{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T01:18:20Z","timestamp":1780363100715,"version":"3.54.1"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T00:00:00Z","timestamp":1632096000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T00:00:00Z","timestamp":1632096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"the State Project for Essential Drug Research and Development of China","award":["2019ZX09201005"],"award-info":[{"award-number":["2019ZX09201005"]}]},{"name":"the State Project for Essential Drug Research and Development of China","award":["2019ZX09721001"],"award-info":[{"award-number":["2019ZX09721001"]}]},{"name":"the Fundamental Research Funds for the Central Public Welfare Research Institutes","award":["ZZ13-YQ-048"],"award-info":[{"award-number":["ZZ13-YQ-048"]}]},{"name":"the Fundamental Research Funds for the Central Public Welfare Research Institutes","award":["ZXKT21008"],"award-info":[{"award-number":["ZXKT21008"]}]},{"name":"Key Research and Development Project of Shandong Province","award":["2017CXGC1301"],"award-info":[{"award-number":["2017CXGC1301"]}]},{"DOI":"10.13039\/501100013076","name":"national major science and technology projects of china","doi-asserted-by":"publisher","award":["2019YFC1708904"],"award-info":[{"award-number":["2019YFC1708904"]}],"id":[{"id":"10.13039\/501100013076","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CACMS Innovation Fund","award":["CI2021A05041"],"award-info":[{"award-number":["CI2021A05041"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cheminform"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Natural products from traditional medicine inherit bioactivity from their source herbs. However, the pharmacological mechanism of natural products is often unclear and studied insufficiently. Pathway fingerprint similarity based on \u201cdrug-target-pathway\u201d heterogeneous network provides new insight into Mechanism of Action (MoA) for natural products compared with reference drugs, which are selected approved drugs with similar bioactivity. Natural products with similar pathway fingerprints may have similar MoA to approved drugs. In our study, XYPI, an andrographolide derivative, had similar anti-inflammatory activity to Glucocorticoids (GCs) and non-steroidal anti-inflammatory drugs (NSAIDs), and GCs and NSAIDs have completely different MoA. Based on similarity evaluation, XYPI has similar pathway fingerprints as NSAIDs, but has similar target profile with GCs. The expression pattern of genes in LPS-activated macrophages after XYPI treatment is similar to that after NSAID but not GC treatment, and this experimental result is consistent with the computational prediction based on pathway fingerprints. These results imply that the pathway fingerprints of drugs have potential for drug similarity evaluation. This study used XYPI as an example to propose a new approach for investigating the pharmacological mechanism of natural products using pathway fingerprint similarity based on a \u201cdrug-target-pathway\u201d heterogeneous network.<\/jats:p>","DOI":"10.1186\/s13321-021-00549-5","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T12:06:17Z","timestamp":1632139577000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Investigation of pharmacological mechanism of natural product using pathway fingerprints similarity based on \u201cdrug-target-pathway\u201d heterogenous network"],"prefix":"10.1186","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3624-4704","authenticated-orcid":false,"given":"Feifei","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhong","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Xi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangbo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,20]]},"reference":[{"key":"549_CR1","doi-asserted-by":"publisher","first-page":"3670","DOI":"10.1016\/j.bbagen.2013.02.008","volume":"1830","author":"GM Cragg","year":"2013","unstructured":"Cragg GM, Newman DJ (2013) Natural products: a continuing source of novel drug leads. Biochim Biophys Acta 1830:3670\u20133695. https:\/\/doi.org\/10.1016\/j.bbagen.2013.02.008","journal-title":"Biochim Biophys Acta"},{"key":"549_CR2","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1039\/b909989c","volume":"27","author":"JJ La Clair","year":"2010","unstructured":"La Clair JJ (2010) Natural product mode of action (MOA) studies: a link between natural and synthetic worlds. Nat Prod Rep 27:969\u2013995. https:\/\/doi.org\/10.1039\/b909989c","journal-title":"Nat Prod Rep"},{"key":"549_CR3","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1016\/j.cell.2007.08.021","volume":"130","author":"TW Corson","year":"2007","unstructured":"Corson TW, Crews CM (2007) Molecular understanding and modern application of traditional medicines: triumphs and trials. Cell 130:769\u2013774. https:\/\/doi.org\/10.1016\/j.cell.2007.08.021","journal-title":"Cell"},{"key":"549_CR4","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/s0021-9673(01)01160-8","volume":"930","author":"HY Cheung","year":"2001","unstructured":"Cheung HY, Cheung CS, Kong CK (2001) Determination of bioactive diterpenoids from Andrographis paniculata by micellar electrokinetic chromatography. J Chromatogr A 930:171\u2013176. https:\/\/doi.org\/10.1016\/s0021-9673(01)01160-8","journal-title":"J Chromatogr A"},{"key":"549_CR5","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1002\/pca.789","volume":"15","author":"N Pholphana","year":"2004","unstructured":"Pholphana N, Rangkadilok N, Thongnest S et al (2004) Determination and variation of three active diterpenoids in Andrographis paniculata (Burm.f.) Nees. Phytochem Anal 15:365\u2013371. https:\/\/doi.org\/10.1002\/pca.789","journal-title":"Phytochem Anal"},{"key":"549_CR6","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/s0378-8741(97)00099-8","volume":"58","author":"RA Burgos","year":"1997","unstructured":"Burgos RA, Caballero EE, S\u00e1nchez NS et al (1997) Testicular toxicity assessment of Andrographis paniculata dried extract in rats. J Ethnopharmacol 58:219\u2013224. https:\/\/doi.org\/10.1016\/s0378-8741(97)00099-8","journal-title":"J Ethnopharmacol"},{"key":"549_CR7","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/1749-8546-5-17","volume":"5","author":"W-W Chao","year":"2010","unstructured":"Chao W-W, Lin B-F (2010) Isolation and identification of bioactive compounds in Andrographis paniculata (Chuanxinlian). Chin Med 5:17. https:\/\/doi.org\/10.1186\/1749-8546-5-17","journal-title":"Chin Med"},{"key":"549_CR8","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s12906-015-0525-7","volume":"15","author":"M Low","year":"2015","unstructured":"Low M, Khoo CS, M\u00fcnch G et al (2015) An in vitro study of anti-inflammatory activity of standardised Andrographis paniculata extracts and pure andrographolide. BMC Complement Altern Med 15:18. https:\/\/doi.org\/10.1186\/s12906-015-0525-7","journal-title":"BMC Complement Altern Med"},{"key":"549_CR9","first-page":"66","volume":"16","author":"S Akbar","year":"2011","unstructured":"Akbar S (2011) Andrographis paniculata: a review of pharmacological activities and clinical effects. Altern Med Rev 16:66\u201377","journal-title":"Altern Med Rev"},{"key":"549_CR10","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.intimp.2017.11.042","volume":"55","author":"M Li","year":"2018","unstructured":"Li M, Yang X, Guan C et al (2018) Andrographolide sulfonate reduces mortality in Enterovirus 71 infected mice by modulating immunity. Int Immunopharmacol 55:142\u2013150. https:\/\/doi.org\/10.1016\/j.intimp.2017.11.042","journal-title":"Int Immunopharmacol"},{"key":"549_CR11","doi-asserted-by":"publisher","first-page":"116","DOI":"10.5152\/eurasianjmed.2018.0010","volume":"50","author":"C Gunaydin","year":"2018","unstructured":"Gunaydin C, Bilge SS (2018) Effects of nonsteroidal anti-inflammatory drugs at the molecular level. Eurasian J Med 50:116\u2013121. https:\/\/doi.org\/10.5152\/eurasianjmed.2018.0010","journal-title":"Eurasian J Med"},{"key":"549_CR12","doi-asserted-by":"publisher","first-page":"52","DOI":"10.2174\/187152312803476255","volume":"11","author":"S Bacchi","year":"2012","unstructured":"Bacchi S, Palumbo P, Sponta A, Coppolino MF (2012) Clinical pharmacology of non-steroidal anti-inflammatory drugs: a review. Antiinflamm Antiallergy Agents Med Chem 11:52\u201364. https:\/\/doi.org\/10.2174\/187152312803476255","journal-title":"Antiinflamm Antiallergy Agents Med Chem"},{"key":"549_CR13","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1007\/s13238-012-2011-z","volume":"3","author":"H Ye","year":"2012","unstructured":"Ye H, Tang K, Yang L et al (2012) Study of drug function based on similarity of pathway fingerprint. Protein Cell 3:132\u2013139. https:\/\/doi.org\/10.1007\/s13238-012-2011-z","journal-title":"Protein Cell"},{"key":"549_CR14","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2020.105077","volume":"160","author":"F Guo","year":"2020","unstructured":"Guo F, Tang X, Zhang W et al (2020) Exploration of the mechanism of traditional Chinese medicine by AI approach using unsupervised machine learning for cellular functional similarity of compounds in heterogeneous networks, XiaoErFuPi granules as an example. Pharmacol Res 160:105077. https:\/\/doi.org\/10.1016\/j.phrs.2020.105077","journal-title":"Pharmacol Res"},{"key":"549_CR15","doi-asserted-by":"publisher","first-page":"9583","DOI":"10.1021\/acs.jmedchem.8b01044","volume":"61","author":"M Iwata","year":"2018","unstructured":"Iwata M, Hirose L, Kohara H et al (2018) Pathway-based drug repositioning for cancers: computational prediction and experimental validation. J Med Chem 61:9583\u20139595. https:\/\/doi.org\/10.1021\/acs.jmedchem.8b01044","journal-title":"J Med Chem"},{"key":"549_CR16","doi-asserted-by":"publisher","first-page":"1911","DOI":"10.1093\/bioinformatics\/bts285","volume":"28","author":"H Ma","year":"2012","unstructured":"Ma H, Zhao H (2012) iFad: an integrative factor analysis model for drug-pathway association inference\u2020. Bioinformatics 28:1911\u20131918. https:\/\/doi.org\/10.1093\/bioinformatics\/bts285","journal-title":"Bioinformatics"},{"key":"549_CR17","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1186\/1471-2164-10-277","volume":"10","author":"UT Shankavaram","year":"2009","unstructured":"Shankavaram UT, Varma S, Kane D et al (2009) Cell Miner: a relational database and query tool for the NCI-60 cancer cell lines. BMC Genomics 10:277. https:\/\/doi.org\/10.1186\/1471-2164-10-277","journal-title":"BMC Genomics"},{"key":"549_CR18","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1109\/TCBB.2015.2462344","volume":"13","author":"C Li","year":"2016","unstructured":"Li C, Yang C, Hather G et al (2016) Efficient drug-pathway association analysis via integrative penalized matrix decomposition. IEEE\/ACM Trans Comput Biol Bioinform 13:531\u2013540. https:\/\/doi.org\/10.1109\/TCBB.2015.2462344","journal-title":"IEEE\/ACM Trans Comput Biol Bioinform"},{"key":"549_CR19","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbaa061","author":"C-C Wang","year":"2021","unstructured":"Wang C-C, Zhao Y, Chen X (2021) Drug-pathway association prediction: from experimental results to computational models. Brief Bioinform. https:\/\/doi.org\/10.1093\/bib\/bbaa061","journal-title":"Brief Bioinform"},{"key":"549_CR20","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.1093\/bioinformatics\/btx800","volume":"34","author":"F Napolitano","year":"2018","unstructured":"Napolitano F, Carrella D, Mandriani B et al (2018) gene2drug: a computational tool for pathway-based rational drug repositioning. Bioinformatics 34:1498\u20131505. https:\/\/doi.org\/10.1093\/bioinformatics\/btx800","journal-title":"Bioinformatics"},{"key":"549_CR21","doi-asserted-by":"publisher","first-page":"89","DOI":"10.6026\/97320630009089","volume":"9","author":"Y Fukuoka","year":"2013","unstructured":"Fukuoka Y, Takei D, Ogawa H (2013) A two-step drug repositioning method based on a protein-protein interaction network of genes shared by two diseases and the similarity of drugs. Bioinformation 9:89\u201393. https:\/\/doi.org\/10.6026\/97320630009089","journal-title":"Bioinformation"},{"key":"549_CR22","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1126\/science.1132939","volume":"313","author":"J Lamb","year":"2006","unstructured":"Lamb J, Crawford ED, Peck D et al (2006) The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313:1929\u20131935. https:\/\/doi.org\/10.1126\/science.1132939","journal-title":"Science"},{"key":"549_CR23","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1016\/j.cell.2017.10.049","volume":"171","author":"A Subramanian","year":"2017","unstructured":"Subramanian A, Narayan R, Corsello SM et al (2017) A next generation connectivity map: L1000 platform and the first 1,000,000 profiles. Cell 171:1437-1452.e17. https:\/\/doi.org\/10.1016\/j.cell.2017.10.049","journal-title":"Cell"},{"key":"549_CR24","doi-asserted-by":"publisher","first-page":"D353","DOI":"10.1093\/nar\/gkw1092","volume":"45","author":"M Kanehisa","year":"2017","unstructured":"Kanehisa M, Furumichi M, Tanabe M et al (2017) KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res 45:D353\u2013D361. https:\/\/doi.org\/10.1093\/nar\/gkw1092","journal-title":"Nucleic Acids Res"},{"key":"549_CR25","doi-asserted-by":"publisher","first-page":"D498","DOI":"10.1093\/nar\/gkz1031","volume":"48","author":"B Jassal","year":"2020","unstructured":"Jassal B, Matthews L, Viteri G et al (2020) The reactome pathway knowledgebase. Nucleic Acids Res 48:D498\u2013D503. https:\/\/doi.org\/10.1093\/nar\/gkz1031","journal-title":"Nucleic Acids Res"},{"key":"549_CR26","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","volume":"1","author":"A Liberzon","year":"2015","unstructured":"Liberzon A, Birger C, Thorvaldsd\u00f3ttir H et al (2015) The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst 1:417\u2013425. https:\/\/doi.org\/10.1016\/j.cels.2015.12.004","journal-title":"Cell Syst"},{"key":"549_CR27","doi-asserted-by":"publisher","first-page":"D613","DOI":"10.1093\/nar\/gkaa1024","volume":"49","author":"M Martens","year":"2021","unstructured":"Martens M, Ammar A, Riutta A et al (2021) WikiPathways: connecting communities. Nucleic Acids Res 49:D613\u2013D621. https:\/\/doi.org\/10.1093\/nar\/gkaa1024","journal-title":"Nucleic Acids Res"},{"key":"549_CR28","doi-asserted-by":"publisher","first-page":"992","DOI":"10.14778\/3402707.3402736","volume":"11","author":"Y Sun","year":"2011","unstructured":"Sun Y, Han J, Yan X et al (2011) Pathsim: Meta path-based top-k similarity search in heterogeneous information networks. Proc VLDB Endow. 11:992\u20131003","journal-title":"Proc VLDB Endow."},{"issue":"Suppl 16","key":"549_CR29","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1186\/1471-2105-14-S16-S3","volume":"14","author":"J Li","year":"2013","unstructured":"Li J, Lu Z (2013) Pathway-based drug repositioning using causal inference. BMC Bioinform 14(Suppl 16):S3. https:\/\/doi.org\/10.1186\/1471-2105-14-S16-S3","journal-title":"BMC Bioinform"},{"key":"549_CR30","doi-asserted-by":"publisher","first-page":"D401","DOI":"10.1093\/nar\/gkt1207","volume":"42","author":"M Kuhn","year":"2014","unstructured":"Kuhn M, Szklarczyk D, Pletscher-Frankild S et al (2014) STITCH 4: integration of protein-chemical interactions with user data. Nucleic Acids Res 42:D401-407. https:\/\/doi.org\/10.1093\/nar\/gkt1207","journal-title":"Nucleic Acids Res"},{"key":"549_CR31","doi-asserted-by":"publisher","first-page":"D955","DOI":"10.1093\/nar\/gkw1118","volume":"45","author":"Y Wang","year":"2017","unstructured":"Wang Y, Bryant SH, Cheng T et al (2017) PubChem BioAssay: 2017 update. Nucleic Acids Res 45:D955\u2013D963. https:\/\/doi.org\/10.1093\/nar\/gkw1118","journal-title":"Nucleic Acids Res"},{"key":"549_CR32","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1177\/2472555216685069","volume":"22","author":"Y Wang","year":"2017","unstructured":"Wang Y, Cheng T, Bryant SH (2017) PubChem bioAssay: a decade\u2019s development toward open high-throughput screening data sharing. SLAS Discov 22:655\u2013666. https:\/\/doi.org\/10.1177\/2472555216685069","journal-title":"SLAS Discov"},{"key":"549_CR33","doi-asserted-by":"publisher","first-page":"21146","DOI":"10.1038\/srep21146","volume":"6","author":"Z Liu","year":"2016","unstructured":"Liu Z, Guo F, Wang Y et al (2016) BATMAN-TCM: a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine. Sci Rep 6:21146. https:\/\/doi.org\/10.1038\/srep21146","journal-title":"Sci Rep"},{"key":"549_CR34","doi-asserted-by":"publisher","first-page":"D433","DOI":"10.1093\/nar\/gki005","volume":"33","author":"C von Mering","year":"2005","unstructured":"von Mering C, Jensen LJ, Snel B et al (2005) STRING: known and predicted protein-protein associations, integrated and transferred across organisms. Nucleic Acids Res 33:D433-437. https:\/\/doi.org\/10.1093\/nar\/gki005","journal-title":"Nucleic Acids Res"},{"key":"549_CR35","doi-asserted-by":"publisher","first-page":"D331","DOI":"10.1093\/nar\/gkw1108","volume":"45","author":"The Gene Ontology Consortium","year":"2017","unstructured":"The Gene Ontology Consortium (2017) Expansion of the Gene Ontology knowledgebase and resources. Nucleic Acids Res 45:D331\u2013D338. https:\/\/doi.org\/10.1093\/nar\/gkw1108","journal-title":"Nucleic Acids Res"},{"key":"549_CR36","unstructured":"hclust function | R Documentation. https:\/\/www.rdocumentation.org\/packages\/stats\/versions\/3.6.1\/topics\/hclust. Accessed 22 Oct 2019"},{"key":"549_CR37","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","volume":"26","author":"MD Robinson","year":"2010","unstructured":"Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26:139\u2013140. https:\/\/doi.org\/10.1093\/bioinformatics\/btp616","journal-title":"Bioinformatics"},{"key":"549_CR38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v025.i01","volume":"25","author":"S L\u00ea","year":"2008","unstructured":"L\u00ea S, Josse J, Husson F (2008) FactoMineR: An R Package for multivariate analysis. J Stat Softw 25:1\u20138","journal-title":"J Stat Softw"}],"container-title":["Journal of Cheminformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13321-021-00549-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13321-021-00549-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13321-021-00549-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T12:11:58Z","timestamp":1632139918000},"score":1,"resource":{"primary":{"URL":"https:\/\/jcheminf.biomedcentral.com\/articles\/10.1186\/s13321-021-00549-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,20]]},"references-count":38,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["549"],"URL":"https:\/\/doi.org\/10.1186\/s13321-021-00549-5","relation":{},"ISSN":["1758-2946"],"issn-type":[{"value":"1758-2946","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,20]]},"assertion":[{"value":"24 February 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 September 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 September 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"68"}}