{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:47:11Z","timestamp":1790844431340,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T00:00:00Z","timestamp":1652400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Agence Nationale de la Recherche"},{"name":"R\u00e9gion Provence Alpes C\u00f4te d\u2019Azur and European funding"},{"name":"PRIMMI"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The increased exploitation of microbial sequencing methods has shed light on the high diversity of new microorganisms named Candidate Phyla Radiation (CPR). CPR are mainly detected via 16S rRNA\/metabarcoding analyses or metagenomics and are found to be abundant in all environments and present in different human microbiomes. These microbes, characterized by their symbiotic\/epiparasitic lifestyle with bacteria, are directly exposed to competition with other microorganisms sharing the same ecological niche. Recently, a rich repertoire of enzymes with antibiotic resistance activity has been found in CPR genomes by using an in silico adapted screening strategy. This reservoir has shown a high prevalence of putative beta-lactamase-encoding genes. We expressed and purified five putative beta-lactamase sequences having the essential domains and functional motifs from class A and class B beta-lactamase. Their enzymatic activities were tested against various beta-lactam substrates using liquid chromatography-mass spectrometry (LC-MS) and showed some beta-lactamase activity even in the presence of a beta-lactamase inhibitor. In addition, ribonuclease activity was demonstrated against RNA that was not inhibited by sulbactam and EDTA. None of these proteins could degrade single- and double-stranded-DNA. This study is the first to express and test putative CPR beta-lactamase protein sequences in vitro. Our findings highlight that the reduced genomes of CPR members harbor sequences encoding for beta-lactamases known to be multifunction hydrolase enzymes.<\/jats:p>","DOI":"10.3390\/ijms23105446","type":"journal-article","created":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T08:37:02Z","timestamp":1652431022000},"page":"5446","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["New Beta-lactamases in Candidate Phyla Radiation: Owning Pleiotropic Enzymes Is a Smart Paradigm for Microorganisms with a Reduced Genome"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2906-1512","authenticated-orcid":false,"given":"Mohamad","family":"Maatouk","sequence":"first","affiliation":[{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"},{"name":"Aix-Marseille Universit\u00e9, IRD, APHM, MEPHI, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5358-1089","authenticated-orcid":false,"given":"Ahmad","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"},{"name":"Aix-Marseille Universit\u00e9, IRD, APHM, MEPHI, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucile","family":"Pinault","sequence":"additional","affiliation":[{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"},{"name":"Aix-Marseille Universit\u00e9, IRD, APHM, MEPHI, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8365-2244","authenticated-orcid":false,"given":"Nicholas","family":"Armstrong","sequence":"additional","affiliation":[{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"},{"name":"Aix-Marseille Universit\u00e9, IRD, APHM, MEPHI, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Said","family":"Azza","sequence":"additional","affiliation":[{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"},{"name":"Aix-Marseille Universit\u00e9, IRD, APHM, MEPHI, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marc","family":"Rolain","sequence":"additional","affiliation":[{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"},{"name":"Aix-Marseille Universit\u00e9, IRD, APHM, MEPHI, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4052-344X","authenticated-orcid":false,"given":"Fadi","family":"Bittar","sequence":"additional","affiliation":[{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"},{"name":"Aix-Marseille Universit\u00e9, IRD, APHM, MEPHI, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Raoult","sequence":"additional","affiliation":[{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"},{"name":"Aix-Marseille Universit\u00e9, IRD, APHM, MEPHI, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/j.cell.2018.02.016","article-title":"Major New Microbial Groups Expand Diversity and Alter Our Understanding of the Tree of Life","volume":"172","author":"Castelle","year":"2018","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41564-017-0012-7","article-title":"Recovery of Nearly 8,000 Metagenome-Assembled Genomes Substantially Expands the Tree of Life","volume":"2","author":"Parks","year":"2017","journal-title":"Nat. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/nature14486","article-title":"Unusual Biology across a Group Comprising More than 15% of Domain Bacteria","volume":"523","author":"Brown","year":"2015","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16048","DOI":"10.1038\/nmicrobiol.2016.48","article-title":"A New View of the Tree of Life","volume":"1","author":"Hug","year":"2016","journal-title":"Nat. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6372","DOI":"10.1038\/ncomms7372","article-title":"Diverse Uncultivated Ultra-Small Bacterial Cells in Groundwater","volume":"6","author":"Luef","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4173","DOI":"10.1038\/s41467-019-12171-z","article-title":"The Distinction of CPR Bacteria from Other Bacteria Based on Protein Family Content","volume":"10","author":"Burstein","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e00414-20","DOI":"10.1128\/mSystems.00414-20","article-title":"Rich Repertoire of Quorum Sensing Protein Coding Sequences in CPR and DPANN Associated with Interspecies and Interkingdom Communication","volume":"5","author":"Bernard","year":"2020","journal-title":"mSystems"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ibrahim, A., Colson, P., Merhej, V., Zgheib, R., Maatouk, M., Naud, S., Bittar, F., and Raoult, D. (2021). Rhizomal Reclassification of Living Organisms. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115643"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1073\/pnas.1419038112","article-title":"Cultivation of a Human-Associated TM7 Phylotype Reveals a Reduced Genome and Epibiotic Parasitic Lifestyle","volume":"112","author":"He","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1814666","DOI":"10.1080\/20002297.2020.1814666","article-title":"Isolation and Cultivation of Candidate Phyla Radiation Saccharibacteria (TM7) Bacteria in Coculture with Bacterial Hosts","volume":"12","author":"Murugkar","year":"2020","journal-title":"J. Oral Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e01069-21","DOI":"10.1128\/spectrum.01069-21","article-title":"Adapted Protocol for Saccharibacteria Cocultivation: Two New Members Join the Club of Candidate Phyla Radiation","volume":"9","author":"Ibrahim","year":"2021","journal-title":"Microbiol. Spectr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1038\/s41587-019-0260-6","article-title":"Targeted Isolation and Cultivation of Uncultivated Bacteria by Reverse Genomics","volume":"37","author":"Cross","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ibrahim, A., Maatouk, M., Raoult, D., and Bittar, F. (2022). Reverse Genomics: Design of Universal Epitope Sets to Isolate All Saccharibacteria Members from the Human Oral Cavity. Microorganisms, 10.","DOI":"10.3390\/microorganisms10030602"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s40168-018-0499-z","article-title":"Stable Isotope Informed Genome-Resolved Metagenomics Reveals That Saccharibacteria Utilize Microbially-Processed Plant-Derived Carbon","volume":"6","author":"Starr","year":"2018","journal-title":"Microbiome"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/s41579-018-0076-2","article-title":"Biosynthetic Capacity, Metabolic Variety and Unusual Biology in the CPR and DPANN Radiations","volume":"16","author":"Castelle","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1128\/AEM.67.1.411-419.2001","article-title":"Investigation of Candidate Division TM7, a Recently Recognized Major Lineage of the Domain Bacteria with No Known Pure-Culture Representatives","volume":"67","author":"Hugenholtz","year":"2001","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s40168-017-0331-1","article-title":"Members of the Candidate Phyla Radiation Are Functionally Differentiated by Carbon- and Nitrogen-Cycling Capabilities","volume":"5","author":"Danczak","year":"2017","journal-title":"Microbiome"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41564-017-0047-9","article-title":"Predicted Microbial Secretomes and Their Target Substrates in Marine Sediment","volume":"3","author":"Orsi","year":"2018","journal-title":"Nat. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13219","DOI":"10.1038\/ncomms13219","article-title":"Thousands of Microbial Genomes Shed Light on Interconnected Biogeochemical Processes in an Aquifer System","volume":"7","author":"Anantharaman","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e00521-21","DOI":"10.1128\/mBio.00521-21","article-title":"Patterns of Gene Content and Co-Occurrence Constrain the Evolutionary Path toward Animal Association in Candidate Phyla Radiation Bacteria","volume":"12","author":"Jaffe","year":"2021","journal-title":"mBio"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5002","DOI":"10.1128\/JB.00542-10","article-title":"The Human Oral Microbiome","volume":"192","author":"Dewhirst","year":"2010","journal-title":"J. Bacteriol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1038\/ismej.2010.30","article-title":"Bacterial Diversity in the Oral Cavity of 10 Healthy Individuals","volume":"4","author":"Bik","year":"2010","journal-title":"ISME J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1056\/NEJMoa043802","article-title":"Molecular Identification of Bacteria Associated with Bacterial Vaginosis","volume":"353","author":"Fredricks","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1038\/nrmicro2537","article-title":"The Skin Microbiome","volume":"9","author":"Grice","year":"2011","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1099\/jmm.0.47719-0","article-title":"Intestinal TM7 Bacterial Phylogenies in Active Inflammatory Bowel Disease","volume":"57","author":"Kuehbacher","year":"2008","journal-title":"J. Med. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"105172","DOI":"10.1016\/j.micpath.2021.105172","article-title":"Exploring the Global Vaginal Microbiome and Its Impact on Human Health","volume":"160","author":"Fenollar","year":"2021","journal-title":"Microb. Pathog."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1128\/MMBR.00016-10","article-title":"Origins and Evolution of Antibiotic Resistance","volume":"74","author":"Davies","year":"2010","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_28","first-page":"170","article-title":"Antibiotic Resistance: A Survival Strategy","volume":"18","author":"Sheldon","year":"2005","journal-title":"Clin. Lab. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nature10388","article-title":"Antibiotic Resistance Is Ancient","volume":"477","author":"King","year":"2011","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/ng.2906","article-title":"Pathogens and Host Immunity in the Ancient Human Oral Cavity","volume":"46","author":"Warinner","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1111\/evo.12597","article-title":"A Generation-Time Effect on the Rate of Molecular Evolution in Bacteria","volume":"69","author":"Weller","year":"2015","journal-title":"Evolution"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"107939","DOI":"10.1016\/j.celrep.2020.107939","article-title":"Acquisition and Adaptation of Ultra-Small Parasitic Reduced Genome Bacteria to Mammalian Hosts","volume":"32","author":"McLean","year":"2020","journal-title":"Cell Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/ng.2536","article-title":"Sequencing Ancient Calcified Dental Plaque Shows Changes in Oral Microbiota with Dietary Shifts of the Neolithic and Industrial Revolutions","volume":"45","author":"Adler","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1111\/omi.12118","article-title":"Bacteria and Archaea Paleomicrobiology of the Dental Calculus: A Review","volume":"31","author":"Huynh","year":"2016","journal-title":"Mol. Oral Microbiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e0089821","DOI":"10.1128\/mSystems.00898-21","article-title":"Small and Equipped: The Rich Repertoire of Antibiotic Resistance Genes in Candidate Phyla Radiation Genomes","volume":"6","author":"Maatouk","year":"2021","journal-title":"mSystems"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"21685","DOI":"10.1038\/s41598-020-78658-8","article-title":"A Protein of the Metallo-Hydrolase\/Oxidoreductase Superfamily with Both Beta-Lactamase and Ribonuclease Activity Is Linked with Translation in Giant Viruses","volume":"10","author":"Colson","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3472","DOI":"10.1016\/j.jmb.2019.04.002","article-title":"\u03b2-Lactamases and \u03b2-Lactamase Inhibitors in the 21st Century","volume":"431","author":"Tooke","year":"2019","journal-title":"J. Mol. Biol."},{"key":"ref_38","first-page":"42","article-title":"Beta-Lactam antibiotics","volume":"21","author":"Gudiol","year":"2003","journal-title":"Enferm. Infecc. Microbiol. Clin."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s10156-013-0640-7","article-title":"The ABCD\u2019s of \u03b2-Lactamase Nomenclature","volume":"19","author":"Bush","year":"2013","journal-title":"J. Infect. Chemother."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"12173","DOI":"10.1038\/s41598-019-48723-y","article-title":"Human Metallo-\u03b2-Lactamase Enzymes Degrade Penicillin","volume":"9","author":"Diene","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.drup.2004.02.003","article-title":"Evolution of the Serine Beta-Lactamases: Past, Present and Future","volume":"7","author":"Hall","year":"2004","journal-title":"Drug Resist. Updat."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Diene, S.M., Pinault, L., Armstrong, N., Azza, S., Keshri, V., Khelaifia, S., Chabri\u00e8re, E., Caetano-Anolles, G., Rolain, J.-M., and Pontarotti, P. (2020). Dual RNase and \u03b2-Lactamase Activity of a Single Enzyme Encoded in Archaea. Life, 10.","DOI":"10.3390\/life10110280"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1089\/mdr.2021.0163","article-title":"The Role of Bacteriophages as Important Reservoirs of Extended-Spectrum Beta-Lactamase Genes in Azerbaijan Hospitals","volume":"28","author":"Mahdavi","year":"2022","journal-title":"Microb. Drug Resist."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1128\/MMBR.62.4.1079-1093.1998","article-title":"Multimodular Penicillin-Binding Proteins: An Enigmatic Family of Orthologs and Paralogs","volume":"62","author":"Goffin","year":"1998","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Kadnikov, V.V., Mardanov, A.V., Beletsky, A.V., Karnachuk, O.V., and Ravin, N.V. (2020). Complete Genome of a Member of a New Bacterial Lineage in the Microgenomates Group Reveals an Unusual Nucleotide Composition Disparity Between Two Strands of DNA and Limited Metabolic Potential. Microorganisms, 8.","DOI":"10.3390\/microorganisms8030320"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.bcp.2016.09.007","article-title":"Antibiotic Use and Microbiome Function","volume":"134","author":"Ferrer","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_47","unstructured":"(2022, March 22). Axenic Culture of a Candidate Division TM7 Bacterium from the Human Oral Cavity and Biofilm Interactions with Other Oral Bacteria. Available online: https:\/\/journals.asm.org\/doi\/epub\/10.1128\/AEM.01827-14."},{"key":"ref_48","unstructured":"(2021, March 01). MOTIF: Searching Protein Sequence Motifs. Available online: https:\/\/www.genome.jp\/tools\/motif\/."},{"key":"ref_49","unstructured":"(2021, March 02). PHYRE2 Protein Fold Recognition Server. Available online: http:\/\/www.sbg.bio.ic.ac.uk\/~phyre2\/html\/page.cgi?id=index."},{"key":"ref_50","unstructured":"(2021, March 02). The Phyre2 Web Portal for Protein Modeling, Prediction and Analysis|Nature Protocols. Available online: https:\/\/www.nature.com\/articles\/nprot.2015.053."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Aziz, R.K., Bartels, D., Best, A.A., DeJongh, M., Disz, T., Edwards, R.A., Formsma, K., Gerdes, S., Glass, E.M., and Kubal, M. (2008). The RAST Server: Rapid Annotations Using Subsystems Technology. BMC Genom., 9.","DOI":"10.1186\/1471-2164-9-75"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e01712-20","DOI":"10.1128\/AAC.01712-20","article-title":"FosM, a New Family of Fosfomycin Resistance Genes Identified in Bacterial Species Isolated from Human Microbiota","volume":"65","author":"Khabthani","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5693","DOI":"10.1128\/JB.00217-06","article-title":"Growth Phase-Dependent Expression of Drug Exporters in Escherichia Coli and Its Contribution to Drug Tolerance","volume":"188","author":"Kobayashi","year":"2006","journal-title":"J. Bacteriol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/s41589-018-0052-1","article-title":"Shared Strategies for \u03b2-Lactam Catabolism in the Soil Microbiome","volume":"14","author":"Crofts","year":"2018","journal-title":"Nat. Chem. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3109\/1040841X.2013.875982","article-title":"Antibiotrophs: The Complexity of Antibiotic-Subsisting and Antibiotic-Resistant Microorganisms","volume":"42","author":"Woappi","year":"2016","journal-title":"Crit. Rev. Microbiol."},{"key":"ref_56","first-page":"1550","article-title":"Study of the Aminoglycoside Subsistence Phenotype of Bacteria Residing in the Gut of Humans and Zoo Animals","volume":"6","author":"Zuidema","year":"2015","journal-title":"Front. Microbiol."},{"key":"ref_57","unstructured":"(2021, December 14). Isolation, Identification and Characterization of Human Intestinal Bacteria with the Ability to Utilize Chloramphenicol as the Sole Source of Carbon and Energy, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/22757630\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/10\/5446\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:10:16Z","timestamp":1760137816000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/10\/5446"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,13]]},"references-count":57,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23105446"],"URL":"https:\/\/doi.org\/10.3390\/ijms23105446","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,13]]}}}