Targeting p38 MAPK signaling pathway and neutrophil extracellular traps: An important anti-inflammatory mechanism of Huangqin Qingre Chubi Capsule in rheumatoid arthritis
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作者:
Li, Yang
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Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Anhui Univ Chinese Med, Clin Med Sch 1, Hefei 230038, Anhui, Peoples R ChinaAnhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Li, Yang
[1
,2
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Liu, Jian
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Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Anhui Acad Chinese Med, Inst Rheumatol, Hefei 230031, Anhui, Peoples R ChinaAnhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Liu, Jian
[1
,3
]
Sun, Yue
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Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Anhui Acad Chinese Med, Inst Rheumatol, Hefei 230031, Anhui, Peoples R ChinaAnhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Sun, Yue
[1
,3
]
Hu, Yuedi
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Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Anhui Univ Chinese Med, Clin Med Sch 1, Hefei 230038, Anhui, Peoples R ChinaAnhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Hu, Yuedi
[1
,2
]
Cong, Chengzhi
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Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Anhui Univ Chinese Med, Clin Med Sch 1, Hefei 230038, Anhui, Peoples R ChinaAnhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Cong, Chengzhi
[1
,2
]
Chen, Yiming
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Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Anhui Univ Chinese Med, Clin Med Sch 1, Hefei 230038, Anhui, Peoples R ChinaAnhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Chen, Yiming
[1
,2
]
Fang, Yanyan
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Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Anhui Acad Chinese Med, Inst Rheumatol, Hefei 230031, Anhui, Peoples R ChinaAnhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
Fang, Yanyan
[1
,3
]
机构:
[1] Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
[2] Anhui Univ Chinese Med, Clin Med Sch 1, Hefei 230038, Anhui, Peoples R China
[3] Anhui Acad Chinese Med, Inst Rheumatol, Hefei 230031, Anhui, Peoples R China
Rheumatoid arthritis (RA) is a common chronic autoimmune disease. Neutrophils release and their extracellular traps (NETs) tend to result in synovial inflammation and cartilage damage. Huangqin Qingre Chubi Capsule (HQC) is an important herbal formulation for RA treatment and has been used for many years. This study applied an interdisciplinary and integrated strategy combining clinical data, integrative bioinformatics, molecular modeling, and both in vitro and in vivo experiments to elucidate the efficacy and potential anti-inflammatory mechanisms of HQC for RA. Retrospective clinical data mining demonstrated that patients with RA treated with HQC exhibited recovery of immuno-inflammatory markers and self-perception. By applying network pharmacological analysis, molecular docking, molecular dynamics simulation, and cellular thermal shift assays, we determined that HQC can directly bind to MAPK14 and target p38 MAPK signaling pathway and NETs formation. Treatment of an adjuvant-induced arthritis rat model combining damp-heat patterns using HQC demonstrated it's effectiveness in reducing the severity of inflammatory arthritis in a dose-dependent manner and downregulated phosphorylation of p38 MAPK and NETs release. In vitro co-culture system mimicking inflammatory microenvironment of RA in vivo revealed that crosstalk between neutrophils (PMNs) and fibroblast- like synoviocytes (FLSs) was manifested by activation of p38 MAPK signaling pathway, release of NETs, and amplification of inflammation, which was blocked by HQC. Mechanistic validation using the p38 MAPK agonist diprovocim demonstrated that HQC inhibited NET formation by modulating the p38 MAPK pathway (mainly by inhibiting its phosphorylation) to exert anti-inflammatory effects. In conclusion, our interdisciplinary and integrated study demonstrated that HQC can target the p38 MAPK signaling pathway to inhibit NET formation and inflammatory response, thereby blocking the crosstalk between PMNs and FLSs to ameliorating RA.
机构:
Univ Ulsan, Coll Med, Dept Biochem & Mol Biol, Seoul 05505, South KoreaUniv Ulsan, Coll Med, Dept Biochem & Mol Biol, Seoul 05505, South Korea
Lee, Ji Ae
Kim, Dong Jin
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Korea Inst Sci & Technol, Brain Sci Inst, Ctr Neuromed, Seoul 02792, South KoreaUniv Ulsan, Coll Med, Dept Biochem & Mol Biol, Seoul 05505, South Korea
Kim, Dong Jin
Hwang, Onyou
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Univ Ulsan, Coll Med, Dept Biochem & Mol Biol, Seoul 05505, South KoreaUniv Ulsan, Coll Med, Dept Biochem & Mol Biol, Seoul 05505, South Korea
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North Sichuan Med Coll, Affiliated Hosp, Dept Pediat, 1 Maoyuan South Rd, Nanchong, Sichuan, Peoples R ChinaNorth Sichuan Med Coll, Affiliated Hosp, Dept Pediat, 1 Maoyuan South Rd, Nanchong, Sichuan, Peoples R China
Lyu, Xiaojiang
Liu, Jiaojiao
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North Sichuan Med Coll, Affiliated Hosp, Dept Pediat, 1 Maoyuan South Rd, Nanchong, Sichuan, Peoples R ChinaNorth Sichuan Med Coll, Affiliated Hosp, Dept Pediat, 1 Maoyuan South Rd, Nanchong, Sichuan, Peoples R China
Liu, Jiaojiao
Liu, Zengrong
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North Sichuan Med Coll, Affiliated Hosp, Dept Pediat, 1 Maoyuan South Rd, Nanchong, Sichuan, Peoples R ChinaNorth Sichuan Med Coll, Affiliated Hosp, Dept Pediat, 1 Maoyuan South Rd, Nanchong, Sichuan, Peoples R China
Liu, Zengrong
Wu, Ying
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North Sichuan Med Coll, Affiliated Hosp, Dept Pediat, 1 Maoyuan South Rd, Nanchong, Sichuan, Peoples R ChinaNorth Sichuan Med Coll, Affiliated Hosp, Dept Pediat, 1 Maoyuan South Rd, Nanchong, Sichuan, Peoples R China
Wu, Ying
Zhu, Ping
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North Sichuan Med Coll, Affiliated Hosp, Dept Pediat, 1 Maoyuan South Rd, Nanchong, Sichuan, Peoples R ChinaNorth Sichuan Med Coll, Affiliated Hosp, Dept Pediat, 1 Maoyuan South Rd, Nanchong, Sichuan, Peoples R China
Zhu, Ping
Liu, Chonghai
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North Sichuan Med Coll, Affiliated Hosp, Dept Pediat, 1 Maoyuan South Rd, Nanchong, Sichuan, Peoples R ChinaNorth Sichuan Med Coll, Affiliated Hosp, Dept Pediat, 1 Maoyuan South Rd, Nanchong, Sichuan, Peoples R China
机构:
Cent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R ChinaCent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R China
Chen, Dayong
Pan, Dan
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Cent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R ChinaCent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R China
Pan, Dan
Tang, Shaolong
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Cent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R ChinaCent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R China
Tang, Shaolong
Tan, Zhihong
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Cent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R ChinaCent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R China
Tan, Zhihong
Zhang, Yanan
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Cent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R ChinaCent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R China
Zhang, Yanan
Fu, Yunfeng
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Cent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R ChinaCent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R China
Fu, Yunfeng
Lue, Guohua
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Cent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R ChinaCent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R China
Lue, Guohua
Huang, Qinghua
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Cent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R ChinaCent Hosp Zhuzhou City, Dept Spine Surg, 116 Changjiang South Rd, Zhuzhou 412000, Hunan, Peoples R China
机构:
Univ Ghana, Coll Hlth Sci, Noguchi Mem Inst Med Res, Dept Parasitol, POB LG 581, Legon, Accra, GhanaUniv Ghana, Coll Hlth Sci, Noguchi Mem Inst Med Res, Dept Parasitol, POB LG 581, Legon, Accra, Ghana
Asiedu, Seth O.
Kwofie, Samuel K.
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Univ Ghana, Coll Basic & Appl Sci, Sch Engn Sci, Dept Biomed Engn, POB LG 77, Legon, Accra, Ghana
Univ Ghana, Coll Basic & Appl Sci, Dept Biochem Cell & Mol Biol, West African Ctr Cell Biol Infect Pathogens, POB LG 54, Accra, GhanaUniv Ghana, Coll Hlth Sci, Noguchi Mem Inst Med Res, Dept Parasitol, POB LG 581, Legon, Accra, Ghana
Kwofie, Samuel K.
Broni, Emmanuel
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Univ Ghana, Coll Basic & Appl Sci, Sch Engn Sci, Dept Biomed Engn, POB LG 77, Legon, Accra, GhanaUniv Ghana, Coll Hlth Sci, Noguchi Mem Inst Med Res, Dept Parasitol, POB LG 581, Legon, Accra, Ghana
Broni, Emmanuel
Wilson, Michael D.
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Univ Ghana, Coll Hlth Sci, Noguchi Mem Inst Med Res, Dept Parasitol, POB LG 581, Legon, Accra, Ghana
Loyola Univ Med Ctr, Dept Med, Maywood, IL 60153 USAUniv Ghana, Coll Hlth Sci, Noguchi Mem Inst Med Res, Dept Parasitol, POB LG 581, Legon, Accra, Ghana
机构:
Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, TaiwanTaipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, Taiwan
Jayakumar, Thanasekaran
Yang, Chun-Ming
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Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, Taiwan
Chi Mei Med Ctr, Dept Neurol, Tainan 710, TaiwanTaipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, Taiwan
Yang, Chun-Ming
Yen, Ting-Lin
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Cathay Gen Hosp, Dept Med Res, Taipei 106, Taiwan
Taipei Med Univ, Coll Med, Sch Med, Dept Pharmacol, Taipei 110, TaiwanTaipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, Taiwan
Yen, Ting-Lin
Hsu, Chia-Yuan
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Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, TaiwanTaipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, Taiwan
Hsu, Chia-Yuan
Sheu, Joen-Rong
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Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, Taiwan
Taipei Med Univ, Coll Med, Sch Med, Dept Pharmacol, Taipei 110, TaiwanTaipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, Taiwan
Sheu, Joen-Rong
Hsia, Chih-Wei
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Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, TaiwanTaipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, Taiwan
Hsia, Chih-Wei
Manubolu, Manjunath
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Ohio State Univ, Dept Evolut Ecol & Organismal Biol, Columbus, OH 43212 USATaipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, Taiwan
Manubolu, Manjunath
Huang, Wei-Chieh
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Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, TaiwanTaipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, Taiwan
Huang, Wei-Chieh
Hsieh, Cheng-Ying
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Taipei Med Univ, Coll Med, Sch Med, Dept Pharmacol, Taipei 110, TaiwanTaipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, Taiwan
Hsieh, Cheng-Ying
Hsia, Chih-Hsuan
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Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, Taiwan
Shin Kong Wu Ho Mem Hosp, Translat Med Ctr, Taipei 111, TaiwanTaipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, Taiwan
机构:Changzhi Med Coll, Dept Hlth Management, Changzhi, Shanxi, Peoples R China
Wei, Jie
Gao, Chen
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Mil Sports Training Ctr Training Management, Dept Sports Med, Dept Cent Mil Commiss, 12 Shejichang Rd, Beijing 100071, Peoples R ChinaChangzhi Med Coll, Dept Hlth Management, Changzhi, Shanxi, Peoples R China
Gao, Chen
Hu, Ke
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Changzhi Med Coll, Dept Hlth Management, Changzhi, Shanxi, Peoples R ChinaChangzhi Med Coll, Dept Hlth Management, Changzhi, Shanxi, Peoples R China
Hu, Ke
Li, Mingyue
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Mil Sports Training Ctr Training Management, Dept Sports Med, Dept Cent Mil Commiss, Beijing, Peoples R China
Mil Sports Training Ctr Training Management, Dept Cent Mil Commiss, Mil Sports Res Off, Beijing, Peoples R ChinaChangzhi Med Coll, Dept Hlth Management, Changzhi, Shanxi, Peoples R China
Li, Mingyue
Li, Jingshi
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机构:Changzhi Med Coll, Dept Hlth Management, Changzhi, Shanxi, Peoples R China
Li, Jingshi
Shen, Mengman
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Mil Sports Training Ctr Training Management, Dept Cent Mil Commiss, Mil Sports Res Off, Beijing, Peoples R ChinaChangzhi Med Coll, Dept Hlth Management, Changzhi, Shanxi, Peoples R China
Shen, Mengman
Zhang, Shuyu
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机构:
Mil Sports Training Ctr Training Management, Dept Cent Mil Commiss, Basketball Project Room, Beijing, Peoples R China
Beidahuang Grp, Dept Rehabil, Gen Hosp, Beijing, Peoples R ChinaChangzhi Med Coll, Dept Hlth Management, Changzhi, Shanxi, Peoples R China
机构:
Binzhou Med Coll, Dept Cardiol, Affiliated Hosp, Binzhou City 256603, Shandong, Peoples R ChinaBinzhou Med Coll, Dept Cardiol, Affiliated Hosp, Binzhou City 256603, Shandong, Peoples R China
Diao, Shu-Ling
Sun, Jing-Wu
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Binzhou Med Coll, Dept Cardiol, Affiliated Hosp, Binzhou City 256603, Shandong, Peoples R ChinaBinzhou Med Coll, Dept Cardiol, Affiliated Hosp, Binzhou City 256603, Shandong, Peoples R China
Sun, Jing-Wu
Ma, Bao-Xin
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Binzhou Med Coll, Dept Cardiol, Affiliated Hosp, Binzhou City 256603, Shandong, Peoples R ChinaBinzhou Med Coll, Dept Cardiol, Affiliated Hosp, Binzhou City 256603, Shandong, Peoples R China
Ma, Bao-Xin
Li, Xiao-Mei
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Binzhou Med Coll, Dept Cardiol, Affiliated Hosp, Binzhou City 256603, Shandong, Peoples R ChinaBinzhou Med Coll, Dept Cardiol, Affiliated Hosp, Binzhou City 256603, Shandong, Peoples R China
Li, Xiao-Mei
Wang, Dong
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Binzhou Med Coll, Dept Cardiol, Affiliated Hosp, Binzhou City 256603, Shandong, Peoples R ChinaBinzhou Med Coll, Dept Cardiol, Affiliated Hosp, Binzhou City 256603, Shandong, Peoples R China
机构:
Univ Paris 13, Sorbonne Paris Cite, Paris, France
INSERM, UMR 1125, Li2P, Bobigny, FranceUniv Paris 13, Sorbonne Paris Cite, Paris, France
Ribon, M.
Seninet, S.
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Univ Paris 13, Sorbonne Paris Cite, Paris, France
INSERM, UMR 1125, Li2P, Bobigny, FranceUniv Paris 13, Sorbonne Paris Cite, Paris, France
Seninet, S.
Matyja, K.
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Univ Paris 13, Sorbonne Paris Cite, Paris, France
INSERM, UMR 1125, Li2P, Bobigny, FranceUniv Paris 13, Sorbonne Paris Cite, Paris, France
Matyja, K.
Sebbag, M.
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Univ Toulouse, Toulouse, France
INSERM, CNRS 1056, UMR 5165, Toulouse, FranceUniv Paris 13, Sorbonne Paris Cite, Paris, France
Sebbag, M.
Clavel, C.
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Univ Toulouse, Toulouse, France
INSERM, CNRS 1056, UMR 5165, Toulouse, FranceUniv Paris 13, Sorbonne Paris Cite, Paris, France
Clavel, C.
Mussard, J.
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Univ Paris 13, Sorbonne Paris Cite, Paris, France
INSERM, UMR 1125, Li2P, Bobigny, FranceUniv Paris 13, Sorbonne Paris Cite, Paris, France
Mussard, J.
Serre, G.
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机构:
Univ Toulouse, Toulouse, France
INSERM, CNRS 1056, UMR 5165, Toulouse, FranceUniv Paris 13, Sorbonne Paris Cite, Paris, France
Serre, G.
Boissier, M. C.
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机构:
Univ Paris 13, Sorbonne Paris Cite, Paris, France
INSERM, UMR 1125, Li2P, Bobigny, France
Avicenne Hosp, AP HP, Dept Rheumatol, Bobigny, FranceUniv Paris 13, Sorbonne Paris Cite, Paris, France
Boissier, M. C.
Decker, P.
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Univ Paris 13, Sorbonne Paris Cite, Paris, France
INSERM, UMR 1125, Li2P, Bobigny, FranceUniv Paris 13, Sorbonne Paris Cite, Paris, France
机构:
Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA
Oregon State Univ, Dept Biochem & Biophys, Corvallis, OR 97331 USAOregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA
Li, Chuan
Zhang, Wei-jian
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机构:
Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA
Oregon State Univ, Dept Biochem & Biophys, Corvallis, OR 97331 USAOregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA
Zhang, Wei-jian
Frei, Balz
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机构:
Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA
Oregon State Univ, Dept Biochem & Biophys, Corvallis, OR 97331 USAOregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA