{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T08:25:39Z","timestamp":1774599939554,"version":"3.50.1"},"reference-count":50,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T00:00:00Z","timestamp":1605657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Typhoid fever, caused by Salmonella enterica serovar Typhi (S. Typhi), is a global health concern and its treatment is problematic due to the rise in antimicrobial resistance (AMR). Rapid detection of patients infected with AMR positive S. Typhi is, therefore, crucial to prevent further spreading. Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated genes (CRISPR-Cas), is an adaptive immune system that initially was used for typing purposes. Later, it was discovered to play a role in defense against phages and plasmids, including ones that carry AMR genes, and, at present, it is being explored for its usage in diagnostics. Despite the availability of whole-genome sequences (WGS), very few studied the CRISPR-Cas system of S. Typhi, let alone in typing purposes or relation to AMR. In the present study, we analyzed the CRISPR-Cas system of S. Typhi using WGS data of 1059 isolates obtained from Bangladesh, India, Nepal, and Pakistan in combination with demographic data and AMR status. Our results reveal that the S. Typhi CRISPR loci can be classified into two groups: A (evidence level &gt;2) and B (evidence level \u22642), in which we identified a total of 47 unique spacers and 15 unique direct repeats. Further analysis of the identified spacers and repeats demonstrated specific patterns that harbored significant associations with genotype, demographic characteristics, and AMR status, thus raising the possibility of their usage as biomarkers. Potential spacer targets were identified and, interestingly, the phage-targeting spacers belonged to the group-A and plasmid-targeting spacers to the group-B CRISPR loci. Further analyses of the spacer targets led to the identification of an S. Typhi protospacer adjacent motif (PAM) sequence, TTTCA\/T. New cas-genes known as DinG, DEDDh, and WYL were also discovered in the S. Typhi genome. However, a specific variant of the WYL gene was only identified in the extensively drug-resistant (XDR) lineage from Pakistan and ciprofloxacin-resistant lineage from Bangladesh. From this work, we conclude that there are strong correlations between variations identified in the S. Typhi CRISPR-Cas system and endemic AMR positive S. Typhi isolates.<\/jats:p>","DOI":"10.3390\/genes11111365","type":"journal-article","created":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T07:41:00Z","timestamp":1605685260000},"page":"1365","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["CRISPR-Cas Diversity in Clinical Salmonella enterica Serovar Typhi Isolates from South Asian Countries"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7769-8035","authenticated-orcid":false,"given":"Arif Mohammad","family":"Tanmoy","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center Rotterdam, 3015 CN Rotterdam, The Netherlands"},{"name":"Child Health Research Foundation, 23\/2 SEL Huq Skypark, Block-B, Khilji Rd, Dhaka 1207, Bangladesh"},{"name":"Laboratoire des Pathog\u00e8nes Emergents, Fondation M\u00e9rieux, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, 69365 Lyon, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0474-0615","authenticated-orcid":false,"given":"Chinmoy","family":"Saha","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center Rotterdam, 3015 CN Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad Saiful Islam","family":"Sajib","sequence":"additional","affiliation":[{"name":"Child Health Research Foundation, 23\/2 SEL Huq Skypark, Block-B, Khilji Rd, Dhaka 1207, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Senjuti","family":"Saha","sequence":"additional","affiliation":[{"name":"Child Health Research Foundation, 23\/2 SEL Huq Skypark, Block-B, Khilji Rd, Dhaka 1207, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florence","family":"Komurian-Pradel","sequence":"additional","affiliation":[{"name":"Laboratoire des Pathog\u00e8nes Emergents, Fondation M\u00e9rieux, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, 69365 Lyon, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8545-5108","authenticated-orcid":false,"given":"Alex","family":"van Belkum","sequence":"additional","affiliation":[{"name":"Data Analytics Unit, bioM\u00e9rieux, 3, Route de Port Michaud, 38390 La Balme Les Grottes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2537-4941","authenticated-orcid":false,"given":"Rogier","family":"Louwen","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center Rotterdam, 3015 CN Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samir Kumar","family":"Saha","sequence":"additional","affiliation":[{"name":"Child Health Research Foundation, 23\/2 SEL Huq Skypark, Block-B, Khilji Rd, Dhaka 1207, Bangladesh"},{"name":"Bangladesh Institute of Child Health, Dhaka Shishu Hospital, Dhaka 1207, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hubert P.","family":"Endtz","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center Rotterdam, 3015 CN Rotterdam, The Netherlands"},{"name":"Laboratoire des Pathog\u00e8nes Emergents, Fondation M\u00e9rieux, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, 69365 Lyon, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Britto, C.D., Wong, V.K., Dougan, G., and Pollard, A.J. (2018). A systematic review of antimicrobial resistance in Salmonella enterica serovar Typhi, the etiological agent of typhoid. PLoS Negl. Trop. Dis., 12.","DOI":"10.1371\/journal.pntd.0006779"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"483","DOI":"10.4056\/sigs.3286690","article-title":"The Genomic Blueprint of Salmonella enterica subspecies enterica serovar Typhi P-stx-12","volume":"7","author":"Ong","year":"2013","journal-title":"Stand. Genom. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/S1473-3099(18)30685-6","article-title":"The global burden of typhoid and paratyphoid fevers: A systematic analysis for the Global Burden of Disease Study 2017","volume":"19","author":"Stanaway","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1093\/cid\/ciy846","article-title":"Progress in typhoid fever epidemiology","volume":"68","author":"Crump","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Tanmoy, A.M., Westeel, E., De Bruyne, K., Goris, J., Rajoharison, A., Sajib, M.S.I., van Belkum, A., Saha, S.K., Komurian-Pradel, F., and Endtz, H.P. (2018). Salmonella enterica serovar Typhi in Bangladesh: Exploration of Genomic Diversity and Antimicrobial Resistance. mBio, 9.","DOI":"10.1128\/mBio.02112-18"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e00105","DOI":"10.1128\/mBio.00105-18","article-title":"Emergence of an Extensively Drug-Resistant Salmonella enterica Serovar Typhi Clone Harboring a Promiscuous Plasmid Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins","volume":"9","author":"Klemm","year":"2018","journal-title":"mBio"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lima, N.C.B., Tanmoy, A.M., Westeel, E., de Almeida, L.G.P., Rajoharison, A., Islam, M., Endtz, H.P., Saha, S.K., de Vasconcelos, A.T.R., and Komurian-Pradel, F. (2019). Analysis of isolates from Bangladesh highlights multiple ways to carry resistance genes in Salmonella Typhi. BMC Genom., 20.","DOI":"10.1186\/s12864-019-5916-6"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Hooda, Y., Sajib, M.S., Rahman, H., Luby, S.P., Bondy-Denomy, J., Santosham, M., Andrews, J.R., Saha, S.K., and Saha, S. (2019). Molecular mechanism of azithromycin resistance among typhoidal Salmonella strains in Bangladesh identified through passive pediatric surveillance. PLoS Negl. Trop. Dis., 13.","DOI":"10.1101\/594531"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1089\/mdr.2018.0109","article-title":"Azithromycin Resistance in Clinical Isolates of Salmonella enterica Serovars Typhi and Paratyphi in Bangladesh","volume":"25","author":"Ahsan","year":"2019","journal-title":"Microb. Drug Resist."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1146\/annurev-micro-090816-093830","article-title":"Evolutionary Genomics of Defense Systems in Archaea and Bacteria","volume":"71","author":"Koonin","year":"2017","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Fabre, L., Le Hello, S., Roux, C., Issenhuth-Jeanjean, S., and Weill, F.-X. (2014). CRISPR is an optimal target for the design of specific PCR assays for Salmonella enterica serotypes Typhi and Paratyphi A. PLoS Negl. Trop. Dis., 8.","DOI":"10.1371\/journal.pntd.0002671"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Fabre, L., Zhang, J., Guigon, G., Le Hello, S., Guibert, V., Accou-Demartin, M., De Romans, S., Lim, C., Roux, C., and Passet, V. (2012). CRISPR typing and subtyping for improved laboratory surveillance of Salmonella infections. PLoS ONE, 7.","DOI":"10.1371\/annotation\/e79cea9a-6716-4519-9e96-31b17bf6a4fb"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2396","DOI":"10.1128\/JB.01480-10","article-title":"The CRISPR\/Cas immune system is an operon regulated by LeuO, H-NS, and leucine-responsive regulatory protein in Salmonella enterica serovar Typhi","volume":"193","author":"Olvera","year":"2011","journal-title":"J. Bacteriol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1099\/mic.0.000414","article-title":"CRISPR-Cas system presents multiple transcriptional units including antisense RNAs that are expressed in minimal medium and upregulated by pH in Salmonella enterica serovar Typhi","volume":"163","author":"Olvera","year":"2017","journal-title":"Microbiology"},{"key":"ref_15","first-page":"D535","article-title":"CRISPRCasdb a successor of CRISPRdb containing CRISPR arrays and cas genes from complete genome sequences, and tools to download and query lists of repeats and spacers","volume":"48","author":"Pourcel","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20180087","DOI":"10.1098\/rstb.2018.0087","article-title":"Origins and evolution of CRISPR-Cas systems","volume":"374","author":"Koonin","year":"2019","journal-title":"Philos. Trans. R. Soc. B"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Makarova, K.S., Wolf, Y.I., and Koonin, E.V. (2013). The Basic Building Blocks and Evolution of CRISPR\u2013Cas Systems, Portland Press Limited.","DOI":"10.1042\/BST20130038"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1038\/nrmicro3569","article-title":"An updated evolutionary classification of CRISPR-Cas systems","volume":"13","author":"Makarova","year":"2015","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1128\/JB.01412-07","article-title":"Phage response to CRISPR-encoded resistance in Streptococcus thermophilus","volume":"190","author":"Deveau","year":"2008","journal-title":"J. Bacteriol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.molcel.2016.02.031","article-title":"Identifying and visualizing functional PAM diversity across CRISPR-Cas systems","volume":"62","author":"Leenay","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1099\/mic.0.000005","article-title":"Characterization and evolution of Salmonella CRISPR-Cas systems","volume":"161","author":"Shariat","year":"2015","journal-title":"Microbiology"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Touchon, M., and Rocha, E.P. (2010). The small, slow and specialized CRISPR and anti-CRISPR of Escherichia and Salmonella. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0011126"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1128\/MMBR.00039-13","article-title":"The Role of CRISPR-Cas Systems in Virulence of Pathogenic Bacteria","volume":"78","author":"Louwen","year":"2014","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11163","DOI":"10.1073\/pnas.1323025111","article-title":"A CRISPR-Cas system enhances envelope integrity mediating antibiotic resistance and inflammasome evasion","volume":"111","author":"Sampson","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e00227-10","DOI":"10.1128\/mBio.00227-10","article-title":"Multidrug-resistant enterococci lack CRISPR-cas","volume":"1","author":"Palmer","year":"2010","journal-title":"MBio"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e01796-15","DOI":"10.1128\/mBio.01796-15","article-title":"Phylogenetic distribution of CRISPR-Cas systems in antibiotic-resistant Pseudomonas aeruginosa","volume":"6","author":"Soriaga","year":"2015","journal-title":"mBio"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.ijantimicag.2017.02.026","article-title":"Correlation between phenotypic antibiotic susceptibility and the resistome in Pseudomonas aeruginosa","volume":"50","author":"Jaillard","year":"2017","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Britto, C.D., Dyson, Z.A., Duchene, S., Carter, M.J., Gurung, M., Kelly, D.F., Murdoch, D.R., Ansari, I., Thorson, S., and Shrestha, S. (2018). Laboratory and molecular surveillance of paediatric typhoidal Salmonella in Nepal: Antimicrobial resistance and implications for vaccine policy. PLoS Negl. Trop. Dis., 12.","DOI":"10.1101\/250142"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/ng.3281","article-title":"Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter-and intracontinental transmission events","volume":"47","author":"Wong","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms12827","article-title":"An extended genotyping framework for Salmonella enterica serovar Typhi, the cause of human typhoid","volume":"7","author":"Wong","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1089\/cmb.2012.0021","article-title":"SPAdes: A new genome assembly algorithm and its applications to single-cell sequencing","volume":"19","author":"Bankevich","year":"2012","journal-title":"J. Comput. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"W246","DOI":"10.1093\/nar\/gky425","article-title":"CRISPRCasFinder, an update of CRISRFinder, includes a portable version, enhanced performance and integrates search for Cas proteins","volume":"46","author":"Couvin","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1089\/crispr.2018.0033","article-title":"Classification and nomenclature of CRISPR-Cas systems: Where from here?","volume":"1","author":"Makarova","year":"2018","journal-title":"Cris. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1186\/1471-2105-10-421","article-title":"BLAST+: Architecture and applications","volume":"10","author":"Camacho","year":"2009","journal-title":"BMC Bioinform."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1093\/bioinformatics\/btu153","article-title":"Prokka: Rapid prokaryotic genome annotation","volume":"30","author":"Seemann","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2986","DOI":"10.1038\/s41596-019-0210-2","article-title":"SHERLOCK: Nucleic acid detection with CRISPR nucleases","volume":"14","author":"Kellner","year":"2019","journal-title":"Nat. Protoc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1126\/science.aar6245","article-title":"CRISPR-Cas12a target binding unleashes indiscriminate single-stranded DNase activity","volume":"360","author":"Chen","year":"2018","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"11","DOI":"10.15585\/mmwr.mm6801a3","article-title":"Emergence of extensively drug-resistant Salmonella Typhi infections among travelers to or from Pakistan\u2014United States, 2016\u20132018","volume":"68","author":"Medalla","year":"2019","journal-title":"Morb. Mortal. Wkly. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1099\/mic.0.036046-0","article-title":"Diversity of CRISPR loci in Escherichia coli","volume":"156","author":"Almendros","year":"2010","journal-title":"Microbiology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1080\/15476286.2015.1085150","article-title":"Polymorphism of CRISPR shows separated natural groupings of Shigella subtypes and evidence of horizontal transfer of CRISPR","volume":"12","author":"Yang","year":"2015","journal-title":"RNA Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s10096-012-1733-4","article-title":"A novel link between Campylobacter jejuni bacteriophage defence, virulence and Guillain\u2013Barr\u00e9 syndrome","volume":"32","author":"Louwen","year":"2013","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/nature09523","article-title":"The CRISPR\/Cas bacterial immune system cleaves bacteriophage and plasmid DNA","volume":"468","author":"Garneau","year":"2010","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/j.cell.2015.12.053","article-title":"Degradation of Phage Transcripts by CRISPR-Associated RNases Enables Type III CRISPR-Cas Immunity","volume":"164","author":"Jiang","year":"2016","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1126\/science.1165771","article-title":"CRISPR Interference Limits Horizontal Gene Transfer in Staphylococci by Targeting DNA","volume":"322","author":"Marraffini","year":"2008","journal-title":"Science"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1046\/j.1365-2958.2000.01838.x","article-title":"Biological significance of a family of regularly spaced repeats in the genomes of Archaea, Bacteria and mitochondria","volume":"36","author":"Mojica","year":"2000","journal-title":"Mol. Microbiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/nmicrobiol.2016.81","article-title":"Anti-cas spacers in orphan CRISPR4 arrays prevent uptake of active CRISPR\u2013Cas IF systems","volume":"1","author":"Almendros","year":"2016","journal-title":"Nat. Microbiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Newire, E., Aydin, A., Juma, S., Enne, V., and Roberts, A. (2019). Identification of a Type IV CRISPR-Cas system located exclusively on IncHI1B\/ IncFIB plasmids in Enterobacteriaceae. bioRxiv.","DOI":"10.1101\/536375"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"102","DOI":"10.3389\/fgene.2014.00102","article-title":"CARF and WYL domains: Ligand-binding regulators of prokaryotic defense systems","volume":"5","author":"Makarova","year":"2014","journal-title":"Front. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Makarova, K.S., and Koonin, E.V. (2015). Annotation and classification of CRISPR-Cas systems. CRISPR, Springer.","DOI":"10.1007\/978-1-4939-2687-9_4"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/nrmicro2577","article-title":"Evolution and classification of the CRISPR\u2013Cas systems","volume":"9","author":"Makarova","year":"2011","journal-title":"Nat. Rev. Microbiol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/11\/1365\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:33:50Z","timestamp":1760178830000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/11\/1365"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,18]]},"references-count":50,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["genes11111365"],"URL":"https:\/\/doi.org\/10.3390\/genes11111365","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,18]]}}}