{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:57:39Z","timestamp":1787003859463,"version":"build-2736575974"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,8,26]],"date-time":"2016-08-26T00:00:00Z","timestamp":1472169600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,8,26]],"date-time":"2016-08-26T00:00:00Z","timestamp":1472169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Folate deficiency in fetal life is strongly associated with structural malformations and linked to intrauterine growth restriction. In addition, limited availability of methyl donors, such as folate, during pregnancy may result in abnormal gene methylation patterns and contribute to developmental programming. The fetus is dependent on placental transfer of folate, however the molecular mechanisms regulating placental folate transport are unknown. We used cultured primary human trophoblast cells to test the hypothesis that mechanistic target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) regulate folate transport by post-translational mechanisms. Silencing raptor (inhibits mTORC1) or rictor (inhibits mTORC2) markedly decreased basal folate uptake. Folate uptake stimulated by insulin + IGF-1 was mediated by mTORC2 but did not involve mTORC1. mTORC1 or mTORC2 silencing markedly decreased the plasma membrane expression of FR-\u03b1 and RFC transporter isoforms without affecting global protein expression. Inhibition of the ubiquitin ligase Nedd4-2 had no effect on folate transport. In conclusion, we report for the first time that mTORC1\/C2 are positive regulators of cellular folate uptake by modulating the cell surface abundance of specific transporter isoforms. We propose that regulation of placental folate transport by mTOR signaling provide a direct link between placental function, gene methylation and fetal programming.<\/jats:p>","DOI":"10.1038\/srep31705","type":"journal-article","created":{"date-parts":[[2016,8,26]],"date-time":"2016-08-26T05:51:53Z","timestamp":1472190713000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Mechanistic target of rapamycin (mTOR) regulates trophoblast folate uptake by modulating the cell surface expression of FR-\u03b1 and the RFC"],"prefix":"10.1038","volume":"6","author":[{"given":"Fredrick J.","family":"Rosario","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa L.","family":"Powell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Jansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,8,26]]},"reference":[{"key":"BFsrep31705_CR1","doi-asserted-by":"publisher","first-page":"295083","DOI":"10.1155\/2012\/295083","volume":"2012","author":"J Safi","year":"2012","unstructured":"Safi, J., Joyeux, L. & Chalouhi, G. E. Periconceptional folate deficiency and implications in neural tube defects. J Pregnancy 2012, 295083, doi: 10.1155\/2012\/295083 (2012).","journal-title":"J Pregnancy"},{"key":"BFsrep31705_CR2","doi-asserted-by":"publisher","first-page":"4760","DOI":"10.3390\/nu5114760","volume":"5","author":"AE Czeizel","year":"2013","unstructured":"Czeizel, A. E., Dudas, I., Vereczkey, A. & Banhidy, F. Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects. Nutrients 5, 4760\u20134775, doi: 10.3390\/nu5114760 (2013).","journal-title":"Nutrients"},{"key":"BFsrep31705_CR3","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/1475-2891-11-75","volume":"11","author":"K Fekete","year":"2012","unstructured":"Fekete, K. et al. Effect of folate intake on health outcomes in pregnancy: a systematic review and meta-analysis on birth weight, placental weight and length of gestation. Nutr J 11, 75, doi: 1475-2891-11-75 10.1186\/1475-2891-11-75 (2012).","journal-title":"Nutr J"},{"key":"BFsrep31705_CR4","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1002\/mnfr.201200084","volume":"57","author":"EM van Uitert","year":"2013","unstructured":"van Uitert, E. M. & Steegers-Theunissen, R. P. Influence of maternal folate status on human fetal growth parameters. Mol Nutr Food Res 57, 582\u2013595, doi: 10.1002\/mnfr.201200084 (2013).","journal-title":"Mol Nutr Food Res"},{"key":"BFsrep31705_CR5","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1111\/1471-0528.13202","volume":"122","author":"VA Hodgetts","year":"2015","unstructured":"Hodgetts, V. A., Morris, R. K., Francis, A., Gardosi, J. & Ismail, K. M. Effectiveness of folic acid supplementation in pregnancy on reducing the risk of small-for-gestational age neonates: a population study, systematic review and meta-analysis. BJOG 122, 478\u2013490, doi: 10.1111\/1471-0528.13202 (2015).","journal-title":"BJOG"},{"key":"BFsrep31705_CR6","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1056\/NEJMra0708473","volume":"359","author":"PD Gluckman","year":"2008","unstructured":"Gluckman, P. D., Hanson, M. A., Cooper, C. & Thornburg, K. L. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 359, 61\u201373 (2008).","journal-title":"N Engl J Med"},{"key":"BFsrep31705_CR7","doi-asserted-by":"publisher","first-page":"673S","DOI":"10.3945\/ajcn.2008.26811D","volume":"89","author":"SH Zeisel","year":"2009","unstructured":"Zeisel, S. H. Importance of methyl donors during reproduction. Am J Clin Nutr 89, 673S\u2013677S (2009).","journal-title":"Am J Clin Nutr"},{"key":"BFsrep31705_CR8","doi-asserted-by":"publisher","first-page":"e4","DOI":"10.1017\/S1462399409000969","volume":"11","author":"R Zhao","year":"2009","unstructured":"Zhao, R., Matherly, L. H. & Goldman, I. D. Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues. Expert Rev Mol Med 11, e4, doi: S1462399409000969 10.1017\/S1462399409000969 (2009).","journal-title":"Expert Rev Mol Med"},{"key":"BFsrep31705_CR9","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.placenta.2009.11.017","volume":"31","author":"N Solanky","year":"2010","unstructured":"Solanky, N., Requena Jimenez, A., D\u2019Souza, S. W., Sibley, C. P. & Glazier, J. D. Expression of folate transporters in human placenta and implications for homocysteine metabolism. Placenta 31, 134\u2013143, doi: 10.1016\/j.placenta.2009.11.017 (2010).","journal-title":"Placenta"},{"key":"BFsrep31705_CR10","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/S1534-5807(02)00145-4","volume":"2","author":"S Sabharanjak","year":"2002","unstructured":"Sabharanjak, S., Sharma, P., Parton, R. G. & Mayor, S. GPI-anchored proteins are delivered to recycling endosomes via a distinct cdc42-regulated, clathrin-independent pinocytic pathway. Dev Cell 2, 411\u2013423, doi: S1534580702001454 (2002).","journal-title":"Dev Cell"},{"key":"BFsrep31705_CR11","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1016\/j.bbamem.2008.03.009","volume":"1778","author":"ES Unal","year":"2008","unstructured":"Unal, E. S., Zhao, R., Qiu, A. & Goldman, I. D. N-linked glycosylation and its impact on the electrophoretic mobility and function of the human proton-coupled folate transporter (HsPCFT). Biochim Biophys Acta 1778, 1407\u20131414, doi: S0005-2736(08)00105-310.1016\/j.bbamem.2008.03.009 (2008).","journal-title":"Biochim Biophys Acta"},{"key":"BFsrep31705_CR12","doi-asserted-by":"publisher","first-page":"5299","DOI":"10.1167\/iovs.07-0288","volume":"48","author":"NS Umapathy","year":"2007","unstructured":"Umapathy, N. S. et al. Cloning and functional characterization of the proton-coupled electrogenic folate transporter and analysis of its expression in retinal cell types. Invest Ophthalmol Vis Sci 48, 5299\u20135305, doi: 48\/11\/5299 10.1167\/iovs.07-0288 (2007).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"BFsrep31705_CR13","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1016\/j.cell.2006.09.041","volume":"127","author":"A Qiu","year":"2006","unstructured":"Qiu, A. et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127, 917\u2013928, doi: 10.1016\/j.cell.2006.09.041 (2006).","journal-title":"Cell"},{"key":"BFsrep31705_CR14","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.1271\/bbb.80112","volume":"72","author":"S Yasuda","year":"2008","unstructured":"Yasuda, S. et al. Placental folate transport during pregnancy. Biosci Biotechnol Biochem 72, 2277\u20132284 (2008).","journal-title":"Biosci Biotechnol Biochem"},{"key":"BFsrep31705_CR15","unstructured":"Carter, M. F. et al. Fetal serum folate concentrations and placental folate transport in obese women. Am J Obstet Gynecol, doi: S0002-9378(11)00243-2 10.1016\/j.ajog.2011.02.053 (2011)."},{"key":"BFsrep31705_CR16","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1002\/glia.22266","volume":"60","author":"BR Bozard","year":"2012","unstructured":"Bozard, B. R. et al. Regulation of proton-coupled folate transporter in retinal Muller cells by the antipsoriatic drug monomethylfumarate. Glia 60, 333\u2013342, doi: 10.1002\/glia.22266 (2012).","journal-title":"Glia"},{"key":"BFsrep31705_CR17","unstructured":"Wani, N. A., Hamid, A., Khanduja, K. L. & Kaur, J. Folate malabsorption is associated with down-regulation of folate transporter expression and function at colon basolateral membrane in rats. Br J Nutr. 1\u20139, doi: S0007114511003710 10.1017\/S0007114511003710 (2011)."},{"key":"BFsrep31705_CR18","doi-asserted-by":"publisher","first-page":"G985","DOI":"10.1152\/ajpgi.00068.2010","volume":"298","author":"HM Said","year":"2010","unstructured":"Said, H. M., Mee, L., Sekar, V. T., Ashokkumar, B. & Pandol, S. J. Mechanism and regulation of folate uptake by pancreatic acinar cells: effect of chronic alcohol consumption. Am J Physiol Gastrointest Liver Physiol 298, G985\u2013G993, doi: ajpgi.00068.2010 10.1152\/ajpgi.00068.2010 (2010).","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"BFsrep31705_CR19","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1017\/S0007114510004538","volume":"105","author":"S Dev","year":"2011","unstructured":"Dev, S., Ahmad Wani, N. & Kaur, J. Regulatory mechanisms of intestinal folate uptake in a rat model of folate oversupplementation. Br J Nutr 105, 827\u2013835, doi: S0007114510004538 10.1017\/S0007114510004538 (2011).","journal-title":"Br J Nutr"},{"key":"BFsrep31705_CR20","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1093\/ajcn\/86.1.159","volume":"86","author":"B Ashokkumar","year":"2007","unstructured":"Ashokkumar, B., Mohammed, Z. M., Vaziri, N. D. & Said, H. M. Effect of folate oversupplementation on folate uptake by human intestinal and renal epithelial cells. Am J Clin Nutr 86, 159\u2013166, doi: 86\/1\/159 (2007).","journal-title":"Am J Clin Nutr"},{"key":"BFsrep31705_CR21","doi-asserted-by":"publisher","first-page":"33602","DOI":"10.1074\/jbc.M110.135640","volume":"285","author":"N Gonen","year":"2010","unstructured":"Gonen, N. & Assaraf, Y. G. The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1. J Biol Chem 285, 33602\u201333613, doi: M110.135640 10.1074\/jbc.M110.135640 (2010).","journal-title":"J Biol Chem"},{"key":"BFsrep31705_CR22","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1002\/jcp.1041110215","volume":"111","author":"Y Eilam","year":"1982","unstructured":"Eilam, Y., Ariel, M. & Grossowicz, N. Effect of insulin on folic-acid transport in cultured fibroblasts. J Cell Physiol 111, 218\u2013222, doi: 10.1002\/jcp.1041110215 (1982).","journal-title":"J Cell Physiol"},{"key":"BFsrep31705_CR23","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1124\/mol.109.055392","volume":"76","author":"JJ Eloranta","year":"2009","unstructured":"Eloranta, J. J. et al. Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter. Mol Pharmacol 76, 1062\u20131071, doi: mol.109.055392 10.1124\/mol.109.055392 (2009).","journal-title":"Mol Pharmacol"},{"key":"BFsrep31705_CR24","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/nrm3757","volume":"15","author":"M Shimobayashi","year":"2014","unstructured":"Shimobayashi, M. & Hall, M. N. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15, 155\u2013162, doi: 10.1038\/nrm3757 (2014).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"BFsrep31705_CR25","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1242\/jcs.125773","volume":"126","author":"M Laplante","year":"2013","unstructured":"Laplante, M. & Sabatini, D. M. Regulation of mTORC1 and its impact on gene expression at a glance. J Cell Sci 126, 1713\u20131719, doi: 10.1242\/jcs.125773 (2013).","journal-title":"J Cell Sci"},{"key":"BFsrep31705_CR26","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1038\/cr.2007.64","volume":"17","author":"Q Yang","year":"2007","unstructured":"Yang, Q. & Guan, K. L. Expanding mTOR signaling Cell Research 17, 666\u2013668 (2007).","journal-title":"Cell Research"},{"key":"BFsrep31705_CR27","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/j.cell.2009.03.046","volume":"137","author":"TR Peterson","year":"2009","unstructured":"Peterson, T. R. et al. DEPTOR is an mTOR inhibitor frquently overexpressed in multiple myeloma cells and required for their survival. Cell 137, 873\u2013886 (2009).","journal-title":"Cell"},{"key":"BFsrep31705_CR28","doi-asserted-by":"publisher","first-page":"C142","DOI":"10.1152\/ajpcell.00330.2008","volume":"296","author":"S Roos","year":"2009","unstructured":"Roos, S., Kanai, Y., Prasad, P. D., Powell, T. L. & Jansson, T. Regulation of placental amino acid transporter activity by mammalian target of rapamycin. Am J Physiol Cell 296, C142\u2013C150 (2009).","journal-title":"Am J Physiol Cell"},{"key":"BFsrep31705_CR29","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1113\/jphysiol.2012.238014","volume":"591","author":"FJ Rosario","year":"2013","unstructured":"Rosario, F. J., Kanai, Y., Powell, T. L. & Jansson, T. Mammalian target of rapamycin signalling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells. J Physiol 591, 609\u2013625, doi: jphysiol.2012.23801410.1113\/jphysiol.2012.238014 (2013).","journal-title":"J Physiol"},{"key":"BFsrep31705_CR30","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1210\/endo-118-4-1567","volume":"118","author":"HJ Kliman","year":"1986","unstructured":"Kliman, H. J., Nestler, J. E., Sermasi, E., Sanger, J. M. & Strauss, J. F. 3rd. Purification, characterization and in vitro differentiation of cytotrophoblasts from human term placentae. Endocrinology 118, 1567\u20131582, doi: 10.1210\/endo-118-4-1567 (1986).","journal-title":"Endocrinology"},{"key":"BFsrep31705_CR31","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.placenta.2008.10.003","volume":"30","author":"K Forbes","year":"2009","unstructured":"Forbes, K., Desforges, M., Garside, R., Aplin, J. D. & Westwood, M. Methods for siRNA-mediated reduction of mRNA and protein expression in human placental explants, isolated primary cells and cell lines. Placenta 30, 124\u2013129, doi: S0143-4004(08)00337-810.1016\/j.placenta.2008.10.003 (2009).","journal-title":"Placenta"},{"key":"BFsrep31705_CR32","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1016\/0002-9378(81)90731-6","volume":"140","author":"RL Phelps","year":"1981","unstructured":"Phelps, R. L., Metzger, B. E. & Freinkel, N. Carbohydrate metabolism in pregnancy. Am J Obstet Gynecol 140, 730 (1981).","journal-title":"Am J Obstet Gynecol"},{"key":"BFsrep31705_CR33","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1093\/ajcn\/87.6.1743","volume":"87","author":"N Jansson","year":"2008","unstructured":"Jansson, N. et al. Maternal hormones linking maternal bodymass index and dietary intake to birth weight. Am J Clin Nutr 87, 1743\u20131749 (2008).","journal-title":"Am J Clin Nutr"},{"key":"BFsrep31705_CR34","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.molcel.2006.03.029","volume":"22","author":"DD Sarbassov","year":"2006","unstructured":"Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt\/PKB. Mol Cell 22, 159\u2013168 (2006).","journal-title":"Mol Cell"},{"key":"BFsrep31705_CR35","doi-asserted-by":"crossref","unstructured":"Rosario, F. J., Dimasuay, K. G., Kanai, Y., Powell, T. L. & Jansson, T. Regulation of Amino Acid Transporter Trafficking by mTORC1 in Primary Human Trophoblast cells is Mediated by the Ubiquitin Ligase Nedd4-2. Clin Sci (Lond), doi: 10.1042\/CS20150554 (2015).","DOI":"10.1042\/CS20150554"},{"key":"BFsrep31705_CR36","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1146\/annurev-nutr-072610-145133","volume":"31","author":"R Zhao","year":"2011","unstructured":"Zhao, R., Diop-Bove, N., Visentin, M. & Goldman, I. D. Mechanisms of membrane transport of folates into cells and across epithelia. Annu Rev Nutr 31, 177\u2013201, doi: 10.1146\/annurev-nutr-072610-145133 (2011).","journal-title":"Annu Rev Nutr"},{"key":"BFsrep31705_CR37","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/nature11083","volume":"485","author":"CC Thoreen","year":"2012","unstructured":"Thoreen, C. C. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109\u2013113, doi: 10.1038\/nature11083 (2012).","journal-title":"Nature"},{"key":"BFsrep31705_CR38","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1016\/S0955-0674(97)80078-6","volume":"9","author":"G Thomas","year":"1997","unstructured":"Thomas, G. & Hall, M. N. TOR signalling and control of cell growth. Curr Opin Cell Biol 9, 782\u2013787 (1997).","journal-title":"Curr Opin Cell Biol"},{"key":"BFsrep31705_CR39","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1513\/pats.200909-096JS","volume":"7","author":"DC Eaton","year":"2010","unstructured":"Eaton, D. C., Malik, B., Bao, H. F., Yu, L. & Jain, L. Regulation of epithelial sodium channel trafficking by ubiquitination. Proc Am Thorac Soc 7, 54\u201364, doi: 10.1513\/pats.200909-096JS (2010).","journal-title":"Proc Am Thorac Soc"},{"key":"BFsrep31705_CR40","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1038\/nrm2672","volume":"10","author":"XM Ma","year":"2009","unstructured":"Ma, X. M. & Blenis, J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10, 307\u2013318 (2009).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"BFsrep31705_CR41","doi-asserted-by":"publisher","first-page":"5575","DOI":"10.1128\/MCB.22.15.5575-5584.2002","volume":"22","author":"T Peng","year":"2002","unstructured":"Peng, T., Golub, T. R. & Sabatini, D. M. The Immunosuppressant Rapamycin Mimics a Starvation-Like Signal Distinct from Amino Acid and Glucose Deprivation. Mol. Cell. Biol. 22, 5575\u20135584 (2002).","journal-title":"Mol. Cell. Biol."},{"key":"BFsrep31705_CR42","doi-asserted-by":"publisher","first-page":"2815","DOI":"10.1158\/0008-5472.CAN-10-4158","volume":"71","author":"JL Yecies","year":"2011","unstructured":"Yecies, J. L. & Manning, B. D. Transcriptional control of cellular metabolism by mTOR signaling. Cancer Res 71, 2815\u20132820, doi: 10.1158\/0008-5472.CAN-10-4158 (2011).","journal-title":"Cancer Res"},{"key":"BFsrep31705_CR43","doi-asserted-by":"publisher","first-page":"35922","DOI":"10.1074\/jbc.M606577200","volume":"47","author":"T Hatanaka","year":"2006","unstructured":"Hatanaka, T., Hatanaka, Y. & Setou, M. Regulation of amino acid transporter ATA2 by ubiquitin ligase Nedd4-2. J Biol Chem 47, 35922\u201335930 (2006).","journal-title":"J Biol Chem"},{"key":"BFsrep31705_CR44","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1113\/jphysiol.2007.129676","volume":"582","author":"S Roos","year":"2007","unstructured":"Roos, S. et al. Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth. J Physiol 582, 449\u2013459 (2007).","journal-title":"J Physiol"},{"key":"BFsrep31705_CR45","doi-asserted-by":"publisher","first-page":"311","DOI":"10.2353\/ajpath.2008.071193","volume":"173","author":"HW Yung","year":"2008","unstructured":"Yung, H. W. et al. Evidence of translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction. Am J Pathol 173, 311\u2013314 (2008).","journal-title":"Am J Pathol"},{"key":"BFsrep31705_CR46","doi-asserted-by":"crossref","unstructured":"Chen, Y. Y. et al. Increased ubiquitination and reduced plasma membrane trafficking of placental amino acid transporter SNAT-2 in human IUGR. Clin Sci (Lond), doi: 10.1042\/CS20150511 (2015).","DOI":"10.1042\/CS20150511"},{"key":"BFsrep31705_CR47","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1210\/en.2010-1153","volume":"152","author":"FJ Rosario","year":"2011","unstructured":"Rosario, F. J. et al. Maternal protein restriction in the rat inhibits placental insulin, mTOR and STAT3 signaling and down-regulates placental amino acid transporters. Endocrinology 152, 1119\u20131129, doi: 10.1210\/en.2010-1153 (2011).","journal-title":"Endocrinology"},{"key":"BFsrep31705_CR48","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1096\/fj.13-242271","volume":"28","author":"JV Kavitha","year":"2014","unstructured":"Kavitha, J. V. et al. Down-regulation of placental mTOR, insulin\/IGF-I signaling and nutrient transporters in response to maternal nutrient restriction in the baboon. FASEB J 28, 1294\u20131305, doi: 10.1096\/fj.13-242271 (2014).","journal-title":"FASEB J"},{"key":"BFsrep31705_CR49","doi-asserted-by":"crossref","unstructured":"Peker, E. et al. The levels of vitamin B12, folate and homocysteine in mothers and their babies with neural tube defects. J Matern Fetal Neonatal Med, 1\u201317, doi: 10.3109\/14767058.2015.1109620 (2015).","DOI":"10.3109\/14767058.2015.1109620"},{"key":"BFsrep31705_CR50","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1016\/S1701-2163(16)32685-8","volume":"29","author":"RD Wilson","year":"2007","unstructured":"Wilson, R. D. et al. Pre-conceptional vitamin\/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can 29, 1003\u20131026 (2007).","journal-title":"J Obstet Gynaecol Can"},{"key":"BFsrep31705_CR51","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1136\/bmj.303.6809.1019","volume":"303","author":"CN Hales","year":"1991","unstructured":"Hales, C. N. et al. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303, 1019\u20131022 (1991).","journal-title":"BMJ"},{"key":"BFsrep31705_CR52","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/pr.2013.2","volume":"73","author":"S Sookoian","year":"2013","unstructured":"Sookoian, S., Gianotti, T. F., Burgueno, A. L. & Pirola, C. J. Fetal metabolic programming and epigenetic modifications: a systems biology approach. Pediatr Res 73, 531\u2013542, doi: 10.1038\/pr.2013.2 (2013).","journal-title":"Pediatr Res"},{"key":"BFsrep31705_CR53","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s12861-015-0053-1","volume":"15","author":"C Sun","year":"2015","unstructured":"Sun, C. et al. Epigenetic regulation of histone modifications and Gata6 gene expression induced by maternal diet in mouse embryoid bodies in a model of developmental programming. BMC Dev Biol 15, 3, doi: 10.1186\/s12861-015-0053-1 (2015).","journal-title":"BMC Dev Biol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep31705","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep31705.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep31705.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T15:53:54Z","timestamp":1672847634000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep31705"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,26]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,10,17]]}},"alternative-id":["BFsrep31705"],"URL":"https:\/\/doi.org\/10.1038\/srep31705","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,26]]},"assertion":[{"value":"24 February 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 May 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 August 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"31705"}}