A Distinct Inflammatory Gene Expression Profile in Patients with Psoriatic Arthritis
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Bayesian Hierarchical Modeling of High-Throughput Genomic Data with Applications to Cancer Bioinformatics and Stem Cell Differentiation
BAYESIAN HIERARCHICAL MODELING OF HIGH-THROUGHPUT GENOMIC DATA WITH APPLICATIONS TO CANCER BIOINFORMATICS AND STEM CELL DIFFERENTIATION by Keegan D. Korthauer A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Statistics) at the UNIVERSITY OF WISCONSIN–MADISON 2015 Date of final oral examination: 05/04/15 The dissertation is approved by the following members of the Final Oral Committee: Christina Kendziorski, Professor, Biostatistics and Medical Informatics Michael A. Newton, Professor, Statistics Sunduz Kele¸s,Professor, Biostatistics and Medical Informatics Sijian Wang, Associate Professor, Biostatistics and Medical Informatics Michael N. Gould, Professor, Oncology © Copyright by Keegan D. Korthauer 2015 All Rights Reserved i in memory of my grandparents Ma and Pa FL Grandma and John ii ACKNOWLEDGMENTS First and foremost, I am deeply grateful to my thesis advisor Christina Kendziorski for her invaluable advice, enthusiastic support, and unending patience throughout my time at UW-Madison. She has provided sound wisdom on everything from methodological principles to the intricacies of academic research. I especially appreciate that she has always encouraged me to eke out my own path and I attribute a great deal of credit to her for the successes I have achieved thus far. I also owe special thanks to my committee member Professor Michael Newton, who guided me through one of my first collaborative research experiences and has continued to provide key advice on my thesis research. I am also indebted to the other members of my thesis committee, Professor Sunduz Kele¸s,Professor Sijian Wang, and Professor Michael Gould, whose valuable comments, questions, and suggestions have greatly improved this dissertation. -
Knowledge Management Enviroments for High Throughput Biology
Knowledge Management Enviroments for High Throughput Biology Abhey Shah A Thesis submitted for the degree of MPhil Biology Department University of York September 2007 Abstract With the growing complexity and scale of data sets in computational biology and chemoin- formatics, there is a need for novel knowledge processing tools and platforms. This thesis describes a newly developed knowledge processing platform that is different in its emphasis on architecture, flexibility, builtin facilities for datamining and easy cross platform usage. There exist thousands of bioinformatics and chemoinformatics databases, that are stored in many different forms with different access methods, this is a reflection of the range of data structures that make up complex biological and chemical data. Starting from a theoretical ba- sis, FCA (Formal Concept Analysis) an applied branch of lattice theory, is used in this thesis to develop a file system that automatically structures itself by it’s contents. The procedure of extracting concepts from data sets is examined. The system also finds appropriate labels for the discovered concepts by extracting data from ontological databases. A novel method for scaling non-binary data for use with the system is developed. Finally the future of integrative systems biology is discussed in the context of efficiently closed causal systems. Contents 1 Motivations and goals of the thesis 11 1.1 Conceptual frameworks . 11 1.2 Biological foundations . 12 1.2.1 Gene expression data . 13 1.2.2 Ontology . 14 1.3 Knowledge based computational environments . 15 1.3.1 Interfaces . 16 1.3.2 Databases and the character of biological data . -
4 Understanding the Role of GNA13 Deregulation in Lymphomagenesis
Integrative Genomics Reveals a Role for GNA13 in Lymphomagenesis by Adrienne Greenough University Program in Genetics and Genomics Duke University Approved: ___________________________ Sandeep Dave, Supervisor ___________________________ Fred Dietrich ___________________________ Jack Keene ___________________________ Yuan Zhuang Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the University Program in Genetics and Genomics in the Graduate School of Duke University 2014 i v ABSTRACT Integrative Genomics Reveals a Role for GNA13 in Lymphomagenesis by Adrienne Greenough University Program in Genetics and Genomics Duke University Approved: ___________________________ Sandeep Dave, Supervisor ___________________________ Fred Dietrich ___________________________ Jack Keene ___________________________ Yuan Zhuang An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the University Program in Genetics and Genomics in the Graduate School of Duke University 2014 Copyright by Adrienne Greenough 2014 Abstract Lymphomas comprise a diverse group of malignancies derived from immune cells. High throughput sequencing has recently emerged as a powerful and versatile method for analysis of the cancer genome and transcriptome. As these data continue to emerge, the crucial work lies in sorting through the wealth of information to hone in on the critical aspects that will give us a better understanding of biology and new insight for how to treat disease. Finding the important signals within these large data sets is one of the major challenges of next generation sequencing. In this dissertation, I have developed several complementary strategies to describe the genetic underpinnings of lymphomas. I begin with developing a better method for RNA sequencing that enables strand-specific total RNA sequencing and alternative splicing profiling in the same analysis. -
Mai Muudatuntuu Ti on Man Mini
MAIMUUDATUNTUU US009809854B2 TI ON MAN MINI (12 ) United States Patent ( 10 ) Patent No. : US 9 ,809 ,854 B2 Crow et al. (45 ) Date of Patent : Nov . 7 , 2017 Whitehead et al. (2005 ) Variation in tissue - specific gene expression ( 54 ) BIOMARKERS FOR DISEASE ACTIVITY among natural populations. Genome Biology, 6 :R13 . * AND CLINICAL MANIFESTATIONS Villanueva et al. ( 2011 ) Netting Neutrophils Induce Endothelial SYSTEMIC LUPUS ERYTHEMATOSUS Damage , Infiltrate Tissues, and Expose Immunostimulatory Mol ecules in Systemic Lupus Erythematosus . The Journal of Immunol @(71 ) Applicant: NEW YORK SOCIETY FOR THE ogy , 187 : 538 - 552 . * RUPTURED AND CRIPPLED Bijl et al. (2001 ) Fas expression on peripheral blood lymphocytes in MAINTAINING THE HOSPITAL , systemic lupus erythematosus ( SLE ) : relation to lymphocyte acti vation and disease activity . Lupus, 10 :866 - 872 . * New York , NY (US ) Crow et al . (2003 ) Microarray analysis of gene expression in lupus. Arthritis Research and Therapy , 5 :279 - 287 . * @(72 ) Inventors : Mary K . Crow , New York , NY (US ) ; Baechler et al . ( 2003 ) Interferon - inducible gene expression signa Mikhail Olferiev , Mount Kisco , NY ture in peripheral blood cells of patients with severe lupus . PNAS , (US ) 100 ( 5 ) : 2610 - 2615. * GeneCards database entry for IFIT3 ( obtained from < http : / /www . ( 73 ) Assignee : NEW YORK SOCIETY FOR THE genecards. org /cgi - bin / carddisp .pl ? gene = IFIT3 > on May 26 , 2016 , RUPTURED AND CRIPPLED 15 pages ) . * Navarra et al. (2011 ) Efficacy and safety of belimumab in patients MAINTAINING THE HOSPITAL with active systemic lupus erythematosus : a randomised , placebo FOR SPECIAL SURGERY , New controlled , phase 3 trial . The Lancet , 377 :721 - 731. * York , NY (US ) Abramson et al . ( 1983 ) Arthritis Rheum . -
Mutational Mechanisms That Activate Wnt Signaling and Predict Outcomes in Colorectal Cancer Patients William Hankey1, Michael A
Published OnlineFirst December 6, 2017; DOI: 10.1158/0008-5472.CAN-17-1357 Cancer Genome and Epigenome Research Mutational Mechanisms That Activate Wnt Signaling and Predict Outcomes in Colorectal Cancer Patients William Hankey1, Michael A. McIlhatton1, Kenechi Ebede2, Brian Kennedy3, Baris Hancioglu3, Jie Zhang4, Guy N. Brock3, Kun Huang4, and Joanna Groden1 Abstract APC biallelic loss-of-function mutations are the most prevalent also exhibiting unique changes in pathways related to prolifera- genetic changes in colorectal tumors, but it is unknown whether tion, cytoskeletal organization, and apoptosis. Apc-mutant ade- these mutations phenocopy gain-of-function mutations in the nomas were characterized by increased expression of the glial CTNNB1 gene encoding b-catenin that also activate canonical nexin Serpine2, the human ortholog, which was increased in WNT signaling. Here we demonstrate that these two mutational advanced human colorectal tumors. Our results support the mechanisms are not equivalent. Furthermore, we show how hypothesis that APC-mutant colorectal tumors are transcription- differences in gene expression produced by these different ally distinct from APC-wild-type colorectal tumors with canonical mechanisms can stratify outcomes in more advanced human WNT signaling activated by other mechanisms, with possible colorectal cancers. Gene expression profiling in Apc-mutant and implications for stratification and prognosis. Ctnnb1-mutant mouse colon adenomas identified candidate Significance: These findings suggest that colon adenomas genes for subsequent evaluation of human TCGA (The Cancer driven by APC mutations are distinct from those driven by WNT Genome Atlas) data for colorectal cancer outcomes. Transcrip- gain-of-function mutations, with implications for identifying tional patterns exhibited evidence of activated canonical Wnt at-risk patients with advanced disease based on gene expression signaling in both types of adenomas, with Apc-mutant adenomas patterns. -
Combinatorial Strategies Using CRISPR/Cas9 for Gene Mutagenesis in Adult Mice
Combinatorial strategies using CRISPR/Cas9 for gene mutagenesis in adult mice Avery C. Hunker A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2019 Reading Committee: Larry S. Zweifel, Chair Sheri J. Mizumori G. Stanley McKnight Program Authorized to Offer Degree: Pharmacology 2 © Copyright 2019 Avery C. Hunker 3 University of Washington ABSTRACT Combinatorial strategies using CRISPR/Cas9 for gene mutagenesis in adult mice Avery C. Hunker Chair of the Supervisory Committee: Larry Zweifel Department of Pharmacology A major challenge to understanding how genes modulate complex behaviors is the inability to restrict genetic manipulations to defined cell populations or circuits. To circumvent this, we created a simple strategy for limiting gene knockout to specific cell populations using a viral-mediated, conditional CRISPR/SaCas9 system in combination with intersectional genetic strategies. A small single guide RNA (sgRNA) directs Staphylococcus aureus CRISPR-associated protein (SaCas9) to unique sites on DNA in a Cre-dependent manner resulting in double strand breaks and gene mutagenesis in vivo. To validate this technique we targeted nine different genes of diverse function in distinct cell types in mice and performed an array of analyses to confirm gene mutagenesis and subsequent protein loss, including IHC, cell-type specific DNA sequencing, electrophysiology, Western blots, and behavior. We show that these vectors are as efficient as conventional conditional gene knockout and provide a viable alternative to complex genetic crosses. This strategy provides additional benefits of 4 targeting gene mutagenesis to cell types previously difficult to isolate, and the ability to target genes in specific neural projections for gene inactivation. -
Regulators of Autophagosome Formation in Drosophila Muscles
RESEARCH ARTICLE Regulators of Autophagosome Formation in Drosophila Muscles Jonathan Zirin1*, Joppe Nieuwenhuis1, Anastasia Samsonova1, Rong Tao1, Norbert Perrimon1,2* 1 Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America, 2 Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America * [email protected] (JZ); [email protected] (NP) Abstract Given the diversity of autophagy targets and regulation, it is important to characterize autop- hagy in various cell types and conditions. We used a primary myocyte cell culture system to assay the role of putative autophagy regulators in the specific context of skeletal muscle. By treating the cultures with rapamycin (Rap) and chloroquine (CQ) we induced an autophagic response, fully suppressible by knockdown of core ATG genes. We screened D. melanoga- ster orthologs of a previously reported mammalian autophagy protein-protein interaction OPEN ACCESS network, identifying several proteins required for autophagosome formation in muscle cells, including orthologs of the Rab regulators RabGap1 and Rab3Gap1. The screen also Citation: Zirin J, Nieuwenhuis J, Samsonova A, Tao R, Perrimon N (2015) Regulators of Autophagosome highlighted the critical roles of the proteasome and glycogen metabolism in regulating Formation in Drosophila Muscles. PLoS Genet 11(2): autophagy. Specifically, sustained proteasome inhibition inhibited autophagosome forma- e1005006. doi:10.1371/journal.pgen.1005006 -
Human Social Genomics in the Multi-Ethnic Study of Atherosclerosis
Getting “Under the Skin”: Human Social Genomics in the Multi-Ethnic Study of Atherosclerosis by Kristen Monét Brown A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Epidemiological Science) in the University of Michigan 2017 Doctoral Committee: Professor Ana V. Diez-Roux, Co-Chair, Drexel University Professor Sharon R. Kardia, Co-Chair Professor Bhramar Mukherjee Assistant Professor Belinda Needham Assistant Professor Jennifer A. Smith © Kristen Monét Brown, 2017 [email protected] ORCID iD: 0000-0002-9955-0568 Dedication I dedicate this dissertation to my grandmother, Gertrude Delores Hampton. Nanny, no one wanted to see me become “Dr. Brown” more than you. I know that you are standing over the bannister of heaven smiling and beaming with pride. I love you more than my words could ever fully express. ii Acknowledgements First, I give honor to God, who is the head of my life. Truly, without Him, none of this would be possible. Countless times throughout this doctoral journey I have relied my favorite scripture, “And we know that all things work together for good, to them that love God, to them who are called according to His purpose (Romans 8:28).” Secondly, I acknowledge my parents, James and Marilyn Brown. From an early age, you two instilled in me the value of education and have been my biggest cheerleaders throughout my entire life. I thank you for your unconditional love, encouragement, sacrifices, and support. I would not be here today without you. I truly thank God that out of the all of the people in the world that He could have chosen to be my parents, that He chose the two of you. -
RABIF/MSS4 Is a Rab-Stabilizing Holdase Chaperone Required for GLUT4 Exocytosis
RABIF/MSS4 is a Rab-stabilizing holdase chaperone required for GLUT4 exocytosis Daniel R. Gulbransona, Eric M. Davisa, Brittany A. Demmitta,b, Yan Ouyanga, Yihong Yec, Haijia Yua,d,1, and Jingshi Shena,1 aDepartment of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309; bInstitute for Behavioral Genetics, University of Colorado, Boulder, CO 80309; cLaboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and dJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China Edited by Jennifer Lippincott-Schwartz, Howard Hughes Medical Institute, Ashburn, VA, and approved August 21, 2017 (received for review July 7, 2017) Rab GTPases are switched from their GDP-bound inactive confor- anabolic hormone insulin facilitates glucose uptake by acutely mation to a GTP-bound active state by guanine nucleotide exchange relocating GLUT4 from intracellular compartments to the cell factors (GEFs). The first putative GEFs isolated for Rabs are RABIF surface (6, 20, 21, 23). Upon the termination of insulin signaling, (Rab-interacting factor)/MSS4 (mammalian suppressor of Sec4) and GLUT4 is retrieved from the plasma membrane through endocy- its yeast homolog DSS4 (dominant suppressor of Sec4). However, tosis and returns to intracellular storage vesicles (6). Importantly, the biological function and molecular mechanism of these molecules the components of GLUT4 exocytosis are also involved in the remained unclear. In a genome-wide CRISPR genetic screen, we regulation of other exocytic pathways such as insulin secretion and isolated RABIF as a positive regulator of exocytosis. -
Genomic Approach in Idiopathic Intellectual Disability Maria De Fátima E Costa Torres
ESTUDOS DE 8 01 PDPGM 2 CICLO Genomic approach in idiopathic intellectual disability Maria de Fátima e Costa Torres D Autor. Maria de Fátima e Costa Torres D.ICBAS 2018 Genomic approach in idiopathic intellectual disability Genomic approach in idiopathic intellectual disability Maria de Fátima e Costa Torres SEDE ADMINISTRATIVA INSTITUTO DE CIÊNCIAS BIOMÉDICAS ABEL SALAZAR FACULDADE DE MEDICINA MARIA DE FÁTIMA E COSTA TORRES GENOMIC APPROACH IN IDIOPATHIC INTELLECTUAL DISABILITY Tese de Candidatura ao grau de Doutor em Patologia e Genética Molecular, submetida ao Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto Orientadora – Doutora Patrícia Espinheira de Sá Maciel Categoria – Professora Associada Afiliação – Escola de Medicina e Ciências da Saúde da Universidade do Minho Coorientadora – Doutora Maria da Purificação Valenzuela Sampaio Tavares Categoria – Professora Catedrática Afiliação – Faculdade de Medicina Dentária da Universidade do Porto Coorientadora – Doutora Filipa Abreu Gomes de Carvalho Categoria – Professora Auxiliar com Agregação Afiliação – Faculdade de Medicina da Universidade do Porto DECLARAÇÃO Dissertação/Tese Identificação do autor Nome completo _Maria de Fátima e Costa Torres_ N.º de identificação civil _07718822 N.º de estudante __ 198600524___ Email institucional [email protected] OU: [email protected] _ Email alternativo [email protected] _ Tlf/Tlm _918197020_ Ciclo de estudos (Mestrado/Doutoramento) _Patologia e Genética Molecular__ Faculdade/Instituto _Instituto de Ciências -
WO 2016/040794 Al 17 March 2016 (17.03.2016) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/040794 Al 17 March 2016 (17.03.2016) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C12N 1/19 (2006.01) C12Q 1/02 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C12N 15/81 (2006.01) C07K 14/47 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/US20 15/049674 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 11 September 2015 ( 11.09.201 5) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 62/050,045 12 September 2014 (12.09.2014) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: WHITEHEAD INSTITUTE FOR BIOMED¬ DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, ICAL RESEARCH [US/US]; Nine Cambridge Center, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Cambridge, Massachusetts 02142-1479 (US). -
Pathway Entry Into the T Lymphocyte Developmental Molecular Dissection of Prethymic Progenitor
The Journal of Immunology Molecular Dissection of Prethymic Progenitor Entry into the T Lymphocyte Developmental Pathway1 C. Chace Tydell,2 Elizabeth-Sharon David-Fung,2,3 Jonathan E. Moore, Lee Rowen,4 Tom Taghon,5 and Ellen V. Rothenberg6 Notch signaling activates T lineage differentiation from hemopoietic progenitors, but relatively few regulators that initiate this program have been identified, e.g., GATA3 and T cell factor-1 (TCF-1) (gene name Tcf7). To identify additional regulators of T cell specification, a cDNA library from mouse Pro-T cells was screened for genes that are specifically up-regulated in intrathymic T cell precursors as compared with myeloid progenitors. Over 90 genes of interest were iden- tified, and 35 of 44 tested were confirmed to be more highly expressed in T lineage precursors relative to precursors of B and/or myeloid lineage. To a remarkable extent, however, expression of these T lineage-enriched genes, including zinc finger transcription factor, helicase, and signaling adaptor genes, was also shared by stem cells (Lin؊Sca-1؉Kit؉CD27؊) and multipotent progenitors (Lin؊Sca-1؉Kit؉CD27؉), although down-regulated in other lineages. Thus, a major fraction of these early T lineage genes are a regulatory legacy from stem cells. The few genes sharply up-regulated between multipotent progenitors and Pro-T cell stages included those encoding transcription factors Bcl11b, TCF-1 (Tcf7), and HEBalt, Notch target Deltex1, Deltex3L, Fkbp5, Eva1, and Tmem131. Like GATA3 and Deltex1, Bcl11b, Fkbp5, and Eva1 were dependent on Notch/Delta signaling for induction in fetal liver precursors, but only Bcl11b and HEBalt were up-regulated between the first two stages of intrathymic T cell development (double negative 1 and double negative 2) corresponding to T lineage specification.