Function and Regulation of Cytochrome P450 4V2 and the Implications in Bietti’s Crystalline Dystrophy

Thesis (Ph.D.)--University of Washington, 2016-06

Theorem for Series in Three-Parameter Mittag-Leffler Function

Mathematics Subject Classification 2010: 26A33, 33E12.

The impact of maternal inflammation and maternal stress in the regulation of neurodevelopment and physiological function

The mechanisms governing fetal development follow a tightly regulated pattern of progression such that interference at any one particular stage is likely to have consequences for all other stages of development in the physiological system that has been affected thereafter. These disturbances can take the form of many different events but two of the most common and widely implicated in causing detrimental effects to the developing fetus are maternal immune activation (MIA) and maternal stress. MIA has been shown to cause an increase in circulating proinflammatory cytokines in both the maternal and fetal circulation. This increase in proinflammatory mediators in the fetus is thought to occur by fetal production rather than through exchange between the maternal-fetal interface. In the case of maternal stress it is increased levels of stress related hormones such as cortisol/corticosterone which is thought to elicit the detrimental effects on fetal development. In the case of both maternal infection and stress the timing and nature of the insult generally dictates the severity and type of effects seen in affected offspring. We investigated the effect of a proinflammatory environment on neural precursor cells of which exposure resulted in a significant decrease in the normal rate of proliferation of NPCs in culture but did not have any effect on cell survival. These effects were seen to be age dependent. Using a restraint stress model we investigated the effects of prenatal stress on the development of a number of different physiological systems in the same cohort of animals. PNS animals exhibited a number of aberrant changes in cardiovascular function with altered responses to stress and hypertension, modifications in respiratory responses to hypercapnic and hypoxic challenges and discrepancies in gastrointestinal innervation. Taken together these findings suggest that both maternal infection and maternal stress are detrimental to the normal development of the fetus.

An Investigation into the Use of Computer-based Simulation Games for Learning and Teaching in Business Management Courses

Computer-based simulation games (CSG) are a form of innovation in learning and teaching. CGS are used more pervasively in various ways such as a class activity (formative exercises) and as part of summative assessments (Leemkuil and De Jong, 2012; Zantow et al., 2005). This study investigates the current and potential use of CGS in Worcester Business School’s (WBS) Business Management undergraduate programmes. The initial survey of off-the-shelf simulation reveals that there are various categories of simulations, with each offering varying levels of complexity and learning opportunities depending on the field of study. The findings suggest that whilst there is marginal adoption of the use CSG in learning and teaching, there is significant opportunity to increase the use of CSG in enhancing learning and learner achievement, especially in Level 5 modules. The use of CSG is situational and its adoption should be undertaken on a case-by-case basis. WBS can play a major role by creating an environment that encourages and supports the use of CSG as well as other forms of innovative learning and teaching methods. Thus the key recommendation involves providing module teams further support in embedding and integrating CSG into their modules.

Problems in number theory and hyperbolic geometry

In the first part of this thesis we generalize a theorem of Kiming and Olsson concerning the existence of Ramanujan-type congruences for a class of eta quotients. Specifically, we consider a class of generating functions analogous to the generating function of the partition function and establish a bound on the primes ℓ for which their coefficients c(n) obey congruences of the form c(ℓn + a) ≡ 0 (mod ℓ). We use this last result to answer a question of H.C. Chan. In the second part of this thesis [S2] we explore a natural analog of D. Calegari’s result that there are no hyperbolic once-punctured torus bundles over S^1 with trace field having a real place. We prove a contrasting theorem showing the existence of several infinite families of pairs (−χ, p) such that there exist hyperbolic surface bundles over S^1 with trace field of having a real place and with fiber having p punctures and Euler characteristic χ. This supports our conjecture that with finitely many known exceptions there exist such examples for each pair ( −χ, p).

Leptin modifies the prosecretory and prokinetic effects of the inflammatory cytokine interleukin-6 on colonic function in Sprague–Dawley rats

Leptin ameliorates the prosecretory and prokinetic effects of the pro-inflammatory cytokine interleukin-6 on rat colon. Leptin also suppresses the neurostimulatory effects of irritable bowel syndrome plasma, which has elevated concentrations of interleukin-6, on enteric neurons. This may indicate a regulatory role for leptin in immune-mediated bowel dysfunction. In addition to its role in regulating energy homeostasis, the adipokine leptin modifies gastrointestinal (GI) function. Indeed, leptin-resistant obese humans and leptin-deficient obese mice exhibit altered GI motility. In the functional GI disorder irritable bowel syndrome (IBS), circulating leptin concentrations are reported to differ from those of healthy control subjects. Additionally, IBS patients display altered cytokine profiles, including elevated circulating concentrations of the pro-inflammatory cytokine interleukin-6 (IL-6), which bears structural homology and similarities in intracellular signalling to leptin. This study aimed to investigate interactions between leptin and IL-6 in colonic neurons and their possible contribution to IBS pathophysiology. The functional effects of leptin and IL-6 on colonic contractility and absorptosecretory function were assessed in organ baths and Ussing chambers in Sprague–Dawley rat colon. Calcium imaging and immunohistochemical techniques were used to investigate the neural regulation of GI function by these signalling molecules. Our findings provide a neuromodulatory role for leptin in submucosal neurons, where it inhibited the stimulatory effects of IL-6. Functionally, this translated to suppression of IL-6-evoked potentiation of veratridine-induced secretory currents. Leptin also attenuated IL-6-induced colonic contractions, although it had little direct effect on myenteric neurons. Calcium responses evoked by IBS plasma in both myenteric and submucosal neurons were also suppressed by leptin, possibly through interactions with IL-6, which is elevated in IBS plasma. As leptin has the capacity to ameliorate the neurostimulatory effects of soluble mediators in IBS plasma and modulated IL-6-evoked changes in bowel function, leptin may have a role in immune-mediated bowel dysfunction in IBS patients.

Practical, appropriate, empirically-validated guidelines for designing educational games

There has recently been a great deal of interest in the potential of computer games to function as innovative educational tools. However, there is very little evidence of games fulfilling that potential. Indeed, the process of merging the disparate goals of education and games design appears problematic, and there are currently no practical guidelines for how to do so in a coherent manner. In this paper, we describe the successful, empirically validated teaching methods developed by behavioural psychologists and point out how they are uniquely suited to take advantage of the benefits that games offer to education. We conclude by proposing some practical steps for designing educational games, based on the techniques of Applied Behaviour Analysis. It is intended that this paper can both focus educational games designers on the features of games that are genuinely useful for education, and also introduce a successful form of teaching that this audience may not yet be familiar with.

SCOOT game event : families as partners in learning

How games can be designed to engage families in learning spaces outside of the classroom. SCOOT Game has been played by families in various science museums and art galleries in Australian capital cities since 2004. Families form groups to collaborate in the game that takes them on an SMS quest through these places engaging them with artworks, historic facts, landmarks, puzzles, street performances etc.

Simulated cataract and low contrast stimuli impair cognitive performance in older adults : implications for neuropsychological assessment and everyday function

Objective: To investigate how age-related declines in vision (particularly contrast sensitivity), simulated using cataract-goggles and low-contrast stimuli, influence the accuracy and speed of cognitive test performance in older adults. An additional aim was to investigate whether declines in vision differentially affect secondary more than primary memory. Method: Using a fully within-subjects design, 50 older drivers aged 66-87 years completed two tests of cognitive performance - letter matching (perceptual speed) and symbol recall (short-term memory) - under different viewing conditions that degraded visual input (low-contrast stimuli, cataract-goggles, and low-contrast stimuli combined with cataract-goggles, compared with normal viewing). However, presentation time was also manipulated for letter matching. Visual function, as measured using standard charts, was taken into account in statistical analyses. Results: Accuracy and speed for cognitive tasks were significantly impaired when visual input was degraded. Furthermore, cognitive performance was positively associated with contrast sensitivity. Presentation time did not influence cognitive performance, and visual gradation did not differentially influence primary and secondary memory. Conclusion: Age-related declines in visual function can impact on the accuracy and speed of cognitive performance, and therefore the cognitive abilities of older adults may be underestimated in neuropsychological testing. It is thus critical that visual function be assessed prior to testing, and that stimuli be adapted to older adults' sensory capabilities (e.g., by maximising stimuli contrast).

Look before you leap : a confidence-based method for selecting species criticality while avoiding negative populations in τ-leaping

The stochastic simulation algorithm was introduced by Gillespie and in a different form by Kurtz. There have been many attempts at accelerating the algorithm without deviating from the behavior of the simulated system. The crux of the explicit τ-leaping procedure is the use of Poisson random variables to approximate the number of occurrences of each type of reaction event during a carefully selected time period, τ. This method is acceptable providing the leap condition, that no propensity function changes “significantly” during any time-step, is met. Using this method there is a possibility that species numbers can, artificially, become negative. Several recent papers have demonstrated methods that avoid this situation. One such method classifies, as critical, those reactions in danger of sending species populations negative. At most, one of these critical reactions is allowed to occur in the next time-step. We argue that the criticality of a reactant species and its dependent reaction channels should be related to the probability of the species number becoming negative. This way only reactions that, if fired, produce a high probability of driving a reactant population negative are labeled critical. The number of firings of more reaction channels can be approximated using Poisson random variables thus speeding up the simulation while maintaining the accuracy. In implementing this revised method of criticality selection we make use of the probability distribution from which the random variable describing the change in species number is drawn. We give several numerical examples to demonstrate the effectiveness of our new method.

Policy analysis of disaster health management in China

Humankind has been dealing with all kinds of disasters since the dawn of time. The risk and impact of disasters producing mass casualties worldwide is increasing, due partly to global warming as well as to increased population growth, increased density and the aging population. China, as a country with a large population, vast territory, and complex climatic and geographical conditions, has been plagued by all kinds of disasters. Disaster health management has traditionally been a relatively arcane discipline within public health. However, SARS, Avian Influenza, and earthquakes and floods, along with the need to be better prepared for the Olympic Games in China has brought disasters, their management and their potential for large scale health consequences on populations to the attention of the public, the government and the international community alike. As a result significant improvements were made to the disaster management policy framework, as well as changes to systems and structures to incorporate an improved disaster management focus. This involved the upgrade of the Centres for Disease Control and Prevention (CDC) throughout China to monitor and better control the health consequences particularly of infectious disease outbreaks. However, as can be seen in the Southern China Snow Storm and Wenchuan Earthquake in 2008, there remains a lack of integrated disaster management and efficient medical rescue, which has been costly in terms of economics and health for China. In the context of a very large and complex country, there is a need to better understand whether these changes have resulted in effective management of the health impacts of such incidents. To date, the health consequences of disasters, particularly in China, have not been a major focus of study. The main aim of this study is to analyse and evaluate disaster health management policy in China and in particular, its ability to effectively manage the health consequences of disasters. Flood has been selected for this study as it is a common and significant disaster type in China and throughout the world. This information will then be used to guide conceptual understanding of the health consequences of floods. A secondary aim of the study is to compare disaster health management in China and Australia as these countries differ in their length of experience in having a formalised policy response. The final aim of the study is to determine the extent to which Walt and Gilson’s (1994) model of policy explains how disaster management policy in China was developed and implemented after SARS in 2003 to the present day. This study has utilised a case study methodology. A document analysis and literature search of Chinese and English sources was undertaken to analyse and produce a chronology of disaster health management policy in China. Additionally, three detailed case studies of flood health management in China were undertaken along with three case studies in Australia in order to examine the policy response and any health consequences stemming from the floods. A total of 30 key international disaster health management experts were surveyed to identify fundamental elements and principles of a successful policy framework for disaster health management. Key policy ingredients were identified from the literature, the case-studies and the survey of experts. Walt and Gilson (1994)’s policy model that focuses on the actors, content, context and process of policy was found to be a useful model for analysing disaster health management policy development and implementation in China. This thesis is divided into four parts. Part 1 is a brief overview of the issues and context to set the scene. Part 2 examines the conceptual and operational context including the international literature, government documents and the operational environment for disaster health management in China. Part 3 examines primary sources of information to inform the analysis. This involves two key studies: • A comparative analysis of the management of floods in China and Australia • A survey of international experts in the field of disaster management so as to inform the evaluation of the policy framework in existence in China and the criteria upon which the expression of that policy could be evaluated Part 4 describes the key outcomes of this research which include: • A conceptual framework for describing the health consequences of floods • A conceptual framework for disaster health management • An evaluation of the disaster health management policy and its implementation in China. The research outcomes clearly identified that the most significant improvements are to be derived from improvements in the generic management of disasters, rather than the health aspects alone. Thus, the key findings and recommendations tend to focus on generic issues. The key findings of this research include the following: • The health consequences of floods may be described in terms of time as ‘immediate’, ‘medium term’ and ‘long term’ and also in relation to causation as ‘direct’ and ‘indirect’ consequences of the flood. These two aspects form a matrix which in turn guides management responses. • Disaster health management in China requires a more comprehensive response throughout the cycle of prevention, preparedness, response and recovery but it also requires a more concentrated effort on policy implementation to ensure the translation of the policy framework into effective incident management. • The policy framework in China is largely of international standard with a sound legislative base. In addition the development of the Centres for Disease Control and Prevention has provided the basis for a systematic approach to health consequence management. However, the key weaknesses in the current system include: o The lack of a key central structure to provide the infrastructure with vital support for policy development, implementation and evaluation. o The lack of well-prepared local response teams similar to local government based volunteer groups in Australia. • The system lacks structures to coordinate government action at the local level. The result of this is a poorly coordinated local response and lack of clarity regarding the point at which escalation of the response to higher levels of government is advisable. These result in higher levels of risk and negative health impacts. The key recommendations arising from this study are: 1. Disaster health management policy in China should be enhanced by incorporating disaster management considerations into policy development, and by requiring a disaster management risk analysis and disaster management impact statement for development proposals. 2. China should transform existing organizations to establish a central organisation similar to the Federal Emergency Management Agency (FEMA) in the USA or the Emergency Management Australia (EMA) in Australia. This organization would be responsible for leading nationwide preparedness through planning, standards development, education and incident evaluation and to provide operational support to the national and local government bodies in the event of a major incident. 3. China should review national and local plans to reflect consistency in planning, and to emphasize the advantages of the integrated planning process. 4. Enhance community resilience through community education and the development of a local volunteer organization. China should develop a national strategy which sets direction and standards in regard to education and training, and requires system testing through exercises. Other initiatives may include the development of a local volunteer capability with appropriate training to assist professional response agencies such as police and fire services in a major incident. An existing organisation such as the Communist Party may be an appropriate structure to provide this response in a cost effective manner. 5. Continue development of professional emergency services, particularly ambulance, to ensure an effective infrastructure is in place to support the emergency response in disasters. 6. Funding for disaster health management should be enhanced, not only from government, but also from other sources such as donations and insurance. It is necessary to provide a more transparent mechanism to ensure the funding is disseminated according to the needs of the people affected. 7. Emphasis should be placed on prevention and preparedness, especially on effective disaster warnings. 8. China should develop local disaster health management infrastructure utilising existing resources wherever possible. Strategies for enhancing local infrastructure could include the identification of local resources (including military resources) which could be made available to support disaster responses. It should develop operational procedures to access those resources. Implementation of these recommendations should better position China to reduce the significant health consequences experienced each year from major incidents such as floods and to provide an increased level of confidence to the community about the country’s capacity to manage such events.

Relationship among CFH and ARMS2 genotypes, macular pigment optical density, and neuroretinal function in persons without age-related macular degeneration

Purpose: To determine whether there is a difference in neuroretinal function and in macular pigment optical density between persons with high- and low-risk gene variants for age-related macular degeneration (AMD) and no ophthalmoscopic signs of AMD, and to compare the results on neuroretinal function to patients with manifest early AMD. Methods and Participants: Neuroretinal function was assessed with the multifocal electroretinogram (mfERG) for 32 participants (22 healthy persons with no AMD and 10 early AMD patients). The 22 healthy participants with no AMD had high- or low-risk genotypes for either CFH (rs380390) and/or ARMS2 (rs10490924). Trough-to-peak response densities and peak-implicit times were analyzed in 5 concentric rings. Macular pigment optical densitometry was assessed by customized heterochromatic flicker photometry. Results: Trough-to-peak response densities for concentric rings 1 to 3 were, on average, significantly greater in participants with high-risk genotypes than in participants with low-risk genotypes and in persons with early AMD after correction for age and smoking (p<0.05). The group peak- implicit times for ring 1 were, on average, delayed in the patients with early AMD compared with the participants with high- or low-risk genotypes, although these differences were not significant. There was no significant correlation between genotypes and macular pigment optical density. Conclusion: Increased neuroretinal activity in persons who carry high-risk AMD genotypes may be due to genetically determined subclinical inflammatory and/or histological changes in the retina. Neuroretinal function in healthy persons genetically susceptible to AMD may be a useful additional early biomarker (in combination with genetics) before there is clinical manifestation.

Games for change and transformative learning : an ethnographic case study

This thesis aims to contribute to a better understanding of how serious games/games for change function as learning frameworks for transformative learning in an educational setting. This study illustrates how the meaning-making processes and learning with and through computer gameplay are highly contingent, and are significantly influenced by the uncertainties of the situational context. The study focuses on SCAPE, a simulation game that addresses urban planning and sustainability. SCAPE is based on the real-world scenario of Kelvin Grove Urban Village, an inner city redevelopment area in Brisbane, Queensland, Australia. The game is embedded within an educational program, and I thus account for the various gameplay experiences of different school classes participating in this program. The networks emerging from the interactions between students/players, educators, facilitators, the technology, the researcher, as well as the setting, result in unanticipated, controversial, and sometimes unintended gameplay experiences and outcomes. To unpack play, transformative learning and games, this study adopts an ecological approach that considers the magic circle of gameplay in its wider context. Using Actor-Network Theory as the ontological lens for inquiry, the methods for investigation include an extensive literature review, ethnographic participant observation of SCAPE, as well as student and teacher questionnaires, finishing with interviews with the designers and facilitators of SCAPE. Altogether, these methods address my research aim to better understand how the heterogeneous actors engage in the relationships in and around gameplay, and illustrate how their conflicting understandings enable, shape or constrain the (transformative) learning experience. To disentangle these complexities, my focus continuously shifts between the following modes of inquiry into the aims „h To describe and analyse the game as a designed artefact. „h To examine the gameplay experiences of players/students and account for how these experiences are constituted in the relationships of the network. „h To trace the meaning-making processes emerging from the various relations of players/students, facilitators, teachers, designers, technology, researcher, and setting, and consider how the boundaries of the respective ecology are configured and negotiated. „h To draw out the implications for the wider research area of game-based learning by using the simulation game SCAPE as an example for introducing gameplay to educational settings. Accounting in detail for five school classes, these accounts represent, each in its own right, distinct and sometimes controversial forms of engagement in gameplay. The practices and negotiations of all the assembled human and non-human actors highlight the contingent nature of gameplay and learning. In their sum, they offer distinct but by no means exhaustive examples of the various relationships that emerge from the different assemblages of human and non-human actors. This thesis, hence, illustrates that game-based learning in an educational setting is accompanied by considerable unpredictability and uncertainty. As ordinary life spills and leaks into gameplay experiences, group dynamics and the negotiations of technology, I argue that overly deterministic assertions of the game¡¦s intention, as well as a too narrowly defined understanding of the transformative learning outcome, can constrain our inquiries and hinder efforts to further elucidate and understand the evolving uncertainties around game-based learning. Instead, this thesis posits that playing and transformative learning are relational effects of the respective ecology, where all actors are networked in their (partial) enrolment in the process of translation. This study thus attempts to foreground the rich opportunities for exploring how game-based learning is assembled as a network of practices.

Spotting the difference : identifying player opponent preferences in FPS games

This paper describes a study designed to understand player responses to artificially intelligent opponents in multi-player First Person Shooter games. It examines the player's ability to tell the difference between artificially intelligent opponents and other human players, and investigates the players' perceptions of these opponents. The study examines player preferences in this regard and identifies the significance of the cues and signs players use to categorise an opponent as artificial or human.