DOCSLIB.ORG

Homocysteine-Methionine Cycle Is A

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Homocysteine-Methionine Cycle Is A HOMOCYSTEINE-METHIONINE CYCLE IS A KEY METABOLIC SENSOR SYSTEM CONTROLLING METHYLATION-REGULATED PATHOLOGICAL SIGNALING - CD40 IS A PROTOTYPIC HOMOCYSTEINE-METHIONINE CYCLE REGULATED MASTER GENE A Thesis Submitted to the Temple University Graduate Board In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE by Chao Gao August 2019 Thesis Approvals: Dr. Hong Wang, Thesis Advisor, Center for Metabolic Disease Research Dr. Xiao-Feng Yang, co-Advisor, Centers for Inflammation, Translational & Clinical Lung Research, Metabolic Disease Research, and Cardiovascular Research Dr. Jun Yu, Center for Metabolic Disease Research Dr. Stefania Gallucci, Department of Microbiology and Immunology © Copyright 2019 by Chao Gao All Rights Reserved ii ABSTRACT Homocysteine-Methionine cycle is a key metabolic sensor system controlling methylation-regulated pathological signaling - CD40 is a prototypic homocysteine- methionine cycle regulated master Chao Gao Master of Science Temple University, 2019 Thesis Advisory Committee Chair: Hong Wang, MD, PhD Homocysteine-Methionine (HM) cycle produces a universal methyl group donor S-adenosylmethionine (SAM), a competitive methylation inhibitor S- adenosylhomocysteine (SAH), and an intermediate amino acid product homocysteine (Hcy). Elevated plasma levels of Hcy is termed as hyperhomocycteinemia (HHcy) which is an established risk factor for cardiovascular disease (CVD) and neural degenerative disease. We were the first to describe methylation inhibition as a mediating biochemical mechanism for endothelial injury and inflammatory monocyte differentiation in HHcy- related CVD and diabetes. We proposed metabolism-associated danger signal (MADS) recognition as a novel mechanism for metabolic risk factor-induced inflammatory responses, independent from pattern recognition receptor (PRR)-mediated pathogen- associated molecular pattern (PAMP)/danger-associated molecular pattern (DAMP) recognition. In this study, we examined the relationship of HM cycle gene expression with methylation regulation in human disease. We selected 115 genes in the extended HM iii cycle, including 31 metabolic enzymes and 84 methyltransferases (MT), examined their mRNA levels in 35 human disease conditions using a set of public databases. We discovered that: 1) HM cycle senses metabolic risk factor and controls SAM/SAH- dependent methylation. 2) Most of metabolic enzymes in HM cycle (8/11) are located in cytosol, while most of the SAM-dependent MTs (61/84) are located in the nucleus, and Hcy metabolism is absent in the nucleus. 3) 11 up-regulated, 3 down-regulated and 24 differentially regulated SAM/SAH-responsive signal pathways are involved in 7 human disease categories. 4) 8 SAM/SAH-responsive H3/H4 hypomethylation sites are identified in 8 disease conditions. We conclude that HM cycle is a key metabolic sensor system which mediates receptor-independent MADS recognition and modulates SAM/SAH-dependent methylation in human disease. We propose that HM metabolism takes place in cytosol and that nuclear methylation equilibration requires nuclear-cytosol transfer of SAM, SAH and Hcy. CD40 is a cell surface molecule which is expressed on antigen presenting cells such as monocyte, macrophage, dendritic cells and neutrophils. The costimulatory pair, CD40 and CD40L, enhances T cell activation and induce chronic inflammatory disease. Also, DNA hypomethylation on CD40 promotor induces inflammatory monocyte differentiation in chronic kidney disease. In order to figure out if CD40 is a prototypic HM cycle regulated master gene, RNA-seq analysis were performed for CD40+ and CD40- monocytes from mouse peripheral blood and 1,093 differentially expressed genes (DEGs) were selected from those two groups. All the DEGs modulate as much as 15 functional gene groups such as cytokines, enzymes and transcriptional factors. iv Furthermore, CD40+ monocytes activated trained immunity pathways especially in Acetyl-CoA generation and mevalonate pathway. In HM cycle, CD40 is a prototypic HM cycle regulated master gene to induce the most of the Hcy metabolic enzymes as well as MT, which can further modulate the methylation-regulated pathological signaling. The studies in this thesis were funded by the National Institutes of Health (NIH) grant to Dr. Hong Wang. v DEDICATION To my dearest family vi ACKNOWLEDGMENTS I would primarily like to thank my thesis advisor Dr. Hong Wang at Temple University Lewis Katz School of Medicine. As a great and dedicative scientist who devoted her life to the research work, she always encouraged me to find out the field I am really interested in and gave me all the freedom to pursue my research. Dr. Wang continuously supported my research and study with her patience, motivation, enthusiasm and immense knowledge. Her guidance helped me in all the time of research and writing of this thesis. Without her great support and encouragement, I cannot go through all the difficulties which I have met during my past two years and finally finish the project and have this thesis. Also, she was always very supportive so I could have opportunities to attend the different international conferences and present my work during past two years. Secondly, I would like to acknowledge Dr. Xiao-Feng Yang, who is my co- advisor and regularly provided scientific suggestions and insightful comments on my project. His hard questions incented me to widen my research from various perspectives. He always supported and motivated us to learn new techniques and build collaborations with other colleagues. Dr. Yang’s credible ideas have been great contributors in the completion of the thesis. Thirdly, I am very grateful to my committee members, Dr. Jun Yu and Dr. Stefania Gallucci, for their encouragement and positive critiques throughout my committee meetings. Without their passionate participation and input, the project could not have been successfully conducted and finished. I would also like to thank our collaborator Dr. Yan Zhou at Temple Health-Fox Chase Cancer Center for RNA-Seq analysis. vii As an international student who first came to the United States after college, I am so delighted to be accepted by the Biomedical Sciences program at Temple University Lewis Katz School of Medicine. It is really a happy time working with all co-workers and staffs in our school and in Dr. Wang and Dr. Yang’s labs. This lab is a sweet home and all our lab members treated me as their family member. I would like to especially thank Xiaohua Jiang for her consistent efforts on lab management. I would like to thank Dr. Pu Fang and Humin Shan for teaching me flow cytometry and single cell suspension. I would like to thank Dr. Hangfei Fu, Ying shao and Remon Cueto for sharing me the strategies on database mining and RNA-seq data analysis. I would also like to thank Jason Saredy for providing great suggestion on scientific writing. Last but not least, I would like to thank my lovely family. The reason why I have the courage to go abroad and pursue further study is their huge encouragement. They always told me to have a broad view and experience during my life and never give up my dream. Without their support, I could not have achieved such an accomplishment. Thanks all the people who have helped me during my study! viii TABLE OF CONTENTS PAGE ABSTRACT ................................................................................................................. iii DEDICATION ............................................................................................................. vi ACKNOWLEDGMENTS .......................................................................................... vii LIST OF FIGURES ..................................................................................................... xi LIST OF TABLES ...................................................................................................... xii LIST OF ABBREVIATIONS .................................................................................... xiii CHAPTER 1. INTRODUCTION .....................................................................................................1 1.1 Overview of Homocysteine and Hyperhomocysteinemia .................................1 1.2 Homocysteine-Methionine (HM) cycle .............................................................1 1.3 Methylation ........................................................................................................2 1.3.1 DNA methylation ......................................................................................4 1.3.2 Protein methylation ...................................................................................4 1.3.3 RNA methylation ......................................................................................5 1.4 Metabolism-associated danger signal (MADS) recognition ..............................6 1.5 CD40 and CD40L ..............................................................................................6 1.6 Hypothesis of Thesis ..........................................................................................7 2. MATERIALS AND METHODS ...............................................................................9 2.1 Selection of extended Homocysteine-Methionine (HM) cycle genes ...............9 2.2 Subcellular localization of extended HM cycle enzymes ..................................9 2.3 Expression profiles of 115 genes in extended HM cycle in 35 pathological ix conditions ..........................................................................................................9
Load more

Recommended publications
  • Concentrative Nucleoside Transporter 3 As a Prognostic Indicator for Favorable Outcome of T(8;21)-Positive Acute Myeloid Leukemi
    488 ONCOLOGY REPORTS 34: 488-494, 2015 Concentrative nucleoside transporter 3 as a prognostic indicator for favorable outcome of t(8;21)-positive acute myeloid leukemia patients after cytarabine-based chemotherapy JU HAN SONG1, KYUNG-MIN CHO1, HYEOUNG-JOON KIM2, YEO-KYEOUNG KIM2, NAN YOUNG KIM2, HEE-JE KIM3, TAE-Hyang LEE3, SEUNG YONG Hwang4 and TAE SUNG KIM1 1Division of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul; 2Genome Research Center for Hematopoietic Diseases, Chonnam National University Hwasun Hospital, Hwasun; 3Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul; 4Division of Molecular and Life Science and GenoCheck Co., Ltd., Hanyang University, Ansan, Republic of Korea Received January 20, 2015; Accepted March 18, 2015 DOI: 10.3892/or.2015.3959 Abstract. Although acute myeloid leukemia (AML) exhibits Introduction diverse responses to chemotherapy, patients harboring the t(8;21) translocation are part of a favorable risk group. Acute myeloid leukemia (AML) is a highly heterogeneous However, the reason why this subgroup is more responsive hematologic malignancy that displays diverse responses to cytarabine-based therapy has not been elucidated. In the to chemotherapy. Although a number of clinical factors present study, we analyzed expression levels of cytarabine affect treatment outcomes, the cytogenetic features of AML metabolism-related genes in patients diagnosed with AML are generally accepted as strong predictors of therapeutic with or without t(8;21) and investigated their correlation with response (1). Pediatric and adult patients carrying the t(8;21) clinical outcomes after cytarabine-based therapy. Among the chromosomal translocation, which is one of the most frequent 8 genes studied, expression of the concentrative nucleoside AML subtypes, are part of a favorable risk group (2).
    [Show full text]
  • Establishing the Pathogenicity of Novel Mitochondrial DNA Sequence Variations: a Cell and Molecular Biology Approach
    Mafalda Rita Avó Bacalhau Establishing the Pathogenicity of Novel Mitochondrial DNA Sequence Variations: a Cell and Molecular Biology Approach Tese de doutoramento do Programa de Doutoramento em Ciências da Saúde, ramo de Ciências Biomédicas, orientada pela Professora Doutora Maria Manuela Monteiro Grazina e co-orientada pelo Professor Doutor Henrique Manuel Paixão dos Santos Girão e pela Professora Doutora Lee-Jun C. Wong e apresentada à Faculdade de Medicina da Universidade de Coimbra Julho 2017 Faculty of Medicine Establishing the pathogenicity of novel mitochondrial DNA sequence variations: a cell and molecular biology approach Mafalda Rita Avó Bacalhau Tese de doutoramento do programa em Ciências da Saúde, ramo de Ciências Biomédicas, realizada sob a orientação científica da Professora Doutora Maria Manuela Monteiro Grazina; e co-orientação do Professor Doutor Henrique Manuel Paixão dos Santos Girão e da Professora Doutora Lee-Jun C. Wong, apresentada à Faculdade de Medicina da Universidade de Coimbra. Julho, 2017 Copyright© Mafalda Bacalhau e Manuela Grazina, 2017 Esta cópia da tese é fornecida na condição de que quem a consulta reconhece que os direitos de autor são pertença do autor da tese e do orientador científico e que nenhuma citação ou informação obtida a partir dela pode ser publicada sem a referência apropriada e autorização. This copy of the thesis has been supplied on the condition that anyone who consults it recognizes that its copyright belongs to its author and scientific supervisor and that no quotation from the
    [Show full text]
  • Mammalian 5€²-Nucleotidases*
    THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 278, No. 47, Issue of November 21, pp. 46195–46198, 2003 Minireview © 2003 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A. -Mammalian 5؅-Nucleotidases* residues the best alignment was between the two deoxynucle otidases and cN-III (10). Two 5Ј-nucleotidases, cN-II and cN- III, exhibit phosphotransferase activity (for reviews see Refs. Published, JBC Papers in Press, August 28, 2003, DOI 10.1074/jbc.R300032200 14 and 15) possibly because of higher stability of the phos- phoenzyme intermediate or faster exchange of the nucleoside Vera Bianchi‡§ and Jozef Spychala¶ product with the nucleoside acceptor. From the ‡Department of Biology, University of Padova, The active site of E. coli 5Ј-nucleotidase, the paradigm for I-35131 Padova, Italy and the ¶Lineberger eN, contains two zinc ions and the catalytic dyad Asp-His (11). Comprehensive Cancer Center, University of North No phosphoenzyme intermediate is formed during catalysis, Carolina, Chapel Hill, North Carolina 27599-7295 but a water molecule performs the nucleophilic attack on the phosphate (16). Nucleoside monophosphate phosphohydrolases or 5Ј-nucle- otidases (members of EC 3.1.3.5 and EC 3.1.3.6) dephosphoryl- Properties, Detection, and Inhibition ate non-cyclic nucleoside monophosphates to nucleosides and of 5؅-Nucleotidases inorganic phosphate. Seven human 5Ј-nucleotidases with dif- All 5Ј-nucleotidases have relatively broad substrate specific- ferent subcellular localization have been cloned (Table I). Se- ities. In agreement with the structural information on the quence comparisons show high homology only between cytoso- active sites (10, 11), all family members except eN are abso- lic 5Ј-nucleotidase IA (cN-IA)1 and B and between cytosolic lutely dependent on magnesium for activity.
    [Show full text]
  • Genes in a Refined Smith-Magenis Syndrome Critical Deletion Interval on Chromosome 17P11.2 and the Syntenic Region of the Mouse
    Downloaded from genome.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Article Genes in a Refined Smith-Magenis Syndrome Critical Deletion Interval on Chromosome 17p11.2 and the Syntenic Region of the Mouse Weimin Bi,1,6 Jiong Yan,1,6 Paweł Stankiewicz,1 Sung-Sup Park,1,7 Katherina Walz,1 Cornelius F. Boerkoel,1 Lorraine Potocki,1,3 Lisa G. Shaffer,1 Koen Devriendt,4 Małgorzata J.M. Nowaczyk,5 Ken Inoue,1 and James R. Lupski1,2,3,8 Departments of 1Molecular & Human Genetics, 2Pediatrics, Baylor College of Medicine, 3Texas Children’s Hospital, Houston, Texas 77030, USA; 4Centre for Human Genetics, University Hospital Gasthuisberg, Catholic University of Leuven, B-3000 Leuven, Belgium; 5Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4J9, Canada Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome associated with behavioral abnormalities and sleep disturbance. Most patients have the same ∼4 Mb interstitial genomic deletion within chromosome 17p11.2. To investigate the molecular bases of the SMS phenotype, we constructed BAC/PAC contigs covering the SMS common deletion interval and its syntenic region on mouse chromosome 11. Comparative genome analysis reveals the absence of all three ∼200-kb SMS-REP low-copy repeats in the mouse and indicates that the evolution of SMS-REPs was accompanied by transposition of adjacent genes. Physical and genetic map comparisons in humans reveal reduced recombination in both sexes. Moreover, by examining the deleted regions in SMS patients with unusual-sized deletions, we refined the minimal Smith-Magenis critical region (SMCR) to an ∼1.1-Mb genomic interval that is syntenic to an ∼1.0-Mb region in the mouse.
    [Show full text]
  • Mapping the Genetic Architecture of Gene Regulation in Whole Blood
    Mapping the Genetic Architecture of Gene Regulation in Whole Blood Katharina Schramm1,2., Carola Marzi3,4,5., Claudia Schurmann6., Maren Carstensen7,8., Eva Reinmaa9,10, Reiner Biffar11, Gertrud Eckstein1, Christian Gieger12, Hans-Jo¨ rgen Grabe13, Georg Homuth6, Gabriele Kastenmu¨ ller14, Reedik Ma¨gi10, Andres Metspalu9,10, Evelin Mihailov10,15, Annette Peters2, Astrid Petersmann16, Michael Roden7,8,17, Konstantin Strauch12,18, Karsten Suhre14,19, Alexander Teumer6,UweVo¨ lker6, Henry Vo¨ lzke20, Rui Wang-Sattler3,4, Melanie Waldenberger3,4, Thomas Meitinger1,2,21, Thomas Illig22, Christian Herder7,8., Harald Grallert3,4,5., Holger Prokisch1,2*. 1 Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany, 2 Institute of Human Genetics, Technical University Munich, Mu¨nchen, Germany, 3 Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany, 4 Institute of Epidemiology II, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany, 5 German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany, 6 Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany, 7 Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Du¨sseldorf, Du¨sseldorf, Germany, 8 German Center for Diabetes Research (DZD e.V.),
    [Show full text]
  • The Emerging Spectrum of Allelic Variation in Schizophrenia
    Molecular Psychiatry (2013) 18, 38 -- 52 & 2013 Macmillan Publishers Limited All rights reserved 1359-4184/13 www.nature.com/mp EXPERT REVIEW The emerging spectrum of allelic variation in schizophrenia: current evidence and strategies for the identification and functional characterization of common and rare variants BJ Mowry1,2 and J Gratten1 After decades of halting progress, recent large genome-wide association studies (GWAS) are finally shining light on the genetic architecture of schizophrenia. The picture emerging is one of sobering complexity, involving large numbers of risk alleles across the entire allelic spectrum. The aims of this article are to summarize the key genetic findings to date and to compare and contrast methods for identifying additional risk alleles, including GWAS, targeted genotyping and sequencing. A further aim is to consider the challenges and opportunities involved in determining the functional basis of genetic associations, for instance using functional genomics, cellular models, animal models and imaging genetics. We conclude that diverse approaches will be required to identify and functionally characterize the full spectrum of risk variants for schizophrenia. These efforts should adhere to the stringent standards of statistical association developed for GWAS and are likely to entail very large sample sizes. Nonetheless, now more than any previous time, there are reasons for optimism and the ultimate goal of personalized interventions and therapeutics, although still distant, no longer seems unattainable. Molecular Psychiatry (2013) 18, 38--52; doi:10.1038/mp.2012.34; published online 1 May 2012 Keywords: CNV; functional genomics; GWAS; schizophrenia; sequencing; SNP THE NATURE OF THE PROBLEM complications (obesity, nicotine dependence, metabolic syndrome 13 Schizophrenia is a chronic psychiatric disorder characterized by and premature mortality), low employment and substantial 14 delusional beliefs, auditory hallucinations, disorganized thought homelessness.
    [Show full text]
  • Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury’S Biological Network Based on Systematic Pharmacology
    ORIGINAL RESEARCH published: 25 June 2021 doi: 10.3389/fphar.2021.601846 Exploring the Regulatory Mechanism of Hedysarum Multijugum Maxim.-Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury’s Biological Network Based on Systematic Pharmacology Kailin Yang 1†, Liuting Zeng 1†, Anqi Ge 2†, Yi Chen 1†, Shanshan Wang 1†, Xiaofei Zhu 1,3† and Jinwen Ge 1,4* Edited by: 1 Takashi Sato, Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of 2 Tokyo University of Pharmacy and Life Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China, Galactophore Department, The First 3 Sciences, Japan Hospital of Hunan University of Chinese Medicine, Changsha, China, School of Graduate, Central South University, Changsha, China, 4Shaoyang University, Shaoyang, China Reviewed by: Hui Zhao, Capital Medical University, China Background: Clinical research found that Hedysarum Multijugum Maxim.-Chuanxiong Maria Luisa Del Moral, fi University of Jaén, Spain Rhizoma Compound (HCC) has de nite curative effect on cerebral ischemic diseases, *Correspondence: such as ischemic stroke and cerebral ischemia-reperfusion injury (CIR). However, its Jinwen Ge mechanism for treating cerebral ischemia is still not fully explained. [email protected] †These authors share first authorship Methods: The traditional Chinese medicine related database were utilized to obtain the components of HCC. The Pharmmapper were used to predict HCC’s potential targets. Specialty section: The CIR genes were obtained from Genecards and OMIM and the protein-protein This article was submitted to interaction (PPI) data of HCC’s targets and IS genes were obtained from String Ethnopharmacology, a section of the journal database.
    [Show full text]
  • Molecular Characterization of Acute Myeloid Leukemia by Next Generation Sequencing: Identification of Novel Biomarkers and Targets of Personalized Therapies
    Alma Mater Studiorum – Università di Bologna Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Dottorato di Ricerca in Oncologia, Ematologia e Patologia XXX Ciclo Settore Scientifico Disciplinare: MED/15 Settore Concorsuale:06/D3 Molecular characterization of acute myeloid leukemia by Next Generation Sequencing: identification of novel biomarkers and targets of personalized therapies Presentata da: Antonella Padella Coordinatore Prof. Pier-Luigi Lollini Supervisore: Prof. Giovanni Martinelli Esame finale anno 2018 Abstract Acute myeloid leukemia (AML) is a hematopoietic neoplasm that affects myeloid progenitor cells and it is one of the malignancies best studied by next generation sequencing (NGS), showing a highly heterogeneous genetic background. The aim of the study was to characterize the molecular landscape of 2 subgroups of AML patients carrying either chromosomal number alterations (i.e. aneuploidy) or rare fusion genes. We performed whole exome sequencing and we integrated the mutational data with transcriptomic and copy number analysis. We identified the cell cycle, the protein degradation, response to reactive oxygen species, energy metabolism and biosynthetic process as the pathways mostly targeted by alterations in aneuploid AML. Moreover, we identified a 3-gene expression signature including RAD50, PLK1 and CDC20 that characterize this subgroup. Taking advantage of RNA sequencing we aimed at the discovery of novel and rare gene fusions. We detected 9 rare chimeric transcripts, of which partner genes were transcription factors (ZEB2, BCL11B and MAFK) or tumor suppressors (SAV1 and PUF60) rarely translocated across cancer types. Moreover, we detected cryptic events hiding the loss of NF1 and WT1, two recurrently altered genes in AML. Finally, we explored the oncogenic potential of the ZEB2-BCL11B fusion, which revealed no transforming ability in vitro.
    [Show full text]
  • WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C12Q 1/68 (2018.01) A61P 31/18 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, C12Q 1/70 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US2018/056167 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 16 October 2018 (16. 10.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/573,025 16 October 2017 (16. 10.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, (71) Applicant: MASSACHUSETTS INSTITUTE OF MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Cambridge, Massachusetts 02139 (US).
    [Show full text]
  • Computational and Experimental Approaches for Evaluating the Genetic Basis of Mitochondrial Disorders
    Computational and Experimental Approaches For Evaluating the Genetic Basis of Mitochondrial Disorders The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Lieber, Daniel Solomon. 2013. Computational and Experimental Approaches For Evaluating the Genetic Basis of Mitochondrial Disorders. Doctoral dissertation, Harvard University. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:11158264 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Computational and Experimental Approaches For Evaluating the Genetic Basis of Mitochondrial Disorders A dissertation presented by Daniel Solomon Lieber to The Committee on Higher Degrees in Systems Biology in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Systems Biology Harvard University Cambridge, Massachusetts April 2013 © 2013 - Daniel Solomon Lieber All rights reserved. Dissertation Adviser: Professor Vamsi K. Mootha Daniel Solomon Lieber Computational and Experimental Approaches For Evaluating the Genetic Basis of Mitochondrial Disorders Abstract Mitochondria are responsible for some of the cell’s most fundamental biological pathways and metabolic processes, including aerobic ATP production by the mitochondrial respiratory chain. In humans, mitochondrial dysfunction can lead to severe disorders of energy metabolism, which are collectively referred to as mitochondrial disorders and affect approximately 1:5,000 individuals. These disorders are clinically heterogeneous and can affect multiple organ systems, often within a single individual. Symptoms can include myopathy, exercise intolerance, hearing loss, blindness, stroke, seizures, diabetes, and GI dysmotility.
    [Show full text]
  • Identification of Transcriptomic Differences Between Lower
    International Journal of Molecular Sciences Article Identification of Transcriptomic Differences between Lower Extremities Arterial Disease, Abdominal Aortic Aneurysm and Chronic Venous Disease in Peripheral Blood Mononuclear Cells Specimens Daniel P. Zalewski 1,*,† , Karol P. Ruszel 2,†, Andrzej St˛epniewski 3, Dariusz Gałkowski 4, Jacek Bogucki 5 , Przemysław Kołodziej 6 , Jolanta Szyma ´nska 7 , Bartosz J. Płachno 8 , Tomasz Zubilewicz 9 , Marcin Feldo 9,‡ , Janusz Kocki 2,‡ and Anna Bogucka-Kocka 1,‡ 1 Chair and Department of Biology and Genetics, Medical University of Lublin, 4a Chod´zkiSt., 20-093 Lublin, Poland; [email protected] 2 Chair of Medical Genetics, Department of Clinical Genetics, Medical University of Lublin, 11 Radziwiłłowska St., 20-080 Lublin, Poland; [email protected] (K.P.R.); [email protected] (J.K.) 3 Ecotech Complex Analytical and Programme Centre for Advanced Environmentally Friendly Technologies, University of Marie Curie-Skłodowska, 39 Gł˛ebokaSt., 20-612 Lublin, Poland; [email protected] 4 Department of Pathology and Laboratory Medicine, Rutgers-Robert Wood Johnson Medical School, One Robert Wood Johnson Place, New Brunswick, NJ 08903-0019, USA; [email protected] 5 Chair and Department of Organic Chemistry, Medical University of Lublin, 4a Chod´zkiSt., Citation: Zalewski, D.P.; Ruszel, K.P.; 20-093 Lublin, Poland; [email protected] St˛epniewski,A.; Gałkowski, D.; 6 Laboratory of Diagnostic Parasitology, Chair and Department of Biology and Genetics, Medical University of Bogucki, J.; Kołodziej, P.; Szyma´nska, Lublin, 4a Chod´zkiSt., 20-093 Lublin, Poland; [email protected] J.; Płachno, B.J.; Zubilewicz, T.; Feldo, 7 Department of Integrated Paediatric Dentistry, Chair of Integrated Dentistry, Medical University of Lublin, M.; et al.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]