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Description
The GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the C9orf72 gene is the most common genetic abnormality associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastatingly progressive neurodegenerative diseases. The discovery of this genetic link confirmed that ALS and FTD reside along a spectrum with clinical and pathological commonalities. Historically understood as diseases resulting in neuronal death, the role of non-neuronal cells like astrocytes is still wholly unresolved. With evidence of cortical neurodegeneration leading to cognitive impairments in C9orf72-ALS/FTD, there is a need to investigate the role of cortical astrocytes in this disease spectrum. Here, a patient-derived induced pluripotent stem cell (iPSC) cortical astrocyte model was developed to investigate consequences of C9orf72-HRE pathogenic features in this cell type. Although there were no significant C9orf72-HRE pathogenic features in cortical astrocytes, transcriptomic, proteomic and phosphoproteomic profiles elucidated global disease-related phenotypes. Specifically, aberrant expression of astrocytic-synapse proteins and secreted factors were identified. SPARCL1, a pro-synaptogenic secreted astrocyte factor was found to be selectively decreased in C9orf72-ALS/FTD iPSC-cortical astrocytes. This finding was further validated in human tissue analyses, indicating that cortical astrocytes in C9orf72-ALS/FTD exhibit a reactive transformation that is characterized by a decrease in SPARCL1 expression. Considering the evidence for substantial astrogliosis and synaptic failure leading to cognitive impairments in C9orf72-ALS/FTD, these findings represent a novel understanding of how cortical astrocytes may contribute to the cortical neurodegeneration in this disease spectrum.
ContributorsBustos, Lynette (Author) / Sattler, Rita (Thesis advisor) / Newbern, Jason (Committee member) / Zarnescu, Daniela (Committee member) / Brafman, David (Committee member) / Mehta, Shwetal (Committee member) / Arizona State University (Publisher)
Created2023
Description
Concerns, such as global warming, greenhouse gas emissions, and changes in hydrological regimes, have been raised in response to the global ecosystem changes caused by humans. Understanding the ecosystem functions is crucial for assisting stakeholders in formulating viable plans to address the issues for a healthier planet. However, a systematic evaluation of recent environmental changes and current ecosystem status, focusing on terrestrial ecosystem carbon-water trade-off, in the Lower Mekong Basin (LMB) is lacking. This dissertation involves: (1) examining the long-term spatiotemporal patterns of ecosystem conditions in response to gains and losses of the forest; (2) evaluating the current consumptive water use variation across all biome and land use types with remotely sensed evapotranspiration (ET) products; (3) analyzing the trade-off between terrestrial carbon and water stress condition during the photosynthesis process in response to different climatic/ecosystem conditions, and (4) developing a spatial optimization model to effectively determine possible reforestation/afforestation options considering the balance between water conservation and carbon fluxes. These studies were conducted with many recently developed algorithms and satellite imagery. This dissertation makes significant contributions and expands the knowledge of the variation in water consumption and carbon assimilation within the ecosystem when different conditions are present. In addition, the spatial optimization model was applied to the entire region to formulate possible reforestation plans under different water-carbon tradeoff scenarios for the first time. The findings and results of this research can be used to provide constructive suggestions to policymakers, managers, planners, government officials, and any other stakeholders in LMB to formulate policies and guidelines for the environmentally responsible and sustainable development of LMB.
ContributorsLi, Yubin (Author) / Myint, Soe (Thesis advisor) / Tong, Daoqin (Thesis advisor) / Muenich, Rebecca (Committee member) / Schaffer-Smith, Danica (Committee member) / Arizona State University (Publisher)
Created2023
Description
APOE encodes for a lipid transport protein and has three allelic variants-APOE ε2, ε3 and ε4 each of which differentially modulate the risk for Alzheimer’s disease (AD). The presence of the ε4 allele of APOE greatly increases AD risk compared to the presence of the more prevalent and risk neutral ε3 allele. An imbalance in the generation and clearance of amyloid beta (Aβ) peptides has been hypothesized to play a key role in driving the disease. APOE4 impacts several AD-relevant cellular processes. However, it is unclear whether these effects represent a gain of toxic function or a loss of function, specifically as it relates to modulating amyloid beta (Aβ) levels. Here, a set of APOE knockout (KO) and APOE4 isogenic human induced pluripotent stem cells (hiPSCs) were generated from a parental APOE3 hiPSC line with a highly penetrant familial AD (fAD) mutation to investigate this with respect to Aβ secretion in neural cultures and Aβ uptake in monocultures of microglia-like cells (iMGLs). Conversion of APOE3 to E4 as well as functionally knocking APOE out from the APOE3 parental line, result in elevated Aβ levels in neural cultures, likely through multiple mechanisms including the altered processing of the precursor protein to Aβ called amyloid precursor protein (APP). In pure neuronal cultures, a shift in the processing of APP was observed with the Aβ-generating amyloidogenic pathway being favored in both APOE3 as well as APOE4 neurons compared to APOE KO neurons, with APOE4 neurons exhibiting a greater shift. In iMGLs derived from the isogenic hiPSC lines, expression of APOE, regardless of the isoform, lowered the uptake of Aβ. Overall, APOE4 modulates Aβ levels through distinct loss of protective and gain of function effects. Dissecting these effects would contribute towards a better understanding of the design of potential APOE-targeted therapeutics in the future.
ContributorsRajaram Srinivasan, Gayathri (Author) / Brafman, David (Thesis advisor) / Plaisier, Christopher (Committee member) / Newbern, Jason (Committee member) / Stabenfeldt, Sarah (Committee member) / Wang, Xiao (Committee member) / Arizona State University (Publisher)
Created2024
Description
Safe, readily available, and reliable sources of water are an essential component of any municipality’s infrastructure. Phoenix, Arizona, a southwestern city, has among the highest per capita water use in the United States, making it essential to carefully manage its reservoirs. Generally, municipal water bodies are monitored through field sampling. However, this approach is limited spatially and temporally in addition to being costly. In this study, the application of remotely sensed reflectance data from Landsat 7’s Enhanced Thematic Mapper Plus (ETM+) and Landsat 8’s Operational Land Imager (OLI) along with data generated through field-sampling is used to gain a better understanding of the seasonal development of algal communities and levels of suspended particulates in the three main terminal reservoirs supplying water to the Phoenix metro area: Bartlett Lake, Lake Pleasant, and Saguaro Lake. Algal abundances, particularly the abundance of filamentous cyanobacteria, increased with warmer temperatures in all three reservoirs and reached the highest comparative abundance in Bartlett Lake. Prymnesiophytes (the class of algae to which the toxin-producing golden algae belong) tended to peak between June and August, with one notable peak occurring in Saguaro Lake in August 2017 during which time a fish-kill was observed. In the cooler months algal abundance was comparatively lower in all three lakes, with a more even distribution of abundance across algae classes. In-situ data from March 2017 to March 2018 were compared with algal communities sampled approximately ten years ago in each reservoir to understand any possible long-term changes. The findings show that the algal communities in the reservoirs are relatively stable, particularly those of the filamentous cyanobacteria, chlorophytes, and prymnesiophytes with some notable exceptions, such as the abundance of diatoms, which increased in Bartlett Lake and Lake Pleasant. When in-situ data were compared with Landsat-derived reflectance data, two-band combinations were found to be the best-estimators of chlorophyll-a concentration (as a proxy for algal biomass) and total suspended sediment concentration. The ratio of the reflectance value of the red band and the blue band produced reasonable estimates for the in-situ parameters in Bartlett Lake. The ratio of the reflectance value of the green band and the blue band produced reasonable estimates for the in-situ parameters in Saguaro Lake. However, even the best performing two-band algorithm did not produce any significant correlation between reflectance and in-situ data in Lake Pleasant. Overall, remotely-sensed observations can significantly improve our understanding of the water quality as measured by algae abundance and particulate loading in Arizona Reservoirs, especially when applied over long timescales.
ContributorsRussell, Jazmine Barkley (Author) / Neuer, Susanne (Thesis advisor) / Fox, Peter (Committee member) / Myint, Soe (Committee member) / Arizona State University (Publisher)
Created2018
Description
Synthetic manipulation of chromatin dynamics has applications for medicine, agriculture, and biotechnology. However, progress in this area requires the identification of design rules for engineering chromatin systems. In this thesis, I discuss research that has elucidated the intrinsic properties of histone binding proteins (HBP), and apply this knowledge to engineer novel chromatin binding effectors. Results from the experiments described herein demonstrate that the histone binding domain from chromobox protein homolog 8 (CBX8) is portable and can be customized to alter its endogenous function. First, I developed an assay to identify engineered fusion proteins that bind histone post translational modifications (PTMs) in vitro and regulate genes near the same histone PTMs in living cells. This assay will be useful for assaying the function of synthetic histone PTM-binding actuators and probes. Next, I investigated the activity of a novel, dual histone PTM binding domain regulator called Pc2TF. I characterized Pc2TF in vitro and in cells and show it has enhanced binding and transcriptional activation compared to a single binding domain fusion called Polycomb Transcription Factor (PcTF). These results indicate that valency can be used to tune the activity of synthetic histone-binding transcriptional regulators. Then, I report the delivery of PcTF fused to a cell penetrating peptide (CPP) TAT, called CP-PcTF. I treated 2D U-2 OS bone cancer cells with CP-PcTF, followed by RNA sequencing to identify genes regulated by CP-PcTF. I also showed that 3D spheroids treated with CP-PcTF show delayed growth. This preliminary work demonstrated that an epigenetic effector fused to a CPP can enable entry and regulation of genes in U-2 OS cells through DNA independent interactions. Finally, I described and validated a new screening method that combines the versatility of in vitro transcription and translation (IVTT) expressed protein coupled with the histone tail microarrays. Using Pc2TF as an example, I demonstrated that this assay is capable of determining binding and specificity of a synthetic HBP. I conclude by outlining future work toward engineering HBPs using techniques such as directed evolution and rational design. In conclusion, this work outlines a foundation to engineer and deliver synthetic chromatin effectors.
ContributorsTekel, Stefan (Author) / Haynes, Karmella (Thesis advisor) / Mills, Jeremy (Committee member) / Caplan, Michael (Committee member) / Brafman, David (Committee member) / Arizona State University (Publisher)
Created2019
Description
The Western Continental United States has a rapidly changing and complex ecosystem that provides valuable resources to a large portion of the nation. Changes in social and environmental factors have been observed to be significantly correlated to usable ground and surface water levels. The assessment of water level changes and their influences on a semi-national level is needed to support planning and decision making for water resource management at local levels. Although many studies have been done in Ground and Surface Water (GSW) trend analysis, very few have attempted determine correlations with other factors. The number of studies done on correlation factors at a semi-national scale and near decadal temporal scale is even fewer. In this study, freshwater resources in GSW changes from 2004 to 2017 were quantified and used to determine if and how environmental and social variables are related to GSW changes using publicly available remotely sensed and census data. Results indicate that mean annual changes of GSW of the study period are significantly correlated with LULC changes related to deforestation, urbanization, environmental trends, as well as social variables. Further analysis indicates a strong correlation in the rate of change of GSW to LULC changes related to deforestation, environmental trends, as well as social variables. GSW slope trend analysis also reveals a negative trend in California, New Mexico, Arizona, and Nevada. Whereas a positive GSW trend is evident in the northeast part of the study area. GSW trends were found to be somewhat consistent in the states of Utah, Idaho, and Colorado, implying that there was no GSW changes over time in these states.
ContributorsReynolds, Ryan (Author) / Myint, Soe (Thesis advisor) / Werth, Susanna (Committee member) / Brazel, Anthony (Committee member) / Arizona State University (Publisher)
Created2018
Description
Soil moisture (θ) is a fundamental variable controlling the exchange of water and energy at the land surface. As a result, the characterization of the statistical properties of θ across multiple scales is essential for many applications including flood prediction, drought monitoring, and weather forecasting. Empirical evidences have demonstrated the existence of emergent relationships and scale invariance properties in θ fields collected from the ground and airborne sensors during intensive field campaigns, mostly in natural landscapes. This dissertation advances the characterization of these relations and statistical properties of θ by (1) analyzing the role of irrigation, and (2) investigating how these properties change in time and across different landscape conditions through θ outputs of a distributed hydrologic model. First, θ observations from two field campaigns in Australia are used to explore how the presence of irrigated fields modifies the spatial distribution of θ and the associated scale invariance properties. Results reveal that the impact of irrigation is larger in drier regions or conditions, where irrigation creates a drastic contrast with the surrounding areas. Second, a physically-based distributed hydrologic model is applied in a regional basin in northern Mexico to generate hyperresolution θ fields, which are useful to conduct analyses in regions and times where θ has not been monitored. For this aim, strategies are proposed to address data, model validation, and computational challenges associated with hyperresolution hydrologic simulations. Third, analyses are carried out to investigate whether the hyperresolution simulated θ fields reproduce the statistical and scaling properties observed from the ground or remote sensors. Results confirm that (i) the relations between spatial mean and standard deviation of θ derived from the model outputs are very similar to those observed in other areas, and (ii) simulated θ fields exhibit the scale invariance properties that are consistent with those analyzed from aircraft-derived estimates. The simulated θ fields are then used to explore the influence of physical controls on the statistical properties, finding that soil properties significantly affect spatial variability and multifractality. The knowledge acquired through this dissertation provides insights on θ statistical properties in regions and landscape conditions that were never investigated before; supports the refinement of the calibration of multifractal downscaling models; and contributes to the improvement of hyperresolution hydrologic modeling.
ContributorsKo, Ara (Author) / Mascaro, Giuseppe (Thesis advisor) / Vivoni, Enrique R. (Thesis advisor) / Myint, Soe (Committee member) / Wang, Zhihua (Committee member) / Muenich, Rebecca (Committee member) / Arizona State University (Publisher)
Created2018
Description
Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, or amyotrophic lateral sclerosis are defined by the loss of several types of neurons and glial cells within the central nervous system (CNS). Combatting these diseases requires a robust population of relevant cell types that can be employed in cell therapies, drug screening, or patient specific disease modeling. Human induced pluripotent stem cells (hiPSC)-derived neural progenitor cells (hNPCs) have the ability to self-renew indefinitely and differentiate into the various neuronal and glial cell types of the CNS. In order to realize the potential of hNPCs, it is necessary to develop a xeno-free scalable platform for effective expansion and differentiation. Previous work in the Brafman lab led to the engineering of a chemically defined substrate—vitronectin derived peptide (VDP), which allows for the long-term expansion and differentiation of hNPCs. In this work, we use this substrate as the basis for a microcarrier (MC)-based suspension culture system. Several independently derived hNPC lines were cultured on MCs for multiple passages as well as efficiently differentiated to neurons. Finally, this MC-based system was used in conjunction with a low shear rotating wall vessel (RWV) bioreactor for the integrated, large-scale expansion and neuronal differentiation of hNPCs. Finally, VDP was shown to support the differentiation of hNPCs into functional astrocytes. Overall, this fully defined and scalable biomanufacturing system will facilitate the generation of hNPCs and their derivatives in quantities necessary for basic and translational applications.
ContributorsMorgan, Daylin (Author) / Brafman, David (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Wang, Xiao (Committee member) / Arizona State University (Publisher)
Created2018
Description
Calcium imaging is a well-established, non-invasive or minimally technique designed to study the electrical signaling neurons. Calcium regulates the release of gliotransmitters in astrocytes. Analyzing astrocytic calcium transients can provide significant insights into mechanisms such as neuroplasticity and neural signal modulation.
In the past decade, numerous methods have been developed to analyze in-vivo calcium imaging data that involves complex techniques such as overlapping signals segregation and motion artifact correction. The hypothesis used to detect calcium signal is the spatiotemporal sparsity of calcium signal, and these methods are unable to identify the passive cells that are not actively firing during the time frame in the video. Statistics regarding the percentage of cells in each frame of view can be critical for the analysis of calcium imaging data for human induced pluripotent stem cells derived neurons and astrocytes.
The objective of this research is to develop a simple and efficient semi-automated pipeline for analysis of in-vitro calcium imaging data. The region of interest (ROI) based image segmentation is used to extract the data regarding intensity fluctuation caused by calcium concentration changes in each cell. It is achieved by using two approaches: basic image segmentation approach and a machine learning approach. The intensity data is evaluated using a custom-made MATLAB that generates statistical information and graphical representation of the number of spiking cells in each field of view, the number of spikes per cell and spike height.
In the past decade, numerous methods have been developed to analyze in-vivo calcium imaging data that involves complex techniques such as overlapping signals segregation and motion artifact correction. The hypothesis used to detect calcium signal is the spatiotemporal sparsity of calcium signal, and these methods are unable to identify the passive cells that are not actively firing during the time frame in the video. Statistics regarding the percentage of cells in each frame of view can be critical for the analysis of calcium imaging data for human induced pluripotent stem cells derived neurons and astrocytes.
The objective of this research is to develop a simple and efficient semi-automated pipeline for analysis of in-vitro calcium imaging data. The region of interest (ROI) based image segmentation is used to extract the data regarding intensity fluctuation caused by calcium concentration changes in each cell. It is achieved by using two approaches: basic image segmentation approach and a machine learning approach. The intensity data is evaluated using a custom-made MATLAB that generates statistical information and graphical representation of the number of spiking cells in each field of view, the number of spikes per cell and spike height.
ContributorsBhandarkar, Siddhi Umesh (Author) / Brafman, David (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Tian, Xiaojun (Committee member) / Arizona State University (Publisher)
Created2019
Description
A global warming of two degrees Celsius is predicted to drive almost half the world's lizard populations to extinction. Currently, the Phoenix metropolitan region in Arizona, USA, is an average of 3 oC warmer than the surrounding desert. Using a bare lot as a control, I placed copper lizard models with data loggers in several vegetation and irrigation treatments that represent the dominant backyard landscaping styles in Phoenix (grassy mesic with mist irrigation, drip irrigated xeric, unirrigated native, and a hybrid style known as oasis). Lizard activity time in summer is currently restricted to a few hours in un-irrigated native desert landscaping, while heavily irrigated grass and shade trees allow for continual activity during even the hottest days. Maintaining the existing diversity of landscaping styles (as part of an ongoing mitigation strategy targeted at humans) will be beneficial for lizards.
Fourteen native lizard species inhabit the desert surrounding Phoenix, AZ, USA, but only two species persist within heavily developed areas. This pattern is best explained by a combination of socioeconomic status, land cover, and location. Lizard diversity is highest in affluent areas and lizard abundance is greatest near large patches of open desert. The percentage of building cover has a strong negative impact on both diversity and abundance. Despite Phoenix's intense urban heat island effect, which strongly constrains the potential activity and microhabitat use of lizards in summer, thermal patterns have not yet impacted their distribution and relative abundance at larger scales.
Fourteen native lizard species inhabit the desert surrounding Phoenix, AZ, USA, but only two species persist within heavily developed areas. This pattern is best explained by a combination of socioeconomic status, land cover, and location. Lizard diversity is highest in affluent areas and lizard abundance is greatest near large patches of open desert. The percentage of building cover has a strong negative impact on both diversity and abundance. Despite Phoenix's intense urban heat island effect, which strongly constrains the potential activity and microhabitat use of lizards in summer, thermal patterns have not yet impacted their distribution and relative abundance at larger scales.
ContributorsAckley, Jeffrey (Author) / Wu, Jianguo (Thesis advisor) / Sullivan, Brian (Thesis advisor) / Myint, Soe (Committee member) / DeNardo, Dale (Committee member) / Angilletta Jr., Michael (Committee member) / Arizona State University (Publisher)
Created2015