1.Correlation between serum HIPK2,ANXA5 and the degree of coronary stenosis and prognosis in patients with acute myocardial infarction
Suna SHI ; Jingmiao BAI ; Xiaojuan LIN ; Mei DONG ; Zili GUO ; Zhenlian LI ; Xiaoling LIU ; Yuanyuan LIU
International Journal of Laboratory Medicine 2025;46(22):2753-2758
Objective To investigate the correlation between serum homeodomain interacting protein ki-nase 2(HIPK2),annexin A5(ANXA5)and coronary stenosis and prognosis in patients with acute myocardial infarction(AMI).Methods A total of 277 AMI patients who received interventional treatment in this hospi-tal from January 2021 to July 2023 were selected as the AMI group,and another 140 cases with normal or very mild stenosis in coronary angiography during the same period were selected as the control group.According to the degree of coronary artery stenosis(Gensini score),the AMI patients were divided into mild coronary arter-y stenosis group(86 cases),moderate coronary artery disease group(111 cases)and severe coronary artery disease group(80 cases).According to the prognosis,they were divided into poor prognosis group(80 cases)and good prognosis group(197 cases).Enzyme-linked immunosorbent assay was used to detect the serum HIPK2 and ANXA5 levels.Spearman correlation analysis was used to analyze the correlation between serum HIPK2 and ANXA5 levels and Gensini score in patients with AMI.Multivariate unconditional Logistic regres-sion was used to determine the relationship between serum HIPK2 and ANXA5 levels and prognosis of AMI patients.Receiver operating characteristic(ROC)curve was used to analyze the predictive efficiency of serum HIPK2 and ANXA5 levels on prognosis of AMI patients.Results Compared with the control group,the ser-um HIPK2 level in the AMI group increased and the ANXA5 level decreased,and the differences were statisti-cally significant(P<0.05).The serum HIPK2 levels in the mild coronary artery stenosis group,moderate coronary artery stenosis group and severe coronary artery stenosis group increased successively,while the ANXA5 levels decreased successively,and the differences were statistically significant(P<0.05).Gensini score was positively correlated with serum HIPK2 level and negatively correlated with serum ANXA5 level in AMI patients(P<0.05).The Gensini score of AMI patients was positively correlated with the serum HIPK2 level(r=0.785,P<0.05),and negatively correlated with the serum ANXA5 level(r=-0.798,P<0.05).Compared with the good prognosis group,the serum HIPK2 level in the poor prognosis group increased(P<0.05),and the ANXA5 level decreased(P<0.05).After adjusting for confounding factors,high HIPK2 was an independent risk factor for poor prognosis in AMI patients(P<0.05),and high ANXA5 was an independ-ent protective factor(P<0.05).The area under the curve of the combined prediction of serum HIPK2 and ANXA5 levels for the prognosis of AMI patients was 0.875,which was greater than 0.778 and 0.784 predic-ted by serum HIPK2 and ANXA5 levels alone(P<0.05).Conclusion The serum HIPK2 level is increased and the ANXA5 level is decreased in patients with AMI,which is related to the aggravation of coronary steno-sis and the poor prognosis.The combination of serum HIPK2 and ANXA5 levels is more effective in predic-ting the prognosis of patients with AMI.
2.Identification of Effective Components of Curcumae Rhizome and Potential Targets for Chronic Pancreatitis:A Study Based on Network Pharmacology and Bioinformatics Analyses
Yang WU ; Chun ZHANG ; Run SHI ; Jing SUN ; Zili ZHANG ; Mei GUO ; Dong XU ; Min TU ; Kuirong JIANG
Journal of Nanjing University of Traditional Chinese Medicine 2025;41(1):78-85
OBJECTIVE To explore the active components of Curcumae Rhizome as well as its potential value for the treatment of chronic pancreatitis(CP)using a combination of network pharmacology and bioinformatic approaches.METHODS Network pharma-cology methods were used to screen the active ingredients of Curcumae Rhizome and potential therapeutic targets for CP,and their ex-pression abundance and distribution in different cell types of CP were further analyzed in combination with CP tissue RNA sequencing data from publicly available databases.Molecular docking was performed to analyze the binding of the active components of Curcumae Rhizome to CP-related targets.Finally,the role of these core targets in pancreatic stellate cell(PSC)activation and related pathways was analyzed by single-cell RNA-sequencing to assess the anti-inflammatory and anti-fibrotic potential of the active ingredients of Curcumae Rhizome in CP treatment.RESULTS The most effective component of Curcumae Rhizome,Hederagenin,was identified by network pharmacological analysis,and its two therapeutic targets associated with CP were identified:LYZ and Rxra.Molecular doc-king results demonstrated that Hederagenin had an extremely strong binding capacity to the Rxra protein(affinity score=-7.392 kcal·mol-1),a core target of CP.Single-cell RNA-sequencing analysis further demonstrated that the hub target Rxra gene was closely associated with PSC activation and played an important role in PTN and TGF-β signaling pathways,the activation of which played a crucial role in the progression of chronic inflammation and fibrosis.CONCLUSION Curcumae Rhizome may provide new clues for the treatment of CP by inhibiting PSC activation.
3.Characteristics of the population of skeletal fluorosis patients and influencing factors on treatment willingness in drinking-tea-borne endemic fluorosis areas in Inner Mongolia Autonomous Region
Xiaojuan YANG ; Na CUI ; Zhiwei GUO ; Zhenlin LI ; Xuan WANG ; Zili CHANG ; Chengxiang ZHAO ; Yijun LIU
Chinese Journal of Endemiology 2025;44(8):639-646
Objective:To investigate the characteristics of the population of skeletal fluorosis patients in drinking-tea-borne endemic fluorosis (referred to as drinking-tea-borne fluorosis) areas in Inner Mongolia Autonomous Region (referred to as Inner Mongolia) and the influencing factors of treatment willingness, and to provide a basis for improving the prevention and control measures of drinking-tea-borne fluorosis and the treatment plan of skeletal fluorosis.Methods:From August to October 2022, a face-to-face questionnaire survey was conducted in key areas of drinking-tea-borne fluorosis in Inner Mongolia (administrative villages with an average daily intake of tea fluoride > 3.5 mg and skeletal fluorosis patients identified by the general survey of drinking-tea-borne fluorosis in Inner Mongolia in 2019), and to investigate the demographic, severity, and treatment status of patients with skeletal fluorosis, analyze the demographic characteristics of patients with skeletal fluorosis and the influencing factors of treatment willingness.Results:A total of 734 patients with skeletal fluorosis were investigated, including 543 mild cases, 125 moderate cases and 66 severe cases. The gender ratio of patients with skeletal fluorosis was 0.71 ∶ 1.00 (305/429), the age was concentrated in > 50 - 70 years old (70.57%, 518/734), the proportion of Mongolians was 94.28% (692/734), the proportion of herders was 97.68% (717/734), the educational level was mainly primary school (54.63%, 401/734), and the proportion of poor households and immigrants who had moved to their current residence was 7.08% (52/734) and 8.04% (59/734), respectively. The distribution of the severity of skeletal fluorosis in patients of different ages, genders, and educational levels was compared, and the differences were statistically significant ( P < 0.05). Fifty-three point two seven percent (391/734) of the patients had a willingness to undergo non-pharmacological treatment, of which 69.82% (273/391) had already started non-pharmacological treatment, with a treatment effectiveness rate of 73.99% (202/273). Sixty-five point two six percent (479/734) of the patients had a willingness to receive medication treatment, of which 7.31% (35/479) had already started medication treatment, with a treatment effectiveness rate of 54.29% (19/35). Zero point two seven percent (2/734) of the patients expressed a willingness to undergo surgical treatment, while no patients underwent surgical treatment. Multivariate logistic regression analysis showed that the age, ethnicity, occupation, educational level, poverty status, immigrants status, and the severity of skeletal fluorosis were all influencing factors of non-pharmacological treatment willingness ( P < 0.05). Occupation, educational level, poverty status, immigrants status, and the severity of skeletal fluorosis were all influencing factors of medication treatment willingness ( P < 0.05). Conclusions:Patients with skeletal fluorosis caused by tea drinking in Inner Mongolia are mainly from Mongolian ethnic groups, herders, middle-aged and elderly people, and those with a lower educational levels. The willingness of patients to receive treatment is influenced by various factors, and corresponding intervention measures can be formulated and taken based on these influencing factors to effectively improve the disease prevention awareness and treatment willingness of patients and the public.
4.Characteristics of the population of skeletal fluorosis patients and influencing factors on treatment willingness in drinking-tea-borne endemic fluorosis areas in Inner Mongolia Autonomous Region
Xiaojuan YANG ; Na CUI ; Zhiwei GUO ; Zhenlin LI ; Xuan WANG ; Zili CHANG ; Chengxiang ZHAO ; Yijun LIU
Chinese Journal of Endemiology 2025;44(8):639-646
Objective:To investigate the characteristics of the population of skeletal fluorosis patients in drinking-tea-borne endemic fluorosis (referred to as drinking-tea-borne fluorosis) areas in Inner Mongolia Autonomous Region (referred to as Inner Mongolia) and the influencing factors of treatment willingness, and to provide a basis for improving the prevention and control measures of drinking-tea-borne fluorosis and the treatment plan of skeletal fluorosis.Methods:From August to October 2022, a face-to-face questionnaire survey was conducted in key areas of drinking-tea-borne fluorosis in Inner Mongolia (administrative villages with an average daily intake of tea fluoride > 3.5 mg and skeletal fluorosis patients identified by the general survey of drinking-tea-borne fluorosis in Inner Mongolia in 2019), and to investigate the demographic, severity, and treatment status of patients with skeletal fluorosis, analyze the demographic characteristics of patients with skeletal fluorosis and the influencing factors of treatment willingness.Results:A total of 734 patients with skeletal fluorosis were investigated, including 543 mild cases, 125 moderate cases and 66 severe cases. The gender ratio of patients with skeletal fluorosis was 0.71 ∶ 1.00 (305/429), the age was concentrated in > 50 - 70 years old (70.57%, 518/734), the proportion of Mongolians was 94.28% (692/734), the proportion of herders was 97.68% (717/734), the educational level was mainly primary school (54.63%, 401/734), and the proportion of poor households and immigrants who had moved to their current residence was 7.08% (52/734) and 8.04% (59/734), respectively. The distribution of the severity of skeletal fluorosis in patients of different ages, genders, and educational levels was compared, and the differences were statistically significant ( P < 0.05). Fifty-three point two seven percent (391/734) of the patients had a willingness to undergo non-pharmacological treatment, of which 69.82% (273/391) had already started non-pharmacological treatment, with a treatment effectiveness rate of 73.99% (202/273). Sixty-five point two six percent (479/734) of the patients had a willingness to receive medication treatment, of which 7.31% (35/479) had already started medication treatment, with a treatment effectiveness rate of 54.29% (19/35). Zero point two seven percent (2/734) of the patients expressed a willingness to undergo surgical treatment, while no patients underwent surgical treatment. Multivariate logistic regression analysis showed that the age, ethnicity, occupation, educational level, poverty status, immigrants status, and the severity of skeletal fluorosis were all influencing factors of non-pharmacological treatment willingness ( P < 0.05). Occupation, educational level, poverty status, immigrants status, and the severity of skeletal fluorosis were all influencing factors of medication treatment willingness ( P < 0.05). Conclusions:Patients with skeletal fluorosis caused by tea drinking in Inner Mongolia are mainly from Mongolian ethnic groups, herders, middle-aged and elderly people, and those with a lower educational levels. The willingness of patients to receive treatment is influenced by various factors, and corresponding intervention measures can be formulated and taken based on these influencing factors to effectively improve the disease prevention awareness and treatment willingness of patients and the public.
5.Identification of Effective Components of Curcumae Rhizome and Potential Targets for Chronic Pancreatitis:A Study Based on Network Pharmacology and Bioinformatics Analyses
Yang WU ; Chun ZHANG ; Run SHI ; Jing SUN ; Zili ZHANG ; Mei GUO ; Dong XU ; Min TU ; Kuirong JIANG
Journal of Nanjing University of Traditional Chinese Medicine 2025;41(1):78-85
OBJECTIVE To explore the active components of Curcumae Rhizome as well as its potential value for the treatment of chronic pancreatitis(CP)using a combination of network pharmacology and bioinformatic approaches.METHODS Network pharma-cology methods were used to screen the active ingredients of Curcumae Rhizome and potential therapeutic targets for CP,and their ex-pression abundance and distribution in different cell types of CP were further analyzed in combination with CP tissue RNA sequencing data from publicly available databases.Molecular docking was performed to analyze the binding of the active components of Curcumae Rhizome to CP-related targets.Finally,the role of these core targets in pancreatic stellate cell(PSC)activation and related pathways was analyzed by single-cell RNA-sequencing to assess the anti-inflammatory and anti-fibrotic potential of the active ingredients of Curcumae Rhizome in CP treatment.RESULTS The most effective component of Curcumae Rhizome,Hederagenin,was identified by network pharmacological analysis,and its two therapeutic targets associated with CP were identified:LYZ and Rxra.Molecular doc-king results demonstrated that Hederagenin had an extremely strong binding capacity to the Rxra protein(affinity score=-7.392 kcal·mol-1),a core target of CP.Single-cell RNA-sequencing analysis further demonstrated that the hub target Rxra gene was closely associated with PSC activation and played an important role in PTN and TGF-β signaling pathways,the activation of which played a crucial role in the progression of chronic inflammation and fibrosis.CONCLUSION Curcumae Rhizome may provide new clues for the treatment of CP by inhibiting PSC activation.
6.Evidence-based clinical guideline for the diagnosis and treatment of surgical site infection in spinal trauma (version 2024)
Zhu GUO ; Chao WANG ; Hongfei XIANG ; Zhongqiang CHEN ; Liang CHEN ; Tongwei CHU ; Shucai DENG ; Jian DONG ; Xinru DU ; Shiqing FENG ; Baorong HE ; Xijing HE ; Jianzhong HU ; Yong HAI ; Qingquan KONG ; Guiqing LIANG ; Qi LIAO ; Zhongjun LIU ; Shaoyu LIU ; Baoge LIU ; Xiaoguang LIU ; Weishi LI ; Li LI ; Fang LI ; Bin LIN ; Shibao LU ; Tao NIU ; Zhenli QIAO ; Dike RUAN ; Yueming SONG ; Haipeng SI ; Jun SHU ; Zhongyi SUN ; Qing WANG ; Zili WANG ; Huan WANG ; Hongli WANG ; Yan WANG ; Xiaolin WU ; Zhanyong WU ; Jinglong YAN ; Tengbo YU ; Qiang ZHANG ; Guoqing ZHANG ; Xuesong ZHANG ; Fengdong ZHAO ; Jie ZHAO ; Zhaomin ZHENG ; Qingsan ZHU ; Dingjun HAO ; Bohua CHEN
Chinese Journal of Trauma 2024;40(12):1057-1070
Spinal surgical site infection (SSI), especially deep SSI after internal fixation is difficult in treatment, with long course of disease and poor prognosis. At present, there are many controversies in the diagnosis and treatment of spinal SSI, with unsatisfactory overall efficacy of its diagnosis and treatment. Besides, no diagnosis and treatment guideline based on evidence-based medicine has been in existence. To this end, the Spinal Infection Group of the Orthopedic Branch of the Chinese Medical Doctor Association and the Spinal Infection Group of the Spinal Surgery Branch of the Chinese Rehabilitation Medicine Association jointly organized relevant experts to formulate Evidence-based clinical guideline for the diagnosis and treatment of surgical site infection in spinal trauma ( version 2024) based on an evidence-based approach. A total of 10 recommendations were proposed on the diagnosis and treatment of spinal SSI, so as to provide a clinical reference for the diagnosis and treatment of spinal SSI.
7.Distribution of physical and chemical water improvement areas of drinking water-borne endemic fluorosis in Inner Mongolia Autonomous Region and the use of household water purifiers
Yijun LIU ; Na CUI ; Zili CHANG ; Xuan WANG ; Yanhong LI ; Zhiwei GUO ; Chengxiang ZHAO ; Zhenlin LI
Chinese Journal of Endemiology 2024;43(1):35-38
Objective:To investigate the distribution of physical and chemical water improvement areas of drinking water-borne endemic fluorosis in Inner Mongolia Autonomous Region, as well as the use of household water purifiers.Methods:From April to October 2021, a survey was conducted in a drinking water-borne endemic fluorosis areas in Inner Mongolia Autonomous Region where physical and chemical water improvement was carried out. The survey included the basic situation of the affected villages (number of permanent households, number of permanent residents, historical water fluoride content) and the use of residential water purifiers. Household peripheral water samples were collected to test the water fluoride content. Water purifier installation rate, normal usage rate, qualified water fluoride rate in normal usage, and the proportion of households covered by filter replacement departments were calculated.Results:In Inner Mongolia Autonomous Region, the physical and chemical water improvement areas of drinking water-borne endemic fluorosis were distributed in 2 735 villages in 11 leagues (cities) throughout the region, with 192 950 permanent households and 540 216 permanent residents. The average historical water fluoride content in all leagues (cities) was 2.18 mg/L, and the current average water fluoride content was 0.40 mg/L. A total of 134 763 water purifiers were installed, with an installation rate of 69.84% (134 763/192 950). A total of 10 773 households were surveyed, with 10 396 households using water purifiers normally and a normal usage rate of 96.50% (10 396/10 773). Among them, 10 158 households had qualified water fluoride of normal usage, with a qualified water fluoride rate of 97.71% (10 158/10 396). Of the 10 396 households using water purifiers normally, 3 974 households (38.23%) had filter cartridges used within one year, and 3 961 households had qualified water fluoride, with a qualified rate of water fluoride of 99.67% (3 961/3 974). Six thousand four hundred and twenty-two households (61.77%) had filter cartridges used for more than one year, with 6 197 households had qualified water fluoride and a qualified rate of water fluoride of 96.50% (6 197/6 422). There was a statistically significant difference in the qualified rate of water fluoride between purifiers with different filter cartridge usage times (χ 2 = 110.73, P < 0.001). Among the 10 773 surveyed households, the filter cartridges replacement department covered 10 470 households, accounting for 97.19% (10 470/10 773). Conclusions:In Inner Mongolia Autonomous Region, the physical and chemical water improvement areas of drinking water-borne endemic fluorosis are widely distributed, and the normal usage rate of household water purifiers is relatively high. The qualified rate of water fluoride in household water purifiers with filter cartridges used for more than one year is low.
8.Evidence-based clinical guideline for the diagnosis and treatment of surgical site infection in spinal trauma (version 2024)
Zhu GUO ; Chao WANG ; Hongfei XIANG ; Zhongqiang CHEN ; Liang CHEN ; Tongwei CHU ; Shucai DENG ; Jian DONG ; Xinru DU ; Shiqing FENG ; Baorong HE ; Xijing HE ; Jianzhong HU ; Yong HAI ; Qingquan KONG ; Guiqing LIANG ; Qi LIAO ; Zhongjun LIU ; Shaoyu LIU ; Baoge LIU ; Xiaoguang LIU ; Weishi LI ; Li LI ; Fang LI ; Bin LIN ; Shibao LU ; Tao NIU ; Zhenli QIAO ; Dike RUAN ; Yueming SONG ; Haipeng SI ; Jun SHU ; Zhongyi SUN ; Qing WANG ; Zili WANG ; Huan WANG ; Hongli WANG ; Yan WANG ; Xiaolin WU ; Zhanyong WU ; Jinglong YAN ; Tengbo YU ; Qiang ZHANG ; Guoqing ZHANG ; Xuesong ZHANG ; Fengdong ZHAO ; Jie ZHAO ; Zhaomin ZHENG ; Qingsan ZHU ; Dingjun HAO ; Bohua CHEN
Chinese Journal of Trauma 2024;40(12):1057-1070
Spinal surgical site infection (SSI), especially deep SSI after internal fixation is difficult in treatment, with long course of disease and poor prognosis. At present, there are many controversies in the diagnosis and treatment of spinal SSI, with unsatisfactory overall efficacy of its diagnosis and treatment. Besides, no diagnosis and treatment guideline based on evidence-based medicine has been in existence. To this end, the Spinal Infection Group of the Orthopedic Branch of the Chinese Medical Doctor Association and the Spinal Infection Group of the Spinal Surgery Branch of the Chinese Rehabilitation Medicine Association jointly organized relevant experts to formulate Evidence-based clinical guideline for the diagnosis and treatment of surgical site infection in spinal trauma ( version 2024) based on an evidence-based approach. A total of 10 recommendations were proposed on the diagnosis and treatment of spinal SSI, so as to provide a clinical reference for the diagnosis and treatment of spinal SSI.
9.Demographic characteristics and treatment of patients with skeletal fluorosis in Inner Mongolia Autonomous Region in 2020
Yijun LIU ; Zili CHANG ; Zhiwei GUO ; Chengxiang ZHAO ; Zhenlin LI
Chinese Journal of Endemiology 2022;41(4):309-312
Objective:To understand the demographic characteristics and treatment intention, treatment status and therapeutic effect of patients with skeletal fluorosis in Inner Mongolia Autonomous Region (reffered to as Inner Mongolia) in order to provide a basis for next step treatment program.Methods:From March to June 2020, a face-to-face questionnaire survey was conducted among 3 570 patients with skeletal fluorosis in 11 leagues (cities) of Inner Mongolia to understand their basic information, treatment intention, treatment status and therapeutic effect. Patients with skeletal fluorosis of different demographic characteristics were compared with each other in their treatment intention and treatment status, and the therapeutic effects of different drugs were compared by χ 2 test. Results:A total of 3570 patients with skeletal fluorosis were investigated. There were slightly more women than men with skeletal fluorosis (1.29 ∶ 1.00, 2 014/1 556). The ages were mainly from 40 to 79 years old (95.4%, 3 406/3 570). Mongols patients accounted for 36.0% (1 285/3 570). Patients with low education (primary school and below) accounted for 82.2% (2 935/3 570). Eighty-five per cent (3 035/3 570) of the patients had drug treatment intention and 37.1% (1 325/3 570) of the patients had drug treatment. Thirty-seven point five per cent (1 338/3 570) of the patients had surgery intention and surgery was performed in 0.2% (8/3 570) of the patients. Combination therapy (98.5%, 194/197) and chondroprotective agents alone (98.3%, 173/176) were more effective than anti-inflammatory and analgesic agents alone (84.2%, 48/57) in the treatment of skeletal fluorosis ( P < 0.05). Surgery was effective (8/8). Conclusions:Most of the patients with skeletal fluorosis are middle-aged and elderly, and the patients with skeletal fluorosis in Mongols account for a certain proportion. At present, all the patients with skeletal fluorosis who have the will to be treated have not been effectively treated, and the means of treatment is relatively single. It should be advocated to carry out various forms of treatment of skeletal fluorosis, so that patients could relieve symptoms, reduce pain and improve their quality of life.
10.Beneficial Effects of Celastrol on Immune Balance by Modulating Gut Microbiota in Experimental Ulcerative Colitis Mice
Li MINGYUE ; Guo WEINA ; Dong YALAN ; Wang WENZHU ; Tian CHUNXIA ; Zhang ZILI ; Yu TING ; Zhou HAIFENG ; Gui YANG ; Xue KAMING ; Li JUNYI ; Jiang FENG ; Sarapultsev ALEXEY ; Wang HUAFANG ; Zhang GE ; Luo SHANSHAN ; Fan HENG ; Hu DESHENG
Genomics, Proteomics & Bioinformatics 2022;20(2):288-303
Ulcerative colitis(UC)is a chronic inflammatory bowel disease caused by many factors including colonic inflammation and microbiota dysbiosis.Previous studies have indicated that celastrol(CSR)has strong anti-inflammatory and immune-inhibitory effects.Here,we investigated the effects of CSR on colonic inflammation and mucosal immunity in an experimental colitis model,and addressed the mechanism by which CSR exerts the protective effects.We characterized the ther-apeutic effects and the potential mechanism of CSR on treating UC using histological staining,intestinal permeability assay,cytokine assay,flow cytometry,fecal microbiota transplantation(FMT),16S rRNA sequencing,untargeted metabolomics,and cell differentiation.CSR administra-tion significantly ameliorated the dextran sodium sulfate(DSS)-induced colitis in mice,which was evidenced by the recovered body weight and colon length as well as the decreased disease activity index(DAI)score and intestinal permeability.Meanwhile,CSR down-regulated the production of pro-inflammatory cytokines and up-regulated the amount of anti-inflammatory mediators at both mRNA and protein levels,and improved the balances of Treg/Thl and Treg/Th1 7 to maintain the colonic immune homeostasis.Notably,all the therapeutic effects were exerted in a gut microbiota-dependent manner.Furthermore,CSR treatment increased the gut microbiota diversity and changed the compositions of the gut microbiota and metabolites,which is probably associated with the gut microbiota-mediated protective effects.In conclusion,this study provides the strong evidence that CSR may be a promising therapeutic drug for UC.

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