Matching Items (98)
Description
Alzheimer’s disease (AD) is a progressive cognitive and behavior disorder that is characterized by the deposition of extracellular Aβ plaques, intracellular neurofibrillary tangles, and neuroinflammation. Aβ is generated by cleavage of the amyloid precursor protein (APP) by β-secretase (BACE1) and, subsequently, y- secretase. In recent years, there has been an increasing interest in studying and understanding inflammation as a therapeutic target for AD. Inflammation manifests in the brain in the form of activated microglia and astrocytes. These cells are able to release high levels of inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α). TNF-α is a major cytokine, which is involved in early inflammatory events and plays a role in the progression of AD pathology. There are currently no treatments that target chronic neuroinflammation. However, previous work in our laboratory with transgenic mice modeling AD suggested that the anti-cancer drug lenalidomide could lower neuroinflammation and slow AD progression, though the cellular and molecular mechanisms are yet to be elucidated. Here we hypothesized that lenalidomide can modulate TNF-α production in microglia and decrease amyloidogenesis. Using immortal cell lines mimicking several brain cell types, we discovered that lenalidomide is likely to decrease inflammation by modulating microglia cells rather than neurons or astrocytes. In addition, the drug may prevent the overexpression of BACE1 upon inflammation, thus blocking the overproduction of Aβ. If confirmed, these results could lead to a better understanding of how inflammation regulates Aβ synthesis and provide novel cellular and molecular therapeutic targets to control the progression AD.
ContributorsGujju, Manasa (Author) / DeCourt, Boris (Thesis director) / Olive, M. Foster (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Nicotine addiction remains a prevalent public health issue, and the FDA has released a statement outlining the systematic reduction of nicotine to non-zero levels in the coming years. Current research has not yet established the effects of abrupt nicotine dose reduction on vulnerability to relapse, nor has abrupt nicotine dose reduction been evaluated in terms of behavioral economic characteristics of demand and elasticity been evaluated for reduced doses of nicotine. Using a rat model, we first evaluated the comparability of between- and within-session protocols for establishing characteristics of demand and elasticity for nicotine to shorten experimental timelines for this study and future studies. We then tested environmental enrichment and sex as factors of elasticity of demand for nicotine. Using a rat model of relapse to cues, we also examined the effects of nicotine dose-reduction on vulnerability to relapse. We found differences in maximum consumption and demand between the between- and within-session protocols, as well as sex differences in elasticity of demand on the within-session protocol where male demand was more elastic than female demand. Additionally, we found that enrichment significantly increased elasticity of demand for nicotine for both males and females. Finally, preliminary analyses revealed that nicotine dose reduction yields more inelastic demand and higher maximum consumption, and these outcomes predict increased time to extinction of the association between nicotine and contingent cues, and increased rates of relapse. These studies highlight the usefulness and validity of within-session protocols, and also illustrate the necessity for rigorous testing of forced dose reduction on nicotine vulnerability.
ContributorsCabrera-Brown, Gabriella Paula (Author) / Gipson-Reichardt, Cassandra (Thesis director) / Olive, M. Foster (Committee member) / Davis, Mary (Committee member) / Sanford School of Social and Family Dynamics (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
Biomarkers are the cornerstone of modern-day medicine. They are defined as any biological substance in or outside the body that gives insight to the body's condition. Doctors and researchers can measure specific biomarkers to diagnose and treat patients, such as the concentration of hemoglobin Alc and its connection to diabetes. There are a variety of methods, or assays, to detect biomarkers, but the most common assay is enzyme-linked immunosorbent assay (ELISA). A new-generation assay termed mass spectrometric immunoassay (MSIA) can measure proteoforms, the different chemical variations of proteins, and their relative abundance. ELISA on the other hand measures the overall concentration of protein in the sample. Measuring each of the proteoforms of a protein is important because only one or two variations could be biologically significant and/or cause diseases. However, running MSIA is expensive. For this reason, an alternative plate-based MSIA technique was tested for its ability to detect the proteoforms of a protein called apolipoprotein C-III (ApoC-III). This technique combines the protein capturing procedure of ELISA to isolate the protein with detection in a mass spectrometer. A larger amount of ApoC-III present in the body indicates a considerable risk for coronary heart disease. The precision of the assay is determined on the coefficient of variation (CV). A CV value is the ratio of standard deviation in relation to the mean, represented as a percentage. The smaller the percentage, the less variation the assay has, and therefore the more ability it has to detect subtle changes in the biomarker. An accepted CV would be less than 10% for single-day tests (intra-day) and less than 15% for multi-day tests (inter-day). The plate-based MSIA was started by first coating a 96-well round bottom plate with 2.5 micrograms of ApoC-III antibody. Next, a series of steps were conducted: a buffer wash, then the sample incubation, followed by another buffer wash and two consecutive water washes. After the final wash, the wells were filled with a MALDI matrix, then spotted onto a gold plate to dry. The dry gold target was then placed into a MALDI-TOF mass spectrometer to produce mass spectra for each spot. The mass spectra were calibrated and the area underneath each of the four peaks representing the ApoC-III proteoforms was exported as an Excel file. The intra-day CV values were found by dividing the standard deviation by the average relative abundance of each peak. After repeating the same procedure for three more days, the inter-day CVs were found using the same method. After completing the experiment, the CV values were all within the acceptable guidelines. Therefore, the plate-based MSIA is a viable alternative for finding proteoforms than the more expensive MSIA tips. To further validate this, additional tests will need to be conducted with different proteins and number of samples to determine assay flexibility.
ContributorsTieu, Luc (Author) / Borges, Chad (Thesis director) / Nedelkov, Dobrin (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
Cases of heroin use and overdose are on the rise in the United States which has created what some call a public health crisis. Previous studies have investigated the beneficial effect of social interaction recovering addicts, and in animal models of addiction, social interaction can prevent or reverse the conditioned rewarding effects of cocaine. This study sought to determine if social interaction would prevent or diminish a conditioned preference for a heroin-paired context. Following establishment of baseline place preference, adult male Sprague-Dawley rats underwent once daily conditioning with either saline, heroin (1 mg/kg), or the animal's cage-mate for a total of 8 conditioning sessions. Assessment of post-conditioning place preference revealed that both the heroin injections and the presence of the cage-mate produced a place preference . In contrast to the findings of previous studies using cocaine as the conditioning drug, it was determined that rats preferred the heroin-paired context over that paired with the cage-mate.. These findings suggest that the protective effects of social interaction found in prior studies using cocaine as the conditioning drug may not extend to opiates, perhaps a result of stronger contextual conditioning and/or rewarding effects of this class of abused drugs.
ContributorsMarble, Krista Lillian (Author) / Olive, M. Foster (Thesis director) / Tomek, Seven (Committee member) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
The RAS/MAPK (RAS/Mitogen Activated Protein Kinase) pathway is a highly conserved, canonical signaling cascade that is highly involved in cellular growth and proliferation as well as cell migration. As such, it plays an important role in development, specifically in development of the nervous system. Activation of ERK is indispensable for the differentiation of Embryonic Stem Cells (ESC) into neuronal precursors (Li z et al, 2006). ERK signaling has also shown to mediate Schwann cell myelination of the peripheral nervous system (PNS) as well as oligodendrocyte proliferation (Newbern et al, 2011). The class of developmental disorders that result in the dysregulation of RAS signaling are known as RASopathies. The molecular and cell-specific consequences of these various pathway mutations remain to be elucidated. While there is evidence for altered DNA transcription in RASopathies, there is little work examining the effects of the RASopathy-linked mutations on protein translation and post-translational modifications in vivo. RASopathies have phenotypic and molecular similarities to other disorders such as Fragile X Syndrome (FXS) and Tuberous Sclerosis (TSC) that show evidence of aberrant protein synthesis and affect related pathways. There are also well-defined downstream RAS pathway elements involved in translation. Additionally, aberrant corticospinal axon outgrowth has been observed in disease models of RASopathies (Xing et al, 2016). For these reasons, this present study examines a subset of proteins involved in translation and translational regulation in the context of RASopathy disease states. Results indicate that in both of the tested RASopathy model systems, there is altered mTOR expression. Additionally the loss of function model showed a decrease in rps6 activation. This data supports a role for the selective dysregulation of translational control elements in RASopathy models. This data also indicates that the primary candidate mechanism for control of altered translation in these modes is through the altered expression of mTOR.
ContributorsHilbert, Alexander Robert (Author) / Newbern, Jason (Thesis director) / Olive, M. Foster (Committee member) / Bjorklund, Reed (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
Description
This study examined perception of K12 schooling systems as experienced by a randomsample of adults in Phoenix, AZ. It explored whether the values purported as key factors
in the American K12 schooling system - as presented in academic literature - were compatible with the lives, interests and goals of ‘users’, student-participants. In addition, it offered opportunity for post-K12 student-participants to share their views on the purposes, goals, and outcomes they held to be important. The sample consisted of 139 post-K12 stu-
dents/individuals residing in Phoenix, AZ. Mean age of student-participants was 29. Results indicated a mismatch between purported K12 schooling goals and important outcomes embedded in the system and values held by the K12 student-participants. The participants in this research generally perceived K12 schooling as valuable, both to themselves and to society at large, but stressed that the deficiencies they perceived in the system were particular to delivery platforms as they relate to the learning styles of students and belonging. Future life skills and success - in and after K12 schooling - whether related to college or not were also of importance. Results revealed that the initial hypothesis of income, age, and ethnicity as
key factors in satisfaction with K12 schooling was not borne-out. Rather it revealed that a sense of belonging and the suitability of learning platforms to the individual learning styles of students were of greatest significance.
ContributorsParker-Anderies, Margaret (Author) / Janssen, Marco (Thesis advisor) / Garcia, David (Committee member) / Mishra, Punya (Committee member) / Arizona State University (Publisher)
Created2022
Description
Psychologists report effect sizes in randomized controlled trials to facilitate interpretation and inform clinical or policy guidance. Since commonly used effect size measures (e.g., standardized mean difference) are not sensitive to heterogeneous treatment effects, methodologists have suggested the use of an alternative effect size δ, a between-subjects causal parameter describing the probability that the outcome of a random participant in the treatment group is better than the outcome of another random participant in the control group. Although this effect size is useful, researchers could mistakenly use δ to describe its within-subject analogue, ψ, the probability that an individual will do better under the treatment than the control. Hand’s paradox describes the situation where ψ and δ are on opposing sides of 0.5: δ may imply most are helped whereas the (unknown) underlying ψ indicates that most are harmed by the treatment. The current study used Monte Carlo simulations to investigate plausible situations under which Hand’s paradox does and does not occur, tracked the magnitude of the discrepancy between ψ and δ, and explored whether the size of the discrepancy could be reduced with a relevant covariate. The findings suggested that although the paradox should not occur under bivariate normal data conditions in the population, there could be sample cases with the paradox. The magnitude of the discrepancy between ψ and δ depended on both the size of the average treatment effect and the underlying correlation between the potential outcomes, ρ. Smaller effects led to larger discrepancies when ρ < 0 and ρ = 1, whereas larger effects led to larger discrepancies when 0 < ρ < 1. It was useful to consider a relevant covariate when calculating ψ and δ. Although ψ and δ were still discrepant within covariate levels, results indicated that conditioning upon relevant covariates is still useful in describing heterogeneous treatment effects.
ContributorsLiu, Xinran (Author) / Anderson, Samantha F (Thesis advisor) / McNeish, Daniel (Committee member) / MacKinnon, David (Committee member) / Arizona State University (Publisher)
Created2023
Description
Mediation analysis is integral to psychology, investigating human behavior’s causal mechanisms. The diversity of explanations for human behavior has implications for the estimation and interpretation of statistical mediation models. Individuals can have similar observed outcomes while undergoing different causal processes or different observed outcomes while receiving the same treatment. Researchers can employ diverse strategies when studying individual differences in multiple mediation pathways, including individual fit measures and analysis of residuals. This dissertation investigates the use of individual residuals and fit measures to identify individual differences in multiple mediation pathways. More specifically, this study focuses on mediation model residuals in a heterogeneous population in which some people experience indirect effects through one mediator and others experience indirect effects through a different mediator. A simulation study investigates 162 conditions defined by effect size and sample size for three proposed methods: residual differences, delta z, and generalized Cook’s distance. Results indicate that analogs of Type 1 error rates are generally acceptable for the method of residual differences, but statistical power is limited. Likewise, neither delta z nor gCd could reliably distinguish between contrasts that had true effects and those that did not. The outcomes of this study reveal the potential for statistical measures of individual mediation. However, limitations related to unequal subpopulation variances, multiple dependent variables, the inherent relationship between direct effects and unestimated indirect effects, and minimal contrast effects require more research to develop a simple method that researchers can use on single data sets.
ContributorsSmyth, Heather Lynn (Author) / MacKinnon, David (Thesis advisor) / Tein, Jenn-Yun (Committee member) / McNeish, Daniel (Committee member) / Grimm, Kevin (Committee member) / Arizona State University (Publisher)
Created2022
Description
The consumption of food, energy, and water (FEW) resources in U.S. households is very carbon-intensive. However, these negative climate change impacts are often invisible due to insufficient awareness and knowledge. Serious games (SGs) can potentially address this issue through an experiential and rigorous approach to simulate household actions and impacts in a playful but realistic setting. This dissertation focuses on: (a) the design and testing of an SG called HomeRUN (Role-play for Understanding Nexus); (b) the effectiveness of gameplay in advancing player knowledge about the upfront costs, financial returns, and greenhouse gas (GHG) emissions of various household decisions; and (c) the effectiveness of intervention messages in increasing FEW conservation to reduce household GHG emissions. The results of gameplay sessions played by 150 university students show that HomeRUN is fun to play, creates a flow experience, and results in experiential learning. The majority of players agreed that the game experience will continue over time to influence their future consumption behaviors to conserve FEW resources. Female players tended to gain more knowledge about financial aspects of interventions, whereas male players were more likely to increase their understandings of GHG emissions and resource consumption after playing HomeRUN. Social comparison intervention messages about energy and food consumption led to the highest reductions in household carbon emissions. The messages associated with each FEW resource tended to be most likely to lead to FEW conservation actions with the game that most closely corresponded to the particular FEW resource addressed in the message. This dissertation advances understandings about the design and use of SGs to foster learning and promote sustainable household FEW consumption.
ContributorsHanif, Muhammad Adnan (Author) / Agusdinata, Datu Buyung (Thesis advisor) / Halvorsen, Kathleen (Committee member) / Janssen, Marco (Committee member) / Arizona State University (Publisher)
Created2021
Description
Copper demand is surging in the U.S. and around the world as countries embrace new forms of energy to combat climate change. But copper mining – while a key strategy to address supply shortages – can serve as a vehicle for injustice by imposing socio-ecological burdens for nearby communities. Due to the growing demand for copper with resulting justice issues, more research is needed to evaluate governance for the mining sector using an environmental justice lens. The National Environmental Policy Act (NEPA) is a key environmental regulation that governs mining in the U.S. Therefore, I used a qualitative case study approach to examine how NEPA requirements shape engagement in public comment opportunities. I selected the Resolution Copper Mine as a case study because of its potential to support the energy transition but pose a significant dilemma for justice: the mine is anticipated to generate 25 percent of the U.S. copper demand each year but disturb lands that hold spiritual significance for Native American Tribes. I used the Institutional Analysis and Development (IAD) framework to analyze institutional dynamics and evaluate the NEPA process for public participation using a procedural justice lens. Drawing on interview data and document analysis, the results show that process rules such as a land exchange bill and the lengths of comment opportunities were among the key barriers for participation. Socioeconomic conditions of communities including access to social resources (i.e. access to internet and technical assistance) and institutional trust posed further barriers for participation. Hence, this study suggests that federal decision-makers should aim to better integrate procedural justice into the NEPA process.
ContributorsLewis, Sydney (Author) / Kellner, Elke (Thesis director) / Janssen, Marco (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2024-05