Ligand-induced endocytosis of receptor tyrosine kinases (RTKs) is a dynamic process governed by numerous protein-protein and protein-lipid interactions. This is a major mechanism of signal termination and is also frequently impaired in cancer. The Cbl family of ubiquitin ligases has been shown to play a key role in downregulation of RTKs, by directing their ligand-induced ubiquitination and subsequent lysosomal degradation. My thesis work has led to the identification of novel, ubiquitin-ligase independent, functions of Cbl in receptor endocytosis. We demonstrated that the adaptor protein CIN85 links Cbl with epidermal growth factor receptor (EGFR) internalization. The three SH3 domains of CIN85 interact with Cbl/Cbl-b in a phosphotyrosine dependent manner, whereas its proline-rich region constitutively binds endophilins, known regulators of plasma membrane invagination. The SH3 domains of CIN85 recognize an atypical proline-arginine (PxxxPR) motif present in Cbl and Cbl-b. Moreover, we showed that numerous endocytic regulatory proteins, among them ASAP1 and Dab2, interact with CIN85 via their PxxxPR motifs. The SH3 domains of CIN85 are able to cluster and exchange its effectors at subsequent stages of EGFR endocytosis, thus participating in the control of receptor internalization, recycling and degradation in the lysosome. We proposed that CIN85 functions as a scaffold molecule implicated in control of multiple steps in downregulation of RTKs. Furthermore, we identified two novel Cbl- and ubiquitin-interacting adaptor proteins named Sts-1 and Sts-2 (Suppressors of T-cell receptor signaling). Ligand-induced and Cbl-mediated recruitment of Sts-1/Sts-2 into activated EGFR complexes led to inhibition of receptor internalization and subsequent block of receptor degradation followed by prolonged mitogenic signaling pathways. Our results indicate that Sts-1 and Sts-2 represent a new class of negative regulators of Cbl functions in receptor endocytosis. In conclusion, this thesis describes novel mechanisms by which Cbl, coupled to its effectors, orchestrates trafficking of RTKs. Detailed understanding of how these processes are controlled under physiological as well as under pathological conditions may be important for future therapeutic approaches.

Vertebrate development requires that cell proliferation be properly coordinated with morphogenesis, the process by which an embryo acquires form, and cell specification, the process by which unique cellular characteristics arise. My work has focused on the investigation of specific genetic networks that we have found to be involved in the regulation of cell proliferation during zebrafish (Danio rerio) development. We have identified two genes, wee1 and lmo4b, that are involved in two distinct, proliferative regulatory mechanisms during development. My work demonstrates that wee1 is required for the progression of the cell cycle after the midblastula transition (MBT). Loss of wee1 abolishes a temporally acquired G2/M checkpoint resulting in widespread cell death. We also found that the wee1-dependent G2/M checkpoint is required for a developmentally programmed deceleration of the cell cycle. In addition, my work shows that lmo4b functions in a spatial manner by restricting the expression of the neural proliferative transcription factor, six3. Loss of lmo4b results in the expansion of neural tissue at the expense of non-neural tissue through the deregulation of six3. This work highlights two cell cycle regulatory mechanisms, wee1 and lmo4b, involved in the zebrafish developmental program that are necessary for proper morphogenesis and cell specification. My analysis of wee1 indicates that temporal maintenance of the G2/M phase transition is the focal point of cell cycle regulation during gastrulation. Following gastrulation, the expression of spatially restricted genes, such as lmo4b, is required to modulate the G1/S phase transition. This research assists in the establishment of a model for cell cycle regulation during zebrafish development.

<p>Due to its nature and function, the lungs are confronted with the unique challenge of rapidly eliminating inhaled pathogens and particulates while limiting inflammatory responses. A disruption in this immune homeostasis may result in respiratory inflammatory diseases, such as allergies or asthma. The alveolar epithelial type II cell and its secretory product, surfactant protein A (SP-A), have been linked to roles in adaptive immunity in the lung. The discovery that type II cells constitutively express major histocompatibility complex class II (MHC II) suggested that type II cells may function to present antigen to T cells. Studies in vitro demonstrated that SP-A inhibits the maturation of bone marrow-derived dendritic cells. The goal of this work was to determine how type II cells and SP-A may be functioning to regulate adaptive immunity in the lungs. The hypothesis tested is that type II cells and SP-A suppress the activity of T cells and dendritic cells in the lungs. As T cells and dendritic cells are critical for the initiation and function of the adaptive immune response, the inhibition of T cell and dendritic cell activity would limit inflammation in the lungs. Although isolated murine type II cells expressed MHC II, they did not express detectable levels of the costimulatory molecules CD80 and CD86 and were poor activators of T cells. Upregulation of MHC II on type II cells by interferon-gamma stimulation did not enhance the ability of type II cells to activate T cells. Instead, the type II cells suppressed T cells from subsequent activation to antigen in an antigen-dependent manner, indicative of tolerance. T cells pre-incubated with type II cells and antigen were suppressed from further activation, even after removal of the type II cells. Using a model of pulmonary infection with Mycoplasma pneumoniae, wildtype mice were found to have fewer mature dendritic cells in the mediastinal lymph nodes than SP-A null mice. The presence of SP-A in the wild-type mice had a suppressive effect on the M. pneumoniae-induced maturation of dendritic cells in the lungs. Together, the data demonstrate that type II cells and SP-A participate in the adaptive immune response by suppressing the activity of T cells and dendritic cells in the lungs.</p> / Dissertation

<p>Organophosphates (OPs) are developmental neurotoxicants but also produce lasting effects on metabolism. This dissertation examines the cellular mechanisms underlying metabolic dysfunction after early-life OP exposure. We administered diazinon (DZN) or parathion (PRT) to rats on postnatal days (PN) 1-4 at doses straddling the threshold for cholinesterase inhibition and assessed the longitudinal effects on hepatic and cardiac cell function mediated through the adenylyl cyclase (AC) signaling cascade, which controls neuronal and hormonal inputs that regulate hepatic glucose metabolism and cardiac contractility. Specifically, we investigated if outcomes of metabolic dysfunction are related to hepatic AC dysregulation. In the liver, DZN elicited parallel upregulation of AC activity itself and of the responses to AC stimulants acting at beta-adrenergic receptors (BARs), glucagon receptors, or G-proteins. The effects intensified from adolescence to adulthood. In contrast, PRT elicited upregulation in adolescence that waned by adulthood. Effects on the liver were more substantial than those in the heart and a brain region (cerebellum) that shares similar AC cascade responses. These findings indicate that OPs produce lasting hepatic AC gain-of-function and alter the trajectory of hepatic cell signaling in a manner consistent with the observed emergence of prediabetes-like metabolic dysfunction. Since the effects are unrelated to cholinesterase inhibition, the various OPs differ in their net impact on AC signaling.</p> <p>We then examined whether OPs directly affect the expression or function of AC signaling elements, using PC12 cells to evaluate effects on transcription of AC pathway genes and on protein function. Whereas different OPs had disparate effects on gene transcription, they had nearly identical effects at the protein level, suggesting that programming occurs post-transcriptionally. We further found that otherwise unrelated developmental toxicants (OPs, dieldrin, nickel) can nevertheless converge on similar outcomes for their impact on the AC pathway, providing a common pathway by which diverse agents can lead to metabolic dysfunction.</p> <p>The standard view of OPs as developmental toxicants that exclusively target the nervous system requires substantial revision. Through their effects on hepatic cell signaling and other metabolic processes, early-life chemical exposures may play an important role in the worldwide increase in obesity and diabetes.</p> / Dissertation

The competitions of communication systems are more drastic with the advance and implement of 3G communication systems. Because 3G communication systems can support many serves, it is necessary to provide communication quality. We will discuss the W-CDMA of 3G communication systems in this paper, and research the modify method for cell search on the environment of mutipath or muticell. Because the cell search will be affected by the communication channel, it will produce the error of received signals, long cell search time and low working efficient. Thus, we propose an interference cancellation in the original system. The proposed system can strengthen the received signal and cancel the interference of signals. It also can reduce the cell search time and accelerate the searching speed.

In this work, we studied the blends of metallic nanoparticle and polymers as a donor/acceptor bulk heterojunction active layer. The mobility of the free charge carriers in thin polymer films is lower, so we blended Pd nanoparticles (Pd NPs) into polymers to improve carrier mobility, and enhance the power conversion efficiency of the polymer solar cell. P3HT was used as a donor material because of its high stability and with high absorption in visible light. PCBM was used as a acceptor material because of its high stability and with high electron transportation. We blended nanoparticles that include different size (5nm and 20nm) and different metal (Pd and Pt) and blended into the P3HT:PCBM active layer, with the device configurations of ITO/PEDOT:PSS/P3HT:PCBM: Pt NPs/Al. Polymer solar cells measured was under AM 1.5G 100mW/cm2 illumination. When we blended Pd NPs and Pt NPs into the active layer, the power conversion efficiency increased from 2.43% to 2.78%. We will study dispersion and characteristic of different size nanoparticles in the active layer.

Thesis (Ph.D.)--University of California, San Francisco, 2009. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3264. Adviser: Renee A. Reijo Pera.

Thesis (Ph.D.)--University of California, San Francisco, 2009. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3265. Adviser: Ronald D. Vale.

Thesis (Ph.D.)--Indiana University, Dept. of Biology, 2009. / Title from PDF t.p. (viewed on Feb. 8, 2010). Source: Dissertation Abstracts International, Volume: 70-05, Section: B, page: 2653. Adviser: James D. Bever.

Thesis (Ph.D.)--University of California, San Francisco, 2009. / Source: Dissertation Abstracts International, Volume: 70-04, Section: B, page: 2016. Adviser: Kevan M. Shokat.