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Proteins are a fundamental unit in biology. Although proteins have been extensively studied, there is still much to investigate. The mechanism by which proteins fold into their native state, how evolution shapes structural dynamics, and the dynamic mechanisms of many diseases are not well understood. In this thesis, protein folding

Proteins are a fundamental unit in biology. Although proteins have been extensively studied, there is still much to investigate. The mechanism by which proteins fold into their native state, how evolution shapes structural dynamics, and the dynamic mechanisms of many diseases are not well understood. In this thesis, protein folding is explored using a multi-scale modeling method including (i) geometric constraint based simulations that efficiently search for native like topologies and (ii) reservoir replica exchange molecular dynamics, which identify the low free energy structures and refines these structures toward the native conformation. A test set of eight proteins and three ancestral steroid receptor proteins are folded to 2.7Å all-atom RMSD from their experimental crystal structures. Protein evolution and disease associated mutations (DAMs) are most commonly studied by in silico multiple sequence alignment methods. Here, however, the structural dynamics are incorporated to give insight into the evolution of three ancestral proteins and the mechanism of several diseases in human ferritin protein. The differences in conformational dynamics of these evolutionary related, functionally diverged ancestral steroid receptor proteins are investigated by obtaining the most collective motion through essential dynamics. Strikingly, this analysis shows that evolutionary diverged proteins of the same family do not share the same dynamic subspace. Rather, those sharing the same function are simultaneously clustered together and distant from those functionally diverged homologs. This dynamics analysis also identifies 77% of mutations (functional and permissive) necessary to evolve new function. In silico methods for prediction of DAMs rely on differences in evolution rate due to purifying selection and therefore the accuracy of DAM prediction decreases at fast and slow evolvable sites. Here, we investigate structural dynamics through computing the contribution of each residue to the biologically relevant fluctuations and from this define a metric: the dynamic stability index (DSI). Using DSI we study the mechanism for three diseases observed in the human ferritin protein. The T30I and R40G DAMs show a loss of dynamic stability at the C-terminus helix and nearby regulatory loop, agreeing with experimental results implicating the same regulatory loop as a cause in cataracts syndrome.
ContributorsGlembo, Tyler J (Author) / Ozkan, Sefika B (Thesis advisor) / Thorpe, Michael F (Committee member) / Ros, Robert (Committee member) / Kumar, Sudhir (Committee member) / Shumway, John (Committee member) / Arizona State University (Publisher)
Created2011
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Description
Multi-task learning (MTL) aims to improve the generalization performance (of the resulting classifiers) by learning multiple related tasks simultaneously. Specifically, MTL exploits the intrinsic task relatedness, based on which the informative domain knowledge from each task can be shared across multiple tasks and thus facilitate the individual task learning. It

Multi-task learning (MTL) aims to improve the generalization performance (of the resulting classifiers) by learning multiple related tasks simultaneously. Specifically, MTL exploits the intrinsic task relatedness, based on which the informative domain knowledge from each task can be shared across multiple tasks and thus facilitate the individual task learning. It is particularly desirable to share the domain knowledge (among the tasks) when there are a number of related tasks but only limited training data is available for each task. Modeling the relationship of multiple tasks is critical to the generalization performance of the MTL algorithms. In this dissertation, I propose a series of MTL approaches which assume that multiple tasks are intrinsically related via a shared low-dimensional feature space. The proposed MTL approaches are developed to deal with different scenarios and settings; they are respectively formulated as mathematical optimization problems of minimizing the empirical loss regularized by different structures. For all proposed MTL formulations, I develop the associated optimization algorithms to find their globally optimal solution efficiently. I also conduct theoretical analysis for certain MTL approaches by deriving the globally optimal solution recovery condition and the performance bound. To demonstrate the practical performance, I apply the proposed MTL approaches on different real-world applications: (1) Automated annotation of the Drosophila gene expression pattern images; (2) Categorization of the Yahoo web pages. Our experimental results demonstrate the efficiency and effectiveness of the proposed algorithms.
ContributorsChen, Jianhui (Author) / Ye, Jieping (Thesis advisor) / Kumar, Sudhir (Committee member) / Liu, Huan (Committee member) / Xue, Guoliang (Committee member) / Arizona State University (Publisher)
Created2011
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Description
Sparsity has become an important modeling tool in areas such as genetics, signal and audio processing, medical image processing, etc. Via the penalization of l-1 norm based regularization, the structured sparse learning algorithms can produce highly accurate models while imposing various predefined structures on the data, such as feature groups

Sparsity has become an important modeling tool in areas such as genetics, signal and audio processing, medical image processing, etc. Via the penalization of l-1 norm based regularization, the structured sparse learning algorithms can produce highly accurate models while imposing various predefined structures on the data, such as feature groups or graphs. In this thesis, I first propose to solve a sparse learning model with a general group structure, where the predefined groups may overlap with each other. Then, I present three real world applications which can benefit from the group structured sparse learning technique. In the first application, I study the Alzheimer's Disease diagnosis problem using multi-modality neuroimaging data. In this dataset, not every subject has all data sources available, exhibiting an unique and challenging block-wise missing pattern. In the second application, I study the automatic annotation and retrieval of fruit-fly gene expression pattern images. Combined with the spatial information, sparse learning techniques can be used to construct effective representation of the expression images. In the third application, I present a new computational approach to annotate developmental stage for Drosophila embryos in the gene expression images. In addition, it provides a stage score that enables one to more finely annotate each embryo so that they are divided into early and late periods of development within standard stage demarcations. Stage scores help us to illuminate global gene activities and changes much better, and more refined stage annotations improve our ability to better interpret results when expression pattern matches are discovered between genes.
ContributorsYuan, Lei (Author) / Ye, Jieping (Thesis advisor) / Wang, Yalin (Committee member) / Xue, Guoliang (Committee member) / Kumar, Sudhir (Committee member) / Arizona State University (Publisher)
Created2013
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Description
Woody plant encroachment is a worldwide phenomenon linked to water availability in semiarid systems. Nevertheless, the implications of woody plant encroachment on the hydrologic cycle are poorly understood, especially at the catchment scale. This study takes place in a pair of small semiarid rangeland undergoing the encroachment of Prosopis velutina

Woody plant encroachment is a worldwide phenomenon linked to water availability in semiarid systems. Nevertheless, the implications of woody plant encroachment on the hydrologic cycle are poorly understood, especially at the catchment scale. This study takes place in a pair of small semiarid rangeland undergoing the encroachment of Prosopis velutina Woot., or velvet mesquite tree. The similarly-sized basins are in close proximity, leading to equivalent meteorological and soil conditions. One basin was treated for mesquite in 1974, while the other represents the encroachment process. A sensor network was installed to measure ecohydrological states and fluxes, including precipitation, runoff, soil moisture and evapotranspiration. Observations from June 1, 2011 through September 30, 2012 are presented to describe the seasonality and spatial variability of ecohydrological conditions during the North American Monsoon (NAM). Runoff observations are linked to historical changes in runoff production in each watershed. Observations indicate that the mesquite-treated basin generates more runoff pulses and greater runoff volume for small rainfall events, while the mesquite-encroached basin generates more runoff volume for large rainfall events. A distributed hydrologic model is applied to both basins to investigate the runoff threshold processes experienced during the NAM. Vegetation in the two basins is classified into grass, mesquite, or bare soil using high-resolution imagery. Model predictions are used to investigate the vegetation controls on soil moisture, evapotranspiration, and runoff generation. The distributed model shows that grass and mesquite sites retain the highest levels of soil moisture. The model also captures the runoff generation differences between the two watersheds that have been observed over the past decade. Generally, grass sites in the mesquite-treated basin have less plant interception and evapotranspiration, leading to higher soil moisture that supports greater runoff for small rainfall events. For large rainfall events, the mesquite-encroached basin produces greater runoff due to its higher fraction of bare soil. The results of this study show that a distributed hydrologic model can be used to explain runoff threshold processes linked to woody plant encroachment at the catchment-scale and provides useful interpretations for rangeland management in semiarid areas.
ContributorsPierini, Nicole A (Author) / Vivoni, Enrique R (Thesis advisor) / Wang, Zhi-Hua (Committee member) / Mays, Larry W. (Committee member) / Arizona State University (Publisher)
Created2013
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Description
The contemporary architectural pedagogy is far removed from its ancestry: the classical Beaux-Arts and polytechnic schools of the 19th century and the Bauhaus and Vkhutemas models of the modern period. Today, the "digital" has invaded the academy and shapes pedagogical practices, epistemologies, and ontologies within it, and this invasion is

The contemporary architectural pedagogy is far removed from its ancestry: the classical Beaux-Arts and polytechnic schools of the 19th century and the Bauhaus and Vkhutemas models of the modern period. Today, the "digital" has invaded the academy and shapes pedagogical practices, epistemologies, and ontologies within it, and this invasion is reflected in teaching practices, principles, and tools. Much of this digital integration goes unremarked and may not even be explicitly taught. In this qualitative research project, interviews with 18 leading architecture lecturers, professors, and deans from programs across the United States were conducted. These interviews focused on advanced practices of digital architecture, such as the use of digital tools, and how these practices are viewed. These interviews yielded a wealth of information about the uses (and abuses) of advanced digital technologies within the architectural academy, and the results were analyzed using the methods of phenomenology and grounded theory. Most schools use digital technologies to some extent, although this extent varies greatly. While some schools have abandoned hand-drawing and other hand-based craft almost entirely, others have retained traditional techniques and use digital technologies sparingly. Reasons for using digital design processes include industry pressure as well as the increased ability to solve problems and the speed with which they could be solved. Despite the prevalence of digital design, most programs did not teach related design software explicitly, if at all, instead requiring students (especially graduate students) to learn to use them outside the design studio. Some of the problems with digital design identified in the interviews include social problems such as alienation as well as issues like understanding scale and embodiment of skill.
ContributorsAlqabandy, Hamad (Author) / Brandt, Beverly (Thesis advisor) / Mesch, Claudia (Committee member) / Newton, David (Committee member) / Arizona State University (Publisher)
Created2012
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Description
The entire history of HIV-1 is hidden in its ten thousand bases, where information regarding its evolutionary traversal through the human population can only be unlocked with fine-scale sequence analysis. Measurable footprints of mutation and recombination have imparted upon us a wealth of knowledge, from multiple chimpanzee-to-human transmissions to patterns

The entire history of HIV-1 is hidden in its ten thousand bases, where information regarding its evolutionary traversal through the human population can only be unlocked with fine-scale sequence analysis. Measurable footprints of mutation and recombination have imparted upon us a wealth of knowledge, from multiple chimpanzee-to-human transmissions to patterns of neutralizing antibody and drug resistance. Extracting maximum understanding from such diverse data can only be accomplished by analyzing the viral population from many angles. This body of work explores two primary aspects of HIV sequence evolution, point mutation and recombination, through cross-sectional (inter-individual) and longitudinal (intra-individual) investigations, respectively. Cross-sectional Analysis: The role of Haiti in the subtype B pandemic has been hotly debated for years; while there have been many studies, up to this point, no one has incorporated the well-known mechanism of retroviral recombination into their biological model. Prior to the use of recombination detection, multiple analyses produced trees where subtype B appears to have first entered Haiti, followed by a jump into the rest of the world. The results presented here contest the Haiti-first theory of the pandemic and instead suggest simultaneous entries of subtype B into Haiti and the rest of the world. Longitudinal Analysis: Potential N-linked glycosylation sites (PNGS) are the most evolutionarily dynamic component of one of the most evolutionarily dynamic proteins known to date. While the number of mutations associated with the increase or decrease of PNGS frequency over time is high, there are a set of relatively stable sites that persist within and between longitudinally sampled individuals. Here, I identify the most conserved stable PNGSs and suggest their potential roles in host-virus interplay. In addition, I have identified, for the first time, what may be a gp-120-based environmental preference for N-linked glycosylation sites.
ContributorsHepp, Crystal Marie, 1981- (Author) / Rosenberg, Michael S. (Thesis advisor) / Hedrick, Philip (Committee member) / Escalante, Ananias (Committee member) / Kumar, Sudhir (Committee member) / Arizona State University (Publisher)
Created2013
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Description
In the middle of the 20th century, juried annuals of Native American painting in art museums were unique opportunities because of their select focus on two-dimensional art as opposed to "craft" objects and their inclusion of artists from across the United States. Their first fifteen years were critical for patronage

In the middle of the 20th century, juried annuals of Native American painting in art museums were unique opportunities because of their select focus on two-dimensional art as opposed to "craft" objects and their inclusion of artists from across the United States. Their first fifteen years were critical for patronage and widespread acceptance of modern easel painting. Held at the Philbrook Art Center in Tulsa (1946-1979), the Denver Art Museum (1951-1954), and the Museum of New Mexico Art Gallery in Santa Fe (1956-1965), they were significant not only for the accolades and prestige they garnered for award winners, but also for setting standards of quality and style at the time. During the early years of the annuals, the art was changing, some moving away from conventional forms derived from the early art training of the 1920s and 30s in the Southwest and Oklahoma, and incorporating modern themes and styles acquired through expanded opportunities for travel and education. The competitions reinforced and reflected a variety of attitudes about contemporary art which ranged from preserving the authenticity of the traditional style to encouraging experimentation. Ultimately becoming sites of conflict, the museums that hosted annuals contested the directions in which artists were working. Exhibition catalogs, archived documents, and newspaper and magazine articles about the annuals provide details on the exhibits and the changes that occurred over time. The museums' guidelines and motivations, and the statistics on the award winners reveal attitudes toward the art. The institutions' reactions in the face of controversy and their adjustments to the annuals' guidelines impart the compromises each made as they adapted to new trends that occurred in Native American painting over a fifteen year period. This thesis compares the approaches of three museums to their juried annuals and establishes the existence of a variety of attitudes on contemporary Native American painting from 1946-1960. Through this collection of institutional views, the competitions maintained a patronage base for traditional style painting while providing opportunities for experimentation, paving the way for the great variety and artistic progress of Native American painting today.
ContributorsPeters, Stephanie (Author) / Duncan, Kate (Thesis advisor) / Fahlman, Betsy (Thesis advisor) / Mesch, Claudia (Committee member) / Arizona State University (Publisher)
Created2012
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Description
We propose a novel solution to prevent cancer by developing a prophylactic cancer. Several sources of antigens for cancer vaccines have been published. Among these, antigens that contain a frame-shift (FS) peptide or viral peptide are quite attractive for a variety of reasons. FS sequences, from either mistake in RNA

We propose a novel solution to prevent cancer by developing a prophylactic cancer. Several sources of antigens for cancer vaccines have been published. Among these, antigens that contain a frame-shift (FS) peptide or viral peptide are quite attractive for a variety of reasons. FS sequences, from either mistake in RNA processing or in genomic DNA, may lead to generation of neo-peptides that are foreign to the immune system. Viral peptides presumably would originate from exogenous but integrated viral nucleic acid sequences. Both are non-self, therefore lessen concerns about development of autoimmunity. I have developed a bioinformatical approach to identify these aberrant transcripts in the cancer transcriptome. Their suitability for use in a vaccine is evaluated by establishing their frequencies and predicting possible epitopes along with their population coverage according to the prevalence of major histocompatibility complex (MHC) types. Viral transcripts and transcripts with FS mutations from gene fusion, insertion/deletion at coding microsatellite DNA, and alternative splicing were identified in NCBI Expressed Sequence Tag (EST) database. 48 FS chimeric transcripts were validated in 50 breast cell lines and 68 primary breast tumor samples with their frequencies from 4% to 98% by RT-PCR and sequencing confirmation. These 48 FS peptides, if translated and presented, could be used to protect more than 90% of the population in Northern America based on the prediction of epitopes derived from them. Furthermore, we synthesized 150 peptides that correspond to FS and viral peptides that we predicted would exist in tumor patients and we tested over 200 different cancer patient sera. We found a number of serological reactive peptide sequences in cancer patients that had little to no reactivity in healthy controls; strong support for the strength of our bioinformatic approach. This study describes a process used to identify aberrant transcripts that lead to a new source of antigens that can be tested and used in a prophylactic cancer vaccine. The vast amount of transcriptome data of various cancers from the Cancer Genome Atlas (TCGA) project will enhance our ability to further select better cancer antigen candidates.
ContributorsLee, HoJoon (Author) / Johnston, Stephen A. (Thesis advisor) / Kumar, Sudhir (Committee member) / Miller, Laurence (Committee member) / Stafford, Phillip (Committee member) / Sykes, Kathryn (Committee member) / Arizona State University (Publisher)
Created2012
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Description

Engineered pavements cover a large fraction of cities and offer significant potential for urban heat island mitigation. Though rapidly increasing research efforts have been devoted to the study of pavement materials, thermal interactions between buildings and the ambient environment are mostly neglected. In this study, numerical models featuring a realistic

Engineered pavements cover a large fraction of cities and offer significant potential for urban heat island mitigation. Though rapidly increasing research efforts have been devoted to the study of pavement materials, thermal interactions between buildings and the ambient environment are mostly neglected. In this study, numerical models featuring a realistic representation of building-environment thermal interactions, were applied to quantify the effect of pavements on the urban thermal environment at multiple scales. It was found that performance of pavements inside the canyon was largely determined by the canyon geometry. In a high-density residential area, modifying pavements had insignificant effect on the wall temperature and building energy consumption. At a regional scale, various pavement types were also found to have a limited cooling effect on land surface temperature and 2-m air temperature for metropolitan Phoenix. In the context of global climate change, the effect of pavement was evaluated in terms of the equivalent CO2 emission. Equivalent CO2 emission offset by reflective pavements in urban canyons was only about 13.9e46.6% of that without building canopies, depending on the canyon geometry. This study revealed the importance of building-environment thermal interactions in determining thermal conditions inside the urban canopy.

ContributorsYang, Jiachuan (Author) / Wang, Zhi-Hua (Author) / Kaloush, Kamil (Author) / Dylla, Heather (Author)
Created2016-08-22
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Description

Despite the fact that seizures are commonly associated with autism spectrum disorder (ASD), the effectiveness of treatments for seizures has not been well studied in individuals with ASD. This manuscript reviews both traditional and novel treatments for seizures associated with ASD. Studies were selected by systematically searching major electronic databases

Despite the fact that seizures are commonly associated with autism spectrum disorder (ASD), the effectiveness of treatments for seizures has not been well studied in individuals with ASD. This manuscript reviews both traditional and novel treatments for seizures associated with ASD. Studies were selected by systematically searching major electronic databases and by a panel of experts that treat ASD individuals. Only a few anti-epileptic drugs (AEDs) have undergone carefully controlled trials in ASD, but these trials examined outcomes other than seizures. Several lines of evidence point to valproate, lamotrigine, and levetiracetam as the most effective and tolerable AEDs for individuals with ASD. Limited evidence supports the use of traditional non-AED treatments, such as the ketogenic and modified Atkins diet, multiple subpial transections, immunomodulation, and neurofeedback treatments. Although specific treatments may be more appropriate for specific genetic and metabolic syndromes associated with ASD and seizures, there are few studies which have documented the effectiveness of treatments for seizures for specific syndromes. Limited evidence supports l-carnitine, multivitamins, and N-acetyl-l-cysteine in mitochondrial disease and dysfunction, folinic acid in cerebral folate abnormalities and early treatment with vigabatrin in tuberous sclerosis complex. Finally, there is limited evidence for a number of novel treatments, particularly magnesium with pyridoxine, omega-3 fatty acids, the gluten-free casein-free diet, and low-frequency repetitive transcranial magnetic simulation. Zinc and l-carnosine are potential novel treatments supported by basic research but not clinical studies. This review demonstrates the wide variety of treatments used to treat seizures in individuals with ASD as well as the striking lack of clinical trials performed to support the use of these treatments. Additional studies concerning these treatments for controlling seizures in individuals with ASD are warranted.

ContributorsFrye, Richard E. (Author) / Rossignol, Daniel (Author) / Casanova, Manuel F. (Author) / Brown, Gregory L. (Author) / Martin, Victoria (Author) / Edelson, Stephen (Author) / Coben, Robert (Author) / Lewine, Jeffrey (Author) / Slattery, John C. (Author) / Lau, Chrystal (Author) / Hardy, Paul (Author) / Fatemi, S. Hossein (Author) / Folsom, Timothy D. (Author) / MacFabe, Derrick (Author) / Adams, James (Author) / Ira A. Fulton Schools of Engineering (Contributor)
Created2013-09-13