Now showing items 2347-2366 of 4336

• #### Mitochondrial Calcium Uptake: LETM1 and MICU1 Are Mitochondrial Proteins That Regulate Mitochondrial Calcium Homeostasis and Cellular Bioenergetics

Mitochondrial calcium (Ca2+) uptake has been studied for over five decades, with crucial insights into its underlying mechanisms enabled by development of the chemi-osmotic hypothesis and appreciation of the considerable voltage present across the inner mitochondrial membrane (ΔΨm) generated by proton pumping by the respiratory chain (Carafoli, 1987; Nicholls, 2005). However, the molecules that regulate mitochondrial Ca2+ uptake have only recently been identified (Jiang et. al., 2009; Perocchi et. al., 2010) and further work was needed to clarify how these molecules regulate mitochondrial Ca2+ uptake. Leucine Zipper EF hand containing Transmembrane Protein 1 (LETM1) acts as a regulator of mitochondrial Ca2+ uptake distinct from the mitochondrial Ca2+ uniporter (MCU) pathway (Jiang et. al., 2009). However, a controversy exists regarding the function of LETM1 (Nowikovsky et. al., 2004). Therefore, I asked if LETM1 played a role in mitochondrial Ca2+ uptake and if LETM1 regulated cellular bioenergetics and basal autophagy. To further characterize mitochondrial calcium uptake, we asked how Mitochondrial Calcium Uptake 1 (MICU1) regulates MCU activity by quantifying basal mitochondrial Ca2+ and MCU uptake rates in MICU1 ablated cells. The following work characterizes the molecules that regulate mitochondrial Ca2+ uptake and their mechanistic function on decoding calcium signals. Since LETM1 is the Ca2+/H+ antiporter, I hypothesize that alterations in LETM1 expression and activity will decrease mitochondrial Ca2+ uptake and will result in impaired mitochondrial bioenergetics. As a regulator of free intracellular Ca2+, mitochondrial Ca2+ uptake and the orchestra of its regulatory molecules have been implicated in many human diseases. Mitochondria act both upstream by regulating cytosolic Ca2+ concentration and as downstream effectors that respond to Ca2+ signals. Recently, LETM1 was proposed as a mitochondrial Ca2+/H+ antiporter (Jiang et. al., 2009); however characterization of the functional role of LETM1-mediated Ca2+ transfer remained unstudied. Therefore the specific aims of this project were to determine how LETM1 regulates Ca2+ homeostasis and bioenergetics under physiological settings. Secondly, this project aimed to characterize how LETM1-dependent Ca2+ signaling regulates ROS production and autophagy. The data presented here confirmed that LETM1 knockdown significantly impairs mitochondrial Ca2+ uptake. Furthermore, in-depth approaches including either deletion of EF-hand or mutation of critical EF-hand residues (D676A D688KLETM1) impaired histamine (GPCR agonist)-induced mitochondrial Ca2+ uptake. Knockdown of LETM1 resulted in bioenergetic collapse and promoted LC3-positive multilamellar vesicle formation, indicative of autophagy induction. Interestingly, knockdown of LETM1 significantly reduced complex IV but not complex I and complex II-mediated oxygen consumption rate (OCR). In contrast, cellular NADH and mitochondrial membrane potential (ΔΨm) were unaltered in both control and LETM1 knockdown cells. LETM1 has been implicated in formation of the supercomplexes of the electron transport chain (Tamai et. al., 2008). In support, these studies show that LETM1 knockdown results in increased reactive oxygen species (ROS) production. These results for the first time demonstrate that LETM1 controls cellular bioenergetics through regulation of mitochondrial Ca2+ and ROS. MICU1 was identified as an essential regulator of the mitochondrial Ca2+ uniporter (Perocchi et. al., 2010). Therefore, this project specifically aimed to determine how MICU1 regulates the mitochondrial Ca2+ uniporter. Interestingly, the data presented here suggest that MICU1 is not necessary for uniporter activity. Instead, loss of MICU1 caused mitochondria to constitutively load Ca2+ at rest which resulted in a host of cellular phenotypes. This result led to further questions on how MICU1 knockdown affects cellular bioenergetics and if MICU1 is essential for cell survival under stress. MICU1 ablation influenced pyruvate dehydrogenase activity and ROS production. Subsequent investigations demonstrated that increased basal ROS left cells poised to ceramide-induced cell death thereby suggesting the role of MICU1 in cell survival. Collectively, the data presented here show that MICU1 is necessary to control constitutive mitochondrial Ca2+ uptake during rest. This work demonstrates that LETM1 regulates a distinct mode of mitochondrial Ca2+ uptake pathway whereas MICU1 controls mitochondrial Ca2+ uniporter activity. Further studies are required to uncover the potential role of these two mitochondrial-resident Ca2+ regulators in health and disease.
• #### Mitochondrial DNA Diversity and its Determinants in the Southwest Pacific

The purpose of this study is to examine mitochondrial DNA variation in the Southwest Pacific and determine what factors contribute to the degree and patterning of the observed variation. Population variation is known to be influenced by factors including demographic history, natural selection, climate, isolation, island area/complexity, and population age, as older populations are generally more diverse. The groups compared are from three regions in the Southwest Pacific; (a) northeast New Guinea, (b) Manus in northern Island Melanesia and (c) Easter Island in eastern Polynesia. MtDNA surveys have revealed highly significant differences in molecular variance across these populations. According to traditional biogeographical theory, the likely determinants of these differences are (a) length of time since initial settlement, (b) the comparative isolation of particular islands or regions since settlement, and (c) the size and complexity of settlement areas. Evidence from archaeology and linguistics provides the necessary framework for the study. Detailed archaeological surveys for several of the study regions provides evidence for settlement dates as well as evidence for isolation and/or frequent contact with other areas, usually in the form of trade and translocation of animals and artifacts. Linguistics, though not as informative as archaeology for settlement dates, provides detailed evidence for isolation and/or contact in the form of language isolates, language families, borrowing and linguistic divergence. The mtDNA haplogroups found in this study belong to several documented haplogroups, some of Melanesian origin, and some of Southeast Asian origin. The distribution of mtDNA variants and the pattern and degree of variation was examined using Analysis of Molecular Variance, standard diversity measures and partial Mantel matrix correlations. There were strong positive correlations between insular area, isolation and degree of variation. There were also measurable differences between inland and coastal populations on the larger islands where diversity in the isolated inland populations was greater than diversity in the coastal population. While there was some confounding of the variables, the results of our analysis indicate that insular area/complexity and isolation influence the pattern of variance more than length of settlement time.
• #### Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-induced Endothelial Cell Activation

Lysophosphatidylcholines (LPCs) are a class of pro-inflammatory lipids that play important roles in atherogenesis. LPC activates endothelial cells (ECs) to upregulate adhesion molecules, cytokines and chemokines, which is the initiation step of atherogenesis. However, the mechanisms underlying LPC-triggered EC activation are not fully understood. Previously considered as the toxic by-products of cellular metabolism, mitochondrial reactive oxygen species (mtROS) are recently found to directly contribute to both the innate and adaptive immune responses. Here we tested a novel hypothesis that mtROS serve as signaling mediators for LPC-induced EC activation. Using electron spin resonance and flow cytometry with mtROS-specific fluorescence probe MitoSOX, we found that several LPC species including LPC 16:0, 18:0, and 18:1 induced mtROS in human primary aortic ECs (HAECs). Mechanistically, our analysis using confocal microscopy and Seahorse XF96 mitochondrial function analyzer showed that LPC induced mtROS via increasing mitochondrial calcium-mediated increase of mitochondrial respiration. In addition, we found that mtROS scavenger MitoTEMPO abolished LPC-induced EC activation by downregulating Intercellular adhesion molecule 1 (ICAM-1) in HAECs. Moreover, our analysis with mass spectrometer analysis of histone H3 lysine acetylation and electrophoretic mobility shift assay (EMSA) showed that MitoTEMPO acts by blocking LPC-induced histone H3 lysine 14 acetylation (H3K14ac) and nuclear translocation of pro-inflammatory transcription factor activator protein-1 (AP-1). Remarkably, all the above effects can be inhibited by anti-inflammatory cytokines interleukin (IL-35) and IL-10. Our results indicate that mtROS are responsible for LPC-induced EC activation, which can be inhibited by anti-inflammatory cytokines. MtROS targeting therapies and anti-inflammatory cytokines such as IL-35 may serve as novel therapeutic targets for vascular inflammation and cardiovascular diseases. The studies in this dissertation were supported by grants from the National Institutes of Health (NIH) funded to Dr. Xiao-Feng Yang.
• #### Mitochondrial response to axonal injury

The failure of axonal regeneration is due to myriad reasons both cell intrinsic and extrinsic. In this thesis, I sought to investigate an intrinsic reason for regeneration failure in the CNS. Specifically, I investigated the role of axonal mitochondria in the axonal response to injury. A viral vector (AAV) containing a mitochondrially targeted fluorescent protein (mitoDsRed) as well as fluorescently tagged LC3 (GFP-LC3), an autophagosomal marker, was injected into primary motor cortex, to label the corticospinal tract (CST), of adult rats. The axons of the CST were then injured by dorsal column lesion at C4-C5. We found that mitochondria in injured CST axons near the injury site are fragmented and fragmentation of mitochondria persists for two weeks before returning to pre-injury lengths. Fragmented mitochondria have consistently been shown to be dysfunctional and detrimental to cellular health. Interestingly, transection of axons within the sciatic nerve resulted in mitochondrial fission but did not result in the fragmentation of mitochondria. Inhibition of Drp1, the GTPase responsible for mitochondrial fission, using a specific pharmacological inhibitor (mDivi-1) blocked fragmentation. Additionally, it was determined that there is increased mitophagy in CST axons following spinal cord injury based on increased colocalization of mitochondria and LC3. In vitro models revealed that mitochondrial calcium uptake is necessary for injury induced mitochondrial fission, as inhibiting mitochondrial calcium uptake using RU360, a mitochondrial calcium uniporter inhibitor, prevented injury induced fission. This phenomenon was also observed in vivo. These studies indicate that following injury, both in vivo and in vitro, axonal mitochondria undergo increased fission, which may result in an ATP deficit that contributes to the lack of regeneration seen in CNS neurons.
• #### Mixed Use and Transit Proximity Premiums: Do Accessible, Multiple-Use Properties Generate Price Premiums?

Mixed-use properties have received increased attention over the last 15 years. There are many perceived benefits of mixed-use development, such as Smart Growth, sustainable development, and urban regentrification. The increased interest in mixed-use developments in suburban, less densely populated areas appears to be motivated by changing consumer preferences and the perceived success of these developments by real estate owners, developers, and governing agencies. Real estate developers, owners and investors have asserted that the financial performance and success of mixed-use projects is better than single-use properties. There is limited data or empirical evidence, in trade publications or academic journals, which supports or disproves this assertion. This research uses data from New York City’s five boroughs to empirically study the effects of a property’s use-type on the financial performance of commercial projects in order to determine if a “mixed-use premium” exists. Initial findings suggest that a property with multiple uses generate between an 8.5%–17% price premium on average, though the magnitude of the premium varies from borough to borough. Further, this research also examines the effects of transit proximity on commercial property values in Manhattan. Relevant stakeholders assume that being closer to public transportation will translate into higher market values. The existing literature is mixed, but there appears to be more evidence for a positive relationship between transit proximity and commercial property values. This study will examine the relationship between transit proximity and commercial property values. Preliminary, adding one subway station within a 0.25 miles radius results in a 14% increase in sales price. Further, a Mixed Use-Transit Proximity interaction variable was created which showed a positive, but non-significant relationship to commercial property values in Manhattan.
• #### Mixotrophy in Freshwater Foodwebs

Environmental heterogeneity in both space and time has significant repercussions for community structure and ecosystem processes. Dimictic lakes provide examples of vertically structured ecosystems that oscillate between stable and mixed thermal layers on a seasonal basis. Vertical patterns in abiotic conditions vary during both states, but with differing degrees of variation. For example, during summer thermal stratification there is high spatial heterogeneity in temperature, nutrients, dissolved oxygen and photosynthetically active radiation. The breakdown of stratification and subsequent mixing of the water column in fall greatly reduces the stability of the water column to a vertical gradient in light. Nutrients and biomass that were otherwise constrained to the depths are also suspended, leading to a boom in productivity. Freshwater lakes are teeming with microbial diversity that responds to the dynamic environment in a seemingly predictable manner. Although such patterns have been well studied for nanoplanktonic phototrophic and heterotrophic populations, less work has been done to integrate the influence of mixotrophic nutrition to the protistan assemblage. Phagotrophy by phytoplankton increases the complexity of nutrient and energy flow due to their dual functioning as producers and consumers. The role of mixotrophs in freshwater planktonic communities also varies depending on the relative balance between taxon-specific utilization of carbon and energy sources that ranges widely between phototrophy and heterotrophy. Therefore, the role of mixotrophy in the microbial food web is difficult to predict because functional types of mixotrophs along a gradient of nutritional strategies contribute differently to nutrient cycling and carbon sequestration. The overall objective of this work was to advance existing knowledge of the abundance and activity of phagotrophy phytoplankton in lacustrine systems. The incorporation of mixotrophy into the microbial food web requires the complement of physiological studies in culture (as described in chapter 2) and quantification of activity (including abundance and bacterivory) in relation to strict phototrophs and heterotrophs in situ (as described in chapter 3 and 4). Information on the physiological ecology of mixotrophic protists is crucial to understanding their role in planktonic food webs and influence on the dynamic microbial community structure in lake ecosystems. An understanding of the ecological functioning of lakes has ultimate consequences for management of water resources, particularly in the face of global climate change.
• #### MLL4-Menin Complex Inhibition Promotes Central Memory In CD8 CAR-T Cells

CAR-T cell immunotherapy is a highly efficacious treatment for CD19-positive hematological malignancies, however, some patients are non-responsive for reasons that are not well understood. Clinical efficacy has been correlated with long-term persistence, a propensity that can be predicted by the differentiation state of transplanted cells. Despite this, decades-old methods for expanding T cells have not been updated to prevent the deleterious effects of excessive differentiation in CAR-T cells. Uncoupling proliferation and differentiation is a long-held goal in the field of immunotherapy with both cytokines and pharmacological approaches being implemented to dissociate these parallel processes. Histone methyltransferases rewire transcriptional programs in T cells and simultaneously regulate multitudes of genes, making them attractive targets for modifying the proliferation-differentiation axis. Despite this, only a handful of studies have examined their role in regulating the transcriptional programs of human CD8+ T cells. MLL4 (encoded by KMT2B) belongs to the six-member group of MLL histone methyltransferases. MLL1, a paralog of MLL4, has been implicated in regulating the maintenance of IL-4 and GATA-3 expression in TH2 CD4 memory T cell populations, however the function of MLL4 in human CD8+ T cells is unknown. We report a critical role for MLL4 in the proliferation and differentiation of CD8+ T cells. CRISPR-Cas9-editing of MLL4 uncoupled the processes of proliferation and differentiation, increasing proliferation but maintaining central memory T cell (TCM)-like populations, allowing for the production of increased numbers of TCM-like CD62L+CD45RO+ cells. Pharmacologically inhibiting the MLL4-Menin complex with MI-2 during T cell expansion enriched the frequency of minimally differentiated TCM-like CD8+ T cells. TCM-associated CD62L, CCR7, CD122 and CD127 surface markers were upregulated and early memory-associated transcription factor TCF7, LEF1, EOMES, and FOXP1 transcripts were increased. CD8+ CAR-T cells expanded in the presence of MI-2 responded earlier, while improving both tumor burden and survival in a NSG xenograft model of human leukemia. This finding has important translational impact in improving the persistence and proliferative capacity of CD8+ CAR-T cells.
• #### Mobile Intimacy: Telepresence, mobile technology, and romantic relationships

Mobile media are quickly becoming primary sources of communication in everyday life. With this progress, comes the ability to experience an array of different degrees and types of presence. Individuals can be both in the physical presence of others as well as present with others at a distance by experiencing telepresence. This study examined the role of mobile media in the context of romantic relationships. It looked at the relationship between the senses of intimacy and telepresence as they were experienced by individuals. The theories of apparatgeist and perpetual contact were employed to describe the relationship between the nature of the technology, the associated behavior of its use, and the experience of various forms of telepresence. Interviews with fourteen participants provided the data analyzed in this qualitative study. These interviews were transcribed and used for a thematic analysis of presence and intimacy experience. The results describe a wide variance and nuanced reality of how individuals sense the presence of each other through mobile technology. These results contribute to an understanding of how individuals understand and talk about their experience of telepresence and also what it means to them in their personal lives.
• #### MOBILE POLLING AND SELF-REGULATION: HOW STUDENTS MAY BE TEMPTED WITH DISTRACTIONS

Mobile polling is a widely used classroom response system at the university level. The current study examines the predictors and outcomes of mobile polling including self-regulation and academic achievement. Furthermore, this study explores whether or not mobile polling benefits some students more than others, specifically those with higher levels of self-regulation. The data was collected from two separate University classrooms taught by the same teacher (n = 66). The first section of students were to use mobile polling software after taking their midterm exam and use the software for the remainder of the semester. The other section of students served as the control group and received the same instruction, Powerpoints, and assignments minus the usage of mobile polling. All students from both classes were given an 89 question survey known as the Barkley Deficits in Executive Function Scale (BDEFS) which measured their ability to self-regulate their behavior. A hierarchical regression model was used to find that mobile polling had no statistical significance on academic achievement at the end of the semester. The only significant predictor throughout the entire study was the initial achievement variable, which was the scores from the midterm exam. Another hierarchical regression model found that self-regulation, measured with the use of the BDEFS system, was not a significant predictor of academic achievement. When initial achievement was controlled for, the Overall EF score from the BDEFS system revealed that self-regulation had zero effect on the variance as denoted by R Square and the R Square change in the regression model. Supplemental analysis revealed that Overall EF is a significant predictor of academic achievement when a Repeated Measures ANOVA was used, though the R Square change was still low. Factor analysis was used to find which questions loaded together under five subscales, truncating the BDEFS system and revealing that Self-Restraint/Inhibition traits were a better predictor than the overall score from the BDEFS questionnaire yet was not a significant predictor of achievement. Finally, a 2 x 2 ANCOVA that investigated the interaction between high/low levels of Self-Regulation and usage of Mobile Polling and found that it did not significantly affect academic achievement. In fact, the highest mean came from the completely opposite group as expected, which was students in the control group with lower levels of self-regulation.
• #### Mobile Technologies and Consumer Insights

Mobile technology is changing the way consumers consume content and connect with others. At the same time, marketers admit that effectively implementing mobile targeting and promoting deals through mobile devices remains a challenge. To address these challenges and reveal consumer insights in the mobile marketing space, I propose a research stream via three essays that investigate the contextual factors that influence consumer receptivity to mobile messages. One of these factors is environmental contexts, such as the crowdedness of a consumer's environment, which is the focus of the first essay. Another factor is the context of social cues and the framing of the mobile message itself, which is the focus of the second essay. Yet another factor is whether the promoted product has social value beyond the consumption value itself, which is the focus of the third essay. How contextual factors may influence consumer receptivity to targeted mobile promotions is complex and is explored in detail in the following studies.
• #### Model-Free Variable Selection For Two Groups of Variables

In this dissertation we introduce two variable selection procedures for multivariate responses. Our procedures are based on sufficient dimension reduction concepts and are model-free. In the first procedure we consider the dual marginal coordinate hypotheses, where the role of the predictor and the response is not important. Motivated by canonical correlation analysis (CCA), we propose a CCA-based test for the dual marginal coordinate hypotheses, and devise a joint backward selection algorithm for dual model-free variable selection. The second procedure is based on ordinary least squares (OLS). We derive and study the asymptotic properties of the OLS-based test under the normality assumption of the predictors as well as an asymmetry assumption. When these assumptions are violated, the asymptotic test with elliptical trimming and clustering is still valid with desirable numerical performances. A backward selection algorithm for the predictor is also provided for the OLS-based test. The performances of the proposed tests and the variable selection procedures are evaluated through synthetic examples and a real data analysis.
• #### Model-Free Variable Selection through Sufficient Dimension Reduction

In this thesis we draw upon the natural connection between the fields of sufficient dimension reduction and variable selection to develop new theory and methods for model-free variable selection. After developing the natural connection between sufficient dimension reduction and model-free variable selection we introduce two approaches to select independent variables important to predicting the response variable without making any assumptions about the function form of the relationship between predictor and response. The first is a stepwise procedure and the second takes a penalized approach. Both are rooted in ordinary least squares regression but with modifications to facilitate model-free variable selection. We also introduce a set of transformations for model-free variable selection. Finally we develop a stepwise procedure that is able to select interaction terms in the model-free setting. We show the effectiveness of these methods through simulation studies and an analysis of real data.
• #### MODELING AND STATISTICAL CONTROL OF A GIMBALED LASER TARGET SYSTEM

The space-based solar power system is an alternative to the ground-based solar power system because of its round-the-clock availability. For the space-based solar power transmission, the accurate pointing of a laser from space to ground poses a challenging control task. A gimbaled laser target system, which is used for pointing laser to a target, is a test bench for such a transmission system. The objective of this research is to determine the optimal controller for the gimbaled laser target system in terms of pointing error and error variation. In order to achieve the objective, we modeled the gimbaled laser target system, simulated the model with the controllers, and tested them on the test bench. In this thesis, we developed a mathematical model of a two-axis gimbaled laser target system. The model consists of a pitch-yaw gimbal for the dynamic laser motion, brushless dc motors for actuating the gimbal, and an image-based position sensor. We used a Proportional-Integral-Derivative (PID) controller as the basis for the performance comparison since it is the most commonly used control method in the industry. Then we compared the PID controller with two statistical control methods - Linear Quadratic Gaussian (LQG), and Minimal Cost Variance (MCV) optimal controllers. We evaluated the pointing performance of the controllers by measuring the mean and the standard deviation of the pointing error. The simulation results indicated that the statistical controllers perform better than the PID controller under Gaussian disturbances. Between the statistical controllers, the LQG method had the smaller pointing error, while the MCV method had the smaller standard deviation of the pointing error. We then implemented the PID, LQG, and MCV controllers in an off-the-shelf dSPACE digital signal processing controller board, and tested the controllers on the test bench in a real time environment. The experimental results showed that the LQG method decreased the mean pointing error by 46.28% compared to the PID method. The LQG method reduced the standard deviation of pointing error by 47.85% compared to the PID method. The MCV method reduced the standard deviation of the pointing error by 53.09% compared to the LQG method. Both the simulation and experimental results showed that the MCV controller improved the pointing error variation performance over the LQG controller significantly, while slightly degrading the pointing error performance of the gimbaled laser target system. Experimental results indicate that the statistical controllers will provide a design parameter either to improve the mean pointing error or the standard deviation of the pointing error for the gimbaled laser target system. Subsequently, we believe that the statistical controllers will improve the space-based solar power transmission efficiency.

• #### MODELING CONSUMERS' CO-CREATION IN TOURISM INNOVATION

The primary purpose of this study is two-fold. First, this study proposes a model to explain the factors predicting consumers' intention to co-create based on the theory of planned behavior. More specifically, this study investigates how perceived benefits, perceived costs, subjective norms, and ability to co-create influence consumers' behavioral intentions toward tourism co-creation. Second, this study seeks to examine differences in the relationships among different constructs in the models in accordance with different contextual settings. To gain a richer understanding of consumers' co-creation behaviors, the study examines the impacts of different co-creation settings as moderating effects among the model's constructs. By using 2 X 2 factorial between-subjects design, two co-creation scale categories (radical and incremental) are matched with two co-creation intensity categories (high involvement and low involvement). The results of this study suggest that proposed antecedent constructs (perceived benefits, perceived costs, subjective norms, and abilities to co-create) are strong indicators to predict consumers' intention to co-create. The study also finds that different co-creation settings have strong moderating effects on the relationships among constructs in the co-creation intention model. The insights from the study results are discussed and important practical implications and subjects for further future research are presented.
• #### Modeling of liquid water and ionic solutions by first-principles simulations

Water is one of the most important materials and has enormous impacts on life. Due to its delicate Hydrogen bond (H-bond) network, water shows various anomalous properties which has not been fully illuminated. Advanced experimental methods, such as scattering experiments and various spectroscopy techniques, have been developed and applied to study the nature of H-bond in liquid water. On the other hand, ab initio molecular dynamics (AIMD) have been widely adopted as an important theoretical tool to provide microscopic information of water on a sub-picosecond timescale. Recent AIMD studies based on the strongly constrained and appropriately normed (SCAN) exchange correlation functional yield an excellent description of the structural, electronic, and dynamic properties of liquid water. In this dissertation, we will focus on studying the structural, electronic and dynamic properties of liquid water as well as the modeling of the hydration structures of ions in aqueous solutions, using AIMD with potential energy surface provided by the novel SCAN functional. In the first work we represent an accurately predicted infrared spectrum of liquid water and show how the improvements are connected to the description of the underlying H-bond network. The second work mainly focusing on modeling the nuclear quantum effects (NQEs) and isotope effect of liquid water with a force field model based on artificial neural network, where qualitative agreements with experimental observations are achieved. In the third work, we study the isotope effect on the x-ray absorption spectra of liquid and attribute observed differences to the structural distinctions between light and heavy water as mentioned in the previous work. And in the last two projects, we systematically show the necessity of including NQEs of the hydrogen atom when modeling chloride ionic solution. Prominent changes in the hydration structure as well as electronic structure can be identified when NQEs are taken into consideration.
• #### MODELING OF THERMO-MECHANICAL BEHAVIOR OF NITINOL ACTUATOR FOR SMART NEEDLE APPLICATION

A large and increasing number of cancer interventions, including both diagnosis and therapy, involve precise placement of needles, which is extremely difficult. This challenge is due to lack of proper actuation of the needle (i.e., actuated from the proximal end, which is far away from the needle tip). To overcome this challenge, we propose to bend the needle using a smart actuator that applies bending forces on the needle body; thereby, improving the navigation of the needle. The smart actuator is designed with shape memory alloy (SMA) wires, namely Nitinol, due to their unique properties such as super-elasticity, shape memory effect, and biocompatibility. For accurate steering of the smart needle, there is a need to understand Nitinol thermo-mechanical behaviors. Various existing SMA constitutive models were investigated and compared. Since SMA is used as an actuator in this project, only one dimensional constitutive models are considered. Two distinct models with different phase transformation kinetic approaches were chosen. The first model was proposed by Terriault and Brailovski (J. Intell. Mat. Systems Structures, 2011) using a modified one dimensional Likhachev formulation. The second model was developed by Brinson (J. Intell. Mat. Systems Structures , 1993). Since all SMA constitutive models are empirically based, several important materials' constants such as Phase Transformation Temperatures are needed. The four Transformation Temperatures are: Martensite start (Ms), Martensite finish (Mf), Austenite start (As), Austenite finish (Af). Differential Scanning Calorimetry (DSC) was used to obtain these constants. These temperatures are also influenced by stress, defined by the Clausius-Clayperon coefficients. The coefficients were obtained by measuring Nitinol temperature and displacement response under various constant stress conditions. In order to study its actuation behavior, Nitinol wires under constant strain configuration and resistance heating were tested for their force response. The thermo-mechanical responses were then compared with numerical simulations. While Terriault and Brailovski resistance heating formulation agrees strongly with temperature responses, the model cannot be used to simulate the actuator mechanical responses. Brinson model simulations of the force responses were found to agree well with experimental results. In conclusion, Terriault and Brailovski resistance heating formulation should be coupled with Brinson model to accurately simulate Nitinol actuation behavior for the smart needle.
• #### MODELING THE OPTICAL SPECTROSCOPY OF AGGREGATES OF DIPOLAR AND QUADRUPOLAR DYE MOLECULES

The field of organic electronics is currently receiving a great deal of attention from theoretical and experimental chemists, physicists and material scientists, especially regarding energy transport and optical behavior. The conventional understanding of photophysical and transport processes in organic aggregates, films and crystals is based on the Frenkel exciton model. However, despite its success, the Frenkel model cannot properly account for several important properties of aggregates of highly polarizable chromophores, such as the charge-transfer character of the ground and excited states (and their associated dipole moments) which can change in response to intermolecular interactions. The essential state model (ESM) is investigated as an alternative to the Frenkel exciton model for understanding absorption and emission in aggregates of polar and high-polarizable chromophores. Polar and high-polarizable chromophores consist of donor and acceptor components linked by a c-conjugated bridge. In thiswork, the ESM is expanded to include local vibronic coupling via an Holsteinstyle Hamiltonian. Emphasis is placed on the divergences from the conventional Kasha model which is based on the Frenkel exciton Hamiltonian and is commonly used to understand the relationship between molecular packing and photophysical properties. Divergences between the current approach and the Kasha model are thoroughly explored for the DA dimers in the weak and strong intermolecular coupling limits. Vibronic signatures which reveal information about molecular packing are compared to those derived from Frenkel exciton theory Specific applications include Davydov splitting in covalently bonded squaraine (DAD) complexes and the general photophysical response of dimers of DA chromophores such as merocyanines dyes.
• #### Modeling Volatility in Option Pricing with Applications

The focus of this dissertation is modeling volatility in option pricing by the Black-Scholes formula. A major drawback of the formula is that the returns from assets are assumed to have constant volatility over time. The empirical evidence is overwhelmingly against it. In this dissertation, we allow random volatility for estimating call option prices by Black-Scholes formula and by Monte Carlo simulation. The Black-Scholes formula follows from an assumption that assets evolve according to a Geometric Brownian Motion with constant volatility. This dissertation allows time-varying random volatility in the Geometric Brownian Motion to outline a proof of the formula, thus addressing this drawback. To estimate option prices with the Black-Scholes, the dissertation considers its expectation with respect to two potential probability models of random volatility. Unfortunately, a closed form expression of the expectation of the formula for computing the option prices is intractable. Then the dissertation settles with using an approximation which to its credit incorporates in it the kurtosis of the probability model of random volatility. To our knowledge, option pricing methods in literature do not incorporate kurtosis information. The option pricing with random volatility is pursued for two stochastic volatility models. One model is a member of generalized auto regressive conditional heteroscedasticity (GARCH). The second is a member of Stochastic Volatility models. For each model, estimation of their parameters is outlined. Two real financial series data are then used to illustrate estimation of the option prices, and compared them with those from the Black-Scholes formula with constant volatility. Motivated by a Monte Carlo procedure in the literature for option pricing when the volatility follows a GARCH model, this dissertation lays a foundation for future research to simulate option prices when the random volatility is assumed to follow a Stochastic Volatility model instead of GARCH.
• #### Modeling, Design, and Control of Heterogeneous Inverter-Based Power Distribution Networks with High DER Penetration

Nowadays, a high penetration level of distributed energy resources (DERs), such as renewables, energy storage, and electric vehicles, are integrated into modern electric power grids, especially power distribution sections, through inverter-based interfaces. Depending on the interfacing technologies and capacities of different DERs, the power distribution networks with inverter-based DERs feature different characteristics, which motivates this dissertation to investigate the modeling, design, and control of heterogeneous inverter-based power distribution networks. First, an example of a DER power distribution network, a PV system, is studied and an optimal design framework for PV systems is proposed considering two objectives, levelized cost of energy (LCOE) and power density (PD). Second, to further improve the performance of the inverter-based distribution networks, the harmonic characteristics of a generic grid-interactive inverter is investigated. A holistic mathematical harmonic state space (M-HSS) model of a grid-interactive inverter is derived to calculate each order of harmonics of grid-connected current. Moreover, to further reduce the computation burden caused by repetitive usage of the mathematical HSS model during the optimal design process, a data-driven HSS (D-HSS) modeling method is proposed by incorporating the data-driven techniques into the aforementioned M-HSS modeling. Based on the M- and D-HSS models, an effective optimal design framework is proposed to determine the closed-loop inverter system parameters. Furthermore, due to the increasing deployment of power electronic devices and nonlinear loads, power grids in the distribution network typically present certain degrees of low and/or high order harmonics. Thus, a harmonic compensation control (HCC) scheme is proposed to ensure that the inverter-based distribution network could provide high-quality grid current injection under distorted grid voltage conditions. Additionally, an energy-stored quasi-Z source converter (qZSC) based interlink converter is proposed for hybrid AC/DC microgrids in the distribution networks. The proposed system not only interlinks both AC and DC sub-microgrids but also incorporates energy storage. The operating principle, operating states as well as control schemes are presented in detail. Finally, another DER power distribution network, a medium voltage DC (MVDC) distribution network, is investigated in the study. First, the dissertation proposes an effective fault management scheme for MVDC networks, which includes a virtual-impedance-based fault current limiter (VI-FCL) on the DC side and a positive-negative-sequence (PNS) control scheme on the AC side. Then, a detailed 2$\omega$ mathematical model of the MVDC network under unbalanced AC voltage conditions is derived to investigate how the 2$\omega$ ripple propagates across the network and the corresponding control scheme is investigated to mitigate the 2$\omega$ ripple.