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Molecular Phylogeny Of Microhylid Frogs (Anura: Microhylidae) With Emphasis On Relationships Among New World Genera, Rafael O. De Sá, Jeffrey W. Streicher, Relebohile Sekonyela, Mauricio C. Forlani, Simon P. Loader, Eli Greenbaum, Stephen Richards, Célio F.B. Haddad

Biology Faculty Publications

Background: Over the last ten years we have seen great efforts focused on revising amphibian systematics. Phylogenetic reconstructions derived from DNA sequence data have played a central role in these revisionary studies but have typically under-sampled the diverse frog family Microhylidae. Here, we present a detailed phylogenetic study focused on expanding previous hypotheses of relationships within this cosmopolitan family. Specifically, we placed an emphasis on assessing relationships among New World genera and those taxa with uncertain phylogenetic affinities (i.e., incertae sedis).

Results: One mitochondrial and three nuclear genes (about 2.8 kb) were sequenced to assess phylogenetic relationships. We utilized an …

Genetic Analysis Of The Hippo Pathway In Mouse Liver, Li Lu

Dissertations and Theses (Open Access)

Cancer therapy and tumor treatment remain unsolved puzzles. Genetic screening for tumor suppressor genes in Drosophila revealed the Hippo-signaling pathway as a kinase cascade consisting of five core components. Disrupting the pathway by deleting the main component genes breaks the balance of cell proliferation and apoptosis and results in epithelial tissue tumorigenesis. The pathway is therefore believed to be a tumor suppressor pathway. However, a corresponding role in mammals is yet to be determined. Our lab began to investigate the tumor suppression function of the potent mammalian Hippo pathway by putting floxed alleles into the mouse genome flanking the functional-domain-expressing …

Fibulin-2 Stabilizes Tumor Extracellular Matrix And Drives Malignant Progression Of Lung Adenocarcinoma, Brandi N. Baird

Dissertations and Theses (Open Access)

The ECM of epithelial carcinomas undergoes structural remodeling during periods of uncontrolled growth, creating regional heterogeneity and torsional stress. How tumors maintain ECM integrity in the face of dynamic biophysical forces is still largely unclear. This study addresses these deficiencies using mouse models of human lung adenocarcinoma. Spontaneous lung tumors were marked by disorganized basement membranes, dense collagen networks, and increased tissue stiffness. Metastasis-prone lung adenocarcinoma cells secreted fibulin-2 (Fbln2), a matrix glycoprotein involved in ECM supra-molecular assembly. Fibulin-2 depletion in tumor cells decreased the intra-tumoral abundance of matrix metalloproteinases and reduced collagen cross-linking and tumor compressive properties resulting in …

Post-Transcriptional Regulation Of Mammalian Gene Expression In Non-Coding Region Of Target Rna, Jing Lin

Dissertations and Theses (Open Access)

Tumor Suppressor Candidate 2 (TUSC2) is a novel tumor suppressor gene located in the human chromosome 3p21.3 region. TUSC2 mRNA transcripts could be detected on Northern blots in both normal lung and some lung cancer cell lines, but no endogenous TUSC2 protein could be detected in a majority of lung cancer cell lines. Mechanisms regulating TUSC2 protein expression and its inactivation in primary lung cancer cells are largely unknown. We investigated the role of the 5’- and 3’-untranslated regions (UTRs) of the TUSC2 gene in the regulation of TUSC2 protein expression. We found that two small upstream open-reading frames (uORFs) …

Mutations In Stat3 Associated With Human Hyper Ige Syndrome Enhance Nfκb And Mapk-Mediated Gene Expression, Nathaniel Greeley

Dissertations and Theses (Open Access)

Hyper IgE syndrome (HIES) is a multisystem disorder resulting in bone and immune system abnormalities. It is associated with mutations in STAT3, which disrupt protein domains responsible for transcriptional function. Patients with HIES display osteoporosis and enhanced inflammatory cytokine production similar to hematopoietic Stat3-deficient mice. Since osteoclast and inflammatory cytokine genes are NFκB targets, these observations indicate a possible deregulation of NFκB signaling in both mice and humans with STAT3-deficiency. Here, we sought to examine the role of STAT3 in the regulation of NFκB-mediated gene expression through analysis of three HIES STAT3 point mutations in both hematopoietic and non- hematopoietic …

Fancm And Faap24 Maintain Genomic Stability Through Cooperative And Unique Functions, Yucai Wang

Dissertations and Theses (Open Access)

Fanconi anemia (FA) is a rare recessive genetic disease with an array of clinical manifestations including multiple congenital abnormalities, progressive bone marrow failure and profound cancer susceptibility. A hallmark of cells derived from FA patients is hypersensitivity to DNA interstrand crosslinking agents such as mitomycin C (MMC) and cisplatin, suggesting that FA- and FA-associated proteins play important roles in protecting cells from DNA interstrand crosslink (ICL) damage. Two genes involved in the FA pathway, FANCM and FAAP24, are of particular interest because they contain DNA interacting domains. However, there are no definitive patient mutations for these two genes, and the …

Development And Characterization Of Novel Ras Inhibitors, Lakiesha Debose

Dissertations and Theses (Open Access)

Ras genes are mutated in 15% of human cancers. Ras GTPases operate as molecular switches regulating cellular processes including proliferation, differentiation, and apoptosis. The three main isoforms of Ras – H-Ras, K-Ras, and N-Ras – inhabit distinct nanodomains of the plasma membrane and intracellular compartments including the Golgi. However, the role of single endogenous Ras isoforms on these compartments remains unclear as most studies have utilized ectopically expressed and mutant forms of Ras proteins. In an effort to develop novel tools that will allow us to abrogate individual endogenous Ras isoforms, we targeted the catalytic domain of p120RasGAP to the …

Anti-Tumor Effects Of The Notch Pathway In Gastrointestinal Stromal Tumors, Amaury G. Dumont

Dissertations and Theses (Open Access)

Gastrointestinal Stromal Tumors (GIST) are sarcomas driven by gain-of-function mutations of KIT or PDGFRA. Although, the introduction of tyrosine kinase inhibitors has dramatically changed the history of this disease, evidences emerge that inhibition of KIT or PDGFRA are not sufficient to cure patients. The developmental pathway Notch has a critical role in the cell fate, regulating cell proliferation and differentiation. Dysregulation of Notch pathway has been implicated in a wide variety of cancers functioning as a tumor promoter or a tumor suppressor in a cell context dependent manner.

Given that Notch activation deregulates the morphogenesis of mesenchymal cells in …

Differential Activity Of The Kras Oncogene By Method Of Activation: Implications For Signaling And Therapeutic Intervention, Nathan Ihle

Dissertations and Theses (Open Access)

Despite having been identified over thirty years ago and definitively established as having a critical role in driving tumor growth and predicting for resistance to therapy, the KRAS oncogene remains a target in cancer for which there is no effective treatment. KRas is activated b y mutations at a few sites, primarily amino acid substitutions at codon 12 which promote a constitutively active state. I have found that different amino acid substitutions at codon 12 can activate different KRas downstream signaling pathways, determine clonogenic growth potential and determine patient response to molecularly targeted therapies. Computer modeling of the KRas structure …

The Role Of The Arched Helicases In Exosome-Mediated Function, A. Alejandra Klauer

Dissertations and Theses (Open Access)

RNA processing and degradation are two important functions that control gene expression and promote RNA fidelity in the cell. A major ribonuclease complex, called the exosome, is involved in both of these processes. The exosome is composed of ten essential proteins with only one catalytically active subunit, called Rrp44. While the same ten essential subunits make up both the nuclear and cytoplasmic exosome, there are nuclear and cytoplasmic exosome cofactors that promote specific exosome functions in each of the cell compartments. To date, it is unclear how the exosome distinguishes between RNA substrates. We hypothesize that compartment specific cofactors may …

Trim24-Regulated Estrogen Response Is Dependent On Specific Histone Modifications In Breast Cancer Cells, Teresa T. Yiu

Dissertations and Theses (Open Access)

In this dissertation, I discovered that function of TRIM24 as a co-activator

of ERα-mediated transcriptional activation is dependent on specific histone

modifications in tumorigenic human breast cancer-derived MCF7 cells. In the first

part, I proved that TRIM24-PHD finger domain, which recognizes unmethylated

histone H3 lysine K4 (H3K4me0), is critical for ERα-regulated transcription.

Therefore, when LSD1-mediated demethylation of H3K4 is inhibited, activation of

TRIM24-regulated ERα target genes is greatly impaired. Importantly, I

demonstrated that TRIM24 and LSD1 are cyclically recruited to estrogen

responsive elements (EREs) in a time-dependent manner upon estrogen

induction, and depletion of their expression exert corresponding time-dependent

effect …

Regulation Of The Heat Shock Response By Thiol-Reactive Compounds In The Yeast Saccharomyces Cerevisiae, Yanyu Wang

Dissertations and Theses (Open Access)

Cells govern their activities and modulate their interactions with the environment to achieve homeostasis. The heat shock response (HSR) is one of the most well studied fundamental cellular responses to environmental and physiological challenges, resulting in rapid synthesis of heat shock proteins (HSPs), which serve to protect cellular constituents from the deleterious effects of stress. In addition to its role in cytoprotection, the HSR also influences lifespan and is associated with a variety of human diseases including cancer, aging and neurodegenerative disorders. In most eukaryotes, the HSR is primarily mediated by the highly conserved transcription factor HSF1, which recognizes target …

Cellular Uptake Of Neutrohpil Elastase Links Inflammation To Adaptive Immunity, Elizabeth A. Mittendorf

Dissertations and Theses (Open Access)

Many tumors arise from sites of inflammation providing evidence that innate immunity is a critical component in the development and progression of cancer. Neutrophils are primary mediators of the innate immune response. Upon activation, an important function of neutrophils is release of an assortment of proteins from their granules including the serine protease neutrophil elastase (NE). The effect of NE on cancer has been attributed primarily to its ability to degrade the extracellular matrix thereby promoting invasion and metastasis. Recently, it was shown that NE could be taken up by lung cancer cells leading to degradation of insulin receptor substrate-1 …

Characterization Of A Novel Role For The To Usled- Like Kinase In Kinetochore Assembly And Function In Caenorhabditis Elegans, Jessica M. De Orbeta

Dissertations and Theses (Open Access)

Chromosome segregation is a critical step during cell division to avoid aneuploidy and promote proper organismal development. Correct sister chromatid positioning and separation during mitosis helps to achieve faithful transmission of genetic material to daughter cells. This prevents improper chromosome partitioning that can potentially result in extrachromosomal fragments, increasing the tumorigenic potential of the cells. The kinetochore is a protenaicious structure responsible for the initiation and orchestration of chromosome movement during mitosis. This highly conserved structure among eukaryotes is required for chromosome attachment to the mitotic spindle and failure to assemble the kinetochore results in aberrant chromosome segregation. Thus elucidating …

Evaluation Of Polymer Gel Dosimeters For Measurements Of Dose And Let In Proton Beams, Kevin M. Vredevoogd

Dissertations and Theses (Open Access)

This project assessed the effectiveness of polymer gel dosimeters as tools for measuring the dose deposited by and LET of a proton beam. A total of three BANG® dosimeter formulations were evaluated: BANG®-3-Pro-2 BANGkits™ for dose measurement and two BANG®-3 variants, the LET-Baseline and LET-Meter dosimeters, for LET measurement. All dosimeters were read out using an OCT scanner. The basic characteristics of the BANGkits™ were assessed in a series of photon and electron irradiations. The dose-response relationship was found to be sigmoidal with a threshold for response of approximately 15 cGy. The active region of the dosimeter, the volume in …

Characterization Of Selective Inhibition Of Adenylyl Cyclase Activity By Small Molecule Inhibitor Nky80, Cameron S. Brand

Dissertations and Theses (Open Access)

The nine membrane-bound isoforms of adenylyl cyclase (AC), via synthesis of the signaling molecule cyclic AMP (cAMP), are involved in many isoform specific physiological functions. Decreasing AC5 activity has been shown to have potential therapeutic benefit, including reduced stress on the heart, pain relief, and attenuation of morphine dependence and withdrawal behaviors. However, AC structure is well conserved, and there are currently no isoform selective AC inhibitors in clinical use.

P-site inhibitors inhibit AC directly at the catalytic site, but with an uncompetitive or noncompetitive mechanism. Due to this mechanism and nanomolar potency in cell-free systems, attempts at ligand-based drug …

Tet1: A Unique Dna Demethylase For Maintenance Of Dna Methylation Pattern, Chunlei Jin

Dissertations and Theses (Open Access)

DNA methylation at the C5 position of cytosine (5-methylcytosine, 5mC) is a crucial epigenetic modification of the genome and has been implicated in numerous cellular processes in mammals, including embryonic development, transcription, X chromosome inactivation, genomic imprinting and chromatin structure. Like histone modifications, DNA methylation is also dynamic and reversible. However, in contrast to well defined DNA methyltransferases, the enzymes responsible for erasing DNA methylation still remain to be studied. The ten-eleven translocation family proteins (TET1/2/3) were recently identified as Fe(II)/2-oxoglutarate (2OG)-dependent 5mC dioxygenases, which consecutively convert 5mC into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine and 5-carboxylcytosine both in vitro and in mammalian …

Homology Cloning, Heterologous Expression And Characterization Of A New Channelrhodopsin, Sing-Yi Hou

Dissertations and Theses (Open Access)

Channelrhodopsins are phototaxis receptors in the plasma membranes of motile unicellular algae. They function as light-gated cation channels and this channel activity has been exploited to trigger action potentials in neurons with light to control neural circuits (“optogenetics"). Four channelrhodopsins were identified in two algal species, Chlamydomonas reinhardtii and Volvox carteri, with known genome sequences; each species contains 2 channelrhodopsins, one absorbing at longer wavelengths and one at shorter wavelengths, named CrChR1 and CrChR2, respectively. Our goals are to expand knowledge of channelrhodopsin mechanisms and also to identify new channelrhodopsins from various algal species with improved properties …

Development Of A Beam-Specific Planning Target Volume And A Robust Plan Analysis To Ol For Proton Therapy, Peter Park

Dissertations and Theses (Open Access)

Proton therapy is growing increasingly popular due to its superior dose characteristics compared to conventional photon therapy. Protons travel a finite range in the patient body and stop, thereby delivering no dose beyond their range. However, because the range of a proton beam is heavily dependent on the tissue density along its beam path, uncertainties in patient setup position and inherent range calculation can degrade thedose distribution significantly. Despite these challenges that are unique to proton therapy, current management of the uncertainties during treatment planning of proton therapy has been similar to that of conventional photon therapy. The goal of …

Immunological Mechanisms Of Extracorporeal Photopheresis In Cutaneous T Cell Lymphoma And Graft Versus Host Disease, Lisa Shiue

Dissertations and Theses (Open Access)

IMMUNOLOGICAL MECHANISMS OF EXTRACORPOREAL PHOTOPHERESIS IN CUTANEOUS T CELL LYMPHOMA AND GRAFT VERSUS HOST DISEASE

Publication No.___________

Lisa Harn-Ging Shiue, B.S.

Supervisory Professor: Madeleine Duvic, M.D.

Extracorporeal photopheresis (ECP) is an effective, low-risk immunomodulating therapy for leukemic cutaneous T cell lymphoma (L-CTCL) and graft versus host disease (GVHD), but whether the mechanism(s) of action in these two diseases is (are) identical or different is unclear. To determine the effects of ECP in vivo, we studied regulatory T cells (T-regs), cytotoxic T lymphocytes (CTLs), and dendritic cells (DCs) by immunofluorescence flow cytometry in 18 L-CTCL and 11 GVHD patients before …

Intraspecific Density Dependence And A Guild Of Consumers Coexisting On One Resource, Mark A. Mcpeek

Dartmouth Scholarship

The importance of negative intraspecific density dependence to promoting species coexistence in a community is well accepted. However, such mechanisms are typically omitted from more explicit models of community dynamics. Here I analyze a variation of the Rosenzweig-MacArthur consumer–resource model that includes negative intraspecific density dependence for consumers to explore its effect on the coexistence of multiple consumers feeding on a single resource. This analysis demonstrates that a guild of multiple consumers can easily coexist on a single resource if each limits its own abundance to some degree, and stronger intraspecific density dependence permits a wider variety of consumers to …

Chapter 11: Genome-Wide Association Studies, William S. Bush, Jason H. Moore

Dartmouth Scholarship

Genome-wide association studies (GWAS) have evolved over the last ten years into a powerful tool for investigating the genetic architecture of human disease. In this work, we review the key concepts underlying GWAS, including the architecture of common diseases, the structure of common human genetic variation, technologies for capturing genetic information, study designs, and the statistical methods used for data analysis. We also look forward to the future beyond GWAS.

Novel Electron Shuttling Compounds, Ramasubramanian Neeraja

All Theses

Electron mediator's usage in remediation technologies might be an excellent alternative to increase the rate of transformation of various contaminants such as nitroamine, polyhalogenated compounds and many others. Employing electron shuttles open up different pathways for the contaminant transformation and the reaction goes to completion at a much faster rate. Anthraquinone-2,6-disulfonate (AQDS) has been known to be a model electron shuttle with good shuttling capacity followed by humic acids. But the necessity for identifying electron shuttles suitable for field applications is important. As remediation technologies will command application of the shuttles on a large scale, tracing shuttles which are cheap, …

The Effects Of Low Dose Ionizing Radiation Exposure On The Metabolic And Mechanical Properties Of Articular Cartilage, Carl Lindburg

All Theses

Radiation therapy is necessary treatment for many cancer patients due to its non-surgical, yet aggressive and efficacious properties. In fact, over 50% of patients with cancer will undergo some form of radiotherapy during the course of their treatment. While the biological response to ionizing radiation has been examined over the years and many adverse effects have been identified, the effects of radiation on mature cartilage and musculoskeletal tissues are not well understood. Bone, once thought to be a tissue relatively resistant to radiation, has recently been shown to have osteoporosis-like bone atrophy after exposure to low doses (2 Gy) of …

Study On Corrosion Activity Of Carbon Steel In Concrete Simulated Pore Solution Under Static Tensile And Compressive Stresses, Yujie Zhang

All Theses

Reinforced concrete is a structure material made up of concrete with relatively lower tensile strength containing reinforcements with higher tensile strength and better ductility, which are embedded into fresh concrete to resist tensile stress in certain regions of concrete. Steel reinforced concrete is most widely used around the world in civil engineering structures, water conservancy and highway construction due to its durability strength and reasonable cost.
However, reinforced concrete structures such as bridges and parking lots slabs inevitably experience variable loads and constant degradation from the aggressive environments, such as marine and deicing salts. Therefore, it is imperative to study …

Examination Of The Effectiveness Of Bioretention Cells And Porous Paving Practices In Aiken, Sc, Casey Johnson

All Theses

This work seeks to quantify the impact and effectiveness of green infrastructure practices, specifically bioretention cells and porous asphalts, for the reduction of peak flow and volume of stormwater that discharges into the headwaters of the Sand River watershed in Aiken, SC. Stormwater runoff flows and volumes were monitored in the upper Sand River watershed that includes the urban Aiken area, along with two nested subwatersheds, prior to, during, and after the construction of the bioretention cells and porous asphalt sites. Flow data from these monitoring stations were analyzed and the data suggested that there was no significant reduction in …

Stranger Of The House: The Evolution Of Sensation's New Man, Laura Mogel

All Theses

While Elaine Showalter argues that the 'crisis in masculinity' occurs with the emergence of the New Woman and the fin de sicle, this thesis suggests that men, specifically here wealthy men, were in crisis long before these phenomena due to their dissolved understanding of their place and position amidst immense changes in Victorian England. An interrogation of 1860s sensation fiction, and specifically Wilkie Collins's Basil and Mary Elizabeth Braddon's Lady Audley's Secret, suggests that men grappled with their position and masculinity prior to the fin de sicle as evidenced by the heroine-prescribed social deaths of Basil and George Talboys. After …

To Kill A Vampire?: Through The Hearth, Charlsie Lamos

All Theses

Long before Dracula was terrorizing English families, Emily Brontë's Heathcliff captivated Victorian audiences. Critics such as James Twitchell propose that Emily Brontë carefully creates the possibility of Heathcliff as a metaphorical vampire, using his unknown parentage and his physical descriptions throughout the novel as evidence for this claim. Indeed, my thesis examines how Heathcliff exhibits characteristics of the vampire in his decimation of the English families in the novel by consuming the Earnshaw's and Linton's properties, monies, and women. In Brontë's and Bram Stoker's novels, the vampires prey upon humanity, consuming property, lives, and bloodlines. However, although vampires are often …

Preliminary Investigation Into The Design Of Thermally Responsive Forster Resonance Energy Transfer Colloids, Monte Bedford

All Theses

While nuclear imaging techniques (Magnetic Resonance Imaging, Computed Tomography, and Positron Emission Tomography) have proven effective for diagnosis and treatment of disease in the human body, fluorescence-enhanced optical imaging offers additional benefits. Fluorescent imaging provides high resolution with real-time response, persistent lifetime (hours to days), cell targeting, and transdermal penetration with minimal physical encumbrance. Malignant cells can be targeted by absorbance of exogenous fluorescent nanoprobe contrast agents. Imaging is improved by fluorescent enhancement, especially by energy transfer between attached dyes. Also for use against cancer are heat-active treatments, such as hyperthermal, photothermal, and chemothermal therapies. Helpful to these treatments is …

Study Of Cell Viability During Laser Direct Writing Of Cell-Alginate Suspension, Hemanth Gudapati

All Theses

Laser-assisted cell printing, developed based on Matrix-assisted pulsed-laser evaporation direct-write (MAPLE DW), a typical LIFT (laser-induced forward transfer) practice, has been emerging as one of the most promising biofabrication techniques. Alginate, particularly sodium alginate, is extensively used as the constituent of bioink in laser-assisted cell printing. However, thus far, studies investigating the effect of alginate gelation on cell viability in laser-assisted cell printing are lacking. The objective of this study is to investigate the effects of gelation, gelation time, sodium alginate concentration, and the effect of operating conditions such as the laser fluence on post-transfer cell viability during laser-assisted cell …