{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:26:31Z","timestamp":1791203191978,"version":"4.2.0"},"reference-count":64,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T00:00:00Z","timestamp":1614038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant to State Key Laboratory of Agrobiotechnology of the Chinese University of Hong Kong","award":["8300052"],"award-info":[{"award-number":["8300052"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Glandular trichome (GT) is the dominant site for artemisinin production in Artemisia annua. Several critical genes involved in artemisinin biosynthesis are specifically expressed in GT. However, the molecular mechanism of differential gene expression between GT and other tissue types remains elusive. Chromatin accessibility, defined as the degree to which nuclear molecules are able to interact with chromatin DNA, reflects gene expression capacity to a certain extent. Here, we investigated and compared the landscape of chromatin accessibility in Artemisia annua leaf and GT using the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) technique. We identified 5413 GT high accessible and 4045 GT low accessible regions, and these GT high accessible regions may contribute to GT-specific biological functions. Several GT-specific artemisinin biosynthetic genes, such as DBR2 and CYP71AV1, showed higher accessible regions in GT compared to that in leaf, implying that they might be regulated by chromatin accessibility. In addition, transcription factor binding motifs for MYB, bZIP, C2H2, and AP2 were overrepresented in the highly accessible chromatin regions associated with artemisinin biosynthetic genes in glandular trichomes. Finally, we proposed a working model illustrating the chromatin accessibility dynamics in regulating artemisinin biosynthetic gene expression. This work provided new insights into epigenetic regulation of gene expression in GT.<\/jats:p>","DOI":"10.3390\/molecules26041194","type":"journal-article","created":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T12:40:16Z","timestamp":1614084016000},"page":"1194","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Chromatin Accessibility Is Associated with Artemisinin Biosynthesis Regulation in Artemisia annua"],"prefix":"10.3390","volume":"26","author":[{"given":"Limeng","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Agrobiotechnology, School of Life Science, The Chinese University of Hong Kong, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1876-1089","authenticated-orcid":false,"given":"Yingzhang","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agrobiotechnology, School of Life Science, The Chinese University of Hong Kong, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianjing","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agrobiotechnology, School of Life Science, The Chinese University of Hong Kong, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,23]]},"reference":[{"key":"ref_1","first-page":"142","article-title":"A new sesquiterpene lactone-qinghaosu","volume":"3","author":"Qinghaosu","year":"1977","journal-title":"Kexue Tongbao"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1038\/nm.2471","article-title":"The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine","volume":"17","author":"Tu","year":"2011","journal-title":"Nat. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"91","DOI":"10.2165\/00003088-200847020-00002","article-title":"Clinical pharmacology of artemisinin-based combination therapies","volume":"47","author":"German","year":"2008","journal-title":"Clin. Pharmacokinet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1002\/ptr.6733","article-title":"Artemisia annua: Trials are needed for COVID-19","volume":"34","author":"Haq","year":"2020","journal-title":"Phytother. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"100474","DOI":"10.1016\/j.imr.2020.100474","article-title":"Is the traditional Chinese herb \u201cArtemisia annua\u201d possible to fight against COVID-19?","volume":"9","author":"Law","year":"2020","journal-title":"Integr. Med. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.molp.2018.03.015","article-title":"The Genome of Artemisia annua Provides Insight into the Evolution of Asteraceae Family and Artemisinin Biosynthesis","volume":"11","author":"Shen","year":"2018","journal-title":"Mol. Plant"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/s11434-015-0980-z","article-title":"Artemisia annua glandular secretory trichomes: The biofactory of antimalarial agent artemisinin","volume":"61","author":"Xiao","year":"2016","journal-title":"Sci. Bull."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1038\/nature04640","article-title":"Production of the antimalarial drug precursor artemisinic acid in engineered yeast","volume":"440","author":"Ro","year":"2006","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/nbt.2054","article-title":"Generation of the potent anti-malarial drug artemisinin in tobacco","volume":"29","author":"Farhi","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1126\/science.1182612","article-title":"The genetic map of Artemisia annua L. identifies loci affecting yield of the antimalarial drug artemisinin","volume":"327","author":"Graham","year":"2010","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Townsend, T., Segura, V., Chigeza, G., Penfield, T., Rae, A., Harvey, D., Bowles, D., and Graham, I.A. (2013). The use of combining ability analysis to identify elite parents for Artemisia annua F1 hybrid production. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061989"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1111\/j.1744-7909.2006.00208.x","article-title":"Effects of overexpression of the endogenous farnesyl diphosphate synthase on the artemisinin content in Artemisia annua L.","volume":"48","author":"Han","year":"2006","journal-title":"J. Integr. Plant Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s11240-017-1173-z","article-title":"Promotion of artemisinin content in Artemisia annua by overexpression of multiple artemisinin biosynthetic pathway genes","volume":"129","author":"Shi","year":"2017","journal-title":"Plant Cell Tissue Organ. Cult."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.chroma.2006.03.121","article-title":"Quantitation of artemisinin and its biosynthetic precursors in Artemisia annua L. by high performance liquid chromatography-electrospray quadrupole time-of-flight tandem mass spectrometry","volume":"1118","author":"Maes","year":"2006","journal-title":"J. Chromatogr. A"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.phytochem.2009.07.009","article-title":"Localization of enzymes of artemisinin biosynthesis to the apical cells of glandular secretory trichomes of Artemisia annua L.","volume":"70","author":"Olsson","year":"2009","journal-title":"Phytochemistry"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1086\/297173","article-title":"Localization of artemisinin and artemisitene in foliar tissues of glanded and glandless biotypes of Artemisia annua L.","volume":"155","author":"Duke","year":"1994","journal-title":"Int. J. Plant Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/j.molp.2019.02.011","article-title":"Artemisinin Biosynthesis in Non-glandular Trichome Cells of Artemisia annua","volume":"12","author":"Judd","year":"2019","journal-title":"Mol. Plant"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1086\/297096","article-title":"Development and Fine-Structure of the Glandular Trichomes of Artemisia annua L.","volume":"154","author":"Duke","year":"1993","journal-title":"Int. J. Plant Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1007\/s00299-007-0420-x","article-title":"Evidence of artemisinin production from IPP stemming from both the mevalonate and the nonmevalonate pathways","volume":"26","author":"Towler","year":"2007","journal-title":"Plant Cell Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1006\/abbi.2000.1962","article-title":"Molecular cloning, expression, and characterization of amorpha-4,11-diene synthase, a key enzyme of artemisinin biosynthesis in Artemisia annua L.","volume":"381","author":"Mercke","year":"2000","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1021\/np050356u","article-title":"Cyclization mechanism of amorpha-4,11-diene synthase, a key enzyme in artemisinin biosynthesis","volume":"69","author":"Kim","year":"2006","journal-title":"J. Nat. Prod."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1016\/j.febslet.2006.01.065","article-title":"Artemisia annua L. (Asteraceae) trichome-specific cDNAs reveal CYP71AV1, a cytochrome P450 with a key role in the biosynthesis of the antimalarial sesquiterpene lactone artemisinin","volume":"580","author":"Teoh","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"21501","DOI":"10.1074\/jbc.M803090200","article-title":"The molecular cloning of artemisinic aldehyde Delta11 reductase and its role in glandular trichome-dependent biosynthesis of artemisinin in Artemisia annua","volume":"283","author":"Zhang","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1139\/B09-032","article-title":"Molecular cloning of an aldehyde dehydrogenase implicated in artemisinin biosynthesis in Artemisia annua","volume":"87","author":"Teoh","year":"2009","journal-title":"Botany"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15150","DOI":"10.1073\/pnas.1611567113","article-title":"Artemisia annua mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism","volume":"113","author":"Czechowski","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1111\/tpj.13509","article-title":"AaMYB1 and its orthologue AtMYB61 affect terpene metabolism and trichome development in Artemisia annua and Arabidopsis thaliana","volume":"90","author":"Jiang","year":"2017","journal-title":"Plant J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.phytochem.2014.02.011","article-title":"Effects of overexpression of AaWRKY1 on artemisinin biosynthesis in transgenic Artemisia annua plants","volume":"102","author":"Han","year":"2014","journal-title":"Phytochemistry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1111\/nph.14373","article-title":"GLANDULAR TRICHOME-SPECIFIC WRKY 1 promotes artemisinin biosynthesis in Artemisia annua","volume":"214","author":"Chen","year":"2017","journal-title":"New Phytol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1111\/nph.12207","article-title":"AaORA, a trichome-specific AP2\/ERF transcription factor of Artemisia annua, is a positive regulator in the artemisinin biosynthetic pathway and in disease resistance to Botrytis cinerea","volume":"198","author":"Lu","year":"2013","journal-title":"New Phytol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1016\/j.molp.2015.04.002","article-title":"TRICHOME AND ARTEMISININ REGULATOR 1 Is Required for Trichome Development and Artemisinin Biosynthesis in Artemisia annua","volume":"8","author":"Tan","year":"2015","journal-title":"Mol. Plant"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.molp.2014.12.004","article-title":"A basic leucine zipper transcription factor, AabZIP1, connects abscisic acid signaling with artemisinin biosynthesis in Artemisia annua","volume":"8","author":"Zhang","year":"2015","journal-title":"Mol. Plant"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1093\/pcp\/pcu090","article-title":"Cloning and characterization of AabHLH1, a bHLH transcription factor that positively regulates artemisinin biosynthesis in Artemisia annua","volume":"55","author":"Ji","year":"2014","journal-title":"Plant Cell Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1093\/mp\/ssr087","article-title":"The jasmonate-responsive AP2\/ERF transcription factors AaERF1 and AaERF2 positively regulate artemisinin biosynthesis in Artemisia annua L.","volume":"5","author":"Yu","year":"2012","journal-title":"Mol. Plant"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s41576-018-0089-8","article-title":"Chromatin accessibility and the regulatory epigenome","volume":"20","author":"Klemm","year":"2019","journal-title":"Nat. Rev. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1105\/tpc.17.00581","article-title":"Profiling of Accessible Chromatin Regions across Multiple Plant Species and Cell Types Reveals Common Gene Regulatory Principles and New Control Modules","volume":"30","author":"Maher","year":"2018","journal-title":"Plant Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1038\/s41477-018-0290-y","article-title":"Cytokinin modulates context-dependent chromatin accessibility through the type-B response regulators","volume":"4","author":"Potter","year":"2018","journal-title":"Nat. Plants"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1080\/07391102.1984.10507569","article-title":"The structural organization of oligonucleosomes","volume":"2","author":"Marion","year":"1984","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/nature07667","article-title":"The DNA-encoded nucleosome organization of a eukaryotic genome","volume":"458","author":"Kaplan","year":"2009","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1016\/j.jmb.2008.04.025","article-title":"Spontaneous access to DNA target sites in folded chromatin fibers","volume":"379","author":"Poirier","year":"2008","journal-title":"J. Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/nmeth890","article-title":"Genome-scale mapping of DNase I sensitivity in vivo using tiling DNA microarrays","volume":"3","author":"Sabo","year":"2006","journal-title":"Nat. Methods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1038\/nmeth.2688","article-title":"Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position","volume":"10","author":"Buenrostro","year":"2013","journal-title":"Nat. Methods"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11485","DOI":"10.1038\/ncomms11485","article-title":"MNase titration reveals differences between nucleosome occupancy and chromatin accessibility","volume":"7","author":"Mieczkowski","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1038\/s41477-019-0548-z","article-title":"The prevalence, evolution and chromatin signatures of plant regulatory elements","volume":"5","author":"Lu","year":"2019","journal-title":"Nat. Plants"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Wang, W., Wang, Y., Zhang, Q., Qi, Y., and Guo, D. (2009). Global characterization of Artemisia annua glandular trichome transcriptome using 454 pyrosequencing. BMC Genom., 10.","DOI":"10.1186\/1471-2164-10-465"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.phytochem.2009.10.015","article-title":"Artemisinin biosynthesis in growing plants of Artemisia annua. A 13CO2 study","volume":"71","author":"Schramek","year":"2010","journal-title":"Phytochemistry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13072-018-0180-6","article-title":"The bromodomain-containing protein Ibd1 links multiple chromatin-related protein complexes to highly expressed genes in Tetrahymena thermophila","volume":"11","author":"Mudalige","year":"2018","journal-title":"Epigenetics Chromatin"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1101\/gad.312850.118","article-title":"SWI\/SNF and RSC cooperate to reposition and evict promoter nucleosomes at highly expressed genes in yeast","volume":"32","author":"Rawal","year":"2018","journal-title":"Genes Dev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8408","DOI":"10.1093\/nar\/gkaa571","article-title":"Chromatin remodeler Ino80C acts independently of H2A.Z to evict promoter nucleosomes and stimulate transcription of highly expressed genes in yeast","volume":"48","author":"Qiu","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.abb.2006.02.026","article-title":"Isoprenoid biosynthesis in Artemisia annua: Cloning and heterologous expression of a germacrene A synthase from a glandular trichome cDNA library","volume":"448","author":"Bertea","year":"2006","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1104\/pp.17.00062","article-title":"Photosynthetic Trichomes Contain a Specific Rubisco with a Modified pH-Dependent Activity","volume":"173","author":"Laterre","year":"2017","journal-title":"Plant Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"R41","DOI":"10.1186\/gb-2014-15-3-r41","article-title":"Dynamics of chromatin accessibility and gene regulation by MADS-domain transcription factors in flower development","volume":"15","author":"Pajoro","year":"2014","journal-title":"Genome Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1101\/gr.258871.119","article-title":"Dynamic transcriptional and chromatin accessibility landscape of medaka embryogenesis","volume":"30","author":"Li","year":"2020","journal-title":"Genome Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1038\/s41477-019-0547-0","article-title":"Widespread long-range cis-regulatory elements in the maize genome","volume":"5","author":"Ricci","year":"2019","journal-title":"Nat. Plants"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/nmeth.3329","article-title":"Identification of active transcriptional regulatory elements from GRO-seq data","volume":"12","author":"Danko","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/nmeth888","article-title":"DNase-chip: A high-resolution method to identify DNase I hypersensitive sites using tiled microarrays","volume":"3","author":"Crawford","year":"2006","journal-title":"Nat. Methods"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie 2","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1093\/bioinformatics\/btv098","article-title":"Sambamba: Fast processing of NGS alignment formats","volume":"31","author":"Tarasov","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"R137","DOI":"10.1186\/gb-2008-9-9-r137","article-title":"Model-based analysis of ChIP-Seq (MACS)","volume":"9","author":"Zhang","year":"2008","journal-title":"Genome Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1093\/bioinformatics\/btv145","article-title":"ChIPseeker: An R\/Bioconductor package for ChIP peak annotation, comparison and visualization","volume":"31","author":"Yu","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: A fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.molcel.2010.05.004","article-title":"Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities","volume":"38","author":"Heinz","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1093\/bioinformatics\/btr064","article-title":"FIMO: Scanning for occurrences of a given motif","volume":"27","author":"Grant","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/4\/1194\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:27:14Z","timestamp":1760160434000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/4\/1194"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,23]]},"references-count":64,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["molecules26041194"],"URL":"https:\/\/doi.org\/10.3390\/molecules26041194","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,23]]}}}