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Real-time Measurement of Glial Progenitor Chemotactic Migration
Year of Dissertation:
Gliomas are the most commonly diagnosed form of central nervous system tumors, occurring primarily in adults. Like many malignant cancers, gliomas pathologically exhibit very aggressive spreading and lead to an average diagnosed survival expectancy of twelve months. This prognosis is due in large part to the uncontrolled division and migration of malignant tumor cells within healthy brain, which makes complete surgical resection impossible. Gliomas are known to contain numerous genotypic and phenotypic alterations that affect cell proliferation and survival. Previous research has indicated that both gliomas and their precursor cells exhibit distinct migration patterns in brain tissue, which may be induced by specific cytokines and their concentration gradients. Here, we investigated the migration of four brain tumor cell (BTCs) lines (U-87 MG; U-251 MG; Daoy; and XFMPDGF) and three RCAS-infected glial progenitor cell (GPCs) populations (GPCLacZ, GPCPDGF, and GPCkRas) toward various growth factors, including but not limited to: EGF, HGF/SF, PDGF-BB, and TGF-α. Mouse neural cultures of nestin expressing glial progenitor cells that have been engineered to display the Avian Leukosis Virus (ALV) target receptor, tv-a, were infected with the RCAS viral vectors RCAS-LacZ, RCAS-PDGF-B, and RCAS-kRas, and are referred to as Ntv-a glial progenitor cells (Ntv-a-GPCs). Upon successful infection, the Ntv-a-GPCs were capable of constitutively producing β-galactosidase, PDGF-B, and kRas, respectively. Additionally, when these viral vectors were injected into the brains of transgenic Ntv-a mouse pups, only the RCAS-PDGF-B viral titer induced gliomas (Dai et al, 2001; Holland et al, 2000). For the purpose of this work it is relevant to note that the Ntv-a cell lines used, with the exception of the XFMPDGF cells, were never injected into the mouse brain. Conversely, the XFMPDGF cell population represents an excised tumor from the brain of a ≤ 12-week-old Ntv-a transgenic mouse having the Ink4a-Arf -/- genetic background. After cranial injection with a RCAS-PDGF-B viral titer, tumors of the oligodendroglioma classification developed within 1-12 weeks in 100% of the injected mice (Tchougounova et al, 2007). We use these oligodendrogliomas as our mouse tumor model. Additionally, Daoy medulloblastomas were used to model the migration of the most common childhood human brain tumor, while the U-87 MG and U-251 MG were used to model glioblastomas, the most common adult brain tumor. The design and characterization of our stand-alone bridged µLane system demonstrated sustained steady-state concentration gradients over 2-3 days while enabling the diffusivity measurement of 0.82 ± 0.01 X 10-6 cm2 / s for Dextran molecules having a molecular weight similar to growth factors examined here. A modified version of this device was then used to examine the migratory response of human MB-derived Daoy, glioblastomas, and neonatal mouse glial progenitors, which has led to the characterization of differential invasion patterns that each cell line utilizes when exposed to various growth factor concentration gradients. This data is fundamental for understanding how BTCs and GPCs use cytokines to communicate with each other and alter cellular functions, specifically migration. Additionally, we demonstrate EGF-induced Akt activation in the migration of MB-derived Daoy cells, and the induced recruitment GPCs towards picomolar concentrations of both HGF and TGF-α. We suggest based on our results that glial progenitors consisting of varying genetic background can migrate in very distinct patterns and may contribute to the selectivity of glioma recruitment/or progenitor sorting.
THE ROLE OF GLUTAMATE IN AXONAL PHYSIOLOGY
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The information within the spinal cord and peripheral nervous system propagates along the nerves in the form of Compound Action Potentials (CAP). Although CAPs were always considered to be steady signals, with constant amplitude and velocity as determined by the conductive properties of the nerves our data show that exogenous glutamate increased the CAP. This increase in CAP was blocked after the addition of the general glutamate receptor antagonist kynurenic acid, the specific glutamate receptor antagonist MK801 and CNQX and prevented when these experiments were performed in a calcium-free medium. The goal of this thesis was to examine the changes in axonal physiology in response to electrical stimulation and to pharmacological manipulation. We found that high frequency stimulation, or addition of exogenous glutamate (100 µM) increases the amplitude of compound action potentials (CAPs) in sciatic nerve preparations. These results were further extended and supported by immunohistochemical experiments showing that axolemma contains glutamate receptors (NMDA, AMPA/kainate and mGluR2), the excitatory amino acid transporter responsible for glutamate uptake (Excitatory Amino Acid Transporter-EAAT), and voltage-gated sodium and calcium channels. Thus, the axolemma of peripheral nerves expresses several proteins important for neuronal communication and modulation of the membrane excitability. Apparently, these proteins embedded into the axonal membrane, can under the influence of electrical stimulation or exogenous glutamate change membrane permeability and ionic conductance leading to an increase in the amplitude of the compound action potentials observed in our experiments. Our results demonstrate of existence of axonal plasticity expressed as a change in the amplitude of the action potential following periods of changed activity accompanied by release of neurotransmitters. Therefore we suggest a mechanism of the process whereby electrical stimulation leads to increased axonal activity and subsequent release of glutamate that through activation of the glutamate receptors results in changes in the amplitude of CAPs. We term this phenomenon as axonal plasticity, which would represent one of the forms of neuronal plasticity. Neuronal plasticity is defined as a treatment-induced change in the neuronal response in spite of unchanged strength of the test stimulation. This observation was long described as a property of central synapses and thought to be the basis of learning (Malenka, 1994). Axonal plasticity , would constitute exclusive property of the axon and could contribute together with synaptic plasticity to modification of the efficiency of neuronal connections. This type of plasticity would be fundamentally different from the synaptic plasticity expressed in CNS in the form of Long-Term Potentiation-LTP (Bliss and Collingridge, 1993), Long-Term Depression-LTD (Dudek et al; 1992), and Spike Timing Dependent Plasticity (STDP) (Markram et al., 1997) which has been intensively investigated for last several decades. We assume that high frequency electrical stimulation induces the release of glutamate from stimulated axons. Subsequent increase in the extracellular glutamate concentration would be responsible for observed increase in CAP. Increase in the amplitude of CAP may be a result of: An increase in the number of activated axons (recruitment), 2) and/or increase in the amplitudes of individual potentials generated by single axons. The mechanisms responsible for each of these changes are very different. In the case of recruitment one can suggest paracrine action of glutamate which released from group of axons would enhance the CAP of their neighbors. The increase in the action potential generated by individual axon could be due to a change in the threshold of this individual axon. Our novel data together with published results clearly indicate that in spite of prevailing notion about "all-or-nothing" property of the action potential, axons and action potentials are capable of conveying the information in an analog manner (Clark and Hausser 2006). Presented results convincingly demonstrate that the amplitude of subsequently generated action potentials can change in a way correlated with the frequency of stimulation, or pharmacological treatment. In both cases the change occurred gradually with each evoked action potential slightly larger than its predecessor. This indicates that the effect was building step by step as the intraaxonal mechanisms have been recruited to contribute to the final effect. We have also observed reduced latency and increased area of CAP after glutamate application. The most obvious explanation for both phenomena would be a recruitment of additional, fast conducting axons which would shorten the latency and increase the area of CAP. Simultaneously this would increase the duration of the entire CAP, as slower conducting axons which contributed to CAP before the treatment would be activated as well.
TARGET ZERO: WHY STATES CHOOSE TO ERADICATE INFECTIOUS DISEASES AND HOW THEY SUCCEED
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Realism has remained the dominant paradigm within international relations for most of the modern era, emphasizing the competitive nature of the international arena and the unlikeliness of states to within it to cooperate. The attempts and further still, successes, by states to eradicate infectious diseases--which remain among the most cooperative enterprises--present a number of challenges to realism's assumptions, particularly with respect to the unlikely world historical-times during which the eradication campaigns took place. As such, a two-part puzzle arises. First, why would states, which are natural competitors, cooperate to eradicate infectious diseases given structural and situational incentives not to do so? Second, when states choose to eradicate infectious diseases, what accounts for success? I tackle these questions in turn, proposing three factors: reputational benefits, rational self-interest, and the interplay of state and non-state actors, all of which, in addition to international institutions help explain the involvement and cooperation of state actors in eradication efforts, particularly at those critical periods. To answer the second question, I offer a five-point rubric which features necessary, if insufficient conditions for the success of any eradication campaign. They are: ways to cure, treat or manage the disease and its spread; monitoring programs; political will; community engagement; and agencies tasked, and adequately equipped to deal with the disease. I answer the proposed questions and apply both sets of factors using three case studies; they include the successful case of smallpox eradication, the first failed campaign against malaria of the 1950s and the modern ongoing effort, and the campaign against guinea worm disease today.
The effects of estrogen on carrageenan-induced nociceptive behaviors and inflammatory mediators in ovariectomized female mice
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Epidemiological studies have shown that pain perception is sexually dimorphic; females tend to experience greater sensitivity to painful stimuli and more chronic pain compared to males. Researchers believe that this dichotomy is caused by the distinct endocrinological profile of females. 17beta -estradiol has been shown to attenuate inflammatory behaviors in both the formalin and carrageenan (Cg) models of inflammation. Research also shows that estrogen affects many inflammatory mediators, including proinflammatory cytokines and prostaglandins (PG). Estrogen plays an important, yet complicated role, in inflammation, and little is known about the specific biochemical mechanisms involved. The objective of this study is to determine if, similar to rats, estrogen attenuates Cg-induced thermal hyperalgesia by altering cytokine or PG release. To that end, female OVX mice were pretreated with various doses of estradiol and injected with 1% Cg. Paw withdrawal latency was recorded prior to, 1 hour, and 5 hours after Cg-treatment in response to a low, medium, and high heat stimuli. Additional animals were treated with indomethacin, a COX blocker. High doses of estradiol caused an increase in nociceptive responses prior to and subsequent to Cg administration. This increase in these pain behaviors was not directly caused by an increase in proinflammatory cytokine levels or a decrease in anti-inflammatory cytokines levels. However, estradiol caused increases in cytokine levels in the untreated paw. Furthermore, treatment with indomethacin caused an attenuation of hyperalgesia. Additionally, indomethacin negated the difference between estradiol- and vehicle-treated mice, indicating that estrogen may interact with prostanoid synthesis. This effect, however, was not seen in the Cg-treated paw, suggesting that estradiol may be increasing hyperalgesia via another pathway as well. Taken together, our results suggest that estrogen's hyperalgesic effects are partly mediated through cytokine up-regulation and prostanoid synthesis, but the main mechanism of action still needs further investigation.
WIGNER HIGH-ELECTRON-CORRELATION REGIME OF NON-UNIFORM DENSITY SYSTEMS: A QUANTAL-DENSITY-FUNCTIONAL-THEORY STUDY
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ABSTRACT WIGNER HIGH-ELECTRON-CORRELATION REGIME OF NON-UNIFORM DENSITY SYSTEMS: A QUANTAL-DENSITY-FUNCTIONAL-THEORY STUDY by DOUGLAS M. ACHAN Advisor: Prof. Lou Massa The Wigner regime of a system of electrons in an external ﬁeld is characterized by a low electron density and a high electron-interaction energy relative to the kinetic energy. The low correlation regime is in turn described by a high electron density and an electron-interaction energy smaller than the kinetic energy. The Wigner regime of a nonuniform electron density system is investigated via quantal density functional theory (QDFT). Within QDFT, the contributions of electron correlations due to the Pauli exclusion principle, Coulomb repul- sion, and correlation-kinetic eﬀects are separately delineated and explicitly deﬁned. The nonuniform electron density system studied is that of Hooke's atom in the Wigner regime for which the exact wave function is derived. As such the results of the QDFT analysis are exact. It is observed that in comparison to the low correlation case, not only is the electron- interaction energy greater than the kinetic energy as a fraction of the total energy, but so are its individual Hartree, Pauli, and Coulomb components. The ionization potential as a fraction of the total energy too is greater. But most signiﬁcantly, in the Wigner regime, the correlation-kinetic energy as a fraction of both the electron-interaction and total energy is substantially greater than in the low correlation case. Hence, it is proposed that the Wigner regime now also be characterized by a high correlation-kinetic energy. The kinetic energy as a fraction of the total energy, however, is less than in the low correlation case. This fact and the high correlation-kinetic energy value in the Wigner regime is explained by the new concept of `quantal compression' of the kinetic energy density derived from QDFT. The corresponding results for the low correlation case are in turn a consequence of a `quantal decompression' of the kinetic energy density. From the QDFT analysis, the exact values for the Kohn-Sham theory `exchange-correlation' and `correlation' energy functionals of the density, and their respective functional derivatives are also obtained. These results ought to be of value in the construction and testing of new approximate energy functionals valid for the Wigner regime.
Interactions and Complexity in Multi-Agent Justification Logic
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We investigate the complexity of Justification Logic and Modal Logic when we allow multiple agents whose justifications affect each other – by including some combination of the axioms t :i φ → t :j φ and t :i φ → !t :j t :i φ (modal cases: [ ]i φ → [ ]j φ and [ ]i φ → [ ]j [ ]i φ ). We discover complexity jumps new for the field of Justification Logic: in addition to logics with their satisfiability problem in the second level of the polynomial hierarchy (as is the usual case until now), there are logics that have PSPACE-complete, EXP-complete and even NEXP-complete satisfiability problems. It is notable how the behavior of several of these justification logics mirrors the behavior of the corresponding multi-modal logics when we restrict modal formulas (in negation normal form) to use no diamonds. Thus we first study the complexity of such diamond-free modal logics and then we deduce complexity properties for the justification logic systems. On the other hand, it is similarly notable how certain lower complexity bounds – the NEXP-hardness bound and the general Sigma 2-hardness bound we present – are more dependent on the behavior of the justifications. The complexity results are interesting for Modal Logic as well, as we give hardness results that hold even for the diamond-free, 1-variable fragments of these multi-modal logics and then we determine the complexity of these logics in a general case.
Registered Sex Offenders in the Community: A Test of Agnew's General Strain Theory
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Over the past two decades, sexual offending and offenders have become a topic of interest among researchers, policymakers, and the public. Since the inception of Registration and Community Notification Laws (RCNLS), researchers have assessed the negative consequences associated with the laws and how they affect sex offenders in the community; however, no study has utilized a criminological framework to do so. Agnew's General Strain Theory, which should be able to account for all crime, suggests that when individuals do not achieve desired goals, have negative stimuli placed on them or positive stimuli taken away, they are more likely to engage in crime. These are conditioned by certain factors, such as coping strategies and self-esteem. This study will synthesize these two distinct fields of research to determine whether the negative consequences of RCNLSs lead to recidivism. In all, surveys were mailed to 4,500 sex offenders with (N=997) in Nebraska, (N=2086) and (N=1417) sex and violent offenders in Kansas and Montana, respectively. These states are similar in population and demographic aspects, though they differ in RCNLSs. Findings lend partial support to GST and suggest that, consistently, anger influences recidivism.
Infrastructure, Production, and Archive: American and Japanese Video Art Production of 1960s and 1970s
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Focusing a study on the infrastructure of artistic production and maintenance opens a space in which to examine the relationship between artistic inspiration and knowledge making, the occurrences and the writing of its history. In the case of the comparative study of the emergence of Japanese and American video art, common artistic technique employed may indicate motivations derived from the technical possibility of the video medium, while the study of infrastructure demonstrates how large-scale funding, formation of archives, the establishment of systems of distribution and channels of education affect the emergence and development of video art as a genre. This thesis analyzes the synchronous and productive rise of video art in the U.S. and Japan from mid-1960s through mid-1970s, while problematizing the systems of knowledge formation and cultural maintenance that produced a different reception of the histories. In reviewing the structure of cultural maintenance today, the digital field inspires an exploration of new avenues for models of infrastructure that is alternative to traditional institutional frameworks. The digital platform as a pedagogical tool, research resource, and discussion forum allows cross-linguistic understanding, networked scholarship, and open accessibility, suggesting an ideal method for knowledge making. Moreover, this thesis suggests the digital platform as a potential catalyst for a collaborative administration of archive and preservation of Japanese experimental film and video, proposing an alternative method of knowledge formation and cultural maintenance moving forward.
The Amphibious Public: A historical geography of municipal swimming and bathing New York City, 1870 - 2013
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Earth & Environmental Sciences
Since 1870, the city of New York has engaged in a project of building and maintaining enclosed sites for municipal bathing, including building floating `river baths' (1870 - 1942), indoor municipal baths (1901 - 1975), eleven enormous outdoor pools built with WPA funds (1936 - present), and outdoor pools of various sizes built under the Lindsay administration (1968 - present). This dissertation explores the changing rationale, over almost 150 years, for the municipal construction of public bathing places in New York City, and the ways in which the physical structures have taken on new social goals, meanings and ideals, both for patrons and for agents of municipal government over time. Each bathhouse and pool is a physical site that belongs to an infrastructural network, and is also bound up in its relationship to reigning ideas about what public space should encompass and for whom it should provide. Throughout, water has been attributed particular characteristics in order to mediate social life in public space, through programs of building, teaching and regulating. These are theorized in terms of public space and the public life that bring them together as a material, technological, symbolic whole. The municipal bathing project has resulted in corporeal publics over time, which produce public social life through the bodies of users, both real and ideal, through infrastructures that integrate materials, water, capital and political will. Contests over who belongs to the corporeal public and how it should be managed, based on race, gender and sexuality, class, and age, are mediated through shifting notions of hygiene and wellness in the urban setting. Research methods include archival research in New York City since 1870, including municipal records, other local archives, newspaper sources, and secondary histories; observation (and some participation) and interviews with the Harlem Honeys and Bears, an African-American senior citizen synchronized swim team; and comparative ethnography of outdoor pools in the summer, including extended participant observation at Kosciuszko Pool and McCarren Pool in Brooklyn, as well as interviews with Parks Department officials.
Building the New American Nation: The U.S. Army and Economic Development, 1787-1860
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This dissertation examines the Army's integral role in the early American political economy. Notwithstanding its small size, the Army proved to be a powerful instrument for promoting economic expansion and guiding the pattern and direction of development. The Army spurred development through two lines of activity: first, the traditional application of coercion and, second, by providing public goods that neither private actors nor state governments could supply. Considering the Army leads me to reconceptualize the early American state as a bifurcated entity: a state of the periphery, dominated by the Army, and a state of the center, in which the Army still influenced economic development but other public institutions also performed key development functions.