{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:06:16Z","timestamp":1792033576496,"version":"4.4.0"},"reference-count":67,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2019,10,15]],"date-time":"2019-10-15T00:00:00Z","timestamp":1571097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"DOI":"10.3389\/fimmu.2019.02396","type":"journal-article","created":{"date-parts":[[2019,10,15]],"date-time":"2019-10-15T04:15:30Z","timestamp":1571112930000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["N-Glycolylneuraminic Acid (Neu5Gc) Null Large Animals by Targeting the CMP-Neu5Gc Hydroxylase (CMAH)"],"prefix":"10.3389","volume":"10","author":[{"given":"Andrea","family":"Perota","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Galli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2019,10,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1002\/cbic.201700077","article-title":"Biochemical, cellular, physiological, and pathological consequences of human loss of N-Glycolylneuraminic acid","volume":"18","author":"Okerblom","year":"2017","journal-title":"Chembiochem"},{"key":"B2","doi-asserted-by":"publisher","first-page":"11751","DOI":"10.1073\/pnas.95.20.11751","article-title":"A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence","volume":"95","author":"Chou","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"B3","doi-asserted-by":"publisher","first-page":"15866","DOI":"10.1074\/jbc.273.25.15866","article-title":"The molecular basis for the absence of N-glycolylneuraminic acid in humans","volume":"273","author":"Irie","year":"1998","journal-title":"J Biol Chem"},{"key":"B4","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1007\/s00251-014-0795-0","article-title":"Parallel evolution of a self-signal: humans and new world monkeys independently lost the cell surface sugar Neu5Gc","volume":"66","author":"Springer","year":"2014","journal-title":"Immunogenetics"},{"key":"B5","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1093\/gbe\/evx251","article-title":"Phylogenetic distribution of CMP-Neu5Ac hydroxylase (CMAH), the enzyme synthetizing the proinflammatory human xenoantigen Neu5Gc","volume":"10","author":"Peri","year":"2018","journal-title":"Genome Biol Evol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1002\/ajpa.23745","article-title":"Evolution in primates by \u201cCatastrophic-selection\u201d interplay between enveloped virus epidemics, mutated genes of enzymes synthesizing carbohydrate antigens, and natural anti-carbohydrate antibodies","volume":"168","author":"Galili","year":"2019","journal-title":"Am J Phys Anthropol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"4340","DOI":"10.1128\/MCB.00379-07","article-title":"N-glycolylneuraminic acid deficiency in mice: implications for human biology and evolution","volume":"27","author":"Hedlund","year":"2007","journal-title":"Mol Cell Biol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1038\/nbt.1651","article-title":"Implications of the presence of N-glycolylneuraminic acid in recombinant therapeutic glycoproteins","volume":"28","author":"Ghaderi","year":"2010","journal-title":"Nat Biotechnol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"17743","DOI":"10.1073\/pnas.1102302108","article-title":"Sexual selection by female immunity against paternal antigens can fix loss of function alleles","volume":"108","author":"Ghaderi","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"B10","doi-asserted-by":"publisher","first-page":"830315","DOI":"10.1155\/2015\/830315","article-title":"CMP-Neu5Ac hydroxylase null mice as a model for studying metabolic disorders caused by the evolutionary loss of Neu5Gc in humans","volume":"2015","author":"Kwon","year":"2015","journal-title":"Biomed Res Int"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1084\/jem.20100575","article-title":"Novel mechanism for the generation of human xeno-autoantibodies against the nonhuman sialic acid N-glycolylneuraminic acid","volume":"207","author":"Taylor","year":"2010","journal-title":"J Exp Med"},{"key":"B12","doi-asserted-by":"publisher","first-page":"3269","DOI":"10.4049\/jimmunol.0902857","article-title":"Immunological property of antibodies against N-glycolylneuraminic acid epitopes in cytidine monophospho-N-acetylneuraminic acid hydroxylase-deficient mice","volume":"184","author":"Tahara","year":"2010","journal-title":"J Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/j.jaci.2017.04.051","article-title":"Exposure to non-microbial N-glycolylneuraminic acid protects farmers' children against airway inflammation and colitis","volume":"141","author":"Frei","year":"2018","journal-title":"J Allergy Clin Immunol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1111\/xen.12142","article-title":"Potential deleterious role of anti-Neu5Gc antibodies in xenotransplantation","volume":"22","author":"Salama","year":"2015","journal-title":"Xenotransplantation"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.1016\/j.burns.2018.02.029","article-title":"Skin xenotransplantation: historical review and clinical potential","volume":"44","author":"Yamamoto","year":"2018","journal-title":"Burns"},{"key":"B16","doi-asserted-by":"publisher","first-page":"2907","DOI":"10.4049\/jimmunol.1301195","article-title":"Long-term IgG response to porcine Neu5Gc antigens without transmission of PERV in burn patients treated with porcine skin xenografts","volume":"191","author":"Scobie","year":"2013","journal-title":"J Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"4655","DOI":"10.1172\/JCI82267","article-title":"Rabbit antithymocyte globulin-induced serum sickness disease and human kidney graft survival","volume":"125","author":"Couvrat-Desvergnes","year":"2015","journal-title":"J Clin Invest"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2501","DOI":"10.1097\/TP.0000000000001686","article-title":"Anti-Gal and Anti-Neu5Gc responses in non-immunosuppressed patients after treatment with rabbit antithymocyte polyclonal IgGs","volume":"101","author":"Salama","year":"2017","journal-title":"Transplantation"},{"key":"B19","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1038\/nrg2842","article-title":"Genome editing with engineered zinc finger nucleases","volume":"11","author":"Urnov","year":"2010","journal-title":"Nat Rev Genet"},{"key":"B20","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1146\/annurev-biochem-060713-035418","article-title":"Genome engineering with targetable nucleases","volume":"83","author":"Carroll","year":"2014","journal-title":"Annu Rev Biochem"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1258096","DOI":"10.1126\/science.1258096","article-title":"Genome editing. The new frontier of genome engineering with CRISPR-Cas9","volume":"346","author":"Doudna","year":"2014","journal-title":"Science."},{"key":"B22","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1038\/nm.3793","article-title":"Therapeutic genome editing: prospects and challenges","volume":"21","author":"Cox","year":"2015","journal-title":"Nat Med"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e264","DOI":"10.1038\/mtna.2015.37","article-title":"Off-target effects in CRISPR\/Cas9-mediated genome engineering","volume":"4","author":"Zhang","year":"2015","journal-title":"Mol Ther Nucleic Acids"},{"key":"B24","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1186\/s13059-015-0823-x","article-title":"Resources for the design of CRISPR gene editing experiments","volume":"16","author":"Graham","year":"2015","journal-title":"Genome Biol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1093\/bioinformatics\/btu743","article-title":"CRISPRdirect: software for designing CRISPR\/Cas guide RNA with reduced off-target sites","volume":"31","author":"Naito","year":"2015","journal-title":"Bioinformatics"},{"key":"B26","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1038\/mt.2016.1","article-title":"Nuclease target site selection for maximizing on-target activity and minimizing off-target effects in genome editing","volume":"24","author":"Lee","year":"2016","journal-title":"Mol Ther"},{"key":"B27","doi-asserted-by":"publisher","first-page":"21645","DOI":"10.1038\/srep21645","article-title":"Mammalian interspecies substitution of immune modulatory alleles by genome editing","volume":"6","author":"Lillico","year":"2016","journal-title":"Sci Rep"},{"key":"B28","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1007\/s11248-016-9932-x","article-title":"Gene targeting, genome editing: from Dolly to editors","volume":"25","author":"Tan","year":"2016","journal-title":"Transgenic Res"},{"key":"B29","doi-asserted-by":"publisher","first-page":"13348","DOI":"10.1038\/srep13348","article-title":"Efficient CRISPR\/Cas9-mediated biallelic gene disruption and site-specific knockin after rapid selection of highly active sgRNAs in pigs","volume":"5","author":"Wang","year":"2015","journal-title":"Sci Rep"},{"key":"B30","doi-asserted-by":"publisher","first-page":"8256","DOI":"10.1038\/srep08256","article-title":"Efficient generation of gene-modified pigs via injection of zygote with Cas9\/sgRNA","volume":"5","author":"Wang","year":"2015","journal-title":"Sci Rep"},{"key":"B31","doi-asserted-by":"publisher","first-page":"12013","DOI":"10.1073\/pnas.1106422108","article-title":"Efficient generation of a biallelic knockout in pigs using zinc-finger nucleases","volume":"108","author":"Hauschild","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"B32","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/xen.12019","article-title":"Double knockout pigs deficient in N-glycolylneuraminic acid and galactose alpha-1,3-galactose reduce the humoral barrier to xenotransplantation","volume":"20","author":"Lutz","year":"2013","journal-title":"Xenotransplantation"},{"key":"B33","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1111\/xen.12161","article-title":"Evaluation of human and non-human primate antibody binding to pig cells lacking GGTA1\/CMAH\/beta4GalNT2 genes","volume":"22","author":"Estrada","year":"2015","journal-title":"Xenotransplantation"},{"key":"B34","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1111\/xen.12131","article-title":"Efficient generation of genetically distinct pigs in a single pregnancy using multiplexed single-guide RNA and carbohydrate selection","volume":"22","author":"Li","year":"2015","journal-title":"Xenotransplantation"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1126\/science.aan4187","article-title":"Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9","volume":"357","author":"Niu","year":"2017","journal-title":"Science"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1981","DOI":"10.1038\/srep01981","article-title":"Production of biallelic CMP-Neu5Ac hydroxylase knock-out pigs","volume":"3","author":"Kwon","year":"2013","journal-title":"Sci Rep"},{"key":"B37","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1111\/xen.12106","article-title":"Generation of CMAH-\/- piglets on GAL-\/- genetic background","volume":"20","author":"Conchon","year":"2013","journal-title":"Xenotransplantation."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1887","DOI":"10.1096\/fj.10-175281","article-title":"Pancreatic beta-cell failure in obese mice with human-like CMP-Neu5Ac hydroxylase deficiency","volume":"25","author":"Kavaler","year":"2011","journal-title":"FASEB J"},{"key":"B39","doi-asserted-by":"publisher","first-page":"987","DOI":"10.2337\/db16-1060","article-title":"Neu5Gc and alpha1-3 GAL xenoantigen knockout does not affect glycemia homeostasis and insulin secretion in pigs","volume":"66","author":"Salama","year":"2017","journal-title":"Diabetes"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e12524","DOI":"10.1111\/xen.12524","article-title":"Generation of cattle knockout for galactose-\u03b11,3-galactose and N-glycolylneuraminic acid antigens","volume":"26","author":"Perota","year":"2019","journal-title":"Xenotransplantation."},{"key":"B41","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.theriogenology.2006.09.011","article-title":"Comparative aspects of somatic cell nuclear transfer with conventional and zona-free method in cattle, horse, pig and sheep","volume":"67","author":"Lagutina","year":"2007","journal-title":"Theriogenology"},{"key":"B42","doi-asserted-by":"publisher","first-page":"2936","DOI":"10.1021\/acsnano.8b07241","article-title":"Biomimetic glyconanoparticle vaccine for cancer immunotherapy","volume":"13","author":"Reuven","year":"2019","journal-title":"ACS Nano"},{"key":"B43","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.actbio.2018.03.055","article-title":"Reducing immunoreactivity of porcine bioprosthetic heart valves by genetically-deleting three major glycan antigens, GGTA1\/beta4GalNT2\/CMAH","volume":"72","author":"Zhang","year":"2018","journal-title":"Acta Biomater"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12535","article-title":"Elicited and pre-existing anti-Neu5Gc antibodies differentially affect human endothelial cells transcriptome","author":"Le Berre","year":"2019","journal-title":"Xenotransplantation."},{"key":"B45","doi-asserted-by":"publisher","first-page":"e0156775","DOI":"10.1371\/journal.pone.0156775","article-title":"Anti-EBOV GP IgGs lacking alpha1-3-galactose and Neu5Gc prolong survival and decrease blood viral load in EBOV-infected guinea pigs","volume":"11","author":"Reynard","year":"2016","journal-title":"PLoS ONE"},{"key":"B46","doi-asserted-by":"publisher","first-page":"178","DOI":"10.3389\/fpubh.2016.00178","article-title":"An old solution for a new problem: antiserum against emerging infectious diseases","volume":"4","author":"Morais","year":"2016","journal-title":"Front Public Health"},{"key":"B47","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/nbt.1521","article-title":"Antigen-specific human polyclonal antibodies from hyperimmunized cattle","volume":"27","author":"Kuroiwa","year":"2009","journal-title":"Nat Biotechnol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"e78119","DOI":"10.1371\/journal.pone.0078119","article-title":"Physiological level production of antigen-specific human immunoglobulin in cloned transchromosomic cattle","volume":"8","author":"Sano","year":"2013","journal-title":"PLoS ONE"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e0130699","DOI":"10.1371\/journal.pone.0130699","article-title":"Species-specific chromosome engineering greatly improves fully human polyclonal antibody production profile in cattle","volume":"10","author":"Matsushita","year":"2015","journal-title":"PLoS ONE"},{"key":"B50","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1111\/xen.12044","article-title":"First quantification of \u03b1-Gal epitope in current glutaraldehyde-fixed heart valve bioprostheses","volume":"20","author":"Naso","year":"2013","journal-title":"Xenotransplantation."},{"key":"B51","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1111\/xen.12260","article-title":"Characterization of immunogenic Neu5Gc in bioprosthetic heart valves","volume":"23","author":"Reuven","year":"2016","journal-title":"Xenotransplantation"},{"key":"B52","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.ijsu.2015.07.009","article-title":"Xenograft bioprosthetic heart valves: Past, present and future","volume":"23","author":"Manji","year":"2015","journal-title":"Int J Surg"},{"key":"B53","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1016\/j.athoracsur.2019.01.054","article-title":"In search of the ideal valve: optimizing genetic modifications to prevent bioprosthetic degeneration","volume":"108","author":"Smood","year":"2019","journal-title":"Ann Thorac Surg"},{"key":"B54","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1016\/j.healun.2009.10.007","article-title":"Gal knockout pig pericardium: new source of material for heart valve bioprostheses","volume":"29","author":"Lila","year":"2010","journal-title":"J Heart Lung Transplant"},{"key":"B55","first-page":"124","article-title":"Anti alpha-gal immune response following porcine bioprosthesis implantation in children","volume":"19","author":"Park","year":"2010","journal-title":"J Heart Valve Dis"},{"key":"B56","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.jtcvs.2010.08.064","article-title":"Cardiac xenotransplantation technology provides materials for improved bioprosthetic heart valves","volume":"141","author":"Mcgregor","year":"2011","journal-title":"J Thorac Cardiovasc Surg"},{"key":"B57","first-page":"222","article-title":"Anti-\u03b1-Gal antibody response following xenogeneic heart valve implantation in adults","volume":"22","author":"Park","year":"2013","journal-title":"J Heart Valve Dis"},{"key":"B58","doi-asserted-by":"publisher","first-page":"112236","DOI":"10.18632\/oncotarget.23096","article-title":"Glycan microarray reveal induced IgGs repertoire shift against a dietary carbohydrate in response to rabbit anti-human thymocyte therapy","volume":"8","author":"Amon","year":"2017","journal-title":"Oncotarget"},{"key":"B59","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.clim.2017.05.006","article-title":"Decrease of blood anti-\u03b11,3 Galactose Abs levels in multiple sclerosis (MS) and clinically isolated syndrome (CIS) patients","volume":"180","author":"Le Berre","year":"2017","journal-title":"Clin Immunol"},{"key":"B60","doi-asserted-by":"publisher","first-page":"e0197464","DOI":"10.1371\/journal.pone.0197464","article-title":"Polyclonal human antibodies against glycans bearing red meat-derived non-human sialic acid N-glycolylneuraminic acid are stable, reproducible, complex and vary between individuals: total antibody levels are associated with colorectal cancer risk","volume":"13","author":"Samraj","year":"2018","journal-title":"PLoS ONE"},{"key":"B61","doi-asserted-by":"publisher","first-page":"e12424","DOI":"10.1111\/xen.12424","article-title":"Evolution of sialic acids: Implications in xenotransplant biology","volume":"25","author":"Paul","year":"2018","journal-title":"Xenotransplantation"},{"key":"B62","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/j.jaci.2014.12.1947","article-title":"The alpha-gal story: lessons learned from connecting the dots","volume":"135","author":"Steinke","year":"2015","journal-title":"J Allergy Clin Immunol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/s40629-016-0098-0","article-title":"The red meat allergy syndrome in Sweden","volume":"25","author":"Apostolovic","year":"2016","journal-title":"Allergo J Int"},{"key":"B64","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1126\/science.1068228","article-title":"Production of \u03b1-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning","volume":"295","author":"Lai","year":"2002","journal-title":"Science"},{"key":"B65","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1126\/science.1078942","article-title":"Production of alpha 1,3-galactosyltransferase-deficient pigs","volume":"299","author":"Phelps","year":"2003","journal-title":"Science"},{"key":"B66","doi-asserted-by":"publisher","first-page":"789","DOI":"10.3389\/fimmu.2019.00789","article-title":"Absence of Neu5Gc and presence of Anti-Neu5Gc antibodies in humans-an evolutionary perspective","volume":"10","author":"Altman","year":"2019","journal-title":"Front Immunol"},{"key":"B67","doi-asserted-by":"publisher","first-page":"5750","DOI":"10.1038\/ncomms6750","article-title":"Ferrets exclusively synthesize Neu5Ac and express naturally humanized influenza A virus receptors","volume":"5","author":"Ng","year":"2014","journal-title":"Nat Commun"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fimmu.2019.02396\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,10,15]],"date-time":"2019-10-15T04:15:31Z","timestamp":1571112931000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fimmu.2019.02396\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,15]]},"references-count":67,"alternative-id":["10.3389\/fimmu.2019.02396"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2019.02396","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,15]]},"article-number":"2396"}}