DOCSLIB.ORG

Role and Regulation of Snon/Skil and PLSCR1 Located at 3Q26.2

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Role and Regulation of Snon/Skil and PLSCR1 Located at 3Q26.2 University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School 9-18-2014 Role and Regulation of SnoN/SkiL and PLSCR1 Located at 3q26.2 and 3q23, Respectively, in Ovarian Cancer Pathophysiology Madhav Karthik Kodigepalli University of South Florida, [email protected] Follow this and additional works at: https://scholarcommons.usf.edu/etd Part of the Cell Biology Commons, Microbiology Commons, and the Molecular Biology Commons Scholar Commons Citation Kodigepalli, Madhav Karthik, "Role and Regulation of SnoN/SkiL and PLSCR1 Located at 3q26.2 and 3q23, Respectively, in Ovarian Cancer Pathophysiology" (2014). Graduate Theses and Dissertations. https://scholarcommons.usf.edu/etd/5426 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Role and Regulation of SnoN/SkiL and PLSCR1 Located at 3q26.2 and 3q23, Respectively, in Ovarian Cancer Pathophysiology by Madhav Karthik Kodigepalli A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Cell and Molecular Biology Department of Cell Biology, Microbiology and Molecular Biology College of Arts and Sciences University of South Florida Major Professor: Meera Nanjundan, Ph.D. Richard Pollenz, Ph.D. Patrick Bradshaw, Ph.D. Sandy Westerheide, Ph.D. Date of Approval: September 18, 2014 Keywords: Chemotherapeutics, phospholipid scramblase, toll-like receptor, interferon, dsDNA Copyright © 2014, Madhav Karthik Kodigepalli Dedication I dedicate this research at the lotus feet of Bhagwan Sri Sathya Sai Baba and all the Masters for I am what I am due to their divine grace. I also dedicate this work to my parents Prabhakar Kodigepalli and Subba Lakshmi Kodigepalli, to my brothers Deepak and Prashanth, and to my loving wife Punashi for their constant support and encouragement which has helped me throughout this journey. Acknowledgments Firstly, I would like to thank my mentor Dr. Meera Nanjundan for all her support and guidance. I am deeply grateful to her for her contribution of time and ideas to make my Ph.D. experience both productive and motivating. I am thankful for all her advice and insightful suggestions without which this dissertation would not have been possible. I wish to thank my committee members Dr. Richard Pollenz, Dr. Patrick Bradshaw and Dr. Sandy Westerheide for all their valuable time and constant support through my Ph.D. I also thank my current and former lab partners Punashi Dutta, Kyle Bauckman, and Dawn Smith for all the stimulating scientific discussions. Additionally, I would like thank all the undergraduate students for their kind assistance in the laboratory. I am also grateful to Dr. Lindsey Shaw who let me rotate in his lab when I first joined the department and has been very supportive and understanding of me. At last, I would like to thank my parents, all my family and friends for their encouragement and moral support. Table of Contents List of Tables ............................................................................................................................................... iv List of Figures ............................................................................................................................................... v Abbreviations .............................................................................................................................................. vii Abstract ...................................................................................................................................................... viii Chapter 1: Introduction ................................................................................................................................. 1 Ovarian Cancer ................................................................................................................................ 1 Current treatment strategies ................................................................................................ 2 Common genetic aberrations .............................................................................................. 2 Amplifications of chromosomal region 3q26 ..................................................................... 3 TGFβ signaling ................................................................................................................... 4 SnoN ................................................................................................................................................ 4 Arsenic Trioxide (As2O3) ................................................................................................................. 6 Programmed Cell Death ................................................................................................................... 7 Autophagy ........................................................................................................................... 7 Apoptosis ............................................................................................................................ 8 Necroptosis ......................................................................................................................... 9 Phospholipid Scramblase: PLSCR Family Members, TMEM16F and Xkr8 ................................ 10 Phospholipids, membrane asymmetry, scramblase activity, and blood coagulation ........ 10 cDNA cloning of “phospholipid scramblases” ................................................................. 11 Gene location and protein structure of PLSCR1 isoforms ................................................ 12 Scramblase activity of PLSCR family members............................................................... 15 Defect in TMEM16/Ano6 is responsible for scramblase activity deficiency in Scott syndrome platelets ...................................................................................................... 17 Regulation, Subcellular Localization, and Functions of PLSCR Family Members ....................... 18 Transcriptional regulation by growth factors, interferons, and Snail ................................ 18 Subcellular localization of PLSCR1 ................................................................................. 19 Role of PLSCR1 in cell signaling/receptor trafficking events and protein-protein interactions ................................................................................................................. 20 Role of PLSCR1 as a DNA-binding protein and transcription factor ............................... 22 Functions of PLSCR1: Innate Immune Recognition, Cell Death Pathways, and Cancer .............. 23 Antiviral functions of PLSCR1 and viral entry ................................................................ 23 Role of PLSCR1 in autoimmune diseases (systemic lupus erythematosus) ..................... 25 PLSCR1 in innate immune responses: TLR signaling...................................................... 25 Role of PLSCR1 in apoptosis and autophagy ................................................................... 26 Role of PLSCR1 in blood and solid cancers ..................................................................... 27 Hypotheses and Objectives ............................................................................................................ 28 Specific Aim 1 (presented in Chapter 3) ........................................................................... 29 Aim 1.1 ................................................................................................................ 29 i Aim 1.2 ................................................................................................................ 29 Specific Aim 2 (presented in Chapter 4) ........................................................................... 29 Aim 2.1 ................................................................................................................ 29 Aim 2.2 ................................................................................................................ 29 Aim 2.3 ................................................................................................................ 29 Specific Aim 3 (presented in Chapter 5) ........................................................................... 29 Aim 3.1 ................................................................................................................ 29 Aim 3.2 ................................................................................................................ 29 Overall Impact and Significance .................................................................................................... 29 Chapter 2: Materials and Methods .............................................................................................................. 31 Culture and Propagation of Cell Lines ........................................................................................... 31 Genomic DNA Isolation and STR profiling .................................................................................. 32 Cellular Treatments with Growth Factors, Chemotherapeutic Agents, and Signaling pathway Inhibitors .......................................................................................................................................
Load more

Recommended publications
  • Constitutive Phospholipid Scramblase Activity of a G Protein-Coupled Receptor
    ARTICLE Received 19 Feb 2014 | Accepted 1 Sep 2014 | Published 8 Oct 2014 DOI: 10.1038/ncomms6115 Constitutive phospholipid scramblase activity of a G protein-coupled receptor Michael A. Goren1, Takefumi Morizumi2, Indu Menon1, Jeremiah S. Joseph3,w, Jeremy S. Dittman1, Vadim Cherezov3, Raymond C. Stevens3, Oliver P. Ernst2,4 & Anant K. Menon1 Opsin, the rhodopsin apoprotein, was recently shown to be an ATP-independent flippase (or scramblase) that equilibrates phospholipids across photoreceptor disc membranes in mammalian retina, a process required for disc homoeostasis. Here we show that scrambling is a constitutive activity of rhodopsin, distinct from its light-sensing function. Upon reconstitution into vesicles, discrete conformational states of the protein (rhodopsin, a metarhodopsin II-mimic, and two forms of opsin) facilitated rapid (410,000 phospholipids per protein per second) scrambling of phospholipid probes. Our results indicate that the large conformational changes involved in converting rhodopsin to metarhodopsin II are not required for scrambling, and that the lipid translocation pathway either lies near the protein surface or involves membrane packing defects in the vicinity of the protein. In addition, we demonstrate that b2-adrenergic and adenosine A2A receptors scramble lipids, suggesting that rhodopsin-like G protein-coupled receptors may play an unexpected moonlighting role in re-modelling cell membranes. 1 Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065, USA. 2 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8. 3 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA. 4 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
    [Show full text]
  • Responses of Bats to White-Nose Syndrome and Implications for Conservation
    University of New Hampshire University of New Hampshire Scholars' Repository Doctoral Dissertations Student Scholarship Spring 2020 Responses of Bats to White-Nose Syndrome and Implications for Conservation Meghan Stark University of New Hampshire, Durham Follow this and additional works at: https://scholars.unh.edu/dissertation Recommended Citation Stark, Meghan, "Responses of Bats to White-Nose Syndrome and Implications for Conservation" (2020). Doctoral Dissertations. 2518. https://scholars.unh.edu/dissertation/2518 This Dissertation is brought to you for free and open access by the Student Scholarship at University of New Hampshire Scholars' Repository. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of University of New Hampshire Scholars' Repository. For more information, please contact [email protected]. RESPONSES OF BATS TO WHITE-NOSE SYNDROME AND IMPLICATIONS FOR CONSERVATION BY MEGHAN A. STARK B.S., University of Alabama at Birmingham, 2013 DISSERTATION Submitted to the University of New Hampshire in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy In Genetics May 2020 i This dissertation was examined and approved in partial fulfillment of the requirements for the degree of Ph.D. in Genetics by: Dissertation Director, Matthew MacManes, Assoc. Prof. UNH MCBS Jeffrey T. Foster, Associate Professor, NAU PMI W. Kelley Thomas, Professor, UNH MCBS Rebecca Rowe, Associate Professor, UNH NREN Thomas Lee, Associate Professor Emeritus, UNH NREN On April 6, 2020 Approval signatures are on file with the University of New Hampshire Graduate School. ii DEDICATION I dedicate this work to all of the strong women in my life: Myra Michele Ange Heather Michelle Coons Kaitlyn Danielle Cagle Brindlee Michelle Coons Patricia Gail Miller Sarah Jean Lane “Here’s to strong women.
    [Show full text]
  • Phospholipid Ebb and Flow Makes Mitochondria Go
    REVIEW Phospholipid ebb and flow makes mitochondria go Michelle Grace Acoba, Nanami Senoo, and Steven M. Claypool Mitochondria, so much more than just being energy factories, also have the capacity to synthesize macromolecules including phospholipids, particularly cardiolipin (CL) and phosphatidylethanolamine (PE). Phospholipids are vital constituents of mitochondrial membranes, impacting the plethora of functions performed by this organelle. Hence, the orchestrated movement of phospholipids to and from the mitochondrion is essential for cellular integrity. In this review, we capture recent advances in the field of mitochondrial phospholipid biosynthesis and trafficking, highlighting the significance of interorganellar communication, intramitochondrial contact sites, and lipid transfer proteins in maintaining membrane homeostasis. We then discuss the physiological functions of CL and PE, specifically how they associate with protein complexes in mitochondrial membranes to support bioenergetics and maintain mitochondrial architecture. Introduction (PS), phosphatidylinositol (PI), and phosphatidylcholine (PC), as Biological membranes give a means of regulated communi- well as sphingolipids, cholesterol, and many lysophospholipids, it cation, as the lipid bilayer itself acts as a platform for many has to recruit from other organelles. This section will focus on the reactions. The amphipathic nature of lipids underlies the mitochondrion’s contribution to the generation of two highly creation of a bilayer; the hydrophobic acyl chains cluster at abundant phospholipids in its membranes: CL and PE (Fig. 1). the middle to get buried, while the hydrophilic head groups face the aqueous surroundings. A diverse array of lipids, in- CL metabolism cluding glycerophospholipids, sphingolipids, and sterols, present CL production. CL is the defining membrane constituent of in different amounts, gives a biological membrane its identity the mitochondrion, the organelle in which it is made (Fig.
    [Show full text]
  • Phosphatidylserine in Non-Apoptotic Cell Death Inbar Shlomovitz1, Mary Speir2,3 and Motti Gerlic1*
    Shlomovitz et al. Cell Communication and Signaling (2019) 17:139 https://doi.org/10.1186/s12964-019-0437-0 REVIEW Open Access Flipping the dogma – phosphatidylserine in non-apoptotic cell death Inbar Shlomovitz1, Mary Speir2,3 and Motti Gerlic1* Abstract The exposure of phosphatidylserine (PS) on the outer plasma membrane has long been considered a unique feature of apoptotic cells. Together with other “eat me” signals, it enables the recognition and phagocytosis of dying cells (efferocytosis), helping to explain the immunologically-silent nature of apoptosis. Recently, however, PS exposure has also been reported in non-apoptotic forms of regulated inflammatory cell death, such as necroptosis, challenging previous dogma. In this review, we outline the evidence for PS exposure in non-apoptotic cells and extracellular vesicles (EVs), and discuss possible mechanisms based on our knowledge of apoptotic-PS exposure. In addition, we examine the outcomes of non-apoptotic PS exposure, including the reversibility of cell death, efferocytosis, and consequent inflammation. By examining PS biology, we challenge the established approach of distinguishing apoptosis from other cell death pathways by AnnexinV staining of PS externalization. Finally, we re- evaluate how PS exposure is thought to define apoptosis as an immunologically silent process distinct from other non-apoptotic and inflammatory cell death pathways. Ultimately, we suggest that a complete understanding of how regulated cell death processes affect the immune system is far from being fully
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Phosphatidylserine, a Death Knell
    Cell Death and Differentiation (2001) 8, 551 ± 563 ã 2001 Nature Publishing Group All rights reserved 1350-9047/01 $15.00 www.nature.com/cdd REVIEW Phosphatidylserine, a death knell# RA Schlegel*,1 and P Williamson2 molecules are sometimes withdrawn from the matrix and hydrolyzed to produce signaling molecules, including 1 Department of Biochemistry and Molecular Biology, Penn State University, prostaglandins, diacylglycerol and ceramides. In recent University Park, PA 16802, USA years, however, a growing body of evidence has suggested 2 Department of Biology, Amherst College, Amherst, MA 01002, USA that physical and chemical properties of the bilayer itself, such * Corresponding author: RA Schlegel, Department of Biochemistry and as the thickness of the hydrophobic core1 or local lateral Molecular Biology, 428 South Frear Laboratory, Penn State University, 2±4 University Park, PA 16802, USA. Tel: (814) 865-6974; Fax: (814) 863-7024; domains of specialized lipid composition may play E-mail: [email protected] significant roles in the assembly and organization of cellular membranes. In addition to these structural contributions to Received 30.8.00; revised 13.11.00; accepted 27.11.00 membrane function, the past few years have also seen the Edited by M Piacentini revelation that a phospholipid itself, and not a derived product, acts on the extracytosolic, external face of the plasma membrane to regulate intercellular interactions. Abstract Appreciation of this new role for phospholipids was Virtually every cell in the body restricts phosphatidylserine galvanized by the demonstration that phosphatidylserine (PS) to the inner leaflet of the plasma membrane by energy- (PS) appears on the surface of apoptotic lymphocytes and dependent transport from the outer to the inner leaflet of the contributes to their phagocytosis by activated macro- phages.5 The functional importance of the phagocytosis of bilayer.
    [Show full text]
  • Identification of Eqtls and Sqtls Associated with Meat Quality in Beef Joel D
    Leal-Gutiérrez et al. BMC Genomics (2020) 21:104 https://doi.org/10.1186/s12864-020-6520-5 RESEARCH ARTICLE Open Access Identification of eQTLs and sQTLs associated with meat quality in beef Joel D. Leal-Gutiérrez*, Mauricio A. Elzo and Raluca G. Mateescu Abstract Background: Transcription has a substantial genetic control and genetic dissection of gene expression could help us understand the genetic architecture of complex phenotypes such as meat quality in cattle. The objectives of the present research were: 1) to perform eQTL and sQTL mapping analyses for meat quality traits in longissimus dorsi muscle; 2) to uncover genes whose expression is influenced by local or distant genetic variation; 3) to identify expression and splicing hot spots; and 4) to uncover genomic regions affecting the expression of multiple genes. Results: Eighty steers were selected for phenotyping, genotyping and RNA-seq evaluation. A panel of traits related to meat quality was recorded in longissimus dorsi muscle. Information on 112,042 SNPs and expression data on 8588 autosomal genes and 87,770 exons from 8467 genes were included in an expression and splicing quantitative trait loci (QTL) mapping (eQTL and sQTL, respectively). A gene, exon and isoform differential expression analysis previously carried out in this population identified 1352 genes, referred to as DEG, as explaining part of the variability associated with meat quality traits. The eQTL and sQTL mapping was performed using a linear regression model in the R package Matrix eQTL. Genotype and year of birth were included as fixed effects, and population structure was accounted for by including as a covariate the first PC from a PCA analysis on genotypic data.
    [Show full text]
  • Downloaded the “Top Edge” Version
    bioRxiv preprint doi: https://doi.org/10.1101/855338; this version posted December 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Drosophila models of pathogenic copy-number variant genes show global and 2 non-neuronal defects during development 3 Short title: Non-neuronal defects of fly homologs of CNV genes 4 Tanzeen Yusuff1,4, Matthew Jensen1,4, Sneha Yennawar1,4, Lucilla Pizzo1, Siddharth 5 Karthikeyan1, Dagny J. Gould1, Avik Sarker1, Yurika Matsui1,2, Janani Iyer1, Zhi-Chun Lai1,2, 6 and Santhosh Girirajan1,3* 7 8 1. Department of Biochemistry and Molecular Biology, Pennsylvania State University, 9 University Park, PA 16802 10 2. Department of Biology, Pennsylvania State University, University Park, PA 16802 11 3. Department of Anthropology, Pennsylvania State University, University Park, PA 16802 12 4 contributed equally to work 13 14 *Correspondence: 15 Santhosh Girirajan, MBBS, PhD 16 205A Life Sciences Building 17 Pennsylvania State University 18 University Park, PA 16802 19 E-mail: [email protected] 20 Phone: 814-865-0674 21 1 bioRxiv preprint doi: https://doi.org/10.1101/855338; this version posted December 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 22 ABSTRACT 23 While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non- 24 neuronal phenotypes, functional studies evaluating these regions have focused on the molecular 25 basis of neuronal defects.
    [Show full text]
  • Literature Mining Sustains and Enhances Knowledge Discovery from Omic Studies
    LITERATURE MINING SUSTAINS AND ENHANCES KNOWLEDGE DISCOVERY FROM OMIC STUDIES by Rick Matthew Jordan B.S. Biology, University of Pittsburgh, 1996 M.S. Molecular Biology/Biotechnology, East Carolina University, 2001 M.S. Biomedical Informatics, University of Pittsburgh, 2005 Submitted to the Graduate Faculty of School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2016 UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Rick Matthew Jordan It was defended on December 2, 2015 and approved by Shyam Visweswaran, M.D., Ph.D., Associate Professor Rebecca Jacobson, M.D., M.S., Professor Songjian Lu, Ph.D., Assistant Professor Dissertation Advisor: Vanathi Gopalakrishnan, Ph.D., Associate Professor ii Copyright © by Rick Matthew Jordan 2016 iii LITERATURE MINING SUSTAINS AND ENHANCES KNOWLEDGE DISCOVERY FROM OMIC STUDIES Rick Matthew Jordan, M.S. University of Pittsburgh, 2016 Genomic, proteomic and other experimentally generated data from studies of biological systems aiming to discover disease biomarkers are currently analyzed without sufficient supporting evidence from the literature due to complexities associated with automated processing. Extracting prior knowledge about markers associated with biological sample types and disease states from the literature is tedious, and little research has been performed to understand how to use this knowledge to inform the generation of classification models from ‘omic’ data. Using pathway analysis methods to better understand the underlying biology of complex diseases such as breast and lung cancers is state-of-the-art. However, the problem of how to combine literature- mining evidence with pathway analysis evidence is an open problem in biomedical informatics research.
    [Show full text]
  • Phosphatidylglycerol Incorporates Into Cardiolipin to Improve
    www.nature.com/scientificreports OPEN Phosphatidylglycerol Incorporates into Cardiolipin to Improve Mitochondrial Activity and Inhibits Received: 3 July 2017 Accepted: 7 March 2018 Infammation Published: xx xx xxxx Wei-Wei Chen1, Yu-Jen Chao1, Wan-Hsin Chang1, Jui-Fen Chan1 & Yuan-Hao Howard Hsu1,2 Chronic infammation and concomitant oxidative stress can induce mitochondrial dysfunction due to cardiolipin (CL) abnormalities in the mitochondrial inner membrane. To examine the responses of mitochondria to infammation, macrophage-like RAW264.7 cells were activated by Kdo2-Lipid A (KLA) in our infammation model, and then the mitochondrial CL profle, mitochondrial activity, and the mRNA expression of CL metabolism-related genes were examined. The results demonstrated that KLA activation caused CL desaturation and the partial loss of mitochondrial activity. KLA activation also induced the gene upregulation of cyclooxygenase (COX)-2 and phospholipid scramblase 3, and the gene downregulation of COX-1, lipoxygenase 5, and Δ-6 desaturase. We further examined the phophatidylglycerol (PG) inhibition efects on infammation. PG supplementation resulted in a 358- fold inhibition of COX-2 mRNA expression. PG(18:1)2 and PG(18:2)2 were incorporated into CLs to considerably alter the CL profle. The decreased CL and increased monolysocardiolipin (MLCL) quantity resulted in a reduced CL/MLCL ratio. KLA-activated macrophages responded diferentially to PG(18:1)2 and PG(18:2)2 supplementation. Specifcally, PG(18:1)2 induced less changes in the CL/MLCL ratio than did PG(18:2)2, which resulted in a 50% reduction in the CL/MLCL ratio. However, both PG types rescued 20–30% of the mitochondrial activity that had been afected by KLA activation.
    [Show full text]
  • Arnau Soler2019.Pdf
    This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Genetic responses to environmental stress underlying major depressive disorder Aleix Arnau Soler Doctor of Philosophy The University of Edinburgh 2019 Declaration I hereby declare that this thesis has been composed by myself and that the work presented within has not been submitted for any other degree or professional qualification. I confirm that the work submitted is my own, except where work which has formed part of jointly-authored publications has been included. My contribution and those of the other authors to this work are indicated below. I confirm that appropriate credit has been given within this thesis where reference has been made to the work of others. I composed this thesis under guidance of Dr. Pippa Thomson. Chapter 2 has been published in PLOS ONE and is attached in the Appendix A, chapter 4 and chapter 5 are published in Translational Psychiatry and are attached in the Appendix C and D, and I expect to submit chapter 6 as a manuscript for publication.
    [Show full text]
  • Analysis of Sequence Architecture at Human-Gibbon Synteny Breaks
    Downloaded from genome.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Girirajan et al Sequencing human-gibbon breakpoints of synteny reveals mosaic new insertions at rearrangement sites Santhosh Girirajan1*, Lin Chen1*, Tina Graves2, Tomas Marques-Bonet1, Mario Ventura3, Catrina Fronick2, Lucinda Fulton2, Mariano Rocchi3, Robert S. Fulton2, Richard K. Wilson2, Elaine R. Mardis2 and Evan E. Eichler1† 1. Department of Genome Sciences, Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, Washington, USA 2. Genome Sequencing Center, Washington University, St. Louis, Missouri, USA 3. Department of Genetics and Microbiology, University of Bari, 70126 Bari, Italy *These authors contributed equally to work †Corresponding author: Evan E. Eichler, PhD University of Washington School of Medicine Howard Hughes Medical Institute Box 355065 Foege S413C, 1705 NE Pacific St. Seattle, WA 98195 E-mail: [email protected] 1 Downloaded from genome.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Girirajan et al ABSTRACT The gibbon genome exhibits extensive karyotypic diversity with an increased rate of chromosomal rearrangements during evolution. In an effort to understand the mechanistic origin and implications of these rearrangement events, we sequenced 24 synteny breakpoint regions in the white-cheeked gibbon (Nomascus leucogenys, NLE) in the form of high-quality BAC insert sequences (4.2 Mbp). While there is a significant deficit of breakpoints in genes, we identified seven human gene structures, involved in signaling pathways (DEPDC4, GNG10), phospholipid metabolism (ENPP5, PLSCR2), β-oxidation (ECH1), cellular structure and transport (HEATR4), and transcription (GIOT1), that have been disrupted in the NLE gibbon lineage.
    [Show full text]