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PIAS1
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<h2 id="function">Function</h2> <p>This gene encodes a member of the mammalian PIAS [protein inhibitor of activated STAT-1 (signal transducer and activator of transcription-1)] family. This member contains a putative zinc-binding motif and a highly acidic region. It inhibits STAT1-mediated gene activation and the DNA binding activity, binds to Gu protein/RNA helicase II/DEAD box polypeptide 21, and interacts with androgen receptor (AR). It functions in testis as a nuclear receptor transcriptional coregulator and may have a role in AR initiation and maintenance of spermatogenesis.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> </p> <h2 id="interactions">Interactions</h2> <p>PIAS1 has been shown to <a href="/facts/Protein-protein_interaction/etvm9Wmg">interact</a> with: </p> <ul><li><a href="/facts/DNMT3A/1gWkklau">DNMT3A</a>,<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a></li> <li><a href="/facts/P53/YEGULLgM">P53</a>,<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a></li> <li><a href="/facts/STAT1/QeeXWjBl">STAT1</a>,<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a></li> <li><a href="/facts/Small_ubiquitin-related_modifier_1/hgwLQYE8">Small ubiquitin-related modifier 1</a>,<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a><a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a></li> <li><a href="/facts/Sp3_transcription_factor/a3Hk98Ea">Sp3 transcription factor</a>,<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> and</li> <li><a href="/facts/UBE2I/tJYXLkrl">UBE2I</a>.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a><a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a></li></ul> <h2 id="further-reading">Further reading</h2> <ul><li>Tan J, Hall SH, Hamil KG, Grossman G, Petrusz P, Liao J, Shuai K, French FS (2000). <a href="https://doi.org/10.1210%2Fmend.14.1.0408">"Protein inhibitor of activated STAT-1 (signal transducer and activator of transcription-1) is a nuclear receptor coregulator expressed in human testis"</a>. <i>Mol. Endocrinol</i>. 14 (1): 14–26. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1210%2Fmend.14.1.0408">10.1210/mend.14.1.0408</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10628744">10628744</a>.</li> <li>Liao J, Fu Y, Shuai K (2000). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC25817">"Distinct roles of the NH2- and COOH-terminal domains of the protein inhibitor of activated signal transducer and activator of transcription (STAT) 1 (PIAS1) in cytokine-induced PIAS1-Stat1 interaction"</a>. <i>Proc. Natl. Acad. Sci. U.S.A</i>. 97 (10): 5267–5272. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/2000PNAS...97.5267L">2000PNAS...97.5267L</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1073%2Fpnas.97.10.5267">10.1073/pnas.97.10.5267</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC25817">25817</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10805787">10805787</a>.</li> <li>Kotaja N, Aittomäki S, Silvennoinen O, Palvimo JJ, Jänne OA (2001). <a href="https://doi.org/10.1210%2Fmend.14.12.0569">"ARIP3 (androgen receptor-interacting protein 3) and other PIAS (protein inhibitor of activated STAT) proteins differ in their ability to modulate steroid receptor-dependent transcriptional activation"</a>. <i>Mol. Endocrinol</i>. 14 (12): 1986–2000. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1210%2Fmend.14.12.0569">10.1210/mend.14.12.0569</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11117529">11117529</a>.</li> <li>Gross M, Liu B, Tan J, French FS, Carey M, Shuai K (2001). <a href="https://doi.org/10.1038%2Fsj.onc.1204489">"Distinct effects of PIAS proteins on androgen-mediated gene activation in prostate cancer cells"</a>. <i>Oncogene</i>. 20 (29): 3880–3887. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2Fsj.onc.1204489">10.1038/sj.onc.1204489</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11439351">11439351</a>.</li> <li>Liu B, Shuai K (2001). <a href="https://doi.org/10.1074%2Fjbc.M101085200">"Induction of apoptosis by protein inhibitor of activated Stat1 through c-Jun NH2-terminal kinase activation"</a>. <i>J. Biol. Chem</i>. 276 (39): 36624–36631. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.M101085200">10.1074/jbc.M101085200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11451946">11451946</a>.</li> <li>Kahyo T, Nishida T, Yasuda H (2001). <a href="https://doi.org/10.1016%2FS1097-2765%2801%2900349-5">"Involvement of PIAS1 in the sumoylation of tumor suppressor p53"</a>. <i>Mol. Cell</i>. 8 (3): 713–718. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS1097-2765%2801%2900349-5">10.1016/S1097-2765(01)00349-5</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11583632">11583632</a>.</li> <li>Weiskirchen R, Moser M, Weiskirchen S, Erdel M, Dahmen S, Buettner R, Gressner AM (2001). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1222169">"LIM-domain protein cysteine- and glycine-rich protein 2 (CRP2) is a novel marker of hepatic stellate cells and binding partner of the protein inhibitor of activated STAT1"</a>. <i>Biochem. J</i>. 359 (Pt 3): 485–96. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1042%2F0264-6021%3A3590485">10.1042/0264-6021:3590485</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1222169">1222169</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11672422">11672422</a>.</li> <li>Megidish T, Xu JH, Xu CW (2002). <a href="https://doi.org/10.1074%2Fjbc.C200001200">"Activation of p53 by protein inhibitor of activated Stat1 (PIAS1)"</a>. <i>J. Biol. Chem</i>. 277 (10): 8255–8259. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.C200001200">10.1074/jbc.C200001200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11788578">11788578</a>.</li> <li>Schmidt D, Müller S (2002). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC122440">"Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity"</a>. <i>Proc. Natl. Acad. Sci. U.S.A</i>. 99 (5): 2872–2877. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/2002PNAS...99.2872S">2002PNAS...99.2872S</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1073%2Fpnas.052559499">10.1073/pnas.052559499</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC122440">122440</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11867732">11867732</a>.</li> <li>Tan JA, Hall SH, Hamil KG, Grossman G, Petrusz P, French FS (2002). <a href="https://doi.org/10.1074%2Fjbc.M109217200">"Protein inhibitors of activated STAT resemble scaffold attachment factors and function as interacting nuclear receptor coregulators"</a>. <i>J. Biol. Chem</i>. 277 (19): 16993–17001. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.M109217200">10.1074/jbc.M109217200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11877418">11877418</a>.</li> <li>Nishida T, Yasuda H (2003). <a href="https://doi.org/10.1074%2Fjbc.M206741200">"PIAS1 and PIASxalpha function as SUMO-E3 ligases toward androgen receptor and repress androgen receptor-dependent transcription"</a>. <i>J. Biol. Chem</i>. 277 (44): 41311–41317. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.M206741200">10.1074/jbc.M206741200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12177000">12177000</a>.</li> <li>Rui HL, Fan E, Zhou HM, Xu Z, Zhang Y, Lin SC (2003). <a href="https://doi.org/10.1074%2Fjbc.M208099200">"SUMO-1 modification of the C-terminal KVEKVD of Axin is required for JNK activation but has no effect on Wnt signaling"</a>. <i>J. Biol. Chem</i>. 277 (45): 42981–42986. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.M208099200">10.1074/jbc.M208099200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12223491">12223491</a>.</li> <li>Sapetschnig A, Rischitor G, Braun H, Doll A, Schergaut M, Melchior F, Suske G (2002). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC129032">"Transcription factor Sp3 is silenced through SUMO modification by PIAS1"</a>. <i>EMBO J</i>. 21 (19): 5206–5215. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1093%2Femboj%2Fcdf510">10.1093/emboj/cdf510</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC129032">129032</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12356736">12356736</a>.</li> <li>Miyauchi Y, Yogosawa S, Honda R, Nishida T, Yasuda H (2003). <a href="https://doi.org/10.1074%2Fjbc.M208319200">"Sumoylation of Mdm2 by protein inhibitor of activated STAT (PIAS) and RanBP2 enzymes"</a>. <i>J. Biol. Chem</i>. 277 (51): 50131–50136. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.M208319200">10.1074/jbc.M208319200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12393906">12393906</a>.</li> <li>Ungureanu D, Vanhatupa S, Kotaja N, Yang J, Aittomaki S, Jänne OA, Palvimo JJ, Silvennoinen O (2004). <a href="https://doi.org/10.1182%2Fblood-2002-12-3816">"PIAS proteins promote SUMO-1 conjugation to STAT1"</a>. <i>Blood</i>. 102 (9): 3311–3313. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1182%2Fblood-2002-12-3816">10.1182/blood-2002-12-3816</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12855578">12855578</a>.</li> <li>Kadaré G, Toutant M, Formstecher E, Corvol JC, Carnaud M, Boutterin MC, Girault JA (2004). <a href="https://doi.org/10.1074%2Fjbc.M308562200">"PIAS1-mediated sumoylation of focal adhesion kinase activates its autophosphorylation"</a>. <i>J. Biol. Chem</i>. 278 (48): 47434–47440. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.M308562200">10.1074/jbc.M308562200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/14500712">14500712</a>.</li> <li>Tallec LP, Kirsh O, Lecomte MC, Viengchareun S, Zennaro MC, Dejean A, Lombès M (2004). <a href="https://doi.org/10.1210%2Fme.2003-0299">"Protein inhibitor of activated signal transducer and activator of transcription 1 interacts with the N-terminal domain of mineralocorticoid receptor and represses its transcriptional activity: implication of small ubiquitin-related modifier 1 modification"</a>. <i>Mol. Endocrinol</i>. 17 (12): 2529–2542. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1210%2Fme.2003-0299">10.1210/me.2003-0299</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/14500761">14500761</a>.</li> <li>Coppola D, Parikh V, Boulware D, Blanck G (2009). "Substantially reduced expression of PIAS1 is associated with colon cancer development". <i>J Cancer Res Clin Oncol</i>. 135 (9): 1287–91. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1007%2Fs00432-009-0570-z">10.1007/s00432-009-0570-z</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/19288270">19288270</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:20383429">20383429</a>.</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K (September 1998). "Inhibition of Stat1-mediated gene activation by PIAS1". Proc Natl Acad Sci U S A. 95 (18): 10626–10631. Bibcode:1998PNAS...9510626L. doi:10.1073/pnas.95.18.10626. PMC 27945. PMID 9724754. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC27945" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC27945</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Valdez BC, Henning D, Perlaky L, Busch RK, Busch H (July 1997). "Cloning and characterization of Gu/RH-II binding protein". Biochem Biophys Res Commun. 234 (2): 335–340. doi:10.1006/bbrc.1997.6642. PMID 9177271. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>"Entrez Gene: PIAS1 protein inhibitor of activated STAT, 1". <a href="https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8554" target="_blank">https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8554</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>"Entrez Gene: PIAS1 protein inhibitor of activated STAT, 1". <a href="https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8554" target="_blank">https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8554</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Ling Y, Sankpal UT, Robertson AK, McNally JG, Karpova T, Robertson KD (2004). "Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription". Nucleic Acids Res. 32 (2): 598–610. doi:10.1093/nar/gkh195. PMC 373322. PMID 14752048. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC373322" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC373322</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Kahyo T, Nishida T, Yasuda H (September 2001). "Involvement of PIAS1 in the sumoylation of tumor suppressor p53". Mol. Cell. 8 (3): 713–8. doi:10.1016/s1097-2765(01)00349-5. PMID 11583632. <a href="https://doi.org/10.1016%2Fs1097-2765%2801%2900349-5" target="_blank">https://doi.org/10.1016%2Fs1097-2765%2801%2900349-5</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Gallagher WM, Argentini M, Sierra V, Bracco L, Debussche L, Conseiller E (June 1999). "MBP1: a novel mutant p53-specific protein partner with oncogenic properties". Oncogene. 18 (24): 3608–16. doi:10.1038/sj.onc.1202937. PMID 10380882. <a href="https://doi.org/10.1038%2Fsj.onc.1202937" target="_blank">https://doi.org/10.1038%2Fsj.onc.1202937</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Liao J, Fu Y, Shuai K (May 2000). "Distinct roles of the NH2- and COOH-terminal domains of the protein inhibitor of activated signal transducer and activator of transcription (STAT) 1 (PIAS1) in cytokine-induced PIAS1-Stat1 interaction". Proc. Natl. Acad. Sci. U.S.A. 97 (10): 5267–72. Bibcode:2000PNAS...97.5267L. doi:10.1073/pnas.97.10.5267. PMC 25817. PMID 10805787. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC25817" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC25817</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Kahyo T, Nishida T, Yasuda H (September 2001). "Involvement of PIAS1 in the sumoylation of tumor suppressor p53". Mol. Cell. 8 (3): 713–8. doi:10.1016/s1097-2765(01)00349-5. PMID 11583632. <a href="https://doi.org/10.1016%2Fs1097-2765%2801%2900349-5" target="_blank">https://doi.org/10.1016%2Fs1097-2765%2801%2900349-5</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Lee BH, Yoshimatsu K, Maeda A, Ochiai K, Morimatsu M, Araki K, Ogino M, Morikawa S, Arikawa J (December 2003). "Association of the nucleocapsid protein of the Seoul and Hantaan hantaviruses with small ubiquitin-like modifier-1-related molecules". Virus Res. 98 (1): 83–91. doi:10.1016/j.virusres.2003.09.001. PMID 14609633. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Sapetschnig A, Rischitor G, Braun H, Doll A, Schergaut M, Melchior F, Suske G (October 2002). "Transcription factor Sp3 is silenced through SUMO modification by PIAS1". EMBO J. 21 (19): 5206–15. doi:10.1093/emboj/cdf510. PMC 129032. PMID 12356736. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC129032" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC129032</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Kahyo T, Nishida T, Yasuda H (September 2001). "Involvement of PIAS1 in the sumoylation of tumor suppressor p53". Mol. Cell. 8 (3): 713–8. doi:10.1016/s1097-2765(01)00349-5. PMID 11583632. <a href="https://doi.org/10.1016%2Fs1097-2765%2801%2900349-5" target="_blank">https://doi.org/10.1016%2Fs1097-2765%2801%2900349-5</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Lee BH, Yoshimatsu K, Maeda A, Ochiai K, Morimatsu M, Araki K, Ogino M, Morikawa S, Arikawa J (December 2003). "Association of the nucleocapsid protein of the Seoul and Hantaan hantaviruses with small ubiquitin-like modifier-1-related molecules". Virus Res. 98 (1): 83–91. doi:10.1016/j.virusres.2003.09.001. PMID 14609633. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Sapetschnig A, Rischitor G, Braun H, Doll A, Schergaut M, Melchior F, Suske G (October 2002). "Transcription factor Sp3 is silenced through SUMO modification by PIAS1". EMBO J. 21 (19): 5206–15. doi:10.1093/emboj/cdf510. PMC 129032. PMID 12356736. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC129032" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC129032</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> </ol>