Biology, life sciences Books

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

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Book SynopsisMountains, Climate and Biodiversity: A comprehensive and up-to-date synthesis for students and researchers Mountains are topographically complex formations that play a fundamental role in regional and continental-scale climates. They are also cradles to all major river systems and home to unique, and often highly biodiverse and threatened, ecosystems. But how do all these processes tie together to form the patterns of diversity we see today? Written by leading researchers in the fields of geology, biology, climate, and geography, this book explores the relationship between mountain building and climate change, and how these processes shape biodiversity through time and space. In the first two sections, you will learn about the processes, theory, and methods connecting mountain building and biodiversity In the third section, you will read compelling examples from around the world exploring the links between mountains, climate and biodiversity Throughout the 31 peer-reviewed chapters,Table of ContentsList of Contributors xi Acknowledgments xvii Foreword by Peter Raven xix Biography of Editors xxiii Glossary xxv About the Companion Website xxxv 1 Mountains, Climate and Biodiversity: An Introduction 1 Carina Hoorn, Allison Perrigo and Alexandre Antonelli Part I Mountains, Relief and Climate 15 2 Simple Concepts Underlying the Structure, Support and Growth of Mountain Ranges, High Plateaus and Other High Terrain 17 Peter Molnar 3 An Overview of Dynamic Topography: The Influence of Mantle Circulation on Surface Topography and Landscape 37 Caroline M. Eakin and Carolina Lithgow‐Bertelloni 4 Mountain Relief, Climate and Surface Processes 51 Peter van der Beek 5 Dating Mountain Building: Exhumation and Surface Uplift 69 Matthias Bernet, Verónica Torres Acosta and Mauricio A. Bermúdez 6 Stable Isotope Paleoaltimetry: Paleotopography as a Key Element in the Evolution of Landscapes and Life 81 Andreas Mulch and C. Page Chamberlain 7 Phytopaleoaltimetry: Using Plant Fossils to Measure Past Land Surface Elevation 95 Robert A. Spicer 8 Cenozoic Mountain Building and Climate Evolution 111 Phoebe G. Aron and Christopher J. Poulsen 9 Paleoclimate 123 Hemmo A. Abels and Martin Ziegler Part II When Biology Meets Mountain Building 135 10 Mountain Geodiversity: Characteristics, Values and Climate Change 137 John E. Gordon 11 Geodiversity Mapping in Alpine Areas 155 Arie C. Seijmonsbergen, Matheus G.G. De Jong, Babs Hagendoorn, Johannes G.B. Oostermeijer and Kenneth F. Rijsdijk 12 Historical Connectivity and Mountain Biodiversity 171 Suzette G.A. Flantua and Henry Hooghiemstra 13 The Environmental Heterogeneity of Mountains at a Fine Scale in a Changing World 187 Andrés J. Cortés and Julia A. Wheeler 14 Mountains, Climate and Mammals 201 Catherine Badgley, Tara M. Smiley and Rachel Cable 15 Inferring Macroevolutionary Dynamics in Mountain Systems from Fossils 217 Daniele Silvestro and Jan Schnitzler 16 The Interplay between Geological History and Ecology in Mountains 231 Catherine H. Graham, Mauricio Parra, Andrés Mora and Camilo Higuera 17 Mountains and the Diversity of Birds 245 Jon Fjeldså 18 Teasing Apart Mountain Uplift, Climate Change and Biotic Drivers of Species Diversification 257 Fabien L. Condamine, Alexandre Antonelli, Laura P. Lagomarsino, Carina Hoorn and Lee Hsiang Liow 19 Upland and Lowland Fishes: A Test of the River Capture Hypothesis 273 James S. Albert, Jack M. Craig, Victor A. Tagliacollo and Paulo Petry 20 Different Ways of Defining Diversity, and How to Apply Them in Montane Systems 295 Hanna Tuomisto 21 A Modeling Framework to Estimate and Project Species Distributions in Space and Time 309 Niels Raes and Jesús Aguirre‐Gutiérrez Part III Mountains and Biota of the World 321 22 Evolution of the Isthmus of Panama: Biological, Paleoceanographic and Paleoclimatological Implications 323 Carlos Jaramillo 23 The Tepuis of the Guiana Highlands 339 Otto Huber, Ghillean T. Prance, Salomon B. Kroonenberg and Alexandre Antonelli 24 Ice‐Bound Antarctica: Biotic Consequences of the Shift from a Temperate to a Polar Climate 355 Peter Convey, Vanessa C. Bowman, Steven L. Chown, Jane E. Francis, Ceridwen Fraser, John L. Smellie, Bryan Storey and Aleks Terauds 25 The Biogeography, Origin and Characteristics of the Vascular Plant Flora and Vegetation of the New Zealand Mountains 375 Matt S. McGlone, Peter Heenan, Timothy Millar and Ellen Cieraad 26 The East African Rift System: Tectonics, Climate and Biodiversity 391 Uwe Ring, Christian Albrecht and Friedemann Schrenk 27 The Alps: A Geological, Climatic and Human Perspective on Vegetation History and Modern Plant Diversity 413 Séverine Fauquette, Jean‐Pierre Suc, Frédéric Médail, Serge D. Muller, Gonzalo Jiménez‐Moreno, Adele Bertini, Edoardo Martinetto, Speranta‐Maria Popescu, Zhuo Zheng and Jacques‐Louis de Beaulieu 28 Cenozoic Evolution of Geobiodiversity in the Tibeto‐Himalayan Region 429 Volker Mosbrugger, Adrien Favre, Alexandra N. Muellner‐Riehl, Martin Päckert and Andreas Mulch 29 Neogene Paleoenvironmental Changes and their Role in Plant Diversity in Yunnan, South‐Western China 449 Zhe‐Kun Zhou, Tao Su and Yong‐Jiang Huang 30 Influence of Mountain Formation on Floral Diversification in Japan, Based on Macrofossil Evidence 459 Arata Momohara 31 The Complex History of Mountain Building and the Establishment of Mountain Biota in Southeast Asia and Eastern Indonesia 475 Robert J. Morley Index 495

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Book SynopsisThis book addresses the difficulties experienced by wet lab researchers with the statistical analysis of molecular biology related data. The authors explain how to use R and Bioconductor for the analysis of experimental data in the field of molecular biology.Table of ContentsForeword, xiii Preface, xv Acknowledgements, xix About the Companion Website, xxi 1 Introduction to R statistical environment, 1 Why R?, 1 Installing R, 2 Interacting with R, 2 Graphical interfaces and integrated development environment (IDE) integration, 3 Scripting and sourcing, 3 The R history and the R environment file, 4 Packages and package repositories, 4 Comprehensive R Archive Network, 5 Bioconductor, 6 Working with data, 7 Basic operations in R, 8 Some basics of graphics in R, 10 Getting help in R, 12 Files for practicing, 13 Study exercises and questions, 14 References, 14 Webliography, 15 2 Simple sequence analysis, 17 Sequence files, 17 FASTA sequence format, 18 GenBank flat file format, 19 Reading sequence files into R, 20 Obtaining sequences from remote databases, 21 Seqinr package, 21 Ape package, 22 Descriptive statistics of nucleotide sequences, 24 Descriptive statistics of proteins, 28 Aligned sequences, 31 Visualization of genes and transcripts in a professional way, 34 Files for practicing, 37 Study exercises and questions, 38 References, 38 Webliography, 39 Packages, 40 3 Annotating gene groups, 41 Enrichment analysis: an overview, 41 Overview of two different methods, 41 Enrichment analysis results, 42 Common aspects of the two different approaches, 43 Overrepresentation analysis, 46 Hypergeometric test using GOstats, 47 ORA analysis using topGO, 48 Enrichment analysis of microarray sets with topGO, 51 Gene set enrichment analysis, 52 GSEA with R, 56 Files for practicing, 61 Study exercises and questions, 61 References, 62 Webliography, 62 Packages, 63 4 Next-generation sequencing: introduction and genomic applications, 65 High-throughput sequencing background, 65 Experimental background, 66 Single-end and paired-end sequencing reads, 67 Assemble reads, 69 How many reads? Depth of coverage, 71 Storing data in files, 72 FASTQ, 72 SAM and BAM files, 76 Variant call format files, 77 General data analysis workflow, 77 Data processing considerations, 78 Quality checking and screening read sequences, 80 Quality checking for one file, 82 Quality inspection for multiple files in a project, 82 Quality filtering of FASTQ files, 83 Handling alignment files and genomic variants, 84 Alignment and variation visualization, 88 Simple handling of VCF files, 89 Genomic applications: low- and medium-depth sequencing, 91 Aneuploidity sequencing and copy number variation identification, 92 SNP identification and validation, 92 Exome sequencing, 93 Genomic region resequencing, 93 Full genome and metagenome sequencing, 94 Files for practicing, 94 Study exercises and questions, 94 References, 95 Webliography, 97 Packages, 97 5 Quantitative transcriptomics: qRT-PCR, 99 Transcriptome, 99 Polymerase chain reaction, 100 Standards for qPCR, 102 R packages, 104 Understanding delta Ct, 104 Calculation of delta Ct, 105 Requirements for real delta Ct calculations, 107 Absolute quantification, 110 Value prediction, the professional way, 114 Relative quantification using the ddCt method, 115 Comparison of two conditions, 116 Comparison of multiple experimental conditions, 118 Quality control with melting curve, 121 Files for practicing, 123 Study exercises and questions, 123 References, 123 Webliography, 124 Packages, 124 6 Advanced transcriptomics: gene expression microarrays, 125 Microarray analysis: probes and samples, 125 Experimental background, 126 Archiving and publishing microarray data, 128 Minimum information standard, 128 Data preprocessing, 128 Accessing data from CEL files, 129 Quality control, 131 Normalization, 132 Differential gene expression, 133 Annotating results, 136 Creating normalized expression set from Illumina data, 138 Automated data access from GEO, 140 Files for practicing, 142 Study exercises and questions, 142 References, 143 Webliography, 144 Packages, 144 7 Next-generation sequencing in transcriptomics: RNA-seq experiments, 145 High-throughput RNA sequencing background, 145 Experimental background, 145 RNA-seq applications, 146 Differential expression with different resolutions, 147 Preparing count tables, 148 Alignment files to read counts, 148 Differential expression in simple comparison, 151 A naive t-test approach, 151 Single factor analysis with edgeR, 153 Differential expression with DESeq, 156 Complex experimental arrangements, 159 Experimental factors and design matrix, 160 GLM with edgeR, 161 GLMs with DESeq, 162 Heatmap visualization, 163 Files for practicing, 164 Study exercises and questions, 164 References, 165 Webliography, 166 Packages, 166 8 Deciphering the regulome: from ChIP to ChIP-seq, 167 Chromatin immunoprecipitation, 167 Experimental background, 168 Fragment analysis, 168 ChIP data in ENCODE, 169 ChIP with tiling microarrays, 169 High-throughput sequencing of ChIP fragments, 176 Connecting annotation to peaks, 181 Analysis of binding site motifs, 182 Files for practicing, 186 Study exercises and questions, 187 References, 187 Webliography, 188 Packages, 189 9 Inferring regulatory and other networks from gene expression data, 191 Gene regulatory networks, 191 Data for gene network inference, 192 Reconstruction of co-expression networks, 193 Gene regulatory network inference focusing of master regulators, 201 Integrated interpretation of genes with GeneAnswers, 207 Files for practicing, 211 Study exercises and questions, 212 References, 213 Packages, 214 10 Analysis of biological networks, 215 A gentle introduction to networks, 215 Networks and their components and features, 215 Random networks, 220 Biological networks, 221 Files for storing network information, 223 Important network metrics in biology, 227 Distance-based measures, 228 Degree and related measures, 230 Vulnerability, 231 Community structure of a network, 234 Graph visualization, 236 Cytoscape, 240 Files for practicing, 241 Study exercises and questions, 241 References, 242 Webliography, 243 Packages, 243 11 Proteomics: mass spectrometry, 245 Mass spectrometry and proteomics: why and how?, 245 File formats for MS data, 246 Accessing the raw data of published studies, 247 Identification of peptides in the samples, 249 Peptide mass fingerprinting, 249 Peptide identification by using MS/MS spectra, 250 Quantitative proteomics, 254 Getting protein-specific annotation, 258 Files for practicing, 259 Study exercises and questions, 259 References, 259 Webliography, 260 Packages, 260 12 Measuring protein abundance with ELISA, 261 Enzyme-linked immunosorbent assays, 261 Accessing ELISA data, 264 Concentration calculation with a standard curve, 264 Preparing reference data, 267 Fitting linear model, 268 Fitting of a logistic model, 269 Concentration calculations by employing models, 270 Comparative calculations using concentrations, 271 Files for practicing, 277 Study exercises and questions, 277 References, 277 Packages, 278 13 Flow cytometry: counting and sorting stained cells, 279 Theoretical aspects of flow cytometry, 279 Experiment types: diagnosis versus discovery, 280 Measurement arrangements, 281 Fluorescent dyes, 281 Tubes versus plates, 285 Instruments, 285 What about data?, 287 Files, 287 Workflows, 288 Data preprocessing, 289 Handling all samples together, 290 Compensation, 292 Quality assurance, 292 Using workflow objects and transformation, 296 Normalization, 298 Cell population identification, 299 Manual gating, 300 Automatic gating, 304 Relating cell populations to external variables, 305 Reporting results, 307 MIFlowCyt, 307 FlowRepository.org, 308 Files for practicing, 308 Study exercises and questions, 309 References, 309 Webliography, 310 Packages, 310 Glossary, 311 Index, 323

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

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Book SynopsisTRANSPORTERS AND DRUG-METABOLIZING ENZYMES IN DRUG TOXICITY Explore up-to-date coverage on the interaction between drug metabolism enzymes, transporters, and drug toxicity with this leading resources Transporters and Drug-Metabolizing Enzymes in Drug Toxicity delivers a comprehensive and updated review of the relationship between drug metabolism, transporters, and toxicity, providing insights into a major challenge in drug development accurate assessment of human drug toxicity. Combining two disciplines frequently considered independently of one another, the book combines drug metabolism and toxicology with a focus on the role of biotransformation on drug toxicity and as a major factor for species and individual differences. Mechanism and species differences in drug metabolizing enzymes and transporters are discussed, as are the methods used to investigate the role of drug metabolizing enzymes and transporters in drug toxicity. Finally, the distinguTable of ContentsPreface xix List of Contributors xxi Part I Overview 1 1 Overview: Drug Metabolism, Transporter-Mediated Uptake and Efflux, and Drug Toxicity 3Albert P. Li 1.1 Drug Toxicity as a Challenge in Drug Development 3 1.2 Fate of an Orally Administered Drug 4 1.3 The Multiple Determinant Hypothesis for Idiosyncratic Drug Toxicity 5 1.4 Concluding Remarks 7 1.4.1 A Comprehensive Approach to Safety Evaluation in Drug Development 7 1.4.2 The Dose Makes the Poison – Paracelsus Updated 8 References 8 2 Transporter, Drug Metabolism, and Drug-Induced Liver Injury in Marketed Drugs 11Minjun Chen, Kristin Ashby, and Yue Wu 2.1 Introduction 11 2.2 Hepatic Metabolism 12 2.2.1 Phase I Metabolism 12 2.2.2 Phase II Metabolism 14 2.3 Reactive Metabolite Formation and Assessment 14 2.3.1 Metabolism and Reactive Metabolites 15 2.3.2 Dose and Reactive Mtabolites 16 2.3.3 Structural Alerts for Avoiding Reactive Metabolites 16 2.3.4 Experimental Approaches for Assessing Reactive Metabolites 18 2.3.4.1 Covalent Binding Assay 18 2.3.4.2 Electrophile Trapping Experiments 18 2.3.4.3 Time Dependent Inactivation of CYP450 Enzymes 19 2.4 Hepatic Transporters 20 2.5 Genetic Variants and Their Impact for Pharmacokinetic Behavior and Safety 24 2.5.1 CYP3A424 2.5.2 CYP3A526 2.5.3 CYP2D626 2.5.4 CYP2C927 2.5.5 CYP2C1927 2.5.6 CYP2B628 2.5.7 UGT1A128 2.5.8 NAT2 28 2.5.9 Hepatic Transporters 29 2.6 Summary 29 Acknowledgment 30 Disclaimer 30 References 30 3 Drug-Metabolism Enzymes and Transporter Activities as Risk Factors of Selected Marketed Drugs Associated with Drug-Induced Fatalities 41Albert P. Li 3.1 Introduction 41 3.2 Acetaminophen 41 3.2.1 Drug Metabolism and Toxicity 42 3.2.2 Transporters and Toxicity 42 3.2.3 Risk Factors 43 3.3 Cerivastatin 43 3.3.1 Drug Metabolism and Toxicity 43 3.3.2 Transporter and Toxicity 44 3.3.3 Risk Factors 44 3.4 Felbamate 45 3.4.1 Drug Metabolism and Toxicity 45 3.4.2 Transporters and Toxicity 46 3.4.3 Risk Factors 46 3.5 Flucloxacillin 46 3.5.1 Drug Metabolism and Toxicity 46 3.5.2 Transporters and Toxicity 47 3.5.3 Risk Factors 47 3.6 Nefazodone 47 3.6.1 Drug Metabolism and Toxicity 48 3.6.2 Transporters and Toxicity 48 3.6.3 Risk Factors 48 3.7 Obeticholic Acid 49 3.7.1 Drug Metabolism and Toxicity 49 3.7.2 Transporters and Toxicity 50 3.7.3 Risk Factors 50 3.8 Sitaxentan 50 3.8.1 Drug Metabolism and Toxicity 51 3.8.2 Transporters and Toxicity 51 3.8.3 Risk Factors 51 3.9 Sorivudine 52 3.9.1 Drug Metabolism and Toxicity 52 3.9.2 Transporters and Toxicity 52 3.9.3 Risk Factors 52 3.10 Tacrine 52 3.10.1 Drug Metabolism and Toxicity 54 3.10.2 Transporters and Toxicity 54 3.10.3 Risk Factors 54 3.11 Terfenadine 55 3.11.1 Drug Metabolism and Toxicity 55 3.11.2 Transporter and Toxicity 56 3.11.3 Risk Factors 56 3.12 Troglitazone (Rezulin®) 56 3.12.1 Drug Metabolism and Toxicity 57 3.12.2 Transporter and Toxicity 57 3.12.3 Risk Factors 58 3.13 Trovafloxacin 58 3.13.1 Metabolism and Toxicity 59 3.13.2 Transporters and Toxicity 59 3.13.3 Risk Factors 59 3.14 Conclusions 60 References 61 Part II Drug Metabolizing Enzymes and Drug Toxicity 79 4 Drug-Metabolizing Enzymes and Drug Toxicity 81Albert P. Li 4.1 Introduction 81 4.2 Drug-Metabolism Enzymes Involved in Metabolic Activation and Detoxification 81 4.3 Cytochrome P450 Monooxygenase (CYP) 82 4.3.1 CYP1A 82 4.3.1.1 Metabolic Activation 82 4.3.1.2 Drug Substrates 83 4.3.1.3 Inducers 83 4.3.1.4 Inhibitors 83 4.3.1.5 Individual Variations 83 4.3.1.6 Involvement in Drug Toxicity 83 4.3.2 CYP2A6 84 4.3.2.1 Substrates 84 4.3.2.2 Inducers 84 4.3.2.3 Inhibitors 84 4.3.2.4 Individual Variations 85 4.3.2.5 Involvement in Drug Toxicity 85 4.3.3 CYP2B6 85 4.3.3.1 Substrates 85 4.3.3.2 Inducers 86 4.3.3.3 Inhibitors 86 4.3.3.4 Individual Variations 86 4.3.3.5 Involvement in Drug Toxicity 86 4.3.4 CYP2C8 87 4.3.4.1 Substrates 87 4.3.4.2 Inducers 87 4.3.4.3 Inhibitors 87 4.3.4.4 Individual Variations 88 4.3.4.5 Involvement in Drug Toxicity 88 4.3.5 CYP2C9 88 4.3.5.1 Substrates 88 4.3.5.2 Inducers 88 4.3.5.3 Inhibitors 88 4.3.5.4 Individual Variations 89 4.3.5.5 Involvement in Drug Toxicity 89 4.3.6 CYP2C19 89 4.3.6.1 Substrates 89 4.3.6.2 Inducers 89 4.3.6.3 Inhibitors 89 4.3.6.4 Individual Variations 90 4.3.6.5 Involvement in Drug Toxicity 90 4.3.7 CYP2D6 90 4.3.7.1 Substrates 90 4.3.7.2 Inducers 90 4.3.7.3 Inhibitors 90 4.3.7.4 Individual Variations 90 4.3.7.5 Involvement in Drug Toxicity 91 4.3.8 CYP2E1 91 4.3.8.1 Substrates 91 4.3.8.2 Inducers 91 4.3.8.3 Inhibitors 91 4.3.8.4 Involvement in Drug Toxicity 91 4.3.9 CYP2J2 92 4.3.9.1 Substrates 92 4.3.9.2 Inhibitors 92 4.3.9.3 Inducers 92 4.3.9.4 Individual Variations 92 4.3.9.5 Involvement in Drug Toxicity 92 4.3.10 CYP3A 93 4.3.10.1 Substrates 93 4.3.10.2 Inducers 93 4.3.10.3 Inhibitors 93 4.3.10.4 Individual Variations 93 4.3.10.5 Involvement in Drug Toxicity 94 4.4 Non-P450 Drug-Metabolizing Enzymes 94 4.4.1 Flavin-Containing Monooxygenases (FMOs) 94 4.4.1.1 Substrates 94 4.4.1.2 Inducers 95 4.4.1.3 Inhibitors 95 4.4.1.4 Individual Variations 95 4.4.1.5 Involvement in Drug Toxicity 95 4.4.2 Monoamine Oxidase (MAO) 95 4.4.2.1 Substrates 96 4.4.2.2 Inducers 96 4.4.2.3 Inhibitors 96 4.4.2.4 Individual Variations 96 4.4.2.5 Involvement in Drug Toxicity 96 4.4.3 Alcohol Dehydrogenase (ADH) and Aldehyde Dehydrogenase (ALDH) 97 4.4.3.1 Substrates 97 4.4.3.2 Inducers 97 4.4.3.3 Inhibitors 97 4.4.3.4 Individual Variations 97 4.4.3.5 Involvement in Drug Toxicity 98 4.4.4 Aldehyde Oxidase (AOX) 98 4.4.4.1 Substrates 98 4.4.4.2 Inducers 98 4.4.4.3 Inhibitors 98 4.4.4.4 Individual Variations 99 4.4.4.5 Involvement in drug toxicity 99 4.4.5 Carboxylesterases (CESs) 99 4.4.5.1 Substrates 99 4.4.5.2 Inducers 99 4.4.5.3 Inhibitors 100 4.4.5.4 Individual Variations 100 4.4.5.5 Involvement in Drug Toxicity 100 4.4.6 N-Acetyltransferase (NAT) 100 4.4.6.1 Substrates 100 4.4.6.2 Inducers 100 4.4.6.3 Inhibitors 101 4.4.6.4 Individual Variations 101 4.4.6.5 Involvement in Drug Toxicity 101 4.4.7 Glutathione Transferase (GST) 101 4.4.7.1 Substrates 101 4.4.7.2 Inducers 102 4.4.7.3 Inhibitors 102 4.4.7.4 Individual Variations 102 4.4.7.5 Involvement in Drug Toxicity 102 4.4.8 Methyltransferase (MT) 103 4.4.8.1 Substrates 103 4.4.8.2 Inhibitors 103 4.4.8.3 Individual Variations 103 4.4.8.4 Involvement in Drug Toxicity 103 4.4.9 Uridine Glucuronosyltransferase (UGT) 103 4.4.9.1 Substrates 104 4.4.9.2 Inducers 104 4.4.9.3 Inhibitors 104 4.4.9.4 Individual Variations 104 4.4.9.5 Involvement in Drug Toxicity 104 4.4.10 Sulfotransferase (SULT) 105 4.4.10.1 Substrates 105 4.4.10.2 Inducers 105 4.4.10.3 Inhibitors 106 4.4.10.4 Individual Variations 106 4.4.10.5 Involvement in Drug Toxicity 106 4.5 Conclusions 106 References 107 5 Genetic Polymorphism of Drug-Metabolizing Enzymes and Drug Transporters in Drug Toxicity 139Ann K. Daly 5.1 Introduction 139 5.2 Drug-Induced Liver Injury 140 5.2.1 Background 140 5.2.2 Polymorphisms Affecting Drug Metabolism and DILI 140 5.2.2.1 Isoniazid 140 5.2.2.2 Diclofenac 146 5.2.2.3 Tolcapone 146 5.2.2.4 Ticlopidine 147 5.2.2.5 Efavirenz 147 5.2.2.6 Troglitazone 147 5.2.3 Polymorphisms Affecting Transporters and DILI 147 5.3 Drug-Induced Skin Injury and Related Hypersensitivity Reactions 149 5.4 Statin-Induced Myopathy 151 5.4.1 Background 151 5.4.2 Cytochromes P450 151 5.4.3 Transporters 152 5.5 Conclusions 154 References 154 6 Acyl Glucuronidation and Acyl-CoA Formation Mechanisms Mediating the Bioactivation and Potential Toxicity of Carboxylic Acid-containing Drugs 167Mark P. Grillo 6.1 Introduction 167 6.2 Phase II Metabolism 171 6.2.1 Glucuronidation 171 6.2.2 Acyl-CoA Thioester Formation 171 6.3 Chemical Stability of Phase II Metabolites 172 6.3.1 Acyl Glucuronide Instability 172 6.3.2 Acyl-CoA Thioester Stability 175 6.4 Phase II Metabolite Chemical Reactivity 176 6.4.1 Acyl Glucuronide Reactivity with Nucleophiles In vitro 176 6.4.2 Acyl-CoA Thioester Reactivity with Nucleophiles In vitro 180 6.5 Phase II Metabolite-Mediated Covalent Binding 183 6.5.1 Acyl Glucuronide-Mediated covalent Binding to protein 183 6.5.2 Acyl-CoA Thioester-Mediated Covalent Binding to Protein 185 6.6 Phase II Metabolite Prediction of Covalent Binding 187 6.6.1 Prediction of Covalent Binding to Protein by Acyl Glucuronides 187 6.6.2 Prediction of Covalent Binding to Protein by Acyl-CoA Thioesters 189 6.7 Studies Directly Comparing Carboxylic Acid Drug Bioactivation by Acyl Glucuronidation and Acyl-CoA Formation 190 6.8 Prediction of Drug-Induced Liver Injury for Carboxylic Acid Drugs 194 6.9 Conclusions 196 References 197 7 Liquid Chromatography-Mass Spectrometry (LC-MS) Quantification of Reactive Metabolites 207Qingping Wang and Chuang Lu 7.1 Introduction 207 7.2 LC-MS Methods Using GSH as a Trapping Reagent 209 7.2.1 LC-MS Approaches at Positive Mode Using Constant Neutral Loss (CNL) Scan or Enhanced Product Ion (EPI) Scan 209 7.2.2 LC-MS Approaches at Negative Mode Using Neutral Loss, Pre-Ion Scan (PIS) and XoPI (Extraction of Product Ion) 212 7.2.3 LC-MS Approaches Using Stable Isotopic-GSH 213 7.2.4 LC-MS Approaches Using Combined XoPI and Stable-Isotopic GSH 214 7.2.5 LC-MS Coupled with Software-Assisted Approach 218 7.2.6 Using GSH Derivatives as Trapping Reagents for Detection and Quantitation 219 7.3 Using Other Trapping Reagents 222 7.4 Identification and Characterization of Rearranged GSH Adducts 222 7.5 Strategies for Optimization and Decision Tree 224 7.6 Summary 226 Acknowledgment 227 Abbreviations 227 References 228 8 Human-Based In Vitro Experimental Approaches for the Evaluation of Metabolism-Dependent Drug Toxicity 235Albert P. Li 8.1 Introduction 235 8.2 Assays for Reactive Metabolites 235 8.2.1 Glutathione Trapping Assay 236 8.2.2 Covalent Binding Assay 236 8.3 Cell-Based Assays for Metabolism-Dependent Toxicity 237 8.4 Primary Human Hepatocyte Assays for Metabolism-Dependent Drug Toxicity 238 8.4.1 In Vitro Screening Assays for Hepatotoxicity 238 8.4.2 Cytotoxic Metabolic Pathway Identification Assay (CMPIA) 238 8.4.3 Metabolic Comparative Cytotoxicity Assay (MCCA) 241 8.4.4 MetMax™ Cryopreserved Human Hepatocytes (MMHH) Metabolic Activation Cytotoxicity Assay (MMACA) 242 8.5 Emerging Hepatocyte Technologies for the Evaluation of Drug Toxicity 242 8.5.1 Human Hepatocytes ROS/ATP Assay for DILI Drugs 242 8.5.2 Long-Term Hepatocyte Cultures 244 8.5.2.1 999Elite™ Long-Term Cultured Human Hepatocytes 244 8.5.2.2 Hepatocyte/Non-Hepatocyte Cocultures 244 8.5.2.3 Human Hepatocyte Spheroids 245 8.5.2.4 Microfluidic 3-Dimensional (3-d) Hepatocyte Cultures 245 8.6 Integrated Discrete Multiple Organ Coculture (IdMOC®) 247 8.7 Conclusion 249 References 251 Part III Drug Transporters and Drug Toxicity 261 9 Mechanism-Based Experimental Models for the Evaluation of BSEP Inhibition and DILI 263William A. Murphy, Chitra Saran, Paavo Honkakoski, and Kim L.R. Brouwer 9.1 Introduction 263 9.1.1 Drug-Induced Liver Injury 263 9.1.2 Bile Acid Homeostasis and Role of Bile Salt Export Pump 264 9.2 Membrane Vesicles to Study BSEP Inhibition 266 9.2.1 Membrane Vesicle Preparations 267 9.2.2 Membrane Vesicle Assays and Data Interpretation 268 9.3 Sandwich-Cultured Hepatocytes to Study BSEP Inhibition 270 9.3.1 B-CLEAR® Assay 270 9.3.2 Uptake and Efflux Studies with Mechanistic Modeling 273 9.4 Other In Vitro Methods to Study BSEP Inhibition 275 9.5 Computational Methods Used to Predict BSEP Inhibition 277 9.6 In Vitro Models as a Predictor of Clinical DILI 278 9.6.1 The C-DILI™ Assay 278 9.7 Preclinical In Vivo Models for the Evaluation of BSEP/Bsep Inhibition and DILI 279 9.8 In Vivo Clinical Biomarkers of BSEP Inhibition and DILI 282 9.8.1 Serum Bile Acids as Clinical Biomarkers 282 9.8.2 Clinical Biomarkers of DILI 283 9.9 Quantitative Systems Toxicology to Predict DILI 284 9.10 Conclusions 287 Funding Information 287 Conflict of Interest 288 Acknowledgments 288 Reference 288 10 Hepatic Bile Acid Transporters in Drug-Induced Cholestasis 307Tao Hu and Hongbing Wang Abbreviations 307 10.1 Introduction 308 10.2 Bile Acid and DIC 308 10.2.1 Bile Acid 309 10.2.1.1 Bile Acid Synthesis 309 10.2.1.2 Bile Acid Transport 310 10.2.2 Cytotoxicity of Bile Acids and DIC 310 10.3 Hepatic Bile Acid Uptake Transporters in DIC 312 10.3.1 Sodium-Taurocholate Cotransporting Polypeptide (NTCP) 312 10.3.1.1 Substrates of NTCP 314 10.3.1.2 Regulation of NTCP 315 10.3.1.3 NTCP and Cholestasis 316 10.3.2 Other Hepatic Bile Acid Uptake Transporters 317 10.4 Hepatic Bile Acid Efflux Transporters in DIC 317 10.4.1 Bile Salt Export Pump (BSEP) 318 10.4.1.1 Substrates of BSEP 318 10.4.1.2 Regulation of BSEP 319 10.4.1.3 Internalization of BSEP 321 10.4.1.4 BSEP and Cholestasis 321 10.4.2 Other Hepatic Bile Acid Efflux Transporters 323 10.4.2.1 MRP2 323 10.4.2.2 MRP3 and MRP4 324 10.5 Bidirectional Bile Acid Transporter OSTα/β 324 10.6 Summary 325 References 326 11 Role of Renal Transporters in Drug–Drug Interactions and Nephrotoxicity 339Yan Zhang and Donald Miller 11.1 Overview of Renal Transporters 339 11.1.1 Basolateral Transporters 340 11.1.2 Apical Transporters 341 11.2 Renal Transporters and Drug–Drug Interactions 343 11.2.1 Impact on the Pharmacokinetics of Drugs 344 11.2.2 Impact on the Drug PD 350 11.3 Renal Transporters and Nephrotoxicity 352 11.3.1 Nephrotoxicity Unrelated to Drug Transporters 353 11.3.2 Nephrotoxicity Related to Drug Transporters 355 11.4 Biomarkers and Nephrotoxicity 359 11.4.1 Biomarkers for Detecting Glomerular Injury 359 11.4.2 Biomarkers for Drug-Induced Injury to Proximal and Distal Tubules 361 11.5 Conclusion 362 References 365 12 Blood–Brain Barrier Transporters and Central Nervous System Drug Response and Toxicity 377Donald W. Miller, Stacey Line, Nur A. Safa, and Yan Zhang 12.1 Over-View of the Brain Barriers 377 12.1.1 Blood–Brain Barrier (BBB) 377 12.1.2 Blood–Cerebrospinal Fluid Barrier (BCSFB) 379 12.1.3 CSF as Predictor of Drug Exposure in the Brain 379 12.1.4 Solute Carriers in the BBB 380 12.1.5 Drug Efflux Transporters in the BBB 380 12.2 General Influence of BBB Transporters on Drug Entry into the Brain 383 12.3 BBB-Transporter Effects on CNS Drug Response 386 12.3.1 Influence of Efflux Transporters on Brain Disposition of Drugs 386 12.3.1.1 Anticancer Agents 386 12.3.1.2 Opioids 388 12.3.2 SLCs and BBB Transport of Drugs 391 12.4 Transporter Considerations Influencing CNS Drug Response 391 12.4.1 Transporter Polymorphisms 391 12.4.1.1 P-gp Polymorphism 391 12.4.1.2 BCRP Polymorphism 393 12.4.1.3 SLC Polymorphism 393 12.4.2 Age-Related Alterations in BBB Transporter Function and Drug Response 394 12.4.3 Disease-Dependent Modulation of BBB Transporters and Drug Response 395 12.4.3.1 Inflammation and Pain 395 12.4.3.2 Epilepsy 396 12.4.4 CNS Toxicity Caused by Drug Interactions at the BBB 398 12.5 Conclusions 400 References 401 13 Ototoxicity and Drug Transport in the Cochlea 413Stefanie Kennon-McGill and Mitchell R. McGill 13.1 Auditory System Anatomy 413 13.1.1 External, Middle, and Inner Ear 413 13.1.1.1 Anatomy of the Inner Ear 414 13.1.1.2 Hair Cell Anatomy 414 13.1.2 Blood–Labyrinth Barrier 415 13.2 Auditory System Physiology 416 13.3 Hearing Loss, Ototoxic Drugs, and Hair Cell Damage 416 13.3.1 Aminoglycosides 417 13.3.2 Platinum Chemotherapeutics 418 13.3.3 Salicylate 419 13.4 Drug Metabolism in the Ear 419 13.4.1 The Importance of Drug Metabolism in the Ear 419 13.4.2 Studies of Drug-Metabolizing Enzymes in Ototoxicity 420 13.4.3 Drug Transporters in the Ear 421 13.5 Conclusion 423 References 423 Part IV Modeling Drug Metabolizing Enzymes-Transporters Interplay for The Prediction of Drug Toxicity 427 14 Application of a PBPK Model Incorporating the Interplay Between Transporters and Drug-Metabolizing Enzymes for the Precise Prediction of Drug Toxicity 429Kazuya Maeda 14.1 Importance of the Consideration of Intracellular Concentration of Drugs in the Tissue for Estimation of Pharmacological/Toxicological Effects of Drugs 429 14.2 Extended Clearance Concept as a Tool to Explain Theoretically Transporter and Drug-Metabolizing Enzyme Interplay 431 14.3 Theoretical Consideration of the Intracellular Concentration of Drugs in the Tissue 433 14.4 The Benefits of Using a PBPK Model for the Accurate Prediction of Pharmacological/Toxicological Effects of Drugs 436 14.5 VCT to Simulate the Distribution of Clinical Outcomes in a Specific Population with Defined Mean and Variability of Parameters in a PBPK Model 440 14.5.1 VCT of Docetaxel to Estimate the Effects on the Risk of Neutropenia of Genetic Polymorphisms in OATP1B3 and MRP2 442 14.5.2 VCT of Oseltamivir and Its Active Metabolite (Ro 64-0802) to Estimate the Effects on Their Brain Exposure of Genetic Polymorphisms in Multiple Uptake/Efflux Transporters 444 14.5.3 VCT of Irinotecan and Its Metabolites to Estimate the Effects of Genetic Polymorphisms in Multiple Uptake/Efflux Transporters on Irinotecan-Induced Side Effects (Neutropenia, Diarrhea) 447 14.6 Conclusions and Future Perspectives 450 References 451 15 The Extended Clearance Model: A Valuable Tool For Drug-Induced Liver Injury Risk Prediction 455Birk Poller, Felix Huth, Vlasia Kastrinou-Lampou, Gerd A. Kullak-Ublick, Michael Arand, and Gian Camenisch 15.1 Introduction 455 15.2 Application of the ECM to Estimate Kpuu Liver 457 15.2.1 Introduction to the ECM: Concepts and Application for the Prediction of Hepatic Clearance and Drug–Drug Interactions 457 15.2.2 Concept of Kpuu Liver 460 15.2.3 Estimation of Kpuu Liver from In Vitro Data Using the ECM 461 15.3 Relevant Concentrations for the DILI Risk Assessment 462 15.3.1 Maximum Plasma Concentrations 464 15.3.2 Maximum Hepatic Inlet Concentrations 464 15.3.3 Maximum Intracellular Hepatocyte Concentrations 465 15.4 Assessing the DIC Risk Using ECM-Based Unbound Intrahepatic Concentrations and Accounting for BSEP Inhibition as a Single Mechanism 465 15.5 Assessing the DILI Risk Using the “1/R-Value Model” to Account for the Inhibition of Multiple Pathways 467 15.5.1 ECM-Based 1/R-Value Model 467 15.5.2 1/R vs Safety Margin Relationship 471 15.6 Discussion and Outlook 473 References 475 Index 481

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Book SynopsisA comprehensive overview of the new business context for biopharma companies, featuring numerous case studies and state-of-the-art marketing models Biotechnology has developed into a key innovation driver especially in the field of human healthcare. But as the biopharma industry continues to grow and expand its reach, development costs are colliding with aging demographics and cost-containment policies of private and public payers. Concurrently, the development and increased affordability of sophisticated digital technologies has fundamentally altered many industries including healthcare. The arrival of new information technology (infotech) companies on the healthcare scene presents both opportunities and challenges for the biopharma business model. To capitalize on new digital technologies from R&D through commercialization requires industry leaders to adopt new business models, develop new digital and data capabilities, and partner with innovators and payers wTable of ContentsForeword By Philip Kotler xi Preface xiii Acknowledgments xvii About The Authors xix Part 1 New Models For Networked Innovation Chapter 1 Digital Evolution of Biotechnology 3 Industry Applications 5 Impact of Megatrends 6 Digital Health Opportunities 6 Infotechnology Initiatives in Healthcare 8 Disruption Risk from Infotech 8 Technology Strategies 11 Big Infotech Strategies 12 Conclusion 21 Summary Points 22 Chapter 2 Biotechnology Financing Strategies 24 The Long Game 24 Financing Strategies for the Long Term at Alnylam 26 Strategic Decisions 30 Geographic Considerations 33 Sources of Financing 33 A Word about Mergers and Acquisitions 43 Summary Points 44 Chapter 3 Success Through Collaboration 46 Alliance Evolution: More Players and New Structures 46 Strategic Alliances: A Stalwart of the Biopharma Industry 50 Janssen and OSE Immunotherapeutics: Deal Strategies in a European Context 52 Alliance versus Acquisition 53 Structure Considerations to Maximize Value 55 Divesting for Focus 55 Doing the Deal 56 Summary Points 65 Part 2 New Business and Marketing Models Chapter 4 Precision Medicine 69 What is Precision Medicine? 69 Targeted Medicines Multiply but Drug-Diagnostic Pairs are Rare 69 Precision Medicine is Happening at Several Levels 71 Multiple Forces, Beyond Science, are Driving Precision Medicine 72 Digital Precision Medicine 74 Precision Medicine in Practice: Lessons from Cancer 75 Challenges: Scientific, Infrastructural, Regulatory, and Commercial 79 Surmounting the Hurdles to Revolutionize Medicine 83 Stakeholder Expansion in Precision Medicine 86 Biopharma Must Drive, not be Driven by, Precision Medicine 87 Precision Medicine’s Future 90 Summary Points 92 Chapter 5 Precision Marketing 94 Introduction 94 Portfolio Shift to Specialty Products 95 Balancing Evidence and Experience 96 R & D and Commercial Coordination 97 Science is the New Marketing 98 Value of Experience: The Consumer Decision Journey 100 Marketing Beyond the Pill 101 Targeting New Consumer Segments 102 New Physician Segments 102 Dual Branding Models 103 New Launch Strategies 105 Companion Diagnostics 105 Global Organization 108 Multichannel Communications 109 Content Marketing 110 Salesforce Strategies 111 Sustainability Strategies: Beyond the Life Cycle 113 Summary Points 118 Chapter 6 Patient Centricity Strategies 120 Introduction 120 Patient Centricity Drivers and Barriers 121 Discovery: Understanding Unmet Needs 123 Designing Patient-Friendly Clinical Trials 125 Connecting the Points of Care 130 Understanding the Patient Journey 135 Organizing for Patient Centricity 138 Who Are You Working For? Bristol-Myers Squibb Employee Engagement Initiative 138 Patient Engagement Metrics 140 Organization Models 142 Summary Points 143 Chapter 7 Drug Pricing In Context 145 Introduction 145 The Economics of Drug Pricing 146 Competing Definitions of Product Value Complicate Drug Pricing 153 Proving Efficacy in the Real World 155 Setting the Pricing Strategy 157 Analyzing New Pricing Models 160 Drug Pricing in the United States: The Pressure Continues to Build 162 Deployment of New Pricing Strategies 163 Experimental Pricing Strategies 165 Financing the Future: Affordability 169 New Tools for Outcomes-Data Capture 170 Conclusion 171 Summary Points 171 Chapter 8 Strategic Payer Engagement 173 Payers Are Not All Alike 173 New Market Forces Increase Payer Power 175 The Increasing Importance of the Consumer in the United States 176 European Payers: High-Level Unity, Low-Level Fragmentation 180 United States Adopts European-Style Cost-Effectiveness Hurdles 181 Payer Engagement Strategies Must be Tailored, Scalable, and Flexible 182 Changing Biopharma-Payer Relationships: From Transactional to Collaborative 185 New Biopharma Organizational Models Needed 187 Biopharma-Payer Engagement Must Move Beyond Experimentation 188 Strategic Payer Engagement Comes in Many Forms 192 Summary Points 193 Part 3 New Models For Digital Health Chapter 9 Digital Health Strategies 197 Introduction 197 Biopharma Digital Strategies 197 Digital Impact on Supply Chain Management 200 Digital Transformation of Commercial Activities 201 Consumer-Centered Trends 206 Provider-Centered Strategies: Telehealth 210 Conclusion 213 Summary Points 213 Chapter 10 Creating Agility Through Data and Analytics 215 Introduction 215 Multiple Forces Converge to Create Data and Analytics Opportunities 216 Healthcare’s Four Data Vectors: Volume, Velocity, Variety, and Veracity 218 Extracting Value from Data Requires New Tools 221 The Analytics Continuum: From Descriptive to Prescriptive 223 Artificial Intelligence: The Potential to Make Drugs Smarter, Faster, and for Less 225 Data Analytics across the Biopharma Value Chain 226 Data and Analytics Challenges 233 Building an Analytics-First Organization: Cultural not Technical Hurdles 238 Conclusion 242 Summary Points 242 Conclusion 243 References 246 Index 273

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Book SynopsisI thoroughly enjoyed reading this book as it has taken me on a journey through time, across the globe and through multiple disciplines. Indeed, we need to be thinking about these concepts and applying them every day to do our jobs better. Farah Magrabi, Macquarie University, Australia The reader will find intriguing not only the title but also the content of the book. I'm also pleased that public health, and even more specifically epidemiology has an important place in this ambitious discussion. Elena Andresen, Oregon Health & Science University, USA This book is very well written and addresses an important topic. It presents many reasons why basic scientists/researchers should establish collaborations and access information outside traditional means and not limit thinking but rather expand such and perhaps develop more innovative and translational research ventures that will advance science and not move it laterally. Gerald Pepe, Eastern Virginia Table of ContentsPreface vii Part One Outcomes of Research 1 1 Pathways of the Research Innovator 3 2 First Dimension: Scientific Impact 21 3 Second Dimension: Public Health Value 37 4 Third Dimension: Economic Development 53 Part Two Headwinds of Research Innovation 69 5 Slowdown and Erosion 71 6 Non‐reproducible Research 89 7 Red Tape and Litigation 109 Part Three Boosters of Research Productivity 131 8 Humanism for Innovation 133 9 Desire to Understand First 151 10 Learning from the Best 169 11 Cracking Public Health Needs 183 12 Engaged Research 197 13 Cross‐cultural Convergence 215 14 Targeting and Repurposing 229 15 Trailblazing Technologies 243 16 Emulating Nature 259 17 Scientific Modeling 273 18 Mastering Bioentrepreneurship 291 19 Art of Scientific Communication 309 Part Four Atmosphere of Excellence 329 20 Quality and Performance Improvement 331 21 Institutional and National Strategies 345 22 International Collaboration and Competition 365 List of of award-winning scientists and serial innovators 381 Subject Index 387

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Book SynopsisAn essential guide to healthcare data problems, sources, and solutions Strategies in Biomedical Data Science provides medical professionals with much-needed guidance toward managing the increasing deluge of healthcare data.Table of ContentsForeword xi Acknowledgments xv Introduction 1 Who Should Read This Book? 3 What’s in This Book? 4 How to Contact Us 6 Chapter 1 Healthcare, History, and Heartbreak 7 Top Issues in Healthcare 9 Data Management 16 Biosimilars, Drug Pricing, and Pharmaceutical Compounding 18 Promising Areas of Innovation 19 Conclusion 25 Notes 25 Chapter 2 Genome Sequencing: Know Thyself, One Base Pair at a Time 27 Content contributed by Sheetal Shetty and Jacob Brill Challenges of Genomic Analysis 29 The Language of Life 30 A Brief History of DNA Sequencing 31 DNA Sequencing and the Human Genome Project 35 Select Tools for Genomic Analysis 38 Conclusion 47 Notes 48 Chapter 3 Data Management 53 Content contributed by Joe Arnold Bits about Data 54 Data Types 56 Data Security and Compliance 59 Data Storage 66 SwiftStack 70 OpenStack Swift Architecture 78 Conclusion 94 Notes 94 Chapter 4 Designing a Data-Ready Network Infrastructure 105 Research Networks: A Primer 108 ESnet at 30: Evolving toward Exascale and Raising Expectations 109 Internet2 Innovation Platform 111 Advances in Networking 113 InfiniBand and Microsecond Latency 114 The Future of High-Performance Fabrics 117 Network Function Virtualization 119 Software-Defined Networking 121 OpenDaylight 122 Conclusion 157 Notes 157 Chapter 5 Data-Intensive Compute Infrastructures 163 Content contributed by Dijiang Huang, Yuli Deng, Jay Etchings, Zhiyuan Ma, and Guangchun Luo Big Data Applications in Health Informatics 166 Sources of Big Data in Health Informatics 168 Infrastructure for Big Data Analytics 171 Fundamental System Properties 186 GPU-Accelerated Computing and Biomedical Informatics 187 Conclusion 190 Notes 191 Chapter 6 Cloud Computing and Emerging Architectures 211 Cloud Basics 213 Challenges Facing Cloud Computing Applications in Biomedicine 215 Hybrid Campus Clouds 216 Research as a Service 217 Federated Access Web Portals 219 Cluster Homogeneity 220 Emerging Architectures (Zeta Architecture) 221 Conclusion 229 Notes 229 Chapter 7 Data Science 235 NoSQL Approaches to Biomedical Data Science 237 Using Splunk for Data Analytics 244 Statistical Analysis of Genomic Data with Hadoop 250 Extracting and Transforming Genomic Data 253 Processing eQTL Data 256 Generating Master SNP Files for Cases and Controls 259 Generating Gene Expression Files for Cases and Controls 260 Cleaning Raw Data Using MapReduce 261 Transpose Data Using Python 263 Statistical Analysis Using Spark 264 Hive Tables with Partitions 268 Conclusion 270 Notes 270 Appendix: A Brief Statistics Primer 290 Content Contributed by Daniel Peñaherrera Chapter 8 Next-Generation Cyberinfrastructures 307 Next-Generation Cyber Capability 308 NGCC Design and Infrastructure 310 Conclusion 327 Note 330 Conclusion 335 Appendix A The Research Data Management Survey: From Concepts to Practice 337 Brandon Mikkelsen and Jay Etchings Appendix B Central IT and Research Support 353 Gregory D. Palmer Appendix C HPC Working Example: Using Parallelization Programs Such as GNU Parallel and OpenMP with Serial Tools 377 Appendix D HPC and Hadoop: Bridging HPC to Hadoop 385 Appendix E Bioinformatics + Docker: Simplifying Bioinformatics Tools Delivery with Docker Containers 391 Glossary 399 About the Author 419 About the Contributors 421 Index 427

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Book SynopsisThe GnRH Neuron and its Control examines the developmental biology of GnRH neurons including their birth in the nasal placode of the early embryo, perinatal programming, and sexual differentiation, in addition to the hypothalamic mechanisms that control GnRH neurons in adulthood to generate pulsatile and surge modes of GnRH secretion throughout the major life stages including aging. The morphology, electrophysiology, signal transduction pathways, transcriptional regulators, and genomics underlying function of the adult GnRH neuron is discussed in detail, as is the neuroendocrinology and cell biology governing the generation of both modes of GnRH release. The book also reviews the neurobiological mechanisms and circuitry responsible for the modulation of the activity of GnRH neurons by season, stress, nutrition, and metabolism, and covers the current and potential therapeutic approaches to regulating GnRH secretion and action. Filled with newly identified research and classical fundaTable of ContentsList of Contributors, vii Series Preface, xi Preface, xiii About the Companion Website, xv PART I Historical Introduction to the GnRH Neuron 1 The Framework Upon Which Current Research on the GnRH Neuron and its Control is Built, 3Tony M. Plant and Allan E. Herbison PART II GnRH Neuron Development 2 Prenatal Development of GnRH Neurons, 15Yufei Shan and Susan Wray 3 Fetal/perinatal Programming Causing Sexual Dimorphism of the Kisspeptin–GnRH Neuronal Network, 43Hiroko Tsukamura, Kei]ichiro Maeda and Yoshihisa Uenoyama 4 Postnatal Development of GnRH Neuronal Function, 61Ei Terasawa PART III GnRH Neuron Biology 5 Regulation of GnRH Gene Expression, 95Hanne M. Hoffmann and Pamela L. Mellon 6 Morphology of the Adult GnRH Neuron, 121Rebecca E. Campbell 7 The Anatomy of the GnRH Neuron Network in the Human, 149Katalin Skrapits and Erik Hrabovszky 8 Electrophysiology of Rodent GnRH Neurons, 177Richard Piet and Allan E. Herbison 9 Anatomy and Physiology of GnRH Neurons and Their Control of Pituitary Function in Fish, 203Yoshitaka Oka PART IV Regulation of GnRH Neuron Function 10 Unveiling the Importance of Glia and Vascular Endothelial Cells in the Control of GnRH Neuronal Function, 227Vincent Prevot and Ariane Sharif 11 Genetic Strategies Examining Kisspeptin Regulation of GnRH Neurons, 259Michael Candlish, Philipp Wartenberg and Ulrich Boehm 12 KNDy Hypothesis for Generation of GnRH Pulses: Evidence from Sheep and Goats, 289Robert L. Goodman, Satoshi Okhura, Hiroaki Okamura, Lique M. Coolen, and Michael N. Lehman 13 Generation of the GnRH Surge and LH Surge by the Positive Feedback Effect of Estrogen, 325Iain Clarke 14 Influence of Stress on the GnRH Neuronal Network, 357Pasha Grachev and Kevin T. O’Byrne 15 Metabolic Regulation of GnRH Neurons, 383Maggie C. Evans and Greg M. Anderson 16 Seasonal Control of the GnRH Neuronal Network as a Means of Uncovering Novel Central Mechanisms Governing Mammalian Reproduction, 411Sébastien Milesi, Paul Klosen and Valerie Simonneaux PART V GnRH in the Clinic 17 Human Genetics of GnRH Neuron Function, 445A. Kemal Topaloglu and L. Damla Kotan 18 Modulators of GnRH Secretion and Therapeutic Applications, 469Claire L. Newton, Ross C. Anderson and Robert P. Millar Index, 499

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Book SynopsisAn accessible guide that introduces students in all areas of life sciences to bioinformatics Basic Applied Bioinformatics provides a practical guidance in bioinformatics and helps students to optimize parameters for data analysis and then to draw accurate conclusions from the results.Table of ContentsPREFACE, xi ACKNOWLEDGEMENTS, xiii LIST OF ABBREVIATIONS, xv SECTION I Molecular Sequences and Structures 1 Retrieval of Sequence(s) from the NCBI Nucleotide Database, 3 2 Retrieval of Protein Sequence from UniProtKB, 9 3 Downloading Protein Structure, 15 4 Visualizing Protein Structure, 19 5 Sequence Format Conversion, 23 6 Nucleotide Sequence Analysis Using Sequence Manipulation Suite (SMS), 31 7 Detection of Restriction Enzyme Sites, 43 SECTION II Sequence Alignment 8 Dot Plot Analysis, 53 9 Needleman–Wunsch Algorithm (Global Alignment), 59 10 Smith–Waterman Algorithm (Local Alignment), 67 11 Sequence Alignment Using Online Tools, 73 SECTION III Basic Local Alignment Search Tools 12 Basic Local Alignment Search Tool for Nucleotide (BLASTn), 81 13 Basic Local Alignment Search Tool for Amino Acid Sequences (BLASTp), 91 14 BLASTx, 103 15 tBLASTn, 109 16 tBLASTx, 113 SECTION IV Primer Designing and Quality Checking 17 Primer Designing – Basics, 121 18 Designing PCR Primers Using the Primer3 Online Tool, 125 19 Quality Checking of the Designed Primers, 139 20 Primer Designing for SYBR Green Chemistry of qPCR, 147 SECTION V Molecular Phylogenetics 21 Construction of Phylogenetic Tree: Unweighted]Pair Group Method with Arithmetic Mean (UPGMA), 151 22 Construction of Phylogenetic Tree: Fitch Margoliash (FM) Algorithm, 159 23 Construction of Phylogenetic Tree: Neighbor]Joining Method, 165 24 Construction of Phylogenetic Tree: Maximum Parsimony Method, 175 25 Construction of Phylogenetic Tree: Minimum Evolution Method, 183 26 Construction of Phylogenetic Tree Using MEGA7, 187 27 Interpretation of Phylogenetic Trees, 197 SECTION VI Protein Structure Prediction 28 Prediction of Secondary Structure of Protein, 211 29 Prediction of Tertiary Structure of Protein: Sequence Homology, 217 30 Protein Structure Prediction Using Threading Method, 223 31 Prediction of Tertiary Structure of Protein: Ab Initio Approach, 229 32 Validation of Predicted Tertiary Structure of Protein, 235 SECTION VII Molecular Docking and Binding Site Prediction 33 Prediction of Transcription Binding Sites, 243 34 Prediction of Translation Initiation Sites, 251 35 Molecular Docking, 257 SECTION VIII Genome Annotation 36 Genome Annotation in Prokaryotes, 265 37 Genome Annotation in Eukaryotes, 269 SECTION IX Advanced Biocomputational Analyses 38 Concepts of Real]Time PCR Data Analysis, 275 39 Overview of Microarray Data Analysis, 283 40 Single Nucleotide Polymorphism (SNP) Mining Tools, 289 41 In Silico Mining of Simple Sequence Repeats (SSR) Markers, 299 42 Basics of RNA]Seq Data Analysis, 305 43 Functional Annotation of Common Differentially Expressed Genes, 313 44 Identification of Differentially Expressed Genes (DEGs), 325 45 Estimating MicroRNA Expression Using the miRDeep2 Tool, 357 46 miRNA Target Prediction, 365 Appendices Appendix A: Usage of Internet for Bioinformatics, 377 Appendix B: Important Web Resources for Bioinformatics Databases and Tools, 381 Appendix C: NCBI Database: A Brief Account, 389 Appendix D: EMBL Databases and Tools: An Overview, 395 Appendix E: Basics of Molecular Phylogeny, 403 Appendix F: Evolutionary Models of Molecular Phylogeny, 411 GLOSSARY, 415 REFERENCES, 423 WEBLIOGRAPHY, 431 INDEX, 435

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Book SynopsisThis book provides a comprehensive review of the chemistry and research illustrating the benefits of polyurethane for immobilizing cells, with dozens of case studies in medical devices and environmental engineering. Offers an essential resource for medical and environmental scientists Provides a multidisciplinary and lucid writing style that uses little or no jargon Extrapolates current technology into advanced areas, especially environmental remediation and medical devices Fills the gap between immobilization research and practical applicationsTable of ContentsPreface ix 1 Polyurethane Chemistry 1 Introduction 1 The Chemistry 2 The Isocyanates 3 The Polyol 5 Cross-Linking 5 The Water Reaction 6 Process 8 The One-Shot Process 8 The Prepolymer Process 10 Post Processing 12 Architecture of Polyurethane Foam 14 Grafting to the Polyurethane Foam 16 Biodegradable PUR 19 Mechanism of Biodegradation 23 More Examples 24 Conclusion 25 References 26 2 Laboratory Practice 29 Introduction 29 Prepolymers 30 Preparation of an Elastomer 30 Preparation of Foam 32 Hydrophobic Foams 32 Hydrophilic Foams 34 Custom Prepolymers, Foams, and Scaffolds 40 Examples 43 Structure–Property Relationships 48 The Special Case of Hydrophilic Polyurethane Foams 50 Physical and Chemical Testing 50 Physical Testing 52 Biocompatibility Testing 54 Process Equipment 54 Metering Pump 55 Mixing Head 55 Tank/Material Retaining Container 55 Machine Manufacturers 56 References 56 3 Scaffolds 59 Introduction 59 Bioscaffolds 61 Examples of Biofilter 65 Elimination of Tobacco Odor from a Cigarette-Manufacturing Plant 67 Treatment of VOCs from an Industrial Plant 68 The Liver as Biofilter 68 Scaffolds for Medical Applications (In Vivo and Extracorporeal) 70 The Liver Model 71 The Extracellular Matrix as Scaffold 72 The Physical Scaffold 73 Design of an Ideal Scaffold 74 Drug Discovery 75 Materials of Construction 77 Ceramics 77 Metals 80 Polymer Scaffolds 82 Poly(lactic Acid) 82 Poly(glycolic Acid) 82 Polycaprolactone 83 Polyurethanes 83 The “Ideal” Scaffold 87 Pore Size and Distribution 89 Void Volume 91 Interconnectedness 96 Surface Area 98 Mechanical Properties 100 Surface Chemistry 100 Specifications of the Ideal Scaffold 101 References 105 4 Immobilization 109 Introduction 109 Methods of Immobilization 111 Immobilization by Adsorption 113 Biofiltration 113 Biotrickling Filter Setup and Operating Conditions 115 The Toluene Reactor 116 The H2S Reactor 120 Biological Treatment of Aquarium Tanks 123 Protein Adsorption 125 The Avidin–Biotin System 126 Application of the Avidin–Biotin System to Cell Adhesion to a Scaffold 128 Adsorption to a Tricalcium Phosphate (TCP) Scaffold Using the Avidin–Biotin System 128 Hepatic Cells on a Fabricated Polycaprolactone Scaffold 131 Summary of Immobilization by Adsorption 132 Immobilization by Extraction 133 Extraction of Pesticides 138 Summary 144 Immobilization by Entrapment 145 Alginate Encapsulation 146 Encapsulation of Pancreatic Islet Cells 148 Encapsulation of Osteoblasts 148 Introduction to the Pancreas Model 149 The Pancreas Model 150 Summary of Encapsulation 154 Immobilization by Covalent Bonding 154 Overview of Covalent Immobilization 156 Substrates Used for Immobilization 157 Alginates 158 Albumin 159 Collagen 159 Synthetic Polymers as Supports 159 Polyethylene 159 Poly l-Lactic Acid 160 Immobilization to Polyvinyl Chloride 161 Ceramics 163 Summary 163 Polyurethane Immobilization 164 Fundamental Principles 164 Prepolymer Chemistry 168 The Immobilization Chemistry 169 Structure and Chemistry of Biomolecules 170 Preparation of Immobilized Biomolecules 171 Notable Uses of Polyurethane for Immobilization 174 Organophosphates 174 Lipases 177 Fibroblasts 178 Collagen 180 Amyloglucosidase 182 Novel Reactor System 184 Endothelialization 185 Creatinine 186 Conclusion to Immobilization 187 References 189 5 Controlled Release from a Hydrogel Scaffold 195 Introduction 195 Release Rates 198 Examples of Hydrogels Used for Controlled Release 198 Polysaccharides 199 Pectin 199 Alginates 200 Carrageenan 200 Agar 200 Starch 200 Proteins 200 Gelatin 200 Casein 201 Other Proteins 201 Controlled Release by Diffusion 201 Reservoir Layer 202 Diffusion Experiments 206 Islet Encapsulation 208 Other Controlled Release Examples 211 Targeted Delivery 211 Stomach 212 Small Intestines 212 Colon 212 Summary and Conclusions 213 References 213 Index 215

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Book SynopsisA comprehensive, edited volume pulling together research on manipulation of the crop microbiome for climate resilient agriculture Microbes for Climate Resilient Agriculture provides a unique collection of data and a holistic view of the subject with quantitative assessment of how agricultural systems will be transformed in coming decades using hidden treasure of microbes. Authored by leaders in the field and edited to ensure conciseness and clarity, it covers a broad range of agriculturally important crops, discusses the impact of climate change on crops, and examines biotechnologically and environmentally relevant microbes. The book encapsulates the understanding of microbial mediated stress management at field level, and will serve as a springboard for novel research findings and new applications in the field. Chapter coverage includes: the role of the phytomicrobiome in maintaining biofuel crop production in a changing climate; the impact of agriculture on soil microbial communitTable of ContentsABOUT THE EDITORS xv LIST OF CONTRIBUTORS xix PREFACE xxiii 1 THE ROLE OF THE PHYTOMICROBIOME IN MAINTAINING BIOFUEL CROP PRODUCTION IN A CHANGING CLIMATE 1Gayathri Ilangumaran, John R. Lamont and Donald L. Smith 1.1 General Background on Climate Change 1 1.2 More Extreme Weather More Often – More Crop Stress 2 1.3 Biofuel Crops – Alternative to Fossil Fuels 3 1.4 Avoiding Competition with Food Production 4 1.5 Fuel Crops Grown on Marginal Lands – Constraints 4 1.6 Plant Response to Stresses Related to Climate Change and Marginal Lands 6 1.7 Sustaining Biofuel Crops Under Stressful Environments 7 1.8 The Phytomicrobiome and Climate Change Conditions 8 1.9 The Phytomicrobiome and Abiotic Plant Stress 8 1.10 Mechanisms of Stress Tolerance in the Phytomicrobiome 9 1.11 Phytomicrobiome Engineering 11 1.12 The Phytomicrobiome in Biofuel Plants 12 1.13 Role of the Phytomicrobiome in Phytoremediation by Biofuel Plants 13 References 14 2 THE IMPACT OF AGRICULTURE ON SOIL MICROBIAL COMMUNITY COMPOSITION AND DIVERSITY IN SOUTHEAST ASIA 25Binu M. Tripathi, Itumeleng Moroenyane and Jonathan M. Adams 2.1 Introduction 25 2.2 The Extent of Soil Microbial Diversity and their Status in Tropical Soils 27 2.3 The Composition and Function of Microbial Communities in Tropical Soils of Southeast Asia 29 2.3.1 Unique Soil Microbial Communities of Southeast Asia and their Potential Drivers 29 2.4 The Impact of Land use Change on Soil Microbial Community Structure and Diversity 31 2.5 The Impact of Land use Change on Soil Functional Gene Diversity 34 2.6 Conclusions 35 References 35 3 CLIMATE CHANGE IMPACT ON PLANT DISEASES: OPINION, TRENDS AND MITIGATION STRATEGIES 41Sachin Gupta, Deepika Sharma and Moni Gupta 3.1 Introduction 41 3.2 Climate Change and Agriculture 42 3.3 Interactions among Global Change Factors 43 3.4 Pathogen–Host Plant Relationship under Changed Scenario 44 3.5 Effect of Climate Change on Plant Diseases 44 3.5.1 Temperature 46 3.5.2 Drought 48 3.5.3 Rainfall 48 3.5.4 CO2 Concentration 48 3.6 Adaptation and Mitigation Strategies for Climate Change 49 3.6.1 Adaptation Strategies 49 3.6.2 Mitigation Strategies 50 3.7 Conclusion and Future Directions 51 References 51 4 MICROALGAE: POTENTIAL AGENTS FOR CARBON DIOXIDE MITIGATION 57Preeti Singh, Rahul Kunwar Singh and Dhananjay Kumar 4.1 Introduction 57 4.2 Carbon Capture and Storage 60 4.3 Carbon Capture by Photosynthesis 60 4.4 CO2 Mitigation by Microalgal Culture 60 4.4.1 The Open Pond System 61 4.4.2 The Closed Photobioreactor System 62 4.4.3 The Environmentally Controlled System 62 4.5 Advantages 62 4.5.1 Integration of Microalgal Culture in Waste Water Treatment 62 4.5.2 Ability of Microalgae to Tolerate the Greenhouse Gases 62 4.6 Carbon Concentrating Mechanism of Microalgae 65 4.7 CO2 Sequestration by Microalgae 65 4.8 Cost Effectiveness 66 4.8.1 Biofertilizer 66 4.8.2 Biofuel 67 4.8.3 Other Products 67 4.9 Conclusion 68 References 68 5 PHOTOSYNTHETIC MICROORGANISMS AND BIOENERGY PROSPECTS: CHALLENGES AND POTENTIAL 75Balkrishna Tiwari, Sindhunath Chakraborty, Ekta Verma and Arun Kumar Mishra 5.1 Introduction 75 5.2 Photosynthetic Microbes 78 5.3 Anoxigenic Photosynthetic Microbes 79 5.3.1 Green Photosynthetic Bacteria 79 5.3.2 Purple Bacteria 82 5.3.3 Heliobacteria 84 5.3.4 Prospects of Anoxigenic Photosynthetic Microbes in Bioenergy Production 86 5.4 Oxygenic Photosynthetic Microbes 87 5.4.1 Cyanobacteria 89 5.4.2 Microalgae 93 5.5 Biomass Production and Challenges 95 5.6 Some Important Issues Associated with Biofuel Production 96 5.6.1 Use of Water 96 5.6.2 Nutrients and Competition with Crops 96 5.6.3 Minimizing Algae Death from Biotic and Abiotic Factors 96 5.6.4 Competition with Petroleum in Terms of Price 97 5.7 Conclusions 97 Acknowledgements 98 References 98 6 AMELIORATION OF ABIOTIC STRESSES IN PLANTS THROUGH MULTI‐FACETED BENEFICIAL MICROORGANISMS 105Usha Chakraborty, Bishwanath Chakraborty and Jayanwita Sarkar 6.1 Introduction 105 6.2 Temperature Stress Alleviation 107 6.2.1 Alleviation by Bacteria 107 6.2.2 Alleviation by Fungi 110 6.3 Water and Salinity Stress Alleviation 112 6.3.1 Alleviation by Bacteria 112 6.3.2 Alleviation by Fungi 118 6.4 Alleviation of Heavy Metal Toxicity 124 6.5 Conclusions 131 References 132 7 ROLE OF METHYLOTROPHIC BACTERIA IN CLIMATE CHANGE MITIGATION 149Manish Kumar, Raghvendra Saxena, Rajesh Singh Tomar, Pankaj K. Rai and Diby Paul 7.1 Introduction 149 7.2 Methylotrophic Bacteria and their Role in Agriculture 151 7.3 Volatile Organic Carbon Mitigation and Methylotrophs 152 7.4 Carbon Cycling and Climate Change 152 7.5 Methylotrophs Mitigating Methane 154 7.6 Methylotrophs Mitigating Methane in Paddy Fields 158 7.7 Conclusions 160 Acknowledgements 160 References 160 8 CONSERVATION AGRICULTURE FOR CLIMATE CHANGE RESILIENCE: A MICROBIOLOGICAL PERSPECTIVE 165Raj Pal Meena and Ankita Jha 8.1 Introduction 165 8.2 The Effect of Climate Change on Agricultural Production 169 8.3 Concepts and Principles of Conservation Agriculture 173 8.4 The Ecological Role of Microbial Biodiversity in Agro‐Ecosystems 177 8.5 Role of Microbial Population in C‐Sequestration, N, P Cycle 179 8.6 Restoring Diversity in Large‐Scale Monocultures 180 8.7 Enhancing Crops vis‐a‐vis Microbial Biodiversity to Reduce Vulnerability 181 8.8 Conclusions 183 References 183 9 ARCHAEAL COMMUNITY STRUCTURE: RESILIENCE TO CLIMATE CHANGE 191M. Thomas, K.K. Pal and R. Dey 9.1 Introduction 191 9.2 Possible Role of Archaea in Agricultural Sustainability 192 9.3 Ecology and Phylogeny of Domain Archaea 193 9.4 Archaeal Contribution to Global Climate Change 194 9.4.1 Archaeal Response to Increased Temperatures 195 9.4.2 Archaeal Response to Biogeochemical Cycles 196 9.5 Archaeal Mechanisms of Adaptation with Respect to Abiotic Changes 200 9.6 Conclusions 200 References 201 10 MYCORRHIZA – HELPING PLANTS TO NAVIGATE ENVIRONMENTAL STRESSES 205Raghvendra Pratap Singh, Geetanjali Manchanda, Mian Nabeel Anwar, Jun Jie Zhang and Yue Zhang Li 10.1 Introduction 205 10.2 Arbuscular Mycorrhizae 207 10.3 Elevated CO2 Levels 209 10.4 High Temperature 211 10.5 Salinity 214 10.6 Conclusions 219 References 220 11 ENDOPHYTIC MICROORGANISMS: FUTURE TOOLS FOR CLIMATE RESILIENT AGRICULTURE 235R. Dey, K.K. Pal, M. Thomas, D.N. Sherathia, V.B. Mandaliya, R.A. Bhadania, M.B. Patel, P. Maida, D.H. Mehta, B.D. Nawade and S.V. Patel 11.1 Introduction 235 11.1.1 Climate Change – Impact and Need for Adaptation 236 11.2 Endophytes and Climate Resilience 239 11.2.1 High Temperature Stress 239 11.2.2 Low Temperature Stress 240 11.2.3 Moisture‐Deficit Stress 240 11.2.4 Salinity Stress 242 11.2.5 Waterlogging Stress 244 11.3 Endophytes and Biotic Stress 245 11.3.1 Plant Diseases 245 11.3.2 Nematode Infestation 247 11.3.3 Insect Pests 247 11.4 Conclusions 247 References 248 12 BACILLUS THURINGIENSIS: GENETIC ENGINEERING FOR INSECT PEST MANAGEMENT 255Gothandapani Sellamuthu, Prabhakaran Narayanasamy and Jasdeep Chatrath Padaria 12.1 Introduction 255 12.2 Biology of Bacillus Thuringiensis 257 12.2.1 Natural Occurrence of Bacillus thuringiensis 257 12.2.2 Classification of Bt Toxins 258 12.2.3 Mode of Action 260 12.3 Biotechnological Approaches of Microbial Genes for Insect Pest Management 261 12.3.1 Microbial Genes and Gene Pyramiding 261 12.3.2 Alternative Insecticidal Genes 262 12.3.3 Gene Pyramiding 262 12.4 Methods for Development of Transgenic Crops 263 12.4.1 Direct Gene Transfer 264 12.4.2 Indirect Gene Transfer 266 12.5 Field Evaluation and Commercially Available Insecticidal Crops 267 12.5.1 Environmental Safety 269 12.5.2 Ecological Balance and Food Safety 270 12.6 Insecticide Resistance 270 12.7 Conclusions 271 References 271 13 MICROBIAL NANOTECHNOLOGY FOR CLIMATE RESILIENT AGRICULTURE 279Prem Lal Kashyap, Pallavi Rai, Raj Kumar, Shikha Sharma, Poonam Jasrotia, Alok Kumar Srivastava and Sudheer Kumar 13.1 Introduction 279 13.2 Microbe Mediated Fabrication of Nanoparticles 281 13.2.1 Bacteria 281 13.2.2 Fungi 286 13.2.3 Algae 287 13.2.4 Viruses 292 13.2.5 Actinomycetes 293 13.3 Nanomaterials for Biotic and Abiotic Stress Management 295 13.3.1 Biotic Stress Management 295 13.3.2 Abiotic Stress Management 306 13.4 Nano‐Fertilizers for Balanced Crop Nutrition 314 13.5 Conclusion and Future Directions 315 References 316 INDEX 345

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Book SynopsisA comprehensive resource on the recent developments of stem cell use in wound healing With contributions from experts in the field, Wound Healing offers a thorough review of the most recent findings on the use of stem cells to heal wounds. This important resource covers both the basic and translational aspects of the field. The contributors reveal the great progress that has been made in recent years and explore a wide range of topics from an overview of the stem cell process in wound repair to inflammation and cancer. They offer a better understanding of the identities of skin stem cells as well as the signals that govern their behavior that contributes to the development of improved therapies for scarring and poorly healing wounds. Comprehensive in scope, this authoritative resource covers a wealth of topics such as: an overview of stem cell regeneration and repair, wound healing and cutaneous wound healing, the role of bone marrow derived stems cells, Table of ContentsList of Contributorsvii 1 Stem Cell Regeneration and Repair – Overview 1Clement D. Marshall, Alessandra A. Moore, Michael T. Longaker, and H. Peter Lorenz 2 Cadherins as Central Modulators of Wound Repair 15Melissa Crawford and Lina Dagnino 3 Tight Junctions and Cutaneous Wound Healing 31Thomas Volksdorf and Johanna M. Brandner 4 The Role of Microvesicles in Cutaneous Wound Healing 43Alexandra Laberge and Véronique J. Moulin 5 Wound Healing and Microenvironment 67Elgin Türköz Uluer, Hafize Seda Vatansever, and Feyzan Őzdal Kurt 6 Wound Healing and the Non-cellular Microenvironment 79Hayley S. Ramshaw, Jasreen Kular, and Michael S. Samuel 7 Contribution of Adipose-Derived Cells to Skin Wound Healing 89Barbara Gawronska-Kozak, Joanna Bukowska, Xiying Wu, Amy Lin Strong, Trivia Frazier, Bruce A. Bunnell, and Jeffrey M. Gimble 8 Role of Bone Marrow-Derived Stem Cells in Wound Healing 103Feyzan Özdal Kurt, Hafize Seda Vatansever, and Elgin Türköz Uluer 9 Role of Vitamin D and Calcium in Epidermal Wound Repair 113Daniel D. Bikle, Chia-ling Tu, and Yuko Oda 10 Oral Mucosal Healing 125Luisa A. DiPietro and Megan Schrementi 11 Role of Adipose-Derived Stem Cells in Wound Healing: An Update from Isolation to Transplantation 133Selami Demirci, Ayşegül Doğan, and Fikrettin Şahin 12 The Hair Follicle as a Wound Healing Promoter and Its Application in Clinical Practice 149Francisco Jimenez, María Luisa Martínez, Eduardo Escario, and Ander Izeta 13 Impaired Wound Healing in Diabetic Ulcers: Accelerated Healing Through Depletion of Ganglioside 167Duncan Hieu M. Dam, Sophia A. Jelsma, and Amy S. Paller 14 Inflammation in Wound Repair: Role and Function of Inflammation in Wound Repair 177Amanda S. MacLeod and Jeffery T. Kwock 15 Inflammation, Wound Healing, and Fibrosis 195Shibnath Ghatak, Vincent C. Hascall, Ricardo Moreno Rodriguez, Roger R. Markwald, and Suniti Misra 16 The Potential Role of Photobiomodulation and Polysaccharide-Based Biomaterials in Wound Healing Applications 211Heidi Abrahamse, Sathish Sundar Dhilip Kumar, and Nicolette Nadene Houreld 17 Is Understanding Fetal Wound Repair the Holy Grail to Preventing Scarring? 225Olivier A. Branford and Kerstin J. Rolfe 18 Inflammation and Cancer 239Suniti Misra, Vincent C. Hascall, Roger R. Markwald, Paul E. O’Brien, and Shibnath Ghatak Index 275

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Book SynopsisCloses the gap between bioscience and mathematics-based process engineering This book presents the most commonly employed approaches in the control of bioprocesses. It discusses the role that control theory plays in understanding the mechanisms of cellular and metabolic processes, and presents key results in various fields such as dynamic modeling, dynamic properties of bioprocess models, software sensors designed for the online estimation of parameters and state variables, and control and supervision of bioprocesses Control in Bioengineering and Bioprocessing: Modeling, Estimation and the Use of Sensors is divided into three sections. Part I, Mathematical preliminaries and overview of the control and monitoring of bioprocess, provides a general overview of the control and monitoring of bioprocesses, and introduces the mathematical framework necessary for the analysis and characterization of bioprocess dynamics. Part II, Observability and control conceptsTable of ContentsPreface xi Part I Overview of the Control and Monitoring of Bioprocesses and Mathematical Preliminaries 1 1 Introduction 3 1.1 Overview of the Control and Monitoring of Bioprocesses 3 1.1.1 Why Nonlinear Control in Bioprocesses? 3 1.2 Improvements to Bioprocesses Productivity 13 1.2.1 Cell Lines 16 1.2.1.1 Cell Culture Process General 18 1.2.2 Microorganism Growth Under Controlled Conditions 18 1.2.3 On the Environment for the Microorganism’s Growth 19 1.2.4 Improving the Productivity for Specific Metabolic Products 21 1.3 Bioprocess Control 22 1.3.1 What is a Bioprocess? 22 1.3.2 Bioprocess Monitoring and Control 23 1.3.3 Stability of Bioprocess 25 1.3.4 Basic Concepts and Controllers 27 1.3.5 Advanced Control Schemes: Multivariable Control, Robust, Fuzzy Logic, Model Predictive Control, or Others 30 1.4 Process Measurements 32 1.4.1 The Drawback for Monitoring Bioprocess 32 1.4.2 Primary on-Line Sensor (e.g. Dissolved Oxygen, Temperature, Culture pH, Pressure, Agitation Rate, Flow Rates, Redox, CO2, and Others) 33 1.4.3 Primary in-Line Sensor 33 1.4.4 Process Analytical Technologies (Gas Analysis, Spectrometers, Infrared, HPLC, PCR, and Others) 34 1.4.5 Software Sensor (e.g. Cell Mass Estimation Via Complex Medium, Primary Carbon Substrate, Concentration Product of Line, Metabolites, Sensor to Computer Via Wireless) 36 1.5 Dynamic Bioprocess Models 40 1.5.1 Bioprocess Modeling for Control Purposes 40 1.5.2 Mass and Energy Balance of the Bioprocess 41 1.5.2.1 Dynamical Mass Balance 41 1.5.2.2 Batch Process 42 1.5.2.3 Fed-Batch 42 1.5.2.4 Continuous 43 1.5.2.5 Energy Balance 43 1.5.3 Black Box, White Box, and Gray Box Models 45 1.5.3.1 Black Box 45 1.5.3.2 White Box 45 1.5.3.3 Gray Box 45 1.5.4 Linear and Nonlinear Models 45 1.5.5 Segregated and Non-segregated Models 46 1.5.6 Structured and Unstructured Models 46 1.5.7 Structured Models 47 1.6 Process Optimization 51 1.6.1 Off-Line and On-Line Optimization of Bioprocesses 51 References 53 2 Mathematical Preliminaries 63 2.1 Systems of Ordinary Differential Equations 63 2.1.1 Differential Equations, Vector Fields, and State-Space Description 64 2.2 Linear Systems 70 2.2.1 The Fundamental Theorem for Linear Systems 70 2.2.2 Linear Systems in R2 71 2.2.3 Complex Eigenvalues 71 2.2.4 Multiple Eigenvalues 72 2.3 Nonlinear Dynamical Systems and its Analysis 72 2.3.1 Preliminary Concepts and Definitions 72 2.3.1.1 Continuous Dynamical Systems 73 2.3.1.2 Phase Space and Phase Portrait 73 2.3.1.3 Trajectories of Autonomous and Non-Autonomous Systems 73 2.3.1.4 The Vector Field 74 2.3.1.5 Lipschitz Condition 74 2.3.2 Existence-Uniqueness Theorem 75 2.3.2.1 Algebraic Properties of Lipschitz Continuous Functions 76 2.3.3 Dependence on Initial Conditions and Parameters 77 2.3.4 The Flow Defined by a Differential Equation 78 2.3.4.1 Differential Flow 78 2.3.5 Equilibrium Points 79 2.3.5.1 Equilibrium 79 2.3.6 The Hartman–Grobman Theorem 80 2.3.7 The Stable Manifold Theorem 81 2.3.8 Saddles, Nodes, Foci, and Centers 82 2.3.9 Center Manifold Theory 84 2.4 Stability Theory via Lyapunov Approach 84 2.4.1 Stability Notions 84 2.4.1.1 Stability 84 2.4.1.2 Asymptotic Stability 85 2.4.1.3 Exponential Stability 86 2.4.2 The Direct Method of Lyapunov (Second Method) 86 2.4.2.1 Positive Function 86 2.4.2.2 Theorem of Lyapunov 87 2.4.2.3 Globally Uniformly Asymptotically Stable of Lyapunov 88 2.4.2.4 Definition Matrices and Functions 88 2.4.3 The Indirect Method of Lyapunov (First Method) 90 2.4.3.1 Linearization 90 2.4.3.2 Stability by Linearization 90 2.4.4 Lasalles Invariance Principle 91 2.4.5 Invariant Set 91 2.4.6 Input/Output Stability 92 2.4.7 General Properties of Linear and Nonlinear Systems 93 2.4.8 Advanced Stability Theory 93 2.4.8.1 Concepts of Stability for Non-Autonomous Systems 93 2.4.8.2 Lyapunov-like Analysis Using Barbalat’s Lemma 94 2.5 Bifurcation Theory 94 2.5.1 Periodic Orbit 95 2.5.2 Limit Cycle 95 2.5.3 Bifurcation of Maps 95 2.5.4 Hyperbolic and Non-Hyperbolic Equilibrium Points 96 2.5.5 Bifurcation Point 96 2.5.6 Lyapunov Exponent 96 2.5.7 Chaos 97 2.5.8 Topological Equivalence 97 2.5.9 Example Bifurcations and Structural Stability of Dynamical Systems 98 2.6 Overview of Non-Smooth Dynamical Systems 99 References 101 Part II Observability and Control Concepts 107 3 State Estimation and Observers 109 3.1 Observability 109 3.1.1 Context and Motivations 109 3.1.2 Linear Observability 112 3.1.3 Nonlinear Observability 113 3.1.4 Geometric Conditions of Observability 114 3.1.4.1 Differential-Algebraic Observability Approach 115 3.1.5 Analytic Conditions for Observability 116 3.1.6 Detectability 116 3.1.7 Unobservable Subspaces 116 3.1.7.1 A Geometric Characterization 117 3.1.8 Unconstructive Subspaces 117 3.2 Observer Designs for Linear Structures 117 3.2.1 Luenberger Observer 118 3.2.2 Kalman Filter 119 3.2.3 Wiener Filter 120 3.3 Observer Designs for Nonlinear Structures 121 3.3.1 Extended Luenberger Observer 121 3.3.2 Extended Kalman Filter 122 3.3.2.1 First-Order Extended Kalman Filter 122 3.3.3 Asymptotic Observers 124 3.3.3.1 High-Gain Observer 124 3.3.4 Adaptive-Gain Observers 126 3.3.4.1 Adaptive High-Gain Observer 126 3.3.5 Sliding-Mode Observers 127 3.3.5.1 Sliding Mode Observers for Linear Uncertain Systems 127 3.3.5.2 Nonlinear Approaches to Sliding Mode Observer Design 130 References 131 4 Control of Bioprocess 135 4.1 The Control Idea 135 4.1.1 General Definitions 136 4.1.2 Controllability of Input/State/Output Systems 138 4.1.3 Steady-Output Controllability 139 4.1.4 Linear Controllability Analysis LTI Test 140 4.1.4.1 Controllable and Reachable Subspaces 140 4.1.4.2 Controllable Matrix Test 140 4.1.4.3 Eigenvector Test for Controllability 140 4.1.4.4 Popov–Belevitch–Hautus 141 4.1.4.5 Lyapunov Test for Controllability 141 4.1.5 Stabilizability 141 4.2 Controllers for Linear Systems 141 4.2.1 Linear Feedback 141 4.2.2 Proportional, Proportional-Integral, Proportional-Integral-Derivative 143 4.2.3 Optimal Control 143 4.2.4 Observer Based Controllers 144 4.3 Nonlinear Controllers 145 4.3.1 Nonlinear Controllability 145 4.3.2 Exact Feedback Linearization 147 4.3.3 Input-Output Linearization 147 4.3.3.1 Lyapunov-Based Control Design Methods 148 4.3.3.2 Back-Stepping Control 148 4.3.4 Nonlinear Sliding Mode 149 4.3.4.1 Sliding Surface Design 149 4.3.4.2 Control Law First-Order Sliding Mode Control 150 4.3.4.3 Control Law Second-Order Sliding Mode Control 151 4.3.4.4 Twisting Algorithm 152 4.3.4.5 Super Twisting Algorithm 152 4.3.4.6 Variable Structure Systems 152 4.3.5 Model Predictive Control 154 4.3.6 Control Using Neural Network 155 4.3.7 Nonlinear Design of Adaptive Controllers 156 4.3.7.1 Identification of Unknown Parameters 156 4.3.7.2 Observer-Based Identification 157 4.3.7.3 Adaptive Control Under Matching Conditions 157 4.3.7.4 Indirect Adaptive Control 158 4.3.7.5 Model Reference Adaptive Control 158 References 161 Part III Software Sensors and Observer-Based Control Schemes for Bioprocess 169 5 Dynamical Behavior of a 3-Dimensional Continuous Bioreactor 171 5.1 Introduction 171 5.2 Bioreactor Modeling 173 5.2.1 Estimation of the Kinetic Parameters 173 5.3 Main Results 175 5.4 Concluding Remarks 181 References 182 6 Observability Analysis Applied to 2D and 3D Bioreactors with Inhibitory and Non-inhibitory Kinetics Models 185 6.1 Introduction 185 6.2 Materials and Methods 186 6.2.1 Kinetic Models of Inhibition 186 6.2.1.1 Dynamics Models 187 6.2.2 Observability Criterion 188 6.3 Results and Discussion 188 6.4 Implementation of a Linear Observer to Check the Results of the Observability Analysis 200 6.5 Conclusion 201 References 202 7 Production System Myco-Diesel for Implementation of “Quality” of the Observability 205 7.1 Introduction 205 7.2 Methodology 206 7.2.1 Local Observability Quality 206 7.2.2 Bioreactor Model 207 7.3 Main Results 208 7.4 Conclusions 213 References 214 8 Regulation of a Continuously Stirred Bioreactor via Modeling Error Compensation 217 8.1 Introduction 217 8.2 Materials and Methods 219 8.2.1 Bioreactor Modeling 219 8.2.2 Mathematical Model 219 8.2.3 Mass Balance Modeling 219 8.3 Input–Output Identified Model 221 8.4 Control Design 221 8.5 Main Results 225 8.6 Concluding Remarks 228 References 229 9 Development of Virtual Sensor Based on the Just-In-Time Model for Monitoring of Biological Control Systems 233 9.1 Introduction 233 9.2 Materials and Methods 235 9.2.1 Kinetic and Simulated Mycoparasitism T. harzianum – C. cladosporioides 235 9.2.2 Mathematical Model 236 9.3 On-line Monitoring (Proposed Nonlinear Observer) 239 9.3.1 Sketch of Proof of Proposition 9.1 240 9.4 Such Approaches, Known as Proposed Just-in-Time Modeling “Hybrid Systems” 242 9.5 Results 243 9.6 Conclusions 249 References 250 10 Virtual Sensor Design for State Estimation in a Photocatalytic Bioreactor for Hydrogen Production 255 10.1 Introduction 255 10.2 Material and Methods 257 10.2.1 Methods 257 10.2.2 Desulfovibrio Alaskensis 6SR 258 10.3 Mathematical Model Development 258 10.3.1 Basic Concepts 258 10.3.2 Proposed Model 258 10.3.3 Determination of Kinetic Parameters 261 10.4 Virtual Sensor Design 262 10.5 Results and Discussion 265 10.6 Conclusions 272 References 273 Index 277

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Book SynopsisPresents an integrated view of the expression of bacterial genetic information, genome architecture and function, and bacterial physiology and pathogenesis This book blends information from the very latest research on bacterial chromosome and nucleoid architecture, whole-genome analysis, cell signaling, and gene expression control with well-known gene regulation paradigms from model organisms (including pathogens) to give readers a picture of how information flows from the environment to the gene, modulating its expression and influencing the competitive fitness of the microbe. Structure and Function of the Bacterial Genome explores the governance of the expression of the genes that make a bacterium what it is, and updates the basics of gene expression control with information about transcription promoter structure and function, the role of DNA as a regulatory factor (in addition to its role as a carrier of genetic information), small RNAs, RNAs that sense chemical signals, ribosomeTable of ContentsPreface xiii 1 The Bacterial Genome – Where the Genes are 1 1.1 Genome Philosophy 1 1.2 The Bacterial Chromosome 4 1.3 Chromosome Replication: Initiation 6 1.4 Chromosome Replication: Elongation 11 1.5 Chromosome Replication: Termination 12 1.6 Replication Produces Physically Connected Products 13 1.7 Decatenating the Sister Chromosomes 13 1.8 Resolving Chromosome Dimers 14 1.9 Segregating the Products of Chromosome Replication 15 1.10 Polar Tethering of Chromosome Origins 20 1.11 Some Bacterial Chromosomes are Linear 20 1.12 Some Bacteria Have More than One Chromosome 21 1.13 Plasmids 22 1.14 Plasmid Replication 22 1.15 Plasmid Segregation 26 1.16 The Nucleoid 28 1.17 The Chromosome Has Looped Domains 29 1.18 The Macrodomain Structure of the Chromosome 29 1.19 The Chromosome Displays Spatial Arrangement Within the Cell 30 1.20 SeqA and Nucleoid Organisation 31 1.21 MukB, a Condensin-Like Protein 32 1.22 MatP, the matS Site and Ter Organisation 33 1.23 MaoP and the maoS Site 34 1.24 SlmA and Nucleoid Occlusion 34 1.25 The Min System and Z Ring Localisation 34 1.26 DNA in the Bacterial Nucleoid 36 1.27 DNA Topology 36 1.28 DNA Topoisomerases: DNA Gyrase 38 1.29 DNA Topoisomerases: DNA Topoisomerase IV 40 1.30 DNA Topoisomerases: DNA Topoisomerase I 40 1.31 DNA Topoisomerases: DNA Topoisomerase III 41 1.32 DNA Replication and Transcription Alter Local DNA Topology 41 1.33 Transcription and Nucleoid Structure 41 1.34 Nucleoid-associated Proteins (NAPs) and Nucleoid Structure 43 1.35 DNA Bending Protein Integration Host Factor (IHF) 44 1.36 HU, a NAP with General DNA-binding Activity 46 1.37 The Very Versatile FIS Protein 47 1.38 FIS and the Early Exponential Phase of Growth 48 1.39 FIS and the Stringent Response 49 1.40 FIS and DNA Topology 49 1.41 Ferritin-Like Dps and the Curved-DNA-binding Protein CbpA 51 1.42 The H-NS Protein: A Silencer of Transcription 53 1.43 StpA: A Paralogue of H-NS 57 1.44 H-NS Orthologues Encoded by Plasmids and Phage 58 1.45 H-NSB/Hfp and H-NS2: H-NS Homologues of HGT Origin 58 1.46 A Truncated H-NS-Like Protein 59 1.47 Hha-like Proteins 59 1.48 Other H-NS Homologues: The Ler Protein from EPEC 60 1.49 H-NS Functional Homologues 62 1.50 H-NS Functional Homologues: Rok from Bacillus spp. 63 1.51 H-NS Functional Homologues: Lsr2 from Actinomycetes 63 1.52 H-NS Functional Homologues: MvaT from Pseudomonas spp. 63 1.53 The Leucine-responsive Regulatory Protein, LRP 64 1.54 Small, Acid-soluble Spore Proteins, SASPs 65 2 Conservation and Evolution of the Dynamic Genome 67 2.1 Disruptive Influences: Mutations 67 2.2 Repetitive Sequences in the Chromosome and Their Influence on Genetic Stability 69 2.3 Contingency Loci and the Generation of Microbial Variety 70 2.4 Rhs: Rearrangement Hotspots 71 2.5 REP Sequences 72 2.6 RIB/RIP, BIME-1, and BIME-2 Elements 73 2.7 ERIC Sequences 73 2.8 Repeat-Mediated Rearrangements: Mechanisms and Frequency 74 2.9 Site-specific Recombination and Phenotypic Variety 74 2.10 Site-Specific Recombination: Bacteriophage Lambda 75 2.11 The Lambda Lysis/Lysogeny Decision 76 2.12 Tyrosine Integrases 77 2.13 Serine Invertases 78 2.14 Large Serine Recombinases 79 2.15 Transposition and Transposable Elements 80 2.16 Pathways of Transposition 82 2.17 Peel-and-paste Transposition 85 2.18 Control of Transposition 88 2.19 Host Factors and Transposition 91 2.20 Integrative and Conjugative Elements (ICE) 91 2.21 Integrons 93 2.22 Introns 96 2.23 Horizontal Gene Transfer 96 2.24 Distinguishing Self from Non-self 99 2.25 Distinguishing Self and Non-self: CRISPR-Cas Systems 99 2.26 Distinguishing Self and Non-self: Argonaute Proteins 102 2.27 Distinguishing Self and Non-self: Restriction Enzymes/Methylases 103 2.28 Distinguishing Self and Non-self: BREX 103 2.29 Self-sacrifice and Other Behaviours Involving Toxin—antitoxin Systems 104 2.30 Conservative Forces: DNA Repair and Homologous Recombination 104 2.31 The RecA Protein 105 2.32 RecA, LexA, and the SOS Response 106 2.33 Holliday Junction Resolution 108 2.34 Mismatch Repair 109 2.35 Non-homologous End Joining 110 3 Gene Control: Transcription and Its Regulation 113 3.1 Transcription: More Than Just Transcribing Genetic Information 113 3.2 RNA Polymerase 113 3.3 The Core Enzyme 114 3.4 The Sigma Factors (and Anti-Sigma Factors) 116 3.5 Promoter Architecture 120 3.6 Stringently Regulated Promoters 120 3.7 Transcription Factors and RNA Polymerase 121 3.8 Transcription Initiation 124 3.9 Transcription Elongation 125 3.10 Transcription Termination: Intrinsic and Rho-Dependent Terminators 127 3.11 Rho and Imported Genes 128 3.12 Rho, R-Loops, and DNA Supercoiling 128 3.13 Rho and Antisense Transcripts 128 3.14 Anti-Termination: Insights from Phage Studies 129 3.15 Transcription Occurs in Bursts 129 4 Gene Control: Regulation at the RNA Level 133 4.1 Antisense Transcripts and Gene Regulation in cis 134 4.2 RNA that Regulates in trans 134 4.3 DsrA and the RpoS/H-NS Link 138 4.4 sRNA Turnover 140 4.5 DEAD-box Proteins 140 4.6 RNA Chaperone Proteins 141 4.7 StpA, H-NS, and RNA Binding 142 4.8 Degradation of mRNA 143 4.9 RNA Folding and Gene Regulation 144 4.10 Transcription Attenuation 145 4.11 Riboswitches 145 4.12 RNA as a Structural Component in the Nucleoid 146 5 Gene Control: Regulation at the Protein Level 149 5.1 Control Beyond DNA and RNA 149 5.2 Translation Machinery and Control: tRNA and rRNA 149 5.3 Translation Machinery and Control: The Ribosome 150 5.4 Translation Initiation 152 5.5 Translation Elongation 154 5.6 Elongation Factor P (EF-P) 155 5.7 Translation Termination 156 5.8 Protein Secretion 157 5.9 Protein Secretion: The Sec Pathway 157 5.10 The Twin Arginine Translocation (Tat) Pathway of Protein Secretion 159 5.11 Type 1 Secretion Systems (T1SS) 160 5.12 Type 2 Secretion Systems (T2SS) 161 5.13 Type 3 Secretion Systems (T3SS) 162 5.14 Type 4 Secretion Systems (T4SS) 164 5.15 Type 5 Secretion Systems (T5SS): The Autotransporters 165 5.16 Type 6 Secretion Systems (T6SS) 166 5.17 Protein Secretion in Gram-Positive Bacteria: SecA1, SecA2, and SrtA 167 5.18 Type 7 Secretion Systems (T7SS) 168 5.19 Protein Modification: Acetylation 168 5.20 Protein Modification: Glycosylation 169 5.21 Protein Modification: Phosphorylation 169 5.22 Protein Splicing 171 5.23 Small Proteins 172 5.24 Selenocysteine and Pyrrolysine: The 21st and 22nd Amino Acids 173 6 Gene Control and Bacterial Physiology 175 6.1 The Bacterial Growth Cycle 175 6.2 Physiology Changes Throughout the Growth Cycle 176 6.3 Generating Physiological Variety from Genetic Homogeneity 178 6.4 Bacterial Economics – Some Basic Principles 179 6.5 Carbon Sources and Metabolism 180 6.6 Gene Control and Carbon Source Utilisation 183 6.7 Anaerobic Respiration 183 6.8 ArcA, Mobile Genetic Elements, and HGT 184 6.9 Stress and Stress Survival in Bacterial Life 185 6.10 Oxygen Stress 185 6.11 Iron Starvation 186 6.12 Siderophores and Iron Capture 188 6.13 TonB-Dependent Transporters 188 6.14 Gene Regulation and Iron Transport 190 6.15 Iron Storage and Homeostasis 191 6.16 Osmotic Stress andWater Relations in Bacteria 191 6.17 Signal Molecules and Stress 193 6.18 The Stringent Response 194 6.19 Regulation of the Acid Stress Response 196 6.20 Alkaline pH Stress Response 200 6.21 Motility and Chemotaxis 201 6.22 Quorum Sensing 203 6.23 Biofilms 205 6.24 ‘Cheating’ as a Lifestyle Strategy 206 6.25 Thermal Regulation 207 6.26 Epigenomics and Phasevarions 209 6.27 Some Unifying Themes 210 7 Gene Control: Global Regulation by H-NS 211 7.1 H-NS is a Global Regulator 211 7.2 H-NS and Foreign DNA 211 7.3 H-NS and Xenogenic Silencing: Three Case Studies 212 7.4 The H-NS Virulence Regulon in Vibrio cholerae 212 7.5 HGT in V. cholerae: The CTXϕ Phage and the VPI1 Island 213 7.6 The ToxRS, ToxT, TcpPH Regulatory Network 215 7.7 Control by VpsR, VpsT, and HapR 215 7.8 Quorum Sensing and Cholera 217 7.9 Chitin and HGT 217 7.10 The H-NS Virulence Regulon in Shigella flexneri 219 7.11 Shigella Infection 221 7.12 The VirF AraC-Like Transcription Factor 222 7.13 VirB: A Recruit from a Plasmid-Partitioning System 222 7.14 The Shigella Virulence Plasmid 223 7.15 The Salmonella H-NS Virulence Gene Regulon 223 7.16 Salmonella’s Pathogenicity Islands (SPI) 224 7.17 SlyA, PhoP/Q, and SPI Gene Expression 227 7.18 Gene Control in SPI1 and SPI2 227 8 An Integrated View of Genome Structure and Function 231 8.1 Networks versus Hierarchies 231 8.2 Regulons, Stimulons, and Heterarchies/Netarchies 232 8.3 Transcription Burstiness and Regulatory Noise 233 8.4 The Significance of Gene Position 234 8.5 Messenger RNA May Not Be Free to Diffuse Far in Bacteria 236 8.6 RNA Polymerase Activity and Genome Organisation 237 8.7 Gene–Gene Interactions in the Folded Chromosome 239 8.8 DNA Supercoiling as a Global Regulator 240 8.9 Modelling the Nucleoid 243 8.10 Synthetic Biology 243 References 247 Index 379

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Book SynopsisIntegrates the various disciplines of the science of health disparities in one comprehensive volume The Science of Health Disparities Research is an indispensable source of up-to-date information on clinical and translational health disparities science. Building upon the advances in health disparities research over the past decade, this authoritative volume informs policies and practices addressing the diseases, disorders, and gaps in health outcomes that are more prevalent in minority populations and socially disadvantaged communities. Contributions by recognized scholars and leaders in the fieldfeaturing contemporary research, conceptual models, and a broad range of scientific perspectivesprovide an interdisciplinary approach to reducing inequalities in population health, encouraging community engagement in the research process, and promoting social justice. In-depth chapters help readers better understand the specifics of minority health and health disparities while demonstrating the importance of advancing theory, refining measurement, improving investigative methods, and diversifying scientific research. In 26 chapters, the book examines topics including the etiology of health disparities research, the determinants of population health, research ethics, and research in African American, Asians, Latino, American Indian, and other vulnerable populations. Providing a unified framework on the principles and applications of the science of health disparities research, this important volume: Defines the field of health disparities science and suggests new directions in scholarship and researchExplains basic definitions, principles, and concepts for identifying, understanding and addressing health disparitiesProvides guidance on both conducting health disparities research and translating the resultsExamines how social, historical and contemporary injustices may influence the health of racial and ethnic minoritiesIllustrates the increasing national and global importance of addressing health disparitiesDiscusses population health training, capacity-building, and the transdisciplinary tools needed to advance health equity A significant contribution to the field, The Science of Health Disparities Research is an essential resource for students and basic and clinical researchers in genetics, population genetics, and public health, health care policymakers, and epidemiologists, medical students, and clinicians, particularly those working with minority, vulnerable, or underserved populations.Table of ContentsList of Contributors ix Foreword xxi Acknowledgements xxiii 1 Definitions, Principles, and Concepts for Minority Health and Health Disparities Research 1Eliseo J. Pérez-Stable, Jennifer Alvidrez, and Carl V. Hill 2 Getting Under the Skin: Pathways and Processes that Link Social and Biological Determinants of Disease 13Chandra L. Jackson, Rada K. Dagher, Jung S. Byun, Tilda Farhat, and Kevin L. Gardner 3 Racial/Ethnic, Socioeconomic, and Other Social Determinants 39Tiffany L. Gary-Webb, Sara E. Baumann, Erik J. Rodriquez, Lydia A. Isaac, and Thomas A. LaVeist 4 Behavioral Determinants in Population Health and Health Disparities Research 59Amelie G. Ramirez, Patricia Chalela, Melanie D. Sabado-Liwag, and Kelvin Choi 5 Sociocultural Environments and Health Disparities Research: Frameworks, Methods, and Promising Directions 77Hortensia Amaro, Samantha Garcia, Inna Arnaudova, and Monica P. Jolles 6 Physical Environment, and Minority Health and Health Disparities Research 95Tracy Bastain, Carrie Breton, Shohreh Farzan, Rima Habre, Jill Johnston, Derrick C. Tabor, Claudia Toledo-Corral, and Elizabeth Vang 7 Genome-wide Genetic Approaches to Metabolic and Inflammatory Health Disparities 109Cheryl A. Winkler 8 Biologic Factors and Molecular Determinants in Inflammatory and Metabolic Diseases 125Marquitta White, Esteban Burchard, Page Goddard, Anup K. Nair, Leslie J. Baier, Federico Fuentes, and Jeffrey B. Kopp 9 Insights into the Genomic Landscape of African Ancestry Populations: Implications for Health and Disease Disparities 139Charles N. Rotimi, Amy R. Bentley, Ayo P. Doumatey, Guanjie Chen, Daniel Shriner, and Adebowale Adeyemo 10 Applying Self‐report Measures in Minority Health and Health Disparities Research 153Mariana Sanchez, Bertha Hidalgo, Adelaida Rosario, Ligia Artiles, Anita L. Stewart, and Anna M. Nápoles 11 Conducting Community-based Participatory Research with Minority Communities to Reduce Health Disparities 171Tung T. Nguyen, Nina Wallerstein, Rina Das, Melanie D. Sabado-Liwag, Valarie Blue Bird Jernigan, Tvli Jacob, Tamela Cannady, Linda Sprague Martinez, Uchenna J. Ndulue, Abigail Ortiz, Andrea Williams Stubbs, Latrice C. Pichon, Sora Park Tanjasiri, Jane Pang, and Kent Woo 12 Racial/Ethnic Health and Healthcare Disparities Measurement: The Application of the Principles and Methods of Causal Inference 187Benjamin Cook, Sarah Forrester, Timothy Creedon, Joan Wasserman, Meryl Sufian, and Jeroan Allison 13 Small Area Estimation and Bayesian Disease Mapping for Minority Health and Health Disparities 203Xingyou Zhang, Benmei Liu, Shumei Yun, and Robert L. Phillips 14 Applications of Big Data Science and Analytic Techniques for Health Disparities Research 221Irene Dankwa-Mullan, Xinzhi Zhang, Phuong-Tu Le, and William T. Riley 15 Complex Systems Science 243Matt Kasman, Nancy Breen, and Ross A. Hammond 16 Improving Equity in Healthcare through Multilevel Interventions 257Margarita Alegria, Jacqueline J. Lloyd, Naomi Ali, and Karissa DiMarzio 17 Using Implementation Science to Move from Knowledge of Disparities to Achievement of Equity 289Lisa A. Cooper, Tanjala S. Purnell, Michael Engelgau, Kristina Weeks, and Jill A. Marsteller 18 Healthcare and Public Policy: Challenges and Opportunities for Research 309Olveen Carrasquillo, Sonjia Kenya, Stuti Dang, Cynthia Lebron, and Tilda Farhat 19 Addressing Disparities in Access to High-quality Care 321Milda Saunders, Regina James, Kesi Williams, and Marshall Chin 20 Health Communication as a Mediator of Health and Healthcare Disparities 339Neda Ratanawongsa, Benyam Hailu, and Dean Schillinger 21 Comparative Effectiveness Research in Health Disparity Populations 359William V. Padula, Rick A. Berzon, Priscah Mujuru, and David O. Meltzer 22 The Role of Electronic Health Records and Health Information Technology in Addressing Health Disparities 375Irene Dankwa-Mullan, Sherine El-Toukhy, Jessamine Winer-Jones, Nora Haney, Morgan Foreman, Kesi Williams, and Anil Jain 23 Precision Medicine and Health Disparities 391Consuelo H. Wilkins, Nancy J. Cox, Sarah C. Stallings, Maria F. Lima, Roy E. Weiss, and Nishadi Rajapakse 24 Recruitment, Inclusion, and Diversity in Clinical Trials 413Bernadette Boden-Albala, Salina P. Waddy, Noa Appleton, Heather Kuczynski, Emily Nangle, and Nina S. Parikh 25 Sexual and Gender Minority Health Disparities: Concepts, Methods, and Future Directions 429Mark L. Hatzenbuehler and John E. Pachankis 26 Workforce Diversity and Capacity Building to Address Health Disparities 445Hannah A. Valantine and Alison F. Davis Index 455

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Book SynopsisProvides a comprehensive description of mass spectrometry basics, applications, and perspectives Mass spectrometry is a modern analytical technique, allowing for fast and ultrasensitive detection and identification of chemical species. It can serve for analysis of narcotics, counterfeit medicines, components of explosives, but also in clinical chemistry, forensic research and anti-doping analysis, for identification of clinically relevant molecules as biomarkers of various diseases. This book describes everything readers need to know about mass spectrometryfrom the instrumentation to the theory and applications. It looks at all aspects of mass spectrometry, including inorganic, organic, forensic, and biological MS (paying special attention to various methodologies and data interpretation). It also contains a list of key terms for easier and faster understanding of the material by newcomers to the subject and test questions to assist lecturers. Knowing how cruciaTable of ContentsList of Contributors xvii Preface xxi 1 Introduction 1Jerzy Silberring and Marek Smoluch 2 A Brief History of Mass Spectrometry 5Marek Smoluch and Jerzy Silberring 3 Basic Definitions 9Marek Smoluch and Kinga Piechura 4 Instrumentation 13 4.1 Ionization Methods 13 4.1.1 Electron Ionization (EI) 13Claudio Iacobucci 4.1.2 Chemical Ionization (CI) 15Claudio Iacobucci 4.1.2.1 Principle of Operation: Positive and Negative Ion Modes 15 4.1.3 Atmospheric Pressure Ionization (API) 21 4.1.3.1 Atmospheric Pressure Chemical Ionization (APCI) 21Claudio Iacobucci 4.1.3.2 Electrospray Ionization (ESI) 22Piotr Suder 4.1.3.3 Nanoelectrospray 38Piotr Suder 4.1.3.4 Desorption Electrospray Ionization (DESI) 42Anna Bodzon‐Kulakowska and Anna Antolak 4.1.3.5 Laser Ablation Electrospray Ionization (LAESI) 49Anna Bodzon‐Kulakowska and Anna Antolak 4.1.3.6 Photoionization 51Jerzy Silberring 4.1.4 Ambient Plasma‐Based Ionization Techniques 54Marek Smoluch 4.1.4.1 Introduction 54 4.1.4.2 Direct Analysis in Real Time (DART) 54 4.1.4.3 Flowing Atmospheric Pressure Afterglow (FAPA) 59 4.1.4.4 Dielectric Barrier Discharge Ionization (DBDI) 61 4.1.5 Matrix‐Assisted Laser Desorption/Ionization (MALDI) 64 4.1.5.1 Introduction 64Przemyslaw Mielczarek and Jerzy Silberring 4.1.5.2 The Role of Matrix 66Przemyslaw Mielczarek and Jerzy Silberring 4.1.5.3 Atmospheric Pressure MALDI 67Giuseppe Grasso 4.1.5.4 MALDI Mass Spectra Interpretation 71Przemyslaw Mielczarek and Jerzy Silberring 4.1.5.5 Desorption/Ionization on Porous Silicon (DIOS) 72Przemyslaw Mielczarek and Jerzy Silberring 4.1.5.6 Surface‐Enhanced Laser Desorption/Ionization (SELDI) 73Przemyslaw Mielczarek and Jerzy Silberring 4.1.5.7 Nanostructure‐Enhanced Laser Desorption/Ionization (NALDI) 74Przemyslaw Mielczarek and Jerzy Silberring 4.1.5.8 Summary 75Przemyslaw Mielczarek and Jerzy Silberring 4.1.6 Inductively Coupled Plasma Ionization (ICP) 78Aleksandra Pawlaczyk and Małgorzata Iwona Szynkowska 4.1.6.1 Introduction 78 4.1.6.2 ICP as a Technique of Elemental Analysis and ICP Principle 78 4.1.6.3 Ionization of Elements and Ionization Efficiency 81 4.1.6.4 Mechanism of ICP Formation 82 4.1.6.5 Ways of Plasma View and Plasma Generation 84 4.1.6.6 Sample Introduction 84 4.1.6.7 Measurement in the ICP‐MS Technique 87 4.1.6.8 Analyzers in ICP‐MS Spectrometers 87 4.1.7 Secondary Ion Mass Spectrometry with Time‐of‐Flight Analyzer (TOF‐SIMS) 93Nunzio Tuccitto 4.1.7.1 Introduction 93 4.1.7.2 TOF‐SIMS Principle of Operation 93 4.1.7.3 The Sputtering of the Sample Surface 94 4.1.7.4 Ionization (Generating Secondary Ions) 95 4.1.7.5 Construction of TOF‐SIMS 96 4.1.7.6 Analytical Capabilities of TOF‐SIMS 98 4.1.7.7 Examples and Spectra Interpretation 102 4.2 Analyzers 107 4.2.1 Time of Flight (TOF) 107Anna Bodzon-Kulakowska and Anna Antolak 4.2.1.1 Introduction 107 4.2.1.2 The Working Rule of TOF Analyzer 108 4.2.1.3 Linear Mode of Operation of TOF 109 4.2.1.4 The Spread of the Kinetic Energy Regarding the Ions of the Same Mass 110 4.2.1.5 Delayed Ion Extraction 111 4.2.1.6 The Reflection Mode 113 4.2.1.7 Orthogonal Acceleration TOF Analyzer 114 4.2.1.8 Summary 116 4.2.2 Ion Mobility Analyzer (IM) 118Anna Antolak and Anna Bodzon-Kulakowska 4.2.2.1 Principle of IM Operation 118 4.2.2.2 Drift Time IMS 118 4.2.2.3 High Field Asymmetric Waveform Ion Mobility Spectrometer (FAIMS) 119 4.2.2.4 Traveling Wave Ion Guides (TWIG) 121 4.2.2.5 IM Spectrum 122 4.2.2.6 Applications 122 4.2.3 Quadrupole Mass Analyzer 124Anna Antolak and Anna Bodzon-Kulakowska 124 4.2.3.1 Construction and Principles of Operation of a Quadrupole 124 4.2.3.2 Behavior of an Ion Inside the Quadrupole 126 4.2.3.3 How Mass Spectrum Is Generated? Changes of U and V 128 4.2.3.4 Spectrum Quality 128 4.2.3.5 Applications of the Quadrupole Analyzer 129 4.2.3.6 Quadrupoles, Hexapoles, and Octapoles as Focusing Elements: Ion Guides 129 4.2.4 Ion Trap (IT) 131Anna Bodzon-Kulakowska and Anna Antolak 4.2.4.1 Introduction 131 4.2.4.2 Behavior of an Ion Inside the Ion Trap 132 4.2.4.3 Analysis of the Ions 133 4.2.4.4 Mass Selective Instability Mode 134 4.2.4.5 Resonant Ejection Mode 135 4.2.4.6 Axial Modulation 137 4.2.4.7 Nonlinear Resonance 137 4.2.4.8 Linear Ion Trap (LIT) 137 4.2.4.9 Applications 139 4.2.5 High‐Resolution Mass Spectrometry 141Piotr Stefanowicz and Zbigniew Szewczuk 4.2.5.1 Introduction 141 4.2.6 Ion Cyclotron Resonance (ICR) 142Piotr Stefanowicz and Zbigniew Szewczuk 4.2.6.1 Introduction 142 4.2.6.2 Cyclotron Frequency 142 4.2.6.3 ICR: Principles of Operation 143 4.2.6.4 Injection of Ions into the ICR Cell 144 4.2.6.5 Trapping Electrodes 145 4.2.6.6 Excitation Electrodes 145 4.2.6.7 Detection Electrodes and Fourier Transform 145 4.2.6.8 FT‐ICR Properties as m/z Analyzer 147 4.2.7 Orbitrap 150Piotr Stefanowicz and Zbigniew Szewczuk 4.2.7.1 History of Development and Principles of Operation 150 4.2.7.2 Analyzing Ions in the Orbitrap 151 4.2.7.3 Orbitrap Properties as m/z Analyzer 152 4.2.7.4 Analytical and Proteomic Applications of Orbitrap 153 4.2.8 Hybrid Mass Spectrometers 158Giuseppe Di Natale 4.2.8.1 A Brief Comparison of Mass Analyzers 158 4.2.8.2 Triple Quadrupoles 159 4.2.8.3 Q‐IT 162 4.2.8.4 Q‐Orbitrap 162 4.2.8.5 Q‐TOF 163 4.2.8.6 IT‐TOF 165 4.2.8.7 IT‐Orbitrap 165 4.2.9 Sector Instruments 169Anna Antolak and Anna Bodzon-Kulakowska 4.2.9.1 Introduction 169 4.2.9.2 Rule of Operation of Magnetic Analyzer (B) 169 4.2.9.3 Electrostatic Sector (E) 172 4.2.9.4 Mass Spectrometers with Magnetic and Electrostatic Sector 174 4.3 Ion Detectors 176 4.3.1 Introduction 176 4.3.2 Electron Multiplier 176 4.3.3 Microchannel Detector 177 4.3.4 Medipix/Timepix Detector 178 4.3.5 Ion Detection in ICR and Orbitrap‐Based Mass Spectrometers 179 5 Hyphenated Techniques 181 5.1 Gas Chromatography Combined with Mass Spectrometry (GC‐MS) 181Anna Drabik 5.1.1 Introduction 181 5.1.2 Detectors 183 5.1.3 Chemical Modifications: Derivatization 186 5.1.4 GC‐MS Analysis 186 5.1.5 Two‐Dimensional Gas Chromatography Linked to Mass Spectrometry 2D GC‐MS 187 5.2 Liquid Chromatography Linked to Mass Spectrometry (LC‐MS) 193 5.2.1 Introduction 193Francesco Bellia 5.2.2 Introduction to Liquid Chromatography 193Anna Drabik 5.2.3 Types of Detectors 195Anna Drabik 5.2.4 Chromatographic Columns 197Anna Drabik 5.2.5 Chromatographic Separation and Quantitation Using MS as a Detector 200Anna Drabik 5.2.6 Construction of an Interface Linking Liquid Chromatograph to the Mass Spectrometer 202Anna Drabik 202 5.2.6.1 Introduction 202 5.2.6.2 ESI Interface 203 5.2.6.3 APCI Connection to MS 204 5.2.6.4 APPI Interface 205 5.2.6.5 LC Connection to MALDI‐MS 205 5.2.6.6 Multidimensional Separations 206 5.3 Capillary Electrophoresis Linked to Mass Spectrometry 209Przemysław Mielczarek and Jerzy Silberring 5.3.1 Introduction 209 5.3.2 Types of Electrophoretic Techniques 210 5.3.3 Capillary Electrophoresis Linked to ESI 211 5.3.3.1 Introduction 211 5.3.3.2 Liquid Sheath Connection 212 5.3.3.3 Sheath‐Free Connection 212 5.3.3.4 Liquid Junction 213 5.3.4 Capillary Electrophoresis Linked to Matrix‐Assisted Laser Desorption/Ionization 214 5.3.4.1 Offline CE‐MALDI‐TOF 214 5.3.4.2 Direct CE‐MALDI‐TOF 214 5.3.4.3 Online CE‐MALDI‐TOF 215 5.3.5 Summary 215 6 Mass Spectrometry Imaging 217Anna Bodzon‐Kulakowska and Anna Antolak 6.1 Introduction 217 6.2 SIMS 218 6.3 MALDI‐IMS 220 6.4 DESI 221 6.5 Analysis of Tissue Sections Using MSI Techniques 221 6.6 Analysis of Individual Cells and Cell Cultures Using MSI Techniques 223 6.7 Analysis with MSI Techniques: Examples 224 6.8 Combinations of Different Imaging Techniques 225 6.9 Summary 227 7 Tandem Mass Spectrometry 231Piotr Suder 7.1 Introduction 231 7.2 Principles 231 7.3 Strategies for MS/MS Experiments 233 7.3.1 Tandem in Space 233 7.3.2 Tandem in Time 234 7.3.3 Multiple Fragmentation 236 7.4 Fragmentation Techniques 236 7.4.1 Introduction 236 7.4.2 (Low‐Energy) Collision‐Induced Dissociation (CID) 237 7.4.3 High‐Energy Collisional Dissociation (HCD) 237 7.4.4 Pulsed Q Collision‐Induced Dissociation (PQD) 238 7.4.5 Electron Capture Dissociation (ECD) 239 7.4.6 Electron Transfer Dissociation (ETD) 239 7.4.7 Electron Detachment Dissociation (EDD) 241 7.4.8 Negative Electron Transfer Dissociation (NETD) 241 7.4.9 Infrared Multiphoton Dissociation (IRMPD) 241 7.4.10 Blackbody Infrared Radiative Dissociation (BIRD) 242 7.4.11 Post‐source Decay (PSD): Metastable Ion Dissociation 242 7.4.12 Surface‐Induced Dissociation (SID) 243 7.4.13 Charge Remote Fragmentation 243 7.4.14 Chemically Activated Fragmentation (CAF) 243 7.4.15 Proton Transfer Reaction (PTR) 244 7.5 Practical Aspects of Fragmentation in Mass Spectrometers 245 7.5.1 In‐Source Fragmentation 245 7.5.2 Triple Quadrupole Fragmentation 246 7.5.3 Ion Traps 249 7.5.4 Time‐of‐Flight Analyzers 250 7.5.5 Combined Time‐of‐Flight Analyzers (TOF/TOF) 251 7.5.6 Hybrid Instruments 252 7.5.7 Mass Spectrometers Equipped with Orbitrap Analyzer 253 7.6 Applications of Tandem Mass Spectrometry in Life Sciences 254 7.7 SWATH Fragmentation 256 8 Mass Spectrometry Applications 261 8.1 Mass Spectrometry in Proteomics 261 8.1.1 Introduction 261Vincenzo Cunsolo and Salvatore Foti 8.1.2 Bottom‐Up Versus Top‐Down Proteomics 262Vincenzo Cunsolo and Salvatore Foti 8.1.2.1 Bottom‐Up Proteomics 262 8.1.2.2 Top‐Down Proteomics 265 8.1.3 Database Search and Protein Identification 267 8.1.4 In‐Depth Structural Characterization of a Single Protein: An Example 269 8.1.5 Quantitative Analysis in Proteomics 273Joanna Ner‐Kluza, Anna Drabik, and Jerzy Silberring 8.1.5.1 Introduction 273 8.1.5.2 Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) 274 8.1.5.3 Isotope‐Coded Affinity Tagging (ICAT) 276 8.1.5.4 Stable Isotope Labeling in Culture (SILAC) 279 8.1.5.5 Stable Isotope Labeling of Mammals (SILAM) 280 8.1.5.6 Mass‐Coded Abundance Tagging (MCAT) 281 8.1.5.7 Label‐Free Techniques 281 8.2 Food Proteomics 285Vera Muccilli and Rosaria Saletti 8.3 Challenges in Analysis of Omics Data Generated by Mass Spectrometry 293Katarzyna Pawlak, Emma Harwood, Fang Yu, and Pawel Ciborowski 8.3.1 Introduction 293 8.3.1.1 How Big Must Big Data Be? 294 8.3.1.2 Do Omics Experiments Generate Unstructured Data? 294 8.3.2 Targeted and Full Unbiased Omics Analysis Based on MS Technology 295 8.3.2.1 Factors Affecting Data Quality 296 8.3.2.2 Speed of MS Data Acquisition: Why Does It Matter? 297 8.3.2.3 Analytical Strategies in Omics Studies 298 8.3.3 Data Analysis and Visualization of Mass Spectrometry Omics Data 300 8.3.3.1 A Brief Introduction to Data Visualization 301 8.3.3.2 Exploration and Preparation of Data for Downstream Statistics and Visualization 304 8.3.3.3 Differential Expression Analysis 305 8.3.3.4 Strategies for Visualization Beyond Three Dimensions 310 8.3.3.5 Bioinformatics Tools 312 8.3.4 Databases and Search Algorithms 315 8.3.4.1 Databases for Proteomics 315 8.3.5 Validation of High‐Throughput Data: Current Challenges 318 8.3.5.1 Analytical Validation 319 8.3.5.2 Statistical Validation 320 8.3.5.3 Bioinformatics Validation 321 8.3.6 Summary and Conclusions 322 8.4 Application of the Mass Spectrometric Techniques in the Earth Sciences 326Robert Anczkiewicz 8.4.1 Introduction 326 8.4.2 Conventional Geochronology 326 8.4.3 In Situ Geochronology 327 8.4.4 Geochemical and Isotopic Tracing 331 8.5 Mass Spectrometry in Space 335Kathrin Altweg 8.5.1 Solar Wind and Plasma 339 8.5.2 Atmospheres of Planets and Moons 339 8.5.3 Comets 340 8.5.4 Interstellar and Cometary Dust 341 8.6 Mass Spectrometry in the Study of Art and Archaeological Objects 345Giuseppe Spoto 8.6.1 Introduction 345 8.6.2 MS Methods for the Study of Inorganic Components of Art and Archaeological Objects 345 8.6.3 MS Methods for the Study of Organic Components of Art and Archaeological Objects 346 8.7 Application of ICP‐MS for Trace Elemental and Speciation Analysis 351Aleksandra Pawlaczyk and Małgorzata Iwona Szynkowska 8.7.1 Introduction 351 8.7.2 Speciation Analysis by ICP‐MS: Examples of Applications 352 8.7.3 Single‐Particle and Single‐Cell Analysis by ICP‐MS: Examples of Applications 353 8.7.4 Imaging by LA‐ICP‐MS Technique 355 8.7.5 Improvements of LA‐ICP‐MS Technique 358 8.7.6 LA‐ICP Mass Spectrometer with LIBS 359 8.8 Mass Spectrometry in Forensic Research 362Marek Smoluch and Jerzy Silberring 8.8.1 Introduction 362 8.8.2 Forgery in Art 362 8.8.3 Psychoactive Substances and Narcotics 363 8.8.4 Counterfeit Drugs and Generation of Metabolites 366 8.8.5 Terrorism/Explosives/Chemical Warfare 367 8.8.6 Future Prospects 368 8.9 Doping in Sport 372Dorota Kwiatkowska 8.10 Miniaturization in Mass Spectrometry 384Marek Smoluch and Jerzy Silberring 9 Appendix 389Kinga Piechura and Marek Smoluch 389 9.1 Pressure Units 389 9.2 Most Commonly Detected Fragments Generated by Electron Impact (EI) Ionization 389 9.3 Trypsin Autolysis Products 393 9.4 Proteolytic Enzymes for Protein Identification 394 9.5 Molecular Masses of Amino Acid Residues 395 9.6 Molecular Masses of Less Common Amino Acid Residues 397 9.7 Internet Databases 400 9.7.1 Literature Databases 400 9.7.2 Scientific Journals 401 9.7.2.1 Journals Related to Mass Spectrometry 402 9.7.3 Bioinformatics Databases 402 9.7.3.1 Protein Databases 402 9.7.3.2 Database of Structures and Functions of Protein 403 9.7.3.3 Other Databases 404 9.7.4 Bioinformatics Tools 404 9.7.5 Useful Websites 405 10 Abbreviations 407Kinga Piechura and Marek Smoluch Index 413

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Book SynopsisEEG Signal Processing and Machine Learning Explore cutting edge techniques at the forefront of electroencephalogram research and artificial intelligence from leading voices in the field The newly revised Second Edition of EEG Signal Processing and Machine Learning delivers an inclusive and thorough exploration of new techniques and outcomes in electroencephalogram (EEG) research in the areas of analysis, processing, and decision making about a variety of brain states, abnormalities, and disorders using advanced signal processing and machine learning techniques. The book content is substantially increased upon that of the first edition and, while it retains what made the first edition so popular, is composed of more than 50% new material. The distinguished authors have included new material on tensors for EEG analysis and sensor fusion, as well as new chapters on mental fatigue, sleep, seizure, neurodevelopmental diseases, BCI, and psychiatric abnormalities. In addition to including aTable of ContentsPreface to the Second Edition xvii Preface to the First Edition xxi List of Abbreviations xxiii 1 Introduction to Electroencephalography 1 1.1 Introduction 1 1.2 History 2 1.3 Neural Activities 5 1.4 Action Potentials 6 1.5 EEG Generation 8 1.6 The Brain as a Network 12 1.7 Summary 12 References 13 2 EEG Waveforms 15 2.1 Brain Rhythms 15 2.2 EEG Recording and Measurement 18 2.2.1 Conventional Electrode Positioning 21 2.2.2 Unconventional and Special Purpose EEG Recording Systems 24 2.2.3 Invasive Recording of Brain Potentials 26 2.2.4 Conditioning the Signals 27 2.3 Sleep 28 2.4 Mental Fatigue 30 2.5 Emotions 30 2.6 Neurodevelopmental Disorders 31 2.7 Abnormal EEG Patterns 32 2.8 Ageing 33 2.9 Mental Disorders 34 2.9.1 Dementia 34 2.9.2 Epileptic Seizure and Nonepileptic Attacks 35 2.9.3 Psychiatric Disorders 39 2.9.4 External Effects 40 2.10 Summary 41 References 42 3 EEG Signal Modelling 47 3.1 Introduction 47 3.2 Physiological Modelling of EEG Generation 47 3.2.1 Integrate-and-Fire Models 49 3.2.2 Phase-Coupled Models 49 3.2.3 Hodgkin–Huxley Model 51 3.2.4 Morris–Lecar Model 54 3.3 Generating EEG Signals Based on Modelling the Neuronal Activities 57 3.4 Mathematical Models Derived Directly from the EEG Signals 61 3.4.1 Linear Models 61 3.4.1.1 Prediction Method 61 3.4.1.2 Prony’s Method 62 3.4.2 Nonlinear Modelling 64 3.4.3 Gaussian Mixture Model 66 3.5 Electronic Models 67 3.5.1 Models Describing the Function of the Membrane 67 3.5.1.1 Lewis Membrane Model 68 3.5.1.2 Roy Membrane Model 68 3.5.2 Models Describing the Function of a Neuron 68 3.5.2.1 Lewis Neuron Model 68 3.5.2.2 The Harmon Neuron Model 71 3.5.3 A Model Describing the Propagation of the Action Pulse in an Axon 72 3.5.4 Integrated Circuit Realizations 72 3.6 Dynamic Modelling of Neuron Action Potential Threshold 72 3.7 Summary 73 References 73 4 Fundamentals of EEG Signal Processing 77 4.1 Introduction 77 4.2 Nonlinearity of the Medium 78 4.3 Nonstationarity 79 4.4 Signal Segmentation 80 4.5 Signal Transforms and Joint Time–Frequency Analysis 83 4.5.1 Wavelet Transform 87 4.5.1.1 Continuous Wavelet Transform 87 4.5.1.2 Examples of Continuous Wavelets 89 4.5.1.3 Discrete-Time Wavelet Transform 89 4.5.1.4 Multiresolution Analysis 90 4.5.1.5 Wavelet Transform Using Fourier Transform 93 4.5.1.6 Reconstruction 94 4.5.2 Synchro-Squeezed Wavelet Transform 95 4.5.3 Ambiguity Function and the Wigner–Ville Distribution 96 4.6 Empirical Mode Decomposition 100 4.7 Coherency, Multivariate Autoregressive Modelling, and Directed Transfer Function 101 4.8 Filtering and Denoising 104 4.9 Principal Component Analysis 107 4.9.1 Singular Value Decomposition 108 4.10 Summary 110 References 110 5 EEG Signal Decomposition 115 5.1 Introduction 115 5.2 Singular Spectrum Analysis 115 5.2.1 Decomposition 116 5.2.2 Reconstruction 117 5.3 Multichannel EEG Decomposition 118 5.3.1 Independent Component Analysis 118 5.3.2 Instantaneous BSS 122 5.3.3 Convolutive BSS 126 5.3.3.1 General Applications 127 5.3.3.2 Application of Convolutive BSS to EEG 128 5.4 Sparse Component Analysis 129 5.4.1 Standard Algorithms for Sparse Source Recovery 130 5.4.1.1 Greedy-Based Solution 130 5.4.1.2 Relaxation-Based Solution 131 5.4.2 k-Sparse Mixtures 131 5.5 Nonlinear BSS 133 5.6 Constrained BSS 134 5.7 Application of Constrained BSS; Example 135 5.8 Multiway EEG Decompositions 136 5.8.1 Tensor Factorization for BSS 139 5.8.2 Solving BSS of Nonstationary Sources Using Tensor Factorization 143 5.9 Tensor Factorization for Underdetermined Source Separation 149 5.10 Tensor Factorization for Separation of Convolutive Mixtures in the Time Domain 153 5.11 Separation of Correlated Sources via Tensor Factorization 153 5.12 Common Component Analysis 154 5.13 Canonical Correlation Analysis 154 5.14 Summary 155 References 155 6 Chaos and Dynamical Analysis 165 6.1 Introduction to Chaos and Dynamical Systems 165 6.2 Entropy 166 6.3 Kolmogorov Entropy 166 6.4 Multiscale Fluctuation-Based Dispersion Entropy 167 6.5 Lyapunov Exponents 167 6.6 Plotting the Attractor Dimensions from Time Series 169 6.7 Estimation of Lyapunov Exponents from Time Series 169 6.7.1 Optimum Time Delay 172 6.7.2 Optimum Embedding Dimension 172 6.8 Approximate Entropy 173 6.9 Using Prediction Order 174 6.10 Summary 175 References 175 7 Machine Learning for EEG Analysis 177 7.1 Introduction 177 7.2 Clustering Approaches 181 7.2.1 k-Means Clustering Algorithm 181 7.2.2 Iterative Self-Organizing Data Analysis Technique 183 7.2.3 Gap Statistics 183 7.2.4 Density-Based Clustering 184 7.2.5 Affinity-Based Clustering 184 7.2.6 Deep Clustering 184 7.2.7 Semi-Supervised Clustering 185 7.2.7.1 Basic Semi-Supervised Techniques 185 7.2.7.2 Deep Semi-Supervised Techniques 186 7.2.8 Fuzzy Clustering 186 7.3 Classification Algorithms 187 7.3.1 Decision Trees 188 7.3.2 Random Forest 189 7.3.3 Linear Discriminant Analysis 190 7.3.4 Support Vector Machines 191 7.3.5 k-Nearest Neighbour 199 7.3.6 Gaussian Mixture Model 200 7.3.7 Logistic Regression 200 7.3.8 Reinforcement Learning 201 7.3.9 Artificial Neural Networks 201 7.3.9.1 Deep Neural Networks 203 7.3.9.2 Convolutional Neural Networks 205 7.3.9.3 Autoencoders 207 7.3.9.4 Variational Autoencoder 208 7.3.9.5 Recent DNN Approaches 209 7.3.9.6 Spike Neural Networks 210 7.3.9.7 Applications of DNNs to EEG 212 7.3.10 Gaussian Processes 212 7.3.11 Neural Processes 213 7.3.12 Graph Convolutional Networks 213 7.3.13 Naïve Bayes Classifier 213 7.3.14 Hidden Markov Model 214 7.3.14.1 Forward Algorithm 216 7.3.14.2 Backward Algorithm 216 7.3.14.3 HMM Design 216 7.4 Common Spatial Patterns 218 7.5 Summary 222 References 223 8 Brain Connectivity and Its Applications 235 8.1 Introduction 235 8.2 Connectivity through Coherency 238 8.3 Phase-Slope Index 240 8.4 Multivariate Directionality Estimation 240 8.4.1 Directed Transfer Function 241 8.4.2 Direct DTF 242 8.4.3 Partial Directed Coherence 243 8.5 Modelling the Connectivity by Structural Equation Modelling 243 8.6 Stockwell Time–Frequency Transform for Connectivity Estimation 246 8.7 Inter-Subject EEG Connectivity 247 8.7.1 Objectives 247 8.7.2 Technological Relevance 247 8.8 State-Space Model for Estimation of Cortical Interactions 249 8.9 Application of Cooperative Adaptive Filters 251 8.9.1 Use of Cooperative Kalman Filter 253 8.9.2 Task-Related Adaptive Connectivity 254 8.9.3 Diffusion Adaptation 255 8.9.4 Brain Connectivity for Cooperative Adaptation 256 8.9.5 Other Applications of Cooperative Learning and Brain Connectivity Estimation 257 8.10 Graph Representation of Brain Connectivity 258 8.11 Tensor Factorization Approach 259 8.12 Summary 262 References 263 9 Event-Related Brain Responses 269 9.1 Introduction 269 9.2 ERP Generation and Types 269 9.2.1 P300 and its Subcomponents 273 9.3 Detection, Separation, and Classification of P300 Signals 274 9.3.1 Using ICA 275 9.3.2 Estimation of Single-Trial Brain Responses by Modelling the ERP Waveforms 277 9.3.3 ERP Source Tracking in Time 278 9.3.4 Time–Frequency Domain Analysis 280 9.3.5 Application of Kalman Filter 284 9.3.6 Particle Filtering and its Application to ERP Tracking 286 9.3.7 Variational Bayes Method 291 9.3.8 Prony’s Approach for Detection of P300 Signals 293 9.3.9 Adaptive Time–Frequency Methods 297 9.4 Brain Activity Assessment Using ERP 298 9.5 Application of P300 to BCI 299 9.6 Summary 300 References 301 10 Localization of Brain Sources 307 10.1 Introduction 307 10.2 General Approaches to Source Localization 308 10.2.1 Dipole Assumption 309 10.3 Head Model 311 10.4 Most Popular Brain Source Localization Approaches 313 10.4.1 EEG Source Localization Using Independent Component Analysis 313 10.4.2 MUSIC Algorithm 313 10.4.3 LORETA Algorithm 317 10.4.4 FOCUSS Algorithm 318 10.4.5 Standardized LORETA 319 10.4.6 Other Weighted Minimum Norm Solutions 320 10.4.7 Evaluation Indices 323 10.4.8 Joint ICA–LORETA Approach 323 10.5 Forward Solutions to the Localization Problem 325 10.5.1 Partially Constrained BSS Method 325 10.5.2 Constrained Least-Squares Method for Localization of P3a and P3b 326 10.5.3 Spatial Notch Filtering Approach 328 10.6 The Methods Based on Source Tracking 333 10.6.1 Deflation Beamforming Approach for EEG/MEG Multiple Source Localization 333 10.6.2 Hybrid Beamforming – Particle Filtering 336 10.7 Determination of the Number of Sources from the EEG/MEG Signals 337 10.8 Other Hybrid Methods 340 10.9 Application of Machine Learning for EEG/MEG Source Localization 340 10.10 Summary 342 References 343 11 Epileptic Seizure Prediction, Detection, and Localization 351 11.1 Introduction 351 11.2 Seizure Detection 357 11.2.1 Adult Seizure Detection from EEGs 357 11.2.2 Detection of Neonatal Seizure 363 11.3 Chaotic Behaviour of Seizure EEG 366 11.4 Seizure Detection from Brain Connectivity 369 11.5 Prediction of Seizure Onset from EEG 369 11.6 Intracranial and Joint Scalp–Intracranial Recordings for IED Detection 384 11.6.1 Introduction to IED 384 11.6.2 iEED-Times IED Detection from Scalp EEG 386 11.6.3 A Multiview Approach to IED Detection 391 11.6.4 Coupled Dictionary Learning for IED Detection 391 11.6.5 A Deep Learning Approach to IED Detection 392 11.7 Fusion of EEG–fMRI Data for Seizure Prediction 396 11.8 Summary 398 References 399 12 Sleep Recognition, Scoring, and Abnormalities 407 12.1 Introduction 407 12.1.1 Definition of Sleep 407 12.1.2 Sleep Disorder 408 12.2 Stages of Sleep 409 12.2.1 NREM Sleep 409 12.2.2 REM Sleep 411 12.3 The Influence of Circadian Rhythms 414 12.4 Sleep Deprivation 415 12.5 Psychological Effects 416 12.6 EEG Sleep Analysis and Scoring 416 12.6.1 Detection of the Rhythmic Waveforms and Spindles Employing Blind Source Separation 416 12.6.2 Time–Frequency Analysis of Sleep EEG Using Matching Pursuit 417 12.6.3 Detection of Normal Rhythms and Spindles Using Higher-Order Statistics 421 12.6.4 Sleep Scoring Using Tensor Factorization 423 12.6.5 Application of Neural Networks 425 12.6.6 Model-Based Analysis 426 12.7 Detection and Monitoring of Brain Abnormalities during Sleep by EEG and Multimodal PSG Analysis 428 12.7.1 Analysis of Sleep Apnoea 428 12.7.2 EEG and Fibromyalgia Syndrome 431 12.7.3 Sleep Disorders of Neonates 431 12.8 Dreams and Nightmares 432 12.9 EEG and Consciousness 433 12.10 Functional Brain Connectivity for Sleep Analysis 433 12.11 Summary 434 References 435 13 EEG-Based Mental Fatigue Monitoring 441 13.1 Introduction 441 13.2 Feature-Based Machine Learning Approaches 443 13.2.1 Hidden Markov Model Application 443 13.2.2 Kernel Principal Component Analysis and Hidden Markov Model 444 13.2.3 Regression-Based Fatigue Estimation 444 13.2.4 Regularized Regression 445 13.2.5 Other Feature-Based Approaches 445 13.3 Measurement of Brain Synchronization and Coherency 446 13.3.1 Linear Measure of Synchronization 446 13.3.2 Nonlinear Measure of Synchronization 448 13.4 Evaluation of ERP for Mental Fatigue 451 13.5 Separation of P3a and P3b 457 13.6 A Hybrid EEG–ERP-Based Method for Fatigue Analysis Using an Auditory Paradigm 463 13.7 Assessing Mental Fatigue by Measuring Functional Connectivity 465 13.8 Deep Learning Approaches for Fatigue Evaluation 472 13.9 Summary 474 References 474 14 EEG-Based Emotion Recognition and Classification 479 14.1 Introduction 479 14.1.1 Theories and Emotion Classification 480 14.1.2 The Physiological Effects of Emotions 482 14.1.3 Psychology and Psychophysiology of Emotion 485 14.1.4 Emotion Regulation 487 14.1.4.1 Agency and Intentionality 490 14.1.4.2 Norm Violation 490 14.1.4.3 Guilt 491 14.1.4.4 Shame 491 14.1.4.5 Embarrassment 491 14.1.4.6 Pride 491 14.1.4.7 Indignation and Anger 491 14.1.4.8 Contempt 491 14.1.4.9 Pity and Compassion 492 14.1.4.10 Awe and Elevation 492 14.1.4.11 Gratitude 492 14.1.5 Emotion-Provoking Stimuli 492 14.2 Effect of Emotion on the Brain 494 14.2.1 ERP Change Due to Emotion 494 14.2.2 Changes of Normal Brain Rhythms with Emotion 497 14.2.3 Emotion and Lateral Brain Engagement 498 14.2.4 Perception of Odours and Emotion: Why Are They Related? 498 14.3 Emotion-Related Brain Signal Processing and Machine Learning 499 14.3.1 Evaluation of Emotion Based on the Changes in Brain Rhythms 500 14.3.2 Brain Asymmetricity and Connectivity for Emotion Evaluation 501 14.3.3 Changes in ERPs for Emotion Recognition 504 14.3.4 Combined Features for Emotion Analysis 504 14.4 Other Physiological Measurement Modalities Used for Emotion Study 507 14.5 Applications 510 14.6 Pain Assessment Using EEG 510 14.7 Emotion Elicitation and Induction through Virtual Reality 512 14.8 Summary 513 References 514 15 EEG Analysis of Neurodegenerative Diseases 525 15.1 Introduction 525 15.2 Alzheimer’s Disease 527 15.2.1 Application of Brain Connectivity Estimation to AD and MCI 528 15.2.2 ERP-Based AD Monitoring 532 15.2.3 Other Approaches to EEG-Based AD Monitoring 532 15.3 Motor Neuron Disease 537 15.4 Parkinson’s Disease 537 15.5 Huntington’s Disease 541 15.6 Prion Disease 542 15.7 Behaviour Variant Frontotemporal Dementia 544 15.8 Lewy Body Dementia 545 15.9 Summary 545 References 546 16 EEG As A Biomarker for Psychiatric and Neurodevelopmental Disorders 551 16.1 Introduction 551 16.1.1 History 551 16.1.1.1 Different Psychiatric and Neurodevelopmental Disorders 553 16.1.1.2 NDD Diagnosis 554 16.2 EEG Analysis for Different NDDs 554 16.2.1 ADHD 554 16.2.1.1 ADHD Symptoms and Possible Treatment 554 16.2.1.2 EEG-Based Diagnosis of ADHD 555 16.2.2 ASD 559 16.2.2.1 ASD Symptoms and Possible Treatment 559 16.2.2.2 EEG-Based Diagnosis of ASD 560 16.2.3 Mood Disorder 561 16.2.3.1 EEG for Monitoring Depression 562 16.2.3.2 EEG for Monitoring Bipolar Disorder 564 16.2.4 Schizophrenia 565 16.2.4.1 Schizophrenia Symptoms and Management 565 16.2.4.2 EEG as the Biomarker for Schizophrenia 566 16.2.5 Anxiety (and Panic) Disorder 568 16.2.5.1 Definition and Symptoms 568 16.2.5.2 EEG for Assessing Anxiety 569 16.2.6 Insomnia 571 16.2.6.1 Symptoms of Insomnia 571 16.2.6.2 EEG for Insomnia Analysis 572 16.2.7 Schizotypal Personality Disorder 572 16.2.7.1 What Is Schizotypal Disorder? 572 16.2.7.2 EEG Manifestation of Schizotypal 573 16.3 Summary 573 References 574 17 Brain–Computer Interfacing Using EEG 581 17.1 Introduction 581 17.1.1 State of the Art in BCI 584 17.1.2 BCI Terms and Definitions 585 17.1.3 Popular BCI Directions 585 17.1.4 Virtual Environment for BCI 586 17.1.5 Evolution of BCI Design 587 17.2 BCI-Related EEG Components 588 17.2.1 Readiness Potential and Its Detection 588 17.2.2 ERD and ERS 588 17.2.3 Transient Beta Activity after the Movement 593 17.2.4 Gamma Band Oscillations 593 17.2.5 Long Delta Activity 593 17.2.6 ERPs 594 17.3 Major Problems in BCI 594 17.3.1 Preprocessing of the EEGs 595 17.4 Multidimensional EEG Decomposition 597 17.4.1 Space–Time–Frequency Method 599 17.4.2 Parallel Factor Analysis 599 17.5 Detection and Separation of ERP Signals 601 17.6 Estimation of Cortical Connectivity 603 17.7 Application of Common Spatial Patterns 606 17.8 Multiclass Brain–Computer Interfacing 609 17.9 Cell-Cultured BCI 610 17.10 Recent BCI Applications 610 17.11 Neurotechnology for BCI 614 17.12 Joint EEG and Other Brain-Scanning Modalities for BCI 617 17.12.1 Joint EEG–fNIRS for BCI 617 17.12.2 Joint EEG–MEG for BCI 618 17.13 Performance Measures for BCI Systems 618 17.14 Summary 619 References 620 18 Joint Analysis of EEG and Other Simultaneously Recorded Brain Functional Neuroimaging Modalities 631 18.1 Introduction 631 18.2 Fundamental Concepts 631 18.2.1 Functional Magnetic Resonance Imaging 631 18.2.1.1 Blood Oxygenation Level Dependence 633 18.2.1.2 Popular fMRI Data Formats 635 18.2.1.3 Preprocessing of fMRI Data 635 18.2.2 Functional Near-Infrared Spectroscopy 636 18.2.3 Magnetoencephalography 640 18.3 Joint EEG–fMRI 640 18.3.1 Relation Between EEG and fMRI 640 18.3.2 Model-Based Method for BOLD Detection 642 18.3.3 Simultaneous EEG–fMRI Recording: Artefact Removal from EEG 644 18.3.3.1 Gradient Artefact Removal from EEG 644 18.3.3.2 Ballistocardiogram Artefact Removal from EEG 645 18.3.4 BOLD Detection in fMRI 652 18.3.4.1 Implementation of Different NMF Algorithms for BOLD Detection 653 18.3.4.2 BOLD Detection Experiments 654 18.3.5 Fusion of EEG and fMRI 659 18.3.5.1 Extraction of fMRI Time Course from EEG 659 18.3.5.2 Fusion of EEG and fMRI; Blind Approach 659 18.3.5.3 Fusion of EEG and fMRI; Model-Based Approach 664 18.3.6 Application to Seizure Detection 664 18.3.7 Investigation of Decision Making in the Brain 666 18.3.8 Application to Schizophrenia 666 18.3.9 Other Applications 667 18.4 EEG–NIRS Joint Recording and Fusion 668 18.5 MEG–EEG Fusion 672 18.6 Summary 672 References 673 Index 681

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Book SynopsisAn unprecedented book that discusses a decades long journey of understanding vision and visual impairment through working with patients with brain damage Edward de Haan, a noted clinical vision researcher for the last 35 years, explains how the healthy brain deals with visual information and reveals how he learned to appreciate what it means to be visually impaired. Through discussions of fascinating case studies, he shows that visual deficits are individually unique. Some patients perceive the world without color, some see objects in a distorted manner, whilst others will claim that they can still see although they are demonstrably blind. The author details his experiences with these patients to demonstrate the manner in which patient work is a unique and vital part of discovering how the brain processes visual information. In doing so, Impaired Vision offers a review of the clinical symptoms related to visual impairment and highlights that the patient sTable of ContentsPreface xi 1 Looking at the Brain 1 1.1 A Short History 1 1.2 The Brain 18 1.3 This Book and the Patients in It 23 2 Blind 29 2.1 A Blind Eye 29 2.2 A Blind Brain 34 2.3 Blind Visual Fields 39 2.4 Imagined Vision 41 3 Partially Blind 45 3.1 Where Is It? 46 3.2 Line Orientation 52 3.3 Seeing Stroboscopically 56 3.4 Shapelessness 58 3.5 A Black‐and‐White World 60 3.6 Rough and Matte or Smooth and Glossy 66 4 Looking but Not Seeing 71 4.1 Wavelength Without Color 71 4.2 Day or Night? 77 4.3 Seeing Without Reading and Strange Connections 82 4.4 What Is That? 87 4.5 Lost and an Unfamiliar House 95 4.6 Face Failures and a Family Affair 99 4.7 I Can’t See Why You Sound Angry and Two Swiss Ladies 103 4.8 Classic Syndromes of the Parietal Lobe 108 5 Seeing Things Differently 113 5.1 Bringing Color to the World 113 5.2 Moldy Faces and Fish Heads 116 5.3 Dislodged Vision 125 5.4 Repetitive Vision 134 5.5 Lost Feelings 138 6 Seeing What Is Not There 143 6.1 Bright Sparks 143 6.2 Lively Perception in Poor Vision 150 6.3 Filling in the Empty Spaces 152 6.4 Neglected but Not Forgotten 156 6.5 Electrified Perceptions 159 6.6 Hallucinations Resulting from Degenerative Disease 163 6.7 Visual Hallucinations in Psychiatric Conditions 172 6.8 Strange Desires 184 7 Knowing the Unseen 187 7.1 Sight Unseen 187 7.2 Split Brain 196 7.3 Pointing in the Right Direction 202 7.4 Vision Without Awareness 209 7.5 Ignored but Not Forgotten 216 8 Oblivion 221 8.1 Seneca’s Trouble 221 8.2 Anosognosia 226 8.3 Neglect Revisited 228 8.4 Lost Colors 229 8.5 My Oil Paintings 231 8.6 Forgetting Your Amnesia 235 9 Vision 241 9.1 Scope of the Visual Brain 242 9.2 Stages of Vision 246 9.3 Damage, Deficits, Distortions, and Delusions 251 9.4 Consciousness 254 9.5 Looking Back 256 Index 261

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Book SynopsisThese volumes teach readers to think beyond apoptosis and describes all of the known processes that cells can undergo which result in cell death This two-volume source on how cells dies is the first, comprehensive collection to cover all of the known processes that cells undergo when they die. It is also the only one of its kind to compare these processes. It seeks to enlighten those in the field about these many processes and to stimulate their thinking at looking at these pathways when their research system does not show signs of activation of the classic apoptotic pathway. In addition, it links activities like the molecular biology of one process (eg. Necrosis) to another process (eg. apoptosis) and contrasts those that are close to each. Volume 1 of Apoptosis and Beyond: The Many Ways Cells Die begins with a general view of the cytoplasmic and nuclear features of apoptosis. It then goes on to offer chapters on targeting the cell death mechanism; microTable of ContentsList of Contributors ix Volume 1 1 General View of the Cytoplasmic and Nuclear Features of Apoptosis 1Humberto De Vitto, Juan P. Valencia, and James A. Radosevich 2 Mitochondria in Focus: Targeting the Cell-Death Mechanism 13Humberto De Vitto, Roberta Palorini, Giuseppina Votta, and Ferdinando Chiaradonna 3 Microbial Programmed Cell Death 49Neal D. Hammer 4 Autophagy 71Mollie K. Rojas, Juel Chowdhury, Khatja Batool, Zane Deliu, and Abdallah Oweidi 5 Cell Injury, Adaptation, and Necrosis 83Sarah G. Fitzpatrick and Sara C. Gordon 6 Necroptosis 99Ben A. Croker, James A. Rickard, Inbar Shlomovitz, Arshed Al-Obeidi, Akshay A. D’Cruz, and Motti Gerlic 7 Ferroptosis 127Ebru Esin Yoruker and Ugur Gezer 8 Anoikis Regulation: Complexities, Distinctions, and Cell Differentiation 145Marco Beauséjour, Ariane Boutin, and Pierre H. Vachon 9 Cornification 183Leopold Eckhart 10 Excitotoxicity 197Julie Alagha, Sulaiman Alshaar, and Zane Deliu 11 Molecular Mechanisms Regulating Wallerian Degeneration 205Mohammad Tauseef and Madeeha Aqil 12 Pyronecrosis 225Maryam Khalili and James A. Radosevich 13 Phenoptosis: Programmed Death of an Organism 237M.V. Skulachev and V.P. Skulachev 14 Molecular Mechanisms Underlying Oxytosis 289Amalia M. Dolga, Sina Oppermann, Maren Richter, Birgit Honrath, Sandra Neitemeier, Anja Jelinek, Goutham Ganjam, and Carsten Culmsee 15 Pyroptosis 317Kate E. Lawlor, Stephanie Conos, and James E. Vince 16 Paraptosis 343Maryam Khalili and James A. Radosevich 17 Hematopoiesis and Eryptosis 367Mollie K. Rojas, Chintan C. Gandhi, and Lawrence E. Feldman Volume 2 18 Cyclophilin D-Dependent Necrosis 375Jatin Mehta and Chandi Charan Mandal 19 Role of Phospholipases in Cell Death 395Manikanda Raja, Juel Chowdhury, and James A. Radosevich 20 TRIAD (Transcriptional Repression-Induced Atypical Death) 411Takuya Tamura and Hitoshi Okazawa 21 Alkylating-Agent Cytotoxicity Associated with O6-Methylguanine 427Latha M. Malaiyandi, Lawrence A. Potempa, Nicholas Marschalk, Paiboon Jungsuwadee, and Kirk E. Dineley 22 Entosis 463Jamuna A. Bai and Ravishankar Rai V. 23 Mitotic Catastrophe 475Raquel De Souza, Lais Costa Ayub, and Kenneth Yip 24 NETosis and ETosis: Incompletely Understood Types of Granulocyte Death and their Proposed Adaptive Benefits and Costs 511Marko Radic 25 Parthanatos: Poly ADP Ribose Polymerase (PARP)-Mediated Cell Death 535Amos Fatokun 26 Methuosis: Drinking to Death 559Madeeha Aqil 27 Oncosis 567Priya Weerasinghe, Sarathi Hallock, Robert Brown, and L. Maximilian Buja 28 Autoschizis: A Mode of Cell Death of Cancer Cells Induced by a Prooxidant Treatment In Vitro and In Vivo 583J. Gilloteaux, J.M. Jamison, D. Arnold, and J.L. Summers 29 Programmed Death 1 (PD1)-Mediated T-Cell Apoptosis and Cancer Immunotherapy 695Chandi Charan Mandal, Jatin Mehta, and Vijay K. Prajapati

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Book SynopsisMANAGEMENT OF GENETIC SYNDROMES THE MOST RECENT UPDATE TO ONE OF THE MOST ESSENTIAL REFERENCES ON MEDICAL GENETICS Cassidy and Allanson's Management of Genetic Syndromes, Fourth Edition is the latest version of a classic text in medical genetics. With newly covered disorders and cutting-edge, up-to-date information, this resource remains the most crucial reference on the management of genetic syndromes in the field of medical genetics for students, clinicians, caregivers, and researchers. The fourth edition includes current information on the identification of genetic syndromes (including newly developed diagnostic criteria), the genetic basis (including diagnostic testing), and the routine care and management for more than 60 genetic disorders. Written by experts, each chapter includes sections on: Incidence Diagnostic criteria Etiology, pathogenesis and genetics Diagnostic testing Differential diagnosis Table of ContentsForeword to the Fourth Edition xi Foreword to the Third Edition xiii Foreword to the Second Edition xv Foreword to the First Edition xvii Preface xix List of Contributors xxi Introduction xxvii 1 Aarskog Syndrome 1Roger E. Stevenson 2 Achondroplasia 9Richard M. Pauli and Lorenzo Botto 3 Alagille Syndrome 31Henry C. Lin and Ian D. Krantz 4 Albinism: Ocular and Oculocutaneous Albinism and Hermansky–Pudlak Syndrome 45C. Gail Summers and David R. Adams 5 Angelman Syndrome 61Charles A. Williams and Jennifer M. Mueller-Mathews 6 Arthrogryposis 75Judith G. Hall 7 ATR-X: α Thalassemia/Mental Retardation-X-Linked 93Richard J. Gibbons 8 Bardet–Biedl Syndrome 107Anne M. Slavotinek 9 Beckwith–Wiedemann Syndrome and Hemihyperplasia 125Cheryl Shuman and Rosanna Weksberg 10 Cardio-Facio-Cutaneous Syndrome 147Maria Inês Kavamura and Giovanni Neri 11 CHARGE Syndrome 157Donna M. Martin, Christine A. Oley, and Conny M. van Ravenswaaij-Arts 12 Coffin–Lowry Syndrome 171R. Curtis Rogers 13 Coffin–Siris Syndrome 185Tomoki Kosho and Noriko Miyake 14 Cohen Syndrome 195Kate E. Chandler 15 Cornelia de Lange Syndrome 207Antonie D. Kline and Matthew Deardorff 16 Costello Syndrome 225Bronwyn Kerr, Karen W. Gripp, and Emma M.M. Burkitt Wright 17 Craniosynostosis Syndromes 241Elizabeth J. Bhoj and Elaine H. Zackai 18 Deletion 1p36 Syndrome 253Agatino Battaglia 19 Deletion 4p: Wolf–Hirschhorn Syndrome 265Agatino Battaglia 20 Deletion 5p Syndrome 281Antonie D. Kline, Joanne M. Nguyen, and Dennis J. Campbell 21 Deletion 22q11.2 (Velo-Cardio-Facial Syndrome/DiGeorge Syndrome) 291Donna M. McDonald-McGinn, Stephanie Jeong, Michael-John McGinn II, Elaine H. Zackai, and Marta Unolt 22 Deletion 22q13 Syndrome: Phelan–McDermid Syndrome 317Katy Phelan, R. Curtis Rogers, and Luigi Boccuto 23 Denys–Drash Syndrome, Frasier Syndrome, and WAGR Syndrome (WT1-related Disorders) 335Joyce T. Turner and Jeffrey S. Dome 24 Down Syndrome 355Aditi Korlimarla, Sarah J. Hart, Gail A. Spiridigliozzi, and Priya S. Kishnani 25 Ehlers–Danlos Syndromes 389Brad T. Tinkle 26 Fetal Alcohol Spectrum Disorders 405H. Eugene Hoyme and Prachi E. Shah 27 Fetal Anticonvulsant Syndrome 425Elizabeth A. Conover, Omar Abdul-Rahman, and H. Eugene Hoyme 28 Fragile X Syndrome and Premutation-Associated Disorders 443Randi J. Hagerman 29 Gorlin Syndrome: Nevoid Basal Cell Carcinoma Syndrome 459Peter A. Farndon and D. Gareth Evans 30 Hereditary Hemorrhagic Telangiectasia 475Jonathan N. Berg and Anette D. Kjeldsen 31 Holoprosencephaly 487Paul Kruszka, Andrea L. Gropman, and Maximilian Muenke 32 Incontinentia Pigmenti 505Dian Donnai and Elizabeth A. Jones 33 Inverted Duplicated Chromosome 15 Syndrome (Isodicentric 15) 515Agatino Battaglia 34 Kabuki Syndrome 529Sarah Dugan 35 47,XXY (Klinefelter Syndrome) and Related X and Y Chromosomal Conditions 539Carole Samango-Sprouse, John M. Graham Jr, Debra R. Counts, and Jeannie Visootsak 36 Loeys–Dietz Syndrome 563Aline Verstraeten, Harry C. Dietz, and Bart L. Loeys 37 Marfan Syndrome 577Uta Francke 38 Mowat–Wilson Syndrome 597David Mowat and Meredith Wilson 39 Myotonic Dystrophy Type 1 611Isis B.T. Joosten, Kees Okkersen, Baziel G.M. van Engelen, and Catharina G. Faber 40 Neurofibromatosis Type 1 629David Viskochil 41 Noonan Syndrome 651Judith E. Allanson and Amy E. Roberts 42 Oculo-Auriculo-Vertebral Spectrum 671Koenraad Devriendt, Luc De Smet, and Ingele Casteels 43 Osteogenesis Imperfecta 683An N. Dang Do and Joan C. Marini 44 Pallister–Hall Syndrome and Greig Cephalopolysyndactyly Syndrome 707Leslie G. Biesecker 45 Pallister–Killian Syndrome 717Emanuela Salzano, Sarah E. Raible, and Ian D. Krantz 46 Prader–Willi Syndrome 735Shawn E. McCandless and Suzanne B. Cassidy 47 Proteus Syndrome 763Leslie G. Biesecker 48 PTEN Hamartoma Tumor Syndrome 775Joanne Ngeow and Charis Eng 49 Rett Syndrome 791Eric E. Smeets 50 Robin Sequence 807Howard M. Saal 51 Rubinstein–Taybi Syndrome 823Leonie A. Menke and Raoul C. M. Hennekam 52 Silver–Russell Syndrome 837Emma L. Wakeling 53 Smith–Lemli–Opitz Syndrome 851Alicia Latham and Christopher Cunniff 54 Smith–Magenis Syndrome 863Ann C.M. Smith and Andrea L. Gropman 55 Sotos Syndrome 895Trevor R.P. Cole and Alison C. Foster 56 Stickler Syndrome 915Mary B. Sheppard and Clair A. Francomano 57 Treacher Collins Syndrome and Related Disorders 927Marilyn C. Jones 58 Trisomy 18 and Trisomy 13 Syndromes 937John C. Carey 59 Tuberous Sclerosis Complex 957Laura S. Farach, Kit Sing Au, and Hope Northrup 60 Turner Syndrome 977Angela E. Lin and Melissa L. Crenshaw 61 VATER/VACTERL Association 995Benjamin D. Solomon and Bryan D. Hall 62 Von Hippel–Lindau Syndrome 1005Samantha E. Greenberg, Luke D. Maese, and Benjamin L. Maughan 63 Williams Syndrome 1021Colleen A. Morris and Carolyn B. Mervis Index 1039

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Book SynopsisA comprehensive resource to sustainability and its application to the environmental, industrial, agricultural and food security sectors Sustainability fills a gap in the literature in order to provide an important guide to the fundamental knowledge and practical applications of sustainability in a wide variety of areas. The authors noted experts who represent a number of sustainability fields bring together in one comprehensive volume the broad range of topics including basic concepts, impact assessment, environmental and the socio-economic aspects of sustainability. In addition, the book covers applications of sustainability in environmental, industrial, agricultural and food security, as well as carbon cycle and infrastructural aspects. Sustainability addresses the challenges the global community is facing due to population growth, depletion of non-renewable resources of energy, environmental degradation, poverty, excessive generation of wastesTable of ContentsEditor Biographies xxiii List of Contributors xxvii Preface xxxiii Part I Fundamentals and Framework 1 1 Introduction to Sustainability and Sustainable Development 3 Prangya R. Rout, Akshaya K. Verma, Puspendu Bhunia, Rao Y. Surampalli, Tian C. Zhang, R.D. Tyagi, S.K. Brar, and M.K. Goyal 1.1 Background and Definition 3 1.2 Basic Concepts and Issues 4 1.3 Evolution of Sustainability and Sustainable Development 7 1.4 Challenges and Solutions 8 1.5 Adaptation and Resilience 8 1.6 Economic, Ecological, Social, Technological and Systems Perspectives 13 1.7 Conclusions 16 References 17 2 The Need, Role and Significance of Sustainability 21 Anita Talan, A.N. Pathak, and R.D. Tyagi 2.1 Introduction 21 2.2 Three Pillars of Sustainability 21 2.3 Primary Goals of Sustainability 27 2.4 Significance of Sustainability 34 2.5 Challenges Toward Sustainability 35 2.6 Sustainable Future 39 2.7 Conclusions 39 References 40 3 Sustainable Development: Dimensions, Intersections and Knowledge Platform 43 Pritee Sharma and Kanak Singh 3.1 Introduction 43 3.2 Understanding Complex Systems 44 3.3 Dimensions of Sustainable Development: Economic Dimension 47 3.4 Dimensions of Sustainable Development: Environmental Dimension 53 3.5 Dimensions of Sustainable Development: Social Dimension 56 3.6 Mapping Social Development Through Sustainable Development Goals (SDGs) 58 3.7 Sustainable Development Indicators 60 3.8 Exploring Knowledge Systems for Sustainability 61 3.9 Conclusion 65 References 65 4 Measurement of Sustainability 69 Rajneesh Singh, Akash Kumar Gupta, Puspendu Bhunia, Rao Y. Surampalli, Tian C. Zhang, Pengzhi Lin, and Yu Chen 4.1 Introduction 69 4.2 Types and Choice of Indicators 70 4.3 Framework of Lifecycle-Based Sustainability Metrics 72 4.4 Technological Aspects of Supply Chain and Process Sustainability 73 4.5 Sustainable Economy Indices 74 4.6 Environmental Indicator for Manufacturing Competitiveness 75 4.7 Monitoring and Evaluation Processes 77 4.8 Conclusion 79 References 79 5 Sustainable Impact Assessment 83 L.R. Kumar, Anita Talan and R.D. Tyagi 5.1 Introduction 83 5.2 Types of Impact Assessment (IA) 83 5.3 Sustainable Impact Assessment (SIA) 86 5.4 Advantages of Conducting Sustainable Impact Assessment 89 5.5 Recent Evolution of Impact Assessment 90 5.6 Different Approaches of SIA 91 5.7 Determining Criteria for Sustainability 93 5.8 Procedure to Follow Impact Assessment 94 5.9 ToSIA – Software Tool for Sustainable Impact Assessment 99 5.10 Case Studies for Use of Sustainable Impact Assessment 103 5.11 Conclusions 106 References 107 6 Analytical Tools and Methodologies to Evaluate Sustainable Development Goals of the United Nations with Special Reference to Asia 111 Gamini Herath 6.1 Introduction 111 6.2 Sustainable Development Goals of the United Nations 112 6.3 Planning and Decision Making Methodologies for the Sustainable Development Goals 112 6.4 Tools to Tackle Interlinked Goals and Policy Incoherence 113 6.5 Carrying Capacity (CC) 116 6.6 Evalution Models Under Uncertainty 117 6.7 Adaptive Management 119 6.8 Multicriteria Decision Analysis (MCDA) 119 6.9 Multiattribute Utility Theory 121 6.10 Conclusions 124 References 124 7 Resilience Engineering and Quantification for Sustainable Systems 129 Anita Talan, Bhoomika Yadav, L.R. Kumar, and R.D. Tyagi 129 7.1 Introduction 129 7.2 Resilience and Sustainability: Definitions, Differences and Similarities 130 7.3 Technical Purposes of Resilience Engineering 132 7.4 Resilience Assessment Approaches 133 7.5 Indicators for Quantifying Successful Resilience and Sustainability 138 7.6 Some Resilient Systems and Associated Codes/Standards 140 7.7 Communal Resilience and Built Environment Sustainability 144 7.8 Risk Analysis and Resilience 149 7.9 Integration of Sustainability and Resilience 151 7.10 Conclusions 152 References 154 Part II Dimensions and Different Aspects 157 8 Economic Development and Sustainability 159 L.R. Kumar, Anita Talan, and R.D. Tyagi 8.1 Introduction 159 8.2 Different Perspectives of Economic Development 159 8.3 Indicators for Economic Development 160 8.4 Economic Development for Sustainability 162 8.5 Economic Policies for Sustainable Development 167 8.6 Economic Development and Environment 170 8.7 Economic Analysis of Sustainable Development 174 8.8 Future Directions for Achieving Economic Sustainable Development 177 8.9 Conclusions 178 References 179 9 Social Dimensions of Sustainability 183 Anita Talan, R.D. Tyagi, and Rao Y. Surampalli 9.1 Introduction 183 9.2 Concepts and Definitions of Social Sustainability 184 9.3 Social Sustainability 185 9.4 Dimensions of Social Sustainability 188 9.5 Gaps in Dimensions of Social Sustainability 193 9.6 Research-based Policies and Federal Perspective Toward Social Sustainability 195 9.7 Social Sustainability – an Integrated Approach 200 9.8 Safety and Security 202 9.9 Future Perspective and Conclusions 203 References 204 10 Social Engineering and Sustainability: Revisiting Popper’s “Piecemeal Approach” 207 Neeraj Mishra 10.1 Introduction 207 10.2 Emergence of Sustainability on the Global Agenda 208 10.3 Concept of Social Engineering 209 10.4 Karl Popper’s Description of Social Engineering 211 10.5 Social Engineering as a Tool for Sustainable Development 214 10.6 Promoting Sustainable Consumption and Bio‐Politics of Sustainability 217 10.7 Social Engineering, Sustainability and Industrial Production 221 10.8 Conclusions 224 References 225 11 Environment Modeling for Sustainable Development 229 Lalit Borana, Bhaskar Jyoti Deka, Jiaxin Guo, and Alicia Kyoungjin An 11.1 Introduction 229 11.2 Environmental Indicators in the Context of Sustainable Development 231 11.3 Overview of Sustainable Development 235 11.4 Role of Sustainability in Environmental Development 237 11.5 Case Studies: Sustainability Management 241 11.6 Modeling of Sustainability 246 11.7 Modeling Tools for Sustainable Development Policies: Vision 2030 – United Nations Department of Economic and Social Affairs 249 11.8 Summary 251 References 251 12 Biodiversity and Sustainability 255 Akshaya K. Verma, Prangya R. Rout, Eunseok Lee, Puspendu Bhunia, Jaeho Bae, Rao Y. Surampalli, Tian C. Zhang, Rajeshwar D. Tyagi, Pengzhi Lin, and Yu Chen 12.1 Introduction 255 12.2 Threats to Biodiversity 257 12.3 Role of Biodiversity in Sustainable Development 268 12.4 Trends of Biodiversity 269 12.5 Conclusions 270 References 271 13 Sustainability of Ecosystem Services (ESs) 277 Carlos S. Osorio‐González, Niranjan Suralikerimath, Krishnamoorthy Hegde, and Satinder K. Brar 13.1 Introduction 277 13.2 Historical Evolution of Ecosystem Services Definition 278 13.3 Framework for Assessing Ecosystem Services 280 13.4 Utilization of Ecosystem Services for Sustainable Development 281 13.5 Recent Advances in Mapping and Measuring Multiple Services 283 13.6 Possible Approaches for Sustainable Use of Ecosystem Services 284 13.7 Challenge and Interlinkage Themes for Researchers 287 13.8 Future Directions and Conclusions 288 References 289 14 Sustainable Infrastructure 295 Gilbert Hinge, Rao Y. Surampalli, and Manish Kumar Goyal 14.1 Infrastructure − An Introduction 295 14.2 Mitigation Policies 299 14.3 Strategic Environmental Assessment 301 14.4 Recycling Reuse and Reclamation 304 14.5 Reverse Logistics 305 14.6 Deconstruction 307 14.7 Summary 308 References 309 15 Industrial Practices in Sustainability 313 K.K. Brar, Dalila Larios Martinez, Mitra Naghdi, Satinder K. Brar, Bhupinder Singh Chadha, Preetinder Singh, and Rao Y. Surampalli 15.1 Introduction 313 15.2 Causes of Environmental Deterioration 314 15.3 Effects of Environmental Degradation 315 15.4 Human-Induced Eye-Opening Environmental Incidents 318 15.5 Sustainable Development 319 15.6 Benefits of Being a Sustainable Business 320 15.7 How to Achieve Sustainable Development 321 15.8 Commitment Toward the Environment 322 15.9 Future Action Needed 335 References 336 16 Challenges of Sustainability in Agricultural Management 339 Jew Das, Srinidhi Jha, Manish Kumar Goyal, and Rao Y. Surampalli 16.1 Introduction 339 16.2 An Overview of Indian Agriculture 341 16.3 Agricultural Sustainability: Environmental, Economic and Social Perspectives 347 16.4 Challenges to Agricultural Sustainability 348 16.5 Road to Sustainable Agriculture: Possible Solutions 352 16.6 Conclusions 354 References 355 17 Food Security and Sustainability 357 Preetika Kuknur Pachapur, Vinayak Laxman Pachapur, Satinder K. Brar, Rosa Galvez, Yann Le Bihan, and Rao Y. Surampalli 17.1 Introduction 357 17.2 Food Needs 358 17.3 Population Growth 359 17.4 Impact of Climate Change on Food Security 360 17.5 International Case Studies 361 17.6 Biofuels and Food Security 364 17.7 Water–Energy–Food Security Nexus 367 17.8 Genetically Modified Foods for Food Security 368 17.9 Horizontal Gene Transfer for Food Security 369 17.10 Future Plans for Food Security 369 References 371 18 Sustainable Healthcare Systems 375 Carlos S. Osorio‐González, Krishnamoorthy Hegde, Satinder K. Brar, Antonio Avalos‐ Ramírez, and Rao Y. Surampalli 18.1 Introduction 375 18.2 Classification of Healthcare Systems 376 18.3 Sustainability and Healthcare Systems 377 18.4 Sustainability Challenges in Healthcare Systems 379 18.5 Categories of Sustainability in Healthcare Systems 381 18.6 Overview of Sustainable Healthcare Systems 384 18.7 Conclusion 390 References 391 19 Ethical Aspects of Sustainability 397 Anita Talan, Rajwinder Kaur, R.D. Tyagi, and Tian C. Zhang 19.1 Introduction 397 19.2 Juxtaposing Ethics, Morality and Sustainable Development 398 19.3 Approaches to Ethics 400 19.4 The Neoliberal Era and Adaptation into the Sustainability Framework 402 19.5 Global Flora and Sustainability 405 19.6 Adaptation and Mitigation of Climate Change: Ethical Perspective 405 19.7 Conclusions 409 References 410 20 Education and Human Resource Development for Sustainability 413 Anita Talan, and R. D Tyagi 20.1 Introduction 413 20.2 Education for Sustainability 413 20.3 Objectives of Education for Sustainable Development 416 20.4 Potential Improvements via Education for Sustainable Development 421 20.5 Global Education and Global Actions of ESD 424 20.6 Sustainability as Human Resource Development 429 20.7 HRD Indicators 432 20.8 Change in HRD for Sustainability 433 20.9 HRD Resources for Sustainable Development 434 20.10 Conclusion 435 References 436 Part III Applications 439 21 Climate Change Adaptation for Sustainable Management of Water in India: Issues and Challenges 441 Adani Azhoni 21.1 Introduction 441 21.2 Climate Change Challenges to India’s Water Management 443 21.3 Adaptation Approaches 444 21.4 Water Management Institutions and Their Role in Adaptation 449 21.5 Indian Water Institutions 450 21.6 Recent Initiatives to Address Climate Change in India 452 21.7 Adaptation for Sustainability: Two Examples 452 21.8 Discussion and Conclusion 454 References 455 22 Sustainability of Carbon Storage and Sequestration 465 Gilbert Hinge, Rao Y. Surampalli, and Manish Kumar Goyal 22.1 Introduction 465 22.2 Carbon Sources and Sinks 466 22.3 Types of Carbon Sequestration 466 22.4 Methods for Quantification of Soil Organic Carbon Stocks 468 22.5 Adaptation and Mitigation Policy for Carbon Management 475 22.6 Conclusions 479 References 479 23 Environmental Degradation and Sustainability 483 Yong Qi, Puspendu Bhunia, Tian C. Zhang, F. Luo, Pengzhi Lin, and Yu Chen 23.1 Introduction 483 23.2 Desertification and Associated Sustainable Strategies 484 23.3 Environmental Pollution and Associated Impacts 486 23.4 Snow Ablation and Glacier Retreat 491 23.5 Dams and Resettlement 492 23.6 Strategies for Sustainable Development While Addressing Environmental Pollution and Degradation 494 23.7 Future Trends 501 23.8 Conclusions 502 References 502 24 Sustainability of River Water Resources Under the Influence of Climate Change 507 Shivam Gupta and Manish Kumar Goyal 24.1 Introduction 507 24.2 Effects of Global Warming on Observed Changes 508 24.3 Water Stress – the Supply Demand Balance 510 24.4 Impacts of Climate Change on Glaciers and Mountainous Water Resources 511 24.5 Sustainable Management of River Water Resources 512 24.6 Case Studies 513 24.7 Conclusions 523 References 523 25 Sustainable Systems for Groundwater Resource Management 527 Manish Kumar Goyal, Srinidhi Jha, and Rao Y. Surampalli 25.1 Introduction 527 25.2 Occurrence and Distribution 530 25.3 Groundwater Usage in the World 533 25.4 Two Main Challenges 536 25.5 Toward Groundwater Sustainability 539 25.6 Looking for Possible Solutions: Primary Solutions 542 25.7 Intuitional and Organizational Reforms: Secondary Solutions 546 25.8 Conclusions 548 References 549 26 Sustainability and Energy Management in Facilities for Wastewater Treatment and Reuse 553 Joseph Sebastian, Pratik Kumar, Krishnamoorthy Hegde, Satinder K. Brar, Mausam Verma, and Rao Y. Surampalli 26.1 Introduction 553 26.2 Sustainable Wastewater Treatment and Reuse 554 26.3 Approaches for Sustainable Wastewater Treatment and Reuse 557 26.4 Sustainable Energy Derived from Wastewater 564 26.5 Conclusions 575 References 576 27 Energy Needs for Sustainable Buildings and Transportation 583 Rehan Khan, Suchit Deshmukh, and Ritunesh Kumar 27.1 Introduction 583 27.2 Building and Energy 584 27.3 Energy for Transportation 594 27.4 Conclusions 602 References 602 28 Remote Sensing and GIS Applications in Sustainability 605 Manish Kumar Goyal, Ashutosh Sharma, and Rao Y. Surampalli 28.1 Introduction 605 28.2 Remote Sensing for Earth Observation (EO) and Data Acquisition 609 28.3 Sustainable Resource Management Using Remote Sensing and GIS 612 28.4 Case Study 613 28.5 Future Perspectives 619 28.6 Conclusions 620 References 620 29 Artificial Intelligence and Computational Sustainability 627 S.K. Ram and R.D. Tyagi 29.1 Introduction 627 29.2 Basic Elements of AI Implementation 628 29.3 Concept of Computational Sustainability 629 29.4 Computational Sustainability and Ecological Preservation 631 29.5 Potential Applications of AI in Various Sectors 632 29.6 AI for UN Sustainable Development Goals 638 29.7 Challenges Associated with AI 638 29.8 AI and Its Socio‐Economic Impact 641 29.9 AI for Developing Countries: A Case Study of Zimbabwe 643 29.10 Conclusions and Future Prospects 645 References 645 Index 651

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Book SynopsisEssentials of Chemical Biology Discover a detailed knowledge of concepts and techniques that shape this unique multi-discipline Chemical Biology is devoted to understanding the way that Biology works at the molecular level. This is a problem-driven multi-discipline, incorporating as it does Organic, Physical, Inorganic, and Analytical Chemistry alongside newer emerging molecular disciplines. In recent years, Chemical Biology has emerged as a vibrant and growing multi-discipline distinct from Biochemistry that is focused on the quantitative analyses of the structures and functions of biological macromolecules and macromolecular lipid assemblies, at first in isolation, then in vitro and in vivo. The second edition of the Essentials of Chemical Biology begins with a thorough introduction to the structure of biological macromolecules and macromolecular lipid assemblies, before moving on to the principles of chemical and biological synthesis, foTable of ContentsPreface x Glossary of Physical and Chemical Terms xii About the Companion Website xviii 1 The Structures of Biological Macromolecules and Lipid Assemblies 1 1.1 General introduction 1 1.2 Protein structures 3 1.3 Carbohydrate structures 20 1.4 Nucleic acid structures 31 1.5 Macromolecular lipid assemblies 53 1.6 Structural forces in biological macromolecules 60 2 Chemical and Biological Synthesis 68 2.1 Introduction to synthesis in chemical biology 68 2.2 Chemical synthesis of peptides and proteins 68 2.3 Chemical synthesis of nucleic acids 75 2.4 Chemical synthesis of oligosaccharides 84 2.5 Chemical synthesis of lipids 87 2.6 Biological synthesis of biological macromolecules 89 2.7 Directed biological synthesis of proteins 97 2.8 Biological syntheses of nucleic acids, oligosaccharides and lipids 102 3 Molecular Biology as a Toolset for Chemical Biology 104 3.1 Key concepts in molecular biology 104 3.2 Tools and techniques in molecular biology 108 3.3 Cloning and identification of genes in DNA 117 3.4 Integrating cloning and expression 123 3.5 Site-directed mutagenesis 125 4 Electronic and Vibrational Spectroscopy 128 4.1 Electronic and vibrational spectroscopy in chemical biology 128 4.2 Ultraviolet-visible spectroscopy 128 4.3 Circular dichroism spectroscopy 134 4.4 Vibrational spectroscopy 138 4.5 Fluorescence spectroscopy 141 4.6 Probing metal centres by absorption spectroscopy 163 5 Magnetic Resonance 164 5.1 Magnetic resonance in chemical biology 164 5.2 Key principles of NMR 164 5.3 Two-dimensional NMR 176 5.4 Multidimensional NMR 180 5.5 Biological macromolecule structural information 183 5.6 Electron paramagnetic resonance spectroscopy: key principles 193 6 Diffraction and Microscopy 199 6.1 Diffraction and microscopy in chemical biology 199 6.2 Key principles of X-ray diffraction 199 6.3 Structural information from X-ray diffraction 206 6.4 Neutron diffraction 216 6.5 Key principles of electron microscopy 217 6.6 Key principles of scanning probe microscopy 224 7 Molecular Recognition and Binding 232 7.1 Molecular recognition and binding in chemical biology 232 7.2 Theoretical models of binding 245 7.3 Analysing molecular recognition and binding 251 7.4 Biological molecular recognition studies 263 8 Kinetics and Catalysis 278 8.1 Catalysis in chemical biology 278 8.2 Steady state kinetic schemes 300 8.3 Pre-steady-state kinetics 323 8.4 Theories of biocatalysis 328 8.5 Electron transfer 346 9 Mass Spectrometry and Proteomics 348 9.1 Mass spectrometry in chemical biology 348 9.2 Key principles in mass spectrometry 349 9.3 Structural analysis of biological macromolecules and lipids by mass spectrometry 359 9.4 The challenge of proteomics 368 9.5 Genomics: assigning function to genes and proteins 375 10 Molecular Selection and Evolution 378 10.1 Chemical biology and the origins of life 378 10.2 Molecular breeding: natural selection acting on self-organisation 383 10.3 Directed evolution of protein function 385 10.4 Directed evolution of nucleic acids 390 10.5 Catalytic antibodies 398 11 Chemical Biology of Cells 401 11.1 General introduction 401 11.2 Array technologies, microfluidics and miniaturisation 401 11.3 Chemical genetics and potential new therapeutics 403 11.4 Chemical cellular dynamics 412 11.5 Chemical biology and in vivo cell connectomics 415 12 Chemical Biology of Stem Cells to Tissue Engineering 421 12.1 General introduction 421 12.2 Chemical stem cell biology 421 12.3 The road to cell therapies 437 12.4 Tissue engineering 439 13 Chemical Biology, Nanomedicine and Advanced Therapeutics 441 13.1 General introduction 441 13.2 The chemical biology approach to gene therapy 441 13.3 Biophysical characterisation of LNPs 467 13.4 Applications of LNPs with small molecule drugs 471 14 Chemical Biology and Advanced Diagnostics Leading to Precision Therapeutic Approaches 472 14.1 General introduction 472 14.2 MRI basic principles leading to diagnostic applications 472 14.3 PET/CT and SPECT fundamentals 477 14.4 Understanding how to control nanoparticle biodistribution behaviour in vivo 478 14.5 Theranostics 479 15 DNA Nanotechnology 489 15.1 Background 489 15.2 Three-dimensional DNA nanostructures 491 15.3 Dynamic DNA nanostructures 496 15.4 Biomedical applications of DNA nanostructures 500 Bibliography 502 Index 519

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Book SynopsisProvides a timely update to a key textbook on human drug metabolism The third edition of this comprehensive book covers basic concepts of teaching drug metabolism, starting from extreme clinical consequences to systems and mechanisms and toxicity. It provides an invaluable introduction to the core areas of pharmacology and examines recent progress and advances in this fast moving field and its clinical impact. Human Drug Metabolism, 3rd Edition begins by covering basic concepts such as clearance and bioavailability, and looks at the evolution of biotransformation, and how drugs fit into this carefully managed biological environment. More information on how cytochrome P450s function and how they are modulated at the sub-cellular level is offered in this new edition. The book also introduces helpful concepts for those struggling with the relationship of pharmacology to physiology, as well as the inhibition of biotransformational activity. Recent advances inTable of ContentsPreface xv 1 Introduction 1 1.1 Therapeutic window 1 1.1.1 Introduction 1 1.1.2 Therapeutic index 3 1.1.3 Changes in dosage 3 1.1.4 Changes in rate of removal 4 1.2 Consequences of drug concentration changes 4 1.2.1 Drug failure 4 1.2.2 Drug toxicity 5 1.3 Clearance 6 1.3.1 Definitions 6 1.3.2 Clearance and elimination 7 1.3.3 Biotransformation prior to elimination 7 1.3.4 Intrinsic clearance 8 1.3.5 Clearance: influencing factors 8 1.4 First pass and drug extraction 9 1.4.1 First pass: gut contribution 9 1.4.2 First pass: hepatic contribution 10 1.4.3 First pass: low‐extraction drugs 12 1.5 First pass and plasma drug levels 13 1.5.1 Introduction 13 1.5.2 Changes in clearance and plasma levels 14 1.6 Drug and xenobiotic metabolism 14 References 15 2 Drug Biotransformational Systems – Origins and Aims 17 2.1 Biotransforming enzymes 17 2.2 Threat of lipophilic hydrocarbons 18 2.3 Cell communication 19 2.3.1 Signal molecule evolution 19 2.3.2 Lipophilic hydrocarbons as signal molecules 20 2.4 False signal molecules: bioprotection 22 2.4.1 Endocrine disruption 22 2.4.2 Endocrine disruption: problems and solutions 23 2.4.3 Endocrine disruption: cosmetic and nutraceutical aspects 24 2.4.4 Endocrine disruption: microRNAs 25 2.5 Sites of biotransforming enzymes 26 2.6 Biotransformation and xenobiotic cell entry 27 2.6.1 Role of the liver 27 2.6.2 Drug and xenobiotic uptake: transporter systems 29 2.6.3 Hepatic and gut uptake (influx) transporter systems 30 2.6.4 Aims of biotransformation 31 2.6.5 Task of biotransformation 32 2.6.6 Phase’s I–III of biotransformation: descriptions and classifications 33 2.6.7 Biotransformation and drug action 34 References 34 3 How Oxidative Systems Metabolise Substrates 37 3.1 Introduction 37 3.2 Capture of lipophilic molecules 37 3.3 Cytochrome P450s: nomenclature and methods of study 38 3.3.1 Classification 38 3.3.2 Methods of analysis 40 3.3.3 CYP key features and capabilities 42 3.4 CYPs: main and associated structures 44 3.4.1 General structure 44 3.4.2 Haem moiety 44 3.4.3 CYP flexible regions 45 3.4.4 Substrate binding in CYPs 46 3.4.5 Homotropic binding in CYPs 47 3.4.6 Heterotropic binding in CYPs 49 3.4.7 CYP complex formation 50 3.4.8 CYP REDOX partners (i): P450 oxidoreductase (POR) 50 3.4.9 CYP REDOX partners (ii): Cytochrome b5 52 3.5 Human CYP families and their regulation 54 3.5.1 CYP regulation: lifespan 55 3.5.2 CYP regulation: transcriptional 56 3.5.3 CYP regulation: post‐translational 58 3.6 Main human CYP families 59 3.6.1 CYP1A series 59 3.6.2 CYP2 series 61 3.6.3 CYP3A series 69 3.7 Cytochrome P450 catalytic cycle 71 3.7.1 Substrate binding 72 3.7.2 Oxygen binding 72 3.7.3 Oxygen scission (splitting) 74 3.7.4 Insertion of oxygen into substrate 75 3.7.5 Release of product 75 3.7.6 Reductions 76 3.8 Flavin monooxygenases (FMOs) 76 3.8.1 Introduction 76 3.8.2 Structure 77 3.8.3 Mechanism of catalysis 78 3.8.4 Variation and expression 80 3.8.5 FMOs in drug development 80 3.9 How CYP isoforms operate in vivo 81 3.9.1 Illustrative use of structures 82 3.9.2 Primary purposes of CYPs 82 3.9.3 Role of oxidation 83 3.9.4 Summary of CYP operations 84 3.10 Aromatic ring hydroxylation 84 3.10.1 Nature of aromatics 84 3.10.2 Oxidation of benzene 85 3.11 Alkyl oxidations 86 3.11.1 Saturated alkyl groups 86 3.11.2 Unsaturated alkyl groups 87 3.11.3 Pathways of alkyl metabolism 89 3.12 Rearrangement reactions 90 3.12.1 Dealkylations 90 3.12.2 Deaminations 93 3.12.3 Dehalogenations 94 3.13 Other oxidation processes 94 3.13.1 Primary amine oxidations 94 3.13.2 Oxidation of alcohol and aldehydes 96 3.13.3 Monoamine oxidase (MAO) 96 3.14 Control of CYP metabolic function 97 References 97 4 Induction of Cytochrome P450 Systems 109 4.1 Introduction 109 4.1.1 How living systems self‐regulate: overview 109 4.1.2 Self‐regulation in drug metabolism 112 4.1.3 Self‐regulatory responses to drugs: summary 117 4.2 Causes of accelerated clearance 117 4.3 Enzyme induction 118 4.3.1 Types of inducers 118 4.3.2 Common features of inducers and clinical significance 120 4.4 Mechanisms of enzyme induction 121 4.4.1 Introduction 121 4.4.2 CYPs 1A1/1A2 and 1B1 induction 122 4.4.3 CYP 2B6 2C8/2C9/C19 and 3A4 induction 126 4.4.4 CYP 2E1 induction 138 4.4.5 CYP2D6 140 4.4.6 Reversal of induction 141 4.4.7 Cell transport systems and induction: P‐glycoprotein 143 4.4.8 Induction processes: summary 148 4.5 Induction: general clinical aspects 149 4.5.1 Introduction 149 4.5.2 Anti‐epileptic agents 150 4.5.3 OTC (over the counter) and online herbal preparations 155 4.5.4 Anticoagulant drugs 158 4.5.5 Oral contraceptives/steroids 160 4.5.6 Antiviral/antibiotic drugs 161 4.5.7 Anticancer drugs 163 4.6 Induction: practical considerations 165 4.7 Induction vs. inhibition: which ‘wins’? 165 4.8 Induction: long‐term impact 166 References 167 5 Cytochrome P450 Inhibition 183 5.1 Introduction 183 5.2 Inhibition of metabolism: general aspects 186 5.3 Mechanisms of reversible inhibition 187 5.3.1 Introduction 187 5.3.2 Competitive inhibition 188 5.3.3 Noncompetitive inhibition 195 5.3.4 Uncompetitive inhibition 196 5.4 Mechanisms of irreversible inhibition 196 5.4.1 Introduction 196 5.4.2 Mechanism‐based quasi‐irreversible inhibitors 198 5.4.3 Mechanism‐based irreversible inhibitors 198 5.5 Clinical consequences of irreversible inhibition 200 5.5.1 Introduction 200 5.5.2 Quasi‐irreversible inhibitors: the SSRIs 201 5.5.3 Mechanism‐based inhibitors: grapefruit juice 213 5.5.4 Mechanism‐based inhibitors: other juice products 216 5.5.5 OTC herbal remedy inhibitors 218 5.6 Cell transport systems and inhibition 220 5.6.1 Uptake (Influx) transporters: OATPs 220 5.6.2 Efflux transporters: P‐glycoprotein (P‐gp) 222 5.7 Major clinical consequences of inhibition of drug clearance 226 5.7.1 Introduction 226 5.7.2 Torsades de pointes (TdP) 227 5.7.3 Sedative effects 232 5.7.4 Muscle damage (rhabdomyolysis) 233 5.7.5 Excessive hypotension 234 5.7.6 Ergotism 235 5.7.7 Excessive anticoagulation 235 5.8 Use of inhibitors for positive clinical intervention 236 5.8.1 Introduction 236 5.8.2 CYP inhibitors and female hormone‐dependent tumours 237 5.8.3 CYP inhibitors and male hormone‐dependent tumours 238 5.8.4 CYP inhibitors and manipulation of prescription drug disposition 239 5.8.5 Use of inhibitors to increase drug efficacy 241 5.8.6 Use of inhibitors to reduce toxic metabolite formation 242 5.8.7 Use of inhibitors to reduce drug costs 245 5.8.8 Use of inhibition in alcoholism 246 5.9 Summary 246 References 246 6 Conjugation and Transport Processes 263 6.1 Introduction 263 6.2 Glucuronidation 265 6.2.1 UGTs 265 6.2.2 UGT mode of operation 266 6.2.3 UGT isoforms 268 6.2.4 UGTs and bilirubin 271 6.2.5 UGTs and bile acids 272 6.2.6 Role of glucuronidation in drug clearance 273 6.2.7 Types of glucuronides formed 274 6.2.8 Control of UGTs 276 6.2.9 Induction of UGTs: clinical consequences 278 6.2.10 UGT inhibition: bilirubin metabolism 280 6.2.11 UGT inhibition: drug clearance 281 6.2.12 Microbiome and drug metabolism: passengers or crew? 282 6.3 Sulphonation 285 6.3.1 Introduction 285 6.3.2 SULT structure related to catalytic operation 287 6.3.3 Control of SULT enzymes 289 6.3.4 SULTs and cancer 289 6.4 The GSH system 290 6.4.1 Introduction 290 6.4.2 GSH system maintenance 292 6.5 Glutathione S‐transferases 293 6.5.1 Structure and location 293 6.5.2 Mode of operation 295 6.5.3 GST classes 296 6.5.4 Control of GSTs: overview 300 6.5.5 Control of GSTs and reactive species 301 6.5.6 Control of GSTs: the nrf2 system 302 6.6 Epoxide hydrolases 304 6.6.1 Nature of epoxides 304 6.6.2 Epoxide hydrolases 304 6.6.3 Epoxide hydrolases: structure, mechanisms of action, and regulation 306 6.7 Acetylation 307 6.8 Methylation 309 6.9 Esterases/amidases 311 6.10 Amino acid conjugation (mainly glycine) 314 6.11 Phase III transport processes 315 6.11.1 Introduction 315 6.11.2 ABC Efflux transporters 315 6.11.3 RLIP76 320 6.12 Biotransformation: integration of processes 320 References 322 7 Factors Affecting Drug Metabolism 331 7.1 Introduction 331 7.2 Genetic polymorphisms 332 7.2.1 Introduction 332 7.2.2 Clinical implications 336 7.2.3 Genetic polymorphisms in CYP systems 341 7.2.4 Genetic polymorphisms in nonconjugative systems 369 7.2.5 Conjugative polymorphisms: acetylation 374 7.2.6 Conjugative polymorphisms: methylation 381 7.2.7 Conjugative polymorphisms: UGT 1A1 385 7.2.8 Conjugative polymorphisms: sulphonation 388 7.2.9 Other conjugative polymorphisms: Glutathione S‐transferases 389 7.2.10 Transporter polymorphisms 390 7.2.11 Polymorphism detection: clinical and practical issues 392 7.3 Effects of age on drug metabolism 395 7.3.1 The elderly 395 7.3.2 Drug clearance in neonates and children 398 7.4 Effects of diet on drug metabolism 401 7.4.1 Polyphenols 401 7.4.2 Barbecued meat 402 7.4.3 Cruciferous vegetables 403 7.4.4 Other vegetable effects on metabolism 404 7.4.5 Caffeine 404 7.4.6 Diet: general effects 405 7.5 Gender effects 406 7.6 Smoking 409 7.7 Effects of ethanol on drug metabolism 412 7.7.1 Context of ethanol usage 412 7.7.2 Ethanol metabolism 413 7.7.3 Ethanol and inhibitors of ALDH 414 7.7.4 Mild ethanol usage and drug clearance 414 7.7.5 Heavy ethanol usage and paracetamol 415 7.7.6 Alcoholic liver disease 416 7.7.7 Effects of cirrhosis on drug clearance 420 7.8 Artificial livers 422 7.9 Effects of disease on drug metabolism 424 7.10 Summary 425 References 426 8 Role of Metabolism in Drug Toxicity 447 8.1 Adverse drug reactions: definitions 447 8.2 Predictable drug adverse effects: type A 448 8.2.1 Intensification of pharmacologic effect: type A1 448 8.2.2 Off‐target reversible effects and methaemoglobin formation: type A2 449 8.2.3 Predictable overdose toxicity: type A3 455 8.3 Unpredictable drug adverse effects: type B 470 8.3.1 Idiosyncratic and overdose toxicity: similarities and differences 470 8.3.2 Type B1 necrosis: troglitazone 471 8.3.3 Type B1 necrosis: trovafloxacin 473 8.3.4 Type B2 reactions: immunotoxicity 476 8.4 Nature of drug‐mediated immune responses 489 8.4.1 Anaphylaxis 489 8.4.2 DRESS/Anticonvulsant hypersensitivity syndrome (AHS) 491 8.4.3 Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) 492 8.4.4 Blood dyscrasias 494 8.4.5 Prediction of idiosyncratic reactions 499 8.5 Type B3 reactions: role of metabolism in cancer 500 8.5.1 Sources of risks of malignancy 500 8.5.2 Risks of malignancy and drug development 501 8.5.3 Environmental carcinogenicity risks 502 8.5.4 Occupational carcinogens 503 8.5.5 Dietary carcinogens: acrylamide 513 8.5.6 Dietary carcinogens: aflatoxins 516 8.6 Summary of biotransformational toxicity 520 References 521 Appendix A Drug Metabolism in Drug Discovery 531 A.1 The pharmaceutical industry 531 A.2 Drug design and biotransformation: strategies 533 A.3 Animal and human experimental models: strategies 537 A.4 In vitro metabolism platforms and methods 539 A.4.1 Analytical techniques 539 A.4.2 Human liver microsomes 541 A.4.3 Heterologous recombinant systems 542 A.4.4 Liver slices 543 A.4.5 Human hepatocytes 543 A.5 Animal model developments in drug metabolism 550 A.5.1 Introduction 550 A.5.2 Genetic modification of animal models 551 A.5.3 ‘Humanized’ mice 552 A.6 Toxicological assays 553 A.6.1 Aims 553 A.6.2 Cell viability assays 554 A.6.3 ‘One compartment’ cell models 555 A.6.4 ‘Two compartment’ models 555 A.6.5 DNA and chromosomal toxicity assays 556 A.6.6 The Ames test 556 A.6.7 Comet assay 557 A.6.8 Micronucleus test 557 A.6.9 Toxicology in drug discovery 558 A.7 In silico approaches 561 A.8 Summary 564 References 565 Appendix B Metabolism of Major Illicit Drugs 571 B.1 Introduction 571 B.2 Opiates 572 B.3 Cocaine 582 B.4 Hallucinogens 585 B.5 Amphetamine derivatives 591 B.6 Cannabis 603 B.7 Dissociative anaesthetics 609 B.8 Charlie Don’t Surf! 616 References 617 Appendix C Examination Techniques 627 C.1 Introduction 627 C.2 A first‐class answer 627 C.3 Preparation 629 C.4 The day of reckoning 632 C.5 Foreign students 633 Appendix D Summary of Major CYP Isoforms and Their Substrates, Inhibitors, and Inducers 635 Index 639

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Book SynopsisWritten by an experienced and well-respected physician and professor, this new volume, building on the previous volume, Ultrasonic Topographical and Pathotopographical Anatomy, also available from Wiley-Scrivener, presents the ultrasonic topographical and pathotopographical anatomy of the head and neck, offering further detail into these important areas for use by medical professionals. This atlas of topographic and pathotopographic human anatomy is a fundamental and practically important book designed for doctors of all specializations and students of medical schools. Here you can find almost everything that is connected with the topographic and pathotopographic human anatomy, including original graphs of logical structures of topographic anatomy and development of congenital abnormalities, topography of different areas in layers, pathotopography, computer and magnetic resonance imaging (MRI) of topographic and pathotopographic anatomy. Also you can find here new theoTable of ContentsAbout the Author vii Introduction ix Part 1 The Head 1 Topographic Anatomy of the Head 1 Cerebral Cranium 1 Basis Cranii Interna 15 The Brain 18 Surgical Anatomy of Congenital Disorders 41 Pathotypography of the Cerebral Part of the Head 42 Facial Head Region 47 The Lymphatic System of the Head 89 Congenital Face Disorders 92 Pathotypography of the Facial Part of the Head 94 Attachment 1: Neurocranial Part Topography 102 Attachment 2: Facial Part Topography 103 Part 2 The Neck 105 Topographic Anatomy of the Neck 105 Fasciae, Superficial and Deep Cellular Spaces and their Relationship with Spaces Adjacent Regions 107 Triangles of the Neck 113 Organs of the Neck 135 Pathography of the Neck 144 Attachment 3: Topography of the Neck 155 Appendix A: Adult 157 Appendix B: Child 165

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Book SynopsisThe most up-to-date reference on phytomicrobiomes available today The Plant Microbiome in Sustainable Agriculture combines the most relevant and timely information available today in the fields of nutrient and food security. With a particular emphasis on current research progress and perspectives of future development in the area, The Plant Microbiome in Sustainable Agriculture is an invaluable reference for students and researchers in the field, as well as those with an interest in microbiome research and development. The book covers both terrestrial and crop associated microbiomes, unveiling the biological, biotechnological and technical aspects of research. Topics discussed include: Developing model plant microbiome systems for various agriculturally important cropsDefining core microbiomes and metagenomes in these model systemsDefining synthetic microbiomes for a sustainable increase in food production and quality The Plant Microbiome in Sustainable Agriculture is written to allTable of ContentsPreface vii List of Contributors ix About the Editors xiii 1 Plant Microbiome: Past, Present and Future 1Akhilendra Pratap Bharati, Ashutosh Kumar, Sunita Kumari, Anjney Sharma, Prem Lal Kashyap, Sudheer Kumar, Madhumita Srivastava, and Alok Kumar Srivastava 2 The Plant Microbiome in Agricultural Sustainability: From Microbe to Microbiome 31Jose Pedro Fonseca, Yuan Wang, and Kirankumar S. Mysore 3 Seed Microbiome and Its Implication in Plant Growth Promotion and Health 47Padmavathi Tallapragada and Usha Seshachla 4 Microbiome: The Holobiont, Its Application and Effect on the Plant System 65Pragati Sahai and Vimlendu Bhushan Sinha 5 Ecology of the Diazotrophic Microbiome 81Preeti Singh, Rahul Kunwar Singh, Dhananjay Kumar, and Shree Prakash Tiwari 6 Functional Microbiome for Crop Improvement Under a Changing Environment 101Abbaci Hocine, Bensidhoum Leila, Houali Karim, and Nabti Elhafid 7 Functional Importance of the Phyllosphere Microbiome and Its Implications in Agriculture 119Parasuraman Paramanantham, Subhaswaraj Pattnaik, and Siddhardha Busi 8 Microbial Consortia: Emerging Conglomerate for Better and Superior Sustainable Agricultural Practices 141Rishi Kumar Verma, Manisha Sachan, and Shivesh Sharma 9 Rhizomicrobiome for Sustainable Crop Growth and Health Management 157Tualar Simarmata, Mieke R. Setiawati, Betty N. Fitriatin, and Diyan Herdiyantoro 10 Mycorrhizal Microbiome: An Ideal Association in Sustainable Agriculture 195Baby Summuna, Sachin Gupta, and Moni Gupta 11 Microbiome-Driven Nutrient Fortification in Plants: The Role of Microbiota in Chemical Transformation and Nutrient Mobilization 211Irina Sidorova and Elena Voronina 12 Engineering Microbes to Improve Crop Health: A New Dimension for Sustainable Agricultural Productivity 231P. Veera Bramhachari, A.M.V.N. Prathyusha, and Ganugula Mohana Sheela 13 Biotechnology of Plant-Associated Microbiomes 243Son Truong Dinh, Van T. Luu, Long Hoa Hoang, Xuan Canh Nguyen, and Cuong Tu Ho 14 Microbiome Genomics and Functional Traits for Agricultural Sustainability 279Amy Novinscak, Antoine Zboralski, Roxane Roquigny, and Martin Filion Index 299

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Book SynopsisExplores the use of conventional and novel technologies to enhance fermentation processes Fermentation Processes reviews the application of both conventional and emerging technologies for enhancing fermentation conditions, examining the principles and mechanisms of fermentation processes, the microorganisms used in bioprocesses, their implementation in industrial fermentation, and more. Designed for scientists and industry professionals alike, this authoritative and up-to-date volume describes how non-conventional technologies can be used to increase accessibly and bioavailability of substrates by microorganisms during fermentation, which in turn promotes microbial?growth and?can improve processes and?productivity across the agri-food, nutraceutical, pharmaceutical, and beverage industries. The text begins by covering the conventional fermentation process, discussing cell division and growth kinetics, current technologies and developments in industrial fermentatTable of ContentsChapter 1. Introduction to conventional fermentation processes 1. 1. Bioprocesses 1.1.1. Production of microbial biomass 1.1.2. Production of microbial metabolites 1.1.3. Production of microbial enzymes 1.1.4. Production of recombinant proteins 1.1.5. Production of microbial plasmids 1.1.6. Bioconversion 1.2. Energetic metabolism 1.2.1. Energy transfer and redox reactions 1.2.2. Aerobic respiration 1.2.3. Anaerobic respiration 1.2.4. Fermentation 1.3. Microorganisms used in fermentation processes 1.3.1. Bacteria 1.3.2. Fungi 1.4. Fermentation technology 1.5. Conclusions 1.6. References Chapter 2. Current developments in industrial fermentation processes 2.1. Introduction 2.2. Main achievements in industrial fermentation 2.2.1. Fermentation processes in food industry 2.2.1.1. Alcoholic beverages 2.2.1.2. Enzymes 2.2.2. Fermentation processes in chemical industry 2.2.2.1. Biofuels 2.2.2.2. Organic acids 2.2.2.3. Triacylglycerols and Polyhydroxyalkanoates 2.2.2.4. Syngas fermentation 2.2.3. Fermentation processes in the pharmaceutical industry 2.2.3.1. Drugs 2.2.3.2. Recombinant proteins 2.3. Current developments in industrial fermentation 2.3.1. Microorganisms 2.3.2. Fermentation Media 2.3.2.1. Types of media sources 2.3.3. Fermentation systems 2.3.3.1. Solid-state fermentation bioreactors 2.3.3.2. Ultrasonic fermentation process 2.3.3.3. Electro fermentation 2.3.4. Fermentation optimization 2.3.5. Fermentation process modeling 2.3.5.1. Mechanistic models 2.3.5.2. Computational fluid dynamics (CFD) 2.3.6. Inhibition of fermentation processes 2.3.6.1. Substrate inhibition 2.3.6.2. pH inhibition 2.3.6.3. Inhibition by un-dissociated acids 2.3.6.4. Temperature inhibition 2.3.6.5. Nitrogen inhibition 2.3.6.6. Inhibition by phosphate 2.3.6.7. Inhibition by sulfide 2.3.6.8. Inhibition by lactic acid bacteria 2.3.6.9. Inhibition by metals 2.3.6.10. Inhibition by phenolic and furanic mixtures 2.4. Conclusions 2.5. References Chapter 3. Culture condition changes for enhancing fermentation processes 3.1. Introduction 3.1.1. Fermentation 3.2. Culture media used for fermentation 3.2.1. The culture media purpose 3.2.2. Media types 3.2.3. Culture media: a quantitative approach 3.2.4. Culture media: a compositional approach 3.2.4.1. Water 3.2.4.2. Energy sources 3.2.4.3. Carbon sources 3.2.4.4. Examples of commonly used carbon sources 3.2.4.5. Nitrogen sources 3.2.4.6. Minerals 3.2.4.7. Chelators 3.2.4.8. Growth factors 3.2.4.9. Buffers 3.2.4.10. Precursors and metabolic regulators to media 3.2.4.11. Precursors and inhibitors 3.2.5. Impact of culture conditions on fermentation processes 3.2.5.1. The temperature 3.2.5.2. The pH 3.2.5.3. The cell concentration 3.2.5.4. The carbon dioxide 3.2.5.5. The ethanol 3.3.1. Pasteur effect 3.3.2. Crabtree effect 3.3.3. Custer effect 3.3.4 Oxygen requirements 3.4. Conclusions 3.5. References Chapter 4. Emerging technologies and their mechanism of action on fermentation 4.1. Introduction 4.2. High hydrostatic pressure (HHP) processing 4.3. Ultrasound (US) 4.4. Pulsed Electric Fields 4.5. Microwaves (MV) 4.6. Conclusions 4.7. References Chapter 5. Biomass fractionation using emerging technologies 5.1. Introduction 5.2. Ultrasound application for biomass fractionation 5.3. Microwave application for biomass fractionation 5.4. Pulsed-electric fields application for biomass fractionation 5.5. Enzyme-assisted fractionation of biomass 5.6. Supercritical fluid fractionation of biomass 5.7. Conclusions 5.8. References Chapter 6. Enhancing microbial growth using emerging technologies 6.1. Introduction 6.2. Microbial stimulation using electric fields 6.3. Microbial stimulation using ultrasounds 6.4. Microbial stimulation using high pressure 6.5. Conclusions 6.6. References

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Book SynopsisWritten and edited by some of the most well-respected authors in the area of the adaptation of plants and animals to climate change, this groundbreaking new work is an extremely important scientific contribution to the study of global warming. Global climate change is one of the most serious and pressing issues facing our planet. Rather than a silver bullet or a single study that solves it, the study of global climate change is like a beach, with each contribution a grain of sand, gathered together as a whole to create a big picture, moving the science forward. This new groundbreaking study focuses on the adaptation and tolerance of plants and animal life to the harsh conditions brought on by climate change or global warming. Using the papers collected here, scientists can better understand global climate change, its causes, results, and, ultimately, the future of life on our planet. The first section lays out a methodology and conceptual direction of the work aTable of ContentsPreface xvii Abstract xix Contributing Authors xxi Modeling and Approaches 1 1 Critical Impacts on Complex Biological and Ecological Systems: Basic Principles of Modeling 3Rem G. Khlebopros, Vladislav G. Soukhovolsky 1.1 Complex Ecological Systems: The Principle of Decomposition, Taking into Account the Characteristic Times of Components 5 1.2 Analysis of Critical Impacts on Complex Systems and Extreme Principles of Modeling 12 1.2.1 Meta-Models of Phase Transitions for Describing Critical Events in Complex Systems 13 1.2.2 A Model of Outbreak as Second-Order Phase Transition 14 1.2.3 The Effect of Modifying Factors on the Development of an Outbreak 21 1.2.4 The Impact of Chemical Compounds on Biological Objects 23 References 26 2 Criticality Concept and Some Principles for Sustainability in Closed Biological Systems and Biospheres 29Nicholas P. Yensen, Karl Y. Biel 2.1 Introduction 31 2.2 History of Manmade Closed Ecosystems 32 2.3 Classification of Closed Biological Systems 33 2.3.1 Terminology 33 2.3.2 Micro Systems 35 2.3.3 Macro Systems 37 2.3.4 The Term Biosphere 39 2.3.5 Noosphere 40 2.4 The Concept of Criticality 40 2.4.1 The Volume-Criticality Principle 42 2.5 Microbiospheres: Descriptions and Discussion 44 2.5.1 The Ecosphere, a Synthetic Microbiosphere 44 2.6 Bioboxes 45 2.7 Experimental vs. Mathematical Models 45 2.7.1 Retrograde Phylogenetic Extinction 46 2.8 Humanospheres: Examples and Discussion 46 2.8.1 Biotubes 47 2.8.2 Shepelev, BIOS 1, 2, and 3 49 2.8.3 Biosphere 2 Laboratory 51 2.8.4 Closed System Missions 52 2.8.5 Open System Missions 53 2.8.6 The End of Biosphere 2 Laboratory or a New Era for Biosphere 2 Laboratory? 54 2.9 The Earth (Biosphere 1) Description and Discussion 55 2.9.1 Earth, a Sample Size of One 55 2.9.2 Biosphere 1 Properties 55 2.10 Oxygen Flux in Closed Systems 59 2.11 The Future of Closed System Work: Concepts and Strategies 61 2.11.1 Education, Research and Consortium Concepts 61 2.11.2 Ecosystems for Space 62 2.11.3 Closed System Challenges 63 2.12 General Conclusions 63 Abbreviations 64 Literature Cited and Used 64 Appendix I. A Description of Biosphere 2 Laboratory 70 3 Accelerated Method for Measuring and Predicting Plants’ Stress Tolerance 73Karl Y. Biel, John N. Nishio 3.1 Introduction 75 3.2 Background 75 3.2.1 Interaction between Anabolism and Catabolism 76 3.2.2 Cooperation between Photosynthesis and Respiration under Stress 78 3.3 How is Stress Tolerance Measured? 79 3.3.1 Testing Possible Artifacts of the Stress Test 81 3.3.2 Effect of Temperature and Chemical Additions on the Oxygen Evolution Stress Assay 84 3.4 Practical Applications 88 3.4.1 Whole Leaf Physiological Responses 90 3.4.2 Effect of Dark and Sodium Nitrate on the Photosynthetic Stress Resistance Index and Photosynthesis in Leaf Slices under Anoxic Conditions 97 3.4.3 Post-Illumination Respiration 98 3.5 Discussion 98 3.6 Perspectives for Application of Method 107 Acknowledgments 109 Abbreviations 110 References 110 Appendix I. Additional Materials and Methods 117 Appendix II. Preliminary Analysis of the Utility of a Novel Stress Resistance Assay on Three Garst Lines of Zea mays, a C4 Plant 118 Results 119 General Conclusion 122 Suggestions 122 Hypotheses 123 4 The Hypotheses of Halosynthesis, Photoprotection, Soil Remediation via Salt-Conduction, and Potential Medical Benefits 125Karl Y. Biel, Nicholas P. Yensen 4.1 Introduction 127 4.2 The Haloconductor Theory 128 4.2.1 The Remediation of Saline Soils 128 4.2.2 New Approach for Soil Remediation via Salt Conducting Plants 130 4.2.3 Advantages of Conductor Plants for Soil Remediation 133 4.2.4 Productivity Considerations 134 4.2.5 Intriguing Productivity Curves in a Clonal Conductor Plant 136 4.3 The Halosynthesis Hypothesis 138 4.3.1 Concept Description and Terminology 139 4.3.2 Hydraulic Considerations and Salt Gradient from Soil to Shoot Surface 140 4.3.3 Salt Glands and Evapotranspirational Halosynthesis 143 4.3.4 The Photoelectric Effect 144 4.3.5 Epidermal Electro-Halosynthesis 144 4.3.6 Salt-Gland Electro-Halosynthesis 144 4.4 Physico- and Bio-Chemical Protection Synergisms 148 4.4.1 Biochemical Protection against Oxygen Radicals 151 4.5 A Case Study, Distichlis 153 4.5.1 Ecophysiology 153 4.5.2 Taxonomy and Geographic Distribution 153 4.5.3 Root-Soil Restructuring Capacity 154 4.5.4 Salt Tolerance 155 4.5.5 Photosynthesis 155 4.5.6 Ammonia Nutrition as a Protector against Salinity 157 4.5.7 Soil Salt Removal and Benefits to Changes in Soil Properties 158 4.6 Potential Medical Benefit of Photo-Halosynthesis 159 4.7 Predictions and Potential Tests of Hypotheses 163 4.7.1 Salt Conduction 163 4.7.2 Halodispersion 165 4.7.3 Metabolism 166 4.7.4 Protection 166 4.7.5 Halosynthesis 166 4.8 General Conclusions 167 Acknowledgments 167 References 167 5 Protective Role of Silicon in Living Organisms 175Vladimir V. Matichenkov, Irina R. Fomina, Karl Y. Biel 5.1 Introduction 176 5.1.1 Agriculture 176 5.1.2 Medicine 177 5.1.3 Microorganisms and Plants 177 5.2 Forms of Silicon 179 5.3 Silicon Cycle in Soil–Plant System 182 5.4 Silicon and Flora 183 5.4.1 Localization of Silicon in Plants 184 5.4.2 Forms of Silicon in Plants 187 5.4.3 Silicon and Water Storage in Plants 188 5.5 Silicon and Plants’ Resistance to Extreme Environments 189 5.6 Silicon as Matrix for Organic Compounds Synthesis 191 5.6.1 Hypothesis on Silicon Participation in Protection of Living Organisms under Stress Conditions 192 5.6.1.1 Premises of Hypothesis 192 5.6.1.2 Hypothesis 195 5.7 New Technologies 197 5.8 General Conclusion 198 Acknowledgments 199 References 199 6 Methanol as Example of Volatile Mediators Providing Plants’ Stress Tolerance 209Karl Y. Biel, Irina R. Fomina 6.1 Introduction 211 6.2 Methanol Application for the Regulation of Productivity 212 6.3 Emission of Methanol from Plants 213 6.3.1 Factors Affecting the Methanol Emission 214 6.3.2 Methanol Sources in Plants 216 6.3.3 Pectin Methylesterases 216 6.3.4 Utilization of Methanol by Plants 218 6.3.5 Ethanol-Water-Soluble Fraction in Different Parts of Plants 219 6.3.6 Ethanol-Water-Insoluble Fractions in Plants 222 6.3.7 DNA Methylation in Plants 223 6.4 Hypothesis of Methanol Influence on Different Levels of Cell Metabolism in C3 Plants 226 6.5 Conclusion 231 Acknowledgments 231 Abbreviations 232 References 232 Experiments 249 7 Patterns of Carbon Metabolism within Leaves 251Karl Y. Biel, Irina R. Fomina, Galina N. Nazarova, Vladislav G. Soukhovolsky, Rem G. Khlebopros, John N. Nishio 7.1 Introduction 253 7.2 Interactions among Light, Leaf Anatomy, the Metabolic Activity, and Environmental Stress Tolerance across Leaves 253 7.2.1 Anatomy and Pattern of Enzymes within the Leaf of Spinacia oleracea 255 7.2.1.1 Leaf Anatomy 255 7.2.1.2 What are the Roles of the Different Cells? 259 7.2.2 Enzyme Activity 263 7.2.2.1 How Does Inverting the Leaves Alter the Distribution of Enzyme Activity within Spinacia oleracea Leaf? 263 7.2.2.2 Summary of Enzyme Activity across Leaves 267 7.2.2.3 Functional Significance to Profiles of Enzyme Activity across Spinacia oleracea Leaves 268 7.2.3 CO2/O2 Gas Exchange 271 7.2.3.1 CO2 Gas Exchange 271 7.2.3.2 HCO3 –-Dependent Oxygen Evolution 274 7.2.4 Enzyme Activity, Carbon Metabolism, and Stress Tolerance across Spinacia oleracea Leaves 276 7.2.5 Light Regulation of Photosynthetic Enzyme Activity across Leaves 281 7.3 Model of Optimal Photosynthesis within a Mesophytic Leaf 282 7.4 General Conclusion 287 Acknowledgments 288 References 288 8 4-Hydroxyphenethyl Alcohol and Dihydroquercetin Increase Adaptive Potential of Barley Plants under Soil Flooding Conditions 301Tamara I. Balakhnina 8.1 Introduction 302 8.1.1 Effect of Soil Flooding on Plants 302 8.2 Effect of 4-Hydroxyphenethyl Alcohol on Growth and Adaptive Potential of Barley Plants at Optimal Soil Watering and Flooding 304 8.2.1 Plant Reactions 304 8.2.1.1 Seed Germination 304 8.2.1.2 Plant Growth 305 8.2.1.3 Lipid Peroxidation Intensity 308 8.2.1.4 Guaiacol Peroxidase Activity 309 8.2.1.5 Discussion 311 8.3 Dihydroquercetin Protects Barley Seeds against Mold and Increases Seedling Adaptive Potential Under Soil Flooding 313 8.3.1 Plant Reactions 313 8.3.1.1 Seed Germination 313 8.3.1.2 Growth Parameters 313 8.3.1.3 Intensity of Lipid Peroxidation 316 8.3.1.4 Activity of Ascorbate Peroxidase 318 8.3.1.5 Discussion 320 Acknowledgments 322 Abbreviations 322 References 323 9 Cooperation of Photosynthetic and Nitrogen Metabolisms 329Anatoly A. Ivanov, Anatoly A. Kosobryukhov 9.1 Introduction 331 9.2 Carbon Uptake and Rubisco 332 9.2.1 Dependence of Carbon Assimilation on Nitrogen Supply 334 9.3 Alternative Electron Acceptors in Photosynthesis 336 9.4 Nitrogen Metabolism 337 9.4.1 Primary Assimilation of Inorganic Nitrogen 337 9.4.1.1 Nitrate Reductase 339 9.4.1.2 Ferredoxin-Dependent Nitrite Reductase 342 9.4.1.3 Glutamine Synthetase/Glutamate Synthase (GS/GOGAT) Cycle 343 9.4.1.4 Glutamate Dehydrogenase 346 9.4.2 Relationship of Photorespiration and Nitrogen Metabolism 346 9.5 Relationship of Carbon and Nitrogen Metabolism in Stress Conditions 349 9.5.1 High CO2 Concentration in the Atmosphere 349 9.5.1.1 Plants’ Growth 349 9.5.1.2 Rubisco Content 350 9.5.1.3 Photosynthetic Acclimation 351 9.5.1.4 Photosynthesis and Nitrogen Content 353 9.5.1.5 Metabolic Changes 355 9.5.2 Low CO2 Concentration in the Atmosphere 360 9.5.3 Water Stress 368 9.5.3.1 Osmotic Homeostasis 368 9.5.3.2 Variability of Plant Response to Drought 369 9.5.3.3 Reactive Oxygen Species 370 9.5.3.4 Metabolic Changes 371 9.5.3.5 Stomata Conductivity and Rubisco Activity 371 9.5.3.6 Enzymes of Nitrogen Metabolism 373 9.5.3.7 Sucrose-Phosphate Synthase 375 9.5.3.8 Increased Plant Resistance to Drought by Nitrogen Supply 376 9.5.4 Salt Stress 377 9.5.4.1 Assimilation of Nitrogen in Salinity Conditions 378 9.5.4.2 Isocitrate Dehydrogenase and Fd-GOGAT 379 9.5.4.3 Proline Accumulation 380 9.5.4.4 Photosynthesis, Photorespiration and Reactive Oxygen Species 380 9.6 Conclusion 381 Abbreviations 382 References 382 10 Physiological Parameters of Fucus vesiculosus and Fucus serratus in the Barents Sea during a Tidal Cycle 439Inna V. Ryzhik, Anatoly A. Kosobryukhov, Evgeniya F. Markovskaya, Mikhail V. Makarov 10.1 Introduction 441 10.2 Materials and Methods 442 10.3 Results 444 10.3.1 Water Content in Algal Thalli 444 10.3.2 The Rate of Photosynthesis 445 10.3.3 Photosynthetic Pigments: Content and Proportion 445 10.3.4 Dependence of the Photosynthetic Rate on the Water Content in the Thallus 446 10.3.5 Potential Rate of Photosynthesis of Fucus vesiculosus 446 10.3.6 Lipid Peroxidation and Catalase Activities in Fucus vesiculosus 448 10.4 Discussion 449 Abbreviations 455 References 455 History and Biography – Tribute 461 11 Benson’s Protocol 463Arthur M. Nonomura, Karl Y. Biel, Irina R. Fomina, Wai-Ki “Frankie” Lam, Daniel P. Brummel, Allison Lauria, Michael S. McBride 11.1 Introduction 465 11.2 Benson–Bassham–Calvin and Lectin Cycles 468 11.3 Types of Photosynthetic Carbon Metabolism in Prokaryotes and Eukaryotes 471 11.4 Regulation of Photosynthates 471 11.5 The Origin and Development of the Carbon Reactions of Photosynthesis 472 11.6 The Next Steps 473 11.6.1 Materials and Methods 474 11.6.2 Results 480 11.6.3 Conclusion 498 11.7 Felicitation 499 References 502 12 Recollection of Yuri S. Karpilov’s Scientific and Social Life 509Karl Y. Biel, Irina R. Fomina 12.1 Introduction 510 12.2 Some Contradictory Discoveries 510 12.3 Official Statement of a Young Scientist in the USSR and His Deed 511 12.4 From the Memories, by Karl Biel 515 12.5 Australian Scientist Professor Barry Osmond Visited Karpilov’s Laboratory in 1971 525 12.6 Moving from Tiraspol to Pushchino, Moscow Region, to the Institute of Photosynthesis of the USSR Academy of Sciences 527 12.7 International Botanical Congress… 530 12.8 And after That, Soon… Unexpected Tragedy 530 12.9 Short Biography of Yuri S. Karpilov 533 Acknowledgments 534 Abbreviations 534 References 534 13 Dr. Nicholas Yensen’s Curriculum Vitae 543Karl Y. Biel, Irina R. Fomina 13.1 Introduction 544 13.2 Biographical Note about Dr. Nicholas Patrick Yensen 545 13.2.1 Education 545 13.2.2 Teaching Experience 545 13.2.3 Founder and Leader of Scientific Organizations 546 13.2.4 Member of Board of Directors, Consultant, and Chairman 546 13.2.5 Languages 547 13.2.6 Oratorical Talent 547 13.2.7 Dr. Yensen’s International Teamwork, Expeditions and Visitations 547 13.2.8 Distinctions 549 13.2.9 Articles, Videos and Documentaries about Dr. Yensen’s Work 549 13.2.10 Skill and Avocation 550 13.3 Conclusion 550 13.4 Addendum 552 Acknowledgements 552 Publications (selected) 553 14 Rem Khlebopros: Life in Science 557Vladislav G. Soukhovolsky, Irina R. Fomina 14.1 Introduction 558 14.2 Life in Science 559 14.3 Selected Scientific Publications and Speeches by Rem G. Khlebopros 566 14.3.1 Video-Interviews about Ecology in Krasnoyarsk 566 14.3.2 Books 566 14.3.3 Articles 567 Acknowledgments 571 Index 573

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Book SynopsisA Detailed Reference on How Modern Biotechnology is using the Biofortification of Crops to Improve the Vitamin and Mineral Content of Edible Plants In this reference, Vitamins and Minerals Bio-Fortification of Edible Plants, authors cover new territory on phytonutrients, focusing on the enhancement and modification of edible crops. This book presents techniques and research findings from modern biotechnology to educate readers on the newest tools and research in the field. Readers will learn how groundbreaking scientific advances have contributed to the nutritional content of edible plants and crops for animals and humans. Inside, readers will find comprehensive information on new concepts of biofortification, including but not limited to: ? Modern biotechnology and its uses for improving the vitamin and mineral content of edible plants ? Potential minerals and vitamins that can be targeted and implemented in agriculture ? Ways of enhancing the nutritional contents of edible plants to address nutritional deficiencies and improve livestock ? Methods of identifying plants that can be used to heal or prevent disease and illness While many books cover the phytonutrients of crops, this reference book reports on methodologies, techniques, and environmental changes used to enhance and improve agricultural products. It is one of the first to provide information on using modern biotechnologies to modify crops with the goal of creating health benefits.Table of ContentsList of Contributors vii Foreword xi 1 Biofortification of Edible Plants: Set the Stage for Better Nutrition 1Noureddine Benkeblia 2 Food Fortification: What’s in It for the Malnourished World? 27Barbara Poniedziałek, Kinga Perkowska, and Piotr Rzymski 3 Modern Biotechnologies and Mineral Biofortification of Edible Crops 45Noureddine Benkeblia and Kathleen L. Hefferon 4 Biotechnologies and Vitamins Biofortification of Edible Crops 71Noureddine Benkeblia and Kathleen L. Hefferon 5 Carotenoids Biofortification of Sweet Potatoes 87Noureddine Benkeblia, Elisabete M. Pinto, and Marta W. Vasconcelos 6 Improving Iron Nutrition in Plant Foods: The Role of Legumes and Soil Microbes 103Mariana Roriz, Marta Barros, Paula M. L. Castro, Susana M. P. Carvalho, and Marta W. Vasconcelos 7 Biofortification of Carotenoids in Agricultural and Horticultural Crops: A Promising Strategy to Target Vitamin A Malnutrition 123Hulikere Jagdish Shwetha, Shivaprasad Shilpa, Bangalore Prabhashankar Arathi, Marisiddaiah Raju, and Rangaswamy Lakshminarayana 8 Agronomic Biofortification from a Stakeholder’s Viewpoint: Evidence from Studies on Iodine-Enriched Foods in Uganda 163Solomon Olum, Joshua Wesana, Walter Odongo, Joseph Mogendi, Collins Okello, Dominic Webale, Anselimo Makokha, Duncan Ongeng, Xavier Gellynck, and Hans De Steur 9 Biofortification of Cereals through Foliar Application of Minerals 191Shahid Hussain, Ayta Umar, Mamoona Amir, and Muhammad Aon10 NAS Overexpression and Rice Zinc Biofortification: An Insight, Current Knowledge, and Outlook 223Yuta Kawakami and Navreet K. Bhullar Index 235

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Book SynopsisA comprehensive review of stress signaling in plants using genomics and functional genomic approaches Improving agricultural production and meeting the needs of a rapidly growing global population requires crop systems capable of overcoming environmental stresses. Understanding the role of different signaling components in plant stress regulation is vital to developing crops which can withstand abiotic and biotic stresses without loss of crop yield and productivity. Emphasizing genomics and functional genomic approaches, Protein Kinases and Stress Signaling in Plants is a comprehensive review of cutting-edge research on stress perception, signal transduction, and stress response generation. Detailed chapters cover a broad range of topics central to improving agricultural production developing crop systems capable of overcoming environmental stresses to meet the needs of a rapidly growing global population. This book describes the field of protein kinases Table of ContentsList of Contributors xv Editor Biography xx Preface xxii 1 Two Component Mediated Stress Signaling in Plants: A Comparative Profiling in Monocots and Dicots 1Priyanka Gupta, Chhaya Yadav, Deepti Singh, Ramsong Chantre Nongpiur, Sneh Lata Singla-Pareek, and Ashwani Pareek 2 Lectin Receptor like Kinase: Spy Eye on Environmental Factors 20Nishat Passricha, Shabnam K. Saifi, Himani Negi, and Narendra Tuteja 3 Photoactivated Protein Kinases in Green Algae and Their Functional Role in Abiotic Stress 37Kumari Sushmita, Manish Singh Kaushik, Irina Sizova, and Suneel Kateriya 4 Emerging Role of Plant GSK3/SHAGGY-like Protein Kinases in Stress Signaling Pathways: A Phylogenetic and Functional Genomic Perspective 86Barkha Ravi, Pooja Verma, and Girdhar K. Pandey 5 Balancing Growth and Defense: Role of Target of Rapamycin and SNF1-Related Protein Kinase 1 in Stress Signaling in Plants 105Mohan Sharma, Muhammed Jamsheer K., Harshita B. Saksena, Sunita Jindal, Manvi Sharma, Dhriti Singh, Archna Tiwari, Prakhar Awasthi, and Ashverya Laxmi 6 SnRK2s: Part and Parcel of ABA Signaling in Plants 133Suhas Balasaheb Karle, Bhavya Nair, and Kundan Kumar 7 Lipid Mediated Regulation of Protein Kinases 147Shatakshi Pandit and Girish Mishra 8 Calcium Dependent Protein Kinases in Plants 192Jamshaid Hussain, Gulnaz Bibi, and Sarfraz Shafiq 9 Regulation of Stress Responses in Plants by Calcium Dependent Protein Kinases 226Deepika, Komal Vitthalrao Mali, Amit Kumar, and Amarjeet Singh 10 Calmodulin-Binding Kinases: Transducers of Abiotic Stress Response in Plants 248Supreet Singh, Amardeep Singh Virdi, and Prabhjeet Singh 11 Calcium/Calmodulin Activated Protein Kinases in Stress Signaling in Plants 266Tushar Khare, Amrita Srivastav, and Vinay Kumar 12 Role of CBL-Interacting Protein Kinases in Regulating Plant Stress Responses 281Pavithran Narayanan, Sibaji K. Sanyal, and Girdhar K. Pandey 13 Casein Kinase2 and Its Dynamism in Abiotic Stress Management 310Tanushree Agarwal and Sudipta Ray 14 Cyclin-Dependent Protein Kinases in the Control of Cell Cycle in Plants 347Hirofumi Harashima and Masami Sekine 15 MAP Kinase as Regulators for Stress Responses in Plants: An Overview 369Deepika Sharma, Neetu Verma, Chandana Pandey, Deepanjali Verma, Prakash Kumar Bhagat, Stanzin Noryang, Kirti Singh, Sumaira Tayyeba, Gopal Banerjee, and Alok Krishna Sinha 16 A Network View of MAP Kinase Pathways in Plant Defense Regulation: What We Have Learned from Genetic Modification Studies? 393Tim Xing and Nora A. Foroud 17 Role of MAP Kinase Signaling in Xanthomonas Pathogen-Rice Interaction 408Durga Bhavani and Subhadeep Chatterjee 18 Role of MAPK Cascade in Local and Systemic Immunity of Plants 422Vishal Patil and Ashis Kumar Nandi 19 Role of Plant Kinases in Combined Stress 445Mahesh Patil and Muthappa Senthil-Kumar 20 Protein Tyrosine Phosphorylation in Plants: Role Under Stress Responses 459Swati Mahiwal, Sibaji K. Sanyal, and Girdhar K. Pandey 21 Role of Kinases for Regulating K+ Homeostasis Under Salt and Drought Stress Conditions 479Jayant Kulkarni, Ashish K. Srivastava, and Suprasanna Penna 22 Plant Peroxisomal Protein Kinases Implicated in Stress-Related Responses 501Amr R.A. Kataya, Jianping Hu, Douglas G. Muench, and Greg B. Moorhead Index 518

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Book SynopsisA comprehensive primer and reference, this book provides pharmacists and health practitioners the relevant science and policy concepts behind biologics, biosimilars, and biobetters from a practical and clinical perspective. Explains what pharmacists need to discuss the equivalence, efficacy, safety, and risks of biosimilars with physicians, health practitioners, and patients about Guides regulators on pragmatic approaches to dealing with these drugs in the context of rapidly evolving scientific and clinical evidence Balances scientific information on complex drugs with practical information, such as a checklist for pharmacists Table of ContentsList of Contributors vii Foreword ix Preface xi 1 Innovator Biologics, Biosimilars, and Biobetters: Terminology, Nomenclature, and Definitions 1 2 Approved Biologic Medicines and Biosimilars in Major Regulatory Jurisdictions 17 3 Status of Biologic Drugs in Modern Therapeutics-Targeted Therapies vs. Small Molecule Drugs 31 4 Major Classes of Biotherapeutics 47 5 Drug Targets for Biologics 71 6 Pivotal Biology, Chemistry, Biochemistry, and Biophysical Concepts of Biologics and Biosimilars 89 7 Biosimilarity and Interchangeability of Biologic Drugs-General Principles, Biophysical Tests, and Clinical Requirements to Demonstrate Biosimilarity 109 8 Pharmacokinetics of Biologics 125 9 Pharmacogenomics of Biologics 147 10 International Regulatory Processes and Policies for Innovator Biologics, Biosimilars, and Biobetters 159 11 Pharmacovigilance of Innovator Biologics and Biosimilars 177 12 Pharmacoeconomics of Biologic Medicines and Biosimilars 195 13 New Emerging Biotherapies: Cutting-Edge Research to Experimental Therapies 213 14 Optimizing Use of Biologic Medicines Using a Quality Use of Medicines Approach 237 15 Knowledge Areas and Competency Standards on Biologic Medicines for Pharmacists and Pharmacy Students 253 16 A Checklist for Pharmacists on Biologics and Biosimilars: Tips to Enhance Patient-Centered Discussions 267 Index 295

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Book SynopsisAs an applied science, Enology is a collection of knowledge from the fundamental sciences including chemistry, biochemistry, microbiology, bioengineering, psychophysics, cognitive psychology, etc., and nourished by empirical observations. The approach used in the Handbook of Enology is thus the same. It aims to provide practitioners, winemakers, technicians and enology students with foundational knowledge and the most recent research results. This knowledge can be used to contribute to a better definition of the quality of grapes and wine, a greater understanding of chemical and microbiological parameters, with the aim of ensuring satisfactory fermentations and predicting the evolution of wines, and better mastery of wine stabilization processes. As a result, the purpose of this publication is to guide readers in their thought processes with a view to preserving and optimizing the identity and taste of wine and its aging potential. This third English edition of The Table of ContentsForeword xi Preface to the Second Edition xiii Preface to the First Edition xv Remarks Concerning the Expression of Certain Parameters of Must and Wine Composition xix Part I – Chemistry of Wine 1 1 Organic Acids in Wine 3 1.1Introduction 3 1.2The Main Organic Acids 3 1.3Different Types of Acidity 8 1.4The Concept of pH and Its Applications 10 1.5Tartrate Precipitation Mechanism and Predicting Its Effects 24 1.6Tests for Predicting Wine Stability 32 1.7Preventing Tartrate Precipitation 41 References 55 2 Alcohols and Other Volatile Compounds 57 2.1Ethanol 57 2.2Other Simple Alcohols 59 2.3Polyols 62 2.4Aliphatic Fatty Acids 65 2.5Esters 66 2.6Miscellaneous Compounds 71 References 74 3 Carbohydrates 75 3.1Introduction 75 3.2Glucose and Fructose 76 3.3Other Sugars 79 3.4Chemical Properties of Sugars 82 3.5Sugar Derivatives 85 3.6Pectic Substances in Grapes 87 3.7Exocellular Polysaccharides from Microorganisms 95 References 101 4 Dry Extract and Minerals 105 4.1Introduction 105 4.2Dry Extract 106 4.3Ash 108 4.4Inorganic Anions 109 4.5Inorganic Cations 109 4.6Iron and the Iron Casse Mechanism 111 4.7Copper and Copper Casse 117 4.8Heavy Metals 121 References 125 5 Nitrogen Compounds 127 5.1Introduction 127 5.2The Various Forms of Nitrogen 127 5.3Amino Acids 130 5.4Other Forms of Nitrogen 136 5.5Proteins and Protein Haze 142 5.6Preventing Protein Haze 151 References 159 6 Phenolic Compounds 161 6.1Introduction 161 6.2Types of Substances 162 6.3Chemical Properties of Anthocyanins and Tannins 173 6.4Anthocyanin and Tannin Assays: Sensory Properties 196 6.5Evolution of Anthocyanins and Tannins as Grapes Ripen 212 6.6Extracting Tannins and Anthocyanins During Winemaking 225 6.7Chemical Reactions Occurring During Bulk and Bottle Aging 228 6.8Precipitation of Coloring Matter (Color Stability) 233 6.9Origin of the Color of White Wines 235 References 238 7 Varietal Aroma 243 7.1The General Concept of Varietal Aroma 243 7.2Terpene Compounds 245 7.3C13-Norisoprenoid Derivatives 253 7.4Methoxypyrazines 257 7.5Sulfur Compounds with a Thiol Function 260 7.6Furanones 270 7.7Lactones 271 7.8Aromas of American Species 274 References 274 Part II – Wine Stabilization and Treatments 281 8 Main Sensory Defects: Chemical Nature, Origins and Consequences 283 8.1Introduction 283 8.2Oxidative Defects 285 8.3Effect of Various Forms of Bacterial Spoilage 289 8.4Microbiological Origin and Properties of Volatile Phenols 294 8.5Cork Taint 310 8.6Sulfur Derivatives and Reduction Odors 316 8.7Premature Aging of Wine Aroma 331 8.8Sensory Defects Associated with Grapes Affected by Various Types of Rot 336 8.9Miscellaneous Defects 343 References 346 9 The Concept of Clarity and Colloidal Phenomena 351 9.1Clarity and Stability 351 9.2The Colloidal State 354 9.3Colloid Reactivity 357 9.4Protective Colloids and Gum Arabic Treatment 363 References 368 10 Clarification and Stabilization Treatments: Fining Wine 369 10.1 Treating Wine 369 10.2 Sedimentation of Particles in Suspension 372 10.3 Racking: Role and Techniques 374 10.4 Theory of Protein Fining 377 10.5 Tannin-Protein Interactions 385 10.6 Effect of Fining on the Organoleptic Quality of Wine: Concept of Overfining 387 10.7 Products Used in Fining 389 10.8 Fining Techniques 396 10.9 Bentonite Treatment 398 10.10 Miscellaneous Clarification Treatments 403 References 406 11 Clarifying Wine by Filtration and Centrifugation 409 11.1 Principles of Filtration 410 11.2 Laws of Filtration 411 11.3 Methods for Assessing Clarification Quality 414 11.4 Filtration Equipment and Filter Aids 416 11.5 How Filter Layers Function 421 11.6 Filtration through Diatomaceous Earth (or Kieselguhr) Precoats 424 11.7 Filtration Through Cellulose-Based Filter Pads 431 11.8 Membrane Filtration 436 11.9 Crossflow Filtration 439 11.10 Effect of Filtration on the Composition and Organoleptic Character of Wine 443 11.11 Centrifugation 447 References 450 12 Stabilizing Wine by Physical and Physicochemical Processes 451 12.1 Introduction 451 12.2 Heat Stabilization 452 12.3 Wine Stabilization Through Physical Processes Under Development 455 12.4 Cold Stabilization 456 12.5 Ion Exchangers 459 12.6 Electrodialysis Applications in Winemaking 466 References 470 13 Aging Red Wines in Tanks and Barrels: Phenomena Occurring During Aging 471 13.1 Oxidation–Reduction Phenomena 471 13.2 Oxidation–Reduction Potential 473 13.3 Influence of Various Factors on Oxidation–Reduction Potential 478 13.4 Development of the Phenolic Characteristics of Red Wines (Color and Flavor) During Aging 484 13.5 Evolution of Aromatic Thiol Composition in Red Wines During Aging 492 13.6 Bottle Aging of Red Wines 498 13.7 Cellar Practices 505 13.8 Barrel Aging of Red Wines 508 13.9 Effect of Barrel Type on the Development of Red Wine 514 13.10 Constraints and Risks of Barrel Aging 525 References 527 Index 531

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Book SynopsisThe book provides a comprehensive detailed summary of current status on skin microbiome research in health and disease as well as key regulatory and legal aspects. In the past decade, interest and technology have greatly advanced to unravel the nature and effect of skin microbiome on our health. Diseases such as atopic dermatitis and acne are at the forefront of this research, but also other conditions such as skin cancer are under investigation. In addition, mapping of the skin microbiome has gone from basic to more detailed with attempts to correlate it to various ages, ethnicities and genders. In parallel to mapping it, a great deal of research is dedicated to understanding its functionality and communication (and hence effect) on human cells. The Skin Microbiome Handbook is a summary of current status of knowledge, research tools and approaches in skin microbiome, in health and disease. It contains the following categories: healthy skin microbiome andTable of ContentsPreface xvii Part 1: Healthy Skin Microbiome and Oral-Skin Interactions 1 1 The Microbiome of Healthy Skin 3Samantha Samaras and Michael Hoptroff 1.1 Introduction 3 1.1.1 Retrospective 3 1.1.2 Next Generation Sequencing 6 1.2 The Skin Microbiome in Health 7 1.2.1 Composition 7 1.2.2 Diversity 10 1.2.3 Uniqueness 13 1.3 Healthy Skin is the Foundation of a Balanced Skin Microbiome 14 1.3.1 Physical Aspects of Skin Impacting the Microbiome 14 1.3.2 Biochemical and Defensive Aspects of Skin Impacting the Microbiome 16 1.3.2.1 The Acid Mantle 16 1.3.2.2 Antimicrobial Lipids (AMLs) 16 1.3.2.3 Antimicrobial Peptides (AMPs) 17 1.3.3 Nutritional and Microenvironmental Aspects of Skin Impacting the Microbiome 18 1.3.3.1 Amino Acids 18 1.3.3.2 Sebaceous Lipids 19 1.3.3.3 Organic Acids and Other Materials 19 1.4 A Balanced Skin Microbiome Supports the Normal Functioning of Healthy Skin 20 1.4.1 Pathogen Exclusion 20 1.4.2 Contribution to Skin pH 20 1.4.3 Microbial Contribution to Skin Barrier Integrity 21 1.5 Conclusion 22 Acknowledgments 23 References 23 2 The Gut Microbiome-Skin Axis: Impact on Skin and Systemic Health 33David Drake 2.1 Introduction 34 2.2 The Gut-Skin Microbiome Axis 35 2.3 The Gut-Skin Microbiome Axis: Principle Pathways 35 2.4 Dysbiosis of the Gut Microbiome and Skin Dyshomeostasis 37 2.4.1 Acne Vulgaris 38 2.4.2 Atopic Dermatitis 39 2.5 Summary and Future Directions 39 References 40 3 The Skin and Oral Microbiome: An Examination of Overlap and Potential Interactions between Microbiome Communities 45Sandra Buerger 3.1 Introduction 45 3.1.1 Focus of the Chapter 45 3.1.2 Definition of Skin Microbiome 47 3.1.3 Definition of Oral Microbiome 48 3.2 Characterization of the Microbiome 48 3.2.1 Variability and Stability of Skin and Oral Microbiome 48 3.2.2 Microbial Community 49 3.2.2.1 Permeant Mutualistic or Commensal Microbes 49 3.2.2.2 Non-Pathogenic Transient Microbes 50 3.2.2.3 Pathogenic Microbes 50 3.3 The Core Skin and Oral Microbiomes 51 3.3.1 Taxonomic Methodology 51 3.3.2 Subgroups of the Microbiome 52 3.3.2.1 Bacteriome 52 3.3.2.2 Mycobiome (and Other Eukaryotic Microbial Members) 52 3.3.2.3 Virome 53 3.4 Interactions Between Skin and Oral Microbiomes 54 3.4.1 Potential for Interactions 54 3.4.2 Quorum Sensing 54 3.4.3 Immune System Development 54 3.4.4 Future Directions 55 3.5 Conclusion 55 Acknowledgments 56 References 56 Part 2: Skin Microbiome Observational Research 59 4 Skin Microbiome Alterations in Skin Diseases 61Travis Whitfill, Gilles R. Dubé and Julia Oh 4.1 Introduction and Background 61 4.2 Interactions Between Microbes and Host 62 4.3 Summary of Known Associations Between Skin Dysbioses and Skin Diseases 64 4.3.1 The Role of S. Aureus in Skin Disease 64 4.3.2 Atopic Dermatitis 64 4.3.3 Acne Vulgaris 66 4.3.4 Psoriasis 67 4.4 Skin Dysbioses in Skin Health 68 4.5 Other Skin Conditions 68 4.6 Therapeutic Approaches to Dysbiosis-Associated Skin Diseases 69 4.6.1 Traditional Methods of Treating Dysbiosis-Associated Skin Diseases 69 4.6.1.1 Atopic Dermatitis 69 4.6.1.2 Acne Vulgaris 69 4.6.2 Emerging Therapeutic Approaches to Treating Dysbiosis-Associated Skin Diseases 70 4.7 Conclusion and Future Directions 71 Acknowledgements 71 References 71 5 The Axillary Microbiome and its Relationship with Underarm Odor 79Alexander Gordon James 5.1 Introduction 80 5.2 Composition of the Axillary Microbiome 86 5.3 16-Androstene Steroids and Axillary Malodour 95 5.4 The Axillary Microbiome, VFAs and Malodour 96 5.5 The Axillary Microbiome, Thioalcohols and Malodour 100 5.6 Perturbation of the Axillary Microbiome 108 5.7 Human Genetics – Influence on Malodour and the Axillary Microbiome 112 5.8 Conclusions and Future Perspectives 115 Acknowledgements 122 References 122 6 Infant Skin Microbiome 131Georgios N. Stamatas 6.1 Introduction 131 6.2 Infant Skin Maturation 132 6.3 Infant Immune System Maturation 133 6.4 Infant Skin Microbiome Dynamics 134 6.5 Mother-Infant Microbial Transmission 137 6.6 Conclusion 138 References 139 Part 3: Skin Microbiome in Disequilibrium and Disease 143 7 Microbiome of Compromised Skin 145Sara Farahmand 7.1 Atopic Dermatitis 146 7.2 Psoriasis 148 7.2.1 Diversity 149 7.2.2 Microbiome Composition 151 7.3 Acne 152 7.4 Rosacea 153 7.5 Seborrheic Dermatitis and Dandruff 155 7.6 Exposome, Skin Barrier, and Skin Microbiome 157 7.6.1 Skin Irritation and Microbiome 157 7.6.2 Diaper Dermatitis 157 7.6.3 Occupational Hand Dermatitis 158 7.6.4 Allergic Contact Dermatitis (ACD) and Skin Microbiome 159 7.7 Conclusion 160 References 163 8 Human Cutaneous Ectoparasites: A Brief Overview and Potential Therapeutic Role for Demodex 171Stephen L. Strobel 8.1 Introduction 171 8.2 Chiggers (Trombiculidae) 172 8.3 Bedbugs (Cimex lectularius and Hemipterus) 173 8.4 Lice 173 8.5 Scabies (Sarcoptes scabiei) 174 8.6 Demodex 175 8.7 The Association Between Demodex, Rosacea and Blepharitis 176 8.8 Hypothesis 177 8.9 Demodex Folliculorum as a Drug Delivery Agent for Early Skin Cancer 177 8.10 Limitations 179 8.11 Conclusion 180 8.12 Future Considerations 181 References 182 9 Dysbiosis of the Skin Microbiome in Atopic Dermatitis 185Joyce Cheng and Tissa Hata 9.1 Introduction 185 9.2 The Healthy Skin Microbiome 186 9.3 The Skin Microbiome in Atopic Dermatitis 187 9.4 Microbiome-Targeted Treatment Strategies 195 9.5 Conclusion 196 References 196 10 The Skin Microbiome of Inverse Psoriasis 203Jennifer Chung, Bruce E. Strober and George M. Weinstock 10.1 Introduction 204 10.2 Methods 205 10.2.1 Subject Population 205 10.2.2 Patient Diagnosis and Characteristics of Populations 206 10.2.3 Specimen Collection 206 10.2.4 Sample DNA Extraction and Sequencing 207 10.2.5 Downstream Sequence Processing and Analysis 207 10.3 Results 208 10.3.1 Cohort Metadata 208 10.3.2 Sequencing Information 208 10.3.3 The Skin Microbiome of Intertriginous Lesion and Non-Lesional Sites on Inverse Psoriasis Subjects 208 10.3.3.1 Psoriasis Lesional Status is Associated with Relative Abundance and Presence of Specific Species 208 10.3.3.2 Psoriatic Lesions Trend to Decrease Taxonomic Diversity 210 10.3.3.3 Psoriatic Lesions are Characterized by Greater Intragroup Variability 212 10.3.4 Inverse Psoriasis vs. Plaque Psoriasis vs. Healthy (All Non-Lesion Sites) 212 10.4 Conclusions & Future Plans 212 Acknowledgements 213 References 214 Part 4: Skin’s Innate Immunity 217 11 Effects of Endogenous Lipids on the Skin Microbiome 219Carol L. Fischer and Philip W. Wertz 11.1 Introduction 219 11.2 Sebaceous Lipids -- Source of Fatty Acids 221 11.3 Stratum Corneum Lipids – Source of Long-Chain Bases 223 11.4 Antimicrobial Activity of Fatty Acids 226 11.5 Antimicrobial Activity of Long-Chain Bases 230 11.6 Conclusion 231 References 231 12 Innate Immunity in Epidermis 237Miroslav Blumenberg 12.1 Introduction 237 12.2 Skin Acts as an Anatomical Physical and Chemical Barrier to Infectious Agents 238 12.3 Epidermal Cells Recognize Conserved Features of Pathogens, as well as the Indicators of Tissue Damage 239 12.4 Defensive Antimicrobial Proteins AMPs 240 12.5 Cytokines, Specific Signals that Activate Inflammation and Further Cellular Protective Mechanisms 242 12.6 Specialized White Blood Cells Identify and Remove Pathogens 243 12.7 Complement System 246 12.8 Innate Immune System Activates the Adaptive Immune System 246 12.9 Antiviral Defenses 247 12.10 Innate Immunity Memory? 247 12.11 Cutaneous Microbiome: A Newly Surfaced Contributor to Innate Immunity 248 12.12 Conclusion 251 12.13 Future Perspectives 252 References 254 Part 5: Testing and Study Design 261 13 Next Generation Sequencing Reveals the Skin Microbiome 263Niamh B O’Hara 13.1 Introduction 263 13.2 Current Approaches to Test the Microbiome 265 13.3 The Genomics Revolution and Metagenomics 266 13.4 Metagenomics and the Skin Microbiome 267 13.5 Our Work at Biotia 268 13.6 Challenges and Solutions in Metagenomics 269 13.7 The Microbial World is our Oyster 272 13.8 The Future of Metagenomics 273 Acknowledgements 273 References 274 14 Three-Dimensional Human Skin Models to Investigate Skin Innate and Immune-Mediated Responses to Microorganisms 277Marisa Meloni and Silvia Balzaretti 14.1 State-of-the-Art and Limits of Skin Microbiota Research 277 14.2 Mechanism-Based Approach to Study Host Response to Associated Microbiome: 3D Skin Models 279 14.3 Understanding S. epidermidis and S. aureus Behavior and Role on Reconstructed Human Epidermis (RHE) 281 14.4 Immuno-Competent Atopic Dermatitis Model 284 14.5 Conclusion and Future Perspectives 286 References 286 15 Cutibacterium acnes (formerly Propionibacterium acnes) In-Vivo Reduction Assay: A Pre-Clinical Pharmacodynamic Assay for Evaluating Antimicrobial/Antibiotic Agents in Development for Acne Treatment 289Stuart R. Lessin and James J. Leyden 15.1 Acne Pathogenesis and the Role of Cutibacterium acnes (formerly Propionibacterium acnes) 290 15.1.1 Introduction 290 15.1.2 Pathogenesis 290 15.1.3 The Role of C. acnes and its Microbiome 290 15.2 Current Therapies and Regulatory Approval 293 15.3 In-Vivo C. acnes Reduction Assay 294 15.4 Correlations of C. acnes Reduction and Clinical Efficacy 297 15.5 Conclusion 300 References 300 Part 6: Regulatory and Legal Aspects for Skin Microbiome Related Products 303 16 Intellectual Property Tools for Protecting, Developing and Growing a Skin Microbiome Brand 305Jeffrey K. Mills 16.1 Introduction 305 16.2 The Tools of Intellectual Property 306 16.2.1 Patents 306 16.2.2 Trademarks 307 16.2.3 Copyrights 308 16.2.4 Trade Secrets/Know-How 309 16.3 Building an Intellectual Property Portfolio for a Skin Microbiome Brand 310 16.3.1 Patents to Define “The Fence” 310 16.3.1.1 Patents “As Sticks” – Enforcement of Infringement 313 16.3.1.2 Patents “As Financial Boosts” – Licensing and Other Agreements 314 16.3.2 Trademarks to Establish Brand Recognition 315 16.3.3 Copyrights to Maintain Information 317 16.3.4 Trade Secrets/Know-How to Keep A Competitive Edge 318 16.4 Conclusion 320 17 Regulatory Aspects of Probiotics and Other Microbial Products Intended for Skin Care: The European Approach 321Atte von Wright 17.1 Introduction 322 17.2 The Governing Bodies and Decision-Making in the EU 322 17.2.1 The Legal Instruments of the EU 323 17.3 Probiotic Foods and the European Regulations 324 17.3.1 The Safety Assessment of Microorganisms by EFSA, The QPS Concept 324 17.3.1.1 The Safety Assessment of Non-QPS Microorganisms 327 17.3.2 The Case of GMMs 328 17.3.3 Microorganisms as Novel Foods 329 17.3.4 Human Probiotics and Functional Claims 329 17.4 Probiotic Skin Care Products as Pharmaceuticals 330 17.4.1 The Authorization Procedure for Medicines 331 17.4.1.1 The Centralized Procedure 332 17.4.1.2 National Authorizations and Authorizations by Mutual Recognition or Decentralized Procedures 333 17.4.2 Bacteria as Medical Devices 334 17.5 Probiotics in Cosmetics 335 17.5.1 Safety Aspects 336 17.5.1.1 Microorganisms on Skin – Problems of Safety Evaluation 337 17.5.2 The Permissible Cosmetic Claims in the EU 338 17.6 Conclusions 338 References 340 Legal Acts and Guidance Documents 340 18 Regulation of Probiotic and Other Live Biologic Products: The United States Approach 343Ronie M. Schmelz 18.1 Introduction 343 18.1.1 U.S. Legislative Landscape 344 18.1.2 Foods 345 18.1.2.1 Permissible Food Claims 350 18.1.2.2 Additional Regulatory Considerations 354 18.1.3 Dietary Supplements 355 18.1.3.1 Permissible Dietary Supplement Claims 357 18.1.3.2 Additional Regulatory Considerations 359 18.1.4 Drugs 360 18.1.4.1 Drug Approval Process 361 18.1.4.2 Additional Regulatory Considerations 364 18.1.5 Cosmetics 364 18.2 Summary of Product Categorization and Regulatory Requirements 365 18.3 Resources 369 18.4 Endnotes 369 19 A Future Research Perspective Is There a Connection Between Sun Exposure, Microbiome and Skin Cancer? 377Nava Dayan 19.1 Introduction 378 19.2 Ultraviolet Light (UV) – The Skin Microbiome and Cancer 378 19.3 Conclusion 386 Acknowledgment 386 References 387 Glossary 389 Index 399

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Book SynopsisMultiblock Data Fusion in Statistics and Machine Learning Explore the advantages and shortcomings of various forms of multiblock analysis, and the relationships between them, with this expert guide Arising out of fusion problems that exist in a variety of fields in the natural and life sciences, the methods available to fuse multiple data sets have expanded dramatically in recent years. Older methods, rooted in psychometrics and chemometrics, also exist. Multiblock Data Fusion in Statistics and Machine Learning: Applications in the Natural and Life Sciences is a detailed overview of all relevant multiblock data analysis methods for fusing multiple data sets. It focuses on methods based on components and latent variables, including both well-known and lesser-known methods with potential applications in different types of problems. Many of the included methods are illustrated by practical examples and are accompanied by a freely available R-package. TTable of ContentsForeword xiii Preface xv List of Figures xvii List of Tables xxxi Part I Introductory Concepts and Theory 1 1 Introduction 3 1.1 Scope of the Book 3 1.2 Potential Audience 4 1.3 Types of Data and Analyses 5 1.3.1 Supervised and Unsupervised Analyses 5 1.3.2 High-, Mid- and Low-level Fusion 5 1.3.3 Dimension Reduction 7 1.3.4 Indirect Versus Direct Data 8 1.3.5 Heterogeneous Fusion 8 1.4 Examples 8 1.4.1 Metabolomics 8 1.4.2 Genomics 11 1.4.3 Systems Biology 13 1.4.4 Chemistry 13 1.4.5 Sensory Science 15 1.5 Goals of Analyses 16 1.6 Some History 17 1.7 Fundamental Choices 17 1.8 Common and Distinct Components 19 1.9 Overview and Links 20 1.10 Notation and Terminology 21 1.11 Abbreviations 22 2 Basic Theory and Concepts 25 2.i General Introduction 25 2.1 Component Models 25 2.1.1 General Idea of Component Models 25 2.1.2 Principal Component Analysis 26 2.1.3 Sparse PCA 30 2.1.4 Principal Component Regression 31 2.1.5 Partial Least Squares 32 2.1.6 Sparse PLS 36 2.1.7 Principal Covariates Regression 37 2.1.8 Redundancy Analysis 38 2.1.9 Comparing PLS, PCovR and RDA 38 2.1.10 Generalised Canonical Correlation Analysis 38 2.1.11 Simultaneous Component Analysis 39 2.2 Properties of Data 39 2.2.1 Data Theory 39 2.2.2 Scale-types 42 2.3 Estimation Methods 44 2.3.1 Least-squares Estimation 44 2.3.2 Maximum-likelihood Estimation 45 2.3.3 Eigenvalue Decomposition-based Methods 47 2.3.4 Covariance or Correlation-based Estimation Methods 47 2.3.5 Sequential Versus Simultaneous Methods 48 2.3.6 Homogeneous Versus Heterogeneous Fusion 50 2.4 Within- and Between-block Variation 52 2.4.1 Definition and Example 52 2.4.2 MAXBET Solution 54 2.4.3 MAXNEAR Solution 54 2.4.4 PLS2 Solution 55 2.4.5 CCA Solution 55 2.4.6 Comparing the Solutions 56 2.4.7 PLS, RDA and CCA Revisited 56 2.5 Framework for Common and Distinct Components 60 2.6 Preprocessing 63 2.7 Validation 64 2.7.1 Outliers 64 2.7.1.1 Residuals 64 2.7.1.2 Leverage 66 2.7.2 Model Fit 67 2.7.3 Bias-variance Trade-off 69 2.7.4 Test Set Validation 70 2.7.5 Cross-validation 72 2.7.6 Permutation Testing 75 2.7.7 Jackknife and Bootstrap 76 2.7.8 Hyper-parameters and Penalties 77 2.8 Appendix 78 3 Structure of Multiblock Data 87 3.i General Introduction 87 3.1 Taxonomy 87 3.2 Skeleton of a Multiblock Data Set 87 3.2.1 Shared Sample Mode 88 3.2.2 Shared Variable Mode 88 3.2.3 Shared Variable or Sample Mode 88 3.2.4 Shared Variable and Sample Mode 89 3.3 Topology of a Multiblock Data Set 90 3.3.1 Unsupervised Analysis 90 3.3.2 Supervised Analysis 93 3.4 Linking Structures 95 3.4.1 Linking Structure for Unsupervised Analysis 95 3.4.2 Linking Structures for Supervised Analysis 96 3.5 Summary 98 4 Matrix Correlations 99 4.i General Introduction 99 4.1 Definition 99 4.2 Most Used Matrix Correlations 101 4.2.1 Inner Product Correlation 101 4.2.2 GCD coefficient 101 4.2.3 RV-coefficient 102 4.2.4 SMI-coefficient 102 4.3 Generic Framework of Matrix Correlations 104 4.4 Generalised Matrix Correlations 105 4.4.1 Generalised RV-coefficient 105 4.4.2 Generalised Association Coefficient 106 4.5 Partial Matrix Correlations 108 4.6 Conclusions and Recommendations 110 4.7 Open Issues 111 Part II Selected Methods for Unsupervised and Supervised Topologies 113 5 Unsupervised Methods 115 5.i General Introduction 115 5.ii Relations to the General Framework 115 5.1 Shared Variable Mode 117 5.1.1 Only Common Variation 117 5.1.1.1 Simultaneous Component Analysis 117 5.1.1.2 Clustering and SCA 123 5.1.1.3 Multigroup Data Analysis 125 5.1.2 Common, Local, and Distinct Variation 126 5.1.2.1 Distinct and Common Components 127 5.1.2.2 Multivariate Curve Resolution 130 5.2 Shared Sample Mode 133 5.2.1 Only Common Variation 133 5.2.1.1 SUM-PCA 133 5.2.1.2 Multiple Factor Analysis and STATIS 135 5.2.1.3 Generalised Canonical Analysis 136 5.2.1.4 Regularised Generalised Canonical Correlation Analysis 139 5.2.1.5 Exponential Family SCA 140 5.2.1.6 Optimal-scaling 143 5.2.2 Common, Local, and Distinct Variation 146 5.2.2.1 Joint and Individual Variation Explained 146 5.2.2.2 Distinct and Common Components 147 5.2.2.3 PCA-GCA 148 5.2.2.4 Advanced Coupled Matrix and Tensor Factorisation 153 5.2.2.5 Penalised-ESCA 156 5.2.2.6 Multivariate Curve Resolution 158 5.3 Generic Framework 159 5.3.1 Framework for Simultaneous Unsupervised Methods 159 5.3.1.1 Description of the Framework 159 5.3.1.2 Framework Applied to Simultaneous Unsupervised Data Analysis Methods 161 5.3.1.3 Framework of Common/Distinct Applied to Simultaneous Unsupervised Multiblock Data Analysis Methods 161 5.4 Conclusions and Recommendations 162 5.5 Open Issues 164 6 ASCA and Extensions 167 6.i General Introduction 167 6.ii Relations to the General Framework 167 6.1 ANOVA-Simultaneous Component Analysis 168 6.1.1 The ASCA Method 168 6.1.2 Validation of ASCA 176 6.1.2.1 Permutation Testing 176 6.1.2.2 Back-projection 178 6.1.2.3 Confidence Ellipsoids 178 6.1.3 The ASCA+ and LiMM-PCA Methods 181 6.2 Multilevel-SCA 182 6.3 Penalised-ASCA 183 6.4 Conclusions and Recommendations 185 6.5 Open Issues 186 7 Supervised Methods 187 7.i General Introduction 187 7.ii Relations to the General Framework 187 7.1 Multiblock Regression: General Perspectives 188 7.1.1 Model and Assumptions 188 7.1.2 Different Challenges and Aims 188 7.2 Multiblock PLS Regression 190 7.2.1 Standard Multiblock PLS Regression 190 7.2.2 MB-PLS Used for Classification 194 7.2.3 Sparse Multiblock PLS Regression (sMB-PLS) 196 7.3 The Family of SO-PLS Regression Methods (Sequential and Orthogonalised PLS Regression) 199 7.3.1 The SO-PLS Method 199 7.3.2 Order of Blocks 202 7.3.3 Interpretation Tools 202 7.3.4 Restricted PLS Components and their Application in SO-PLS 203 7.3.5 Validation and Component Selection 204 7.3.6 Relations to ANOVA 205 7.3.7 Extensions of SO-PLS to Handle Interactions Between Blocks 212 7.3.8 Further Applications of SO-PLS 215 7.3.9 Relations Between SO-PLS and ASCA 215 7.4 Parallel and Orthogonalised PLS (PO-PLS) Regression 217 7.5 Response Oriented Sequential Alternation 222 7.5.1 The ROSA Method 222 7.5.2 Validation 225 7.5.3 Interpretation 225 7.6 Conclusions and Recommendations 228 7.7 Open Issues 229 Part III Methods for Complex Multiblock Structures 231 8 Complex Block Structures; with Focus on L-Shape Relations 233 8.i General Introduction 233 8.ii Relations to the General Framework 234 8.1 Analysis of L-shape Data: General Perspectives 235 8.2 Sequential Procedures for L-shape Data Based on PLS/PCR and ANOVA 236 8.2.1 Interpretation of X1, Quantitative X2-data, Horizontal Axis First 236 8.2.2 Interpretation of X1, Categorical X2-data, Horizontal Axis First 238 8.2.3 Analysis of Segments/Clusters of X1 Data 240 8.3 The L-PLS Method for Joint Estimation of Blocks in L-shape Data 246 8.3.1 The Original L-PLS Method, Endo-L-PLS 247 8.3.2 Exo- Versus Endo-L-PLS 250 8.4 Modifications of the Original L-PLS Idea 252 8.4.1 Weighting Information from X3 and X1 in L-PLS Using a Parameter α252 8.4.2 Three-blocks Bifocal PLS 253 8.5 Alternative L-shape Data Analysis Methods 254 8.5.1 Principal Component Analysis with External Information 254 8.5.2 A Simple PCA Based Procedure for Using Unlabelled Data in Calibration 255 8.5.3 Multivariate Curve Resolution for Incomplete Data 256 8.5.4 An Alternative Approach in Consumer Science Based on Correlations Between X3 and X1 257 8.6 Domino PLS and More Complex Data Structures 258 8.7 Conclusions and Recommendations 258 8.8 Open Issues 260 Part IV Alternative Methods for Unsupervised and Supervised Topologies 261 9 Alternative Unsupervised Methods 263 9.i General Introduction 263 9.ii Relationship to the General Framework 263 9.1 Shared Variable Mode 263 9.2 Shared Sample Mode 265 9.2.1 Only Common Variation 265 9.2.1.1 DIABLO 265 9.2.1.2 Generalised Coupled Tensor Factorisation 266 9.2.1.3 Representation Matrices 267 9.2.1.4 Extended PCA 272 9.2.2 Common, Local, and Distinct Variation 273 9.2.2.1 Generalised SVD 273 9.2.2.2 Structural Learning and Integrative Decomposition 273 9.2.2.3 Bayesian Inter-battery Factor Analysis 275 9.2.2.4 Group Factor Analysis 276 9.2.2.5 OnPLS 277 9.2.2.6 Generalised Association Study 278 9.2.2.7 Multi-Omics Factor Analysis 278 9.3 Two Shared Modes and Only Common Variation 281 9.3.1 Generalised Procrustes Analysis 282 9.3.2 Three-way Methods 282 9.4 Conclusions and Recommendations 283 9.4.1 Open Issues 284 10 Alternative Supervised Methods 287 10.i General Introduction 287 10.ii Relations to the General Framework 287 10.1 Model and Focus 288 10.2 Extension of PCovR 288 10.2.1 Sparse Multiblock Principal Covariates Regression, Sparse PCovR 288 10.2.2 Multiway Multiblock Covariates Regression 289 10.3 Multiblock Redundancy Analysis 292 10.3.1 Standard Multiblock Redundancy Analysis 292 10.3.2 Sparse Multiblock Redundancy Analysis 294 10.4 Miscellaneous Multiblock Regression Methods 295 10.4.1 Multiblock Variance Partitioning 296 10.4.2 Network Induced Supervised Learning 296 10.4.3 Common Dimensions for Multiblock Regression 298 10.5 Modifications and Extensions of the SO-PLS Method 298 10.5.1 Extensions of SO-PLS to Three-Way Data 298 10.5.2 Variable Selection for SO-PLS 299 10.5.3 More Complicated Error Structure for SO-PLS 299 10.5.4 SO-PLS Used for Path Modelling 300 10.6 Methods for Data Sets Split Along the Sample Mode, Multigroup Methods 304 10.6.1 Multigroup PLS Regression 304 10.6.2 Clustering of Observations in Multiblock Regression 306 10.6.3 Domain-Invariant PLS, DI-PLS 307 10.7 Conclusions and Recommendations 308 10.8 Open Issues 309 Part V Software 311 11 Algorithms and Software 313 11.1 Multiblock Software 313 11.2 R package multiblock 313 11.3 Installing and Starting the Package 314 11.4 Data Handling 314 11.4.1 Read From File 314 11.4.2 Data Pre-processing 315 11.4.3 Re-coding Categorical Data 316 11.4.4 Data Structures for Multiblock Analysis 317 11.4.4.1 Create List of Blocks 317 11.4.4.2 Create data.frame of Blocks 317 11.5 Basic Methods 318 11.5.1 Prepare Data 319 11.5.2 Modelling 319 11.5.3 Common Output Elements Across Methods 319 11.5.4 Scores and Loadings 320 11.6 Unsupervised Methods 321 11.6.1 Formatting Data for Unsupervised Data Analysis 321 11.6.2 Method Interfaces 322 11.6.3 Shared Sample Mode Analyses 322 11.6.4 Shared Variable Mode 322 11.6.5 Common Output Elements Across Methods 323 11.6.6 Scores and Loadings 324 11.6.7 Plot From Imported Package 325 11.7 ANOVA Simultaneous Component Analysis 325 11.7.1 Formula Interface 325 11.7.2 Simulated Data 325 11.7.3 ASCA Modelling 325 11.7.4 ASCA Scores 326 11.7.5 ASCA Loadings 326 11.8 Supervised Methods 327 11.8.1 Formatting Data for Supervised Analyses 327 11.8.2 Multiblock Partial Least Squares 328 11.8.2.1 MB-PLS Modelling 328 11.8.2.2 MB-PLS Summaries and Plotting 328 11.8.3 Sparse Multiblock Partial Least Squares 328 11.8.3.1 Sparse MB-PLS Modelling 328 11.8.3.2 Sparse MB-PLS Plotting 329 11.8.4 Sequential and Orthogonalised Partial Least Squares 330 11.8.4.1 SO-PLS Modelling 330 11.8.4.2 Måge Plot 331 11.8.4.3 SO-PLS Loadings 332 11.8.4.4 SO-PLS Scores 333 11.8.4.5 SO-PLS Prediction 334 11.8.4.6 SO-PLS Validation 334 11.8.4.7 Principal Components of Predictions 336 11.8.4.8 CVANOVA 336 11.8.5 Parallel and Orthogonalised Partial Least Squares 337 11.8.5.1 PO-PLS Modelling 337 11.8.5.2 PO-PLS Scores and Loadings 338 11.8.6 Response Optimal Sequential Alternation 339 11.8.6.1 ROSA Modelling 339 11.8.6.2 ROSA Loadings 340 11.8.6.3 ROSA Scores 340 11.8.6.4 ROSA Prediction 340 11.8.6.5 ROSA Validation 341 11.8.6.6 ROSA Image Plots 342 11.8.7 Multiblock Redundancy Analysis 343 11.8.7.1 MB-RDA Modelling 343 11.8.7.2 MB-RDA Loadings and Scores 343 11.9 Complex Data Structures 344 11.9.1 L-PLS 344 11.9.1.1 Simulated L-shaped Data 344 11.9.1.2 Exo-L-PLS 344 11.9.1.3 Endo-L-PLS 344 11.9.1.4 L-PLS Cross-validation 345 11.9.2 SO-PLS-PM 345 11.9.2.1 Single SO-PLS-PM Model 346 11.9.2.2 Multiple Paths in an SO-PLS-PM Model 346 11.10 Software Packages 347 11.10.1 R Packages 347 11.10.2 MATLAB Toolboxes 348 11.10.3 Python 349 11.10.4 Commercial Software 349 References 351 Index 373

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Book SynopsisThe fourth medical atlas in this new series on the human body and filled with detailed pictures, this atlas details the topographical and pathotopographical anatomy of the pelvis, spine, and limbs, a useful reference for medical professionals and students alike. Written by an experienced and well-respected physician and professor, this new volume, building on the previous volume, Ultrasonic Topographical and Pathotopographical Anatomy, and its sequels, also available from Wiley-Scrivener, presents the ultrasonic topographical and pathotopographical anatomy of the pelvis, spine, and limbs, offering further detail into these important areas for use by medical professionals. This series of atlases of topographic and pathotopographic human anatomy is a fundamental and practically important series designed for doctors of all specializations and students of medical schools. Here you can find almost everything that is connected with the topographic and pathotopoTable of ContentsIntroduction vii Part 1: The Pelvis 1 Part 2: The Spine 69 Part 3: The Limbs 91 Conclusion 185 About the Author 199

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Book SynopsisWritten by an experienced and well-respected physician and professor, this new volume combines the entire previous four books, Ultrasonic Topographical and Pathotopographical Anatomy, and its three sequels, also available from Wiley-Scrivener, presenings the ultrasonic topographical and pathotopographical anatomy of the entire body, offering further detail into these important areas for use by medical professionals. This comprehensive and exhaustive medical atlas of topographic and pathotopographic human anatomy is a fundamental and practically important book designed for doctors of all specializations and students of medical schools. Here you can find almost everything that is connected with the topographic and pathotopographic human anatomy, including original graphs of logical structures of topographic anatomy and development of congenital abnormalities, topography of different areas in layers, pathotopography, computer and magnetic resonance imaging (MRI) of topographic aTable of ContentsPreface ix Part 1: Ultrasonic Topographical and Pathotopographical Anatomy 1 Topography and Pathotopography of the Head 3 2 Topography and Pathotopography of the Neck 25 3 Topographical and Pathotopographical Anatomy of the Chest 43 4 Topographical and Pathotopographical Anatomy of the Abdomen 61 5 Topographical and Pathotopographical Anatomy of the Retroperitoneal Space 91 6 Topography and Pathotopography of the Pelvis 103 Topographical anatomy of the pelvic organs 103 Topography of the female pelvis 104 Topography of male pelvis 107 Ultrasonic topographical anatomy of male pelvis 108 7 Topography and Pathotopography of Lower Extremity 123 8 Conclusion 153 Part 2: Topographical and Pathotopographical Medical Atlas of the Head and Neck 9 Introduction 159 10 The Head 163 Topographic Anatomy of the Head 163 Cerebral Cranium 163 Basis Cranii Interna 177 The Brain 180 Surgical Anatomy of Congenital Disorders 203 Pathotopography of the Cerebral Part of the Head 204 Facial Head Region 209 Dentes-Teeth 226 The Lymphatic System of the Head 251 Congenital Face Disorders 254 Pathotopography of the Facial Part of the Head 256 Attachment 1: Neurocranial Part Topography 264 Attachment 2: Facial Part Topography 265 11 The Neck 267 Topographic Anatomy of the Neck 267 Fasciae, Superficial and Deep Cellular Spaces and their Relationship with Spaces Adjacent Regions 269 Triangles of the Neck 275 Organs of the Neck 297 Pathography of the Neck 306 Attachment 3: Topography of the Neck 317 Part 3: Topographical and Pathotopographical Medical Atlas of the Chest, Abdomen, Lumbar Region, and Retroperitoneal Space 12 The Chest 321 Topographic Anatomy of the Chest 321 Chest Cavity Organs Projection and Layers of Chest 322 Surgical Anatomy of Thoracic Wall Congenital Malformation 337 Thoracic Cavity 338 Mediastinum Topography 343 13 Abdomen 371 Topographic Anatomy of Anterolateral Abdomen Wall 371 Surgical Anatomy of Congenital Malformations of Anterior Lateral Abdominal Wall 384 Abdominal Region Topography 385 Peritoneum and Abdominal Cavity Levels 385 Abdominal Cavity Organs 392 14 Lumbar Region and Retroperitoneal Space 431 Topographic Anatomy of Lumbar Region and Retroperitoneal Space 431 Topographic Anatomy of Lumbar Region 431 Topographical anatomy of retroperitoneal space 437 Organs of Retroperitoneal Space 440 Surgical Anatomy of Congenital Malformations 450 15 Pathotography of the Chest 459 Abdominal Cavity 467 Retroperitoneal Space 487 Part 4: Topographical and Pathotopographical Medical Atlas of the Pelvis, Spine, and Limbs 16 Introduction 501 17 The Pelvis 503 Topographic Anatomy of the Pelvis 503 Individual, Gender and Age Differences 503 The Organs of the Male Pelvis 512 The Topography of the Vas Deferens 520 The Organs of the Female Pelvis 523 Defects of the Genitourinary System in Children 530 Perineum Topography 531 Pudendal Region in Men 533 Pudendal Region in Women 538 The Topography of the External Female Genitalia 538 Surgical Anatomy of Congenital Pelvic and Perineum 542 Anus. Ischiorectal Fossa. Perineal Rectum 546 Surgical Anatomy of Congenital Malformations of the External Genitalia 551 Pathotophography of the Peivis 553 18 The Spine 571 Topographic Anatomy of the Spine 571 Individual and Age Differences of the Spine 573 The Spinal Cord and Nerve Roots 573 Surgical Anatomy of the Malformations of the Spine and Spinal Cord 581 Pathotopography of the Spine 583 19 The Limbs 593 Topographic Anatomy of the Upper Limb 593 Supra Brachium – Shoulder Girdle 593 Shoulder 598 Forearm 603 Hand 612 Surgical Anatomy of Congenital Malformations of the Upper Limb 618 Pathotopography of the Upper Limbs 621 Topographic Anatomy of Lower Limbs 634 Gluteal Region 635 Femur 636 Canals of Thigh 648 Shin 652 Foot 664 Pathotopography of the Lower Limbs 671 Conclusion 687 Appendix A 701 Appendix B 709

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Book SynopsisPresents the latest knowledge of improving the stress tolerance, yield, and quality of rice crops One of the most important cereal crops, rice provides food to more than half of the world population. Various abiotic stressescurrently impacting an estimated 60% of crop yieldsare projected to increase in severity and frequency due to climate change. In light of the threat of global food grain insecurity, interest in molecular rice breeding has intensified in recent years. Progress has been made, but there remains an urgent need to develop stress-tolerant, bio-fortified rice varieties that provide consistent and high-quality yields under both stress and non-stress conditions. Molecular Breeding for Rice Abiotic Stress Tolerance and Nutritional Quality is the first book to provide comprehensive and up-to-date coverage of this critical topic, containing the physiological, biochemical, and molecular information required to develop effective engineering strategies for enhancing rice yield.Table of ContentsPreface xix List of Contributors xxi 1 Rice Adaptation to Climate Change: Opportunities and Priorities in Molecular Breeding 1Vikram Jeet Singh, Kunnummal Kurungara Vinod, Subbaiyan Gopala Krishnan and Ashok K. Singh 2 Molecular Breeding for Improving Salinity Tolerance in Rice: Recent Progress and Future Prospects 26Sandeep Chapagain, Lovepreet Singh, Richard Garcia, Rajat Pruthi, Jonathan Concepcion, Sapphire Coronejo and Prasanta K. Subudhi 3 Molecular Breeding for Improving Drought Tolerance in Rice: Recent Progress and Future Perspectives 53Ratna R. Majumder, Sandeep Sakhale, Shailesh Yadav, Nitika Sandhu, Lutful Hassan, Md. Amir Hossain and Arvind Kumar 4 Molecular Breeding for Improving Flooding Tolerance in Rice: Recent Progress and Future Perspectives 75Ramani K. Sarkar, Jangi N. Reddy and Satya R. Das 5 Molecular Breeding for Improving Heat Stress Tolerance in Rice: Recent Progress and Future Perspectives 92Bui Chi Buu, Cho Young Chan and Nguyen Thi Lang 6 Molecular Breeding for Improving Cold Tolerance in Rice: Recent Progress and Future Perspectives 120Ning Xiao and Jian-Min Chen 7 Molecular Breeding for Lower Cadmium Accumulation in Rice Grain: Progress and Perspectives 131Dongping Li, Xiaohua Hao and Liangbi Chen 8 Molecular Breeding for Improving Arsenic Stress Tolerance in Rice: Recent Progress and Future Perspectives 163Nourollah Ahmadi and Julien Frouin 9 Molecular Breeding for Improving Ozone Tolerance in Rice: Recent Progress and Future Perspectives 180Md. Ashrafuzzaman, Robert Henry and Michael Frei 10 Molecular Breeding Strategies for Enhancing Rice Yields Under Low Light Intensity 201Mayank Rai, Suvendhu S. Dutta and Wricha Tyagi 11 Harnessing Tolerance to Low Phosphorus in Rice: Recent Progress and Future Perspectives 215Wricha Tyagi, Erneica N. Nongbri and Mayank Rai 12 Molecular Breeding for Improving Nitrogen Use Efficiency in Rice: Progress and Perspectives 234Chirravuri N. Neeraja, Sitapati R. Voleti, Subrahmanyam Desiraju, Surekha Kuchi, Sonali Bej, Krishnakanth Talapanti and Raghuveer R. Puskur 13 Dissecting the Molecular Basis of Drought-Induced Oxidative Stress Tolerance in Rice 249Amit K. Pradhan, Sabnoor Y. Jyoti, Zina M. Shandilya, Mehzabin Rehman, Debanjali Saikia, Junu Poudel, Jyotirmay Kalita, Kongkona Borborah, Uma K. Chowra, Jnandabhiram Chutia, Lakshminarayana R. Vemireddy and Bhaben Tanti 14 Manipulation of Photosynthesis to Increase Rice Yield Potential 274Prabuddha Dehigaspitiya and Saman Seneweera 15 Molecular Breeding for Improved β-carotene Synthesis in Golden Rice: Recent Progress and Future Perspectives 287Swapan K. Datta, Shuvobrata Majumder and Karabi Datta 16 Increasing Grain Zinc Concentration in Rice 304Naoya Miyazaki, Miki Ogasawara and Ryo Ishikawa 17 Molecular Breeding for Iron Bio-Fortification in Rice Grain: Recent Progress and Future Perspectives 315Elssa Pandit, Swapnil Pawar, Priyadarshini Sanghamitra and Sharat K. Pradhan 18 Aromatic Rices: Evolution, Genetics and Improvement through Conventional Breeding and Biotechnological Methods 341Lakshminarayana R. Vemireddy, Bhaben Tanti, Lipika Lahkar and Zina M. Shandilya 19 Genetic Engineering for Increasing Antioxidant Content in Rice: Recent Progress and Future Perspectives 358Qinlong Zhu, Jiantao Tan, Bin Wang and Yao-Guang Liu 20 Molecular Breeding Approaches for Improvement and Development of Water Saving Aerobic Rice 382Rahul K. Meena, Kuldeep Kumar, Saurabh K. Dubey, Ashish K. Singh, Adarsh Kumar, Deepanshu Jayaswal, Badal Singh, Rajinder Jain and Sunita Jain 21 Targeting the Ascorbate-Glutathione Pathway and the Glyoxalase Pathway for Genetic Engineering of Abiotic Stress-Tolerance in Rice 398Mohammad A. Hossain, Tahsina S. Hoque, Abbu Zaid, Shabir H. Wani, Mohammad G. Mostofa and Robert Henry Index 428

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Book SynopsisUnderstand new modes of analysing metabolomic data Metabolomics is the study of metabolites, small molecules and chemical substrates within cells or larger structures which collectively make up the metabolome. The field of metabolomics stands to benefit enormously from chemometrics, an approach which brings advanced statistical techniques to bear on data of this kind. Data Analysis and Chemometrics for Metabolomics constitutes an accessible introduction to chemometric techniques and their applications in the field of metabolomics. Thoroughly and accessibly written by a leading expert in chemometrics, and printed in full-colour, it brings robust data analysis into conversation with the metabolomic field to the immense benefit of practitioners. Data Analysis and Chemometrics for Metabolomics readers will also find: Statistical insights into the nature of metabolomic hypothesis testing, validation, and more All metabolomics data sets from the book on a companion website Case studies from

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Book SynopsisDemystifies the academic career path with practical advice With the number of people being awarded PhDs growing far more rapidly than the supply of academic jobs, those at an early-career stage must think strategically in order to be competitive and successful. Navigating an Academic Career: A Brief Guide for PhD students, Post docs, and New Faculty is a concise and conversational manual that guides readers through starting their academic journey, surviving the demands of their first academic position, and thriving in academia and beyond. Volume highlights include: Firsthand perspective on the characteristics of a successful academic Guidance on interviewing, negotiating, branding, and other essential soft skills Tips for effective time management and writing high-impact research papers Insights into developing leadership skills and mentoring others The American Geophysical Union promotes discovTable of ContentsPreface vii About the Author ix Part I: The PhD Student and Postdoc Years 1 1 An Academic Career 3 2 Traits of Successful Scientists 7 3 Avoiding a PhD in Anxiety 11 4 Getting Your First Academic Job 15 5 The Academic Matthew Effect 19 Part II: Surviving and Thriving in the First Few Years 23 6 Paper Writing Gone Hollywood 25 7 The Perfect Department 27 8 Ethics in the Real World 31 9 Research Brand Identity 35 10 The 1‐Hour Workday 39 11 Orchestrating a Powerful Research Group 41 12 Proposal Writing Hacks 43 Part III: Tenure and Beyond 47 13 Mentoring the Middle 49 14 Research Visits and Academic Growth Spurts 53 15 On Leadership 57 16 The Sustainable Professor 61 17 A Scientist Looks at 60 63 Postface 67 Acknowledgments 69 Notes 73 Further Reading 77 Index 81

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Book SynopsisAn insightful and illuminating discussion of the impact humans have had on Earth In A Primer on Human Impacts on the Environment: The Conceptual Approach, distinguished environmental scientist Liam Heneghan explores the intricate relationships between humanity and Earth in an accessible and engaging style. Replete with real-world examples and drawing from classic and contemporary scholarship, the author adapts the fundamental conceptual models of the environmental disciplines to assess the risks human beings are taking with their home planet. The conceptual approach of this primer challenges readers to think across multiple disciplines to reveal the ?big picture? that is all too often lost in the details of contemporary environmental studies. Readers will also find: A thorough introduction to conceptual modeling, showing how systems models can be adapted and applied in a rapidly changing world Comprehensive explorations of the human impact on thTable of ContentsPreface Chapter 1 A Manifesto for Conceptual Thinking in Environmental Disciplines Chapter 2 A Conceptual Approach to Environmental Science Chapter 3 A Short Chapter on the Definition of Definitions Chapter 4 Everything is connected (but some things are more connected than are others) Chapter 5 Complex Environmental Systems Chapter 6 All or nothing? Or, what, exactly, is an environment? Chapter 7 Life and environment: the indissoluble link Chapter 8 Gaia, the Noösphere, and the Anthropocene Chapter 9 The Anthropocene and the Concept of Limits Chapter 10 Limited and limiting models Chapter 11 Collapse and the Anthropocene Chapter 12 How to conceive a (climate) crisis Chapter 13 Risking Life: Basics of Biological Diversity Chapter 14 Risking life: Is the Sixth Extinction Catastrophic? Chapter 15 Conceiving a Future: the need for interdisciplinarity Chapter 16 The Three Futures Index

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Book SynopsisA guide to the role microbes play in the enhanced production and productivity of agriculture to feed our growing population Phytomicrobiome Interactions and Sustainable Agricultureoffers an essential guide to the importance of Phytomicrobiome' and explores its various components. The authors noted experts on the topic explore the key benefits of plant development such as nutrient availability, amelioration of stress and defense to plant disease. Throughout the book, the authors introduce and classify the corresponding Phytomicrobiome components and then present a detailed discussion related to its effect on plant development: controlling factors of this biome, its behaviour under the prevailing climate change condition and beneficial effects. The book covers the newly emerging technical concept of Phytomicrobiome engineering, which is an advanced concept to sustain agricultural productivity in recent climatic scenario. The text is filled with comprehensive, cutting edge data, makiTable of ContentsList of Contributors xii Preface xvi About the Editors xviii 1 Plant Root Exudate Analysis: Recent Advances and Applications 1Shulbhi Verma and Amit Verma 1.1 Introduction 1 1.2 Root Exudates Composition: Collection and Analysis 3 1.3 Role of Root Exudates in Shaping Rhizospheric Microbiomes 5 1.4 Applications of Root Exudation 6 1.5 Conclusion and Future Prospects 7 References 10 2 Phytoproteomics: A New Approach to Decipher Phytomicrobiome Relationships 15Prachie Sharma and Kapila Kumar 2.1 Introduction 15 2.2 Phytomicrobiome 16 2.3 Phytomicrobiome: The Communication via Signaling 18 2.4 Proteomics 19 2.4.1 Gel-Based Protein Separation Techniques 21 2.4.2 Non-Gel Protein Separation Techniques 21 2.5 Analysis of Phytomicrobial Interactions Using Proteomics Approaches 22 2.6 Conclusion and Future Prospects 26 References 28 3 Metagenomics: An Approach to Unravel the Plant Microbiome and Its Function 32Ravindra Soni, Deep Chandra Suyal, Balram Sahu, and Suresh Chandra Phulara 3.1 Introduction 32 3.2 Metagenomics 33 3.3 Metagenomics of Plant Rhizosphere 33 3.4 Metagenomics of Plant Phyllosphere 35 3.5 Metagenomics of Plant Endosphere 36 3.6 In-silico Tools for Metagenome Analysis 37 3.6.1 Mothur 37 3.6.2 Quantitative Insights into Microbial Ecology (QIIME) 37 3.6.3 MEta Genome Analyzer (MEGAN) 38 3.7 Recent Progress in Metagenomic Studies of Plant Microbiome 38 3.8 Conclusion and Future Prospects 38 References 38 4 Combating the Abiotic Stress Through Phytomicrobiome Studies 45Hemant S. Maheshwari, Abhishek Bharti, Richa Agnihotri, Ajinath Dukare, B. Jeberlin Prabina, Saurabh Gangola, and Mahaveer P. Sharma 4.1 Introduction 45 4.1.1 Abiotic Stress and Phytomicrobiome 45 4.1.2 Role of Signaling in Phytomicrobiome Interactions 46 4.2 Phytomicrobiome Signaling Compounds 47 4.2.1 Root Exudates and Plant Volatiles Compounds 47 4.2.2 Microbial Volatile Organic Compounds 47 4.2.3 Quorum Sensing 48 4.2.4 Underground Phytomicrobiome Signaling 48 4.3 Mechanisms of Phytomicrobiome Associated with Abiotic Stress Tolerance 49 4.3.1 Drought Stress Alleviation 50 4.3.2 Salinity Stress Mitigation 53 4.3.3 Heavy Metal Toxicity 55 4.3.4 Low-Temperature Stress 56 4.3.5 Nutrient Deficiency 56 4.3.6 Flooding or Water Submergence 56 4.4 Importance of Phytomicrobiome Engineering for Crop Stress Alleviation 57 4.5 Omics Strategies in Phytomicrobiome Studies 58 4.6 Conclusion and Future Prospects 59 Acknowledgments 59 References 60 5 Microbial Diversity of Phyllosphere: Exploring the Unexplored 66Rakhi Dhankhar, Aparajita Mohanty, and Pooja Gulati 5.1 Introduction 66 5.2 Origin of Phyllosphere Microflora 67 5.3 Tools to Study Phyllomicrobiome 68 5.3.1 Conventional Methods 69 5.3.2 Microscopic Techniques 69 5.3.3 First-Generation Molecular Techniques 70 5.3.4 Next-Generation Sequencing Methods 70 5.3.5 Omics and Bioinformatics Approaches 76 5.3.6 Other Molecular Methods 77 5.4 Biodiversity of Phyllosphere 77 5.5 Microbial Adaptation to Phyllosphere 78 5.5.1 Adaptation to Abiotic Stresses 79 5.5.2 Adaptation to Biotic Stresses 80 5.5.3 Adaptation to Nutrient Scarcity 81 5.6 Interaction of Phyllomicrobiota with Plants 81 5.6.1 Positive Interactions 82 5.6.2 Negative Interactions 83 5.7 Significance of Phyllomicrobiome Studies 83 5.8 Conclusion and Future Prospects 84 References 85 6 Rhizosphere Engineering: An Effective Approach for Sustainable Modern Agriculture 91Reema Mishra, Tripti Grover, Pooja Gulati, and Aparajita Mohanty 6.1 Introduction 91 6.2 Natural Plant–Microbe Interactions in Rhizosphere 92 6.3 Molecular Mechanisms in Plant–Microbe Interactions in Rhizosphere 93 6.4 Biochemical Components in Rhizosphere Signaling 94 6.5 Tools and Techniques in Rhizosphere Engineering 96 6.5.1 Stable Isotope Probing (SIP) 96 6.5.2 DNA Arrays 97 6.5.3 Fluorescence In Situ Hybridization (FISH) 97 6.5.4 Bioreporters 97 6.5.5 Genomics 98 6.5.6 Transcriptomics 98 6.5.7 Proteomics 99 6.5.8 Metabolomics 99 6.6 Rhizosphere Components Amenable to Engineering 100 6.6.1 Soil Modification 100 6.6.2 Plant Amendment 100 6.6.2.1 Root Exudate Modification 100 6.6.2.2 Root Architecture Modification 101 6.6.2.3 Enhancing Abiotic Stress Tolerance in Plants 101 6.6.2.4 Enhancing Biotic Stress Tolerance in Plants 103 6.6.2.5 Engineering Metabolic Pathways in Plants 105 6.6.3 Engineering Microbial Populations 107 6.7 Conclusion and Future Prospects 107 Acknowledgment 108 References 108 7 Plant Communication with Associated: Its Components, Composition and Role in Maintaining Plant Homeostasis 118Dibyajit Lahiri, Moupriya Nag, Sayantani Garai, Bandita Dutta, and Rina Rani Ray 7.1 Introduction 118 7.2 Biofilm and Rhizospheric Interactions 119 7.3 Biofilm Formation at the Root Rhizosphere 120 7.3.1 The Components of Biofilm Matrix 121 7.3.2 Bacterial Quorum Sensing 122 7.4 Genetic Features Responsible for Bacterial Cell Adhesion to Plant System 125 7.4.1 Chemotaxis Motility 125 7.4.2 Substrate Utilization and Transport 125 7.4.3 Lipopolysaccharide and Membrane Proteins 126 7.4.4 Plant Cell Wall Modification 127 7.4.5 Adhesion and Biofilm Formation 128 7.4.6 Stress Protection 128 7.4.7 Bacterial Secretion System 129 7.4.8 Transcriptional Regulators and Sensor Proteins 130 7.5 Nutrient Interactions 138 7.5.1 Release and Activation of Minerals 138 7.5.2 Nutrient Recycling 138 7.5.3 Nitrogen Dynamics 138 7.5.4 Ionic Modification 139 7.6 Biotic Interaction 140 7.6.1 Symbiosis 140 7.6.2 Synergy 140 7.6.3 Competition 140 7.6.4 Antagonism 141 7.6.5 Pathogenesis 142 7.7 Conclusion and Future Prospects 142 References 143 8 Phytomicrobiome: Synergistic Relationship in Bioremediation of Soil for Sustainable Agriculture 150Nimmy Srivastava 8.1 Introduction 150 8.2 Phytoremediation 151 8.2.1 Process of Phytoremediation 151 8.2.2 Strategies for Phytoremediation 151 8.3 Phytomicrobe Interactions and Rhizomediation 152 8.3.1 Principle of Phytomicrobiome Interaction During Rhizomediation 152 8.3.2 Removal of Inorganic Contaminants 154 8.3.3 Removal of Organic Pollutants 154 8.3.4 Factors Affecting Rhizomediation 157 8.4 Conclusion and Future Prospects 157 References 158 9 Rhizospheric Biology: Alternate Tactics for Enhancing Sustainable Agriculture 164Kalpana Bhatt and Pankaj Bhatt 9.1 Introduction 164 9.2 Engineering the Rhizosphere 165 9.2.1 Rhizosphere and Rhizobia 165 9.2.2 Root Exudates: Chemical Nature and Types 167 9.2.3 Factors Affecting Root Exudate 168 9.3 Engineering Soil Microbial Populations and Plant–Microbe Interactions 169 9.3.1 Microorganisms in Soil 169 9.3.2 Soil Modification: Altering Microbial Populations 170 9.4 Plant Growth-Promoting Rhizobacteria: Mechanisms, Potential, and Usages 170 9.4.1 Direct Mechanisms 171 9.4.1.1 Biological N2 Fixation 171 9.4.1.2 Phosphate Solubilization 173 9.4.1.3 Zinc Solubilization 174 9.4.1.4 Siderophore Production 174 9.4.1.5 Production of Phytohormones 174 9.4.1.6 ACC (1-Aminocyclopropane-1-Carboxylate) Deaminase Activity 175 9.4.2 Indirect Mechanisms 175 9.5 Plant–Microbe Interaction 176 9.6 Biofertilizers and its Applications 177 9.7 Plant Genetic Engineering 177 9.8 Conclusion and Future Prospects 178 Acknowledgments 178 References 179 10 Application of Inorganic Amendments to Improve Soil Fertility 187Sunita Chauhan and Shweta Kulshreshtha 10.1 Introduction 187 10.2 Impact of Bhoochetna Movement in Southern India 188 10.3 Sustainable Agriculture 188 10.3.1 Healthy Soil and Soil Quality 189 10.3.2 Soil Quality 189 10.3.3 Soil Quality Indicator 190 10.3.4 Soil Quality Index 191 10.4 Factors to Be Considered While Selecting a Soil Amendment 192 10.5 Advantages of Soil Amendments 194 10.6 Land Modeling 194 10.7 Major Applications of Soil Amendments 195 10.7.1 Phyto-Stabilization in Polluted or Contaminated Soils 195 10.7.2 Restoration of Soil 196 10.7.2.1 Soil Acidity/pH Soil Amendments 196 10.7.2.2 Mineral Soil Amendments and Conditioners 196 10.7.2.3 Different Types of Inorganic Amendments 197 10.8 Combination Strategy for Soil Quality Improvement 202 10.9 Conclusion and Future Prospects 203 References 203 11 Improved Plant Resistance by Phytomicrobiome Community Towards Biotic and Abiotic Stresses 207Neha Trivedi 11.1 Introduction 207 11.2 Microbes and Plants 207 11.2.1 Abiotic Stress Responses and Microbe-Mediated Mitigation in Plants 208 11.2.2 Microbial-Induced Response to Stresses 208 11.3 Response of Abiotic Response on Plant 209 11.3.1 Induced Systemic Tolerance (IST) 209 11.3.2 Metabolic Changes in Plants Induced by Microbes During Stress 209 11.3.2.1 Metabolic Cross-Talk in Plants After Stress Induction 210 11.3.2.2 Activation of Antioxidant Mechanism 210 11.3.2.3 Activation of Systemically Induced Resistance 210 11.4 Role of Phytohormones in Increasing Abiotic and Biotic Stress Tolerance 211 11.5 Gene Transfer in Plants 212 11.6 Conclusion and Future Prospects 212 References 212 12 Bioprospecting: At the Interface of Plant and Microbial Communities 217Madan L. Verma, Varsha Rani, Reena Kumari, Deepka Sharma, Sanjeev Kumar, and Rekha Kushwaha 12.1 Introduction 217 12.2 Plant-Associated Microbial Communities 218 12.3 Beneficial Effects of Plant-Associated Microbial Communities 222 12.3.1 Rhizoremediation 223 12.3.2 Plant Growth–Promoting Rhizobacteria (PGPR) 223 12.3.3 Biotic and Abiotic Stress Resistance 224 12.3.4 Signalomics 226 12.4 Role of Microbial Processing (Signals) in Facilitating Plant Growth 226 12.5 Conclusion and Future Prospects 230 Acknowledgments 230 References 231 13 Advances in Omics and Bioinformatics Tools for Phyllosphere Studies 240Hina Bansal 13.1 Introduction 240 13.2 Recent Trends and Approaches 241 13.3 Computing for Biology 243 13.4 Bioinformatics in Microbial Research 243 13.5 Phyllosphere Microbiome Studies Based on Genome-Wide Association 245 13.6 Omics Strategies and Their Integration 246 13.6.1 Metagenomics 246 13.6.2 Metatranscriptomics 246 13.6.3 Metabolomics 247 13.6.4 Proteomics 247 13.7 Conclusion and Future Prospects 248 References 248 14 Microbial Mediated Zinc Solubilization in Legumes for Sustainable Agriculture 254Pawan Saini, Sharon Nagpal, Pooja Saini, Arun Kumar, and Mudasir Gani 14.1 Introduction 254 14.2 Chronological Events of Zinc Biology 255 14.3 Role of Zinc in Living System 256 14.3.1 Essentiality of Zinc in Humans 256 14.3.2 Essentiality of Zinc in Plants 257 14.4 Zinc Deficiency vs. Zinc Toxicity in Crop Plants 259 14.5 Availability of Zinc in Soil Environment 260 14.6 Factors Affecting Zinc Availability to Plants 261 14.7 Response of Legume Crops to Zinc 262 14.8 Microbial Mediated Zinc Solubilization in Legume Crops 263 14.8.1 Zinc-Solubilizing Bacteria (ZnSB) 264 14.8.2 Zinc-Solubilizing Fungi (ZnSF) 265 14.9 Conclusion and Future Prospects 266 References 266 15 Composition and Interconnections in Phyllomicrobiome 277Meghmala Waghmode, Aparna Gunjal, Neha Patil, and Sonali Shinde 15.1 Introduction 277 15.2 Significance of Phyllospheremicrobiota 279 15.3 Phyllosphere Microorganisms as Plant Growth Regulator 280 15.3.1 Plant Growth Hormones Production by Phyllosphere Microorganisms 280 15.3.2 Phosphorus Solubilization by Phyllosphere Microorganisms 280 15.3.3 Siderophores Production by Phyllosphere Microorganisms 280 15.3.4 Phyllosphere Microorganisms as Biocontrol Agents Against the Phytopathogens 280 15.3.5 Phyllosphere Microorganisms to Reduce Biotic and Abiotic Stress 281 15.3.6 Synthesis of 1-Aminocyclopropane-1-Carboxylate Deaminase (ACC) 282 15.3.7 Phyllosphere Microorganisms in Nitrogen-Fixation 282 15.3.8 Frost Injury and Frost Control by Altering the Phyllosphere Microbiota 282 15.3.9 Remediation of Toxic Pollutants 283 15.3.10 Plant Probiotics 283 15.3.11 Role of Phyllosphere Microorganisms in Climate Change 284 15.3.12 Phyllosphere Microorganisms in Nutrient Yield and Increase of Plant Growth 284 15.3.13 Plant Hormones as Colonization Mediators of the Plant Leaves 284 15.4 Plant–Pathogen Interactions Mediated by Phyllosphere Microbiome 285 15.4.1 Interaction Dependent on the Ionome 285 15.4.2 Role of Secretory Systems and Secretory Products 285 15.4.3 Quorum Sensing 286 15.5 Conclusion and Future Prospects 286 References 286

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Book SynopsisX-Ray Fluorescence in Biological Sciences Discover a comprehensive exploration of X-ray fluorescence in chemical biology and the clinical and plant sciences In X-Ray Fluorescence in Biological Sciences: Principles, Instrumentation, and Applications, a team of accomplished researchers delivers extensive coverage of the application of X-ray fluorescence (XRF) in the biological sciences, including chemical biology, clinical science, and plant science. The book also explores recent advances in XRF imaging techniques in these fields. The authors focus on understanding and investigating the intercellular structures and metals in plant cells, with advanced discussions of recently developed micro-analytical methods, like energy dispersive X-ray fluorescence spectrometry (EDXRF), total reflection X-ray fluorescence spectrometry (TXRF), micro-proton induced X-ray emission (micro-PIXE), electron probe X-ray microanalysis (EPXMA), synchrotron-based X-ray fluorescence Table of ContentsChapter No. Primary Author Contact Authors Chapter Title 1 Kanishka Rawat Kanishka Rawat X-ray Fluorescence and Comparison with Other Analytical Methods (AAS, ICP-AES, LA-ICP-MS, IC, LIBS, SEM-EDS, and XRD) 2 Eva Marguí Eva Marguí X-ray Fluorescence for Multi-elemental Analysis of Vegetation Samples 3 А.G. Revenko А.G. Revenko X-ray Fluorescence Studies of Tea and Coffee 4 Nand Lal Mishra Nand Lal Mishra Total Reflection X-ray Fluorescence Analysis of Biological Samples 5 Changling Lao Changling Lao Micro X-ray Fluorescence and X-ray Absorption Near Edge Structure Analysis of Heavy Metals in Microorganism 6 Yeasmin Nahar Jolly Yeasmin Nahar Jolly Use of Energy Dispersive X-ray Fluorescence for Clinical Diagnosis 7 Nuray Kup Aylikci Nuray Kup Aylikci Preparation of Sample for X-ray Fluorescence Analysis 8 M.K. Tiwari M.K. Tiwari Elemental Analysis Using Synchrotron Radiation X-ray Fluorescence 9 KatarinaVogel Mikuš KatarinaVogel Mikuš Synchrotron Radiation Based Micro X-ray Fluorescence Spectroscopy of Plant Materials 10 Jian Liu Jian Liu Micro X-ray Fluorescence Analysis of Toxic Elements in Plants 11 Jing Yuan Jing Yuan Micro X-ray Fluorescence Studies of Earthworm (Benthonic fauna) in Soils and Sediments 12 V.A.Trunova V.A.Trunova Synchronous Radiation X-ray Fluorescence Analysis of Microelements in Biopsy Tissues 13 Nand Lal Mishra Nand Lal Mishra Total Reflection X-ray Fluorescence Analysis of Marine Organisms, Blood, Oral Fluids, Hairs, Nails, Kidney Stones, Urine and Cancerous Tissues 14 M.K. Tiwari M.K. Tiwari Recent Developments in X-ray Fluorescence for Characterization of Nano-Structured Materials 15 Artem S. Maltsev Artem S. Maltsev Total-Reflection X-ray Fluorescence Analysis of Alcoholic and Non-Alcoholic Beverages 16 Tsenddavaa Amartaivan Tsenddavaa Amartaivan Trace Elements Analysis of Blood Samples and Serum using Total Reflection X-ray Fluorescence 17 Navgeet Kaur Navgeet Kaur Basics and Fundamentals of X-rays 18 Rakesh K. Sindhu Rakesh K. Sindhu General Principle, Procedures and Detectors of X-ray Fluorescence 19 Neslihan Ekinci Neslihan Ekinci Quantitative Analysis in X-ray Fluorescence System 20 Marco Carminati Marco Carminati Electronics and Instrumentation for X-ray Fluorescence 21 Marijan Nečemer Katarina Vogel-Mikuš Energy Dispersive X-ray Fluorescence Analysis of Biological Materials 22 Galina Pashkova Artem S. Maltsev X-ray Fluorescence Analysis of Milk and Dairy Products 23 E.V. Chuparina E.V. Chuparina X-ray Fluorescence Analysis of Medicinal Plants 24 Neera Yadav Neera Yadav X-ray Fluorescence Studies of Animal and Human Cell Biology 25 Kamya Goyal Anju Goyal Toxic and Essential Elemental Studies of Human Organs using X-ray Fluorescence 26 Hiroshi Yoshii Hiroshi Yoshii X-ray Fluorescence for Rapid Detection of Uranium in Blood Extracted from Wounds 27 D. Bolortuya D. Bolortuya X-ray Fluorescence Analysis of Human Hair 28 Vivek K. Singh Vivek K. Singh X-ray Fluorescence Spectrometry to Study Gallstones, Kidney Stones, Hair, Nails, Bones, Teeth and Cancerous Tissues 29 Dra. Mónica Orduña Cordero Dra. Mónica Orduña Cordero Sampling and Sample Preparation for Chemical Analysis of Plants by Wavelength Dispersive X-ray Fluorescence 30 Harinderjit Singh Harinderjit Singh X-ray Fluorescence Analysis in Medical Biology 31 А.G. Revenko А.G. Revenko X-ray Fluorescence Analysis in Pharmacology 32 Héctor Jorge Sánchez Héctor Jorge Sánchez X-ray Fluorescence and State-of-the-Art Related Techniques to the Study of Teeth, Tartar and Oral Tissues 33 Harpreet Singh Kainth Harpreet Singh Kainth Recent Advances in Wavelength Dispersive X-ray Fluorescence Techniques 34 Vitaly Panchuk Dmitry Kirsanov Chemometric Processing of X-ray Fluorescence Data 35 Shilpa Chakrabarti Neera Yadav X-ray Crystallography in Medicinal Biology 36 Kanishka Rawat Kanishka Rawat Historical Fundamentals of X-ray Instruments and Present Trends in Biological Science 37 P. Zuzaan D. Bolortuya X-ray Fluorescence Studies of Biological Objects in Mongolia 38 Jun Kawai Jun Kawai Arsenic Analysis 39 Rakesh K. Sindhu Rakesh K. Sindhu X-ray Fluorescence: Current Trends and Future Scope

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Book SynopsisFocusing on phytochemicals and their potential for drug discovery, this book offers a comprehensive resource on poisonous plants and their applications in chemistry and in pharmacology. Provides a comprehensive resource on phytotoxins, covering historical perspectives, modern applications, and their potential in drug discoveryCovers the mechanisms, benefits, risks and management protocols of phytotoxins in a scientific laboratory and the usefulness in drug discoveryPresents chapters in a carefully designed, clear order, making it an ideal resource for the academic researcher or the industry professional at any stage in their careerTable of ContentsList of Contributors xvii List of Figures xxi List of Tables xxiii Preface xxv Editors xxvii 1 Historical Use of Toxic Plants 1Godwin Anywar 1.1 Introduction to Toxic Plants 1 1.2 Poisonous Plants as Sources of Traditional and Modern Medicines 2 1.3 Toxic Plants and Justice 4 1.3.1 Toxic Plants in Capital Punishment 4 1.3.2 Trial by Ordeal 4 1.4 Toxic Plants in Poisoned Weapons 6 1.4.1 Arrow Poisons 6 1.5 Plant Fishing Poisons/Piscicides/Ichthyotoxins 6 1.6 Poisonous Plants as Food 7 1.7 Poisonous Plants as Biopesticides 9 1.8 Toxic Psychoactive Plants for Recreational and Religious Purposes 9 1.9 Poisonous Plants in Warfare and Bioterrorism 10 1.10 Poisonous Plants as Carcinogens and Teratogens 11 1.11 Conclusion 12 References 12 2 Classification of Phytotoxins and their Mechanisms of Action 19Andrew G. Mtewa, Chukwuebuka Egbuna, Kennedy J. Ngwira, Fanuel Lampiao, Umang Shah, and Thokozani Kachulu Mtewa 2.1 Introduction 20 2.1.1 Endophytic Phytotoxins 20 2.1.2 Secondary Metabolites 21 2.2 Possible Categorization 21 2.2.1 Biological Characteristics 21 2.2.2 Chemical Characteristics 22 2.3 Currently Available Classification Tools 24 2.4 Role of Phytotoxin Classification 25 2.4.1 Drug Discovery 25 2.4.2 Environmental Monitoring 25 2.4.3 Phytotoxins, Aquatic Life, and Water Quality 26 2.4.4 Air Contamination 26 2.4.5 Food Contamination 26 2.4.6 Security and Safety Services 27 2.4.7 Agricultural 27 2.5 Brief Mechanisms of Action 27 2.6 Conclusion 28 References 28 3 Poisonous Plants as Sources of Anticancer and Other Drugs 31Félicien Mushagalusa Kasali, Andrew G. Mtewa, and Gaétan Tabakam 3.1 Introduction 31 3.2 Poisonous Plants in the Treatment of Cancer and Other Diseases 32 3.3 Poisonous Plant-Based Anticancer Drugs that are on the Market 33 3.4 Poisonous Plant-Based Drugs Against Other Diseases that are on the Market 33 3.5 Conclusion 33 References 75 4 Drugs in Clinical Practice from Toxic Plants and Phytochemicals 79Tadele Mekuriya Yadesa, Patrick Engeu Ogwang, and Casim Umba Tolo 4.1 Introduction 80 4.2 Drugs in Clinical Practice from Toxic Plants 81 4.2.1 Curare 81 4.2.2 Drugs Acting on the Central Nervous System 81 4.2.2.1 Morphine 81 4.2.2.2 Cocaine 82 4.2.2.3 Ergot Alkaloids 83 4.2.3 Atropine, Scopolamine, and Hyoscyamine 84 4.2.4 Physostigmine and Other Acetylcholinesterase Inhibitors 85 4.2.5 Antitumor Agents 85 4.2.5.1 Podophyllotoxin and Etoposide 85 4.2.5.2 Taxanes 86 4.2.5.3 Vincristine and Vinblastine 87 4.2.6 Other Drugs 88 4.2.6.1 Cardiac Glycosides 88 4.2.6.2 Colchicine 89 4.2.6.3 Coumarins 89 4.2.6.4 Nicotine and the Neonicotinoids 90 References 90 5 Toxicology and Health Benefits of Plant Alkaloids 95Ibrahim Chikowe, Andrew G. Mtewa, and Duncan C. Sesaazi 5.1 Introduction 95 5.2 Pharmacological Properties of Alkaloids 97 5.3 Toxicological Properties of Alkaloids 100 5.4 Acute and Chronic Toxicities 100 5.4.1 Genotoxicity and Tumorigenicity 101 5.4.2 Lung Toxicity, Neurotoxicity, and Teratogenicity 102 5.5 Factors that Influence the Toxicological Profile of Alkaloids 102 5.6 Conclusion 103 References 103 6 Chemical and Pharmacological Mechanisms of Plant-Derived Neurotoxins 109Amanjot Annu, Reuben S. Maghembe, Andrew G. Mtewa, and G.M. Narasimha Rao 6.1 Introduction 110 6.2 Nerve Agents 110 6.3 Chemical Mechanisms of Neurotoxicity Induced by Organophosphate Nerve Agents 111 6.4 Mustards 112 6.4.1 Effect of HD on Skin 113 6.4.2 Effect of HD on Other Organs 113 6.4.3 The Activation of HD 114 6.4.4 Mechanism of Action 115 6.5 Plant Natural Neurotoxins 116 6.6 Plant Glycosides 118 6.7 Conclusion 119 References 119 7 Phytosedatives for Drug Discovery 123Shahira M. Ezzat, Ahmed Zayed, and Mohamed A. Salem 7.1 Introduction 123 7.2 Treatment of Neuropsychological Disorders: The Current Scenario 124 7.3 Phytosedatives: Desirable Alternatives to Synthesized Drugs 125 7.4 Different Classes of Phytosedatives 125 7.4.1 Flavonoids 126 7.4.2 Alkaloids 128 7.4.3 Essential Oils 129 7.4.4 Other Classes of Phytosedatives 130 7.5 Plants with Reported Sedative Actions 130 7.6 Conclusion 152 References 152 8 Mushroom Species and Classification: Bioactives in Poisonous and Edible Mushrooms 163Sadia Zafar, Farhat Jabeen, Muhammad Akram, Zarfishan Riaz, and Naveed Munir 8.1 Introduction 163 8.2 Classification of Mushrooms 164 8.2.1 Edible Mushrooms 165 8.2.2 Non-Edible Mushrooms 165 8.3 Bioactive Agents in Mushroom Species 165 8.4 Bioactive Agents in Non-Edible Mushroom Species 166 8.4.1 Polysaccharides 166 8.4.2 Glucans 166 8.4.3 Polysaccharide–Protein Complexes 174 8.4.4 Terpenes 174 8.4.5 Phenolic Compounds 175 8.4.6 Peptides and Proteins 176 8.5 Other Bioactive Compounds of Mushroom Species 176 8.6 Conclusion 176 References 177 9 Toxicity Protocols for Natural Products in the Drug Development Process 189Tamirat Bekele Beressa, Amanjot Annu, and Andrew G. Mtewa 9.1 Introduction 190 9.2 In Vitro Toxicity Testing for Natural Products 190 9.2.1 Cell Culture Method for Toxicity Testing 191 9.2.2 Cell Culture for Acute Toxicology Testing 192 9.3 Methods Used for In Vitro Toxicity Studies 193 9.3.1 MTT Assay 193 9.3.2 Neutral Red Uptake Assay 193 9.3.3 Lactate Dehydrogenase Assay 194 9.4 In Vitro Models for Liver Toxicity 194 9.5 In Vitro Models for Nephrotoxicity Studies 194 9.6 In Vitro Model for Dermal Toxicity Testing 195 9.7 Mutagenicity Testing In Vitro 195 9.7.1 Bacterial Cell System 196 9.8 Reproductive and Teratogenicity Studies In Vitro 196 9.8.1 H295R Steroidogenesis Assay 197 9.8.2 Embryonic Stem Cell Test 197 9.8.3 Whole Rat Embryo Cultures 197 9.9 In Vivo Toxicity Testing of Natural Products 198 9.9.1 Acute Toxicity Testing 198 9.9.2 Subchronic Toxicity Testing 200 9.9.3 Chronic Toxicity Testing 201 9.9.4 Dermal and Ocular Toxicity 203 9.9.5 Toxicity Testing for Fertility and Reproduction 204 9.9.6 Combined Repeated Dose Toxicity Study with Reproduction/Developmental Testing 206 9.9.7 In Vivo Carcinogenicity Testing 207 9.10 Conclusion 208 References 208 10 Quality Control for the Safety of Natural Products 213Tadele Mekuriya Yadesa, Patrick Engeu Ogwang, and Casim Umba Tolo 10.1 Introduction 214 10.2 Quality Assurance of Herbal Products 215 10.3 Methods of Quality Control for Herbal Products 216 10.3.1 DNA-Based Technologies 216 10.3.2 Good Practice Guidelines 216 10.3.3 Chemoprofiling 217 10.3.4 Toxicology 217 10.3.5 Monographs and Pharmacopeias 217 10.3.6 Preclinical Evidence of Safety and Efficacy 217 10.3.7 Systems Biology 218 10.3.8 Animal Experimentation 218 10.3.9 Clinical Evidence of Safety and Efficacy 218 10.4 WHO Guidelines for Quality Standardization of Herbal Formulations 219 10.4.1 Quality Control of Crude Material 219 10.4.2 Identity of Plant Material 219 10.4.3 Safety Assessment and Documentation 220 10.5 Concept of Validation in Herbal Products 220 10.6 Challenges Related to Quality Control and Monitoring the Safety of Herbal Products 221 References 222 11 Secondary Metabolites and Toxins of Microbial Origin for the Treatment of Diseases 225Dharmandra Baria, Umang Shah, Chukwuebuka Egbuna, and Andrew G. Mtewa 11.1 Introduction 226 11.2 Antimicrobial Agents from Microbial Sources 227 11.3 Antifungal Agents from Microbial Sources 229 11.4 Anticancer Agents from Microbial Sources 230 11.5 Hypocholesterolemic Agents from Microbial Sources 235 11.6 Immunosuppressants from Microbial Sources 237 11.7 Enzyme Inhibitors from Microbial Sources 239 11.8 Antiparasitic Agents from Microbial Sources 240 11.9 Recent Advances in Drug Discovery from Microbial Sources 241 References 243 12 Development of Phyto-Antidotes Against Adverse Chemical Agents 249Roman Lysiuk, Petro Oliynyk, Halyna Antonyak, and Dmytro Voronenko 12.1 Introduction 249 12.2 Heavy Metals and their Effects on the Body 251 12.3 Detoxification Properties of Biologically Active Substances of Plant-Based Foods 253 12.3.1 Pectins 253 12.3.2 Phytin 254 12.3.3 Betalains 255 12.3.4 Phytochelatins 256 12.3.5 Ellagic Acid 257 12.3.6 Miscellaneous 258 12.4 Current State of Clinical Application of Phyto-Antidotes 259 12.5 Further Prospects in the Search for Promising Phyto-Antidotes 260 12.6 Conclusions 261 References 262 13 Nanoformulated Herbal Drug Delivery as Efficient Antidotes Against Systemic Poisons 269Prabir Kumar Kulabhusan, Shailaja Agrawal, Jaison Jeevanandam, and Michael K. Danquah 13.1 Introduction 269 13.2 Herbal Phytochemicals as Antidotes for Systemic Poisons 271 13.2.1 Herbal Phytochemicals as Antidotes for Heavy Metal Poisoning 272 13.2.2 Herbal Phytochemicals as Antidotes for Snake Venom Poisoning 275 13.3 Nanoformulated Herbal Phytochemicals as Antidotes 276 13.3.1 Inorganic Nanoparticles 278 13.3.2 Micelles and Liposomes 279 13.3.3 Polymeric Nanoparticles 281 13.4 Mechanism of Nanoformulated Herbal Phytochemicals against Systemic Poisoning 281 13.5 Future Perspectives 283 13.6 Conclusion 285 References 285 14 Phytochemical-Based Nanoparticles as Foes and Friends 295Charles Oluwaseun Adetunji, Oluwaseyi Olaniyan, Juliana Bunmi Adetunji, and Itoan Roli 14.1 Introduction 295 14.2 Phytochemicals Used in the Synthesis of Nanoparticles 297 14.3 Anti-Inflammatory Effects of Nanoparticles 297 14.4 Wound-Healing Effects of Nanoparticles 299 14.5 Antiparasitic, Antifungal, and Antibacterial Activities of Nanoparticles 300 14.6 Neuroprotective Effects of Nanoparticles 304 14.7 Cardioprotective Effects of Nanoparticles 307 14.8 Anticancer Effects of Nanoparticles 308 14.9 Advantages of Nanoparticles 311 14.10 Disadvantages of Nanoparticles 311 14.11 Conclusion and Future Directions 312 References 313 15 Application of Metabolomics in Emergency Phytochemical Poisoning and Remediation 323Mohamed A. Salem, Ahmed Zayed, and Shahira M. Ezzat 15.1 Introduction 324 15.2 Traditional Use of Medicinal Plants 325 15.3 Natural Products: Safety and Toxicity 328 15.3.1 Safety 328 15.3.2 Toxicity and Natural Killers 329 15.4 Biological Systems in Phytochemical Poisoning and Remediation 330 15.5 Metabolomics: An Important Functional Genomics Tool 332 15.5.1 Essential Components of a Metabolomics Workflow 333 15.5.2 Sample Preparation 334 15.5.3 Analytical Methods in Metabolomics 334 15.5.4 Metabolite Identification 335 15.5.5 Data Processing and Analysis 335 15.5.6 Pathway Analysis 335 15.6 Assessment of Toxicity of Herbal Medicines Using Metabolomics 335 15.7 Application of Metabolomics in Emergency Phytochemical Poisoning and Remediation 336 15.7.1 Hepatotoxicity of Triptolide 337 15.7.2 Hepatotoxicity of Noscapine 337 15.8 Conclusion 338 References 338 16 Methods for the Detection and Identification of Phytotoxins 349Senyo Botchie and Andrew G. Mtewa 16.1 Introduction 350 16.2 Phytotoxins 350 16.2.1 Importance of Toxins 351 16.3 Methods Generally Used for Phytotoxin Detection 352 16.3.1 Biological Method Review of Detecting Phytotoxins 352 16.3.2 Chemical and Microbiological Reagents 352 16.4 Protease Inhibition Detection Protocol 354 16.4.1 Exposure of the Protease Detection Plate to a Protease Inhibitor or Bacterial Growth (Step 1) 354 16.4.2 Exposure to a Protease-Containing Solution (Step 2) 355 16.4.3 Detecting Zones of Protease Inhibition (Step 3) 355 16.5 Isolation of Phytotoxins from Microorganisms 355 16.5.1 Detection of Phytotoxins Isolated from Fungi 356 16.5.2 Purification of the Extracted Phytotoxins 356 16.6 Conclusion 356 References 357 17 Categorization, Management, and Regulation of Potentially Weaponizable Toxic Plants 359Muhammad Akram and Rabia Zahid 17.1 Introduction 359 17.2 Management of Weaponized Natural Food Agents 360 17.3 Techniques Used for Extraction, Segregation, and Decontamination of Phytochemicals 361 17.3.1 Solvent-Based Extraction of Phenolic Compounds 361 17.3.2 Microwave-Associated Extraction 361 17.3.3 Ultrasound-Assisted Extraction 362 17.4 Techniques for Identification of Bioactive Compounds 362 17.4.1 Ultraviolet–Visible Spectroscopy 362 17.4.2 Infrared Spectroscopy 363 17.4.3 Nuclear Magnetic Resonance Spectroscopy 363 17.4.4 Mass Spectrometry 363 17.5 Types of Natural Phytotoxins 363 17.5.1 Aquatic Biotoxins 363 17.5.2 Glycosides 364 17.5.3 Other Common Phytotoxins 364 17.6 Conclusion 365 References 365 18 In Silico Modeling as a Tool to Predict and Characterize Plant Toxicity 367Charles Oluwaseun Adetunji, William Peter Mitembo, Chukwuebuka Egbuna, and G.M. Narasimha Rao 18.1 Introduction 368 18.2 Components of In Silico Toxicity Methods 368 18.2.1 Databases 369 18.2.2 Molecular Descriptors 369 18.2.3 Toxicity Models and Modeling Software 369 18.2.4 Simulation Packages 369 18.3 Modeling Methods 371 18.4 Structural Alerts/Rule Based 371 18.5 Statistical Structure-Based Activity Relationship Models 373 18.5.1 Read-Across 373 18.6 Conclusion 374 References 375 Index 379

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Book SynopsisVeterinary Microbiology Comprehensive reference work on the bacterial, fungal, and viral pathogens that cause animal diseases Veterinary Microbiology, Fourth Edition presents comprehensive information based on the most recent research, diagnostic, and clinical publications for bacterial, fungal, and viral animal diseases. The information provided is intended to be most relevant for veterinary students and practitioners. The text is supported throughout by high-quality and full-color images to aid learning. A companion website offers chapter content, supplemental information, and figures from the book in PowerPoint format. Sample topics discussed within the book include: Pathogenic bacteriology: includes major classifications and genera of bacteria associated with veterinary infectious disease Pathogenic mycology: dermatophytes, agents of subcutaneous mycoses, and agents of systemic mycoses Pathogenic virology: includes RNA and DTable of ContentsList of Contributors xii Acknowledgments xviii Preface xix About the Companion Website xx Part I Introduction 1 1 Microbial Infections of Animals 3D. Scott McVey, Melissa Kennedy, and Charles Czuprynski 2 Basic Bacteriology 11Tiruvoor G. Nagaraja 3 Basic Mycology 29Charles Czuprynski and M.M. Chengappa 4 Basic Virology 35Mohamed A. Abouelkhair and Melissa Kennedy Part II Bacteriology 41 5 Family Enterobacteriaceae 43Rodney A. Moxley 6 Enterobacteriaceae: Escherichia 56Rodney A. Moxley 7 Enterobacteriaceae: Salmonella 75Rodney A. Moxley 8 Family Yersiniaceae 88Rodney A. Moxley 9 Enterobacteriaceae: Shigella 100Rodney A. Moxley 10 Pasteurellaceae: Avibacterium, Bibersteinia, Mannheimia, and Pasteurella 108William B. Crosby and Amelia R. Woolums 11 Pasteurellaceae: Actinobacillus 118Bradley W. Fenwick and Andrew N. Rycroft 12 Pasteurellaceae: Glaesserella, Haemophilus, and Histophilus 129Amelia R. Woolums 13 Bordetella 136Bradley W. Fenwick 14 Brucella 151S.C. Olsen and P. Boggiatto 15 Burkholderia mallei and Burkholderia pseudomallei 162Sanjeev Narayanan 16 Francisella tularensis 168Marilynn A. Larson and Peter C. Iwen 17 Moraxella 176John Dustin Loy and Gabriele Maier 18 Pseudomonas 183Deepti Pillai 19 Taylorella 187Megan E. Jacob 20 Spirilla I: Borrelia 192Roman R. Ganta 21 Spiral-Curved Organisms II: Brachyspira and Lawsonia 196Gerald E. Duhamel 22 Spiral-Curved Organisms III: Campylobacter and Arcobacter 207Gerald E. Duhamel 23 Spirilla IV: Helicobacter– the Spiral Microorganisms of the Gastrointestinal Tract and Liver 219Megan E. Jacob 24 Spirochetes V: Leptospira 225Sreekumari Rajeev 25 Staphylococcus 231George C. Stewart 26 Streptococcus and Enterococcus 240George C. Stewart 27 Trueperella 252Tiruvoor G. Nagaraja 28 Bacillus 257George C. Stewart 29 Corynebacterium 265Tiruvoor G. Nagaraja 30 Erysipelothrix 273Timothy Frana and Axel Neubauer 31 Listeria 280Sanjeev Narayanan 32 Rhodococcus 286Seth P. Harris and Joshua Daniels 33 Gram-Negative, Non-Spore-Forming Anaerobes 294Tiruvoor G. Nagaraja 34 Clostridium 309Iman Mehdizadeh Gohari and John F. Prescott 35 Filamentous Bacteria: Actinomyces, Nocardia, Dermatophilus, and Streptobacillus 335Megan E. Jacob 36 Mycobacteria 345Raul G. Barletta and David J. Steffen 37 Chlamydiaceae: Chlamydia 360Roman R. Ganta 38 Mollicutes 364Bonto Faburay and D. Scott McVey 39 Rickettsiaceae and Coxiellaceae: Rickettsia and Coxiella 377Roman R. Ganta 40 Anaplasmataceae: Anaplasma 381Roman R. Ganta 41 Anaplasmataceae: Ehrlichia and Neorickettsia 386Roman R. Ganta 42 Bartonellaceae 392Kathryn E. Reif Part III Fungi 405 43 Yeasts: Cryptococcus, Malassezia, and Candida 407Lisa M. Pohlman and M.M. Chengappa 44 Dermatophytes 418M.M. Chengappa and Lisa M. Pohlman 45 Agents of Subcutaneous Mycoses 425Lisa M. Pohlman and M.M. Chengappa 46 Agents of Systemic Mycoses 433Lisa M. Pohlman and M.M. Chengappa Part IV Viruses 449 47 Parvoviridae 451Rebecca P. Wilkes 48 Circoviridae 469Pablo Piñeyro and Sheela Ramamoorthy 49 Asfarviridae and Iridoviridae 478Melissa Kennedy, Gustavo Delhon, D. Scott McVey, Hiep Vu, and Manuel Borca 50 Papillomaviridae and Polyomaviridae 484Mohamed A. Abouelkhair and Melissa Kennedy 51 Adenoviridae 489Yunjeong Kim and Kyeong-Ok Chang 52 Herpesviridae 496Rebecca P. Wilkes and Jobin Kattoor 53 Poxviridae 522Gustavo Delhon 54 Picornaviridae 533Luis L. Rodriguez and Jonathan Arzt 55 Caliciviridae 543Mohamed A. Abouelkhair and Melissa Kennedy 56 Togaviridae and Flaviviridae 552Christopher C.L. Chase 57 Orthomyxoviridae 573Wenjun Ma 58 Bunyavirales 589William C. Wilson, Dana Mitzel, Lee W. Cohnstaedt, Leela Noronha, Barbara S. Drolet, and D. Scott McVey 59 Paramyxoviridae, Pneumoviridae, Filoviridae, and Bornaviridae 596Stefan Niewiesk and Michael Oglesbee 60 Rhabdoviridae 609Susan M. Moore and D. Scott McVey 61 Coronaviridae and Tobaniviridae 622Udeni B.R. Balasuriya, Yun Young Go, and Mariano Carossino 62 Arteriviridae and Roniviridae 659Udeni B. R. Balasuriya, Mariano Carossino, and Yun Young Go 63 Reoviridae 679Barbara S. Drolet, Bethany L. McGregor, Lee W. Cohnstaedt, William C. Wilson, and D. Scott McVey 64 Birnaviridae 693Melissa Kennedy and Donald L. Reynolds 65 Retroviridae 698Jean-Pierre Frossard 66 Transmissible Spongiform Encephalopathies 728Jürgen A. Richt and Nicholas Haley Part V Control of Infectious Diseases 743 67 Immune Responses to Infectious Agents 745Laurel J. Gershwin 68 Laboratory Diagnosis 760D. Scott McVey, Bruce Brodersen, Duan Loy, and John Dustin Loy 69 Antimicrobial Chemotherapy and Antimicrobial Resistance 771Michael D. Apley 70 Vaccines 803D. Scott McVey, Jishu Shi, and Donald Reynolds 71 Disinfection and Sterilization 813John Dustin Loy, D. Scott McVey, and M.M. Chengappa 72 Epidemiology of Infectious Diseases 818Natalia Cernicchiaro, Ana R.S. Oliveira, and Lee W. Cohnstaedt Index 829

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Book SynopsisTable of ContentsList of Contributors x Preface xvii About the Editor xix Acknowledgments xxi 1 An Overview of Genome-Engineering Methods 1Sushmita, Gurminder Kaur, Santosh Kumar Upadhyay, and Praveen Chandra Verma 2 Distribution of Nutritional and Mineral Components in Important Crop Plants 22Katarina Vogel-Mikuš, Paula Pongrac, Ivan Kreft, Primož Pelicon, Primož Vavpetič, Boštjan Jenčič, Johannes Teun van Elteren, Peter Kump, Sudhir P. Singh, and Marjana Regvar 3 Application of Genome Engineering Methods for Quality Improvement in Important Crops 43Sajid Fiaz, Sher Aslam Khan, Galal Bakr Anis, Habib Ali, Mohsin Ali, Kazim Ali, Mehmood Ali Noor, Sibtain Ahmad, and Bilal Ahmad Asad 4 Genome Engineering for Enriching Fe and Zn in Rice Grain and Increasing Micronutrient Bioavailability 69Conrado Dueñas, Jr., Gela Myan B. Mota, Norman Oliva, and Inez H. Slamet-Loedin 5 Development of Carotenoids Rich Grains by Genome Engineering 83Vikrant Gautam, Gurwinder Singh Rana, Pankaj Kumar, and Santosh Watpade 6 CRISPR-Cas9 System for Agriculture Crop Improvement 97Ashish Sharma, Poorwa Kamal Badola, and Prabodh Kumar Trivedi 7 Contribution of Crop Biofortification in Mitigating Vitamin Deficiency Globally 112Siddhant Chaturvedi, Roni Chaudhary, and Siddharth Tiwari 8 Genome Editing Approaches for Trait Improvement in the Hairy Root Cultures of the Economically Important Plants 131Pravin Prakash, Rakesh Srivastava, Ajay Kumar, Gurminder Kaur, and Praveen Chandra Verma 9 Phytic Acid Reduction in Cereal Grains by Genome Engineering: Potential Targets to Achieve Low Phytate Wheat 146Ajay K. Pandey, Sipla Aggarwal, Varsha Meena, and Anil Kumar 10 Genome Engineering for Nutritional Improvement in Pulses 157Chirag Uppal, Ajinder Kaur, and Chhaya Sharma 11 The Survey of Genetic Engineering Approaches for Oil/Fatty Acid Content Improvement in Oilseed Crops 181Kaushal Kumar Bhati, Riyazuddin Riyazuddin, Ashish Kumar Pathak, and Anuradha Singh 12 Genome-Editing Mediated Improvement of Biotic Tolerance in Crop Plants 199Krishan Mohan Rai and Harpal Singh 13 Genome Engineering and Essential Mineral Enrichment of Crops 210Erum Shoeb, Uzma Badar, Srividhya Venkataraman, Ghyda Murad Hashim, and Kathleen Hefferon 14 Genome Editing to Develop Disease Resistance in Crops 224Kashaf Zafar, Azka Noureen, Muhammad Jawad Akbar Awan, Naveed Anjum, Muhammad Qasim Aslam, Muhammad Zuhaib Khan, Imran Amin, and Shahid Mansoor 15 Biotechnological Approaches for Nutritional Improvement in Potato (Solanum tuberosum L.) 253Chandrama Prakash Upadhyaya and Deepak Singh Bagri 16 Genome Engineering Strategies for Quality Improvement in Tomato 281Tian Wang, Hongyan Zhang, and Hongliang Zhu 17 Genome Editing for Biofortification of Rice: Current Implications and Future Aspects 297Suchismita Roy and Praveen Soni 18 Genome Editing for Improving Abiotic Stress Tolerance in Rice 314Shweta Roy, Nirbhay Kumar Kushwaha, Hasthi Ram, and Praveen Soni 19 Role of Genome Engineering for the Development of Resistant Starch-Rich, Allergen-Free and Processing Quality Improved Cereal Crops 333Anuradha Singh, Amit Yadav, Joy K. Roy, and Kaushal Kumar Bhati 20 Engineering of Plant Metabolic Pathway for Nutritional Improvement: Recent Advances and Challenges 351Sameer Dixit, Akanchha Shukla, Vinayak Singh, and Santosh Kumar Upadhyay 21 Genome Engineering for Food Security 380Sajid Fiaz, Sher Aslam Khan, Mehmood Ali Noor, Afifa Younas, Habib Ali, Kazim Ali, Mahmoud Mohamed Gaballah, and Galal Bakr Anis Index 391

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Book SynopsisTable of ContentsPreface ix Part I Beyond the Mainland 1 1 Introduction 3 2 History of Island Studies 9 3 Island Faunas: Types and Origins 18 Types of Islands 19 Dispersals to Islands 21 The Candidate Species 29 Composition of Island Faunas 34 Part II The Islands and Their Faunas 41 4 Cyprus 43 Geology and Palaeogeography 44 Historical Palaeontology 44 Biozones and Faunal Units 47 Pleistocene 48 Peculiarities and Evolution of Endemic Mammals 50 5 Crete 56 Geology and Palaeogeography 57 Historical Palaeontology 57 Biozones and Faunal Units 61 Peculiarities and Evolution of Endemic Mammals 66 6 Gargano 82 Geology and Palaeogeography 83 Historical Palaeontology 85 Biozones and Faunal Units 88 Evolution and Peculiarities of Endemic Mammals 93 7 Sicily 110 Geology and Geography 111 Historical Palaeontology 111 Biozones and Faunal Units 114 Peculiarities and Evolution of Endemic Mammals 120 8 Malta 128 Geology and Palaeogeography 129 Historical Palaeontology 129 Biozones and Faunal Units 133 Peculiarities and Evolution of Endemic Mammals 137 9 Sardinia and Corsica 142 Geology and Palaeogeography 143 Historical Palaeontology 144 Biozones and Faunal Units 151 Peculiarities and Evolution of Endemic Mammals 160 10 The Balearic Islands 178 Geology and Palaeogeography 179 Historical Palaeontology 180 Biozones and Faunal Units 182 Peculiarities and Evolution of Endemic Lineages 187 11 Madagascar 200 Geology and Palaeogeography 201 Historical Palaeontology 205 Biozones and Faunal Units 210 12 Java 236 Geology and Palaeogeography 237 Historical Palaeontology 238 Biozones and Faunal Units 245 Peculiarities and Evolution of Endemic Mammals 258 13 Flores 269 Geology and Palaeogeography 270 Historical Palaeontology 271 Biozones and Faunal Units 275 Peculiarities and Evolution of Endemic Mammals 282 14 Sulawesi 297 Geology and Palaeogeography 298 Historical Palaeontology 300 Biozones and Faunal Units 302 Peculiarities and Evolution of Endemic Mammals 306 15 The Philippines 312 Geology and Palaeogeography 313 Historical Palaeontology 315 Biozones and Faunal Units 318 Peculiarities and Evolution of Endemic Mammals 323 16 Japan: Honshu, Shikoku, and Kyushu 331 Geology and Palaeogeography 332 Historical Palaeontology 334 Biozones and Faunal Units 337 Peculiarities and Evolution of Endemic Mammals 345 17 Japan: The Southern and Central Ryukyu Islands 354 Geology and Palaeogeography 355 Historical Palaeontology 358 Biozones and Faunal Units 360 Peculiarities and Evolution of Endemic Mammals 367 18 The Californian Channel Islands 377 Geology and Palaeogeography 378 Historical Palaeontology 379 Biozones and Faunal Units 380 Peculiarities and Evolution of Endemic Mammals 381 19 The Greater Antilles 388 Geology and Palaeogeography 389 Historical Palaeontology 392 Peculiarities and Evolution of Endemic Mammals 399 20 The Lesser Antilles 425 Geology and Palaeogeography 426 Historical Palaeontology 427 Peculiarities and Evolution of Endemic Mammals 429 Part III Species and Processes 435 21 An Overview of Endemic Species 437 Proboscidea: Mammoths, Elephants, and Stegodons 438 Primates 439 Sloths 440 Lagomorpha: Rabbits, Hares, and Pikas 441 Rodentia: Rats, Dormice, Hamsters, and Caviomorphs 443 Insect-eaters: Shrews, Moonrats, Solenodons, Tenrecs, and Allies 445 Ruminantia: Deer and Bovids 448 Hippopotamidae: Hippos 449 Suidae: Pigs 449 Carnivora: Dogs, Hyenas, Otters, and Martens 449 Carnivora: Felids 451 22 Speciation Processes in Island Environments 455 What Influences Speciation? 456 Types of Speciation on Islands 465 23 The Island Rule: Dwarfism and Gigantism 477 The Island Rule: A Graded Trend 478 The Island Rule in Detail 488 24 Parallel Patterns and Trends 503 Evolutionary Changes in the Teeth 506 Evolutionary Skeletal Changes 512 Evolutionary Brain Changes 515 Evolutionary Changes in Life History 519 25 Extinction of Island Mammals 527 The Island Prison 529 The Burden of Body Mass 529 Extinction Debt 530 Natural Disasters 531 Tectonics and Sea Level 531 Impact of Exotic Competitors 533 Impact of Exotic Predators 534 Genetic Disorders and Infections 536 Habitat Loss 537 Hunting to Extinction 539 Index 547

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