| List of Contributors |
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xiii | |
| Preface |
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xix | |
| Part I Introduction and Overview |
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1 | (24) |
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1 The Basics of Stem Cells and Their Utility as Platforms to Model Teratogen Action and Human Developmental and Degenerative Disorders |
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3 | (22) |
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1.1 Stem Cell Types and Basic Function |
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3 | (3) |
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6 | (3) |
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1.2.1 Poised Chromatin of the Pluripotent Epigenome |
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6 | (1) |
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1.2.2 Undirected Differentiation of Pluripotent Cells to Embryoid Bodies |
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7 | (1) |
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1.2.3 Directed Differentiation of Pluripotent Cells |
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8 | (1) |
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1.3 In vitro Uses of Pluripotent Cells |
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9 | (4) |
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1.3.1 Pluripotent Cells for Toxicology |
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9 | (2) |
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1.3.2 Pluripotent Cells for Teratology |
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11 | (1) |
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1.3.3 Limitations of Pluripotent Stem Cells |
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12 | (1) |
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1.4 Adult Stem Cells In vivo |
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13 | (1) |
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1.5 Emerging Trends in Stem Cell Culture |
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14 | (4) |
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15 | (1) |
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16 | (1) |
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17 | (1) |
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1.5.4 Other Cell Types with Stem-Cell-Like Properties |
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18 | (1) |
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18 | (2) |
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1.6.1 iPSCs, Pharmacogenomics, and Predictive Teratology |
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18 | (1) |
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1.6.2 Stem Cell Systems for Environmental Toxicology |
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19 | (1) |
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20 | (5) |
| Part II Using Pluripotent Cells for the Detection and Analysis of Teratogens |
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25 | (94) |
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2 Stem Cells and Tissue Engineering Technologies for Advancing Human Teratogen Screening |
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27 | (32) |
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27 | (1) |
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28 | (1) |
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2.2 Current DART Regulatory Guidelines and Methods |
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29 | (4) |
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29 | (1) |
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2.2.2 Terminologies and Definitions |
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29 | (1) |
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2.2.3 Testing Methodologies |
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30 | (2) |
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2.2.4 Limitations of Animal-Based DART Testing |
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32 | (1) |
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2.3 In vitro Animal-Based Models for Developmental Toxicity Testing |
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33 | (9) |
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2.3.1 Current In vitro Animal-Based Models for Developmental Toxicity Testing |
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33 | (2) |
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35 | (1) |
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35 | (1) |
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36 | (2) |
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2.3.5 New Engineering and Microfabrication Technologies for Model Improvement |
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38 | (4) |
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2.4 In vitro Stem-Cell-Based Developmental Toxicity Models |
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42 | (8) |
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2.4.1 Embryonic Stem Cell Test (EST) |
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42 | (3) |
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2.4.2 ReproGlo Reporter Assay |
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45 | (1) |
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2.4.3 Metabolite Biomarker Assay Using hESCs |
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46 | (1) |
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2.4.4 Mesoendoderm Biomarker-Based Human Pluripotent Stem Cell Test (hPST) |
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47 | (1) |
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2.4.5 The Micropatterned Human Pluripotent Stem Cell Test (g-hPST) |
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48 | (2) |
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2.5 Conclusion and Future Directions |
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50 | (1) |
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51 | (8) |
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3 Use of Embryoid Bodies for the Detection of Teratogens and Analysis of Teratogenic Mechanisms |
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59 | (12) |
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3.1 Embryoid Body Assays: Background |
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59 | (4) |
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3.1.1 Teratogens and Teratogenesis |
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59 | (1) |
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3.1.2 Classic Protocols for Teratogen Assays |
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60 | (2) |
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3.1.3 Pluripotent Stem Cell Technology and its Applications for Teratogen Detection |
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62 | (1) |
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3.2 Detection of Teratogens Using EBs |
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63 | (2) |
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3.2.1 Formation of Embryoid Bodies for Teratogen Assays |
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63 | (2) |
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3.2.2 Cytotoxicity versus Teratogenicity |
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65 | (1) |
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65 | (1) |
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3.3 Teratogenic Mechanisms |
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65 | (2) |
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3.3.1 EB Growth and Morphogenesis |
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65 | (1) |
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66 | (1) |
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3.3.3 Alternative Analyses |
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67 | (1) |
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67 | (1) |
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67 | (4) |
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4 Stem-Cell-Based In vitro Morphogenesis Models to Investigate Developmental Toxicity of Chemical Exposures |
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71 | (20) |
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71 | (2) |
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4.2 Stem-Cell-Based In vitro Morphogenesis Model |
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73 | (10) |
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4.2.1 Mouse P19C5 EB as an In vitro Gastrulation Model |
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73 | (4) |
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4.2.2 Quantitative Evaluation of Morphogenetic Impact |
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77 | (1) |
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4.2.3 Detection of Developmentally Toxic Exposures Using Morphometric Analyses |
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78 | (3) |
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4.2.4 Investigations into the Molecular Mechanisms of Teratogen Actions Using P19C5 EBs |
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81 | (2) |
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4.3 Future Directions: Enhancing Morphogenesis-Based Assays |
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83 | (2) |
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4.3.1 Analyses of Changes in Gene Expression Relevant for Teratogenesis |
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83 | (1) |
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4.3.2 Detection of Proteratogens Using Metabolic Systems |
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84 | (1) |
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4.3.3 Representation of Additional Developmental Regulator Signals |
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84 | (1) |
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4.3.4 Recapitulation of Human Embryogenesis Using Human Embryonic Stem Cells |
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85 | (1) |
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85 | (1) |
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86 | (1) |
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86 | (5) |
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5 Risk Assessment Using Human Pluripotent Stem Cells: Recent Advances in Developmental Toxicity Screens |
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91 | (28) |
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91 | (1) |
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5.2 Animal Embryo Studies to Evaluate Developmental Toxicity |
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91 | (3) |
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5.3 Usage of Mouse Embryonic Stem Cells in Developmental Toxicity |
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94 | (2) |
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5.4 Alternative Endpoint Read-Out Approaches in the EST |
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96 | (3) |
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5.4.1 Simple and Complex Methods - Trends Are Ever Changing |
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96 | (2) |
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5.4.2 Genomics, Transcriptomics, Proteomics, and Metabolomics |
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98 | (1) |
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5.5 Novel Methods and Protocols to Replicate Human Development |
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99 | (6) |
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5.5.1 Human Embryonic Stem Cells |
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100 | (3) |
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5.5.2 Multipotent Stem Cells and Beyond |
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103 | (2) |
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105 | (1) |
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105 | (1) |
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106 | (13) |
| Part III Human Developmental Pathologies Mediated by Adult Stem Cells |
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119 | (166) |
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6 Modeling the Brain in the Culture Dish: Advancements and Applications of Induced Pluripotent Stem-Cell-Derived Neurons |
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121 | (38) |
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121 | (1) |
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6.2 Methods to Generate Patient-Derived Neurons |
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122 | (5) |
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6.2.1 Directed Differentiation of Neurons from Pluripotent Stem Cells |
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122 | (1) |
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6.2.2 Dopaminergic Neurons |
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123 | (1) |
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6.2.3 Glutamatergic Neurons |
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123 | (1) |
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6.2.4 GABAergic Interneurons |
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124 | (1) |
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125 | (1) |
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6.2.6 Other Neurons (Serotonergic and Motor) |
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126 | (1) |
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6.2.7 Limitations of Directed Differentiation |
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127 | (1) |
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6.3 Neuronal Induction from Fibroblasts and hiPSCs |
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127 | (5) |
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6.3.1 Induced Neurons (iNeurons) |
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128 | (1) |
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6.3.2 Dopaminergic iNeurons |
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129 | (1) |
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6.3.3 Glutamatergic iNeurons |
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130 | (1) |
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6.3.4 Induced GABAergic Interneurons |
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130 | (1) |
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6.3.5 Induced Medium Spiny Neurons |
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131 | (1) |
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6.3.6 Serotonergic iNeurons |
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131 | (1) |
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6.3.7 Induced Motor Neurons |
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131 | (1) |
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6.3.8 Limitations of Neuronal Induction |
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132 | (1) |
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6.4 Cerebral Organoids: Neural Modeling in Three Dimensions |
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132 | (4) |
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6.4.1 Current Methods for Deriving Cerebral Organoids |
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132 | (2) |
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6.4.2 Applications of Cerebral Organoids: Disease Modeling |
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134 | (1) |
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6.4.3 Limitations in the Use of Cerebral Organoids |
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135 | (1) |
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6.5 Epigenetic Considerations in hiPSC Donor Cell Choice |
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136 | (1) |
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137 | (3) |
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6.6.1 Techniques to Age hiPSCs |
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137 | (1) |
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6.6.2 Aging and Dedifferentiation |
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138 | (1) |
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139 | (1) |
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6.7 Drug Testing Using hiPSCs |
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140 | (2) |
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6.7.1 Facilitating Clinical Trials |
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140 | (1) |
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6.7.2 Titrating Drug Dosage |
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140 | (1) |
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6.7.3 Evaluating Chemotherapies |
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141 | (1) |
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6.7.4 Steering Personalized Medicine |
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141 | (1) |
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6.7.5 Forging Neural Networks |
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142 | (1) |
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6.8 Promises in the Field |
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142 | (3) |
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6.8.1 High-Throughput Automation |
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142 | (1) |
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6.8.2 Neural Tissue Engineering Using hiPSCs |
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142 | (1) |
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6.8.3 hiPSC-Based Transplantation Therapies |
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143 | (1) |
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6.8.4 Advances Using Gene-Editing Technologies |
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144 | (1) |
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145 | (1) |
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146 | (13) |
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7 Modeling Genetic and Environment Interactions Relevant to Huntington's and Parkinson's Disease in Human Induced Pluripotent Stem Cells (hiPSCs)-Derived Neurons |
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159 | (14) |
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7.1 Gene-Environment Interactions Assessed in hiPSC-Derived Neurons |
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159 | (1) |
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7.2 Modeling of Neurological Diseases with hiPSCs |
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160 | (2) |
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7.3 Cell Viability Assays |
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162 | (1) |
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163 | (1) |
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164 | (1) |
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7.6 Neurite Length by Immunocytochemistry (ICC) |
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164 | (2) |
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166 | (1) |
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167 | (6) |
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8 Alcohol Effects on Adult Neural Stem Cells - A Novel Mechanism of Neurotoxicity and Recovery in Alcohol Use Disorders |
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173 | (50) |
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173 | (2) |
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8.2 The "Birth" of the Study of "Neuronal Cell Birth" |
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175 | (5) |
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8.3 Components of Adult Stem-Cell-Driven Neurogenesis |
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180 | (9) |
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8.3.1 Permissive Sites of Adult Neurogenesis in Brain |
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180 | (2) |
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8.3.2 Stem Cells Versus Progenitors |
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182 | (2) |
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184 | (3) |
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8.3.4 Differentiation and Migration |
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187 | (1) |
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8.3.5 Cell Survival and Integration |
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188 | (1) |
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8.4 Alcohol Effects on Adult Neural Stem Cells and Neurogenesis |
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189 | (7) |
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189 | (4) |
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8.4.2 Differentiation and Migration |
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193 | (1) |
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8.4.3 Survival and Integration |
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194 | (2) |
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8.5 Extrinsic Factors Influence the Neurogenic Niche |
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196 | (2) |
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8.6 Alcohol and the Niche |
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198 | (2) |
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200 | (1) |
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201 | (22) |
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9 Fetal Alcohol Spectrum Disorders: A Stem-Cellopathy? |
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223 | (38) |
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9.1 Fetal Alcohol Spectrum Disorders |
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223 | (2) |
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225 | (9) |
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9.2.1 Totipotent Stem Cells |
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227 | (3) |
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9.2.2 Placental Stem Cells - Trophoblast |
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230 | (1) |
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9.2.3 Embryonic Stem Cells and Induced Pluripotent Stem Cells |
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231 | (3) |
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234 | (1) |
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234 | (1) |
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235 | (3) |
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9.4.1 Cardiac Development |
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235 | (2) |
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237 | (1) |
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238 | (5) |
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9.5.1 Neuroectoderm Development |
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238 | (1) |
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239 | (1) |
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9.5.3 Neural Tube Development |
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240 | (3) |
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243 | (2) |
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9.6.1 Fetal Origin of Adult Stem Cells |
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243 | (1) |
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244 | (1) |
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245 | (1) |
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245 | (1) |
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246 | (15) |
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10 Toxicological Responses in Keratinocyte Interfollicular Stem Cells |
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261 | (24) |
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10.1 Epidermal Keratinocyte Stem Cells |
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261 | (6) |
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267 | (2) |
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269 | (4) |
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273 | (1) |
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10.5 Conclusions and Prospective Considerations |
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274 | (1) |
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275 | (10) |
| Part IV Recent Innovations in Stem Cell Bioassay and Platform Development |
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285 | (56) |
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11 Stem-Cell Microscale Platforms for Toxicology Screening |
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287 | (22) |
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287 | (1) |
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11.2 Stem Cell Models for Toxicology Assessment |
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288 | (2) |
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11.3 Biomimetic Microscale Systems for Drug Screening |
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290 | (3) |
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11.3.1 Design and Microfabrication: Soft Lithography and Replica Molding |
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290 | (2) |
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11.3.2 Microcontact Printing and Surface Patterning |
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292 | (1) |
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11.3.3 Robotic Spotting and Printing |
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292 | (1) |
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11.4 Microtechnologies for Drug Discovery |
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293 | (1) |
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11.5 Devices for High-Throughput Toxicology Studies |
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294 | (1) |
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11.6 Cellular Microarray Platforms |
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295 | (3) |
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11.7 Microfluidic Platforms |
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298 | (3) |
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11.8 Conclusions and Future Perspectives |
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301 | (1) |
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301 | (1) |
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302 | (7) |
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12 HepaRG Cells as a Model for Hepatotoxicity Studies |
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309 | (32) |
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Christiane Guguen-Guillouzo |
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309 | (1) |
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12.2 Characteristics of HepaRG Cells |
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310 | (6) |
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12.2.1 A Bipotent Human Liver Cell Line |
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310 | (4) |
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12.2.2 HepaRG Hepatocytes Express Liver-Specific Functions |
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314 | (1) |
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12.2.3 Long-Term Functional Stability of HepaRG Hepatocytes |
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315 | (1) |
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12.3 Biotransformation and Detoxification Activities |
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316 | (4) |
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12.3.1 Drug Metabolism Capacity |
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316 | (2) |
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12.3.2 Biokinetics and Intrinsic Clearances |
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318 | (1) |
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319 | (1) |
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320 | (8) |
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12.4.1 Hepatotoxicity Screening |
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320 | (2) |
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12.4.2 Cellular Cytotoxicity |
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322 | (2) |
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12.4.3 Genotoxicity and Carcinogenicity Screening |
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324 | (1) |
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12.4.4 Identification of Target Genes |
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325 | (1) |
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326 | (1) |
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327 | (1) |
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328 | (1) |
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12.5 Conclusions and Perspectives |
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328 | (1) |
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329 | (1) |
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330 | (11) |
| Index |
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341 | |
Lisainfo e-raamatute kohta