{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T01:31:38Z","timestamp":1789781498809,"version":"4.0.1"},"reference-count":66,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,2,3]],"date-time":"2018-02-03T00:00:00Z","timestamp":1517616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The discoveries made over the past few years have modified the current immunological paradigm. It turns out that innate immunity cells can mount some kind of immunological memory, similar to that observed in the acquired immunity and corresponding to the defense mechanisms of lower organisms, which increases their resistance to reinfection. This phenomenon is termed trained innate immunity. It is based on epigenetic changes in innate immune cells (monocytes\/macrophages, NK cells) after their stimulation with various infectious or non-infectious agents. Many infectious stimuli, including bacterial or fungal cells and their components (LPS, \u03b2-glucan, chitin) as well as viruses or even parasites are considered potent inducers of innate immune memory. Epigenetic cell reprogramming occurring at the heart of the phenomenon may provide a useful basis for designing novel prophylactic and therapeutic strategies to prevent and protect against multiple diseases. In this article, we present the current state of art on trained innate immunity occurring as a result of infectious agent induction. Additionally, we discuss the mechanisms of cell reprogramming and the implications for immune response stimulation\/manipulation.<\/jats:p>","DOI":"10.3390\/ijms19020456","type":"journal-article","created":{"date-parts":[[2018,2,5]],"date-time":"2018-02-05T04:29:42Z","timestamp":1517804982000},"page":"456","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":86,"title":["Infectious Agents as Stimuli of Trained Innate Immunity"],"prefix":"10.3390","volume":"19","author":[{"given":"Paulina","family":"Rusek","sequence":"first","affiliation":[{"name":"Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha St. 12\/16, 90-237 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3944-3760","authenticated-orcid":false,"given":"Mateusz","family":"Wala","sequence":"additional","affiliation":[{"name":"Department of Plant Physiology and Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Banacha St. 12\/16, 90-237 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Druszczy\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha St. 12\/16, 90-237 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Fol","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha St. 12\/16, 90-237 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nrmicro.2016.12","article-title":"Metabolic crosstalk between host and pathogen: Sensing, adapting and competing","volume":"14","author":"Olive","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_2","unstructured":"Abbas, K.A., Lichtman, A.H., and Pillai, S. (2015). Cellular and Molecular Immunology, Elsevier Saunders. [8th ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1002\/eji.201545497","article-title":"Innate immune memory: Implications for host responses to damage-associated molecular patterns","volume":"46","author":"Netea","year":"2016","journal-title":"Eur. J. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1126\/science.aaf1098","article-title":"Trained immunity: A program of innate immune memory in health and disease","volume":"352","author":"Netea","year":"2016","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7961","DOI":"10.1074\/jbc.M115.699645","article-title":"Fungal chitin induces trained immunity in human monocytes during cross-talk of the host with Saccharomyces cerevisiae","volume":"291","author":"Rizzetto","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1111\/eci.12132","article-title":"Training innate immunity: The changing concept of immunological memory in innate host defence","volume":"43","author":"Netea","year":"2013","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/icb.2014.101","article-title":"Beyond receptors and signaling: Epigenetic factors in the regulation of innate immunity","volume":"93","author":"Mehta","year":"2015","journal-title":"Immunol. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nrg3173","article-title":"Histone methylation: A dynamic mark in health, disease and inheritance","volume":"13","author":"Greer","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nrg3230","article-title":"Functions of DNA methylation: Islands, start sites, gene bodies and beyond","volume":"13","author":"Jones","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Saeed, S., Quintin, J., Kerstens, H.H., Rao, N.A., Aghajanirefah, A., Matarese, F., Cheng, S.C., Ratter, J., Berentsen, K., and van der Ent, M.A. (2014). Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science, 345.","DOI":"10.1126\/science.1251086"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"T\u00f6pfer, E., Boraschi, D., and Italian, P. Innate immune memory: The latest frontier of adjuvanticity. J. Immunol. Res., 2015.","DOI":"10.1155\/2015\/478408"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.chom.2012.06.006","article-title":"Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes","volume":"12","author":"Quintin","year":"2012","journal-title":"Cell Host Microbe"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.smim.2014.09.006","article-title":"BCG-induced protection: Effects on innate immune memory","volume":"26","author":"Netea","year":"2014","journal-title":"Semin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.molcel.2012.07.030","article-title":"A high-throughput chromatin immmunoprecipitation approach reveals principles of dynamic gene regulation in mammals","volume":"47","author":"Garber","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1038\/nature09589","article-title":"Suppression of inflammation by a synthetic histone mimic","volume":"468","author":"Nicodeme","year":"2010","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.cell.2012.12.018","article-title":"Latent enhancers activated by stimulation in differentiated cells","volume":"152","author":"Ostuni","year":"2013","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1101\/gad.232502","article-title":"Dynamic changes in histone H3 Lys 9 methylation occurring at tightly regulated inducible inflammatory genes","volume":"16","author":"Saccani","year":"2002","journal-title":"Genes Dev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1084\/jem.20112343","article-title":"Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response","volume":"209","author":"Fang","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bultman, S.J. (2017). Interplay between diet, gut microbiota, epigenetic events, and colorectal cancer. Mol. Nutr. Food Res., 61.","DOI":"10.1002\/mnfr.201500902"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"75","DOI":"10.4161\/epi.26488","article-title":"Clinical significance and the interaction between non-coding RNAs and the epigenetics machinery challenges and opportunities in oncology","volume":"9","author":"Maia","year":"2014","journal-title":"Epigenetics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s13148-015-0144-7","article-title":"Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases","volume":"7","author":"Paul","year":"2015","journal-title":"Clin. Epigenet."},{"key":"ref_22","first-page":"55","article-title":"Gut microbiota, epigenetic modification and colorectal cancer","volume":"9","author":"Rezasoltani","year":"2017","journal-title":"Iran. J. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/nature10434","article-title":"Peripheral education of the immune system by colonic commensal microbiota","volume":"478","author":"Lathrop","year":"2011","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1126\/science.1223490","article-title":"Interactions between the microbiota and the immune system","volume":"336","author":"Hooper","year":"2012","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.cell.2014.03.011","article-title":"Role of microbiota in immunity and inflammation","volume":"157","author":"Belkaid","year":"2014","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1165\/rcmb.2013-0341OC","article-title":"Training modifies innate immune responses in blood monocytes and in pulmonary alveolar macrophages","volume":"51","author":"Frellstedt","year":"2014","journal-title":"Am. J. Respir. Cell Mol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Neville, B.A., D\u2019Enfert, C., and Bougnoux, M.E. (2015). Candida albicans commensalism in the gastrointestinal tract. FEMS Yeast Res., 15.","DOI":"10.1093\/femsyr\/fov081"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"567","DOI":"10.2217\/fmb.16.1","article-title":"Adaptation of Candida albicans to commensalism in the gut","volume":"11","author":"Prieto","year":"2016","journal-title":"Future Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1111\/cei.12642","article-title":"Defective trained immunity in patients with STAT-1-dependent chronic mucocutaneaous candidiasis","volume":"181","author":"Ifrim","year":"2015","journal-title":"Clin. Exp. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Buro, L.J., Chipumuro, E., and Henriksen, M.A. (2010). Menin and RNF20 recruitment is associated with dynamic histone modifications that regulate signal transducer and activator of transcription 1 (STAT1)-activated transcription of the interferon regulatory factor 1 gene (IRF1). Epigenet. Chromatin, 3.","DOI":"10.1186\/1756-8935-3-16"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/icb.2017.13","article-title":"Evaluation of trained immunity by \u03b2-1, 3 (d)-glucan on murine monocytes in vitro and duration of response in vivo","volume":"95","author":"Williams","year":"2017","journal-title":"Immunol. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"S56","DOI":"10.1016\/j.jinf.2016.04.023","article-title":"Treatment options for chronic mucocutaneous candidiasis","volume":"72","author":"Netea","year":"2016","journal-title":"J. Infect."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2880","DOI":"10.1074\/jbc.M113.520577","article-title":"Crystal structure of the tetrameric fibrinogen-like recognition domain of fibrinogen C domain containing 1 (FIBCD1) protein","volume":"289","author":"Shrive","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1146\/annurev-biochem-060713-035600","article-title":"Biosynthesis and export of bacterial lipopolysaccharides","volume":"83","author":"Whitfield","year":"2014","journal-title":"Annu. Rev. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.smim.2016.03.001","article-title":"The cells that mediate innate immune memory and their functional significance in inflammatory and infectious diseases","volume":"28","author":"Gardiner","year":"2016","journal-title":"Semin. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1128\/iai.51.2.668-674.1986","article-title":"Evidence for macrophage-mediated protection against lethal Candida albicans infection","volume":"51","author":"Bistoni","year":"1986","journal-title":"Infect. Immun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1080\/02681218880000401","article-title":"Immunomodulation by a low-virulence, agerminative variant of Candida albicans. Further evidence for macrophage activation as one of the effector mechanisms of nonspecific anti-infectious protection","volume":"26","author":"Bistoni","year":"1988","journal-title":"J. Med. Vet. Mycol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1111\/j.1365-3083.1992.tb03132.x","article-title":"The role of BCG\/PPD-activated macrophages in resistance against systemic candidiasis in mice","volume":"36","author":"Poell","year":"1992","journal-title":"Scand. J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"17537","DOI":"10.1073\/pnas.1202870109","article-title":"Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes","volume":"109","author":"Kleinnijenhuis","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Quintin, J., Cheng, S.C., van der Meer, J.W.M., and Netea, M.G. (2014). Innate immune memory: Towards a better understanding of host defense mechanism. Curr. Opin. Immunol., 29.","DOI":"10.1016\/j.coi.2014.02.006"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1093\/trstmh\/tru168","article-title":"Trained immunity: Consequences for the heterologous effects of BCG vaccination","volume":"109","author":"Kleinnijenhuis","year":"2015","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/joim.12449","article-title":"Trained immunity: A new avenue for tuberculosis vaccine development","volume":"279","author":"Lerm","year":"2016","journal-title":"J. Intern. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.clim.2014.10.005","article-title":"BCG-induced trained immunity in NK cells: Role for non-specific protection to infection","volume":"155","author":"Kleinnijenhuis","year":"2014","journal-title":"Clin. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1189\/jlb.5RI0315-096R","article-title":"Trained innate immunity as underlaying mechanism for the long-term, nonspecific effects of vaccines","volume":"98","author":"Blok","year":"2015","journal-title":"J. Leukoc. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1128\/CVI.00349-16","article-title":"In-vitro experimental model of trained innate immunity in human primary monocytes","volume":"23","author":"Bekkering","year":"2016","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1159\/000355628","article-title":"Long-lasting effects of BCG vaccination on both heterologous Th1\/Th17 responses and innate trained immunity","volume":"6","author":"Kleinnijenhuis","year":"2014","journal-title":"J. Innate Immun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1126\/science.1190689","article-title":"Hemocyte differentiation mediates innate immune memory in Anopheles gambiae mosquitoes","volume":"329","author":"Rodrigues","year":"2010","journal-title":"Science"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"162","DOI":"10.4049\/jimmunol.179.1.162","article-title":"Plasmodium falciparum infection causes proinflammatory priming of human TLR responses","volume":"179","author":"McCall","year":"2007","journal-title":"J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1086\/314689","article-title":"Interferon-\u03b3 responses are associated with resistance to reinfection with Plasmodium falciparum in young African children","volume":"179","author":"Luty","year":"1999","journal-title":"J. Infect. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1086\/339408","article-title":"Absolute levels and ratios of proinflammatory and anti-inflammatory cytokine production in vitro predict clinical immunity to Plasmodium falciparum malaria","volume":"185","author":"Dodoo","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Hong, M., and Bertoletti, A. Tolerance and immunity to pathogens in early life: Insights from HBV infection. Semin. Immunopathol., 2017.","DOI":"10.1007\/s00281-017-0641-1"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Hong, M., Sandalova, E., Low, D., Gehring, A.J., Fieni, S., Amadei, B., Urbani, S., Chong, Y.-S., Guccione, E., and Bertoletti, A. (2014). Trained immunity in newborn infants of HBV-infected mothers. Nat. Commun., 6.","DOI":"10.1038\/ncomms7588"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1159\/000356035","article-title":"A prime time for trained immunity: Innate immune memory in newborns and infants","volume":"105","author":"Levy","year":"2014","journal-title":"Neonatology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/pr.2012.48","article-title":"Responsiveness of human monocytes to the commensal bacterium Staphylococcus epidermidis develops late in gestation","volume":"72","author":"Strunk","year":"2012","journal-title":"Pediatr. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e43897","DOI":"10.1371\/journal.pone.0043897","article-title":"A neonatal model of intravenous Staphylococcus epidermidis infection in mice <24 h old enables characterization of early innate immune responses","volume":"7","author":"Kronforst","year":"2012","journal-title":"PLoS ONE"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1136\/bmj.311.7003.481","article-title":"Non-specific beneficial effect of measles immunisation: Analysis of mortality studies from developing countries","volume":"311","author":"Aaby","year":"1995","journal-title":"Br. Med. J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1046\/j.1523-1747.2002.00643.x","article-title":"Inverse association between melanoma and previous vaccinations against tuberculosis and smallpox: Results of the FEBIM study","volume":"119","author":"Pfahlberg","year":"2002","journal-title":"J. Investig. Dermatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1586\/14760584.5.2.277","article-title":"Bacillus Calmette-Gu\u00e9rin vaccination and infant mortality","volume":"5","author":"Roth","year":"2006","journal-title":"Expert Rev. Vaccines"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1001\/jama.2014.470","article-title":"Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections","volume":"311","author":"Benn","year":"2014","journal-title":"JAMA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1093\/cid\/civ144","article-title":"Nonspecific (heterologous) protection of neonatal BCG vaccination against hospitalization due to respiratory infection and sepsis","volume":"60","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Aaby, P., Benn, C., Nielsen, J., Lisse, I.M., Rodrigues, A., and Ravn, H. (2012). Testing the hypothesis that diphtheria-tetanus-pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries. BMJ Open, 2.","DOI":"10.1136\/bmjopen-2011-000707"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.smim.2016.05.005","article-title":"Unravelling the nature of non-specific effects of vaccines\u2014A challenge for innate immunologists","volume":"28","author":"Jensen","year":"2016","journal-title":"Semin. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.3324\/haematol.2016.149252","article-title":"\u201cTrained immunity\u201d: Consequences for lymphoid malignancies","volume":"101","author":"Stevens","year":"2016","journal-title":"Haematologica"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1002\/eji.201343403","article-title":"Detection of a TLR2 agonist by hematopoietic stem and progenitor cells impacts the function of the macrophages they produce","volume":"43","author":"Ng","year":"2013","journal-title":"Eur. J. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1016\/j.immuni.2015.05.011","article-title":"Bone-marrow-resident NK cells prime monocytes for regulatory function during infection","volume":"42","author":"Askenase","year":"2015","journal-title":"Immunity"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e01817","DOI":"10.1128\/mBio.01817-14","article-title":"Bone marrow dendritic cells from mice with an altered microbiota provide interleukin 17A-dependent protection against Entamoeba histolytica colitis","volume":"5","author":"Burgess","year":"2014","journal-title":"MBio"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/2\/456\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:53:41Z","timestamp":1760194421000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/2\/456"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,3]]},"references-count":66,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2018,2]]}},"alternative-id":["ijms19020456"],"URL":"https:\/\/doi.org\/10.3390\/ijms19020456","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,2,3]]}}}