Doctor of Philosophy, University of Akron, 2024, Biomedical Engineering

Myocardial infarction commonly known as heart attack, is a type of cardiovascular disease which occurs when the flow of blood is restricted to a part of the heart muscle for a prolonged period, leading to tissue damage or cell death due to lack of oxygen and nutrients. Several tissue engineering strategies have been implemented to regenerate the damaged cardiac tissue and improve cardiac function post myocardial infarction. One of the most promising strategies for cardiac regeneration is using injectable hydrogels derived from decellularized myocardial tissue. Compared with other natural or synthetic biomaterials, the decellularized cardiac extracellular matrix (ECM) hydrogels provide cardiac- specific microenvironment including ECM composition and biochemical cues which supports the cell attachment, growth, migration, and differentiation. Due to these advantages, decellularized cardiac ECM hydrogels have been widely explored for various cardiac tissue engineering applications. However, as the decellularized myocardial tissue is lyophilized and milled into a powder to form hydrogel, the material properties and the ability to induce angiogenesis (formation of new blood vessels) is greatly affected. To address this issue, we developed a hybrid hydrogel (Fn-cECM) by combining decellularized cardiac ECM hydrogel (cECM) solution and fibrin (Fn) solution and investigated their material properties and evaluated their interactions with therapeutic cells. We observed that the Fn-cECM hybrid hydrogel exhibited enhanced degradation, gelation kinetics and storage modulus compared to the cECM hydrogel. Additionally, we observed significant capillary network formation and angiogenic sprouting for human umbilical vein endothelial cells (HUVECs) and human mesenchymal stem cells (hMSCs) spheroids. Based on our promising outcomes, we evaluated the feasibility of fabricating granular hydrogels using cECM and Fn-cECM microgels produced via extrusion fragmentation to overcome the limita (open full item for complete abstract)

Committee: Ge Zhang (Advisor); Ge Zhang (Committee Chair); Qin Liu (Committee Member); Hossein Ravanbakhsh (Committee Member); Weinan Xu (Committee Member); Jiang Zhe (Committee Member) Subjects: Biomedical Engineering; Biomedical Research

Doctor of Philosophy, The Ohio State University, 2023, Mechanical Engineering

The extracellular matrix (ECM) is a 3D non-cellular polymer network that is present within all tissues and organs. The ECM is complex, dynamically remodeling, and crucial for maintaining homeostasis of the cellular microenvironment. The ECM provides not only a physical scaffold for cells, but also regulates various processes such as proliferation, migration, and differentiation of cells. Crosstalk between ECM constituents can occur either physically where cell-ECM interactions are regulated by the biophysical properties of the host tissue, or biochemically, through signaling molecules. On a biochemical level, interactions can happen through direct cell signaling, or through the ECM-mediated capture and release of potent signaling molecules. Studies have reported the effect of certain circulating molecules, like extracellular nucleic acids, and platelet derived growth factor (PDGF) in disease progression, such as in the case of cancer, cardiovascular, fibrotic, Parkinson, Alzheimer, and kidney diseases. On a biophysical level, modulation of the mechanical properties of the ECM by cells is believed to significantly influence the progression of certain diseased tissue such as in fibrosis, healing wounds, or the stroma of tumors, all of which are known to exhibit ECM remodeling through the cross-linking of fibrillar collagen and/or deposition of non-collagenous ECM. In addition, slowly moving interstitial flow through the ECM plays a major role in modulating cancer cell migration that may promote metastasis by redistributing morphogens, leading to chemotaxis, or through the activation of cell-surface mechanosensors, such as focal adhesion proteins, that promote cell motility. Here, I present hybrid in vitro systems that utilize microfluidic devices and DNA-based nanoscale sensors that enable measuring biochemical cues and biophysical forces in the ECM at a sub-cellular level. This thesis is organized into three parts. Part 1 covers engineering the ECM with DNA-b (open full item for complete abstract)

Committee: Carlos Castro (Advisor); Benjamin Walter (Committee Member); Jonathan Song (Advisor); Gunjan Agarwal (Committee Member) Subjects: Biomedical Engineering; Mechanical Engineering; Nanotechnology

Bachelor of Science (BS), Ohio University, 2023, Biological Sciences

Fibrosis, a pathological process characterized by excess extracellular matrix (ECM) deposition, can occur in many internal organs and tissues in response to various stimuli. As fibrosis progresses, scarring occurs, which ultimately leads to tissue dysfunction and organ failure. Patients with acromegaly, a rare disease usually caused by a benign, GH-producing pituitary tumor, have been reported to have prominent ECM deposition and scarring in certain tissues, which is indicative of fibrosis. In bGH transgenic mice, which express high levels of bovine growth hormone, several tissues [white adipose tissue (WAT), heart, intestine, and kidney] demonstrate a fibrotic phenotype. However, there is no previous research that investigates various bGH tissues – particularly from mice derived from a single cohort – for fibrosis. Additionally, WAT fibrosis is associated with obesity and lipodystrophy, and seems to be particularly associated with excess GH. This study aims to investigate the role of different cell types and genes involved in the development and progression of WAT fibrosis and determine if fibrosis is increased in BAT, liver, quad, kidney, lung, and spleen of aged bGH mice. Results of this thesis included a striking observation of increased fibrosis in all bGH tissues examined. For WAT, decreases in fibrosis-associated RNA expression in 3-month-old bGH mice via qPCR analysis was only observed in the perigonadal depot and not the subcutaneous depot that has more prominent collagen deposition. Interestingly, we observed an intriguing increase in fibrosis-associated RNA expression in a population of adipose stem and progenitor cells in 6-month-old mice within subcutaneous bGH WAT. These results indicate a potential common GH-induced mechanism of fibrosis across bGH tissues and pave the way for future research into WAT fibrosis.

Committee: Darlene Berryman (Advisor) Subjects: Biology; Biomedical Research

Doctor of Philosophy, The Ohio State University, 2020, Biomedical Engineering

The extracellular matrix is extensively reorganized throughout breast cancer progression. This reorganization contributes to cancer cell invasion and intravasation and is an independent prognostic factor for breast cancer patients. Cancer-associated fibroblasts appear to play a major role in this reorganization but the cellular signaling pathways contributing to this reorganization remain unclear. We show here that loss of the tumor suppressor phosphatase and tensin homolog (Pten) in fibroblasts promotes extracellular matrix alignment both in vitro and in vivo through increasing cell traction forces. Furthermore, low stromal PTEN expression correlated with high mammographic density, one of the major risk factors for breast cancer development. Matrix reorganization was concomitant with a marked increase in collagen deposition within the mammary gland. We therefore investigated the mechanism of collagen deposition and showed that loss of PTEN upregulated SPARC, which mediated both collagen and fibronectin assembly without modulating cell traction force. To further determine how Pten loss connected to matrix alignment, we designed a novel screening platform to examine matrix alignment in vitro using fibroblast-derived matrices, automated microscopy, and automated image analysis through MATLAB. We discovered a number of novel matrix alignment modulators, including protein kinase C (PKC), dual specificity tyrosine regulated kinase 1b (DYRK1b), platelet-derived growth factor receptor β (PDGFRβ), and Janus kinase (JAK), among others. The effect of these markers on patient survival was examined using publicly available patient datasets. Finally, we examined the effects of hypoxia and matrix metalloproteinase activity on matrix organization.

Committee: Jennifer Leight (Advisor); Samir Ghadiali (Committee Member); Jonathan Song (Committee Member) Subjects: Biomedical Engineering

MS, University of Cincinnati, 2019, Engineering and Applied Science: Chemical Engineering

Skin tissue constitutes the largest and most exposed organ in the human body, yet there is a lack in proper therapies to prevent scarring and infection in severe injuries. Therefore, the overall objective of this project is to engineer a biocompatible surface to help aid and promote enhanced regeneration in the body's native wound repair process. Biomimetic surfaces and materials have shown great potential in a variety of tissue engineering applications; however, none have come close to complete imitation of the body's complex systems. In this work, we seek to engineer an aligned, bioactive material capitalizing on a key structural and bioactive component found in all tissues throughout the body, the extracellular matrix (ECM). Within its interconnected network of fibers and proteins, the ECM instructs organizational, structural, and functional purposes and plays a key role in the dermal wound repair process as the provisional matrix that directs cell behavior. The ECM is secreted and assembled by cells and, when decellularized, maintains unique cell-derived biochemical and biomechanical cues. A decellularized, cell-assembled ECM therefore has powerful potential for use as a bioactive surface that mimics the skin tissue's native scaffold. The cell-secreted matrix, while mimetic of native ECM in composition and fibril organization, is produced with no particular orientation in vitro and therefore it lacks key topographical characteristics of native ECM. Therefore, we engineered topographically micropatterned biomaterials to help guide the alignment of cells and their cell-assembled matrix. Through studying the alignment and confluency of the resulting ECM, we determined optimum micropatterned geometries for the assembly of an aligned ECM on biomaterials. The aligned ECM, following decellularization, was characterized for use as a bioactive material to guide cell migration, promote cell proliferation, and direct cell orientation. The guided assembl (open full item for complete abstract)

Committee: Greg Harris Ph.D. (Committee Chair); Anastasios Angelopoulos Ph.D. (Committee Member); Yoonjee Park Ph.D. (Committee Member) Subjects: Chemical Engineering

Master of Sciences (Engineering), Case Western Reserve University, 2017, Biomedical Engineering

Patient-derived xenografts (PDX) are living ex situ tumor models that aid clinicians in selecting potent therapies for cancer patients. Unfortunately, a liver PDX is difficult to develop due to poor liver tumor engraftment in mice hosts. Tissue engineering studies have suggested that beneficial factors may exist in extracellular matrix (ECM) that can enhance tumor viability after transplant. We conducted comparative analysis of three published decellularization protocols for efficient cell removal. ECM samples produced by Freeze-thaw with Triton X-100 (TX-100), Sodium Dodecyl Sulfate (SDS) with TX-100, and TX-100 alone, were analyzed with nuclear labeling and structural analysis. SDS with TX- 100 was efficient and caused minimal alterations to the matrix structure. Additionally, we demonstrated with developed assays that liver cell lines can respond to isolated decellularized matrix and mimic in vivo liver activity. The work completed provides confidence to study the effects of decellularized liver matrix on patient-derived liver tumors.

Committee: Samuel Senyo PhD (Advisor); Eben Alsberg PhD (Committee Member); Analisa DiFeo PhD (Committee Member); Anirban Sen Gupta PhD (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, The Ohio State University, 2017, Biochemistry Program, Ohio State

Breast cancer remains the leading cause of cancer-related mortality in women worldwide. One of the many confounding factors in the treatment of this malignancy is the cellular heterogeneity of the breast. The normal breast is comprised of epithelial ducts, which are surrounded by a layer of basement membrane that separates the stroma from the ducts. The stroma itself is composed of yet other cell types- adipocytes, fibroblasts, immune cells, endothelial cells that make up blood vessels and pericytes that hug the endothelial cells. In the past decade, the tumor microenvironment, the stroma of the tumor, has emerged as a hallmark of cancer. Different components of this “microenvironment” become activated and fuel tumor progression to give rise to more aggressive, metastatic disease. While earlier diagnoses and development of targeted therapies have improved patient outcomes, this heterogeneity is still a cause for therapeutic resistance and metastatic spread, both of which encumber treatment and challenge patient survival. In this study, we report on the roles of Platelet-Derived Growth Factor Receptors (PDGFRs) alpha and beta in mammary carcinoma. PDGFRs are receptor tyrosine kinases, which upon ligand binding initiate a signaling cascade that results in major cellular processes such as proliferation and migration. They act in an oncogenic capacity in certain types of cancers of the lung, brain and blood. In an autocrine capacity, i.e. signaling within the tumor cells, their oncogenic role in breast cancer was reported, however their role in the stroma of breast cancer remains understudied. The central goal of this study thus was to elucidate the roles of PDGFRa and PDGFRß signaling in the mammary gland microenvironment, in both development and carcinogenesis. To address this question, genetic mouse models of stroma-specific activation of either PDGFRa or PDGFRß were utilized. We have found that while activation of PDGFRa abrogated mammary gland development, PDGFRß a (open full item for complete abstract)

Committee: Michael Ostrowski Ph.D. (Advisor); Gustavo Leone Ph.D. (Committee Member); Thomas Ludwig Ph.D. (Committee Member); Samir Ghadiali Ph.D. (Committee Member); Matthew Ringel M.D. (Committee Member) Subjects: Biochemistry; Biology; Cellular Biology; Mechanics; Molecular Biology; Oncology

Doctor of Philosophy, The Ohio State University, 2016, Biomedical Engineering

Volume overload (VO) induced heart failure results from an increase in blood volume (preload) to the heart. The heart responds to increases in hemodynamic load through compensative remodeling. VO has a distinct pattern of remodeling compared to pressure overload induced heart failure, which results in fibrosis. VO results in a net decrease in extracellular matrix (ECM). This loss of ECM contributes to the progression of the disease due to the loss of structural integrity. Since cardiac fibroblasts (CFs) are the main cells responsible for maintaining ECM in the heart, we characterized the in vitro phenotype of CFs isolated from a rat VO model, aortocaval fistula (ACF). Compared to sham operated animals, ACF fibroblasts displayed a phenotype that we described as “hypofibrotic”. ACF CFs secreted relatively less collagen and profibrotic molecules, such as a-smooth muscle actin (aSMA) and connective tissue growth factor (CTGF). Interestingly, ACFs produce approximately twice as much transforming growth factor-ß1 (TGF-ß), a key profibrotic stimulus, as their sham counterparts. However, there were no changes in the canonical TGF-ß pathway that could account for the hypofibrotic phenotype observed in ACF fibroblasts. Since others have shown that the cytoskeleton and the Rho/ROCK pathway play a role in fibroblast phenotype, we characterized the actin cytoskeleton in sham and ACF fibroblasts. We found that ACF CFs have significantly less F-actin than sham CFs. We were able to show that it is possible the actin cytoskeleton might account for phenotypic differences in CFs by chemically altering the amounts of F-actin and G-actin. When the cells were treated with a ROCK inhibitor, which allows F-actin to depolymerize into G-actin, CFs displayed a more hypofibrotic phenotype. Conversely, enhancement of F-actin with jasplakinolide treatment forced the CFs to have a profibrotic phenotype. Numerous studies have linked substrate modulus with effects on the cytoskeleton. S (open full item for complete abstract)

Committee: Keith Gooch PhD (Advisor); Jun Liu PhD (Committee Member); Pamela Lucchesi PhD (Committee Member); Aaron Trask PhD (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy (PhD), Ohio University, 2016, Chemistry and Biochemistry (Arts and Sciences)

Cell adhesion is an important early step of cancer metastasis, yet the roles of sialylation in regulating integrin-mediated breast cancer cell adhesion in comparison to migration and invasion are not well-understood. The role of sialylation on alpha5 beta1 and alpha2 beta1 integrins in the regulation of adhesion between breast cancer cells and extracellular matrix (ECM) was studied. Our data showed that alpha2, alpha5 and beta1 integrins had considerable alpha 2,6 sialylation on MDA-MB-231 cells, whereas signals from MCF-7 cells were undetectable. Cleavage of alpha 2,6 sialylation increased adhesion of MDA-MB-231 cells to ECM, while adhesion of MCF-7 cells was unaffected, consistent with the latter's lack of endogenous alpha 2,6 sialylated surface integrins. Neither surface expression of alpha5 beta1 and alpha2 beta1 integrins, nor activated beta 1 integrin, changed in MDA-MB-231 cells after sialidase treatment. However, sialidase treatment did not have significant impact on migration or invasion of MDA-MB-231 cells. Integrins not only play an important role in adhesion of cancer cells, but also have a direct connection with ionizing radiation-induced atherosclerosis, which is an adverse effect observed after radiotherapy. However, minimal attention has been given to monocytes/macrophages, which are exposed to the radiation at the same time. Under flow conditions using a parallel plate flow chamber to mimic physiological shear stress, we demonstrate here that the avidity between very late antigen-4 (VLA-4) of RAW264.7 cells and its ligand vascular cell adhesion molecule-1 (VCAM-1), was increased after low dose (0.5 Gy), but was reduced after higher dose (5 Gy) treatment of ionizing radiation. Treating the cells with free radical scavenger N-acetyl-L-cysteine reduced the avidity between RAW264.7 cells and VCAM-1 to a similar level. These results suggest that ionizing radiation regulates adhesive interactions between VLA-4 and VCAM-1, and that reactive oxygen spe (open full item for complete abstract)

Committee: Shiyong Wu (Advisor) Subjects: Biochemistry

Doctor of Engineering, Cleveland State University, 2016, Washkewicz College of Engineering

Localized host inflammatory microenvironment resulting from several neuropathologies (e.g., trauma, amyotrophic lateral sclerosis (ALS), glioblastomas) leads to progressive degeneration of neuronal tissue and destruction of axonal tracts in the adult central nervous system (CNS). Failure to reinstate healthy cells and axonal connections under these conditions can severely compromise locomotion and cognitive function, resulting in muscle atrophy, paralysis and even death. Annually, thousands of people are diagnosed with various neuropathologies and a majority of them succumb to these conditions soon after. The adult CNS has a limited ability for self-repair, which necessitates repair strategies focused on ameliorating secondary cellular degeneration, promoting endogenous repair mechanisms, and exogenous cell replacement therapy. Currently, pharmacological and surgical treatments options are limited in their outcomes for these types of ailments. Neural stem cells (NSCs) isolated from the embryonic and adult striatum have the capacity to divide and differentiate into various neuronal and glial lineages, thus demonstrating their utility in regenerating lost neuronal populations. To further investigate their clinical potential, in this work, we first developed and tested the utility of uncrosslinked 3D biological hydrogels (compressive strength < 600 Pa) for their ability to promote murine NSC survival, differentiation into desired lineages and neurite outgrowth, in the presence (or absence) of exogenous cues such as retinoic acid. In the second step, the influence of an activated murine microglia in regulating the phenotype and genotype of murine NSCs within a localized 3D coculture microenvironment was investigated, and the key cytokines and chemokines which regulate NSC survival, differentiation and neurite outgrowth were identified. Finally, in the third step, the effects of paracrine-signaling between adult human NSCs and human pediatric glioblastoma cells within a (open full item for complete abstract)

Committee: Chandra Kothapalli Ph.D. (Committee Chair); Nolan Holland Ph.D. (Committee Member); Xue-Long Sun Ph.D. (Committee Member); Joanne Belovich Ph.D. (Committee Member); Moo-Yeal Lee Ph.D. (Committee Member) Subjects: Biomedical Engineering; Medicine; Neurosciences

Doctor of Business Administration, Cleveland State University, 2014, Monte Ahuja College of Business

This dissertation provides empirical evidences in global cross-listed stocks trading volume and pricing. The first essay documents the global trading volume distribution of cross-listed stocks and examines factors that make a host market competitive in attracting order flows from the counterpart domestic market. The results show that host markets are more successful in attracting trading volume when they have a higher information factor, have lower bid-ask spreads, provide better investor protection and information disclosure, share the common language or legal origin with the counterpart home markets and locate closer to the home market. The second essay investigates the market competitiveness among rival host markets based on a unique sample of global firms simultaneously cross-listed in multiple foreign countries. I present the global cross-listings and trading volume distributions cross host-home markets as well as over time, and provide robust evidences that host markets are more successful in attracting trading volume from other competing markets when they have lower bid-ask spreads, better legal protection, more market liquidity, higher level of financial development, and where the firms with longer listing history. Interesting, I consistently find that host countries with English common law origins are able to attract trading volume while French civil law origin host countries attract less trading activities. The third essay investigates the cross-listed stock price discovery process. I use synchronous trading data and the error correction model to find that prices on the home and the U.S. markets are co-integrated and mutually adjusting. The price adjustment in response to price disparity happens in both the home market and the U.S. (host) market. In most cases, domestic prices are dominant for the price discovery. However, I also observe a statistically significant amount of feedback from the U.S. markets. The greater the competition offered by the U.S. (open full item for complete abstract)

Committee: Haigang Zhou PhD (Committee Chair); Alan Reichert PhD (Committee Member); Xiankui (Bill) Hu PhD (Committee Member); Walter Rom PhD (Committee Member) Subjects: Finance

Master of Science in Biomedical Engineering, Cleveland State University, 2014, Washkewicz College of Engineering

Vascular diseases such as atherosclerosis and aneurysms are characterized by the over-proliferation and migration of aortic SMCs, and degradation of ECM within the vessel wall, leading to compromise in cell-cell and cell-matrix signaling pathways. Recent tissue engineering approaches to regulate SMC over-proliferation and enhance healthy ECM synthesis showed promise, but resulted in low crosslinking efficiency and matrix deposition yields. In this study, the benefits of exogenous nitric oxide cues, delivered from GSNO, to cell proliferation and matrix deposition by adult human aortic SMCs within 3D biomimetic cultures have been explored. The first experiment utilized a microfluidic platform with two adjacent, permeable 3D culture chambers, to enable paracrine signaling between vascular cell cocultures. Healthy HA-SMCs were cultured in these devices within 3D collagen hydrogels, either alone or in the presence of human aortic ECs cocultures, and exogenously supplemented with varying GSNO dosages (0-100 nM) for 21 days. Results showed that EC cocultures stimulated SMC proliferation within GSNO free cultures. However, with increasing GSNO concentration, SMC proliferation decreased in the presence or absence of EC cocultures, while EC proliferation increased. GSNO (100 nM) significantly enhanced the total protein amount synthesized by SMCs, in the presence or absence of EC cocultures, while lower dosages offered marginal benefits. On a per cell basis, multi-fold increases in the synthesis and deposition of elastin, GAGs, hyaluronic acid and LOX were noted at higher GSNO dosages, and coculturing with ECs significantly furthered these trends. The matrix yields of these proteins reached almost 40 - 51 % within selective cocultures receiving GSNO. Similar increases in TIMP-1 and MMP-9 levels were noted within cocultures with increasing GSNO dosages, although MMP-2 levels remained attenuated. These quantitative assay data were strongly supported by immunofluorescence image (open full item for complete abstract)

Committee: Chandra Kothapalli PhD (Committee Chair); Nolan Holland PhD (Committee Member); Moo-Yeal Lee PhD (Committee Member) Subjects: Anatomy and Physiology; Biochemistry; Biomedical Engineering; Biomedical Research; Cellular Biology; Engineering; Health; Health Care; Medicine; Pharmaceuticals

PhD, University of Cincinnati, 2010, Engineering and Applied Science: Biomedical Engineering

The objective of this thesis was to design self-assembling biomaterials whose physical and biological properties can be systematically adjusted to modulate cell growth and differentiation. The intended applications of these biomaterials include defined 3D cell culture scaffolds as well as coatings for existing prosthetics. The complex and dynamic nature of extracellular matrices necessitates the precise integration and adjustment of multiple physical, chemical, and biological features within engineered biomaterials, but this has been challenging for previous scaffolds owing to the fact that these features tend not to be adjustable independently. Instead, these properties tend to be conflated and entangled, limiting the ability to systematically engineer scaffolds with multiple components. As a step towards addressing this issue, this thesis describes the development of a modular self-assembling biomaterial system capable of incorporating multiple physical or biological functions into precisely defined biomaterials without affecting other material properties. Three families of different biological and physical functionalities were designed, synthesized, and investigated: those that modulate matrix mechanics, those that mediate cell-matrix binding, and those that can release soluble effector molecules. All materials were based on a short, synthetic, self-assembling peptide sequence, Q11, which formed self-supporting hydrogels in physiological conditions. To independently modulate matrix mechanics, Q11 derivatives were developed possessing chemoselective functional groups that could be polymerized via native chemical ligation. This method produced significantly stiffened gels, which also significantly enhanced endothelial cell proliferation in an independent manner. To develop modular self-assembling ligand-bearing peptides, endothelial cell-interactive ligands, RGDS, REDV, IKVAV, and YIGSR amino acid sequences were added to the N-terminus of Q11 (X-Q11). The incorpo (open full item for complete abstract)

Committee: Daria Narmoneva PhD (Committee Chair); Joel Collier PhD (Committee Member); Marepalli Rao PhD (Committee Member); Jason Shearn PhD (Committee Member) Subjects: Biomedical Research

Doctor of Philosophy, The Ohio State University, 2008, East Asian Languages and Literatures

This dissertation is a data-driven exploration of the syntax, semantics, and pragmatics of the Japanese accusative-quotative construction (also known as the "subject to object raising" construction, or "exceptional case marking" construction (ECM), or "prolepsis" construction). An example: Hanako wa Tarou o baka da to omotte iru "Hanako believes Tarou to be an idiot." A special type of statement of propositional attitude, it exhibits epistemic specificity, and its construal involves more than one context of interpretation. Accusative subjects are interpreted as specific with respect to the beliefs of the agent of attitude (ruling out unambiguously non-specific indefinite noun phrases). A semantic and pragmatic constraint covers this observation: Accusative-quotative constructions cannot embed predications denoting existential assertions as evaluated under the domain of the belief operator generated by the matrix verb. The constraint accounts for the lack of certain scope ambiguities involving existential quantification, the inadmissability of weak cardinal floating quantifiers hosted by accusative subjects, the impossibility of embedding specificational pseudoclefts in accusative-quotative complements, and the impossibility of construing wh-accusative subjects with questions embedded in accusative-quotative complements. Furthermore, because predications with past or future tense reference and predications referring to events or temporary states depend on eventualities for their interpretations, they can only be licensed in accusative-quotative complements either through generic quantification over eventualities, or by referring to discourse antecedent eventualities supplied in the context. Such reference obviates the need for existential quantification over eventualities. One semantic/pragmatic constraint provides a unified and more observationally adequate account than analyses that refer to the distinction between tensed and un-tensed predicates, or between stage- (open full item for complete abstract)

Committee: Mineharu Nakayama PhD (Advisor); James Unger PhD (Committee Member); Etsuyo Yuasa PhD (Committee Member) Subjects: Linguistics

Doctor of Philosophy, The Ohio State University, 2007, Animal Science

Failure to terminate the inflammatory response results in chronic inflammation that may lead to disease or cancer, especially in epithelial cells. We explored mammary epithelial cells as a model to identify mechanisms of anti-inflammatory activity in epithelia alone in the absence of immune cells. Bacterial endotoxin (ET) added to SCp2 mammary secretory epithelial cells: (1) induced both interleukin-6 (IL-6) secretion and nitric oxide (NO) production, but with unexpected delay in expression of mRNA for iNOS compared to IL-6; and (2) NFκB activation by 1 h after ET application (post-ET) that was transient for NFκB/p65 but persisted for NFκB/p50. Selective inhibition of NFκB activation by Wedelolactone reduced ET-induced expression of IL-6 mRNA and protein but not iNOS mRNA or NO production, suggesting differences in ET-induced IL-6 and iNOS regulation via NFκB activation. Serum supplementation but not soluble extracellular matrix (EHS) enhanced ET-induced IL-6 mRNA expression and protein secretion without affecting iNOS mRNA expression or NO production, confirming the different modes of regulation of IL-6 and iNOS expressions. Culturing SCp2 cells on a confluent monolayer of SCg6 mouse mammary myoepithelial cells increased IL-6 secretion dramatically even in the absence of ET, with ET treatment further increasing IL-6 secretion but having little effect on induction of NO production over that for SCp2 cells alone; showing importance of microenvironment and cell-cell interaction in regulation of inflammation and likely its link to cancer in epithelia. ET-induced inflammation in SCp2 cells was used to screen and identify anti-inflammatory fractions of methanol extracts of wild Lebanese Centaurea ainetensis, used in Lebanese folk medicine to treat inflammatory diseases. A partially purified solid phase (SPE columns) methanolic elution fraction of C. ainetensis followed by methanol gradient elution on reverse phase HPLC chromatography (RP-HPLC) strongly inhibited ET-induc (open full item for complete abstract)

Committee: Floyd Schanbacher (Advisor); Charles Brooks (Other); James DeWille (Other); Joy Pate (Other) Subjects:

Master of Science (MS), Ohio University, 2010, Industrial and Systems Engineering (Engineering and Technology)

Fuel maps are utilized by the fuel injection system as a guide for accurate delivery of fuel under a specified load. A fuel map is determined by the manufacturer and usually not manipulated. This research involves exhaust gas oxygen data collection using an original equipment engine control module (ECM), artificial neural network (ANN) modeling, response surface generation that will act as the new fuel map, implementing the map into the ECM, and testing. ANN modeling is used first to predict volumetric efficiency (VE) values in the fuel map, then used to optimize the VE values based on the air to fuel ratio. The results are then compared with an alternative optimization technique and the original equipment fuel map. Optimization of the fuel map will provide physical performance, economic, and environmental gains. Applying this methodology would allow the fuel map to be updated using little expert knowledge.

Committee: Gary R. Weckman PhD (Advisor); Helmut Paschold PhD (Committee Member); Namkyu Park PhD (Committee Member); Tao Yuan PhD (Committee Member) Subjects: Artificial Intelligence; Industrial Engineering; Systems Design; Transportation

Doctor of Philosophy, Case Western Reserve University, 2011, Biomedical Engineering

Rotator cuff tendon injury is a debilitating health concern that affects more than 40% of the aging population. Despite advances in surgical treatment, the failure rate of rotator cuff repairs ranges 20-90%. Naturally-occurring extracellular matrices (ECMs) have been recently investigated as augmentation scaffolds, but none has yet demonstrated both the appropriate biological and mechanical properties. This dissertation proposes to enrich fascia ECM with high molecular weight tyramine substituted-hyaluronan (TS-HA) for rotator cuff repair. The central hypothesis is that TS-HA treatment will decrease chronic inflammation without decreasing the time-zero or post-implantation mechanical properties of fascia. The specific aims are to develop a TS-HA treatment method and to evaluate the host response and concomitant mechanical properties of treated fascia in a rat abdominal wall model. TS-HA treatment increased the HA content of fascia by an order of magnitude to ~1% tissue weight. The incorporated HA was distributed throughout the ECM and, upon cross-linking, was retained as a hydrogel network. Cross-linked TS-HA treated fascia exhibited an increased macrophage and giant cell response and a lower density of fibroblast-like cells than water treated controls. Treated fascia, with or without cross-linking, exhibited a predominantly M2 pro-remodeling macrophage profile similar to water controls, which is suggestive of constructive tissue remodeling. All grafts exhibited a chronic lymphocytic response that is suggestive of an immune response to the fascia xenograft. Fascia samples in all groups demonstrated time-dependent decreases in mechanical properties. Cross-linked TS-HA treated fascia exhibited a lower toe-region elastic modulus and trended towards a higher transition strain than water treated controls not only after implantation, but also at time zero. These findings demonstrate that HA augmentation can alter both the host response and the mechanical properties of f (open full item for complete abstract)

Committee: Kathleen Derwin PhD (Advisor); Roger Marchant PhD (Committee Chair); Eben Alsberg PhD (Committee Member); Thomas Bauer MD, PhD (Committee Member); Vince Hascall PhD (Committee Member) Subjects: Biomedical Engineering

Master of Sciences, Case Western Reserve University, 2009, Pathology

When T cells adhere to the ECM, under certain circumstances they will polarize and exhibit the morphology of a migrating cell. We are investigating three specific questions: (a) What environmental signals modulate T cell cytoskeletal reorganization, especially vimentin, the intermediate filament? (b) Which Rho GTPase is involved in vimentin polarization on discrete ECM ligands, such as collagen type I and fibronectin? (c) What is the mechanism and function of vimentin reorganization upon engagement of distinct ECM ligands? Our preliminary findings demonstrate that (a) certain but not all inside-out and outside-in signals lead to integrin activation that results in T cell cytoskeletal rearrangement, particularly vimentin polarization, on ECM ligands. (b) Rho GTPases differentially modulate vimentin polarization when T cells adhere to distinct ECM ligands. This work sets a base for further investigation of the potential role vimentin plays in lymphocyte migration and signaling.

Committee: Nicholas Ziats PhD (Committee Chair); Alan Levine PhD (Advisor); Steven Eppell PhD (Committee Member); Clive Hamlin PhD (Committee Member) Subjects:

MS, University of Cincinnati, 2012, Engineering and Applied Science: Mechanical Engineering

Pulse electrochemical micromachining (PECMM) is an unconventional noncontact manufacturing method suitable for the production of micro sized components on a wide range of electrically conductive engineering materials such as metals, semiconductors, and metal matrix composites. Absence of tool wear is a major advantage expected of PECMM. However, tools are often chemically corroded by certain electrolytes used in PECMM. In this thesis a novel approach i.e. cryogenic treatment of in-house made microtools has been studied to reduce/eliminate tool wear in PECMM. An automated PECMM system has been designed and built in-house. A LabVIEW based process monitoring system has been developed for accurate gap control. An analytical model has been developed for the prediction of diameter of the tools produced by PECMM. Using this noncontact machining system ultra-high aspect ratio (400) tungsten microtools have been fabricated for wide range of applications from neural implants to deep micro hole drilling. Excessive wear was noticed during the application of these tools in the micromachining of difficult to machine tungsten carbide. Cryogenic treatment was performed on tungsten microtools to improve the corrosion resistance and obtain increased tool life in PECMM. Process parameters for the PECMM of tungsten carbide metal matric composite were established to ensure higher machining accuracy with lesser short circuits. By using optimum cryogenic cycle parameters, 200% increase in material removal rate, and 45% reduction in tool wear was achieved in the pulse electrochemical micromachining of tungsten carbide metal matrix composite using cryogenically treated microtools.

Committee: Sundaram Murali Meenakshi PhD (Committee Chair); Hongdao Huang PhD (Committee Member); Anil Mital PhD PE (Committee Member) Subjects: Mechanics