DOCSLIB.ORG

Table of Contents

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Table of Contents ROLE OF Ca2+-PERMEABLE CATION CHANNELS IN Ca2+ SIGNALLING AND NECROTIC CELL DEATH by BRIAN J. WISNOSKEY Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Department of Physiology and Biophysics CASE WESTERN RESERVE UNIVERSITY August 2004 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of ______________________________________________________ candidate for the Ph.D. degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. 1 Table of Contents Table of Contents………………………………………………………………………….1 List of Tables……………………………………………………………………………...3 List of Figures……………………………………………………………………………..4 Statistical Analysis………………………………………………………………………...6 Acknowledgements………………………………………………………………………..7 List of Abbreviations……………………………………………………………………...8 Abstract…………………………………………………………………………………..10 Chapter 1: Introduction…………………………………………………………………. 12 Figures……………………………………………………………………………………31 Chapter 2: Activation of vanilloid receptor type I (TRPV1 channel) in the endoplasmic reticulum fails to activate store-operated Ca2+ entry…………………..………………...35 Introduction………………………………………………………………………………36 Materials and Methods…………………………………………………………………...38 Results..…………………………………………………………………………………..44 Discussion………………………………………………………………………………..52 Figures……………………………………………………………………………………56 2 Chapter 3: Maitotoxin-induced changes in plasmalemmal permeability in bovine aortic endothelial cells: Divalent cation specificity and selectivity…………………………….76 Introduction……………………………………………………………………………....77 Materials and Methods…………………………………………………………………...79 Results..……………………………………………………………………………….….84 Discussion…………………………………………………………………………….….93 Tables…………………………………………………………………………………….98 Figures……………………………………………………………………………………99 Chapter 4: Summary and future directions……………………………………………..124 Summary (Chapter 2)…………………………………………………………………...125 Future directions (Chapter 2)…………………………………………………………...127 Summary (Chapter 3)…………………………………………………………………...132 Future directions (Chapter 3)…………………………………………………………...134 Figures…………………………………………………………………………………..142 Bibliography……………………………………………………………………………146 3 List of Tables Table 1. Divalent cation selectivity of known Ca2+ binding domains…………………..98 4 List of Figures Chapter 1 Fig. 1.1. Possible effect of TRPV1 on store operated Ca2+ entry……………………..…32 Fig. 1.2. The maitotoxin-induced cell death cascade in bovine aortic endothelial cells...34 Chapter 2 Fig. 2.1. Time course of TRPV1 expression in Sf9 insect cells.……………..…………57 Fig. 2.2. Concentration-response relationship for TRPV1 agonists………………….....59 Fig. 2.3. Agonist-induced release of Ca2+ from internal stores in TRPV1-expressing Sf9 cells…………………………………………………………………………………..61 Fig. 2.4. Localization of TRPV1 to the Endoplasmic Reticulum…………………….…63 Fig. 2.5. Effect of thapsigargin and RTX on Ba2+ influx in control and TRPV1- expressing Sf9 cells………………………………………………………………………65 Fig. 2.6. Effect of 2-APB on thapsigargin- and RTX-induced Ba2+ influx in TRPV1-expressing Sf9 cells……………………………………………………………..67 Fig. 2.7. Overlap of RTX- and thapsigargin-sensitive Ca2+ stores………………..…….69 Fig. 2.8. Effect of 2-APB on thapsigargin-induced Ba2+ influx in absence or presence of RTX-induced store release in TRPV1-expressing Sf9 cells………......…71 Fig. 2.9. Concentration-response relationship for TRPV1 agonists in HEK cells stably expressing TRPV1……………………………………………………….….73 Fig. 2.10. Effect of 2-APB on thapsigargin- and RTX-induced Ca2+ influx in TRPV1-expressing HEK cells…………………………………………………...……75 Chapter 3 Fig. 3.1. Effect of MTX on plasmalemmal permeability………………………...…….100 5 2+ Fig. 3.2. Effect of ionomycin on the change in [Ca ]i and EB uptake in BAECs……..102 Fig. 3.3. Effect of divalent substitution on COP activation and cell lysis…………..….104 Fig. 3.4. Comparison of Ca2+ with Sr2+……………………………………………...…106 Fig. 3.5. Effect of Ca2+ replacement by Ba2+ on the MTX concentration-response curve…………………………………………………………………………….………108 Fig. 3.6. Effect of Ca2+ replacement by Ba2+ on the MTX concentration-response curve - dose response…………………………………………………………….…..…110 2+ 2+ Fig. 3.7. Effect of BAPTA-loading on MTX-induced change in [Ca ]i and [Ba ]i and the change in the associated EB uptake…………………………………………....112 Fig. 3.8. Effect of Ca2+ readmission on COP activation and cell lysis………………....114 Fig. 3.9. Simultaneous measurement of MTX-induced GFP loss and EB uptake in single BAECs………………………………………………………………….……..116 Fig. 3.10. Effect of Ba2+ on MTX-induced cell death cascade in single BAECs. ……..119 Fig. 3.11. Composite single cell fluorescence data……………………………….……121 Fig. 3.12. Average single cell responses..………………………………………….…..123 Chapter 4 2+ 2+ Fig. 4.1. Effect of Mg on MTX-induced rise in [Ca ]i and EB uptake……….……..143 Fig. 4.2. Effect of calpeptin on loss of cell associated GFP and EB uptake …………..145 6 Statistical analysis All experiments were performed at least 3 times. Unless otherwise indicated, the lines shown are mean values from 3 independent experiments. Symbols represent mean ± SE values at selected time points. Where indicated, values were compared using the paired Student t-test with p < 0.05 considered significant. 7 Acknowledgements I would like to express my sincere gratitude to my thesis advisor Dr. William Schilling, as well all of the members of the Schilling lab: Dr. Mark Estacion, Dr. Monu Goel, Dr. William Sinkins, Milana Belich, and Jabe Best. I would also like to thank the members of the Metrohealth Rammelkamep Center research staff including Dr. Eckhard Ficker, Dr. Diana Kunze, Dr. Angelina Ramirez-Navarro, Dr. David Kline, Pat Glazebrook, Maria Buniel, Kristie Takacs, Dr. Frank Sah, and Dr. Glenn Kirsch. I appreciate the knowledge and support each of you offered me as well as your friendship throughout my education. I would also like to express my thanks to the members of my dissertation committee including Dr. Tom Egelhoff, Dr. Stephen Jones, Dr. Robert Harvey, Dr. David Friel, Dr. Maureen McEnery, Dr. Michael Romero, Dr. Eric Glende and Dr. Richard Eckert for their time and guidance during the course of my education. Finally, I would like to thank the Department of Physiology and Biophysics for the educational opportunities that they have provided me. I would like to especially thank Dr. George Dubyak (Cell Physiology program), Dr. Ulrich Hopfer (Biophysics program), as well as the department chairman, Dr. Antonio Scarpa. 8 List of Abbreviations 2-ABP, 2-aminoethoxydiphenyl borate cADPR, cyclic adenosine diphosphate ribose CaNSC, Ca2+ permeable nonselective cation channel CaMKII, Calmodulin kinase II 2+ 2+ [Ca ]i, cytosolic free Ca concentration DAG, diacylglycerol DRG, dorsal root ganglion ER, endoplasmic reticulum EB, Ethidium bromide GPCR, G-protein coupled receptor 12-HETE, 12-hydroxyeicosatetraenoic acid 12-HPETE, 12-hydroperoxy-eicosatetraenoic acid HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HBS, Hepes buffered saline 2+ ICRAC, Ca release activated current InsP3, inositol-1,4,5-trisphosphate IP3R, inositol-1,4,5-trisphosphate receptor MES, 2-[N-morpholino]ethanesulfonic acid MTX, Maitotoxin NAD, Nicotanamide adenine dinucleotide NO, nitric oxide PI3K, phosphatidylinositol-3 kinase 9 PIP2, phosphatidylinositol-4,5-bisphosphate PLC, phospholipase C PrI, Propidium iodide RTK, receptor tyrosine kinase RTX, resiniferatoxin ROS, reactive oxygen species SOC, store-operated channel SOCE, store-operated Ca2+ entry TRP, transient receptor potential TRPV1, vanilloid receptor type 1, VR1 10 ROLE OF Ca2+-PERMEABLE CATION CHANNELS IN Ca2+ SIGNALLING AND NECROTIC CELL DEATH Abstract By Brian J. Wisnoskey To evaluate the interaction of the vanilloid receptor (TRPV1) with endogenous Ca2+ signalling mechanisms, TRPV1 was heterologously expressed in insect Sf9 and HEK cells. In the absence of extracellular Ca2+, stimulation of TRPV1 with agonists capsaicin and resiniferatoxin (RTX) caused a release of Ca2+ from internal stores. This release was not blocked by U73122 suggesting phospholipase C was not involved. Substantial overlap occurred between the TRPV1- and thapsigargin-sensitive Ca2+ pools, and TRPV1 immunofluorescence colocalized with the endoplasmic reticulum targeting motif "…KDEL…". To determine if TRPV1-induced release of Ca2+ from internal stores activated endogenous store-operated Ca2+ entry, the effect of 2-APB on Ba2+ was evaluated. 2-ABP blocked thapsigargin-induced Ba2+ influx, but not RTX-induced Ba2+ influx. In the combined presence of thapisgargin and RTX, the 2-APB sensitive component was essentially identical to the thapsigargin-induced component. These results indicate that TRPV1 forms agonist-sensitive channels in the endoplasmic reticulum, which when activated, release Ca2+ from internal stores but fail to activate store-operated Ca2+ entry. 11 Maitotoxin (MTX), a potent marine toxin, is a tool for the study of a Ca2+- overload induced necrotic/oncotic cell death. Upon stimulation with MTX, bovine aortic endothelial cells (BAEC) undergo sequential changes in plasmalemmal permeability. 2+ Initially, MTX activates CaNSC leading to an increase in [Ca ]i. Second is
Load more

Recommended publications
  • Chronic Pelvic Pain M
    Guidelines on Chronic Pelvic Pain M. Fall (chair), A.P. Baranowski, S. Elneil, D. Engeler, J. Hughes, E.J. Messelink, F. Oberpenning, A.C. de C. Williams © European Association of Urology 2008 TABLE OF CONTENTS PAGE 1. INTRODUCTION 5 1.1 The guideline 5 1.1.1 Publication history 5 1.2 Level of evidence and grade recommendations 5 1.3 References 6 1.4 Definition of pain (World Health Organization [WHO]) 6 1.4.1 Innervation of the urogenital system 7 1.4.2 References 8 1.5 Pain evaluation and measurement 8 1.5.1 Pain evaluation 8 1.5.2 Pain measurement 8 1.5.3 References 9 2. CHRONIC PELVIC PAIN 9 2.1 Background 9 2.1.1 Introduction to urogenital pain syndromes 9 2.2 Definitions of chronic pelvic pain and terminology (Table 4) 11 2.3 Classification of chronic pelvic pain syndromes 12 Table 3: EAU classification of chronic urogenital pain syndromes (page 10) Table 4: Definitions of chronic pain terminology (page 11) Table 5: ESSIC classification of types of bladder pain syndrome according to the results of cystoscopy with hydrodistension and of biopsies (page 13) 2.4 References 13 2.5 An algorithm for chronic pelvic pain diagnosis and treatment 13 2.5.1 How to use the algorithm 13 2.6 Prostate pain syndrome (PPS) 15 2.6.1 Introduction 16 2.6.2 Definition 16 2.6.3 Pathogenesis 16 2.6.4 Diagnosis 17 2.6.5 Treatment 17 2.6.5.1 Alpha-blockers 17 2.6.5.2 Antibiotic therapy 17 2.6.5.3 Non-steroidal anti-inflammatory drugs (NSAIDs) 17 2.6.5.4 Corticosteroids 17 2.6.5.5 Opioids 17 2.6.5.6 5-alpha-reductase inhibitors 18 2.6.5.7 Allopurinol 18 2.6.5.8
    [Show full text]
  • A Review of the Effects of Pain and Analgesia on Immune System Function and Inflammation: Relevance for Preclinical Studies
    Comparative Medicine Vol 69, No 6 Copyright 2019 December 2019 by the American Association for Laboratory Animal Science Pages 520–534 Overview A Review of the Effects of Pain and Analgesia on Immune System Function and Inflammation: Relevance for Preclinical Studies George J DeMarco1* and Elizabeth A Nunamaker2 One of the most significant challenges facing investigators, laboratory animal veterinarians, and IACUCs, is how to bal- ance appropriate analgesic use, animal welfare, and analgesic impact on experimental results. This is particularly true for in vivo studies on immune system function and inflammatory disease. Often times the effects of analgesic drugs on a particu- lar immune function or model are incomplete or don’t exist. Further complicating the picture is evidence of the very tight integration and bidirectional functionality between the immune system and branches of the nervous system involved in nociception and pain. These relationships have advanced the concept of understanding pain as a protective neuroimmune function and recognizing pathologic pain as a neuroimmune disease. This review strives to summarize extant literature on the effects of pain and analgesia on immune system function and inflammation in the context of preclinical in vivo studies. The authors hope this work will help to guide selection of analgesics for preclinical studies of inflammatory disease and immune system function. Abbreviations and acronyms: CB,Endocannabinoid receptor; CD,Crohn disease; CFA, Complete Freund adjuvant; CGRP,Calcitonin gene-related
    [Show full text]
  • Professor Peter Goldreich Member of the Board of Adjudicators Chairman of the Selection Committee for the Prize in Astronomy
    The Shaw Prize The Shaw Prize is an international award to honour individuals who are currently active in their respective fields and who have recently achieved distinguished and significant advances, who have made outstanding contributions in academic and scientific research or applications, or who in other domains have achieved excellence. The award is dedicated to furthering societal progress, enhancing quality of life, and enriching humanity’s spiritual civilization. Preference is to be given to individuals whose significant work was recently achieved and who are currently active in their respective fields. Founder's Biographical Note The Shaw Prize was established under the auspices of Mr Run Run Shaw. Mr Shaw, born in China in 1907, was a native of Ningbo County, Zhejiang Province. He joined his brother’s film company in China in the 1920s. During the 1950s he founded the film company Shaw Brothers (HK) Limited in Hong Kong. He was one of the founding members of Television Broadcasts Limited launched in Hong Kong in 1967. Mr Shaw also founded two charities, The Shaw Foundation Hong Kong and The Sir Run Run Shaw Charitable Trust, both dedicated to the promotion of education, scientific and technological research, medical and welfare services, and culture and the arts. ~ 1 ~ Message from the Chief Executive I warmly congratulate the six Shaw Laureates of 2014. Established in 2002 under the auspices of Mr Run Run Shaw, the Shaw Prize is a highly prestigious recognition of the role that scientists play in shaping the development of a modern world. Since the first award in 2004, 54 leading international scientists have been honoured for their ground-breaking discoveries which have expanded the frontiers of human knowledge and made significant contributions to humankind.
    [Show full text]
  • Purinergic P2 Receptors As Targets for Novel Analgesics
    Pharmacology & Therapeutics 110 (2006) 433 – 454 www.elsevier.com/locate/pharmthera Purinergic P2 receptors as targets for novel analgesics Geoffrey Burnstock * Autonomic Neuroscience Centre, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK Abstract Following hints in the early literature about adenosine 5V-triphosphate (ATP) injections producing pain, an ion-channel nucleotide receptor was cloned in 1995, P2X3 subtype, which was shown to be localized predominantly on small nociceptive sensory nerves. Since then, there has been an increasing number of papers exploring the role of P2X3 homomultimer and P2X2/3 heteromultimer receptors on sensory nerves in a wide range of organs, including skin, tongue, tooth pulp, intestine, bladder, and ureter that mediate the initiation of pain. Purinergic mechanosensory transduction has been proposed for visceral pain, where ATP released from epithelial cells lining the bladder, ureter, and intestine during distension acts on P2X3 and P2X2/3, and possibly P2Y, receptors on subepithelial sensory nerve fibers to send messages to the pain centers in the brain as well as initiating local reflexes. P1, P2X, and P2Y receptors also appear to be involved in nociceptive neural pathways in the spinal cord. P2X4 receptors on spinal microglia have been implicated in allodynia. The involvement of purinergic signaling in long-term neuropathic pain and inflammation as well as acute pain is discussed as well as the development of P2 receptor antagonists as novel analgesics. D
    [Show full text]
  • Phytochem Referenzsubstanzen
    High pure reference substances Phytochem Hochreine Standardsubstanzen for research and quality für Forschung und management Referenzsubstanzen Qualitätssicherung Nummer Name Synonym CAS FW Formel Literatur 01.286. ABIETIC ACID Sylvic acid [514-10-3] 302.46 C20H30O2 01.030. L-ABRINE N-a-Methyl-L-tryptophan [526-31-8] 218.26 C12H14N2O2 Merck Index 11,5 01.031. (+)-ABSCISIC ACID [21293-29-8] 264.33 C15H20O4 Merck Index 11,6 01.032. (+/-)-ABSCISIC ACID ABA; Dormin [14375-45-2] 264.33 C15H20O4 Merck Index 11,6 01.002. ABSINTHIN Absinthiin, Absynthin [1362-42-1] 496,64 C30H40O6 Merck Index 12,8 01.033. ACACETIN 5,7-Dihydroxy-4'-methoxyflavone; Linarigenin [480-44-4] 284.28 C16H12O5 Merck Index 11,9 01.287. ACACETIN Apigenin-4´methylester [480-44-4] 284.28 C16H12O5 01.034. ACACETIN-7-NEOHESPERIDOSIDE Fortunellin [20633-93-6] 610.60 C28H32O14 01.035. ACACETIN-7-RUTINOSIDE Linarin [480-36-4] 592.57 C28H32O14 Merck Index 11,5376 01.036. 2-ACETAMIDO-2-DEOXY-1,3,4,6-TETRA-O- a-D-Glucosamine pentaacetate 389.37 C16H23NO10 ACETYL-a-D-GLUCOPYRANOSE 01.037. 2-ACETAMIDO-2-DEOXY-1,3,4,6-TETRA-O- b-D-Glucosamine pentaacetate [7772-79-4] 389.37 C16H23NO10 ACETYL-b-D-GLUCOPYRANOSE> 01.038. 2-ACETAMIDO-2-DEOXY-3,4,6-TRI-O-ACETYL- Acetochloro-a-D-glucosamine [3068-34-6] 365.77 C14H20ClNO8 a-D-GLUCOPYRANOSYLCHLORIDE - 1 - High pure reference substances Phytochem Hochreine Standardsubstanzen for research and quality für Forschung und management Referenzsubstanzen Qualitätssicherung Nummer Name Synonym CAS FW Formel Literatur 01.039.
    [Show full text]
  • Trpa1) Activity by Cdk5
    MODULATION OF TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY A, MEMBER 1 (TRPA1) ACTIVITY BY CDK5 A dissertation submitted to Kent State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Michael A. Sulak December 2011 Dissertation written by Michael A. Sulak B.S., Cleveland State University, 2002 Ph.D., Kent State University, 2011 Approved by _________________, Chair, Doctoral Dissertation Committee Dr. Derek S. Damron _________________, Member, Doctoral Dissertation Committee Dr. Robert V. Dorman _________________, Member, Doctoral Dissertation Committee Dr. Ernest J. Freeman _________________, Member, Doctoral Dissertation Committee Dr. Ian N. Bratz _________________, Graduate Faculty Representative Dr. Bansidhar Datta Accepted by _________________, Director, School of Biomedical Sciences Dr. Robert V. Dorman _________________, Dean, College of Arts and Sciences Dr. John R. D. Stalvey ii TABLE OF CONTENTS LIST OF FIGURES ............................................................................................... iv LIST OF TABLES ............................................................................................... vi DEDICATION ...................................................................................................... vii ACKNOWLEDGEMENTS .................................................................................. viii CHAPTER 1: Introduction .................................................................................. 1 Hypothesis and Project Rationale
    [Show full text]
  • A Rapid Capsaicin-Activated Current in Rat Trigeminal Ganglion Neurons (Pain/Taste/Nociceptive Fibers/Ph/Capsazepine) L
    Proc. Natl. Acad. Sci. USA Vol. 91, pp. 738-741, January 1994 Neurobiology A rapid capsaicin-activated current in rat trigeminal ganglion neurons (pain/taste/nociceptive fibers/pH/capsazepine) L. LIu* AND S. A. SIMONt Departments of *Neurobiology and tAnesthesiology, Duke University Medical Center, Durham, NC 27710 Communicated by Irving T. Diamond, October 15, 1993 ABSTRACT A subpopulation of pain fibers are activated Na2HPO4, 5.6 mM D-glucose, and 10 mM Hepes. They were by capsaicin, the ingredient in red peppers that produces a then incubated for 40 min at 37°C in HBSS containing 1 mg burning sensation when eaten or placed on skin. Previous of collagenase per ml (type XI-S), triturated with a flamed studies on dorsal root ganglion neurons indicated thatcapsaicin Pasteur pipette, and finally incubated at 37°C for 6 min with activates sensory nerves via a single slowly activating and 0.1 mg of DNase I per ml (type IV). Then they were inactivating inward current. In rat trigeminal neurons, we retriturated and washed/centrifuged three times in HBSS. identified a second capsaicin-activated inward current. This They were then resuspended in F-14 medium (GIBCO) current can be distinguished from the slow one in that it rapidly containing 10%o fetal calf serum in a Petri dish. The cultures activates and inactivates, requires Ca2+ for activation, and is were maintained in an incubator at 37°C equilibrated with 5% insensitive to the potent capsaicin agonist resiniferatoxin. The CO2. Most patch clamp experiments were done on cells rapid current, like the slower one, is inhibited by ruthenium cultured for 12-24 hr.
    [Show full text]
  • Mcgovern Institute for Brain Research
    McGovern Institute for Brain Research The McGovern Institute for Brain Research at MIT is a research and teaching institute committed to advancing human understanding and communications. The goal of the McGovern Institute is to investigate and ultimately understand the biological basis of higher brain function in humans. The Institute is conducting interdisciplinary research that combines and extends the results of recent breakthroughs in three major, interrelated areas: systems and computational neuroscience, imaging and cognitive neuroscience, and genetic and cellular neuroscience. Activities We initiated a faculty search during spring 2007. Although we reviewed over 100 applications, we ultimately decided not to make an offer and will instead run the search again in 2007–2008. We held our second annual imaging symposium at the McGovern Institute on May 15, 2007. The co-organizers of this year’s event were Christopher Moore, Alan Jasanoff, and Charles Jennings. The theme, “Plumbing the Mind: Brain Activation and the Regulation of Cerebral Blood Flow,” brought together people working on the physiological mechanisms of neurovascular coupling with others interested in the development of brain imaging technology, especially (but not exclusively) fMRI. Held in the brain and cognitive sciences complex, it was an oversubscribed event that was incredibly well received. The Institute’s Annual Scolnick Prize lecture and dinner was held May 21, 2007. The winner, Dr. David Julius, gave a late afternoon talk, followed by a well-attended dinner at the McGovern Institute. The Scolnick Prize recognizes an outstanding discovery or significant advance in the field of neuroscience. The McGovern Institute held its 5th annual retreat June 3–5 at the Newport Marriott in Newport, Rhode Island.
    [Show full text]
  • Wake Forest Magazine Offers a 70 Class Notes Series of Milestones Along with the Millstones in the Story of Women at the University
    CAMPUS DURING COVID-19 | WFU WOMEN: A HISTORY OF THEIR OWN | KAREN BAYNES-DUNNING (’89): UNDAUNTED SPRING 2021 R E A D I N G t h e R I V E R THE MAGAZINE OF WAKE FOREST UNIVERSITY FEATURES 38 COPING IN THE PANDEMIC Photography by Ken Bennett Wake Forest’s director of photography captured the first month of the fall semester, when campus community members embraced “Show Humanitate.” 2 52 READING THE RIVER LESSONS FROM A TIME OF By Carol L. Hanner UPHEAVAL Yadkin Riverkeeper Brian Fannon (’89) By Kerry M. King (’85) combines biology, history and a love of water Six alumni reflect on student life in the for his exceptional life in the flow. 1960s and early ’70s and how 2020 echoes those times. 18 88 UNDAUNTED CONSTANT & TRUE By Maria Henson (’82) By Sophie Hollis (’19) Karen Baynes-Dunning (’89) infuses arduous A young grad learns about isolation and work for social justice and children’s progress reaching out in a pandemic. with lessons from wondrous family lore. 34 DEPARTMENTS A HISTORY OF THEIR OWN 66 Around the Quad Illustration by Lisa Perrin As women move into their second century of 69 Philanthropy voting rights, Wake Forest Magazine offers a 70 Class Notes series of milestones along with the millstones in the story of women at the University. WAKEFOREST FROM theh PRESIDENT MAGAZINE 2019 ROBERT SIBLEY this issue of wake forest magazine is the first of 2021, a year MAGAZINE OF THE YEAR that will mark the University’s continuing challenges with the COVID-19 pandemic and an upcoming personal milestone for me and my wife, Julie.
    [Show full text]
  • 2014-2015 Annual Report
    THE HELEN HAY WHITNEY FOUNDATION 2014-2015 Annual REport 20 Squadron Boulevard, Suite 630 New City, NY 10956 www.hhwf.org Tel: (845) 639-6799 Fax: (845) 639-6798 THE HELEN HAY WHITNEY FOUNDATION BOARD OF TRUSTEES Averil Payson Meyer, President Steven C. Harrison, Ph.D., Vice President Lisa A. Steiner, M.D., Vice President W. Perry Welch, Treasurer Thomas M. Jessell, Ph.D. Payne W. Middleton Thomas P. Sakmar, M.D. Stephen C. Sherrill SCIENTIFIC ADVISORY COMMITTEE Steven C. Harrison, Ph.D., Chairman David J. Anderson, Ph.D. Daniel Kahne, Ph.D. Philippa Marrack, Ph.D. Markus Meister, Ph.D. Barbara J. Meyer, Ph.D. Julie A. Theriot, Ph.D. Jonathan S. Weissman, Ph.D. S. Lawrence Zipursky, Ph.D. ADMINISTRATIVE DIRECTOR and SECRETARY Robert Weinberger Page 1 REPORT OF THE VICE PRESIDENT AND CHAIRMAN, SCIENTIFIC ADVISORY COMMITTEE I am pleased to report on two years of activity for the Scientific Advisory Committee. Our charge, to select an outstanding group of Fellows each year and to respond as needed to advisory issues that occasionally arise during the tenure of their fellowship, is always a stimulating one, and the talks from third-year Fellows at the Annual Meeting continue to give remarkably positive feedback. Our partnerships with HHMI, the Simons Foundation, and Merck have benefitted the program greatly. We have three Simons Fellows, eight HHMI Fellows and two Merck Fellows, in addition to the eleven we now support from endowment income. (Let me add, on behalf of the SAC, a note of thanks to Perry Welch, the Treasurer of the Foundation, who oversees that endowment with great dedication and insight.) A class of 24 means the competition is fierce, and we continue to identify an extraordinary group of young biomedical scientists.
    [Show full text]
  • Systemic Chemical Desensitization of Peptidergic Sensory Neurons with Resiniferatoxin Inhibits Experimental Periodontitis
    The Open Dentistry Journal, 2011, 5, 1-6 1 Open Access Systemic Chemical Desensitization of Peptidergic Sensory Neurons with Resiniferatoxin Inhibits Experimental Periodontitis Torbjørn Breivik1,2,*, Yngvar Gundersen2, Per Gjermo1, Inge Fristad3 and Per Kristian Opstad2 1Department of Periodontology, Faculty of Dentistry, University of Oslo, Norway 2Norwegian Defence Research Establishment, Division for Protection, Kjeller, Norway 3Department of Clinical Dentistry - Endodontics, University of Bergen, Bergen, Norway Abstract: Background and objective: The immune system is an important player in the pathophysiology of periodontitis. The brain controls immune responses via neural and hormonal pathways, and brain-neuro-endocrine dysregulation may be a central determinant for pathogenesis. Our current knowledge also emphasizes the central role of sensory nerves. In line with this, we wanted to investigate how desensitization of peptidergic sensory neurons influences the progression of ligature- induced periodontitis, and, furthermore, how selected cytokine and stress hormone responses to Gram-negative bacterial lipopolysaccharide (LPS) stimulation are affected. Material and methods: Resiniferatoxin (RTX; 50 μg/kg) or vehicle was injected subcutaneously on days 1, 2, and 3 in stress high responding and periodontitis-susceptible Fischer 344 rats. Periodontitis was induced 2 days thereafter. Progres- sion of the disease was assessed after the ligatures had been in place for 20 days. Two h before decapitation all rats re- ceived LPS (150 μg/kg i.p.) to induce a robust immune and stress response. Results: Desensitization with RTX significantly reduced bone loss as measured by digital X-rays. LPS provoked a signifi- cantly higher increase in serum levels of the pro-inflammatory cytokine tumour necrosis factor (TNF)-, but lower serum levels of the anti-inflammatory cytokine interleukin (IL)-10 and the stress hormone corticosterone.
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]