ASU Electronic Theses and Dissertations
This collection includes most of the ASU Theses and Dissertations from 2011 to present. ASU Theses and Dissertations are available in downloadable PDF format; however, a small percentage of items are under embargo. Information about the dissertations/theses includes degree information, committee members, an abstract, supporting data or media.
In addition to the electronic theses found in the ASU Digital Repository, ASU Theses and Dissertations can be found in the ASU Library Catalog.
Dissertations and Theses granted by Arizona State University are archived and made available through a joint effort of the ASU Graduate College and the ASU Libraries. For more information or questions about this collection contact or visit the Digital Repository ETD Library Guide or contact the ASU Graduate College at gradformat@asu.edu.
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- Creators: Ghirlanda, Giovanna
- Creators: Chassin, Laurie
Description
Research has shown that a developmental process of maturing out of alcohol involvement occurs during young adulthood, and that this process is related to both young adult role transitions (e.g., marriage) and personality developmental (e.g., decreased disinhibition and neuroticism). The current study extended past research by testing whether protective marriage and personality effects on maturing out were stronger among more severe late adolescent drinkers, and whether protective marriage effects were stronger among those who experienced more personality development. Parental alcoholism and gender were tested as moderators of marriage, personality, and late adolescent drinking effects on maturing out; and as distal predictors mediated by these effects. Participants were a subsample (N = 844; 51% children of alcoholics; 53% male, 71% non-Hispanic Caucasian, 27% Hispanic; Chassin, Barrera, Bech, & Kossak-Fuller, 1992) from a larger longitudinal study of familial alcoholism. Hypotheses were tested with latent growth models characterizing alcohol consumption and drinking consequence trajectories from late adolescence to adulthood (age 17-40). Past findings were replicated by showing protective effects of becoming married, sensation-seeking reductions, and neuroticism reductions on the drinking trajectories. Moderation tests showed that protective marriage effects on the drinking trajectories were stronger among those with higher pre-marriage drinking in late adolescence (i.e., higher growth intercepts). This might reflect role socialization mechanisms such that more severe drinking produces more conflict with the demands of new roles (i.e., role incompatibility), thus requiring greater drinking reductions to resolve this conflict. In contrast, little evidence was found for moderation of personality effects by late adolescent drinking or for moderation of marriage effects by personality. Parental alcoholism findings suggested complex moderated mediation pathways. Parental alcoholism predicted less drinking reduction through decreasing the likelihood of marriage (mediation) and muting marriage's effect on the drinking trajectories (moderation), but parental alcoholism also predicted more drinking reduction through increasing initial drinking in late adolescence (mediation). The current study provides new insights into naturally occurring processes of recovery during young adulthood and suggests that developmentally-tailored interventions for young adults could harness these natural recovery processes (e.g., by integrating role incompatibility themes and addressing factors that block role effects among those with familial alcoholism).
ContributorsLee, Matthew R. (Author) / Chassin, Laurie (Thesis advisor) / Corbin, William R. (Committee member) / Mackinnon, David P (Committee member) / Presson, Clark C. (Committee member) / Arizona State University (Publisher)
Created2013
Description
Past literature has indicated that the majority of people with alcohol problems never seek treatment and that this is especially true of women. Relatively few studies have investigated how different types of alcohol-related consequences longitudinally predict men and women's perceived need for treatment and their utilization of treatment services. The current study sought to expand the literature by examining whether gender moderates the links between four frequently endorsed types of consequences and perceived need for or actual utilization of treatment. Two-hundred thirty-seven adults ages 21-36 completed a battery of questionnaires at two time points five years apart. Results indicated that there were four broad types of consequences endorsed by both men and women. Multiple-group models and Wald chi square tests indicated that there were no significant relationships between consequences and treatment outcomes. No gender moderation was found but post-hoc power analyses indicated that the study was underpowered to detect moderation. Researchers need to continue to study factors that predict utilization of alcohol treatment services and the process of recovery so that treatment providers can better address the needs of people with alcohol-related consequences in the areas of referral procedures, clinical assessment, and treatment service provision and planning.
ContributorsBeltran Gonzalez, Iris (Author) / Chassin, Laurie (Thesis advisor) / Tein, Jenn-Yun (Committee member) / Corbin, William (Committee member) / Barrera, Jr., Manuel (Committee member) / Arizona State University (Publisher)
Created2013
Description
Cyanovirin-N (CV-N) is a naturally occurring lectin originally isolated from the cyanobacteria Nostoc ellipsosporum. This 11 kDa lectin is 101 amino acids long with two binding sites, one at each end of the protein. CV-N specifically binds to terminal Manα1-2Manα motifs on the branched, high mannose Man9 and Man8 glycosylations found on enveloped viruses including Ebola, Influenza, and HIV. wt-CVN has micromolar binding to soluble Manα1-2Manα and also inhibits HIV entry at low nanomolar concentrations. CV-N's high affinity and specificity for Manα1-2Manα makes it an excellent lectin to study for its glycan-specific properties. The long-term aim of this project is to make a variety of mutant CV-Ns to specifically bind other glycan targets. Such a set of lectins may be used as screening reagents to identify biomarkers and other glycan motifs of interest. As proof of concept, a T7 phage display library was constructed using P51G-m4-CVN genes mutated at positions 41, 44, 52, 53, 56, 74, and 76 in binding Domain B. Five CV-N mutants were selected from the library and expressed in BL21(DE3) E. coli. Two of the mutants, SSDGLQQ-P51Gm4-CVN and AAGRLSK-P51Gm4-CVN, were sufficiently stable for characterization and were examined by CD, Tm, ELISA, and glycan array. Both proteins have CD minima at approximately 213 nm, indicating largely β-sheet structure, and have Tm values greater than 40°C. ELISA against gp120 and RNase B demonstrate both proteins' ability to bind high mannose glycans. To more specifically determine the binding specificity of each protein, AAGRLSK-P51Gm4-CVN, SSDGLQQ-P51Gm4-CVN, wt-CVN, and P51G-m4-CVN were sent to the Consortium for Functional Glycomics (CFG) for glycan array analysis. AAGRLSK-P51Gm4-CVN, wt-CVN, and P51G-m4-CVN, have identical specificities for high mannose glycans containing terminal Manα1-2Manα. SSDGLQQ-P51Gm4-CVN binds to terminal GlcNAcα1-4Gal motifs and a subgroup of high mannose glycans bound by P51G-m4-CVN. SSDGLQQ-wt-CVN was produced to restore anti-HIV activity and has a high nanomolar EC50 value compared to wt-CVN's low nanomolar activity. Overall, these experiments show that CV-N Domain B can be mutated and retain specificity identical to wt-CVN or acquire new glycan specificities. This first generation information can be used to produce glycan-specific lectins for a variety of applications.
ContributorsRuben, Melissa (Author) / Ghirlanda, Giovanna (Thesis advisor) / Allen, James (Committee member) / Wachter, Rebekka (Committee member) / Arizona State University (Publisher)
Created2013
Description
Juvenile offenders suffer from substance use disorders at higher rates than adolescents in the general public. Substance use disorders also predict an increased risk for re-offending. Therefore, it is important that these juveniles, in particular, receive the appropriate substance use disorder treatment. The present study used logistic regression to test whether race/ethnicity would moderate the match between substance use disorder diagnosis and the receipt of a substance use disorder related service in a sample of male, serious juvenile offenders. Results showed that among those with a substance use disorder diagnosis, there were no race/ethnicity differences in the receipt of the appropriate service. However, among those without a substance use disorder diagnosis, non-Hispanic Caucasians were more likely to receive substance use service than were Hispanics or African-Americans. Post-hoc analyses revealed that when using a broader definition of substance use problems, significant differences by race/ethnicity in the prediction of service receipt were only observed at low levels of substance use problems. These findings shed light on how race/ethnicity may play a role in the recommendation of substance use disorder services in the juvenile justice system.
ContributorsMansion, Andre (Author) / Chassin, Laurie (Thesis advisor) / Dishion, Thomas (Committee member) / Knight, George (Committee member) / Arizona State University (Publisher)
Created2013
Description
Levels of heavy episodic drinking peak during emerging adulthood and contribute to the experience of negative consequences. Previous research has identified a number of trait-like personality characteristics that are associated with drinking. Studies of the Acquired Preparedness Model have supported positive expectancies, and to a lesser extent negative expectancies, as mediators of the relation between trait-like characteristics and alcohol outcomes. However, expectancies measured via self-report may reflect differences in learned expectancies in spite of similar alcohol-related responses, or they may reflect true individual differences in subjective responses to alcohol. The current study addressed this gap in the literature by assessing the relative roles of expectancies and subjective response as mediators within the APM in a sample of 236 emerging adults (74.7% male) participating in a placebo-controlled alcohol challenge study. The study tested four mediation models collapsed across beverage condition as well as eight separate mediation models with four models (2 beverage by 2 expectancy/subjective response) for each outcome (alcohol use and alcohol-related problems). Consistent with previous studies, SS was positively associated with alcohol outcomes in models collapsed across beverage condition. SS was also associated with positive subjective response in collapsed models and in the alcohol models. The hypothesized negative relation between SS and sedation was not significant. In contrast to previous studies, neither stimulation nor sedation predicted either weekly drinking or alcohol-related problems. While stimulation and alcohol use appeared to have a positive and significant association, this relation did not hold when controlling for SS, suggesting that SS and stimulation account for shared variability in drinking behavior. Failure to find this association in the placebo group suggests that, while explicit positive expectancies are related to alcohol use after controlling for levels of sensation seeking, implicit expectancies (at least as assessed by a placebo manipulation) are not. That the relation between SS and stimulation held only in the alcohol condition in analyses separate by beverage condition indicates that sensation seeking is a significant predictor of positive subjective response to alcohol (stimulation), potentially above and beyond expectancies.
ContributorsScott, Caitlin (Author) / Corbin, William (Thesis advisor) / Shiota, Michelle (Committee member) / Chassin, Laurie (Committee member) / Arizona State University (Publisher)
Created2012
Description
Spinal muscular atrophy (SMA) is a neurodegenerative disease that results in the loss of lower body muscle function. SMA is the second leading genetic cause of death in infants and arises from the loss of the Survival of Motor Neuron (SMN) protein. SMN is produced by two genes, smn1 and smn2, that are identical with the exception of a C to T conversion in exon 7 of the smn2 gene. SMA patients lacking the smn1 gene, rely on smn2 for production of SMN. Due to an alternative splicing event, smn2 primarily encodes a non-functional SMN lacking exon 7 (SMN D7) as well as a low amount of functional full-length SMN (SMN WT). SMN WT is ubiquitously expressed in all cell types, and it remains unclear how low levels of SMN WT in motor neurons lead to motor neuron degradation and SMA. SMN and its associated proteins, Gemin2-8 and Unrip, make up a large dynamic complex that functions to assemble ribonucleoproteins. The aim of this project was to characterize the interactions of the core SMN-Gemin2 complex, and to identify differences between SMN WT and SMN D7. SMN and Gemin2 proteins were expressed, purified and characterized via size exclusion chromatography. A stable N-terminal deleted Gemin2 protein (N45-G2) was characterized. The SMN WT expression system was optimized resulting in a 10-fold increase of protein expression. Lastly, the oligomeric states of SMN and SMN bound to Gemin2 were determined. SMN WT formed a mixture of oligomeric states, while SMN D7 did not. Both SMN WT and D7 bound to Gemin2 with a one-to-one ratio forming a heterodimer and several higher-order oligomeric states. The SMN WT-Gemin2 complex favored high molecular weight oligomers whereas the SMN D7-Gemin2 complex formed low molecular weight oligomers. These results indicate that the SMA mutant protein, SMN D7, was still able to associate with Gemin2, but was not able to form higher-order oligomeric complexes. The observed multiple oligomerization states of SMN and SMN bound to Gemin2 may play a crucial role in regulating one or several functions of the SMN protein. The inability of SMN D7 to form higher-order oligomers may inhibit or alter those functions leading to the SMA disease phenotype.
ContributorsNiday, Tracy (Author) / Allen, James P. (Thesis advisor) / Wachter, Rebekka (Committee member) / Ghirlanda, Giovanna (Committee member) / Arizona State University (Publisher)
Created2012
Description
The hypothalamus pituitary adrenal (HPA) axis and the human genome are important components of the biological etiology of externalizing disorders. By studying the associations between specific genetic variants, diurnal cortisol, and externalizing symptoms we can begin to unpack this complex etiology. It was hypothesized that genetic variants from the corticotropine releasing hormone receptor 1 (CRHR1), FK506 binding protein 51 (FKBP5), catechol-O-methyl transferase (COMT), and dopamine transporter (DAT1) genes and diurnal cortisol intercepts and slopes would separately predict externalizing symptoms. It was also hypothesized that genetic variants would moderate the association between cortisol and externalizing. Participants were 800 twins (51% boys), 88.5% Caucasian, M=7.93 years (SD=0.87) participating in the Wisconsin Twin Project. Hierarchical Linear Modeling (HLM) was used to separate the variance associated with state and trait cortisol measured across three consecutive days and trait cortisol measures were used. There were no main effects of genes on externalizing symptoms. The evening cortisol intercept, the morning cortisol slope and the evening cortisol slope predicted externalizing, but only in boys, such that boys with higher cortisol and flatter slopes across the day also had more externalizing symptoms. The morning cortisol intercept and CRHR1 rs242924 interacted to predict externalizing in both boys and girls, with GG carriers significantly higher compared to TT carriers at one standard deviation below the mean of morning cortisol. For boys only there was a significant interaction between the DAT1 variable number tandem repeat (VNTR) and the afternoon slope and a significant slope for 9/9 carriers and 9/10 carriers such that when the slope was more steep, boys carrying a nine had fewer externalizing symptoms but when the slope was less steep, they had more. Results confirm a link between diurnal trait cortisol and externalizing in boys, as well as moderation of that association by genetic polymorphisms. This is the first study to empirically examine this association and should encourage further research on the biological etiology of externalizing disorder symptoms.
ContributorsSwann, Gregory (Author) / Lemery-Chalfant, Kathryn (Thesis advisor) / Chassin, Laurie (Committee member) / Doane-Sampey, Leah (Committee member) / Arizona State University (Publisher)
Created2012
Description
This thesis explores a wide array of topics related to the protein folding problem, ranging from the folding mechanism, ab initio structure prediction and protein design, to the mechanism of protein functional evolution, using multi-scale approaches. To investigate the role of native topology on folding mechanism, the native topology is dissected into non-local and local contacts. The number of non-local contacts and non-local contact orders are both negatively correlated with folding rates, suggesting that the non-local contacts dominate the barrier-crossing process. However, local contact orders show positive correlation with folding rates, indicating the role of a diffusive search in the denatured basin. Additionally, the folding rate distribution of E. coli and Yeast proteomes are predicted from native topology. The distribution is fitted well by a diffusion-drift population model and also directly compared with experimentally measured half life. The results indicate that proteome folding kinetics is limited by protein half life. The crucial role of local contacts in protein folding is further explored by the simulations of WW domains using Zipping and Assembly Method. The correct formation of N-terminal β-turn turns out important for the folding of WW domains. A classification model based on contact probabilities of five critical local contacts is constructed to predict the foldability of WW domains with 81% accuracy. By introducing mutations to stabilize those critical local contacts, a new protein design approach is developed to re-design the unfoldable WW domains and make them foldable. After folding, proteins exhibit inherent conformational dynamics to be functional. Using molecular dynamics simulations in conjunction with Perturbation Response Scanning, it is demonstrated that the divergence of functions can occur through the modification of conformational dynamics within existing fold for β-lactmases and GFP-like proteins: i) the modern TEM-1 lactamase shows a comparatively rigid active-site region, likely reflecting adaptation for efficient degradation of a specific substrate, while the resurrected ancient lactamases indicate enhanced active-site flexibility, which likely allows for the binding and subsequent degradation of different antibiotic molecules; ii) the chromophore and attached peptides of photocoversion-competent GFP-like protein exhibits higher flexibility than the photocoversion-incompetent one, consistent with the evolution of photocoversion capacity.
ContributorsZou, Taisong (Author) / Ozkan, Sefika B (Thesis advisor) / Thorpe, Michael F (Committee member) / Woodbury, Neal W (Committee member) / Vaiana, Sara M (Committee member) / Ghirlanda, Giovanna (Committee member) / Arizona State University (Publisher)
Created2014
Interactions driving the collapse of islet amyloid polypeptide: implications for amyloid aggregation
Description
Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37-residue intrinsically disordered hormone involved in glucose regulation and gastric emptying. The aggregation of hIAPP into amyloid fibrils is believed to play a causal role in type 2 diabetes. To date, not much is known about the monomeric state of hIAPP or how it undergoes an irreversible transformation from disordered peptide to insoluble aggregate. IAPP contains a highly conserved disulfide bond that restricts hIAPP(1-8) into a short ring-like structure: N_loop. Removal or chemical reduction of N_loop not only prevents cell response upon binding to the CGRP receptor, but also alters the mass per length distribution of hIAPP fibers and the kinetics of fibril formation. The mechanism by which N_loop affects hIAPP aggregation is not yet understood, but is important for rationalizing kinetics and developing potential inhibitors. By measuring end-to-end contact formation rates, Vaiana et al. showed that N_loop induces collapsed states in IAPP monomers, implying attractive interactions between N_loop and other regions of the disordered polypeptide chain . We show that in addition to being involved in intra-protein interactions, the N_loop is involved in inter-protein interactions, which lead to the formation of extremely long and stable β-turn fibers. These non-amyloid fibers are present in the 10 μM concentration range, under the same solution conditions in which hIAPP forms amyloid fibers. We discuss the effect of peptide cyclization on both intra- and inter-protein interactions, and its possible implications for aggregation. Our findings indicate a potential role of N_loop-N_loop interactions in hIAPP aggregation, which has not previously been explored. Though our findings suggest that N_loop plays an important role in the pathway of amyloid formation, other naturally occurring IAPP variants that contain this structural feature are incapable of forming amyloids. For example, hIAPP readily forms amyloid fibrils in vitro, whereas the rat variant (rIAPP), differing by six amino acids, does not. In addition to being highly soluble, rIAPP is an effective inhibitor of hIAPP fibril formation . Both of these properties have been attributed to rIAPP's three proline residues: A25P, S28P and S29P. Single proline mutants of hIAPP have also been shown to kinetically inhibit hIAPP fibril formation. Because of their intrinsic dihedral angle preferences, prolines are expected to affect conformational ensembles of intrinsically disordered proteins. The specific effect of proline substitutions on IAPP structure and dynamics has not yet been explored, as the detection of such properties is experimentally challenging due to the low molecular weight, fast reconfiguration times, and very low solubility of IAPP peptides. High-resolution techniques able to measure tertiary contact formations are needed to address this issue. We employ a nanosecond laser spectroscopy technique to measure end-to-end contact formation rates in IAPP mutants. We explore the proline substitutions in IAPP and quantify their effects in terms of intrinsic chain stiffness. We find that the three proline mutations found in rIAPP increase chain stiffness. Interestingly, we also find that residue R18 plays an important role in rIAPP's unique chain stiffness and, together with the proline residues, is a determinant for its non-amyloidogenic properties. We discuss the implications of our findings on the role of prolines in IDPs.
ContributorsCope, Stephanie M (Author) / Vaiana, Sara M (Thesis advisor) / Ghirlanda, Giovanna (Committee member) / Ros, Robert (Committee member) / Lindsay, Stuart M (Committee member) / Ozkan, Sefika B (Committee member) / Arizona State University (Publisher)
Created2013
Description
Telomerase is a unique reverse transcriptase that has evolved specifically to extend the single stranded DNA at the 3' ends of chromosomes. To achieve this, telomerase uses a small section of its integral RNA subunit (TR) to reiteratively copy a short, canonically 6-nt, sequence repeatedly in a processive manner using a complex and currently poorly understood mechanism of template translocation to stop nucleotide addition, regenerate its template, and then synthesize a new repeat. In this study, several novel interactions between the telomerase protein and RNA components along with the DNA substrate are identified and characterized which come together to allow active telomerase repeat addition. First, this study shows that the sequence of the RNA/DNA duplex holds a unique, single nucleotide signal which pauses DNA synthesis at the end of the canonical template sequence. Further characterization of this sequence dependent pause signal reveals that the template sequence alone can produce telomerase products with the characteristic 6-nt pattern, but also works cooperatively with another RNA structural element for proper template boundary definition. Finally, mutational analysis is used on several regions of the protein and RNA components of telomerase to identify crucial determinates of telomerase assembly and processive repeat synthesis. Together, these results shed new light on how telomerase coordinates its complex catalytic cycle.
ContributorsBrown, Andrew F (Author) / Chen, Julian J. L. (Thesis advisor) / Jones, Anne (Committee member) / Ghirlanda, Giovanna (Committee member) / Arizona State University (Publisher)
Created2014