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Characterization of Peptide Polymer Interactions in Poly(alkylcyanoacrylate) Nanoparticles: A Mass Spectrometric Approach
Full text linkDrug/polymer interactions occur during in situ polymerization of poly(alkylcyanoacrylate) (PACA) formulations. We have used MALDI ionization coupled tandem time-of-flight (TOF) mass spectrometry as an accurate method to characterize covalent peptide/polymer interactions of PACA nanoparticles with the bioactives D-Lys6-GnRH, insulin, [Asn1-Val5]-angiotensin II, and fragments of insulin-like growth factor 1 (IGF-1 (1-3)) and human adrenocorticotropic hormone (h-ACTH, (18-39)) at the molecular level. Covalent interactions forming peptide/PACA co-polymers were identified for D-Lys6-GnRH, [Asn1- Val5]-angiotensin II and IGF-1 (1-3). D-Lys6-GnRH and [Asn1-Val5]-angiotensin II were modified at their histidine side chain within the peptide, whilst IGF-1 (1-3) was modified at the C-terminal glutamic acid residue. The more complex protein insulin did not co-polymerize despite the presence of 2 histidine residues. This might be explained by the engagement of histidine residues in the folding and sterical arrangement of insulin under polymerization conditions. As expected, h-ACTH (18-39) that does not contain histidine residues did not co- polymerize. Lowering the pH did not prevent the co-polymerization of PACA with D-Lys6- GnRH or IGF-1 (1-3). Conclusively, protein and peptide bioactives are potentially reactive towards PACA nanoparticles via various mechanisms with limited interference of pH. Histidines and C-terminal glutamic acid residues have been identified as potential sites of interaction. The likelihood of their engagement in co-polymerization, however, seems dependant on their sterical availability. The potential for co-polymerization should be considered when designing a PACA delivery system for protein and peptide biopharmaceuticals.Peer Reviewe
A culturally safe public health research framework
Full text linkThe concept of cultural safety arose in Aotearoa me Te Waipounamu/New Zealand in the late 1980's in response to the differential health experience and negative health outcomes of the first nation people of Aotearoa me Te Waipounamu/New Zealand, the New Zealand Maori. It was introduced and developed by Maori nurses initially, as they recognised the effect culture had on health and understood safety as a common nursing concept. The concept of cultural safety has developed into a discipline which is taught as part of all nursing and midwifery curricula in Aotearoa me Te Waipounamu/New Zealand. As cultural safety has developed the concept of culture has been extended to include people who differ from the nurse by reason of: age, migrant status, sexual preference, socioeconomic status, religious persuasion, gender, ethnicity, and in Aotearoa me Te Waipounamu/New Zealand, the Treaty of Waitangi status of the nurse and recipient/s of her/his care.
Nationally and internationally, health experience and health outcomes are poorer for people of minority group status than for people who are part of the dominant group. Public-health research is therefore generally conducted on, or with, people with minority group status. Public-health researchers, by education, are members of the dominant culture and may be unaware that their own and their clients' responses may relate to one/other or both cultures being diminished, demeaned or disempowered. Experience has demonstrated that public health researchers do not always ensure the safety of their own culture or the culture being researched.
This study' s objective was to develop a flexible, culturally safe public health research framework for researchers to use when researching people who are culturally different from themselves. The study will argue that the use of such a framework will contribute significantly to improved health outcomes for people with minority status and will assist the movement towards emancipatory social change.
The methods undertaken included: gaining permission from Irihapeti Ramsden, the architect of cultural safety to undertake the research, conducting a literature review, consideration of primary sources and their key concepts, consulting widely with people in the field of public health and cultural safety, self reflecting on the writers own personal and professional experience and finally designing the culturally safe public health research framework
The Funny Side of Being a Maori Comedian
Full text linkStand-up comedy is a genre of performance that can provide a discursive space for negotiating social and political issues. Typically reliant on autobiographical content, embodied performance, and audience engagement, ethnic, racial, or cultural identity can play a significant role in stand-up comedy performance. Literature on the role of ethnic identity in the practice of New Zealand comedians has been limited to date. This research therefore focused on exploring the experiences, values, and practices of contemporary Māori stand-up comedians through a qualitative, ethnographically-informed, and mixed-methods approach. This included semi-structured interviews with five male Māori comedians, alongside an analysis of their set material (i.e. scripts and transcripts), presentation of self in their on-stage performances (through live and recorded shows), and off-stage professional branding (including social media pages, posters, and professional profiles). The analysis explored findings from each of these areas to show that Māori comedians adapt their practice around awareness of the ethnic makeup of specific audiences, and craft on-stage characters accordingly. Māori comedians embody the roles of “pride comedians” using comedy as a medium to resist harmful, racist, or stereotyping narratives. For this set of participants, this specifically involved performances focusing intersectional elements of their identity in relation to structural issues. The comedians examined used the epidictic quality of stand-up to change perceptions of the Māori community by the wider Pākeha (New Zealand European) population, as well as to engage in dialogue within their own communities about what it means to be Māori today
Ngā ture o ngā iwi taketake/Wishes are not laws: McGirt v Oklahoma – one of the most important US Supreme Court cases of all time?
Full text linkStephen Young discusses the United States Supreme Court case of McGirt v Oklahoma, where the State of Oklahoma was found not to have jurisdiction to convict Jimcy McGirt for crimes committed on a Creek Reservation
Regulation of cardiac function by nitric oxide and calcium/calmodulin-dependent protein kinase II
Full text linkNitric oxide (NO) is a gaseous signaling molecule that plays a role in cardiac contraction and relaxation. One of the pathways of NO signaling is through S-nitrosylation, which is the covalent attachment of a NO moiety to the thiol side chain of a cysteine residue. One downstream target of NO via S-nitrosylation is the calcium handling protein calcium-calmodulin dependent protein kinase II (CaMKII). There is evidence that the S-nitrosylation of CaMKII promotes calcium mishandling in cardiomyocytes, which is the precursor of cardiac arrhythmias. The role of CaMKII in the whole heart during NO exposure is yet to be understood. Therefore, the aim of this thesis was to determine how CaMKII modification by NO and β-adrenergic stimulation can affect cardiac contractility and arrhythmias.
With the use of echocardiography, cardiac function was compared between wild type (WT) mice and transgenic mice lacking cardiac CaMKIIδ (KO), and loss of CaMKIIδ did not severely alter cardiac structure and function. To determine if NO and CaMKIIδ did affect cardiac function, the hearts were isolated from the mice and treated with different concentrations of a NO donor (GSNO). GSNO reduced contractility measured as left ventricular (LV) developed pressure and increased heart rate in WT mice whereas KO mice showed no response to GSNO treatment. WT mice were susceptible to arrhythmias and the number of arrhythmic events increased with increasing GSNO concentration. There was no change in the number of arrhythmic events in the KO mouse hearts with GSNO treatment compared to baseline. Therefore, CaMKIIδ removal was cardioprotective, as it prevented arrhythmias during acute GSNO treatment.
Having established a role for CaMKII in determining the effects of acute NO treatment on cardiac function, I then focused on a model of chronically elevated NO. Chronic GSNO treatment of WT and KO mice involved a 5-week supplementation with GSNO in drinking water, followed by measurement of cardiac function in isolated hearts from these mice with and without GSNO. Echocardiographic data from WT and KO mice showed no effect of GSNO treatment after 5-week GSNO supplementation. The isolated hearts showed no difference in cardiac function at baseline. Following subsequent GSNO treatment, the LV developed pressure and rates of contraction and relaxation decreased compared to baseline in WT and KO hearts. Both animal models showed a trend towards increased number of arrhythmic events, suggesting that knocking out CaMKIIδ from the heart did not prevent the KO hearts from developing arrhythmias in the chronic treatment compared to the acute treatment.
β-adrenergic stimulation using the β-adrenergic receptor agonist (ISO) enhanced cardiac contractility and arrhythmias in both WT and KO hearts. However, ISO induced an increase in arrhythmic events in WT hearts, but not in KO hearts, suggesting that the presence of CaMKII enhanced the susceptibility of WT hearts to ISO-induced cardiac stress. To determine the effect of NO treatment and β-adrenergic stimulation on cardiac function, WT hearts were treated with ISO and GSNO. There were two groups, ISO-GSNO (ISO before GSNO treatment) and GSNO-ISO (GSNO before ISO treatment). In both groups, ISO increased contraction and relaxation. GSNO did not alter cardiac contractility compared to baseline except in the ISO-GSNO group. ISO-GSNO induced cardiac arrhythmias, and GSNO treatment prolonged the arrhythmias. Interestingly, in the GSNO-ISO group, there was no increase in arrhythmic events compared to baseline. This finding provided evidence of a differential role of NO in the heart.
Overall, the findings in this thesis show, for the first time, CaMKII plays a role in the development of arrhythmias in the whole heart during NO signaling. Additionally, this thesis highlights the dual role of NO in preventing or prolonging cardiac arrhythmias during β-adrenergic stimulation
The 'Niu Movement' - Effectiveness and acceptability of circuit based exercise in Pacific Islands communities
No full textBackground
For Pacific communities, while health is a collective responsibility, the ability of an individual to contribute to communal obligations can enhance health outcomes. Physical activity is a key component of optimal health. A culturally responsive and sensitive community exercise program is important for increasing levels of physical activity, and thus the positive benefits, within Pacific peoples. Forming meaningful partnerships between communities and research groups may enhance the longevity and acceptability of physical activity programs. The purpose of this study was to document the process, efficacy and acceptability of an exercise program, the ‘Niu Movement,’ for use in Pacific communities. It is the first formal investigation of the use of Cook Islands dance (aerobic component) and coconut cream preparation (resistance component) as a physical activity initiative. Additionally, the research utilised the ‘Tivaivai Research Methodology’ to ensure that Pacific, and more specifically Cook Islands, perspectives were central to research decisions made. Methods
The ‘Niu Movement’ was developed by researchers in partnership with Pacific communities. Extensive consultation was conducted with Pacific Trust Otago, Te Marae Ora (Cook Islands Ministry of Health), Church ministers and community leaders within Dunedin, New Zealand and Rarotonga, Cook Islands. These consultations provided for approval of the exercise modality, methods of measurement, the research team and recruitment methods before any formal investigation commenced. Both sites utilised recruitment via posters at community centres and presentations and community functions. At baseline and post-intervention participants underwent basic anthropometric assessment (height, weight, waist and hip circumference); blood pressure; physical capacity (six-minute walk test - 6MWT); and function (the short physical performance battery - SPPB); and a questionnaire of program acceptability. Energy expenditure associated with the Niu Movement program was also collected using the SenseWear Pro Armband (SenseWear Pro Armband - BodyMedia, Pittsburgh, PA), in a single session after program familiarisation. The program was tested for acceptability and suitability as a pilot study conducted in Dunedin, New Zealand and conducted on a larger scale later in Rarotonga, Cook Islands. Both locations utilised the same methodology. Each study was a pre- post quantitative design; within group mixed-model regression comparing baseline and post measures in both cohorts were applied using STATA (Stata Data Management – IDRE Stats – UCLA).
Results
Twenty-eight Pacific participants (age: 32±15.3, female: 68%) completed baseline and post-intervention testing for the eight-week pilot protocol (Dunedin) and 93 Cook Islands participants (age: 41.1±14.1, female: 91.4%) completed the 12-week protocol (Rarotonga). No adverse events of any kind were reported during either protocol. Energy expenditure data suggested the program to be low-moderate intensity. Dunedin and Rarotonga, revealed significant mean reductions in systolic blood pressure (-5.3mmHg and - 8.9mmHg, respectively), waist (-3.1cm and -3.2cm, respectively) and hip circumference (-3.5cm and -2.9cm, respectively) and a significant increase in distance covered in 6MWT (+58.6m and +54.6m, respectively). High levels of satisfaction were recorded for enjoyment and willingness to participate in the future (4.9±0.3 and 4.7±0.8, out of a possible 5, respectively).
Conclusion
The ‘Niu Movement’ findings suggest the program is safe and acceptable within the specific Pacific and Cook Islands communities tested. The results show promise for implementation of the program within Pacific communities throughout the region. Furthermore, the findings suggest there is potential to influence future health promotion initiatives to include more culturally specific and relevant modes of movement
Risk and resilience in beginning reading in New Zealand
No full textThis thesis aimed to extend the knowledge base regarding children’s risk and resilience in reading acquisition during their early schooling. In New Zealand (NZ) and other English speaking countries, children typically start their schooling lives with large differences in their emergent literacy skills. To understand the developmental and educational implications of these skill differences, research is needed to establish methods for describing children’s developing skills. To this end, we undertook three separate studies investigating ways for describing children’s emergent literacy and progress in beginning reading.
Study one investigated the tools that NZ new entrant teachers use to screen and monitor children’s oral language and emergent literacy skills. The results of this Qualtrics NZ-wide online survey indicated teachers use a variety of methods. These ranged from informal teacher-developed tasks to published measures, with instructional book level most commonly used to monitor children’s literacy progress. Furthermore, teachers indicated that they desired new tools that were NZ-specific, current, user-friendly, efficient to use, and focussed on both oral language and phonological awareness skills.
Study two evaluated the usefulness of progress monitoring (i.e., repeated assessments) with a NZ sample of children in their first year of school. Children were assessed twice-weekly for eight weeks with two early literacy skill tasks (phonological awareness and grapheme-phoneme correspondence). Growth modelling indicated three distinct growth trajectories during this window (i.e., latent classes) for both tasks: typical, developing (i.e., started lower but then improved), and limited progress (i.e., started lower with little change). Furthermore, class membership differentiated children’s mid-year and year-end literacy skills, indicating predictive validity. These results support consideration of monitoring progress on early literacy skill development to aid in an earlier identification of children at risk of reading acquisition difficulties, prior to the traditional screening at age six in NZ.
Study three modelled the contributions of school-entry literacy and early literacy trajectories to literacy progress at year-end. School-entry assessment comprised adult-child shared reading with embedded activities assessing a child’s oral language and emergent literacy skills (concurrent validity evaluated in Study 3a). To model early literacy trajectories (Study 3b), children were assessed on three fluency-based tasks (phonological awareness, grapheme-phoneme correspondence, and word identification), every fourth school week over their first six months of schooling (i.e., five sessions). Results indicated both direct and indirect contributions (via early literacy trajectories) of skills at school-entry to reading progress after one year of schooling.
Overall, this thesis demonstrates that: (a) there is a desire for NZ-context, research-based, and current tools for use by new entrant teachers; and (b) skills at school entry and developmental growth during the first year of school are important considerations for early literacy researchers and practitioners. A potential practice implication is that using the right tools within a two-stage screening approach—school-entry screening augmented by monitoring children’s early skill acquisition progress—may help teachers identify those children at risk for reading acquisition difficulties within six months of school-entry in NZ. This combined approach could inform targeted instruction based on each child’s specific learning support needs
The Mirosa Report
No full textThis report forms Appendix B of the Briefing to investigate food waste in New Zealand, Report of the Environment Committee, March 2020. The full report is available at https://www.parliament.nz/resource/en-NZ/SCR_96164/cebeaf7cf20b40245fdf5c60601d83a2ac5b105f .Food waste is a major issue in New Zealand. As a nation, we waste an estimated $872 million
worth of food a year. This represents 122,500 tonnes of food sent to landfills—enough to feed
everyone in Dunedin for two years.1 Members of the Environment Committee are concerned
about the waste and decided to invite briefings from various organisations and individuals to
find out more about the extent of the problem and investigate what can be done to reduce
food waste
Geochemical characterisation of scheelite from New Zealand
Full text linkThe trace element and isotopic compositions of scheelite CaWO4 from a variety of deposits in New Zealand were measured using LA-ICPMS and LASS-ICPMS. As part of this, a new method for determining in-situ Sm-Nd isotopic compositions of scheelite using a beam diameter of 193 μm was developed and used to broadly date the timing of scheelite mineralisation at Barrytown and gain insights into fluid-rock interaction at Batemans Creek and Canaan Downs. This method used Tory Hill Titanite as a primary calibration standard and was able to replicate the Sm-Nd isotope compositions of Tory Hill Apatite and two well characterised scheelite crystals (OU15013 and OU13940) showing that matrix matching was not an important source of variation in the results. The scheelite crystals were used as secondary, in-house standards as reconnaissance work found small portions of some fragments with significant isotopic variations. Metamorphic scheelite from W + Au deposits within the Otago Schist did not contain enough Sm or Nd for in-situ isotope analyses via LA-ICPMS.
At Barrytown the trace element, REE and Sm-Nd isotopic compositions of scheelite were determined using LASS-ICPM. Variations in trace element and REE compositions corresponded to primary growth textures revealed by CL imaging. With an analytical resolution of 193 μm, individual grains showed chondrite normalised REE compositions that mostly ranged from n- to u-shaped and corresponded to variations in Sm-Nd isotope compositions. The Sm-Nd isotope compositions plotted as linear arrays on isochron diagrams and provided robust regression ages that overlap with the emplacement of the Barrytown Granite pluton. Due to geological and analytical limitations, multiple grains across an outcrop were required to construct statistically reasonable isochrons; however, multiple analyses within a single grain of scheelite from the Archean Young Davidson Gold mine gave an isochron age that is consistent with the known age constrains of scheelite mineralisation in the deposit.
At Canaan Downs and Batemans Creek scheelite trace element, REE and Sr, Sm, Nd isotopic compositions were determined by LA-ICPMS. The variable initial isotopic compositions from the deposit to the grain scales in these two deposits meant that dating the timing of scheelite mineralisation via the Sm-Nd isochron method was not possible. Instead, insights into the sources of components in the mineralising fluids were established. At Canaan Downs, the compositions are generally considered to represent variable fluid compositions due to interaction of magmatic-derived hydrothermal fluids with blocks of marble that are mapped within the contacts of the granite. At Batemans Creek, the elemental and isotopic compositions of scheelite varied according to the host rock compositions and the textural context (disseminated versus vein) of the scheelite grains. These variations were considered to arise due to variable contribution of components from compositionally distinct wall rocks or preferential breakdown of minerals by the hydrothermal fluids.
For orogenic scheelite, trace element, REE and Sr isotope compositions were determined by LA-ICPMS and found to be distinctive between Type 1 and Type 2 mineralisation styles in the Otago Schist. Scheelite within Type 1 mineralisation has heterogenous REE compositions and variable Sr isotope compositions, from the deposit to the grain scale. These highly variable compositions are proposed to reflect localised sourcing of components by the mineralising fluids, resulting in a greater sensitivity of scheelite compositions to fine-scale variations in host rock compositions. On the other hand, Type 2 deposits all have a set of n- to u-shaped REE patterns and more homogenous Sr isotope compositions at the deposit scale, which are proposed to reflect the regional source of the fluids, the larger size of mineralised structures, more extensive wall-rock interaction and greater availability of transporting ligands that promotes mixing and homogenisation of fluid inputs.
Finally, fluid inclusions in vein-quartz from Boanerges Peak and magmatic scheelite from Canaan Downs, Barrytown and Batemans Creek were investigated. Inclusions from Boanerges Peak had very similar properties to vein-quartz inclusions from Lake Hawea and reflect similar styles of mineralisation at these two localities. The similarities were used to loosely infer the conditions of mineralisation at 350 – 400 oC and 4.1 – 6.0 kbar. Inclusions in scheelite from the magmatic deposits had salinities between 3.5 to 5.6 wt% NaCl equivalent and Batemans Creek had around 10 mol% CO2 in inclusions from Dunphy Granite-hosted and Greenland Group-hosted veins. These inclusion compositions are broadly consistent with fluid compositions of magmatic W-Sn deposits from around the world. Homogenisation and decrepitation temperatures were generally between 200 and 300 oC and possibly represent minimum temperatures of hydrothermal fluids that moved through these deposits.
Low-frequency Raman spectroscopy in pharmaceutical applications
Full text linkLow-frequency Raman (LFR) spectroscopy was used to probe a variety of pharmaceutical systems within a framework of different analysis scenarios, including macro and bulk analysis, in-situ monitoring of solid-state transformations upon exposure to different environmental conditions (for example, temperature and/or relative humidity) and during the dissolution process, and spatial analysis of solid dosage forms. Better LFR data interpretation was facilitated by the use of chemometrics and complimentary analysis using other commonly used techniques such as powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS) as well as computational simulations employing molecular quantum mechanics.
The first chapter gives an in-depth background on the solid-state forms, including their structural, thermodynamic and kinetic descriptors. An overview on the LFR theory, instrumentation and (chemometric) data analysis employed in this thesis is also provided together with additional details related to the other aforementioned utilized complimentary analytical techniques. In the second chapter a series of pharmaceutically relevant entities with increasing molecular complexity were investigated using variable temperature LFR spectroscopy and computational simulations. The combination of these experimental and theoretical approaches allowed to elucidate the nature of various low-energy vibrational modes, and, ultimately, establish a protocol for the preliminary computational analysis of LFR spectral features of similar pharmaceuticals.
In the third chapter celecoxib (a popular anti-inflammatory agent) was used as a model compound to investigate compression-induced destabilization in melt-quenched amorphous drugs. Destabilization was assessed via the physical stability and dissolution performance of these phases using LFR spectroscopy among other complimentary techniques. Stability studies in the glassy and supercooled states as well as surface dissolution measurements allowed for the identification of the combined impact of preparation method and compression parameters on these properties. Most notably, although a slower cooling rate during the melt-quenching process gave an amorphous phase with a higher intrinsic physical stability, it also promoted increased sensitivity to compression-induced destabilization.
The fourth chapter further explored the compression-induced destabilization phenomenon in melt-quenched amorphous solid dispersions. Three different polymers (hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and polyvinylpyrrolidone/vinyl acetate (PVP/VA)) in the concentration range of 1-10% w/w were used to formulate amorphous celecoxib systems with varied intermolecular interactions between the drug and polymer moieties. Dynamic LFR and DSC measurements in the supercooled state revealed the differences in the crystallization behavior. Polymer loading was found to significantly reduce the sensitivity to compression-induced destabilization within these samples with minimal differences observed between different polymer types.
In the fifth chapter development of a new Raman subtechnique - spatially/micro-spatially offset low frequency Raman spectroscopy (SOLFRS/micro-SOLFRS) is described with its main applications aimed toward the nondestructive spatial analysis of solid dosage forms. The capabilities of this technique was tested using several model formulations comprised of celecoxib and several excipients of crystalline and amorphous nature forming a variety of different (multi-layer/multi-component) tablets. In all of the explored scenarios, the LFR spectral domain was superior to more commonly used mid-frequency Raman (MFR) or fingerprint region, where it enhanced or enabled the determination of different layer (i.e., coating) thicknesses as well as the spatial analysis of solid-state form transformations.
Lastly, the final chapter gives a brief overview of the main findings as well as provides insight into potential future directions for the application of them in relation to both research and industry based pharmaceutical settings