DOCSLIB.ORG

Expression of C-Jun Is Not Mandatory for Mouse Hepatocyte Proliferation Induced by Two Nuclear Receptor Ligands: TCPOBOP and T3

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Expression of C-Jun Is Not Mandatory for Mouse Hepatocyte Proliferation Induced by Two Nuclear Receptor Ligands: TCPOBOP and T3 AperTO - Archivio Istituzionale Open Access dell'Università di Torino Expression of c-jun is not mandatory for mouse hepatocyte proliferation induced by two nuclear receptor ligands: TCPOBOP and T3 This is the author's manuscript Original Citation: Availability: This version is available http://hdl.handle.net/2318/113530 since Published version: DOI:10.1016/j.jhep.2011.02.016 Terms of use: Open Access Anyone can freely access the full text of works made available as "Open Access". Works made available under a Creative Commons license can be used according to the terms and conditions of said license. Use of all other works requires consent of the right holder (author or publisher) if not exempted from copyright protection by the applicable law. (Article begins on next page) 09 October 2021 This Accepted Author Manuscript (AAM) is copyrighted and published by Elsevier. It is posted here by agreement between Elsevier and the University of Turin. Changes resulting from the publishing process - such as editing, corrections, structural formatting, and other quality control mechanisms - may not be reflected in this version of the text. The definitive version of the text was subsequently published in Expression of c-jun is not mandatory for mouse hepatocyte proliferation induced by two nuclear receptor ligands: TCPOBOP and T3, volume 55, issue 5, Nov 2011, http://www.sciencedirect.com/science/article/pii/S0168827811001991. You may download, copy and otherwise use the AAM for non-commercial purposes provided that your license is limited by the following restrictions: (1) You may use this AAM for non-commercial purposes only under the terms of the CC-BY-NC-ND license. (2) The integrity of the work and identification of the author, copyright owner, and publisher must be preserved in any copy. (3) You must attribute this AAM in the following format: Creative Commons BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/deed.en), [+http://www.sciencedirect.com/science/article/pii/S0168827811001991] Expression of c-jun is not mandatory for mouse hepatocyte proliferation induced by two nuclear receptor ligands: TCPOBOP and T3 Vera P. Leoni1, Giovanna M. Ledda-Columbano1, Monica Pibiri1, Christian Saliba1, Andrea Perra1, Marta A. Kowalik1, Oli M.V. Grober2, Maria Ravo2, 3, Alessandro Weisz2, 3, Joseph Locker4, Elena Ghiso5, Silvia Giordano5, Amedeo Columbano1, , 1 Department of Toxicology, University of Cagliari, Italy 2 Department of General Pathology, Second University of Naples, Italy 3 Laboratory of Molecular Medicine, University of Salerno, Italy 4 Department of Pathology, Albert Einstein College of Medicine, NY, USA 5 Institute for Cancer Research and Treatment, University of Turin Medical School, Italy Background & Aims Mice lacking c-jun in the liver display impaired regeneration after partial hepatectomy (PH), and were reported to be more resistant to chemically-induced hepatocellular carcinoma (HCC). We investigated the role of c-jun in normal and preneoplastic hepatocyte proliferation induced by ligands of nuclear receptors, which cause liver hyperplasia in the absence of cell loss/death. Methods The effect of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) on hepatocyte proliferation was determined in c-jun conditional knockout (c-junΔli) or in mouse liver where c-jun has been silenced. To study the role of c-jun in HCC development, c-junΔli and WT mice were given diethylnitrosamine (DENA) followed by repeated injections of TCPOBOP. Results Hepatocyte proliferation induced by TCPOBOP was associated with a stronger proliferative response and earlier S phase entry in c-junΔli mice, compared to WT animals. Moreover, silencing of c-jun in the liver of CD-1 mice caused increased hepatocyte proliferation. A stronger hepatocyte proliferative response of c-junΔli mice was observed also following treatment with a ligand of thyroid hormone receptor. Finally, loss ofc-jun did not inhibit the development of HCC induced by DENA and promoted by TCPOBOP. Conclusions (i) c-jun may, under certain conditions, negatively regulate proliferation of normal hepatocytes, (ii) c-jun is not an absolute requirement for DENA/TCPOBOP-induced HCC formation, suggesting that the therapeutic potential of c-jun/JNK inhibition in liver tumors might be impaired by an increased stimulation of cell growth due to blockade of the c-jun pathway. Keywords Nuclear receptors; Hepatocellular carcinoma; Cell cycle; Liver hyperplasia Abbreviations AP-1, activating protein-1; PH, partial hepatectomy; JNK, c-jun-N-terminal kinase; HCC, hepatocellular carcinoma; PPAR-α, peroxisome proliferator-activated receptor- alpha; TCPOBOP, 1,4-bis(2-(3,5-dichloropyridyloxy)benzene; TR, thyroid hormone receptor; T3, triiodothyronine; CAR, constitutive androstane receptor; NF-κB, nuclear factor- κB; STAT3, signal transducer activator of transcription-3; C/EBP, CCAAT/enhancer binding protein; TNF-α, tumor necrosis factor-alpha; TNFR, tumor necrosis factor receptor; IL- 6, interleukin-6; BrdU, 2-bromodeoxyuridine; DENA, diethylnitrosamine; PCNA,proliferating cell nuclear antigen; HGF, hepatocyte growth factor; TGF-α, transforming growth factor- alpha; PB, phenobarbital; SHRNA, short hairpin RNA; IEGs, immediate early genes; Gadd45β, growth-arrest and DNA damage-β; Cyp2b10, cytochrome 2b10 INTRODUCTION c-jun is a member of AP-1 (activating protein-1) transcription factor which binds DNA as heterodimers of Jun and Fos-like subunits. Jun is involved in the regulation of many different biological processes, including proliferation, differentiation, neoplastic transformation, and apoptosis [1]. In the foetal liver, c-jun is required for cell survival. Mature hepatocytes, in contrast, are viable in the absence of c-jun [2]. A critical role of c-jun in liver regeneration has been suggested by the finding that conditional deletion of c-jun in adult livers impaired liver regeneration after 2/3 partial hepatectomy (PH) [2]. Experiments performed in several double-knockout mouse models showed that inactivation of p53, p21, or p38 restored normal regeneration in c-jun conditional knockout mice (c-junΔli) [3]. Moreover, studies on chemically-induced hepatocellular carcinomas (HCCs) showed that the number and size of tumors were reduced when c-junwas inactivated shortly after initiation of the tumorigenic process. The impaired tumor development correlated with increased levels of p53 [4], suggesting that c-jun prevents apoptosis by antagonizing p53 activity. In recent years an increasing number of agents (primary mitogens) capable of inducing hepatocyte proliferation have been identified [5]. In contrast to liver regeneration after cell loss/injury, the proliferative process induced by primary mitogens is not preceded by cell death/loss, and thus leads to liver enlargement (direct hyperplasia). Among these mitogens, several are ligands of nuclear receptors of the steroid/thyroid hormone nuclear receptor superfamily [6]. Functioning as ligand-activated transcription factors, they regulate the expression of genes involved in lipid metabolism, adipogenesis, xenobiotic detoxification, differentiation, etc. [7], [8] and [9]. Notably, most of the changes observed after PH and considered essential for liver regeneration [10] do not occur in liver hyperplasia induced by ligands of nuclear receptors. Indeed, neither activation of transcription factors, such as NF-κB, STAT3, and C/EBP, nor a relevant role for cytokines, such as TNF-α and IL-6, could be observed in rats or mice after treatment with agonists of constitutive androstane receptor (CAR), peroxisome proliferators activated receptor-α (PPARα), and thyroid hormone receptor (TR) [11],[12] and [13]. Since activation of latent pre- existing transcription factors is thought to induce the expression of immediate early genes (IEGs), a relevant question that needs to be addressed is whether IEGs are really required for cell cycle progression. This study was aimed at investigating whether c-jun (i) is an absolute requirement for the entry into and progression of cell cycle in nuclear receptor-mediated liver hyperplasia, and, (ii) is required for the growth and progression of carcinogen-initiated cells to HCC. MATERIALS AND METHODS Animals c-jun conditional knockout female mice (c-junΔli) were generated by crossing transgenic mice carrying a floxed allele of c-jun (c-junf/f, control mice) with transgenic mice carrying floxed alleles of c-jun and Alfp-Cre allele [2], kindly donated by E.F. Wagner (CNIO, Madrid). Genotyping of all mice was determined by Southern blot and PCR analysis ( Supplementary Fig. 1). CD-1 mice were purchased from Charles River (Milano, Italy). All experimental procedures were in accordance with the Universities Federation for Animal Welfare Handbook on the Care and Management of Laboratory Animals and the guidelines of the animal ethics committee of the University of Cagliari. Liver cell proliferation Hepatocyte proliferation was induced by a single gavage treatment with TCPOBOP (3 mg/kg body weight, a gift of Dr. B.A. Diwan, Frederick Cancer Center, MD). Mice were given 2- bromodeoxyuridine (BrdU, Sigma Chem Co., Milano) dissolved in drinking water (1 mg/ml) and sacrificed 96 h later. For kinetic studies, mice received a single intraperitoneal dose of BrdU (100 mg/kg) and were sacrificed 2 h later. For T3 experiments, mice were fed a T3-supplemented diet (4 mg/kg diet) for 5 days. Lentivirus production, cell transduction, and mice injection Lentiviruses were produced as described elsewhere [14]. For detailed experimental
Load more

Recommended publications
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Prevalence and Significance of Nonsense-‐Mediated Mrna Decay
    Prevalence and Significance of Nonsense-Mediated mRNA Decay Coupled with Alternative Splicing in Diverse Eukaryotic Organisms By Courtney Elizabeth French A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Molecular and Cell Biology in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Steven E. Brenner, Co-Chair Professor Donald C. Rio, Co-Chair Professor Britt A. Glaunsinger Professor Sandrine Dudoit Spring 2016 Prevalence and Significance of Nonsense-Mediated mRNA Decay Coupled with Alternative Splicing in Diverse Eukaryotic Organisms Copyright 2016 by Courtney Elizabeth French Abstract Prevalence and Significance of Nonsense-Mediated mRNA Decay Coupled with Alternative Splicing in Diverse Eukaryotic Organisms by Courtney Elizabeth French Doctor of Philosophy in Molecular and Cell Biology University of California, Berkeley Professor Steven E. Brenner, Co-Chair Professor Donald C. Rio, Co-Chair Alternative splicing plays a crucial role in increasing the amount of protein diversity and in regulating gene expression at the post-transcriptional level. In humans, almost all genes produce more than one mRNA isoform and, while the fraction varies, many other species also have a substantial number of alternatively spliced genes. Alternative splicing is regulated by splicing factors, often in a developmental time- or tissue-specific manner. Mis- regulation of alternative splicing, via mutations in splice sites, splicing regulatory elements, or splicing factors, can lead to disease states, including cancers. Thus, characterizing how alternative splicing shapes the transcriptome will lead to greater insights into the regulation of numerous cellular pathways and many aspects of human health. A critical tool for investigating alternative splicing is high-throughput mRNA sequencing (RNA-seq).
    [Show full text]
  • Die Inhibin/Aktivin Expression in Gynäkologischen Krebszellen Und Selektive Expression Der Inhibin Beta E Untereinheit Unter ER-Stressinduktion
    Aus der Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe - Innenstadt der Ludwig-Maximilians-Universität München Direktor: Prof. Dr. med. Klaus Friese Die Inhibin/Aktivin Expression in gynäkologischen Krebszellen und selektive Expression der Inhibin beta E Untereinheit unter ER-Stressinduktion Dissertation zum Erwerb des Doktorgrades der Medizin an der Medizinischen Fakultät der Ludwig-Maximilians-Universität zu München vorgelegt von Christina Matsingou aus Thessaloniki 2013 Mit Genehmigung der Medizinischen Fakultät der Universität München Berichterstatter: Prof. Dr. med. Ioannis Mylonas Mitberichterstatter: Prof. Dr. Werner Meier Prof. Dr. Doris Mayr Mitbetreuung durch den promovierten Mitarbeiter: Dr. rer. nat. Ansgar Brüning Dekan: Prof. Dr. med. Dr. h.c. M. Reiser, FACR, FRCR Tag der mündlichen Prüfung: 12.12.2013 II Meinen Eltern in Dankbarkeit gewidmet. Ὁ μὲν βίος βραχύς, ἡ δὲ τέχνη μακρή, ὁ δὲ καιρὸς ὀξύς, ἡ δὲ πεῖρα σφαλερή, ἡ δὲ κρίσις χαλεπή. Ιπποκράτης ο Κώος (460–377 π. Χ.) Das Leben ist kurz, die Kunst ist lang, die Gelegenheit flüchtig, die Erfahrung trüge- risch, das Urteil schwierig. Hippokrates von Kos (um 460–377 v. Chr.) III Inhaltsverzeichnis Abkürzungsverzeichnis .................................................................................. 1 1 Zusammenfassung .................................................................................... 4 2 Einleitung ................................................................................................. 6 2.1 Nelfinavir und weitere Proteaseinhibitoren
    [Show full text]
  • Identification of Genetic Factors Underpinning Phenotypic Heterogeneity in Huntington’S Disease and Other Neurodegenerative Disorders
    Identification of genetic factors underpinning phenotypic heterogeneity in Huntington’s disease and other neurodegenerative disorders. By Dr Davina J Hensman Moss A thesis submitted to University College London for the degree of Doctor of Philosophy Department of Neurodegenerative Disease Institute of Neurology University College London (UCL) 2020 1 I, Davina Hensman Moss confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Collaborative work is also indicated in this thesis. Signature: Date: 2 Abstract Neurodegenerative diseases including Huntington’s disease (HD), the spinocerebellar ataxias and C9orf72 associated Amyotrophic Lateral Sclerosis / Frontotemporal dementia (ALS/FTD) do not present and progress in the same way in all patients. Instead there is phenotypic variability in age at onset, progression and symptoms. Understanding this variability is not only clinically valuable, but identification of the genetic factors underpinning this variability has the potential to highlight genes and pathways which may be amenable to therapeutic manipulation, hence help find drugs for these devastating and currently incurable diseases. Identification of genetic modifiers of neurodegenerative diseases is the overarching aim of this thesis. To identify genetic variants which modify disease progression it is first necessary to have a detailed characterization of the disease and its trajectory over time. In this thesis clinical data from the TRACK-HD studies, for which I collected data as a clinical fellow, was used to study disease progression over time in HD, and give subjects a progression score for subsequent analysis. In this thesis I show blood transcriptomic signatures of HD status and stage which parallel HD brain and overlap with Alzheimer’s disease brain.
    [Show full text]
  • Transcriptome-Wide Association Study of Attention Deficit Hyperactivity Disorder Identifies Associated Genes and Phenotypes
    bioRxiv preprint doi: https://doi.org/10.1101/642231; this version posted May 24, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Transcriptome-wide association study of attention deficit hyperactivity disorder identifies associated genes and phenotypes Calwing Liao1,2, Alexandre D. Laporte2, Dan Spiegelman2, Fulya Akçimen1,2, Ridha Joober3, Patrick A. Dion2,4, Guy A. Rouleau1,2,4 1Department of Human Genetics, McGill University, Montréal, Quebec, Canada 2Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada 3Department of Psychiatry, McGill University, Montréal, Quebec, Canada 4Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada Word count: 2,619 excluding abstract and references Figures: 2 Tables: 3 Keywords: ADHD, transcriptome-wide association study, KAT2B, TMEM161B, amygdala, prefrontal cortex *Correspondence: Dr. Guy A. Rouleau Montreal Neurological Institute and Hospital Department of Neurology and Neurosurgery 3801 University Street, Montreal, QC Canada H3A 2B4. Tel: +1 514 398 2690 Fax: +1 514 398 8248 E-mail: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/642231; this version posted May 24, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental psychiatric disorders.
    [Show full text]
  • 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).
    [Show full text]
  • Downloaded from Ensembl
    UCSF UC San Francisco Electronic Theses and Dissertations Title Detecting genetic similarity between complex human traits by exploring their common molecular mechanism Permalink https://escholarship.org/uc/item/1k40s443 Author Gu, Jialiang Publication Date 2019 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California by Submitted in partial satisfaction of the requirements for degree of in in the GRADUATE DIVISION of the UNIVERSITY OF CALIFORNIA, SAN FRANCISCO AND UNIVERSITY OF CALIFORNIA, BERKELEY Approved: ______________________________________________________________________________ Chair ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ Committee Members ii Acknowledgement This project would not have been possible without Prof. Dr. Hao Li, Dr. Jiashun Zheng and Dr. Chris Fuller at the University of California, San Francisco (UCSF) and Caribou Bioscience. The Li lab grew into a multi-facet research group consist of both experimentalists and computational biologists covering three research areas including cellular/molecular mechanism of ageing, genetic determinants of complex human traits and structure, function, evolution of gene regulatory network. Labs like these are the pillar of global success and reputation
    [Show full text]
  • Predict AID Targeting in Non-Ig Genes Multiple Transcription Factor
    Downloaded from http://www.jimmunol.org/ by guest on September 26, 2021 is online at: average * The Journal of Immunology published online 20 March 2013 from submission to initial decision 4 weeks from acceptance to publication Multiple Transcription Factor Binding Sites Predict AID Targeting in Non-Ig Genes Jamie L. Duke, Man Liu, Gur Yaari, Ashraf M. Khalil, Mary M. Tomayko, Mark J. Shlomchik, David G. Schatz and Steven H. Kleinstein J Immunol http://www.jimmunol.org/content/early/2013/03/20/jimmun ol.1202547 Submit online. Every submission reviewed by practicing scientists ? is published twice each month by http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://www.jimmunol.org/content/suppl/2013/03/20/jimmunol.120254 7.DC1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 26, 2021. Published March 20, 2013, doi:10.4049/jimmunol.1202547 The Journal of Immunology Multiple Transcription Factor Binding Sites Predict AID Targeting in Non-Ig Genes Jamie L. Duke,* Man Liu,†,1 Gur Yaari,‡ Ashraf M. Khalil,x Mary M. Tomayko,{ Mark J. Shlomchik,†,x David G.
    [Show full text]
  • A Network Inference Approach to Understanding Musculoskeletal
    A NETWORK INFERENCE APPROACH TO UNDERSTANDING MUSCULOSKELETAL DISORDERS by NIL TURAN A thesis submitted to The University of Birmingham for the degree of Doctor of Philosophy College of Life and Environmental Sciences School of Biosciences The University of Birmingham June 2013 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 Musculoskeletal disorders are among the most important health problem affecting the quality of life and contributing to a high burden on healthcare systems worldwide. Understanding the molecular mechanisms underlying these disorders is crucial for the development of efficient treatments. In this thesis, musculoskeletal disorders including muscle wasting, bone loss and cartilage deformation have been studied using systems biology approaches. Muscle wasting occurring as a systemic effect in COPD patients has been investigated with an integrative network inference approach. This work has lead to a model describing the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators. This model has shown for the first time that oxygen dependent changes in the expression of epigenetic modifiers and not chronic inflammation may be causally linked to muscle dysfunction.
    [Show full text]
  • Virtual Reality of HBV, HCV and HIV-1 Infection, and Hepatocellular Carcinogenesis with AI Machine Learning
    Arch Clin Biomed Res 2020; 4 (3): 089-129 DOI: 10.26502/acbr.50170092 Research Article The Quantum microRNA Immunity in Human Virus-Associated Diseases: Virtual Reality of HBV, HCV and HIV-1 Infection, and Hepatocellular Carcinogenesis with AI Machine Learning Yoichi Robertus Fujii* Kawada-Cho, 106-6, Atsuta-Ku, Nagoya, 456-0065, Japan *Corresponding author: Yoichi Robertus Fujii, Kawada-Cho, 106-6, Atsuta-Ku, Nagoya, 456-0065, Japan, Tel: 81-52-682-7003; E-mail: [email protected] Received: 21 April 2020; Accepted: 28 April 2020; Published: 06 May 2020 Citation: Yoichi Robertus Fujii. The Quantum microRNA Immunity in Human Virus-Associated Diseases: Virtual Reality of HBV, HCV and HIV-1 Infection, and Hepatocellular Carcinogenesis with AI Machine Learning. Archives of Clinical and Biomedical Research 4 (2020): 089-129. Abstract Objectives: Since virus-related hepatocellular Materials and Methods: The information of the carcinoma (HCC) is quite complexed, the etiology of miRNA biomarker panels in hepatitis B virus (HBV), virus-associated HCC is remained unclear. We have hepatitis C virus (HCV) and human previously shown that the microRNA (miRNA) immunodeficiency virus type 1 (HIV-1) infection, entangling sorter (METS) analysis with quantum virus-related fibrosis (cirrhosis), and virus-associated miRNA/miRNA language is available for the HCCs was extracted from database. The miRNA hub etiology investigation in silico from miRNA in the panels was selected by both protein/protein biomarker panels of human cancers to predict interaction and carcinogenic protein function. The carcinogenesis. To further investigate the etiology of statistical analysis upon tumorigenesis was calculated human virus-associated diseases on the stage minus by Prediction One.
    [Show full text]
  • Deeppheno: Predicting Single Gene Knockout Phenotypes Maxat Kulmanov 1, and Robert Hoehndorf1,∗
    bioRxiv preprint doi: https://doi.org/10.1101/839332; this version posted November 13, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. i i “main” — 2019/11/13 — 7:46 — page 1 — #1 i i Advance Access Publication Date: Day Month Year Manuscript Category Subject Section DeepPheno: Predicting single gene knockout phenotypes Maxat Kulmanov 1, and Robert Hoehndorf1,∗ 1Computational Bioscience Research Center, Computer, Electrical and Mathematical Sciences & Engineering Division, King Abdullah University of Science and Technology, 4700 King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia ∗To whom correspondence should be addressed. Associate Editor: XXXXXXX Received on XXXXX; revised on XXXXX; accepted on XXXXX Abstract Motivation: Predicting the phenotypes resulting from molecular perturbations is one of the key challenges in genetics. Both forward and reverse genetic screen are employed to identify the molecular mechanisms underlying phenotypes and disease, and these resulted in a large number of genotype–phenotype association being available for humans and model organisms. Combined with recent advances in machine learning, it may now be possible to predict human phenotypes resulting from particular molecular aberrations. Results: We developed DeepPheno, a method for predicting the phenotypes resulting from complete loss-of-function in single genes. DeepPheno uses the functional annotations with gene products to predict the phenotypes resulting from a loss-of-function; additionally, we employ a two-step procedure in which we predict these functions first and then predict phenotypes.
    [Show full text]
  • SUPPLEMENTARY MATERIALS and METHODS PBMC Transcriptomics
    BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Gut SUPPLEMENTARY MATERIALS AND METHODS PBMC transcriptomics identifies immune-metabolism disorder during the development of HBV-ACLF Contents l Supplementary methods l Supplementary Figure 1 l Supplementary Figure 2 l Supplementary Figure 3 l Supplementary Figure 4 l Supplementary Figure 5 l Supplementary Table 1 l Supplementary Table 2 l Supplementary Table 3 l Supplementary Table 4 l Supplementary Tables 5-14 l Supplementary Table 15 l Supplementary Table 16 l Supplementary Table 17 Li J, et al. Gut 2021;0:1–13. doi: 10.1136/gutjnl-2020-323395 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Gut SUPPLEMENTARY METHODS Test for HBV DNA The levels of HBV DNA were detected using real-time PCR with a COBAS® AmpliPrep/COBAS® TaqMan 48 System (Roche, Basel, Switzerland) and HBV Test v2.0. Criteria for diagnosing cirrhosis Pathology The gold standard for the diagnosis of cirrhosis is a liver biopsy obtained through a percutaneous or transjugular approach.1 Ultrasonography was performed 2-4 hours before biopsy. Liver biopsy specimens were obtained by experienced physicians. Percutaneous transthoracic puncture of the liver was performed according to the standard criteria. After biopsy, patients were monitored in the hospital with periodic analyses of haematocrit and other vital signs for 24 hours. Cirrhosis was diagnosed according to the globally agreed upon criteria.2 Cirrhosis is defined based on its pathological features under a microscope: (a) the presence of parenchymal nodules, (b) differences in liver cell size and appearance, (c) fragmentation of the biopsy specimen, (d) fibrous septa, and (d) an altered architecture and vascular relationships.
    [Show full text]