Biotechnology Books

Book SynopsisProvides an introductory survey of nanotechnology. Based on the highly acclaimed 2003 Wiley title Introduction to Nanotechnology , This new textbook includes problem sets for each chapter, updated material from the earlier book, and rewritten sections to be more pedagogical in nature. .Trade Review"This book would be an excellent choice for a one- or two-semester course in a materials science, chemistry, or physics course. It would also be of interest to any of our readers interested in learning about nanotechnology. It is written to provide the reader with a sound foundation for understanding the key fundamentals of nanotechnology. This book will be popular." (IEEE Electrical Insulation Magazine, January/February 2009)Table of ContentsPreface xv 1. Physics of Bulk Solids 1 1.1 Structure 1 1.1.1 Size Dependence of Properties 1 1.1.2 Crystal Structures 2 1.1.3 Face-Centered Cubic Nanoparticles 7 1.1.4 Large Face-Centered Cubic Nanoparticles 9 1.1.5 Tetrahedrally Bonded Semiconductor Structures 10 1.1.6 Lattice Vibrations 14 1.2 Surfaces of Crystals 16 1.2.1 Surface Characteristics 16 1.2.2 Surface Energy 17 1.2.3 Face-Centered Cubic Surface Layers 18 1.2.4 Surfaces of Zinc Blende and Diamond Structures 21 1.2.5 Adsorption of Gases 23 1.2.6 Electronic Structure of a Surface 25 1.2.7 Surface Quantum Well 26 1.3 Energy Bands 26 1.3.1 Insulators, Semiconductors, and Conductors 26 1.3.2 Reciprocal Space 27 1.3.3 Energy Bands and Gaps of Semiconductors 28 1.3.4 Effective Mass 34 1.3.5 Fermi Surfaces 35 1.4 Localized Particles 36 1.4.1 Donors, Acceptors, and Deep Traps 36 1.4.2 Mobility 37 1.4.3 Excitons 38 Problems 40 References 41 2. Methods of Measuring Properties of Nanostructures 43 2.1 Introduction 43 2.2 Structure 44 2.2.1 Atomic Structures 44 2.2.2 Crystallography 45 2.2.3 Particle Size Determination 50 2.2.4 Surface Structure 54 2.3 Microscopy 54 2.3.1 Transmission Electron Microscopy 54 2.3.2 Field Ion Microscopy 59 2.3.3 Scanning Microscopy 59 2.4 Spectroscopy 66 2.4.1 Infrared and Raman Spectroscopy 66 2.4.2 Photoemission, X-Ray, and Auger Spectroscopy 72 2.4.3 Magnetic Resonance 78 2.5 Various Bulk Properties 81 2.5.1 Mechanical Properties 81 2.5.2 Electrical Properties 81 2.5.3 Magnetic Properties 82 2.5.4 Other Properties 82 Problems 82 References 83 3. Properties of Individual Nanoparticles 85 3.1 Introduction 85 3.2 Metal Nanoclusters 86 3.2.1 Magic Numbers 86 3.2.2 Theoretical Modeling of Nanoparticles 88 3.2.3 Geometric Structure 91 3.2.4 Electronic Structure 94 3.2.5 Reactivity 97 3.2.6 Fluctuations 100 3.2.7 Magnetic Clusters 100 3.2.8 Bulk-to-Nano Transition 103 3.3 Semiconducting Nanoparticles 104 3.3.1 Optical Properties 104 3.3.2 Photofragmentation 106 3.3.3 Coulomb Explosion 107 3.4 Rare-Gas and Molecular Clusters 107 3.4.1 Inert-Gas Clusters 107 3.4.2 Superfluid Clusters 108 3.4.3 Molecular Clusters 109 3.4.4 Nanosized Organic Crystals 111 3.5 Methods of Synthesis 111 3.5.1 RF Plasma 111 3.5.2 Chemical Methods 111 3.5.3 Thermolysis 112 3.5.4 Pulsed-Laser Methods 114 3.5.5 Synthesis of Nanosized Organic Crystals 114 3.6 Summary 118 Problems 118 4. The Chemistry of Nanostructures 121 4.1 Chemical Synthesis of Nanostructures 121 4.1.1 Solution Synthesis 121 4.1.2 Capped Nanoclusters 122 4.1.3 Solgel Processing 124 4.1.4 Electrochemical Synthesis of Nanostructures 125 4.2 Reactivity of Nanostructures 125 4.3 Catalysis 127 4.3.1 Nature of Catalysis 127 4.3.2 Surface Area of Nanoparticles 127 4.3.3 Porous Materials 131 4.4 Self-Assembly 135 4.4.1 The Self-Assembly Process 135 4.4.2 Semiconductor Islands 136 4.4.3 Monolayers 139 Problems 141 5. Polymer and Biological Nanostructures 143 5.1 Polymers 143 5.1.1 Polymer Structure 143 5.1.2 Sizes of Polymers 146 5.1.3 Nanocrystals of Polymers 148 5.1.4 Conductive Polymers 151 5.1.5 Block Copolymers 152 5.2 Biological Nanostructures 154 5.2.1 Sizes of Biological Nanostructures 154 5.2.2 Polypeptide Nanowire and Protein Nanoparticles 160 5.2.3 Nucleic Acids 162 5.2.3.1 DNA Double Nanowire 162 5.2.3.2 Genetic Code and Protein Synthesis 166 5.2.3.3 Proteins 167 5.2.3.4 Micelles and Vesicles 169 5.2.3.5 Multilayer Films 172 Problems 174 References 174 6. Cohesive Energy 177 6.1 Ionic Solids 177 6.2 Defects in Ionic Solids 183 6.3 Covalently Bonded Solids 185 6.4 Organic Crystals 186 6.5 Inert-Gas Solids 190 6.6 Metals 191 6.7 Conclusion 193 Problems 193 7. Vibrational Properties 195 7.1 The Finite One-Dimensional Monatomic Lattice 195 7.2 Ionic Solids 197 7.3 Experimental Observations 199 7.3.1 Optical and Acoustical Modes 199 7.3.2 Vibrational Spectroscopy of Surface Layers of Nanoparticles 201 7.3.2.1 Raman Spectroscopy of Surface Layers 201 7.3.2.2 Infrared Spectroscopy of Surface Layers 201 7.4 Phonon Confinement 207 7.5 Effect of Dimension on Lattice Vibrations 209 7.6 Effect of Dimension on Vibrational Density of States 211 7.7 Effect of Size on Debye Frequency 215 7.8 Melting Temperature 216 7.9 Specific Heat 218 7.10 Plasmons 220 7.11 Surface-Enhanced Raman Spectroscopy 222 7.12 Phase Transitions 223 Problems 226 References 227 8. Electronic Properties 229 8.1 Ionic Solids 229 8.2 Covalently Bonded Solids 232 8.3 Metals 234 8.3.1 Effect of Lattice Parameter on Electronic Structure 235 8.3.2 Free-Electron Model 235 8.3.3 The Tight-Binding Model 239 8.4 Measurements of Electronic Structure of Nanoparticles 242 8.4.1 Semiconducting Nanoparticles 242 8.4.2 Organic Solids 248 8.4.3 Metals 250 Problems 251 9. Quantum Wells, Wires, and Dots 253 9.1 Introduction 253 9.2 Fabricating Quantum Nanostructures 253 9.2.1 Solution Fabrication 254 9.2.2 Lithography 257 9.3 Size and Dimensionality Effects 261 9.3.1 Size Effects 261 9.3.2 Size Effects on Conduction Electrons 263 9.3.3 Conduction Electrons and Dimensionality 264 9.3.4 Fermi Gas and Density of States 265 9.3.5 Potential Wells 268 9.3.6 Partial Confinement 272 9.3.7 Properties Dependent on Density of States 273 9.4 Excitons 275 9.5 Single-Electron Tunneling 276 9.6 Applications 280 9.6.1 Infrared Detectors 280 9.6.2 Quantum Dot Lasers 280 Problems 285 References 285 10. Carbon Nanostructures 287 10.1 Introduction 287 10.2 Carbon Molecules 287 10.2.1 Nature of the Carbon Bond 287 10.2.2 New Carbon Structures 289 10.3 Carbon Clusters 289 10.3.1 Small Carbon Clusters 289 10.3.2 Buckyball 292 10.3.3 The Structure of Molecular C60 293 10.3.4 Crystalline C60 296 10.3.5 Larger and Smaller Buckyballs 300 10.3.6 Buckyballs of Other Atoms 300 10.4 Carbon Nanotubes 301 10.4.1 Fabrication 301 10.4.2 Structure 304 10.4.3 Electronic Properties 306 10.4.4 Vibrational Properties 312 10.4.5 Functionalization 314 10.4.6 Doped Carbon Nanotubes 322 10.4.7 Mechanical Properties 325 10.5 Nanotube Composites 327 10.5.1 Polymer–Carbon Nanotube Composites 327 10.5.2 Metal–Carbon Nanotube Composites 329 10.6 Graphene Nanostructures 330 Problems 335 11. Bulk Nanostructured Materials 337 11.1 Solid Methods for Preparation of Disordered Nanostructures 337 11.1.1 Methods of Synthesis 337 11.1.2 Metal Nanocluster Composite Glasses 340 11.1.3 Porous Silicon 343 11.2 Nanocomposites 347 11.2.1 Layered Nanocomposites 347 11.2.2 Nanowire Composites 349 11.2.3 Composites of Nanoparticles 350 11.3 Nanostructured Crystals 351 11.3.1 Natural Nanocrystals 351 11.3.2 Crystals of Metal Nanoparticles 352 11.3.3 Arrays of Nanoparticles in Zeolites 355 11.3.4 Nanoparticle Lattices in Colloidal Suspensions 357 11.3.5 Computational Prediction of Cluster Lattices 358 11.4 Electrical Conduction in Bulk Nanostructured Materials 359 11.4.1 Bulk Materials Consisting of Nanosized Grains 359 11.4.2 Nanometer-Thick Amorphous Films 364 11.5 Other Properties 364 Problems 365 12. Mechanical Properties of Nanostructured Materials 367 12.1 Stress–Strain Behavior of Materials 367 12.2 Failure Mechanisms of Conventional Grain-Sized Materials 370 12.3 Mechanical Properties of Consolidated Nano-Grained Materials 371 12.4 Nanostructured Multilayers 374 12.5 Mechanical and Dynamical Properties of Nanosized Devices 376 12.5.1 General Considerations 376 12.5.2 Nanopendulum 378 12.5.3 Vibrations of a Nanometer String 380 12.5.4 The Nanospring 381 12.5.5 The Clamped Beam 382 12.5.6 The Challenges and Possibilities of Nanomechanical Sensors 385 12.5.7 Methods of Fabrication of Nanosized Devices 387 Problems 390 13. Magnetism in Nanostructures 393 13.1 Basics of Ferromagnetism 393 13.2 Behavior of Powders of Ferromagnetic Nanoparticles 398 13.2.1 Properties of a Single Ferromagnetic Nanoparticle 398 13.2.2 Dynamics of Individual Magnetic Nanoparticles 400 13.2.3 Measurements of Superparamagnetism and the Blocking Temperature 402 13.2.4 Nanopore Containment of Magnetic Particles 405 13.3 Ferrofluids 406 13.4 Bulk Nanostructured Magnetic Materials 413 13.4.1 Effect of Nanosized Grain Structure on Magnetic Properties 413 13.4.2 Magnetoresistive Materials 416 13.4.3 Carbon Nanostructured Ferromagnets 424 13.5 Antiferromagnetic Nanoparticles 429 Problems 430 14. Nanoelectronics, Spintronics, Molecular Electronics, and Photonics 433 14.1 Nanoelectronics 433 14.1.1 N and P Doping and PN Junctions 433 14.1.2 MOSFET 435 14.1.3 Scaling of MOSFETs 436 14.2 Spintronics 440 14.2.1 Definition and Examples of Spintronic Devices 440 14.2.2 Magnetic Storage and Spin Valves 440 14.2.3 Dilute Magnetic Semiconductors 445 14.3 Molecular Switches and Electronics 449 14.3.1 Molecular Switches 449 14.3.2 Molecular Electronics 453 14.3.3 Mechanism of Conduction through a Molecule 458 14.4 Photonic Crystals 459 Problems 465 Reference 466 15. Superconductivity in Nanomaterials 467 15.1 Introduction 467 15.2 Zero Resistance 467 15.2.1 The Superconducting Gap 469 15.2.2 Cooper Pairs 470 15.3 The Meissner Effect 472 15.3.1 Magnetic Field Exclusion 472 15.3.2 Type I and Type II Superconductors 474 15.4 Properties of Flux 478 15.4.1 Quantization of Flux 478 15.4.2 Vortex Configurations 479 15.4.3 Flux Creep and Flux Flow 480 15.4.4 Vortex Pinning 484 15.5 Dependence of Superconducting Properties on Size Effects 484 15.6 Resistivity and Sheet Resistance 484 15.7 Proximity Effect 488 15.8 Superconductors as Nanomaterials 490 15.9 Tunneling and Josephson Junctions 491 15.9.1 Tunneling 491 15.9.2 Weak Links 491 15.9.3 Josephson Effect 493 15.9.4 Josephson Junctions 494 15.9.5 Ultrasmall Josephson Junctions 494 15.10 Superconducting Quantum Interference Device (Squid) 495 15.11 Buckministerfullerenes 496 15.11.1 The Structure of C60 and Its Crystal 496 15.11.2 Alkali-Doped C60 496 15.11.3 Superconductivity in C60 497 Problems 498 References 499 Appendix A Formulas for Dimensionality 501 A.1 Introduction 501 A.2 Delocalization 501 A.3 Square and Parabolic Wells 502 A.4 Partial Confinement 503 Appendix B Tabulations of Semiconducting Material Properties 507 Appendix C Face-Centered Cubic and Hexagonal Close-Packed Nanoparticles 515 C.1 Introduction 515 C.2 Face-Centered Cubic Nanoparticles 515 C.3 Hexagonal Close-Packed Nanoparticles 519 Index 521

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Book SynopsisThis book highlights the importance and recent success of computational intelligence methods over a diverse range of bioinformatics problems. It encourages others to use these methods and approaches in their research, while also serving as an introduction to computational intelligence methods and applications to the consumers of the research.Table of ContentsPreface. Contributors. Part One Gene Expression Analysis and Systems Biology. 1. Hybrid of Neural Classifi er and Swarm Intelligence in Multiclass Cancer Diagnosis with Gene Expression Signatures (Rui Xu, Georgios C. Anagnostopoulos, and Donald C. Wunsch II). 1.1 Introduction. 1.2 Methods and Systems. 1.3 Experimental Results. 1.4 Conclusions. 2. Classifying Gene Expression Profi les with Evolutionary Computation (Jin-Hyuk Hong and Sung-Bae Cho). 2.1 DNA Microarray Data Classifi cation. 2.2 Evolutionary Approach to the Problem. 2.3 Gene Selection with Speciated Genetic Algorithm. 2.4 Cancer Classifi ction Based on Ensemble Genetic Programming. 2.5 Conclusion. 3. Finding Clusters in Gene Expression Data Using EvoCluster (Patrick C. H. Ma, Keith C. C. Chan, and Xin Yao). 3.1 Introduction. 3.2 Related Work. 3.3 Evolutionary Clustering Algorithm. 3.4 Experimental Results. 3.5 Conclusions. 4. Gene Networks and Evolutionary Computation (Jennifer Hallinan). 4.1 Introduction. 4.2 Evolutionary Optimization. 4.3 Computational Network Modeling. 4.4 Extending Reach of Gene Networks. 4.5 Network Topology Analysis. 4.6 Summary. Part Two Sequence Analysis and Feature Detection. 5. Fuzzy-Granular Methods for Identifying Marker Genes from Microarray Expression Data (Yuanchen He, Yuchun Tang, Yan-Qing Zhang, and Rajshekhar Sunderraman). 5.1 Introduction. 5.2 Traditional Algorithms for Gene Selection. 5.3 New Fuzzy-Granular-Based Algorithm for Gene Selection. 5.4 Simulation. 5.5 Conclusions. 6. Evolutionary Feature Selection for Bioinformatics (Laetitia Jourdan, Clarisse Dhaenens, and El-Ghazali Talbi). 6.1 Introduction. 6.2 Evolutionary Algorithms for Feature Selection. 6.3 Feature Selection for Clustering in Bioinformatics. 6.4 Feature Selection for Classifi cation in Bioinformatics. 6.5 Frameworks and Data Sets. 6.6 Conclusion. 7. Fuzzy Approaches for the Analysis CpG Island Methylation Patterns (Ozy Sjahputera, Mihail Popescu, James M. Keller, and Charles W. Caldwell). 7.1 Introduction. 7.2 Methods. 7.3 Biological Signifi cance. 7.4 Conclusions. Part Three Molecular Structure and Phylogenetics. 8. Protein–Ligand Docking with Evolutionary Algorithms(René Thomsen). 8.1 Introduction. 8.2 Biochemical Background. 8.3 The Docking Problem. 8.4 Protein–Ligand Docking Algorithms. 8.5 Evolutionary Algorithms. 8.6 Effect of Variation Operators. 8.7 Differential Evolution. 8.8 Evaluating Docking Methods. 8.9 Comparison between Docking Methods. 8.10 Summary. 8.11 Future Research Topics. 9. RNA Secondary Structure Prediction Employing Evolutionary Algorithms (Kay C. Wiese, Alain A. Deschênes, and Andrew G. Hendriks). 9.1 Introduction. 9.2 Thermodynamic Models. 9.3 Methods. 9.4 Results. 9.5 Conclusion. 10. Machine Learning Approach for Prediction of Human Mitochondrial Proteins (Zhong Huang, Xuheng Xu, and Xiaohua Hu). 10.1 Introduction. 10.2 Methods and Systems. 10.3 Results and Discussion. 10.4 Conclusions. 11. Phylogenetic Inference Using Evolutionary Algorithms(Clare Bates Congdon). 11.1 Introduction. 11.2 Background in Phylogenetics. 11.3 Challenges and Opportunities for Evolutionary Computation. 11.4 One Contribution of Evolutionary Computation: Graphyl. 11.5 Some Other Contributions of Evolutionary computation. 11.6 Open Questions and Opportunities. Part Four Medicine. 12. Evolutionary Algorithms for Cancer Chemotherapy Optimization (John McCall, Andrei Petrovski, and Siddhartha Shakya). 12.1 Introduction. 12.2 Nature of Cancer. 12.3 Nature of Chemotherapy. 12.4 Models of Tumor Growth and Response. 12.5 Constraints on Chemotherapy. 12.6 Optimal Control Formulations of Cancer Chemotherapy. 12.7 Evolutionary Algorithms for Cancer Chemotherapy Optimization. 12.8 Encoding and Evaluation. 12.9 Applications of EAs to Chemotherapy Optimization Problems. 12.10 Related Work. 12.11 Oncology Workbench. 12.12 Conclusion. 13. Fuzzy Ontology-Based Text Mining System for Knowledge Acquisition, Ontology Enhancement, and Query Answering from Biomedical Texts (Lipika Dey and Muhammad Abulaish). 13.1 Introduction. 13.2 Brief Introduction to Ontologies. 13.3 Information Retrieval form Biological Text Documents: Related Work. 13.4 Ontology-Based IE and Knowledge Enhancement System. 13.5 Document Processor. 13.6 Biological Relation Extractor. 13.7 Relation-Based Query Answering. 13.8 Evaluation of the Biological Relation Extraction Process. 13.9 Biological Relation Characterizer. 13.10 Determining Strengths of Generic Biological Relations. 13.11 Enhancing GENIA to Fuzzy Relational Ontology. 13.12 Conclusions and Future Work. References. Appendix Feasible Biological Relations. Index.

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Book SynopsisA real-world guide to the production and manufacturing of biopharmaceuticals While much has been written about the science of biopharmaceuticals, there is a need for practical, up-to-date information on key issues at all stages of developing and manufacturing commercially viable biopharmaceutical drug products. This book helps fill the gap in the field, examining all areas of biopharmaceuticals manufacturing, from development and formulation to production and packaging. Written by a group of experts from industry and academia, the book focuses on real-world methods for maintaining product integrity throughout the commercialization process, clearly explaining the fundamentals and essential pathways for all development stages. Coverage includes: Research and early development phase?appropriate approaches for ensuring product stability Development of commercially viable formulations for liquid and lyophilized dosage forms Trade Review"This book is intended as a comprehensive look at the growing area of producing and manufacturing biopharmaceuticals, right the way through from development to commercialisation. Each chapter is written by an expert in that area and authors hail from both industry and academia." (TCE- The Chemical Engineer, 1 December 2010)Table of Contents Introduction (John Carpenter). Part I Preformulation and Development of Stability Indicating Assays: Biophysical Characterization Techniques. 1. The Structure of Biological Therapeutics (Sherry Martin-Moe, Y. John Wang, Tim Osslund, Tahir Mahmood, Rohini Deshpande, and Susan Hershenson). 2. Chemical Instability in Peptide and Protein Pharmaceuticals (Elizabeth M. Topp, Lei Zhang, Hong Zhao, Robert W. Payne, Gabriel J. Evans and Mark Cornell Manning). 3. Physical Instability in Peptide and Protein Pharmaceuticals (Byeong Chang and Bernice Yang). 4. Immunogenicity of Therapeutic Proteins (Steven J Swanson). 5. Preformulation Research: Assessing Protein Solution Behavior Early During Therapeutic Development (Bernardo Perez-Ramirez, Nicholas Guziewicz and Robert Simler). 6. Formulation Development of Phase I/II Biopharmaceuticals: An Efficient and Timely Approach (Nicholas W. Warne). 7. Late Stage Formulation Development and Characterization of Biopharmaceuticals (Adeolla O Grillo). 8. An Empirical Phase Diagram/ High Throughput Screening Approach to the Characterization and Formulation of Biopharmaceuticals (Sangeeta B. Joshi; Akhilesh Bhambhani; Yuhong Zeng; and C. Russell Middaugh). 9. Fluorescence and Phosphorescence Methods to Probe Protein Structure and Stability in Ice: the Case of Azurin (Giovanni Strambini). 10. Applications of Sedimentation Velocity Analytical Ultracentrifugation (Tom Laue). 11. Field Flow Fractionation with Multi-angle Light Scattering for Measuring Particle Size of Virus-like Particles (Joyce A Sweeney and Christopher Hamm). 12. Light Scattering Techniques and their Application to Formulation and Aggregation Concerns (Philip Wyatt and Michael Larkin). Part 2 Development of a Formulation for Liquid Dosage Form. 13. Efficient Approaches to Formulation Development of Biopharmaceuticals (Rajiv Nayar and Mitra Mosharraf). 14. Prediction of Protein Aggregation Propensities from Primary Sequence Information (Mark Cornell Manning, Gabriel J. Evans, Cody M. Van Pelt and Robert W. Payne). 15. High Concentration Antibody Formulations (Steven J. Shire, Jun Liu, Wolfgang Friess, Susanne Matheus and Hanns-Christian Mahler). 16. Development of Formulations for Therapeutic Monoclonal Antibodies and Fc Fusion Proteins (Sampath kumar Krishnan, Monica M. Pallitto and Margaret S. Ricci). 17. Reversible Self-Association of Pharmaceutical Proteins: Characterization and Case Studies (Vikas K. Sharma, Harminder Bajaj and Devendra S. Kalonia). Part 3 Development of Formulation for Lyophilized Dosage Form. 18. Design of a Formulation for Freeze Drying (Feroz Jameel and Mike J. Pikal). 19. Protein Conformation and Reactivity in Amorphous Solids (Lei Zhang, Sandipan Sinha and Elizabeth M. Topp). 20. The Impact of Buffer on Solid-State Properties and Stability of Freeze-Dried Dosage Forms (Evgenyi Y. Shalaev and Larry A. Gatlin). 21. Stabilization of Lyophilized Pharmaceuticals by Control of Molecular Mobility: Impact of Thermal History (Suman Luthra and Micheal J. Pikal). 22. Structural Analysis of Proteins in Dried Matrices (Andrea Hawe, Sandipan Sinha, Wolfgang Friess and Wim Jiskoot). 23. The Impact of Formulation and Drying Processes on the Characteristics and Performance of Biopharmaceutical Powders (Vu L. Truong and Ahmad M. Abdul-Fattah). Part 4 Manufacturing Sciences. 24. Manufacturing Fundamentals for Biopharmaceuticals (Maninder Hora). 25. Protein Stability during Bioprocessing (Mark Cornell Manning, Gabriel J. Evans and Robert W. Payne). 26. Freezing and Thawing of Protein Solutions (Satish Singh and Sandeep Neema). 27. Strategies for Bulk Storage and Shipment of Proteins (Feroz Jameel, Chakradhar Padala and Theodore W. Randolph). 28. Drying Process Methods for Biopharmaceutical Products: An Overview (Ahmad M. Abdul-Fattah and Vu L. Truong). 29. Spray Drying of Biopharmaceuticals and Vaccines (Jim Searles and Govindan (Dan) Mohan). 30. Development and Optimization of Freeze Drying Process (Feroz Jameel and Jim Searles). 31. Considerations for Successful Lyophilization Process Scale-up, Technology Transfer and Routine Production (Samir Sane and Chung C. Hsu). 32. Process Robustness in Freeze-Drying of Biopharmaceuticals (D.Q. Wang, D. MacLean and X. Ma). 33. Filling Processes and Technologies for Liquid Biopharmaceuticals (Ananth Sethuraman, Xiaogang Pan, Bhavya Mehta and Vinay Radhakrishnan). 34. Leachables and Extractables (Jim Castner, Pedro Benites and Michael Bresnick). 35. Primary Container/Closure Selection for Biopharmaceuticals (Olivia Henderson). 36. Pre-filled Syringes for Biopharmaceuticals (Robert Swift and Robin Hwang). 37. Impact of Manufacturing Processes on the Drug Product Stability and Quality (Nitin Rathore, Rahul S. Rajan and Erwin Freund). Index.

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Book SynopsisBiointerfaces are central to biology and medicine and crucial in research relating to implants, biosensors, drug delivery, proteomics, and many other fields.Trade Review"Ohshima (pharmaceutical science, Tokyo U. of Science) sets out a set of tools for discussing various phenomena at biological interfaces - such as cell surfaces - in terms of biophysical chemistry." (SciTech Book News, December 2010) Table of ContentsPreface xiii List of Symbols xv Part I Potential and Charge at Interfaces 1 1 Potential and Charge of a Hard Particle 3 1.1 Introduction 3 1.2 The Poisson-Boltzmann Equation 3 1.3 Plate 6 1.3.1 Low Potential 8 1.3.2 Arbitrary Potential: Symmetrical Electrolyte 8 1.3.3 Arbitrary Potential: Asymmetrical Electrolyte 13 1.3.4 Arbitrary Potential: General Electrolyte 14 1.4 Sphere 16 1.4.1 Low Potential 17 1.4.2 Surface Charge Density-Surface Potential Relationship: Symmetrical Electrolyte 18 1.4.3 Surface Charge Density-Surface Potential Relationship: Asymmetrical Electrolyte 21 1.4.4 Surface Charge Density-Surface Potential Relationship: General Electrolyte 22 1.4.5 Potential Distribution Around a Sphere with Arbitrary Potential 25 1.5 Cylinder 31 1.5.1 Low Potential 32 1.5.2 Arbitrary Potential: Symmetrical Electrolyte 33 1.5.3 Arbitrary Potential: General Electrolytes 34 1.6 Asymptotic Behavior of Potential and Effective Surface Potential 37 1.6.1 Plate 38 1.6.2 Sphere 41 1.6.3 Cylinder 42 1.7 Nearly Spherical Particle 43 References 45 2 Potential Distribution Around a Nonuniformly Charged Surface and Discrete Charge Effects 47 2.1 Introduction 47 2.2 The Poisson-Boltzmann Equation for a Surface with an Arbitrary Fixed Surface Charge Distribution 47 2.3 Discrete Charge Effect 56 References 62 3 Modified Poisson-Boltzmann Equation 63 3.1 Introduction 63 3.2 Electrolyte Solution Containing Rod-like Divalent Cations 63 3.3 Electrolyte Solution Containing Rod-like Zwitterions 70 3.4 Self-atmosphere Potential of Ions 77 References 82 4 Potential and Charge of a Soft Particle 83 4.1 Introduction 83 4.2 Planar Soft Surface 83 4.2.1 Poisson–Boltzmann Equation 83 4.2.2 Potential Distribution Across a Surface Charge Layer 87 4.2.3 Thick Surface Charge Layer and Donnan Potential 90 4.2.4 Transition Between Donnan Potential and Surface Potential 91 4.2.5 Donnan Potential in a General Electrolyte 92 4.3 Spherical Soft Particle 93 4.3.1 Low Charge Density Case 93 4.3.2 Surface Potential–Donnan Potential Relationship 95 4.4 Cylindrical Soft Particle 100 4.4.1 Low Charge Density Case 100 4.4.2 Surface Potential–Donnan Potential Relationship 101 4.5 Asymptotic Behavior of Potential and Effective Surface Potential of a Soft Particle 102 4.5.1 Plate 102 4.5.2 Sphere 103 4.5.3 Cylinder 104 4.6 Nonuniformly Charged Surface Layer: Isoelectric Point 104 References 110 5 Free Energy of a Charged Surface 111 5.1 Introduction 111 5.2 Helmholtz Free Energy and Tension of a Hard Surface 111 5.2.1 Charged Surface with Ion Adsorption 111 5.2.2 Charged Surface with Dissociable Groups 116 5.3 Calculation of the Free Energy of the Electrical Double Layer 118 5.3.1 Plate 119 5.3.2 Sphere 120 5.3.3 Cylinder 121 5.4 Alternative Expression for Fel 122 5.5 Free Energy of a Soft Surface 123 5.5.1 General Expression 123 5.5.2 Expressions for the Double-Layer Free Energy for a Planar Soft Surface 127 5.5.3 Soft Surface with Dissociable Groups 128 References 130 6 Potential Distribution Around a Charged Particle in a Salt-Free Medium 132 6.1 Introduction 132 6.2 Spherical Particle 133 6.3 Cylindrical Particle 143 6.4 Effects of a Small Amount of Added Salts 146 6.5 Spherical Soft Particle 152 References 162 Part II Interaction Between Surfaces 163 7 Electrostatic Interaction of Point Charges in an Inhomogeneous Medium 165 7.1 Introduction 165 7.2 Planar Geometry 166 7.3 Cylindrical Geometry 180 References 185 8 Force and Potential Energy of the Double-Layer Interaction Between Two Charged Colloidal Particles 186 8.1 Introduction 186 8.2 Osmotic Pressure and Maxwell Stress 186 8.3 Direct Calculation of Interaction Force 188 8.4 Free Energy of Double-Layer Interaction 198 8.4.1 Interaction at Constant Surface Charge Density 199 8.4.2 Interaction at Constants Surface Potential 200 8.5 Alternative Expression for the Electric Part of the Free Energy of Double-Layer Interaction 201 8.6 Charge Regulation Model 201 References 202 9 Double-Layer Interaction Between Two Parallel Similar Plates 203 9.1 Introduction 203 9.2 Interaction Between Two Parallel Similar Plates 203 9.3 Low Potential Case 207 9.3.1 Interaction at Constant Surface Charge Density 208 9.3.2 Interaction at Constant Surface Potential 211 9.4 Arbitrary Potential Case 214 9.4.1 Interaction at Constant Surface Charge Density 214 9.4.2 Interaction at Constant Surface Potential 224 9.5 Comparison Between the Theory of Derjaguin and Landau and the Theory of Verwey and Overbeek 226 9.6 Approximate Analytic Expressions for Moderate Potentials 227 9.7 Alternative Method of Linearization of the Poisson–Boltzmann Equation 231 9.7.1 Interaction at Constant Surface Potential 231 9.7.2 Interaction at Constant Surface Charge Density 234 References 240 10 Electrostatic Interaction Between Two Parallel Dissimilar Plates 241 10.1 Introduction 241 10.2 Interaction Between Two Parallel Dissimilar Plates 241 10.3 Low Potential Case 244 10.3.1 Interaction at Constant Surface Charge Density 244 10.3.2 Interaction at Constant Surface Potential 251 10.3.3 Mixed Case 252 10.4 Arbitrary Potential: Interaction at Constant Surface Charge Density 252 10.4.1 Isodynamic Curves 252 10.4.2 Interaction Energy 258 10.5 Approximate Analytic Expressions for Moderate Potentials 262 References 263 11 Linear Superposition Approximation for the Double-Layer Interaction of Particles at Large Separations 265 11.1 Introduction 265 11.2 Two Parallel Plates 265 11.2.1 Similar Plates 265 11.2.2 Dissimilar Plates 270 11.2.3 Hypothetical Charge 276 11.3 Two Spheres 278 11.4 Two Cylinders 279 References 281 12 Derjaguin’s Approximation at Small Separations 283 12.1 Introduction 283 12.2 Two Spheres 283 12.2.1 Low Potentials 285 12.2.2 Moderate Potentials 286 12.2.3 Arbitrary Potentials: Derjaguin’s Approximation Combined with the Linear Superposition Approximation 288 12.2.4 Curvature Correction to Derjaguin’ Approximation 290 12.3 Two Parallel Cylinders 292 12.4 Two Crossed Cylinders 294 References 297 13 Donnan Potential-Regulated Interaction Between Porous Particles 298 13.1 Introduction 298 13.2 Two Parallel Semi-infinite Ion-penetrable Membranes (Porous Plates) 298 13.3 Two Porous Spheres 306 13.4 Two Parallel Porous Cylinders 310 13.5 Two Parallel Membranes with Arbitrary Potentials 311 13.5.1 Interaction Force and Isodynamic Curves 311 13.5.2 Interaction Energy 317 13.6 pH Dependence of Electrostatic Interaction Between Ion-penetrable Membranes 320 References 322 14 Series Expansion Representations for the Double-Layer Interaction Between Two Particles 323 14.1 Introduction 323 14.2 Schwartz’s Method 323 14.3 Two Spheres 327 14.4 Plate and Sphere 342 14.5 Two Parallel Cylinders 348 14.6 Plate and Cylinder 353 References 356 15 Electrostatic Interaction Between Soft Particles 357 15.1 Introduction 357 15.2 Interaction Between Two Parallel Dissimilar Soft Plates 357 15.3 Interaction Between Two Dissimilar Soft Spheres 363 15.4 Interaction Between Two Dissimilar Soft Cylinders 369 References 374 16 Electrostatic Interaction Between Nonuniformly Charged Membranes 375 16.1 Introduction 375 16.2 Basic Equations 375 16.3 Interaction Force 376 16.4 Isoelectric Points with Respect To Electrolyte Concentration 378 Reference 380 17 Electrostatic Repulsion Between Two Parallel Soft Plates After Their Contact 381 17.1 Introduction 381 17.2 Repulsion Between Intact Brushes 381 17.3 Repulsion Between Compressed Brushes 382 References 387 18 Electrostatic Interaction Between Ion-Penetrable Membranes In a Salt-free Medium 388 18.1 Introduction 388 18.2 Two Parallel Hard Plates 388 18.3 Two Parallel Ion-Penetrable Membranes 391 References 398 19 van der Waals Interaction Between Two Particles 399 19.1 Introduction 399 19.2 Two Molecules 399 19.3 A Molecule and a Plate 401 19.4 Two Parallel Plates 402 19.5 A Molecule and a Sphere 404 19.6 Two Spheres 405 19.7 A Molecule and a Rod 407 19.8 Two Parallel Rods 408 19.9 A Molecule and a Cylinder 408 19.10 Two Parallel Cylinders 410 19.11 Two Crossed Cylinders 412 19.12 Two Parallel Rings 412 19.13 Two Parallel Torus-Shaped Particles 413 19.14 Two Particles Immersed In a Medium 417 19.15 Two Parallel Plates Covered with Surface Layers 418 References 419 20 DLVO Theory of Colloid Stability 420 20.1 Introduction 420 20.2 Interaction Between Lipid Bilayers 420 20.3 Interaction Between Soft Spheres 425 References 429 Part III Electrokinetic Phenomena at Interfaces 431 21 Electrophoretic Mobility of Soft Particles 433 21.1 Introduction 433 21.2 Brief Summary of Electrophoresis of Hard Particles 433 21.3 General Theory of Electrophoretic Mobility of Soft Particles 435 21.4 Analytic Approximations for the Electrophoretic Mobility of Spherical Soft Particles 440 21.4.1 Large Spherical Soft Particles 440 21.4.2 Weakly Charged Spherical Soft Particles 444 21.4.3 Cylindrical Soft Particles 447 21.5 Electrokinetic Flow Between Two Parallel Soft Plates 449 21.6 Soft Particle Analysis of the Electrophoretic Mobility of Biological Cells and Their Model Particles 454 21.6.1 RAW117 Lymphosarcoma Cells and Their Variant Cells 454 21.6.2 Poly(N-isopropylacrylamide) Hydrogel-Coated Latex 455 21.7 Electrophoresis of Nonuniformly Charged Soft Particles 457 21.8 Other Topics of Electrophoresis of Soft Particles 463 References 464 22 Electrophoretic Mobility of Concentrated Soft Particles 468 22.1 Introduction 468 22.2 Electrophoretic Mobility of Concentrated Soft Particles 468 22.3 Electroosmotic Velocity in an Array of Soft Cylinders 475 References 479 23 Electrical Conductivity of a Suspension of Soft Particles 480 23.1 Introduction 480 23.2 Basic Equations 480 23.3 Electrical Conductivity 481 References 484 24 Sedimentation Potential and Velocity in a Suspension of Soft Particles 485 24.1 Introduction 485 24.2 Basic Equations 485 24.3 Sedimentation Velocity of a Soft Particle 490 24.4 Average Electric Current and Potential 490 24.5 Sedimentation Potential 491 24.6 Onsager’s Reciprocal Relation 494 24.7 Diffusion Coefficient of a Soft Particle 495 References 495 25 Dynamic Electrophoretic Mobility of a Soft Particle 497 25.1 Introduction 497 25.2 Basic Equations 497 25.3 Linearized Equations 499 25.4 Equation of Motion of a Soft Particle 501 25.5 General Mobility Expression 501 25.6 Approximate Mobility Formula 503 References 506 26 Colloid Vibration Potential in a Suspension of Soft Particles 508 26.1 Introduction 508 26.2 Colloid Vibration Potential and Ion Vibration Potential 508 References 513 27 Effective Viscosity of a Suspension of Soft Particles 515 27.1 Introduction 515 27.2 Basic Equations 516 27.3 Linearized Equations 518 27.4 Electroviscous Coefficient 520 27.5 Approximation for Low Fixed-Charge Densities 523 27.6 Effective Viscosity of a Concentrated Suspension of Uncharged Porous Spheres 527 Appendix 27a 530 References 531 Part IV other Topics 533 28 Membrane Potential and Donnan Potential 535 28.1 Introduction 535 28.2 Membrane Potential and Donnan Potential 535 References 541 Index 543

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Book SynopsisExplores current and emerging applications of microbes as cancer-fighting agents WILEY SERIES IN BIOTECHNOLOGY AND BIOENGINEERING Anurag S. Rathore, Series Editor Today, treatment options for cancer patients typically include surgery, radiation therapy, immunotherapy, and chemotherapy. While these therapies have saved lives and reduced pain and suffering, cancer still takes millions of lives every year around the world. In recent years, researchers have been working on a new strategy: developing microbes and microbial products that specifically attack cancer cells. This book breaks new ground in emerging cancer treatment modalities by presenting recent advances in the use of microorganisms and viruses as well as their products in cancer therapy. Seventeen chapters review the application of live microorganisms, high and low molecular weight products derived from microorganisms, and microbial products fused to cancertargeting molecules. In addition, theTable of ContentsPreface ix Contributors xi Part I Live/Attenuated Bacteria and Viruses as Anticancer Agents 1 1 Salmonella Typhimurium Mutants Selected to Grow Only in Tumors to Eradicate Them in Nude Mouse Models 3Robert M. Hoffman 2 The Use of Living Listeria Monocytogenes as an Active Immunotherapy for the Treatment of Cancer 13John Rothman, Anu Wallecha, Paulo Cesar Maciag, Sandra Rivera, Vafa Shahabi, and Yvonne Paterson 3 Bacillus Calmette–Guerin (BCG) for Urothelial Carcinoma of the Bladder 49Timothy P. Kresowik and Thomas S. Griffith 4 Live Clostridia: A Powerful Tool in Tumor Biotherapy 71Lieve Van Mellaert, Ming Q Wei, and Jozef Anné 5 Bifi dobacterium as a Delivery System of Functional Genes for Cancer Gene Therapy 99Geng-Feng Fu, Yan Yin, Bi Hu, and Gen-Xing Xu 6 Replication-Selective Viruses for the Treatment of Cancer 119Padma Sampath and Steve H. Thorne 7 Engineering Herpes Simplex Virus for Cancer Oncolytic Virotherapy 141Jason S. Buhrman, Tooba A. Cheema, and Giulia Fulci Part II Bacterial Products as Anticancer Agents 179 8 Promiscuous Anticancer Drugs from Pathogenic Bacteria: Rational Versus Intelligent Drug Design 181Arsénio M. Fialho and Ananda M. Chakrabarty 9 Arginine Deiminase and Cancer Therapy 199Lynn Feun, M. Tien Kuo, Ming You, Chung Jing Wu, Medhi Wangpaichitr, and Niramol Savaraj 10 Cytosine Deaminase/5-Fluorocytosine Molecular Cancer Chemotherapy 219Sergey A. Kaliberov and Donald J. Buchsbaum 11 Bacterial Proteins against Metastasis 243Anna Maria Elisabeth Walenkamp 12 Pseudomonas Exotoxin A-Based Immunotoxins for Targeted Cancer Therapy 269Philipp Wolf and Ursula Elsässer-Beile 13 Denileukin Diftitox in Novel Cancer Therapy 289Lin-Chi Chen and Nam H. Dang 14 The Application of Cationic Antimicrobial Peptides in Cancer Treatment: Laboratory Investigations and Clinical Potential 309Ashley L. Hilchie and David W. Hoskin 15 Prodiginines and Their Potential Utility as Proapoptotic Anticancer Agents 333Neil R. Williamson, Suresh Chawrai, Finian J. Leeper, and George P.C. Salmond 16 Farnesyltransferase Inhibitors of Microbial Origins in Cancer Therapy 367Jingxuan Pan and Sai-Ching Jim Yeung 17 The Use of RNA and CpG DNA as Nucleic Acid-Based Therapeutics 379Jörg Vollmer Part III Patents On Bacteria/Bacterial Products as Anticancer Agents 403 18 The Role and Importance of Intellectual Property Generation and Protection in Drug Development 405Arsénio M. Fialho and Ananda M. Chakrabarty Index 421

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Book SynopsisSix years after its first edition, Computed Tomography: Principles, Design, Artifacts, and Recent Advances, Second Edition provides and updated overview of the evolution of CT, the mathematical and physical aspects of the technology, and the fundamentals of image reconstruction algorithms.Table of ContentsPreface. Nomenclature and Abbreviations. 1. Introduction. 1.1 Conventional X-ray Tomography. 1.2 History of Computed Tomography. 1.3 Different Generations of CT Scanners. 1.4 Problems. References. 2. Preliminaries. 2.1 Mathematics Fundamentals. 2.2 Fundamentals of X-ray Physics. 2.3 Measurement of Line Integrals and Data Conditioning. 2.4 Sampling Geometry and Sinogram. 2.5 Problems. References. 3. Image Reconstruction. 3.1 Introduction. 3.2 Several Approaches to Image Reconstruction. 3.3 The Fourier Slice Theorem. 3.4 The Filtered Backprojection Algorithm. 3.5 Fan-Beam Reconstruction. 3.6 Iterative Reconstruction. 3.7 Problems. References. 4. Image Presentation. 4.1 CT Image Display. 4.2 Volume Visualization. 4.3 Impact of Visualization Tools. 4.4 Problems. References. 5. Key Performance Parameters of the CT Scanner. 5.1 High-Contrast Spatial Resolution. 5.2 Low-Contrast Resolution. 5.3 Temporal Resolution. 5.4 CT Number Accuracy and Noise. 5.5 Performance of the Scanogram. 5.6 Problems. References. 6. Major Components of the CT Scanner. 6.1 System Overview. 6.2 The X-ray Tube and High-Voltage Generator. 6.3 The X-ray Detector and Data-Acquisition Electronics. 6.4 The Gantry and Slip Ring. 6.5 Collimation and Filtration. 6.6 The Reconstruction Engine. 6.7 Problems. References. 7. Image Artifacts: Appearances, Causes, and Corrections. 7.1 What Is an Image Artifact? 7.2 Different Appearances of Image Artifacts. 7.3 Artifacts Related to System Design. 7.4 Artifacts Related to X-ray Tubes. 7.5 Detector-induced Artifacts. 7.6 Patient-induced Artifacts. 7.7 Operator-induced Artifacts. 7.8 Problems. References. 8. Computer Simulation Analysis. 8.1 What Is Computer Simulation? 8.2 Simulation Overview. 8.3 Simulation of Optics. 8.4 Computer Simulation of Physics-related Performance. 8.5 Problems. References. 9. Helical or Spiral CT. 9.1 Introduction. 9.2 Terminology and Reconstruction. 9.3 Slice Sensitivity Profile and Noise. 9.4 Helically Related Image Artifacts. 9.5 Problems. References. 10. Miltislice CT. 10.1 The Need for Multislice CT. 10.2 Detector Configurations of Multislice CT. 10.3 Nonhelical Mode of Reconstruction. 10.4 Multislice Helical Reconstruction. 10.5 Multislice Artifacts. 10.6 Problems. References. 11. X-ray Radiation and Dose-Reduction Techniques. 11.1 Biological Effects of X-ray Radiation. 11.2 Measurement of X-ray dose. 11.3 Methodologies for Dose Reduction. 11.4 Problems. References. 12. Advanced CT Applications. 12.1 Introduction. 12.2 Cardiac Imaging. 12.3 CT Fluoroscopy. 12.4 CT Perfusion. 12.5 Screening and Quantitative CT. 12.6 Dual-Energy CT. 12.7 Problems. References. Glossary. Index.

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Book Synopsisa must-read for all modern bio-scientists and engineers working in the field of biotechnology.Trade Reviewa must-read for all modern bio-scientists and engineers working in the field of biotechnology. (Biotechnology Journal July 2012)Table of ContentsPREFACE xiii 1 Introduction 1 1.1 Scope of Design / 1 1.2 Definition of Biomechatronic Products / 3 1.3 Principles of Biomechatronics / 4 1.4 Brief History of the Development of Biomechatronic Products and Engineering / 7 1.5 Aim of This Book / 9 References / 10 PART I FUNDAMENTALS 13 2 Conceptual Design Theory 15 2.1 Systematic Design / 15 2.1.1 Design for Products / 15 2.1.2 Origin of the Design Task / 18 2.1.3 Development of Design Thinking / 18 2.1.4 Recent Methods / 20 2.2 Basics of Technical Systems / 21 2.2.1 Energy, Material, and Signals and Their Conversion / 22 2.2.2 Interrelationships of Functions / 22 2.2.3 Interrelationship of Constructions / 25 2.2.4 Interrelationship of Systems / 25 2.3 Psychology in the Systematic Approach / 25 2.4 A General Working Methodology / 26 2.4.1 Analysis for Resolving Technical Problems / 27 2.4.2 Abstraction of Interrelationships of Systems / 28 2.4.3 Synthesis of the Technical System / 28 2.5 Conceptual Design / 28 2.6 Abstraction inOrder to Identify Essential Problems / 29 2.7 Developing the Concepts / 31 2.7.1 Organizing the Development Process / 33 2.8 Concluding Remarks / 34 References / 35 3 Biotechnology and Mechatronic Design 37 3.1 Transduction of the Biological Science into Biotechnology / 37 3.2 Biological Sciences and Their Applications / 39 3.3 Biotechnology and Bioengineering / 42 3.4 Applying Mechatronic Theory to Biotechnology: Biomechatronics / 44 3.5 Conclusions / 47 References / 48 4 Methodology for Utilization of Mechatronic Design Tools 49 4.1 Idea of Applying the Mechatronic Design Tools / 49 4.2 Table of User Needs / 51 4.3 List of Target Specifications / 52 4.4 Concept Generation Chart / 52 4.4.1 Basic Concept Component Chart / 53 4.4.2 Permutation Chart / 54 4.5 Concept Screening Matrix / 55 4.6 Concept Scoring Matrix / 56 4.7 Hubka–Eder Mapping / 57 4.7.1 Overview Hubka–Eder Map / 57 4.7.2 Zoom-in Hubka–Eder Mapping / 59 4.8 Functions Interaction Matrix / 60 4.8.1 Functions Interaction Matrix for Systems and Subsystems / 60 4.8.2 Functions Interaction Matrix for Systems and Transformation Process / 61 4.8.3 Design Structure Matrix / 61 4.9 Anatomical Blueprint / 62 4.10 Conclusions / 63 References / 63 PART II APPLICATIONS 65 5 Blood Glucose Sensors 67 5.1 Background of Blood Glucose Analysis / 67 5.2 Specification of Needs for Blood Glucose Analysis / 70 5.3 Design of Blood Glucose Sensors / 71 5.3.1 Generation of Sensor Concepts / 71 5.4 Description of the Systems Involved in the Design Concepts for Glucose Blood Sensors / 76 5.4.1 Biological Systems / 77 5.4.2 Technical Systems / 77 5.4.3 Information Systems / 78 5.4.4 Management and Goal Systems / 78 5.4.5 Human Systems / 79 5.4.6 Active Environment / 79 5.4.7 Interactions Between the Systems and Functions of the Design / 79 5.4.8 Anatomical Blueprints from the Functions Interaction Matrix Analysis / 81 5.5 Conclusions / 82 References / 82 6 Surface Plasmon Resonance Biosensor Devices 85 6.1 Introduction / 85 6.2 Design Requirements on SPR Systems / 88 6.2.1 Needs and Specifications of an SPR Design / 88 6.3 Mechatronic Design Approach of SPR Systems / 89 6.3.1 Generation of Design Alternatives / 89 6.3.2 Hubka–Eder Mapping of the Design Alternatives / 92 6.4 Detailed Design of Critical SPR Subsystems / 99 6.4.1 Design of the Sensor Surface / 100 6.4.2 Design of the Fluidic System / 103 6.5 Conclusions / 109 References / 109 7 A Diagnostic Device for Helicobacter pylori Infection 113 7.1 Diagnostic Principle of Helicobacter Infection / 113 7.2 Mechatronic Analysis of Urea Breath Test Systems / 117 7.2.1 Mission and Specification for a Urea Breath Tests / 117 7.2.2 Generation of UBT Design Concepts / 118 7.2.3 Screening and Scoring of UBT Design Concepts / 119 7.3 Description of the Systems Involved in the Design Concepts for the Urea Breath Tests / 124 7.3.1 Biological Systems Involved / 124 7.3.2 Technical Systems Alternatives / 126 7.3.3 Information Systems (SIS) Required / 127 7.3.4 Management and Goal Systems Required / 127 7.3.5 Human Systems Involved in the Testing / 127 7.3.6 Active Environment That Can Influence / 128 7.4 Aspects of the Design for Efficient Manufacture / 128 7.5 Conclusions / 131 References / 131 8 Microarray Devices 135 8.1 Principles, Methods, and Applications of Microarrays / 135 8.1.1 Principles and Technology / 135 8.1.2 Fabrication Methods / 136 8.1.3 Companies Developing Microarrays / 138 8.1.4 Applications of DNA Microarrays / 139 8.2 Specification of Needs / 141 8.3 Design of Microarrays / 142 8.3.1 Generation of cDNA Microarray Concepts / 142 8.4 Description of the Systems Involved in the Design Concepts / 145 8.4.1 Biological Systems / 146 8.4.2 Technical Systems / 147 8.4.3 Information System / 147 8.4.4 Management and Goal Systems and the Human Systems / 147 8.4.5 Active Environment / 147 8.4.6 Interaction Analysis / 148 8.5 Conclusions / 149 References / 149 9 Microbial and Cellular Bioreactors 153 9.1 Bioreactor Development During the 1970s–1990s / 153 9.2 Missions, User Needs, and Specifications for Bioreactors / 158 9.2.1 Design Mission and User Needs / 158 9.2.2 Target Specifications / 158 9.3 Analysis of Systems for Conventional Bioreactors / 161 9.3.1 Biological Systems in the Bioreactor / 161 9.3.2 Technical Systems / 164 9.3.3 Studying the Interactions of the Systems / 166 9.3.4 Penicillin Production in a Metabolically Engineered Penicillium strain (Case 1) / 168 9.3.5 A Bioreactor System Producing a Recombinant Protein in CHO Cell Culture (Case 2) / 171 9.3.6 Information Systems / 173 9.3.7 Management and Goal Systems / 177 9.3.8 Human Systems / 179 9.3.9 Active Environment / 179 9.4 Novel Bioreactor Designs / 180 9.4.1 Microbioreactors / 180 9.4.2 Bioreactors with Immobilized Cells / 183 9.4.3 Bioreactors for Tissue and Stem Cell Cultures / 185 9.4.4 Bioreactors for Plant Cell Cultures / 186 9.5 Conclusions / 187 References / 187 10 Chromatographic Protein Purification 193 10.1 Background of Chromatographic Protein Purification / 193 10.2 Specification of Needs for Protein Purification Systems / 197 10.3 Design of Purification Systems / 199 10.3.1 Generation of Design Alternatives / 199 10.3.2 Screening the Design Alternatives / 201 10.3.3 Analysis of the Generated Alternatives for a Chromatography System / 202 10.3.4 Interactions Between Key Systems and the Transformation Process / 206 10.4 Unit Operation Purification in a FVIII Production Process (Case 1) / 208 10.5 Micropurification System Based on a Multichip Device (Case 2) / 209 10.6 Conclusions / 211 References / 212 11 Stem Cell Manufacturing 215 11.1 State of the Art of Stem Cell Manufacturing / 215 11.2 Needs and Target Specifications for Scaled-Up Stem Cell Manufacturing / 218 11.3 Setting Up an Efficient Manufacturing System by Using Biomechatronic Conceptual Design / 220 11.3.1 Generating Process Alternatives / 220 11.3.2 Hubka–Eder Map for a Human Embryonic Stem Cell Process / 220 11.4 Conclusions / 225 References / 226 12 Bioartificial Organ-Simulating Devices 229 12.1 Introduction / 229 12.2 Design of Bioartificial Organ-Simulation Devices / 232 12.2.1 Needs and Specifications / 232 12.2.2 Evaluation of the Design Concepts / 236 12.3 Analysis of Bioartificial Liver Systems / 239 12.3.1 Biological Systems / 239 12.3.2 Technical Systems / 241 12.3.3 Information Systems / 242 12.3.4 Management and Goals Systems / 243 12.3.5 Human Systems / 243 12.4 Conclusions / 244 References / 244 13 Applications to Process Analytical Technology and Quality by Design 249 13.1 PAT and QbD Concepts / 249 13.2 Needs of the PAT/QbD Players and Resulting Specifications / 253 13.3 Application of Design Methodology to PAT/QbD / 255 13.3.1 Concept Generation for a PAT/QbD System Structure / 255 13.3.2 Hubka–Eder Mapping of the PAT/QbD Transformation Process for a Pharmaceutical Process / 257 13.3.3 Analysis of Effects / 259 13.4 Applying Mechatronic Design on a PAT System for Online Software Sensing in a Bioprocess (Case) / 260 13.5 Conclusions / 263 References / 263 GLOSSARY 267 INDEX 275

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Book SynopsisThis book provides a broad survey of models and efficient algorithms for Nonnegative Matrix Factorization (NMF). This includes NMF's various extensions and modifications, especially Nonnegative Tensor Factorizations (NTF) and Nonnegative Tucker Decompositions (NTD).Trade Review"[A] focus on the algorithms that are most useful in practice and aim to derive and implement, in MATLAB, efficient and simple iterative algorithms that work with real-world data." (Book News, December 2009)Table of ContentsPreface. Acknowledgments. Glossary of Symbols and Abbreviations. 1 Introduction – Problem Statements and Models. 1.1 Blind Source Separation and Linear Generalized Component Analysis. 1.2 Matrix Factorization Models with Nonnegativity and Sparsity Constraints. 1.2.1 Why Nonnegativity and Sparsity Constraints? 1.2.2 Basic NMF Model. 1.2.3 Symmetric NMF. 1.2.4 Semi-Orthogonal NMF. 1.2.5 Semi-NMF and Nonnegative Factorization of Arbitrary Matrix. 1.2.6 Three-factor NMF. 1.2.7 NMF with Offset (Affine NMF). 1.2.8 Multi-layer NMF. 1.2.9 Simultaneous NMF. 1.2.10 Projective and Convex NMF. 1.2.11 Kernel NMF. 1.2.12 Convolutive NMF. 1.2.13 Overlapping NMF. 1.3 Basic Approaches to Estimate Parameters of Standard NMF. 1.3.1 Large-scale NMF. 1.3.2 Non-uniqueness of NMF and Techniques to Alleviate the Ambiguity Problem. 1.3.3 Initialization of NMF. 1.3.4 Stopping Criteria. 1.4 Tensor Properties and Basis of Tensor Algebra. 1.4.1 Tensors (Multi-way Arrays) – Preliminaries. 1.4.2 Subarrays, Tubes and Slices. 1.4.3 Unfolding – Matricization. 1.4.4 Vectorization. 1.4.5 Outer, Kronecker, Khatri-Rao and Hadamard Products. 1.4.6 Mode-n Multiplication of Tensor by Matrix and Tensor by Vector, Contracted Tensor Product. 1.4.7 Special Forms of Tensors. 1.5 Tensor Decompositions and Factorizations. 1.5.1 Why Multi-way Array Decompositions and Factorizations? 1.5.2 PARAFAC and Nonnegative Tensor Factorization. 1.5.3 NTF1 Model. 1.5.4 NTF2 Model. 1.5.5 Individual Differences in Scaling (INDSCAL) and Implicit Slice Canonical Decomposition Model (IMCAND). 1.5.6 Shifted PARAFAC and Convolutive NTF. 1.5.7 Nonnegative Tucker Decompositions. 1.5.8 Block Component Decompositions. 1.5.9 Block-Oriented Decompositions. 1.5.10 PARATUCK2 and DEDICOM Models. 1.5.11 Hierarchical Tensor Decomposition. 1.6 Discussion and Conclusions. 2 Similarity Measures and Generalized Divergences. 2.1 Error-induced Distance and Robust Regression Techniques. 2.2 Robust Estimation. 2.3 Csiszár Divergences. 2.4 Bregman Divergence. 2.4.1 Bregman Matrix Divergences. 2.5 Alpha-Divergences. 2.5.1 Asymmetric Alpha-Divergences. 2.5.2 Symmetric Alpha-Divergences. 2.6 Beta-Divergences. 2.7 Gamma-Divergences. 2.8 Divergences Derived from Tsallis and Rényi Entropy. 2.8.1 Concluding Remarks. 3 Multiplicative Iterative Algorithms for NMF with Sparsity Constraints. 3.1 Extended ISRA and EMML Algorithms: Regularization and Sparsity. 3.1.1 Multiplicative NMF Algorithms Based on the Squared Euclidean Distance. 3.1.2 Multiplicative NMF Algorithms Based on Kullback-Leibler I-Divergence. 3.2 Multiplicative Algorithms Based on Alpha-Divergence. 3.2.1 Multiplicative Alpha NMF Algorithm. 3.2.2 Generalized Multiplicative Alpha NMF Algorithms. 3.3 Alternating SMART: Simultaneous Multiplicative Algebraic Reconstruction Technique. 3.3.1 Alpha SMART Algorithm. 3.3.2 Generalized SMART Algorithms. 3.4 Multiplicative NMF Algorithms Based on Beta-Divergence. 3.4.1 Multiplicative Beta NMF Algorithm. 3.4.2 Multiplicative Algorithm Based on the Itakura-Saito Distance. 3.4.3 Generalized Multiplicative Beta Algorithm for NMF. 3.5 Algorithms for Semi-orthogonal NMF and Orthogonal Three-Factor NMF. 3.6 Multiplicative Algorithms for Affine NMF. 3.7 Multiplicative Algorithms for Convolutive NMF. 3.7.1 Multiplicative Algorithm for Convolutive NMF Based on Alpha-Divergence. 3.7.2 Multiplicative Algorithm for Convolutive NMF Based on Beta-Divergence. 3.7.3 Efficient Implementation of CNMF Algorithm. 3.8 Simulation Examples for Standard NMF. 3.9 Examples for Affine NMF. 3.10 Music Analysis and Decomposition Using Convolutive NMF. 3.11 Discussion and Conclusions. 4 Alternating Least Squares and Related Algorithms for NMF and SCA Problems. 4.1 Standard ALS Algorithm. 4.1.1 Multiple Linear Regression – Vectorized Version of ALS Update Formulas. 4.1.2 Weighted ALS. 4.2 Methods for Improving Performance and Convergence Speed of ALS Algorithms. 4.2.1 ALS Algorithm for Very Large-scale NMF. 4.2.2 ALS Algorithm with Line-Search. 4.2.3 Acceleration of ALS Algorithm via Simple Regularization. 4.3 ALS Algorithm with Flexible and Generalized Regularization Terms. 4.3.1 ALS with Tikhonov Type Regularization Terms. 4.3.2 ALS Algorithms with Sparsity Control and Decorrelation. 4.4 Combined Generalized Regularized ALS Algorithms. 4.5 Wang-Hancewicz Modified ALS Algorithm. 4.6 Implementation of Regularized ALS Algorithms for NMF. 4.7 HALS Algorithm and its Extensions. 4.7.1 Projected Gradient Local Hierarchical Alternating Least Squares (HALS) Algorithm. 4.7.2 Extensions and Implementations of the HALS Algorithm. 4.7.3 Fast HALS NMF Algorithm for Large-scale Problems. 4.7.4 HALS NMF Algorithm with Sparsity, Smoothness and Uncorrelatedness Constraints. 4.7.5 HALS Algorithm for Sparse Component Analysis and Flexible Component Analysis. 4.7.6 Simplified HALS Algorithm for Distributed and Multi-task Compressed Sensing. 4.7.7 Generalized HALS-CS Algorithm. 4.7.8 Generalized HALS Algorithms Using Alpha-Divergence. 4.7.9 Generalized HALS Algorithms Using Beta-Divergence. 4.8 Simulation Results. 4.8.1 Underdetermined Blind Source Separation Examples. 4.8.2 NMF with Sparseness, Orthogonality and Smoothness Constraints. 4.8.3 Simulations for Large-scale NMF. 4.8.4 Illustrative Examples for Compressed Sensing. 4.9 Discussion and Conclusions. 5 Projected Gradient Algorithms. 5.1 Oblique Projected Landweber (OPL) Method. 5.2 Lin’s Projected Gradient (LPG) Algorithm with Armijo Rule. 5.3 Barzilai-Borwein Gradient Projection for Sparse Reconstruction (GPSR-BB). 5.4 Projected Sequential Subspace Optimization (PSESOP). 5.5 Interior Point Gradient (IPG) Algorithm. 5.6 Interior Point Newton (IPN) Algorithm. 5.7 Regularized Minimal Residual Norm Steepest Descent Algorithm (RMRNSD). 5.8 Sequential Coordinate-Wise Algorithm (SCWA). 5.9 Simulations. 5.10 Discussions. 6 Quasi-Newton Algorithms for Nonnegative Matrix Factorization. 6.1 Projected Quasi-Newton Optimization. 6.1.1 Projected Quasi-Newton for Frobenius Norm. 6.1.2 Projected Quasi-Newton for Alpha-Divergence. 6.1.3 Projected Quasi-Newton for Beta-Divergence. 6.1.4 Practical Implementation. 6.2 Gradient Projection Conjugate Gradient. 6.3 FNMA algorithm. 6.4 NMF with Quadratic Programming. 6.4.1 Nonlinear Programming. 6.4.2 Quadratic Programming. 6.4.3 Trust-region Subproblem. 6.4.4 Updates for A. 6.5 Hybrid Updates. 6.6 Numerical Results. 6.7 Discussions. 7 Multi-Way Array (Tensor) Factorizations and Decompositions. 7.1 Learning Rules for the Extended Three-way NTF1 Problem. 7.1.1 Basic Approaches for the Extended NTF1 Model. 7.1.2 ALS Algorithms for NTF1. 7.1.3 Multiplicative Alpha and Beta Algorithms for the NTF1 Model. 7.1.4 Multi-layer NTF1 Strategy. 7.2 Algorithms for Three-way Standard and Super Symmetric Nonnegative Tensor Factorization. 7.2.1 Multiplicative NTF Algorithms Based on Alpha- and Beta-Divergences. 7.2.2 Simple Alternative Approaches for NTF and SSNTF. 7.3 Nonnegative Tensor Factorizations for Higher-Order Arrays. 7.3.1 Alpha NTF Algorithm. 7.3.2 Beta NTF Algorithm. 7.3.3 Fast HALS NTF Algorithm Using Squared Euclidean Distance. 7.3.4 Generalized HALS NTF Algorithms Using Alpha- and Beta-Divergences. 7.3.5 Tensor Factorization with Additional Constraints. 7.4 Algorithms for Nonnegative and Semi-Nonnegative Tucker Decompositions. 7.4.1 Higher Order SVD (HOSVD) and Higher Order Orthogonal Iteration (HOOI) Algorithms. 7.4.2 ALS Algorithm for Nonnegative Tucker Decomposition. 7.4.3 HOSVD, HOOI and ALS Algorithms as Initialization Tools for Nonnegative Tensor Decomposition. 7.4.4 Multiplicative Alpha Algorithms for Nonnegative Tucker Decomposition. 7.4.5 Beta NTD Algorithm. 7.4.6 Local ALS Algorithms for Nonnegative TUCKER Decompositions. 7.4.7 Semi-Nonnegative Tucker Decomposition. 7.5 Nonnegative Block-Oriented Decomposition. 7.5.1 Multiplicative Algorithms for NBOD. 7.6 Multi-level Nonnegative Tensor Decomposition - High Accuracy Compression and Approximation. 7.7 Simulations and Illustrative Examples. 7.7.1 Experiments for Nonnegative Tensor Factorizations. 7.7.2 Experiments for Nonnegative Tucker Decomposition. 7.7.3 Experiments for Nonnegative Block-Oriented Decomposition. 7.7.4 Multi-Way Analysis of High Density Array EEG – Classification of Event Related Potentials. 7.7.5 Application of Tensor Decompositions in Brain Computer Interface – Classification of Motor Imagery Tasks. 7.7.6 Image and Video Applications. 7.8 Discussion and Conclusions. 8 Selected Applications. 8.1 Clustering. 8.1.1 Semi-Binary NMF. 8.1.2 NMF vs. Spectral Clustering. 8.1.3 Clustering with Convex NMF. 8.1.4 Application of NMF to Text Mining. 8.1.5 Email Surveillance. 8.2 Classification. 8.2.1 Musical Instrument Classification. 8.2.2 Image Classification. 8.3 Spectroscopy. 8.3.1 Raman Spectroscopy. 8.3.2 Fluorescence Spectroscopy. 8.3.3 Hyperspectral Imaging. 8.3.4 Chemical Shift Imaging. 8.4 Application of NMF for Analyzing Microarray Data. 8.4.1 Gene Expression Classification. 8.4.2 Analysis of Time Course Microarray Data. References. Index.

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Book SynopsisVarious plant metabolites are useful for human life, and the induction and reduction of these metabolites using modern biotechnical technique is of enormous potential important especially in the fields of agriculture and health.Trade Review"Summing Up: Recommended. Upper-division undergraduates through professionals." (Choice, 1 January 2012)Table of ContentsList of Contributors xiii Preface xv 1 Biosynthesis and Metabolism of Starch and Sugars 1 Frederik Börnke and Sophia Sonnewald 1.1 Introduction 1 1.2 Carbon Partitioning in Mesophyll Cells 2 1.3 Sucrose Biosynthesis in Source Leaves 3 1.4 Starch Metabolism in Source Leaves 7 1.5 Sucrose to Starch Conversion in Storage Organs 12 1.6 Metabolic Engineering of Carbohydrate Metabolism 14 1.7 Engineering Soluble Sugars 16 1.8 Production of Novel Carbohydrates in Transgenic Plants 17 1.9 Network Analysis of Carbohydrate Metabolism 18 Acknowledgements 19 References 19 2 Lipid Biosynthesis 27 David Hildebrand 2.1 Introduction 27 2.2 Fatty Acid Synthesis 29 2.3 Fatty Acid Desaturases 32 2.4 Lipid Signals 38 2.5 Algae 38 2.6 Membrane Synthesis 39 2.7 TAG Biosynthesis 43 2.8 Genetic Engineering of Oilseed for Industrial Uses 46 2.9 Plant Oils as a Renewable Resource 48 Acknowledgements 51 References 52 3 Symbiotic Nitrogen Fixation 67 Hiroshi Kouchi 3.1 Nitrogen Fixing Organisms and the Nitrogenase System 67 3.2 Symbiotic Nodule Formation in Legume Plants 70 3.3 Mutual Interactions between Host Cells and Bacteroids in Legume Nodules 76 3.4 Molecular Genetic Approaches to the Host Regulation of Nitrogen Fixation 83 Acknowledgements 92 References 92 4 Sulfur Metabolism 103 Hideki Takahashi 4.1 Introduction 103 4.2 Sulfate Transport 104 4.3 Sulfate Reduction 111 4.4 Cysteine Biosynthesis 114 4.5 Methionine Biosynthesis 117 4.6 Regulators for Coordination of Sulfur Metabolism 118 References 121 5 Nucleotide Metabolism 135 Rita Zrenner and Hiroshi Ashihara 5.1 Introduction 135 5.2 Pyrimidine Metabolism 136 5.3 Purine Metabolism 142 5.4 Pyridine Metabolism 149 5.5 Biotechnological Approaches 152 References 156 6 Purine Alkaloid Metabolism 163 Hiroshi Ashihara, Shinjiro Ogita and Alan Crozier 6.1 Introduction 163 6.2 Classification of Purine Alkaloids 166 6.3 Occurrence of Purine Alkaloids 166 6.4 Biosynthesis of Caffeine 167 6.5 Catabolism of Caffeine 171 6.6 Physiological and Ecological Aspects of Purine Alkaloid Metabolism in Plants 173 6.7 Metabolic Engineering of Caffeine In Planta 176 References 184 7 Nicotine Biosynthesis 191 Tsubasa Shoji and Takashi Hashimoto 7.1 Introduction 191 7.2 Pathways and Enzymes 192 7.3 Compartmentation and Trafficking 200 7.4 Gene Regulation 203 7.5 Metabolic Engineering 207 7.6 Recent Developments 208 7.7 Summary 208 References 208 8 Terpenoid Biosynthesis 217 Dae-Kyun Ro 8.1 Introduction 217 8.2 Terpenoid Diversity 218 8.3 Mechanistic Aspects of Terpenoid Biogenesis 222 8.4 Terpene Synthase – Structure, Evolution and Engineering 223 8.5 Two Distinct Pathways for Isopentenyl Diphosphate (IPP) Biosynthesis 225 8.6 Subcellular and Cellular Compartmentalisations of Terpenoid Metabolism 228 8.7 Gene Clusters in Terpenoid Metabolism 230 8.8 Metabolic Engineering of Terpenoid Metabolism 231 8.9 Concluding Remarks 235 References 235 9 Benzylisoquinoline Alkaloid Biosynthesis 241 Isabel Desgagn´e-Penix and Peter J Facchini 9.1 Introduction 241 9.2 Biosynthesis 242 9.3 Localisation and Transport of Benzylisoquinoline Alkaloids and their Biosynthetic Enzymes 249 9.3.1 Cellular and Subcellular Localisation 249 9.3.2 Transport 251 9.4 Regulation 251 9.4.1 Gene Regulation 251 9.4.2 Signal Transduction 251 9.5 Application to Biotechnology 252 9.5.1 Mutagenesis 252 9.5.2 Genetic Transformation and Metabolic Engineering 252 9.5.3 Metabolic Engineering 254 9.6 Conclusions 254 References 254 10 Monoterpenoid Indole Alkaloid Biosynthesis 263 Vincenzo De Luca 10.1 Introduction 263 10.2 Monoterpenoid Indole Alkaloid (MIA) Biosynthesis 265 10.3 MIA Pathway Gene Discovery will be Enhanced by Large-Scale Sequencing and Comparative Analyses 271 10.4 Developmental and Environmental Regulation of MIA Biosynthesis 272 10.5 Metabolic Engineering using Enzymes with Altered Substrate Specificity 282 10.6 Conclusion 282 Acknowledgements 283 References 283 11 Flavonoid Biosynthesis 293 Indu B. Jaganath and Alan Crozier 11.1 Introduction 293 11.2 Advances in Molecular Approaches for Flavonoid Biosynthetic Pathway Elucidation 294 11.3 The Flavonoid Biosynthetic Pathway as it is Today 299 11.4 Conclusions 311 References 313 12 Pigment Biosynthesis I. Anthocyanins 321 Yoshihiro Ozeki, Yuki Matsuba, Yutaka Abe, Naoyuki Umemoto and Nobuhiro Sasaki 12.1 Introduction 321 12.2 The Anthocyanin Biosynthetic Pathway 322 12.3 Glycosylation of Anthocyanidins 325 12.4 Acylation of Anthocyanin Glycosides 327 12.5 Transport of Anthocyanins from Cytosol to Vacuoles 331 12.6 Concluding Remarks 335 References 336 13 Pigment Biosynthesis II: Betacyanins and Carotenoids 343 Masaaki Sakuta and Akemi Ohmiya 13.1 Betacyanins 343 13.2 Carotenoids 350 13.3 Metabolic Engineering of Carotenoids 357 References 361 14 Metabolomics in Plant Biotechnology 373 Yozo Okazaki, Akira Oikawa, Miyako Kusano, Fumio Matsuda and Kazuki Saito 14.1 Introduction 373 14.2 Analytical Technologies 373 14.3 Informatics Techniques 376 14.4 Biotechnological Application 378 Acknowledgements 381 References 381 Index 389

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Book SynopsisThere is an increasing need throughout the biomedical sciences for a greater understanding of knowledge-based systems and their application to genomic and proteomic research. This book discusses knowledge-based and statistical approaches, along with applications in bioinformatics and systems biology. The text emphasizes the integration of different methods for analysing and interpreting biomedical data. This, in turn, can lead to breakthrough biomolecular discoveries, with applications in personalized medicine. Key Features: Explores the fundamentals and applications of knowledge-based and statistical approaches in bioinformatics and systems biology. Helps readers to interpret genomic, proteomic, and metabolomic data in understanding complex biological molecules and their interactions. Provides useful guidance on dealing with large datasets in knowledge bases, a common issue in bioinformatics. Written by leading international experts in thisTable of Contents Preface. List of Contributors. PART I FUNDAMENTALS. Section 1 Knowledge-Driven Approaches. 1 Knowledge-based bioinformatics (Eric Karl Neumann). 1.1 Introduction. 1.2 Formal reasoning for bioinformatics. 1.3 Knowledge representations. 1.4 Collecting explicit knowledge. 1.5 Representing common knowledge. 1.6 Capturing novel knowledge. 1.7 Knowledge discovery applications. 1.8 Semantic harmonization: the power and limitation of ontologies. 1.9 Text mining and extraction. 1.10 Gene expression. 1.11 Pathways and mechanistic knowledge. 1.12 Genotypes and phenotypes. 1.13 The Web's role in knowledge mining. 1.14 New frontiers. 1.15 References. 2 Knowledge-driven approaches to genome-scale analysis (Hannah Tipney and Lawrence Hunter). 2.1 Fundamentals. 2.2 Challenges in knowledge-driven approaches. 2.3 Current knowledge-based bioinformatics tools. 2.4 3R systems: reading, reasoning and reporting the way towards biomedical discovery. 2.5 The Hanalyzer: a proof of 3R concept. 2.6 Acknowledgements. 2.7 References. 3 Technologies and best practices for building bio-ontologies (Mikel Egaña Aranguren, Robert Stevens, Erick Antezana, Jesualdo Tomás Fernández-Breis, Martin Kuiper, and Vladimir Mironov). 3.1 Introduction. 3.2 Knowledge representation languages and tools for building bio-ontologies. 3.3 Best practices for building bio-ontologies. 3.4 Conclusion. 3.5 Acknowledgements. 3.6 References. 4 Design, implementation and updating of knowledge bases (Sarah Hunter, Rolf Apweiler, and Maria Jesus Martin). 4.1 Introduction. 4.2 Sources of data in bioinformatics knowledge bases. 4.3 Design of knowledge bases. 4.4 Implementation of knowledge bases. 4.5 Updating of knowledge bases. 4.6 Conclusions. 4.7 References. Section 2 Data-Analysis Approaches. 5 Classical statistical learning in bioinformatics (Mark Reimers). 5.1 Introduction. 5.2 Significance testing. 5.3 Exploratory analysis. 5.4 Classification and prediction. 5.5 References. 6 Bayesian methods in genomics and proteomics studies (Ning Sun and Hongyu Zhao). 6.1 Introduction. 6.2 Bayes theorem and some simple applications. 6.3 Inference of population structure from genetic marker data. 6.4 Inference of protein binding motifs from sequence data. 6.5 Inference of transcriptional regulatory networks from joint analysis of protein–DNA binding data and gene expression data. 6.6 Inference of protein and domain interactions from yeast two-hybrid data. 6.7 Conclusions. 6.8 Acknowledgements. 6.9 References. 7 Automatic text analysis for bioinformatics knowledge discovery (Dietrich Rebholz-Schuhmann and Jung-jae Kim). 7.1 Introduction. 7.2 Information needs for biomedical text mining. 7.3 Principles of text mining. 7.4 Development issues. 7.5 Success stories. 7.6 Conclusion. 7.7 References. PART II APPLICATIONS. Section 3 Gene and Protein Information. 8 Fundamentals of gene ontology functional annotation (Varsha K. Khodiyar, Emily C. Dimmer, Rachael P. Huntley, and Ruth C. Lovering). 8.1 Introduction. 8.2 Gene Ontology (GO). 8.3 Comparative genomics and electronic protein annotation. 8.4 Community annotation. 8.5 Limitations. 8.6 Accessing GO annotations. 8.7 Conclusions. 8.8 References. 9 Methods for improving genome annotation (Jonathan Mudge and Jennifer Harrow). 9.1 The basis of gene annotation. 9.2 The impact of next generation sequencing on genome annotation. 9.3 References. 10 Sequences from prokaryotic, eukaryotic, and viral genomes available clustered according to phylotype on a Self-Organizing Map (Takashi Abe, Shigehiko Kanaya, and Toshimichi Ikemura). 10.1 Introduction. 10.2 Batch-learning SOM (BLSOM) adapted for genome informatics. 10.3 Genome sequence analyses using BLSOM. 10.4 Conclusions and discussion. 10.5 References. Section 4 Biomolecular Relationships and Meta-Relationships. 11 Molecular network analysis and applications (Minlu Zhang, Jingyuan Deng, Chunsheng V. Fang, Xiao Zhang, and Long Jason Lu). 11.1 Introduction. 11.2 Topology analysis and applications. 11.3 Network motif analysis. 11.4 Network modular analysis and applications. 11.5 Network comparison. 11.6 Network analysis software and tools. 11.7 Summary. 11.8 Acknowledgement. 11.9 References. 12 Biological pathway analysis: an overview of Reactome and other integrative pathway knowledge bases (Robin A. Haw, Marc E. Gillespie, and Michael A. Caudy). 12.1 Biological pathway analysis and pathway knowledge bases. 12.2 Overview of high-throughput data capture technologies and data repositories. 12.3 Brief review of selected pathway knowledge bases. 12.4 How does information get into pathway knowledge bases? 12.5 Introduction to data exchange languages. 12.6 Visualization tools. 12.7 Use case: pathway analysis in Reactome using statistical analysis of high-throughput data sets. 12.8 Discussion: challenges and future directions of pathway knowledge bases. 12.9 References. 13 Methods and challenges of identifying biomolecular relationships and networks associated with complex diseases/phenotypes, and their application to drug treatments (Mie Rizig). 13.1 Complex traits: clinical phenomenology and molecular background. 13.2 Why it is challenging to infer relationships between genes and phenotypes in complex traits? 317 13.3 Bottom-up or top-down: which approach is more useful in delineating complex traits key drivers? 13.4 High-throughput technologies and their applications in complex traits genetics. 13.5 Integrative systems biology: a comprehensive approach to mining high-throughput data. 13.6 Methods applying systems biology approach in the identification of functional relationships from gene expression data. 13.7 Advantages of networks exploration in molecular biology and drug discovery. 13.8 Practical examples of applying systems biology approaches and network exploration in the identification of functional modules and disease-causing genes in complex phenotypes/diseases. 13.9 Challenges and future directions. 13.10 References. Trends and conclusion. Index.

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Book SynopsisStable radicals - molecules with odd electrons which are sufficiently long lived to be studied or isolated using conventional techniques - have enjoyed a long history and are of current interest for a broad array of fundamental and applied reasons, for example to study and drive novel chemical reactions, in the development of rechargeable batteries or the study of free radical reactions in the body. In Stable Radicals: Fundamentals and Applied Aspects of Odd-Electron Compounds a team of international experts provide a broad-based overview of stable radicals, from the fundamental aspects of specific classes of stable neutral radicals to their wide range of applications including synthesis, materials science and chemical biology. Topics covered include: triphenylmethyl and related radicals polychlorinated triphenylmethyl radicals: towards multifunctional molecular materials phenalenyls, cyclopentadienyls, and other carbon-centered radicals<Trade Review "This is a worthwhile and insightful anthology and leaves the reader with the impression that novel prospects and discoveries could surface at any moment from junctions on the stable radical chemical topology." (Angewandte Chemie, 2011) Table of Contents Preface xv List of Contributors xvii 1. Triarylmethyl and Related Radicals 1 Thomas T. Tidwell 1.1 Introduction 1 1.1.1 Discovery of the triphenylmethyl radical 1 1.1.2 Bis(triphenylmethyl) peroxide 3 1.2 Free radical rearrangements 4 1.3 Other routes to triphenylmethyl radicals 5 1.4 The persistent radical effect 7 1.5 Properties of triphenylmethyl radicals 8 1.6 Steric effects and persistent radicals 9 1.7 Substituted triphenylmethyl radicals and dimers 9 1.8 Tris(heteroaryl)methyl and related triarylmethyl radicals 12 1.9 Delocalized persistent radicals: analogues of triarylmethyl radicals 14 1.10 Tetrathiatriarylmethyl (TAM) and related triarylmethyl radicals 16 1.11 Perchlorinated triarylmethyl radicals 20 1.12 Other triarylmethyl radicals 23 1.13 Diradicals and polyradicals related to triphenylmethyl 24 1.14 Outlook 28 Acknowledgements 28 References 28 2. Polychlorotriphenylmethyl Radicals: Towards Multifunctional Molecular Materials 33 Jaume Veciana and Imma Ratera 2.1 Introduction 33 2.2 Functional molecular materials based on PTM radicals 35 2.2.1 Materials with magnetic properties 37 2.2.2 Materials with electronic properties 53 2.2.3 Materials with optical properties 65 2.3 Multifunctional switchable molecular materials based on PTM radicals 69 2.3.1 Photo switchable molecular systems 69 2.3.2 Redox switchable molecular systems 70 2.4 Conclusions 75 References 76 3. Phenalenyls, Cyclopentadienyls, and Other Carbon-Centered Radicals 81 Yasushi Morita and Shinsuke Nishida 3.1 Introduction 81 3.2 Open shell graphene 82 3.3 Phenalenyl 84 3.4 2,5,8-Tri-tert-butylphenalenyl radical 86 3.5 Perchlorophenalenyl radical 92 3.6 Dithiophenalenyl radicals 94 3.7 Nitrogen-containing phenalenyl systems 97 3.7.1 Molecular design and topological isomers 97 3.7.2 2,5,8-Tri-tert-butyl-1,3-diazaphenalenyl 97 3.7.3 Hexaazaphenalenyl derivatives 102 3.7.4 β-Azaphenalenyl derivatives 103 3.8 Oxophenalenoxyl systems 106 3.8.1 Molecular design and topological isomers 106 3.8.2 3-Oxophenalenoxyl (3OPO) system 108 3.8.3 4- and 6-Oxophenalenoxyl (4OPO, 6OPO) systems 110 3.8.4 Redox-based spin diversity 114 3.8.5 Molecular crystalline secondary battery 115 3.8.6 Spin-center transfer and solvato-/thermochromism 117 3.9 Phenalenyl-based zwitterionic radicals 119 3.10 π-Extended phenalenyl systems 122 3.10.1 Triangulenes 122 3.10.2 Trioxytriangulene with redox-based spin diversity nature 125 3.10.3 Bis- and tris-phenalenyl system and singlet biradical characters 125 3.11 Curve-structured phenalenyl system 130 3.12 Non-alternant stable radicals 131 3.12.1 Cyclopentadienyl radicals 131 3.12.2 Cyclopentadienyl radicals within a larger π-electronic framework 135 3.13 Stable triplet carbenes 136 3.14 Conclusions 139 Acknowledgements 139 References 140 4. The Nitrogen Oxides: Persistent Radicals and van der Waals Complex Dimers 147 D. Scott Bohle 4.1 Introduction 147 4.2 Synthetic access 149 4.3 Physical properties 149 4.4 Structural chemistry of the monomers and dimers 150 4.4.1 Nitric oxide and dinitrogen dioxide 150 4.4.2 Nitrogen dioxide and dinitrogen tetroxide 152 4.5 Electronic structure of nitrogen oxides 153 4.6 Reactivity of nitric oxide and nitrogen dioxide and their van der Waals complexes 155 4.7 The kinetics of nitric oxide’s termolecular reactions 156 4.8 Biochemical and organic reactions of nitric oxide 158 4.9 General reactivity patterns 160 4.9.1 Oxidation 160 4.9.2 Reduction 161 4.9.3 Coordination 162 4.9.4 Addition of nucleophiles 162 4.9.5 General organic reactions 165 4.9.6 Reactions with other nucleophiles 165 4.10 The colored species problem in nitric oxide chemistry 166 4.11 Conclusions 166 References 166 5. Nitroxide Radicals: Properties, Synthesis and Applications 173 Hakim Karoui, François Le Moigne, Olivier Ouari and Paul Tordo 5.1 Introduction 173 5.2 Nitroxide structure 174 5.2.1 Characteristics of the aminoxyl group 174 5.2.2 X-ray structures of nitroxides 175 5.2.3 Quantum mechanical (QM), molecular dynamics (MD) and molecular mechanics (MM) calculations 177 5.2.4 Influence of solvent polarity on the EPR parameters of nitroxides 180 5.3 Nitroxide multiradicals 181 5.3.1 Electron spin–spin exchange coupling 182 5.3.2 Miscellaneous aspects of di- and polynitroxides 184 5.4 Nitronyl nitroxides (NNOs) 185 5.4.1 Synthesis of nitronyl nitroxides 186 5.4.2 Nitronyl nitroxide as a nitric oxide trap 186 5.4.3 Nitronyl nitroxides as building blocks for magnetic materials 188 5.5 Synthesis of nitroxides 191 5.5.1 Oxidation of amines 191 5.5.2 Oxidation of hydroxylamines 191 5.5.3 Chiral nitroxides 191 5.5.4 Nitroxide design for nitroxide mediated polymerization (NMP) 193 5.6 Chemical properties of nitroxides 196 5.6.1 The Persistent Radical Effect 197 5.6.2 Redox reactions 197 5.6.3 Approaches to improve the resistance of nitroxides toward bioreduction 198 5.6.4 Hydrogen abstraction reactions 199 5.6.5 Cross-coupling reactions 200 5.6.6 Nitroxides in synthetic sequences 200 5.7 Nitroxides in supramolecular entities 206 5.7.1 Interaction of nitroxides with cyclodextrins 207 5.7.2 Interaction of nitroxides with calix[4]arenes 209 5.7.3 Interaction of nitroxides with curcubiturils 210 5.7.4 Interaction of nitroxides with micelles 211 5.7.5 Fullerene-linked nitroxides 212 5.8 Nitroxides for dynamic nuclear polarization (DNP) enhanced NMR 213 5.8.1 DNP for biological NMR and real-time metabolic imaging 213 5.8.2 Nitroxides as polarizing agents for DNP 214 5.9 Nitroxides as pH-sensitive spin probes 216 5.10 Nitroxides as prefluorescent probes 217 5.11 EPR-spin trapping technique 217 5.11.1 Immuno spin trapping 219 5.11.2 Conclusion 219 5.12 Conclusions 220 References 220 6. The Only Stable Organic Sigma Radicals: Di-tert-Alkyliminoxyls 231 Keith U. Ingold 6.1 Introduction 231 6.2 The discovery of stable iminoxyls 232 6.2.1 Synthesis of di-tert-butyl ketoxime 233 6.2.2 Synthesis of di-tert-butyliminoxyl 234 6.2.3 Stability of di-tert-butyliminoxyl 235 6.3 Hydrogen atom abstraction by di-tert-butyliminoxyl 236 6.3.1 The O−H bond dissociation enthalpy (BDE) in (Me 3 C) 2 C=NOH 236 6.3.2 Oxidation of hydrocarbons with di-tert-butyliminoxyl 237 6.3.3 Oxidation of phenols with di-tert-butyliminoxyl 238 6.3.4 Oxidation of amines with di-tert-butyliminoxyl 239 6.3.5 Oxidation of di-tert-butylketoxime with di-tert-butyliminoxyl 239 6.4 Other reactions and non-reactions of di-tert-butyliminoxyl 241 6.5 Di-tert-alkyliminoxyls more sterically crowded than di-tert-butyliminoxyl 241 6.6 Di-(1-Adamantyl)iminoxyl: a truly stable σ radical 242 References 243 7. Verdazyls and Related Radicals Containing the Hydrazyl [R 2 N−NR] Group 245 Robin G. Hicks 7.1 Introduction 245 7.2 Verdazyl radicals 246 7.2.1 Synthesis of verdazyls 246 7.2.2 Stability, physical properties and electronic structure of verdazyls 250 7.2.3 Verdazyl radical reactivity 256 7.2.4 Inorganic verdazyl analogues 264 7.3 Tetraazapentenyl radicals 265 7.4 Tetrazolinyl radicals 266 7.5 1,2,4-Triazolinyl radicals 268 7.6 1,2,4,5-Tetrazinyl radicals 269 7.7 Benzo-1,2,4-triazinyl radicals 270 7.8 Summary 273 References 273 8. Metal Coordinated Phenoxyl Radicals 281 Fabrice Thomas 8.1 Introduction 281 8.2 General properties of phenoxyl radicals 282 8.2.1 Electronic structure and stabilization 282 8.2.2 Electrochemistry of phenoxyl radicals 283 8.2.3 Structure of non-coordinated phenoxyl radicals 284 8.2.4 UV-Vis spectroscopy 284 8.2.5 EPR spectroscopy 284 8.3 Occurrence of tyrosyl radicals in proteins 285 8.4 Complexes with coordinated phenoxyl radicals 287 8.4.1 General ligand structures 287 8.4.2 Vanadium complexes 290 8.4.3 Chromium complexes 291 8.4.4 Manganese complexes 292 8.4.5 Iron complexes 294 8.4.6 Cobalt complexes 297 8.4.7 Nickel complexes 299 8.4.8 Copper complexes 303 8.4.9 Zinc complexes 310 8.5 Conclusions 313 8.6 Abbreviations 313 References 313 9. The Synthesis and Characterization of Stable Radicals Containing the Thiazyl (SN) Fragment and Their Use as Building Blocks for Advanced Functional Materials 317 Robin G. Hicks 9.1 Introduction 317 9.2 Radicals based exclusively on sulfur and nitrogen 319 9.2.1 NS• and SNS• 319 9.2.2 S3 N3• 320 9.2.3 S3 N2•+ and related radical cations 320 9.2.4 Poly(thiazyl), (SN)X 322 9.3 “Organothiazyl” radicals 323 9.3.1 Thioaminyl radicals 323 9.3.2 1,2,3,5-Dithiadiazolyl radicals 329 9.3.3 1,3,2,4-Dithiadiazolyl radicals 336 9.3.4 1,3,2-Dithiazolyl radicals 339 9.3.5 1,2,3-Dithiazolyl radicals 342 9.3.6 Bis(1,2,3-dithiazole) and related radicals 345 9.3.7 1,2,4-Thiadiazinyl radicals 348 9.3.8 1,2,4,6-Thiatriazinyl and -selenatriazinyl radicals 349 9.3.9 Larger cyclic thiazyl radicals 355 9.4 Thiazyl radicals as “advanced materials” 355 9.4.1 Charge transport properties of thiazyl radicals 356 9.4.2 Thiazyl radical-based charge transfer salts 360 9.4.3 Magnetic properties of thiazyl radicals 364 9.5 Conclusions 373 References 373 10. Stable Radicals of the Heavy p-Block Elements 381 Jari Konu and Tristram Chivers 10.1 Introduction 381 10.2 Group 13 element radicals 382 10.2.1 Boron 382 10.2.2 Aluminum, gallium, and indium 384 10.3 Group 14 element radicals 388 10.3.1 Cyclic group 14 radicals 389 10.3.2 Acyclic group 14 radicals 391 10.4 Group 15 element radicals 395 10.4.1 Phosphorus 395 10.4.2 Arsenic, antimony, and bismuth 400 10.5 Group 16 element radicals 400 10.5.1 Sulfur 400 10.5.2 Selenium and tellurium 401 10.6 Group 17 element radicals 402 10.7 Summary and future prospects 403 References 404 11. Application of Stable Radicals as Mediators in Living-Radical Polymerization 407 Andrea R. Szkurhan, Julie Lukkarila and Michael K. Georges 11.1 Introduction 407 11.2 Living polymerizations 408 11.2.1 Living-radical polymerization background 408 11.3 Stable free radical polymerization 409 11.3.1 Background of the work performed at the Xerox Research Centre of Canada 409 11.3.2 General considerations and mechanism 410 11.3.3 Unimolecular initiators 411 11.3.4 Persistent radical effect 413 11.3.5 Requirements of stable radicals as mediating agents 413 11.3.6 Nitroxides as mediating agents 414 11.3.7 Nitroxides and their ability to moderate polymerizations 414 11.3.8 Rate enhancement of stable free radical polymerization through the use of additives 416 11.4 Non-nitroxide-based radicals as mediating agents 416 11.4.1 Triazolinyl radicals 416 11.4.2 Verdazyl radicals 417 11.4.3 Other radicals as mediators 418 11.5 Aqueous stable free radical polymerization processes 420 11.5.1 Living-radical miniemulsion polymerization 421 11.5.2 Emulsion polymerization 422 11.5.3 Other aqueous polymerization processes 423 11.6 The application of stable free radical polymerization to new materials 423 11.6.1 Statistical copolymers 423 11.6.2 Block copolymers 424 11.7 Conclusions 425 List of abbreviations 425 References 425 12. Nitroxide-Catalyzed Alcohol Oxidations in Organic Synthesis 433 Christian Brückner 12.1 Introduction 433 12.2 Mechanism of TEMPO-catalyzed alcohol oxidations 434 12.3 Nitroxides used as catalysts 435 12.3.1 Monomeric nitroxides 435 12.3.2 Ionic liquid nitroxides 436 12.3.3 Supported nitroxides 436 12.4 Chemoselectivity: oxidation of primary vs secondary alcohols 437 12.5 Chemoselectivity: oxidation of primary vs benzylic alcohols 438 12.6 Oxidation of secondary alcohols to ketones 439 12.7 Oxidations of alcohols to carboxylic acids 439 12.7.1 Oxidations leading to linear carboxylic acids 439 12.7.2 (Diol) oxidations leading to lactones 443 12.8 Stereoselective nitroxide-catalyzed oxidations 444 12.9 Secondary oxidants used in nitroxide-catalyzed reactions 446 12.9.1 Elemental halogens 446 12.9.2 Sodium hypochlorite (bleach) 446 12.9.3 Bis(acetoxy)iodobenzene (BAIB) 447 12.9.4 Oxygen (air) 448 12.9.5 Peroxides 449 12.9.6 Other organic secondary oxidants 450 12.9.7 Anodic, electrochemical oxidation 451 12.10 Use of nitroxide-catalyzed oxidations in tandem reactions 451 12.11 Predictable side reactions 453 12.11.1 Oxidations of sulfur 453 12.11.2 Oxidations of nitrogen 453 12.11.3 Oxidations of carbon 454 12.12 Comparison with other oxidation methods 454 12.13 Nitroxide-catalyzed oxidations and green chemistry 455 Acknowledgements 456 References 456 13. Metal–Nitroxide Complexes: Synthesis and Magnetostructural Correlations 461 Victor Ovcharenko 13.1 Introduction 461 13.2 Two types of nitroxide for direct coordination of the metal to the nitroxyl group 462 13.2.1 Complexes containing only >N−•O as a coordinating group 462 13.2.2 Complexes containing >N−•O and other functional groups as donor fragments 464 13.3 Ferro- and ferrimagnets based on metal–nitroxide complexes 465 13.3.1 Molecular magnets based on 1-D systems 470 13.3.2 Molecular magnets based on 2-D systems 474 13.3.3 Molecular magnets based on 3-D systems 480 13.4 Heterospin systems based on polynuclear compounds of metals with nitroxides 483 13.4.1 Reactions whose products retain both the multinuclear fragment and nitroxide 484 13.4.2 Transformation of polynuclear fragments in reactions with nitroxides 487 13.4.3 Transformation of both the polynuclear fragment and the starting nitroxide 489 13.5 Breathing crystals 490 13.6 Other studies of metal–nitroxides 494 13.6.1 Analytical applications 494 13.6.2 NMR spectroscopy 494 13.6.3 Stabilization of nitroxides with β-hydrogen atoms 496 13.6.4 Increased reactivity 496 13.6.5 Hidden exchange interactions 497 13.6.6 Contrast agents 499 13.7 Conclusions 500 References 500 14. Rechargeable Batteries Using Robust but Redox Active Organic Radicals 507 Takeo Suga and Hiroyuki Nishide 14.1 Introduction 507 14.2 Redox reaction of organic radicals 508 14.3 Mechanism and performance of an organic radical battery 509 14.4 Molecular design and synthesis of redox active radical polymers 512 14.4.1 Poly(methacrylate)s and poly(acrylate)s 512 14.4.2 Poly(vinyl ether)s and poly(allene)s 514 14.4.3 Poly(cyclic ether)s 514 14.4.4 Poly(norbornene)s 514 14.4.5 Poly(acetylene)s 514 14.4.6 Poly(styrene)s 515 14.4.7 Combination of radicals with biopolymers and ionic liquids 515 14.5 A totally organic-based radical battery 515 14.6 Conclusions 517 References 518 15. Spin Labeling: A Modern Perspective 521 Lawrence J. Berliner 15.1 Introduction 521 15.2 The early years 522 15.3 Advantages of nitroxides 523 15.4 Applications of spin labeling to biochemical and biological systems 524 15.4.1 Stoichiometry and specificity: proteins and enzymes 524 15.4.2 The reporter group approach: who makes the news? 525 15.5 Distance measurements 526 15.5.1 Metal–spin label distance measurements 526 15.5.2 Spin label–spin label distance measurements 526 15.5.3 Example of strong dipolar interactions 527 15.5.4 Multiple-quantum EPR and distance measurements 528 15.6 Site directed spin labeling (SDSL): how is it done? 529 15.6.1 The SDSL paradigm 530 15.6.2 SDSL parameters 530 15.7 Other spin labeling applications 531 15.7.1 pH sensitive spin labels 532 15.7.2 Spin labeled DNA – structure, dynamics and sequence analysis 532 15.8 Conclusions 534 References 534 16. Functional in vivo EPR Spectroscopy and Imaging Using Nitroxide and Trityl Radicals 537 Valery V. Khramtsov and Jay L. Zweier 16.1 Introduction 537 16.2 Nitroxyl radicals 538 16.3 Triarylmethyl (trityl) radicals 539 16.4 In vivo EPR oximetry using nitroxyl and trityl probes 539 16.4.1 Magnetic resonance approaches for in vivo oximetry 540 16.4.2 Nitroxide probes for EPR oximetry 540 16.4.3 TAM oximetric probes 545 16.5 EPR spectroscopy and imaging of pH using nitroxyl and trityl probes 547 16.5.1 pH-sensitive nitroxyl radicals 547 16.5.2 Dual function pH- and oxygen-sensitive trityl radicals 553 16.6 Redox- and thiol-sensitive nitroxide probes 556 16.6.1 Nitroxides as redox-sensitive EPR probes 556 16.6.2 Disulfide nitroxide biradicals as GSH-sensitive EPR probes 558 16.7 Conclusions 562 Acknowledgements 563 References 563 17. Biologically Relevant Chemistry of Nitroxides 567 Sara Goldstein and Amram Samuni 17.1 Introduction 567 17.2 Mechanisms of nitroxide reactions with biologically relevant small radicals 569 17.3 Nitroxides as SOD mimics 571 17.4 Nitroxides as catalytic antioxidants in biological systems 573 17.5 Conclusions 576 Acknowledgements 576 References 576 Index 579

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Book SynopsisBiophysical Bone Behaviour: Principles and Applications is the culmination of efforts to relate the biophysical phenomena in bone to bone growth and electrical behavior. Behari develops a bridge between physics and biology of bone leading to its clinical applications, primarily electro stimulations in fracture healing and osteoporosis. The book is based upon authors own research work and his review articles in the area, and updated with the latest research results. The first book dedicated to biophysical bone behavior Develops the relationship between the biophysics and biology of bone into an integral unit Spans basic biophysical studies and clinical applications Links the various topics together to give readers a holistic understanding of the area Presents all major research findings about bone and biophysics Readers can access the full list of references at the companion website: Table of ContentsPreface. Acknowledgements. About the Book. 1 Elements of Bone Biophysics. 1.1 Introduction. 1.2 Structural Aspect of Bone. 1.2.1 Elementary Constituents of Bone. 1.2.2 The Fibers. 1.2.3 Collagen Synthesis. 1.2.4 Bone Matrix (Inorganic Component). 1.3. Classification of Bone Tissues. 1.3.1 Compact Bone. 1.3.2 Fine Cancellous Bone. 1.3.3 Coarse Cancellous Bone. 1.4 Lamellation. 1.4.1 The Cement. 1.5 Role of Bone Water. 1.6 Bone Metabolism. 1.6.1 Ca and P Metabolism. 1.7 Osteoporosis. 1.8 Bone Cells. 1.8.1 Osteoblasts. 1.8.2 Osteoblast Differentiation. 1.8.3 Osteoclast. 1.8.4 Osteoclast Differentiation. 1.8.5 The Osteocytes. 1.8.6 Mathematical Formulation. 1.9 Bone Remodeling. 1.10 Biochemical Markers of Bone and Collagen. 1.11 Summary. 2 Piezoelectricity in Bone. 2.1 Introduction. 2.2 Piezoelectric Effect. 2.2.1 Properties Relating to Piezoelectricity. 2.3 Physical Concept of Piezoelectricity. 2.3.1 Piezoelectric Theory. 2.4 Sound Propagated in a Piezoelectric Medium. 2.5 Equivalent Single-Crystal Structure of Bone. 2.6 Piezoelectric Properties of Dry Compact Bones. 2.6.1 Piezoelectric Properties of Dry and Wet Collagens. 2.6.2 Measurement of Piezoelectricity in Bone. 2.7 Bone Structure and Piezoelectric Properties. 2.8 Piezoelectric Transducers. 2.8.1 Transducer Vibration. 2.8.2 Transverse-Effect Transducer. 2.9 Ferroelectricity in Bone. 2.9.1 Experimental Details. 2.10 Two-Phase Mineral-Filled Plastic Composites. 2.10.1 Material Properties. 2.10.2 Bone Mechanical Properties. 2.11 Mechanical Properties of Cancellous Bone: Microscopic View. 2.12 Ultrasound and Bone Behavior. 2.12.1 Biochemical Coupling. 2.13 Traveling Wave Characteristics. 2.14 Viscoelasticity in Bone. 2.15 Discussion. 3 Bioelectric Phenomena in Bone. 3.1 Macroscopic Stress-Generated Potentials of Moist Bone. 3.2 Mechanism of Biopotential Generation. 3.3 Stress-Generated Potentials (SGPs) in Bone. 3.4 Streaming Potentials and Currents of Normal Cortical Bone: Macroscopic Approach. 3.4.1 Streaming Potential and Current Dependence on Bone Structure and Composition: Macroscopic View. 3.5 Microscopic Potentials and Models of SP Generation in Bone. 3.6 Stress-Generated Fields of Trabecular Bone. 3.7 Biopotential and Electrostimulation in Bone. 3.7.1 Electrode Implantation. 3.7.2 Control Data. 3.7.3 Pulsating Fields. 3.7.4 DC Stimulation. 3.7.5 Electromagnetic Field (50 Hz) Stimulation Along with Radio Frequency Field Coupling. 3.7.6 Continuous Fields. 3.7.7 Impedance Measurements. 3.8 Origin of Various Bioelectric Potentials in Bone. 4 Solid State Bone Behavior. 4.1 Introduction. 4.2 Electrical Conduction in Bone. 4.2.1 Bone as a Semiconductor. 4.2.2 Bone Dielectric Properties. 4.3 Microwave Conductivity in Bone. 4.4 Electret Phenomena. 4.4.1 Thermo Electret. 4.4.2 Electro Electret. 4.4.3 Magneto Electret. 4.5 Hall Effect in Bone. 4.5.1 Hall Effect, Hall Mobility and Drift Mobility. 4.5.2 Magnetic Field Dependence of the Hall Coefficient in Apatite. 4.6 Photovoltaic Effect. 4.7 PN Junction Phenomena in Bone. 4.7.1 Breakdown Phenomenon of PN Junction. 4.7.2 Behavior of the PN Junction Under IR and UV Conditions. 4.7.3 Photoelectromagnetic (PEM) Effect. 4.7.4 Life Time of Charge Carriers. 4.8 Bone Electrical Parameters in Microstrip Line Configuration. 4.8.1 Theoretical Formulation. 4.9 Bone Physical Properties and Ultrasonic Transducer. 5 Bioelectric Phenomena: Electrostimulation and Fracture Healing. 5.1 Introduction. 5.2 Biophysics of Fracture. 5.2.1 Mechanisms of Bone Fracture. 5.2.2 Mechanical Stimulation to Enhance Fracture Repair. 5.3 Bone Fracture Healing. 5.3.1 Histologic Fractures. 5.3.2 Growth Hormone (GH) Effect on Fracture Healing. 5.3.3 Biological Principles. 5.3.4 Cell Array Model for Repairing or Remodeling Bone. 5.4 Electromagnetic Field and Fracture Healing. 5.4.1 Methods in Bone Fracture Healing. 5.4.2 Stimulation by Constant Direct Current Sources. 5.4.3 Pulsed Electromagnetic Fields (PEMFs). 5.4.4 Inductive Coupling. 5.4.5 Capacitive Coupling. 5.4.6 Mechanism of Action. 5.4.7 Mechanism of PEMF Interaction at the Cellular Level. 5.4.8 Spatial Coherence. 5.4.9 Effects of EMFs on Signal Transduction in Bone. 5.4.10 The Biophysical Interaction Concept of Window. 5.4.11 Mechanisms for EMF Effects on Bone Signal Transduction. 5.5 Venous Pressure and Bone Formation. 5.6 Ultrasound and Bone Repair. 5.6.1 Ultrasonic Attenuation. 5.6.2 Measurements on Human Tibiae. 5.6.3 Measurements on Models. 5.7 SNR Analysis for EMF, US and SGP Signals. 5.7.1 Ununited Fractures. 5.8 Low Energy He-Ne Laser Irradiation and Bone Repair. 5.9 Electrostimulation of Osteoporosis. 5.10 Other Techniques: Use of Nanoparticles. 5.11 Possible Mechanism Involved in Osteoporosis. 6 Biophysical Parameters Affecting Osteoporosis. 6.1 Introduction. 6.1.1 Osteoporosis in Women. 6.1.2 Osteoporosis in Men. 6.1.3 Osteoporosis Types. 6.1.4 Spinal Cord Injury (SCI). 6.1.5 Effect of Microgravity. 6.1.6 Bone Loss. 6.1.7 Secondary Osteoporosis. 6.2 Senile and Postmenopausal Osteoporosis. 6.2.1 Type of Bone Pathogenesis. 6.2.2 Risk Factors for Fractures. 6.2.3 Fracture Risk Models. 6.3 Theoretical Analysis of Fracture Prediction by Distant BMD Measurement Sites. 6.4 Markers of Osteoporosis. 6.4.1 Structural Changes. 6.4.2 Biophysical Parameters. 6.5 Osteoporosis Interventions. 6.6 Role of Estrogen. 6.6.1 Steroid-Induced Osteoporosis. 6.6.2 Impact of HRT on Osteoporotic Fractures. 6.6.3 Role of Estrogen–Progesterone Combination. 6.7 Glucocorticoid. 6.8 Vitamin D and Osteoporosis. 6.9 Role of Calcitonin. 6.10 Calcitonin and Glucocorticoids. 6.11 Parathyroid Hormone (PTH). 6.12 Role of Prostaglandins. 6.13 Thiazide Diuretics (TD). 6.14 Effects of Fluoride. 6.15 Role of Growth Hormone (GH). 6.16 Cholesterol. 6.17 Interleukin 1 (IL-1). 6.18 Bisphosphonates (BPs). 6.19 Adipocyte Hormones. 6.20 Mechanism of Action of Antiresorptive Agents. 6.21 Genetic Studies of Osteoporosis. 6.22 Nutritional Aspects in Osteoporosis. 6.22.1 Biochemical Markers. 6.22.2 Salt Intake. 6.22.3 Calcium. 6.22.4 Protein. 6.22.5 Lactose. 6.22.6 Phosphorous. 6.22.7 Lymphotoxin. 6.22.8 Dietary Fiber, Oxalic Acid and Phytic Acid. 6.22.9 Alcohol. 6.22.10 Caffeine. 6.22.11 Other Factors. 6.23 Osteoporosis: Prevention and Treatment. 6.23.1 Gene Therapy. 6.24 Non-invasive Techniques. 6.24.1 Electrical Stimulation and Osteoporosis. 6.24.2 Ultrasonic Methods. 6.25 Conclusion. 7 Non-Invasive Techniques used to Measure Osteoporosis. 7.1 Introduction. 7.2 Measurement of the Mineral Content. 7.2.1 Clinical Measurements. 7.2.2 Calibration and Accuracy. 7.2.3 Limitations. 7.2.4 Singh Index. 7.3 Bone Densitometric Methods. 7.3.1 Radiographic Methods. 7.4 X-ray Tomography. 7.5 Skeleton Roentgenology. 7.6 Metacarpal Index. 7.7 Analysis of Radiographic Methods. 7.8 Direct Photon Absorption Method. 7.8.1 Theory. 7.8.2 Clinical Applications. 7.9 Limitations of the Method. 7.10 Dual-Photon Absorptiometry (DPA). 7.10.1 Theoretical Background. 7.10.2 Procedure. 7.10.3 Nature of Attenuation. 7.10.4 Reproducibility. 7.11 Computed Tomography (CT). 7.11.1 Instrumentation and Clinical Procedure. 7.11.2 Quantitative Computed Tomography (QCT). 7.12 Modification of CT Methods. 7.12.1 CT Methods: Benefits and Risks. 7.12.2 Discussion. 7.13 Methods Based on Compton Scattering. 7.13.1 Technique. 7.14 Coherent and Compton Scattering. 7.14.1 Clinical Applications. 7.15 Dual Energy Technique. 7.15.1 Dual Energy X-ray Absorptiometry (DEXA). 7.15.2 Theoretical Formulation and Instrumentation. 7.15.3 Technical Details. 7.15.4 Simulation Studies. 7.16 Neutron Activation Analysis. 7.16.1 Technique. 7.16.2 Site Choice. 7.16.3 Dose. 7.16.4 Limitations. 7.17 Infrasound Method for Bone Mass Measurements. 7.17.1 The Ultrasonic Measurement: Concepts and Technique. 7.17.2 Stress Wave Propagation in Bone and its Clinical Use. 7.17.3 Measurement of Bone Parameters. 7.17.4 Ultrasound System. 7.17.5 Procedure for Obtaining Patient Data. 7.17.6 Analysis of Patient Data. 7.17.7 Verification of the In Vivo Bone Parameters. 7.18 Other Techniques. 7.18.1 Magnetic Resonance Imaging (MRI). 7.19 Relative Advantages and Disadvantages of the Various Techniques. References. Index.

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Book SynopsisBioelectrochemistry: Fundamentals, Experimental Techniques and Application, covers the fundamental aspects of the chemistry, physics and biology which underlie this subject area. It describes some of the different experimental techniques that can be used to study bioelectrochemical problems and it describes various applications of biolelectrochemisty including amperometric biosensors, immunoassays, electrochemistry of DNA, biofuel cells, whole cell biosensors, in vivo applications and bioelectrosynthesis. By bringing together these different aspects, this work provides a unique source of information in this area,approaching the subject from a cross-disciplinary viewpoint.Trade Review"All chapters are readable and packed with information, all are well referenced and up-to-date. The bookis highly recommended to those with interests in bioelectrochemistry and its applications." (Chromatographia, September 2010)Table of ContentsList of Contributors. Preface. 1 Bioenergetics and Biological Electron Transport (Philip N. Bartlett). 1.1 Introduction. 1.2 Biological Cells. 1.3 Chemiosmosis. 1.3.1 The Proton Motive Force. 1.3.2 The Synthesis of ATP. 1.4 Electron Transport Chains. 1.4.1 The Mitochondrion. 1.4.2 The NADH–CoQ Reductase Complex. 1.4.3 The Succinate–CoQ Reductase Complex. 1.4.4 The CoQH2–Cyt c Reductase Complex. 1.4.5 The Cyt c Oxidase Complex. 1.4.6 Electron Transport Chains in Bacteria. 1.4.7 Electron Transfer in Photosynthesis. 1.4.8 Photosystem II. 1.4.9 Cytochrome bf Complex. 1.4.10 Photosystem I. 1.4.11 Bacterial Photosynthesis. 1.5 Redox Components. 1.5.1 Quinones. 1.5.2 Flavins. 1.5.3 NAD(P)H. 1.5.4 Hemes. 1.5.5 Iron–Sulfur Clusters. 1.5.6 Copper Centres. 1.6 Governing Principles. 1.6.1 Spatial Separation. 1.6.2 Energetics: Redox Potentials. 1.6.3 Kinetics: Electron Transfer Rate Constants. 1.6.4 Size of Proteins. 1.6.5 One-Electron and Two-Electron Couples. 1.7 ATP Synthase. 1.8 Conclusion. References. 2 Electrochemistry of Redox Enzymes (James F. Rusling, Bingquan Wang and Sei-eok Yun). 2.1 Introduction. 2.1.1 Historical Perspective. 2.1.2 Examples of Soluble Mediators. 2.1.3 Development of Protein-Film Voltammetry and Direct Enzyme Electrochemistry. 2.2 Mediated Enzyme Electrochemistry. 2.2.1 Electron Mediation. 2.2.2 Wiring with Redox Metallopolymer Hydrogels. 2.2.3 Wiring with Conducting Polymers. 2.2.4 NAD(P)þ/NAD(P)H Dependent Enzymes. 2.2.5 Regeneration of NAD(P)H from NAD(P)þ. 2.2.6 Regeneration of NAD(P)þ from NAD(P)H. 2.3 Direct Electron Transfer between Electrodes and Enzymes. 2.3.1 Enzymes in Solution. 2.3.2 Enzyme-Film Voltammetry: Basic Theory. 2.3.3 Adsorbed and Coadsorbed Enzyme Monolayers. 2.3.4 Self-Assembled Monolayers and Covalently Attached Enzymes. 2.3.5 Enzymes on Carbon Nanotube Electrodes. 2.3.6 Enzymes in Lipid Bilayer Films. 2.3.7 Polyion Films and Layer-by-Layer Methods. 2.4 Outlook for the Future. Acknowledgements. References. 3 Biological Membranes and Membrane Mimics (Tibor Hianik). 3.1 Introduction. 3.2 Membrane Structure and Composition. 3.2.1 Membrane Structure. 3.2.2 Membrane Lipids. 3.2.3 Membrane Proteins. 3.3 Models of Membrane Structure. 3.3.1 Lipid Monolayers. 3.3.2 Bilayer Lipid Membranes (BLM). 3.3.3 Supported Bilayer Lipid Membranes. 3.3.4 Liposomes. 3.4 Ordering, Conformation and Molecular Dynamics of Lipid Bilayers. 3.4.1 Structural Parameters of Lipid Bilayers Measured by X-ray Diffraction. 3.4.2 Interactions between Bilayers. 3.4.3 Dynamics and Order Parameters of Bilayers Determined by EPR and NMR Spectroscopy and by Optical Spectroscopy Methods. 3.5 Phase Transitions of Lipid Bilayers. 3.5.1 Lyotropic and Thermotropic Transitions. 3.5.2 Thermodynamics of Phase Transitions. 3.5.3 Trans–Gauche Isomerization. 3.5.4 Order Parameter. 3.5.5 Cooperativity of Transition. 3.5.6 Theory of Phase Transitions. 3.6 Mechanical Properties of Lipid Bilayers. 3.6.1 Anisotropy of Mechanical Properties of Lipid Bilayers. 3.6.2 The Model of an Elastic Bilayer. 3.6.3 Mechanical Properties of Lipid Bilayers and Protein–Lipid Interactions. 3.7 Membrane Potentials. 3.7.1 Diffusion Potential. 3.7.2 Electrostatic Potentials. 3.7.3 Methods of Surface Potential Measurement. 3.8 Dielectric Relaxation. 3.8.1 The Basic Principles of the Measurement of Dielectric Relaxation. 3.8.2 Application of the Method of Dielectric Relaxation to BLMs and sBLMs. 3.9 Transport Through Membranes. 3.9.1 Passive Diffusion. 3.9.2 Facilitated Diffusion of Charged Species Across Membranes. 3.9.3 Mechanisms of Ionic Transport. 3.9.4 Active Transport Systems. 3.10 Membrane Receptors and Cell Signaling. 3.10.1 Physical Reception. 3.10.2 Principles of Hormonal Reception. 3.10.3 Taste and Smell Reception. 3.11 Lipid-Film Coated Electrodes. 3.11.1 Modification of Lipid-Film Coated Electrodes by Functional Macromolecules. 3.11.2 Bioelectrochemical and Analytical Applications of Lipid Coated Electrodes. Acknowledgements. References. 4 NAD(P)-Based Biosensors (L. Gorton and P. N. Bartlett). 4.1 Introduction. 4.2 Electrochemistry of NAD(P)þ/NAD(P)H. 4.3 Direct Electrochemical Oxidation of NAD(P)H. 4.3.1 General Observations. 4.3.2 Effect of Adsorption. 4.3.3 Mechanism and Kinetics. 4.4 Soluble Cofactors. 4.4.1 Implications of the Low Eo0 Value for Practical Applications. 4.4.2 Special Prerequisites for Biosensors Based on NAD(P)-Dependent Dehydrogenases. 4.5 Mediators for Electrocatalytic NAD(P)H Oxidation. 4.5.1 Other Mediating Functionalities and Metal Coated Electrodes. 4.5.2 Electropolymerisation. 4.5.3 Carbon Paste. 4.5.4 Gold Nanoparticles. 4.6 Construction of Biosensors from NAD(P)H-Dependent Dehydrogenases. 4.6.1 Entrapment Behind a Membrane. 4.6.2 Covalent Attachment to a Nylon Net or Membrane. 4.6.3 Cross-Linking. 4.6.4 Entrapment in a Polymer Film. 4.6.5 Carbon Paste. 4.6.6 Self-Assembled Monolayers. 4.7 Conclusions. Acknowledgements. References. 5 Glucose Biosensors (Josep M. Montornes, Mark S. Vreeke and Ioanis Katakis). 5.1 Introduction to Glucose Sensors. 5.2 Biosensors. 5.2.1 Types of Sensors. 5.2.2 Transduction Mode. 5.3 Application Areas. 5.3.1 Clinical. 5.3.2 Food and Fermentation. 5.4 Design Requirements. 5.4.1 Disposable Glucose Sensor. 5.4.2 Continuous Glucose Sensor. 5.4.3 Implantable Glucose Sensor. 5.5 Biosensor Construction. 5.5.1 Artificial Mediators. 5.5.2 Immobilization of GOx. 5.5.3 Inner and Outer Membrane Function. 5.6 From Product Design Requirements to Performance. 5.6.1 Design Exercise for the Disposable Glucose Sensor. 5.7 Conclusions. Acknowledgement. References. 6 Phenolic Biosensors (Ulla Wollenberger, Fred Lisdat, Andreas Rose and Katrin Streffer). 6.1 Introduction. 6.2 Enzymes Used for Phenol Biosensors. 6.2.1 Phenol Oxidation by Water-Producing Oxidases and Oxygenases. 6.2.2 Reducing Enzymes. 6.3 Design of Phenol Biosensors. 6.3.1 Oxygen Consumption. 6.3.2 Bioelectrocatalysis Based on Phenol-Oxidizing Enzymes. 6.3.3 Electrocatalytic Sensors Based on Quinone-Reducing Enzymes. 6.4 Applications. 6.4.1 Waste Water Treatment. 6.4.2 Sensitive Label Detectors. 6.4.3 Catecholamines. 6.5 Summary and Conclusions. Acknowledgements. References. 7 Whole-Cell Biosensors (H. Shiku, K. Nagamine, T. Kaya, T. Yasukawa and T. Matsue). 7.1 Introduction. 7.2 Whole-Cell Biosensors Probing Cellular Functions. 7.2.1 Redox Reactions in Whole Cells. 7.2.2 Responses on a Microbial Chip with Collagen Gel. 7.3 Whole-Cell Microdevices Fabricated Using Bio-MEMS Technologies. 7.3.1 Potentiometric Devices: LAPS and ISFET. 7.3.2 Other Electrochemical Devices: Amperometric and Impedance Sensors. 7.3.3 Improvement of Cell Culture within Microenvironments. 7.4 Genetically Engineered Whole-Cell Microdevices. 7.4.1 Sensors with Gene-Modified Bacteria. 7.4.2 Transcriptional Responses on a Microbial Chip with Collagen Gel. 7.4.3 Cellular Devices for High-Throughput Screening. 7.4.4 Microdevice for On-Chip Transfection and On-Chip Transformation. 7.5 Conclusions. References. 8 Modelling Biosensor Responses (P. N. Bartlett, C. S. Toh, E. J. Calvo and V. Flexer). 8.1 Introduction. 8.2 Enzyme Kinetics. 8.2.1 Equilibrium and Steady-State. 8.2.2 Analysis of Enzyme Kinetic Data. 8.2.3 The Significance of KMS for Biosensor Applications. 8.3 Modelling Enzyme Electrodes. 8.3.1 The Flux Diagram for the Membrane|Enzyme|Electrode. 8.3.2 Solving the Coupled Diffusion/Reaction Problem for the Membrane Enzyme|Electrode. 8.3.3 Deriving a Complete Kinetic Model. 8.3.4 Experimental Verification of Approximate Analytical Kinetic Models. 8.4 Numerical Simulation Methods. 8.4.1 Explicit Numerical Methods. 8.4.2 The Crank–Nicholson Method. 8.4.3 Other Simulation Methods. 8.5 Modelling Redox Mediated Enzyme Electrodes. 8.5.1 Steady-State Kinetics. 8.5.2 Homogeneous Mediated Enzyme Electrode. 8.6 Modelling Homogeneous Enzyme with Attached Redox Mediator. 8.7 Non-Steady-State Techniques for Homogeneous Enzyme Systems. 8.7.1 Extraction of Kinetic Parameters. 8.8 The Heterogeneous Mediated Mechanism. 8.8.1 Enzyme Monolayers with Soluble Redox Mediator. 8.8.2 Enzyme Multilayers. 8.9 Conclusions. Acknowledgements. References. 9 Bioelectrosynthesis–Electrolysis and Electrodialysis (Derek Pletcher). 9.1 Introduction. 9.2 Setting the Scene. 9.2.1 Electrolytic Production of Organic Compounds. 9.2.2 Technological Factors. 9.2.3 Enzymes in Organic Synthesis. 9.2.4 Combining Enzyme Chemistry and Electrosynthesis. 9.3 Mechanisms of and Approaches to Bioelectrosynthesis. 9.3.1 Homogeneous Systems. 9.3.2 Electrode Coatings. 9.4 Examples of Syntheses. 9.4.1 The Oxidation of Alcohols and Diols. 9.4.2 The Oxidation of 4-Alkylphenols. 9.4.3 The Synthesis of Dihydroxyacetone Phosphate. 9.4.4 The Site Specific Oxidation of Sugars. 9.4.5 Hydroxylation of Unactivated C–H Bonds. 9.4.6 Reduction of Carbonyl Compounds. 9.4.7 Hydrogenation. 9.4.8 Conclusions. 9.5 Electrodialysis. 9.6 Conclusions. References. 10 Biofuel Cells (G. Tayhas R. Palmore). 10.1 Introduction. 10.2 Fundamentals of Fuel Cells. 10.2.1 How Fuel Cells Work. 10.2.2 Equations that Govern the Performance of a Fuel Cell. 10.3 Economics of Conventional Fuel Cells and Biofuel Cells. 10.4 Biofuel Cells that use Micro-Organisms as the Catalytic Element. 10.5 Biofuel Cells that use Oxidoreductases as the Catalytic Element. 10.6 Future Directions in Biofuel Cell Research. Acknowledgements. References. 11 Electrochemical Immunoassays (Julia Yakovleva and Jenny Emneus). 11.1 Introduction. 11.2 Basic Concepts in Immunoassay. 11.2.1 Antibodies: Structure, Properties and Production. 11.2.2 Classification of Immunoassays. 11.3 Electrochemical Immunoassays (ECIA). 11.3.1 Labels in ECIAs. 11.3.2 Electrochemical Detection Principles. 11.4 Different Assay Formats and Applications. 11.4.1 Heterogeneous ECIA. 11.4.2 Homogeneous ECIAs. 11.4.3 Electrochemical Immunosensors. 11.5 Future Perspectives and Recent Trends. References. 12 Electrochemical DNA Assays (Ana Maria Oliveira-Brett). 12.1 Introduction. 12.2 Electrochemistry of DNA. 12.2.1 Reduction. 12.2.2 Oxidation. 12.3 Adsorption of DNA at Electrode Surfaces. 12.3.1 Guanine Adsorbates. 12.3.2 Adsorbed dsDNA and ssDNA. 12.4 Electrochemistry for Sensing/Probing DNA Interactions. 12.4.1 Biomarkers for DNA Damage. 12.4.2 DNA–Metal Interactions. 12.4.3 DNA–Drug Interactions. 12.5 DNA Electrochemical Biosensors. 12.5.1 In Situ DNA Oxidative Damage. 12.5.2 DNA Hybridisation. 12.5.3 DNA Microarrays. 12.6 Conclusions. Acknowledgements. References. 13 In Vivo Applications: Glucose Monitoring, Fuel Cells (P. Vadgama and M. Schoenleber). 13.1 Introduction. 13.2 Biocompatibility. 13.2.1 General Concepts. 13.2.2 Protein Constituents. 13.2.3 Blood. 13.2.4 Tissue. 13.3 Materials Interfacing Strategy. 13.4 Implanted Glucose Biosensors. 13.4.1 Electrode Designs for Tissue Monitoring. 13.4.2 Electrode Designs for Blood Monitoring. 13.4.3 Early Phase Tissue Response. 13.4.4 Open Microflow. 13.4.5 Bioelectrochemical Fuel Cells. 13.5 Conclusions. References. Index.

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Book SynopsisThis book presents ways to analyze complex bioprocesses and drug delivery systems using control theory. Filled with detailed examples, case studies, computer projects, and step-by-step solutions to numerical problems using computational software, it addresses issues and solves problems that dominate both fields.Trade Review"This text — featuring examples from the biological sciences, including novel drug-delivery systems — will help students and pharmaceutical researchers to develop a better understanding of process dynamics and control theory, so that they can analyze and solve a variety of problems in bioprocess and drug-delivery systems." (Chemical Engineering Progress, 21 May 2013)Table of ContentsPreface xi Acknowledgments xv 1 Introduction 1 1.1 The Role of Process Dynamics and Control in Branches of Biology 1 1.2 The Role of Process Dynamics and Control in Drug-Delivery Systems 10 1.3 Instrumentation 12 1.4 Summary 18 Problems 18 References 19 2 Mathematical Models 21 2.1 Background 22 2.2 Dynamics of Bioreactors 27 2.3 One- and Two-Compartment Models 34 2.4 Enzyme Kinetics 37 2.5 Summary 39 Problems 39 References 41 3 Linearization and Deviation Variables 43 3.1 Computer Simulations 43 3.2 Linearization of Systems 44 3.3 Glycolytic Oscillation 55 3.4 Hodgkin–Huxley Model 57 3.5 Summary 60 Problems 61 References 63 4 Stability Considerations 65 4.1 Definition of Stability 65 4.2 Steady-State Conditions and Equilibrium Points 79 4.3 Phase-Plane Diagrams 80 4.4 Population Kinetics 80 4.5 Dynamics of Bioreactors 83 4.6 Glycolytic Oscillation 85 4.7 Hodgkin–Huxley Model 87 4.8 Summary 88 Problems 88 References 91 5 Laplace Transforms 93 5.1 Definition of Laplace Transforms 93 5.2 Properties of Laplace Transforms 95 5.3 Laplace Transforms of Functions, Derivatives, and Integrals 96 5.4 Laplace Transforms of Linear Ordinary Differential Equation (ODE) and Partial Differential Equation (PDE) 104 5.5 Continuous Fermentation 108 5.6 Two-Compartment Models 110 5.7 Gene Regulation 111 5.8 Summary 113 Problems 113 Reference 115 6 Inverse Laplace Transforms 117 6.1 Heaviside Expansions 117 6.2 Residue Theorem 126 6.3 Continuous Fermentation 134 6.4 Degradation of Plasmid DNA 136 6.5 Constant-Rate Intravenous Infusion 138 6.6 Transdermal Drug-Delivery Systems 139 6.7 Summary 146 Problems 146 References 148 7 Transfer Functions 149 7.1 Input–Output Models 149 7.2 Derivation of Transfer Functions 150 7.3 One- and Two-Compartment Models: Michaelis–Menten Kinetics 154 7.4 Controlled-Release Systems 157 7.5 Summary 158 Problems 158 8 Dynamic Behaviors of Typical Plants 163 8.1 First-, Second- and Higher-Order Systems 163 8.2 Reduced-Order Models 167 8.3 Transcendental Transfer Functions 169 8.4 Time Responses of Systems with Rational Transfer Functions 171 8.5 Time Responses of Systems with Transcendental Transfer Functions 190 8.6 Bone Regeneration 192 8.7 Nitric Oxide Transport to Pulmonary Arterioles 193 8.8 Transdermal Drug Delivery 194 8.9 Summary 194 Problems 195 References 197 9 Closed-loop Responses with P, Pi, and Pid Controllers 199 9.1 Block Diagram of Closed-Loop Systems 200 9.2 Proportional Control 203 9.3 PI Control 204 9.4 PID Control 206 9.5 Total Sugar Concentration in a Glutamic Acid Production 207 9.6 Temperature Control of Fermentations 209 9.7 DO Concentration 213 9.8 Summary 214 Problems 215 References 217 10 Frequency Response Analysis 219 10.1 Frequency Response for Linear Systems 219 10.2 Bode Diagrams 227 10.3 Nyquist Plots 229 10.4 Transdermal Drug Delivery 232 10.5 Compartmental Models 236 10.6 Summary 239 Problems 239 References 240 11 Stability Analysis of Feedback Systems 243 11.1 Routh–Hurwitz Stability Criterion 243 11.2 Root Locus Analysis 248 11.3 Bode Stability Criterion 249 11.4 Nyquist Stability Criterion 254 11.5 Cheyne–Stokes Respiration 257 11.6 Regulation of Biological Pathways 262 11.7 Pupillary Light Reflex 264 11.8 Summary 265 Problems 265 References 267 12 Design of Feedback Controllers 269 12.1 Tuning Methods for Feedback Controllers 269 12.2 Regulation of Glycemia 279 12.3 Dissolved Oxygen Concentration 282 12.4 Control of Biomass in a Chemostat 284 12.5 Controlled Infusion of Vasoactive Drugs 285 12.6 Bone Regeneration 286 12.7 Fed-Batch Biochemical Processes 288 12.8 Summary 289 Problems 289 References 291 13 Feedback Control of Dead-time Systems 293 13.1 Smith Predictor-Based Methods 294 13.2 Control of Biomass 300 13.3 Zymomonas mobilis Fermentation for Ethanol Production 302 13.4 Fed-Batch Cultivation of Acinetobacter calcoaceticus Rag-1 304 13.5 Regulation of Glycemia 304 13.6 Summary 306 Problems 306 References 309 14 Cascade and Feedforward Control Strategies 311 14.1 Cascade Control 311 14.2 Feedforward Control 317 14.3 Insulin Infusion 321 14.4 A Gaze Control System 323 14.5 Control of pH 326 14.6 Summary 330 Problems 331 References 333 15 Effective Time Constant 335 15.1 Linear Second-Order ODEs 335 15.2 Sturm–Liouville (SL) Eigenvalue Problems 337 15.3 Relaxation Time Constant 340 15.4 Implementation in Mathematica ® 342 15.5 Controlled-Release Devices 342 15.6 Summary 343 Problems 344 References 345 16 Optimum Control and Design 347 16.1 Orthogonal Collocation Techniques 348 16.2 Dynamic Programming 350 16.3 Optimal Control of Drug-Delivery Rates 350 16.4 Optimal Design of Controlled-Release Devices 351 16.5 Implementation in Mathematica ® 352 16.6 Summary 358 Problems 359 References 360 Index 361 Preface xi Acknowledgments xv 1 Introduction 1 1.1 The Role of Process Dynamics and Control in Branches of Biology 1 1.2 The Role of Process Dynamics and Control in Drug-Delivery Systems 10 1.3 Instrumentation 12 1.4 Summary 18 Problems 18 References 19 2 Mathematical Models 21 2.1 Background 22 2.2 Dynamics of Bioreactors 27 2.3 One- and Two-Compartment Models 34 2.4 Enzyme Kinetics 37 2.5 Summary 39 Problems 39 References 41 3 Linearization and Deviation Variables 43 3.1 Computer Simulations 43 3.2 Linearization of Systems 44 3.3 Glycolytic Oscillation 55 3.4 Hodgkin–Huxley Model 57 3.5 Summary 60 Problems 61 References 63 4 Stability Considerations 65 4.1 Definition of Stability 65 4.2 Steady-State Conditions and Equilibrium Points 79 4.3 Phase-Plane Diagrams 80 4.4 Population Kinetics 80 4.5 Dynamics of Bioreactors 83 4.6 Glycolytic Oscillation 85 4.7 Hodgkin–Huxley Model 87 4.8 Summary 88 Problems 88 References 91 5 Laplace Transforms 93 5.1 Definition of Laplace Transforms 93 5.2 Properties of Laplace Transforms 95 5.3 Laplace Transforms of Functions, Derivatives, and Integrals 96 5.4 Laplace Transforms of Linear Ordinary Differential Equation (ODE) and Partial Differential Equation (PDE) 104 5.5 Continuous Fermentation 108 5.6 Two-Compartment Models 110 5.7 Gene Regulation 111 5.8 Summary 113 Problems 113 Reference 115 6 Inverse Laplace Transforms 117 6.1 Heaviside Expansions 117 6.2 Residue Theorem 126 6.3 Continuous Fermentation 134 6.4 Degradation of Plasmid DNA 136 6.5 Constant-Rate Intravenous Infusion 138 6.6 Transdermal Drug-Delivery Systems 139 6.7 Summary 146 Problems 146 References 148 7 Transfer Functions 149 7.1 Input–Output Models 149 7.2 Derivation of Transfer Functions 150 7.3 One- and Two-Compartment Models: Michaelis–Menten Kinetics 154 7.4 Controlled-Release Systems 157 7.5 Summary 158 Problems 158 8 Dynamic Behaviors of Typical Plants 163 8.1 First-, Second- and Higher-Order Systems 163 8.2 Reduced-Order Models 167 8.3 Transcendental Transfer Functions 169 8.4 Time Responses of Systems with Rational Transfer Functions 171 8.5 Time Responses of Systems with Transcendental Transfer Functions 190 8.6 Bone Regeneration 192 8.7 Nitric Oxide Transport to Pulmonary Arterioles 193 8.8 Transdermal Drug Delivery 194 8.9 Summary 194 Problems 195 References 197 9 Closed-loop Responses with P, Pi, and Pid Controllers 199 9.1 Block Diagram of Closed-Loop Systems 200 9.2 Proportional Control 203 9.3 PI Control 204 9.4 PID Control 206 9.5 Total Sugar Concentration in a Glutamic Acid Production 207 9.6 Temperature Control of Fermentations 209 9.7 DO Concentration 213 9.8 Summary 214 Problems 215 References 217 10 Frequency Response Analysis 219 10.1 Frequency Response for Linear Systems 219 10.2 Bode Diagrams 227 10.3 Nyquist Plots 229 10.4 Transdermal Drug Delivery 232 10.5 Compartmental Models 236 10.6 Summary 239 Problems 239 References 240 11 Stability Analysis of Feedback Systems 243 11.1 Routh–Hurwitz Stability Criterion 243 11.2 Root Locus Analysis 248 11.3 Bode Stability Criterion 249 11.4 Nyquist Stability Criterion 254 11.5 Cheyne–Stokes Respiration 257 11.6 Regulation of Biological Pathways 262 11.7 Pupillary Light Reflex 264 11.8 Summary 265 Problems 265 References 267 12 Design of Feedback Controllers 269 12.1 Tuning Methods for Feedback Controllers 269 12.2 Regulation of Glycemia 279 12.3 Dissolved Oxygen Concentration 282 12.4 Control of Biomass in a Chemostat 284 12.5 Controlled Infusion of Vasoactive Drugs 285 12.6 Bone Regeneration 286 12.7 Fed-Batch Biochemical Processes 288 12.8 Summary 289 Problems 289 References 291 13 Feedback Control of Dead-time Systems 293 13.1 Smith Predictor-Based Methods 294 13.2 Control of Biomass 300 13.3 Zymomonas mobilis Fermentation for Ethanol Production 302 13.4 Fed-Batch Cultivation of Acinetobacter calcoaceticus Rag-1 304 13.5 Regulation of Glycemia 304 13.6 Summary 306 Problems 306 References 309 14 Cascade and Feedforward Control Strategies 311 14.1 Cascade Control 311 14.2 Feedforward Control 317 14.3 Insulin Infusion 321 14.4 A Gaze Control System 323 14.5 Control of pH 326 14.6 Summary 330 Problems 331 References 333 15 Effective Time Constant 335 15.1 Linear Second-Order ODEs 335 15.2 Sturm–Liouville (SL) Eigenvalue Problems 337 15.3 Relaxation Time Constant 340 15.4 Implementation in Mathematica ® 342 15.5 Controlled-Release Devices 342 15.6 Summary 343 Problems 344 References 345 16 Optimum Control and Design 347 16.1 Orthogonal Collocation Techniques 348 16.2 Dynamic Programming 350 16.3 Optimal Control of Drug-Delivery Rates 350 16.4 Optimal Design of Controlled-Release Devices 351 16.5 Implementation in Mathematica ® 352 16.6 Summary 358 Problems 359 References 360 Index 361

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Book SynopsisNeural engineering is a discipline that uses engineering techniques to understand, repair, replace, enhance, or treat diseases of neural systems. Currently, no book other than this one covers this broad range of topics within motor rehabilitation technology.Table of ContentsCONTRIBUTORS ix PREFACE xv PART I INJURIES OF THE NERVOUS SYSTEM 1 1 Diseases and Injuries of the Central Nervous System Leading to Sensory–Motor Impairment 3 Dejan B. Popoviæ and Thomas Sinkjær 2 Peripheral and Spinal Plasticity after Nerve Injuries 21 Xavier Navarro 3 Motor Control Modules of Human Movement in Health and Disease 39 Yuri P. Ivanenko, Germana Cappellini, Marco Molinari, and Francesco Lacquaniti PART II SIGNAL DETECTION AND CONDITIONING 61 4 Progress in Peripheral Neural Interfaces 63 Shaoyu Qiao, Kevin A. Mauser, and Ken Yoshida 5 Multimodal, Multisite Neuronal Recordings for Brain Research 95 Ulrich G. Hofmann, Peter Detemple, and Yijing Xie 6 Surface Electromyogram Detection 113 Alberto Botter, Marco Gazzoni, and Roberto Merletti 7 Methods for Noninvasive Electroencephalogram Detection 137 Christoph Guger and Günter Edlinger 8 Spike Sorting 155 Di Ge and Dario Farina 9 Wavelet Denoising and Conditioning of Neural Recordings 173 Luca Citi and Silvestro Micera 10 Instantaneous Cross-Correlation Analysis of Neural Ensembles with High Temporal Resolution 183 António R.C. Paiva, Il Park, José C. Príncipe, and Justin C. Sanchez 11 Unsupervised Decomposition Methods for Analysis of Multimodal Neural Data 199 Felix Biessmann, Frank C. Meinecke, and Klaus-Robert Müller PART III FUNCTION REPLACEMENT (PROSTHESES AND ORTHOSIS) 235 12 Brain–Computer Interfaces 237 José del R. Millán 13 Movement-Related Cortical Potentials and Their Application in Brain–Computer Interfacing 253 Kim Dremstrup, Ying Gu, Omar Feix do Nascimento, and Dario Farina 14 Introduction to Upper Limb Prosthetics 267 Bernhard Graimann and Hans Dietl 15 Myoelectric Prostheses and Targeted Reinnervation 291 Levi Hargrove, Erik Scheme, and Kevin Englehart 16 Controlling Prostheses Using PNS Invasive Interfaces for Amputees 311 Jacopo Carpaneto, Luca Citi, Stanisa Raspopovic, Jacopo Rigosa, and Silvestro Micera 17 Exoskeletal Robotics for Functional Substitution 327 José Luis Pons, Juan C. Moreno, and Eduardo Rocon PART IV FUNCTION RESTORATION 349 18 Methods for Movement Restoration 351 Dejan B. Popoviæ, and Mirjana B. Popoviæ 19 Advanced User Interfaces for Upper Limb Functional Electrical Stimulation 377 Elaine A. Corbett, Christian Ethier, Emily R. Oby, Konrad Kording, Eric J. Perreault, and Lee E. Miller 20 Customized Modeling and Simulations for the Control of FES-Assisted Walking of Individuals with Hemiplegia 401 Strahinja Došen and Dejan B. Popoviæ 21 ActiGait: A Partly Implantable Drop-Foot Stimulator System 421 Birgit Larsen and Andrei Patriciu 22 Selectivity of Peripheral Neural Interfaces 433 Winnie Jensen and Kristian Rauhe Harreby PART V REHABILITATION THROUGH NEUROMODULATION 461 23 Brain–Computer Interface Applied to Motor Recovery after Brain Injury 463 Janis J. Daly 24 Functional Electrical Therapy of Upper Extremities 477 Mirjana B. Popoviæ and Dejan B. Popoviæ 25 Gait Rehabilitation Using Nociceptive Withdrawal Refl ex–Based Functional Electrical Therapy in Stroke Patients 493 Ole K. Andersen and Erika G. Spaich 26 Robot–Assisted Neurorehabilitation 505 Vittorio Sanguineti, Maura Casadio, Lorenzo Masia, Valentina Squeri, and Pietro G. Morasso 27 Paired Associative Stimulation 529 Natalie Mrachacz-Kersting 28 Operant Conditioning of Spinal Reflexes for Motor Rehabilitation after CNS Damage 549 Aiko K. Thompson and Jonathan R. Wolpaw INDEX 571

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Book SynopsisComputational Fluid-Structure Interaction: Methods and Applications takes the reader from the fundamentals of computational fluid and solid mechanics to the state-of-the-art in computational FSI methods, special FSI techniques, and solution of real-world problems. Leading experts in the field present the material using a unique approach that combines advanced methods, special techniques, and challenging applications. This book begins with the differential equations governing the fluid and solid mechanics, coupling conditions at the fluidsolid interface, and the basics of the finite element method. It continues with the ALE and spacetime FSI methods, spatial discretization and time integration strategies for the coupled FSI equations, solution techniques for the fully-discretized coupled equations, and advanced FSI and spacetime methods. It ends with special FSI techniques targeting cardiovascular FSI, parachute FSI, and wind-turbine aerodynamics and FSI. Key feaTrade Review“Computational Fluid-Structure Interaction: Methods and Applications is a comprehensive reference for researchers and practicing engineers who would like to advance their existing knowledge on these subjects. It is also an ideal text for graduate and senior-level undergraduate courses in computational fluid mechanics and computational FSI.” (Expofairs, 18 October 2013)Table of ContentsSeries Preface xi Preface xiii Acknowledgements xix 1 Governing Equations of Fluid and Structural Mechanics 1 1.1 Governing Equations of Fluid Mechanics 1 1.1.1 Strong Form of the Navier–Stokes Equations of Incompressible Flows 1 1.1.2 Model Differential Equations 5 1.1.3 Nondimensional Equations and Numbers 6 1.1.4 Some Specific Boundary Conditions 7 1.1.5 Weak Form of the Navier–Stokes Equations 10 1.2 Governing Equations of Structural Mechanics 12 1.2.1 Kinematics 12 1.2.2 Principle of Virtual Work and Variational Formulation of Structural Mechanics 14 1.2.3 Conservation of Mass 15 1.2.4 Structural Mechanics Formulation in the Current Configuration 15 1.2.5 Structural Mechanics Formulation in the Reference Configuration 17 1.2.6 Additional Boundary Conditions of Practical Interest 18 1.2.7 Some Constitutive Models 19 1.2.8 Linearization of the Structural Mechanics Equations: Tangent Stiffness and Equations of Linear Elasticity 22 1.2.9 Thin Structures: Shell, Membrane, and Cable Models 25 1.3 Governing Equations of Fluid Mechanics in Moving Domains 31 1.3.1 Kinematics of ALE and Space–Time Descriptions 31 1.3.2 ALE Formulation of Fluid Mechanics 33 2 Basics of the Finite Element Method for Nonmoving-Domain Problems 37 2.1 An Abstract Variational Formulation for Steady Problems 37 2.2 FEM Applied to Steady Problems 38 2.3 Construction of Finite Element Basis Functions 42 2.3.1 Construction of Element Shape Functions 43 2.3.2 Finite Elements Based on Lagrange Interpolation Functions 46 2.3.3 Construction of Global Basis Functions 49 2.3.4 Element Matrices and Vectors and their Assembly into the Global Equation System 51 2.4 Finite Element Interpolation and Numerical Integration 53 2.4.1 Interpolation by Finite Elements 53 2.4.2 Numerical Integration 55 2.5 Examples of Finite Element Formulations 58 2.5.1 Galerkin Formulation of the Advection–Diffusion Equation 58 2.5.2 Stabilized Formulation of the Advection–Diffusion Equation 59 2.5.3 Galerkin Formulation of Linear Elastodynamics 62 2.6 Finite Element Formulation of the Navier–Stokes Equations 65 2.6.1 Standard Essential Boundary Conditions 65 2.6.2 Weakly Enforced Essential Boundary Conditions 70 3 Basics of the Isogeometric Analysis 73 3.1 B-Splines in 1D 74 3.2 NURBS Basis Functions, Curves, Surfaces, and Solids 75 3.3 h-, p-, and k-Refinement of NURBS Meshes 77 3.4 NURBS Analysis Framework 78 4 ALE and Space–Time Methods for Moving Boundaries and Interfaces 83 4.1 Interface-Tracking (Moving-Mesh) and Interface-Capturing (Nonmoving-Mesh) Techniques 83 4.2 Mixed Interface-Tracking/Interface-Capturing Technique (MITICT) 84 4.3 ALE Methods 84 4.4 Space–Time Methods 86 4.5 Advection–Diffusion Equation 89 4.5.1 ALE Formulation 89 4.5.2 Space–Time Formulation 91 4.6 Navier–Stokes Equations 92 4.6.1 ALE Formulation 92 4.6.2 Generalized-α Time Integration of the ALE Equations 95 4.6.3 Space–Time Formulation 98 4.7 Mesh Moving Methods 106 5 ALE and Space–Time Methods for FSI 111 5.1 FSI Formulation at the Continuous Level 111 5.2 ALE Formulation of FSI 114 5.2.1 Spatially-Discretized ALE FSI Formulation with Matching Fluid and Structure Discretizations 114 5.2.2 Generalized-α Time Integration of the ALE FSI Equations 118 5.2.3 Predictor–Multicorrector Algorithm and Linearization of the ALE FSI Equations 120 5.3 Space–Time Formulation of FSI 123 5.3.1 Core Formulation 123 5.3.2 Interface Projection Techniques for Nonmatching Fluid and Structure Interface Discretizations 127 5.4 Advanced Mesh Update Techniques 129 5.4.1 Solid-Extension Mesh Moving Technique (SEMMT) 129 5.4.2 Move-Reconnect-Renode Mesh Update Method (MRRMUM) 132 5.4.3 Pressure Clipping 134 5.5 FSI Geometric Smoothing Technique (FSI-GST) 136 6 Advanced FSI and Space–Time Techniques 139 6.1 Solution of the Fully-Discretized Coupled FSI Equations 139 6.1.1 Block-Iterative Coupling 140 6.1.2 Quasi-Direct Coupling 141 6.1.3 Direct Coupling 142 6.2 Segregated Equation Solvers and Preconditioners 144 6.2.1 Segregated Equation Solver for Nonlinear Systems (SESNS) 144 6.2.2 Segregated Equation Solver for Linear Systems (SESLS) 145 6.2.3 Segregated Equation Solver for Fluid–Structure Interactions (SESFSI) 146 6.3 New-Generation Space–Time Formulations 149 6.3.1 Mesh Representation 150 6.3.2 Momentum Equation 150 6.3.3 Incompressibility Constraint 151 6.4 Time Representation 151 6.4.1 Time Marching Problem 151 6.4.2 Design of Temporal NURBS Basis Functions 153 6.4.3 Approximation in Time 154 6.4.4 An Example: Circular-Arc Motion 154 6.5 Simple-Shape Deformation Model (SSDM) 157 6.6 Mesh Update Techniques in the Space–Time Framework 158 6.6.1 Mesh Computation and Representation 158 6.6.2 Remeshing Technique 158 6.7 Fluid Mechanics Computation with Temporal NURBS Mesh 159 6.7.1 No-Slip Condition on a Prescribed Boundary 159 6.7.2 Starting Condition 160 6.8 The Surface-Edge-Node Contact Tracking (SENCT-FC) Technique 163 6.8.1 Contact Detection and Node Sets 164 6.8.2 Contact Force and Reaction Force 165 6.8.3 Solving for the Contact Force 167 7 General Applications and Examples of FSI Modeling 171 7.1 2D Flow Past an Elastic Beam Attached to a Fixed, Rigid Block 171 7.2 2D Flow Past an Airfoil Attached to a Torsion Spring 174 7.3 Inflation of a Balloon 175 7.4 Flow Through and Around a Windsock 177 7.5 Aerodynamics of Flapping Wings 181 7.5.1 Surface and Volume Meshes 181 7.5.2 Flapping-Motion Representation 185 7.5.3 Mesh Motion 186 7.5.4 Fluid Mechanics Computation 187 8 Cardiovascular FSI 191 8.1 Special Techniques 194 8.1.1 Mapping Technique for Inflow Boundaries 194 8.1.2 Preconditioning Technique 195 8.1.3 Calculation of Wall Shear Stress 195 8.1.4 Calculation of Oscillatory Shear Index 196 8.1.5 Boundary Condition Techniques for Inclined Inflow and Outflow Planes 197 8.2 Blood Vessel Geometry, Variable Wall Thickness, Mesh Generation, and Estimated Zero-Pressure (EZP) Geometry 198 8.2.1 Arterial-Surface Extraction from Medical Images 198 8.2.2 Mesh Generation and EZP Arterial Geometry 199 8.2.3 Blood Vessel Wall Thickness Reconstruction 201 8.3 Blood Vessel Tissue Prestress 203 8.3.1 Tissue Prestress Formulation 203 8.3.2 Linearized Elasticity Operator 204 8.4 Fluid and Structure Properties and Boundary Conditions 205 8.4.1 Fluid and Structure Properties 205 8.4.2 Boundary Conditions 205 8.5 Simulation Sequence 209 8.6 Sequentially-Coupled Arterial FSI (SCAFSI) Technique 210 8.7 Multiscale Versions of the SCAFSI Technique 213 8.8 Computations with the SSTFSI Technique 215 8.8.1 Performance Tests for Structural Mechanics Meshes 215 8.8.2 Multiscale SCAFSI Computations 218 8.8.3 WSS Calculations with Refined Meshes 222 8.8.4 Computations with New Surface Extraction, Mesh Generation, and Boundary Condition Techniques 225 8.8.5 Computations with the New Techniques for the EZP Geometry, Wall Thickness, and Boundary-Layer Element Thickness 230 8.9 Computations with the ALE FSI Technique 233 8.9.1 Cerebral Aneurysms: Tissue Prestress 236 8.9.2 Total Cavopulmonary Connection 240 8.9.3 Left Ventricular Assist Device 250 9 Parachute FSI 259 9.1 Parachute Specific FSI-DGST 261 9.2 Homogenized Modeling of Geometric Porosity (HMGP) 262 9.2.1 HMGP in its Original Form 265 9.2.2 HMGP-FG 266 9.2.3 Periodic n-Gore Model 267 9.3 Line Drag 269 9.4 Starting Point for the FSI Computation 271 9.5 “Symmetric FSI” Technique 274 9.6 Multiscale SCFSI M2C Computations 275 9.6.1 Structural Mechanics Solution for the Reefed Stage 275 9.6.2 Fabric Stress Computations 278 9.7 Single-Parachute Computations 280 9.7.1 Various Canopy Configurations 280 9.7.2 Various Suspension Line Length Ratios 288 9.8 Cluster Computations 293 9.8.1 Starting Conditions 294 9.8.2 Computational Conditions 295 9.8.3 Results 297 9.9 Techniques for Dynamical Analysis and Model-Parameter Extraction 299 9.9.1 Contributors to Parachute Descent Speed 299 9.9.2 Added Mass 311 10 Wind-Turbine Aerodynamics and FSI 315 10.1 Aerodynamics Simulations of a 5MW Wind-Turbine Rotor 317 10.1.1 5MW Wind-Turbine Rotor Geometry Definition 317 10.1.2 ALE-VMS Simulations Using NURBS-based IGA 322 10.1.3 Computations with the DSD/SST Formulation Using Finite Elements 325 10.2 NREL Phase VI Wind-Turbine Rotor: Validation and the Role of Weakly-Enforced Essential Boundary Conditions 328 10.3 Structural Mechanics of Wind-Turbine Blades 334 10.3.1 The Bending-Strip Method 334 10.3.2 Time Integration of the Structural Mechanics Equations 340 10.4 FSI Coupling and Aerodynamics Mesh Update 342 10.5 FSI Simulations of a 5MW Wind-Turbine Rotor 343 10.6 Pre-Bending of the Wind-Turbine Blades 344 10.6.1 Problem Statement and the Pre-Bending Algorithm 346 10.6.2 Pre-Bending Results for the NREL 5MW Wind-Turbine Blade 349 References 353 Index 373

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Book SynopsisA practical guide to the most useful bioprocess techniques for . Bioprocess Production of Flavor, Fragrance, and Color Ingredients In these days of increasing consumer preference for natural foods, biological production of food ingredients is more important than ever before. This book is an in-depth review of bioprocess production of flavor, fragrance, and color ingredients, including esters, aldehydes, lactones, pyrazines, terpenoids, dairy flavors such as methyl ketones, and savory flavors such as HVPs, nucleotides, yeast autolysates, and extracts. Technologies of interest to the food and flavor industry are also covered, including genetic engineering and plant tissue culture, with specific examples taken from flavors and fragrances. Additionally, one entire chapter is devoted to nontechnical issues such as regulation of biotechnology products in foods, consumer perception of the new biotechnology, definition and importance of the word natural, and other related issues. The book addrTable of ContentsOverview of Bioprocess Flavor and Fragrance Production (F.Welsh). Development and Regulation of Flavor, Fragrance, and ColorIngredients Produced by Biotechnology (C. Manley). Aliphatic, Aromatic, and Lactone Compounds (D. Armstrong & L.Brown). Fermentation Production of Pyrazines and Terpenoids for Flavors andFragrances (E. Seitz). Savory Flavors (T. Nagodawithana). Dairy Flavors (D. Eaton). Production of Food Colorants by Fermentation (G. Jacobson & J.Wasileski). Plant Tissue Culture (O. Sahai). Genetic Engineering and Other Advanced Technologies (A.Gabelman). Index.

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Book SynopsisThis book is about how a knowledge and understanding of biological products and processes can lead to new insights in the synthesis, design and processing of inorganic-based materials. This approach is called 'biomimetics'. The book attempts to survey the new frontiers of biomimetic materials chemistry.Table of ContentsFrom the Contents: Biomineralization and Biomimetic Chemistry/ Biomimetic Strategies and Materials Processing/ Biogenic Cadmium Sulfide Semiconductors/ Biomimetic Synthesis of Nanoscale Particles in Organized Protein Cages/ Biomimetic Approaches to Nanoscale Fabrication/ Template-directed Nucleation and Growth of Inorganic Materials/ Construction of Organized Particulate Films by the Langmuir-Blodgett Technique/ Organization of Semiconductor Nanocrystals for Electrical Spectroscopies/ Polyamino Acids as Antiscalants, Dispersants, Antifreezes and Absorbent Gelling Materials/ Bacterial Fibers and their Mineralized Products: Bionites/ Biomimetic Inorganic-organic Composites/ Organoceramic Nanocomposites/ Ceramics Processing with Biogenic Additives.

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Book SynopsisA unique, accessible guide to the application of engineering methods to biological systems. Presenting for the first time a practical, design-oriented, interdisciplinary approach to transport phenomena involving biological systems, Biological Process Engineering emphasizes the common aspects of the three main transport processes-fluid flow, heat transfer, and mass transfer. In clear and simple terms, it explores the relevance of these processes to broadly defined biological systems such as the growth of microbes in bioreactors, the leaching of pollutants into groundwater, and the chemistry of food manufacturing. Reaching well beyond standard applications in medicine and the environment to areas of biotechnology, aquaculture, agriculture, and food processing, this book promotes analogical thinking that will lead to creative solutions. While keeping the mathematics to a minimum, it explains principles of effective system modeling and demonstrates a wide variety of problem-solvinTable of ContentsSystems Concepts for Transport Processes. Fluid Flow Systems. Heat Transfer Systems. Mass Transfer. Life Systems. References. Index.

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Book SynopsisWhile many books on medical instrumentation only cover hospital instrumentation, this comprehensive book also encompasses measurements in the growing fields of molecular biology and biotechnology, including applications such as cell engineering, tissue engineering, and biomaterials.Table of ContentsPreface. 1. Measurement Systems (Kevin Hugo). 2. Basic Concepts of Electronics (Hong Cao). 3. Analysis of Molecules in Clinical Medicine (Mat Klein). 4. Surface Characterization in Biomaterials and Tissue Engineering (Jorge E. Monzon). 5. Hematology (Susanne Clark Cazzanti). 6. Cellular Measurements in Biomaterials and Tissue Engineering (Jeffrey S. Schowalter). 7. Nervous Systems (Jang-Zern Tsai). 8. Heart and Circulation (Supan Tungjitkusolmun). 9. Lung, Kidney, Bone, and Skin (Shilpa Sawale). 10. Body Temperature, Heat, Fat, and Movement (Chao-Min Wu). Index.

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Book Synopsis"The biotech industry is a complex, rapidly evolving, and critical industry. The industry holds great commercial and societal promise, but it is also filled with hype, confusion, and risks.Table of ContentsPreface xi Acknowledgments xvii CHAPTER 1 Overview 1 CHAPTER 2 Pharmaceuticals 43 CHAPTER 3 Medicine and Agriculture 77 CHAPTER 4 Computing, Biomaterials, and the Military 105 CHAPTER 5 Infrastructure 142 CHAPTER 6 Financing 175 CHAPTER 7 Regional Analysis 217 CHAPTER 8 Outlook 295 Appendix 319 Glossary 329 Sources and Further Reading 337 Index 347

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Book SynopsisA considerable body of knowledge has grown in the search for effective ways to obtain nonlinear dynamic models from stimulus-response data in a practical context. This book summarizes some 30 years of research progress in that arena, and details the most recent methodologies that offer practical solutions to this daunting problem.Trade Review"...a perfect research tool, as reference book, and even as a textbook. I highly recommend it to everyone interested in nonlinear dynamics." (Journal of Intelligent & Fuzzy Systems, Vol. 16, No. 2, 2005) "...a well-written methodology book...a useful addition to [researchers, engineers and graduate students']...personal libraries." (E-STREAMS, September 2005)Table of ContentsPrologue xiii 1 Introduction 1 1.1 Purpose of this Book 1 1.2 Advocated Approach 4 1.3 The Problem of System Modeling in Physiology 6 1.3.1 Model Specification and Estimation 10 1.3.2 Nonlinearity and Nonstationarity 12 1.3.3 Definition of the Modeling Problem 13 1.4 Types of Nonlinear Models of Physiological Systems 13 Example 1.1. Vertebrate Retina 15 Example 1.2. Invertebrate Photoreceptor 18 Example 1.3. Volterra analysis of Riccati Equation 19 Example 1.4. Glucose-Insulin Minimal Model 21 Example 1.5. Cerebral Autoregulation 22 1.5 Deductive and Inductive Modeling 24 Historical Note #1: Hippocratic and Galenic Views of 26 Integrative Physiology 2 Nonparametric Modeling 29 2.1 Volterra Models 31 2.1.1 Examples of Volterra Models 37 Example 2.1. Static Nonlinear System 37 Example 2.2. L–N Cascade System 38 Example 2.3. L–N–M “Sandwich” System 39 Example 2.4. Riccati System 40 2.1.2 Operational Meaning of the Volterra Kernels 41 Impulsive Inputs 42 Sinusoidal Inputs 43 Remarks on the Meaning of Volterra Kernels 45 2.1.3 Frequency-Domain Representation of the Volterra Models 45 2.1.4 Discrete-Time Volterra Models 47 2.1.5 Estimation of Volterra Kernels 49 Specialized Test Inputs 50 Arbitrary Inputs 52 Fast Exact Orthogonalization and Parallel-Cascade Methods 55 Iterative Cost-Minimization Methods for Non-Gaussian 55 Residuals 2.2 Wiener Models 57 2.2.1 Relation between Volterra and Wiener Models 60 The Wiener Class of Systems 62 Examples of Wiener Models 63 Comparison of Volterra/Wiener Model Predictions 64 2.2.2 Wiener Approach to Kernel Estimation 67 2.2.3 The Cross-Correlation Technique for Wiener Kernel Estimation 72 Estimation of h0 73 Estimation of h1 (𝜏) 73 Estimation of h2 (𝜏1, 𝜏2) 74 Estimation of h3 (𝜏1, 𝜏2, 𝜏3) 75 Some Practical Considerations 77 Illustrative Example 78 Frequency-Domain Estimation of Wiener Kernels 78 2.2.4 Quasiwhite Test Inputs 80 CSRS and Volterra Kernels 84 The Diagonal Estimability Problem 85 An Analytical Example 86 Comparison of Model Prediction Errors 88 Discrete-Time Representation of the CSRS Functional Series 89 Pseudorandom Signals Based on m-Sequences 89 Comparative Use of GWN, PRS, and CSRS 92 2.2.5 Apparent Transfer Function and Coherence Measurements 93 Example 2.5. L–N Cascade System 96 Example 2.6. Quadratic Volterra System 97 Example 2.7. Nonwhite Gaussian Inputs 98 Example 2.8. Duffing System 98 Concluding Remarks 99 2.3 Efficient Volterra Kernel Estimation 100 2.3.1 Volterra Kernel Expansions 101 Model Order Determination 104 2.3.2 The Laguerre Expansion Technique 107 Illustrative Examples 112 2.3.3 High-Order Volterra Modeling with Equivalent Networks 122 2.4 Analysis of Estimation Errors 125 2.4.1 Sources of Estimation Errors 125 2.4.2 Estimation Errors Associated with the Cross-Correlation 127 Technique Estimation Bias 128 Estimation Variance 130 Optimization of Input Parameters 131 Noise Effects 134 Erroneous Scaling of Kernel Estimates 136 2.4.3 Estimation Errors Associated with Direct Inversion Methods 137 2.4.4 Estimation Errors Associated with Iterative 139 Cost-Minimization Methods Historical Note #2: Vito Volterra and Norbert Wiener 140 3 Parametric Modeling 145 3.1 Basic Parametric Model Forms and Estimation Procedures 146 3.1.1 The Nonlinear Case 150 3.1.2 The Nonstationary Case 152 3.2 Volterra Kernels of Nonlinear Differential Equations 153 Example 3.1. The Riccati Equation 157 3.2.1 Apparent Transfer Functions of Linearized Models 158 Example 3.2. Illustrative Example 160 3.2.2 Nonlinear Parametric Models with Intermodulation 161 3.3 Discrete-Time Volterra Kernels of NARMAX Models 164 3.4 From Volterra Kernel Measurements to Parametric Models 167 Example 3.3. Illustrative Example 169 3.5 Equivalence Between Continuous and Discrete Parametric Models 171 Example 3.4. Illustrative Example 175 3.5.1 Modular Representation 177 4 Modular and Connectionist Modeling 179 4.1 Modular Form of Nonparametric Models 179 4.1.1 Principal Dynamic Modes 180 Illustrative Examples 186 4.1.2 Volterra Models of System Cascades 191 The L–N–M, L–N, and N–M Cascades 194 4.1.3 Volterra Models of Systems with Lateral Branches 198 4.1.4 Volterra Models of Systems with Feedback Branches 200 4.1.5 Nonlinear Feedback Described by Differential Equations 202 Example 1. Cubic Feedback Systems 204 Example 2. Sigmoid Feedback Systems 209 Example 3. Positive Nonlinear Feedback 213 Example 4. Second-Order Kernels of Nonlinear 215 Feedback Systems Nonlinear Feedback in Sensory Systems 216 Concluding Remarks on Nonlinear Feedback 220 4.2 Connectionist Models 223 4.2.1 Equivalence between Connectionist and Volterra Models 223 Relation with PDM Modeling 230 Illustrative Examples 232 4.2.2 Volterra-Equivalent Network Architectures for Nonlinear 235 System Modeling Equivalence with Volterra Kernels/Models 238 Selection of the Structural Parameters of the VEN Model 238 Convergence and Accuracy of the Training Procedure 240 The Pseudomode-Peeling Method 244 Nonlinear Autoregressive Modeling (Open-Loop) 246 4.3 The Laguerre-Volterra Network 246 Illustrative Example of LVN Modeling 249 Modeling Systems with Fast and Slow Dynamic (LVN-2) 251 Illustrative Examples of LVN-2 Modeling 255 4.4 The VWM Model 260 5 A Practitioner’s Guide 265 5.1 Practical Considerations and Experimental Requirements 265 5.1.1 System Characteristics 266 System Bandwidth 266 System Memory 267 System Dynamic Range 267 System Linearity 268 System Stationarity 268 System Ergodicity 268 5.1.2 Input Characteristics 269 5.1.3 Experimental Characteristics 270 5.2 Preliminary Tests and Data Preparation 272 5.2.1 Test for System Bandwidth 272 5.2.2 Test for System Memory 272 5.2.3 Test for System Stationarity and Ergodicity 273 5.2.4 Test for System Linearity 274 5.2.5 Data Preparation 275 5.3 Model Specification and Estimation 276 5.3.1 The MDV Modeling Methodology 277 5.3.2 The VEN/VWM Modeling Methodology 278 5.4 Model Validation and Interpretation 279 5.4.1 Model Validation 279 5.4.2 Model Interpretation 281 Interpretation of Volterra Kernels 281 Interpretation of the PDM Model 282 5.5 Outline of Step-by-Step Procedure 283 5.5.1 Elaboration of the Key Step # 5 284 6 Selected Applications 285 6.1 Neurosensory Systems 286 6.1.1 Vertebrate Retina 287 6.1.2 Invertebrate Retina 396 6.1.3 Auditory Nerve Fibers 302 6.1.4 Spider Mechanoreceptor 307 6.2 Cardiovascular System 320 6.3 Renal System 333 6.4 Metabolic-Endocrine System 342 7 Modeling of Multiinput/Multioutput Systems 359 7.1 The Two-Input Case 360 7.1.1 The Two-Input Cross-Correlation Technique 362 7.1.2 The Two-Input Kernel-Expansion Technique 362 7.1.3 Volterra-Equivalent Network Models with Two Inputs 364 Illustrative Example 366 7.2 Applications of Two-Input Modeling to Physiological Systems 369 7.2.1 Motion Detection in the Invertebrate Retina 369 7.2.2 Receptive Field Organization in the Vertebrate Retina 370 7.2.3 Metabolic Autoregulation in Dogs 378 7.2.4 Cerebral Autoregulation in Humans 380 7.3 The Multiinput Case 389 7.3.1 Cross-Correlation-Based Method for Multiinput Modeling 390 7.3.2 The Kernel-Expansion Method for Multiinput Modeling 393 7.3.3 Network-Based Multiinput Modeling 393 7.4 Spatiotemporal and Spectrotemporal Modeling 395 7.4.1 Spatiotemporal Modeling of Retinal Cells 398 7.4.2 Spatiotemporal Modeling of Cortical Cells 401 8 Modeling of Neuronal Systems 407 8.1 A General Model of Membrane and Synaptic Dynamics 408 8.2 Functional Integration in the Single Neuron 414 8.2.1 Neuronal Modes and Trigger Regions 417 Illustrative Examples 427 8.2.2 Minimum-Order Modeling of Spike-Output Systems 432 The Reverse-Correlation Technique 432 Minimum-Order Wiener Models 435 Illustrative Example 439 8.3 Neuronal Systems with Point-Process Inputs 439 8.3.1 The Lag-Delta Representation of P–V or P–W Kernels 445 8.3.2 The Reduced P–V or P–W Kernels 446 8.3.3 Examples from the Hippocampal Formation 450 Single-Input Stimulation in Vivo and Cross-Correlation 450 Technique Single-Input Stimulation in Vitro and Laguerre-Expansion 455 Technique Dual-Input Stimulation in the Hippocampal Slice 457 Nonlinear Modeling of Synaptic Dynamics 461 8.4 Modeling of Neuronal Ensembles 463 9 Modeling of Nonstationary Systems 467 9.1 Quasistationary and Recursive Tracking Methods 468 9.2 Kernel Expansion Method 469 9.2.1 Illustrative Example 474 9.2.2 A Test of Nonstationarity 475 9.2.3 Linear Time-Varying Systems with Arbitrary Inputs 479 9.3 Network-Based Methods 480 9.3.1 Illustrative Examples 481 9.4 Applications to Nonstationary Physiological Systems 484 10 Modeling of Closed-Loop Systems 489 10.1 Autoregressive Form of Closed-Loop Model 490 10.2 Network Model Form of Closed-Loop Systems 491 Appendix I Function Expansions 495 Appendix II Gaussian White Noise 499 Appendix III Construction of the Wiener Series 503 Appendix IV Stationarity, Ergodicity, and Autocorrelation Functions of Random Processes 505 References 507 Index 535

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Book SynopsisCommercial Biosensors offers professionals an in-depth look at some of the most significant applications of commercially available biosensor-based instrumentation in the medical, bioprocess, and environmental fields. Featuring contributions by an international team of scientists, the book provides readers with an unparalleled opportunity to see how their colleagues around the world are using these powerful new tools. Commercial Biosensors is divided into three sections. In the first, which is devoted to applications of biosensors to clinical samples, the authors explore how biosensors are currently being used for in-home diabetes monitoring, point-of-care diagnostics, and noninvasive sensing, and biomedical research. The second section deals with cutting-edge applications of biosensors in bioprocess control- for example, measuring glucose, sucrose, glutamate, or choline concentrations during food and beverage production and measuring ethanol concentration during beer fermentatTable of ContentsAPPLICATIONS TO CLINICAL SAMPLES. Biosensors for Personal Diabetes Management (T. Henning & D. Cunningham). Microfabricated Sensors and the Commercial Development of the i-Stat Point-of-Care System (G. Davis). Noninvasive Biosensors in Clinical Analysis (G. Palleschi, et al.). Surface Plasmon Resonance (R. Earp & R. Dessy). Biosensors Based on Evanescent Waves (D. Purvis, et al.). APPLICATIONS TO BIOPROCESS SAMPLES. Applications of Biosensor-Based Instruments to the Bioprocess Industry (J. Woodward & R. Spokane). APPLICATIONS TO ENVIRONMENTAL SAMPLES. Application of Biosensors to Environmental Samples (K. Riedel). Index.

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Book SynopsisAnalytical techniques based on separation processes, such aschromatography and electrophoresis, are finding a growing range ofapplications in chemical, pharmaceutical and clinical laboratories.The Wiley Separation Science Series provides the analyst in theselaboratories with well focused books covering individualtechniques, so that they can be applied more efficiently andeffectively to contemporary analytical problems. In biotechnology,biochemistry and molecular biology, the characterization andanalysis of biomolecules such as proteins, oligosaccharides andnucleic acids are of great importance. High performance liquidchromatography (HPLC) has become one of the key analytical tools inthese fields, providing rapid purification and quantitativeanalysis of biomolecules. High Performance Liquid Chromatography: Principles and Methods inBiotechnology covers the most important theoretical and practicalaspects of the application of HPLC to the biosciences, includingsample preparation,Table of ContentsIntroduction to Chromatography in Biotechnology (C. Simpson). The Principles of Separation by High Performance LiquidChromatography (R. Scott). Column Selection in High Performance Liquid Chromatography (R.Eksteen). Detection and Identification in Biochromatography (I. Krull, etal.). Sample Preparation (A. Rizzi & I. Maurer-Fogy). The Preparative HPLC of Biomolecules (G. Cox). The Application of HPLC for Nucleic Acid Analysis (J. Wages &E. Katz). High-pH Anion Exchange Chromatography of Recombinant GlycoproteinGlycans (R. Townsend). The Application of HPLC for Proteins (K. Benedek). Alternative Bioseparation Techniques (P. Righetti, et al.). Index.

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Book SynopsisNatural Products, broadly defined as high value chemical entities derived from plants or microbial sources, have been known and exploited for many years. In recent years, as the need for higher potency and predictability of such products has increased, more sophisticated concentration and isolation procedures have been developed. With the passage of time, such procedures have been rationalized in terms of scientific principles but, in general, theory has followed behind practice, leading at any given time to an absence from the literature of methods which are truly state of the art. Downstream Processing of Natural Products: A Practical Handbook is a highly practical manual which addresses this issue, and guides researchers and industrial workers through the many potential pitfalls of natural product isolation. The contributors to this volume, all of whom have wide practical experience in this field, present state-of-the-art techniques and observations. The three main stages of naturalTable of ContentsPartial table of contents: Broth Conditioning and Clarification (D. Mackay). Cell Disruption: A Practical Approach (E. Keshavarz-Moore). Solvent Extraction of Fermentation Broth (L. Weatherley). Chemically Assisted Solvent Extraction (C. King). Process Integration in Biotechnology (J. Asenjo & E.Leser). Displacement Chromatography (D. Wallworth). Affinity Chromatography (S. Burton). High-Performance Liquid Chromatography (P. Shelley). Lyophilization (J. Snowman). Instrumentation and Process Control (J. Noble & K.Robins). Scale-Up Considerations (J. Noble & R. Davies). GMP and Quality Control (D. Sherwood). Index.

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Book SynopsisYeasts are the world''s premier industrial micro-organisms. In addition to their wide exploitation in the production of foods, beverages and pharmaceuticals, yeasts also play significant roles as model eukaryotic cells in furthering our knowledge in the biological and biomedical sciences. In order for modern biotechnology to fully exploit the activities of yeasts, it is essential to appreciate aspects of yeast cell physiology. In recent years, however, our knowledge of yeast physiological phenomena has lagged behind that of yeast genetics and molecular biology. Yeast Physiology and Biotechnology redresses the balance by linking key aspects of yeast physiology with yeast biotechnology. Individual chapters provide broad and timely coverage of yeast cytology, nutrition, growth and metabolism - important aspects of yeast cell physiology which are pertinent to the practical uses of yeasts in industry. The final chapter reviews traditional, modern and emerging biotechnologies in which rolesTable of ContentsIntroduction to Yeasts. Yeast Cytology. Yeast Nutrition. Yeast Growth. Yeast Metabolism. Yeast Technology. Index.

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Book SynopsisWritten by an exceptionally experienced author in the area of medical equipment product design, this text presents a comprehensive overview of such sound principles and state-of-the-art techniques covering a whole host of material types, biocompatability, the design process and future trends within this exciting field.Trade Review"This is a handbook of commercially available materials which are commonly used for medical devices" (Aslib Book Guide, Vol. 64, No. 1, January 1999)Table of ContentsMATERIALS. Material Available. Material Selection Processes. Ferrous Metals. Non-Ferrous Metals. Polymers. Poly(vinyl chloride)(PVC). Other Materials. Adhesives. Corrosion and Degradation. Biocompatability. Filters and Membranes. Fibre Optics. Battery Selection. DESIGN. Training and Education for Design. Design Process and Factors. Microengineering. Prototyping. Sterilisation. Standards. Specifications. Packaging. Communication in Design. Product Liability. Patents and Registration. Quality Assurance. Manufacturing Methods. FUTURE TRENDS. Future Trends. Environmental Issues. INFORMATION. Sourcing. Glossary. Index.

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Book SynopsisThe manufacture and commercialization of optically-active products and intermediates is a rapidly evolving field. There have been significant new developments since the first volume of Chirality in Industry was published.Table of ContentsPartial table of contents: Chiral Drugs: Regulatory Aspects (J. Blumenstein). Synthesis of Enantiomerically Pure Nucleosides (B. Bray, etal.). PHYSICAL METHODS AND CLASSICAL RESOLUTION. Crystal Science Techniques in the Manufacture of Chiral Compounds(W. Wood). BIOLOGICAL METHODS AND CHIRAL POOL SYNTHESES. Development of a Multi-Stage Chemical and Biological Process for anOptically Active Intermediate for an Anti-Glaucoma Drug (A. Blacker& R. Holt). ASYMMETRIC SYNTHESES BY CHEMICAL METHODS. Asymmetric Hydrocyanation of Vinylarenes (A. Casalnuovo & T.Rajanbabu). Sharpless Asymmetric Epoxidation: Scale-up and IndustrialProduction (W. Shum & M. Cannarsa). Index.

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Book SynopsisIn Biology Is Technology, author Robert Carlson offers a uniquely informed perspective on the endeavors that contribute to current progress in the science of biological systems and the technology used to manipulate them.Trade ReviewA thoughtful attempt to put what we think we know about biotechnology into a larger context, by a physicist-turned-bioentrepreneur. * The Economist *Biology Is Technology is essential reading for anyone who wishes to understand the current state of biotechnology and the opportunities and dangers it may create. -- Alex Soojung-Kim Pang * American Scientist *[Carlson] presents an informative view of the future prospects for biotechnology and its regulation. -- Michael A. Goldman * Nature *In this new book, bioengineer Robert H. Carlson forecasts the rise of the cell and the subsequent emergence of biological techniques for making fuels, synthetic DNA that builds new organisms, and reverse-engineered viruses for making vaccines. Biologists, Carlson says, are the new engineers, and the future is in remodeling life as we know it. * Wired *Since Rob Carlson is the authoritative tracker of progress in biotech, this book is the most complete—and exciting—chronicle of the technological revolution that promises to dominate this century. -- Stewart Brand, author of Whole Earth Discipline: An Ecopragmatist ManifestoCarlson clearly frames a fresh future for biotechnology. Each chapter, from technology trends to property rights and biosecurity conundrums, invites close reading and vibrant discussion. -- Drew Endy, Department of Bioengineering, Stanford University, and the BioBricks FoundationBiology Is Technology makes a tremendous contribution to public analysis of a very important emerging field. Although various commentators have discussed particular aspects of synthetic biology (e.g., risk regulation, intellectual property considerations), I am not aware of a book that encapsulates all of the varying strands of the debate. In addition, the book takes a set of provocative and interesting stances on the subjects that it addresses. It is obviously written by someone who has been a longstanding participant in, and commentator on, the field. Although I do not necessarily agree with all of the positions taken by the book, they are well-defended and thought through. -- Arti K. Rai, Duke Law SchoolTable of Contents* Acknowledgments * What Is Biology? * Building with Biological Parts * Learning to Fly (or Yeast, Geese, and 747s) * The Second Coming of Synthetic Biology * A Future History of Biological Engineering * The Pace of Change in Biological Technologies * The International Genetically Engineered Machines Competition (iGEM) * Reprogramming Cells and Building Genomes * The Promise and Peril of Biological Technologies * The Sources of Innovation and the Effects of Existing and Proposed Regulations * Laying the Foundations for a Bio-Economy * Of Straightjackets and Springboards for Innovation * Open Source Biology, or Open Biology? * What Makes a Revolution? * Notes * Index

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Book SynopsisThe second volume in a series designed to keep agricultural leaders abreast of the most up-to-date information concerning global agriculture, Perspectives in World Food and Agriculture, Volume 2 brings together cutting-edge agricultural research and the latest views on agricultural policy. Written by internationally renowned researchers, scientists, and academics, Volume 2 includes: The UN''s approaches to address global food security and poverty An essay by the World Food Prize Laureat Globalization, emerging diseases, and invasive specie Environmental sustainability Plant-derived vaccines, antibiotic bans, and health impacts The future of agricultural biotechnology The pivotal rTable of ContentsForeword (Kenneth M. Quinn). Preface. Acknowledgements.. Section I: Frontiers in Addressing World Hunger and Poverty. 1. Introduction to the Millennium Development Goals. 2. The Human Development report 2003 (Sakiko Fukuda-Parr). 3. World Food Day Remarks: Agricultural Productivity in the Developing World (Andrew S. Natsios). 4. The Millennium Compact and the End of Hunger (Jeffrey D. Sachs). 5. Globalization and World Hunger: An Independent Monitoring of Progress (Per Pinstrup-Andersen). 6. Defeating Hunger and Famine: The View from Africa (H.E. Wilberforce Kisamba-Mugerwa). 7. How to Reduce Poverty and Malnutrition Through Science and Technology (Ann Veneman). 8. Feeding the World: The View from Iowa (Tom Vilsack). 9. Donor Role in Agriculture and Rural Development and in Hunger Reduction (Kevin Cleaver). 10. Environmental Sustainability and Food Security (Jeffrey McNeely). 11. Toward a Hunger-Free World: The Final Milestone (M.S. Swaminathan). 12. Global Health and Food Security: Imperatives for the Future (Ady Barkan and Josh Ruxin). 13. Ending Hunger in America (H. Eric Schockman). Section II: Frontiers in Addressing Health and Nutrition. 14. Educate Girls (Catherine Bertini). 15. Plant-Derived Vaccines to Overcome Current Constraints in Global Immunization (Charles J. Arntzen, Guruatma Khalsa, adn Richard T. Mahoney). 16. The Effect of Banning Antibiotics for Growth Promotion in Poultry and Swine Production in Denmark (Hanne-Dorthe Embog and Henridk C. Wegener). 17. Implications of More Restricted Antimicrobial Access Policy: Issues Related to U.S. Pork Production (Dermot J. Hayes and Helen H. Jensen). Section III: Frontiers in Food, Agriculture, and Global Climate Change. 18. Global Warming and Agriculture (Cynthia Rosenzweig and Daniel Hillel). 19. Technological Choice and the Changing Structure of Agriculture: Farming to Sequester Carbon and Reduce Global Warming (Luther Tweeten and Mariah Tanner). Section IV: Frontiers in Agriculture and Rural Development in Industrialized Countries. 20. Farm Programs and Agricultural Choices in Rural America (B4uce A. Babcock). 21. A Time for Change in U.S. Rural Policy (Mark Drabenstott). 22. Agriculture - A Short History (from Demestication to Present) (Colin S. Scanes and Richard L. Willham). Section V: trends and Outlook for World Food and Agriculture. 23. Factors Affecting World Agriculture (John Beghin, Jay Fabiosa, Fengxia Dong, Amani El Obeid, Frank Fuller, Chad Hart, Holger Matthey, Alexander Saak, Simla Tokgoz, Seth Meyer, and Eric Wailes). Index.

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Book SynopsisCoverage of basic Anaerobic Biotechnology principles Practical applications of principles and processes Thorough coverage of cost-effective and sustainable means of treating waste water and resource reclamation.Table of ContentsCONTRIBUTORS, xi PREFACE, xiii 1 OVERVIEW OF ANAEROBIC BIOTECHNOLOGY, 1 Samir Kumar Khanal 1.1 Anaerobic Biotechnology and Bioenergy Recovery, 1 1.2 Historical Development, 3 1.3 Importance of Anaerobic Biotechnology in Overall Waste Treatment, 5 1.4 Definition and Principle of Anaerobic Processes, 6 1.5 Important Considerations in Anaerobic Biotechnology, 8 1.6 Merits of Anaerobic Biotechnology, 15 1.7 Limitations of Anaerobic Process, 22 References, 25 2 MICROBIOLOGY AND BIOCHEMISTRY OF ANAEROBIC BIOTECHNOLOGY, 29 Samir Kumar Khanal 2.1 Background, 29 2.2 Organics Conversion in Anaerobic Systems, 29 2.3 Process Microbiology, 32 References, 41 3 ENVIRONMENTAL FACTORS, 43 Samir Kumar Khanal 3.1 Background, 43 3.2 Temperature, 43 3.3 Operating pH and Alkalinity, 47 3.4 Nutrients, 55 3.5 Toxic Materials, 56 3.6 Redox Potential or Oxidation–Reduction Potential, 59 References, 61 4 KINETICS AND MODELING IN ANAEROBIC PROCESSES, 65 Keshab Raj Sharma 4.1 Background, 65 4.2 Basic Elements, 66 4.3 Stepwise Approach to Modeling, 69 4.4 Modeling of pH Change, 79 4.5 Modeling of Energy Generation, 87 References, 92 5 ANAEROBIC REACTOR CONFIGURATIONS FOR BIOENERGY PRODUCTION, 93 Samir Kumar Khanal 5.1 Background, 93 5.2 Strategies for Decoupling HRT and SRT, 93 5.3 Classification of Anaerobic Bioreactors, 94 5.4 Membrane Technology for Syngas Fermentation to Ethanol, 112 References, 114 6 MOLECULAR TECHNIQUES IN ANAEROBIC BIOTECHNOLOGY: APPLICATION IN BIOENERGY GENERATION, 115 Srisuda Dhamwichukorn 6.1 Background, 115 6.2 Molecular Techniques in Anaerobic Biotechnology, 115 6.3 Fundamentals of Molecular Techniques, 116 6.4 Phylogenetic Analysis, 117 6.5 Molecular Techniques for Microbial Community Structure Analysis: DNA Fingerprinting, Clone Library, and Fluorescent in Situ Hybridization, 118 6.6 Molecular Techniques for Functional Analysis, 121 6.7 Nucleic Acid Extraction of Anaerobic Cells/Isolates and Sludge, 123 6.8 Molecular Techniques for Structure and Function Analysis, 123 6.9 Postgenomic Approaches for Bioenergy Research, 128 References, 130 7 BIOENERGY RECOVERY FROM SULFATE-RICH WASTE STREAMS AND STRATEGIES FOR SULFIDE REMOVAL, 133 Samir Kumar Khanal 7.1 Background, 133 7.2 Sulfate-Reducing Bacteria, 133 7.3 High-Strength Sulfate-Rich Wastewater, 135 7.4 Methane Recovery from High-Strength Sulfate-Laden Wastewater, 135 7.5 Important Considerations in Treatment and Methane Recovery from High-Strength Sulfate-Laden Wastewater, 137 7.6 Interactions between MPB and SRB, 143 7.7 Sulfide Removal, 149 References, 157 8 BIOENERGY GENERATION FROM RESIDUES OF BIOFUEL INDUSTRIES, 161 Samir Kumar Khanal 8.1 Background, 161 8.2 Bioethanol Feedstocks, 162 8.3 Biodiesel Feedstocks, 163 8.4 Ethanol Production, 163 8.5 Thin Stillage Characterization, 171 8.6 Cassava-Based Ethanol Production, 183 8.7 Cellulose-Based Ethanol Production, 185 8.8 Bioenergy Recovery from Crude Glycerin, 186 References, 187 9 BIOHYDROGEN PRODUCTION: FUNDAMENTALS, CHALLENGES, AND OPERATION STRATEGIES FOR ENHANCED YIELD, 189 Samir Kumar Khanal 9.1 Background, 189 9.2 Biological Hydrogen Production, 190 9.3 Microbiology of Dark Fermentation, 191 9.4 Hydrogen Production Pathway through Dark Fermentation, 192 9.5 Suppression of Hydrogen Consumers, 196 9.6 Hydrogen Yield, 199 9.7 Important Considerations in Biohydrogen Production, 200 9.8 Limitations of Dark Fermentation and Potential Remedial Options, 210 9.9 Technoeconomic Analysis of Hydrogen Fermentation, 213 References, 215 10 MICROBIAL FUEL CELL: NOVEL ANAEROBIC BIOTECHNOLOGY FOR ENERGY GENERATION FROM WASTEWATER, 221 Hong Liu 10.1 Background, 221 10.2 How Does a Microbial Fuel Cell Work?, 222 10.3 Stoichiometry and Energetics, 223 10.4 Electrochemically Active Microbes and Electron Transfer Mechanisms, 225 10.5 Evaluation of MFC Performance, 228 10.6 MFC Designs and Electrode Materials, 231 10.7 Operational Factors Affecting MFC Performance, 239 10.8 Opportunities and Challenges for MFCs in Wastewater Treatment, 242 References, 243 11 PRETREATMENT OF HIGH-SOLIDS WASTES/RESIDUES TO ENHANCE BIOENERGY RECOVERY, 247 Santha Harikishan 11.1 Background, 247 11.2 Efficiency of Sludge Pretreatment, 248 11.3 Ultrasound Pretreatment, 250 11.4 Chemical and Physical Pretreatment, 257 11.5 Thermal Hydrolysis, 261 11.6 Impact of Improved Digestibility on Overall Process Economics, 264 References, 264 12 BIOGAS PROCESSING AND UTILIZATION AS AN ENERGY SOURCE, 267 Santha Harikishan 12.1 Background, 267 12.2 Biogas Production, 267 12.3 Factors Affecting Digester Gas Production, 269 12.4 Biogas Composition, 270 12.5 Biogas Impurities, 272 12.6 Biogas Cleaning for Effective Utilization, 274 12.7 Biogas Utilization, 279 12.8 Future of Biogas as a Renewable Resource, 290 References, 291 INDEX, 293

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Book SynopsisThe present book volume presents a holistic view of the aspects of nanobiomaterials incl. their stellar merits and limitations, applications in diverse fields, their futuristic promise in the fields of biomedical science and drug delivery. The federal & regulatory issues on the usage of nanobiomaterials have been assigned due consideration.Table of ContentsApplications of Nano-Based Biomaterials. Nanocoutured Metallic Biomaterials and Surface Functionalization of Titanium-based Alloys for Medical Applications. Graphene-Polymer Nanocomposites for Biomedical Applications. Lipid-based Nanocarriers in Lymphatic Transport of Drugs: Retrospect and Prospects. Nanotechnology in Early Diagnosis of Cancer. Dendrimers: Emerging Anti-Infective Nanomedicines. Production and Utilization of Nanofibers. Fibro-Porous Composite Nano-Biomaterials for Enhanced Bio-Integration. Nanocarriers Mediated Protein Delivery. Nanotechnology-Based Prodrug Conjugates for Site-Specific Antineoplastic Therapy. Osteomyelitis: Therapeutic Management using Nanomedicines.Nanostructured Lipid Carriers-Mediated Methotraxate Delivery Evokes Transcription Factors to Induce Selective Apoptosis in Rheumatoid Arthritis.Superparamagnetic Iron Oxide Nanoparticles for Magnetic Hyperthermia Applications. Development of In-house Nano-hydroxyapatite Particles for Dental Applications.

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Book SynopsisFollowing on from earlier titles in this series, this volume presents further material generated by the World Bank/ISNAR/Australian government biotechnology study. It covers the present status and future prospects for the application of biotechnology to solve agricultural and environmental problems in a number of developing countries. Particular focus is given on to developments that have taken place over the last decade.Table of ContentsPart I: Introductory Review 1.1: Agricultural Biotechnology: Global Challenges and Emergin Science,G J Persley Part II: Asia/Pacific China, Qifa Zhang 2.1: India, Manju Sharma 2.2: Indonesia, P J Dart, I H Slamet-Loedin, and E Sukara 2.3: Pakistan, Yusuf Zafar 2.4: Philippines, Reynaldo E de la Cruz 2.5: Thailand,Morakot Tanticharoen Part III: Africa 3.1: Egypt, Magdy A Madkour 3.2: Kenya, N K Olembo 3.3: Zimbabwe, C J Chetsanga Part IV: Latin America 4.1: Brazil, Maria J A Sampaio 4.2: Colombia, R Torres and C Falconi 4.3: Costa Rica, A Sittenfeld, A M Espinoza, M Munoz, and A Zamora

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Book SynopsisThe potato is economically a very important crop in many parts of the world. All improvements through potato breeding or biotechnology must be based on a thorough knowledge of potato genetics. This book fills a major gap in the current literature for an up-to-date account of this topic and its implications for crop improvement. Written by authorities from the UK, USA, Canada, Peru, Netherlands, Germany, Sweden and Poland, this major reference work will be indispensible for workers in plant genetics, breeding and biotechnology.Table of Contents1: Production of monohaploids of Solanum tuberosum L. and their use ingenetics, molecular biology and breeding, E Jacobsen and M S RamannaCellular and molecular genetics 2: Tissue culture, G Wenzel 3: Somaclonal variation, A Kumar 4: Molecular genetics, K N WatanabeEnvironmental stress, morphology and quality 5: Environmental stress and its impact on potato yield, M E Vayda 6: Inheritance of morphological and tuber characteristics, R Ortiz and ZHuaman 7: Inheritance of table and processing quality, M F B Dale and G R MackayInheritance of resistance to pests and diseases 8: Inheritance of resistance to nematodes, M.S. Phillips 9: Inheritance of resistance to viruses, K M Swiezynski 10: Inheritance of resistance to late blight, V Umaerus and M Umaerus 11: Inheritance of resistance to warm-growing-season fungal diseases, J JPavek and D L Corsini 12: Inheritance of resistance to fungal diseases of tubers, R L Wastie 13: Inheritance of resistance to bacterial diseases, J G Elphinstone 14: Inheritance of resistance to insects and mites, K V Raman et al.Potato breeding 15: Breeding strategies for clonally propagated potatoes, J E Bradshaw and GR Mackay 16: Breeding potatoes based on true seed propagation, A M Golmirzaie, PMalagamba and N Pallais 17: Introgression of genes from wild species, including molecular and cellularapproaches, J G Th Hermsen

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Book SynopsisProponents of Integrated Pest Management (IPM) advocate its use to reduce or eliminate the use of chemical pesticides in agriculture, since excessive pesticide use may be a threat to both human health and the environment. Proponents of biotechnology believe that the use of novel products, such as transgenic plants with insect resistance, will reduce the need for chemical pesticides. However the use of such novel products within IPM systems may also create potential risks. This volume reviews such issues and discusses the potential benefits of and constraints to the applications of biotechnology in IPM systems, especially in developing countries. It also considers the related policy issues confronting decision-makers in national agricultural research systems and international development agencies. The book consists of revised versions of papers presented at a conference hosted by the Rockefeller Foundation and held in Bellagio, Italy in October 1993.Table of ContentsSection One: Linking Biotechnology and Integrated Pest Management 1: Needs and opportunities, Max J Whittan, Richard A Jefferson and David Dall 2: Integrated pest management and biotechnology: An analysis of their potential for integration, Jeff Waage 3: Integrated pest management in developing countries, Lim Guan Soon Section Two: Case Studies of IPM Integration and of Using Biocontrol Agents in IPM Systems 4: Integrated pest management: Rice case-study, Peter E Kenmore 5: Soybean in Brazi,l Flavio Moscardi and D R Sosa-Gómez 6: India: An overview, Nandini V Katre 7: Cassava in Africa, Hans R Herren Section Three: Using Biotechnology for New Biocontrol Agents 8: Biological products for IPM, Pamela Marrone 9: Novel biocontrol agents, Marjorie A Hoy Section Four: Biotechnology and Plant Breeding 10: Marker-assisted plant breeding, Rebecca J Nelson 11: Modern plant breeding: an Overview, Ivan W Buddenhagen Section Five: Case Studies: Transgenic Plants in IPM Systems 12: Insect-resistant crop plants, David A Fischhoff 13: Cotton in Australia, W James Peacock, D J Llewellyn and G P Fitt 14: Virus-resistant transgenic plants, Roger Beachy Section Six: Alternative Strategies with Transgenes for Insect Resistance 15: Can we slow adaptation by pests to insect resistant transgenic crops?, Richard T Roush 16: Deploying pesticidal crops in developing countries, Fred Gould Section Seven: Other Components in IPM Systems 17: New diagnostics, Mark E Whalon 18: Virus/vector control, Michael E Irwin and Lowell R Nault Section Eight: New Opportunities 19: Vector control, Elizabeth Evans 20: Insect vectors of human diseases, Christopher F Curtis 21: Molecular genetics Veronica Rodriguêz and K Vijiy Raghavan Section Nine: Investment Implications and Future Directions 22: A view from industry, Ben J Mifflin 23: Future directions for international development agencies, Gabrielle J Persley, Gary Toennisen and Peter Dart

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Book SynopsisThis multi-authored book provides a comprehensive review of citrus breeding, including relevant genetics, molecular biology and biotechnology. Topics discussed include origin and Taxonomy, hybridization and see procedures, triploid breeding, mutation breeding, selection for fruit traits, tree characters and disease resistant, rootstock breeding, soil adaptation, nucellar embryony, cytogenetics, mapping, gene cloning, chromosome transfer technology, haploidy, flow cytometry and somaclonal variation.Table of Contents1: Citrus Breeding: Introduction and Objectives 2: A Comprehesive Citrus Genetic Improvement Program 3: Origin and Taxonomy 4: Germplasm Resource 5: Nuceller Embryony 6: Cytogenetics 7: Haploidy 8: Seedlessness and Ploidy Manipulations 9: Somatic Hybridization 10: Single Chromosome Transfer

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Book SynopsisOrnamental plants include herbaceous plants produced as bedding plants, greenhouse pot plants and cut flowers, as well as bulbs, trees, shrubs and vines. Ornamental plant production is of major and increasing importance worldwide. Basic scientific research in recent years has provided a better understanding of plant regeneration, genetics, growth and development. This has led to the development of technologies which can significantly improve ornamental species. This book reviews recent advances in the biotechnology of ornamentals. For example, genes have recently been identified for flower characteristics and pest resistance and these have been engineered into ornamental species. The book is divided into four main parts and is written by authors from the USA, UK, Canada, Netherlands, Australia and New Zealand. It is aimed primarily at workers in horticulture and plant biotechnology, but will also be of interest to plant physiologists, geneticists and molecular biologists.Table of ContentsPart 1: Supporting Technologies 1: The Commercialization of Biotechnology, K L Giles, Department of Horticulture Science, University of Saskatchewan, Canada and M McLaughlin, Ag-West Biotech, Saskatoon, Canada 2: Somatic Embryogenesis in Ornamentals, S A Merkle, Daniel B Warnell School of Forest Resources, University of Georgia, Athens, USA 3: Axillary Shoot Proliferation, J E Preece, Department of Plant and Soil Science, Southern Illinois University, USA 4: Adventitious Shoot Regeneration, R R Tripepi, Plant Science Division, University of Idaho, USA 5: Approaches to Understanding Maturation or Phase Change, W P Hackett and J R Murray, Department of Horticultural Science, University of Minnesota, USA Part 2: Genetics 6: Transformation Protocols for Ornamental Plants, S C Deroles, M R Boase and I Konczak, New Zealand Institute for Crop & Food Research Ltd, New Zealand 7: Reproductive Barriers in Flowering Plants, N Nass, A E Clarke and E Newbiggin, Plant Cell Biology Research Centre, School of Botany, University of Melbourne, Australia 8: Genome Mapping, R Whetten, Department of Forestry, North Carolina State University, USA 9: Cultivar Identification Using Molecular Methods, S Rajapakse, and R E Ballard, Department of Biological Sciences, Clemson University, USA 10: Somaclonal Variation, H Bouman and G de Klerk, Centre for Plant Tissue Culture Research, The Netherlands 11: T-DNA Insertion Mutagenesis for Improvement of Ornamentals, M A Jenks and K A Feldmann, Department of Plant Sciences, University of Arizona, USA Part 3: Plant Growth and Development 12: Biotechnological Approaches to Modifying Plant Form, B H McCown, Department of Horticulture, University of Wisconsin-Madison, USA 13: Molecular Events Associated with Floral Evocation, B R Jordan, New Zealand Institute for Crop & Food Research Ltd, New Zealand and R G Anthony, Department of Biochemistry, Royal Holloway College, University of London, UK 14: Manipulation of Flower Shape, A R Van der Krol and O Vorst, Department of Plant Physiology, Agricultural University Wageningen, The Netherlands 15: Flower Colour, K M Davies and K E Schwinn, New Zealand Institute for Crop & Food Research Ltd. Part 4: Abiotic and Biotic Stress 16: Prospects for the Improvement of Tolerance to Abiotic Stresses Using Recombinant DNA Approaches, C L Guy, Department of Environmental Horticulture,University of Florida, USA 17: Engineering for Bacterial and Fungal Disease Resistance, H J M Löffler and D E A Florak, DLO Centre for Plant Breeding and Reproduction Research, The Netherlands 18: Biotechnological Approaches for Virus resistance in Floral Crops, M E Daub, R K Jones and J W Moyer, Department of Plant Pathology, North Carolina State University, USA 19: Biotechnological Approaches to Study and Improve Insect Resistance of Woody Plants, NB Klopfenstein, USDA Forest Service, National Agroforestry Centre, University of Nebraska, USA and ER Hart, Dept. of Entomology and Forestry, Iowa State University, USA 20: Genetic Engineering of Horticultural and Forestry Crops for Herbicide Tolerance, D E Riemenschneider, Forestry Sciences Laboratory, Wisconsin, USA

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Book SynopsisAdvances in molecular and cell biology have led to the development of a whole range of techniques for manipulating genomes, collectively termed biotechnology. Although much of the focus in the plant sciences has been on the direct manipulation of plant genomes, biotechnology has also catalyzed a renewed emphasis on the importance of biological and genetic diversity and its conservation. The methods of biotechnology now permit a greater understanding of both species and genetic diversity in plants, the mechanisms by which that variation is generated in nature, and the significance of that variation in the adaptation of plants to their environment. They allow the development of rapid methods for screening germplasm for specific characters and promote more effective conservation strategies by defining the extent of genetic diversity. Tissue culture-based techniques are available for conserving germplasm that cannot be maintained by more traditional methods. Also sophisticated informaticsTable of Contents1: An Overview J A Callow, B V Ford-Lloyd and H J Newbury 2: Use of molecular marker techniques for description of plant genetic variation A L Westman and S Kresovich 3: Genetic diversity - population structure and conservation M D Hayward and N R Sackville Hamilton 4: Genenomic relationships, conserved synteny and wide-hybrids D A Laurie, G J Bryan and J W Snape 5: Molecular markers and the management of genetic resources in seed genebanks: a case study of rice B V Ford-Lloyd, M T Jackson and H J Newbury 6: In vitro conservation methods F Engelmenn 7: Conservation of DNA: DNA banking R P Adams 8: Genetic resources and plant breeding M J Kearsey 9: Gene identification, isolation and transfer I D Godwin 10: Importance of biotechnology for germplasm health and quarantine H Barker and L Torrance 11: Biodiversity for bioindustries G Tamayo, W F Naider and A Sittenfeld 12: Internet resources for the biologist M L Anderson and S W Cartinhour

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Book SynopsisThe use of inducible gene expression systems is a rapidly developing area of plant molecular biological research. There is considerable interest in the use of these systems as research tools, not only because they allow expression of genes which may be, for example, developmentally lethal, but also because they allow for controlled experiments to be performed in a true isogenic background. They also have the potential to provide a means by which desired characters are expressed in field-based systems in the future.Table of Contents1: Inducible Control of Gene Expression: An Overview, P H S Reynolds 2: Use of the TN10-Encoded Tetracycline Repressor to Control Gene Expression, C Gatz, Universität Göttingen, Germany 3: Ecdysteroid Agonist-inducible Control of Gene Expression in Plants, A Martinez and I Jepson, Zeneca Agrochemicals, Bracknell, UK 4: Glucocorticoid-inducible Gene Expression in Plants, T Aoyama, Institute for Chemical Research, Kyoto University, Japan 5: Tissue-specific, Copper-controllable Gene Expression in Plants, V L Mett and P H S Reynolds, The Horticulture and Food Research Institute of New Zealand 6: Nitrate Inducibility of Gene Expression Using the Nitrite Reductase Gene Promoter, S J Rothstein and S Sivasankar, University of Guelph, Canada 7: Use of Heat Shock Promoters to Control Gene Expression in Plants, R T Nagao, University of Georgia, USA and W B Gurley, University of Florida, USA 8: Wound-inducible Genes in Plants, L Zhou and R Thornburg, Iowa State University, USA 9: Developmental Targeting of Gene Expression by the Use of a Senescence-specific Promoter, S Gan, University of Kentucky, USA and R M Amasino, University of Wisconsin, Madison, USA 10: Abscisic Acid- and Stress-induced Promoter Switches in the Control of Gene Expression, Q Shen, Monsanto Company, Chesterfield, USA and T-H D Ho, Washington University, St. Louis, USA 11: Potential Use of Hormone Responsive Elements to Control Gene Expression in Plants, T J Guilfoyle and G Hagen, University of Missouri, Columbia

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Book SynopsisMajor research is now directed at improving the nutritional quality of eggs, and at using eggs in other products. Due to the decline in the consumption of eggs in the past few decades, researchers from many disciplines have been lead to look at the egg beyond its traditional food value, and to focus on economically viable biomedical, nutraceutical and ovo-biotechnologies. Written by international experts, this book is based on proceedings of the Second International Symposium on Egg Nutrition and Newly Emerging Ovo-Biotechnologies, held in Banff, Canada, in April 1998. It includes 39 chapters, covering food fats and health, egg consumption, egg lipids and nutrition, ovo-technologies, and food food safety.Table of Contents1: Dietary Fat and Disease: What Do We Know and Where Do We Stand?, D. Kritchevsky 2: Food Cholesterol and its Plasma Lipid and Lipoprotein Response: Is Food Cholesterol Still a Problem or Overstated?, W.H. Howell 3: Eggs, Dietary Cholesterol and Heart Disease Risk: An International Perspective, D.J. McNamara 4: Egg Products Around the World: Today and Tomorrow, G. Zeidler 5: Eggs as a Functional Food Alternative to Fish and Supplements for the Consumption of DHA, M.E. Van Elswyk et al. 6: Biological Activities of Conjugated Linoleic Acids and Designer Eggs, B.A. Watkins, A.A. Devitt, L. Yu, and M.A. Latour 7: Safe Use of Microalgae (DHAGOLD™) in Laying Hen Feed for the Production of DHA-Enriched Eggs, J.R. Abril, W.R. Barclay, and P.G. Abril 8: Molecular Modification of Egg Proteins for Functional Improvement, S. Nakai 9: Eggs as a Functional Food: Technology Update, C.M. Hasler 10: Preparation of Antigen Specific IgY for Food Application, H.H. Sunwoo et al. 11: Applications of Egg Immunoglobulins in Immunoaffinity Chromatography, E.C.Y. Li-Chan 12: Using Egg Antibodies to Treat Diseases, M. Coleman 13: Re-evaluation of Liquid Egg Pasteurization Technology: Newly Emerging and Industrial Application, Theory and Practice, G.W. Froning, D.L. Peters, and S.S. Sumner 14: Processing and Cooling Shell Eggs to Enhance Safety and Quality, P.A. Curtis 15: Effects of Cryogenic Cooling of Shell Eggs on Interior Quality and Microbiological Integrity, D.R. Jones, J.B. Tharrington, P.A. Curtis, K.E. Anderson, and F.T. Jones 16: Effect of Feeding Organic Selenium in Diets of Laying Hens on Egg Selenium Content, A.H. Cantor et al. 17: Influence of Eggshell 49 on Shell Quality of Hens Grouped According to Shell Quality, R.D. Miles and C.W. Comer

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Book SynopsisOf special interest to those countries that are relatively new to the biotechnology field, this unique data source describes emerging biotechnology trends in developing countries and in Central and Eastern Europe. It includes information on government policy and legislation, biotechnology programmes, research centres, universities, private companies, and national societies and organisations in each country.Table of Contents1: Policy and Regulation, G T Tzotzos 2: International Initiatives in Agri-Food Biotechnology, J Komen 3: International Initiatives in Medical Biotechnology, T Crompton 4: Country Profiles 4.1: Belarus, 4.2: Brazil, 4.3: Bulgaria, 4.4: Chile, 4.5: China, 4.6: Colombia, 4.7: Cuba, 4.8: Egypt, 4.9: Hungary, 4.10: India, 4.11: Kenya, 4.12: Korea, 4.13: Kuwait, 4.14: Latvia, 4.15: Lithuania, 4.16: Malaysia, 4.17: Mexico, 4.18: Morocco, 4.19: Nigeria, 4.20: Pakistan, 4.21: Philippines, 4.22: Poland, 4.23: Russian Federation, 4.24: South Africa, 4.25: Thailand, 4.26: Ukraine, 4.27: Venezuela, 4.28: Zimbabwe 5: Appendices: 6: Directory of Research Centres 7: International Agricultural Biotechnology Initiatives 8: Acronyms

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Book SynopsisBased on ISNAR seminars, this book provides information and case studies distilling information on policies for development and implementation of new agricultural biotechnologies. It covers key managerial and policy issues that research directors, program managers and policymakers face when building capacity and competency in biotechnology.Table of ContentsSECTION I: Addressing Management and Policy Issues I: Identifying Needs and Priorities: A Decision-Making Framework for Agricultural Biotechnology 2: The Debate on Genetically Modified Organisms: Relevance for the South 3: Agricultural Biotechnology Research Indicators and Managerial Considerations in Four Developing Countries SECTION II: Setting and Implementing Priorities 4: Methods for Priority Setting in Agricultural Biotechnology Research 5: Setting Research Priorities for the Chilean Biotechnology Program 6: Managing Biotechnology in AARD, Indonesia: Priorities, Funding, and Implementation SECTION III: Maximizing Benefits from Resources 7: Issues in Human Resource Management and Development 8: Managing Bioprospecting and Biotechnology for Conservation and Sustainable Use of Biological Diversity 9: Managing Genetic Resources and Biotechnology at IRRI's Rice Genebank 10: International Collaboration in Agricultural Biotechnology 11: Public- and Private-Sector Biotechnology Research and the Role of International Collaboration 12: Indo-Swiss Collaboration in Biotechnology: Lessons Learned and Future Strategies SECTION IV: Ensuring Environmental Responsibility 13: Biosafety Management: Key to the Environmentally Responsible Use of Biotechnology 14: Formulating Guidelines for Field-Testing in the Philippines 15: Addressing Public Acceptance Issues for Biotechnology: Experiences from Japan 16: Balancing Needs for Productivity and Sustainability: Genetic Engineering of Rice at IRRI 17: Managing Target Pest Adaptation: The Case of Bt Transgenic Plant Deployment SECTION V: Managing IPR, Proprietary Science, and Technology Transfer 18: Intellectual Property Rights and Agricultural Biotechnology 19: Agricultural Research and the Management of Intellectual Property 20: Managing Intellectual Property in Embrapa: A Question of Policy and a Change of Heart 21: Managing Proprietary Science and Institutional Inventories for Agricultural Biotechnology 22: International Collaboration: Intellectual Property Management and Partner-Country Perspectives 23: Industrial Research and Business Development: Experiences from the Singapore Institute of Molecular Agrobiology 24: Introducing Transgenic Crops in India: A Joint Venture Approach

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Book SynopsisThis book presents the perspectives of policy-makers and economists on a highly topical subject. Plant breeding patents, the ownership of biological innovation and associated intellectual property rights (IPR) are the subject of increased attention worldwide. They are particularly relevant in the field of agricultural biotechnology, but until recently evoked little policy analysis. IPRs are particularly relevant in the field of agricultural biotechnology. They are issues affecting public and private sector organizations and companies, and are significant for developing as well as developed countries.Table of Contents1: Introduction, V Santaniello et al. 2: Patent and Other Private Legal Rights for Biotechnology Inventions (Intellectual Property Rights - IPR), D D Evenson, P.L.L.C., Washington, USA 3: Intellectual Property Rights of Plant Varieties and of Biotechnology in the European Union, V Santaniello 4: Intellectual Property Rights under the Convention on Biological Diversity, W Lesser, Cornell University, USA 5: An Economic Approach to Identifying An ‘Effective Sui Generis System’ for Plant Variety Protection Under TRIPS, W Lesser 6: Recent Intellectual Property Rights Controversies and Issues at the CGIAR, S H Bragdon, IPGRI, Rome, Italy 7: Economics of Intellectual Property Rights for Agricultural Technology, R E Evenson 8: The Market Value of Farmers’ Rights, R Mendelsohn, Yale University, USA 9: International Crop Breeding in a World of Proprietary Technology, B D Wright, University of California, USA 10: Knowledge Management and the Economics of Agricultural Biotechnology, D Zilberman and C Yarkin, University of California, USA and A Heiman, Hebrew University, Israel 11: Comparing Allocation of Resources in Public and Private Research, S Lemarié, Université Pierre-Mendès, Grenoble, France 12: Biotechnology Inventions: What Can We Learn From Patents?, D K N Johnson, Wellesley College, Massachusetts, USA and V Santaniello 13: Biotechnology Inventions: Patent Data Evidence, A Zohrabyan, Yale University, USA and R E Evenson 14: Property Rights and Regulations for Transgenic Crops in North America, G Carlson and M Marra, North Carolina State University, USA 15: Intellectual Property Rights, Canola and Public Research in Canada, P W B Phillips, University of Saskatchewan, Canada

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Book SynopsisPlant genotyping, or DNA fingerprinting of plants, is a technology that has matured and is poised for widespread practical application in the fields of breeding, commerce and research. This book examines the technologies available and their application in the analysis of:Wild plant populationsGermplasm collections Plant breedingContributors include leading research workers in this field from North America, Europe and Australasia.Table of Contents1: Molecular markers available for use in plant genotyping 2: Plant genotyping by analysis of single nucleotide polymorphisms, K J Edwards and R Mogg, University of Bristol, UK 3: Plant genotyping by analysis of microsatellites T A Holton, Southern Cross University, Australia 4: Plant genotyping using arbitrarily amplified DNA, G Caetano-Anollés, University of Oslo, Norway 5: Plant genotyping based upon analysis of single nucleotide polymorphisms using microarrays, B Lemieux, University ofDelaware, USAGenotyping plant genetic resource collections 6: Genotyping in plant genetic resources, B V Ford-Lloyd, University of Birmingham, UK 7: Applications of molecular marker techniques to the use of international germplasm collections, M Warburton and D Hoisington, Applied Biotechnology Center, CIMMYT, México Genotyping cultivated and wild germplasm 8: Molecular analysis of wild plant germplasm: the case of tea tree (Melaleuca alternifolia), L S Lee, M Rossetto, L Homer, R J Henry, Southern Cross University, Australia 9: Genotyping Pacific Island Taro (Colocasia esculenta (L.) Schott) germplasm, I D Godwin, E S Mace and Nurzuhairawaty,The University of Queensland, Australia 10: Molecular marker systems for sugarcane germplasm analysis, G M Cordeiro, Southern Cross University, Australia 11: Microsatellite analysis in cultivated hexaploid wheat and wild wheat relatives, A McLauchlan, R J Henry, Southern Cross University, Australia, P G Isaac, Agrogene, France and K J Edwards, University of Bristol, UK 12: Comparison of RFLP & AFLP marker systems for assessing genetic diversity in Australian barley varieties & breeding, K Chalmers, University of Adelaide, South Australia Development of molecular markers for use in plant genotyping 13: Discovery and application of single nucleotide polymorphism markers in plants, D Bhattramakki and A Rafalski, DuPont Agricultural Products, USA 14: Producing and exploiting enriched microsatellite libraries, T L Maguire, University of Queensland, Australia 15: Sourcing of SSR markers from related plant species, M Rossetto, Southern Cross University, Australia 16: Microsatellites derived from ESTs, and their comparison with those derived by other methods, K D Scott, Southern Cross University, AustraliaTechnical developments and issues in plant genotyping 17: Plant DNA Extraction, R J Henry, Southern Cross University, Australia 18: Collection, reporting and storage of microsatellite genotype data, N Harker, Southern Cross University, Australia 19: Commercial applications of plant genotyping, L S Lee and R J Henry, Southern Cross University, Australia 20: Non-gel based techniques for plant genotyping, R Kota, Southern Cross University, Australia 21: Using molecular information for decision support in wheat breeding, H Eagles, CRC for Molecular Plant Breeding, M Cooper, The University of Queensland, R Shorter, CSIRO Tropical Agriculture, P Fox, CIMMYT, 22: Application of DNA profiling to an outbreeding forage species, J Forster, E Jones, R Kölliker, M Drayton, M Dupal, K Guthridge, La Trobe University, Australia & K Smith, Pastoral & Veterinary Institute, Australia

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Book SynopsisThis book contains edited and revised papers from a conference on 'Science and Technology for Managing Plant Genetic Diversity in the 21st Century' held in Malaysia in June 2000, organised by the International Plant Genetic Resources Institute (IPGRI). It includes keynote papers and some 40 additional ones, covering ten themes.The major scientific challenges to developing a global vision for the next century are identified and key research objectives are also discussed.Table of Contents1: The applications of genomic sciences for a better understanding of genepools 2: Technologies and strategies for ex situ conservation 3: The deployment and management of genetic diversity in agroecosystems 4: The role of bioinformatics in conservation and use 5: In situ conservation of wild species 6: Indicators for sustainable management of genetic resources 7: Germplasm enhancement and pre-breeding 8: Exploring underused species - diverse options 9: Implications of gene transformation techniques for ex situ conservation choices 10: GIS applications for genetic resources management 11: The economics of managing genetic resources and the role of private and public sectors

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Book SynopsisDuring the past twenty-five years, biotechnology has revolutionized agricultural research. The enormous potential, together with a landmark decision by the US Supreme Court to allow the patenting of genetically-engineered organisms has encouraged private sector companies to invest in agricultural biotechnology research programmes. This has contributed to a rapid growth in interest in intellectual property rights as applied to this subject.The first edition of this book was published in 1998. Now fully revised and updated it presents definitive information on intellectual property law in a simplified form (with a minimum of legal jargon). New chapters have been added which cover plant variety protection and farmers rights, and additional case studies.Table of ContentsPart I: Issues and Principles 1: Introduction to intellectual properties, F H Erbisch and B L Smiler, Hagan & Schaeff, Ohio, USA 2: Acquiring protection for improved germplasm and inbred lines, J H Barton, Stanford University, CA, USA 3: Transferring intellectual properties, F H Erbisch and A J Fischer, US Patent and Trademark Office, Washington, DC, USA 4: Capacity building in intellectual property management in agricultural biotechnology, K M Maredia and F H Erbisch 5: Plant variety protection in the USA, J M Strachan, USDA, Maryland, USA 6: Farmers' rights over plant genetic resources in the South: Challenges and Opportunities, K Patel, University of Guelph, Canada 7: Economic aspects of Intellectual Property Rights in Agricultural Biotechnology, M K Maredia, J F Oehmke, Michigan State University, USA and D Byerlee, The World Bank, Washington, DC, USA Part II: Country and Regional Case Studies 8: Egypt, A El-Azab, Academy of Scientific Research and Technology, Giza, Egypt 9: South Africa, R A Wolson, University of Cape Town, South Africa 10: Australia, M Blakeney, University of London, London, UK 11: China, T Loke-Khoon, Baker & McKenzie, Hong Kong 12: Issues on Intellectual Property Rights associated with agrobiotechnology in Japan, K N Watanabe, University of Tsukuba, Japan and A Komamine, Institute of Evolutionary Biology, Tokyo, Japan 13: India, P Ganguli, Indian Institute of Technology, Mumbai, India 14: Intellectual Property Rights in the Russian Federation, T A Young, Texas A&M University System, USA and D Shulgin, The Ural State Technical University, Russia 15: Andean Pact countries of Latin America, W R Jaffé, Agroecológica Platom C.A., Venezuela and E Arteaga-Marcano, Ministerio de Ciencia y Tecnología, Venezuela 16: Costa Rica, S Salazar, Costa Rica 17: European Union, R S Crespi, Consultant, UK 18: Indonesia, T Subagyo, UNEP-GEF, Indonesia 19: Exercising Intellectual Property Rights management in Brazil: research, technology transfer and agribusiness after TRIPS, M J Amstalden Sampio, Embrapa, Brazil, M Maia de Rocha, INPI, Brazil and E A B Brito da Cunha, SPRI, Brazil

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Book Synopsis

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Book SynopsisA comprehensive introduction to using modeling and simulation programs in drug discovery and development Biopharmaceutical modeling has become integral to the design and development of new drugs. Influencing key aspects of the development process, including drug substance design, formulation design, and toxicological exposure assessment, biopharmaceutical modeling is now seen as the linchpin to a drug''s future success. And while there are a number of commercially available software programs for drug modeling, there has not been a single resource guiding pharmaceutical professionals to the actual tools and practices needed to design and test safe drugs. A guide to the basics of modeling and simulation programs, Biopharmaceutics Modeling and Simulations offers pharmaceutical scientists the keys to understanding how they work and are applied in creating drugs with desired medicinal properties. Beginning with a focus on the oral absorption of drugs, the bookTrade Review“This book serves as an invaluable source of information for the formulation scientist, the preclinical, translational or clinical pharmacokineticist, as well as the modeling and simulation scientist.” (ChemMedChem, 1 April 2013)Table of ContentsPREFACE xxv LIST OF ABBREVIATIONS xxix 1 INTRODUCTION 1 1.1 An Illustrative Description of Oral Drug Absorption: The Whole Story 1 1.2 Three Regimes of Oral Drug Absorption 2 1.3 Physiology of the Stomach, Small Intestine, and Colon 5 1.4 Drug and API Form 6 1.4.1 Undissociable and Free Acid Drugs 6 1.4.2 Free Base Drugs 6 1.4.3 Salt Form Cases 6 1.5 The Concept of Mechanistic Modeling 7 References 8 2 THEORETICAL FRAMEWORK I: SOLUBILITY 10 2.1 Definition of Concentration 10 2.1.1 Total Concentration 11 2.1.2 Dissolved Drug Concentration 11 2.1.3 Effective Concentration 12 2.2 Acid–Base and Bile-Micelle-Binding Equilibriums 13 2.2.1 Monoprotic Acid and Base 14 2.2.2 Multivalent Cases 16 2.2.3 Bile-Micelle Partitioning 17 2.2.4 Modified Henderson–Hasselbalch Equation 18 2.2.5 Kbm from Log Poct 19 2.3 Equilibrium Solubility 19 2.3.1 Definition of Equilibrium Solubility 19 2.3.2 pH–Solubility Profile (pH-Controlled Region) 21 2.3.3 Solubility in a Biorelevant Media with Bile Micelles (pH-Controlled Region) 23 2.3.4 Estimation of Unbound Fraction from the Solubilities with and without Bile Micelles 25 2.3.5 Common Ionic Effect 25 2.3.6 Important Conclusion from the pH–Equilibrium Solubility Profile Theory 27 2.3.7 Yalkowsky’s General Solubility Equation 27 2.3.8 Solubility Increase by Converting to an Amorphous Form 29 2.3.9 Solubility Increase by Particle Size Reduction (Nanoparticles) 30 2.3.10 Cocrystal 31 References 31 3 THEORETICAL FRAMEWORK II: DISSOLUTION 33 3.1 Diffusion Coefficient 34 3.1.1 Monomer 34 3.1.2 Bile Micelles 35 3.1.3 Effective Diffusion Coefficient 36 3.2 Dissolution and Particle Growth 36 3.2.1 Mass Transfer Equations: Pharmaceutical Science Versus Fluid Dynamics 37 3.2.2 Dissolution Equation with a Lump Sum Dissolution Rate Coefficient (kdiss) 38 3.2.3 Particle Size and Surface Area 39 3.2.3.1 Monodispersed Particles 39 3.2.3.2 Polydispersed Particles 41 3.2.4 Diffusion Layer Thickness I: Fluid Dynamic Model 41 3.2.4.1 Reynolds and Sherwood Numbers 42 3.2.4.2 Disk (Levich Equation) 45 3.2.4.3 Tube (Graetz Problem) 45 3.2.4.4 Particle Fixed to Space (Ranz–Marshall Equation) 46 3.2.4.5 Floating Particle 47 3.2.4.6 Nonspherical Particle 49 3.2.4.7 Minimum Agitation Speed for Complete Suspension 51 3.2.4.8 Other Factors 52 3.2.5 Diffusion Layer Thickness II: Empirical Models for Particles 52 3.2.6 Solid Surface pH and Solubility 53 3.3 Nucleation 56 3.3.1 General Description of Nucleation and Precipitation Process 56 3.3.2 Classical Nucleation Theory 57 3.3.2.1 Concept of Classical Nucleation Theory 58 3.3.2.2 Mathematical Expressions 58 3.3.3 Application of a Nucleation Theory for Biopharmaceutical Modeling 61 References 61 4 THEORETICAL FRAMEWORK III: BIOLOGICAL MEMBRANE PERMEATION 64 4.1 Overall Scheme 64 4.2 General Permeation Equation 66 4.3 Permeation Rate Constant, Permeation Clearance, and Permeability 66 4.4 Intestinal Tube Flatness and Permeation Parameters 68 4.5 Effective Concentration for Intestinal Membrane Permeability 70 4.5.1 Effective Concentration for Unstirred Water Layer Permeation 70 4.5.2 Effective Concentration for Epithelial Membrane Permeation: the Free Fraction Theory 70 4.6 Surface Area Expansion by Plicate and Villi 71 4.7 Unstirred Water Layer Permeability 73 4.7.1 Basic Case 73 4.7.2 Particles in the UWL (Particle Drifting Effect) 74 4.8 Epithelial Membrane Permeability (Passive Processes) 76 4.8.1 Passive Transcellular Membrane Permeability: pH Partition Theory 76 4.8.2 Intrinsic Passive Transcellular Permeability 77 4.8.2.1 Solubility–Diffusion Model 77 4.8.2.2 Flip-Flop Model 79 4.8.2.3 Relationship between Ptrans,0 and log Poct 80 4.8.3 Paracellular Pathway 83 4.8.4 Relationship between log Doct, MW, and Fa% 84 4.9 Enteric Cell Model 84 4.9.1 Definition of Papp 86 4.9.2 Enzymatic Reaction: Michaelis–Menten Equation 87 4.9.3 First-Order Case 1: No Transporter and Metabolic Enzymes 88 4.9.4 First-Order Case 2: Efflux Transporter in Apical Membrane 91 4.9.5 Apical Efflux Transporter with Km and Vmax 95 4.9.6 Apical Influx Transporter with Km and Vmax 100 4.9.7 UWL and Transporter 100 4.9.7.1 No Transporter 101 4.9.7.2 Influx Transporter and UWL 101 4.9.7.3 Efflux Transporter 101 4.10 Gut Wall Metabolism 103 4.10.1 The Qgut Model 104 4.10.2 Simple Fg Models 104 4.10.3 Theoretical Consideration on Fg 104 4.10.3.1 Derivation of the Fg Models 105 4.10.3.2 Derivation of the Anatomical Fg Model 107 4.10.4 Interplay between CYP3A4 and P-gp 108 4.11 Hepatic Metabolism and Excretion 114 References 115 5 THEORETICAL FRAMEWORK IV: GASTROINTESTINAL TRANSIT MODELS AND INTEGRATION 122 5.1 GI Transit Models 122 5.1.1 One-Compartment Model/Plug Flow Model 122 5.1.2 Plug Flow Model 123 5.1.3 Three-Compartment Model 124 5.1.4 S1I7CX (X = 1–4) Compartment Models 124 5.1.5 Convection–Dispersion Model 126 5.1.6 Tapered Tube Model 126 5.2 Time-Dependent Changes of Physiological Parameters 127 5.2.1 Gastric Emptying 127 5.2.2 Water Mass Balance 128 5.2.3 Bile Concentration 129 5.3 Integration 1: Analytical Solutions 129 5.3.1 Dissolution Under Sink Condition 130 5.3.1.1 Monodispersed Particles 130 5.3.1.2 Polydispersed Particles 131 5.3.2 Fraction of a Dose Absorbed (Fa%) 132 5.3.3 Approximate Fa% Analytical Solutions 1: Case-by-Case Solution 133 5.3.3.1 Permeability-Limited Case 134 5.3.3.2 Solubility-Permeability-Limited Case 135 5.3.3.3 Dissolution-Rate-Limited Case 137 5.3.4 Approximate Fa% Analytical Solutions 2: Semi-General Equations 137 5.3.4.1 Sequential First-Order Kinetics of Dissolution and Permeation 137 5.3.4.2 Minimum Fa% Model 138 5.3.5 Approximate Fa% Analytical Solutions 3: FaSS Equation 139 5.3.5.1 Application Range 140 5.3.5.2 Derivation of Fa Number Equation 140 5.3.5.3 Refinement of the FaSS Equation 141 5.3.5.4 Advantage of FaSS Equation 146 5.3.5.5 Limitation of FaSS Equation 146 5.3.6 Interpretations of Fa Equations 146 5.3.7 Approximate Analytical Solution for Oral PK Model 147 5.4 Integration 2: Numerical Integration 147 5.4.1 Virtual Particle Bins 149 5.4.2 The Mass Balance of Dissolved Drug Amount in Each GI Position 149 5.4.3 Controlled Release of Virtual Particle Bin 150 5.5 In Vivo FA From PK Data 150 5.5.1 Absolute Bioavailability and Fa 151 5.5.2 Relative Bioavailability Between Solid and Solution Formulations 151 5.5.3 Relative Bioavailability Between Low and High Dose 152 5.5.4 Convolution and Deconvolution 152 5.5.4.1 Convolution 153 5.5.4.2 Deconvolution 154 5.6 Other Administration Routes 156 5.6.1 Skin 156 References 157 6 PHYSIOLOGY OF GASTROINTESTINAL TRACT AND OTHER ADMINISTRATION SITES IN HUMANS AND ANIMALS 160 6.1 Morphology of Gastrointestinal Tract 160 6.1.1 Length and Tube Radius 160 6.1.2 Surface Area 161 6.1.2.1 Small Intestine 161 6.1.2.2 Colon 163 6.1.3 Degree of Flatness 164 6.1.3.1 Small Intestine 164 6.1.3.2 Colon 164 6.1.4 Epithelial Cells 165 6.1.4.1 Apical and Basolateral Lipid Bilayer Membranes 165 6.1.4.2 Tight Junction 168 6.1.4.3 Mucous Layer 168 6.2 Movement of the Gastrointestinal Tract 170 6.2.1 Transit Time 170 6.2.1.1 Gastric Emptying Time (GET) 170 6.2.1.2 Small Intestinal Transit Time 170 6.2.1.3 Colon Transit Time 171 6.2.2 Migrating Motor Complex 171 6.2.3 Agitation 173 6.2.3.1 Mixing Pattern 173 6.2.3.2 Agitation Strength 175 6.2.3.3 Unstirred Water Layer on the Intestinal Wall 176 6.3 Fluid Character of the Gastrointestinal Tract 178 6.3.1 Volume 178 6.3.1.1 Stomach 178 6.3.1.2 Small Intestine 178 6.3.1.3 Colon 179 6.3.2 Bulk Fluid pH and Buffer Concentration 179 6.3.2.1 Stomach 181 6.3.2.2 Small Intestine 181 6.3.2.3 Colon 181 6.3.3 Microclimate pH 181 6.3.3.1 Small Intestine 181 6.3.3.2 Colon 182 6.3.4 Bile Micelles 182 6.3.4.1 Stomach 183 6.3.4.2 Small Intestine 183 6.3.4.3 Colon 185 6.3.5 Enzymes and Bacteria 185 6.3.6 Viscosity, Osmolality, and Surface Tension 185 6.4 Transporters and Drug-Metabolizing Enzymes in the Intestine 186 6.4.1 Absorptive Drug Transporters 186 6.4.1.1 PEP-T1 186 6.4.1.2 OATP 186 6.4.2 Efflux Drug Transporters 186 6.4.2.1 P-gp 186 6.4.3 Drug-Metabolizing Enzymes 186 6.4.3.1 CYP3A4 186 6.4.3.2 Glucuronyl Transferase and Sulfotransferase 188 6.5 Intestinal and Liver Blood Flow 188 6.5.1 Absorption Sites Connected to Portal Vein 188 6.5.2 Villous Blood Flow (Qvilli) 188 6.5.3 Hepatic Blood Flow (Qh) 188 6.6 Physiology Related to Enterohepatic Recirculation 189 6.6.1 Bile Secretion 189 6.6.2 Mass Transfer into/from the Hepatocyte 190 6.6.2.1 Sinusoidal Membrane (Blood to Hepatocyte) 190 6.6.2.2 Canalicular Membrane (Hepatocyte to Bile Duct) 191 6.7 Nasal 191 6.8 Pulmonary 193 6.8.1 Fluid in the Lung 193 6.8.2 Mucociliary Clearance 193 6.8.3 Absorption into the Circulation 194 6.9 Skin 194 References 196 7 DRUG PARAMETERS 206 7.1 Dissociation Constant (pKa) 206 7.1.1 pH Titration 207 7.1.2 pH–UV Shift 207 7.1.3 Capillary Electrophoresis 207 7.1.4 pH–Solubility Profile 208 7.1.5 Calculation from Chemical Structure 208 7.1.6 Recommendation 208 7.2 Octanol–Water Partition Coefficient 208 7.2.1 Shake Flask Method 209 7.2.2 HPLC Method 210 7.2.3 Two-Phase Titration Method 210 7.2.4 PAMPA-Based Method 210 7.2.5 In Silico Method 210 7.2.6 Recommendation 210 7.3 Bile Micelle Partition Coefficient (Kbm) 211 7.3.1 Calculation from Solubility in Biorelevant Media 211 7.3.2 Spectroscopic Method 212 7.3.3 Recommendations 212 7.4 Particle Size and Shape 212 7.4.1 Microscope 213 7.4.2 Laser Diffraction 215 7.4.3 Dynamic Laser Scattering (DLS) 215 7.4.4 Recommendations 215 7.5 Solid Form 215 7.5.1 Nomenclature 215 7.5.1.1 Crystalline and Amorphous 215 7.5.1.2 Salts, Cocrystals, and Solvates 216 7.5.1.3 Hydrate 217 7.5.2 Crystal Polymorph 217 7.5.2.1 True Polymorph and Pseudopolymorph 217 7.5.2.2 Kinetic Resolution versus Stable Form 217 7.5.2.3 Dissolution Profile Advantages of Less Stable Forms 218 7.5.2.4 Enantiotropy 218 7.5.3 Solid Form Characterization 219 7.5.3.1 Polarized Light Microscopy (PLM) 219 7.5.3.2 Powder X-Ray Diffraction (PXRD) 219 7.5.3.3 Differential Scanning Calorimeter (DSC) and Thermal Gravity (TG) 220 7.5.3.4 High Throughput Solid Form Screening 221 7.5.4 Wettability and Surface Free Energy 222 7.5.5 True Density 222 7.6 Solubility 223 7.6.1 Terminology 223 7.6.1.1 Definition of Solubility 223 7.6.1.2 Intrinsic Solubility 223 7.6.1.3 Solubility in Media 223 7.6.1.4 Initial pH and Final pH 224 7.6.1.5 Supersaturable API 224 7.6.1.6 Critical Supersaturation Concentration and Induction Time 224 7.6.1.7 Dissolution Rate and Dissolution Profile 225 7.6.2 Media 225 7.6.2.1 Artificial Stomach Fluids 225 7.6.2.2 Artificial Small Intestinal Fluids 225 7.6.3 Solubility Measurement 225 7.6.3.1 Standard Shake Flask Method 225 7.6.3.2 Measurement from DMSO Sample Stock Solution 227 7.6.3.3 Solid Surface Solubility 228 7.6.3.4 Method for Nanoparticles 228 7.6.4 Recommendation 228 7.6.4.1 Early Drug Discovery Stage (HTS to Early Lead Optimization) 229 7.6.4.2 Late Lead Optimization Stage 229 7.6.4.3 Transition Stage between Discovery and Development 229 7.7 Dissolution Rate/Release Rate 230 7.7.1 Intrinsic Dissolution Rate 230 7.7.2 Paddle Method 230 7.7.2.1 Apparatus 231 7.7.2.2 Fluid Condition 231 7.7.2.3 Agitation 232 7.7.3 Flow-Through Method 233 7.7.4 Multicompartment Dissolution System 233 7.7.5 Dissolution Permeation System 233 7.7.6 Recommendation 235 7.8 Precipitation 235 7.8.1 Kinetic pH Titration Method 235 7.8.2 Serial Dilution Method 236 7.8.3 Two-Chamber Transfer System 236 7.8.4 Nonsink Dissolution Test 236 7.9 Epithelial Membrane Permeability 240 7.9.1 Back-Estimation from Fa% 241 7.9.2 In Situ Single-Pass Intestinal Perfusion 241 7.9.3 Cultured Cell Lines (Caco-2, MDCK, etc.) 243 7.9.4 PAMPA 244 7.9.5 Estimation of Ptrans,0 from Experimental Apparent Membrane Permeability 246 7.9.6 Estimation of Ptrans,0 from Experimental log Poct 247 7.9.7 Mechanistic Investigation 247 7.9.8 Limitation of Membrane Permeation Assays 247 7.9.8.1 UWL Adjacent to the Membrane 249 7.9.8.2 Membrane Binding 250 7.9.8.3 Low Solubility 250 7.9.8.4 Differences in Paracellular Pathway 251 7.9.8.5 Laboratory to Laboratory Variation 251 7.9.8.6 Experimental Artifacts in Carrier-Mediated Membrane Transport 251 7.9.9 Recommendation for Pep and Peff Estimation 251 7.9.9.1 Hydrophilic Drugs 251 7.9.9.2 Lipophilic Drugs 252 7.9.9.3 Drugs with Medium Lipophilicity 252 7.10 In Vivo Experiments 252 7.10.1 P.O 252 7.10.2 I.V 253 7.10.3 Animal Species 253 7.10.4 Analysis 254 References 254 8 VALIDATION OF MECHANISTIC MODELS 266 8.1 Concerns Related to Model Validation Using In Vivo Data 267 8.2 Strategy for Transparent and Robust Validation of Biopharmaceutical Modeling 267 8.3 Prediction Steps 268 8.4 Validation for Permeability-Limited Cases 279 8.4.1 Correlation Between Fa% and Peff Data for Humans (Epithelial Membrane Permeability-Limited Cases PL-E) 279 8.4.2 Correlation Between In Vitro Permeability and Peff and/or Fa% (PL-E Cases) 283 8.4.2.1 Caco-2 283 8.4.2.2 PAMPA 285 8.4.2.3 Experimental log Poct and pKa 285 8.4.3 Peff for UWL Limited Cases 287 8.4.4 Chemical Structure to Peff, Fa%, and Caco-2 Permeability 288 8.5 Validation for Dissolution-Rate and Solubility-Permeability-Limited Cases (without the Stomach Effect) 290 8.5.1 Fa% Prediction Using In Vitro Dissolution Data 290 8.5.2 Fa% Prediction Using In Vitro Solubility and Permeability Data 292 8.6 Validation for Dissolution-Rate and Solubility-Permeability-Limited Cases (with the Stomach Effect) 305 8.6.1 Difference Between Free Base and Salts 305 8.6.2 Simulation Model for Free Base 305 8.6.3 Simulation Results 307 8.7 Salts 307 8.8 Reliability of Biopharmaceutical Modeling 311 References 311 9 BIOEQUIVALENCE AND BIOPHARMACEUTICAL CLASSIFICATION SYSTEM 322 9.1 Bioequivalence 322 9.2 The History of BCS 324 9.3 Regulatory Biowaiver Scheme and BCS 326 9.3.1 Elucidation of BCS Criteria in Regulatory Biowaiver Scheme 327 9.3.1.1 Congruent Condition of Bioequivalence 328 9.3.1.2 Equivalence of Dose Number (Do) 329 9.3.1.3 Equivalence of Permeation Number (Pn) 329 9.3.1.4 Equivalence of Dissolution Number (Dn) 329 9.3.2 Possible Extension of the Biowaiver Scheme 331 9.3.2.1 Dose Number Criteria 331 9.3.2.2 Permeability Criteria 332 9.3.3 Another Interpretation of the Theory 332 9.3.3.1 Another Assumption about Dissolution Test 332 9.3.3.2 Assessment of Suitability of Dissolution Test Based on Rate-Limiting Process 333 9.3.4 Validation of Biowaiver Scheme by Clinical BE Data 333 9.3.5 Summary for Regulatory BCS Biowaiver Scheme 334 9.4 Exploratory BCS 335 9.5 In Vitro–In Vivo Correlation 335 9.5.1 Levels of IVIVC 335 9.5.2 Judgment of Similarity Between Two Formulations (f2 Function) 336 9.5.3 Modeling the Relationship Between f2 and Bioequivalence 336 9.5.4 Point-to-Point IVIVC 337 References 338 10 DOSE AND PARTICLE SIZE DEPENDENCY 340 10.1 Definitions and Causes of Dose Nonproportionality 340 10.2 Estimation of the Dose and Particle Size Effects 341 10.2.1 Permeability-Limited Cases (PL) 341 10.2.2 Dissolution-Rate-Limited (DRL) Cases 341 10.2.3 Solubility–Epithelial Membrane Permeability Limited (SL-E) Cases 342 10.2.4 Solubility-UWL-Permeability-Limited Cases 344 10.3 Effect of Transporters 344 10.4 Analysis of In Vivo Data 345 References 346 11 ENABLING FORMULATIONS 347 11.1 Salts and Cocrystals: Supersaturating API 347 11.1.1 Scenarios of Oral Absorption of Salt 349 11.1.2 Examples 350 11.1.2.1 Example 1: Salt of Basic Drugs 350 11.1.2.2 Example 2: Salt of Acid Drugs 352 11.1.2.3 Example 3: Other Supersaturable API Forms 353 11.1.3 Suitable Drug for Salts 353 11.1.3.1 pKa Range 353 11.1.3.2 Supersaturability of Drugs 355 11.1.4 Biopharmaceutical Modeling of Supersaturable API Forms 357 11.2 Nanomilled API Particles 358 11.3 Self-Emulsifying Drug Delivery Systems (Micelle/Emulsion Solubilization) 360 11.4 Solid Dispersion 363 11.5 Supersaturable Formulations 364 11.6 Prodrugs to Increase Solubility 365 11.7 Prodrugs to Increase Permeability 365 11.7.1 Increasing Passive Permeation 366 11.7.2 Hitchhiking the Carrier 366 11.8 Controlled Release 366 11.8.1 Fundamentals of CR Modeling 367 11.8.2 Simple Convolution Method 368 11.8.3 Advanced Controlled-Release Modeling 368 11.8.4 Controlled-Release Function 368 11.8.5 Sustained Release 368 11.8.5.1 Objectives to Develop a Sustained-Release Formulation 368 11.8.5.2 Suitable Drug Character for Sustained Release 369 11.8.5.3 Gastroretentive Formulation 369 11.8.6 Triggered Release 369 11.8.6.1 Time-Triggered Release 369 11.8.6.2 pH-Triggered Release 369 11.8.6.3 Position-Triggered Release 371 11.9 Communication with Therapeutic Project Team 371 References 373 12 FOOD EFFECT 379 12.1 Physiological Changes Caused by Food 379 12.1.1 Food Component 380 12.1.2 Fruit Juice Components 380 12.1.3 Alcohol 382 12.2 Types of Food Effects and Relevant Parameters in Biopharmaceutical Modeling 382 12.2.1 Delay in Tmax and Decrease in Cmax 382 12.2.2 Positive Food Effect 383 12.2.2.1 Bile Micelle Solubilization 383 12.2.2.2 Increase in Hepatic Blood Flow 388 12.2.2.3 Increase in Intestinal Blood Flow 388 12.2.2.4 Inhibition of Efflux Transporter and Gut Wall Metabolism 389 12.2.2.5 Desaturation of Influx Transporter 391 12.2.3 Negative Food Effect 391 12.2.3.1 Bile Micelle Binding/Food Component Binding 391 12.2.3.2 Inhibition of Uptake Transporter 392 12.2.3.3 Desaturation of First-Pass Metabolism and Efflux Transport 394 12.2.3.4 Viscosity 398 12.2.3.5 pH Change in the Stomach 398 12.2.3.6 pH Change in the Small Intestine 398 12.3 Effect of Food Type 398 12.4 Biopharmaceutical Modeling of Food Effect 401 12.4.1 Simple Flowchart and Semiquantitative Prediction 401 12.4.2 More Complicated Cases 402 References 403 13 BIOPHARMACEUTICAL MODELING FOR MISCELLANEOUS CASES 412 13.1 Stomach pH Effect on Solubility and Dissolution Rate 412 13.1.1 Free Bases 413 13.1.2 Free Acids and Undissociable Drugs 413 13.1.3 Salts 413 13.1.4 Chemical and Enzymatic Degradation in the Stomach and Intestine 413 13.2 Intestinal First-Pass Metabolism 414 13.3 Transit Time Effect 415 13.3.1 Gastric Emptying Time 415 13.3.2 Intestinal Transit Time 415 13.4 Other Chemical and Physical Drug–Drug Interactions 415 13.4.1 Metal Ions 415 13.4.2 Cationic Resins 416 13.5 Species Difference 417 13.5.1 Permeability 417 13.5.2 Solubility/Dissolution 418 13.5.3 First-Pass Metabolism 419 13.6 Validation of GI Site-Specific Absorption Models 421 13.6.1 Stomach 421 13.6.2 Colon 422 13.6.3 Regional Difference in the Small Intestine: Fact or Myth? 422 13.6.3.1 Transporter 422 13.6.3.2 Bile-Micelle Binding and Bimodal Peak Phenomena 422 References 426 14 INTESTINAL TRANSPORTERS 430 14.1 Apical Influx Transporters 431 14.1.1 Case Example 1: Antibiotics 431 14.1.2 Case Example 2: Valacyclovir 433 14.1.3 Case Example: Gabapentin 434 14.2 Efflux Transporters 435 14.2.1 Effect of P-gp 435 14.2.2 Drug–Drug Interaction (DDI) via P-gp 437 14.3 Dual Substrates 438 14.3.1 Talinolol 438 14.3.2 Fexofenadine 441 14.4 Difficulties in Simulating Carrier-Mediated Transport 442 14.4.1 Absorptive Transporters 442 14.4.1.1 Discrepancies Between In Vitro and In Vivo Km Values 442 14.4.1.2 Contribution of Other Pathways 443 14.4.2 Efflux Transporters 443 14.5 Summary 445 References 446 15 STRATEGY IN DRUG DISCOVERY AND DEVELOPMENT 452 15.1 Library Design 452 15.2 Lead Optimization 453 15.3 Compound Selection 455 15.4 API Form Selection 455 15.5 Formulation Selection 455 15.6 Strategy to Predict Human Fa% 456 References 457 16 EPISTEMOLOGY OF BIOPHARMACEUTICAL MODELING AND GOOD SIMULATION PRACTICE 459 16.1 Can Simulation be so Perfect? 459 16.2 Parameter Fitting 460 16.3 Good Simulation Practice 461 16.3.1 Completeness 461 16.3.2 Comprehensiveness 462 References 463 APPENDIX A GENERAL TERMINOLOGY 464 A.1 Biopharmaceutic 464 A.2 Bioavailability (BA% or F) 464 A.3 Drug Disposition 465 A.4 Fraction of a Dose Absorbed (Fa) 465 A.5 Modeling/Simulation/In Silico 465 A.6 Active Pharmaceutical Ingredient (API) 465 A.7 Drug Product 465 A.8 Lipophilicity 465 A.9 Acid and Base 466 A.10 Solubility 466 A.11 Molecular Weight (MW) 466 A.12 Permeability of a Drug 466 APPENDIX B FLUID DYNAMICS 468 B.1 Navier–Stokes Equation and Reynolds Number 468 B.2 Boundary Layer Approximation 469 B.3 The Boundary Layer and Mass Transfer 470 B.4 The Thickness of the Boundary Layer 470 B.4.1 99% of Main Flow Speed 471 B.4.2 Displacement Thickness 471 B.4.3 Momentum Thickness 471 B.5 Sherwood Number 471 B.6 Turbulence 473 B.7 Formation of Eddies 474 B.8 Computational Fluid Dynamics 474 References 476 INDEX 477

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