Note: Cover -- Title Page -- Copyright -- Contents -- List of Contributors -- Chapter 1 Introduction -- 1.1 Introduction -- 1.2 Enzyme Technology -- 1.3 Microbial Process Engineering -- 1.3.1 Bioreactor Development -- 1.3.2 Measurement and Monitoring -- 1.3.3 Modeling and Control -- 1.3.4 Solid-State Fermentation -- 1.4 Plant Cell Culture -- 1.5 Animal Cell Culture -- 1.6 Environmental Bioengineering -- 1.7 Composition of the Volume -- References -- Part I Enzyme Technology -- Chapter 2 Enzyme Technology: History and Current Trends -- 2.1 The Early Period up to 1890 -- 2.1.1 Observations and Empirical Results -- 2.1.2 Theoretical Approaches -- 2.2 The Period from 1890 to 1940 -- 2.2.1 Scientific Progress -- 2.2.2 Theoretical Developments -- 2.2.3 Technological Developments -- 2.3 A New Biocatalyst Concept - Immobilized Enzymes -- 2.3.1 Fundamental Research -- 2.3.2 Examples of Industrial Development: The Case of Penicillin Amidase (PA) - Penicillin Hydrolysis and Derivatives -- 2.3.3 Examples of Industrial Development: The Case of Sugar Isomerization -- 2.4 Expanding Enzyme Application after the 1950s -- 2.5 Recombinant Technology - A New Era in Biocatalysis and Enzyme Technology -- 2.5.1 New Enzymes - A Key to Genetic Engineering -- 2.5.2 Analytical and Diagnostic Enzymes -- 2.5.3 Expanding Market of Industrial Enzymes -- 2.6 Current Strategies for Biocatalyst Search and Tailor Design -- 2.6.1 Enzyme Discovery from the Metagenome or Protein Databases -- 2.6.2 Protein Engineering of Enzymes -- 2.6.3 Enzyme Cascade Reactions -- 2.6.4 Metabolic Engineering -- 2.7 Summary and Conclusions -- Acknowledgment -- Abbreviations -- References -- Chapter 3 Molecular Engineering of Enzymes -- 3.1 Introduction -- 3.2 Protein Engineering: An Expanding Toolbox -- 3.2.1 From Sequence to Fold and Function. , 3.2.2 Improving Enzyme Properties by Rational Design and Directed Evolution -- 3.2.3 Designing Smart Libraries -- 3.2.4 In Vivo Continuous Directed Evolution -- 3.2.5 Diversification of Enzyme Functionalities by Recombination -- 3.3 High-Throughput Screening Systems -- 3.4 Engineered Enzymes for Improved Stability and Asymmetric Catalysis -- 3.4.1 Stability -- 3.4.1.1 Cellulases -- 3.4.1.2 Lipases -- 3.4.2 Asymmetric Biocatalysis -- 3.5 De Novo Design of Catalysts: Novel Activities within Common Scaffolds -- 3.6 Conclusions -- References -- Chapter 4 Biocatalytic Process Development -- 4.1 A Structured Approach to Biocatalytic Process Development -- 4.2 Process Metrics -- 4.2.1 Reaction Yield -- 4.2.2 Productivity -- 4.2.3 Biocatalyst Yield -- 4.2.4 Product Concentration -- 4.3 Technologies for Implementation of Biocatalytic Processes -- 4.3.1 Biocatalyst Engineering -- 4.3.1.1 Protein and Genetic Engineering -- 4.3.1.2 Biocatalyst Immobilization -- 4.3.2 Reaction Engineering -- 4.3.2.1 Reactant Supply -- 4.3.2.2 Product Removal -- 4.3.2.3 Two-Phase Systems -- 4.4 Industrial Development Examples -- 4.4.1 Development of a Biocatalytic Route to Atorvastatin (Developed by Codexis Inc., USA) -- 4.4.2 Development of a Biocatalytic Route to Sitagliptin (Developed by Codexis Inc., USA and Merck and Co., USA) -- 4.5 Future Outlook -- 4.6 Concluding Remarks -- References -- Chapter 5 Development of Enzymatic Reactions in Miniaturized Reactors -- 5.1 Introduction -- 5.2 Fundamental Techniques for Enzyme Immobilization -- 5.2.1 Enzyme Immobilization by Adsorption -- 5.2.1.1 Monoliths and Particles -- 5.2.1.2 Synthetic Polymer Membranes and Papers -- 5.2.1.3 Adsorption to Channel Walls -- 5.2.2 Enzyme Immobilization by Entrapment -- 5.2.2.1 Silica-Based Matrices -- 5.2.2.2 Non-Silica-based Matrices -- 5.2.3 Enzyme Immobilization by Affinity Labeling. , 5.2.3.1 His-Tag/Ni-NTA System -- 5.2.3.2 GST-Tag/Glutathione System -- 5.2.3.3 Avidin/Biotin System -- 5.2.3.4 DNA Hybridization System -- 5.2.3.5 Other Techniques Using Nucleotides for Enzyme Immobilization -- 5.2.4 Enzyme Immobilization by Covalent Linking -- 5.2.4.1 Immobilization to Solid Supports -- 5.2.4.2 Direct Immobilization to a Channel Wall -- 5.2.4.3 Enzyme Polymerization -- 5.2.5 Enzyme Immobilization by Other Techniques Using Organisms -- 5.2.6 Application of Immobilized Enzymes in Microfluidics -- 5.3 Novel Techniques for Enzyme Immobilization -- 5.3.1 Polyketone Polymer: Enzyme Immobilization by Hydrogen Bonds -- 5.3.2 Thermoresponsive Hydrogels -- 5.3.3 Immobilization Methods Using Azide Chemistry -- 5.3.3.1 Staudinger Ligation -- 5.3.3.2 Click Chemistry -- 5.3.4 Graphene-Based Nanomaterial as an Immobilization Support -- 5.3.5 Immobilization Methods Using Proteins Modified with Solid-Support-Binding Modules -- 5.4 Conclusions and Future Perspectives -- Abbreviations -- References -- Part II Microbial Process Engineering -- Chapter 6 Bioreactor Development and Process Analytical Technology -- 6.1 Introduction -- 6.2 Bioreactor Development -- 6.2.1 Parallel Bioreactor Systems for High-Throughput Processing -- 6.2.1.1 Microtiter Plate Systems -- 6.2.1.2 Stirred-Tank Reactor Systems -- 6.2.1.3 Microfluidic Microbioreactor Systems -- 6.2.1.4 Bubble Column Systems -- 6.2.1.5 Comparison of Various Parallel-Use Micro-/Mini-Bioreactor System -- 6.2.2 Single-Use Disposable Bioreactor Systems -- 6.2.2.1 Features of Single-Use Bioreactors -- 6.2.2.2 Sensors and Monitoring -- 6.2.2.3 Single-Use Bioreactors in Practical Use -- 6.3 Monitoring and Process Analytical Technology -- 6.3.1 Monitoring and State Recognition -- 6.3.1.1 Sensors for Monitoring Bioprocesses -- 6.3.1.2 Spectrometry -- 6.3.2 Process Analytical Technology (PAT). , 6.3.2.1 PAT Tools -- 6.3.2.2 PAT Implementations -- 6.4 Conclusion -- Abbreviations -- References -- Chapter 7 Omics-Integrated Approach for Metabolic State Analysis of Microbial Processes -- 7.1 General Introduction -- 7.2 Transcriptome Analysis of Microbial Status in Bioprocesses -- 7.2.1 Introduction -- 7.2.2 Microbial Response to Stress Environments and Identification of Genes Conferring Stress Tolerance in Bioprocesses -- 7.2.3 Transcriptome Analysis of the Ethanol-Stress-Tolerant Strain Obtained by Evolution Engineering -- 7.3 Analysis of Metabolic State Based on Simulation in a Genome-Scale Model -- 7.3.1 Introduction -- 7.3.2 Reconstruction of GSMs and Simulation by FBA -- 7.3.3 Using Prediction of Metabolic State for Design of Metabolic Modification -- 7.4 13C-Based Metabolic Flux Analysis of Microbial Processes -- 7.4.1 Introduction -- 7.4.2 Principles of 13C-MFA -- 7.4.3 Examples of 13C-MFA in Microbial Processes -- 7.5 Comprehensive Phenotypic Analysis of Genes Associated with Stress Tolerance -- 7.5.1 Introduction -- 7.5.2 Development of a High-Throughput Culture System -- 7.5.3 Calculation of Specific Growth Rate -- 7.5.4 Results of Comprehensive Analysis of Yeast Cells Under Conditions of High Osmotic Pressure and High Ethanol Concentration -- 7.5.5 Identification of Genes Conferring Desirable Phenotypes Based on Integration with the Microarray Analysis Method -- 7.6 Multi-Omics Analysis and Data Integration -- 7.7 Future Aspects for Developing the Field -- Acknowledgments -- References -- Chapter 8 Control of Microbial Processes -- 8.1 Introduction -- 8.2 Monitoring -- 8.2.1 Online Measurements -- 8.2.2 Filtering, Online Estimation, and Software Sensors -- 8.2.3 Algorithm of Extended Kalman Filter and Its Application to Online Estimation of Specific Rates -- 8.3 Bioprocess Control -- 8.3.1 Control of Fed-Batch Culture. , 8.3.2 Online Optimization of Continuous Cultures -- 8.3.3 Cascade Control for Mixed Cultures -- 8.3.4 Supervision and Fault Detection -- 8.4 Recent Trends in Monitoring and Control Technologies -- 8.4.1 Sensor Technologies and Analytical Methods -- 8.4.2 Control Technologies -- 8.5 Concluding Remarks -- Abbreviations -- References -- Part III Plant Cell Culture and Engineering -- Chapter 9 Contained Molecular Farming Using Plant Cell and Tissue Cultures -- 9.1 Molecular Farming - Whole Plants and Cell/Tissue Cultures -- 9.2 Plant Cell and Tissue Culture Platforms -- 9.2.1 Cell Suspension Cultures -- 9.2.2 Tissue Cultures -- 9.2.3 Light-Dependent Expression Platforms -- 9.3 Comparison of Whole Plants and In Vitro Culture Platforms -- 9.4 Technical Advances on the Road to Commercialization -- 9.4.1 Improving the Quantity of Recombinant Proteins Produced in Cell Suspension Cultures -- 9.4.2 Improving the Quality and Consistency of Recombinant Proteins Produced in Cell Suspension Cultures -- 9.5 Regulatory and Industry Barriers on the Road to Commercialization -- 9.6 Outlook -- Acknowledgments -- References -- Chapter 10 Bioprocess Engineering of Plant Cell Suspension Cultures -- 10.1 Introduction -- 10.2 Culture Development and Maintenance -- 10.3 Choice of Culture System -- 10.4 Engineering Considerations -- 10.4.1 Cell Growth and Morphology -- 10.4.2 Gas Requirements -- 10.4.3 Aggregation -- 10.4.4 Medium Rheology -- 10.4.5 Shear Sensitivity -- 10.5 Bioprocess Parameters -- 10.5.1 Medium Composition and Optimization -- 10.5.2 Temperature and pH -- 10.5.3 Agitation -- 10.5.4 Aeration -- 10.6 Operational Modes -- 10.7 Bioreactors for Plant Cell Suspensions -- 10.7.1 Conventional Bioreactors -- 10.7.1.1 Stirred-Tank Reactors -- 10.7.1.2 Pneumatic Bioreactors -- 10.7.2 Disposable Bioreactors -- 10.8 Downstream Processing. , 10.8.1 Specialized Metabolite Extraction and Purification.

Note: Cover -- Title Page -- Copyright -- Contents -- Foreword: Cyanobacteria Biotechnology -- Acknowledgments -- Part I Core Cyanobacteria Processes -- Chapter 1 Inorganic Carbon Assimilation in Cyanobacteria: Mechanisms, Regulation, and Engineering -- 1.1 Introduction - The Need for a Carbon‐Concentrating Mechanism -- 1.2 The Carbon‐Concentrating Mechanism (CCM) Among Cyanobacteria -- 1.2.1 Ci Uptake Proteins/Mechanisms -- 1.2.2 Carboxysome and RubisCO -- 1.3 Regulation of Ci Assimilation -- 1.3.1 Regulation of the CCM -- 1.3.2 Further Regulation of Carbon Assimilation -- 1.3.3 Metabolic Changes and Regulation During Ci Acclimation -- 1.3.4 Redox Regulation of Ci Assimilation -- 1.4 Engineering the Cyanobacterial CCM -- 1.5 Photorespiration -- 1.5.1 Cyanobacterial Photorespiration -- 1.5.2 Attempts to Engineer Photorespiration -- 1.6 Concluding Remarks -- Acknowledgments -- References -- Chapter 2 Electron Transport in Cyanobacteria and Its Potential in Bioproduction -- 2.1 Introduction -- 2.2 Electron Transport in a Bioenergetic Membrane -- 2.2.1 Linear Electron Transport -- 2.2.2 Cyclic Electron Transport -- 2.2.3 ATP Production from Linear and Cyclic Electron Transport -- 2.3 Respiratory Electron Transport -- 2.4 Role of Electron Sinks in Photoprotection -- 2.4.1 Terminal Oxidases -- 2.4.2 Hydrogenase and Flavodiiron Complexes -- 2.4.3 Carbon Fixation and Photorespiration -- 2.4.4 Extracellular Electron Export -- 2.5 Regulating Electron Flux into Different Pathways -- 2.5.1 Electron Flux Through the Plastoquinone Pool -- 2.5.2 Electron Flux Through Fdx -- 2.6 Spatial Organization of Electron Transport Complexes -- 2.7 Manipulating Electron Transport for Synthetic Biology Applications -- 2.7.1 Improving Growth of Cyanobacteria -- 2.7.2 Production of Electrical Power in BPVs -- 2.7.3 Hydrogen Production -- 2.7.4 Production of Industrial Compounds. , 2.8 Future Challenges in Cyanobacterial Electron Transport -- References -- Chapter 3 Optimizing the Spectral Fit Between Cyanobacteria and Solar Radiation in the Light of Sustainability Applications -- 3.1 Introduction -- 3.2 Molecular Basis and Efficiency of Oxygenic Photosynthesis -- 3.3 Fit Between the Spectrum of Solar Radiation and the Action Spectrum of Photosynthesis -- 3.4 Expansion of the PAR Region of Oxygenic Photosynthesis -- 3.5 Modulation and Optimization of the Transparency of Photobioreactors -- 3.6 Full Control of the Light Regime: LEDs Inside the PBR -- 3.7 Conclusions and Prospects -- References -- Part II Concepts in Metabolic Engineering -- Chapter 4 What We Can Learn from Measuring Metabolic Fluxes in Cyanobacteria -- 4.1 Central Carbon Metabolism in Cyanobacteria: An Overview and Renewed Pathway Knowledge -- 4.1.1 Glycolytic Routes Interwoven with the Calvin Cycle -- 4.1.2 Tricarboxylic Acid Cycling -- 4.2 Methodologies for Predicting and Quantifying Metabolic Fluxes in Cyanobacteria -- 4.2.1 Flux Balance Analysis and Genome‐Scale Reconstruction of Metabolic Network -- 4.2.2 13C‐Metabolic Flux Analysis -- 4.2.3 Thermodynamic Analysis and Kinetics Analysis -- 4.3 Cyanobacteria Fluxome in Response to Altered Nutrient Modes and Environmental Conditions -- 4.3.1 Autotrophic Fluxome -- 4.3.2 Photomixotrophic Fluxome -- 4.3.3 Heterotrophic Fluxome -- 4.3.4 Photoheterotrophic Fluxome -- 4.3.5 Diurnal Metabolite Oscillations -- 4.3.6 Nutrient States' Impact on Metabolic Flux -- 4.4 Metabolic Fluxes Redirected in Cyanobacteria for Biomanufacturing Purposes -- 4.4.1 Restructuring the TCA Cycle for Ethylene Production -- 4.4.2 Maximizing Flux in the Isoprenoid Pathway -- 4.4.2.1 Measuring Precursor Pool Size to Evaluate Potential Driving Forces for Isoprenoid Production -- 4.4.2.2 Balancing Intermediates for Increased Pathway Activity. , 4.4.2.3 Kinetic Flux Profiling to Detect Bottlenecks in the Pathway -- 4.5 Synopsis and Future Directions -- Acknowledgments -- References -- Chapter 5 Synthetic Biology in Cyanobacteria and Applications for Biotechnology -- 5.1 Introduction -- 5.2 Getting Genes into Cyanobacteria -- 5.2.1 Transformation -- 5.2.2 Expression from Episomal Plasmids -- 5.2.3 Delivery of Genes to the Chromosome -- 5.3 Basic Synthetic Control of Gene Expression in Cyanobacteria -- 5.3.1 Quantifying Transcription and Translation in Cyanobacteria -- 5.3.2 Controlling Transcription with Synthetic Promoters -- 5.3.2.1 Constitutive Promoters -- 5.3.2.2 Regulated Promoters that Are Sensitive to Added Compounds (Inducible) -- 5.3.2.3 CRISPR Interference for Transcriptional Repression -- 5.3.3 Controlling Translation -- 5.3.3.1 Ribosome Binding Sites (Cis‐Acting) -- 5.3.3.2 Riboswitches (Cis‐Acting) -- 5.3.3.3 Small RNAs (Trans‐Acting) -- 5.4 Exotic Signals for Controlling Expression -- 5.4.1 Oxygen -- 5.4.2 Light Color -- 5.4.3 Cell Density or Growth Phase -- 5.4.4 Engineering Regulators for Altered Sensing Properties: State of the Art -- 5.5 Advanced Regulation: The Near Future -- 5.5.1 Logic Gates and Timing Circuits -- 5.5.2 Orthogonal Transcription Systems -- 5.5.3 Synthetic Biology Solutions to Increase Stability -- 5.5.4 Synthetic Biology Solutions for Cell Separation and Product Recovery -- 5.6 Conclusions -- Acknowledgments -- References -- Chapter 6 Sink Engineering in Photosynthetic Microbes -- 6.1 Introduction -- 6.2 Source and Sink -- 6.3 Regulation of Sink Energy in Plants -- 6.3.1 Sucrose and Other Signaling Carbohydrates -- 6.3.2 Hexokinases -- 6.3.3 Sucrose Non‐fermenting Related Kinases -- 6.3.4 TOR Kinase -- 6.3.5 Engineered Pathways as Sinks in Photosynthetic Microbes -- 6.3.6 Sucrose -- 6.3.7 2,3‐Butanediol -- 6.3.8 Ethylene -- 6.3.9 Glycerol. , 6.3.10 Isobutanol -- 6.3.11 Isoprene -- 6.3.12 Limonene -- 6.3.13 P450, an Electron Sink -- 6.4 What Are Key Source/Sink Regulatory Hubs in Photosynthetic Microbes? -- 6.5 Concluding Remarks -- Acknowledgment -- References -- Chapter 7 Design Principles for Engineering Metabolic Pathways in Cyanobacteria -- 7.1 Introduction -- 7.2 Cofactor Optimization -- 7.2.1 Recruiting NADPH‐Dependent Enzymes Wherever Possible -- 7.2.2 Engineering NADH‐Specific Enzymes to Utilize NADPH -- 7.2.3 Increasing NADH Pool in Cyanobacteria Through Expression of Transhydrogenase -- 7.3 Incorporation of Thermodynamic Driving Force into Metabolic Pathway Design -- 7.3.1 ATP Driving Force in Metabolic Pathways -- 7.3.2 Increasing Substrate Pool Supports the Carbon Flux Toward Products -- 7.3.3 Product Removal Unblocks the Limitations of Product Titer -- 7.4 Development of Synthetic Pathways for Carbon Conserving Photorespiration and Enhanced Carbon Fixation -- 7.5 Summary and Future Perspective on Cyanobacterial Metabolic Engineering -- References -- Chapter 8 Engineering Cyanobacteria for Efficient Photosynthetic Production: Ethanol Case Study -- 8.1 Introduction -- 8.2 Pathway for Ethanol Synthesis in Cyanobacteria -- 8.2.1 Pyruvate Decarboxylase and Type II Alcohol Dehydrogenase -- 8.2.2 Selection of Better Enzymes in the Pdc-AdhII Pathway -- 8.2.3 Systematic Characterization of the PdcZM-Slr1192 Pathway -- 8.3 Selection of Optimal Cyanobacteria "Chassis," Strain for Ethanol Production -- 8.3.1 Synechococcus PCC 6803 and Synechococcus PCC 7942 -- 8.3.2 Synechococcus PCC 7002 -- 8.3.3 Anabaena PCC 7120 -- 8.3.4 Nonconventional Cyanobacteria Species -- 8.4 Metabolic Engineering Strategies Toward More Efficient and Stable Ethanol Production -- 8.4.1 Enhancing the Carbon Flux via Overexpression of Calvin Cycle Enzymes -- 8.4.2 Blocking Pathways that Are Competitive to Ethanol. , 8.4.3 Arresting Biomass Formation -- 8.4.4 Engineering Cofactor Supply -- 8.4.5 Engineering Strategies Guided by In Silico Simulation -- 8.4.6 Stabilizing Ethanol Synthesis Capacity in Cyanobacterial Cell Factories -- 8.5 Exploring the Response in Cyanobacteria to Ethanol -- 8.5.1 Response of Cyanobacterial Cells Toward Exogenous Added Ethanol -- 8.5.2 Response of Cyanobacteria to Endogenous Synthesized Ethanol -- 8.6 Metabolic Engineering Strategies to Facilitate Robust Cultivation Against Biocontaminants -- 8.6.1 Engineering Cyanobacteria Cell Factories to Adapt for Selective Environmental Stresses -- 8.6.2 Engineering Cyanobacteria Cell Factories to Utilize Uncommon Nutrients -- 8.7 Conclusions and Perspectives -- References -- Chapter 9 Engineering Cyanobacteria as Host Organisms for Production of Terpenes and Terpenoids -- 9.1 Terpenoids and Industrial Applications -- 9.2 Terpenoid Biosynthesis in Cyanobacteria -- 9.2.1 Methylerythritol‐4‐Phosphate Pathway -- 9.2.2 Formation of Terpene Backbones -- 9.3 Natural Occurrence and Physiological Roles of Terpenes and Terpenoids in Cyanobacteria -- 9.4 Engineering Cyanobacteria for Terpenoid Production -- 9.4.1 Metabolic Engineering -- 9.4.1.1 Terpene Synthases -- 9.4.1.2 Increasing Supply of Terpene Backbones -- 9.4.1.3 Engineering the Native MEP Pathway -- 9.4.1.4 Implementing the MVA Pathway -- 9.4.1.5 Enhancing Precursor Supply -- 9.4.2 Optimizing Growth Conditions for Production -- 9.4.3 Product Capture and Harvesting -- 9.5 Summary and Outlook -- Acknowledgments -- References -- Chapter 10 Cyanobacterial Biopolymers -- 10.1 Polyhydroxybutryate -- 10.1.1 Introduction -- 10.1.2 PHB Metabolism in Cyanobacteria -- 10.1.3 Industrial Applications of PHB -- 10.1.3.1 Physical Properties of PHB and Its Derivatives -- 10.1.3.2 Biodegradability -- 10.1.3.3 Application of PHB as a Plastic. , 10.1.3.4 Reactor Types.

Note: Intro -- METABOLOME ANALYSIS -- CONTENTS -- PREFACE -- LIST OF CONTRIBUTORS -- PART I: CONCEPTS AND METHODOLOGY -- 1 Metabolomics in Functional Genomics and Systems Biology -- 1.1 From genomic sequencing to functional genomics -- 1.2 Systems biology and metabolic models -- 1.3 Metabolomics -- 1.4 Future perspectives -- 2 The Chemical Challenge of the Metabolome -- 2.1 Metabolites and metabolism -- 2.2 The structural diversity of metabolites -- 2.2.1 The chemical and physical properties -- 2.2.2 Metabolite abundance -- 2.2.3 Primary and secondary metabolism -- 2.3 The number of metabolites in a biological system -- 2.4 Controlling rates and levels -- 2.4.1 Control by substrate level -- 2.4.2 Feedback and feedforward control -- 2.4.3 Control by "pathway independent" regulatory molecules -- 2.4.4 Allosteric control -- 2.4.5 Control by compartmentalization -- 2.4.6 The dynamics of the metabolism-the mass flow -- 2.4.7 Control by hormones -- 2.5 Metabolic channeling or metabolons -- 2.6 Metabolites are arranged in networks that are part of a cellular interactome -- 3 Sampling and Sample Preparation -- 3.1 Introduction -- 3.2 Quenching-the first step -- 3.2.1 Overview on metabolite turnover -- 3.2.2 Different methods for quenching -- 3.2.3 Quenching microbial and cell cultures -- 3.2.4 Quenching plant and animal tissues -- 3.3 Obtaining metabolites from biological samples -- 3.3.1 Release of intracellular metabolites -- 3.3.2 Structure of the cell envelopes-the main barrier to be broken -- 3.3.3 Cell disruption methods -- 3.3.4 Nonmechanical disruption of cell envelopes -- 3.3.5 Mechanical disruption of cell envelopes -- 3.4 Metabolites in the extracellular medium -- 3.4.1 Metabolites in solution -- 3.4.2 Metabolites in the gas phase -- 3.5 Improving detection via sample concentration -- 4 Analytical Tools -- 4.1 Introduction. , 4.2 Choosing a methodology -- 4.3 Starting point-samples -- 4.4 Principles of chromatography -- 4.4.1 Basics of chromatography -- 4.4.2 The chromatogram and terms in chromatography -- 4.5 Chromatographic systems -- 4.5.1 Gas chromatography -- 4.5.2 HPLC systems -- 4.6 Mass spectrometry -- 4.6.1 The mass spectrometer-an overview -- 4.6.2 GC-MS-the EI ion source -- 4.6.3 LC-MS-the ESI ion source -- 4.6.4 Mass analyzer-the quadrupole -- 4.6.5 Mass analyzer-the ion-trap -- 4.6.6 Mass analyzer-the time-of-flight -- 4.6.7 Detection and computing in MS -- 4.7 The analytical work-flow -- 4.7.1 Separation by chromatography -- 4.7.2 Mass spectrometry -- 4.7.3 General analytical considerations -- 4.8 Data evaluation -- 4.8.1 Structure of data -- 4.8.2 The chromatographic separation -- 4.8.3 Mass spectral data -- 4.8.4 Exporting data for processing -- 4.9 Beyond the core methods -- 4.9.1 Developments in chromatography -- 4.9.2 Capillary electrophoresis -- 4.9.3 Tandem MS and advanced scanning techniques -- 4.9.4 NMR spectrometry -- 4.10 Further reading -- 5 Data Analysis -- 5.1 Organizing the data -- 5.2 Scales of measurement -- 5.2.1 Qualitative data -- 5.2.2 Quantitative data -- 5.3 Data structures -- 5.4 Preprocessing of data -- 5.4.1 Calibration of data -- 5.4.2 Combining profile scans -- 5.4.3 Filtering -- 5.4.4 Centroid calculation -- 5.4.5 Internal mass scale correction -- 5.4.6 Binning -- 5.4.7 Baseline correction -- 5.4.8 Chromatographic profile matching -- 5.5 Deconvolution of spectroscopic data -- 5.6 Data standardization (normalization) -- 5.7 Data transformations -- 5.7.1 Principal component analysis -- 5.7.2 Fisher discriminant analysis -- 5.8 Similarities and distances between data -- 5.8.1 Continuous functions -- 5.8.2 Binary functions -- 5.9 Clustering techniques -- 5.9.1 Hierarchical clustering -- 5.9.2 k-means clustering. , 5.10 Classification techniques -- 5.10.1 Decision theory -- 5.10.2 k-nearest neighbor -- 5.10.3 Tree-based classification -- 5.11 Integrated tools for automation, libraries, and data evaluation -- PART II-CASE STUDIES AND REVIEWS -- 6 Yeast Metabolomics: The Discovery of New Metabolic Pathways in Saccharomyces cerevisiae -- 6.1 Introduction -- 6.2 Brief description of the methodology used -- 6.2.1 Sample preparation -- 6.2.2 The analysis -- 6.3 Early discoveries -- 6.4 Yeast stress response gives evidence of alternative pathway for glyoxylate biosynthesis in S. cerevisiae -- 6.5 Biosynthesis of glyoxylate from glycine in S. cerevisiae -- 6.5.1 Stable isotope labeling experiment to investigate glycine catabolism in S. cerevisiae -- 6.5.2 Data leveraged for speculation -- 7 Microbial Metabolomics: Rapid Sampling Techniques to Investigate Intracellular Metabolite Dynamics-An Overview -- 7.1 Introduction -- 7.2 Starting with a simple sampling device proposed by Theobald et al. (1993) -- 7.3 An improved device reported by Lange et al. (2001) -- 7.4 Sampling tube device by Weuster-Botz (1997) -- 7.5 Fully automated device by Schaefer et al. (1999) -- 7.6 The stopped-flow technique by Buziol et al. (2002) -- 7.7 The BioScope: a system for continuous-pulse experiments -- 7.8 Conclusions and perspectives -- 8 Plant Metabolomics -- 8.1 Introduction -- 8.2 History of plant metabolomics -- 8.3 Plants, their metabolism and metabolomics -- 8.3.1 Plant structures -- 8.3.2 Plant metabolism -- 8.4 Specific challenges in plant metabolomics -- 8.4.1 Light dependency of plant metabolism -- 8.4.2 Extraction of plant metabolites -- 8.4.3 Many cell types in one tissue -- 8.4.4 The dynamical range of plant metabolites -- 8.4.5 Complexity of the plant metabolome -- 8.4.6 Development of databases for metabolomics-derived data in plant science. , 8.5 Applications of metabolomics approaches in plant research -- 8.5.1 Phenotyping -- 8.5.2 Functional genomics -- 8.5.3 Fluxomics -- 8.5.4 Metabolic trait analysis -- 8.5.5 Systems biology -- 8.6 Future perspectives -- 9 Mass Profiling of Fungal Extract from Penicillium Species -- 9.1 Introduction -- 9.2 Methodology for screening of fungi by DiMS -- 9.2.1 Cultures -- 9.2.2 Extraction -- 9.2.3 Analysis by direct infusion mass spectrometry -- 9.3 Discussion -- 9.3.1 Initial data processing -- 9.3.2 Metabolite prediction -- 9.3.3 Chemical diversity and similarity -- 9.4 Conclusion -- 10 Metabolomics in Humans and Other Mammals -- 10.1 Introduction -- 10.2 A brief history of mammalian metabolomics -- 10.3 Sample preparation for mammalian metabolomics studies -- 10.3.1 Working with blood -- 10.3.2 Working with urine -- 10.3.3 Working with cerebrospinal fluid -- 10.3.4 Working with cells and tissues -- 10.4 Sample analysis -- 10.4.1 GC-MS analysis of urine, plasma, and CSF -- 10.4.2 LC-MS analysis of urine, blood, and CFS -- 10.4.3 NMR analysis of CSF, urine, and blood -- 10.5 Applications -- 10.5.1 Identification and classification of metabolic disorders -- 10.6 Future outlook -- INDEX.

Note: Cover -- Title Page -- Copyright -- Dedication -- Contents -- List of Contributors -- About the Series Editors -- Preface -- Volume 1 -- Part I Industrial Biotechnology: From Pioneers to Visionary -- Chapter 1 History of Industrial Biotechnology -- 1.1 The Beginning of Industrial Microbiology -- 1.2 Primary Metabolites and Enzymes -- 1.3 The Antibiotic Era -- 1.4 The Biotechnology Era Between 1970 and 2015 -- 1.5 How Pioneering Developments Led to Genetic Engineering -- References -- Chapter 2 Synthetic Biology: An Emerging Approach for Strain Engineering -- 2.1 Introduction -- 2.2 Basic Elements -- 2.3 Functional and Robust Modules -- 2.4 Microbial Communities -- 2.5 Conclusions and Future Prospects -- Acknowledgments -- References -- Chapter 3 Toward Genome-Scale Metabolic Pathway Analysis -- 3.1 Introduction -- 3.2 DD Method -- 3.3 Calculating Short EFMs in Genome-Scale Metabolic Networks -- 3.4 Conclusions -- Acknowledgments -- References -- Chapter 4 Cell-Free Synthetic Systems for Metabolic Engineering and Biosynthetic Pathway Prototyping -- 4.1 Introduction -- 4.2 Background -- 4.3 The Benefits of Cell-Free Systems -- 4.4 Challenges and Opportunities in Cell-Free Systems -- 4.5 Recent Advances -- 4.6 Summary -- Acknowledgments -- References -- Part II Multipurpose Bacterial Cell Factories -- Chapter 5 Industrial Biotechnology: Escherichia coli as a Host -- 5.1 Introduction -- 5.2 E. coli Products -- 5.3 Rewiring Central Metabolism -- 5.4 Alternative Carbon Sources -- 5.5 E. coli Techniques and Concerns -- 5.6 Conclusions -- References -- Chapter 6 Industrial Microorganisms: Corynebacterium glutamicum -- 6.1 Introduction -- 6.2 Physiology and Metabolism -- 6.3 Genetic Manipulation of Corynebacterium glutamicum -- 6.4 Systems Biology of Corynebacterium glutamicum -- 6.5 Application in Biotechnology -- 6.6 Conclusions and Perspectives. , References -- Chapter 7 Host Organisms: Bacillus subtilis -- 7.1 Introduction and Scope -- 7.2 Identification of Genetic Traits Pertinent to Enhanced Biosynthesis of a Value Product -- 7.3 Traits to Be Engineered for Enhanced Synthesis and Secretion of Proteinaceous Products -- 7.4 Engineering of Genetic Traits in Bacillus subtilis -- 7.5 Genome Reduction -- 7.6 Significance of Classical Strain Improvement in Times of Synthetic Biology -- 7.7 Resource-Efficient B. subtilis Fermentation Processes -- 7.8 Safety of Bacillus subtilis -- 7.9 Bacillus Production Strains on the Factory Floor: Some Examples -- Acknowledgments -- References -- Chapter 8 Host Organism: Pseudomonas putida -- 8.1 Introduction -- 8.2 Physiology and Metabolism -- 8.3 Genetic Manipulation -- 8.4 Systems Biology -- 8.5 Application in Biotechnology -- 8.6 Future Outlook -- References -- Part III Exploiting Anaerobic Biosynthetic Power -- Chapter 9 Host Organisms: Clostridium acetobutylicum/Clostridium beijerinckii and Related Organisms -- 9.1 Introduction -- 9.2 Microorganisms -- 9.3 Bacteriophages -- 9.4 ABE Fermentation of Solvent-Producing Clostridium Strains -- 9.5 Genome-Based Comparison of Solvent-Producing Clostridium Strains -- 9.6 Regulation of Solvent Formation in C. acetobutylicum -- 9.7 Genetic Tools for Clostridial Species -- 9.8 Industrial Application of ABE Fermentation -- Acknowledgments -- References -- Chapter 10 Advances in Consolidated Bioprocessing Using Clostridium thermocellum and Thermoanaerobacter saccharolyticum -- 10.1 Introduction -- 10.2 CBP Organism Development Strategies -- 10.3 Plant Cell Wall Solubilization by C. thermocellum -- 10.4 Bioenergetics of C. thermocellum Cellulose Fermentation -- 10.5 Metabolic Engineering -- 10.6 Summary and Future Directions -- Acknowledgments -- References -- Chapter 11 Lactic Acid Bacteria -- 11.1 Introduction. , 11.2 Fermented Foods -- 11.3 Industrially Relevant Compounds -- 11.4 Conclusions -- Conflict of Interest -- References -- Volume 2 -- Part IV Microbial Treasure Chests for High-Value Natural Compounds -- Chapter 12 Host Organisms: Myxobacterium -- 12.1 Introduction into the Myxobacteria -- 12.2 Phylogeny and Classification -- 12.3 Physiology -- 12.4 Growth and Nutritional Requirements -- 12.5 Genetics and Genomics -- 12.6 Secondary Metabolism -- 12.7 Myxococcus -- 12.8 Sorangium -- 12.9 Outlook -- References -- Chapter 13 Host Organism: Streptomyces -- 13.1 Introduction -- 13.2 Streptomyces Genome Manipulation Toolkits -- 13.3 Hosts for Heterologous Production of Natural Products -- Acknowledgments -- References -- Part V Extending the Raw Material Basis for Bioproduction -- Chapter 14 Extreme Thermophiles as Metabolic Engineering Platforms: Strategies and Current Perspective -- 14.1 Introduction -- 14.2 Bioprocessing Advantages for Extremely Thermophilic Hosts -- 14.3 Biobased Chemicals and Fuels: Targets and Opportunities -- 14.4 Considerations for Selecting an Extremely Thermophilic Host -- 14.5 General Strategies for Genetic Manipulation of Extreme Thermophiles -- 14.6 Limitations and Barriers to Genetic Modification of Extreme Thermophiles -- 14.7 Current Status of Metabolic Engineering Efforts and Prospects in Extreme Thermophiles -- 14.8 Metabolic Engineering of Extreme Thermophiles - Tool Kit Needs -- 14.9 Conclusions and Future Perspectives -- Acknowledgments -- References -- Chapter 15 Cyanobacteria as a Host Organism -- 15.1 Introduction and Relevance: Cyanobacteria as a Host Organism -- 15.2 General Description of Cyanobacteria -- 15.3 Genetic Tools -- 15.4 Improving Photosynthetic Efficiency -- 15.5 Direct Conversion of CO2 into Biofuels and Chemicals -- 15.6 Conclusions -- References -- Chapter 16 Host Organisms: Algae. , 16.1 Introduction to Algae as an Industrial Organism -- 16.2 Algal Genetic Engineering -- 16.3 Therapeutic and Nutraceutical Applications -- 16.4 Bioenergy Applications -- 16.5 Other Industrial Applications -- 16.6 Industrial-Scale Algal Production -- 16.7 Conclusions and Potential of Algal Platforms -- References -- Part VI Eukaryotic Workhorses: Complex Cells Enable Complex Products -- Chapter 17 Host Organisms: Mammalian Cells -- 17.1 Introduction -- 17.2 Basics of Cellular Structure and Metabolism -- 17.3 The Genome of CHO Cells -- 17.4 Molecular Biology Tools -- 17.5 Kinetics of Growth and Product Formation -- 17.6 Intracellular Metabolome Analysis -- 17.7 Proteome and Gene Expression Analysis -- 17.8 Improving Cellular Performance by Genetic and Metabolic Engineering -- 17.9 Outlook -- References -- Chapter 18 Industrial Microorganisms: Saccharomyces cerevisiae and other Yeasts -- 18.1 Industrial Application of Yeasts -- 18.2 Baker's Yeast as Versatile Host for Metabolic Engineering -- 18.3 Protein Production in Yeasts -- 18.4 Lipid Production in Yeasts -- 18.5 Pentose-Utilizing Yeasts -- 18.6 Conclusions -- Conflict of Interest -- References -- Chapter 19 Industrial Microorganisms: Pichia pastoris -- 19.1 Physiology and Genetics of Pichia pastoris -- 19.2 Methylotrophic Metabolism -- 19.3 Application for the Production of Recombinant Proteins -- 19.4 Application of P. pastoris for Metabolite Production -- 19.5 Conclusion -- References -- Index -- EULA.

Note: Intro -- Related Titles -- Title Page -- Copyright -- Table of Contents -- List of Contributors -- About the Series Editors -- Chapter 1: Integrative Analysis of Omics Data -- Summary -- 1.1 Introduction -- 1.2 Omics Data and Their Measurement Platforms -- 1.3 Data Processing: Quality Assessment, Quantification, Normalization, and Statistical Analysis -- 1.4 Data Integration: From a List of Genes to Biological Meaning -- 1.5 Outlook and Perspectives -- References -- Chapter 2: 13C Flux Analysis in Biotechnology and Medicine -- 2.1 Introduction -- 2.2 Theoretical Foundations of 13C MFA -- 2.3 Metabolic Flux Analysis in Biotechnology -- 2.4 Metabolic Flux Analysis in Medicine -- 2.5 Emerging Challenges for 13C MFA -- 2.6 Conclusion -- Acknowledgments -- Disclosure -- References -- Chapter 3: Metabolic Modeling for Design of Cell Factories -- Summary -- 3.1 Introduction -- 3.2 Building and Refining Genome-Scale Metabolic Models -- 3.3 Strain Design Algorithms -- 3.4 Case Studies -- 3.5 Conclusions -- Acknowledgments -- References -- Chapter 4: Genome-Scale Metabolic Modeling and In silico Strain Design of Escherichia coli -- 4.1 Introduction -- 4.2 The COBRA Approach -- 4.3 History of E. coli Metabolic Modeling -- 4.4 In silico Model-Based Strain Design of E. coli Cell Factories -- 4.5 Future Directions of Model-Guided Strain Design in E. coli -- References -- Chapter 5: Accelerating the Drug Development Pipeline with Genome-Scale Metabolic Network Reconstructions -- Summary -- 5.1 Introduction -- 5.2 Metabolic Reconstructions in the Drug Development Pipeline -- 5.3 Species-Level Microbial Reconstructions -- 5.4 The Human Reconstruction -- 5.5 Community Models -- 5.6 Personalized Medicine -- 5.7 Conclusion -- References -- Chapter 6: Computational Modeling of Microbial Communities -- Summary -- 6.1 Introduction -- 6.2 Ecological Models. , 6.3 Genome-Scale Metabolic Models -- 6.4 Concluding Remarks -- References -- Chapter 7: Drug Targeting of the Human Microbiome -- Summary -- 7.1 Introduction -- 7.2 The Human Microbiome -- 7.3 Association of the Human Microbiome with Human Diseases -- 7.4 Drug Targeting of the Human Microbiome -- 7.5 Future Perspectives -- 7.6 Concluding Remarks -- Acknowledgments -- References -- Chapter 8: Toward Genome-Scale Models of Signal Transduction Networks -- 8.1 Introduction -- 8.2 The Potential of Network Reconstruction -- 8.3 Information Transfer Networks -- 8.4 Approaches to Reconstruction of ITNs -- 8.5 The rxncon Approach to ITNWR -- 8.6 Toward Quantitative Analysis and Modeling of Large ITNs -- 8.7 Conclusion and Outlook -- Acknowledgments -- References -- Chapter 9: Systems Biology of Aging -- Summary -- 9.1 Introduction -- 9.2 The Biology of Aging -- 9.3 The Mathematics of Aging -- 9.4 Future Challenges -- Conflict of Interest -- References -- Chapter 10: Modeling the Dynamics of the Immune Response -- 10.1 Background -- 10.2 Dynamics of NF-κB Signaling -- 10.3 JAK/STAT Signaling -- 10.4 Conclusions -- Acknowledgments -- References -- Chapter 11: Dynamics of Signal Transduction in Single Cells Quantified by Microscopy -- 11.1 Introduction -- 11.2 Single-Cell Measurement Techniques -- 11.3 Microscopy -- 11.4 Imaging Signal Transduction -- 11.5 Conclusions -- References -- Chapter 12: Image-Based In silico Models of Organogenesis -- Summary -- 12.1 Introduction -- 12.2 Typical Workflow of Image-Based In silico Modeling Experiments -- 12.3 Application: Image-Based Modeling of Branching Morphogenesis -- 12.4 Future Avenues -- References -- Chapter 13: Progress toward Quantitative Design Principles of Multicellular Systems -- Summary -- 13.1 Toward Quantitative Design Principles of Multicellular Systems. , 13.2 Breaking Multicellular Systems into Distinct Functional and Spatial Modules May Be Possible -- 13.3 Communication among Cells as a Means of Cell-Cell Interaction -- 13.4 Making Sense of the Combinatorial Possibilities Due to Many Ways that Cells Can Be Arranged in Space -- 13.5 From Individual Cells to Collective Behaviors of Cell Populations -- 13.6 Tuning Multicellular Behaviors -- 13.7 A New Framework for Quantitatively Understanding Multicellular Systems -- Acknowledgments -- References -- Chapter 14: Precision Genome Editing for Systems Biology - A Temporal Perspective -- Summary -- 14.1 Early Techniques in DNA Alterations -- 14.2 Zinc-Finger Nucleases -- 14.3 TALENs -- 14.4 CRISPR-Cas9 -- 14.5 Considerations of Gene-Editing Nuclease Technologies -- 14.6 Applications -- 14.7 A Focus on the Application of Genome-Engineering Nucleases on Chromosomal Rearrangements -- 14.8 Future Perspectives -- References -- Index -- End User License Agreement.

Note: Cover -- Title Page -- Copyright -- Contents -- About the Series Editors -- Chapter 1 Platform Technology for Therapeutic Protein Production -- 1.1 Introduction -- 1.2 Overall Trend Analysis -- 1.2.1 Mammalian Cell Lines -- 1.2.2 Brief Introduction of Advances and Techniques -- 1.3 General Guidelines for Recombinant Cell Line Development -- 1.3.1 Host Selection -- 1.3.2 Expression Vector -- 1.3.3 Transfection/Selection -- 1.3.4 Clone Selection -- 1.3.4.1 Primary Parameters During Clone Selection -- 1.3.4.2 Clone Screening Technologies -- 1.4 Process Development -- 1.4.1 Media Development -- 1.4.2 Culture Environment -- 1.4.3 Culture Mode (Operation) -- 1.4.4 Scale‐up and Single‐Use Bioreactor -- 1.4.5 Quality Analysis -- 1.5 Downstream Process Development -- 1.5.1 Purification -- 1.5.2 Quality by Design (QbD) -- 1.6 Trends in Platform Technology Development -- 1.6.1 Rational Strategies for Cell Line and Process Development -- 1.6.2 Hybrid Culture Mode and Continuous System -- 1.6.3 Recombinant Human Cell Line Development for Therapeutic Protein Production -- 1.7 Conclusion -- Acknowledgment -- Conflict of Interest -- References -- Chapter 2 Cell Line Development for Therapeutic Protein Production -- 2.1 Introduction -- 2.2 Mammalian Host Cell Lines for Therapeutic Protein Production -- 2.2.1 CHO Cell Lines -- 2.2.2 Human Cell Lines -- 2.2.3 Other Mammalian Cell Lines -- 2.3 Development of Recombinant CHO Cell Lines -- 2.3.1 Expression Systems for CHO Cells -- 2.3.2 Cell Line Development Process Using CHO Cells Based on Random Integration -- 2.3.2.1 Vector Construction -- 2.3.2.2 Transfection and Selection -- 2.3.2.3 Gene Amplification -- 2.3.2.4 Clone Selection -- 2.3.3 Cell Line Development Process Using CHO Cells Based On Site‐Specific Integration -- 2.4 Development of Recombinant Human Cell Lines -- 2.4.1 Necessity for Human Cell Lines. , 2.4.2 Stable Cell Line Development Process Using Human Cell Lines -- 2.5 Important Consideration for Cell Line Development -- 2.5.1 Clonality -- 2.5.2 Stability -- 2.5.3 Quality of Therapeutic Proteins -- 2.6 Conclusion -- References -- Chapter 3 Transient Gene Expression‐Based Protein Production in Recombinant Mammalian Cells -- 3.1 Introduction -- 3.2 Gene Delivery: Transient Transfection Methods -- 3.2.1 Calcium Phosphate‐Based Transient Transfection -- 3.2.2 Electroporation -- 3.2.3 Polyethylenimine‐Based Transient Transfection -- 3.2.4 Liposome‐Based Transient Transfection -- 3.3 Expression Vectors -- 3.3.1 Expression Vector Composition and Preparation -- 3.3.2 Episomal Replication -- 3.3.3 Coexpression Strategies -- 3.4 Mammalian Cell Lines -- 3.4.1 HEK293 Cell‐Based TGE Platforms -- 3.4.2 CHO Cell‐Based TGE Platforms -- 3.4.3 TGE Platforms Using Other Cell Lines -- 3.5 Cell Culture Strategies -- 3.5.1 Culture Media for TGE -- 3.5.2 Optimization of Cell Culture Processes for TGE -- 3.5.3 qp‐Enhancing Factors in TGE‐Based Culture Processes -- 3.5.4 Culture Longevity‐Enhancing Factors in TGE‐Based Culture Processes -- 3.6 Large‐Scale TGE‐Based Protein Production -- 3.7 Concluding Remarks -- References -- Chapter 4 Enhancing Product and Bioprocess Attributes Using Genome‐Scale Models of CHO Metabolism -- 4.1 Introduction -- 4.1.1 Cell Line Optimization -- 4.1.2 CHO Genome -- 4.1.2.1 Development of Genomic Resources of CHO -- 4.1.2.2 Development of Transcriptomics and Proteomics Resources of CHO -- 4.2 Genome‐Scale Metabolic Model -- 4.2.1 What Is a Genome‐Scale Metabolic Model -- 4.2.2 Reconstruction of GEMs -- 4.2.2.1 Knowledge‐Based Construction -- 4.2.2.2 Draft Reconstruction -- 4.2.2.3 Curation of the Reconstruction -- 4.2.2.4 Conversion to a Computational Format -- 4.2.2.5 Model Validation and Evaluation -- 4.3 GEM Application. , 4.3.1 Common Usage and Prediction Capacities of Genome‐Scale Models -- 4.3.2 GEMs as a Platform for Omics Data Integration, Linking Genotype to Phenotype -- 4.3.3 Predicting Nutrient Consumption and Controlling Phenotype -- 4.3.4 Enhancing Protein Production and Bioprocesses -- 4.3.5 Case Studies -- 4.4 Conclusion -- Acknowledgments -- References -- Chapter 5 Genome Variation, the Epigenome and Cellular Phenotypes -- 5.1 Phenotypic Instability in the Context of Mammalian Production Cell Lines -- 5.2 Genomic Instability -- 5.3 Epigenetics -- 5.3.1 DNA Methylation -- 5.3.2 Histone Modifications -- 5.3.3 Downstream Effectors -- 5.3.4 Noncoding RNAs -- 5.4 Control of CHO Cell Phenotype by the Epigenome -- 5.5 Manipulating the Epigenome -- 5.5.1 Global Epigenetic Modification -- 5.5.1.1 Manipulating Global DNA Methylation -- 5.5.1.2 Manipulating Global Histone Acetylation -- 5.5.2 Targeted Epigenetic Modification -- 5.5.2.1 Targeted Histone Modification -- 5.5.2.2 Targeted DNA Methylation -- 5.6 Conclusion and Outlook -- References -- Chapter 6 Adaption of Generic Metabolic Models to Specific Cell Lines for Improved Modeling of Biopharmaceutical Production and Prediction of Processes -- 6.1 Introduction -- 6.1.1 Constraint‐Based Models -- 6.1.2 Limitations of Flux Balance Analysis -- 6.1.2.1 Thermodynamically Infeasible Cycles -- 6.1.2.2 Genetic Regulation -- 6.1.2.3 Limitation of Intracellular Space -- 6.1.2.4 Multiple States in the Solution -- 6.1.2.5 Biological Objective Function -- 6.1.2.6 Kinetics and Metabolite Concentrations -- 6.2 Main Source of Optimization Issues with Large Genome‐Scale Models: Thermodynamically Infeasible Cycles -- 6.2.1 Definition of Thermodynamically Infeasible Fluxes -- 6.2.2 Loops Involving External Exchange Reactions -- 6.2.2.1 Reversible Passive Transporters from Major Facilitator Superfamily (MFS). , 6.2.2.2 Reversible Passive Antiporters from Amino Acid‐Polyamine‐organoCation (APC) Superfamily -- 6.2.2.3 Na+‐linked Transporters -- 6.2.2.4 Transport via Proton Symport -- 6.2.3 Tools to Identify Thermodynamically Infeasible Cycles -- 6.2.3.1 Visualizing Fluxes on a Network Map -- 6.2.3.2 Algorithms Developed -- 6.2.4 Methods Available to Remove Thermodynamically Infeasible Cycles -- 6.2.4.1 Manual Curation -- 6.2.4.2 Software and Algorithms Developed for the Removal of Thermodynamically Infeasible Loops from Flux Distributions -- 6.3 Consideration of Additional Biological Cellular Constraints -- 6.3.1 Genetic Regulation -- 6.3.1.1 Advantages of Considering Gene Regulation in Genome‐Scale Modeling -- 6.3.1.2 Methods Developed to Take into Account a Feedback of FBA on the Regulatory Network -- 6.3.2 Context Specificity -- 6.3.2.1 What Are Context‐Specific Models (CSMs)? -- 6.3.2.2 Methods and Algorithms Developed to Reconstruct Context‐Specific Models (CSMs) -- 6.3.2.3 Performance of CSMs -- 6.3.2.4 Cautions About CSMs -- 6.3.3 Molecular Crowding -- 6.3.3.1 Consequences on the Predictions -- 6.3.3.2 Methods Developed to Account for a Total Enzymatic Capacity into the FBA Framework -- 6.4 Conclusion -- References -- Chapter 7 Toward Integrated Multi‐omics Analysis for Improving CHO Cell Bioprocessing -- 7.1 Introduction -- 7.2 High‐Throughput Omics Technologies -- 7.2.1 Sequencing‐Based Omics Technologies -- 7.2.1.1 Historical Developments of Nucleotide Sequencing Techniques -- 7.2.1.2 Genome Sequencing of CHO Cells -- 7.2.1.3 Transcriptomics of CHO Cells -- 7.2.1.4 Epigenomics of CHO Cells -- 7.2.2 Mass Spectrometry‐Based Omics Technologies -- 7.2.2.1 Mass Spectrometry Techniques -- 7.2.2.2 Proteomics of CHO Cells -- 7.2.2.3 Metabolomics/Lipidomics of CHO Cells -- 7.2.2.4 Glycomics of CHO Cells -- 7.3 Current CHO Multi‐omics Applications. , 7.3.1 Bioprocess Optimization -- 7.3.2 Cell Line Characterization -- 7.3.3 Engineering Target Identification -- 7.4 Future Prospects -- References -- Chapter 8 CRISPR Toolbox for Mammalian Cell Engineering -- 8.1 Introduction -- 8.2 Mechanism of CRISPR/Cas9 Genome Editing -- 8.3 Variants of CRISPR‐RNA‐guided Endonucleases -- 8.3.1 Diversity of CRISPR/Cas Systems -- 8.3.2 Engineered Cas9 Variants -- 8.4 Experimental Design for CRISPR‐mediated Genome Editing -- 8.4.1 Target Site Selection and Design of gRNAs -- 8.4.2 Delivery of CRISPR/Cas9 Components -- 8.5 Development of CRISPR/Cas9 Tools -- 8.5.1 CRISPR/Cas9‐mediated Gene Editing -- 8.5.1.1 Gene Knockout -- 8.5.1.2 Site‐Specific Gene Integration -- 8.5.2 CRISPR/Cas9‐mediated Genome Modification -- 8.5.2.1 Transcriptional Regulation -- 8.5.2.2 Epigenetic Modification -- 8.5.3 RNA Targeting -- 8.6 Genome‐Scale CRISPR Screening -- 8.7 Applications of CRISPR/Cas9 for CHO Cell Engineering -- 8.8 Conclusion -- Acknowledgment -- References -- Chapter 9 CHO Cell Engineering for Improved Process Performance and Product Quality -- 9.1 CHO Cell Engineering -- 9.2 Methods in Cell Line Engineering -- 9.2.1 Overexpression of Engineering Genes -- 9.2.2 Gene Knockout -- 9.2.3 Noncoding RNA‐mediated Gene Silencing -- 9.3 Applications of Cell Line Engineering Approaches in CHO Cells -- 9.3.1 Enhancing Recombinant Protein Production -- 9.3.2 Repression of Cell Death and Acceleration of Growth -- 9.3.3 Modulation of Posttranslational Modifications to Improve Protein Quality -- 9.4 Conclusions -- References -- Chapter 10 Metabolite Profiling of Mammalian Cells -- 10.1 Value of Metabolic Data for the Enhancement of Recombinant Protein Production -- 10.2 Technologies Used in the Generation of Metabolic Data Sets -- 10.2.1 Targeted and Untargeted Metabolic Analysis. , 10.2.2 Analytical Technologies Used in the Generation of Metabolite Profiles.

Note: Cover -- Title Page -- Copyright -- Dedication -- Contents -- List of Contributors -- About the Series Editors -- Preface -- Part I Enabling and Improving Large-Scale Bio-production -- Chapter 1 Industrial-Scale Fermentation -- 1.1 Introduction -- 1.2 Industrial-Scale Fermentation Today -- 1.3 Engineering and Design Aspects -- 1.4 Industrial Design Examples -- 1.5 Cost Analysis for the Manufacture of Biotechnological Products -- 1.6 Influence of Process- and Facility-Related Aspects on Cost Structure -- Acknowledgments -- References -- Chapter 2 Scale-Down: Simulating Large-Scale Cultures in the Laboratory -- 2.1 Introduction -- 2.2 Heterogeneities at Large Scale and the Need for Scaling Down -- 2.3 Bioreactor Scale-Down -- 2.4 Tools to Study Cell Responses to Environmental Heterogeneities -- 2.5 Physiological Effects of Environmental Heterogeneities -- 2.6 Improvements Based on Scale-Down Studies: Bioreactor Design and Cell Engineering -- 2.7 Perspectives -- Acknowledgment -- References -- Chapter 3 Bioreactor Modeling -- 3.1 Large-Scale Industrial Fermentations: Challenges for Bioreactor Modeling -- 3.2 Bioreactors -- 3.3 Compartment and Hybrid Multizonal/Computational Fluid Dynamics Approaches for the Description of Large-Scale Bioreactor Phenomena -- 3.4 Computational Fluid Dynamics Modeling: Unstructured Continuum Approach (Euler-Euler) -- 3.5 Computational Fluid Dynamics Modeling: Structured Segregated Approach (Euler-Lagrange) -- 3.6 Conclusion -- 3.7 Outlook -- References -- Chapter 4 Cell Culture Technology -- 4.1 Introduction -- 4.2 Overview of Applications for Cell Culture Products and Tissue Engineering -- 4.3 Fundamentals -- 4.4 Bioreactors for Cell Culture -- 4.5 Downstream -- 4.6 Regulatory and Safety Issues -- 4.7 Conclusions and Outlook -- References -- Part II Getting Out More: Strategies for Enhanced Bioprocessing. , Chapter 5 Production of Fuels and Chemicals from Biomass by Integrated Bioprocesses -- 5.1 Introduction -- 5.2 Utilization of Starchy Biomass -- 5.3 Utilization of Lignocellulosic Biomass -- 5.4 Conclusions and Perspectives -- Acknowledgment -- References -- Chapter 6 Solid-State Fermentation -- 6.1 Introduction -- 6.2 Fundamentals Aspects of SSF -- 6.3 Factors Affecting Solid-State Fermentation -- 6.4 Scale-Up -- 6.5 Product Recovery -- 6.6 Bioreactor Designing -- 6.7 Kinetics and Modeling -- 6.8 Applications -- 6.9 Challenges in SSF -- 6.10 Summary -- References -- Chapter 7 Cell Immobilization: Fundamentals, Technologies, and Applications -- 7.1 Introduction -- 7.2 Fundamentals of Cell Immobilization -- 7.3 Immobilization with Support Materials -- 7.4 Self-Immobilization -- 7.5 Immobilized Cells and their Applications -- 7.6 Bioreactors for Cell Immobilization -- 7.7 Challenges and Recommendations for Future Research -- 7.8 Conclusions -- References -- Part III Molecules for Human Use: High-Value Drugs, Flavors, and Nutraceuticals -- Chapter 8 Anticancer Drugs -- 8.1 Natural Products as Anticancer Drugs -- 8.2 Anticancer Drug Production -- 8.3 Important Anticancer Natural Products -- 8.4 Prospects -- References -- Chapter 9 Biotechnological Production of Flavors -- 9.1 History -- 9.2 Survey on Today's Industry -- 9.3 Regulations -- 9.4 Flavor Production -- 9.5 Biotechnological Production of Flavors -- 9.6 Vanillin -- 9.7 2-Phenylethanol -- 9.8 Benzaldehyde -- 9.9 Lactones -- 9.10 Raspberry Ketone -- 9.11 Green Notes -- 9.12 Nootkatone -- 9.13 Future Perspectives -- References -- Chapter 10 Nutraceuticals (Vitamin C, Carotenoids, Resveratrol) -- 10.1 Introduction -- 10.2 Vitamin C -- 10.3 Carotenoids -- 10.4 Resveratrol -- 10.5 Future Perspectives -- References -- Part IV Industrial Amino Acids. , Chapter 11 Glutamic Acid Fermentation: Discovery of Glutamic Acid-Producing Microorganisms, Analysis of the Production Mechanism, Metabolic Engineering, and Industrial Production Process -- 11.1 Introduction -- 11.2 Discovery of the Glutamic Acid-Producing Bacterium C. glutamicum -- 11.3 Analysis of the Mechanism of Glutamic Acid Production by C. glutamicum -- 11.4 Metabolic Engineering of C. glutamicum for Glutamic Acid Production -- 11.5 Glutamic Acid Fermentation by Other Microorganisms -- 11.6 Industrial Process of Glutamic Acid Production -- 11.7 Future Perspectives -- References -- Chapter 12 l-Lysine -- 12.1 Uses of l-Lysine -- 12.2 Biosynthesis and Production of l-Lysine -- 12.3 The Chassis Concept: Biotin Prototrophy and Genome Reduction -- 12.4 l-Lysine Biosensors for Strain Selection and on-Demand Flux Control -- 12.5 Perspective -- References -- Part V Bio-Based Monomers and Polymers -- Chapter 13 Diamines for Bio-Based Materials -- 13.1 Introduction -- 13.2 Diamine Metabolism in Bacteria -- 13.3 Putrescine - 1,4-Diaminobutane -- 13.4 Cadaverine - 1,5-Diaminopentane -- 13.5 Conclusions and Perspectives -- References -- Chapter 14 Microbial Production of 3-Hydroxypropionic Acid -- 14.1 Introduction -- 14.2 3-HP Obtained from Native Producers -- 14.3 Synthesis of 3-HP from Glucose -- 14.4 Synthesis of 3-HP from Glycerol -- 14.5 Bridging the Gap Between Glucose and Glycerol in 3-HP Production -- 14.6 Other Strains for 3-HP Production from Glycerol -- 14.7 Limitations of 3-HP Synthesis -- 14.8 Conclusions and Future Prospects -- Acknowledgments -- References -- Chapter 15 Itaconic Acid - An Emerging Building Block -- 15.1 Background, History, and Economy -- 15.2 Biosynthesis of Itaconic Acid -- 15.3 Production Conditions for Itaconic Acid -- 15.4 Physiological Effects and Metabolism of Itaconic acid. , 15.5 Metabolic Engineering for Itaconic Acid Production -- 15.6 Outlook -- Acknowledgments -- References -- Part VI Top-Value Platform Chemicals -- Chapter 16 Microbial Production of Isoprene: Opportunities and Challenges -- 16.1 Introduction -- 16.2 The Milestones of Isoprene Production -- 16.3 Microbial Production of Isoprene: Out of the Laboratory -- 16.4 Main Challenges for Bioisoprene Production -- 16.5 Future Prospects -- Acknowledgments -- References -- Chapter 17 Succinic Acid -- 17.1 Introduction -- 17.2 Development of Succinic Acid Producers and Fermentation Strategies -- 17.3 Succinic Acid Recovery and Purification -- 17.4 Summary -- Acknowledgments -- References -- Part VII Biorenewable Fuels -- Chapter 18 Ethanol: A Model Biorenewable Fuel -- 18.1 Introduction -- 18.2 Metabolic Engineering: Design, Build, Test, Learn -- 18.3 Biomass Deconstruction -- 18.4 Closing Remarks -- Acknowledgments -- References -- Chapter 19 Microbial Production of Butanols -- 19.1 Introduction -- 19.2 A Historical Perspective of n-Butanol Production -- 19.3 ABE Fermentation -- 19.4 n-Butanol Production in Non-native Producers -- 19.5 Isobutanol Production -- 19.6 Summary and Outlook -- Acknowledgments -- References -- Index -- EULA.