Meiosis is a specialized form of cell division where chromosomes are duplicated once and segregated twice, in order to reduce the chromosome number by half to generate haploid gametes. In contrast to mitosis, oocyte meiosis in many species occurs in the absence of centrosomes, the microtubule organizing centers that nucleate...
Short interfering RNAs (siRNAs) and microRNAs (miRNAs) are both processed from longer, double-stranded RNA (dsRNA) presursors by a member of the Dicer (Dcr) family of proteins. siRNAs generally arise from perfectly base-paired dsRNAs, whereas miRNAs are excised from 60-70 nt pre-miRNA hairpins containing multiple bulges and mismatches within the duplexed...
Pain normally subserves a vital role in the survival of the organism by prompting the avoidance of situations associated with tissue damage. However, the sensation of pain can become dissociated from its normal physiological role when the pain-sensing nervous system becomes hypersensitive, a condition known as neuropathic pain. Currently available...
Previous research has shown that creative insight problem-solving is distinct from systematic analytical problem-solving. Behaviorally, a positive mood has shown to facilitate insights but without knowing the processes that are fundamental to insight, the mechanisms as to how a positive mood facilitates insights have remained unspecified. Here, we investigate the...
TGF-β has been named the molecular Jekyll and Hyde of cancer due to its ability to both suppress and promote tumor development. Components of the TGF-β signaling pathway are often mutated in cancer to inhibit the tumor suppressor roles of TGF-β. Our lab studies how a 3-alanine deletion in the...
The studies in this thesis are directed towards defining the signaling mechanisms that regulate astrogliosis after SCI and towards developing potential therapeutic techniques for modifying this process. The central hypothesis is that alteration of the extracellular milieu after SCI can limit the deleterious effects of glial scar formation and enhance...
Latent membrane protein 2A (LMP2A) and LMP2B are viral proteins expressed during Epstein-Barr virus (EBV) latency in EBV-infected B cells both in cell culture and in vivo. Although Lyn has been shown to be important in mediating LMP2A signaling, it is still unclear if Lyn is used preferentially or if...
Herpes simplex virus (HSV) infection of host cells requires virus attachment to the cell surface and subsequent membrane fusion between the virus envelope and host cell membrane to deliver the nucleocapsid containing the viral genome into the host cell. A proposed mechanism for HSV glycoprotein-induced membrane fusion is gD binding...
A pyramidal neuron receives thousands of inputs spread throughout its dendritic tree, which it must integrate into a decision about whether or not to fire action-potential output. Since action potentials are the primary means by which these neurons communicate with their network partners, understanding this input-output relationship is critical for...
Synapses in the central nervous system vary widely in how they transmit and store information. The properties of short-term and long-term plasticity, in particular, seem to be specific for each class of synapse studied. The types of plasticity expressed at a particular synapse determine how it processes, transmits and possibly...
PilD is an enzyme that processes prepilins that are part of the type II protein secretion apparatus and the type IV piliation machinery. Using a <em>Legionella pneumophila pilDlacZ</em> fusion strain to measure transcription, we observed a 20% increase in beta-galactosidase levels at 30°C vs. 37°C. At 25°C and 17°C vs....
Epstein Barr Virus (EBV) is associated with malignancies of lymphoid and epithelial origin. While the precise role of EBV in oncogenesis remains elusive, latent membrane protein 2A (LMP2A) is detected in all EBV-associated malignancies, implicating LMP2A in their pathogenesis. Interestingly, LMP2A is expressed in EBV-associated malignancies such as Burkitt's Lymphoma,...
Many ion channels are localized in specific subcellular domain of the neurons, and the proper localization is critical for the function of ion channels. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (h channels) are asymmetrically distributed in the CA1 pyramidal neurons, enriched in the distal apical dendrites. H current, generated by h...
The growth cone is a highly specialized motile structure with a distinctive and dynamically variable morphology. Current understanding of actin-based protrusive motility has been formulated in terms of the dendritic nucleation/array treadmilling model for lamellipodial protrusion and the convergent-elongation model for filopodial protrusion, that were based upon results obtained primarily...
HspB2 was discovered as a chaperone of muscular dystrophy protein kinase (DMPK) and originally named, DMPK binding protein (MKBP) and presently called HspB2. Functionally, MKBP binds to DMPK and stabilizes its kinase activity, thereby accelerating the progression of muscular dystrophy. Although other binding partners of HspB2 have been found, the...
A comprehensive understanding of how image processing occurs in the primary visual cortex (V1) requires learning what aspects of neuronal responses are driven by strong feed-forward input from the lateral geniculate nucleus (LGN), and what aspects arise due to the densely recurrent network operating within the cortex itself. From an...
Activin, a member of the TGF-b superfamily, controls a variety of physiological events from the cell cycle to reproductive health. Activin activates the Smad signaling pathway through ActRII/B and ALK4 receptors. The regulation of activin signaling is carried out in part by the inhibitor protein follistatin. The mechanistic details of...
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...
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...
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 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...
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...
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...
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...
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,...
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,...
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...
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 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...
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...
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...
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...
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...
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...
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...
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...
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...