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Calcium calmodulin dependent protein kinase II in the development of atherosclerosis
No full textAtherosclerosis is the leading cause of death in the developed world. The accumulation of low-density lipoprotein cholesterol (LDL-C) in the arterial wall leads to the formation of foam cell lesions. The growth of lesions is influenced by a number of genetic and lifestyle factors. Over-time, lesions encroach the vessel lumen, impeding blood flow and increasing risk of cardiovascular events including myocardial infarction and stroke. Statins have been effective at reducing risk for cardiovascular events, however, even when target LDL-C levels are met there remains a significant residual risk. Clearly, a detailed investigation into the mechanism of foam cell lesion growth is required to explore new drug targets to ease the burden on the health care system.
Calcium/calmodulin-dependent protein kinase II (CaMKII) is a nodal signalling protein in endothelial cell (EC) and vascular smooth muscle cell (VSMC) physiology. In vascular disease, CaMKII has been shown to promote endothelial dysfunction and vascular smooth muscle cell proliferation. Both of these pathologies are involved in the early stages of atherosclerosis so it is intriguing to speculate that CaMKII also contributes to atherosclerosis. We have previously shown systemic inhibition of CaMKII in an atherosclerotic model (ApoE-/- mice) reduces foam cell lesion development. However, there are multiple isoforms of CaMKII and associated splice variants. These sub-types are differentially expressed in the tissues of the body and have shown contrasting roles. A global inhibition of CaMKII is not a feasible target due to the important physiological functions of these multiple isoforms. Therefore, it is crucial we identify the isoform(s) contributing to foam cell lesion growth so a more specific therapeutic target can be explored.
Firstly, the predominant isoforms of CaMKII were identified in the major cell types of the vasculature. The aortic tree was dissected from ApoE-/- mice at 13- (early atherosclerosis) and 20-weeks (mid-atherosclerosis). In addition, human umbilical vein endothelial cells (HUVECs), human coronary artery endothelial cells (HCAECs) and human coronary artery smooth muscle cells (HCASMCs) were cultured. PCR and Western blotting was run for CaMKII delta and gamma isoforms. Results showed CaMKII delta as the predominant isoform in human and mouse vascular cells. In addition, at the mRNA level, delta splice variants 2, 3 and 6 were detected. CaMKII delta expression was high at 13-weeks in the ApoE-/- mouse and levels persisted at 20-weeks, suggesting the delta isoform is the most likely isoform contributing to atherosclerosis.
To investigate if CaMKII signalling contributed to foam cell lesion development, we next employed a genetic approach. ApoE-/-‑mice were crossed with CaMKIIdelta-/- to generate a novel ApoE-/-CaMKIIdelta-/- (dKO) mouse model. At 20-weeks there was extensive atherosclerosis in the aortic sinus of female, but not male groups. Histological analysis showed there was a strikingly significant reduction in foam cell lesion content in female ApoE-/-CaMKIIdelta-/-, compared to ApoE-/-CaMKIIdelta+/+ litter mate controls. This indicates the CaMKII isoform is a critical player in the early development of atherosclerosis.
To further test the mechanistic role of CaMKII delta in foam cell lesion development, an opposite strategy was performed whereby an AAV-mediated overexpression approach was utilised. ApoE-/-CaMKIIdelta-/- mice were put on a high-fat diet at 12-weeks to accelerate atherogenesis. At 16-weeks of age, the left carotid arteries of ApoE-/-CaMKII-/- mice were ligated to increase shear stress and further promote foam cell lesion growth in a localised area. AAV-particles harbouring the CaMKIIdelta2 or control (scrambled) gene sequence were then introduced to the ligated left carotid artery. Ligation of the carotid artery led to a range of variation in foam cell lesion progression. Histological analysis of the carotid artery revealed the foam cell lesion area and stenosis from CaMKIIdelta2-mCherry mice showed a trend towards an increase, despite low n numbers due to adverse complications in 20% of the ligated mice.
In summary, a number of genetic and molecular biological techniques have been used to provide evidence to show CaMKII contributes to the early stages of atherosclerosis. Importantly, there is still work that needs to be done to further validate this mechanism and the potential contribution of other delta variants and/or other isoforms. This novel study has provided foundation evidence of CaMKII as a specific target for treatment. The results provide impetus to continue the investigation of CaMKII that ultimately, could lead to a pharmacological intervention to treat the early progression of atherosclerosis
Fibre Intakes and the Main Food Sources of Fibre in Adolescent Males
No full textBackground: Based on the 2008/09 New Zealand Adult Nutrition Survey, the mean dietary fibre intake in adolescent males aged between 15 and 18 years was at 21.9 grams (g) per day, which was well below the adequate intake (AI) for their age group of 28 g/day. Given the role of dietary fibre in promoting optimal health as well as the potential of changing dietary patterns and food sources over time, an update on the dietary fibre intakes of New Zealand adolescent males is warranted.
Objective: To determine the current mean intake of dietary fibre and the main food sources of fibre in New Zealand adolescent males aged between 15 and 18 years.
Methods: The Survey of Nutrition Dietary Assessment and Lifestyle (SuNDiAL) study is an ongoing clustered, cross-sectional survey in New Zealand that began in 2019. The data presented in this thesis were collected between February and April 2020. Male participants were enrolled from 6 high schools nationwide in Otago, Wellington, Christchurch, Rotorua, Tauranga and Auckland. High schools were selected based on a student roll of at least four hundred. Socio- demographics and bowel habits were self-reported with an online questionnaire. Height and weight were measured, and a Body Mass Index z-score was generated for each participant. Dietary data were assessed via two interviewer-led 24-hour multi-pass dietary recalls on non-consecutive days. The dietary data entered into FoodWorks 9 (Xyris Software, Australia) were used to estimate mean energy and fibre intakes for each participant. These were adjusted for within-person variation using a Multiple Source Method (MSM) program to represent usual intakes. The proportion of total fibre intake provided from the 33 food groups was estimated using Stata Statistical Analysis Software 16.0 (StrataCorp, Texas).
Results: One hundred and thirty-five male participants enrolled in our study. One hundred and two of those completed one 24-hour recall and seventy-two completed a second recall. Overall, the mean fibre intake was at 24.1 g/day (95% CI: 22.2, 25.9), which was lower than the AI of 28 g/day. Bread was the single largest food source of fibre intake contributing to eighteen percent, with thirty-nine percent of the male participants consuming white bread, followed by grains and pasta, and fruits at almost twelve percent and vegetables at eleven percent. Only one hundred and twenty-nine male participants completed the bowel habits questionnaire. Fifty percent of the male participants had bowel movements of either 5, 6 or 7 times a week, with the greatest frequency at 7 times a week, and sixty-eight percent had a Type 3 stool type on the Bristol Stool Chart, indicating regular bowel habits with a normal stool consistency among the adolescent male population.
Conclusion: The mean dietary fibre intake of this convenience sample of adolescent schoolboys was lower than the recommended. Given the influence of dietary fibre on optimal health promotion and chronic disease prevention, encouraging and supporting the adolescent male population to increase fibre-dense foods and whole grains consumption in accordance with the New Zealand dietary guidelines may help in achieving their AI for dietary fibre
Irish in Aotearoa: Mapping the Irish Community and People of Irish heritage in New Zealand
No full textThe connections between Ireland and New Zealand are burgeoning. To better understand and recognise the shape of these connections, research on the Irish in Aotearoa was commissioned by the Embassy of Ireland, Wellington. This is an exciting project mapping Irish citizens and community across all 16 regions of New Zealand. This is also an ambitious project, encompassing such a large geographical spread. The research findings and associated interactive maps of the Irish in Aotearoa New Zealand are just the beginning of possibilities for future research. The results of this project are well placed to enable further connections to be made among Irish immigrants, community groups and government representatives. Indeed, like the census data, these results may also have an impact on business connections. Figures already highlight that Ireland and New Zealand have a developing trade network.
There are two distinct aspects to the following research. In the first part, the New Zealand census returns have been analysed to account for people of Irish ethnicity currently living in New Zealand. Figures prove that the number of Irish immigrants moving to New Zealand and staying long term has been steadily increasing over the last four census returns from 2001 to the most recent returns in 2018. Analysing these figures in more detail, it is possible to gain a deeper insight to the contemporary Irish population in Aotearoa New Zealand. The regions in which Irish populations mainly reside continues to change with an evolving economic climate. This report provides evidence of the increase in numbers of skilled Irish immigrants moving to the Canterbury region since the 2011 earthquakes to help with the rebuild of Christchurch, for example.
Due to the high number of Irish among the early New Zealand settlers, it is estimated that approximately one in every six people in New Zealand has Irish heritage. These figures have yet to be confirmed by statistics. Therefore, this research project includes the use of online surveys to glean more information about New Zealanders of Irish heritage or with an affinity for Ireland. The first survey sought details from individuals and saw an impressive response with 2,932 people included in this research. Over 65 percent of the total responses are from people of Irish heritage. These results are therefore the most detailed information gathered to date on New Zealanders of Irish heritage. It is significant that the majority of those, 84 percent, have family bonds closely related to their Irish ancestors, ranging from an Irish born parent to an Irish born great grandparent
Intrinsic reward driven exploration for deep reinforcement learning
No full textDeep reinforcement learning has become one of the hottest research topics in machine learning. In reinforcement learning, agents interact with the environment and try to maximise the expected cumulative reward. The goal of reinforcement learning is to find a policy to maximise the agent’s total cumulative rewards. Unfortunately, some environments can only provide extremely sparse rewards, so the agent needs to learn a strategy to explore in its environment more efficiently to find these rewards. However, it is known that exploration in complex environments is a key challenge of deep reinforcement learning, especially for tasks where rewards are very sparse.
In this thesis, intrinsic reward driven exploration strategies are investigated. The agent driven by this intrinsic reward can explore expeditiously, so as to find the sparse extrinsic rewards provided by the environment. Recently, surprise has been used as an intrinsic reward that encourages systematic and efficient exploration. We first define a novel intrinsic reward function called assorted surprise, and propose Variational Assorted Surprise Exploration (VASE) algorithm to approximate this assorted surprise in a tractable way, with the help of Bayesian neural networks. Then we apply VASE algorithm to continuous control problems and large scale Atari video games respectively. Experimental results show that VASE performs well across these tasks. Then we discover that all surprise based exploration methods will lose exploration efficiency in areas where the environmental transition is discontinuous. To solve this problem, we propose Mutual Information Minimising Exploration (MIME) algorithm. We show that MIME can explore as efficiently as surprise based methods in other areas of the environment but much better in areas with discontinuous transitions
Cost-(in)effective public good provision: An experimental exploration
No full textThis paper investigates the determinants of cost-(in)effective giving to public goods. We conduct a pre-registered experiment to elucidate how factors at the institutional and individual levels shape individual contributions and the cost-effectiveness of those contributions in a novel public good game. In particular, we examine the role of consequential uncertainty over the value of public good contributions (institutional level) as well as individual characteristics like risk and ambiguity attitudes, giving type, and demographics (individual level). We nd that consequential uncertainty tends to reduce overall contributions, but not the cost-effectiveness of those contributions. Meanwhile, cost-effectiveness varies by giving type-which is a novel result that is consistent with hypotheses we generate from theory-but other individual characteristics have little influence on contributions or cost-effectiveness. Our work has important positive and normative implications for charitable giving and public good provision in the real world, and it is particularly germane to emerging online crowdfunding and patronage platforms that confront users with a multitude of competing opportunities for giving
Weight loss intentions and methods in New Zealand adolescents
No full textBackground: Weight control behaviours, particularly weight loss, are prevalent amongst adolescents of all body sizes. Methods of weight control encompass a broad range of actions, from exercising and eating more healthy foods to vomiting or starvation. There is limited research on weight-loss intentions and methods amongst adolescents in New Zealand and the relation to weight perception and body mass index (BMI).
Objective: This study aims to investigate weight control intentions and behaviours amongst a sample of male and female adolescents in New Zealand by (a) determining the prevalence of weight loss methods, body image perception, and weight loss intentions of a sample of adolescents in New Zealand; (b) identifying the association between weight perception and weight loss intentions; and (c) establishing the association between BMI with weight perception, weight loss intentions and methods in New Zealand adolescents.
Design: This is an observational cross-sectional study amongst 15-18-year-old New Zealand adolescents for the SuNDiAL (Survey of Nutrition, Dietary Assessment, and Lifestyles) project. Data collection occurred in two phases; February - November 2019 and February - May 2020. This study assessed methods of weight control through an online, self-administered questionnaire. Trained researchers collected anthropometric measures.
Results: In a sample of 246 females and 124 males, nearly half of the females (48%) and 28% of the males were currently attempting to lose weight; 34% of these females were of a healthy weight. Conversely, 2% of females were trying to gain weight, compared with 27% of males. More females than males reported using unhealthy weight loss methods in the past year; skipping meals (40% vs 22% ), vomiting (3% vs 2%), eating very little food (39% vs 15%), or smoking cigarettes (8% vs 1%). Among the participants, females were more likely to perceive themselves as heavier than males.
Conclusion: Intention to lose weight remains prevalent, and unhealthy weight loss methods are
not uncommon among New Zealand adolescents, particularly females. Further efforts and
discussion is required to resolve this double burden of body weight concerns and the potential development of disordered eating patterns
NZDep2018 analysis of census 2018 variables - DHB18: Canterbury
No full textFor further information about data sources, interpretation of the graphs, and cautions, please see the separate Introduction Chapter
All data relating to the 2018 census is provided by Stats NZ, https://www.stats.govt.nz/
NZDep2018 analysis of census 2018 variables - DHB22: Southern
No full textFor further information about data sources, interpretation of the graphs, and cautions, please see the separate Introduction Chapter
All data relating to the 2018 census is provided by Stats NZ, https://www.stats.govt.nz/
NZDep2018 analysis of census 2018 variables - TA001: Far North District
No full textFor further information about data sources, interpretation of the graphs, and cautions, please see the separate Introduction Chapter
All data relating to the 2018 census is provided by Stats NZ, https://www.stats.govt.nz/
NZDep2018 analysis of census 2018 variables - TA002: Whangarei District
No full textFor further information about data sources, interpretation of the graphs, and cautions, please see the separate Introduction Chapter
All data relating to the 2018 census is provided by Stats NZ, https://www.stats.govt.nz/