多重耐药寡养单胞菌的基因组学研究进展
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国家自然科学基金(31800118,32260032);江西双千计划(jxsq2019101054);江西省自然科学基金(20171BAB205110)


Advances in genomics of multi-drug resistant Stenotrophomonas
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    摘要:

    寡养单胞菌(Stenotrophomonas)是一类广泛分布于自然环境中的革兰氏阴性非发酵细菌,环境适应能力较强,尤其具备高度耐受抗生素的能力,被认为是耐药基因(antimicrobial resistance, AMR)传播的“物流转运仓库”。临床上寡养单胞菌检出率逐年提高,且耐受抗生素能力及其种类呈现增加态势。本文围绕寡养单胞菌基因组编码的多样性耐药因子,结合基因组学工具开发、抗生素耐药分子机制的研究进展,针对耐药相关因子所涉及的进化/变异和序列编辑技术展开综述。寡养单胞菌的比较基因组学(comparative genomics)研究,可推动耐药菌高效监测与扩散风险防控、解析微生物适应环境关键机制和设计靶向药物。

    Abstract:

    Stenotrophomonas species are non-fermentative Gram-negative bacteria that are widely distributed in environment and are highly resistant to numerous antibiotics. Thus, Stenotrophomonas serves as a reservoir of genes encoding antimicrobial resistance (AMR). The detection rate of Stenotrophomonas is rapidly increasing alongside their strengthening intrinsic ability to tolerate a variety of clinical antibiotics. This review illustrated the current genomics advances of antibiotic resistant Stenotrophomonas, highlighting the importance of precise identification and sequence editing. In addition, AMR diversity and transferability have been assessed by the developed bioinformatics tools. However, the working models of AMR in Stenotrophomonas are cryptic and urgently required to be determined. Comparative genomics is envisioned to facilitate the prevention and control of AMR, as well as to gain insights into bacterial adaptability and drug development.

    参考文献
    [1] SÁNCHEZ MB. Antibiotic resistance in the opportunistic pathogen Stenotrophomonas maltophilia[J]. Frontiers in Microbiology, 2015, 6:658.
    [2] FERREIRA MA, PEREIRA ML, DOS SANTOS KV. Drug-induced tolerance:the effects of antibiotic pre-exposure in Stenotrophomonas maltophilia[J]. Future Microbiology, 2020, 15:497-508.
    [3] ABDA EM, KRYSCIAK D, KROHN-MOLT I, MAMAT U, SCHMEISSER C, FÖRSTNER KU, SCHAIBLE UE, KOHL TA, NIEMAN S, STREIT WR. Phenotypic heterogeneity affects Stenotrophomonas maltophilia K279a colony morphotypes and β-lactamase expression[J]. Frontiers in Microbiology, 2015, 6:1373.
    [4] BANERJEE R, ROY D. Codon usage and gene expression pattern of Stenotrophomonas maltophilia R551-3 for pathogenic mode of living[J]. Biochemical and Biophysical Research Communications, 2009, 390(2):177-181.
    [5] ADAMEK M, LINKE B, SCHWARTZ T. Virulence genes in clinical and environmental Stenotrophomas maltophilia isolates:a genome sequencing and gene expression approach[J]. Microbial Pathogenesis, 2014, 67/68:20-30.
    [6] MACDONALD LC, WEILER EB, BERGER BW. Engineering broad-spectrum digestion of polyuronides from an exolytic polysaccharide lyase[J]. Biotechnology for Biofuels, 2016, 9:43.
    [7] LIU ZH, DAI YJ, HUAN Y, LIU ZX, SUN L, ZHOU QW, ZHANG WJ, SANG Q, WEI H, YUAN S. Different utilizable substrates have different effects on cometabolic fate of imidacloprid in Stenotrophomonas maltophilia[J]. Applied Microbiology and Biotechnology, 2013, 97(14):6537-6547.
    [8] XIONG WL, YIN C, WANG YQ, LIN SJ, DENG ZX, LIANG RB. Characterization of an efficient estrogen-degrading bacterium Stenotrophomonas maltophilia SJTH1 in saline-, alkaline-, heavy metal-contained environments or solid soil and identification of four 17β-estradiol-oxidizing dehydrogenases[J]. Journal of Hazardous Materials, 2020, 385:121616.
    [9] de TONI CH, RICHTER MF, CHAGAS JR, HENRIQUES JAP, TERMIGNONI C. Purification and characterization of an alkaline serine endopeptidase from a feather-degrading Xanthomonas maltophilia strain[J]. Canadian Journal of Microbiology, 2002, 48(4):342-348.
    [10] LI M, YANG LR, XU G, WU JP. Screening, purification and characterization of a novel cold-active and organic solvent-tolerant lipase from Stenotrophomonas maltophilia CGMCC 4254[J]. Bioresource Technology, 2013, 148:114-120.
    [11] WAGHMARE SR, GURAV AA, MALI SA, NADAF NH, JADHAV DB, SONAWANE KD. Purification and characterization of novel organic solvent tolerant 98 kDa alkaline protease from isolated Stenotrophomonas maltophilia strain SK[J]. Protein Expression and Purification, 2015, 107:1-6.
    [12] DUNNE C, MOËNNE-LOCCOZ Y, de BRUIJN FJ, O'GARA F. Overproduction of an inducible extracellular serine protease improves biological control of Pythium ultimum by Stenotrophomonas maltophilia strain W81[J]. Microbiology, 2000, 146(8):2069-2078.
    [13] RYAN RP, MONCHY S, CARDINALE M, TAGHAVI S, CROSSMAN L, AVISON MB, BERG G, van der LELIE D, DOW JM. The versatility and adaptation of bacteria from the genus Stenotrophomonas[J]. Nature Reviews Microbiology, 2009, 7(7):514-525.
    [14] KALIDASAN V, JOSEPH N, KUMAR S, AWANG HAMAT R, NEELA VK. Iron and virulence in Stenotrophomonas maltophilia:all we know so far[J]. Frontiers in Cellular and Infection Microbiology, 2018, 8:401.
    [15] CROSSMAN LC, GOULD VC, DOW JM, VERNIKOS GS, OKAZAKI A, SEBAIHIA M, SAUNDERS D, ARROWSMITH C, CARVER T, PETERS N, Aldem E, Kerhornou K, Lord A, Murphy L, Seeger K, Squares R, Rutter S, Quail MA, Rajandream MA, HARRIS D, et al. The complete genome, comparative and functional analysis of Stenotrophomonas maltophilia reveals an organism heavily shielded by drug resistance determinants[J]. Genome Biology, 2008, 9(4):R74.
    [16] BROOKE JS. Advances in the microbiology of Stenotrophomonas maltophilia[J]. Clinical Microbiology Reviews, 2021, 34(3):e0003019.
    [17] 胡付品, 郭燕, 朱德妹, 汪复, 蒋晓飞, 徐英春, 张小江, 张朝霞, 季萍, 谢轶, 康梅, 王传清, 王爱敏, 徐元宏, 沈继录, 孙自镛, 陈中举, 倪语星, 孙景勇, 褚云卓, 等. 2017年CHINET中国细菌耐药性监测[J]. 中国感染与化疗杂志, 2018(3):241-251. HU FP, GUO Y, ZHU DM, WANG F, JIANG XF, XU YC, ZHANG XJ, ZHANG ZX, JI P, XIE Y, KANG M, WANG CQ, WANG AM, XU YH, SHEN JL, SUN ZY, CHEN ZJ, NI XY, SUN JY, CHU YZ, et al. Antimicrobial resistance profile of clinical isolates in hospitals across China:report from the CHINET surveillance program, 2017[J]. Chinese Journal of Infection and Chemotherapy, 2018(3):241-251(in Chinese).
    [18] 胡付品, 郭燕, 朱德妹, 汪复, 蒋晓飞, 徐英春, 张小江, 张朝霞, 季萍, 谢轶, 康梅, 王传清, 王爱敏, 徐元宏, 沈继录, 孙自镛, 陈中举, 倪语星, 孙景勇, 褚云卓, 等. 2018年CHINET中国细菌耐药性监测[J]. 中国感染与化疗杂志, 2020(1):1-10. HU FP, GUO Y, ZHU DM, WANG F, JIANG XF, XU YC, ZHANG XJ, ZHANG ZX, JI P, XIE Y, KANG M, WANG CQ, WANG AM, XU YH, SHEN JL, SUN ZY, CHEN ZJ, NI YX, SUN JY, CHU YZ, et al. CHINET surveillance of bacterial resistance in China:2018 report[J]. Chinese Journal of Infection and Chemotherapy, 2020(1):1-10(in Chinese).
    [19] 胡付品, 郭燕, 朱德妹, 汪复, 蒋晓飞, 徐英春, 张小江, 张朝霞, 季萍, 谢轶, 康梅, 王传清, 王爱敏, 徐元宏, 黄颖, 孙自镛, 陈中举, 倪语星, 孙景勇, 褚云卓, 等. 2019年CHINET三级医院细菌耐药监测[J]. 中国感染与化疗杂志, 2020(3):233-243. HU FP, GUO Y, ZHU DM, WANG F, JIANG XF, XU YC, ZHANG XJ, ZHANG ZX, JI P, XIE Y, KANG M, WANG CQ, WANG AM, XU YH, HUANG Y, SUN ZY, CHEN ZJ, NI YX, SUN JY, CHU YZ, et al. CHINET surveillance of bacterial resistance across tertiary hospitals in 2019[J]. Chinese Journal of Infection and Chemotherapy, 2020(3):233-243(in Chinese).
    [20] 胡付品, 郭燕, 朱德妹, 汪复, 蒋晓飞, 徐英春, 张小江, 张朝霞, 季萍, 谢轶, 康梅, 王传清, 王爱敏, 徐元宏, 黄颖, 孙自镛, 陈中举, 倪语星, 孙景勇, 褚云卓, 等. 2020年CHINET中国细菌耐药监测[J]. 中国感染与化疗杂志, 2021(4):377-387. HU FP, GUO Y, ZHU DM, WANG F, JIANG XF, XU YC, ZHANG XJ, ZHANG ZX, JI P, XIE Y, KANG M, WANG CQ, WANG AM, XU YH, HUANG Y, SUN ZY, CHEN ZJ, NI YX, SUN JY, CHU YZ, et al. CHINET surveillance of bacterial resistance:results of 2020[J]. Chinese Journal of Infection and Chemotherapy, 2021(4):377-387(in Chinese).
    [21] 胡付品. "CHINET在线"网站正式上线[J]. 中国感染与化疗杂志, 2017, 17(2):197. HU FP. The website "CHINET Online" was officially launched[J]. Chinese Journal of Infection and Chemotherapy, 2017, 17(2):197(in Chinese).
    [22] BAYER-SANTOS E, CENENS W, MATSUYAMA BY, OKA GU, di SESSA G, MININEL I, ALVES TL, FARAH CS. The opportunistic pathogen Stenotrophomonas maltophilia utilizes a type IV secretion system for interbacterial killing[J]. PLoS Pathogens, 2019, 15(9):e1007651.
    [23] DUMONT AL, KARABA SM, CIANCIOTTO NP. Type II secretion-dependent degradative and cytotoxic activities mediated by Stenotrophomonas maltophilia serine proteases StmPr1 and StmPr2[J]. Infection and Immunity, 2015, 83(10):3825-3837.
    [24] YANG TC, HUANG YW, HU RM, HUANG SC, LIN YT. AmpDI is involved in expression of the chromosomal L1 and L2β-lactamases of Stenotrophomonas maltophilia[J]. Antimicrobial Agents and Chemotherapy, 2009, 53(7):2902-2907.
    [25] ADEGOKE AA, STENSTRÖM TA, OKOH AI. Stenotrophomonas maltophilia as an emerging ubiquitous pathogen:looking beyond contemporary antibiotic therapy[J]. Frontiers in Microbiology, 2017, 8:2276.
    [26] GOULD VC, AVISON MB. SmeDEF-mediated antimicrobial drug resistance in Stenotrophomonas maltophilia clinical isolates having defined phylogenetic relationships[J]. Journal of Antimicrobial Chemotherapy, 2006, 57(6):1070-1076.
    [27] LI J, LIU SY, FU JF, YIN JH, ZHAO J, ZHONG CQ, CAO GX. Co-occurrence of colistin and meropenem resistance determinants in a Stenotrophomonas strain isolated from sewage water[J]. Microbial Drug Resistance:Larchmont, N Y, 2019, 25(3):317-325.
    [28] ULLAH S, JI K, LI J, XU YC, JIANG CJ, ZHANG HM, HUANG M, FENG YJ. Characterization of NMCR-2, a new non-mobile colistin resistance enzyme:implications for an MCR-8 ancestor[J]. Environmental Microbiology, 2021, 23(2):844-860.
    [29] KHAN A, PETTAWAY C, DIEN BARD J, ARIAS CA, BHATTI MM, HUMPHRIES RM. Evaluation of the performance of manual antimicrobial susceptibility testing methods and disk breakpoints for Stenotrophomonas maltophilia[J]. Antimicrobial Agents and Chemotherapy, 2021, 65(5):e02631-20.
    [30] KHAN A, ARIAS CA, ABBOTT A, DIEN BARD J, BHATTI MM, HUMPHRIES RM. Evaluation of the vitek 2, phoenix, and MicroScan for antimicrobial susceptibility testing of Stenotrophomonas maltophilia[J]. Journal of Clinical Microbiology, 2021, 59(9):e0065421.
    [31] LI J, TAI C, DENG ZX, ZHONG WH, HE YQ, OU HY. VRprofile:gene-cluster-detection-based profiling of virulence and antibiotic resistance traits encoded within genome sequences of pathogenic bacteria[J]. Briefings in Bioinformatics, 2018, 19(4):566-574.
    [32] BORTOLAIA V, KAAS RS, RUPPE E, ROBERTS MC, SCHWARZ S, CATTOIR V, PHILIPPON A, ALLESOE RL, REBELO AR, FLORENSA AF, FAGELHAUER L, CHAKRABORTY T, NEUMANN B, WERNER G, BENDER JK, STINGL K, NGUYEN M, COPPENS J, XAVIER BB, MALHOTRA-KUMAR S, et al. ResFinder 4.0 for predictions of phenotypes from genotypes[J]. The Journal of Antimicrobial Chemotherapy, 2020, 75(12):3491-3500.
    [33] LIU B, ZHENG DD, ZHOU SY, CHEN LH, YANG J. VFDB 2022:a general classification scheme for bacterial virulence factors[J]. Nucleic Acids Research, 2022, 50(D1):D912-D917.
    [34] CARATTOLI A, ZANKARI E, GARCÍA- FERNÁNDEZ A, VOLDBY LARSEN M, LUND O, VILLA L, MØLLER AARESTRUP F, HASMAN H. In silico detection and typing of plasmids using PlasmidFinder and plasmid multilocus sequence typing[J]. Antimicrobial Agents and Chemotherapy, 2014, 58(7):3895-3903.
    [35] ALCOCK BP, RAPHENYA AR, LAU TTY, TSANG KK, BOUCHARD M, EDALATMAND A, HUYNH W, NGUYEN ALV, CHENG AA, LIU SH, MIN SY, Miroshnichenko A, Tran HK, Werfalli RE, Nasir JA, Oloni M, Speicher DJ, Florescu A, Singh B, Faltyn M, et al. CARD 2020:antibiotic resistome surveillance with the comprehensive antibiotic resistance database[J]. Nucleic Acids Research, 2020, 48(D1):D517-D525.
    [36] FENG Y, ZOU SM, CHEN HF, YU YS, RUAN Z. BacWGSTdb 2.0:a one-stop repository for bacterial whole-genome sequence typing and source tracking[J]. Nucleic Acids Research, 2020, 49(D1):D644-D650.
    [37] PAL C, BENGTSSON-PALME J, RENSING C, KRISTIANSSON E, LARSSON DGJ. BacMet:antibacterial biocide and metal resistance genes database[J]. Nucleic Acids Research, 2014, 42(Database issue):D737-D743.
    [38] BERTELLI C, LAIRD MR, WILLIAMS KP, Simon Fraser University Research Computing Group, LAU BY, HOAD G, WINSOR GL, BRINKMAN FS. IslandViewer 4:expanded prediction of genomic islands for larger-scale datasets[J]. Nucleic Acids Research, 2017, 45(W1):W30-W35.
    [39] WANG M, GOH YX, TAI C, WANG H, DENG ZX, OU HY. VRprofile2:detection of antibiotic resistance-associated mobilome in bacterial pathogens[J]. Nucleic Acids Research, 2022, 50(W1):W768-W773.
    [40] LIU M, LI XB, XIE YZ, BI DX, SUN JY, LI J, TAI C, DENG ZX, OU HY. ICEberg 2.0:an updated database of bacterial integrative and conjugative elements[J]. Nucleic Acids Research, 2019, 47(D1):D660-D665.
    [41] MCCUTCHEON JG, LIN A, DENNIS JJ. Isolation and characterization of the novel bacteriophage AXL3 against Stenotrophomonas maltophilia[J]. International Journal of Molecular Sciences, 2020, 21(17):6338.
    [42] PETERS DL, MCCUTCHEON JG, DENNIS JJ. Characterization of novel broad-host-range bacteriophage DLP3 specific to Stenotrophomonas maltophilia as a potential therapeutic agent[J]. Frontiers in Microbiology, 2020, 11:1358.
    [43] MCCUTCHEON JG, DENNIS JJ. The potential of phage therapy against the emerging opportunistic pathogen Stenotrophomonas maltophilia[J]. Viruses, 2021, 13(6):1057.
    [44] DAMNJANOVIĆ D, VÁZQUEZ-CAMPOS X, ELLIOTT L, WILLCOX M, BRIDGE WJ. Characterisation of bacteriophage vB_SmaM_Ps15 infective to Stenotrophomonas maltophilia clinical ocular isolates[J]. Viruses, 2022, 14(4):709.
    [45] ENAULT F, BRIET A, BOUTEILLE L, ROUX S, SULLIVAN MB, PETIT MA. Phages rarely encode antibiotic resistance genes:a cautionary tale for virome analyses[J]. The ISME Journal, 2017, 11(1):237-247.
    [46] XU YC, CHEN HY, ZHANG HM, ULLAH S, HOU TJ, FENG YJ. The MCR-3 inside linker appears as a facilitator of colistin resistance[J]. Cell Reports, 2021, 35(7):109135.
    [47] MOJICA MF, HUMPHRIES R, LIPUMA JJ, MATHERS AJ, RAO GG, SHELBURNE SA, FOUTS DE, VAN DUIN D, BONOMO RA. Clinical challenges treating Stenotrophomonas maltophilia infections:an update[J]. JAC-Antimicrobial Resistance, 2022, 4(3):dlac040.
    [48] NAS MY, WHITE RC, DUMONT AL, LOPEZ AE, CIANCIOTTO NP. Stenotrophomonas maltophilia encodes a VirB/VirD4 type IV secretion system that modulates apoptosis in human cells and promotes competition against heterologous bacteria, including Pseudomonas aeruginosa[J]. Infection and Immunity, 2019, 87(9):e00457-19.
    [49] NAS MY, GABELL J, CIANCIOTTO NP. Effectors of the Stenotrophomonas maltophilia type IV secretion system mediate killing of clinical isolates of Pseudomonas aeruginosa[J]. mBio, 2021, 12(3):e0150221.
    [50] LI J, YAO YF, XU HH, HAO LM, DENG ZX, RAJAKUMAR K, OU HY. SecReT6:a web-based resource for type VI secretion systems found in bacteria[J]. Environmental Microbiology, 2015, 17(7):2196-2202.
    [51] AHMAD S, WANG BY, WALKER MD, TRAN HKR, STOGIOS PJ, SAVCHENKO A, GRANT RA, MCARTHUR AG, LAUB MT, WHITNEY JC. An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp[J]. Nature, 2019, 575(7784):674-678.
    [52] XIE LL, ZHOU AP, ZHAO J, TANG YH, ZHAO R, ZHOU YP, CAO GX, ZHONG CQ, LI J. Comparative insights into multiple drug resistance determinants in Stenotrophomonas maltophilia MER1[J]. Journal of Global Antimicrobial Resistance, 2021, 27:20-25.
    [53] GRÖSCHEL MI, MEEHAN CJ, BARILAR I, DIRICKS M, GONZAGA A, STEGLICH M, CONCHILLO-SOLÉ O, SCHERER IC, MAMAT U, LUZ CF, de BRUYNE K, UTPATEL C, YERO D, GIBERT I, DAURA X, KAMPMEIER S, RAHMAN NA, KRESKEN M, van der WERF TS, ALIO I, et al. The phylogenetic landscape and nosocomial spread of the multidrug-resistant opportunist Stenotrophomonas maltophilia[J]. Nature Communications, 2020, 11:2044.
    [54] PEI TT, LI H, LIANG XY, WANG ZH, LIU GF, WU LL, KIM H, XIE ZP, YU M, LIN SJ, XU P, DONG TG. Intramolecular chaperone-mediated secretion of an Rhs effector toxin by a type VI secretion system[J]. Nature Communications, 2020, 11:1865.
    [55] LI J, XIE LL, QIAN SL, TANG YH, SHEN MJ, LI SS, WANG J, XIONG L, LU J, ZHONG WH. A type VI secretion system facilitates fitness, homeostasis, and competitive advantages for environmental adaptability and efficient nicotine biodegradation[J]. Applied and Environmental Microbiology, 2021, 87(9):e03113-20.
    [56] WANG TT, DU X, JI LX, HAN YY, DANG J, WEN J, WANG YR, PU QQ, WU M, LIANG HH. Pseudomonas aeruginosa T6SS-mediated molybdate transport contributes to bacterial competition during anaerobiosis[J]. Cell Reports, 2021, 35(2):108957.
    [57] KARABA SM, WHITE RC, CIANCIOTTO NP. Stenotrophomonas maltophilia encodes a type II protein secretion system that promotes detrimental effects on lung epithelial cells[J]. Infection and Immunity, 2013, 81(9):3210-3219.
    [58] LIRA F, BERG G, MARTÍNEZ JL. Double-face meets the bacterial world:the opportunistic pathogen Stenotrophomonas maltophilia[J]. Frontiers in Microbiology, 2017, 8:2190.
    [59] BERG G, MARTINEZ JL. Friends or foes:can we make a distinction between beneficial and harmful strains of the Stenotrophomonas maltophilia complex?[J]. Frontiers in Microbiology, 2015, 6:241.
    [60] KUMAR S, BANSAL K, PATIL PP, KAUR A, KAUR S, JASWAL V, GAUTAM V, PATIL PB. Genomic insights into evolution of extensive drug resistance in Stenotrophomonas maltophilia complex[J]. Genomics, 2020, 112(6):4171-4178.
    [61] WU CJ, CHEN Y, LI LH, WU CM, LIN YT, MA CH, YANG TC. Roles of SmeYZ, SbiAB, and SmeDEF efflux systems in iron homeostasis of Stenotrophomonas maltophilia[J]. Microbiology Spectrum, 2022, 10(3):e0244821.
    [62] SHIH YL, WU CM, LU HF, LI LH, LIN YT, YANG TC. Involvement of the hemP-hemA-smlt0796- smlt0797 operon in hemin acquisition by Stenotrophomonas maltophilia[J]. Microbiology Spectrum, 2022, 10(3):e0032122.
    [63] LU HF, TSAI YC, LI LH, LIN YT, YANG TC. Role of AzoR, a LysR-type transcriptional regulator, in SmeVWX pump-mediated antibiotic resistance in Stenotrophomonas maltophilia[J]. Journal of Antimicrobial Chemotherapy, 2021, 76(9):2285-2293.
    [64] LI LH, LU HF, LIU YF, LIN YT, YANG TC. FadACB and smeU1VWU2X contribute to oxidative stress-mediated fluoroquinolone resistance in Stenotrophomonas maltophilia[J]. Antimicrobial Agents and Chemotherapy, 2022, 66(4):e0204321.
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唐宇航,方诗琦,谢琳琳,孙超,李珊珊,周爱萍,曹广祥,李骏. 多重耐药寡养单胞菌的基因组学研究进展[J]. 生物工程学报, 2023, 39(4): 1314-1331

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  • 收稿日期:2022-07-06
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  • 在线发布日期: 2023-04-14
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