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Description
The RNA editing enzyme adenosine deaminase acting on double stranded RNA 2 (ADAR2) converts adenosine into inosine in regions of double stranded RNA. Here, it was discovered that this critical function of ADAR2 was dysfunctional in amyotrophic lateral sclerosis (ALS) mediated by the C9orf72 hexanucleotide repeat expansion, the most common genetic abnormality associated with ALS. Typically a nuclear protein, ADAR2 was localized in cytoplasmic accumulations in postmortem tissue from C9orf72 ALS patients. The mislocalization of ADAR2 was confirmed using immunostaining in a C9orf72 mouse model and motor neurons differentiated from C9orf72 patient induced pluripotent stem cells. Notably, the cytoplasmic accumulation of ADAR2 coexisted in neurons with cytoplasmic accumulations of TAR DNA binding protein 43 (TDP-43). Interestingly, ADAR2 overexpression in mammalian cell lines induced nuclear depletion and cytoplasmic accumulation of TDP-43, reflective of the pathology observed in ALS patients. The mislocalization of TDP-43 was dependent on the catalytic activity of ADAR2 and the ability of TDP-43 to bind directly to inosine containing RNA. In addition, TDP-43 nuclear export was significantly elevated in cells with increased RNA editing. Together these results describe a novel cellular mechanism by which alterations in RNA editing drive the nuclear export of TDP-43 leading to its cytoplasmic mislocalization. Considering the contribution of cytoplasmic TDP-43 to the pathogenesis of ALS, these findings represent a novel understanding of how the formation of pathogenic cytoplasmic TDP-43 accumulations may be initiated. Further research exploring this mechanism will provide insights into opportunities for novel therapeutic interventions.
ContributorsMoore, Stephen Philip (Author) / Sattler, Rita (Thesis advisor) / Zarnescu, Daniela (Committee member) / Brafman, David (Committee member) / Van Keuren-Jensen, Kendall (Committee member) / Mangone, Marco (Committee member) / Arizona State University (Publisher)
Created2021
Description
Machine learning (ML) and deep learning (DL) has become an intrinsic part of multiple fields. The ability to solve complex problems makes machine learning a panacea. In the last few years, there has been an explosion of data generation, which has greatly improvised machine learning models. But this comes with a cost of high computation, which invariably increases power usage and cost of the hardware. In this thesis we explore applications of ML techniques, applied to two completely different fields - arts, media and theater and urban climate research using low-cost and low-powered edge devices. The multi-modal chatbot uses different machine learning techniques: natural language processing (NLP) and computer vision (CV) to understand inputs of the user and accordingly perform in the play and interact with the audience. This system is also equipped with other interactive hardware setups like movable LED systems, together they provide an experiential theatrical play tailored to each user. I will discuss how I used edge devices to achieve this AI system which has created a new genre in theatrical play. I will then discuss MaRTiny, which is an AI-based bio-meteorological system that calculates mean radiant temperature (MRT), which is an important parameter for urban climate research. It is also equipped with a vision system that performs different machine learning tasks like pedestrian and shade detection. The entire system costs around $200 which can potentially replace the existing setup worth $20,000. I will further discuss how I overcame the inaccuracies in MRT value caused by the system, using machine learning methods. These projects although belonging to two very different fields, are implemented using edge devices and use similar ML techniques. In this thesis I will detail out different techniques that are shared between these two projects and how they can be used in several other applications using edge devices.
ContributorsKulkarni, Karthik Kashinath (Author) / Jayasuriya, Suren (Thesis advisor) / Middel, Ariane (Thesis advisor) / Yu, Hongbin (Committee member) / Arizona State University (Publisher)
Created2021
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
Cities globally are experiencing substantial warming due to ongoing urbanization and climate change. However, existing efforts to mitigate urban heat focus mainly on new technologies, exacerbate social injustices, and ignore the need for a sustainability lens that considers environmental, social, and economic perspectives. Heat in urban areas is amplified and urgently needs to be considered as a critical sustainability issue that crosses disciplinary and sectoral (traditional) boundaries. The missing urgency is concerning because urban overheating is a multi-faceted threat to the well-being and performance of individuals as well as the energy efficiency and economy of cities. Urban heat consequences require transformation in ways of thinking by involving the best available knowledge engaging scientists, policymakers, and communities. To do so, effective heat mitigation planning requires a considerable amount of diverse knowledge sources, yet urban planners face multiple barriers to effective heat mitigation, including a lack of usable, policy-relevant science and governance structures. To address these issues, transdisciplinary approaches, such as co-production via partnerships and the creation of usable, policy-relevant science, are necessary to allow for sustainable and equitable heat mitigation that allow cities to work toward multiple Sustainable Development Goals (SDGs) using a systems approach. This dissertation presents three studies that contribute to a sustainability lens on urban heat, improve the holistic and multi-perspective understanding of heat mitigation strategies, provide contextual guidance for reflective pavement as a heat mitigation strategy, and evaluate a multilateral, sustainability-oriented, co-production partnership to foster heat resilience equitably in cities. Results show that science and city practice communicate differently about heat mitigation strategies while both avoid to communicate disservices and trade-offs. Additionally, performance evaluation of heat mitigation strategies for decision-making needs to consider multiple heat metrics, people, and background climate. Lastly, the partnership between science, city practice, and community needs to be evaluated to be accountable and provide a pathway of growth for all partners. The outcomes of this dissertation advance research and awareness of urban heat for science, practice, and community, and provide guidance to improve holistic and sustainable decision-making in cities and partnerships to address SDGs around urban heat.
ContributorsSchneider, Florian Arwed (Author) / Middel, Ariane (Thesis advisor) / Vanos, Jennifer K (Committee member) / Withycombe Keeler, Lauren (Committee member) / Arizona State University (Publisher)
Created2023
Description
Extreme heat and its human impacts are significant public health challenges that disproportionately affect certain populations. Often, people with the least resources to cope with the heat also live in the hottest regions of cities. Previous heat vulnerability research has predominantly been conducted at a coarse geographic scale, yet translating relationships measured at aggregated scales to the individual level can result in ecological fallacy. Prior work has also primarily studied the most severe health outcomes: hospitalization/emergency care and mortality. It is likely that magnitudes more people are experiencing negative health impacts from heat that do not necessarily result in medical care. Such less severe impacts are under-researched in the literature.This dissertation addresses these knowledge gaps by identifying how social characteristics and physical measurements of heat at the individual and household level act independently and in concert to influence human heat-related outcomes, especially less severe outcomes. In the first paper, meta-analysis was used to quantify the summary effects of vulnerability indicators on incidence of heat-related illness. More proximal vulnerability indicators (e.g., residential air conditioning use, indoor heat exposure, etc.) tended to have the strongest impact on odds of experiencing heat-related illness than more distal indicators. In the next paper, indoor air temperature observations were related to the social characteristics of the residents. The strongest predictor of indoor air temperature was the residents’ ideal thermally comfortable temperature, despite affordability. In the final paper, fine scale biometeorological observations of the outdoor thermal environment near residents’ homes were linked to their experience with heat-related illness. The outdoor thermal environment appeared to have a stronger, more consistent impact on heat-related illness among households in a lower income neighborhood compared to a higher income one. These findings affirm the value of employing residential heat mitigation solutions at the individual and household scale, indoors and outdoors. Across all chapters, the indoor thermal environment, and the ability to modify it, had a clear impact on residents’ comfort and health. Solutions that target the most proximal causal factors of heat-related illness will likely have the greatest impact on reducing the burden of heat on human health and well-being.
ContributorsWright, Mary K (Author) / Hondula, David M (Thesis advisor) / Larson, Kelli L (Committee member) / Middel, Ariane (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
The measurement of the radiation and convection that the human body experiences are important for ensuring safety in extreme heat conditions. The radiation from the surroundings on the human body is most often measured using globe or cylindrical radiometers. The large errors stemming from differences in internal and exterior temperatures and indirect estimation of convection can be resolved by simultaneously using three cylindrical radiometers (1 cm diameter, 9 cm height) with varying surface properties and internal heating. With three surface balances, the three unknowns (heat transfer coefficient, shortwave, and longwave radiation) can be solved for directly. As compared to integral radiation measurement technique, however, the bottom mounting using a wooden-dowel of the three-cylinder radiometers resulted in underestimated the total absorbed radiation. This first part of this thesis focuses on reducing the size of the three-cylinder radiometers and an alternative mounting that resolves the prior issues. In particular, the heat transfer coefficient in laminar wind tunnel with wind speed of 0.25 to 5 m/s is measured for six polished, heated cylinders with diameter of 1 cm and height of 1.5 to 9 cm mounted using a wooden dowel. For cylinders with height of 6 cm and above, the heat transfer coefficients are independent of the height and agree with the Hilpert correlation for infinitely long cylinder. Subsequently, a side-mounting for heated 6 cm tall cylinder with top and bottom metallic caps is developed and tested within the wind tunnel. The heat transfer coefficient is shown to be independent of the flow-side mounting and in agreement with the Hilpert correlation.
The second part of this thesis explores feasibility of employing the three-cylinder concept to measuring all air-flow parameters relevant to human convection including mean wind speed, turbulence intensity and length scale. Heated cylinders with same surface properties but varying diameters are fabricated. Uniformity of their exterior temperature, which is fundamental to the three-cylinder anemometer concept, is tested during operation using infrared camera. To provide a lab-based method to measure convection from the cylinders in turbulent flow, several designs of turbulence-generating fractal grids are laser-cut and introduced into the wind tunnel.
ContributorsGupta, Mahima (Author) / Rykaczewski, Konrad (Thesis advisor) / Pathikonda, Gokul (Thesis advisor) / Middel, Ariane (Committee member) / Arizona State University (Publisher)
Created2024
Description
The global increase in urbanization has raised questions about urban sustainability to which multiple research communities have entered. Those communities addressing interest in the urban heat island (UHI) effect and extreme temperatures include land system science, urban/landscape ecology, and urban climatology. General investigations of UHI have focused primarily on land surface and canopy layer air temperatures. The surface temperature is of prime importance to UHI studies because of its central rule in the surface energy balance, direct effects on air temperature, and outdoor thermal comfort. Focusing on the diurnal surface temperature variations in Phoenix, Arizona, especially on the cool (green space) island effect and the surface heat island effect, the dissertation develops three research papers that improve the integration among the abovementioned sub-fields. Specifically, these papers involve: (1) the quantification and modeling of the diurnal cooling benefits of green space; (2) the optimization of green space locations to reduce the surface heat island effect in daytime and nighttime; and, (3) an evaluation of the effects of vertical urban forms on land surface temperature using Google Street View. These works demonstrate that the pattern of new green spaces in central Phoenix could be optimized such that 96% of the maximum daytime and nighttime cooling benefits would be achieved, and that Google Street View data offers an alternative to other data, providing the vertical dimensions of land-cover for addressing surface temperature impacts, increasing the model accuracy over the use of horizontal land-cover data alone. Taken together, the dissertation points the way towards the integration of research directions to better understand the consequences of detailed land conditions on temperatures in urban areas, providing insights for urban designs to alleviate these extremes.
ContributorsZhang, Yujia (Author) / Turner, Billie (Thesis advisor) / Murray, Alan T. (Committee member) / Myint, Soe W (Committee member) / Middel, Ariane (Committee member) / Arizona State University (Publisher)
Created2018
Description
Urban-induced heating is a challenge to the livability and health of city dwellers. It is a complex issue that many cities are facing, and a more urgent hazard in hot urban deserts (HUDs) than elsewhere due to already high temperatures and aridity. The challenge compounds in the absence of more localized heat mitigation understanding. In addition, over-reliance on evidence from temperate regions is disconnected from the actualities of extreme bioclimatic dynamics found in HUDs. This dissertation is an integration of a series of studies that inform urban climate relationships specific to HUDs. This three-paper dissertation demonstrates heat mitigation aspirational goals from actualities, depicts local urban thermal drivers in Kuwait, and then tests morphological sensitivity of selected thermal modulation strategies in one neighborhood in Kuwait City.
The first paper is based on a systematic literature review where evidence from morphological mitigation strategies in HUDs were critically reviewed, synthesized and integrated. Metrics, measurements, and methods were extracted to examine the applicability of the different strategies, and a content synthesis identified the levels of strategy success. Collective challenges and uncertainties were interpreted to compare aspirational goals from actualities of morphological mitigation strategies.
The second paper unpacks the relationship of urban morphological attributes in influencing thermal conditions to assess latent magnitudes of heat amelioration strategies. Mindful of the challenges presented in the first study, a 92-day summer field-measurement campaign captured system dynamics of urban thermal stimuli within sub-diurnal phenomena. A composite data set of sub-hourly air temperature measurements with sub-meter morphological attributes was built, statistically analyzed, and modeled. Morphological mediation effects were found to vary hourly with different patterns under varying weather conditions in non-linear associations. Results suggest mitigation interventions be investigated and later tested on a site- use and time-use basis.
The third paper concludes with a simulation-based study to conform on the collective findings of the earlier studies. The microclimate model ENVI-met 4.4, combined with field measurements, was used to simulate the effect of rooftop shade-sails in cooling the near ground thermal environment. Results showed significant cooling effects and thus presented a novel shading approach that challenges orthodox mitigation strategies in HUDs.
The first paper is based on a systematic literature review where evidence from morphological mitigation strategies in HUDs were critically reviewed, synthesized and integrated. Metrics, measurements, and methods were extracted to examine the applicability of the different strategies, and a content synthesis identified the levels of strategy success. Collective challenges and uncertainties were interpreted to compare aspirational goals from actualities of morphological mitigation strategies.
The second paper unpacks the relationship of urban morphological attributes in influencing thermal conditions to assess latent magnitudes of heat amelioration strategies. Mindful of the challenges presented in the first study, a 92-day summer field-measurement campaign captured system dynamics of urban thermal stimuli within sub-diurnal phenomena. A composite data set of sub-hourly air temperature measurements with sub-meter morphological attributes was built, statistically analyzed, and modeled. Morphological mediation effects were found to vary hourly with different patterns under varying weather conditions in non-linear associations. Results suggest mitigation interventions be investigated and later tested on a site- use and time-use basis.
The third paper concludes with a simulation-based study to conform on the collective findings of the earlier studies. The microclimate model ENVI-met 4.4, combined with field measurements, was used to simulate the effect of rooftop shade-sails in cooling the near ground thermal environment. Results showed significant cooling effects and thus presented a novel shading approach that challenges orthodox mitigation strategies in HUDs.
ContributorsAlKhaled, Saud R A H (Author) / Coseo, Paul (Thesis advisor) / Brazel, Anthony (Thesis advisor) / Middel, Ariane (Committee member) / Cheng, Chingwen (Committee member) / Arizona State University (Publisher)
Created2019
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