Na Cocer Peptides 
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INGINGO ZOSE N'AMAKURU Y’IBICURUZWA BITANZWE KURI URU RUBUGA BISANZWE KUBONA AMAKURU N'INTEGO Z'UBUREZI.
Ibicuruzwa byatanzwe kururu rubuga bigenewe gusa mubushakashatsi bwa vitro. Mu bushakashatsi bwa vitro (Ikilatini: * mu kirahure *, bisobanura mu bikoresho by'ibirahure) bikorwa hanze y'umubiri w'umuntu. Ibicuruzwa ntabwo ari imiti, ntabwo byemejwe n’ikigo cy’Amerika gishinzwe ibiryo n’ibiyobyabwenge (FDA), kandi ntigomba gukoreshwa mu gukumira, kuvura, cyangwa gukiza indwara iyo ari yo yose y’ubuvuzi, indwara, cyangwa indwara. Birabujijwe rwose n'amategeko kwinjiza ibyo bicuruzwa mumubiri wabantu cyangwa inyamaswa muburyo ubwo aribwo bwose.
Mubyerekeranye nubumenyi bwubuzima, gusaza byahoze ari ingingo nkuru yubushakashatsi. Mu gihe ubushakashatsi ku buryo bwo gusaza bukomeje kwiyongera, uruhare rwa nicotinamide adenine dinucleotide (NAD +) muri gahunda yo kurwanya gusaza rwakomeje kwitabwaho. Nka coenzyme igira uruhare mubikorwa byinshi byingenzi bya physiologique muri selile, NAD + byagaragaye ko bifitanye isano rya bugufi no gusaza.
Igishushanyo 1 Imikorere yibinyabuzima ya NAD. NAD igenga uburinganire bwingufu, gusubiza ibibazo, hamwe na homeostasis ya selile ikoresheje sirtuins, PARPs, na enzymes zitandukanye za redox.
Incamake yimikorere ya Physiologique ya NAD +
NAD + ni coenzyme igaragara cyane muri selile, yitabira inzira zitandukanye zingenzi zifatika. Iraboneka cyane muburyo bubiri muri selile: ifishi ya okiside (NAD +) nuburyo bwagabanijwe (NADH), bushobora guhuza. Iringaniza rifite imbaraga ningirakamaro mu gukomeza metabolisme isanzwe.
1. Metabolism yingufu: NAD + igira uruhare runini muguhumeka. Mu nzira ya metabolism yingufu nka glycolysis, cycle ya tricarboxylic, na fosifori ya okiside, NAD + ikora nka electron, yakira electron zasohotse mugihe cya okiside ya metabolike ya metabolike kugirango ibe NADH. Nyuma yaho, NADH yohereza electron mumurongo wubuhumekero wa mitochondrial, aho fosifori ya okiside itanga adenosine triphosphate (ATP), igatanga ingufu kuri selile. Ubu buryo butuma ingirabuzimafatizo zishobora gukomeza kubona imbaraga zihagije zo gukomeza ibikorwa bisanzwe byumubiri, nko gukura kwakagari, kugabana, no gusana.
Mugihe cya glycolysis, 3-fosifogilecerate yohereza atome ya hydrogène kuri NAD + ikozwe na 3-fosifogisile dehydrogenase, ikabyara NADH na 1,3-diphosphoglycerate. Nyuma, NADH yohereza electron muri ogisijeni ikoresheje urunigi rw'ubuhumekero muri mitochondria, amaherezo ikabyara amazi no guhuza synthesis ya ATP. Ibi byerekana ko NAD + ari kimwe mu bintu by'ingenzi bigize ingufu za selile metabolisme, kandi impinduka ziterwa nazo zigira ingaruka ku buryo butaziguye ku musaruro w'ingufu.
2. Gusana ADN: NAD + ni substrate yumuryango wa polymerase (ADP-ribose) polymerase (PARP). PARP imaze kumenya no guhambira ku mbuga za ADN yangiritse, ikoresha NAD + nka substrate kugirango yimure amatsinda ya ADP-ribose ubwayo cyangwa izindi poroteyine, ikora iminyururu ya poly (ADP-ribose) (PAR). Iminyururu ya PAR irashobora kwinjiza no gukora urutonde rwa poroteyine zigira uruhare mu gusana ADN, nka ADN ligase na ADN polymerase, bityo bigatangira inzira yo gusana ADN. Iyo ingirabuzimafatizo zangijwe na ADN zatewe nimpamvu nkimirasire ya ultraviolet cyangwa imiti, sisitemu ya PARP-NAD + yihutira gusana ADN yangiritse no kubungabunga umutekano wa genomic. Niba urwego rwa NAD + rudahagije, ibikorwa bya PARP birabujijwe, biganisha ku kugabanya ubushobozi bwo gusana ADN, kongera ihungabana rya genomic, no kwihutisha gusaza kwa selile n'indwara.
3. Guhindura poroteyine nyuma yubusobanuro: NAD + nayo igira uruhare mubikorwa bya catalitiki ya proteine z'umuryango wa sirtuin. Sirtuins ni icyiciro cya NAD + -bishingiye kuri deacetylase ishobora gukuraho acetyl ihinduka mubisigazwa bya lysine kuri proteyine. Ihinduka rya deacetylation rigenga ibikorwa, ituze, hamwe nubutaka bwa poroteyine nyinshi, bityo bikagira ingaruka kuri metabolism selile, ibisubizo byimyitwarire, gusaza, nibindi bikorwa bya physiologique. Kurugero, SIRT1 irashobora kugenga ibikorwa byimpapuro zandikirwa nka p53 na FOXO binyuze muguhindura deacetylation, bityo bikagira ingaruka kumuzunguruko, apoptose, hamwe na antioxydeant stress. Iyo selile zifite ibibazo, SIRT1 deacetylates p53 ukoresheje NAD +, bityo bikabuza ibikorwa bya p53 kwanduza, kugabanya kubaho kwa apoptose, no kongera ubushobozi bwimibereho ya selile.
Impinduka muri NAD + Urwego mugihe cyo gusaza
Ubushakashatsi bwerekanye ko uko imyaka igenda ishira, NAD + igabanuka gahoro gahoro mubice byinshi ningirangingo z'umubiri. Iri gabanuka ryagaragaye mu moko atandukanye, harimo inyamaswa z’inyamabere, nematode, n’isazi z’imbuto, byerekana ko kugabanuka kwa NAD + bishobora kuba ibintu byabitswe mu gihe cyo gusaza.
1 . Mu mitsi ya skeletale, gusaza biherekejwe no kugabanuka kwibikorwa byimisemburo yingenzi mumuhanda wa NAD + biosynthetic, bigatuma kugabanuka kwa NAD +. Imvugo n'ibikorwa bya NAD + ikoresha imisemburo nka CD38 yiyongera, kwihuta kwa NAD + kandi amaherezo bigatuma igabanuka rikabije rya NAD + mumitsi ya skeletale. Mu mwijima, usibye impinduka zavuzwe haruguru muri synthesis no gutesha agaciro inzira, gusaza bishobora no kugira ingaruka kubikorwa bya transport bya NAD +, biganisha ku busumbane mukwirakwiza kwa NAD + no kugabanya imbaraga zayo.
2. Ihuriro nindwara ziterwa nimyaka: Kugabanuka kurwego rwa NAD + bifitanye isano rya bugufi no gutangira no gutera imbere kwindwara zitandukanye ziterwa nimyaka. Mu ndwara zifata umutima, kugabanuka kwingirabuzimafatizo ya myocardial NAD + iterwa no gusaza bitera ihungabana ryingufu za metabolisme, guhagarika umutima kwa okiside, hamwe na apoptose selile myocardial, bityo bikongera imikorere mibi yumutima. Mu ndwara zifata ubwonko nk'indwara ya Alzheimer n'indwara ya Parkinson, kugabanuka k'urwego rwa neuronal NAD + bigira ingaruka ku gusana ADN no kuri poroteyine homeostasis, bigatuma habaho gukusanya poroteyine za neurotoxique ndetse n'urupfu rwa neuronal. Indwara za metabolike nka diyabete nazo zifitanye isano no kugabanuka kwa NAD +, kubera ko kubura NAD + byangiza imisemburo ya insuline no kumva insuline, bigatuma amaraso ya glucose adasanzwe.
Uburyo bwagabanutse urwego rwa NAD + butera gusaza
1. ** Ingufu ziterwa na metabolism **: NAD + igira uruhare runini muri metabolism yingufu. Uko imyaka igenda yiyongera, kugabanuka kurwego rwa NAD + biganisha ku kwangirika kwingufu za metabolisme no kugabanya umusaruro wa ATP. Ibi ntabwo bigira ingaruka kumikorere isanzwe yimikorere ya selile ahubwo binatera urukurikirane rwibisubizo byindishyi, nko gukwirakwiza mitochondial ikabije hamwe nuburyo budasanzwe. Mitochondria nimbaraga za selile; iyo NAD + idahagije, imikorere yubuhumekero bwa mitochondial irabangamiwe, bigatuma umusaruro wubwoko bwa ogisijeni ikora (ROS) mugihe cyo gutwara electron. ROS ikabije irashobora kwibasira ADN ya mitochondial, proteyine, na lipide, bikarushaho guhungabanya imiterere n'imikorere ya mito-iyambere, bigatera inzitizi mbi yihutisha gusaza kwa selile.
Igishushanyo 2 Uburyo buteganijwe bwerekana uburyo gusaza bigira ingaruka kuri metabolism NAD. Gusaza bihagarika uburinganire hagati ya synthesis ya NAD no gutesha agaciro, bigatuma urwego rwa NAD rugabanuka mubice bitandukanye.
2. Gukusanya ibyangiritse kuri ADN: Nka substrate ya PARP, kugabanya urwego rwa NAD + bigabanya ubushobozi bwo gusana ADN. Iyo kwangirika kwa ADN bidashobora gusanwa neza mugihe gikwiye, biganisha ku guhungabana kwa genomique, bikusanya umubare munini wa mutation hamwe na chromosomal idasanzwe. Iyangirika rya genetike ribangamira imikorere isanzwe ya physiologique selile, igira ingaruka ku gukwirakwira kwingirabuzimafatizo, gutandukana, na apoptose, bityo bigatuma gusaza kwa selile. Kwangirika kwa ADN kandi gukora inzira zijyanye no gusaza inzira zerekana ibimenyetso muri selile, nka p53-p21 na p16INK4a-Rb, bikarushaho gutuma habaho gusaza kwa selile.
3. Kugabanya inzira zerekana ibimenyetso bya senescence: NAD + -bigenga biterwa na poroteyine z'umuryango wa sirtuin bigira uruhare runini mugutunganya inzira zerekana ibimenyetso bya senescence. Mugihe urwego rwa NAD + rugabanuka, ibikorwa bya sirtuin birabujijwe, biganisha ku kugabanuka kwa deacetylation ya poroteyine zo hasi. Kugabanya ibikorwa bya SIRT1 bivamo p53 kuba muburyo bwa acetylée cyane, byongera ibikorwa bya transcription ya p53, biganisha kumufata cycle na apoptose; icyarimwe, intege nke za deacetylation yibintu byandikirwa FOXO na SIRT1 bigira ingaruka kumyuka mibi ya antioxydeant selile no kugenzura metabolike. Byongeye kandi, impinduka mubikorwa byabandi bagize umuryango wa sirtuin nka SIRT3 na SIRT6 nazo zigira ingaruka kumikorere ya mito-iyambere, ituze rya genomique, hamwe nibisubizo bitera umuriro, hamwe bigatera imbere gutera imbere kwa selile.
Ingamba zo kurwanya gusaza zo kongera urwego rwa NAD +
Urebye isano ya hafi hagati yo kugabanuka kwa NAD + no gusaza, ingamba zo gutinza gusaza wongera urwego rwa NAD + zahindutse ahantu h’ubushakashatsi.
1. Kuzuza NAD + Ababanjirije: Kuzuza NAD + ibanziriza ni uburyo busanzwe bwo kongera urwego rwa NAD +. Ibisanzwe NAD + ibanziriza harimo nicotinamide (NAM), nicotinamide mononucleotide (NMN), na nicotinamide riboside (NR). Ibibanziriza bishobora guhinduka muri NAD + binyuze munzira yihariye ya metabolike muri selile, bityo ikongera urwego rwayo.
Nikotinamide (NAM): NAM ni uburyo bwa vitamine B3 ishobora guhinduka muri nicotinamide mononucleotide (NMN) binyuze mu gikorwa cya nicotinamide fosiforiibosyltransferase (NAMPT), hanyuma igakoreshwa mu guhuza NAD +. Kwiyongera kwinshi kwa NAM birashobora gutanga ibitekerezo bibuza ibikorwa bya NAMPT, bikagabanya ubushobozi bwayo bwo kongera urwego rwa NAD +. Gukoresha igihe kirekire cyane gukoresha NAM bishobora gutera ingaruka nko guhindagura uruhu, ariko mugihe gikwiye, NAM irashobora kongera urwego rwimitsi ya NAD +, kunoza metabolisme yingufu, no kongera imikorere yo gusana ADN.
Nikotinamide mononucleotide (NMN): NMN ni intangiriro itaziguye mu nzira ya NAD + biosynthetic. Ubushakashatsi bwerekanye ko umunwa NMN winjizwa vuba kandi ugahinduka NAD +, ukongera urwego rwa NAD + mubice bitandukanye. Mu bushakashatsi bw’inyamaswa, inyongera ya NMN yerekanye iterambere ryinshi mu bijyanye n’imyaka iterwa no guhindagurika kwa metabolike, imikorere mibi yumutima nimiyoboro, nindwara zifata ubwonko. Kurugero, mu mbeba zishaje, inyongera ya NMN yongereye ubushobozi bwa lokomoteri, kongera insulitifike ya insuline, kugabanya impinduka ziterwa nimyaka ziterwa numutima mumutima, kandi byongera imikorere yubwenge. Byongeye kandi, NMN yerekanwe guteza imbere biogenezi ya mito-iyambere, kongera imikorere ya mito-iyambere, no kugabanya kwangirika kwatewe na okiside.
Nikotinamide riboside (NR): NR nubundi buryo bwiza bwa NAD + bushobora guhinduka muri NMN binyuze muri fosifora na nicotinamide riboside kinase (NRK), hanyuma igakoreshwa muguhuza NAD +. Kimwe na NMN, inyongera hamwe na NR irashobora kongera urwego rudasanzwe rwa NAD +, kunoza imikorere ya metabolike, no gutinda gusaza. Imbeba zishaje, inyongera ya NR irashobora guhindura inzira zo guhinduranya no guhangayika, kongera ubushobozi bwa chromatin-ihuza imbaraga zamasaha yisaha ya BMAL1, kugarura injyana yubuhumekero ya mitochondial hamwe nibikorwa bya circadian, kandi bigasubiza igice cyimiterere yimiterere yimbeba zashaje niz'imbeba zikiri nto.
Igishushanyo cya 3 Icyitegererezo cyerekana inzira ya salvage ya NAD + nicotinamide riboside (NR) ihinduka kuri NAD +.
2. Kugena imisemburo ya NAD + metabolike:
Gukora NAD + synthase: NAMPT ni enzyme igabanya igipimo mumuhanda wa NAD + biosynthetic, kandi ibikorwa byiyongera birashobora guteza imbere NAD + synthesis. Bimwe mubintu bisanzwe, nka resveratrol na apigenin, wasangaga bikora NAMPT, bityo umusaruro wa NAD +. Resveratrol ni uruganda rwa polifenolike ruboneka mu ruhu rwinzabibu, vino itukura, nibindi bimera. Irashobora kugenzura mu buryo butaziguye imvugo ya NAMPT ukoresheje inzira ya SIRT1-PGC-1α yerekana inzira, bityo ikongera urwego rwa NAD +. Kuvura Resveratrol bitezimbere imbaraga za metabolisme, bigabanya kwangirika kwa okiside, kandi bikongerera igihe cyimbeba zishaje.
Kubuza imisemburo ya NAD +: CD38 ni enzyme nini ya NAD + ikoresha enzyme imvugo n'ibikorwa byiyongera uko imyaka igenda ishira, byihuta kwangirika kwa NAD +. Guhagarika ibikorwa bya CD38 bigabanya gukoresha NAD + kandi bikomeza urwego rwa NAD +. Bimwe mu bice bito bya molekile, nka 78c na apigenin, byavuzwe ko bibuza ibikorwa bya CD38. Gukoresha inhibitori ya CD38 birashobora kongera urwego rwa NAD + kandi bigateza imbere imikorere mibi yumubiri, nko kongera imikorere yumutima no kunoza imiterere ya metabolike.
3. Ibikorwa byubuzima: Ibintu byubuzima nabyo bigira ingaruka zikomeye kurwego rwa NAD +.
Imyitozo ngororangingo: Imyitozo isanzwe itera inzira ya NAD + biosynetike kandi ikongera urwego rwa NAD +. Imyitozo ya aerobic hamwe namahugurwa yimbaraga birashobora kongera imvugo nibikorwa bya NAMPT mumitsi ya skeletale, bigatera NAD + synthesis. Imyitozo ngororamubiri irashobora kandi kugenga imvugo ya NAD + ijyanye na metabolism, igahindura imikorere ya mito-iyambere, kandi ikongera ubushobozi bwa antioxydeant selile. Mubaturage bageze mu zabukuru, imyitozo ngororamubiri iringaniye irashobora kongera neza NAD + mu mitsi, igatera imbaraga imitsi n'imikorere ya moteri, kandi igabanya umuvuduko wo gusaza.
Kubuza imirire: Kubuza imirire, nko kugabanya kalori (CR) no kwiyiriza ubusa rimwe na rimwe (NIBA), bizwi nkingamba zifatika zo gutinda gusaza. Ubu buryo bwimirire bugira ingaruka zo kurwanya gusaza muguhindura NAD + metabolism. CR na NIBA ukora poroteyine z'umuryango wa sirtuin nka SIRT1, kuzamura NAD + synthesis no kuyikoresha. Kubuza imirire birashobora kandi kugabanya guhagarika umutima, kunoza imikorere ya metabolike, no kugabanya ibyago byindwara ziterwa nimyaka. Mu bushakashatsi bw’inyamaswa, guhagarika calorie yigihe kirekire birashobora kongera cyane urwego rwa NAD + kandi bikongerera igihe cyubwoko bwinshi.
Ingaruka zo gusaza Ingaruka zo Kongera NAD + Urwego
1 .
Kunoza imikorere ya Metabolike: Ku mbeba zishaje, kuzuza NMN cyangwa NR birashobora kongera insuline, kugabanya urugero rwa glucose yamaraso, no kunoza imitekerereze ya lipide. Inyongera ya NAD + ibanziriza irashobora kongera aside irike mu mubiri wa adipose, kugabanya ikwirakwizwa ry’amavuta, no kugabanya ibyago by’indwara ziterwa n'umubyibuho ukabije. Kongera urwego rwa NAD + birashobora kandi kunoza imikorere ya metabolike yumwijima, kongera ubushobozi bwumwijima wangiza imiti nuburozi, kandi bigakomeza imikorere yumubiri yumubiri.
Kurinda Imikorere Yumutima: Mugihe cyo gusaza, sisitemu yumutima nimiyoboro y'amaraso ihinduka muburyo bwimikorere no mumikorere, nka hypertrophyie myocardial no kugabanya ubukana bwimitsi. Kwiyongera hamwe nababanjirije NAD + birashobora kunoza imikorere yumutima no kuruhuka, kugabanya fibrosis ya myocardial, no kugabanya kwangirika kwa okiside. Mubyitegererezo byinyamanswa, kongerwaho na NMN cyangwa NR birashobora kugabanya umuvuduko wamaraso, kunoza imikorere ya endoteliyale yimitsi, no kugabanya ibyago byindwara zifata umutima. Muburyo bwa myocardial infarction, kongera urwego rwa NAD + birashobora guteza imbere selile ya myocardial kubaho no gusana, kugabanya ingano ya infarct, no kunoza imikorere yumutima.
Ingaruka za Neuroprotective: Mubitegererezo byindwara zifata ubwonko, kwiyongera kwa NAD + byerekana ingaruka zikomeye za neuroprotective. Ubushakashatsi bwerekanye ko kuzuzanya na NMN cyangwa NR bishobora guteza imbere imikorere yubwenge, kugabanya neuroinflammation, no kugabanya kwegeranya kwa poroteyine za neurotoxic. Mubyitegererezo byimbeba ya Alzheimer, kwiyongera hamwe na NAD + ibanziriza irashobora kugabanya umusaruro β-amyloide, bikabuza fosifori ikabije ya tau proteine, kurinda neurone kwangirika, bityo bigahindura ubushobozi bwo kwiga no kwibuka.
Igihe kirekire cyo kubaho: Mubinyabuzima bitandukanye byikitegererezo, kongera urwego rwa NAD + byagaragaye ko byongerera igihe. Muri nematode nisazi zimbuto, kongera urwego rwa NAD + binyuze muri manipulation genetique cyangwa kuzuzanya na NAD + ibanziriza irashobora kwagura ubuzima bwabo. Mubushakashatsi bwimbeba, kuzuza igihe kirekire hamwe na NMN cyangwa NR nabyo byerekanaga icyerekezo cyo kubaho igihe kirekire, nubwo izi ngaruka zishobora gutandukana mubushakashatsi butandukanye. Muri rusange, ibyagaragaye byerekana ingaruka nziza zo kongera urwego rwa NAD + mubuzima.
Umwanzuro
Nka coenzyme yingenzi muri selile, NAD + igira uruhare rukomeye mubikorwa byingenzi byumubiri nka metabolism yingufu, gusana ADN, no guhindura poroteyine nyuma yubusobanuro. Uko imyaka igenda yiyongera, kugabanuka kurwego rwa NAD + bifitanye isano rya bugufi no gusaza no gutangira n'indwara zitandukanye ziterwa n'imyaka. Ingamba zo kongera urwego rwa NAD +, nko kuzuza NAD + ibanziriza, kugenga imisemburo ya NAD + metabolike, hamwe n’ubuzima bwo mu mibereho, byagaragaje ingaruka zikomeye zo kurwanya gusaza mu bushakashatsi bw’inyamaswa, harimo kunoza imikorere ya metabolike, kurinda sisitemu yumutima nimiyoboro n’imitsi, ndetse no kuramba.
Inkomoko
[1] Chubanava S, Treebak J T. Imyitozo ngororamubiri isanzwe irinda neza kugabanuka kwatewe no gusaza kugabanuka kwimitsi ya skeletale NAD [J]. Ubushakashatsi bwa Gerontologiya, 2023.173: 112109.DOI: 10.1016 / j.exger.2023.112109.
[2] Soma M, Lalam S K. Uruhare rwa nicotinamide mononucleotide (NMN) mu kurwanya gusaza, kuramba, hamwe n’ubushobozi bwo kuvura indwara zidakira [J]. Raporo y’ibinyabuzima bya molecular, 2022,49 (10): 9737-9748.DOI: 10.1007 / s11033-022-07459-1.
[3] Kurisha A, Yera D, Cen Y. Abagenzuzi ba molekile Ntoya yibasiye NAD (+) Enzymes ya Biosynthetic [J]. Ubuvuzi bwa miti yubu, 2022.29 (10): 1718-1738.DOI: 10.2174 / 0929867328666210531144629.
[4] Yuan Y, Liang B, Liu X, n'abandi. Kwibasira NAD +: ni ingamba zisanzwe zo gutinda gusaza k'umutima? [J]. Ivumburwa ry'urupfu rw'akagari, 2022,8. https://api.semanticscholar.org/CorpusID:248393418
[5] Levine DC, Hong H, Weidemann BJ, n'abandi. NAD (+) Igenzura Gusubiramo Gahunda Zinyuze muri PER2 Guhindura Nucleaire Kurwanya Gusaza [J]. Akagari ka molekile, 2020,78 (5): 835-849.DOI: 10.1016 / j.molcel.2020.04.010.
[6] Fang EF, Hou Y, Lautrup S, n'abandi. Kwiyongera kwa NAD (+) kugarura mitofagy kandi bigabanya gusaza byihuse muri syndrome ya Werner [J]. Itumanaho rya Kamere, 2019,10 (1): 5284.DOI: 10.1038 / s41467-019-13172-8.
[7] Yaku K, Okabe K, Nakagawa T. NAD metabolism: Ingaruka zo gusaza no kuramba [J]. Isubiramo ry'ubushakashatsi, 2018,47: 1-17.DOI: 10.1016 / j.arr.2018.05.006.
[8] Chaturvedi P, Tyagi S C. NAD (+): Umukinnyi ukomeye mumitsi yumutima na skeletale kuvugurura no gusaza [J]. Ikinyamakuru cya Physiologiya ya Cellular, 2018,233 (3): 1895-1896.DOI: 10.1002 / jcp.26014.
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