In Silico Analysis of Coding Snps and 3
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Diagnosing Platelet Secretion Disorders: Examples Cases
Diagnosing platelet secretion disorders: examples cases Martina Daly Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Disclosures for Martina Daly In compliance with COI policy, ISTH requires the following disclosures to the session audience: Research Support/P.I. No relevant conflicts of interest to declare Employee No relevant conflicts of interest to declare Consultant No relevant conflicts of interest to declare Major Stockholder No relevant conflicts of interest to declare Speakers Bureau No relevant conflicts of interest to declare Honoraria No relevant conflicts of interest to declare Scientific Advisory No relevant conflicts of interest to declare Board Platelet granule release Agonists (FIIa, Collagen, ADP) Signals Activation Shape change Membrane fusion Release of granule contents Platelet storage organelles lysosomes a granules Enzymes including cathepsins Adhesive proteins acid hydrolases Clotting factors and their inhibitors Fibrinolytic factors and their inhibitors Proteases and antiproteases Growth and mitogenic factors Chemokines, cytokines Anti-microbial proteins Membrane glycoproteins dense (d) granules ADP/ATP Serotonin histamine inorganic polyphosphate Platelet a-granule contents Type Prominent components Membrane glycoproteins GPIb, aIIbb3, GPVI Clotting factors VWF, FV, FXI, FII, Fibrinogen, HMWK, FXIII? Clotting inhibitors TFPI, protein S, protease nexin-2 Fibrinolysis components PAI-1, TAFI, a2-antiplasmin, plasminogen, uPA Other protease inhibitors a1-antitrypsin, a2-macroglobulin -
Comprehensive Analysis of Differentially Expressed Lncrnas Mirnas and Mrna and Their Cerna Network of Patients with Rare-Earth Pneumoconiosis
fgene-12-700398 July 13, 2021 Time: 17:18 # 1 ORIGINAL RESEARCH published: 19 July 2021 doi: 10.3389/fgene.2021.700398 Comprehensive Analysis of Differentially Expressed lncRNAs miRNAs and mRNA and Their ceRNA Network of Patients With Rare-Earth Pneumoconiosis Xue-min Shi, Yu-chao Bai, Yan-rong Gao, Ning Bu, Hai-yan Song, Li-hua Huang, Yu-hang Zhao* and Su-hua Wang* School of Public Health, Baotou Medical College, Baotou, China Rare-earth pneumoconiosis (REP) is the main occupational disease of rare earth exposed workers and there is no specific treatment. In this study, we performed high-throughput sequencing on the plasma of nine REP to describe and analyze the expression profiles of long non-coding RNA (lncRNA), micro RNA (miRNA) and Edited by: Duc-Hau Le, mRNA and investigate their regulatory networks. Our results identified a total of 125 Vingroup Big Data Institute, Vietnam lncRNAs, 5 miRNAs, and 82 mRNAs were differentially expressed in the plasma of Reviewed by: patients with REP. Furthermore, Ontology (GO) and Kyoto Encyclopedia of Genes and Eman Toraih, Genomes (KEGG) analysis were used to analyze the differentially expressed non-coding Tulane University, United States Isha Monga, RNAs (ncRNA). We found the differential expression of ncRNA are mainly related to Columbia University Irving Medical the response of cells to stimulation, Hedgehog signaling pathway and so on. We Center, United States also constructed lncRNA-miRNA-mRNA networks to further explore their underlying *Correspondence: Yu-hang Zhao mechanism and possible relationships in REP. We found that in the competitive [email protected] endogenous RNA (ceRNA) networks, lncRNA acts as a sponge of miRNA to regulate the Su-hua Wang target gene. -
ZCCHC8, the Nuclear Exosome Targeting Component, Is Mutated in Familial Pulmonary Fibrosis and Is Required for Telomerase RNA Maturation
Downloaded from genesdev.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation Dustin L. Gable,1,2,3 Valeriya Gaysinskaya,2,3 Christine C. Atik,2,3 C. Conover Talbot Jr.,4 Byunghak Kang,5 Susan E. Stanley,1,2,3 Elizabeth W. Pugh,6 Nuria Amat-Codina,2,3 Kara M. Schenk,7 Murat O. Arcasoy,8 Cory Brayton,5 Liliana Florea,6 and Mary Armanios2,3,6,9,10 1Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; 2Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA; 3Telomere Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA; 4Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; 5Department of Comparative and Molecular Pathobiology, 6Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA; 7Osler Medical Housestaff Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; 8Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27708, USA; 9Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA Short telomere syndromes manifest as familial idiopathic pulmonary fibrosis; they are the most common premature aging disorders. We used genome-wide linkage to identify heterozygous loss of function of ZCCHC8, a zinc-knuckle containing protein, as a cause of autosomal dominant pulmonary fibrosis. ZCCHC8 associated with TR and was required for telomerase function. -
Environmental Influences on Endothelial Gene Expression
ENDOTHELIAL CELL GENE EXPRESSION John Matthew Jeff Herbert Supervisors: Prof. Roy Bicknell and Dr. Victoria Heath PhD thesis University of Birmingham August 2012 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT Tumour angiogenesis is a vital process in the pathology of tumour development and metastasis. Targeting markers of tumour endothelium provide a means of targeted destruction of a tumours oxygen and nutrient supply via destruction of tumour vasculature, which in turn ultimately leads to beneficial consequences to patients. Although current anti -angiogenic and vascular targeting strategies help patients, more potently in combination with chemo therapy, there is still a need for more tumour endothelial marker discoveries as current treatments have cardiovascular and other side effects. For the first time, the analyses of in-vivo biotinylation of an embryonic system is performed to obtain putative vascular targets. Also for the first time, deep sequencing is applied to freshly isolated tumour and normal endothelial cells from lung, colon and bladder tissues for the identification of pan-vascular-targets. Integration of the proteomic, deep sequencing, public cDNA libraries and microarrays, delivers 5,892 putative vascular targets to the science community. -
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. -
ATR Pathway Inhibition Is Synthetically Lethal in Cancer Cells with ERCC1 Deficiency
Published OnlineFirst March 24, 2014; DOI: 10.1158/0008-5472.CAN-13-3229 Cancer Therapeutics, Targets, and Chemical Biology Research ATR Pathway Inhibition Is Synthetically Lethal in Cancer Cells with ERCC1 Deficiency Kareem N. Mohni, Gina M. Kavanaugh, and David Cortez Abstract The DNA damage response kinase ATR and its effector kinase CHEK1 are required for cancer cells to survive oncogene-induced replication stress. ATR inhibitors exhibit synthetic lethal interactions, with deficiencies in the DNA damage response enzymes ATM and XRCC1 and with overexpression of the cell cycle kinase cyclin E. Here, we report a systematic screen to identify synthetic lethal interactions with ATR pathway–targeted drugs, rationalized by their predicted therapeutic utility in the oncology clinic. We found that reduced function in the ATR pathway itself provided the strongest synthetic lethal interaction. In addition, we found that loss of the structure-specific endonuclease ERCC1-XPF (ERCC4) is synthetic lethal with ATR pathway inhibitors. ERCC1- deficient cells exhibited elevated levels of DNA damage, which was increased further by ATR inhibition. When treated with ATR or CHEK1 inhibitors, ERCC1-deficient cells were arrested in S-phase and failed to complete cell-cycle transit even after drug removal. Notably, triple-negative breast cancer cells and non–small cell lung cancer cells depleted of ERCC1 exhibited increased sensitivity to ATR pathway–targeted drugs. Overall, we concluded that ATR pathway–targeted drugs may offer particular utility in cancers with reduced ATR pathway function or reduced levels of ERCC4 activity. Cancer Res; 74(10); 1–11. Ó2014 AACR. Introduction repair pathway such as homologous recombination or post- – Replicating DNA is sensitive to a wide array of endogenous replicative repair to remove the PARP DNA complexes (7). -
Genomic Approaches to Reproductive Disorders
Genomic Approaches to Reproductive Disorders Aleksandar Rajkovic Dept Obstetrics Gynecology and Reproductive Sciences University of Pittsburgh Magee Womens Research Institute Pittsburgh, PA Preconceptional Care Scope • Half of Pregnancies are Unintended • Medical Conditions • Mental Conditions • Immunization History • Nutritional Issues • Family History/Genetic Risk • Occupational/Environmental Exposures • Tobacco/Drug Abuse • Social Issues Preconceptional genetic screening Ethnic: Sickle cell disease Tay–Sachs disease Pan-ethnic: cystic fibrosis fragile X syndrome Spinal muscular atrophy Mendelian Inheritance • 5593 phenotypes for which molecular basis known • 3452 genes with phenotype causing mutation • Over 15,000 mutations to date known Preconceptional Pan Ethnic Testing • Screens for known mutations in more than 100 genes, easy on genetic counsellors • The screen is pan-ethnic • Useful also for couples undergoing IVF and potentially PGD • 1:5 will be carriers of a Mendelian disorder. • $600 (529 Euros) for the couple Genetic Counselling • Objective of the test • Test Methodology • Type of sample required (parents, siblings) • Possible outcomes (abnormal results, result of unknown clinical significance) ClinVar Stars and their interpretation Number of golden stars No submitter provided an interpretation with assertion criteria (no assertion criteria provided), none or no interpretation was provided (no assertion provided) At least one submitter provided an interpretation with assertion criteria (criteria provided, single submitter) -
Snps) Distant from Xenobiotic Response Elements Can Modulate Aryl Hydrocarbon Receptor Function: SNP-Dependent CYP1A1 Induction S
Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2018/07/06/dmd.118.082164.DC1 1521-009X/46/9/1372–1381$35.00 https://doi.org/10.1124/dmd.118.082164 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 46:1372–1381, September 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Single Nucleotide Polymorphisms (SNPs) Distant from Xenobiotic Response Elements Can Modulate Aryl Hydrocarbon Receptor Function: SNP-Dependent CYP1A1 Induction s Duan Liu, Sisi Qin, Balmiki Ray,1 Krishna R. Kalari, Liewei Wang, and Richard M. Weinshilboum Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics (D.L., S.Q., B.R., L.W., R.M.W.) and Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.K.), Mayo Clinic, Rochester, Minnesota Received April 22, 2018; accepted June 28, 2018 ABSTRACT Downloaded from CYP1A1 expression can be upregulated by the ligand-activated aryl fashion. LCLs with the AA genotype displayed significantly higher hydrocarbon receptor (AHR). Based on prior observations with AHR-XRE binding and CYP1A1 mRNA expression after 3MC estrogen receptors and estrogen response elements, we tested treatment than did those with the GG genotype. Electrophoretic the hypothesis that single-nucleotide polymorphisms (SNPs) map- mobility shift assay (EMSA) showed that oligonucleotides with the ping hundreds of base pairs (bp) from xenobiotic response elements AA genotype displayed higher LCL nuclear extract binding after (XREs) might influence AHR binding and subsequent gene expres- 3MC treatment than did those with the GG genotype, and mass dmd.aspetjournals.org sion. -
Hyperphosphorylation Repurposes the CRL4B E3 Ligase to Coordinate Mitotic Entry and Exit
Research Collection Doctoral Thesis Identification and Characterization of Novel Cullin 4-based E3 Ligases in Somatic Cell Division Author(s): da Graça Gilberto, Samuel Filipe Publication Date: 2017 Permanent Link: https://doi.org/10.3929/ethz-b-000219014 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH NO. 24583 Identification and characterization of novel Cullin 4-based E3 ligases in somatic cell division A thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH ZURICH (Dr. sc. ETH Zurich) Presented by SAMUEL FILIPE DA GRAÇA GILBERTO MSc in Biochemistry, University of Lisbon Born on 21.02.1988 Citizen of Portugal Accepted on the recommendation of Prof. Dr. Matthias Peter Prof. Dr. Anton Wutz 2017 Table of contents 1. General introduction ..................................................................................................................1 1.1. The ubiquitylation machinery ....................................................................................................... 1 1.2. Principles of cell cycle regulation: a focus on CRLs and the APC/C .............................................. 3 1.3. Cullin-4 RING E3 ligases: cell-cycle regulation and beyond ........................................................ 14 1.4. Functional distinctions between CUL4A and CUL4B .................................................................. -
Elucidating the Role of POT1 C-Terminal Mutations in Cancer
Science Highlight – MarchApril 2017 2017 Elucidating the Role of POT1 C-terminal Mutations in Cancer The ends of our chromosomes are protected by nucleoprotein complexes known as telomeres. The hetero-hexameric shelterin complex (POT1, TPP1, TRF1, TRF2, TIN2 RAP1) binds single and double-stranded telomeric DNA and plays a critical role in telomere length regulation and maintenance [1]. POT1, a protein component of shelterin, binds single stranded telomeric DNA with high affinity and specificity using its two N-terminal OB folds. The C-terminus of POT1 is involved in TPP1 binding and together they are involved in regulating telomerase access to the telomeric overhang and suppression of undesired ATR dependent DNA damage response at telomeres. Naturally occurring mutations of POT1 are associated with familial melanoma and glioma and chronic lymphocytic leukemia [2-4]. How these two proteins interact with each other to form a functional telomeric complex and how POT1 naturally occurring mutations contribute to malignant cancer is currently unknown. Using the method of single-wavelength anomalous dispersion (SAD) and a mercury derivative the structure of POT1 C-terminal domain (POT1C) in complex with its TPP1 interacting domain to 2.1 Å resolution was determined. The data was collected at SSRL BL12-2 and the study was published in Nature Communications, 8:14928 (April 2017). The structure revealed that POT1C consists of an OB fold and a holiday junction resolvase domain both of which are involved in extensive contacts with the TPP1 polypeptide, a long coil with four helices (Figure 1). The atomic structure of POT1C- TPP1 was then used to design a host of biochemical and cell based assays geared toward understanding the role of POT1C naturally occurring mutations in cancer. -
A POT1 Mutation Implicates Defective Telomere End Fill-In and Telomere Truncations in Coats Plus
Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus Hiroyuki Takai,1,8 Emma Jenkinson,2,8 Shaheen Kabir,1 Riyana Babul-Hirji,3 Nasrin Najm-Tehrani,4 David A. Chitayat,5,6 Yanick J. Crow,2,7,9 and Titia de Lange1,9 1The Rockefeller University, New York, New York 10065, USA; 2Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, United Kingdom; 3Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1Z5, Canada; 4Department of Pediatrics, Division of Opthalmology and Visions Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1Z5, Canada; 5The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada; 6Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1Z5, Canada; 7UMR 1163, Institut National de la Santé et de la Recherche Médicale, Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Hôpital Necker, Paris 75015, France Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase α (polα)/ primase-dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. -
Supp Material.Pdf
Simon et al. Supplementary information: Table of contents p.1 Supplementary material and methods p.2-4 • PoIy(I)-poly(C) Treatment • Flow Cytometry and Immunohistochemistry • Western Blotting • Quantitative RT-PCR • Fluorescence In Situ Hybridization • RNA-Seq • Exome capture • Sequencing Supplementary Figures and Tables Suppl. items Description pages Figure 1 Inactivation of Ezh2 affects normal thymocyte development 5 Figure 2 Ezh2 mouse leukemias express cell surface T cell receptor 6 Figure 3 Expression of EZH2 and Hox genes in T-ALL 7 Figure 4 Additional mutation et deletion of chromatin modifiers in T-ALL 8 Figure 5 PRC2 expression and activity in human lymphoproliferative disease 9 Figure 6 PRC2 regulatory network (String analysis) 10 Table 1 Primers and probes for detection of PRC2 genes 11 Table 2 Patient and T-ALL characteristics 12 Table 3 Statistics of RNA and DNA sequencing 13 Table 4 Mutations found in human T-ALLs (see Fig. 3D and Suppl. Fig. 4) 14 Table 5 SNP populations in analyzed human T-ALL samples 15 Table 6 List of altered genes in T-ALL for DAVID analysis 20 Table 7 List of David functional clusters 31 Table 8 List of acquired SNP tested in normal non leukemic DNA 32 1 Simon et al. Supplementary Material and Methods PoIy(I)-poly(C) Treatment. pIpC (GE Healthcare Lifesciences) was dissolved in endotoxin-free D-PBS (Gibco) at a concentration of 2 mg/ml. Mice received four consecutive injections of 150 μg pIpC every other day. The day of the last pIpC injection was designated as day 0 of experiment.