DOCSLIB.ORG

Downloaded from the Segmental Duplication Database Website (

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Downloaded from the Segmental Duplication Database Website ( THE PATHOGENICITY OF COPY NUMBER VARIANTS IN CHILDREN WITH INTELLECTUAL DISABILITY by Farah R Zahir B.Sc., Genetics, Biochemistry, Microbiology, Bangalore University, 2003 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Medical Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) August 2011 © Farah R Zahir 2011 Abstract Intellectual disability affects 1-3% of individuals globally, and, for half the cases, the cause is unknown. Recent studies using whole genome microarray genomic hybridization have shown that submicroscopic genomic imbalance causes intellectual disability in at least 10% of idiopathic cases with normal conventional cytogenetic analysis. I established genotype- phenotype correlations for de novo copy number variants detected by previous whole genome array genome hybridization studies performed by our group in children with intellectual disability. These genotype-phenotype correlations show that genomic imbalance of genes belonging to the epigenetic regulatory category, among others, are causative of intellectual disability. I hypothesized that dosage changes in the broad functional category of genes encoding epigenetic regulatory proteins are more likely to be pathogenic for intellectual disability than dosage changes in other kinds of genes. Epigenetic regulatory proteins include those with DNA methylation, histone modification or chromatin remodeling activity. I have selected all known genes encoding epigenetic regulatory proteins and defined probes to interrogate these candidate genes for copy number alteration as part of a custom targeted microarray design that selectively investigates all candidate genes associated with intellectual disability. We have conducted comparative genome hybridization on 177 patients with idiopathic intellectual disability using this array and on both normal parents of each affected child. We identified and independently validated 16 cases with de novo CNVs involving the epigenetic regulatory candidates. 7 of the 16 CNVs involve the same exon of the JARID2 gene, while the other 9 CNVs affect different genes. I discuss genotype-phenotype correlations for these cases and show that epigenetic perturbation by way of disruption of genes that encode epigenetic regulators is an important cause for intellectual disability. ii Preface This dissertation is comprised of both published and unpublished material as follows; Chapter 2, 3 and 4 are verbatim reproductions of published manuscripts. The papers detail genotype-phenotype correlations for four patients identified to have previously unknown genetic defects by studies undertaken at the Medical Genetics Research Unit in collaboration with the British Columbia Genome Sciences Center and headed by Dr. Jan M. Friedman. This study and the subsequent genotype-phenotype correlations studies arising from this work that are detailed below were approved by the University of British Columbia Clinical Research Ethics Board (certificate number C04-0537). For chapter 2, ‗Novel deletions of 14q11.2 associated with intellectual disability and similar minor anomalies in three children‘ (Journal of Medical Genetics. 2007 Sep;44(9):556-61), chapter 3, ‗A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1α’ (Journal of Medical Genetics. 2008 Apr;45(4):239-43) and chapter 4, ‘A novel de novo 1.1 Mb duplication of 17q21.33 associated with cognitive impairment and other anomalies‘ (American Journal of Medical Genetics Part A. 2009 Jun;149A(6):1257-62.), I was solely in charge of researching the genotype-phenotype correlation and preparing the manuscripts with input from all contributing authors. Chapters 5 and 6 are verbatim reproductions of published manuscripts for which I was a contributing author. Chapter 5, ‗Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognizable syndrome‘ (Journal of Medical Genetics. 2010 Mar;47(3):155-61), contains a clinical comparison and discussion of candidate genes for a newly defined Intellectual Disability syndrome. I contributed clinical data on the patient from our center included in this study and also assisted with researching candidate genes for the syndrome. Chapter 6 ‗The duplication 8q12 Case: A characteristic syndrome associated with microduplication of 8q12, inclusive of CHD7‘ (European Journal of Medical Genetics. 2009 Nov-Dec;52(6):436-9.) contains a detailed clinical case report of a patient with a novel genetic defect detected in the same study iii headed by Dr. Jan M Friedman that led to the works appearing in chapters 2, 3 and 4. For this case I contributed an extensive genotype-phenotype correlation analysis, delineating candidate genes. The manuscript was prepared by Dr. Anna Lehman, who provided the clinical description of the patient. Chapters 1 and 8 contain large sections that are taken from two published review papers that I prepared. The discussion of microarrays appearing in chapter 1, the main technology underlying experiments detailed in this thesis, is taken from ‗The impact of array genomic hybridization on mental retardation research: a review of current technologies and their clinical utility‘ (Clinical Genetics. 2007 Oct;72(4):271-87) a review article published in 2007 written with Dr. Jan M. Friedman as my co-author. I have updated the text as required to reflect current knowledge for sections reproduced from this work. The sections introducing epigenetics and discussing the contribution of epigenetic regulation to neurodevelopment contained in chapter 1 and chapter 8 are taken from the review article, ‗Epigenetic impacts on neurodevelopment: pathophysiological mechanisms and genetic modes of action‘ (Pediatric Research. 2011 May;69(5 Pt 2):92R-100R) that I wrote in collaboration with Dr. Carolyn Brown. Chapter 7 is previously unpublished. The chapter details the main project of my doctoral research that I conducted in collaboration with Dr. Tracy Tucker who was in charge of a study to design and test a microarray probing selected genes. I was in charge of the selection of candidate genes to test my research hypothesis, which I contributed to the design (36% of the design). Dr. Jan Friedman, Dr. Sylvie Langlois and Dr. Patrice Eydoux provided the rest of the gene selection. Dr. Jacques Michaud (CHU Sainte-Justine, Montreal) provided patient samples and clinical reports. I was solely in charge of the entire validation component of the study that used an independent technology to assess the findings of the microarray. I have contributed this chapter as a joint primary author to a manuscript in preparation by Dr. Tracy Tucker detailing the results of this project. This study was approved by the University of British Columbia Clinical Research Ethics Board (certificate number H07-00392). iv Table of Contents Abstract .............................................................................................................................. ii Preface ................................................................................................................................iii Table of Contents ............................................................................................................... v List of Tables ......................................................................................................................xi List of Figures ...................................................................................................................xii List of Abbreviations ........................................................................................................ xiv Acknowledgements ...........................................................................................................xv Dedication ......................................................................................................................... xvi Chapter 1: Introduction .................................................................................................... 1 1.1 Definition of Intellectual Disability ............................................................................ 1 1.2 Etiology of Intellectual Disability .............................................................................. 1 1.2.1 The genetic etiology of Intellectual Disability ................................................ 2 1.2.1.1 Cytogenetically detectable genetic aberrations ............................................. 2 1.2.1.2 Genetic aberrations not detectable cytogenetically.................................... 2 1.2.1.3 Single gene mutations ............................................................................... 3 1.3 Epigenetics - definition and overview of epigenetic processes ................................ 4 1.4 Epigenetic perturbation in neurogenetic disorders .................................................. 7 1.4.1 Dosage change of genes encoding epigenetic factors as the mechanism of pathogenicity ...........................................................................................................11 1.5 Microarray technology ...........................................................................................12 1.5.1 Types of arrays and factors that influence their effective resolution ................14 1.5.2 The bioinformatics of AGH ..............................................................................17 1.5.3 Comparison to reference genome(s) ...............................................................18
Load more

Recommended publications
  • A Novel Small-Molecule Inhibitor of Endosomal Tlrs Reduces Inflammation and Alleviates Autoimmune Disease Symptoms in Murine Models
    cells Article A Novel Small-Molecule Inhibitor of Endosomal TLRs Reduces Inflammation and Alleviates Autoimmune Disease Symptoms in Murine Models 1, 1, 1, 1 Mahesh Chandra Patra y , Asma Achek y, Gi-Young Kim y, Suresh Panneerselvam , Hyeon-Jun Shin 1, Wook-Yong Baek 2, Wang Hee Lee 1, June Sung 1, Uisuk Jeong 1, Eun-Young Cho 1, Wook Kim 1, Eunha Kim 1, Chang-Hee Suh 2 and Sangdun Choi 1,* 1 Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea; [email protected] (M.C.P.); [email protected] (A.A.); [email protected] (G.-Y.K.); [email protected] (S.P.); [email protected] (H.-J.S.); [email protected] (W.H.L.); [email protected] (J.S.); [email protected] (U.J.); [email protected] (E.-Y.C.); [email protected] (W.K.); [email protected] (E.K.) 2 Department of Rheumatology, Ajou University School of Medicine, Suwon 16499, Korea; [email protected] (W.-Y.B.); [email protected] (C.-H.S.) * Correspondence: [email protected] These authors have contributed equally to this work. y Received: 15 February 2020; Accepted: 7 July 2020; Published: 9 July 2020 Abstract: Toll-like receptors (TLRs) play a fundamental role in the inflammatory response against invading pathogens. However, the dysregulation of TLR-signaling pathways is implicated in several autoimmune/inflammatory diseases. Here, we show that a novel small molecule TLR-inhibitor (TAC5) and its derivatives TAC5-a, TAC5-c, TAC5-d, and TAC5-e predominantly antagonized poly(I:C) (TLR3)-, imiquimod (TLR7)-, TL8-506 (TLR8)-, and CpG-oligodeoxynucleotide (TLR9)-induced signaling pathways.
    [Show full text]
  • Identification of Potential Key Genes and Pathway Linked with Sporadic Creutzfeldt-Jakob Disease Based on Integrated Bioinformatics Analyses
    medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Identification of potential key genes and pathway linked with sporadic Creutzfeldt-Jakob disease based on integrated bioinformatics analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 , Iranna Kotturshetti 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. 3. Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka 562209, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Abstract Sporadic Creutzfeldt-Jakob disease (sCJD) is neurodegenerative disease also called prion disease linked with poor prognosis. The aim of the current study was to illuminate the underlying molecular mechanisms of sCJD. The mRNA microarray dataset GSE124571 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened.
    [Show full text]
  • Hippo and Sonic Hedgehog Signalling Pathway Modulation of Human Urothelial Tissue Homeostasis
    Hippo and Sonic Hedgehog signalling pathway modulation of human urothelial tissue homeostasis Thomas Crighton PhD University of York Department of Biology November 2020 Abstract The urinary tract is lined by a barrier-forming, mitotically-quiescent urothelium, which retains the ability to regenerate following injury. Regulation of tissue homeostasis by Hippo and Sonic Hedgehog signalling has previously been implicated in various mammalian epithelia, but limited evidence exists as to their role in adult human urothelial physiology. Focussing on the Hippo pathway, the aims of this thesis were to characterise expression of said pathways in urothelium, determine what role the pathways have in regulating urothelial phenotype, and investigate whether the pathways are implicated in muscle-invasive bladder cancer (MIBC). These aims were assessed using a cell culture paradigm of Normal Human Urothelial (NHU) cells that can be manipulated in vitro to represent different differentiated phenotypes, alongside MIBC cell lines and The Cancer Genome Atlas resource. Transcriptomic analysis of NHU cells identified a significant induction of VGLL1, a poorly understood regulator of Hippo signalling, in differentiated cells. Activation of upstream transcription factors PPARγ and GATA3 and/or blockade of active EGFR/RAS/RAF/MEK/ERK signalling were identified as mechanisms which induce VGLL1 expression in NHU cells. Ectopic overexpression of VGLL1 in undifferentiated NHU cells and MIBC cell line T24 resulted in significantly reduced proliferation. Conversely, knockdown of VGLL1 in differentiated NHU cells significantly reduced barrier tightness in an unwounded state, while inhibiting regeneration and increasing cell cycle activation in scratch-wounded cultures. A signalling pathway previously observed to be inhibited by VGLL1 function, YAP/TAZ, was unaffected by VGLL1 manipulation.
    [Show full text]
  • Supp Table 6.Pdf
    Supplementary Table 6. Processes associated to the 2037 SCL candidate target genes ID Symbol Entrez Gene Name Process NM_178114 AMIGO2 adhesion molecule with Ig-like domain 2 adhesion NM_033474 ARVCF armadillo repeat gene deletes in velocardiofacial syndrome adhesion NM_027060 BTBD9 BTB (POZ) domain containing 9 adhesion NM_001039149 CD226 CD226 molecule adhesion NM_010581 CD47 CD47 molecule adhesion NM_023370 CDH23 cadherin-like 23 adhesion NM_207298 CERCAM cerebral endothelial cell adhesion molecule adhesion NM_021719 CLDN15 claudin 15 adhesion NM_009902 CLDN3 claudin 3 adhesion NM_008779 CNTN3 contactin 3 (plasmacytoma associated) adhesion NM_015734 COL5A1 collagen, type V, alpha 1 adhesion NM_007803 CTTN cortactin adhesion NM_009142 CX3CL1 chemokine (C-X3-C motif) ligand 1 adhesion NM_031174 DSCAM Down syndrome cell adhesion molecule adhesion NM_145158 EMILIN2 elastin microfibril interfacer 2 adhesion NM_001081286 FAT1 FAT tumor suppressor homolog 1 (Drosophila) adhesion NM_001080814 FAT3 FAT tumor suppressor homolog 3 (Drosophila) adhesion NM_153795 FERMT3 fermitin family homolog 3 (Drosophila) adhesion NM_010494 ICAM2 intercellular adhesion molecule 2 adhesion NM_023892 ICAM4 (includes EG:3386) intercellular adhesion molecule 4 (Landsteiner-Wiener blood group)adhesion NM_001001979 MEGF10 multiple EGF-like-domains 10 adhesion NM_172522 MEGF11 multiple EGF-like-domains 11 adhesion NM_010739 MUC13 mucin 13, cell surface associated adhesion NM_013610 NINJ1 ninjurin 1 adhesion NM_016718 NINJ2 ninjurin 2 adhesion NM_172932 NLGN3 neuroligin
    [Show full text]
  • Regulated T Cell Pre-Mrna Splicing As Genetic Marker of T Cell Suppression
    Regulated T cell pre-mRNA splicing as genetic marker of T cell suppression by Boitumelo Mofolo Thesis presented for the degree of Master of Science (Bioinformatics) Institute of Infectious Disease and Molecular Medicine University of Cape Town (UCT) Supervisor: Assoc. Prof. Nicola Mulder August 2012 University of Cape Town The copyright of this thesis vests in the author. No quotation from it or information derived from it is to be published without full acknowledgementTown of the source. The thesis is to be used for private study or non- commercial research purposes only. Cape Published by the University ofof Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author. University Declaration I, Boitumelo Mofolo, declare that all the work in this thesis, excluding that has been cited and referenced, is my own. Signature Signature Removed Boitumelo Mofolo University of Cape Town Copyright©2012 University of Cape Town All rights reserved 1 ABSTRACT T CELL NORMAL T CELL SUPPRESSION p110 p110 MV p85 PI3K AKT p85 PI3K PHOSPHORYLATION NO PHOSHORYLATION HIV cytoplasm HCMV LCK-011 PRMT5-006 SHIP145 SIP110 RV LCK-010 VCL-204 ATM-016 PRMT5-018 ATM-002 CALD1-008 LCK-006 MXI1-001 VCL-202 NRP1-201 MXI1-007 CALD1-004 nucleus Background: Measles is a highly contagious disease that mainly affects children and according to the World Health Organisation (WHO), was responsible for over 164000 deaths in 2008, despite the availability of a safe and cost-effective vaccine [56]. The Measles virus (MV) inactivates T- cells, rendering them dysfunctional, and results in virally induced immunosuppression which shares certain features with thatUniversity induced by HIV.
    [Show full text]
  • Research Study on Analysis/Use Technologies Of
    NEDO -PR- 9601 . t-Afr 9 <*, t y y a m m m;s'i <d m % ¥fi69^3fl OF THS D0< nr §NS SrX^;i/dr — SE5fe tt0>iA ?T Y)/3? X h U — DISCLAIMER Portions of this document may be illegible electronic image products. Images are produced from the best available original document. mm) 140 (m ^ a m) ZUMtLfzo 8 B X (##%) R% i. m ^ mm sbs i ftJX v n. #&#%%## 1$ (±cAc # @± 1. $ i 2. i s. 3 4. 21#E#y/A#$rxtHtT 3 #2# rfJ cf fMf 6 i %#±% rfrW #tf 7 i-i rf: W #ff 7 i - 2 ##m# 14 (1) 14 (2) 24 (3) xk# w- 27 ( 4 ) iSlS# -t 7* )V <7)fSS TUa mi 34 (5) 'E-60te6O#S TfrW mu 40 1-3 SX f'JX 44 (1) 44 (2) mm 48 1 —- 11-4—4 Mmzx&nfe htb #± 51 (1) cDNA-fishing urn 51 (2) hybridization HTB 54 1-1-5 ww 55 1 - 2 HTB 58 2. 59 2 -1 a 7 4 mem 59 2-1-1 Fluorescent Differential Display(FDD) mem 60 2-1-2 Molecular Indexing mem ## 62 2-1-3 cDNA Microarray mem 63 2-1-4 c 66 2-2 ####? 72 2-2-1 #* 72 2-2-2 m @z (## 74 3. &#?)#%?### 84 3 -1 84 3 - 1 -1 1%^ c 84 (1) e 84 (2) e 85 3 - 1 - 2 HI S3 92 (1) HTB 93 (2) y;i/y7 T& HTB #2 93 (3) 7 y TXV > T& ## $ 95 (4) >##& HTB #± 98 3 - l - 3 om#; HTB mz 98 (1) t^x^xx? >vi HTB #± 99 (2) 77-/^4'7'V'yK&/7 — /\/f7'V yK& e# $ 99 (3) 7 T-y^4 77 W# HTffi 103 3- 2 105 (1) X# 105 (2) amwuy < i/-y 3 > 109 4.
    [Show full text]
  • Characterization of the Prohormone Complement in Cattle Using Genomic
    BMC Genomics BioMed Central Research article Open Access Characterization of the prohormone complement in cattle using genomic libraries and cleavage prediction approaches Bruce R Southey*1,2, Sandra L Rodriguez-Zas2 and Jonathan V Sweedler1 Address: 1Department of Chemistry, University of Illinois, Urbana, IL, USA and 2Department of Animal Sciences, University of Illinois, Urbana IL, USA Email: Bruce R Southey* - [email protected]; Sandra L Rodriguez-Zas - [email protected]; Jonathan V Sweedler - [email protected] * Corresponding author Published: 16 May 2009 Received: 10 December 2008 Accepted: 16 May 2009 BMC Genomics 2009, 10:228 doi:10.1186/1471-2164-10-228 This article is available from: http://www.biomedcentral.com/1471-2164/10/228 © 2009 Southey et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Neuropeptides are cell to cell signalling molecules that regulate many critical biological processes including development, growth and reproduction. These peptides result from the complex processing of prohormone proteins, making their characterization both challenging and resource demanding. In fact, only 42 neuropeptide genes have been empirically confirmed in cattle. Neuropeptide research using high-throughput technologies such as microarray and mass spectrometry require accurate annotation of prohormone genes and products. However, the annotation and associated prediction efforts, when based solely on sequence homology to species with known neuropeptides, can be problematic. Results: Complementary bioinformatic resources were integrated in the first survey of the cattle neuropeptide complement.
    [Show full text]
  • The Hypothalamus As a Hub for SARS-Cov-2 Brain Infection and Pathogenesis
    bioRxiv preprint doi: https://doi.org/10.1101/2020.06.08.139329; this version posted June 19, 2020. 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-NC-ND 4.0 International license. The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis Sreekala Nampoothiri1,2#, Florent Sauve1,2#, Gaëtan Ternier1,2ƒ, Daniela Fernandois1,2 ƒ, Caio Coelho1,2, Monica ImBernon1,2, Eleonora Deligia1,2, Romain PerBet1, Vincent Florent1,2,3, Marc Baroncini1,2, Florence Pasquier1,4, François Trottein5, Claude-Alain Maurage1,2, Virginie Mattot1,2‡, Paolo GiacoBini1,2‡, S. Rasika1,2‡*, Vincent Prevot1,2‡* 1 Univ. Lille, Inserm, CHU Lille, Lille Neuroscience & Cognition, DistAlz, UMR-S 1172, Lille, France 2 LaBoratorY of Development and PlasticitY of the Neuroendocrine Brain, FHU 1000 daYs for health, EGID, School of Medicine, Lille, France 3 Nutrition, Arras General Hospital, Arras, France 4 Centre mémoire ressources et recherche, CHU Lille, LiCEND, Lille, France 5 Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and ImmunitY of Lille (CIIL), Lille, France. # and ƒ These authors contriButed equallY to this work. ‡ These authors directed this work *Correspondence to: [email protected] and [email protected] Short title: Covid-19: the hypothalamic hypothesis 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.08.139329; this version posted June 19, 2020. 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.
    [Show full text]
  • Identification of Potential and Novel Target Genes in Pituitary Prolactinoma by Bioinformatics Analysis
    AIMS Neuroscience, 8(2): 254–283. DOI: 10.3934/Neuroscience.2021014 Received: 05 November 2020 Accepted: 29 January 2021 Published: 07 February 2021 http://www.aimspress.com/journal/aimsph Research article Identification of potential and novel target genes in pituitary prolactinoma by bioinformatics analysis 1 2 3 4, Vikrant Ghatnatti , Basavaraj Vastrad , Swetha Patil , Chanabasayya Vastrad * and Iranna Kotturshetti5 1 Department of Endocrinology, J N Medical College, Belagavi and KLE Academy of Higher Education & Research 590010, Karnataka, India 2 Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India 3 Department of Obstetrics and Gynaecology, J N Medical College, Belagavi and KLE Academy of Higher Education & Research 590010, Karnataka, India 4 Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India 5 Department of Ayurveda, Rajiv Gandhi Education Society’s Ayurvedic Medical College, Ron 562209, Karanataka, India * Correspondence: Email: [email protected]; Tel: 919480073398. Abstract: Pituitary prolactinoma is one of the most complicated and fatally pathogenic pituitary adenomas. Therefore, there is an urgent need to improve our understanding of the underlying molecular mechanism that drives the initiation, progression, and metastasis of pituitary prolactinoma. The aim of the present study was to identify the key genes and signaling pathways associated with pituitary prolactinoma using bioinformatics analysis. Transcriptome microarray dataset GSE119063 was downloaded from Gene Expression Omnibus (GEO) database. Limma package in R software was used to screen DEGs. Pathway and Gene ontology (GO) enrichment analysis were conducted to identify the biological role of DEGs. A protein-protein interaction (PPI) network was constructed and analyzed by using HIPPIE database and Cytoscape software.
    [Show full text]
  • Whole Genome Sequencing Identifies Multiple Loci for Critical Illness Caused by COVID-19
    medRxiv preprint doi: https://doi.org/10.1101/2021.09.02.21262965; this version posted September 8, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . 1 Whole genome sequencing identifies multiple loci for critical 2 illness caused by COVID-19 3 ‡,1 ‡,2,3 2 1 4 Athanasios Kousathanas , Erola Pairo-Castineira , Konrad Rawlik , Alex Stuckey , Christopher 1 1 2,4 5 2 5 A Odhams , Susan Walker , Clark D Russell , Tomas Malinauskas , Jonathan Millar , Katherine 5 2 2 6 7 2 6 S Elliott , Fiona Griffiths , Wilna Oosthuyzen , Kirstie Morrice , Sean Keating , Bo Wang , Daniel 1 3 2 2 3 1 7 Rhodes , Lucija Klaric , Marie Zechner , Nick Parkinson , Andrew D. Bretherick , Afshan Siddiq , 1 1 8 9 10,11 8 Peter Goddard , Sally Donovan , David Maslove , Alistair Nichol , Malcolm G Semple , Tala 1 1 1 1 5 1 9 Zainy , Fiona Maleady-Crowe , Linda Todd , Shahla Salehi , Julian Knight , Greg Elgar , Georgia 1 1 1,12 1 13 10 Chan , Prabhu Arumugam , Tom A Fowler , Augusto Rendon , Manu Shankar-Hari , Charlotte 14 15 16 17,18 19 11 Summers , Charles Hinds , Peter Horby , Danny McAuley , Hugh Montgomery , Peter J.M. 20,21 22 23 7 12 Openshaw , Yang Wu, Jian Yang , Paul Elliott , Timothy Walsh , GenOMICC Investigators , 6 6 24 13 23andMe , Covid-19 Human Genetics Initiative , Angie Fawkes , Lee Murphy , Kathy Rowan , 3 3 3,25 1,26 *,2 14 Chris P Ponting , Veronique Vitart , James F Wilson , Richard H Scott , Sara Clohisey , *,1 *,2 *,1,27 *,2,3,4,7 15 Loukas Moutsianas , Andy Law , Mark J Caulfield , J.
    [Show full text]
  • Exploring the Possible Mechanism and Drug Targets of Huang-Qi-Gui
    Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2020, Article ID 2363262, 12 pages https://doi.org/10.1155/2020/2363262 Research Article Exploring the Possible Mechanism and Drug Targets of Huang-Qi-Gui-Zhi-Wu-Wu Decoction for the Treatment of Chemotherapy-Induced Peripheral Neuropathy on Network Pharmacology Jia-lin Gu ,1,2 Guo-li Wei,1,3 Yu-zhu Ma,1,2 Jin-zhi Zhang,1,2 Yi Ji,1,2 Ling-chang Li,1,3 Jia-lin Yu,1,3 Can-hong Hu,1,3 and Jie-ge Huo 1,3 1Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, China 2Graduate School, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210046, China 3Department of Oncology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu 210028, China Correspondence should be addressed to Jie-ge Huo; [email protected] Received 14 April 2020; Revised 7 November 2020; Accepted 12 November 2020; Published 23 November 2020 Academic Editor: Adolfo Andrade-Cetto Copyright © 2020 Jia-lin Gu et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of anticancer treatment, which may influence its successful completion. )e Huang-Qi-Gui-Zhi-Wu-Wu decoction (HQGZWWD) has been widely used to treat CIPN in China although the pharmacological mechanisms involved have not been clarified. Using the network pharmacology approach, this study investigated the potential pathogenesis of CIPN and the therapeutic mechanisms exerted by the HQGZWWD herbal formula in CIPN.
    [Show full text]
  • Loss of Grand Histone H3 Lysine 27 Trimethylation Domains Mediated Transcriptional Activation in Esophageal Squamous Cell Carcinoma
    www.nature.com/npjgenmed ARTICLE OPEN Loss of grand histone H3 lysine 27 trimethylation domains mediated transcriptional activation in esophageal squamous cell carcinoma Jian Yuan 1,2,6, Qi Jiang1,2,6, Tongyang Gong 3,6, Dandan Fan1,2,6, Ji Zhang1,2, Fukun Chen1,2, Xiaolin Zhu3, Xinyu Wang1,2, ✉ ✉ ✉ Yunbo Qiao5, Hongyan Chen 3 , Zhihua Liu 3 and Jianzhong Su 1,2,4 Trimethylation of histone H3 lysine 27 trimethylation (H3K27me3) may be recruited by repressive Polycomb complexes to mediate gene silencing, which is critical for maintaining embryonic stem cell pluripotency and differentiation. However, the roles of aberrant H3K27me3 patterns in tumorigenesis are not fully understood. Here, we discovered that grand silencer domains (breadth > 50 kb) for H3K27me3 were significantly associated with epithelial cell differentiation and exhibited high gene essentiality and conservation in human esophageal epithelial cells. These grand H3K27me3 domains exhibited high modification signals involved in gene silencing, and preferentially occupied the entirety of topologically associating domains and interact with each other. We found that widespread loss of the grand H3K27me3 domains in of esophageal squamous cell carcinomas (ESCCs) were enriched in genes involved in epithelium and endothelium differentiation, which were significantly associated with overexpression with increase of active modifications of H3K4me3, H3K4me1, and H3K27ac marks, as well as DNA hypermethylation in the gene bodies. A total of 208 activated genes with loss of grand H3K27me3 domains in ESCC were identified, where the higher expression and 1234567890():,; mutation of T-box transcription factor 20 (TBX20) were associated with worse patients’ outcomes. Our results showed that knockdown of TBX20 may have led to a striking defect in esophageal cancer cell growth and carcinogenesis-related pathway, including cell cycle and homologous recombination.
    [Show full text]