We hypothesised that higher levels of FD would predict sustained goal pursuit when PF is high and SCI is low. Participants included 388 first-year students (76.3% female), who completed a battery of self-report measures, including the Psychopathic Personality Inventory-Revised (PPI-R), Personalised Psychological Flexibility Index (PPFI), Comprehensive Assessment of Acceptance and Commitment Therapy processes (CompACT), and Valuing Questionnaire (VQ). Results indicated that FD was positively associated with valued goal pursuit, while SCI demonstrated a consistent negative association. Although PF as a whole did not moderate the association between FD and goal pursuit, specific facets—namely Acceptance, Behavioural Awareness, and Openness to Experience—did. These facets buffered the negative impact of SCI, reducing its disruptive effect on goal achievement. Furthermore, SCI negatively moderated the FD-goal pursuit link, underscoring its detrimental influence on goal-directed behaviour. These findings support the moderated-expression model of successful psychopathy, demonstrating that facets of PF and SCI moderate the association between psychopathic traits and the pursuit of valued goals. Further research is warranted to explore these associations and their implications for interventions aimed at fostering adaptive functioning.</p
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