Strongly Correlated Systems Under High Magnetic Field: A Mixed Landau Levels Description for Fractional Quantum Hall Effect

Bandyopadhyay, Sumanta Washington University in St. Louis ProQuest Disser 2019 해외박사(DDOD)

Strong correlation among electrons under high magnetic field gives rise to an entirely new arena of emergent physics, namely fractional quantum Hall effect. Such systems have entirely different elementary degrees of freedom and generally, demand non-perturbative approaches to develop a better understanding. In the literature, there are several analytical methodologies and numerical toolkits available to study such a system. Clustering of zeros, parent Hamiltonian, off-diagonal order parameter, parton construction, matrix product states are to be named among a few of those popular methodologies in the existing literature. Most of these methods work well in the lowest Landau level or holomorphic wavefunction framework. It is, however, imperative to develop such methodology to study systems with Landau levels mixing to study more exotic as well as experimentally relevant states. In this work, we have developed particular methodologies, which denounce the traditional importance of the analytic properties of first quantized model wavefunction thereby extend the existing parent Hamiltonian, topological order-parameter, matrix product states descriptions to mixed Landau level systems. Such extension produces a deeper, compact and holistic understanding of universal physics of exotic phases in strongly correlated systems from the microscopic viewpoint, as well as produces interesting new results. Our second quantized/ non-analytic approach allows us to construct the ``entangled Pauli principle", a guidebook to extract universal/topological properties such as braiding statistics, fractional charge quantization, topological degeneracy of the ground states starting from a relatively simple many-body wavefunction, ``root pattern" of fractional quantum Hall state. Such an entangled Pauli principle can be derived from a microscopic parent Hamiltonian setting, thereby provide us a potential tool to probe the non-universal physics in quantum Hall fluids as well. Essentially, entangled Pauli principle is the ``DNA" of fractional quantum Hall states. Using this guiding principle, we have shown ground states with non-abelian excitations, such as Majorana fermion or Fibonacci fermion can be stabilized for two-particle interaction. Fibonacci fermion supports universal quantum gates, thereby a potential candidate for the topologically protected universal quantum computer. Entangled Pauli principle, along with a recently developed topological order parameter for composite fermions, gives rise to Parent Hamiltonian description for composite fermions as well.

Adiabatic Dark Matter Density Cusps Around Supermassive Black Holes and Dark Matter Detection

Medeiros da Rosa, Augusto Washington University in St. Louis ProQuest Disser 2019 해외박사(DDOD)

The growth of a black hole surrounded by dark matter can lead to a significant enhancement of the dark matter density close to the hole. We investigate this effect, focusing on the phenomenologically interesting case where the black hole is supermassive and is embedded in a galactic dark matter halo, although the formalism developed does not depend on that fact. Due to the enhanced gravitational potential, the dark matter will tend to cluster around the black hole. The precise details of this clustering will, in general, depend on the formation process of the black hole. However, if the black hole grows slowly with respect to the orbital timescales of the local galactic potential, the density cusp only depends on the black hole's mass and spin, as well as on the local distribution of orbits.The density cusp generated by the growing black hole is called an adiabatic spike. In the context of dark matter density cusps, these spikes were first investigated by Gondolo and Silk (1999), using a phase space analysis. General relativistic effects originating from the black hole's mass were calculated by Sadeghian, Ferrer, and Will (2013), revealing an enhancement of the density in the spike. Our work extends this calculation to include the effects of spin. We find a further enhancement to the spike that is strongly dependent on the black hole's spin parameter, meaning that it cannot be ignored for rapidly spinning black holes. We estimate its impact in local annihilation rates for two particular physical processes: particle dark matter annihilation in the s-channel, and the merger rate of binaries composed of primordial black holes in the local universe. We also present a derivation of the two-body collision rate per four-volume in terms of the phase space distribution that can be used in any coordinate system.

Development of Novel Tumor-Targeted Compounds for Boron Neutron Capture Therapy

Luderer, Micah John Washington University in St. Louis ProQuest Disser 2019 해외박사(DDOD)

Glioblastoma multiforme (GBM) represents the most common primary brain tumor among adults. Despite surgical resection and aggressive chemoradiotherapy regimens, the current 2- and 5-year survival rates are only 27% and 9.8%, respectively. The low survival stems from the poor response to conventional therapy and underscores the critical need to develop new therapeutic approaches for GBM treatment. The high recurrence rate observed in GBM is in part attributed to the hypoxic (poorly oxygenated) tumor microenvironment. Hypoxic tumor conditions have been shown to increase metastasis, promote angiogenesis, and confer resistance to chemotherapy and radiation. Hypoxic tissues are inherently radiation resistant due to a diminished oxygen enhancement effect. Additionally, limited diffusion of oxygen and small molecules to hypoxic tissues mitigates the efficacy of chemotherapeutics. Therefore, due to its unique mechanism of cell death, boron neutron capture therapy (BNCT) has the potential to become an alternative treatment modality for cancer patients where radiation and chemotherapy have fallen short. However, before the full clinical potential of BNCT is realized, there is a dire need to either develop novel tumor-targeted compounds or improve the localized delivery of existing BNCT agents. The work outlined in this dissertation aims to address both these needs. First, a series of novel boronated compounds have been synthesized capable of targeting the hypoxic (and often therapy resistant) tumor microenvironment. Second, the local tumor delivery of several boronated agents has been improved utilizing a thermal sensitive liposome delivery system. BNCT utilizes the nuclear fission reaction that occurs when a boron-10 isotope (10B) captures a neutron. Upon 10B neutron capture, the resulting unstable 11B isotope undergoes a nuclear fission reaction (10B(n,alpha,gamma)7Li) to release an alpha particle (4He), lithium-7 (7Li) ion and gamma radiation. The generated particles have a limited path length of approximately 5-10 microns, thereby localizing the cytotoxic effect. Therefore, the biggest treatment hurdle for BNCT is the requirement to preferentially deliver boron to the tumor with minimal accumulation in the surrounding normal tissue. Therefore, we hypothesized that the hypoxic tumor microenvironment could be exploited to improve preferential delivery of boronated compounds to the tumor. To begin the dissertation, a novel boronated 2-nitroimidazole derivative (B-381) has been synthesized in a single step reaction. It has long been recognized that 2-nitroimidazole derivatives have preferential retention in hypoxic cells compared to normoxic cells. Therefore, we hypothesized that B-381 would have preferential retention in hypoxic glioma cells by exploiting the unique metabolism and retention of 2-nitroimidazoles in hypoxia. Towards this end, the cellular uptake of B-381 in D54 glioma cells was evaluated in vitroo and in vivo compared to 4-borono-L-phenylalanine (BPA), the most commonly investigated agent in BNCT clinical trials. Unlike BPA, B-381 illustrated preferential retention in hypoxic glioma cells compared to normoxic glioma cells in vitro. in vivo, B-381 illustrated significantly higher long-term tumor retention compared to BPA, with 9.5-fold and 6.5-fold higher boron levels at 24 and 48 h, respectively. While these initial studies supported the unique retention of B-381 in hypoxic cells, it was desirable to improve the total boron content delivered to the tumor. To further improve total boron content delivered to the tumor, thermal sensitive liposomes (TSLs) were investigated. A DPPC/DSPC/DSPE-PEG2000 /Cholesterol TSL was designed capable of having a stable drug payload at 37°C while releasing >90% of the drug payload at 42°C. Therefore, by locally inducing mild hyperthermia in vivo (42-43°C), it is possible to trigger a localized release of boronated drug within the tumor vasculature. Using both B-381 and BPA, TSLs can significantly improve tumor boron delivery at 42°C compared to normal tissue temperature (37°C). In summary, B-381 is effectively administered as both a free agent or incorporated into a thermal sensitive liposome formulation. B-381 represents a new class of BNCT agents in which their selectivity to tumors is based on a hypoxic tumor metabolism. Further studies are warranted to evaluate boronated 2-nitroimidazoles as well as boron-containing thermal sensitive liposomes for future BNCT clinical trials.

Nanoparticle T Cell Engagers as a Modular Platform for Cancer Immunotherapy

Alhallak, Kinan Washington University in St. Louis ProQuest Disser 2021 해외박사(DDOD)

Enantioselective Synthesis of β-Amino Acid Derivatives Using Amidine-Based and Bifunctional Organocatalysts

Straub, Matthew Robert Washington University in St. Louis ProQuest Disser 2021 해외박사(DDOD)

Method Development for Enhancing Sensitivity of Dynamic Nuclear Polarization Nuclear Magnetic Resonance Spectroscopy for Structural Studies of PKC-Drug Interactions

Judge, Patrick Terrence Washington University in St. Louis ProQuest Disser 2021 해외박사(DDOD)

Exploring Contextual Differences in Environment and Policy Strategies to Promote Physical Activity in Disadvantaged Communities

Serrano, Natalicio Hector Washington University in St. Louis ProQuest Disser 2021 해외박사(DDOD)

Etv2/Myct1 Axis in the Regulation of Tumor Angiogenesis and Anti-Tumor Immunity

Kabir, Ashraf Ul Washington University in St. Louis ProQuest Disser 2021 해외박사(DDOD)

Angiogenesis is a critical determinant of neoplastic growth and metastatic spread. As such, anti-angiogenic approaches have long been tried to throttle down tumor progression. However, current anti-angiogenic treatments so far have produced modest clinical benefits. Further in-depth research has provided rationales behind these disappointing and apparent perplexing clinical outcomes. It is now established that VEGF (vascular endothelial growth factor) and other prominent current angiogenic targets are neither specific to the vascular system nor the pathological conditions explaining the sub-optimal angiogenic control following the existing treatments. This suggests that anti-angiogenesis could still be a viable strategy for cancer patients should there are targets exclusive for tumor angiogenesis. The goal for my Ph.D. dissertation has been to identify novel angiogenic targets and their mechanism(s) of action in controlling tumor angiogenesis and growth.In aim 1, I have demonstrated that ETS transcription factor Etv2, which is critical for the endothelial and hematopoietic development exclusively in the developmental phase but stays silent in the adult phase, is reactivated in the endothelium of both the human cancers and mouse models of tumors. Etv2 deficiency renders the tumor vasculature similar to normal vessels and reduces tumor growth. Oxidative stress in the tumor environment is likely the driver to initiate Etv2 expression in the endothelial cells.Despite being a promising and exclusive target for tumor angiogenesis, it is challenging to utilize Etv2 as a therapeutic target because transcription factors are generally considered non-druggable. To address this, in aim 2, I have identified Myct1, a direct downstream target of Etv2, as a novel and endothelial-specific angiogenic gene. MYCT1 is a cell membrane-localized protein that makes it targetable by antibody-mediated approaches. Myct1 deficient endothelial cells lose migratory angiogenic phenotype in vitro and demonstrate normalized vascular functions in the in vivo tumor models. Moreover, Myct1 deficiency promotes an anti-tumor immune microenvironment that leads to limited tumor growth. Combined Myct1 targeting drastically improves the outcome of the anti-PD1 immunotherapy in the mouse models.The data presented in this dissertation have collectively identified the Etv2-Myct1 axis as a novel endothelial-specific regulator of tumor angiogenesis and tumor immunity. Myct1-targeted anti-angiogenic treatment could provide significantly better outcomes compared to the existing treatments, especially in combination with the immune checkpoint blockade immunotherapy.

The Immunoregulation of Autoimmune Diabetes

Hu, Hao Washington University in St. Louis ProQuest Disser 2021 해외박사(DDOD)

Examining Mental Health in Northern Haiti

Galvin, Michael Washington University in St. Louis ProQuest Disser 2021 해외박사(DDOD)

Mental health is a severely neglected field in low- and middle-income countries globally. Populations in countries such as Haiti demonstrate a high level of need for mental health services despite a lack of services and trained professionals. In addition to the dearth of biomedical services, local belief systems and explanatory models lead a majority of the population to rely on traditional medicine as their first option for care.The goal of this dissertation is to characterize mental health beliefs, practices, and services in northern Haiti by examining the relationship between traditional beliefs and mental illness, assessing the impact of traumatic events on mental and physical health, and identifying predictors of mental health outcomes. Using a mixed-methods approach, this dissertation utilized in-depth interviews, focus group discussions, as well as anxiety, depression, and functionality scales to assess the status of mental health care in early 21st century northern Haiti.Study findings indicate that mental illness is strongly impacted by traumatic events experienced in the context of society-scale crises, which have a significant effect on physical and mental health. Ongoing socio-political crises in particular result in high levels of violence and disorder which affect population- and individual-level mental health. Culturally-competent, evidence-based mental health services, such as those offered at Sant Sante Mantal Mon Pele (SSMMP) represent a unique opportunity for treatment for those suffering from mental illness in this region. However, the vast majority of patients requiring mental health care first seek treatment from traditional healers such as Vodou priests, whose approach within the Vodou cosmology differs significantly from the biomedical model. Vodou priests use a variety of means to treat patients suffering from mental illness including prayer, leaves for teas and baths, as well as combinations of perfumes, rum, human remains and other powdered concoctions. Additionally, until structural factors that result in entrenched poverty, violence, and political and social chaos can be addressed, already high levels of trauma, and poor physical and mental health, will likely continue to rise. Future research could focus on how to build and expand biomedical mental health services that are culturally-adapted to local explanatory models, and find ways to sustainably collaborate with traditional healers that avoid conflict.