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Palmer, Benjamin CliveSensitization Effects on Environmentally Enhanced Cracking of 5XXX Series Alloys: Macro and Mesoscale Observations
Master of Sciences (Engineering), Case Western Reserve University, 2017, Materials Science and Engineering
The focus of this study was on the tensile behavior and damage development in 5083- H131 Al-Mg alloy sensitized to different levels. Samples were tested in the as-received state, after sensitization at 175°C for 100hrs, or 80°C for >500hrs. Tensile testing was conducted under moderate (50%RH) or low (<1%RH) humidity environments to determine the environmental effects on the mechanical behavior of the material. Three different deformation/fracture modes were present depending on the sensitization level and testing environment. Interrupted tensile tests and microscopy revealed that strain was more heterogeneously distributed in the highly sensitized specimens compared to the as-received ones. Differential scanning calorimetry was also performed as a means of determining the degree of sensitization of specimens thermally exposed at temperatures from 60-175°C. This technique was able to detect the presence of Mg-rich phase(s) at thermal exposures as low as 60°C, though it has quantitative limits due to the resolution limit.

Committee:

John Lewandowski, Dr. (Advisor); David Schwam, Dr. (Committee Member); Clare Rimnac, Dr. (Committee Member)

Subjects:

Materials Science; Mechanical Engineering

Keywords:

Environment-enhanced-cracking; Stress corrosion cracking; 3-D tomography; Aluminum-magnesium alloys; Differential scanning calorimetry

Chirieleison, Steven MorrowXIAP-MEDIATED INNATE IMMUNE SIGNALING IN INFLAMMATORY BOWEL DISEASE
Doctor of Philosophy, Case Western Reserve University, 2017, Pathology
Inflammatory bowel disease (IBD) encompasses a heterogeneous group of autoinflammatory disorders of the gastrointestinal tract. Collectively, IBD afflicts over one million Americans and is one of only a few diseases with rising incidence. IBD patients suffer from a number of symptoms and sequelae including severe abdominal pain, bloody diarrhea, anemia, malnutrition, failure to thrive, colonic fistulas and strictures, and a significantly increased risk for the development of colonic cancer. While the etiology of IBD is enigmatic, clinical sequencing has brought to light the important role of the innate immune system in the pathology of IBD. Recently, sequencing of pediatric IBD patients has uncovered mutations to the X-linked inhibitor of apoptosis (XIAP) protein. The work presented here highlights the molecular role of XIAP mutation in mediating innate immune signaling defects that contribute to the pathogenesis of inflammatory bowel disease. It confirms the cognate kinase of XIAP, RIPK2 as a unique pharmacologic target using a synthetic approach. It identifies the consequence of patient-sourced XIAP mutations, which show both loss of NOD2 signaling and cell death susceptibility. Lastly, it outlines a set of experiments to identify novel XIAP-regulated pathways and features to continue unraveling XIAP’s role in IBD. Collectively, this work provides not only new insight into the pathogenesis of XIAP-driven IBD, but also provides a platform for future efforts aimed at investigation into mechanisms of inflammatory disease driven by protein mutation and at pharmacologic discovery for disease intervention.

Committee:

Parameswaran Ramakrishnan, Dr, (Committee Chair); Christine McDonald, Dr. (Committee Member); George Dubyak, Dr. (Committee Member); Xiaoxia Li, Dr. (Committee Member); Derek Abbott, Dr. (Committee Member); Clive Hamlin, Dr. (Committee Member)

Subjects:

Biochemistry; Immunology; Molecular Biology

Whitson, Jeremy ALens Adaptation to Glutathione Deficiency: Implications for Cataract
Doctor of Philosophy, Case Western Reserve University, 2017, Pathology
The antioxidant glutathione (GSH) protects lens proteins from post-translational modifications that result in their aggregation and cataract formation. With age, the human lens becomes increasingly depleted of GSH, which contributes to the development of age-related cataract. In order to gain a comprehensive understanding of the role of GSH in the pathogenesis of age-related cataract, I set out to study the consequences of and adaptations to GSH-deficiency in the lens using the Lens Glutathione Synthesis Knockout (LEGSKO) mouse model of cataract. The questions addressed in this thesis are: 1) How does the LEGSKO lens maintain >1 mM GSH despite a complete lack of GSH synthesis? and 2) What gene expression and signaling changes are associated with lens GSH deficiency? The first of these questions was addressed by measuring lens uptake of isotopically-labeled GSH using an LC-MS/MS system. I determined that mouse lenses obtain exogenous GSH in two ways: from the aqueous humor via an active transport mechanism and from the vitreous humor via passive diffusion. It was found that mouse eyes have a high concentration of GSH in their vitreous humor and a low concentration of GSH in their aqueous humor and, because of this, nearly all the GSH in the LEGSKO lens is derived from equilibration with the vitreous pool. It was also found that the eyes of humans and other large animals lack this high vitreous GSH concentration. The second question of this thesis was addressed by comparing the transcriptomic profiles of wild-type control lenses, chronically GSH-deficient LEGSKO lenses, and acutely/severely GSH-deficient buthionine sulfoximine-treated (BSO;GSH synthesis inhibitor) LEGSKO lenses using RNA-Seq technology. These data show that the most robust responses to GSH-deficiency in the lens are upregulation of detoxifying genes, including metallothioneins, aldehyde dehydrogenases, and carboxylesterase, activation of epithelial-mesenchymal transition (EMT) signaling, and alterations to lipid homeostasis and transport systems. These findings suggest that GSH plays a role in EMT-mediated posterior secondary cataract and implicate new potential targets for cataract therapeutics. This body of work greatly expands knowledge of the benefits and regulation of GSH in the lens, consequences of its loss, and other genes which promote lens clarity.

Committee:

Vincent Monnier (Advisor); Xingjun Fan (Advisor); Alan Tartakoff (Committee Chair); John Mieyal (Committee Member); Maria Hatzoglou (Committee Member); Xiongwei Zhu (Committee Member); Clive Hamlin (Committee Member)

Subjects:

Biology; Biomedical Research; Pathology

Keywords:

cataract, glutathione, EMT, lens, transcriptome, homeostasis

Jamalzadeh, RezaMicrogrid Optimal Power Flow Based On Generalized Benders Decomposition
Doctor of Philosophy, Case Western Reserve University, 2018, EECS - System and Control Engineering
The future distribution system is envisioned to be a network of distributed energy resources (DER), being able to operate in both the grid connected and islanded modes. In essence, the future electrical distribution systems will operate as medium-voltage (MV) microgrids. This dissertation presents a study of the optimal power flow (OPF) based on generalized benders decomposition (GBD) for optimally scheduling DERs and managing voltage regulation device operations to enable the economic and secure operations of the future MV distribution systems. Key model considerations include multi-phase unbalanced distribution system network, conservation voltage reduction (CVR), and multi-interval energy scheduling. Further, the optimal operating decisions are studied when the MV microgrid is in different operational modes, such as the 1) grid-connected mode, 2) islanded mode, and 3) grid-connected to islanded mode transition. Excellent algorithm performance has been achieved on the IEEE test feeder models. The use of an external engine for solving the unbalanced power flow and obtaining the sensitivities for the decomposed sub-problems allows the OPF to handle scaled-up models with the increased number of decision variables, constraints, and network buses. To support solution of large-scale problems, parallel computational strategies are recommended in order to achieve solution performance required by operations. Among the output of the GBD-based OPF, the primal solution provides optimal operation set point decisions while the dual solution provides system marginal-cost based energy prices such as the locational marginal prices (LMP) for single-phase nodes. These important OPF outcomes can facilitate the economic electricity market design in the distribution system involving both DERs and end-use demands. In this dissertation, a new method based on the GBD-based OPF has also been proposed using the unbalanced power system model linearized around the near-optimal operational state to calculate LMPs for single-phase buses and support the economic market design of the distribution system. Also in this dissertation, the approximation of nodal voltage sensitivities is studied based on observations made about the radial distribution system. As a result, voltage sensitivities can be efficiently computed for all network nodes simply based on the power flow solution and topology searches. The results are validated on the IEEE test feeder models using the perturbation analysis. The proposed method can be applied to large unbalanced radial distribution systems for supporting distribution system planning and operation.

Committee:

Mingguo Hong, PhD (Advisor); Kenneth Loparo, PhD (Committee Member); Vira Chankong, PhD (Committee Member); Evren Gurkan-Cavusoglu, PhD (Committee Member)

Subjects:

Electrical Engineering; Energy

Keywords:

Active distribution system operation; conservation voltage reduction; distributed energy resources; generalized benders decomposition; locational marginal price; microgrid; optimal power flow; unbalanced distribution system; voltage sensitivity

Badiee, Mohsen

Mechanistic Insights into

The Physiology of Bile acids and Retinoids

Doctor of Philosophy, Case Western Reserve University, 2018, Chemistry

Studying and understanding small molecule-protein interactions are critically important to gain insight into the biological function of a protein or the catalytic activity of an enzyme. Chemical and biophysical approaches are frequently used to characterize these interactions. Herein, we used synthetic organic chemistry and calorimetry, two-dimensional NMR spectroscopy, and X-ray crystallography to understand the mechanistic biochemistry of two distinctive mammalian proteins, ileal-bile acid binding protein (I-BABP) in the gastrointestinal tract and retinal pigment epithelium-specific protein 65kDa (RPE65) in the eye.

I-BABP is abundantly expressed in the ileum where it interacts with bile acids, the major metabolites of cholesterol. It is now established that bile acids, in addition to their roles in facilitating food digestion, act as versatile signaling molecules in different regulatory pathways including their own biosynthesis. In the enterohepatic circulation of bile acids, I-BABP plays a vital role as a cytoplasmic buffering agent and a potential regulator of cell signaling. Understanding the mechanism regulating bile acid/I-BABP interactions is a key step in providing a model for bile acid signaling. We utilized chemical synthesis and biophysical approaches to characterize binding profiles of I-BABP and various physiological bile acids. The central finding described herein is that I-BABP binds to most bile acids with high positive cooperativity and site-selectivity and aspects of this binding profile are conserved between human and mouse. Surprisingly mouse I-BABP did not bind to mouse-specific bile acids, rather maintained a binding profile similar to that of humans. These results support an important role of I-BABP as a modulator in bile acid signaling pathway, and not as a buffering agent.

RPE65 is an essential enzyme of the retinoid (visual) cycle that regenerates 11- cis-retinal by isomerizing all-trans-retinyl ester to 11-cis-retinol during phototransduction for photoreceptors in vertebrates. The mechanism of stereoselective retinoid isomerization has remained elusive because of uncertainty about how retinoids bind to the RPE65 active site. The crystal structure of an enzyme-ligand complex is key to delineate the catalytic activity, but it has been difficult to obtain due to the poor water-solubility of retinoids. Moreover, the clinical significance of the interaction of RPE65 with retinoid cycle modulators such as emixustat in eye disease is not clear. To this end, I synthesized a series of analogs around a lead compound, emixustat, which has better water solubility than natural ligands. In summary, these chemicals enabled us: to propose a mechanism for stereoselective isomerization by RPE65, an atypical member of carotenoid cleavage oxygenases (CCOs), to introduce principles for developing a next generation of visual cycle modulators, and to develop a better inhibitor for basic studies of the visual cycle.

Next, we expanded our structural studies to CAO1, another member of the CCO family. CCOs generally cleave a carbon-carbon double bond in carotenoids and stilbenoids under oxidative conditions. An iron cofactor, which is coordinated by four histidine residues, is a common feature of all CCOs and required for catalytic activity. However the mechanism used by most CCOs is distinct from RPE65 which catalyzes non-oxidative cleavage of an ester. Many aspects of this iron center and the catalytic activity of CCOs are not fully understood due to the absence of suitable inhibitors. Here, I designed and developed a series of analogs based on resveratrol (the natural substrate of CAO1) to develop an inhibitor for use in structural studies.

Committee:

Gregory Tochtrop, Dr. (Advisor); Micheal Zagorski, Dr. (Committee Chair); Paul Carey, Dr. (Committee Member); John Mieyal, Dr. (Committee Member); Rajesh Viswanathan, Dr. (Committee Member)

Subjects:

Biochemistry; Chemistry

Keywords:

mouse I-BABP, binding, ITC, HSQC, RPE65 inhibitors, carotenoid cleavage dioxygenase, enzyme mechanism

Gifford, RoyFactors Contributing to Sustainable Brand Growth
Doctor of Philosophy, Case Western Reserve University, 2017, Management
Brand leaders are responsible for leading brand building activities in very complex systems within organizations (e.g., sales, marketing, operations, finance). Firms spend an enormous amount of resources to support brand building activities in their complex systems. Ad spending worldwide reached $513 billion in 2015, 5% growth versus 2014. Global R&D spending reached $480 billion in 2015. Despite this level of spending and focus, brand deaths occur (e.g., Oldsmobile, Plymouth, and Woolworth Stores). Yet, some (e.g., John Deere) have demonstrated continued brand growth over time. The fact is that some brand leaders are successful at driving brand performance and some are not. What is the secret to staying relevant to consumers across generations of consumers (e.g., Boomers, Generation Xers, and Millennials)? Research shows that brands with the ability to emotionally connect with their consumers have innovative product offerings that create value with consumers. But, what impact do the feelings and behaviors of brand leaders and consumers have on brand engagement to drive brand performance? I began my research journey (study #1) with the goal of exploring the differences between growing brand leaders and declining brand leaders. I found that leaders who exhibit emotional intelligence, hope, and social identity build stronger emotional connections between their brands and consumers, which leads to sustainable brand growth. In study #2, I explored how organizational behavior impacts a brand leader’s market orientation. This study was the first to link the feelings and behaviors of leaders to market orientation. Based on my findings, I discovered that a brand leader’s shared values with the firm and participation in their brand community impact a firm’s level of market orientation. I believe these findings start to reveal insights into how brand leaders drive business performance by increasing brand engagement with consumers. In study #3, I answered what motivates a consumer to participate in a brand community. I believe these findings will provide key insights to brand leaders trying to build stronger emotional bonds between their brands and consumers. Previous research has shown the outcomes of consumers interacting with brands in a brand community and the results of consumers participating in a brand community. However, there is a gap in research regarding why consumers are motivated to participate in a brand community. I found evidence to suggest that a consumer’s conformity motivation, brand loyalty, and attachment style increase their brand community participation. This research shows that the feelings and behaviors of brand leaders and consumers increase brand engagement to drive brand performance. I found that the brand community is a source of the emotional connection that drives engagement between the brand leader and the brand as well as the consumer and the brand. It is truly a tale of two individuals (brand leader and consumer) engaging with the brand at a crossroads called brand community. I believe these will be important learnings for researchers and practitioners who seek to understand this phenomenon to position their brands for sustainable long-term growth.

Committee:

Casey Newmeyer (Committee Chair); William Ross (Committee Member); Rakesh Niraj (Committee Member); James Gaskin (Committee Member); Roger Saillant (Committee Member)

Subjects:

Management; Marketing; Organizational Behavior

Keywords:

emotional intelligence; market orientation; brand community; sustainable brand growth; brand leaders; consumers

Wallat, Jaqueline DianeFluorous Nanoparticle Platform for Cancer Imaging and Treatment
Doctor of Philosophy, Case Western Reserve University, 2018, Macromolecular Science and Engineering
This thesis work highlights the fabrication and use of a fluorous copolymer nanoparticle platform for drug delivery with 19F magnetic resonance imaging potential. Throughout this work, low-molecular weight random copolymers comprised of approximately equal molar concentrations of oligio(ethylene glycol methyl ether methacrylate) OEGMEMA and trifluoroethyl methacrylate TFEMA were synthesized using atom-transfer radical polymerization from an azide-functionalized initiator. In water, the copolymer self-assembles into micelles of approximately 250 nm. The azide end group provides a handle to react with an alkyne-functionalized cargo via copper catalyzed azide-alkyne cycloaddition (CuAAc), which is a robust, high-yielding, and facile reaction. The 19F NMR and MRI properties of a 5 kDa micelle were analyzed for the particle, and to enable in vitro and in vivo particle tracking, a near-infra red fluorescent dye was attached to the chain end of the copolymer via the CuAAc reaction. The biodistribution of the fluorescently labeled fluorous micelle was evaluated in vivo in breast and ovarian cancer models. This system showed exceptional uptake into tumors via passive tumor targeting with little uptake in non-tumor tissue. These promising results prompted the investigation of this micelle to serve as a drug delivery vehicle for a photodynamic therapy (PDT) reagent in two types of skin cancer. The fluorous micelle showed enhanced production of reaction oxygen species, a critical component for treatment with PDT, but often limited in the hypoxic tumor environment. The delivery of the PDT to skin cancer cells was favorable, indicating this fluorous micelle could effectively serve as a drug delivery vehicle for PDT. To extend this system toward commercially available chemotherapeutics, we sought to site-selectively deliver the chemotherapeutic Doxorubicin (DOX). The DOX was covalently modified via an acid-sensitive linkage and attached to the micelle via the CuAAC reaction. pH sensitivity enables selective delivery in acidic environments such as the tumor microenvironment or lysosomal cell compartment. The DOX-copolymer showed pH triggered release of active DOX from the carrier. In vitro, the DOX-copolymer demonstrated uptake into two in vitro models for ovarian cancer and demonstrated efficient cancer killing. Taken together, this work highlights the use of a fluorous copolymer synthesized via ATRP to enable facile fabrication of drug delivery and imaging vehicles for cancer via the CuAAc reaction.

Committee:

Jonathan Pokorski, PhD (Advisor); David Schiraldi, PhD (Committee Member); Horst von Recum, PhD (Committee Member); Gary Wnek, PhD (Committee Member)

Subjects:

Polymer Chemistry; Polymers

Keywords:

Fluorous, Nanoparticle, Cancer, ATRP, Treatment, DOX, copolymer

Gross, Carol AIndividual Differences in the Addition Strategy Task in Adolescents
Master of Arts, Case Western Reserve University, 2017, Psychology
Strategies used to solve addition problems without pencil and paper have been evaluated and connected to math achievement in multiple studies of children and adults. However, only a few studies have used adolescent samples, and addition strategies have not been evaluated in a behavior genetic framework. In this study the addition strategies used by a group of adolescent twins (77 MZ pairs and 136 DZ pairs) from the Western Reserve Reading and Math Project were evaluated. Participants solved 20 addition problems (14 simple and 6 complex) and reported the strategies that they used to solve each problem. Memory based strategies included retrieval and decomposition and procedural strategies included counting. Measures of strategy use on the task were taken from previous studies of children and adults. The measures that best characterized adolescent strategy use were the child and adult measures that described frequency of retrieval and decomposition. All measures of strategy use had significant nonshared environmental influences, and none of the measures had significant shared environmental influences. Further, strategy use measures for complex problems had a significant estimate of heritability.

Committee:

Lee Thompson (Advisor)

Subjects:

Cognitive Psychology; Developmental Psychology; Psychology

Keywords:

math; addition strategies; twins; behavior genetics

Stevens, Nicholas DavidLulu's Daughters: Portraying the Anti-Heroine in Contemporary Opera, 1993-2013
Doctor of Philosophy, Case Western Reserve University, 2017, Musicology
In this dissertation, I argue that opera’s anti-heroine archetype – one of the most familiar in the genre’s historical canon – returned to prominence at the turn of the twenty-first century, along with many of its typical tropes and plot trajectories. Between 1993 and 2013, four leading composers chose to update and adapt the basic idea of a transgressive heroine who rises in her society only to fall silent in the end. Each of the creative teams behind these works finds a novel way to modernize, transform, disrupt, or critique opera’s long tradition of doomed anti-heroines – but each also draws upon a common, historically rooted set of musical and dramatic devices in characterizing their compromised protagonists. Like Alban Berg’s Lulu of 1935, these operas incorporate forms of American popular music into modernist scores; all partake of and thematize audiovisual media, such as film, photography, and phonography. In an introduction, I trace the phenomenon of opera’s anti-heroine back to its historical heyday, and discuss the methodological and theoretical frameworks in which I operate. In the first two case studies, grouped under the heading Remembering the Twentieth Century, I examine new opera’s depictions of two real women who came of age between the wars. Margaret, Duchess of Argyll becomes a complex concatenation of archetypes in Thomas Ades and Philip Hensher’s Powder Her Face, and Anais Nin, the posthumous librettist and sole physical character of Louis Andriessen’s Anais Nin, becomes an insatiable femme fatale in the Dutch composer’s tightly edited biographical sketch. The second pair of case studies, American Dreams, Southern Scenes, and European (Re)visions, opens with a look at a third quasi-biographical account of a female celebrity’s rise and demise: Mark-Anthony Turnage and Richard Thomas’s Anna Nicole, a satire influenced by the tabloid culture of the 1990s and 2000s. In the final chapter, I turn to a work that eschews the depiction of a real woman, instead featuring a new version of a pre-existing operatic femme fatale: Berg’s Lulu, reimagined as an African-American native of New Orleans in Olga Neuwirth’s American Lulu. I conclude by suggesting paths forward, for both scholarship and contemporary opera.

Committee:

Susan McClary, PhD (Advisor); Daniel Goldmark, PhD (Committee Member); Francesca Brittan, PhD (Committee Member); Susanne Vees-Gulani, PhD (Committee Member); Sherry Lee, PhD (Committee Member)

Subjects:

Film Studies; Fine Arts; Gender Studies; Music; Theater Studies

Keywords:

media; jazz; popular music; chamber opera; monodrama; postopera; music theatre; gender; archetype; Berg, Alban; Ades, Thomas; Andriessen, Louis; Neuwirth, Olga; Turnage, Mark-Anthony; Nin, Anais; tabloid culture; modernism; narrative; voice

Varghai, KavehThe Production of Hydroxyapatite Standards, Used for Post CBCT Scan Hounsfield Unit Calibration
Master of Sciences, Case Western Reserve University, Biomedical Engineering
We think that we can help ease patients’ concerns by altering diagnostic x-rays. Our goal is to use CT information to pre-surgically determine the likelihood of success of an operation. This technique could help expectation setting or, moreover, could help oral physicians make procedural decisions which result in higher rates of implant stability and functionality. Currently, cone beam computerized tomographies (CBCT) are commonly used in the dental community for morphological assessment of the mandible and maxilla. Previous studies have shown the potential of using a single set of phantoms in the oral cavity, to derive Hounsfield Units (HU). However, due to the polychromatic x-ray source in CBCT scanners, variation in average grey level for a single phantom exists, as a function of location. This thesis will focus on using common biomaterials, used in biomedical implants, to design and fabricate a set of standards, small enough so that a single set is fixed adjacent to the region of interest (ROI). This set of phantoms would allow dental clinicians to quantitatively assess bone quality by ultimately comparing derived HU to mass density without the need for expensive medical software.

Committee:

Steven Eppell, Ph.D (Advisor); Russell Wang, DDS, MSD (Committee Member); David Wilson, Ph.D (Committee Member)

Subjects:

Biomedical Engineering

Seshadri, Dhruv RamakrishnaImmuno-nanotherapeutics to Inhibit Macrophage Polarization for Non-Small-Cell Lung Cancers
Master of Sciences, Case Western Reserve University, 2017, Biomedical Engineering
Lung cancer is the leading cause of cancer-related mortalities in the USA with a five-year survival rate of ~15%. For patients with Non-Small-Cell Lung Cancer (NSCLC), chemotherapy, oncogene targeted therapy, or immunotherapy are the primary modes of treatment. Response rates to immunotherapies for NSCLCs are < 20%, due to the tumor micro-environment (TME) that favors immune-evasion and pro-tumorigenic pathways such as macrophage polarization from a pro-inflammatory (M1) to a pro-tumorigenic/angiogenic (M2) phenotype. Additionally, the TME is compromised by the chronic enzymatic breakdown of the elastic matrix which catalyzes polarization. Exogenous delivery of Doxycycline (DOX) has shown to inhibit the M1-M2 phenotypic switch. We explored the utility of antibody-conjugated DOX-poly(ethylene glycol)-poly(lactic glycolic-acid) (PEG-PLGA) nanoparticles (NPs) to inhibit macrophage polarization and demonstrate that steady-state release of DOX from these NPs is possible in a low dose range to inhibit polarization and repolarize macrophages back to the M1 phenotype.

Committee:

Anand Ramamurthi (Advisor); Eben Alsberg (Committee Member); Colin Drummond (Committee Member)

Subjects:

Biomedical Engineering; Biomedical Research; Polymer Chemistry; Polymers

Keywords:

Tumor Microenvironment, Nanomedicine, Nanoparticles, Polymers, Lung Cancer, Macrophages, Immunotherapy, Extracellular Matrix, Elastin

Rafique, SubrinaGrowth, Characterization and Device Demonstration of Ultra-Wide Bandgap ß-Ga2O3 by Low Pressure Chemical Vapor Deposition
Doctor of Philosophy, Case Western Reserve University, EECS - Electrical Engineering

High power semiconductor device technology has significant impact on the society as they can directly contribute to worldwide energy conservation. The main market segments for high-power, high-frequency semiconductor devices are industrial motors, hybrid and electric vehicles, RF and power supply, wireless infrastructure and broadcast and communication satellites. Si-based technology has been serving the power electronics market till today. However, Si based power devices are approaching their theoretical performance limits from the viewpoint of material properties. Wide bandgap (WBG) semiconductors featured with higher breakdown electric field have tremendous advantages over existing Si based technology. They can operate at higher voltages, temperatures and switching frequencies with greater efficiencies resulting in less loss. They also enable significantly reduced system level volumes due to decreased cooling requirements and smaller passive components contributing to overall lower system costs. Once widely used, wide bandgap semiconductor based power electronics technologies can save over 25% of the worldwide annual energy consumption.

Ultra-wide bandgap (UWBG) semiconductor material gallium oxide (Ga2O3) with a room temperature bandgap of ~4.9 eV, much higher than GaN (Eg~3.4 eV) and SiC (Eg~3.2 eV), is a promising candidate for next generation power devices and deep ultraviolet (DUV) photodetectors (PDs). It possesses excellent material properties and outstanding chemical and thermal stability at elevated temperatures. Most attractively, Ga2O3 substrate can be produced by low cost and scalable melting based methods. In this dissertation, a new epitaxial method based on low pressure chemical vapor deposition (LPCVD) is developed and demonstrated for the first time to grow high quality Ga2O3 based thin films and nanomaterials with fast growth rate and controllable doping. For the LPCVD growth of Ga2O3, argon (Ar) is employed as carrier gas. High purity gallium pellets (Alfa Aesar, 99.99999%) are used as the group III precursor. Oxygen (O2) and Silicon Tetrachloride (SiCl4) are the group VI precursor and n-dopant source, respectively. Proof of concept prototypes of ß-Ga2O3 thin films based PDs and Schottky barrier diode (SBD) have been demonstrated using LPCVD grown Ga2O3 thin films. The maximum room temperature electron Hall mobility achieved for LPCVD heteroepitaxial Ga2O3 thin films is 106.6 cm2/V·s with an n-type carrier concentration of 4.83x1017 cm-3. The room temperature carrier concentrations achieved so far for the (010) and (001) LPCVD homoepitaxial thin films are ~1.4x1018 cm-3 and ~6.6x1017 cm-3 with mobilities of ~72 cm2/V. s and ~42 cm2/V. s respectively. Advancement of LPCVD growth of high quality ß-Ga2O3 will open up new opportunities for high performance power electronic and optoelectronic devices.

Committee:

Hongping Zhao (Advisor)

Subjects:

Electrical Engineering

Shoop, Jessica ASENIOR INFORMATION TECHNOLOGY (IT) LEADER CREDIBILITY: KNOWLEDGE SCALE, MEDIATING KNOWLEDGE MECHANISMS, AND EFFECTIVENESS
Doctor of Philosophy, Case Western Reserve University, 2017, Management
This dissertation explains leader effectiveness in the context of the senior information technology (IT) leader who plays a pivotal role in the execution and delivery of corporate IT services. Considered leaders of leaders, senior IT leaders typically report to the Chief Information Officer (CIO). Using a sequential three-phase mixed methods study the thesis makes four contributions; (1) through qualitative inquiry shows that effective senior IT leaders maintain a balance of domain knowledge and emotional and social aptitudes; (2) develops and validates a four-dimensional scale to measure the level of IT leader domain knowledge; (3) demonstrates nomological and predictive validity of the scale and evaluates the impact of IT leader domain knowledge in solving managerial problems and brokering knowledge to others; (4) the studies combine to a build cohesive argument that leadership credibility wherein technical domain knowledge forms the other component is a critical antecedent for leadership effectiveness. The validation is founded on a sample of 104 senior IT leaders and 490 IT leader subordinates within a global IT service firm. Overall, our findings suggest that the so far neglected effect of IT domain knowledge forms not only an important but vital component influencing overall senior IT leader effectiveness. This has consequences for both established theories of leader credibility and leader effectiveness in highly specialized technical domains. Practically the study underscores the importance of hiring and maintaining senior IT leaders with strong technical credentials.

Committee:

Kalle Lyytinen, Ph.D. (Committee Chair); Jagip Singh, Ph.D. (Committee Member); Genevieve Bassellier, Ph.D. (Committee Member); John King, Ph.D. (Committee Member)

Subjects:

Business Administration; Information Systems; Information Technology; Management

Keywords:

Senior IT Leaders; Leadership Effectiveness; Credibility; Domain Knowledge; Leader Knowledge; Knowledge Mechanisms; Scale Development; Multi-dimensional Scale Validity; Mixed Methods

Miranda, David JMusic Blocks: Design and Preliminary Evaluation of Interactive Tangible Block Games with Audio and Visual Feedback for Cognitive Assessment and Training
Master of Engineering, Case Western Reserve University, 2018, EMC - Mechanical Engineering
Tangible Geometric Games (TAG-Games) were developed initially for automated cognitive assessment using custom sensor-integrated blocks (SIG-Blocks). Building on this existing technology, Music Blocks focuses on incorporating music and audio feedback in TAG-Games to examine the potential of tangible games for cognitive training and assessment. New block enclosure and game board designs implement textures that portray information tangibly. Game algorithms support real-time gameplay and data collection. For preliminary game evaluation, a small scale human subject study was conducted involving 17 participants. Among the five Music Blocks games created, Direction Blocks, MineSweeper, and Password Blocks were tested along with three subtests of the Wechsler Adult Intelligence Test – Fourth Edition (Block Design, Digit Span, and Matrix Reasoning). Initial assessment concluded that tangible games pair best with audio-visual stimuli. Individual games correlated well with some subtests from WAIS-IV. Other results, the limitations, and conclusions of this study are discussed within the text.

Committee:

Kiju Lee (Committee Chair); Ming-Chun Huang (Committee Member); Marc Buchner (Committee Member)

Subjects:

Cognitive Psychology; Computer Science; Mechanical Engineering; Music

Keywords:

tangible games; cognitive assessment; music games; block games; computerized cognitive assessment; audio-tangible games

Tedeschi, Frank AIDENTIFICATION OF CELLULAR RNA BINDING SITES OF DEAD-BOX HELICASES
Doctor of Philosophy, Case Western Reserve University, 2018, Biochemistry
Ded1p and Dbp2p are two conserved DEAD-box helicases whose mammalian orthologs DDX3 and DDX5 are linked to tumorigenesis and interact with diverse viruses. Ded1p is a critical component of translation initiation, whereas Dbp2p has been implicated in transcription, ribosome biogenesis, mRNP assembly, nuclear export, and lncRNA function. Although each helicase has been implicated in essential biological processes, their cellular targets and physical functions in the cell are not well understood. In order to characterize their RNA interactions as well as help define the physical functions of these helicases, the RNA binding sites must first be determined. Here I identify the binding sites of Ded1p and Dbp2p by UV-crosslinking, denaturing tandem affinity purification, and Next Generation Sequencing. Ded1p’s RNA binding sites reveal an association with mRNA downstream of near-cognate initiation codons in the 5’ UTR. Additionally, Ded1p interacts with the scanning translation pre-initiation complex at the mRNA entry channel. Integration of the Ded1p-RNA binding data with ribosome profiling and dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) show Ded1p’s impact on translation initiation is connected to the repression of alternative translation initiation codons that are proximal to mRNA structure in the 5’ UTR. Crosslinking of Dbp2p revealed binding to mRNAs and ribosomal RNAs consistent with Dbp2p’s implication in mRNA export and ribosome biogenesis. Unexepectedly, however, Dbp2p exhibited marked crosslinking to non-coding RNAs, including snoRNA, snRNAs, and tRNAs. In snoRNAs, Dbp2p preferentially crosslinks at sites near the 3’ ends. These sites coincide with regions where RNA-DNA hybrids (R-loops) form. Dbp2p binding sites also correlated with binding of Sen1p, another RNA helicase that functions in transcription termination and 3' processing of non-coding RNAs. I show that Dbp2p interacts in an RNA-independent manner with Sen1p in vivo. Collectively, our data link Dbp2p to non-coding RNAs, Sen1p, and R-loops. The transcriptome-wide connection to R-loops across the genome provides a unifying theme for diverse cellular roles of Dbp2p. Identification of the cellular RNA binding sites of Ded1p and Dbp2p have helped lead to the development of a physical model for Ded1p repression of alternative initiation sites and the implication of Dbp2p in a global role linking snoRNA, Sen1p, and R-loops.

Committee:

Eckhard Jankowsky (Advisor)

Subjects:

Biochemistry; Bioinformatics

Keywords:

Ded1p; Helicase; DEAD-box; Dbp2p; iCLIP

Morrison, Rachel LouiseUnderstanding the Interaction between Grain Boundaries and Precipitates in Ni-Al Using Molecular Dynamics
Master of Sciences, Case Western Reserve University, 2018, Materials Science and Engineering
This thesis investigates the interaction between gamma' precipitates and grain boundaries in a Ni-Al system during deformation. This interaction is investigated using molecular dynamics, and gamma'/boundary configurations were built to investigate how the orientation, size, and interaction of gamma' change the deformation behavior of the grain boundary. The gamma' aided in nucleating defects (i.e., dislocations) that contributed to the boundary sliding mechanism. By increasing the size of precipitates that bisect the boundary, the boundary becomes stronger, whereas increasing the size of precipitates adjacent to the boundary makes the boundary weaker. Additionally, the interaction of multiple gamma' plays a role in grain boundary sliding behavior. Low concentrations of gamma' produce sliding dominated by atomic shuffling, whereas high concentrations of gamma' produce sliding dominated by dislocation emission. More work is needed to investigate the effects of temperature, initial defects, and different grain boundary configurations on sliding behavior.

Committee:

Jennifer Carter (Committee Chair); John Lewandowski (Committee Member); David Matthiesen (Committee Member)

Subjects:

Materials Science

Keywords:

grain boundary sliding; nickel superalloys; molecular dynamics

Mitchell, Marcus B.Forms Unconfined: The Figure of the Muscular Woman, Physical Culture, and Victorian Literature
Doctor of Philosophy, Case Western Reserve University, 2018, English
This dissertation examines contradictory representations of the figure of the muscular woman in Victorian fiction and the periodical press. Throughout the second half of the nineteenth century, writers debated whether the muscular female body should be celebrated as a fresh alternative to the wasp-waisted ideal of female beauty or condemned for its perceived destabilization of established social and aesthetic codes of feminine decorum. Within this debate, commentators advanced competing views about the efficacy of rigorous physical fitness regimens for women, the relationship between muscularity and women’s reproductive capacities, and the coherence of female musculature and traditional formulations of womanhood. These conflicting views illuminated wider cultural concerns about national fitness and changing configurations of gender. My project analyzes representations of muscular women in chapters that focus on women’s physical fitness commentaries, magazine illustrations, sensation narratives, and New Woman novels in order to demonstrate how muscular women necessitated revisions to Victorian cultural configurations of beauty, motherhood, femininity, and masculinity. The dissertation also explores connections between the muscular woman’s unconventional embodiment of physical culture ideals and the “transgressive” forms of the literary genres in which she appeared. I argue that depictions of muscular women in Victorian fiction and the periodical press reveal fissures and contradictions in the gender and sexual ideologies underpinning Victorian physical culture, thus illuminating the muscular woman’s versatility as both a fictional character and real-life social conundrum. My project demonstrates how muscular women’s bodies could figure as both objects of social construction and agents of social change, as they called into question Victorian cultural understandings of gender, sexuality, and female physicality. The muscular woman’s challenge to the boundaries of aesthetic form became a model for new forms of literary experimentation. By considering the muscular woman’s embodiment both alongside and within new forms of Victorian fiction, this project uncovers how parallel transgressions of gender and genre exposed the tensions and contradictions of Victorian cultural and aesthetic ideals.

Committee:

Athena Vrettos (Advisor); Christopher Flint (Committee Member); Kurt Koenigsberger (Committee Member); Renee Sentilles (Committee Member)

Subjects:

British and Irish Literature; Gender; Literature

Keywords:

muscular women; physical culture; Victorian literature; femininity; womanhood; female physicality; muscularity; periodical press; aesthetic

Moffett, UtahInvestigation of a Heat Spreading Layer for Wing De-icing
Master of Sciences (Engineering), Case Western Reserve University, 2018, EMC - Aerospace Engineering
A heat spreading layer is investigated for use with the HeatCoat TM anti-icing system. Carbon-based materials such as graphite, carbon fibers, and carbon nanotubes were investigated for their favorable thermal properties, characterized with XRD, Raman spectroscopy, and thermal conductivity testing. Synthetic graphite was found to have the highest thermal conductivity and is therefore the most desirable heat spreading material for the antiicing system application. A finite element thermal analysis of the HeatCoat TM and heat spreading layer was performed to determine the effect of the heat spreading layer in- and through-plane thermal conductivity on the anti-icing performance. Through-plane thermal conductivity proved to be unimportant, but the in-plane thermal conductivity should be higher than 200 W/m-K to minimize the appearance of cold spots and maximize energy savings. In addition, the system performed best when the thermal interface resistance between the heaters and the heat spreader was at most 10^6 m^2K/W.

Committee:

Vikas Prakash (Committee Chair); Alexis Abramson (Committee Member); Yasuhiro Kamotani (Committee Member); James T'ien (Committee Member)

Subjects:

Aerospace Materials; Engineering; Materials Science; Mechanical Engineering

Keywords:

Carbon nanotubes; de-icing; thermal conductivity

Tanenbaum, Joseph EliasThe Association of Health Care Delivery and Payment Innovations with Avoidable Hospitalizations
Doctor of Philosophy, Case Western Reserve University, 2018, Epidemiology and Biostatistics
The annual cost of cardiovascular disease (CVD) in the United States is estimated to exceed $1.2 trillion by 2035, with the costs of CVD hospitalizations driving that estimate. Despite this projected growth, many hospitalizations for CVD are potentially preventable if patients receive appropriate and timely ambulatory care. The role that health care delivery and payment reform may play in attenuating the expected rise in both the rate of CVD hospitalizations and associated costs is currently unknown. Examples of innovative models of health care delivery and payment include the patient centered medical home (PCMH), shared savings accountable care organizations (ACO), meaningful use of electronic medical records (EMR), and the presence of regional health improvement collaboratives (RHIC). Despite widespread adoption during the last decade, uncertainty exists about the effect of these four approaches on patient outcomes and cost of care for cardiovascular conditions. No prior study mapped the evolution of the health care market penetration of these four approaches. Chapter 2 of this dissertation asks whether and to what extent establishing a specific type of RHIC can reduce CVD hospitalization rates and associated costs in a large urban county in Ohio. I show that establishing a provider-led, primary care-focused quality improvement initiative that focuses on disseminating best practices can successfully avert preventable CVD hospitalizations. Next, chapter 3 quantifies trends in adoption of PCMH, ACO, and meaningful use of EMR among primary care providers (PCPs) in Ohio. I show that substantial heterogeneity exists in the primary care market penetration of PCMH, ACO, and EMR across Ohio. This variation is associated with differences in county characteristics and RHIC presence, and the evolution of the adoption of these interventions occurred linearly over time. In chapter 4, I exploit this heterogeneity in PCMH, ACO, EMR, and RHIC market penetration in year 2015 to measure the effect of primary care market penetration of PCMH, ACO, EMR, and RHIC on rates of preventable CVD hospitalization. I show that none of the four approaches were associated with a differential change in CVD hospitalization rates overall. Finally, chapter 5 summarizes the key results of this dissertation and establishes follow-up studies to be completed as part of my post-doctoral work.

Committee:

Siran Koroukian, PhD (Committee Chair); Randall Cebul, MD (Advisor); Thomas Love, PhD (Committee Member); Mark Votruba, PhD (Committee Member); Dougalas Einstadter, MD (Committee Member); Catherine Stein, PhD (Committee Member)

Subjects:

Economics; Epidemiology; Health Care

Keywords:

PCMH; ACO; EMR; RHIC; Meaningful Use; HITECH; ACA; Affordable Care Act

Gbur, Janet LInclusion Effects on the Lifetime Performance of Superelastic Nitinol Wires
Doctor of Philosophy, Case Western Reserve University, 2018, Materials Science and Engineering

Miniaturization of Nitinol-based medical devices requires increased performance from less material, and therefore necessitates investigation of the connection between material processing and performance. Moreover, it is imperative to understand how impurities that result from processing affect its lifetime performance. Research on the microcleanliness (i.e. presence of nonmetallic inclusions, intermetallic particles, etc.) of fine Nitinol wires and its effect on fatigue performance are not frequently found in literature.

This study compared a manufacturer-defined standard (SP) and high (HP) purity, Nitinol superelastic (SE) fine (< 140 μm) wire. Nonmetallic inclusion (NMI) chemistry was determined to be TixNiyOz with varied morphology, occurring with/without pores. Combined NMI/pore area percentages ranged from 0.08% ± 0.04% (HP) to 1.44% ± 0.26 (SP) when measured with scanning electron microscopy (SEM). Plasma focused ion beam (PFIB) serial sectioning was also used characterize the combined NMI/pore volume percentages yielding 0.09% (HP) and 0.47% (SP).

Differential scanning calorimetry was used to identify SE transformation temperatures. Microindentation hardness measurements showed gradients with the center of the wire measuring 359 ± 6.4 HK (HP) and 329 ± 7.2 HK (SP) while mid-radius values were similar for both at 366 ± 5.1 HK and 361 ± 6.0 HK, respectively. Higher tensile and upper plateau strengths were observed in SP (1573 MPa and 515 MPa, respectively) than HP (1420 MPa and 392 MPa, respectively) with greater reduction in area for HP (92.2%) vs. SP (80.2%). Fatigue enhancement was observed in HP wires in flex bending fatigue at strain amplitudes (εa) from 0.67-11% with a run-out at 106 cycles and rotating bending fatigue (εa= 1.2-1.5%) though run-out at 108 cycles. Fractography showed crack initiation attributed to NMIs/pores at the surface or sub-surface with feature areas ranging from submicron to 20.4 μm2.

Characterization techniques showed that HP contained less large-dimension NMIs/pores than SP leading to less potential stress concentrations and points for crack initiation. These differences in relative purity were reflected in the fatigue results where the HP exhibited enhanced fatigue resistance in both low cycle fatigue and high cycle fatigue regimes.

Committee:

John Lewandowski (Advisor); Sunniva Collins (Committee Member); Ina Martin (Committee Member); Matthew Willard (Committee Member)

Subjects:

Materials Science

Keywords:

Non-metallic inclusion; fatigue; wire; biomedical; Nitinol

Kinser, Jonathan A.Beneath the Smoke of the Flaming Circle: Extinguishing the Fiery Cross of the 1920s Klan in the North
Doctor of Philosophy, Case Western Reserve University, 2017, History
By the end of 1925, the Ku Klux Klan had lost most of its members across the United States. This work examines opposition to the group from 1922 to 1926. It seeks to understand the decline in membership the 1920s Klan experienced after its power peaked in 1923 and 1924. To do so, it examines anti-Klan activity in Steubenville, Ohio; Williamson County, Illinois; and in Ohio’s Mahoning Valley with a focus on Niles, Ohio. Legal efforts to oppose the Klan by the Knights of Columbus and two foreign-language newspapers in the Mahoning Valley are explored. However, examining the role of the Knights of the Flaming Circle, a rival organization, in opposing the Klan in these locations is the primary focus. The Knights of the Flaming Circle emerged as an opponent to the Klan in August of 1923 and spread from Pennsylvania into Ohio and Illinois. Initially, the group, founded in Kane, Pennsylvania, championed the causes of liberty and equality and announced its intention to challenge the Klan in an orderly and legal fashion. However, as the organization spread to the industrial cities of Western Pennsylvania and Ohio, the tone of the organization’s rhetoric changed, and, the threat of violence between it and the Klan loomed. The threat became a reality when the Flaming Circle movement reached the coalfields of Williamson County in late 1923. Not long after, Niles, Ohio, joined Williamson County, as the other primary location of conflicts between the factions. From August 1923 to early 1925, the Flaming Circle’s fierce opposition to the Klan resonated around the country due to numerous violent riots and because these incidents were covered by the local and national press. This ensured that even people not located in areas where the two groups were active had constant updates anytime there was trouble. As a result of the conflicts, and a host of other complicating factors, Klan membership dropped significantly across the United States. This study seeks to understand what motivated both sides to engage in such violent behavior toward each other and to analyze why the Knights of the Flaming Circle were successful in helping to halt the Klan movement in the North.

Committee:

David Hammack, PhD (Committee Chair); John Grabowski, PhD (Committee Member); John Flores, PhD (Committee Member); Kevin McMunigal, JD (Committee Member)

Subjects:

American History; History; Law; Mass Media; Modern History; Public Policy; Regional Studies; Religious History; Social Studies Education; World History

Keywords:

Ku Klux Klan; Knights of the Flaming Circle; Youngstown; Williamson County; Niles; Steubenville; Kane; Ohio history; Jonathan Kinser; 1920s; anti-Klan; Catholics; immigrants; Italians; Slovaks; Knights of Columbus; riot; KKK; decline of the KKK; religion

Holloway, Jimeka JBRINGING SOCIAL INNOVATION TO SCALE: LEVERAGING RELATIONAL CAPITAL AND RISK-TAKING BEHAVIORS OF ACTORS IN COMPLEX ECOSYSTEMS
Doctor of Philosophy, Case Western Reserve University, 2017, Management
Social entrepreneurs are change agents that seek to maximize their use of limited financial resources to create long-term, lasting solutions to complex issues such as youth unemployment, recidivism, lack of home ownership, and a high rate of health disparities. Philanthropists, impact investors, and intermediaries play an imperative role in creating systems and influencing the strategies, choices, and intentions of these social entrepreneurs. The impact investing industry experiences inadequacies that limit its impact. These inadequacies include the lack of efficient intermediation, which indicates high search and transaction expenses, fragmented demand and supply, multifaceted deals, and underdeveloped networks (Kickul & Lyons, 2012). There is a need to study the interpersonal relationships among all of the key stakeholders in the ecosystem. This dissertation implements an exploratory sequential mixed methods approach in a 3-strand study to reveal the perspectives of a wide range of stakeholders in the social innovation ecosystem, such as social and commercial entrepreneurs, social enterprise staff and management, beneficiary groups, philanthropic and investment intermediaries, and funding bodies. The behaviors and practices of actors within the social impact investment ecosystem range from simple, informal responses for use in “everyday interactions” to more complex, formal structures. In the first qualitative study, I focus on the individual and organizational processes used to spark social enterprise in communities of economic distress. In the second quantitative study, I analyze the role of social enterprise financing and their social mission, geographic proximity, and risk absorption. Based on findings from the initial qualitative study and the quantitative study, I articulate a research model to study the tensions, issues, and challenges of philanthropic dyads in the social innovation ecosystem. The final strand of the three-part study examines the impact of investor relationships with intermediaries and investees. This research uses a qualitative, multi-case comparative research design. Examining stakeholder relationships in multiple social impact investments enables the identification of patterned behaviors that have endured across investments, across different settings, and diffused beyond the initial occurrence, indicating the emergence of new logics, structures, and processes. I develop a theoretical model that offers testable propositions for further exploration. Key findings include the following leverage points for practitioners and academics alike: social entrepreneurs engaging in continuous, experiential learning to point out barriers in the system; philanthropic intermediaries and impact investors explicitly addressing the challenge of mission drift when expanding the resource pool; and social entrepreneurs using co-creative strategies based on localized knowledge to scale best practices. Specifically, our findings highlight the journey of impact investors to be more strategic in using impact investments in scaling social innovation and making a better social impact. This dissertation posits a deep consideration of the relational context in which key actors in the social sector operate to influence both unexpected and expected consequences that will shape the vitality of the U.S.

Committee:

Richard Boland , Ph.D. (Committee Chair); Paul Salipante, Ph.D. (Committee Member); David Hammack , Ph.D. (Committee Member); Roman Sheremeta, Ph.D. (Committee Member)

Subjects:

Entrepreneurship; Social Research; Systems Design

Keywords:

social innovation ecosystem; impact investment; social enterprise financing; program related investments; collective impact; complex adaptive systems; social capital; coopetition

Ewing, GabrielKnowledge Transfer from Expert Demonstrations in Continuous State-Action Spaces
Master of Sciences, Case Western Reserve University, 2018, EECS - Computer and Information Sciences
In this thesis, we address the task of reinforcement learning in continuous state and action spaces. Specifically, we consider multi-task reinforcement learning, where a sequence of reinforcement learning tasks have to be solved, and inverse reinforcement learning, where a reward function has to be learned from expert demonstrations. We also use trees to represent models, rewards, and value functions in our domains. First, we design an algorithm to learn from demonstration in the presence of a non- smooth reward function. Second, we design another algorithm to perform offline reinforcement learning in the same scenario. This allows us to re-use experiences to help with new tasks. Third, we introduce a method to incorporate weak knowledge about policies with online learning in policy gradient algorithms. These contributions allow us to create a pipeline that efficiently learns and transfers knowledge across a sequence of tasks. We demonstrate our approaches on the task of learning control of a prosthetic arm from expert demonstrations under various scenarios in simulation.

Committee:

Soumya Ray, Dr. (Advisor); Michael Fu, Dr. (Committee Member); M. Cenk Cavusoglu, Dr. (Committee Member); Michael Lewicki, Dr. (Committee Member)

Subjects:

Computer Science

Keywords:

Machine learning; reinforcement learning; continuous actions; knowledge transfer; prostheses

Liu, YuchiDEVELOPMENT OF DYNAMIC PHOSPHORUS-31 AND OXYGEN-17 MAGNETIC RESONANCE SPECTROSCOPY AND IMAGING TECNIQUES FOR PRECLINICAL ASSESSMENT OF ENERGY METABOLISM IN VIVO
Doctor of Philosophy, Case Western Reserve University, 2018, Biomedical Engineering
Adenosine triphosphate (ATP) is the energy currency that maintains physiological activities of the cell. The major source of ATP in aerobic organisms is oxidative phosphorylation occurred in mitochondria. Disruptions of oxidative phosphorylation are associated with various metabolic diseases. Hetero-nuclei MRI plays an important role in assessing functional cell processes such as oxidative metabolism. Specifically, phosphorous-31 (31P) and oxygen-17 (17O) MRS/MRI provide a non-invasive tool to probe mitochondrial oxidative capacity and oxygen consumption, respectively. However, hetero-nuclei MRI in general is challenging due to the low in vivo concentrations and low MR sensitivity. Long acquisition time is usually required even with low spatial resolution. In this thesis, novel approaches for imaging 31P and 17O with high spatial resolution and temporal resolution were developed and demonstrated in small animals at high fields. In particular, this thesis focused on fast 31P MR Spectroscopic Imaging (MRSI) and 17O MRI approaches with non-Cartesian encoding schemes that assess mitochondrial function in skeletal muscle and cerebral oxygen metabolism/water movement across the blood-brain barrier (BBB), respectively. 15 Four projects are described in this thesis. First, an ischemia-reperfusion protocol was established to evaluate mitochondrial oxidative capacity in type 2 diabetic rats using 31P MRS. Second, a fast dynamic 31P MRSI method using a low-rank model was developed and demonstrated in rat skeletal muscle during ischemia-reperfusion. Third, a dynamic 17O MRI method using golden-angle radial acquisition combined with k-space weighted image contrast (KWIC) reconstruction was developed and validated in simulation studies and phantom experiments. Finally, the 17O MRI method was demonstrated in a mouse model with glioblastoma (GBM) to assess the water movement across BBB after a bolus in injection of 17O-labeled water. The 17O MRI approach was also applied to a mouse model of middle cerebral artery occlusion (MCAO) in 17O-labeled gas inhalation experiments to assess cerebral oxygen metabolism in vivo. The success of these studies will pave the way for fast metabolic imaging using 31P and 17O MRI techniques and allow for the assessment of metabolic alterations in various disease models, such as diabetes, ischemic stroke, etc.

Committee:

Xin Yu, Sc.D. (Advisor); Nicole Seiberlich, Ph.D. (Committee Chair); Mark Griswold, Ph.D. (Committee Member); John Kirwan, Ph.D. (Committee Member); Nicola Lai, Ph.D. (Committee Member)

Subjects:

Biomedical Engineering

Keywords:

magnetic resonance imaging, magnetic resonance spectroscopy, energy metabolism, phosphorus-31, oxygen-17

Lessieur Contreras, Emma MercedesGenetic Modifiers of CEP290-Dependent Retinal Pathology
Doctor of Philosophy, Case Western Reserve University, 2018, Molecular Medicine
Genetic Modifiers of CEP290-Dependent Retinal Pathology Abstract by EMMA MERCEDES LESSIEUR CONTRERAS `Ciliopathies” is the coined term to refer to the broad array of human recessive disorders that have been attributed to disturbances in ciliary genes. One of the most intriguing ciliopathy-associated genes is CEP290. Mutations in this gene can lead to phenotypically distinct diseases that invariably present retinal involvement. Despite the identification of more than 130 mutations in CEP290, efforts to establish direct genotype-phenotype correlation have been unsuccessful. Here, I investigated one of the leading hypotheses in the field that proposes that the phenotypic variability observed in ciliopathies is the effect of mutations in second-site genetic modifiers. I tested this hypothesis in zebrafish cep290. For such purpose, first, I generated and characterized a zebrafish ahi1 mutant (Chapter 2). Next, I determined how loss of Cep290 impacts photoreceptor function and survival by analysis of two mutant alleles of cep290 in zebrafish (Chapter 3). Lastly, I investigated if heterozygous mutations in cilia genes have detrimental effects on homozygous mutations of cep290 (Chapter 3). And found that combined homozygosity of cep290 and heterozygosity in cilia genes ahi1 but not cc2d2a elicits visual acuity defects without exacerbation of photoreceptor degeneration, suggesting that loss of cep290 is differentially sensitive to the loss of one allele of ahi1 or cc2d2a. I believe that this work is highly significant since expands our understanding of the phenotypic diversity originated from mutations in CEP290, one of the most commonly ciliopathy causative genes. Furthermore, the establishment of a new cep290 animal model promises to be a useful tool for further study of the debilitating diseases emerging from mutations in this gene.

Committee:

Brian Perkins, Ph.D. (Advisor); Bela Anand-Apte, M.B.B.S.; Ph.D. (Committee Chair); Jonathan Sears, M.D. (Committee Member); Stephanie Hagstrom, Ph.D. (Committee Member); Oliver Wessely, Ph.D. (Committee Member)

Subjects:

Genetics; Health Sciences; Medicine; Molecular Biology; Ophthalmology

Keywords:

photoreceptor; cilia; ciliopathies; zebrafish; CEP290

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