Chemistry Books

Book SynopsisAn important resource that puts the focus on understanding and handling of organic crystals in drug development Since a majority of pharmaceutical solid-state materials are organic crystals, their handling and processing are critical aspects of drug development. Pharmaceutical Crystals: Science and Engineering offers an introduction to and thorough coverage of organic crystals, and explores the essential role they play in drug development and manufacturing. Written contributions from leading researchers and practitioners in the field, this vital resource provides the fundamental knowledge and explains the connection between pharmaceutically relevant properties and the structure of a crystal. Comprehensive in scope, the text covers a range of topics including: crystallization, molecular interactions, polymorphism, analytical methods, processing, and chemical stability. The authors clearly show how to find solutions for pharmaceutical form selection and cryTable of ContentsList of Contributors xiii Preface xv 1 Crystallography 1Susan M. Reutzel-Edens and Peter Müller 1.1 Introduction 1 1.2 History 6 1.3 Symmetry 7 1.3.1 Symmetry in Two Dimensions 7 1.3.2 Symmetry and Translation 11 1.3.3 Symmetry in Three Dimensions 12 1.3.4 Metric Symmetry of the Crystal Lattice 13 1.3.5 Conventions and Symbols 14 1.3.6 Fractional Coordinates 15 1.3.7 Symmetry in Reciprocal Space 15 1.4 Principles of X-ray Diffraction 17 1.4.1 Bragg’s Law 17 1.4.2 Diffraction Geometry 19 1.4.3 Ewald Construction 19 1.4.4 Structure Factors 21 1.4.5 Statistical Intensity Distribution 22 1.4.6 Data Collection 23 1.5 Structure Determination 24 1.5.1 Space Group Determination 24 1.5.2 Phase Problem and Structure Solution 25 1.5.3 Structure Refinement 28 1.5.3.1 Resonant Scattering and Absolute Structure 32 1.6 Powder Methods 33 1.6.1 Powder Diffraction 34 1.6.2 NMR Crystallography 35 1.7 Crystal Structure Prediction 39 1.8 Crystallographic Databases 41 1.9 Conclusions 42 References 43 2 Nucleation 47Junbo Gong and Weiwei Tang 2.1 Introduction 47 2.2 Classical Nucleation Theory 48 2.2.1 Thermodynamics 48 2.2.2 Kinetics of Nucleation 51 2.2.3 Metastable Zone 53 2.2.4 Induction Time 58 2.2.5 Heterogeneous Nucleation 60 2.3 Nonclassical Nucleation 63 2.3.1 Two-Step Mechanism 63 2.3.2 Prenucleation Cluster Pathway 66 2.4 Application of Primary Nucleation 66 2.4.1 Understanding and Control of Polymorphism 66 2.4.2 Liquid–Liquid Phase Separation 71 2.5 Secondary Nucleation 73 2.5.1 Origin from Solution 74 2.5.2 Origin from Crystals 75 2.5.3 Kinetics 76 2.5.4 Application to Continuous Crystallization 76 2.5.5 Crystal Size Distribution 79 2.5.6 Seeding 80 2.6 Summary 81 References 82 3 Solid-state Characterization Techniques 89Ann Newman and Robert Wenslow 3.1 Introduction 89 3.2 Techniques 90 3.2.1 X-ray Powder Diffraction (XRPD) 90 3.2.2 Thermal Methods 94 3.2.2.1 Differential Scanning Calorimetry 94 3.2.2.2 Thermogravimetric Analysis (TGA) 95 3.2.3 Spectroscopy 97 3.2.3.1 Infrared (IR) 97 3.2.3.2 Raman Spectroscopy 99 3.2.3.3 Solid-state Nuclear Magnetic Resonance (SSNMR) 101 3.2.4 Water Sorption 105 3.2.5 Microscopy 106 3.3 Case Study LY334370 Hydrochloride (HCl) 109 3.4 Summary 114 References 114 4 Intermolecular Interactions and Computational Modeling 123Alessandra Mattei and Tonglei Li 4.1 Introduction 123 4.2 Foundation of Intermolecular Interactions 124 4.2.1 Electrostatic Interactions 125 4.2.2 van der Waals Interactions 126 4.2.3 Hydrogen-bonding Interactions 127 4.2.4 π–π Interactions 129 4.3 Intermolecular Interactions in Organic Crystals 130 4.3.1 Approaches to Crystal Packing Description 130 4.3.2 Impact of Intermolecular Interactions on Crystal Packing 136 4.3.3 Impact of Intermolecular Interactions on Crystal Properties 138 4.4 Techniques for Intermolecular Interactions Evaluation 140 4.4.1 Crystallography 140 4.4.2 Spectroscopy 141 4.4.3 Computational Methods 142 4.4.3.1 Lattice Energy 144 4.4.3.2 Interaction Energy of Molecular Pairs from Crystal Structures 147 4.5 Advances in Understanding Intermolecular Interactions 149 4.5.1 Crystal Structure Prediction 150 4.5.2 Electronic Structural Analysis 152 References 160 5 Polymorphism and Phase Transitions 169Haichen Nie and Stephen R. Byrn 5.1 Concepts and Overview 169 5.2 Thermodynamic Principles of Polymorphic Systems 175 5.2.1 Monotropy and Enantiotropy 176 5.2.2 Phase Rule 179 5.2.3 Phase Diagrams 179 5.2.4 Phase Stability Rule 182 5.2.4.1 Heat of Transition Rule 182 5.2.4.2 Heat of Fusion Rule 182 5.2.4.3 Entropy of Fusion Rule 183 5.2.4.4 Heat Capacity Rule 183 5.2.4.5 Density Rule 183 5.2.4.6 Infrared Rule 183 5.2.5 Crystallization of Polymorphs 184 5.2.5.1 Ostwald’s Rule of Stages 184 5.2.5.2 Nucleation 184 5.3 Stabilities and Phase Transition 189 5.3.1 Thermodynamic Stability 189 5.3.2 Chemical Stability 189 5.3.3 Polymorphic Interconversions of Pharmaceuticals 192 5.3.3.1 Effects of Heat, Compression, and Grinding on Polymorphic Transformation 192 5.3.3.2 Solution-mediated Phase Transformation of Drugs 193 5.4 Impact on Bioavailability by Polymorphs 194 5.5 Regulatory Consideration of Polymorphism 196 5.6 Novel Approaches for Preparing Solid State Forms 199 5.6.1 High-throughput Crystallization Method 200 5.6.2 Capillary Growth Methods 200 5.6.3 Laser-induced Nucleation 201 5.6.4 Heteronucleation on Single Crystal Substrates 201 5.6.5 Polymer Heteronucleation 201 5.7 Hydrates and Solvates 202 5.7.1 Thermodynamics of Hydrates 203 5.7.2 Formation of Hydrates 204 5.7.3 Desolvation Reactions 205 5.7.4 Phase Transition of Solvates/Hydrates in Formulation and Process Development 207 5.8 Summary 209 References 210 6 Measurement and Mathematical Relationships of Cocrystal Thermodynamic Properties 223Gislaine Kuminek, Katie L. Cavanagh, and Naír Rodríguez-Hornedo 6.1 Introduction 223 6.2 Structural and Thermodynamic Properties 224 6.2.1 Structural Properties 224 6.2.2 Thermodynamic Properties 226 6.2.2.1 Cocrystal Ksp and Solubility 226 6.2.2.2 Transition Points 229 6.2.2.3 Supersaturation Index Diagrams 231 6.2.3 A Word of Caution About Cmax Obtained from Kinetic Studies 232 6.3 Determination of Cocrystal Thermodynamic Stability and Supersaturation Index 234 6.3.1 Keu Measurement and Relationships Between Ksp, SCC, and SA 234 6.3.2 Cocrystal Solubility and Ksp 241 6.3.3 Cocrystal Supersaturation Index and Drug Solubilization 243 6.4 What Phase Solubility Diagrams Reveal 246 6.5 Cocrystal Discovery and Formation 249 6.5.1 Molecular Interactions That Play an Important Role in Cocrystal Discovery 249 6.5.2 Thermodynamics of Cocrystal Formation Provide Valuable Insight into the Conditions Where Cocrystals May Form 251 6.6 Cocrystal Solubility Dependence on Ionization and Solubilization of Cocrystal Components 253 6.6.1 Mathematical Forms of Cocrystal Solubility and Stability 253 6.6.2 General Solubility Expressions in Terms of the Sum of Equilibrium Concentrations 257 6.6.3 Applications 258 6.7 Conclusions and Outlook 265 References 265 7 Mechanical Properties 273Changquan Calvin Sun 7.1 Introduction 273 7.1.1 Importance of Mechanical Properties in Pharmaceutical Manufacturing 273 7.1.2 Basic Concepts Related to Mechanical Properties 274 7.1.2.1 Stress, Strain, and Poisson’s Ratio 274 7.1.2.2 Elasticity, Plasticity, and Brittleness 276 7.1.2.3 Classification of Mechanical Response 277 7.2 Characterization of Mechanical Properties 278 7.2.1 Experimental Techniques 278 7.2.1.1 Single Crystals 278 7.2.1.2 Bulk Powders 281 7.2.1.3 Tablet Mechanical Properties 282 7.3 Structure–Property Relationship 284 7.3.1 Anisotropy of Organic Crystals 284 7.3.2 Crystal Plasticity, Elasticity, and Fracture 286 7.3.3 Role of Dislocation on Mechanical Properties 287 7.3.4 Effects of Crystal Size and Shape on Mechanical Behavior 289 7.4 Conclusion and Future Outlook 290 References 291 8 Primary Processing of Organic Crystals 297Peter L.D. Wildfong, Rahul V. Haware, Ting Xu, and Kenneth R. Morris 8.1 Introduction 297 8.1.1 Solid Form 297 8.1.2 Morphology 298 8.2 Primary Manufacturing: Processing Materials to Yield Drug Substance 300 8.2.1 Crystallization (Solidification Processing) 301 8.2.1.1 Solvent Power 303 8.2.1.2 Solvent Classification 305 8.2.1.3 Batch Crystallization 307 8.2.1.4 Continuous Crystallization 308 8.2.2 Filtration and Washing 309 8.2.3 Drying (Removal of Crystallization Solvent) 313 8.2.4 Preliminary Particle Sizing 315 8.3 Challenges During Solidification Processing 319 8.3.1 Polymorphism 320 8.3.1.1 Cooling Crystallization 322 8.3.1.2 Solvent Selection 325 8.3.1.3 Antisolvent Crystallization 328 8.3.1.4 Selective Crystallization Using Additives 328 8.3.2 Hydrate and Organic Solvate Formation 329 8.3.2.1 Hydrate Formation 329 8.3.2.2 Organic Solvate Formation 335 8.3.3 Solvent-mediated Transformations (SMTs) 337 8.3.4 Morphology/Habit Control 342 8.3.4.1 Predicting Solvent Effects on Crystal Habit 343 8.3.4.2 Influence of Morphology on Surface Wetting 346 8.3.5 Crystallization Process Control 349 8.4 Summary and Concluding Remarks 350 References 351 9 Secondary Processing of Organic Crystals 361Peter L.D. Wildfong, Rahul V. Haware, Ting Xu, and Kenneth R. Morris 9.1 Introduction 361 9.1.1 Structure and Symmetry 361 9.1.2 Process-induced Transformations (PITs) in 2 Manufacturing 362 9.2 Secondary Manufacturing–Processing Materials to Yield Drug Products 365 9.2.1 Milling of Organic Crystals 366 9.2.1.1 Materials Properties Influencing Milling 366 9.2.1.2 Physical Transformations Associated with Milling 371 9.2.1.3 Chemical Transformations Associated with Milling 375 9.2.2 Pharmaceutical Blending 378 9.2.3 Granulation of Pharmaceutical Materials 382 9.2.3.1 Wet Granulation 384 9.2.3.2 Potential Transformations During Wet Granulation 385 9.2.3.3 Hydration and Dehydration 385 9.2.3.4 Solvent-mediated Transformations (SMT) 388 9.2.3.5 Polymorphic Transitions During Granulation 390 9.2.3.6 Salt Breaking 392 9.2.3.7 Formulation Considerations in Wet Granulation 392 9.2.3.8 Risk Assessment and Summary 394 9.2.4 Consolidation of Organic Crystals 395 9.2.4.1 Materials Properties Contributing to Effective Consolidation 397 9.2.4.2 Structural and Molecular Properties Contributing to Effective Consolidation 402 9.2.4.3 Macroscopic Properties Affecting Effective Consolidation 403 9.2.4.4 Compaction-induced Material Transformations 404 9.2.4.5 Compression Temperature and Material Transformation 407 9.2.5 Data Management Approaches 408 9.3 Summary and Concluding Remarks 411 9.3.1 Development History 411 9.3.2 Risk Assessment 412 References 412 10 Chemical Stability and Reaction 427Alessandra Mattei and Tonglei Li 10.1 Introduction 427 10.2 Overview of Organic Solid-state Reactions 429 10.2.1 Photochemical Reactions 431 10.2.2 Thermal Reactions 432 10.2.3 Mechanochemical Reactions 433 10.2.4 Hydrolysis Reactions 434 10.2.5 Oxidative Reactions 434 10.3 Mechanisms of Organic Solid-state Reactions 436 10.3.1 General Theoretical Concepts 436 10.3.2 Crystal Packing Effects on the Course of Organic Solid-state Reactions 438 10.3.2.1 Perfect Crystals and Topochemical Control of Organic Solid-state Reactions 438 10.3.2.2 Crystal Defects and Nontopochemical Control of Organic Solid-state Reactions 440 10.4 Kinetics of Chemical Reactions: From Homogeneous to Heterogeneous Systems 445 10.4.1 Fundamental Principles of Chemical Kinetics 445 10.4.2 Solid-state Reaction Kinetics 446 10.5 Factors Affecting Chemical Stability 448 10.5.1 Moisture 448 10.5.2 Temperature 448 10.5.3 Pharmaceutical Processing 450 10.6 Strategies to Prevent Chemical Reactions 452 10.6.1 Formulation-related Approaches 453 10.6.2 Prodrugs 454 References 455 11 Crystalline Nanoparticles 463Yi Lu, Wei Wu, and Tonglei Li 11.1 Introduction 463 11.2 Top-down Technology 467 11.2.1 Media Milling (MM) 467 11.2.2 High-pressure Homogenization (HPH) 468 11.3 Bottom-up Technology 471 11.3.1 Precipitation by Solvent–Antisolvent Mixing 471 11.3.1.1 Sonoprecipitation 473 11.3.1.2 CIJP 473 11.3.1.3 HGCP 476 11.3.2 Supercritical Fluid Techniques 476 11.3.2.1 RESS 478 11.3.2.2 SAS 479 11.3.3 Precipitation by Removal of Solvent 479 11.3.3.1 SFL 479 11.3.3.2 CCDF 479 11.4 Nanoparticle Stabilization 480 11.5 Applications 482 11.5.1 Oral Drug Delivery 482 11.5.2 Parenteral Drug Delivery 484 11.5.3 Pulmonary Drug Delivery 485 11.5.4 Ocular Drug Delivery 486 11.5.5 Dermal Drug Delivery 486 11.6 Characterization of Crystalline Nanoparticles 487 11.6.1 Particle Size and Size Distribution 487 11.6.2 Surface Charge 487 11.6.3 Morphology 491 11.6.4 Crystallinity 491 11.6.5 Dissolution 491 References 492 Index 503

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Book SynopsisThe definitive guide to the myriad analytical techniques available to scientists involved in biotherapeutics research Analytical Characterization of Biotherapeutics covers all current and emerging analytical tools and techniques used for the characterization of therapeutic proteins and antigen reagents.Table of ContentsList of Contributors xv 1 Introduction to Biotherapeutics 1Jennie R. Lill 1.1 Introduction 1 1.2 Types of Biotherapeutics and Manufacturing Systems 2 1.3 Types of Analyses Performed 5 1.4 Future perspectives 6 Acknowledgments 11 References 11 2 Mass Spectrometric Characterization of Recombinant Proteins 15Corey E. Bakalarski, Wendy Sandoval, and Jennie R. Lill 2.1 Introduction 16 2.1.1 Ionization 16 2.1.1.1 Matrix Assisted Laser Desorption Ionization 17 2.1.1.2 Electrospray Ionization 19 2.1.2 Mass Analyzers for Intact Molecular Weight Measurement of Biotherapeutics 20 2.1.2.1 Time of Flight and Quadrupole Time of Flight Mass Spectrometers 20 2.1.2.2 High‐Resolution Intact Mass Measurement and Native MS 21 2.1.2.3 Ion Mobility Spectrometry 22 2.1.3 Software for the Analysis of Intact Molecular Weight Measurements 24 2.1.4 Separation Devices for the Characterization of Biotherapeutics 25 2.1.4.1 High‐performance Liquid Chromatography 25 2.1.4.2 Capillary Electrophoresis 26 2.1.4.3 Microfluidic Chromatographic Devices 28 2.2 Peptide Mass Fingerprinting 29 2.3 Tandem Mass Spectrometric Characterization of Biomolecules 30 2.3.1 Bottom‐Up MS 33 2.3.2 Proteoinformatic Analysis of Bottom‐Up Proteomic Data Sets 34 2.3.3 Top‐Down MS 36 2.4 Conclusions and Perspectives 37 References 37 3 Characterizing the Termini of Recombinant Proteins 43Nestor Solis and Christopher M. Overall 3.1 Introduction 44 3.2 Gel Electrophoresis and Edman Sequencing 46 3.3 Mass Spectrometric Approaches for Characterizing True Starts of Proteins 49 3.3.1 Top‐Down Approaches 49 3.3.2 Current Caveats in Mass Spectrometric Identification of Protein Termini 54 3.3.3 Bottom‐up Approaches for Identification of N‐ and C‐Terminal Peptides 55 3.3.4 Amino Terminal Orientated Mass Spectrometry 56 3.3.5 Determining the True Start of Proteins from ATOMS LC‐MS/MS Data 61 3.4 Conclusions 64 References 66 4 Assessing Activity and Conformation of Recombinant Proteins 73Diego Ellerman, Till Maurer, and Justin M. Scheer 4.1 Introduction 74 4.2 Circular Dichroism 75 4.2.1 Applications of CD 77 4.2.1.1 Thermal Stability Analysis 77 4.2.1.2 Characterization of the Effect of PEGylation 77 4.2.1.3 Formulation and Stability Studies 77 4.2.1.4 Analysis of Biosimilars 78 4.2.2 Technical Improvements 78 4.3 DSC and Isothermal Titration Calorimetry 79 4.3.1 Use of DSC and ITC in Therapeutics Discovery 80 4.3.2 Protein Conjugation 82 4.3.3 Formulation and Stability 82 4.3.4 Analysis of Biosimilars 83 4.4 Hydrogen–Deuterium Exchange–Mass Spectrometry 85 4.4.1 Applications of HDX 86 4.4.1.1 Ligand‐induced Conformational Changes and Mapping Interaction Sites 86 4.4.1.2 Applications in Protein Engineering 86 4.4.1.3 Comparability and Biosimilar Studies 88 4.4.1.4 Formulation and Aggregation Analysis 89 4.4.2 Technical Improvements and Challenges 89 4.5 Nuclear Magnetic Resonance 90 4.5.1 Applications of NMR 92 4.5.1.1 Flexible Proteins 92 4.5.1.2 Mapping Protein–Protein Interactions 93 4.5.1.3 Epitope Mapping 94 4.5.1.4 Protein Dynamics 94 4.5.1.5 Protein Conjugates and Complexes 94 4.5.1.6 Posttranslational Modifications 95 4.5.1.7 Biosimilars 95 4.6 Concluding Remarks 96 References 98 5 Structural Characterization of Recombinant Proteins and Antibodies 111Paola Di Lello and Patrick Lupardus 5.1 Introduction 112 5.2 Antigens, Epitopes, and Paratopes 113 5.2.1 Rationale for Structural Characterization of Epitopes 113 5.3 Choice of Analytical Method for Epitope Mapping 117 5.3.1 EM for Epitope Analysis 117 5.3.2 Epitope and Paratope Mapping by NMR 118 5.3.2.1 Epitope/Paratope Mapping by Chemical Shift Perturbations 119 5.3.2.2 Final Considerations 122 5.3.3 Epitope Mapping by X‐ray Crystallography 122 5.4 Recombinant Antigen Generation 123 5.4.1 E. coli Expression of Antigens 124 5.4.2 Insect Cell Expression of Antigens 125 5.4.3 Mammalian Expression of Antigens 126 5.5 N‐linked Glycosylation 127 5.5.1 E. coli Expression to Remove Glycosylation as a Factor 128 5.5.2 Manipulating N‐linked Glycans on Antigens 128 5.6 Antibody Generation for Crystallography 129 5.7 Crystallization of Antibody/Antigen Complexes 130 5.8 Conclusion 131 References 131 6 Antibody de novo Sequencing 139Natalie Castellana and Adrian Guthals 6.1 Introduction 139 6.2 Technical Details on Antibody de novo Sequencing 141 6.2.1 Achieving Complete Protein Coverage 141 6.2.2 Achieving High Sequencing Accuracy 142 6.2.3 Handling Protein Modifications 143 6.2.4 Handling Sample Purity 143 6.3 Bioinformatics Workflow 146 6.3.1 Spectral Preprocessing 146 6.3.2 Spectral Alignment‐based Approach 146 6.3.3 Sequence Homology‐based Approaches 147 6.3.4 Semi‐automated and Manual de novo Sequencing 149 6.4 Sequence Validation 149 6.4.1 Mass Spectrometry‐based Statistics 149 6.4.2 Intact Mass Comparison 150 6.4.3 Synthetic Peptides 150 6.5 Conclusions 150 References 151 7 Characterization of Antibody–Drug Conjugates 155Yichin Liu 7.1 Introduction 156 7.2 Characterization of DAR Utilizing MS 157 7.2.1 The Stability of Conjugation Chemistry and the Cleavable Linker of ADC 157 7.2.2 Historical Usage of Hydrophobic Interaction Chromatography in ADC Characterization 158 7.2.3 Intact MS Detection under Denaturing Condition 159 7.2.4 Intact MS Characterization under Native Conditions 159 7.2.5 Middle‐down and Bottom‐up MS Approach in Mapping Drug Conjugates 161 7.3 Structural Characterization of ADC 162 7.3.1 Ion‐Mobility Mass Spectrometry 162 7.3.2 Hydrogen–Deuterium Exchange Mass Spectrometry 163 7.4 Characterization of ADC Catabolism by MS 163 7.5 Conclusions 164 References 165 8 Characterization of Bispecific or Other Hybrid Molecules 169T. Noelle Lombana and Christoph Spiess 8.1 Introduction 170 8.1.1 Bispecific Antibody Applications 170 8.2 Overview of the Various Bispecific Formats 172 8.2.1 Purification from Mixtures 175 8.2.2 Bispecific Antibodies and Alternative Scaffolds with Tethered Domains 176 8.2.3 Bispecific Molecules with Engineered Mutations 177 8.2.4 Native Bispecific IgG with Dual Binding Behavior 178 8.2.5 Bispecific Antibody Conjugates 179 8.3 Alternatives to Bispecific Antibodies: Antibody Mixtures 179 8.4 Characterization of the Bispecific Molecule 180 8.4.1 Characterization by Bioanalytical Methods 180 8.4.2 Characterization by Mass Spectrometry Methods 183 8.4.2.1 General Considerations 183 8.4.2.2 Purity Analysis of the Final Bispecific Antibody 183 8.4.2.3 Antibody Mixtures 184 8.4.2.4 Increasing Resolution 185 8.4.3 Characterization of Bispecific Antibodies by Binding Assays 185 8.4.4 Developability Assessment of the Bispecific Antibody 186 8.4.4.1 Expression 186 8.4.4.2 Physicochemical Properties 187 8.4.4.3 Chemical Modifications 187 8.4.4.4 Characterization of In Vivo Properties 188 8.5 Conclusions 189 References 190 9 Bio‐Repository 199Anne Baldwin, Kurt Schroeder, Lovejit Singh, and Karen Billeci 9.1 Introduction 199 9.2 Large Molecule Repository Management 202 9.2.1 Informatics 202 9.2.2 Automation 206 9.2.2.1 Automated Refrigerated or Freezer Stores 206 9.2.2.2 Lab Automation 207 9.3 Challenges and Future Perspectives for Working with Diverse Biological Reagent Types 208 References 209 10 Characterization of Residual Host Cell Protein Impurities in Biotherapeutics 211Denise Krawitz, Jason C. Rouse, Justin B. Sperry, Wendy Sandoval, and Martin Vanderlaan 10.1 Introduction 212 10.2 HCP Measurement and Reporting 212 10.2.1 Antibodies to HCPs 213 10.2.2 Guidance on HCP Limits and Testing 215 10.3 Methods to Characterize Host Cell Impurities 217 10.3.1 HCP‐ELISA 217 10.3.2 SDS‐PAGE and Western Blots 217 10.3.3 MS Methods for HCP Analysis 219 10.3.3.1 Gel Electrophoresis and MALDI or nanoLC‐MS/MS 220 10.3.3.2 Two Dimensional LC‐MS/MS 221 10.3.3.3 Targeted MS Analysis 223 10.3.3.4 Ultrahigh‐Resolution 1D LC‐MS/MS 224 10.3.3.5 Top‐down Proteomics 227 10.4 Use of HCP‐ELISA and Orthogonal 1D LC‐MS/MS in Practice 228 10.4.1 Pros and Cons of MS for Orthogonal HCP Analysis 231 10.4.2 Considerations and MS Evolution 232 10.5 Risk of HCPs Present in Products 232 10.6 Conclusions 233 References 234 11 Analytical Tools for Biologics Molecular Assessment 239Wilson Phung, Wendy Sandoval, Robert F. Kelley, and Jennie R. Lill 11.1 Introduction to Molecular Assessment 240 11.2 Molecular Assessment 243 11.3 Biotherapeutic Stability 244 11.3.1 Deamidation and Isomerization of Asparagine 246 11.3.2 Oxidation 246 11.4 Physical Degradation 248 11.5 Yield and Structural Stability 249 11.6 Posttranslational Modifications 250 11.7 Analytical Techniques 251 11.8 Summary 252 References 254 12 Glycan Characterization: Determining the Structure, Distribution, and Localization of Glycoprotein Glycans 257John B. Briggs 12.1 Introduction 258 12.2 Glycan Labeling 264 12.3 Compositional Analysis 266 12.3.1 Neutral Sugar Analysis 267 12.3.2 Sialic Acid Analysis 269 12.4 Glycan Release 272 12.4.1 Release of N‐linked Glycans 272 12.4.2 Release of O‐linked Glycans 274 12.5 Determining Sites of Glycosylation 276 12.5.1 MS‐Based Screening for Glycopeptides 278 12.5.2 Identification of Glycosylation Sites by Analysis of Native Glycopeptides 279 12.5.3 Identification of N‐linked Glycosylation Sites by Enzymatic Labeling of Glycosylation Sites 281 12.5.4 Identification of O‐linked Glycosylation Sites by Chemical Labeling of Glycosylation Sites 283 12.5.5 Identification of Glycosylation Sites by Edman Degradation 285 12.6 Determining N‐linked Glycan Distribution 286 12.6.1 Assessing Glycan Distribution by MS 287 12.6.1.1 Assessing Glycan Distribution by Mass Spectrometric Analysis of Glycoproteins 287 12.6.1.2 Assessing Glycan Distribution by Mass Spectrometric Analysis of Glycopeptides 294 12.6.1.3 Determining Glycan Distribution by Mass Spectrometric Analysis of Native Glycans 294 12.6.1.4 Determining Glycan Distribution by Mass Spectrometric Analysis of Derivatized Glycans 298 12.6.2 Assessing Glycan Distribution by Chromatography and CE 300 12.6.2.1 Analysis of N‐linked Glycans by CE 300 12.6.2.2 Analysis of N‐linked Glycans by HILIC 303 12.6.2.3 Determining Glycan Distribution by HPAEC 305 12.7 Comparison of Methods Used in Determining Glycan Distribution 307 12.8 Assessing N‐linked Glycan Structure 309 12.8.1 Characterization of Glycan Structure Using Standards and Enzymatic Studies 309 12.8.2 Characterization of Glycan Linkage by Methylation Analysis 310 12.8.3 Characterization of Glycan Structure by MS2 312 12.8.4 Characterization of Glycan Structure by NMR 317 References 320 Index 333

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Book SynopsisA Comprehensive Guide to Crucial Attributes of Therapeutic Proteins in Biological Pharmaceuticals With this book, Dr. Raju offers a valuable resource for professionals involved in research and development of biopharmaceutical and biosimilar drugs. This is a highly relevant work, as medical practitioners have increasingly turned to biopharmaceutical medicines in their search for safe and reliable treatments for complex diseases, while pharmaceutical researchers seek to expand the availability of biopharmaceuticals and create more affordable biosimilar alternatives. Readers receive a thorough overview of the major co-translational modifications (CTMs) and post-translational modifications (PTMs) of therapeutic proteins relevant to the development of biotherapeutics. The majority of chapters detail individual CTMs and PTMs that may affect the physicochemical, biochemical, biological, pharmacokinetic, immunological, toxicological etc. properties of proteins. In additTable of ContentsPreface xv About the Author xix Abbreviations xxi 1 Introduction to Co- and Post-translational Modifications of Proteins 1 Brief Introductions to Individual Chapters 8 Chapter 2: Acetylation of Proteins 8 Chapter 3: C-Terminal Lys or Arg Clipping of Proteins 8 Chapter 4: Cysteinylation of Proteins 8 Chapter 5: Deamidation of Proteins 8 Chapter 6: Glycation of Proteins 9 Chapter 7: Glycosylation of Proteins 9 Chapter 8: N-glycosylation of Proteins 9 Chapter 9: O-glycosylation of Proteins 10 Chapter 10: Hydroxylation of Proteins 10 Chapter 11: Methylation of Proteins 10 Chapter 12: Oxidation of Proteins 11 Chapter 13: Phosphorylation of Proteins 11 Chapter 14: Prenylation of Proteins 11 Chapter 15: Proteolysis of Proteins 11 Chapter 16: Selenylation of Proteins 12 Chapter 17: Signal Peptides of Proteins 12 Chapter 18: Sulfation of Proteins and Glycoproteins 12 Chapter 19: SUMOylation 12 Chapter 20: Ubiquitination 13 Chapter 21: Other PTMs 13 References 13 2 Acetylation of Proteins 17 Introduction 17 Mechanism of N-acetylation at the N-termini of Proteins 19 Mechanism of N-acetylation and N-deacetylation of Lysine Residues 21 Mechanism of O-acetylation of Sugar Residues 21 Biological Significance of Protein Acetylation 22 Acetylation in Recombinant Therapeutic Proteins 23 Methods to Analyze Acetylation in Proteins and Carbohydrates 23 References 24 3 C-terminal Lys or Arg Clipping in Proteins 31 Introduction 31 Biological Significance of C-terminal Lys or Arg Clipping in Proteins 31 Analysis of C-terminal Lys or Arg Clipping in Proteins 32 References 32 4 Cysteinylation of Proteins 35 Introduction 35 Biological Significance of Cysteinylation of Proteins 35 Cysteinylation and Trisulfide Bonds in Recombinant Therapeutic Proteins 36 Analysis of Cysteinylation of Proteins 36 References 37 5 Deamidation of Proteins 39 Introduction 39 Mechanism of Deamidation of Proteins 40 Physicochemical Characteristics of Deamidated Proteins 42 Biological Significance of Deamidation of Proteins 43 Deamidation and Immunogenicity 43 Deamidation and Pharmacokinetics Properties of Proteins 44 Deamidation in Recombinant Therapeutic Proteins 44 Methods for the Analysis of Deamidation in Proteins 44 References 45 6 Glycation of Proteins 51 Introduction 51 Mechanism of Protein Glycation 52 Glycation of Proteins in Human 54 Protein Glycation and Human Diseases 55 Glycation in Recombinant Therapeutic Proteins 56 Methods to Analyze Protein Glycation 57 References 58 7 Glycosylation of Proteins 63 Introduction 63 Glycans and Aglycans 64 Glycosidic Bonds 64 Aldoses and Ketoses 66 Anomeric Groups: α- and β-Configurations 69 Natural Diversity of Glycans 70 Glycans and Enzymes 71 N-glycosylation 71 O-glycosylation 72 Phospho-Serine Glycosylation 72 GPI-Anchors (Glypiation) 72 C-mannosylation 73 References 73 8 N-glycosylation of Proteins 77 Introduction 77 Mechanism of N-glycosylation of Proteins 81 Biosynthesis of N-Glycans 81 Biosynthesis of Lipid-linked Precursor Oligosaccharide 81 En Bloc Transfer of the Precursor Oligosaccharide to Nascent Polypeptide Chain 82 Processing of the Glycan 82 Additional Processing of Oligosaccharide Unit for Chain Elongation and/or Modifications 83 Microheterogeneity of N-Glycans 84 Species-Specific N-glycosylation 85 Functions of N-glycans 87 Physicochemical Functions of N-glycans 87 Biological Functions of N-glycans 88 Impact of N-Glycans on Pharmacokinetic Properties of Proteins 88 N-Glycans and Human Diseases 89 N-glycosylation of RTPs 89 Methods to Analyze N-Glycans 90 References 92 9 O-glycosylation of Proteins 101 Introduction 101 Biosynthesis of O-Glycans 103 Biosynthesis of Mucin Type O-Glycans 103 Biosynthesis of O-linked GlcNAc on Proteins 105 Biosynthesis of O-linked Fucose on Proteins 106 Biosynthesis of O-linked Glc Residues 107 Biosynthesis of O-linked Gal Residues 107 Biosynthesis of O-linked Man Residues 107 O-Glycans on Hydroxyproline Residues 108 Physicochemical Properties of O-Glycosylated Proteins 108 Biological Functions of O-Glycans 108 O-glycosylation in RTPs 110 Analysis of O-Glycans 111 References 113 10 Hydroxylation of Proteins 119 Introduction 119 Mechanism of Hydroxylation 120 Mechanism of Hydroxylation in Organic Molecules 120 Mechanism of Hydroxylation in Biomolecules 121 Prolyl 4-Hydroxylase 123 Prolyl 3-Hydroxylase 123 Lysyl 5-Hydroxylase 123 Phenylalanine Hydroxylase 123 Tyrosine Hydroxylase 124 Biological Significance of Hydroxylation 124 Hydroxylation in RTPs 126 Analysis of Hydroxylation 126 References 127 11 Methylation of Proteins 133 Introduction 133 Mechanism of Protein Methylation 135 Chemical Methylation Reactions 135 Biological Methylation Reactions 135 Methylation of Arg Residues 135 Methylation of Lys Residues 137 Methylation of Prenylcysteine Residues 137 Methylation of Protein Phosphatase 2A 137 Methylation of Isoaspartyl Residues 138 O-Methylation of Sugar Residues 138 Physicochemical and Biological Significance of Methylation of Proteins 139 Methylation in RTPs 140 Methods to Analyze Methylation in Proteins and Glycoproteins 140 References 141 12 Oxidation of Proteins 147 Introduction 147 Mechanism of Protein Oxidation 149 Methionine (Met) Oxidation 149 Cysteine (Cys) Oxidation 150 Tryptophan (Trp) Oxidation 151 Tyrosine (Tyr) Oxidation 153 Oxidation of Other Amino Acid Residues and Protein Backbone 155 Oxidation in RTPs 155 Met Oxidation in mAbs 157 Analytical Methods to Measure Protein Oxidation 157 References 158 13 Phosphorylation of Proteins 163 Introduction 163 Mechanism of Protein Phosphorylation in Living Cells 164 Mg2+ Mediated Mechanism of Protein Phosphorylation 165 Protein Kinase-Based Mechanism of Protein Phosphorylation 166 Mechanism of Dephosphorylation of Proteins by Phosphatases 166 Protein Kinases 167 Serine Kinases 167 Tyrosine Kinases 168 Physicochemical and Biological Functions of Protein Phosphorylation 169 Phosphorylation in RTPs 169 Methods to Analyze Protein Phosphorylation 170 Gel Electrophoresis 170 Mass Spectrometry 171 Enrichment of Phosphoproteins 171 Enrichment of Phosphorylated Peptides 171 References 171 14 Prenylation of Proteins 177 Introduction 177 Mechanism of Protein Prenylation 177 Biological Significance of Prenylation of Proteins 179 Analysis of Prenylation of Proteins 179 References 179 15 Proteolysis of Proteins 183 Introduction 183 Chemical Proteolysis 184 Enzymatic Proteolysis 185 Biological Significance of Proteolysis 187 Post-translational Processing of Proteins by Proteolysis 187 Intracellular and Extracelluar Degradation of Proteins by Proteases 189 Proteolysis and Food Digestion 190 Role of Proteases in Apoptosis 190 Role of Proteolysis in Human Diseases 191 Use of Proteases in Laboratories 191 Sources of Proteases 193 Proteolysis in RTPs 193 Chemical Proteolysis in RTPs 193 Enzymatic Proteolysis in RTPs 194 Analytical Methods for the Detection of Proteolysis of Proteins 195 References 196 16 Selenylation 203 Introduction 203 Biological Significance of Selenylation of Proteins 203 References 205 17 Signal Peptides 207 Introduction 207 Biological Significance of Signal Peptides 207 Signal Peptides in RTPs 208 References 208 18 Sulfation of Proteins and Glycoproteins 211 Introduction 211 Biosynthesis of PAPS 212 Sulfation Reactions in the Cytosol 213 Sulfation in the Golgi Compartments 215 Sulfation of Tyrosine Residues 215 Mechanism of Tyrosine Sulfation 216 Biological Functions of Tyr Sulfation 216 Sulfation of Glycosaminoglycans (GAGs) and Proteoglycans 217 Biological Functions of GAGs 219 Sulfation in RTPs 220 Analysis of Sulfation in Biomolecules 221 Analysis of Tyr Sulfation 222 Analysis of Sulfated Glycoconjugates 222 Colorimetric Methods to Analyze Sulfated Glycoconjugates 222 Electrophoretic Methods to Analyze Sulfated Glycoconjugates 223 Chromatographic Methods to Analyze Sulfated Glycoconjugates 223 Analysis of Sulfated Glycoconjugates by Mass Spectrometry 224 References 224 19 SUMOylation 231 Introduction 231 Mechanism of SUMOylation 232 Biological Significance of SUMOylation 232 References 232 20 Ubiquitination 235 Introduction 235 Mechanism of Ubiquitination 235 Biological Significance of Ubiquitination 236 References 236 21 Other CTMs and PTMs of Proteins 239 Adenylylation or AMPylation 239 ADP-Ribosylation 239 Amidation 239 Arginylation 240 Butyrylation 240 Carbamylation 240 Carbonylation 240 γ-Carboxylation 241 Citrullination 241 Diphthamide 241 Formylation 241 Glypiation 242 Hypusine Formation 242 Iodination 242 Lipoylation 243 Malonylation 243 Myristoylation 243 Neddylation 243 Palmitoylation 244 Polyglutamylation 244 Polyglycylation 244 Propionylation 245 Pupylation 245 Pyroglutamate Formation 245 S-Glutathionylation 245 S-Nitrosylation 247 References 247 Appendix A 253 Index 271

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Book SynopsisThe demand for synthetic procedures that can be duplicated may be less egregious today than in 1921, but there is still a need. To date, Organic Syntheses has filled this need with 90 volumes of checked experimentals; and with the culmination of Kay Brummond's term as a member of the editorial board, the addition of Volume 91.Table of ContentsDiscussion Addendum: Resolution of 1,1'-Bi-2-Naphthol; (R)-(+)- and (S)-(-)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl(BINAP) 1David L. Hughes Discussion Addendum for: Practical Synthesis of Novel Chiral Allenamides: (R)-4-Phenyl-3-(1,2-propadienyl)oxazoldin-2-one 12Yong-Chua Teo and Richard P. Hsung N-Carboxylated-2-substituted Indoles and 2,3-Disubstituted-2,3-dihydro-4-quinolones from 2-Alkynylbenzamides 27Noriko Okamoto, Kei Takeda, and Reiko Yanada Pd-Catalyzed External-CO-Free Carbonylation: Preparation of 2,4,6-Trichlorophenyl 3,4-Dihydronaphthalene-2-Carboxylate 39Hideyuki Konishi, Tsuyoshi Ueda, and Kei Manabe Rhodium-Catalyzed Direct Amination of Arene C-H Bonds Using Azides as the Nitrogen Source 52Sae Hume Park, Yoosu Park, and Sukbok Chang Synthesis of Alkynyliodonium Salts: Preparation of Phenyl (phenylethynyl)iodonium Trifluoroacetate 60Luke I. Dixon, Michael A. Carroll, George J. Ellames and Thomas J. Gregson Palladium-catalyzed 1,4-Addition of Terminal Alkynes to Conjugated Enones 72Feng Zhou, Liang Chen and Chao-Jun Li Cross-Coupling of Alkenyl/Aryl Carboxylates with Grignard Reagents via Fe-Catalyzed C-O Bond Activation 83Bi-Jie Li, Xi-Sha Zhang and Zhang-Jie Shi Preparation of 5-Hydroxycyclopentenones Via Conjugate Addition-Initiated Nazarov Cyclization 93Joshua L. Brooks, Yu-Wen Huang, and Alison J. Frontier Synthesis of Arylboronic Pinacol Esters from Corresponding Arylamines 106Di Qiu, He Meng, Liang Jin, Shengbo Tang, Shuai Wang, Fangyang Mo, Yan Zhang and Jianbo Wang Preparation of Alkanesulfonyl Chlorides from S-Alkyl Isotghiourea Salts via N-Chlorosuccinimide Mediated Oxidative Chlorosulfonation 116Zhanhui Yang and Jiaxi Xu DABCO-bis(sulfur dioxide), DABSO, as an easy-to-handle source of SO2: Sulfonamide preparation 125Edward J. Emmett and Michael C. Willis One-pot Preparation of (S)-N-[(S)-1-Hydroxy-4-metghyl-1,1-diphenylpentan-2-yl]pyrrolidine-2-carboxamide from L-Proline 137Wacharee Hamying, Nonognaphat Duangdee, and Albrecht Berkessel Enantioselective Rhodium-Catalyzed [2+2+2] Cycloaddition of Pentenyl Isocyanate and 4-Ethynylanisole: Preparation and Use of Taddol-pyrrolidine Phosphoramidite 150Kevin M. Oberg, Timothy J. Martin, Mark Emil Oinen, Derek M. Dalton, Rebecca Keller Friedman, Jamie M. Neely, and Tomislav Rovis Synthesis and Use of a Trifluoromethylated Azomethine Ylide Precursor: Ethyl 1-Benzyl-trans-5-(trifluoromethyl)pyrrolidine-3-carboxylate 162Daniel M. Allwood, Duncan L. Browne and Steven V. Ley Enantioselective Organocatalytic-α-Arylation of Aldehydes 175Pernille H. Poulsen, Mette Overgaard, Kim L. Jensen and Kari Anker Jørgensen Synthesis of 4,5-Disubstituted 2-aminothiazoles from α,β-Unsaturated Ketones: Preparation of S-benzyl-4-methyl-2-aminothiazolium Hydrochloride salt 185Antonio Bermejo Gómez, Nanna Ahlsten, Ana E. Platero-Prats and Belen Martin-Matute Sodium Methoxide-Catalyzed Direct Amidation of Esters 201Kazushi Agura, Takashi Ohshima, Yukiko Hayashi, And Kazushi Mashima Synthesis of Tetrasubstituted 1H-Pyrazoles by Copper-mediated Coupling of Enaminones with Nitriles 211Mamta Suri and Frank Glorius Synthesis of 1,3-Dimethyl-3-(p-tolyl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one by Cu(II)-Mediated Direct Oxidative Coupling 221Chandan Dey and E. Peter Kundig Preparation of (R)-4-Cyclohexyl-2,3-butadien-1-ol 233Juntao Ye and Shengming Discussion Addendum for: Formation of y-Keto Esters from β-Keto Esters: Methyl 5,5-dimethyl-4-oxohexanoate 248Yashoda M. D. Bhogadhi and Charles K. Zercher Ni-catalyzed Reductive Cleavage of Methyl 3-Methoxy-2-Naphthoate 260Josep Cornella, Cayetana Zarate, and Ruben Martin Indium-Catalyzed Heteroaryl-Heteroaryl Bond Formation through Nucleophilic Aromatic Substitution: Preparation of 2-Methyl-3-(thien-2-yl)-1H-indole 273Yuta Nagase and Teruhisa Tsuchimoto Synthesis of 2,3-Disubstituted Benzofurans by the Palladium-Catalyzed Coupling of 2-Iodoanisoles and Terminal Alkynes, Followed by Electrophilic Cyclization: 3-Iodo-2-phenylbenzofuran 283Tuanli Yao, Dawei Yue, and Richard C. Larock Enantioselective Preparation of (S)-5-Oxo-5,6-dihydro-2H-oyran-2-yl Benzoate 293Tamas Benkovics, Adrian Ortiz, Zhiwei Guo, Animesh Goswami and Prashant Deshpande Iron-Catalyzed Selective Conjugate Addition of Aryl Grignard Reagents to 2,4-Alkadienoates: tert-Butyl (Z)-5-Phenyl-3-hexenoate 307Takeshi Hata, Hideyuki Goto, Tomofumi Yokomizo, and Hirokazu Urabe 3-Hydrixymethyl-3-phenylcyclopropene 322Ramajeyam Selvaraj, Srinvasa R. Chintala, Michael T. Taylor and Joseph M. Fox Enantioselective Synthesis of α- and β-Boc-protected 6-Hydroxy-pyranones: Carbohydrate Building Blocks 338Sumit O. Bajaj, Jamison R. Farnsworth and George A. O'Doherty

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Book SynopsisThe interpretation and evaluation of scientific evidence and its presentation in a court of law is central both to the role of the forensic scientist as an expert witness and to the interests of justice. This book aims to provide a thorough and detailed discussion of the principles and practice of evidence interpretation and evaluation by using real cases by way of illustration. The presentation is appropriate for students of forensic science or related disciplines at advanced undergraduate and master''s level or for practitioners engaged in continuing professional development activity. The book is structured in three sections. The first sets the scene by describing and debating the issues around the admissibility and reliability of scientific evidence presented to the court. In the second section, the principles underpinning interpretation and evaluation are explained, including discussion of those formal statistical methods founded on Bayesian inference. The following chaptTable of ContentsPreface xvi Part 1 1 1 An Introduction to the Admissibility of Expert Scientific Opinion 3 1.1 Admissibility, Reliability and Scientific Evidence 3 1.2 The Impact of the DNA Revolution 5 1.3 The Miscarriage of Justice 6 1.3.1 The United Kingdom 7 1.3.2 The United States 8 1.3.3 Canada 8 1.3.4 Australia 9 1.4 DNA Reveals Wrongful Convictions 9 1.5 The Causes of Wrongful Conviction 10 1.6 Unreliable Scientific Evidence 11 1.6.1 The Status and Expertise of the Expert Witness 11 1.6.2 The Expert is not Impartial 12 1.6.3 The Evidence was Wrong 13 1.6.4 Exaggerated Evaluation by the Expert 13 1.6.5 Unethical Behaviour 14 1.6.6 Human Error 14 1.6.7 Non-validated Methodology 15 1.6.8 Overconfidence in New Techniques 15 1.7 The Scientist and the Laboratory 16 1.8 Conclusions 17 References 17 Further Reading 18 2 Admissibility from the Legal Perspective 20 2.1 Admissibility, Relevance and Reliability of Evidence 20 2.2 Admissibility in the United States 22 2.2.1 Reliability and the Frye Test 22 2.2.2 Meeting the Frye Criterion: US v Stifel 1970 23 2.2.3 Admissibility and the Gatekeeper Role: The Daubert Test 23 2.2.4 The Daubert Trilogy 25 2.2.5 General Electric v Joiner 1997 25 2.2.6 Kumo Tire Company v Patrick Carmichael 1999 26 2.2.7 Post]Daubert Hearings: US v Dennis Mooney 2002 26 2.3 Admissibility in Canada 27 2.3.1 R v Mohan 1994 27 2.3.2 R v Abbey 2009 29 2.3.3 R v Trochym 2007 29 2.4 Admissibility in Australia 30 2.4.1 R v Bonython 1984 30 2.4.2 Makita v Sprowles 2001 31 2.4.3 Dasreef Pty Limited v Hawchar 2011 31 2.5 Admissibility in England and Wales 32 2.5.1 R v Turner 1975 33 2.5.2 R v Gilfoyle 2001 33 2.5.3 R v Luttrell 2004 34 2.6 Conclusions on Admissibility 35 2.6.1 Relevance and Expertise 35 2.6.2 The Scientific Basis of the Opinion 35 2.6.3 Weight of Evidence 37 References 37 Further Reading 38 3 Forensic Science and the Law: The Path Forward 39 3.1 National and Legal Developments in the United States 39 3.1.1 Federal Rules of Evidence 40 3.1.2 Strengthening Forensic Science in the United States 2009 41 3.1.3 US Reference Manual on Scientific Evidence 43 3.2 National and Legal Developments in Canada 44 3.2.1 Legal Enquiries into Miscarriages of Justice 44 3.2.2 The Science Manual for Canadian Judges 45 3.3 National and Legal Developments in Australia 46 3.3.1 The Uniform Rules of Evidence 47 3.4 National and Legal Developments in England and Wales 48 3.4.1 Forensic Science on Trial 2005 49 3.4.2 The Law Commission Report 2011 49 3.4.3 The Royal Statistical Society Guides 51 3.4.4 HCSTSC Report Forensic Science 2013 52 3.4.5 UK Government Response (2013) to the Law Commission Report 52 3.5 Conclusions 53 References 53 Further Reading 54 4 Scientific Opinion and the Law in Practice 56 4.1 Scientific Opinion and the Judicial System 56 4.1.1 Adversarial and Inquisitorial Systems of Justice 56 4.1.2 Scientific Evidence Within the Inquisitorial System 57 4.1.3 Inquisitorial Versus Adversarial 57 4.2 The Scientist in Court 58 4.3 The Role and Duties of the Scientific Expert Witness 59 4.3.1 Definitions of the Role 59 4.3.2 Duties and Responsibilities of the Expert Witness 60 4.4 Quality Control of Analysis and Opinion 61 4.4.1 An Australian Standard for Forensic Analysis 61 4.4.2 Regulation of Forensic Science in the United Kingdom 62 4.4.3 Codes of Conduct and Practice 62 4.4.4 Accreditation of the Expert 63 4.5 Conclusion 63 References 64 Further Reading 64 Part 2 65 5 Fundamentals of the Interpretation and Evaluation of Scientific Evidence 67 5.1 Analysis, Interpretation and Evaluation 67 5.2 The Role and Outcomes of Forensic Investigation 68 5.2.1 Investigative Forensic Science 68 5.2.2 Evaluative Forensic Science 69 5.3 Fact and Opinion 69 5.3.1 Categorisation of Opinions 70 5.3.2 Factual Opinion 70 5.3.3 Investigative Opinion 70 5.4 Expert Opinion and the Forensic Science Paradigm 70 5.4.1 Categorical Opinion 71 5.4.2 Posterior Probabilities 72 5.4.3 Explanations 73 5.4.4 Where Does this Take Us? 74 5.5 What are Propositions? 74 5.5.1 The Hierarchy of Propositions 74 5.5.2 The Importance of Activity Level 75 5.6 Competing Propositions in the Court 76 References 77 Further Reading 77 6 Case Studies in Expert Opinion 78 6.1 Case Study 1: Facial Comparison Evidence 78 6.1.1 The Crime and Conviction 78 6.1.2 Expert Evidence and Opinion 79 6.1.3 Opinion in Atkins 80 6.2 Case Study 2: Ear]mark Identification 81 6.2.1 The Crime and the Evidence 81 6.2.2 Interpreting the Evidence and Challenges to the Opinion 81 6.2.3 The Conclusion of the Appeal 83 6.2.4 Opinion in Dallagher 83 6.3 Case Study 3: Glass and Gunshot Residue 84 6.3.1 The Crime and Trial 84 6.3.2 Analysis and Interpretation of the Scientific Evidence 84 6.3.3 Propositions for Evaluation 85 6.3.4 Evaluative Opinion: Glass 86 6.3.5 Evaluative Opinion: GSR 86 6.3.6 Opinion in Bowden 88 6.4 Conclusions 88 References 88 Further Reading 89 7 Formal Methods for Logical Evaluation 90 7.1 Frequentist and Bayesian Approaches to Evaluation 90 7.1.1 The Frequentist Approach to Formulating Opinion 90 7.1.2 The Logical Evaluation of Evidence 91 7.1.3 The Debate on Formulating Opinion 92 7.2 The Likelihood Ratio Method 92 7.3 Expressing Opinion Through Likelihood Ratio 93 7.3.1 Statements of Evaluative Opinion 93 7.3.2 Likelihood Ratio and Verbal Equivalent Statements 94 7.4 Evaluation and Bayes’ Theorem 94 7.4.1 Bayes’ Theorem: Prior and Posterior Odds 95 7.4.2 Combining Likelihood Ratios 97 7.5 Prior Odds 97 7.6 Posterior Probabilities 99 7.6.1 Opinion and Posterior Probabilities 99 7.6.2 The Prosecutor’s Fallacy 99 7.7 Working Out Conditional Probabilities and Likelihood Ratio 100 7.7.1 Likelihood Ratio at Source Level 100 7.7.2 Likelihood Ratio at Activity Level 101 7.8 Conclusions 102 References 102 Further Reading 103 8 Case Studies in Probabilistic Opinion 104 8.1 People v Collins 1968 104 8.2 R v Michael Shirley 2003 105 8.2.1 A Logical Evaluation of Scientific Evidence 106 8.2.2 The Outcome of the Appeal 108 8.3 R v D J Adams 1996, 1998 108 8.3.1 The Crime and the Evidence 109 8.3.2 A Probabilistic Analysis of the Evidence: Prior Odds 109 8.3.3 The Non]Scientific Evidence 110 8.3.4 The Scientific Evidence 111 8.3.5 Total Likelihood Ratio and Posterior Odds 112 8.3.6 The Appeals 113 8.3.7 Review of the Issues in R v D J Adams 114 8.4 The Defendant’s Fallacy: R v J 2009 115 8.5 Conclusion 116 References 116 Further Reading 116 9 Cognitive Bias and Expert Opinion 117 9.1 Cognitive Bias 117 9.2 Contextual Bias 118 9.2.1 Confirmation Bias 119 9.2.2 Expectation Bias 119 9.2.3 Motivational Bias 119 9.2.4 Anchoring 120 9.3 Other Sources of Bias 120 9.4 Fingerprint Examination: A Case Study in Bias 120 9.4.1 The Review of the Brandon Mayfield Case 2004 120 9.4.2 The Fingerprint Inquiry Scotland 2009 121 9.4.3 Bias Within Fingerprint Examination 121 9.5 Mitigating Bias 122 9.6 Mitigating Bias Versus Research on Traces 123 9.7 Conclusions 124 References 124 Further Reading 125 Part 3 127 10 The Evaluation of DNA Profile Evidence 129 10.1 DNA Profiling Techniques – A Brief History 130 10.2 Databases in DNA Profiling 131 10.2.1 Allele Frequency Databases 131 10.2.2 Identification Databases 131 10.3 Interpretation and Evaluation of Conventional DNA Profiles 131 10.3.1 Combined Probability of Inclusion (CPI) or Exclusion (CPE) 132 10.3.2 Random Match Probability (RMP) 132 10.3.3 Likelihood Ratio 133 10.4 Suspect Identification from a DNA Database 133 10.4.1 The Frequentist Interpretation 133 10.4.2 The Likelihood Ratio Approach 134 10.4.3 Database Search Evidence in Court 134 10.5 Case Studies of DNA in the Court 135 10.5.1 R v Andrew Philip Deen 1994 135 10.5.2 Issues Raised by Expert Opinion in R v Deen 136 10.5.3 R v Alan Doheny 1996 138 10.5.4 The Doheny Trial 138 10.5.5 The Doheny Appeal 139 10.5.6 R v Gary Adams 1996 140 10.5.7 Challenges to the Interpretation of DNA Profiles: US v Shea 1997 141 10.6 Current Practice for Evaluating DNA Profile Evidence 142 10.6.1 The Impact of Doheny and Adams in the United Kingdom 142 10.6.2 Current Practice in the United Kingdom 144 10.6.3 Current Practice in Australia 145 10.7 DNA – The Only Evidence 146 10.8 Errors and Mistakes in Forensic DNA Analysis 147 10.8.1 Adam Scott 2012 147 10.8.2 R v S 2013 148 10.8.3 Laboratory Error Rates Versus the RMP 148 10.9 Conclusions 149 References 149 Further Reading 150 11 Low Template DNA 151 11.1 Technical Issues 151 11.1.1 Terminology 151 11.1.2 Samples 152 11.1.3 Technical Issues in Interpretation 152 11.1.4 Quantitative Evaluation in LTDNA Profiles 153 11.2 Importance of the Chain of Custody: Queen v Sean Hoey 2007 154 11.3 The Caddy Report 2008 155 11.4 Case Studies in LTDNA opinion in the UK Courts 156 11.4.1 Partial Profiles 156 11.4.2 Quantities of DNA; Interpretive Issues on Transfer 157 11.4.3 Very Low Quantities of DNA 159 11.4.4 Opinion Without Statistics 160 11.4.5 Experts Differ in Opinion 162 11.5 LTDNA in Jurisdictions Outside the United Kingdom 163 11.5.1 United States 164 11.5.2 Australia 165 11.6 Conclusions 167 References 167 Further Reading 168 12 Footwear Marks in Court 169 12.1 The Analysis and Interpretation of Footwear Marks 169 12.2 Match Opinion: R v D S Hall 2004 170 12.2.1 The Crime and the Evidence 170 12.2.2 Footwear Mark Evidence and Opinion 171 12.2.3 Review of Expert Opinion in R v Hall 172 12.3 The Likelihood Ratio Approach to Evaluation of Footwear Marks 172 12.4 Standardising Scales for Expert Opinion 173 12.4.1 SWGTREAD Scales of Opinion 173 12.4.2 ENFSI Scales of Opinion 175 12.5 Challenges to Opinion on Footwear Evidence: R v T 2010 175 12.5.1 Outline of the Footwear Mark Evidence in R v T 176 12.5.2 The Expert Witness’ Notes 177 12.5.3 Evaluation Using an Alternative Database 179 12.5.4 The Summary by the Appeal Court Judge 179 12.6 Discussion of R v T 180 12.6.1 Terminology, Probabilities and Statistical Methodology 180 12.6.2 Footwear Databases 181 12.6.3 Was the Jury Told the Basis of the Expert Opinion? 182 12.6.4 The Appeal Court Ruling: Bayes, Mathematics and Formulae 183 12.7 Footwear Mark Evidence After R v T: R v South 2011 184 12.7.1 The Crime and Evidence 184 12.7.2 Evaluation of the Footwear Evidence 184 12.7.3 Review of the Expert Opinion 185 12.8 ENFSI Recommendations on Logical Evaluation 2015 186 12.9 Conclusions 187 References 187 Further Reading 188 13 Fingerprints and Finger]Marks – Identifying Individuals? 189 13.1 Fingerprint Identification on Trial 189 13.2 ACE]V: A Scientific Method? 190 13.3 Evaluation Criteria 191 13.3.1 Thresholds for Categorical Evaluation 191 13.3.2 The Balthazard Model 192 13.3.3 Identification Thresholds and the Points Standard in the United Kingdom 192 13.3.4 The Basis of the Non]Numeric (Holistic) Approach 193 13.3.5 Identification Thresholds in Other Jurisdictions 194 13.3.6 R v Buckley 1999 194 13.4 Evolution of the Basis of Fingerprint Opinion in the Court 196 13.5 A Critical Summary of Fingerprint Identification 198 13.6 Challenges to Fingerprint Testimony 198 13.6.1 R v P K Smith 2011 198 13.6.2 Shirley McKie and the Scottish Fingerprint Inquiry 1997–2011 200 13.7 Identifying a Mark from a Database 202 13.7.1 AFIS Versus Manual Systems 202 13.7.2 The Madrid Bombing Case (Brandon Mayfield) 2004 203 13.8 Admissibility of Fingerprint Evidence 204 13.8.1 US v Byron Mitchell 2004 204 13.8.2 US v Llera Plaza 2002 205 13.9 Towards a Probabilistic Evaluation of Fingerprint Evidence 206 13.10 Conclusions 208 References 208 Further Reading 209 14 Trace Evidence, Databases and Evaluation 210 14.1 Analytical Methodologies for Glass, Fibres and GSR 210 14.1.1 Glass Analysis 211 14.1.2 Fibre Analysis 211 14.1.3 GSR Analysis 211 14.2 Databases for Source and Activity Levels 212 14.2.1 Source Level 212 14.2.2 Activity Level 212 14.2.3 Glass 213 14.2.4 Fibres 213 14.2.5 GSR 213 14.2.6 Statistical Models and Case Pre]Assessment 214 14.3 Glass Evidence in Court 214 14.3.1 R v Abadom 1983 214 14.3.2 R v Lewis]Barnes 2014 215 14.3.3 R v L and Others 2010 216 14.3.4 People v Smith 2012 216 14.3.5 Review of the Evaluation of Trace Glass Evidence 217 14.4 Fibre Evidence in Court: R v Dobson 2011, R v Norris 2013 218 14.4.1 Fibre Evidence: Dobson 219 14.4.2 Fibre Evidence: Norris 220 14.4.3 Review of the Evaluation of the Fibre Evidence 221 14.5 Gunshot Residue (GSR) Evidence in Court 222 14.5.1 R v Wooton and Others 2012 222 14.5.2 R v Gjikokaj 2014 224 14.5.3 Review of the Evaluation of GSR Evidence 225 14.5.4 R v George 2007 226 14.6 Conclusions 227 References 227 Further Reading 227 15 Firearm and Tool]Mark Evidence 229 15.1 Pattern Matching of Mechanical Damage 229 15.2 The Interpretation and Evaluation of Tool]Mark Evidence 230 15.2.1 US Opinion 230 15.2.2 UK Opinion 232 15.3 Critical Review of Tool]Mark Evaluation 232 15.4 Consecutive Matching Striations 234 15.5 Databases 234 15.6 Tool]Marks and Evaluation by Likelihood Ratio 235 15.7 Firearms Evidence in the US Courts 236 15.7.1 United States v Hicks 2004 236 15.7.2 United States v Darryl Green et al. 2005 237 15.7.3 US v Glynn 2008 240 15.8 Concluding Comments on Firearms Cases 241 References 241 Further Reading 242 16 Expert Opinion and Evidence of Human Identity 243 16.1 Introduction to Ear]Marks 243 16.2 R v Kempster 2003, 2008 244 16.2.1 The First Appeal 2003 245 16.2.2 The Second Appeal 2008 245 16.2.3 Conclusions From R v Kempster 246 16.3 State v Kunze 1999 247 16.3.1 The Frye Hearing 247 16.3.2 The Trial 248 16.3.3 The Appeal 249 16.4 Review of Ear]Mark Cases 249 16.5 Introduction to Bite]Mark Evidence 250 16.6 The ABFO Guidelines and Expert Opinion 250 16.7 Bite]Mark Cases in the United States 251 16.7.1 People v Marx 1975 252 16.7.2 The Appeal 252 16.7.3 State v Garrison 1978 253 16.7.4 State v Stinson 1986 254 16.7.5 Bite]Mark Testimony in the Courts 255 16.8 Body Biometrics: Facial Mapping and Gait 255 16.8.1 R v Hookway 1999 255 16.8.2 R v Otway 2011 256 16.9 Conclusion 257 References 257 Further Reading 258 17 Questioned Documents 259 17.1 Handwriting and Signature Comparison – A Scientific Methodology? 260 17.2 Scales of Expert Opinion 261 17.3 Jarrold v Isajul and Others 2013 263 17.3.1 Dr Strach’s Testimony 264 17.3.2 Mr Holland’s Testimony 264 17.3.3 Mr Lacroix’s Testimony 265 17.3.4 The Appeal Court Judge’s Conclusion 265 17.4 Gale v Gale 2010 266 17.4.1 ESDA Analysis 267 17.4.2 Signature Analysis 267 17.5 The Bridgewater Four (R v Hickey and Others) 1997 268 17.5.1 Molloy’s ‘Confession’ 269 17.6 R v Previte 2005 270 17.7 Admissibility and Other Issues in Handwriting and Signature Evidence 271 17.8 Admissibility and Evaluation in the US Courts 272 17.8.1 US v Starzecpyzel 1995 272 17.8.2 US v Velasquez 1995 274 17.9 Conclusions 275 References 275 Further Reading 276 18 Bloodstain Pattern Analysis 277 18.1 The Nature of Bloodstain Pattern Evidence 277 18.2 Issues for BPA Expert Opinion in the Courts 278 18.2.1 The Scientific Basis of BPA 278 18.2.2 Who is the Expert? 279 18.2.3 The Courts’ and Lawyers’ Knowledge of BPA 280 18.2.4 The Evaluation and Significance of BPA Evidence 280 18.3 The Scientific Basis of Bloodstain Pattern Analysis: The Murder of Marilyn Sheppard 281 18.4 Three Approaches to the Presentation of Blood Evidence 282 18.4.1 Activity and Propositions: R v Thompson 2013 283 18.4.2 No Expert Testimony: R v White 1998 283 18.4.3 Reconstructing Activity as a Narrative: R v Hall 2010 284 18.5 The Problem of Expirated Blood 285 18.5.1 R v O’Grady 1995, 1999 286 18.5.2 R v Jenkins: The Trial and First Appeal 1999 287 18.5.3 R v Jenkins: The Second Appeal (2004) and Two More Retrials 289 18.6 Experts in Disagreement: R v Perlett 2006 289 18.7 Conclusions 291 References 291 Further Reading 292 19 Conflicting Expert Opinion: SIDS and the Medical Expert Witness 293 19.1 Eminent Experts: Issues and Conflicts 293 19.2 R v Clark 2000, 2003 294 19.2.1 The Testimony of Meadow 295 19.2.2 The Second Appeal 2003 297 19.3 A Bayesian Analysis: Murder or SIDS? 298 19.3.1 Pr(H2) – The Probability of Two SIDS Deaths in the Same Family 298 19.3.2 Pr(H1) – The Probability of Two Murdered Infants in the Same Family 299 19.3.3 The Posterior Odds 299 19.4 R v Cannings 2004 300 19.5 Trupti Patel 2003 302 19.5.1 The Rib Fracture Evidence 302 19.5.2 The Judge’s Summing Up 303 19.6 Conclusions 304 References 304 Further Reading 305 Appendix: Some Legal Terminology 306 Index of Cases, Individuals and Inquiry Reports 307 General Index 309

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Book SynopsisThe Advances in Chemical Physics series provides the chemical physics field with a forum for critical, authoritative evaluations of advances in every area of the discipline. This volume explores topics from Thermodynamic Properties of Polyelectrolyte Solutions to ion-binding of polyelectrolytes. The book features: The only series of volumes available that presents the cutting edge of research in chemical physics Contributions from experts in this field of research Representative cross-section of research that questions established thinking on chemical solutions An editorial framework that makes the book an excellent supplement to an advanced graduate class in physical chemistry or chemical physics Table of ContentsPreface to the Series vii Preface ix Introductory Remarks 1 Thermodynamic Properties of Polyelectrolyte Solutions 21 Ionization Equilibrium and Potentiometric Titration of Weak Polyelectrolytes 67 Molecular Conformation of Linear Polyelectrolytes 115 Radius of Gyration and Intrinsic Viscosity of Linear Polyelectrolytes 153 Transport Phenomena of Linear Polyelectrolytes 193 Ion-Binding 241 Author Index 277 Subject Index 281

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Book SynopsisCovering a key topic due to growing research into the role of signaling mechanisms in toxicology, this book focuses on practical approaches for informatics, big data, and complex data sets. Combines fundamentals / basics with experimental applications that can help those involved in preclinical drug studies and translational research Includes detailed presentations of study methodology and data collection, analysis, and interpretation Discusses tools like experimental design, sample handling, analytical measurement techniques Table of ContentsList of Contributors xv About the Editors xvii Preface xix 1 Introduction to Cellular Signal Transduction: The Connection Between a Biological System and Its Surroundings 1Jonathan W. Boyd, Richard R. Neubig, Alice Han, and Maren Prediger 1.1 Starting Big, but Ending Small 3 1.1.1 Key Features of Signal Transduction 3 1.2 Responding to Our Environment: Sensory Perception Begins and Ends with Signal Transduction 4 1.2.1 Taste (Gustation) 4 1.2.2 Smell (Olfaction) 5 1.2.3 Sight (Vision) 6 1.2.4 Sound (Audition) 6 1.2.5 Touch (Somatosensation) 8 1.3 Primary Transport Systems Involved in Signal Transduction 8 1.3.1 Ion Channels, Transporters, and Ion Pumps 9 1.3.2 Receptors 10 1.3.3 Endocytosis 10 1.3.4 Exosomes 11 1.4 Key Organelles Involved in Signal Transduction 12 1.4.1 Mitochondria 12 1.4.2 Endoplasmic Reticulum 14 1.4.3 Nucleus 15 References 16 2 Mechanisms of Cellular Signal Transduction 21Richard R. Neubig, Jonathan W. Boyd, Julia A. Mouch, and Nicole Prince 2.1 Posttranslational Modifications and Their Roles in Signal Transduction 22 2.1.1 Phosphorylation 22 2.1.2 Acylation 24 2.1.3 Alkylation 25 2.1.4 Glycosylation 26 2.1.5 Other PTMs 27 2.2 Receptors 27 2.3 Receptor Signaling Mechanisms 29 2.3.1 Basic Principles of Signal Transduction Mechanisms 29 2.3.1.1 Selectivity and Recognition 31 2.3.1.2 Flexible Modularity 31 2.3.1.3 Molecular Switches 34 2.3.1.4 GPCRs and Second Messengers 36 2.3.1.5 Amplification 39 2.3.1.6 Turn‐Off Mechanisms 40 2.3.1.7 Localization 40 2.3.1.8 Biased Signaling/Functional Selectivity 41 2.4 Receptor Tyrosine Kinases 42 2.5 Steroid Receptors 43 2.6 Reactive Oxygen Species (ROS) 43 2.7 Summary 44 References 44 3 From Cellular Mechanisms to Physiological Responses: Functional Signal Integration Across Multiple Biological Levels 49Robert H. Newman 3.1 Introduction 49 3.2 Cellular Information Flow: Mechanisms of Cellular Signal Integration and Regulation 50 3.2.1 The InsR‐aPKC‐NF‐κB Signaling Axis 51 3.2.2 Modes of Regulation in InsR‐PKC‐NF‐κB Signaling Axis 54 3.2.3 Transcriptional Regulation 54 3.2.4 Regulating the Regulators: Phosphatase‐Mediated Regulation of Signaling Molecules 59 3.3 Crosstalk and Functional Signal Integration in Response to Insulin in Hepatocytes 60 3.4 Systemic Signal Integration 65 3.4.1 Pancreatic β‐Cells 65 3.4.2 Skeletal Muscles 66 3.4.3 Adipose Tissue 67 3.5 Dysregulation of Insulin Signaling in the Etiology of Type 2 Diabetes 67 References 69 4 Signal Transduction in Disease: Relating Cell Signaling to Morbidity and Mortality 73Patricia E. Ganey and Sean A. Misek 4.1 Introduction 73 4.2 Fibrosis as an Example of Complex Signaling 75 4.2.1 Development of Liver Fibrosis 75 4.2.2 Animal Models of Hepatic Fibrosis 76 4.2.3 Activation of Hepatic Stellate Cells 77 4.2.4 Epithelial‐to‐Mesenchymal Transition (EMT) 78 4.2.5 Other Cellular Interactions in Fibrosis 78 4.2.6 Intracellular Signaling Pathways Critical to Liver Fibrosis 80 4.2.6.1 TGF‐β1 80 4.2.6.2 Kinase Pathways Involved in Fibrotic Responses 82 4.2.6.3 HIF‐1α 83 4.2.6.4 miRNA 84 4.2.6.5 Toll‐Like Receptors (TLRs) 84 4.3 Cancer Drug Resistance: Complex Cellular and Population Changes 85 4.3.1 Genomic Resistance Mechanisms 85 4.3.2 Non‐genomic Mechanisms 88 4.3.3 Non‐cancer Drug Resistance Paradigms 88 4.3.4 Tumor Heterogeneity as a Driver of Drug Resistance 89 4.3.5 Mutational Drivers of Drug Resistance 90 4.3.6 Drug‐Induced Rewiring of Signaling Networks as a Mechanism of Drug Resistance 91 4.3.7 Parallel Pathways and Combination Treatments 93 4.3.8 Epigenetic Mechanisms of Drug Resistance 95 4.3.9 Summary of Cancer Drug Resistance 97 4.4 Summary 98 References 98 5 Experimental Design in Signal Transduction 113Weimin Gao, Meghan Cromie, Qian Wang, Zhongwei Liu, Song Tang, and Julie Vrana Miller 5.1 Overview of Basic Experimental Design 113 5.1.1 Independent Sample t Test 114 5.1.2 Completely Randomized Analysis of Variance (ANOVA) 114 5.1.3 t Test for Dependent Sample Design 115 5.1.4 Randomized Block Design 115 5.1.5 Completely Randomized Factorial Design 116 5.1.6 Summary 116 5.2 Aseptic Technique 116 5.2.1 Sterile Work Environment and Laminar‐Flow Hood 117 5.2.2 Good Personal Hygiene Practices 117 5.2.3 Sterile Reagents and Materials 118 5.2.4 Sterile Handling 118 5.3 Biological Sample Collection, Processing, and Pretreatment Technology 119 5.3.1 Sample Collection 119 5.3.1.1 Sample Collection In Vivo 119 5.3.1.2 Cell Culture In Vitro 120 5.3.2 Sample Processing 121 5.3.2.1 DNA Isolation 121 5.3.2.2 RNA Extraction 121 5.3.2.3 Protein Extraction 122 5.4 Sample Storage 122 5.5 Common In Vitro Studies in Toxicology/Pharmacology 123 5.5.1 Cytotoxicity Studies 123 5.5.2 Viability Assays 123 5.5.2.1 Trypan Blue 123 5.5.2.2 Erythrosin 124 5.5.2.3 Crystal Violet Staining 124 5.5.2.4 Neutral Red Staining 125 5.5.3 Survival Assays 125 5.5.3.1 Clonogenic or Colony Formation Assay 125 5.5.3.2 Cell Cycle Analysis: Flow Cytometry 126 5.5.4 DNA Damage Assays 126 5.5.4.1 Comet Assay 127 5.5.4.2 Sister Chromatid Exchange Assay 127 5.5.5 Southern Blot and DNA Sequencing 127 5.5.5.1 Southern Blot 127 5.5.5.2 DNA Sequencing 128 5.5.5.3 Transfection and Gene Silencing 128 5.5.6 RNA Quantification and Identification 128 5.5.6.1 Northern Blot 128 5.5.6.2 Promoter Deletion Analysis 129 5.5.6.3 RNase Protection Assay 129 5.5.7 Gene Expression 129 5.5.7.1 Quantitative Real‐Time Polymerase Chain Reaction (qRT‐PCR) 130 5.5.7.2 Microarray 130 5.5.8 Protein‐Related Assays 131 5.5.8.1 Bradford Assay 131 5.5.8.2 Enzyme-Linked Immunosorbent Assay (ELISA) 131 5.5.8.3 Western Blot and 2D Gel Electrophoresis 131 5.5.8.4 Immunolocalization 132 5.5.8.5 Immunoprecipitation Assays 132 5.5.8.6 Chromatin Immunoprecipitation (ChIP) 132 5.5.9 Epigenetics 133 5.5.9.1 Bisulfite Pyrosequencing 133 5.5.9.2 ChIP‐on‐Chip 133 5.5.9.3 Multiplex miRNA Profiling 134 5.6 Common In Vivo Studies in Toxicology 134 5.6.1 Toxicological Endpoints 134 5.6.1.1 Maximum Tolerated Dose (MTD) 134 5.6.1.2 Acute, Subchronic, and Chronic Toxicity 135 5.6.1.3 Reproductive and Developmental Toxicity 135 5.6.1.4 Genotoxicity and Carcinogenicity Studies 136 5.6.2 Routes of Exposure 136 5.6.2.1 Oral, Dermal, and Inhalation 136 5.6.2.2 Exposure via Injection 137 5.6.3 Animal Models 137 5.6.3.1 Rodent Studies 137 5.6.3.2 Other Studies 138 5.7 Basic Advantages and Disadvantages Associated with Sample Types 138 5.8 Human Epidemiology Studies 138 5.8.1 Nonexperimental Studies 139 5.8.2 Experimental Studies 139 5.8.3 Molecular Epidemiology 140 5.9 Examples of Tox‐ and Pharm‐Based Experiments Relevant to Signal Transduction Endpoints 140 5.9.1 Cytotoxicity 141 5.9.1.1 Nicotine‐Derived Nitrosamine Ketone (NNK) 141 5.9.1.2 Doxorubicin (DOX) 142 5.9.1.3 Curcumin 142 5.9.1.4 Combination Effects of Cisplatin and/or Leptomycin B (LMB) 143 5.9.2 DNA Damage 143 5.9.3 Cell Cycle and Apoptosis 145 5.9.4 ROS Induction in A549 Cells After LMB and Epigallocatechin Gallate (EGCG) Treatment 146 5.9.5 Signaling Pathways 146 5.9.5.1 Metabolizing Alterations After Chemical Exposure 146 5.9.5.2 p53 Signaling Pathways 148 5.9.6 Protein Kinase B (Akt/PKB)/Mechanistic Target of Rapamycin (mTOR) Pathway Analysis Using Multiblot 150 5.9.7 Discovery of Unrecognized Pathways/Molecules Using Proteomics 150 5.10 Coupling Experimental Results Within the Larger Literature Framework to Generate Information 152 5.10.1 Cell Proliferation–EGFR Pathway 152 5.10.2 Cell Cycle 154 5.10.3 Signal‐Mediated Cell Death 156 5.10.4 Reactive Oxygen Species (ROS) 161 References 162 6 Techniques for Measuring Cellular Signal Transduction 171Julie Vrana Miller, Weimin Gao, Meghan Cromie, and Zhongwei Liu 6.1 Introduction 171 6.2 High‐Throughput Versus High‐Content Data 172 6.2.1 Ergodic and Nonergodic Systems 173 6.3 Methods to Measure Signal Transduction Data 173 6.3.1 Microscopy 173 6.3.1.1 Widefield Epifluorescence Microscopy 173 6.3.1.2 Confocal Microscopy 174 6.3.1.3 Immunohistochemistry 175 6.3.1.4 FRET 178 6.3.2 Enzyme‐Linked Immunosorbent Assay (ELISA) 179 6.3.2.1 Competitive ELISA 179 6.3.2.2 Sandwich ELISA 180 6.3.2.3 Direct Cellular ELISA 180 6.3.2.4 Multiplex Suspension Array Assays 181 6.3.2.5 Electrochemiluminescence (ECL) Array 182 6.3.3 Gel Electrophoresis 183 6.3.4 Western Blot 183 6.3.5 Protein Nuclear Magnetic Resonance (NMR) 186 6.4 Techniques to Generate Large Datasets for Signal Transduction Network Analysis 187 6.4.1 ’‐omics Using Mass Spectrometry 187 6.4.1.1 Separation Techniques 188 6.4.1.2 Phosphoprotein Enrichment for Phosphoproteomics: IMAC, MOAC, and SMOAC 189 6.4.1.3 Quantitation with Chemical Tags: iTRAQ and TMT 190 6.4.2 RNA Sequencing (RNA‐Seq) 190 6.5 Bioenergetics 191 6.5.1 Oxygen Consumption 191 6.5.2 Reactive Oxygen Species (ROS) Fluorescent Probes 192 6.5.3 ATP Assays 193 6.5.4 Nicotinamide Adenine Dinucleotide (NADH) Assay 193 6.5.5 Mitochondrial Membrane Potential 194 6.6 Relating Signaling to Cellular Outcome Using Relevant Assays 194 6.6.1 MTT/MTS/WST Assays 194 6.6.2 LDH Assay 195 6.6.3 Resazurin Assay (Alamar Blue) 196 6.6.4 Cell Death: Plasma Membrane Degradation Assay 196 6.7 Summary 196 References 197 7 Computational Methods for Signal Transduction: A Network Approach 201Giovanni Scardoni, Gabriele Tosadori, John Morris, Sakshi Pratap, Carlo Laudanna, and Alice Han 7.1 Introduction 201 7.2 Network Construction 203 7.2.1 Introduction to Network Construction 203 7.2.2 Network Construction from a Probe 203 7.2.3 Mapping Methodology 204 7.2.4 Small Networks 208 7.2.5 Large Networks 208 7.3 Facing the Network Analysis 209 7.3.1 Centralities Definition and Description 211 7.3.2 Global Parameters 211 7.3.2.1 Diameter (ΔG) 211 7.3.2.2 Average Distance 212 7.3.3 Local Parameters 213 7.3.3.1 Degree 213 7.3.3.2 Eccentricity 214 7.3.3.3 Closeness 215 7.3.3.4 Radiality 215 7.3.3.5 Centroid Value 217 7.3.3.6 Stress 219 7.3.3.7 S.‐P. Betweenness 219 7.3.3.8 Eigenvector 220 7.3.3.9 Bridging Centrality 221 7.3.3.10 Edge Betweenness 221 7.3.3.11 Normalization and Relative Centralities 222 7.3.4 Clusters 222 7.4 Employing Centrality Analysis to Evaluate Stressed Biological Systems 224 7.5 Interference Notion: How to Perform Virtual Knockout Experiments on Biological Networks 226 7.5.1 Integrating Experimental Dataset into a Topological Analysis 227 7.5.2 Integrating Expression or Activation Levels as Nodes Attributes 228 7.5.3 Edge Attributes as Distance in a Computation 228 7.6 Network Analysis Software 229 7.6.1 Cytoscape and Its Apps 229 7.6.1.1 structureViz/RINalyzer 231 7.6.1.2 CentiScaPe 231 7.6.1.3 PesCa 231 7.6.1.4 Interference 231 7.6.1.5 clusterMaker2 232 7.6.1.6 chemViz 233 7.6.2 Other Tools 233 7.6.2.1 Gephi 233 7.6.2.2 D3.js 234 7.6.2.3 VisANT 234 7.7 Conclusions 236 References 236 8 A Toxicological Application of Signal Transduction: Early Cellular Changes Can Be Indicative of Toxicity 239Julie Vrana Miller, Nicole Prince, Julia A. Mouch, and Jonathan W. Boyd 8.1 Introduction 239 8.2 Classification of Toxic Agent and Exposure Effects: A Toxicological Perspective 240 8.2.1 Dose–Response for Chemical Exposure Toxicity Testing and Risk Assessment 240 8.2.2 Chemical Mixtures 241 8.2.3 Mode of Action Versus Mechanism of Action 242 8.3 Early Cellular Changes Post‐exposure 244 8.3.1 Intracellular Signaling Perturbations Associated with Exposure 245 8.3.2 Bioenergetic Changes Post‐exposure 248 8.3.3 Time Scale of Exposure Effects 249 8.4 Experimentally Testing Early Cellular Changes that May Contribute to Exposure Sensing and Response 250 8.4.1 Paradigm Shift Toward In Vitro Cell Culture 250 8.4.2 Real‐Time In Vitro Assays to Measure Early Cellular Changes 251 8.4.2.1 Using NADH and Oxygen Consumption to Predict ATP Generation 252 8.4.3 Prediction of Posttranslational Phosphorylation Response for Mixtures 253 8.4.3.1 Using Bliss Independence (Response Addition) to Predict Relative Phosphorylation During Critical Signaling Events 253 References 256 Appendix A 262 9 Future Research in Signaling 267Jonathan W. Boyd, Nicole Prince, and Marc Birringer 9.1 Translational Research and a Spatiotemporal Understanding of Signal Transduction 267 9.2 Integrating Second Messengers into Signal Transduction 270 9.3 Understanding Crosstalk in Signal Transduction 272 9.4 Posttranslational Modifications (PTMs) and Target Identification in Signal Transduction 274 9.5 Epigenetic Endpoints in Signal Transduction 276 9.6 The Integration of Nutrition and Signal Transduction 278 9.6.1 Cellular AMPK Signaling 281 9.6.2 Cellular TOR Signaling 282 9.6.3 Gut Microbiota 282 9.6.4 The Integration of Endocrine Gut Signaling 283 References 284 Index 291

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Book SynopsisProvides a broad range of information from basic principles to advanced applications of biosensors and nanomaterials in health care diagnostics This book utilizes a multidisciplinary approach to provide a wide range of information on biosensors and the impact of nanotechnology on the development of biosensors for health care. It offers a solid background on biosensors, recognition receptors, biomarkers, and disease diagnostics. An overview of biosensor-based health care applications is addressed. Nanomaterial applications in biosensors and diagnostics are included, covering the application of nanoparticles, magnetic nanomaterials, quantum dots, carbon nanotubes, graphene, and molecularly imprinted nanostructures. The topic of organ-specific health care systems utilizing biosensors is also incorporated to provide deep insight into the very recent advances in disease diagnostics. Biosensors and Nanotechnology: Applications in Health Care Diagnostics is compTable of ContentsList of Contributors xi Preface xv Acknowledgments xvii Section 1 Introduction to Biosensors, Recognition Elements, Biomarkers, and Nanomaterials 1 1 General Introduction to Biosensors and Recognition Receptors 3Frank Davis and Zeynep Altintas 1.1 Introduction to Biosensors 3 1.2 Enzyme‐ Based Biosensors 4 1.3 DNA‐ and RNA‐Based Biosensors 5 1.4 Antibody‐Based Biosensors 7 1.5 Aptasensors 8 1.6 Peptide‐Based Biosensors 10 1.7 MIP‐Based Biosensor 11 1.8 Conclusions 12 References 13 2 Biomarkers in Health Care 17Adama Marie Sesay, Pirkko Tervo, and Elisa Tikkanen 2.1 Introduction 17 2.2 Biomarkers 18 2.2.1 Advantage and Utilization of Biomarkers 18 2.2.2 Ideal Characteristics of Biomarkers 19 2.3 Biological Samples and Biomarkers 20 2.4 Personalized Health and Point‐of‐Care Technology 22 2.5 Use of Biomarkers in Biosensing Technology 24 2.6 Biomarkers in Disease Diagnosis 26 2.7 Conclusions 29 References 30 3 The Use of Nanomaterials and Microfluidics in Medical Diagnostics 35Jon Ashley and Yi Sun 3.1 Introduction 35 3.2 Nanomaterials in Medical Diagnostics (Bottom‐Up Approach) 36 3.2.1 Carbon Nanomaterials 37 3.2.2 Metallic Nanoparticles 39 3.2.2.1 Quantum Dots 39 3.2.2.2 Magnetic Nanoparticles (Fe2O3, FeO, and Fe3O4) 41 3.2.2.3 Gold Nanoparticles 41 3.2.2.4 Silver Nanoparticles 42 3.2.2.5 Nanoshells 42 3.2.2.6 Nanocages 43 3.2.2.7 Nanowires 43 3.2.3 Polymer‐Based Nanoparticles 44 3.3 Application of Microfluidic Devices in Clinical Diagnostics (Top‐Down Approach) 45 3.3.1 Unique Features of Microfluidic Devices 45 3.3.2 Applications of Microfluidic Devices in Medical Diagnostics 46 3.3.2.1 Types of Microfluidic POC Devices 47 3.3.2.2 Benchtop Microfluidic Instruments 47 3.3.2.3 Small, Lightweight Microfluidic Devices 49 3.3.2.4 Simple Un‐instrumented Microfluidic Systems 50 3.4 Integration of Microfluidics with Nanomaterials 52 3.5 Future Perspectives of Nanomaterial and Microfluidic‐Based Diagnostics 53 References 54 Section 2 Biosensor Platforms for Disease Detection and Diagnostics 59 4 SPR‐Based Biosensor Technologies in Disease Detection and Diagnostics 61Zeynep Altintas and Wellington M. Fakanya 4.1 Introduction 61 4.2 Basic Theoretical Principles 63 4.3 SPR Applications in Disease Detection and Diagnostics 66 4.3.1 SPR Biosensors in Cancer Detection 66 4.3.2 SPR Sensors in Cardiac Disease Detection 68 4.3.3 SPR Sensors in Infectious Disease Detection 71 4.4 Conclusions 72 References 74 5 Piezoelectric‐Based Biosensor Technologies in Disease Detection and Diagnostics 77Zeynep Altintas and Noor Azlina Masdor 5.1 Introduction 77 5.2 QCM Biosensors 78 5.3 Disease Diagnosis Using QCM Biosensors 80 5.3.1 Cancer Detection Using QCM Biosensors 82 5.3.2 Cardiovascular System Disorder Detection Using Biosensors 85 5.3.3 Pathogenic Disease Detection Using QCM Biosensors 88 5.4 Conclusions 90 References 91 6 Electrochemical‐Based Biosensor Technologies in Disease Detection and Diagnostics 95Andrea Ravalli and Giovanna Marrazza 6.1 Introduction 95 6.2 Electrochemical Biosensors: Definitions, Principles, and Classifications 96 6.3 Biomarkers in Clinical Applications 102 6.3.1 Electrochemical Biosensors for Tumor Markers 102 6.3.2 Electrochemical Biosensors for Cardiac Markers 110 6.3.3 Electrochemical Biosensors for Autoimmune Disease 115 6.3.4 Electrochemical Biosensors for Autoimmune Infectious Disease 116 6.4 Conclusions 118 References 118 7 MEMS‐Based Cell Counting Methods 125Mustafa Kangul, Eren Aydın, Furkan Gokce, Ozge Zorlu, Ebru Ozgur, and Haluk Kulah 7.1 Introduction 125 7.2 MEMS‐Based Cell Counting Methods 126 7.2.1 Optical Cell Counting Methods 126 7.2.1.1 Quantification of the Cells by Detecting Luminescence 127 7.2.1.2 Quantification of the Cells via High‐Resolution Imaging Techniques 130 7.3 Electrical and Electrochemical Cell Counting Methods 131 7.3.1 Impedimetric Cell Quantification 133 7.3.2 Voltammetric and Amperometric Cell Quantification 135 7.4 Gravimetric Cell Counting Methods 136 7.4.1 Deflection‐Based Cell Quantification 136 7.4.2 Resonant‐Based Cell Quantification 138 7.4.2.1 Theory of the Resonant‐Based Sensors 138 7.4.2.2 Actuation and Sensing Methods of Resonators in MEMS Applications 140 7.4.2.3 Resonator Structure Types Used for Cell Detection Applications 145 7.5 Conclusion and Comments 149 References 151 8 Lab‐on‐a‐Chip Platforms for Disease Detection and Diagnosis 155Ziya Isiksacan, Mustafa Tahsin Guler, Ali Kalantarifard, Mohammad Asghari, and Caglar Elbuken 8.1 Introduction 155 8.2 Continuous Flow Platforms 156 8.3 Paper‐Based LOC Platforms 161 8.4 Droplet‐Based LOC Platforms 166 8.5 Digital Microfluidic‐Based LOC Platforms 169 8.6 CD‐Based LOC Platforms 172 8.7 Wearable LOC Platforms 174 8.8 Conclusion and Outlook 176 References 177 Section 3 Nanomaterial’s Applications in Biosensors and Diagnostics 183 9 Applications of Quantum Dots in Biosensors and Diagnostics 185Zeynep Altintas, Frank Davis, and Frieder W. Scheller 9.1 Introduction 185 9.2 Quantum Dots: Optical Properties, Synthesis, and Surface Chemistry 186 9.3 Biosensor Applications of QDs 187 9.4 Other Biological Applications of QDs 191 9.5 Water Solubility and Cytotoxicity 194 9.6 Conclusion 196 References 197 10 Applications of Molecularly Imprinted Nanostructures in Biosensors and Diagnostics 201Deniz Aktas‐Uygun, Murat Uygun, and Sinan Akgol 10.1 Introduction 201 10.2 Molecular Imprinted Polymers 202 10.3 Imprinting Approaches 204 10.4 Molecularly Imprinted Nanostructures 205 10.5 MIP Biosensors in Medical Diagnosis 207 10.6 Diagnostic Applications of MIP Nanostructures 210 10.7 Conclusions 212 References 213 11 Smart Nanomaterials: Applications in Biosensors and Diagnostics 219Frank Davis, Flavio M. Shimizu, and Zeynep Altintas 11.1 Introduction 219 11.2 Metal Nanoparticles 221 11.3 Magnetic Nanoparticles 226 11.4 Carbon Nanotubes 231 11.5 Graphene 235 11.6 Nanostructured Metal Oxides 242 11.7 Nanostructured Hydrogels 247 11.8 Nanostructured Conducting Polymers 254 11.9 Conclusions and Future Trends 260 References 262 12 Applications of Magnetic Nanomaterials in Biosensors and Diagnostics 277Zeynep Altintas 12.1 Introduction 277 12.2 MNP‐Based Biosensors for Disease Detection 279 12.3 MNPs in Cancer Diagnosis and Therapy 284 12.4 Cellular Applications of MNPs in Biosensing, Imaging, and Therapy 289 12.5 Conclusions 290 References 291 13 Graphene Applications in Biosensors and Diagnostics 297Adina Arvinte and Adama Marie Sesay 13.1 Introduction 297 13.2 Graphene and Biosensors 298 13.2.1 Structure 298 13.2.2 Preparation 299 13.2.3 Properties 301 13.2.4 Commercialization in the Field of Graphene Sensors 302 13.2.5 Latest Developments in Graphene‐based Diagnosis 303 13.3 Medical Applications of Graphene 303 13.3.1 Electrochemical Graphene Biosensors for Medical Diagnostics 304 13.3.1.1 Glucose Detection 304 13.3.1.2 Cysteine Detection 307 13.3.1.3 Cholesterol Detection 309 13.3.1.4 Hydrogen Peroxide (H2O2) 310 13.3.1.5 Glycated Hemoglobin 312 13.3.1.6 Neurotransmitters 312 13.3.1.7 Amyloid‐Beta Peptide 315 13.3.2 Electrochemical Graphene Aptasensors 316 13.3.2.1 Nucleic Acids 316 13.3.2.2 Cancer Cell 318 13.3.3 Optical Graphene Sensors for Medical Diagnostics 319 13.4 Conclusions 322 Acknowledgments 322 References 322 Section 4 Organ-Specific Health Care Applications for Disease Cases Using Biosensors 327 14 Optical Biosensors and Applications to Drug Discovery for Cancer Cases 329Zeynep Altintas 14.1 Introduction 329 14.2 Biosensor Technology and Coupling Chemistries 332 14.3 Optical Biosensors for Drug Discovery 335 14.4 Computational Simulations and New Approaches for Drug–Receptor Interactions 341 14.5 Conclusions 343 References 344 15 Biosensors for Detection of Anticancer Drug–DNA Interactions 349Arzum Erdem, Ece Eksin, and Ece Kesici 15.1 Introduction 349 15.2 Electrochemical Techniques 351 15.3 Optical Techniques 356 15.4 Electrochemical Impedance Spectroscopy Technique 358 15.5 QCM Technique 360 15.6 Conclusions 361 Acknowledgments 361 References 361 Index

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Book SynopsisProvides a comprehensive examination of emergency management and offers concepts and strategies for creating effective programs This book looks at the larger context within which emergency management response occurs, and stresses the development of a program to address a wide range of issues. Not limited to traditional emergency response to natural disasters, it addresses a conceptual model capable of integrating multiple disciplines and dealing with unexpected emergencies. Emergency Management: Concepts and Strategies for Effective Programs, Second Edition starts by focusing on the three pillars on which successful emergency management is based: an understanding of history, knowledge of social science research, and technical expertise in emergency management operations. It provides insight as to how emergency management has evolved and suggests reasons why the current method of response planning doesn't work as well as it should. The book then goes on toTable of ContentsPreface to the Second Edition xiii Preface to the First Edition xv Introduction xvii 1 Historical Perspectives: The Evolution of Emergency Management 1 Why Study History? 2 Lessons from History 5 The Advent of Disaster Legislation 14 The Growth of Disaster Bureaucracy 22 From Military to Civilian Leadership 23 Civil Defense and Disaster Relief Merge 27 Conclusion 32 2 Historical Perspectives: Toward a National Response Strategy 33 The Origins of National Planning 34 September 11 and the Impact of Homeland Security 36 The Marginalization of Emergency Management 36 Capabilities‐based Planning Replaces All‐Hazards Planning 39 The Pendulum Swings Back: Hurricane Katrina 43 A Failed Response? 43 Degraded Capabilities and Confused Planning 45 Reform and New Planning Concepts 47 Conclusion 49 3 Social Science and the Beginnings of Emergency Management Theory 51 Social Science as an Emergency Management Tool 51 Social Science Evolves Emergency Management Theory 52 Emergencies, Disasters, and Catastrophes 54 Disaster Mythology 65 Organizational Response 69 Conclusion 71 4 The Emergency Manager: Evolving Roles and Shifting Paradigms 73 Conflicting Roles 74 The Emergency Manager as Program Manager 78 Toward Professionalization 84 Emergency Management as a Field 84 Emergency Management as a Discipline 88 Emergency Management as a Profession 89 Conclusion 90 5 Establishing the Emergency Management Program 93 Program Administration 94 Developing a Governance Structure 94 The Administrative Plan 99 Strategic Planning 99 Formulating Vision 101 Establishing Goals and Objectives 106 Developing the Strategic Plan 108 Enabling Authorities and Legislation 109 Grant Requirements 111 Best Practices 112 Program Elements 113 Resource Management 113 Training 115 Finance 116 Program Evaluation 118 Quantitative Assessment Tools 118 Qualitative Assessment Tools 119 Exercise Programs 120 Actual Incidents 123 Corrective Action Program 124 Conclusion 125 6 Assessing Risk 127 The Nature of Risk 128 Risk Assessment Methodologies 129 Hazard Identification 133 Hazard Analysis 140 Simple Matrix Analysis 140 Indicators and Numerical Ranking 143 THIRA and Context Analysis 148 Intuition 149 Impact Analysis 150 Business Impact Analysis (BIA) 150 Adaptive Business Continuity 154 Continuity of Government/Continuity of Operations 155 Federal Guidance 155 Critical Functions and Process Analysis 158 Conclusion 160 7 Developing Strategy 163 A New Look at an Old Model 164 Risk Management Strategy 166 Mitigation Strategy 168 Recovery Strategy 173 Response Strategy 180 Preparedness Strategy 185 Using Strategy to Guide Planning 187 Conclusion 189 8 Planning Concepts 191 Plans Versus Planning 191 The Planning Continuum 197 Planning Methodologies 201 Planning Assumptions 201 Scenario‐Based Planning 202 Functional Planning 205 Capabilities‐Based Planning 207 Effective Planning 208 Simplicity in Planning 209 Operational Phases 210 All‐Hazards Planning 212 Decentralized Execution 212 Putting the Pieces Together 214 General Planning Principles 215 Conclusion 217 9 Planning Techniques and Methods 219 Establish a Planning Structure 219 Use a Meeting Facilitation Process 222 Meeting Agenda 225 Conducting the Meeting 226 The Meeting Memorandum 227 Develop an Action Plan and Set Deadlines 229 Managing Multiple Projects 230 Annual Work Plans 230 Graphic Planning Tools 231 Facilitate Decision‐Making 232 Use Common Plan Formats 234 Determining Plan Content 236 Use Graphic Tools 238 Use Exercises to Test Concepts 242 Keep it Simple 244 Conclusion 245 10 Coordinating Response 247 Operational Response 247 Incident Management Systems 251 Unified and Area Commands 256 Multiagency Coordination Systems 258 Emergency Operations Centers 264 Communications and Interoperability 269 Information Processing 272 Mutual Aid 273 Resource Management and Logistics 274 The Joint Information Center 276 Conclusion 278 11 Leading in Crisis 279 Principles of Emergency Management 280 Program Leadership 282 Building a Leadership Team 282 Establishing Relationships 284 Making Decisions 285 Operational Leadership 286 The Effects of Crisis 286 Barriers to Decision‐Making 287 Crisis Decision‐Making 289 Conclusion 291 12 Crisis Management 293 Barriers to Crisis Management 294 Disengagement and Inexperience 294 Common Leadership Problems 295 Appropriate Roles for Senior Officials 297 Crisis Management 299 Identifying the Crisis 299 Isolating the Crisis 300 Preparing for Crisis Management 301 Hurricane Katrina: Crisis Management Failure 302 Increasing Organizational Effectiveness 304 Crisis Communications 305 Strategic Recovery Issues 307 Catastrophic Events 312 Conclusion 315 Conclusion 317 Bibliography 321 Index 327

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Book SynopsisA valuable handbook containing reviews, practical methods and standard operating procedures.Table of ContentsList of Contributors xvii Preface xxvi Acknowledgements xxviii Section I Introduction 1 1 Introduction: Cyanobacteria, Cyanotoxins, Their Human Impact, and Risk Management 3Geoffrey A. Codd, Jussi Meriluoto, and James S. Metcalf 1.1 Introduction 3 1.2 Cyanotoxins 4 1.3 Exposure Routes, Exposure Media, and At‐Risk Human Activities 6 1.4 Cyanobacterial Blooms and Cyanotoxins in Relation to Human Pressures on Water Resources and Climate Change 7 1.5 Aims of the Handbook 7 References 8 Section II Cyanobacteria 9 2 Ecology of Cyanobacteria 11Jean‐François Humbert and Jutta Fastner 2.1 Introduction 11 2.2 Environmental Conditions Leading to Cyanobacterial Blooms 12 2.3 Population Dynamics of Cyanobacteria 13 2.4 Spatial Distribution of Cyanobacteria in Freshwater Ecosystems 15 2.5 Ecology of the Production of Toxins by Cyanobacteria 16 2.6 General Conclusions 17 References 17 3 Picocyanobacteria: The Smallest Cell‐Size Cyanobacteria 19Iwona Jasser and Cristiana Callieri 3.1 Introduction 19 3.2 Records of Toxic Picocyanobacteria 21 3.3 Summary 25 References 26 4 Expansion of Alien and Invasive Cyanobacteria 28Mikołaj Kokociński, Reyhan Akçaalan, Nico Salmaso, Maya Petrova Stoyneva‐Gärtner, and Assaf Sukenik 4.1 Introduction 28 4.2 Definition of Invasive/Alien Species: Nomenclature Problems 29 4.2.1 Invasive Species Concept in Cyanobacteria 29 4.3 Occurrence of Invasive and Alien Cyanobacteria 31 4.4 Factors Enhancing the Expansion of Alien Cyanobacteria 33 4.5 Impact of Cyanobacterial Invasion on Ecosystem 34 References 36 Section III Sampling, Monitoring and Risk Management 41 5 Health and Safety During Sampling and in the Laboratory 43Roberta Congestri, James S. Metcalf , Luca Lucentini, and Federica Nigro Di Gregorio 5.1 Introduction 43 5.2 Sampling Safety 43 5.3 Laboratory Safety 44 5.4 Cyanotoxin Production and Application 45 5.5 Contamination due to Equipment, Glassware, and Accidents 45 References 45 6 Basic Guide to Detection and Monitoring of Potentially Toxic Cyanobacteria 46Nico Salmaso, Cécile Bernard , Jean‐François Humbert, Reyhan Akçaalan, Meriç Albay, Andreas Ballot , Arnaud Catherine, Jutta Fastner , Kerstin Häggqvist, Mária Horecká, Katarzyna Izydorczyk, Latife Köker , Jiří Komárek, Selma Maloufi, Joanna Mankiewicz‐Boczek, James S. Metcalf , Antonio Quesada, Catherine Quiblier , and Claude Yéprémian 6.1 Introduction 47 6.2 Monitoring of Cyanobacteria: Sampling Strategies 48 6.3 Cyanobacterial Identification and Quantification 55 Appendix 6.1 Testing Phytoplankton Distributions: χ2 Test (Pearson Goodness‐of‐Fit Test) 63 References 66 7 Case Studies of Environmental Sampling, Detection, and Monitoring of Potentially Toxic Cyanobacteria 70Kerstin Häggqvist, Reyhan Akçaalan, Isidora Echenique‐Subiabre, Jutta Fastner , Mária Horecká, Jean‐François Humbert, Katarzyna Izydorczyk, Tomasz Jurczak, Mikołaj Kokociński, Tore Lindholm, Joanna Mankiewicz‐Boczek, Antonio Quesada, Catherine Quiblier, and Nico Salmaso 7.1 Introduction 71 7.2 Shallow Lakes 71 7.3 Deep Lakes 74 7.4 Reservoirs 75 7.5 Rivers 77 7.6 The Baltic Sea 78 7.7 Waterbodies Used for Drinking Water Production 79 References 81 8 New Tools for the Monitoring of Cyanobacteria in Freshwater Ecosystems 84Jean‐François Humbert and Andrea Törökné 8.1 Introduction 84 8.2 Use of Photosynthetic Pigments for the In Situ Quantification of Cyanobacteria and Other Phytoplankton in Water 85 8.3 Integration of Physicochemical and Fluorescence Sensors in Buoys 86 8.4 New Methods for Automatic Cell Counting in Water Samples 86 References 87 9 Remote Sensing of Cyanobacterial Blooms in Inland, Coastal, and Ocean Waters 89Peter D. Hunter , Mark W. Matthews , Tiit Kutser , and Andrew N. Tyler 9.1 Introduction 89 9.2 Bio‐optical Properties of Marine and Inland Waters 90 9.3 Platforms and Sensors 91 9.4 Overview of Approaches 92 9.5 Case Study Examples 95 9.6 Future Prospects 96 References 98 10 The Italian System for Cyanobacterial Risk Management in Drinking Water Chains 100Luca Lucentini, Liliana La Sala , Rossella Colagrossi , and Roberta Congestri 10.1 Introduction 100 10.2 Risk Assessment of Toxic Cyanobacterial Outbreaks in Water for Human Consumption in Italy 101 10.3 Framework of Risk Management of Toxic Cyanobacterial Outbreaks in Water for Human Consumption 102 10.4 Risk Information and Communication 106 References 106 Section IV Toxins and Bioactive/Noxious Compounds from Cyanobacteria 107 11 Microcystins and Nodularins 109Arnaud Catherine, Cécile Bernard, Lisa Spoof , and Milena Bruno 11.1 Chemical Characteristics and Diversity of Microcystins and Nodularins 109 11.2 Biosynthesis and Genetics of MC and NOD Production 110 11.3 Occurrence of MCs and NODs 112 11.4 Toxicological Effects and Associated Health Risk 113 11.5 Available Methods for the Analysis of MCs and NODs 117 References 118 12 Cylindrospermopsin and Congeners 127Mikołaj Kokociński, Ana Maria Cameán, Shmuel Carmeli, Remedios Guzmán‐Guillén, Ángeles Jos, Joanna Mankiewicz‐Boczek , James S. Metcalf , Isabel Maria Moreno, Ana Isabel Prieto, and Assaf Sukenik 12.1 Chemical Characteristics of Cylindrospermopsin and Congeners 127 12.2 Genes Involved in CYN Biosynthesis 128 12.3 CYN Producers and Distribution 128 12.4 Toxicity of CYN 129 12.5 The Biological Role of CYN 132 12.6 Degradation of CYN 132 12.7 Available Methods for Determining CYN in Waters 132 References 133 13 Anatoxin‐a, Homoanatoxin‐a, and Natural Analogues 138Milena Bruno, Olivier Ploux, James S. Metcalf , Annick Mejean, Barbara Pawlik‐Skowronska, and Ambrose Furey 13.1 Introduction 138 13.2 Chemical Structure, Synthesis, and Reactivity 138 13.3 Biosynthesis of ANTX, HANTX, and dihydroANTX 140 13.4 Occurrence and Producing Strains 140 13.5 Toxicity and Pharmacology 141 13.6 Analytical Methodologies 142 References 144 14 Saxitoxin and Analogues 148Andreas Ballot, Cécile Bernard, and Jutta Fastner 14.1 Introduction 148 14.2 Toxicity of STXs 149 14.3 Occurrence 149 14.4 Genetics and Biosynthesis 150 14.5 Detection Methods 151 14.6 Guidance Values or National Regulations or Recommendations for Managing STXs 152 References 152 15 Anatoxin‐a(S) 155James S. Metcalf and Milena Bruno 15.1 Chemical Structure of Anatoxin‐a(S) 155 15.2 Biosynthesis 155 15.3 Occurrence and Producing Strains 156 15.4 Toxicology and Pharmacology 156 15.5 Analytical Methods for Determination and Quantification 157 References 158 16 β‐N‐Methylamino‐l‐Alanine and (S)‐2,4‐Diaminobutyric Acid 160Olivier Ploux, Audrey Combes, Johan Eriksson, and James S. Metcalf 16.1 Historical Overview 160 16.2 Structure, Synthesis, and Molecular Properties 161 16.3 Neurotoxicity 161 16.4 Methods for Identification and Quantification 162 16.5 Occurrence in Cyanobacteria, Plants, and Animals 162 References 163 17 Lipopolysaccharide Endotoxins 165Sílvia Monteiro, Ricardo Santos, Luděk Bláha, and Geoffrey A. Codd 17.1 Lipopolysaccharide Endotoxins: Structure 165 17.2 Occurrence of LPS Endotoxins 167 17.3 Toxic Effects of LPS Endotoxins 168 17.4 Methods for Determination of LPS Endotoxins 169 References 170 18 Cyanobacterial Retinoids 173Kunimitsu Kaya and Tomoharu Sano 18.1 Introduction 173 18.2 Detection of Retinoids Produced by Cyanobacteria 174 18.3 Chemistry and Analysis of Retinoids 175 18.4 Malformations by Cyanobacterial Retinoids 176 18.5 Concluding Remarks 176 References 176 19 Other Cyanobacterial Bioactive Substances 179Tina Elersek, Luděk Bláha, Hanna Mazur‐Marzec, Wido Schmidt, and Shmuel Carmeli 19.1 Introduction 179 19.2 Aeruginosins and Spumigins 182 19.3 Anabaenopeptins 184 19.4 Biogenic Amines 185 19.5 Depsipeptides 186 19.6 Endocrine Disruptors and Novel Tumour Promoters 187 19.7 Lyngbyatoxins and Other Toxins Produced by Lyngbya majuscula 188 19.8 Microginins 189 19.9 Microviridins 189 References 190 20 Taste and Odour Compounds Produced by Cyanobacteria 196Triantafyllos Kaloudis, Theodoros M. Triantis, and Anastasia Hiskia 20.1 Cyanobacterial Taste and Odour Compounds in Water Resources 196 20.2 Analytical Methods for Taste and Odour Compounds 197 References 199 Section V Screening and Trace Analysis of Cyanotoxins 203 21 Determination of Cyanotoxins by High‐Performance Liquid Chromatography with Photodiode Array 205Anastasia Hiskia, Lisa Spoof , Triantafyllos Kaloudis, and Jussi Meriluoto 21.1 Introduction: Application of High‐Performance Liquid Chromatography for Different Classes of Cyanotoxins 205 21.2 HPLC of Microcystins and Nodularins 206 21.3 HPLC of Anatoxins 208 21.4 HPLC of Cylindrospermopsin 208 21.5 Advantages and Disadvantages of HPLC‐PDA 208 References 209 22 Determination of Cyanotoxins by High‐Performance Liquid Chromatography with Fluorescence Derivatization 212James S. Metcalf and Paulo Baptista Pereira 22.1 Principle of the Technique and Why It Is Used for Cyanotoxins 212 22.2 Types of Reactions for Analysing Paralytic Shellfish Toxins Using High‐Performance Liquid Chromatography with Fluorescence Derivatization 213 22.3 Types of Reactions for Analysing β‐N‐Methylamino‐l‐Alanine and Isomers by HPLC‐FLD 216 22.4 Need for Confirmatory Techniques with HPLC‐FLD 216 References 216 23 Liquid Chromatography–Mass Spectrometry 218Josep Caixach, Cintia Flores, Lisa Spoof , Jussi Meriluoto, Wido Schmidt, Hanna Mazur‐Marzec, Anastasia Hiskia, Triantafyllos Kaloudis, and Ambrose Furey 23.1 Introduction 218 23.2 Ion Sources 220 23.3 Types of Mass Analysers 225 23.4 Application of LC‐MS in Cyanotoxin Analyses 233 23.5 Overview of Quantitation: Cyanobacterial Toxins 235 23.6 Ion Suppression/Enhancement Considerations 237 23.7 High‐Resolution Mass Spectrometry (HRMS) 239 23.8 MS Experiments for the Detection of Unknown Cyanotoxins 242 23.9 Performance Criteria of LC‐MS Methods for Identification and Quantification of Cyanotoxins 249 References 251 24 Capillary Electrophoresis of Cyanobacterial Toxins 258Gábor Vasas 24.1 Basic Theory and Introduction of Capillary Electrophoresis 258 24.2 Selection of Separation Methods 259 24.3 Detection Methods 259 24.4 CE Methods of Cyanobacterial Toxins 260 24.5 Future Perspectives 262 References 262 25 Immunoassays and Other Antibody Applications 263James S. Metcalf and Geoffrey A. Codd 25.1 Introduction 263 25.2 Production of Antibodies versus Cyanotoxins 264 25.3 Applications of Cyanotoxin Antibodies 264 25.4 Cyanotoxin Localisation and Quantification Using Antibodies 265 25.5 Other Cyanotoxin Antibody‐Related Technologies 265 References 266 26 Protein Phosphatase Inhibition Assays 267James S. Metcalf , Anastasia Hiskia, and Triantafyllos Kaloudis 26.1 Background and Molecular Mechanism of Protein Phosphatase Inhibition 267 26.2 Classes of Compounds that Inhibit Protein Phosphatases 268 26.3 Effects of Microcystins on Cyanobacterial Protein Phosphatases 268 26.4 The Basis of the PPIA Assay for Microcystins and Its Evolution 268 26.5 Comparison of PPIA with Other Analytical Methods for Microcystins 268 26.6 Commercially Available Kits for Microcystins 269 26.7 Improvements to the PPIA Assay to Make It More Specific to Microcystins 269 26.8 Conclusions about the Effectiveness of the PPIA Assay for Microcystins and Nodularins in Different Matrices 269 References 270 27 Bioassay Use in the Field of Toxic Cyanobacteria 272Luděk Bláha, Ana Maria Cameán , Valérie Fessard , Daniel Gutiérrez‐Praena , Ángeles Jos , Benjamin Marie , James S. Metcalf , Silvia Pichardo , María Puerto , Andrea Törökné , Gábor Vasas, and Bojana Žegura 27.1 Introduction 272 27.2 Drivers and Objectives for Bioassay Use 273 27.3 Classification and Terminology 274 27.4 Bioassays for the Effect Evaluation 275 27.5 Bioassays for Monitoring 276 27.6 Conclusions and Future Perspectives 278 References 278 28 Molecular Tools for the Detection of Toxigenic Cyanobacteria in Natural Ecosystems 280Jean‐François Humbert 28.1 Introduction 280 28.2 Molecular Methods for the Monitoring of Potentially Toxic Cyanobacteria 281 28.3 Strengths and Limitation of These Molecular Approaches 282 28.4 Conclusions 282 References 283 Section VI Methodological Considerations 285 29 Method Validation Guidelines for the Analysis of Cyanotoxins 287Theodoros M. Triantis, Triantafyllos Kaloudis, and Anastasia Hiskia 29.1 Introduction: Method Validation as a Requirement for Laboratory Accreditation 287 29.2 Performance Criteria and Validation Protocols for the Analysis of Cyanotoxins in Environmental Studies 288 29.3 Validation Issues Concerning the Analysis of Cyanotoxins 290 References 291 30 Interpretation, Significance, and Reporting of Results 292Geoffrey A. Codd, Jutta Fastner , Tore Lindholm, Jussi Meriluoto, and James S. Metcalf 30.1 Introduction 292 30.2 Interpretation and Significance of Results 293 30.3 Reporting of Results and Maximization of Benefits 294 30.4 Examples, Debriefing 294 References 296 31 Lessons from the Užice Case: How to Complement Analytical Data 298Zorica Svirčev , Damjana Drobac , Nada Tokodi , Dunja Đenić , Jelica Simeunović , Anastasia Hiskia , Triantafyllos Kaloudis , Biljana Mijović , Stamenko Šušak , Mlađan Protić , Milka Vidović , Antonije Onjia , Sonja Nybom , Tamara Važić , Tamara Palanački Malešević , Tamara Dulić , Dijana Pantelić , Marina Vukašinović , and Jussi Meriluoto 31.1 Introduction 299 31.2 Vrutci Reservoir and the Cyanobacterial Bloom Detected in December 2013 299 31.3 Analytical Work: Toxin Analyses of Water, Cyanobacterial Biomass, and Fish from Reservoir Vrutci 301 31.4 Complementary Data on Toxicity and Observed Health Problems 302 31.5 Analytical and Supplementary Results Combined: A Plausible Reconstruction of Events in Vrutci Reservoir and the City of Užice 306 31.6 Conclusions from the Užice Case 306 References 307 32 Selection of Analytical Methodology for Cyanotoxin Analysis 309Jussi Meriluoto , James S. Metcalf and Geoffrey A. Codd 32.1 Introduction 309 32.2 General Comparison of Physicochemical Analyses, Biochemical Methods, and Bioassays 309 32.3 Guidance for Selecting and Using Standard Operating Procedures Found in this Handbook 310 32.4 Methodology versus Required Response Time 311 32.5 Influence of Waterbody History on the Choice of Methods 312 32.6 Integration of the Results Obtained: Making Sense 312 Section VII Standard Operating Procedures (SOPs) 313 SOP 1 Cyanobacterial Samples: Preservation, Enumeration, and Biovolume Measurements 315Arnaud Catherine, Selma Maloufi, Roberta Congestri, Emanuela Viaggiu, and Renata Pilkaityte SOP 2 Chlorophyll a Extraction and Determination 331Claude Yéprémian, Arnaud Catherine, Cécile Bernard, Roberta Congestri, Tina Elersek, and Renata Pilkaityte SOP 3 Phycocyanin Extraction and Determination 335Claude Yéprémian, Arnaud Catherine, Cécile Bernard, Roberta Congestri, Tina Elersek, and Renata Pilkaityte SOP 4 Analysis of Picocyanobacteria Abundance in Epifluorescence Microscopy 339Iwona Jasser and Cristiana Callieri SOP 5 Estimation of Cyanobacteria Biomass by Marker Pigment Analysis 343Jean‐Pierre Descy SOP 6 Extraction of Cyanotoxins from Cyanobacterial Biomass 350Leonardo Cerasino, Jussi Meriluoto, Luděk Bláha, Shmuel Carmeli, Triantafyllos Kaloudis, and Hanna Mazur‐Marzec SOP 7 Solid‐Phase Extraction of Microcystins and Nodularin from Drinking Water 354Theodoros M. Triantis, Triantafyllos Kaloudis, Sevasti-Kiriaki Zervou, and Anastasia Hiskia SOP 8 Extraction of Microcystins from Animal Tissues 358Ondřej Adamovský and Luděk Bláha SOP 9 Analysis of Microcystins by Online Solid Phase Extraction–Liquid Chromatography Tandem Mass Spectrometry 362Cintia Flores and Josep Caixach SOP 10 Determination of Microcystins and Nodularin in Filtered and Drinking Water by LC‐MS/MS 372Theodoros M. Triantis, Triantafyllos Kaloudis, Sevasti-Kiriaki Zervou, and Anastasia Hiskia SOP 11 Analysis of Microcystins and Nodularin by Ultra High‐Performance Liquid Chromatography Tandem Mass Spectrometry 379Leonardo Cerasino SOP 12 Analysis of Microcystins in Animal Tissues Using LC‐MS/MS 385Jiří Kohoutek and Luděk Bláha SOP 13 Quantitative Screening of Microcystins and Nodularin in Water Samples with Commercially Available ELISA Kits 390Triantafyllos Kaloudis, Theodoros M. Triantis, and Anastasia Hiskia SOP 14 Quantitative Screening of Microcystins and Nodularin in Water Samples with Commercially Available PPIA Kits 393Triantafyllos Kaloudis, Theodoros M. Triantis, and Anastasia Hiskia SOP 15 Solid‐Phase Extraction of Cylindrospermopsin from Filtered and Drinking Water 396Theodoros M. Triantis, Triantafyllos Kaloudis, and Anastasia Hiskia SOP 16 Determination of Cylindrospermopsin in Filtered and Drinking Water by LC‐MS/MS 399Theodoros M. Triantis, Triantafyllos Kaloudis, and Anastasia Hiskia SOP 17 Solid‐Phase Extraction of Anatoxin‐a from Filtered and Drinking Water 405Theodoros M. Triantis, Triantafyllos Kaloudis, and Anastasia Hiskia SOP 18 Determination of Anatoxin‐a in Filtered and Drinking Water by LC‐MS/MS 408Theodoros M. Triantis, Triantafyllos Kaloudis, and Anastasia Hiskia SOP 19 Analysis of Anatoxin‐a and Cylindrospermopsin by Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry 413Leonardo Cerasino SOP 20 Extraction and Chemical Analysis of Saxitoxin and Analogues in Water 418Lutz Imhof and Wido Schmidt SOP 21 Extraction of BMAA from Cyanobacteria 432James S. Metcalf, Sandra A. Banack, and Paul A. Cox SOP 22 Analysis of β-N‐Methylamino‐l‐Alanine by UHPLC‐MS/MS 435James S. Metcalf, William B. Glover, Sandra A. Banack, and Paul A. Cox SOP 23 Extraction and LC‐MS/MS Analysis of Underivatised BMAA 439Elisabeth J. Faassen SOP 24 Extraction, Purification, and Testing of LPS from Cyanobacterial Samples 447Lucie Bláhová and Luděk Bláha SOP 25 Extraction and Chemical Analysis of Planktopeptin and Anabaenopeptins 452Hanna Mazur‐Marzec, Tina Elersek, and Agata Błaszczyk SOP 26 Thamnocephalus Test 462Andrea Törökné SOP 27 Determination of Geosmin and 2‐Methylisoborneol in Water by HS‐SPME‐GC/MS 469Triantafyllos Kaloudis, Theodoros M. Triantis, and Anastasia Hiskia SOP 28 Rapid Analysis of Geosmin and 2‐Methylisoborneol from Aqueous Samples Using Solid‐Phase Extraction and GC‐MS 475Christine Edwards, Craig McKenzie, Carlos Joao Pestana, Kyari Yates, and Linda A. Lawton SOP 29 Basic Validation Protocol for the Analysis of Cyanotoxins in Environmental Samples 481Triantafyllos Kaloudis, Theodoros M. Triantis, and Anastasia Hiskia Section VIII Appendices 487 Appendix 1 Cyanobacterial Species and Recent Synonyms 489 Appendix 2 Cyanobacteria Associated With the Production of Cyanotoxins 501 Appendix 3 Tables of Microcystins and Nodularins 526 Index 538

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Book SynopsisProtein carbonylation has attracted the interest of a great number of laboratories since the pioneering studies at the Earl Stadtman's lab at NIH started in early 1980s. Since then, detecting protein carbonyls in oxidative stress situations became a highly efficient tool to uncover biomarkers of oxidative damage in normal and altered cell physiology. In this book, research groups from several areas of interest have contributed to update the knowledge regarding detection, analyses and identification of carbonylated proteins and the sites where these modifications occur. The scientific community will benefit from these reviews since they deal with specific, detailed technical approaches to study formation and detection of protein carbonyls. Moreover, the biological impact of such modifications in metabolic, physiologic and structural functions and, how these alterations can help understanding the downstream effects on cell function are discussed. Oxidative sTable of ContentsList of Contributors xii Preface xvi 1 Reactive Oxygen Species Signaling from the Perspective of the Stem Cell 1Saghi Ghaffari and Raymond Liang 1.1 Introduction 1 1.2 ROS Regulation 2 1.3 ROS Signaling 3 1.4 ROS and Stem Cells 5 1.5 ROS, Metabolism, and Epigenetic Influence 9 1.6 Stem Cells and Mitochondria 9 1.7 ROS and Stem Cell Aging 12 2 Analysis of Protein Carbonylation 24Ashraf G. Madian, Fred E. Regnier, and Ao Zeng 2.1 Introduction 24 2.2 In Vivo Carbonylation Reactions 27 2.3 Analytical Derivatization of Carbonylated Groups 34 2.4 Selective Purification and/or Detection of Carbonylated Proteins and Peptides 36 2.5 Oxidative Stress]Based PTMS Not Involving Carbonylation 38 3 Diversity of Protein Carbonylation Pathways: Direct Oxidation,Glycoxidation, and Modifications by Lipid Peroxidation Products 48Maria Fedorova 3.1 Introduction 48 3.2 Pathways of Protein Carbonylation 49 3.3 Analytical Methods for Detection of Total and Specific Protein Carbonylation 57 3.4 Protein Susceptibility to Different Carbonylation Pathways and Modifications Cross]Talk 67 4 Protein Carbonylation by Reactive Lipids 83Koji Uchida 4.1 Introduction 83 4.2 Chemistry of Protein Carbonylation by Reactive Lipid Aldehydes 84 4.3 Antigenicity of Protein Carbonyls 87 4.4 Thiolation of Protein Carbonyls 89 4.5 Reductive Amination]Based Fluorescent Labeling of Protein Carbonyls 91 5 Mechanism and Functions of Protein Decarbonylation 97Yuichiro J. Suzuki 5.1 Protein Carbonylation 97 5.2 Primary Protein Carbonylation in Cell Signaling 98 5.3 Discovery and Mechanisms of Protein Decarbonylation 101 5.4 Proposed Functions of Protein Decarbonylation in Oxidative Stress and Redox Signaling 103 6 Carbonylated Proteins and Their Metabolic Regulation: Overview of Mechanisms, Target Proteins, and Characterization Using Proteomic Methods 110Somaieh Afiuni]Zadeh and Timothy J. Griffin 6.1 Metabolic Regulation and Reactive Oxygen Species 110 6.2 ROS and Protein Carbonylation 111 6.3 Metabolic Control and Characteristics of Carbonylated Proteins 113 6.4 Protein Targets of Carbonylation and Implications in Human Health 114 6.5 Technologies and Methods for Characterizing Protein Carbonylation 118 6.6 Emerging Multifunctional Reagents for Protein Carbonylation Analysis via MS 119 6.7 Emerging Methods for Characterizing Carbonylated Protein Networks and Affected Pathways 123 7 Oxidative Stress and Protein Carbonylation in Malaria 131Maria Linares, Antonio Puyet, Amalia Diez, and Jose M. Bautista 7.1 Introduction 131 7.2 Oxidative Stress during Malaria Infection 132 7.3 Protein Carbonylation in Plasmodium and Oxidative Targeting of Antimalarials 137 7.4 Oxidative Dysfunction in Host Tissues 143 7.5 Host Tolerance to Malaria by Modulation of Oxidative Stress Responses 148 7.6 Perspectives 153 8 Protein Carbonylation in Brains of Subjects with Selected Neurodegenerative Disorders 167Tanea T. Reed and D. Allan Butterfield 8.1 Introduction to Protein Carbonylation 167 8.2 Relationship between ROS and Oxidative Stress 169 8.3 An Overview of Some Neurodegenerative Diseases 171 8.4 Role of Protein Carbonylation in Brains of Subjects with AD 174 8.5 An Introduction to Tauopathies 185 8.6 An Introduction to Amyotrophic Lateral Sclerosis 186 9 Cigarette Smoke]Induced Protein Carbonylation: Focus on Recent Human Studies 206Graziano Colombo, Maria Lisa Garavaglia, Aldo Milzani, and Isabella Dalle]Donne 9.1 Introduction 206 9.2 Protein Carbonylation in Human Smokers 212 9.3 Protein Carbonylation in Cultured Human Cell Models of Exposure to CS 218 9.4 Limitations and Congruence of In Vivo and In Vitro Human Studies 228 10 Chronic Obstructive Pulmonary Disease and Oxidative Damage 241Esther Barreiro 10.1 Introduction 242 10.2 Protein Oxidation in Tissues 244 10.3 Antioxidants in Skeletal Muscle Fibers 247 10.4 Implications of Protein Carbonylation in COPD Skeletal Muscle Dysfunction 249 10.5 Muscle Protein Carbonylation and Exercise in COPD Patients 252 10.6 Protein Carbonylation in Muscles Exposed to Chronic Cigarette Smoke 253 10.7 Protein Carbonylation in Cancer Cachexia Models 255 10.8 Protein Carbonylation as a Predisposing Mechanism of Lung Cancer in COPD 257 11 Protein Carbonylation in Aging and Senescence 272Jeannette Konig, Tobias Jung and Tilman Grune 11.1 Introduction 272 11.2 Protein Oxidation during Aging 274 11.3 Chemistry of Protein Carbonylation and Fate of Carbonylated Proteins 277 11.4 Protein Carbonyls in Cellular Aging Models 279 11.5 Protein Carbonylation in Aging Organisms 280 12 Adipose Carbonylation and Mitochondrial Dysfunction 291Amy K. Hauck, Dalay H. Olson, Joel S. Burrill, and David A. Bernlohr 12.1 Introduction 291 12.2 Reactive Oxygen Species (ROS) 292 12.3 Oxidative Stress and Obesity 298 12.4 Detection of Protein Carbonylation 303 12.5 Outcomes of Protein Carbonylation 306 13 Protein Carbonylation in Plants 321Ian Max Moller, Jesper F. Havelund, and Adelina Rogowska]Wrzesinska 13.1 Introduction 322 13.2 Turnover of Reactive Oxygen Species in Plants 323 13.3 Methods Used in Plants for Quantifying and Identifying Carbonylation Sites 325 13.4 Protein Carbonylation in Plants 326 13.5 Protein Carbonylation in Plant Mitochondria 328 13.6 Protein Carbonylation in Seeds 333 14 Specificity of Protein Carbonylation and Its Relevance in Aging 340Elisa Cabiscol, Jordi Tamarit, and Joaquim Ros 14.1 Introduction 340 14.2 Specificity of Protein Oxidative Damage 341 14.3 Protein Carbonylation in Aging 348 Index 384

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Book SynopsisThe number-one guide, internationally, to all aspects of forensic isotope analysis, thoroughly updated and revised and featuring many new case studies This edition of the internationally acclaimed guide to forensic stable isotope analysis uses real-world examples to bridge discussions of the basic science, instrumentation and analytical techniques underlying forensic isotope profiling and its various technical applications. Case studies describe an array of applications, many of which were developed by the author himself. They include cases in which isotope profiling was used in murder, and drugs-related crime investigations, as well as for pharmaceutical and food authenticity control studies. Updated with coverage of exciting advances occurring in the field since the publication of the 1st edition, this 2nd edition explores innovative new techniques and applications in forensic isotope profiling, as well as key findings from originaTable of ContentsSeries Foreword xi Foreword: Dame Sue Black xiii Foreword: Mark Harrison xv Foreword to the 1st Edition xvii Book Endorsements xix Preface to the 2nd Edition xxi List of Abbreviations xxv About the Companion Website xxvii Introduction: Stable Isotope ‘Profiling’ or Chemical ‘DNA’: A New Dawn for Forensic Chemistry? xxix I How it Works 1 I.1 What are Stable Isotopes? 2 I.2 Natural Abundance Variation of Stable Isotopes 4 I.3 Chemically Identical and Yet Not the Same 12 I.4 Isotope Effects, Mass Discrimination and Isotopic Fractionation 15 I.4.1 Physical Chemistry Background 15 I.4.2 Fractionation Factor α and Enrichment Factor ε 17 I.4.3 Isotopic Fractionation in Rayleigh Processes 19 I.4.3.1 Isotopic Fractionation Summary 20 I.5 Stable Isotopic Distribution and Isotopic Fractionation of Light Elements in Nature 22 I.5.1 Hydrogen 22 I.5.2 Oxygen 26 I.5.3 Carbon 27 I.5.4 Nitrogen 30 I.5.5 Sulfur 32 I.5.6 Isoscapes 35 I.6 Stable Isotope Forensics in Everyday Life 40 I.6.1 “Food Forensics” 42 I.6.1.1 Authenticity and Provenance of Single-Seed Vegetable Oils 42 I.6.1.2 Authenticity and Provenance of Beverages 45 I.6.1.3 Caveats 49 I.6.2 Authenticity and Provenance of other Premium Products 53 I.6.3 Counterfeit Pharmaceuticals 54 I.6.4 Environmental Forensics 59 I.6.5 Wildlife Forensics 61 I.6.6 Anti-Doping Control 62 I.7 Summary of Part I 65 References Part I 67 II Instrumentation, Analytical Techniques and Data Quality 81 II.1 Mass Spectrometry versus Isotope Ratio Mass Spectrometry 82 II.1.1 Stability, Isotopic Linearity and Isotopic Calibration 85 II.2 Instrumentation for Stable Isotope Analysis 90 II.2.1 Dual-Inlet IRMS Systems 92 II.2.2 Continuous-Flow IRMS Systems 93 II.2.3 Bulk Material Stable Isotope Analysis 94 II.2.3.1 13C, 15N and 34S 94 II.2.3.2 2H and 18O 96 II.2.4 Compound-Specific Stable Isotope Analysis of Volatile Organic Compounds 98 II.2.4.1 Compound-Specific 13C or 15N Analysis by GC/C-IRMS 98 II.2.4.2 Compound-Specific 2H or 18O Analysis by GC/HTC-IRMS 100 II.2.4.3 Position-Specific Isotope Analysis 101 II.2.5 Compound-Specific 13C/15N Analysis of Polar, Non-Volatile Organic Compounds by LC-IRMS 101 II.2.6 Compound-Specific Isotope Analysis and Forensic Compound Identification 103 II.3 Quality Control and Quality Assurance in Continuous-Flow Isotope Ratio Mass Spectrometry 106 II.3.1 Compliance with IUPAC Guidelines is a Prerequisite not a Luxury 106 II.3.2 The Identical Treatment Principle 111 II.3.3 The Importance of Scale Normalization 112 II.3.3.1 Scale Normalization of Measured δ2H Values to VSMOW 114 II.3.3.2 Scale Normalization of Measured δ13C Values to VPDB 120 II.3.3.3 Scale Normalization of Measured δ18O Values to VSMOW 122 II.3.3.4 Scale Normalization of Measured δ15N Values to Air 126 II.3.3.5 Scale Normalization of Measured δ34S Values to VCDT 127 II.4 Points of Note for Stable Isotope Analysis 128 II.4.1 Preparing for Analysis 128 II.4.2 Generic Considerations for BSIA 131 II.4.2.1 Scale Normalization of BSIA 132 II.4.2.2 Keeping Your Powder Dry 134 II.4.2.3 Isobaric Interference 135 II.4.2.4 Ionization Quench Effect 137 II.4.3 Particular Considerations for BSIA 140 II.4.3.1 Bulk 15N Analysis of Nitrates 140 II.4.3.2 Bulk 2H Analysis of Nitrogen-Rich Compounds 141 II.4.3.3 Total δ2H versus True δ2H Values 141 II.4.3.4 Organic Compounds with Exchangeable Hydrogen and Implications for 2H Abundance Analysis 144 II.4.3.4.1 Chemical and Biochemical Considerations – Example: Hair 152 II.4.3.5 2H Analysis of Human Hair 158 II.4.3.5.1 Two-Point Equilibration with Water at Ambient Temperature 161 II.4.3.5.2 Two-Point End-Member Comparative Equilibration 166 II.4.3.5.3 On-Line Two-Point End-Member Comparative Steam Equilibration 170 II.4.4 Points of Note for CSIA 172 II.4.4.1 Scale Normalization of GC-IRMS Analyses 172 II.4.4.2 Isotope Effects in GC-IRMS during Sample Injection 175 II.4.4.3 The Chromatographic Isotope Effect in GC-IRMS 176 II.4.4.4 Derivatization of Polar Compounds for GC-IRMS 178 II.4.4.5 Compound-Specific 2H Analysis of N- or Cl-Rich Compounds 181 II.5 Statistical Analysis of Stable Isotope Data within a Forensic Context 183 II.5.1 Chemometric Analysis 183 II.5.2 Bayesian Analysis 185 II.6 Quality Control and Quality Assurance in Forensic Stable Isotope Analysis 194 II.6.1 Accreditation to ISO 17025 195 II.6.1.1 Who Assesses the Assessors? 197 II.6.2 The Forensic Isotope Ratio Mass Spectrometry Network 205 II.7 Summary of Part II 207 II.A How to Set Up a Laboratory for Continuous-Flow Isotope Ratio Mass Spectrometry 209 II.A.1 Pre-Installation Requirements 210 II.A.2 Laboratory Location 210 II.A.3 Temperature Control 211 II.A.4 Power Supply 212 II.A.5 Gas Supply 213 II.A.6 Forensic Laboratory Considerations 216 II.A.7 Finishing Touches 217 II.B Sources of International Reference Materials and Tertiary Standards 219 II.C Selected Sample Preparation Protocols 220 II.C.1 Derivatization of Amino Acids for Compound Specific Isotope Analysis by GC-IRMS 220 II.C.2 Acid Digest of Carbonate from Bio-apatite for 13C and 18O Analysis 223 II.C.3 Preparing Silver Phosphate from Bio-apatite for 18O Analysis 225 II.C.4 Two-Point Water Equilibration Protocol for Determination of Non-ex δ2H Values of Human Hair 227 II.D Internet Sources of Guidance and Policy Documents 231 References Part II 233 III Stable Isotope Forensics: Case Studies and Current Research 247 III.1 Forensic Context 248 III.1.1 Legal Context 249 III.2 Distinguishing Drugs 255 III.2.1 Natural and Semisynthetic Drugs 255 III.2.1.1 Marijuana 255 III.2.1.2 Morphine and Heroin 257 III.2.1.3 Cocaine 259 III.2.2 Synthetic Drugs 263 III.2.2.1 Amphetamines 263 III.2.2.2 Methamphetamine: Synthesis and Isotopic Signature 264 III.2.2.2.1 Two Different Synthetic Routes – Clandestine Conditions 268 III.2.2.3 MDMA: Synthesis and Isotopic Signature 270 III.2.2.3.1 Three Different Synthetic Routes – Controlled Conditions 273 III.2.2.3.2 One Synthetic Route – Variable Conditions 279 III.2.3 “Legal Highs” and “Designer Drugs” 284 III.2.3.1 Mephedrone 284 III.2.3.2 Piperazines 287 III.2.4 Excipients 291 III.2.5 Conclusions 293 III.3 Elucidating Explosives 296 III.3.1 Stable Isotope Analysis of Explosives and Precursors 297 III.3.1.1 Ammonium Nitrate (AN) 298 III.3.1.2 Hexamine, RDX, C4 and Semtex 300 III.3.1.3 Isotopic Product/Precursor Relationship 305 III.3.1.3.1 RDX and HMX 305 III.3.1.3.2 HMTD and TATP 309 III.3.1.4 Hydrogen Peroxide 315 III.3.2 Potential Pitfalls 321 III.3.3 Conclusions 323 III.4 Matching Matchsticks 324 III.4.1 13C-Bulk Isotope Analysis 325 III.4.2 18O-Bulk Isotope Analysis 326 III.4.3 2H-Bulk Isotope Analysis 328 III.4.4 Matching Matches from Fire Scenes 330 III.4.5 Conclusions 331 III.5 Provenancing People 333 III.5.1 Stable Isotope Abundance Variation in Human Tissue 336 III.5.1.1 Hair and Nails 338 III.5.1.1.1 Characteristics of Hair 340 III.5.1.1.2 Characteristics of Nails 342 III.5.1.1.3 Diagenetic Changes of Keratin 342 III.5.1.1.4 2H Isotopic Record in Hair and Nail 343 III.5.1.1.5 18O Isotopic Record in Hair and Nail 345 III.5.1.1.6 13C Isotopic Record in Hair and Nail 346 III.5.1.1.7 15N Isotopic Record in Hair and Nail 347 III.5.1.2 Bone and Teeth 350 III.5.1.2.1 Chemical Composition of Bone and Teeth 351 III.5.1.2.2 Static versus Remodelling Tissue Compartments 352 III.5.1.2.3 Diagenetic Changes of Bone and Teeth Mineral 354 III.5.1.2.4 Diagenetic Changes of Type I Collagen 356 III.5.1.2.5 18O Isotopic Record in Carbonate and Phosphate from Bio-apatite 357 III.5.1.2.6 13C Isotopic Record in Carbonate from Bio-apatite 363 III.5.1.2.7 Isotopic Record in Type I Collagen 364 III.5.1.3 Trophic Level Shift Effect on Stable Isotope Abundance Values in Human Tissue 365 III.5.2 Case Examples 370 III.5.2.1 The Skull from the Sea 371 III.5.2.2 A Human Life Recorded in Hair 375 III.5.2.3 Found in Newfoundland 379 III.5.2.4 The Case of “The Scissor Sisters” 384 III.5.2.5 Too Short a Life 390 III.5.2.6 Saltair Sally 393 III.5.2.7 A Tale of Two Cultures 394 III.5.3 Conclusions and Caveats 397 III.6 Stable Isotope Forensics of Other Physical Evidence 401 III.6.1 Microbial Isotope Forensics 402 III.6.2 Toxins and Poisons 404 III.6.3 Paper, Plastic (Bags) and Parcel Tape 404 III.6.3.1 Paper 404 III.6.3.2 Plastic and Plastic Bags 407 III.6.3.3 Parcel Tape 408 III.6.4 Conclusions 412 III.7 Evaluative Interpretation of Forensic Stable Isotope Data 413 III.7.1 Not Scale Referenced δ-Values 415 III.7.2 Unresolved Contradictory Data 418 III.7.2.1 Example: “Geographic Provenance of a Murder Victim” 418 III.7.2.2 Example: “Manslaughter due to Negligence” 420 III.7.3 Foregone Conclusions 422 III.7.4 Logical Fallacies 424 III.7.5 Untested Assumptions 426 III.7.6 Conclusion 428 III.8 Summary of Part III 430 III.A An Abridged List of Forensic Stable Isotope Laboratories Worldwide 432 References Part III 434 Recommended Reading 453 Author’s Biography 459 Acknowledgements 461 Index 463

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Book SynopsisPATAI's Chemistry of Functional Groups publishes comprehensive reviews on all aspects of specific functional groups.Table of Contents1. Recent advances in acid–base and solvation properties of metal phenolates 1 Erick L. Bastos and Caroline O. Machado 2. Photophysical and structural properties of rare-earth phenolate compounds 61 Ercules E. S. Teotonio, Lucas C. V. Rodrigues, Hermi F. Brito, Maria Claudia F. C. Felinto, and Oscar M. L. Malta 3. Advances in the catalysis of organic processes by metal phenolates 125 Maria Elisa da Silva Serra and Dina M. B. Murtinho 4. Metal complexes with oligo(salen)-type ligands 153 Shigehisa Akine 5. Coordination chemistry and applications of phenolic homooxa and homoazacalixarene–metal complexes 195 Paula M. Marcos and Peter J. Cragg 6. Coordination chemistry and applications of phenolic thiacalixarene–metal complexes 237 Peter J. Cragg and Paula M. Marcos 7. Recent advances in the field of phenoxyl radical–metal complexes 269 Yuichi Shimazaki 8. Polymerization catalysis by metal phenolates 295 Samuel Dagorne and Charles Romain 9. Recent advances in biomimetic metal phenolates 339 Gabriella Tamasi and Renzo Cini 10. Contemporary use of azophenolates and related species in the determination of metal cations 383 Maja Ponikvar-Svet and Joel F. Liebman 11. Advances in the analytical chemistry of metal phenolates 407 Jacob Zabicky Subject index 449

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Book SynopsisWith new graphical data added to this revision of the original classic, this volume is still the largest and most comprehensive collection of thermodynamic data on carbon dioxide ever produced, the ONLY book of its kind in print. With carbon dioxide sequestration gaining in popularity around the world in the scientific and engineering communities, having this data in an easy-to-access format is more useful and timely than ever. With data that is accurate down to within a fraction of a degree, this handbook offers, in one volume, literally thousands of data points that any engineer or chemist would need when dealing with carbon dioxide. Not available in other formats, these easy-to-read tables are at your fingertips and are accessed within seconds and does away with the need for constantly working with mathematical formulas. Carbon dioxide is used in many fields, across many industries, including the oil and gas industry and food processing. Even coffee is decaffeinatedTable of ContentsAcknowledgement ix Preface to Second Edition xi Preface to First Edition xiii Introduction xv 1 Density (kg/m3) of Saturated Carbon Dioxide 1 2 Enthalpy (J/mol) of Saturated Carbon Dioxide 3 3 Entropy (J/mol•K) of Saturated Carbon Dioxide 5 4 Heat Capacity, CP, (J/mol•K) of Saturated Carbon Dioxide 7 5 Density (kg/m3) of Carbon Dioxide as a Function of Temperature and Pressure 9 6 Enthalpy (J/mol) of Carbon Dioxide as a Function of Temperature and Pressure 149 7 Entropy (J/mol•K) of Carbon Dioxide as a Function of Temperature and Pressure 289 8 Heat Capacity, CP, (J/mol•K) of Carbon Dioxide as a Function of Temperature and Pressure 429

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Book SynopsisA guide to the issues relevant to the design, analysis, and interpretation of toxicity studies that examine chemicals for use in the environment Statistical Analysis of Ecotoxicity Studies offers a guide to the design, analysis, and interpretation of a range of experiments that are used to assess the toxicity of chemicals. While the book highlights ecotoxicity studies, the methods presented are applicable to the broad range of toxicity studies. The text contains myriad datasets (from laboratory and field research) that clearly illustrate the book's topics. The datasets reveal the techniques, pitfalls, and precautions derived from these studies. The text includes information on recently developed methods for the analysis of severity scores and other ordered responses, as well as extensive power studies of competing tests and computer simulation studies of regression models that offer an understanding of the sensitivity (or lack thereof) of various methods and the quality of parameterTable of ContentsPreface ix Acknowledgments xi About the Companion Website xiii 1. An Introduction to Toxicity Experiments 1 1.1 Nature and Purpose of Toxicity Experiments 1 1.2 Regulatory Context for Toxicity Experiments 7 1.3 Experimental Design Basics 8 1.4 Hierarchy of Models for Simple Toxicity Experiments 12 1.5 Biological vs. Statistical Significance 13 1.6 Historical Control Information 15 1.7 Sources of Variation and Uncertainty 15 1.8 Models with More Complex Structure 16 1.9 Multiple Tools to Meet a Variety of Needs or Simple Approaches to Capture Broad Strokes? 16 2. Statistical Analysis Basics 19 2.1 Introduction 19 2.2 NOEC/LOEC 19 2.3 Probability Distributions 24 2.4 Assessing Data for Meeting Model Requirements 29 2.5 Bayesian Methodology 30 2.6 Visual Examination of Data 30 2.10 Time‐to‐Event Data 37 2.11 Experiments with Multiple Controls 38 3. Analysis of Continuous Data: NOECs 47 3.1 Introduction 47 3.2 Pairwise Tests 47 3.3 Preliminary Assessment of the Data to Select the Proper Method of Analysis 53 3.4 Pairwise Tests When Data do not Meet Normality or Variance Homogeneity Requirements 62 3.5 Trend Tests 67 3.6 Protocol for NOEC Determination of Continuous Response 75 3.7 Inclusion of Random Effects 75 3.8 Alternative Error Structures 76 3.9 Power Analyses of Models 77 Exercises 81 4. Analysis of Continuous Data: Regression 89 4.1 Introduction 89 4.2 Models in Common Use to Describe Ecotoxicity Dose–Response Data 92 4.3 Model Fitting and Estimation of Parameters 95 4.4 Examples 104 4.5 Summary of Model Assessment Tools for Continuous Responses 112 Exercises 114 5. Analysis of Continuous Data with Additional Factors 123 5.1 Introduction 123 5.2 Analysis of Covariance 123 5.3 Experiments with Multiple Factors 135 Exercises 41 6. Analysis of Quantal Data: NOECs 157 6.1 Introduction 157 6.2 Pairwise Tests 157 6.3 Model Assessment for Quantal Data 160 6.4 Pairwise Models that Accommodate Overdispersion 162 6.5 Trend Tests for Quantal Response 165 6.6 Power Comparisons of Tests for Quantal Responses 168 6.7 Zero‐Inflated Binomial Responses 172 6.8 Survival‐ or Age‐Adjusted Incidence Rates 175 Exercises 179 7. Analysis of Quantal Data: Regression Models 181 7.1 Introduction 181 7.2 Probit Model 181 7.3 Weibull Model 188 7.4 Logistic Model 188 7.5 Abbott’s Formula and Normalization to the Control 190 7.6 Proportions Treated as Continuous Responses 197 7.7 Comparison of Models 198 7.8 Including Time‐Varying Responses in Models 199 7.9 Up‐and‐Down Methods to Estimate LC50 204 7.10 Methods for ECx Estimation When there is Little or no Partial Mortality 206 Exercises 215 8. Analysis of Count Data: NOEC and Regression 219 8.1 Reproduction and Other Nonquantal Count Data 219 8.2 Transformations to Continuous 219 8.3 GLMM and NLME Models 223 8.4 Analysis of Other Types of Count Data 228 Exercises 237 9. Analysis of Ordinal Data 243 9.1 Introduction 243 9.2 Pathology Severity Scores 243 9.3 Developmental Stage 249 Exercises 255 10. Time‐to‐Event Data 259 10.1 Introduction 259 10.2 Kaplan–Meier Product‐Limit Estimator 261 10.3 Cox Regression Proportional Hazards Estimator 266 10.4 Survival Analysis of Grouped Data 268 Exercises 271 11. Regulatory Issues 275 11.1 Introduction 275 11.2 Regulatory Tests 275 11.3 Development of International Standardized Test Guidelines 276 11.4 Strategic Approach to International Chemicals Management (SAICM) 279 11.5 The United Nations Globally Harmonized System of Classification and Labelling of Chemicals (GHS) 279 11.6 Statistical Methods in OECD Ecotoxicity Test Guidelines 279 11.7 Regulatory Testing: Structures and Approaches 279 11.8 Testing Strategies 287 11.9 Nonguideline Studies 291 12. Species Sensitivity Distributions 293 12.1 Introduction 293 12.2 Number, Choice, and Type of Species Endpoints to Include 294 12.3 Choice and Evaluation of Distribution to Fit 294 12.4 Variability and Uncertainty 300 12.5 Incorporating Censored Data in an SSD 302 Exercises 307 13. Studies with Greater Complexity 309 13.1 Introduction 309 13.2 Mesocosm and Microcosm Experiments 310 13.3 Microplate Experiments 316 13.4 Errors‐in‐Variables Regression 321 13.5 Analysis of Mixtures of Chemicals 323 13.6 Benchmark Dose Models 326 13.7 Limit Tests 327 13.8 Minimum Safe Dose and Maximum Unsafe Dose 329 13.9 Toxicokinetics and Toxicodynamics 331 Exercises 343 Appendix 1 Dataset 345 Appendix 2 Mathematical Framework 347 A2.3 Method of Maximum Likelihood 350 A2.4 Bayesian Methodology 352 A2.5 Analysis of Toxicity Experiments 354 A2.6 Newton’s Optimization Method 358 Table A3.3 Linear and Quadratic Contrast A2.7 The Delta Method 359 Coefficients 366 A2.8 Variance Components 360 Table A3.4 Williams’ Test tᾱ ,k for α = 0.05 367 Appendix 3 Tables Table A3.1 Studentized Maximum Distribution 364 Table A3.2 Studentized Maximum Modulus Distribution 365 Table A3.3 Linear and Quadratic Contrast Coefficients 366 Table A3.4 Williams’ Test t̅α,k for α = 0.05 367 References 371 Author Index 385 Subject Index 389

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Book SynopsisA combination of oxidation methods and C?H bond functionalization, this book emphasizes mechanistic understanding and critical analysis of synthetic reactions to offer a guide or manual for practicing chemists. Combines oxidation methods and C?H bond functionalization, two of the most important aspects of organic synthesis Deals with C?H bonds, an area of dynamic and continuous research across chemistry and catalysis Helps readers understand the fundamental and applied differences among various oxidation methods and reactions Covers mechanistic details, conditions, oxidation reagents, and practical aspects of different reactionsTable of ContentsPreface xi1 Introduction 11.1 What Is Oxidation of C—H Bonds? 11.2 Chemical Synthesis and Oxidation of C—H Bonds 21.3 C—H Bonds 61.4 Concepts in This Book 15References 172 Oxidation of Methane 192.1 Methane 192.2 Methyl sp³ C—H Bond 202.3 Oxidations of Methyl sp³ C—H Bond 212.4 Summary 35References 363 Oxidation of Alkyl sp³ C—H Bond 393.1 Alkane 393.2 Alkyl sp³ C—H Bonds 403.3 Oxidations of Alkyl sp³ C—H Bond 423.4 Summary 61References 624 Oxidation of Alkyl sp³ C—H Bond Assisted by Directing Group 654.1 Directing Group 654.2 Alkyl sp³ C—H Bonds with Directing Groups 664.3 Directed Oxidations of Alkyl sp³ C—H Bond 674.4 Summary 97References 975 Oxidation of Alkyl sp³ C—H Bond Adjacent to Unsaturated Carbon Atom 1015.1 Alkyl α-sp³ C—H Bond 1015.2 Alkyl sp³ C—H Bonds Adjacent to Unsaturated Carbon Atoms 1025.3 Oxidations of Alkyl sp³ C—H Bond Adjacent to Unsaturated Carbon Atom 1035.4 Summary 138References 1386 Oxidation of Alkyl sp³ C—H Bond Adjacent to Heteroatom 1436.1 Alkyl sp³ C—H Bonds Adjacent to Heteroatoms 1436.2 Oxidations of Alkyl sp³ C—H Bond Adjacent to Heteroatom 1446.3 Summary 166References 1677 Oxidation of Alkenyl or Carbonyl sp² C—H Bond 1717.1 Alkenyl and Carbonyl sp² C—H Bonds 1717.2 Oxidations of Alkenyl and Carbonyl sp² C—H Bonds 1728 Oxidation of Alkynyl spC—H Bond 2098.1 spC—H Bonds 2098.2 Oxidations of spC—H Bond 2108.3 Summary 232References 2329 Oxidation of Benzene 2359.1 Introduction 2359.2 Oxidations of Phenyl sp2 C—H Bond 2379.3 Summary 277References 27910 Oxidation of Aryl sp² C—H Bond on Substituted Benzene 28310.1 Introduction 28310.2 Formation of C—C Bond 28410.3 Formation of C—N Bond 31310.4 Formation of C—O Bond 31610.5 Formation of C—S Bond 32210.6 Formation of C—Halogen Bond 32310.7 Summary 331References 33311 Oxidation of Aryl sp² C—H Bond Assisted by Directing Group 33711.1 Introduction 33711.2 Formation of C—C Bond 33711.3 Formation of C—N Bond 40011.4 Formation of C—O Bond 40611.5 Formation of C—S Bond 41211.6 Formation of C—Halogen Bond 41411.7 Summary 424References 42612 Oxidation of Aryl sp² C—H Bond on Heteroarene or Perfluoroarene 43312.1 Introduction 43312.2 Formation of C—C Bond 43412.3 Formation of C—N Bond 45912.4 Formation of C—O Bond 46112.5 Formation of C—Halogen Bond 46212.6 Cross-Coupling of Dual Aryl sp² C—H Bonds on Directing-Group-Containing Arenes, Heteroarenes, or Polyfluoroarenes 46812.7 Summary 477References 47813 Oxidative Cross-Coupling of Aryl sp² C—H Bond with Inert C—H Bond 48313.1 Introduction 48313.2 Oxidative Coupling of Simple Arenes with Alkanes (Alkylation of Arenes) 48413.3 Oxidative Coupling of Simple Arenes with Alkenes (Alkenylation of Arenes) 48613.4 Oxidative Cross-Coupling of Simple Arenes (Arylation of Arenes) 49013.5 Summary 498References 499Index 501

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Book SynopsisThis volume of Advances in Chemical Physics is dedicated, by the contributors, to Moshe Shapiro, formerly Canada Research Chair in Quantum Control in the Department of Chemistry at the University of British Columbia and Jacques Mimran Professor of Chemical Physics at the Weizmann Institute, who passed away on December 3, 2013. It focuses primarily on the interaction of light with molecules, one of Moshe's longstanding scientific loves. However, the wide range of topics covered in this volume constitutes but a small part of Moshe's vast range of scientific interests, which are well documented in over 300 research publications and two books.Table of ContentsContributors to Volume 159 ix Preface to the Series xi Dynamics of Photochemical Reactions of Organic Carbonyls and their Clusters 1by Dorit Shemesh and R. Benny Gerber Photoinduced Bond Cleavage as a Probe of Mode Specificity and Intramolecular Dynamics in Rovibrationally Excited Triatomic to 10 Atom Molecules 23by Salman Rosenwaks and Ilana Bar Controlling Quantum Dynamics with Assisted Adiabatic Processes 51by Shumpei Masuda and Stuart A. Rice From Coherent to Incoherent Dynamical Control of Open Quantum Systems 137by Gershon Kurizki and Analia Zwick Piecewise Adiabatic Passage in Polarization Optics: an Achromatic Polarization Rotator 219by Bruce W. Shore, Andon Rangelov, Nikolay V. Vitanov and Klaas Bergmann Ultrafast and Efficient Control of Coherent Electron Dynamics via SPODS 235by Tim Bayer, Matthias Wollenhaupt, Hendrike Braun and Thomas Baumert Toward Coherent Control Around the Quantum-Classical Boundary 283by Hiroyuki Katsuki and Kenji Ohmori Effects of Electromagnetic Fields on Molecular Scattering 313by R. V. Krems Quantum Dynamics by Partitioning Technique 349by Ioannis Thanopulos Laser Control of Ultrafast Molecular Rotation 395by Valery Milner and John W. Hepburn Index 413

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Book SynopsisThe updated and expanded guide for handling industrial wastes and designing a wastewater treatment plant The revised and updated second edition of Practical Wastewater Treatment provides a hands-on guide to industrial wastewater treatment theory, practices, and issues. It offers information for the effective design of water and wastewater treatment facilities and contains material on how to handle the wide-variety of industrial wastes. The book is based on a course developed and taught by the author for the American Institute of Chemical Engineers. The author reviews the most current industrial practices and goals, describes how the water industry works, and covers the most important aspects of the industry. In addition, the book explores a wide-range of approaches for managing industrial wastes such as oil, blood, protein and more. A comprehensive resource, the text covers such basic issues as water pollution, wastewater treatment techniques, sampTable of ContentsAcknowledgments xvii Preface xix 1 Composition, Chemistry, and Regulatory Framework 1 1.1 Water Composition 1 1.2 Water Characteristics and Physical Properties 2 1.2.1 Solubility of Gases in Water 4 1.2.1.1 Nitrogen 4 1.2.2 Henry’s Law 6 1.3 Solution Chemistry: Salts and Ions in Water 10 1.4 Disassociation Constants for Weak Acid and Bases 12 1.4.1 Common Minerals Dissolved in Freshwater and Seawater 15 1.5 Sources of Water 16 1.5.1 Groundwater 16 1.5.2 Groundwater Quality 17 1.5.3 Other Principal Contaminants in Groundwater 18 1.5.4 Movement of Groundwater 19 1.6 Analytical Methods 19 1.7 Laboratory Guidance 22 1.8 Regulatory Framework of Water Regulations 24 1.8.1 What Is Quality Water? 24 1.8.2 Water Quality Standards 25 1.8.3 Water Quality Standards in the United States 26 1.8.4 Establishing Water Quality Standards 26 1.8.5 Effluent Standards and Guidance 26 1.8.6 Mixing Zones 27 1.8.7 Discharge Permits 28 1.8.8 US Penalty Policies – Enforcement of Permit Conditions 28 1.8.9 Water Quality Discharge Basics in the US 29 1.8.10 How Water Quality Standards Are Established 32 1.8.11 UK Water Effluent Quality Standard 37 1.8.12 EU Water Quality Standards and Effluent Limits 39 1.8.13 Other Water Quality Requirements 40 1.8.13.1 US Primary and Secondary Drinking Water Standards 40 1.8.13.2 WHO Drinking Water Quality Guidelines 43 1.8.13.3 EU Drinking Water Directives 43 1.8.13.4 UK Drinking Water Standards 43 1.9 Water Use Data and Some Discharge Characteristics 43 1.9.1 Water Use by Municipalities 45 1.9.2 Agricultural Water 47 1.9.3 Cooling Water 47 1.9.4 Boiler Water 48 1.9.5 Other Industrial Water Quality Requirements 49 1.9.5.1 Steel Industry 50 1.9.5.2 Paper Industry 50 1.9.5.3 Petrochemical Industry 50 1.9.5.4 Petroleum Exploration and Production Operations 51 Notes 52 2 What is Water Pollution? 59 2.1 Pollution Defined 59 2.2 Chemical Industry 60 2.3 Cooling Towers 63 2.4 Boilers 64 2.5 Iron and Steel Industry 66 2.6 Mining Industries 67 2.7 Fracking for Oil and Gas 68 2.8 Petroleum Exploration 71 2.9 Petroleum Refining 73 2.10 Agricultural and Food Processing 75 2.11 Crop Water Use 75 2.12 Vegetable and Fruit Processing 76 2.13 Animal Farming and Concentrated Animal Feeding Operations 77 2.14 Livestock and Concentrated Animal Feeding Operations 78 2.15 Slaughterhouse and Meat Packing and Processing Wastes 82 2.16 Dairy Wastes 83 2.17 Measuring Pollution 83 2.18 The Sampling Plan 85 2.19 Analytical Methods and the Role of the Laboratory 87 2.19.1 The Analytical Plan 90 2.19.2 The Effects of Pollution on the Environment 90 2.19.3 Oxygen Depletion – Biochemical Oxygen Demand 91 2.19.4 Oxygen Uptake in a Stream —The Oxygen Sag Equation 93 2.19.5 Biology of Polluted Water 95 2.19.6 Nitrogen 96 2.19.7 Phosphorus 97 Notes 98 3 Groundwater and its Treatment 103 3.1 Hydraulics of Groundwater 104 3.2 Soil Particles and Surface Areas 106 3.3 Well Hydraulics 107 3.4 Well Packing and Screens 109 3.5 Trenches 109 3.5.1 Orifices and Pipe Losses 111 3.6 Compressible Flow 113 3.6.1 Calculation of Expansion Factor 114 3.6.2 Groundwater Hydraulics 115 3.7 Groundwater Treatment 117 Notes 123 4 Statistics of Measurements 125 4.1 Introduction to Statistical Measurements: Background 125 4.2 Significant Figures 126 4.3 Probable Error 127 4.4 Repeat Measurements 128 4.5 Net Process Measurements 129 4.5.1 Calibration 129 4.5.2 How to Measure Your Flow Accurately 130 4.5.2.1 Gurley Current Meter 130 4.6 Statistical Distributions for Environmental Events 133 4.6.1 Weibull Distributions 134 4.7 Black Swans and Data Analysis 135 4.7.1 Black Swans 135 4.7.2 Data Analysis 136 4.7.3 Outliers 136 Notes 137 5 The Flow of Water and Wastewater 139 5.1 Statistical Basis for Error Estimation 139 5.2 Open Channel Hydraulics 140 5.3 Froude Number 147 5.4 Types of Flowmeters 150 5.5 Weir Plates 155 5.6 Alignment Errors 156 5.7 Samples and Sampling 158 5.8 Conclusion 161 Notes 161 6 Troubleshooting and Emergency Planning 163 6.1 Fault Tree Analysis 163 6.2 Reverse Fault Tree Analysis 166 6.2.1 Bow Tie Analysis 166 6.3 Analysis: The Five Whys 168 6.4 Regulatory Requirements 169 6.5 Software Solutions 169 6.6 Emergency Response Planning 170 Notes 170 7 Chemistry and Analyses 173 7.1 Aquatic Testing 173 7.2 Bacterial Testing 174 7.3 Dissolved Organic Materials – BOD, COD, and TOC 175 7.3.1 BOD vs ThOD 179 7.3.2 Chemical Oxygen Demand 181 7.3.3 TOC 183 7.4 Common Ion Species 183 7.4.1 Most Important Chemicals in the Water Environment 185 7.4.2 pH 185 7.4.3 Carbonate Chemistry 186 7.4.4 Alkalinity 186 7.5 Hardness 189 7.6 Chemical Water Softening 192 7.6.1 Excess Lime Process 193 7.7 Nitrogen 194 7.8 Phosphorus 197 7.9 Sulfur 198 7.10 Chlorine 198 7.11 Other Halogens 199 7.12 Metals 199 7.13 Solids 201 7.14 Organic Chemicals 205 Notes 206 8 Basic Water and Wastewater Treatment Techniques 209 8.1 Removal of Metals 209 8.2 Chromium 211 8.2.1 Other Chromium Reduction Reactions 212 8.3 Arsenic 213 8.4 Cadmium 213 8.5 Iron 214 8.6 Zinc 214 8.7 Mercury 214 8.8 Radium 215 8.9 Anions 218 8.9.1 Cyanide 218 8.9.2 Nitrates and Nitrites 219 8.10 Solvents and Oils 220 8.11 Chlorinated Organics 221 8.11.1 PCBs 222 8.11.2 DDT 223 Notes 225 9 Biological Wastewater Treatment 227 9.1 The Microbial World 227 9.2 Order of Treatment 233 9.3 Types of Organisms 234 9.4 Chemistry and Activated Sludge 238 9.5 Growth Conditions and Nitrification 239 9.6 Denitrification and Phosphate Removal 240 9.7 Biological Growth Equation 241 9.7.1 The Monod Equation 242 9.7.2 Microbial Decay 243 9.7.3 Effect of Temperature and pH on Rate of Reactions 245 9.8 Principles of Biological Treatment Systems 245 9.9 Activated Sludge and its Variations 248 9.10 Substrate Removal Definitions 250 9.11 Trickling Filters and Variations 252 9.12 Clarification for Biological Removals 254 9.13 Other Solids Removals 255 9.14 Biological Synthesis and Oxidation 255 9.15 Biological Treatment of Toxic Wastes 257 9.16 Modeling the Biological Process 257 9.16.1 Modeling Notes Before One Starts 258 9.16.2 Free Wastewater Treatment Modeling Platforms 261 9.16.2.1 SSSP 261 9.16.2.2 STEADY 261 9.16.2.3 JASS 262 9.16.2.4 Stoat 262 9.16.3 Commercially Available Modeling Tools 263 9.16.3.1 GPSX 263 9.16.3.2 SUMO 264 9.16.3.3 SIMBA 265 9.16.3.4 Biowin 267 9.16.3.5 WEST 268 9.16.4 Modeling Summary 268 Notes 270 10 Anaerobic Treatment 273 10.1 Basic Anaerobic Processes for Wastewater 273 10.2 Phosphorus Removal 275 10.3 Basic Anaerobic Processes for Digestion and Treatment 276 10.4 Anaerobic Pretreatment 278 10.5 Upflow Anaerobic Sludge Blanket Reactors 281 10.6 Other Digester Configurations 283 10.7 Siloxane Removals 283 10.8 Sludge Digestion 284 10.9 Gas Production Emphasis 286 10.10 New Technologies 287 10.11 Sludge Treatment 288 10.12 Anaerobic Digester Model ADM1 288 10.13 Struvite and Anaerobic Processes 289 Notes 290 11 Precipitation and Sedimentation 293 11.1 Theory of Sedimentation 293 11.2 Clarifiers and their Design 294 11.2.1 Bulk Velocity – Surface Loading Rate 294 11.2.2 Hydraulic Detention Time 296 11.3 Lamellas and Specialty Devices 298 11.3.1 Lamellas 298 11.3.2 Membrane Filters 299 Note 301 12 Granular Filtration Theory and Practice 303 12.1 Granular Media Filtration 303 12.1.1 Sizing of Filters by Flow Rate 303 12.1.2 Uniformity Coefficient and Effective Grain Size 306 12.2 Filtration Hydraulics 306 12.3 Particle Size Removals 307 12.4 Backwash Hydraulics 307 12.4.1 Use of Air in the Backwash of Granular Filtration Systems 310 Notes 312 13 Skin Filtration 313 13.1 Introduction 313 13.2 Microstrainers and Screens 313 13.3 Belt Filters 316 13.4 Plate and Frame Filters 316 13.5 Cloth vs. Paper Filters 319 13.6 Precoat 320 13.7 Head Loss Through Cloth Filters 322 13.8 Bag Filters 323 Notes 324 14 Membrane Filters and Reverse Osmosis 325 14.1 Introduction 325 14.2 Design Values 330 14.3 Process Selection 330 14.3.1 Ultrafiltration Membrane Selection 330 14.3.2 Cellulose Acetate Membranes 331 14.3.3 Polysulfone Membranes 331 14.3.4 Polyamide Membranes 331 14.3.5 Polyacrylonitrile Membranes 331 14.3.6 Ultrafiltration Modules 332 14.4 Reverse Osmosis 333 14.5 Mass Transfer Theory 333 14.6 Membrane Design Software 334 14.7 Membrane Materials 336 14.8 Membrane Configurations 337 14.9 RO Design Considerations 338 14.9.1 Feedwater Supply Considerations 338 14.9.2 Pressure Pumping 338 14.9.3 Membrane Considerations 341 14.9.4 Post-treatment 341 14.10 Design Parameters 341 Notes 344 15 Disinfection 347 15.1 Introduction 347 15.2 Rate of Kill – Disinfection Parameters 347 15.2.1 Chick’s Law 347 15.2.2 Harmful Organisms 348 15.3 Chlorine 353 15.3.1 Ammonia, Chlorine, and Chloramines 354 15.3.2 Other Types of Chlorine 355 15.3.3 Other Reactions with Chlorine 355 15.3.4 Chlorine Safety 355 15.3.5 Chlorine Dioxide 356 15.4 Ozone 357 15.5 Ultraviolet Light 358 15.5.1 LED Lighting 360 15.6 Other Disinfecting Compounds 360 15.6.1 Potassium Permanganate 360 15.6.2 Hydrogen Peroxide and Ozone 361 15.6.3 PAA: Peracetic Acid 362 15.6.4 Bromine 364 15.6.5 Iodine 365 15.6.5.1 Types of Iodinators 365 15.6.5.2 Careful Use of Iodine 365 15.7 Disinfection by Ultra Filtration 366 Notes 367 16 Phosphorus and Nitrogen Removal 369 16.1 General 369 16.2 BardenPho© Processes 373 16.3 Chemical Phosphorus Removal 375 16.4 Nitrogen Removal 378 16.4.1 Nitrogen Chemistry and Forms 378 16.4.2 Ammonia 378 16.4.3 Nitrate 379 16.4.4 Nitrification 379 16.4.4.1 Ammonia Stripping 388 16.4.4.2 Ion Exchange 390 16.5 Conclusions 392 Notes 392 17 Carbon Adsorption 395 17.1 Introduction 395 17.2 The Freundlich and Langmuir Equations 396 17.3 Carbon Adsorption Physical Coefficients and Economics 397 17.4 Other Considerations 397 17.4.1 Carbon Regeneration 397 17.4.2 The PACTTM Process 397 17.4.3 Wet Air Regeneration for PACT Systems 398 Note 401 18 Ion Exchange 403 18.1 Resins 403 18.2 Physical Characteristics 403 18.3 Chemical Structure 404 18.3.1 Selectivity 404 18.3.2 Selectivity Coefficient 405 18.4 Design Considerations 406 18.4.1 Pretreatment 406 19 Dissolved Air Flotation and Techniques 409 19.1 Design Basics for DAF 409 19.2 Operating Parameters 410 19.3 Theory and Design 411 19.4 Ranges of Data 412 19.5 Electroflotation 413 19.5.1 Electroflotation Theory and Design 414 19.6 Electrocoagulation 415 Notes 416 20 Coagulation, Flocculation and Chemical Treatment 419 20.1 Introduction 419 20.2 Sols 421 20.3 Flocculation and Mixing 422 20.4 Practice 423 20.5 Modeling 424 Notes 424 21 Heat Transfer Processes: Boilers, Heat Exchangers and Cooling Towers 425 21.1 Boilers 425 21.2 Boiler Classifications 426 21.2.1 Fire Tube Boilers 426 21.2.2 Water Tube Boilers 426 21.3 Boiler Water Quality Requirements 427 21.4 Cooling Towers 430 Notes 431 22 Evaluating an Existing Wastewater Treatment Plant Design using Modeling Software 433 22.1 Step 1: Information Gathering 433 22.2 Step 2: Model Selection 435 22.3 Step 3: Laboratory and Other Data Organization 438 22.3.1 Generating the Flows Without the Data 439 22.3.2 Getting the Hydraulics and the Tankage Correct 440 22.3.2.1 When You Cannot Dye-test Your Tanks – a Procedure 441 22.4 Step 4: Flow Sheet Setup and Model Organization 443 22.5 Step 5: Model Compilation and Setup 444 22.5.1 Initial Values versus Derived Values 445 22.5.2 Integrator Settings 445 22.6 Step 6: Input and Output File Preparation 445 22.7 Step 7: Initialization of the Model Parameters and First Runs 445 22.7.1 What to Balance or Adjust 446 22.7.2 What to Key in on During Your Modeling 446 22.8 Step 8: Parameter Adjustments 446 Notes 447 Index 449

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Book SynopsisThe first book to offer a blueprint for overcoming the challenges to successfully quantifying biomarkers in living organisms The demand among scientists and clinicians for targeted quantitation experiments has experienced explosive growth in recent years. While there are a few books dedicated to bioanalysis and biomarkers in general, until now there were none devoted exclusively to addressing critical issues surrounding this area of intense research. Target Biomarker Quantitation by LC-MS provides a detailed blueprint for quantifying biomarkers in biological systems. It uses numerous real-world cases to exemplify key concepts, all of which were carefully selected and presented so as to allow the concepts they embody to be easily expanded to future applications, including new biomarker development. Target Biomarker Quantitation by LC-MS primarily focuses on the assay establishment for biomarker quantitationa critical issue rarely treated in depth. ITable of ContentsList of Contributors xv Preface xix Abbreviations xxiii Part I Overview 1 1 Overview of Targeted Quantitation of Biomarkers and Its Applications 3Naidong Weng 1.1 Introduction 3 1.2 Biomarker Definition 4 1.3 Current Challenges of a Biomarker 5 1.4 Biomarker Validation Process 6 1.5 Current Regulatory Requirement for Target Biomarker Quantitation 6 1.6 Challenges of Biomarker Quantitation 7 1.7 Current Technologies for Biomarker Quantitation 8 1.7.1 LC–MS 8 1.7.2 GC–MS 8 1.7.3 Ligand]Binding Assay 9 1.7.4 Flow Cytometry 9 1.7.5 Quantitative PCR (qPCR) 9 1.8 Current Biomarker Quantitation Applications 9 1.8.1 Protein Biomarkers 9 1.8.2 Peptide Biomarkers 10 1.8.3 RNA Biomarkers 11 1.8.4 Nucleotide Biomarkers 11 1.8.5 Small Molecule Biomarkers 11 1.9 Conclusion and Future Perspective 12 References 13 2 Translational Application of Biomarkers 17Ray Bakhtiar 2.1 Introduction 17 2.2 Translational Medicine 17 2.3 Biomarkers 18 2.4 Biomarker Categories 18 2.5 Neurobiological Disorders 21 2.6 Cardiovascular Disorders 22 2.7 Chronic Obstructive Pulmonary Disease 23 2.8 Oncology 24 2.9 Biomarker Measurements and Regulatory Considerations 26 2.10 Conclusions 27 References 29 3 Current Regulatory Guidance Pertaining Biomarker Assay Establishment and Industrial Practice of Fit]for]Purpose and Tiered Approach 35Naidong Weng 3.1 Introduction 35 3.2 Current Regulatory Guidance and Interpretation 36 3.3 Current Industrial Discussion and Recommendations 37 3.4 Considerations for Assay Validation and Sample Analysis 39 3.4.1 Sensitivity 40 3.4.2 Specificity and Selectivity 40 3.4.3 Matrix Effects and Sample Variables 40 3.4.3.1 Authentic Analyte/Authentic Matrix Approach 40 3.4.3.2 Surrogate Analyte/Authentic Matrix Approach 40 3.4.3.3 Authentic Analyte/Surrogate Matrix Approach 40 3.4.4 Accuracy/Precision 40 3.4.5 Stability 41 3.4.6 Sample Analysis Consideration 41 3.5 Examples of Fit]for]Purpose and Tiered Approach 41 3.5.1 Relative Quantification of Glyco]isoforms of Intact Apolipoprotein C3 in Human Plasma by LC]HRMS 41 3.5.2 Quantification of 4β]Hydroxycholesterol Endogenous Biomarker for CYP3A4 Activity in Plasma Samples 41 3.5.3 Quantitation of Leukotriene B4 in Human Sputum as a Biomarker Using UPLC–MS/MS 42 3.6 Conclusion 42 References 42 4 Modern Liquid Chromatography and Mass Spectrometry for Targeted Biomarker Quantitation 45Wenying Jian 4.1 Introduction 45 4.2 Liquid Chromatography 45 4.2.1 Importance of Separation 45 4.2.2 Basic Principle of LC 47 4.2.3 Major Modes of LC Used for Targeted Biomarker Quantitation 47 4.2.4 Modern LC Technologies 49 4.2.4.1 HPLC and UHPLC 49 4.2.4.2 Miniaturized Column LC 50 4.2.4.3 2D]LC 51 4.3 Mass Spectrometry 51 4.3.1 Major Types of MS Used for Targeted Biomarker Quantitation 51 4.3.2 Ionization Techniques 54 4.3.3 Ion Mobility 54 4.3.4 Fragmentation Mode 55 4.3.5 Emerging MS Techniques 56 4.3.5.1 MS Imaging 56 4.3.5.2 Other Surface Analysis MS Techniques 58 4.4 Summary and Future Perspectives 58 References 59 5 Comparison Between LC–MS and Ligand]Binding Assay Approaches for Biomarker Quantification 65QingQing Wang, Lili Guo, and Ian A. Blair 5.1 General Considerations: LBAs or LC–MS Assays 65 5.2 General Quantification Approaches 66 5.3 Analytical Issues Specifically Related to LBAs 67 5.3.1 There Is No Sample Pretreatment in Most LBAs 67 5.3.2 It Is Hard to Distinguish Biomarkers and Their Variants by LBAs 68 5.4 Analytical Features Specifically Related to LC–MS Methods 68 5.4.1 Proper Sample Preparation Generates Better Data 69 5.4.2 Biomarkers and Their Variants Can Be Distinguished 69 5.4.3 Stable Isotope]Labeled Internal Standard Used for Assuring the Assay Accuracy 71 5.5 Case Studies: Comparison Between ELISA and LC–MS 72 5.5.1 Steroid Analysis 72 5.5.2 Apolipoprotein A1 74 5.6 Summary and Future Perspective 74 References 74 6 Sample Preparation Methods for Targeted Biomarker Quantification by LC]MS 79Shichen Shen, Bo An, and Jun Qu 6.1 Introduction 79 6.2 Sample Preparation Strategies for Small Molecule Biomarkers 79 6.2.1 Primary Issues to Address for Sample Preparation 80 6.2.1.1 Matrix Effects 80 6.2.1.2 Sensitivity and Selectivity 81 6.2.1.3 Selection of Calibration Methods 82 6.2.2 Sample Preparation Techniques 82 6.2.2.1 Dilute]and]Shoot 82 6.2.2.2 Protein Precipitation (PPT) 82 6.2.2.3 Liquid–Liquid Extraction (LLE) 82 6.2.2.4 Solid]Phase Extraction (SPE) 84 6.3 Sample Preparation Strategies for Macromolecule Biomarkers 86 6.3.1 Considerations for Sample Preparation 86 6.3.1.1 Matrix Effects 86 6.3.1.2 Recovery of the Signature Peptide from the Target Analyte 86 6.3.1.3 Selection of Calibration Methods 88 6.3.1.4 Sensitivity and Selectivity 89 6.3.2 Methods for Protein Extraction 89 6.3.3 Methods for Protein and Peptide Enrichment 89 6.3.3.1 Immunoaffinity Capture (IC) 90 6.3.3.2 Sample Fractionation 90 6.3.3.3 Depletion of High Abundance Proteins (HAPs) 91 6.3.4 Methods for Protein Denaturation, Reduction, and Alkylation 92 6.3.5 Methods for Proteolytic Digestion 93 6.4 Conclusive Remarks 94 References 95 7 Overcome the Endogenous Levels in Biomarker Quantitation Using LC–MS 107Guowen Liu 7.1 Introduction 107 7.2 How Does Matrix Effect Affect Quantitation? 108 7.3 Commonly Used Strategies 109 7.3.1 Authentic Analyte in Authentic Matrix (Standard Addition) 109 7.3.2 Surrogate Analyte in Authentic Matrix 109 7.3.3 Authentic Analyte in Surrogate Matrix 112 7.4 Discussions and Future Perspectives 114 References 115 Part II Challenges and Approaches 119 8 Sample Collection for Targeted Biomarker Quantitation by LC–MS 121Yuzhong Deng and Xiaorong Liang 8.1 Introduction 121 8.2 Timing of Biomarker Sample Collection 121 8.3 Matrix Type 122 8.3.1 Serum or Plasma 122 8.3.2 Urine 123 8.3.3 Tissue 123 8.4 Collection Methods 124 8.4.1 Plasma Sample Collection 124 8.4.1.1 Anticoagulants 124 8.4.1.2 Stabilizing Agents 125 8.4.1.3 Temperature and Timing before Initial Processing 126 8.4.1.4 Endogenous Degradation 126 8.4.2 Urine Sample Collection 127 8.4.3 Tissue Sample Collection 128 8.5 Sample Storage Stability 128 8.5.1 Storage of Blood]Derived Fluids and Urine Samples 128 8.5.2 Storage of Tissue Samples 129 8.5.3 Freeze/Thaw Effect 129 8.6 Summary 129 References 130 9 Nonspecific Binding in LC–MS Bioanalysis 137Aimin Tan and John C. Fanaras 9.1 Introduction 137 9.2 Identification and Evaluation of NSB 137 9.2.1 Common Scenarios and Indicators for Potential NSB Issues 137 9.2.2 Confirmation/Identification and Evaluation of NSB 138 9.2.3 NSB versus Stability Issue 139 9.3 Causes for NSB 140 9.4 Overcoming NSB Challenges 140 9.4.1 Solubilization of Compounds 140 9.4.2 Overview of Measures for Overcoming NSB Challenges 141 9.4.3 Application Examples 143 9.5 Conclusion 144 References 146 10 Strategies for Improving Sensitivity for Targeted Quantitation by LC–MS 149Long Yuan and Qin C. Ji 10.1 Introduction 149 10.2 Sample Preparation Strategies for Improving Sensitivity 150 10.2.1 Protein Precipitation 151 10.2.2 Liquid–Liquid Extraction 152 10.2.3 Solid]Phase Extraction 153 10.2.4 Immunoaffinity Extraction 154 10.2.5 Chemical Derivatization 155 10.2.6 Online Sample Preparation 155 10.3 LC Separation Strategies for Improving Sensitivity 156 10.3.1 Optimization of Mobile Phase 156 10.3.2 2D]LC 157 10.3.3 Low]Flow LC 157 10.4 MS Detection Strategies for Improving Sensitivity 160 10.4.1 SRM 160 10.4.2 High]Resolution Mass Spectrometry (HRMS) 162 10.4.3 IMS 163 10.5 Conclusions 163 References 163 11 Strategies to Improve Specificity for Targeted Biomarker Quantitation by LC–MS 171Yuan]Qing Xia and Jeffrey D. Miller 11.1 Introduction 171 11.2 Differential Mobility Spectrometry 171 11.3 High]Resolution Mass Spectrometry 175 11.4 Conclusions 180 References 180 12 Biomarker Quantitation Using Relative Approaches 183Shane M. Lamos and Katrina E. Wiesner 12.1 Introduction 183 12.2 Relative Quantitation Isotope Labeling Approaches 183 12.2.1 Enzymatic Isotopic Incorporation 183 12.2.2 Metabolic Isotopic Incorporation 185 12.2.3 Chemical Labeling (Nonisobaric) 187 12.2.4 Chemical Labeling (Isobaric) 188 12.3 Conclusions 191 References 192 Part III Applications 195 13 Targeted Quantification of Amino Acid Biomarkers Using LC]MS 197Barry R. Jones, Raymond F. Biondolillo, and John E. Buckholz 13.1 Introduction 197 13.2 Amino Acids as Biomarkers 198 13.2.1 Biomarker of Heart Failure 199 13.2.2 Citrulline as Biomarker of Intestinal Failure 199 13.2.3 Oncological Biomarkers 200 13.2.4 Branched]Chain Amino Acids in Diabetes and Cancer 200 13.2.5 Inborn Errors of Metabolism 200 13.2.6 Biomarker of Phenylketonuria (PKU) 201 13.2.7 Amino Acid Supplementation 201 13.3 Methods of Measurement 201 13.3.1 LC]MS Considerations for Measurement of 2]Hydroxyglutarate 202 13.4 Accuracy, Precision, Selectivity, and Stability Considerations 203 13.4.1 Accuracy 203 13.4.1.1 Accuracy: Surrogate Matrix 203 13.4.1.2 Accuracy: Surrogate Analyte 205 13.4.1.3 Surrogate Matrix/Analyte Considerations for Multiplexed Amino Acid Assays 205 13.4.2 Precision 206 13.4.3 Selectivity 206 13.4.4 Stability 207 13.5 Assay Design 207 13.6 Conclusion 207 References 208 14 Targeted Quantification of Peptide Biomarkers: A Case Study of Amyloid Peptides 211Lieve Dillen, Marc De Meulder, and Tom Verhaeghe 14.1 Overview 211 14.2 Challenges and Approaches 212 14.2.1 Multiply Charged Ions: SRM Versus HRMS 212 14.2.2 Adsorption–Solubility–Stability Aspects 214 14.2.3 Blank Matrix–Internal Standard–Surrogate Analytes 214 14.2.4 Extraction–Sample Pretreatment 215 14.3 Application to the Quantification of Alzheimer’s Disease Biomarkers 216 14.3.1 Introduction: Amyloid Peptides in CSF as Biomarkers for Alzheimer’s Disease 216 14.3.2 LC]MS/MS Method for Analysis of Amyloid Peptides in CSF in Support of Preclinical Development 216 14.3.3 LC]MS/MS Method for Analysis of Amyloid Peptides in CSF in Support of Clinical Development 217 14.3.4 Comparison of Immunoassay and UHPLC]MS/MS: Are the Results Comparable? 219 14.4 Conclusion 222 References 222 15 Targeted Protein Biomarker Quantitation by LC]MS 227Yongle Pang, Chuan Shi, and Wenying Jian 15.1 Introduction 227 15.2 Sample Preparation for Targeted Protein Biomarker Quantitation 231 15.2.1 Protein Precipitation 232 15.2.2 Solid Phase Extraction 232 15.2.3 Abundant Protein Depletion 232 15.2.4 Affinity Enrichment 233 15.3 “Bottom]Up” Approach for Targeted Protein Biomarker Quantitation Using LC]MS 233 15.3.1 Surrogate Peptide Selection 233 15.3.2 Sample Pretreatment Prior to Proteolytic Digestion 234 15.3.3 Proteolytic Digestion 234 15.3.4 LC]MS Analysis 235 15.4 “Top Down” Approach for Targeted Protein Biomarker Quantitation Using LC]MS 235 15.5 Key Considerations in Targeted Protein Biomarker Quantitation Using LC]MS 236 15.5.1 Preanalytical Considerations 236 15.5.2 Internal Standard 236 15.5.3 Reference Standard 237 15.5.4 Improving Sensitivity of the Assay 238 15.5.5 Improving Throughput of the Assay 238 15.5.6 Correlating MS Data with LBA Data 239 15.6 Summary and Future Perspectives 239 References 240 16 Glycoprotein Biomarkers 245Shuwei Li, Stefani N. Thomas, and Shuang Yang 16.1 Introduction 245 16.2 Technologies for Glycoprotein Analysis 246 16.2.1 Glycoprotein Enrichment 246 16.2.1.1 Techniques for the Enrichment of Glycoproteins 246 16.2.1.2 Hybrid Chemical Metabolic Labeling 248 16.2.2 Glycan Analysis 251 16.2.2.1 In]Solution Glycan Analysis 251 16.2.2.2 Solid]Phase Glycan Analysis 252 16.2.3 Automated Platform for Processing Clinical Specimens 252 16.2.4 MS Analysis of Glycoproteins 254 16.2.4.1 Bottom]Up Approaches 254 16.2.4.2 Top]Down Approaches 254 16.2.4.3 MS/MS Fragmentation Methods for Glycopeptides 254 16.3 Glycoprotein Biomarker Quantification Using LC]MS 255 16.3.1 Quantification by Stable Isotope Labeling 255 16.3.2 Metabolic Labeling Strategies 255 16.3.3 Label]Free Glycoprotein Quantification 257 16.3.4 Methods for Targeted Quantification Using LC]MS/MS 259 16.4 Protein Biomarkers for Clinical Applications 259 16.4.1 FDA]Approved Glycoprotein Biomarkers 259 16.4.2 Classes of Biomarkers 260 16.4.3 New Glycoprotein Biomarker Discovery 260 16.5 Summary and Future Direction 264 References 265 17 Targeted Lipid Biomarker Quantitation Using Liquid Chromatography–Mass Spectrometry (LC–MS) 273Ashkan Salamatipour, Ian A. Blair, and Clementina Mesaros 17.1 Introduction of Lipids 273 17.2 LC–MS Analysis of Lipids 276 17.3 Examples of LC–MS Analysis of Lipids 278 17.3.1 Omega]6]Derived Eicosanoids 278 17.3.2 Docosahexaenoic Acid (DHA) 279 17.3.3 N]Acylethanolamines (NAEs) and Eicosanoids 281 17.3.4 Arachidonic Acid (AA) 282 17.4 Summary and Future Directions 283 References 283 18 Targeted LC–MS Quantification of Androgens and Estrogens for Biomarker Development 289Daniel Tamae 18.1 Introduction 289 18.1.1 History of Estrogen and Androgen Quantification 289 18.1.2 Androgen Biosynthesis and Metabolism 290 18.1.3 Estrogen Biosynthesis and Metabolism 290 18.2 Current Considerations in Biomarker Validation 292 18.3 Current Considerations in LC–MS Method Development 293 18.3.1 Chromatography 293 18.3.2 Direct Detection Methods 293 18.3.3 Derivatization Strategies 294 18.3.4 Stable Isotope Standards 295 18.3.5 Hydrolysis of Conjugated Steroids 296 18.4 Clinical Application of LC–MS Quantification of Estrogens and Androgens 296 18.4.1 Reference Ranges of Estrogens and Androgens 296 18.4.2 Estrogens in Postmenopausal Women and Low Androgens in Aging Men 297 18.4.3 Estrogens and Breast Cancer 297 18.4.4 Androgens and Prostate Cancer 298 18.5 Conclusion and Perspective 301 References 301 19 Steroid Biomarkers 307Mike (Qingtao) Huang, Shefali Patel, and Zhongping (John) Lin 19.1 Introduction 307 19.2 Sterols as Endogenous Biomarkers and Their Quantitation 307 19.2.1 4β]OHC as a P450 3A4/5 Endogenous Biomarker 307 19.2.2 Quantitation of 4β]OHC in Human and Animal Species 310 19.2.3 24S]OHC and 27]OHC as Biomarkers 311 19.2.4 Quantitation of 24S]OHC and 27]OHC 312 19.3 Cortisol and 6 β]Hydroxycortisol (6β]HC) as Biomarkers and Their Quantitation 312 19.3.1 Cortisol and 6β]HC as Biomarkers 312 19.3.2 Measurement of Cortisol and 6β]HC 313 19.3.2.1 Measurement of Cortisol in Serum 313 19.3.2.2 Measurement of Cortisol and 6β]HC in Urine 314 19.3.2.3 Measurement of Cortisol in Saliva and Hair 315 19.4 Summary 316 References 316 20 Bile Acids as Biomarkers 321Clara John, Philipp Werner, Joerg Heeren, and Markus Fischer 20.1 Introduction 321 20.2 Analytical Platform for Bile Acids 323 20.3 Summary 327 References 327 21 Biomarkers for Vitamin Status and Deficiency: LC]MS Based Approach 331Stanley (Weihua) Zhang and Jonathan Crowther 21.1 Introduction to Vitamin and Vitamin Deficiency 331 21.2 Detection of Vitamin D by LC]MS/MS and Comparison with Other Methods 332 21.2.1 Vitamin D and Vitamin D Deficiency 332 21.2.2 Target the Right Metabolites 332 21.2.3 Analytical Challenges 332 21.2.4 History of Vitamin D Quantification Assays 333 21.2.5 Quantification of 25(OH)D by LC]MS/MS 334 21.2.5.1 Considerations in Assay Development and Validation 334 21.2.5.2 Sample Preparation 335 21.2.5.3 LC]MS/MS 335 21.2.5.4 Method Comparison and Standardization 336 21.3 Other Vitamin Biomarkers 338 21.3.1 Retinol: Biomarkers of Vitamin A Status and Deficiency 338 21.3.2 Folic Acid: Biomarkers for Vitamin B9 Dietary Intake 339 21.3.3 Vitamin C: An Appropriate Biomarker of Vitamin C Intake 340 21.4 Conclusions and Perspectives 340 References 341 22 Quantitation of Acyl]Coenzyme A Thioesters as Metabolic Biomarkers 347Nathaniel Snyder 22.1 Introduction 347 22.2 Structure and Function of Acyl]CoAs 347 22.3 Detection and Quantitation of Acyl]CoAs 349 22.4 Acyl]CoA Analysis for Current Drug Targets 352 22.5 Acyl]CoAs as Biomarkers in Metabolic Disease 352 22.6 The Involvement of Acyl]CoAs in Drug Metabolism 353 References 353 23 Neurotransmitter Biomarkers 357Guodong Zhang 23.1 Introduction 357 23.2 Chromatographic Platforms of Biological Measurement for Neurotransmitters 358 23.2.1 Challenges for Neurotransmitter Measurement 358 23.2.2 LBA, LC, GC, and CE 358 23.2.3 LC–MS/MS 359 23.3 Bioanalytical Methodologies 359 23.3.1 Sample Preparation Strategies 359 23.3.2 Sensitivity and Chromatography Enhancement by Chemical Derivatization Using LC]MS/MS 362 23.3.3 Chromatographic Strategies for LC]MS/MS Assays 362 23.3.4 NTs Stability and Sample Collection 363 23.3.5 Case Studies 367 23.4 Conclusion 367 References 367 24 Targeted Quantification of Carbohydrate Biomarkers Using LC–MS 371Cong Wei and Hong Gao 24.1 Introduction 371 24.2 Overview 371 24.2.1 Clinical Diagnostic Carbohydrate Biomarkers 371 24.2.2 Overview of Bioanalytical Analysis of Carbohydrate Biomarker 372 24.3 Bioanalytical Method Development for Carbohydrate Biomarkers 374 24.3.1 Sample Preparation 374 24.3.1.1 Sample Preparation by Solid]Phase Extraction (SPE) 374 24.3.1.2 Sample Preparation by Liquid–Liquid Extraction (LLE) 376 24.3.1.3 Sample Preparation by Derivatization 378 24.3.1.4 Sample Preparation by Enzymatic Digestion or Chemical Reduction 378 24.3.2 Chromatography and Column Options 380 24.3.2.1 HILIC for LC–MS/MS Bioanalysis 381 24.3.2.2 Porous Graphic Hypercarb Chromatography for LC–MS/MS Bioanalysis 381 24.3.2.3 Reversed]Phase Chromatography for LC–MS/MS Bioanalysis 382 24.3.2.4 Reversed]Phase Ion]Pair Chromatography for LC–MS Bioanalysis 382 24.3.3 LC–MS/MS Analysis 383 24.4 Conclusions 384 References 384 25 Nucleoside/Nucleotide Biomarkers 389Guodong Zhang 25.1 Introduction 389 25.2 Chromatographic Platforms for Nucleosides/Nucleotides 390 25.2.1 Challenges for Nucleosides and Nucleotides Measurement 390 25.2.2 Conventional Immunoassays, CE, GC and HPLC 390 25.2.3 LC–MS/MS 391 25.3 Bioanalytical Methodologies 391 25.3.1 Sample Preparation Strategies 391 25.3.2 Chromatographic Strategies for LC–MS/MS Assays 394 25.4 Nucleoside/Nucleotide Biomarkers and Case Studies 398 25.5 Conclusion 399 References 402 26 LC–MS of RNA Biomarkers 407Michael G. Bartlett, Babak Basiri, and Ning Li 26.1 Introduction 407 26.2 Role in Disease and Therapeutics 408 26.3 Role of Mass Spectrometry in RNA Biomarkers 409 26.4 LC–MS Approaches for RNA Determination 411 26.4.1 Sample Preparation 411 26.4.2 Ion]Pair Chromatography 413 26.4.3 Capillary Chromatography 414 26.4.4 Liquid Chromatography–Inductively Coupled Plasma Mass Spectrometry 415 26.5 Case Studies 415 26.5.1 Single Nucleotide Polymorphisms as Biomarkers 415 26.5.2 Small Interfering RNA Determination 416 26.5.3 MicroRNA Determination 416 References 418 Index 425

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Book SynopsisVolume 88 represents the tenth single-chapter-volume produced in our 73-year history. Such single-chapter volumes represent definitive treatises on extremely important chemical transformations. The success of the research efforts over the past 20 years forms the basis for the single chapter in this volume namely, Hydroamination of Alkenes by Alexander L. Reznichenko and Kai C. Hultzsch. The authors have compiled an enormous (and growing) literature and distilled it into an extraordinarily useful treatise on all aspects of the hydroamination process.Table of Contents1. Hydroamination of AlkenesAlexander L. Reznichenko and Kai C. Hultzsch 1 Cumulative Chapter Titles by Volume 555 Author Index, Volumes 1–88 571 Chapter and Topic Index, Volumes 1–88 577

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Book SynopsisThe Reviews in Computational Chemistry series brings together leading authorities in the field to teach the newcomer and update the expert on topics centered on molecular modeling, such as computer-assisted molecular design (CAMD), quantum chemistry, molecular mechanics and dynamics, and quantitative structure-activity relationships (QSAR). This volume, like those prior to it, features chapters by experts in various fields of computational chemistry. Topics in Volume 29 include: Noncovalent Interactions in Density-Functional TheoryLong-Range Inter-Particle Interactions: Insights from Molecular Quantum Electrodynamics (QED) TheoryEfficient Transition-State Modeling using Molecular Mechanics Force Fields for the Everyday ChemistMachine Learning in Materials Science: Recent Progress and Emerging ApplicationsDiscovering New Materials via a priori Crystal Structure PredictionIntroduction to Maximally Localized Wannier FunctionsMethods for a Rapid and Automated Description of Proteins: ProteTable of ContentsContributors x Preface xii Contributors to Previous Volumes xv 1 Noncovalent Interactions in Density Functional Theory 1Gino A. DiLabio and Alberto Otero-de-la-Roza Introduction 1 Overview of Noncovalent Interactions 3 Theory Background 9 Density-Functional Theory 9 Failure of Conventional DFT for Noncovalent Interactions 17 Noncovalent Interactions in DFT 20 Pairwise Dispersion Corrections 20 Potential-Based Methods 42 Minnesota Functionals 47 Nonlocal Functionals 54 Performance of Density Functionals for Noncovalent Interactions 59 Description of Noncovalent Interactions Benchmarks 59 Performance of Dispersion-Corrected Methods 66 Noncovalent Interactions in Perspective 74 Acknowledgments 78 References 79 2 Long-Range Interparticle Interactions: Insights from Molecular Quantum Electrodynamics (QED) Theory 98Akbar Salam Introduction 98 The Interaction Energy at Long Range 101 Molecular QED Theory 104 Electrostatic Interaction in Multipolar QED 112 Energy Transfer 114 Mediation of RET by a Third Body 119 Dispersion Potential between a Pair of Atoms or Molecules 123 Triple–Dipole Dispersion Potential 128 Dispersion Force Induced by External Radiation 132 Macroscopic QED 136 Summary 141 References 143 3 Efficient Transition State Modeling Using Molecular Mechanics Force Fields for the Everyday Chemist 152Joshua Pottel and Nicolas Moitessier Introduction 152 Molecular Mechanics and Transition State Basics 154 Molecular Mechanics 154 Transition States 157 Ground State Force Field Techniques 158 Introduction 158 ReaxFF 159 Reaction Force Field 161 Seam 163 Empirical Valence Bond/Multiconfiguration Molecular Dynamics 166 Asymmetric Catalyst Evaluation 169 TSFF Techniques 173 Introduction 173 Q2MM 175 Conclusion and Prospects 178 References 178 4 Machine Learning in Materials Science: Recent Progress and Emerging Applications 186Tim Mueller, Aaron Gilad Kusne, and Rampi Ramprasad Introduction 186 Supervised Learning 188 A Formal Probabilistic Basis for Supervised Learning 189 Supervised Learning Algorithms 199 Unsupervised Learning 213 Cluster Analysis 215 Dimensionality Reduction 226 Selected Materials Science Applications 237 Phase Diagram Determination 237 Materials Property Predictions Based on Data from Quantum Mechanical Computations 240 Development of Interatomic Potentials 245 Crystal Structure Predictions (CSPs) 249 Developing and Discovering Density Functionals 250 Lattice Models 251 Materials Processing and Complex Materials Behavior 256 Automated Micrograph Analysis 257 Structure–Property Relationships in Amorphous Materials 260 Additional Resources 263 Summary 263 Acknowledgments 264 References 264 5 Discovering New Materials via A Priori Crystal Structure Prediction 274Eva Zurek Introduction and Scope 274 Crystal Lattices and Potential Energy Surfaces 276 Calculating Energies and Optimizing Geometries 281 Methods to Predict Crystal Structures 282 Following Soft Vibrational Modes 283 Random (Sensible) Structure Searches 284 Simulated Annealing 285 Basin Hopping and Minima Hopping 287 Metadynamics 288 Particle Swarm Optimization 289 Genetic Algorithms and Evolutionary Algorithms 291 Hybrid Methods 292 The Nitty-Gritty Aspects of Evolutionary Algorithms 294 Workflow 294 Selection for Procreation 295 Evolutionary Operators 297 Maintaining Diversity 299 The XtalOpt Evolutionary Algorithm 300 Practical Aspects of Carrying out an Evolutionary Structure Search 303 Crystal Structure Prediction at Extreme Pressures 312 Note in Proof 315 Conclusions 316 Acknowledgments 317 References 317 6 Introduction to Maximally Localized Wannier Functions 327Alberto Ambrosetti and Pier Luigi Silvestrelli Introduction 327 Theory 329 Bloch States 329 Wannier Functions 331 Maximally Localized Wannier Functions: Γ-Point Formulation 333 Extension to Brillouin-Zone k]Point Sampling 336 Degree of WF Localization 337 Entangled Bands and Subspace Selection 338 Applications 340 Charge Visualization 340 Charge Polarization 344 Bonding Analysis 348 Amorphous Phases and Defects 351 Electron Transport 354 Efficient Basis Sets 356 Hints About MLWFs Numerical Computation 361 Brief Review of the Presently Available Computational Tools 361 MLWF Generation 362 References 363 7 Methods for a Rapid and Automated Description of Proteins: Protein Structure, Protein Similarity, and Protein Folding 369Zhanyong Guo and Dieter Cremer Introduction 369 Protein Structure Description Methods Based on Frenet Coordinates and/or Coarse Graining 373 The Automated Protein Structure Analysis (APSA) 375 The Curvature–Torsion Description for Idealized Secondary Structures 378 Identification of Helices, Strands, and Coils 384 Difference between Geometry-Based and H]Bond-Based Methods 385 Combination of Geometry-Based and H-Bond]Based Methods 388 Chirality of SSUs 388 What is a Regular SSU? 389 A Closer Look at Helices: Distinction between α- and 310-Helices 391 Typical Helix Distortions 395 Level 2 of Coarse Graining: The Curved Vector Presentation of Helices 398 Identification of Kinked Helices 402 Analysis of Turns 406 Introduction of a Structural Alphabet 409 Derivation of a Protein Structure Code 411 Description of Protein Similarity 416 Qualitative and Quantitative Assessment of Protein Similarity 417 The Secondary Code and Its Application in Connection with Protein Similarity 423 Description of Protein Folding 423 Concluding Remarks 426 Acknowledgments 428 References 428 Index 439

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Book SynopsisThis volume incorporates 13 contributions from renowned experts from the relevant research fields that are related biodegradable and biobased polymers and their environmental and biomedical applications. Specifically, the book highlights: Developments in polyhydroxyalkanoates applications in agriculture, biodegradable packaging material and biomedical field like drug delivery systems, implants, tissue engineering and scaffolds The synthesis and elaboration of cellulose microfibrils from sisal fibres for high performance engineering applications in various sectors such as the automotive and aerospace industries, or for building and construction The different classes and chemical modifications of tannins Electro-activity and applications of Jatropha latex and seed The synthesis, properties and applications of poly(lactic acid) The synthesis, processing and properties of poly(butylene succinate), its copolymers, coTable of ContentsPreface xvii 1 Biomedical Applications for Thermoplastic Starch 1 Antonio José Felix de Carvalho and Eliane Trovatti 1.1 Starch as Source of Material in the Polymer Industry 1 1.2 Starch in Plastic Material and Thermoplastic Starch 2 1.3 Uses of Starch and TPS in Biomedical and Pharmaceutical Fields 5 1.3.1 Native Starch (Granule) as Pharmaceutical Excipient 6 1.3.2 Gelatinized and Thermoplastic Starch in Biomedical Application 6 1.3.3 Starch-based Scaffolds 10 1.3.4 Starch-based Biosorbable Materials - Degradation Inside Human Body 12 1.3.5 Cell Response to Starch and Its Degradation Products 15 1.4 Conclusion and Future Perspectives for Starch-based Polymers 16 Acknowledgment 16 References 16 2 Polyhydroxyalkanoates: The Application of Eco-Friendly Materials 25 G.V.N. Rathna, Bhagyashri S. Thorat Gadgil and Naresh Killi 2.1 Introduction 25 2.2 Natural Occurrence 26 2.3 Bio-Synthetic/ Semi-Synthetic Approach 29 2.4 Environmental Aspects 31 2.5 Applications 33 2.6 Biomedical Applications 33 2.6.1 Drug Delivery 34 2.6.2 Implants and Scaffolds 36 2.7 Biodegradable Packaging Material 38 2.8 Agriculture 44 2.9 Other Applications 45 2.10 Scope of PHAs 46 2.11 Conclusions 46 References 47 3 Cellulose Microfibrils from Natural Fiber Reinforced Biocomposites and its Applications 55 Atul P Johari, Smita Mohanty and Sanjay K Nayak 3.1 Introduction 55 3.1.1 Industrial Applications 57 3.2 Natural Fibers: Applications and Limitations 58 3.3 Plant-based Fibers 59 3.4 Chemical Composition, structure and Properties of Sisal Fiber 60 3.4.1 Cellulose Fibers 61 3.4.2 Hemicellulose 61 3.4.3 Lignin 62 3.4.4 Pectin 63 3.4.5 Bio-based and Biodegradable Polymers 63 3.5 Biocomposites 64 3.6 Classification of Biocomposites 65 3.6.1 Green Composites 65 3.6.2 Hybrid Composites 66 3.7 Biocomposites of CMF Reinforced of Poly (lactic acid) 67 3.7.1 Extraction of Cellulose Microfibrils from Sisal Fiber 67 3.7.2 CMF Extraction Process 69 3.7.3 Fabrication of PLA/CMF Biocomposite 72 3.8 Effect of CMF Reinforcement on the Mechanical Properties of PLA 72 3.9 FT-IR Analysis of Untreated Sisal Fiber (UTS), Mercerized Sisal Fiber (MSF) and Cellulose Microfibrils (CMF) 73 3.10 Crystalline Structure of UTS, MSF and CMF 75 3.11 Particle Size Determination: Transmission Electron Microscopy (TEM) 76 3.12 Thermal Properties 77 3.12.1 Differential Scanning Calorimetry of CMF Reinforced PLA biocomposites 77 3.12.2 Thermo Gravimetric Analysis of CMF Reinforced PLA Biocomposites 79 3.12.3 Dynamic Mechanical Analysis (DMA) of CMF Reinforced PLA Biocomposites 82 3.13 Scanning Electron Microscopy 85 3.13.1 Surface Morphology of Sisal Fiber (USF, MSF and CMF) 85 3.13.2 Surface Morphology of CMF Reinforced PLA References 91 4 Tannins: A Resource to Elaborate Aromatic and Biobased Polymers 97 Alice Arbenz and Luc Avérous 4.1 Introduction 97 4.2 Tannin Chemistry 98 4.2.1 Historical Outline 98 4.2.2 Classification and Chemical Structure of Vascular Plant Tannins 99 4.2.3 Hydrolysable Tannins 99 4.3 Complex Tannins 101 4.4 Condensed Tannins 101 4.5 Non-vascular Plant Tannins 103 4.5.1 Phlorotannins with Ether Bonds 104 4.5.2 Phlorotannins with Phenyl bonds 104 4.5.3 Phlorotannins with Ether and Phenyl bonds 105 4.5.4 Phlorotannins with Ibenzo-p-dioxin Links 106 4.6 Extraction of Tannins 106 4.7 Chemical Modification 108 4.7.1 General Background 108 4.7.2 Heterocycle Reactivity 108 4.8 Heterocyclic Ring Opening with Acid 110 4.9 Sulfonation 112 4.9.1 Reactivity of Nucleophilic Sites 113 4.9.2 Bromination 114 4.9.3 Reactions with Aldehydes 116 4.9.4 Reaction with the Hexamine 117 4.10 Mannich Reaction 119 4.11 Coupling Reaction 119 4.11.1 Michael Reaction 119 4.11.2 Oxa-Pictet-Spengler Reaction 120 4.11.3 Functionalization of the Hydroxyl Groups 121 4.11.4 Acylation 121 4.12 Etherification 124 4.12.1 Substitution by Ammonia 127 4.12.2 Reactions Between Tannin and Epoxy Groups 128 4.13 Alkoxylation 129 4.13.1 Reaction with Isocyanates 130 4.14 Toward Biobased Polymers and Materials 130 4.14.1 Adhesives 130 4.14.2 Phenol-formaldehyde Foam Type 132 4.15 Materials Based on Polyurethane 133 4.15.1 Polyurethanes Foams 133 4.15.2 Non-porous Polyurethane Materials 133 4.16 Materials Based on Polyesters 134 4.16.1 Materials Based on Epoxy Resins 134 4.17 Conclusion 135 Acknowledgments 136 References 136 5 Electroactivity and Applications of Jatropha Latex and Seed 149 S. S. Pradhan and A. Sarkar 5.1 Introduction 149 5.2 Plant Latex 150 5.3 Jatropha Latex 151 5.3.1 Chemistry 151 5.4 Jatropha Seed 151 5.5 Material Preparation 151 5.6 Microscopic Observations 153 5.6.1 X-ray Diffraction 153 5.6.2 Electronic or Vibrational Properties 154 5.7 Electroactivity in Jatropha Latex 157 5.7.1 Ionic Liquid Property 157 5.8 Electroactivity in Jatropha Latex 158 5.8.1 DC Volt-ampere Characteristics 162 5.8.2 Temperature Variation of AC Conductivity 164 5.9 Applications 165 5.10 Conclusion 167 Acknowledgements 168 References 168 6 Characteristics and Applications of PLA 171 Sandra Domenek and Violette Ducruet 6.1 Introduction 171 6.2 Production of PLA 172 6.2.1 Production of Lactic Acid 172 6.2.2 Synthesis of PLA 174 6.3 Physical PLA properties 179 6.4 Microstructure and Thermal properties 181 6.4.1 Amorphous Phase of PLA 181 6.4.2 Crystalline Structure of PLA 183 6.4.3 Crystallization Kinetics of PLA 185 6.4.4 Melting of PLA 187 6.5 Mechanical Properties of PLA 188 6.6 Barrier Properties of PLA 190 6.6.1 Gas Barrier Properties of PLA 190 6.6.2 Water Vapour Permeability of PLA 193 6.6.3 Permeability of Organic Vapours through PLA 194 6.7 Degradation Behaviour of PLA 195 6.7.1 Thermal Degradation 195 6.7.2 Hydrolysis 196 6.7.3 Biodegradation 198 6.8 Processing 200 6.9 Nanocomposites 202 6.10 Applications 204 6.10.1 Biomedical Applications of PLA 204 6.10.2 Packaging Applications Commodity of PLA 205 6.10.3 Textile Applications 208 6.10.4 Automotive Applications of PLA 209 6.10.5 Building Applications 210 6.10.6 Other Applications of PLA 210 6.11 Conclusion 211 References 211 7 PBS Makes Its Entrance into the Family of Biobased Plastics 225 Laura Sisti, Grazia Totaro and Paola Marchese 7.1 Introduction 225 7.2 PBS Market 227 7.3 PBS Production 229 7.3.1 Succinic Acid Production 230 7.3.2 1,4-Butanediol Production 233 7.3.3 Synthesis of PBS 234 7.4 Properties of PBS 237 7.5 Copolymers of PBS 240 7.5.1 Random Copolymers 240 7.5.2 Block Copolymers 247 7.5.3 Chain Branching 250 7.6 PBS Composites and Nanocomposites 253 7.6.1 Inorganic Fillers 253 7.6.2 Natural Fibers 258 7.7 Degradation and Recycling 262 7.7.1 Enzymatic Degradation 262 7.7.2 Non Enzymatic Degradation 266 7.7.3 Natural Weathering Degradation 266 7.7.4 Thermal Degradation 267 7.7.5 Recycling 267 7.8 Processing and Applications of PBS and its Copolymers 269 7.9 Conclusions 273 Abbreviations 273 References 274 8 Development of Biobased Polymers and Their Composites from Vegetable Oils 289 Patit P. Kundu and Rakesh Das 8.1 Introduction 289 8.2 Source and Functional Groups of Vegetable Oil 290 8.3 Direct Cross-Linking of Vegetable Oil for Polymer Synthesis 292 8.3.1 Cationic Polymerization 292 8.4 Free Radical Polymerization 295 8.5 Chemical Modification of Vegetable Oils for Polymer Synthesis 297 8.5.1 Synthesis of Polymers after Epoxidation of Vegetable Oils 297 8.6 Polymer Synthesis after Esterification of Vegetable Oils 299 8.7 Polyol and Polyurethanes from Vegetable Oils 302 8.8 Polymer Composites and Nanocomposites from Vegetable Oils 306 8.9 Conclusions 311 References 312 9 Polymers as Drug Delivery Systems 323 Magdy W. Sabaa 9.1 Introduction 323 9.2 Types of Modified Drug Delivery Systems 324 9.3 Concept of Drug Delivery Matrix 325 9.4 Polymeric Materials as Carriers for Drug Delivery Systems 326 9.4.1 Polysaccharides and Modified Polysaccharides as Matrices for Drug Delivery Systems 326 9.4.2 pH-sensitive as Drug Delivery Systems 331 9.4.3 Thermo-sensitive as Drug Delivery Systems 335 9.4.4 Light-sensitive as Drug Delivery Systems 338 9.5 Conclusions 340 References 341 10 Nanocellulose as a Millennium Material with Enhancing Adsorption Capacities 351 Norhene Mahfoudhi and Sami Boufi 10.1 Introduction 351 10.2 From Cellulose to Nanocellulose 353 10.3 General Remarks about Adsorption Phenomena 355 10.4 Nanobibrillated Cellulose as a Novel Adsorbent 359 10.5 NFC in Heavy Metal Adsorption 363 10.6 NFC as an Adsorbent for Organic Pollutants 372 10.7 NFC in Oil Adsorption 373 10.8 NFC in Adsorption of Dyes 376 10.9 Nanofibrillar Cellulose as a Flocculent for Waste Water 379 10.10 NFC in CO2 Adsorption 380 10.11 Conclusion 381 References 381 11 Towards Biobased Aromatic Polymers from Lignins 387 Stephanie Laurichesse and Luc Avérous 387 11.1 Introduction 388 11.2 Lignin Chemistry 389 11.2.1 Historical Outline 389 11.2.2 Chemical Structure 390 11.2.3 Physical Properties 391 11.3 Isolation of Lignin from Wood 393 11.3.1 The Biorefinery Concept 393 11.3.2 Extraction Processes and their Resulting Technical Lignins 394 11.4 Chemical Modification 398 11.4.1 General Background 398 11.4.2 Fragmentation of Lignin 399 11.4.3 Pyrolysis 401 11.4.4 Gasification 403 11.4.5 Oxidation 403 11.4.6 Liquefaction 404 11.4.7 Enzymatic Oxidation 406 11.4.8 Outlook 407 11.5 Synthesis of New Chemical Active Sites 407 11.5.1 Alkylation/Dealkylation 407 11.5.2 Hydroxalkylation 409 11.5.3 Amination 410 11.5.4 Nitration 411 11.6 Functionalization of Hydroxyl Groups 412 11.6.1 Esterification 412 11.6.2 Phenolation 415 11.6.3 Etherification and Ring Opening Polymerisations 416 11.6.4 Urethanisation 418 11.7 Toward Lignin Based Polymers and Materials 420 11.7.1 Lignin as a Viable Route for Polymers Syntheses 420 11.7.2 ATRP - A Useful Method to Develop Lignin-Based Functional Material 422 11.7.3 High Performance Material Made with Lignin: Carbon Fibers 423 11.7.4 Toward Commercialized Lignin-based Polymers 424 11.8 Conclusion 424 Acknowledgments 425 References 425 12 Biopolymers – Proteins (Polypeptides) and Nucleic Acids 439 S. Georgiev, Z. Angelova and T. Dekova 12.1 Structure of Protein Molecules 440 12.1.1 Peptide Bonds 441 12.1.2 Secondary Structure of Protein Molecule 441 12.1.3 Tertiary Structure of Proteins 442 12.1.4 Quaternary Structure of Proteins 443 12.2 Abnormal Haemoglobin 444 12.3 Methods for Proteome Analysis 446 12.4 Advantages of the Method 446 12.5 Study of Proteins with Post-Translational Modifications 447 12.6 Biodegradable Polymers 448 12.6.1 DNA The Molecule of Heredity 451 12.6.2 Experiments Designate DNA as the Genetic Material 452 12.6.3 Bacterial Transformation Implicates DNA as the Substance of Genes 452 12.6.4 Identification of RNA as the Genetic Material 454 12.6.5 The Structures of DNA and RNA 455 12.6.6 Left Handed DNA Helices 456 12.6.7 Some DNA Molecules are Circular instead of Linear 456 12.6.8 RNA as the Genetic Material (Structure) 457 12.6.9 Hammerhead Ribozymes HHRs 458 12.7 Regulation Gene Function Through RNA Interfering and MicroRNA Pathways 460 12.7.1 How dsRNA can Switch off Expression of a Gene? 461 12.7.2 MicroRNAs Also Control the Expression of Some Genes 463 12.8 DNA Vaccines 464 12.9 Conclusion 467 References 467 13 Tamarind Seed Polysaccharide-based Multiple-unit Systems for Sustained Drug Release 471 Amit Kumar Nayak 471 13.1 Introduction 471 13.2 Tamarind Seed Polysaccharide 473 13.2.1 Sources and Extraction 473 13.3 Composition 474 13.4 Properties 474 13.5 Use of Tamarind Seed Polysaccharide in Drug Delivery 475 13.6 Tamarind Seed Polysaccharide-based Microparticle/Beads for Sustained Drug Delivery 476 13.7 Extrusion-Spheronization Method 476 13.7.1 Tamarind Seed Polysaccharide Spheroids Containing Diclofenac Sodium 476 13.8 Ionotropic-Gelation Method 478 13.8.1 Tamarind Seed Polysaccharide-alginate Beads Containing Diclofenac Sodium 478 13.8.2 Tamarind Seed Polysaccharide-alginate Mucoadhesive Microspheres Containing Gliclazide 480 13.8.3 Tamarind Seed Polysaccharide-alginate Mucoadhesive Beads Containing Metformin HCl 481 13.7.4 Tamarind Seed Polysaccharide-pectinate Mucoadhesive Beads Containing Metformin HCl 481 13.8.5 Tamarind Seed Polysaccharide-gellan Mucoadhesive Beads Containing Metformin HCl 483 13.9 Covalent Crosslinking 485 13.9.1 Chitosan-Tamarind Seed Polysaccharide Interpenetrating Polymeric Network Microparticles Containing Aceclofenac 485 13.10 Combined Ionotropic-Gelation/Covalent Crosslinking 488 13.10.1 Interpenetrated Polymer Network Microbeads Containing Diltiazem-Indion 254® Complex made of Tamarind Seed Polysaccharide and Sodium Alginate 488 13.11 By Ionotropic Emulsion-gelation 489 13.11.1 Oil-entrapped Tamarind Seed Polysaccharide- Alginate Blend Floating Beads Containing Diclofenac Sodium 489 13.12 Conclusion 490 References 490 Index 493

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Book SynopsisStrong bonds form stronger materials. For this reason, the investigation on thermal degradation of materials is a significantly important area in research and development activities. The analysis of thermal stability can be used to assess the behavior of materials in the aggressive environmental conditions, which in turn provides valuable information about the service life span of the materiel. Unlike other books published so far that have focused on either the fundamentals of thermal analysis or the degradation pattern of the materials, this book is specifically on the mechanism of degradation of materials. The mechanism of rapturing of chemical bonds as a result of exposure to high-temperature environment is difficult to study and resulting mechanistic pathway hard to establish. Limited information is available on this subject in the published literatures and difficult to excavate. Chapters in this book are contributed by the experts working on thermal degradation and analysTable of ContentsPreface xv Part 1: Degradation of Polymers 1 Thermal Stability of Organic Monolayers Covalently Grafted on Silicon Surfaces 3Florent Yang, Philippe Allongue, Francois Ozanam and Jean-Noel Chazalviel 1.1 Introduction 3 1.2 Alkyl-Grafted Surfaces 8 1.3 Alkoxy-Grafted Surfaces 15 1.4 Surfaces Grafted with Aryl Groups 19 1.5 Surfaces Grafted via Si–N Linkages 22 1.6 Summary 27 References 30 2 Thermal Analysis to Discriminate the Stability of Biomedical Ultrahigh-Molecular-Weight Polyethylenes Formulations 39Maria Jose Martinez-Morlanes and Francisco Javier Medel 2.1 Introduction 39 2.2 Suitability of TGA Analysis for the Study of Stability of Medical Polyethylene 42 2.3 Activation Energies of Degradation Processes in the Thermal Decomposition of UHMWPE 56 References 58 3 Materials Obtained by Solid-State Thermal Decomposition of Coordination Compounds and Metal–Organic Coordination Polymers 63Oana Carp 3.1 Introduction 63 3.2 Coordination Compounds and Metal–Organic Coordination Polymers as Precursors of Oxides 65 3.3 Coordination Compounds and Metal–Organic Coordination Polymers as Precursors of Sulfides 72 3.4 Coordination Compounds as Precursors of Composites 74 3.5 Coordination Compounds and Metal–Organic Coordination Polymers as Precursors of New Complexes 74 3.6 Coordination Compounds and Metal–Organic Coordination Polymers as Precursor of Metals 75 3.7 Coordination Compounds as Precursor of Nitrides 76 3.8 Other Materials 77 3.9 Conclusions 77 References 78 4 Methods for Limiting the Flammability of High-Density Polyethylene with Magnesium Hydroxide 85Joanna Lenża, Maria Sozańska and Henryk Rydarowski 4.1 Introduction 85 4.2 Experimental Part 88 4.3 Results and Discussion 91 4.4 Conclusions 99 References 100 5 Thermal Analysis in the Study of Polymer (Bio)-degradation 103Joanna Rydz, Marta Musioł and Henryk Janeczek 5.1 Introduction 103 5.2 Differential Scanning Calorimetry 105 5.3 Dynamic Mechanical Analysis 112 5.4 Thermogravimetric Analysis 115 5.5 Conclusions 120 Acknowledgments 121 References 121 6 Thermal and Oxidative Degradation Behavior of Polymers and Nanocomposites 127Gauri Ramasubramanian and Samy Madbouly 6.1 Introduction 127 6.2 Thermal Degradation 131 6.3 Chemical and Oxidative Degradation 137 6.4 Photo-oxidation 143 6.5 Environmental and Biological Degradation 148 6.6 Degradation of Polymer Nanocomposites 154 6.7 Conclusions 162 References 162 7 Thermal Degradation Effects on Polyurethanes and Their Nanocomposites 165Ivan Navarro-Baena, Marina P. Arrieta, Alicia Mujica-Garcia, Valentina Sessini, Jose M. Kenny and Laura Peponi 7.1 Introduction 165 7.2 Main Techniques Used for Studying the Thermal Degradation Process 167 7.3 Degradation Mechanisms 169 7.4 Chemical Approaches Used to Improve the Thermal Stability of PU 171 7.5 Thermal Degradation of PU Based on Natural Sources 172 7.6 Nanocomposites 174 7.7 PU Electrospun Fibers 181 7.8 Conclusions 184 References 184 8 Controllable Thermal Degradation of Thermosetting Epoxy Resins 191Zhonggang Wang 8.1 Introduction 191 8.2 Ester-, Carbamate-, and Carbonate-Linked Reworkable Epoxy Resins 193 8.3 Ether-Linked Reworkable Epoxy Resins 195 8.4 Phosphate- and Phosphite-Linked Reworkable Epoxy Resins 196 8.5 Sulfite-Linked Reworkable Epoxy Resins 204 References 207 9 Mechanism of Thermal Degradation of Vinylidene Chloride Barrier Polymers 209Bob A. Howell 9.1 Introduction 209 9.2 Discussion 210 9.3 Conclusions 218 References 219 10 Role of Mass Spectrometry in the Elucidation of Thermal Degradation Mechanisms in Polymeric Materials 221Paola Rizzarelli and Sabrina Carroccio 10.1 Introduction 221 10.2 Thermogravimetry-Mass Spectrometry (TG-MS) 224 10.3 Gas Chromatography-Mass Spectrometry (GC-MS) and Pyrolysis-Gas Chromatography/Mass Spectrometry (Py-GC/MS) 228 10.4 Direct Pyrolysis Mass Spectrometry (DPMS) 237 10.5 Matrix-Assisted Laser Desorption Ionisation Mass Spectrometry (MALDI MS) 242 10.6 Other Mass Spectrometric Techniques 246 10.7 Conclusions 249 References 251 11 The Mechanism of Poly(styrene) Degradation 259Bob A. Howell 11.1 Introduction 259 11.2 Discussion 260 11.3 Conclusions 266 References 266 12 The Use of Thermal Volatilization Analysis of Polylactic Acid and Its Blends with Starch 269Derval dos Santos Rosa, Claudio Roberto Passatore, and Jose Ricardo Nunes de Macedo 12.1 Introduction 269 12.2 Use of TVA 271 12.3 TVA as an Analytic Technique 272 12.4 TVA-PLA Investigation 274 12.5 TVA – Thermoplastic Starch 276 12.6 Analyses of TVA – PLA and Their Mixtures with Thermoplastic Starch 280 12.7 Conclusions 282 Acknowledgments 282 References 282 Part 2: Degradation of Other Materials 13 Reaction Mechanisms in Thermal Analysis of Amazon Oilseeds 287Orquidea Vasconcelos dos Santos, Carlos Emmerson and Suzana Caetano da Silva Lannes 13.1 Introduction 287 13.2 Oxidative Stability 297 References 299 14 Thermal Degradation of Cellulose and Cellulosic Substrates 301Jenny Alongi and Giulio Malucelli 14.1 Introduction 301 14.2 Thermal and Thermo-oxidative Degradation of Cellulose 302 14.3 Factors Affecting Cellulose Thermal Degradation: Charring/Volatilisation Competition 318 14.4 Conclusions 329 References 330 15 Thermal Decomposition Behavior of Sodium Alkoxides of Relevance to Fast Reactor Technology 333K. Chandran, M. Kamruddin, S. Anthonysamy and V. Ganesan 15.1 Introduction 333 15.2 Preparation of Sodium Alkoxides 334 15.3 Characterization of Sodium Alkoxides 339 15.4 Thermal Decomposition of Sodium Alkoxides 348 15.5 Kinetic Analysis 364 References 390 16 Thermal Degradation and Morphological Characteristics of Bone Products 393F. Miculescu, A. Maidaniuc, G.E. Stan, M. Miculescu, S.I. Voicu, L.T.Ciocan 16.1 Introduction and Objectives 393 16.2 Short Overview on the Thermal Analysis Experimental Methods 396 16.3 Morpho-structural Changes Induced by the Thermal Treatments Applied to Hard Tissues. Bone Degradation Mechanism 400 16.4 Conclusions 408 References 408 17 Processes and Mechanisms in Hydrothermal Degradation of Waste Electric and Electronic Equipment 411Yu Luling, He Wenzhi and Li Guangming 17.1 Introduction 411 17.2 Application of Hydrothermal Degradation in Treatment of WEEE 414 17.3 Mechanism of Hydrothermal Degradation for Treatment of WEEE 418 17.4 Conclusion 431 Acknowledgements 431 References 431 18 Heat Transfer Mechanism and Thermomechanical Analysis of Masonry Structures (Mortars and Bricks) Subjected to High Temperatures 437M.E. Macia Torregrosa and J. Camacho Diez 18.1 Introduction: State of the Art 437 18.2 Heat Transfer Mechanisms through a Masonry Element under Load 442 18.3 Influence of High Temperatures on the Structural Behavior of a Masonry Element 444 18.4 Factors Involved in the Behavior of the Masonry Subjected to High Temperatures 444 18.5 Properties of the Ceramic Pieces 449 18.6 Properties of the Mortar 456 References 463 19 Application of Vibrational Spectroscopy to Elucidate Protein Conformational Changes Promoted by Thermal Treatment in Muscle-Based Food 467A.M. Herrero, P. Carmona, F. Jimenez-Colmenero and C. Ruiz-Capillas 19.1 Introduction 467 19.2 Protein Structure 468 19.3 Muscle-Based Food Proteins: Thermal treatment 468 19.4 Vibrational Spectroscopic Methods and Protein Structure 469 19.5 Vibrational Spectroscopy to Elucidate Structural Changes Induced by Thermal Treatment in Muscle Foods 473 19.6 Conclusions 479 Acknowledgements 479 References 480 20 Thermal Activation of Layered Hydroxide-Based Catalysts 483Milica Hadnadjev-Kostic, Tatjana Vulic and Radmila Marinkovic-Neducin 20.1 Introduction 483 20.2 LDH General Properties 484 20.3 Thermal Activation of LDH-Based Catalysts – Thermal Decomposition Pathway from LDH to Mixed Oxides 490 20.4 Properties of Thermally Activated LDHs 495 20.5 Application of LDH-Based Materials 501 20.6 Synthesis Methods of Ti-Containing LDH-Based Materials 502 20.7 Synthesis Methods for the Association of TiO2 and LDH-Based Catalysts 502 20.8 Conclusions and Perspectives 509 References 510 21 Thermal Decomposition of Natural Fibers: Kinetics and Degradation Mechanisms 515Matheus Poletto, Heitor L. Ornaghi Junior and Ademir J. Zattera 21.1 Introduction 515 21.2 Theoretical Background 516 21.3 Chemical Composition of the Natural Fibers 522 21.4 XRD Analysis Applied to Natural Fibers 524 21.5 Thermogravimetric Analysis of Natural Fibers 527 21.6 Kinetic Degradation and Reaction Mechanisms in the Solid State of Natural Fibers 532 21.7 Conclusion 541 References 541 22 On the Kinetic Mechanism of Non-isothermal Degradation of Solids 547Lyubomir T. Vlaev, Velyana G. Georgieva, and Mariana P. Tavlieva 22.1 Introduction 547 22.2 Mathematical Background in the Thermogravimetry 549 22.3 Kinetic Mechanism of the Thermal Degradation of CaC2O4・H2O 561 22.4 Kinetic Mechanism of the Thermal Degradation of Chitin 567 22.5 Kinetic Mechanism of the Thermal Degradation of Rice Husks 571 22.6 Conclusions 574 Acknowledgments 575 References 575 Index 579

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Book SynopsisDescribes the most common imaging technologies and their diagnostic applications so that pharmacists and other health professionals, as well as imaging researchers, can understand and interpret medical imaging science This book guides pharmacists and other health professionals and researchers to understand and interpret medical imaging. Divided into two sections, it covers both fundamental principles and clinical applications. It describes the most common imaging technologies and their use to diagnose diseases. In addition, the authors introduce the emerging role of molecular imaging including PET in the diagnosis of cancer and to assess the effectiveness of cancer treatments. The book features many illustrations and discusses many patient case examples. Medical Imaging for Health Professionals: Technologies and Clinical Applications offers in-depth chapters explaining the basic principles of: X-Ray, CT, and Mammography Technology; Nuclear Medicine ImaginTable of ContentsPreface xxi Acknowledgments xxiii 1 Introduction to Medical Imaging 2Raymond M. Reilly 1.1 Medical Imaging Procedures 2 1.2 Radiation Doses from Medical Imaging Procedures 4 1.3 Summary 8 References 9 2 X‐Ray, CT, and Mammography Technology 11Raymond M. Reilly 2.1 Introduction 11 2.2 X‐Rays 11 2.3 Radiography 15 2.4 Computed Tomography 16 2.5 Mammography 23 2.6 Summary 25 References 26 Additional Reading 26 3 Nuclear Medicine Imaging Technology 27Raymond M. Reilly 3.1 Introduction 27 3.2 Scintillation Detectors 28 3.3 The Gamma Camera 31 3.4 Single Photon Emission Computed Tomography 37 3.5 Positron Emission Tomography 38 3.6 Multimodality Imaging – SPECT/CT, PET/CT, and PET/MR 41 3.7 Summary 42 References 42 4 Radionuclide Production and Radiopharmaceuticals 46Noor Al‐saden and Raymond M. Reilly 4.1 Introduction 46 4.2 Production of Radionuclides 47 4.3 Radiopharmaceutical Preparation and Supply 57 4.4 Radiopharmaceuticals for Cardiac Imaging 58 4.5 Radiopharmaceuticals for Tumor Imaging 63 4.6 Radiopharmaceuticals for Brain/CNS Imaging 70 4.7 Radiopharmaceuticals for Renal Imaging 74 4.8 Radiopharmaceuticals for Hepatobiliary Imaging 76 4.9 Radiopharmaceuticals for Bone Imaging 77 4.10 Radiopharmaceuticals for Lung Imaging 79 4.11 Radiopharmaceuticals for Thyroid/Parathyroid Imaging 80 4.12 Radiopharmaceuticals for Imaging Infection/Inflammation 83 4.14 Summary 85 Reference 85 Additional Reading 85 5 Magnetic Resonance Imaging (MRI) Technology 87Raymond M. Reilly 5.1 Introduction 87 5.2 Principles of MRI 87 5.3 Components of the MRI System 98 5.4 MRI Safety Considerations 100 5.5 MRI Contrast Agents 102 5.6 Summary 104 References 105 Additional Reading 105 6 Ultrasound Imaging Technology 107Raymond M. Reilly 6.1 Principles of Ultrasound Imaging 107 6.2 Doppler US 111 6.3 US Contrast Agents 112 6.4 Summary 113 References 113 Additional Reading 113 7 Cardiac Imaging 117Laura Jimenez‐Juan, Shaheeda Ahmed, and Katherine Zukotynski 7.1 Introduction 117 7.2 Cardiovascular Magnetic Resonance Imaging (CMR) 117 7.3 Cardiovascular MRI Techniques 118 7.4 Echocardiography 129 7.5 Nuclear Cardiology 133 7.6 Summary 140 References 140 8 Lung Imaging 146Anastasia Oikonomou 8.1 Introduction 146 8.2 Chest Radiograph – Projections 146 8.3 Normal Findings in a Chest X‐Ray 148 8.4 Normal Findings in a Chest CT 155 8.5 Pneumonia 158 8.6 Tuberculosis 159 8.7 Chronic Obstructive Pulmonary Disease 163 8.8 Pleural Effusion 167 8.9 Pneumothorax 169 8.10 Pulmonary Embolism 170 8.11 Solitary Pulmonary Nodule 172 8.12 Lung Cancer 176 8.13 Summary 178 References 180 9 Breast Imaging 186Hemi Dua and Jagbir Khinda 9.1 Introduction 186 9.2 Risk Factors for Breast Cancer 186 9.3 Guidelines for Breast Cancer Screening 187 9.4 Breast Anatomy 189 9.5 Imaging Techniques 191 9.6 Mammography 191 9.7 Ultrasound Imaging 197 9.8 Breast MRI 198 9.9 PEM and Breast‐Specific Gamma Camera Imaging 202 9.10 Contrast‐Enhanced Spectral Mammography 202 9.11 The ABCs of Breast Imaging – Image Interpretation 203 9.12 BI‐RADS Assessment Categories 209 9.13 Image‐Guided Breast Intervention 209 9.14 Extramammary Staging 219 9.15 Breast Lymphoscintigraphy 220 9.16 Summary 220 References 220 10 Endocrine Gland Imaging 225Katerina Mastrocostas, Kim May Lam, Shereen Ezzat, and Sangeet Ghai 10.1 Introduction 225 10.2 The Thyroid Gland 225 10.3 Thyroid Hormone Diseases 227 10.4 Thyroid Cancer 240 10.5 The Parathyroid Glands 244 10.6 The Adrenal Glands 249 10.7 Mass Lesions of the Adrenal Cortex 250 10.8 Mass Lesions of the Adrenal Medulla 253 10.9 Other Neuroendocrine Diseases 255 10.10 Summary 259 Additional Reading 260 11 Abdominal Imaging 264Vivek Singh and Chirag Patel 11.1 Introduction 264 11.2 Surgical Sieve 265 11.3 Peritoneum/Mesentery 265 11.4 Acute Peritoneal Pathologies 266 11.5 Gastrointestinal Tract 270 11.6 Inflammatory Bowel Disease 279 11.7 Colorectal Adenocarcinoma 282 11.8 Hepatic System 287 11.9 Diffuse Hepatic Disease 289 11.10 Focal Hepatic Disease 292 11.11 Biliary Tract 300 11.12 Gallbladder 301 11.13 Bile Ducts 304 11.14 Pancreas 306 11.15 Spleen/Lymph Nodes 313 11.16 Summary 316 Reference 317 Additional Reading 317 12 Genitourinary Tract Imaging 320Sarah Johnson 12.1 Introduction 320 12.2 GU System Imaging Modalities 321 12.3 Evaluation of the Kidneys and Collecting Systems 328 12.4 Bladder and Urethra 343 12.5 Testicles 345 12.6 Prostate 348 12.7 Female Genitourinary Tract 350 12.8 Pediatric Genitourinary Tract 360 12.9 Summary 364 References 364 13 Imaging of the Head, Neck, Spine, and Brain 371Laila Alshafai, Eugene Yu, and Sylvain Houle 13.1 Introduction 371 13.2 Imaging the Skull and Brain 372 13.4 Imaging the Head and Neck 390 13.5 PET and SPECT Neuroimaging 396 13.6 Summary 401 References 401 14 Musculoskeletal Imaging 404Rakesh Mohankumar and Ali Naraghi 14.1 Introduction 404 14.2 Plain Radiography (X‐rays) 404 14.3 Computed Tomography 408 14.4 Magnetic Resonance Imaging 411 14.5 Ultrasound 413 14.6 Applications of Musculoskeletal Imaging 415 14.7 Summary 435 Additional Reading 435 15 Molecular Imaging with Positron Emission Tomography 439Ur Metser, Noam Tau, and Amit Singnurkar 15.1 Introduction 439 15.2 PET Probes Including 18F‐FDG 440 15.3 18F‐FDG PET in Oncology 442 15.4 18F‐FDG PET in Non‐Oncology Indications 453 15.5 Overview of Other PET Radiopharmaceuticals 460 15.6 Multimodal Imaging – PET/CT Versus PET/MR 468 15.7 Summary 470 References 470 Index 485

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Book SynopsisProvides practical guidance on pharmaceutical analysis, written by leading experts with extensive industry experience Analytical Testing for the Pharmaceutical GMP Laboratory presents a thorough overview of the pharmaceutical regulations, working processes, and drug development best practices used to maintain the quality and integrity of medicines. With a focus on smaller molecular weight drug substances and products, the book provides the knowledge necessary for establishing the pharmaceutical laboratory to support Quality Systems while maintaining compliance with Good Manufacturing Practices (GMP) regulations. Concise yet comprehensive chapters contain up-to-date coverage of drug regulations, pharmaceutical analysis methodologies, control strategies, testing development and validation, method transfer, electronic data documentation, and more. Each chapter includes a table of contents, definitions of acronyms, a reference list, and ample tables and figures. Addressing the principaTable of ContentsDedication ((Einstein quotation)) Preface About the Editor Biographies of Contributing Authors Editorial Notes Dedication Acknowledgments Chapter 1 – Drug Regulations and the Pharmaceutical Laboratories 1.1 Introduction 1.2 Food and Drug Administration: Role and its Regulations 1.2.1 Code of Federal Regulations 1.2.2 FDA Guidance Documents 1.2.3 FDA Manual of Policies and Procedures 1.3 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and its Role 1.3.1 ICH background 1.3.2 ICH Structure 1.3.3 ICH Organization 1.3.3.1 Steering Committee 1.3.3.2 Global Cooperation Group 1.3.3.3 MedDRA Management Board 1.3.3.4 Working Groups 1.3.3.5 Secretariat 1.3.3.6 Coordinators 1.3.4 ICH Topics 1.4 Pharmaceutical Analysis 1.4.1 Analytical Testing 1.4.2 Interaction Between the Analytical Development Department and Other Functional Areas 1.4.3 Drug Development Process 1.4.3.1 Toxicological Phase 1.4.3.2 Investigational New Drug 1.4.3.3 Clinical Phase 1.4.3.4 Registration Phase 1.4.3.5 New Drug Application 1.4.3.6 Post-Approval Phase References List of Abbreviations   Chapter 2 – Good Manufacturing Practices (GMPs) and the Quality Systems 2.1 Introduction to Good Manufacturing Practices 2.2 Objectives of GMPs 2.2.1 Definitions 2.2.2 Organization of 21 CFR Regulations 2.3 Personnel Qualifications and Responsibilities – Subpart B 2.3.1 Responsibilities of Quality Control Unit 2.3.2 Personnel Qualifications and Responsibilities 2.4 Equipment – Subpart D 2.4.1 Metrology Functions 2.4.2 Qualification Phases 2.5 Laboratory Controls – Subpart I 2.5.1 General Requirements 2.5.2 Testing and Release for Distribution 2.5.3 Stability Program 2.5.4 Retention Program 2.6 Records and Reports 2.7 Pharmaceutical Quality 2.7.1 Quality Manual 2.7.2 Quality Risk Management 2.7.3 Product Quality Review 2.7.4 Pharmaceutical Quality Systems References List of Abbreviations   Chapter 3 – Analytical Techniques Used in the GMP Laboratory 3.1 Introduction 3.2 Definitions 3.2.1 Raw Data and Analytical Data 3.2.2 Analyses 3.2.3 Analytical Documents 3.3 Basic Laboratory Procedures 3.3.1 Balances 3.3.2 Volumetric Glassware 3.3.3 Potentiometry (ion-selective electrode) and pH Test 3.3.4 The Density Test 3.3.5 The Friability Test 3.3.6 The Hardness Test 3.3.7 The Titration Test 3.3.8 The Karl Fischer Titration – Water Determination 3.3.9 Loss on Drying 3.3.10 Residue on Ignition/Sulfated Ash 3.3.11 Thermal Gravimetric Analysis 3.3.12 Differential Scanning Calorimetry 3.3.13 The Disintegration Test 3.3.14 Particulate Matter 3.3.15 Osmolality 3.4 Chromatography 3.4.1 High-Performance Liquid Chromatography 3.4.1.1 Normal Phase Separation Mode 3.4.1.2 Reversed-Phase Separation Mode 3.4.1.3 Other HPLC Separation Modes 3.4.2 Ultra-High Pressure Liquid Chromatography 3.4.3 Detectors of Liquid Chromatography 3.4.4 System Suitability Tests for Chromatographic Methods 3.4.5 Maintenance of HPLC and UHPLC 3.4.6 Gas Chromatography 3.4.6.1 Residual Solvents 3.4.6.2 Hyphenated Technologies 3.4.7 Thin Layer Chromatography 3.4.8 Bio-Pharmaceutical Separations 3.4.8.1 Capillary Zone Electrophoresis 3.4.8.2 Isoelectric focusing 3.4.8.3 Sodium dodecyl sulfate-Polyacrylamide Gel electrophoresis (SDS-Page) 3.5 Spectroscopic Sciences 3.5.1 Ultraviolet-Visible 3.5.2 Infrared Absorption 3.5.3 Mass Spectroscopy 3.5.4 Atomic Absorption, Inductively-Coupled Plasma, Inductively Coupled Plasma/Mass Spectrometry, and Inductively Coupled Plasma/Optical Emission Spectrometry 3.5.5 Nuclear Magnetic Resonance Spectroscopy 3.5.6 X-ray Absorption and X-ray Emission Spectrometry 3.6 Uniformity of Dosage Units 3.6.1 Weight Variation 3.6.2 Acceptance Criteria per USP <905> 3.7 Elemental Analysis 3.8 Appearance 3.9 Visual Inspection 3.10 Microbiological Testing 3.10.1 Microbial Limits 3.10.2 Sterility 3.10.3 Bacterial Endotoxin 3.10.4 Antimicrobial Effectiveness Testing 3.11 Summary References List of Abbreviations   Chapter 4 – Control Strategies for Pharmaceutical Development 4.1 Introduction 4.2 Quality by Design Concept 4.3 Risk Management 4.3.1. Risk Assessment 4.3.1.1. Risk identification 4.3.1.2. Risk assessment 4.3.2. Risk Control 4.4 Establishing Specifications 4.4.1. What is specification? 4.4.2. Typical tests included in the specification of a small molecule drug 4.4.1. Drug substance 4.4.2. Drug product 4.4.3. Typical tests included in the specification of biological drugs 4.4.3.1. Drug substance 4.4.3.2. Drug product 4.4.4. Considerations of setting acceptance criteria 4.4.4.1. Process capability 4.4.4.2. Impact of drug substance to drug product specification 4.4.4.3. Release vs. shelf life 4.5 Design of Experiments (DoE) 4.5.1 Common terms: 4.5.2 Conducting the study 4.5.3 Results interpretation 4.5.4 Summary 4.6 Common Statistical Analysis 4.6.1 Mean, standard deviation (SD) and relative standard deviation (RSD) 4.6.2 Confidence interval 4.6.3 Statistical Significance (T-test) 4.6.4 Outlier Detection 4.7 Summary References   Chapter 5 – Development and Validation of Analytical Procedures 5.1 Introduction 5.2 Method Development 5.2.1 Physical, Chemical, and Microbiological Procedures 5.3 Qualification, Validation, and Verification 5.3.1 Qualification 5.3.2 Validation 5.3.3 Verification 5.3.4 Frequency of Study 5.4 Validation Parameters 5.4.1 Accuracy 5.4.2 Precision 5.4.3 Specificity 5.4.4 Quantitation and Detection Limits 5.4.5 Linearity 5.4.6 Range 5.4.7 Robustness 5.4.8 Suitability System Testing 5.4.9 Sample Stability during Analysis 5.4.10 Tie the Pieces Together 5.5 Validation for Physical, Chemical, Biotechnological and Microbiological Procedures 5.6 Validation for In-process, Environmental, Release and Stability Procedures 5.6.1 In-Process Procedures 5.6.2 Environmental Procedures 5.6.3 Release and Stability Procedures 5.7 Other Procedures 5.7.1 Process Analytical Technology (PAT) 5.7.2 Parametric Release and Real-Time Release 5.8 Validation of Procedures in Continuous and Batch Manufacturing 5.9 Summary References List of Abbreviations   Chapter 6 – Transfer of Analytical Procedures 6.1 Introduction 6.2 Purpose of method transfer 6.3 Transfer options 6.3.1 Method Transfer Plan 6.3.2 Comparative Testing 6.3.3 Co-Validation 6.3.4 Extended Validation or Partial Validation 6.3.5 Transfer Waiver 6.4 Method Transfer Process 6.4.1 Preparation Phase 6.4.1.1 Select a Method Transfer Team 6.4.1.2 Method Transfer Package 6.4.2 Gap Analysis 6.4.2.1 Equipment Capabilities 6.4.2.2 Facilities Readiness 6.4.2.3 Analyst Qualifications 6.4.2.4 Materials used in the Transfer 6.4.3 Method Training Phase 6.4.3.1 Method Familiarization 6.4.3.2 Method Demonstration 6.4.4 Method Qualification Phase 6.5 Transfer Protocol 6.5.1 Content of a Transfer Protocol 6.5.2 Objectives/Scope 6.5.3 Roles and Responsibilities 6.5.3.1 Transferring Laboratory 6.5.3.2 Receiving Laboratory 6.5.4 Assessment of Receiving Lab 6.5.5 Materials, Facilities, and Instrumentation 6.5.6 Analyst Training 6.5.7 Qualification Procedure 6.5.8 Acceptance Criteria 6.5.9 Protocol Amendment and Deviation 6.6 Method Transfer Report 6.6.1 Objectives 6.6.2 Data Evaluation 6.6.3 Conclusion of Transfer Report 6.6.4 Analytical Transfer File 6.7 Related Documents 6.8 Handling Transfer Failures 6.9 Transfer to a Contract Lab 6.10 Transfer to an International Site 6.11 Summary References List of Abbreviations   Chapter 7 – Dissolution Testing in the Pharmaceutical Laboratory 7.1 Introduction 7.2 Regulatory and Compendial Role in Dissolution Testing 7.3 Theory 7.4 Equipment Operation and Sources of Error 7.5 Common Errors of Dissolution Apparatus 7.6 Dissolution Method Considerations 7.7 Method Development 7.8 Poorly Soluble Drugs 7.9 Setting Specifications 7.10 Harmonization 7.11 Method Validation 7.12 Validation of Product Performance Parameters 7.13 Validation of the Analytical finish 7.14 Method Transfer Considerations 7.15 Good Manufacturing Practices in the Dissolution Testing Laboratory 7.16 Summary 7.17 Resources References List of Abbreviations   Chapter 8 – Analytical Records and the Documentation System 8.1 Introduction 8.1.1 Types of Documents 8.2 GMP for Records and Reports–Subpart J 8.2.1 General Requirements 8.2.2 Equipment Cleaning and Use Log 8.2.3 Component, Drug Product Container, Closure, and Labeling Records 8.2.4 Master Production and Control Records 8.2.5 Batch Production and Control Records 8.2.6 Production Record Review 8.2.7 Laboratory Records 8.3 Keeping Good Records 8.3.1 Writing Good Procedures 8.3.2 Following Procedures 8.4 Raw Data Documentation 8.4.1 Data Recording Practices 8.4.2 Witness Responsibilities 8.4.3 Changes in Notebook 8.4.4 Recording Date and Time 8.4.5 Voiding and Restoring GMP Records 8.4.6 Computer Collected Data 8.4.7 Reporting Analytical Results 8.4.7.1 Decimal Places and Significant Figures 8.4.7.2 Mathematical Operations 8.4.7.3 Rounding Rules 8.4.7.4 Reporting Impurity Results 8.5 Sampling, Reagents, Standards, Reference standards 8.5.1 Samples 8.5.2 Reagents 8.5.3 Analytical Standards 8.5.4 Reference Standards 8.6 Drug Substance Analysis 8.7 Drug Product Analysis 8.8 Batch Release 8.8.1 Batch Packaging Record 8.8.2 Batch Processing Record 8.8.3 Distribution Record 8.9 Establishment of Specifications 8.9.1 Content of Specifications 8.9.2 Setting Specifications 8.9.3 Periodic Revisions 8.9.4 Test Procedures 8.10 Out-of-Specification Results 8.10.1 Lab Phase Investigation 8.10.1.1 Identifying an OOS Result 8.10.1.2 Laboratory Error 8.10.1.3 Determining Root Cause 8.10.1.4 Retesting 8.10.1.5 Outlier Test 8.10.1.6 Averaging Results 8.10.1.7 Field Alert Report 8.10.2 Full Scale Investigation 8.11 Compendial Testing 8.11.1 Validation and Verification of Compendial Procedures 8.11.2 USP Reference Standards 8.12 Standard Operating Procedures 8.12.1 Control of SOPs 8.12.2 Format of SOPs 8.12.3 Flow of documents 8.13 Analytical Documents 8.13.1 Hierarchy of Documentation System 8.13.2 Analytical Protocols 8.13.3 Analytical Reports 8.13.4 Annual Product Review 8.13.5 Change of documentation 8.14 Quality Assurance 8.14.1 Six Quality Systems and Supporting Programs 8.14.2 Quality System Performance 8.14.3 Lifecycle Management Approach for Analytical Procedures 8.14.4 Audit and Inspection Program 8.15 Summary References List of Abbreviations   Chapter 9 – The Stability Program 9.1. Introduction 9.2. Regulatory Requirement for Stability Testing 9.3. Types of Stability Studies 9.3.1. Stability Studies of Materials Used in Clinical Development 9.3.2. Stability Studies of an Active Pharmaceutical Ingredient (API) or Drug Substance (DS) 9.3.3. Stability Studies to Support Formulation Development 9.3.4. Stability Studies to Support Drug Product (DP) Registration 9.3.5. Stability Studies to Support Marketed Products 9.3.6. Bulk Stability 9.3.7. In-Process Testing 9.3.8. In-Use Testing 9.3.9. Stability Studies to Support Excursions 9.4. Stability Program 9.4.1. Fundamental Principle of Stability 9.4.2. Specifications 9.5. Stability Chambers 9.6. Stability Sample Management 9.6.1. Study Start Date 9.6.2. Sample Pull Dates 9.6.3. Study End Date 9.6.4. Sample Inventory 9.7. Stability Protocol 9.7.1. Deviation of Stability Protocol 9.7.2. Study Cancellation 9.7.3. Reduce Testing with Bracketing and Matrixing 9.8. Stability Report 9.9. Annual Product Review (APR) 9.10. Summary References List of Abbreviations   Chapter 10 – Laboratory Information Management System (LIMS) and Electronic Data 10 Introduction 10.1 Analytica Data to Support Quality decisions 10.2 Quality System 10.3 Metrics in Quality Management 10.4 Material Management 10.5 Product Release 10.6 Stability Studies 10.7 Cleaning Validation – Contamination Control 10.8 Equipment Management (Metrology) 10.9 Laboratory Operations 10.10 Automation of Risk Management 10.11 Automated Training Management 10.12 SOPs and Document Management 10.13 Audit Management and Compliance 10.14 Corrective and Preventive Actions (CAPA) 10.15 Change Management 10.16 Computer Systems Validation 10.17 Data Integrity – Regulatory Evolution 10.18 Data Integrity 10.19 Quality Data 10.20 Benefits of Computerized Systems 10.21 Big Data References List of Abbreviations Index

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Book SynopsisPromoting a continued and much-needed renaissance in biopharmaceutical manufacturing, this book covers the different strategies and assembles top-tier technology experts to address the challenges of antibody purification. Updates existing topics and adds new ones that include purification of antibodies produced in novel production systems, novel separation technologies, novel antibody formats and alternative scaffolds, and strategies for ton-scale manufacturing Presents new and updated discussions of different purification technologies, focusing on how they can address the capacity crunch in antibody purification Emphasizes antibodies and innovative chromatography methods for processingTable of ContentsPreface xxiii List of Contributors xxvii 1 Downstream Processing of Monoclonal Antibodies: Current Practices and Future Opportunities 1Brian Kelley 1.1 Introduction 1 1.2 A Brief History of Current Good Manufacturing Process mAb and Intravenous Immunoglobulin Purification 2 1.3 Current Approaches in Purification Process Development: Impact of Platform Processes 4 1.4 Typical Unit Operations and Processing Alternatives 7 1.5 VLS Processes: Ton‐Scale Production and Beyond 10 1.6 Process Validation 12 1.7 Product Life Cycle Management 13 1.8 Future Opportunities 16 1.9 Conclusions 18 Acknowledgments 19 References 19 2 The Development of Antibody Purification Technologies 23John Curling 2.1 Introduction 23 2.2 Purification of Antibodies by Chromatography Before Protein A 25 2.3 Antibody Purification After 1975 28 2.4 Additional Technologies for Antibody Purification 31 2.5 Purification of mAbs Approved in North America and Europe 34 2.6 Current Antibody Process Technology Developments 40 Acknowledgments 45 References 46 3 Harvest and Recovery of Monoclonal Antibodies: Cell Removal and Clarification 55Abhinav A. Shukla and Eric Suda 3.1 Introduction 55 3.2 Centrifugation 59 3.3 Microfiltration 62 3.4 Depth Filtration 67 3.5 Flocculation 70 3.6 Absolute Filtration 71 3.7 Expanded Bed Adsorption Chromatography 73 3.8 Harvesting in Single‐Use Manufacturing 74 3.9 Comparison of Harvest and Clarification Unit Operations 74 References 76 4 Next‐Generation Clarification Technologies for the Downstream Processing of Antibodies 81Nripen Singh and Srinivas Chollangi 4.1 Introduction 81 4.2 Impurity Profiles in Cell Cultures 83 4.3 Precipitation 84 4.4 Affinity Precipitation 89 4.5 Flocculation 90 4.6 Toxicity of Flocculants and Precipitants and Their Residual Clearance 96 4.7 Depth Filtration 97 4.8 Considerations for the Implementation of New Clarification Technologies 102 4.9 Conclusions and Future Perspectives 103 Acknowledgments 104 References 104 5 Protein A‐Based Affinity Chromatography 113Suresh Vunnum, Ganesh Vedantham and Brian Hubbard 5.1 Introduction 113 5.2 Properties of Protein A and Commercially Available Protein A Resins 114 5.3 Protein A Chromatography Step Development 118 5.4 Additional Considerations During Development and Scale‐Up 123 5.5 Virus Removal/Inactivation 127 5.6 Validation and Robustness 128 5.7 Conclusions 129 Acknowledgment 130 References 130 6 Purification of Human Monoclonal Antibodies: Non‐Protein A Strategies 135Alahari Arunakumari and Jue Wang 6.1 Introduction 135 6.2 Integrated Process Design for Human Monoclonal Antibody Production 136 6.3 Purification Process Designs for HuMabs 136 6.4 Conclusions 149 Acknowledgments 151 References 152 7 Hydrophobic Interaction Chromatography for the Purification of Antibodies 155Judith Vajda and Egbert Muller 7.1 Introduction 155 7.2 HIC With mAbs 156 7.3 HIC with Membrane Adsorbers 173 7.4 Future Perspectives 174 References 175 8 Purification of Monoclonal Antibodies by Mixed‐Mode Chromatography 181Pete Gagnon 8.1 Introduction 181 8.2 A Brief History 182 8.3 Prerequisites for Industrial Implementation 183 8.4 Mechanisms, Screening, and Method Development 185 8.5 Capture Applications 192 8.6 Polishing Applications 193 8.7 Sequential Capture/Polishing Applications 193 8.8 Future Prospects 193 Acknowledgments 194 References 194 9 Advances in Technology and Process Development for Industrial‐Scale Monoclonal Antibody Purification 199Nuno Fontes and Robert Van Reis 9.1 Introduction 199 9.2 Affinity Purification Platform 200 9.3 Advances in the Purification of mAbs by CEX Chromatography 201 9.4 High‐Performance Tangential Flow Filtration 209 9.5 A New Nonaffinity Platform 211 References 213 10 Alternatives to Packed‐Bed Chromatography for Antibody Extraction and Purification 215Jorg Thommes, Richard M. Twyman and Uwe Gottschalk 10.1 Introduction 215 10.2 Increasing the Selectivity of Harvest Procedures: Flocculation and Filter Aids 216 10.3 Solutions for Antibody Extraction, Concentration, and Purification 218 10.4 Antibody Purification and Formulation Without Chromatography 220 10.5 Membrane Adsorbers 223 10.6 Conclusions 225 References 226 11 Process‐Scale Precipitation of Impurities in Mammalian Cell Culture Broth 233Judy Glynn 11.1 Introduction 233 11.2 Precipitation of DNA and Protein—Other Applications 235 11.3 A Comprehensive Evaluation of Precipitants for the Removal of Impurities 236 11.4 Industrial‐Scale Precipitation 241 11.5 Cost of Goods Comparison 243 11.6 Summary 244 Acknowledgments 244 References 244 12 Charged Ultrafiltration and Microfiltration Membranes for Antibody Purification 247Mark R. Etzel and Abhiram Arunkumar 12.1 Introduction 247 12.2 Charged UF Membranes 248 12.3 Concentration Polarization and Permeate Flux 248 12.4 Stagnant Film Model 249 12.5 Sieving Coefficient 250 12.6 Mass Transfer Coefficient 251 12.7 Mass Balance Models 251 12.8 Scale‐Up Strategies and the Constant Wall Concentration (Cw) Approach 253 12.9 Membrane Cascades 255 12.10 Protein Fractionation Using Charged UF Membranes 256 12.11 Case Study 257 12.12 Charged MF Membranes 259 12.13 Virus Clearance 260 12.14 Salt Tolerance 261 12.15 Conclusions 264 Acknowledgments 264 References 264 13 Disposable Prepacked‐Bed Chromatography for Downstream Purification: Form, Fit, Function, and Industry Adoption 269Stephen K. Tingley 13.1 Introduction 269 13.2 Development‐Scale Prepacked Column Applications 271 13.3 Process‐Scale Prepacked Column Applications 275 13.4 Basic Technical Datasets 278 13.5 Independent Industry Assessments of “Fit for Purpose” 285 13.6 Case Study 1: Cation‐Exchange Polishing Chromatography 285 13.7 Case Study 2: Prepacked Columns for Pilot‐/Large‐Scale Bioprocessing 287 13.8 Prepacked Columns—Fit 292 13.9 The Economics of Prepacked Column Technologies 295 13.10 The Implementation of Disposable Prepacked Columns 297 13.11 Conclusions 300 References 301 14 Integrated Polishing Steps for Monoclonal Antibody Purification 303Sanchayita Ghose, Mi Jin, Jia Liu, John Hickey and Steven Lee 14.1 Introduction 303 14.2 Polishing Steps for Antibody Purification 304 14.3 Integration of Polishing Steps 316 14.4 Conclusions 320 Acknowledgment 320 References 320 15 Orthogonal Virus Clearance Applications in Monoclonal Antibody Production 325Joe X. Zhou 15.1 Introduction 325 15.2 Model Viruses and Virus Assays 326 15.3 Virus Clearance Strategies at Different Development Stages 328 15.4 Orthogonal Virus Clearance During mAb Production 328 15.5 Conclusions and Future Perspectives 338 Acknowledgments 339 References 339 16 Development of a Platform Process for the Purification of Therapeutic Monoclonal Antibodies 343Yuling Li, Min Zhu, Haibin Luo and Justin R. Weaver 16.1 Introduction 343 16.2 Chromatography Steps in the Platform Process 345 16.3 Virus Inactivation 352 16.4 UF/DF Platform Considerations 352 16.5 Platform Development: Virus Filtration and Bulk Fill 354 16.6 Addressing Future Challenges in Downstream Processing 356 16.7 Representative Platform Processes 356 16.8 Developing a Virus Clearance Database Using a Platform Process 359 16.9 Summary 361 References 361 17 The Evolution of Platform Technologies for the Downstream Processing of Antibodies 365Lee Allen 17.1 Introduction 365 17.2 The Definition of a Platform Purification Process 366 17.3 The Dominant Process Design 367 17.4 The Evolution of Unit Operations 372 17.5 Adapting the Platform Process for Product‐Specific Issues 382 17.6 Future Perspectives—Future Evolutionary Pathways 382 17.7 Concluding Remarks 383 Acknowledgments 384 References 384 18 Countercurrent Chromatography for the Purification of Monoclonal Antibodies, Bispecific Antibodies, and Antibody–Drug Conjugates 391Thomas Muller‐Spath and Massimo Morbidelli 18.1 Introduction 391 18.2 Chromatography to Reduce Product Heterogeneity 392 18.3 Definition of Performance Parameters 394 18.4 Gradient Chromatography for Biomolecules 394 18.5 Continuous and Countercurrent Chromatography 395 18.6 Multicolumn Countercurrent Solvent Gradient Purification 397 18.7 Scalability of Multicolumn Countercurrent Chromatography 403 18.8 Online Process Monitoring for Multicolumn Countercurrent Chromatography 404 18.9 Outlook 405 References 405 19 The Evolution of Continuous Chromatography: From Bulk Chemicals to Biopharma 409Marc Bisschops 19.1 Introduction 409 19.2 Continuous Chromatography in Traditional Process Industries 410 19.3 Continuous Chromatography in the Biopharmaceutical Industry 413 19.4 Advantages of Continuous Chromatography 420 19.5 Implementation Aspects of Continuous Chromatography 422 19.6 Regulatory Aspects 424 19.7 Conclusions 426 References 427 20 Accelerated Seamless Antibody Purification: Simplicity is Key 431Benoit Mothes 20.1 Introduction 431 20.2 Accelerated Seamless Antibody Purification 432 20.3 Advantages of the ASAP Process 437 20.4 Scaling Up the ASAP Process 438 20.5 New Perspectives 440 20.6 Conclusion 442 Acknowledgments 442 Suggested Reading 443 21 Process Economic Drivers in Industrial Monoclonal Antibody Manufacture 445Suzanne S. Farid 21.1 Introduction 445 21.2 Challenges When Striving for the Cost‐Effective Manufacture of mAbs 446 21.3 Cost Definitions and Benchmark Values 448 21.4 Economies of Scale 450 21.5 Overall Process Economic Drivers 453 21.6 DSP Drivers At High Titers 457 21.7 Process Economic Trade‐Offs for Downstream Process Bottlenecks 459 21.8 Summary and Outlook 461 References 462 22 Design and Optimization of Manufacturing 467Andrew Sinclair 22.1 Introduction 467 22.2 Process Design and Optimization 468 22.3 Modeling Approaches 470 22.4 Process Modeling in Practice 481 22.5 Impact of the Process on the Facility 491 Acknowledgments 492 References 492 23 Smart Design for an Efficient Facility With a Validated Disposable System 495Joe X. Zhou, Jason Li, Michael Cui and Haojun Chen 23.1 Design and Optimization of a Manufacturing Facility 495 23.2 Validation of a Disposable System 507 23.3 Conclusion 512 Acknowledgments 512 References 512 24 High‐Throughput Screening and Modeling Technologies for Process Development in Antibody Purification 515Tobias Hahn, Thiemo Huuk and Jurgen Hubbuch 24.1 Introduction 515 24.2 Adsorption Isotherms 516 24.3 Batch Chromatography 519 24.4 Column Chromatography 524 References 532 25 Downstream Processing of Monoclonal Antibody Fragments 537Mariangela Spitali 25.1 Introduction 537 25.2 Production of Antibody Fragments for Therapeutic Use 538 25.3 Downstream Processing 539 25.4 Improving the Pharmacological Characteristics of Antibody Fragments 552 25.5 Conclusions 553 Acknowledgments 555 References 555 26 Downstream Processing of Fc Fusion Proteins, Bispecific Antibodies, and Antibody–Drug Conjugates 559Abhinav A. Shukla and Carnley L. Norman 26.1 Introduction 559 26.2 Biochemical Properties 562 26.3 Purification From Mammalian Expression Systems 576 26.4 Purification From Microbial Production Systems 585 26.5 Future Innovations 587 Acknowledgment 589 References 589 27 Manufacturing Concepts for Antibody–Drug Conjugates 595Thomas Rohrer 27.1 Introduction 595 27.2 Targeting Components 596 27.3 Cytotoxic Drugs 600 27.4 Chemically Labile Linkers 602 27.5 General Process Overview 602 27.6 Facility Design and Supporting Technology 604 27.7 Single‐Use Equipment 607 27.8 Manufacturing ADCs 608 27.9 Analytical Support for ADC Manufacturing 609 27.10 Raw Materials Supply Chain 611 27.11 Conclusion 611 Acknowledgments 613 References 613 28 Purification of IgM and IgA 615Charlotte Cabanne and Xavier Santarelli 28.1 Introduction 615 28.2 Purification of IgM 616 28.3 Purification of IgA 621 28.4 Conclusion 623 Acknowledgments 623 References 623 29 Purification of Monoclonal Antibodies From Plants 631Zivko L. Nikolov, Jeffrey T. Regan, Lynn F. Dickey and Susan L. Woodard 29.1 Introduction 631 29.2 Antibody Production in Plants 632 29.3 Downstream Processing of Antibodies Produced in Plants 636 29.4 Purification of Plant‐Derived Antibodies Using Protein A Resins 641 29.5 Purification of Plant‐Derived Antibodies Using Non‐Protein A Media 642 29.6 Polishing Steps 643 29.7 Conclusions 645 Acknowledgment 645 References 645 30 Very‐Large‐Scale Production of Monoclonal Antibodies in Plants 655Johannes F. Buyel, Richard M. Twyman and Rainer Fischer 30.1 Introduction 655 30.2 Process Schemes for mAb Production in Plants 656 30.3 Scalable Process Models 661 30.4 Process Adaptation for VLS Requirements 663 30.5 Translation into VLS Applications 666 References 667 31 Trends in Formulation and Drug Delivery for Antibodies 673Hanns‐Christian Mahler and Roman Mathas 31.1 Introduction 673 31.2 Degradation Pathways 674 31.3 Physical Instability 674 31.4 Chemical Instability 676 31.5 How to Achieve Product Stability 678 31.6 Developability: Molecule Selection and Elimination of Degradation Hotspots 679 31.7 Stabilizing an Antibody in a Liquid Formulation 679 31.8 Stabilizing an Antibody by Drying 681 31.9 Choice of Adequate Primary Packaging 682 31.10 Minimizing Stress During Drug Product Processing 683 31.11 Implementation of a Formulation Strategy 685 31.12 Hot Topics 685 31.13 Summary 689 References 690 32 Antibody Purification: Drivers of Change 699Narahari Pujar, Duncan Low and Rhona O’Leary 32.1 Introduction 699 32.2 The Changing Regulatory Environment—Pharmaceutical Manufacturing for the 21st Century 701 32.3 Technology Drivers—Advances and Innovations 707 32.4 Economic Drivers 708 32.5 Conclusions 711 Acknowledgment 712 References 713 Index 717

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Book SynopsisFragmentation: Toward Accurate Calculations on Complex Molecular Systems introduces the reader to the broad array of fragmentation and embedding methods that are currently available or under development to facilitate accurate calculations on large, complex systems such as proteins, polymers, liquids and nanoparticles.Table of ContentsList of Contributors xi Preface xv 1 Explicitly Correlated Local Electron Correlation Methods 1Hans-Joachim Werner, Christoph Koppl, Qianli Ma, and Max Schwilk 1.1 Introduction 1 1.2 Benchmark Systems 3 1.3 Orbital-Invariant MP2 Theory 6 1.4 Principles of Local Correlation 9 1.5 Orbital Localization 10 1.6 Local Virtual Orbitals 12 1.7 Choice of Domains 24 1.8 Approximations for Distant Pairs 26 1.9 Local Coupled-Cluster Methods (LCCSD) 33 1.10 Triple Excitations 41 1.11 Local Explicitly Correlated Methods 41 1.12 Technical Aspects 53 1.13 Comparison of Local Correlation and Fragment Methods 57 1.14 Summary 60 Appendix A: The LCCSD Equations 63 Appendix B: Derivation of the Interaction Matrices 65 References 67 2 Density and Potential Functional Embedding: Theory and Practice 81 Kuang Yu, Caroline M. Krauter, Johannes M. Dieterich, and Emily A. Carter 2.1 Introduction 81 2.2 Theoretical Background 82 2.3 Density Functional Embedding Theory 84 2.4 Potential Functional Embedding Theory 101 2.5 Summary and Outlook 109 Acknowledgments 111 References 111 3 Modeling and Visualization for the Fragment Molecular Orbital Method with the Graphical User Interface FU, and Analyses of Protein–Ligand Binding 119 Dmitri G. Fedorov and Kazuo Kitaura 3.1 Introduction 119 3.2 Overview of FMO 120 3.3 Methodology 120 3.4 GUI Development 128 3.5 Conclusions 136 Acknowledgments 137 References 137 4 Molecules-in-Molecules Fragment-Based Method for the Accurate Evaluation of Vibrational and Chiroptical Spectra for Large Molecules 141K. V. Jovan Jose and Krishnan Raghavachari 4.1 Introduction 141 4.2 Computational Methods and Theory 142 4.3 Results and Discussion 146 4.4 Summary 157 4.5 Conclusions 158 Acknowledgments 159 References 159 5 Effective Fragment Molecular Orbital Method 165Casper Steinmann and Jan H. Jensen 5.1 Introduction 165 5.2 Effective Fragment Molecular Orbital Method 168 5.3 Summary and Future Developments 180 References 180 6 Effective Fragment Potential Method: Past, Present, and Future 183Lyudmila V. Slipchenko and Pradeep K. Gurunathan 6.1 Overview of the EFP Method 183 6.2 Milestones in the Development of the EFP Method 185 6.3 Present: Chemistry at Interfaces and Photobiology 192 6.4 Future Directions and Outlook 202 References 203 7 Nucleation Using the Effective Fragment Potential and Two-Level Parallelism 209Ajitha Devarajan, Alexander Gaenko, Mark S. Gordon, and Theresa L. Windus 7.1 Introduction 209 7.2 Methods 211 7.3 Results 217 7.4 Conclusions 223 Acknowledgments 223 References 224 8 Five Years of Density Matrix Embedding Theory 227Sebastian Wouters, Carlos A. Jime´nez-Hoyos, and Garnet K.L. Chan 8.1 Quantum Entanglement 227 8.2 Density Matrix Embedding Theory 228 8.3 Bath Orbitals from a Slater Determinant 230 8.4 The Embedding Hamiltonian 232 8.5 Self-Consistency 234 8.6 Green’s Functions 236 8.7 Overview of the Literature 237 8.8 The One-Band Hubbard Model on the Square Lattice 237 8.9 Dissociation of a Linear Hydrogen Chain 240 8.10 Summary 240 Acknowledgments 241 References 241 9 Ab initio Ice, Dry Ice, and Liquid Water 245So Hirata, Kandis Gilliard, Xiao He, Murat Kec¸eli, Jinjin Li, Michael A. Salim, Olaseni Sode, and Kiyoshi Yagi 9.1 Introduction 245 9.2 Computational Method 247 9.3 Case Studies 256 9.4 Concluding Remarks 284 9.5 Disclaimer 284 Acknowledgments 284 References 285 10 A Linear-Scaling Divide-and-Conquer Quantum Chemical Method for Open-Shell Systems and Excited States 297Takeshi Yoshikawa and Hiromi Nakai 10.1 Introduction 297 10.2 Theories for the Divide-and-Conquer Method 298 10.3 Assessment of the Divide-and-Conquer Method 307 10.4 Conclusion 318 References 319 11 MFCC-Based Fragmentation Methods for Biomolecules 323Jinfeng Liu, Tong Zhu, Xiao He, and John Z. H. Zhang 11.1 Introduction 323 11.2 Theory and Applications 324 11.3 Conclusion 345 Acknowledgments 346 References 346 Index 349

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Book SynopsisFUNDAMENTALS OF PORPHYRIN CHEMISTRY An indispensable and concise overview of the chemistry of porphyrins and related molecules In Fundamentals of Porphyrin Chemistry: A 21st Century Approach, a team of distinguished researchers delivers a compact and accessible introduction to the broad field of porphyrin chemistry. It discusses the basics of porphyrin synthesis and structure, as well as that of related molecules, and the current and future roles that porphyrins play in chemical transformations, materials design and synthesis, energy capture and transduction, human health, and the environment. This edited volume is a self-contained tutorial on concepts of critical importance to porphyrin chemistry and serves as the foundation for discussions about the applications of porphyrin-related compounds found in the second volume. This book contains: A thorough introduction to porphyrins, including their structure, nomenclature, naturally occurrTable of ContentsVolume 1 List of Contributors xiii 1 An Introduction to Porphyrins for the Twenty-First Century 1Penelope J. Brothers and Mathias O. Senge 1.1 Why Porphyrins? 1 1.2 The Natural World of Porphyrins 3 1.3 Brief History of Porphyrins 4 1.4 Practical Applications 5 1.5 Porphyrins for the Twenty-First Century 7 2 It's All in the Name 9Mathias O. Senge 2.1 Basic Structure and Nomenclature of Porphyrins 9 2.2 General Classes of Porphyrin Systems 11 2.3 Naturally Occurring Porphyrins 15 2.4 Special Aspects of Porphyrin Nomenclature 24 2.5 Porphyrin Stenography 30 3 Organic Synthesis and Reactivity of Porphyrins 37Mathias O. Senge and Alina Meindl 3.1 Introduction 37 3.2 Synthesis of meso-Substituted Porphyrins from Pyrrole Building Blocks 39 3.3 Synthesis of Β-Substituted Porphyrins from Pyrrole Building Blocks 52 3.4 Total Synthesis of Other Porphyrin(oid)s 57 3.5 Reactivity of Porphyrins 66 3.6 Transition-Metal-Catalyzed Reactions at the Porphyrin Macrocycle 79 3.7 Peripheral Functionalization 91 3.8 Examples of Classic and Contemporary Target Systems 103 4 Coordination Chemistry 141Penelope J. Brothers and Abhik Ghosh 4.1 Introduction 142 4.2 Overview of the Coordination Chemistry of Porphyrin and its Analogues 143 4.3 Metallation, Demetallation, and Characterization 152 4.4 Main Group Elements 158 4.5 Transition Metals 170 4.6 Lanthanides and Actinides 197 4.7 Organometallic Porphyrin Complexes 204 5 Phthalocyanines and Porphyrazines 241Ümit Isci and Fabienne Dumoulin 5.1 Phthalocyanines and Porphyrazines: Structures and Syntheses of Peculiar Members of the Porphyrin Family 241 5.2 Synthetic Methods and Strategies 247 5.3 Preparation and Characterization of Precursors 250 5.4 Formation of Macrocycles with Asymmetric Substitution Patterns 262 5.5 Lanthanide Double- and Multi-Decker Derivatives 272 5.6 Other Double- and Multi-Decker Derivatives 276 5.7 Reactions on Phthalocyanines and Porphyrazines 278 5.8 Conclusion 289 6 Oxidation and Reduction of Porphyrins 303Christian Brückner and Nisansala Hewage 6.1 Introduction: Scope and Limits of This Chapter 303 6.2 Reductions of Porphyrins 304 6.3 Oxidations of Porphyrins 311 6.4 Metal-Centered and Resonance-Stabilized Π-System Redox Events 330 7 Corroles and Contracted Porphyrins 349Daniel T. Gryko and Mariusz Tasior 7.1 Introduction 349 7.2 Corroles 349 7.3 Isocorroles 368 7.4 N-Confused Corroles 369 7.5 Heteroanalogues of Corroles 369 7.6 Norcorroles 373 7.7 Outlook 374 8 Heteroporphyrins and Carbaporphyrins 385Timothy D. Lash 8.1 Introduction 385 8.2 Mono- and Diheteroporphyrins (O, S, Se, Te) 386 8.3 Tetraoxa-, Tetrathia-, and Tetraselenaporphyrin Dications 397 8.4 Phosphaporphyrins 400 8.5 Carbaporphyrinoid Systems 402 8.6 True Carbaporphyrins 405 8.7 Azuliporphyrins 416 8.8 Neo-Confused Porphyrins 427 8.9 Benziporphyrins 427 8.10 Miscellaneous Carbaporphyrinoid Systems 434 8.11 Dicarbaporphyrinoids 439 8.12 Tetracarbaporphyrinoids 445 8.13 Related Porphyrin Analogues 447 8.14 Conclusions 448 9 Expanded Porphyrins 453Atsuhiro Osuka and Takayuki Tanaka 9.1 Historical Background 453 9.2 One-Pot Synthesis of Expanded Porphyrins 455 9.3 Size-Selective Syntheses of Expanded Porphyrins 461 9.4 Möbius Aromatic Expanded Porphyrins 466 9.5 Giant Expanded Porphyrins 471 References 473 Volume 2 List of Contributors xiii 10 Fundamentals of Porphyrin and Metalloporphyrin Stereochemistry 479W. Robert Scheidt 11 Porphyrins: Electronic Structure and Ultraviolet/Visible Absorption Spectroscopy 505M. Cather Simpson and Nina I. Novikova 12 Photoinduced Electron and Energy Transfer 587Eugeny A. Ermilov and Beate Röder 13 NMR Spectroscopy of Porphyrins 611Craig J. Medforth 14 Spin States in Iron Porphyrins 631Mikio Nakamura 15 Electrochemical Properties of Porphyrin-Type Complexes 661Tebello Nyokong 16 Heme Proteins -- Structure and Function 709Sk Amanullah, Chandradeep Ghosh, Somdatta Ghosh Dey and Abhishek Dey 17 Chlorophylls 743Hitoshi Tamiaki 18 Vitamin B12 and Cofactor F430 777Bernhard Kräutler and Bernhard M. Jaun Index 815

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Book SynopsisFully updated and revised, this new edition of a highly successful text provides students, clinicians, and academics with a thorough introduction to aging and mental health. The third edition of Aging and Mental Health is filled with new updates and features, including the impact of the DSM-5 on diagnosis and treatment of older adults. Like its predecessors, it uses case examples to introduce readers to the field of aging and mental health. It also provides both a synopsis of basic gerontology needed for clinical work with older adults and an analysis of several facets of aging well. Introductory chapters are followed by a series of chapters that describe the major theoretical models used to understand mental health and mental disorders among older adults. Following entries are devoted to the major forms of mental disorders in later life, with a focus on diagnosis, assessment, and treatment issues. Finally, the book focuses on the settings and contexts ofTrade Review"Segal, Qualls, and Smyer tackle the formidable problem of translating the entire DSM-5 into terms that are both specific to the aging population, but that also incorporate broader concepts in clinical psychology. ...The task of creating a syllabus is certainly made far more effi- cient with the availability of this text than would other- wise be the case. ... One might hope that the availability of this and other undergraduate and graduate texts in the field along with the growing population of older adults will continue to put pressure on departments in clinical psychology as well as in internship and postdoctoral sites to address the mental health needs of aging individuals. The authors continue to perform a great service to the profession by providing such a comprehensive and up-to-date volume." - Susan Krauss Whitbourne, PhD, Institute of Gerontology, University of Massachusetts, BostonTable of ContentsPreface xi Part I Introduction 1 1 Mental Health and Aging: An Introduction 3 2 Basic Gerontology for Working with Older Adults 21 3 Psychological Bases of Positive Mental Health 45 Part II Models of Mental Health in Later Life 65 Part II Introduction 65 4 Psychodynamic Model 69 with co-author Lacey Edwards 5 Cognitive‐Behavioral Model 89 6 Stress and Coping Model 117 7 Family Systems Model 145 Part II Summary and Commentary: Choosing Among Models of Mental Disorders in Later Life 165 Part III Introduction to Mental Disorders 171 Part III Introduction 171 8 Cognitive Impairment and Neurocognitive Disorders 175 9 Major Depression and Bipolar Disorder 207 10 Serious Mental Disorders in Older Adults: Schizophrenia and Other Late‐Life Psychoses 241 Stephen J. Bartels, Karen L. Fortuna, and John A. Naslund 11 Anxiety Disorders, Hoarding Disorder, and Post‐Traumatic Stress Disorder 281 12 Sexual Disorders, Sleep Disorders, and Chronic Pain 313 13 Substance‐Related Disorders and Personality Disorders 343 Part IV Settings and Contexts of Mental Health 375 Part IV Introduction 375 14 Health Services Delivery Systems 377 15 Housing, Social Services, and Mental Health 393 16 Family and Friend Relationships, and Caregiving 407 17 Ethical Issues in Work with Older Adults: Advanced Care, Financial Decision‐Making, and the Impacts of Climate Change 423 Epilogue 445 Index 447

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Book Synopsis30 tutorials and more than 100 exercises in chemoinformatics, supported by online software and data sets Chemoinformatics is widely used in both academic and industrial chemical and biochemical research worldwide. Yet, until this unique guide, there were no books offering practical exercises in chemoinformatics methods.Table of ContentsList of Contributors xv Preface xvii About the Companion Website xix Part 1 Chemical Databases 1 1 Data Curation 3 Gilles Marcou and Alexandre Varnek Theoretical Background 3 Software 5 Step‐by‐Step Instructions 7 Conclusion 34 References 36 2 Relational Chemical Databases: Creation, Management, and Usage 37 Gilles Marcou and Alexandre Varnek Theoretical Background 37 Step‐by‐Step Instructions 41 Conclusion 65 References 65 3 Handling of Markush Structures 67 Timur Madzhidov, Ramil Nugmanov, and Alexandre Varnek Theoretical Background 67 Step‐by‐Step Instructions 68 Conclusion 73 References 73 4 Processing of SMILES, InChI, and Hashed Fingerprints 75 João Montargil Aires de Sousa Theoretical Background 75 Algorithms 76 Step‐by‐Step Instructions 78 Conclusion 80 References 81 Part 2 Library Design 83 5 Design of Diverse and Focused Compound Libraries 85 Antonio de la Vega de Leon, Eugen Lounkine, Martin Vogt, and Jürgen Bajorath Introduction 85 Data Acquisition 86 Implementation 86 Compound Library Creation 87 Compound Library Analysis 90 Normalization of Descriptor Values 91 Visualizing Descriptor Distributions 92 Decorrelation and Dimension Reduction 94 Partitioning and Diverse Subset Calculation 95 Partitioning 95 Diverse Subset Selection 97 Combinatorial Libraries 98 Combinatorial Enumeration of Compounds 98 Retrosynthetic Approaches to Library Design 99 References 101 Part 3 Data Analysis and Visualization 103 6 Hierarchical Clustering in R 105 Martin Vogt and Jürgen Bajorath Theoretical Background 105 Algorithms 106 Instructions 107 Hierarchical Clustering Using Fingerprints 108 Hierarchical Clustering Using Descriptors 111 Visualization of the Data Sets 113 Alternative Clustering Methods 116 Conclusion 117 References 118 7 Data Visualization and Analysis Using Kohonen Self‐Organizing Maps 119 João Montargil Aires de Sousa Theoretical Background 119 Algorithms 120 Instructions 121 Conclusion 126 References 126 Part 4 Obtaining and Validation QSAR/QSPR Models 127 8 Descriptors Generation Using the CDK Toolkit and Web Services 129 João Montargil Aires de Sousa Theoretical Background 129 Algorithms 130 Step‐by‐Step Instructions 131 Conclusion 133 References 134 9 QSPR Models on Fragment Descriptors 135 Vitaly Solov’ev and Alexandre Varnek Abbreviations 135 Data 136 ISIDA_QSPR Input 137 Data Split Into Training and Test Sets 139 Substructure Molecular Fragment (SMF) Descriptors 139 Regression Equations 142 Forward and Backward Stepwise Variable Selection 142 Parameters of Internal Model Validation 143 Applicability Domain (AD) of the Model 143 Storage and Retrieval Modeling Results 144 Analysis of Modeling Results 144 Root‐Mean Squared Error (RMSE) Estimation 148 Setting the Parameters 151 Analysis of n‐Fold Cross‐Validation Results 151 Loading Structure‐Data File 153 Descriptors and Fitting Equation 154 Variables Selection 155 Consensus Model 155 Model Applicability Domain 155 n‐Fold External Cross‐Validation 155 Saving and Loading of the Consensus Modeling Results 155 Statistical Parameters of the Consensus Model 156 Consensus Model Performance as a Function of Individual Models Acceptance Threshold 157 Building Consensus Model on the Entire Data Set 158 Loading Input Data 159 Loading Selected Models and Choosing their Applicability Domain 160 Reporting Predicted Values 160 Analysis of the Fragments Contributions 161 References 161 10 Cross‐Validation and the Variable Selection Bias 163 Igor I. Baskin, Gilles Marcou, Dragos Horvath, and Alexandre Varnek Theoretical Background 163 Step‐by‐Step Instructions 165 Conclusion 172 References 173 11 Classification Models 175 Igor I. Baskin, Gilles Marcou, Dragos Horvath, and Alexandre Varnek Theoretical Background 176 Algorithms 178 Step‐by‐Step Instructions 180 Conclusion 191 References 192 12 Regression Models 193 Igor I. Baskin, Gilles Marcou, Dragos Horvath, and Alexandre Varnek Theoretical Background 194 Step‐by‐Step Instructions 197 Conclusion 207 References 208 13 Benchmarking Machine‐Learning Methods 209 Igor I. Baskin, Gilles Marcou, Dragos Horvath, and Alexandre Varnek Theoretical Background 209 Step‐by‐Step Instructions 210 Conclusion 222 References 222 14 Compound Classification Using the scikit‐learn Library 223 Jenny Balfer, Jürgen Bajorath, and Martin Vogt Theoretical Background 224 Algorithms 225 Step‐by‐Step Instructions 230 Naïve Bayes 230 Decision Tree 231 Support Vector Machine 234 Notes on Provided Code 237 Conclusion 238 References 239 Part 5 Ensemble Modeling 241 15 Bagging and Boosting of Classification Models 243 Igor I. Baskin, Gilles Marcou, Dragos Horvath, and Alexandre Varnek Theoretical Background 243 Algorithm 244 Step by Step Instructions 245 Conclusion 247 References 247 16 Bagging and Boosting of Regression Models 249 Igor I. Baskin, Gilles Marcou, Dragos Horvath, and Alexandre Varnek Theoretical Background 249 Algorithm 249 Step‐by‐Step Instructions 250 Conclusion 255 References 255 17 Instability of Interpretable Rules 257 Igor I. Baskin, Gilles Marcou, Dragos Horvath, and Alexandre Varnek Theoretical Background 257 Algorithm 258 Step‐by‐Step Instructions 258 Conclusion 261 References 261 18 Random Subspaces and Random Forest 263 Igor I. Baskin, Gilles Marcou, Dragos Horvath, and Alexandre Varnek Theoretical Background 264 Algorithm 264 Step‐by‐Step Instructions 265 Conclusion 269 References 269 19 Stacking 271 Igor I. Baskin, Gilles Marcou, Dragos Horvath, and Alexandre Varnek Theoretical Background 271 Algorithm 272 Step‐by‐Step Instructions 273 Conclusion 277 References 278 Part 6 3D Pharmacophore Modeling 279 20 3D Pharmacophore Modeling Techniques in Computer‐Aided Molecular Design Using LigandScout 281 Thomas Seidel, Sharon D. Bryant, Gökhan Ibis, Giulio Poli, and Thierry Langer Introduction 281 Theory: 3D Pharmacophores 283 Representation of Pharmacophore Models 283 Hydrogen‐Bonding Interactions 285 Hydrophobic Interactions 285 Aromatic and Cation‐π Interactions 286 Ionic Interactions 286 Metal Complexation 286 Ligand Shape Constraints 287 Pharmacophore Modeling 288 Manual Pharmacophore Construction 288 Structure‐Based Pharmacophore Models 289 Ligand‐Based Pharmacophore Models 289 3D Pharmacophore‐Based Virtual Screening 291 3D Pharmacophore Creation 291 Annotated Database Creation 291 Virtual Screening‐Database Searching 292 Hit‐List Analysis 292 Tutorial: Creating 3D‐Pharmacophore Models Using LigandScout 294 Creating Structure‐Based Pharmacophores From a Ligand‐Protein Complex 294 Description: Create a Structure‐Based Pharmacophore Model 296 Create a Shared Feature Pharmacophore Model From Multiple Ligand‐Protein Complexes 296 Description: Create a Shared Feature Pharmacophore and Align it to Ligands 297 Create Ligand‐Based Pharmacophore Models 298 Description: Ligand‐Based Pharmacophore Model Creation 300 Tutorial: Pharmacophore‐Based Virtual Screening Using LigandScout 301 Virtual Screening, Model Editing, and Viewing Hits in the Target Active Site 301 Description: Virtual Screening and Pharmacophore Model Editing 302 Analyzing Screening Results with Respect to the Binding Site 303 Description: Analyzing Hits in the Active Site Using LigandScout 305 Parallel Virtual Screening of Multiple Databases Using LigandScout 305 Virtual Screening in the Screening Perspective of LigandScout 306 Description: Virtual Screening Using LigandScout 306 Conclusions 307 Acknowledgments 307 References 307 Part 7 The Protein 3D‐Structures in Virtual Screening 311 21 The Protein 3D‐Structures in Virtual Screening 313 Inna Slynko and Esther Kellenberger Introduction 313 Description of the Example Case 314 Thrombin and Blood Coagulation 314 Active Thrombin and Inactive Prothrombin 314 Thrombin as a Drug Target 314 Thrombin Three‐Dimensional Structure: The 1OYT PDB File 315 Modeling Suite 315 Overall Description of the Input Data Available on the Editor Website 315 Exercise 1: Protein Analysis and Preparation 316 Step 1: Identification of Molecules Described in the 1OYT PDB File 316 Step 2: Protein Quality Analysis of the Thrombin/Inhibitor PDB Complex Using MOE Geometry Utility 320 Step 3: Preparation of the Protein for Drug Design Applications 321 Step 4: Description of the Protein‐Ligand Binding Mode 325 Step 5: Detection of Protein Cavities 328 Exercise 2: Retrospective Virtual Screening Using the Pharmacophore Approach 330 Step 1: Description of the Test Library 332 Step 2.1: Pharmacophore Design, Overview 333 Step 2.2: Pharmacophore Design, Flexible Alignment of Three Thrombin Inhibitors 334 Step 2.3: Pharmacophore Design, Query Generation 335 Step 3: Pharmacophore Search 337 Exercise 3: Retrospective Virtual Screening Using the Docking Approach 341 Step 1: Description of the Test Library 341 Step 2: Preparation of the Input 341 Step 3: Re‐Docking of the Crystallographic Ligand 341 Step 4: Virtual Screening of a Database 345 General Conclusion 350 References 351 Part 8 Protein‐Ligand Docking 353 22 Protein‐Ligand Docking 355 Inna Slynko, Didier Rognan, and Esther Kellenberger Introduction 355 Description of the Example Case 356 Methods 356 Ligand Preparation 359 Protein Preparation 359 Docking Parameters 360 Description of Input Data Available on the Editor Website 360 Exercises 362 A Quick Start with LeadIT 362 Re‐Docking of Tacrine into AChE 362 Preparation of AChE From 1ACJ PDB File 362 Docking of Neutral Tacrine, then of Positively Charged Tacrine 363 Docking of Positively Charged Tacrine in AChE in Presence of Water 365 Cross‐Docking of Tacrine‐Pyridone and Donepezil Into AChE 366 Preparation of AChE From 1ACJ PDB File 366 Cross‐Docking of Tacrine‐Pyridone Inhibitor and Donepezil in AChE in Presence of Water 367 Re‐Docking of Donepezil in AChE in Presence of Water 370 General Conclusions 372 Annex: Screen Captures of LeadIT Graphical Interface 372 References 375 Part 9 Pharmacophorical Profiling Using Shape Analysis 377 23 Pharmacophorical Profiling Using Shape Analysis 379 Jérémy Desaphy, Guillaume Bret, Inna Slynko, Didier Rognan, and Esther Kellenberger Introduction 379 Description of the Example Case 380 Aim and Context 380 Description of the Searched Data Set 381 Description of the Query 381 Methods 381 Rocs 381 VolSite and Shaper 384 Other Programs for Shape Comparison 384 Description of Input Data Available on the Editor Website 385 Exercises 387 Preamble: Practical Considerations 387 Ligand Shape Analysis 387 What are ROCS Output Files? 387 Binding Site Comparison 388 Conclusions 390 References 391 Part 10 Algorithmic Chemoinformatics 393 24 Algorithmic Chemoinformatics 395 Martin Vogt, Antonio de la Vega de Leon, and Jürgen Bajorath Introduction 395 Similarity Searching Using Data Fusion Techniques 396 Introduction to Virtual Screening 396 The Three Pillars of Virtual Screening 397 Molecular Representation 397 Similarity Function 397 Search Strategy (Data Fusion) 397 Fingerprints 397 Count Fingerprints 397 Fingerprint Representations 399 Bit Strings 399 Feature Lists 399 Generation of Fingerprints 399 Similarity Metrics 402 Search Strategy 404 Completed Virtual Screening Program 405 Benchmarking VS Performance 406 Scoring the Scorers 407 How to Score 407 Multiple Runs and Reproducibility 408 Adjusting the VS Program for Benchmarking 408 Analyzing Benchmark Results 410 Conclusion 414 Introduction to Chemoinformatics Toolkits 415 Theoretical Background 415 A Note on Graph Theory 416 Basic Usage: Creating and Manipulating Molecules in RDKit 417 Creation of Molecule Objects 417 Molecule Methods 418 Atom Methods 418 Bond Methods 419 An Example: Hill Notation for Molecules 419 Canonical SMILES: The Canon Algorithm 420 Theoretical Background 420 Recap of SMILES Notation 420 Canonical SMILES 421 Building a SMILES String 422 Canonicalization of SMILES 425 The Initial Invariant 427 The Iteration Step 428 Summary 431 Substructure Searching: The Ullmann Algorithm 432 Theoretical Background 432 Backtracking 433 A Note on Atom Order 436 The Ullmann Algorithm 436 Sample Runs 440 Summary 441 Atom Environment Fingerprints 441 Theoretical Background 441 Implementation 443 The Hashing Function 443 The Initial Atom Invariant 444 The Algorithm 444 Summary 447 References 447 Index 449

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Book SynopsisAn applied approach to teaching forensic microscopy in educational settings, featuring new experiments and an up-to-date overview of the field Practical Forensic Microscopy: A Laboratory Manual, 2nd Edition, is a unique resource that brings the microscopic procedures used by real-world forensic investigators to the college laboratory, providing hands-on knowledge of the microscopes and microscopic techniques used in the field. Presenting a balanced, skills-based approach to the subject, this student-friendly lab manual contains dozens of experiments designed to cover the various microscopic evidence disciplines, including examinations of fingerprints, firearm, toolmark, shoeprint and tire impressions, gunshots, fibers, soil, glass breakage, drugs, semen, and human hair. The second edition includes revised and updated experiments that reflect current technologies and techniques used in forensic science, including new experiments examining plastic fiTable of ContentsPreface ix Acknowledgments xi Laboratory Safety xiii Microscope Maintenance xv The Micro Kit xvii About the Companion Website xix Experiments 1 1 Stereomicroscope 3 Experiment 1A: Familiarization with the Stereomicroscope 5 2 Compound Light Microscope 13 Experiment 2A: Familiarization with the Compound Light Microscope 15 Experiment 2B: Measurements Using the Ocular Micrometer 23 Experiment 2C: Microscopic Mounting Techniques 29 Experiment 2D: Determining Refractive Index 35 3 Polarized Light Microscope 47 Experiment 3A: Familiarization with the Polarized Light Microscope 49 Experiment 3B: Determining Refractive Index of Anisotropic Materials 57 Experiment 3C: Determining Sign of Elongation and Birefringence 63 4 Fluorescence Microscope 69 Experiment 4A: Familiarization with the Fluorescence Microscope 71 5 Phase Contrast Microscope 77 Experiment 5A: Familiarization with the Phase Contrast Microscope 79 Application Experiments 85 6 Experiment 6: Physical Match Examinations 87 7 Experiment 7: Construction Examinations of Evidence 93 8 Experiment 8: Lamp Filament Examinations 103 9 Experiment 9: Fingerprint Examination and Comparison 113 10 Experiment 10: Tool Mark Examinations 121 11 Experiment 11: Firearms Examinations 127 Experiment 11A: Gunshot Residue Examinations 135 12 Experiment 12: Shoe and Tire Impression Examinations 145 13 Experiment 13: Botanical Examinations 151 14 Experiment 14: Paint Examinations 159 15 Experiment 15: Cigarette Butt Examinations 165 16 Experiment 16: Document Examinations 173 17 Experiment 17: Hair Examinations 183 Experiment 17A: Animal Hair Examinations 195 Experiment 17B: Determination of Racial and Somatic Origin Characteristics of Human Hair 205 Experiment 17C: Human Hair Examinations and Comparisons 213 Experiment 17D: Evaluation of Human Hair for DNA 223 18 Experiment 18: Feather Examinations 231 19 Experiment 19: Glass Breakage Determinations 239 Experiment 19A: Glass Examinations 247 20 Experiment 20: Fiber Examinations 257 Experiment 20A: Natural Fiber Examinations 265 Experiment 20B: Man-made Fiber Examinations 279 Experiment 20C: Fiber Comparisons 289 21 Experiment 21: Soil Examinations 295 Experiment 21A: Identification of Minerals in Soil 303 22 Experiment 22: Microchemical Testing – Inorganic Ions 317 23 Experiment 23: Building Material Examinations 329 24 Experiment 24: Explosive Residue Examinations 337 25 Experiment 25: Food Condiment Examinations 345 26 Experiment 26: Plastic Film Examinations 355 27 Experiment 27: Microscopic Examination of Controlled Substances 363 28 Experiment 28: Semen Examinations 377 Application Experiments, Instrumental Microscopy 383 29 Experiment 29: Fourier Transform Infrared Microspectrometry Examinations 385 30 Experiment 30: UV-Visible-NIR Microspectrophotometry Examinations 395 31 Experiment 31: Thermal Microscopy Examinations 405 32 Experiment 32: Scanning Electron Microscopy Examinations 413 33 Experiment 33: Case Study Scenario 423 Appendices 429 A Optical Properties of Natural Fibers 431 B Optical Properties of Man-made Fibers 433 C Michel-Lévy Chart 437 D Dispersion Staining Graph 439 E Circle Template 441 Glossary of Microscopy Terms 443 Index 453

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Book SynopsisProvides a comprehensive introduction to ion exchange for beginners and in-depth coverage of the latest advances for those already in the field As environmental and energy related regulations have grown, ion exchange has assumed a dominant role in offering solutions to many concurrent problems both in the developed and the developing world. Written by an internationally acknowledged leader in ion exchange research and innovation, Ion Exchange:inEnvironmental Processes is both a comprehensive introduction to the science behind ion exchange and an expert assessment of the latest ion exchange technologies. Its purpose is to provide a valuable reference and learning tool for virtually anyone working in ion exchange or interested in becoming involved in that incredibly fertile field. Written for beginners as well as those already working the in the field, Dr. SenGupta provides stepwise coverage, advancing from ion exchange fundamentals to trace ion exchTable of ContentsPreface xiii Acknowledgment xvii 1 Ion Exchange and Ion Exchangers: An Introduction 1 1.1 Historical Perspective 1 1.2 Water and Ion Exchange: An Eternal Kinship 6 1.3 Constituents of an Ion Exchanger 9 1.4 What is Ion Exchange and What it is Not? 10 1.5 Genesis of Ion Exchange Capacity 12 1.5.1 Inorganic 12 1.5.2 Organic/Polymeric Ion Exchanger 13 1.5.3 Strong-Base Type I and Type II Anion Exchanger 20 1.6 Biosorbent, Liquid Ion Exchanger, and Solvent Impregnated Resin 23 1.6.1 Biosorbent 23 1.6.2 Liquid Ion Exchange 25 1.6.3 Solvent-Impregnated Resins 27 1.7 Amphoteric Inorganic Ion Exchangers 28 1.8 Ion Exchanger versus Activated Carbon: Commonalities and Contrasts 33 1.9 Ion Exchanger Morphologies 34 1.10 Widely Used Ion Exchange Processes 34 1.10.1 Softening 35 1.10.2 Deionization or Demineralization 40 Summary 44 References 45 2 Ion Exchange Fundamentals 50 2.1 Physical Realities 50 2.2 Swelling/Shrinking: Ion Exchange Osmosis 51 2.3 Ion Exchange Equilibrium 55 2.3.1 Genesis of Non-Ideality 57 2.4 Other Equilibrium Constants and Equilibrium Parameters 59 2.4.1 Corrected Selectivity Coefficient 59 2.4.2 Selectivity Coefficient, K IXse 60 2.4.3 Separation Factor (α A B) 60 2.4.4 Separation Factor: Homovalent Ion Exchange 61 2.4.5 Separation Factor: Heterovalent Exchange 62 2.4.6 Physical Reality of Selectivity Reversal: Role of Le Châtelier’s Principle 65 2.4.7 Equilibrium Constant: Inconsistencies and Potential Pitfalls 66 2.5 Electrostatic Interaction: Genesis of Counterion Selectivity 69 2.5.1 Monovalent–Monovalent Coulombic Interaction 69 2.6 Ion Exchange Capacity: Isotherms 73 2.6.1 Batch Technique 75 2.6.2 Regenerable Mini-Column Method 79 2.6.3 Step-Feed Frontal Column Run 81 2.7 The Donnan Membrane Effect in Ion Exchanger 84 2.7.1 Coion Invasion or Electrolyte Penetration 84 2.7.2 Role of Cross-linking 90 2.7.3 Genesis of the Donnan Potential 90 2.8 Weak-Acid and Weak-Base Ion Exchange Resins 92 2.8.1 pKa Values of Weak Ion Exchange Resins 94 2.8.2 Weak-Acid and Weak-Base Functional Groups 96 2.9 Regeneration 98 2.9.1 Selectivity Reversal in Heterovalent Ion Exchange 100 2.9.2 pH Swings 101 2.9.3 Ligand Exchange with Metal Oxides 105 2.9.4 Use of Co-Solvent 106 2.9.5 Dual-Temperature Regeneration 108 2.9.6 Carbon Dioxide Regeneration 111 2.9.7 Regeneration with Water 112 2.10 Resin Degradation and Trace Toxin Formation 112 2.10.1 Formation of Trace Nitrosodimethylamine (NDMA) from Resin Degradation 114 2.11 Ion Exclusion and Ion Retardation 115 2.11.1 Ion Exclusion 115 2.11.2 Ion Retardation 116 2.12 Zwitterion and Amino Acid Sorption 118 2.12.1 Interaction with a Cation Exchanger: Role of pH 119 2.13 Solution Osmotic Pressure and Ion Exchange 121 2.14 Ion Exchanger as a Catalyst 124 Summary 126 References 127 3 Trace Ion Exchange 130 3.1 Genesis of Selectivity 130 3.2 Trace Isotherms 136 3.3 Multi-Component Equilibrium 138 3.4 Agreement with Henry’s Law 140 3.5 Multiple Trace Species: Genesis of Elution Chromatography 143 3.5.1 Determining Separation Factor from Elution Chromatogram 143 3.6 Uphill Transport of Trace Ions: Donnan Membrane Effect 149 3.7 Trace Leakage 151 3.8 Trace Fouling by Natural Organic Matter 153 3.9 Ion Exchange Accompanied by Chemical Reaction 156 3.9.1 Precipitation 156 3.9.2 Complexation 157 3.9.3 Redox Reaction 157 3.10 Monovalent–Divalent Selectivity 158 3.10.1 Effect of Charge Separation: Mechanistic Explanation 158 3.10.2 Nitrate/Sulfate and Chloride/Sulfate Selectivity in Anion Exchange 160 3.10.3 Genesis of Nitrate-Selective Resin 162 3.10.4 Chromate Ion Selectivity 164 3.11 Entropy-Driven Selective Ion Exchange: The Case of Hydrophobic Ionizable Organic Compound (HIOC) 166 3.11.1 Focus of the Study and Related Implications 167 3.11.2 Nature of Solute–Sorbent and Solute–Solvent Interactions 169 3.11.3 Experimental Observations: Stoichiometry, Affinity Sequence, and Cosolvent Effect 173 3.11.4 Energetics of the Sorption Process 177 3.11.5 Unifying Hydrophobic Interaction: From Gas–Liquid to Liquid–Solid System 179 3.11.6 Effect of Polymer Matrix and Solute Hydrophobicity 182 3.12 Linear Free Energy Relationship and Relative Selectivity 183 3.13 Simultaneous Removal of Target Metal Cations and Anions 186 3.14 Deviation from Henry’s Law 188 3.14.1 Ions Forming Polynuclear Species 188 3.15 Tunable Sorption Behaviors of Amphoteric Metal Oxides 192 3.16 Ion Sieving 195 3.17 Trace Ion Removal 201 3.17.1 Uranium(VI) 201 3.17.2 Radium 203 3.17.3 Boron 204 3.17.4 Perchlorate (ClO − 4) 205 3.17.5 Emerging Contaminants of Concern and Multi-Contaminant Systems 208 3.17.6 Arsenic and Phosphorus: As(V), P(V), and As(III) 210 3.17.7 Fluoride (F −) 214 Summary 215 References 216 4 Ion Exchange Kinetics: Intraparticle Diffusion 224 4.1 Role of Selectivity 224 4.2 State of Water Molecules inside Ion Exchange Materials 232 4.3 Activation Energy Level in Ion Exchangers: Chemical Kinetics 235 4.3.1 Activation Energy Determination from Experimental Results 236 4.4 Physical Anatomy of an Ion Exchanger: Gel, Macroporous and Fibrous Morphology 242 4.4.1 Gel-Type Ion Exchanger Beads 242 4.4.2 Macroporous Ion Exchanger Beads 243 4.4.3 Ion Exchange Fibers 246 4.5 Column Interruption Test: Determinant of Diffusion Mechanism 248 4.6 Observations Related to Ion Exchange Kinetics 250 4.6.1 Effect of Concentration on Half-time (t 1∕2) 251 4.6.2 Major Differences in Ion Exchange Rate 252 4.6.3 Chemically Similar Counterions with Significant Differences in Intraparticle Diffusivity 252 4.6.4 Effect of Competing Ion Concentrations: Gel versus Macroporous 254 4.6.5 Intraparticle Diffusion during Regeneration 255 4.6.6 Shell Progressive Kinetics versus Slow Diffusing Species 255 4.7 Interdiffusion Coefficients for Intraparticle Diffusion 257 4.8 Trace Ion Exchange Kinetics 264 4.8.1 Chlorophenols as the Target Trace Ions 264 4.8.2 Intraparticle Diffusion inside a Macroporous Ion Exchanger 266 4.8.3 Effect of Sorption Affinity on Intraparticle Diffusion 268 4.8.4 Solute Concentration Effect 271 4.9 Rectangular Isotherms and Shell Progressive Kinetics 272 4.9.1 Anomalies in Arrival Sequence of Solutes 274 4.9.2 Quantitative Interpretation 275 4.10 Responses to Observations in Section 4.6 276 4.10.1 Effect of Concentration on Half-time (t 1∕2) 276 4.10.2 Slow Kinetics of Weak-Acid Resin 277 4.10.3 Chemically Similar Counterions: Drastic Difference in Intraparticle Diffusivity 277 4.10.4 Gel versus Macroporous 278 4.10.5 Intraparticle Diffusion during Regeneration 278 4.10.6 Shrinking Core or Shell Progressive Kinetics 279 4.11 Rate-Limiting Step: Dimensionless Numbers 280 4.11.1 Implications of Biot Number: Trace Ion Exchange 281 4.12 Intraparticle Diffusion: From Theory to Practice 284 4.12.1 Reducing Diffusion Path Length: Short-Bed Process and Shell–Core Resins 285 4.12.2 Development of Bifunctional Diphonix ® Resin 288 4.12.3 Ion Exchanger as a Host for Enhanced Kinetics 289 Summary 292 References 293 5 Solid- and Gas-Phase Ion Exchange 297 5.1 Solid-Phase Ion Exchange 297 5.1.1 Poorly Soluble Solids 297 5.1.2 Desalting by Ion Exchange Induced Precipitation 303 5.1.3 Separation of Competing Solid Phases 305 5.1.4 Recovery from Ion Exchange Sites of Soil 306 5.1.5 Composite or Cloth-like Ion Exchanger (CIX) 307 5.1.6 Heavy Metals (Me 2+) with Solids Possessing High Buffer Capacity 309 5.1.7 Ligand-Induced Metal Recovery with a Chelating Exchanger 315 5.2 Coagulant Recovery from Water Treatment Sludge 317 5.2.1 Development of Donnan IX Membrane Process 318 5.2.2 Alum Recovery: Governing Donnan Equilibrium 318 5.2.3 Process Validation 322 5.3 Gas Phase Ion Exchange 323 5.3.1 Sorption of Acidic and Basic Gases 324 5.3.2 CO2and SO2 Capture with Weak-Base Anion (WBA) Exchanger 325 5.3.3 Effect of Ion Exchanger Morphology 327 5.3.4 Redox Active Gases: Hydrogen Sulfide and Oxygen 330 5.4 CO2 Gas as a Regenerant for IX Softening Processes: A Case Study 334 Summary 339 References 340 6 Hybrid Ion Exchange Nanotechnology (HIX-Nanotech) 345 6.1 Magnetically Active Polymer Particles (MAPPs) 347 6.1.1 Characterization of MAPPs 351 6.1.2 Factors Affecting Acquired Magnetic Activity 353 6.1.3 Retention of Magnetic Activity and Sorption Behavior 355 6.2 Hybrid Nanosorbents for Selective Sorption of Ligands (e.g., HIX-NanoFe) 357 6.2.1 Synthesis of Hybrid Ion Exchange Nanomaterials 359 6.2.2 Characterization of Hybrid Nanosorbents 361 6.2.3 Parent Anion Exchanger versus Hybrid Anion Exchanger (HAIX-NanoFe(III)): A Comparison 363 6.2.4 Support of Hybrid Ion Exchangers: Cation versus Anion 365 6.2.5 Efficiency of Regeneration and Field Application 369 6.2.6 Hybrid Ion Exchange Fibers: Simultaneous Perchlorate and Arsenic Removal 370 6.3 HAIX-NanoZr(IV): Simultaneous Defluoridation and Desalination 376 6.3.1 Field-Scale Validation 377 6.4 Promise of HIX-Nanotechnology 381 Summary 383 References 384 7 Heavy Metal Chelation and Polymeric Ligand Exchange 391 7.1 Heavy Metals and Chelating Ion Exchangers 391 7.1.1 Heavy Metals: What are They? 391 7.1.2 Properties of Heavy Metals and Separation Strategies 393 7.1.3 Emergence of Chelating Exchangers 395 7.1.4 Lewis Acid–Base Interactions in Chelating Ion Exchangers 398 7.1.5 Regeneration, Kinetics and Metals Affinity 402 7.2 Polymeric Ligand Exchange 405 7.2.1 Conceptualization and Characterization of the Polymeric Ligand Exchanger (ple) 406 7.2.2 Sorption of Polymeric Ligand Exchangers 407 7.2.3 Validation of Ligand Exchange Mechanism 410 Summary 413 References 413 8 Synergy and Sustainability 417 8.1 Waste Acid Neutralization: An Introduction 417 8.1.1 Underlying Scientific Concept 418 8.1.2 Mechanical Work through a Cyclic Engine 421 8.2 Improving Stability of Anaerobic Biological Reactors 423 8.2.1 Potential Use of Selective Ion Exchanger 424 8.2.2 Ion Exchange Fibers: Characterization and Performance 424 8.3 Sustainable Aluminum-Cycle Softening for Hardness Removal 429 8.3.1 Current Status and Challenges 429 8.3.2 Sodium-Free Approaches and Alternatives to Na-Cycle Softening 429 8.3.3 Underlying Scientific Approach of Al-cycle Cation Exchange 430 8.3.4 Comparison in Performance: Na-Cycle versus Al-Cycle 432 8.3.5 Regeneration Efficiency and Calcium Removal Capacity 436 8.3.6 Sustainability Issues and New Opportunities 438 8.4 Closure 438 Summary 439 References 440 A Commercial Ion Exchangers 445 B Different Units of Capacity, Concentration, Mass, and Volume 457 B.1 Capacity 457 B.2 Concentration (Expressed as CaCO 3) 457 B.3 Mass 458 B.4 Volume 458 C Table of Solubility Product constants at 25 ∘ c 459 D Acid and Base dissociation constants at 25 ∘ c 461 Periodic Table and Atomic Weights of Elements 463 Index 467

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Book SynopsisThis is the second volume in a four-volume series aimed at guiding the pharmaceutical industry toward sustainability. After analyzing and exposing some of the backward and ill-conceived notions that guide the present state of the industry, this volume presents key theories and new, groundbreaking solutions for re-thinking the processes involved in the engineering of pharmaceuticals and offers a fundamental paradigm shift. The 4 volumes in this ambitious project are: Volume 1: Practice, Analysis, and Methodology Volume 2: Theories and Solutions Volume 3: Applications for Mental Disorder Treatments Volume 4: Applications for Physical Disorder Treatments This ground-breaking set of books is a unique and state-of-the-art study that only appears here, within these pages. A fascinating study for the engineer, scientist, and pharmacist working in the pharmaceutical industry and interested in sustainabiTable of ContentsPreface ix 1 Introduction 1 1.1 Opening Statement 1 1.2 The Way Out: How Do We Make Use of Existing Knowledge? 1 1.3 The Driver of The Knowledge Model 3 1.4 The Proof of The Pudding is in The Eating! 7 1.5 The Proof is in The Pudding 8 1.6 Summary of Introduction 9 2 Nature-Science Approach: Some Further Consequences 11 2.1 Cognitive Dissonance 11 2.1.1 Summary Remarks about Theories that Disconnect Conscience from Humanity 11 2.2 Foods for Thought 12 2.2.1 Artificial Food Addiction 12 2.2.2 Organic and Mechanical Frequencies 13 2.3 Example from CCD Analysis 17 2.4 A New Approach to Product Characterization 22 2.5 A New Paradigm 25 2.5.1 Violation of Characteristic Time 25 2.5.2 Observation of Nature: Importance of Intangibles 25 2.5.3 Analogy of Physical Phenomena 28 2.5.4 Intangible Cause to Tangible Consequence 28 2.5.5 Removable Discontinuities: Phases and Renewability of Materials 30 2.5.6 Redefining Force and Energy 37 2.5.6.1 Force 37 2.5.6.2 Energy 38 2.6 What is a Natural Energy Source? 42 2.7 The Science of Water and Oil 47 2.7.1 Comparison between Water and Petroleum 50 2.7.2 Combustion and Oxidation 65 2.7.3 Natural Energy vs. Artificial Energy 67 2.8 From Natural Energy to Natural Mass 72 2.9 Avalanche Theory of Mass and Energy 98 2.10 Aims of Modeling Natural Phenomena 106 2.11 Simultaneous Characterization of Matter and Energy 108 2.12 Implications 110 2.13 Consequences of Nature-Science for Classical Set Theory and Conventional Notions of Mensuration 114 2.14 Conclusions 116 2.14.1 Need for a Change 116 2.14.2 The Nature Science Approach 117 3 A Knowledge-Based Cognition Model 119 3.1 Abstract 119 3.2 Introduction 120 3.3 The Current Cognitive Model 125 3.3.1 Policy-Making and The Aphenomenal Model 126 3.3.2 The Aphenomenal Model in ‘Science’ 132 3.3.2.1 Example 1: Aphenomenal Time Function 134 3.3.3 Fear and Perception 148 3.4 What is Human Thought Material (HTM)? 151 3.5 Knowledge through Experience or Delinearized History? 154 3.6 HTM from The Standpoint of Nature-Science 156 3.6.1 Cognition with Conscious and Conscientious Participation 156 3.7 The Basic Quantum of HTM 157 3.8 Freedom of Intention 169 3.8.1 The Knowledge-Based Cognition Process 171 3.9 Conclusions 177 4 Implications of a Comprehensive Material Balance Equation for Detecting Causes of Medical Disorders 179 4.1 Summary 179 4.2 Introduction 180 4.3 Paradox and New Science 183 4.3.1 Obesity Paradox 184 4.3.2 Obesity/Mortality Paradox 184 4.3.3 Simpson’s Paradox 184 4.3.4 Low Birth Weight Paradox 187 4.3.5 Prevention Paradox 188 4.3.6 The Novelty Paradox 189 4.3.7 The Paradox of Worsening Conditions With Medications 190 4.3.8 The Prostate Paradox 192 4.3.9 The Health-Lifespan Paradox 192 4.3.10 Smoker’s Paradox 193 4.3.11 Paradox of The Natural 193 4.3.12 The French Paradox 194 4.3.13 Paradox of Aging 194 4.3.14 Paradox of Translational Medicine 194 4.3.15 Peto’s Paradox 195 4.3.16 TGF-β Paradox 195 4.3.17 Hispanic Paradox 195 4.4 Origin of Paradox: Implication of Probability Assumptions 196 4.4.1 Probability of Creation and Life 199 4.5 A Word About Inductive and Conductive Rules 201 4.6 Deconstructing Game Theory 208 4.6.1 Impact of The Deliberate “Hunger Game” 226 4.6.2 The Prisoner’s Dilemma 237 4.7 Towards Explaining Phenomena 253 4.7.1 Blood-Brain Barrier and Cancer 253 4.7.2 New Drug that Works on Cells that Mutate Faster and Works on Smokers 254 4.7.3 Wireless Energy Transfer 256 4.7.4 “Curing” Colorblindness 258 4.7.5 Surgical Intervention—Recapitulating the HSSA Model 260 4.7.6 Editing Embryo: To Engineer or Not to Engineer 264 4.7.7 From ‘Original Sin’ to ‘Original’ Lunacy 265 4.7.8 Teenagers’ Heavy Pot Smoking Tied to Memory Problems (or “How Many Angels can Dance on the Head of a Pin” Updated) 268 4.7.9 Cigarettes – Even a Fetus can Tell What’s Harmful 269 4.7.10 Water, or: Commodification of The Most Abundant Fluid on EarTh271 4.7.11 Accelerating in Reverse 273 4.7.12 Recycling The “Hunger Games” Mantra 276 4.7.13 The Ultimate of ‘Original Sin’ 278 4.7.14 Fifteen Immune-System Boosting Foods (via WebMD) 282 4.7.14.1 Elderberry 282 4.7.14.2 Acai Berry 282 4.7.14.3 Oysters 282 4.7.14.4 Watermelon 283 4.7.14.5 Cabbage 283 4.7.14.6 Almonds 283 4.7.14.7 Grapefruit 283 4.7.14.8 Wheat Germ 283 4.7.14.9 Low-Fat Yogurt 283 4.7.14.10 Garlic 284 4.7.14.11 Spinach 284 4.7.14.12 Tea 284 4.7.14.13 Sweet Potato 284 4.7.14.14 Broccoli 284 4.7.14.15 Button Mushrooms 284 4.7.15 OK for Food… But Not Pets? 285 5 Conclusion and Recommendation 287 5.1 The Importance of Being Earnest About Cognition versus Perception 287 5.2 HSSAN Degradation 288 5.3 Greening of Pharmaceutical Industry 289 5.3.1 Phases of Life 289 5.3.2 Recognize The Stimulant 290 5.3.3 Remove Negative Stimulant in Order to Reverse The Symptoms 290 5.3.4 Replacement of Artificial with Natural 291 5.3.5 Medicines and Therapies with Natural Substitutes 291 5.3.6 Mental Conditioning and Staged Prevention 291 References and Bibliography 295 Appendix 319 Index 353

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Book SynopsisWater is the Earth''s most precious resource. Until recent years, water was often overlooked as being overly abundant or available, but much has changed all over the world. As climate change, human encroachment on environmental areas, and deforestation become greater dangers, the study of groundwater has become more important than ever and is growing as one of the most important areas of science for the future of life on Earth. This three-volume set is the most comprehensive and up-to-date treatment of hydrogeochemistry that is available. The first volume lays the foundation of the composition, chemistry, and testing of groundwater, while volume two covers practical applications such as mass transfer and transport. Volume three, which completes the set, is an advanced study of the environmental analysis of groundwater and its implications for the future. This first volume in the set is an important milestone in hydrogeochemistry, covering the fundamentals of groundwateTable of ContentsPreface xv Introduction 1 1 Analytical Composition and Properties of Ground Water 19 1.1 Moisture 21 1.2 Mineral Components 29 1.2.1 Testing and Preparation 30 1.2.2 Chemical Analysis 34 1.2.3 Processing of Analysis Results 35 1.3 Gas Components 41 1.3.1 Testing and Preparation 43 1.3.2 Analysis of the Natural Gas Composition 49 1.3.3 Conversions of Gas Analysis Results 52 1.4 Organic Components 56 1.4.1 Testing and Preparation 60 1.4.2 Analysis of Organic Substance 68 1.4.2.1 General Content of Organic Matter 68 1.4.2.2 Content of Organic Component Groups 70 1.4.2.3 Content of Individual Organic Components 74 1.4.3 Conversion of Analysis Results 74 1.5 Substances in the Dispersed State 76 1.5.1 Inert Suspended Particles 78 1.5.1.1 Methods of Study 79 1.5.2 Living Organisms 80 1.5.2.1 Pathogen Microorganisms 81 1.5.2.2 Biochemical Microorganisms 86 1.5.2.3 Methods of Study 86 1.6 Properties of Ground Water 89 1.6.1 Organoleptic and Balneological Properties 90 1.6.2 Chemical Properties 96 1.6.3 Physical Properties 113 2 Hydrogeochemical Testing 125 2.1 Assignment and Purpose of Hydrogeochemical Testing 126 2.1.1 Regime and Scope of Testing 127 2.1.2 Measured Parameters and Their Errors 128 2.2 Logistics of Field Testing 131 2.2.1 Natural Conditions and Previous Studies of the Area 132 2.2.2 Planning the Testing Regime and Points 133 2.2.3 Preparation of Wells and Equipment 138 2.2.4 Preparation of Analytical Base 148 2.2.4.1 Selection of Property and Composition Parameters 150 2.2.4.2 Substantiation of Margin of Error Measurements 151 2.2.4.3 Selection of Chemical Analysis Technique 164 2.2.4.4 Selection of a Laboratory and Executants 197 2.2.5 Field Testing Protocol 202 2.2.6 Sample Safekeeping and Delivery to the Laboratory 212 3 Processing of Testing Results 215 3.1 Processing and Systematization of Observed Values 216 3.1.1 Checking the Observed Values 216 3.1.2 Systematizing the Observed Values 219 3.1.3 Control of Measurement Quality 222 3.1.3.1 Sensitivity of Testing Techniques 224 3.1.3.2 Precision of Testing Results 225 3.1.3.3 Testing Correctness of the Results 228 3.1.3.4 Systematic Error of the Testing Results 229 3.1.3.5 Testing Results’ Accuracy 231 3.1.4 Measurements Results and Their Reliability 232 3.1.4.1 Mathematical Expectation 232 3.1.4.2 Confidence Interval 233 3.2 Modeling of the Hydrogeochemical Condition 237 3.2.1 Empirical–statistical Modeling 238 3.2.1.1 Anomalies and Background 238 3.2.1.2 Water Distinction in Quality Parameters 240 3.2.1.3 Search for the Factors 244 3.2.2 Space–time Modeling 247 3.2.2.1 Autocorrelation Metamodels 249 3.2.2.2 Semivariance Metamodels 254 3.3 Classification and Visualization of Hydrogeochemical Parameters 261 3.3.1 Chemical Classification of Ground Waters 262 3.3.2 Graphic Imaging of the Water Composition 269 3.3.3 Graphic Comparison of Different Composition Waters 272 3.3.4 Hydrogeochemical Maps and Cross–sections 276 3.3.4.1 Making Hydrogeochemical Maps 278 3.3.4.2 Generating Hydrogeochemical Cross–sections 288 Symbols 291 References 297 Index 301

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Book SynopsisWater is the Earth''s most precious resource. Until recent years, water was often overlooked as being overly abundant or available, but much has changed all over the world. As climate change, human encroachment on environmental areas, and deforestation become greater dangers, the study of groundwater has become more important than ever and is growing as one of the most important areas of science for the future of life on Earth. This three-volume set is the most comprehensive and up-to-date treatment of hydrogeochemistry that is available. The first volume lays the foundation of the composition, chemistry, and testing of groundwater, while volume two covers practical applications such as mass transfer and transport. Volume three, which completes the set, is an advanced study of the environmental analysis of groundwater and its implications for the future. This third volume focuses more deeply on the analysis of groundwater and the practical applications of these analyseTable of ContentsAbstract xi Preface xiii Spontaneous Processes and Mineral Equilibrium xv 1 Chemical Reactions 1 1.1 Real Water Solution 2 1.1.1 Properties of Water Solution 3 1.1.2 Composition of Water Solution 7 1.1.3 Structure of the Water Solution 13 1.1.4 Basis Components of a Solution 18 1.2 Spontaneous Processes 21 1.2.1 Energy of Spontaneous Processes 25 1.2.2 Direction of the Spontaneous Processes 27 1.2.3 Chemical Potential 28 1.2.4 Thermodynamical Concentration 32 1.2.4.1 Activities in Ideal Solutions 33 1.2.4.2 Activities in Real Solutions 37 1.3 Chemical Reactions 48 1.3.1 Restrictions of Spontaneous Reactions 49 1.3.2 Law of Mass Action 52 1.3.3 Equilibrium Constants of Reactions 55 1.3.4 Direction of Reactions 61 1.3.5 Reaction Rate 65 1.3.5.1 Elementary Reactions 66 1.3.5.2 Complex Reactions 72 1.3.6 Dependent and Independent Reactions 77 2 Hydrogeochemical Processes 81 2.1 Homogenous Processes 82 2.1.1 Electron Exchange 82 2.1.1.1 The Mechanism of Redox Processes 84 2.1.1.2 Oxidation Potential 88 2.1.1.3 Determination of Oxidation Potential 91 2.1.1.4 Oxygen Fugacity 97 2.1.2 Proton Exchange 98 2.1.2.1 Mechanism of Acid-based Reactions 99 2.1.2.2 Hydrogen Parameter 100 2.1.2.3 Buffer Systems 103 2.1.2.4 Determination of Solution’s pH 105 2.1.3 Complexation 107 2.1.3.1 Mechanism of Complexation 108 2.1.3.2 Stability of Complex Formations 115 2.1.3.3 Complexation Function 119 2.1.4 Real Composition of Water 125 2.1.4.1 Rates of Homogenous Processes 126 2.1.4.2 Ionic Equilibrium in the Solution 127 2.1.4.3 Models of Water Solution’s Composition 130 2.2 Heterogeneous Processes 134 2.2.1 Phase Rules 136 2.2.2 Mass Transfer by Mineral Components 140 2.2.2.1 Mineral-salt Complex of Rocks 142 2.2.2.2 Adsorption and Desorption 146 2.2.2.3 Ion Exchange 161 2.2.2.4 Surface Complexation 187 2.2.2.5 Adsorption and Desorption Rate 201 2.2.2.6 Dissolution and Minerogenesis 207 2.2.3 Mass Transfer of Nonpolar Components 304 2.2.3.1 Mass Transfer with Underground Gas 312 2.2.3.2 Mass Transfer with Nonpolar Substances 325 2.2.3.3 Distribution of Nonpolar Components 341 2.2.4 Equilibrium of Heterogeneous Processes 343 2.3 Bio-geochemical Processes 347 2.3.1 Biogeochemical Cycle 348 2.3.2 Niches of the Detrital Trophic Chain 354 2.3.3 Biodegradation of Organic Matter 370 2.2.3.1 Reactions of Biodegradation 372 2.3.3.2 Digestion 377 2.3.4 Rates of Biochemical Processes 383 2.3.5 Redox Geochemical Zoning 392 2.4 Isotopic Processes 399 2.4.1 Radioactive Decay 400 2.4.1.1 Primordial Radionuclides 400 2.4.1.2 Cosmogenic Radionuclides 403 2.4.2 Balanced Fractionating 407 2.4.3 Isotopic Mixing 414 2.4.4 Ground Water Chronometry 416 3 Migration of Elements 421 3.1 Migration forms 422 3.1.1 Subsurface Transporters 423 3.1.2 Aquaphiles 426 3.1.2.1 Estimates of Migration Capability 427 3.1.2.2 Properties of Aquaphilic Migration Forms 451 3.1.3 Organophiles 480 3.1.3.1 Amphiphilic Organophiles 481 3.1.3.2 Nonpolar Organophiles 486 3.1.4 Gasophiles 487 3.2 Mixing and Mass Transport 494 3.2.1 Hydrodynamic Dispersion 496 3.2.1.1 Diffusion Mixing 496 3.2.1.2 Advective Mixing 502 3.2.1.3 Dynamic Dispersivity and Methods of its Determination 505 3.2.2 Advection-dispersion Mass Transport 510 3.2.2.1 Equation of Advection-dispersion Mass Transport 511 3.2.2.2 Analytical Solution of Mass Transport Equations 513 4 Hydrogeochemical Forecasting 541 4.1 Methods of Forecasting 541 4.2 Model Forecasting Method 545 4.2.1 Problem Identification 547 4.2.2 Construction of Mathematical Models 548 4.2.2.1 Types of Hydrogeochemical Models 550 4.2.2.2 Selection of a Computation Process 559 4.2.2.3 Input Data 565 4.2.2.4 Selection of the Program Software 569 4.2.3 Reliability of Model Forecasting Results 570 Symbols 581 References 593 Normative Publications 608 Appendices 609 I Thermodynamic Properties of Mineral Forms of Migration 609 II The Partition Coefficients of the Gas Components 609 III Physical and Chemical Properties of Organic Compounds 609 APPENDIX I Thermodynamic Properties of Mineral Forms of Migration 611 A. Cation Generating Elements 611 B. Complex Generating Elements 627 C. Ligand Generating Elements 668 D. Salt and Minerals 677 APPENDIX II The Partition Coefficients of the Gas Components 685 А. Underground Gases of Methane Composition 685 B. Underground Gases of Nitrogen Composition 695 C. Underground Gases of Carbon dioxide Composition 697 APPENDIX III Physical and Chemical Properties of Organic Compounds. 698 A. Physical and Chemical Properties of Organic Carbon Compounds 698 B. Physical and Chemical Properties of Pesticides 709 Index 715

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Book SynopsisWater is the Earth''s most precious resource. Until recent years, water was often overlooked as being overly abundant or available, but much has changed all over the world. As climate change, human encroachment on environmental areas, and deforestation become greater dangers, the study of groundwater has become more important than ever and is growing as one of the most important areas of science for the future of life on Earth. This three-volume set is the most comprehensive and up-to-date treatment of hydrogeochemistry that is available. The first volume lays the foundation of the composition, chemistry, and testing of groundwater, while volume two covers practical applications such as mass transfer and transport. Volume three, which completes the set, is an advanced study of the environmental analysis of groundwater and its implications for the future. This third volume focuses more deeply on the analysis of groundwater and the practical applications of these analyse

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Book SynopsisThis unique, self-contained resource is the first volume on electron paramagnetic resonance (EPR) spectroscopy in the eMagRes Handbook series. The 27 chapters cover the theoretical principles, the common experimental techniques, and many important application areas of modern EPR spectroscopy. EPR Spectroscopy: Fundamentals and Methods is presented in four major parts: A: Fundamental Theory, B: Basic Techniques and Instrumentation, C: High-Resolution Pulse Techniques, and D: Special Techniques. The first part of the book gives the reader an introduction to basic continuous-wave (CW) EPR and an overview of the different magnetic interactions that can be determined by EPR spectroscopy, their associated theoretical description, and their information content. The second provides the basics of the various EPR techniques, including pulse EPR, and EPR imaging, along with the associated instrumentation. Parts C and D builds on parts A and B and offer introductory accounts of a Table of ContentsContributors xi Series Preface xv Preface xvii Part A: Fundamental Theory 1 1 Continuous-Wave EPR 3 Art van der Est 2 EPR Interactions – g-Anisotropy 17 Peter Gast and Edgar J.J. Groenen 3 EPR Interactions – Zero-field Splittings 29 Joshua Telser 4 EPR Interactions – Coupled Spins 63 Eric J.L. McInnes and David Collison 5 EPR Interactions – Hyperfine Couplings 81 Marina Bennati 6 EPR Interactions – Nuclear Quadrupole Couplings 95 Stefan Stoll and Daniella Goldfarb 7 Quantum Chemistry and EPR Parameters 115 Frank Neese 8 Spin Dynamics 143 Akiva Feintuch and Shimon Vega 9 Relaxation Mechanisms 175 Sandra S. Eaton and Gareth R. Eaton Part B: Basic Techniques and Instrumentation 193 10 Transient EPR 195 Stefan Weber 11 Pulse EPR 215 Stefan Stoll 12 EPR Instrumentation 235 Edward Reijerse and Anton Savitsky 13 EPR Imaging 261 Boris Epel and Howard J. Halpern 14 EPR Spectroscopy of Nitroxide Spin Probes 277 Enrica Bordignon Part C: High-Resolution Pulse Techniques 303 15 FT-EPR 305 Michael K. Bowman, Hanjiao Chen, and Alexander G. Maryasov 16 Hyperfine Spectroscopy – ENDOR 331 Jeffrey R. Harmer 17 Hyperfine Spectroscopy – ELDOR-detected NMR 359 Daniella Goldfarb 18 Hyperfine Spectroscopy – ESEEM 377 Sabine Van Doorslaer 19 Dipolar Spectroscopy – Double-resonance Methods 401 Gunnar Jeschke 20 Dipolar Spectroscopy – Single-resonance Methods 425 Peter P. Borbat and Jack H. Freed 21 Shaped Pulses in EPR 463 Philipp E. Spindler, Philipp Schöps, Alice M. Bowen, Burkhard Endeward, and Thomas F. Prisner Part D: Special Techniques 483 22 Pulse Techniques for Quantum Information Processing 485 Gary Wolfowicz and John J.L. Morton 23 Rapid-scan EPR 503 Gareth R. Eaton and Sandra S. Eaton 24 EPR Microscopy 521 Aharon Blank 25 Optically Detected Magnetic Resonance (ODMR) 537 Etienne Goovaerts 26 Electrically Detected Magnetic Resonance (EDMR) Spectroscopy 559 Christoph Boehme and Hans Malissa 27 Very-high-frequency EPR 581 Alexander Schnegg Index 603

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Book SynopsisThe Advances in Chemical Physics series provides the chemical physics field with a forum for critical, authoritative evaluations of advances in every area of the discipline.Table of ContentsContributors List ix Preface to the Series xi Thermodynamic Perturbation Theory for Associating Molecules 1 Bennett D. Marshall and Walter G. Chapman Path Integrals and Effective Potentials in the Study of Monatomic Fluids at Equilibrium 49 Luis M. Sesé Spontaneous Symmetry Breaking in Matter Induced by Degeneracies and Pseudodegeneracies 159 Isaac B. Bersuker Mean Field Electrostatics Beyond the Point Charge Description 209 Derek Frydel First‐Passage Processes in Cellular Biology 261 Srividya Iyer‐Biswas and Anton Zilman Theoretical Modeling of Vibrational Spectra and Proton Tunneling in Hydrogen‐Bonded Systems 307 Marek Janusz Wójcik Index 343

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Book SynopsisRecent technological advances have provided unique opportunities for the exploration of alternatives to the industrial use of chemically produced synthetic colors. The most promising developments in this area have been in bio-pigmentation derived from microorganisms. This groundbreaking book reviews the current state of the science of bio-pigmentation, providing important insights into the molecular mechanisms of microbial biosynthesis of industrial pigments. Featuring contributions by leading researchers from both industry and academe, it explores the latest advances in the use of bio-pigments as safe, sustainable alternatives to chemically synthesized pigments, and provides extensive coverage the most promising sources of bio-pigments within the food, feed, and pharmaceutical industries. Proposes microbial uniqueness of coloration in variety of food, feed and pharmaceuticals Covers the basic science behind bio-pigmentation as well as the latest advances in the fielTable of ContentsList of Contributors xv Introduction xvii 1 Introduction of Natural Pigments From Microorganisms 1Siyuan Wang, Fuchao Xu, and Jixun Zhan 1.1 Introduction 1 1.2 Microbial Pigments from Eukaryotic Sources 2 1.2.1 Pigments from Algae 2 1.2.2 Pigments from Fungi 4 1.2.3 Pigments from Yeasts 7 1.3 Natural Pigments from Prokaryotes 9 1.3.1 Natural Pigments from Cyanobacteria 9 1.3.2 Natural Pigments from Bacteria 10 1.4 Conclusion 16 References 16 2 Establishing Novel Cell Factories Producing Natural Pigments In Europe 23Gerit Tolborg, Thomas Isbrandt, Thomas Ostenfeld Larsen, and Mhairi Workman 2.1 Introduction 23 2.2 Colorants 25 2.2.1 Classification of Colorants 25 2.2.2 Monascus Pigments 26 2.2.3 Biosynthesis of Monascus Pigments 29 2.2.4 Derivatives of Monascus Pigments 31 2.3 Screening for Monascus Pigment-Producing Cell Factories for the European Market 32 2.3.1 Cell Factory Selection and Identification 32 2.3.2 From Single Pigment Producers to High-Performance Cell Factories 33 2.4 Assessment of the Color Yield 34 2.4.1 Pigment Purification and Quantification 34 2.4.2 Detection and Identification 37 2.4.3 Quantification 38 2.4.4 CIELAB 41 2.5 Optimizing Cellular Performance: Growth and Pigment Production 41 2.5.1 Assessment of Classical Physiological Parameters 42 2.5.2 Media Composition 42 2.5.3 Cultivation Parameters 44 2.5.4 Type of Cultivation 46 2.5.5 Metabolic Engineering 48 2.6 Pigment Properties 50 2.7 Conclusion 51 References 51 3 Color-Producing Extremophiles 61Eva García-López, Alberto Alcázar, Ana María Moreno, and Cristina Cid 3.1 Introduction 61 3.2 Color-Producing Extremophiles 62 3.2.1 Thermophiles and Hyperthermophiles 63 3.2.2 Psychrophiles and Psychrotolerants 63 3.2.3 Alkaliphiles 66 3.2.4 Acidophiles 66 3.2.5 Piezophiles and Piezotolerants 66 3.2.6 Halophiles and Halotolerants 67 3.2.7 Radiophiles 67 3.3 Microbial Pigments 68 3.3.1 Chlorophylls and Bacteriochlorophylls 68 3.3.2 Carotenoids and Phycobilins 69 3.3.3 Violacein 70 3.3.4 Prodigiosin 70 3.3.5 Pyocyanin 70 3.3.6 Azaphilones 70 3.3.7 Bacteriorhodopsin 71 3.3.8 Cytochromes 71 3.3.9 Other 72 3.4 Biotechnological Applications of Microbial Pigments from Extremophiles 73 3.4.1 Applications in the Food Industry 74 3.4.2 Applications in the Pharmaceutical Industry 77 3.4.3 Applications in the Textile Industry 78 3.4.4 Applications as Laboratory Tools 78 3.4.5 Applications in Bioremediation 79 3.4.6 Development of Microbial Fuel Cells 79 3.4.7 Biotechnological Production of Natural Pigments 80 3.5 Conclusion 80 Acknowledgments 80 References 80 4 Current Carotenoid Production Using Microorganisms 87Laurent Dufossé 4.1 Introduction 87 4.2 β-carotene 88 4.2.1 B. trispora 88 4.2.2 Phycomyces blakesleeanus 90 4.2.3 Mucor circinelloides 91 4.2.4 Applications 91 4.3 Lycopene 91 4.3.1 B. trispora 92 4.3.2 Fusarium sporotrichioides 93 4.4 Astaxanthin 93 4.4.1 X. dendrorhous, Formerly Phaffia rhodozyma 94 4.4.2 Agrobacterium aurantiacum and Other Bacteria 95 4.4.3 Advantages over Other Carotenoids 95 4.4.4 Astaxanthin for Salmon and Trout Feeds 96 4.4.5 Astaxanthin for Humans 97 4.5 Zeaxanthin 97 4.6 Canthaxanthin 98 4.7 Torulene and Thorularhodin 99 4.8 Prospects for Carotenoid Production by Genetically Modified Microorganisms 99 4.8.1 Escherichia coli and Other Hosts 99 4.8.2 Directed Evolution and Combinatorial Biosynthesis 101 4.9 Conclusion 102 References 104 5 C50 Carotenoids: Occurrence, Biosynthesis, Glycosylation, and Metabolic Engineering For Their Overproduction 107Nadja A. Henke, Petra Peters-Wendisch, Volker F. Wendisch, and Sabine A.E. Heider 5.1 Introduction 107 5.2 Occurrence and Biological Function of C50 Carotenoids 108 5.3 Biosynthesis of C50 Carotenoids 110 5.4 Glycosylation of C50 Carotenoids 114 5.5 Overproduction of C50 Carotenoids by Metabolic Engineering 115 5.6 Conclusion 118 Acknowledgments 119 References 119 6 Biopigments and Microbial Biosynthesis of 𝛃-Carotenoids 127Rosemary C. Nwabuogu, Jennifer Lau, and Om V. Singh 6.1 Introduction 127 6.2 Characterization of Biological Pigments 129 6.2.1 Tetrapyrrole Derivatives 129 6.2.2 N-heterocyclic Derivatives 130 6.2.3 Isoprenoid Derivatives 131 6.2.4 Benzopran Derivatives 132 6.2.5 Quinones 132 6.2.6 Melanins 133 6.3 Biosynthetic Routes of β-carotene 133 6.3.1 Fermentation of β-carotene 138 6.4 Molecular Regulation of β-carotene Biosynthesis 146 6.5 Commercialization of β-carotene 147 6.6 Conclusion 151 References 151 7 Biotechnological Production of Melanins With Microorganisms 161Guillermo Gosset 7.1 Introduction 161 7.2 Microbial Production of Melanins 163 7.3 Production of Melanins with Engineered Microorganisms 165 7.4 Conclusion 169 References 170 8 Biochemistry and Molecular Mechanisms of Monascus Pigments 173Changlu Wang, Di Chen, and Jiancheng Qi 8.1 Introduction 173 8.2 Monascus Pigments 174 8.3 The Properties of Monascus Pigments 176 8.3.1 Solubility 176 8.3.2 Stability 177 8.3.3 Safety 177 8.4 Functional Properties of Monascus Pigments 177 8.4.1 Antimicrobial Activities 178 8.4.2 Anti-inflammatory Activities 178 8.4.3 Anti-obesity Activities 178 8.4.4 Anticancer Activities 178 8.5 Biosynthetic Pathway of Monascus Pigments 179 8.6 Biosynthetic Pathway of Related Genes 181 8.7 Factors Affecting Monascus Pigment Production 184 8.7.1 Solid-State Fermentation 185 8.7.2 Submerged Fermentation 186 8.7.3 Carbon Source 186 8.7.4 Nitrogen Source 187 8.7.5 Temperature 187 8.7.6 Light 187 References 187 9 Diversity and Applications of Versatile Pigments Produced By Monascus Sp 193Sunil H. Koli, Rahul K. Suryawanshi, Chandrashekhar D. Patil, and Satish V. Patil 9.1 Introduction 193 9.2 Pigment-Producing Monascus Strains 195 9.3 Various Types of Monascus Pigments 199 9.4 Extraction and Purification of Monascus Pigments 203 9.5 Detection and Purification 204 9.5.1 UV-Vis Spectrophotometric Methods 204 9.5.2 Column Chromatography 204 9.5.3 Thin-Layer Chromatography 205 9.5.4 High-Performance Liquid Chromatography 205 9.6 Applications 206 9.6.1 Food Colorants 206 9.6.2 Biological Role 206 9.7 Conclusion 209 Acknowledgments 209 References 209 10 Microbial Pigment Production Utilizing Agro-Industrial Waste and Its Applications 215Chidambaram Kulandaisamy Venil, Nur Zulaikha Binti Yusof, Claira Arul Aruldass, and Wan Azlina Ahmad 10.1 Introduction 215 10.2 Agro-industrial Waste Generation: A Scenario 216 10.3 Microbial Pigments 216 10.4 Production of Microbial Pigments Utilizing Agro-industrial Waste from Different Industries 223 10.5 Case Study: Production of Violacein by Chromobacterium violaceum Grown in Agricultural Wastes 225 10.5.1 Introduction 225 10.5.2 Materials and Methods 226 10.5.3 Results and Discussion 229 10.6 Conclusion 235 Acknowledgments 235 References 235 11 Microbial Pigments: Potential Functions and Prospects 241P. Akilandeswari and B.V. Pradeep 11.1 Introduction 241 11.1.1 Pigments 242 11.1.2 Types of Pigments 242 11.1.3 Microbial Pigments 242 11.1.4 Use of Pigments 243 11.1.5 Advantages of Natural Pigments 243 11.1.6 Disadvantages of Synthetic Dyes 243 11.2 Potential Sources of Microbial Pigments 244 11.2.1 Actinomycetes 244 11.2.2 Bacteria 245 11.2.3 Fungi 245 11.3 Physical Factors Influencing Microbial Pigments 246 11.4 Chemical Factors Influencing Microbial Pigments 247 11.5 Fermentation Practices in Pigment Production 248 11.5.1 Solid-State Fermentation 248 11.5.2 Submerged Fermentation 248 11.6 Characterization and Purification Analysis 249 11.7 Biocolors from Microbes and their Potential Functions 250 11.7.1 Pharmaceutical Industry 250 11.7.2 Food Colorants 255 11.7.3 Textile Dyeing 256 References 257 12 The Microbial World of Biocolor Production 263Roshan Gul, Raman Kumar, and Anil K. Sharma 12.1 Introduction 263 12.2 Pigments Produced by Microorganisms 265 12.3 Classification of Pigments 265 12.3.1 Riboflavin 265 12.3.2 β-carotene 265 12.3.3 Canthaxanthin 268 12.3.4 Carotenoids 268 12.3.5 Prodigiosin 268 12.3.6 Phycocyanin 268 12.3.7 Violacein 268 12.3.8 Astaxanthin 268 12.4 Benefits and Applications of Microbial Pigments 269 12.5 Conclusion 272 References 273 Index 279

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Book SynopsisThis third volume in a four-volume set offers new theories and applications for the diagnosis and treatment of mental disorders. Having laid the groundwork in the first two volumes, the authors now embark on significant, real-life scenarios that apply their philosophy to mental disorder treatments. The goal of the project is to take the industry toward sustainability, not just in terms of the chemical engineering used to create medicines, but also environmentally, economically, and personally. Their unique approach uses a more holistic and philosophically cohesive method for treating mental disorders, making the industry greener and the patient healthier. The four volumes in The Greening of Pharmaceutical Engineering are: Volume 1: Practice, Analysis, and Methodology Volume 2: Theories and Solutions Volume 3: Applications for Mental Disorder Treatments Volume 4: Applications for Physical Disorder Treatments<Table of ContentsPreface xi 1 Introduction 1 1.1 What If We Have Been in a Collective Delusional State? 1 1.2 Have We Been Bankrupted to Become Unhealthy? 3 1.3 Grounding Is Necessary but with What? 9 1.4 Do We Even Know the Difference Between a Genius and an Insane Person? 9 1.5 Is There a Continuity Among Depression, Dementia, and Schizophrenia? 10 1.6 How Can We Stop Being Self-Destructive? 11 1.7 Start Living Rather Than Making a Living: Make Humanity Great Again 11 2 A Model for Humanity and Human Behavior 13 2.1 Introduction 13 2.2 What Is a Human? 14 2.3 Aristotle’s Definition of Humans 38 2.4 Cognitive Process in Humans 49 2.5 The Nature Science Model of Humanity 86 3 Chemical Drugs for Mental Health Disorder 95 3.1 Introduction 95 3.2 Basic Anatomy 97 3.3 Antidepressants 107 3.4 Something ‘Left’ to Say About Serotonin 121 3.5 Connection of the Heart to Depression: The Intangible to the Tangible. 134 3.6 Additional Concerns 139 3.7 Bias in the Medical Research 145 3.8 Schizophrenia 161 3.9 Additional Comments and Conclusions 177 4 Psychological Grounding 179 4.1 Introduction 179 4.2 Culture of Fear 180 4.3 Have We Been Programed to Be Illogical? 184 4.4 Eurocentric Prejudice 206 4.5 Movement from Original Sin to Original Gene 212 4.6 Purpose of Life and Ideal Behavior 217 4.7 Looking at the Big Picture 227 4.8 The Truth Criterion 238 4.9 The Need for a Logical Standard 245 4.10 The Invocation of God 252 4.11 Is Invocation of God a Sound Premise? 254 4.12 Fundamental Traits of Phenomenal Entities 257 4.13 The Absolute Set of Fundamental Premises 261 4.14 Sufficiency of the Absolute Premises 264 4.15 Scientific Cognition Based on the Absolute Set of Fundamental Premises 265 5 Drivers of Mental Ailments and Natural Remedy 269 5.1 Introduction 269 5.2 Cause of Depression 270 5.3 Intangible Treatments for Depression 273 5.4 Tangible Treatments for Depression 298 6 Schizophrenia as a Tangible Expression of Mental Disorder 319 6.1 Introduction 319 6.2 Delinearized History of Schizophrenia 320 6.3 Intangible Treatments for Schizophrenia 329 6.4 Tangible Treatment of Schizophrenia 341 7 The Myopic Mindset of Self-Destruction 353 7.1 Introduction 353 7.2 The Oppression Syndrome 354 7.3 Gujarat Syndrome 370 8 Optimization of Lifestyle 383 8.1 Introduction 383 8.2 What Is Addiction? 385 8.3 Addictions that Start off as ‘Normal’ 386 8.4 Addiction and Compulsion 399 8.5 Towards Finding a Cure to Addiction 401 8.6 Dynamic Optimization 412 9 Conclusions 415 9.1 Summary 415 9.2 Conclusions of Chapter 2 416 9.3 Conclusions of Chapter 3 417 9.4 Conclusions of Chapter 4 418 9.5 Conclusions of Chapter 5 419 9.6 Conclusions of Chapter 6 419 9.7 Conclusions of Chapter 7 420 9.8 Conclusions of Chapter 8 421 References and Bibliography 423 Appendix A: 99 Godly Qualities of Humans 495 Appendix B: Diet for Sharpening the Brain 533 Appendix C: An Overall Guideline for Living 561 Index 583

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Book SynopsisThis book emphasizes the use of four complex plane formalisms (impedance, admittance, complex capacitance, and modulus) in a simultaneous fashion. The purpose of employing these complex planes for handling semicircular relaxation using a single set of measured impedance data (ac small-signal electrical data) is highly underscored. The current literature demonstrates the importance of template version of impedance plot whereas this book reflects the advantage of using concurrent four complex plane plots for the same data. This approach allows extraction of a meaningful equivalent circuit model attributing to possible interpretations via potential polarizations and operative mechanisms for the investigated material system. Thus, this book supersedes the limitations of the impedance plot, and intends to serve a broader community of scientific and technical professionals better for their solid and liquid systems. This book addresses the following highlighted contents for tTable of ContentsBackground of this Book xiii Acknowledgments xxiii 1 Introduction to Immittance Spectroscopy 1 1.1 Basic Definition and Background 1 1.2 Scope and Limitation 5 1.3 Applications of the Immittance Studies to Various Material Systems 6 1.4 Concept of the Linear Circuit Elements: Resistance, Capacitance, and Inductance 9 1.5 Concept of Impedance, Admittance, Complex Capacitance, and Modulus 13 1.6 Immittance Functions 21 1.7 Series Resonant Circuit 22 1.8 Parallel Resonant Circuit 23 1.9 Capacitance and Inductance in Alternating Current 24 Problems 24 References 25 2 Basics of Solid State Devices and Materials 27 2.1 Overview of the Fundamentals of Physical Electronics 27 2.2 Basics of Semiconductors 33 2.3 Single-Crystal and Polycrystal Materials 35 2.4 SCSJ and MPCHPH Systems 37 2.5 Representation of the Competing Phenomena 42 2.6 Effect of Normalization of the Electrical Parameters 43 Problems 46 References 47 3 Dielectric Representation and Operative Mechanisms 49 3.1 Dielectric Constant of Materials: Single Crystals and Polycrystals 49 3.2 Dielectric Behavior of Materials: Single Crystals and Polycrystals 53 3.3 Origin of Frequency Dependence 58 3.4 Effect of Polarization 60 3.5 Equivalent Circuit Representation of the Mechanisms and Processes 67 3.6 Defects and Traps 69 3.7 Point Defects and Stoichiometric Defects 77 3.8 Leaky Systems 78 Problems 79 References 80 4 Ideal Equivalent Circuits and Models 85 4.1 Concept of Equivalent Circuit 85 4.2 Simple and Basic Circuits in Complex Planes: R, C, R-C Series, and R-C Parallel 86 4.3 Debye Circuits: Single Relaxation 89 4.4 Duality of the Equivalent Circuits: Multiple Circuits for a Single Plane 97 4.5 Duality of Equivalent Circuits between Z*- and M*-Planes for Relaxations without Intercept 98 4.6 Duality of Equivalent Circuits between Y*- and C*-Planes for Relaxations without Intercept 100 4.7 Duality of Equivalent Circuits for Simultaneous Z*-, Y*-, C*-, and M*-Planes’ Relaxations 102 4.8 Proposition of Equivalent Circuit: Polycrystalline Grains and Grain Boundaries 103 Problems 105 References 106 5 Debye and Non-Debye Relaxations 109 5.1 Ideal Systems 109 5.2 Non-Ideal Systems 116 5.3 Non-Ideal Systems Implying Distributed Time Constants 122 5.4 D-C Representation, Depression Parameter, and Equivalent Circuit: Conventional Domain 128 5.5 Depression Parameter Based on ωτpeak = 1: Complex Domain 134 5.6 Optimization of ZHF: Complex Domain 137 5.7 Depression Parameter β Based on ωτpeak = 1 139 5.8 Feature of the Depression Parameter β Based on ωτ π 1 145 5.9 Analysis of the Havriliak-Negami Representation 146 5.10 Geometrical Interpretation of H-N Relaxation at the Limiting Case 151 5.11 Extraction of the Relaxation Time τ and the H-N Depression Parameters α and β 154 5.12 Checking Generalized Depression Parameter β when α is Real 159 5.13 Checking Generalized Depression Parameter α when β is Real 160 5.14 Effect of α and β on the H-N Distribution Function 162 5.15 Meaning of the Depression Parameters α and β 166 5.16 Relaxation function with Respect to the Depression Parameters α and β 168 Problems 170 References 170 6 Modeling and Interpretation of the Data 175 6.1 Equivalent Circuit Model for the Single Complex Plane (SCP) Representation 175 6.2 Models and Circuits 177 6.3 Nonconventional Circuits 184 6.4 Multiple Equivalent Circuits for Multiple Relaxations in a Single Complex Plane 186 6.5 Single Equivalent Circuit for Multiple Complex Planes 187 6.6 Equivalent Circuit for Resonance 189 6.7 Single Equivalent Circuit from Z*- and M*-Planes 189 6.8 Temperature and Bias Dependence of the Equivalent Circuit Modeling 190 6.9 Equivalent Circuit: Zinc Oxide (ZnO) Based Varistors 191 6.10 Equivalent Circuit: Lithium Niobate LiNbO3 Single Crystal 196 6.11 Equivalent Circuit: Polycrystalline Yttria (Y2O3) 200 6.12 Equivalent Circuit: Polycrystalline Calcium Zirconate (CaZrO3) 201 6.13 Equivalent Circuit: Polycrystalline Calcium Stannate (CaSnO3) 202 6.14 Equivalent Circuit: Polycrystalline Titanium Dioxide (TiO2) 203 6.15 Equivalent Circuit: Multi-Layered Thermoelectric Device (Alternate SiO2/SiO2+Ge Thin-Film) 204 6.16 Equivalent Circuit: Polycrystalline Tungsten Oxide (WO3) 206 6.17 Equivalent Circuit: Biological Material – E. Coli Bacteria 207 Problems 208 References 209 7 Data-Handling and Analyzing Criteria 213 7.1 Acquisition of the Immittance Data 213 7.2 Lumped Parameter/Complex Plane Analysis (LP/CPA) 214 7.3 Spectroscopic Analysis (SA) 222 7.4 Bode Plane Analysis (BPA) 225 7.5 Misrepresentation of the Measured Data 227 7.6 Misinterpretation of the Bode Plot: Equivalent Circuit 230 Problems 232 References 233 8 Liquid Systems 241 8.1 Non-Crystalline Systems: Liquids 241 8.2 Warburg and Faradaic Impedances 245 8.3 Constant Phase Element (CPE) 249 8.4 Biological Liquid: E. Coli Bacteria 251 Problems 255 References 256 9 Case Study 259 9.1 Analysis of the Measured Data: Aspects of Data-Handling/Analyzing Criteria 259 9.2 Case 1: Proper Physical Geometrical Factors 260 9.3 Case 2: Improper Normalization 262 9.4 Case 3: Effect of Electrode and Lead Wire 264 9.5 Case 4: Identification of Contributions to the Terminal Immittance 265 9.6 Case 5: Use of Proper Unit 267 9.7 Case 6: Demonstration of the Invalid Plot 270 9.8 Case 7: Obscuring Frequency Dependence 271 9.9 Case 8: Misnomer Nomenclature for the Complex Plane Plot 273 9.10 Case 9: Extraction of Equivalent Circuit from the Straight Line or the Non-Relaxation Curve 274 Problems 277 References 278 10 Analysis of the Complicated Mott-Schottky Behavior 283 10.1 Capacitance – Voltage (C-V) Measurement 283 10.2 The Mott-Schottky Plot 287 10.3 Arbitrary Measurement Frequency and Construction of the Deceiving Mott-Schottky Plot 296 10.4 Frequency-Independent Representation 297 10.5 Extraction of the Device-Related Parameters 299 Problems 302 References 303 11 Analysis of the Measured Data 307 11.1 Introduction and Background of the Immittance Data Analysis 307 11.2 Measurement of the Immittance Data and Complex Plane Analysis 312 11.3 Nonlinear Least Squares Estimation 314 11.3.1 Gauss-Newton Method (Algorithm) of Least Squares Estimation 317 11.3.2 Levenberg-Marquardt Method (Algorithm) of Least Squares Estimation 320 11.3.3 Numerical Procedure to Calculate Jacobian Matrix 321 11.3.4 Error Analysis: Analysis of Errors in Regression 321 11.3.5 Selection of the Weights 322 11.4 Complex Nonlinear Least Squares (CNLS) Fitting of the Data 323 11.4.1 Procedure 1: Geometrical Fitting in the Complex Plane 323 11.4.2 Procedure 2: Simultaneous Fitting of Real and Imaginary Parts 328 11.5 Graphical User Interface Implementation of the Nonlinear Least Square Procedures: Implementation of CNLS using MATLAB 330 11.5.1 Input Data Generation 330 11.5.2 Input Data Processing 331 11.5.2.1 Visualization of the Measured (Raw) Data 332 11.5.2.2 Selection of Data Points for Fitting 333 11.5.2.3 Fitting of the Semicircle: Geometric Fitting 334 11.5.2.4 Calculation of the Parameters from the Semicircle Fitting 335 11.5.2.5 Calculation of the Parameters from the Simultaneous Fitting of Real and Imaginary Parts 336 11.5.3 Output Generation: Output File 337 11.5.3.1 Parameters from the Semicircle Fitting 337 11.5.3.2 Nonlinear Regression: Semicircle Fitting Output 337 11.5.3.3 Linear Regression: Line Fitting Output 338 11.5.3.4 Parameters from Simultaneous Fitting of Real and Imaginary Data 338 11.5.3.5 Nonlinear Regression: Simultaneous Fitting of Real and Imaginary Data Output 338 11.5.3.6 Measured Data used in Analysis 339 11.6 Effect of Fitting Procedure, Measurement Noise, and Solution Algorithm on the Estimated Parameters 340 11.7 Case Studies: CNLS Fitting of the Measured Data in the Complex Planes 342 11.7.1 M*-Plane Fitting: R-C Parallel Circuit 343 11.7.2 C*- and M*-Plane Representations of the Lithium Niobate (LN) Crystal 344 11.7.3 Z*- and Y*-Plane Representations of Multi-Layered Junction Device 349 11.7.4 Y*-plane Representation of the E. Coli Bacteria in Brain Heart Infusion Medium 351 11.8 Summary 353 Problems 355 References 357 12 Items for Appendix 363 12.1 Appendix – A: Sample Input Data for the R-C Parallel Circuit 363 12.2 Appendix – B: R-C Parallel Circuit Data Analysis Output in Z*-Plane 364 12.3 Appendix – C: R-C Parallel Circuit Data Analysis Output in M*-Plane 368 12.4 Appendix – D: Lithium Niobate Crystal Data Analysis Output in C*-Plane 370 12.5 Appendix – E: Multilayer Junction Thermoelectric Device Data Analysis Output in Y*-Plane 372 Index

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Book SynopsisThis book focuses on the chemistry of marine polymers, waterborne polymers, and water-resistant polymers, as well as the special applications of these materials. After the chemistry of marine polymers and their types are discussed, the uses of these polymers are detailed, as well as various analytical and characterization testing methods. The book also emphasizes the polymers that are most environmentally-friendly along with their origin and industrial applications. The polymers from these 3 types serve a variety of industries including medical equipment and devices, outdoor coatings and corrosion protection, food packaging, saltwater and freshwater marine purposes such as marine ropes, boat coatings, pipeline protection, and marine well application, to name just a few.Table of ContentsPreface ix 1 Marine Polymers 1 1.1 Marine Microbes 1 1.2 Marine Microgels 2 1.3 Polymer Production from Marine Algae 2 1.3.1 Recovery of Lipids Algae 5 1.3.2 Conversion of Algal Lipids into Hydrocarbons 6 1.3.3 Conversion of Algal Lipids into Polymers 6 1.3.4 Crosslinking of Phenolic Polymers 6 1.4 Marine Bioadhesive Analogs 7 1.5 Medical Applications 8 1.5.1 Metalloproteinases 9 1.5.2 Fucoidans 10 1.6.3 Chitosan 12 1.5.4 Collagen 14 1.5.5 Shark Collagen for Cell Culture and Zymography 15 1.5.6 Glycosaminoglycans 16 1.5.7 Anticholinesterase 16 1.5.8 Terpenoids 18 1.5.9 Membrane-Active Peptides 19 1.6 Polymer Production from Marine Sponge 19 1.7 Chitin and Chitosan from Marine Origin 20 1.8 Carbohydrates 22 1.8.1 Polysaccharides of Marine Origin 23 1.8.2 Oligosaccharides 23 1.9 Poly(3-hydroxy butyrate) from Marine Bacteria 25 1.10 Metal Ion Absorption 26 1.11 Fish Elastin Polypeptide 26 1.12 Cosmetic Uses 27 1.13 Protein Hydrolyzate 28 References 28 2 Marine Applications 35 2.1 Marine Polymer Coatings 35 2.1.1 Dextrine-Modified Chitosan Marine Polymer Coatings 35 2.1.2 Marine Structure Coated with an Acrylic Water-Swellable Polymer 36 2.1.3 Styrene Copolymer Compositions 43 2.1.4 Ethylene-Vinyl Acetate Emulsion Copolymers 43 2.1.5 Epoxy Coatings 45 2.1.6 Composites from Plant Oils 48 2.1.7 Inherently Metal Binding Poly(amine) Quinone Polymers 56 2.2 Foams 61 2.2.1 Polyimide Foams 61 2.3 Antifouling 63 2.3.1 Fouling Problems 63 2.3.2 Mechanism of Fouling 64 2.3.3 Fouling Control 65 2.3.4 Nontoxic Polymer Surfaces 66 2.3.5 Amphiphilic Polymers 66 2.3.6 Fouling Release Properties of Metal Surfaces 67 2.3.7 Copper Marine Cladding Composition 68 2.3.8 Preventive Agents against Adhesion of Marine Organisms 70 2.3.9 Self-Polishing Paint 71 2.3.10 Copper-Nickel Epoxy Coating 73 2.3.11 Antifouling Paint 74 2.3.12 Cationic Poly(siloxane)s 75 2.4 Electrochemical Impedance and Noise Data for PolymerCoated Steel 78 2.5 Seawater Immersion Ageing of Glass-Fiber Reinforced Polymer Laminates 78 2.6 Post-Fire Mechanical Properties of Marine Polymer Composites 79 2.7 Corrosion 80 2.7.1 Iron-Containing Substrata 80 2.7.2 Polymethylenepolyamine dipropionamides 80 2.7.3 Thioheterocyclic Rust and Corrosion-Inhibiting Agents 81 2.7.4 Epoxy Compounds 82 2.7.5 Poly(aniline) Graft Copolymers 82 2.7.6 Imidazolines 83 2.8 Marine Ropes 84 2.9 Marine Diesel Engine Lubricants 85 2.9.1 Dispersant Additive Composition 85 2.9.2 Overbased Alkyphenates 85 2.9.3 Overbased Metal Salts 86 2.9.4 Alkylsalicylate Lubricant Compositions 87 2.9.5 Biodegradable Lubricants 88 2.10 Lubricant for Smoothing Caulking Joints 89 2.11 Marine Well Applications 89 2.11.1 Marine Oil Spills Oil Separation and Disposal Systems 89 2.11.2 Marine Umbilicals 91 2.11.3 Hagfish Slime 94 2.11.4 Adhesive Compositions 94 2.11.5 Bit Lubricants 95 References 96 3 Waterborne Polymers 103 3.1 Analytical and Characterization Techniques 103 3.1.1 Surface Tension 104 3.2 Synthesis Methods 104 3.2.1 Atom Transfer Radical Polymerization 104 3.3 Aqueous Dispersions of Pigments 105 3.4 Waterborne Coatings 106 3.4.1 Food Packaging 107 3.4.2 Unsaturated Polyesters 109 3.4.3 Coatings with Pendant Allyl Groups 109 3.4.4 UV-Curable Latex Coating 114 3.4.5 Poly(urethane)s 122 3.4.6 Acrylic Coatings 145 3.4.7 Epoxy Coatings 148 3.4.8 Phenol Resins 148 3.4.9 Amide Resins 149 3.4.10 Poly(carbodiimide)s 149 3.4.11 Silicones 152 3.5 Special Applications 153 3.5.1 Waterborne Silicone Mold Release Agents 153 3.5.2 Stabilizers for Sandy Soil 154 3.5.3 Water, Oil, and Stain Repellency 154 3.5.4 Protective Coatings for Culturally Significant Objects 155 3.5.5 Waterborne Adhesives 155 3.5.6 Latex 156 3.5.7 Wet Labeling 159 3.5.8 Aqueous Polymeric Dispersions 161 3.5.9 Waterborne Soft-Feeling Coatings 163 3.5.10 Waterborne Polymeric Photoinitiators 165 References 166 4 Water-Resistant Polymers 173 4.1 Coatings 173 4.1.1 Polyolefin Coatings 173 4.1.2 Adherent Coatings 176 4.1.3 Wire Coatings 177 4.2 Biodegradable Resins 178 4.3 Water-Based Printing Inks 179 4.4 Reinforcing Fibers 181 4.5 Paper Industry Applications 183 4.5.1 Ketene Dimers 183 4.5.2 Anhydrides for Sizing 184 4.5.3 Epoxidized Soybean Oil 185 4.6 Masonry Products 186 4.7 Medical Uses 189 4.7.1 Tissue Engineering 189 4.7.2 Tooth Cleaning 189 4.8 Membranes 192 4.8.1 Microfiltration Membranes 192 4.8.2 Biobased Nanofiber Membranes 193 4.9 Personal Care Compositions 194 4.10 Package Uses 195 4.10.1 Adhesives for Beverage Labels 195 4.11 Grouting Compositions 197 4.11.1 Alginates 198 4.11.2 Dopamine 198 4.12 Xerogels 200 References 202 Index 207 Acronyms 207 Chemicals 209 General Index 218

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Book SynopsisIs zero waste engineering possible? This book outlines how to achieve zero waste engineering, following natural pathways that are truly sustainable. Using methods that have been developed in various areas for sustainability purposes, such as new mathematical models, recyclable material selection, and renewable energy, the authors probe the principles of zero waste engineering and how it can be applied to construction, energy production, and many other areas of engineering. This groundbreaking new volume: Explores new scientific principles on which sustainability and zero waste engineering can be based Presents new models for energy efficiency, cooling processes, and natural chemical and material selection in industrial applications and business Explains how green buildings and green homes can be efficiently built and operated with zero waste Offers case histories and successful experiments in sustainability and zeroTable of ContentsPreface xiii 1 Introduction 1 1.1 Background 1 1.2 The Deficiency of Current Engineering Practices 8 1.3 The Zero-Waste Approach 17 1.4 Scope of the Book 17 1.5 Organization of the Book 19 2 A Delinearized History of Time and Its Impact on Scientific Cognition 23 2.1 Introduction 23 2.2 The Importance of The Continuous Long-Term History 28 2.3 Delinearized History of Time and Knowledge 32 2.4 Role of Water, Air, Clay and Fire in Scientific Characterization 52 2.5 A Reflection on the Purposes of Sciences 70 2.6 Role of Intention in Technology Development 86 2.7 Cyclic Nature of Civilization 90 2.8 About the “New Science” of Time and Motion 98 2.9 What is New Versus what is Permitted: Science and the Establishment? 117 2.10 The Nature-Science Approach 127 2.11 Conclusions 134 3 Towards Modeling of Zero-Waste Engineering Processes with Inherent Sustainability 137 3.1 Introduction 137 3.2 Development of a Sustainable Model 139 3.3 Problem with the Current Model: The Case of Electricity 140 3.4 How Could We Have Averted the Downturn? 161 3.4.1 Violation of Characteristic Time 167 3.5 Observation of Nature: Importance of Intangibles 169 3.6 Analogy of Physical Phenomena 173 3.7 Intangible Cause to Tangible Consequence 174 3.8 Removable Discontinuities: Phases and Renewability of Materials 175 3.9 Rebalancing Mass and Energy 176 3.10 ENERGY — The Existing Model 178 3.11 Conclusions 181 4 The Formulation of a Comprehensive Mass and Energy Balance Equation 183 4.1 Introduction 183 4.2 The Law of Conservation of Mass and Energy 188 4.3 Continuity of Matter and Phase Transition 189 4.4 The Science of Water and Oil 205 4.5 From Natural Energy to Natural Mass 230 4.6 The Avalanche Theory of Mass and Energy 256 4.7 Aims of Modeling Natural Phenomena 262 4.8 Simultaneous Characterization of Matter and Energy 264 4.9 Consequences of Nature-Science for Classical Set Theory and Conventional Notions of Mensuration 269 4.10 Conclusions 271 5 Colony Collapse Disorder (CCD) and Honey Sugar Saccharine Aspartame (HSSA) Degradation in Modern Engineering 273 5.1 Introduction 273 5.2 Background 274 5.3 The Need for the Science of Intangibles 275 5.4 The Need for Multidimensional Study 284 5.5 Assessing the Overall Performance of a Process 290 5.6 Facts about Honey and the Science of Intangibles 295 5.7 CCD In Relation to Science of Tangibles 303 5.8 Possible Causes of CCD 311 5.9 The HSS®A® (Honey → Sugar → Saccharin® → Aspartame®) Pathway 322 5.10 Honey and Cancer 344 5.11 The Sugar Culture and Beyond 362 5.12 The Culture of the Artificial Sweetener 368 5.13 The Honey-Sugar-Saccharin-Aspartame Degradation in Everything 406 5.14 The Nature Science Approach 411 5.15 A New Approach to Product Characterization 413 5.16 A Discussion 416 5.17 Conclusions 419 6 Zero-Waste Lifestyle with Inherently Sustainable Technologies 421 6.1 Introduction 421 6.2 Energy from Kitchen Waste (KW) and Sewage 425 6.3 Utilization of Produced Waste in a Desalination Plant 432 6.4 Solar Aquatic Process to Purify Desalinated/Waste Water 438 6.5 Direct Use of Solar Energy 445 6.6 Sustainability Analysis 451 7 A Novel Sustainable Combined Heating/Cooling/Refrigeration System 455 7.1 Introduction 455 7.2 Einstein Refrigeration Cycle 458 7.3 Thermodynamic Model and its Cycle’s Energy Requirement 460 7.4 Solar Cooler and Heat Engine 463 7.5 Actual Coefficient of Performance (COP) Calculation 464 7.6 Absorption Refrigeration System 466 7.7 Calculation of Global Efficiency 468 7.8 Solar Energy Utilization in the Refrigeration Cycle 475 7.9 The New System 476 7.8 Pathway Analysis 478 7.9 Sustainability Analysis 482 7.10 Conclusions 484 8 A Zero-Waste Design for Direct Usage of Solar Energy 487 8.1 Introduction 487 8.2 The prototype 491 8.3 Results and Discussion of Parabolic Solar Technology 495 8.4 Conclusions 502 9 Investigation of Vegetable Oil as The Thermal Fluid in A Parabolic Solar Collector 503 9.1 Introduction 503 9.2 Experimental Setup and Procedures 507 9.3 Experimental Procedure 511 9.4 Results and Discussion 511 9.5 Conclusions 515 10 The Potential of Biogas in Zero-Waste Mode of a Cold-Climate Environment 517 10.1 Introduction 517 10.2 Background 518 10.3 Biogas Fermentation 520 10.4 Factors Involved in Anaerobic Digestion 521 10.5 Heath and Environmental Issue 526 10.6 Digesters in Cold Countries 528 10.7 Experimental Setup and Procedures 529 10.8 Discussion 532 10.9 Conclusions 536 11 The New Synthesis: Application of All Natural Materials for Engineering Applications 537 11.1 Introduction 537 11.2 Metal Waste Removal with Natural Materials 538 11.3 Natural Materials as Bonding Agents 544 12 Economic Assessment of Zero-Waste Engineering 569 12.1 Introduction 569 12.2 Delinearized History of the Modern Era 570 12.3 Insufficiency of Conventional Economic Models 581 12.4 The New Synthesis 584 12.5 The New Investment Model, Conforming to the Information Age 587 12.6 The Most Important Research Questions in the Information Age 590 12.7 Future Engineering Projects 594 12.8 Economics of Zero-Waste Engineering Projects 595 12.9 Quality of Energy 605 12.10 Conclusions 607 13 General Conclusions and Recommendations 609 13.1 Summary 609 13.2 Conclusions 613 13.3 Recommendations 615 13.4 Future Projects 616 References and Bibliography 619 Index 665

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Book SynopsisThis book will have the recent information on the developments in the emerging field of environmental-friendly coatings. Crucial aspects associtaed with coating research will be presented in form of the indivudual chapters. Close attention will be paid to include essential aspects that are necessary to understand the porperties and applications of the novel materials. Different methods and techniques of synthesis and charcaterization will be detailed as individual chapters. It will also discuss the characterization techniques used in the area of such coatings. there will be chapters that descirbe the current status and future prospects. The topics will be selected so they are easy to understand and useful to new scholars as well as advanced learners. No book has been written on this subject so far.Table of ContentsPreface xi 1 Novel Bio-based Polymers for Coating Applications 1 Harjoyti Kalita, Deep Kalita, Samim Alam, Andrey Chernykh, Ihor Tarnavchyk, James Bahr, Satyabrata Samanta, Anurad Jayasooriyama, Shashi Fernando, Sermadurai Selvakumar, Dona Suranga Wickramaratne, Mukund Sibi, and Bret J. Chisholm 1.1 Introduction 1 1.2 Polymers Based on Plant Oils 3 1.2.1 Properties of Homopolymers and Their Surface Coatings 5 1.2.2 Properties of Copolymers and Their Surface Coatings 7 1.3 Polymers Based on Cardanol 9 1.4 Polymers Based on Eugenol 10 1.5 Conclusion 14 Acknowledgments 14 Disclaimer 14 References 15 2 Deposition of Environmentally Compliant Cerium-Containing Coatings and Primers on Copper-Containing Aluminium Aircraft Alloys 17 Stephan V. Kozhukharov 2.1 Importance and Indispensability of the Corrosion-Protective Coating Layers 17 2.1.1 Employment of Reliable Materials for the Aircraft Industry 17 2.1.2 Corrosion Phenomena, Basic Definitions and Concepts 20 2.1.3 Brief Summary 22 2.2 Introduction to the Cerium Conversion Primer Layers 23 2.2.1 Background and Basic Definitions 23 2.2.2 Deposition Methods 23 2.2.3 Technical Stages of CeCC Deposition 25 2.2.3.1 Preliminary Treatment Procedures 25 2.2.3.2 Deposition Process, Mechanisms and Factors 28 2.2.3.3 Posterior Sealing Procedures 37 2.2.4 Brief Summary 37 2.3 Elaboration of Hybrid and Composite Upper and Finishing Coating Layers 38 2.3.1 Advantages of the Hybrid Coatings Systems 38 2.3.2 Technological Bases of the Sol–Gel Approach 43 2.3.3 Hybrid Nanocomposite Primer Coatings: Basic Concepts 46 2.3.4 Corrosion Inhibitors as Self-Healing Coating Ingredients 47 2.3.4.1 Rare Earth Salts as Corrosion Inhibitors 47 2.3.4.2 Organic Compounds as Corrosion Inhibitors 52 2.3.5 Technological Features of the Production of Hybrid Nanocomposite Primer Coatings 53 2.3.6 Alternatives for the Inhibitor Containing Self-Healing Coatings 54 2.3.6.1 Coatings with Recuperative Microcapsules 54 2.3.6.2 Exterior Ice-Phobic and UV Protective Finishes 55 2.3.7 Brief Summary 57 Acknowledgment 58 References 58 3 Ferrites as Non-toxic Pigments for Eco-friendly Corrosion Protection Coatings 71 D.O. Grigoriev, T. Vakhitov, and S.N. Stepin 3.1 Introduction 71 3.2 Crystalline Structure, Physicochemical Properties, and Inhibition Mechanism of Ferrites 72 3.3 Methods for the Preparation of Ferrites 76 3.3.1 Ceramic Method 76 3.3.2 Ceramic Method with Utilizing Industrial Wastes 78 3.3.3 Other Methods of Ferrites Preparation 79 3.4 Novel Types of Ferrite Pigments 81 3.5 Ferrite-Based Multifunctional Coatings 83 3.6 Conclusion 84 Acknowledgement 84 References 84 4 Application of Coatings and Films in Fruits and Vegetables 87 R.K. Dhall 4.1 Introduction 87 4.2 Coatings versus Films 88 4.3 Structural Matrix: Hydrocolloids and Lipids 88 4.4 Application of Hydrocolloids Coatings 89 4.5 Application of Lipid Coatings 91 4.6 Application of Composite Coatings 91 4.7 Addition of Active Compounds 93 4.7.1 Antimicrobial Coatings 93 4.7.2 Antioxidant Coatings 95 4.7.3 Texture Enhances 96 4.7.4 Nutraceutical Coatings 97 4.8 Nanotechnology 97 4.9 Commercial Application of Edible Coatings 98 4.10 Problems Associated with Edible Coatings 98 4.11 Regulatory Status and Food Safety Issues 104 4.12 Conclusions 105 References 106 5 Development of Novel Biobased Epoxy Films with Aliphatic and Aromatic Amine Hardeners for the Partial Replacement of Bisphenol A in Primer Coatings 121 Rafael S. Peres, Carlos A. Ferreira, Carlos Alemán, and Elaine Armelin 5.1 Introduction 121 5.2 Recent Advances on Vegetable Oils Chemistry 123 5.3 Control of the Epoxidation Reaction of Vegetable Oils 125 5.4 Spectroscopy Characterization of Epoxidized Linseed Oil Cured with Amine Hardeners 128 5.5 Thermal Properties of Epoxidized Linseed Oil Cured with Amine Hardeners 134 5.6 Swelling, Wettability and Morphology of New Epoxy Films 136 5.7 Mechanical Properties of Epoxidized Linseed Oil Cured with Amine Hardeners 139 5.8 Applications of Vegetable Oils in Coatings 140 5.9 Conclusions 142 Acknowledgments 142 References 143 6 Silica-Based Sol–Gel Coatings: A Critical Perspective from a Practical Viewpoint 149 Rosaria Ciriminna, Alexandra Fidalgo, Giovanni Palmisano, Laura M. Ilharco, and Mario Pagliaro 6.1 Introduction: Need of Practical Perspective 149 6.2 A Green, Simple Technology 151 6.3 The Market 152 6.4 Conclusions 157 Acknowledgements 157 References 158 7 Fatty Acid-Based Waterborne Coatings 161 Mónica Moreno, Monika Goikoetxea, and María J. Barandiaran 7.1 Introduction 161 7.2 Fatty Acids as Raw Materials 163 7.2.1 Chemical Modification of Fatty Acids for Free Radical Polymerization 164 7.3 Polymerization of Fatty Acid-Based Monomers in Aqueous Media 167 7.3.1 Emulsion Polymerization 167 7.3.2 Miniemulsion Polymerization 170 7.3.3 Effect of Preserving Alkyl Double Bonds 172 7.3.3.1 Kinetics and Microstructural Properties 172 7.3.3.2 Auto-Oxidative Curing and Mechanical Properties 174 7.3.3.3 Effect of Incorporating α-MBL as Comonomer 175 7.4 Incorporation of Fatty Acid Derivatives in Waterborne Coatings 176 7.5 Conclusion 178 References 179 8 Environmentally Friendly Coatings 183 Xiaofeng Ren, Lei Meng, and Mark Soucek 8.1 Waterborne Coatings 183 8.1.1 Introduction of Waterborne Coatings 183 8.1.2 History of Waterborne Coatings 184 8.1.3 Category of Waterborne Coatings 186 8.1.3.1 Water-Reducible Coatings 187 8.1.3.2 Latex Coatings 187 8.1.3.3 Emulsion Coatings 188 8.1.4 Development and Prospect of Waterborne Coatings 192 8.1.4.1 Development of Resins Used in Waterborne Systems 192 8.1.4.2 Combination of Waterborne with Other Techniques 194 8.2 Seed Oil-Based Coatings 195 8.2.1 Seed Oils 195 8.2.2 Seed Oil-Based Coatings from Copolymerization with Vinyl Monomers 198 8.2.2.1 Seed Oil-Based Reactive Diluents for Coating Applications 198 8.2.3 Seed Oil-Based Epoxy for UV-Curable Coatings 201 8.2.4 Seed Oil-Based Polyurethanes 205 8.2.5 Seed Oil-Based Thiol-ene Chemistry in UV-Curable Coatings 206 8.2.6 Seed Oil-Based Organic–Inorganic Coatings 209 8.2.7 Seed Oil-Based Alkyd Coatings 211 8.2.7.1 Introduction of Alkyds 211 8.2.7.2 Modified Alkyds for Coatings 213 8.3 Conclusion 219 References 219 9 Low-Temperature Aqueous Coatings for Solar Thermal Absorber Applications 225 Saleh Khamlich and Malik Maaza 9.1 Introduction 225 9.2 Samples Preparation 228 9.3 Structural and Morphological Investigations of α-Cr2O3 Monodispersed Meso-Spherical Particles 228 9.3.1 Raman Spectroscopic Study 228 9.3.2 Attenuated Total Reflection Study 229 9.3.3 Field-Emission Scanning Electron Microscopy (FESEM) and Energy-Dispersive X-Ray Analysis (EDX) 230 9.4 Growth Mechanism 231 9.4.1 Development of a Mathematical Model [Lifshitz–Slyozov–Wagner (LSW) Model] 232 9.4.1.1 Basic Assumptions 232 9.4.1.2 Mathematical Formulation 233 9.5 Potential Applications in Solar Absorbers 238 9.5.1 Diffuse Reflectance and the Infrared Emissivity (ε) Study of α-Cr2O3 Meso-spherical Particles 239 9.6 Conclusions 240 Acknowledgements 240 References 241 10 Eco-Friendly Recycled Pharmaceutical Inhibitor/Waste Particle Containing Hybrid Coatings for Corrosion Protection 245 Victoria Bustos, Liseth Concha, Carmina Menchaca-Campos, Jorge Uruchurtu, Mario A. Romero, Marcos Esparza, Alba Covelo, Miguel Hernandez, and Estela Sarmiento 10.1 Introduction 245 10.1.1 Recycled Pharmaceutical Inhibitors 246 10.1.2 Hybrid Coatings 247 10.2 Hybrid Coating Preparation 247 10.2.1 Recycled Pharmaceutical Inhibitors 247 10.2.2 Mesoporous Particles 248 10.2.3 Hybrid Coating 248 10.2.3.1 Characterization 248 10.3 Hybrid Coatings Performance 249 10.3.1 Materials Characterization 249 10.3.2 Electrochemical Inhibitor Evaluation 249 10.3.2.1 Potentiodynamic Polarization 250 10.3.2.2 Electrochemical Impedance 251 10.3.3 Electrochemical Hybrid Coating Evaluation 253 10.4 Conclusions 254 Acknowledgment 255 References 255 11 Chemical Interaction of Modified Zinc–Phosphate Green Pigment on Waterborne Coatings in Steel 257 Miguel Hernandez, Alba Covelo, and Jorge Uruchurtu 11.1 Introduction 257 11.2 Cathodic Delamination of Coatings 258 11.3 Modified Zinc–Phosphate Pigment 260 11.4 Conclusions 263 Acknowledgement 263 References 263 12 Development of Soybean Oil-Based Polyols and Their Applications in Urethane and Melamine-Cured Thermoset Coatings 265 Senthilkumar Rengasamy and Vijay Mannari 12.1 Introduction 265 12.2 Experimental 266 12.2.1 Raw Materials 266 12.2.2 Standard Testing Methods 267 12.2.3 Coating Composition and Sample Preparation 267 12.2.4 Synthesis of ESO-Based Phosphate Ester Polyol (ESO–Polyol) 267 12.2.5 Synthesis of Epoxidized Soybean Oil Monoglyceride (EMG) 267 12.2.6 Synthesis of EMG-Based Phosphate Ester Polyol (EMG Polyol) 268 12.2.7 Synthesis of EMG-Based Phthalic Acid Ester Polyol (EMG–PEP) 269 12.3 Results and Discussion 270 12.3.1 Characterization of Polyols 270 12.3.2 Proton NMR Characterization 271 12.3.3 FTIR Characterization 271 12.3.4 Urethane and Melamine-Cured Film Properties 273 12.4 Conclusion 275 Acknowledgements 276 References 276 13 Powder Coatings from Recycled Polymers and Renewable Resources 279 Martino Colonna, Claudio Gioia, Annamaria Celli, and Alessandro Minesso 13.1 Introduction 279 13.2 Powder Coating as a Green Approach to Coatings 280 13.3 The Use of Materials from Renewable Resources in Powder Coating Applications 283 13.4 The Use of Recycled Polymers for the Preparation of Coatings 286 13.5 Powder Coatings from the Combined Chemical Recycle of Polymers and the Use of Renewable Resources 289 13.5.1 Depolymerization of PET with Isosorbide 292 13.5.1.1 Catalysts Used for the Depolymerization of PET with Isosorbide 292 13.5.1.2 Depolymerization Process 292 13.5.1.3 Polycondensation after Glycolysis with Isosorbide 293 13.5.2 Coatings Application Tests 293 13.5.2.1 Blooming Resistance 294 13.5.2.2 Effect of Overbaking 295 13.5.2.3 Effect of Ageing 296 13.5.2.4 Solvent Resistance 296 13.5.3.5 Boiling Water Resistance Tests 297 13.6 Conclusions 297 References 29814 Th e Synthesis and Applications of Non-isocyanate Based Polyurethanes as Environmentally Friendly “Green” Coatings 301 Peter Zarras, Paul A. Goodman, Alfred J. Baca, Joshua E. Baca, and Shelley Vang 14.1 Introduction to Isocyanate-based Polyurethane Chemistry 301 14.2 Synthesis of Isocyanates 302 14.3 Toxicological Properties of Isocyanates 303 14.4 Synthesis of Phosgene-free Precursors 304 14.5 Non-isocyanate-based Polyurethanes (NIPU) 305 14.5.1 Polycondensation Reaction 306 14.5.2 Polyaddition Reaction 308 14.5.3 Additional Polymerization Reactions Leading to Non-isocyanate Polyurethanes (NIPU) 309 14.6 Applications of Non-isocyanate Polyurethanes (NIPU) 310 14.7 Conclusions 311 Acknowledgements 311 References 311

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Book SynopsisDetails methods for computing valid limits of detection.Table of ContentsPreface xv Acknowledgment xix About the Companion Website xx 1 Background 1 1.1 Introduction 1 1.2 A Short List of Detection Limit References 2 1.3 An Extremely Brief History of Limits of Detection 2 1.4 An Obstruction 3 1.5 An Even Bigger Obstruction 3 1.6 What Went Wrong? 4 1.7 Chapter Highlights 5 References 5 2 Chemical Measurement Systems and their Errors 9 2.1 Introduction 9 2.2 Chemical Measurement Systems 9 2.3 The Ideal CMS 10 2.4 CMS Output Distributions 12 2.5 Response Function Possibilities 12 2.6 Nonideal CMSs 15 2.7 Systematic Error Types 15 2.7.1 What Is Fundamental Systematic Error? 16 2.7.2 Why Is an Ideal Measurement System Physically Impossible? 16 2.8 Real CMSs, Part 1 17 2.8.1 A Simple Example 18 2.9 Random Error 19 2.10 Real CMSs, Part 2 21 2.11 Measurements and PDFs 22 2.11.1 Several Examples of Compound Measurements 22 2.12 Statistics to the Rescue 23 2.13 Chapter Highlights 24 References 24 3 The Response, Net Response, and Content Domains 25 3.1 Introduction 25 3.2 What is the Blank’s Response Domain Location? 27 3.3 False Positives and False Negatives 28 3.4 Net Response Domain 29 3.5 Blank Subtraction 29 3.6 Why Bother with Net Responses? 31 3.7 Content Domain and Two Fallacies 31 3.8 Can an Absolute Standard Truly Exist? 33 3.9 Chapter Highlights 34 References 34 4 Traditional Limits of Detection 37 4.1 Introduction 37 4.2 The Decision Level 37 4.3 False Positives Again 38 4.4 Do False Negatives Really Matter? 40 4.5 False Negatives Again 40 4.6 Decision Level Determination Without a Calibration Curve 41 4.7 Net Response Domain Again 41 4.8 An Oversimplified Derivation of the Traditional Detection Limit, XDC 42 4.9 Oversimplifications Cause Problems 43 4.10 Chapter Highlights 43 References 43 5 Modern Limits of Detection 45 5.1 Introduction 45 5.2 Currie Detection Limits 46 5.3 Why were p and q Each Arbitrarily Defined as 0.05? 48 5.4 Detection Limit Determination Without Calibration Curves 49 5.5 A Nonparametric Detection Limit Bracketing Experiment 49 5.6 Is There a Parametric Improvement? 51 5.7 Critical Nexus 52 5.8 Chapter Highlights 53 References 53 6 Receiver Operating Characteristics 55 6.1 Introduction 55 6.2 ROC Basics 55 6.3 Constructing ROCs 57 6.4 ROCs for Figs 5.3 and 5.4 59 6.5 A Few Experimental ROC Results 60 6.6 Since ROCs may Work Well, Why Bother with Anything Else? 64 6.7 Chapter Highlights 65 References 65 7 Statistics of an Ideal Model CMS 67 7.1 Introduction 67 7.2 The Ideal CMS 67 7.3 Currie Decision Levels in all Three Domains 70 7.4 Currie Detection Limits in all Three Domains 71 7.5 Graphical Illustrations of eqns 7.3–7.8 72 7.6 An Example: are Negative Content Domain Values Legitimate? 74 7.7 Tabular Summary of the Equations 76 7.8 Monte Carlo Computer Simulations 77 7.9 Simulation Corroboration of the Equations in Table 7.2 78 7.10 Central Confidence Intervals for Predicted x Values 80 7.11 Chapter Highlights 81 References 81 8 If Only the True Intercept is Unknown 83 8.1 Introduction 83 8.2 Assumptions 83 8.3 Noise Effect of Estimating the True Intercept 83 8.4 A Simple Simulation in the Response and NET Response Domains 84 8.5 Response Domain Effects of Replacing the True Intercept by an Estimate 86 8.6 Response Domain Currie Decision Level and Detection Limit 88 8.7 NET Response Domain Currie Decision Level and Detection Limit 88 8.8 Content Domain Currie Decision Level and Detection Limit 89 8.9 Graphical Illustrations of the Decision Level and Detection Limit Equations 89 8.10 Tabular Summary of the Equations 90 8.11 Simulation Corroboration of the Equations in Table 8.1 91 8.12 Chapter Highlights 93 9 If Only the True Slope is Unknown 95 9.1 Introduction 95 9.2 Possible “Divide by Zero” Hazard 96 9.3 The t Test for tslope 96 9.4 Response Domain Currie Decision Level and Detection Limit 97 9.5 NET Response Domain Currie Decision Level and Detection Limit 97 9.6 Content Domain Currie Decision Level and Detection Limit 97 9.7 Graphical Illustrations of the Decision Level and Detection Limit Equations 98 9.8 Tabular Summary of the Equations 99 9.9 Simulation Corroboration of the Equations in Table 9.1 99 9.10 Chapter Highlights 101 References 101 10 If the True Intercept and True Slope are Both Unknown 103 10.1 Introduction 103 10.2 Important Definitions, Distributions, and Relationships 104 10.3 The Noncentral t Distribution Briefly Appears 105 10.4 What Purpose Would be Served by Knowing 𝛿? 106 10.5 Is There a Viable Way of Estimating 𝛿? 106 10.6 Response Domain Currie Decision Level and Detection Limit 107 10.7 NET Response Domain Currie Decision Level and Detection Limit 107 10.8 Content Domain Currie Decision Level and Detection Limit 108 10.9 Graphical Illustrations of the Decision Level and Detection Limit Equations 108 10.10 Tabular Summary of the Equations 109 10.11 Simulation Corroboration of the Equations in Table 10.3 109 10.12 Chapter Highlights 109 References 111 11 If Only the Population Standard Deviation is Unknown 113 11.1 Introduction 113 11.2 Assuming 𝜎0 is Unknown, How may it be Estimated? 114 11.3 What Happens if 𝜎0 is Estimated by s0? 114 11.4 A Useful Substitution Principle 116 11.5 Response Domain Currie Decision Level and Detection Limit 116 11.6 NET Response Domain Currie Decision Level and Detection Limit 117 11.7 Content Domain Currie Decision Level and Detection Limit 117 11.8 Major Important Differences From Chapter 7 117 11.9 Testing for False Positives and False Negatives 120 11.10 Correction of a Slightly Misleading Figure 121 11.11 An Informative Screencast 121 11.12 Central Confidence Intervals for 𝜎 and s 122 11.13 Central Confidence Intervals for YC and YD 122 11.14 Central Confidence Intervals for XC and XD 123 11.15 Tabular Summary of the Equations 123 11.16 Simulation Corroboration of the Equations in Table 11.1 123 11.17 Chapter Highlights 125 References 125 12 If Only the True Slope is Known 127 12.1 Introduction 127 12.2 Response Domain Currie Decision Level and Detection Limit 127 12.3 NET Response Domain Currie Decision Level and Detection Limit 128 12.4 Content Domain Currie Decision Level and Detection Limit 128 12.5 Graphical Illustrations of the Decision Level and Detection Limit Equations 128 12.6 Tabular Summary of the Equations 128 12.7 Simulation Corroboration of the Equations in Table 12.1 129 12.8 Chapter Highlights 129 13 If Only the True Intercept is Known 131 13.1 Introduction 131 13.2 Response Domain Currie Decision Level and Detection Limit 132 13.3 NET Response Domain Currie Decision Level and Detection Limit 132 13.4 Content Domain Currie Decision Level and Detection Limit 132 13.5 Tabular Summary of the Equations 133 13.6 Simulation Corroboration of the Equations in Table 13.1 133 13.7 Chapter Highlights 135 References 135 14 If all Three Parameters are Unknown 137 14.1 Introduction 137 14.2 Response Domain Currie Decision Level and Detection Limit 137 14.3 NET Response Domain Currie Decision Level and Detection Limit 138 14.4 Content Domain Currie Decision Level and Detection Limit 138 14.5 The Noncentral t Distribution Reappears for Good 138 14.6 An Informative Computer Simulation 139 14.7 Confidence Interval for xD, with a Major Proviso 142 14.8 Central Confidence Intervals for Predicted x Values 143 14.9 Tabular Summary of the Equations 143 14.10 Simulation Corroboration of the Equations in Table 14.1 143 14.11 An Example: DIN 32645 145 14.12 Chapter Highlights 146 References 147 15 Bootstrapped Detection Limits in a Real CMS 149 15.1 Introduction 150 15.2 Theoretical 151 15.2.1 Background 151 15.2.2 Blank Subtraction Possibilities 151 15.2.3 Currie Decision Levels and Detection Limits 152 15.3 Experimental 153 15.3.1 Experimental Apparatus 153 15.3.2 Experiment Protocol 153 15.3.3 Testing the Noise: Is It AGWN? 156 15.3.4 Bootstrapping Protocol in the Experiments 157 15.3.5 Estimation of the Experimental Noncentrality Parameter 160 15.3.6 Computer Simulation Protocol 160 15.4 Results and Discussion 161 15.4.1 Results for Four Standards 161 15.4.2 Results for 3–12 Standards 162 15.4.3 Toward Accurate Estimates of XD 163 15.4.4 How the XD Estimates Were Obtained 164 15.4.5 Ramifications 165 15.5 Conclusion 165 Acknowledgments 166 References 166 15.6 Postscript 167 15.7 Chapter Highlights 167 16 Four Relevant Considerations 169 16.1 Introduction 169 16.2 Theoretical Assumptions 170 16.3 Best Estimation of 𝛿 171 16.4 Possible Reduction in the Number of Expressions? 172 16.5 Lowering Detection Limits 174 16.6 Chapter Highlights 178 References 178 17 Neyman–Pearson Hypothesis Testing 181 17.1 Introduction 181 17.2 Simulation Model for Neyman–Pearson Hypothesis Testing 181 17.3 Hypotheses and Hypothesis Testing 183 17.3.1 Hypotheses Pertaining to False Positives 183 17.3.1.1 Hypothesis 1 183 17.3.1.2 Hypothesis 2 183 17.3.2 Hypotheses Pertaining to False Negatives 185 17.3.2.1 Hypothesis 3 185 17.3.2.2 Hypothesis 4 185 17.4 The Clayton, Hines, and Elkins Method (1987–2008) 189 17.5 No Valid Extension for Heteroscedastic Systems 191 17.6 Hypothesis Testing for the 𝛿critical Method 192 17.6.1 Hypothesis Pertaining to False Positives 192 17.6.1.1 Hypothesis 5 192 17.6.2 Hypothesis Pertaining to False Negatives 192 17.6.2.1 Hypothesis 6 192 17.7 Monte Carlo Tests of the Hypotheses 192 17.8 The Other Propagation of Error 193 17.9 Chapter Highlights 197 References 197 18 Heteroscedastic Noises 199 18.1 Introduction 199 18.2 The Two Simplest Heteroscedastic NPMs 199 18.2.1 Linear NPM 201 18.2.2 Experimental Corroboration of the Linear NPM 202 18.2.3 Hazards with Heteroscedastic NPMs 203 18.2.4 Example: A CMS with Linear NPM 204 18.3 Hazards with ad hoc Procedures 206 18.4 The HS (“Hockey Stick”) NPM 207 18.5 Closed-Form Solutions for Four Heteroscedastic NPMs 209 18.6 Shot Noise (Gaussian Approximation) NPM 210 18.7 Root Quadratic NPM 211 18.8 Example: Marlap Example 20.13, Corrected 211 18.9 Quadratic NPM 211 18.10 A Few Important Points 212 18.11 Chapter Highlights 212 References 213 19 Limits of Quantitation 215 19.1 Introduction 215 19.2 Theory 217 19.3 Computer Simulation 219 19.4 Experiment 221 19.5 Discussion and Conclusion 223 Acknowledgments 224 References 224 19.6 Postscript 225 19.7 Chapter Highlights 226 20 The Sampled Step Function 227 20.1 Introduction 227 20.2 A Noisy Step Function Temporal Response 229 20.3 Signal Processing Preliminaries 230 20.4 Processing the Sampled Step Function Response 231 20.5 The Standard t-Test for Two Sample Means When the Variance is Constant 232 20.6 Response Domain Decision Level and Detection Limit 233 20.7 Hypothesis Testing 233 20.8 Is There any Advantage to Increasing Nanalyte? 233 20.9 NET Response Domain Decision Level and Detection Limit 235 20.10 NET Response Domain SNRs 235 20.11 Content Domain Decision Level and Detection Limit 235 20.12 The RSDB–BEC Method 236 20.13 Conclusion 237 20.14 Chapter Highlights 237 References 237 21 The Sampled Rectangular Pulse 239 21.1 Introduction 239 21.2 The Sampled Rectangular Pulse Response 239 21.3 Integrating the Sampled Rectangular Pulse Response 240 21.4 Relationship Between Digital Integration and Averaging 242 21.5 What is the Signal in the Sampled Rectangular Pulse? 243 21.6 What is the Noise in the Sampled Rectangular Pulse? 243 21.7 The Noise Bandwidth 244 21.8 The SNR with Matched Filter Detection of the Rectangular Pulse 245 21.9 The Decision Level and Detection Limit 245 21.10 A Square Wave at the Detection Limit 246 21.11 Effect of Sampling Frequency 247 21.12 Effect of Area Fraction Integrated 247 21.13 An Alternative Limit of Detection Possibility 248 21.14 Pulse-to-Pulse Fluctuations 248 21.15 Conclusion 249 21.16 Chapter Highlights 250 References 250 22 The Sampled Triangular Pulse 251 22.1 Introduction 251 22.2 A Simple Triangular Pulse Shape 251 22.3 Processing the Sampled Triangular Pulse Response 253 22.4 The Decision Level and Detection Limit 254 22.5 Detection Limit for a Simulated Chromatographic Peak 254 22.6 What Should Not be Done? 256 22.7 A Bad Play, in Three Acts 256 22.8 Pulse-to-Pulse Fluctuations 258 22.9 Conclusion 258 22.10 Chapter Highlights 259 References 259 23 The Sampled Gaussian Pulse 261 23.1 Introduction 261 23.2 Processing the Sampled Gaussian Pulse Response 262 23.3 The Decision Level and Detection Limit 263 23.4 Pulse-to-Pulse Fluctuations 263 23.5 Conclusion 264 23.6 Chapter Highlights 264 References 264 24 Parting Considerations 267 24.1 Introduction 267 24.2 The Measurand Dichotomy Distraction 269 24.3 A “New Definition of LOD” Distraction 273 24.4 Potentially Important Research Prospects 274 24.4.1 Extension to Method Detection Limits 274 24.4.2 Confidence Intervals in the Content Domain 275 24.4.3 Noises Other Than AGWN 275 24.5 Summary 276 References 277 Appendix A Statistical Bare Necessities 279 Appendix B An Extremely Short Lightstone® Simulation Tutorial 299 Appendix C Blank Subtraction and the 𝜂1∕2 Factor 311 Appendix D Probability Density Functions for Detection Limits 321 Appendix E The Hubaux and Vos Method 325 Bibliography 331 Glossary of Organization and Agency Acronyms 335 Index 337

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Book SynopsisWorking from basic chemical principles, Metals in Medicine, 2nd Edition describes a wide range of metal-based agents for treating and diagnosing disease. Thoroughly revised and restructured to reflect significant research activity and advances, this new edition contains extensive updates and new pedagogical features while retaining the popular feature boxes and end-of-chapter problems of the first edition. Topics include: Metallo-Drugs and their action Platinum drugs for treating cancer Anticancer agents beyond cisplatin including ruthenium, gold, titanium and gallium Responsive Metal Complexes Treating arthritis and diabetes with metal complexes Metal complexes for killing bacteria, parasites and viruses Metal ion imbalance and its links to diseases including Alzheimer''s, Wilson''s and Menkes disease Metal complexes for detecting disease Nanotechnology in medicine Now iTable of ContentsFeature Boxes xv Preface to the Second Edition xvii Preface to the First Edition xix Acknowledgments xxi About the Companion Website xxiii 1 Inorganic Chemistry Basics 1 1.1 Introduction 1 1.2 Crystal Field Theory 1 1.3 Molecular Orbital Theory 12 1.4 Absorption Spectra of Metal Complexes 22 1.5 Magnetic Properties of Metal Complexes 33 1.6 Structure and Reactivity of Metal Complexes 35 2 Metallo-Drugs and Their Action 59 2.1 Introduction 59 2.2 Proteins asTargets forMetallo-Drugs 59 2.3 DNAas aTarget forMetallo-Drugs 71 2.4 Reaction of Metal Complexes in the Biological Milieu 76 2.5 Evaluating the Pharmacological Effects of Agents 79 2.6 FromDiscoverytotheClinic 82 3 Platinum Drugs for Treating Cancer 91 3.1 Introduction 91 3.2 Cisplatin 91 3.3 Carboplatin 115 3.4 Oxaliplatin 126 3.5 RegionallyUsedPlatinumDrugs 133 3.6 Platinum Agents in Preclinical Development 135 4 Anticancer Agents Beyond Cisplatin 157 4.1 Introduction 157 4.2 Ruthenium Anticancer Agents 157 4.3 Gold Anticancer Agents 173 4.4 Titanium Compounds for Treating Cancer 181 4.5 Gallium for Treating Cancer 187 4.6 Other Anticancer Active Metal Complexes 194 5 Responsive Metal Complexes 217 5.1 Introduction 217 5.2 Prodrug Activation by Redox 217 5.3 ProdrugActivationbypH 225 5.4 Prodrug Activation by Enzymes 227 5.5 ProdrugActivationbyLight 229 5.6 Photodynamic Therapy 233 6 Metal Complexes for Treating Arthritis and Diabetes 245 6.1 Introduction 245 6.2 ChemistryofGoldinBiologicalMedia 245 6.3 Gold Compounds for Treating Arthritis 247 6.4 Vanadium Compounds for Treating Diabetes 263 7 Metal Complexes for Killing Parasites, Bacteria and Viruses 285 7.1 Introduction 285 7.2 Malaria 285 7.3 Leishmaniasis 293 7.4 American Trypanosomiasis (Chagas Disease) 298 7.5 Human African Trypanosomiasis 301 7.6 Tuberculosis 301 7.7 PepticUlcerDisease 306 7.8 Syphilis 311 7.9 Bacterial Infections 312 7.10 Acquired Immunodeficiency Syndrome (AIDS) 314 8 Metal Ion Imbalance in the Body 329 8.1 Introduction 329 8.2 Alzheimer’s Disease 329 8.3 LithiumandtheBrain 337 8.4 Wilson’s Disease: Copper Overload 338 8.5 Menkes Disease: Copper Deficiency 340 8.6 Beta-Thalassemia: IronOverload 342 8.7 Iron-Deficiency Anemia 344 8.8 Calcium Imbalance 344 8.9 ChelationTherapy 346 9 Metal Complexes for Detecting Disease 357 9.1 Introduction 357 9.2 Technetium in Diagnostic Nuclear Medicine 358 9.3 Metal Compounds as Contrast Agents for MRI 371 9.4 Radiotherapy 382 10 Nanomedicine 395 10.1 Introduction 395 10.2 Circulation, Uptake, and Elimination of Nanoparticles 396 10.3 Nanoscience for Treating Cancer 407 10.4 Nanoparticles for Detecting Disease 419 10.5 Theranostic Nanoparticles 426 10.6 Cytotoxicity of Nanoparticles 428 Index 441

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Book SynopsisMagnetic Resonance Imaging in Tissue Engineering provides a unique overview of the field of non-invasive MRI assessment of tissue engineering and regenerative medicine Establish a dialogue between the tissue-engineering scientists and imaging experts and serves as a guide for tissue engineers and biomaterial developers alikeProvides comprehensive details of magnetic resonance imaging (MRI) techniques used to assess a variety of engineered and regenerating tissues and organsCovers cell-based therapies, engineered cartilage, bone, meniscus, tendon, ligaments, cardiovascular, liver and bladder tissue engineering and regeneration assessed by MRIIncludes a chapter on oxygen imaging method that predominantly is used for assessing hypoxia in solid tumors for improving radiation therapy but has the ability to provide information on design strategies and cellular viability in tissue engineering regenerative medicineTable of ContentsList of Plates xiii About the Editors xix List of Contributors xxi Foreword xxv Preface xxvii Book Summary xxxi Part I Enabling Magnetic Resonance Techniques for Tissue Engineering Applications 1 1 Stem Cell Tissue Engineering and Regenerative Medicine: Role of Imaging 3 Bo Chen, Caleb Liebman, Parisa Rabbani, and Michael Cho 1.1 Introduction 3 1.2 3D Biomimetics 5 1.3 Assessment of Stem Cell Differentiation and Tissue Development 8 1.4 Description of Imaging Modalities for Tissue Engineering 8 1.4.1 Optical Microscopy 9 1.4.2 Fluorescence Microscopy 9 1.4.3 Multiphoton Microscopy 11 1.4.4 Magnetic Resonance Imaging 14 Acknowledgments 15 References 15 2 Principles and Applications of Quantitative Parametric MRI in Tissue Engineering 21 Mrignayani Kotecha 2.1 Introduction 21 2.2 Basics of MRI 25 2.2.1 Nuclear Spins 25 2.2.2 Radio Frequency Pulse Excitation and Relaxation 28 2.2.3 From MRS to MRI 31 2.3 MRI Contrasts for Tissue Engineering Applications 32 2.3.1 Chemical Shift 33 2.3.2 Relaxation Times—T1 and T2 33 2.3.3 Water Apparent Diffusion Coefficient 36 2.3.4 Fractional Anisotropy 37 2.4 X‐Nuclei MRI for Tissue Engineering Applications 38 2.5 Preparing Engineered Tissues for MRI Assessment 38 2.5.1 In Vitro Assessment 38 2.5.2 In Vivo Assessment 39 2.6 Limitations of MRI Assessment in Tissue Engineering 39 2.7 Future Directions 40 2.7.1 Biomolecular Nuclear Magnetic Resonance 40 2.7.2 Cell–ECM–Biomaterial Interaction 40 2.7.3 Quantitative MRI 40 2.7.4 Standardization of MRI Methods for In Vitro and In Vivo Assessment 40 2.7.5 Super‐Resolution MRI Techniques 41 2.7.6 Magnetic Resonance Elastography 41 2.7.7 Benchtop MRI 41 2.8 Conclusions 41 References 42 3 High Field Sodium MRS/MRI: Application to Cartilage Tissue Engineering 49 Mrignayani Kotecha 3.1 Introduction 49 3.2 Sodium as an MR Probe 50 3.3 Pulse Sequences 53 3.3.1 Pulse Sequences for Measuring TSC 53 3.3.2 TQC Pulse Sequences for Measuring ωQ and ω0τc 54 3.4 Assessment of Tissue‐Engineered Cartilage 55 3.4.1 Proteoglycan Assessment 57 3.4.2 Assessment of Tissue Anisotropy and Molecular Dynamics 60 3.4.3 Assessment of Osteochondral Tissue Engineering 61 3.5 Sodium Biomarkers for Engineered Tissue Assessment 63 3.5.1 Engineered Tissue Sodium Concentration (ETSC) 63 3.5.2 Average Quadrupolar Coupling (ωQ) 64 3.5.3 Motional Averaging Parameter (ω0τc) 64 3.6 Future Directions 64 3.7 Summary 64 References 65 4 SPIO‐Labeled Cellular MRI in Tissue Engineering: A Case Study in Growing Valvular Tissues 71 Elnaz Pour Issa and Sharan Ramaswamy 4.1 Setting the Stage: A Clinical Problem Requiring a Tissue Engineering Solution 71 4.2 SPIO Labeling of Cells 72 4.2.1 Ferumoxides 72 4.2.2 Transfection Agents 73 4.2.3 Labeling Protocols 75 4.3 Applications 76 4.3.1 Traditional Usage of SPIO‐Labeled Cellular MRI 76 4.3.2 SPIO‐Labeled Cellular MRI in Tissue Engineering 76 4.4 Case Study: SPIO‐Labeled Cellular MRI for Heart Valve Tissue Engineering 77 4.4.1 Experimental Design 77 4.4.2 Potential Approaches—In Vitro 78 4.4.3 Potential Approaches—In Vivo 81 4.5 Conclusions and Future Outlook 83 Acknowledgment 84 References 84 5 Magnetic Resonance Elastography Applications in Tissue Engineering 91 Shadi F. Othman and Richard L. Magin 5.1 Introduction 91 5.2 Introduction to MRE 93 5.2.1 Theoretical Basis of MRE 94 5.2.2 The Inverse Problem and Direct Algebraic Inversion 96 5.2.3 Direct Algebraic Inversion Algorithm 101 5.3 Current Applications of MRE in Tissue Engineering and Regenerative Medicine 108 5.3.1 In Vitro TE μMRE 108 5.3.2 In Vivo TE μMRE 110 5.4 Conclusion 114 References 114 6 Finite‐Element Method in MR Elastography: Application in Tissue Engineering 117 Yifei Liu and Thomas J. Royston 6.1 Introduction 117 6.2 FEA in MRE Inversion Algorithm Verification 118 6.3 FEM in Stiffness Estimation from MRE Data 120 6.4 FEA in Experimental Validation in Tissue Engineering Application 121 6.5 Conclusions and Discussion 124 Acknowledgment 125 References 125 7 In Vivo EPR Oxygen Imaging: A Case for Tissue Engineering 129 Boris Epel, Mrignayani Kotecha, and Howard J. Halpern 7.1 Introduction 129 7.2 History of EPROI 131 7.3 Principles of EPR Imaging 132 7.4 EPR Oxymetry 134 7.5 EPROI Instrumentation and Methodology 135 7.5.1 EPR Frequency 135 7.5.2 Resonators 135 7.5.3 Magnets 136 7.5.4 EPR Imagers 137 7.6 Spin Probes for Pulse EPR Oxymetry 138 7.7 Image Registration 139 7.8 Tissue Engineering Applications 140 7.8.1 EPROI in Scaffold Design 140 7.8.2 EPROI in Tissue Engineering 142 7.9 Summary and Future Outlook 142 Acknowledgment 142 References 143 Part II Tissue‐Specific Applications of Magnetic Resonance Imaging in Tissue Engineering 149 8 Tissue‐Engineered Grafts for Bone and Meniscus Regeneration and Their Assessment Using MRI 151 Hanying Bai, Mo Chen, Yongxing Liu, Qimei Gong, Ling He, Juan Zhong, Guodong Yang, Jinxuan Zheng, Xuguang Nie, Yixiong Zhang, and Jeremy J. Mao 8.1 Overview of Tissue Engineering with MRI 151 8.2 Assessment of Bone Regeneration by Tissue Engineering with MRI 152 8.3 MRI for 3D Modeling and 3D Print Manufacturing in Tissue Engineering 157 8.4 Assessment of Menisci Repair and Regeneration by Tissue Engineering with MRI 161 8.5 Conclusion 168 Acknowledgments 168 References 169 9 MRI Assessment of Engineered Cartilage Tissue Growth 179 Mrignayani Kotecha and Richard L. Magin 9.1 Introduction 179 9.2 Cartilage 181 9.3 Cartilage Tissue Engineering 182 9.3.1 Cells 183 9.3.1.1 Chondrocytes 183 9.3.1.2 Stem Cells 183 9.3.2 Biomaterials 183 9.3.3 Growth Factors 184 9.3.4 Growth Conditions 184 9.4 Animal Models in Cartilage Tissue Engineering 184 9.5 Tissue Growth Assessment 186 9.6 MRI in the Assessment of Tissue‐Engineered Cartilage 187 9.7 Periodic Assessment of Tissue‐Engineered Cartilage Using MRI 187 9.7.1 Assessment of Tissue Growth In Vitro 187 9.7.1.1 Accounting for Scaffold in Tissue Assessment 191 9.7.2 Assessment of Tissue Growth In Vivo 191 9.7.3 Assessment of Tissue Anisotropy and Dynamics 193 9.7.3.1 Assessment of Macromolecule Composition 194 9.7.3.2 Assessment of Tissue Anisotropy 198 9.8 Summary and Future Directions 199 References 200 10 Emerging Techniques for Tendon and Ligament MRI 209 Braden C. Fleming, Alison M. Biercevicz, Martha M. Murray, Weiguo Li, and Vincent M. Wang 10.1 Tendon and Ligament Structure, Function, Injury, and Healing 209 10.2 MRI Studies of Tendon and Ligament Healing 211 10.3 MRI and Contrast Mechanisms 219 10.3.1 Conventional MRI Techniques 219 10.3.2 Advanced MR Techniques 222 10.4 Significance and Conclusion 228 Acknowledgments 228 References 228 11 MRI of Engineered Dental and Craniofacial Tissues 237 Anne George and Sriram Ravindran 11.1 Introduction 237 11.2 Scaffolds 238 11.3 Extracellular Matrix 238 11.4 Tissue Regeneration of Dental–Craniofacial Complex 239 11.4.1 Advantages of Using ECM Scaffolds with Stem Cells 240 11.4.2 Stem Cells 242 11.5 MRI in Tissue Engineering and Regeneration 243 11.5.1 MRI of Human DPSCs 243 11.5.2 MRI of Tissue‐Engineered Osteogenic Scaffolds 244 11.5.3 MRI of Chondrogenic Scaffolds with Cells In Vitro 244 11.5.4 MRI of Chondrogenic Scaffolds with Cells In Vivo 245 11.5.5 MRI Can Differentiate Between Engineered Bone and Engineered Cartilage 246 11.5.6 MRI to Assess Angiogenesis 246 11.6 Challenges and Future Directions for MRI in Tissue Engineering 246 Acknowledgments 247 References 247 12 Osteochondral Tissue Engineering: Noninvasive Assessment of Tissue Regeneration 251 Tyler Stahl, Abeid Anslip, Ling Lei, Nilse Dos Santos, Emmanuel Nwachuku, Thomas DeBerardino, and Syam Nukavarapu 12.1 Introduction 251 12.2 Osteochondral Tissue Engineering 252 12.2.1 Osteochondral Tissue 252 12.2.2 Biomaterials/Scaffolds 252 12.2.3 Cells 255 12.2.4 Growth Factors 256 12.3 Clinical Methods for Osteochondral Defect Repair and Assessment 257 12.3.1 Diagnostic Modalities 257 12.3.2 Treatment Methods 260 12.3.2.1 Microfracture 260 12.3.2.2 Autografts and Allografts 260 12.3.2.3 Tissue Engineering Grafts 262 12.4 MRI Assessment of Tissue Engineered Osteochondral Grafts 262 12.4.1 In Vitro Assessment 263 12.4.2 In Vivo Assessment 264 12.5 MRI Assessment Correlation with Histology 264 12.6 Conclusions and Challenges 265 Acknowledgments 265 References 265 13 Advanced Liver Tissue Engineering Approaches and Their Measure of Success Using NMR/MRI 273 Haakil Lee, Rex M. Jeffries, Andrey P. Tikunov, and Jeffrey M. Macdonald 13.1 Introduction 273 13.2 MRS and MRI Compatibilization—Building Compact RF MR Probes for BALs 278 13.3 Multinuclear MRS of a Hybrid Hollow Fiber–Microcarrier BAL 280 13.3.1 Viability by 31P MRS 282 13.3.2 Quantifying Drug Metabolic Activity and Oxygen Distribution by 19F MRS 284 13.4 1H MRI of a Hollow Fiber Multicoaxial BAL 286 13.4.1 BAL Integrity and Quality Assurance 286 13.4.2 Inoculation Efficiency and Prototype Redesign Iteration 288 13.4.3 Flow Dynamics 289 13.4.4 Diffusion‐Weighted and Functional Annotation Screening Technology (FAST) Dynamic Contrast MRI 291 13.5 Magnetic Contrast Agents Used in MRI of Liver Stem Cell Therapy 293 13.6 31P and 13C MRS of a Fluidized‐Bed BAL Containing Encapsulated Hepatocytes 294 13.6.1 31P MRS Resolution, SNR, Viability, and pH 296 13.6.2 13C MRS to Monitor Real‐Time Metabolism 296 13.7 Future Studies 298 13.7.1 Dynamic Nuclear Polarization 298 13.7.2 Constructing Artificial Organs 300 13.8 Discussion 301 Acknowledgment 303 References 303 14 MRI of Vascularized Tissue‐Engineered Organs 311 Hai‐Ling Margaret Cheng 14.1 Introduction 311 14.2 Importance of Vascularization in Tissue Engineering 312 14.3 Vessel Formation and Maturation: Implications for Imaging 314 14.4 Imaging Approaches to Assess Vascularization 317 14.5 Dynamic Contrast‐Enhanced MRI for Imaging Vascular Physiology 318 14.6 Complementary MRI Techniques to Study Vascularization 321 14.7 Considerations for Preclinical Models and Translation to Clinical Implementation 325 14.8 Future Directions 326 14.9 Conclusions 327 References 327 15 MRI Tools for Assessment of Cardiovascular Tissue Engineering 333 Laurence H. Jackson, Mark F. Lythgoe, and Daniel J. Stuckey 15.1 The Heart and Heart Failure 333 15.2 Cardiac Engineering and Cell Therapy 334 15.3 Imaging Heart Failure 336 15.3.1 Cine MRI 336 15.3.2 Regional Heart Function 338 15.3.3 Viability Imaging 340 15.3.4 Relaxometry and Parametric Imaging 342 15.3.5 Myocardial Perfusion Imaging 344 15.4 Imaging Cardiac Regeneration 346 15.5 Monitoring Cardiac Regeneration 348 15.5.1 MRI to Track Stem Cells 348 15.5.2 MRI to Track Engineered Tissues 353 15.6 Translational Potential and Future Directions 355 References 357 16 Peripheral Nerve Tissue Engineering and Regeneration Observed Using MRI 367 Shan‐Ho Chan and Shan‐hui Hsu 16.1 Introduction 367 16.2 Receiver Coils Commonly Applied in Nerve Tissue Engineering 368 16.3 Various Tools for Real‐Time Monitoring of the Nerve Regeneration 368 16.4 Current Materials, Methods, and Concepts in Peripheral Nerve Repair 368 16.5 MRI Parameters in Peripheral Nerve Tissue Engineering 371 16.6 Advantages of Real‐Time Monitoring of Nerve Regeneration Using MRI 373 16.7 Choosing Animal Models for MRI Studies of Peripheral Nerve Tissue Engineering 374 16.8 Imaging Ability Through Nerve Conduits of Peripheral Nerve Tissue Engineering 375 16.9 Further Imaging Functions of MRI in Peripheral Nerve Tissue Engineering 376 16.10 Tractography in Peripheral Nerve Tissue Engineering 376 16.11 Novel Contrast Agents 378 16.12 Conclusions 378 References 379 Index 383

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