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Understanding Allosteric Arginine Mutations Using Macromolecular Rate Theory
Get PDFEnzyme catalysed reaction rates have been traditionally modelled with the Arrhenius and Eyring-Polanyi equations. These models assume that the reaction rate is exponential with temperature, and thus the natural log of the reaction rate versus 1/T is linear. Significant deviations from these models at high temperatures has traditionally been attributed to thermal denaturation. An increasing body of evidence has shown that denaturation alone is insufficient to account for these deviations from Arrhenius behaviour. Macromolecular rate theory (MMRT) accounts for these deviations with the introduction of the activation heat capacity (Δ‡) to the rate equation. The activation heat capacity is a consequence of the restriction in conformational freedom along the reaction coordinate, as an enzyme moves from the enzyme-substrate complex to the transition state complex – thus for an enzymatic reaction the activation heat capacity is negative. A non-zero activation heat capacity imparts temperature dependence to the activation entropy and activation enthalpy, introducing curvature to the rate equation independent of thermal denaturation. The activation heat capacity may itself be temperature dependent. MMRT equations of increasing complexity have been developed to reflect this and are suitable for different applications.
This thesis explores the effects of allosteric arginine mutations on the temperature dependence of enzyme rates through the lens of MMRT and evolution using the model enzyme MalL. An in-depth analysis of a previously characterised arginine mutant is described along with four additional arginine mutants. The arginine mutants were designed to mimic urea ligand binding across the enzyme surface. These mutants were characterised kinetically and with biophysical methods. Two were further characterised structurally, with high resolution structures being produced. These mutant enzymes showed significant rate improvements at low temperatures, suggesting two possible mechanisms for evolution towards psychrophily. These arginine mutants showed significant improvement in crystallographic resolution, indicating surface arginine mutations may be a general route for crystallographic improvement
Adaptation of the safewards model to the New Zealand context: A mixed-methods evaluative study
No full textBackground: Mental health inpatient units can provide a sanctuary for people to recover from mental illness. However, research has shown these units to be sites of conflict, in an environment that service users do not experience as therapeutic. To support a therapeutic environment, the safety and wellbeing of service users and staff need protection through reduced conflict and containment rates. Conflict can be physical or verbal aggression, self-harm, suicide attempt, absconding, substance misuse and medication refusal. Containment involves methods used to control conflict, including administration of sedative medication, coerced intramuscular medication, increased level of observation, restraint and seclusion. The Safewards model, originating in the United Kingdom in 2015, proposes 10 interventions to address conflict and containment. These interventions are centred on: therapeutic relationships; person-centeredness; teamwork; and least restrictive care. This research pursued active transformation through codesign of an adapted Safewards model to fit the socio-cultural context of New Zealand.
Objective: This thesis with publication describes the adaptation of the Safewards model to the New Zealand context. Cultural adaptation was critical due to significant health outcome disparities between Māori and non-Māori populations and the disproportionate representation of Māori within mental health services. The research sought to discover what a New Zealand model required, what the perspectives of inpatient tangata whai ora and staff were of the developed model and what changes it made to rates of conflict, containment and the ward atmosphere. Participants: Tangata whai ora and staff from the study setting were recruited to participate in focus groups before and after the implementation of the New Zealand Safewards model. Phase one focus groups included 15 staff and three tangata whai ora. Phase three focus groups included 13 staff and four tangata whai ora.
Methods: This is a mixed-methods evaluative study structured into three distinct phases, using methods of participatory action research. The adapted Safewards model was implemented for 12 months, with a staggered introduction of 11 interventions. Qualitative data were derived from the thematic analysis of focus groups. Quantitative data were from the Patient-Staff Conflict Checklist, Essen Climate Evaluation Schema, Fidelity Checklist and Te Whatu Ora Waikato service data.
Findings: A New Zealand Safewards model must: reflect a Te Ao Māori worldview; align with current practices; adapt Safewards interventions; and gain acceptance. Change management is one process that can reduce barriers to change. The adapted Safewards model reduced conflict, increased patient cohesion and improved the sense of safety perceived from staff and tangata whai ora in the study setting. The outcomes of this study hold the potential to contribute to the formulation and implementation of a New Zealand Safewards model, while also bearing relevance for the international adaptation of Safewards to culturally diverse countries and healthcare systems
Concepts of proportionality in investment protection of patents and access to health resources
No full textThis thesis seeks to demonstrate why investment protection of patented health resources is disproportionate and how the disproportionate power can be mitigated. The argument asserts that the protection of patented health resources under international investment agreements (“IIAs”) goes beyond the intended purpose of intellectual property (“IP”) law and can hinder access to health resources. While IP rights are significant components of IIAs, their inclusion within the scope of investment allows investors to challenge measures against their IP rights through the investor-state dispute mechanism (“ISDS”). A measure can be subject to a review of arbitral tribunals even though such measure serves the public interest.
The ISDS system imposes an additional legal layer for states. Such layer can hinder the rights to have a healthy life, rights to life and living a life with dignity, conflicting states’ human rights obligations. Therefore, this thesis argues that investment protection disproportionately benefits the patent holders. Consequently, this thesis scrutinises how this disproportionate benefit can be mitigated. To this end, this thesis investigates case law in investment arbitration where arbitral tribunals have applied (ii)judicial proportionality to determine if judicial proportionality can mitigate the disproportionate protection of patented health resources as an investment. This thesis further reveals midlevel proportionality in newly concluded IIAs where the purpose is to restore disproportionate investment protection of patented health resources. This thesis presents the first comprehensive analysis on proportionality principle in the context of patent and international investment law
Digital afterlives: A verbatim play about death in a digital age
No full textDeath could be considered the ultimate uniting factor (it comes for us all). However, it is not a homogenous occurrence but an experience as individual and nuanced as the lives we live. Consequently, Digital Afterlives: A Verbatim Play About Death in a Digital Age was created not as a prescriptive but descriptive research output that honours the nuance and subjectivity of experiences of loss and individual grief journeys. Constructed entirely from empirical materials collected in recorded interviews, the play illuminates some of the experiences encountered by bereaved New Zealanders as they navigate the contemporary digital griefscape
A community psychology-based evaluation of the you good? You Good! program delivered by Jade speaks up educational trust in Aotearoa. Empowering tamariki emotional literacy, supporting mental health and encouraging well-being.
No full textThis evaluation was completed for Jade Speaks Up (JSU) Educational Trust to provide feedback from school teachers and whānau who were involved in the You Good? You Good! (YG?YG!) program, delivered by JSU Educational Trust to schools across Aotearoa. The evaluation goal was to collate the narratives of participating school staff, whānau, and JSU Educational Trust trainers, contrasting experiences and perspectives to determine program effectiveness.
This program is for schools, management, and teachers who work with tamariki, to help teachers and students understand anxiety and develop skills and strategies to have self-agency. JSU Educational Trust developed YG?YG! in 2021, and in 2022 the YG?YG! pilot program was implemented.
This evaluation had three research objectives: 1) Identify and collate the experiences of school staff and other key stakeholders when implementing the YG?YG!, 2) Identify the strengths and barriers to inclusion for tamariki in schools where the program was delivered, and 3) Draw on the stakeholder narratives to assess the program's ability to achieve its goal: enable tamariki to be more agentic in responding to early signs of anxiety in themselves and others.
Information for this evaluation was collected from four sources: 1) Focus groups with JSU trainers, 2) Interviews with school staff, 3) Online surveys with school staff, 4) Archival supervision, and 5) Literature review. Data collected was interpreted through the use of thematic analysis, informed by Community Psychology principles, and the “Six C” framework, guided by He Awa Whiria.
Thematic analysis was completed by coding themes and categories from data sources. The findings from this empirical research engagement informed the analysis and discussion on program effectiveness.
The findings and analysis found that forming a program design and approach informed with respect for the community’s needs and world-views can enable recognition, awareness and inclusion. A way for the program to begin to do so is to collaborate with communities.
Including researchers from a local community can enable empowerment, build social power, and create responses that promote the needs of the involved communities. The program can champion the field and those they work with by being accountable and enabling transparency.
The program can take an inclusive approach to sustaining its relationships, content relevance, and development for tamariki emotional well-being. The program can work on cultivating and empowering participants to be active partners, enabling the program to be shaped with equity in mind.
Key to program efficacy is acknowledging change and encompassing adaptation. The way to do this is to consider local health issues driven by who experience them, elevating the voice of the community.
Change and need cannot be determined without considering the voice of involved communities. By taking participants feedback, the program can create change for tamariki mental health, whilst acknowledging system and structural barriers, striving for community competence.
Importance lies within the work the program does to enable and support those affected by external factors. The program can acknowledge these challenges, and provide hope that community competence can be achieved.
To conclude, recommendations are presented for JSU Educational Trust to consider
A light in the dark; an investigation of fetal visual perception
No full textHow does a fetus engage with their visual world? Prenatal developmental trajectories are primarily unexplored, with fetal visual perception the most poorly understood of all sensory systems. In the third trimester, fetuses not only possess the ability to process perceptual information, but recent research suggests that enough light penetrates the womb to enable a visual experience. Understanding fetal visual capabilities has the potential to reshape our knowledge of both visual and psychological developmental trajectories. This thesis sits at the intersection of developmental psychology, medical imaging, and vision science. The overall aim of this work is to assess fetal visual function through novel experimental paradigms. We employed 2D ultrasound to visualize the fetal lens and index eye movements in response to light stimuli presented in utero. Tracking fetal eye movements in response to visual stimuli beyond light / no light has never been previously attempted. Three separate experiments explore central elements of fetal visual perception and cognition, including differential fetal responding to temporal and nasal visual fields, anticipatory gaze, and fetal sensitivity to agentive motion cues. The results of these studies demonstrate that the fetus actively engages with their visual environment exhibiting a preference for stimuli presented in their temporal visual field and the ability to perform anticipatory visual gaze, specifically that fetuses can use an auditory cue to anticipate the appearance of a light stimulus. These experiments and new methods offer new key insights into early sensory and psychological development
Anhedonia: He kohinga whiti mai i te tirohanga o ngā wahanga e rima o te pōuri / A collection of poetry themed around loss presented through the lens of the five stages of grief
No full textAnhedonia is a collection of personal experiences centred around loss examined through the lens of the five stages of grief (denial, anger, bargaining, depression, and acceptance) and framed within a personal confessional postmodernism style. It was also influenced by the collected works of Federico Garcia Lorca, Sylvia Plath, Cassandra Barnett (Ngāti Huri, Raukawa), Kirsty Dunn (Te Aupōuri, Te Rarawa), and Ngahuia Te Awekotuku (Te Arawa, Tūhoe).
While loss and grief are intrinsically linked to death, within this collection, I further explore other forms of loss and grief. I touch on my loss of cultural identity, mind, and self. As a student, I have been diving deeper into my cultural identity of being Māori and what that means to me. I have lost many things throughout my life at the hands of abuse, depression, grief, and mental health. The poetry within this collection will continue to serve as a blunt reminder of the experiences (both positive and negative) that I have endured or witnessed over the last couple of decades.
I have seen a multitude of losses (in its many variations) as I continue the dance to discover what the mortality of not only myself but those around me means to me. While everyone will experience feelings of grief and loss, I have framed my own experiences in my interpretation of our collective mortality
Practicing equity, access and inclusion in work-integrated learning
No full textAs work-integrated learning (WIL) expands in higher education, there is increasing attention on ensuring equitable access and inclusion for all students. These challenges are not unique to WIL, albeit WIL has some unique facets, but are pertinent to all parts of higher education and society more broadly. The WIL community recognizes that equity, diversity, and inclusion is their most significant professional development need, and with scholarship slowly on the rise, it is timely for a Special Issue dedicated to the topic within the context of WIL. This Special Issue includes 12 papers exploring equity, access, and inclusion within the context of WIL. Emergent themes include language, common barriers, disclosure, considerations for inclusive workplaces, curriculum, and assessments, as well as critical reflection, partnering with students, and resilience. It is intended that this Special Issue will continue the advancement of the journey for a more equitable society
Building beyond formality: Navigating Jamaica’s informal construction sector through class, culture and economic resilience
No full textThis doctoral thesis is an exploration of Jamaica’s informal construction sector, unpacking its labour distinctiveness, actors, and activities while examining its deep-seated connections to the island’s historical, cultural, and socio-economic context. Through nine months of ethnographic engagement with an informal building construction crew, the thesis provides insights into the motivations of workers, interactions in the workplace, the culture of informal construction, and contributions to the national economy.
At its core, the study questions the persistence of Jamaica’s informal construction industry within the hegemonic context of a Western market economy. In this context, I examine the dynamics of class culture, including the rituals and forms of exchange among workers in this industry. The blurred lines between formal and informal aspects of building construction as well as the reproduction of technical knowledge also hint at reasons for the tenacity of the informal economy.
I critically engage with the concept of precarity to examine the long history of precarious lives in Jamaica. I explore the dichotomy of alienation versus ownership, emphasising the informal sector’s capacity to foster a sense of ownership in contrast to the alienation often experienced in formal systems. I also shine a light on gender disparities, discuss performances of masculinity and unveil the roles and experiences of women in this male-dominated environment. Finally, the study addresses the significant impacts of the 2019 Sars Cov2 pandemic on the social and economic realities within informal construction
Exploring the mānuka phyllosphere microbiome
No full textThe surface of plant leaves, termed phyllosphere, is a ubiquitous microbial habitat that harbours diverse communities of microorganisms. Although a growing body of experimental evidence demonstrates that these microorganisms can have an influential role in host physiology, the ecological processes that drive the assembly of natural phyllosphere communities remain poorly understood.
Leptospermum scoparium (mānuka) is an indigenous New Zealand tea tree widely known for the non-peroxide antibacterial properties of its honey. However, the host physiological traits associated with these properties exhibit variation that remain unexplained despite decades of research. Considering a preliminary study that identified spatially persistent host association in the mānuka phyllosphere microbiome with patterns congruent with those of a microbial community under strong host selection, the primary objective of this research was to generate a holistic understanding of the ecological processes underpinning community assembly in the natural mānuka phyllosphere.
Since the host specificity of the mānuka phyllosphere microbiome was unquantified, this PhD thesis research began with a multi-species, spatially hierarchical survey of a native forest to understand the relative influence of host species identity versus distance on the phyllosphere microbiome of mānuka and ecologically similar, adjacent native plant species. The results revealed that the relative influence of host species identity on the phyllosphere microbiome was quantitatively stronger in mānuka compared to other plant species, and mānuka species-specificity was not associated with leaf morphological traits.
Using a pair of morphologically indistinguishable and naturally co-occurring plant species (mānuka and Kunzea ericoides [kānuka]), I then explored the relative influence of host species identity and leaf morphology on inter-host dispersal. Specifically, I addressed a longstanding yet under-examined hypothesis that the relative strength of the phyllosphere microbiome as a source of dispersing microorganisms (i.e., source-strength) is contingent on leaf morphology. The results revealed considerable spatial heterogeneity among morphologically indistinguishable leaves at small spatial scales and suggested that mānuka may act as a stronger source of phyllosphere microorganisms than kānuka. These findings suggest that source-strength is determined by the quantitative difference in the relative strength of host selection among plant species.
To contextualise this apparent spatial stability and host species-specificity of the mānuka phyllosphere microbiome, temporal variation was investigated by replicate sampling in three different seasons. My results revealed that the relative influence of individual host trees was larger than the season, and specific phyllosphere taxa persisted across time. Additionally, my results revealed an increased core microbiome during summer flowering, suggesting an association between host selection strength and host phenology.
Lastly, I explored the relationship between the mānuka phyllosphere microbiome and mānuka honey quality. I sampled trees and honey from three adjacent mānuka populations known to exhibit visually discrete phenological traits (i.e., flowering time). My results revealed correlations between phyllosphere community composition and chemical properties of mānuka honey, including the primary constituent of mānuka’s non-peroxide antibacterial properties (i.e., methylglyoxal).
Through the incorporation of spatial and temporal sampling designs, as well as a multi-disciplinary case study, this thesis provides a holistic understanding of the relative influence of host selection (abiotic and biotic), dispersal (short- and long-distance), and climate, on the assembly of the mānuka phyllosphere microbiome. These results also provide new perspectives on prevailing controversies (e.g., host selection vs. dispersal), address unverified hypotheses (e.g., source-strength), and illustrate a path forward that will allow the emergence of a coherent and generalisable understanding of phyllosphere microbial ecology