Matching Items (43)
Description
Rewired biological pathways and/or rewired microRNA (miRNA)-mRNA interactions might also influence the activity of biological pathways. Here, rewired biological pathways is defined as differential (rewiring) effect of genes on the topology of biological pathways between controls and cases. Similarly, rewired miRNA-mRNA interactions are defined as the differential (rewiring) effects of miRNAs on the topology of biological pathways between controls and cases. In the dissertation, it is discussed that how rewired biological pathways (Chapter 1) and/or rewired miRNA-mRNA interactions (Chapter 2) aberrantly influence the activity of biological pathways and their association with disease.
This dissertation proposes two PageRank-based analytical methods, Pathways of Topological Rank Analysis (PoTRA) and miR2Pathway, discussed in Chapter 1 and Chapter 2, respectively. PoTRA focuses on detecting pathways with an altered number of hub genes in corresponding pathways between two phenotypes. The basis for PoTRA is that the loss of connectivity is a common topological trait of cancer networks, as well as the prior knowledge that a normal biological network is a scale-free network whose degree distribution follows a power law where a small number of nodes are hubs and a large number of nodes are non-hubs. However, from normal to cancer, the process of the network losing connectivity might be the process of disrupting the scale-free structure of the network, namely, the number of hub genes might be altered in cancer compared to that in normal samples. Hence, it is hypothesized that if the number of hub genes is different in a pathway between normal and cancer, this pathway might be involved in cancer. MiR2Pathway focuses on quantifying the differential effects of miRNAs on the activity of a biological pathway when miRNA-mRNA connections are altered from normal to disease and rank disease risk of rewired miRNA-mediated biological pathways. This dissertation explores how rewired gene-gene interactions and rewired miRNA-mRNA interactions lead to aberrant activity of biological pathways, and rank pathways for their disease risk. The two methods proposed here can be used to complement existing genomics analysis methods to facilitate the study of biological mechanisms behind disease at the systems-level.
This dissertation proposes two PageRank-based analytical methods, Pathways of Topological Rank Analysis (PoTRA) and miR2Pathway, discussed in Chapter 1 and Chapter 2, respectively. PoTRA focuses on detecting pathways with an altered number of hub genes in corresponding pathways between two phenotypes. The basis for PoTRA is that the loss of connectivity is a common topological trait of cancer networks, as well as the prior knowledge that a normal biological network is a scale-free network whose degree distribution follows a power law where a small number of nodes are hubs and a large number of nodes are non-hubs. However, from normal to cancer, the process of the network losing connectivity might be the process of disrupting the scale-free structure of the network, namely, the number of hub genes might be altered in cancer compared to that in normal samples. Hence, it is hypothesized that if the number of hub genes is different in a pathway between normal and cancer, this pathway might be involved in cancer. MiR2Pathway focuses on quantifying the differential effects of miRNAs on the activity of a biological pathway when miRNA-mRNA connections are altered from normal to disease and rank disease risk of rewired miRNA-mediated biological pathways. This dissertation explores how rewired gene-gene interactions and rewired miRNA-mRNA interactions lead to aberrant activity of biological pathways, and rank pathways for their disease risk. The two methods proposed here can be used to complement existing genomics analysis methods to facilitate the study of biological mechanisms behind disease at the systems-level.
ContributorsLi, Chaoxing (Author) / Dinu, Valentin (Thesis advisor) / Kuang, Yang (Thesis advisor) / Liu, Li (Committee member) / Wang, Xiao (Committee member) / Arizona State University (Publisher)
Created2017
Description
Childhood Apraxia of Speech (CAS) is a severe motor speech disorder that is difficult to diagnose as there is currently no gold-standard measurement to differentiate between CAS and other speech disorders. In the present study, we investigate underlying biomarkers associated with CAS in addition to enhanced phenotyping through behavioral testing. Cortical electrophysiological measures were utilized to investigate differences in neural activation in response to native and non-native vowel contrasts between children with CAS and typically developing peers. Genetic analysis included full exome sequencing of a child with CAS and his unaffected parents in order to uncover underlying genetic variation that may be causal to the child’s severely impaired speech and language. Enhanced phenotyping was completed through extensive behavioral testing, including speech, language, reading, spelling, phonological awareness, gross/fine motor, and oral and hand motor tasks. Results from cortical electrophysiological measures are consistent with previous evidence of a heightened neural response to non-native sounds in CAS, potentially indicating over specified phonological representations in this population. Results of exome sequencing suggest multiple genetic variations contributing to the severely affected phenotype in the child and provide further evidence of heterogeneous genomic pathways associated with CAS. Finally, results of behavioral testing demonstrate significant impairments evident across tasks in CAS, suggesting underlying sequential processing deficits in multiple domains. Overall, these results have the potential to delineate functional pathways from genetic variations to the brain to observable behavioral phenotypes and motivate the development of preventative and targeted treatment approaches.
ContributorsVose, Caitlin (Author) / Peter, Beate (Thesis advisor) / Liu, Li (Committee member) / Brewer, Gene (Committee member) / Arizona State University (Publisher)
Created2018
Description
Circular RNAs (circRNAs) are a class of endogenous, non-coding RNAs that are formed when exons back-splice to each other and represent a new area of transcriptomics research. Numerous RNA sequencing (RNAseq) studies since 2012 have revealed that circRNAs are pervasively expressed in eukaryotes, especially in the mammalian brain. While their functional role and impact remains to be clarified, circRNAs have been found to regulate micro-RNAs (miRNAs) as well as parental gene transcription and may thus have key roles in transcriptional regulation. Although circRNAs have continued to gain attention, our understanding of their expression in a cell-, tissue- , and brain region-specific context remains limited. Further, computational algorithms produce varied results in terms of what circRNAs are detected. This thesis aims to advance current knowledge of circRNA expression in a region specific context focusing on the human brain, as well as address computational challenges.
The overarching goal of my research unfolds over three aims: (i) evaluating circRNAs and their predicted impact on transcriptional regulatory networks in cell-specific RNAseq data; (ii) developing a novel solution for de novo detection of full length circRNAs as well as in silico validation of selected circRNA junctions using assembly; and (iii) application of these assembly based detection and validation workflows, and integrating existing tools, to systematically identify and characterize circRNAs in functionally distinct human brain regions. To this end, I have developed novel bioinformatics workflows that are applicable to non-polyA selected RNAseq datasets and can be used to characterize circRNA expression across various sample types and diseases. Further, I establish a reference dataset of circRNA expression profiles and regulatory networks in a brain region-specific manner. This resource along with existing databases such as circBase will be invaluable in advancing circRNA research as well as improving our understanding of their role in transcriptional regulation and various neurological conditions.
The overarching goal of my research unfolds over three aims: (i) evaluating circRNAs and their predicted impact on transcriptional regulatory networks in cell-specific RNAseq data; (ii) developing a novel solution for de novo detection of full length circRNAs as well as in silico validation of selected circRNA junctions using assembly; and (iii) application of these assembly based detection and validation workflows, and integrating existing tools, to systematically identify and characterize circRNAs in functionally distinct human brain regions. To this end, I have developed novel bioinformatics workflows that are applicable to non-polyA selected RNAseq datasets and can be used to characterize circRNA expression across various sample types and diseases. Further, I establish a reference dataset of circRNA expression profiles and regulatory networks in a brain region-specific manner. This resource along with existing databases such as circBase will be invaluable in advancing circRNA research as well as improving our understanding of their role in transcriptional regulation and various neurological conditions.
ContributorsSekar, Shobana (Author) / Liang, Winnie S (Thesis advisor) / Dinu, Valentin (Thesis advisor) / Craig, David (Committee member) / Liu, Li (Committee member) / Arizona State University (Publisher)
Created2018
Description
22q11.2 Deletion Syndrome (22q11.2DS) is one of the most frequent chromosomal microdeletion syndromes in humans. This case study focuses on the language and reading profile of a female adult with 22q11.2 Deletion Syndrome who was undiagnosed until the age of 27 years old. To comprehensively describe the participant's profile, a series of assessment measures was administered in the speech, language, cognition, reading, and motor domains. Understanding how 22q11.2DS has impacted the life of a recently diagnosed adult will provide insight into how to best facilitate long-term language and educational support for this population and inform future research.
ContributorsPhilp, Jennifer Lynn (Author) / Scherer, Nancy (Thesis director) / Peter, Beate (Committee member) / Department of Speech and Hearing Science (Contributor) / Sanford School of Social and Family Dynamics (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Simulation theory states that text comprehension is achieved by simulating (or imagining) text content using motor, perceptual, and emotional systems. Hence, motor skill should correlate with comprehension skill. In fact, previous research has linked fine motor skills (FMS) with word processing and mathematical skills. I predicted a positive relationship between FMS and reading comprehension. Children enrolled in a reading comprehension intervention were assessed on FMS using the Movement ABC-2. There was a significant correlation between FMS and comprehension of narrative texts, but contrary to the prediction, the correlation was negative. Also unexpected, the control condition performed better on comprehension questions than the intervention conditions. To try to understand these results, we examined the time each child took to answer the comprehension questions. Many children answered the questions quickly, and average time to answer the questions was strongly correlated with comprehension scores. Children may have been answering questions quickly (and randomly) in order to advance to the next story. Nonetheless, the data do not support a relationship between FMS and reading comprehension.
ContributorsWeiss, Julia (Author) / Glenberg, Arthur (Thesis director) / Gomez Franco, Ligia (Committee member) / Peter, Beate (Committee member) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2018-12
Description
Phylogenetic analyses that were conducted in the past didn't have the ability or functionality to inform and implement useful public health decisions while using clustering. Models can be constructed to conduct any further analyses for the result of meaningful data to be used in the future of public health informatics. A phylogenetic tree is considered one of the best ways for researchers to visualize and analyze the evolutionary history of a certain virus. The focus of this study was to research HIV phylodynamic and phylogenetic methods. This involved identifying the fast growing HIV transmission clusters and rates for certain risk groups in the US. In order to achieve these results an HIV database was required to retrieve real-time data for implementation, alignment software for multiple sequence alignment, Bayesian analysis software for the development and manipulation of models, and graphical tools for visualizing the output from the models created. This study began by conducting a literature review on HIV phylogeographies and phylodynamics. Sequence data was then obtained from a sequence database to be run in a multiple alignment software. The sequence that was obtained was unaligned which is why the alignment was required. Once the alignment was performed, the same file was loaded into a Bayesian analysis software for model creation of a phylogenetic tree. When the model was created, the tree was edited in a tree visualization software for the user to easily interpret. From this study the output of the tree resulted the way it did, due to a distant homology or the mixing of certain parameters. For a further continuation of this study, it would be interesting to use the same aligned sequence and use different model parameter selections for the initial creation of the model to see how the output changes. This is because one small change for the model parameter could greatly affect the output of the phylogenetic tree.
ContributorsNandan, Meghana (Author) / Scotch, Matthew (Thesis director) / Liu, Li (Committee member) / Biomedical Informatics Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
The purpose of this project was to investigate the hypothesis that adults with dyslexia tend to have lower accuracies in and take longer to process tasks involving the serial order of letters, compared to age and gender-matched controls. In Experiment 1, participants evaluated word pairs for differences. Half of the word pairs that they evaluated were the same, whereas the remaining word pairs differed along specific parameters such as sequential rearrangements ("left" vs "felt"), left/right reversals ("cob" vs "cod"), up/down reversals ("best" vs "pest"), homophones ("grown" vs "groan"), visual letter similarities ("tight" vs "fight"), and generic substitutions ("moan" vs "loan"). The response times and accuracies of both groups were recorded. In Experiment 2, the participants spelled single words to dictation using the spelling subtest from the Wechsler Individual Achievement Test\u2014II. Spelling errors were evaluated for errors such as sequential rearrangements, left/right reversals, homophones, substitutions, orthographic violations, omissions, and insertions. An example of a spelling error is the word "excitement" misspelled as "excietment", which involves a sequential rearrangement error. Another example is the word "apparently" misspelled as "aparently,", which involves an error of omission. Error frequencies within these error types for both groups were recorded. Experiment 3 evaluated whether left/right reversal errors during the letter-naming Rapid Automatized Naming and Rapid Alternating Stimulus (RAN/RAS) task were associated with left/right errors during word pair comparison and spelling and whether these visual reversal errors were also associated with errors of serial order. The group with dyslexia was split into two groups: group 1 included participants who did not make any left/right reversals during the RAN/RAS task and group 2 included participants who did make left/right reversals during the RAN/RAS task. The accuracies and reaction times of these three groups during the comparison and spelling assessments were recorded. The results of experiment 1 revealed that that adults with dyslexia had a significantly higher reaction time and lower accuracy during the sequential rearrangement and left/right reversal conditions. Experiment 2 demonstrated that the group with dyslexia made significantly more spelling errors during the homophone and omission conditions. The results of Experiment 3 showed associations between the sequential rearrangement and left/right conditions in both the word pair comparison and spelling task for participants with dyslexia who made left/right reversals during the RAN/RAS task. Overall, the participants with dyslexia who made left/right reversals during the RAN/RAS task seemed to have greater difficulty understanding the orientation of letters that occur on a horizontal plane, since this underlying pattern of errors was also seen throughout the spelling and word comparison tasks. These results show that left/right reversals and errors of serial order are evident in some, but not all adults with dyslexia. These errors may also characterize a distinct subtype of dyslexia. Further, errors of left/right reversal and serial order appear to be associated, so left/right reversals may represent a special form of serial order error that involves a change in the order of visual processing in the horizontal but not vertical axis of letter orientation.
ContributorsAlbert, Andria (Author) / Peter, Beate (Thesis director) / Gray, Shelley (Committee member) / School of International Letters and Cultures (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-12
Description
Cancer is the second leading cause of death in the United States. Cancer is a serious, complex disease which causes cells to grow uncontrollably, causing millions of deaths per year [1]. Cancer is usually caused by a combination of environmental variables and biological pathways. The pathways have a very robust structure normally, but are altered because of cancer, resulting in a loss of connectivity between pathways. In order detect these pathways, a PageRank-based method called Pathways of Topological Rank Analysis (PoTRA) was created, which measures the relative rankings of the genes in each pathway. Applying this algorithm will allow us to figure out what pathways differed significantly in areas with cancer and areas without cancer. This would allow scientists to focus on specific pathways in order to learn more about the cancer and find more effective ways to treat it. So far, analysis using PoTRA has been successfully conducted on hepatocellular carcinoma (HCC) and its subtypes, resulting in all significant pathways found being cancer-associated. Now, using the TCGA data stored in Google Cloud's BigQuery, we created a pipeline to apply PoTRA to other cancer data sets and see how well it cross-applies to other cancers. The results show that even though some modification may need to be made to adapt to other datasets, many significant pathways were found for both HCC and breast cancer.
ContributorsMahesh, Sunny Nishant (Author) / Valentin, Dinu (Thesis director) / Liu, Li (Committee member) / Computer Science and Engineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
The International Dyslexia Association defines dyslexia as a learning disorder that is characterized by poor spelling, decoding, and word recognition abilities. There is still no known cause of dyslexia, although it is a very common disability that affects 1 in 10 people. Previous fMRI and MRI research in dyslexia has explored the neural correlations of hemispheric lateralization and phonemic awareness in dyslexia. The present study investigated the underlying neurobiology of five adults with dyslexia compared to age- and sex-matched control subjects using structural and functional magnetic resonance imaging. All subjects completed a large battery of behavioral tasks as part of a larger study and underwent functional and structural MRI acquisition. This data was collected and preprocessed at the University of Washington. Analyses focused on examining the neural correlates of hemispheric lateralization, letter reversal mistakes, reduced processing speed, and phonemic awareness. There were no significant findings of hemispheric differences between subjects with dyslexia and controls. The subject making the largest amount of letter reversal errors had deactivation in their cerebellum during the fMRI language task. Cerebellar white matter volume and surface area of the premotor cortex was the largest in the individual with the slowest reaction time to tapping. Phonemic decoding efficiency had a high correlation with neural activation in the primary motor cortex during the fMRI motor task (r=0.6). Findings from the present study suggest that brain regions utilized during motor control, such as the cerebellum, premotor cortex, and primary motor cortex, may have a larger role in dyslexia then previously considered. Future studies are needed to further distinguish the role of the cerebellum and other motor regions in relation to motor control and language processing deficits related to dyslexia.
ContributorsHoulihan, Chloe Carissa Prince (Author) / Rogalsky, Corianne (Thesis director) / Peter, Beate (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Music is part of cultures all over the world and is entrenched in our daily lives, and yet little is known about the neural pathways responsible for how we perceive music. The property of "dissonance" is central to our understanding of the emotional meaning in music, and this study is a preliminary step in understanding how this property of music is perceived. Twenty-four participants with normal hearing listened to melodies and ranked their degrees of dissonance. Melodies that are categorized as "dissonant" according to Western music theory were ranked as more "dissonant" to a significant degree across the 9 conditions (3 conditions of scale: Major, Neapolitan Minor, and Oriental; 3 conditions of wrong notes: no wrong notes, diatonic wrong notes, and non-diatonic wrong notes). As expected, the familiar Major scale was identified as more consonant across all wrong note conditions than the other scales. Notably, a significant interaction was found, with diatonic and non-diatonic notes not perceived differently in both of the unfamiliar scales, Neapolitan and Oriental. This study suggests that the context of musical scale does influence how we create expectations of music and perceive dissonance. Future studies are necessary to understand the mechanisms by which scales drive these expectations.
ContributorsBlumenstein, Nicole Rose (Author) / Rogalsky, Corianne (Thesis director) / Peter, Beate (Committee member) / FitzPatrick, Carole (Committee member) / School of Music (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12