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Strategies to Increase ß-Cell Mass Expansion
This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Strategies to increase -cell mass expansion Drynda, Robert Lech Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. Oct. 2021 Strategies to increase β-cell mass expansion A thesis submitted by Robert Drynda For the degree of Doctor of Philosophy from King’s College London Diabetes Research Group Division of Diabetes & Nutritional Sciences Faculty of Life Sciences & Medicine King’s College London 2017 Table of contents Table of contents ................................................................................................. -
Transcriptomic Profiling of Pancreatic Alpha, Beta and Delta Cell Populations Identifies Delta Cells As a Principal Target for Ghrelin in Mouse Islets
Diabetologia (2016) 59:2156–2165 DOI 10.1007/s00125-016-4033-1 ARTICLE Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets Alice E. Adriaenssens1 & Berit Svendsen2,3 & Brian Y. H. Lam1 & Giles S. H. Yeo1 & Jens J. Holst2,3 & Frank Reimann1 & Fiona M. Gribble 1 Received: 15 March 2016 /Accepted: 1 June 2016 /Published online: 7 July 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract using islets with delta cell restricted expression of the calcium Aims/hypothesis Intra-islet and gut–islet crosstalk are critical reporter GCaMP3, and in perfused mouse pancreases. in orchestrating basal and postprandial metabolism. The aim Results A database was constructed of all genes expressed in of this study was to identify regulatory proteins and receptors alpha, beta and delta cells. The gene encoding the ghrelin underlying somatostatin secretion though the use of receptor, Ghsr, was highlighted as being highly expressed transcriptomic comparison of purified murine alpha, beta and enriched in delta cells. Activation of the ghrelin receptor and delta cells. raised cytosolic calcium levels in primary pancreatic delta Methods Sst-Cre mice crossed with fluorescent reporters were cells and enhanced somatostatin secretion in perfused used to identify delta cells, while Glu-Venus (with Venus re- pancreases, correlating with a decrease in insulin and gluca- ported under the control of the Glu [also known as Gcg]pro- gon release. The inhibition of insulin secretion by ghrelin was moter) mice were used to identify alpha and beta cells. -
Role of Negative Regulation of Immune Signaling Pathways in Neutrophil Function
Role of negative regulation of immune signaling pathways in neutrophil function Veronica Azcutia *, Charles A. Parkos *, Jennifer C. Brazil * *Department of Pathology, University of Michigan, Ann Arbor, MI 48109 USA. Summary statement: Review on how PMN functions are negatively regulated by immune signaling pathways. Running title: Negative regulation of PMN function. Send correspondence to V.A and J.C.B, and the Editorial and Production Office information to V.A.: *Veronica Azcutia, Ph.D. Department of Pathology, University of Michigan. Biomedical Science Research Building (BSRB),109 Zina Pitcher Place, Ann Arbor, MI 48109 USA. This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/JLB.3MIR0917-374R. This article is protected by copyright. All rights reserved. Tel: (734)-936-1856, Fax: (734)-615-2331, e-Mail: [email protected] *Jennifer C. Brazil, Ph.D. Department of Pathology, University of Michigan. Biomedical Science Research Building (BSRB),109 Zina Pitcher Place, Ann Arbor, MI 48109 USA. Tel: (734)-936-1856, Fax: (734)-615-2331, e-Mail: [email protected] Key words: neutrophils, ITIM, inflammation. Total character count: 43,451; 2 Figures: Figure 1 and 2 are in color; 89 references; 144 words in Abstract; 12 words in summary statement. Abbreviations A(A2)AR = adenosine receptor BM = bone marrow CEACAM = carcinoembryonic antigen-related cell adhesion molecule Csk = C-terminal Scr kinase fMLF = formyl-methionyl-leucyl phenylalanine peptide GAP = GTPase activating proteins GEF = guanine nucleotide exchange factor G-CSF = Granulocyte colony stimulating factor G-CSFR = Granulocyte colony stimulating factor receptor GPCR = G protein coupled receptor GRK = G protein coupled receptor kinase IBD = Inflammatory bowel disease ICAM-1 = Intracellular Adhesion molecule-1 2 This article is protected by copyright. -
Oncostatin M Exhibit Elevated Responsiveness to IL-31 Receptor
IL-31 Receptor (IL-31RA) Knockout Mice Exhibit Elevated Responsiveness to Oncostatin M This information is current as Janine Bilsborough, Sherri Mudri, Eric Chadwick, Brandon of September 28, 2021. Harder and Stacey R. Dillon J Immunol 2010; 185:6023-6030; Prepublished online 18 October 2010; doi: 10.4049/jimmunol.0902769 http://www.jimmunol.org/content/185/10/6023 Downloaded from References This article cites 29 articles, 6 of which you can access for free at: http://www.jimmunol.org/content/185/10/6023.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IL-31 Receptor (IL-31RA) Knockout Mice Exhibit Elevated Responsiveness to Oncostatin M Janine Bilsborough,1 Sherri Mudri,1 Eric Chadwick,2 Brandon Harder,3 and Stacey R. Dillon IL-31 signals through the heterodimeric receptor IL-31RA and oncostatin M receptor (OSMR), and has been linked with the development of atopic dermatitis, a Th2 cytokine-associated disease in humans. -
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. -
Respiratory Viral Infection Function for Innate Defense Against Airway Epithelial Versus Immune Cell Stat1
Airway Epithelial versus Immune Cell Stat1 Function for Innate Defense against Respiratory Viral Infection This information is current as Laurie P. Shornick, Audrey G. Wells, Yong Zhang, Anand of September 27, 2021. C. Patel, Guangming Huang, Kazutaka Takami, Moises Sosa, Nikhil A. Shukla, Eugene Agapov and Michael J. Holtzman J Immunol 2008; 180:3319-3328; ; doi: 10.4049/jimmunol.180.5.3319 Downloaded from http://www.jimmunol.org/content/180/5/3319 Supplementary http://www.jimmunol.org/content/suppl/2008/02/20/180.5.3319.DC1 Material http://www.jimmunol.org/ References This article cites 47 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/180/5/3319.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 27, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Airway Epithelial versus Immune Cell Stat1 Function for Innate Defense against Respiratory Viral Infection1 Laurie P. -
Oncostatin M Is a Proinflammatory Mediator. in Vivo Effects Correlate with Endothelial Cell Expression of Inflammatory Cytokines and Adhesion Molecules
Oncostatin M is a proinflammatory mediator. In vivo effects correlate with endothelial cell expression of inflammatory cytokines and adhesion molecules. V Modur, … , G A Zimmerman, T M McIntyre J Clin Invest. 1997;100(1):158-168. https://doi.org/10.1172/JCI119508. Research Article Oncostatin M is a member of the IL-6 family of cytokines that is primarily known for its effects on cell growth. Endothelial cells have an abundance of receptors for oncostatin M, and may be its primary target. We determined if oncostatin M induces a key endothelial cell function, initiation of the inflammatory response. We found that subcutaneous injection of oncostatin M in mice caused an acute inflammatory reaction. Oncostatin M in vitro stimulated: (a) polymorphonuclear leukocyte (PMN) transmigration through confluent monolayers of primary human endothelial cells; (b) biphasic PMN adhesion through rapid P-selectin expression, and delayed adhesion mediated by E-selectin synthesis; (c) intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 accumulation; and (d) the expression of PMN activators IL-6, epithelial neutrophil activating peptide-78, growth-related cytokine alpha and growth-related cytokine beta without concomitant IL-8 synthesis. The nature of the response to oncostatin M varied with concentration, suggesting high and low affinity oncostatin M receptors independently stimulated specific responses. Immunohistochemistry showed that macrophage-like cells infiltrating human aortic aneurysms expressed oncostatin M, so it is present during a chronic inflammatory reaction. Therefore, oncostatin M, but not other IL-6 family members, fulfills Koch's postulates as an inflammatory mediator. Since its effects on endothelial cells differ significantly from established mediators like TNFalpha, it may uniquely contribute to the inflammatory cycle. -
Supplementary Table 1: Adhesion Genes Data Set
Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like, -
Learning from Cadherin Structures and Sequences: Affinity Determinants and Protein Architecture
Learning from cadherin structures and sequences: affinity determinants and protein architecture Klára Fels ıvályi Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Klara Felsovalyi All rights reserved ABSTRACT Learning from cadherin structures and sequences: affinity determinants and protein architecture Klara Felsovalyi Cadherins are a family of cell-surface proteins mediating adhesion that are important in development and maintenance of tissues. The family is defined by the repeating cadherin domain (EC) in their extracellular region, but they are diverse in terms of protein size, architecture and cellular function. The best-understood subfamily is the type I classical cadherins, which are found in vertebrates and have five EC domains. Among the five different type I classical cadherins, the binding interactions are highly specific in their homo- and heterophilic binding affinities, though their sequences are very similar. As previously shown, E- and N-cadherins, two prototypic members of the subfamily, differ in their homophilic K D by about an order of magnitude, while their heterophilic affinity is intermediate. To examine the source of the binding affinity differences among type I cadherins, we used crystal structures, analytical ultracentrifugation (AUC), surface plasmon resonance (SPR), and electron paramagnetic resonance (EPR) studies. Phylogenetic analysis and binding affinity behavior show that the type I cadherins can be further divided into two subgroups, with E- and N-cadherin representing each. In addition to the affinity differences in their wild-type binding through the strand-swapped interface, a second interface also shows an affinity difference between E- and N-cadherin. -
Guthrie Cdna Resource Center
cDNA Resource Center cDNA Resource Center Catalog cDNA Resource Center Missouri University of Science and Technology 400 W 11th Rolla, MO 65409 TEL: (573) 341-7610 FAX: (573) 341-7609 EMAIL: [email protected] www.cdna.org September, 2008 1 cDNA Resource Center Visit our web site for product updates 2 cDNA Resource Center The cDNA Resource Center The cDNA Resource Center is a service provided by the faculty of the Department of Biological Sciences of Missouri University of Science and Technology. The purpose of the cDNA Resource Center is to further scientific investigation by providing cDNA clones of human proteins involved in signal transduction processes. This is achieved by providing high quality clones for important signaling proteins in a timely manner. By high quality, we mean that the clones are • Sequence verified • Propagated in a versatile vector useful in bacterial and mammalian systems • Free of extraneous 3' and 5' untranslated regions • Expression verified (in most cases) by coupled in vitro transcription/translation assays • Available in wild-type, epitope-tagged and common mutant forms (e.g., constitutively- active or dominant negative) By timely, we mean that the clones are • Usually shipped within a day from when you place your order. Clones can be ordered from our web pages, by FAX or by phone. Within the United States, clones are shipped by overnight courier (FedEx); international orders are shipped International Priority (FedEx). The clones are supplied for research purposes only. Details on use of the material are included on the Material Transfer Agreement (page 3). Clones are distributed by agreement in Invitrogen's pcDNA3.1+ vector. -
Gene Expression Within the Periaqueductal Gray Is Linked to Vocal Behavior and Early- Onset Parkinsonism in Pink1 Knockout Rats Cynthia A
Kelm-Nelson and Gammie BMC Genomics (2020) 21:625 https://doi.org/10.1186/s12864-020-07037-4 RESEARCH ARTICLE Open Access Gene expression within the periaqueductal gray is linked to vocal behavior and early- onset parkinsonism in Pink1 knockout rats Cynthia A. Kelm-Nelson1* and Stephen Gammie2 Abstract Background: Parkinson’s disease (PD) is a degenerative disease with early-stage pathology hypothesized to manifest in brainstem regions. Vocal deficits, including soft, monotone speech, result in significant clinical and quality of life issues and are present in 90% of PD patients; yet the underlying pathology mediating these significant voice deficits is unknown. The Pink1−/− rat is a valid model of early-onset PD that presents with analogous vocal communication deficits. Previous work shows abnormal α-synuclein protein aggregation in the periaqueductal gray (PAG), a brain region critical and necessary to the modulation of mammalian vocal behavior. In this study, we used high-throughput RNA sequencing to examine gene expression within the PAG of both male and female Pink1−/− rats as compared to age-matched wildtype controls. We used a bioinformatic approach to (1) test the hypothesis that loss of Pink1 in the PAG will influence the differential expression of genes that interact with Pink1, (2) highlight other key genes that relate to this type of Mendelian PD, and (3) catalog molecular targets that may be important for the production of rat vocalizations. Results: Knockout of the Pink1 gene resulted in differentially expressed genes for both male and female rats that also mapped to human PD datasets. Pathway analysis highlighted several significant metabolic pathways. -
Coexpression of Human Somatostatin Receptor-2 (SSTR2) and SSTR3 Modulates Antiproliferative Signaling and Apoptosis Sajad a War and Ujendra Kumar*
War and Kumar Journal of Molecular Signaling 2012, 7:5 http://www.thrombosisjournal.com/7/1/5 RESEARCH ARTICLE Open Access Coexpression of human somatostatin receptor-2 (SSTR2) and SSTR3 modulates antiproliferative signaling and apoptosis Sajad A War and Ujendra Kumar* Abstract Background: Somatostatin (SST) via five Gi coupled receptors namely SSTR1-5 is known to inhibit cell proliferation by cytostatic and cytotoxic mechanisms. Heterodimerization plays a crucial role in modulating the signal transduction pathways of SSTR subtypes. In the present study, we investigated human SSTR2/SSTR3 heterodimerization, internalization, MAPK signaling, cell proliferation and apoptosis in HEK-293 cells in response to SST and specific agonists for SSTR2 and SSTR3. Results: Although in basal conditions, SSTR2 and SSTR3 colocalize at the plasma membrane and exhibit heterodimerization, the cell surface distribution of both receptors decreased upon agonist activation and was accompanied by a parallel increase in intracellular colocalization. Receptors activation by SST and specific agonists significantly decreased cAMP levels in cotransfected cells in comparison to control. Agonist-mediated modulation of pERK1/2 was time and concentration-dependent, and pronounced in serum-deprived conditions. pERK1/2 was inhibited in response to SST; conversely receptor-specific agonist treatment caused inhibition at lower concentration and activation at higher concentration. Strikingly, ERK1/2 phosphorylation was sustained upon prolonged treatment with SST but not with receptor-specific agonists. On the other hand, SST and receptor-specific agonists modulated p38 phosphorylation time-dependently. The receptor activation in cotransfected cells exhibits Gi-dependent inhibition of cell proliferation attributed to increased PARP-1 expression and TUNEL staining, whereas induction of p21 and p27Kip1 suggests a cytostatic effect.