Doctor of Philosophy

dissertationThrough the production of milk, the mammary gland provides nutritional and immunological protection for newborns. However, lactation is required for only short periods of time in the adult animal, which allows the mammary gland to develop through a series of distinct stages. During embryogenesis and puberty, the gland establishes an extensive network of epithelial ducts, which then undergo widespread branching and differentiation during pregnancy to maximize milk production. Throughout this process, the mammary gland relies on coordination of major cellular processes, including proliferation, invasion, and differentiation. As many of these pathways become aberrantly regulated during breast cancer, understanding mechanisms that regulate mammary gland development has important disease implications. Although previous studies have characterized several systemic hormones and local factors central to mammary development, little is known about the downstream mediators of these pathways. To identify new factors, we established a three-dimensional model of mammary branching morphogenesis using primary mammary epithelial cells (MECs) stimulated with fibroblast growth factor-2 (FGF2). We performed a forward chemical genetic screen to identify compounds that modulate FGF2-induced branching and discovered a novel bis-aryloxadiazole, called 1023, which completely blocks branching through activation of the aryl hydrocarbon receptor (AHR). iv Using 1023 as a molecular probe, we found AHR activation blocks mammary branching through upregulation of desmosomal adhesion. These results identified desmosomes as a novel target of AHR signaling and suggested desmosomes are downregulated to facilitate mammary branching. Supporting this hypothesis, we found desmosomes absent in the mammary glands of pregnant mice in a cell-type specific manner. These results suggest desmosomes control initiation of mammary branching, and may also be targeted during breast cancer to promote cellular invasion. We also investigated mechanisms of AHR activation and the impact of AHR on mammary differentiation. We performed a structure activity relationship study of 1023 and defined moieties of the molecule critical for AHR stimulation. Moreover, we investigated the effect of AHR on mammary differentiation and elucidated a transcriptional mechanism through which the AHR pathway directly blocks lactation in MECs. Since several environmental pollutants stimulate AHR, these studies provide mechanistic insight for how toxins impair mammary function

Design Optimization of Transistors Used for Neural Recording

Neurons cultured directly over open-gate field-effect transistors result in a hybrid device, the neuron-FET. Neuron-FET amplifier circuits reported in the literature employ the neuron-FET transducer as a current-mode device in conjunction with a transimpedance amplifier. In this configuration, the transducer does not provide any signal gain, and characterization of the transducer out of the amplification circuit is required. Furthermore, the circuit requires a complex biasing scheme that must be retuned to compensate for drift. Here we present an alternative strategy based on the design approach to optimize a single-stage common-source amplifier design. The design approach facilitates in circuit characterization of the neuron-FET and provides insight into approaches to improving the transistor process design for application as a neuron-FET transducer. Simulation data for a test case demonstrates optimization of the transistor design and significant increase in gain over a current mode implementation

Probing quark gluon plasma with jets

We study multiple scatterings of jets on constituents of quark gluon plasma and introduce energy--energy correlations to quantify their effects. The effects from a longitudinally expanding plasma on medium as well as high energy jets are found to be significant at both RHIC and LHC energies. Because jets escape from the plasma long before the completion of mixed phase, these effects are free from complications of final state hadronic interactions and decays. These suggest that jets can be used to probe the plasma that might be created in future high energy heavy ion collisions.Comment: 15 pages, 6 figures in 5 ps files included, McGill/94-1

Math and Coding Connections in Elementary

In this session, participants learn ways to use coding tools in elementary classrooms to provide engaging and motivating contexts for students to develop and use mathematical and computational reasoning. Integrating technology to support mathematics learning in meaningful ways is often challenging, and discussions in this session will emphasize the synergies among technology, coding, and mathematics for supporting skills with coding tools

A Precision Calculation of the Next-to-Leading Order Energy-Energy Correlation Function

The O(alpha_s^2) contribution to the Energy-Energy Correlation function (EEC) of e+e- -> hadrons is calculated to high precision and the results are shown to be larger than previously reported. The consistency with the leading logarithm approximation and the accurate cancellation of infrared singularities exhibited by the new calculation suggest that it is reliable. We offer evidence that the source of the disagreement with previous results lies in the regulation of double singularities.Comment: 6 pages, uuencoded LaTeX and one eps figure appended Complete paper as PostScript file (125 kB) available at: http://www.phys.washington.edu/~clay/eecpaper1/paper.htm

Graphene as Transparent Electrode for Direct Observation of Hole Photoemission from Silicon to Oxide

The outstanding electrical and optical properties of graphene make it an excellent alternative as a transparent electrode. Here we demonstrate the application of graphene as collector material in internal photoemission (IPE) spectroscopy; enabling the direct observation of both electron and hole injections at a Si/Al2O3 interface and successfully overcoming the long-standing difficulty of detecting holes injected from a semiconductor emitter in IPE measurements. The observed electron and hole barrier heights are 3.5 eV and 4.1 eV, respectively. Thus the bandgap of Al2O3 can be further deduced to be 6.5 eV, in close agreement with the valued obtained by vacuum ultraviolet spectroscopic ellipsometry analysis. The detailed optical modeling of a graphene/Al2O3/Si stack reveals that by using graphene in IPE measurements the carrier injection from the emitter is significantly enhanced and the contribution of carrier injection from the collector electrode is minimal. The method can be readily extended to various IPE test structures for a complete band alignment analysis and interface characterization.Comment: 15 pages, 5 figure

Chemical imaging of single catalyst particles with scanning μ-XANES-CT and μ-XRF-CT

The physicochemical state of a catalyst is a key factor in determining both activity and selectivity; however these materials are often not structurally or compositionally homogeneous. Here we report on the 3-dimensional imaging of an industrial catalyst, Mo-promoted colloidal Pt supported on carbon. The distribution of both the active Pt species and Mo promoter have been mapped over a single particle of catalyst using microfocus X-ray fluorescence computed tomography. X-ray absorption near edge spectroscopy (XANES) and extended X-ray absorption fine structure revealed a mixed local coordination environment, including the presence of both metallic Pt clusters and Pt chloride species, but also no direct interaction between the catalyst and Mo promoter. We also report on the benefits of scanning μ-XANES computed tomography for chemical imaging, allowing for 2- and 3-dimensional mapping of the local electronic and geometric environment, in this instance for both the Pt catalyst and Mo promoter throughout the catalyst particle

Cancer Cell-Extrinsic Roles for the Androgen Receptor in Prostate Cancer

Given the central role of the androgen receptor (AR) in prostate cancer cell biology, AR-targeted therapies have been the backbone of prostate cancer treatment for over 50 years. New data indicate that AR is expressed in additional cell types within the tumor microenvironment. Moreover, targeting AR for the treatment of prostate cancer has established side effects such as bone complications and an increased risk of developing cardiometabolic disease, indicating broader roles for AR. With the advent of novel technologies, such as single-cell approaches and advances in preclinical modeling, AR has been identified to have clinically significant functions in other cell types. In this mini-review, we describe new cancer cell-extrinsic roles for AR within the tumor microenvironment as well as systemic effects that collectively impact prostate cancer progression and patient outcomes