High-Endothelial Cell-Derived S1P Regulates Dendritic Cell Localization
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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. -
In Sickness and in Health: the Immunological Roles of the Lymphatic System
International Journal of Molecular Sciences Review In Sickness and in Health: The Immunological Roles of the Lymphatic System Louise A. Johnson MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK; [email protected] Abstract: The lymphatic system plays crucial roles in immunity far beyond those of simply providing conduits for leukocytes and antigens in lymph fluid. Endothelial cells within this vasculature are dis- tinct and highly specialized to perform roles based upon their location. Afferent lymphatic capillaries have unique intercellular junctions for efficient uptake of fluid and macromolecules, while expressing chemotactic and adhesion molecules that permit selective trafficking of specific immune cell subsets. Moreover, in response to events within peripheral tissue such as inflammation or infection, soluble factors from lymphatic endothelial cells exert “remote control” to modulate leukocyte migration across high endothelial venules from the blood to lymph nodes draining the tissue. These immune hubs are highly organized and perfectly arrayed to survey antigens from peripheral tissue while optimizing encounters between antigen-presenting cells and cognate lymphocytes. Furthermore, subsets of lymphatic endothelial cells exhibit differences in gene expression relating to specific func- tions and locality within the lymph node, facilitating both innate and acquired immune responses through antigen presentation, lymph node remodeling and regulation of leukocyte entry and exit. This review details the immune cell subsets in afferent and efferent lymph, and explores the mech- anisms by which endothelial cells of the lymphatic system regulate such trafficking, for immune surveillance and tolerance during steady-state conditions, and in response to infection, acute and Citation: Johnson, L.A. -
A Benchmarking Study on Virtual Ligand Screening Against Homology Models of Human Gpcrs
bioRxiv preprint doi: https://doi.org/10.1101/284075; this version posted March 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. A benchmarking study on virtual ligand screening against homology models of human GPCRs Victor Jun Yu Lima,b, Weina Dua, Yu Zong Chenc, Hao Fana,d aBioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, Matrix No. 07-01, 138671, Singapore; bSaw Swee Hock School of Public Health, National University of Singapore, 12 Science Drive 2, 117549, Singapore; cDepartment of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Singapore; dDepartment of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558 To whom correspondence should be addressed: Dr. Hao Fan, Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, Matrix No. 07-01, 138671, Singapore; Telephone: +65 64788500; Email: [email protected] Keywords: G-protein-coupled receptor, GPCR, X-ray crystallography, virtual screening, homology modelling, consensus enrichment 1 bioRxiv preprint doi: https://doi.org/10.1101/284075; this version posted March 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract G-protein-coupled receptor (GPCR) is an important target class of proteins for drug discovery, with over 27% of FDA-approved drugs targeting GPCRs. However, being a membrane protein, it is difficult to obtain the 3D crystal structures of GPCRs for virtual screening of ligands by molecular docking. -
Endothelial Venules in a Mucosal Site in Naive Lymphocyte Adhesion to High Primary Role of Peripheral Node Addressin Phenotypic
Nasal-Associated Lymphoid Tissue: Phenotypic and Functional Evidence for the Primary Role of Peripheral Node Addressin in Naive Lymphocyte Adhesion to High This information is current as Endothelial Venules in a Mucosal Site of October 1, 2021. Keri L. Csencsits, Mark A. Jutila and David W. Pascual J Immunol 1999; 163:1382-1389; ; http://www.jimmunol.org/content/163/3/1382 Downloaded from References This article cites 50 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/163/3/1382.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 October 1, 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 © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Nasal-Associated Lymphoid Tissue: Phenotypic and Functional Evidence for the Primary Role of Peripheral Node Addressin in Naive Lymphocyte Adhesion to High Endothelial Venules in a Mucosal Site1 Keri L. Csencsits, Mark A. Jutila, and David W. -
T-Cell Trafficking Facilitated by High Endothelial Venules Is Required for Tumor Control After Regulatory T-Cell Depletion
Published OnlineFirst September 7, 2012; DOI: 10.1158/0008-5472.CAN-12-1912 Cancer Microenvironment and Immunology Research T-Cell Trafficking Facilitated by High Endothelial Venules Is Required for Tumor Control after Regulatory T-Cell Depletion James P. Hindley1, Emma Jones1, Kathryn Smart1, Hayley Bridgeman1, Sarah N. Lauder1, Beatrice Ondondo1, Scott Cutting1, Kristin Ladell1, Katherine K. Wynn1, David Withers2, David A. Price1, Ann Ager1, Andrew J. Godkin1, and Awen M. Gallimore1 Abstract The evolution of immune blockades in tumors limits successful antitumor immunity, but the mechanisms underlying this process are not fully understood. Depletion of regulatory T cells (Treg), a T-cell subset that dampens excessive inflammatory and autoreactive responses, can allow activation of tumor-specific T cells. However, cancer immunotherapy studies have shown that a persistent failure of activated lymphocytes to infiltrate tumors remains a fundamental problem. In evaluating this issue, we found that despite an increase in T- cell activation and proliferation following Treg depletion, there was no significant association with tumor growth rate. In contrast, there was a highly significant association between low tumor growth rate and the extent of T-cell infiltration. Further analyses revealed a total concordance between low tumor growth rate, high T-cell infiltration, and the presence of high endothelial venules (HEV). HEV are blood vessels normally found in secondary lymphoid tissue where they are specialized for lymphocyte recruitment. Thus, our findings suggest that Treg depletion may promote HEV neogenesis, facilitating increased lymphocyte infiltration and destruction of the tumor tissue. These findings are important as they point to a hitherto unidentified role of Tregs, the manipulation of which may refine strategies for more effective cancer immunotherapy. -
High Endothelial Venules and Lymphatic Vessels in Tertiary Lymphoid Organs: Characteristics, Functions, and Regulation
MINI REVIEW published: 09 November 2016 doi: 10.3389/fimmu.2016.00491 High Endothelial Venules and Lymphatic Vessels in Tertiary Lymphoid Organs: Characteristics, Functions, and Regulation Nancy H. Ruddle* Department of Epidemiology of Microbial Diseases, School of Public Health, Yale University School of Medicine, New Haven, CT, USA High endothelial venules (HEVs) and lymphatic vessels (LVs) are essential for the function of the immune system, by providing communication between the body and lymph nodes (LNs), specialized sites of antigen presentation and recognition. HEVs bring in naïve and central memory cells and LVs transport antigen, antigen-presenting cells, and lymphocytes in and out of LNs. Tertiary lymphoid organs (TLOs) are accumulations of lymphoid and stromal cells that arise and organize at ectopic sites in response to chronic inflammation in autoimmunity, microbial infection, graft rejection, and cancer. TLOs are distinguished from primary lymphoid organs – the thymus and bone marrow, and secondary lymphoid organs (SLOs) – the LNs, spleen, and Peyer’s patches, in that Edited by: they arise in response to inflammatory signals, rather than in ontogeny. TLOs usually Andreas Habenicht, do not have a capsule but are rather contained within the confines of another organ. Ludwig Maximilian University of Their structure, cellular composition, chemokine expression, and vascular and stromal Munich, Germany support resemble SLOs and are the defining aspects of TLOs. T and B cells, antigen- Reviewed by: Ingrid E. Dumitriu, presenting cells, fibroblast reticular cells, and other stromal cells and vascular elements St. George’s University including HEVs and LVs are all typical components of TLOs. A key question is whether of London, UK Olivier Thaunat, the HEVs and LVs play comparable roles and are regulated similarly to those in LNs. -
GPCR Expression Profiles Were Determined Using
Supplemental Figures and Tables for Tischner et al., 2017 Supplemental Figure 1: GPCR expression profiles were determined using the NanoString nCounter System in 250 ng of pooled cell RNA obtained from freshly isolated CD4 T cells from naïve lymph nodes (CD4ln), spinal cord infiltrating CD4 T cells at peak EAE disease (CD4sc), and primary lung endothelial cells (luEC). Supplemental Figure 2: Array design and quality controls. A, Sorted leukocytes or endothelial cells were subjected to single‐cell expression analysis and re‐evaluated based on the expression of various identity‐defining genes. B, Expression of identity‐defining and quality control genes after deletion of contaminating or reference gene‐negative cells. Expression data are calculated as 2(Limit of detection(LoD) Ct – sample Ct) ; LoD Ct was set to 24. Supplemental Figure 3: Overview over GPCR expression frequencies in different freshly isolated immune cell populations and spinal cord endothelial cells as determined by single cell RT‐PCR. Abbreviations: CD4ln‐Tcon/CD4ln‐Treg, conventional (con) and regulatory (reg) CD4 T cells from lymph nodes (CD4ln) of naïve mice; CD4dr/CD4sc, CD4 T cells from draining lymph nodes (dr) or spinal cord (sc) at peak EAE disease; CD4spn2D/ CD4spn2DTh1/ CD4spn2DTh17, splenic CD4 T cells from 2D2 T cell receptor transgenic mice before (2D) and after in vitro differentiation towards Th1 (2DTh1) or Th17 (2DTh17); MonoSpn, splenic monocytes; CD11b_sc, spinal cord infiltrating CD11b‐ positive cells; sc_microglia, Ccr2neg,Cx3cr1pos microglia from spinal cord at peak disease; sc_macrophages, CCr2pos;Cx3cr1lo/neg macrophages from spinal cord at peak disease; BMDM_M1/BMDM_M2, bone marrow‐derived macrophages differentiated towards M1 or M2; ECscN and ECscEAE, spinal cord endothelial cells from naïve mice (N) and at peak EAE disease (EAE); SMC, smooth muscle cells from various vessel types (included as positive control to ascertain primer functionality). -
High Endothelial Venules (Hevs? Are Specialized Postcapillary Venules Found in Lymphoid Tissues That Support High Levels of Lymphocyte Extra- Vasation from the Blood
High endothelialvenules (HEVs): specialized endotheliumfor lymphocytemigration Jean-Philippe Girard and Timothy A. Springer High endothelial venules (HEVs? are specialized postcapillary venules found in lymphoid tissues that support high levels of lymphocyte extra- vasation from the blood. Here, Jean-Philippe Girard and Timothy Springer highlight the unique properties of HEV endotbelium, discuss the mol- ecular mechanisms controlling HE V specialization and review evidence suggesting that HEVs could play an important role in the patbogenesis of chronic inflammatory diseases. While patrolling the body in search of foreign antigen, The specialized endothelium of HEVs lymphocytes continuously circulate from blood, through Structurd feutures of HEVs lymphoid and other tissues, and back through the lym- The endothelial cells of HEVs have a ‘plump’, al- phatics to the blood. This process, called lymphocyte most cuboidal, appearance very different from the flat recirculation, allows the dissemination of the immune morphology of endothelial cells that line other vessels, response throughout the body, and thereby provides an and are therefore called high endothelial cells by ref- effective immune surveillance for foreign Invaders and erence to their thickness (Fig. 1). Another characteris- alterations in the body’s own cells’J. tic of HIS’s, revealed by light-microscopic examina- The first critical step in lymphocyte migration tion, is the presence of a large number of lymphocytes from circulation into tissue is the adhesion of within their walls. This illustrates the function of HEVs lymphocytes to vascular endothelium. In lymphoid in lymphocyte recruitment, and explains why these ves- organs, lymphocyte adherence and transendothelial sels were implicated in lymphocyte traffic from the time migration occur at specialized postcapillary vascular of their initial description”. -
Lymph Nodes High Endothelial Venule Expansion in Factor A
B Cell-Derived Vascular Endothelial Growth Factor A Promotes Lymphangiogenesis and High Endothelial Venule Expansion in Lymph Nodes This information is current as of September 26, 2021. Binita Shrestha, Teruto Hashiguchi, Takashi Ito, Naoki Miura, Kazunori Takenouchi, Yoko Oyama, Ko-ichi Kawahara, Salunya Tancharoen, Yuya Ki-i, Noboru Arimura, Narimasa Yoshinaga, Satoshi Noma, Chandan Shrestha, Takao Nitanda, Shinichi Kitajima, Kimiyoshi Arimura, Masahiro Sato, Taiji Sakamoto and Ikuro Downloaded from Maruyama J Immunol 2010; 184:4819-4826; Prepublished online 22 March 2010; doi: 10.4049/jimmunol.0903063 http://www.jimmunol.org/ http://www.jimmunol.org/content/184/9/4819 Supplementary http://www.jimmunol.org/content/suppl/2010/03/22/jimmunol.090306 Material 3.DC1 References This article cites 38 articles, 15 of which you can access for free at: by guest on September 26, 2021 http://www.jimmunol.org/content/184/9/4819.full#ref-list-1 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 *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. -
Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina
Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Olivares, A. M., A. S. Jelcick, J. Reinecke, B. Leehy, A. Haider, M. A. Morrison, L. Cheng, D. F. Chen, M. M. DeAngelis, and N. B. Haider. 2017. “Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina.” Scientific Reports 7 (1): 690. doi:10.1038/s41598-017-00788-3. http://dx.doi.org/10.1038/ s41598-017-00788-3. Published Version doi:10.1038/s41598-017-00788-3 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:33029769 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA www.nature.com/scientificreports OPEN Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina Received: 9 November 2016 A. M. Olivares1, A. S. Jelcick2, J. Reinecke2, B. Leehy2, A. Haider1, M. A. Morrison3, L. Cheng1, Accepted: 13 March 2017 D. F. Chen1, M. M. DeAngelis3 & N. B. Haider1 Published: xx xx xxxx Regulation of biological processes occurs through complex, synergistic mechanisms. In this study, we discovered the synergistic orchestration of multiple mechanisms regulating the normal and diseased state (age related macular degeneration, AMD) in the retina. We uncovered gene networks with overlapping feedback loops that are modulated by nuclear hormone receptors (NHR), miRNAs, and epigenetic factors. -
Lymphocyte Recirculation
Lymphocyte Recirculation Chapter 15 Naïve lymphocytes enter lymph nodes Lymphocyte Migration and from the blood circulation Lymphocytes return Inflammation to blood via the thoracic duct Antigens from infected area go to lymph nodes via the lymphatic system I. Primary Lymphoid II. Secondary - Lymph Nodes -Spleen -MALT Lymphatic vessels Leukocytes are constantly moving between sites where - Collect interstitial fluid and carry antigens may be It (lymph), via a system of encountered: progressively larger vessels, into regional lymph nodes. 1 2 - Spleen (via afferent lymphatic vessels). - Lymph nodes - Other secondary -Lymph leaves the lymph nodes lymphoid tissues via efferent lymphatic vessels, - Other tissues – which eventually drain back especially skin and into the circulatory system (via mucosal surfaces the thoracic duct). 3 Leukocytes accumulate at sites of inflammation 1 CHOICES: Antigen capture: (APC) or 1) If no antigen is present: lymphocytes Macrophages: capture and process particulate routinely enter and leave secondary lymphoid antigens (via phagocytosis) tissues Dendritic cells: capture and process non- 2) If antigen enters the secondary lymphoid particulate antigens (via endocytosis) tissue: Lymphocyte proliferation in response to antigen B cells: capture and process antigens that bind to occurs within the lymphoid tissue. surface BCR (via endocytosis) After several days, antigen-activated lymphocytes begin leaving the lymphoid tissue. Dendritic cells: originate in bone marrow, capture antigen within tissues and transport antigen to secondary lymphoid tissue. Lymphocytes can enter lymphoid tissues in two ways: 1 1) Direct entry into lymph nodes via afferent lymphatics 2) Entry from blood capillaries across specialized endothelial cells (high-walled endothelial cells) present in the postcapillary venules (High Endothelial Venules= HEV) within the secondary 2 lymphoid tissue. -
G Protein-Coupled Receptors
Alexander, S. P. H., Christopoulos, A., Davenport, A. P., Kelly, E., Marrion, N. V., Peters, J. A., Faccenda, E., Harding, S. D., Pawson, A. J., Sharman, J. L., Southan, C., Davies, J. A. (2017). THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: G protein-coupled receptors. British Journal of Pharmacology, 174, S17-S129. https://doi.org/10.1111/bph.13878 Publisher's PDF, also known as Version of record License (if available): CC BY Link to published version (if available): 10.1111/bph.13878 Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Wiley at https://doi.org/10.1111/bph.13878 . Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2017/18: G protein-coupled receptors. British Journal of Pharmacology (2017) 174, S17–S129 THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: G protein-coupled receptors Stephen PH Alexander1, Arthur Christopoulos2, Anthony P Davenport3, Eamonn Kelly4, Neil V Marrion4, John A Peters5, Elena Faccenda6, Simon D Harding6,AdamJPawson6, Joanna L Sharman6, Christopher Southan6, Jamie A Davies6 and CGTP Collaborators 1 School of Life Sciences,