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- All Subjects: Sustainability
- 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
ABSTRACT Water resources in many parts of the world are subject to increasing stress because of (a) the growth in demand caused by population increase and economic development, (b) threats to supply caused by climate and land cover change, and (c) a heightened awareness of the importance of maintaining water supplies to other parts of the ecosystem. An additional factor is the quality of water management. The United States-Mexican border provides an example of poor water management combined with increasing demand for water resources that are both scarce and uncertain. This dissertation focuses on the problem of water management in the border city of Ciudad Juarez, Chihuahua. The city has attracted foreign investment during the last few decades, largely due to relatively low environmental and labor costs, and to a range of tax incentives and concessions. This has led to economic and population growth, but also to higher demand for public services such as water which leads to congestion and scarcity. In particular, as water resources have become scarce, the cost of water supply has increased. The dissertation analyzes the conditions that allow for the efficient use of water resources at sustainable levels of economic activity--i.e., employment and investment. In particular, it analyzes the water management strategies that lead to an efficient and sustainable use of water when the source of water is either an aquifer, or there is conjunctive use of ground and imported water. The first part of the dissertation constructs a model of the interactive effects of water supply, wage rates, inward migration of labor and inward investment of capital. It shows how growing water scarcity affects population growth through the impact it has on real wage rates, and how this erodes the comparative advantage of Ciudad Juarez--low wages--to the point where foreign investment stops. This reveals the very close connection between water management and the level of economic activity in Ciudad Juarez. The second part of the dissertation examines the effect of sustainable and efficient water management strategies on population and economic activity levels under two different settings. In the first Ciudad Juarez relies exclusively on ground water to meet demand--this reflects the current situation of Ciudad Juarez. In the second Ciudad Juarez is able both to import water and to draw on aquifers to meet demand. This situation is motivated by the fact that Ciudad Juarez is considering importing water from elsewhere to maintain its economic growth and mitigate the overdraft of the Bolson del Hueco aquifer. Both models were calibrated on data for Ciudad Juarez, and then used to run experiments with respect to different environmental and economic conditions, and different water management options. It is shown that for a given set of technological, institutional and environmental conditions, the way water is managed in a desert environment determines the long run equilibrium levels of employment, investment and output. It is also shown that the efficiency of water management is consistent with the sustainability of water use and economic activity. Importing water could allow the economy to operate at higher levels of activity than where it relies solely on local aquifers. However, at some scale, water availability will limit the level of economic activity, and the disposable income of the residents of Ciudad Juarez.
ContributorsGarduno Angeles, Gustavo Leopoldo (Author) / Perrings, Charles (Thesis advisor) / Holway, Jim (Thesis advisor) / Aggarwal, Rimjhim (Committee member) / Arizona State University (Publisher)
Created2011
Description
The greatest challenge facing humanity in the twenty-first century is our ability to reconcile the capacity of natural systems to support continued improvement in human welfare around the globe. Over the last decade, the scientific community has attempted to formulate research agendas in response to what they view as the problems of sustainability. Perhaps the most prominent and wide-ranging of these efforts has been sustainability science, an interdisciplinary, problem-driven field that seeks to address fundamental questions on human-environment interactions. This project examines how sustainability scientists grapple with and bound the deeply social, political and normative dimensions of both characterizing and pursuing sustainability. Based on in-depth interviews with leading researchers and a content analysis of the relevant literature, this project first addresses three core questions: (1) how sustainability scientists define and bound sustainability; (2) how and why various research agendas are being constructed to address these notions of sustainability; (3) and how scientists see their research contributing to societal efforts to move towards sustainability. Based on these results, the project explores the tensions between scientific efforts to study and inform sustainability and social action. It discusses the implications of transforming sustainability into the subject of scientific analysis with a focus on the power of science to constrain discourse and the institutional and epistemological contexts that link knowledge to societal outcomes. Following this analysis, sustainability science is repositioned, borrowing Herbert Simon's concept, as a "science of design." Sustainability science has thus far been too focused on understanding the "problem-space"--addressing fundamental questions about coupled human-natural systems. A new set objectives and design principles are proposed that would move the field toward a more solutions-oriented approach and the enrichment of public reasoning and deliberation. Four new research streams that would situate sustainability science as a science of design are then discussed: creating desirable futures, socio-technical change, sustainability values, and social learning. The results serve as a foundation for a sustainability science that is evaluated on its ability to frame sustainability problems and solutions in ways that make them amenable to democratic and pragmatic social action.
ContributorsMiller, Thaddeus R. (Author) / Minteer, Ben A (Thesis advisor) / Redman, Charles L. (Committee member) / Sarewitz, Daniel (Committee member) / Wiek, Arnim (Committee member) / Arizona State University (Publisher)
Created2011
Description
The uncertainty of change inherent in issues such as climate change and regional growth has created a significant challenge for public decision makers trying to decide what adaptation actions are needed to respond to these possible changes. This challenge threatens the resiliency and thus the long term sustainability of our social-ecological systems. Using an empirical embedded case study approach to explore the application of advanced scenario analysis methods to regional growth visioning projects in two regions, this dissertation provides empirical evidence that for issues with high uncertainty, advanced scenario planning (ASP) methods are effective tools for helping decision makers to anticipate and prepare to adapt to change.
ContributorsQuay, Ray (Author) / Pijawka, David (Thesis advisor) / Shangraw, Ralph (Committee member) / Holway, James (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
Consumer goods supply chains have gradually incorporated lean manufacturing principles to identify and reduce non-value-added activities. Companies implementing lean practices have experienced improvements in cost, quality, and demand responsiveness. However certain elements of these practices, especially those related to transportation and distribution may have detrimental impact on the environment. This study asks: What impact do current best practices in lean logistics and retailing have on environmental performance? The research hypothesis of this dissertation establishes that lean distribution of durable and consumable goods can result in an increased amount of carbon dioxide emissions, leading to climate change and natural resource depletion impacts, while lean retailing operations can reduce carbon emissions. Distribution and retailing phases of the life cycle are characterized in a two-echelon supply chain discrete-event simulation modeled after current operations from leading organizations based in the U.S. Southwest. By conducting an overview of critical sustainability issues and their relationship with consumer products, it is possible to address the environmental implications of lean logistics and retailing operations. Provided the waste reduction nature from lean manufacturing, four lean best practices are examined in detail in order to formulate specific research propositions. These propositions are integrated into an experimental design linking annual carbon dioxide equivalent emissions to: (1) shipment frequency between supply chain partners, (2) proximity between decoupling point of products and final customers, (3) inventory turns at the warehousing level, and (4) degree of supplier integration. All propositions are tested through the use of the simulation model. Results confirmed the four research propositions. Furthermore, they suggest synergy between product shipment frequency among supply chain partners and product management due to lean retailing practices. In addition, the study confirms prior research speculations about the potential carbon intensity from transportation operations subject to lean principles.
ContributorsUgarte Irizarri, Gustavo Marco Antonio (Author) / Golden, Jay S. (Thesis advisor) / Dooley, Kevin J. (Thesis advisor) / Boone, Christopher G. (Committee member) / Basile, George M. (Committee member) / Arizona State University (Publisher)
Created2011