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The role of Mdm2 in estrogen-mediated breast cancer cell proliferation
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Estrogen signaling is important in breast cancer development and progression. Mdm2, a negative regulator of the p53 tumor suppressor, is often over-expressed in estrogen receptor positive breast cancers. To study the role of Mdm2 in the estrogen-mediated breast cancer cell proliferation, we examined the effect of estrogen on the p53-Mdm2 pathway in estrogen receptor positive and p53 wild-type MCF-7 breast cancer cells. Estrogen-mediated increase in cell proliferation correlated with increased Mdm2, but no concomitant decrease in the p53 protein level. Blocking Mdm2 expression with inducible shRNA inhibited estrogen-mediated cell proliferation and colony formation in soft agar. Mdm2 knockdown in the presence of estrogen increased p21 and the percent of cells in the G1 phase. Interestingly, knockdown of p53 had no effect on the estrogen-mediated cell proliferation. Estrogen also up-regulated the Mdm2 protein levels in cells exposed to the DNA damaging agent, etoposide, and the Mdm2 inhibitor, Nutlin-3. In turn, estrogen inhibited etoposide- and Nutlin-3-induced transcription of puma, a pro-apoptotic p53 target gene, without changing the p53 protein levels or p53 recruitment to the chromatin. The decrease in puma gene transcription correlated with a decrease in Puma protein and an increase in Bcl-2 protein, an anti-apoptotic estrogen receptor target. Overall, our findings suggest that estrogen signals to an Mdm2-mediated pathway to provoke cell proliferation and that this pathway is associated with inhibition of the G1 checkpoint.
For Right and Might: The Militarization of the Cold War and the Remaking of American Democracy
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This dissertation examines how Cold War defense spending shaped the evolution of American political culture and public policy from the 1940s until the 1990s. It argues that the Cold War economy contributed to the realignment of American politics in the postwar era. The fight against global communism abroad altered the structure, purpose, and public perception of the federal government following World War II, but also subsidized corporations, suburban communities, and individuals affected by defense spending. The militarization of the Cold War therefore created various dependents of America's military and defense apparatus that continuously pressed for more defense spending during the Cold War, even if increases in the military budget were strategically and economically gratuitous. Americans in communities dependent upon defense contractors for employment and economic growth lobbied their political representatives to allocate more defense contracts to their towns, while defense companies and contractors formed alliances with activists, politicians, defense workers, and labor unions to ensure their profitability in the face of cuts to the defense budget. The combination of these forces created a unique "Cold War coalition" that worked to keep the defense economy active in shaping the domestic and foreign policies of the United States. As the constitutive elements of the defense economy were threatened with defense cuts and a thaw in the Cold War after the 1960s, they increasingly gravitated toward political figures and officials who promised continued defense spending. After the economic crisis of the 1970s, residents of such "Cold War communities" saw job losses to inflation and stagnation, but also to a drawdown in the Vietnam War and the era of détente. By the end of the Cold War, communities reliant upon the Department of Defense for employment supported "conservative" proposals for the reduction of federal taxes and government influence in regulating local economies, while also campaigning for additional federal defense contracts to keep local economies afloat. By exploring the realignment of American politics through the context of global events--and their impact on local politics--this dissertation considers how the personal livelihoods and political prejudices of Americans shaped both national politics and foreign affairs.
Ideology and Decision Making in School-Based Counseling
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The present study built on the design and results from the pilot study in an attempt to explore the relationship between psychologists' personal ideologies and the decisions they make in school-based counseling. Of particular interest was whether higher levels of self-reported ideology were related to support of relevant school policies. Participants included 166 psychologists who responded to an online survey that included questions related to personal and professional ideologies, attitudes toward school policies, training and preparedness in four areas of interest, and hypothetical scenarios. Consistency among responses in areas including theoretical orientation, political party, and training and preparedness in ethics and multicultural issues limited the analyses that could be performed to compare different populations. Correlation data indicated that there was no relationship between those who reported to be religious and those who reported that they were not religious, though slight differences were noted qualitatively. There was also no difference between responses of individuals who had not taken a class but felt prepared as compared with responses of the rest of the population. Correlation data also indicated some associations between the school policies related to liberal/conservative political views and the vignette designed toward that ideology.
Between sites: Critical convergences at the personal, interpersonal, and institutional levels in a service learning course
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Set within the context of the increasing emphasis on civic engagement and transformative education, this work addresses service learning as a form of civic engagement that holds both the risks of acriticality and critical potential. This study examines the capacity for the critical consciousness and relationality that define the primary commitments of critical service learning (see Kinefuchi, 2010). Thus, this study is grounded in the ways that the circuits of privilege and dispossession were breached in a service learning course where college students travelled to mentor adolescent girls who were in a secure residential facility. The narratives of former service learning students were analyzed to excavate the service learning experience at three sites which contextualize moments of critical dialogue: the personal, the interpersonal, and the institutional level. Three themes emerged from the analysis: (1) the position of the mentor between being an agent and recipient of transformation; (2) the discourses of sameness and difference deployed to forge solidarities; and, (3) the negotiation of the boundary between the inside and outside as a marker of the personal-societal dispossession of the service learning site and those within it. The findings indicated that people blur the line that separates self/other as they acknowledge mutual impact, implicate themselves in constructing a vision of girls' well-being, and grapple with counter/representations of the facility and the girls from their temporary position as `insiders' within the facility. These findings are held in tension by participants' intermittent recognition of the facility as a space of dispossession, however, and their resistance to writing themselves into it. The findings suggest that the positions, discourses, and critical meanings are moments across this service learning experience that can be `visual aids' for intergroup processes. The future directions based on this work suggest intentionally deploying these moments in order to explore the flows of comfort, connection, remembrance, trauma, loss, and disintegration on which circuits of dispossession and privilege run (Ayala & Galletta, 2012; Fine & Ruglis, 2009).
The Effects of Thyroid Hormone Insufficiency During Development On Cortical Morphology And The Behavioural Manifestations
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The central hypothesis of this work is that developmental thyroid insufficiency impacts the development of the rat cerebral cortex by altering cortical volume and the number of cortical neurons. In addition, as these neuroanatomical changes caused by milder forms of developmental hypothyroidism or hypothyroxinemia may have both immediate and long term consequences on certain aspects of behaviour, the investigation sought to determine if the alterations in morphology, including the change in relative cortical volume, and the change in the number of cortical neurons in the rat brain, led to behavioral manifestations. Hypothyroidism was induced by the administration of graded levels of the antithyroid agent propylthiouracil (PTU) to suppress thyroid hormone production. The number of neurons was estimated, using unbiased sampling techniques, to determine whether the cellular composition of cortex was altered following developmental TH insufficiency. To determine if these cortical alterations led to changes in behaviour, a battery of behavioural tests were performed which included maternal retrieval (PND 4), maternal separation anxiety (PND 6), Barnes maze (PND 48 and PND 86), social interaction social approach (PND 48-50), and open field (PND 46). Taken together, the results presented here support the hypothesis that developmental hypothyroidism and hypothyroxinemia induced by chemical thyroid hormone suppression (PTU) cause alterations in the morphology of the cerebral cortex by altering cortical volume and changing the number of cortical neurons in the rat brain. Furthermore these alterations ultimately lead to changes in certain aspects of behaviour. These results have important clinical relevance because several studies suggest that developmental disabilities ranging from mild dyslexia to severe mental retardation can be attributed to alterations in cortical morphology resulting from abnormal cortical development.
Hypertonic Lower Extremities in Infants: Correlation to Motor Function Scores at Thirteen Months of Age
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Exploring a large data set, hypertonicity of the lower extremities has been incidentally identified as occurring in one out of every five infants, whether term or preterm. This retrospective, longitudinal, descriptive, quantitative study examined data from 463 functionally and structurally normal infants and identified infants that were considered to be hypertonic at either hospital discharge and at one month of corrected gestational age to determine what their motor capabilities were at 13 months of age. Understanding the correlation will assist in determining whether early intervention is indicated for these infants. Multiple statistical analyses revealed no correlation between hypertonicity as a young infant and the Bayley-II motor function score at 13 months of age. The Roy Adaptation model was used as the conceptual framework of the study and ordinal regression was utilized to analyze the data.
Moving Beyond Mirroring - A social Affordance Model of Sensorimotor Integration during Action Perception
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The discovery of so-called `mirror neurons' - found to respond similarly to own actions and the observation similar actions performed by others - have been enormous influential in the cognitive sciences and beyond. Due to the self-other symmetry these neurons have been hypothesized as underlying a `mirror mechanism' that lets us share representations and thereby ground core social cognitive functions from intention understanding to linguistic abilities and empathy. I argue that mirror neurons are important for rather different reasons. Rather than a symmetric ubiquitous or context-independent mechanism, I propose that these neurons are part of broader sensorimotor integrative circuits, which help us navigate and predict the social affordance space that we meet others in. To develop both the critical and positive project I discuss the interpretive choices and the debate surrounding the mirror neuron research and show how the field is marred by highly questionable assumptions about motor and social cognition. The very discovery of mirror neurons and the broader sensorimotor fronto-parietal circuits of which these neurons are a part, actually challenge many of these tacitly held assumptions empirically. The findings of sensorimotor goal representations at levels of abstraction well beyond the actual sensory information and kinetic movements challenge the idea of motor cognition as primarily output production. Additionally, the focus on social cognition as a process of 3rd person mindreading and attribution of hidden mental states seems misguided given that sensorimotor processes precisely suggest a developmentally primary 2nd person understanding of the mental lives and actions of others. I propose a Social Affordance model suggesting that the broader sensorimotor findings in fronto-parietal circuits support representations not just of other people's actions but of the overall social affordance space. It is a process that monitors concrete goals and teleological possibilities that the environment affords respectively oneself and other present agents. With this model I hypothesize that the complex spectrum of parallel sensorimotor integrations are indeed essential not only to normal action choices but also to social cognitive abilities, as the sensorimotor teleological representations let us relate to others and understand their action choices in a shared pragmatic and intentional context.
Evolution of Innate Immunity in African Catarrhines
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Innate immunity is the first line of host defense against invading pathogens, involves activation of innate immune cells via Toll-like receptors (TLRs) and is a major factor affecting host susceptibility to infectious disease. African catarrhine primates share high genomic identity, yet appear to differ in their susceptibility to bacterial infections (i.e. Gram-negative bacterial sepsis, Neisseria gonorrhoeae, Mycobacterium). These species are hypothesized to have divergent evolutionary histories of pathogen exposure due to differences in geographic distribution and behaviour. The goals of this research were to 1) clarify if the early innate immune responses of African catarrhine species have functionally diverged, and 2) examine possible associations between these responses and pathogen type, primate evolutionary landscape and disease susceptibility. To examine if African catarrhines have evolved different early innate immune responses to environment-specific pathogens, fresh whole blood from Homo, Pan and Papio was stimulated with TLR2 and TLR4 -detected molecular components from pathogens unevenly distributed across primate evolutionary habitats (i.e. Mycobacterium, Yersinia pestis) for 90 minutes. Immune activation was assessed by quantifying expression of genes associated with the early innate immune response by real-time PCR. This study shows that Homo and Pan blood leukocytes typically mount similar early cytokine and chemokine responses to stimuli, while the more distantly related Papio mounts opposing responses. The divergence of Homo/Pan and Papio cytokine/chemokine induction broadly agrees with observed differences in susceptibility to bacterial diseases, however no association was found between putative pathogen/primate evolutionary environment and gene induction. While early innate immune responses tend to agree with primate evolutionary relationships, there are some notable exceptions to this pattern, including some cytokine responses that are agonist/pathogen-specific (i.e. IL-1β, TNFα, IL-10, IL-6). Taken together, this data suggests a significant divergence between hominoid and baboon early innate immune responses since these species shared a last common ancestor 23-29 million years ago.
Historical Relationships between Land Elevation and Socioeconomic Status in New York City: A Mixed Methods GIS Approach
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Earth & Environmental Sciences
The role that topography has played in the development of New York City is essential to understanding its present urban form and foreseeing its changes. Geographers and economists have generally agreed that for cities in the United States, socioeconomic status increases with land elevation. This seemingly simple relationship between elevation and class, however, is complicated by factors such as technological innovations, economic shifts, politics, cultural perceptions, and the idiosyncrasies of cities and the neighborhoods within them. The lack of comprehensive research in this area coupled with conflicting findings warranted further exploration into the complex and changing relationships between elevation and social class. This longitudinal study utilized a mixed methods GIS approach to reveal historical relationships between land elevation and socioeconomic status in New York City, and explain factors that may mediate these relationships. This study departed from the traditional use of regression results by mapping standardized residuals clusters, which were found to be an extremely efficient way of pinpointing anomalous areas that would be appropriate case study areas for in-depth, qualitative analysis. Relative elevation was found to be a better determinant of socioeconomic status than absolute elevation for three out of ten analysis years examined. The presence of urban fringe uses on high elevation land was affirmed. The persistence of historical settlement patterns was also affirmed, and it was found that this persistence was able to withstand technological, economic, cultural, and significant physical topography changes. Public policy, such as through the use of zoning tools and eminent domain, was the most influential force in the transformation of historical land use and settlement patterns. Climate change is poised to become another powerful force in the transformation of cities, and should be incorporated into future studies that examine the relationship between physical topography and residential or land use patterns.
Entropy of Jammed Granular Matter
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Granular matter can be considered a non-equilibrium system, such that equilibrium statistics is insufficient to describe the dynamics. A phase transition occurs when granular materials are compressed such that a nonzero stress develops in response to a strain deformation. This transition, referred to as the jamming transition, occurs at a critical volume fraction, depending on friction and preparation protocol. Analysis of the jamming transition produces a phase diagram of jammed granular matter for identical spheres, characterized by the critical volume fraction, and the average coordination number. The boundaries of the phase diagram are related to well-defined upper and lower limits in the density of disordered packings; random close packing (RCP) and random loose packing (RLP). Frictional systems, such as granular matter, exhibit an inherent path dependency resulting in the loss of energy conservation, an important facet of equilibrium statistics. It has been suggested Edwards that the volume-force (V-F) ensemble, wherein volume replaces energy as the conservative quantity, may provide a sufficient framework to create a statistical ensemble for jammed granular matter. Treating a jammed system via the V-F ensemble introduces an analogue to temperature in equilibrium systems. This analogue, "compactivity", measures how compact a system could be and governs fluctuation in the volume statistics. Randomness in statistical systems is typically characterized by entropy, the equation of state derived from the number of microstates available to the system. In equilibrium statistical mechanics, entropy provides the link between these microstates and the macroscopic thermodynamic properties of the system. Therefore, calculating the entropy within the V-F ensemble can relate the available microscopic volume for each grain to the macroscopic system properties. The entropy is shown to be minimal at RCP and maximal at the minimum RLP limit, via several methods utilizing simulations and theoretical models. Within this framework RCP is achieved in the limit of minimal compactivity and RLP is achieved in the limit of maximal compactivity. The boundaries of a phase diagram for jammed matter could thereby be defined by the limits of zero and infinite compactivities, characterizing the RCP and RLP limits of granular matter.