E2F-2 is a Retinoblastoma (Rb)-regulated transcription factor induced during terminal erythroid maturation. Cyclin E-mediated Rb hyper-phosphorylation induces E2F transcriptional activator functions. E2F-2-loss causes reduced peripheral red blood cell (RBC) counts, without altering relative abundances of erythroblast subpopulations. To determine how E2F-2 regulates RBC production, we comprehensively studied erythropoiesis using knockout...
Understanding the nature of quantum effects in dense biological systems is of great interestto many scientists today. It seems that the question is not does quantum mechanics dictatebiological processes, but rather by how much and to what extent. A big challenge though in thisfield is how to properly test and...
The formation of neuronal inclusions is one of the hallmarks of neurodegenerative diseases. These structures are composed of aggregated proteins, molecular chaperones, and components of the ubiquitin-proteasome system (UPS). Co-localization of aggregated proteins with cell-homeostasis maintaining machinery indicates that the cell may be failing in an attempt to clear these...
In the process of development of a multicellular organism, cells must make stable, binary fate decisions in response to intercellular signaling. A critical question is how weak or transient activation of signaling pathways achieves a robust and long-term switch in gene expression, and thus determines cell fate. I report that...
CD4-positive T cells express ligands for E- and P-selectins, carbohydrate-binding adhesion molecules that are induced on inflamed endothelium. The interaction between selectins and the selectin ligands facilitates the migration of T cells to sites of inflammation. The fucosyltransferase FucT-VII is essential for selectin ligand formation but the signaling and transcriptional...
Reactivation of latent human cytomegalovirus is of significant concern in immunocompromised transplant patients. However, the mechanisms controlling reactivation of latent CMV have not been understood. It is likely that reactivation is initiated by induction of IE gene expression. In this thesis, I studied molecular mechanisms leading to transcriptional activation of...
Arsenic trioxide (As<sub>2</sub>0<sub>3</sub>) is an arsenic-derivative that exhibits potent growth inhibitory effects against malignant cells. The remarkable antitumor effects of As<sub>2</sub>0<sub>3</sub> in vitro and in vivo have prompted the development of various clinical trials that established its activity in acute promyelocytic leukemia (APL). As<sub>2</sub>0<sub>3</sub> is part of the standard treatment...
Most women diagnosed with epithelial ovarian carcinoma (EOC) initially present with metastases, but little is known about the regulation of ovarian tumor cell dissemination by the tumor microenvironment. Because ovarian cancer cell dissemination is mostly limited to the peritoneal cavity and often results in the accumulation of malignant ascites, the...
The goal of this study was to investigate the properties of the retinal ganglion cell receptive field at low light levels. There has been considerable interest in whether the surround of a ganglion cell receptive field disappears and the center expands in size under scotopic conditions. The previous data from...
The goal of this dissertation was to examine the influence of motivational incentives on visual spatial attention in patients with probable Alzheimer's Disease (PRAD), patients with mild cognitive impairment (MCI) and healthy age-matched control subjects (EC). Specifically, I compared the ability of monetary incentives to influence behavioral and neural performance...
The primary function of the human urinary bladder is to store urine, while maintaining a permeability barrier that protects underlying tissues from noxious urinary components. Inflammatory diseases of the bladder, including urinary tract infection (UTI) and interstitial cystitis (IC), afflict millions of patients in the US annually and cause significant...
RNA interference (RNAi) is a newly discovered gene control pathway that silences gene expression in response to double-stranded RNA. This sequence-specific downregulation occurs at the level of mRNA stability, and is directed by the double-stranded RNA trigger itself. RNAi can be separated into two distinct steps; during the initiation phase,...
Epstein-Barr virus (EBV) is a human gamma-herpesvirus that primarily infects B cells and epithelial cells. While the glycoproteins required for entry into these two cell types differ, the gH/gL glycoprotein complex is essential for entry into both epithelial and B cells. Analysis of gH protein sequences from three gamma-herpesviruses: EBV,...
The ubiquitin-proteasome system degrades regulatory proteins and thereby controls a broad range of cellular processes such as the cell cycle, DNA-repair, gene transcription and signal transduction. The proteasome typically degrades its substrates completely into small peptides. However, biological exceptions do occur. For example, the activity of a handful of transcriptional...
A comprehensive understanding of human memory requires both cognitive and neural descriptions of memory processes along with a conception of how memory processing drives behavioral responses and subjective experiences. Noninvasive neuroimaging techniques have greatly extended our understanding of the functional characteristics of human memory, and how neural events give rise...
Hypoxia is a reduction in the normal level of oxygen tension and occurs during acute and chronic vascular disease, pulmonary disease, and cancer. The key transcription factor that regulates the cellular responses to hypoxia is hypoxia-inducible-factor-1 (HIF-1). Understanding how HIF-1 is regulated is fundamental for understanding the biology of tumor...
The extracellular matrix (ECM) is an environment rich in structural and signaling molecules, including growth factors and cytokines. Together, these signals are capable of changing cellular morphology and gene expression in response to extracellular environmental cues. Structural proteins in the ECM such as laminin transduce their signals through integrin receptors...
Initial studies described the ability of CD4+CD25+ T regulatory (Treg) cells in suppressing autoimmune diseases in animal models. An emerging interest has focused on the potential role of Treg cells in cancer development and progression as they have been shown to suppress anti-tumor immunity. In the present study, CD4+CD25- T...
The response to reduced levels of oxygen (hypoxia) is essential for embryonic development by promoting the proper formation of vascular networks. Conversely, hypoxia also promotes the development of pathophysiological processes such as pulmonary hypertension and cancer. The main mediator of responses to hypoxia within the cell is the transcription factor...
Gonadotropin releasing hormone (GnRH) neurons comprise the final pathway through which the central nervous system exerts its control over the hypothalamic-pituitary-gonadal (HPG) axis. GnRH is released in a pulsatile manner, and conveyed to the anterior pituitary gland to stimulate synthesis and secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating...