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Articles 1 - 8 of 8
Full-Text Articles in Life Sciences
The Splice Is Not Right: Splice-Site-Creating Mutations In Cancer Genomes, Reyka Glencora Jayasinghe
The Splice Is Not Right: Splice-Site-Creating Mutations In Cancer Genomes, Reyka Glencora Jayasinghe
Arts & Sciences Electronic Theses and Dissertations
Accurate interpretation of cancer mutations in individual tumors is a prerequisite for precision medicine. Large-scale sequencing studies, such as The Cancer Genome Atlas (TCGA) project, have worked to address the functional consequences of genomic mutations, with the larger goal of determining the underlying mechanisms of cancer initiation and progression. Many studies have focused on characterizing non-synonymous somatic mutations that alter amino acid sequence, as well as splice disrupting mutations at splice donors and acceptors. Current annotation methods typically classify mutations as disruptors of splicing if they fall on the consensus intronic dinucleotide splice donor, GT, the splice acceptor, AG. Splice …
The Role Of Apolipoprotein E In Regulating Tau Pathogenesis And Neurodegeneration In A Tauopathy Mouse Model, Yang Shi
Arts & Sciences Electronic Theses and Dissertations
APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). APOE4 increases brain amyloid-β (Aβ) pathology relative to other APOE isoforms. However, whether APOE independently influences tau pathology, the other pathological hallmark of AD and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human APOE knock in (KI) or APOE knockout (KO) background, we show that the presence of human APOE, regardless of APOE isoforms, leads to various degrees of brain atrophy in 9-month old P301S mice, whereas APOE ablation strongly protects against neurodegeneration. In particular, P301S/E4 mice develop …
The Costs Of A Big Brain: How Region Scaling And Energetic Costs Influence Brain Size Evolution In Weakly Electric African Fishes (Mormyridae), Kimberley Varunee Sukhum
The Costs Of A Big Brain: How Region Scaling And Energetic Costs Influence Brain Size Evolution In Weakly Electric African Fishes (Mormyridae), Kimberley Varunee Sukhum
Arts & Sciences Electronic Theses and Dissertations
Brains control an organismճ ability to sense, remember, and respond to the frequently changing world. Brains are composed of multiple regions and systems, which are associated with different processes. These regions are homologous across all vertebrates yet vary greatly in size and shape across clades. While regions can function independently, they also interact extensively. These characteristics make it difficult to predict whether regions can change in size independently from other regions in response to selection (mosaic evolution hypothesis), or whether the brain evolves as a single concerted organ (concerted evolution hypothesis). Further, many traits such as cognition, behavioral flexibility, and …
The Role Of Membrane Excitability In Insulin Regulation, Christopher Howard Emfinger
The Role Of Membrane Excitability In Insulin Regulation, Christopher Howard Emfinger
Arts & Sciences Electronic Theses and Dissertations
In mammals, ATP-sensitive K+ (KATP) channels are essential regulators of insulin secretion from pancreatic islet [beta]-cells, illustrated by the finding that gain-of-function mutations in KATP channels (KATP-GOF) cause neonatal diabetes mellitus (NDM). However, variability in symptom severity and effectiveness of treatment is seen in NDM, even for those with the same mutation and in the same family. Short-term treatment of mice expressing KATP-GOF mutations in [beta]-cells (KATP-GOF mice) with the KATP blocker glibenclamide during disease onset results in two outcomes: one subset becomes severely diabetic (non-remitters), whereas the other subset remains below the glucose levels at which significant side effects …
Viral Mhc Class I Evasion Affects Anti-Viral T Cell Development And Responses, Elvin James Lauron
Viral Mhc Class I Evasion Affects Anti-Viral T Cell Development And Responses, Elvin James Lauron
Arts & Sciences Electronic Theses and Dissertations
Cytotoxic CD8+ T cells (CTLs) play a critical role in protective immunity against viruses, a fact underscored by the evolution of viral CTL evasion mechanisms. For instance, many viruses commonly target the major histocompatibility complex class I (MHCI) antigen presentation pathway to prevent CTLs from recognizing infected cells. A striking example of this is cowpox virus (CPXV), which interferes with MHCI antigen presentation through two distinct mechanisms. One mechanism of CPXV-mediated MHCI inhibition is to retain MHCI molecules in the endoplasmic reticulum (ER). The second mechanism is to prevent antigen peptide loading onto MHCI molecules. When combined these mechanisms result …
Multi-Omics Portraits Of Cancer, Kuan-Lin Huang
Multi-Omics Portraits Of Cancer, Kuan-Lin Huang
Arts & Sciences Electronic Theses and Dissertations
Precision oncology demands accurate portrayal of a disease at all molecular levels. However, current large-scale studies of omics are often isolated by data types. I have been developing computational tools to conduct integrative analyses of omics data, identifying unique molecular etiology in each tumor. Particularly, this dissertation presents the following contributions to the computational omics of cancer: (1) uncovering the predisposition landscape in 33 cancers and how germline genome collaborates with somatic alterations in oncogenesis; (2) pioneering methods to combine genomic and proteomic data to identify treatment opportunities; and (3) revealing selective phosphorylation of kinase-substrate pairs. These findings advance our …
Circadian Regulation Of Temozolomide Sensitivity In Glioblastoma, Emily A. Slat
Circadian Regulation Of Temozolomide Sensitivity In Glioblastoma, Emily A. Slat
Arts & Sciences Electronic Theses and Dissertations
The safety and efficacy of multiple cancer chemotherapeutics can vary as a function of when during the day they are delivered. This study aimed to improve the treatment of glioblastoma multiforme (GBM), the most common brain cancer, by testing the efficacy of the DNA alkylator Temozolomide (TMZ) on GBM in vitro and in vivo as a function of time of day. We found cell-intrinsic, daily rhythms in susceptibility of GBM tumor cells (mouse astrocytes deficient in NF1 and p53 signaling) to TMZ in vitro. The greatest TMZ-induced DNA damage response, activation of apoptosis and growth inhibition, occurred near the peak …
Regulation Of Epithelial Proliferation And Migration By Apical-Basal Polarity Proteins, Gregory Vincent Schimizzi
Regulation Of Epithelial Proliferation And Migration By Apical-Basal Polarity Proteins, Gregory Vincent Schimizzi
Arts & Sciences Electronic Theses and Dissertations
Epithelial cells line all the outside surfaces of the body where they perform essential roles in maintaining homeostasis. In addition, epithelial tissues are implicated in many disease processes and are the most common tissue type to give rise to human cancer. Therefore, a thorough understanding of epithelial development and homeostasis has broad implications for understanding human development, health, and disease. The establishment and maintenance of apical-basal polarity is a defining characteristic and essential feature of functioning epithelia. Proper apical-basal polarity (ABP) is required for epithelial tissues to carry out their functions, which include absorption, secretion, barrier formation, and collective migration. …