{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T20:07:30Z","timestamp":1777493250947,"version":"3.51.4"},"reference-count":64,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T00:00:00Z","timestamp":1636934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Complex disease states, like bacterial chondronecrosis with osteomyelitis (BCO), not only result in physiological symptoms, such as lameness, but also a complex systemic reaction involving immune and growth factor responses. For the modern broiler (meat-type) chickens, BCO is an animal welfare, production, and economic concern involving bacterial infection, inflammation, and bone attrition with a poorly defined etiology. It is, therefore, critical to define the key inflammatory and bone-related factors involved in BCO. In this study, the local bone and systemic blood profile of inflammatory modulators, cytokines, and chemokines was elucidated along with inflammasome and key FGF genes. BCO-affected bone showed increased expression of cytokines IL-1\u03b2, while BCO-affected blood expressed upregulated TNF\u03b1 and IL-12. The chemokine profile revealed increased IL-8 expression in both BCO-affected bone and blood in addition to inflammasome NLRC5 being upregulated in circulation. The key FGF receptor, FGFR1, was significantly downregulated in BCO-affected bone. The exposure of two different bone cell types, hFOB and chicken primary chondrocytes, to plasma from BCO-affected birds, as well as recombinant TNF\u03b1, resulted in significantly decreased cell viability. These results demonstrate an expression of proinflammatory and bone-resorptive factors and their potential contribution to BCO etiology through their impact on bone cell viability. This unique profile could be used for improved non-invasive detection of BCO and provides potential targets for treatments.<\/jats:p>","DOI":"10.3390\/cells10113174","type":"journal-article","created":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T08:19:20Z","timestamp":1636964360000},"page":"3174","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Local and Systemic Cytokine, Chemokine, and FGF Profile in Bacterial Chondronecrosis with Osteomyelitis (BCO)-Affected Broilers"],"prefix":"10.3390","volume":"10","author":[{"given":"Alison","family":"Ramser","sequence":"first","affiliation":[{"name":"Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA"},{"name":"Department of Poultry Science, Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR 72701, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Greene","sequence":"additional","affiliation":[{"name":"Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Wideman","sequence":"additional","affiliation":[{"name":"Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sami","family":"Dridi","sequence":"additional","affiliation":[{"name":"Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA"},{"name":"Department of Poultry Science, Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR 72701, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"325","DOI":"10.3382\/ps\/pev320","article-title":"Bacterial chondronecrosis with osteomyelitis and lameness in broilers: A review","volume":"95","author":"Wideman","year":"2016","journal-title":"Poult. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1080\/03079450050118386","article-title":"Bacterial chondronecrosis with osteomyelitis (\u2019femoral head necrosis\u2019) of broiler chickens: A review","volume":"29","author":"McNamee","year":"2000","journal-title":"Avian Pathol."},{"key":"ref_3","first-page":"183","article-title":"Bone circulatory disturbances in the development of spontaneous bacterial chondronecrosis with osteomyelitis: A translational model for the pathogenesis of femoral head necrosis","volume":"3","author":"Wideman","year":"2013","journal-title":"Front. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nri2094","article-title":"Cytokines in the pathogenesis of rheumatoid arthritis","volume":"7","author":"McInnes","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Rim, Y.A., Nam, Y., and Ju, J.H. (2020). The Role of Chondrocyte Hypertrophy and Senescence in Osteoarthritis Initiation and Progression. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072358"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2414","DOI":"10.1016\/j.bbagen.2014.02.030","article-title":"Cartilage tissue engineering: Molecular control of chondrocyte differentiation for proper cartilage matrix reconstruction","volume":"1840","author":"Demoor","year":"2014","journal-title":"Biochim. Biophys. Acta (BBA) Gen. Subj."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1902\/jop.1992.63.9.736","article-title":"Inhibition of Bone DNA and Collagen Production by Surface-Associated Material From Bacteria Implicated in the Pathology of Periodontal Disease","volume":"63","author":"Meghji","year":"1992","journal-title":"J. Periodontol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"728619","DOI":"10.1155\/2014\/728619","article-title":"The Macrophage Inflammatory Proteins MIP1\u03b1(CCL3) and MIP2\u03b1(CXCL2) in Implant-Associated Osteomyelitis: Linking Inflammation to Bone Degradation","volume":"2014","author":"Dapunt","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.4049\/jimmunol.145.10.3297","article-title":"IL-6 is produced by osteoblasts and induces bone resorption","volume":"145","author":"Ishimi","year":"1990","journal-title":"J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1016\/j.ajpath.2019.06.013","article-title":"Double-Stranded RNA Is a Novel Molecular Target in Osteomyelitis Pathogenesis","volume":"189","author":"Greene","year":"2019","journal-title":"Am. J. Pathol."},{"key":"ref_11","first-page":"421746","article-title":"Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells","volume":"2015","author":"Sasso","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"555","DOI":"10.3109\/08820139.2013.822766","article-title":"The role of cytokines in inflammatory bone loss","volume":"42","author":"Lerner","year":"2013","journal-title":"Immunol. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s41232-017-0043-8","article-title":"Role of fibroblast growth factors in bone regeneration","volume":"37","author":"Charoenlarp","year":"2017","journal-title":"Inflamm. Regen."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5568","DOI":"10.1210\/en.2005-0762","article-title":"Thyroid Hormones Regulate Fibroblast Growth Factor Receptor Signaling during Chondrogenesis","volume":"146","author":"Barnard","year":"2005","journal-title":"Endocrinology"},{"key":"ref_15","first-page":"101107","article-title":"Skeletal FGFR1 signaling is necessary for regulation of serum phosphate level by FGF23 and normal life span","volume":"27","author":"Takashi","year":"2021","journal-title":"Biochem. Biophys. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"870","DOI":"10.3382\/ps.2011-01907","article-title":"A wire-flooring model for inducing lameness in broilers: Evaluation of probiotics as a prophylactic treatment","volume":"91","author":"Wideman","year":"2012","journal-title":"Poult. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13781","DOI":"10.1073\/pnas.1206494109","article-title":"ERK1\/2 activation is a therapeutic target in age-related macular degeneration","volume":"109","author":"Dridi","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Carter, L.E., Kilroy, G., Gimble, J.M., and Floyd, Z.E. (2012). An improved method for isolation of RNA from bone. BMC Biotechnol., 12.","DOI":"10.1186\/1472-6750-12-5"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"640968","DOI":"10.3389\/fvets.2021.640968","article-title":"Spirulina platensis Inclusion Reverses Circulating Pro-inflammatory (Chemo)cytokine Profiles in Broilers Fed Low-Protein Diets","volume":"8","author":"Mullenix","year":"2021","journal-title":"Front. Vet. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100801","DOI":"10.1016\/j.psj.2020.10.055","article-title":"Research Note: Phytobiotics modulate the expression profile of circulating inflammasome and cyto(chemo)kine in whole blood of broilers exposed to cyclic heat stress","volume":"100","author":"Greene","year":"2021","journal-title":"Poult. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative CT method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1177\/1091581815584918","article-title":"Cytokines","volume":"34","author":"Ramani","year":"2015","journal-title":"Int. J. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.1016\/j.bbamcr.2014.05.014","article-title":"Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease","volume":"1843","author":"Turner","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1097\/AIA.0b013e318034194e","article-title":"Cytokines, Inflammation, and Pain","volume":"45","author":"Zhang","year":"2007","journal-title":"Int. Anesthesiol. Clin."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1359\/JBMR.040805","article-title":"Interleukin-1\u03b2 and TNF-\u03b1 Act in Synergy to Inhibit Longitudinal Growth in Fetal Rat Metatarsal Bones","volume":"19","author":"Chrysis","year":"2004","journal-title":"J. Bone Miner. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1677\/joe.1.06958","article-title":"Ceramide inhibition of chondrocyte proliferation and bone growth is IGF-I independent","volume":"191","author":"MacRae","year":"2006","journal-title":"J. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Yu, Y., Wang, S., and Zhou, Z. (2020). Cartilage Homeostasis Affects Femoral Head Necrosis Induced by Methylprednisolone in Broilers. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21144841"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/S0092-8674(01)00237-9","article-title":"The TNF and TNF Receptor Superfamilies: Integrating Mammalian Biology","volume":"104","author":"Locksley","year":"2001","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/BF02918612","article-title":"Tumor necrosis factor receptors--structure and function","volume":"11","author":"Rothe","year":"1992","journal-title":"Immunol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/0092-8674(94)90372-7","article-title":"The TNF receptor superfamily of cellular and viral proteins: Activation, costimulation, and death","volume":"76","author":"Smith","year":"1994","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4818","DOI":"10.1210\/endo.142.11.8511","article-title":"Effect of IL-6 on IGF binding protein-3: A study in IL-6 transgenic mice and in patients with systemic juvenile idiopathic arthritis","volume":"142","author":"Meazza","year":"2001","journal-title":"Endocrinology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1128\/iai.64.7.2371-2380.1996","article-title":"Bacterially induced bone destruction: Mechanisms and misconceptions","volume":"64","author":"Nair","year":"1996","journal-title":"Infect. Immun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1186\/s12864-019-6411-9","article-title":"Proximal femoral head transcriptome reveals novel candidate genes related to epiphysiolysis in broiler chickens","volume":"20","author":"Peixoto","year":"2019","journal-title":"BMC Genom."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e358","DOI":"10.1038\/emm.2017.100","article-title":"Stimulation of osteoclast migration and bone resorption by C-C chemokine ligands 19 and 21","volume":"49","author":"Lee","year":"2017","journal-title":"Exp. Mol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"988","DOI":"10.3389\/fimmu.2019.00988","article-title":"The IL-12 Cytokine and Receptor Family in Graft-vs.-Host Disease","volume":"10","author":"Bastian","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"a028548","DOI":"10.1101\/cshperspect.a028548","article-title":"Targeting IL-10 Family Cytokines for the Treatment of Human Diseases","volume":"11","author":"Wang","year":"2019","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/s41575-018-0084-8","article-title":"IL-12, IL-23 and IL-17 in IBD: Immunobiology and therapeutic targeting","volume":"16","author":"Moschen","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"154892","DOI":"10.1016\/j.cyto.2019.154892","article-title":"A systematic review on the functional role of Th1\/Th2 cytokines in type 2 diabetes and related metabolic complications","volume":"126","author":"Mahlangu","year":"2020","journal-title":"Cytokine"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1080\/08830185.2019.1632842","article-title":"Synergy between Th1 and Th2 responses during Mycobacterium tuberculosis infection: A review of current understanding: The paper discusses the importance of simultaneous induction of Th1\/Th2 responses to design and develop vaccine against TB","volume":"38","author":"Abebe","year":"2019","journal-title":"Int. Rev. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S0167-5699(97)80019-9","article-title":"The Th1\/Th2 paradigm","volume":"18","author":"Romagnani","year":"1997","journal-title":"Immunol. Today"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.3389\/fimmu.2019.02182","article-title":"Chemokines in Physiological and Pathological Bone Remodeling","volume":"10","author":"Brylka","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/cmi.2017.134","article-title":"Chemokines in homeostasis and diseases","volume":"15","author":"Chen","year":"2018","journal-title":"Cell Mol. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3582","DOI":"10.1002\/jcb.23289","article-title":"Physical and functional interactions between Runx2 and HIF-1\u03b1 induce vascular endothelial growth factor gene expression","volume":"112","author":"Kwon","year":"2011","journal-title":"J. Cell Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1136\/ard.61.8.730","article-title":"Addition of interleukin 1 (IL1) and IL17 soluble receptors to a tumour necrosis factor \u03b1 soluble receptor more effectively reduces the production of IL6 and macrophage inhibitory protein-3\u03b1 and increases that of collagen in an in vitro model of rheumatoid synoviocyte activation","volume":"61","author":"Chevrel","year":"2002","journal-title":"Ann. Rheum. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1046\/j.1365-2249.2001.01542.x","article-title":"Selective recruitment of CCR6-expressing cells by increased production of MIP-3\u03b1 in rheumatoid arthritis","volume":"125","author":"Matsui","year":"2001","journal-title":"Clin. Exp. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1002\/jcp.20905","article-title":"CCL20 chemokine induces both osteoblast proliferation and osteoclast differentiation: Increased levels of CCL20 are expressed in subchondral bone tissue of rheumatoid arthritis patients","volume":"210","author":"Lisignoli","year":"2007","journal-title":"J. Cell. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3892\/ijo.2015.3234","article-title":"IL-8, a novel messenger to cross-link inflammation and tumor EMT via autocrine and paracrine pathways (Review)","volume":"48","author":"Long","year":"2016","journal-title":"Int. J. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Kaiser, P., and St\u00e4heli, P. (2014). Chapter 10-Avian Cytokines and Chemokines, Elsevier Ltd.. [2nd ed.].","DOI":"10.1016\/B978-0-12-396965-1.00010-8"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"16408","DOI":"10.1074\/jbc.M800998200","article-title":"Re-evaluation of Chicken CXCR1 Determines the True Gene Structure","volume":"283","author":"Poh","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"8508","DOI":"10.1074\/jbc.M208231200","article-title":"Angiogenic Effects of Interleukin 8 (CXCL8) in Human Intestinal Microvascular Endothelial Cells Are Mediated by CXCR2","volume":"278","author":"Heidemann","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4353","DOI":"10.1210\/endo.139.10.6247","article-title":"Human osteoclasts and osteoclast-like cells synthesize and release high basal and inflammatory stimulated levels of the potent chemokine interleukin-8","volume":"139","author":"Rothe","year":"1998","journal-title":"Endocrinology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/BF00310163","article-title":"Dexamethasone regulates IL-1 beta and TNF-alpha-induced interleukin-8 production in human bone marrow stromal and osteoblast-like cells","volume":"55","author":"Chaudhary","year":"1994","journal-title":"Calcif. Tissue Int."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Pathak, J.L., Bakker, A.D., Verschueren, P., Lems, W.F., Luyten, F.P., Klein-Nulend, J., and Bravenboer, N. (2015). CXCL8 and CCL20 enhance osteoclastogenesis via modulation of cytokine production by human primary osteoblasts. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0131041"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.bone.2014.01.015","article-title":"Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans","volume":"61","author":"Kamalakar","year":"2014","journal-title":"Bone"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.4049\/jimmunol.0903900","article-title":"NLRC5 Limits the Activation of Inflammatory Pathways","volume":"185","author":"Benko","year":"2010","journal-title":"J. Immunol."},{"key":"ref_56","first-page":"1","article-title":"Inflammasomes as therapeutic targets in human diseases","volume":"6","author":"Li","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41413-019-0046-y","article-title":"Collagen type II suppresses articular chondrocyte hypertrophy and osteoarthritis progression by promoting integrin \u03b21\u2212SMAD1 interaction","volume":"7","author":"Lian","year":"2019","journal-title":"Bone Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.3389\/fphar.2019.01352","article-title":"Emerging Roles for NLRC5 in Immune Diseases","volume":"10","author":"Wang","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/nature02168","article-title":"The International HapMap Project","volume":"426","author":"Gibbs","year":"2003","journal-title":"Nature"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Chicharro-Alc\u00e1ntara, D., Rubio-Zaragoza, M., Dami\u00e1-Gim\u00e9nez, E., Carrillo-Poveda, J.M., Cuervo-Serrato, B., Pel\u00e1ez-Gorrea, P., and Sopena-Juncosa, J.J. (2018). Platelet Rich Plasma: New Insights for Cutaneous Wound Healing Management. J. Funct. Biomater., 9.","DOI":"10.3390\/jfb9010010"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1517\/14712598.2016.1118458","article-title":"Platelet-rich plasma for bone healing and regeneration","volume":"16","author":"Oryan","year":"2016","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.cytogfr.2005.03.001","article-title":"Bad bones, absent smell, selfish testes: The pleiotropic consequences of human FGF receptor mutations","volume":"16","author":"Wilkie","year":"2005","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1074\/jbc.M116.763342","article-title":"Raf Kinases Are Essential for Phosphate Induction of ERK1\/2 Phosphorylation in Hypertrophic Chondrocytes and Normal Endochondral Bone Development","volume":"292","author":"Papaioannou","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e10","DOI":"10.1161\/01.RES.87.7.e10","article-title":"Phosphate Regulation of Vascular Smooth Muscle Cell Calcification","volume":"87","author":"Jono","year":"2000","journal-title":"Circ. Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/3174\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:30:20Z","timestamp":1760167820000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/3174"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,15]]},"references-count":64,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["cells10113174"],"URL":"https:\/\/doi.org\/10.3390\/cells10113174","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,15]]}}}