本文選題：骨膜蛋白 + 正畸　； 參考：《南方醫(yī)科大學(xué)》2014年博士論文

【摘要】：研究背景和目的： 長期以來,正畸治療錯合畸形的一個突出問題就是臨床治療療程長,也是眾多牙頜畸形患者特別是成年患者決定是否矯治的關(guān)鍵因素之一。研究如何在對牙周組織、牙根和牙髓無可逆性損傷的條件下加快正畸牙齒移動,縮短正畸治療療程,成為本學(xué)科的研究熱點和難點。現(xiàn)在人們的研究熱點逐漸集中到機體對正畸力的生物學(xué)反應(yīng)上。在正畸臨床中發(fā)現(xiàn)沒有牙周膜的粘連牙或者種植牙都不能發(fā)生移動,這就提示我們：如果只有力的作用,而沒有牙周膜的改建,牙齒還不能移向所希望的位置或維持在必要的位置上,因此正畸牙齒移動有賴于牙周組織的相應(yīng)反應(yīng),正畸牙齒的移動必須以牙周膜和牙槽骨的改建為前提。 在正畸治療過程中,機械力刺激通過牙齒傳遞到牙周膜,引發(fā)和激活其內(nèi)部各種效應(yīng)細胞的生物代謝活性,從而影響牙周組織的塑形和改建,最終使牙齒移動到位。也就是說牙周膜是正畸治療的生理介質(zhì),它是一種變異的骨膜,具有明顯的骨沉積和骨吸收能力；位于牙骨質(zhì)與牙槽骨兩種硬組織之間,由致密結(jié)締組織所構(gòu)成,多數(shù)纖維排列成束,其兩端分別埋于牙骨質(zhì)內(nèi)牙槽窩的骨壁里,使牙齒固位于牙槽窩內(nèi)。膠原纖維成束狀排列,它可充分緩沖和吸收作用力,在牙周組織、牙周膜損傷修復(fù)中起著至關(guān)重要的作用。牙周膜在接受機械力刺激后,通過信號轉(zhuǎn)導(dǎo)系統(tǒng)將力學(xué)刺激轉(zhuǎn)化為生物學(xué)信號,引起牙周組織代謝的改變和牙槽骨改建等一系列生物學(xué)反應(yīng),這是一個十分復(fù)雜的過程,涉及到多種信號轉(zhuǎn)導(dǎo)分子和通道以及各種基質(zhì)蛋白、細胞因子。 骨膜蛋白(Periostin,PN)是一種新發(fā)現(xiàn)的多功能細胞外基質(zhì)蛋白,分子量為90kD,在骨膜和牙周韌帶定位表達。骨膜蛋白可被轉(zhuǎn)化生長因子β(TGFβ)誘導(dǎo)表達,其支持細胞粘附、膠原蛋白的交聯(lián)和調(diào)節(jié)纖維形成,對牙周組織的完整性、牙齒發(fā)育、萌出以及機械應(yīng)激導(dǎo)致的組織修復(fù)和再生發(fā)揮著重要的作用；被認為是對牙周膜穩(wěn)態(tài)調(diào)節(jié)有關(guān)鍵作用的細胞外基質(zhì)蛋白,其可能對牙周病及正畸牙移動中牙周組織改建也起著關(guān)鍵的作用。 PN與TGF-β1的關(guān)系越來越受各界的關(guān)注,多項研究表明PN參與多個系統(tǒng)疾病的發(fā)生發(fā)展,且其表達與TGF-β1有密切關(guān)系。氣道上皮細胞分泌PN可激活TGF-β1,進而促進氣道纖維化并降低氣道彈性導(dǎo)致哮喘發(fā)生；在心臟方面研究發(fā)現(xiàn)PN參與心肌膠原的合成和成熟,培養(yǎng)鼠胚胎時期的成纖維細胞,經(jīng)TGF-β1刺激后,PN蛋白基因敲除后膠原的合成量僅為野生型的胚胎鼠膠原合成量的32%。由此可見PN蛋白是成纖維細胞合成分泌膠原的主要信號通道。Norris研究發(fā)現(xiàn)在PN基因敲除小鼠中心肌表現(xiàn)出較低的膠原蛋白變性溫度,說明交聯(lián)的膠原蛋白水平降低,PN可調(diào)節(jié)Ⅰ型膠原纖維形成,而且能夠與Ⅰ型膠原直接相互作用,從而成為纖維結(jié)締組織的生物力學(xué)特性的重要作用介質(zhì)。Rios利用X線及Micro-ct觀察敲除骨膜蛋白基因的小鼠牙齒牙周膜發(fā)育狀況,牙齒發(fā)育萌出到建立正常咬合前,PN-null小鼠牙周膜于正常對照組相比無差別；牙齒萌出承受咀嚼力后3月齡實驗組小鼠牙周組織出現(xiàn)明顯破壞、牙周附著降低、牙槽骨吸收,表明在咬合力作用下骨膜蛋白在維持牙周膜的完整性和功能方面起著不可或缺的作用,在功能減退組的表達水平的改變可能會被認為是一種對環(huán)境變化的適應(yīng)形式。 Choi降低Wistar大鼠的右上第一磨牙咬合后的研究結(jié)果顯示：最初牙周膜纖維數(shù)量減少、纖維變薄、隨后牙周膜纖維和它們在牙槽骨的附著排列變得混亂,最終牙周膜纖維失去其網(wǎng)狀結(jié)構(gòu)。PNmRNA表達在24h大幅下調(diào),這一變化持續(xù)在整個實驗過程中。證實在缺乏機械應(yīng)力的情況下,伴隨著牙周膜中PN水平的減少,牙周膜纖維系統(tǒng)開始出現(xiàn)退化。Wen對TGF-β1和FAK調(diào)節(jié)PN在牙周成纖維細胞中的表達的作用進行了研究,用TGF-β1處理顯著增加PNmRNA水平,粘著斑激酶(Focal Adhesion Kinase FAK)抑制劑有衰減作用。即使用循環(huán)應(yīng)力刺激后,FAK敲除的成纖維細胞中也沒有檢測至PNmRNA的表達。這些結(jié)果提示,PN蛋白在人牙周膜中強烈表達,可能會涉及FAK依賴的通路的調(diào)節(jié)。最新研究證實炎癥介質(zhì)(TNF-α)和細菌毒素因子(LPS)能顯著降低牙周膜成纖維細胞表達骨膜蛋白,表明PN在牙周病發(fā)生發(fā)展過程中是一個重要因子。這也提示我們在牙周患者進行正畸治療時,口腔衛(wèi)生的清潔護理、炎癥的治療控制是多么重要的前提；否則牙周組織遭到破壞、正畸牙周組織的改建、骨組織改建和正畸牙齒的移動根本無從談起。 PN作為一種重要的細胞外基質(zhì)蛋白已引起廣泛的關(guān)注,在全身多個系統(tǒng)都具有重要的作用,現(xiàn)對其研究也日漸深入。PN作為應(yīng)力作用下維持牙周膜的完整性和功能方面起著必不可少作用的關(guān)鍵因子,對其體外方面研究多集中于牙周膜細胞加力機械刺激,涉及多因素體內(nèi)研究卻相對較少。通過建立小鼠正畸牙齒移動模型來研究PN在正畸牙齒移動過程中牙周組織改建作用還未見相關(guān)報道,PN在各疾病中特別是牙周組織的作用及其機制的研究尚不清楚。本研究將首次建立小鼠正畸牙齒移動模型,運用定量免疫組化、Micro-ct、QRT-PCR、 Westernblot以及敲除PN基因小鼠等方法研究PN在牙周膜改建調(diào)控作用及相關(guān)信號通路。由于小鼠牙周膜過少,難以進行蛋白水平功能檢測。本實驗擬通過收集正畸臨床患者拔除前磨牙牙周膜,采用QRT-PCR和蛋白組學(xué)技術(shù)進一步研究PN在正畸牙周組織改建作用的分子信號通路,深入探討PN在正畸牙齒移動過程中牙周組織改建及其分子機制。為進一步系統(tǒng)性探討機械力作用下牙周組織改建的分子生物學(xué)機制開辟了一條新途徑,有助于更好的理解正畸牙齒移動的機理,從而為加快牙齒移動的正畸臨床研究提供理論依據(jù)。 方法： 1.利用自制口腔微型裝置建立小鼠正畸牙移動模型 利用自制口腔微型裝置和口腔顯微鏡在小鼠切牙和第一磨牙之間用NI-TI拉簧固定、加力20g,分別在加力1、3、5、7d后處死小鼠,固定、脫鈣、制作小鼠第一磨牙牙周組織石蠟切片,觀察HE染色牙周組織形態(tài)學(xué)和磨牙間變化。 2.觀察小鼠正畸牙齒移動中牙周膜PN表達的變化 建立小鼠正畸牙移動模型,分別在加力1、3、5、7d后處死小鼠,制作免疫組化切片,用免疫組織化學(xué)和圖像定量分析技術(shù)檢測牙周膜PN表達的變化。 3.PN基因敲除小鼠基因型的鑒定 剪取基因敲除小鼠尾部0.5cm放入標記好的EP管內(nèi),提取DNA,根據(jù)設(shè)計引物進行PCR擴增,擴增產(chǎn)物經(jīng)1.5%瓊脂糖凝膠電泳后取出置于紫外燈下觀察并拍照。鑒定基因小鼠標準為：PN+/+基因型小鼠PCR擴增產(chǎn)物為691bp, PN-/-基因型小鼠是PCR擴產(chǎn)物為500bp。 4.Micro-ct影像學(xué)檢查 處死C57BL和PN基因敲除小鼠,分離上下頜骨,分別選取各組小鼠上、下頜骨,標記好各組標本,固定于專用掃描管中,使用顯微CT成像系統(tǒng)進行斷層掃描成像,對牙周組織進行評估。 5.RT-PCR檢測小鼠牙移動牙周膜改建中與PN相關(guān)信號通路調(diào)控因子 建立小鼠正畸牙移動模型,分為C57小鼠未加力組、C57小鼠加力組、PN-null小鼠未加力組、PN-null、鼠加力組,分別加力5d后處死,拔出牙齒放于盛有裂解液的EP管中,實時熒光定量PC檢測牙周膜中PN、TGF-B1、FAK相關(guān)信號通路調(diào)控因子的表達,并統(tǒng)計分析各組之間PN、TGF-B1、FAK表達的相關(guān)性。 6.RT-PC檢測人正畸和未正畸牙周膜中與PN相關(guān)信號通路調(diào)控因子 對照組為重度擁擠病例,實驗組為牙列整齊、牙弓前突病例。對照組和實驗組均為拔出前磨牙的青少年正畸患者,實時熒光定量PCR檢測牙周膜中PN、TGF-B1、FAK相關(guān)信號通路調(diào)控因子的表達,并統(tǒng)計分析各組之間PN、TGF-B1、FAK表達的相關(guān)性。 7Westernblot檢測人正畸和未正畸牙周膜中與PN相關(guān)信號通路調(diào)控因子 Westernblot檢測人正畸和未正畸牙周膜中PN、TGF-B1、FAK、P-Akt、AKT相關(guān)信號通路調(diào)控因子的表達,并統(tǒng)計分析各組之間PN、TGF-B1、FAK、P-Akt、AKT表達的相關(guān)性。 結(jié)果 1.加力過程中牙齒按設(shè)定的方向移動,加力組第一磨牙與第二磨牙之間出現(xiàn)間隙。加力組張力側(cè)牙周間隙變寬,牙周膜中纖維排列疏松,細胞成份增多,牙槽表面可見活躍的成骨細胞和新骨沉積,壓力側(cè)牙周間隙縮窄。 2.PN在牙周膜呈陽性表達,著色相對較淺,分布較均勻。正畸加力組大鼠牙周膜中PN表達增強,牙周膜陽性染色強。與Od對照組比較,加力實驗各組牙周膜PN表達均增強(P0.05),與1d組比較,3d、5d組牙周膜PN表達均增強(P0.05),7d加力實驗組PN表達無統(tǒng)計學(xué)意義(P0.05)。與3d加力組比較,5d、7d加力實驗組(P0.05)差異無統(tǒng)計學(xué)意義(P0.05)；與5d加力實驗組比較,7d加力實驗組牙周膜PN表達顯著減弱,(P0.01)。5d組是小鼠整個牙齒移動改建周期中PN表達量最高。 3.1泳道只有一個目的條帶,亮度強,條帶范圍在691bp處,根據(jù)判定標準判定為WT小鼠。2泳道也只有一個目的條帶,亮度較強,條帶范圍在500bp左右,因此根據(jù)判定標準判定為PN-/-小鼠。 4.小鼠Micro-ct三維重建圖顯示：與對照組C57小鼠相比,PN-null、鼠牙周組織破壞,牙槽骨出現(xiàn)明顯的水平吸收,磨牙根分叉區(qū)完全暴露。小鼠Micro-ct曲面斷層圖顯示：與對照組C57小鼠相比,PN-nul1小鼠牙周組織破壞,牙槽骨出現(xiàn)明顯的吸收,牙槽脊頂消失,牙周膜連續(xù)性中斷破壞。 5.與C57未加力對照組相比,C57小鼠牙加力實驗組牙周膜中PNmRNA表達增強,(P0.05)差值有統(tǒng)計學(xué)意義；FAK mRNA表達顯著增強,(P0.05)差值有統(tǒng)計學(xué)意義；TGF-B1mRNA表達顯著增強(P0.05)差值有統(tǒng)計學(xué)意義。與PN-null未加力對照組相比,PN-nul1加力實驗組牙周膜中FA mRNA表達增強(P0.05)差值有統(tǒng)計學(xué)意義,TGF-B1mRNA表達顯著增強,(P0.01)差值有統(tǒng)計學(xué)意義。與PN-null未加力對照組相比,C57未加力組牙周膜TGF-B1mRNA表達顯著減少,(P0.01)差值有統(tǒng)計學(xué)意義,FAKmRNA表達顯著增強,(P0.01)差值有統(tǒng)計學(xué)意義。與PN-nul1加力組相比,C57加力實驗組牙周膜TGF-BmRNA表達減少,(P0.05)差值有統(tǒng)計學(xué)意義；FAKmRNA表達顯著增強,(P0.01)差值有統(tǒng)計學(xué)意義。 6.與人正畸未加力對照組相比,人正畸加力實驗組牙周膜中PNmRNA表達顯著增強,(P0.01)差值有統(tǒng)計學(xué)意義；FAKmRNA表達顯著增強,(P0.01)差值有統(tǒng)計學(xué)意義；TGF-B1mRNA表達顯著增強,(P0.05)差值有統(tǒng)計學(xué)意義。 7.與未正畸組相比,人正畸組牙周膜PN、TGF-B1、FAK、P-Akt的蛋白表達均顯著增高,(P0.01)差值均有統(tǒng)計學(xué)意義。與未正畸組相比,人正畸組牙周膜Ak、a-tublin的蛋白表達均沒有明顯差異,(P0.05)差值無統(tǒng)計學(xué)意義 結(jié)論 1.首次成功建立了小鼠正畸加力模型,小鼠正畸牙齒移動過程中,牙周膜中PN表達增強且貫穿牙周膜改建的全過程,從而確定PN參與了小鼠牙齒移動中的牙周膜改建。 2.PN是保持牙周膜的結(jié)構(gòu)和功能完整性所必需的,是正畸作用下牙周膜的改建過程一個重要分子環(huán)節(jié),發(fā)揮著轉(zhuǎn)導(dǎo)調(diào)控作用。 3.TGF-B1-PN-FAK信號通路參與調(diào)控了正畸作用下牙周膜的改建過程,FAK可能通過除TGF-B1-PN-FAK信號通路之外的其他途徑參與了牙周膜改建的過程。 4.TGF-B1-PN-FAK可能通過激活下游的Akt磷酸化信號通路,對正畸力牙周膜改建中進行調(diào)控。
[Abstract]:Background and purpose of the study :

For a long time , one of the outstanding problems of orthodontic treatment is the long duration of clinical treatment , and the key factors for determining whether to correct the orthodontic tooth movement under the condition of no reversible damage to periodontal tissue , root and pulp .

in that proces of orthodontic treatment , the mechanical force stimulate the transmission of teeth to the periodontal membrane , initiate and activate the biological metabolic activity of various effector cells in the periodontal ligament , thereby influencing the shaping and reconstruction of the periodontal tissue , and finally moving the teeth into place .
The periodontal ligament is composed of compact connective tissue , which is composed of dense connective tissue , the two ends of which are respectively embedded in the bone wall of the alveolar cavity of the alveolar bone , so that the teeth are fixed in the alveolar cavity .

Periostin ( PN ) is a newly discovered extracellular matrix protein with a molecular weight of 90kD . It is expressed in bone and periodontal ligament . The bone membrane protein can be expressed by transforming growth factor - 尾 ( TGF - 尾 ) , which supports cell adhesion , collagen cross - linking and regulation of fiber formation , plays an important role in the tissue repair and regeneration of periodontal tissues , tooth development , eruption and mechanical stress .
It is believed that extracellular matrix protein plays a key role in the steady state regulation of periodontal ligament , which may play a key role in periodontal disease and orthodontic tooth movement .

The relationship between PN and TGF - 尾1 is more and more concerned , and many researches have shown that PN is involved in the development of multiple system diseases , and its expression is closely related to TGF - 尾1 . The secretion of PN in airway epithelial cells can activate TGF - 尾1 , thus promoting airway fibrosis and reducing airway elasticity leading to asthma .
The study found that PN was involved in the synthesis and maturation of collagen in cardiac muscle cells . After stimulation of TGF - 尾1 , the collagen synthesis was only 32 % of the wild type mouse collagen synthesis .
In the experimental group , the periodontal tissues of the experimental group were significantly damaged , the periodontal attachment decreased and the alveolar bone resorption , indicating that the membrane protein plays an indispensable role in maintaining the integrity and function of the periodontal ligament , and the change of the expression level in the hypofunctional group may be regarded as an adaptive form of environmental change .

The results showed that the expression of PNmRNA in periodontal ligament fibroblasts was significantly decreased by treatment with TGF - 尾1 . The results suggested that the expression of PNmRNA in periodontal ligament fibroblasts was significantly decreased by treatment with TGF - 尾1 .
Otherwise , the periodontal tissue is destroyed , the remodeling of the orthodontic periodontal tissue , the alteration of the bone tissue and the movement of the orthodontic tooth are never started .

PN , as an important extracellular matrix protein , has attracted extensive attention and plays an important role in the development of periodontal ligament cells .

Method :

1 . Establishment of mouse orthodontic tooth movement model by self - made oral micro - device

Using a self - made oral micro - device and an oral microscope , a NI - TI tension spring was used to fix the teeth of the mouse and the first molar , and 20 g were added , and the mice were sacrificed after 1 , 3 , 5 and 7 days respectively , and the paraffin sections of the first molar periodontal tissues of the mice were made , and the morphological and molar changes of the periodontal tissues were observed with HE staining .

2 . Observe the change of periodontal ligament PN expression in orthodontic tooth movement in mice

The mice were sacrificed after 1 , 3 , 5 and 7 days respectively , and the mice were sacrificed after 1 , 3 , 5 and 7 days respectively , and immunohistochemistry and image analysis were used to detect the change of PN expression in periodontal ligament .

3 . Identification of Gene Knockout Mice

The gene knockout mice were subjected to PCR amplification by 1.5 % agarose gel electrophoresis . The PCR amplified products were 691bp in PN + / + genotype mice and 500 bp for PN - / - genotype mice .

4 . Micro - ct imaging examination

C57BL and PN gene knockout mice were sacrificed and the mandible was isolated . Each group of mice were divided into two groups : the mandible , the marked group and the special scanning tube . The CT imaging system was used to perform the tomographic imaging , and the periodontal tissues were evaluated .

5 . RT - PCR Detection of Regulation Factors of PN - related Signal Pathway in Dental Movement of Mouse Teeth

The model of mouse orthodontic tooth movement was established , which was divided into C57 mice without stress group , C57 mouse additive group , PN - null mice without force group , PN - null and mouse additive force group . After 5 days of addition of PN - null mice , the expression of PN , TGF - B1 in the periodontal ligament was detected by real - time fluorescence quantitative PC , and the correlation between the expression of PN , TGF - B1 and focal adhesion in periodontal ligament was detected by real - time fluorescence quantitative PC .

6 . RT - PC Detection of the Regulation Factors of PN - related Signal Pathway in Orthodontist and Unorthodontic periodontal ligament

In the control group , there were severe congestion cases in the experimental group . The control group and the experimental group were orthodontic patients with premolar teeth , and the expression of PN , TGF - B1 in the periodontal ligament was detected by real - time fluorescence quantitative PCR , and the correlation between the expression of PN , TGF - B1 and focal adhesion in the periodontal ligament was analyzed by real - time quantitative PCR .

Regulation factors of PN related signal pathway in orthodontic and orthodontic periodontal ligament by 7 Western blot

Western blot was used to detect the expression of PN , TGF - B1 , focal adhesion molecule - 1 , P - 3 - 3 in human orthodontist and non - orthodontic periodontal ligament , and to analyze the correlation between the expression of PN , TGF - B1 , focal adhesion kinase , P - 3 - 3 and P - 3 - 3 in each group .

Results

1 . When the teeth are moved in the set direction during the addition process , there is a gap between the first molar and the second molar in the addition force . The periodontal gap in the tension side of the force group becomes wider , the fibrous arrangement in the periodontal ligament is loose , the cell components are increased , the active osteoblasts and new bone deposits can be seen on the surface of the alveolar groove , and the pressure side periodontal gap is narrowed .

2 . PN was positive in the periodontal ligament , the color was relatively shallow and the distribution was more uniform . Compared with the control group , the expression of PN in periodontal ligament was enhanced ( P0.05 ) . Compared with the control group , the expression of PN in periodontal ligament increased significantly ( P0.05 ) .
Compared with the 5d group , the expression of PN in the periodontal ligament of the experimental group decreased significantly after 7 days ( P0.01 ) , and the expression of PN was the highest in the 5d group .

3.1 The lane has only one target band , the intensity is strong , the band range is 691bp , it is judged as WT mice according to the determination standard . The lane also has only one target band , the brightness is stronger , the band range is about 500bp , and therefore , it is judged as PN - / - mouse according to the determination standard .

4 . Mouse Micro - ct 3 - D reconstruction showed that PN - null mice were destroyed and alveolar bone was completely exposed when compared with control group C57 mice . The mouse micro - ct surface tomographic image showed that PN - nul1 mice were destroyed by periodontal tissue and alveolar ridge disappeared and periodontal ligament continuity was disrupted compared with control group C57 mice .

5 . Compared with the C57 untreated control group , the expression of PNmRNA in the periodontal ligament of C57 mice increased significantly ( P0.05 ) .
The mRNA expression was significantly increased , ( P0.05 ) , and the difference was statistically significant .
Compared with the control group , there was a significant difference in the expression of TGF - B mRNA in the periodontal ligament ( P0.05 ) . Compared with the control group , the expression of TGF - B1 mRNA was significantly increased ( P0.01 ) . Compared with the PN - null unenhanced control group , the expression of TGF - B mRNA in the untreated group was significantly increased ( P0.01 ) .
The expression of FAKmRNA was significantly increased ( P0.01 ) .

6 . Compared with the untreated control group , PNmRNA expression was significantly increased in the periodontal ligament of the experimental group ( P0.01 ) .
The expression of FAKmRNA was significantly increased ( P0.01 ) .
The expression of TGF - B 1 mRNA was significantly increased ( P0.05 ) .

7 . Compared with non - orthodontic group , the expression of protein in periodontal ligament PN , TGF - B1 , focal adhesion kinase and P - 3 in orthodontic group was significantly higher than that in the untreated group ( P0.01 ) . There was no significant difference in protein expression in the periodontal ligament , Ak , a - tufa in the orthodontic group compared with the unorthodontist group ( P0.05 ) .

Conclusion

1 . For the first time , the mouse orthodontic force model was successfully established . During orthodontic tooth movement , the PN expression in periodontal ligament was enhanced and through the whole process of periodontal ligament reconstruction , so it was determined that PN was involved in the reconstruction of periodontal ligament in mouse tooth movement .

2 . PN is necessary to maintain the structural and functional integrity of periodontal ligament . It is an important element in the remodeling process of periodontal ligament under the action of orthodontic treatment .

3 . The TGF - B1 - PN - focal adhesion pathway is involved in the alteration of periodontal ligament during orthodontic treatment , which may be involved in the reconstruction of periodontal ligament by other ways than TGF - B1 - PN - focal adhesion pathway .

4 . TGF - B1 - PN - PKP may regulate the remodeling of orthodontic periodontal ligament by activating the downstream phosphorylation signaling pathway .
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R783.5

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