Recent Advances in the Quantitative Characterisation of Mechanical Scale Failure

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著作一：荧光分析法 (第三版)许金钩王尊本主编

有机化学1.David A. Evans,* Daniel Seidel, Magnus Rueping, Hon Wai Lam, Jared T. Shaw, and C. Wade Downey, A New Copper Acetate-Bis(oxazoline)-Catalyzed, Enantioselective Henry Reaction, J. AM. CHEM. SOC. 2003, 125, 12692-12693.2. Brian D. Dangel and Robin Pol,Catalysis by Amino Acid-Derived Tetracoordinate Complexes: Enantioselective Addition of Dialkylzincs to Aliphatic and Aromatic Aldehydes, Org. Lett. 2007, 2, 3003.3. Benjamin List, Proline-catalyzed asymmetric reactions, Tetrahedron, 2002, 58, 5573.4. Vishnu Maya, Monika Raj, and Vinod K. Singh, Highly Enantioselective Organocatalytic Direct Aldol Reaction in an Aqueous Medium, Org. Lett. 2007, 9, 2593.5. Sanzhong Luo, Jiuyuan Li, Hui Xu, Long Zhang, and Jin-Pei Cheng, Chiral Amine-Polyoxometalate Hybrids as Highly Efficient and Recoverable Asymmetric Enamine Catalysts, Org. Lett. 2007, 9, 3675.6. Xiao-Ying Xu, Yan-Zhao Wang, and Liu-Zhu Gong, Design of Organocatalysts for Asymmetric Direct Syn-Aldol Reactions, Org. Lett. 2007, 9, 4247.7. Jung Woon Yang, Maria T. Hechavarria Fonseca, Nicola Vignola, and Benjamin List, Metal-Free, Organocatalytic Asymmetric Transfer Hydrogenation of a,b-Unsaturated Aldehydes, Angew. Chem. Int. Ed. 2005, 44, 108–110.8. Giuseppe Bartoli, Massimo Bartolacci, Marcella Bosco, et. al., The Michael Addition of Indoles to r,â-Unsaturated Ketones Catalyzed by CeCl3â7H2O-NaI Combination Supported on Silica Gel, J. Org. Chem. 2003, 68, 4594-4597.9. Jayasree Seayad, Abdul Majeed Seayad, and Benjamin List, Catalytic Asymmetric Pictet-Spengler Reaction, J. AM. CHEM. SOC. 2006, 128, 1086-1087.10. Jingjun Yin, Matthew P. Rainka, Xiao-Xiang Zhang, and Stephen L. Buchwald, A Highly Active Suzuki Catalyst for the Synthesis of Sterically Hindered Biaryls: Novel Ligand Coordination, J. AM. CHEM. SOC. 9 VOL. 124, NO. 7, 2002 1162.11. Ulf M. Lindstro¨m, Stereoselective Organic Reactions in Water, Chem. Rev. 2002, 102, 2751-2772 .12. Sanzhong Luo, Hui Xu, Jiuyuan Li, Long Zhang, and Jin-Pei Cheng, A Simple Primary-Tertiary Diamine-Brønsted Acid Catalyst for Asymmetric Direct Aldol Reactions of Linear Aliphatic Ketones, J. AM. CHEM. SOC. 2007, 129, 3074-3075.13. Xin Cui, Yuan Zhou, Na Wang, Lei Liu and Qing-Xiang Guo, N-Phenylurea as an inexpensive and efficient ligand for Pd-catalyzed Heck and room-temperature Suzuki reactions, TL, 2007, 48, 163.14. Yoshiharu Iwabuchi, Mari Nakatani, Nobiko Yokoyama, and Susumi Hatakeyama, Chiral Amine-Catalyzed Asymmetric Baylis-Hillman Reaction: A Reliable Route to Highly Enantiomerically Enriched (r-Methylene-â-hydroxy)esters, J. Am. Chem. Soc. 1999, 121, 10219-10220.15. Satoko Kezuka, Taketo Ikeno, and Tohru Yamada, Optically Active â-Ketoiminato Cationic Cobalt(III) Complexes: Efficient Catalysts for Enantioselective Carbonyl-Ene Reaction of Glyoxal Derivatives, Org. Lett. 2001, 3, 1937.分析化学16. Lei Liu, Qin-Xiang Guo, Isokinetic relationship, isoequilibrium relationship, and enthalpy-entropy compensation , Chem. Rev. 2001, 101, .17. Sui-Yi Lin, Shi-Wei Liu, Chia-Mei Lin, and Chun-hsien Chen,Recognition of Potassium Ion in Water by 15-Crown-5 Functionalized Gold Nanoparticles, Anal. Chem. 2002, 74, 330-33518. Mikhail V. Rekharsky and Yoshihisa Inoue, Complexation and Chiral Recognition Thermodynamics of 6-Amino-6-deoxy-â-cyclodextrin with Anionic, Cationic, and Neutral Chiral Guests: Counterbalance between van der Waals and Coulombic Interactions, J. AM. CHEM. SOC., 2002, 124: 813-82619. Yu Liu, Li Li, Zhi Fan, Heng-Yi Zhang, Xue Wu, Xu-Dong Guan, Shuang-Xi Liu, Supramolecular Aggregates Formed by Intermolecular Inclusion Complexation of Organo-Selenium Bridged Bis(cyclodextrin)s with Calix[4]arene Derivative, nano letters, 2002, 2:257-262.20. CARLITO B. LEBRILLA, The Gas-Phase Chemistry of Cyclodextrin InclusionComplexes, Acc. Chem. Res. 2001, 34: 653-66121. Jian-Jun Wu, Yu Wang, Jian-Bin Chao, Li-Na Wang, and Wei-Jun Jin. Room Temperature Phosphorescence of 1-Bromo-4-(bromoacetyl) Naphthalene Induced Synergetically by -cyclodextrin and Brij30 in the Presence of Oxygen. The Journal of Physical Chemistry: B, 2004, 108: 8915-8919.22. Xiang-feng Guo, Xu-hong Qian, and Li-hua Jia. A Highly Selective and Sensitive Fluorescent Chemosensor for Hg2+in Neutral Buffer Aqueous Solution. J. Am. Chem. Soc. 2004,126: 2272-2273.23. Yu Wang, Jian-Jun Wu, Yu-Feng Wang, Li-Pin Qin, Wei-Jun Jin. Selective Sensing of Cu (Ⅱ) at ng ml-1level Based on Phosphorescence Quenching of 1-Bromo-2-methylnaphthalene Sandwiched in Sodium Deoxycholate Dimer. Chem. Commun. 2005, 1090-1091.24. Yong-fen Chen and Zeev Rosenzweig(2002) Luminescent CdS Quantum Dots as Selective Ion Probes. Anal. Chem., 74: 5132-513825. Thorfinnur Gunnlaugsson, Mark Glynn, Gillian M. Tocci (née Hussey), Paul E. Kruger, Frederick M. Pfeffer Anion recognition and sensing in organic and aqueous media using luminescent and colorimetric sensors. Coordination Chemistry Reviews 2006, 250: 3094–3117.26. E.M. Martin Del Valle, Cyclodextrins and their uses: a review, Process Biochemistry 2004, 39 : 1033–104627. Ahmet Gu rses, Mehmet Yalcin, Cetin Dogar,Electrocoagulation of some reactive dyes: a statistical investigation of some electrochemical variables, Waste Management 22 (2002) 491–428. K. Lang, J. Mosinger, D.M. Wagnerová, V oltammetric studies of anthraquinone dyes adsorbed at a hanging mercury drop electrode using fast pulse techniques, Coordination Chemistry Reviews 248 (2004) 321–35029. You Qin Li, Yu Jing Guo, Xiu Fang Li, Jing Hao Pan, Electrochemical studies of the interaction of Basic Brown G with DNA and determination of DNA, 2007,71: 123-128.30. P.J. Almeida, J.A. Rodrigues, A.A. Barros, A.G. Fogg, Photophysical properties of porphyrinoid sensitizers non-covalently bound to host molecules; models for photodynamic therapy, Analytica Chimica Acta 385 (1999) 287-293.无机化学31. Silvia Miret, Robert J. Simpson, and Andrew T. McKie, PHYSIOLOGY ANDMOLECULAR BIOLOGY OF DIETARY IRON ABSORPTION, Annu. Rev. Nutr. 2003. 23:283–301.32. Joy J. Winzerling and John H. Law, COMPARATIVE NUTRITION OF IRON AND COPPER, Annu. Rev. Nutr. 1997. 17:501–26.33. Kurt Dehnicke and Andreas Greiner, Unusual Complex Chemistry of Rare-Earth Elements: Large Ionic Radii—Small Coordination Numbers, Angew. Chem. Int. Ed. 2003, 42, No. 12, 1341-1354.34. Todor Dudev, Principles Governing Mg, Ca, and Zn Binding and Selectivity in Proteins, Chem. Rev. 2003, 103, 773-787.35. Maria M. O. Pena, Jaekwon Lee and Dennis J. Thiele, A Delicate Balance: Homeostatic Control of Copper Uptake and Distribution, J. Nutr. 129: 1251–1260, 1999.36. Elza V. Kuzmenkina, Colin D. Heyes, and G. Ulrich Nienhaus, Single-molecule Forster resonance energy transfer study of protein dynamics under denaturing conditions, PNAS, October 25, 2005, vol. 102 _ no. 43 _ 15471–15476.37. Simon Silver, Bacterial resistances to toxic metal ions - a review, Gene 179 (1996) 9-19.38. David A Zacharias, Geoffrey S Baird and Roger Y Tsien, Recent advances in technology for measuring and manipulating cell signals, Current Opinion in Neurobiology 2000, 10:416–421.39. Edward Luk Laran T. Jensen Valeria C. Culotta, The many highways for intracellular trafficking of metals, J Biol Inorg Chem (2003) 8: 803–809.40. JOHN B. VINCENT, Elucidating a Biological Role for Chromium at a Molecular Level, Acc. Chem. Res. 2000, 33, 503-510.41. Mark D. Harrison, Christopher E. Jones, Marc Solioz, Intracellular copper routing: the role of copper chaperones, TIBS 25 – JANUARY 2000, 29-32.42. R.J.P. Williams, My past and a future role for inorganic biochemistry, Journal of Inorganic Biochemistry 100 (2006) 1908–1924.43. Gray H B., ‘Biological Inorganic Chemistry at the Beginning of the 21th Century’, PNAS, 2003, 100(7), 3563-3583.物理化学/应用化学44.Chemistry of Aerogels and Their Applications, Alain C. Pierre and Ge´rard M.Pajonk, Chem. Rev. 2002, 102, -4265.45.Mechanisms of catalyst deactivation, Calvin H. Bartholomew, Applied Catalysis A:General 212 (2001) 17–60.anic chemistry on solid surfaces, Zhen Ma, Francisco Zaera, Surface ScienceReports , 61 (2006) 229–281.47.Heterogeneous catalysis: looking forward with molecular simulation, J.W.Andzelm, A.E. Alvarado-Swaisgood, F.U. Axe, M.W. Doyle, G. Fitzgerald 等，Catalysis Today，50 (1999) 451-477.48.Current Trends in the Improvement and Development of Catalyst PreparationMethods，N. A. Pakhomov and R. A. Buyanov，Kinetics and Catalysis, V ol. 46, No. 5, 2005, pp. 669–683.49.Temperature-programmed desorption as a tool to extract quantitative kinetic orenergetic information for porous catalysts，J.M. Kanervo ∗, T.J. Keskitalo, R.I.Slioor, A.O.I. Krause，Journal of Catalysi s 238 (2006) 382–393.50.Adsorption _ from theory to practice，A. Da˛browski，Advances in Colloid andInterface Science93（2001）135-224.51.Characterization of solid acids by spectroscopy，Eike Brunner，Catalysis Today，38 (1997) 361-376.52.Chemical Strategies To Design Textured Materials: from Microporous andMesoporous Oxides to Nanonetworks and Hierarchical Structures，Galo J. de A. A.Soler-Illia, Cle´ment Sanchez等，Chem. Rev.2002, 102, 4093-4138.53.Solid-State Nuclear Magnetic Resonance，Cecil Dybowski，Shi Bai, and Scott vanBramer，Anal. Chem. 2004, 76, 3263-3268.54.Aerogel applications，Lawrence W. Hrubesh，Journal of Non-Crystalline Solids225_1998.335–342.55.Application of computational methods to catalytic systems，Fernando Ruette,Morella S´anchezb, Anibal Sierraalta, Journal of Molecular Catalysis A: Chemical 228 (2005) 211–225.56.Applications of molecular modeling in heterogeneous catalysis research，Linda J.Broadbelt1, Randall Q. Snurr，Applied Catalysis A: General 200 (2000) 23–46. 57.IR spectroscopy in catalysis，Janusz Ryczkowski，Catalysis Today 68 (2001)263–381.58.The surface chemistry of catalysis: new challenges ahead，Francisco Zaera，Surface Science 500 (2002) 947–965.药学60. Peishan Xie, Sibao Chen, Yi-zeng Liang, Xianghong Wang, Runtao Tian, Roy Upton，Chromatographic fingerprint analysis—a rational approach for quality assessment of traditional Chinese herbal medicine，J. Chromatogr. A 1112 (2006) 171–180.61. Yi-Zeng Lianga, Peishan Xieb, Kelvin Chan, Quality control of herbal medicines, Journal of Chromatography B, 812 (2004) 53–70.62. 刘昌孝, 代谢组学的发展与药物研究开发, 天津药学2005 年4 月第17 卷第2 期.63. 徐曰文，林东海，刘昌孝，代谢组学研究现状与展望，药学学报2005, 40 (9) : 769 – 774。

中国肾移植受者巨细胞病毒感染临床诊疗指南（2023_版）

· 指南与共识·中国肾移植受者巨细胞病毒感染临床诊疗指南（2023版）中华医学会器官移植学分会　中国医师协会器官移植医师分会　中国医疗保健国际交流促进会肾脏移植学分会　【摘要】　近几年在实体器官移植（SOT ）受者巨细胞病毒（CMV ）感染诊疗领域，无论是诊断方法还是新型抗CMV 药物都有了一些新的进展，对CMV 感染的诊治产生了积极的影响。

为了进一步规范中国肾移植术后CMV 感染的管理，中华医学会器官移植学分会组织了国内多个学科相关领域专家，参考《中国实体器官移植受者巨细胞病毒感染诊疗指南（2016版）》和国内外已发表的最新文献和指南，制定了《中国肾移植受者巨细胞病毒感染诊疗指南（2023版）》，新版指南更新了CMV 流行病学，CMV 感染的危险因素和普遍性预防的研究进展，新增CMV 感染定义，细化CMV 血症和CMV 病的诊断标准，并对新型抗CMV 药物进行了介绍。

【关键词】　肾移植；实体器官移植；巨细胞病毒；感染；病毒血症；巨细胞病毒病；普遍性预防；抢先治疗【中图分类号】　R617, R373　【文献标志码】 A 【文章编号】 1674-7445（2024）03-0001-20Clinical diagnosis and treatment guidelines for cytomegalovirus infection in kidney transplant recipients in China (2023edition) Branch of Organ Transplantation of Chinese Medical Association, Branch of Organ Transplantation Physician of Chinese Medical Doctor Association, Branch of Kidney Transplantation of China International Exchange and Promotive Association for Medical and Health Care. *The First Affiliated Hospital of Xi 'an Jiaotong University , Xi 'an 710061, China Correspondingauthors:DingXiaoming,Email:***************.cnXueWujun,Email:******************.cn【Abstract 】 In recent years, there have been significant advances in the diagnosis and treatment of cytomegalovirus (CMV) infection in solid organ transplant (SOT) recipients, including diagnostic method and anti-CMV drugs. These advancements have had a positive impact on the management of CMV infection in SOT recipients. To further standardize the management of CMV infection after kidney transplantation in China, Branch of Organ Transplantation of Chinese Medical Association organized a multidisciplinary group of experts in relevant fields. They referred to the ‘Diagnosis and Treatment Guidelines for Cytomegalovirus Infection in Solid Organ Transplant Recipients in China (2016 edition)’ and the latest published literature and guidelines, resulting in the development of the ‘Clinical Diagnosis and Treatment Guidelines for Cytomegalovirus Infection in Kidney Transplant Recipients in China (2023 edition)’. The updated guideline includes CMV epidemiology, research progress on the risk factors and universal prevention of CMV infection, the definition for CMV infection, detailed diagnostic criteria for CMV viremia and CMV disease, as well as an introduction to new anti-CMV drugs.【Key words 】 Kidney transplantation; Solid organ transplantation; Cytomegalovirus; Infection; Viremia;Cytomegalovirus disease; Universal prevention; Preemptive therapyDOI: 10.3969/j.issn.1674-7445.2024096基金项目：国家自然科学基金（82370802、82170766、82270789、81970646）；陕西省卫生健康肾脏移植科研创新平台（2023PT-06）执笔作者单位： 710061　西安，西安交通大学第一附属医院（丁小明）；首都医科大学附属北京友谊医院（林俊）；首都医科大学附属北京朝阳医院（胡小鹏）；复旦大学附属中山医院（戎瑞明）；西安交通大学第一附属医院（郑瑾）通信作者：丁小明，Email ：***************.cn ；薛武军，Email ：******************.cn第 15 卷　第 3 期器官移植Vol. 15　No.3　2024 年 5 月Organ Transplantation May 2024　巨细胞病毒（cytomegalovirus，CMV）是一种全球传播广泛的β-疱疹病毒，原发感染之后在体内会呈潜伏状态，当人体的免疫功能下降时病毒会被再激活。

第十届上海市科学与工程计算方法学术研讨会日程表.

目录第十届上海市科学与工程计算方法学术研讨会通知 (1)第十届上海市科学与工程计算方法学术研讨会日程表 (3)大会邀请报告 (7)历年上海市科学与工程计算方法研讨会一览表 (11)上海金融学院简介 (12)上海金融学院应用数学系简介 (14)上海金融学院相关区域地图 (15)第十届上海市科学与工程计算方法学术研讨会通知为了推进上海地区计算科学理论与应用的发展，加强计算科学研究人员之间的学术交流、合作与联系，由上海市高校计算科学E—研究院和上海金融学院联合举办的“第十届上海市科学与工程计算方法学术研讨会”定于2014年11月22日(周六) 在上海金融学院举行。

会议组织委员会：郭本瑜(上海师范大学) 马和平（上海大学) 王翼飞（上海大学)程晋(复旦大学) 田红炯（上海师范大学) 黄建国(上海交通大学)苏仰峰(复旦大学) 羊丹平(华东师范大学) 徐承龙(同济大学)何志庆(华东理工大学) 顾桂定(上海财经大学) 刘永辉(上海对外经贸大学)时间：2014年11月22日(周六) 8:45－17:00地点：上海市浦东新区上川路995号上海金融学院会议日程安排：上午08: 45—09: 00 开幕式09: 00—10: 20 大会邀请报告(每个报告40分钟)10: 20—10: 40 茶歇10: 40—12: 00 大会邀请报告(每个报告40分钟)中午12: 00—14: 00 午餐下午14: 00—15: 20 分组报告(每个报告20分钟)15: 20—15: 40 茶歇15: 40—17: 00 分组报告(每个报告20分钟) 热烈欢迎从事科学与工程计算的科技工作者、高校教师和研究生踊跃参加研讨会并作学术报告。

联系方式：沈春根：*******************Tel：139****3948刘永辉：**************.cn Tel：136****8109宋心一：***************.cn Tel：139****3496李瑞：************.cn Tel：138****9612第十届上海市科学与工程计算方法学术研讨会日程表(2014年11月22日)大会邀请报告Computational Challenges in Quantitative Finance: HighDimensionality and Non-Smoothness王小群(清华大学)摘要: Problems with a large number of variables are coming to play an ever more important role in financial applications, such as in the pricing of options and the estimation of sensitivities (Greeks). High dimensional problems pose immense challenges for practi cal computations because of the “curse of dimensionality”. In this talk I will touch briefly on recent advances in understanding the success of quasi-Monte Carlo methods for high dimensional problems, and propose methods that deal with the high dimensionality and non-smoothness for problems in quantitative finance.王小群，清华大学数学科学系教授，2009年获国家杰出青年科学基金，2011年被聘为清华大学教育部长江学者特聘教授。

Cancer Epigenetics From Mechanism to Therapy

Leading EdgeReviewCancer Epigenetics:From Mechanism to TherapyMark A.Dawson1,2and Tony Kouzarides1,*1Gurdon Institute and Department of Pathology,University of Cambridge,Tennis Court Road,Cambridge CB21QN,UK2Department of Haematology,Cambridge Institute for Medical Research and Addenbrooke’s Hospital,University of Cambridge,Hills Road, Cambridge CB20XY,UK*Correspondence:t.kouzarides@/10.1016/j.cell.2012.06.013The epigenetic regulation of DNA-templated processes has been intensely studied over the last15 years.DNA methylation,histone modiﬁcation,nucleosome remodeling,and RNA-mediated target-ing regulate many biological processes that are fundamental to the genesis of cancer.Here,we present the basic principles behind these epigenetic pathways and highlight the evidence suggest-ing that their misregulation can culminate in cancer.This information,along with the promising clin-ical and preclinical results seen with epigenetic drugs against chromatin regulators,signiﬁes that it is time to embrace the central role of epigenetics in cancer.Chromatin is the macromolecular complex of DNA and histone proteins,which provides the scaffold for the packaging of our entire genome.It contains the heritable material of eukaryotic cells.The basic functional unit of chromatin is the nucleosome. It contains147base pairs of DNA,which is wrapped around a histone octamer,with two each of histones H2A,H2B,H3, and H4.In general and simple terms,chromatin can be subdi-vided into two major regions:(1)heterochromatin,which is highly condensed,late to replicate,and primarily contains inac-tive genes;and(2)euchromatin,which is relatively open and contains most of the active genes.Efforts to study the coordi-nated regulation of the nucleosome have demonstrated that all of its components are subject to covalent modiﬁcation,which fundamentally alters the organization and function of these basic tenants of chromatin(Allis et al.,2007).The term‘‘epigenetics’’was originally coined by Conrad Wad-dington to describe heritable changes in a cellular phenotype that were independent of alterations in the DNA sequence. Despite decades of debate and research,a consensus deﬁnition of epigenetics remains both contentious and ambiguous(Berger et al.,2009).Epigenetics is most commonly used to describe chromatin-based events that regulate DNA-templated pro-cesses,and this will be the deﬁnition we use in this review. Modiﬁcations to DNA and histones are dynamically laid down and removed by chromatin-modifying enzymes in a highly regulated manner.There are now at least four different DNA modiﬁcations(Baylin and Jones,2011;Wu and Zhang,2011) and16classes of histone modiﬁcations(Kouzarides,2007;Tan et al.,2011).These are described in Table1.These modiﬁcations can alter chromatin structure by altering noncovalent interac-tions within and between nucleosomes.They also serve as docking sites for specialized proteins with unique domains that speciﬁcally recognize these modiﬁcations.These chromatin readers recruit additional chromatin modiﬁers and remodeling enzymes,which serve as the effectors of the modiﬁcation.The information conveyed by epigenetic modiﬁcations plays a critical role in the regulation of all DNA-based processes, such as transcription,DNA repair,and replication.Conse-quently,abnormal expression patterns or genomic alterations in chromatin regulators can have profound results and can lead to the induction and maintenance of various cancers.In this Review,we highlight recent advances in our understanding of these epigenetic pathways and discuss their role in oncogen-esis.We provide a comprehensive list of all the recurrent cancer mutations described thus far in epigenetic pathways regulating modiﬁcations of DNA(Figure2),histones(Figures3,4,and5), and chromatin remodeling(Figure6).Where relevant,we will also emphasize existing and emerging drug therapies aimed at targeting epigenetic regulators(Figure1).Characterizing the EpigenomeOur appreciation of epigenetic complexity and plasticity has dramatically increased over the last few years following the development of several global proteomic and genomic technol-ogies.The coupling of next-generation sequencing(NGS)plat-forms with established chromatin techniques such as chromatin immunoprecipitation(ChIP-Seq)has presented us with a previ-ously unparalleled view of the epigenome(Park,2009).These technologies have provided comprehensive maps of nucleo-some positioning(Segal and Widom,2009),chromatin confor-mation(de Wit and de Laat,2012),transcription factor binding sites(Farnham,2009),and the localization of histone(Rando and Chang,2009)and DNA(Laird,2010)modiﬁcations.In addi-tion,NGS has revealed surprising facts about the mammalian transcriptome.We now have a greater appreciation of the fact that most of our genome is transcribed and that noncoding RNA may play a fundamental role in epigenetic regulation(Ama-ral et al.,2008).Most of the complexity surrounding the epigenome comes from the modiﬁcation pathways that have been identiﬁed.12Cell150,July6,2012ª2012Elsevier Inc.Recent improvements in the sensitivity and accuracy of mass spectrometry (MS)instruments have driven many of these discoveries (Stunnenberg and Vermeulen,2011).Moreover,although MS is inherently not quantitative,recent advances in labeling methodologies,such as stable isotope labeling by amino acids in cell culture (SILAC),isobaric tags for relative and absolute quantiﬁcation (iTRAQ),and isotope-coded afﬁnity tag (ICAT),have allowed a greater ability to provide quantitative measurements (Stunnenberg and Vermeulen,2011).These quantitative methods have generated ‘‘protein recruit-ment maps’’for histone and DNA modiﬁcations,which contain proteins that recognize chromatin modiﬁcations (Bartke et al.,2010;Vermeulen et al.,2010).Many of these chromatin readers have more than one reading motif,so it is important to under-stand how they recognize several modiﬁcations either simulta-neously or sequentially.The concept of multivalent engagement by chromatin-binding modules has recently been explored by using either modiﬁed histone peptides (Vermeulen et al.,2010)or in-vitro-assembled and -modiﬁed nucleosomes (Bartkeet al.,2010;Ruthenburg et al.,2011).The latter approach in particular has uncovered some of the rules governing the recruit-ment of protein complexes to methylated DNA and modiﬁed histones in a nucleosomal context.The next step in our under-standing will require a high-resolution in vivo genomic approach to detail the dynamic events on any given nucleosome during the course of gene expression.Epigenetics and the Cancer ConnectionThe earliest indications of an epigenetic link to cancer were derived from gene expression and DNA methylation studies.These studies are too numerous to comprehensively detail in this review;however,the reader is referred to an excellent review detailing the history of cancer epigenetics (Feinberg and Tycko,2004).Although many of these initial studies were purely correl-ative,they did highlight a potential connection between epige-netic pathways and cancer.These early observations have been signiﬁcantly strengthened by recent results from the Inter-national Cancer Genome Consortium (ICGC).Whole-genomeTable 1.Chromatin Modiﬁcations,Readers,and Their Function Chromatin Modiﬁcation NomenclatureChromatin-Reader MotifAttributed Functionand Cit,citrulline.Reader domains:MBD,methyl-CpG-binding domain;PHD,plant homeodomain;MBT,malignant brain tumor domain;PWWP,proline-tryptophan-tryptophan-proline domain;BRCT,BRCA1C terminus domain;UIM,ubiquitin interaction motif;IUIM,inverted ubiquitin interaction motif;SIM,sumo interaction motif;and PBZ,poly ADP-ribose binding zinc ﬁnger.aThese are established binding modules for the posttranslational modiﬁcation;however,binding to modiﬁed histones has not been ﬁrmly established.Cell 150,July 6,2012ª2012Elsevier Inc.13sequencing in a vast array of cancers has provided a catalog of recurrent somatic mutations in numerous epigenetic regulators (Forbes et al.,2011;Stratton et al.,2009).A central tenet in analyzing these cancer genomes is the identiﬁcation of ‘‘driver’’mutations (causally implicated in the process of oncogenesis).A key feature of driver mutations is that they are recurrently found in a variety of cancers,and/or they are often present at a high prevalence in a speciﬁc tumor type.We will mostly concentrate our discussions on suspected or proven driver mutations in epigenetic regulators.For instance,malignancies such as follicular lymphoma contain recurrent mutations of the histone methyltransferase MLL2in close to 90%of cases (Morin et al.,2011).Similarly,UTX ,a histone demethylase,is mutated in up to 12histologi-cally distinct cancers (van Haaften et al.,2009).Compilation of the epigenetic regulators mutated in cancer highlights histone acetylation and methylation as the most widely affected epige-netic pathways (Figures 3and 4).These and other pathways that are affected to a lesser extent will be described in the following sections.Deep sequencing technologies aimed at mapping chromatin modiﬁcations have also begun to shed some light on the origins of epigenetic abnormalities in cancer.Cross-referencing of DNA methylation proﬁles in human cancers with ChIP-Seq data for histone modiﬁcations and the binding of chromatinregulators have raised intriguing correlations between cancer-associated DNA hypermethylation and genes marked with ‘‘bivalent’’histone modiﬁcations in multipotent cells (Easwaran et al.,2012;Ohm et al.,2007).These bivalent genes are marked by active (H3K4me3)and repressive (H3K27me3)histone modi-ﬁcations (Bernstein et al.,2006)and appear to identify transcrip-tionally poised genes that are integral to development and lineage commitment.Interestingly,many of these genes are targeted for DNA methylation in cancer.Equally intriguing are recent comparisons between malignant and normal tissues from the same individuals.These data demonstrate broad domains within the malignant cells that contain signiﬁcant alter-ations in DNA methylation.These regions appear to correlate with late-replicating regions of the genome associated with the nuclear lamina (Berman et al.,2012).Although there remains little mechanistic insight into how and why these regions of the genome are vulnerable to epigenetic alterations in cancer,these studies highlight the means by which global sequencing plat-forms have started to uncover avenues for further investigation.Genetic lesions in chromatin modiﬁers and global alterations in the epigenetic landscape not only imply a causative role for these proteins in cancer but also provide potential targets for therapeutic intervention.A number of small-molecule inhibitors have already been developed against chromatin regulators (Figure 1).These are at various stages of development,andthreeFigure 1.Epigenetic Inhibitors as Cancer TherapiesThis schematic depicts the process for epigenetic drug development and the current status of various epigenetic therapies.Candidate small molecules are ﬁrst tested in vitro in malignant cell lines for speciﬁcity and phenotypic response.These may,in the ﬁrst instance,assess the inhibition of proliferation,induction of apoptosis,or cell-cycle arrest.These phenotypic assays are often coupled to genomic and proteomic methods to identify potential molecular mechanisms for the observed response.Inhibitors that demonstrate potential in vitro are then tested in vivo in animal models of cancer to ascertain whether they may provide therapeutic beneﬁt in terms of survival.Animal studies also provide valuable information regarding the toxicity and pharmacokinetic properties of the drug.Based on these preclinical studies,candidate molecules may be taken forward into the clinical setting.When new drugs prove beneﬁcial in well-conducted clinical trials,they are approved for routine clinical use by regulatory authorities such as the FDA.KAT,histone lysine acetyltransferase;KMT,histone lysine methyltransferase;RMT,histone arginine methyltransferase;and PARP,poly ADP ribose polymerase.14Cell 150,July 6,2012ª2012Elsevier Inc.of these(targeting DNMTs,HDACs,and JAK2)have already been granted approval by the US Food and Drug Administra-tion(FDA).This success may suggest that the interest in epige-netic pathways as targets for drug discovery had been high over the past decade.However,the reality is that theﬁeld of drug discovery had been somewhat held back due to concerns over the pleiotropic effects of both the drugs and their targets. Indeed,some of the approved drugs(against HDACs)have little enzyme speciﬁcity,and their mechanism of action remains contentious(Minucci and Pelicci,2006).The belief and investment in epigenetic cancer therapies may now gain momentum and reach a new level of support following the recent preclinical success of inhibitors against BRD4,an acetyl-lysine chromatin-binding protein(Dawson et al.,2011; Delmore et al.,2011;Filippakopoulos et al.,2010;Mertz et al., 2011;Zuber et al.,2011).The molecular mechanisms governing these impressive preclinical results have also been largely uncovered and are discussed below.This process is pivotal for the successful progression of these inhibitors into the clinic. These results,along with the growing list of genetic lesions in epigenetic regulators,highlight the fact that we have now entered an era of epigenetic cancer therapies.Epigenetic Pathways Connected to CancerDNA MethylationThe methylation of the5-carbon on cytosine residues(5mC)in CpG dinucleotides was theﬁrst described covalent modiﬁca-tion of DNA and is perhaps the most extensively characterized modiﬁcation of chromatin.DNA methylation is primarily noted within centromeres,telomeres,inactive X-chromosomes,and repeat sequences(Baylin and Jones,2011;Robertson,2005). Although global hypomethylation is commonly observed in malignant cells,the best-studied epigenetic alterations in cancerare the methylation changes that occur within CpG islands, which are present in 70%of all mammalian promoters.CpG island methylation plays an important role in transcriptional regu-lation,and it is commonly altered during malignant transforma-tion(Baylin and Jones,2011;Robertson,2005).NGS platforms have now provided genome-wide maps of CpG methylation. These have conﬁrmed that between5%–10%of normally unme-thylated CpG promoter islands become abnormally methylated in various cancer genomes.They also demonstrate that CpG hypermethylation of promoters not only affects the expression of protein coding genes but also the expression of various noncoding RNAs,some of which have a role in malignant trans-formation(Baylin and Jones,2011).Importantly,these genome-wide DNA methylome studies have also uncovered intriguing alterations in DNA methylation within gene bodies and at CpG‘‘shores,’’which are conserved sequences upstream and downstream of CpG islands.The functional relevance of these regional alterations in methylation are yet to be fully deciphered, but it is interesting to note that they have challenged the general dogma that DNA methylation invariably equates with transcriptional silencing.In fact,these studies have established that many actively transcribed genes have high levels of DNA methylation within the gene body,suggesting that the context and spatial distribution of DNA methylation is vital in transcrip-tional regulation(Baylin and Jones,2011).Three active DNA methyltransferases(DNMTs)have been identiﬁed in higher eukaryotes.DNMT1is a maintenance methyl-transferase that recognizes hemimethylated DNA generated during DNA replication and then methylates newly synthesized CpG dinucleotides,whose partners on the parental strand are already methylated(Li et al.,1992).Conversely,DNMT3a and DNMT3b,although also capable of methylating hemimethylated DNA,function primarily as de novo methyltransferases to estab-lish DNA methylation during embryogenesis(Okano et al.,1999). DNA methylation provides a platform for several methyl-binding proteins.These include MBD1,MBD2,MBD3,and MeCP2. These in turn function to recruit histone-modifying enzymes to coordinate the chromatin-templated processes(Klose and Bird,2006).Although mutations in DNA methyltransferases and MBD proteins have long been known to contribute to developmental abnormalities(Robertson,2005),we have only recently become aware of somatic mutations of these key genes in human malig-nancies(Figure2).Recent sequencing of cancer genomes has identiﬁed recurrent mutations in DNMT3A in up to25%of patients with acute myeloid leukemia(AML)(Ley et al.,2010). Importantly,these mutations are invariably heterozygous and are predicted to disrupt the catalytic activity of the enzyme. Moreover,their presence appears to impact prognosis(Patel et al.,2012).However,at present,the mechanisms bywhich Figure2.Cancer Mutations Affecting Epigenetic Regulators of DNA MethylationThe5-carbon of cytosine nucleotides are methylated(5mC)by a family of DNMTs.One of these,DNMT3A,is mutated in AML,myeloproliferative diseases(MPD),and myelodysplastic syndromes(MDS).In addition to its catalytic activity,DNMT3A has a chromatin-reader motif,the PWWP domain, which may aid in localizing this enzyme to chromatin.Somatically acquired mutations in cancer may also affect this domain.The TET family of DNA hydroxylases metabolizes5mC into several oxidative intermediates,including 5-hydroxymethylcytosine(5hmC),5-formylcytosine(5fC),and5-carbox-ylcytosine(5caC).These intermediates are likely involved in the process of active DNA demethylation.Two of the three TET family members are mutated in cancers,including AML,MPD,MDS,and CMML.Mutation types are as follows:M,missense;F,frameshift;N,nonsense;S,splice site mutation;and T,translocation.Cell150,July6,2012ª2012Elsevier Inc.15these mutations contribute to the development and/or mainte-nance of AML remains elusive.Understanding the cellular consequences of normal and aber-rant DNA methylation remains a key area of interest,especially because hypomethylating agents are one of the few epigenetic therapies that have gained FDA approval for routine clinical use(Figure1).Although hypomethylating agents such as azaci-tidine and decitabine have shown mixed results in various solid malignancies,they have found a therapeutic niche in the myelo-dysplastic syndromes(MDS).Until recently,this group of disor-ders was largely refractory to therapeutic intervention,and MDS was primarily managed with supportive care.However,several large studies have now shown that treatment with azacitidine, even in poor prognosis patients,improves their quality of life and extends survival time.Indeed,azacitidine is theﬁrst therapy to have demonstrated a survival beneﬁt for patients with MDS (Fenaux et al.,2009).The molecular mechanisms governing the impressive responses seen in MDS are largely unknown. However,recent evidence would suggest that low doses of these agents hold the key to therapeutic beneﬁt(Tsai et al., 2012).It is also emerging that the combinatorial use of DNMT and HDAC inhibitors may offer superior therapeutic outcomes (Gore,2011).DNA Hydroxy-Methylation and Its Oxidation Derivatives Historically,DNA methylation was generally considered to be a relatively stable chromatin modiﬁcation.However,early studies assessing the global distribution of this modiﬁcation during embryogenesis had clearly identiﬁed an active global loss of DNA methylation in the early zygote,especially in the male pronucleus.More recently,high-resolution genome-wide mapping of this modiﬁcation in pluripotent and differentiated cells has also conﬁrmed the dynamic nature of DNA methylation, evidently signifying the existence of an enzymatic activity within mammalian cells that either erases or alters this chromatin modiﬁcation(Baylin and Jones,2011).In2009,two seminal manuscripts describing the presence of5-hydroxymethylcyto-sine(5hmC)offered theﬁrst insights into the metabolism of 5mC(Kriaucionis and Heintz,2009;Tahiliani et al.,2009).The ten-eleven translocation(TET1–3)family of proteins have now been demonstrated to be the mammalian DNA hydroxy-lases responsible for catalytically converting5mC to5hmC. Indeed,iterative oxidation of5hmC by the TET family results in further oxidation derivatives,including5-formylcytosine(5fC) and5-carboxylcytosine(5caC).Although the biological signiﬁ-cance of the5mC oxidation derivatives is yet to be established, several lines of evidence highlight their importance in transcrip-tional regulation:(1)they are likely to be an essential intermediate in the process of both active and passive DNA demethylation,(2) they preclude or enhance the binding of several MBD proteins and,as such,will have local and global effects by altering the recruitment of chromatin regulators,and(3)genome-wide mapping of5hmC has identiﬁed a distinctive distribution of this modiﬁcation at both active and repressed genes,including its presence within gene bodies and at the promoters of bivalently marked,transcriptionally poised genes(Wu and Zhang,2011). Notably,5hmC was also mapped to several intergenic cis-regu-latory elements that are either functional enhancers or insulator elements.Consistent with the notion that5hmC is likely to have a role in both transcriptional activation and silencing, the TET proteins have also been shown to have activating and repressive functions(Wu and Zhang,2011).Genome-wide mapping of TET1has demonstrated it to have a strong prefer-ence for CpG-rich DNA and,consistent with its catalytic function, it also been localized to regions enriched for5mC and5hmC. The TET family of proteins derive their name from the initial description of a recurrent chromosomal translocation, t(10;11)(q22;q23),which juxtaposes the MLL gene with TET1in a subset of patients with AML(Lorsbach et al.,2003).Notably, concurrent to the initial description of the catalytic activity for the TET family of DNA hydroxylases,several reports emerged describing recurrent mutations in TET2in numerous hematolog-ical malignancies(Cimmino et al.,2011;Delhommeau et al., 2009;Langemeijer et al.,2009)(Figure2).Interestingly,TET2-deﬁcient mice develop a chronic myelomonocytic leukemia (CMML)phenotype,which is in keeping with the high prevalence of TET2mutations in patients with this disease(Moran-Crusio et al.,2011;Quivoron et al.,2011).The clinical implications of TET2mutations have largely been inconclusive;however,in some subsets of AML patients,TET2mutations appear to confer a poor prognosis(Patel et al.,2012).Early insights into the process of TET2-mediated oncogenesis have revealed that the patient-associated mutations are largely loss-of-function muta-tions that consequently result in decreased5hmC levels and a reciprocal increase in5mC levels within the malignant cells that harbor them.Moreover,mutations in TET2also appear to confer enhanced self-renewal properties to the malignant clones (Cimmino et al.,2011).Histone ModiﬁcationsIn1964,Vincent Allfrey prophetically surmised that histone modiﬁcations might have a functional inﬂuence on the regulation of transcription(Allfrey et al.,1964).Nearly half a century later, theﬁeld is still grappling with the task of unraveling the mecha-nisms underlying his enlightened statement.In this time,we have learned that these modiﬁcations have a major inﬂuence, not just on transcription,but in all DNA-templated processes (Kouzarides,2007).The major cellular processes attributed to each of these modiﬁcations are summarized in Table1.The great diversity in histone modiﬁcations introduces a remarkable complexity that is slowly beginning to be ing transcription as an example,we have learned that multiple coexisting histone modiﬁcations are associated with activation,and some are associated with repression. However,these modiﬁcation patterns are not static entities but a dynamically changing and complex landscape that evolves in a cell context-dependent fashion.Moreover,active and repres-sive modiﬁcations are not always mutually exclusive,as evi-denced by‘‘bivalent domains.’’The combinatorial inﬂuence that one or more histone modiﬁcations have on the deposition, interpretation,or erasure of other histone modiﬁcations has been broadly termed‘‘histone crosstalk,’’and recent evidence would suggest that crosstalk is widespread and is of great bio-logical signiﬁcance(Lee et al.,2010).It should be noted that the cellular enzymes that modify histones may also have nonhistone targets and,as such,it has been difﬁcult to divorce the cellular consequences of individual histone modiﬁcations from the broader targets of many of these16Cell150,July6,2012ª2012Elsevier Inc.enzymes.In addition to their catalytic function,many chromatin modiﬁers also possess‘‘reader’’domains allowing them to bind to speciﬁc regions of the genome and respond to information conveyed by upstream signaling cascades.This is important, as it provides two avenues for therapeutically targeting these epigenetic regulators.The residues that line the binding pocket of reader domains can dictate a particular preference for speciﬁc modiﬁcation states,whereas residues outside the binding pocket contribute to determining the histone sequence speciﬁcity.This combination allows similar reader domains to dock at different modiﬁed residues or at the same amino acid displaying different modiﬁcation states.For example,some methyl-lysine readers engage most efﬁciently with di/tri-methyl-ated lysine(Kme2/3),whereas others prefer mono-or unmethy-lated lysines.Alternatively,when the same lysines are now acet-ylated,they bind to proteins containing bromodomains(Taverna et al.,2007).The main modiﬁcation binding pockets contained within chromatin-associated proteins is summarized in Table1. Many of the proteins that modify or bind these histone modiﬁ-cations are misregulated in cancer,and in the ensuing sections, we will discuss the most extensively studied histone modiﬁca-tions in relation to oncogenesis and novel therapeutics. Histone Acetylation.The Nε-acetylation of lysine residues is a major histone modiﬁcation involved in transcription,chromatin structure,and DNA repair.Acetylation neutralizes lysine’s posi-tive charge and may consequently weaken the electrostatic interaction between histones and negatively charged DNA.For this reason,histone acetylation is often associated with a more ‘‘open’’chromatin conformation.Consistent with this,ChIP-Seq analyses have conﬁrmed the distribution of histone acetyla-tion at promoters and enhancers and,in some cases,throughout the transcribed region of active genes(Heintzman et al.,2007; Wang et al.,2008).Importantly,lysine acetylation also serves as the nidus for the binding of various proteins with bromodo-mains and tandem plant homeodomain(PHD)ﬁngers,which recognize this modiﬁcation(Taverna et al.,2007).Acetylation is highly dynamic and is regulated by the competing activities of two enzymatic families,the histone lysine acetyltransferases(KATs)and the histone deacetylases (HDACs).There are two major classes of KATs:(1)type-B,which are predominantly cytoplasmic and modify free histones,and(2) type-A,which are primarily nuclear and can be broadly classiﬁedinto the GNAT,MYST,and CBP/p300families.KATs were theﬁrst enzymes shown to modify histones.The importance of theseﬁndings to cancer was immediately apparent,as one of these enzymes,CBP,was identiﬁed by its ability to bind the transforming portion of the viral oncoprotein E1A(Bannister and Kouzarides,1996).It is now clear that many,if not most,of the KATs have been implicated in neoplastic transformation,and a number of viral oncoproteins are known to associate with them.There are numerous examples of recur-rent chromosomal translocations(e.g.,MLL-CBP[Wang et al., 2005]and MOZ-TIF2[Huntly et al.,2004])or coding mutations (e.g.,p300/CBP[Iyer et al.,2004;Pasqualucci et al.,2011]) involving various KATs in a broad range of solid and hematolog-ical malignancies(Figure3).Furthermore,altered expression levels of several of the KATs have also been noted in a range of cancers(Avvakumov and Coˆte´,2007;Iyer et al.,2004).In some cases,such as the leukemia-associated fusion gene MOZ-TIF2,we know a great deal about the cellular conse-quences of this translocation involving a MYST family member. MOZ-TIF2is sufﬁcient to recapitulate an aggressive leukemia in murine models;it can confer stem cell properties and reacti-vate a self-renewal program when introduced into committed hematopoietic progenitors,and much of this oncogenic potential is dependent on its inherent and recruited KAT activity as well as its ability to bind to nucleosomes(Deguchi et al.,2003;Huntly et al.,2004).Despite these insights,the great conundrum with regards to unraveling the molecular mechanisms by which histone acetyl-transferases contribute to malignant transformation has been dissecting the contribution of altered patterns in acetylation on histone and nonhistone proteins.Although it is clear that global histone acetylation patterns are perturbed in cancers(Fraga Figure 3.Cancer Mutations Affecting Epigenetic Regulators Involved in Histone AcetylationThese tables provide somatic cancer-associated mutations identiﬁed in histone acetyltransferases and proteins that contain bromodomains(which recognize and bind acetylated histones).Several histone acetyltransferases possess chromatin-reader motifs and,thus,mutations in the proteins may alter both their catalytic activities as well as the ability of these proteins to scaffold multiprotein complexes to chromatin.Interestingly,sequencing of cancer genomes to date has not identiﬁed any recurrent somatic mutations in histone deacetylase enzymes.Abbreviations for the cancers are as follows: AML,acute myeloid leukemia;ALL,acute lymphoid leukemia;B-NHL,B-cell non-Hodgkin’s lymphoma;DLBCL,diffuse large B-cell lymphoma;and TCC, transitional cell carcinoma of the urinary bladder.Mutation types are as follows:M,missense;F,frameshift;N,nonsense;S,splice site mutation;T, translocation;and D,deletion.Cell150,July6,2012ª2012Elsevier Inc.17。

三重四级杆质谱技术在中药研究中的应用进展

第33卷第3期2018年5月Vol.33No.3May2018内蒙古民族大学学报（自然科学版）Journal of Inner Mongolia University for NationalitiesDOI：10.14045/ki.15-1220.2018.03.007三重四级杆质谱技术在中药研究中的应用进展柏慧，张仁慈，王曦烨，刘景林，许良（内蒙古民族大学化学化工学院，天然产物化学及功能分子合成自治区重点实验室，内蒙古通辽028042）〔摘要〕中药活性成分的定性和定量分析一直是解决中药质量标志物及建立中药质量控制方法的主要手段.随着质谱技术的发展，三重四极杆质谱技术在中药成分分析工作中得到了广泛的应用.三重四极杆质谱法具有准确、高效、适宜多种类型药物检测等优点.因此，该技术在中药研究中得到了广泛的应用.本文对三重四级杆质谱技术在中药研究中的应用近期进展进行综述.〔关键词〕三重四级杆质谱；中药研究；应用进展〔中图分类号〕O657.63〔文献标识码〕A〔文章编号〕1671-0185（2018）03-0208-05The Application Progress of Triple Quadrupole MassSpectrometry in Studies of Traditional Chinese MedicineBAI Hui，ZHANG Ren-ci，WANG Xi-ye，LIU Jing-lin，XU Liang（College of Chemistry and Chemical Engineering，Inner Mongolia Key Laboratory of Natural Products Chemis-try and Functional Molecules Synthesis，Inner Mongolia University for Nationalities，Tongliao028042，China）Abstract：The qualitative and quantitative analysis of active components of Chinese herbal medicines is being usedto determine their material basis in traditional Chinese medicine（TCM）and to establish quality control.The analy-sis of triple quadrupole mass spectrometry has been widely applied in the analysis of traditional Chinese medicine.Itis accurate，efficient and suitable for all kinds of drug testing.This paper reviews the recent advances in the applica-tion of triple quadrupole mass spectrometry in traditional Chinese medicine studies.Key words：Triple quadrupole mass spectrometry；Traditional Chinese medicine research；Application progress一直以来，中药难以进入国际药品主流市场的主要原因为尚未全面阐释中药药效物质及作用机制，未能建立与国际接轨的质量标准和安全标准.即，中药中是否含有有害物质以及有害物质的含量是否足以引起不良反应甚至致癌、中药中有效成分含量究竟有多少等问题，都使得西方学者对中药的质量和安全性抱有怀疑态度.因此，通过利用高效准确的质谱分析技术进行中药中各种成分的定性、定量分析研究，对加快中药标准化、现代化和推动中药国际化都有重要意义.众所周知，由于中药种类繁多、成分众多结构复杂，微量乃至痕量成分较多，因此，其化学成分的全面检测成为中药研究的瓶颈问题之一〔1〕.目前，三重四级杆质谱技术已经被广泛地应用到中药研究领域，同时正在和色谱技术及各种计算机技术得到结合，使得该技术在中药研究领域中的应用范围不断拓展〔2〕.三重四极杆质谱技术是一种新型的药物成分分析方法，通过利用分子量的不同，采用多重离子对监测（MRM）技术，有效地排除杂质干扰，增加专属性和灵敏度，并做出快速的分析〔3〕.近年来该技术在分析基金项目：国家自然科学基金资助项目（81260682，81560702）；内蒙古自治区科技创新引导项目及内蒙古民族大学特色交叉学科群建设项目（MDXK003）作者简介：柏慧，内蒙古民族大学化学化工学院硕士研究生.许良为通讯作者.209第3期柏慧等：三重四级杆质谱技术在中药研究中的应用进展化学领域尤其在中药研究领域得到日益广泛的应用.三重四级杆质谱仪是目前质谱领域中最具代表性的定量分析仪器，它具有分析时间短、可分析成分多、定量准确等特点.目前，除了广泛应用于中药多组分体外质量控制研究方面之外，还广泛应用于中药多组分体内药物代谢动力学方面的研究.可见，三重四级杆质谱技术已在中药药物研究方面有了广泛的应用.值得注意的是，三重四级杆质谱仪也有它一定的不足之处，例如在高分辨率和多级串级质谱等定性能力方面比较差一些.不过这完全可以通过配备离子阱仪器或QTOF仪器等来弥补三重四极杆定性能力不足的弱势.总的来说，在三重四级杆质谱技术在对天然药物成分、中药复方药物有效成分定量分析方面体现出特有的优势.1三重四级杆质谱技术在中药研究中的应用近年来，三重四级杆质谱技术在中药残留农药检测、中药定性定量分析、非法掺入化学药物的中药制剂的检测、中成药制剂的质量控制、对中药体内代谢产物的分析、对中药中有害物质含量的测定等方面被广泛应用.1.1对中药残留农药进行检测我国中药生产经常出现农药残留超标等问题，极大的影响了中药走进国际药品市场，也使中药的国际地位受到影响，这极大的延缓了中药现代化和国际化的进程〔4〕.中药中有害残留物分析属于痕量分析范畴，技术难度较大，分析方法验证技术要求不同于常规的常量或微量分析.因此，提高中药农药残留检测准确性就成了一个重要的课题〔5〕.王建国等利用气相色谱-三重四级杆串联质谱（GC-MS/MS）分析中草药中1，2，4-三氯苯等85种农药残留物.其中，茯苓样品检出乐果0.15mg/kg、乙拌磷0.21mg/kg、马拉硫磷0.40mg/kg；白芍样品中检出乐果0.16mg/kg、乙拌磷0.25mg/kg、马拉硫磷0.39mg/kg〔6〕.徐宜宏等曾采用气相色谱-三重四级杆串联质谱法建立了五味子中117种农药残留同时检测的方法〔7〕.李俊等建立了测定鱼腥草中百草枯和乙草胺残留物的三重四级杆气相色谱质谱方法〔8〕.以上三个实验结果显示，应用三重四级杆质谱法对中药农药残留进行检验，具有准确性高、快速高效的特点.1.2对中药进行定性分析用三重四级杆质谱法对中药成分进行定性分析方面已有报道.韩豪等利用超高效液相色谱-三重四级杆串联质谱联用技术（UPLC-MS/MS），对黑豆皮中花青苷类物质进行定性分析.在黑豆皮中检测出共15种花青苷类物质.通过对黑豆皮花青苷类物质的分析，建立了UPLC-MS/MS检测黑豆皮中花青苷类物质方法〔9〕.周丽等曾采用微波辅助法，以80%甲醇作为溶剂提取经冻干后紫山药块根和地上茎叶中的多酚类物质，提取物经超高效液相色谱分离、电喷雾串联三重四级杆质谱正和负离子方式检测分析.分析得到29种酚类化合物〔10〕.1.3对中药成分进行定量分析朱根华等采用三重四级杆液质联用（HPLC-MS-MS）法，建立金樱子中白桦脂酸含量测定方法.质谱采用大气压电喷雾离子源，选择性离子流模式（负离子）.结果显示白桦脂酸的平均样回收率为98.3%（RSD2.6%）〔11〕.李占彬等曾采用高效液相色谱-串联三重四级杆质谱法（LC-MS/MS），针对姜茶中的姜黄素做过定量分析，其结果显示，该方法对于中药成分的定量检测来说简便、快速、溶剂用量少，可消除姜油带来的干扰，结果准确可靠，适合进行批量样品的测定〔12〕.徐新蕊等利用超高效液相色谱-三重四极杆质谱法同时测定乌头汤中8种成分，实验证明该方法快速、简便、重复性好，可用于同时测定乌头汤中的8种成分以及乌头汤的质量控制〔13〕.另外，侯佳等〔14〕曾经采用超高液相色谱-三重四级杆质谱同时测定灯盏细辛药材中的绿原酸、新绿原酸、隐绿原酸、野黄芩苷、灯盏甲素、芹菜素等的含量.1.4对非法掺入化学药物的中药制剂进行检测一些不法分子在中药制剂中违法掺加化学成分以提升短期药效，牟取暴利，但是从长远来看，这些化210内蒙古民族大学学报2018年学成分对患者的伤害非常大.因此，如何准确检测中药制剂中掺入化学药物已成为药物分析工作者面临的挑战.首先以治疗糖尿病的降糖类中药制剂或保健品为例，在降糖类保健食品中，发现非法添加的降糖类化学药品多达十几种，有些保健食品中竟然同时添加2～3种降糖化学药品，尤其以格列苯脲、格列齐特、格列吡嗪和盐酸苯乙双胍这四种临床上治疗糖尿病较为常用的西药被添加到保健品中最为常见.这4种西药降糖效果好，在西医临床上也是被允许使用，但是药物代谢作用强烈，患者若长期服用此类保健品，会导致持续低血糖、损害肝脏、溶血性贫血和再生性贫血等症状，并且对高危人群诱发严重的不良反应，甚至会危及生命〔15〕.因此，应该谨遵医嘱，控制药物用量.而违法商贩为了达到其销售更多保健品的目的，往往添加这些有害成分，患者在不知情的情况下，长期服用会严重影响其健康.因此，急需对市面上的降糖类保健品加强违禁西药药物成分的检测与监控.其次，抗风湿类中药中非法掺入萘普生、吲哚美辛、双氯芬酸钠的情况比较常见.蓝献泉等为建立抗风湿类中成药和保健品中非法添加双氯芬酸钠的快速筛查方法，采用一种化学方法进行快速筛查，同时建立高效液相色谱法测定含量，并用高效液相色谱-二极管阵列检测器和超高效液相色谱-串联三重四级杆质谱联用仪对样品进行确证〔16〕.其三，减肥药也是违法添加化学制剂的重灾区.随着人们生活品质的不断提高，肥胖逐渐成为一种社会性问题.肥胖患者容易患上高血压、糖尿病、冠心病等疾病，因此很多人会寻求减肥药作为辅助减肥手段，但是不法商家为了使他们的减肥保健品短期内出现明显效果，往往会添加一些违禁的化学药品，长期服用，对患者的身体健康影响很大〔17〕.其中，西布曲明就是一种较为常见的减肥保健品中经常被非法添加的一种化学成分.李文杰等为了建立快速定性检测减肥胶囊中添加的西布曲明的DART-MS/MS方法，且检出限达1ppm，效果良好〔18〕.最后，中药保健品种掺入提高产品参数的化学药物或人工合成制剂的情况也是屡见不鲜.刘秀红等曾采用高效液相色谱-串联三重四级杆质谱为分析手段对蜂王浆/蜂王浆冻干粉中掺入的人工合成癸烯酸进行鉴别和测定〔19〕.以上实验报告显示，利用三重四级杆质谱法对中药和中药类保健品进行化学成分的检测，其灵敏度和准确度均良好，可以有效分析鉴别中药制剂中违法添加的西药成分.1.5对中成药制剂进行质量控制我国的中成药质量标准从无到有、从不完善到提高完善，历经了不同阶段的发展.目前，中成药质量标准正在向更高层次迈进.但长期以来中成药质量控制问题一直是中成药制药生产中的一个难点.这主要是由于中成药成分复杂，药效物质基础不明确，原料药材易受品种、产地、加工方法等因素的影响，使得中成药的质量评价成为阻碍中成药走向现代化的障碍〔20〕.但是，随着人们对中药材产品的关注和对药材品质要求的提升，采用高效准确的质谱技术来解决中药整体特性的质量控制已经成为现实.姚慧等利用超高效液相色谱-电喷雾串联三重四级杆质谱法（UPLC-ESI-MS）同时测定了贞芪扶正胶囊中红景天苷、毛蕊异黄酮-7-O-β-D-葡萄糖苷和黄芪甲苷含量〔21〕.另外，张炜等〔22〕利用超高效液相色谱-串联电喷雾三重四级杆质谱（UPLC-MS/MS）法检测妇康宁片中掺加的山麦冬.1.6对中药体内代谢产物的分析欧阳辉等曾利用超高效液相色谱—三重四级杆线性离子肼复合质谱（UPLC-Q-trap-MS）分析白头翁皂苷D体外肠道菌群孵育样品.实验结果显示，采用三重四级杆质谱法对鉴定及分析中药体内代谢产物具有可行性〔23〕.1.7对中药配伍禁忌的机制的研究陈艳琰等曾采用超高效液相色谱-串联四级杆飞行时间质谱（UPLC-Q-TOF/MS）及超高效液相色谱-串联三重四级杆质谱（UPLC-TQ/MS）联用集成技术，研究芫花与甘草合煎液中化学成分相互作用及211第3期柏慧等：三重四级杆质谱技术在中药研究中的应用进展其变化特点，揭示其“反”的可能特征与机制.该实验显示，在中药配伍禁忌的研究工作中，三重四级杆质谱技术在成分的分析鉴定方面有一定优势〔24〕.1.8对中药中有害物质含量的定量分析不可否认的是，很多中药材中确实含有有害物质，古语说是药三分毒就是这个道理.在《黄帝内经》中就有将药分为大毒、常毒、小毒、无毒等四类的记载，其中对用中药治病也有这样的描述“大毒治病，十去其六；常毒治病，十去其七；小毒治病，十去其八；无毒治病，十去其九；谷肉果菜，食养尽之.无使过之，伤其正也.不尽，行复如法.”旨在告诫人们中药也有其副作用.所以，中药的用量应该要适量，以能帮助病人驱邪为宜，扶正固本之事则应由没有毒副作用的食疗完成.但是，现代人盲目崇尚非化学、纯自然的理念.认为中药不是化学的，源自天然，毒副作用一定很小.其实，中药和西药一样，也都是化学元素构成的，也同样存在毒副作用，中药的毒性成分更复杂.因此，强化对中药中有害物质含量的测定就显得尤为重要.有学者研究发现，中国台湾和整个亚洲地区的肝癌组织广泛地可测到提示有马兜铃酸及其衍生物暴露的基因突变，认为肝癌可能与含马兜铃酸中药的使用有关.除此之外，含马兜铃酸中草药可引起肾脏毒性和泌尿系肿瘤，已被广泛证实.这种毒性主要集中于马兜铃科马兜铃属和细辛属的马兜铃酸成分中，曾在中国及东亚、东南亚地区的医药领域应用极为广泛〔25〕.针对马兜铃酸可能引起较重副作用的情况，下一步，会通过进一步规范药物用量、加强含马兜铃酸中药的基础研究、选择合适的产地、炮制方法及提取工艺，同时加强相关中药材、饮片及中成药中马兜铃酸含量的监测等方式来尽量降低用药风险〔26〕.李功辉等采用超高效液相色谱—三重四极杆串联质谱建立复杂中药基质中马兜铃酸Ⅰ的定性定量测定方法.结果显示，此法对测定中药材中的马兜铃酸含量的准确度、精密度均良好.该方法简便、快速、灵敏度高，专属性强，可以用于含有或者可能含有马兜铃酸Ⅰ成分中药材的检测.结果表明，不同种类药材中马兜铃酸Ⅰ的含量差异明显，尤以朱砂莲中马兜铃酸Ⅰ含量最高.同时，该检测结果也可为马兜铃科中药材中马兜铃酸Ⅰ的限量及其合理使用提供实验基础和参考依据〔27〕.2应用展望综上所述，三重四级杆质谱技术已成为中药成分分析中强有力的工具.该技术因具备灵敏度高、抗干扰能力强等特点，因此对样品的净化处理要求低，处理方法将会变得更加简便、快速.在不远的将来，该技术与现代样品预处理技术和化学计量学方法相结合，在中药和蒙药等传统民族药现代研究中微量甚至痕量质量标志物检测方面将发挥更大作用.同时，在环境检测、生物医学药学、毒物分析等众多领域的检测中发挥越来越重要的作用〔28〕.参考文献〔1〕任惠娟，任现志.液相色谱质谱联用技术及其在中药现代化研究中的应用〔J〕.山西中医，2014，4（4）：54-55.〔2〕李翠翠.超高效液相色谱法在西药分析中的应用探讨〔J〕.科学与财富，2014，4（4）：361-362.〔3〕王少敏，张甦，毛丹，等.分散固相萃取-超高效液相色谱-三重四级杆液质法测定中药材中展青霉素〔J〕.中国卫生检验杂志，2014，3（3）：337-340.〔4〕李明辰，季宇彬，郎朗.中药中农药残留的研究现状〔J〕.黑龙江科技信息，2016，3（1）：231-232.〔5〕王京辉，许玮仪，孙磊，等.中药中有害残留物痕量检测分析方法验证原则探讨〔J〕.药物分析杂志，2012，9（9）：1704-1709.〔6〕王建国，魏玉霞，王芳，等.气相色谱-三重四级杆串联质谱法快速检测中草药中85种农药残留〔J〕.黑龙江科技信息，2017，3（1）：324-330.〔7〕徐宜宏，蒋施，付海滨，等.气相色谱-三重四级杆质谱法同时测定五味子中117种农药残留量〔J〕.福建分析测试，2012，5（9）：1-10.〔8〕李俊，王震，郭晓关，等.测定鱼腥草中百草枯和乙草胺残留的三重四级杆气相色谱质谱法〔J〕.山地农业生物学报，2012，4（8）：341-344.212内蒙古民族大学学报2018年〔9〕韩豪，江海，张志健，等.超高效液相色谱-三重四级杆串联质谱联用技术定性分析黑豆皮中花青苷类物质〔J〕.食品与发酵工业，2014，8（08）：194-200.〔10〕周丽，史新敏，任香梅，等.UHPLC-DAD-ESI-MS/MS法分析紫山药块根和茎叶中酚类物质〔J〕.现代食品科技，2016，11（11）：310-315.〔11〕朱根华，万彦婷，卢珂，等.三重四级杆液质联用法测定金樱子中白桦脂酸〔J〕.中国实验方剂学杂志，2011，5（3）：55-57.〔12〕李占彬，杨昌彪，谭红，等.高效液相色谱-串联三重四级杆质谱法快速测定姜茶中的姜黄素〔J〕.分析仪器，2014，2（3）：65-68.〔13〕徐新蕊，单文静，吴健.超高效液相色谱-三重四极杆质谱法同时检测乌头汤中8种主要成分〔J〕.中国医药导报，2017，3（1）：174-151.〔14〕侯佳，邹欢，李勇军，等.超高效液相色谱-三重四级杆质谱同时测定灯盏细辛中10种指标成分的含量〔J〕.天然产物研究与开发，2016，9（9）：1397-1401.〔15〕曹梅荣，李强，张冬生，等.超高效液相色谱-串联质谱法快速检测降糖类保健食品中的10种非法添加物〔J〕.药物分析杂志，2015，8（8）：896-901.〔16〕蓝献泉，黄义纯，黄红雯，等.抗风湿类中成药及保健品中非法添加双氯芬酸钠的快速筛查方法研究〔J〕.中南药学，2014，9（9）：902-905.〔17〕许立，吴鸳鸯，寿林均，等.高效液相色谱-串联质谱法同时测定减肥类保健食品中27种违法添加化学药品〔J〕.食品工业科技，2017，13（7）：248-256.〔18〕李文杰，程显隆，李卫健，等.DART-MS/MS法快速直接分析减肥保健品中非法添加的盐酸西布曲明〔J〕.中国药事，2012，2（2）：147-149.〔19〕刘秀红，徐锦忠.蜂王浆制品中掺入人工癸烯酸的鉴别和测定〔J〕.食品研究与开发，2016，10（5）：140-143.〔20〕曹骋，刘梦，楚汪杰，等.《国家基本药物目录》中中成药品种的质量标准现状及发展趋势分析〔J〕.中国药房，2017，9（5）：1153-1155.〔21〕姚慧，刘小花，陈心悦，等.UPLC-ESI-MS法测定贞芪扶正胶囊中毛蕊异黄酮-7-O-β-D-葡萄糖苷、红景天苷和黄芪甲苷的含量〔J〕.分析测试技术与仪器，2016，4（12）：204-208.〔22〕张炜，宋文静，武嘉庚，等.UPLC-MS/MS法检测妇康宁片中掺加的山麦冬〔J〕.中成药，2017，4（4）：867-869.〔23〕欧阳辉，郭宜城，何明珍.UPLC-Q-trap-MS鉴定白头翁皂苷D在大鼠离体肠道菌群中的代谢产物〔J〕.中草药，2014，4（2）：523-526.〔24〕陈艳琰，钱大玮，尚尔鑫，等.基于化学成分相互作用探讨芜花与甘草配伍禁忌的机制〔J〕.药学学报，2012，8（8）：1043-1048.〔25〕梁爱华，高月，张伯礼.含马兜铃酸中药的安全性问题及对策〔J〕.中国食品药品监管，2017，11（11）：17-20〔26〕田婧卓，梁爱华，刘靖，等.从马兜铃酸含量影响因素探讨含马兜铃酸中药的风险控制〔J〕.中国中药杂志，2017，24（12）：4679-4686.〔27〕李功辉，陈莎，邬兰，等.UPLC-QQQ-MS测定中药材中马兜铃酸Ⅰ的含量〔J〕.中国实验方剂学杂志，2017，13（7）：61-65.〔28〕舒蓉，易凤，刘家良，等.气相色谱—三重四级杆串联质谱技术的研究进展〔J〕.化学工程与装备，2016，10（10）：196-198.〔责任编辑郑瑛〕。

NLRP3和Caspase-1在颞下颌关节骨关节炎滑膜中的表达

NLRP3和Caspase-1在颞下颌关节骨关节炎滑膜中的表达李艳艳，冯亚平，柯金，龙星(武汉大学口腔医院口腔颌面外科，湖北武汉430079#[摘要]目的：探究&LRP3 炎症小体（&ACHT, and PYD dom/ins-cont/ining protein 3 in fl/m m/som e)和腕天蛋白酶-1 (cysteinyl aspartate specific proteinase，Caspase-1)在颗下颌关节骨关节炎（temporomandibular joint osteoarthritis，TM JOA)患者滑膜细胞中的表达。

方法：分离人颞下颌关节滑膜组织并进行滑膜细胞培养，另取3例髁突肥大患者的滑膜组织作为对照组。

实时定量聚合酶链式反应(real-time quantitative polymerase chain reaction，（T-P C()法检测滑膜细胞中&L(P3和C/s p/s e-1的基因表达，W estern blot检测滑膜细胞中&L(P3和C/s p/s e-1的表达。

结果：TM JO A患者滑膜细胞中的&L(P3和C/s p/s e-1的表达显著高于对照组(！<0.05)。

结论:&L(P3和C/s p/s e-1在TM JO A滑膜细胞中高表达，说明它们与TM JOA发生发展密切相关，这将有助于进明其分子机制。

[关键词]颞下颌关节骨关节炎'滑膜；&L(P3炎性小体'半胱氨酸蛋白酶-1[中图分类号](782[文献标志码]A DOI：10.3969/j.issn.1005-4979.2021.02.003Expression of NLRP3 and Caspase-1 in synovium of temporomandibular joint osteoarthritisLI Yanyan，FENG Yoping，KE Jin，LONG Xing(Department of Oral and Maxillofacial Surgery，Hospital of Stomatology，Wuhan University，Wuhan430079，Hubei Province，China)[Abstract] Objective: To investigate the expression of NLRP3 (NACHT, LRR and PYD domains-containing protein 3 in- fl/m m/som e) and C/sp/se-1 in the synovium of temporomandibular joint osteoarthritis (TMJOA). Methods：Synovial tissues were collected from TMJ of patients and synovial cells were cultured. Synovial tissues of three patients with condylar hypertrophy were taken as control group. Real-time PCR was used to examine the gene expression of NLRP3 and C/s- p/se-1 in synovial cells. The protein expressions of NLRP3 and C/sp/se-1 in synovial cells were detected by Western blot.Results：The expressions of NLRP3 and Caspase-1 in the synovial cells of TMJOA were significantly increased than the control group (P<0.05). Conclusion：NLRP3 and C/sp/se-1 were increased in the synovial cells of TMJOA and closely related to the occurrence and development of TMJOA, which will help to further clarify its molecular mechanism.[Keywords] temporomandibular joint osteoarthritis; synovium; NLRP3 infl/m m/some; C/sp/se-1颞下颌关节骨关节炎（temporomandibular joint osteoarthritis，TMJOA)是一种以关节软骨破坏、软骨下骨退行性和滑膜炎症为的性，关节区疼痛、口，面：形，患者的的研究表明，滑膜炎与关节软骨软骨下骨的行性收稿日期：2020-05-14 修回日期：2020-06-18基金项目：科学基（81870789)作者简介：（1995—)，，人，硕士研究生.E-m/il: *********************.cn通信作者：，医师.E-m/il:*************.cn;龙星，主任医师.E-m/il: ****************.cn 相关_。

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Advanced Calculus with Applications in Statistics2.A History of Probability and Statistics and Their Applications before 17503.Markov Decision Processes: Discrete Stochastic Dynamic Programming4.Probability and Statistical Inference5.Continuous Univariate Distributions, V ol. 16.Continuous Univariate Distributions, Vol. 27.The Theory of Measures and Integration8.Robust Statistics: Theory and Methods9.Finite Mixture Models10.Generalized, Linear, and Mixed Models11.Statistics of Extremes: Theory and Applications12.Modes of Parametric Statistical Inference13.Univariate Discrete Distributions14.Contemporary Bayesian Econometrics and Statistics15.Approximation Theorems of Mathematical Statistics16.Image Processing and Jump Regression Analysis17.Operational Risk : Modeling Analytics18.Design and Analysis of Experiments, Introduction to Experimental Design19.Introductory Biostatistics for the Health Sciences: Modern ApplicationsIncluding Bootstrap20.Linear Models in Statistics21.Statistics for Research22.Applied Logistic Regression23.Operational Subjective Statistical Methods: A Mathematical, Philosophical,and Historical Introduction24.Probability and Measure, 2nd Edition25.Theory of Preliminary Test and Stein-Type Estimation with Applications26.The EM Algorithm and Extensions27.The Theory of Response-Adaptive Randomization in Clinical Trials28.Models for Probability and Statistical Inference: Theory and Applications29.Applied Life Data Analysis30.Structural Equation Modelling: A Bayesian Approach31.Bootstrap Methods: A Guide for Practitioners and Researchers32.Nonparametric Analysis of Univariate Heavy-Tailed Data: Research andPractice33.Applied Linear Regression, 3rd edition34.Theory of Probability: A Critical Introductory Treatment35.Financial Derivatives in Theory and Practice36.Quantitative Methods in Population Health: Extensions of Ordinary Regression37.Statistical Methods for Survival Data Analysis38.Applied Bayesian Modelling39.Spatial Statistics, 2004-0840.Approximate Dynamic Programming: Solving the Curses of Dimensionality41.Variance Components42.Time Series: Applications to Finance43.Generalized Least Squares44.Statistical Analysis With Missing Data45.Long-Memory Time Series: Theory and Methods46.Statistical Models and Methods for Lifetime Data47.Uncertainty Analysis with High Dimensional Dependence Modelling48.Simulation and the Monte Carlo Method49.A Matrix Handbook for Statisticians50.Meta Analysis: A Guide to Calibrating and Combining Statistical Evidence51.Precedence-Type Tests and Applications52.Statistical Meta-Analysis with Applications53.Management of Data in Clinical Trials54.Periodically Correlated Random Sequences: Spectral Theory and Practice55.Design and Analysis of Experiments, Advanced Experimental Design56.Methods and Applications of Linear Models : Regression and the Analysis ofVariancebinatorial Methods in Discrete Distributions58.Nonparametric Regression Methods for Longitudinal Data Analysis:Mixed-Effects Modeling Approaches59.Response Surfaces, Mixtures, and Ridge Analyses60.Variations on Split Plot and Split Block Experiment Designs61.Recent Advances in Quantitative Methods in Cancerand Human Health Risk Assessment62.The Construction of Optimal Stated Choice Experiments: Theory and Methods63.Nonparametric Density Estimation: The L1 View64.Applied MANOV A and Discriminant Analysis65.Survey Errors and Survey Costs66.Statistical Advances in the Biomedical Sciences: Clinical Trials,Epidemiology, Survival Analysis, and Bioinformaticstent Curve Models: A Structural Equation Perspective68.Regression Diagnostics: Identifying Influential Data and Sources ofCollinearity69.Reliability and Risk: A Bayesian Perspective70.Environmental Statistics71.Bayes Linear Statistics, Theory & Methods72.Introductory Stochastic Analysis for Finance and Insurance73.Bayesian Models for Categorical Data74.Bayesian Statistical Modelling75.Weibull Models76.Analysis of Financial Time Series77.Linear Model Theory: Univariate, Multivariate, and Mixed Models78.An Introduction to Categorical Data Analysis79.Bayesian Statistics and Marketing80.Statistical Shape Analysis81.Nonparametric Statistics with Applications to Science and Engineering82.Longitudinal Data Analysis83.Regression Models for Time Series Analysis84.Introduction to Nonparametric Regression85.Statistical Modeling by Wavelets86.Case Studies in Reliability and Maintenance87.The Geometry of Random Fields88.Biostatistics : A Methodology For the Health Sciences89.Planning, Construction, and Statistical Analysis of Comparative Experiments90.Statistical Size Distributions in Economics and Actuarial Sciences91.Modern Experimental Designparative Statistical Inference93.Methods of Multivariate Analysis94.Robust Statistics95.Order Statistics96.Fourier Analysis of Time Series : An Introduction97.Spatial Statistics 1981-0498.Clinical Trials : A Methodologic Perspective99.Numerical Issues in Statistical Computing for the Social Scientist100.Nonlinear Regression101.Preparing for the Worst : Incorporating Downside Risk in Stock MarketInvestments 102.Nonlinear Regression Analysis and Its Applications103.Mixed Models : Theory and Applications104.Discrete Distributions : Applications in the Health Sciences105.Design and Analysis of Clinical Trials : Concepts and Methodologies106.Applied Bayesian Modeling and Causal Inference from Incomplete-DataPerspectives 107.Flowgraph Models for Multistate Time-?–to-Event Data108.Randomization in Clinical Trials: Theory and Practice109.Regression With Social Data: Modeling Continuous and Limited ResponseVariables 110.Regression Analysis by Example111.Categorical Data Analysis112.Statistical Methods for Reliability Data113.Elements of Stochastic Processes Wit114.Random Graphs for Statistical Pattern Recognition115.Construction and Assessment of Classification Rules116.The Statistical Analysis of Failure Time Data117.Statistical Analysis of Finite Mixture Distributions118.Modern Applied U-Statistics119.Applied Multiway Data Analysis。

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Wiley Series in Probability and Statistics1. A Course in Time Series Analysis2. A Primer on Experiments with Mixtures3. A Probabilistic Analysis of the Sacco and Vanzetti Evidence4. A User's Guide to Principal Components5. A Weak Convergence Approach to the Theory of Large Deviations6.Accelerated Testing: Statistical Models, Test Plans, and Data Analysis7.Advanced Calculus with Applications in Statistics, Second Edition8.Alternative Methods of Regression9.An Elementary Introduction to Statistical Learning Theory10.An Introduction to Categorical Data Analysis, Second Edition11.An Introduction to Probability and Statistics, Second Edition12.An Introduction to Regression Graphics13.Analysis of Financial Time Series14.Analysis of Financial Time Series, Second Edition15.Analysis of Financial Time Series, Third Edition, Third Edition16.Analysis of Ordinal Categorical Data, Second Edition17.Analyzing Microarray Gene Expression Data18.Applications of Statistics to Industrial Experimentation19.Applied Bayesian Modeling and Causal Inference from Incomplete-DataPerspectives: An Essential Journey with Donald Rubin's Statistical Family20.Applied Bayesian Modelling21.Applied Life Data Analysis22.Applied Linear Regression, Third Edition23.Applied MANOVA and Discriminant Analysis, Second Edition24.Applied Multiway Data Analysis25.Applied Regression Including Computing and Graphics26.Applied Spatial Statistics for Public Health Data27.Applied Survival Analysis: Regression Modeling of Time-to-Event Data, SecondEdition28.Approximate Dynamic Programming: Solving the Curses of Dimensionality29.Approximate Dynamic Programming: Solving the Curses of Dimensionality, SecondEdition30.Approximation Theorems of Mathematical Statistics31.Aspects of Multivariate Statistical Theory32.Aspects of Statistical Inference33.Batch Effects and Noise in Microarray Experiments: Sources and Solutions34.Bayes Linear Statistics: Theory and Methods35.Bayesian Analysis for the Social Sciences36.Bayesian Analysis of Stochastic Process Models37.Bayesian Methods and Ethics in a Clinical Trial Design38.Bayesian Models for Categorical Data39.Bayesian Networks: An Introduction40.Bayesian Statistical Modelling, Second Edition41.Bayesian Statistics and Marketing42.Bayesian Theory43.Bias and Causation44.Biostatistical Methods in Epidemiology45.Biostatistical Methods: The Assessment of Relative Risks46.Biostatistical Methods: The Assessment of Relative Risks, Second Edition47.Biostatistics: A Methodology for the Health Sciences, Second Edition48.Bootstrap Methods: A Guide for Practitioners and Researchers, Second Edition49.Business Survey Methods50.Case Studies in Reliability and Maintenance51.Categorical Data Analysis, Second Edition52.Causality: Statistical Perspectives and Applications53.Clinical Trial Design: Bayesian and Frequentist Adaptive Methods54.Clinical Trials: A Methodologic Perspective, Second Edition55.Cluster Analysis, 5th Editionbinatorial Methods in Discrete Distributionsparative Statistical Inference, Third Edition58.Constrained Statistical Inference: Inequality, Order, and Shape Restrictions59.Contemporary Bayesian Econometrics and Statistics60.Continuous Multivariate Distributions: Models and Applications, Volume 1,Second Edition61.Convergence of Probability Measures, Second Edition62.Counting Processes and Survival Analysis63.Decision Theory64.Design and Analysis of Clinical Trials: Concepts and Methodologies, SecondEdition65.Design and Analysis of Experiments: Advanced Experimental Design, Volume 266.Design and Analysis of Experiments: Introduction to Experimental Design, Volume1, Second Edition67.Design and Analysis of Experiments: Special Designs and Applications, Volume 368.Directional Statistics69.Dirichlet and Related Distributions: Theory, Methods and Applications70.Discrete Distributions: Applications in the Health Sciences71.Discriminant Analysis and Statistical Pattern Recognition72.Empirical Model Building73.Empirical Model Building: Data, Models, and Reality, Second Edition74.Environmental Statistics: Methods and Applications75.Exploration and Analysis of DNA Microarray and Protein Array Data76.Exploratory Data Mining and Data Cleaning77.Exploring 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before 175097.Image Processing and Jump Regression Analysis98.Inference and Prediction in Large Dimensions99.Introduction to Nonparametric Regression100.Introduction to Statistical Time Series, Second Edition101.Introductory Stochastic Analysis for Finance and Insurancetent Class and Latent Transition Analysis: With Applications in the Social, Behavioral, and Health Sciencestent Curve Models: A Structural Equation Perspectivetent Variable Models and Factor Analysis: A Unified Approach, 3rd Edition105.Leading Personalities in Statistical Sciences: From the Seventeenth Century to the Present106.Lévy Processes in Finance: Pricing Financial Derivatives107.Linear Models: The Theory and Application of Analysis of Variance108.Linear Statistical Inference and its Applications: Second Editon109.Linear Statistical Models110.LISP-STAT: An Object-Oriented Environment for Statistical Computing and Dynamic Graphics111.Longitudinal Data Analysis112.Long-Memory Time Series: Theory and Methods113.Loss Distributions114.Loss Models: From Data to Decisions, Third Edition115.Management of Data in Clinical Trials, Second Edition116.Markov Decision Processes: Discrete Stochastic Dynamic Programming117.Markov Processes and Applications118.Markov Processes: Characterization and Convergence119.Mathematics of Chance120.Measurement Error Models121.Measurement Errors in Surveys122.Meta Analysis: A Guide to Calibrating and Combining Statistical Evidence 123.Methods and Applications of Linear Models: Regression and the Analysis of Variance124.Methods for Statistical Data Analysis of Multivariate Observations, Second Edition125.Methods of Multivariate Analysis, Second Edition126.Methods of Multivariate Analysis, Third Edition127.Mixed Models: Theory and Applications128.Mixtures: Estimation and Applications129.Modelling Under Risk and Uncertainty: An Introduction to Statistical, Phenomenological and Computational Methods130.Models for Investors in Real World Markets131.Models for Probability and Statistical Inference: Theory and Applications 132.Modern Applied U-Statistics133.Modern Experimental Design134.Modes of Parametric Statistical Inference135.Multilevel Statistical Models, 4th Edition136.Multiple Comparison Procedures137.Multiple Imputation for Nonresponse in Surveys138.Multiple Time Series139.Multistate Systems Reliability Theory with Applications140.Multivariable Model-Building: A pragmatic approach to regression analysis based on fractional polynomials for modelling continuous variables141.Multivariate Density Estimation: Theory, Practice, and Visualization142.Multivariate Observations143.Multivariate Statistics: High-Dimensional and Large-Sample Approximations 144.Nonlinear Regression145.Nonlinear Regression Analysis and Its Applications146.Nonlinear Statistical Models147.Nonparametric Analysis of Univariate Heavy-Tailed Data: Research and Practice148.Nonparametric Regression Methods for Longitudinal Data Analysis: Mixed-Effects Modeling Approaches149.Nonparametric Statistics with Applications to Science and Engineering 150.Numerical Issues in Statistical Computing for the Social Scientist151.Operational Risk: Modeling Analytics152.Optimal Learning153.Order Statistics, Third Edition154.Periodically Correlated Random Sequences: Spectral Theory and Practice 155.Permutation Tests for Complex Data: Theory, Applications and Software 156.Planning and Analysis of Observational Studies157.Planning, Construction, and Statistical Analysis of Comparative Experiments158.Precedence-Type Tests and Applications159.Preparing for the Worst: Incorporating Downside Risk in Stock Market Investments160.Probability and Finance: It's Only a Game!161.Probability: A Survey of the Mathematical Theory, Second Edition162.Quantitative Methods in Population Health: Extensions of Ordinary Regression163.Random Data: Analysis and Measurement Procedures, Fourth Edition164.Random Graphs for Statistical Pattern Recognition165.Randomization in Clinical Trials: Theory and Practice166.Recent Advances in Quantitative Methods in Cancer and Human Health Risk Assessment167.Records168.Regression Analysis by Example, Fourth Edition169.Regression Diagnostics: Identifying Influential Data and Sources of Collinearity170.Regression Graphics: Ideas for Studying Regressions Through Graphics171.Regression Models for Time Series Analysis172.Regression with Social Data: Modeling Continuous and Limited Response Variables173.Reliability and Risk: A Bayesian Perspective174.Reliability: Modeling, Prediction, and Optimization175.Response Surfaces, Mixtures, and Ridge Analyses, Second Edition176.Robust Estimation & Testing177.Robust Methods in Biostatistics178.Robust Regression and Outlier Detection179.Robust Statistics180.Robust Statistics, Second Edition181.Robust Statistics: Theory and Methods182.Runs and Scans with Applications183.Sampling, Third Edition184.Sensitivity Analysis in Linear Regression185.Sequential Estimation186.Shape & Shape Theory187.Simulation and the Monte Carlo Method188.Simulation and the Monte Carlo Method, Second Edition189.Simulation and the Monte Carlo Method: Solutions Manual to Accompany, Second Edition190.Simulation: A Modeler's Approach191.Smoothing and Regression: Approaches, Computation, and Application192.Smoothing of Multivariate Data: Density Estimation and Visualization193.Spatial Statistics194.Spatial Statistics and Spatio-Temporal Data: Covariance Functions and Directional Properties195.Spatial Tessellations: Concepts and Applications of Voronoi Diagrams, Second Edition196.Stage-Wise Adaptive Designs197.Statistical Advances in the Biomedical Sciences: Clinical Trials, Epidemiology, Survival Analysis, and Bioinformatics198.Statistical Analysis of Profile Monitoring199.Statistical Design and Analysis of Experiments: With Applications to Engineering and Science, Second Edition200.Statistical Factor Analysis and Related Methods: Theory and Applications 201.Statistical Inference for Fractional Diffusion Processes202.Statistical Meta-Analysis with Applications203.Statistical Methods for Comparative Studies: Techniques for Bias Reduction 204.Statistical Methods for Forecasting205.Statistical Methods for Quality Improvement, Third Edition206.Statistical Methods for Rates and Proportions, Third Edition207.Statistical Methods for Survival Data Analysis, Third Edition208.Statistical Methods for the Analysis of Biomedical Data, Second Edition 209.Statistical Methods in Diagnostic Medicine210.Statistical Methods in Diagnostic Medicine, Second Edition211.Statistical Methods in Engineering and Quality Assurance212.Statistical Methods in Spatial Epidemiology, Second Edition213.Statistical Modeling by Wavelets214.Statistical Models and Methods for Lifetime Data, Second Edition215.Statistical Rules of Thumb, Second Edition216.Statistical Size Distributions in Economics and Actuarial Sciences217.Statistical Texts for Mixed Linear Models218.Statistical Tolerance Regions: Theory, Applications, and 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294Vol.29No.4 20098Journal of Chinese Society for Corrosion and Protection Aug.2009
Diﬀusion Barrier Coating System and Oxidation
Behavior of Coated Alloys
T.NARITA
(Research Group of Advanced Coatings,Hokkaido University,Kita-13,Nishi-8,Kita-Ku,Sapporo060-8628,Japan)
1Introduction
Research into the formation of Re-based alloys
is in progress in our laboratory to provide a diﬀu-
sion barrier layer between heat-resistant alloys and
Al reservoir layers,which assist in the formation and
maintenance a protective Al2O3scale for long periods.
Coatings with a two-layered structure comprised of in-
ner Re-based alloy layer and outerβ-NiAl layer with
or without Pt addition were successfully formed on
various heat resistant alloys such as Ni-based single-
crystal superalloys,Ni-based heat resistant alloys,Ni-
Mo based alloy,Ni-Cr based alloy,and Fe-based al-
loys.The duplex layer coating proposed is generally
termed a diﬀusion barrier coating system;DBC sys-
tem.
In the present investigation concept of the DBC
system is introduced and oxidation behavior of the
various heat-resistant alloys with the DBC system is
given.Particular attention was paid to the structure
and composition of the coatings before and after the
high temperature oxidation with or without an exter-
nal stress.
2Concept
Figure1shows a schematic cross section of the al-
loys with the DBC system.Diﬀusionﬂux of Al(as one
of examples)across the diﬀusion barrier layer should
be given by a Fick′sﬁrst law,and it is clearly shown
that low chemical diﬀusivity,low solubility,and low
driving force are essential.Particularly,maintaining
of barrier layer thickness is one of key issues for the
DBC system at high temperature and long periods.
4M.Sch¨u tze et al:Recent Advances in the Quantitative Characterisation of (313)
Corresponding author:M.Sch¨u tze,E-mail:gellermann@dechema.de can be described by their own equations,a multilevel
approach was introduced for this diagram where each
level (in Fig.2levels 1to 4are assumed)yields a fur-
ther reﬁnement of the model and a more detailed de-
scription of the quantitative role of each subparame-
ter.
A recent study assessed the quantitative inﬂu-
ence of each of these parameters on the critical strain
to scale failure and revealed that the most critical
parameter is the defect size (pores,ﬁssures,crevices,
microcracks)in the oxide scale [4].The role of the
physical defect size becomes particularly clear if one
looks at the equations in ref.4and the potential
de-
Fig.1The scale failure diagram developed in EPRI-
report FP 686[2]which is based on a critical
oxide scale thickness at which the respective
failure modes occur
31429。