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Full-Text Articles in Medicine and Health Sciences
Pumilio Proteins Regulate Translation In Embryonic Stem Cells And Are Essential For Early Embryonic Development, Katherine Elizabeth Uyhazi
Pumilio Proteins Regulate Translation In Embryonic Stem Cells And Are Essential For Early Embryonic Development, Katherine Elizabeth Uyhazi
Yale Medicine Thesis Digital Library
Embryonic stem (ES) cells are defined by their dual abilities to self-renew and to differentiate into any cell type in the body. This vast potential is precisely controlled by spatial and temporal gene regulation at transcriptional, post-transcriptional, and epigenetic levels. Recent studies have revealed several transcription factors that are essential for stem cell self-renewal and pluripotency, but the role of translational control in ES cells is poorly understood. Translational control is a fundamental mechanism of gene regulation during early development, and likely explains the discrepancies between the transcriptome and proteome profiles of stem cells and their differentiated progeny. Pumilio proteins …
Mature Dendritic Cells Use Endocytic Receptors To Capture And Present Antigens, Craig Daniel Platt
Mature Dendritic Cells Use Endocytic Receptors To Capture And Present Antigens, Craig Daniel Platt
Yale Medicine Thesis Digital Library
In response to inflammatory stimuli, dendritic cells (DCs) trigger maturation, a terminal differentiation program required to initiate T lymphocyte responses. A hallmark of maturation is downregulation of endocytosis, widely assumed to restrict the ability of mature DCs to capture and present antigens encountered after the initial stimulus. We found that mature DCs continue to internalize antigens, especially by receptor-mediated endocytosis and phagocytosis. These antigens were transported to lysosomal compartments, loaded onto MHCII, and presented efficiently to T cells, both in vitro and in vivo. Antigens were also presented on MHCI with high efficiency. While mature DCs down-regulate macropinocytosis, they capture …
Implementing Partially Effective Hiv Prevention Programs: Changes In Sexual Risk Behavior And Epidemic Impact In Sub-Saharan Africa, Kyeen Mesesan
Implementing Partially Effective Hiv Prevention Programs: Changes In Sexual Risk Behavior And Epidemic Impact In Sub-Saharan Africa, Kyeen Mesesan
Yale Medicine Thesis Digital Library
While there is no magic bullet that can completely prevent HIV transmission and halt the HIV/AIDS pandemic, governments and policy makers have an array of partially-effective HIV prevention programs from which to choose, including the use of existing interventions (e.g. education and condom use) and technologies under development (e.g. microbicides and vaccines). Complex decisions regarding if, when, and how to implement various programs with partial efficacy must be made, often in the absence of data on program outcomes. Additionally, the quantitative tradeoff between program-related decreases in HIV transmission and the effects of risk behavior change is often unknown. The potential …
Memory T Cells And The Endothelium In Allograft Rejection, Stephen Lawrence Shiao
Memory T Cells And The Endothelium In Allograft Rejection, Stephen Lawrence Shiao
Yale Medicine Thesis Digital Library
Organ transplantation has become increasingly important as a treatment for many human diseases. Despite the dramatic improvements in immunosuppression in recent years, acute and chronic rejection remain significant problems. It has become increasingly evident that the presence of T cell memory correlates with both acute and chronic rejection episodes. Endothelial cells (EC) have been shown to preferentially activate memory T cells and, as the lining of every transplanted organ, they are in a unique position to provide signals to alloreactive memory T cells. EC activation of memory T cells depends in part on the costimulatory molecule LFA-3 in addition to …
Biochemical And Functional Characterization Of The Tapasin/Erp57 Conjugate, David Ryan Peaper
Biochemical And Functional Characterization Of The Tapasin/Erp57 Conjugate, David Ryan Peaper
Yale Medicine Thesis Digital Library
Recognition of MHC class I/peptide complexes is required for the generation of CD8+ T cell responses. Peptide loading onto MHC class I/beta2m dimers occurs in the ER and involves both specific proteins and cellular chaperones. Tapasin is essential for peptide loading onto most MHC class I alleles, and it forms a mixed disulfide with the glycoprotein specific oxidoreductase ERp57. I have characterized the biochemical requirements for tapasin/ERp57 conjugate formation and addressed potential functions for ERp57 in peptide loading. Tapasin specifically recruits ERp57 into a mixed disulfide at the expense of free ERp57 in the ER. Other components of the MHC …
B Cells At The Interface Of Innate And Adaptive Immunity In Systemic Lupus Erythematosus: Requirements For The Activation Of Autoreactive B Cells In Autoimmune Disease, Sean Ryan Christensen
B Cells At The Interface Of Innate And Adaptive Immunity In Systemic Lupus Erythematosus: Requirements For The Activation Of Autoreactive B Cells In Autoimmune Disease, Sean Ryan Christensen
Yale Medicine Thesis Digital Library
Systemic autoimmune disease is characterized by loss of immunologic tolerance to a restricted set of self-nuclear antigens. These macromolecular complexes can be grouped into two categories: DNA-containing autoantigens such as chromatin, and RNA containing autoantigens such as Smith antigen (Sm) and related ribonucleoprotein complexes. Elucidating the mechanism for selective targeting of these molecules in systemic lupus erythematosus (SLE) may provide clues to the etiology of disease. We hypothesized that Toll-like receptors (TLRs), germline-encoded pattern-recognition receptors of the innate immune system, could dictate target antigen specificity in SLE. Using genetic ablation of various TLRs in murine models of SLE, we have …
Molecular Classification And Prediction Of Metastatic Potential In Early Malignant Melanoma: Improvement Of Prognostic Accuracy By Quantitative In Situ Proteomic Analysis, Aaron J. Berger
Yale Medicine Thesis Digital Library
The incidence of cutaneous malignant melanoma continues to increase every year, and remains the leading cause of skin cancer death in industrialized countries. In spite of the aggressive nature of advanced melanoma, there are no standard biological assays in clinical usage that can predict metastasis. This may be due, in part, to the inadequacy of reproducible assessment of protein expression using traditional immunohistochemistry. This dissertation will discuss the use of tissue microarrays combined with quantitative in situ molecular analysis of protein expression to allow prediction of melanoma metastasis. Through the identification and validation of novel prognostic biomarkers, we seek to …
Positive And Negative Modulatory Roles Of Platelet Endothelial Cell Adhesion Molecule-1 Signaling In Endothelial Cell Migration: Coordination Of Rho Signaling And Targeting Of Shp-2 Tyrosine Phosphatase Activity, Dita Gratzinger
Yale Medicine Thesis Digital Library
Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), an immunoglobulin family adhesion molecule, is involved in endothelial migration and angiogenesis. We found that PECAM-1 deficient endothelial cells exhibit enhanced nondirected single cell motility and extension formation at the expense of wound-healing migration. These in vitro endothelial behaviors model aspects of highly developmentally and pathophysiologically relevant processes. Wound healing migration may model the reendothelialization of denuded vasculature following balloon angioplasty or the remodeling of vascular endothelium under variant flow conditions, while single cell motility is prominently involved in developmental processes such as endocardial-mesenchymal transition within the cardiac cushion. A specific deficiency of RhoGTP …
The Rotational Orientation Of The T Cell Receptor Bound To Peptide: Mhc, Sangwook Tim Yoon
The Rotational Orientation Of The T Cell Receptor Bound To Peptide: Mhc, Sangwook Tim Yoon
Yale Medicine Thesis Digital Library
The T cell receptor (TCR) is the multi-chained cell surface molecule that mediates the specific recognition of antigen by the T cell. The alpha and beta chains of the TCR are members of the immunoglobulin gene superfamily and form the antigen binding components of the TCR. Although the function of alphabeta-TCRs has been well characterized, less is known about their molecular structure. Current three-dimensional structural models of TCR are based on the similarities in primary sequence between the TCR with immunoglobulin genes. Models of the ternary structure of the TCR and MHC complex have also been proposed. These models, however, …
The Regulation Of Tyrosine Phosphorylation During The Differentiation Of A Human Leukemia, David Alan Frank
The Regulation Of Tyrosine Phosphorylation During The Differentiation Of A Human Leukemia, David Alan Frank
Yale Medicine Thesis Digital Library
HL-60 promyelocytic leukemia cells are an excellent model system for studying hematopoietic differentiation. This study sought to determine how tyrosine phosphorylation and the enzymes which regulate it are controlled during HL-60 differentiation.HL-60 cells normally contain about 1.5% of their phosphoaminoacids as phosphotyrosine. Upon granulocytic differentiation, phosphotyrosine content decreases to 0.1 to 0.3% of phosphoaminoacids. HL-60 cells possess a tyrosine kinase activity located in the particulate fraction which can phosphorylate a number of tyrosine-containing substrates in a time- and temperature-dependent fashion. It has a k$\sb{\rm m}$ for ATP of about 20 uM, a pH optimum of 6.4, and a preference for …
Mitomycin C And Porfiromycin: Studies On Bioactivation And Cytotoxicity In Cultured Cell Lines, Paula Marie Fracasso
Mitomycin C And Porfiromycin: Studies On Bioactivation And Cytotoxicity In Cultured Cell Lines, Paula Marie Fracasso
Yale Medicine Thesis Digital Library
Solid neoplasms are known to contain deficient or poorly functional vascular beds and as a result populations of cells in these solid tumors may contain hypoxic or poorly oxygenated tumor cells. These hypoxic tumor cells may form a therapeutically resistant cell population within the tumor difficult to eradicate by ionizing radiation and most existing chemotherapeutic agents. As a consequence, this dissertation has investigated the mechanism of bioactivation and cytotoxicity of mitomycin C and porfiromycin, structurally similar antibiotics which are selectively cytotoxic to hypoxic cells.Mitomycin C was preferentially cytotoxic to hypoxic EMT6 and V79 cells in culture, but was not selectively …
Noradrenergic Modulation Of Lateral Geniculate Neurons: Physiological And Pharmacological Studies, Michael Andrew Rogawski
Noradrenergic Modulation Of Lateral Geniculate Neurons: Physiological And Pharmacological Studies, Michael Andrew Rogawski
Yale Medicine Thesis Digital Library
The physiological actions of norepinephrine (NE) were examined in the rat dorsal lateral geniculate nucleus (LGNd) using extracellular single cell recording and microiontophoresis. Prolonged, low current iontophoretic applications of NE consistently elicited an increase in the firing rate of LGNd neurons which was delayed in onset and prolonged after cessation of the ejection. Sympathomimetic amines other than NE also activated LGNd neurons with varying degrees of effectiveness. On the basis of the relative potencies of a series of these agonists and the ability of iontophoretically applied (alpha)-antagonists to selectively block the facilitatory action of NE, it is concluded that NE …
The Development And Characterization Of Markers For The Variable Regions Of Mouse Dnp Binding Antibodies, Jerome Bernard Zeldis
The Development And Characterization Of Markers For The Variable Regions Of Mouse Dnp Binding Antibodies, Jerome Bernard Zeldis
Yale Medicine Thesis Digital Library
No abstract provided.