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- Genre: Doctoral Dissertation
Description
Alzheimer's Disease (AD) is a debilitating neurodegenerative disease. The disease leads to dementia and loss of cognitive functions and affects about 4.5 million people in the United States. It is the 7th leading cause of death and is a huge financial burden on the healthcare industry. There are no means of diagnosing the disease before neurodegeneration is significant and sadly there is no cure that controls its progression. The protein beta-amyloid or Aâ plays an important role in the progression of the disease. It is formed from the cleavage of the Amyloid Precursor Protein by two enzymes - â and ã-secretases and is found in the plaques that are deposits found in Alzheimer brains. This work describes the generation of therapeutics based on inhibition of the cleavage by â-secretase. Using in-vitro recombinant antibody display libraries to screen for single chain variable fragment (scFv) antibodies; this work describes the isolation and characterization of scFv that target the â-secretase cleavage site on APP. This approach is especially relevant since non-specific inhibition of the enzyme may have undesirable effects since the enzyme has been shown to have other important substrates. The scFv iBSEC1 successfully recognized APP, reduced â-secretase cleavage of APP and reduced Aâ levels in a cell model of Alzheimer's Disease. This work then describes the first application of bispecific antibody therapeutics to Alzheimer's Disease. iBSEC1 scFv was combined with a proteolytic scFv that enhances the "good" pathway (á-secretase cleavage) that results in alternative cleavage of APP to generate the bispecific tandem scFv - DIA10D. DIA10D reduced APP cleavage by â-secretase and steered it towards the "good" pathway thus increasing the generation of the fragment sAPPá which is neuroprotective. Finally, treatment with iBSEC1 is evaluated for reduced oxidative stress, which is observed in cells over expressing APP when they are exposed to stress. Recombinant antibody based therapeutics like scFv have several advantages since they retain the high specificity of the antibodies but are safer since they lack the constant region and are smaller, potentially facilitating easier delivery to the brain
ContributorsBoddapati, Shanta (Author) / Sierks, Michael (Thesis advisor) / Arizona State University (Publisher)
Created2011
Description
This study utilized symbolic interaction as a framework to examine the impact of mobility on four veteran elementary general music teachers' identities, roles, and perceptions of role support. Previous research has focused on teacher identity formation among preservice and novice teachers; veteran teachers are less frequently represented in the literature. Teacher mobility research has focused on student achievement, teachers' reasons for moving, and teacher attrition. The impact of mobility on veteran teachers' identities, roles, and perceptions of role support has yet to be considered. A multiple case design was employed for this study. The criteria for purposeful selection of the participants were elementary general music teachers who had taught for at least ten years, who had changed teaching contracts and taught in at least two different schools, and who were viewed as effective music educators by fine arts coordinators. Data were collected over a period of eight months through semi-structured interviews, email correspondence, observations, review of videotapes of the participants' teaching in previous schools, and collection of artifacts. Data were analyzed within and across cases. The cross-case analysis revealed themes within the categories of identity, role, and role support for the participants. The findings suggest that the participants perceived their music teacher roles as multi-dimensional. They claimed their core identities remained stable over time; however, shifts in teacher identity occurred throughout their years as teachers. The participants asserted that mobility at the start of their careers had a positive impact because they each were challenged to solidify their own teacher identities and music teacher roles in varied school contexts. Mobility negatively impacted role and teacher practices during times when the participants adjusted to new school climates and role expectations. Role support varied depending upon school context, and the participants discovered active involvement in the school community was an effective means of seeking and acquiring role support. Reflection experiences in music teacher preparation programs, as well as mentoring and professional development geared toward teacher identity formation and role maturation, may assist teachers in matching their desired school context with their teacher identities and perceptions of the music teacher role.
ContributorsGray, Lori F (Author) / Stauffer, Sandra (Committee member) / Schmidt, Margaret (Committee member) / Sullivan, Jill (Committee member) / Bush, Jeffrey (Committee member) / Tobias, Evan (Committee member) / Arizona State University (Publisher)
Created2011
Description
More than 30% of college entrants are placed in remedial mathematics (RM). Given that an explicit relationship exists between students' high school mathematics and college success in science, technology, engineering, and mathematical (STEM) fields, it is important to understand RM students' characteristics in high school. Using the Education Longitudinal Survey 2002/2006 data, this study evaluated more than 130 variables for statistical and practical significance. The variables included standard demographic data, prior achievement and transcript data, family and teacher perceptions, school characteristics, and student attitudinal variables, all of which are identified as influential in mathematical success. These variables were analyzed using logistic regression models to estimate the likelihood that a student would be placed into RM. As might be expected, student test scores, highest mathematics course taken, and high school grade point average were the strongest predictors of success in college mathematics courses. Attitude variables had a marginal effect on the most advantaged students, but their effect cannot be evaluated for disadvantaged students, due to a non-random pattern of missing data. Further research should concentrate on obtaining answers to the attitudinal questions and investigating their influence and interaction with academic indicators.
ContributorsBarber, Rebecca (Author) / Garcia, David R. (Thesis advisor) / Powers, Jeanne (Committee member) / Rodrigue Mcintyre, Lisa (Committee member) / Arizona State University (Publisher)
Created2011
Description
The discipline of rhetoric and composition established the Writing Program Administrators Outcomes Statement (WPA OS) to fulfill a general expectation about the skills and knowledge students should be able to demonstrate by the end of first-year composition. Regardless of pedagogy used, academic preparation of the teacher, or preference of particular topics or types of assignments, the WPA OS is versatile. This dissertation employs a problem-solution argument showcasing methods to improve assignments through intentional use of the WPA OS for a fluid conversation throughout first-year composition and a more clear articulation of course goals. This dissertation includes summation, analysis, and synthesis of documents that inform first-year composition curriculum from foundational organizations within the field, including National Council of Teachers of English, Council of Writing Program Administrators, National Writing Project, and Conference on College Composition and Communication. This study uses the WPA OS as a lens to examine and revise writing assignments that aid in students' comprehension of the WPA OS with particular focus on the areas of rhetorical knowledge and critical thinking, reading, and writing. Framing assignment design with theoretically grounded content and the use of common topics throughout first-year composition is one way to operationalize the WPA OS. Using common topics throughout course content presents opportunities for teachers to include detailed scaffolding in assignments that expand students' literate practices and engage students as critical thinkers and writers. This study explores how using the topic of family, a common topic to all students, provides a rich bank of social, historical, and cultural elements for research and writing. The topic of family seamlessly employs multimodal composition, which presents students with opportunities for developing rhetorical knowledge and expanding students' literacies. This dissertation displays evidence of praxis of the WPA OS from assignment development to presentation of student samples. This study recommends the use of common topics and intentional application of the WPA OS to construct assignments that clearly articulate learning goals in first-year composition.
ContributorsRankins-Robertson, Sherry, 1976- (Author) / Roen, Duane H. (Thesis advisor) / Miller, Keith (Committee member) / Lauer, Claire (Committee member) / Arizona State University (Publisher)
Created2011
Description
Neurostimulation methods currently include deep brain stimulation (DBS), optogenetic, transcranial direct-current stimulation (tDCS), and transcranial magnetic stimulation (TMS). TMS and tDCS are noninvasive techniques whereas DBS and optogenetic require surgical implantation of electrodes or light emitting devices. All approaches, except for optogenetic, have been implemented in clinical settings because they have demonstrated therapeutic utility and clinical efficacy for neurological and psychiatric disorders. When applied for therapeutic applications, these techniques suffer from limitations that hinder the progression of its intended use to treat compromised brain function. DBS requires an invasive surgical procedure that surfaces complications from infection, longevity of electrical components, and immune responses to foreign materials. Both TMS and tDCS circumvent the problems seen with DBS as they are noninvasive procedures, but they fail to produce the spatial resolution required to target specific brain structures. Realizing these restrictions, we sought out to use ultrasound as a neurostimulation modality. Ultrasound is capable of achieving greater resolution than TMS and tDCS, as we have demonstrated a ~2mm lateral resolution, which can be delivered noninvasively. These characteristics place ultrasound superior to current neurostimulation methods. For these reasons, this dissertation provides a developed protocol to use transcranial pulsed ultrasound (TPU) as a neurostimulation technique. These investigations implement electrophysiological, optophysiological, immunohistological, and behavioral methods to elucidate the effects of ultrasound on the central nervous system and raise questions about the functional consequences. Intriguingly, we showed that TPU was also capable of stimulating intact sub-cortical circuits in the anesthetized mouse. These data reveal that TPU can evoke synchronous oscillations in the hippocampus in addition to increasing expression of brain-derived neurotrophic factor (BDNF). Considering these observations, and the ability to noninvasively stimulate neuronal activity on a mesoscale resolution, reveals a potential avenue to be effective in clinical settings where current brain stimulation techniques have shown to be beneficial. Thus, the results explained by this dissertation help to pronounce the significance for these protocols to gain translational recognition.
ContributorsTufail, Yusuf Zahid (Author) / Tyler, William J (Thesis advisor) / Duch, Carsten (Committee member) / Muthuswamy, Jitendran (Committee member) / Santello, Marco (Committee member) / Tillery, Stephen H (Committee member) / Arizona State University (Publisher)
Created2011
Description
Patients with Alzheimer's disease (AD) exhibit a significantly higher incidence of unprovoked seizures compared to age-matched non-AD controls, and animal models of AD (i.e., transgenic human amyloid precursor protein, hAPP mice) display neural hyper-excitation and epileptic seizures. Hyperexcitation is particularly important because it contributes to the high incidence of epilepsy in AD patients as well as AD-related synaptic deficits and neurodegeneration. Given that there is significant amyloid-β (Aβ) accumulation and deposition in AD brain, Aβ exposure ultimately may be responsible for neural hyper-excitation in both AD patients and animal models. Emerging evidence indicates that α7 nicotinic acetylcholine receptors (α7-nAChR) are involved in AD pathology, because synaptic impairment and learning and memory deficits in a hAPPα7-/- mouse model are decreased by nAChR α7 subunit gene deletion. Given that Aβ potently modulates α7-nAChR function, that α7-nAChR expression is significantly enhanced in both AD patients and animal models, and that α7-nAChR play an important role in regulating neuronal excitability, it is reasonable that α7-nAChRs may contribute to Aβ-induced neural hyperexcitation. We hypothesize that increased α7-nAChR expression and function as a consequence of Aβ exposure is important in Aβ-induced neural hyperexcitation. In this project, we found that exposure of Aβ aggregates at a nanomolar range induces neuronal hyperexcitation and toxicity via an upregulation of α7-nAChR in cultured hippocampus pyramidal neurons. Aβ up-regulates α7-nAChRs function and expression through a post translational mechanism. α7-nAChR up-regulation occurs prior to Aβ-induced neuronal hyperexcitation and toxicity. Moreover, inhibition of α7-nAChR or deletion of α7-nAChR prevented Aβ induced neuronal hyperexcitation and toxicity, which suggests that α7-nAChRs are required for Aβ induced neuronal hyperexcitation and toxicity. These results reveal a profound role for α7-nAChR in mediating Aβ-induced neuronal hyperexcitation and toxicity and predict that Aβ-induced up-regulation of α7-nAChR could be an early and critical event in AD etiopathogenesis. Drugs targeting α7-nAChR or seizure activity could be viable therapies for AD treatment.
ContributorsLiu, Qiang (Author) / Wu, Jie (Thesis advisor) / Lukas, Ronald J (Committee member) / Chang, Yongchang (Committee member) / Sierks, Michael (Committee member) / Smith, Brian (Committee member) / Vu, Eric (Committee member) / Arizona State University (Publisher)
Created2011
Description
Systemic lupus erytematosus (SLE) is an autoimmune disease where the immune system is reactive to self antigens resulting in manifestations like glomerulonephritis and arthritis. The immune system also affects the central nervous system (known as CNS-SLE) leading to neuropsychiatric manifestations such as depression, cognitive impairment, psychosis and seizures. A subset of pathogenic brain-reactive autoantibodies (BRAA) is hypothesized to bind to integral membrane brain proteins, affecting their function, leading to CNS-SLE. I have tested this BRAA hypothesis, using our lupus-mouse model the MRL/lpr mice, and have found it to be a reasonable explanation for some of the manifestations of CNS-SLE. Even when the MRL/lpr had a reduced autoimmune phenotype, their low BRAA sera levels correlated with CNS involvement. The correlation existed between BRAA levels to integral membrane protein and depressive-like behavior. These results were the first to show a correlation between behavioral changes and BRAA levels from brain membrane antigen as oppose to cultured neuronal cells. More accurate means of predicting and diagnosing lupus and CNS-SLE is necessary. Using microarray technology I was able to determine peptide sets that could be predictive and diagnostic of lupus and each specific CNS manifestation. To knowledge no test currently exists that can effectively diagnose lupus and distinguish between each CNS manifestations. Using the peptide sets, I was able to determine possible natural protein biomarkers for each set as well as for five monoclonal BRAA from one MRL/lpr. These biomarkers can provide specific targets for therapy depending on the manifestation. It was necessary to investigate how these BRAA enter the brain. I hypothesized that substance P plays a role in altering the blood-brain barrier (BBB) allowing these BRAA to enter and affect brain function, when bound to its neurokinin-1 receptor (NK-1R). Western blotting results revealed an increase in the levels of NK-1R in the brain of the MRL/lpr compared to the MRL/mp. These MRL/lpr with increased levels of both NK-1R and BRAA displayed CNS dysfunction. Together, these results demonstrate that NK-1R may play a role in CNS manifestations. Overall, the research conducted here, add to the role that BRAA are playing in CNS-lupus.
ContributorsWilliams, Stephanie (Author) / Hoffman, Steven A (Thesis advisor) / Conrad, Cheryl (Committee member) / Chen, Julian (Committee member) / Orchinik, Miles (Committee member) / Arizona State University (Publisher)
Created2011
Description
Cognitive function is multidimensional and complex, and research indicates that it is impacted by age, lifetime experience, and ovarian hormone milieu. One particular domain of cognitive function that is susceptible to age-related decrements is spatial memory. Cognitive practice can affect spatial memory when aged in both males and females, and in females alone ovarian hormones have been found to alter spatial memory via modulating brain microstructure and function in many of the same brain areas affected by aging. The research in this dissertation has implications that promote an understanding of the effects of cognitive practice on aging memory, why males and females respond differently to cognitive practice, and the parameters and mechanisms underlying estrogen's effects on memory. This body of work suggests that cognitive practice can enhance memory when aged and that estrogen is a probable candidate facilitating the observed differences in the effects of cognitive practice depending on sex. This enhancement in cognitive practice effects via estrogen is supported by data demonstrating that estrogen enhances spatial memory and hippocampal synaptic plasticity. The estrogen-facilitated memory enhancements and alterations in hippocampal synaptic plasticity are at least partially facilitated via enhancements in cholinergic signaling from the basal forebrain. Finally, age, dose, and type of estrogen utilized are important factors to consider when evaluating estrogen's effects on memory and its underlying mechanisms, since age alters the responsiveness to estrogen treatment and the dose of estrogen needed, and small alterations in the molecular structure of estrogen can have a profound impact on estrogen's efficacy on memory. Collectively, this dissertation elucidates many parameters that dictate the outcome, and even the direction, of the effects that cognitive practice and estrogens have on cognition during aging. Indeed, many parameters including the ones described here are important considerations when designing future putative behavioral interventions, behavioral therapies, and hormone therapies. Ideally, the parameters described here will be used to help design the next generation of interventions, therapies, and nootropic agents that will allow individuals to maintain their cognitive capacity when aged, above and beyond what is currently possible, thus enacting lasting improvement in women's health and public health in general.
ContributorsTalboom, Joshua S (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Conrad, Cheryl D. (Committee member) / Neisewander, Janet L (Committee member) / West, Stephen G. (Committee member) / Arizona State University (Publisher)
Created2011
Description
An accurate sense of upper limb position is crucial to reaching movements where sensory information about upper limb position and target location is combined to specify critical features of the movement plan. This dissertation was dedicated to studying the mechanisms of how the brain estimates the limb position in space and the consequences of misestimation of limb position on movements. Two independent but related studies were performed. The first involved characterizing the neural mechanisms of limb position estimation in the non-human primate brain. Single unit recordings were obtained in area 5 of the posterior parietal cortex in order to examine the role of this area in estimating limb position based on visual and somatic signals (proprioceptive, efference copy). When examined individually, many area 5 neurons were tuned to the position of the limb in the workspace but very few neurons were modulated by visual feedback. At the population level however decoding of limb position was somewhat more accurate when visual feedback was provided. These findings support a role for area 5 in limb position estimation but also suggest that visual signals regarding limb position are only weakly represented in this area, and only at the population level. The second part of this dissertation focused on the consequences of misestimation of limb position for movement production. It is well known that limb movements are inherently variable. This variability could be the result of noise arising at one or more stages of movement production. Here we used biomechanical modeling and simulation techniques to characterize movement variability resulting from noise in estimating limb position ('sensing noise') and in planning required movement vectors ('planning noise'), and compared that to the variability expected due to noise in movement execution. We found that the effects of sensing and planning related noise on movement variability were dependent upon both the planned movement direction and the initial configuration of the arm and were different in many respects from the effects of execution noise.
ContributorsShi, Ying (Author) / Buneo, Christopher A (Thesis advisor) / Helms Tillery, Stephen (Committee member) / Santello, Marco (Committee member) / He, Jiping (Committee member) / Santos, Veronica (Committee member) / Arizona State University (Publisher)
Created2011
Description
Higher education institutions in the state of Arizona have experienced a reduction in government funding due to the economic challenges the state is facing combined with an ongoing national recession. Three higher education institutions studied are located in Phoenix, Arizona. The three higher education institutions are Phoenix College, Arizona State University and The University of Phoenix. An analysis of documents made public by each institution was conducted and high level administrators at each institution were interviewed to learn about revenue streams currently active and planned. The results of this set of analyses were presented to the leadership team of Phoenix College in a three-hour strategic planning and priority setting meeting. The action research study assisted Phoenix College administrators in gaining knowledge about and initiating action plans to increase revenue through entrepreneurial strategies. Increased funding is necessary to offset reductions in state aid and property tax revenues. Implementing entrepreneurial strategies to increase funding can promote self-reliance and flexibility and can mitigate the damage to institutional mission success that is threatened by reductions in traditional funding. The strategic planning and priority setting exercise conducted at Phoenix College produced three immediate outcomes: it informed the community of practice about entrepreneurial strategies to increase funding that are in use by higher education institutions located in greater Phoenix, Arizona; it influenced the community of practice to examine entrepreneurial revenue streams and; it committed the leadership team to pursuing and enlarging three additional revenue streams.
ContributorsKakar, Casandra Gwen (Author) / Clark, Christopher M. (Thesis advisor) / De Los Santos Jr., Alfredo G. (Committee member) / Giovannini, Eugene (Committee member) / Arizona State University (Publisher)
Created2011