本文選題：金欣口服液 + 呼吸道合胞病毒��； 參考：《南京中醫(yī)藥大學(xué)》2015年博士論文

【摘要】：背景：肺炎是常見的小兒肺系疾病,在綜合性醫(yī)院兒科住院病例單病種統(tǒng)計中居首位,WHO列為全球3種重要兒科疾病之一。在我國小兒急性下呼吸道感染中,病毒約占1/3,并呈上升趨勢,其中以呼吸道合胞病毒(Respiratory Syncytial Virus; RSV)最多。RSV肺炎以熱證為多見,其中痰熱閉肺證是RSV肺炎最為常見和重要的一種證候。一個證候包含了多臟器多指標(biāo)間的復(fù)雜聯(lián)系,很難用單一指標(biāo)或某幾個指標(biāo)的簡單疊加來闡釋證候物質(zhì)基礎(chǔ)。如何科學(xué)、全面地闡述中醫(yī)證候的實質(zhì)和內(nèi)涵是現(xiàn)代中醫(yī)學(xué)亟需解決的一個重要問題。國內(nèi)外研究表明,對于小兒病毒性肺炎的治療,西藥尚缺乏理想藥物,唯一被美國兒科協(xié)會推薦為“也許可以使用”的藥物是利巴韋林。中醫(yī)藥治療有一定的優(yōu)勢,且已經(jīng)為大量臨床和實驗研究所證實。南京中醫(yī)藥大學(xué)汪受傳教授領(lǐng)銜的本課題組從事中醫(yī)藥治療小兒病毒性肺炎研究近20年,研制了有效中藥方劑金欣口服液,具有宣肺開閉、清熱解毒、化痰止咳等功效。課題組前期已經(jīng)對金欣口服液在RSV感染方面的作用進(jìn)行了大量研究,然而,由于金欣口服液活性化學(xué)成分的復(fù)雜性,目前金欣口服液對RSV肺炎的整體代謝網(wǎng)絡(luò)調(diào)控作用仍不清楚。代謝組學(xué)(Metabonomics)是關(guān)于生物體內(nèi)源性代謝物種類、數(shù)量及其變化規(guī)律的一門新興學(xué)科,是系統(tǒng)生物學(xué)技術(shù)的重要組成部分。由于代謝物是生物體所有基因、蛋白功能活動的終點,因而被視作生物體整體功能狀態(tài)的“生化表型”,能夠即時、靈敏、真實的表現(xiàn)在各種外界因素的刺激下生物體整體功能狀態(tài)的應(yīng)答與調(diào)節(jié),避免了既往采用單一或少數(shù)幾個指標(biāo)來研究某種生理、病理變化的弊端。代謝組學(xué)技術(shù)在方法學(xué)上融整體、動態(tài)、綜合分析于一體的特點,與中醫(yī)學(xué)的整體觀念相一致。因此本課題采用代謝組學(xué)方法,結(jié)合其他生化檢測,全面表征RSV肺炎痰熱閉肺證所導(dǎo)致的代謝物組變化,嘗試闡明RSV肺炎痰熱閉肺證的本質(zhì)和金欣口服液對RSV感染小鼠的治療作用。目的：研究RSV肺炎痰熱閉肺證患兒血漿和尿液的代謝特征,探討RSV肺炎痰熱閉肺證的證候?qū)嵸|(zhì)；研究RSV肺炎BALB/c小鼠血漿和肺組織的代謝特征,探討金欣口服液對RSV肺炎BALB/c小鼠的干預(yù)作用及可能的代謝調(diào)控機制。方法：RSV肺炎痰熱閉肺證代謝組學(xué)的臨床實驗：選擇符合中西醫(yī)診斷條件的RSV肺炎痰熱閉肺證患兒30例,設(shè)為疾病組,同時設(shè)健康正常組30例。分別采集兩組兒童的血漿和尿液,采用超高效液相色譜-二維線性離子阱質(zhì)譜聯(lián)用儀(Ultra-performance Liquid Chromatography coupled with Linear Ion Trap Quadrupole Orbitrap Mass Spectrometry, UPLC-LTQ/Orbitrap-MS)檢測兩組的血漿和尿液的代謝產(chǎn)物,建立小兒RSV肺炎痰熱閉肺證的證候相關(guān)代謝譜,利用主成分分析(Principal Component Analysis, PCA)和正交偏最小二乘法(Orthogonal Partial Least Squares Discriminant Analysis, OPLS-DA)對檢測的矩陣數(shù)據(jù)進(jìn)行統(tǒng)計分析,篩選潛在的血漿、尿液生物標(biāo)記物,分析相關(guān)代謝通路,探索RSV肺炎痰熱閉肺證的代謝特征本質(zhì)。金欣口服液干預(yù)RSV肺炎BALB/c小鼠的動物實驗：RSV滴鼻感染BALB/c小鼠,金欣口服液進(jìn)行干預(yù),并設(shè)利巴韋林為陽性對照,6天后分別采集小鼠血漿、肺組織,行肺組織病理切片形態(tài)學(xué)分析來評價肺部病變情況,基于UPLC-LTQ/Orbitrap-MS研究各組小鼠血漿和肺組織整體代謝變化,利用PCA和OPLS-DA分析檢測數(shù)據(jù),篩選潛在的血漿、肺組織生物標(biāo)記物,分析相關(guān)代謝通路,評價金欣口服液的藥效,闡明金欣口服液的代謝調(diào)控機制。結(jié)果：RSV肺炎痰熱閉肺證代謝組學(xué)的臨床實驗：1.血漿代謝組學(xué)模式識別分析結(jié)果顯示,RSV肺炎痰熱閉肺證患兒與健康正常組兒童主成分積分值大部分集中分布于散點圖的橢圓形(95%置信區(qū))區(qū)域內(nèi),雖有一定的分離趨勢,但仍存在交叉重疊,進(jìn)一步構(gòu)建OPLS-DA模型,模型參數(shù)分別為R2Y=0.907, Q2=0.567(血漿上層樣本)和R2Y=0.816, Q2=0.619 (血漿下層樣本),正常組和RSV肺炎痰熱閉肺證組沿第一主成份t[1]軸方向能完全分離,無交叉和重疊,說明兩組在代謝特征方而具有明顯差異：篩選了21個潛在生物標(biāo)記物,并鑒定了其中的20個；其中SM(18：2/24：0)、SM(d18:2/24:1)、SM(d18:0/18:1)等鞘磷脂,TG(16:0/18:1/22:6)、TG(16:0/18:0/22:6)、 TG(16:0/20:4/22:5)、TG(18:1/18:3/20:4)、TG(16:0/20:3/22:4)等甘油三酯在RSV肺炎痰熱閉肺證患兒血漿中呈上調(diào)趨勢,PC(18:0/18:2)、PC(18:0/18:1)、PC(16:0/20:3)、PC(18:0/20:3)、 PC(16:0/22:5)、PC(18:2/20:0)、LysoPC(18:2)等磷脂酰膽堿,TG(14:0/16:0/18:2)、TG(14：0/16：0/16：1)等甘油三酯在RSV肺炎痰熱閉肺證患兒血漿中呈下調(diào)趨勢,此外,還發(fā)現(xiàn)了Bilirubin、Carnitine、Tryptophan等與RSV肺炎痰熱閉肺證有關(guān)的物質(zhì),較正常兒顯著下降。2.尿液代謝組學(xué)模式識別分析結(jié)果顯示,采用PCA方法對RSV肺炎痰熱閉肺證患兒與健康正常組兒童樣本建模,大部分樣本集中分布于散點圖的橢圓形(95%置信區(qū))區(qū)域內(nèi),雖有一定的分離趨勢,但仍存在交叉重疊,進(jìn)一步建立OPLS-DA模型,參數(shù)分別為R2Y=0.865, Q2=0.580 (a Q色譜柱所測尿液樣本)和R2Y=0.902, Q2=0.593 (HILIC色譜柱所測尿液樣本),正常組和RSV肺炎痰熱閉肺證組完全分離,說明兩組在代謝物方面具有明顯差異；篩選了15個差異性生物標(biāo)記物,并鑒定了其中11個；Acetylcarnitine. 3-Methylglutarylcarnitine、1-Pyrroline-4-hydroxy-2-carboxylate、Kynurenine、Tryptophan、 Acetylspermidine、Cytosine、Tryptamine等在RSV肺炎痰熱閉肺證患兒尿液中呈上調(diào)趨勢,Methyldopa、N-Methylhydantoin等在RSV肺炎痰熱閉肺證患兒尿液中呈下調(diào)趨勢。金欣口服液干預(yù)RSV肺炎BALB/c小鼠的動物實驗：1.RSV感染BALB/c小鼠后肺組織病理改變主要表現(xiàn)為間質(zhì)性肺炎,肺泡壁充血增厚,間質(zhì)有單核巨噬細(xì)胞及中性粒細(xì)胞浸潤,支氣管上皮細(xì)胞無明顯變性、壞死,支氣管管腔及肺泡腔無明顯滲出物；金欣口服液干預(yù)后肺部充血及炎癥有不同程度的減輕。病理評分結(jié)果顯示治療組較模型組顯著下降。2.RSV感染6天后,BALB/c模型小鼠與正常小鼠血漿數(shù)據(jù)基于OPLS-DA模型能完全分離,模型參數(shù)分別為R2Y=0.917,Q2=0.835(血漿上層樣本)和R2Y=0.967,Q2=0.936(血漿下層樣本),表明造模成功,RSV感染引起了小鼠血漿代謝特征的變化；篩選并鑒定25個生物標(biāo)記物；其中PC(18:1/22:6).PC(18:0/205)等磷脂酰膽堿和TG(18:1/18:2/18:2)、 TG(18:1/18:1/18:2)等甘油三酯在模型組小鼠血漿中較正常組顯著增加,PC(18:1/18:3)、 PC(18:0/22:6)、PC(P-18:1/22:2)、PC(O-18:0/22:6)、PC(O-20:0/22:6). PC(16:0/20:4)、 PC(P-20:0/14:0)、LysoPC(16:0)、LysoPC(18:2)、LysoPC(18:0)、LysoPC(20:4)、LysoPC(18:1)、 LysoPC(22:6)等磷脂酰膽堿,SM(d18:1/24:1).SM(d18:0/18:1).SM(d18:2/24:1)、 Phytosphingosine等鞘脂質(zhì)和TG(16:0/18:0/14:0).TG(16:0/16:0/18:0)等甘油三酯在模型組小鼠血漿中較正常組顯著下‘降,此外,PE(18:3/19:0)、Phytanic acid等也呈下調(diào)趨勢。基于所篩選出的生物標(biāo)記物,我們評價了金欣口服液的藥效,發(fā)現(xiàn)金欣口服液能不同程度的回調(diào)其中11個生物標(biāo)記物,且主要通過調(diào)節(jié)甘油磷脂的代謝通路而發(fā)揮作用。3.RSV感染6天后,基于BALB/c模型小鼠與正常組小鼠肺組織數(shù)據(jù)構(gòu)建OPLS-DA模型,兩組完全分離,無交叉和重疊,模型參數(shù)分別為R2Y=0.879,Q2=0.789(肺組織上層樣本)和R2Y=0.918,Q2=0.853(肺組織下層樣本),表明造模成功,RSV感染引起了小鼠肺組織代謝網(wǎng)絡(luò)的變化；篩選并鑒定25個生物標(biāo)記物；其中PC(18:0/18:1)、 PC(18:0/18:2)、PC(22:6/18:2)、PC(18:2/20:4)、PC(P-20:0/14:0)、LysoPC(18:0)、LysoPC(16:0)、 LysoPC(18:1)、LysoPC(20:4)、LysoPC(18:2)等磷脂酰膽堿,SM(40:1)、SM(d18:1/20:0)、 Sphinganine、Phytosphingosine等鞘脂質(zhì)和TG(18：1/18：1/18：1)、TG(18:1/16:0/20:1)、 TG(18:1/18:1/18:2)、TG(18:1/18:2/18:2)、TG(16:0/18:0/22:6)、TG(18:1/18:0/20:1)等甘油三酯在RSV肺炎BALB/c小鼠中含量較正常組顯著下降,此外,Phytanic acid、Leucine、 Phenylalanine、Choline、LysoPE(16:0)等亦與RSV感染有關(guān),在模型組小鼠中呈下調(diào)趨勢�；谒Y選出的生物標(biāo)記物評價金欣口服液的抗病毒藥效,結(jié)果發(fā)現(xiàn)金欣口服液能不同程度的回調(diào)肺組織中16個生物標(biāo)記物,主要通過調(diào)節(jié)苯丙氨酸、酪氨酸和色氨酸生物合成、苯丙氨酸代謝、纈氨酸、亮氨酸和異亮氨酸的生物合成、甘油磷脂代謝、鞘脂質(zhì)代謝通路而發(fā)揮作用。結(jié)論：1. UPLC-LTQ/Orbitrap-MS分析代謝組學(xué)能夠初步闡釋并區(qū)分RSV肺炎痰熱閉肺證與健康正常兒二者不同的代謝模式。2.RSV肺炎痰熱閉肺證患兒血漿和尿液中主要以色氨酸、甘油磷脂代謝紊亂為標(biāo)志。3.RSV肺炎BALB/c小鼠血漿和肺組織主要表現(xiàn)為苯丙氨酸、酪氨酸和色氨酸生物合成、苯丙氨酸代謝、纈氨酸、亮氨酸和異亮氨酸的生物合成、甘油磷脂代謝、鞘磷脂代謝發(fā)生紊亂。4.金欣口服液能夠明顯減輕RSV感染小鼠的肺部炎癥。5.金欣口服液能夠部分調(diào)整RSV感染引起的代謝紊亂,主要通過調(diào)節(jié)苯丙氨酸,酪氨酸和色氨酸生物合成、苯丙氨酸代謝、纈氨酸、亮氨酸和異亮氨酸的生物合成、甘油磷脂代謝、鞘脂質(zhì)代謝通路而發(fā)揮作用。
[Abstract]:Background: pneumonia is a common disease of children's lung system. It ranks first in the statistics of single disease of pediatric cases in a comprehensive hospital. WHO is one of the 3 major diseases of Pediatrics in the world. In our country, the virus accounts for about 1/3 in acute lower respiratory tract infection in children and is on the rise, among which the Respiratory Syncytial Virus; RSV) is the most important. Multiple.RSV pneumonia is commonly seen with heat syndrome, of which phlegm heat closed lung syndrome is the most common and important syndrome of RSV pneumonia. A syndrome includes complex connections between multiple organs and multiple indicators. It is difficult to explain the basis of syndromes with a single index or a simple superposition of some indexes. Culvert is an important problem to be solved in modern Chinese medicine. Research at home and abroad has shown that western medicine is still lack of ideal drugs for the treatment of viral pneumonia in children. The only drug recommended by the American Pediatrics Association as "may be used" is ribavirin. It has a definite advantage and has been a large number of clinical and experimental studies. It has been confirmed that the research group, led by Professor Wang received by Professor Wang of Nanjing University of Chinese Medicine, has been engaged in the study of Chinese medicine for the treatment of viral pneumonia in children for nearly 20 years, and has developed an effective oral liquid of Chinese medicine, Jinxin oral liquid, which has the effect of opening and closing lung, clearing heat and detoxifying, eliminating phlegm and relieving cough. However, due to the complexity of the active chemical components of Jinxin oral liquid, the role of Jinxin oral liquid in regulating the overall metabolic network of RSV pneumonia is still unclear. Metabolomics (Metabonomics) is a new subject about the species, quantity and variation of endogenous metabolites of organisms, and is the importance of systematic biological technology. Because the metabolite is the end of all the genes of the organism and the functional activity of the protein, the metabolite is regarded as the "biochemical phenotype" of the whole functional state of the organism, which can be immediately, sensitive and true in response to the response and regulation of the overall functional state of the organism under the stimuli of various external factors, avoiding the previous use of a single or a few. The metabolic histopathological technique combines the characteristics of the whole, the dynamic and the comprehensive analysis in a combination with the whole concept of traditional Chinese medicine. Therefore, this subject uses metabonomics and other biochemical tests to comprehensively characterize the metabolite changes caused by RSV pneumonia and phlegm heat closure. To try to clarify the essence of RSV pneumonia and phlegm heat closed lung syndrome and the therapeutic effect of Jinxin oral liquid on RSV infected mice. Objective: To study the metabolic characteristics of plasma and urine in children with RSV pneumonia phlegm heat closed syndrome, explore the syndrome essence of RSV pneumonia and phlegm heat closed syndrome, study the metabolic characteristics of plasma and lung tissue of RSV pneumonia BALB/c rats, and explore Jinxin The intervention effect of oral liquid on RSV pneumonia BALB/c mice and the possible metabolic regulation mechanism. Methods: the clinical experiment of the metabolic group of RSV pneumonia sputum heat closed lung syndrome: 30 children with RSV pneumonia and heat closed syndrome were selected in accordance with the diagnosis and treatment of Chinese and Western medicine. The disease group was set up and 30 cases of normal healthy group were set up. The plasma and urine of two groups of children were collected respectively. Liquid, using Ultra-performance Liquid Chromatography coupled with Linear Ion Trap Quadrupole Orbitrap Mass Spectrometry, detecting the metabolites of plasma and urine in two groups by super high performance liquid chromatography and two-dimensional linear ion trap mass spectrometry (coupled with Quadrupole Orbitrap Mass Spectrometry). Principal Component Analysis (PCA) and orthogonal partial least squares (Orthogonal Partial Least Squares Discriminant Analysis, OPLS-DA) were used to analyze the detected matrix data, screening potential plasma, urine biomarkers, analysis of related metabolic pathways, and exploring RSV pneumonia phlegm heat closed lung syndrome. The nature of metabolic characteristics. Jinxin oral liquid intervention in RSV pneumonia BALB/c mice: RSV infection BALB/c mice, Jinxin oral liquid intervention, and set Leigh Bhave Lin as the positive control, 6 days later, collect the mice plasma, lung tissue, pathological section of lung tissue morphologic analysis to evaluate the pulmonary pathological changes, based on UPLC-LTQ/Orb Itrap-MS studied the changes in the whole metabolism of plasma and lung tissue in each group. Using PCA and OPLS-DA to analyze the data, screening potential plasma, biomarkers of lung tissue, analyzing related metabolic pathways, evaluating the efficacy of Jinxin oral liquid and clarifying the metabolic regulation mechanism of Jinxin oral liquid. Results: the metabolic group of RSV pneumonia phlegm heat closed lung syndrome is the following. Bed experiment: 1. the results of pattern recognition analysis of plasma metabolomics show that the main components of the main components of the children with RSV pneumonia and phlegm heat closed syndrome and the healthy normal group are mostly distributed in the ellipse (95% confidence area) area of the scatter plot. Although there is a certain trend of separation, there are still overlapping overlaps, and the OPLS-DA model is further constructed and the model parameters are further constructed. R2Y=0.907, Q2=0.567 (plasma upper samples) and R2Y=0.816, Q2=0.619 (sample of lower plasma), normal group and RSV pneumonia sputum heat closed lung syndrome group can be completely separated along the direction of the first principal component t[1] axis, no cross and overlap, indicating that the two groups have distinct differences in metabolic characteristics: screening 21 potential biomarkers and identifying 20 of them are SM (18:2/24:0), SM (d18:2/24:1), SM (d18:0/18:1) and other sphingomyelin, TG (16:0/18:1/22:6), TG (16:0/18:0/22:6), TG (16:0/20:4/22:5), etc. 0/20:3), PC (16:0/22:5), PC (18:2/20:0), LysoPC (18:2) and other phosphatidylcholine, TG (14:0/16:0/18:2), TG (14:0/16:0/16:1) and other triglycerides were downregulated in the plasma of children with phlegm heat closed lung syndrome of RSV pneumonia. Besides, the substances related to the syndrome of sputum heat closure were also found to be more significant than those of normal children. .2. urine metabolomics model identification analysis results showed that the PCA method was used to model children with RSV pneumonia and phlegm heat closed lung syndrome and healthy normal group. Most of the samples were distributed in the ellipse (95% confidence area) area of the scatter plot. Although there was a certain trend of separation, there were still overlapping overlaps, and the OPLS-DA model was further established. The parameters were R2Y=0.865, Q2=0.580 (urine samples measured by a Q column) and R2Y=0.902, Q2=0.593 (urine samples from HILIC chromatograph), the normal group and RSV pneumonia phlegm heat closed lung syndrome group were completely separated, indicating that the two groups were significantly different in the metabolites, and 15 differential biomarkers were screened and 11 of them were identified; Acety Lcarnitine. 3-Methylglutarylcarnitine, 1-Pyrroline-4-hydroxy-2-carboxylate, Kynurenine, Tryptophan, Acetylspermidine, Cytosine, Tryptamine and so on were up-regulated in the urine of children with pneumonia and phlegm heat closed syndrome. Methyldopa, N-Methylhydantoin and so on were downregulated in the urine of children with phlegm heat closed lung syndrome. The intervention of RSV pneumonia BALB/c mice: the pathological changes of lung tissue in 1.RSV infected BALB/c mice were mainly interstitial pneumonia, alveolar wall hyperemia and thickening, interstitial infiltration of mononuclear macrophages and neutrophils, no obvious degeneration and necrosis of bronchial epithelial cells, no obvious exudation in bronchiolus tracheal cavity and alveolar cavity; Jinxin mouth. The results of pathological score showed that the treatment group was significantly lower than the model group for 6 days after.2.RSV infection. The plasma data of BALB/c model mice and normal mice were completely separated based on the OPLS-DA model, and the model parameters were R2Y=0.917, Q2=0.835 (plasma upper samples) and R2Y=0.967, Q2=0.936 (Q2=0.936). RSV infection caused the changes of plasma metabolic characteristics in mice, and 25 biomarkers were screened and identified, including PC (18:1/22:6).PC (18:0/205) and TG (18:1/18:2/18:2), TG (18:1/18:1/18:2) and other glycerol three esters in the model mice plasma were significantly increased, PC (18:1/18). 3), PC (18:0/22:6), PC (P-18:1/22:2), PC (O-18:0/22:6), PC (O-20:0/22:6), PC (16:0/20:4), PC (P-20:0/14:0). /16:0/18:0) the triglyceride and other triglycerides in the model mice plasma were significantly lower than those in the normal group. In addition, PE (18:3/19:0) and Phytanic acid were also down downward. Based on the selected biomarkers, we evaluated the efficacy of Jinxin oral liquid and found that Jinxin oral liquid could adjust 11 biomarkers in varying degrees. After 6 days of regulating the metabolic pathway of glycerol phospholipid, the OPLS-DA model was constructed based on the lung tissue data of the BALB/c model mice and the normal group. The two groups were completely separated, without cross and overlap, the model parameters were R2Y=0.879, Q2=0.789 (upper lung tissue samples) and R2Y=0.918, Q2=0.853 (the lower lung tissue samples). RSV infection caused the changes in the metabolic network of lung tissue in mice; 25 biomarkers were screened and identified, including PC (18:0/18:1), PC (18:0/18:2), PC (22:6/18:2), PC (18:2/20:4), PC (P-20:0/14:0), LysoPC. Inganine, Phytosphingosine and other sheath lipids and TG (18:1/18:1/18:1), TG (18:1/16:0/20:1), TG (18:1/18:1/18:2), TG (18:1/18:2/18:2), TG (16:0/18:0/22:6), etc. It is also associated with RSV infection and down trend in the model mice. Based on the selected biomarkers to evaluate the antiviral effect of Jinxin oral liquid, it is found that Jinxin oral liquid can adjust 16 biomarkers in different degrees of lung tissue, mainly by regulating phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine. Metabolism, valine, leucine and isoleucine biosynthesis, glycerol phospholipid metabolism, sheath lipid metabolism pathway. Conclusion: 1. UPLC-LTQ/Orbitrap-MS analysis of metabolomics can preliminarily explain and distinguish between RSV pneumonia phlegm heat closed lung syndrome and healthy normal children with different metabolic patterns.2.RSV pneumonia phlegm heat closed lung syndrome children's plasma The plasma and lung tissue of.3.RSV pneumonia BALB/c mice were mainly characterized by tryptophan and glycerol phospholipid metabolism disorder as the main manifestation of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, valine, leucine and isoleucine biosynthesis, glycerin phospholipid metabolism, and sphingomyelin metabolism disorder.4. Jinxin orally The liquid can obviously reduce the lung inflammation in RSV infected mice.5. Jinxin oral liquid can partly adjust the metabolic disorder caused by RSV infection, mainly by regulating phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, valine, leucine and isoleucine biosynthesis, glycerin phospholipid metabolism, sheath lipid metabolism pathway. Volatiles.
【學(xué)位授予單位】：南京中醫(yī)藥大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R272

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