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蓝舌病病毒利用泛素−蛋白酶体系统调控视黄酸诱导基因I信号传导

鲁丹枫, 张振兴, 李占鸿, 朱沛, 李卓然

鲁丹枫, 张振兴, 李占鸿, 等. 蓝舌病病毒利用泛素−蛋白酶体系统调控视黄酸诱导基因I信号传导[J]. 华南农业大学学报, 2025, 46(4): 480-491. DOI: 10.7671/j.issn.1001-411X.202412036
引用本文: 鲁丹枫, 张振兴, 李占鸿, 等. 蓝舌病病毒利用泛素−蛋白酶体系统调控视黄酸诱导基因I信号传导[J]. 华南农业大学学报, 2025, 46(4): 480-491. DOI: 10.7671/j.issn.1001-411X.202412036
LU Danfeng, ZHANG Zhenxing, LI Zhanhong, et al. Bluetongue virus regulates retinoic acid inducible gene I signal transduction through the ubiquitin-proteasome system[J]. Journal of South China Agricultural University, 2025, 46(4): 480-491. DOI: 10.7671/j.issn.1001-411X.202412036
Citation: LU Danfeng, ZHANG Zhenxing, LI Zhanhong, et al. Bluetongue virus regulates retinoic acid inducible gene I signal transduction through the ubiquitin-proteasome system[J]. Journal of South China Agricultural University, 2025, 46(4): 480-491. DOI: 10.7671/j.issn.1001-411X.202412036

蓝舌病病毒利用泛素−蛋白酶体系统调控视黄酸诱导基因I信号传导

基金项目: 

云南省万人计划青年拔尖人才专项(YNWR-QNBJ-2020-211);国家自然科学基金(32360883,32460889);云南省热带亚热带动物病毒病重点实验室开放课题(2024RW002)

详细信息
    作者简介:

    鲁丹枫,主要从事动物虫媒病毒研究,E-mail: ldf3129554@163.com

    通讯作者:

    李卓然,主要从事动物虫媒病毒研究,E-mail: lizhuoran85@126.com

  • 中图分类号: S855.3

Bluetongue virus regulates retinoic acid inducible gene I signal transduction through the ubiquitin-proteasome system

  • 摘要:
    目的 

    视黄酸诱导基因I(Retinoic acid inducible gene I, RIG-I)泛素化修饰链上第48位赖氨酸(Lysine, Lys)残基连接的多泛素链能够调控RIG-I蛋白的稳定性,以防止RIG-I信号和宿主抗病毒反应的过度激活。本研究旨在探讨蓝舌病病毒(Bluetongue virus, BTV)是否也通过影响RIG-I的泛素化修饰调控其信号传导而利于自身增殖。

    方法 

    以BTV感染永生化绵羊肺动脉血管内皮(Sheep pulmonary artery endothelial cells, SPAE)细胞,分别利用蛋白酶体抑制剂MG-132和去泛素化酶(Deubiquitinase, DUB)抑制剂PR-619处理细胞,通过RT-qPCR分别检测环指蛋白125(Ring finger protein 125, RNF125)、泛素特异性蛋白酶4(Ubiquitin-specific protease 4, USP4)、RIG-I、干扰素调节因子3(Interferon regulatory factor 3, IRF3)和干扰素α(Interferon α, IFN-α)的转录水平以及BTV基因组拷贝数;利用免疫印迹(Western blotting)和ELISA检测以上蛋白的表达水平;采用免疫荧光(Immunofluorescence)检测IRF3核转移水平。

    结果 

    BTV感染上调RNF125、RIG-I、IRF3和IFN-α的转录和表达水平,转录水平上调1.20~8.68倍,表达水平上调0.06~3.94倍;尽管USP4的转录水平轻微上调,但是表达水平下调。蛋白酶体抑制剂MG-132显著抑制RIG-I的降解,并导致IRF3细胞核转移率在感染后24 h(24 hour post-infection, 24 hpi)和48 hpi较未处理对应组别分别上升9.67%和8.66%,IFN-α表达水平在48 hpi上调至未处理对应组别的2.18倍,BTV基因组拷贝数在24和48 hpi分别降低至未处理对应组别的73.63%和85.37%。DUB抑制剂PR-619处理明显促进RIG-I降解,IRF3细胞核转移率在24和48 hpi较未处理对应组别分别下降8.00%和16.67%,IFN-α表达水平在24 hpi下调至未处理对应组别的56.50%,BTV基因组拷贝数在24和48 hpi分别增加至未处理对应组别的0.92和0.49倍。

    结论 

    BTV利用泛素−蛋白酶体系统(Ubiquitin-proteasome system)调控宿主RIG-I信号传导而利于自身增殖。

    Abstract:
    Objective 

    The polyubiquitin chain linked to lysine (Lys) residues at 48th position of ubiquitination modification chain of retinoic acid inducible gene I (RIG-I) regulates RIG-I protein stability to prevent over-activation of RIG-I signaling and host antiviral responses. The aim of the study was to explore whether bluetongue virus (BTV) also regulated RIG-I signaling by affecting ubiquitination modification of RIG-I for its own reproductive benefit.

    Method 

    The immortalized sheep pulmonary artery endothelial cells (SPAE) were infected with BTV, and then were treated with the proteasome inhibitor MG-132 and the deubiquitinase (DUB) inhibitor PR-619, respectively. The transcriptional levels of ring finger protein 125 (RNF125), ubiquitin-specific protease 4 (USP4), RIG-I, interferon regulatory factor 3 (IRF3), and interferon α (IFN-α), along with the genomic copy numbers of BTV were detected using RT-qPCR. The expression levels of proteins mentioned above were detected with Western blotting and ELISA. Immunofluorescence were conducted to analyze the nuclear translocation ratio of IRF3.

    Result 

    BTV infection upregulated the transcriptional levels of RNF125, RIG-I, IRF3, and IFN-α from 1.20 to 8.68-fold, and expression levels from 0.06 to 3.94-fold, respectively. Although the transcriptional level of USP4 gene slightly increased, the expression level of USP4 was downregulated. Treatment with the proteasome inhibitor MG-132 significantly suppressed RIG-I degradation induced by BTV infection; The nuclear translocation ratio of IRF3 in MG-132 treated SPAE cells increased by 9.67% and 8.66% compared with their untreated counterparts at 24 hours post-infection (24 hpi) and 48 hpi; The expression level of IFN-α increased by 2.18-fold comparing with that of the corresponding untreated group at 48 hpi; The genomic copy numbers of BTV decreased to 73.63% and 85.37% of those of the untreated counterparts at 24 and 48 hpi, respectively. Treatment with DUB inhibitor PR-619 obviously promoted RIG-I degradation; The nuclear translocation ratio of IRF3 in PR-619 treated SPAE cells decreased by 8.00% and 16.67% compared with their untreated counterparts at 24 and 48 hpi; The expression level of IFN-α decreased to 56.50% comparing with that of the corresponding untreated group at 24 hpi; The copy numbers of BTV genome increased to 0.92-fold and 0.49-fold of the untreated counterparts at 24 and 48 hpi, respectively.

    Conclusion 

    BTV utilized the ubiquitin-proteasome system (UPS) to regulate host RIG-I signaling to favor viral propagation.

  • 全氟辛酸(Perfuorooctanoic aid, PFOA)是一种耐光解、水解和生物降解的人工合成的全氟类化合物,因含有诸多碳氟键而具有极其稳定的性质,常被用作防油脂或防水剂以及衣服、家具和其他产品的保护性涂层,此外还可用作地板抛光剂、黏合剂、消防泡沫和电线绝缘等[1-3]。随着PFOA的广泛应用,在大气、河流、土壤等环境介质中均检测出PFOA残留:上海市41个室内灰尘样本中PFOA平均质量分数为279.4 ng/g,长江流域重庆段地表水中PFOA的检出率为100%,质量浓度在1.16~49.87 ng/L之间,全国31个省(自治区、直辖市)土壤中PFOA 的平均质量分数为0.35 ng/g[4-6],人类和动物可通过饮食饮水等方式暴露于PFOA,且由于PFOA半衰期长,有生物累积效应,故能在体内聚积,进而引发毒性,但不同物种、不同暴露年龄,引发毒性的浓度不同且差异较大[7]。研究发现,PFOA具有免疫毒性、发育毒性和内分泌干扰毒性[8]。在雌性生殖系统中,PFOA暴露会抑制卵巢激素分泌,损害卵泡发育,导致卵巢功能丧失[9]。并且PFOA还可通过氧化应激和凋亡显著抑制孕鼠黄体功能[10]。此外,新生大鼠注射PFOA可以减少生长卵泡和次级卵泡的数量[11]。虽然已有研究报道了PFOA暴露对生殖系统的影响,但关于PFOA对卵母细胞影响的研究依然很少。已知PFOA可以通过血卵屏障进入卵泡液[12],本试验通过给小鼠灌服PFOA模拟体内暴露来探讨其对小鼠卵母细胞成熟率及成熟质量的影响。通过检测活性氧(Reactive oxygen species,ROS)水平、纺锤体形态、细胞骨架来评估卵母细胞暴露于PFOA后的细胞变化。本研究将有助于揭示PFOA影响卵母细胞发育过程的毒理学机制,并引起人们对PFOA安全性的关注。

    6周龄体质量相近的昆明雌性小鼠,购买于广东省实验动物中心。

    PFOA(171468, Sigma),ROS检测试剂盒 (S0033, Beyotime),β-tubulin (T5293, Sigma),内磷酸化组蛋白H2A.X(Phospho-histone H2A.X,P-H2A.X,sc-51748, Santa Cruz),FITC偶联山羊抗鼠IgG (A11029, LIFE),Hoechst 33342 (H3570, LIFE),孕马血清促性腺激素(PMSG,宁波第二激素厂),人绒毛膜促性腺激素(hCG,宁波第二激素厂),透明质酸酶(H3506,Sigma)

    PFOA:超纯水溶解,配制不同浓度的PFOA以使得最终基于小鼠体质量的质量分数为0、5、10和20 mg/kg。

    CO2培养箱,体视显微镜,荧光倒置显微镜。

    将160只6周龄的昆明小鼠随机分为对照组、低剂量组、中剂量组和高剂量组,每个剂量组5个重复,每个重复8只小鼠。分笼后,先适应环境7 d,再进行药物灌服试验。饲养环境为12 h光照、12 h 黑暗交替,饮食饮水自由。

    适应环境1周后,以每天0、5、10、20 mg/kg的剂量分别给对照组、低剂量组、中剂量组和高剂量组小鼠灌服PFOA,每次灌服0.2 mL,连续灌服14 d。剂量及时间的选定参照PFOA相关的体内试验[13]

    小鼠连续灌服PFOA 2周后进行超排处理,每只小鼠注射10 IU PMSG,间隔48 h后注射10 IU hCG,再间隔13.5 h后颈部脱臼处死,用体积分数为75%的乙醇溶液浸泡30 s消毒,随后解剖取出输卵管,找到膨大部,在含有PBS缓冲液的培养皿中用尖头镊撕开膨大部,用口吸管移出卵母细胞,放入预热好的1 g/L的透明质酸酶溶液中,处理2 min,待颗粒细胞脱掉以后将卵母细胞转移至PBS缓冲液中洗3遍。收集同一剂量处理组的小鼠卵母细胞至少100个。

    卵母细胞排出第一极体视为成熟,取出卵母细胞后统计第一极体的排出率。

    每个剂量组随机取25~30个卵母细胞放入含有1 μmol/L DCFH-DA的成熟培养液液滴中洗涤2~3遍,再放入37 ℃、CO2体积分数为5%的培养箱孵育20 min。而后用DPBS-PVA缓冲液洗3次,每次1 min。在荧光显微镜下用同一曝光参数观察并拍照,应用ImageJ软件分析平均荧光强度[14]

    四孔板每个孔加入200 μL固定液,然后置于37 ℃、CO2体积分数为5%的培养箱预热30 min,每个剂量组随机取25~30个卵母细胞置入四孔板中,于培养箱中固定30 min。然后将卵母细胞放入加有洗脱缓冲液的四孔板中于培养箱内封闭2 h。再用β-tubulin(按照1∶1000的体积比稀释)或P-H2A.X(按照1∶200的体积比稀释) 4 ℃条件下孵育过夜。次日用洗脱缓冲液洗涤3次,每次10 min。然后与FITC偶联山羊抗鼠IgG(按照1∶100的体积比稀释)在37 ℃条件下孵育1 h。之后,避光环境下用洗脱缓冲液洗涤3次,每次10 min。用Hoechst 33342室温下进行DNA染色5 min。最后,将卵母细胞固定在载玻片上,并在荧光显微镜下观察和拍照。

    每组试验重复5次,用SPSS 23.0进行单因素方差分析,采用LSD法进行多重比较分析,数据结果以平均值±标准误表示,作图软件为GraphPad 8。

    与对照组相比,每日灌服不同剂量(5、10和20 mg/kg)PFOA小鼠的卵母细胞成熟率有明显下降(表1)。10和20 mg/kg剂量组小鼠的卵母细胞成熟率分别下降了14.28%和28.17%;5 mg/kg剂量组和对照组差异不显著(P>0.05),10 mg/kg组和对照组差异显著(P<0.05),20 mg/kg组和对照组差异极显著(P<0.01)。5、10和20 mg/kg组别之间两两相比差异显著(P<0.05)。

    表  1  PFOA对小鼠卵母细胞成熟率的影响
    Table  1.  Effect of PFOA on maturation of mouse oocytes
    每日剂量/(mg·kg−1)
    Daily dose
    细胞总数
    Total cell count
    第一极体排出率1)/%
    Discharge rate of first polar body
    0(CK) 108 91.23±0.010a
    5 111 85.50±0.123a
    10 104 78.20±0.015b
    20 101 65.53±0.372c
     1) 同列数据后的不同小写字母表示差异显著(P<0.05, LSD法)
     1)Different lowercase letters in the same column indicate significant differences(P<0.05, LSD method)
    下载: 导出CSV 
    | 显示表格

    与对照组相比,每日灌服不同剂量PFOA小鼠的卵母细胞内ROS含量有明显升高(图1)。10和20 mg/kg组中卵母细胞内ROS含量分别升高了135%和177%;5 mg/kg组和对照组差异不显著(P>0.05),10和20 mg/kg组与对照组相比差异显著(P<0.05),10与20 mg/kg组之间差异不显著(P>0.05)(图2)。

    图  1  不同剂量 PFOA暴露的卵母细胞内活性氧(ROS)荧光图像
    Figure  1.  Fluorescence images of reactive oxygen species (ROS) in oocytes exposed to different doses of PFOA
    a: 0 (CK);b: 5 mg/kg;c: 10 mg/kg;d: 20 mg/kg
    图  2  不同剂量 PFOA暴露的卵母细胞内活性氧(ROS)荧光强度
    柱子上方的不同小写字母表示差异显著(P<0.05, LSD法)
    Figure  2.  The fluorescence intensities of reactive oxygen species (ROS) in oocytes exposed to different doses of PFOA
    Different lowercase letters on bars indicate significant differences(P< 0.05, LSD method)

    每日灌服不同剂量PFOA的小鼠卵母细胞P-H2A.X免疫荧光结果显示,细胞内DNA损伤情况有明显升高(图3)。其中,5、10和20 mg/kg组P-H2A.X 比例分别比对照组升高了47%、133%和171%。5 mg/kg组与对照组差异显著(P<0.05),10、20 mg/kg组与对照组相比差异极显著(P<0.01),10和20 mg/kg组之间差异不显著(P>0.05)(图4)。

    图  3  不同剂量PFOA暴露的卵母细胞内P-H2A.X荧光图像
    Figure  3.  Fluorescence images of P-H2A.X in oocytes exposed to different doses of PFOA
    图  4  不同剂量PFOA暴露的卵母细胞DNA损伤比例
    柱子上方的不同小写字母表示差异显著(P<0.05, LSD法)
    Figure  4.  DNA damage rates of oocytes exposed to different doses of PFOA
    Different lowercase letters on bars indicate significant differences (P< 0.05, LSD method)

    每日灌服不同剂量PFOA的小鼠卵母细胞β-tubulin、Hoechst 33342免疫荧光结果显示,细胞内纺锤体形态和染色体排列有明显异常(图5),且与PFOA剂量呈正相关。与对照组相比,10和20 mg/kg组中卵母细胞β-tubulin形态异常,染色体非整齐排列的比例分别升高了65.06%和75.60%。5 mg/kg组与对照组差异不显著(P>0.05),10、20 mg/kg组与对照组相比均差异显著(P<0.05),10和20 mg/kg组之间差异不显著(P>0.05)(图6)。

    图  5  不同剂量PFOA暴露的卵母细胞骨架荧光图像
    Figure  5.  Fluorescence images of cytoskeleton of oocytes exposed to different doses of PFOA
    图  6  不同剂量PFOA暴露的卵母细胞骨架异常比例
    柱子上方的不同小写字母表示差异显著(P<0.05, LSD法)
    Figure  6.  The proportions of abnormal cytoskeleton in oocytes exposed to different doses of PFOA
    Different lowercase letters on bars indicate significant differences (P< 0.05, LSD method)

    近年来,人们对环境污染物的关注度越来越高。PFOA作为一种稳定的有机化合物给工业和制造业带来便利的同时也带来了诸多“副作用”。PFOA在环境中持久存在,使得人类或动物很容易受到污染。饮食、饮水是人类暴露PFOA的主要途径。本试验通过给小鼠灌服PFOA模拟人类的暴露途径,观察PFOA对雌性哺乳动物的生殖毒性。结果证实了PFOA可通过氧化应激、DNA损伤和细胞骨架受损降低卵母细胞成熟率以及成熟质量。

    ROS是细胞代谢的天然副产物,对细胞信号转导、稳态调节有着重要作用。当ROS的产生和中和不平衡时就会引起氧化应激。过量的ROS会导致脂质过氧化、蛋白降解、DNA损伤等[15]。研究发现,环境污染物和毒素往往会增加细胞内ROS的产生,最终诱导细胞内氧化应激并发挥毒性[16]。已有研究表明PFOA可引起小鼠卵巢内ROS升高,且呈剂量依赖性[15]。为了研究PFOA对卵母细胞发育能力的影响,我们检测了细胞内ROS水平,发现PFOA可显著增加细胞内ROS含量,诱导氧化应激,进而抑制卵母细胞发育,且剂量越高,氧化应激越强。

    据报道,ROS相关氧化应激可诱导DNA损伤[17]。P-H2A.X被用作鉴定DNA损伤,在细胞发生DNA双链断裂的数分钟内,H2AX的139位丝氨酸残基被ATM、ATR、PRKC基因磷酸化形成P-H2A.X。因此,P-H2A.X的出现与DNA双链断裂紧密关联,故其可作为DNA双链断裂的标志物[18]。已有研究报道毒性化学制剂可诱导细胞DNA损伤,如双酚AF(Bisphenol AF)通过增加氧化应激和DNA损伤对小鼠卵母细胞体外成熟产生负面影响,对羟基苯甲酸丁酯(Butylparaben)通过DNA损伤抑制猪卵母细胞的体外成熟[19-20]。于是我们猜测,PFOA暴露会诱导卵母细胞DNA双链断裂。试验结果也证实了我们的猜想,PFOA处理组的P-H2A.X阳性卵母细胞比例显著高于对照组,提示PFOA暴露可通过诱导DNA双链断裂来抑制卵母细胞的成熟。

    在减数分裂进程中,染色体的正确分离主要取决于染色体−微管的稳定连接。纺锤体微管的形态异常引起染色体的错误分离,导致卵母细胞和进一步胚胎发育过程中产生异倍体和基因组的不稳定现象。研究发现越来越多的环境毒素与纺锤体形态异常、染色体分裂错误有关。研究报道双酚A替代物双酚芴可引起卵母细胞骨架受损[21];邻苯二甲酸单酯能够干扰减数分裂过程中染色体分离和配子形成[22]。本研究中,PFOA处理后的卵母细胞有很大比例出现纺锤体异常和染色体错位。微管、肌动蛋白丝和染色质相互作用完成染色体分离,建立细胞不对称[2324]β-tublin在PFOA处理的卵母细胞中的异常定位是纺锤体缺陷的原因之一。纺锤体缺陷导致异常的染色体排列。因此,本文结果表明,PFOA暴露可通过诱导纺锤体缺陷和染色体排列异常进而抑制卵母细胞的成熟。这些发现有助于提高人们对PFOA生殖毒性的认识,为今后的研究提供参考依据。未来可以对PFOA损伤哺乳动物卵母细胞的分子机制做进一步研究。

    综上所述,本研究评估了PFOA体内暴露对小鼠卵母细胞的影响,结果表明PFOA暴露会通过诱导ROS生成、DNA损伤、纺锤体形态发育缺陷、染色体排列异常等途径影响卵母细胞成熟率及成熟质量。

  • 图  1   抑制剂MG-132和PR-619对SPAE细胞存活率的影响

    *和**分别表示细胞存活率在P<0.05和P<0.01水平显著降低(t检验)。

    Figure  1.   Effect of inhibitors MG-132 and PR-619 on survival rates of SPAE cells

    * and ** indicate that the cell survival rate significantly decreased at P<0.05 and P<0.01 levels respectively (t test).

    图  2   抑制剂MG-132(A~D) 和PR-619(E~H) 对BTV感染SPAE细胞基因转录水平的影响

    *和**分别表示在P<0.05和P<0.01水平差异显著(t检验)。

    Figure  2.   Effects of inhibitors MG-132 (A−D) and PR-619 (E−H) on gene transcriptional levels of BTV-infected SPAE cells

    * and ** indicate significant differences at P<0.05 and P<0.01 levels respectively (t test).

    图  3   利用Western-blotting检测抑制剂处理BTV感染SPAE细胞的蛋白表达水平

    Figure  3.   Detection of protein expression levels in BTV-infected SPAE cells treated with inhibitors by Western blotting

    图  4   抑制剂MG-132(A~D)和PR-169(E~H)对BTV感染SPAE细胞蛋白表达水平的影响

    *和**分别表示在P<0.05和P<0.01水平差异显著(t检验)。

    Figure  4.   Effects of inhibitors MG-132 (A−D) and PR-169 (E−H) on protein expression levels of BTV-infected SPAE cells

    * and ** indicate significant differences at P<0.05 and P<0.01 levels respectively (t test)

    图  5   利用免疫荧光检测抑制剂处理BTV感染SPAE细胞的IRF3核转移水平

    Figure  5.   Detection of IRF3 nuclear translocation level in BTV-infected SPAE cells treated with inhibitors by immunofluorescence

    图  6   抑制剂处理BTV感染SPAE细胞IRF3核转移水平的变化

    *和**分别表示在P<0.05和P<0.01水平差异显著(t检验)。

    Figure  6.   Changes of nuclear translocation ratio of IRF3 in BTV-infected SPAE cells treated with inhibitors

    * and ** indicate significant differences at P<0.05 and P<0.01 levels respectively (t test).

    图  7   抑制剂处理BTV感染SPAE细胞IFN-α基因转录水平(A、C)和IFN-α蛋白表达水平(B、D)变化

    *和**分别表示在P<0.05和P<0.01水平差异显著(t检验)。

    Figure  7.   Changes in IFN-α gene transcriptional levels (A, C) and IFN-α protein expression levels (B, D) in BTV-infected SPAE cells treated with inhibitors

    * and ** indicate significant differences at P<0.05 and P<0.01 levels respectively (t test)

    图  8   抑制剂处理BTV感染SPAE细胞BTV基因组拷贝数变化

    *和**分别表示在P<0.05和P<0.01水平差异显著(t检验)。

    Figure  8.   Changes in BTV genome copy numbers of BTV-infected SPAE cells treated with inhibitors

    * and ** indicate significant differences at P<0.05 and P<0.01 levels respectively (t test)

    表  1   RT-qPCR使用的引物和探针

    Table  1   The primers and probe used for RT-qPCR

    基因名称
    Gene name
    正向引物序列(5'→3')
    Forward primer sequence
    反向引物序列(5'→3')
    Reverse primer sequence
    参考文献或序列
    Reference or sequence
    RIG-I GCCTTAAAGAACTGGATTGA ATACCCATTGTCTGATTTGTT [20]
    USP4 CGACATAAATTCCCTTGCCAC CGTGCTTCTCATACGTCTCAG XM_004018463
    RNF125 TGCCGTTCTTGCATCGCTA CACCTTGCTGTTGTCTCTCCA XM_027960741
    IRF3 GAGGACCACAGCAAGGACTC TGTCTGCCATTGTCTTGAGC [21]
    IFN-α GCACTGGATCAGCAGCTCACTG CTCAAGACTTCTGCTCTGACAACCT [22]
    18S GATCCATTGGAGGGCAAGTCT GCAGCAACTTTAATATACGCTATTGG [23]
    下载: 导出CSV
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