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Activin and inhibin
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<h2 id="structure">Structure</h2> <p>The activin and inhibin protein complexes are both dimeric in structure, and, in each complex, the two monomers are linked to one another by a single <a href="/facts/Disulfide_bond/eDx5Xtlg">disulfide bond</a>.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> In addition, both complexes are derived from the same family of related genes and proteins but differ in their subunit composition.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> Below is a list of the most common inhibin and activin complexes and their subunit composition: </p> <table><tbody><tr><td><table><tbody><tr><th rowspan="2">Class</th><th rowspan="2">Activity</th><th rowspan="2">Complex</th><th colspan="3">Dimer subunits</th></tr><tr><th>1</th><th>2</th></tr><tr><td rowspan="2">Inhibin</td><td rowspan="2">inhibits FSH secretion</td><td>Inhibin A</td><td><a href="/facts/INHA/2oHnuHWT">α</a></td><td><a href="/facts/INHBA/rCtng35V">βA</a></td></tr><tr><td>Inhibin B</td><td>α</td><td><a href="/facts/INHBB/1eqqPxAY">βB</a></td></tr><tr><td rowspan="3">Activin</td><td rowspan="3">stimulates FSH secretion</td><td>Activin A</td><td>βA</td><td>βA</td></tr><tr><td>Activin AB</td><td>βA</td><td>βB</td></tr><tr><td>Activin B</td><td>βB</td><td>βB</td></tr></tbody></table></td><td></td></tr></tbody></table> <p>The alpha and beta subunits share approximately 25% <a href="/facts/Homology_(biology)/muctKlyT">sequence similarity</a>, whereas the similarity between beta subunits is approximately 65%.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p><p>In mammals, four beta subunits have been described, called activin βA, activin βB, activin βC and activin βE. Activin βA and βB are identical to the two beta subunits of inhibin. A fifth subunit, activin βD, has been described in <i><a href="/facts/African_clawed_frog/khG1KPrd">Xenopus laevis</a></i>. Two activin βA subunits give rise to activin A, one βA, and one βB subunit gives rise to activin AB, and so on. Various, but not all theoretically possible, heterodimers have been described.<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> The subunits are linked by a single covalent disulfide bond. </p><p>The <a href="/facts/INHBC/8rjQmYDn">βC</a> subunit is able to form activin heterodimers with βA or βB subunits but is unable to dimerize with inhibin α.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p> <h2 id="function">Function</h2> <h3>Activin</h3> <p>Activin is produced in the <a href="/facts/Gonad/36BUam2x">gonads</a>, <a href="/facts/Pituitary_gland/gdrQyldF">pituitary gland</a>, <a href="/facts/Placenta/7XUoks1b">placenta</a>, and other organs: </p> <ul><li>In the <a href="/facts/Ovarian_follicle/7eKGUwb6">ovarian follicle</a>, activin increases FSH binding and FSH-induced <a href="/facts/Aromaticity/wK0DzRY6">aromatization</a>. It participates in <a href="/facts/Androgen/Rxey0HxX">androgen</a> synthesis enhancing <a href="/facts/Luteinizing_hormone/a6znte2S">LH</a> action in the <a href="/facts/Ovary/z2hG6bNy">ovary</a> and <a href="/facts/Testicle/Doy40hoq">testis</a>. In the male, activin enhances <a href="/facts/Spermatogenesis/8u8XNEV6">spermatogenesis</a>.</li> <li>Activin is strongly expressed in wounded <a href="/facts/Skin/4havlLzG">skin</a>, and overexpression of activin in <a href="/facts/Epidermis_(skin)/JvRABubP">epidermis</a> of <a href="/facts/Genetically_modified_organism/6emCmpsc">transgenic</a> <a href="/facts/Mouse/6m1X7m0g">mice</a> improves wound healing and enhances <a href="/facts/Scar/XSQ92JoG">scar</a> formation. Its action in wound repair and skin <a href="/facts/Morphogenesis/zHJh8Eae">morphogenesis</a> is through stimulation of <a href="/facts/Keratinocyte/drqhJjuS">keratinocytes</a> and <a href="/facts/Stromal_cell/31AA691H">stromal cells</a> in a dose-dependent manner.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a></li> <li>Activin also regulates the <a href="/facts/Morphogenesis/zHJh8Eae">morphogenesis</a> of branching organs such as the <a href="/facts/Prostate/mrBdSsf7">prostate</a>, <a href="/facts/Lung/gTWXI6Fj">lung</a>, and especially <a href="/facts/Kidney/HBspPrv9">kidney</a>. Activin A increased the expression level of <a href="/facts/Type-I_collagen/LDHK4FbA">type-I collagen</a> suggesting that activin A acts as a potent activator of <a href="/facts/Fibroblast/n08KsFll">fibroblasts</a>.</li> <li>Lack of activin during development results in neural developmental defects.</li> <li>Upregulation of Activin A drives pluripotent <a href="/facts/Stem_cell/qgB9dFrI">stem cells</a> into a mesoendodermal fate, and thus provides a useful tool for stem cell <a href="/facts/Cellular_differentiation/bCVqUG7w">differentiation</a> and <a href="/facts/Organoid/1KxCLSMA">organoid</a> formation.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a></li></ul> <h3>Inhibin</h3> <p>In both females and males, inhibin inhibits <a href="/facts/Follicle-stimulating_hormone/n6CwdebD">FSH</a> production. Inhibin does not inhibit the secretion of GnRH from the hypothalamus.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> However, the overall mechanism differs between the sexes: </p> <h4>In females</h4> <p>Inhibin is produced in the <a href="/facts/Gonads/36BUam2x">gonads</a>, <a href="/facts/Pituitary_gland/gdrQyldF">pituitary gland</a>, <a href="/facts/Placenta/7XUoks1b">placenta</a>, <a href="/facts/Corpus_luteum/rA91PnaC">corpus luteum</a> and other organs. </p><p>FSH stimulates the secretion of inhibin from the <a href="/facts/Granulosa_cell/8KhMa9I3">granulosa cells</a> of the ovarian follicles in the <a href="/facts/Ovary/z2hG6bNy">ovaries</a>. In turn, inhibin suppresses FSH. </p> <ul><li><i>Inhibin B</i> reaches a peak in the early- to mid-<a href="/facts/Menstrual_cycle/AY6Y9xxM">follicular phase</a>, and a second peak at <a href="/facts/Ovulation/0K3MLdAv">ovulation</a>.</li> <li><i>Inhibin A</i> reaches its peak in the mid-<a href="/facts/Menstrual_cycle/AY6Y9xxM">luteal phase</a>.</li></ul> <p>Inhibin secretion is diminished by <a href="/facts/Gonadotropin-releasing_hormone/hSsFPpdj">GnRH</a>, and enhanced by <a href="/facts/Insulin-like_growth_factor/gYqfrKPy">insulin-like growth factor</a>-1 (IGF-1). </p> <h4>In males</h4> <p>It is secreted from the <a href="/facts/Sertoli_cell/JSC6Np8s">Sertoli cells</a>,<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> located in the <a href="/facts/Seminiferous_tubules/Jytp8phd">seminiferous tubules</a> inside the <a href="/facts/Testes/Doy40hoq">testes</a>. <a href="/facts/Androgens/Rxey0HxX">Androgens</a> stimulate inhibin production; this <a href="/facts/Protein/Jxmagu3E">protein</a> may also help to locally regulate <a href="/facts/Spermatogenesis/8u8XNEV6">spermatogenesis</a>.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> </p> <h2 id="mechanism-of-action">Mechanism of action</h2> <h3>Activin</h3> <p>As with other members of the superfamily, activins interact with two types of cell surface <a href="/facts/Transmembrane_receptor/0YGSjDdL">transmembrane receptors</a> (Types I and II) which have intrinsic <a href="/facts/Serine/threonine-specific_protein_kinase/QKSTb82e">serine/threonine kinase</a> activities in their cytoplasmic domains: </p> <ul><li><a href="/facts/Activin_type_1_receptors/Vq3ejx2w">Activin type 1 receptors</a>: <a href="/facts/ACVR1/aTN1deUj">ACVR1</a>, <a href="/facts/ACVR1B/1ugouTel">ACVR1B</a>, <a href="/facts/ACVR1C/3u9nwhkf">ACVR1C</a></li> <li><a href="/facts/Activin_type_2_receptors/T0dW6Ksz">Activin type 2 receptors</a>: <a href="/facts/ACVR2A/KyoCakpl">ACVR2A</a>, <a href="/facts/ACVR2B/fXxR2cwg">ACVR2B</a></li></ul> <p>Activin binds to the Type II receptor and initiates a cascade reaction that leads to the recruitment, phosphorylation, and activation of Type I activin receptor. This then interacts with and then phosphorylates <a href="/facts/Mothers_against_decapentaplegic_homolog_2/xlS5oygm">SMAD2</a> and <a href="/facts/Mothers_against_decapentaplegic_homolog_3/6j6Go6va">SMAD3</a>, two of the cytoplasmic <a href="/facts/R-SMAD/mXeS2gHM">SMAD</a> proteins. </p><p>Smad3 then translocates to the nucleus and interacts with <a href="/facts/Mothers_against_decapentaplegic_homolog_4/cgvz1vKP">SMAD4</a> through multimerization, resulting in their modulation as <a href="/facts/Transcription_factor/wro0DPHe">transcription factor</a> complexes responsible for the expression of a large variety of genes. </p> <h3>Inhibin</h3> <p>In contrast to activin, much less is known about the mechanism of action of inhibin, but may involve competing with activin for binding to activin receptors and/or binding to inhibin-specific receptors.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> </p> <h2 id="clinical-significance">Clinical significance</h2> <h3>Activin</h3> <p>Activin A is more plentiful in the <a href="/facts/Adipose_tissue/PxxedB6e">adipose tissue</a> of obese, compared to lean persons.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> Activin A promotes the proliferation of <a href="/facts/Adipocyte/FuM7LlaK">adipocyte</a> <a href="/facts/Progenitor_cell/qW1KMDC1">progenitor cells</a>, while inhibiting their <a href="/facts/Cellular_differentiation/bCVqUG7w">differentiation</a> into adipocytes.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> Activin A also increases inflammatory <a href="/facts/Cytokine/SdWpWABH">cytokines</a> in <a href="/facts/Macrophage/z7hkQu3o">macrophages</a>.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> </p><p>A <a href="/facts/Mutation/Ee4NnWbY">mutation</a> in the gene for the activin receptor <a href="/facts/ACVR1/aTN1deUj">ACVR1</a> results in <a href="/facts/Fibrodysplasia_ossificans_progressiva/GCzLIT8L">fibrodysplasia ossificans progressiva</a>, a fatal disease that causes muscle and soft tissue to gradually be replaced by bone tissue.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> This condition is characterized by the formation of an extra skeleton that produces immobilization and eventually death by suffocation.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> The mutation in ACVR1 causes activin A, which normally acts as an antagonist of the receptor and blocks <a href="/facts/Osteogenesis/N6mMDQvR">osteogenesis</a> (bone growth), to behave as an agonist of the receptor and to induce hyperactive bone growth.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> On 2 September 2015, <a href="/facts/Regeneron_Pharmaceuticals/vyQ48MRH">Regeneron Pharmaceuticals</a> announced that they had developed an <a href="/facts/Antibody/MX8pdTdP">antibody</a> for <a href="/facts/Activin_A/jLwLmlGs">activin A</a> that effectively cures the disease in an <a href="/facts/Animal_model/xPBrtWUX">animal model</a> of the condition.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> </p><p>Mutations in the ACVR1 gene have also been linked to cancer, especially <a href="/facts/Glioma/I2gN3x11">diffuse intrinsic pontine glioma</a>(DIPG).<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a><a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a><a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> </p><p>Elevated Activin B levels with normal Activin A levels provided a possible <a href="/facts/Biomarker/nk2LgXtq">biomarker</a> for <a href="/facts/Myalgic_encephalomyelitis/chronic_fatigue_syndrome/UwTEusF5">myalgic encephalomyelitis/chronic fatigue syndrome</a>.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> </p><p>Activin A is overexpressed in many <a href="/facts/Cancer/PVW6n1D0">cancers</a>. It was shown to promote <a href="/facts/Carcinogenesis/PC8wc1Mf">tumorigenesis</a> by hampering the <a href="/facts/Adaptive_immune_system/bc7zT1Jo">adaptive</a> <a href="/facts/Cancer_immunology/wu5YzX6d">anti-tumor immune response</a> in <a href="/facts/Melanoma/qdT7E97Y">melanoma</a>.<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> </p> <h3>Inhibin</h3> <p>Quantification of inhibin A is part of the prenatal <a href="/facts/Quad_screen/pK4D8S4d">quad screen</a> that can be administered during pregnancy at a gestational age of 16–18 weeks. An elevated inhibin A (along with an increased <a href="/facts/Beta-hCG/AKeIq9nd">beta-hCG</a>, decreased <a href="/facts/Alpha-fetoprotein/FRzKt0dw">AFP</a>, and a decreased <a href="/facts/Estriol/JYgLMeay">estriol</a>) is suggestive of the presence of a fetus with <a href="/facts/Down_syndrome/Y4XEQSMS">Down syndrome</a>.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> As a screening test, abnormal quad screen test results need to be followed up with more definitive tests. </p><p>It also has been used as a marker for <a href="/facts/Ovarian_cancer/fsWbh3Tn">ovarian cancer</a>.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a><a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> </p><p>Inhibin B may be used as a marker of <a href="/facts/Spermatogenesis/8u8XNEV6">spermatogenesis</a> function and <a href="/facts/Male_infertility/wrF5RGjs">male infertility</a>. The mean serum inhibin B level is significantly higher among fertile men (approximately 140 pg/mL) than in infertile men (approximately 80 pg/mL).<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> In men with <a href="/facts/Azoospermia/5kycIv0S">azoospermia</a>, a positive test for inhibin B slightly raises the chances for successfully achieving pregnancy through <a href="/facts/Testicular_sperm_extraction/VPJLgoyx">testicular sperm extraction</a> (TESE), although the association is not very substantial, having a sensitivity of 0.65 (95% confidence interval [CI]: 0.56–0.74) and a specificity of 0.83 (CI: 0.64–0.93) for prediction the presence of sperm in the testes in non-obstructive azoospermia.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> </p> <h2 id="external-links">External links</h2> <ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=Activin">Activin</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li> <li><a href="https://meshb.nlm.nih.gov/record/ui?name=Inhibin">Inhibin</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li> <li>Grusch M, Kreidl E (1 August 2008). <a href="http://www.scitopics.com/Activin_and_follistatin_in_liver_biology_and_hepatocellular_carcinoma.html">"Activin and follistatin in liver biology and hepatocellular carcinoma"</a>. <i>SciTopics</i>. Elsevier. <a href="https://web.archive.org/web/20081209123618/http://www.scitopics.com/Activin_and_follistatin_in_liver_biology_and_hepatocellular_carcinoma.html">Archived</a> from the original on 9 December 2008. Retrieved 24 December 2008.</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Vale W, Rivier J, Vaughan J, McClintock R, Corrigan A, Woo W, et al. (1986). "Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid". Nature. 321 (6072): 776–9. Bibcode:1986Natur.321..776V. doi:10.1038/321776a0. PMID 3012369. S2CID 4365045. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Ling N, Ying SY, Ueno N, Shimasaki S, Esch F, Hotta M, et al. (1986). "Pituitary FSH is released by a heterodimer of the beta-subunits from the two forms of inhibin". Nature. 321 (6072): 779–82. Bibcode:1986Natur.321..779L. doi:10.1038/321779a0. PMID 3086749. S2CID 38100413. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Chen YG, Wang Q, Lin SL, Chang CD, Chuang J, Chung J, et al. (May 2006). "Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis". Experimental Biology and Medicine. 231 (5): 534–44. doi:10.1177/153537020623100507. PMID 16636301. S2CID 39050907. <a href="http://www.ebmonline.org/cgi/pmidlookup?view=long&pmid=16636301" target="_blank">http://www.ebmonline.org/cgi/pmidlookup?view=long&pmid=16636301</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Sulyok S, Wankell M, Alzheimer C, Werner S (October 2004). "Activin: an important regulator of wound repair, fibrosis, and neuroprotection". Molecular and Cellular Endocrinology. 225 (1–2): 127–32. doi:10.1016/j.mce.2004.07.011. PMID 15451577. S2CID 6943949. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>van Zonneveld P, Scheffer GJ, Broekmans FJ, Blankenstein MA, de Jong FH, Looman CW, et al. (March 2003). "Do cycle disturbances explain the age-related decline of female fertility? Cycle characteristics of women aged over 40 years compared with a reference population of young women". Human Reproduction. 18 (3): 495–501. doi:10.1093/humrep/deg138. PMID 12615813. <a href="https://doi.org/10.1093%2Fhumrep%2Fdeg138" target="_blank">https://doi.org/10.1093%2Fhumrep%2Fdeg138</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Makanji Y, Zhu J, Mishra R, Holmquist C, Wong WP, Schwartz NB, et al. (October 2014). "Inhibin at 90: from discovery to clinical application, a historical review". Endocrine Reviews. 35 (5): 747–94. doi:10.1210/er.2014-1003. PMC 4167436. PMID 25051334. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167436" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167436</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Burger HG, Igarashi M (April 1988). "Inhibin: definition and nomenclature, including related substances". The Journal of Clinical Endocrinology and Metabolism. 66 (4): 885–6. PMID 3346366. <a href="/wiki/PMID_(identifier)" target="_blank">/wiki/PMID_(identifier)</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Robertson DM, Burger HG, Fuller PJ (March 2004). "Inhibin/activin and ovarian cancer". Endocrine-Related Cancer. 11 (1): 35–49. doi:10.1677/erc.0.0110035. PMID 15027884. S2CID 12202820. <a href="https://doi.org/10.1677%2Ferc.0.0110035" target="_blank">https://doi.org/10.1677%2Ferc.0.0110035</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Kingsley DM (January 1994). "The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms". Genes & Development. 8 (2): 133–46. doi:10.1101/gad.8.2.133. PMID 8299934. <a href="https://doi.org/10.1101%2Fgad.8.2.133" target="_blank">https://doi.org/10.1101%2Fgad.8.2.133</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Ying SY (December 1987). "Inhibins and activins: chemical properties and biological activity". Proceedings of the Society for Experimental Biology and Medicine. 186 (3): 253–64. doi:10.3181/00379727-186-42611a. PMID 3122219. S2CID 36872324. <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>Burger HG, Igarashi M (April 1988). "Inhibin: definition and nomenclature, including related substances". The Journal of Clinical Endocrinology and Metabolism. 66 (4): 885–6. PMID 3346366. <a href="/wiki/PMID_(identifier)" target="_blank">/wiki/PMID_(identifier)</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Kingsley DM (January 1994). "The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms". Genes & Development. 8 (2): 133–46. doi:10.1101/gad.8.2.133. PMID 8299934. <a href="https://doi.org/10.1101%2Fgad.8.2.133" target="_blank">https://doi.org/10.1101%2Fgad.8.2.133</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Xu P, Hall AK (November 2006). "The role of activin in neuropeptide induction and pain sensation". Developmental Biology. 299 (2): 303–9. doi:10.1016/j.ydbio.2006.08.026. PMID 16973148. <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>Deli A, Kreidl E, Santifaller S, Trotter B, Seir K, Berger W, et al. (March 2008). 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