發(fā)布時(shí)間：2018-05-06 10:36

  本文選題：SIV + 中國(guó)恒河猴��； 參考：《廣州中醫(yī)藥大學(xué)》2017年博士論文

【摘要】：目的:對(duì)比不同進(jìn)展類(lèi)型SIV感染中國(guó)恒河猴T淋巴細(xì)胞免疫活化水平,線粒體抗病毒蛋白水平,探索長(zhǎng)期不進(jìn)展型SIV感染猴的內(nèi)在病理機(jī)制。通過(guò)對(duì)不同進(jìn)展類(lèi)型SIV感染中國(guó)恒河猴的SIVmac239反復(fù)攻毒,探索長(zhǎng)期不進(jìn)展型感染猴免疫活化水平的穩(wěn)定性,以及反復(fù)感染對(duì)正常進(jìn)展型和長(zhǎng)期不進(jìn)展型SIV感染猴的影響。通過(guò)觀察青蒿琥酯對(duì)SIV感染中國(guó)恒河猴免疫活化水平的干預(yù)作用,從調(diào)節(jié)免疫異常激活的角度尋找中醫(yī)藥干預(yù)艾滋病的治療策略。方法:1.不同進(jìn)展類(lèi)型SIV感染中國(guó)恒河猴模型免疫特征對(duì)比研究:將17只中國(guó)恒河猴按照是否感染,感染后血漿病毒載量,以及感染后存活時(shí)間,分為健康對(duì)照(healthy control,HC)組;典型進(jìn)展(typical progressor,TP)組;長(zhǎng)期不進(jìn)展(viremiccontrollor,VC)組;精英控制(elite controllor,EC)組。檢測(cè)免疫活化調(diào)節(jié)相關(guān)指標(biāo),兩周后重復(fù)檢測(cè)以驗(yàn)證相關(guān)指標(biāo)的穩(wěn)定性。2.中國(guó)恒河猴SIV重復(fù)攻毒研究:SIV感染中國(guó)恒河猴8只,其中正常進(jìn)展型4只,精英控制型4只。4只正常進(jìn)展型恒河猴隨機(jī)分為攻毒組和對(duì)照組,每組2只;4只精英控制型恒河猴隨機(jī)分為攻毒組和對(duì)對(duì)照組,每組2只。攻毒組在第0周、第4周和第8周以5MID100(5倍100%感染劑量)靜脈注射SIVmac239病毒懸液1 mL。3.青蒿琥酯對(duì)SIV感染中國(guó)恒河猴模型干預(yù)研究:健康中國(guó)恒河猴8只,復(fù)制艾滋模型,待進(jìn)展到平臺(tái)期,分為2組,青蒿琥酯治療組4只,生理鹽水對(duì)照組4只。青蒿琥酯連續(xù)給藥8周,分別于給藥前,給藥后2周、4周、6周、8周,停藥后4周、8周檢測(cè)免疫活化調(diào)節(jié)相關(guān)指標(biāo)。結(jié)果:1.不同進(jìn)展類(lèi)型SIV感染中國(guó)恒河猴模型免疫特征對(duì)比研究結(jié)果TP組病毒載量為典型的潛伏期水平,平均值為lg 5.25 copies/ml。VC組較TP組低(P0.05),平均值為lg4.02 copies/ml。EC組病毒載量長(zhǎng)期處于測(cè)不出的水平,即小于50copies/ul。HC組、TP組和EC組白細(xì)胞計(jì)數(shù)相近,VC組高于其他三組。HC組CD4細(xì)胞比例最高,三個(gè)感染組之間未見(jiàn)明顯差異,都略低于HC組。CD4計(jì)數(shù)是TP組最低,略低于其他三組。CD8細(xì)胞比例四組恒河猴未見(jiàn)明顯差異。HC組CD4/CD8比值高于其他三個(gè)感染組,TP、VC和EC組CD4/CD8比值無(wú)差異。四個(gè)組中,TP單核細(xì)胞比例平均數(shù)最高,其次是VC組和EC組,HC組最低。單核細(xì)胞計(jì)數(shù)是VC組最高,其次是TP組和EC組,HC組最低。HC組恒河猴CD4細(xì)胞表面CD69表達(dá)水平維持在較低水平,其他三組感染猴都有不同程度的升高。TP組CD69水平最高,明顯高于其他三個(gè)組,與HC組之間差異最大(P0.01),而VC組和EC組低于TP組,但是高于HC組。四組恒河猴CD4細(xì)胞表面CD25表達(dá)水平的相對(duì)情況與CD69類(lèi)似,TP組最高(與HC組比較P0.01),VC組次之(與HC組比較P0.05)。HC猴CD8細(xì)胞的CD69表達(dá)水平較低,而另外三組恒河猴則有所升高。CD8細(xì)胞CD25表達(dá)水平與CD69情況相似,HC組水平較低而其他三組都略有升高,TP組升高最明顯。TP型恒河猴和VC型恒河猴CD4細(xì)胞的CD38表達(dá)水平高于HC猴。EC型恒河猴CD38表達(dá)水平低于TP組(P0.01)和VC組(P0.01)。EC組CD4細(xì)胞HLA-DR表達(dá)與TP組(P0.05)和VC組(P0.05)差異顯著。EC組CD38表達(dá)比例低于HC猴,平均值在10%以下,但是兩組差異無(wú)統(tǒng)計(jì)學(xué)顯著性。EC組CD8細(xì)胞CD38表水平TP組(P0.01)和VC組(P0.05)差異顯著。EC組CD8細(xì)胞表達(dá)HLA-DR表達(dá)與TP組(P0.01)和VC組(P0.01)比較有統(tǒng)計(jì)學(xué)差異。三個(gè)感染組恒河猴CD4細(xì)胞PD-1表達(dá)水平相近,HC組略高于三個(gè)感染組。CD8細(xì)胞的PD-1表達(dá)水平也是三個(gè)感染組水平相似,但是相較HC組有所下降,且下降幅度大于CD4細(xì)胞結(jié)果。組間比較在統(tǒng)計(jì)學(xué)上無(wú)顯著性。三個(gè)感染組SIV特異性CD8細(xì)胞比值都有所下降,其中EC組下降最少,其次是VC組。TP猴SIV特異性CD8比值下降最嚴(yán)重,與HC猴差異顯著(P0.01)。EC組明顯高于TP組(P0.01)。SIV特異性CD8細(xì)胞絕對(duì)值,TP組低于HC組,而VC組和EC組則高于HC組,其中EC組最高,但統(tǒng)計(jì)學(xué)上無(wú)顯著性。SIV特異性CD8細(xì)胞的PD-1表達(dá)水平,VC和EC兩個(gè)長(zhǎng)期不進(jìn)展組與HC在同一水平,TP組均數(shù)高于其他三組。SIV感染中國(guó)恒河猴CD8細(xì)胞CD38表達(dá)水平和HLA-DR表達(dá)水平均與SIV特異性CD8細(xì)胞比值成反比。VC和EC兩個(gè)長(zhǎng)期不進(jìn)展組Treg比值與HC組基本一致,而TP顯著高于另外三個(gè)組,差異有統(tǒng)計(jì)學(xué)意義。Treg絕對(duì)數(shù)在四組恒河猴中未見(jiàn)明顯差異,TP組均值略高于其他三組。在全部17只恒河猴中,Treg的Ki67表達(dá)率顯著高于非Treg CD4細(xì)胞,前者中位數(shù)大約是后者的12倍。在全部4組恒河猴的CD4細(xì)胞中,CTLA-4在Treg上的表達(dá)率明顯高于在非Treg細(xì)胞上的表達(dá)比例。VC和EC兩個(gè)長(zhǎng)期不進(jìn)展組相比HC組和TP組,CTLA-4表達(dá)水平都有下調(diào),TP和VC、EC組之間差異顯著(P0.05)。CTLA-4在非Treg上的表達(dá)水平,TP高于其他三組。2.中國(guó)恒河猴SIV重復(fù)感染實(shí)驗(yàn)研究正常進(jìn)展型恒河猴TP-A在第一次攻毒后出現(xiàn)乏力、畏寒、消瘦,在第22天死亡,尸體行系統(tǒng)解剖,未見(jiàn)明顯異常。其余恒河猴未見(jiàn)明顯癥狀。精英控制猴EC-A病毒載量無(wú)變化,EC-B在第三次攻毒后上升至可測(cè)水平,但水平保持在3以下,維持至少8周,在第三次攻毒后16周之前恢復(fù)至測(cè)不出水平。TP-A猴在第一次攻毒后白細(xì)胞明顯下降,第2周達(dá)到最低點(diǎn),第3周有所回升。TP-B猴在第二次攻毒后白細(xì)胞有所上升,持續(xù)3周后恢復(fù)到實(shí)驗(yàn)前水平。實(shí)驗(yàn)第16周后有所下降。EC-A和EC-B在重復(fù)攻毒后白細(xì)胞出現(xiàn)反復(fù)波動(dòng),最高水平達(dá)12×103/μl,最低低至12×103/μl,第三次攻毒4周后趨于穩(wěn)定。TP-B猴在二次攻毒后淋巴細(xì)胞比值波動(dòng)增大,第三次攻毒后緩慢上升。EC-A和EC-B在第一次和第三次攻毒后淋巴細(xì)胞比值有所波動(dòng),波動(dòng)結(jié)束后數(shù)值高于實(shí)驗(yàn)前。TP-B猴純真CD4細(xì)胞比值在第一次攻毒后波動(dòng)較大,第二次和第三次攻毒后波動(dòng)明顯減小,但數(shù)值都略低于攻毒前。TP-A猴在第一次攻毒后CD4細(xì)胞增殖水平上升,2周后下降。TP-B猴純真CD4細(xì)胞在第一次和第二次攻毒后低于反復(fù)攻毒前水平。TP-B純真CD8細(xì)胞在第二次攻毒后明顯低于實(shí)驗(yàn)前。TP-A猴在第一次攻毒后Treg比值大幅上升。TP-A猴Treg細(xì)胞CTLA-4表達(dá)水平在第一次攻毒后迅上升,2周后達(dá)到最高點(diǎn)后開(kāi)始下降。TP-A猴在第一次攻毒后CD4細(xì)胞CD38表達(dá)水平迅速大幅上升,第3周達(dá)到實(shí)驗(yàn)前大約3倍水平,而TP-B猴在每次攻毒后出現(xiàn)下降。TP-A猴CD4細(xì)胞HLA-DR表達(dá)水平在第一次攻毒后持續(xù)上升,直至第3周。TP-B猴CD8細(xì)胞CD38表達(dá)水平在第二次攻毒1周后大幅上升,隨后維持在較高水平維持相對(duì)波動(dòng)。TP-A猴在第一次攻毒后CD8細(xì)胞HLA-DR表達(dá)水平迅速大幅下降直至第3周。3.青蒿琥酯治療SIV感染中國(guó)恒河猴模型的實(shí)驗(yàn)研究給藥8周內(nèi),白細(xì)胞計(jì)數(shù)從第4周開(kāi)始下降,第6周降至最低點(diǎn)后開(kāi)始回升。停藥后白細(xì)胞繼續(xù)上升,停藥4周回升至下降前水平。給藥第6周淋巴細(xì)胞比例上升至最高點(diǎn),明顯高于對(duì)照組(P0.05),隨后下降。給藥8周內(nèi),治療組嗜中性粒細(xì)胞比例從第4周開(kāi)始出現(xiàn)下降,至第6周明顯低于對(duì)照組(P0.05),后緩慢回升。給藥組CD8細(xì)胞比例和計(jì)數(shù)在停藥后較對(duì)照組低,其中停藥4周和8周CD8比例的差異有統(tǒng)計(jì)學(xué)意義(P0.05)。在給藥4周,給藥組CD8細(xì)胞的CD69表達(dá)水平明顯低于對(duì)照組(P0.05)。給藥后,治療組CD8細(xì)胞HLA-DR和CD38表達(dá)水平開(kāi)始下降,到第4周兩者都明顯低于對(duì)照組(P0.05)。該兩項(xiàng)指標(biāo)從第6周開(kāi)始回升,兩組差異消失。給藥2周后HLA-DR+CD8細(xì)胞計(jì)數(shù)下降百分比明顯大于對(duì)照組(P0.01),停藥4周和8周下降百分比也大于對(duì)照組(P0.05)。給藥第2周和停藥第4周,CD38+CD8細(xì)胞計(jì)數(shù)下降百分比都大于對(duì)照組(P0.05)。給藥后4周,CD8細(xì)胞CD107a表達(dá)下降。結(jié)論:結(jié)論一:長(zhǎng)期不進(jìn)展型較正常進(jìn)展型有更完善的CD8細(xì)胞功能。CD4/CD8比值不能評(píng)價(jià)SIV感染中國(guó)恒河猴的病程進(jìn)展類(lèi)型。長(zhǎng)期不進(jìn)展型SIV感染中國(guó)恒河猴CD4 T淋巴細(xì)胞和調(diào)節(jié)性T細(xì)胞活化明顯低于正常進(jìn)展猴,其中精英控制型恒河猴CD8 T淋巴細(xì)胞活化明顯低于正常進(jìn)展猴。CD8細(xì)胞異常激活水平越高,對(duì)SIV具有殺傷性的細(xì)胞比例就越低。存在除了抗病毒免疫以外的其他抑制淋巴細(xì)胞異常激活的機(jī)制。結(jié)論二:精英型SIV感染中國(guó)恒河猴淋巴細(xì)胞免疫水平的穩(wěn)定性較典型進(jìn)展型恒河猴強(qiáng)。重復(fù)攻毒可抑制TP猴CD4細(xì)胞和CD8細(xì)胞更新,加速TP猴病情進(jìn)展,可使EC型恒河猴病毒量一過(guò)性上升。。結(jié)論三:青蒿琥酯可改善SIV感染中國(guó)恒河猴細(xì)胞毒性T細(xì)胞免疫異常激活。青蒿琥酯治療中出現(xiàn)的嗜中性粒細(xì)胞下降是可逆的。
[Abstract]:Objective: To compare the immune activation level of T lymphocyte in Chinese Ganges RIver monkeys with different progressive types of SIV, the level of mitochondrial antiviral protein and explore the internal pathological mechanism of long term non progressive SIV infected monkeys. Through repeated attack on the SIVmac239 of different progressive type SIV infected Ganges RIver monkeys in China, the immune activation of chronic infective monkeys was explored. Level stability, and the effect of repeated infection on normal progressing and long-term unprogressing SIV infected monkeys. Through the observation of the intervention of artesunate to the immune activation level of SIV infected Ganges RIver monkeys in China, from the angle of regulating the activation of immune abnormality, the treatment strategy of interfering with AIDS was found. Method: 1. different SIV sense of different progression types Comparative study on immune characteristics of Ganges RIver monkey model: 17 Chinese Ganges RIver monkeys were divided into healthy control (healthy control, HC) group according to whether infection, post infection plasma viral load, and the survival time after infection; typical progress (typical progressor, TP) group; long term non progression (viremiccontrollor, VC) group; elite control (Elite controllor,) EC group. Detection of immune activation regulation related indicators, two weeks after repeated tests to verify the stability of the related indicators.2. Chinese Ganges RIver monkey SIV repeat attack study: SIV infected 8 Chinese monkeys, of which 4 were normal progressing, 4 of elite control type.4 normal progressive Ganges RIver monkeys were divided into the attack group and the control group, 2 in each group; 4 Elite control The Ganges RIver monkey was randomly divided into the attack group and the control group, with 2 rats in each group. In the zeroth week, fourth and eighth weeks, the SIVmac239 virus suspension of 1 mL.3. artesunate was injected with 5MID100 (5 times the 100% infection dose) to the intervention study of the Chinese Ganges RIver monkey model infected by SIV: 8 healthy Chinese Ganges RIver monkeys, replicating the AIDS model, and waiting for the platform stage, 2 groups were divided into 2 groups: artesunate treatment group 4, saline control group 4. Artesunate was given for 8 weeks, respectively, before administration, 2 weeks, 4 weeks, 6 weeks, 8 weeks after administration, 4 weeks after stopping, 8 weeks to detect immune activation regulation related indexes. Results: the immune response of TP group of Ganges RIver monkey model in different types of advanced types of advanced type 1. infection For the typical latent period level, the average value of LG 5.25 copies/ml.VC group was lower than that of the TP group (P0.05), the average value of the lg4.02 copies/ml.EC group was not found for a long time, that is, less than the 50copies/ul.HC group, the white cell count of TP and EC groups was similar, and the VC group was higher than the other three groups of.HC group, and the three infected groups were not found. The significant difference was slightly lower than group HC.CD4 count is the lowest in group TP, slightly lower than the proportion of other three groups of.CD8 cells in four groups of Ganges RIver monkeys, no significant difference in.HC group CD4/CD8 ratio is higher than the other three infection groups, TP, VC and EC group CD4/CD8 ratio no difference. Four groups, TP mononuclear ratio is the highest, followed by VC group and group, the lowest. Mononuclear group. Cell count was the highest in group VC, followed by group TP and group EC. The CD69 expression level of CD4 cell surface in the lowest.HC group of group HC was maintained at a lower level. The other three groups of infected monkeys had the highest level of CD69 in the.TP group, obviously higher than the other three groups, and the difference between the HC group and the HC group (P0.01), while the VC group and the group were lower than those in the.TP group, but higher but higher than those in the group. In group HC, the relative level of CD25 expression on the surface of CD4 cells in four groups of Ganges RIver monkeys was similar to that of CD69. Group TP was the highest (compared with HC group, P0.01), VC group was lower (compared with HC group, P0.05).HC monkey CD8 cell expression level was lower, while the other three groups were higher than those in the other groups. The level of CD38 expression in the CD4 cells of the.TP Ganges RIver monkey and VC type Ganges RIver monkey was higher than that of the HC monkey.EC type Ganges RIver monkey. The expression level of the CD38 expression level was lower than that of the TP group (P0.01) and the VC group (P0.01). In the two groups, there was no significant difference in the CD8 cell CD38 surface level TP group (P0.01) and VC group (P0.05) in group.EC, and the expression of CD8 cell HLA-DR expression in.EC group was significantly different from that in TP group (P0.01) and that of the three group. The expression level of Ganges RIver monkey cells was similar, and the group was slightly higher than that of the three infected groups. The level of PD-1 expression was also similar in the three infection groups, but compared with the HC group, the decrease was greater than that of the CD4 cells. The comparison between the groups was not statistically significant. The ratio of SIV specific CD8 cells in the three infected groups decreased, and the EC group decreased the least, followed by the SIV specific CD8 ratio of the.TP monkey in the VC group was the most serious, and the most serious. The difference of HC monkey significantly (P0.01) was significantly higher than that of group TP (P0.01).SIV specific CD8 cell absolute value, TP group was lower than group HC, while VC and EC group was higher than HC group, which was the highest in group.EC, but there was no significant difference between two groups of long period non progression and other three. The CD38 expression level and HLA-DR expression level of group.SIV infected Ganges RIver monkey CD8 cells were inversely proportional to the ratio of SIV specific CD8 cells to.VC and EC, the Treg ratio was basically consistent with the HC group, while TP was significantly higher than the other three groups. There was no significant difference between the absolute number of the four groups of the four groups of Ganges RIver monkeys. The value of Treg was significantly higher than that of the other three groups. The Ki67 expression rate of Treg was significantly higher than that of non Treg CD4 cells, the median of the former was about 12 times that of the latter. In all 4 groups of Ganges RIver monkey CD4 cells, the expression rate of CTLA-4 in Treg was significantly higher than that in the non Treg cell expression.VC and EC two long-term non progression groups compared to the HC group and the HC group. TP group, the expression level of CTLA-4 was down, TP and VC, the difference between EC group was significant (P0.05) the expression level of.CTLA-4 in non Treg, TP higher than the other three groups of.2. Chinese monkey SIV repeated infection experimental study of normal progressive Ganges RIver monkey TP-A in the first attack after the first attack of fatigue, fear cold, emaciation, died in twenty-second days, the body was dissected, the body dissection, no systematic anatomy, not seen There was no obvious symptom in the other Ganges RIver monkeys. The elites control monkey EC-A virus load did not change, the EC-B increased to the measurable level after the third attack, but the level remained below 3, maintained at least 8 weeks, and recovered to the undetected.TP-A monkey before the first attack of poison after the third attack, and the leukocyte decreased significantly after the first attack of poison, and reached second weeks. The lowest point, third weeks after the recovery of.TP-B monkeys after second attacks of white blood cells increased, after 3 weeks after the recovery to the pre experiment level. After sixteenth weeks, the experiment decreased.EC-A and EC-B after repeated attacks of leukocytes repeated fluctuations, the highest level of 12 x 103/ Mu L, the lowest to 12 * 103/ Mu L, third times after 4 weeks of attack to stabilize.TP-B monkey The fluctuation of lymphocyte ratio increased after the two attack of poison. After the third attack, the ratio of.EC-A and EC-B fluctuated at the first and third times of attack. The value of the pure CD4 cell ratio of the.TP-B monkey was higher than that before the experiment. The fluctuation of the ratio of the pure CD4 cells after the first attack was larger, and the fluctuation of the second and third attack after the attack was obviously reduced. Small, but the value is slightly lower than before the first attack of.TP-A monkey CD4 cell proliferation level after the first attack, 2 weeks after the decrease of.TP-B monkey pure CD4 cells after the first and second attacks were lower than before repeated attack of.TP-B pure CD8 cells after second attacks were significantly lower than before the first attack of the Treg ratio of the.TP-A monkey after the first attack on the Treg ratio. The expression level of CTLA-4 in the Treg cell of.TP-A monkey increased rapidly after the first attack. After 2 weeks, the expression level of CD38 in the CD4 cell of the.TP-A monkey increased rapidly after the first attack, and the level of the CD38 was about 3 times before the experiment, while the TP-B monkey decreased the CD4 cell HLA-DR expression level in.TP-A monkey after each attack. After the first attack of poison, the CD38 expression level of CD8 cells in.TP-B monkeys increased significantly after the second attack for 1 weeks, and then maintained at a relatively high level of relative fluctuation in the HLA-DR expression level of CD8 cells in CD8 cells after the first attack of poison to the third weeks of.3. artesunate for SIV infection in China's Ganges RIver monkey model. In the 8 weeks, the white blood cell count began to decline from fourth weeks and to the lowest point after sixth weeks. After the drug stopped, the leukocyte continued to rise and the drug was stopped for 4 weeks to the pre descending level. The proportion of lymphocytes increased to the highest point for sixth weeks, obviously higher than the control group (P0.05), and then decreased. The treatment group was neutrophils within 8 weeks. The ratio of cells decreased from fourth weeks to sixth weeks, obviously lower than that of the control group (P0.05), and then slowly recovered. The proportion and count of CD8 cells in the administration group were lower than those of the control group, of which the difference in the proportion of CD8 in 4 weeks and 8 weeks was statistically significant (P0.05). The expression level of CD8 cells in the administration group was significantly lower than that of the control group for 4 weeks (P0 .05). After administration, the expression level of HLA-DR and CD38 in the CD8 cells in the treatment group began to decrease, and both were significantly lower than the control group at fourth weeks (P0.05). The two indexes began to rise from sixth weeks and the two groups disappeared. The percentage of HLA-DR+CD8 cell counts decreased significantly after 2 weeks of Administration (P0.01), and the percentage of the decrease in 4 and 8 weeks was greater than that of the control group. The percentage of CD38+CD8 cell counts decreased more than that of the control group (P0.05) for second weeks and fourth weeks. Conclusion: the CD107a expression of CD8 cells decreased at 4 weeks after administration. Conclusion: a better CD8 cell function.CD4/CD8 ratio of long-term non progression type than normal progression type can not evaluate the progression of SIV infection of Ganges RIver monkeys in China. The activation of CD4 T lymphocyte and regulatory T cell in Chinese Ganges RIver monkey was significantly lower than that of normal progressing monkey. The activation of CD8 T lymphocyte in the elite controlled Ganges RIver monkey was significantly lower than that of normal progressing monkey.CD8 cells, the higher the abnormal activation level of.CD8 cells, the lower the percentage of cytotoxic cells to SIV. Other mechanisms other than immunization to inhibit the abnormal activation of lymphocyte. Conclusion two: the stability of lymphocyte immunity in Ganges RIver monkey is stronger than that of typical progressive Ganges RIver monkey. Repeated attack can inhibit the renewal of CD4 and CD8 cells in TP monkey and accelerate the progression of TP monkey, which can increase the amount of EC type Ganges RIver monkey virus in one over sex. Three: artesunate can improve the activation of immune abnormalities in the cytotoxic T cells of SIV infected Ganges RIver monkeys in China. The neutrophils decline in artesunate treatment is reversible.

【學(xué)位授予單位】：廣州中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R259;R-332

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