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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
Ethnic identity has consistently been associated with Latino youths' psychosocial well-being; however, an area that has received much less attention is how parents' characteristics inform their ethnic socialization efforts and, in turn, youths' ethnic identity. In addition, we know little about how this process unfolds in specific at-risk samples of youth, such as adolescent mothers. Thus, the current prospective study examined how mothers' cultural characteristics informed adolescents' and mothers' reports of ethnic socialization, and how this, in turn, informed adolescents' ethnic identity exploration and resolution among a sample of 193 adolescent mothers and their mothers. In addition, the current study tested whether mothers' ethnic identity affirmation was directly related to adolescents' ethnic identity affirmation over time. Results indicated that mothers' familism was associated with increases in mothers' reports of maternal ethnic socialization, and, in turn, with increases in ethnic identity exploration for foreign-born adolescents, and decreases in ethnic identity exploration for U.S.-born adolescents. In addition, adolescents' reports of familial ethnic socialization were associated with increases in their ethnic identity exploration and resolution. Finally, mothers' ethnic identity affirmation was associated with increases in adolescents' ethnic identity affirmation. Findings are discussed with special attention to the importance of mothers' cultural values in how they socialize their adolescents, and this impact on adolescents' ethnic identity, as well as the implications this study has for interventions focused on bolstering positive outcomes for adolescent mothers.
ContributorsDerlan, Chelsea L (Author) / Umaña-Taylor, Adriana J. (Thesis advisor) / Knight, George P. (Committee member) / Updegraff, Kimberly A. (Committee member) / Arizona State University (Publisher)
Created2012
Description
Dietary protein is known to increase postprandial thermogenesis more so than carbohydrates or fats, probably related to the fact that amino acids have no immediate form of storage in the body and can become toxic if not readily incorporated into body tissues or excreted. It is also well documented that subjects report greater satiety on high- versus low-protein diets and that subject compliance tends to be greater on high-protein diets, thus contributing to their popularity. What is not as well known is how a high-protein diet affects resting metabolic rate over time, and what is even less well known is if resting metabolic rate changes significantly when a person consuming an omnivorous diet suddenly adopts a vegetarian one. This pilot study sought to determine whether subjects adopting a vegetarian diet would report decreased satiety or demonstrate a decreased metabolic rate due to a change in protein intake and possible increase in carbohydrates. Further, this study sought to validate a new device called the SenseWear Armband (SWA) to determine if it might be sensitive enough to detect subtle changes in metabolic rate related to diet. Subjects were tested twice on all variables, at baseline and post-test. Independent and related samples tests revealed no significant differences between or within groups for any variable at any time point in the study. The SWA had a strong positive correlation to the Oxycon Mobile metabolic cart but due to a lack of change in metabolic rate, its sensitivity was undetermined. These data do not support the theory that adopting a vegetarian diet results in a long-term change in metabolic rate.
ContributorsMoore, Amy (Author) / Johnston, Carol (Thesis advisor) / Appel, Christy (Thesis advisor) / Gaesser, Glenn (Committee member) / Arizona State University (Publisher)
Created2012
Description
In somatic cells, the mitotic spindle apparatus is centrosomal and several isoforms of Protein Kinase C (PKC) have been associated with the mitotic spindle, but their role in stabilizing the mitotic spindle is unclear. Other protein kinases such as, Glycogen Synthase Kinase 3â (GSK3â) also have been shown to be associated with the mitotic spindle. In the study in chapter 2, we show the enrichment of active (phosphorylated) PKCæ at the centrosomal region of the spindle apparatus in metaphase stage of 3T3 cells. In order to understand whether the two kinases, PKC and GSK3â are associated with the mitotic spindle, first, the co-localization and close molecular proximity of PKC isoforms with GSK3â was studied in metaphase cells. Second, the involvement of inactive GSK3â in maintaining an intact mitotic spindle was shown. Third, this study showed that addition of a phospho-PKCæ specific inhibitor to cells can disrupt the mitotic spindle microtubules. The mitotic spindle at metaphase in mouse fibroblasts appears to be maintained by PKCæ acting through GSK3â. The MAPK pathway has been implicated in various functions related to cell cycle regulation. MAPKK (MEK) is part of this pathway and the extracellular regulated kinase (ERK) is its known downstream target. GSK3â and PKCæ also have been implicated in cell cycle regulation. In the study in chapter 3, we tested the effects of inhibiting MEK on the activities of ERK, GSK3â, PKCæ, and á-tubulin. Results from this study indicate that inhibition of MEK did not inhibit GSK3â and PKCæ enrichment at the centrosomes. However, the mitotic spindle showed a reduction in the pixel intensity of microtubules and also a reduction in the number of cells in each of the M-phase stages. A peptide activation inhibitor of ERK was also used. Our results indicated a decrease in mitotic spindle microtubules and an absence of cells in most of the M-phase stages. GSK3â and PKCæ enrichment were however not inhibited at the centrosomes. Taken together, the kinases GSK3â and PKCæ may not function as a part of the MAPK pathway to regulate the mitotic spindle.
ContributorsChakravadhanula, Madhavi (Author) / Capco, David G. (Thesis advisor) / Chandler, Douglas (Committee member) / Clark-Curtiss, Josephine (Committee member) / Newfeld, Stuart (Committee member) / Arizona State University (Publisher)
Created2012
Description
Cognitive function declines with normal age and disease states, such as Alzheimer's disease (AD). Loss of ovarian hormones at menopause has been shown to exacerbate age-related memory decline and may be related to the increased risk of AD in women versus men. Some studies show that hormone therapy (HT) can have beneficial effects on cognition in normal aging and AD, but increasing evidence suggests that the most commonly used HT formulation is not ideal. Work in this dissertation used the surgically menopausal rat to evaluate the cognitive effects and mechanisms of progestogens proscribed to women. I also translated these questions to the clinic, evaluating whether history of HT use impacts hippocampal and entorhinal cortex volumes assessed via imaging, and cognition, in menopausal women. Further, this dissertation investigates how sex impacts responsiveness to dietary interventions in a mouse model of AD. Results indicate that the most commonly used progestogen component of HT, medroxyprogesterone acetate (MPA), impairs cognition in the middle-aged and aged surgically menopausal rat. Further, MPA is the sole hormone component of the contraceptive Depo Provera, and my research indicates that MPA administered to young-adult rats leads to long lasting cognitive impairments, evident at middle age. Natural progesterone has been gaining increasing popularity as an alternate option to MPA for HT; however, my findings suggest that progesterone also impairs cognition in the middle-aged and aged surgically menopausal rat, and that the mechanism may be through increased GABAergic activation. This dissertation identified two less commonly used progestogens, norethindrone acetate and levonorgestrel, as potential HTs that could improve cognition in the surgically menopausal rat. Parameters guiding divergent effects on cognition were discovered. In women, prior HT use was associated with larger hippocampal and entorhinal cortex volumes, as well as a modest verbal memory enhancement. Finally, in a model of AD, sex impacts responsiveness to a dietary cognitive intervention, with benefits seen in male, but not female, transgenic mice. These findings have clinical implications, especially since women are at higher risk for AD diagnosis. Together, it is my hope that this information adds to the overarching goal of optimizing cognitive aging in women.
ContributorsBraden, Brittany Blair (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Neisewander, Janet L (Committee member) / Conrad, Cheryl D. (Committee member) / Baxter, Leslie C (Committee member) / Arizona State University (Publisher)
Created2012
Description
The use of bias indicators in psychological measurement has been contentious, with some researchers questioning whether they actually suppress or moderate the ability of substantive psychological indictors to discriminate (McGrath, Mitchell, Kim, & Hough, 2010). Bias indicators on the MMPI-2-RF (F-r, Fs, FBS-r, K-r, and L-r) were tested for suppression or moderation of the ability of the RC1 and NUC scales to discriminate between Epileptic Seizures (ES) and Non-epileptic Seizures (NES, a conversion disorder that is often misdiagnosed as ES). RC1 and NUC had previously been found to be the best scales on the MMPI-2-RF to differentiate between ES and NES, with optimal cut scores occurring at a cut score of 65 for RC1 (classification rate of 68%) and 85 for NUC (classification rate of 64%; Locke et al., 2010). The MMPI-2-RF was completed by 429 inpatients on the Epilepsy Monitoring Unit (EMU) at the Scottsdale Mayo Clinic Hospital, all of whom had confirmed diagnoses of ES or NES. Moderated logistic regression was used to test for moderation and logistic regression was used to test for suppression. Classification rates of RC1 and NUC were calculated at different bias level indicators to evaluate clinical utility for diagnosticians. No moderation was found. Suppression was found for F-r, Fs, K-r, and L-r with RC1, and for all variables with NUC. For F-r and Fs, the optimal RC1 and NUC cut scores increased at higher levels of bias, but tended to decrease at higher levels of K-r, L-r, and FBS-r. K-r provided the greatest suppression for RC1, as well as the greatest increases in classification rates at optimal cut scores, given different levels of bias. It was concluded that, consistent with expectations, taking account of bias indicator suppression on the MMPI-2-RF can improve discrimination of ES and NES. At higher levels of negative impression management, higher cut scores on substantive scales are needed to attain optimal discrimination, whereas at higher levels of positive impression management and FBS-r, lower cut scores are needed. Using these new cut scores resulted in modest improvements in accuracy in discrimination. These findings are consistent with prior research in showing the efficacy of bias indicators, and extend the findings to a psycho-medical context.
ContributorsWershba, Rebecca E (Author) / Lanyon, Richard I (Thesis advisor) / Barrera, Manuel (Committee member) / Karoly, Paul (Committee member) / Millsap, Roger E (Committee member) / Arizona State University (Publisher)
Created2013
Description
Recommendations made by expert groups are pervasive throughout various life domains. Yet not all recommendations--or expert groups--are equally persuasive. This research aims to identify factors that influence the persuasiveness of recommendations. More specifically, this study examined the effects of decisional cohesion (the amount of agreement among the experts in support of the recommendation), framing (whether the message is framed as a loss or gain), and the domain of the recommendation (health vs. financial) on the persuasiveness of the recommendation. The participants consisted of 1,981 undergraduates from Arizona State University. The participants read a vignette including information about the expert group making a recommendation--which varied the amount of expert agreement for the recommendation--and the recommendation, which was framed as either a gain or loss. Participants then responded to questions about the persuasiveness of the recommendation. In this study, there was a linear main effect of decisional cohesion such that the greater the decisional cohesion of the expert group the more persuasive their recommendation. In addition, there was a main effect of domain such that the health recommendation was more persuasive than the financial recommendation. Contrary to predictions, there was no observed interaction between the amount of decisional cohesion and the framing of the recommendation nor was there a main effect of framing. Further analyses show support for a mediation effect indicating that high levels of decisional cohesion increased the perceived entitativity of the expert group--the degree to which the group was perceived as a unified, cohesive group¬--which increased the recommendation's persuasiveness. An implication of this research is that policy makers could increase the persuasiveness of their recommendations by promoting recommendations that are unanimously supported by their experts or at least show higher levels of decisional cohesion.
ContributorsVotruba, Ashley M (Author) / Kwan, Virginia S.Y. (Thesis advisor) / Saks, Michael J. (Committee member) / Demaine, Linda (Committee member) / Arizona State University (Publisher)
Created2013
Description
Although aggression is sometimes thought to be maladaptive, evolutionary theories of resource control and dominance posit that aggression may be used to gain and maintain high social prominence within the peer group. The success of using aggression to increase social prominence may depend on the form of aggression used (relational versus physical), the gender of the aggressor, and the prominence of the victim. Thus, the current study examined the associations between aggression and victimization and social prominence. In addition, the current study extended previous research by examining multiple forms of aggression and victimization and conceptualizing and measuring social prominence using social network analysis. Participants were 339 6th grade students from ethnically diverse backgrounds (50.4% girls). Participants completed a peer nomination measure assessing relational and physical aggression and victimization. They also nominated friends within their grade, which were used to calculate three indices of social prominence, using social network analysis. As expected, results indicated that relational aggression was associated with higher social prominence, particularly for girls, whereas physical aggression was less robustly associated with social prominence. Results for victimization were less clear, but suggested that, for girls, those at mid-levels of social prominence were most highly victimized. For boys, results indicated that those both high and low in prominence were most highly relationally victimized, and those at mid-levels of prominence were most highly physically victimized. These findings help inform intervention work focused on decreasing overall levels of aggressive behavior.
ContributorsAndrews, Naomi C. Z (Author) / Hanish, Laura D. (Thesis advisor) / Martin, Carol Lynn (Committee member) / Updegraff, Kimberly A (Committee member) / Arizona State University (Publisher)
Created2013
Description
DNA has recently emerged as an extremely promising material to organize molecules on nanoscale. The reliability of base recognition, self-assembling behavior, and attractive structural properties of DNA are of unparalleled value in systems of this size. DNA scaffolds have already been used to organize a variety of molecules including nanoparticles and proteins. New protein-DNA bio-conjugation chemistries make it possible to precisely position proteins and other biomolecules on underlying DNA scaffolds, generating multi-biomolecule pathways with the ability to modulate inter-molecular interactions and the local environment. This dissertation focuses on studying the application of using DNA nanostructure to direct the self-assembly of other biomolecular networks to translate biochemical pathways to non-cellular environments. Presented here are a series of studies toward this application. First, a novel strategy utilized DNA origami as a scaffold to arrange spherical virus capsids into one-dimensional arrays with precise nanoscale positioning. This hierarchical self-assembly allows us to position the virus particles with unprecedented control and allows the future construction of integrated multi-component systems from biological scaffolds using the power of rationally engineered DNA nanostructures. Next, discrete glucose oxidase (GOx)/ horseradish peroxidase (HRP) enzyme pairs were organized on DNA origami tiles with controlled interenzyme spacing and position. This study revealed two different distance-dependent kinetic processes associated with the assembled enzyme pairs. Finally, a tweezer-like DNA nanodevice was designed and constructed to actuate the activity of an enzyme/cofactor pair. Using this approach, several cycles of externally controlled enzyme inhibition and activation were successfully demonstrated. This principle of responsive enzyme nanodevices may be used to regulate other types of enzymes and to introduce feedback or feed-forward control loops.
ContributorsLiu, Minghui (Author) / Yan, Hao (Thesis advisor) / Liu, Yan (Thesis advisor) / Chen, Julian (Committee member) / Zhang, Peiming (Committee member) / Arizona State University (Publisher)
Created2013
Description
Approximately one-third of Iraq and Afghanistan veterans develop mental health problems, yet only 35-40% of those with mental disorders are seeking mental healthcare (Hoge, et al., 2004; Vogt, 2011). Military spouses may be an important resource for facilitating treatment seeking (Warner, et al., 2008), especially if service member mental health issues are impacting the marriage. Military spouses might be hesitant to encourage service member help-seeking, however, due to perceived threat of adverse military career consequences. For this study, 62 military wives completed an online survey. As part of the survey, participants were randomly assigned to one of four vignettes containing a description of a hypothetical military husband with mental health symptoms. Each vignette presented different combinations of marital conflict (high versus low) and service member concerns about adverse career consequences (high versus low). Wives rated on a five-point scale how likely they were to encourage the hypothetical military husband to seek help. It was hypothesized that spouses would be more willing to encourage help-seeking when concerns about adverse military career consequences were low and marital distress was high. No main effects or interaction effect were found for marriage and career. Perceived stigma about seeking mental health treatment in the military, psychological identification as a military spouse, and experience and familiarity with military mental healthcare policies failed to moderate the relationship between marital conflict, career concerns, and encouragement of help-seeking. Correlational analyses revealed that (1) greater experience with military mental healthcare (first- or secondhand), and (2) greater perceptions of stigma regarding seeking mental healthcare in the military each were associated with decreased perceptions of military supportiveness of mental healthcare. Therefore, although the experimental manipulation in this study did not lead to differences in military spouses' encouragement of a hypothetical military service member to seek mental health services, other findings based on participants' actual experiences suggest that experiences with military mental healthcare may generate or reinforce negative perceptions of military mental healthcare. Altering actual experiences with military mental healthcare, in addition to perceptions of stigma, may be a useful area of intervention for military service members and spouses.
ContributorsHermosillo, Lori (Author) / Roberts, Nicole (Thesis advisor) / Burleson, Mary (Committee member) / Tinsley, Barbara (Committee member) / Arizona State University (Publisher)
Created2013