Now showing items 19376-19395 of 20306

    • Turkish Musical Influences upon Carlo Domeniconi's Variations on an Anatolian Folk Song and Koyunbaba: Implications for Performance

      Patterson, R. Thomas; Sönmezler, Ahmet; Hamann, Donald L.; Sturman, Janet L.; Patterson, R. Thomas (The University of Arizona., 2013)
      The structure and content of Carlo Domeniconi's Variations on an Anatolian Folk Song and Koyunbaba are heavily influenced by Turkish folk music. A stylistic and accurate performance of these pieces becomes possible through the study of Turkish folk music and its performance practices. This document provides information that may help the reader understand what some of the aspects of Turkish folk music are and show how Italian composer and guitarist Carlo Domeniconi (b. 1947) used them in two of his most popular solo classical guitar compositions. This document not only serves as an informative tool to highlight several characteristics of Turkish folk music but also as a guide to interpret Variations on an Anatolian Folk Song and Koyunbaba in the Turkish style. Chapter four, Performer's Guide, includes a number of musical examples that are specifically edited to bring out Turkish stylistic aspects of interpretation. Many performers can benefit from these detailed musical examples.
    • Turkish Pre-Service Elementary School Teachers' Perceptions of Giftedness and Factors Affecting Their Referral Decisions

      Lopez, Francesca A.; Erdimez, Omer; Lopez, Francesca A.; Marx, Ronald; Mather, Nancy (The University of Arizona., 2017)
      The purpose of this study was to detect Turkish pre-service elementary school teachers' perceptions of giftedness and factors affecting their referral decisions through eleven profiles (scenarios) originally created by five experts in the field of gifted education and semi-structured interview questions created for this study. The original profiles were translated from English to Turkish and adapted to be more relevant to Turkish culture. These profiles were named as Student Profiles Survey in this study. The profiles were varied based on characteristics embedded in each profile and I was able to create eight versions (pile) of the Student Profiles Survey. Profiles in each version (pile) of Student Profiles Survey differed from each other based on the characteristics embedded in each profile. Participants of the study were Turkish pre-service elementary school teachers who were attending two colleges of Education at Gaziantep University, namely Gaziantep College of Education and Nizip College of Education. A total of 204 Turkish pre-service elementary school teachers participated in the study and filled out the different versions of Student Profiles Survey. Approximately 25 pre-service teachers filled out each version of Student Profiles Survey. In addition, 16 of the pre-service teachers were asked for a follow-up interview. The convergent parallel mixed-methods design was used to shed light on the research questions. The findings from quantitative and qualitative analyses were combined to support each other and to better investigate Turkish pre-service elementary school teachers' perceptions of giftedness and factors affecting their referral decisions. The results of this study indicated that Profile 11 was the most appropriate and Profile 4 was the least appropriate profile for Turkish pre-service elementary school teachers' perceptions of giftedness. Turkish pre-service elementary school teachers explained their reasons for including the students in the profiles to gifted education programs mostly based on the personal, academic, and social characteristics of the students embedded in the profiles but they did not often referred students' characteristics when they were explaining their reasons for exclusion. Rather than explaining their reasons based on characteristics of the students, Turkish pre-service teachers increased their expectations and created excuses to underestimate the potentials of the students in the profiles when they were asked to explain their reasons for exclusion. The results of factorial ANOVAs indicated that Turkish pre-service elementary school teachers' referral decisions were influenced by the following factors: Students’ and pre-service teachers’ gender, students' ability areas, personality traits of the students, words describing the student, and students' length of passion.
    • Turning points and adaptations: A case study of four women in poverty

      Snow, David A.; Smith, Kelly Eitzen (The University of Arizona., 1999)
      This research is an in-depth exploration of turning points and adaptations in the lives of four women living below the poverty line in Tucson, Arizona. From the most extremely impoverished woman living on the streets to the housed, poor working woman, a life history approach is used to explore the mechanisms by which these four women fell into, stayed in, and may eventually climb out of poverty. While the life history reveals great complexity among the women, it also reveals common turning points among their troubled lives. All four women have had a least one parent who was an alcoholic and/or drug addict, all four women quit pursuing their education after high school and have a history of low-wage, low-mobility jobs. All four women have had prolonged relationships with men who were alcoholic and/or drug addicts and were physically abusive. Finally, all four women have had major health problems which have hindered their ability to work. It is concluded that the life history method and the emphasis on turning points and adaptations is an improvement over quantitative studies which gloss over the true mechanisms behind poverty and fail to capture real lives.
    • Turning points in Social Security: Explaining legislative change, 1935-1985.

      Tynes, Sheryl Renee. (The University of Arizona., 1988)
      This work is a sociological analysis of factors that led to the political success of old-age insurance in the United States from 1935-1985. Archival documents, the Congressional Record, House Ways and Means and Senate Finance Committee Hearings, and secondary sources were used to piece together the social and political history of the program. The historical record was assessed in light of the pluralist, neo-Marxist and neo-Weberian theoretical frameworks typically utilized to study political change. Two key arguments are put forth. First, analyses that focus on the long-term process of social and political change are required to distinguish between the unique and the general. Other works that focus on isolated time periods cannot make these distinctions. It is also through longitudinal analysis that causality can be determined. Insights gained from a broader time-frame relate to specification of economic, political, and demographic shifts that shape the political agenda. Second, meso-level specification of organizational actors is necessary to assess the logic behind these actors' shifting positions. Organizational theory carries the analysis further than do previous theoretical perspectives, primarily because it specifies which political actors, either inside or outside the polity, attempt to influence their environment. It is through an organizational theory framework that we can determine effective strategies for instituting social change. Finally, using organizational theory and extrapolating from past events, some predictions for the future of Social Security are suggested.
    • TVET (Technical Vocational Education Training) Contributions toward Education Policy, Economic Sustainability, Development, and Poverty Abatement in a Globalized Economy: A Wicked Problem

      Koyama, Jill; Frick, Sumaya; Bosworth, Kris; Lee, Jenny (The University of Arizona., 2022)
      This dissertation is a study of policy stakeholders (N=24) in four countries within the regional Caribbean Community and Common Market (CARICOM) policy environment. The scope was to identify how they navigated and interpreted conceptualizations of TVET and general education, which have been explicitly tied to national and regional sustainability, development, poverty abatement and skilled labor migration initiatives. Despite variable levels of codified TVET policy, academic centric institutional frameworks, and political will, education policy stakeholders recognized the substantive impact of TVET on their nations and the region. Supported by networked regional knowledge exchanges that are informed by shared tenets central to the Ideal Caribbean Person, they strategically implemented nationally adapted blended TVET and academic education policy. As such, this policy environment has operationalized a rarely seen collaborative governance institutional design and learning system, quadruple-loop learning. At the national level, quadruple-learning principals conditioned calculated risk-taking and innovation, which productively informed regional knowledge exchanges and policy. As an effective tool to recognize, identify, and manage wicked problems, the outcome of this research is a new quadruple-loop learning policy model useful across different regions, national contexts, and connected institutional systems. Data was collected from interviews, policy documents, environmental scans, and public records. Analysis methods employed triangulating coded data, and network and policy analyses to produce modified comparative multi-site case studies and a comparative analysis of case study findings. Keywords: Caribbean, CARICOM, development, education policy, Ideal Caribbean Person, poverty abatement, networks, regional policy, skilled labor migration, social networks, sustainability, TVET, quadruple-loop learning, wicked problems
    • The TWEAK-Fn14 Ligand Receptor Axis Promotes Glioblastoma Cell Invasion and Survival Via Activation of Multiple GEF-Rho GTPase Signaling Systems

      Tran, Nhan; Kim, Suwon; Fortin Ensign, Shannon Patricia; Tran, Nhan; Kim, Suwon; Martinez, Jesse; Cress, Anne; Bishop, Maria (The University of Arizona., 2013)
      Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors, characterized by a highly invasive cell population. GB tumors develop treatment resistance and ultimately recur; the median survival is nearly fifteen months and importantly, the invading cell population is attributed with having a decreased sensitivity to therapeutics. Thus, there remains a necessity to identify the genetic and signaling mechanisms that promote tumor spread and therapeutic resistance in order to develop new targeted treatment strategies to combat this rapidly progressive disease. TWEAK-Fn14 ligand-receptor signaling is one mechanism in GB that promotes cell invasiveness and survival, and is dependent upon the activity of multiple Rho GTPases including Rac1. Here, we show that Cdc42 is essential in Fn14-mediated Rac1 activation. We identified two guanine nucleotide exchange factors (GEFs), Ect2 and Trio, involved in the TWEAK-induced activation of Cdc42 and Rac1, respectively, as well as in the subsequent TWEAK-Fn14 directed glioma cell migration and invasion. In addition, we characterized the role of SGEF in promoting Fn14-induced Rac1 activation. SGEF, a RhoG-specific GEF, is overexpressed in GB tumors and promotes TWEAK-Fn14-mediated glioma invasion. Moreover, we characterized the correlation between SGEF expression and TMZ resistance, and defined a role for SGEF in promoting the survival of glioma cells. SGEF mRNA and protein expression are regulated by the TWEAK-Fn14 signaling axis in an NF-kB dependent manner and inhibition of SGEF expression sensitizes glioma cells to TMZ treatment. Lastly, gene expression analysis of SGEF depleted GB cells revealed altered expression of a network of DNA repair and survival genes. Thus TWEAK-Fn14 signaling through the GEF-Rho GTPase systems which include the Ect2, Trio, and SGEF activation of Cdc42 and/or Rac1 presents a pathway of attractive drug targets in glioma therapy, and SGEF signaling represents a novel target in the setting of TMZ refractory, invasive GB cells.
    • The Twelve Etudes of Heitor Villa-Lobos: Didactic purpose within concert repertoire

      Patterson, Thomas; Joyce, Joseph Patrick (The University of Arizona., 2006)
      The subject of this document is the embedded didactic purpose of concert pieces for the guitar written by Heitor Villa-Lobos that have been titled etude. The Twelve Etudes of Heitor Villa-Lobos are unique examples of virtuoso concert pieces that also serve as studies of numerous aspects of guitar technique; I will attempt to demonstrate how these didactic elements are contained within these works and how they can be used to improve technique by performing a brief pedagogical analysis of each piece. This document will be limited to six of the Twelve Etudes for Guitar written in 1929 and first published in 1953. Each etude will be analyzed from a pedagogical perspective. A pedagogical analysis is the analysis of a piece to extract any didactic purpose the composer clearly had implied from the music; that is, not creating new exercises out of patterns or certain technical difficulties, but using the piece only in its original form. The existing literature concerning the Twelve Etudes for Guitar by Heitor Villa-Lobos has been limited to theoretical analysis and historical matters, with the exception of the work by Abel Carlevaro. The use of these pieces lies primarily in concert performance because of the compositional quality and technical difficulty. Also, any didactic intention of most of the etudes is not easily seen on the surface as with many other collections of works titled etudes. Therefore, the need for a study such as this is evidenced primarily in this lack of attention to the purely pedagogical significance of these etudes.
    • Twentieth century fire patterns in the Gila/Aldo Leopold Wilderness areas, New Mexico and the Selway-Bitterroot Wilderness area, Idaho/Montana

      Swetnam, Thomas W.; Rollins, Matthew Gregory (The University of Arizona., 2000)
      I used archives of wildfire perimeters (fire atlases) within a geographic information system (GIS) to describe and evaluate fire frequency patterns for the 20th century in the 486,673-ha Gila/Aldo Leopold Wilderness Complex (GALWC), New Mexico and the 785,090-ha Selway-Bitterroot Wilderness Complex (SBWC) in Idaho and Montana. I addressed questions about changing 20th century fire frequencies and landscape-scale controls of fire frequency by analyzing fire atlases along with data for topography, vegetation, and climate. Similarities and differences in comparisons between study areas highlight important aspects of fire regimes and strengthen my interpretation and inference. In the GALWC, fire rotations were shortest during the recent wildfire use period (1975-1993) and longest during the pre-modern suppression period (1909-1946). In the SBWC, fire rotations were shortest during the pre-modern suppression period (1880-1934) and longest during the modern suppression period (1935-1975). Elevations with the highest fire frequencies differed between study areas. However, forest types found at these elevations are characterized by similar overstory tree species. Steeper northeastern slopes in the GALWC and southwestern slopes in the SBWC burned most frequently. I assert that, in the GALWC, horizontal fuel continuity is a main factor determining fire frequency. In the SBWC, fuel moisture status limits fire frequency. Fires are most frequent in areas where ignitions occur and neither fuel continuity nor fuel moisture are likely to limit fire spread. Three statistical modeling approaches were used to produce maps of reburn probabilities. Log-likelihood modeling provided the most satisfactory results, while logistic regression and classification and regression trees yielded statistically insignificant models. Empirical models contributed to the assertion that fuel continuity limits fire frequency in the GALWC while fuel moisture limits fire frequency in the SBWC. Mapped fire perimeters provide a valuable source of spatial historical information for describing the role of large fires over broad areas. This dissertation enhances scientific knowledge about broad scale changes in fire regimes. Comparisons between areas facilitate identification of unique versus general patterns. Results provide a contemporary baseline for comparison with estimates of Pre-EuroAmerican fire frequencies, and a historical, spatial context for modeling and managing future fire regimes.
    • Twentieth-century Spanish composers for the harp: A study of Spanish folk elements in selected solo harp works of Jesus Guridi, Gerardo Gombau and Victorino Echevarria

      McLaughlin, Carrol; Rodriguez-Rios, Lizary (The University of Arizona., 2004)
      The purpose of this document is to examine the Spanish folk elements used in original compositions for the harp written by the Spanish composers Jesus Guridi, Gerardo Gombau and Victorino Echevarria. The document demonstrates that the harp is particularly suitable to convey the essence of the rhythmic, harmonic and melodic elements of traditional Spanish folk music. Spanish composers, particularly Jesus Guridi (Viejo Zortzico) Gerardo Gombau (Apunte Betico) and Victorino Echevarria (Capricho Andaluz), adapted elements of Spanish folk music such as cante jondo to create original nationalistic music that is idiomatic for the harp, resulting in effective concert pieces for the instrument's repertoire. The first chapter is devoted to the arrival and development of the harp in Spain. The second chapter discusses a history of the harp department at the Real Conservatorio Superior de Musica of Madrid which was established in 1830. This chapter also includes biographical and historical information about harp professors that taught there and the role that this conservatory played in developing distinctive Spanish compositions for the modern harp. Chapter three will discuss the harpists who inspired twenty-century Spanish composers. The subsequent three chapters will cover Jesus Guridi's, Gerardo Gombaus and Victorino Echevarria's lives, influences, and an analysis of their harp compositions: Viejo Zortzico , Apunte Betico and Capricho Andaluz respectively, highlight the Spanish folk elements used, and how composers incorporated these elements into their compositions to create a distinctive sound and fascinating show pieces for the concert harpist.
    • Twintrons: Introns-within-introns in the chloroplast genes of Euglena gracilis.

      Copertino, Donald Woodward.; Hallick, Richard B.; Bohnert, Hans J.; Dieckmann, Carol; Matsuda, Kaoru; Parker, Roy; Vierling, Elizabeth (The University of Arizona., 1992)
      The chloroplast genes of Euglena gracilis contain more than 100 introns. A comparison of intron content and position among plastid and prokaryote genes has led to the hypothesis that introns have been inserted into chloroplast genes during evolution. Several Euglena loci contain unusual introns. These introns have been characterized by direct primer extension cDNA sequencing, cDNA cloning and sequencing, and northern hybridization. The psbF locus has a 1042 nt intron that appears to be one group II intron inserted into domain V of another group II intron. It was determined that a 618 nt internal intron is first excised from the 1042 nt intron, resulting in a partially spliced pre-mRNA containing a 424 nt group II intron with a spliced domain V. The 424 nt intron is then removed to yield the mature psbF mRNA. The term "twintron" was used to define this new genetic element. Splicing of the internal and external introns occurs via lariat intermediates. The splicing of the 409 nt intron of the rps3 gene was also examined. This intron is a "mixed" twintron, composed of a 311 nt group II intron internal to a 98 nt group III intron. The splicing of four additional introns with mean lengths twice typical group III introns, three within the rpoC1 gene and one within the rpl16 gene, was analyzed. The 1604 nt intron in the psbC gene, which encodes orf458, was also examined. These introns are group III twintrons. Orf458 is encoded within the internal group III intron of the psbC twintron. Splicing of internal introns in three of the five group III twintrons involves multiple 5'- and/or 3'-splice sites. Excised group III introns accumulate as lariat RNAs. Twintrons represent evidence for intron insertion during gene evolution. One possible mechanism for twintron formation is by intron transposition. The disruption of functional domains by internal introns may necessitate a sequential in vivo splicing pathway, requiring excision of internal introns prior to excision of external introns. The origins of alternative splicing and a possible evolutionary relationship between group II, group III and nuclear pre-mRNA introns are discussed.
    • TWO ASPECTS OF REALITY IN THE POETRY OF PEDRO SALINAS: A SYMBOLOGICAL STUDY

      Komonchak, Bernadette, 1933- (The University of Arizona., 1974)
    • Two Case Studies of First Year Second Career Male Teachers: The Beliefs They Hold and the Pactices They Conduct to Teach All Students

      Anders, Patricia L.; Unterreiner, Ann M.; Anders, Patricia L.; Goodman, Yetta; Moll, Luis C. (The University of Arizona., 2006)
      The intentions expressed by second career individuals about entering the field of education, to make a difference in the lives of young people, mirror many of the philosophical frameworks of teaching for democracy that are found in the literature (Banks, 2005; Nieto, 1999; Dewey, 1916; Parker, 2003). An interest in how the interconnections of teaching to make a difference and teaching for democracy are enacted in second career teacher's classrooms. Four dimensions of teaching for democracy are suggested as a model of socially responsive teaching to study how teaching to make difference is enacted in the beliefs and practices of two second career teachers. The four dimensions include: 1) An ethic of care (Noddings, 1994); 2) Reflexive action (Grant & Zeichner, 1996; Schon, 1987); 3) Learning communities (Brooks & Brooks, 1999; Nieto, 1999; Richardson, 1997); and 4) Managed chaos (Bruner, 1986; Jenlink, 2004).Qualitative case study research was conducted to investigate how two newly certified second career male teachers articulate the beliefs they hold and conduct their practices to teach all children. From the constant comparison analysis common themes of classroom environment, curricular choices, and instructional approaches were identified and anchored the development of the cases. Across cases, the theme of 'life history' emerged as influential in the beliefs and practices to teach to make a difference. An extended analysis was conducted across cases to examine the links of the four dimensions of teaching for democracy present in the stories of each teacher's first year of teaching.Findings of this research study indicates 'life history' impacts the beliefs and practices of second career teachers to teach all students and can be linked to dimensions of teaching for democracy. Students' personal stories are sources for understanding and enhancing an awareness of racial, cultural, and economic diversity in teacher preparation programs (LaBoskey, 2006). This understanding is at the heart of the democratic ideal and a fundamental belief of those "directly responsible for ...creating and sustaining processes of conscious, self-guided evolution...the design of a future society" (Jenlink, 2002, p. 395).
    • TWO CASE STUDIES OF PROTEIN FOLD EVOLUTION: BACTERIOPHAGE CRO PROTEINS AND INSECT SALIVARY LIPOCALINS

      Cordes, Matthew H. J.; Roessler, Christian George; Cordes, Matthew H. J.; Ghosh, Indraneel; McEvoy, Megan; Montfort, William (The University of Arizona., 2010)
      Natural proteins can evolve new three-dimensional structures through mutations in their amino acid sequence. For protein families that exhibit such structural diversity, a major challenge is to understand the scope and nature of structure variation and its relationship to sequence evolution. The Cordes laboratory has begun using transitive homology-based methods to identify, target and structurally characterize natural sequences intermediate between pairs of proteins with distant sequence similarity and different structures. As a proof of principle, this dissertation describes structural studies of two proteins in different families as separate case studies, one involving secondary structure evolution and the other involving topological rearrangement. In the first case, crystallography was applied to solve the structure of a sequence intermediate identified through transitive homology analysis of the Cro transcription regulator family. Comparison with another member resulted in finding two proteins with significant sequence similarity yet different secondary structure compositions and folds. In the second case, transitive homology analysis was applied to look at two members of the insect salivary lipocalins, one with the canonical sequential all-antiparallel β-barrel topology, and another with a unique strand-swapped topology. Three sequence intermediate members were found that each have direct sequence similarity to both topologically distinct relatives. Targeting these sequence intermediate members for structural characterization by NMR led to assignment of the canonical lipocalin topology for one intermediate. The results from these two cases indicate that structurally diverse families may contain members with similar sequences but different folds. As such, transitive homology mapping offers a method to identify and target those members for structural characterization.
    • Two contrasting explanations of involvement violations: Orientation response or affective reaction?

      Burgoon, Judee; Le Poire, Beth Ann.; Burgoon, Michael; Bailey, Bill; Sigelman, Carol; Daniel, Terry; Schwartz, Gary (The University of Arizona., 1991)
      Among theories that address the impact of variations in immediacy behaviors during ongoing interactions are nonverbal expectancy violations and discrepancy arousal theories. This study of the effects of violations of expectations on arousal and reciprocity and compensation in the medical student-patient relationship proposed that (1) nonverbal expectancy violations theory would be more valid than discrepancy arousal theory in predicting outcomes, (2) violations of expectations would be followed by an orientation response as indicated by both physiological indicators and nonverbal behaviors, and (3) physiological indicators of arousal intensity would be associated with nonverbal indicators of arousal intensity. The results indicate that neither nonverbal expectancy violations nor discrepancy arousal theory's predictions were entirely valid, as high and very high involvement (including touch and close proximity) were met with reciprocity of high involvement, while low and very low involvement (negative violations of expectations) were met with reciprocity of low involvement. Additionally, all violations of expectations were followed by increases in arousal rather than the orientation response. Finally, arousal was generally predictive of nonverbal indicators of arousal intensity, thus offering less obtrusive ways to measure arousal.
    • Two Cooks in the Kitchen: Effects of Shared Decision-Making about Food Provisioning among Dual-Income Earning Couples in the United States

      Curran, Melissa A.; Ligon, Victoria K.; McDonald, Daniel A.; Pitts, Margaret J. (The University of Arizona., 2021)
      This dissertation includes two related manuscripts pertaining to the study of shared decision-making and food provisioning; the first study (Chapter II) describes the development of the scale used in this dissertation, and the second (Chapter III) describes the use of that scale to examine the relationship between shared decision-making and household food waste. The purpose of the first study (Chapter II) was to develop a new measurement tool to capture shared decision-making within U.S. couples across the full spectrum of food provisioning stages, including acquisition (activities related to purchasing food and managing food inventory), preparation and cooking (activities related to the transformation of ingredients into edible states), and clean-up and disposal (activities related to the storage and disposal of uneaten foods and the cleaning of materials and spaces associated with eating). Based on role theory and data highlighting significant structural changes to U.S. household compositions over the past decades, this research attempts to identify the degree to which individuals in coupled relationships perceived that both partners engaged in household decision-making within food provisioning domains. For the first study, two independent samples of U.S. adults (N=277 and N=441) were used to test and validate the proposed new measurement tool. Using best practices for scale development, this study presents the results of exploratory factor analysis, reliability testing, and construct validity predictions, to present a new 19-item scale measuring shared decision-making about food provisioning. This scale can also be divided into three theoretically meaningful sub-scales measuring shared decision-making about food acquisition (8 items), food preparation and cooking (4 items), and food clean-up and disposal (7 items). The purpose of the second study (Chapter III) was to examine the relationship between the Independent Variable (IV), shared decision-making about household food provisioning, and the Dependent Variable (DV), self-reported food waste (RQ1), using the newly developed scale (presented in study 1). In addition, this research sought to examine the theory of planned behavior constructs of attitudes, subjective norms, and perceived behavioral control to avoid wasting food, to determine the degree to which shared decision-making about household food provisioning might be associated with each of these predictive constructs (RQ2). Data for this second study came from a Qualtrics Panel survey in which a group of 441 participants were recruited to complete an extensive online survey about food decision-making, self-reported food wastage, and other related measures. Multiple regression hypothesis testing revealed that higher levels of shared decision-making about food clean-up and disposal was associated with higher levels of self-reported food wastage. In addition, it was found that individuals in coupled relationships who reported higher levels of shared decision-making about cooking and food preparation felt a stronger sense of control over their ability to prevent food waste. Combined, these studies offer a preliminary exploration of the relationship between shared decision-making and household food waste generation, as well as numerous opportunities for follow-up work. Most significantly, future scholarship is needed to further explore the degree to which couples make decisions independently in shared contexts versus engaging in explicit communication about food provisioning practices. Gaining clarity around the meaning of shared decision-making will offer new opportunities to explore the impact that multiple decision-makers within a household may have on the household’s overall production of waste.
    • Two Different Approaches Towards Development of Therapeutics for Neurological Disorders

      Khanna, May; Mollasalehi, Niloufar; Montfort, William R.; Horton, Nancy C.; Jewett, John C.; Tomasiak, Thomas M. (The University of Arizona., 2021)
      The research focuses on two different approaches towards drug discovery for neurodegenerative diseases Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS). Neurodegeneration is a progressive deterioration of neural structures leading to cognitive or motor impairment. There is still no effective therapy for any of the most common neurodegenerative diseases and the available therapies only lower the rate of the disease progression or manage the symptoms. Although neurodegenerative diseases exhibit distinct clinical characteristics, they usually present aggregation of specific protein(s) along with neuroinflammation among others. The first investigated approach towards discovering therapeutics is the use of small molecules targeting the N-terminal domain of transactive response (TAR) DNA binding protein-43 (TDP-43), a critical factor in neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s disease (AD) to disrupt the aggregation of TDP-43. Targeting the N-terminal domain (NTD) of TDP-43 by in silico docking, a small molecule called nTRD022 have been discovered binding to the NTD of TDP-43 that allosterically affects the RNA binding of the protein leading to disruption of RNA binding to TDP-43 and improving the muscle strength, as an ALS related phenotype, in Drosophila fly MS models which could potentially be further developed as ALS therapeutic. The second approach focuses on developing a systematic evolution of ligands by exponential enrichment (SELEX) to generate therapeutic aptamers. Aptamers are short nucleic acid ligands that are able to specifically recognize a target with high specificity and high affinity. They have been widely used in therapeutic and diagnostic applications for neurodegenerative diseases over the last two decades. However, due to their relatively recent development, there are not as many aptamers in clinical trials as expected. In this study, aptamers have been developed against autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG), a component of myelin sheath necessary for its structural integrity. The aptamer was developed to specifically target MOG antibody to disrupt the interaction between the antibody and MOG protein to protect the myelin sheath degeneration in motor neurons in MS patients. The developed aptamer, NM02, showed binding affinity towards MOG antibody in low micro molar range.
    • Two different molecular pathways of immunomodulation by retinoids and carotenoids.

      Watson, Ronald R.; Prabhala, Rao H.; Yocum, D.; Perterson, E.; Hendrix, M. (The University of Arizona., 1989)
      Epidemiological studies suggest that both retinoid and carotenoid intakes are inversely correlated with the incidence of human cancers. Animal studies show that both retinoids and carotenoids inhibit tumor cell growth. Both retinoids and carotenoids activate the cytotoxicity function of macrophages in animal experiments. The purpose of this study is to evaluate the molecular mechanism for 13-cis retinoic acid (13-cRA) and beta-carotene (BC) induced immunomodulation which could explain their anti-cancer affects. The effects of 13-cRA and BC were studied on various subpopulations of T-lymphocytes both in vitro and in vivo. For in vitro studies, peripheral blood mononuclear cells (PBMC) were incubated with test compounds at clinically achievable concentrations (10⁻⁸M) for three days. Then the cells were stained with monoclonal antibodies followed by the analysis of flow cytometer. For in vivo studies, PBMC were collected from Barrett's esophagus or oral leukoplakia patients during treatment with 13-cRA (1mg/kg/day) or BC (30 mg/day), respectively. Then the cells were analyzed with monoclonal antibodies and flow cytometry. Both compounds showed the capability of stimulating different subpopulations of T-lymphocytes. 13-cRA predominantly increased the number of T-helper cells, their interleukin 2 (IL-2) receptors and their response to mitogens. Whereas, BC elevated the number of Natural Kill (NK) cells, their IL-2 receptors and their cytotoxicity against K562 target cells. Though these immunomodulatory effects appeared to be unaffected by the presence and cytotoxic functions of macrophages, cytokines seemed to have an important role in the retinoid- and carotenoid-induced immunomodulation. Plasma levels of IL-2 and tumor necrosis factor (TNF) measured by ELISA procedures were increased in patients treated for two months with 13-cRA and BC respectively. Anti-IL-2 and anti-TNF antibodies blocked the retinoic- and carotenoid-induced immunomodulation in in vitro studies. These results indicate that 13-cRA, activating T-helper cells with IL-2 production, and BC, activating NK cells with TNF release, induced immunostimulation which might be able to provide the anti-cancer affects in part seen in epidemiological studies.
    • Two Dimensional Finite Volume Model for Simulating Unsteady Turbulent Flow and Sediment Transport

      Duan, Jennifer; Yu, Chunshui; Yeh, Jim; Valdes, Juan; Lansey, Kevin; Duan, Jennifer (The University of Arizona., 2013)
      The two-dimensional depth-averaged shallow water equations have attracted considerable attentions as a practical way to solve flows with free surface. Compared to three-dimensional Navier-Stokes equations, the shallow water equations give essentially the same results at much lower cost. Solving the shallow water equations by the Godunov-type finite volume method is a newly emerging area. The Godunov-type finite volume method is good at capturing the discontinuous fronts in numerical solutions. This makes the method suitable for solving the system of shallow water equations. In this dissertation, both the shallow water equations and the Godunov-type finite volume method are described in detail. A new surface flow routing method is proposed in the dissertation. The method does not limit the shallow water equations to open channels but extends the shallow water equations to the whole domain. Results show that the new routing method is a promising method for prediction of watershed runoff. The method is also applied to turbulence modeling of free surface flow. The κ - ε turbulence model is incorporated into the system of shallow water equations. The outcomes prove that the turbulence modeling is necessary for calculation of free surface flow. At last part of the dissertation, a total load sediment transport model is described and the model is tested against 1D and 2D laboratory experiments. In summary, the proposed numerical method shows good potential in solving free surface flow problems. And future development will be focusing on river meandering simulation, non-equilibrium sediment transport and surface flow - subsurface flow interaction.