The Approach to Stability for Delayed Feedback Control of Chaos for 1-dimensional Maps

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CNN综述

CNN综述

由 来
什么是CNN?
• 目前公认的 目前公认的CNN: :
• 细胞神经网络是一个有大体相同动力学性质的细胞 组成的二维或三维或N维阵列 维阵列, 组成的二维或三维或 维阵列,以神经细胞的联系 方式为背景,来实现一种局部连接的, 方式为背景,来实现一种局部连接的,且可设计的 人工神经网络。 人工神经网络。 • 一个细胞神经网络应当满足如下条件 一个细胞神经网络应当满足如下条件: • 1,每一个细胞只与(2R+1)^2个相邻的细胞连 ,每一个细胞只与( ) 个相邻的细胞连 接,每个细胞都接受自己和邻域其他单元的反馈信 反馈的多少由相应的反馈模板和控制模板确定。 号,反馈的多少由相应的反馈模板和控制模板确定。 该条件确保了细胞神经网路的电路可实现性。 该条件确保了细胞神经网路的电路可实现性。 • 2,所有细胞的输入值都是连续的,输入输出关系 ,所有细胞的输入值都是连续的, 都是连续的非线性单调函数。 都是连续的非线性单调函数。
CNN的理论发展(一)
——变形细胞神经网络相关理论研究 变形细胞神经网络相关理论研究
理 论
类型三: 类型三:变形细胞神经网络及稳定性研究
在细胞神经网络研究中,还有一个重要的方 面就是变形的细胞神经网络。由于初始的细 胞神经网络本身结构非常简单,带来的相应 的弱点就是其功能不够强大,而且非线性内 容不够丰富,这样为了实现更为强大的功能, 对细胞神经网络的改进就一直为大家所关注。
• • • CNN多值稳定及灰度处理理论研究 多值稳定及灰度处理理论研究 CNN联想记忆研究 联想记忆研究 变形细胞神经网络及稳定性研究
二、CNN模板设计 模板设计
下面对近10年的 下面对近 年的CNN文献进行综述 年的 文献进行综述
CNN的理论发展(一)

异地学费代偿流程

异地学费代偿流程

异地学费代偿流程Due to the high cost of studying abroad, many students rely on education loan to fund their studies. 由于留学成本高昂,许多学生依赖教育贷款来资助他们的学业。

Once they graduate and start working, the burden of repaying the loan can be overwhelming. 一旦他们毕业并开始工作,偿还贷款的压力可能会很大。

To alleviate this burden, some students opt for tuition fee deferment programs offered by banks or financial institutions. 为了减轻这种压力,一些学生选择由银行或金融机构提供的学费代偿计划。

A typical tuition fee deferment program works by allowing a student to delay repaying their education loan for a certain period of time, usually until they secure a job and start earning a steady income. 典型的学费代偿计划通过允许学生延迟偿还其教育贷款一段时间来运作,通常是直到他们找到工作并开始稳定工作。

During this deferment period, the bank or financial institution that provided the loan will cover the student's monthly tuition fee payments. 在此延迟期间,提供贷款的银行或金融机构将支付学生每月的学费。

如果你有多余的钱存着还是花掉英语作文

如果你有多余的钱存着还是花掉英语作文

Saving or Spending Extra Money: A DelicateDilemmaIn the realm of personal finance, the debate surrounding whether to save or spend extra money is a timeless one. For many, the mere mention of having additional funds brings forth a range of emotions, from excitement to trepidation. The question is not just about money; it's about values, goals, and the overall vision for one's life.On the one hand, saving money offers a sense ofsecurity and stability. It's a nest egg for the future, a cushion against unexpected expenses or financial emergencies. Having a savings account can provide peace of mind, knowing that there's a financial safety net in place. This approach also aligns with the principle of delayed gratification, which suggests that saving now for future rewards is often more beneficial than immediate indulgence. Moreover, saving allows for investment opportunities. Whether it's putting money into a retirement account, stocks, or other financial instruments, saving can lead to financial growth over time. This growth, in turn, canenhance one's financial security and even provide the means to pursue dreams or achieve long-term goals.However, the temptation to spend extra money can be strong. It's human nature to want to enjoy the fruits of our labor, and there's certainly nothing wrong withtreating oneself occasionally. Spending can bring instant gratification and enhance our quality of life, whether it's through a luxurious vacation, a new piece of technology, or simply indulging in a favorite hobby.The key lies in finding a balance between saving and spending. It's important to have a clear understanding of one's financial goals and to allocate funds accordingly. For instance, setting aside a portion of extra money for savings while allowing for some discretionary spending can strike a harmonious balance. This approach allows for both financial security and the enjoyment of life's pleasures. It's also worth noting that the decision to save or spend is often influenced by personal values and life experiences. Some may value stability and security aboveall else, while others may be more inclined to live in the moment and enjoy life's experiences. There's no right orwrong answer; it's about finding what works best for each individual.In conclusion, the debate surrounding whether to save or spend extra money is highly personal and nuanced. It's essential to carefully consider one's financial goals, values, and life experiences to make informed decisions. Finding a balance between saving for the future and enjoying the present can lead to a fulfilling and financially secure life.**存钱还是花钱:一个微妙的困境**在个人财务领域,关于是否应该储存或花费多余的钱的争论是一个永恒的话题。

美国DMF目录及要求

美国DMF目录及要求

Drug SubstanceChemistry, Manufacturing, and Controls InformationDRAFT GUIDANCEThis guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 180 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.For questions regarding this draft document contact (CDER) Stephen Miller (301) 827-2392, (CBER) Chris Joneckis (301) 435-5681, or (CVM) Dennis Bensley (301) 827-6956.U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Review (CBER)Center for Veterinary Medicine (CVM)January 2004CMCDrug Substance Chemistry, Manufacturing, and Controls InformationAdditional copies are available from:Office of Training and CommunicationDivision of Drug Information, HFD-240Center for Drug Evaluation and ResearchFood and Drug Administration5600 Fishers LaneRockville, MD 20857(Tel) 301-827-4573/cder/guidance/index.htmorOffice of Communication, Training andManufacturers Assistance, HFM-40Center for Biologics Evaluation and ResearchFood and Drug Administration1401 Rockville Pike, Rockville, MD 20852-1448/cber/guidelines.htm.(Tel) Voice Information System at 800-835-4709 or 301-827-1800orCommunications Staff, HFV-12Center for Veterinary MedicineFood and Drug Administration7519 Standish PlaceRockville, MD 20855(Tel) 301-827-3800/cvm/guidanc/published.htmU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Review (CBER)Center for Veterinary Medicine (CVM)January 2004CMCTABLE OF CONTENTS1I. INTRODUCTION (1)II. BACKGROUND (3)A. The Common Technical Document — Quality (CTD-Q) Format (3)B. Content of an Application (4)C. Additional Guidance (4)D. References to Other Applications or Master Files (MFs) (5)1. Other Applications (5)2. Master Files (MFs) (6)III. GENERAL INFORMATION (S.1) (8)A. Nomenclature (S.1.1) (8)B. Structure (S.1.2) (8)C. General Properties (S.1.3) (9)IV. MANUFACTURE (S.2) (10)A. Manufacturers (S.2.1) (10)B. Description of Manufacturing Process and Process Controls (S.2.2) (10)1. Flow Diagram (11)2. Description of the Manufacturing Process and Process Controls (12)3. Reprocessing, Reworking, Recycling, Regeneration, and Other Operations (15)C. Control of Materials (S.2.3) (18)1. Starting Materials (18)2. Reagents, Solvents, and Auxiliary Materials (19)3. Diluents (20)D. Controls of Critical Steps and Intermediates (S.2.4) (20)E. Process Validation and/or Evaluation (S.2.5) (23)F. Manufacturing Process Development (S.2.6) (23)V. CHARACTERIZATION (S.3) (24)A. Elucidation of Structure and Other Characteristics (S.3.1) (24)1. Elucidation of Structure (24)2. Physicochemical Characterization (25)3. Biological and Other Relevant Characteristics (26)B. Impurities (S.3.2) (27)VI. CONTROL OF DRUG SUBSTANCE (S.4) (29)1 Alphanumeric designations in parentheses that follow headings show where information should be placed in applications that are submitted in Common Technical Document (CTD) format.A. Specification (S.4.1) (29)B. Analytical Procedures (S.4.2) (34)C. Validation of Analytical Procedures (S.4.3) (35)D. Batch Analyses (S.4.4) (35)1. Batch Analysis Reports (36)2. Collated Batch Analyses Data (36)E. Justification of Specification (S.4.5) (37)VII. REFERENCE STANDARDS OR MATERIALS (S.5) (40)VIII. CONTAINER CLOSURE SYSTEM (S.6) (40)IX. STABILITY (S.7) (41)A. Stability Summary and Conclusions (S.7.1) (41)B. Postapproval Stability Protocol and Stability Commitment (S.7.2) (41)C. Stability Data (S.7.3) (41)1. Primary Stability Studies (41)2. Supporting Stability Studies (42)3. Stress Studies (42)X. APPENDICES (A) (43)A. Facilities and Equipment (A.1) (43)B. Adventitious Agents Safety Evaluation (A.2) (44)1. Nonviral Adventitious Agents (45)2. Viral Adventitious Agents (45)XI. REGIONAL INFORMATION (R) (46)A. Executed Production Records (R.1.S) (46)B. Comparability Protocols (R.2.S) (46)C. Methods Validation Package (R.3.S) (46)XII. LITERATURE REFERENCES (3.3) (47)ATTACHMENT 1: (48)STARTING MATERIALS FOR SYNTHETIC DRUG SUBSTANCES (48)ATTACHMENT 2: (56)STARTING MATERIALS OF PLANT OR ANIMAL ORIGIN (56)GLOSSARY (59)GUIDANCE FOR INDUSTRY2Drug SubstanceChemistry, Manufacturing, and Controls Information12345678910111213If you plan to submit comments on this draft guidance, to expedite FDA review of your14comments, please:15∙Clearly explain each issue/concern and, when appropriate, include a proposed revision and the rationale and/or justification for the proposed revision.1617∙Identify specific comments by line numbers; use the pdf version of the document whenever 18possible.19∙If possible, e-mail an electronic copy (Word) of the comments you have submitted to the20docket to cummingsd@.212223I. INTRODUCTION2425Information on the chemistry, manufacturing, and controls (CMC) for the drug substance must 26be submitted to support the approval of original new drug applications (NDAs), abbreviated new 27drug applications (ANDAs), new animal drug applications (NADAs), and abbreviated new28animal drug applications (ANADAs).3 This guidance provides recommendations on the CMC 29information for drug substances that should be submitted to support these applications. The30guidance is structured to facilitate the preparation of applications submitted in Common31Technical Document (CTD) format.3233This guidance addresses the information to be submitted for drug substances to ensure continued 34drug substance and drug product quality (i.e., the identity, strength, quality, purity, and potency).2 This guidance has been prepared by Drug Substance Technical Subcommittee of the Chemistry Manufacturing andControls Coordinating Committee (CMC CC) in the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluations and Research (CBER) and the Center for Veterinary Medicine (CVM) at the FDA.3 See 21 CFR 314.50(d)(1) and 514.1(b)This guidance provides recommendations on the information that should be included for the3536following topics:37∙Nomenclature, structure, and general drug substance properties3839∙Manufacture40∙Characterization41∙Control of drug substance42∙Reference standards or materials43∙Container closure system44∙Stability45The recommendations provided in this guidance apply to the following types of drug substances:464748∙Drug substances manufactured by chemical synthesis49∙Highly purified and well characterized drug substances derived from plants or animals 4 50∙Semisynthetic drug substances manufactured by the chemical modification of a highly 51purified and well characterized intermediate derived from plants or animals52∙The synthetic portion of the manufacturing process for semisynthetic drug substances53manufactured by the chemical modification of an intermediate produced by conventional 54fermentation.5556The guidance does not provide specific recommendations relating to the following:5758∙Monoclonal antibodies59∙Peptides60∙Oligonucleotides61∙Radiopharmaceuticals62∙Medical gases63∙Drug substances that are not well characterized (e.g., botanicals, some proteins) derived 64from plants or animals65∙Drug substances derived using transgenic technology66∙Drug substances derived directly from or manufacturing operations involving67fermentation (conventional fermentation or using rDNA technology) or tissue or cell68culture.6970More detailed guidance on the content of an application may be available in separate guidance 71documents for specific types of drug substances (see section II.C). Applicants with drug72substances not specifically covered by this (Drug Substance guidance) or another guidance can 73apply the content recommendations in this guidance, as scientifically appropriate, and/or can74contact the appropriate chemistry review teams for guidance.754 For purposes of this guidance, d rug substances derived from plants or animals does not include materials producedby plant cell fermentation, animal cell or tissue culture, or through use of transgenic technology (e.g.,biotechnology-derived protein drug products).FDA’s guidance docume nts, including this guidance, do not establish legally enforceable7677responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 78be viewed only as recommendations, unless specific regulatory or statutory requirements arecited. The use of the word should in Agency guidances means that something is suggested or7980recommended, but not required.8182This guidance, when finalized, will replace the guidance entitled Submitting Supporting83Documentation in Drug Applications for the Manufacture of Drug Substances (February 1987).848586II. BACKGROUND8788A. The Common Technical Document — Quality (CTD-Q) Format89In November 2000, the International Conference on Harmonisation of Technical9091Requirements for Registration of Pharmaceuticals for Human Use (ICH) issued92harmonized guidance for the format of drug product applications (i.e., Common93Technical Document (CTD)). The CTD describes a format for applications that94(supplemented with regional information) can be used for submission to the regulatory 95authorities in the United States, European Union, and Japan. One focus of this effort was 96harmonizing the format for quality information (i.e., chemistry, manufacturing, and97controls) that will be submitted in an application. FDA’s guidance on M4Q: The CTD —98Quality describes the format for the quality information submitted in Module 3 of an99application and provides additional information on formatting aspects of an application. 100Applicants can submit NDAs, ANDAs, NADAs, and ANADAs using the CTD-Q101format.5Applicants should review FDA’s guidance on M4Q: The CTD — Quality and 102other related CTD guidance documents for detailed formatting recommendations on103preparing an application in CTD format.104105Module 3 of each NDA and ANDA should include the specified CTD sections: Drug 106Substance (3.2.S), Drug Product (3.2.P), Appendices (3.2.A), Regional Information107(3.2.R), and Literature References (3.3). In some cases, the majority of information to 108address the drug substance sections will be incorporated by reference from a master file 109(see section II.D.2). However, an applicant should still provide information to address 110some of the drug substance subsections. Recommendations on the content of the drug 111product section (3.2.P) of Module 3 will be the provided in the guidance Drug Product —112Chemistry, Manufacturing, and Controls Information (Drug Product guidance), when 113finalized.6 The Appendices, Regional Information, and Literature References sections 114include information for both drug substance and drug product, as appropriate.1155 The information in animal drug applications is commonly presented in the order of the required CMC informationspecified under section § 514.1(b)(4) and (5). Although the CTD-Q format was developed for human drugs, thedrug substance information to support NADAs and ANADAs can be formatted according to the CTD-Q format or any alternative format that provides the appropriate information to support the application.6 A draft version of this guidance published on January 28, 2003 (68 FR 4219).116This Drug Substance guidance has been organized in a format conforming to Module 3 of 117the CTD, and it provides CMC content recommendations specific to drug substance,118including recommendations for the Appendices, Regional Information, and Literature 119References sections. Alphanumeric designations in parentheses corresponding to the 120CTD format follow relevant headings and text to show where information is to be placed 121in the CTD.7 Recommendations specific to drug product, including recommendations for 122the Appendices, Regional Information and Literature References sections, will be123provided in the Drug Product guidance.124125Multiple Drug Substances in an Application126127When an application is submitted for a drug product involving two or more drug128substances (e.g., combination drug product, copackaged drug products), information for 129each drug substance should be presented separately in the application. Information130presented separately means one complete S section for one drug substance followed by 131other complete S sections for additional drug substances. All of the information pertinent 132to each one of the drug substances (general information, manufacture, characterization, 133control, standards, container closure system, and stability) should be provided in a single 134section.135136B. Content of an Application137The application should include information in every S subsection for each of the drug 138139substances and manufacturing schemes (e.g., alternative processes, manufacturing site) 140intended for approval under the application. Information should be provided in theAppendices, Regional Information, and Literature References sections for each of the 141142drug substances and manufacturing schemes, as appropriate. If an Appendices or143Regional Information subsection or the Literature References section is not applicable, 144this should be stated in the application.145146C. Additional Guidance147148This Drug Substance guidance and the Drug Product guidance, when finalized, will be 149the primary content guidances for NDA and ANDA applicants. For quality, the general 150format guidance is M4Q: The CTD — Quality. These are the first guidances an applicant 151should consider when preparing the quality section (i.e., chemistry, manufacturing, and 152controls) of an NDA or ANDA (Module 3).153This guidance references ICH guidance documents cited in the CTD-Q and FDA’s154155guidances on general technical topics (i.e., stability, container closure systems, analytical 156procedures and methods validation, sterilization process validation, drug master files, and7 Arabic numbers have been assigned to specific sections of the CTD. For example, the designation 3.2 before S, P,A, and R indicates Module 3, Body of Data section 2. Where this guidance discusses Module 3, Body of Datasection 2, for brevity, the initial designation 3.2 is not repeated throughout the rest of the guidance (e.g., 3.2.S.1.3reads S.1.3).157environmental assessments) rather than incorporating this detailed information. These 158guidances are referenced in the text and/or listed at the end of a section. An applicant159should refer to these guidances for recommendations on the detailed information that160should be included in the application to address the general technical topic.161162Finally, an applicant should consider guidances that are available for specific technical 163issues or type (e.g., synthetic peptides) of drug substance when preparing its application. 164These guidances provide additional recommendations on unique scientific and technical 165aspects of the topic. Some references to these types of guidances are included in this166guidance. However, the references are given only as examples, and the list is not meant 167to be all-inclusive. Some examples of these types of guidance include the following:168∙Submission of Chemistry, Manufacturing, and Controls Information for Synthetic 169170Peptide Substances171∙Submission of Chemistry, Manufacturing and Controls Information for a172Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody173Product for In Vivo Use, CBER/CDER (under development)174∙Botanical Drug Products (under development)∙Fermentation Derived Drug Substances and Intermediates and Associated Drug 175176Products (under development)177∙Synthetic Oligonucleotides; Submission of Chemistry, Manufacturing, and178Controls Information (under development)179∙Radiopharmaceutical Drug Products: Chemistry, Manufacturing and ControlsInformation (under development)180181182FDA continues to update existing and publish new guidance documents. An applicant 183should use current guidance when preparing an NDA, ANDA, NADA or ANADA184submission.8185186D. References to Other Applications or Master Files (MFs)1871881. Other Applications189190In some cases, chemistry, manufacturing, and controls information about drug substances 191is provided in one application by reference to pertinent information in another application. 192This situation is less common than inclusion of information by reference to a MF and193usually occurs when the same firm submits both applications.194An applicant must identify in the application all other referenced applications, and each 195reference to information submitted in another application must identify where the196information can be found in the referenced application (21 CFR 314.50(a)(1) and197514.1(a)). If the referenced application was submitted by a firm other than the applicant,the referencing application must contain a written statement that authorizes the reference, 1988Current guidance documents are available on the Internet at /cder/guidance/index.htm,/cber/guidelines.htm, and /cvm/guidance/published.htm.199signed by the holder of the referenced application (21 CFR 314.50(g)(1), 314.420(b). and 200514.1(a)).9 Copies of letters of authorization (LOAs) should be submitted in Module 1 of 201the NDA or ANDA or in the appropriate section of an NADA or ANADA.2022032. Master Files (MFs)204205This guidance describes chemistry, manufacturing, and controls information for drug206substances that should be submitted to the Agency as part of the process of seeking theapproval of an NDA, ANDA, NADA, or ANADA. When a drug substance is207208manufactured by a firm other than the applicant, much of this information is frequently 209provided by reference to one or more Type II MFs rather than directly in an application. 210The CMC information in a Type II MF can be organized in CTD-Q format. Under FDA's 211regulations, an application can incorporate by reference all or part of the contents of any 212MF to address particular drug substance issues if the MF holder provides written213authorization (i.e., LOA) to the applicant and the authorization is included in the214application (Module 1 for an NDA or ANDA or in the appropriate section of an NADAor ANADA). The authorization must specifically identify the material being215216incorporated by reference (21 CFR 314.420 and 514.1(a)). The incorporated material217should be identified by name, reference number, volume and page number of the MF, anddate of submission. See 21 CFR 314.420, CDER’s guidance on Drug Master Files, and 218219CVM’s guidance on Preparation and Submission of Veterinary Master Files for moreinformation.220221222Both the applicant and the drug substance manufacturer (MF holder) contribute to223establishing and maintaining the identity, strength, quality, purity, and potency of the224applicant's drug products by manufacturing and controlling the drug substance in225accordance with the information submitted in the application and, by reference, in the MF. 226The following recommendations pertain to location of information in the MF and/or227application when an applicant and Type II MF holder are different firms.228229∙General Information (S.110): Both the MF and the application should include this 230information. These sections should contain similar, though not necessarily identical, 231information. For example, if an applicant performed screening studies and232established the existence of multiple polymorphs, information concerning these233polymorphs might be present in the application but not in the MF.234235∙Manufacture (S.2): The application should identify in S.2.1 the manufacturers of 236each drug substance with appropriate administrative information (see section IV.A). 237The MF should include this information for its manufacturing operations and any9 CVM discourages the reference of NDAs or ANDAs for drug substance information. In these instances, CVMrecommends that the drug substance information be included in a master file or incorporated in the applicant’sNADA or ANADA.10 Alphanumeric designations in parentheses that follow headings show where information should be placed inapplications that are submitted in Common Technical Document (CTD) format.238contract facilities that are used (e.g., intermediate manufacturers, laboratories). In239general, a MF can be referenced for the information recommended in S.2.2 through240S.2.6. However, the information should be augmented by the applicant, as241appropriate. For example, if the applicant micronizes drug substance purchased from242a MF holder the information on the micronization process should be included in the243application.244245∙Characterization (S.3): In general, a MF can be referenced for this information.However, the information should be augmented by the applicant, as appropriate. For 246247example, characterization information on physical properties critical to the applicant’s248product, such as solid state form or particle size distribution, should be included in249S.3.1 by the applicant under certain circumstances (e.g., applicant manipulates the250physical property (micronizes), the MF holder has not characterized the physical251property). Furthermore, information on an applicant’s studies to characterizeimpurities (S.3.2) can be warranted to support the applicant’s drug substance controls. 252253254∙Control of Drug Substance (S.4): In general, information recommended in S.4 should be provided in both the MF and the application. However, reference to an MF 255256can be appropriate for some of the information in S.4.2 through S.4.5 if the MF257holder and applicant are working together to develop the drug substance controls.Both the MF and the application should include a drug substance specification (S.4.1). 258259The MF could include more than one drug substance specification if the holder sellsdifferent technical grades of the drug substance (e.g., micronized and nonmicronized). 260261262∙Reference Standards (S.5): In general, information should be provided in both the 263MF and the application. However, reference to a MF can be appropriate for some of264the information if the MF holder and applicant are working together to develop the265reference standard.266267∙Container Closure System (S.6): In general, MFs can be referenced for this268information. However, the information should be augmented by the applicant, as269appropriate.270271∙Stability (S.7): In general, MFs can be referenced for this information. However, the information should be augmented by the applicant, as appropriate. For example, 272273an applicant might perform stress studies to support the analytical procedures it used274to control the drug substance.275276∙Appendices (A): In general, MFs can be referenced for this information. However, 277the information should be augmented by the applicant, as appropriate.278279∙Regional Information (R): Comparability protocols can be included in both the MF 280and application (R.2.S). A methods validation package should be included in theapplication (R.3.S).281282∙Literature References (3.3): Both the MF and the application should include283284literature references as warranted.285Type II MFs for drug substance intermediates can also be submitted in the CTD-Q format. 286287However, not all sections of the CTD-Q format would apply (e.g., S.4). The CMC288information provided to support an intermediate should be appropriate for the particularsituation (e.g., process, complexity of the molecule).289290291III. GENERAL INFORMATION (S.1)292293294General information on the nomenclature, structure, and general properties of the drug substance, should be provided in S.1.295296297A. Nomenclature (S.1.1)298299All appropriate names or designations for the drug substance should be provided in S.1.1. 300Any codes, abbreviations, or nicknames used in the application to identify the drug301substance should also be listed, including the following, if they exist or have been302proposed. A name that has not yet been finalized should be identified as proposed in the 303list.304305∙United States Adopted Name (USAN)∙Compendial name11306307∙Chemical names (e.g., Chemical Abstracts Service (CAS), International Union of 308Pure and Applied Chemistry (IUPAC))∙Company names or laboratory codes309310∙Other nonproprietary names (e.g., International Nonproprietary Name (INN),311British Approved Name (BAN), Japanese Accepted Name (JAN))312∙Chemical Abstracts Service (CAS) Registry Number313314B. Structure (S.1.2)315316Information on the chemical structure of the drug substance should be provided in S.1.2. 317This information should include:318319∙one or more drawings to show the overall chemical structure of the drug substance, 320including stereochemistry321∙molecular formula322∙molecular weight323324For a naturally derived protein drug substance, the information should include:11 A compendial name is a name that appears in an official compendium as defined in the Federal Food, Drug, andCosmetic Act (e.g., United States Pharmacopeia (USP)) (§ 201(j) (21 U.S.C. 32(i)).325326∙the schematic amino acid sequence indicating glycosylation sites or other327posttranslational modifications∙ a general description of the molecule (e.g., shape, disulfide bonds, subunit328329composition)330∙number of amino acid residues331∙molecular weight332333C. General Properties (S.1.3)334A list should be provided of the general physicochemical properties of the drug substance. 335336Other relevant properties of the drug substance should also be listed. Relevant properties 337are those physical, chemical, biological and microbiological attributes relating to theidentity, strength, quality, purity, and/or potency of the drug substance and, as338339appropriate, drug product. The information should include, as appropriate:340341∙ A general description (e.g., appearance, color, physical state)342∙Melting or boiling points343∙Optical rotation344∙Solubility profile (aqueous and nonaqueous, as applicable)345∙Solution pH346∙Partition coefficients347∙Dissociation constants348∙Identification of the physical form (e.g., polymorph, solvate, or hydrate) that will 349be used in the manufacture of the drug product350∙Biological activities351352For a naturally derived protein drug substance, additional information should be included, 353such as:354355∙Isoelectric point356∙Extinction coefficient357∙Any unique spectral characteristics358359If the drug substance can exist in more than one physical form, the information included 360in S.1.3 should be for the form (or forms) of the drug substance that will be used in the 361manufacture of the drug product. Detailed information on the characterization (e.g., X-362ray powder diffraction data, thermal analysis curves) of these and other physical forms 363and conditions required to produce one form or another should be provided in S.3.1.364。

交通流

交通流

Network impacts of a road capacity reduction:Empirical analysisand model predictionsDavid Watling a ,⇑,David Milne a ,Stephen Clark baInstitute for Transport Studies,University of Leeds,Woodhouse Lane,Leeds LS29JT,UK b Leeds City Council,Leonardo Building,2Rossington Street,Leeds LS28HD,UKa r t i c l e i n f o Article history:Received 24May 2010Received in revised form 15July 2011Accepted 7September 2011Keywords:Traffic assignment Network models Equilibrium Route choice Day-to-day variabilitya b s t r a c tIn spite of their widespread use in policy design and evaluation,relatively little evidencehas been reported on how well traffic equilibrium models predict real network impacts.Here we present what we believe to be the first paper that together analyses the explicitimpacts on observed route choice of an actual network intervention and compares thiswith the before-and-after predictions of a network equilibrium model.The analysis isbased on the findings of an empirical study of the travel time and route choice impactsof a road capacity reduction.Time-stamped,partial licence plates were recorded across aseries of locations,over a period of days both with and without the capacity reduction,and the data were ‘matched’between locations using special-purpose statistical methods.Hypothesis tests were used to identify statistically significant changes in travel times androute choice,between the periods of days with and without the capacity reduction.A trafficnetwork equilibrium model was then independently applied to the same scenarios,and itspredictions compared with the empirical findings.From a comparison of route choice pat-terns,a particularly influential spatial effect was revealed of the parameter specifying therelative values of distance and travel time assumed in the generalised cost equations.When this parameter was ‘fitted’to the data without the capacity reduction,the networkmodel broadly predicted the route choice impacts of the capacity reduction,but with othervalues it was seen to perform poorly.The paper concludes by discussing the wider practicaland research implications of the study’s findings.Ó2011Elsevier Ltd.All rights reserved.1.IntroductionIt is well known that altering the localised characteristics of a road network,such as a planned change in road capacity,will tend to have both direct and indirect effects.The direct effects are imparted on the road itself,in terms of how it can deal with a given demand flow entering the link,with an impact on travel times to traverse the link at a given demand flow level.The indirect effects arise due to drivers changing their travel decisions,such as choice of route,in response to the altered travel times.There are many practical circumstances in which it is desirable to forecast these direct and indirect impacts in the context of a systematic change in road capacity.For example,in the case of proposed road widening or junction improvements,there is typically a need to justify econom-ically the required investment in terms of the benefits that will likely accrue.There are also several examples in which it is relevant to examine the impacts of road capacity reduction .For example,if one proposes to reallocate road space between alternative modes,such as increased bus and cycle lane provision or a pedestrianisation scheme,then typically a range of alternative designs exist which may differ in their ability to accommodate efficiently the new traffic and routing patterns.0965-8564/$-see front matter Ó2011Elsevier Ltd.All rights reserved.doi:10.1016/j.tra.2011.09.010⇑Corresponding author.Tel.:+441133436612;fax:+441133435334.E-mail address:d.p.watling@ (D.Watling).168 D.Watling et al./Transportation Research Part A46(2012)167–189Through mathematical modelling,the alternative designs may be tested in a simulated environment and the most efficient selected for implementation.Even after a particular design is selected,mathematical models may be used to adjust signal timings to optimise the use of the transport system.Road capacity may also be affected periodically by maintenance to essential services(e.g.water,electricity)or to the road itself,and often this can lead to restricted access over a period of days and weeks.In such cases,planning authorities may use modelling to devise suitable diversionary advice for drivers,and to plan any temporary changes to traffic signals or priorities.Berdica(2002)and Taylor et al.(2006)suggest more of a pro-ac-tive approach,proposing that models should be used to test networks for potential vulnerability,before any reduction mate-rialises,identifying links which if reduced in capacity over an extended period1would have a substantial impact on system performance.There are therefore practical requirements for a suitable network model of travel time and route choice impacts of capac-ity changes.The dominant method that has emerged for this purpose over the last decades is clearly the network equilibrium approach,as proposed by Beckmann et al.(1956)and developed in several directions since.The basis of using this approach is the proposition of what are believed to be‘rational’models of behaviour and other system components(e.g.link perfor-mance functions),with site-specific data used to tailor such models to particular case studies.Cross-sectional forecasts of network performance at specific road capacity states may then be made,such that at the time of any‘snapshot’forecast, drivers’route choices are in some kind of individually-optimum state.In this state,drivers cannot improve their route selec-tion by a unilateral change of route,at the snapshot travel time levels.The accepted practice is to‘validate’such models on a case-by-case basis,by ensuring that the model—when supplied with a particular set of parameters,input network data and input origin–destination demand data—reproduces current mea-sured mean link trafficflows and mean journey times,on a sample of links,to some degree of accuracy(see for example,the practical guidelines in TMIP(1997)and Highways Agency(2002)).This kind of aggregate level,cross-sectional validation to existing conditions persists across a range of network modelling paradigms,ranging from static and dynamic equilibrium (Florian and Nguyen,1976;Leonard and Tough,1979;Stephenson and Teply,1984;Matzoros et al.,1987;Janson et al., 1986;Janson,1991)to micro-simulation approaches(Laird et al.,1999;Ben-Akiva et al.,2000;Keenan,2005).While such an approach is plausible,it leaves many questions unanswered,and we would particularly highlight two: 1.The process of calibration and validation of a network equilibrium model may typically occur in a cycle.That is to say,having initially calibrated a model using the base data sources,if the subsequent validation reveals substantial discrep-ancies in some part of the network,it is then natural to adjust the model parameters(including perhaps even the OD matrix elements)until the model outputs better reflect the validation data.2In this process,then,we allow the adjustment of potentially a large number of network parameters and input data in order to replicate the validation data,yet these data themselves are highly aggregate,existing only at the link level.To be clear here,we are talking about a level of coarseness even greater than that in aggregate choice models,since we cannot even infer from link-level data the aggregate shares on alternative routes or OD movements.The question that arises is then:how many different combinations of parameters and input data values might lead to a similar link-level validation,and even if we knew the answer to this question,how might we choose between these alternative combinations?In practice,this issue is typically neglected,meaning that the‘valida-tion’is a rather weak test of the model.2.Since the data are cross-sectional in time(i.e.the aim is to reproduce current base conditions in equilibrium),then in spiteof the large efforts required in data collection,no empirical evidence is routinely collected regarding the model’s main purpose,namely its ability to predict changes in behaviour and network performance under changes to the network/ demand.This issue is exacerbated by the aggregation concerns in point1:the‘ambiguity’in choosing appropriate param-eter values to satisfy the aggregate,link-level,base validation strengthens the need to independently verify that,with the selected parameter values,the model responds reliably to changes.Although such problems–offitting equilibrium models to cross-sectional data–have long been recognised by practitioners and academics(see,e.g.,Goodwin,1998), the approach described above remains the state-of-practice.Having identified these two problems,how might we go about addressing them?One approach to thefirst problem would be to return to the underlying formulation of the network model,and instead require a model definition that permits analysis by statistical inference techniques(see for example,Nakayama et al.,2009).In this way,we may potentially exploit more information in the variability of the link-level data,with well-defined notions(such as maximum likelihood)allowing a systematic basis for selection between alternative parameter value combinations.However,this approach is still using rather limited data and it is natural not just to question the model but also the data that we use to calibrate and validate it.Yet this is not altogether straightforward to resolve.As Mahmassani and Jou(2000) remarked:‘A major difficulty...is obtaining observations of actual trip-maker behaviour,at the desired level of richness, simultaneously with measurements of prevailing conditions’.For this reason,several authors have turned to simulated gaming environments and/or stated preference techniques to elicit information on drivers’route choice behaviour(e.g. 1Clearly,more sporadic and less predictable reductions in capacity may also occur,such as in the case of breakdowns and accidents,and environmental factors such as severe weather,floods or landslides(see for example,Iida,1999),but the responses to such cases are outside the scope of the present paper. 2Some authors have suggested more systematic,bi-level type optimization processes for thisfitting process(e.g.Xu et al.,2004),but this has no material effect on the essential points above.D.Watling et al./Transportation Research Part A46(2012)167–189169 Mahmassani and Herman,1990;Iida et al.,1992;Khattak et al.,1993;Vaughn et al.,1995;Wardman et al.,1997;Jou,2001; Chen et al.,2001).This provides potentially rich information for calibrating complex behavioural models,but has the obvious limitation that it is based on imagined rather than real route choice situations.Aside from its common focus on hypothetical decision situations,this latter body of work also signifies a subtle change of emphasis in the treatment of the overall network calibration problem.Rather than viewing the network equilibrium calibra-tion process as a whole,the focus is on particular components of the model;in the cases above,the focus is on that compo-nent concerned with how drivers make route decisions.If we are prepared to make such a component-wise analysis,then certainly there exists abundant empirical evidence in the literature,with a history across a number of decades of research into issues such as the factors affecting drivers’route choice(e.g.Wachs,1967;Huchingson et al.,1977;Abu-Eisheh and Mannering,1987;Duffell and Kalombaris,1988;Antonisse et al.,1989;Bekhor et al.,2002;Liu et al.,2004),the nature of travel time variability(e.g.Smeed and Jeffcoate,1971;Montgomery and May,1987;May et al.,1989;McLeod et al., 1993),and the factors affecting trafficflow variability(Bonsall et al.,1984;Huff and Hanson,1986;Ribeiro,1994;Rakha and Van Aerde,1995;Fox et al.,1998).While these works provide useful evidence for the network equilibrium calibration problem,they do not provide a frame-work in which we can judge the overall‘fit’of a particular network model in the light of uncertainty,ambient variation and systematic changes in network attributes,be they related to the OD demand,the route choice process,travel times or the network data.Moreover,such data does nothing to address the second point made above,namely the question of how to validate the model forecasts under systematic changes to its inputs.The studies of Mannering et al.(1994)and Emmerink et al.(1996)are distinctive in this context in that they address some of the empirical concerns expressed in the context of travel information impacts,but their work stops at the stage of the empirical analysis,without a link being made to net-work prediction models.The focus of the present paper therefore is both to present thefindings of an empirical study and to link this empirical evidence to network forecasting models.More recently,Zhu et al.(2010)analysed several sources of data for evidence of the traffic and behavioural impacts of the I-35W bridge collapse in Minneapolis.Most pertinent to the present paper is their location-specific analysis of linkflows at 24locations;by computing the root mean square difference inflows between successive weeks,and comparing the trend for 2006with that for2007(the latter with the bridge collapse),they observed an apparent transient impact of the bridge col-lapse.They also showed there was no statistically-significant evidence of a difference in the pattern offlows in the period September–November2007(a period starting6weeks after the bridge collapse),when compared with the corresponding period in2006.They suggested that this was indicative of the length of a‘re-equilibration process’in a conceptual sense, though did not explicitly compare their empiricalfindings with those of a network equilibrium model.The structure of the remainder of the paper is as follows.In Section2we describe the process of selecting the real-life problem to analyse,together with the details and rationale behind the survey design.Following this,Section3describes the statistical techniques used to extract information on travel times and routing patterns from the survey data.Statistical inference is then considered in Section4,with the aim of detecting statistically significant explanatory factors.In Section5 comparisons are made between the observed network data and those predicted by a network equilibrium model.Finally,in Section6the conclusions of the study are highlighted,and recommendations made for both practice and future research.2.Experimental designThe ultimate objective of the study was to compare actual data with the output of a traffic network equilibrium model, specifically in terms of how well the equilibrium model was able to correctly forecast the impact of a systematic change ap-plied to the network.While a wealth of surveillance data on linkflows and travel times is routinely collected by many local and national agencies,we did not believe that such data would be sufficiently informative for our purposes.The reason is that while such data can often be disaggregated down to small time step resolutions,the data remains aggregate in terms of what it informs about driver response,since it does not provide the opportunity to explicitly trace vehicles(even in aggre-gate form)across more than one location.This has the effect that observed differences in linkflows might be attributed to many potential causes:it is especially difficult to separate out,say,ambient daily variation in the trip demand matrix from systematic changes in route choice,since both may give rise to similar impacts on observed linkflow patterns across re-corded sites.While methods do exist for reconstructing OD and network route patterns from observed link data(e.g.Yang et al.,1994),these are typically based on the premise of a valid network equilibrium model:in this case then,the data would not be able to give independent information on the validity of the network equilibrium approach.For these reasons it was decided to design and implement a purpose-built survey.However,it would not be efficient to extensively monitor a network in order to wait for something to happen,and therefore we required advance notification of some planned intervention.For this reason we chose to study the impact of urban maintenance work affecting the roads,which UK local government authorities organise on an annual basis as part of their‘Local Transport Plan’.The city council of York,a historic city in the north of England,agreed to inform us of their plans and to assist in the subsequent data collection exercise.Based on the interventions planned by York CC,the list of candidate studies was narrowed by considering factors such as its propensity to induce significant re-routing and its impact on the peak periods.Effectively the motivation here was to identify interventions that were likely to have a large impact on delays,since route choice impacts would then likely be more significant and more easily distinguished from ambient variability.This was notably at odds with the objectives of York CC,170 D.Watling et al./Transportation Research Part A46(2012)167–189in that they wished to minimise disruption,and so where possible York CC planned interventions to take place at times of day and of the year where impacts were minimised;therefore our own requirement greatly reduced the candidate set of studies to monitor.A further consideration in study selection was its timing in the year for scheduling before/after surveys so to avoid confounding effects of known significant‘seasonal’demand changes,e.g.the impact of the change between school semesters and holidays.A further consideration was York’s role as a major tourist attraction,which is also known to have a seasonal trend.However,the impact on car traffic is relatively small due to the strong promotion of public trans-port and restrictions on car travel and parking in the historic centre.We felt that we further mitigated such impacts by sub-sequently choosing to survey in the morning peak,at a time before most tourist attractions are open.Aside from the question of which intervention to survey was the issue of what data to collect.Within the resources of the project,we considered several options.We rejected stated preference survey methods as,although they provide a link to personal/socio-economic drivers,we wanted to compare actual behaviour with a network model;if the stated preference data conflicted with the network model,it would not be clear which we should question most.For revealed preference data, options considered included(i)self-completion diaries(Mahmassani and Jou,2000),(ii)automatic tracking through GPS(Jan et al.,2000;Quiroga et al.,2000;Taylor et al.,2000),and(iii)licence plate surveys(Schaefer,1988).Regarding self-comple-tion surveys,from our own interview experiments with self-completion questionnaires it was evident that travellersfind it relatively difficult to recall and describe complex choice options such as a route through an urban network,giving the po-tential for significant errors to be introduced.The automatic tracking option was believed to be the most attractive in this respect,in its potential to accurately map a given individual’s journey,but the negative side would be the potential sample size,as we would need to purchase/hire and distribute the devices;even with a large budget,it is not straightforward to identify in advance the target users,nor to guarantee their cooperation.Licence plate surveys,it was believed,offered the potential for compromise between sample size and data resolution: while we could not track routes to the same resolution as GPS,by judicious location of surveyors we had the opportunity to track vehicles across more than one location,thus providing route-like information.With time-stamped licence plates, the matched data would also provide journey time information.The negative side of this approach is the well-known poten-tial for significant recording errors if large sample rates are required.Our aim was to avoid this by recording only partial licence plates,and employing statistical methods to remove the impact of‘spurious matches’,i.e.where two different vehi-cles with the same partial licence plate occur at different locations.Moreover,extensive simulation experiments(Watling,1994)had previously shown that these latter statistical methods were effective in recovering the underlying movements and travel times,even if only a relatively small part of the licence plate were recorded,in spite of giving a large potential for spurious matching.We believed that such an approach reduced the opportunity for recorder error to such a level to suggest that a100%sample rate of vehicles passing may be feasible.This was tested in a pilot study conducted by the project team,with dictaphones used to record a100%sample of time-stamped, partial licence plates.Independent,duplicate observers were employed at the same location to compare error rates;the same study was also conducted with full licence plates.The study indicated that100%surveys with dictaphones would be feasible in moderate trafficflow,but only if partial licence plate data were used in order to control observation errors; for higherflow rates or to obtain full number plate data,video surveys should be considered.Other important practical les-sons learned from the pilot included the need for clarity in terms of vehicle types to survey(e.g.whether to include motor-cycles and taxis),and of the phonetic alphabet used by surveyors to avoid transcription ambiguities.Based on the twin considerations above of planned interventions and survey approach,several candidate studies were identified.For a candidate study,detailed design issues involved identifying:likely affected movements and alternative routes(using local knowledge of York CC,together with an existing network model of the city),in order to determine the number and location of survey sites;feasible viewpoints,based on site visits;the timing of surveys,e.g.visibility issues in the dark,winter evening peak period;the peak duration from automatic trafficflow data;and specific survey days,in view of public/school holidays.Our budget led us to survey the majority of licence plate sites manually(partial plates by audio-tape or,in lowflows,pen and paper),with video surveys limited to a small number of high-flow sites.From this combination of techniques,100%sampling rate was feasible at each site.Surveys took place in the morning peak due both to visibility considerations and to minimise conflicts with tourist/special event traffic.From automatic traffic count data it was decided to survey the period7:45–9:15as the main morning peak period.This design process led to the identification of two studies:2.1.Lendal Bridge study(Fig.1)Lendal Bridge,a critical part of York’s inner ring road,was scheduled to be closed for maintenance from September2000 for a duration of several weeks.To avoid school holidays,the‘before’surveys were scheduled for June and early September.It was decided to focus on investigating a significant southwest-to-northeast movement of traffic,the river providing a natural barrier which suggested surveying the six river crossing points(C,J,H,K,L,M in Fig.1).In total,13locations were identified for survey,in an attempt to capture traffic on both sides of the river as well as a crossing.2.2.Fishergate study(Fig.2)The partial closure(capacity reduction)of the street known as Fishergate,again part of York’s inner ring road,was scheduled for July2001to allow repairs to a collapsed sewer.Survey locations were chosen in order to intercept clockwiseFig.1.Intervention and survey locations for Lendal Bridge study.around the inner ring road,this being the direction of the partial closure.A particular aim wasFulford Road(site E in Fig.2),the main radial affected,with F and K monitoring local diversion I,J to capture wider-area diversion.studies,the plan was to survey the selected locations in the morning peak over a period of approximately covering the three periods before,during and after the intervention,with the days selected so holidays or special events.Fig.2.Intervention and survey locations for Fishergate study.In the Lendal Bridge study,while the‘before’surveys proceeded as planned,the bridge’s actualfirst day of closure on Sep-tember11th2000also marked the beginning of the UK fuel protests(BBC,2000a;Lyons and Chaterjee,2002).Trafficflows were considerably affected by the scarcity of fuel,with congestion extremely low in thefirst week of closure,to the extent that any changes could not be attributed to the bridge closure;neither had our design anticipated how to survey the impacts of the fuel shortages.We thus re-arranged our surveys to monitor more closely the planned re-opening of the bridge.Unfor-tunately these surveys were hampered by a second unanticipated event,namely the wettest autumn in the UK for270years and the highest level offlooding in York since records began(BBC,2000b).Theflooding closed much of the centre of York to road traffic,including our study area,as the roads were impassable,and therefore we abandoned the planned‘after’surveys. As a result of these events,the useable data we had(not affected by the fuel protests orflooding)consisted offive‘before’days and one‘during’day.In the Fishergate study,fortunately no extreme events occurred,allowing six‘before’and seven‘during’days to be sur-veyed,together with one additional day in the‘during’period when the works were temporarily removed.However,the works over-ran into the long summer school holidays,when it is well-known that there is a substantial seasonal effect of much lowerflows and congestion levels.We did not believe it possible to meaningfully isolate the impact of the link fully re-opening while controlling for such an effect,and so our plans for‘after re-opening’surveys were abandoned.3.Estimation of vehicle movements and travel timesThe data resulting from the surveys described in Section2is in the form of(for each day and each study)a set of time-stamped,partial licence plates,observed at a number of locations across the network.Since the data include only partial plates,they cannot simply be matched across observation points to yield reliable estimates of vehicle movements,since there is ambiguity in whether the same partial plate observed at different locations was truly caused by the same vehicle. Indeed,since the observed system is‘open’—in the sense that not all points of entry,exit,generation and attraction are mon-itored—the question is not just which of several potential matches to accept,but also whether there is any match at all.That is to say,an apparent match between data at two observation points could be caused by two separate vehicles that passed no other observation point.Thefirst stage of analysis therefore applied a series of specially-designed statistical techniques to reconstruct the vehicle movements and point-to-point travel time distributions from the observed data,allowing for all such ambiguities in the data.Although the detailed derivations of each method are not given here,since they may be found in the references provided,it is necessary to understand some of the characteristics of each method in order to interpret the results subsequently provided.Furthermore,since some of the basic techniques required modification relative to the published descriptions,then in order to explain these adaptations it is necessary to understand some of the theoretical basis.3.1.Graphical method for estimating point-to-point travel time distributionsThe preliminary technique applied to each data set was the graphical method described in Watling and Maher(1988).This method is derived for analysing partial registration plate data for unidirectional movement between a pair of observation stations(referred to as an‘origin’and a‘destination’).Thus in the data study here,it must be independently applied to given pairs of observation stations,without regard for the interdependencies between observation station pairs.On the other hand, it makes no assumption that the system is‘closed’;there may be vehicles that pass the origin that do not pass the destina-tion,and vice versa.While limited in considering only two-point surveys,the attraction of the graphical technique is that it is a non-parametric method,with no assumptions made about the arrival time distributions at the observation points(they may be non-uniform in particular),and no assumptions made about the journey time probability density.It is therefore very suitable as afirst means of investigative analysis for such data.The method begins by forming all pairs of possible matches in the data,of which some will be genuine matches(the pair of observations were due to a single vehicle)and the remainder spurious matches.Thus, for example,if there are three origin observations and two destination observations of a particular partial registration num-ber,then six possible matches may be formed,of which clearly no more than two can be genuine(and possibly only one or zero are genuine).A scatter plot may then be drawn for each possible match of the observation time at the origin versus that at the destination.The characteristic pattern of such a plot is as that shown in Fig.4a,with a dense‘line’of points(which will primarily be the genuine matches)superimposed upon a scatter of points over the whole region(which will primarily be the spurious matches).If we were to assume uniform arrival rates at the observation stations,then the spurious matches would be uniformly distributed over this plot;however,we shall avoid making such a restrictive assumption.The method begins by making a coarse estimate of the total number of genuine matches across the whole of this plot.As part of this analysis we then assume knowledge of,for any randomly selected vehicle,the probabilities:h k¼Prðvehicle is of the k th type of partial registration plateÞðk¼1;2;...;mÞwhereX m k¼1h k¼1172 D.Watling et al./Transportation Research Part A46(2012)167–189。

addtive经典

addtive经典

OPTIMAL CONTROL APPLICATIONS AND METHODSOptim.Control Appl.Meth.(2013)Published online in Wiley Online Library().DOI:10.1002/oca.2060Stability criteria for continuous-time systems with additivetime-varying delaysXun-Lin Zhu1,*,†,Youyi Wang2and Xin Du31Department of Mathematics,Zhengzhou University,Zhengzhou450001,China2School of Electrical and Electronic Engineering,Nanyang Technological University,Singapore639798,Singapore 3School of Mechatronic Engineering and Automation,Shanghai University,Shanghai200072,ChinaSUMMARYThis paper studies the problem of stability analysis for continuous-time systems with two additive time-varying delay components.By taking the independence and the variation of the additive delay components into consideration,more general type of Lyapunov functionals are defined.Together with a tighter estimation of the upper bound of the cross-product terms derived from the derivatives of the Lyapunov functionals, less conservative delay-dependent stability criteria are established in terms of bining with a reciprocally convex combination technique,the newly obtained stability conditions are also less complex. Two numerical examples are given to illustrate the effectiveness and the significant improvement of the proposed method.Copyright©2013John Wiley&Sons,Ltd.Received24June2012;Revised6October2012;Accepted31October2012KEY WORDS:additive time-varying delays;delay-dependent stability;Lyapunov functional;LMIs1.INTRODUCTIONTime delay is a common phenomenon in many industrial systems.The practical examples of time delay systems include engineering,communications,and biological systems[1,2].The existence of delay in a practical system may induce instability,oscillation,and poor performance.During the last two decades,the stability problem of linear continuous-time systems with time delay has received considerable attention[3–11].The stability criteria for time-delayed systems can be classified into two categories,namely,delay independent and delay dependent.As we know delay-dependent results are looser than the delay-independent ones when the delays are small.So a great number of delay-dependent stability results have been reported in the literature;see,for example,[3–5]and the references therein.Recently,a new model of system with two additive time-varying delay components was proposed in[7].This model has a strong application background in remote control and networked control. Take a state-feedback networked control for example.Because the physical plant,controller,sensor, and actuator are located at different places,signals are transmitted from one device to another.Thus, time delays happen.Among those delays,there are two network-induced ones:one from sensor to controller and the other from controller to actuator.With the two delays considered,the closed-loop system will have two additive time delays in the state.Because of the network transmission conditions,the two delays are generally time varying with different properties;it is not reasonable to combine them together.Therefore,it is of significance to consider stability for systems with two additive time-varying delay components.*Correspondence to:Xun-Lin Zhu,Department of Mathematics,Zhengzhou University,Zhengzhou450001,China.†E-mail:hntjxx@X-L.ZHU,Y.W ANG AND X.DUIn[7],stability study was conducted,and a delay-dependent stability criterion was obtained;it was further improved in[8],where a marginally delayed state was exploited to construct Lyapunov functional and more free weighting matrices were introduced to estimate the upper bound of the derivative of the Lyapunov functional.A similar analysis method was also applied to neural networks[12],and it was improved in[13]by remaining some integral terms.Recently,a less con-servative result for stability analysis of continuous-time systems with additive delays was reported in[11].However,because an incorrect inequality was used,the main result given in[11]may con-tain errors.It is worth pointing out that the information of the additive delays are not suitably taken into account in the aforementioned works and the introducing of many slack variables inevitably increases the computational burden,which motivates the study of this paper.In this paper,the problem of stability analysis for continuous-time systems with two additive time-varying delay components is investigated.By considering the independence and the variation of two additive time-varying delay components,new Lyapunov functionals are -bining with a tighter estimation of the derivative of the Lyapunov functionals and a reciprocally convex combination technique[6],new delay-dependent stability criteria with less conservatism and less complexity are derived in terms of LMIs.Numerical examples are also given to show the effectiveness and the significant improvement of the proposed method.Notation:Throughout this paper,a real symmetric matrix P>0.>0/denotes P being a positive definite(positive semidefinite)matrix,and A>B.A>B/means A B>0.>0/.I is used to denote an identity matrix with proper dimension.Matrices,if not explicitly stated,are assumed to have compatible dimensions.The symmetric terms in a symmetric matrix are denoted by .2.PROBLEM FORMULATIONConsider a time delay system with two additive time-varying delays as follows[7,8]:P x.t/D Ax.t/C Bx.t d1.t/ d2.t//,(1) where x.t/2R n is the state vector and A and B are constant matrices.The time delays d1.t/and d2.t/are time-varying differentiable functions that satisfy06d1.t/6d1,06d2.t/6d2,(2) andP d.t/6 1,P d2.t/6 2,(3)1where d1,d2and 1, 2are constants.Naturally,we denoted.t/D d1.t/C d2.t/,(4)d D d1C d2,(5)D 1C 2.(6) Obviously,system(1)belongs to a special class of systems with single delay:P x.t/D Ax.t/C Bx.t .t//,(7) where .t/satisfies06 .t/6d and P .t/6 .For system(1)with additive time-varying delay components,the works in[7,8]provided the results of stability analysis,respectively.Recently,a less conservative result was reported in[11], which improved the stability criteria given in[7,8,11].However,because an incorrect inequality was used,the main result given in[11]may contain errors,which motivates the study.In addition, with the introducing of many slack variables,the computational burden is inevitably increased.In this paper,less conservative and less complex stability criteria for system(1)with additive time-varying delay components satisfying conditions(2)and(3)will be proposed,which can improve the existing ones significantly.Through this paper,the following lemmas will be used.CONTINUOUS-TIME SYSTEMS WITH ADDITIVE TIME-V ARYING DELAYSLemma1([3])For any positive symmetric constant matrix M2R n n and scalars r1and r2satisfying r1<r2,a vector function!WŒr1,r2 !R n such that the integrations concerned are well defined,thenÂZ r2r1!.s/d sÃTMÂZ r2r1!.s/d sÃ6.r2 r1/Z r2r1!T.s/M!.s/d s.(8)Lemma2For any positive symmetric constant matrix Z2R n n and scalars r i.i D1,2,3,4/and r satisfying r>0,06r2 r16r,and r4D r .r2 r1/C r3,there exists a vector function!such that the integrations concerned are well defined,then the following inequality is trueZ r2 r1!T.s/Z!.s/d s CZ r4r3!T.s/Z!.s/d s>1r24R r2r1!.s/d sR r4r3!.s/d s35TÄZ TZ24R r2r1!.s/d sR r4r3!.s/d s35,(9)if there exists a matrix T such thatÄZ TZ>0.(10)ProofFrom(10),it is easy to seeÄZ TZ>0.For the case of0<r2 r1<r,it is easy to see that0<r4 r3<r.From Lemma1,we haveZ r2 r1!T.s/Z!.s/d s CZ r4r3!T.s/Z!.s/d s>1r2 r1'T1Z'1C1r .r2 r1/'T2Z'2D 1rÂ1Cr .r2 r1/r2 r1Ã'T1Z'1 C1rÂ1Cr2 r1r .r2 r1/Ã'T2Z'2D 1r'T1Z'1C1r'T2Z'2C1r'T1T'2C1r'T2T T'1C1r264qr .r2 r1/r2 r1'1qr2 r1r .r2 r1/'2375TÄZ TZ264qr .r2 r1/r2 r1'1qr2 r1r .r2 r1/'2375>1r'T1Z'1C1r'T2Z'2C1r'T1T'2C1r'T2T T'1,where'1DZ r2r1!.s/d s,'2DZ r4r3!.s/d s. So inequality(9)holds if0<r2 r1<r.X-L.ZHU,Y .W ANG AND X.DUFor the case of r 2D r 1,it follows that r 4D r C r 3and '1D 0.From Lemma 1,it is easy to see that inequality (9)holds.Similarly,inequality (9)also holds for r 2 r 1D r .Thus,the result is established.3.MAIN RESULTS3.1.New stability criterionFirst,a Lyapunov functional is constructed as follows:V.x t /D V 1.x t /C V 2.x t /C V 3.x t /,(11)whereV 1.x t /D x T.t/P x.t/CZt t d.t/x T .s/Q 1x.s/d sCZt t d 1.t/x T.s/Q 2x.s/d s C Ztt d 1x T .s/Q 3x.s/d s ,V 2.x t /D Z t d 1t dx T .s/Q 4x.s/d s ,V 3.x t /DZ 0 d 1Ztt C ÂP x T.s/R 1P x.s/d s d ÂC Zd 1 dZt t C ÂP x T .s/R 2P x.s/d s d ÂCZ0 dZ tt C ÂP x T .s/R 3P x.s/d s d Â,and P D P T >0,Q i D Q T i>0.i D 1,2,3,4/,and R j D R T j >0.j D 1,2,3/are to be determined.Now,we give a new stability criterion for the origin of systems (1)–(3)with d 1>0and d 2>0as follows.Theorem 1For given scalars d 1>0,d 2>0and 1, 2,the origin of system (1)with two additive time-varying delay components satisfying conditions (2)and (3)is globally asymptotically stable if there existmatrices P D P T >0,Q i D Q T i >0.i D 1,2,3,4/,R j D R Tj >0.j D 1,2,3/,and T i .i D 1,2,3/,such thatˆ<0,(12)ÄR i T iR i>0,.i D 1,2,3/(13)whereˆD 2666666666664ˆ11ˆ12ˆ131d 1T 11d 1T 30ˆ221d 1T T 3C 1d 2R 31d 1R 3C1d 2T T 3 1d 2T T3 ˆ331d 1.R 1 T 1/ 1d 1T 3 1d 2T T 31d 2T T 3 ˆ441d 2.R 2 T 2/1d 2T 2ˆ55ˆ56ˆ663777777777775,CONTINUOUS-TIME SYSTEMS WITH ADDITIVE TIME-V ARYING DELAYSˆ11D PA C A T P C Q1C Q2C Q3 1d1.R1C R3/C A T.d1R1C d2R2C dR3/A,ˆ12D PB 1d1T3C A T.d1R1C d2R2C dR3/B,ˆ13D 1d1.R1C R3/1d1T1,ˆ22D .1 /Q1 1d1R31d2R3C B T.d1R1C d2R2C dR3/B,ˆ33D .1 1/Q2 2d1R1C1d1T1C T T11d1R31d2R3,ˆ44D Q3C Q4 1d1R11d2R2,ˆ55D 2d2R21d1R31d2R3C1d2T2C T T2,ˆ56D 1d2.R2C R3 T2/,ˆ66D Q4 1d2.R2C R3/.ProofDenoteÁ.t/D col¹x.t/,x.t d.t//,x.t d1.t//,x.t d1/,x.t d1 d2.t//,x.t d/º,1.t/D x.t/ x.t d1.t//,2.t/D x.t d1.t// x.t d1/,3.t/D x.t d1/ x.t d1 d2.t//,4.t/D x.t d1 d2.t// x.t d/,5.t/D x.t d.t// x.t d1 d2.t//,6.t/D x.t d1.t// x.t d.t//.Taking the time derivative of V i.x t/.i D1,2,3/along the trajectory of(1)yields that P V1.x t/D2x T.t/PŒAx.t/C Bx.t d.t// C x T.t/.Q1C Q2C Q3/x.t/.1 P d.t//x T.t d.t//Q1x.t d.t//.1 P d1.t//x T.t d1.t//Q2x.t d1.t//x T.t d1/Q3x.t d1/6x T.t/.PA C A T P/x.t/C x T.t/PBx.t d.t//C x T.t d.t//B T P x.t/C x T.t/.Q1C Q2C Q3/x.t/.1 /x T.t d.t//Q1x.t d.t//.1 1/x T.t d1.t//Q2x.t d1.t//x T.t d1/Q3x.t d1/,(14)P V2.x t/D x T.t d1/Q4x.t d1/ x T.t d/Q4x.t d/,(15)P V 3.x t/D P x T.t/d1R1C d2R2C dR3ÁP x.t/Z tt d1P x T.s/R1P x.s/d sZ t d1t dP x T.s/R2P x.s/d sZ tt dP x T.s/R3P x.s/d s.(16)Now,we estimate the upper bounds of the last three terms on the right side of equality(16).X-L.ZHU,Y .W ANG AND X.DUNote thatZ t t d 1P x T .s/R 1P x.s/d s DZ t t d 1.t/P x T.s/R 1P x.s/d sZt d 1.t/t d 1P x T .s/R 1P x.s/d s ,Zt d 1t d P x T.s/R 2P x.s/d s D Zt d 1t d 1 d 2.t/P x T.s/R 2P x.s/d sZt d 1 d 2.t/t dP x T .s/R 2P x.s/d s ,andZtt d P x T.s/R 3P x.s/d s DZ t t d 1.t/P x T.s/R 3P x.s/d sZt d.t/t d 1 d 2.t/P x T .s/R 3P x.s/d sZt d 1 d 2.t/t dP x T.s/R 3P x.s/d sZt d 1.t/t d.t/P x T .s/R 3P x.s/d s .From Lemma 2and (13),we haveP V 3.x t /6ÁT .t/A T d 1R 1C d 2R 2C dR 3ÁA Á.t/1d 1Ä 1.t/ 2.t/T ÄR 1T 1 R 1 Ä1.t/2.t/1d 2Ä 3.t/ 4.t/T ÄR 2T 2 R 2 Ä 3.t/ 4.t/1d 1Ä 1.t/ 5.t/T ÄR 3T 3 R 3 Ä 1.t/ 5.t/1d 2Ä 4.t/ 6.t/T ÄR 3T 3 R 3 Ä4.t/ 6.t/,(17)whereA DA B0000.So combining (14)and (15)with (17)yieldsP V.xt /6ÁT .t/ˆÁ.t/,(18)which shows that system (1)is globally asymptotically stable if ˆ<0.This ends the proof.Remark 1In Theorem 1,a sufficient condition of globally asymptotical stability for the origin of system (1)with two successive time-varying delays satisfying conditions (2)and (3)is given in terms ofLMIs.Different from [13],the term R t d 1t d P x T.s/R 2P x.s/d s is decomposed as the sum of twocross-product terms,whereas the term R tt d P x T.s/R 3P x.s/d s is decomposed as the sum of four cross-product terms.With an appropriate assembly,the reciprocally convex combination technique[6]can be applied,then the upper bound of P V3.x t /is estimated more tightly,and the conservatism of the obtained stability criterion is reduced.Meanwhile,fewer variables are involved in Theorem 1,and the computational complexity is also reduced.Table I provides a comparison of the number of the variables involved in Theorem 1and in some existing results.Remark 2It is worth pointing out that an inequalityZ t d 1t dP x T .s/R 3P x.s/d s 6Z t d 1.t/t d.t/P x T .s/R 3P x.s/d s(19)CONTINUOUS-TIME SYSTEMS WITH ADDITIVE TIME-V ARYING DELAYSTable parison of the numbers of the variables involved.Methods Number of variables involvedTheorem 1in [11]19.5n 2C 3.5n Theorem 1in [8]36.5n 2C 8.5n Theorem 1in [7]12.5n 2C 4.5n Theorem 17n 2C 4nis used to estimate the upper bound of P V3in [11].However,this inequality is not always true.A counterexample,which shows that the main result given in [11]may be incorrect is given as follows.Example 1Consider the delayed systemP x.t/D 2x.t/C 1.9x.t d 1.t/ d 2.t//,(20)where d 1.t/D 1C sin t 2and d 2.t/Á0.5.It is easy to see that d 1D 2and d D 2.5.For the initial value x.0/D 0.5,the curve of state response with fixed sampling step 0.001s is depicted in Figure 1,which shows that the system is asymptotically stable.The corresponding response of jj P x.t/jj 2for t 2Œ1,3.5 is depicted in Figure 2.Obviously,if we select t D 4,then inequality (19)does not hold for system (20).When d 1D 0or d 2D 0,system (1)reduces to system (7)with single delay.Without loss of generality,suppose that d 2D 0.By letting Q 2D Q 4D 0and R 2D R 3D 0in Lyapunov functional (11),along a similar line as in the derivation of Theorem 1,a stability criterion for delayed system (7)can be derived as follows.Corollary 1For given scalars d >0and ,the origin of delayed system (7)is globally asymptotically stableif there exist matrices P D P T >0,Q i D Q T i >0.i D 1,3/,R 1D R T1>0,and a matrix T 1,such that<0,(21)ÄR 1T 1R 1>0,(22)2040608010012014016000.050.10.150.20.250.30.350.40.450.5Time(s)R e s p o n s e o f x (t )Figure 1.State response of system (20).X-L.ZHU,Y .W ANG AND X.DU11.522.533.500.10.20.30.40.50.60.70.80.9Time(s)Figure 2.Response of jj P x.t/jj 2for t 2Œ1,3.5 .whereD 264 11PB C 1.R 1 T 1/C dA T R 1B1T 1221d.R 1 T 1/Q 3 1d R 1375, 11D PA C A T P C Q 1C Q 31dR 1C dA T R 1A , 22D .1 /Q 1 1d 2R 1 T 1 T T1 C dB T R 1B .3.2.Further improvementIn (11),the relationship of the upper bounds d 1and d 2of two additive delay components is not taken into consideration.To make up this deficiency,a new type of Lyapunov functionals can be defined asQ V.xt /D V 1.x t /C Q V 2.x t /C Q V 3.x t /C Q V 4.x t /,(23)where V 1.x t /is defined in (11)and Q V2.x t /D Z t t d 2x T .s/Q 4x.s/d s C Zt d 2t d 2 d 1.t/x T .s/Q 5x.s/d sCZt d 2t dx T .s/Q 6x.s/d s ,Q V3.x t /D Zd 1Ztt C ÂP x T.s/R 1P x.s/d s d ÂC Zd 2 dZt t C ÂP x T .s/R 2P x.s/d s d ÂCZ0 dZ tt C ÂP x T .s/R 3P x.s/d s d Â,Q V4.x t /D .d 2 d 1/Zd 1 d 2Zt t C ÂP x T .s/R 4P x.s/d s d Â,and P D P T >0,Q i D Q T i>0.i D 1,2,:::,6/,R j D R Tj >0.j D 1,2,3,4/are to be determined.CONTINUOUS-TIME SYSTEMS WITH ADDITIVE TIME-V ARYING DELAYSRemark 3Different from [7,8,11],the information about d.t/,d 1.t/,and d 2.t/is fully considered in Lyapunov functional (23).When d 2.t/reaches the upper bound d 2,d.t/reduces to d 2C d 1.t/andit varies within the interval Œd 2,d ,so Q V2.x t /and the second term in Q V3.x t /are defined,and this situation is neglected in construction of (11).Meanwhile,Q V4.x t /is nonnegative whether d 16d 2or d 1>d pared with the Lyapunov functional in (11),the interval Œ d ,0 is divided more finely in (23),which makes full use of the information about d 1.t/and d 2.t/.Obviously,Lyapunov functional (23)is more general than that in [7,8,11],and the resulting stability criterion may be less conservative.Now,an improved stability criterion is given as follows.Theorem 2For given scalars d 1>0,d 2>0and 1, 2,the origin of system (1)with two additive time-varying delay components satisfying conditions (2)and (3)is globally asymptotically stable if thereexist matrices P D P T >0,Q i D Q T i >0.i D 1,2,:::,6/,R j D R Tj >0.j D 1,2,3,4/,and matrices T i .i D 1,2,3/,such that‰<0,(24)ÄR i T iR i>0,.i D 1,2,3/(25)where‰D 2666666666664‰11‰12‰131d 1T 10 1d 1T 31d 1T 3‰221d 2R 3 T T301d 2.R 3 T 3/0‰331d 1.R 1 T 1/01d 1T 3C 1d 2T 3 1d 1T 3 ‰44R 400 ‰551d 1.R 2 T 2/1d 1T 2 ‰66‰67‰773777777777775,‰11D PA C A T P C Q 1C Q 2C Q 3C Q 4 1d 1.R 1C R 3/C A T d 1R 1C d 1R 2C dR 3C d 212R 4 A ,‰12D PB C A T d 1R 1C d 1R 2C dR 3C d 212R 4 B ,‰13D 1d 1.R 1C R 3 T 1/,‰22D .1 /Q 1 1d 22R 3 T 3 T T 3 C B T d 1R 1C d 1R 2C dR 3C d 212R 4 B ,‰33D .1 1/Q 2 1d 1 2R 1C R 3 T 1 T T1 1d 2R 3,‰44D Q 3 1d 1R 1 R 4,‰55D Q 5C Q 6 Q 4 1d 1R 2 R 4,‰66D .1 1/Q 5 1d 1 2R 2C R 3 T 2 T T2 1d 2R 3,‰67D 1d 1.R 2C R 3 T 2/,‰77D Q 6 1d 1.R 2C R 3/.X-L.ZHU,Y .W ANG AND X.DUProofDenote .t/D col ¹ 1.t/, 2.t/º,with 1.t/D col ¹x.t/,x.t d.t//,x.t d 1.t//,x.t d 1/ºand 2.t/D ¹x.t d 2/,x.t d 2 d 1.t//,x.t d /º.Taking the time derivative of Q V3.x.t//yields that P Q V 3.x t /D P x T .t/ d 1R 1C d 1R 2C dR 3ÁP x.t/Z t t d 1P x T .s/R 1P x.s/d s Zt d 2t dP x T.s/R 2P x.s/d sZt t dP x T .s/R 3P x.s/d s .(26)From Lemma 2,it follows thatZ tt d 1P x T .s/R 1P x.s/d s 61d 1Ä 1.t/ 2.t/ T ÄR 1T 1 R 1 Ä 1.t/ 2.t/ ,(27)Z t d 2t dP x T .s/R 2P x.s/d s D Z t d 2t d 2 d 1.t/P x T .s/R 2P x.s/d s Z t d 2 d 1.t/t dP x T .s/R 2P x.s/d s 61d 1Ä7.t/ 8.t/T ÄR 2T 2 R 2Ä7.t/ 8.t/,(28)andZtt dP x T.s/R 3P x.s/d s DZ t t d 1.t/P x T.s/R 3P x.s/d sZ t d 2 d 1.t/t d P x T .s/R 3P x.s/d sZt d 1.t/t d.t/P x T.s/R 3P x.s/d s Zt d.t/t d 2 d 1.t/P x T .s/R 3P x.s/d s ,61d 1Ä 1.t/8.t/ T ÄR 3T 3 R 3 Ä1.t/ 8.t/ 1d 2Ä 6.t/ 9.t/T ÄR 3T 3R 3Ä6.t/ 9.t/,(29)where 1.t/, 2.t/,and 6.t/are defined in the proof of Theorem 1and7.t/D x.t d 2/ x.t d 2 d 1.t//, 8.t/D x.t d 2 d 1.t// x.t d/. 9.t/D x.t d.t// x.t d 2 d 1.t//.From Lemma 1,it follows thatP Q V 4.x t /6d 212 T .t/B T R 4Bx.t d 1/ x.t d 2/T R 4 x.t d 1/ x.t d 2/ ,(30)whereB DA B00000.So combining (14)with (27)–(30),we haveP Q V.xt /6 T .t/‰ .t/,(31)which implies that the globally asymptotical stability of system (1)can be guaranteed if ‰<0and(25)are true.Thus,the proof is completed.CONTINUOUS-TIME SYSTEMS WITH ADDITIVE TIME-V ARYING DELAYSRemark4Different from[7,8,11,12],P Q V3.x t/is not overly bounded.Following the idea presented in the proof of Theorem1,the cross-product terms are appropriately decomposed,and a less conservative stability criterion is obtained by using Lemma2,which will be verified in the next section. Remark5In some cases,the upper bounds of the derivatives of delays may be unknown.Regarding such circumstances,rate-independent criteria for delays only satisfying(2)can be derived from Theorems1and2by setting Q2D Q5D0and Q1D0,respectively,and the details are omitted here for brevity.4.ILLUSTRATIVE EXAMPLESIn this section,two numerical examples are given to demonstrate the benefits of the proposed method.Example2([7])Consider the delayed system(1)withA D Ä200 0.9,B DÄ101 1.First,we intend tofind the upper bound d2of d2.t/when d1is known,below which the system is asymptotically stable.If 1D0.1and 2D0.8,the corresponding upper bounds d2for various d1derived by Theorems1and2and the corresponding ones in[7,8,11]are listed in Table II. Then,we intend tofind the upper bound d1of d1.t/when d2is known.For the case of 1D0.1 and 2D0.8,the corresponding upper bounds d1derived by various methods are listed in Table III. When system(1)is regarded as one with single delay,Corollary1in this paper is applicable to the aforementioned case,and the allowable upper bound of d obtained by Corollary1in this paper is1.873.For unknown 1and 2,the corresponding results obtained by Theorems1and2with Q1D Q2D Q5D0are listed in Tables IV and V,respectively,which shows the improvement of Theorem2over Theorem1.Table II.Calculated upper bounds of d2with 1D0.1and 2D0.8.Methods d111.21.5[11]d20.5180.4520.377[8]d20.5120.4060.283[7]d20.4150.3760.284[14]d20.5950.4630.312Theorem1d20.8730.6730.398Theorem2d20.9830.8490.671Table III.Calculated upper bounds of d1with 1D0.1and 2D0.8.Methods d20.10.20.3[8]d12.3001.7791.453[7]d12.2631.6961.324[14]d12.3401.8331.531Theorem1d12.3981.9281.667Theorem2d13.0572.6472.329X-L.ZHU,Y.W ANG AND X.DUTable IV.Calculated upper bounds of d2with unknown 1and 2.Methods d111.21.5Theorem1d20.8680.6680.368Theorem2d20.8680.6680.395Table V.Calculated upper bounds of d1with unknown 1and 2.Methods d20.10.20.3Theorem1d11.7681.6681.568Theorem2d12.0821.8081.633Table VI.Calculated upper bounds of d2for Example2with d1D0.1.[14][6]Corollary1Theorem1Theorem20.9350.9430.9430.9530.961Table VII.Calculated upper bounds of d1for Example2with d2D0.1.[14][6]Corollary1Theorem1Theorem20.9350.9430.9430.9530.963 Example3([14])Consider the delayed system(1)withA D Ä010 0.1,B DÄ000.375 1.15.Here,although matrix A is marginally stable,A C B is Hurwitz.Similar to the proof of Lemma1 in[15],one canfind that there exists a positive scalar d>0such that the system is stable for 06d.t/6d.If 1D0.1and 2D0.2,the corresponding upper bounds d2for d1D0.1derived by Theorems1and2and the corresponding ones in[14]and[6]are listed in Table VI.In contrast, the upper bounds d1for d2D0.1derived by various methods are listed in Table VII.From these data,one canfind that the stability criteria given in[7,8,11,14]may be conservative, and Theorems1and2in this paper improve the existing ones significantly.5.CONCLUSIONIn this paper,the delay-dependent stability problem of continuous-time systems with two additive time-varying delay components has been investigated.By defining appropriate Lyapunov function-als and estimating the derivatives of the Lyapunov functional more tightly,we derived new less conservative delay-dependent stability criteria in terms of LMIs.Because a reciprocally convex approach is employed,the computational complexity is also reduced.Some numerical examples are given to illustrate the effectiveness of the presented criteria and the significant improvement over the existing results.ACKNOWLEDGEMENTSThe authors would like to thank Professor Hong Wang and the reviewers for their valuable comments and helpful suggestions.CONTINUOUS-TIME SYSTEMS WITH ADDITIVE TIME-V ARYING DELAYSThis work was supported by the National Natural Science Foundation of China under Grants61174085 and61074040,the Scientific Research Foundation for the Returned Overseas Chinese Scholars,State Education Ministry,the Training Excellent Young Teachers in Shanghai Universities(B37-0109-10-008), and the Shanghai University Innovation Foundation(Grant No.A.10-0109-10-014).REFERENCES1.Gao Z,Ding SX.State and disturbance estimator for time-delay systems with application to fault estimation andsignal compensation.IEEE Transactions on Signal Processing2007;55(12):5541–5551.2.Gao Z,Breikin T,Wang H.Reliable observer-based control against sensor failures for systems with time delaysin both state and input.IEEE Transactions on Systems Man and Cybernetics-Part A Systems and Humans2008;38(5):1018–1029.3.Gu K.An integral inequality in the stability problem of time-delay systems.Proceedings of39th IEEE Conferenceon Decision and Control,Sydney,Australia,2000;2805–2810.4.Moon YS,Park P,Kwon WH,Lee YS.Delay-dependent robust stabilization of uncertain state-delayed systems.International Journal of Control2001;74:1447–1455.5.Lee YS,Moon YS,Kwon WH,Park PG.Delay-dependent robust H1control for uncertain systems with astate-delay.Automatica2004;40:65–72.6.Park P,Ko JW,Jeong C.Reciprocally convex approach to stability of systems with time-varying delays.Automatica2011;47(1):235–238.m J,Gao H,Wang C.Stability analysis for continuous system with two additive time-varying delay components.Systems&Control Letters2007;56(1):16–24.8.Gao H,Chen T,Lam J.A new delay system approach to network-based control.Automatica2008;44(1):39–52.9.Zhu XL,Wang Y,Yang GH.New stability criteria for continuous-time systems with interval time-varying delay.IET Control Theory&Applications2010;4(6):1101–1107.10.Shao H.New delay-dependent stability criteria for systems with interval delay.Automatica2009;45(3):744–749.11.Rajeeb Dey G,Sandip Ghosh R,Rakshit A.Stability analysis for continuous system with additive time-varyingdelays:a less conservative results.Applied Mathematics and Computation2010;215(10):3740–3745.12.Zhao Y,Gao H,Mou S.Asymptotic stability analysis of neural networks with successive time delay components.Neurocomputing2008;71:2848–2856.13.Shao H,Han QL.New delay-dependent stability criteria for neural networks with two additive time-varying delaycomponents.IEEE Transactions on Neural Networks2011;22(5):812–818.14.Shao H,Han QL.On stabilization for systems with two additive time-varying input delays arising from networkedcontrol systems.Journal of The Franklin Institute2012;349:2033–2046.15.Zhu XL,Yang H,Wang Y,Wang YL.New stability criterion for linear switched systems with time-varying delay.International Journal of Robust and Nonlinear Control2012.DOI:10.1002/rnc.2882,to appear.。

ICH 指导原则文件目录(中英文)

人用药品注册技术要求国际协调会(ICH)文件目录ICH的论题主要分为四类,因此ICH根据论题的类别不同而进行相应的编码分类:1. “Q”类论题:Q代表QUALITY,指那些与化工和医药,质量保证方面的相关的论题。

Q1/Q2...Q10都属于这类。

2. “S”类论题:S代表SAFETY,指那些与实验室和动物实验,临床前研究方面的相关的论题。

3. “E”类论题:E代表EFFICACY,指那些与人类临床研究相关的课题。

4. “M”类论题:M代表MULTIDISCIPLINARY, 指那些不可单独划入以上三个分类的交叉涉及的论题。

同时M又细分为5个小类:M1: 常用医学名词(Med DRA)M2: 药政信息传递之电子标准M3: 与临床试验相关的临床前研究时间的安排M4: 常规技术文件(CTD)M5: 药物词典的数据要素和标准一、ICH. 质量部分(Quality)稳定性1.Quality质量2.Q1: Stability稳定性3.Q1A(R2): Stability Testing of New Drug Substances and Products 新原料药和制剂的稳定性试验4.Q1B: Photostability Testing of New Drug Substances and Products 新原料药和制剂的光稳定性试验5.Q1C: Stability Testing for New Dosage Forms 新剂型的稳定性试验6.Q1D: Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products原料药和制剂稳定性试验的交叉和矩阵设计 Q1E: Evaluation of Stability Data 稳定性数据的评估7.Q1F: Stability Data Package for Registration Applications in Climatic Zones III andIV在气候带III和IV,药物注册申请所提供的稳定性数据8.Q2: Analytical Validation分析验证9.Q2(R1): Validation of Analytical Procedures: Text and Methodology分析程序的验证:正文及方法论10.Q3: Impurities 杂质11.Q3A(R2): Impurities in New Drug Substances 新原料药中的杂质12.Q3B(R2): Impurities in New Drug Products (Revised Guideline) 新制剂中的杂质13.Q3C(R3): Impurities: Guideline for Residual Solvents 杂质:残留溶剂指南Impurities: Guideline for Residual Solvents (Maintenance) 杂质:残留溶剂指南(保留)PDE for Tetrahydrofuran (in Q3C(R3)) 四氢呋喃的日允许接触剂量PDE for N-Methylpyrrolidone (in Q3C(R3)) N-甲基吡咯烷酮的日允许接触剂量14.Q4: Pharmacopoeias药典15.Q4A: Pharmacopoeial Harmonisation 药典的协调16.Q4B: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions药典内容的评估及推荐为用于ICH地区17.Q4B Annex1 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regionson Residue on Ignition/Sulphated Ash General Chapter附录1 药典内容的评估及推荐为用于ICH地区关于灼烧残渣/灰分常规篇18.Q4B Annex2 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regionson Test for Extractable Volume of Parenteral Preparations General Chapter附录2 药典内容的评估及推荐为用于ICH地区关于注射剂可提取容量测试常规篇19.Q4B Annex3 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regionson Test for Particulate Contamination: Sub-Visible Particles General Chapter附录3 药典内容的评估及推荐为用于ICH地区关于颗粒污染物测试:不溶性微粒常规篇20.Q5: Quality of Biotechnological Products 生物技术制品质量21.Q5A(R1): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin来源于人或者动物细胞系的生物技术产品的病毒安全性评估22.Q5B: Quality of Biotechnological Products: Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein Products生物技术产品的质量:源于重组DNA的蛋白质产品的生产中所用的细胞中的表达构建分析23.Q5C: Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products生物技术产品的质量:生物技术/生物产品的稳定性试验24.Q5D: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products用于生产生物技术/生物产品的细胞底物的起源和特征描述25.Q5E: Comparability of Biotechnological/Biological Products Subject to Changes inTheir Manufacturing Process基于不同生产工艺的生物技术产品/生物产品的可比较性26.Q6: Specifications规格27.Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (including decision trees) 质量规格:新原料药和新制剂的检验程序和可接收标准:化学物质(包括决定过程)28.Q6B: Specifications: Test Procedures and Acceptance Criteria for29.Biotechnological/Biological Products质量规格:生物技术/生物产品的检验程序和可接收标准30.Q7: Good Manufacturing Practices (GMP)31.Q7A: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients活性药物成份的GMP指南32.Q8: Pharmaceutical Development药物研发33.Annex to Q8Q8附录34.Q9: Quality Risk Management质量风险管理35.Q10: Pharmaceutical Quality System药物质量体系二、ICH.安全性部分(Safety) 致癌试验1.S1A Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals 药物致癌试验的必要性2.S1B Testing for Carcinogenicity of Pharmaceuticals 药物致癌试验3.S1C(R2) Dose Selection for Carcinogenicity Studies of Pharmaceuticals药物致癌试验的剂量选择4.S1C’药物致癌试验的剂量选择的附件:补充剂量限度和有关注释遗传毒性5.S2(R1) Guidance on Genotoxicity Testing and Data Interpretation forPharmaceuticals Intended for Human Use 人用药物的遗传毒性试验和数据分析指导原则6.S2A药物审评遗传毒性试验的特殊性指导原则7.S2B遗传毒性:药物遗传毒性试验标准组合药代8.S3A Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposurein Toxicity Studies 毒代动力学指导原则:毒性研究中全身暴露的评价9.S3B Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies药代动力学:重复给药的组织分布研究指导原则慢性毒性10.S4Duration of Chronic Toxicity Testing in Animals (Rodent and Non RodentToxicity Testing) 动物慢性毒性试验的周期(啮齿类和非啮齿类)生殖毒性11.S5(R2) Detection of Toxicity to Reproduction for Medicinal Products andToxicity to Male Fertility (the Addendum dated November 1995 has beenincorporated into the core guideline in November 2005 )12.S5A药品的生殖毒性检测13.S5B雄性生育力毒性其他14.S6Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals 生物技术药品的临床前安全性试验15.S7A Safety Pharmacology Studies for Human Pharmaceuticals 人用药物的安全性药理研究16.S7B The Non-clinical Evaluation of the Potential for Delayed VentricularRepolarization (QT Interval Prolongation) by Human Pharmaceuticals人用药延迟心室复极化(QT间期延长)潜在作用的非临床评价指导原则17.S8Immunotoxicity Studies for Human Pharmaceuticals人类药品的免疫毒性研究18.S9 Nonclinical Evaluation for Anticancer Pharmaceuticals抗癌药物的临床前评价19.S10 Photosafety Evaluation三、ICH.临床部分(Efficacy)1.E1The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions 评价临床长期给药方案的安全性2.E2A Definitions and Standards for Expedited Reporting 快速报告的定义和标准3.E2B(R3) Data Elements for Transmission of Individual Case Safety Reports个体病例安全性报告传递的数据要素4.E2C Periodic Benefit-Risk Evaluation Report 上市药品定期安全性更新报告5.E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting批准后安全性数据管理:快速报告的定义和标准6.E2E Pharmacovigilance Planning药物警戒计划7. E2F Development Safety Update Report8.E3Structure and Content of Clinical Study Reports 临床研究报告的结构与内容9.E4Dose-Response Information to Support Drug Registration 新药注册所需量-效关系的资料10.E5(R1)Ethnic Factors in the Acceptability of Foreign Clinical Data 对国外临床研究资料的种族因素的可接受性11.E6(R1) Good Clinical Practice: Consolidated Guideline 药品临床研究规范(GCP)一致性指导原则12.E7Studies in Support of Special Populations: Geriatrics 老年人群的临床研究13.E8General Considerations for Clinical Trials 临床试验的一般考虑14.E9Statistical Principles for Clinical Trials 临床试验统计原则15.E10Choice of Control Group and Related Issues in Clinical Trials 对照组的选择16.E11Clinical Investigation of Medicinal Products in the Pediatric Population 儿童人群的临床研究17.E12按治疗分类的各类药物临床评价E12 Principles for Clinical Evaluation of New Antihypertensive Drugs18.E14The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs 非抗心律失常药物致QT/QTc间期延长及潜在心律失常作用的临床评价19.E15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories20.E16 Biomarkers Related to Drug or Biotechnology Product Development: Context, Structure and Format of Qualification Submissions四、ICH.综合部分 (Multidisciplinary)1.M1医学术语Med DRA2.M2Electronic Transmission of Individual Case Safety Reports MessageSpecification (ICH ICSR DTD Version 2.1) companion document to E2B(R3)注册资料传递所需的电子代码3.M3Guidance on Nonclinical Safety Studies for the Conduct of Human ClinicalTrials and Marketing Authorization for Pharmaceuticals与临床研究有关的临床前研究的时间安排4.M4 Organisation of the Common Technical Document for the Registration ofPharmaceuticals for Human Use (Edited with Numbering and Section Header Changes, September 2002). Including the Annex : the Granularity Document(Revised November 2003).CTD(common technical document)(包括CTD、CTD-Q、CTD-S、CTD-E和eCTD)药品词汇的数据要素和标准5.M4Q (R1) The Common Technical Document for the Registration ofPharmaceuticals for Human Use: Quality (Edited with Numbering and Section Header Changes, September 2002)6.M4S (R2) The Common Technical Document for the Registration ofPharmaceuticals for Human Use: Safety (Edited with Numbering and SectionHeader Changes, September 2002)7.M4E (R1) The Common Technical Document for the Registration ofPharmaceuticals for Human Use: Efficacy (Edited with Numbering and Section Header Changes, September 2002)8.M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities inPharmaceuticals to Limit Potential Carcinogenic Risk Reference:1. 《ICH 药品注册的国际要求》2. 3. /health/Health/yx/yao/2007-08-07/6326.html。

具有区间时变时滞的细胞神经网络的时滞相关渐近稳定性分析

具有区间时变时滞的细胞神经网络的时滞相关渐近稳定性分析【关键词】神经网络;时变时滞;渐近稳定;线性矩阵不等式(lmi)0 引言细胞神经网络是由chua和yang于1988年提出的,此后得到了广泛的应用研究,例如,运用到信号处理,静态图像处理,模式识别,解非线性代数方程,最优化问题和移动物体速度的确定等各个方面,在过去数十年引起许多学者的关注。

然而,在人工神经网络的电路设计中,由于信号传输速度的有限性,不可避免的存在着时滞问题,因此,对时滞神经网络进行分析具有更重要的理论意义和实际价值。

目前关于神经网络稳定性研究成果主要分为时滞相关和时滞无关两大类。

由于时滞相关稳定条件包含了时滞信息,特别是当时滞很小时,比时滞无关条件具有更低的保守性。

以往,时滞相关的稳定条件通常是用确定模型变换法和交叉项界定的技术得到系统稳定的充分条件,比如中立变换、参数变化等等,利用newton-leibniz 公式,通过在lyapunov-krasovskii泛函导数中添加一些零项,引入辅助变量且利用广义的状态变量,得到一些保守性较低的稳定判据。

但是由于在模型变换过程中,使用的固定权来表示的各项的关系,会引起一定的保守性。

近年来, he 等人提出一种自由权矩阵方法,对时滞神经网络系统进行研究,该方法降低了以往由于对神经网络系统进行模型变换而带来的保守性,得到一系列时滞相关稳定性条件。

本文基于he 等人提出的自由权矩阵方法,研究了具有区间时滞的细胞神经网络系统时滞相关渐近稳定性问题,在lyapunov-krasovskii泛函导数求导的过程中保留了各有用项,得到了一个以线性矩阵不等式(lmi)表示的系统时滞相关稳定的充分条件。

最后,数值实例表明了本文方法的有效性和优越性。

1 问题描述考虑如下的具有区间时变时滞的细胞神经网络系统4 结论本文对具有区间时滞神经网络系统进行研究,得到系统渐近稳定的时滞相关稳定条件,通过选择适当的lyapunov-krasovskii泛函,得到具有更低保守性的基于线性矩阵不等式(lmi)的神经网络系统渐近稳定的时滞相关稳定的充分条件。

ICH指导原则文件目录(中英文)

ICH指导原则文件目录(中英文)人用药品注册技术要求国际协调会(ICH)文件目录ICH的论题主要分为四类,因此ICH根据论题的类别不同而进行相应的编码分类:1. “Q”类论题:Q代表QUALITY,指那些与化工和医药,质量保证方面的相关的论题。

Q1/Q2...Q10都属于这类。

2. “S”类论题:S代表SAFETY,指那些与实验室和动物实验,临床前研究方面的相关的论题。

3. “E”类论题:E代表EFFICACY,指那些与人类临床研究相关的课题。

4. “M”类论题:M代表MULTIDISCIPLINARY, 指那些不可单独划入以上三个分类的交叉涉及的论题。

同时M又细分为5个小类:M1: 常用医学名词(Med DRA)M2: 药政信息传递之电子标准M3: 与临床试验相关的临床前研究时间的安排M4: 常规技术文件(CTD)M5: 药物词典的数据要素和标准一、ICH. 质量部分(Quality)稳定性1.Quality质量2.Q1: Stability稳定性3.Q1A(R2): Stability Testing of New Drug Substances and Products 新原料药和制剂的稳定性试验4.Q1B: Photostability Testing of New Drug Substances and Products 新原料药和制剂的光稳定性试验5.Q1C: Stability Testing for New Dosage Forms 新剂型的稳定性试验6.Q1D: Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products原料药和制剂稳定性试验的交叉和矩阵设计 Q1E: Evaluation of Stability Data 稳定性数据的评估7.Q1F: Stability Data Package for Registration Applications in Climatic Zones III andIV在气候带III和IV,药物注册申请所提供的稳定性数据8.Q2: Analytical Validation分析验证9.Q2(R1): Validation of Analytical Procedures: Text and Methodology分析程序的验证:正文及方法论10.Q3: Impurities 杂质11.Q3A(R2): Impurities in New Drug Substances 新原料药中的杂质12.Q3B(R2): Impurities in New Drug Products (Revised Guideline) 新制剂中的杂质13.Q3C(R3): Impurities: Guideline for Residual Solvents 杂质:残留溶剂指南Impurities: Guideline for Residual Solvents (Maintenance) 杂质:残留溶剂指南(保留)PDE for Tetrahydrofuran (in Q3C(R3)) 四氢呋喃的日允许接触剂量PDE for N-Methylpyrrolidone (in Q3C(R3)) N-甲基吡咯烷酮的日允许接触剂量14.Q4: Pharmacopoeias药典15.Q4A: Pharmacopoeial Harmonisation 药典的协调16.Q4B: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions药典内容的评估及推荐为用于ICH地区17.Q4B Annex1 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regionson Residue on Ignition/Sulphated Ash General Chapter附录1 药典内容的评估及推荐为用于ICH地区关于灼烧残渣/灰分常规篇18.Q4B Annex2 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regionson Test for Extractable Volume of Parenteral Preparations General Chapter附录2 药典内容的评估及推荐为用于ICH地区关于注射剂可提取容量测试常规篇19.Q4B Annex3 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regionson Test for Particulate Contamination: Sub-Visible Particles General Chapter附录3 药典内容的评估及推荐为用于ICH地区关于颗粒污染物测试:不溶性微粒常规篇20.Q5: Quality of Biotechnological Products 生物技术制品质量21.Q5A(R1): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin来源于人或者动物细胞系的生物技术产品的病毒安全性评估22.Q5B: Quality of Biotechnological Products: Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived ProteinProducts生物技术产品的质量:源于重组DNA的蛋白质产品的生产中所用的细胞中的表达构建分析23.Q5C: Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products生物技术产品的质量:生物技术/生物产品的稳定性试验24.Q5D: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products用于生产生物技术/生物产品的细胞底物的起源和特征描述25.Q5E: Comparability of Biotechnological/Biological Products Subject to Changes inTheir Manufacturing Process基于不同生产工艺的生物技术产品/生物产品的可比较性26.Q6: Specifications规格27.Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (including decision trees) 质量规格:新原料药和新制剂的检验程序和可接收标准:化学物质(包括决定过程)28.Q6B: Specifications: Test Procedures and Acceptance Criteria for29.Biotechnological/Biological Products质量规格:生物技术/生物产品的检验程序和可接收标准30.Q7: Good Manufacturing Practices (GMP)31.Q7A: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients活性药物成份的GMP指南32.Q8: Pharmaceutical Development药物研发33.Annex to Q8Q8附录34.Q9: Quality Risk Management质量风险管理35.Q10: Pharmaceutical Quality System药物质量体系二、ICH.安全性部分(Safety) 致癌试验1.S1A Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals 药物致癌试验的必要性2.S1B Testing for Carcinogenicity of Pharmaceuticals 药物致癌试验3.S1C(R2) Dose Selection for Carcinogenicity Studies of Pharmaceuticals药物致癌试验的剂量选择4.S1C’药物致癌试验的剂量选择的附件:补充剂量限度和有关注释遗传毒性5.S2(R1) Guidance on Genotoxicity Testing and Data Interpretation forPharmaceuticals Intended for Human Use 人用药物的遗传毒性试验和数据分析指导原则6.S2A药物审评遗传毒性试验的特殊性指导原则7.S2B遗传毒性:药物遗传毒性试验标准组合药代8.S3A Note for Guidance on T oxicokinetics: The Assessment of Systemic Exposurein Toxicity Studies 毒代动力学指导原则:毒性研究中全身暴露的评价9.S3B Pharmacokinetics: Guidance for Repeated Dose TissueDistribution Studies药代动力学:重复给药的组织分布研究指导原则慢性毒性10.S4Duration of Chronic T oxicity Testing in Animals (Rodent and Non RodentToxicity Testing) 动物慢性毒性试验的周期(啮齿类和非啮齿类)生殖毒性11.S5(R2) Detection of T oxicity to Reproduction for Medicinal Products andToxicity to Male Fertility (the Addendum dated November 1995 has beenincorporated into the core guideline in November 2005 )12.S5A药品的生殖毒性检测13.S5B雄性生育力毒性其他14.S6Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals 生物技术药品的临床前安全性试验15.S7A Safety Pharmacology Studies for Human Pharmaceuticals 人用药物的安全性药理研究16.S7B The Non-clinical Evaluation of the Potential for Delayed VentricularRepolarization (QT Interval Prolongation) by Human Pharmaceuticals人用药延迟心室复极化(QT间期延长)潜在作用的非临床评价指导原则17.S8Immunotoxicity Studies for Human Pharmaceuticals人类药品的免疫毒性研究18.S9 Nonclinical Evaluation for Anticancer Pharmaceuticals 抗癌药物的临床前评价19.S10 Photosafety Evaluation三、ICH.临床部分(Efficacy)1.E1The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-T erm Treatment of Non-Life-Threatening Conditions 评价临床长期给药方案的安全性2.E2A Definitions and Standards for Expedited Reporting 快速报告的定义和标准3.E2B(R3) Data Elements for Transmission of Individual Case Safety Reports个体病例安全性报告传递的数据要素4.E2C Periodic Benefit-Risk Evaluation Report 上市药品定期安全性更新报告5.E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting批准后安全性数据管理:快速报告的定义和标准6.E2E Pharmacovigilance Planning药物警戒计划7. E2F Development Safety Update Report8.E3Structure and Content of Clinical Study Reports 临床研究报告的结构与内容9.E4Dose-Response Information to Support Drug Registration 新药注册所需量-效关系的资料10.E5(R1)Ethnic Factors in the Acceptability of Foreign Clinical Data 对国外临床研究资料的种族因素的可接受性11.E6(R1) Good Clinical Practice: Consolidated Guideline 药品临床研究规范(GCP)一致性指导原则12.E7Studies in Support of Special Populations: Geriatrics 老年人群的临床研究13.E8General Considerations for Clinical Trials 临床试验的一般考虑14.E9Statistical Principles for Clinical Trials 临床试验统计原则15.E10Choice of Control Group and Related Issues in Clinical Trials 对照组的选择16.E11Clinical Investigation of Medicinal Products in the Pediatric Population 儿童人群的临床研究17.E12按治疗分类的各类药物临床评价E12 Principles for Clinical Evaluation of New Antihypertensive Drugs18.E14The Clinical Evaluation of QT/QT c Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs 非抗心律失常药物致QT/QT c间期延长及潜在心律失常作用的临床评价19.E15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories20.E16 Biomarkers Related to Drug or Biotechnology Product Development: Context, Structure and Format of Qualification Submissions四、ICH.综合部分 (Multidisciplinary)1.M1医学术语Med DRA2.M2Electronic Transmission of Individual Case Safety Reports MessageSpecification (ICH ICSR DTD Version 2.1) companion document to E2B(R3)注册资料传递所需的电子代码3.M3Guidance on Nonclinical Safety Studies for the Conduct of Human ClinicalTrials and Marketing Authorization for Pharmaceuticals与临床研究有关的临床前研究的时间安排4.M4 Organisation of the Common Technical Document for the Registration ofPharmaceuticals for Human Use (Edited with Numbering and Section Header Changes, September 2002). Including the Annex : the Granularity Document(Revised November 2003).CTD(common technical document)(包括CTD、CTD-Q、CTD-S、CTD-E和eCTD)药品词汇的数据要素和标准5.M4Q (R1) The Common Technical Document for the Registration ofPharmaceuticals for Human Use: Quality (Edited with Numbering and Section Header Changes, September 2002)6.M4S (R2) The Common Technical Document for the Registration ofPharmaceuticals for Human Use: Safety (Edited with Numbering and SectionHeader Changes, September 2002)7.M4E (R1) The Common Technical Document for the Registration ofPharmaceuticals for Human Use: Efficacy (Edited with Numbering and Section Header Changes, September 2002)8.M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities inPharmaceuticals to Limit Potential Carcinogenic Risk Reference:1. 《ICH 药品注册的国际要求》2. /doc/d6990802.html,3./doc/d6990802.html,/health/Health/yx/yao/20 07-08-07/6326.html。

关于为什么晚婚的英语作文

关于为什么晚婚的英语作文In contemporary society, the phenomenon of delayed marriage has become increasingly prevalent. This shift in societal norms has been observed across various cultures and countries, with more individuals choosing to marry later in life or forgoing marriage altogether. The reasons for this trend are multifaceted, encompassing economic, social, and personal factors. This essay aims to explore the various dimensions that contribute to the decision to marry later in life.Economic ConsiderationsOne of the primary reasons for delayed marriage is economic. The financial burden of establishing a household and starting a family has grown significantly over the past few decades. Young adults today are often saddled with student loan debt, which can delay their ability to afford the costs associated with marriage, such as a home or a wedding ceremony. Additionally, economic instability and the need for dual incomes have led many to prioritize career advancement over marital commitments.Educational PursuitsHigher education has become a standard expectation for many individuals, which often extends the period of study and professional training well into a person's late twenties orearly thirties. As a result, the pursuit of advanced degrees and professional qualifications can postpone the age at which individuals feel ready to settle down and marry.Changing Social NormsSociety's view on marriage has evolved, with theinstitution no longer being seen as a necessary milestone in an individual's life. There is a greater acceptance of cohabitation and non-traditional family structures, which reduces the pressure to marry. Furthermore, the stigma associated with being single has diminished, allowing individuals to remain unmarried without facing societal judgment.Personal Growth and IndependenceMany people are choosing to marry later as a means to achieve personal growth and independence. They value the time spent in self-discovery and the opportunity to establishtheir own identities before entering into a lifelong commitment. This period of exploration can lead to a more mature and self-aware individual who is better equipped to navigate the complexities of a marital relationship.Career PrioritizationCareer ambitions often take precedence over marital considerations, particularly in a competitive job market. Individuals may delay marriage to focus on career development, networking, and the pursuit of professional success. Thedesire to achieve financial stability and career satisfaction before settling down is a common reason for the trend of delayed marriage.Fear of CommitmentThe fear of commitment can also be a factor in the decision to postpone marriage. With the availability of information on high divorce rates and the challenges of maintaining a long-term relationship, some individuals may be hesitant to take the plunge. They may opt to delay marriage until they feel confident in their choice of partner andtheir ability to sustain a healthy relationship.Technological InfluenceThe advent of online dating and social media has changed the way people meet and interact, which can influence the decision to marry. The ease of meeting new people and the ability to maintain a wide social network can lead to a more selective approach to choosing a life partner. This, in turn, can result in a longer period of dating and evaluation before deciding to marry.Health and Lifestyle ChoicesHealth consciousness and lifestyle choices are also playing a role in the decision to delay marriage. Many individuals are prioritizing their physical and mental well-being, engaging in activities such as travel, fitness, and personal hobbies. They may choose to marry later to maintaina certain lifestyle or to ensure that their future spouse shares similar health and lifestyle goals.ConclusionThe decision to marry later in life is a complex and personal one, influenced by a variety of factors. Economic pressures, educational goals, changing social attitudes, personal growth, career ambitions, fear of commitment, technological influences, and health and lifestyle choices all contribute to the trend of delayed marriage. As society continues to evolve, it is likely that the institution of marriage will also adapt to reflect the diverse needs and desires of contemporary individuals.。

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The Approach to Stability for Delayed Feedback Control of Chaos for 1-dimensional Maps
J. Keith Thomas and Edward H. Hellen∗ University of North Carolina Greensboro, Department of Physics and Astronomy, Greensboro, NC 27402
II.
THEORY
The goal here is to predict the behavior of the convergence of system values caused by the control algorithm in Eq. (2). The unperturbed return map is xn+1 = f (xn , a0 ). The fixed 2
Hale Waihona Puke (6)where fa (a − a0 ) (7) fx where we used the result for when x and a are changed while holding f (x, a) constant, l = x′ − xn = (x∗ − xn ) − fa ∆a fx ∆x = − (8)
FIG. 1: Portion of return maps showing unperturbed f (x, a0 ) and perturbed f (x, a) maps.
Next we remove reference to the fixed point in Eq. (4) expressing it only in terms of differences of successive system values. The derivation is as follows. From the return maps shown in Fig. 1: (xn+1 − xn ) = (xn+1 − x∗ ) + (x∗ − xn ) and xn+1 − x∗ = −fx l 3 (5)
point x* satisfies x∗ = f (x∗ , a0 ). Chaotic behavior is stabilized by perturbing parameter an about the value a0 so as to move the system value x towards the unstable fixed point x∗ . A linear expansion of the return map about x∗ and a0 gives xn+1 = f (xn , an ) = f (x∗ , a0 ) + fx (xn − x∗ ) + fa (an − a0 ) where fx and fa are the partial derivatives. This is rewritten as (xn+1 − x∗ ) = fx (xn − x∗ ) + fa B (xn − xn−1 ) where we included our perturbation Eq. (2). (4) (3)
1
I.
INTRODUCTION
It is well known that proportional feedback methods can control chaos for systems described by 1-dimensional maps.1,2,3,4 Typically in these methods a system parameter is perturbed by an amount proportional to the difference between the current system value and the unstable fixed point. Pyragas introduced an alternative in which the perturbation is proportional to the difference between the current system value and a previous system value.5 This delayed feedback control (DFC) method works without knowledge of unstable fixed points or orbits, and does not require computational analysis. Here we apply this method to finite difference return maps and derive the mathematical form of the approach to stability and verify it experimentally with an electronic circuit. We find a variety of behaviors for the approach to stability depending on the gain of the feedback. We consider the 1-dimensional finite difference map for system value x with system parameter a xn+1 = f (xn , an ) . Using the DFC method on successive system values, the perturbation of an is ∆an = an − a0 = B (xn − xn−1 ) (2) (1)
arXiv:0807.2637v1 [nlin.CD] 16 Jul 2008
(Dated: July 16, 2008)
Abstract
We derive the mathematical form of the approach to stability for a delayed proportional feedback control method applied to a chaotic finite difference 1-dimensional map. Unlike the more common chaos control methods, this method does not use the unstable fixed points or require computational analysis. We verify the mathematical predictions by using an analog electronic circuit realization of a finite difference quadratic return map. Changing the feedback gain produces distinctly different types of approach to stability.
where a0 is the unperturbed parameter value and B is the feedback gain. [So Eq. (1) is equivalent to xn+1 = f (xn , xn−1 , a0 )]. Feedback is applied only when the magnitude of (xn − xn−1 ) is within a specified window for control. This method is based on the idea that in a neighborhood of a fixed point of Eq. (1) the difference between successive system values decreases when the distance from the system value to the fixed value decreases. Therefore DFC has the desired property of the perturbation vanishing when the system value attains the unstable fixed value. We note that the application of DFC to successive system values is essentially a derivative control method since the perturbation uses the difference in system values per iteration.6

(xn+1 − xn ) − 1
fa B fx − f1 x
(xn − xn−1 )
(10)
Equation (10) allows us to eliminate the fixed point in Eq. (4) resulting in (xn+1 − xn ) = (fx + fa B ) (xn − xn−1 ) − fa B (xn−1 − xn−2 ) characteristic equation s2 − (fx + fa B ) s + fa B = 0. Roots are fx + fa B ± s± = 2 giving solution
for the case ∆x = (x′ − x∗ ). Equation (7) becomes (xn − x∗ ) =
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