Chemistry Books

Book SynopsisA comprehensive guide to data analysis techniques for physical scientists, providing a valuable resource for advanced undergraduate and graduate students, as well as seasoned researchers. The book begins with an extensive discussion of the foundational concepts and methods of probability and statistics under both the frequentist and Bayesian interpretations of probability. It next presents basic concepts and techniques used for measurements of particle production cross-sections, correlation functions, and particle identification. Much attention is devoted to notions of statistical and systematic errors, beginning with intuitive discussions and progressively introducing the more formal concepts of confidence intervals, credible range, and hypothesis testing. The book also includes an in-depth discussion of the methods used to unfold or correct data for instrumental effects associated with measurement and process noise as well as particle and event losses, before ending with a presentatiTrade Review'This ambitious book provides a comprehensive, rigorous, and accessible introduction to data analysis for nuclear and particle physicists working on collider experiments, and outlines the concepts and techniques needed to carry out forefront research with modern collider data in a clear and pedagogical way. The topic of particle correlation functions, a seemingly straightforward topic with conceptual pitfalls awaiting the unaware, receives two full chapters. Professor Pruneau presents these concepts carefully and systematically, with precise definitions and extensive discussion of interpretation. These chapters should be required reading for all practitioners working in this area.' Peter Jacobs, Lawrence Berkeley National Laboratory'The techniques described in this textbook on correlation functions, and on efficiency and acceptance of an experimental apparatus, are key to understanding the approach used in many contemporary large-scale experiments; they are relevant for theoretical and experimental researchers alike, both in nuclear and particle physics and in many other areas where large data volumes and multi-dimensional data are investigated. I consider this an important and unique addition to the current literature on the subject.' Peter Braun-Munzinger, GSI Helmholtzzentrum fur Schwerionenforschung, Germany'This text is a very welcome addition to the books available in the area. It provides concise and eminently readable information on probability and statistics but also deals in quite some detail with many of the techniques used currently in running high-energy and nuclear physics experiments but not covered in standard texts. A case in point is the beautiful exposé on Kalman filtering, and the sections which deal with particle identification techniques. Presented so that theoretical researchers can get much-needed information on how data analysis works in such environments, the text is also very well suited to all students of experimental physics, and is particularly interesting for students and more senior researchers alike who have specialized in large nuclear and particle physics experiments.' Johanna Stachel, University of Heidelberg'Data Analysis Techniques for Physical Scientists is both monumental and accessible. While targeted towards data analysis methods in nuclear and particle physics, its breadth and depth insure that it will be of interest to a much broader audience across the physical sciences. Designed as a textbook, with ample problems and expository text, this wonderful new addition to the literature is also suitable for self-study and as a reference. As such, it is the book that I will first recommend to my students, be they undergraduates or graduate students.' W. A. Zajc, Columbia University, New York'The text is clearly written, and the book is well laid out with numerous useful illustrations. For its target audience, this is an excellent book.' A. H. Harker, Contemporary Physics'Data Analysis Techniques for Physical Scientists offers an accessible but rigorous and comprehensive presentation of data analysis techniques in modern large-scale experiments. Furthermore, much of the book is applicable beyond the physical sciences; it is a useful resource on probability and statistics that would benefit anyone who works with large data sets. Taken as a whole, it is an exceptional general reference for graduate students and seasoned experimental researchers alike.' Emilie Martin-Hein, Physics TodayTable of ContentsPreface; How to read this book; 1. The scientific method; Part I. Foundation in Probability and Statistics: 2. Probability; 3. Probability models; 4. Classical inference I: estimators; 5. Classical inference II: optimization; 6. Classical inference III: confidence intervals and statistical tests; 7. Bayesian inference; Part II. Measurement Techniques: 8. Basic measurements; 9. Event reconstruction; 10. Correlation functions; 11. The multiple facets of correlation functions; 12. Data correction methods; Part III. Simulation Techniques: 13. Monte Carlo methods; 14. Collision and detector modeling; List of references; Index.

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Book SynopsisThe olive oil market is increasingly international. Levels of consumption and production are growing, particularly in new markets outside the Mediterranean region.Trade Review"The authors here do a good job contextualizing taste integration and experimental design in the context of olive oil. . . Olive Oil Sensory Science is an erudite and up-to-date resource."(Olive Oil Times, 5 June 2014) "Each chapter of Olive Oil Sensory Science is written by the best researchers and industry professionals in the field throughout the world. . . This book is an invaluable resource for olive oil scientists, product development and marketing personnel on the role of sensory evaluation in relation to current and future market trends." (Teatronaturale International, 3 April 2014)Table of ContentsList of Contributors xiii Olive Oil Sensory Science: an Overview xv Erminio Monteleone and Susan Langstaff Part I 1 Quality Excellence in Extra Virgin Olive Oils 3 Claudio Peri 1.1 Introduction 3 1.2 Part 1. The standards of excellent olive oil 4 1.3 Part 2. The control of critical processing parameters 19 1.4 Part 3. The marketing of excellent olive oils 27 References 30 2 The Basis of the Sensory Properties of Virgin Olive Oil 33 Agnese Taticchi, Sonia Esposto, and Maurizio Servili 2.1 Sensory attributes of virgin olive oil 33 2.2 Agronomic and technological aspects of production that affect sensory properties and their occurrence in olive oil 42 2.3 Conclusion 49 References 50 3 Sensory Perception and Other Factors Affecting Consumer Choice of Olive Oil 55 Hely Tuorila and Annamaria Recchia 3.1 Introduction 55 3.2 The sensory system 56 3.3 Affective responses to salient sensory attributes of olive oil 63 3.4 Nonsensory aspects of consumer behavior 66 3.5 Conclusion 73 Acknowledgment 73 References 74 4 Sensory Quality Control 81 Susan Langstaff 4.1 Introduction 81 4.2 Historical perspective 81 4.3 Standard methods 83 4.4 Legislative standards 83 4.5 Parameters used to evaluate olive oil quality 84 4.6 Organoleptic assessment – aroma and flavor 86 4.7 IOC taste panel development 86 4.8 IOC terminology for virgin olive oils 87 4.9 IOC profile sheet 91 4.10 “Ring tests” 91 4.11 IOC classification of olive oil grades 93 4.12 Other certification systems 95 4.13 Designing a sensory quality control program 98 4.14 New developments and future opportunities 98 4.15 Conclusion 105 References 106 5 Sensory Methods for Optimizing and Adding Value to Extra Virgin Olive Oil 109 Erminio Monteleone 5.1 Introduction 109 5.2 Perceptual maps 110 5.3 Conventional descriptive analysis 113 5.4 Alternative descriptive methods to conventional descriptive analysis 127 5.5 Perceptual maps from similarity data 130 5.6 Temporal aspects of sensory characteristics of olive oils: Time–Intensity (TI) and Temporal Dominance of Sensations (TDS) 133 References 137 6 Consumer Research on Olive Oil 141 Claudia Delgado, Metta Santosa, Aurora G´omez-Rico, and Jean-Xavier Guinard 6.1 Introduction 141 6.2 Applications to olive oil 148 6.3 Conclusion 167 References 167 7 Sensory Functionality of Extra Virgin Olive Oil 171 Caterina Dinnella 7.1 Introduction 171 7.2 The Temporal Dominance of Sensation method 177 7.3 Comparing the sensory functionality of extra virgin olive oils with a varied sensory style 184 7.4 Conclusion 191 Acknowledgments 192 References 192 8 Investigating the Culinary Use of Olive Oils 195 Sara Spinelli 8.1 Introduction 195 8.2 Methodological approaches in the study of oil–food pairing 198 8.3 An original approach to studying the sensory functionality of oils in culinary preparations 204 8.4 Conclusion 220 References 221 Part II 9 Olive Oils from Spain 229 Agust´ý Romero, Anna Claret, and Luis Guerrero 9.1 Historical perspective 229 9.2 Geographic and climatic characteristics 230 9.3 Main sensory properties of Spanish olive oils 235 9.3.1 Main Spanish olive-growing areas 238 References 246 10 Olive Oils from Italy 247 Marzia Migliorini 10.1 Introduction 247 10.2 PDO and PGI extra virgin olive oils in Italy 250 10.3 Conclusion 267 References 267 11 Olive Oils from Greece 269 Vassilis Zampounis, Kostas Kontothanasis, and Efi Christopoulou 11.1 Historical perspective 269 11.2 Geographical and climatic characteristics 270 11.3 Overview of olive-producing regions 270 11.4 Messinia–Kalamata 275 11.5 Sensory characteristics of the major Greek olive varieties 281 11.6 Three typical examples of sensory analysis 283 References 286 12 Olive Oils from California 289 Alexandra Kicenik Devarenne and Susan Langstaff 12.1 Overview of olive oils from California 289 12.2 California climate and geography 289 12.3 History 290 12.4 Consumption and production 291 12.5 Production systems 292 12.6 California designations of olive oils 293 12.7 Chemistry of California olive oils 293 12.8 Olive varieties in California 294 12.9 Olive oil regions in California 298 12.10 Conclusion 309 References 309 13 Olive Oils from Australia and New Zealand 313 Leandro Ravetti and Margaret Edwards 13.1 Overview of olive oil industry 313 13.2 Main chemical characteristics of olive oils 317 13.3 Principal olive varieties in Australia and New Zealand 321 13.4 Overview of olive growing regions and principal olive oil styles 325 13.5 Conclusion 334 Acknowledgments 335 References 336 14 Olive Oils from South America 337 Adriana Turcato and Susana Mattar 14.1 The origins of olive growing in South America 337 14.2 Olive growing in Argentina 338 14.3 Other olive-growing countries in South America 340 14.4 Brief geographic description of Argentina 344 14.5 Characterization of San Juan’s olive oils 346 14.6 Sensory profiles 350 14.7 Correlations between sensory and chemical parameters 355 14.8 Conclusion 356 Acknowledgments 356 References 356 Further reading 356 Index 359

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Book SynopsisServes as a practical reference for those involved in Secondary Ion Mass Spectrometry (SIMS) Introduces SIMS along with the highly diverse fields (Chemistry, Physics, Geology and Biology) to it is applied using up to date illustrations Introduces the accepted fundamentals and pertinent models associated with elemental and molecular sputtering and ion emission Covers the theory and modes of operation of the instrumentation used in the various forms of SIMS (Static vs Dynamic vs Cluster ion SIMS) Details how data collection/processing can be carried out, with an emphasis placed on how to recognize and avoid commonly occurring analysis induced distortions Presented as concisely as believed possible with All sections prepared such that they can be read independently of each otherTrade Review“It is well worth owning if you want to learn about this exciting surface science technique for studying materials.” (IEEE Electrical Engineering magazine, 1 May 2015) “The entire book, and especially the second part, is a good reference work for users of D-SIMS and S-SIMS and for those working in other methods in analytical chemistry and the applied scientific fields, including the biosciences, where SIMS is now becoming a major experimental method.” (Anal Bioanal Chem, 21 February 2015)Table of ContentsForeword xi Preface xiii Acknowledgments xvi List of Constants xvii 1 Introduction 1 1.1 Matter and The Mass Spectrometer 1 1.2 Secondary Ion Mass Spectrometry 4 1.2.1 History 6 1.2.2 Physical Basis 8 1.2.2.1 Sensitivity and Detection Limits 9 1.2.3 Application Fields 12 1.3 Summary 18 SECTION I PRINCIPLES 21 2 Properties of Atoms, Ions, Molecules, and Solids 23 2.1 The Atom 23 2.1.1 Atomic Structure 23 2.1.1.1 Atomic Mass 25 2.1.1.2 Atomic Density 27 2.2 Electronic Structure of Atoms and Ions 27 2.2.1 Stationary States 28 2.2.1.1 Quantum Numbers 28 2.2.1.2 Spectroscopic and X-ray Notation 29 2.2.1.3 Ionization Potential and Electron Affinity 31 2.2.2 Bonding and the Resulting Properties of Solids 32 2.2.2.1 Bands and the Density of States 34 2.2.2.2 Work Function 35 2.2.2.3 Image Field 36 2.2.2.4 Electronic Excitation 36 2.3 Summary 42 3 Sputtering and Ion Formation 44 3.1 The Fundamentals of SIMS 44 3.1.1 Secondary Ion Generation 45 3.2 Sputtering 46 3.2.1 Sputtering by Ion Impact 47 3.2.1.1 Linear Cascade Model 50 3.2.1.2 Other Sputtering Models 54 3.2.1.3 Simulations 60 3.2.2 Sputter Rates and Sputter Yields 67 3.2.2.1 Sputter Yield Dependence on Primary Ion Conditions 69 3.2.2.2 Sputter Yield Dependence on Substrate 76 3.2.3 Sputter-induced damage 81 3.2.3.1 Recoil Implantation, Cascade Mixing, Diffusion, and Segregation 83 3.2.3.2 Substrate Amorphization and Re-crystallization 85 3.2.3.3 Surface Roughening and Surface Smoothing 86 3.3 Ionization/Neutralization 88 3.3.1 Ion–Solid Interactions 90 3.3.2 Secondary Ion Yields 93 3.3.2.1 Ionization Potential and Electron Affinity 95 3.3.2.2 Matrix Effects 97 3.3.2.3 Electronic Excitation 113 3.3.3 Models for Atomic Secondary Ions 121 3.3.3.1 LTE Formalism 123 3.3.3.2 Bond Breaking Model 124 3.3.3.3 Kinetic Emission Model 129 3.3.4 Models for Molecular Secondary Ions 130 3.3.4.1 Models for Molecular Ion Emission in SIMS 132 3.3.4.2 Models for Molecular Ion Emission in MALDI 135 3.4 Summary 138 SECTION II PRACTICES 145 4 Instrumentation Used in SIMS 147 4.1 The Science of Measurement 147 4.1.1 SIMS in its various forms 148 4.1.1.1 Static SIMS 148 4.1.1.2 Dynamic SIMS 149 4.1.1.3 Cluster Ion SIMS 150 4.2 Hardware 151 4.2.1 Vacuum 152 4.2.1.1 Vacuum and the Kinetic Theory of Gases 153 4.2.1.2 Pumping Systems 156 4.2.2 Primary Ion Columns 159 4.2.2.1 Ion Sources 161 4.2.3 Secondary Ion Columns 167 4.2.3.1 Mass Filters 170 4.2.3.2 Energy Filters 182 4.2.3.3 Detectors 184 4.3 Summary 191 5 Data Collection and Processing 195 5.1 The Art of Measurement 195 5.1.1 Data Formats and Definitions 196 5.1.1.1 Mass Spectra 197 5.1.1.2 Depth Profiling 201 5.1.1.3 Imaging 204 5.2 Sample Preparation and Handling 208 5.2.1 Preparation in the Materials Sciences 209 5.2.2 Preparation in the Earth Sciences 210 5.2.3 Preparation in the Biosciences 212 5.2.4 Sample Handling 213 5.3 Data Collection 215 5.3.1 Secondary Ion Mass, Energy, and Intensity Scales 216 5.3.1.1 Referencing the Mass, Energy, and Intensity Scales 216 5.3.1.2 Charge Buildup 218 5.3.1.3 Isobaric Interferences 221 5.3.2 Instrument Operation Modes 225 5.3.2.1 Primary Ion Beam Operation Modes 225 5.3.2.2 Secondary Ion Imaging Modes 231 5.3.2.3 The O2 Leak Methodology 233 5.3.2.4 Depth Profiling and Related Aspects 234 5.4 Data Processing 248 5.4.1 Spectral Identification 249 5.4.1.1 Atomic and Unfragmented Molecular Emissions 249 5.4.1.2 Heavily Fragmented Molecular Emissions 250 5.4.2 Quantification of the Depth Scale 251 5.4.2.1 Ex situ Methods 254 5.4.2.2 In situ Methods 256 5.4.3 Quantification of the Concentration Scale 259 5.4.3.1 The RSF Method 260 5.4.3.2 Fabrication of Reference Materials 265 5.5 Summary 268 Appendix A 273 A.1 Periodic Table of the Elements 273 A.2 Isotopic Masses, Natural Isotope Abundances, Atomic Weights, and Mass Densities of the Elements 273 A.3 1st and 2nd Ionization Potentials and Electron Affinities of the Elements 280 A.4 Work–Function Values of Elemental Solids 283 A.5 SIMS Detection Limits of Selected Elements 286 A.6 Charged Particle Beam Transport 288 A.6.1 Ion Beam Trajectories 288 A.6.1.1 Liouville’s Theorem 289 A.6.1.2 Phase Space Dynamics 289 A.6.1.3 Ray Tracing Methods 289 A.6.2 Optical Properties 290 A.6.2.1 Aberrations 290 A.6.2.2 Diffraction and the Diffraction Limit 292 A.7 Some Statistical Distributions of Interest 293 A.7.1 Gaussian Distribution 294 A.7.2 Poisson Distribution 294 A.7.3 Lorentzian Distributions 294 A.8 SIMS Instrument Designs 294 A.8.1 Physical Electronics 6600 295 A.8.2 ASI SHRIMP I, II, and IV 296 A.8.3 SHRIMP RG 297 A.8.4 Cameca IMS-1280 298 A.8.5 Cameca IMS 7f 299 A.8.6 Cameca nanoSIMS 50 300 A.8.7 Ion-Tof TOF-SIMS 5 302 A.8.8 Physical Electronics nano-SIMS 303 A.8.9 Ionoptika J105-3D Chemical Imager 303 A.8.10 Q-Star Chemical Imager 304 A.8.11 SIMS Instrument Capability Table 305 A.8.12 SIMS Instrument/Component Vendor List 308 A.9 Additional SIMS Methods of Interest 311 A.9.1 Matrix Transferable RSFs 312 A.9.2 The Infinite Velocity Method 313 A.9.3 Lattice Valency Model 314 A.9.4 PCOR-SIMSTM Method 315 A.10 Additional Spectroscopic/Spectrometric Techniques 316 A.10.1 Photon Spectroscopies 317 A.10.1.1 IR, RAIRS, ATR, and DRIFTS 317 A.10.1.2 Raman, SERS, and TERS 318 A.10.1.3 EDX, WDS, and LEXES 319 A.10.1.4 XRF and TXRF 320 A.10.1.5 VASE 320 A.10.2 Electron Spectroscopies 321 A.10.2.1 XPS and UPS 321 A.10.2.2 AES and SAM 321 A.10.2.3 EELS, REELS, and HREELS 322 A.10.3 Ion Spectroscopies/Spectrometries 322 A.10.3.1 GD-MS, GD-OES, and ICP-MS 322 A.10.3.2 MALDI and ESI-MS 323 A.10.3.3 SNMS and RIMS 324 A.10.3.4 APT 324 A.10.3.5 Ion Scattering Methods 325 A.10.3.6 ERD, NRA, NAA, and PIXE 326 A.11 Additional Microscopies 327 A.11.1 SEM 328 A.11.2 HIM 328 A.11.3 TEM 329 A.11.4 SPM (AFM and STM)-Based Techniques 329 A.12 Diffraction/Reflection Techniques of Interest 331 A.12.1 XRD and GID 332 A.12.2 GID 332 A.12.3 XRR 333 A.12.4 LEED 333 A.12.5 RHEED 333 A.12.6 Neutron Diffraction 333 Technique Acronym List 335 Abbreviations Commonly used in SIMS 338 Glossary of Terms 340 Questions and Answers 347 References 350 Index 359

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Table of ContentsList of Contributors xiii Foreword xvii Preface xix 1 Contemporary Protein Analysis by Ion Mobility Mass Spectrometry 1Johannes P.C. Vissers and James I. Langridge 1.1 Introduction 1 1.2 Traveling-Wave Ion Mobility Mass Spectrometry 1 1.3 IM–MS and LC–IM–MS Analysis of Simple and Complex Mixtures 2 1.4 Outlook 7 Acknowledgment 8 References 8 2 High-Resolution Accurate Mass Orbitrap and Its Application in Protein Therapeutics Bioanalysis 11Hongxia Wang and Patrick Bennett 2.1 Introduction 11 2.2 Triple Quadrupole Mass Spectrometer and Its Challenges 11 2.3 High-Resolution Mass Spectrometers 12 2.4 Quantitation Modes on Q Exactive Hybrid Quadrupole Orbitrap 13 2.5 Protein Quantitation Approaches Using Q Exactive Hybrid Quadrupole Orbitrap 14 2.6 Data Processing 16 2.7 Other Factors That Impact LC–MS-based Quantitation 16 2.8 Conclusion and Perspectives of LC–HRMS in Regulated Bioanalysis 18 References 18 3 Current Methods for the Characterization of Posttranslational Modifications in Therapeutic Proteins Using Orbitrap Mass Spectrometry 21Zhiqi Hao, Qiuting Hong, Fan Zhang, Shiaw-Lin Wu, and Patrick Bennett 3.1 Introduction 21 3.2 Characterization of PTMs Using Higher-Energy Collision Dissociation 23 3.3 Application of Electron Transfer Dissociation to the Characterization of Labile PTMs 26 3.4 Conclusion 31 Acknowledgment 32 References 32 4 Macro- to Micromolecular Quantitation of Proteins and Peptides by Mass Spectrometry 35Suma Ramagiri, Brigitte Simons, and Laura Baker 4.1 Introduction 35 4.2 Key Challenges of Peptide Bioanalysis 36 4.3 Key Features of LC/MS/MS-Based Peptide Quantitation 38 4.4 Advantages of the Diversity of Mass Spectrometry Systems 41 4.5 Perspectives for the Future 41 References 42 5 Peptide and Protein Bioanalysis Using Integrated Column-to-Source Technology for High-Flow Nanospray 45Shane R. Needham and Gary A. Valaskovic 5.1 Introduction – LC–MS Has Enabled the Field of Protein Biomarker Discovery 45 5.2 Integration of Miniaturized LC with Nanospray ESI-MS Is a Key for Success 46 5.3 Micro- and Nano-LC Are Well Suited for Quantitative Bioanalysis 47 5.4 Demonstrating Packed-Emitter Columns Are Suitable for Bioanalysis 49 5.5 Future Outlook 51 References 52 6 Targeting the Right Protein Isoform: Mass Spectrometry-Based Proteomic Characterization of Alternative Splice Variants 55Jiang Wu 6.1 Introduction 55 6.2 Alternative Splicing and Human Diseases 55 6.3 Identification of Splice Variant Proteins 56 6.4 Conclusion 64 References 64 7 The Application of Immunoaffinity-Based Mass Spectrometry to Characterize Protein Biomarkers and Biotherapeutics 67Bradley L. Ackermann and Michael J. Berna 7.1 Introduction 67 7.2 Overview of IA-MS Methods 69 7.3 IA-MS Applications – Biomarkers 74 7.3.1 Peptide Biomarkers 74 7.4 IA-MS Applications – Biotherapeutics 81 7.5 Future Direction 84 References 85 8 Semiquantification and Isotyping of Antidrug Antibodies by Immunocapture-LC/MS for Immunogenicity Assessment 91Jianing Zeng, Hao Jiang, and Linlin Luo 8.1 Introduction 91 8.2 Multiplexing Direct Measurement of ADAs by Immunocapture-LC/MS for Immunogenicity Screening, Titering, and Isotyping 93 8.3 Indirect Measurement of ADAs by Quantifying ADA Binding Components 95 8.4 Use of LC–MS to Assist in Method Development of Cell-Based Neutralizing Antibody Assays 96 8.5 Conclusion and Future Perspectives 97 References 97 9 Mass Spectrometry-Based Assay for High-Throughput and High-Sensitivity Biomarker Verification 99Xuejiang Guo and Keqi Tang 9.1 Background 99 9.2 Sample Processing Strategies 100 9.3 Advanced Electrospray Ionization Mass Spectrometry Instrumentation 102 9.4 Conclusion 105 References 105 10 Monitoring Quality of Critical Reagents Used in Ligand Binding Assays with Liquid Chromatography Mass Spectrometry (LC–MS) 107Brian Geist, Adrienne Clements-Egan, and Tong-Yuan Yang 10.1 Introduction 107 10.2 Case Study Examples 114 10.3 Discussion 122 Acknowledgment 126 References 126 11 Application of Liquid Chromatography-High Resolution Mass Spectrometry in the Quantification of Intact Proteins in Biological Fluids 129Stanley (Weihua) Zhang, Jonathan Crowther, and Wenying Jian 11.1 Introduction 129 11.2 Workflows for Quantification of Proteins Using Full-Scan LC-HRMS 131 11.3 Internal Standard Strategy 133 11.4 Calibration and Quality Control (QC) Sample Strategy 135 11.5 Common Issues in Quantification of Proteins Using LC-HRMS 135 11.6 Examples of LC-HRMS-Based Intact Protein Quantification 137 11.7 Conclusion and Future Perspectives 138 Acknowledgment 140 References 140 12 LC–MS/MS Bioanalytical Method Development Strategy for Therapeutic Monoclonal Antibodies in Preclinical Studies 145Hongyan Li, Timothy Heath, and Christopher A. James 12.1 Introduction: LC-MS/MS Bioanalysis of Therapeutic Monoclonal Antibodies 145 12.2 Highlights of Recent Method Development Strategies 146 12.3 Case Studies of Preclinical Applications of LC–MS/MS for Monoclonal Antibody Bioanalysis 154 12.4 Conclusion and Future Perspectives 156 References 158 13 Generic Peptide Strategies for LC–MS/MS Bioanalysis of Human Monoclonal Antibody Drugs and Drug Candidates 161Michael T. Furlong 13.1 Introduction 161 13.2 A Universal Peptide LC–MS/MS Assay for Bioanalysis of a Diversity of Human Monoclonal Antibodies and Fc Fusion Proteins in Animal Studies 161 13.3 An Improved “Dual” Universal Peptide LC–MS/MS Assay for Bioanalysis of Human mAb Drug Candidates in Animal Studies 165 13.4 Extending the Universal Peptide Assay Concept to Human mAb Bioanalysis in Human Studies 170 13.5 Internal Standard Options for Generic Peptide LC–MS/MS Assays 173 13.6 Sample Preparation Strategies for Generic Peptide LC–MS/MS Assays 175 13.7 Limitations of Generic Peptide LC–MS/MS Assays 177 13.8 Conclusion 178 Acknowledgments 178 References 178 14 Mass Spectrometry-Based Methodologies for Pharmacokinetic Characterization of Antibody Drug Conjugate Candidates During Drug Development 183Yongjun Xue, Priya Sriraman, Matthew V. Myers, Xiaomin Wang, Jian Chen, Brian Melo, Martha Vallejo, Stephen E. Maxwell, and Sekhar Surapaneni 14.1 Introduction 183 14.2 Mechanism of Action 183 14.3 Mass Spectrometry Measurement for DAR Distribution of Circulating ADCs 186 14.4 Total Antibody Quantitation by Ligand Binding or LC–MS/MS 189 14.5 Total Conjugated Drug Quantitation by Ligand Binding or LC–MS/MS 193 14.6 Catabolite Quantitation by LC–MS/MS 196 14.7 Preclinical and Clinical Pharmacokinetic Support 197 14.8 Conclusion and Future Perspectives 198 References 198 15 Sample Preparation Strategies for LC–MS Bioanalysis of Proteins 203Long Yuan and Qin C. Ji 15.1 Introduction 203 15.2 Sample Preparation Strategies to Improve Assay Sensitivity 205 15.3 Sample Preparation Strategies to Differentiate Free, Total, and ADA-Bound Proteins 213 15.4 Sample Preparation Strategies to Overcome Interference from Antidrug Antibodies or Soluble Target 214 15.5 Protein Digestion Strategies 214 15.6. Conclusion 215 Acknowledgment 216 References 216 16 Characterization of Protein Therapeutics by Mass Spectrometry 221Wei Wu, Hangtian Song, Thomas Slaney, Richard Ludwig, Li Tao, and Tapan Das 16.1 Introduction 221 16.2 Variants Associated with Cysteine/Disulfide Bonds in Protein Therapeutics 221 16.3 N–C-Terminal Variants 225 16.4 Glycation 226 16.5 Oxidation 226 16.6 Discoloration 228 16.7 Sequence Variants 230 16.8 Glycosylation 232 16.9 Conclusion 240 References 240 Index 251

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Book SynopsisOffers an overview of endocrine disruption phenomena. This book lists the major environmental chemicals of concern and their mechanism of endocrine disruption including remedial measures for them. It also focuses on removal processes of various EDCs by biotic and abiotic transformation/degradation.Trade Review“This book is a great resource for those wanting an overview of this grand collaborative enterprise, or for those preparing the next generation for investigating, problem-solving, and managing our bio-chemical future, giving us a chance to balance modern living with safety.” (Endocrine Disruptors, 1 October 2014)Table of ContentsForeword xiv Preface xviii Acronyms xxi Glossary xxvi 1 Environmental Endocrine Disruptors 1 1.1 Introduction 1 1.1.1 The Endocrine System 1 1.1.2 Endocrine Disrupting Chemicals (EDCs) 3 1.1.3 Sources of EDCs in the Environment 4 1.1.4 Deleterious Effects of EDCs on Wildlife and on Humans 6 1.1.5 Endocrine Disruption Endpoints 6 1.2 Salient Aspects about Endocrine Disruption 7 1.2.1 Low-Dose Effects and Nonmonotonic Dose Responses 7 1.2.2 Exposures during Periods of Heightened Susceptibility in Critical Life Stages 9 1.2.3 Delayed Dysfunction 11 1.2.4 Importance of Mixtures 11 1.2.5 Transgenerational Epigenetic Effects 12 1.3 Historical Perspective of Endocrine Disruption 12 1.4 Scope and Layout of this Book 19 1.5 Conclusion 20 References 21 Part I Mechanisms Of Hormonal Action And Putative Endocrine Disruptors 27 2 Mechanisms of Endocrine System Function 29 2.1 Introduction 29 2.2 Hormonal Axes 29 2.2.1 Hypothalamus–Pituitary–Gonad (HPG) Axis 31 2.2.2 The Hypothalamic–Pituitary–Thyroid (HPT) Axis 33 2.2.3 The Hypothalamic–Pituitary–Adrenal (HPA) Axis 34 2.3 Hormonal Cell Signaling 35 2.3.1 Receptors and Hormone Action 35 2.3.2 Genomic Signaling Pathway 36 2.3.3 Rapid-Response Pathway (Nongenomic Signaling) 38 2.3.4 Receptor Agonists Partial Agonists and Antagonists 40 2.4 Sex Steroids 41 2.4.1 Physiologic Estrogens 41 2.4.2 Androgens 43 2.5 Thyroid Hormones 45 2.6 Conclusions and Future Prospects 46 References 47 3 Environmental Chemicals Targeting Estrogen Signaling Pathways 51 3.1 Introduction 51 3.1.1 Gonadal Estrogen Function Disruptors 52 3.2 Steroidal Estrogens 54 3.2.1 Physiologic Estrogens 55 3.2.2 17α-Ethinylestradiol (EE2) 55 3.2.3 Phytoestrogens 57 3.2.4 Mycoestrogen – Zearalenone (ZEN) 59 3.3 Nonsteroidal Estrogenic Chemicals 60 3.3.1 Diethylstilbestrol (DES) 60 3.3.2 Organochlorine Insecticides 62 3.3.3 Polychlorinated Biphenyls (PCBs) 65 3.3.4 Alkyphenols 65 3.3.5 Parabens (Hydroxy Benzoates) 73 3.3.6 Sun Screens (Chemical UV Filters) 74 3.4 Metalloestrogens 75 3.4.1 Cadmium (Cd) 76 3.4.2 Lead (Pb) 76 3.4.3 Mercury (Hg) 77 3.4.4 Arsenic (As) 77 3.5 Conclusion and Future Prospects 78 References 78 4 Anti-Androgenic Chemicals 91 4.1 Introduction 91 4.2 Testosterone Synthesis Inhibitors 92 4.2.1 Phthalates 92 4.3 Androgen Receptor (AR) Antagonists 96 4.3.1 Organochlorine (OC) Pesticides 96 4.3.2 Organophosphorus (OP) Insecticides 98 4.3.3 Bisphenol A (BPA) 99 4.3.4 Polybrominated Diphenyl Ethers (PBDEs) 99 4.3.5 Vinclozolin (VZ) 100 4.3.6 Procymidone 101 4.4 AR Antagonists and Fetal Testosterone Synthesis Inhibitors 102 4.4.1 Prochloraz 102 4.4.2 Linuron 103 4.5 Comparative Anti-Androgenic Effects of Pesticides to Androgen Agonist DHT 103 4.6 Conclusions and Future Prospects 103 References 104 5 Thyroid-Disrupting Chemicals 111 5.1 Introduction 111 5.2 Thyroid Synthesis Inhibition by Interference in Iodide Uptake 113 5.2.1 Perchlorate 113 5.3 TH Transport Disruptors and Estrogen Sulfotransferases Inhibitors 114 5.3.1 Polychlorinated Biphenyls (PCBs) 114 5.3.2 Triclosan 116 5.4 Thyroid Hormone Level Disruptors 117 5.4.1 Polybrominated Diphenyl Ethers (PBDEs) 117 5.5 Selective Thyroid Hormone Antagonists 119 5.5.1 Bisphenols 119 5.5.2 Perfluoroalkyl Acids (PFAAs) 120 5.5.3 Phthalates 120 5.6 Conclusions and Future Prospects 121 References 121 6 Activators of PPAR RXR AhR and Steroidogenic Factor 1 126 6.1 Introduction 126 6.2 Peroxisome Proliferator-Activated Receptor (PPAR) Agonists 127 6.2.1 Organotin Antifoulant Biocides 128 6.2.2 Perfluoroalkyl Compounds (PFCs) 130 6.2.3 Phthalates 132 6.3 Aryl Hydrocarbon Receptor (AhR) Agonists 133 6.3.1 Polychlorinated-Dibenzodioxins (PCDDs) and -Dibenzofurans (PCDFs) 133 6.3.2 Coplanar Polychlorinated Biphenyls 135 6.3.3 Substituted Urea and Anilide Herbicides 135 6.4 Steroidogenesis Modulator (Aromatase Expression Inducer) 136 6.4.1 Atrazine 136 6.5 Conclusions and Future Prospects 138 References 139 7 Effects of EDC Mixtures 146 7.1 Introduction 146 7.2 Combined Effect of Exposure to Multiple Chemicals 146 7.3 Mixture Effects of Estrogenic Chemicals 148 7.4 Mixture Effects of Estrogens and Anti-Estrogens 151 7.5 Mixture Effects of Anti-Androgens 152 7.5.1 Anti-Androgens with Common Mechanism of Action 152 7.5.2 Anti-Androgens with Different Modes of Action 154 7.5.3 Chronic Exposure of Low Dose Mixture of Anti-Androgens Versus Acute Exposure to High Dose Individual Compounds 156 7.6 Mixture Effects of Thyroid Disrupting Chemicals 157 7.7 Mixture Effects of Chemicals Acting via AhR 158 7.8 Conclusions and Future Prospects 158 References 161 8 Environmentally Induced Epigenetic Modifications and Transgenerational Effects 166 8.1 Introduction 166 8.2 Regulatory Epigenetic Modifications 168 8.2.1 Methylation of Cytosine Residues in the DNA and Impact on Gene Expression (Transcriptional Silencing) 168 8.2.2 Remodeling of Chromatin Structure through Post-Translational Modifications of Histone Tails (Determinants of Accessibility) 170 8.2.3 Regulation of Gene Expression by Noncoding RNAs 173 8.2.4 DNA Demethylation 174 8.2.5 Assays for Epigenetic Modification 175 8.3 Epigenetic Dysregulation Effects of Endocrine Disruption 176 8.3.1 Bisphenol A (BPA): A Case Study 177 8.3.2 DEHP 179 8.4 Environmental Epigenetic Effects of Heavy Metals Exposure 179 8.4.1 Cadmium 180 8.4.2 Arsenic 180 8.4.3 Nickel 180 8.4.4 Lead 181 8.5 Transgenerational Inheritance of Environmentally Induced Epigenetic Alterations 181 8.5.1 DES 182 8.5.2 Vinclozolin 183 8.5.3 Methoxychlor 185 8.5.4 BPA 185 8.5.5 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) 185 8.6 Transgenerational Actions of EDCs Mixture on Reproductive Disease 186 8.7 Conclusions and Future Prospects 187 References 188 Part II Removal Mechanisms Of Edcs Through Biotic And Abiotic Processes 195 9 Biodegradations and Biotransformations of Selected Examples of EDCs 197 9.1 Introduction 197 9.2 Natural and Synthetic Steroidal Estrogens 199 9.2.1 17β-Estradiol and Estrone 199 9.2.2 17α-Ethynylestradiol 202 9.3 Alkylphenols 205 9.3.1 4-n-Nonylphenol (4-NP1) 205 9.3.2 4-tert-Nonylphenol Isomer 4-(1-Ethyl-1,4-Eimethylpentyl) Phenol (NP112) 208 9.3.3 4-tert-Nonylphenol Isomer 4-[1-Ethyl-1,3-Dimethylpentyl] Phenol (4-NP111) 210 9.3.4 4-n- and 4-tert-Octylphenols 212 9.3.5 Bisphenol A 214 9.4 Phthalates 220 9.4.1 Di-n-butyl Phthalate (DBP) 221 9.4.2 n-Butyl Benzyl Phthalate (BBP) 222 9.4.3 Di-(2-ethylhexyl) Phthalate (DEHP) 223 9.4.4 Di-n-octyl Phthalate (DOP) 226 9.5 Insecticides 226 9.5.1 Methoxychlor 226 9.6 Fungicides 228 9.6.1 Vinclozolin 228 9.6.2 Procymidone 231 9.6.3 Prochloraz 232 9.7 Herbicides 232 9.7.1 Linuron 232 9.7.2 Atrazine 233 9.8 Polychlorinated Biphenyls (PCBs) 236 9.9 Polybrominated Diphenyl Ethers (PBDEs) 238 9.9.1 2,2’,4,4’ -Tetrabromodiphenyl Ether (BDE-47) 238 9.9.2 2,2’,4,4’,5-Penta-bromodiphenyl Ether (BDE-99) 243 9.9.3 3,3’,4,4’,5,5’,6,6’-Decabromodiphenyl Ether (BDE-209) 243 9.10 Triclosan 245 9.11 Conclusions and Future Prospects 245 References 246 10 Abiotic Degradations/Transformations of EDCs Through Oxidation Processes 254 10.1 Introduction 254 10.2 Natural and Synthetic Estrogens 256 10.2.1 17β-Estradiol (E2) and Estrone (E1) 256 10.2.2 17α-Ethinylestradiol (EE2) 260 10.3 Bisphenol A 260 10.3.1 Chlorination with HOCl 263 10.3.2 Catalytic Oxidation with H2O2 263 10.3.3 Oxidation with KMnO4 266 10.3.4 Oxidation with MnO2 267 10.3.5 Treatment with Zero-Valent Aluminum 267 10.3.6 Ozonation 267 10.3.7 Fenton Reaction 270 10.3.8 Photolytic and Photocatalytic Degradation 272 10.4 4-Octylphenol and 4-Nonylphenol 272 10.4.1 Chlorination 272 10.4.2 Ozonation 274 10.4.3 Photocatalytic Degradation 274 10.5 Parabens 274 10.5.1 Ozonation 276 10.5.2 Photocatalytic Degradation 276 10.6 Phthalates – Photocatalytic Degradation 276 10.6.1 Dibutyl Phthalate (DBP) 277 10.6.2 n-Butyl Benzylphthalate 277 10.6.3 Di(2-Ethylhexyl)phthalate (DEHP) 279 10.7 Linuron 279 10.7.1 Treatment with O3 UV and UV/O3 279 10.8 Atrazine 281 10.8.1 Fenton Reaction 281 10.8.2 Reaction with Ozone Ozone/H2O2 and Ozone/OH Radicals 282 10.8.3 Treatment with δ-MnO2 282 10.8.4 Reductive Dechlorination 282 10.8.5 Photocatalytic Degradation 282 10.9 Polybrominated Diphenyl Ether (PBDE) Flame Retardants 282 10.9.1 Photochemical Degradation 282 10.9.2 TiO2-Mediated Photocatalytic Debromination 284 10.9.3 Zero-Valent Iron Reductive Debromination 285 10.10 Triclosan 285 10.10.1 Clorination with HOCl 285 10.10.2 Oxidation with KMnO4/MnO2 286 10.10.3 Ozonation 286 10.10.4 Photochemical Transformation 286 10.11 PFOA and PFOS 289 10.11.1 Modified Fenton Reaction 289 10.11.2 Sonochemical Degradation 289 10.11.3 Photocatalytic Reaction 289 10.12 Conclusions 289 References 290 Part III Screening And Testing For Potential Edcs Implications For Water Quality Sustainability Policy And Regulatory Issues And Green Chemistry Principles In The Design Of Safe Chemicals And Remediation Of Edcs 297 11 Screening and Testing Programs for EDCs 299 11.1 Introduction 299 11.2 Endocrine Disruptor Screening Program (EDSP) 300 11.2.1 EDSP Tier 1 301 11.2.2 EDSP Tier 2 302 11.3 Assays for the Detection of Chemicals that Alter the Estrogen Signaling Pathway 304 11.3.1 The ER Binding Assay (USEPA OPPTS 890.1250) 304 11.3.2 ERα Transcriptional Activation Assay (USEPA OPPTS 890.1300; OECD 455) 304 11.3.3 Aromatase Assay (USEPA OPPTS 890.1200) 306 11.3.4 In vivo Uterotrophic Bioassay in Rodents (USEPA OPPTS 890.1600; OECD 440) 307 11.3.5 Pubertal Female Rat Assay (USEPA OPPTS 890.1450) 308 11.3.6 Twenty-One-Day Fish Reproduction Assay (USEPA OPPTS 890.1350; OECD 229) 308 11.4 Assays for the Detection of Chemicals that Alter the Androgenic Signaling Pathway 308 11.4.1 AR Binding Assay (Rat Prostate Cytosol) (USEPA OPPTS 890.1150) 309 11.4.2 H295R Steroidogenesis Assay (USEPA OPPTS 890.1550) 309 11.4.3 Hershberger Bioassay in Rats for Androgenicity (USEPA OCSPP 890.1400; OECD 441) 309 11.4.4 Pubertal Male Rat Assay (USEPA OPPTS 890.1500) 310 11.4.5 Strengths and Limitations of Assays for Interference with Androgen Action 310 11.5 Assays for the Detection of Chemicals that Alter the HPT Axis 311 11.5.1 Amphibian Metamorphosis Assay (OPPTS 890.1100) 311 11.5.2 Strengths and Limitations of Thyroid Disrupting Chemical Assays 311 11.6 The USEPA’s EDSP21 Work Plan 312 11.6.1 The USEPA ToxCast Program 313 11.6.2 Tox21 HTS Programs 314 11.7 Conclusions and Future Prospects 316 References 317 12 Trace Contaminants: Implications for Water Quality Sustainability 320 12.1 Introduction 320 12.2 Trace Contaminants Sources in Water 321 12.3 Wastewater Reclamation Processes 323 12.3.1 Primary Treatment: Sedimentation/Coagulation 323 12.3.2 Secondary Treatment: Removal by Physical Methods or Biological Process 324 12.3.3 Tertiary Treatment: Redox Processes 325 12.4 Indirect Water Reuse Systems 326 12.4.1 Removal of Trace Contaminants for Potable Water Reuse Applications 326 12.5 Leaching of Contaminants in Water – the Case of Bottled Water 327 12.6 Water Quality Sustainability and Health Effects 328 12.7 Toxicological Implications 329 12.8 Regulatory Structures to Maintain Water Quality 330 12.9 Conclusions and Future Prospects 331 References 333 13 Policy and Regulatory Considerations for EDCs 339 13.1 Introduction 339 13.2 Regulating Paradigm Shift in Conventional Toxicology 340 13.2.1 Downward Movement of Safe Thresholds 341 13.2.2 Nonmonotonic Low-Dose Effects (Nonthreshold substances) 341 13.2.3 Sensitivity of Development Periods 342 13.2.4 Cumulative Exposures to Multiple EDCs (Exposures can be Additive) 342 13.2.5 Long Latency Between Exposure and Effect (Delayed Effects) 343 13.3 Policy Options for EDC Regulation 344 13.3.1 Scientific Uncertainty and Precautionary Policy 344 13.3.2 Shifting the Burden of Proving Safe Products 345 13.3.3 Need to Broaden the Risk Assessment 346 13.3.4 Cutting-Edge Bioassays Showing Developmental Endpoints 346 13.4 Controversy on Regulatory Framework for EDCs 348 13.4.1 Diversity of Viewpoints of the Risk Assessors and the Endocrine Scientists 348 13.4.2 A Debate on EU Regulatory Framework for EDCs 350 13.5 Conclusions and Future Prospects 351 References 353 14 Green Chemistry Principles in the Designing and Screening for Safe Chemicals and Remediation of EDCs 357 14.1 Introduction 357 14.2 Benign by Design Chemicals 358 14.3 Chemical Endocrine Disruption Screening Protocol 361 14.3.1 Tiered Protocol for Endocrine Disruption 361 14.4 Green Oxidative Remediation of EDCs 363 14.4.1 Catalytic Oxidation Processes 364 14.5 Conclusions and Future Prospects 366 References 368 Index 371

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Book SynopsisThe third edition of this highly popular scientific reference continues to provide a unique approach to flavors, flavor chemistry and natural products. Dictionary of Flavors features entries on all flavor ingredients granted G.R.A.S. status, compounds used in the formulation of food flavors, and related food science and technology terms. Allergies and intolerances are addressed, along with strategies to avoid allergenic compounds. This latest edition has been fully updated to reflect new ingredients available on the market, as well as developments in safety standards and the international regulatory arena. Dolf De Rovira applies his extensive experience to make this the most comprehensive guide to flavors available.Table of ContentsIntroduction viNon-Text and Numerical Abbreviations viiDictionary of Flavors 3Flavor Ingredient and Miscellaneous Charts 325Appendix I: Abbreviations and Acronyms (Regulatory Issues and Organizations) 574Appendix II: Nutraceuticals Overview 579Appendix III: List of Chemicals 608Appendix IV: Natural Flavoring Complexes and other Miscellaneous Charts 610Appendix V: List of Figures 618References 620

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Book SynopsisIt has long been recognized that metal spin states play a central role in the reactivity of important biomolecules, in industrial catalysis and in spin crossover compounds. As the fields of inorganic chemistry and catalysis move towards the use of cheap, non-toxic first row transition metals, it is essential to understand the important role of spin states in influencing molecular structure, bonding and reactivity. Spin States in Biochemistry and Inorganic Chemistry provides a complete picture on the importance of spin states for reactivity in biochemistry and inorganic chemistry, presenting both theoretical and experimental perspectives. The successes and pitfalls of theoretical methods such as DFT, ligand-field theory and coupled cluster theory are discussed, and these methods are applied in studies throughout the book. Important spectroscopic techniques to determine spin states in transition metal complexes and proteins are explained, and the use of NMR for the analyTrade Review"Spin States in Biochemistry and Inorganic Chemistry: Influence on Structure and Reactivity, edited by Marcel Swart and Miquel Costas is impressive testimony to the advances in theory, computations, and experiment, especially regarding transition metals in recent years, and a revealing look at how much remains to be developed....The authors provide detailed comparison of various computational methods with each other and with experimental data in many cases. Each chapter is an extensively referenced focused review article. Chapters 1-3 emphasize computational methods....No single monograph can encompass a topic as broad as the title of this book, which is almost the entire chemistry of the periodic table. However, for the selected topics, the volume provides a very valuable concise snapshot of the field.Computational chemistry for compounds of CHNO have advanced to the point that many experimentalists can routinely apply standard methods in Gaussian and other such programs with confidence, guided only by the state of the art described in other publications. This book shows that in spite of enormous effort related to transition metal energy states and spin states, even the expert computational chemists need to proceed with caution and compare many functionals"- (Gareth Eaton- December 2016)Table of ContentsAbout the Editors xv List of Contributors xvii Foreword xxi Acknowledgments xxiii 1 General Introduction to Spin States 1Marcel Swart and Miquel Costas 1.1 Introduction 1 1.2 Experimental Chemistry: Reactivity, Synthesis and Spectroscopy 2 1.3 Computational Chemistry: Quantum Chemistry and Basis Sets 4 2 Application of Density Functional and Density Functional Based Ligand Field Theory to Spin States 7Claude Daul, Matija Zlatar, Maja Gruden-Pavlovic and Marcel Swart 2.1 Introduction 7 2.2 What Is the Problem with Theory? 9 2.2.1 Density Functional Theory 9 2.2.2 LF Theory: Bridging the Gap Between Experimental and Computational Coordination Chemistry 11 2.3 Validation and Application Studies 15 2.3.1 Use of OPBE, SSB-D and S12g Density Functionals for Spin-State Splittings 17 2.3.2 Application of LF-DFT 21 2.4 Concluding Remarks 25 3 Ab Initio Wavefunction Approaches to Spin States 35Carmen Sousa and Coen de Graaf 3.1 Introduction and Scope 35 3.2 Wavefunction-Based Methods for Spin States 35 3.2.1 Single Reference Methods 36 3.2.2 Multireference Methods 37 3.2.3 MR Perturbation Theory 39 3.2.4 Variational Approaches 40 3.2.5 Density Matrix Renormalization Group Theory 40 3.3 Spin Crossover 41 3.3.1 Choice of Active Space and Basis Set 41 3.3.2 The HS–LS Energy Difference 43 3.3.3 Light-Induced Excited Spin State Trapping (LIESST) 45 3.3.4 Spin Crossover in Other Metals 47 3.4 Magnetic Coupling 47 3.5 Spin States in Biochemical and Biomimetic Systems 50 3.6 Two-State Reactivity 52 3.7 Concluding Remarks 52 4 Experimental Techniques for Determining Spin States 59Carole Duboc and Marcello Gennari 4.1 Introduction 59 4.2 Magnetic Measurements 61 4.2.1 g-Anisotropy and Zero-Field Splitting (zfs) 64 4.2.2 Unquenched Orbital Moment in the Ground State 64 4.2.3 Exchange Interactions 64 4.2.4 Spin Transitions and Spin Crossover 66 4.3 EPR Spectroscopy 66 4.4 Mössbauer Spectroscopy 70 4.5 X-ray Spectroscopic Techniques 74 4.6 NMR Spectroscopy 77 4.7 Other Techniques 80 4.A Appendix 81 4.A.1 Theoretical Background 81 4.A.2 List of Symbols 82 5 Molecular Discovery in Spin Crossover 85Robert J. Deeth 5.1 Introduction 85 5.2 Theoretical Background 85 5.2.1 Spin Transition Curves 88 5.2.2 Light-Induced Excited Spin State Trapping 89 5.3 Thermal SCO Systems: Fe(II) 90 5.4 SCO in Non-d6 Systems 93 5.5 Computational Methods 95 5.6 Outlook 98 6 Multiple Spin-State Scenarios in Organometallic Reactivity 103Wojciech I. Dzik, Wesley Böhmer and Bas de Bruin 6.1 Introduction 103 6.2 "Spin-Forbidden" Reactions and Two-State Reactivity 104 6.3 Spin-State Changes in Transition Metal Complexes 107 6.3.1 Influence of the Spin State on the Kinetics of Ligand Exchange 108 6.3.2 Stoichiometric Bond Making and Breaking Reactions 109 6.3.3 Spin-State Situations Involving Redox-Active Ligands 115 6.4 Spin-State Changes in Catalysis 119 6.4.1 Catalytic (Cyclo)oligomerizations 119 6.4.2 Phillips Cr(II)/SiO2 Catalyst 121 6.4.3 SNS–CrCl3 Catalyst 123 6.5 Concluding Remarks 125 7 Principles and Prospects of Spin-States Reactivity in Chemistry and Bioinorganic Chemistry 131Dandamudi Usharani, Binju Wang, Dina A. Sharon and Sason Shaik 7.1 Introduction 131 7.2 Spin-States Reactivity 132 7.2.1 Two-State and Multi-State Reactivity 133 7.2.2 Origins of Spin-Selective Reactivity: Exchange-Enhanced Reactivity and Orbital Selection Rules 137 7.2.3 Considerations of Exchange-Enhanced Reactivity versus Orbital-Controlled Reactivity 140 7.2.4 Consideration of Spin-State Selectivity in H-Abstraction: The Power of EER 142 7.2.5 The Origins of Mechanistic Selection – Why Are C–H Hydroxylations Stepwise Processes? 146 7.3 Prospects of Two-State Reactivity and Multi-State Reactivity 148 7.3.1 Probing Spin-State Reactivity 148 7.3.2 Are Spin Inversion Probabilities Useful for Analyzing TSR? 150 7.4 Concluding Remarks 151 8 Multiple Spin-State Scenarios in Gas-Phase Reactions 157Jana Roithová 8.1 Introduction 157 8.2 Experimental Methods for the Investigation of Metal-Ion Reactions 158 8.3 Multiple State Reactivity: Reactions of Metal Cations with Methane 160 8.4 Effect of the Oxidation State: Reactions of Metal Hydride Cations with Methane 163 8.5 Two-State Reactivity: Reactions of Metal Oxide Cations 164 8.6 Effect of Ligands 171 8.7 Effect of Noninnocent Ligands 174 8.8 Concluding Remarks 177 9 Catalytic Function and Mechanism of Heme and Nonheme Iron(IV)–Oxo Complexes in Nature 185Matthew G. Quesne, Abayomi S. Faponle, David P. Goldberg and Sam P. de Visser 9.1 Introduction 185 9.2 Cytochrome P450 Enzymes 186 9.2.1 Importance of Cytochrome P450 Enzymes 187 9.2.2 P450 Activation of Long-Chain Fatty Acids 188 9.2.3 Heme Monooxygenases and Peroxygenases 188 9.2.4 Catalytic Cycle of Cytochrome P450 Enzymes 188 9.3 Nonheme Iron Dioxygenases 190 9.3.1 Cysteine Dioxygenase 191 9.3.2 AlkB Repair Enzymes 192 9.3.3 Nonheme Iron Halogenases 194 9.4 Conclusions 197 9.5 Acknowledgments 197 10 Terminal Metal–Oxo Species with Unusual Spin States 203Sarah A. Cook, David C. Lacy and Andy S. Borovik 10.1 Introduction 203 10.2 Bonding 204 10.2.1 Bonding Considerations: Tetragonal Symmetry 204 10.2.2 Bonding Considerations: Trigonal Symmetry 205 10.2.3 Methods of Characterization 206 10.3 Case Studies 206 10.3.1 Iron–Oxo Chemistry 206 10.3.2 Manganese–Oxo Chemistry 212 10.3.3 Cautionary Tales: Late Transition Metal Oxido Complexes 217 10.3.4 Effects of Redox Inactive Metal Ions 217 10.3.5 Metal–Oxyl Complexes 218 10.4 Reactivity 218 10.4.1 General Concepts: Proton versus Electron Transfer 218 10.4.2 Spin State and Reactivity 220 10.5 Summary 220 11 Multiple Spin Scenarios in Transition-Metal Complexes Involving Redox Non-Innocent Ligands 229Florian Heims and Kallol Ray 11.1 Introduction 229 11.2 Survey of Non-Innocent Ligands 231 11.3 Identification of Non-Innocent Ligands 232 11.3.1 X-ray Crystallography 232 11.3.2 EPR Spectroscopy 234 11.3.3 Mössbauer Spectroscopy 235 11.3.4 XAS Spectroscopy 236 11.4 Selected Examples of Biological and Chemical Systems Involving Non-Innocent Ligands 237 11.4.1 Copper–Radical Interaction 237 11.4.2 Iron–Radical Interaction 246 11.5 Concluding Remarks 252 12 Molecular Magnetism 263Guillem Aromí, Patrick Gamez and Olivier Roubeau 12.1 Introduction 263 12.2 Molecular Magnetism: Motivations, Early Achievements and Foundations 264 12.3 Molecular Nanomagnets (MNM) 265 12.3.1 Single-Molecule Magnets 266 12.3.2 Single-Chain Magnets (SCM) 268 12.3.3 Single-Ion Magnets (SIM) 271 12.4 Switchable Systems 273 12.4.1 Spin Crossover (SCO) 273 12.4.2 Valence Tautomerism (VT) 273 12.4.3 Charge Transfer (CT) 275 12.4.4 Light-Driven Ligand-Induced Spin Change (LD-LISC) 276 12.4.5 Photoswitching (PS) Through Intermetallic CT 277 12.5 Molecular-Based Magnetic Refrigerants 278 12.5.1 The Magneto-Caloric Effect, Its Experimental Determination and Key Parameters 278 12.5.2 Molecular to Extended Framework Coolers Towards Applications 280 12.6 Quantum Manipulation of the Electronic Spin for Quantum Computing 282 12.6.1 Organic Radicals 283 12.6.2 Transition Metal Clusters 284 12.6.3 Lanthanides as Realization of Qubits 285 12.6.4 Engineering of Molecular Quantum Gates with Lanthanide Qubits 285 12.7 Perspectives Toward Applications and Concluding Remarks 287 13 Electronic Structure, Bonding, Spin Coupling, and Energetics of Polynuclear Iron–Sulfur Clusters – A Broken Symmetry Density Functional Theory Perspective 297Kathrin H. Hopmann, Vladimir Pelmenschikov, Wen-Ge Han Du and Louis Noodleman 13.1 Introduction 297 13.2 Iron–Sulfur Coordination: Geometric and Electronic Structure 298 13.3 Spin Polarization Splitting and the Inverted Level Scheme 300 13.4 Spin Coupling and the Broken Symmetry Method 300 13.5 Electron Localization and Delocalization 301 13.6 Polynuclear Systems – Competing Heisenberg Interactions and Spin-Dependent Delocalization 303 13.7 Preamble to Three Major Topics: Iron–Sulfur–Nitrosyls, Adenosine-5'-Phosphosulfate Reductase, and the Proximal Cluster of Membrane-Bound [NiFe]-Hydrogenase 303 13.7.1 Nonheme Iron Nitrosyl Complexes 303 13.7.2 Adenosine-5'-Phosphosulfate Reductase 310 13.7.3 Proximal Cluster of O2-Tolerant Membrane-Bound [NiFe]-Hydrogenase in Three Redox States 315 13.8 Concluding Remarks 318 13.9 Acknowledgments 319 14 Environment Effects on Spin States, Properties, and Dynamics from Multi-level QM/MM Studies 327Alexander Petrenko and Matthias Stein 14.1 Introduction 327 14.1.1 Environmental Effects 328 14.1.2 Hybrid QM/MM Embedding Schemes 329 14.2 The Quantum Spin Hamiltonian – Linking Theory and Experiment 332 14.3 The Solvent as an Environment 335 14.3.1 Fourier Transform Infrared Spectroscopy 336 14.3.2 Nuclear Magnetic Resonance 336 14.3.3 Electron Paramagnetic Resonance 336 14.4 Effect of Different Levels of QM and MM Treatment 338 14.4.1 Convergence and Caveats at the QM Level 338 14.4.2 Accuracy of the MM Part 341 14.4.3 QM versus QM/MM Methods 341 14.5 Illustrative Bioinorganic Examples 343 14.5.1 Cytochrome P450 343 14.5.2 Hydrogenase Enzymes 349 14.5.3 Photosystem II and the Effect of QM Size 354 14.6 From Static Spin-State Properties to Dynamics and Kinetics of Electron Transfer 357 14.7 Final Remarks and Conclusions 359 14.8 Acknowledgments 362 15 High-Spin and Low-Spin States in {FeNO}7, FeIV=O, and FeIII–OOH Complexes and Their Correlations to Reactivity 369Edward I. Solomon, Kyle D. Sutherlin and Martin Srnec 15.1 Introduction 369 15.2 High- and Low-Spin {FeNO}7 Complexes: Correlations to O2 Activation 372 15.2.1 Spectroscopic Definition of the Electronic Structure of High-Spin {FeNO}7 372 15.2.2 Computational Studies of S = 3/2 {FeNO}7 Complexes and Related {FeO2}8 Complexes 375 15.2.3 Extension to IPNS and HPPD: Implications for Reactivity 377 15.2.4 Correlation to {FeNO}7 S = 1/2 385 15.3 Low-Spin (S = 1) and High-Spin (S = 2) FeIV=O Complexes 386 15.3.1 FeIV=O S = 1 Complexes: π* FMO 386 15.3.2 FeIV=O S = 2 Sites: π* and σ* FMOs 390 15.3.3 Contributions of FMOs to Reactivity 392 15.4 Low-Spin (S = 1/2) and High-Spin (S = 5/2) FeIII–OOH Complexes 396 15.4.1 Spin State Dependence of O–O Bond Homolysis 396 15.4.2 FeIII–OOH S = 1/2 Reactivity: ABLM 398 15.4.3 FeIII–OOH Spin State-Dependent Reactivity: FMOs 399 15.5 Concluding Remarks 401 15.6 Acknowledgments 402 16 NMR Analysis of Spin Densities 409Kara L. Bren 16.1 Introduction and Scope 409 16.2 Spin Density Distribution in Transition Metal Complexes 410 16.3 NMR of Paramagnetic Molecules 412 16.3.1 Chemical Shifts 413 16.3.2 Relaxation Rates 414 16.4 Analysis of Spin Densities by NMR 416 16.4.1 Factoring Contributions to Hyperfine Shifts 416 16.4.2 Relaxation Properties and Spin Density 418 16.4.3 DFT Approaches to Analyzing Hyperfine Shifts 419 16.4.4 Natural Bond Orbital Analysis 420 16.4.5 Application and Practicalities 421 16.5 Probing Spin Densities in Paramagnetic Metalloproteins 422 16.5.1 Heme Proteins 422 16.5.2 Iron-Sulfur Proteins 425 16.5.3 Copper Proteins 427 16.6 Conclusions and Outlook 429 17 Summary and Outlook 435Miquel Costas and Marcel Swart 17.1 Summary 435 17.2 Outlook 436 Index 439

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Book SynopsisThe Essential Reference for the Field, Featuring Protocols, Analysis, Fundamentals, and the Latest Advances Impedance Spectroscopy: Theory, Experiment, and Applications provides a comprehensive reference for graduate students, researchers, and engineers working in electrochemistry, physical chemistry, and physics. Covering both fundamentals concepts and practical applications, this unique reference provides a level of understanding that allows immediate use of impedance spectroscopy methods. Step-by-step experiment protocols with analysis guidance lend immediate relevance to general principles, while extensive figures and equations aid in the understanding of complex concepts. Detailed discussion includes the best measurement methods and identifying sources of error, and theoretical considerations for modeling, equivalent circuits, and equations in the complex domain are provided for most subjects under investigation. Written by a team of expert contributTable of ContentsPreface to the Third Edition xi Preface to the Second Edition xiii Preface to the First Edition xv Contributors to the Third Edition xvii Chapter 1 Fundamentals of Impedance Spectroscopy 1J. Ross Macdonald and William B. Johnson 1 1.1 Background, Basic Definitions, and History 1 1.1.1 The Importance of Interfaces 1 1.1.2 The Basic Impedance Spectroscopy Experiment 2 1.1.3 Response to a Small-Signal Stimulus in the Frequency Domain 3 1.1.4 Impedance-Related Functions 5 1.1.5 Early History 6 1.2 Advantages and Limitations 7 1.2.1 Differences between Solid-State and Aqueous Electrochemistry 9 1.3 Elementary Analysis of Impedance Spectra 10 1.3.1 Physical Models for Equivalent Circuit Elements 10 1.3.2 Simple RC Circuits 11 1.3.3 Analysis of Single Impedance Arcs 12 1.4 Selected Applications of IS 16 Chapter 2 Theory 21Ian D. Raistrick, J. Ross Macdonald, and Donald R. Franceschetti 21 2.1 The Electrical Analogs of Physical and Chemical Processes 21 2.1.1 Introduction 21 2.1.2 The Electrical Properties of Bulk Homogeneous Phases 23 2.1.2.1 Introduction 23 2.1.2.2 Dielectric Relaxation in Materials with a Single Time Constant 23 2.1.2.3 Distributions of Relaxation Times 27 2.1.2.4 Conductivity and Diffusion in Electrolytes 34 2.1.2.5 Conductivity and Diffusion: A Statistical Description 36 2.1.2.6 Migration in the Absence of Concentration Gradients 38 2.1.2.7 Transport in Disordered Media 40 2.1.3 Mass and Charge Transport in the Presence of Concentration Gradients 45 2.1.3.1 Diffusion 45 2.1.3.2 Mixed Electronic–Ionic Conductors 49 2.1.3.3 Concentration Polarization 50 2.1.4 Interfaces and Boundary Conditions 51 2.1.4.1 Reversible and Irreversible Interfaces 51 2.1.4.2 Polarizable Electrodes 52 2.1.4.3 Adsorption at the Electrode–Electrolyte Interface 54 2.1.4.4 Charge Transfer at the Electrode–Electrolyte Interface 56 2.1.5 Grain Boundary Effects 60 2.1.6 Current Distribution: Porous and Rough Electrodes—The Effect of Geometry 62 2.1.6.1 Current Distribution Problems 62 2.1.6.2 Rough and Porous Electrodes 63 2.2 Physical and Electrochemical Models 67 2.2.1 The Modeling of Electrochemical Systems 67 2.2.2 Equivalent Circuits 67 2.2.2.1 Unification of Immittance Responses 67 2.2.2.2 Distributed Circuit Elements 69 2.2.2.3 Ambiguous Circuits 75 2.2.3 Modeling Results 79 2.2.3.1 Introduction 79 2.2.3.2 Supported Situations 80 2.2.3.3 Unsupported Situations: Theoretical Models 84 2.2.3.4 Equivalent Network Models 96 2.2.3.5 Unsupported Situations: Empirical and Semiempirical Models 97 Chapter 3 Measuring Techniques and Data Analysis 107Michael C. H. McKubre, Digby D. Macdonald, Brian Sayers, and J. Ross Macdonald 107 3.1 Impedance Measurement Techniques 107 3.1.1 Introduction 107 3.1.2 Frequency Domain Methods 108 3.1.2.1 Audio Frequency Bridges 108 3.1.2.2 Transformer Ratio Arm Bridges 110 3.1.2.3 Berberian–Cole Bridge 112 3.1.2.4 Considerations of Potentiostatic Control 115 3.1.2.5 Oscilloscopic Methods for Direct Measurement 116 3.1.2.6 Phase-Sensitive Detection for Direct Measurement 118 3.1.2.7 Automated Frequency Response Analysis 119 3.1.2.8 Automated Impedance Analyzers 122 3.1.2.9 The Use of Kramers–Kronig Transforms 124 3.1.2.10 Spectrum Analyzers 126 3.1.3 Time-Domain Methods 128 3.1.3.1 Introduction 128 3.1.3.2 Analog-to-Digital Conversion 129 3.1.3.3 Computer Interfacing 133 3.1.3.4 Digital Signal Processing 135 3.1.4 Conclusions 138 3.2 Commercially Available Impedance Measurement Systems 139 3.2.1 General Measurement Techniques 139 3.2.1.1 Current-to-Voltage (I–E) Conversion Techniques 139 3.2.1.2 Measurements Using 2-, 3-, or 4-Terminal Techniques 144 3.2.1.3 Measurement Resolution and Accuracy 146 3.2.1.4 Single Sine and FFT Measurement Techniques 148 3.2.2 Electrochemical Impedance Measurement Systems 152 3.2.2.1 System Configuration 152 3.2.2.2 Why Use a Potentiostat? 152 3.2.2.3 Multi-electrode Techniques 153 3.2.2.4 Effects of Connections and Input Impedance 154 3.2.2.5 Verification of Measurement Performance 155 3.2.2.6 Floating Measurement Techniques 156 3.2.2.7 Multichannel Techniques 157 3.2.3 Materials Impedance Measurement Systems 157 3.2.3.1 System Configuration 157 3.2.3.2 Measurement of Low Impedance Materials 158 3.2.3.3 Measurement of High Impedance Materials 158 3.2.3.4 Reference Techniques 159 3.2.3.5 Normalization Techniques 159 3.2.3.6 High Voltage Measurement Techniques 160 3.2.3.7 Temperature Control 160 3.2.3.8 Sample Holder Considerations 161 3.3 Data Analysis 161 3.3.1 Data Presentation and Adjustment 161 3.3.1.1 Previous Approaches 161 3.3.1.2 Three-Dimensional Perspective Plotting 162 3.3.1.3 Treatment of Anomalies 164 3.3.2 Data Analysis Methods 166 3.3.2.1 Simple Methods 166 3.3.2.2 Complex Nonlinear Least Squares 167 3.3.2.3 Weighting 168 3.3.2.4 Which Impedance-Related Function to Fit? 169 3.3.2.5 The Question of “What to Fit” Revisited 169 3.3.2.6 Deconvolution Approaches 169 3.3.2.7 Examples of CNLS Fitting 170 3.3.2.8 Summary and Simple Characterization Example 172 Chapter 4 Applications of Impedance Spectroscopy 175 4.1 Characterization of Materials 175N. Bonanos, B. C. H. Steele, and E. P. Butler 175 4.1.1 Microstructural Models for Impedance Spectra of Materials 175 4.1.1.1 Introduction 175 4.1.1.2 Layer Models 176 4.1.1.3 Effective Medium Models 183 4.1.1.4 Modeling of Composite Electrodes 191 4.1.2 Experimental Techniques 194 4.1.2.1 Introduction 194 4.1.2.2 Measurement Systems 195 4.1.2.3 Sample Preparation: Electrodes 199 4.1.2.4 Problems Associated with the Measurement of Electrode Properties 201 4.1.3 Interpretation of the Impedance Spectra of Ionic Conductors and Interfaces 203 4.1.3.1 Introduction 203 4.1.3.2 Characterization of Grain Boundaries by IS 204 4.1.3.3 Characterization of Two-Phase Dispersions by IS 215 4.1.3.4 Impedance Spectra of Unusual Two-Phase Systems 218 4.1.3.5 Impedance Spectra of Composite Electrodes 219 4.1.3.6 Closing Remarks 224 4.2 Characterization of the Electrical Response of Wide-Range-Resistivity Ionic and Dielectric Solid Materials by Immittance Spectroscopy 224J. Ross Macdonald 224 4.2.1 Introduction 224 4.2.2 Types of Dispersive Response Models: Strengths and Weaknesses 225 4.2.2.1 Overview 225 4.2.2.2 Variable-Slope Models 226 4.2.2.3 Composite Models 227 4.2.3 Illustration of Typical Data Fitting Results for an Ionic Conductor 233 4.2.4 Utility and Importance of Poisson–Nernst–Planck (PNP) Fitting Models 239 4.2.4.1 Introduction 239 4.2.4.2 Selective History of PNP Work 240 4.2.4.3 Exact PNP Responses at All Four Immittance Levels 243 4.3 Solid-State Devices 247William B. Johnson, Wayne L. Worrell, Gunnar A. Niklasson, Sara Malmgren, Maria Strømme, and S. K. Sundaram 247 4.3.1 Electrolyte–Insulator–Semiconductor (EIS) Sensors 248 4.3.2 Solid Electrolyte Chemical Sensors 254 4.3.3 Photoelectrochemical Solar Cells 258 4.3.4 Impedance Response of Electrochromic Materials and Devices 263 4.3.4.1 Introduction 263 4.3.4.2 Materials 265 4.3.4.3 Theoretical Background 266 4.3.4.4 Experimental Results on Single Materials 270 4.3.4.5 Experimental Results on Electrochromic Devices 280 4.3.4.6 Conclusions and Outlook 280 4.3.5 Fast Processes in Gigahertz–Terahertz Region in Disordered Materials 281 4.3.5.1 Introduction 281 4.3.5.2 Lunkenheimer–Loidl Plot and Scaling of the Processes 282 4.3.5.3 Dynamic Processes 285 4.3.5.4 Final Remarks 292 4.4 Corrosion of Materials 292Michael C. H. McKubre, Digby D. Macdonald, and George R. Engelhardt 292 4.4.1 Introduction 292 4.4.2 Fundamentals 293 4.4.3 Measurement of Corrosion Rate 293 4.4.4 Harmonic Analysis 297 4.4.5 Kramers–Kronig Transforms 303 4.4.6 Corrosion Mechanisms 306 4.4.6.1 Active Dissolution 306 4.4.6.2 Active–Passive Transition 308 4.4.6.3 The Passive State 312 4.4.7 Reaction Mechanism Analysis of Passive Metals 324 4.4.7.1 The Point Defect Model 324 4.4.7.2 Prediction of Defect Distributions 334 4.4.7.3 Optimization of the PDM on the Impedance Data 335 4.4.7.4 Sensitivity Analysis 339 4.4.7.5 Extraction of PDM Parameters from EIS Data 343 4.4.7.6 Simplified Method for Expressing the Impedance of a Stationary Barrier Layer 349 4.4.7.7 Comparison of Simplified Model with Experiment 355 4.4.7.8 Summary and Conclusions 359 4.4.8 Equivalent Circuit Analysis 360 4.4.8.1 Coatings 365 4.4.9 Other Impedance Techniques 366 4.4.9.1 Electrochemical Hydrodynamic Impedance (EHI) 366 4.4.9.2 Fracture Transfer Function (FTF) 368 4.4.9.3 Electrochemical Mechanical Impedance 370 4.5 Electrochemical Power Sources 373Evgenij Barsoukov, Brian E. Conway, Wendy G. Pell, and Norbert Wagner 373 4.5.1 Special Aspects of Impedance Modeling of Power Sources 373 4.5.1.1 Intrinsic Relation between Impedance Properties and Power Source Performance 373 4.5.1.2 Linear Time-Domain Modeling Based on Impedance Models: Laplace Transform 374 4.5.1.3 Expressing Electrochemical Model Parameters in Electrical Terms, Limiting Resistances, and Capacitances of Distributed Elements 376 4.5.1.4 Discretization of Distributed Elements, Augmenting Equivalent Circuits 379 4.5.1.5 Nonlinear Time-Domain Modeling of Power Sources Based on Impedance Models 381 4.5.1.6 Special Kinds of Impedance Measurement Possible with Power Sources: Passive Load Excitation and Load Interrupt 384 4.5.2 Batteries 386 4.5.2.1 Generic Approach to Battery Impedance Modeling 386 4.5.2.2 Lead–Acid Batteries 396 4.5.2.3 Nickel–Cadmium Batteries 398 4.5.2.4 Nickel–Metal Hydride Batteries 399 4.5.2.5 Li-ion Batteries 400 4.5.3 Nonideal Behavior Developed in Porous Electrode Supercapacitors 406 4.5.3.1 Introduction 406 4.5.3.2 Equivalent Circuits and Representation of Electrochemical Capacitor Behavior 409 4.5.3.3 Impedance and Voltammetry Behavior of Brush Electrode Models of Porous Electrodes 417 4.5.3.4 Deviations from Ideality 421 4.5.4 Fuel Cells 424 4.5.4.1 Introduction 424 4.5.4.2 Alkaline Fuel Cells (AFCs) 437 4.5.4.3 Polymer Electrolyte Fuel Cells (PEFCs) 443 4.5.4.4 The Solid Oxide Fuel Cells (SOFCs) 454 4.6 Dielectric Relaxation Spectroscopy 459C. M. Roland 459 4.6.1 Introduction 459 4.6.2 Dielectric Relaxation 460 4.6.2.1 Ion Conductivity 462 4.6.2.2 Dielectric Modulus 467 4.6.2.3 Use of Impedance Function in Dielectric Relaxation Experiments 467 4.6.2.4 Summary 472 4.7 Electrical Structure of Biological Cells and Tissues: Impedance Spectroscopy, Stereology, and Singular Perturbation Theory 472Robert S. Eisenberg 472 4.7.1 Impedance Spectroscopy of Biological Structures Is a Platform Resting on Four Pillars 474 4.7.1.1 Anatomical Measurements 474 4.7.1.2 Impedance Measurements 475 4.7.1.3 Measurement Difficulties 476 4.7.1.4 Future Measurements 476 4.7.1.5 Interpreting Impedance Spectroscopy 477 4.7.1.6 Fitting Data 477 4.7.1.7 Results 477 4.7.1.8 Future Perspectives 478Acronym and Model Definitions 479References 481 Index 517

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Book SynopsisThis book continues the legacy of a well-established reference within the pharmaceutical industry providing perspective, covering recent developments in technologies that have enabled the expanded use of biomarkers, and discussing biomarker characterization and validation and applications throughout drug discovery and development. Explains where proper use of biomarkers can substantively impact drug development timelines and costs, enable selection of better compounds and reduce late stage attrition, and facilitate personalized medicine Helps readers get a better understanding of biomarkers and how to use them, for example which are accepted by regulators and which still non-validated and exploratory Updates developments in genomic sequencing, and application of large data sets into pre-clinical and clinical testing; and adds new material on data mining, economics, and decision making, personal genetic tools, and wearable monitoring Includes Table of ContentsList of Contributors vii Preface xiii Part I Biomarkers and Their Role in Drug Development 1 1 Biomarkers are Not New 3Ian Dews 2 Biomarkers: Facing the Challenges at the Crossroads of Research and Health Care 15Gregory J. Downing 3 Enabling Go/No Go Decisions 31J. Fred Pritchard and M. Lynn Pritchard 4 Developing a Clinical Biomarker Method with External Resources: A Case Study 43Ross A. Fredenburg Part II Identifying New Biomarkers: Technology Approaches 51 5 Imaging as a Localized Biomarker: Opportunities and Challenges 53Jonathan B. Moody, Philip S. Murphy, and Edward P. Ficaro 6 Imaging for Early Clinical Drug Development: Integrating Imaging Science with Drug Research 89Philip S. Murphy, Mats Bergstrom, Jonathan B. Moody, and Edward P. Ficaro 7 Circulating MicroRNAs as Biomarkers in Cardiovascular and Pulmonary Vascular Disease: Promises and Challenges 113Miranda K. Culley and Stephen Y. Chan Part III Characterization, Validation, and Utilization 139 8 Characterization and Validation of Biomarkers in Drug Development: Regulatory Perspective 141Federico Goodsaid 9 Fit-for-Purpose Method Validation and Assays for Biomarker Characterization to Support Drug Development 149Jean W. Lee, Yuling Wu, and Jin Wang 10 Applying Statistics Appropriately for Your Biomarker Application 177Mary Zacour Part IV Biomarkers in Discovery and Preclinical Safety 219 11 Qualification of Safety Biomarkers for Application to Early Drug Development 221William B. Mattes and Frank D. Sistare 12 A Pathologist’s View of Drug and Biomarker Development 233Robert W. Dunstan 13 Development of Serum Calcium and Phosphorus as Safety Biomarkers for Drug-Induced Systemic Mineralization: Case Study with the MEK Inhibitor PD0325901 255Alan P. Brown 14 New Markers of Kidney Injury 281Sven A. Beushausen Part V Translating from Preclinical to Clinical and Back 307 15 Biomarkers from Bench to Bedside and Back – Back-Translation of Clinical Studies to Preclinical Models 309Damian O'Connell, David Adler, Frank Kramer, and Matthias Ocker 16 Translational Medicine – A Paradigm Shift in Modern Drug Discovery and Development: The Role of Biomarkers 333Giora Z. Feuerstein, Salvatore Alesci, Frank L.Walsh, J. Lynn Rutkowski, and Robert R. Ruffolo Jr. 17 Clinical Validation and Biomarker Translation 347Ji-Young V. Kim, Raymond T. Ng, Robert Balshaw, Paul Keown, Robert McMaster, Bruce McManus, Karen Lam, and Scott J. Tebbutt 18 Predicting and Assessing an Inflammatory Disease and Its Complications: Example from Rheumatoid Arthritis 365Christina Trollmo and Lars Klareskog 19 Validating In Vitro Toxicity Biomarkers Against Clinical Endpoints 379Calvert Louden and Ruth A. Roberts Part VI Biomarkers in Clinical Trials 389 20 Opportunities and Pitfalls Associated with Early Utilization of Biomarkers: A Case Study in Anticoagulant Development 391Kay A. Criswell 21 Integrating Molecular Testing into Clinical Applications 409Anthony A. Killeen Part VII Big Data, Data Mining, and Biomarkers 421 22 IT Supporting Biomarker-Enabled Drug Development 423Michael Hehenberger 23 Identifying Biomarker Profiles Through the Epidemiologic Analysis of Big Health Care Data – Implications for Clinical Management and Clinical Trial Design: A Case Study in Anemia of Chronic Kidney Disease 447Gregory P. Fusco 24 Computational Biology Approaches to Support Biomarker Discovery and Development 469Bin Li, Hyunjin Shin, William L. Trepicchio, and Andrew Dorner Part VIII Lessons Learned: Practical Aspects of Biomarker Implementation 485 25 Biomarkers in Pharmaceutical Development: The Essential Role of Project Management and Teamwork 487Lena King, Mallé Jurima-Romet, and Nita Ichhpurani 26 Novel and Traditional Nonclinical Biomarker Utilization in the Estimation of Pharmaceutical Therapeutic Indices 505Bruce D. Car, Brian Gemzik, and William R. Foster Part IX Where are We Heading and What Do We Really Need? 515 27 Ethics of Biomarkers: The Borders of Investigative Research, Informed Consent, and Patient Protection 517Sara Assadian, Michael Burgess, Breanne Crouch, Karen Lam, and Bruce McManus 28 Anti-Unicorn Principle: Appropriate Biomarkers Don't Need to Be Rare or Hard to Find 537Michael R. Bleavins and Ramin Rahbari 29 Translational Biomarker Imaging: Applications, Trends, and Successes Today and Tomorrow 553Patrick McConville and Deanne Lister Index 585

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