Bioinformatics Commons^™

The Role Of Parkin In Mitochondrial Dna, Eliezer Lichter

Theses & Dissertations

Mitochondria are at the center of biological phenomena such as aging and diseases, especially neurodegenerative diseases. While the discovery of mitochondria only came approximately 200 years after the cell was discovered, a lot of progress has been made since. The mitochondrial genome encodes proteins vital for mitochondrial function. These proteins are only a subset of the proteins present in mitochondria; the rest are nuclear encoded. The nucleus also encodes cytosolic proteins vital for mitochondrial maintenance. One of these is Parkin, an E3 ubiquitin ligase that ubiquitinates mitochondrial proteins as mitochondria become depolarized. Its activity has been shown to be involved …

Innate Immunity In The Pathobiology And Treatment Of Infectious And Neurodegenerative Diseases, Mai Mostafa

Theses & Dissertations

Mononuclear phagocytes (MPs; monocytes, macrophages, and dendritic cells) are the governors of innate immunity which is the body’s first line of defense against microbial pathogens. They act beneficial or detrimental. They are crucial for an effective non-specific immune response to invading pathogens by engulfing, destroying, then eliciting an adaptive specific immune response. Given their pivotal functions in the host immune defense, studying MP immune responses in disease is paramount important for understanding disease pathobiology and uncovering therapeutic strategies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the driver of acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) amongst …

Metagenome-Wide Associations And Metabolic Modeling To Predict The Biomarkers For Colorectal Cancer, Nagavardhini Avuthu

Theses & Dissertations

Colorectal cancer (CRC) is the most common malignancy and the second most common cause of cancer-related deaths in the world. It is a multifactorial disease mediated by genetic, environmental, and lifestyle factors. Over time, the accumulation of genetic and epigenetic changes results in the activation of oncogenes and deactivation of tumor suppressor genes in the colon and rectal region which finally leads to tumor development. The gut microbiome is the main factor linking the effects of diet and environmental factors to host metabolism. Several studies showed the dysbiosis of gut microbiota in CRC patients with an increased proportion of pathogenic …

Immunological Factors Associated With Siv/ Shiv Persistence In Diverse Tissue Niches, Omalla A. Olwenyi

Theses & Dissertations

The significant challenge towards a successful HIV cure lies in eradicating persistent viral reservoirs across diverse tissue niches. As a result, HIV-infected individuals have to resort to lifelong antiretroviral therapy. Recent news of supposed HIV eradication in a second patient has further re-invigorated the fields of HIV cure. However, a few barriers remain, such as the lack of currently available assays to accurately quantify viral reservoirs, limited information on cellular factors associated with persistence, and varied dynamics of the viral reservoir in various body compartments. Lastly, HIV-infected individuals live different lifestyles stemming from comorbid substance abuse including consumption of morphine, …

Integrative Analysis Of Multi-Omics Kinome Data And Virtual Screening Of Identified Targets With Pan-Cancer Application, Siddesh Southekal

Theses & Dissertations

Cancer is a heterogeneous disease characterized by the uncontrolled growth and dissemination of abnormal cells. Unfortunately, it is also challenging to treat due to the heterogeneous nature of the tumors and the lack of known drugs that are effective against all tumor subpopulations.

The human protein kinases represent an essential and diverse family of enzymes and are often dysregulated in cancer. The human kinome comprises only around 2% of all coding genes of the human genome but phosphorylates about 30% of cellular proteins critical for regulating various biological processes such as cell proliferation, cell cycle progression, apoptosis, motility, growth, differentiation, …

Strainiq: An N-Gram-Based Method To Identify And Quantify Microbial Communities In Metagenomic Samples, Sanjit Pandey

Theses & Dissertations

Microbes are ubiquitous in nature, and they play vital roles in various processes associated with metabolism in the human body, photosynthesis in plants, or decomposition of waste in the environment. Hence, it is essential to understand how the composition of microbial communities affects the ecosystem of different environments ranging from ocean floors to hot springs to the human body. Microbial communities present in different human body sites are of particular importance due to their implications in the cause and prevention of human diseases. The traditional approaches limit microbial research to exclusively studying species that can be successfully cultured in the …

Mucin And Splice Variant Profiles Of Pancreatic Adenocarcinoma Predict Patient Survival And Subtyping, Christopher M. Thompson

Theses & Dissertations

PDAC is a pancreatic epithelial malignancy and demonstrates aggressive progression and bleak patient prognosis. Despite decades of research, the evolution of novel diagnostics and intervention modalities for PDAC is stagnant. This dissertation explores the characteristic aberrant and elevated expression of mucins in PDAC. Beginning with the hypothesis that mucins are associated with disease aggressiveness, analysis of PDAC patient survival in TCGA revealed no associations between single mucin expression and patient survival. This led to the underlying issue of PDAC tumor cellularity since this disease demonstrates variability in the proportion of cancer cells within the tumor. Tumor purity assessed with the …

Reach, Effectiveness, Adoption, And Maintenance Of Mobile Electronic Clinical Decision Support Tools Deployed As Part Of National Quality Improvement Projects, Ellen K. Kerns

Theses & Dissertations

Electronic clinical decision support (ECDS) tools are often developed within quality improvement (QI) projects to increase adherence with the latest clinical practice guidelines. However, the potential reach and maintenance of ECDS use beyond the time and location of their associated project are very limited. Deploying ECDS using a mobile app (mECDS) has shown the potential to be a viable method of overcoming these limitations. However, it is unclear what pattern the reach and adoption of such a tool might follow and what effect this use has on clinical practice. Our team developed an app which contained two different mECDS tools …

Development Of In-Silico Pipelines For Identification And Characterization Of Biomarker Panels And Therapeutic Interventions In Gastro-Intestinal (Gi) Cancers, Pranita Atri

Theses & Dissertations

Gastro-intestinal (GI) malignancies, including gastric, colorectal, and pancreatic cancers, have maintained their high overall mortality due to a lack of prognostic and diagnostic biomarkers and potential therapeutic modalities. While efforts have been made to improve both early detection and therapeutic interventions in these cancers, failure of conventional approaches have proven to be a big challenge, and alternate approaches are needed. Computational biology approaches owing to lesser time and more per target success rate offer a unique solution here. The current study explored the use of computational biology techniques to study the various aspects relating to GI malignancies. First, we sought …

Genomic And Transcriptomic Alterations In Metabolic Regulators And Implications For Anti-Tumoral Immune Response, Ryan J. King

Theses & Dissertations

Metabolic and immune alterations are ubiquitous hallmarks of cancer that are established during the foundational mutations and are further selected upon to generate highly aggressive tumors. Recent evidence suggests that cancer cells employ an altered metabolism to induce immune evasion. To further discover the relationship between metabolism and immunity in cancer, this thesis aimed to discover potential candidates of interest by first examining the mucin family for differences, as they exert a wide range of activities in cancer, including altered metabolism and immune alterations. Unique differences lead to further profiling in pancreatic and esophageal cancer. In pancreatic cancer, CD73 was …

The Role Of The Cxcr3 Signaling Axes In Pancreatic Ductal Adenocarcinoma, Andrew C. Cannon

Theses & Dissertations

Numerous cytokines promote pancreatic ductal adenocarcinoma (PDAC) progression and suppress anti-tumor immune response leading to poor prognosis in PDAC patients. Despite this, many cytokines, have not been investigated in PDAC. Bioinformatic analyses of PDAC microarray and RNA-Seq datasets were used to identify cytokines overexpressed in PDAC, confirm the expression of cognate receptors, determine the association of cytokines with patient survival and define key underlying molecular associations. Bioinformatic findings were validated using immunohistochemical (IHC) staining, comparative cytokine qPCR-array in Kras^LSL-G12D:TP53^LSL-R172H:Pdx1-Cre (KPC) and Kras^LSL-G12D:Pdx1-Cre (KC) PDAC models and multicolor immunofluorescence staining. Tail-vein injections of PDAC cells …

The Evolving Management Of Aortic Valve Disease: Trends In The Utilization And Cost Of Savr, Tavr, And Medical Therapy, Andrew Goldsweig

Theses & Dissertations

Aortic stenosis (AS) and regurgitation (AR) may be treated with surgical aortic valve replacement (SAVR), transcatheter AVR (TAVR), or medical therapy (MT). Data are lacking regarding usage and cost of SAVR, TAVR, and MT for patients hospitalized with aortic valve disease. From the Nationwide Readmissions Database, we determined utilization and cost trends for SAVR, TAVR, and MT in patients with aortic valve disease admitted 2012-2016 for valve replacement, heart failure, unstable angina, non-ST-elevation myocardial infarction, or syncope. From 2012 through 2016, there was a 48.1% increase in the number of patients hospitalized for aortic valve disease annually. Overall, 19.9%, 6.7%, …

Red Panda: A Novel Method For Detecting Variation In Single-Cell Rna Sequencing, Adam Cornish

Theses & Dissertations

Single-cell sequencing enables the rapid acquisition of genomic and transcriptomic data from individual cells to better understand genetic diseases, such as cancer or autoimmune disorders, which are often affected by changes in rare cells. Currently, no existing software is aimed at identifying single nucleotide variations or micro (1-50bp) insertions and deletions in single-cell RNA sequencing (scRNA-seq) data. However, generating high quality data is vital to the study of the aforementioned diseases, among others. Our goal is to create such a tool and use in-house sequencing to validate its effectiveness. Our software employs the unique information found in scRNA-seq data to …

An Evaluation Of The Use Of A Clinical Research Data Warehouse And I2b2 Infrastructure To Facilitate Replication Of Research, Bret Gardner

Theses & Dissertations

Replication of clinical research is requisite for forming effective clinical decisions and guidelines. While rerunning a clinical trial may be unethical and prohibitively expensive, the adoption of EHRs and the infrastructure for distributed research networks provide access to clinical data for observational and retrospective studies. Herein I demonstrate a means of using these tools to validate existing results and extend the findings to novel populations. I describe the process of evaluating published risk models as well as local data and infrastructure to assess the replicability of the study. I use an example of a risk model unable to be replicated …

Functional Signature Ontology-Based Identification And Validation Of Novel Therapeutic Targets And Natural Products For The Treatment Of Cancer, Beth Neilsen

Theses & Dissertations

Multiple studies have revealed that Ras-driven tumors acquire vulnerabilities by adapting cellular mechanisms that promote uncontrolled proliferation and suppress apoptosis. Kinase Suppressor of Ras 1 (KSR1) modulates ERK activation downstream of oncogenic Ras, and knockdown of KSR1 selectively kills malignant, Ras-driven cancer cells, but does not kill immortalized, non-transformed human colon epithelial cells (HCECs). KSR1^-/- mice are fertile and phenotypically normal, but resistant to Ras-driven tumor formation suggesting KSR1 represents a vulnerability in cancer cells.

To identify additional vulnerabilities in cancer, a screening approach termed Functional Signature Ontology (FUSION) was used to screen 14,355 genes and 1,200 natural product …

Focus: A Graph Approach For Data-Mining And Domain-Specific Assembly Of Next Generation Sequencing Data, Julia Sommer

Theses & Dissertations

Next Generation Sequencing (NGS) has emerged as a key technology leading to revolutionary breakthroughs in numerous biomedical research areas. These technologies produce millions to billions of short DNA reads that represent a small fraction of the original target DNA sequence. These short reads contain little information individually but are produced at a high coverage of the original sequence such that many reads overlap. Overlap relationships allow for the reads to be linearly ordered and merged by computational programs called assemblers into long stretches of contiguous sequence called contigs that can be used for research applications. Although the assembly of the …

Transcriptome Profiling Of Cleft Palate Intgf-Beta3 Knockout Mice Alleles: Rna-Seq Analysis Of Tgf-Beta3 Mice, Kelsey White

Theses & Dissertations

Background: Orofacial clefts are the most common craniofacial birth defect with a complex, combinatorial etiology. Tgf-b3 regulates palatal fusion in mice; Tgf-b3 knockout mice have cleft palate (CP) lacking other major deformities. The genes downstream of Tgf-b3 during palatogenesis remain largely unexplored. Our objective was to analyze the global transcriptome changes and their contribution to CP and identify novel Tgf-b3 associated genes involved in formation of CP. We used RNA-sequencing to analyze and compare the whole transcriptome of Tgf-b3 alleles during palatal growth and fusion in mice.

Results: …

Comparative Molecular Characterization Of Typical And Exceptional Responders In Glioblastoma, Kristin Wipfler

Theses & Dissertations

Glioblastoma (GBM) is the most common and the deadliest type of primary brain tumor, with a median survival time of only 15 months despite aggressive treatment. Although most patients have an extremely poor prognosis, a small number of patients survive far beyond the median survival time. Investigation of these “exceptional responders” has sparked a great deal of interest and is becoming an important focus in the field of cancer research. To investigate the molecular differences between typical and exceptional responders in GBM, comparative analyses of copy number, methylation, gene expression, miRNA expression, and protein expression data sets from The Cancer …

Global Gene Expression Profiling Of Healthy Human Brain And Its Application In Studying Neurological Disorders, Simarjeet K. Negi

Theses & Dissertations

The human brain is the most complex structure known to mankind and one of the greatest challenges in modern biology is to understand how it is built and organized. The power of the brain arises from its variety of cells and structures, and ultimately where and when different genes are switched on and off throughout the brain tissue. In other words, brain function depends on the precise regulation of gene expression in its sub-anatomical structures. But, our understanding of the complexity and dynamics of the transcriptome of the human brain is still incomplete. To fill in the need, we designed …

Chimerscope: A Novel Alignment-Free Algorithm For Fusion Gene Prediction Using Paired-End Short Reads, You Li

Theses & Dissertations

Fusion genes are those that result from the fusion of two or more genes, and they are typically generated due to the perturbations in the genome structure in cancer cells. In turn, fusion genes can contribute to tumor formation and progression by promoting the expression of an oncogene, deregulation of a tumor-suppressor, or producing much more active abnormal proteins. More importantly, oncogenic fusion genes are specifically expressed in the tumor cells, which provide enormous diagnostic and therapeutic advantages for cancer treatment. With the development of next-generation sequencing (NGS) technology, RNA-Seq becomes increasingly popular for transcriptomic study because of its high …

Restriction Enzyme Generated Next-Generation Sequencing Libraries And Genetic Risk Modifiers Of Brca1 Mutation Carriers, Bradley Downs

Theses & Dissertations

Next-generation sequencing (NGS) is a high throughput technique used to sequence large amounts of DNA in a short amount of time. However, a limitation to NGS is that the generated data is in a single consensus sequence without distinguishing between variants on homologous chromosomes. Separating or phasing the variants from the maternal and paternal chromosomes can provide information about the genetic origin of disease and information about how DNA nucleotide alterations interact in cis. This dissertation explores a new technical method of using restriction enzymes during NGS library preparation and its ability to increase the amount of phasing information that …

The Role Of Oncogenic Kras In Initiation, Progression And Maintenance Of Pancreatic Cancer, Nirakar Rajbhandari

Theses & Dissertations

Pancreatic cancer is a lethal disease that is almost invariably associated with a KRAS gene mutation. Due to a very high frequency of gain-of-function mutations within the KRAS gene, and its proven role in initiation of pancreatic cancer in animal models, mutant KRAS is considered a rational therapeutic target. To determine the potential role of oncogenic KRAS in pancreatic tumor maintenance in vivo, we generated a mouse model with a Doxycycline regulated expression of oncogenic KRAS (KRAS^G12D) in pancreas. Using this reversible model, we demonstrated that the expression of oncogenic KRAS in a Cdkn2a deficient background was …

Classification Of Breast Cancer Patients Using Somatic Mutation Profiles And Machine Learning Approaches, Suleyman Vural

Theses & Dissertations

The high degree of heterogeneity observed in breast cancers makes it very difficult to classify cancer patients into distinct clinical subgroups and consequently limits the ability to devise effective therapeutic strategies. In this study, we explore the use of gene mutation profiles to classify, characterize and predict the subgroups of breast cancers. We analyzed the whole exome sequencing data from 358 ethnically similar breast cancer patients in The Cancer Genome Atlas (TCGA) project. Identified somatic and non-synonymous single nucleotide variants were assigned a quantitative score (C-score) that represents the extent of negative impact on the function of the gene. Using …

Functional Characterization Of The Roles Of Endocytic Recycling Regulator Ehd1 Using In Vivo And In Vitro Analyses, Priyanka Arya

Theses & Dissertations

Endocytic recycling is a fundamental cellular process that allows the precise regulation of the membrane components and receptors at the cell surface. Recent studies have established that the C-terminal Eps15 homology domain-containing (EHD) proteins function as key regulators of this process. Four highly-conserved members of the EHD protein family in mammals, EHD1-EHD4, play shared as well as unique roles in endocytic trafficking. Studies presented here demonstrate a critical role of EHD1 in the normal ocular development in mice. Ehd1 knockout mice generated in our laboratory displayed gross ocular phenotypes including the anophthalmia, microphthalmia, and congenital cataracts. Hematoxylin and eosin (H&E) …