DOCSLIB.ORG

Microtubule Depolymerization Attenuates WNT4/Camkiiα Signaling in Mouse Uterus and Leads to Implantation Failure

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Microtubule Depolymerization Attenuates WNT4/Camkiiα Signaling in Mouse Uterus and Leads to Implantation Failure 158 1 REPRODUCTIONRESEARCH Microtubule depolymerization attenuates WNT4/CaMKIIα signaling in mouse uterus and leads to implantation failure Vinay Shukla1,2, Jyoti Bala Kaushal1,2, Rohit Kumar1, Pooja Popli1, Promod Kumar Agnihotri3, Kalyan Mitra2,4 and Anila Dwivedi1,2 1Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India, 2Academy of Scientific and Innovative Research (AcSIR), CSIR-CDRI Campus, Lucknow, India, 3Division of Toxicology & Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, India and 4Electron Microscopy Unit, SAIF, CSIR-Central Drug Research Institute, Lucknow, India Correspondence should be addressed to A Dwivedi; Email: [email protected] Abstract Microtubule (MT) dynamics plays a crucial role in fertilization and early embryonic development; however its involvement in uterus during embryo implantation remains unclear. Herein, we report the effect of microtubule depolymerization during embryo implantation in BALB/c mice. Intrauterine treatment with depolymerizing agent nocodazole at pre-implantation phase (D4, 07:00 h) in mice resulted into mitigation in receptivity markers viz. LIF, HoxA10, Integrin-β3, IHH, WNT4 and led to pregnancy failure. MT depolymerization in endometrial epithelial cells (EECs) also inhibited the blastocyst attachment and the adhesion. The decreased expression of MT polymerization-related proteins TPPP and α/β-tubulin in luminal and glandular epithelial cells along with the alteration in morphology of pinopodes in the luminal epithelium was observed in nocodazole receiving uteri. Nocodazole treatment also led to increased intracellular Ca+2 levels in EECs, which indicated that altered Ca+2 homeostasis might be responsible for implantation failure. Microtubule depolymerization inhibited WNT4 and Fz-2 interaction, thereby suppressing the downstream WNT4/CaMKIIα signaling cascades calmodulin and calcineurin which led to attenuation of NF-κB transcriptional promoter activity in EECs. MT depolymerization or CaMKIIα knockdown inhibited the transcription factor NFAT and NF-κB expression along with reduced secretion of prostaglandins PGE2 and PGF2α in mouse EECs. Overall, MT depolymerization impaired the WNT4/CaMKIIα signaling and suppressed the secretion of PGE2 and PGF2α in EECs which may be responsible for implantation failure in mice. Reproduction (2019) 158 47–59 Introduction secretion of progesterone (Sawyer et al. 1979). Although MT dynamics plays a crucial role in early embryonic For successful pregnancy, a blastocyst competent development and fertilization (Wu et al. 1996, Yan for implantation needs to be synchronized with the et al. 2006, Watanabe et al. 2016), its involvement in proliferation and differentiation of specific uterine cell embryo implantation is not completely understood. types under the influence of steroids mainly estradiol Earlier studies show that uterine tubulin levels rise and progesterone (Wang & Dey 2006, Bazer et al. 2009, rapidly in the endometrium and myometrium during Huang et al. 2017, Kaczyński et al. 2018). Impaired pre-implantation period in rabbits (Fujimoto & Saldana embryo implantation and/or decidual aberrations are 1976). In mice, the MT-associated protein HURP plays thought to be responsible for infertility and recurrent a crucial role in embryo implantation (Tsai et al. 2008). pregnancy loss (Cha et al. 2012). Although several Other MT-regulator protein, stathmin, has been reported attempts have been made to explain the molecular in rat during embryo implantation (Tamura et al. 2003) aspects of embryo implantation failure in past decade, and also in human endometrium during pre-receptive the underlying mechanisms still remain unclear. (LH + 2) and receptive (LH + 7) phases (Domínguez et al. The ability of the cytoskeleton to deform and reform is 2009) as well as in uterine fluid at secretory phase of critical for cellular differentiation at the time of embryo menstrual cycle (Bhutada et al. 2014). In our earlier invasion (Paule et al. 2010). Microtubules (MTs) are study, we have also demonstrated the expression of structural components and their dynamic instability tubulin polymerization promoting protein 3 (TPPP3) can lead to sub-cellular movement, mitotic block, cell during endometrial receptivity in human (Manohar et al. cycle arrest, protein trafficking, vesicle transport, axonal 2014a) and have recently demonstrated its functional extension and even cell death (Lopez & Valentine role in mice and hESCs (Shukla et al. 2018, 2019). 2015). MTs are also involved in the transport and © 2019 Society for Reproduction and Fertility https://doi.org/10.1530/REP -18-0611 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via https://rep.bioscientifica.com Downloaded from Bioscientifica.com at 09/26/2021 07:57:48AM via free access -18-0611 48 V Shukla and others Though the literature indicates that MT polymerization Microtubule depolymerization in mouse uterus with the might be important for endometrial functions, its help of microtubule-depolymerizing agent, nocodazole significance particularly in embryo implantation is not We used microtubule-depolymerizing agent nocodazole to yet known. The current study was undertaken to explore evaluate the role of MT polymerization on early pregnancy the significance and functional role of MT polymerization events (Lagos-Cabré & Moreno 2008). The intrauterine during early implantation phase in mice. Nocodazole injection surgery was done on pre-implantation stage i.e. on disrupts MTs by binding to β-tubulin (Mitchison & Kirschner D4 (07:00 h) of pregnancy (Maurya et al. 2013). Nocodazole 1984) and has been used as a MT-depolymerizing agent (300 nM, 2 μL) or vehicle was injected into uterine horn in in several studies (Choi et al. 2011, Guo et al. 2012, mice. We first optimized the concentration of effective dose Isshiki et al. 2015, Signoretto et al. 2016). Therefore, to of nocodazole by assessing the effect of nocodazole at varying prove our hypothesis, the effect of MT-depolymerizing concentrations in mice. At 300 nM, nocodazole suppressed agent (nocodazole) was studied on morphological the embryo implantation by ~90%. Whereas at lower characteristics, receptivity markers and downstream concentrations, the suppressing effect on implantation was not signaling mechanisms regulating implantation and significant. Therefore, we selected the optimized effective dose pregnancy establishment in mouse uterus. Materials and methods Reagents and chemicals To induce MT depolymerization, nocodazole (Calbiochem, Merck Millipore) was used. Lysis buffer, Bradford reagent, Collagenase, DNase, protease inhibitor cocktail (PIC), PIPES, MgCl2, EGTA, PBS, cell culture media, FBS, osmium tetroxide, penicillin streptomycin antibiotics and Cy3 secondary antibodies were purchased from Sigma-Aldrich. Anti-fade reagent with DAPI from Life Technologies, Thermo Fisher Scientific, nylon cell strainer from BD Biosciences (NJ, USA) and fluorescein isothiocyanate (FITC) were procured from Santa Cruz Biotechnology. Immunoblot PVDF membrane was purchased from Merck Millipore. ECL reagent was purchased from GE Healthcare. Antibodies Antibodies for TPPP (sc-98687), α-tubulin (sc-8035), β-tubulin (sc-5274), WNT4 (sc-376279), LIF (sc-20087), IHH (sc-13088), Fz-2 (sc-68328), HoxA10 (sc-17159), Integrin-β3 (sc-52685), NF-κB p50 (sc-53744), Cytokeratin (sc-57004), Vimentin (sc- 32322), ERα (sc-543), PR (sc-538), JNK (sc-572) and GAPDH Figure 1 Investigation of TPPP expression during window of (sc-32233) were procured from Santa Cruz Biotechnology. implantation. (A) The expression analysis of TPPP was done in uterine Antibody for NF-κB p65 (#8242) was procured from Cell protein fraction through immunoblotting. Representative immunoblot Signaling Technology and STAT3 (610189) was procured from images showing the expression of TPPP on different days of BD Biosciences. pregnancy. GAPDH was used as a control to correct for loading (upper panel). Densitometric quantitation of protein expression levels is shown as fold changes (lower panel). Number of animals per Mouse implantation model group = 5. (B) The mRNA expression of Tppp genes in mouse early pregnancy was analyzed by real-time PCR. Number of animals per Adult female virgin BALB/c mice (3 months old, ~26 g) were group = 5. (C) Hormonal regulation of TPPP using delayed used in this study. All the animal protocols were approved implantation model. To maintain delayed implantation, by Institutional Animal Ethical Committee of CSIR-Central ovariectomized mouse was injected subcutaneously with P4 Drug Research Institute, Lucknow, India. Female mice were (1 mg/0.1 mL sesame oil/mouse) from D4 to D7. E2 (25 ng/0.1 mL of co-caged with fertile (2:1) and were checked next morning sesame oil/mouse) was given to P4-primed mouse to terminate delayed implantation on D8. TPPP protein expression in vehicle, for copulation plug. The day on which copulatory plug was delayed (P4) and activated uterus (E2 + P4) was analyzed by observed, was designated as D1 of pregnancy. Uterine tissues immunoblotting (left panel). Number of animals per group = 5. were collected from these animals during different days of Densitometric quantitation of protein expression levels is shown the pre-implantation period. The excised uterine horn (D5, as fold changes (right panel). Three replicates (individual animal 08:00 h) was flushed gently through the oviductal end with as a replicate) were used in each group. P values: aP < 0.001, 1 mL sterile PBS to obtain embryo (Shukla et
Load more

Recommended publications
  • Nitrate Prodrugs Able to Release Nitric Oxide in a Controlled and Selective
    Europäisches Patentamt *EP001336602A1* (19) European Patent Office Office européen des brevets (11) EP 1 336 602 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: C07C 205/00, A61K 31/00 20.08.2003 Bulletin 2003/34 (21) Application number: 02425075.5 (22) Date of filing: 13.02.2002 (84) Designated Contracting States: (71) Applicant: Scaramuzzino, Giovanni AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU 20052 Monza (Milano) (IT) MC NL PT SE TR Designated Extension States: (72) Inventor: Scaramuzzino, Giovanni AL LT LV MK RO SI 20052 Monza (Milano) (IT) (54) Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases (57) New pharmaceutical compounds of general effects and for this reason they are useful for the prep- formula (I): F-(X)q where q is an integer from 1 to 5, pref- aration of medicines for prevention and treatment of in- erably 1; -F is chosen among drugs described in the text, flammatory, ischemic, degenerative and proliferative -X is chosen among 4 groups -M, -T, -V and -Y as de- diseases of musculoskeletal, tegumental, respiratory, scribed in the text. gastrointestinal, genito-urinary and central nervous sys- The compounds of general formula (I) are nitrate tems. prodrugs which can release nitric oxide in vivo in a con- trolled and selective way and without hypotensive side EP 1 336 602 A1 Printed by Jouve, 75001 PARIS (FR) EP 1 336 602 A1 Description [0001] The present invention relates to new nitrate prodrugs which can release nitric oxide in vivo in a controlled and selective way and without the side effects typical of nitrate vasodilators drugs.
    [Show full text]
  • Targeting the Deubiquitinase STAMBP Inhibits NALP7 Inflammasome
    ARTICLE Received 19 Jul 2016 | Accepted 8 Mar 2017 | Published 11 May 2017 DOI: 10.1038/ncomms15203 OPEN Targeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity Joseph S. Bednash1, Nathaniel Weathington1, James Londino1, Mauricio Rojas1, Dexter L. Gulick1, Robert Fort1, SeungHye Han1, Alison C. McKelvey1, Bill B. Chen1 & Rama K. Mallampalli1,2,3 Inflammasomes regulate innate immune responses by facilitating maturation of inflammatory cytokines, interleukin (IL)-1b and IL-18. NACHT, LRR and PYD domains-containing protein 7 (NALP7) is one inflammasome constituent, but little is known about its cellular handling. Here we show a mechanism for NALP7 protein stabilization and activation of the inflammasome by Toll-like receptor (TLR) agonism with bacterial lipopolysaccharide (LPS) and the synthetic acylated lipopeptide Pam3CSK4. NALP7 is constitutively ubiquitinated and recruited to the endolysosome for degradation. With TLR ligation, the deubiquitinase enzyme, STAM-binding protein (STAMBP) impedes NALP7 trafficking to lysosomes to increase NALP7 abundance. STAMBP deubiquitinates NALP7 and STAMBP knockdown abrogates LPS or Pam3CSK4-induced increases in NALP7 protein. A small-molecule inhibitor of STAMBP deubiquitinase activity, BC-1471, decreases NALP7 protein levels and suppresses IL-1b release after TLR agonism. These findings describe a unique pathway of inflammasome regulation with the identification of STAMBP as a potential therapeutic target to reduce pro-inflammatory stress. 1 Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, UPMC Montefiore, NW 628, Pittsburgh, Pennsylvania 15213, USA. 2 Departments of Cell Biology and Physiology and Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. 3 Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240, USA.
    [Show full text]
  • Open Access Availability of Scientific Publications
    Analytical Support for Bibliometrics Indicators Open access availability of scientific publications Analytical Support for Bibliometrics Indicators Open access availability of scientific publications* Final Report January 2018 By: Science-Metrix Inc. 1335 Mont-Royal E. ▪ Montréal ▪ Québec ▪ Canada ▪ H2J 1Y6 1.514.495.6505 ▪ 1.800.994.4761 [email protected] ▪ www.science-metrix.com *This work was funded by the National Science Foundation’s (NSF) National Center for Science and Engineering Statistics (NCSES). Any opinions, findings, conclusions or recommendations expressed in this report do not necessarily reflect the views of NCSES or the NSF. The analysis for this research was conducted by SRI International on behalf of NSF’s NCSES under contract number NSFDACS1063289. Analytical Support for Bibliometrics Indicators Open access availability of scientific publications Contents Contents .............................................................................................................................................................. i Tables ................................................................................................................................................................. ii Figures ................................................................................................................................................................ ii Abstract ............................................................................................................................................................
    [Show full text]
  • Obesity and Reproduction: a Committee Opinion
    Obesity and reproduction: a committee opinion Practice Committee of the American Society for Reproductive Medicine American Society for Reproductive Medicine, Birmingham, Alabama The purpose of this ASRM Practice Committee report is to provide clinicians with principles and strategies for the evaluation and treatment of couples with infertility associated with obesity. This revised document replaces the Practice Committee document titled, ‘‘Obesity and reproduction: an educational bulletin,’’ last published in 2008 (Fertil Steril 2008;90:S21–9). (Fertil SterilÒ 2015;104:1116–26. Ó2015 Use your smartphone by American Society for Reproductive Medicine.) to scan this QR code Earn online CME credit related to this document at www.asrm.org/elearn and connect to the discussion forum for Discuss: You can discuss this article with its authors and with other ASRM members at http:// this article now.* fertstertforum.com/asrmpraccom-obesity-reproduction/ * Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace. he prevalence of obesity as a exceed $200 billion (7). This populations have a genetically higher worldwide epidemic has underestimates the economic burden percent body fat than Caucasians, T increased dramatically over the of obesity, since maternal morbidity resulting in greater risks of developing past two decades. In the United States and adverse perinatal outcomes add diabetes and CVD at a lower BMI of alone, almost two thirds of women additional costs. The problem of obesity 23–25 kg/m2 (12). and three fourths of men are overweight is also exacerbated by only one third of Known associations with metabolic or obese, as are nearly 50% of women of obese patients receiving advice from disease and death from CVD include reproductive age and 17% of their health-care providers regarding weight BMI (J-shaped association), increased children ages 2–19 years (1–3).
    [Show full text]
  • Multiple Myeloma Inhibitory Activity of Plant Natural Products
    cancers Review Multiple Myeloma Inhibitory Activity of Plant Natural Products Karin Jöhrer 1 and Serhat Sezai Ҫiҫek 2,* 1 Tyrolean Cancer Research Institute, Innrain 66, 6020 Innsbruck, Austria; karin.joehrer@tkfi.at 2 Department of Pharmaceutical Biology, Kiel University, Gutenbergstraße 76, 24118 Kiel, Germany * Correspondence: [email protected] Simple Summary: Multiple myeloma is the second most common hematological cancer and is still incurable. Although enhanced understanding of the disease background and the development of novel therapeutics during the last decade resulted in a significant increase of overall survival time, almost all patients relapse and finally succumb to their disease. Therefore, novel medications are urgently needed. Nature-derived compounds still account for the majority of new therapeutics and especially for the treatment of cancer often serve as lead compounds in drug development. The present review summarizes the data on plant natural products with in vitro and in vivo activity against multiple myeloma until the end of 2020, focusing on their structure–activity relationship as well as the investigated pathways and involved molecules. Abstract: A literature search on plant natural products with antimyeloma activity until the end of 2020 resulted in 92 compounds with effects on at least one human myeloma cell line. Compounds were divided in different compound classes and both their structure–activity-relationships as well as eventual correlations with the pathways described for Multiple Myeloma were discussed. Each of the major compound classes in this review (alkaloids, phenolics, terpenes) revealed interesting candidates, such as dioncophyllines, a group of naphtylisoquinoline alkaloids, which showed pronounced Citation: Jöhrer, K.; Ҫiҫek, S.S.
    [Show full text]
  • A 0.70% E 0.80% Is 0.90%
    US 20080317666A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0317666 A1 Fattal et al. (43) Pub. Date: Dec. 25, 2008 (54) COLONIC DELIVERY OF ACTIVE AGENTS Publication Classification (51) Int. Cl. (76) Inventors: Elias Fattal, Paris (FR); Antoine A6IR 9/00 (2006.01) Andremont, Malakoff (FR); A61R 49/00 (2006.01) Patrick Couvreur, A6II 5L/12 (2006.01) Villebon-sur-Yvette (FR); Sandrine A6IPI/00 (2006.01) Bourgeois, Lyon (FR) (52) U.S. Cl. .......................... 424/1.11; 424/423; 424/9.1 (57) ABSTRACT Correspondence Address: Drug delivery devices that are orally administered, and that David S. Bradlin release active ingredients in the colon, are disclosed. In one Womble Carlyle Sandridge & Rice embodiment, the active ingredients are those that inactivate P.O.BOX 7037 antibiotics, such as macrollides, quinolones and beta-lactam Atlanta, GA 30359-0037 (US) containing antibiotics. One example of a Suitable active agent is an enzyme Such as beta-lactamases. In another embodi ment, the active agents are those that specifically treat colonic (21) Appl. No.: 11/628,832 disorders, such as Chrohn's Disease, irritable bowel syn drome, ulcerative colitis, colorectal cancer or constipation. (22) PCT Filed: Feb. 9, 2006 The drug delivery devices are in the form of beads of pectin, crosslinked with calcium and reticulated with polyethylene imine. The high crosslink density of the polyethyleneimine is (86). PCT No.: PCT/GBO6/OO448 believed to stabilize the pectin beads for a sufficient amount of time such that a Substantial amount of the active ingredi S371 (c)(1), ents can be administered directly to the colon.
    [Show full text]
  • Web of Science™ Core Collection Current Contents Connect®
    WEB OF SCIENCE™ CORE COLLECTION CURRENT CONTENTS CONNECT® XML USER GUIDE March, 2020 Table of Contents Overview 3 Support and Questions 4 Selection Criteria 5 XML Schemas 7 Schema Diagram 8 Source Record Identifiers 9 Document and Source Titles 11 Source Author Names 12 Full Names and Abbreviations 13 Chinese Author Names 13 Authors and Addresses 15 Research and Reprint Addresses 17 Organizations 18 Contributors 19 Cited References 21 Citations to Articles from Journal Supplements 22 Issue Information in the Volume Field 23 Cited Authors in References to Proceedings and Patents 23 © 2020 Clarivate Analytics 1 Counting Citations 24 Times Cited File 25 Delivery Schedule 26 Corrections and Gap Records 27 Deletions 28 Journal Lists and Journal Changes 29 Appendix 1 Subject Categories 30 Subject Catagories (Ascatype) 30 Web of Science™ Core Collection Subject Areas (Traditional Ascatype) 30 Research Areas (Extended Ascatype) 34 Current Contents Subject Codes 38 Current Contents Editions and Subjects 38 Appendix 2 Document Types 43 Document Types 43 Web of Science Core Collection Document Types 43 Current Contents Connect Document Types 44 Appendix 3 Abbreviations and Acronyms 46 Address Abbreviations 46 Country Abbreviations 51 Cited Patent Country Abbreviations 57 © 2020 Clarivate Analytics 2 Overview Your contract for raw data entitles you to get timely updates, which you may store and process according to the terms of your agreement. The associated XML schemas describe the record structure of the data and the individual elements that define
    [Show full text]
  • Late-Breaking Abstracts
    Late‐Breaking Abstracts ___________________________________________________________________ Late‐Breaking Abstracts Table of Contents Pg 2 Adaptive and Auto‐Immunity Abstracts LB708 – LB712 Pg 4 Carcinogenesis and Cancer Genetics Abstracts LB713 – LB715 Pg 6 Cell‐Cell Interactions in the Skin Abstracts LB716 – LB722 Pg 9 Epidermal Structure and Barrier Function Abstracts LB723 – LB730 Pg 13 Genetic Disease, Gene Regulation, and Gene Therapy Abstracts LB731 – LB735 Pg 15 Innate Immunity, Microbiology, and Microbiome Abstracts LB736 – LB740 Pg 18 Patient Population Research Abstracts LB741 – LB771 Pg 33 Patient‐Targeted Research Abstracts LB772 – LB782 Pg 39 Pharmacology and Drug Development Abstracts LB783 – LB795 Pg 45 Photobiology Abstracts LB796 – LB802 Pg 48 Pigmentation and Melanoma Abstracts LB803 – LB804 Pg 49 Skin of Color Abstracts LB805 ‐ LB806 Pg 50 Skin, Appendages, and Stem Cell Biology Abstracts LB807 Pg 51 Tissue Regeneration and Wound Healing Abstracts LB808 – LB811 Pg 53 Translational Studies Abstracts LB812 – LB823 Pg 59 Author Index Pg 65 Keyword Index 1 Adaptive and Auto-Immunity LB708 ILC1-like innate lymphocytes in human autoimmunity: Lessons from Alopecia Areata R. Laufer Britva1, A. Keren1, M. Bertolini2, R. Paus3, 4, A. Gilhar1 1Technion Israel Institute of Technology, Haifa, Haifa, Israel, 2Monasterium, Münster, Germany, 3Department of Dermatology & Cutaneous Surgery, University of Miami School of Medicine, Miami, Florida, United States, 4Dermatology Research Centre, University of Manchester, Manchester, Germany Innate lymphoid cells type 1 (ILC1) express NKG2D and produce large amounts of IFN-γ, i.e. two key elements in the pathogenesis of alopecia areata (AA). In this study, we aimed to explore a possible involvement of ILC1-like cells in human AA by using ex-vivo and in-vivo models for human AA.
    [Show full text]
  • {Replace with the Title of Your Dissertation}
    SYNTHESIS AND EVALUATION OF PARTHENOLIDE ANALOGUES: CHEMICAL PROBES AND THERAPEUTIC AGENTS A Thesis SUBMITTED TO THE FACULTY OF UNIVERSITY OF MINNESOTA BY Dan Wang IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE Advisor: Dr. Daniel A. Harki MARCH 2013 © Dan Wang 2013 Acknowledgements I would like to begin by thanking my advisor, Dr. Dan Harki for his mentorship and support over these years. Your wisdom, knowledge and enthusiasm for science were a guiding light throughout my graduate school career. I wouldn’t be where I am without your vision, encouragement and advise. Additional thanks goes to Professor Rick Wagner, Professor Chengguo Xing and Professor Mark Distefano for serving on my dissertation committee, and for the helpful critiques and suggestions provided throughout my graduate career. Then, I would like to extend my sincere thanks to every past and present member of Harki group. Thank you all for the scientific help you have provided me all these years as well as being a constant source of support. In particular, Dr. Fred Meece for guiding me into the “parthenolide field” and Joe Hexum and Tim Andrew for providing some of the biological data in chapter 2. I would also like to thank and recognize my collaborators for all their assistance with regards to my projects. In particular, I would like to thank Professor David Largaespada, Sue Rathe and Zohar Sachs for their help and valuable discussion in primary AML cells; Professor John Ohlfest and Chani Becker for performing the brain tumor animal studies; Dr. Victor G. Young, Jr.
    [Show full text]
  • Assessment Report Triclosan Chemical Abstracts Service
    Assessment Report Triclosan Chemical Abstracts Service Registry Number 3380-34-5 Environment and Climate Change Canada Health Canada November 2016 Assessment Report: Triclosan 2016-11-26 En14-259/2016E-PDF 978-0-660-05976-1 Information contained in this publication or product may be reproduced, in part or in whole, and by any means, for personal or public non-commercial purposes, without charge or further permission, unless otherwise specified. You are asked to: Exercise due diligence in ensuring the accuracy of the materials reproduced; Indicate both the complete title of the materials reproduced, as well as the author organization; and Indicate that the reproduction is a copy of an official work that is published by the Government of Canada and that the reproduction has not been produced in affiliation with or with the endorsement of the Government of Canada. Commercial reproduction and distribution is prohibited except with written permission from the author. For more information, please contact Environment and Climate Change Canada’s Inquiry Centre at 1-800-668-6767 (in Canada only) or 819-997-2800 or email to [email protected]. © Her Majesty the Queen in Right of Canada, represented by the Minister of the Environment, 2016. Aussi disponible en français Assessment Report: Triclosan 2016-11-26 Synopsis An assessment of triclosan has been conducted under the Canadian Environmental Protection Act, 1999 (CEPA) to determine if it poses a risk to Canadians and their environment. Triclosan was also scheduled for re-evaluation under Health Canada’s Pest Management Regulatory Agency (PMRA) pesticide re-evaluation program pursuant to the Pest Control Products Act (PCPA).
    [Show full text]
  • Information for Authors and Journal Policies
    Information for Authors and Journal Policies ARTICLE TYPES ................................................ 2 Prepublication Embargo ................................... 11 Original Investigations ........................................ 2 Copyright........................................................... 11 Case Series .................................................... 2 Article Access ................................................... 12 Clinical Trial .................................................... 2 Open Access User Licenses ......................... 12 Decision Analysis or Cost-Effectiveness Open Access Publication Fee ....................... 12 Analysis ................................................ 2 Compliance With NIH Public Access Policy . 12 Diagnostic Test Study..................................... 2 Article Preproofs ............................................... 12 Observational Study ....................................... 2 Article Proofs .................................................... 12 Quality Improvement Study ............................ 3 Page Charges ................................................... 12 Systematic Review or Meta-analysis.............. 3 Color Reproduction Charges ............................ 12 Research Letters ................................................ 3 Share Link and Reprints ................................... 13 Case Reports ..................................................... 4 Retained Author Rights .................................... 13 Features ............................................................
    [Show full text]
  • Localized Rnas Involves Silencing and Clustering After Transport Konstadinos Moissoglu1†, Kyota Yasuda1,2,3†, Tianhong Wang1†, George Chrisafis1, Stavroula Mili1*
    RESEARCH ARTICLE Translational regulation of protrusion- localized RNAs involves silencing and clustering after transport Konstadinos Moissoglu1†, Kyota Yasuda1,2,3†, Tianhong Wang1†, George Chrisafis1, Stavroula Mili1* 1Laboratory of Cellular and Molecular Biology,Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States; 2Program of Mathematical and Life Sciences, Graduate School of Integrated Science for Life, Hiroshima University, Higashi-Hiroshima, Japan; 3Laboratory for Comprehensive Bioimaging, RIKEN Center for Biosystems Dynamics Research, Suita, Japan Abstract Localization of RNAs to various subcellular destinations is a widely used mechanism that regulates a large proportion of transcripts in polarized cells. In many cases, such localized transcripts mediate spatial control of gene expression by being translationally silent while in transit and locally activated at their destination. Here, we investigate the translation of RNAs localized at dynamic cellular protrusions of human and mouse, migrating, mesenchymal cells. In contrast to the model described above, we find that protrusion-localized RNAs are not locally activated solely at protrusions, but can be translated with similar efficiency in both internal and peripheral locations. Interestingly, protrusion-localized RNAs are translated at extending protrusions, they become translationally silenced in retracting protrusions and this silencing is accompanied by coalescence of single RNAs into larger heterogeneous RNA clusters. This work describes a distinct mode of *For correspondence: translational regulation of localized RNAs, which we propose is used to regulate protein activities [email protected] during dynamic cellular responses. DOI: https://doi.org/10.7554/eLife.44752.001 †These authors contributed equally to this work Competing interests: The authors declare that no Introduction competing interests exist.
    [Show full text]