Loading…

Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement

Danger patterns on microbes or damaged host cells bind and activate C1, inducing innate immune responses and clearance through the complement cascade. How these patterns trigger complement initiation remains elusive. Here, we present cryo-electron microscopy analyses of C1 bound to monoclonal antibo...

Full description

Saved in:
Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2018-02, Vol.359 (6377), p.794-797
Main Authors: Ugurlar, Deniz, Howes, Stuart C, de Kreuk, Bart-Jan, Koning, Roman I, de Jong, Rob N, Beurskens, Frank J, Schuurman, Janine, Koster, Abraham J, Sharp, Thomas H, Parren, Paul W H I, Gros, Piet
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c366t-2f28c2356364df8b0a608868d7be0417bc152ceae978055b26d07876c01618043
cites cdi_FETCH-LOGICAL-c366t-2f28c2356364df8b0a608868d7be0417bc152ceae978055b26d07876c01618043
container_end_page 797
container_issue 6377
container_start_page 794
container_title Science (American Association for the Advancement of Science)
container_volume 359
creator Ugurlar, Deniz
Howes, Stuart C
de Kreuk, Bart-Jan
Koning, Roman I
de Jong, Rob N
Beurskens, Frank J
Schuurman, Janine
Koster, Abraham J
Sharp, Thomas H
Parren, Paul W H I
Gros, Piet
description Danger patterns on microbes or damaged host cells bind and activate C1, inducing innate immune responses and clearance through the complement cascade. How these patterns trigger complement initiation remains elusive. Here, we present cryo-electron microscopy analyses of C1 bound to monoclonal antibodies in which we observed heterogeneous structures of single and clustered C1-immunoglobulin G1 (IgG1) hexamer complexes. Distinct C1q binding sites are observed on the two Fc-CH2 domains of each IgG molecule. These are consistent with known interactions and also reveal additional interactions, which are supported by functional IgG1-mutant analysis. Upon antibody binding, the C1q arms condense, inducing rearrangements of the C1r s proteases and tilting C1q's cone-shaped stalk. The data suggest that C1r may activate C1s within single, strained C1 complexes or between neighboring C1 complexes on surfaces.
doi_str_mv 10.1126/science.aao4988
format article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2003038845</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2002528917</sourcerecordid><originalsourceid>FETCH-LOGICAL-c366t-2f28c2356364df8b0a608868d7be0417bc152ceae978055b26d07876c01618043</originalsourceid><addsrcrecordid>eNpdkEFP3DAQRi1UBNuFc2-VpV64ZHdsJ459rFYtRULiAJwjx5nsGm3sre2A-u8xYuHQ04w0bz59eoR8Y7BijMt1sg69xZUxodZKnZAFA91UmoP4QhYAQlYK2uacfE3pCaDctDgj51zXta41X5DuPsfZ5jliomGkG1bdbK8ZPcTw7Aakzie33eVUlhzoLrzQwfgtRnowOWP0NKINW--yC54am92zySXJhumwxwl9viCno9knvDzOJXn8_eth86e6vbu-2fy8rayQMld85Mpy0Ugh62FUPRgJSkk1tD1CzdresoZbNKhbBU3TczlAq1ppgUmmoBZLcvWeW5r_nTHlbnLJ4n5vPIY5dby4AKFU3RT0x3_oU5ijL-3eKN5wpVlbqPU7ZWNIKeLYHaKbTPzXMeje3HdH993Rffn4fsyd-wmHT_5DtngFTYaBMQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2002528917</pqid></control><display><type>article</type><title>Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement</title><source>American Association for the Advancement of Science</source><source>Alma/SFX Local Collection</source><creator>Ugurlar, Deniz ; Howes, Stuart C ; de Kreuk, Bart-Jan ; Koning, Roman I ; de Jong, Rob N ; Beurskens, Frank J ; Schuurman, Janine ; Koster, Abraham J ; Sharp, Thomas H ; Parren, Paul W H I ; Gros, Piet</creator><creatorcontrib>Ugurlar, Deniz ; Howes, Stuart C ; de Kreuk, Bart-Jan ; Koning, Roman I ; de Jong, Rob N ; Beurskens, Frank J ; Schuurman, Janine ; Koster, Abraham J ; Sharp, Thomas H ; Parren, Paul W H I ; Gros, Piet</creatorcontrib><description>Danger patterns on microbes or damaged host cells bind and activate C1, inducing innate immune responses and clearance through the complement cascade. How these patterns trigger complement initiation remains elusive. Here, we present cryo-electron microscopy analyses of C1 bound to monoclonal antibodies in which we observed heterogeneous structures of single and clustered C1-immunoglobulin G1 (IgG1) hexamer complexes. Distinct C1q binding sites are observed on the two Fc-CH2 domains of each IgG molecule. These are consistent with known interactions and also reveal additional interactions, which are supported by functional IgG1-mutant analysis. Upon antibody binding, the C1q arms condense, inducing rearrangements of the C1r s proteases and tilting C1q's cone-shaped stalk. The data suggest that C1r may activate C1s within single, strained C1 complexes or between neighboring C1 complexes on surfaces.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aao4988</identifier><identifier>PMID: 29449492</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Alarmins - chemistry ; Alarmins - ultrastructure ; Antibodies, Monoclonal - chemistry ; Antibodies, Monoclonal - ultrastructure ; Avidity ; Binding Sites ; Complement ; Complement Activation ; Complement C1 - chemistry ; Complement C1 - ultrastructure ; Complement component C1 ; Complement component C1q ; Cryoelectron Microscopy ; Damage ; Electron microscopy ; Hazards ; Hexamers ; Humans ; Immune clearance ; Immune response ; Immune system ; Immunoglobulin G ; Immunoglobulin G - chemistry ; Immunoglobulin G - genetics ; Immunoglobulin G - ultrastructure ; Immunoglobulins ; Initiation complex ; Innate immunity ; Microscopy ; Monoclonal antibodies ; Mutagenesis ; Pattern recognition</subject><ispartof>Science (American Association for the Advancement of Science), 2018-02, Vol.359 (6377), p.794-797</ispartof><rights>Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</rights><rights>Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c366t-2f28c2356364df8b0a608868d7be0417bc152ceae978055b26d07876c01618043</citedby><cites>FETCH-LOGICAL-c366t-2f28c2356364df8b0a608868d7be0417bc152ceae978055b26d07876c01618043</cites><orcidid>0000-0001-8841-3851 ; 0000-0001-6129-1882 ; 0000-0002-4365-3859 ; 0000-0002-9738-9926 ; 0000-0002-9300-6633 ; 0000-0002-7165-5771 ; 0000-0003-1717-2549 ; 0000-0002-1990-2333 ; 0000-0002-7782-2585 ; 0000-0001-6736-7147</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,2884,2885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29449492$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ugurlar, Deniz</creatorcontrib><creatorcontrib>Howes, Stuart C</creatorcontrib><creatorcontrib>de Kreuk, Bart-Jan</creatorcontrib><creatorcontrib>Koning, Roman I</creatorcontrib><creatorcontrib>de Jong, Rob N</creatorcontrib><creatorcontrib>Beurskens, Frank J</creatorcontrib><creatorcontrib>Schuurman, Janine</creatorcontrib><creatorcontrib>Koster, Abraham J</creatorcontrib><creatorcontrib>Sharp, Thomas H</creatorcontrib><creatorcontrib>Parren, Paul W H I</creatorcontrib><creatorcontrib>Gros, Piet</creatorcontrib><title>Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Danger patterns on microbes or damaged host cells bind and activate C1, inducing innate immune responses and clearance through the complement cascade. How these patterns trigger complement initiation remains elusive. Here, we present cryo-electron microscopy analyses of C1 bound to monoclonal antibodies in which we observed heterogeneous structures of single and clustered C1-immunoglobulin G1 (IgG1) hexamer complexes. Distinct C1q binding sites are observed on the two Fc-CH2 domains of each IgG molecule. These are consistent with known interactions and also reveal additional interactions, which are supported by functional IgG1-mutant analysis. Upon antibody binding, the C1q arms condense, inducing rearrangements of the C1r s proteases and tilting C1q's cone-shaped stalk. The data suggest that C1r may activate C1s within single, strained C1 complexes or between neighboring C1 complexes on surfaces.</description><subject>Alarmins - chemistry</subject><subject>Alarmins - ultrastructure</subject><subject>Antibodies, Monoclonal - chemistry</subject><subject>Antibodies, Monoclonal - ultrastructure</subject><subject>Avidity</subject><subject>Binding Sites</subject><subject>Complement</subject><subject>Complement Activation</subject><subject>Complement C1 - chemistry</subject><subject>Complement C1 - ultrastructure</subject><subject>Complement component C1</subject><subject>Complement component C1q</subject><subject>Cryoelectron Microscopy</subject><subject>Damage</subject><subject>Electron microscopy</subject><subject>Hazards</subject><subject>Hexamers</subject><subject>Humans</subject><subject>Immune clearance</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunoglobulin G</subject><subject>Immunoglobulin G - chemistry</subject><subject>Immunoglobulin G - genetics</subject><subject>Immunoglobulin G - ultrastructure</subject><subject>Immunoglobulins</subject><subject>Initiation complex</subject><subject>Innate immunity</subject><subject>Microscopy</subject><subject>Monoclonal antibodies</subject><subject>Mutagenesis</subject><subject>Pattern recognition</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNpdkEFP3DAQRi1UBNuFc2-VpV64ZHdsJ459rFYtRULiAJwjx5nsGm3sre2A-u8xYuHQ04w0bz59eoR8Y7BijMt1sg69xZUxodZKnZAFA91UmoP4QhYAQlYK2uacfE3pCaDctDgj51zXta41X5DuPsfZ5jliomGkG1bdbK8ZPcTw7Aakzie33eVUlhzoLrzQwfgtRnowOWP0NKINW--yC54am92zySXJhumwxwl9viCno9knvDzOJXn8_eth86e6vbu-2fy8rayQMld85Mpy0Ugh62FUPRgJSkk1tD1CzdresoZbNKhbBU3TczlAq1ppgUmmoBZLcvWeW5r_nTHlbnLJ4n5vPIY5dby4AKFU3RT0x3_oU5ijL-3eKN5wpVlbqPU7ZWNIKeLYHaKbTPzXMeje3HdH993Rffn4fsyd-wmHT_5DtngFTYaBMQ</recordid><startdate>20180216</startdate><enddate>20180216</enddate><creator>Ugurlar, Deniz</creator><creator>Howes, Stuart C</creator><creator>de Kreuk, Bart-Jan</creator><creator>Koning, Roman I</creator><creator>de Jong, Rob N</creator><creator>Beurskens, Frank J</creator><creator>Schuurman, Janine</creator><creator>Koster, Abraham J</creator><creator>Sharp, Thomas H</creator><creator>Parren, Paul W H I</creator><creator>Gros, Piet</creator><general>The American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-8841-3851</orcidid><orcidid>https://orcid.org/0000-0001-6129-1882</orcidid><orcidid>https://orcid.org/0000-0002-4365-3859</orcidid><orcidid>https://orcid.org/0000-0002-9738-9926</orcidid><orcidid>https://orcid.org/0000-0002-9300-6633</orcidid><orcidid>https://orcid.org/0000-0002-7165-5771</orcidid><orcidid>https://orcid.org/0000-0003-1717-2549</orcidid><orcidid>https://orcid.org/0000-0002-1990-2333</orcidid><orcidid>https://orcid.org/0000-0002-7782-2585</orcidid><orcidid>https://orcid.org/0000-0001-6736-7147</orcidid></search><sort><creationdate>20180216</creationdate><title>Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement</title><author>Ugurlar, Deniz ; Howes, Stuart C ; de Kreuk, Bart-Jan ; Koning, Roman I ; de Jong, Rob N ; Beurskens, Frank J ; Schuurman, Janine ; Koster, Abraham J ; Sharp, Thomas H ; Parren, Paul W H I ; Gros, Piet</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c366t-2f28c2356364df8b0a608868d7be0417bc152ceae978055b26d07876c01618043</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Alarmins - chemistry</topic><topic>Alarmins - ultrastructure</topic><topic>Antibodies, Monoclonal - chemistry</topic><topic>Antibodies, Monoclonal - ultrastructure</topic><topic>Avidity</topic><topic>Binding Sites</topic><topic>Complement</topic><topic>Complement Activation</topic><topic>Complement C1 - chemistry</topic><topic>Complement C1 - ultrastructure</topic><topic>Complement component C1</topic><topic>Complement component C1q</topic><topic>Cryoelectron Microscopy</topic><topic>Damage</topic><topic>Electron microscopy</topic><topic>Hazards</topic><topic>Hexamers</topic><topic>Humans</topic><topic>Immune clearance</topic><topic>Immune response</topic><topic>Immune system</topic><topic>Immunoglobulin G</topic><topic>Immunoglobulin G - chemistry</topic><topic>Immunoglobulin G - genetics</topic><topic>Immunoglobulin G - ultrastructure</topic><topic>Immunoglobulins</topic><topic>Initiation complex</topic><topic>Innate immunity</topic><topic>Microscopy</topic><topic>Monoclonal antibodies</topic><topic>Mutagenesis</topic><topic>Pattern recognition</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ugurlar, Deniz</creatorcontrib><creatorcontrib>Howes, Stuart C</creatorcontrib><creatorcontrib>de Kreuk, Bart-Jan</creatorcontrib><creatorcontrib>Koning, Roman I</creatorcontrib><creatorcontrib>de Jong, Rob N</creatorcontrib><creatorcontrib>Beurskens, Frank J</creatorcontrib><creatorcontrib>Schuurman, Janine</creatorcontrib><creatorcontrib>Koster, Abraham J</creatorcontrib><creatorcontrib>Sharp, Thomas H</creatorcontrib><creatorcontrib>Parren, Paul W H I</creatorcontrib><creatorcontrib>Gros, Piet</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Aluminium Industry Abstracts</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Ceramic Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Computer and Information Systems Abstracts</collection><collection>Corrosion Abstracts</collection><collection>Ecology Abstracts</collection><collection>Electronics &amp; Communications Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Materials Business File</collection><collection>Mechanical &amp; Transportation Engineering Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ANTE: Abstracts in New Technology &amp; Engineering</collection><collection>Engineering Research Database</collection><collection>Aerospace Database</collection><collection>Copper Technical Reference Library</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Civil Engineering Abstracts</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts – Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ugurlar, Deniz</au><au>Howes, Stuart C</au><au>de Kreuk, Bart-Jan</au><au>Koning, Roman I</au><au>de Jong, Rob N</au><au>Beurskens, Frank J</au><au>Schuurman, Janine</au><au>Koster, Abraham J</au><au>Sharp, Thomas H</au><au>Parren, Paul W H I</au><au>Gros, Piet</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2018-02-16</date><risdate>2018</risdate><volume>359</volume><issue>6377</issue><spage>794</spage><epage>797</epage><pages>794-797</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><abstract>Danger patterns on microbes or damaged host cells bind and activate C1, inducing innate immune responses and clearance through the complement cascade. How these patterns trigger complement initiation remains elusive. Here, we present cryo-electron microscopy analyses of C1 bound to monoclonal antibodies in which we observed heterogeneous structures of single and clustered C1-immunoglobulin G1 (IgG1) hexamer complexes. Distinct C1q binding sites are observed on the two Fc-CH2 domains of each IgG molecule. These are consistent with known interactions and also reveal additional interactions, which are supported by functional IgG1-mutant analysis. Upon antibody binding, the C1q arms condense, inducing rearrangements of the C1r s proteases and tilting C1q's cone-shaped stalk. The data suggest that C1r may activate C1s within single, strained C1 complexes or between neighboring C1 complexes on surfaces.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>29449492</pmid><doi>10.1126/science.aao4988</doi><tpages>4</tpages><orcidid>https://orcid.org/0000-0001-8841-3851</orcidid><orcidid>https://orcid.org/0000-0001-6129-1882</orcidid><orcidid>https://orcid.org/0000-0002-4365-3859</orcidid><orcidid>https://orcid.org/0000-0002-9738-9926</orcidid><orcidid>https://orcid.org/0000-0002-9300-6633</orcidid><orcidid>https://orcid.org/0000-0002-7165-5771</orcidid><orcidid>https://orcid.org/0000-0003-1717-2549</orcidid><orcidid>https://orcid.org/0000-0002-1990-2333</orcidid><orcidid>https://orcid.org/0000-0002-7782-2585</orcidid><orcidid>https://orcid.org/0000-0001-6736-7147</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0036-8075
ispartof Science (American Association for the Advancement of Science), 2018-02, Vol.359 (6377), p.794-797
issn 0036-8075
1095-9203
language eng
recordid cdi_proquest_miscellaneous_2003038845
source American Association for the Advancement of Science; Alma/SFX Local Collection
subjects Alarmins - chemistry
Alarmins - ultrastructure
Antibodies, Monoclonal - chemistry
Antibodies, Monoclonal - ultrastructure
Avidity
Binding Sites
Complement
Complement Activation
Complement C1 - chemistry
Complement C1 - ultrastructure
Complement component C1
Complement component C1q
Cryoelectron Microscopy
Damage
Electron microscopy
Hazards
Hexamers
Humans
Immune clearance
Immune response
Immune system
Immunoglobulin G
Immunoglobulin G - chemistry
Immunoglobulin G - genetics
Immunoglobulin G - ultrastructure
Immunoglobulins
Initiation complex
Innate immunity
Microscopy
Monoclonal antibodies
Mutagenesis
Pattern recognition
title Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-07T06%3A00%3A03IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Structures%20of%20C1-IgG1%20provide%20insights%20into%20how%20danger%20pattern%20recognition%20activates%20complement&rft.jtitle=Science%20(American%20Association%20for%20the%20Advancement%20of%20Science)&rft.au=Ugurlar,%20Deniz&rft.date=2018-02-16&rft.volume=359&rft.issue=6377&rft.spage=794&rft.epage=797&rft.pages=794-797&rft.issn=0036-8075&rft.eissn=1095-9203&rft_id=info:doi/10.1126/science.aao4988&rft_dat=%3Cproquest_cross%3E2002528917%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c366t-2f28c2356364df8b0a608868d7be0417bc152ceae978055b26d07876c01618043%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2002528917&rft_id=info:pmid/29449492&rfr_iscdi=true