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Title: THE IMPACT OF ERAP1 FUNCTIONS ON INNATE AND ADAPTIVE IMMUNITY IN HUMAN DISEASE MODELS
Creator: Blake, Maja Kristin K.
Date: 2022
Collection: Electronic Theses & Dissertations
Description: ERAP1 has long been appreciated for its role in antigen presentation during the adaptive immune response. It is a peptidase in the endoplasmic reticulum that trims peptide antigens prior to their loading onto awaiting MHC-1. However, ERAP1 has also been shown to play an important role in innate immune responses, although the mechanisms underlying these associations have been unclear. The ERAP1 gene has also been linked to a number of autoimmune diseases including, but not limited to Multiple...
Show moreERAP1 has long been appreciated for its role in antigen presentation during the adaptive immune response. It is a peptidase in the endoplasmic reticulum that trims peptide antigens prior to their loading onto awaiting MHC-1. However, ERAP1 has also been shown to play an important role in innate immune responses, although the mechanisms underlying these associations have been unclear. The ERAP1 gene has also been linked to a number of autoimmune diseases including, but not limited to Multiple Sclerosis, Ankylosing Spondylitis, and Ulcerative Colitis. In addition, it is known to be altered in various tumor types as a means of immune evasion, and inhibitors for ERAP1 have shown promising results against tumors in vitro. Therefore, ERAP1’s significance in the susceptibility to diverse diseases is vast, and further study into how this protein participates in both innate and adaptive immune response mechanisms is justified. Our lab has previously published that immune cells and animals deficient in ERAP1 display proinflammatory phenotypes. In this dissertation, the mechanism as to how disruptions in normal ERAP1 function leads to proinflammatory phenotypes is studied. First, proinflammatory mechanisms within a critical innate immune cell, macrophages, are discerned using both ex vivo models and an in vivo inducible colitis mouse model. ERAP1 deficiency in the setting of a murine model of autoimmunity is also evaluated, revealing both disturbances in B cell development and function as dependent on normal ERAP1 activity, and that these disturbances can lead to exaggerated neuroinflammation in several murine models of MS. ERAP1 dependent proinflammatory mechanisms within B cells are further studied ex vivo using global RNA sequencing technology along with flow cytometry-based methods. Together, the results of these studies reveal that loss of ERAP1 function causes enhanced ER stress within the cell, leading to UPR activation, increased inflammasome activity, and evidence of increased pyroptosis. Given the broad spectrum of ERAP1 functions on immune cell functions, we capitalized on these insights to determine how ERAP1 inhibition might impact diseases such as cancer. Specifically, our results confirmed that that ERAP1 inhibition promoted NK cell directed tumor killing, a modality that had never been attempted until now. In conclusion, this dissertation capitalizes upon insights gained from human genetic studies associating ERAP1 with a variety of human disease susceptibilities, identifying the molecular mechanisms underlying these associations, and also illuminates possible new therapies for human diseases derived from study of ERAP1.
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Title: Electrical Weed Control in Integrated Weed Management : Impacts on Vegetable Production, Weed Seed Germination, and Soil Microbial Communities
Creator: Galbraith, Christopher G.
Date: 2023
Collection: Electronic Theses & Dissertations
Description: Electrical weeding is an emerging practice for late-season weed control that is being adopted in numerous cropping systems and agricultural industries, including Michigan vegetable production. However, little scientific research has been conducted directly evaluating the performance of electrical weeding and its effects on the agroecosystem. The objectives of the research program were to investigate electrical weeding in terms of 1) weed control, 2) crop injury, 3) economic viability, as well...
Show moreElectrical weeding is an emerging practice for late-season weed control that is being adopted in numerous cropping systems and agricultural industries, including Michigan vegetable production. However, little scientific research has been conducted directly evaluating the performance of electrical weeding and its effects on the agroecosystem. The objectives of the research program were to investigate electrical weeding in terms of 1) weed control, 2) crop injury, 3) economic viability, as well as its effects on 4) weed seed germinability and 5) rhizosphere microbial communities. Field trials at Hart, MI in 2021 and 2022 investigated these research objectives in conventional carrot and organic green bean production systems. Late-season weed control methods including one hand-weeding event (HW), one electrical weeder pass (1P), two electrical weeder passes performed consecutively [2P(ST)], one pass followed by one pass after a 14-day interval [2P(14d)], two passes followed by one pass after a 14-day interval (3P), and no late-season control (NLC) were evaluated in both carrot and green beans. Early-season weed control methods [low, medium, and intensive herbicide programs, weed-free, and no early-season control (NEC)] were also included in the carrot trials in order to produce different weed densities within which to assess the performance of the late-season weed control methods. In carrot, use of the intensive herbicide program typically led to lower densities of above-canopy redroot pigweed compared to NEC or the low herbicide program. There was no difference reported in redroot pigweed control with respect to early-season weed control methods after performing the various late-season weed control methods in 2021. However, in 2022, redroot pigweed control tended to be higher for treatments that caused initially lower weed densities (weed-free and intensive herbicide program). Increasing passes above 2P(ST) did not provide any higher control of redroot pigweed in carrot, while 3P did have higher weed control in green beans. Foliar injury did not exceed 10% in carrot and 20% for green beans. Electrical weeding did not cause any internal damage to carrot root tissue or have any effect on carrot root length. Hand weeding was correlated with a yield increase in 2022, whereas none of the electrical treatments led to any difference in yield in either year that was not related to natural variation in weed pressure. For green beans, neither electrical weeding nor hand weeding led to a yield difference in both years. Hand weeding had a significantly higher cost acre-1 than all electrical treatments in both years (19.6 and 28.4 times higher than 1P in carrot and green bean, respectively) due to the greater amount of time required. The range of time and cost acre-1 observed relates to the differences in weed pressure, where fields with higher weed competition requiring longer hand and electrical weeding times. Electrical weed control was found to significantly reduce redroot pigweed seed germination in 2021 (10 to 14%) but not in 2022. However, germination did not differ between early- or late season weed control methods in either year. Electrical weeding did not generally lead to differences in NH4+ or NO3- that would indicate changes in N mineralization in the rhizosphere. Microbial biomass C was higher after 1P than NLC in 2021. Apart from this, there were no differences in microbial biomass C or N reported with respect to early-season or late-season weed control methods in either year. Informed by the experimental results, growers can make more pragmatic decisions around investing in electrical weeding equipment based on its weed control performance, risk of crop injury, and economic feasibility compared with alternative late-season control practices. As well, electrical weeding has the potential to be an effective integrated weed management solution in vegetable production for control of the weed seedbank with little to no significant impacts on rhizosphere microbial communities.
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Title: IDENTIFYING LEVERAGE POINTS TO CREATE RESILIENCE TO CLIMATE SHOCKS IN DRYLAND SOCIAL-ECOLOGICAL SYSTEMS
Creator: Sharma, Shubhechchha
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Drylands cover approximately 40 percent of the earth’s land area and support more than a billion people, most of whom live in Sub-Saharan Africa (SSA), where agro-pastoralism is the major food system. Climate-related shocks such as drought, water-scarcity, diseases and pests, and food price spikes have profoundly impacted household food security among dryland agro-pastoralists, especially in Tanzania. Thus, there is a need to investigate mechanisms to ensure the future resilience of...
Show moreDrylands cover approximately 40 percent of the earth’s land area and support more than a billion people, most of whom live in Sub-Saharan Africa (SSA), where agro-pastoralism is the major food system. Climate-related shocks such as drought, water-scarcity, diseases and pests, and food price spikes have profoundly impacted household food security among dryland agro-pastoralists, especially in Tanzania. Thus, there is a need to investigate mechanisms to ensure the future resilience of livelihoods and food systems in these regions. The goal of this dissertation is to use resilience thinking approaches to identify points of intervention in dryland SES, to manage both present and future climate risks. Resilience assessment is guided by three major questions: “resilience of what, to what, and for whom”.Paper-I explores “resilience of what, to what, for whom” through the use of systems archetypes for a Maasai dryland agro-pastoralist food system in Northern Tanzania. The paper identified three system archetypes— Escalation, Limits to Growth, and Shifting the Burden—to (1) pinpoint the elements, patterns, and relationships that make up agro-pastoralist food systems; and (2) find leverage points to address the archetypical patterns limiting food security. The paper suggests a need for institutional strengthening and polycentricity to deal with food insecurity among agro-pastoralists. Paper-II explores what shocks Tanzanian food systems are responding to and how, i.e., “resilience of what, to what”. The paper used randomly sampled household data collected at national level through secondary sources to understand how different adaptive capacities influence their ability to deal with climate shocks, particularly with respect to ensuring food security, measured in terms of dietary diversity and household consumption expenditure. Through Structural Equation Modeling (SEM), the paper drew a path model that indicated investment in wealth and income diversification and investment in infrastructure were able to mediate the impact of shocks on food security. Paper-III similarly explores “resilience of what, to what” but using System Dynamics Modeling (SDM). The model allowed the exploration of feedback mechanisms and interactions between the population, livestock, and crop sub-sectors with food security in agro-pastoralist food systems in Naitolia village in Tanzania. The goal of the model was also to evaluate effectiveness of multiple policy scenarios required for food security. Out of four simulated scenarios, the model identified enhancing mechanisms for food production, along with reducing post-harvest losses and livestock predation, as most likely to result in a food sufficient scenario in the future. In creating these analyses and findings, the dissertation recommends four major leverage points to support food security through both present and future climate shocks : (1) maintaining diversity and redundancy in income and assets that provide insurance against failures; (2) fostering connectivity between multiple actors across networks for promoting bridging social capital; (3) ensuring polycentric governance so that the right well-connected institutions at the right time can deal with both agro-pastoralist rights to food and respond to disturbance and uncertainty. The dissertation also creates methodological advancement in the understanding of food security in complex systems under climate shocks, by utilizing a variety of approaches that support system thinking - systems archetypes, statistical modeling, and simulation through a system dynamics model.
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Title: When the War Raged On : Montana Territory, the Politics of Authority, and National Reconstruction
Creator: Andrella, Jennifer
Date: 2022
Collection: Electronic Theses & Dissertations
Description: In July 1861, the US House Committee on Territories drafted the first Reconstruction bill to detail a procedure for readmitting Southern states into the Union. Expecting a quick end to the Civil War, the earliest framers of Reconstruction recommended that rebellious states be assigned into an unorganized status as territories. It was a pragmatic solution that placed the South firmly in the control of a Republican Congress; a plan that complemented the Committee on Territories’ simultaneous...
Show moreIn July 1861, the US House Committee on Territories drafted the first Reconstruction bill to detail a procedure for readmitting Southern states into the Union. Expecting a quick end to the Civil War, the earliest framers of Reconstruction recommended that rebellious states be assigned into an unorganized status as territories. It was a pragmatic solution that placed the South firmly in the control of a Republican Congress; a plan that complemented the Committee on Territories’ simultaneous pursuit of territorial expansion in the trans-Mississippi West. Indeed, between 1861 and 1868 Congress incorporated seven Western territories to consolidate federal power in a growing domain. From the onset of the war, federal actors envisioned Reconstruction as a national process. Yet, the reality on the ground seldom matched their strategic plans. This dissertation analyzes Reconstruction from the vantage point of the Northwestern Great Plains. Using Montana Territory as a case study, I examine how relations between and among Native American nations, settlers, and government officials defined Reconstruction at both local and federal levels. The federal government had enduring political and economic interests in the Northwestern Plains prior to the outbreak of the war. Between 1828 and 1865, the region emerged as the last US stronghold of the global fur trade, cycled through several mining booms, and showed a promising future for homesteading and ranching. The Northwestern Plains were and are the homelands to a mosaic of Native American nations who asserted their rights to sovereignty by demanding federal recognition of their territorial, political, economic, and cultural autonomy. As these lands became contested under the pressure of US settlement, Native actors continued to press for visibility against local and federal modes of authority. The lived experiences of Native actors unveil some of the critical limitations of Reconstruction; that the expansion of citizenship, suffrage, and labor protections coincided with land dispossession, colonization, and erasure. By the time this study concludes in 1883, it becomes apparent that the dissolution of Reconstruction rested in the program’s failure to resolve the nation’s most fundamental questions over belonging, space, and power.I argue that Reconstruction was a process that experimented with federal and local forms of authority, settler colonialism, and state formation which came under stress after the onset of war in 1861. Republican governance throughout the Civil War and Reconstruction introduced new federal economic and political imperatives, destabilized local patterns of power among settlers, and opened new threats to Indigenous sovereignty. Using cartography, personal and mass communication, artwork, literature, and government records, this study portrays a version of Reconstruction that was fluid, chaotic, and often violent as western civil institutions either broke down or competed for primacy. By integrating the historiographies of Reconstruction, Western history, and Native American ethnohistory this study challenges the notion that federal state formation in the West (and state restoration in the South) were linear processes ushered by a collective of federal actors. Moreover, the existing literature on both Reconstruction and Western territorial expansion has overstated the ability of the federal government to produce communal order through efforts like military occupation, property laws, and multitiered administrative systems such as the Bureau of Indian Affairs. By essentializing the scale of local forces that stacked against federal administration in distant, contested spaces like Montana, the ambitious designs to restore and expand the Union ultimately produced a more exclusionary, unstable, and violent nation.
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Title: Synthesis of HIV-1 GP41 Including FP and MPER by Native Chemical Ligation with Applications to SSNMR. Expression, Solubilization, and Purification of SARS-CoV-2 Spike Protein Subunit 2
Creator: Wolfe, Robert John
Date: 2022
Collection: Electronic Theses & Dissertations
Description: AbstractSynthesis of HIV-1 GP41 Including FP and MPER by Native Chemical Ligation with Applications to SSNMR. Expression, Solubilization, and Purification of SARS-CoV-2 Spike Protein Subunit 2 By Rob Wolfe Human immunodeficiency virus type 1 (HIV-1) and Coronavirus 2019 (Covid-19) have caused substantial risk to public health worldwide. Both HIV-1 and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are membrane enveloped viruses which cause acquired immune deficiency...
Show moreAbstractSynthesis of HIV-1 GP41 Including FP and MPER by Native Chemical Ligation with Applications to SSNMR. Expression, Solubilization, and Purification of SARS-CoV-2 Spike Protein Subunit 2 By Rob Wolfe Human immunodeficiency virus type 1 (HIV-1) and Coronavirus 2019 (Covid-19) have caused substantial risk to public health worldwide. Both HIV-1 and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are membrane enveloped viruses which cause acquired immune deficiency syndrome (AIDS) and COVID-19 in humans, respectively. The process by which these viruses initiate the infection by membrane fusion of the viral and host cells is similar. However, they differ in which membrane protein is responsible for the fusion process. The HIV-1 glycoprotein 41 (Gp41) is a single-pass integral viral membrane protein containing a ~170-residue ectodomain that is important for membrane fusion between virus and host cells. The ectodomain includes the fusion peptide (FP), N-helical region (NHR), loop, C-helical region (CHR) and viral membrane-proximal external region (MPER). The ectodomain mediates joining (fusion) of the HIV-1 and host cell membranes, which is in an initial step in infection. The ectodomain also adopts different structures, including a final hyper thermostable state. Some data supports a fusion role for this final state. Like HIV-1, SARS2-CoV-2 is enveloped by a membrane that is obtained during budding from an infected host cell. Infection of a new cell requires fusion of the virus membrane with a membrane of the target cell and subsequent deposition of the viral nucleocapsid in the cytoplasm. This process is catalyzed by the Spike (S) protein subunit 2 (S2). My research has focused on the production and characterization of several protein constructs (with or without FP) and the characterization of S2_816-1273, a large S2 protein construct containing all regions including the FP, transmembrane (TM) and the cytoplasmic tail (CT). The expression vector used is pET-24a(+). Biophysical characterization comparisons between S2_816-1273 and shorter constructs including S2_903-998SGGRGG1153-1207 and S2_903-998SGGRGG1163-1207 were performed. Biophysical characterization techniques such as circular dichroism (CD) spectroscopy, size exclusion chromatography (SEC), mass spectrometry (MS), and vesicle fusion assays were used in this study. In addition, this work also describes development and application of native chemical ligation (NCL) methods to produce most of the HIV glycoprotein-41 (gp41) ectodomain. NCL with yields up to 45% were achieved between the chemically synthesized N-terminal FP (gp41512-534) and bacterially synthesized hairpin with MPER (HM) (gp41535-581/SGGRGG/628-683) segments. The hairpin is the NHR-loop-CHR region. These high yields were achieved by solubilizing the HM segment in guanidinium chloride and imidazole which worked together to fully denature the reactants, facilitating the NCL reaction via exposure of the reactant termini. HM was produced with fractional 13C or 2H-labelings that were respectively in the 14-82% and 18% to 54% ranges. The synthesized FP included a non-native N-terminal H6G6D4K tag, which allowed for the binding of FP-HM to a metal-affinity column at the Nterminus to facilitate the separation of unreacted HM. FP-HM was then released from the column by enterokinase-catalyzed cleavage. My work will help future scientists synthesize site-specific 13C and 2H labeled large protein constructs since this is the first time that large Gp41 constructs including full MPER have been synthesized in mg quantities using a combination of bacterial expression system and solid phase peptide synthesis. Furthermore, this methodology is applicable to many proteins that cannot be easily characterized by other methods inside of the lipid bilayer, such as crystallography.
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Title: 3D Printed Fluidic Devices for Biomedical Applications
Creator: Redman, Nathan Abraham
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Antimicrobial resistance represents an imminent and growing threat to global health. It is estimated that antimicrobial resistance will cause 10 million deaths a year by 2050. The testing of clinical infections for susceptibility to antimicrobial drugs is therefore critical. However, current methods of susceptibility testing are prohibitively slow, and they require pathogen isolation and culture. This inability to rapidly screen infections causes serious problems including patient mortality...
Show moreAntimicrobial resistance represents an imminent and growing threat to global health. It is estimated that antimicrobial resistance will cause 10 million deaths a year by 2050. The testing of clinical infections for susceptibility to antimicrobial drugs is therefore critical. However, current methods of susceptibility testing are prohibitively slow, and they require pathogen isolation and culture. This inability to rapidly screen infections causes serious problems including patient mortality by sepsis, over-prescription of broad-spectrum antibiotics, and the accelerated spread of antimicrobial resistance in human pathogens. Faster susceptibility testing is required to more effectively treat sepsis and prevent the unnecessary selection for resistant pathogenic strains more effectively. Quantifying drug susceptibility at the single-cell level on a multiphase chip platform will eliminate the need for culture and enable drug susceptibility screening within minutes. Antibiotics often alter extracellular levels of adenosine triphosphate (ATP) in susceptible microbial cells, while leaving resistant cells mostly unaffected. An individual microbial cell will contain ~1-5 attomoles of ATP, which is only detectable if confined to extremely small reaction volumes. Here we propose a multiphase (immiscible aqueous and ether) microfluidics platform combined with a microcapillary system (Chapters 2,3). This system will confine individual pathogens and challenge drugs inside droplets of nanoliter-scale volume to enable detection of drug-induced alteration of ATP release from susceptible cells. This system will enable more informed and specific prescription of drugs to both improve patient outcomes and relieve unnecessary selective pressure for the spread of antimicrobial resistance.The same 3D printing tools that apply well to multiphase fluidic devices are also leveraged to address biomedical challenges in tangent fields. Progress in the fields of organoid modeling and regenerative tissue printing are discussed (Chapter 4).
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Title: ANALYSIS OF EJECTOR-STYLE MICROBUBBLE GENERATORS : MASS-TRANSFER PROPERTIES, MATHEMATICAL MODELING, AND DESIGN ALGORITHM
Creator: Wang, Ziwei
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Gas-to-liquid mass transfer is a rate-limiting step for many commercial-scale operations in the chemical, biochemical, pharmaceutical, and wastewater-treatment industries. The use of microbubbles with a diameter on the100 μm scale has been shown to provide high volumetric mass-transfer rates due to its high gas contact area per volume. However, the use of microbubbles in commercial processes has been hampered by the lack of design algorithms with which to fabricate high-performance,...
Show moreGas-to-liquid mass transfer is a rate-limiting step for many commercial-scale operations in the chemical, biochemical, pharmaceutical, and wastewater-treatment industries. The use of microbubbles with a diameter on the100 μm scale has been shown to provide high volumetric mass-transfer rates due to its high gas contact area per volume. However, the use of microbubbles in commercial processes has been hampered by the lack of design algorithms with which to fabricate high-performance, microbubble-sparged gas-liquid contacting equipment. The goals of this study were to identify the type of microbubble generator best suited to provide high volumetric mass transfer rates in commercial-scale equipment, characterize the mass-transfer properties, develop models able to predict the mass-transfer rate as a function of the key independent variables, and use the models to develop a design algorithm suitable to use microbubble sparging in industrial processes. The study began with a literature review of microbubble generators that considered factors including the mechanism, safety, cost, and scalability, with the goal of identifying generators suited to cost-effectively provide extremely high mass transfer in commercial-scale equipment. Microbubble generators that used liquid turbulence were found to have the best combination of properties for such applications. In collaboration with the Michigan Biotechnology Institute, a 300-L bioreactor was customized for use with either a RiverForest microbubble ejector and a conventional ring sparger. E.coli batch growth experiments were conducted to compare the growth rates using the two aeration methods. The E.coli growth rate observed during microbubble aeration was about twice that observed with the traditional ring sparger. Mathematical models describing the performance properties of both a microbubble ejector and a Modified Jameson Cell were developed. The models included energy requirements, mass transfer rates, gas and liquid flow patterns, and clearance of spent bubbles. The models predicted that the ejector would be more energy-efficient for applications requiring higher mass-transfer rates and lower gas volume fractions, whereas the Modified Jameson Cell would be more energy-efficient for applications requiring lower mass-transfer rates and higher gas void fractions. Moreover, the ejector generator was considered to have operational advantages over the modified Jameson Cell in terms of surfactant requirement and scalability. Based on these advantages, ejector generators were used for subsequent studies. A novel flow system was developed to measure the mass-transfer rate of microbubble produced by an ejector generator. A mathematical model was developed to reproduce experimental trends and estimate the effective microbubble diameter generated as a function of the gas and liquid flow rates. New axial mixing and two-phase friction factor correlations were developed for the model fidelity. The mathematical model was used to determine the effective microbubble diameter that best reproduced the dissolved oxygen profile for various combinations of gas and liquid velocities. The results were used to develop a correlation to predict the effective microbubble size as a function of system properties. The predictive power of this correlation has utility for industrial process design and scale-up applications. The friction factor and microbubble diameter correlations developed in this study were used to develop additional models to simulate the microbubble mass-transfer in large reactors that are sparged with arrays of microbubble ejectors. The models simulated flow from each ejector using an entrainment model for jet cones. They also simulated arrangement of ejectors into triangular arrays to estimate insufficiently aerated volume and optimize ejector spacing. Collectively, the models developed in this study provide powerful new design tools that enable rational design, optimization, and scale-up of ejector microbubble sparger arrays for commercial-scale reactors that require extremely high volumetric mass-transfer rates.
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Title: SEX DIFFERENCES IN HYPERTENSION AND THE ROLE OF ENDOTHELIAL TRPV4 CHANNELS IN CEREBROVASCULAR AND COGNITIVE FUNCTION
Creator: Chambers, Laura Christine
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Vascular cognitive impairment and dementia (VCID) describes a spectrum of cognitive disorders that have a cerebrovascular origin. VCID can range from mild cognitive impairment to frank vascular dementia. The mechanisms behind VCID development are not fully understood and there are no effective treatments available. VCID arises from functional impairment in the small arteries and arterioles in the brain. Hypertension, which affects nearly half of all American adults, is the leading modifiable...
Show moreVascular cognitive impairment and dementia (VCID) describes a spectrum of cognitive disorders that have a cerebrovascular origin. VCID can range from mild cognitive impairment to frank vascular dementia. The mechanisms behind VCID development are not fully understood and there are no effective treatments available. VCID arises from functional impairment in the small arteries and arterioles in the brain. Hypertension, which affects nearly half of all American adults, is the leading modifiable risk factor for VCID. Hypertension impairs cerebrovascular function that can starve neurons of necessary nutrients, increasing risk of cognitive impairment. My studies focus on cerebral parenchymal arterioles (PAs), which direct blood flow from the pial circulation to the capillaries. Because they lack collateral connections, PAs are considered the weak link in the cerebral perfusion. The occlusion of a single PA creates a discrete column of ischemic tissue that can produce cognitive impairment. PAs are dependent on TRPV4 channels for endothelium-dependent dilation, and there is a strong link between TRPV4 and cognitive function. Previous studies in male rodents showed that hypertension impairs TRPV4-mediated dilation in PAs, and this was associated with memory impairments. When mineralocorticoid receptor (MR) antagonists are administered alongside developing hypertension, these impairments are prevented. However, it is thus far unknown whether MR antagonist treatment can reverse cerebrovascular and cognitive impairments after they have developed. My first aim tests the hypothesis that rats with established hypertension will have impaired TRPV4 function in PAs that is associated with cognitive impairment, and that treatment with the MR antagonist eplerenone can reverse this damage after its development. My second aim focuses on sex differences in hypertension, as this is a major gap in the literature. Thus far, all studies linking TRPV4 function to cognition have been conducted in male mice. Given that estrogen is vasoprotective in other vascular beds, I hypothesize that hypertensive female mice would be protected against impaired TRPV4 function in PAs, and from the associated cognitive deficits observed in male mice. Lastly, my third aim addresses the importance of TRPV4 channels specifically in the endothelium. There is a consistent link between TRPV4 impairment and cognitive dysfunction, but due to the channel’s ubiquitous expression, its role in endothelial cells is unknown. Here, I test the hypothesis that male and female mice with endothelial TRPV4 channel deletion will have cognitive impairment. My studies show that MR antagonism reverses cerebrovascular and cognitive damage in hypertension, and that female sex protects against the development of these impairments. Further, I show that endothelial TRPV4 channel deletion results in cognitive dysfunction and increased inflammation in both male and female mice. My studies show for the first time that young female mice have preserved TRPV4 channel function in PAs that is associated with preserved cognitive function. Further, my data suggest the MR is a promising therapeutic target in hypertensive patients because it not only protects against neurovascular damage but can reverse it after it has developed.
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Title: ANTI-DEFICIT FRAMING TYC TRANSFER STUDENTS’ SELF-EFFICACY AS CONTEXTUALLY IMPACTED BY EDUCATION ENVIRONMENTS
Creator: Wood, Laura
Date: 2022
Collection: Electronic Theses & Dissertations
Description: The work in this dissertation aims to support a more equitable science education culture that better supports students who have historically and continue to be inequitably pushed out of science. Our equity-oriented and anti-deficit research agenda led us to study community college and transfer students as well as their self-efficacy and self-efficacy experiences. This dissertation opens by overviewing the state of STEM education and explaining how research approaches often frame students in...
Show moreThe work in this dissertation aims to support a more equitable science education culture that better supports students who have historically and continue to be inequitably pushed out of science. Our equity-oriented and anti-deficit research agenda led us to study community college and transfer students as well as their self-efficacy and self-efficacy experiences. This dissertation opens by overviewing the state of STEM education and explaining how research approaches often frame students in deficit ways. Chapter 1 introduces the author's researcher positionality and relevant literature to her research approaches. The author's research agenda prioritizes supporting marginalized students in STEM through studying the construct of self-efficacy. After reviewing the research framing, Chapter 2 introduces relevant literature about self-efficacy and two-year college (TYC) transfer student experiences. Chapter 2 ends by addressing how the author's research positionality aligns with and impacts the ways she researches self-efficacy and TYC transfer students. Afterwards, each body chapter (Chapters 3, 4, and 5) opens with a transition situating it in the broader story of the dissertation. Chapter 3 opens by reminding readers of the reasons for our qualitative approach to studying self-efficacy. Then, it describes the development of a qualitative codebook for self-efficacy. Chapter 4 opens by explaining our shift to a narrative analysis case study of a single transfer student. This chapter ultimately diverged from self-efficacy, and Chapter 4 will discuss the reasons and the results of that narrative analysis, stating that supporting characters were instrumental in a transfer student’s success story. The chapter ends with implications for universities to learn from TYCs. The dissertation transitions to Chapter 5 by broadening out from a single student’s case study to a positively impactful course experience at a TYC for STEM students intending to transfer. This chapter describes design considerations learned from the course as well as opportunities the course provided for student self-efficacy experiences. Chapter 6 discusses the story across all three body chapters as situated in the research framing and concludes the dissertation.
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Title: Perinatal HIV Exposure and Infection and its Association with Caregiver Depression Symptoms and Child Executive Function
Creator: Brewer, Sarah Kathleen
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Survival is possible for children perinatally exposed to or infected by Human Immunodeficiency Virus (HIV) in the post-combined antiretroviral therapy era, but the long-term effects of HIV exposure on children and their caregivers are still being explored. Identifying factors affecting children’s ability to thrive within an HIV context has great public health significance, particularly within a sub-Saharan context where the burden of HIV is felt disproportionately by women and children....
Show moreSurvival is possible for children perinatally exposed to or infected by Human Immunodeficiency Virus (HIV) in the post-combined antiretroviral therapy era, but the long-term effects of HIV exposure on children and their caregivers are still being explored. Identifying factors affecting children’s ability to thrive within an HIV context has great public health significance, particularly within a sub-Saharan context where the burden of HIV is felt disproportionately by women and children. Additionally, caregiver mental health is an important focus given its bidirectional relationship with child behavior. Previous studies on these topics have not included a full complement of HIV exposure or infection groups, considered how caregivers’ mental health may depend on child serostatus, and or are investigated in HIV endemic areas. The three aims presented in this dissertation will explore how perinatal HIV infection and exposure can affect caregivers and school-aged children. In Aim one, we compare depressive symptoms among caregivers of 3 groups of 6-10 year old children in Uganda with known HIV exposure status: children HIV-infected perinatally (CPHIV, n=102), children born to HIV-infected mothers, but HIV negative (CPHEU, n=101), and HIV-unexposed, uninfected community controls (CHUU, n=103). Caregiver depression symptoms were assessed using the Hopkins Symptom Checklist. In Aims two and three, child executive functioning (EF) assessed by caregiver report was compared across the three HIV exposure groups; effect modification of these associations by social support and wealth was also explored. We used random effects general linear models to estimate mean differences among the three HIV exposure groups. Adjusted models included caregiver age, education, social support, lifetime trauma, and wealth as covariates. In aim one, we observed that perinatal HIV exposure status was associated with mean caregiver depression symptoms. Specifically, in unadjusted analyses, depression symptoms were higher among CPHEU compared to CPHIV caregivers (unstandardized beta coefficient [B]=-3.5, 95% confidence interval [CI] -5.3, -1.8). We also observed that caregiver social support modified the findings above (p < 0.10) with CPHEU caregivers with lower social support and lower wealth reporting higher caregiver depressive symptoms compared to CPHIV caregivers. We repeated all analyses within the subsample of biological mothers to examine whether their own diagnostic status drove any findings we observed; our pattern of results remained unchanged. For Aim two, in our unadjusted analyses, perinatal HIV exposure was not associated with the Global Executive Composite (GEC) and Metacognition Index (MCI) scores of EF. However, for the Behavioral Regulation Index (BRI), the CPHIV group had lower levels of problems relative to the CHUU and CPHEU groups (B= -0.40, 95% CI -0.77, -0.03, B=-0.40, 95%CI -0.76, -0.02 respectively). For Aim three, we observed that the child’s sex and caregiver depression symptoms modified the association between HIV status and specific subscales of EF. Future directions for this work should include investigation into what drives the difference in caregiver depression symptoms between exposure groups. Additionally, collecting longitudinal measures of child EF and caregiver depression would help further interrogate time order between caregiver and child functioning among families affected by HIV. Lastly, continued investigation on how our findings relate to outcomes linked to EF such as academic achievement and behavioral problems would help to establish the importance of EF as a potential intervention target to improve school readiness.
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Title: The Construct Development and Measurement of Contributive Justice
Creator: Scott, William Campbell
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Organizational justice has long since been considered multi-dimensional. However, the dimensionality of organizational justice has been stagnant in recent years, consisting primarily of distributive, procedural, interpersonal, and informational justice. When further examining the meaning of justice and fairness in organizations, it becomes apparent that these organizational justice dimensions are not capturing an important element of justice, that being the equality of opportunity. This is an...
Show moreOrganizational justice has long since been considered multi-dimensional. However, the dimensionality of organizational justice has been stagnant in recent years, consisting primarily of distributive, procedural, interpersonal, and informational justice. When further examining the meaning of justice and fairness in organizations, it becomes apparent that these organizational justice dimensions are not capturing an important element of justice, that being the equality of opportunity. This is an important absence because the opportunity to contribute in organizations will likely affect both organizational outcomes and personal outcomes outside of work. Therefore, building upon previous work, the construct of contributive justice in organizations was introduced and defined as the fairness of opportunities to contribute to core work processes. Contributive justice consists of two dimensions, the equal opportunity to engage in complex labor, and the equal opportunity to participate in decision-making processes. A measure was constructed to capture these dimensions, along with specific subdimensions. In a sample of 534 full-time employees, the results suggested that the contributive justice measure was a reliable two-factor measure that was discriminable from the other organizational justice dimensions and was positively correlated with other variables such as meaningful work, instrumental voice, inclusion, empowerment, and self-esteem. Contributive justice was also found to have incremental validity over the other organizational justice dimensions. These results suggest the importance of contributive justice as an aspect of organizational fairness and employee well-being.
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Title: DEVELOPMENT OF 3D BIOACTIVE AND ANTIBACTERIAL SILICATE-BASED SCAFFOLDS FOR BONE TISSUE REGENERATION IN LOAD-BEARING APPLICATIONS
Creator: Marsh, Adam Christoph
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Current gold-standard approaches to addressing the needs of bone defects in load-bearing applications entail the use of either autographs or allographs. Both solutions, however, are imperfect as both autographs and allographs carry the risk of additional trauma, threat of disease transmission, and potential donor rejection respectively. Porous 3D scaffolds are attractive alternatives, illuminating a potential path towards achieving the ideal scaffold for targeting bone tissue regeneration in...
Show moreCurrent gold-standard approaches to addressing the needs of bone defects in load-bearing applications entail the use of either autographs or allographs. Both solutions, however, are imperfect as both autographs and allographs carry the risk of additional trauma, threat of disease transmission, and potential donor rejection respectively. Porous 3D scaffolds are attractive alternatives, illuminating a potential path towards achieving the ideal scaffold for targeting bone tissue regeneration in load-bearing applications, usurping autographs to become the new gold-standard. To unlock the full healing potential of 3D scaffolds, such scaffolds must be multifunctional such that (1) their mechanical performance meets the requisite requirements as dictated by the mechanical performance characteristics of interest for native bone tissue, (2) they stimulate the necessary biological responses for bone tissue regeneration, and (3) they exhibit antibacterial characteristics to combat the threat of infection. To date, no reports document 3D scaffolds exhibiting all three performance characteristics. The aim of this dissertation, therefore, is to deliver 3D scaffolds that are mechanically competent, possess and exhibit inherent and advanced antibacterial characteristics, and are successful at providing the needed biological characteristics for bone tissue regeneration. To achieve this, this dissertation implements a multidisciplinary approach, utilizing comprehensive structural characterization across a wide range of scales to elucidate process – performance relationships to execute scientifically driven modifications to engineer and deliver a 3D scaffold to successfully target bone tissue regeneration in load-bearing applications. A silver-doped bioactive glass-ceramic (Ag-BG) composition was selected as the material for scaffold synthesis due to its inherent and attractive antibacterial and biological performance characteristics. Two fundamentally different processing approaches were utilized for synthesizing Ag-BG scaffolds: the polymer foam replication technique and fused filament fabrication (FFF). The Ag-BG scaffolds studied herein were found to exhibit advanced antibacterial performance characteristics against methicillin-resistant Staphylococcus aureus (MRSA), a common pathogen implicated in osteomyelitis development, able to combat MRSA both in planktonic and biofilm forms. Ag-BG scaffolds demonstrated the ability to form an apatite-like layer when immersed in simulated body fluid (SBF), an indicator that Ag-BG scaffolds will induce the necessary mineralization for bone tissue regeneration, in addition to exhibiting attractive cell viability, proliferation, and differentiation characteristics when studied in vitro. The mechanical performance of Ag-BG scaffolds reported herein saw progressive improvements in each iteration of Ag-BG scaffold synthesis, achieving desirable mechanical competency and reliability as a result of the multidisciplinary approach formulated. In addition to the exploration of developing 3D antibacterial and biological silicate-based scaffolds capable of targeting bone tissue regeneration in load-bearing applications, foundational work towards the development of class II hybrid scaffolds comprised of gelatin methacryloyl (GelMA) and Ag-BG for targeting softer tissue regeneration. The novel syntheses applied to the successful molecular coupling of GelMA and Ag-BG presents an attractive class II hydrogel showing great promise as a compatible ink for 3D bioprinting cell-laden scaffolds capable of targeting tissue regeneration of more sophisticated systems.
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Title: Molecular epidemiology, pangenomic diversity, and comparative genomics of Campylobacter jejuni
Creator: Rodrigues, Jose Alexandre
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Campylobacter jejuni, the leading cause of bacterial gastroenteritis in the United States, is often resistant to commonly used antibiotics and has been classified as a serious threat to public health. Through this work, we sought to evaluate infection trends, quantify resistance frequencies, identify epidemiological factors associated with infection, and use whole-genome sequencing (WGS) as well as comparative phylogenomic and pangenomic approaches to understand circulating C. jejuni...
Show moreCampylobacter jejuni, the leading cause of bacterial gastroenteritis in the United States, is often resistant to commonly used antibiotics and has been classified as a serious threat to public health. Through this work, we sought to evaluate infection trends, quantify resistance frequencies, identify epidemiological factors associated with infection, and use whole-genome sequencing (WGS) as well as comparative phylogenomic and pangenomic approaches to understand circulating C. jejuni populations in Michigan. C. jejuni isolates (n=214) were collected from patients via an active surveillance system at four metropolitan hospitals in Michigan between 2011 and 2014. Among the 214 C. jejuni isolates, 135 (63.1%) were resistant to at least one antibiotic. Resistance was observed for all nine antibiotics tested yielding 11 distinct resistance phenotypes. Tetracycline resistance predominated (n=120; 56.1%) followed by resistance to ciprofloxacin (n= 49; 22.9%), which increased from 15.6% in 2011 to 25.0% in 2014. Notably, patients with ciprofloxacin resistant infections were more likely to report traveling in the past month (Odds Ratio (OR): 3.0; 95% confidence interval (CI): 1.37, 6.68) and international travel (OR: 9.8; 95% CI: 3.69, 26.09). To further characterize these strains, we used WGS to examine the pangenome and investigate the genomic epidemiology of this set of C. jejuni strains recovered from Michigan patients. Among the 214 strains evaluated, 83 unique multilocus sequence types (STs) were identified that were classified as belonging to 19 previously defined clonal complexes (CCs). Core-gene phylogenetic reconstruction based on 615 genes identified three clades, with Clade I comprising six subclades (IA-IF) and predominating (83.2%) among the strains. Because specific cattle-associated STs, such as ST-982, predominated among strains from Michigan patients, we also examined a collection of 72 C. jejuni strains from cattle recovered during an overlapping time period by WGS. Several phylogenetic analyses demonstrated that most cattle strains clustered separately within the phylogeny, but a subset clustered together with human strains. Hence, we used high quality single nucleotide polymorphism (hqSNP) profiling to more comprehensively examine those cattle and human strains that clustered together to evaluate the likelihood of interspecies transmission. Notably, this method distinguished highly related strains and identified clusters comprising strains from both humans and cattle. For instance, 88 SNPs separated a cattle and human strain that were previously classified as ST-8, while the human and cattle derived ST-982 strains differed by >200 SNP differences. These findings demonstrate that highly similar strains were circulating among Michigan patients and cattle during the same time period and highlight the potential for interspecies transmission and diversification within each host. In all, the data presented illustrate that WGS and pangenomic analyses are important tools for enhancing our understanding of the distribution, dissemination, and evolution of specific pathogen populations. Combined with more traditional phenotypic and genotypic approaches, these tools can guide the development of public health prevention and mitigation strategies for C. jejuni and other foodborne pathogens.
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Title: DEVELOPING LIGNIN-BASED EPOXY AND POLYURETHANE RESINS
Creator: Nikafshar, Saeid
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Lignin, the most abundant natural aromatic polymer, is currently produced as by-product during biorefinery and chemical pulping processes. Lignin is rich in hydroxyl functional groups (both phenolic and aliphatic OH), making it an excellent raw material for synthesizing epoxy and polyurethane resins. However, there are several challenges in utilizing unmodified lignins as feedstock for product development, including high polydispersity/heterogeneity, low reactivity, poor accessibility of...
Show moreLignin, the most abundant natural aromatic polymer, is currently produced as by-product during biorefinery and chemical pulping processes. Lignin is rich in hydroxyl functional groups (both phenolic and aliphatic OH), making it an excellent raw material for synthesizing epoxy and polyurethane resins. However, there are several challenges in utilizing unmodified lignins as feedstock for product development, including high polydispersity/heterogeneity, low reactivity, poor accessibility of hydroxyl groups for reaction with co-monomers low solubility in common organic solvents, and dark color. There are significant variations in lignin characteristics, depending on the source of biomass and isolation methods. Therefore, in-depth lignin characterization is needed to provide the basic knowledge of the structural, chemical, and thermal properties to facilitate lignin valorization.This study was focused on lignin characterization and development of lignin-based epoxy and polyurethane resins. First, a wide range of lignin samples was fully characterized by measuring their ash contents, elemental analyses, hydroxyl contents, chemical structures, molar mass distributions, and thermal properties. Next, a novel method was developed to measure the reactivity of thirteen different unmodified lignins toward biobased epichlorohydrin (ECH). A partial least square regression (PLS-R) model (with 92 % fitting accuracy and 90 % prediction ability) was created to study the correlation between lignin properties and epoxy content. The results showed that lignins with higher phenolic hydroxyl contents and lower molecular weights were more suitable for replacing 100 % of toxic bisphenol A (BPA) in the formulation of resin precursors. Additionally, two epoxidized lignin samples (with the highest epoxy contents) were cured using a biobased hardener (Cardolite from cashew nutshell), showed comparable thermomechanical performances and thermal stabilities to a petroleum-based epoxy system. Biobased waterborne polyurethane resins (PUDs) were also developed by entirely replacing the petroleum-based polyol and the internal emulsifier with either alkaline pre-extraction lignins or enzymatic hydrolysis lignins as well as tartaric acid (a biobased diacid). The formulated resins had zero VOC (volatile organic compound), which was achieved by replacing toxic n-methyl-2-pyrrolidone (NMP) with cyrene (a biobased solvent). To further improve the mechanical properties of our biobased PUD resins, 20 wt.% of lignin was substituted with low hydroxyl value soy-polyol, which increased their tensile strength and elongation at break to 87% and 68% of a commercial PUD resin. The results of this study demonstrated that it is imperative to fully characterize lignin and choose the right lignin for each specific application. This approach enabled us to entirely replace petroleum-based raw materials (BPA and polyol) with lignin and formulate biobased epoxy and polyurethane resins.
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Title: ASSESSING THE DETERMINANTS THAT PARSE THE LYASE AND MUTASE ACTIVITIES OF A PLANT AMINOMUTASE, AND DEVELOPING A REGIOSELECTIVE COUPLING REACTION FOR A TRIALKYL PYRAZINE.
Creator: Attanayake, Gayanthi Kumari
Date: 2021
Collection: Electronic Theses & Dissertations
Description: This dissertation is mainly contributed with two main projects. The first project is based on aminomutase enzyme. Recent discovery of MIO-dependent aminomutases on the biosynthetic pathways of biologically active, medicinal compounds in plants and microorganisms raises interest in further understanding how they catalyze β-amino acid building blocks. A tyrosine aminomutase isolated from Japanese rice, Oryza sativa (OsTAM), converts α-tyrosine to β-tyrosine (75%) and makes an acrylate, p...
Show moreThis dissertation is mainly contributed with two main projects. The first project is based on aminomutase enzyme. Recent discovery of MIO-dependent aminomutases on the biosynthetic pathways of biologically active, medicinal compounds in plants and microorganisms raises interest in further understanding how they catalyze β-amino acid building blocks. A tyrosine aminomutase isolated from Japanese rice, Oryza sativa (OsTAM), converts α-tyrosine to β-tyrosine (75%) and makes an acrylate, p-coumarate (25%), as a by-product. OsTAM is the first TAM to have slight phenylalanine aminomutase (PAM) activity (3%). This may not be surprising since the active sites of OsTAM and TcPAM from Taxus plants differ by only two residues (Y125 and N446 of OsTAM compared to C107 and K427 of TcPAM, respectively) positioned similarly near the aryl ring of their substrates. We anticipated by changing key active site residues of OsTAM to nonpolar side chains found in TcPAM would improve the binding of substituted phenylalanine substrates. Another feature of MIO-aminomutases, highlighted in a previous study,1 is a hinge-gate inner loop that opens and closes the entry to the active site. We changed hydrophilic for more hydrophobic residues within the OsTAM loop like in TcPAM to make it function as a more efficient PAM and expected the mutants to produce a greater proportion of the β-amino acid over acrylate compared to that made by wild-type OsTAM. Our data suggested that a combination of active site mutants and loop mutants generally increased the turnover of OsTAM for para-substituted substrates over the other meta- and ortho- regioisomers to their corresponding cinnamates, and not to the β-amino acids, as the major products. These findings suggest that while active site residues may be involved primarily in creating broad substrate selectivity, their role along with that of the inner loop to parse the reaction toward β-amino acids remains elusive.The second project mainly focused on regioselective synthesis of ethyl dimethyl pyrazine. Alkylpyrazines are important heterocyclic compounds used as flavorants in the food and beverage industries. This study developed a regioselective synthesis of 2-ethyl-3,5-dimethylpyrazine (235-EDMP) over its 3-ethyl-2,5-dimethyl isomer (325-EDMP). Our first attempts explored how steric direct the coupling orientations between diamines to diketones to access 235-EDMP. Also, various physical parameters of the reaction conditions were changed, such as reduced temperature, the order-of-addition of reactants, and supplementation with chiral zeolites (Montmorillonite phyllosilicates) to template the orientation of the coupling partners to direct the regiochemistry of the reaction. Each reaction trial resulted in 50:50 mixtures of the ethyl dimethylpyrazine regioisomers. An alternative approach was explored to direct the regioselectivity of the reactions; acyloins (α-hydroxy ketone) replaced the diketone as the electrophilic coupling reactant used in the previous trial experiments. The hydroxy ketone reactants were made biocatalytically with pyruvate decarboxylase (E.C. 4.1.1.1). The coupling reaction between 2-hydroxypentan-3-one and propane-1,2-diamine resulted in the desired 235-EDMP at >70% (~77 mg total) relative to 30% 325-EDMP in the product mixture. The 3-hydroxypentan-2-one acyloin congener bio catalyzed and reacted with propane-1,2-diamine as proof of principle to make 325-EDMP (~60% relative abundance, ~57 mg) over the 235-EDMP. These results hinted toward a mechanism directed by the hydroxy ketone electrophilicity and the sterics at each nucleophilic center of the diamine.
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Title: Life Cycle Monitoring of Reversible Adhesive Bonded Joints using Guided Waves
Creator: Palanisamy, Rajendra Prasath
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Recent advancements in automotive, aerospace, civil and wind-energy industries have resulted in an ever-increasing demand for lightweight, cost-effective, rapidly manufactured and recyclable/reusable of structural components. Adopting composite materials is a popular solution to achieve light-weighting, however it requires complex joining methods compared to traditional mechanical fasteners. Electromagnetic targeted heating of nano-Fe3O4 reinforced thermoplastic adhesives (Reversible-Adhesive...
Show moreRecent advancements in automotive, aerospace, civil and wind-energy industries have resulted in an ever-increasing demand for lightweight, cost-effective, rapidly manufactured and recyclable/reusable of structural components. Adopting composite materials is a popular solution to achieve light-weighting, however it requires complex joining methods compared to traditional mechanical fasteners. Electromagnetic targeted heating of nano-Fe3O4 reinforced thermoplastic adhesives (Reversible-Adhesive) is an emerging technique for rapid assembly, dis-assembly, and re-assembly of bonded composite parts. Alternate magnetic field applied to the dispersed ferromagnetic nanoparticles (FMNP) within a thermoplastic adhesive results in these particles acting as nano-heaters and rapidly heating the surrounding material resulting in melting and flow of the adhesive, which upon cooling forms a structural bond. This process can be repeated and hence termed reversible adhesive. Reversible-adhesive bonded composite structures (RBCS) offer a greater advantage over thermosets or mechanical joints such as rapid processing, easy repair, quick disassembly, and possible re-usability of components. However, it is essential to accurately measure the temperature of the adhesive during processing and repair, since overheating may cause chemical degradation and underheating may introduce improper bonds. Adhesively bonded composite structures provide a more uniform stress distribution in the bond-line than riveted joints resulting in higher fatigue life. However, modeling the physics behind crack initiation and propagation inside bonded regions is challenging especially under fatigue loading. As a result, real-time in-service bond monitoring is required to ensure structural safety. In addition to monitoring the damage state, prediction of damage area and remaining useful life of the component is imperative. Thus, this research work focusses on developing a life cycle monitoring solution for RBCS using the guided wave (GW) technique. Ultrasonic guided waves were made to propagate across the bond-line of the joint by exciting and sensing them using miniature piezoelectric wafers. Analysis of dispersion relations and dynamic wave propagation were performed using finite element modeling (FEM). Fundamental longitudinal mode L_0 at 35 kHz was found optimal for bond process monitoring. Mapping between the FE-simulated transmission coefficient of L_0 and actual temperature of the thermoplastic adhesive was established using the DMA test data. Real-time guided wave measurements were used as feedback in the discrete control of the induction heater so as to provide optimal bonding and prevent adhesive degradation. The developed ultrasonic technique was successfully validated by fiber-optic temperature sensing. Results indicate that the bondlines processed with GW control offer better ultimate strength compared to uncontrolled processing.Guided wave modal and frequency sensitivity analysis for fatigue damage was performed. Based on the analysis, symmetric mode at 85 kHz was found optimal for fatigue damage detection. Further, a damage propagation model based on Paris law was developed to estimate remaining useful life in terms of the GW signal features. Finally, the remaining useful life of the lap-joint was predicted and validated experimentally. One of the major advantages of reversible adhesive is its ability to repair/heal the damage. The controlled processing technique developed earlier was used for controlled healing of fatigue damaged joints. Experimental investigation proves the healed-bond line have returned to its original strength. A holistic approach of a complete lifecycle monitoring of bonded joints was aimed at increasing the confidence in the use of bonded joints relative to mechanical fasteners, and can be easily extended to other structural applications.
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Title: DATA DRIVEN BASED ESTIMATION AND CONTROL FOR AUTOMOTIVE SYSTEMS
Creator: Tang, Jian
Date: 2022
Collection: Electronic Theses & Dissertations
Description: This dissertation focuses on predicting the system responses and using them to improve the automotive system performance based on the data-driven based algorithms. Two applications included are multivariable borderline knock prediction and control and tire-road friction coefficient estimation. Internal combustion engines are core components of traditional and hybrid passenger vehicles and also widely used for off road applications. When the combustion is limited by the engine knock, it is...
Show moreThis dissertation focuses on predicting the system responses and using them to improve the automotive system performance based on the data-driven based algorithms. Two applications included are multivariable borderline knock prediction and control and tire-road friction coefficient estimation. Internal combustion engines are core components of traditional and hybrid passenger vehicles and also widely used for off road applications. When the combustion is limited by the engine knock, it is desired to operate it as close to its borderline knock limit as possible to optimize combustion efficiency. Traditionally, this limit is detected by sweeping tests of related control parameters, which is expensive and time-consuming; and also, the detected borderline knock limit often is relatively conservative. When more advanced control parameters (subsystems) are added, these sweeping tests lead to tremendous higher test cost. An intelligent and efficient way to predict borderline knock without detailed knowledge of combustion dynamics is proposed. This supervised-learning based Bayesian optimization method is assisted by a surrogate model trained based on the system statistic properties. A two-control-parameter (spark timing and intake valve timing) case is demonstrated for optimizing two competing objectives (knock intensity (KI) and fuel economy). A complete borderline knock control structure is proposed and divided into three parts. The first part is about offline training with necessary modifications of the Bayesian optimization algorithm. Engine tests are conducted under two different operational conditions to obtain knock borderline limit, indicating the proposed algorithm is able to reduce required experimental budget (cost and time) significantly. The predicted mean Pareto front and its variance can be used to find the optimum control parameters at borderline knock limit for the best fuel economy possible. Smooth response surfaces of surrogate models can also be used as the initial model to be updated in real-time. The second part is an online updating process, based on the offline-trained surrogate model, using modified likelihood ratio controller. Principal component analysis indicated that spark timing is the most sensitive factor affecting the Pareto front. A two-buffer design was proposed to update the surrogate model under different rates so that both short-term compensation for environment changes and long-term for slow engine aging effect are covered. Both simulation and engine test results indicate that the proposed control strategy is able to update the machine-learned surrogate models in real-time, which outperforms the conventional knock control strategy and offline-trained knock limit, and especially reduces the conservativeness of borderline knock control significantly. Finally, to reduce cycle-to-cycle combustion variations, a real-time cycle-wised knock compensation scheme is developed based on the measured exhaust temperature when the engine is operated close to its knock borderline. To make model-based control possible, ?-Markov COVER (COVariance Equivalent Realization) system identification was used to obtain a linearized engine exhaust temperature model from change of spark timing to associated variations of exhaust temperature and knock intensity (KI). Accordingly, a Linear–Quadratic–Gaussian (LQG) controller is designed to minimizing the KI fluctuations based on change (?) of exhaust temperature. For the entire control architecture, results of three test scenarios indicated that the spark timing can be further advanced while maintaining the same knock intensity level due to reduced knock combustion variations. For the vehicle dynamics research, estimation of tire-road friction coefficient is very important due to new active safety control systems, especially for autonomous vehicles that rely on the accurate estimation of road surface conditions to find vehicle operational boundary and achieve the best performance possible. Several cause- and effect-based methods were proposed with their own limitations. A new evaluation criterion associated with slip-ratio is found based on CarSim simulation data on different road conditions; and strong correlation between proposed criterion and tire-road friction under different road surface conditions is observed. Note that the data-driven based method proposed in this dissertation only utilizes the statistic information from existing production vehicle sensors without increasing hardware cost. A computational cheap black-box model of proposed criterion and tire-road friction can be obtained and augmented with the existing dual-Kalman filter estimation algorithm, which improves tire-road friction estimation.
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Title: Total synthesis of pyrrole-alkaloid-like natural products and analogues
Creator: Hubbell, Grace E.
Date: 2022
Collection: Electronic Theses & Dissertations
Description: The pyrrole-alkaloid family of natural products represents a wide range of biological activities, making the synthesis of these types of scaffolds a worthy endeavor. Of particular interest to our lab is the inhibitory activity of some of these natural products towards the human 20S proteasome, a validated target for the treatment of specific cancer including multiple myeloma and mantle cell lymphoma. With this in mind, the synthesis of scaffolds which bear structural similarity to these...
Show moreThe pyrrole-alkaloid family of natural products represents a wide range of biological activities, making the synthesis of these types of scaffolds a worthy endeavor. Of particular interest to our lab is the inhibitory activity of some of these natural products towards the human 20S proteasome, a validated target for the treatment of specific cancer including multiple myeloma and mantle cell lymphoma. With this in mind, the synthesis of scaffolds which bear structural similarity to these natural products was endeavored. Herein, the synthesis of pyrrole-alkaloid-like scaffolds is represented in several approaches: small molecule design of bromoindolophakellstatins, methodology development, and total synthesis. The development of a novel Rh(III)-catalyzed C-H activation/annulation between 2-imidazolones and N-pivaloyloxybenzohydroxamates is reported, which facilitates access to urea-fused tetrahydroisoquinolone scaffolds which are reminiscent of members of the pyrrole-alkaloid family. Efforts towards the syntheses of bromoindolophakellstatin small molecules is also described. Lastly, route development towards the total syntheses of nagelamide M and the ugibohlin natural products and the particular challenges associated with these approaches are discussed.
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Title: Depression Detection in Social Media via Differential Text Embedding
Creator: alfadhli, Norah
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Deep learning models have shown promising results for depression detection using social media data (i.e., Twitter), but the difficulties of maintaining explainability and few-shot adaptation of models for new problems remain an open challenge. Another challenging aspect of the problem of depression detection in social media is the fact that the number of instances belonging to the depressed class are in a minority when compared to the number of instances belonging to the non-depressed class....
Show moreDeep learning models have shown promising results for depression detection using social media data (i.e., Twitter), but the difficulties of maintaining explainability and few-shot adaptation of models for new problems remain an open challenge. Another challenging aspect of the problem of depression detection in social media is the fact that the number of instances belonging to the depressed class are in a minority when compared to the number of instances belonging to the non-depressed class. This, especially, makes it harder for supervised machine learning algorithms to learn and predict depressed class instances.In this study, we proposed a simple solution to this problem by generating \textit{differential embeddings} using the Sentence BERT transformer architecture. More specifically, we proposed a few-shot model that can leverage state-of-the-art (SOTA) representation learning techniques and used it in supervised and unsupervised tasks. We constructed a small set of dysfunctional thought patterns in the embedding space, i.e., a set of clinically-backed depression symptoms. We then used SBERT embedding vectors to measure the similarities between different tweets and anchor points as a distance in the vector space, or fed them directly into the machine learning model. We assessed the capability of our approach on two different datasets. We trained supervised and unsupervised models using different approaches that were derived from Sentence-BERT and the anchor points. Results show that the proposed solution improved SBERT in both supervised and unsupervised tasks.
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Title: EVOLUTION OF FIRE INDUCED RESTRAINT FORCES AND THEIR EFFECT ON THE FIRE RESPONSE OF PRESTRESSED CONCRETE BEAMS
Creator: KUMAR, PUNEET
Date: 2023
Collection: Electronic Theses & Dissertations
Description: Precast prestressed concrete (PC) construction provides numerous advantages over traditional reinforced concrete (RC) construction, in terms of speed of construction, better quality control, cost-effectiveness, better space utilization, and optimized production. Owing to these advantages, the use of PC construction in the built environment has increased significantly in recent decades. While the structural behavior of PC members is well understood at ambient temperatures, there is a lack of...
Show morePrecast prestressed concrete (PC) construction provides numerous advantages over traditional reinforced concrete (RC) construction, in terms of speed of construction, better quality control, cost-effectiveness, better space utilization, and optimized production. Owing to these advantages, the use of PC construction in the built environment has increased significantly in recent decades. While the structural behavior of PC members is well understood at ambient temperatures, there is a lack of understanding on the evolution of fire induced restraint forces in PC beams and their effect on the fire resistance of PC beams. Further, the fire resistance of PC members is currently evaluated using prescriptive design approaches which do not account for all critical factors governing the fire response of PC beams, including realistic restraint conditions, and therefore, current fire resistance provisions may not provide realistic predictions of fire performance. Therefore, a detailed experimental and numerical study is conducted to evaluate the evolution of fire induced restraint forces and to quantify their effect on the fire response of PC beams. Fire resistance tests were conducted on four PC beams under restrained and unrestrained end conditions. Test variables included fire exposure, restraint conditions, load level, and concrete strength. The fire response of the beams was traced throughout the fire exposure duration by measuring sectional temperatures, beam deflections, and fire induced restraint forces. All four beams were designed as per current building code recommendations to have a fire resistance of 4 hours, however, all four beams attained failure within 2 hours of fire exposure. A numerical model was developed for tracing the fire response of PC beams under specified fire, loading, and restraint conditions. The model accounts for critical factors governing the fire response of PC beams including fire-induced restraint forces, cracking and crushing of concrete, spalling, material and geometric non-linearity, and geometry of the beam. For modeling fire-induced restraint forces a new efficient spring idealization framework for connections is implemented. Also, the cracking and crushing of concrete is captured by developing a new modified adaptive temperature-dependent failure envelope. The developed numerical model was validated by comparing response predictions from the model with measured data in fire tests. Results from these comparisons show that the model can capture the fire response of PC beams with reasonable accuracy in both thermal and structural domains. The validated numerical model is applied to carry out a series of parametric studies on the effect of fire-induced restraint forces on the response of PC beams. The effect of cross-sectional shape, support conditions, the gap in connection, level of prestress, and concrete cover thickness on the evolution of fire induced restraint forces is studied for PC and equivalent RC beams. Results from parametric studies show that current prescriptive codes and standards may over-predict fire resistance of PC beams by as high as 100%, PC beams develop 5% to 20% lower restraint forces than equivalent RC beams, and for PC beams with gaps of more than 50 mm experience minimal restraint forces. Also, the fire-induced restraint forces can be either beneficial or detrimental and can significantly alter the fire response of the PC beam, and therefore, should be included in the design process. Based on the results from the fire tests and parametric studies, simplified recommendations are proposed for evaluating the fire resistance of PC beams.
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