Incorporation of DPP6a and DPP6K variants in ternary Kv4 channel complex reconstitutes properties of A-type K current in rat cerebellar granule cells
Dipeptidyl peptidase-like protein 6 (DPP6) proteins co-assemble with Kv4 channel α-subunits and Kv channel-interacting proteins (KChIPs) to form channel protein complexes underlying neuronal somatodendritic A-type potassium current (I(SA)). DPP6 proteins are expressed as N-terminal variants (DPP6a,...
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| description | Dipeptidyl peptidase-like protein 6 (DPP6) proteins co-assemble with Kv4 channel α-subunits and Kv channel-interacting proteins (KChIPs) to form channel protein complexes underlying neuronal somatodendritic A-type potassium current (I(SA)). DPP6 proteins are expressed as N-terminal variants (DPP6a, DPP6K, DPP6S, DPP6L) that result from alternative mRNA initiation and exhibit overlapping expression patterns. Here, we study the role DPP6 variants play in shaping the functional properties of I(SA) found in cerebellar granule (CG) cells using quantitative RT-PCR and voltage-clamp recordings of whole-cell currents from reconstituted channel complexes and native I(SA) channels. Differential expression of DPP6 variants was detected in rat CG cells, with DPP6K (41 ± 3%)>DPP6a (33 ± 3%)>>DPP6S (18 ± 2%)>DPP6L (8 ± 3%). To better understand how DPP6 variants shape native neuronal I(SA), we focused on studying interactions between the two dominant variants, DPP6K and DPP6a. Although previous studies did not identify unique functional effects of DPP6K, we find that the unique N-terminus of DPP6K modulates the effects of KChIP proteins, slowing recovery and producing a negative shift in the steady-state inactivation curve. By contrast, DPP6a uses its distinct N-terminus to directly confer rapid N-type inactivation independently of KChIP3a. When DPP6a and DPP6K are co-expressed in ratios similar to those found in CG cells, their distinct effects compete in modulating channel function. The more rapid inactivation from DPP6a dominates during strong depolarization; however, DPP6K produces a negative shift in the steady-state inactivation curve and introduces a slow phase of recovery from inactivation. A direct comparison to the native CG cell I(SA) shows that these mixed effects are present in the native channels. Our results support the hypothesis that the precise expression and co-assembly of different auxiliary subunit variants are important factors in shaping the I(SA) functional properties in specific neuronal populations. |
| doi_str_mv | 10.1371/journal.pone.0038205 |
| format | Article |
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DPP6 proteins are expressed as N-terminal variants (DPP6a, DPP6K, DPP6S, DPP6L) that result from alternative mRNA initiation and exhibit overlapping expression patterns. Here, we study the role DPP6 variants play in shaping the functional properties of I(SA) found in cerebellar granule (CG) cells using quantitative RT-PCR and voltage-clamp recordings of whole-cell currents from reconstituted channel complexes and native I(SA) channels. Differential expression of DPP6 variants was detected in rat CG cells, with DPP6K (41 ± 3%)>DPP6a (33 ± 3%)>>DPP6S (18 ± 2%)>DPP6L (8 ± 3%). To better understand how DPP6 variants shape native neuronal I(SA), we focused on studying interactions between the two dominant variants, DPP6K and DPP6a. Although previous studies did not identify unique functional effects of DPP6K, we find that the unique N-terminus of DPP6K modulates the effects of KChIP proteins, slowing recovery and producing a negative shift in the steady-state inactivation curve. By contrast, DPP6a uses its distinct N-terminus to directly confer rapid N-type inactivation independently of KChIP3a. When DPP6a and DPP6K are co-expressed in ratios similar to those found in CG cells, their distinct effects compete in modulating channel function. The more rapid inactivation from DPP6a dominates during strong depolarization; however, DPP6K produces a negative shift in the steady-state inactivation curve and introduces a slow phase of recovery from inactivation. A direct comparison to the native CG cell I(SA) shows that these mixed effects are present in the native channels. Our results support the hypothesis that the precise expression and co-assembly of different auxiliary subunit variants are important factors in shaping the I(SA) functional properties in specific neuronal populations.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0038205</identifier><identifier>PMID: 22675523</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alternative Splicing - genetics ; Amino Acid Sequence ; Amyotrophic lateral sclerosis ; Animals ; Apoptosis ; Biology ; Cerebellum ; Cerebellum - cytology ; Channels ; Conserved Sequence - genetics ; Cytoplasmic Granules - enzymology ; Deactivation ; Depolarization ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - chemistry ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - genetics ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - metabolism ; Evolution, Molecular ; Gene expression ; Genes ; Granular materials ; Granule cells ; Inactivation ; Ion Channel Gating - physiology ; Kinetics ; Laboratory animals ; Molecular Sequence Data ; mRNA ; Multiprotein Complexes - metabolism ; N-Terminus ; Neurons ; Peptidase ; Polymerase chain reaction ; Potassium ; Properties (attributes) ; Protein Isoforms - chemistry ; Protein Isoforms - genetics ; Protein Isoforms - metabolism ; Protein Structure, Tertiary ; Proteins ; Rats ; Rats, Sprague-Dawley ; Recovery ; RNA ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Rodents ; Shal Potassium Channels - metabolism ; Steady state ; Studies ; Xenopus ; Xenopus laevis</subject><ispartof>PloS one, 2012-06, Vol.7 (6), p.e38205-e38205</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Jerng, Pfaffinger. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Jerng, Pfaffinger. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-6c5c5c6e21ca502794b966a1dd4b7245fd67620f88f187881e598044d281fa2c3</citedby><cites>FETCH-LOGICAL-c692t-6c5c5c6e21ca502794b966a1dd4b7245fd67620f88f187881e598044d281fa2c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366920/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366920/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2101,2927,23865,27923,27924,53790,53792,79471,79472</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22675523$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Bondarenko, Vladimir E.</contributor><creatorcontrib>Jerng, Henry H</creatorcontrib><creatorcontrib>Pfaffinger, Paul J</creatorcontrib><title>Incorporation of DPP6a and DPP6K variants in ternary Kv4 channel complex reconstitutes properties of A-type K current in rat cerebellar granule cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Dipeptidyl peptidase-like protein 6 (DPP6) proteins co-assemble with Kv4 channel α-subunits and Kv channel-interacting proteins (KChIPs) to form channel protein complexes underlying neuronal somatodendritic A-type potassium current (I(SA)). DPP6 proteins are expressed as N-terminal variants (DPP6a, DPP6K, DPP6S, DPP6L) that result from alternative mRNA initiation and exhibit overlapping expression patterns. Here, we study the role DPP6 variants play in shaping the functional properties of I(SA) found in cerebellar granule (CG) cells using quantitative RT-PCR and voltage-clamp recordings of whole-cell currents from reconstituted channel complexes and native I(SA) channels. Differential expression of DPP6 variants was detected in rat CG cells, with DPP6K (41 ± 3%)>DPP6a (33 ± 3%)>>DPP6S (18 ± 2%)>DPP6L (8 ± 3%). To better understand how DPP6 variants shape native neuronal I(SA), we focused on studying interactions between the two dominant variants, DPP6K and DPP6a. Although previous studies did not identify unique functional effects of DPP6K, we find that the unique N-terminus of DPP6K modulates the effects of KChIP proteins, slowing recovery and producing a negative shift in the steady-state inactivation curve. By contrast, DPP6a uses its distinct N-terminus to directly confer rapid N-type inactivation independently of KChIP3a. When DPP6a and DPP6K are co-expressed in ratios similar to those found in CG cells, their distinct effects compete in modulating channel function. The more rapid inactivation from DPP6a dominates during strong depolarization; however, DPP6K produces a negative shift in the steady-state inactivation curve and introduces a slow phase of recovery from inactivation. A direct comparison to the native CG cell I(SA) shows that these mixed effects are present in the native channels. Our results support the hypothesis that the precise expression and co-assembly of different auxiliary subunit variants are important factors in shaping the I(SA) functional properties in specific neuronal populations.</description><subject>Alternative Splicing - genetics</subject><subject>Amino Acid Sequence</subject><subject>Amyotrophic lateral sclerosis</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biology</subject><subject>Cerebellum</subject><subject>Cerebellum - cytology</subject><subject>Channels</subject><subject>Conserved Sequence - genetics</subject><subject>Cytoplasmic Granules - enzymology</subject><subject>Deactivation</subject><subject>Depolarization</subject><subject>Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - chemistry</subject><subject>Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - genetics</subject><subject>Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - metabolism</subject><subject>Evolution, Molecular</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Granular materials</subject><subject>Granule cells</subject><subject>Inactivation</subject><subject>Ion Channel Gating - physiology</subject><subject>Kinetics</subject><subject>Laboratory animals</subject><subject>Molecular Sequence Data</subject><subject>mRNA</subject><subject>Multiprotein Complexes - metabolism</subject><subject>N-Terminus</subject><subject>Neurons</subject><subject>Peptidase</subject><subject>Polymerase chain reaction</subject><subject>Potassium</subject><subject>Properties (attributes)</subject><subject>Protein Isoforms - chemistry</subject><subject>Protein Isoforms - genetics</subject><subject>Protein Isoforms - metabolism</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Recovery</subject><subject>RNA</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Rodents</subject><subject>Shal Potassium Channels - metabolism</subject><subject>Steady state</subject><subject>Studies</subject><subject>Xenopus</subject><subject>Xenopus laevis</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9tq3DAQhk1padK0b1BaQaG0F7vVybJ9U1jS07KBhJ5uhSyPdx20kiPJS_Igfd_K2U3YLbkouvAw_uYf_yNPlr0keEpYQT5cusFbZaa9szDFmJUU54-yY1IxOhEUs8d78VH2LIRLjHNWCvE0O6JUFHlO2XH2Z261873zKnbOIteiTxcXQiFlm9togTbKd8rGgDqLIqSW_gYtNhzplbIWDNJu3Ru4Rh60syF2cYgQUO9dDz52KUyas0m86QEtkB68BxtHrdQRafBQgzHKo6VXdjCQUsaE59mTVpkAL3bPk-zXl88_T79Nzs6_zk9nZxMtKhonQufpCKBEqxzTouJ1JYQiTcPrgvK8bUSR7Ldl2ZKyKEsCeVVizhtaklZRzU6y11vd3rggdxMNkjCap4niiiRiviUapy5l77t18i-d6uRtwvmlVMmmNiBrhhtc66oAzHjR8JI3nNcNJVhXIq9HrY-7bkO9hkanQXhlDkQP39huJZduIxkTyS9OAu92At5dDRCiXHdhHJiy4Ib03ZhUyS8tioS--Qd92N2OWqpkoLOtS331KCpnvCgIEYKKRE0foNJpYN2lS4e2S_mDgvcHBYmJcB2XaghBzn98_3_2_Pch-3aPXYEycRWcGcZfNxyCfAtq70Lw0N4PmWA5bs_dNOS4PXK3Pans1f4F3RfdrQv7C60cFIY</recordid><startdate>20120604</startdate><enddate>20120604</enddate><creator>Jerng, Henry H</creator><creator>Pfaffinger, Paul J</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120604</creationdate><title>Incorporation of DPP6a and DPP6K variants in ternary Kv4 channel complex reconstitutes properties of A-type K current in rat cerebellar granule cells</title><author>Jerng, Henry H ; Pfaffinger, Paul J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-6c5c5c6e21ca502794b966a1dd4b7245fd67620f88f187881e598044d281fa2c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Alternative Splicing - genetics</topic><topic>Amino Acid Sequence</topic><topic>Amyotrophic lateral sclerosis</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biology</topic><topic>Cerebellum</topic><topic>Cerebellum - cytology</topic><topic>Channels</topic><topic>Conserved Sequence - genetics</topic><topic>Cytoplasmic Granules - enzymology</topic><topic>Deactivation</topic><topic>Depolarization</topic><topic>Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - chemistry</topic><topic>Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - genetics</topic><topic>Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - metabolism</topic><topic>Evolution, Molecular</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Granular materials</topic><topic>Granule cells</topic><topic>Inactivation</topic><topic>Ion Channel Gating - physiology</topic><topic>Kinetics</topic><topic>Laboratory animals</topic><topic>Molecular Sequence Data</topic><topic>mRNA</topic><topic>Multiprotein Complexes - metabolism</topic><topic>N-Terminus</topic><topic>Neurons</topic><topic>Peptidase</topic><topic>Polymerase chain reaction</topic><topic>Potassium</topic><topic>Properties (attributes)</topic><topic>Protein Isoforms - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jerng, Henry H</au><au>Pfaffinger, Paul J</au><au>Bondarenko, Vladimir E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Incorporation of DPP6a and DPP6K variants in ternary Kv4 channel complex reconstitutes properties of A-type K current in rat cerebellar granule cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-06-04</date><risdate>2012</risdate><volume>7</volume><issue>6</issue><spage>e38205</spage><epage>e38205</epage><pages>e38205-e38205</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Dipeptidyl peptidase-like protein 6 (DPP6) proteins co-assemble with Kv4 channel α-subunits and Kv channel-interacting proteins (KChIPs) to form channel protein complexes underlying neuronal somatodendritic A-type potassium current (I(SA)). DPP6 proteins are expressed as N-terminal variants (DPP6a, DPP6K, DPP6S, DPP6L) that result from alternative mRNA initiation and exhibit overlapping expression patterns. Here, we study the role DPP6 variants play in shaping the functional properties of I(SA) found in cerebellar granule (CG) cells using quantitative RT-PCR and voltage-clamp recordings of whole-cell currents from reconstituted channel complexes and native I(SA) channels. Differential expression of DPP6 variants was detected in rat CG cells, with DPP6K (41 ± 3%)>DPP6a (33 ± 3%)>>DPP6S (18 ± 2%)>DPP6L (8 ± 3%). To better understand how DPP6 variants shape native neuronal I(SA), we focused on studying interactions between the two dominant variants, DPP6K and DPP6a. Although previous studies did not identify unique functional effects of DPP6K, we find that the unique N-terminus of DPP6K modulates the effects of KChIP proteins, slowing recovery and producing a negative shift in the steady-state inactivation curve. By contrast, DPP6a uses its distinct N-terminus to directly confer rapid N-type inactivation independently of KChIP3a. When DPP6a and DPP6K are co-expressed in ratios similar to those found in CG cells, their distinct effects compete in modulating channel function. The more rapid inactivation from DPP6a dominates during strong depolarization; however, DPP6K produces a negative shift in the steady-state inactivation curve and introduces a slow phase of recovery from inactivation. A direct comparison to the native CG cell I(SA) shows that these mixed effects are present in the native channels. Our results support the hypothesis that the precise expression and co-assembly of different auxiliary subunit variants are important factors in shaping the I(SA) functional properties in specific neuronal populations.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22675523</pmid><doi>10.1371/journal.pone.0038205</doi><tpages>e38205</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1325003091 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Alternative Splicing - genetics Amino Acid Sequence Amyotrophic lateral sclerosis Animals Apoptosis Biology Cerebellum Cerebellum - cytology Channels Conserved Sequence - genetics Cytoplasmic Granules - enzymology Deactivation Depolarization Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - chemistry Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - genetics Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - metabolism Evolution, Molecular Gene expression Genes Granular materials Granule cells Inactivation Ion Channel Gating - physiology Kinetics Laboratory animals Molecular Sequence Data mRNA Multiprotein Complexes - metabolism N-Terminus Neurons Peptidase Polymerase chain reaction Potassium Properties (attributes) Protein Isoforms - chemistry Protein Isoforms - genetics Protein Isoforms - metabolism Protein Structure, Tertiary Proteins Rats Rats, Sprague-Dawley Recovery RNA RNA, Messenger - genetics RNA, Messenger - metabolism Rodents Shal Potassium Channels - metabolism Steady state Studies Xenopus Xenopus laevis |
| title | Incorporation of DPP6a and DPP6K variants in ternary Kv4 channel complex reconstitutes properties of A-type K current in rat cerebellar granule cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-09T07%3A14%3A58IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Incorporation%20of%20DPP6a%20and%20DPP6K%20variants%20in%20ternary%20Kv4%20channel%20complex%20reconstitutes%20properties%20of%20A-type%20K%20current%20in%20rat%20cerebellar%20granule%20cells&rft.jtitle=PloS%20one&rft.au=Jerng,%20Henry%20H&rft.date=2012-06-04&rft.volume=7&rft.issue=6&rft.spage=e38205&rft.epage=e38205&rft.pages=e38205-e38205&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0038205&rft_dat=%3Cgale_plos_%3EA477116626%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1325003091&rft_id=info:pmid/22675523&rft_galeid=A477116626&rft_doaj_id=oai_doaj_org_article_b30d0bc97e0347d484d44bd210c965b1&rfr_iscdi=true |