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Thesis advisor: Donnah Canavan / Abstract Energy is an emerging concept in social psychology. Baumeister et. al., likening energy to a muscle, have defined exertion of self control as an energy depleting behavior. Energy depletion is measured by reduced performance on a subsequent self-control task. In contrast, Canavan's work on social energy focuses on energy generation and replenishment. Social energy is produced when two or more people are intrinsically interested in the same thing and form a satisfying relationship over this interest. Individuals high in social energy exert more effort, persist longer, and perform better. The present study was conducted in a 2x2 ANOVA design with Social Energy and Depletion as the independent variables and persistence and performance as the dependent variables. Participants worked in groups of two or three groups and were randomly assigned to conditions. In High Social Energy, they imagined managing The Beatles. In the No Social Energy, they imagined managing a cover band playing Beatle's songs. The participants then performed either a depleting or non-depleting proofreading task. Afterwards, the dependent variables were assessed in several tasks: a handgrip task and a measure of creativity and persistence. The results indicate: (1) no significant effect of depletion on the handgrip task and (2) no significant effect of social energy on any of the behavioral measures (i.e. handgrip task or creativity measure). In conclusion, the results did not support either the Depletion or Social Energy behavioral predictions. In the questionnaire data differences between Social Energy and No Social Energy showed significantly higher energy states, social energy, intrinsic motivation, flow, and most important more effort and hard work. The study does improve upon former Social Energy studies in terms of its conceptualization because it successfully manipulated No Social Energy and presented a more sophisticated conceptualization of energy. The manipulations of Social Energy and Depletion interfered with each other making it impossible to test the hypotheses. Paper to be presented at the annual Psychology Honors Conference, Psychology Department, Boston College, Chestnut Hill, Massachusetts, May 2005. / Thesis (BS) — Boston College, 2005. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Psychology. / Discipline: College Honors Program.

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Thesis (Ph.D.)--Uniformed Services University of the Health Sciences, 2006 / Typescript (photocopy)

N-acetylaspartate (NAA) is one of the most abundant molecules in the mammalian central nervous system (CNS). The current paradigm suggests that NAA is synthesized in neurons by the enzyme N-acetyltransferase 8-like (NAT8L) and hydrolyzed into aspartate and acetate by the enzyme aspartoacylase (ASPA) in oligodendrocytes. Although the function of NAA is not well understood, several hypotheses have been proposed since its discovery several decades ago. Among the most cited theory is the concept of acetate delivery to oligodendrocytes via NAA for the synthesis of fatty acids for myelin lipids and myelination. Another concept suggests that NAA functions as a molecular water pump to remove molecular water from oxidative phosphorylation. In contrast, disruption of NAA metabolism has been associated with oxidative stress contributing to neurodegeneration, as seen in Canavan disease, a monogenic disorder associated with loss-of-function mutations in ASPA. Accumulation of NAA in the CNS and peripheral organs is pathognomonic for Canavan disease (CD) and is used clinically to diagnose this rare disease. Symptoms typically occur within months after birth and primarily manifest in the CNS with spongy degeneration of the white matter. Initially, affected patients present with poor feeding, lack of head control, hydrocephalus; later, they miss developmental milestones and develop seizures. Only supportive treatment is available possibly helping patients to survive past the first couple of years. Gene therapy has been considered early on for the treatment of CD. The first trial in humans demonstrated safety but did not result in symptomatic improvement. In addition to gene therapy for the treatment of CD, NAA has gained increasing interest in neurodegenerative and psychiatric disorders, but also in adipose tissue. Here, we are investigating the function of NAA in the context of ASPA deficiency, aka Canavan disease. We found that impaired NAA metabolism caused by ASPA mutations is characterized by a neurometabolic profile that suggests cellular shift from glucose towards fatty acid metabolism for energy production. Although, we found a similar metabolic signature in asymptomatic mice within days after birth, longitudinal comparison suggest that disease progression leads to fatty acid depletion, which is not present in asymptomatic mice, potentially challenging the concept that NAA-derived acetate is essential for lipid synthesis in the myelinating brain. Using rAAV to determine the reversibility of this metabolic phenotype, we found that early treatment prevents loss of myelin, normalizes the neurometabolic phenotype and keeps Canavan mice asymptomatic; in contrast, later treatment only allows for partial normalization of the neurometabolome, despite adequate ASPA gene delivery by rAAV, independent of ubiquitous or astrocyte-restricted hASPA expression. Furthermore, we found that non-enzymatically active hASPA might play a ubiquitous role in glucose uptake regulation in vivo. Importantly, we identified brain regions with metabolic changes that also correspond to the areas with significant histopathologic alterations. Finally, we confirmed the glycolytic changes in a Canavan disease patient cell line using Seahorse metabolic analyzer, demonstrating the decreased rate of glycolysis for energy production. Overall, our findings reveal a novel metabolic phenomenon in Canavan disease and NAA metabolism that allows to assign a novel function of N-acetylaspartate.

Canavan’s Disease is a fatal Central Nervous System disorder caused by genetic defects in the enzyme – aspartoacylase and currently has no effective treatment options. We report additional phenotypes in a stringent preclinical aspartoacylase knockout mouse model. Using this model, we developed a gene therapy strategy with intravenous injections of the aspartoacylase gene packaged in recombinant adeno associated viruses (rAAVs). We first investigated the CNS gene transfer abilities of rAAV vectors that can cross the blood-brain-barrier in neonatal and adult mice and subsequently used different rAAV serotypes such as rAAV9, rAAVrh.8 and rAAVrh.10 for gene replacement therapy. A single intravenous injection rescued lethality, extended survival and corrected several disease phenotypes including motor dysfunctions. For the first time we demonstrated the existence of a therapeutic time window in the mouse model. In order to limit off-target effects of viral delivery we employed a synthetic strategy using microRNA mediated posttranscriptional detargeting to restrict rAAV expression in the CNS. We followed up with another approach to limit peripheral tissue distribution. Strikingly, we demonstrate that intracerebroventricular administration of a 50-fold lower vectors dose can rescue lethality and extend survival but not motor functions. We also study the contributions of several peripheral tissues in a primarily CNS disorder and examine several molecular attributes behind pathogenesis of Canavan’s disease using primary neural cell cultures. In summary, this thesis describes the potential of novel rAAV-mediated gene replacement therapy in Canavan’s disease and the use of rAAVs as a tool to tease out its pathological mechanism.

The Tide Lords series of fantasy novels set out to examine the issue of immortality. Its purpose was to look at the desirability of immortality, specifically why people actively seek it. It was meant to examine the practicality of immortality, specifically — having got there, what does one do to pass the time with eternity to fill? I also wished to examine the notion of true immortality — immortals who could not be killed. What I did not anticipate when embarking upon this series, and what did not become apparent until after the series had been sold to two major publishing houses in Australia and the US, was the strength of the immortality tropes. This series was intended to fly in the face of these tropes, but confronted with the reality of such a work, the Australian publishers baulked at the ideas presented, requesting the series be re-written with the tropes taken into consideration. They wanted immortals who could die, mortals who wanted to be immortal. And a hero with a sense of humour. This exegesis aims to explore where these tropes originated. It will also discuss the ways I negotiated a way around the tropes, and was eventually able to please the publishers by appearing to adhere to the tropes, while still staying true to the story I wanted to tell. As such, this discussion is, in part, an analysis of how an author negotiates the tensions around writing within a genre while trying to innovate within it.

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