The Bone Marrow Niche in the Pathogenesis of Multiple Myeloma a Role for Wnt Signaling and Adrenomedullin

Total Page:16

File Type:pdf, Size:1020Kb

The Bone Marrow Niche in the Pathogenesis of Multiple Myeloma a Role for Wnt Signaling and Adrenomedullin A role for Wnt signaling and Adrenomedullin and signaling Wnt for A role Myeloma Multiple of niche in the pathogenesis marrow The bone The bone marrow niche in the pathogenesis of Multiple Myeloma A role for Wnt signaling and Adrenomedullin pracownia DTP i grafiki www.przygotowalniaDTP.pl ISBN 978-83-63861-16-2 Kinga Anna Kocemba okladka_nowa.indd 1-3 2014-01-20 11:57:46 The bone marrow niche in the pathogenesis of Multiple Myeloma A role for Wnt signaling and Adrenomedullin The bone marrow niche in the pathogenesis of Multiple Myeloma A role for Wnt signaling and Adrenomedullin Kinga Anna Kocemba The research described in this thesis was funded by the Dutch Cancer Society Editing Przygotowalnia Pracownia DTP i Grafiki Graphic design and typesetting Przygotowalnia Pracownia DTP i Grafiki Cover: Antelope Canyon, Arizona, USA by Kinga Anna Kocemba © Copyright by Kinga Anna Kocemba ISBN 978-83-63861-16-2 Amsterdam–Kraków 2014 Pracownia DTP i Grafiki ul. Łużycka 71c/9 30–693 Kraków przygotowalnia.dtp@gmail.com www.przygotowalniaDTP.pl Moim rodzicom To my parents The bone marrow niche in the pathogenesis of Multiple Myeloma A role for Wnt signaling and Adrenomedullin academisch proefschrift ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. D.C. van den Boom ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op donderdag 6 maart 2014, te 14:00 uur door Kinga Anna Kocemba geboren te Oświęcim, Polen Promotiecommissie promotor Prof. dr. S.T. Pals co-promotor Dr. M. Spaargaren overige leden Dr. M.M. Maurice Prof. dr. C.J.M. van Noesel Prof. dr. M.H.J. van Oers Prof. dr. P. Sonneveld Prof. dr. K. Vanderkerken Faculteit der Geneeskunde Contents 9 chapter 1 General introduction 37 chapter 2 Wnt signaling reaching gale force during multiple myeloma progression 59 chapter 3 Transcriptional silencing of the Wnt-antagonist DKK1 by promoter methylation is associated with enhanced Wnt signaling in advanced multiple myeloma 87 chapter 4 Loss of CYLD expression unleashes Wnt signaling in multiple myeloma and is associated with aggressive disease 111 chapter 5 N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation 143 chapter 6 The hypoxia target adrenomedullin is aberrantly expressed in multiple myeloma and promotes angiogenesis 201 chapter 7 Summary and discussion 213 chapter 8 Nederlandse samenvatting Acknowledgments Curriculum vitae Chapter 11 General introduction B CELL DEVELOPMENT AND B-lineaGE MALIGNANCIES The development of B cells is characterized by sequential molecular events regu- lated by B-lineage specific transcription factors. During early development in the 1 bone marrow, B cells acquire the ability to express cell surface-bound immuno- globulins, which constitutie the antigen-binding part of the B cell receptor (BCR) multiprotein complex.1 BCR diversity, required for antigen recognition, is gen- erated by somatic recombination, combining various gene segments within the 3 immunoglobuline (Ig) heavy and light chain loci. The heavy chain is assembled from Variable (V), Diversity (D) and Joining (J) gene segments that somatically 4 recombine with the Constant (C) region exons, generating unique immunoglobu- lins of diverse antigenic specificity. The light chain variable region (which can be of 5 kappa or lambda type) is composed of only a V and J gene segment. The diversity of the IgV regions is further enhanced by addition of nucleotides at the junctions 6 of the segments. Upon successful rearrangement of Ig light and heavy chain genes, a complete IgM molecule is expressed at the cell surface, which is required for sur- 7 vival. Non self-reactive immature B cells exit the bone marrow, whereas self-reac- tive immature B cells undergo apoptosis (clonal deletion), or generate a new B cell receptor by receptor editing.2,3,4,5 The immature B cell then migrate to the second- ary lymphoid organs, i.e. lymph nodes, spleen and mucosa-associated lymphoid tissue (MALT), to complete the process of maturation. Upon antigen encounter, these naive B cells may undergo antigen-specific B cell differentiation. Initially, antigen is internalized by the BCR and processed peptides are presented by MHC class II molecules to Th cells. This interaction with Th cells provides the B cells with co-stimulatory signals, crucial for further differentiation. B cells may now differen- tiate into short-lived plasmablast outside of the germinal center (GC), or migrate into a primary follicle to initiate the formation of a GC.6,7 Germinal centers can be 11 Chapter 1 subdivided in two distinct zones, called the dark and light zones. Rapidly prolifer- ating B cells (centroblasts) form the dark zone of the GC. In this zone, somatic hy- permutation (SHM) of the immunoglobulin genes of the B cells takes place.8–10 This involves introduction of point mutations by the enzyme called activation-induced cytidine deaminase (AID), which deaminates cytidines to uracil. This results in C-T and G-A transitions in the V region of immunoglobulin (Ig) genes, creat- ing Ig variants with altered affinity for a particular antigen.11 The mutated B cells (centrocytes) migrate to the light zone of the GC. Here, they re-encounter antigen presented by the follicular dendritic cells (FDC), and a selection process, based on the affinity of the BCR for antigen, is initiated. Depending on the strength of BCR signal, B cells will receive a survival and proliferation signal from the FDCs and Th cells, or will die by apoptosis.12–14 High affinity B cells will process antigen and present this to antigen-specific T cells,15 which provide stimulatory signals (e.g. T cell receptor (TCR)/CD3-MHC class II, CD40-CD40L, CD80/86-CD28 and several cytokines),6,13,16–18 resulting in class switch recombination (CSR) and further differentiation into either memory B cells or plasma cells.9,17,18 VDJ recombination (VDJR), as well as (CSR) and SHM, involve the genera- tion of DNA breaks, potentially dangerous events that predispose to chromosomal translocations Indeed, the DNA breaks that are induced by VDJR, CSR and SHM coincide with the sites of chromosomal translocations that involve the IgH or IgL loci in many lymphoid malignancies.19–21 For instance, chromosomal translocation that involve the IgH switch region and the partner oncogene (e.g. BCL-2, BCL6, c-MYC, CCND1, CCND3, FGFR3-MMSET and MAFC), have been identified in follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), Burkitt’s lymphoma and multiple myeloma (MM).22–25 Moreover, during the SHM process in the GC, AID can introduce mutations in non-immunoglobulin genes, e.g. the oncogenes BCL6, MYC, PIM1, PAX5.19,26 In general, each lymphoma subtype resembles a B cell trapped at the particular stage of B cell development (Figure 1), as determined by the presence or absence of somatic hypermutation and the gene expression profile.27,28 For instance, for Burkitt lymphoma, follicular lymphoma, and the germinal center B cell-like (GCB) sub- type of diffuse large B cell lymphoma (DLBCL), the normal cellular counterpart is the germinal center B cell,29,30 whereas the activated B cell-like (ABC) subtype of DLBCL resembles post-germinal center B cells/plasmablasts.29 Mucosa-associated lymphoid tissue (MALT) lymphomas are extra nodal in origin and phenotypically related to post-germinal center marginal zone B cells.31 Hairy cell leukemia has mutated Ig genes and class switched Ig heavy chains, along with a gene expression profile pointing to post-germinal center memory B cell as a cell of origin.32 12 General introduction 1 Figure 1. Normal B cell development and the related stages of B cell malignancy Schematic representation of B cell differentiation. The malignant counterparts are indicated by italic font. BM-bone marrow, ALL-acute lymphoblastic leukemia, MALT-mucosa associated lymphoid tis- sue, MCL-mucosa associated lymphoid tissue, DLBCL-diffuse large B cell lymphoma, CLL-chronic 3 lymphocytic leukemia, FL-follicular lymphoma, MM-multiple myeloma. 4 MULTIPLE MYELOMA 5 Multiple myeloma (MM) is characterized by a clonal proliferation of plasma cells 6 (PCs) in the bone marrow (BM), often associated with pancytopenia and osteolyt- ic bone disease. It is one of the most frequent hematological cancers and remains 7 largely incurable, despite high-dose chemotherapy with additional stem cells sup- port. The presence of somatic hypermutation of the immunoglobulin variable region genes in MM cells indicates that the cell of origin in myeloma is a post-ger- minal center B cell.33,34 In the majority of cases MM arises from a pre-malignant expansion of plasma cells called monoclonal gammopathy of undetermined sig- nificance (MGUS), with a prevalence of approximately 3% and 5% in people older than 50 and 70 years, respectively.35,36 Based on chromosomal studies, two main cytogenetic subgroups can be discriminated: a group characterized by a high in- cidence of five recurrent IgH translocations and loss of chromosome 13/13q14; and a hyperdiploid group, characterized by multiple trisomies.24 The recurrent translocations in the non-hyperdiploid group involve the IgH switch region 14q32 13 Chapter 1 and the translocation partners: cyclin D1 (CCND1) (11q13), cyclin D3 (CCND3) (6p21), MAFC (16q23), FGFR3 and MMSET (4p16), and MAFB (20q11).37 Hyperdiploid myeloma is characterized by trisomies of multiple odd chromosomes (3, 5, 7, 9, 11, 15, 19, and 21). Together with t(11;14), hyperdiploidy confers a rela- tively favorable prognosis, whereas MAFC, MAFB, or FGFR3/MMSET activa- tion and deletion of chromosome 13 and/or 17 are associated with a poor prog- nosis.38,39 Interestingly, there is no single genetic event that distinguishes MGUS from MM. However, several genetic aberrations have been associated with disease progression.
Recommended publications
  • Investigation of Candidate Genes and Mechanisms Underlying Obesity
    Prashanth et al. BMC Endocrine Disorders (2021) 21:80 https://doi.org/10.1186/s12902-021-00718-5 RESEARCH ARTICLE Open Access Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules G. Prashanth1 , Basavaraj Vastrad2 , Anandkumar Tengli3 , Chanabasayya Vastrad4* and Iranna Kotturshetti5 Abstract Background: Obesity associated type 2 diabetes mellitus is a metabolic disorder ; however, the etiology of obesity associated type 2 diabetes mellitus remains largely unknown. There is an urgent need to further broaden the understanding of the molecular mechanism associated in obesity associated type 2 diabetes mellitus. Methods: To screen the differentially expressed genes (DEGs) that might play essential roles in obesity associated type 2 diabetes mellitus, the publicly available expression profiling by high throughput sequencing data (GSE143319) was downloaded and screened for DEGs. Then, Gene Ontology (GO) and REACTOME pathway enrichment analysis were performed. The protein - protein interaction network, miRNA - target genes regulatory network and TF-target gene regulatory network were constructed and analyzed for identification of hub and target genes. The hub genes were validated by receiver operating characteristic (ROC) curve analysis and RT- PCR analysis. Finally, a molecular docking study was performed on over expressed proteins to predict the target small drug molecules. Results: A total of 820 DEGs were identified between
    [Show full text]
  • Noelia Díaz Blanco
    Effects of environmental factors on the gonadal transcriptome of European sea bass (Dicentrarchus labrax), juvenile growth and sex ratios Noelia Díaz Blanco Ph.D. thesis 2014 Submitted in partial fulfillment of the requirements for the Ph.D. degree from the Universitat Pompeu Fabra (UPF). This work has been carried out at the Group of Biology of Reproduction (GBR), at the Department of Renewable Marine Resources of the Institute of Marine Sciences (ICM-CSIC). Thesis supervisor: Dr. Francesc Piferrer Professor d’Investigació Institut de Ciències del Mar (ICM-CSIC) i ii A mis padres A Xavi iii iv Acknowledgements This thesis has been made possible by the support of many people who in one way or another, many times unknowingly, gave me the strength to overcome this "long and winding road". First of all, I would like to thank my supervisor, Dr. Francesc Piferrer, for his patience, guidance and wise advice throughout all this Ph.D. experience. But above all, for the trust he placed on me almost seven years ago when he offered me the opportunity to be part of his team. Thanks also for teaching me how to question always everything, for sharing with me your enthusiasm for science and for giving me the opportunity of learning from you by participating in many projects, collaborations and scientific meetings. I am also thankful to my colleagues (former and present Group of Biology of Reproduction members) for your support and encouragement throughout this journey. To the “exGBRs”, thanks for helping me with my first steps into this world. Working as an undergrad with you Dr.
    [Show full text]
  • Identification of QTL for Resistance Against Two Fungal Pathogens, Pyrenophora Teres F
    Fluturë Novakazi Institut für Resistenzforschung und Stresstoleranz Identification of QTL for resistance against two fungal pathogens, Pyrenophora teres f. teres and Bipolaris sorokiniana, in a barley (Hordeum vulgare L.) diversity set Dissertationen aus dem Julius Kühn-Institut Julius Kühn-Institut Bundesforschungsinstitut für Kulturpflanzen Kontakt | Contact: Fluturë Novakazi Beethovenstraße 24 18069 Rostock Die Schriftenreihe ,,Dissertationen aus dem Julius Kühn-lnstitut“ veröffentlicht Doktorarbeiten, die in enger Zusammenarbeit mit Universitäten an lnstituten des Julius Kühn-lnstituts entstan- den sind. The publication series „Dissertationen aus dem Julius Kühn-lnstitut“ publishes doctoral disser- tations originating from research doctorates and completed at the Julius Kühn-Institut (JKI) either in close collaboration with universities or as an outstanding independent work in the JKI research fields. Der Vertrieb dieser Monographien erfolgt über den Buchhandel (Nachweis im Verzeichnis liefer- barer Bücher - VLB) und OPEN ACCESS unter: https://www.openagrar.de/receive/openagrar_mods_00005667 The monographs are distributed through the book trade (listed in German Books in Print - VLB) and OPEN ACCESS here: https://www.openagrar.de/receive/openagrar_mods_00005667 Wir unterstützen den offenen Zugang zu wissenschaftlichem Wissen. Die Dissertationen aus dem Julius Kühn-lnstitut erscheinen daher OPEN ACCESS. Alle Ausgaben stehen kostenfrei im lnternet zur Verfügung: http://www.julius-kuehn.de Bereich Veröffentlichungen. We advocate open access to scientific knowledge. Dissertations from the Julius Kühn-lnstitut are therefore published open access. All issues are available free of charge under http://www.julius-kuehn.de (see Publications). Bibliografische Information der Deutschen Nationalbibliothek Die Deutsche Nationalbibliothek verzeichnet diese Publikation In der Deutschen Nationalbibliografie: detaillierte bibliografische Daten sind im lnternet über http://dnb.d-nb.de abrufbar.
    [Show full text]
  • Appendix 2. Significantly Differentially Regulated Genes in Term Compared with Second Trimester Amniotic Fluid Supernatant
    Appendix 2. Significantly Differentially Regulated Genes in Term Compared With Second Trimester Amniotic Fluid Supernatant Fold Change in term vs second trimester Amniotic Affymetrix Duplicate Fluid Probe ID probes Symbol Entrez Gene Name 1019.9 217059_at D MUC7 mucin 7, secreted 424.5 211735_x_at D SFTPC surfactant protein C 416.2 206835_at STATH statherin 363.4 214387_x_at D SFTPC surfactant protein C 295.5 205982_x_at D SFTPC surfactant protein C 288.7 1553454_at RPTN repetin solute carrier family 34 (sodium 251.3 204124_at SLC34A2 phosphate), member 2 238.9 206786_at HTN3 histatin 3 161.5 220191_at GKN1 gastrokine 1 152.7 223678_s_at D SFTPA2 surfactant protein A2 130.9 207430_s_at D MSMB microseminoprotein, beta- 99.0 214199_at SFTPD surfactant protein D major histocompatibility complex, class II, 96.5 210982_s_at D HLA-DRA DR alpha 96.5 221133_s_at D CLDN18 claudin 18 94.4 238222_at GKN2 gastrokine 2 93.7 1557961_s_at D LOC100127983 uncharacterized LOC100127983 93.1 229584_at LRRK2 leucine-rich repeat kinase 2 HOXD cluster antisense RNA 1 (non- 88.6 242042_s_at D HOXD-AS1 protein coding) 86.0 205569_at LAMP3 lysosomal-associated membrane protein 3 85.4 232698_at BPIFB2 BPI fold containing family B, member 2 84.4 205979_at SCGB2A1 secretoglobin, family 2A, member 1 84.3 230469_at RTKN2 rhotekin 2 82.2 204130_at HSD11B2 hydroxysteroid (11-beta) dehydrogenase 2 81.9 222242_s_at KLK5 kallikrein-related peptidase 5 77.0 237281_at AKAP14 A kinase (PRKA) anchor protein 14 76.7 1553602_at MUCL1 mucin-like 1 76.3 216359_at D MUC7 mucin 7,
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2014/0304845 A1 Loboda Et Al
    US 201403.04845A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0304845 A1 Loboda et al. (43) Pub. Date: Oct. 9, 2014 54) ALZHEMIERS DISEASE SIGNATURE Publicationublication ClassificatiClassification MARKERS AND METHODS OF USE (51) Int. Cl. (71) Applicant: MERCKSHARP & DOHME CORP, CI2O I/68 (2006.01) Rahway, NJ (US) AOIK 67/027 (2006.01) (52) U.S. Cl. (72) Inventors: SIES yet.sS); CPC .......... CI2O I/6883 (2013.01); A0IK 67/0275 Icnaei NepoZnyn, Yeadon, (2013.01) le.East,Italia; David J. Stone, Wyncote, USPC .............. 800/12:536/23.5:536/23.2:506/17 (US); Keith Tanis, Quakertown, PA (US); William J. Ray, Juniper, FL (US) (57) ABSTRACT (21) Appl. No.: 14/354,622 Methods, biomarkers, and expression signatures are dis 1-1. closed for assessing the disease progression of Alzheimer's (22) PCT Filed: Oct. 26, 2012 disease (AD). In one embodiment, BioAge (biological age), NdStress (neurodegenerative stress), Alz (Alzheimer), and (86). PCT No.: PCT/US12A62218 Inflame (inflammation) are used as biomarkers of AD pro S371 (c)(1), gression. In another aspect, the invention comprises a gene (2), (4) Date: Apr. 28, 2014 signature for evaluating disease progression. In still another Related U.S. Application Data abiliticises in (60) Provisional application No. 61/553,400, filed on Oct. used to identify animal models for use in the development and 31, 2011. evaluation of therapeutics for the treatment of AD. Patent Application Publication Oct. 9, 2014 Sheet 1 of 16 US 2014/0304845 A1 Y : : O O O O O O O O D O v v CN On cy Patent Application Publication Oct.
    [Show full text]
  • Supp Table 6.Pdf
    Supplementary Table 6. Processes associated to the 2037 SCL candidate target genes ID Symbol Entrez Gene Name Process NM_178114 AMIGO2 adhesion molecule with Ig-like domain 2 adhesion NM_033474 ARVCF armadillo repeat gene deletes in velocardiofacial syndrome adhesion NM_027060 BTBD9 BTB (POZ) domain containing 9 adhesion NM_001039149 CD226 CD226 molecule adhesion NM_010581 CD47 CD47 molecule adhesion NM_023370 CDH23 cadherin-like 23 adhesion NM_207298 CERCAM cerebral endothelial cell adhesion molecule adhesion NM_021719 CLDN15 claudin 15 adhesion NM_009902 CLDN3 claudin 3 adhesion NM_008779 CNTN3 contactin 3 (plasmacytoma associated) adhesion NM_015734 COL5A1 collagen, type V, alpha 1 adhesion NM_007803 CTTN cortactin adhesion NM_009142 CX3CL1 chemokine (C-X3-C motif) ligand 1 adhesion NM_031174 DSCAM Down syndrome cell adhesion molecule adhesion NM_145158 EMILIN2 elastin microfibril interfacer 2 adhesion NM_001081286 FAT1 FAT tumor suppressor homolog 1 (Drosophila) adhesion NM_001080814 FAT3 FAT tumor suppressor homolog 3 (Drosophila) adhesion NM_153795 FERMT3 fermitin family homolog 3 (Drosophila) adhesion NM_010494 ICAM2 intercellular adhesion molecule 2 adhesion NM_023892 ICAM4 (includes EG:3386) intercellular adhesion molecule 4 (Landsteiner-Wiener blood group)adhesion NM_001001979 MEGF10 multiple EGF-like-domains 10 adhesion NM_172522 MEGF11 multiple EGF-like-domains 11 adhesion NM_010739 MUC13 mucin 13, cell surface associated adhesion NM_013610 NINJ1 ninjurin 1 adhesion NM_016718 NINJ2 ninjurin 2 adhesion NM_172932 NLGN3 neuroligin
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • On SARS-Cov-2, Tropical Medicine and Bioinformatics: Analysis of the SARS-Cov-2 Molecular Features and Epitope Prediction for Antibody Or Vaccine Development
    ACTA SCIENTIFIC MICROBIOLOGY (ISSN: 2581-3226) Volume 4 Issue 1 January 2021 Research Article On SARS-CoV-2, Tropical Medicine and Bioinformatics: Analysis of the SARS-Cov-2 Molecular Features and Epitope Prediction for Antibody or Vaccine Development Joshua Angelo Hermida Mandanas* Received: November 24, 2020 Tropical Medicine Scientist and Immunobiologist, Philippine Medical Technology Published: December 08, 2020 Professional/National Lecturer, University of the Philippines Manila, Philippines © All rights are reserved by Joshua Angelo *Corresponding Author: Joshua Angelo Hermida Mandanas, Tropical Medicine Hermida Mandanas. Scientist and Immunobiologist, Philippine Medical Technology Professional/National Lecturer, University of the Philippines Manila, Philippines. Abstract Introduction: SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the cause of COVID-19 which is the pandemic as of the current time. It is a global public health emergency and is still on the loose of spreading more infections and deaths. Bioinformat- ics offer extensive visualization and analysis of combined molecular, cellular, biochemical and immunobiologic aspects of SARS-CoV-2 which is indeed vital for antibody and vaccine development. Objectives: This paper presents the SARS-CoV-2 molecular virologic, biochemical, cellular and immunobiologic features and gives a basic B cell linear epitope prediction of the SARS-CoV-2 spike (S) glycoprotein using bioinformatics which both can serve as a guide for development of vaccines or antibody-based treatments. Methods: Several bioinformatic methods were used, from sequence analysis (Uniprot), structural correlation (PDB), molecular mod- elling (UCSF Chimera) and illustration (Biorender), B cell linear epitope prediction tools, conservancy analysis and search of related epitopes (IEDB) together with determination of disordered regions (GlobPlot and DisEMBL).
    [Show full text]
  • Forms of Supplemental Selenium in Vitamin-Mineral
    University of Kentucky UKnowledge Theses and Dissertations--Animal and Food Sciences Animal and Food Sciences 2019 FORMS OF SUPPLEMENTAL SELENIUM IN VITAMIN-MINERAL MIXES DIFFERENTIALLY AFFECT SEROLOGICAL AND HEPATIC PARAMETERS OF GROWING BEEF STEERS GRAZING ENDOPHYTE-INFECTED TALL FESCUE Yang Jia University of Kentucky, yang.jia@uky.edu Digital Object Identifier: https://doi.org/10.13023/etd.2019.028 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Jia, Yang, "FORMS OF SUPPLEMENTAL SELENIUM IN VITAMIN-MINERAL MIXES DIFFERENTIALLY AFFECT SEROLOGICAL AND HEPATIC PARAMETERS OF GROWING BEEF STEERS GRAZING ENDOPHYTE- INFECTED TALL FESCUE" (2019). Theses and Dissertations--Animal and Food Sciences. 97. https://uknowledge.uky.edu/animalsci_etds/97 This Doctoral Dissertation is brought to you for free and open access by the Animal and Food Sciences at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Animal and Food Sciences by an authorized administrator of UKnowledge. For more information, please contact UKnowledge@lsv.uky.edu. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known.
    [Show full text]
  • Identifying Protein Partners of the Neuronal Transmembrane Protein Neto2
    IDENTIFYING PROTEIN PARTNERS OF THE NEURONAL TRANSMEMBRANE PROTEIN NETO2 BY VIVEK MAHADEVAN A thesis submitted in conformity with the requirements for the degree of Master of Science, Department of Molecular Genetics, University of Toronto © Copyright by Vivek Mahadevan 2010 Abstract IDENTIFYING PROTEIN PARTNERS OF THE NEURONAL TRANSMEMBRANE PROTEIN NETO2 Vivek Mahadevan Master of Science, Department of Molecular Genetics University of Toronto, Copyright by Vivek Mahadevan 2010 The neuronal transmembrane proteins Neto1 and Neto2, along with different protein partners, are known to perform multiple roles in diverse processes including axon guidance in the developing nervous system and synaptic plasticity in the adult brain. My project focuses on identifying the membrane bound interacting partners of Neto2 using Membrane Yeast Two Hybrid (MYTH). By performing MYTH screens for the Neto2 molecule using human adult and embryonic whole brain cDNA libraries, I have identified several novel membrane bound putative interacting partners including VAMP associated protein B (VAPB) and Glutamate transporter EAAT3-associated protein (GTRAP3-18), which play diverse functions during the glutamatergic neurotransmission. Initial studies to validate these interactions in vivo are currently underway by co-immunoprecipitation approach using mouse brain tissue. If these two candidate proteins are confirmed to be true interactors, it will open important avenues of research for the Neto2 protein during excitatory neurotransmission in the mammalian central nervous system. ii Acknowledgements First and foremost, my deepest gratitude goes to my supervisor Dr. Roderick McInnes, for giving me a wonderful opportunity to be a part of an exciting project in his exciting lab! Thanks Rod, for sharing your experience, motivation and the quest for excellence.
    [Show full text]
  • Sc-154478-SH
    SANTA CRUZ BIOTECHNOLOGY, INC. TMEM53 shRNA Plasmid (m): sc-154478-SH BACKGROUND CHROMOSOMAL LOCATION TMEM53 (transmembrane protein 53) is a 247 amino acid protein encoded by Genetic locus: Tmem53 (mouse) mapping to 4 D1. a gene mapping to human chromosome 1. Chromosome 1 is the largest human chromosome spanning about 260 million base pairs and making up 8% of the PRODUCT human genome. There are about 3,000 genes on chromosome 1, and consider- TMEM53 shRNA Plasmid (m) is a pool of 3 target-specific lentiviral vector ing the great number of genes there are also a large number of diseases asso- plasmids each encoding 19-25 nt (plus hairpin) shRNAs designed to knock ciated with chromosome 1. Notably, the rare aging disease Hutchinson-Gilford down gene expression. Each plasmid contains a puromycin resistance gene progeria is associated with the LMNA gene which encodes Lamin A. When for the selection of cells stably expressing shRNA. Each vial contains 20 µg defective, the LMNA gene product can build up in the nucleus and cause char- of lyophilized shRNA plasmid DNA. Suitable for up to 20 transfections. Also acteristic nuclear blebs. The mechanism of rapidly enhanced aging is unclear see TMEM53 siRNA (m): sc-154478 and TMEM53 shRNA (m) Lentiviral and is a topic of continuing exploration. The MUTYH gene is located on chro- Particles: sc-154478-V as alternate gene silencing products. mosome 1 and is partially responsible for familial adenomatous polyposis. Stickler syndrome, Parkinson’s, Gaucher disease and Usher syndrome are also STORAGE AND RESUSPENSION associated with chromosome 1. A breakpoint has been identified in 1q which disrupts the DISC1 gene and is linked to schizophrenia.
    [Show full text]
  • Behind Melanocortin Antagonist Overexpression in the Zebrafish Brain: a Behavioral and Transcriptomic Approach
    Behind melanocortin antagonist overexpression in the zebrafish brain: a behavioral and transcriptomic approach 1 1 1 1 1 Raúl Guillot , Raúl Cortés , Sandra Navarro , Morena Mischitelli , Víctor García-Herranz , Elisa 2 3 4 5 6 Sánchez 1, Laura Cal , Juan Carlos Navarro , Jesús Míguez , Sergey Afanasyev , Aleksei Krasnov , 2 1 Roger D Cone 7, Josep Rotllant *, Jose Miguel Cerdá-Reverter * 1 Control of Food Intake Group, Department of Fish Physiolgy and Biotechnology, Instituto de 2 Acuicultura de Torre de la Sal (IATS-CSIC). Castellón, Spain, 12595. Aquatic Molecular Pathobiology Group, Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones 3 Científicas (CSIC). Vigo, Spain. Lipid Group, Department of Biology, Culture and Pathology of Marine Species, Instituto de Acuicultura de Torre de la Sal (IATS-CSIC). Castellón, Spain, 12595. 4 Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, 5 Facultade de Bioloxía, Universidade de Vigo, Vigo, Spain, 36310. Sechenov Institute of Evolutionary Physiology and Biochemistry, M. Toreza Av. 44, Saint Petersburg 194223, Russia 6 Nofima Marine, Norwegian Institutes of Food, Fisheries & Aquaculture Research, 5010 1432 Ås 7 Norway. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 702 Light Hall (0165), Nashville, Tennessee 37232–0165. *Corresponding authors and reprint requests: José Miguel Cerdá-Reverter, Instituto de Acuicultura de Torre de la Sal, CSIC. Torre la Sal s/n, 12595, Ribera de Cabanes, Castellón, Spain. Tel. (+34) 964319500 Fax (+34) 964319509. E-mail: jm.cerda.reverter@csic.es Josep Rotllant, Instituto de Investigaciones Marinas, CSIC. Eduardo Cabello, 36208, Vigo (Pontevedra), Spain. Tel. (+34) 986-231930 Fax (+34) 986 292 762.
    [Show full text]