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Zhao, YueAutomatic Prevention and Recovery of Aircraft Loss-of-Control by a Hybrid Control Approach
Doctor of Philosophy (PhD), Ohio University, 2016, Electrical Engineering & Computer Science (Engineering and Technology)
In this dissertation, an integrated automatic flight controller for fixed-wing aircraft Loss-of-Control (LOC) Prevention and Recovery (iLOCPR) is designed. The iLOCPR system comprises: (i) a baseline flight controller for six degrees-of-freedom (6DOF) trajectory tracking for nominal flight designed by trajectory linearization, (ii) a bandwidth adaption augmentation to the baseline controller for LOC prevention using the timevarying PD-eigenvalues to trade tracking performance for increased stability margin and robustness in the presence of LOC-prone flight conditions, (iii) a controller reconfiguration for LOC arrest by switching from the trajectory tracking task to the aerodynamic angle tracking in order to recover and maintain healthy flight conditions at the cost of temporarily abandoning the mission trajectory, (iv) a guidance trajectory designer for mission restoration after the successful arrest of a LOC upset, and (v) a supervisory discrete-eventdriven Automatic Flight Management System (AFMS) to autonomously coordinate the control modes (i) - (iv). Theoretical analysis and simulation results are shown for the effectiveness of the proposed methods.

Committee:

Jim Zhu (Advisor); Douglas Lawrence (Committee Member); Frank Van Grass (Committee Member); Robert Williams (Committee Member); Aili Guo (Committee Member); Sergiu Aizicovici (Committee Member)

Subjects:

Aerospace Engineering; Engineering

Keywords:

Aircraft Loss-of-control; hybrid; arrest; prevention; recovery; flight control system; arrest; guidance; trajectory linearization control; switching mode; reconfiguration; bandwidth adaptation; multiple-time-scale nested loop

Lin, Ho-PiCelecoxib: Its non-cox-2 targets and its anti-cancer effects
Doctor of Philosophy, The Ohio State University, 2005, Pharmacy
Our previous work showed that celecoxib (Celebrex®), a nonsteroidal anti-inflammatory drug (NSAID, cyclooxygenase-2 inhibitor) was unique among other cyclooxygenase-2 (COX-2) inhibitors in its superior ability to induce prostate cancer cell death, indicating the involvement of non-COX-2 components in the mode of action of celecoxib. To test this hypothesis, we investigated the effect of COX-2 depletion on apoptosis by tetracycline controllable COX-2 antisense constructs and performed a structure-activity analysis of the COX-2 inhibitor celecoxib in PC-3 cells. Both strategies came out with the same conclusion, which is the unique apoptotic inducing activity of celecoxib comes from interfering with other important signaling pathways. We then focused on one of the most promising pathways, PI3K/PDK-1/Akt pathway, which was previously demonstrated in our laboratory to be severely interrupted by celecoxib. Further target identification showed that PDK-1 is one of major targets. Later, we learned that inhibition of PI3K/PDK-1/Akt pathway alone can only induce apoptotic cell death in LNCap cells but not PC3 cells, and further elucidated that the significantly higher level of Bcl-xL in PC3 cells is attributable to this discrepancy. However, the observations of quick apoptotic death in PC3 cells triggered by celecoxib indicate that other yet unidentified targets are also involved. By studying growth inhibitory effects in Human Umbilical Vein Endothelial Cells (HUVECs), we were able to identify cyclin dependent kinases (CDKs), are important targets in addition to PDK-1 for celecoxib. In conclusion, celecoxib trigger its anti-cancer effect through interfering with multiple signaling pathways. This study was used as a fundamental basis in our laboratory for developing novel anti-cancer agents, targeting pathways important for cancer cell survival and growth, based on structural modifications starting from celecoxib.

Committee:

Ching-Shih Chen (Advisor)

Keywords:

Celecoxib; COX-2; Akt; PI3K; PDK1; CDKs; Apoptosis; Cell cycle arrest; HUVECs

Finkeldey, Jessica GraceThe Influence of Skin Color on the Likelihood of Experiencing Arrest in Adulthood
Master of Arts (MA), Bowling Green State University, 2014, Sociology
Research has long documented that darker skinned people generally experience more social and economic disadvantage than those with lighter skin, but little research has examined the effect of skin tone on criminal justice system outcomes. The few studies that have been conducted tend to find darker black and Latino individuals are treated harsher than their lighter counterparts, but most of these studies focus on disparities in sentencing. Only two studies have examined the effect of skin color on police contact. In addition, researchers have yet to examine how skin color affects CJS outcomes for other minority groups. Furthermore, most studies rely on official institutional data. Using data from the National Longitudinal Study of Adolescent Health, the current research examined the influence skin color has on adult arrests for black, Latino, Asian, and white respondents. The current study is important because it goes beyond studies on racial disparities in arrest by examining skin color as a characteristic associated with race and ethnicity. Analyses revealed that darker skinned individuals were more likely to experience an arrest than those with lighter skin, although the relationship between skin tone and arrest was moderated by gender within some racial/ethnic subgroups. Specifically, darker skin tones were associated with adult arrests for black men, Latino men and women, Asian women, and white men and women. In addition, age and irritability magnified the relationship between skin color and arrest for Latinos. Notably, the relationship between skin tone and arrest for these subgroups persisted even after controlling for deviant behavior; thus, darker skinned individuals were not more likely to be arrested because they were more deviant. Furthermore, this study found some evidence that other life outcomes, especially education, act as pathways that explain why darker skin might lead to adult arrests. Overall, the current research indicates skin tone is an important characteristic that affects the likelihood of experiencing an arrest in adulthood.

Committee:

Stephen Demuth (Advisor); Gary Oates (Committee Member); Matthew VanEseltine (Committee Member)

Subjects:

Criminology; Sociology

Keywords:

Skin Color; Arrest; Colorism; Race; Add Health

Neigh, Gretchen N.Neural and immune changes that occur following psychological and physical stressors
Doctor of Philosophy, The Ohio State University, 2004, Neuroscience
Exposure to stressors can influence the onset and progression of both physical and mental disease, and the effects of stressors on physiology and behavior are, at least in part, mediated by the hypothalamic pituitary adrenal (HPA) axis. The hippocampus is a component of the HPA axis that is susceptible to stressor-induced damage and alterations in the cytoarchitecture of the hippocampus can alter HPA axis function and subsequently immune function. The first series of experiments examined the role of stressor-induced energetic shortage, as signaled by increased concentrations of glucocorticoids, in suppression of immune function and neurogenesis. Mice supplemented with pyruvate, a potent producer of cellular energy, had a lower cumulative exposure to elevated concentrations of glucocorticoids and did not exhibit the restraint-induced suppression of immune function that was evident in restrained mice that did not receive pyruvate supplementation. Pyruvate was not protective against stressor-induced changes in neurogenesis. However, exposure to stressors increased the proportion of proliferating astrocytes in the hippocampus, as compared to neurons. The second set of experiments examined the effects of damage to the hippocampus, by cardiac arrest and resuscitation, on behavior as well as immune function. Cardiac arrest and resuscitation increased anxiety-like behavior, decreased social interaction, and impaired spatial memory. In addition, prior exposure to a restraint stressor augmented post-arrest anxiety-like behavior. The behavioral deficits observed were attributed to hippocampal damage, a reduction in dendritic spines, and an increase in the reactive microglia in the hippocampus. Furthermore, hippocampal damage following cardiac arrest and resuscitation altered HPA axis activity and augmented cell-mediated immune function as compared to mice that were exposed to cardiac arrest and resuscitation but did not sustain brain damage. In addition, the relationship between hippocampal damage and immune function appeared to be bidirectional, as survival following cardiac arrest and resuscitation was compromised in mice that were immunized with a novel protein prior to the cardiac arrest procedure. In conclusion, the work described in this dissertation adds to the body of literature that describes the relationship between the HPA axis and the immune system.

Committee:

Randy Nelson (Advisor); A. DeVries (Advisor); Firdaus Dhabhar (Other)

Keywords:

stress; hippocampus; HPA axis; cardiac arrest; psychoneuroimmunology; corticosterone; housing; pyruvate

Weil, Zachary M.Social And Temporal Determinants Of Brain, Behavior And Immune Function
Doctor of Philosophy, The Ohio State University, 2008, Neuroscience
In this dissertation, I will consider the consequences (physiological, behavioral, and susceptibility to injury) associated with adaptations to both changing biological times and alterations in the social environment. To that end This dissertation is divided into three sections. Section I (chapters 2 and 3) describe a series of experiments that investigate how the social environment regulates inflammatory and behavioral responses to acute administration. Those experiments were designed to determine how animals parse competing behavioral and physiological priorities in order to maximize fitness and survive infection. Section II (chapters 4 and 5) describe the first photoperiodism experiments in this dissertation (see below). Briefly, photoperiodism is the use of day length to regulate seasonal changes in physiology and behavior. Cell-mediated immune responses are typically enhanced in short winter-like day lengths. These experiments were designed to address the role of photoperiod exposure early in life and also the modulatory effects of social housing on photoperiod-mediated changes in the immune system. Section III (chapters 6-9) includes four experiments that investigated temporal and social factors that regulate functional outcomes following cardiac arrest and cardiopulmonary resuscitation. This final set of experiments was conducted to describe and investigate natural fluctuations in ischemic outcomes. I investigated ischemic outcomes at different times of day (chapter 6), after differential social housing (chapter 7), and after sleep deprivation (chapter 8). All of these experiments focused on the role of social and temporal variables in the regulation of inflammatory responses to ischemia.

Committee:

Randy Nelson (Advisor); Courtney A Devries (Committee Member); Gary Berntson (Committee Member); Georgia Bishop (Committee Member); Courtney Lynch (Committee Member)

Subjects:

Biomedical Research

Keywords:

neuroscience; neuroendocrinology; inflammation; cardiac arrest; seasonality; circadian rhythms; photoperiodism; sickness behaviors.

Rai, Urvashi Spindle Assembly Checkpoint Stability Depends on Integrity of the Nucleolus and Septins in Saccharomyces cerevisiae
Doctor of Philosophy, Case Western Reserve University, 2017, Molecular Biology and Microbiology
The spindle assembly checkpoint (SAC), also known as the spindle or mitotic checkpoint, arrests the metaphase-to-anaphase transition when the chromosomes are not properly attached to the mitotic spindle. In S. cerevisiae (budding yeast), at the end of G2 phase, the bud is large and the nucleus stretches between mother and daughter (bud) cells. We impose a “Medial Nuclear Division (MND) arrest” by depleting the activator of the anaphase-promoting complex, Cdc20. At MND arrest, the spindle checkpoint stabilizes a metaphase-like intermediate in which the nuclear envelope spans the bud neck while chromatin, the spindle pole bodies, and the spindle repeatedly translocate through a narrow constriction at the level of bud neck. Despite the ongoing chromatin transits, the nucleolus (organized around rDNA repeats on the right arm of chromosome XII) remains in the mother domain, marking the polarity of the nucleus. The restriction of the nucleolus can be attributed to its massive structure, since reduction of rDNA transcription fragments the nucleolus and these fragments enter the bud domain. AT MND arrest, the nucleus is encircled by a cortical ring of conserved septin proteins. During chromatin transits, repeated traversal of the spindle and spindle pole bodies through bud neck are surprising since the bud neck restricts diffusion of membrane proteins between mother and bud. In this study, we demonstrate that inactivation of septins allows arrested cells to complete the cell cycle, with the alternate APC activator, Cdh1, being necessary and sufficient for cells to escape this checkpoint arrest. Thus, control elements both internal and external to the nuclear envelope at the level of the bud neck determine whether features of the cell cycle will modulate stability and possible escape from checkpoints. Both stability and escape could have direct cancer relevance.

Committee:

Alan Tartakoff (Advisor); David McDonald (Committee Chair); Kristian Baker (Committee Member); Zhenghe Wang (Committee Member)

Subjects:

Biology; Cellular Biology; Molecular Biology

Keywords:

Cell Cycle Arrest; Spindle Assembly Checkpoint; SAC; Cdc20; Nucleolus; Septins; Yeast

Prakash, AnandInvestigating The Triggers For Activating The Cellular DNA Damage Response During Adenovirus Infection
Doctor of Philosophy, Miami University, 2014, Microbiology
Cellular genomic integrity is constantly attacked by a variety of exogenous and endogenous agents. In response to damaged DNA, the cell activates a DNA damage response (DDR) pathway to maintain genomic integrity. Cells can also activate DDRs in response to infection with several types of viruses. The cellular DDR pathway involves sensing DNA damage by the Mre11, Rad50, Nbs1 (MRN) sensor complex, which activates downstream ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR) kinases. These kinases phosphorylate downstream effector proteins implicated in cell cycle arrest, DNA repair, and, if the damage is irreparable, apoptosis. The induction of DDRs includes focal accumulation and phosphorylation of several DDR proteins. Adenovirus (Ad) mutants that lack early region 4 (E4) activate a cellular DDR. E4 proteins normally inactivate the MRN sensor complex and prevent downstream DDR signaling involved in DNA repair and cell cycle checkpoint arrest in wild-type Ad5 infections. The characteristics of Ad infection that activate the cellular DDR are not well understood. We have investigated the ability of replication defective and replication competent Ad mutants to activate cellular DDRs and G2/M cell cycle arrest. Ad infection induced early focal accumulation of DDR proteins such as Mre11, Mdc1, phosphorylated ATM (pATM), phosphorylated Chk2 (pChk2), and 53BPI, independent of the replication status of the mutants studied. However, Mre11 and pATM foci were transient in replication defective infections and were only maintained in infections with replication competent mutants. Viral DNA replication was correlated with amplification of pATM levels as well as its substrates, pChk2 and pNbs1. Furthermore, we found that G2/M cell cycle arrest was not activated by a replication defective mutant or a mutant expressing the E4orf3 encoded 11kDa protein. Our results suggest that the initial induction of DDR foci does not require viral DNA replication. In contrast, viral DNA replication is important for maintenance of DDR proteins at viral replication centers, amplification of pATM, pChk2, and pNbs1, and G2/M cell cycle arrest.

Committee:

Eileen Bridge (Committee Chair); Gary Janssen (Committee Member); Joseph Carlin (Committee Member); Xiao-Wen Cheng (Committee Member); David Pennock (Committee Member)

Subjects:

Microbiology

Keywords:

Adenovirus; E4orf3; E4 11kDa; E4orf6; E4 34kDa; ATM; Mdc1; foci; phosphorylation; DDR; arrest; replication

YU, XIAOHUA ANNIETIME HISTORY ANALYSIS OF THE DYNAMIC RESPONSE OF HORIZONTAL LIFELINES
MS, University of Cincinnati, 2003, Engineering : Civil Engineering
Workers at elevated positions must be protected from falling or from hazardous consequences of falls. A horizontal lifeline system (HLL) is a commonly used fall arrest system (FAS) that provides protection such that when a fall does occur, the fall would be stopped promptly in a manner that prevents injury. Although the HLL systems have been in use for several decades, the design of these systems is generally completed using simple methods. One popular design method is based on a simplified energy balance analysis, which is to predict the maximum force and the maximum displacement for a fall of one person. This method may be applied to the special case of multiple persons falling only with the restrictive assumption that all people in the system must fall precisely simultaneously. It is generally regarded that this assumption is implausible and furthermore, the validity of consequent solution has not been verified because of limitation of the analysis method. The present research shows the simultaneous-fall assumption may result in an unconservative solution. In this paper, a numerical time-history method is introduced. Based on this method, two computer programs are developed: one for the single-person fall and the second for the two-person fall. Satisfactory agreement has been found in comparison with previous research results. Using these programs, an extensive parametric analysis has been conducted on the configuration of the HLL system. Suggestions for design optimization are provided.

Committee:

Dr. Frank Weisgerber (Advisor)

Subjects:

Engineering, Civil

Keywords:

Horizontal Lifeline; HLL; Time-History; Dynamic; Fall Arrest System; FAS

Yeh, Ting-YuanThe Role of Oxygen in Cardiopulmonary Resuscitation and Post Resuscitation Period – A Mitochondrial Perspective
Doctor of Philosophy, The Ohio State University, 2010, Biophysics

Sudden cardiac arrest is a leading cause of death in the United States and is responsible for more than 300,000 deaths every year. For the last fifty years, the guidelines of cardiopulmonary resuscitation (CPR) have been the standards to revive cardiac arrest patients. However, the major components of CPR have not changed since its birth and the success rate of CPR remains unsatisfied (5-18%). My work presented in the dissertation mainly focuses on the role of oxygen during the resuscitation and post-resuscitation periods as well as correspondent mitochondrial functions. There are four parts in the dissertation. In chapter 2, a rat CPR model was used to demonstrate that oxygen is critical during resuscitation in order to achieve return of spontaneous circulation (ROSC). Additionally, there was no significant difference between the treatment groups (21% oxygen vs. 100% oxygen resuscitation) in terms of survival rates or neurological outcome. In chapter 3, mitochondrial functions were examined in the hearts undergoing 15 minutes of cardiac arrest and 10 minutes of CPR as compared to the hearts undergoing 25 minutes of cardiac arrest. The results suggest that, despite the inherent low oxygen delivery, CPR after prolonged cardiac arrest preserves heart mitochondrial function and morphology. It demonstrates the beneficial effects of CPR from a subcellular perspective for the first time. Preservation of mitochondrial function is reflected by improved mitochondrial respiration, electron transport chain (ETC) complex activities, and preservation of the ETC proteins. Meanwhile, complex I is the most sensitive ETC complex to ischemic injury and its activity is positively correlated with mitochondrial respiration.

In chapter 4, a rat cardiopulmonary bypass (CPB) model was done to study the effects of hyperoxygenation during the post-resuscitation period. After 25 minutes of normothermic cardiac arrest, hyperoxic reperfusion for one hour with CPB did show advantages compared to normoxic reperfusion in some aspects, including better systemic hemodynamics, less lactic acidosis and a small but significantly better cardiac relaxation. In addition, the benefits were also demonstrated by a better mitochondrial respiratory function. Finally, in chapter 5, a simplified method was developed to concentrate mitochondrial membrane complexes. It is a modified 2-D blue native/blue native PAGE (BN/BN-PAGE) which can be easily done with a mini-gel apparatus. Once completed, the concentrated protein complex in the gel strip is ready for SDS-PAGE or proteomic studies. Unwanted loss of protein complex is minimized, which is critical whenever the amount of mitochondrial sample is limited.

Committee:

Mark Angelos (Advisor); Barbara Rita Alevriadou (Committee Member); Jonathan Davis (Committee Member)

Subjects:

Biomedical Research

Keywords:

Cardiac arrest; Resuscitation; Mitochondria; Cardiopulmonary bypass; Heart; Electron transport chain; Blue native PAGE

Lytle, Daniel JDecision Making in Criminal Justice Revisited: Toward a General Theory of Criminal Justice
PhD, University of Cincinnati, 2013, Education, Criminal Justice, and Human Services: Criminal Justice
The study of correlates of decision-making has been an important and integral part of criminal justice research. While this important research has been studied largely since the conception of criminal justice research, the attempts to take stock and determine what the body of research collectively “knows” has been limited. These limitations have included both the method of synthesis and also the focus of the synthesis. Traditionally, criminal justice scholars have taken stock of correlate research by using narrative literature review techniques. While this research does make some contribution to the field, it is flawed because of the inherent problems in all narrative reviews, namely, double counting studies, and the subjective nature of narrative reviews. The flaw has been that reviews have focused on a few important variables, race and gender, and not on a more comprehensive view. This dissertation seeks to expand upon the current state of correlates of decision-making research by conducting a meta-analysis to examine decision making across the system, specifically, arrest, sentencing, and parole revocation. Results indicated that several variables are important at multiple stages of the criminal justice system. These predictors are both legal and extra-legal variables, legal predictors of decision-making included seriousness of the offense, and the offender’s prior criminal record, while extra-legal predictors of decision-making included race, gender, and ethnicity. These findings were not mitigated by moderating factors, but instead persisted across moderator categories. In addition to system-wide correlates, there were several factors, which were unique to a specific decision point, these included, at arrest, suspect demeanor, and, at sentencing, mode of conviction.

Committee:

Lawrence Travis, Ph.D. (Committee Chair); William R. King, Ph.D. (Committee Member); James Frank, Ph.D. (Committee Member); Paula Smith, Ph.D. (Committee Member)

Subjects:

Criminology

Keywords:

criminal justice;decision making;arrest;sentencing;parole revocation;meta-analysis;

Myer, Andrew JamesHurricane Katrina, Citizen Displacement, and Social Control: A Test of the Threat and Benign Neglect Hypotheses and an Investigation of the Crime-Arrest Relationship
PhD, University of Cincinnati, 2010, Education, Criminal Justice, and Human Services: Criminal Justice
A guiding theory often used by criminologist to examine the application of social control is the conflict perspective. This perspective asserts that social control is used as a tool to protect elite segments of society. The conflict theory posits an increase in social control when elite groups are threatened, the threat hypothesis. While the benign neglect hypothesis predicts a decrease in crime control when the population under threat is a non-elite population. One of the main concerns of this paper is to address limitations in the oft studied threat hypothesis and the understudied benign neglect hypothesis. Two limitations of previous studies of conflict hypotheses are (1) lack of a direct measure of threat and (2) aggregation bias. This research will employ a more direct measure of a threatening event: the displacement of citizens to Houston, Texas, by Hurricane Katrina, moving beyond the reliance between the correlation of structural antecedents and social control. This research will also investigate aggregation bias by evaluating conflict hypotheses at a level below the city—the traditional unit of analysis of past research. To this end, this research will use time series analysis to directly account for social control pre- and post-displacement to determine if any changes in the administration of social control occurred as a result of the displacement. Finally, this paper also attempts to examine the role that social context plays in the reciprocal relationship between crimes and arrests. Past research on the crime arrest relationship has been mixed. Cross sectional designs often corroborate predictions of economic theory, while the more rigorous time series designs fail to provide similar results. Recent research suggests that the social context of an area may exert an influence on this relationship. To this end, this investigation will employ bivariate time series techniques to examine the role that social context plays in the reciprocal relationship between crimes and arrests.

Committee:

Mitchell Chamlin, PhD (Committee Chair); James Frank, PhD (Committee Member); Francis Cullen, PhD (Committee Member)

Subjects:

Criminology

Keywords:

Threat;Benign Neglect;Crime-Arrest Relationship;Direct Measurement;Aggregation Bias

Yang, Ya-TingMolecularly targeted therapy for ovarian cancer
Doctor of Philosophy, The Ohio State University, 2006, Pharmacy
Ovarian cancer is the most lethal gynecological malignancy among women in the United States. One in sixty-eight women will develop ovarian cancer in their lifetime. The current first-line treatment for ovarian cancer is cisplatin. However, the tumors relap and are typically unresponsive to cisplatin treatment. Therefore, the resistance to cisplatin therapy has been a critical hurdle in the management of recurrent ovarian cancer. The mechanisms responsible for cisplatin resistance are multifactorial that there is no single factor that can account for the resistance in every cell. In the search for new therapies to overcome/bypass cisplatin resistance, histone deacetylases (HDACs) and the PI3K/PDK-1/Akt pathway have been considered some of the most promising targets. These targets have been implicated in the tumorigenesis of many cancer types including ovarian cancers. In the first part of this study, we assessed the anticancer effects of (S)-HDAC42, a novel HDAC inhibitor developed in our laboratory, in both cisplatin-sensitive and -resistant ovarian cancer cells in vitro, as well as in an ovarian cancer xenograft mouse model in vivo. In the second part, OSU03012, a PDK-1 inhibitor also developed in our laboratory, was evaluated in ovarian cancer cells in vitro. Our results show that (S)-HDAC42 (i) induced apoptosis in ovarian cancer cells at low doses regardless of cisplatin sensitivity; (ii) induced cell cycle arrest at the G2/M phase with concurrent down-regulation of Cdc2 and cyclin B1 protein; (iii) stimulated cell differentiation; (iv) effectively inhibited tumor growth in CP70 tumor xenograft-bearing nude mice; and (v) enhanced the suppression of CP70 tumor growth by cisplatin in combination treatment. The results of the second part of this project show that OSU03012 (i) effectively suppressed ovarian cancer cell growth as determined by MTT assay, irrespective of cisplatin sensitivity; (ii) caused downregulation of PDK-1/Akt signaling as indicated by the dephosphorylation of Akt and its downstream effector, p27; (iii) induced ovarian cancer cell apoptosis; (iv) stimulated cell cycle arrest at G1 or S phase; and (v) additively augmented cisplatin-mediated cytotoxicity in ovarian cancer cells. In conclusion, these findings indicate that HDACs and PDK-1/Akt pathway play important roles in ovarian cancer survival, as the inhibition of either target greatly hinders the survival of ovarian cancers. Moreover, the novel HDAC inhibitor, (S)-HDAC42, and PDK-1 inhibitor, OSU03012, are promising anticancer agents for the treatment of ovarian cancer, either administered alone or in combination with cisplatin.

Committee:

Ching-Shih Chen (Advisor); Robert Brueggemeier (Other); Pui-Kai Li (Other); Tatiana Oberyszyn (Other)

Keywords:

ovarian cancer; cisplatin resistance; HDAC inhibitor; PDK-1 inhbitor; cell cycle arrest; apoptosis; cell differentiation

Odom, Daniel Patrickcleavage arrest, a member of the beta-transducin superfamily essential for preblastoderm development in Drosophila
Doctor of Philosophy, Case Western Reserve University, 1994, Genetics
Through the availability of numerous mutants in Drosophila, this organism has provided a wealth of information on the control of the cell cycle. In particular, mitoses in early embryonic development in Drosophila offer a unique model for studying how pre- and post-replicative gap phases ( G1 and G2) may be constrained. Unlike most eukaryotic mitoses, the first 13 zygotic divisions (or preblastoderm divisions) in Drosophila occur extremely rapidly because of lack of discernible G1 and G2 phases. Genes controlling specifically these divisions have been identified: they are the maternal effect genes controlling preblastoderm divisions. Maternal effect genes encode products that are synthesized during oogenesis and stored in the egg for the future zygote's use. Hence maternal effect genes controlling preblastoderm divisions are genes active in the mother (i.e. in oogenesis) and required to direct or control the first 13 zygotic divisions. Females unable to produce such factors generate eggs which cannot support zygotic development, and hence these females are considered sterile. This study introduces a novel member of the class of maternal effect genes controlling preblastoderm divisions – the female sterile gene, cleavage arrest (cle). cle was identified through mutants generated by excision of a transposable element; excision of the element concomitantly removed portions of the surrounding genome that contain cle gene sequences. In total, five cle mutant alleles were recovered. Analysis of the mutants' developmental phenotypes, and characterization of associated molecular defects are presented. In brief, positive identification of the cle gene was achieved by rescuing the mutant effects by transformation, or reintroducing sequences found to be deleted in mutants. The gene sequence was determined and implications of its predicted protein structure are discussed. Expression of cle RNA and protein during development were also determined.

Committee:

Anthony Mahowald (Advisor)

Keywords:

Cleavage arrest; beta-transducin superfamily; preblastoderm development; Drosophila

Makara, Michael AMolecular physiology of ankyrin-G in the heart: Critical regulator of cardiac cellular excitability and architecture.
Doctor of Philosophy, The Ohio State University, 2016, Biomedical Sciences
Cardiovascular disease is the leading cause of death in the United States, claiming nearly 800,000 lives each year. Regardless of the underlying cardiovascular dysfunction, nearly 50% of these patients die of sudden cardiac arrest caused by arrhythmia. Development and sustainment of cardiac arrhythmia begins with dysfunction of excitability and structure at the cellular level. Therefore, in order to improve therapeutic options for these patients, a basic understanding of the molecular mechanisms regulating cardiac cellular excitability and structure is required. Decades of research have demonstrated that intracellular scaffolding polypeptides known as ankyrins are critical for the regulation of cellular excitability and structure in multiple cell types. Ankyrin-G (ANK3) is critical for regulation of action potentials in neurons and lateral membrane development in epithelial cells. Given its central importance for cellular physiology in excitable and non-excitable cell types, we hypothesized that functional ankyrin-G expression is critical for proper cardiac function. To test this hypothesis in vivo, we generated cardiac-specific ankyrin-G knockout (cKO) mice. In the absence of ankyrin-G, mice display significant reductions in membrane targeting of the voltage-gated sodium channel Nav1.5. This disruption in turn causes severely reduced whole cell sodium current, leading to significant conduction abnormalities, bradycardia, and ventricular arrhythmia and atrioventricular nodal block following infusion of NaV channel antagonists. In addition to regulating cardiac excitability, we also demonstrate a critical role for ankyrin-G in the regulation of the cardiomyocyte cytoarchitecture. Specifically, ankyrin-G cKO mice show disrupted cellular distribution of the desmosomal protein plakophilin-2 (PKP2) at baseline. In a setting of pressure overload-induced heart failure we observed severe disruptions to the cellular localization of PKP2. Further, as desmosomes mediate the integration of the intermediate filament protein desmin, we demonstrate the reduced expression of desmin at the intercalated disc (ID) in the setting of mislocalized PKP2. Mechanistically, we correlate these molecular changes with significant reductions in systolic function and increased propensity for bradyarrhythmia in ankyrin-G cKO mice following transverse aortic constriction (TAC). As ankyrin-G is significantly increased two weeks post TAC, we hypothesize that ankyrin-G expression is required for the early, compensatory phase of ventricular remodeling. Our hypothesis is further strengthened by the observation that functional ankyrin-G expression is severely reduced in multiple forms of human heart failure. We conclude that ankyrin-G is a critical regulator of both excitability and molecular architecture of the intercalated disc. We further hypothesize that remodeling of this ankyrin-G-dependent molecular environment is a critical step in the development of human arrhythmia and structural heart diseases.

Committee:

Peter Mohler (Advisor); Noah Weisleder (Committee Chair); Thomas Hund (Committee Member); Philip Binkley (Committee Member)

Subjects:

Cellular Biology; Physiology

Keywords:

ankyrin; arrhythmia; heart; failure; sodium channel; plakophilin; CaMKII; spectrin; intercalated disc; late sodium current; cardiovascular disease; sudden cardiac arrest; SCN5A

Coyne, Michelle A.Predicting Arrest Probability Across Time: A Test of Competing Perspectives
PhD, University of Cincinnati, 2015, Education, Criminal Justice, and Human Services: Criminal Justice
Criminal involvement is non-randomly distributed across individuals and across groups. Debate regarding the etiology of differences in criminal involvement remains. Using data from the National Longitudinal Survey of Youth 1997, the current study examined latent class membership in the probability of arrest over a 15-year time span starting when participants were 12-16 years-old and ending when they were 28-31 years-old. Latent class regressions were employed to prospectively investigate whether various demographic and criminological risk factors from the base wave could predict class membership. Models were also estimated separately by sex and by race to identify potentially important differences and consistencies in class structure and risk prediction. Results from the latent class growth analyses resulted in two to three classes characterized by an abstainer group, an adolescent-limited group, and a stable moderate-level chronic group. In general, being male, increased substance use, and increased delinquency were consistent predictors of class membership. Regarding race and sex differences, being a minority was moderately related to class membership in males but was not significant for females. Being male was a very strong predictor of class membership for Black and Hispanic participants but a relatively weak predictor for White participants. Overall, results supported a general risk factor perspective over a gender or race specific risk perspective. Across race, sex, and cohort, self-reported delinquency was the strongest risk predictor of class membership, suggesting that differential arrest probability is predominantly explained by differential involvement in delinquent behavior.

Committee:

John Wright, Ph.D. (Committee Chair); Matt DeLisi, Ph.D. (Committee Member); J.C. Barnes, Ph.D. (Committee Member); Francis Cullen, Ph.D. (Committee Member)

Subjects:

Criminology

Keywords:

arrest;risk;prediction;latent class;life-course;criminology

Sivko, Gloria SCharacterization and regulation of C/EBPδ in human mammary epithelial cell G0 growth arrest
Doctor of Philosophy, The Ohio State University, 2004, Veterinary Biosciences
CCAAT/Enhancer binding proteins (C/EBPs) are members of the leucine zipper family of transcription factors and play key roles in cell growth, differentiation and apoptosis. C/EBP family member, C/EBPδ, plays an important role in the G0 growth arrest of mouse mammary epithelial cells in vitro and in mouse mammary gland involution in vivo. The role of C/EBPδ in human mammary epithelial cells has not yet been established. Serial Analysis of Gene Expression (SAGE) analysis of human breast tumors, however, has recently demonstrated that C/EBPδ is one of a subset of genes that is down-regulated in breast cancer. These results suggest that C/EBPδ may play an important role in human mammary epithelial cell growth control. The goal of this dissertation project was three-fold. First, characterize the expression of C/EBPδ and determine its role in G0 growth arrest in normal and tumorigenic human mammary epithelial cells. Secondly, investigate upstream signaling regulators of the C/EBPδ promoter. And lastly, investigate signaling events important for the initiation and maintenance of G0 growth arrest in human mammary epithelial cells. In summary, this dissertation has revealed that activation of the JAK/STAT3 signaling pathway is required for the induction of C/EBPδ and plays a key role in the induction of G0 growth arrest of human mammary epithelial cells. This growth inhibitory signaling pathway is increasingly disrupted in mammary epithelial cells as cells progress from normal to neoplastic. Activation of the STAT3 signaling pathway in normal mammary epithelial cells and the initiation and maintenance of G0 growth arrest is the result of transcriptional up-regulation and secretion of growth inhibitory cytokines (LIF, IL-6, OSM) into the media, establishing an autocrine regulatory mechanism.

Committee:

Jim DeWille (Advisor)

Subjects:

Biology, Molecular

Keywords:

human mammary epithelial cells; cytokine; breast cancer; CCAAT/Enhancer Binding Protein (C/EBP); CCAAT/Enhancer Binding Protein &948; (C/EBP&948;); G0 Growth Arrest

Johnson, Royel MontelMeasuring the Influence of Juvenile Arrest on the Odds of Four-Year College Enrollment for Black Males: An NLSY Analysis
Doctor of Philosophy, The Ohio State University, 2015, Educational Studies
Black male youth make up 16% of all public school students in the United States, though they constitute 31% of all juvenile arrests. Very little is known from research about the long-term consequences for such contact on their odds of college enrollment. Thus, the purpose of this study was to test the relationship between Black males' early contact with the criminal justice system through arrest on their probability of enrolling in a four-year college, using a nationally representative sample of approximately 1100 Black males who participated in the National Longitudinal Study of Youth (1997). Survey data were analyzed using descriptive, chi-square, and hierarchical binomial logistic regression techniques. Results expose pervasive limits on Black males' college-going, reveal the statistically significant influence of early arrest on college entry, and have far-reaching implications for research, policy, and outreach.

Committee:

Terrell Strayhorn (Committee Chair); Antionette Errante (Committee Member); Tatiana Suspitsyna (Committee Member)

Subjects:

Criminology; Higher Education

Keywords:

Black males, juvenile arrest, college enrollment, juvenile justice

Finkeldey, Jessica GraceParental Incarceration, Identity, and Adult Children's Antisocial Behavior
Doctor of Philosophy (Ph.D.), Bowling Green State University, 2017, Sociology
Although parental incarceration is associated with adolescent and adult children's antisocial activity, the underlying mechanisms explaining this association have not been fully examined. I assessed whether parental incarceration was associated with identifying as a troublemaker/partier during adolescence and, subsequently, young adulthood. I also examined identity as a mediator in the association between parental incarceration and general antisocial behavior, instrumental crime, and arrest during young adulthood. For each of these analyses, I also examined whether the importance of parents' approval moderated the influence of parental incarceration. For all young adult outcomes, I separately assessed the influence of maternal and paternal incarceration. Lastly, I examined the direct and indirect effects of parental incarceration on antisocial behavior and instrumental crime during young adulthood using structural equation modeling. For my theoretical lens, I drew on labeling theory and the integrated psychosocial model of criminal social identity. I used longitudinal data from the Toledo Adolescent Relationships Study (TARS) (n = 1,321) and official incarceration records. Parental incarceration was positively associated with identifying as a troublemaker/partier during adolescence and young adulthood, but only for those for whom parental approval was important. Parental incarceration was positively associated with adults' behavioral outcomes, and identifying as a troublemaker/partier, in part, mediated these associations. I also found that maternal, compared to no maternal, incarceration exhibited a strong positive effect, whereas paternal, compared to no paternal, incarceration was not as strong or consistent of an effect. Analyses also provided evidence that maternal incarceration only influenced behavior among young adults who desired parental approval. Finally, structural equation models illustrated that parental incarceration indirectly influenced young adults' involvement in antisocial behavior and instrumental crime through identifying as a troublemaker/partier during adulthood.

Committee:

Monica Longmore, PhD (Advisor); Wendy Watson, PhD (Other); Peggy Giordano, PhD (Committee Member); Wendy Manning, PhD (Committee Member); Raymond Swisher, PhD (Committee Member)

Subjects:

Criminology; Sociology

Keywords:

Parental Incarceration; Maternal Incarceration; Paternal Incarceration; Identity; Parent Approval; Antisocial Behavior; Instrumental Crime; Arrest; Intergenerational Transmission; Toledo Adolescent Relationships Study; TARS

Reyes, RyanSorafenib and 2-Deoxyglucose: The Future of Hepatocellular Carcinoma Therapy
Master of Science, The Ohio State University, 2016, Biomedical Sciences
Sorafenib therapy has been shown to have only a small clinical benefit for liver cancer patients. There is an urgent needed to develop new therapeutic strategies for the treatment of advanced stage HCC. In this report, we screened several repurposed therapeutics in order to identify synergistic drug combinations. We demonstrate that the combination of 2-deoxy-glucose and sorafenib drastically inhibit HCC cell viability in Hep3B, Huh7 and sorafenib resistant Huh7 cells. Cell cycle analysis revealed that this therapeutic combination induced complete G0/G1 arrested HCC cells. Our studies suggest that this cell-cycle arrest is due to the depletion of cellular ATP. Overall, this report provides strong evidence for the clinical potential of sorafenib + 2-deoxyglucose combination therapy.

Committee:

Samson Jacob, PhD (Advisor); Kalpana Ghoshal, PhD (Committee Member)

Subjects:

Medicine; Molecular Biology; Therapy

Keywords:

Sorafenib; 2-Deoxyglucose; 2DG; Combination therapy; Synergy; Sorafenib Resistance; Liver Cancer; HCC; Cell cycle arrest; Proliferation; Growth; Therapy; Hepatocellular Carinoma

Benoit, Justin LOut-of-Hospital Cardiac Arrest Patients Have Better Outcomes with Endotracheal Intubation Compared to Supraglottic Airway Placement: A Meta-Analysis
MS, University of Cincinnati, 2015, Medicine: Clinical and Translational Research
Objective: Overall survival from out-of-hospital cardiac arrest (OHCA) is less than 10%. After initial bag-valve mask ventilation, 80% of patients receive an advanced airway, either by endotracheal intubation (ETI) or placement of a supraglottic airway (SGA). The objective of this study was to compare patient outcomes for these two advanced airway methods in OHCA patients treated by Emergency Medical Services (EMS). Methods: A dual-reviewer search was conducted in PubMed, Scopus, and the Cochrane Database to identify all relevant peer-reviewed articles. Exclusion criteria were traumatic arrests, pediatric patients, physician/nurse intubators, rapid sequence intubation, video devices, and older airway devices. Outcomes were (1) return of spontaneous circulation, (2) survival to hospital admission, (3) survival to hospital discharge, and (4) neurologically intact survival to hospital discharge. Results were adjusted for covariates when available, and combined using meta-analysis techniques and the random effects model. Results: From 3,454 titles, 10 observational studies fulfilled all criteria, with 34,533 ETI patients and 41,116 SGA patients. Important covariates were similar between groups. Patients who received ETI had statistically significant higher odds of return of spontaneous circulation (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.05-1.55), survival to hospital admission (OR 1.34, CI 1.02-1.75), and neurologically intact survival (OR 1.33, CI 1.09-1.61) compared to SGA. Survival to hospital discharge was not statistically different (OR 1.15, CI 0.97-1.37). Conclusions: Patients with OHCA who receive ETI by EMS are more likely to obtain return of spontaneous circulation, survive to hospital admission, and survive neurologically intact when compared to SGA.

Committee:

Erin Nicole Haynes, Dr.P.H. (Committee Chair); Jason McMullan, M.D. (Committee Member); Christopher Lindsell, Ph.D. (Committee Member)

Subjects:

Surgery

Keywords:

Out-of-Hospital Cardiac Arrest;Emergency Medical Services;Prehospital;Airway Management;Endotracheal Intubation;Supraglottic Airways

Zhang, YingjieMolecular mechanisms of transcriptional control of C/EBPD expression in mammary epithelial cells and functional analysis of C/EBPδ in contact inhibition
Doctor of Philosophy, The Ohio State University, 2006, Veterinary Biosciences
CCAAT/Enhancer Binding Protein Delta (C/EBPD) gene transcription is highly induced in G0 growth arrested mammary epithelial cells and “loss of function” alterations in C/EBPD have been reported in human breast cancer. This work investigated three aspects of C/EBPD the mechanisms of transcriptional regulation of C/EBPD gene, genes directly regulated by C/EBPD, and the phenotypes of loss of C/EBPD function. In chapter 2, we showed that C/EBPD promoter is maintained in a constitutively “open” chromatin conformation and preloaded with transcriptional activators (Sp1 and CREB) and pre-initiation complex components (TBP and RNA Pol II). However its activation is dependent on binding of pSTAT3 under growth arrest plus Oncostatin M treatment, which results in recruitment of coactivators (NCoA/SRC1 and CBP/p300), phosphorylation of CREB and RNA Pol II (pPolII) and active transcription of C/EBPD gene. We also demonstrated that C/EBPD expression is repressed in proliferating mammary epithelial cells by c-Myc via a mechanism that involves the binding of c-Myc:Max dimers to C/EBPD promoter-bound Miz-1. In chapter 3, we used the ChIP-chip technique to globally screen for C/EBPD protein binding genomic targets. Human 12k CGI microarray was hybridized with DNA recovered from C/EBPD-v5 ChIP assays under contact inhibition condition of MCF-12A cells. We identified 289 C/EBPD-v5 bound loci and 102 of them are linked to protein coding genes. 14 candidate genes were validated to be regulated by C/EBPD-v5 using conventional ChIP analysis and reverse transcription PCR assays. We reported the first time that C/EBPD plays a role on contact inhibition by regulating extracellular adhesion proteins and their downstream signaling components. We also identified 12 tumor suppressors and growth inhibitors in this study as novel C/EBPD direct targets suggesting C/EBPD’s role on tumor suppression. In chapter 4, we characterized the phenotypes of C/EBPD -/- MEFs related to the potential tumor suppression role of C/EBPD. C/EBPD -/- MEFs showed decrease in contact inhibition and cell-cell adherence at high cell density due to lacking C/EBPD expression. In addition the loss of C/EBPD enhances cell migration, which implies to C/EBPD’s role on inhibiting tumor metastasis. The work of dissertation opens new avenues of research of C/EBPD related to cancer development.

Committee:

Jim DeWille (Advisor)

Subjects:

Biology, Molecular

Keywords:

C/EBPD; breast cancer; growth arrest; transcription regulation; chromatin; ChIP; ChIP-chip; contact inhibition; MEF; cell migration

Wagner, Mark WDNA Mismatch Repair–Dependent and –Independent G2 Cell Cycle Arrest and Apoptotic Signaling Pathways After Alkylating Damage
Doctor of Philosophy, Case Western Reserve University, 2007, Environmental Health Science
Cells deficient in MMR display a loss of G2 cell cycle checkpoint arrest and resistance to the alkylating agent, N–methyl–N′–nitro–N–nitrosoguanidine (MNNG), or the fluorinated thymidine analog, 5–fluoro–2′–deoxyuridine (FdUrd). Here, we investigated signaling pathways involved in differential G2 arrest and apoptotic responses using isogenic MMR–proficient and —deficient cells exposed to either MNNG or FdUrd. Contrary to published data, we demonstrated that these cell lines exhibited equal Chk1 phosphorylation in response to MNNG in spite of MMR status. Furthermore, both caffeine and Gö6976, that abrogate G2 arrest by inhibiting ATM/ATR and Chk1, respectively, only partially abrogated G2 arrest, but did so in a MMR–independent manner. Similarly, disruption of Chk1 by shRNA partially abrogated G2 arrest, but did so in an MMR–independent manner, completely abrogating G2 arrest in MMR–deficient cells and only partially affecting MMR–competent cells. Collectively, our data strongly suggest that while the ATR/Chk1 pathway is activated in response to MNNG exposure, it is not facilitated by MMR signaling. These data strongly suggested a separate MMR–dependent G2 arrest pathway. We then examined the role of c–Abl kinase in MMR–dependent cell cycle signaling and apoptosis. Disruption of c–Abl activity, either by STI571 (Gleevec™, a c–Abl inhibitor) addition or infection with c–Abl–specific shRNA, abolished MMR–dependent G2 arrest and apoptosis. Decreased MMR–dependent p73α stabilization and Gadd45α protein expression, in response to MNNG exposure noted in c–Abl knockdown cells. Blocking both ATR/Chk1 and c–Abl–dependent G2 arrest signaling pathways completely abrogated G2 arrest in MMR–proficient cells in response to MNNG exposure. Our data strongly suggest that two overlapping G2 arrest pathways are triggered after MNNG exposures: (i) a MMR–dependent hMLH1/c–Abl/p73α/Gadd45α signaling pathway leading from G2 arrest responses to eventual apoptotic cell death; and (ii) a separate but simultaneously functioning, MMR-independent ATR/Chk1 signaling pathway leading to G2 cell cycle checkpoint arrest responses. Understanding these separate signaling pathways may allow their manipulation to avoid error–prone (i.e., MMR–independent mediated) from error–free (MMR–mediated) G2 arrest responses and apoptosis that are important in carcinogenesis.

Committee:

David Boothman (Advisor)

Subjects:

Biology, Molecular

Keywords:

MMR; G2 arrest; Apoptosis; c-Abl