VictorJuiz/thesis huggingface dataset:
DNA Replication and Trinucleotide Repeat Instability in Myotonic Dystrophy Type 1
Keywords: DNA replication
neurodegeneration
triplet repeat
cis-element
instability
model system

The expansion of gene-specific trinucleotide repeats is responsible for a growing list of human disorders, including myotonic dystrophy type 1 (DM1). Repeat instability for most of these disorders, including DM1, is characterized by complex patterns of inherited and ongoing tissue-specific instability and pathogenesis. While the mechanistic basis behind the unique locus-specific instability of trinucleotide repeats is currently unknown, DNA metabolic processes are likely to play a role. My thesis involves investigating the contribution of DNA replication to the trinucleotide instability of myotonic dystrophy type 1. Herein I have designed an in vivo primate model system, based on the SV40 replication system, to assess the contribution of DNA replication to DM1 repeat instability. This system allows the assessment, under controlled conditions, and manipulation of variables that may affect replication-associated repeat instability, under a primate cellular system. Using the SV40 model system, I not only confirmed previous observations that repeat length and replication direction affect repeat instability, but also for the first time determined that the location of the replication origin relative to the repeat tract plays an important role in repeat instability. This novel observation allowed for the development of a fork-shift model of repeat instability, in which cis-elements adjacent to the repeat tract affect replication, in turn altering the propensity for repeat instability. To further my study of DNA replication in DM1 repeat instability, I have mapped the origin of replication adjacent to the DM1 locus in human patient cells and the tissues of DM1 transgenic mice actively undergoing repeat instability. The position of the replication origins adjacent to the repeat tract at the DM1 locus places several known cis-elements, including CTCF binding sites, in a position to alter replication as predicted by the fork-shift model. My analysis of the CTCF sites showed them capable of altering replication and repeat instability at the DM1 locus. Taken together these results suggest that the placement of replication origins, repeat tracts and cis-elements, may mark trinucleotide repeat tracts, such as the DM1, for locus-, tissue- and development-specific replication-associated repeat instability.
Real and Complex Dynamics of Unicritical Maps
Keywords: holomorphic dynamics

In this thesis, we prove two results. The first concerns the dynamics of typical maps in families of higher degree unimodal maps, and the second concerns the Hausdorff dimension of the Julia sets of certain quadratic maps. In the first part, we construct a lamination of the space of unimodal maps whose critical points have fixed degree d greater than or equal to 2 by the hybrid classes. As in [ALM], we show that the hybrid classes laminate neighbourhoods of all but countably many maps in the families under consideration. The structure of the lamination yields a partition of the parameter space for one-parameter real analytic families of unimodal maps of degree d and allows us to transfer a priori bounds from the phase space to the parameter space. This result implies that the statistical description of typical unimodal maps obtained in [ALM], [AM3] and [AM4] also holds in families of higher degree unimodal maps, in particular, almost every map in such a family is either regular or stochastic. In the second part, we prove the Poincare exponent for the Fibonacci map is less than two, which implies that the Hausdor ff dimension of its Julia set is less than two.
Rewriting Marpole: The Path to Cultural Complexity in the Gulf of Georgia.
Keywords: Northwest Coast
Archaeology
Marpole
IDA

This dissertation examines prehistoric culture change in the Gulf of Georgia region of the Northwest Coast of North America during the Locarno Beach (3500 – 1100 BP) and Marpole (2000 – 1100 BP) periods. The Marpole culture has traditionally been seen to possess all the traits associated with complex hunter-gatherers on the Northwest Coast (hereditary inequality, multi-family housing, storage-based economies, resource ownership, wealth accumulation, etc.) while the Locarno Beach culture has not. This research examined artifact and faunal assemblages as well as data for art and mortuary architecture from a total of 164 Gulf of Georgia archaeological site components. Geographic location and ethnographic language distribution were also compared to the archaeological data. Analysis was undertaken using Integrative Distance Analysis (IDA), a new statistical methodology developed in the course of this research. Results indicated that Marpole culture was not a regional phenomenon but rather was much more spatially and temporally discrete than previously known. Artifactual assemblages identified as Marpole were restricted to the areas of the Fraser River, northern Gulf Islands and portions of Vancouver Island, an area contiguous with both Mitchell’s (1971b) “Fraser River Fishermen” economic sub-area and the ethnographic territory of the Downriver and Island Halkomelem peoples. In contrast, the geographic area of Mitchell’s (1971b) “Straits Reef-net Fishermen”, the ethnographic territory of the Straits Salish, showed no sign of Marpole culture but rather a presence of Late Locarno Beach culture. The pattern found in artifacts was replicated in the distribution of art and mortuary architecture variation suggesting the cultural differences between Marpole and Late Locarno Beach cultures was real and not a statistical anomaly. The matching distribution of prehistoric cultural variability and the ethnographic pattern of language groups indicate a long standing and stable cultural dynamic within the Gulf of Georgia.
Design and Analysis of Coded Cooperation in Relay Networks
Keywords: Communications Engineering
Relay Networks
Coded Cooperation

This dissertation deals with wireless communications using cooperating relay nodes. Specifically, this dissertation relaxes two restrictive conditions ubiquitous in the current literature. First, the assumption that relay nodes can perform complex calculations is lifted. Demodulate-encode-forward (DEF) is a low-complexity relaying scheme where the relay is asked only to demodulate, not decode, a source transmission. The implementation of DEF and various methods that can be used with DEF to improve the performance while satisfying the hardware complexity limitations are detailed here. Second, we remove the assumption that the relays either transmit the complete source codeword or not transmit at all. When relays have limited resources, each relay may only be able to transmit part of the source codeword. Fractional cooperation, which allows nodes to transmit a fraction of the source codeword, is proposed and analyzed. Fractional cooperation is also very flexible because coordination between relaying nodes is not required. A third contribution of this dissertation is the use of the union-Bhattacharyya bound (UBB) to analyze relay networks. The bound has the significant advantage of accounting for the specifics of the system parameters and coding scheme used. The UBB is shown here to provide an effective and efficient scheme for relay selection, performance prediction, and system design. It can also be used to distribute relay resources in order to optimize the total energy consumed and error rate performance. A sub-optimal distributed algorithm that can be used to solve the optimization problems is introduced.
Children's Understanding of Intentional Causation in Moral Reasoning About Harmful Behaviour
Keywords: theory of mind
moral reasoning
intention understanding
developmental differences

When evaluating a situation that results in harm, it is critical to consider how a person’s prior intention may have been causally responsible for the action that resulted in the harmful outcome. This thesis examined children’s developing understanding of intentional causation in reasoning about harmful outcomes, and the relation between this understanding and mental-state reasoning. Four-, 6-, and 8-year-old children, and adults, were told eight stories in which characters’ actions resulted in harmful outcomes. Story types differed in how the actions that resulted in harm were causally linked to their prior intentions such that: (1) characters wanted to, intended to, and did perform a harmful act; (2) they wanted and intended to perform a harmful act, but instead, accidentally brought about the harmful outcome; (3) they wanted and intended to perform a harmful act, then changed their mind, but accidentally brought about the harmful outcome; (4) they did not want or intend to harm, but accidentally brought about a harmful outcome. Participants were asked to judge the characters’ intentions, make punishment judgments, and justify their responses. Additionally, children were given first- and second-order false-belief tasks, commonly used to assess mental-state reasoning. The results indicated that intention judgment accuracy improved with age. However, all age groups had difficulty evaluating the intention in the deviant causal chain scenario (Searle, 1983), in which the causal link between intention and action was broken but a harmful intention was maintained. Further, the results showed a developmental pattern in children’s punishment judgments based on their understanding of intentional causation, although the adults’ performance did not follow the same pattern. Also, younger children referred to the characters’ intentions less frequently in their justifications of their punishment judgments. The results also revealed a relation between belief-state reasoning and intentional-causation reasoning in scenarios that did not involve, or no longer involved, an intention to harm. Further, reasoning about intentional causation was related to higher-level understanding of mental states. The implications of these findings in clarifying and adding to previous research on the development of understanding of intentional causation and intentions in moral reasoning are discussed.
Quantifying Effects of Oppositely and Similarly Related Semantic Stimuli on Design Concept Creativity
Keywords: Engineering Design
Concept Generation
Design Stimuli
Language
Creativity

Creativity is important in the design and manufacture of successful products, yet neither creativity nor the early stages of design are well understood. This lack of understanding limits the tools that can be developed to support the crucial earlier stages of design that ultimately determine product success. My research aims to better understand creativity by studying and quantifying the potential of semantic stimuli (words) presented during concept generation. Natural language was chosen as design stimuli because language provides a systematic framework for stimuli generation. Furthermore, natural language is ubiquitous and intimately related to cognitive functions required in design such as reasoning and memory. Ultimately, the results of this research will assist in the development of early-design support tools. In a series of four experiments, the effects of semantic stimuli oppositely and similarly related to the experiment problem were examined with respect to creativity and designers’ language patterns. Results show that opposite-stimulus concepts were significantly more creative than similar-stimulus concepts. It also was observed that opposite stimuli elicited designer behaviours that may encourage creative concepts. These results suggest that the use of oppositely related stimulus words is a practical method for encouraging creative design.
Evolutionary Ecology of Social Interactions among Plants
Keywords: social evolution
sex allocation
animal foraging
mathematical model
competition
cooperation

Neighbouring plants can interact strongly, competing for resources including light, water, animal mutualists, and local germination sites. From an evolutionary perspective, this implies that a plant’s best resource acquisition strategy will usually depend on the traits of its neighbours, and for plants in particular, neighbours are often genealogical relatives. Here, I use a combination of theory and experiments to expose some important consequences of social interactions among plants. The first model analyzes selection on traits used to attract pollinators, showing that competitive interactions (in the absence of local relatedness) can select for exaggerated secondary sexual characters. To complement this model, I performed experiments that confirm the mechanisms by which adaptive pollinator foraging naturally leads to interactions among plants. The observed foraging behaviour (of bumble bees) also provides unique evidence for ‘Bayesian foraging’, a sophisticated type of resource assessment that depends on prior experience in a particular environment. A second model considers how selection on the sex allocation of cosexual, animal-dispersed plants leads to competition and cooperation over local germination sites, sometimes leading to the origin of gender dimorphism. The model reveals novel ecological contexts in which disruptive selection on sex allocation can arise, and in general, illustrates how selection for cooperation can facilitate or inhibit evolutionary diversification. In the models considered here, cooperation is indiscriminant, but plants might also assess the relatedness of neighbours and cooperate with kin over non-kin. In the final chapter, I present experimental evidence that is consistent with preferential cooperation over soil resources among sibling plants. This study is the first to link a potentially cooperative resource allocation strategy with an increase in the mean fitness of related plants.
Identification and Characterization of Potential Modulators of TEK/TIE-2 Signaling
Keywords: Tek/Tie-2
SAGE
MAGE
Angiogenesis

The development of a functional vascular system is impinged upon the restructuring of a primitive vasculature into a more complex and mature vessel network via a process known as angiogenesis. Of particular importance to this vascular remodeling process is the function of the Tek/Tie-2 receptor tyrosine kinase. Mouse gene-targeting studies have shown that Tie-2 deficient embryos succumb to embryonic death at embryonic day 9.5 due to insufficient sprouting and remodeling of the primary capillary plexus. Over the years, the functions and the signaling pathways downstream of Tie-2 receptor have been elucidated; however, the repertoire of genes controlled by Tie-2 signaling leading to angiogenesis had not been studied. To identify the underlying genetic mechanisms, transcriptomes from Tie-2 wild-type (WT) and knockout (KO) embryonic day 8.5 yolk sac tissues were quantitatively analyzed using a gene expression profiling technique called Serial Analysis of Gene Expression (SAGE). Tie-2 WT and KO SAGE libraries were constructed, sequenced and compared to identify genes that were differentially expressed. A list of candidate genes was selected for further validation using semi-quantitative PCR that included 4933402E13Rik, a novel transcript encoding a protein product containing the melanoma-associated antigen (MAGE) domain. Initial characterization of 4933402E13Rik suggested a murine-specific expression profile restricted to the yolk sac, embryo, placenta, testis, endothelial and embryonic stem cells. The expression of 4933402E13Rik in mouse endothelial cells was found to be regulated by Tie-2 signaling since down-regulation of Tie-2 level via siRNA knockdown resulted in decreased 4933402E13Rik mRNA expression. In contrast, stimulation of Tie-2 in mouse endothelial cells using its ligand, Angiopoietin-1, increased 4933402E13Rik mRNA levels. Additionally, 4933402E13Rik expression was found to be modulated through epigenetics especially by histone deacetylation. Mouse endothelial cells treated with Trichostatin A, a potent inhibitor of histone deacetylase, led to an increase in the expression of 4933402E13Rik. Taken together, the results of this study shed new insight on the repertoire of genes implicated in Tie-2 signaling. The identification of 4933402E13Rik as a novel gene modulated by Tie-2 provides a new avenue of research on Tie-2 signaling that may contribute further to our understanding of vascular development.
Verdazyl Radicals as Mediators in Living Radical Polymerizations and as Novel Substrates for Heterocyclic Syntheses
Keywords: stable free radical
living radical polymerization
verdazyl
cycloaddition
rearrangement
diversity-oriented synthesis
azomethine imine

Verdazyl radicals are a family of multicoloured stable free radicals. Aside from the defining backbone of four nitrogen atoms, these radicals contain multiple highly modifiable sites that grant them a high degree of derivatization. Despite having been discovered more than half a century ago, limited applications have been found for the verdazyl radicals and little is known about their chemistry. This thesis begins with an investigation to determine whether verdazyl radicals have a future as mediating agents in living radical polymerizations and progresses to their application as substrates for organic synthesis, an application that to date has not been pursued either with verdazyl or nitroxide stable radicals. The first part of this thesis describes the successful use of the 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical as a mediating agent for styrene and n-butyl acrylate stable free radical polymerizations. The study of other verdazyl derivatives demonstrated the impact of steric and electronic properties of the verdazyl radicals on their ability to mediate polymerizations. The second part of this thesis outlines the initial discovery and the mechanistic elucidation of the transformation of the 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical into an azomethine imine, which in the presence of dipolarophiles, undergoes a [3+2] 1,3-dipolar cycloaddition reaction to yield unique pyrazolotetrazinone structures. The reactivity of the azomethine imine and the scope of the reaction were also examined. The third part of this thesis describes the discovery and mechanistic determination of a base-induced rearrangement reaction that transforms the verdazyl-derived pyrazolotetrazinone cycloadducts into corresponding pyrazolotriazinones or triazole structures. The nucleophilicity, or the lack thereof, of the base employed leading to various rearrangement products was examined in detail. The final part of this thesis demonstrates the compatibility of the verdazyl-initiated cycloaddition and rearrangement reactions with the philosophy of diversity-oriented synthesis in generating libraries of heterocycles. A library of verdazyl-derived heterocycles was generated in a short amount of time and was tested non-specifically for biological activity against acute myeloid leukemia and multiple myeloma cell lines. One particular compound showed cell-killing activity at the 250 mM range, indicating future potential for this chemistry in the field of drug discovery.
Structure-function Relationships in the Inositol 1,4,5-Trisphosphate Receptor
Keywords: calcium
ion channel

The divalent Ca2+ metal ion acts as a universal second messenger in virtually all eukaryotic cells from fungi to plants to mammals. In mammals, Ca2+ signaling is vital to a variety of physiological processes including fertilization, cell proliferation, secretion, and muscular contraction. In electrochemically non-excitable tissues, the release of Ca2+ from intracellular stores such as the endoplasmic reticulum is tightly regulated by the inositol 1,4,5-trisphosphate receptor (IP3R). The IP3R Ca2+ release channel is activated by the binding of the small molecule inositol 1,4,5-trisphosphate (IP3) in response to extracellular stimuli such as hormones, growth factors, and neurotransmitters. The conformational changes accompanying IP3 binding were investigated using a biophysical approach. A specific focus of this work is to decipher how signals of ligand binding are transmitted from the N-terminal IP3-binding core to the C-terminal channel domain. To such end, biophysical studies of the ligand-induced conformational changes within the N-terminal domain of IP3R (a.a. 1 – 604) were performed. The results implicated the presence of two flexible linkers which join stably folded domains. This prompted the proposal of a model in which an equilibrium mixture of conformational substrates containing compact and more extended structures co-exist. Determinants within the N- and C-terminal regions of IP3R have previously been reported to be critical to channel function. Employing nuclear magnetic resonance (NMR) as well as biochemical methods, an intermolecular interaction between the S4-S5 linker, the cytoplasmic loop between the fourth and fifth transmembrane helices of IP3R, and the suppressor domain was identified. The determination of the crystal structure of the suppressor domain from isoform type 3 IP3R (IP3R3SUP) allowed us to map the residues involved in this interaction to one face of the molecule. The characterization of this interaction provides insight into the N- and C-terminal determinants essential to the IP3R channel gating mechanism.
A Longitudinal Investigation into the Association of Smoking and Depression among Adolescents: Exposures, Outcomes, and Auxiliary Hypotheses
Keywords: Depression
Smoking

Introduction: The association between smoking and depression has been well established, but the nature of the relationship has not been determined. A synthesis of longitudinal studies examining the onset of smoking and depression among adolescents demonstrated consistent evidence of both smoking predicting depression and depression predicting smoking in multiple populations; however, more work is needed to develop and test the mechanisms associated with the onset of the co-occurrence of smoking and depression. This thesis examines the role of a broad range of potential confounders on the relationship between smoking and depression, and investigates a potential mechanism of effect. Method: Analyses were conducted using the Nicotine Dependence in Teens (NDIT) cohort which included 1293 students initially aged 12-13 years recruited from all grade seven classes in a convenience sample of ten secondary schools in Montreal, Canada surveyed twenty times over five years. Multiple regressions were performed to examine the temporal relationship of potential confounders on the relationship between smoking and depression and to empirically observe variables that could be intermediate on pathways between smoking and depression. A growth curve model was developed to test the effect of perceived self medication on changes in depression scores over time. Results: A concept map of the smoking and depression relationship in the NDIT cohort was developed according to the results of proportional hazard and fixed effect regressions in which friend smoking, stress, and anxiety-associated variables were identified as intermediate variables. Perceived self-medication was associated with decelerated rates of change of depressive symptoms over times, suggesting that smoking may increase mean levels of stress and depressive symptoms, but may offer the perception of control. Conclusion: In concert, this thesis suggests a model in which stress and the perceived control of psychobiological function using cigarettes lead to the development of increased depressive symptoms and increased cigarette use.