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The biochemistry and phylogeny of CysE: An antimicrobial target
No full textNeisseria gonorrhoeae is an obligate human pathogen and the causative agent of the sexually transmitted infection (STI), gonorrhoea. There are over 87 million gonorrhoea cases per year globally, making it the second most prevalent bacterial STI. The rapid emergence of antimicrobial-resistant strains has led N. gonorrhoeae to being labelled as a priority pathogen for the development of new antimicrobials by the World Health Organisation. One strategy for identifying new antimicrobials is through targeting pathways required for virulence and mitigation of oxidative stress, such as sulphur assimilation pathways. This thesis investigates the potential of targeting the de novo cysteine biosynthetic enzyme, serine acetyltransferase, from N. gonorrhoeae (NgCysE) for new antimicrobials.
In this thesis, we present the kinetic and structural characterisation of NgCysE. NgCysE has serine acetyltransferase activity and is sensitive to feedback inhibition by L cysteine. Small-angle X-ray scattering demonstrates NgCysE is a single hexameric species in solution with subtle conformational changes upon binding of its inhibitor L-cysteine. Using X-ray crystallography, we present two NgCysE structures, with L-malate (2.01 Å) and substrate L-serine (2.8 Å), bound. NgCysE crystallises as a homohexamer with 3:2-fold symmetry with each monomer containing a N-terminal α-helical SATase and C-terminal left-handed β-helix domain. Additionally, we see extensive density for the C-terminal α-helical tails because of domain swapping, resulting in one of the most complete CysE crystal structures to date.
The high resolution NgCysE structure was used for structure-based virtual inhibitor screening to identify potential inhibitors of NgCysE. Virtual screening produced 28 hit compounds that were tested in vitro, with the most potent inhibitor, compound 2, demonstrating inhibition in the low micromolar range. Analysis of compound 2 docking reveals interactions with both NgCysE substrate binding sites, serine and acetyl-CoA. This is the first reported inhibitor of NgCysE and provides a starting point for development of new antimicrobials for treating gonorrhoea infection.
Lastly, we present the phylogenetic analysis of truncated and full-length CysE isoforms across the bacterial kingdom. We demonstrate that a truncated isoform has a discrete truncation of four α-helices from the N-terminal SATase domain and is the predominant isoform for Gram-positive bacteria. The functional implications of this truncation are explored using predictive modelling and demonstrate that CysE is likely to exist as a trimer rather than the hexamer seen for the full-length isoform. This highlights the diversity of CysE isoforms and paves the way for determining the evolutionary origin of these isoforms.
Collectively, this thesis highlights the merit in the emerging field of CysE inhibition. Moreover, we provide the basis for the future development of not only NgCysE inhibitors, but also the development of CysE inhibitors for other bacterial pathogens
Articulate the Kiwi way: perception insights from a language game corpus
No full textThis short communication reports on folk perceptions of New Zealand English lexical variation, specifically regarding which Māori loanwords are widely known by New Zealanders. We inspect the words used in a popular board game which has recently produced a New Zealand Edition – Articulate – and comb through these for all loanword uses, drawing comparisons with linguistics research and two popular websites containing lists of “Māori words every New Zealander should know” (Ministry for Culture and Heritage, 2022). We find remarkable overlap between the loanwords used in the board game and the former, but not the latter. The most frequent loanwords included are social culture loanwords, in line with research in other genres. The lack of consistency in spelling and macron usage leads us to believe that board games such as Articulate constitute rich sources for folk perceptions of language varieties, showing that even small-scale corpora can provide inroads into thorny questions regarding perceptions of contact-induced lexical variation
Measuring virtue: An aristotelian perspective on advancing positive psychology
No full textIn philosophical discourse, flourishing is widely thought to require the development and exercise of virtues. Positive psychology, as the science of happiness and flourishing, should, therefore, include the scientific investigation of the virtues. However, the main classification of virtues and strengths, the Values in Action Inventory of Strengths (VIA-IS), faces major criticisms that, if not addressed, may undermine the credibility of positive psychology as a science. One such criticism is that virtue-based classifications lack a conceptual foundation; another is that these classifications may harm individuals by attaching potentially stigmatising labels to them. In this paper, we propose that positive psychologists can address these critiques by taking an interdisciplinary approach, which involves adopting a philosophically rich Aristotelian theory of virtue, and further developing this approach through empirical research. Adopting a philosophical theory will provide a strong conceptual base for psychologists, guiding the construction of measures and the formation of hypotheses about virtues. However, as many scholars acknowledge, it is difficult to measure all aspects of Aristotelian virtues, such as emotions, reasons, and attitudes. Another aim of this paper is, therefore, to suggest appropriate methods for measuring these aspects of Aristotelian virtues
Historical museum samples reveal signals of selection and drift in response to changing insecticide use in an agricultural pest moth
No full textIn response to environmental and human-imposed selective pressures, agroecosystem pests frequently undergo rapid evolution, with some species having a remarkable capacity to rapidly develop pesticide resistance. Temporal sampling of genomic data can comprehensively capture such adaptive changes over time, for example, by elucidating allele frequency shifts in pesticide resistance loci in response to different pesticides. Here, we leveraged museum specimens spanning over a century of collections to generate temporal contrasts between pre- and post-insecticide populations of an agricultural pest moth, Helicoverpa armigera. We used targeted exon sequencing of 254 samples collected across Australia from the pre-1950s (prior to insecticide introduction) to the 1990s, encompassing decades of changing insecticide use. Our sequencing approach focused on genes that are known to be involved in insecticide resistance, environmental sensation, and stress tolerance. We found an overall lack of spatial and temporal population structure change across Australia. In some decades (e.g., 1960s and 1970s), we found a moderate reduction of genetic diversity, implying stochasticity in evolutionary trajectories due to genetic drift. Temporal genome scans showed extensive evidence of selection following insecticide use, although the majority of selected variants were low impact. Finally, alternating trajectories of allele frequency change were suggestive of potential antagonistic pleiotropy. Our results provide new insights into recent evolutionary responses in an agricultural pest and show how temporal contrasts using museum specimens can improve mechanistic understanding of rapid evolution
The role of intuition in social work practice: Differing understandings and attitudes
No full textThere has been a long debate about the use of intuition in helping professions, including social work. Often viewed negatively in professional contexts, intuition is nonetheless used as a form of risk assessment. The current research examined methods of identifying child sexual abuse. A mixed methods approach was taken, with 98 participants completing an online questionnaire and 24 taking part in in-depth interviews. The participants demonstrated varied perceptions of intuition and its usefulness. Although some participants were strongly critical of its use, for others, intuition or ‘gut feelings’ were preferred to formal assessment tools. However, what was discussed as intuition, rather than a form of ‘sixth sense’, was often based on tacit knowledge; for example, abused young people’s observable behaviours combined with known risk factors such as certain family characteristics. Therefore, concerns about the use of intuition may be based on incorrect assumptions
“Who wants to do something about rising prices?”: Consumer protest and the campaign against rising prices in Aotearoa New Zealand, 1966-1981
No full textThis thesis is a historical analysis of the Campaign Against Rising Prices (CARP), an organisation of women that fought against rising prices in Aotearoa New Zealand between 1966 and 1981. They were particularly distinguished by their use of targeted economic boycotts in the late 1960s and 1970s, and they were also prolific in their correspondence with governments of the day. Using archival records left by the two main branches in Auckland and Wellington, this thesis pieces together the story of CARP and its branches, and asks: Why did CARP emerge when it did, and why did it choose to take the actions it took? What was CARP able to achieve between 1966 and 1981, and to what extent was CARP successful in achieving its goals? Why did CARP dissolve in 1981? Where does CARP fit within the bigger picture of Aotearoa New Zealand in the 1960s and 1970s?
In answering these questions, this thesis will show that, during its time, CARP was a complex and flourishing site of protest, engaged in multiple different forms of protest and able to command attention, from the Government, the media, and the public. They cultivated strong ties with the trade union movement of the 1960s and 1970s, enabled by personal links between many of the women who led CARP and union leaders in Auckland and Wellington. They consistently maintained a rigid focus on ‘rising prices’, and attempted to position themselves as ‘non-political’ in the face of an antagonistic relationship with multiple governments, and accusations of being a front for Communist agitation. CARP were always an organisation led and supported by women, and initially collectively identified itself as a ‘housewives organisation’, but over time CARP de-emphasised gendered identity, and as such remained outside the larger ‘women’s movement’ of the 1970s. This thesis argues that we can understand the reasoning behind CARP’s formation, and decision-making, by understanding the background context of New Zealand’s socioeconomic conditions in the 1960s and 1970s, and the connections CARP had to growing domestic protest, the trade unions, and second-wave feminism. Understanding how CARP operated, and the context of the late 1970s, also allows us to understand why CARP dissolved in 1981, after several years of winding down. In the process, this thesis seeks to position CARP within the wider historiography on protest, labour, and gender in Aotearoa New Zealand, and bring it out of the obscurity it has had within New Zealand history since its dissolution in 1981
Modeling behavioral patterns of family violence aggressors
No full textBackground setting: The presumption that family violence will repeat and escalate is embedded in practices including risk assessment and case management. However, there is limited evidence that further episodes are inevitable, or that subsequent episodes will increase in severity. Therefore, we need to better understand temporal patterns in aggressor behavior to inform how risk is conceptualized in practice.
Methods: For a sample of 2115 family violence aggressors who came to police attention in Integrated Safety Response catchment areas in Aotearoa New Zealand, we collected information New Zealand Police routinely recorded about reported harm between 2018 and 2020. We used a hidden Markov model to estimate the latent (i.e., unmeasurable) states behind the information reported to police, and modeled aggressors’ movement between those states over time.
Results: We identified three latent states. The first contained low or no reported harm, the second contained low probabilities of reported harm, and the third involved a high probability of reported verbal abuse and a moderate probability of reported physical violence. We identified four pathways through the latent states over the two-year follow-up period, which we called No reported harm, High reported harm, Low reported harm, and De-escalation.
Conclusions: The findings add to the body of research indicating that family violence aggressors do not inevitably repeat or escalate their harmful behavior, and that a small subset of cases account for a large proportion of reported harm. This study demonstrates how information that police routinely collect can be used to estimate aggressors’ latent behavioral states and model pathways communicating the probability that they will continue to come to police attention for family violence, contributing to improved risk assessment and practice
National identity and environmentalism: Why national narcissism might undermine pro-environmental efforts
No full textThe extant literature recognizes national identity as a pivotal factor motivating both individual and collective actions to tackle environmental problems. Yet, prior research shows mixed evidence for the relationship between national identity and environmentalism. Here, we propose a theoretical approach that articulates distinctions between different forms of national identity and their differential associations with environmental attitudes and behaviors. Specifically, we argue that it is key to differentiate national identification, which reflects a positive attachment to one's country and ties to other compatriots, from national narcissism, which reflects viewing one's country as exceptional and deserving of special treatment. In contrast to national identification, national narcissism is consistently associated with lower environmental concern and predicts support for anti-environmental policies. We show that this is likely due to national narcissism being linked to belief in climate-related conspiracy theories, support for policies that challenge external pressures yet present the nation in a positive light (e.g., greenwashing), and focusing on short-term benefits for the nation. Extending past individual-level findings, we report a pre-registered analysis across 56 countries examining whether national narcissism is also linked to objective indices of lower environmental protection at the country level of analysis. Results revealed a negative relationship between countries' environmental performance and country-level national narcissism (while adjusting for national identification and GDP per capita). We discuss the theoretical and practical implications of our approach and the country-level findings for advancing research in the field
Techno-economic optimization of a hybrid energy system with limited grid connection in pursuit of net zero carbon emissions for New Zealand
No full textAs New Zealand moves towards net zero carbon emissions by 2050, multiple factors must be considered including increased electrical load due to electrification, variability of renewable energy generators, required storage capacity, system economics and limitations on grid transmission capacity. Complex and region-specific interactions between the various design choices involved are likely to require an understanding of a range of optimal and near-optimal designs for proposed micro-grid systems as opposed to a single optimal point. This work develops a novel multiscale optimization algorithm for optimization from a univariate capacity optimization approach to a multivariate one. This enhanced algorithm is applied to a grid-connected hybrid energy system consisting of local wind and solar generation, battery storage, and a limited grid connection for industrial and residential loads. This analysis is repeated for current 2023 and forecasted net zero 2050 grid conditions. Development of local generation allows for a 36.8% reduction of levelized cost of electricity in the 2023 case and a 38.6% reduction in the 2050 case. This results in a projected reduction of 19920 tonnes of CO2/yr. The algorithm and methodology developed are broadly applicable to optimization of next-generation energy grids
Adapting and implementing the Sunny Start DANCE programme in New Zealand: A pilot study
No full textThis study aimed to evaluate the implementation of the Sunny Starts DANCE parent training programme in the New Zealand context. Sunny Start’s primary focus is to enhance the quality of social interactions between parents and their toddlers with Autism Spectrum Disorder (ASD). Parent training involved teaching parents basic interaction methods to increase their child’s skills through play-based interactions in face-to-face sessions and during the child’s bedtime and morning routines. This training aimed to provide the child with learning opportunities, increase their access to reinforcement, and, in turn, enhance the quality of parent-child interactions. Participants included one parent-child dyad, wherein the child, while not formally diagnosed with ASD, displayed some skill deficits consistent with this disorder. Multiple probe designs across parent and child behaviours and settings were used to evaluate parent and child responses, harmonious engagement, and indices of happiness. Results indicate that some measures increased during face-to-face sessions, whilst little to no improvement occurred during routine sessions. Strengths, limitations, social validity, the validity of findings, generalisation, research implications, clinical implications and future directions are discussed