Neuroinflammation and the Glial Response Contribute to Both Beneficial and Pathological Outcomes in Multiple Disease Models

Cherry, Jonathan D University of Rochester 2015 해외박사(DDOD)

Neuroinflammation has been considered a driver of pathology and cognitive dysfunction for many years; however, not all inflammation results in the same outcome. The brain is sensitive to a wide variety of inflammatory stimuli that can result in different outcomes depending on the type of exposure, environment, and underlying pathological processes. In order to gain a better understanding of the relationship between neuroinflammation and brain pathology, we developed three models comprising unique inflammatory stimuli. The first model aimed to understand how peripheral inflammation contributes to neuroinflammation. To accomplish this, a 10% total body area full thickness thermal burn was used to induce significant peripheral inflammation without lethality. Prior to burn injury, mice were subjected to 0 or 5 Gy whole body gamma radiation. Typically, only doses over 15 Gy are sufficient to induce neuroinflammation, so a possible combinative effect of combination injury was investigated. Mice were followed out to 6 hours, 1 week, or 6 months. Combination injury resulted in a significant elevation of mRNA for both the vascular marker ICAM-1 and the inflammatory marker TNFbeta at 6 hours. Interestingly, combination injury also showed increased IL-6 serum protein levels suggesting elevated peripheral inflammation as well. Furthermore, enhanced glial cell activation by CD68 and Iba1 immunohistochemistry was seen at all time points for the combination injury. Lastly, combination injury lead to significant learning and memory deficits compared to the single injuries alone, suggesting a functional synergy between peripheral inflammation arising from burn and brain radiation injury. In addition to cognitive dysfunction, neuroinflammation has been posited to be a driver of pathology in many diseases. One prominent case is Alzheimer's disease (AD). To explore this relationship, the APP/PS1 AD mouse model was subjected to 0, 10, or 100 cGy 56Fe particle galactic cosmic radiation (GCR). Six months after exposure, irradiated mice showed decreased cognitive abilities. Interestingly, in male mice we observed acceleration of Abeta plaque pathology using Congo red and 6E10 staining, which was confirmed via ELISA. No microglial activation was observed at this time point, but elevated ICAM-1 levels were seen, suggesting a potential vascular mechanism. These two studies suggest that neuroinflammation is a detrimental process leading to cognitive dysfunction and pathology. However, neuroinflammation is a normal response to injury that likely has protective functions. Interestingly, several studies have demonstrated that blocking neuroinflammation does not always mitigate pathology, and in some cases, enhances it. This suggests a more complex nature to neuroinflammation than previously thought. The last model explored these seeming paradoxical findings that in some cases, neuroinflammation can result in amelioration of pathology. Using an adeno-associated viral vector carrying a human IL-1beta cDNA to transduce mice, neuroinflammation was induced in one hippocampus of 8-month-old APP/PS1 mice for 4 weeks, while the other hemisphere received a control viral injection. We observed a robust activation of alternatively activated, anti-inflammatory (M2) microglia using the marker Arg1. This increase in Arg1+ microglia coincided with a reduction in Abeta plaques. Arg1+ microglia were shown to contain Abeta suggesting they were the mechanism of clearance. When IL-4 was used to specifically induce Arg1+ microglia, there was significant plaque reduction. Conversely, blocking induction of Arg1+ microglia during chronic inflammation impaired plaque clearance. Together these findings demonstrate that Arg1+ microglia are necessary and sufficient for Abeta plaque reduction during neuroinflammation. Overall, these three models of neuroinflammation provide a better understanding of how inflammation influences both cognitive function and disease progression. Furthermore, they can guide us towards possible avenues for immunomodulatory therapy of brain disorders.

Structure and its relation to the bulk properties of germanium-phosphorus-sulfur glass

Cherry, Brian R Indiana University 2001 해외박사(DDOD)

Germanium sulfide glasses are practical host materials for rare-earth ions due to their large refractive index and low maximum phonon energy. These properties respectively result in large emission cross-sections and low non-radiative decay rates for optical transitions. Consequently, germanium sulfide glasses doped with rare-earth ions are of interest for a variety of photonic applications, including optical amplifiers and near IR sources. While the structure, bulk properties, and their relationship in comparable oxides have been studied in great detail, the same is not true for sulfides. Our particular interest here is in how phosphorus, as an additive, interacts with the GeS₂ network. From a more fundamental view, germanium phosphorus sulfur (Ge-P-S) glass provides an ideal system for the study of covalent network formation. A variety of different solid-state NMR techniques, including MAS <super>31 </super>P-<super>31</super>P second moment, and 2D-PASS (phase-adjusted separation of spinning sidebands), as well as neutron and X-ray diffraction and Raman spectroscopy, were utilized to obtain structural information on Ge-P-S glasses. The structural model generated is then related to bulk properties including the glass transition temperature (T_g), density, molar volume, and refractive index.

Melodrama, parody, and the transformations of an American genre (Harriet Beecher Stowe, George Aiken, William W. Pratt, W. H. Smith)

Cherry, James M City University of New York 2005 해외박사(DDOD)

In this dissertation, I discuss various intersections between parody and melodrama on the American stage of the nineteenth and twentieth centuries. The most popular genre of the nineteenth century, melodrama still serves as the spine of many artistic productions today. But while most genres of significance are given parodic treatments, melodrama is the rare form that exists in the popular imagination as a parody of itself. This dissertation thus tracks the varying integrations of the two forms in American performance. The first chapter situates the dissertation in the vast critical literature about parody and melodrama, comparing their initial disparagements at the hands of critics, as well as their recent scholarly reclamations. The two chapters that follow focus on the parodies of some of America's most significant dramatic works. The second chapter examines the parodies of the most performed play in American history, the Stowe/Aiken version of Uncle Tom's Cabin , while the third centers on two notable temperance dramas: The Drunkard by William W. Pratt, and Ten Nights in a Barroom by W. H. Smith. In these chapters I argue that the numerous parodic emergences, varying from early minstrel travesty and burlesque to postmodernist reinventions and nostalgic simulations, reveal important responses to dominant political discourses. While the melodramas articulate a vision of America, the parodies answer this enunciation, some with scorn, some with kindness, but always with critique. Grouped together, the parodies disclose the different ways that the parodic impulse can manifest itself. The fourth chapter takes up a discussion of present-day melodrama performance in the always-nostalgic form of "old-fashioned melodrama"---the hybrid of the continual cross-pollination between parody and melodrama---in contemporary productions of amateur and tourist theatres of the American West and the San Francisco Mime Troupe. Like their parodic forebears, these performances also reveal widely differing perspectives regarding the meaning of the melodramatic narrative and certainty of the myth of America. Parodic subversion and transformation reveal and destabilize the artifice of constructs, allowing for narratological growth and development. Persistent parodic re-workings of melodrama may be seen as attempts to offer contributions to the articulation of "America.".

Technology Integration in Education: An Examination of Technology Adoption in Teaching and Learning by Secondary Teachers in Minnesota

Cherry, Jennifer E University of Minnesota 2014 해외박사(DDOD)

The purpose of this study was to explore possible causal factors for level of teachers' adoption of technology in teaching and learning. Furthering the understanding of the factors related to teachers' technology adoption may facilitate increased levels of technology integration in the teaching and learning process. Based on previous research and Rogers' (2003) diffusion of innovations theory, the ex post facto causal comparative research design examined relationships between teachers' technology adoption and age, gender, level of education, teaching experience, technology anxiety, perceived barriers to technology integration, technology available for use in teaching, training sources utilized, and the main predictor variable subject area. Utilizing online survey methods, the Kotrlik-Redmann Technology Integration Survey (2002) was utilized to collect data from 187 Minnesota teachers within the subject areas of business, English language arts, math, science, and social studies. Statistical analysis of the data, conducted via SPSS, included descriptive statistics, ANOVA and Gabriel's post hoc tests, Pearson's chi-square tests, and multiple regression techniques. Findings suggest that technology adoption was significantly associated with the predictor variables technology anxiety, barriers to technology integration, technology available for teaching, and whether or not the teacher utilized college courses as a training source. Further, teachers' level of technology adoption differed by subject area. Business teachers adopted technology at significantly higher levels than other subject area teachers, especially math and science teachers. The findings of the study revealed technology anxiety perceived by teachers was fairly low. No significant main effects were found for technology anxiety between subject area teachers. Technology anxiety was negatively correlated with technology adoption, as technology anxiety increased teachers' level of technology adoption decreased. Teachers in this study reported low-to-moderate barriers to integrating technology in teaching and learning, with business teachers experiencing significantly lower barriers than other teachers. The findings of this study revealed a negative relationship between technology integration barriers and technology adoption, as barriers decreased, technology adoption increased. Most teachers utilized a variety of training sources such as self-teaching, workshops/conferences, colleagues, and completing college courses. Business teachers were most likely and social studies teachers were least likely to use college courses as a training source. Whether or not a teacher utilized college courses or self-teaching as a technology training source were significantly related to technology adoption. Findings of the study revealed a positive relationship between technology available and technology adoption, as the technology available for teaching increased teachers' level of technology adoption increased. Further, relationships existed between subject area and the technologies teachers had available for their use in teaching. Business teachers had significantly more technology available for their use than math or science teachers.

Design and evaluation of elastic exoskeletons for human running

Cherry, Michael S University of Michigan 2010 해외박사(DDOD)

Humans bounce along the ground when they hop and run, providing spring-like function with their muscles and tendons. Compliant elastic mechanisms could assist this motion by contributing additional elastic storage and return. This in turn would decrease the demands on the human leg, making it easier to hop or run. I developed an elastic knee brace and an elastic lower limb exoskeleton that add parallel stiffness to the human knee joint and entire leg, respectively. The objective of this dissertation was to determine how humans are affected by the parallel elasticity when they hop and run. In the elastic knee orthosis study, ten subjects hopped on one leg with and without stiffness added in parallel to the knee. The mean brace stiffness was 5.6 N-m/°, effectively 31.5% of total knee stiffness when hopping in this condition. When subjects hopped at fixed (2.2 Hz) and preferred frequencies, knee extensor muscle activation levels and biological knee stiffness decreased (P<.05). This indicated that elastic knee exoskeletons could be effective at reducing the metabolic cost of locomotion in bouncing gaits. However, this study also identified critical shortcomings to a joint-based approach for exoskeletons that assist running. The elastic whole limb exoskeleton was used to explore effects of adding parallel leg elasticity with a non-joint-based system. Six subjects ran with and without the exoskeleton at 2.3 m/s. While running in the exoskeleton there was a significant increase in metabolic cost as well as hip flexor and extensor muscle activation levels during the swing phase (P<.0001). The exoskeleton was designed to provide 30--50% of leg stiffness in two conditions. While running, the exoskeleton provided only 18.4% and 19.2% of leg stiffness, and only 7.0% and 7.2% of the peak vertical force transmitted to the ground. This discrepancy was due to motion of the exoskeleton waist harness on subjects and controller functionality. This dissertation provides clear suggestions for design of future exoskeletons that could assist with human running. It is expected that future devices that build on the successes of these prototypes will benefit healthy individuals and those with decreased muscle function.

Information in games

Cherry, Joshua Scott University of Michigan 2011 해외박사(DDOD)

In the first chapter, we tightly bound from the outside the set of sequential equilibrium payoffs in repeated games of private monitoring. To do this, we develop a tractable new solution concept for standard repeated games with perfect monitoring: Markov Perfect Correlated Equilibrium generalizes the operator approach of Abreu, Pearce, and Stacchetti (1990), but instead takes correlated equilibrium of the auxiliary game. We show that for any private monitoring structure, the set of sequential equilibrium payoffs of a repeated game is contained within the set of Markov Perfect Correlated Equilibrium payoffs. The second chapter extends the Blackwell (1953) comparison of experiments to a strategic setting. We introduce a new partial order more strategically informative---information held by players is "better"---and prove it is equivalent to the partial order more strategically valuable ---the ability to induce more equilibrium payoff vectors in all Bayesian games. The centerpiece application is to repeated games with private monitoring where the more strategically informative order ranks monitoring structures. Consequently, we can show when a change in monitoring structure will weakly expand the set of sequential equilibria. The third chapter deals with the tragedy of the commons. When effort imposes negative externalities, competition results in excessive aggregate effort. One way to curb these excesses is for subsets of competitors to form groups which share output or gross revenue. In theory, if the right number of groups forms, Nash equilibrium aggregate effort should fall to the socially optimal level. We investigate experimentally whether individuals manage to form the efficient number of groups and to invest within the chosen groups as theory predicts. Although we observe some systematic departures from theory, we find that subjects vote in most cases to divide themselves into the optimal number of output-sharing groups and, when investing within such groups, curtail inefficiency by 50% to 71%.

Laboratory infection of zebrafish (Danio rerio) and channel catfish (Ictalurus punctatus) with the protozoan parasite Ichthyophthirius multifiliis: A model for parasite persistence

Cherry, Bryan University of Pennsylvania 2003 해외박사(DDOD)

The protozoan parasite Ichthyophthirius multifiliis (Ich) is believed capable of infecting nearly all species of freshwater fish. Ich typically causes high mortality in fish populations leading to catastrophic host mortality and parasite extinction. It seems clear that the parasite is not maintained on any of the host species in which we normally encounter it. The purpose of this thesis was to examine and describe the quantitative and qualitative properties of the kind of host-pathogen relationship that might allow Ich to become established as an endemic infection in a host species population. The model host was the laboratory-reared TLF strain of zebrafish (Danio rerio). Zebrafish, individually and in cohorts, were infected with Ich and the burden of parasitism, distribution of parasites, and progress of infection over time were examined. As a control and comparison species, fingerling channel catfish (Ictalurus punctatus) were concurrently infected. A mathematical model of Ich infection dynamics was developed to account for the observed outcomes of infection. TLF zebrafish were found to suffer much less severe infection, as measured by total number of parasites per fish, than catfish exposed to similar numbers of infective stage parasites. Zebrafish experienced much lighter gill infection than catfish, and parasites collected from zebrafish demonstrated significantly lower reproductive potential (measured as number of new infective stages produced) than parasites collected from catfish. Zebrafish cohorts infected with Ich experienced lower cumulative host mortality than catfish cohorts infected with Ich. From the point of view of population dynamics, the differences between the two systems turn out to be quantitative, rather than qualitative, in the sense that a single mathematical model can be used to describe both host-pathogen systems. The systems differ only in the numerical values assigned to the model parameters. While the TLF zebrafish might not be the natural reservoir host of Ich, it does represent a laboratory model of one suite of mechanisms for the persistence of this parasite in nature.

Epigenetic and hormonal regulation of stem cell maintenance in the Drosophila testis niche

Cherry, Christopher Michael The Johns Hopkins University 2010 해외박사(DDOD)

Stem cells play an essential role in the production, maintenance, and repair of tissues. Although much has been learned through the study of stein cells in culture (in vitro), it is critical that these specialized cells are analyzed in the context of their natural environments ( in vivo), or niches, to understand the role of niche signaling in their behavior. The stem cells of the Drosophila testis are some of the best-understood adult stem cells and the ability to analyze them in vivo has demonstrated the importance of niche signaling in stem cell biology. It is clear that local niche signals are critical for the maintenance of testis stem cells, however less is known about the role of epigenetic regulation or the contribution of systemic signaling in their function. For my thesis work I characterized the role of the ATP-dependent chromatin remodeling complex NURF as well as the steroid-hormone ecdysone in the maintenance of Drosophila testis stem cells. In the testis, local Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signaling maintains germline stem cells (GSCs) and somatic stem cells (cyst progenitor cells, or CPCs) in a single niche. NURF positively regulates JAK-STAT signaling within GSCs and CPCs to ensure their maintenance. The Drosophila ecdysone pathway is a well-characterized steroid-hormone signaling pathway that coordinates embryogenesis, larval molting, and metamorphosis. I found that ecdysone signaling is required to maintain both GSCs and CPCs and that the NURF complex interacts with the ecdysone pathway to ensure testis stem cell maintenance. This work helps to characterize the role of epigenetic regulation and systemic signaling in the maintenance of stem cells within endogenous niches and in general contributes to what is known about the regulation of stem cells in vivo.

Effects of modeling software on fifth-grade students' construction of computer-based models: A classroom study comparing two software designs

Cherry, Gina University of Colorado at Boulder 2003 해외박사(DDOD)

One promising approach to supporting science learning focuses on the creation and use of computer-based models that represent how and why things work. Activities with models and simulations have the potential to help children organize, develop, test, and refine their ideas about science, enabling robust understanding of science concepts. In this study, I explore the ways in which the design of modeling software affects the cognitive, social, and design processes in which students engage when creating models. I address these issues in the context of a modeling environment called EcoWorlds, which allows learners to create models of imaginary animals and ecosystems. My analysis focuses on a specific design task that is part of the modeling process. I compare two versions of the EcoWorlds software that differ in several respects: the role of the software in introducing background knowledge; the types of constraints the software imposes on student expression; and the ways in which the software guides students to think scientifically. I look at the effects of these software design decisions on two aspects of the learning environment that reflect opportunities for learning: the types of conversations students have while engaged in the activity, and students' ability to express their ideas about animals in the software. I also consider the way in which these design decisions affect the ability of teachers to incorporate model-building activities in typical elementary school classrooms. The results suggest that the version of the software that provides students with background knowledge about the domain creates more opportunities for learning than does the more open-ended version of the software.

Toward Catalytic Hydrogenolysis of Chlorofluorocarbons with Group 8 and 9 Complexes

Cherry, Sophia Dang Tran University of Washington 2016 해외박사(DDOD)

Chlorofluorocarbons (CFCs) are man-made chemicals used for aerosols and refrigerants. CFCs are the sole cause of the hole in the ozone layer, and thus the use and production of these chemicals have been banned. There are, however, still CFCs waiting for disposal. Currently, CFCs are disposed of by burning in the presence of O2 and CH4 to form HF, HCl, and CO2. This thesis discusses a targeted catalytic cycle for the transformation of CFCs to HCFCs (hydrochlorofluorocarbons). Chapter 2 discusses the development of multiple systems suitable for the hydrogenolysis of dichloromethane, and the acid-base limitations for CFC hydrogenolysis specifically. Chapter 3 discusses another targeted system for catalysis, (tBuPOCOP)Rh(CO) (tBuPOCOP = kappa3-C6H3-1,3-[OP(tBu) 2]2). Pincer ligand metallation is presumed to proceed via initial coordination to the phosphorous atoms followed by C---H oxidative addition. While investigating the use of this system, protonation of ( tBuPOCOP)Rh(CO) resulted in formation of [(tBuPOCOP)Rh(CO)H][B(C 6F5)4]. When examined in the solid state, the compound was revealed to have an agostic interaction between Cipso---H and rhodium. This is one of few examples of an intermediate in the metallation of pincer ligands. The rhodium complex has been fully investigated in the solution state. Our studies have revealed exaggerated steric effects in (POCOP)Rh(CO) complexes in comparison to iridium analogues.