Cell and Developmental Biology Commons^™

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 …

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 …

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 …

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 …

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 …

Expansion Of Human Induced Pluripotent Stem Cells On Synthetic Substrate In Defined Medium, Huantong Yao

Graduate Theses and Dissertations

Human induced pluripotent stem cells (hiPSCs) have the potential to generate patient-specific cells to treat many incurable diseases by cell replacement therapy. However, so far the culture of hiPSCs depends greatly on feeder cells or Matrigel which has safety issues. Thus, chemically defined substrates that could provide niches necessary for cell attachment and proliferation are preferred for clinical application of hiPSCs. Recently, Corning Life Sciences has developed synthetic peptide-functionalized cell culture surface, referred to as Corning® Synthemax that support self-renewal and differentiation of human embryonic stem cell (hESC). In this work, we have collaborated with Corning to investigate the attachment, …

Reactive Oxygen Species Mediated Dna Damage In Human Lung Alveolar Epithelial (A549) Cells From Exposure To Non-Cytotoxic Mfi-Type Zeolite Nanoparticles, Kunal Bhattacharya, Pratap Naha, Izabela Naydenova, Svetlana Mintova, Hugh Byrne

Articles

Increasing utilization of engineered nanoparticles in the field of electronics and biomedical applications demands an assessment of risk associated with deliberate or accidental exposure. Metal based nanoparticles are potentially most important of all the nanoparticles in terms of health risks. Microporousalumino-silicates and pure silicates named as zeolites and zeo-type materials with variety of structures, chemical compositions, particle sizes and morphologies have a significant number of industrial uses such as in catalysis, sorption and ion-exchange processes. In particular, the nanosized particles due to their unique properties are used in hybrid organic-inorganic materials for photography, photonics, electronics, labeling, imaging, and sensing. The …

Glutaredoxin 2 (Grx2) Knockout Increases Sensitivity To Oxidative Stress In Mouse Lens Epithelial Cells, Hongli Wu, Liren Lin, Frank Giblin, Ye-Sheh Ho, Marjorie F. Lou

School of Veterinary and Biomedical Sciences: Faculty Publications

Glutaredoxin belongs to the oxidoreductase family with cytosolic glutaredoxin 1 (Grx1) and mitochondrial gluraredoxin 2 (Grx2) isoforms. Of the two isozymes, the function of Grx2 is not well understood. This paper studied the effect of Grx2 deletion on cellular function using primary lens epithelial cell cultures isolated from Grx2 gene knockout (KO) and wild type (WT) mice. We found that both cell types showed similar growth patterns and morphology, and comparable mitochondrial glutathione pool and complex I activity. Cells with deleted Grx2 did not show affected Grx1 or thioredoxin (Trx) expression but exhibited high sensitivity to oxidative stress. Under treatment …

Phenotypic Plasticity Of Rattlesnake Trophic Morphology, Matthew Thomas Smith

Graduate Theses and Dissertations

The trophic morphology of gape-limited predators constrains the shape and size of prey items they can ingest. Trophic morphology consists of any morphological feature that is involved in the handling and ingestion of food. Diet has a profound effect on the morphology of many gape-limited predators. Identifying how prey type and resource level affect the morphology of different populations is an essential step in understanding the mechanisms contributing to patterns of morphological diversity. Species interactions (Chapter 1) induce plasticity in morphology that can lead to increased fitness, morphological divergence, and eventually speciation.

In Chapter 2, a laboratory study tested the …

The Principal Genetic Determinants For Nasopharyngeal Carcinoma In China Involve The Hla Class I Antigen Recognition Groove, Minzhong Tang, J. A. Lautenberger, Xiaojiang Gao, Efe Sezgin, Sher L. Hendrickson, Jennifer L. Troyer, Victor A. David, Li Guan, Carl Mcintosh, Xiuchan Guo, Yuming Zheng, Jian Liao, Hong Deng, Michael Malasky, Bailey Kessing, Cheryl Winkler, Mary Carrington, Guy De The, Yi Zeng, Stephen J. O'Brien

Biology Faculty Articles

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (P_{HLA-A-aa-site-62}= 7.4×10⁻²⁹; P _{HLA-B-aa-site-116}= 6.5×10⁻¹⁹; P _{HLA-C-aa-site-156} = 6.8×10 …

Blt1 And Mid1 Provide Overlapping Membrane Anchors To Position The Division Plane In Fission Yeast, Merce Guzman-Vendrell, Suzanne Baldissard, Maria Almonacid, Adeline Mayeux, Anne Paoletti, James B. Moseley

Dartmouth Scholarship

Spatial control of cytokinesis is essential for proper cell division. The molecular mechanisms that anchor the dynamic assembly and constriction of the cytokinetic ring at the plasma membrane remain unclear. In the fission yeast Schizosaccharomyces pombe, the cytokinetic ring is assembled in the cell middle from cortical node precursors that are positioned by the anillin-like protein Mid1. During mitotic entry, cortical nodes mature and then compact into a contractile ring positioned in the cell middle. The molecular link between Mid1 and medial cortical nodes remains poorly defined. Here we show that Blt1, a previously enig- matic cortical node protein, promotes …

Is Belief Larger Than Fact: Expectations, Optimism And Reality For Translational Stem Cell Research, Tania M. Bubela, Matthew D. Li, Mohamed Hafez, Mark Bieber, Harold Atkins

Office of the Provost

Background: Stem cell (SC) therapies hold remarkable promise for many diseases, but there is a significant gulf between public expectations and the reality of progress toward clinical application. Public expectations are fueled by stakeholder arguments for research and public funding, coupled with intense media coverage in an ethically charged arena. We examine media representations in light of the expanding global landscape of SC clinical trials, asking what patients may realistically expect by way of timelines for the therapeutic and curative potential of regenerative medicine?
Methods: We built 2 international datasets: (1) 3,404 clinical trials (CT) containing 'stem cell*' from ClinicalTrials.gov …

Regulation Of Sensory Neurogenesis In The Trigeminal Placode: Notch Pathway Genes, Pax3 Isoforms, And Wnt Ligands, Jason Samuel Adams

Theses and Dissertations

This dissertation is divided into three chapters, each discussing the study of different regulatory molecules involved in sensory neurogenesis occurring in the trigeminal placode. Chapter one is a spatiotemporal description of Notch pathway genes in chick opV placode by stage-specific expression analysis, showing expression of many Notch pathway genes and effectors in the opV placode. Notch pathway gene expression is primarily confined to the ectoderm with highest expression of these genes at the beginning stages of peak neuronal differentiation. This information preceded studies of the functional roles that Notch signaling has in the opV placode and how it may affect …

T-Cell Activation Is Enhanced By Targeting Il-10 Cytokine Production In Toll-Like Receptor-Stimulated Macrophages, Ryan Walk, Steven Elliott, Felix C. Blanco, Jason A. Snyder, Ashley M. Jacobi, Scott Rose, Mark Behlke, Aliasger Salem, Stanislav Vukmanovic, Anthony D. Sandler

Surgery Faculty Publications

Toll-like receptor (TLR) agonists represent potentially useful cancer vaccine adjuvants in their ability to stimulate antigen-presenting cells (APCs) and subsequently amplify the cytotoxic T-cell response. The purpose of this study was to characterize APC responses to TLR activation and to determine the subsequent effect on lymphocyte activation. We exposed murine primary bone marrow-derived macrophages to increasing concentrations of agonists to TLRs 2, 3, 4, and 9. This resulted in a dose-dependent increase in production of not only tumor necrosis factor–alpha (TNF-α), a surrogate marker of the proinflammatory response, but also interleukin 10 (IL-10), a well-described inhibitory cytokine. Importantly, IL-10 secretion …

Scribble Acts In The Drosophila Fat-Hippo Pathway To Regulate Warts Activity, Shilpi Verghese, Indrayani Waghmare, Hailey Kwon, Katelin Hanes, Madhuri Kango-Singh

Biology Faculty Publications

Epithelial cells are the major cell-type for all organs in multicellular organisms. In order to achieve correct organ size, epithelial tissues need mechanisms that limit their proliferation, and protect tissues from damage caused by defective epithelial cells. Recently, the Hippo signaling pathway has emerged as a major mechanism that orchestrates epithelial development. Hippo signaling is required for cells to stop proliferation as in the absence of Hippo signaling tissues continue to proliferate and produce overgrown organs or tumors. Studies in Drosophila have led the way in providing a framework for how Hippo alters the pattern of gene transcription in target …

Spectral Cross Correlation As A Supervised Approach For The Analysis Of Complex Raman Datasets: The Case Of Nanoparticles In Biological Cells, Mark Keating, Franck Bonnier, Hugh Byrne

Articles

Spectral Cross-correlation is introduced as a methodology to identify the presence and subcellular distribution of nanoparticles in cells. Raman microscopy is employed to spectroscopically image biological cells previously exposed to polystyrene nanoparticles, as a model for the study of nano-bio interactions. The limitations of previously deployed strategies of K-means clustering analysis and principal component analysis are discussed and a novel methodology of Spectral Cross Correlation Analysis is introduced and compared with the performance of Classical Least Squares Analysis, in both unsupervised and supervised modes. The previous study demonstrated the feasibility of using Raman spectroscopy to map cells and identify polystyrene …

Elimination Of The Vesicular Acetylcholine Transporter In The Forebrain Causes Hyperactivity And Deficits In Spatial Memory And Long-Term Potentiation, Amanda C. Martyn, Xavier De Jaeger, Ana C. Magalhaes, Rohit Kesarwani, Daniela F. Goncalves, Sanda Raulic, Monica S. Guzman, Michael F. Jackson, Ivan Izquierdo, John F. Macdonald, Marco A. M. Prado, Vania F. Prado

Anatomy and Cell Biology Publications

Basal forebrain cholinergic neurons, which innervate the hippocampus and cortex, have been implicated in many forms of cognitive function. Immunolesion-based methods in animal models have been widely used to study the role of acetylcholine (ACh) neurotransmission in these processes, with variable results. Cholinergic neurons have been shown to release both glutamate and ACh, making it difficult to deduce the specific contribution of each neurotransmitter on cognition when neurons are eliminated. Understanding the precise roles of ACh in learning and memory is critical because drugs that preserve ACh are used as treatment for cognitive deficits. It is therefore important to define …

The Cancer Stem Cell Conundrum In Multiple Myeloma, Robert G. Hawley

Anatomy and Regenerative Biology Faculty Publications

No abstract provided.

Tributyltin And Dibutyltin Alter Secretion Of Tumor Necrosis Factor Alpha From Human Natural Killer Cells And A Mixture Of T Cells And Natural Killer Cells, Kelsi Hurt, Tasia Hurd-Brown, Margaret Whalen

Chemistry Faculty Research

Butyltins (BTs) have been in widespread use. Tributyltin (TBT) has been used as a biocide in a variety of applications and is found in human blood samples. Dibutyltin (DBT) has been used as a stabilizer in polyvinyl chloride plastics and as a de-worming agent in poultry. DBT, like TBT, is found in human blood. Human natural killer (NK) cells are the earliest defense against tumors and viral infections and secrete the cytokine tumor necrosis factor-alpha (TNF-α). TNF-α is an important regulator of adaptive and innate immune responses. TNF-α promotes inflammation and an association between malignant transformation and inflammation has been …