Biology, life sciences Books

Book SynopsisA comprehensive and timely review of developments in the field, Cell and Molecular Biology of Stem Cell Imaging features original and review articles written by experts in their fields.Table of ContentsContributors vii Preface xi 1 Cell and Molecular Biology and Imaging of Stem Cells: Stem Cells from the Amniotic Fluid and Placenta 1Amritha Kidiyoor, Sean V. Murphy, and Anthony Atala 2 Biomaterials as Artificial Niches for Pluripotent Stem Cell Engineering 21Kyung Min Park and Sharon Gerecht 3 Low-Intensity Ultrasound in Stem Cells and Tissue Engineering 45Byung Hyune Choi, Kil Hwan Kim, Mrigendra Bir Karmacharya, Byoung-Hyun Min and So Ra Park 4 Mammalian Neo-Oogenesis from Ovarian Stem Cells In Vivo and In Vitro 67Antonin Bukovsky and Michael R. Caudle 5 Oct4-EGFP Transgenic Pigs as a New Tool for Visualization of Pluripotent and Reprogrammed Cells 137Monika Nowak-Imialek and Heiner Niemann 6 Regulation of Adult Intestinal Stem Cells through Thyroid Hormone-Induced Tissue Interactions during Amphibian Metamorphosis 153Atsuko Ishizuya-Oka 7 Stem Cell Therapy for Veterinary Orthopedic Lesions 173Anna Paula Balesdent Barreira and Ana Liz Garcia Alves 8 Sex Steroid Combinations in Regenerative Medicine for Brain and Heart Diseases: The Vascular Stem Cell Niche and a Clinical Proposal 193Antonin Bukovsky and Michael R. Caudle 9 Hair Follicle Stem Cells 211Hilda Amalia Pasolli 10 The Potential of Using Induced Pluripotent Stem Cells in Skin Diseases 223Shigeki Ohta, Ophelia Veraitch, Hideyuki Okano, Manabu Ohyama, and Yutaka Kawakami 11 Mitochondrial Differentiation in Early Embryo Cells and Pluripotent Stem Cells 247Heide Schatten, Qing-Yuan Sun, and Randall S. Prather 12 The Role of Centrosomes in Cancer Stem Cell Functions 259Heide Schatten Index 281

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Book SynopsisMicroRNAs in Medicine provides an access point into the current literature on microRNA for both scientists and clinicians, with an up-to-date look at what is happening in the emerging field of microRNAs and their relevance to medicine.Table of ContentsForeword ix Sir David Baulcombe Preface xi Contributors xiii 1 MICRORNAS: A BRIEF INTRODUCTION 1 Charles H. Lawrie PART I: MICRORNAS AS PHYSIOLOGICAL REGULATORS 25 2 MICRORNA REGULATION OF STEM CELL FATE AND REPROGRAMMING 27 Erika Lorenzo Vivas, Gustavo Tiscornia, and Juan Carlos Izpisua Belmonte 3 MICRORNAS AS REGULATORS OF IMMUNITY 41 Donald T. Gracias and Peter D. Katsikis 4 REGULATION OF SENESCENCE BY MICRORNAS 59 Ioannis Grammatikakis and Myriam Gorospe 5 THE EMERGENCE OF GEROMIRS: A GROUP OF MICRORNAS IMPLICATED IN AGING 77 Alejandro P. Ugalde, Agnieszka Kwarciak, Xurde M. Caravia, Carlos López-Otín, and Andrew J. Ramsay 6 MICRORNAS AND HEMATOPOIESIS 91 Sukhinder K. Sandhu and Ramiro Garzon 7 MICRORNAS IN PLATELET PRODUCTION AND ACTIVATION 101 Leonard C. Edelstein, Srikanth Nagalla, and Paul F. Bray PART II: MICRORNAS IN INFECTIOUS DISEASE: HOST–PATHOGEN INTERACTIONS 117 8 MICRORNAS AS KEY PLAYERS IN HOST-VIRUS INTERACTIONS 119 Aurélie Fender and Sébastien Pfeffer 9 MICRORNA EXPRESSION IN AVIAN HERPESVIRUSES 137 Yongxiu Yao and Venugopal Nair 10 FUNCTION OF HUMAN CYTOMEGALOVIRUS MICRORNAS AND POTENTIAL ROLES IN LATENCY 153 Natalie L. Reynolds, Jon A. Pavelin, and Finn E. Grey 11 INVOLVEMENT OF SMALL NON-CODING RNA IN HIV-1 INFECTION 165 Guihua Sun, John J. Rossi, and Daniela Castanotto 12 MICRORNA IN MALARIA 183 Panote Prapansilp and Gareth D.H. Turner PART III: CANCER 199 13 THE MICRORNA DECALOGUE OF CANCER INVOLVEMENT 201 Tanja Kunej, Irena Godnic, Minja Zorc, Simon Horvat, and George A. Calin 14 MICRORNAS AS ONCOGENES AND TUMOR SUPPRESSORS 223 Eva E. Rufi no-Palomares, Fernando J. Reyes-Zurita, Jose Antonio Lupiáñez, and Pedro P. Medina 15 LONG NON-CODING RNAS AND THEIR ROLES IN CANCER 245 Yolanda Sánchez and Maite Huarte 16 REGULATION OF HYPOXIA RESPONSES BY MICRORNA EXPRESSION 267 Carme Camps, Adrian L. Harris, and Jiannis Ragoussis 17 CONTROL OF RECEPTOR FUNCTION BY MICRORNAS IN BREAST CANCER 287 Claudia Piovan and Marilena V. Iorio 18 MICRORNAS IN HUMAN PROSTATE CANCER: FROM PATHOGENESIS TO THERAPEUTIC IMPLICATIONS 311 Mustafa Ozen and Omer Faruk Karatas 19 MICRORNA SIGNATURES AS BIOMARKERS OF COLORECTAL CANCER 329 Katrin Pfütze, Xiaoya Luo, and Barbara Burwinkel 20 GENETIC VARIATIONS IN MICRORNA-ENCODING SEQUENCES AND MICRORNA TARGET SITES ALTER LUNG CANCER SUSCEPTIBILITY AND SURVIVAL 343 Ming Yang and Dongxin Lin 21 MICRORNA IN MYELOPOIESIS AND MYELOID DISORDERS 353 Sara E. Meyer and H. Leighton Grimes 22 MICRORNA DEREGULATION BY ABERRANT DNA METHYLATION IN ACUTE LYMPHOBLASTIC LEUKEMIA 371 Xabier Agirre and Felipe Prósper 23 ROLE OF MIRNAS IN THE PATHOGENESIS OF CHRONIC LYMPHOCYTIC LEUKEMIA 383 Veronica Balatti, Yuri Pekarsky, Lara Rizzotto, and Carlo M. Croce 24 MICRORNA IN B-CELL NON-HODGKIN’S LYMPHOMA: DIAGNOSTIC MARKERS AND THERAPEUTIC TARGETS 403 Nerea Martínez, Lorena Di Lisio, and Miguel Angel Piris 25 MICRORNAS IN DIFFUSE LARGE B-CELL LYMPHOMA 419 Izidore S. Lossos and Alvaro J. Alencar 26 THE ROLE OF MICRORNAS IN HODGKIN’S LYMPHOMA 435 Wouter Plattel, Joost Kluiver, Arjan Diepstra, Lydia Visser, and Anke van den Berg 27 MICRORNA EXPRESSION IN CUTANEOUS T-CELL LYMPHOMAS 449 Cornelis P. Tensen PART IV: HEREDITARY AND OTHER NON-INFECTIOUS DISEASES 463 28 MICRORNAS AND HEREDITARY DISORDERS 465 Matías Morín and Miguel A. Moreno-Pelayo 29 MICRORNAS AND CARDIOVASCULAR DISEASES 477 Koh Ono 30 MICRORNAS AND DIABETES 495 Romano Regazzi 31 MICRORNAS IN LIVER DISEASES 509 Patricia Munoz-Garrido, Marco Marzioni, Elizabeth Hijona, Luis Bujanda, and Jesus M. Banales 32 MICRORNA REGULATION IN MULTIPLE SCLEROSIS 523 Andreas Junker 33 THE ROLE OF MICRORNAS IN ALZHEIMER’S DISEASE 539 Shahar Barbash and Hermona Soreq 34 CURRENT VIEWS ON THE ROLE OF MICRORNAS IN PSYCHOSIS 553 Aoife Kearney, Javier A. Bravo, and Timothy G. Dinan PART V: CIRCULATING MICRORNAS AS CELLULAR MESSENGERS AND NOVEL BIOMARKERS 567 35 CIRCULATING MICRORNAS AS NON-INVASIVE BIOMARKERS 569 Heidi Schwarzenbach and Klaus Pantel 36 CIRCULATING MICRORNAS AS CELLULAR MESSENGERS 589 Kasey C. Vickers 37 RELEASE OF MICRORNA-CONTAINING VESICLES CAN STIMULATE ANGIOGENESIS AND METASTASIS IN RENAL CARCINOMA 607 Federica Collino, Cristina Grange, and Giovanni Camussi PART VI: THERAPEUTIC USES OF MICRORNAS: CURRENT PERSPECTIVES AND FUTURE DIRECTIONS 623 38 MICRORNA REGULATION OF CANCER STEM CELLS AND MICRORNAS AS POTENTIAL CANCER STEM CELL THERAPEUTICS 625 Can Liu and Dean G. Tang 39 THERAPEUTIC MODULATION OF MICRORNAS 639 Achim Aigner and Hannelore Dassow 40 LOCKED NUCLEIC ACIDS AS MICRORNA THERAPEUTICS 663 Henrik Ørum Index 673

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Book Synopsis* Integrated textbook combining three subjects, haematology, clinical biochemistry and immunology to provide a one-stop text on blood science, in line with the new IBMS and NHS training structure * Suitable for blood science courses opening in many universities at senior Undergraduate level (units) and Masters level.Table of ContentsPreface, xiii Acknowledgements, xv List of Abbreviations, xvii About the Companion Website, xxi 1 Introduction to Blood Science, 1 1.1 What is blood science?, 1 1.2 Biochemistry, 6 1.3 Blood transfusion, 8 1.4 Genetics, 10 1.5 Haematology, 14 1.6 Immunology, 17 1.7 The role of blood science in modern healthcare, 19 1.8 What this book will achieve, 22 Summary, 23 References, 23 Further reading, 23 Web sites, 23 2 Analytical Techniques in Blood Science, 25 2.1 Venepuncture, 25 2.2 Anticoagulants, 26 2.3 Sample identification and tracking, 27 2.4 Technical and analytical confidence, 27 2.5 Major techniques, 32 2.6 Molecular genetics, 43 2.7 Point of care testing, 47 2.8 Health and safety in the laboratory, 48 Summary, 49 Further reading, 50 Web sites, 50 3 The Physiology of the Red Blood Cell, 51 3.1 Introduction, 51 3.2 The development of blood cells, 52 3.3 Erythropoiesis, 56 3.4 The red cell membrane, 58 3.5 The cytoplasm of the red cell, 60 3.6 Oxygen transport, 66 3.7 Recycling the red cell, 68 3.8 Red cell indices in the full blood count, 69 3.9 Morphology of the red cell, 72 Summary, 74 Further reading, 74 4 The Pathology of the Red Blood Cell, 75 4.1 Introduction: diseases of red cells, 75 4.2 Anaemia resulting from attack on, or stress to, the bone marrow, 78 4.3 Anaemia due to deficiency, 80 4.4 Intrinsic defects in the red cell, 85 4.5 External factors acting on healthy cells, 100 4.6 Erythrocytosis and polycythaemia, 103 4.7 Molecular genetics and red cell disease, 105 4.8 Inclusion bodies, 105 4.9 Case studies, 105 Summary, 107 References, 107 Further reading, 107 5 White Blood Cells in Health and Disease, 109 5.1 Introduction, 109 5.2 Leukopoiesis, 111 5.3 Neutrophils, 115 5.4 Lymphocytes, 116 5.5 Monocytes, 117 5.6 Eosinophils, 118 5.7 Basophils, 119 5.8 Leukocytes in action, 120 5.9 White cells in clinical medicine, 127 5.10 Case studies, 132 Summary, 132 Further reading, 133 6 White Blood Cell Malignancy 135 6.1 The genetic basis of leukocyte malignancy, 135 6.2 Tissue techniques in haemato-oncology, 139 6.3 Leukaemia, 141 6.4 Lymphoma, 149 6.5 Myeloma and related conditions, 152 6.6 Myelofibrosis and myelodysplasia, 157 6.7 Case studies, 157 Summary, 158 Further reading, 159 Guidelines, 159 7 The Physiology and Pathology of Haemostasis, 161 7.1 The blood vessel wall, 162 7.2 Platelets, 163 7.3 The coagulation pathway, 165 7.4 Haemostasis as the balance between thrombus formation and removal, 168 7.5 The haemostasis laboratory, 171 7.6 The pathology of thrombosis, 173 Summary, 175 Further reading, 175 8 The Diagnosis and Management of Disorders of Haemostasis, 177 8.1 Thrombosis 1: overactive platelets and thrombocytosis, 177 8.2 Thrombosis 2: overactive coagulation, 181 8.3 Haemorrhage 1: platelet underactivity and thrombocytopenia, 193 8.4 Haemorrhage 2: coagulation underactivity, 199 8.5 Disseminated intravascular coagulation, 203 8.6 Molecular genetics in haemostasis, 204 8.7 Case studies, 205 Summary, 206 References, 206 Further reading, 207 Guidelines, 207 Web sites, 207 9 Immunopathology, 209 9.1 Introduction, 209 9.2 Basics of the immune system, 210 9.3 Humoral immunity, 212 9.4 Immunopathology 1: immunodeficiency, 215 9.5 Immunopathology 2: hypersensitivity, 221 9.6 Immunopathology 3: autoimmune disease, 226 9.7 Immunotherapy, 232 9.8 The immunology laboratory, 234 9.9 Case studies, 238 Summary, 239 References, 240 Further reading, 240 Guidelines, 240 Web sites, 240 10 Immunogenetics and Histocompatibility, 241 10.1 The genetics of antigen recognition, 241 10.2 Human leukocyte antigens, 245 10.3 Transplantation, 251 10.4 Autoimmunity and human leukocyte antigens, 257 Summary, 260 Further reading, 260 Guidelines, 260 Web sites, 260 11 Blood Transfusion, 261 11.1 Blood collection and processing, 262 11.2 Blood groups, 265 11.3 Laboratory practice of blood transfusion, 273 11.4 Clinical practice of blood transfusion, 279 11.5 Hazards of blood transfusion, 281 Summary, 284 References, 284 Further reading, 284 Guidelines, 284 Web sites, 285 12 Waste Products, Electrolytes and Renal Disease, 287 12.1 Renal anatomy and physiology, 287 12.2 Homeostasis, 288 12.3 Excretion, 295 12.4 Renal endocrinology, 297 12.5 Renal disease, 298 12.6 Case studies, 301 Summary, 303 Further reading, 303 Guidelines, 303 Web sites, 303 13 Hydrogen Ions, pH, and Acid–Base Disorders, 305 13.1 Ions and molecules, 305 13.2 Blood gases, 308 13.3 Acidosis (pH <7.3), 312 13.4 Alkalosis (pH >7.5), 313 13.5 Mixed acid–base conditions, 314 13.6 Clinical interpretation, 314 13.7 Case studies, 315 Summary, 316 Further reading, 317 Web site, 317 14 Glucose, Lipids and Atherosclerosis, 319 14.1 Glucose, 319 14.2 Dyslipidaemia, 333 14.3 Atherosclerosis, 343 14.4 Case studies, 347 Summary, 348 Further reading, 348 Guidelines, 349 Web sites, 349 15 Calcium, Phosphate, Magnesium and Bone Disease, 351 15.1 Calcium, 352 15.2 Phosphates, 355 15.3 Magnesium, 355 15.4 The laboratory, 355 15.5 Disorders of calcium homeostasis, 357 15.6 Disorders of phosphate homeostasis, 360 15.7 Disorders of magnesium homeostasis, 362 15.8 Bone physiology, 363 15.9 Bone disease, 364 15.10 Case studies, 368 Summary, 369 Further reading, 370 Guidelines, 370 Web sites, 370 16 Nutrients and Gastrointestinal Disorders, 371 16.1 Nutrients, 371 16.2 The intestines, 375 16.3 Case studies, 381 Summary, 382 Further reading, 382 Guidelines, 382 17 Liver Function Tests and Plasma Proteins, 383 17.1 Anatomy and physiology of the liver, 384 17.2 Liver function tests, 389 17.3 Diseases of the liver, 390 17.4 Plasma proteins, 396 17.5 Case studies, 405 Summary, 406 Further reading, 406 Web sites, 406 18 Hormones and Endocrine Disorders, 407 18.1 Endocrine physiology, 407 18.2 The pathology of the endocrine system, 417 18.3 Case studies, 434 Summary, 435 Further reading, 435 Web sites, 436 19 Cancer and Tumour Markers, 437 19.1 General concepts in cancer biology, 437 19.2 Blood science and cancer, 440 19.3 Molecular genetics, 444 19.4 Case studies, 445 Summary, 446 Further reading, 446 Guidelines, 447 Web sites, 447 20 Inherited Metabolic Disorders, 449 20.1 The genetics of inheritance, 449 20.2 Molecular inherited metabolic disorders, 451 20.3 Organelle inherited metabolic disorders, 455 20.4 Antenatal diagnosis and neonatal screening, 455 20.5 Case studies, 456 Summary, 457 Further reading, 457 21 Drugs and Poisons, 459 21.1 Toxicology, 459 21.2 Toxicology of specific compounds, 461 21.3 Therapeutic drug monitoring, 465 21.4 Case studies, 468 Summary, 469 References, 469 Further reading, 469 22 Case Reports in Blood Science, 471 Abbreviations, 471 Case report 1, 472 Anaemia, hypercalcaemia, proteinuria, myeloma Case report 2, 473 Diabetes, glycated haemoglobin, chronic renal failure Case report 3, 474 Acute kidney injury, leucocytosis, neutrophilia, viruses Case report 4, 475 Part 1: Obesity, colorectal cancer, CEA, hypothyroidism. Part 2: Alcoholism, raised GGT and triacylglycerols Case report 5, 477 Part 1: No abnormalities. Part 2: Asthma, raised IgE. Part 3: Falling haemoglobin, rising ESR, lung cancer Case report 6, 479 Hypothyroidism, marginally reduced haemoglobin Case report 7, 480 Raised CRP, ESR, rheumatoid factor and anti-nuclear antibodies; borderline anti-dsDNA antibodies, low C3, low eGFR and so mild renal failure, systemic lupus erythematosus Case report 8, 481 Normal blood results in renal transplantation Case report 9, 482 Falling albumin, eGFR, haemoglobin, red cell count and platelets, rising ESR, white cell count and neutrophila, CRP, urea and creatinine, septicaemia Case report 10, 484 Microcytic anaemia, thrombocytopenia, lymphocytosis, abnormal LFTs, falling albumin, raised CRP, myositis with raised CK, viruses Case report 11, 486 Acidosis, hyperglycaemia, diabetic ketoacidosis, acute renal injury, raised urea and creatinine Case report 12, 487 Low haemoglobin, thrombocytopenia, raised CRP and d-dimers, abnormal LFTs, malaria, pregnancy Case report 13, 488 Raised aldosterone, hypernatraemia, hypokalaemia, Conn’s syndrome Case report 14, 489 Paediatric diabetic ketoacidosis, hyperglycaemia, low bicarbonate, raised phosphates, ALP and proteins References, 490 Appendix: Reference Ranges, 491 Further Reading, 493 Glossary, 495 Index, 519

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Book SynopsisNeuropsychopharmacology is a relatively new subject area in the neurosciences.Table of ContentsPreface xiii About the Companion Website xv 1 Introduction to Neuropsychopharmacology 1 1.1 Overview 1 1.2 A Brief Overview of the Anatomy and Function of the Brain 2 1.2.1 The Brainstem 2 1.2.2 The Metencephalon 3 1.2.3 Diencephalon 4 1.2.4 The Telencephalon 5 1.2.5 The Cerebral Ventricles and Cerebrospinal Fluid 7 1.3 Important Neurotransmitters 7 1.3.1 GABA and GABA Receptors 7 1.3.2 Glutamate and Glutamate Receptors 10 1.4 Central Nervous System Stimulant and Depressant Drugs 11 1.5 Central Nervous System (CNS) Stimulant Drugs 13 1.5.1 Psychomotor Stimulants 13 1.5.2 Analeptic Drugs 19 1.6 Depressant Drugs 21 1.6.1 Benzodiazepines 21 1.6.2 Other Depressant Drugs 23 1.7 Genetics 23 1.8 Electroencephalography and Imaging Techniques 24 1.8.1 Electroencephalography 24 1.8.2 X-Rays 24 1.8.3 Computed Tomography 24 1.8.4 Positron Emission Tomography 25 1.8.5 Magnetic Resonance Imaging 25 1.8.6 Functional MRI 25 1.9 Diagnostic Criteria for Mental Disorders 25 1.10 Animals Models for CNS Disorders 26 1.11 Summary 27 2 Parkinson’s Disease 28 2.1 Overview 28 2.2 Historical Background 28 2.3 Epidemiology 29 2.4 Primary Clinical Features 29 2.5 Secondary Clinical Features 30 2.6 Parkinson’s Disease and the Extrapyramidal System 31 2.7 Neurotransmission in the Extrapyramidal System and Parkinson’s Disease 33 2.7.1 Modulation of the Direct and Indirect Pathways 35 2.8 Causes of Parkinson’s Disease 36 2.8.1 Genes and Parkinson’s Disease 37 2.8.2 Environmental Neurotoxins 39 2.8.3 Oxidative Stress 41 2.9 Summary 42 2.10 Pharmacotherapy for Parkinson’s Disease 42 2.10.1 L-DOPA (L-Dihydroxyphenylalanine) 43 2.10.2 L-DOPA Treatment 44 2.10.3 Adverse Effects of L-DOPA 44 2.10.4 Adverse Effects after Long-Term Treatment 46 2.10.5 Alternative Formulations of L-DOPA and Other Pharmacological Agents 48 2.11 Nonmotor Symptoms of Parkinson’ Disease and the Development of a New Hypothesis 53 2.12 Pharmacological and Nonpharmacological Strategies for Treatment of Other Motor and Nonmotor Symptoms of Parkinson’s Disease 55 2.13 Other Nonpharmacological Methods of Treating Parkinson’s Disease 56 2.13.1 Lesions of the Globus Pallidus or Subthalamic Nucleus 56 2.13.2 Neurostimulation 57 2.13.3 Brain Grafts 57 2.14 Possible Future Strategies to Treat Parkinson’s Disease 58 2.14.1 Stem Cell Therapy 58 2.14.2 Gene Therapy 58 2.15 Early Diagnosis for Treatment of Parkinson’s Disease 59 2.16 Summary and Conclusions 59 3 Memory, Dementia and Alzheimer’s Disease 61 3.1 Overview 61 3.2 Learning and Memory 61 3.2.1 Temporal Stages of Learning, Memory and Recall 62 3.2.2 Where are STM and LTM Stored in the Brain? 67 3.3 Overview of Dementia 69 3.4 Alzheimer’s Disease (AD) 71 3.4.1 Clinical Symptoms of Alzheimer’s Disease 72 3.4.2 Neuropathological Changes 74 3.4.3 Molecular Pathology 74 3.4.4 Staging of Alzheimer’s Disease 80 3.4.5 Onset of Alzheimer’s Disease 80 3.4.6 Neurochemical Changes in Alzheimer’s Disease 82 3.4.7 Pharmacotherapy of Alzheimer’s Disease 85 3.4.8 Future Pharmacological Strategies in the Treatment of Alzheimer’s Disease 88 3.4.9 Cardiovascular Disease 91 3.4.10 Conclusions 91 3.5 Summary 92 4 Epilepsy 93 4.1 Overview 93 4.2 Background 94 4.3 Classification and Types of Epilepsy 94 4.3.1 Focal Seizures 94 4.3.2 Generalized Seizures 95 4.3.3 Epilepsy Syndromes 97 4.3.4 Epidemiology 98 4.4 Underlying Causes of Epilepsy 98 4.5 Epileptic Mechanisms 99 4.5.1 Electrophysiological Mechanisms 99 4.5.2 Mechanisms Underpinning Drug Treatment of Epilepsy 100 4.6 Pharmacotherapy 101 4.6.1 Valproate (Valproic Acid and Sodium Valproate) 101 4.6.2 Phenytoin 105 4.6.3 Carbamazepine 106 4.6.4 Ethosuximide 107 4.6.5 Gabapentin 107 4.6.6 Pregabalin 108 4.6.7 Lamotrigine 109 4.6.8 Tiagabine 109 4.6.9 Topiramate 110 4.6.10 Levetiracetam 110 4.6.11 Retigabine 111 4.6.12 Zonisamide 111 4.6.13 Benzodiazepines 112 4.6.14 Barbiturates 112 4.7 Vagal Nerve Stimulation 113 4.8 Summary 113 5 Attention Deficit Hyperactivity Disorder 115 5.1 Overview 115 5.2 Background to ADHD 116 5.3 Diagnostic Criteria for ADHD 118 5.4 ADHD and Comorbidity 119 5.5 Epidemiology 120 5.6 Aetiology of ADHD 120 5.6.1 Genetic Factors 120 5.6.2 Environmental Factors 121 5.7 The Pathophysiology of ADHD 122 5.7.1 The Prefrontal Cortex, Executive Function and ADHD 122 5.7.2 Frontocortical-Striatal Networks and ADHD 126 5.8 The Biochemical Hypothesis of ADHD 130 5.9 Executive Functional Skills, Neurodevelopment and ADHD 132 5.10 Summary of the Pathophysiology of ADHD 135 5.11 Management of ADHD 135 5.11.1 Pharmacotherapy 136 5.11.2 Nonpharmacological Management of ADHD 142 5.12 Summary and Conclusions 144 6 Affective Disorders 1: Depression 147 6.1 Outline 147 6.2 Emotion, Mood and Affective Disorders 148 6.3 Background to Depression 149 6.4 Clinical Features of Major Depressive Disorder 150 6.4.1 Subtypes of Depressive Disorders 150 6.5 Epidemiology 152 6.6 Causes of Depression 153 6.6.1 Genetic Influences 153 6.6.2 Biochemical Hypotheses of Depression 154 6.7 Stress, Learned Helplessness and Depression 163 6.7.1 Stress and MDD 164 6.7.2 What is Stress? 164 6.7.3 Stress and Depression 166 6.7.4 Brain Derived Neurotropic Factor, Neurotropic Effects and Depression 167 6.7.5 Genetics, Stress and Depression 168 6.7.6 Early-Life Stress, Depression and Epigenetics 169 6.7.7 Depression and Inflammation 171 6.7.8 Depression and Glutamate 171 6.7.9 Depression and Physical Diseases 171 6.8 Drug Treatment of Depression 172 6.8.1 Overview 172 6.8.2 Types of Antidepressant Drug 174 6.8.3 Possible Future Drugs for MDD 186 6.9 Nonpharmacological Treatments for Depression 187 6.9.1 Electroconvulsive Therapy 187 6.9.2 Transcranial Magnetic Stimulation 188 6.9.3 Vagus Nerve Stimulation 189 6.9.4 Phototherapy (Light Therapy) 189 6.9.5 Deep Brain Stimulation 190 6.9.6 Cognitive Behavioural Therapy 190 6.9.7 Interpersonal Therapy 191 6.9.8 Behavioural Therapy 192 6.9.9 Mindfulness-Based Cognitive Therapy 192 6.10 Summary 192 7 Affective Disorders 2: Bipolar Disorder 194 7.1 Outline 195 7.2 Background to Bipolar Disorder 195 7.3 Clinical Features of Bipolar Disorder and Diagnostic Criteria 196 7.3.1 Symptoms of Mania 196 7.3.2 Symptoms of Hypomania 197 7.3.3 Symptoms of Depression 197 7.3.4 Categories of Bipolar Disorder 197 7.3.5 Rapid Cycling 197 7.3.6 Mixed Features 197 7.3.7 Cyclothymia 198 7.3.8 Suicide 198 7.3.9 Course of Illness 198 7.4 Epidemiology 198 7.5 Cause of Bipolar Disorder 199 7.5.1 Genetic Factors 199 7.5.2 Environmental Factors 199 7.5.3 Neurobiology of Bipolar Disorder 199 7.6 Management of Bipolar Disorder 201 7.6.1 Pharmacotherapy 201 7.6.2 Drugs Used in the Treatment of Bipolar Disorder 204 7.7 Pregnancy and Bipolar Disorder 208 7.8 Psychological Treatments 208 7.8.1 Psychoeducation 208 7.8.2 Family-Focused Treatment 209 7.8.3 Cognitive Behavioural Therapy 209 7.8.4 Interpersonal and Social Rhythm Therapy 209 7.8.5 Lifestyle Changes 210 7.9 Summary and Conclusions 210 8 Anxiety Disorders 211 8.1 Overview 211 8.2 Background 212 8.3 Anxiety Disorders and Diagnostic Criteria 212 8.3.1 Generalized Anxiety Disorder 212 8.3.2 Social Anxiety Disorder 213 8.3.3 Panic Attack and Panic Disorder 214 8.3.4 Agoraphobia 215 8.3.5 Others Types of Anxiety Disorders 216 8.4 Neurobiology of Anxiety Disorders 216 8.4.1 Fear and the Amygdala 216 8.4.2 Anatomy and Circuitry of the Amygdala 217 8.4.3 Physiological Responses to Fear-Eliciting Stimuli 217 8.4.4 Conditioned Fear Response 220 8.4.5 Conditioned Fear Extinction 223 8.5 Worry 224 8.6 Are there Other Anxiety Circuits? 225 8.7 Neurotransmitters and Anxiety Disorders 225 8.8 Management of Anxiety Disorders 226 8.8.1 Pharmacotherapy 226 8.8.2 Psychosocial Therapies 232 8.9 Summary and Outcomes 234 9 Sleep and Sleep Disorders 236 9.1 Overview 236 9.2 Introduction 237 9.3 Physiology of Sleep 238 9.3.1 Stages of Sleep 238 9.3.2 The Ascending Reticular Activating System 240 9.3.3 Slow Wave Sleep Mechanisms 242 9.3.4 Rapid Eye Movement Sleep Mechanisms 245 9.4 Sleep Disorders 246 9.4.1 Insomnia 246 9.4.2 Hypersomnia or Hypersomnolence 254 9.5 Summary and Conclusions 257 10 Schizophrenia 259 10.1 Overview 259 10.2 Background 260 10.3 Clinical Features of Schizophrenia 264 10.3.1 Phases of Schizophrenia 264 10.3.2 Diagnostic Criteria for Schizophrenia 265 10.3.3 Violence, Self-Harm and Suicide 265 10.3.4 General Physical Health and Mortality 266 10.4 Epidemiology 266 10.5 Pathology 266 10.6 Aetiology 267 10.6.1 Genetics of Schizophrenia 267 10.6.2 Environmental Risk Factors 268 10.7 Developmental Hypothesis of Schizophrenia 270 10.8 Biochemical Hypotheses 270 10.8.1 Dopamine and the Dopamine Hypothesis of Schizophrenia 270 10.8.2 The Mesolimbic System and Schizophrenia 273 10.8.3 The Mesocortical System and Schizophrenia 273 10.8.4 Glutamate, GABA and Dopamine: A Revised Hypothesis of Schizophrenia 274 10.9 Management of Schizophrenia 277 10.9.1 Pharmacotherapy 277 10.9.2 Nonpharmacological Management of Schizophrenia 288 10.10 Summary and Conclusions 288 11 Drug Abuse and Addiction 290 11.1 Outline 290 11.2 Background 291 11.3 Neurobiology of Substance Abuse and Addiction 293 11.3.1 The Mesolimbic Reward Systems and Addictive Drugs 293 11.3.2 Extensions of the Hypothesis 298 11.3.3 Transition from Hedonic Actions to Habits to Compulsions 300 11.3.4 Summary 301 11.4 Risk Factors 301 11.4.1 Environmental Factors 301 11.4.2 Genetic Factors 302 11.5 Management of Addiction 302 11.5.1 Alcohol 306 11.5.2 Heroin 307 11.6 Summary 308 References 310 Index 327

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Book SynopsisMetabolic Syndrome and Neurological Disorders compiles data and analyses of the cluster of common pathologies to generate a complete, updated guide to the link between metabolic syndrome and neurological disorders.Table of ContentsForeword Mark P. Mattson xi Preface Tahira Farooqui and Akhlaq A. Farooqui xiii Acknowledgments Tahira Farooqui and Akhlaq A. Farooqui xv Contributors xvii 1 Insulin Resistance and Metabolic Failure Underlie Alzheimer Disease 1 Suzanne M. de la Monte and Ming Tong 2 Insulin Receptor and the Pathophysiology of Alzheimer Disease 31 Johanna Zemva and Markus Schubert 3 Contribution of Insulin Resistance in Pathogenesis of Alzheimer Disease 51 Adnan Erol 4 Insulin–Leptin Signaling in the Brain 75 Vicente Barrios, Emma Burgos-Ramos, and Jes´us Argente 5 The Janus Face of Insulin in Brain 85 Ana Duarte, Emanuel Candeias, S´onia C. Correia, Renato X. Santos, Cristina Carvalho, Susana Cardoso, Ana I. Pl´acido, Maria S. Santos, Catarina R. Oliveira, and Paula I. Moreira 6 Modulation of Cognition by Insulin and Aging: Implications for Alzheimer Disease 115 Maite Solas and Maria J. Ram´ýrez 7 Contribution of Phospholipid, Sphingolipids, and Cholesterol-Derived Lipid Mediators in the Pathogenesis of Metabolic Syndrome and Neurological Disorders 137 Akhlaq A. Farooqui and Tahira Farooqui 8 Lipids, Cholesterol, and Oxidized Cholesterol in Alzheimer Amyloid Beta-Mediated Neurotoxicity 163 Mun’delanji C. Vestergaard, Masamune Morita, Tsutomu Hamada, and Masahiro Takagi 9 Of Sound Mind and Body: Dietary Lifestyles, Promotion of Healthy Brain Aging, and Prevention of Dementia in Healthy Individuals 179 Giulio Maria Pasinetti, Amanda Bilski, Lap Ho, Jun Wang, Mario Ferruzzi, Masahito Yamada, Kenjiro Ono, and Salvatore Mannino 10 Metabolic Syndrome as an Independent Risk Factor of Silent Brain Infarction 191 Jae-Sung Lim and Hyung-Min Kwon 11 Neurochemical Linkage Among Metabolic Syndrome, Alzheimer Disease, and Depression 197 Undurti N. Das 12 Alterations in the Endocannabinoid System as a Link Between Unbalanced Energy Homeostasis, Neuroinflammation, and Neurological and Neuropsychiatric Disorders 219 Tiziana Bisogno and Vincenzo Di Marzo 13 Metabolic Syndrome, Alzheimer Disease, Schizophrenia, and Depression: Role for Leptin, Melatonin, Kynurenine Pathways, and Neuropeptides 235 George Anderson and Michael Maes 14 Binge Eating and Metabolic Syndrome 249 Ignacio J´auregui-Lobera 15 Phytochemical Principles in the Traditional Indian System of Medicine Used for the Management of Metabolic Syndrome 261 Syed Ibrahim Rizvi and Neetu Mishra 16 Oxidative Stress and Obesity: Their Impact on Metabolic Syndrome 275 Morihiro Matsuda and Iichiro Shimomura 17 The Relationship Among Obesity, Inflammation, and Insulin Resistance 283 Jean-Philippe Bastard and Bruno F`eve 18 Involvement of Adipocytokines in Pathogenesis of Insulin Resistance, Obesity, and Metabolic Syndrome 297 Hardik Gandhi and Ramachandran Balaraman 19 Obesity, Inflammation, and Vascular Disease: Novel Insight in the Role of Adipose Tissue 311 Paolo Calabro, Enrica Golia, Valeria Maddaloni, Giuseppe Limongelli, Brunella Ziello, Fabio Fimiani, Ilaria Jane Romano, Mario Crisci, Maria Giovanna Russo, Edward T.H. Yeh, and Raffaele Calabro 20 Is Diabetes a Risk Factor for Parkinson Disease? 327 Akhlaq A. Farooqui and Tahira Farooqui 21 Role of Iron in the Pathogenesis of Diabetes and Metabolic Syndrome 335 Lu Cai 22 Contributions of AMP Kinase to the Pathogenesis of Type 2 Diabetes and Neurodegenerative Diseases 363 Mohamed Kodiha, Hicham Mahboubi, and Ursula Stochaj 23 A_ Deposition, Insulin Signaling, and Tau Phosphorylation in Animal Models of Alzheimer Disease and Diabetes 383 Naoyuki Sato and Ryuichi Morishita 24 In Vivo Evidence of the Convergence of Type 2 Diabetes and Alzheimer Disease 395 Sun Ah Park 25 Metabolic Syndrome and its Impact on Cardiovascular Disease 409 John A. Larry 26 Contribution of Inflammation, Adiponectin, and Obesity in Cardiovascular Diseases 423 Harald Mangge and Gunter Almer 27 Brain and Cardiovascular Diseases: Molecular Aspects 439 Ewa Szczepanska-Sadowska 28 Molecular Aspects of Dietary–Exercise Regimen for the Prevention of Metabolic Syndrome 461 Wataru Aoi 29 Ghrelin, Lipid Metabolism, and Metabolic Syndrome 475 Pablo B. Mart´ýnez de Morentin, Sulay Tovar, Rub´en Nogueiras, Miguel L´opez, and Carlos Di´eguez 30 Leptin and Cognitive Function 485 Jenni Harvey 31 Fructose, Sugar Consumption, and Metabolic Diseases 501 Virgile Lecoultre and Luc Tappy 32 Inflammation-Mediated Cognitive and Emotional Alterations in Experimental Models of Metabolic Syndrome 515 Nathalie Castanon and Sophie Lay´e 33 Summary and Perspective 529 Tahira Farooqui and Akhlaq A. Farooqui Index 539 Color plate section is located between pages 196 and 197.

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Book SynopsisWritten by a team of leading international specialists, this book comprehensively covers current knowledge of the chemical ecology of insect parasitoids. Chapters are organized in order to present the most significant discoveries of the last few decades, and on their potential application in pest control strategies.Trade Review“This volume will contribute to future syntheses and help integrate insect parasitoids within chemical and community ecology and, hopefully, eventual strategic applications in pest management programs. Summing Up: Recommended. Graduate students, researchers/faculty, and professionals.” (Choice, 1 January 2014) Table of ContentsContributors xi 1 Chemical ecology of insect parasitoids: towards a new era 1 Stefano Colazza and Eric Wajnberg Abstract 1 1.1 Introduction 1 1.2 Integrating behavioural ecology and chemical ecology in insect parasitoids 3 1.3 The use of chemical ecology to improve the efficacy of insect parasitoids in biological control programmes 4 1.4 Overview 5 1.5 Conclusions 6 Acknowledgements 6 References 7 Part 1 Basic concepts 9 2 Plant defences and parasitoid chemical ecology 11 Paul J. Ode Abstract 11 2.1 Introduction 12 2.2 Plant defences against a diversity of attackers 13 2.2.1 Plant defence signalling pathways 13 2.2.2 Plant volatiles and parasitoids 16 2.2.3 Plant toxins and parasitoids 18 2.2.4 Cross-talk between plant defence pathways 21 2.3 Above-ground–below-ground interactions and parasitoids 24 2.4 Climate change and parasitoid chemical ecology 25 2.5 Conclusions 28 Acknowledgements 28 References 28 3 Foraging strategies of parasitoids in complex chemical environments 37 Nicole Wäschke, Torsten Meiners and Michael Rostás Abstract 37 3.1 Introduction 37 3.2 Chemical complexity 40 3.2.1 Plant species diversity and habitat location 40 3.2.2 Variability in host plant traits and their effects on parasitoid host location 42 3.3 Foraging strategies of parasitoids in chemically complex environments 48 3.3.1 Behavioural responses to chemical complexity 48 3.3.2 Learning, sensory fi lters and neural constraints affecting strategies for dealing with complexity 50 3.3.3 Infl uences of life history traits on foraging strategy 51 3.4 Conclusions 53 References 54 4 Chemical ecology of insect parasitoids in a multitrophic above- and below-ground context 64 Roxina Soler, T. Martijn Bezemer and Jeffrey A. Harvey Abstract 64 4.1 Introduction 65 4.2 Influence of root feeders on above-ground insect herbivores 67 4.3 Influence of soil-borne symbionts on above-ground insect herbivores 69 4.4 Plant-mediated effects of root feeders and soil-borne symbionts on growth and development of parasitoids 70 4.5 Effects of root-feeding insects on HIPVs and host location of parasitoids 74 4.6 Expanding an above–below-ground bitrophic reductionist perspective 76 Acknowledgement 79 References 79 5 A hitch-hiker’s guide to parasitism: the chemical ecology of phoretic insect parasitoids 86 Martinus E. Huigens and Nina E. Fatouros Abstract 86 5.1 Phoresy 87 5.2 Prevalence of phoretic parasitoids 87 5.3 Important parasitoid and host traits 90 5.3.1 Parasitoid traits 90 5.3.2 Host traits 92 5.4 Chemical espionage on host pheromones 93 5.4.1 Espionage on male aggregation pheromone 93 5.4.2 Espionage on sex pheromones 98 5.4.3 Espionage on anti-sex pheromones 99 5.5 Coevolution between phoretic spies and hosts 100 5.6 Biological control 103 5.7 Future perspectives 103 Acknowledgements 104 References 105 6 Novel insights into pheromone-mediated communication in parasitic hymenopterans 112 Joachim Ruther Abstract 112 6.1 Introduction 113 6.2 Pheromones and sexual behaviour 119 6.2.1 Volatile sex attractants 119 6.2.2 Female-derived courtship pheromones 124 6.2.3 Male-derived courtship pheromones 127 6.3 Other pheromones 128 6.3.1 Marking pheromones 128 6.3.2 Putative alarm and appeasement pheromones 129 6.3.3 Aggregation pheromones 130 6.3.4 Anti-aggregation pheromones 130 6.4 Variability in pheromone-mediated sexual behaviour 131 6.4.1 Innate plasticity of pheromone behaviour 131 6.4.2 Learnt plasticity of pheromone behaviour 131 6.4.3 Plasticity of pheromone behaviour caused by abiotic factors 132 6.5 Pheromone biosynthesis 132 6.6 Evolution of parasitoid sex pheromones 133 6.7 Conclusions and outlook 135 References 136 7 Chemical ecology of tachinid parasitoids 145 Satoshi Nakamura, Ryoko T. Ichiki and Yooichi Kainoh Abstract 145 7.1 Introduction 146 7.2 Long-range orientation 155 7.2.1 Long-range orientation by direct type parasitoids 155 7.2.2 Long-range orientation by indirect type parasitoids 157 7.2.3 Host pheromones used by direct type parasitoids 158 7.3 Short-range orientation 159 7.3.1 Short-range orientation by direct type parasitoids 159 7.3.2 Short-range orientation by indirect type parasitoids 161 7.4 Conclusions 163 Acknowledgements 163 References 164 8 Climate change and its effects on the chemical ecology of insect parasitoids 168 Jarmo K. Holopainen, Sari J. Himanen and Guy M. Poppy Abstract 168 8.1 On climate change and chemical ecology 169 8.2 Direct climate change impacts on parasitoids 171 8.3 Climate change and bottom-up impacts on parasitoids: herbivore host and plant host quality 172 8.4 Impacts of climate change-related abiotic stresses on parasitoid ecology and behaviour 175 8.4.1 Impacts of elevated temperature 175 8.4.2 Precipitation and drought 176 8.4.3 Gaseous reactive air pollutants 177 8.4.4 Atmospheric CO2 concentration 179 8.4.5 Parasitoid response to combined abiotic stresses 180 8.5 Climate change impacts on biological control 181 8.6 Ecosystem services provided by parasitoids: impact of changing climate 182 8.7 Future research directions and conclusions 184 References 185 Part 2 Applied concepts 191 9 Chemical ecology of insect parasitoids: essential elements for developing effective biological control programmes 193 Torsten Meiners and Ezio Peri Abstract 193 9.1 Introduction 194 9.2 Essential elements in parasitoid chemical ecology 196 9.3 Manipulation of the population levels of natural enemies by semiochemicals 201 9.4 Limits and perspectives of behavioural manipulation of parasitoids by applying semiochemicals 204 9.5 Cautionary example: interspecifi c competitive interactions in parasitoids 210 9.6 Conclusions 212 References 213 10 The application of chemical cues in arthropod pest management for arable crops 225 Maria Carolina Blassioli-Moraes, Miguel Borges and Raul Alberto Laumann Abstract 225 10.1 Arable crops: characteristics of the systems and trophic interactions mediated by chemical cues 226 10.2 Methodologies for using chemical cues to attract and retain parasitoids in arable crops 227 10.2.1 Direct application of semiochemicals 228 10.2.2 Environmental manipulation 236 10.3 Final considerations 237 Acknowledgements 239 References 239 11 Application of chemical cues in arthropod pest management for orchards and vineyards 245 Stefano Colazza, Ezio Peri and Antonino Cusumano Abstract 245 11.1 Introduction 246 11.2 Pheromone-based tactics in orchards and vineyards 247 11.2.1 Host sex pheromones 247 11.2.2 Parasitoid pheromones 248 11.3 Allelochemical-based manipulation in orchards and vineyards 249 11.3.1 Herbivore-induced plant volatiles (HIPVs) 249 11.3.2 Host-associated volatiles (HAVs) 257 11.4 Conclusions 260 Acknowledgement 261 References 261 12 Application of chemical cues in arthropod pest management for organic crops 266 Marja Simpson, Donna M.Y. Read and Geoff M. Gurr Abstract 266 12.1 Introduction: organic farming and compatibility of chemical cues 267 12.2 Overview of plant defences involving plant volatiles 268 12.3 The use of synthetic HIPVs in pest management 269 12.4 Arthropod pest management strategies used in organic farming 273 12.5 Potential for extending chemical cue use in organic systems 275 12.6 Conclusions 277 References 277 13 Application of chemical cues in arthropod pest management for forest trees 282 Timothy D. Paine Abstract 282 13.1 Forest insect herbivores and natural enemy host/prey finding 283 13.2 Introduction to forest systems 285 13.3 Examples from North America 287 13.3.1 Native bark beetles in plantation and unmanaged forests 287 13.3.2 Introduced defoliator in urban and unmanaged forests 288 13.3.3 Introduced wood borer in plantation and urban environments 289 13.4 Conclusions 290 References 291 Index 296

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Book SynopsisStem Cells: A Short Course is a comprehensive text for students delving into the rapidly evolving discipline of stem cell research. Comprised of eight chapters, the text addresses all of the major facets and disciplines related to stem cell biology and research. A brief history of stem cell research serves as an introduction, followed by coverage of stem cell fundamentals; chapters then explore embryonic and fetal amniotic stem cells, adult stem cells, nuclear reprogramming, and cancer stem cells. The book concludes with chapters on stem cell applications, including the role of stem cells in drug discovery and therapeutic applications in spinal cord injury, brain damage, neurological and autoimmune disorders, among others. Written by a leader in the field, Stem Cells: A Short Course appeals to both students and instructors alike, appealing to academic enthusiasm for stem cell research and applications.Table of ContentsPreface to the Professor xvii Preface to the Student xxi Acknowledgments xxiii List of Figures xxv List of Tables xxxvii List of Case Studies xxxix List of Focus Boxes xli 1 A HISTORY OF STEM CELL RESEARCH 1 Early Studies 1 Hematopoietic Stem Cell Discovery 4 Mouse Embryonic Stem Cell Discovery 6 Successful Neural Stem Cell Culture 7 The Discovery of Cancer Stem Cells 8 Human Embryonic Stem Cell Discovery 9 Stem Cells And Cloning 11 Cord Blood Embryonic]Like Stem Cells—An Alternative to Es and Adult Stem Cells 14 Breakthrough In Spinal Cord Injury Repair 15 The Generation of ips Cells 16 iPS Cells Derived from Keratinocytes 20 iPS Induction Without the Use of Viruses 20 Transposon]Mediated iPS 21 Protein]Based iPS 22 The Discovery of Human Amniotic Stem Cells 24 Human Embryonic Stem Cells Generated Without Embryo Destruction 25 Human Cloning 25 Mesenchymal Stem Cell]Derived Human Knee Cartilage 27 The First Clinical Trial Using Human Embryonic Stem Cells 28 Mitochondrial DNA: A Barrier To Autologous Cell Therapeutics 29 Induced Pluripotency And The Potential To Save Endangered Species 30 Chapter Summary 33 Key Terms 37 Review Questions 39 Thought Question 40 Suggested Readings 40 2 FUNDAMENTALS OF STEM CELLS 43 Basic in Vitro Cell Culture—A Historical Perspective 43 Stem Cell Culture—Optimal Conditions and Techniques 48 Embryonic Stem Cell Culture 49 Hematopoietic Stem Cell Culture 52 Notch Regulation of HSC Proliferation 52 Other Drivers of HSC Proliferation 53 Adipose]Derived Stem Cell Culture 54 The Study of Embryonic Development 56 Embryonic Development and the Origin of Stem Cells 56 Early Events in Embryogenesis 56 Germ Cell Development 61 Basic Properties of Stem Cells 63 Long]Term Self]Renewal 63 Different Potency Capabilities 63 Totipotency 64 Pluripotency 65 Multipotency 68 Oligopotency 68 Unipotency 69 Types of Stem Cells 70 Embryonic Stem Cells 70 Fetal Stem Cells 70 Amniotic Stem Cells 71 Adult Stem Cells 71 Induced Pluripotency (iPS) Cells 71 Cancer Stem Cells 71 The Potential of Stem Cells in Medicine and Medical Research 71 Therapeutics 71 Tissue Engineering 71 Cell Therapy 73 Cell]Based Drug Screening 75 Chapter Summary 77 Key Terms 80 Review Questions 83 Thought Question 84 Suggested Readings 85 3 EMBRYONIC STEM, FETAL, AND AMNIOTIC STEM CELLS 87 ES Cells 87 Basic Properties 87 Pluripotency 87 Indefinite Replicative Capacity 89 Signaling and Transcriptional Control of ES Cell Replication 90 Examples of ES Cells 92 Mouse ES Cells 92 Rat ES Cells 95 Nonhuman Primate ES Cells 97 Human ES Cells 100 EC Cells 103 Embryonal Germ Cells 105 EG Cell Growth Factor Signaling 105 Comparing Embryonically Derived Cells 106 Fetal Stem Cells 108 Basic Properties 108 Amniotic Fluid Stem Cells 108 Wharton’s Jelly Stem Cells 109 Amniotic Membrane Stem Cells 110 Placental Stem Cells 110 Chapter Summary 112 Key Terms 114 Review Questions 115 Thought Question 116 Suggested Reading 116 4 ADULT STEM CELLS 118 Discovery and Origin of ASCs 118 Basic Properties of ASCs 118 Self]Renewal 119 Multipotency 119 Examples of ASCs 120 Hematopoietic Stem Cells 122 Morphology and Marker Expression 123 Sources 123 Signaling and Multipotency 123 Muscle]Derived Stem Cells 127 Myosatellite Cell Morphology and Marker Expression 129 Sources 129 Signaling, Transcriptional Control, and Multipotency 129 Adipose]Derived Stem Cells 130 Morphology and Marker Expression 130 Sources 131 Signaling and Multipotency 132 Mesenchymal Stem Cells 134 Morphology and Marker Expression 134 Sources 136 Signaling and Multipotency 136 Neural Stem Cells 140 Morphology and Marker Expression 141 Sources and Origins 143 Signaling and Multipotency 146 Endothelial Stem Cells 150 Morphology and Marker Expression 150 Sources and Origins 152 Signaling and Multipotency 153 Chapter Summary 156 Key Terms 158 Review Questions 161 Thought Question 162 Suggested Readings 162 5 NUCLEAR REPROGRAMMING 164 Examples of Nuclear Reprogramming in Nature 166 Cell Fusion 166 Cell Fusion for the Generation of Hybridomas 169 Mechanisms of Cell Fusion 172 Comparison of Cell Fusion Techniques 173 Electrofusion 173 Pegylation 173 Viral Induction 173 Mechanism of Nuclear Reprogramming in Cell Fusion 175 Somatic Cell Nuclear Transfer 176 Method for the Production of SCNT]Derived Cells 177 Somatic Cell Nuclear Transfer for the Creation of Stem Cells 178 Basic Properties of SCNT]Derived Stem Cells 180 Examples of SCNT]Derived Stem Cells 181 A Note Regarding Genomic Abnormalities in SCNT]Derived Clones 182 Telomeric Length 182 DNA Methylation and Epigenetics 183 X]Chromosome Inactivation 185 Induced Pluripotency 185 Breakthrough in the Production of iPS Cells 187 Methods for the Production of iPS Cells 191 Retroviral and Lentiviral Gene Delivery 192 Adenoviral Gene Delivery 195 Sendai Viral Gene Delivery 196 Plasmid]Based Gene Delivery 196 mRNA Delivery 198 MicroRNA Induction 199 Transposon Delivery 200 Direct Protein Delivery 200 Basic Properties of iPS Cells 201 A General Comparison of iPS Cells and Embryonic Stem Cells 203 Examples of Derived iPS Cells 205 Mouse Embryonic Fibroblast]Derived iPS Cells 206 Human Adult Skin]Derived iPS Cells 209 Advantages of ips Cells Over Other Cell Types 210 Origin and Bioethics 211 Patient Specificity 211 Broad Lineage Differentiation Potential 211 “Unlimited” Supply 211 Ease of Generation 212 Chapter Summary 212 Key Terms 214 Review Questions 217 Thought Question 218 Suggested Readings 218 6 CANCER STEM CELLS 220 Background on The Origins of Cancer 220 Discovery and Origin of Cancer Stem Cells 221 Basic Properties of Cancer Stem Cells 225 A Comparison of Cancer Stem Cells and Normal Stem Cells 226 Signaling Pathways Involved in Cancer Stem Cell Transformation 228 Examples of Cancer Stem Cells 229 Breast 229 Central Nervous System 229 Colon 231 Ovary 233 Pancreas 233 Prostate 234 Melanoma 235 Multiple Myeloma 237 Strategies for Treatment Targeting Cancer Stem Cells 238 Melanoma Treatment Targeting Chimeric Antigen Receptor 238 Multiple Myeloma Treatment Targeting CD20 239 Chapter Summary 240 Key Terms 241 Review Questions 243 Thought Question 244 Suggested Readings 244 7 STEM CELLS AS DRUG DISCOVERY PLATFORMS 245 Embryonic Stem Cells and Mouse Models of Gene Function 245 Stem Cell]Based Screening Assays 250 Stem Cells as Lineage Resources for HTS 250 Embryonic Stem Cells as a Resource 251 Adult Stem Cells as a Resource 253 iPS Cells as a Resource 254 Cancer Stem Cell Screens 256 Reprogramming Screens 258 Analysis of Disease Pathways 261 Stem Cells As A Toxicity]Testing Platform 267 Stem Cells as a Resource for Developmental Toxicity Testing 267 Stem Cells as a Source for Post]Natal Environmental Toxicity Testing 268 Cardiotoxicity 269 Hepatotoxicity 272 Chapter Summary 273 Key Terms 274 Review Questions 276 Thought Question 277 Suggested Readings 277 8 THERAPEUTIC APPLICATIONS OF STEM CELLS 279 History of Stem Cells as Therapeutics 279 History of Tissue Engineering 279 Disease]Specific Treatment and Patient Trials 282 Stem Cell]Based Patient Trials: An Overview 282 Cardiomyopathy and Cardiovascular Disease (CV) 284 Neuropathies and Neurodegenerative Diseases 286 Spinal Cord Injury 286 Brain Damage 288 Parkinson’s Disease 292 Autoimmune Disorders 292 Corneal Defects 296 Hematopoietic Disorders 297 Sickle Cell Disease 297 Wiskott–Aldrich Syndrome 299 Cancer 300 Muscular Dystrophy 301 Liver Disorders 303 Veterinary Applications 306 Equine 307 Canine 309 Osteoarthritis (OA) 309 Myocardial Infarction 311 Spinal Cord Injury 313 Stem Cells as an Emerging Industry 314 Seminal Discoveries Driving the Growth of a New Industry 317 Regulation and Reimbursement of Stem Cell Commercialization 320 A Word about Induced Pluripotency and Commercialization 320 Chapter Summary 321 Key Terms 324 Review Questions 326 Thought Question 327 Suggested Readings 328 About the Author 330 Index 331

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Book SynopsisStereological methods provide researchers with unparalleled quantitative data from tissue samples and allow for well-evidenced research advances in a broad range of scientific fields. Presenting a concise introduction to the methodology and application of stereological research in neuroscience,Neurostereologyprovides a fuller understanding of the use of these methods in research and a means for replicating successful scientific approaches. Providing sound footing for future research,Neurostereologyis a useful tool for basic and clinical researchers and advanced students looking to integrate these methods into their research.Table of ContentsContributors ix Preface xiii 1 Stereological Estimation of Brain Volume and Surface Area from MR Images 3 Niyazi Acer and Mehmet Turgut Background 3 The Cavalieri Principle 3 Volume Estimation Using Spatial Grid of Points 7 Surface Area Estimation 8 Isotropic Cavalieri Design 14 Sections Analyzed with Independent Grid Design 14 Surface Area Using the Invariator 16 Volume and Surface Area Estimation Using Segmentation Method 17 Discussion 18 References 19 Webliography 21 Appendix A: R Commands for Point Counting Method 21 Appendix B: R Commands for Vertical Section to Estimate Surface Area 23 2 Cell Proliferation in the Brains of Adult Rats Exposed to Traumatic Brain Injury 27 Sandra A. Acosta, Naoki Tajiri, Paula C. Bickford, and Cesar V. Borlongan Background 27 Materials and Methods 28 Results 29 Discussion 33 Acknowledgments 37 References 37 3 Age Effects in Substantia Nigra of Asian Indians 39 Phalguni Anand Alladi Background 39 Materials and Methods 40 Discussion 43 Acknowledgments 48 References 49 4 Design-Based Stereology in the Brain Bank Setting 53 Mark W. Burke Background 53 Specimen Preparation 53 A Practical Application of Design-Based Stereology 57 Results 59 Conclusion 60 References 61 5 Practical Stereology for Preclinical Neurotoxicology 63 Mark T. Butt Background 63 Specimen Quality 64 Practical Stereology 70 Software Validation/Verifi cation 70 References 72 6 An Overabundance of Prefrontal Cortex Neurons Underlies Early Brain Overgrowth in Autism 73 Eric Courchesne, Peter R. Mouton, Michael E. Calhoun, Clelia Ahrens-Barbeau, Melodie J. Hallet, Cynthia Carter Barnes, Karen Pierce, and Katarina Semendeferi Background 73 Methods 74 Results 78 Discussion 80 Acknowledgments 81 References 82 7 Order in Chaos: Stereological Studies of Nervous Tissue 85 Peter Dockery Background 85 The Stereological Approach 85 Axonal Number and Composition in the Murine Optic Nerve 91 Axonal and Fiber Size Distributions 92 The Myelin Sheath 93 Conclusion 94 References 95 8 Comparative Stereology Studies of Brains from Marine Mammals 99 Nina Eriksen and Bente Pakkenberg Background 99 Description of Different Marine Mammalian Brains 99 Parts of the Brain 102 References 109 Appendix: Cited Stereological Approaches 110 9 Quantitative Assessment of Hippocampus Architecture Using the Optical Disector 113 Shozo Jinno Background 113 The Hippocampus 114 Conclusion 123 References 123 10 The Possible Applications (and Pitfalls!) of Stereological Analysis in Postmortem Brain Research 129 Ahmad A. Khundakar and Alan J. Thomas Background 129 The Legacy of Two-Dimensional (2D) Analysis 129 Density: A Necessary Evil 130 “Come on, Feel the Noise”: Recognizing Confounding Factors 130 “I Am Not a Number”: The Importance of Sound Patient Clinical History 131 Lessons Learned from Stereology: Toward a More Unifi ed Approach to Brain Banking and Postmortem Tissue Research (and Beyond!) 132 Obtain the Full Reference Volume or “Make Do and Mend” 133 Turn Down the “Noise” 134 “Check the Information, Expand the Knowledge” 135 Show Your Work! 135 Conclusion 136 Acknowledgments 136 References 136 11 Visualization of Blood Vessels in Two-Dimensional and Three-Dimensional Environments for Vascular Stereology in the Brain 139 Zerina Lokmic Background 139 Vascular Stereology of Tissue Sections 139 Visualization of Brain Blood Vessels 142 Conclusion 149 Acknowledgment 149 References 149 12 Blood Flow Analysis in Epilepsy Using a Novel Stereological Approach 153 Rocio Leal-Campanario, Luis Alarcon-Martinez, Susana Martinez-Conde, Michael Calhoun, and Stephen Macknik Background 153 Materials and Methods 155 Results 166 Discussion 172 References 173 13 AD-Type Neuron Loss in Transgenic Mouse Models 177 Kebreten F. Manaye and Peter R. Mouton Background 177 Materials and Methods 179 Results 182 Discussion 185 Acknowledgments 187 References 188 14 Quantification in Populations of Nonuniformly Distributed Cells in the Human Cerebral Cortex 191 William L. Maxwell Background 191 Materials and Methods 191 Results 196 Discussion 205 References 208 15 The Effects of High-Fat Diet on the Mouse Hypothalamus: A Stereological Study 211 Mohammad Reza Namavar, Samira Raminfard, Zahra Vojdani Jahromi, and Hassan Azari Background 211 Materials and Methods 212 Results 213 Discussion 215 Acknowledgments 217 References 218 16 2D and 3D Morphometric Analyses Comparing Three Rodent Models 221 JiHyuk Park and S. Omar Ahmad Background 221 Materials and Methods 221 Results 226 Discussion 230 References 235 17 A Stereologic Perspective on Autism Neuropathology 237 Neha Uppal and Patrick R. Hof Background 237 Cortical Areas 237 Hippocampus 248 Noncortical Areas 249 Conclusions 253 References 254 Index 257

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Book SynopsisAn extensive update of a successful textbook on skill acquisition for sport students. Praised for its clarity of writing style and presentation the new edition will be an essential buy for those needing a practical, sport-focused introduction to the theory and application of human motor skills.Table of ContentsPreface xiii Acknowledgements xix About the Companion Website xxi 1 Skill, Ability and Performance 1 Learning objectives 1 Skill 2 Classification of skills 3 Ability 6 Genes 8 The ability–skill interaction 10 Summary 12 Theories of performance 12 Information processing theory 13 Ecological psychology theories 17 Conclusion 20 Summary 20 Skill 20 Ability 20 Ability-skill interaction 21 Information processing theory 21 Ecological psychology theories 22 Test your knowledge 22 Part one 22 Part two 24 Additional reading 24 2 Sensation and Perception of External Information 25 Learning objectives 25 Information processing theory, sensation and perception 26 Definition of Perception 27 Signal detection theory 28 Pattern recognition 30 Selective attention 33 Visual search 36 Quiet eye 37 Individual differences 37 Summary 39 Ecological psychology and perception 39 Criticisms of the ecological approach 43 Summary 43 Developmental factors 43 Vision 43 Audition 44 Perceptual development and the environment 44 Conclusion 44 Summary 45 Information processing theory and perception 45 Ecological psychology and perception 47 Developmental factors 47 Test your knowledge 48 Part one 48 Part two 50 Part three 51 Additional reading 51 3 Decision Making and Working Memory 53 Learning objectives 53 Decision making 54 Working memory and decision making 54 Dynamical systems theory and goal achievement 58 Child development 58 Piagetian theory 59 Mental space theory 60 Domain-specificity theories 60 Information processing theory and cognitive development 61 Ecological psychology theories of cognitive development 61 Summary 62 Ageing 65 Research findings and problems with research design 65 Conclusion 67 Summary 68 Information processing theory and decision making 68 Working memory and decision making 68 Functional brain regions and working memory 68 Dynamical systems theory and goal achievement 69 Developmental issues 69 Research 69 Test your knowledge 70 Part one 70 Part two 71 Part three 72 Additional reading 72 4 Reaction Time 73 Learning objectives 73 Reaction time, movement time and response time: definitions 74 Inter- and intraindividual differences 76 Hick–Hyman Law 77 Probability and choice reaction time 77 Psychological refractory period 78 Stimulus and response factors 79 Central executive tasks and reaction time 84 Arousal and reaction time 84 Development and reaction time 85 Ageing 85 Reaction time research findings as evidence for and against information processing theory 85 Summary 86 Test your knowledge 87 Part one 87 Part two 88 Part three 89 Additional reading 89 5 Anticipation 91 Learning objectives 91 Interceptive actions 92 Information processing theory and interceptive actions 92 Watching the object to be intercepted 93 Action systems theory and interceptive actions 94 Perceptual anticipation 95 Information processing theory and perceptual anticipation 95 Ecological psychology and perceptual anticipation 96 Development and anticipation 102 Summary 103 Information processing theory and interceptive actions 103 Action systems theory and interceptive actions 103 Watching the ball and interceptive actions 103 Information processing theory and perceptual anticipation 103 Ecological psychology and perceptual anticipation 103 Research paradigms in perceptual anticipation 104 Research results 104 Developmental factors 104 Test your knowledge 104 Part one 104 Part two 106 Part three 107 Additional reading 107 6 Motor Control 109 Learning objectives 109 Central nervous system–peripheral nervous system interaction 110 Types of feedback 113 Summary 119 Information processing theory and efferent organization 119 Motor programmes 120 Summary 123 Ecological psychology and motor control 123 Visual guidance of movement 125 Summary 126 Development and motor control 127 Neurological and physiological growth 127 Adolescence 128 Ageing 129 Theories of motor development 129 Ecological psychology and motor development 130 Motor performance 131 Ageing 132 Practical implications 132 Mini-games 133 Conditioned games 133 Gender issues 134 Physical stress during performance 134 Summary 135 Brain and motor control 135 Proprioception 135 Motor programmes 135 Ecological psychology and motor control 135 Developmental issues 136 Theories of motor development 136 Motor performance 136 Test your knowledge 137 Part one 137 Part two 138 Additional reading 139 7 Memory 141 Learning objectives 141 Information processing theory and short-term memory 142 Sensory information store 142 Short-term memory 142 Forgetting in short-term memory 143 Short-term motor memory 144 Information processing theory and long-term memory 147 Long-term motor memory 147 Declarative long-term memory 148 Non-declarative long-term memory 148 Regional brain functions and memory 149 Development and short-term and long-term memory 150 Ecological psychology and attunement to affordances 151 Summary 152 Sensory information store 152 Short-term memory 152 Short-term motor memory 152 Long-term memory 153 Long-term motor memory 153 Declarative memory 153 Non-declarative memory 153 Regional brain functions 153 Development 153 Ecological psychology and attunement to affordances 154 Test your knowledge 154 Part one 154 Part two 155 Additional reading 156 8 Learning I: Types, theories, styles and measurement 157 Learning objectives 157 Types of learning 158 Explicit learning 158 Implicit learning 159 Mental rehearsal 163 Cognitive theories of learning 163 Fitts and Posner’s three stage theory 164 Gentile’s model of learning 164 Adams’ closed loop theory of learning 165 Schmidt’s schema theory 166 Anderson’s adaptive control of thought (ACT*) theory 167 Observational learning theory 168 Dynamical systems theory and learning 168 Learning and coaching/teaching styles 170 Learning styles 171 Coaching/teaching styles 172 Optimal periods of learning 176 Measuring learning 176 Types of tests used to infer learning 179 Summary 182 Cognitive theories of learning 182 Dynamical systems theory and learning 183 Learning styles 183 Coaching/teaching styles 183 Practical implications 184 Measurement 184 Test your knowledge 184 Part one 184 Part two 185 Part three 186 Additional reading 187 9 Learning II: Instruction, Practice, Transfer of Training and Feedback 189 Learning objectives 189 Instruction 190 Analogy as a form of instruction 191 Focus of attention 191 Demonstration 192 Mirror neurons 193 Practice 193 Types of practice 193 Variability of practice 198 Contextual interference 199 Dynamical systems theory and practice 200 Transfer of training 201 Transfer theories 202 Bilateral transfer 204 Feedback 205 Observation 205 Timing and precision of feedback 208 Summary 213 Feedback formats 213 Practical implications 214 Deciding on session content 215 Deciding on the type of instruction 216 Practice, observation and feedback 217 Observation 218 Feedback 219 Summary 221 Instruction and demonstration 221 Practice 221 Deliberate practice 221 Variability of practice 221 Contextual interference 221 Dynamical systems theory and practice 222 Transfer of training 222 Feedback 223 Practical implications 223 Test your knowledge 224 Part one 224 Part two 226 Part three 227 Part four 228 Additional reading 228 10 Motivation, Arousal, and Learning and Performance 229 Learning objectives 229 Motivation 229 Motivational theories 230 Self-determination theory 230 Achievement motivation theory 231 Achievement goal theory 232 Summary 233 Practical implications 233 Developmental issues 234 Arousal and performance 235 Arousal-performance theories 235 Regional brain functions and arousal 240 Practical implications 241 High levels of arousal 243 Summary 247 Motivation 247 Arousal 248 Theories of arousal-performance interaction 248 Regional brain functions and arousal 249 Practical implications 249 Test your knowledge 250 Part one 250 Part two 251 Part three 252 Additional reading 252 11 Conclusion 253 State of the art 253 Skill 253 Abilities 254 Perception 254 Decision making 255 Reaction time 255 Anticipation 255 Motor control 255 Memory 255 Learning 256 Practice 256 Arousal and performance 256 Information processing theory versus ecological psychology theories 256 Neuroscientific input 258 Appendix 1: Writing an Academic Paper 259 Version one 259 Version two 260 Appendix 2: Test Your Knowledge Answers 263 Chapter 1 263 Part one 263 Part two 263 Chapter 2 263 Part one 263 Part two 264 Part three 264 Chapter 3 265 Part one 265 Part two 265 Part three 266 Chapter 4 266 Part one 266 Part two 267 Part three 267 Chapter 5 268 Part one 268 Part two 268 Part three 269 Chapter 6 270 Part one 270 Part two 271 Chapter 7 272 Part one 272 Part two 272 Chapter 8 272 Part one 272 Part two 272 Part three 273 Chapter 9 273 Part one 273 Part two 273 Part three 274 Part four 274 Chapter 10 275 Part one 275 Part two 276 Part three 276 Appendix 3: Calculating variable error 277 References 279 Index 291

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Book SynopsisDNA technology is evolving rapidly, with new methods and a fast-growing vocabulary. This unique dictionary offers current, detailed and accessible information on DNA technology to lecturers, researchers and students throughout the biomedical and related sciences. The third edition is a major update, with over 3000 references from mainstream journals and data from the very latest research going well beyond the remit of most science dictionaries. It provides clear explanations of terms, techniques, and tests, including commercial systems, with detailed coverage of many important procedures and methods, and includes essay-style entries on many major topics to assist newcomers to the field. It covers topics relevant to medicine (diagnosis, genetic disorders, gene therapy); veterinary science; biotechnology; biochemistry; pharmaceutical science/drug development; molecular biology; microbiology; epidemiology; genomics; environmental science; plant science/agriculture; taxonomy; anTrade Review“It might be worth keeping this excellent reference book in mind though.” (Reference Reviews, 1 November 2013) “Summing Up: Recommended. Upper-level undergraduates and above.” (Choice, 1 August 2013) Table of ContentsPreface vii Notes for the user ix Ready reference xiii Dictionary 1 Appendix: Alphabetical list of genera 505

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Book SynopsisIntroduction to Pain and its relation to Nervous System Disorders provides an accessible overview of the latest developments in the science underpinning pain research, including, but not limited to, the physiological, pathological and psychological aspects.Table of ContentsList of contributors ix Foreword xiii Acknowledgements xv Notes on authors xvii Introduction 1Anna A. Battaglia Section I: Neurobiology of pain: Recent advances 11 1 Anatomy of pain pathways 13Andrew J. Todd 2 Spinal plasticity of the nociceptive system: The role of central sensitisation in chronic pain states 35Alban Latrémolière 3 Symptoms and pathology in neuropathic pain 89Matthew Thakur and Stephen B. McMahon 4 Recent advances in neuroimmune interactions in neuropathic pain: The role of microglia 123Elizabeth A. Old, Louise S. C. Nicol and Marzia Malcangio 5 Genetics and epigenetics of pain 149Franziska Denk and Stephen B. McMahon 6 The cannabinoid system and its role in nociception 169Massimiliano Beltramo 7 EphB receptors and persistent pain 201Isabella Gavazzi Section II: Pain in the brain 225 8 Brain imaging in experimental pain 227Massieh Moayedi and Tim V. Salomons 9 Placebo effects in pain 249Luana Colloca, Adam P. Horin and Damien Finniss 10 Psychology and pain 267Lance M. McCracken Section III: Pain in the lifecycle and in nervous system disorders 281 11 Pain in neonates and infants 283Fiona Moultrie, Segzi Goksan, Ravi Poorun and Rebeccah Slater 12 How do people with autism spectrum disorders (ASD) experience pain? 295Cecile Rattaz, Amandine Dubois and Amaria Baghdadli 13 Pain and depression: The janus factor of human suffering 317Angela Iannitelli and Paola Tirassa 14 Pain in multiple sclerosis: From classification to treatment 345Claudio Solaro and Michele Messmer Uccelli 15 Pain perception in dementia 361Miriam Kunz and Stefan Lautenbacher 16 The role of cognitive impairment in the placebo and nocebo effects 373Martina Amanzio 17 An overview of pain in Parkinson’s disease 387Panagiotis Zis, Elisaveta Sokolov and Kallol Ray Chaudhuri Appendix: Interviews with chronic pain patients 409 Index 413

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Book SynopsisCircadian rhythms, the biological oscillations based around our 24-hour clock, have a profound effect on human physiology and healthy cellular function.Table of ContentsList of Contributors xiii Preface xvii Part I Fundamental Concepts 1 1 Cytosolic and Transcriptional Cycles Underlying Circadian Oscillations 3Michael H. Hastings and John S. O’Neill 1.1 Introduction 3 1.2 Assembling the transcriptional feedback loop 5 1.3 Keeping the transcriptional clockworks in tune 9 1.4 Building posttranslational mechanisms into the circadian pacemaker 13 1.5 Is the transcriptional clock paramount? 15 1.6 Conclusion: cytoscillators, clocks and therapies 18 References 18 2 Molecular Determinants of Human Circadian Clocks 25Steven A. Brown 2.1 Molecular elements of human clocks: a brief review 25 2.2 Peripheral and central clocks 26 2.3 Signaling to peripheral circadian clocks 28 2.4 Human peripheral and central clocks 29 2.5 Human genetics 29 2.6 Technologies for measurement of human circadian clocks 30 2.7 Cellular methods 30 2.8 Omics]based methods to analyze human clocks 32 2.9 Summary and outlook 33 References 33 3 The Suprachiasmatic Nucleus (SCN): Critical Points 37Christopher S. Colwell, Paul Witkovsky, and Rae Silver 3.1 SCN is site of master circadian pacemaker in mammals 37 3.2 SCN receives photic information through a specialized light detection pathway 39 3.3 SCN neurons are endogenous single cell oscillators that generate rhythms in neural activity 40 3.4 The SCN has circuit level organization that is just beginning to be unraveled 42 3.5 Coupling with the SCN circuit is mediated by a set of peptides with VIP on top of the hierarchy 44 3.6 SCN outputs 44 3.7 SCN in aging and disease 50 References 51 4 Sleep and Circadian Rhythms: Reciprocal Partners in the Regulation of Physiology and Behavior 57Ralph Mistlberger 4.1 Introduction 57 4.2 What is sleep 59 4.3 Circadian regulation of sleep 60 4.4 Reciprocity: sleep–wake feedback to the circadian clock 69 4.5 Conclusions: Circadian clocks and sleep are intertwined processes 73 References 73 5 Circadian Regulation of Arousal and its Role in Fatigue 81David R. Bonsall and Mary E. Harrington 5.1 Defining arousal 81 5.2 Brain structures important for arousal 83 5.3 Neurochemicals signaling the states of arousal 84 5.4 Circadian regulation of the arousal system 86 5.5 Influence of input pathways on circadian regulation of arousal 88 5.6 Sustained states of fatigue: a disorder of the arousal network? 88 5.7 Conclusions 90 References 91 Part II Circadian Regulation of Major Physiological Systems 95 6 Physiology of the Adrenal and Liver Circadian Clocks 97Alexei Leliavski and Henrik Oster 6.1 Introduction 97 6.2 Circadian control of adrenal function 98 6.3 Circadian control of liver function 101 6.4 Conclusion 105 References 105 7 Nutrition and Diet as Potent Regulators of the Liver Clock 107Yu Tahara and Shigenobu Shibata 7.1 Introduction 107 7.2 Food is a “zeitgeber”: The FEO in the brain 107 7.3 The FEO in peripheral tissues 109 7.4 What should we eat? What types of food can stimulate the peripheral clock? 110 7.5 When should we eat? Application to human life science 112 7.6 Circadian rhythm and obesity and diabetes 113 References 116 8 The Cardiovascular Clock 119R. Daniel Rudic 8.1 Introduction 119 8.2 The vascular clock 119 8.3 Circadian clock regulation of the endothelial cell layer of blood vessels 120 8.4 The circadian clock in vascular disease 121 8.5 The circadian clock and vascular cell signaling 122 8.6 The circadian rhythm in blood pressure, nighttime hypertension, and cardiovascular disease in humans 123 8.7 Diabetes, obesity, and blood pressure 125 8.8 AT influences the circadian rhythm in experimental hypertension 126 8.9 The circadian clock and fluid balance 127 8.10 The circadian clock and peripheral vascular resistance 127 8.11 Conclusion 130 References 130 9 Hypertension Caused by Disruption of the Circadian System: Blood Pressure Regulation at Multiple Levels 135Hitoshi Okamura, Miho Yasuda, Jean]Michel Fustin, and Masao Doi 9.1 Introduction 135 9.2 Effects of deleting Cry genes 135 9.3 Reduced a-adrenoceptor responsiveness in peripheral vessels and primary aldosteronism of Cry-null mice 138 9.4 Rapid blood pressure control system: enhanced baroreflex in Cry-null mice 139 9.5 Conclusion 141 References 141 10 Chronobiology of Micturition 143Akihiro Kanematsu and Hiromitsu Negoro 10.1 Introduction 143 10.2 Human studies 144 10.3 Animal models 146 10.4 The circadian clock and micturition 147 10.5 The clock in the bladder 148 10.6 Future directions 150 References 151 11 Disruption of Circadian Rhythms and Development of Type 2 Diabetes Mellitus: Contributions to Insulin Resistance and Beta]cell Failure 155Aleksey V. Matveyenko 11.1 Introduction 155 11.2 Mechanisms underlying pathophysiology of Type 2 diabetes mellitus: interaction between insulin resistance and beta-cell failure 156 11.3 Mechanisms underlying the association between circadian disruption and T2DM; potential role of obesity and insulin resistance 160 11.4 Mechanisms underlying the association between circadian disruption and T2DM; potential role of impaired beta-cell secretory function and mass 162 11.5 Conclusion 165 References 166 12 Circadian Clock Control of the Cell Cycle and Links to Cancer 169T. Katherine Tamai and David Whitmore 12.1 Introduction 169 12.2 Epidemiology 169 12.3 Does circadian clock disruption have any relevance in a clinical setting? 170 12.4 Circadian clock control of the cell cycle in healthy tissues 171 12.5 How might the cellular circadian clock regulate cell cycle timing? 173 12.6 Clock disruption and cancer 177 12.7 Does alteration in clock gene expression in human tumors correlate with the survival of patients? 178 12.8 Circadian]based chemotherapy (Chronotherapy): timing cancer treatment to improve survival 178 12.9 Conclusion 180 References 180 13 How Shift Work and a Destabilized Circadian System may Increase Risk for Development of Cancer and Type 2 Diabetes 183An Pan, Elizabeth Devore, and Eva S. Schernhammer 13.1 Introduction 183 13.2 Shift work and cancer 184 13.3 Shift work and obesity, metabolic syndrome, and type 2 diabetes 194 13.4 Conclusions and perspective of future studies 205 References 205 14 Circadian Rhythms in Immune Function 211Kandis Adams, Oscar Castanon-Cervantes, and Alec J. Davidson 14.1 Introduction 211 14.2 Daily variations in health and disease 212 14.3 Early evidence of circadian regulation on immunity 212 14.4 Clinical relevance of circadian regulation of the immune system 213 14.5 The circadian system communicates time of day information to immune cells and tissues 214 14.6 Immune effector cells under circadian regulation 214 14.7 Circadian disruption role in immune pathology and disease 216 14.8 The effects of clock gene alterations on immune functions 217 14.9 Conclusions 217 References 218 Part III Clocks in the Central Nervous System 221 15 Circadian Clock, Reward and Addictive Behavior 223Urs Albrecht 15.1 Introduction 223 15.2 Evidence for a time of day basis of addictive behavior 223 15.3 Drugs, circadian clock genes and addictive behavior 224 15.4 Links between feeding, addictive behavior and the clock 228 15.5 Treatment of addiction changing the circadian clock 229 References 231 16 How a Disrupted Clock may Cause a Decline in Learning and Memory 235Christopher S. Colwell 16.1 Introduction 235 16.2 Molecular clockwork expressed in brain regions central to learning and memory including the hippocampus, amygdala, and cortex 236 16.3 The circadian clockwork regulates intracellular signaling pathways known to be important to learning and memory 237 16.4 The circadian system impacts electrical activity and synaptic plasticity 238 16.5 The circadian system regulates neuroendocrine secretions that are well known to alter learning and memory processes 240 16.6 Disruptions of the circadian timing system alter learned behavior 241 16.7 Conclusions 245 References 245 17 Circadian Rhythms in Mood Disorders 249Colleen A. McClung 17.1 Introduction 249 17.2 Categories of rhythm disruptions 251 17.3 Seasonal affective disorder 252 17.4 Treatments for mood disorders alter rhythms 253 17.5 Human genetic studies 257 17.6 Animal studies 257 17.7 SCN output]rhythmic hormones and peptides 260 17.8 Regulation of mood]related brain circuits by the SCN and circadian genes 262 17.9 Neuroinflammation 263 17.10 Cell cycle regulation/neurogenesis 264 17.11 Conclusions 265 References 265 18 Sleep and Circadian Rhythm Disruption in Psychosis 271Stuart N. Peirson and Russell G. Foster 18.1 Introduction 271 18.2 Psychosis 273 18.3 Sleep and circadian rhythm disruption in psychosis 275 18.4 Possible mechanisms underlying SCRD in psychosis 277 18.5 Conclusions 280 References 281 19 Alzheimer’s Disease and the Mistiming of Behavior 283Roxanne Sterniczuk and Michael Antle 19.1 Introduction 283 19.2 Behavioral changes 283 19.3 Physiological changes 285 19.4 Neurological changes 286 19.5 Modeling AD 289 19.6 Chronobiological treatment of AD symptomology 290 19.7 Conclusion 292 References 293 20 Circadian Dysfunction in Parkinson’s Disease 295Christopher S. Colwell 20.1 Introduction 295 20.2 Dysfunction in the circadian system may contribute to the nonmotor symptoms of PD 296 20.3 Dopaminergic treatments for the motor symptoms of PD may contribute to circadian disruption 297 20.4 PD models show sleep and possible circadian disruption 298 20.5 Possible underlying mechanisms 300 20.6 Conclusion 301 References 302 21 Circadian Dysfunction in Huntington’s Disease 305A. Jennifer Morton 21.1 Introduction 305 21.2 Mechanisms underlying sleep and circadian rhythm generation 305 21.3 Circadian disruption in HD 306 21.4 Circadian disruption in animal models of HD 306 21.5 Circadian disruption of peripheral clocks and metabolism in HD 311 21.6 Pharmacological manipulation of circadian disruption in HD mice 311 21.7 Environmental modulation of circadian disruption in HD mice 311 21.8 Clinical changes in sleep in HD 312 21.9 Disturbance in sleep architecture in HD 312 21.10 Pathology underlying changes in sleep and circadian activity in HD 313 21.11 The orexin system in HD 313 21.12 The role of non]SCN oscillators in HD 314 21.13 Consequences of sleep–wake disturbance in HD 314 21.14 Cognitive dysfunction and mood disturbance in HD 315 21.15 Management of circadian disturbance in HD 315 21.16 Conclusions 317 References 318 22 The Aging Clock 321Stephan Michel, Gene D. Block, and Johanna H. Meijer 22.1 Introduction 321 22.2 The effects of aging on rhythmic behaviors 321 22.3 The effects of aging on components of the circadian system 323 22.4 Molecular rhythms in steady state 328 22.5 The effects of aging on the resetting behavior of central and peripheral oscillators 329 22.6 The effects of the circadian system on aging and age]related disease: Circadian misalignment andlongevity 330 22.7 Therapeutic possibilities for agerelated circadian disorders 331 22.8 Conclusions 332 References 332 23 Can we Fix a Broken Clock? 337Analyne M. Schroeder and Christopher S. Colwell 23.1 Introduction 337 23.2 Light therapy 339 23.3 Scheduled meals 340 23.4 Scheduled exercise 341 23.5 Scheduled sleep 343 23.6 Pharmacological targeting of the circadian system 343 23.7 Conclusions 345 References 346 Index 351

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Book Synopsis* Provides broad overview of the developmental biology of both Xenopus laevis and Xenopus tropicalis * Cellular to systems development in key biomedical model organisms * Timely synthesis of the field of Xenopus biology * Highlights key biomedical and basic biological findings unlocked by Xenopus .Table of ContentsContributors vii Preface ix Section I Oocyte and Early Embryo 1 1 Transcription in the Xenopus Oocyte Nucleus 3 Joseph G. Gall 2 RNA Localization during Oogenesis in Xenopus laevis 16 James O. Deshler 3 From Oocyte to Fertilizable Egg: Regulated mRNA Translation and the Control of Maternal Gene Expression 38 Chad E. Cragle & Angus M. MacNicol 4 Polarity of Xenopus Oocytes and Early Embryos 60 Malgorzata Kloc 5 Germ-Cell Specification in Xenopus 75 Mary Lou King Section II Midblastula Transition, Gastrulation, and Neurulation 101 6 The Xenopus Embryo as a Model System to Study Asymmetric Furrowing in Vertebrate Epithelial Cells 103 Jacek Z. Kubiak, Isabelle Chartrain, & Jean-Pierre Tassan 7 Induction and Differentiation of the Xenopus Ciliated Embryonic Epidermis 112 Marie Cibois, Pierluigi Scerbo, Virginie Thomé, Andrea Pasini, & Laurent Kodjabachian 8 Wnt Signaling during Early Xenopus Development 130 François Fagotto 9 Neural Tube Closure in Xenopus 163 Hitoshi Morita, Makoto Suzuki, & Naoto Ueno Section III Metamorphosis and Organogenesis 187 10 Primordial Germ Cell Migration 189 Aliaksandr Dzementsei & Tomas Pieler 11 Development of Gonads, Sex Determination, and Sex Reversal in Xenopus 199 Rafa³ P. Piprek & Jacek Z. Kubiak 12 The Xenopus Pronephros: A Kidney Model Making Leaps toward Understanding Tubule Development 215 Rachel K. Miller, Moonsup Lee, & Pierre D. McCrea 13 Development of Neural Tissues in Xenopus laevis 239 William A. Muñoz, Amy K. Sater, & Pierre D. McCrea 14 The Development of the Immune System in Xenopus 264 Louis Du Pasquier 15 Neural Regeneration in Xenopus Tadpoles during Metamorphosis 293 Mauricio Moreno, Karina Tapia, & Juan Larrain Section IV Novel Techniques and Approaches 309 16 Atomic Force Microscopy Imaging of Xenopus laevis Oocyte Plasma Membrane 311 Francesco Orsini 17 Size Scaling of Subcellular Organelles and Structures in Xenopus laevis and Xenopus tropicalis 325 Lisa J. Edens & Daniel L. Levy 18 A Model for Retinal Regeneration in Xenopus 346 Masasuke Araki 19 The Xenopus Model for Regeneration Research 368 Ying Chen & Gufa Lin 20 Genomics and Genome Engineering in Xenopus 383 Léna Vouillot, Aurore Thélie, Thibault Scalvenzi, & Nicolas Pollet Index 403

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Book SynopsisTranslational Gastroenterology: Organogenesis to Disease bridges the gap between basic and clinical research by providing information on GI (gastrointestinal) organ development discovered through scientific inquiry, alongside clinical observations of acquired and congenital abnormalities. Paired chapters, written from basic science and clinical viewpoints, review the major biological pathways and molecules at work in organ ontogeny and disease. In addition to a comprehensive survey of GI organ development and pathologies, the book also highlights model organisms and new areas of research, with chapters devoted to recent advances in the field of GI stem cell biology, and the potential for tissue engineering of GI organs. The topics covered provide a unique window onto current activity in the field of gastroenterology, fostering enhanced knowledge for developmental biologists as well as for clinical practitioners. Notable features include the following: BaTable of ContentsList of Contributors ix Foreword xiii Preface xv 1 Endoderm Development: From Progenitors to Organ Buds 1David A.F. Loebel, Keren Kaufman-Francis, Yoji Kojima, Henry C.Y. Chung, and Patrick P.L. Tam 2 Genetic and Cellular Mechanisms Regulating Esophageal Development 15Wei-Yao Ku and Jianwen Que 3 Congenital and Acquired Diseases of the Esophagus 27Iljana Gaffar, Yousef El-Gohary, and George Gittes 4 Basic Science of Stomach Development 43Tae-Hee Kim and Ramesh A. Shivdasani 5 Congenital and Acquired Diseases of the Stomach 57Ramon U. Jin and Jason C. Mills 6 The Pylorus: Development and Disease 73Ajay Prakash, Aaron M. Udager, and Deborah L. Gumucio 7 Basic Science of Small Intestinal Development 85Cayla A. Thompson and Michele A. Battle 8 Clinical Small Intestine 99Michael A. Helmrath and Kavita Deonarine 9 Basic Science of Colon Development 113Mattheus C.B. Wielenga and Gijs R. van den Brink 10 Congenital and Acquired Diseases of the Colon 125Jennifer J. Freeman and Daniel H. Teitelbaum 11 Intestinal Serosa 139Nichelle I. Winters and David M. Bader 12 Basic Science of Liver Development 151Ann DeLaForest and Stephen A. Duncan 13 Congenital and Acquired Diseases of the Liver 165Zahida Khan, Edgar N. Tafaleng, Kyle A. Soltys, and Ira J. Fox 14 Developmental Biology of the Pancreas 179L. Charles Murtaugh 15 Congenital Disorders of the Pancreas 193Mark Lowe 16 Enteric Nervous System Development 209E. Michelle Southard-Smith and Melissa A. Musser 17 Congenital and Acquired Disorders of the Enteric Nervous System 225Robert O. Heuckeroth 18 Gut Development in the Sea Urchin 241Megan L. Martik and David R. McClay 19 Intestinal Stem Cell Specification in the Drosophila Midgut 253Neus Rafel and Benjamin Ohlstein 20 The Caenorhabditis elegans Intestine 263James D. McGhee, Tobias Wiesenfahrt, and Aidan E. Dineen 21 Xenopus as a Model for GI Development 275Zheng Zhang and Aaron M. Zorn 22 Zebrafish Models of GI Development and Disease 289Ashley Alvers and Michel Bagnat 23 Gastrointestinal Stem Cells 303Elise S. Demitrack and Linda C. Samuelson 24 Translating Embryonic Development into Models of Human Gastrointestinal Development and Disease 317Stacy R. Finkbeiner and Jason R. Spence Index 327

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Book SynopsisPopulation Genetics and Microevolutionary Theory Explore the fundamentals of the biological implications ofpopulation genetic theoryIn the newly revised Second Edition of Population Genetics and Microevolutionary Theory, accomplished researcher and author Alan R. Templeton delivers a fulsome discussion of population genetics with coverage of exciting new developments in the field, including new discoveries in epigenetics and genome-wide studies. The book prepares students to successfully apply population genetics analytical tools by providing a solid foundation in microevolutionary theory. The book emphasizes that population structure forms the underlying template upon which quantitative genetics and natural selection operate and is a must-read for future population and evolutionary geneticists and those who wish to work in genetic epidemiology or conservation biology. You'll learn about a wide array of topics, including quantitative genetics, the interactions of natural selection with other evolutionary forces, and selection in heterogeneous environments and age-structured populations. Appendices that cover genetic survey techniques and probability and statistics conclude the book. Readers will also benefit from the inclusion of:A thorough introduction to population genetics, including the scope of the subject, its premises, and the Hardy-Weinberg Model of MicroevolutionAn exploration of systems of mating, including a treatment of the use of runs of homozygosity to show pedigree inbreeding in distant ancestorsA practical discussion of genetic drift, including the use of effective sizes in conservation biology (with a discussion of African rhinos as an example)A concise examination of coalescence, including a treatment of the infinite sites modelPerfect for graduate students in genetics and evolutionary biology programs and advanced undergraduate biology majors, Population Genetics and Microevolutionary Theory will also earn a place in the libraries of students taking courses in conservation biology, human genetics, bioinformatics, and genomics.Table of ContentsPreface to the 2nd Edition ix Chapter 1. The Scope and Basic Premises of Population Genetics 1-1 Basic Premises of Population Genetics 1-1 Population Genomics1-12 Section 1: Population Structure and History Chapter 2. Modeling Evolution and the Hardy-Weinberg Law 2-1 How to Model Microevolution 2-1 The Hardy-Weinberg Model 2-4 Hardy-Weinberg for Two Loci2-19 Chapter 3. Systems of Mating 3-1 Inbreeding 3-1 Assortative Mating3-25 Disassortative Mating3-45 Chapter 4. Genetic Drift 4-1 Basic Evolutionary Properties of Genetic Drift 4-2 Founder and Bottleneck Effects 4-7 Genetic Drift and Disequilibrium4-11 Genetic Drfit, Disequilibrium, and System of Mating4-13 Effective Population Size4-18 Chapter 5. Genetic Drift in Large Populations and Coalescence 5-1 Newly Arisen Mutations 5-1 Neutral Alleles 5-3 The Coalescent5-22 Chapter 6. Gene Flow and Population Subdivision 6-1 Gene Flow Between Two Local Populations 6-1 The Balance of Gene Flow and Drift 6-6 An Example of the Balance of Drift and Gene Flow6-27 Factors Influencing The Amount and Patter of Gene Flow6-42 Total Effective Population Size in Subdivided Populations6-62 Multiple Modes of Inheritance and Population Structure6-71 Admixture6-76 Identifying Subpopulations and Population Structure6-81 A Final Warning6-96 Chapter 7. Population History 7-1 Inferring Historical Effective Population Sizes 7-6 Inferring Historical Gene Flow Patterns and Admixture 7-11 Using Haplotype Trees to Study Population History 7-19 Model Based Approaches to Phylogeographic Analysis 7-56 Direct Studies Over Space and Past Times 7-70 Historical Population Genetics and Macroevolution 7-75 Section 2: Genotype and Phenotype Chapter 8. Basic Quantitative Genetic Definitions and Theory 8-1 “Simple” Mendelian Phenotypes 8-2 Nature Versus Nurture? 8-7 The Fisherian Model of Quantitative Genetics8-13 Chapter 9. Quantitative Genetics: Unmeasured Genotypes 9-1 Correlation Between Relatives 9-2 The Distinction Between Heritability and Inheritance9-17 Response to Selection9-19 The Problem of Between-Population Differences in Mean Phenotype 9-21 Controlled Crosses for the Analysis of Between Population Differences 9-30 The Balance Between Mutation, Drift, and Gene Flow Upon Phenotypic Variance 9-36 Chapter 10. Quantitative Genetics: Measured Genotypes 10-1 Marker Association Studies 10-5 Candidate Loci10-35 Candidate Loci and Genetic Architecture10-51 Section 3: Natural Selection and Adaptation Chapter 11. Natural Selection 11-1 The Fundamental Equation of Natural Selection: Measured Genotypes 11-4 Sickle-Cell Anemia as an Example of Natural Selection 11-10 Adaptation as a Polygenic Process 11-24 The Fundamental Theorem of Natural Selection: Unmeasured Genotypes 11-29 Some Implications of the Fundamental Equations of Natural Selection 11-33 The Course of Adaptation and Natural Selection 11-47 Chapter 12. Interactions of Natural Selection with Other Evolutionary Forces and the Detection of Natural Selection 12-1 The Interaction of Natural Selection with Mutation 12-3 The Interaction of Natural Selection with Mutation and System of Mating 12-8 The Interaction of Natural Selection with Gene Flow 12-12 The Interaction of Natural Selection with Genetic Drift 12-21 The Interactions of Natural Selection, Genetic Drift, and Gene Flow 12-28 The Interactions of Natural Selection, Genetic Drift, and Mutation 12-45 The Interactions of Natural Selection, Genetic Drift, Mutation, and Recombination 12-65 Candidate Loci 12-71 Quantitative Genetic Approaches to Detecting Selection 12-75 The Neutralist/Selectionist Debate 12-80 Chapter 13. Units and Targets of Selection 13-1 The Unit of Selection 13-4 Targets of Selection Below the Level of the Individual 13-18 Targets of Selection Above the Level of the Individual 13-51 Chapter 14. Selection in Heterogeneous Environments 14-1 Coarse-Grained Spatial Heterogeneity 14-4 Coarse-Grained Temporal Heterogeneity 14-34 Fine-Grained Heterogeneity 14-56 Coevolution 14-74 Chapter 15. Selection in Age-Structured Populations 15-1 Life History and Fitness 15-3 The Evolution of Senescence 15-13 Abnormal Abdomen: An Example of Selection in an Age-Structured Population 15-24 Overview 15-63 Appendices Appendix 1. Genetic Survey Techniques A1-1 Appendix 2. Probability and Statistics A2-1 References R-1 Index

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Book SynopsisHistory of Anatomy: An International Perspective is unique in its global approach to studying the development of human anatomy. Though it references widely known anatomists, such as Aristotle, Galen, and Bell, the book also pay homage to less famous contributors to the field and explains their findings.Table of ContentsPreface xi Acknowledgments xiii 1 Africa 1 1.1 Egypt 2 1.1.1 The Edwin Smith Papyrus 2 1.1.2 The Ebers Papyrus 2 1.1.3 The Kahun Papyrus 3 1.1.4 Egyptian Anatomy in General 3 1.1.5 Neurological Anatomy 4 1.1.6 Cardiovascular Anatomy 6 1.1.7 Reproductive Anatomy 6 1.2 Algeria 7 1.2.1 Jean Baptiste Paulin Trolard 7 Bibliography 11 2 Asia 13 2.1 China 13 2.1.1 Correcting the Errors in the Forest of Medicine 14 2.1.2 Hua Tuo 17 2.1.3 Conclusion 19 2.2 Japan 19 2.2.1 Feudal Japan (1186–1868) 19 2.2.2 Shinnin Kawaguchi 23 2.2.3 Genpaku Sugita 24 2.2.4 Ryotaku Maeno 25 2.2.5 Shoteki Fuseya 27 2.2.6 Otsuki Gentaku 27 2.2.7 Koji Harada and Ryoetsu Hoshino 28 2.2.8 Human Dissection 28 2.2.9 Seishu Hanaoka 29 2.2.10 Buntaro Adachi 31 2.2.11 Sunao Tawara 36 2.3 India 39 2.3.1 Sushruta 39 Bibliography 44 3 Europe 49 3.1 Austria 50 3.1.1 Heinrich Obersteiner 50 3.1.2 Emil Zuckerkandl 55 3.2 Czechoslovakia 59 3.2.1 Vincent Alexander Bochdalek 59 3.3 England 62 3.3.1 Richard Lower 63 3.3.2 John Browne 71 3.3.3 James Drake 75 3.3.4 Francis Sibson 81 3.3.5 William Turner 87 3.4 France 90 3.4.1 Jacobus Sylvius 90 3.4.2 Charles Estienne 94 3.4.3 Raymond de Vieussens 96 3.4.4 Pierre Dionis 98 3.4.5 Félix Vicq d’Azyr 101 3.4.6 Marie‐François Xavier Bichat 105 3.4.7 François Magendie 109 3.4.8 Jules Germain Cloquet 114 3.4.9 Augusta Déjerine‐Klumpke 120 3.5 Germany 122 3.5.1 Adam Christian Thebesius 122 3.5.2 Franz Kaspar Hesselbach 125 3.5.3 Hubert von Luschka 128 3.5.4 Adolf Wallenberg 132 3.5.5 Korbinian Brodmann 135 3.6 Greece 141 3.6.1 Aristotle 141 3.6.2 Galen 145 3.6.3 Polybus 147 3.7 Holland 148 3.7.1 Franciscus Sylvius 149 3.7.2 Niels Stensen 150 3.7.3 Pieter Camper 154 3.8 Ireland 160 3.8.1 Abraham Colles 160 3.9 Italy 164 3.9.1 Leonardo da Vinci 165 3.9.2 Vidus Vidius (Guido Guidi) 167 3.9.3 Giambattista Canano 170 3.9.4 Matteo Realdo Colombo 172 3.9.5 Costanzo Varolio (Constantius Varolius) 174 3.9.6 Giulio Cesare Casseri 176 3.9.7 Giovanni Maria Lancisi 180 3.9.8 Giovanni Battista Morgagni 188 3.9.9 Ruggero Ferdinando Antonio Guiseppe Vincenzo Oddi 192 3.10 Norway 196 3.10.1 Johan Georg Ræder 196 3.11 Scotland 200 3.11.1 Andrew Fyfe the Elder 200 3.11.2 Sir John Struthers 204 3.11.3 Charles Bell 208 3.12 Spain 213 3.12.1 Antonio de Gimbernat y Arbós 213 3.13 Sweden 216 3.13.1 Emanuel Swedenborg 216 3.14 Switzerland 219 3.14.1 Wilhelm His Senior 219 3.14.2 Wilhelm His Junior 221 Bibliography 222 4 Middle East 251 4.1 Anatomy in the Bible and Talmud 251 4.1.1 Neuroanatomy 251 4.1.2 General Anatomy 255 4.2 Anatomy in the Qur’an and Hadeeth 256 4.2.1 History of the Qur’an and Hadeeth 257 4.2.2 The Cardiovascular System 257 4.2.3 Contributions to Medicine 258 4.3 Persia 259 4.3.1 Following the Establishment of the Persian Empire (Sixth to Seventh Century CE) 259 4.3.2 Abu Zakariya Yuhanna ibn Masawaih, Mesue 262 4.3.3 Ali ibn Sahl Rabban al‐Tabari 262 4.3.4 Abubakr Muhammad Ibn Zakaria Razi, Rhazes 262 4.3.5 Abubakr Rabi ibn Ahmad Joveini Bukhari 263 4.3.6 Ali ibn Abbas al‐Majusi, Hally Abbas 264 4.3.7 Abu Ali al‐Hussain ibn Abdallah ibn Sina, Avicenna 265 4.3.8 Zinn‐ol‐Abedin Seyed Esmail ibn al‐Hussain ibn Mohammad ibn Ahmad al‐Jorjani, Hakim Jorjani 267 4.4 From the Mongol Invasion of Persia to the Foundations of Modern Anatomy 268 4.4.1 Nasir al‐Din Tusi 268 4.4.2 Mansur ibn Muhammad ibn Ahmad ibn Yusuf ibn Ilyas, Ibn Ilyas 269 4.4.3 The Safavid Period (1501–1722 CE) and the Reconciliation of Prophetic and Galenic Traditions 274 4.5 Baghdad 275 4.5.1 Ibn Jazlah 275 Bibliography 277 5 North America 285 5.1 United States 285 5.1.1 Henry Jacob Bigelow 285 5.1.2 Oliver Wendell Holmes 288 Bibliography 295 Index 297

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Book SynopsisEvolutionary developmental biology jumps a step further in Evolutionary Developmental Anthropology to survey the correlation between evolutionary developmental anthropology and primate and human morphological evolution.Table of ContentsContributors vii Foreword: Humans from Embryos ix Günter P. Wagner 1 Introduction to Evo‐Devo‐Anthro 1 Campbell Rolian and Julia C. Boughner 2 Chondrocranial Growth, Developmental Integration and Evolvability in the Human Skull 17 Neus Martínez‐Abadías, Mireia Esparza, Torstein Sjøvold and Benedikt Hallgrímsson 3 The Tooth of the Matter: The Evo‐Devo of Coordinated Phenotypic Change 35 Julia C. Boughner 4 Genetic Regulation of Amelogenesis and Implications for Hominin Ancestors 61 Rodrigo S. Lacruz 5 Evo‐Devo Sheds Light on Mechanisms of Human Evolution: Limb Proportions and Penile Spines 77 Philip L. Reno 6 Out on a Limb: Development and the Evolution of the Human Appendicular Skeleton 101 Nathan M. Young and Terence D. Capellini 7 Tinkering with Growth Plates: A Developmental Simulation of Limb Bone Evolution in Hominoids 139 Campbell Rolian 8 Origin, Development, and Evolution of Primate Muscles, with Notes on Human Anatomical Variations and Anomalies 167 Rui Diogo and Bernard Wood 9 The Evolutionary Biology of Human Neurodevelopment: Evo‐Neuro‐Devo Comes of Age 205 Bernard Crespi and Emma Leach 10 Evolving the Developing Cortex: Conserved Gradients of Neurogenesis Scale and Channel New Functions in Primates 231 Christine J. Charvet and Barbara L. Finlay 11 Growing Up Fast, Maturing Slowly: The Evolution of a Uniquely Modern Human Pattern of Brain Development 261 Philipp Gunz 12 FOXP2 and the Genetic and Developmental Basis of Human Language 285 Carles Lalueza‐Fox 13 Assembly Instructions Included 297 Kenneth Weiss and Anne Buchanan Index 317

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Book SynopsisNeurodevelopmental disorders arise from disturbances to various processes of brain development, which can manifest in diverse ways. They encompass many rare genetic syndromes as well as common, heritable conditions such as intellectual disability, autism, ADHD, schizophrenia and many types of epilepsy.Table of ContentsList of Contributors vii ForewordKevin J. Mitchell ix 1 The Genetic Architecture of Neurodevelopmental Disorders 1Kevin J. Mitchell 2 Overlapping Etiology of Neurodevelopmental Disorders 29Eric Kelleher and Aiden Corvin 3 The Mutational Spectrum of Neurodevelopmental Disorders 49Nancy D. Merner, Patrick A. Dion, and Guy A. Rouleau 4 The Role of Genetic Interactions in Neurodevelopmental Disorders 69Jason H. Moore and Kevin J. Mitchell 5 Developmental Instability, Mutation Load, and Neurodevelopmental Disorders 81Ronald A. Yeo and Steven W. Gangestad 6 Environmental Factors and Gene–Environment Interactions 111John McGrath 7 The Genetics of Brain Malformations 129M. Chiara Manzini and Christopher A. Walsh 8 Disorders of Axon Guidance 155Heike Blockus and Alain Chédotal 9 Synaptic Disorders 195Catalina Betancur and Kevin J. Mitchell 10 Human Stem Cell Models of Neurodevelopmental Disorders 239Peter Kirwan and Frederick J. Livesey 11 Animal Models for Neurodevelopmental Disorders 261Hala Harony-Nicolas and Joseph D. Buxbaum 12 Cascading Genetic and Environmental Effects on Development: Implications for Intervention 275Esha Massand and Annette Karmiloff-Smith 13 Human Genetics and Clinical Aspects of Neurodevelopmental Disorders 289Gholson J. Lyon and Jason O'Rawe 14 Progress Toward Therapies and Interventions for Neurodevelopmental Disorders 319Ayokunmi Ajetunmobi and Daniela Tropea Subject Index 345 Gene Index 353

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Book SynopsisStem Cell Nanoengineeringreviews theapplications ofnanotechnology in the fields of stem cells, tissue engineering, and regenerative medicine. Topics addressed include various types of stem cells, underlying principles of nanobiotechnology, the making of nano-scaffolds, nano tissue engineering, applications of nanotechnology in stem cell tracking and molecular imaging, nano-devices, as well asstem cell nano-engineering from bench to bedside. Written by renowned experts in their respective fields, chapters describe and explore a wide variety of topics in stem cellnanoengineering, making the book a valuable resource for both researchers and clinicians in biomedical and bioengineering fields.Table of ContentsAbout the Editors ix Contributors xi Preface xvii Part 1 An Introduction to Stem Cells 1 1 Adult Stem Cells 3 Andreas Nussler and Sahar Olsadat Sajadian 2 Pluripotent Stem Cells 25 Hossein Azizi, Akbar Hajizadeh Moghaddam, and Thomas Skutella 3 Interactions of Stem Cells and Components of the Extracellular Matrix 35 Anna K. Blakney, Julie J. Antetomaso, Winnie W. Leung, and Deok-Ho Kim 4 Regenerative Medicine and Cell Therapy: Past, Present, and Future 47 Hooman Sadri-Ardekani and Anthony Atala Part 2 An Introduction to Nanotechnology 67 5 Principles of Nanotechnology 69 Jerzy Leszczynski 6 Stem-Cell Nanoengineering: Explorations in a Rapidly Moving Field 87 Abhalaxmi Singh and Sanjeeb K. Sahoo Part 3 Nanostructures for Stem-Cell Engineering – Engineering Approach 97 7 Nanopatterned Surfaces for Stem-Cell Engineering 99 Waleed Ahmed El-Said, Tae-Hyung Kim, Ki-Bum Lee, and Jeong-Woo Choi 8 Biomimetic Nanostructures by Electrospinning and Electrospraying 123 Elham Vatankhah, Molamma P. Prabhakaran, and Seeram Ramakrishna 9 Nanoparticles for Stem-Cell Engineering 143 Esmaiel Jabbari 10 Toxicology of Nanobiomaterials 171 Shahin Bonakdar and Omid Mashinchian Part 4 Control of Stem-Cell Fate by Engineering of Microenvironment 185 11 Stem-Cell Responses to Surface Nanotopographies 187 Peng-Yuan Wang and Wei-Bor Tsai 12 Control of Mesenchymal Stem-Cell Fate by Engineering the Nanoenvironment 205 Habib Nikukar, Stuart Reid, Mathis O. Riehle, Adam S.G. Curtis, and Matthew J. Dalby 13 Delivery of Molecules and Genes/Small Interfering RNA into Stem Cells by Nanoengineering 223 Mohsen Ashjari Part 5 Nanotissue Engineering – Biological Approach along with Differentiation 243 14 Expansion of Stem Cells by Nanotissue Engineering 245 Amir Mellati and Hu Zhang 15 Nanotissue Engineering of Neural Cells 265 Sasan Jalili-Firoozinezhad, Fahimeh Mirakhori, and Hossein Baharvand 16 Nanotechnology and Cardiovascular Tissue Engineering 285 Savneet Kaur and Upasana Rishiraj 17 Nanotissue Engineering of Musculoskeletal Cells 299 Mohamadreza Baghaban Eslaminejad, Leila Taghiyar, and Fatemeh Safari 18 Nanotissue Engineering of Skin Cells 315 Daisy M. Ramos, Aditi Subramanian, Aja Aravamudhan, Matthew Harmon, Roshan James, Namdev B. Shelke, and Sangamesh G. Kumbar 19 High-Throughput Screening of Stem Cell Self-Renewal and Differentiation on Nanomaterials 327 Perry T. Yin, Tae-Hyung Kim, Jeong-Woo Choi, and Ki-Bum Lee Part 6 Nanotechnology in Stem-Cell Imaging 345 20 Nanotechnology for Cellular Imaging 347 Miroslaw Janowski, P. Walczak, and J.W.M. Bulte Part 7 Nanotissue Engineering and Clinical Applications 363 21 Advancing Translational Nanotechnology to Clinical Application 365 Michelle Griffin, Shima Salmasi, Naghmeh Naderi, Peter E. Butler, and Alexander M. Seifalian 22 Stem-Cell Nanoengineering from Bench to Bed 381 Omid Mashinchian, Shahin Bonakdar, Shahriar Sharifi, and Morteza Mahmoudi Index 397

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Book SynopsisThe Handbook of Behavioral Genetics and Phenotyping represents an integrative approach to neurobehavioural genetics; worldwide experts in their field will review all chapters. Advanced overviews of neurobehavioural characteristics will add immense value to the investigation of animal mutants and provide unique information about the genetics and behavioural understanding of animal models, under both normal and pathological conditions. Cross-species comparisons of neurobehavioural phenotypes will pave the way for an evolutionary understanding of behaviour. Moreover, while biological sciences are progressing towards a holistic approach to investigate the complexity of organisms (i.e., systems biology approach), an integrated analysis of behavioural phenotyping is still lacking. The Handbook of Behavioral Genetics and Phenotyping strengthens the cross-talk within disciplines that investigate the fundamental basis of behaviour and genetics. This will be the first volume in which traditioTable of ContentsList of Contributors xix Preface xxv 1 Genetic Screens in Neurodegeneration 1Abraham Acevedo Arozena and Silvia Corrochano Introduction 1 The Genetics of Neurodegenerative Disorders 2 Neurodegeneration Disease Models 4 Genetic Approaches to Discover New Genes Related to Neurodegeneration Using Disease Models 5 Saccharomyces cerevisiae 6 Caenorhabditis elegans 8 Drosophila melanogaster 9 Danio rerio 10 Mus musculus 11 Human Cellular Models and Post-mortem Material 14 The Future 14 Acknowledgments 15 References 15 2 Computational Epigenomics 19Mattia Pelizzola Background 19 Profiling and Analyzing the Methylation of Genomic DNA 19 Experimental Methods 20 Data Analysis 20 Array-based Methods 20 Sequencing-based Methods 20 Profiling and Analyzing Histone Marks 26 Experimental Methods 26 Data Analysis 27 Issues of Array-based Methods 27 Issues of NGS-based Methods 27 Integration with Other Omics Data 31 Chromatin States 32 Unraveling the Cross-talk Between Epigenetic Layers 33 References 33 3 Behavioral Phenotyping in Zebrafish: The First Models of Alcohol Induced Abnormalities 37Robert Gerlai Introduction 37 Alcohol Related Human Disorders: A Growing Unmet Medical Need 37 Unraveling Alcohol Related Mechanisms: The Importance of Animal Models 38 Face Validity: The First Step in Modeling a Human Disorder 39 Acute Effects of Alcohol in Zebrafish: A Range of Behavioral Responses 39 Chronic Alcohol Exposure Induced Behavioral Responses in Zebrafish 41 Effects of Embryonic Alcohol Exposure 42 Behavioral Phenotyping: Are We There Yet? 46 Assembling the Behavioral Test Battery 49 Concluding Remarks 50 References 50 4 How does Stress Affect Energy Balance? 53Maria Razzoli, Cheryl Cero, and Alessandro Bartolomucci Introduction 53 Stress 54 Energy Balance and Metabolic Disorders 55 Pro-adipogenic Stress Mediators 57 Pro-lipolytic Effect of Stress Mediators 57 How does Stress Affect Energy Balance? 57 Animal Models of Chronic Stress and their Impact on Energy Balance 58 Physical and Psychological (non-social) Chronic Stress Models 58 Mild Chronic Pain Models – Mild Tail Pinch, Foot Shock 58 Thermal Models – Cold and Heat Stress 64 Chronic Mild Stress Models: Chronic Mild Stress, Chronic Variable Stress, etc. 64 Restraint or Immobilization 65 Chronic Social Stress Models 66 Social Isolation, Individual Housing 66 Unstable Social Settings 66 Visible Burrow System 67 Intermittent Social Defeat (Resident/Intruder Procedure) 67 Chronic Psychosocial Stress, Sensory Contact, and Chronic Defeat stress 68 Stress, Recovery, and Maintenance: Insights on Adaptive and Maladaptive Effects of Stress 69 Molecular Mechanisms of Stress-Induced Negative and Positive Energy Balance 70 Serotonin (5-hydroxytryptamine, 5HT) 71 Orexin 71 Neuropeptide Y (NPY) 72 Ghrelin and Growth Hormone Secretagogue Receptor (GHSR) 72 Glucagon like Peptide 1 (GLP1) 73 Leptin 73 Amylin 74 Norepinephrine and β3-Adrenergic Receptor 74 Conclusion 74 References 75 5 Interactions of Experience-Dependent Plasticity and LTP in the Hippocampus During Associative Learning 91Agnès Gruart, Noelia Madroñal, María Teresa Jurado-Parras, and José María Delgado-García Introduction: Study of Learning and Memory Processes in Alert Behaving Mammals 91 Changes in Synaptic Strength During Learning and Memory 92 Classical Conditioning 92 Instrumental Conditioning 95 Changes in Synaptic Strength Evoked by Actual Learning can be Modified by Experimentally Evoked Long-term Potentiation 96 Other Experimental Constraints on the Study of the Physiological Basis of Learning Processes 100 Factors Modifying Synaptic Strength (Environment, Aging, and Brain Degenerative Diseases) 101 Different Genetic and Pharmacological Manipulations Able to Modify Synaptic Strength 103 Functional Relationships Between Experimentally Evoked LTP and Associative Learning Tasks 106 Future Perspectives 108 Context and Environmental Constraints 108 Other Forms of Learning and Memory Processes 109 Cortical Circuits and Functional States During Associative Learning 109 References 110 6 The Genetics of Cognition in Schizophrenia: Combining Mouse and Human Studies 115Diego Scheggia and Francesco Papaleo Background 115 Genetics of Schizophrenia 116 Cognitive (dys)functions in Schizophrenia 117 Translating Cognitive Symptoms in Animal Models 119 Executive Control 120 Performance in Schizophrenia 122 Animal Models 124 Working Memory 125 Performance in Schizophrenia 126 Animal Models 127 Control of Attention 128 Performance in Schizophrenia 130 Animal Models 130 Concluding Remarks 131 References 132 7 The Biological Basis of Economic Choice 143David Freestone and Fuat Balci Introduction 143 Translating from Animals to Humans 144 Reinforcement Learning in the Brain 145 Subjective Value 146 The Midbrain Dopamine System Updates Value 147 From Stimulus Value to Action Value 150 Model Based Learning 150 The Prefrontal Cortex Encodes Value 152 The Basal Ganglia Selects Actions 153 Optimal Decisions: Benchmarks for the Analysis of Choice Behavior 155 The Drift Diffusion Model 157 Temporal Risk Assessment 158 Timed-response Inhibition for Reward-rate Maximization 160 Timed Response Switching 163 Temporal Bisection 164 Numerical Risk Assessment 166 Rodent Version of Balloon Analog Risk Task 167 Conclusion 167 Acknowledgments 168 References 168 8 Interval-timing Protocols and Their Relevancy to the Study of Temporal Cognition and Neurobehavioral Genetics 179Bin Yin, Nicholas A. Lusk, and Warren H. Meck Introduction 179 Application of a Timing, Immersive Memory, and Emotional Regulation (Timer) Test Battery 190 Neural Basis of Interval Timing 191 What Makes a Mutant Mouse “Tick”? 193 Proposal of a TIMER Test Battery and Its Application in Reverse Genetics 199 Behavioral Test Battery Applications in Forward Genetics 202 Order of Behavioral Tasks 205 Location and Time of Behavioral Testing 205 Summary 205 References 206 Appendix I 226 Limitations of the individual-trials analysis for data obtained in the peak-interval (PI) procedure 226 9 Toolkits for Cognition: From Core Knowledge to Genes 229Giorgio Vallortigara and Orsola Rosa Salva Introduction 229 Core Knowledge: The Domestic Chick as a System Model 230 Numerical Competence 230 Physical Properties 230 Geometry of Space 232 Animate Agents 232 A Comparative Perspective on the Genetic and Evolutionary Bases of Social Behavior 236 From Social Experience to Genes 239 From Genes to Social Behavior 241 Future Directions 243 Conserved Mechanisms for Social Core Knowledge 243 Interactions Between Experience and Genomic Information 243 Neurogenetic Basis of Social Predispositions 243 Epigenetics and the Development of the Social Brain 244 Spatial Cognition, Another Promising Core-knowledge Domain 244 References 245 10 Quantitative Genetics of Behavioral Phenotypes 253Elzbieta Kostrzewa and Martien J.H. Kas Human Studies of Quantitative Traits 253 Mouse Studies of Quantitative Traits 254 Classical Inbred Mice 254 Quantitative Trait Loci (QTL) Analysis 254 Knock-out (KO) Mouse Lines 256 Use of Mice as Animal Model for Complex Human Traits 257 Comparative Genomic Approaches 257 Evolutionarily Conserved Behavioral Phenotypes 257 Physical Activity – Definitions and Methods of Phenotypic Measurement 258 Current Results of Quantitative Genetic Basis of PA in Humans 259 Current Results of Quantitative Genetic Basis of PA in Mice 260 KO Studies 260 QTL Studies 261 An Overlap of Genetic Findings Between the Species 261 Conclusions 265 References 265 11 Behavioral Phenotyping in Genetic Mouse Models of Autism Spectrum Disorders: A Translational Outlook 271Maria Luisa Scattoni, Caterina Michetti, Angela Caruso, and Laura Ricceri Introduction 271 Measuring Social behavior in ASD Mouse Models 272 Social Interaction Tests 272 Male-female 277 Female-female 278 Male-male 278 Social-approach 279 Sociability Test Phase 280 Social Novelty 280 Social Recognition 280 Repetitive Behavior 281 Motor Stereotypies 281 Restricted Interests 281 Behavioral Inflexibility 282 Behavioral Tests Targeting other ASD Symptoms 282 Anxiety 282 Epilepsy 283 Behavioral Phenotyping in ASD Mouse Pups 283 Future Directions: ASD Mouse Models as a Resource for Gene-environment Interaction Studies 284 Acknowledgments 285 References 285 12 Genetics of Human Sleep and Sleep Disorders 295Birgitte Rahbek Kornum The Mystery of Human Sleep 295 Sleep is Essential for Mammalian Life 295 The Function of Sleep 296 Extended Wakefulness Induces Sleep 296 Homeostatic and Circadian Regulation of Sleep and Wake 297 Adenosine and Sleep Homeostasis 298 Resistance to Sleep Loss is a Stable Phenotype 299 Genetic Markers of Response to Sleep Loss 299 A Unique Activity Pattern Characterizes the Sleeping Brain 300 Sleep Stages and Sleep Cycles 300 Genetics of the Human Sleep Electroencephalography 301 Normal Sleep Architecture is Lost in Fatal Familial Insomnia 303 Circadian Regulation of Sleep and Associated Disorders 304 Circadian Regulation of Sleep 304 Molecular Regulation of the Circadian Clock 305 The Central Circadian Clock is Entrained By Light 306 Circadian Rhythm Sleep Disorders 307 Advanced Sleep Phase Syndromes 307 Delayed Sleep Phase Syndromes 308 Short Sleep Times in Healthy Individuals 308 Destabilization of Sleep States and Narcolepsy 309 Normal Regulation of Sleep Architecture 309 Wakefulness is Associated with Cortical Activation 309 The Preoptic Area Contains Sleep-promoting Neurons 309 Mutual Inhibition Regulates Transitions Between Wake and Sleep 310 Regulation of REM Sleep 311 Narcolepsy, A Disorder of Wakefulness and REM Sleep 311 Narcolepsy with Cataplexy is Caused By Hypocretin Deficiency 312 Autoimmunity Toward Hypocretin Neurons 312 Genetic Evidence Supports the Autoimmune Hypothesis of Narcolepsy 313 Restless Legs Syndrome, A Developmental Sleep Disorder 314 Restless Legs Syndrome, A Mysterious Urge to Move 314 Restless Legs Syndrome and Dopamine Disturbances 315 Iron Deficiency Exacerbates RLS Symptoms 315 Genetic Studies Suggest Developmental Defects 316 Unresolved Issues and Future Perspectives 316 What is the Molecular and Neuroanatomical Basis for the Ultradian Rhythm of NREM-REM Sleep? 317 What is the Genetic Basis for Individual Variation in Complex Sleep Features such as Sleep Spindles and K-Complexes? 317 What is the Basis for the Individual Differences in Resistance to Sleep Loss? 317 Are Homeostatic and Circadian Mechanisms Genuinely Independent or Are They Intimately Linked? 318 What Controls the Molecular and Anatomical Diversity of Sleep Regulatory Networks Across Species? 318 References 319 13 The Endocannabinoid System in the Control of Behavior 323Edgar Soria-Gomez, Mathilde Metna, Luigi Bellocchio, Arnau Busquets-Garcia, and Giovanni Marsicano Introduction 323 Cannabinoid Effects and Endocannabinoid Functions 324 Role of the ECS in Memory Processes 325 Memory: General Background 325 Role of the ECS in Synaptic Plasticity 325 Memory Impairment Produced by Exogenous Cannabinoids 326 Cannabinoid Regulation of Memory: Neurobiological Mechanisms 327 Role of the ECS in Fear Processes 329 Fear: General Background 329 The ECS as an Endogenous Regulator of Fear Responses 331 Cannabinoid Regulation of Fear: Neurobiological Mechanisms 332 Implication of the ECS in Fear Coping Behaviors 333 Role of the ECS in Feeding Behavior 336 Feeding Behavior: General Background 336 The ECS as an Endogenous Regulator of Feeding Behavior 337 The ECS and Food Reward Circuits 338 The ECS in the Hypothalamic Appetite Network 338 The ECS in the Caudal Brainstem and Gastrointestinal Tract 340 Bimodal Control of Stimulated Food Intake by the ECS in the Brain 341 Paraventricular Hypothalamus Versus Ventral Striatum in Hypophagia induced by the ECS 342 The Olfactory Bulb and the Hyperphagic Action of the ECS 342 Conclusions 343 References 344 14 Epigenetics in Brain Development and Disease 357Elisabeth J. Radford, Anne C. Ferguson-Smith, and Sacri R. Ferrón Introduction 357 Epigenetics and Neurodevelopment 358 Histone Modifications 358 DNA Methylation 361 Hydroxymethylation 364 Genomic Imprinting 364 Non-coding RNAs 365 Neurodevelopmental Disorders with an Epigenetic Basis 366 Rett Syndrome 366 Coffin–Lowry Syndrome 367 Rubinstein–Taybi Syndrome 367 Alpha-thalassemia Mental Retardation Syndrome 367 Imprinted Neurodevelopmental Disorders 368 Trinucleotide Repeat Disorders 368 Fragile X Syndrome 370 Friedreich’s Ataxia 370 Myotonic Dystrophy 371 Huntington’s Disease (HD) 371 Epigenetics of Neurodegenerative Disorders 372 Parkinson´s Disease (PD) 372 Alzheimer´s Disease (AD) 373 The Impact of the Environment on the Epigenome 374 Epigenetic Therapy in Neurodevelopment 375 Untargeted Treatment 375 Targeted Epigenetic Modulation 377 Concluding Remarks 377 Acknowledgments 377 References 378 15 Impact of Postnatal Manipulations on Offspring Development in Rodents 395Diego Oddi, Alessandra Luchetti, and Francesca Romana D’Amato Introduction 395 Early Postnatal Environment in Laboratory Altricial Rodents 396 Rodents’ Responses to Postnatal Environment and Early Manipulations 397 Assessing Pups’ Responses to Postnatal Environment and Early Manipulation 397 Neonatal Ultrasonic Calls: Isolation-induced Vocalizations and Maternal Potentiation 397 Searching for Social Contact: Homing and Huddling Behaviors 398 Early-life Environment and Stress-Response 398 Separation from the Mother 399 Mother’s Stress 400 The Cross-fostering Paradigm 401 Repeated Cross-fostering as a Model of Early Maternal Environment Instability 403 Environmental Enrichment 405 Conclusions 406 References 407 16 Exploring the Roles of Genetics and the Epigenetic Mechanism DNA Methylation in Honey Bee (Apis Mellifera) Behavior 417Christina M. Burden and Jonathan E. Bobek Introduction 417 Genetics of Adult Honey Bee Biology and Behavior 418 Nurse to Forager Transition 418 Forager Preference 420 Techniques for Investigating the Genetic Bases of Behavior 420 QTL Mapping 421 RNA Techniques 421 Microarrays 421 RNA Sequencing 422 Experimentally Modulating the Genes Correlated with Specific Behaviors to Test Causality 422 DNA Methylation and Honey Bee Behavior 423 Honey Bee DNA Methylation Machinery and Genome-Wide Patterns 423 DNA Methylation and Task Specialization 424 DNA Methylation and Memory Consolidation 425 Techniques for Detecting and Assaying DNA Methylation 426 The Technological Bases for Most DNA Methylation Assays 426 Methylation-specific Restriction Endonucleases 426 Protein-mediated Precipitation of Methylated DNA 428 Bisulfite Conversion 428 Assaying Single CpGs, Short Sequences, and Target Regions 429 Analyzing Genome-wide DNA Methylation Patterns: Microarray-based Methodologies 431 Analyzing Genome-wide DNA Methylation Patterns: Sequencing-based Methodologies 432 Techniques for Manipulating DNA Methylation 434 Pharmacological Manipulation of DNA Methylation 434 RNA Interference as a DNMT Blockade 434 Concluding Remarks and Future Perspectives 435 References 436 17 Genetics and Neuroepigenetics of Sleep 443Glenda Lassi and Federico Tinarelli Defining Sleep 443 Sleep is Genetically Determined 445 EEG and Heritable Traits 445 Sleep Disorders and Genes 446 Sleep and Gene Expression 447 Epigenetics 448 DNA Methylation 450 Posttranslational Modifications (PTMs) 450 RNA interference 452 Neuroepigenetics 453 Two Neurodevelopmental Disorders with Opposing Imprinting Profiles and Opposing Sleep Phenotypes 453 Neuroepigenetics of Sleep 454 Fruit Fly 454 Rodent Models 454 Human Beings 456 Sleep and Parent-of-origin Effects 458 Conclusions 460 References 460 18 Behavioral Phenotyping Using Optogenetic Technology 469Stephen Glasgow, Carolina Gutierrez Herrera, and Antoine Adamantidis Introduction 469 Microbial Opsins 470 Fast Excitation Using Channelrhodopsin-2 and Its Variants 470 Fast Optical Silencing 474 Alternative strategies for cell-type specific modulation of neural activity 476 Targeting systems 476 Light Delivery in the Animal Brain 478 Recording Light-evoked Neuronal Activity 479 Behavioral Phenotyping 479 In-vivo Optogenetics: Defining Circuits 480 Perspectives 484 Acknowledgments 484 References 484 19 Phenotyping Sleep: Beyond EEG 489Sibah Hasan, Russell G. Foster, and Stuart N. Peirson Sleep Research 489 Phenotyping Sleep in Humans 490 Introduction 490 Actigraphy 490 Cardiorespiratory Signals 491 EEG 492 Phenotyping Sleep in Animal Models 494 Introduction 494 EEG 494 Introduction 494 Tethered EEG 496 Telemetered EEG 496 NeuroLogger EEG 498 Beyond EEG 498 Infrared Beam Break 499 Movement Based on Implanted Magnets 499 Piezo-electric Sensors 499 Video Tracking 500 Future Perspectives 501 Acknowledgements 502 References 502 20 A Cognitive Neurogenetics Screening System with a Data-Analysis Toolbox 507C.R. Gallistel, Fuat Balci, David Freestone, Aaron Kheifets, and Adam King Introduction 507 Mechanisms, Not Procedures 508 Functional Specificity 508 No Group Averages 509 Physiologically Meaningful Measures 509 Importance of Large-scale Screening and Minimal Handling 511 Utilizable Archived Data with Intact Data Trails 511 The System 512 The Toolbox 513 Core Commands 516 Powerful Graphics Commands 517 Results 518 Summary 523 References 524 21 Mapping the Connectional Architecture of the Rodent Brain with fMRI 527Adam J. Schwarz and Alessandro Gozzi Introduction 527 MRI Mapping of Functional Connectivity in the Rodent Brain 528 Networks of Functional Covariance 528 Connectivity of Neurotransmitter Systems 529 The Dopaminergic System 529 The Serotonergic System 531 Resting State BOLD fMRI 532 Connectivity Networks of the Rodent Brain 533 Do Rodent Brains have a Default Mode Network? 536 Use of Anesthesia and Other Methodological Considerations 539 Transgenic Models: Genetic Manipulation of Functional Connectivity Patterns 541 Future Perspectives 543 References 545 22 Cutting Edge Approaches for the Identification and the Functional Investigation of miRNAs in Brain Science 553Emanuela de Luca, Federica Marinaro, Francesco Niola, and Davide De Pietri Tonelli Introduction 553 History 553 Biology and Functions in the Brain 553 Identification of Novel MicroRNAs in the Brain 555 miRNA Extraction and Purification 556 miRNA Cloning 556 Computational Identification of Novel miRNAs 557 RNA Sequencing (RNA-Seq) 558 miRNA expression analysis in the brain 559 miRNA profiling 559 Analysis of miRNA Expression in Tissue 559 Target Identification 560 Computational Identification of Targets 561 Proteomics 561 RISC-associated miRNA Targets 562 RNomics 563 miRNA Manipulation/Target Validation 565 miRNA Inhibition 565 miRNA Over-expression 566 Target Validation 567 New Frontiers in Small RNA-based Technologies to Cure Nervous System Deficits 567 Use of miRNAs in Gene Therapy 567 Use of miRNAs in Gene Therapy in the Brain Requires Improved Delivery Strategies 571 Conclusion and Perspectives 572 Are Circulating miRNAs Novel Biomarkers for Brain Diseases? 572 Use of miRNAs in Cell Reprogramming Technology 573 Are miRNAs Just the “Tip of the Iceberg”? Emerging Classes of Noncoding RNAs and Novel Scenarios 574 Acknowledgments 575 Competing Financial Interests 575 References 575 Index 585

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Book SynopsisThere is no escaping the fact that theisland biogeography of the North Atlantic Regionissingularlypeculiar. Sitting inthenorth of the Atlantic Ocean, these islands have been subjected to largescale shifts in climate over the last few million years, unlike the other island groups further south which were likelymorebuffered from thevicissitudes of Quaternary climate changes.Uniquely for a groupof islandsthere is only one documented extinctionin the North Atlantic(the Great Auk), and those in the insects are local eventsrelating to species that are distributed throughout the Palaearctic region. Over half the insect species in Iceland and Greenlandare introduced. The faunas, excluding Greenland, arepredominantlyofPalaearcticoriginand have close affinities with the faunas ofScandinavia andthe British Isles and.These unique physical and biological characteristics have interested biologists and biogeographers forcenturies. The key debates concerningthebiogeographyof the North Atlantic islandsstillrumble on:Do the biota reflect crypticrefugiaor otherwise, or tabula rasa and recolonization?How important werehuman communities in shaping the existing biota and biogeographical patterns?Throw into this mixcurrent concerns over global warming,and we can now ask,how resilient is the biota to change, either natural or anthropogenic? This volume draws together a range of researchers with longstanding research interests in the region, from diverseacademicbackgrounds, to evaluatesome ofthese questions.Table of ContentsList of Contributors vii Introduction xiJon P. Sadler and Eva Panagiotakopulu Section I: Remote Origins 1 1 The Opening of the North Atlantic 3Brian G. J. Upton 2 Cenozoic Vegetation and Phytogeography of the Sub-arctic North Atlantic 29Friðgeir Grímsson, Thomas Denk and Reinhard Zetter 3 Interglacial Biotas from the North Atlantic Islands 51Ole Bennike and Jens Böcher Section II: Origins of the Present Biota 83 4 Origin and Dispersal of the North Atlantic Vascular Plant Floras 85Christian Brochmann and Inger G. Alsos 5 The Aquatic Fauna of the North Atlantic Islands with Emphasis on Iceland 103Gísli Már Gíslason 6 The Vascular Floras of High-Latitude Islands with Special Reference to Iceland 113Thóra Ellen Thórhallsdóttir 7 Quaternary Vertebrates from the North Atlantic Islands 147Ole Bennike and Bernd Wagner 8 North Atlantic Insect Faunas, Fossils and Pitfalls 161Eva Panagiotakopulu Section III: Human Impact 185 9 Landnám and the North Atlantic Flora 187Kevin J. Edwards, Egill Erlendsson and J. Edward Schofield 10 Origin of the Northeast Atlantic Islands Bird Fauna: Scenarios of Ecosystem Development 215Aevar Petersen and Bergur Olsen 11 Human Impact on North Atlantic Biota: Farming and Farm Animals, Fishing, Sealing and Whaling 251Ingrid Mainland and Jennifer Harland Section IV: Conservation in a Warming World 273 12 A Fleet of Silver: Local Knowledge Perceptions of Sea Ice from Iceland and Labrador/Nunatsiavut 275Astrid E. J. Ogilvie, Brian T. Hill and Gaston R. Demarée 13 Biodiversity Conservation in the Faroe Islands Under Changing Climate and Land Use 293Anna Maria Fosaa 14 Biodiversity Conservation in Iceland Under Changing Climate 303Erlingur Hauksson 15 The Natural Environment and Its Biodiversity in Greenland During the Present Climate Change 339Ib Johnsen and Henning Heide-Jørgensen Index 359

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Book SynopsisAs pressures on Australia''s inland waters intensify from population growth, expanding resource development and climate change, there is an urgent need to manage and protect these special areas. Understanding their ecology underpins their wise management and conservation. Australian Freshwater Ecology vividly describes the physical, chemical and biological features of wetlands, lakes, streams, rivers and groundwaters in Australia. It presents the principles of aquatic ecology linked to practical management and conservation, and explains the causes, mechanisms, effects and management of serious environmental problems such as altered water regimes, eutrophication, salinization, acidification and sedimentation of inland waters. Key features: contributions from a diverse, highly qualified team of aquatic ecologists whose expertise spans the ecology and management of standing and running waters in Australia sections covering groundwaters, biodivTrade Review “This excellent volume is certain to inspire a new generation of freshwater ecologists, in Australia and beyond, to go out and learn more about these incredibly diverse and vulnerable environments.” (Freshwater Biology, 2 June 2015) Table of ContentsAbout this book, xi About the companion website, xii PART I: PROCESSES IN AQUATIC ECOSYSTEMS, 1 1 Australian waters: diverse, variable and valuable, 3 1.1 The challenge for aquatic ecologists, 3 1.2 Defi ning some common terms, 6 1.3 Australian inland waters: their diversity and distribution, 6 1.4 The water regime: ‘where, when and to what extent water is present’, 7 1.4.1 Water budgets, scale issues and human influences on water regimes, 7 1.4.2 Components of the water regime, 8 1.4.3 Water regime variability, 9 1.5 Linkages in aquatic ecosystems: from molecular bonds to global exchanges, 11 1.5.1 Wonderful water and its molecular linkages, 11 1.5.2 Linkages at the catchment scale, 12 1.5.3 Linkages at the global scale: the hydrological cycle, 13 1.5.4 Continental linkages and surface waters in Australia, 15 1.5.5 Continental linkages and groundwaters in Australia, 19 1.6 The structure of this book, 20 2 Physical processes in standing waters, 21 2.1 Depth and physical processes, 21 2.2 Let there be light ..., 21 2.2.1 Light reaching the water surface, 21 2.2.2 Light below the water surface, 22 2.2.3 Seeing through water: Secchi discs and quantum sensors, 24 2.3 The euphotic zone, 24 2.4 Light and life, 25 2.5 Temperature and stratification, 25 2.5.1 Causes of stratifi cation, 26 2.6 Using circulation patterns to classify standing waters, 27 2.7 Ecological implications of the different types of stratifi cation and mixing, 29 2.8 Deep versus shallow standing waters: depth matters, 31 2.8.1 How deep standing waters form, 32 2.8.2 How shallow standing waters form, 32 2.9 Synthesis, 35 3 Chemical processes in standing waters, 37 3.1 ‘There’s a certain chemistry ...’, 37 3.2 Dissolved gases, 37 3.2.1 Oxygen, 38 3.2.2 Carbon dioxide, 41 3.2.3 Hydrogen, 42 3.2.4 Methane, 43 3.3 Sources of ions, 45 3.4 Ionic composition of Australian standing waters, 45 3.5 Conductivity, salinity and total dissolved solids, 45 3.6 Ionic composition and trophic state, 47 3.6.1 Some common anions, 47 3.6.2 Some common cations, 48 3.7 Redox reactions and redox potential, 50 3.8 Redox reactions and some common metals, 51 3.9 Nutrients, nutrient limitation and ecological stoichiometry, 52 3.9.1 Phosphorus, 53 3.9.2 Nitrogen, 55 3.9.3 Carbon, 58 3.10 Water regime, drying and water chemistry, 60 3.10.1 What happens to water chemistry during a wetting-drying cycle?, 60 3.11 Synthesis, 62 4 Biological processes in standing waters, 63 4.1 Biological players on a physical and chemical stage, 63 4.2 Major ecological zones and habitats, 64 4.3 Blurred boundaries and mobile assemblages, 66 4.4 Trophic groups and sources of energy, 66 4.5 Producers, 69 4.5.1 An ecological classification of producers, 72 4.5.2 Microscopic aquatic plants, 72 4.5.3 Macroscopic aquatic plants, 74 4.5.4 Plants living in water: benefits and constraints, 76 4.5.5 Alternative states: changes in plant dominance in shallow waterbodies, 77 4.6 Consumers, 80 4.6.1 Decomposers: the importance of microbes and fungi, 80 4.6.2 Invertebrate detritivores, 81 4.6.3 Invertebrate herbivores, 82 4.6.4 Invertebrate carnivores, 83 4.6.5 Vertebrate herbivores, 84 4.6.6 Vertebrate carnivores, 85 4.6.7 Predation and trophic cascades, 86 4.6.8 Trophic cascades and biomanipulation, 87 4.6.9 How vertebrates use waterbodies: linkages and subsidies, 87 4.7 Biological processes in temporary standing waters, 90 4.8 Biological processes in saline standing waters, 94 4.9 Synthesis, 95 5 Physical processes in running waters, 97 5.1 Flow and the diversity of running waters, 97 5.2 Scale, ecological hierarchies and networks, 97 5.3 A hierarchical classification of physical features, 99 5.3.1 Physical features and channel flows, 101 5.4 Hydrology and stream flow, 103 5.4.1 Measuring discharge, 103 5.4.2 Measuring current velocity, 104 5.5 Hydrographs, catchment characteristics and groundwater interactions, 106 5.6 Flow variability and its implications, 108 5.7 The physical process of transport, 110 5.7.1 The sources of sediment, 111 5.7.2 Sediment particle size and distribution, 112 5.7.3 Current velocity, erosion and transport, 113 5.7.4 Sediment dynamics and channel form, 114 5.7.5 Floodplain sedimentation and billabong formation, 115 5.8 River profi les and longitudinal changes in physical features, 118 5.9 Synthesis, 119 6 Chemical processes in running waters, 120 6.1 The complex web of factors, 120 6.2 Dissolved gases, 120 6.3 Ionic composition of Australian rivers, 123 6.4 Sources of ions, 124 6.5 Nutrients and nutrient spiralling, 126 6.5.1 Transport and retention of nutrients, 128 6.6 Carbon and organic matter, 129 6.6.1 Dissolved organic matter in rivers, 130 6.6.2 Solute processes: dissolved substances in running waters, 132 6.7 Longitudinal changes in chemical features, 133 6.8 Synthesis, 135 7 Biological processes in running waters, 136 7.1 Factors affecting biological processes at various scales, 136 7.2 Zones and habitats: parallels and contrasts with standing waters, 136 7.3 Living with flow, 138 7.4 Sources of energy in running waters, 142 7.4.1 Producers, 142 7.4.2 The distribution of different life-forms of producers, 143 7.4.3 Open-water producers in large rivers, 146 7.4.4 Classifying consumers in running waters, 146 7.4.5 Invertebrate herbivores, 147 7.4.6 Invertebrate carnivores, 149 7.4.7 Vertebrate herbivores, 150 7.4.8 Vertebrate carnivores, 151 7.4.9 Decomposers, 154 7.4.10 Functional feeding groups, 157 7.5 The fate of a dead eucalypt leaf that falls into a stream ..., 158 7.6 Conceptual models of running-water ecosystems, 160 7.7 The role of disturbance, 163 7.7.1 Post-disturbance recolonization processes, 164 7.7.2 Recolonization, dispersal and biogeography in Australian running waters, 168 7.7.3 Setting the biogeographic scene: ancient rocks, variable climates, 170 7.7.4 Some biogeographic patterns in Australian inland waters, 170 7.8 Synthesis, 173 8 Groundwater processes and management, 174 8.1 Out of sight, out of mind?, 174 8.2 An integrated definition of groundwaters, 174 8.3 Physical processes in groundwaters, 176 8.3.1 Groundwater discharge, permeability, porosity and Darcy’s Law, 178 8.3.2 Physical processes between groundwaters and surface waters, 180 8.3.3 Groundwater temperature, 183 8.4 Chemical processes in groundwaters, 184 8.4.1 Principal chemical processes in groundwater, 184 8.4.2 Chemical processes along gradients of dissolved oxygen, 186 8.5 Biological processes in groundwaters, 187 8.5.1 Groundwater microbiology, 188 8.5.2 Buried treasures in Australia: groundwater invertebrates and fishes, 190 8.5.3 Biodiversity and ecology of Australian groundwater fauna, 191 8.5.4 Physical, chemical and biological drivers of groundwater ecological processes, 193 8.5.5 Groundwater-dependent ecosystems (GDEs), 195 8.6 Management issues in Australian groundwaters, 197 8.7 Ecosystem services and conservation of Australian groundwaters, 201 8.8 Synthesis, 202 PART II: MANAGEMENT OF AQUATIC ECOSYSTEMS, 205 9 Management issues: water regime, 207 9.1 ‘When the well is dry ...’, 207 9.2 Changes to water regimes by humans in Australia: a brief history, 207 9.2.1 Changing water regime, changing processes, 210 9.3 Diverse impoundments with diverse effects, 211 9.3.1 Impoundments as ecological barriers, 214 9.3.2 Impoundments and estuaries, 215 9.4 Ecological effects of water extraction, 216 9.4.1 Ecological effects of drainage and irrigation, 218 9.4.2 Ecological effects of inter-basin transfers, 219 9.4.3 Ecological effects of urbanization, 220 9.5 Water regimes and environmental watering, 221 9.5.1 Environmental watering: ecological objectives and outcomes, 223 9.5.2 Environmental watering: risks and tactics, 225 9.6 ‘Breaking down the barriers’: fishways and dam removal, 226 9.7 Synthesis, 227 10 Management issues: physical features, 229 10.1 Changing physical features, changing processes, 229 10.2 Human activities and the physical environment, 230 10.2.1 Human changes to catchments, 230 10.2.2 Human changes to basins and channels, 232 10.3 Sedimentation: a physical process with negative fallout, 235 10.3.1 Human activities and sedimentation, 236 10.3.2 Ecological effects of sedimentation, 238 10.3.3 Management of sedimentation, 239 10.4 Physical processes and land-water interfaces, 241 10.4.1 Ecological roles of fringing and riparian zones, 241 10.4.2 Threats to land-water interfaces, 243 10.4.3 Management of land-water interfaces, 245 10.5 Recovering natural physical complexity, 248 10.6 Synthesis, 249 11 Management issues: water quality, 250 11.1 What is water quality?, 250 11.2 Managing water quality, 250 11.3 Eutrophication, 253 11.3.1 Natural and anthropogenic eutrophication, 253 11.3.2 Drivers, stressors and processes of eutrophication, 253 11.3.3 Ecological impacts and effects on ecosystem services, 256 11.3.4 Management of eutrophication, 258 11.4 Salinization, 259 11.4.1 Natural and anthropogenic salinization, 259 11.4.2 Drivers, stressors and processes of salinization, 259 11.4.3 Ecological impacts and effects on ecosystem services, 261 11.4.4 Management of salinization, 262 11.5 Acidifi cation, 264 11.5.1 Natural and anthropogenic acidifi cation, 264 11.5.2 Drivers, stressors and processes of acidification, 264 11.5.3 Ecological impacts and effects on ecosystem services, 267 11.5.4 Management of acidification, 268 11.6 Pollution, 269 11.6.1 Drivers, stressors and processes of pollution, 269 11.6.2 Ecological impacts and effects on ecosystem services, 271 11.6.3 Management of pollution, 273 11.7 Water quality guidelines, 274 11.8 Monitoring and assessing water quality, 275 11.8.1 Condition monitoring, 275 11.8.2 Detecting environmental impacts, 277 11.9 Multiple stressors and models of ecosystem change, 277 11.10 Synthesis, 279 12 Management issues: biodiversity conservation and climate change, 281 12.1 What is biodiversity and why does it need conservation?, 281 12.1.1 Setting priorities in biodiversity conservation, 281 12.2 Aquatic landscapes: networks and mosaics of habitats, 283 12.3 Protected areas for conserving freshwater communities, 284 12.4 Having good connections: dispersal and connectivity in conservation, 286 12.5 Protecting refuges to conserve aquatic communities, 287 12.6 Conserving aquatic species and populations, 288 12.6.1 The special challenge of conserving species with complex life histories, 288 12.6.2 The spatial extent of populations and metapopulations, 289 12.6.3 What are ‘Evolutionarily Significant Units’?, 289 12.6.4 Hidden biodiversity: cryptic species, 290 12.6.5 Endemic species and relictual faunas, 290 12.7 Threatened communities and species, 291 12.8 In the wrong place: ‘exotic aquatics’ and invasive species, 293 12.8.1 Invasive predators and competitors, 294 12.8.2 Domestic and hybridizing invasive aquatic species, 294 12.8.3 Invasive ‘ecosystem engineers’, 297 12.8.4 Potential effects of climate change on aquatic invasive species, 298 12.9 Climate change and Australian aquatic ecosystems, 299 12.9.1 Effects of increased water temperature, 300 12.9.2 Effects of changes to the hydrological cycle and water regimes, 300 12.9.3 Effects of sea-level rise, 301 12.9.4 Effects of changes to atmospheric conditions, 302 12.9.5 Effects of reduced snow cover and alpine warming, 302 12.9.6 How do these climatic changes affect freshwater species and ecosystems?, 302 12.9.7 Planned adaptation to climate change in aquatic ecosystems, 305 12.10 Synthesis, 307 13 Integrating ecology and management: a synthesis, 308 13.1 The ‘big picture’: integrating ecology and management, 308 13.2 The ‘bigger picture’: integrating social, economic and political goals, 309 13.3 Strategic adaptive management in aquatic ecology, 311 13.4 Resolving conflicts in freshwater management: a role for aquatic ecologists?, 313 13.5 Future challenges and opportunities: where to from here?, 315 13.6 Synthesis, 319 References, 321 Index, 347

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Book SynopsisTable of ContentsLIST OF CONTRIBUTORS xix PREFACE xxiii ACKNOWLEDGMENTS xxv ABOUT THE COMPANION WEBSITE xxvii SECTION I BIOENERGY FUNDAMENTALS 1 1 INTRODUCTION TO BIOENERGY 3Samir Kumar Khanal and Yebo Li 1.1 Energy 3 1.2 Non-renewable Energy 5 1.3 Renewable Energy 10 1.4 Why Renewable Energy? 11 1.5 Bioenergy 13 References 17 Exercise Problems 18 2 UNITS AND CONVERSIONS 19Samir Kumar Khanal 2.1 Introduction 19 2.2 Units of Measurement 19 2.3 Useful Units and Conversions 21 2.4 Energy and Heat 25 2.5 Volume–Mass Relationship 29 2.6 Ideal Gas Law 29 2.7 Henry’s Law 30 References and Further Reading 32 Exercise Problems 32 3 MASS AND ENERGY BALANCES 33Devin Takara and Samir Kumar Khanal 3.1 Introduction 33 3.2 Mass Balances 33 3.3 Enthalpy 35 3.4 Energy Balances 36 References and Further Reading 39 Exercise Problems 39 4 THERMODYNAMICS AND KINETICS OF BASIC CHEMICAL REACTIONS 42Devin Takara and Samir Kumar Khanal 4.1 Introduction 42 4.2 Reaction Thermodynamics 43 4.3 Reaction Kinetics 46 References and Further Reading 48 Exercise Problems 48 5 ORGANIC AND CARBOHYDRATE CHEMISTRY 50Xiaolan Luo and Yebo Li 5.1 Introduction 50 5.2 Structural Formulas and Classification of Organic Compounds 51 5.3 Aliphatic Compounds 52 5.4 Aromatic Compounds 61 5.5 Heterocyclic Compounds 62 5.6 Carbohydrates 63 5.7 Proteins and Lipids 66 References and Further Reading 69 Exercise Problems 70 6 PLANT STRUCTURAL CHEMISTRY 71Samir Kumar Khanal Saoharit Nitayavardhana and Rakshit Devappa 6.1 Introduction 71 6.2 Carbohydrates and Their Classification 72 6.3 Main Constituents of Plant Biomass 73 6.4 Plant Cell Wall Architecture 80 References 85 Exercise Problems 86 7 MICROBIAL METABOLISMS 88Arul M. Varman Lian He and Yinjie J. Tang 7.1 Introduction 88 7.2 Carbon Metabolisms 89 7.3 Metabolic Models 93 References 104 Exercise Problems 105 Appendix 7.1 Code Useful for Example 7.2 105 SECTION II BIOENERGY FEEDSTOCKS 107 8 STARCH-BASED FEEDSTOCKS 109Xumeng Ge and Yebo Li 8.1 Introduction 109 8.2 Corn 110 8.3 Sweet Potato 116 8.4 Cassava 120 8.5 Comparison of Composition Yield and Energy Potential of Corn Sweet Potato and Cassava 124 References 125 Exercise Problems 126 9 OILSEED-BASED FEEDSTOCKS 127Chengci Chen and Marisol Berti 9.1 Introduction 127 9.2 Soybean 128 9.3 Rapeseed and Canola 132 9.4 Oil Palm 135 9.5 Jatropha 136 9.6 Camelina 138 9.7 Yield and Oil Content of Major Oilseed Feedstocks 139 References 140 Exercise Problems 142 10 LIGNOCELLULOSE-BASED FEEDSTOCKS 143Sudhagar Mani 10.1 Introduction 143 10.2 Feedstock Availability and Production 144 10.3 Feedstock Logistics 151 References 167 Exercise Problems 168 11 ALGAE-BASED FEEDSTOCKS 170Xumeng Ge Johnathon P. Sheets Yebo Li and Sudhagar Mani 11.1 Introduction 170 11.2 Algae Classification Cell Structure and Characteristics 171 11.3 Mechanism of Algal Growth 172 11.4 Algal Growth Conditions 174 11.5 Steps in Algal-Biodiesel Production 176 References 195 Exercise Problems 196 SECTION III BIOLOGICAL CONVERSION TECHNOLOGIES 199 12 PRETREATMENT OF LIGNOCELLULOSIC FEEDSTOCKS 201Chang Geun Yoo and Xuejun Pan 12.1 Introduction 201 12.2 What Does Pretreatment Do? 202 12.3 Physical Pretreatment 205 12.4 Thermochemical Pretreatment 207 12.5 Other Pretreatments 216 12.6 Co-products from Lignocellulosic Feedstock Pretreatment 219 References 220 Exercise Problems 221 13 ENZYMATIC HYDROLYSIS 224David Hodge and Wei Liao 13.1 Introduction 224 13.2 Nomenclature and Classification of Hydrolases 225 13.3 Enzyme Kinetics 226 13.4 Enzymatic Hydrolysis of Carbohydrates 240 References 246 Exercise Problems 247 14 ETHANOL FERMENTATION 250Saoharit Nitayavardhana and Samir Kumar Khanal 14.1 Introduction 250 14.2 Biochemical Pathway 252 14.3 Byproducts Formation during Ethanol Fermentation 263 14.4 Microbial Cultures 264 14.5 Environmental Factors Affecting Ethanol Fermentation 267 14.6 Industrial Fuel-Grade Ethanol Production 268 References 274 Exercise Problems 275 15 BUTANOL FERMENTATION 277Victor Ujor and Thaddeus Chukwuemeka Ezeji 15.1 Introduction 277 15.2 Butanol Fermentation 279 15.3 Factors Affecting Butanol Fermentation 285 15.4 Substrates for Butanol Fermentation 287 15.5 Advanced Butanol Fermentation Techniques and Downstream Processing 288 References 292 Exercise Problems 294 16 SYNGAS FERMENTATION 296Mark R. Wilkins Hasan K. Atiyeh and Samir Kumar Khanal 16.1 Introduction 296 16.2 Stoichiometry 297 16.3 Syngas-Fermenting Bacteria 298 16.4 Factors Affecting Syngas Fermentation 303 16.5 Product Recovery 308 References 309 Exercise Problems 311 17 FUNDAMENTALS OF ANAEROBIC DIGESTION 313Samir Kumar Khanal and Yebo Li 17.1 Introduction 313 17.2 Organic Conversion in an Anaerobic Process 315 17.3 Stoichiometry of Methane Production 320 17.4 Important Considerations in Anaerobic Digestion 323 17.5 Anaerobic Digestion Model No. 1 (ADM1) 331 References 334 Exercise Problems 336 18 BIOGAS PRODUCTION AND APPLICATIONS 338Samir Kumar Khanal and Yebo Li 18.1 Introduction 338 18.2 Anaerobic Digestion Systems 338 18.3 Biogas Cleaning and Upgrading 354 18.4 Biogas Utilization 357 18.5 Digestate 358 References 358 Exercise Problems 359 19 MICROBIAL FUEL CELLS 361Hongjian Lin Hong Liu Jun Zhu and Venkataramana Gadhamshetty 19.1 Introduction 361 19.2 How Does a Microbial Fuel Cell (MFC) Work? 363 19.3 Electron Transfer Processes 365 19.4 Electrical Power and Energy Generation 370 19.5 Design and Operation of an MFC 377 References 381 Exercise Problems 382 SECTION IV THERMAL CONVERSION TECHNOLOGIES 385 20 COMBUSTION FOR HEAT AND POWER 387Sushil Adhikari Avanti Kulkarni and Nourredine Abdoulmoumine 20.1 Introduction 387 20.2 Fundamentals of Biomass Combustion 389 20.3 Biomass Properties and Preprocessing 393 20.4 Biomass Furnaces 395 20.5 Power Generation 397 20.6 Biomass Co-firing with Coal 402 20.7 Environmental Impact and Emissions of Biomass Combustion 404 References 405 Exercise Problems 405 21 GASIFICATION 407Sushil Adhikari and Nourredine Abdoulmoumine 21.1 Introduction 407 21.2 Fundamentals of Gasification 408 21.3 Gasifiers 410 21.4 Feedstock Preparation and Characterization 414 21.5 Gasification Mass and Energy Balance 416 21.6 Gas Cleanup 419 21.7 Applications of Biomass Gasification 419 References 421 Exercise Problems 421 Appendix 422 22 PYROLYSIS 423Manuel Garcia-Perez 22.1 Introduction 423 22.2 Slow vs. Fast Pyrolysis 425 22.3 Pyrolysis Reactions and Mechanisms 426 22.4 Single-Particle Models 431 22.5 Bio-Oil 432 22.6 Charcoal 434 22.7 Bio-oil Refining 434 References 437 Exercise Problems 438 SECTION V BIOBASED REFINERY 439 23 SUGAR-BASED BIOREFINERY 441Samir Kumar Khanal and Saoharit Nitayavardhana 23.1 Introduction 441 23.2 Stoichiometry 442 23.3 Sugarcane Ethanol 443 23.4 Sweet Sorghum Ethanol 446 23.5 Sugar Beet Ethanol 447 23.6 Biochemicals and Biopolymers 448 References 450 Exercise Problems 451 24 STARCH-BASED BIOREFINERY 453Samir Kumar Khanal and Saoharit Nitayavardhana 24.1 Introduction 453 24.2 Stoichiometry of Starch to Ethanol 455 24.3 Integrated Farm-Scale Biorefinery 464 References 465 Exercise Problems 466 25 LIGNOCELLULOSE-BASED BIOREFINERY 467Scott C. Geleynse Michael Paice and Xiao Zhang 25.1 Introduction 467 25.2 Cell Structure of Lignocellulosic Feedstocks 468 25.3 Stoichiometry and Energy Content 468 25.4 Lignocellulosic Biomass Conversion to Fuel 472 25.5 Co-Products from Lignocellulose-Based Biorefinery 473 25.6 Industrial Lignocellulose-Based Biorefinery 476 References 478 Exercise Problems 480 26 LIPID-BASED BIOREFINERY 481B. Brian He J. H. Van Gerpen Matthew J. Morra and Armando G. McDonald 26.1 Introduction 481 26.2 Lipid-Based Feedstocks 483 26.3 Chemical Properties of Lipids 484 26.4 Biodiesel from Lipids 491 26.5 Lipid-Based Biorefinery 498 References 501 Exercise Problems 502 SECTION VI BIOENERGY SYSTEM ANALYSIS 505 27 TECHNO-ECONOMIC ASSESSMENT 507Ganti S. Murthy 27.1 Introduction 507 27.2 What Is Techno-Economic Analysis? 508 27.3 Basic Steps in TEA 509 27.4 Tools Software and Data Sources for Performing TEA 517 References 518 Exercise Problems 518 28 LIFE-CYCLE ASSESSMENT 521Ganti S. Murthy 28.1 Introduction 521 28.2 What Is Life-Cycle Assessment (LCA)? 522 28.3 Procedure for LCA 524 28.4 Tools Available to Perform LCA 533 28.5 Advanced Topics 533 References 539 Exercise Problems 541 29 GOVERNMENT POLICY AND STANDARDS FOR BIOENERGY 544Sami Kumar Khanal Gal Hochman Ajay Shah and Jeffrey M. Bielicki 29.1 Overview of the Bioenergy Market 544 29.2 Rationale for Government Intervention 546 29.3 Government Intervention through Policy Tools 550 29.4 Biofuels Policy Implementations: Existing Policy Instruments 550 29.5 Implications of Biofuels Policies 559 References 561 Exercise Problems 561 INDEX 563

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Book Synopsis

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Book SynopsisNitrogen is arguably the most important nutrient required by plants. However, the availability of nitrogen is limited in many soils and although the earth's atmosphere consists of 78. 1% nitrogen gas (N2) plants are unable to use this form of nitrogen.Table of ContentsBiological Nitrogen Fixation VOLUME 1 Chapter 1. Introduction Frans J. de Bruijn Section 1. Focus Chapters Chapter 2. Recent advances in Understanding Nitrogenases and How They Work William Newton Chapter 3. Evolution and Taxonomy of Nitrogen-fixing Organisms with emphasis on Rhizobia Kristina Lindstrom Chapter 4. Evolution of Rhizobium Nodulation: From Nodule Specific Genes (Nodulins) to Recruitment of Common Processes Ton Bisseling Chapter 5. Bioengineering Nitrogen Acquisition in Rice: Promises for Global Food Security Herbert Kronzucker Section 2. Chemistry and Biochemistry of Nitrogenases Chapter 6. An Overview of Fe-S Protein Biogenesis from Prokaryotes to Eukaryotes Mahipal Kesawat Chapter 7. Biosynthesis of the Iron-Molybdenum Cofactor of Nitrogenase Luis Rubio Chapter 8. Distribution and Ecological Niches of Nitrogenases Alexander Glazer Section 3. Expression and Regulation of Nitrogen Fixation Genes and Nitrogenase Chapter 9. Regulation of nif Gene Expression in Azotobacter vinelandii Cesar Poza-Carrion, Luis Rubio Chapter 10. Coupling of Regulation between Nitrogen and Carbon Metabolism in Nitrogen Fixing Pseudomonas stutzeri A1501 Lin Min Chapter 11. Regulation of NItrogen Fixation and Molybdenum Transport in Rhodobacter capsulatus Bernd Masepohl Chapter 12. Metabolic Regulation of Nitrogenase Activity in Rhodospirillum rubrum: The Role of PII Proteins and Membrane Sequestration Stefan Nordlund Chapter 13. How Does the DraG-PII Complex Regulate Nitrogenase Activity in Azospirillum brasilense? Xiao-Dan Li Chapter 14. Fe Protein Over-expression Can Enhance the Nitrogenase Activity of Azotobacter vinelandii Papri Nag Chapter 15. FNR-like Proteins in Rhizobia: Past and Future Lourdes Girard Section 4. Taxonomy and Evolution of Nitrogen Fixing Organisms Chapter 16. Exploring Alternative Paths for the Evolution of Biological Nitrogen Fixation John Peters Chapter 17. Phylogeny, Diversity, Geographical Distribution and Host Range of Legume-Nodulating Betaproteobacteria: What Is the Role of Plant Taxonomy? Lionel Moulin, Euan James Chapter 18. Bradyrhizobium, The Ancestor of All Rhizobia: Phylogeny of Housekeeping and Nitrogen-fixation Genes Mariangela Hungria Chapter 19. Interaction between Host and Rhizobial Strains: Affinities and Coevolution Mario Aguilar Chapter 20. Assessment of Nitrogenase Diversity in the Environment Daniel Buckley Section 5. Genomics of Nitrogen Fixing Organisms Chapter 21. Genetic Regulation of Symbiosis Island Transfer in Mesorhizobium loti Joshua Ramsay, Clive Ronson Chapter 22. The Azotobacter vinelandii Genome: An Update Joao C. Setubal Chapter 23. The Genome Sequence of the Novel Rhizobial Species Microvirga lotononidis Strain WSM3557. Julie Ardley Chapter 24. Genome Characteristics of Frankia sp. Reflect Host Range and Host Plant Biogeography Philippe Normand, David Benson Chapter 25. Core and Accessory Henomes of The Diazotroph Azospirillum Florence Wisniewski-Dye Chapter 26. Pangenome Evolution in The Symbiotic Nitrogen Fixer Sinorhizobium meliloti Marco Galardini Chapter 27. Pangenomic Analysis of The Rhizobiales Using The GET_HOMOLOGUES Software Package Pablo Vinuesa Section 6. Physiology and Metabolism of Nitrogen Fixing Organisms Chapter 28. Metabolism of Photosynthetic Bradyrhizobia During Root and Stem Symbiosis with Aeschynomene legumes Benjamin Gourion Chapter 29. A Plethora of Terminal Oxidases and Their Biogenesis Factors in Bradyrhizobium japonicum Hauke HenneckeChapter 30. Rhizobial Extracytoplasmic Function (ECF) Factors and Their Role in Oxidative Stress Response of Bradyrhizobium japonicumHans-Martin Fischer Chapter 31. Role of the Bacterial BacA ABC-transporter in Chronic Infection of Nodule Cells by Rhizobium Peter Mergaert Chapter 32. Molecular Keys to Broad Host Range in Sinorhizobium fredii NGR234, USDA257 and HH103 Wolfgang Streit Chapter 33. Motility and Chemotaxis in the Rhizobia Michael Hynes Chapter 34. The Pts/Ntr System Globally Regulates ATP-dependent Transporters in Rhizobium leguminosarum Jurgen Prell Section 7. Nitrogen Fixing Organisms, the Plant Rhizosphere and Stress Tolerance Chapter 35. Actinorhizal Root Exudates Alter the Physiology, Surface Properties and Plant Infectivity of Frankia Louis Tisa Chapter 36. Exopolysaccharide Production in Rhizobia is Regulated by Environmental Factors Monika Janczarek Chapter 37. Regulation of Symbiotically-Important Functions by Quorum Sensing in the Sinorhizobium meliloti-Alfalfa Interaction Juan Gonzales Chapter 38. Lumichrome as a Bacterial Signal Molecule Influencing Plant Growth Felix Dakora Chapter 39. Genes Involved in Desiccation Resistance of Rhizobia and Other Bacteria Michael KahnChapter 40. The General Stress Response in Alpha-rhizobia Claude Bruand Section 8. Physiology and Regulation of Nodulation Chapter 41. The Root Hair: A Single Cell Model for Systems Biology Marc Libault Chapter 42. How Transcriptomics Revealed New Information on Actinorhizal Symbioses Establishment and Evolution Valerie Hocher Chapter 43. Molecular Biology of Infection and Nodule Development in Discaria trinervis – Frankia Actinorhizal Symbiosis Sergio Svistoonoff Chapter 44. Lotus japonicus Nodulates When It Sees Red Akihiro Suzuki Chapter 45. Out of Water of A New Model Legume: The Nod-independent Aeschynomene evenia Jean-Francois Arrighi Chapter 46. Phosphorus Use Efficiency for N2 Fixation in The Rhizobial Symbiosis with Legumes Jean –Jacques Drevon Chapter 47. Regulation of Nodule Development by Short and Long Distance Auxin Transport Ulrike Mathesius Chapter 48. Functional Analysis of Nitrogen-Fixing Root Nodule Symbioses Induced by Frankia: Transport and Metabolic Interactions Alison Berry Chapter 49. NOOT-dependent Control of Nodule Identity: Nodule Homeosis and Meristem Perturbation Pascal Ratet Volume 2 Section 9. Recognition in Nodulation Chapter 50. Roles for Flavonoids in Symbiotic Root-Rhizosphere Interactions Ulrike Mathesius Chapter 51. Nod Factor Recognition in Medicago truncatula Jean Jacques Bono Chapter 52. Role of Ectoapyrases in Nodulation Gary Stacey Chapter 53. Role of Rhizobium Cellulase CelC2 in Root Colonization and Infection Pedro Mateos Chapter 54. Nod Factor-Induced Calcium Signaling in Legumes Giles Oldroyd Chapter 55. Signalling and Communication between Actinorhizal Plants and Frankia During the Intracellular Symbiotic Process Claudine Franche Section 10. Infection and Nodule Ontogeny Chapter 56. The Role of Hormones in Rhizobial Infection Jeremy Murray Chapter 57. Nuclear Ca2+ Signaling Reveals Active Bacterial-Host Signaling throughout Rhizobial Infection in Root Hairs of Medicago truncatula David Barker Chapter 58. A Pectate Lyase Required for Plant-Cell Wall Remodelling During Infection of Legumes by Rhizobia Allan Downie Chapter 59. Dissecting The Roles in Outer and Inner Root Cell Layers of Plant Genes That Control Rhizobial Infection and Nodule Organogenesis Clare Gough Chapter 60. The Medicago truncatula NIP/LATD Transporter Is Essential for Nodulation and Appropriate Root Architecture Rebecca Dickstein Chapter 61. A MYB Coiled Coil Type Transcription Factor Interacts with NSP2 and Is Essential for Nodulation in Lotus japonicus Zhongming Zhang Chapter 62. AP2/ERF Transcription Factors and Root Nodulation Fernanda de Carvalo-Niebel Chapter 63. Identification of Medicago truncatula Genes Required for Rhizobial Invasion and Bacteroid Differentiation Peter Kalo Chapter 64. Multifacetted Roles of Nitric Oxide in Rhizobium-Legume Symbioses Eliane Meilhoc Chapter 65. Profiling Symbiotic Responses of Sinorhizobium fredii Strain NGR234 with RNA-seq Xavier Perret Chapter 66. Computational and Experimental Evidence That Auxin Accumulation in Nodule and Lateral Root Primordia Occurs by Different Mechanisms Eva Elisabeth Deinum Section 11. Transitions from the Bacterial to the Bacteroid State Chapter 67. Bacteroid Differentiation in Legume Nodules: Role of AMP-like Host Peptides in the Control of the Endosymbiont Eva Kondorosi Chapter 68. The Symbiosome Membrane Penelope Smith Section 12. Nitrogen Fixation, Assimilation and Senescence in Nodules Chapter 69. Nodulin Intrinsic Proteins: Facilitators of Water and Ammonia Transport across the Symbiosome Membrane Daniel Roberts Chapter 70. Leghemoglobins with Nitrated Hemes in Legume Root Nodule Manuel Becana Chapter 71. The Role of 1-aminocyclopropane-1-carboxylase Enzyme in Leguminous Nodule Senescence Neung Teaumroong Section 13. Microbial “Omics”Chapter 72. Pool-Seq Analysis of Microsymbiont Selection by the Legume Plant Host Juan Imperial Chapter 73. Contribution of the RNA Chaperone Hfq to Environmental Fitness and Symbiosis in Sinorhizobium meliloti José I. Jimenes-Zurdo Chapter 74. Biodiversity, Symbiotic Efficiency and Genomics of Rhizobium tropici and Related Species Mariangela Hungria Chapter 75. The Frankia alni Symbiotic Transcriptome Philippe Normand Chapter 76. A Comprehensive Survey of Soil Rhizobiales Using High-Throughput DNA Sequencing Ryan Jones Chapter 77. Gene Targeted Metagenomics of Diazotrophs in Coastal Saline Soil Bhanavath Jha Section 14. Plant “Omics” and Functional Genetics Chapter 78. The Medicago truncatula Genome Frederic Debellé Chapter 79. Leveraging Large-Scale Approaches to Dissect the Rhizobia-Legume Symbiosis Oswaldo Valdes-Lopez Chapter 80. LegumeIP: An Integrative Platform for Comparative Genomics and Transcriptomics of Model Legumes Patrick Xuechun Zhao Chapter 81. Databases of Transcription Factors in Legumes Lam-son Phan Tran Chapter 82. Functional Genomics of Symbiotic Nitrogen Fixation in Legumes with a Focus on Transcription Factors and Membrane Transporters Michael Udvardi Chapter 83. Retrotransposon (Tnt1)-insertion Mutagenesis in Medicago as a Tool for Genetic Dissection of Symbiosis in Legumes Michael Udvardi Section 15. Cyanobacteria and Archaea Chapter 84. Marine Titrogen Fixation: Organisms, Significance, Enigmas and Future Directions Jonathan Zehr Chapter 85. Requirement of Cell Wall Remodelling for Cell-Cell Communication and Cell Differentiation in Filamentous Cyanobacteria of the Order Nostocales Karl Forchhammer Chapter 86. Nitrogen Fixation in the Oxygenic Phototrophic Prokaryotes (Cyanobacteria): The Fight Against Oxygen Enrique Flores Chapter 87. Underestimation of Marine Dinitrogen Fixation: A Novel Method and Novel Diazotrophic Habitats Ruth SchmitzSection 16. Diazotrophic Plant Growth Promoting Rhizobacteria and Non-Legumes Chapter 88. One Hundred Years Discovery of Nitrogen-Fixing Rhizobacteria Claudine ElmerichChapter 89. Symbiotic Nitrogen Fixation in Legumes: Perspectives on the Diversity and Evolution of Nodulation by Rhizobium and Burkholderia Species Ann Hirsch Chapter 90. Agronomic Applications of Azospirillum and Other PGPR Yaacov Okon Chapter 91. Auxin Signaling in Azospirillum brasilense: A Proteome Analysis Stijn Spaepen Chapter 92. Genetic and Functional Characterization of Paenibacillus riograndensis: A Novel Plant Growth Promoting Bacterium Isolated from Wheat Luciane Passaglia Chapter 93. Role of Herbaspirillum seropedicae LPS in Plant Colonization Rose Adele Monteiro Chapter 94. Culture-independent Assessment of Diazotrophic Bacteria in Sugarcane and Isolation of Bradyrhizobium spp. from Field Grown Sugarcane Plants Using Legume Trap Plants Anton Hartmann Chapter 95. How Fertilization Affects the Selection of Plant Growth Promoting Rhizobacteria by Host Plants Luciane Passaglia Section 17. Field Studies, Inoculum Preparation, Applications of Nod Factors Chapter 96. Appearance of Membrane Compromised, Viable But Not Culturable and Culturable Rhizobial Cells As A Consequence of Desiccation Jan VriezenChapter 97. Making the Most of High Quality Inoculants Rosalind DeakerChapter 98. Rhizobiophages As Markers in The Selection of Symbiotically Efficient Rhizobia for Legumes Felix Dakora Chapter 99. Nitrogen Fixation with Soybean: The Perfect Symbiosis? Mariangela Hungria Chapter 100. Nodule Functioning and Symbiotic Efficiency of Cowpea and Soybean Varieties in Africa Flora Pule Meulenberg Chapter 101. Microbial Quality of Commercial Inoculants to Increase BNF and Nutrient Use Efficiency Didier Lesueur Chapter 102. Developed Fungal-Bacterial Biofilms Having Nitrogen Fixers: Universal Biofertilizers for Legumes and Non-legumes H.M. Herath Chapter 103. Phenotypic Variation in Azospirillum spp. and Other Root-Associated Bacteria Anton Hartmann Chapter 104. The physiological mechanisms of desiccation tolerance in rhizobia Andrea Casteriano Chapter 105. Food Grain Legumes: Their Contribution to Soil Fertility and Human Nutrition and Health in Africa Felix Dakora Chapter 106. Plant Breeding for Biological Nitrogen Fixation: A Review Peter KennedyChapter 107. LCO Applications Provide Improved Responses with Legumes and Non-legumes Stewart Smith Section 18 Nitrogen Fixation and Cereals Chapter 108. The Quest for Biological Nitrogen Fixation in Cereals : A Perspective and Prospective Frans J. de Bruijn Chapter 109. Environmental and Economic Impacts of Biological N2 Fixing (BNF) Cereal Crops Perrin Beatty Chapter 110. Conservation of the Symbiotic Signalling Pathway between Legumes and Cereals: Did Nodulation Constraints Drive Legume Symbiotic Genes to Become Specialised During Evolution? Charles Rosenberg Chapter 111. Occurrence and Ecophysiology of the Natural Endophytic Rhizobium-rice Association, and Translational Assessment of its Biofertilizer Performance within the Egypt Nile Delta Youssef Yanni Section 19. Concluding Chapters Chapter 112. The Relevance of N-fixation and N-recyling for Insect Biomass and N-balances of Ecosystems Martin Heil Chapter 113. Rapid Identification of Nodule Bacteria with MALDI-TOF Mass Spectrometry Xavier Perret Chapter 114. The Microbe-Free Plant: Fact or Artefact? Martin Heil

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Book SynopsisThe simplicity and lack of redundancy in their regulatory genes have made ascidians one of the most useful species in studying developmental genomics. In Developmental Genomics of Ascidians, Dr.Trade Review"In his preface, the author describes Developmental Genomics of Ascidians as his “last and largest contribution to ascidian developmental biology” (p. xi). This book is indeed a major accomplishment and a great resource for the community" (The Quarterly Review of Biology 2016)Table of ContentsPREFACE ix CHAPTER 1 A BRIEF INTRODUCTION TO ASCIDIANS 1 CHAPTER 2 THE DEVELOPMENT OF TADPOLE LARVAE AND SESSILE JUVENILES 9 CHAPTER 3 GENOMICS, TRANSCRIPTOMICS, AND PROTEOMICS 19 CHAPTER 4 RESEARCH TOOLS 31 CHAPTER 5 THE FUNCTION AND REGULATION OF MATERNAL TRANSCRIPTS 41 CHAPTER 6 LARVAL TAIL MUSCLE 53 CHAPTER 7 ENDODERM 63 CHAPTER 8 EPIDERMIS 69 CHAPTER 9 NOTOCHORD 77 CHAPTER 10 THE LARVAL AND ADULT NERVOUS SYSTEMS 89 CHAPTER 11 MESENCHYME 107 CHAPTER 12 MAKING BLUEPRINT OF CHORDATE BODY: DYNAMIC ACTIVITIES OF REGULATORY GENES 113 CHAPTER 13 DEVELOPMENT OF THE JUVENILE HEART 137 CHAPTER 14 GERM-CELL LINE, GAMETES, FERTILIZATION, AND METAMORPHOSIS 145 CHAPTER 15 INNATE IMMUNE SYSTEM AND BLOOD CELLS 159 CHAPTER 16 COLONIAL ASCIDIANS: ASEXUAL REPRODUCTION AND COLONY SPECIFICITY 167 CHAPTER 17 EVOLUTIONARY DEVELOPMENTAL GENOMICS 175 INDEX 193

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Book SynopsisIn light of the discovery of Autoimmune Syndrome Induced by Adjuvants, or ASIA, Vaccines and Autoimmunity explores the role of adjuvants specifically aluminum in different vaccines and how they can induce diverse autoimmune clinical manifestations in genetically prone individuals.Table of ContentsContributors ix Introduction 1Yehuda Shoenfeld, Nancy Agmon-Levin and Lucija Tomljenovic Part I: Mosaic of Autoimmunity 1 Role of Adjuvants in Infection and Autoimmunity 11Eitan Israeli, Miri Blank, and Yehuda Shoenfeld 2 Infections as Adjuvants for Autoimmunity: The Adjuvant Effect 25Quan M. Nhu and Noel R. Rose 3 Experimental Models of Adjuvants 35Nicola Bassi, Mariele Gatto, Anna Ghirardello, and Andrea Doria 4 Answers to Common Misconceptions Regarding the Toxicity of Aluminum Adjuvants in Vaccines 43Lucija Tomljenovic and Christopher A. Shaw 5 Allergy and Autoimmunity Caused by Metals: A Unifying Concept 57Vera Stejskal 6 Genetics and Vaccinology 65John Castiblanco and Juan-Manuel Anaya 7 Silicone and Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA) 79Yair Levy and Rotem Baytner-Zamir 8 Silicone Breast Implants and Autoimmune/Inflammatory Syndrome induced by Adjuvants (ASIA): A Literature Search 87Elisabetta Borella, Eitan Israeli, and Yehuda Shoenfeld 9 Autoantibodies Induced by Vaccine 93Nataša Toplak and Tadej Av¢§cin 10 The ASIA Syndrome Registry 103Ignasi Rodriguez-Pinto and Yehuda Shoenfeld 11 Vaccination in Autoimmune Diseases 107Carla Goncalves, Schahin Saad, Clovis A. Silva, and Eloisa Bonfa 12 Vaccination in Patients with Autoimmune Inflammatory Rheumatic Diseases 113Abdulla Watad, Alessandra Soriano, and Yehuda Shoenfeld Part II: Studies on Autoimmune Conditions Induced by Vaccination 13 Measles, Mumps, and Rubella Vaccine: A Triad to Autoimmunity 129Carlo Perricone, Guido Valesini, and Yehuda Shoenfeld 14 Yellow Fever Vaccine and Autoimmunity 135Roger A. Levy and Rodrigo Poubel V. Rezende 15 Antiphospholipid Syndrome and Vaccines 141Miri Blank and Paola Cruz-Tapias 16 Hepatitis B Vaccination and Autoimmunity 147Daniel S. Smyk, Lazaros I. Sakkas, Yehuda Shoenfeld, and Dimitrios P. Bogdanos 17 Adverse Reactions to Human Papillomavirus Vaccines 163Lucija Tomljenovic and Christopher A. Shaw 18 Influenza Vaccine and Autoimmune Diseases 175Luis J. Jara, Gabriela Medina, Pilar Cruz Dominguez, Olga Vera-Lastra, Miguel A. Saavedra, Monica Vazquez del Mercado, and Minoru Satoh 19 Vaccines and Autoimmunity: Meningococcal Vaccines 185Giovanna Passaro, Alessandra Soriano, and Raffaele Manna 20 Pneumococcal Vaccines and Autoimmune Phenomena 191Elisabetta Borella, Nancy Agmon-Levin, Andrea Doria, and Yehuda Shoenfeld 21 BCG and Autoimmunity 197Luigi Bernini, Carlo Umberto Manzini, and Clodoveo Ferri Part III: Autoimmune Diseases Solicited by Vaccination 22 Systemic Lupus Erythematosus Induced by Vaccines 209Nurit Katz-Agranov and Gisele Zandman-Goddard 23 Vasculitides 223Alessandra Soriano, Rotem Inbar, Giovanna Passaro, and Raffaele Manna 24 Vaccinations in Rheumatoid Arthritis 233Eitan Giat and Merav Lidar 25 Undifferentiated Connective-Tissue Diseases 247Maria Martinelli, Carlo Perricone, and Yehuda Shoenfeld 26 Vaccines, Infections, and Alopecia Areata 255Yaron Zafrir, Sharon Baum, Nancy Agmon-Levin, and Yehuda Shoenfeld 27 Aluminum Particle Biopersistence, Systemic Transport, and Long-Term Safety: Macrophagic Myofasciitis and Beyond 261Romain K. Gherardi, Josette Cadusseau, and Francois-Jerome Authier 28 Immune Thrombocytopenic Purpura: Between Infections and Vaccinations 271Carlo Perricone, Maurizio Rinaldi, Roberto Perricone, and Yehuda Shoenfeld 29 Vaccinations and Type 1 Diabetes 283Alessandro Antonelli, Silvia Martina Ferrari, Andrea Di Domenicantonio, Ele Ferrannini, and Poupak Fallahi 30 Narcolepsy and H1N1 vaccine 291María -Teresa Arango, Shaye Kivity, Nancy Agmon-Levin, Gili Givaty, Joab Chapman, and Yehuda Shoenfeld 31 Non-nutritional Environmental Factors Associated with Celiac Disease: Infections and Vaccinations 301Aaron Lerner 32 Polymyalgia Rheumatica 307Alessandra Soriano and Raffaele Manna 33 Acute Disseminated Encephalomyelitis: Idiopathic, Post-infectious, and Post-vaccination 311Dimitrios Karussis and Panayiota Petrou 34 Fibromyalgia, Chronic Fatigue, Functional Disorders, and Vaccination: Where Do We Stand? 331Jacob N. Ablin and Dan Buskila 35 Bullous Dermatoses, Infectious Agents, and Vaccines 337Yaron Zafrir, Nancy Agmon-Levin, and Sharon Baum 36 Infections, Vaccinations, and Chronic Fatigue Syndrome 345Hussein Mahagna, Naim Mahroum, and Howard Amital 37 Myositis and Vaccines 349Ignasi Rodriguez-Pinto and Yehuda Shoenfeld Index 359

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Book SynopsisNanoparticles are the building blocks for nanotechnology; they are better built, long lasting, cleaner, safer, and smarter products for use across industries, including communications, medicine, transportation, agriculture and other industries. Controlled size, shape, composition, crystallinity, and structure-dependent properties govern the unique properties of nanotechnology. Bio-Nanoparticles: Biosynthesis and Sustainable Biotechnological Implications explores both the basics of and advancements in nanoparticle biosynthesis. The text introduces the reader to a variety of microorganisms able to synthesize nanoparticles, provides an overview of the methodologies applied to biosynthesize nanoparticles for medical and commercial use, and gives an overview of regulations governing their use. Authored by leaders in the field, Bio-Nanoparticles: Biosynthesis and Sustainable Biotechnological Implications bridges the gap between biology and technology, and is an iTable of ContentsList of Contributors xv Introduction xvii 1 Diversity of Microbes in Synthesis of Metal Nanoparticles: Progress and Limitations 1Mahendra Rai, Irena Maliszewska, Avinash Ingle, Indarchand Gupta, and Alka Yadav 1.1 Introduction 1 1.2 Synthesis of Nanoparticles by Bacteria 2 1.3 Synthesis of Nanoparticles by Fungi 9 1.4 Synthesis of Nanoparticles by Algae 12 1.5 Applications of Metal Nanoparticles 16 1.5.1 Nanoparticles as Catalyst 16 1.5.2 Nanoparticles as Bio]membranes 17 1.5.3 Nanoparticles in Cancer Treatment 17 1.5.4 Nanoparticles in Drug Delivery 17 1.5.5 Nanoparticles for Detection and Destruction of Pesticides 17 1.5.6 Nanoparticles in Water Treatment 18 1.6 Limitations of Synthesis of Biogenic Nanoparticles 18 References 20 2 Role of Fungi Toward Synthesis of Nano]Oxides 31Rajesh Ramanathan and Vipul Bansal 2.1 Introduction 31 2.2 Fungus]mediated Synthesis of Nanomaterials 34 2.2.1 Biosynthesis of Binary Nano]oxides using Chemical Precursors 34 2.2.2 Biosynthesis of Complex Mixed]metal Nano]oxides using Chemical Precursors 39 2.2.3 Biosynthesis of Nano]oxides using Natural Precursors employing Bioleaching Approach 42 2.2.4 Biosynthesis of nano]oxides employing bio]milling approach 44 2.3 Outlook 46 References 47 3 Microbial Molecular Mechanisms in Biosynthesis of Nanoparticles 53Atmakuru Ramesh, Marimuthu Thiripura Sundari, and Perumal Elumalai Thirugnanam 3.1 Introduction 53 3.2 Chemical Synthesis of Metal Nanoparticles 54 3.2.1 Brust–Schiffrin Synthesis 55 3.3 Green Synthesis 57 3.4 Biosynthesis of Nanoparticles 58 3.5 Mechanisms for Formation or Synthesis of Nanoparticles 61 3.5.1 Biomineralization using Magnetotactic Bacteria (MTB) 61 3.5.2 Reduction of Tellurite using Phototroph Rhodobacter capsulatus 62 3.5.3 Formation of AgNPs using Lactic Acid and Bacteria 62 3.5.4 Microfluidic Cellular Bioreactor for the Generation of Nanoparticles 62 3.5.5 Proteins and Peptides in the Synthesis of Nanoparticles 65 3.5.6 NADH]dependent Reduction by Enzymes 65 3.5.7 Sulfate and Sulfite Reductase 66 3.5.8 Cyanobacteria 67 3.5.9 Cysteine Desulfhydrase in Rhodopseudomonas palustris 68 3.5.10 Nitrate and Nitrite reductase 68 3.6 E xtracellular Synthesis of Nanoparticles 69 3.6.1 Bacterial Excretions 69 3.6.2 Fungal Strains 71 3.6.3 Yeast: Oxido]reductase Mechanism 72 3.6.4 Plant Extracts 73 3.7 Conclusion 76 References 78 4 Biofilms in Bio]Nanotechnology: Opportunities and Challenges 83Chun Kiat Ng, Anee Mohanty, and Bin Cao 4.1 Introduction 83 4.2 Microbial Synthesis of Nanomaterials 84 4.2.1 Overview 84 4.2.2 Significance of Biofilms in Biosynthesis of Nanomaterials 89 4.2.3 Synthesis of Nanomaterials using Biofilms 90 4.3 Interaction of Microbial Biofilms with Nanomaterials 90 4.3.1 Nanomaterials as Anti]biofilm Agents 90 4.3.2 Nanomaterials as a Tool in Biofilm Studies 92 4.4 Future Perspectives 93 References 94 5 Extremophiles and Biosynthesis of Nanoparticles: Current and Future Perspectives 101Jingyi Zhang, Jetka Wanner, and Om V. Singh 5.1 Introduction 101 5.2 Synthesis of Nanoparticles 104 5.2.1 Microorganisms: An Asset in Nanoparticle Biosynthesis 104 5.2.2 E xtremophiles in Nanoparticle Biosynthesis 104 5.3 Mechanism of Nanoparticle Biosynthesis 108 5.4 Fermentative Production of Nanoparticles 111 5.5 Nanoparticle Recovery 114 5.6 Challenges and Future Perspectives 115 5.7 Conclusion 115 References 116 6 Biosynthesis of Size-Controlled Metal and Metal Oxide Nanoparticles by Bacteria 123Chung-Hao Kuo, David A. Kriz, Anton Gudz, and Steven L. Suib 6.1 Introduction 123 6.2 Intracellular Synthesis of Metal Nanoparticles by Bacteria 124 6.3 E xtracellular Synthesis of Metal Nanoparticles by Bacteria 129 6.4 Synthesis of Metal Oxide and Sulfide Nanoparticles by Bacteria 131 6.5 Conclusion 135 References 135 7 Methods of Nanoparticle Biosynthesis for Medical and Commercial Applications 141Shilpi Mishra, Saurabh Dixit, and Shivani Soni 7.1 Introduction 141 7.2 Biosynthesis of Nanoparticles using Bacteria 144 7.2.1 Synthesis of Silver Nanoparticles by Bacteria 144 7.2.2 Synthesis of Gold Nanoparticles by Bacteria 145 7.2.3 Synthesis of other Metallic Nanoparticles by Bacteria 145 7.3 Biosynthesis of Nanoparticles using Actinomycete 146 7.4 Biosynthesis of Nanoparticles using Fungi 147 7.5 Biosynthesis of Nanoparticles using Plants 148 7.6 Conclusions 149 References 149 8 Microbial Synthesis of Nanoparticles: An Overview 155Sneha Singh, Ambarish Sharan Vidyarthi, and Abhimanyu Dev 8.1 Introduction 156 8.2 Nanoparticles Synthesis Inspired by Microorganisms 157 8.2.1 Bacteria in NPs Synthesis 162 8.2.2 Fungi in NPs Synthesis 167 8.2.3 Actinomycetes in NPs Synthesis 170 8.2.4 Yeast in NPs Synthesis 171 8.2.5 Virus in NPs Synthesis 173 8.3 Mechanisms of Nanoparticles Synthesis 174 8.4 Purification and Characterization of Nanoparticles 176 8.5 Conclusion 177 References 179 9 Microbial Diversity of Nanoparticle Biosynthesis 187Raveendran Sindhu, Ashok Pandey, and Parameswaran Binod 9.1 Introduction 187 9.2 Microbial-mediated Nanoparticles 187 9.2.1 Gold 188 9.2.2 Silver 190 9.2.3 Selenium 191 9.2.4 Silica 192 9.2.5 Cadmium 192 9.2.6 Palladium 193 9.2.7 Zinc 193 9.2.8 Lead 194 9.2.9 Iron 195 9.2.10 Copper 195 9.2.11 Cerium 196 9.2.12 Microbial Quantum Dots 196 9.2.13 Cadmium Telluride 197 9.2.14 Iron Sulfide-greigite 198 9.3 Native and Engineered Microbes for Nanoparticle Synthesis 198 9.4 Commercial Aspects of Microbial Nanoparticle Synthesis 199 9.5 Conclusion 200 References 200 10 S ustainable Synthesis of Palladium(0) Nanocatalysts and their Potential for Organohalogen Compounds Detoxification 205Michael Bunge and Katrin Mackenzie 10.1 Introduction 205 10.2 Chemically Generated Palladium Nanocatalysts for Hydrodechlorination: Current Methods and Materials 206 10.2.1 Pd Catalysts 206 10.2.2 Data Analysis 207 10.2.3 Pd as Dehalogenation Catalyst 207 10.2.4 Intrinsic Potential vs. Performance 208 10.2.5 Concepts for Pd Protection 210 10.3 Bio-supported Synthesis of Palladium Nanocatalysts 211 10.3.1 Background 211 10.4 Current Approaches for Synthesis of Palladium Catalysts in the Presence of Microorganisms 212 10.4.1 Pd(II)-Tolerant Microorganisms for Future Biotechnological Approaches 213 10.4.2 Controlling Size and Morphology during Bio-Synthesis 214 10.4.3 Putative and Documented Mechanisms of Biosynthesis of Palladium Nanoparticles 215 10.4.4 Isolation of Nanocatalysts from the Cell Matrix and Stabilization 216 10.5 Bio-Palladium(0)-nanocatalyst Mediated Transformation of Organohalogen Pollutants 217 10.6 Conclusions 218 References 219 11 E nvironmental Processing of Zn Containing Wastes and Generation of Nanosized Value-Added Products 225Abhilash and B.D. Pandey 11.1 Introduction 225 11.1.1 World Status of Zinc Production 226 11.1.2 E nvironmental Impact of the Process Wastes Generated 226 11.1.3 Production Status in India 227 11.1.4 Recent Attempts at Processing Low-Grade Ores and Tailings 228 11.2 Physical/Chemical/Hydrothermal Processing 229 11.2.1 E xtraction of Pb-Zn from Tailings for Utilization and Production in China 229 11.2.2 Vegetation Program on Pb-Zn Tailings 229 11.2.3 Recovering Valuable Metals from Tailings and Residues 229 11.2.4 E xtraction of Vanadium, Lead and Zinc from Mining Dump in Zambia 230 11.2.5 Recovery of Zinc from Blast Furnace and other Dust/Secondary Resources 230 11.2.6 Treatment and Recycling of Goethite Waste 231 11.2.7 Other Hydrometallurgical Treatments of Zinc-based Industrial Wastes and Residues 231 11.3 Biohydrometallurgical Processing: International Scenario 233 11.3.1 Bioleaching of Zn from Copper Mining Residues by Aspergillus niger 233 11.3.2 Bioleaching of Zinc from Steel Plant Waste using Acidithiobacillus ferrooxidans 234 11.3.3 Bacterial Leaching of Zinc from Chat (Chert) Pile Rock and Copper from Tailings Pond Sediment 234 11.3.4 Dissolution of Zn from Zinc Mine Tailings 234 11.3.5 Microbial Diversity in Zinc Mines 234 11.3.6 Chromosomal Resistance Mechanisms of A. ferrooxidans on Zinc 235 11.3.7 Bioleaching of Zinc Sulfides by Acidithiobacillus ferrooxidans 235 11.3.8 Bioleaching of High-sphalerite Material 235 11.3.9 Bioleaching of Low-grade ZnS Concentrate and Complex Sulfides (Pb-Zn) using Thermophilic Species 236 11.3.10 Improvement of Stains for Bio-processing of Sphalerite 236 11.3.11 Tank Bioleaching of ZnS and Zn Polymetallic Concentrates 237 11.3.12 Large-Scale Development for Zinc Concentrate Bioleaching 237 11.3.13 Scale-up Studies for Bioleaching of Low-Grade Sphalerite Ore 238 11.3.14 Zinc Resistance Mechanism in Bacteria 238 11.4 Biohydrometallurgical Processing: Indian Scenario 238 11.4.1 E lectro-Bioleaching of Sphalerite Flotation Concentrate 239 11.4.2 Bioleaching of Zinc Sulfide Concentrate 239 11.4.3 Bioleaching of Moore Cake and Sphalarite Tailings 239 11.5 Synthesis of Nanoparticles 240 11.6 Applications of Zinc-based Value-added Products/Nanomaterials 244 11.6.1 Hydro-Gel for Bio-applications 244 11.6.2 Sensors 244 11.6.3 Biomedical Applications 245 11.6.4 Antibacterial Properties 245 11.6.5 Zeolites in biomedical applications 246 11.6.6 Textiles 246 11.6.7 Prospects of Zinc Recovery from Tailings and Biosynthesis of Zinc-based Nano-materials 246 11.7 Conclusions and Future Directions 247 References 248 12 Interaction Between Nanoparticles and Plants: Increasing Evidence of Phytotoxicity 255Rajeshwari Sinha and S.K. Khare 12.1 Introduction 255 12.2 Plant–Nanoparticle Interactions 256 12.3 E ffect of Nanoparticles on Plants 256 12.3.1 Monocot Plants 257 12.3.2 Dicot Plants 257 12.4 Mechanisms of Nanoparticle]induced Phytotoxicity 257 12.4.1 Endocytosis 257 12.4.2 Transfer through Ion Channels Post]ionization 262 12.4.3 Aquaporin Mediated 262 12.4.4 Carrier Proteins Mediated 262 12.4.5 Via Organic Matter 262 12.4.6 Complex Formation with Root Exudates 262 12.4.7 Foliar Uptake 263 12.5 E ffect on Physiological Parameters 263 12.5.1 Loss of Hydraulic Conductivity 263 12.5.2 Genotoxic Effects 263 12.5.3 Absorption and Accumulation 263 12.5.4 Generation of Reactive Oxygen Species (ROS) 264 12.5.5 Biotransformation of NPs 264 12.6 Genectic and Molecular Basis of NP Phytotoxicity 266 12.7 Conclusions and Future Perspectives 266 References 267 13 Cytotoxicology of Nanocomposites 273Horacio Bach 13.1 Introduction 273 13.2 Cellular Toxicity 274 13.2.1 Mechanisms of Cellular Toxicity 274 13.2.2 E ffect of Glutathione (GSH) in Oxidative Stress 276 13.2.3 Damage to Cellular Biomolecules 277 13.3 Nanoparticle Fabrication 281 13.3.1 Physico]chemical Characteristics of NPs 282 13.3.2 Cellular Uptake 284 13.3.3 Factors Affecting the Internalization of NPs 287 13.4 Immunological Response 289 13.4.1 Cytokine Production 289 13.4.2 Cytotoxicity, Necrosis, Apoptosis, and Cell Death 290 13.5 Factors to Consider to Reduce the Cytotoxic Effects of NP 292 13.6 Conclusions and Future Directions 293 References 294 14 Nanotechnology: Overview of Regulations and Implementations 303Om V. Singh and Thomas Colonna 14.1 Introduction 303 14.2 Scope of Nanotechnology 305 14.3 Safety Concerns Related to Nanotechnology 310 14.4 Barriers to the Desired Regulatory Framework 311 14.4.1 Regulatory Framework in the United States 312 14.4.2 Global Efforts toward Regulation of Nanotechnology 315 14.5 Biosynthesis of Microbial Bio]nanoparticles: An Alternative Production Method 317 14.6 Conclusion 325 References 326 Name index 331 Subject index 333

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Book SynopsisNeuroinflammation has long been studied for its connection to the development and progression of Multiple Sclerosis. In recent years, the field has expanded to look at the role of inflammatory processes in a wide range of neurological conditions and cognitive disorders including stroke, amyotrophic lateral sclerosis, and autism. Researchers have also started to note the beneficial impacts of neuroinflammation in certain diseases. Neuroinflammation: New Insights into Beneficial and Detrimental Functions provides a comprehensive view of both the detriments and benefits of neuroinflammation in human health. Neuroinflammation: New Insights into Beneficial and Detrimental Functions opens with two chapters that look at some fundamental aspects of neuroinflammation in humans and rodents. The remainder of the book is divided into two sections which examine both the detrimental and beneficial aspects of inflammation on the brain, spinal cord and peripheral nerves,Table of ContentsList of Contributors xi Preface xvii PART I Introduction 1 1 Immune Response in the Human Central Nervous System in Multiple Sclerosis and Stroke 3Hans Lassmann Introduction 3 The Concept of Neuroinflammation 3 Basic Principles of Immune Surveillance and Inflammation by Adaptive Immune Responses 4 Inflammation in the Central Nervous System of Patients with Multiple Sclerosis 7 Inflammation in Stroke Lesions 11 Microglia Activation and Macrophage Response 12 Granulocyte Infiltration 12 Conclusions 15 References 15 2 In Vivo Imaging of Glial and Immune Cell Responses in Central Nervous System Injury and Disease 21Alexandre Paré and Steve Lacroix Introduction 21 Intravital Microscopy in the CNS and Its Challenges 22 In Vivo Imaging of the CNS Following Sterile Injury 24 In Vivo Imaging of the CNS in Disorders with an Inflammatory Component 27 Conclusion 32 Acknowledgments 33 References 33 PART II Detrimental Aspects of Inflammation 39 3 Roles of CD4 and CD8 T Lymphocytes in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis 41Nathalie Arbour and Alexandre Prat Introduction 41 T Lymphocytes: Central Immune Cells 42 Autoreactive T Lymphocytes 42 From Peripheral Activation to CNS Extravasation 45 Role of CD4 T Lymphocytes in MS and EAE: Th1 versus Th17 46 Role of CD8 T Lymphocytes in MS and EAE 47 Regulatory T Lymphocytes in MS and EAE 48 Conclusions 49 Acknowledgements 49 References 49 4 Microglia and Macrophage Responses and Their Role after Spinal Cord Injury 53Antje Kroner, Andrew D. Greenhalgh, and Samuel David Introduction 53 Microglial Responses to Injury 54 Interactions between Microglia and Other Cell Types in Signaling Responses to Injury 57 Entry of Peripheral Macrophages and Differences with Microglia 59 Diverse Roles of Macrophages/Microglia in CNS Injury and Disease 60 Macrophage Polarization in SCI 61 Concluding Remarks 66 Acknowledgements 66 References 66 5 The Complexity of the Innate Immune System Activation in Stroke Pathogenesis 71María Isabel Cuartero, Ignacio Lizasoain, María Ángeles Moro, and Ivan Ballesteros Activation of the Brain Innate Immunity After Stroke 71 Myeloid Heterogeneity in Brain Ischemia 76 Concluding Remarks 81 References 81 6 Neuroinflammation in Aging 87Ashley M. Fenn, Diana M. Norden, and Jonathan P. Godbout Increased CNS Inflammation in Response to Immune Challenge is Adaptive and Beneficial 87 The CNS Microenvironment Shifts to a Proinflammatory State with Aging 88 Microglial Priming 88 Microglial Regulation 90 Immune Reactivity of Glia Contributes to Cognitive and Behavioral Deficits 97 Conclusions 100 References 100 7 Peripheral and Central Immune Mechanisms in Neuropathic Pain 107Ji Zhang Introduction 107 Inflammation in Neuropathic Pain 108 Contribution of Peripheral Immune Cells to the Pathogenesis of Neuropathic Pain 109 Critical Roles of Spinal Glial Activation in Neuropathic Pain 111 Significance of Neural Barriers in Inflammatory Response along Pain Transmission Pathway 114 Imbalance of Pro- and Anti-inflammatory Responses in Neuropathic Pain 115 Challenges in Translating Anti-inflammatory Therapeutic Strategies for the Relief of Neuropathic Pain 115 Acknowledgement 117 References 117 8 Inflammation in the Pathogenesis of Inherited Peripheral Neuropathies 123Janos Groh, Dennis Klein, Antje Kroner, and Rudolf Martini Inherited Peripheral Neuropathies 123 Subtype-Specific Molecular Patterns of CMT1 124 Molecular Commonalities of CMT1 Subtypes–a Link to Inflammation 125 The Impact of Innate Immune Reactions in Mouse Models of CMT1 126 The Impact of Adaptive Immune Reactions in Mouse Models of CMT1 129 Implications for Putative Therapeutic Approaches 130 Synopsis 132 Acknowledgements 132 References 133 9 Obesity- and Neuroinflammation-Associated Mood and Cognitive Disorders 139Nathalie Castanon, Giamal Luheshi, and Sophie Layé Introduction 139 Neuropsychiatric Comorbidity in Obesity 140 Animal Models of Obesity and MetS 140 Mechanisms Underlying the Association between Obesity/MetS and Neuropsychiatric Symptoms 142 Neuroinflammation, Sickness Behavior, and Neuropsychiatric Symptoms 143 Role of Neuroinflammation in Neuropsychiatric Symptoms Associated with Obesity and MetS 146 Conclusions 148 References 149 10 Viral Infections of the Central Nervous System: Pathogenic and Protective Effects of Neuroinflammation 155John G. Walsh and Christopher Power Introduction 155 Nervous System Infection and Inflammation 157 HIV-1 Infection: Neurological and Neuropathological Features 158 WNV Infection and Neuropathology 162 Future Perspectives 166 References 167 PART III Beneficial Aspects of Inflammation 173 11 The Interplay between the Peripheral and Local Immune Response in Recovery from Acute Central Nervous System Injuries 175Catarina Raposo and Michal Schwartz Paradigm of Protective Autoimmunity 175 Dichotomy between Microglia and Infiltrating Monocyte-Derived Macrophages 176 Infiltrating Macrophages Promote Inflammation Resolution and Axonal Regeneration 177 The Two Faces of Tregs in CNS Repair 178 Protective Autoimmunity Works at the Specialized Choroid Plexus Gate 179 Inflammation, the Old Villain in Spinal Cord Repair 181 Comprehensive View of the Protective Autoimmune Network: the Link between Autoimmune T Cells and Inflammation-Resolving Cells 181 Acknowledgments 183 References 183 12 Inflammation and Optic Nerve Regeneration 189Lukas Andereggen, Ephraim F. Trakhtenberg, Yin Yuqin, and Larry I. Benowitz Introduction 189 Background 190 Effects of inflammation on RGC survival and Optic Nerve Regeneration 192 Oncomodulin as a Key Mediator of Inflammation-Induced Regeneration 193 Synergistic Effects of Combinatorial Treatments 198 Conclusions 200 Acknowledgments 200 References 200 13 Effects of Macrophages and Monocytes in Remyelination of the CNS 205Muktha Natrajan, Bibiana Bielekova, and Robin J.M. Franklin Introduction 205 Myelin Debris Inhibits OPC Differentiation and Remyelination 207 Monocyte-Derived Macrophages are the Main Actors in Myelin Debris Phagocytosis 209 Switching from M1 to M2 Macrophages Promotes CNS Remyelination 211 Ageing Impairs Macrophage Function, Myelin Debris Clearance, and Remyelination 212 Macrophages Release Growth and Neurotrophic Factors that Promote Remyelination 213 Concluding Remarks 215 References 215 14 Microglia Involvement in Rett Syndrome 221Noël C. Derecki, James C. Cronk, and Jonathan Kipnis Introduction to Rett Syndrome and MeCP2 221 Experimental Mouse Models Used in the Study of Rett Syndrome 222 The Cellular Players in Central Nervous System Pathology of Rett Syndrome 223 Microglia: From Footnote to First-Line 224 Microglia: the Tissue-Resident Macrophages of the Brain 225 Replacement/Augmentation of MICROGLIA as A potential therapy in Rett Syndrome 228 Gene Therapy 229 Conclusions 230 References 230 15 The Role of Regulatory T Cells and Microglia in Amyotrophic Lateral Sclerosis 235David R. Beers, Weihua Zhao, Kristopher G. Hooten, and Stanley H. Appel Overview of Amyotrophic Lateral Sclerosis 235 Overview of ALS Animal Models 237 Overview of Regulatory T Cells 238 Immunologic Aspects of Microglia and Tregs in ALS 240 T Cells and ALS 242 Tregs and ALS 243 Cytokines and ALS 244 Conclusions 245 References 247 16 An Adaptive Role for TNFin Synaptic Plasticity and Neuronal Function 251Renu Heir and David Stellwagen Introduction 251 Developmental Roles of TNFα 252 TNFα in Presynaptic Function 252 TNFα effects on postsynaptic receptor trafficking 252 TNFα and Synaptic Plasticity 255 Glial Release of TNFα During Plasticity 256 TNFα-mediated homeostatic plasticity in vivo 258 TNFα-Mediated Plasticity in the Striatum 258 Implications of TNFα-Mediated Synaptic Regulation 259 References 260 17 Resolution of Inflammation in the Lesioned Central Nervous System 265Jan M. Schwab, Harald Prüss, and Charles N Serhan Introduction 265 Mechanisms of Resolution 267 Resolution Deficit Following CNS Lesions 268 Immunobiology of Resolution in CNS Lesions–Impaired Resolution Contributes to Neuropathology 269 Late Degeneration/“Tertiary” Injury and Autoimmunity as a Consequence of Failed Resolution of Inflammation in CNS Lesions? 271 Evidence for the Effectiveness of Pro-resolution Mediators in CNS Lesions 273 Conclusion 274 Acknowledgement 275 References 275 Index 281

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Book SynopsisMicroorganisms are essential for the production of many foods, including cheese, yoghurt, and bread, but they can also cause spoilage and diseases. Quantitative Microbiology of Food Processing: Modeling the Microbial Ecology explores the effects of food processing techniques on these microorganisms, the microbial ecology of food, and the surrounding issues concerning contemporary food safety and stability. Whilst literature has been written on these separate topics, this book seamlessly integrates all these concepts in a unique and comprehensive guide. Each chapter includes background information regarding a specific unit operation, discussion of quantitative aspects, and examples of food processes in which the unit operation playsa major role in microbial safety. This is the perfect text for those seeking to understand the quantitative effects of unit operations and beyond on the fate of foodborne microorganisms in different foods. Quantitative Microbiology of FTable of ContentsList of contributors xvi Part I Introductory section 1 1 Introduction to the microbial ecology of foods 3 D. Roy and G. LaPointe 1.1 Introduction 3 1.2 Role of food characteristics and environment on microbial fate 4 1.3 Understanding microbial growth, death, persistence, competition, antagonism and survival in food 8 1.4 Methods to study the microbial ecology of foods 11 1.5 Perspectives on applying food ecosystem modeling 12 References 13 2 Predictive microbiology: mathematics towards understanding the fate of food‐borne microorganisms in food processing 16 P.N. Skandamis and E.Z. Panagou 2.1 Introduction 16 2.2 Probability and kinetic models for food processing and HACCP 18 2.3 Thermal inactivation 32 2.4 Non‐thermal inactivation and modeling stress‐adaptation strategies 34 2.5 Fermentation: a dynamic environment for microbial growth and pathogen inactivation 38 2.6 Colonial versus planktonic type of growth: modes of microbial existence on surfaces and in liquid, semi‐liquid, and solid foods 41 2.7 Modeling microbial transfer between processing equipment and foods 45 2.8 Alternative multivariate approaches: the use of bioinformatics for characterizing spoilage and product classification 49 References 51 3 Principles of unit operations in food processing 68 A. Ibarz and P.E.D. Augusto 3.1 Introduction 68 3.2 Principles of transport phenomena 68 3.3 Principles and unit operations of momentum transfer 69 3.4 Principles and unit operations of heat transfer 73 3.5 Principles and unit operations of mass transfer 81 3.6 Conclusions 82 References 83 Part II Impact of unit operations on microorganisms of relevance in foods 85 4 Impact of materials handling at pre‐ and post‐harvest operations on the microbial ecology of foods of vegetable origin 87 A.N. Olaimat, P.J. Delaquis, and R.A. Holley 4.1 Introduction 87 4.2 The production environment 90 4.3 Soil 91 4.4 Fertilizers derived from animal wastes 92 4.5 Irrigation 93 4.6 Harvesting and handling 98 4.7 Postharvest processing 99 4.8 Packaging, storage, and transportation 101 4.9 Conclusions 103 References 103 5 Impact of heating operations on the microbial ecology of foods 117 E. Xanthakis and V.P. Valdramidis 5.1 Background and basic information of heating operations 117 5.2 Quantitative aspects and how unit operations impact on food‐borne microorganisms 131 5.3 Application of F‐value concept 132 5.4 Dealing with non‐linearity 133 5.5 Development of new concepts to assess heat processes 135 5.6 Microbial safety and stability of heating operations: challenges and perspectives 136 References 136 6 Impact of refrigeration operations on the microbial ecology of foods 142 L. Huang 6.1 Introduction 142 6.2 Refrigeration as a unit operation 143 6.3 Dynamic effect of chilling on growth of C. perfringens during cooling 147 References 158 7 Impact of dehydration and drying operations on the microbial ecology of foods 160 F. Pérez‐Rodríguez, E. Carrasco, and A. Valero 7.1 Introduction 160 7.2 Modeling the drying process in food 161 7.3 Modeling microbial survival/inactivation in drying/dehydration processes 163 7.4 Example of application/development of predictive microbiology models for describing microbial death during drying processes 169 7.5 Conclusions 173 References 173 8 Impact of irradiation on the microbial ecology of foods 176 S. Unluturk 8.1 Introduction 176 8.2 Ionizing radiation 176 8.3 Non‐ionizing radiation 180 References 187 9 Impact of high‐pressure processing on the microbial ecology of foods 194 S. Mukhopadhyay, D.O. Ukuku, V. Juneja, and R. Ramaswamy 9.1 Introduction 194 9.2 Processing operation 195 9.3 Bacteria and enzyme inactivation 195 9.4 Effect of high pressure on fruit and vegetable products 198 9.5 Effect of HHP on meat and other food products 198 9.6 Effect of added antimicrobial on pathogen inactivation by high‐pressure processing (hurdle approach) 199 9.7 High‐pressure carbon dioxide (HPCD) disinfection 200 9.8 Effect of HHP on bacteria, virus, insects, and other organisms 201 9.9 Effect of HHP on quality: color, flavor, texture, sugar, totally soluble, and insolubles 203 9.10 Advantages and disadvantages of using HHP 205 9.11 Applications and conclusions 205 References 206 10 Impact of Vacuum packaging, modified and controlled atmosphere on the microbial ecology of foods 217 L. Angiolillo, A. Conte, and M.A.D. Nobile 10.1 Introduction 217 10.2 Vacuum packaging 218 10.3 Controlled atmosphere 219 10.4 Modified atmosphere packaging 220 References 223 11 Impact of fermentation on the microbial ecology of foods 226 M. Mataragas, K. Rantsiou, and L. Cocolin 11.1 Introduction 226 11.2 Fermentations: microbial ecology and activity 227 11.3 Factors affecting food‐borne pathogen inactivation during fermentation 227 11.4 Challenge tests 229 11.5 Predictive modeling 230 11.6 Conclusions 236 References 236 12 Impact of forming and mixing operations on the microbial ecology of foods: focus on pathogenic microorganisms 241 J.C.C.P. Costa, G.D. Posada‐Izquierdo, F. Perez‐Rodriguez, and R.M. Garcia‐Gimeno 12.1 Forming 241 12.2 Homogenizing 244 12.3 Mixing 246 References 248 13 Impact of specific unit operations on food‐borne microorganisms: curing, salting, extrusion, puffing, encapsulation, absorption, extraction, distillation, and crystallization 250 E. Ortega‐Rivas, S.B. Perez‐Vega, and I. Salmeron 13.1 Introductory remarks 250 13.2 Burden of food‐borne illnesses 250 13.3 Food safety and food quality 251 13.4 Prevention and control through processing 251 13.5 Conclusions and prospects for the future 260 References 261 14 Impact of food unit operations on virus loads in foods 263 D. Li, A.D. Keuckelaere, and M. Uyttendaele 14.1 Introduction 263 14.2 The use of surrogate viruses to assess inactivation processes 263 14.3 Virus contamination in food processing 264 14.4 Survival of virus in the food processing chain 267 14.5 Effect of food preservation techniques on the virus load 267 14.6 Conclusion and perspectives 280 References 281 15 Impact of food unit operations on parasites in foods: focus on selected parasites within the fresh produce industry 288 L.J. Robertson 15.1 Background and introduction 288 15.2 Detection of selected parasites in fresh produce 299 15.3 Effects of fresh produce treatments on selected parasites 303 15.4 Conclusion 315 References 316 16 Impact of food unit operations on probiotic microorganisms 327 A. Gandhi and N.P. Shah 16.1 Introduction 327 16.2 Probiotic products 328 16.3 probiotics and environmental stress: cellular mechanisms and resistance 328 16.4 Enhancing stress resistance of probiotics 332 16.5 Conclusion 334 References 334 Part III Microbial ecology of food products 339 17 Microbial ecology of fresh vegetables 341 J. Zheng, J. Kase, A. De Jesus, S. Sahu, A.E. Hayford, Y. Luo, A.R. Datta, E.W. Brown, and R. Bell 17.1 Introduction 341 17.2 Prevalence and diversity of microbial communities on fresh vegetables (post‐harvest) 341 17.3 Post‐harvest persistence, colonization, and survival on fresh vegetables 342 17.4 Routes of contamination during post‐harvest handling of fresh and fresh‐cut vegetables 345 17.5 Microbial adaptation on produce commodity 347 17.6 Effective post‐harvest intervention technologies 348 References 350 18 Microbial ecology of fruits and fruit‐based products 358 S. Paramithiotis, E.H. Drosinos, and P.N. Skandamis 18.1 Introduction 358 18.2 Fresh whole fruits 359 18.3 Minimally processed fruits 367 18.4 Processed fruits 372 Acknowledgments 374 References 374 19 Microbial ecology of cereal and cereal‐based foods 382 A. Bevilacqua, M. Sinigaglia, and M.R. Corbo 19.1 Introduction 382 19.2 Sourdough 382 19.3 Ethnic fermented foods 384 19.4 Spoilage of cereals and cereal products 385 References 388 20 Microbial ecology of nuts, seeds, and sprouts 390 M.S. Rhee, S.A. Kim, and N.H. Kim 20.1 Introduction 390 20.2 Definition and classification of nuts, seeds, and sprouts 390 20.3 Microbial ecology of nuts and seeds 391 20.4 Microbial ecology of sprouts and their corresponding seeds 400 20.5 Implications and perspectives 409 References 410 21 Microbial ecology of eggs: a focus on Salmonella and microbial contamination in post‐harvest table shell egg production 416 S.C. Ricke 21.1 Introduction 416 21.2 Historical and current trends in commercial egg production 417 21.3 Egg production management on the farm and incidence of Salmonella 420 21.4 Egg processing and microbial contamination: general aspects 421 21.5 Microbial contamination during egg collection at the farm to in‐line processing 423 21.6 Microbial contamination during transportation to off‐line egg processing facilities 424 21.7 Microbial contamination during egg processing 425 21.8 Egg washwater and sanitation 426 21.9 Egg retail and microbial contamination 428 21.10 Conclusions and future directions 429 Acknowledgment 431 References 431 22 Microbial ecology of beef carcasses and beef products 442 X. Yang 22.1 Introduction 442 22.2 Carcass production process 442 22.3 Carcass breaking 451 References 455 23 Microbial ecology of pork meat and pork products 463 L. Iacumin and J. Carballo 23.1 Introduction 463 23.2 Pork meat as a substrate for microbial growth: chemical and physical characteristics 464 23.3 Microbial ecology of fresh pork meat: sources of contamination and microbial groups 465 23.4 Microbial ecology of chilled pork meat 467 23.5 Microbial ecology of vacuum/modified atmosphere packaged pork meat 468 23.6 Microbial ecology of marinated pork meat 469 23.7 Microbial ecology of cured and fermented/ripened pork meats 470 23.8 Microbial ecology of high‐pressure preserved pork meat 473 References 474 24 Microbial ecology of poultry and poultry products 483 S. Buncic, D. Antic, and B. Blagojevic 24.1 Introduction 483 24.2 Microbial hazard identification and prioritization 483 24.3 Microbial aspects of poultry processing at abattoirs 484 24.4 Microbial aspects of derived poultry meat products 492 References 497 25 Microbial ecology of seafoods: a special emphasis on the spoilage microbiota of North Sea seafood 499 K. Broekaert, G. Vlaemynck, and M. Heyndrickx 25.1 Introduction 499 25.2 Total viable counts (TVC s) and microorganisms identified depends on the method used 499 25.3 The initial microbiota of marine fish 501 25.4 Raw seafood 503 25.5 Processing – lightly preserved seafood 506 25.6 A case study: brown shrimp (Crangon crangon) (adapted from Broekaert et al. 2013) 509 References 513 26 Microbial ecology of mayonnaise, margarine, and sauces 519 O. Sagdic, F. Tornuk, S. Karasu, M.Z. Durak, and M. Arici 26.1 Introduction 519 26.2 Mayonnaise 519 26.3 Margarine 523 26.4 Sauces and salad dressings 525 26.5 Conclusion 527 References 529 27 Microbial ecology of confectionary products, honey, sugar, and syrups 533 M. Nascimento and A. Mondal 27.1 Introduction 533 27.2 Cocoa and chocolate 533 27.3 Nuts and peanut butter 535 27.4 Honey 538 27.5 Sugar 539 27.6 Syrups 539 27.7 Conclusion 540 References 540 28 Microbial ecology of wine 547 E. Vaudano, A. Costantini, and E. Garcia‐Moruno 28.1 Introduction 547 28.2 Biodiversity of grape microorganisms 547 28.3 Microorganism ecology in winemaking 548 28.4 Microorganism ecology during aging 550 28.5 Microbial identification by classical methods 551 28.6 Microbial identification by molecular methods 551 References 555 29 Microbial diversity and ecology of bottled water 560 C.M. Manaia and O.C. Nunes 29.1 Definitions of bottled water 560 29.2 Characteristics of mineral and spring water 562 29.3 Useful methods to study bottled water microbiota 565 29.4 Microbiological diversity 568 29.5 Bottling effect 573 29.6 Microbiological contamination 574 29.7 A new perspective on microbiological quality and safety 576 Acknowledgments 577 References 577 Part IV Closing section 581 30 Microbial risk assessment: integrating and quantifying the impacts of food processing operations on food safety 583 J.‐C. Augustin, M. Ellouze, and L. Guillier 30.1 Introduction 583 30.2 Basic processes encountered during food processing operations 584 30.2.1 Microbial processes 584 30.3 Risk‐based objectives for each processing operation 590 30.4 Conclusion 595 References 596 31 Quorum sensing and microbial ecology of foods 600 V.A. Blana, A. Lianou, and G.‐J.E. Nychas 31.1 Introduction 600 31.2 Quorum sensing and microbial behavior 601 31.3 Quorum sensing and food ecology 606 31.4 Quorum quenching 610 References 611 32 Heterogeneity in Bacillus subtilis spore germination and outgrowth: an area of key challenges for “omics” in food microbiology 617 R. Pandey and S. Brul 32.1 Bacterial spores in the food industry 617 32.2 The Bacillus genus 618 32.3 Sporulation cycle 618 32.4 Endospore structure and its resistance 619 32.5 Spore germination and outgrowth 620 32.6 Heterogeneity in bacterial (spore) physiology during germination and outgrowth 623 32.7 Steps towards single‐cell physiology and “omics” measurements 625 References 626 33 Role of stress response on microbial ecology of foods and its impact on the fate of food‑borne microorganisms 631 A. Alvarez‐Ordóñez, M. López, and M. Prieto 33.1 Introduction 631 33.2 Acquisition of permanent stress tolerance through adaptive mutagenesis 631 33.3 Transient adaptive responses to stress: modulation of membrane fluidity as an example 634 33.4 Using food components to survive under harsh conditions 636 33.5 The balance between self‐preservation and nutritional competence (SPANC) 639 33.6 Conclusions and future prospects 641 Acknowledgment 643 References 643 Index 649

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Book SynopsisThe Genomics Applications in Crop Improvement two volume set brings together a diverse field of international experts in plant breeding genomics to share their experiences in the field, from success stories to lessons learnt. In recent years advances in genetics and genomics have greatly enhanced our understanding of the structural and functional aspects of plant genomes. Several novel genetic and genomics approaches such as association genetics, advanced back-cross QTL analysis, allele mining, comparative and functional genomics, transcriptomics, proteomics, etc. offer unprecedented opportunities to examine crop genetic variation and utilize this variability for breeding purposes. Enhancing the prediction of the phenotype from a genotype using genomics tools is referred to as ''genomics-assisted breeding''. To date, genomics-assisted breeding has shown its potential for crop improvement in several crops, however these successes have been largely restricted to temperate cereTable of ContentsTranslational Genomics for Crop Breeding: Volume 1 - Biotic Stress Foreword vii Preface ix Chapter 1 Translational Genomics in Crop Breeding for Biotic Stress Resistance: An Introduction 1 Rajeev K. Varshney and Roberto Tuberosa Chapter 2 Bacterial Blight Resistance in Rice 11 Yanjun Kou and Shiping Wang Chapter 3 The Genetic Basis of Disease Resistance in Maize 31 Tiffany Jamann, Rebecca Nelson, and Peter Balint-Kurti Chapter 4 Genomics-Assisted Breeding for Fusarium Head Blight Resistance in Wheat 45 Hermann Buerstmayr, Maria Buerstmayr, Wolfgang Schweiger, and Barbara Steiner Chapter 5 Virus Resistance in Barley 63 Frank Ordon and Dragan Perovic Chapter 6 Molecular Breeding for Striga Resistance in Sorghum 77 Santosh P. Deshpande, Abdalla Mohamed, and Charles Thomas Hash, Jr. Chapter 7 Nematode Resistance in Soybean 95 Tri D. Vuong, Yongqing Jiao, J. Grover Shannon, and Henry T. Nguyen Chapter 8 Marker-Assisted Selection for Biotic Stress Resistance in Peanut 125 Mark D. Burow, Soraya C. M. Leal-Bertioli, Charles E. Simpson, Peggy Ozias-Akins, Ye Chu, Nicholas N. Denwar, Jennifer Chagoya, James L. Starr, M´arcio C. Moretzsohn, Manish K. Pandey, Rajeev K.Varshney, C. Corley Holbrook, and David J. Bertioli Chapter 9 Organization of Genes Conferring Resistance to Anthracnose in Common Bean 151 Juan Jose Ferreira, Ana Campa, and James D. Kelly Chapter 10 Enabling Tools for Modern Breeding of Cowpea for Biotic Stress Resistance 183 Bao-Lam Huynh, Jeffrey D. Ehlers, Timothy J. Close, Ndiaga Cisse, Issa Drabo, Ousmane Boukar, Mitchell R. Lucas, Steve Wanamaker, Marti Pottorff, and Philip A. Roberts Chapter 11 Disease Resistance in Chickpea 201 Teresa Mill´an, Eva Madrid, Muhammad Imtiaz, Mohamed Kharrat, and Weidong Chen Chapter 12 Resistance to Late Blight in Potato 221 Jadwiga Sliwka and Ewa Zimnoch-Guzowska Chapter 13 Late Blight of Tomato 241 Marcin Nowicki, Elÿzbieta U. Kozik, and Majid R. Foolad Chapter 14 Marker-Assisted Selection for Disease Resistance in Lettuce 267 I. Simko Chapter 15 Marker-Assisted Breeding for Cassava Mosaic Disease Resistance 291 E. Okogbenin, I. Moreno, J. Tomkins, C.M. Fauquet, G. Mkamilo, and M. Fregene Chapter 16 Genetics and Gene Mapping of Disease Resistance in Brassica 327 Genyi Li and Peter B.E. McVetty Appendix I – Contributors 345 Appendix II – Reviewers 351 Index 353 Color plate section can be found between pages 182 and 183. Translational Genomics for Crop Breeding: Volume 2 - Improvement for Abiotic Stress, Quality and Yield Improvement Foreword vii Preface ix Chapter 1 Translational Genomics for Crop Breeding: Abiotic Stress Tolerance, Yield, and Quality, An Introduction 1 Rajeev K. Varshney and Roberto Tuberosa Chapter 2 Applying Genomics Tools for Breeding Submergence Tolerance in Rice 9 Endang M. Septiningsih, Bertrand C. Y. Collard, Sigrid Heuer, Julia Bailey-Serres, Abdelbagi M. Ismail, and David J. Mackill Chapter 3 Genomics Applications to Salinity Tolerance Breeding in Rice 31 J. Damien Platten, Michael J. Thomson, and Abdelbagi M. Ismail Chapter 4 Marker-Assisted Introgression of Major QTLs for Grain Yield Under Drought in Rice 47 Arvind Kumar, Shalabh Dixit, and Amelia Henry Chapter 5 Molecular Breeding for Phosphorus-efficient Rice 65 Sigrid Heuer, J.H. Chin, R. Gamuyao, S.M. Haefele, and M. Wissuwa Chapter 6 Aluminum Tolerance in Sorghum and Maize 83 Jurandir V. Magalhaes, Lyza G. Maron, Miguel A. Pi˜neros, Claudia T. Guimar˜aes, and Leon V. Kochian Chapter 7 Freezing Tolerance in the Triticeae 99 Galiba Gabor, Eric J. Stockinger, Enrico Francia, Justyna Milc, Gabor Kocsy, and Nicola Pecchioni Chapter 8 Molecular Breeding for Stay-Green: Progress and Challenges in Sorghum 125 Vincent Vadez, Santosh Deshpande, Jana Kholova, Punna Ramu, and C. Tom Hash Chapter 9 Genetic Improvement of Grain Quality in Japonica Rice 143 Kiyosumi Hori and Masahiro Yano Chapter 10 Biofortified Maize – A Genetic Avenue for Nutritional Security 161 Raman Babu, Natalia Palacios, and BM Prasanna Chapter 11 Marker-Assisted Backcrossing Selection for High O/L Ratio in Cultivated Peanut 177 Padmalatha Koilkonda, Chikara Kuwata, Masanobu Fukami, Kenta Shirasawa, Koh Aoki, Satoshi Tabata, Makoto Hasegawa, Hiroyuki Kiyoshima, Shigeru Suzuki, Shigemi Sasamoto, Atsushi Kurabayashi, Hisano Tsuruoka, Tsuyuko Wada, and Sachiko Isobe Chapter 12 Genomics-Assisted Breeding for Tomato Fruit Quality in the Next-Generation Omics Age 193 Matthew P. Kinkade and Majid R. Foolad Chapter 13 Improvement of Yield per se in Sugarcane 211 M. Gouy, S. Nibouche, J.Y. Hoarau, and L. Costet Appendix I – Contributors 239 Appendix II – Reviewers 243 Index 245 Color plate section can be found between pages 82 and 83.

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Book SynopsisExplore the latest research in anthropological genetics and understand the genome's role in cultural and social development A Companion to Anthropological Genetics illustrates the role of genetic analysis in advancing the modern study of human origins, populations, evolution, and diversity. Broad in scope, this essential reference work establishes and explores the relationship between genetic research and the major questions of anthropological study. Through contributions by leading researchers, this collection explores molecular genetics and evolutionary mechanisms in the context of macro- and microevolution, paleontology, phylogeny, diet, and disease, with detailed explanations of quantitative methods, including coalescent and approximate Bayesian computation. With an emphasis on contextualizing new and developing genetic research within anthropological frameworks, this text offers critical perspective on the conditions of molecular evolution that accompany cultural and social traTable of ContentsAbout the Editor xi Notes on Contributors xiii Preface xix Part I Anthropological Genetics in Context 1 1 History and Evolution of Anthropological Genetics 3Michael H. Crawford 2 The Ethics of Genetic Ancestry Testing 17Nanibaa’ A. Garrison and Jessica D. Bardill 3 Community‐Oriented Research and the Future of Anthropological Genetics 37Ripan S. Malhi Part II Macroevolution and Phylogenetics 45 4 Calibrating the Clock 47Murray P. Cox 5 Primate Genomics and Phylogenetics 57Christopher A. Schmitt and Omer Gokcumen 6 The Neanderthal and Denisovan Genomes 69Sloan R. Williams 7 Evaluating Correspondence in Phenotypic Variation, Genetic Diversity, Geography, and Environmental Factors 89Noreen von Cramon‐Taubadel 8 Simulating Human Demographic Processes and Patterns of Genetic Variation 107Aida T. Miró‐Herrans Part III Microevolution: Colonization, Dispersal, and Differentiation 121 9 Human Population Structure and History 123John H. Relethford 10 Regional Patterns of Variation: Concepts and Applications 137Graciela S. Cabana 11 Genetic Variation and the Colonization of Eurasia 151Toomas Kivisild 12 Homo sapiens Dispersal and the Peopling of the Americas 165Rafael Bisso‐Machado and Nelson Jurandi Rosa Fagundes 13 Ancient DNA and Bioarcheology 187Jennifer A. Raff Part IV Human Adaptation: Natural Selection and Physiological Variation 199 14 Tempo of Recent Human Evolution 201Michael D. Weight and Henry C. Harpending 15 Natural Selection and Adaptation to Extreme Environments: High Latitudes and Altitudes 219Abigail W. Bigham 16 Sensory Polymorphisms and Dietary Adaptation 233Carrie C. Veilleux 17 The Evolution of the Human Pigmentation Phenotype 251Heather L. Norton 18 Anthropological Genetics and Growth and Development 267Bradford Towne, Ellen W. Demerath, and Stefan A. Czerwinski 19 Epigenetics and Human Variation 293Amy L. Non and Zaneta M. Thayer Part V Anthropology, Genetics, and the Evolution of Health and Disease 309 20 The Primate Immune System: A Survey of Innate and Acquired Immune Genes 311Leslie A. Knapp and Nicole S. Torosin 21 Genetics, Evolutionary Medicine, and the Evolution of Human Pathogens 327Amanda VanSteelandt and Anne C. Stone References 343 Index 445

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Book SynopsisDiscussing recent advances in the field of matrix metalloproteinase (MMP) research from a multidisciplinary perspective, Matrix Metalloproteinase Biologyis a collection of chapters written by leaders in the field of MMPs.Table of ContentsList of Contributors ix 1 Matrix Metalloproteinases: From Structure to Function 1Maciej J. Stawikowski and Gregg B. Fields 1.1 Introduction 1 1.2 Structures of MMPs 1 1.2.1 General MMP structure and domain organization 1 1.2.2 Catalytic domain 2 1.2.3 Catalytic mechanism 3 1.2.4 Fibronectin type II-like inserts 3 1.2.5 Linker region 4 1.2.6 Hemopexin-like domain 6 1.2.7 Transmembrane domain and cytoplasmic tail 7 1.3 Overview of MMP substrate specificity 8 1.3.1 ECM substrates 9 1.3.2 Cell surface substrates 10 1.3.3 Intracellular MMP targets 11 1.4 Selective mechanisms of action 13 1.4.1 Collagenolysis 13 1.4.2 Gelatinolysis 15 Acknowledgments 16 References 16 2 Dynamics and Mechanism of Substrate Recognition by Matrix Metalloproteases 23Ivan E. Collier and Gregory I. Goldberg 2.1 Introduction 23 2.2 Conformational flexibility of MMPs is inexorably linked to collagen proteolysis 24 2.3 Dynamics of MMP-2 and MMP-9 interaction with gelatin 26 2.4 Surface diffusion: a common mechanism for substrate interaction adapted by MMP-2 and MMP-9 26 2.5 Dynamics of MMP interaction with collagen fibrils 28 2.6 Mechanism of interaction of MMP-1, MMP-2, MMP-9, and MMP-14 with collagen substrate involves surface diffusion 28 2.7 Mechanism of MMP-1 diffusion on native collagen fibrils 30 2.8 Triple helical collagen cleavage – diffusion coupling 31 2.9 Conclusions 34 References 36 3 Matrix Metalloproteinases: From Structure to Function 41Marco Fragai and Claudio Luchinat 3.1 Introduction 41 3.2 Classification and structural features 42 3.3 Catalytic mechanism 45 3.4 Intra- and inter-domain flexibility 47 3.5 Elastin and collagen degradation 47 References 54 4 Metzincin Modulators 61Dmitry Minond 4.1 Inhibitors 61 4.1.1 Antibodies: targeting beyond the active site 61 4.1.2 Peptide-based inhibitors 65 4.1.3 Small molecules: non-zinc binding exosite inhibitors 68 4.1.4 Protein-based inhibitors 78 Summary and future directions 80 References 81 5 Therapeutics Targeting Matrix Metalloproteinases 85Jillian Cathcart, Ashleigh Pulkoski-Gross, Stanley Zucker, and Jian Cao 5.1 Introduction 85 5.2 Peptidomimetic MMP inhibitors 86 5.3 Structure-based MMPI drug design 87 5.4 Mechanism-based MMPI design 89 5.5 Allosteric MMPI design 90 5.6 Macromolecular MMP inhibitors 91 5.7 Chemically-modified tetracyclines 93 5.8 Alternative approaches 94 5.9 MMPs as anti-targets 95 5.10 Conclusions 97 References 98 6 Matrix Metalloproteinase Modification of Extracellular Matrix-Mediated Signaling 103Howard C. Crawford and Sharon M. Stack 6.1 Introduction 103 6.2 The extracellular matrix as a source for signaling ligands 104 6.3 ECM and mechanosensory signal transduction 106 6.4 Matrix remodeling and modification of mechano-sensory signaling 108 6.5 Conclusions and future directions 109 References 109 7 Meprin and ADAM Metalloproteases: Two Sides of the Same Coin? 115Christoph Becker-Pauly and Stefan Rose-John 7.1 Introduction 115 7.2 Meprin metalloproteases 116 7.3 Structure of meprin α and meprin β 116 7.4 Proteomics for the identification of meprin substrates 118 7.5 Meprins in health and disease 118 7.6 Proteolytic back-and-forth of meprins and ADAMs 119 7.7 Collagen fibril formation 119 7.8 Angiogenesis and cancer 120 7.9 Inflammation 121 7.10 ADAM Proteases 121 7.11 The ADAM family of proteases 123 7.12 Orchestration of different pathways by ADAM17 123 7.13 Regulation of ADAM17 activity 123 7.14 Role of ADAM17 in vivo 125 7.15 Role of ADAM17 in humans 125 References 126 8 Subtracting Matrix Out of the Equation: New Key Roles of Matrix Metalloproteinases in Innate Immunity and Disease 131Antoine Dufour and Christopher M. Overall 8.1 The tale of a frog’s tail 131 8.2 The MMP family 132 8.3 Making the cut as immune regulators 133 8.4 Enter the “omics” era: genomics, proteomics and degradomics 137 8.5 ECM versus non-ECM MMP substrates 138 8.6 Moonlighting protein substrates: intracellular proteins cleaved outside the cell 142 8.7 Intracellular protein substrates cleaved inside the cell by MMPs 143 8.8 Non-proteolytic roles of MMPs: missed in the myth? 145 8.9 The fairy tail of a frog has an unexpected ending 149 Acknowledgements 149 References 149 9 MMPs: From Genomics to Degradomics 153Barbara Grünwald, Pascal Schlage, Achim Krüger, and Ulrich auf dem Keller 9.1 Introduction 153 9.1.1 Genomics: general aspects 154 9.1.2 The genomics approach to MMP function in cancer 155 9.1.3 Taking first steps towards MMP inhibition in cancer therapy 156 9.1.4 Lessons from the failure of unselective MMP inhibition 157 9.1.5 Limitations of the genomic approach to MMP function 160 9.1.6 Approaching proteolysis as a system 161 9.2 Degradomics – An Overview 164 9.2.1 Global assessment of MMP expression and activity 166 9.2.2 Defining MMP active site specificity 168 9.2.3 MMP substrate degradomics 169 9.2.4 Targeted degradomics 171 9.2.5 Data integration and repositories 173 9.3 Conclusions 174 Acknowledgments 174 References 174 10 MMPs in Biology and Medicine 183Di Jia, Roopali Roy, and Marsha A. Moses 10.1 Introduction 183 10.2 Functional roles of MMPs and ADAMs 184 10.2.1 ECM remodeling 184 10.2.2 Processing of growth factors and receptors 185 10.2.3 Modulation of cell migration, invasion, proliferation, and epithelial to mesenchymal transition (EMT) 186 10.2.4 Regulation of angiogenesis 187 10.3 MMPs as diagnostic and prognostic biomarkers of cancer 187 10.3.1 Breast cancer 188 10.3.2 Prostate cancer 189 10.3.3 Lung cancer 190 10.3.4 Pancreatic cancer 191 10.3.5 Ovarian cancer 192 10.4 MMPs/ADAMs as diagnostic and prognostic biomarkers for non-neoplastic diseases 192 10.4.1 Cardiovascular diseases 193 10.4.2 Endometriosis 193 10.4.3 Preeclampsia 195 10.4.4 Arthritis 196 10.5 MMPs as biomarkers of therapeutic efficacy 197 10.6 MMP-specific molecular imaging for noninvasive disease detection 201 10.7 Conclusions 202 Acknowledgments 203 References 203 Index 215

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Book SynopsisOver the past 20 years the study of the frozen Arctic and Southern Oceans and sub-arctic seas has progressed at a remarkable pace. This third edition of Sea Ice gives insight into the very latest understanding of the how sea ice is formed, how we measure (and model) its extent, the biology that lives within and associated with sea ice and the effect of climate change on its distribution. How sea ice influences the oceanography of underlying waters and the influences that sea ice has on humans living in Arctic regions are also discussed. Featuring twelve new chapters, this edition follows two previous editions (2001 and 2010), and the need for this latest update exhibits just how rapidly the science of sea ice is developing. The 27 chapters are written by a team of more than 50 of the worlds' leading experts in their fields. These combine to make the book the most comprehensive introduction to the physics, chemistry, biology and geology of sea ice that there is. ThiTable of ContentsList of contributors vii Preface xi 1 Overview of sea ice growth and properties 1 Chris Petrich and Hajo Eicken 2 Sea ice thickness distribution 42 Christian Haas 3 Snow in the sea ice system: friend or foe? 65 Matthew Sturm and Robert A. Massom 4 Sea ice and sunlight 110 Donald K. Perovich 5 The sea ice–ocean boundary layer 138 Miles G. McPhee 6 The atmosphere over sea ice 160 Ola Persson and Timo Vihma 7 Sea ice and Arctic Ocean oceanography 197 Finlo Cottier, Michael Steele and Frank Nilsen 8 Oceanography and sea ice in the Southern Ocean 216 Michael P. Meredith and Mark A. Brandon 9 Methods of satellite remote sensing of sea ice 239 Gunnar Spreen and Stefan Kern 10 Gaining (and losing) Antarctic sea ice: variability, trends and mechanisms 261 Sharon Stammerjohn and Ted Maksym 11 Losing Arctic sea ice: observations of the recent decline and the long-term context 290 Walter N. Meier 12 Sea ice in Earth system models 304 Dirk Notz and Cecilia M. Bitz 13 Sea ice as a habitat for Bacteria, Archaea and viruses 326 Jody W. Deming and R. Eric Collins 14 Sea ice as a habitat for primary producers 352 Kevin R. Arrigo 15 Sea ice as a habitat for micrograzers 370 David A. Caron, Rebecca J. Gast and Marie-Ève Garneau 16 Sea ice as a habitat for macrograzers 394 Bodil A. Bluhm, Kerrie M. Swadling and Rolf Gradinger 17 Dynamics of nutrients, dissolved organic matter and exopolymers in sea ice 415 Klaus M. Meiners and Christine Michel 18 Gases in sea ice 433 Jean-Louis Tison, Bruno Delille and Stathys Papadimitriou 19 Transport and transformation of contaminants in sea ice 472 Feiyue Wang, Monika Púcko and Gary Stern 20 Numerical models of sea ice biogeochemistry 492 Martin Vancoppenolle and Letizia Tedesco 21 Arctic marine mammals and sea ice 516 Kristin L. Laidre and Eric V. Regehr 22 Antarctic marine mammals and sea ice 534 Marthán N. Bester, Horst Bornemann and Trevor McIntyre 23 A feathered perspective: the influence of sea ice on Arctic marine birds 556 Nina J. Karnovsky and Maria V. Gavrilo 24 Birds and Antarctic sea ice 570 David Ainley, Eric J. Woehler and Amelie Lescroël 25 Sea ice is our beautiful garden: indigenous perspectives on sea ice in the Arctic 583 Henry P. Huntington, Shari Gearheard, Lene Kielsen Holm, George Noongwook, Margaret Opie and Joelie Sanguya 26 Advances in palaeo sea ice estimation 600 Leanne Armand, Alexander Ferry and Amy Leventer 27 Ice in subarctic seas 630 Hermanni Kaartokallio, Mats A. Granskog, Harri Kuosa and Jouni Vainio Index 645

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Book SynopsisTechnological advances have greatly increased the potential for, and practicability of, using medical neurotechnologies to revolutionize how a wide array of neurological and nervous system diseases and dysfunctions are treated.Table of Contents1. The Historical Foundation of Bionics Nick Donaldson and Giles.S. Brindley 1.1 Bionics Past & Future 1.2 History in 1973 1.2.1 Biomaterials 1.2.2 Nerve Stimulation & Recording 1.2.3 Transistors 1.2.4 Conclusion 1.3 Anaesthesia 1.4 Aseptic Surgery 1.5 Clinical Observation & Experiments 1.6 Hermetic Packages 1.6.1 Vacuum Methods 1.6.2 Welding 1.6.3 Glass 1.6.4 Glass Ceramics & Solder Glasses 1.6.5 Ceramics 1.6.6 Microcircuit Technologies 1.6.7 Leak Testing 1.7 Encapsulation (Electrical Insulation) 1.7.1 Insulation 1.7.2 Under-water insulation 1.7.3 Silicones 1.7.4 Primers 1.8 Early Implanted Devices 1.9 Afterword References 2. Development of Stable Long-Term Electrode Tissue Interfaces for Recording and Stimulation Jens Schouenborg 2.1 Introduction 2.2 Tissue responses in the brain to an implanted foreign body 2.2.1 Acute tissue responses 2.2.2 Chronic tissue responses 2.2.3 On the importance of physiological conditions 2.3 Brain Computer Interfaces (BCI) - state of the art 2.4 Biocompatibility of BCI – on the importance of mechanical compliance 2.5 Novel electrode constructs and implantation procedures 2.5.1 Methods to implant ultraflexible electrodes 2.5.2 Surface configurations 2.5.3 Matrix embedded electrodes 2.5.4 Electrode arrays encorporating drugs 2.6 Concluding remarks Acknowledgements References 3. Electrochemical Principles of Safe Charge Injection Stuart F. Cogan, David J. Garrett and Rylie A. Green 3.1 Introduction 3.2 Charge Injection Requirements 3.2.1 Stimulation Levels for Functional Responses 3.2.2 Tissue damage thresholds 3.2.3 Charge Injection Processes 3.2.4 Capacitive Charge Injection 3.2.5 Faradaic Charge Injection 3.2.6 Stimulation Waveforms 3.2.7 Voltage Transient Analysis 3.3 Electrode Materials 3.3.1 Non-noble Metal Electrodes 3.3.2 Noble metals 3.3.3 High Surface Area Capacitor Electrodes 3.3.4 Three-dimensional Noble Metal Oxide Films 3.4 Factors Influencing Electrode Reversibility 3.4.1 In vivo versus saline charge injection limits 3.4.2 Degradation Mechanisms and Irreversible Reactions 3.5 Emerging Electrode Materials 3.5.1 Intrinsically conductive polymers 3.5.2 Carbon Nanotubes and Conductive Diamond 3.6 Conclusion References 4. Principles of Recording from an Electrical Stimulation of Neural Tissue James B. Fallon and Paul M. Carter 4.1 Introduction 4.2 Anatomy and physiology of neural tissue 4.2.1 Active Neurons 4.3 Physiological principles of recording from neural tissue 4.3.1 Theory of recording 4.3.2 Recording electrodes 4.3.3 Amplification 4.3.4 Imaging 4.4 Principles of Stimulation of Neural Tissue 4.4.1 Introduction 4.4.2 Principles of Neural Stimulator Design 4.4.3 Modelling Nerve Stimulation 4.4.4 The Activating Function 4.4.5 Properties of Nerves Under Electrical Stimulation 4.5 Safety of Electrical Stimulation 4.5.1 Safe Stimulation Limits 4.5.2 Metabolic Stress 4.5.3 Electrochemical Stress 4.6 Conclusion References 5. Wireless Neurotechnology for Neural Prostheses Arto Nurmikko, David Borton and Ming Yin 5.1 Introduction 5.2 Rationale and overview of Technical Challenges Associated with Wireless Neuroelectronic Interfaces 5.3 Wireless Brain Interfaces Require Specialized Microelectronics 5.3.1 Lessons learned from Cabled Neural Interfaces 5.3.2 Special Demands for Compact Wireless Neural Interfaces 5.4 Illustrative Microsystems for High Data Rate Wireless Brain Interfaces in Primates 5.5 Power Supply and Management for Wireless Neural Interfaces 5.6 Packaging and Challenges in Hermetic Sealing 5.7 Deployment of High Data Rate Wireless Recording in Freely Moving Large Animals 5.8 Summary and Prospects for High Data Rate Brain Interfaces for Neural Prostheses Acknowledgements References 6. Preclinical Testing of Neural Prostheses Douglas McCreery 6.1 Introduction 6.2 Biocompatibility testing of neural implants 6.3 Testing for mechanical and electrical integrity 6.4 In vitro accelerated testing and accelerated aging of neural implants 6.5 In vivo testing of neural prostheses 6.6 Conclusion References 7. Auditory and Visual Neural Prostheses Robert K. Shepherd, Peter M. Seligman, Mohit N. Shivdasani 7.1 Introduction 7.2 Auditory prostheses 7.2.1 The Auditory system 7.2.2 Hearing loss 7.2.3 Cochlear implants 7.2.4 Central auditory prostheses 7.2.5 Combined electric and acoustic stimulation 7.2.6 Bilateral cochlear implants 7.2.7 Future directions 7.3 Visual prostheses 7.3.1 The Visual system 7.3.2 Vision loss 7.3.3 Retinal prostheses 7.3.4 Central visual prostheses 7.3.5 Perception through a vision prosthesis 7.3.6 Future directions 7.4 Sensory prostheses and brain plasticity 7.5 Conclusions Acknowledgments References 8. Neurobionics: Treatments for Disorders of the Central Nervous System Hugh McDermott 8.1 Introduction 8.2 Psychiatric conditions 8.2.1 Obsessive-compulsive disorder 8.2.2 Major depression 8.3 Movement disorders 8.3.1 Essential Tremor 8.3.2 Parkinson’s disease 8.3.3 Dystonia 8.3.4 Tourette syndrome 8.4 Epilepsy 8.5 Pain 8.6 Future directions Acknowledgements References 9. Brain Computer Interfaces David M. Brandman and Leigh R. Hochberg 9.1 Introduction 9.2 Motor Physiology 9.2.1 Neurons are the fundamental unit of the Brain 9.2.2 Movement occurs through coordinated activity between multiple regions of the nervous system 9.2.3 Motor Cortex: a first source for iBCI signals 9.2.4 The Parietal Cortex is implicated in spatial coordination 9.2.5 The premotor and supplementary motor cortices are engaged in movement goals 9.2.6 Functional brain organization is constantly changing 9.2.7 Section Summary 9.3 The Clinical Population for Brain Machine Interfaces 9.3.1 Paralysis may result from damage to the motor system 9.3.2 Individuals with spinal cord injuries develop motor impairments that may impact hand function 9.3.3 Individuals with LIS develop motor impairment that impacts communication 9.4 BCI Modalities 9.4.1 BCI Modalities 9.4.2 Electrodes placed in the cortex record action potentials from neurons 9.4.3 Raw voltage signals are processed into spikes 9.5 BCI Decoding and applications 9.5.1 BCI decoders convert neural information into control of devices 9.5.2 BCI decoders allow for the control of prosthetic devices 9.6 Future directions 9.6.1 Scientific and engineering directions for developing BMI technology 9.6.2 Clinical directions for development of BCI technology 9.7 Conclusion References 10. Taking a Device to Market: Regulatory and Commercial Issues John L. Parker 10.1 Introduction 10.2 Basic Research 10.3 Preclinical Development 10.4 Clinical trials and approval to sell 10.5 Building a Business not a product 10.6 Conclusions References 11. Ethical Considerations in the Development of Neural Prostheses Frank J. Lane, Kristian P. Nitsch, and Marcia Scherer 11.1 Introduction 11.2 Individuals with Disabilities & Technology Development 11.3 Ethical Principles of Biomedical Research 11.4 Conclusions References Appendix: Companies Developing and/or Marketing Bionic Devices

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Book SynopsisComputational and high-throughput methods, such as genomics, proteomics, and transcriptomics, known collectively as -omics, have been used to study plant biology for well over a decade now. This book provides an introduction to key omicsbased methods and their application in plant breeding.Trade Review“Accessible to advanced students, researchers, and professionals, Omics in Plant Breeding will be an essential entry point into this innovative and exciting field.” (Biotechnology, Agronomy, Society and Environment, 1 October 2014) Table of ContentsList of Contributors ix Foreword xiii 1 Omics: Opening up the "Black Box" of the Phenotype 1Roberto Fritsche-Neto and Aluizio Borem The Post-Genomics Era 3 The Omics in Plant Breeding 4 Genomics, Precision Genomics, and RNA Interference 5 Transcriptomics and Proteomics 8 Metabolomics and Physiognomics 8 Phenomics 9 Bioinformatics 10 Prospects 10 References 10 2 Genomics 13Antonio Costa de Oliveira, Luciano Carlos da Maia, Daniel da Rosa Farias, and Naciele Marini The Rise of Genomics 13 DNA Sequencing 13 Development of Sequence-based Markers 18 Genome Wide Selection (GWS) 25 Structural and Comparative Genomics 27 References 28 3 Transcriptomics 33Carolina Munari Rodrigues, Valeria S. Mafra, and Marcos Antonio Machado Methods of Studying the Transcriptome 34 Applications of Transcriptomics Approaches for Crop Breeding 46 Conclusions and Future Prospects 51 Acknowledgements 51 References 51 4 Proteomics 59Ilara Gabriela F. Budzinski, Thais Regiani, Monica T. Veneziano Labate, Simone Guidetti-Gonzalez, Danielle Izilda R. da Silva, Maria Juliana Calderan Rodrigues, Janaina de Santana Borges, Ivan Miletovic Mozol, and Carlos Alberto Labate History 59 Different Methods for the Extraction of Total Proteins 60 Subcellular Proteomics 64 Post-Translational Modifications 66 Quantitative Proteomics 69 Perspectives 72 References 73 5 Metabolomics 81Valdir Diola (in memoriam), Danilo de Menezes Daloso, and Werner Camargos Antunes Introduction 81 Metabolomic and Biochemical Molecules 83 Technologies for Metabolomics 83 Metabolomic Database Analysis 86 Metabolomics Applications 89 Metabolomics-assisted Plant Breeding 91 Associative Genome Mapping and mQTL Profiles 95 Large-scale Phenotyping Using Metabolomics 97 Conclusion and Outlook 98 References 99 6 Physionomics 103Frederico Almeida de Jesus, Agustin Zsogon, and Lazaro Eustaquio Pereira Peres Introduction 103 Early Studies on Plant Physiology and the Discovery of Photosynthesis 104 Biochemical Approaches to Plant Physiology and the Discovery of Plant Hormones 104 Genetic Approaches to Plant Physiology and the Discovery of Hormone Signal Transduction Pathways 106 Alternative Genetic Models for Omics Approaches in Plant Physiology 112 "Physionomics" as an Integrator of Various Omics for Functional Studies and Plant Breeding 117 Acknowledgements 121 References 121 7 Phenomics 127Roberto Fritsche-Neto, Aluizio Borem, and Joshua N. Cobb Introduction 127 Examples of Large-scale Phenotyping 128 Important Aspects for Phenomics Implementation 134 Main Breeding Applications 141 Final Considerations 144 References 144 8 Electrophoresis, Chromatography, and Mass Spectrometry 147Thais Regiani, Ilara Gabriela F. Budzinski, Simone Guidetti-Gonzalez, Monica T. Veneziano Labate, Fernando Cotinguiba, Felipe G. Marques, Fabricio E. Moraes, and Carlos Alberto Labate Introduction 147 Two-dimensional Electrophoresis (2DE) 148 Chromatography 150 Mass Spectrometry 155 Data Analysis 161 References 164 9 Bioinformatics 167J. Miguel Ortega and Fabricio R. Santos Introduction 167 The "Omics" Megadata and Bioinformatics 167 Hardware for Modern Bioinformatics 169 Software for Genomic Sequencing 170 Software for Contig Assembling 172 Assembly Using the Graph Theory 173 New Approaches in Bioinformatics for DNA and RNA Sequencing 174 Databases, Identification of Homologous Sequences and Functional Annotation 175 Annotation of a Complete Genome 179 Computational System with Chained Tasks Manager (Workflow) 181 Applications for Studies in Plants 182 Final Considerations 183 References 184 10 Precision Genetic Engineering 187Thiago J. Nakayama, Aluizio Borem, Lucimara Chiari, Hugo Bruno Correa Molinari, and Alexandre Lima Nepomuceno Introduction 187 Zinc Finger Nucleases (ZFNs) 190 Transcription Activator-like Effector Nucleases (TALENs) 193 Meganucleases (LHEs: LAGLIDADG Homing Endonucleases) 194 Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) 195 Implications and Perspectives of the use of PGE in Plant Breeding 197 References 202 11 RNA Interference 207Francisco J.L. Aragao, Abdulrazak B. Ibrahim, and Maria Laine P. Tinoco Introduction 207 Discovery of RNAi 208 Mechanism of RNA Interference 209 Applications in Plant Breeding: Naturally Occurring Gene Silencing and Modification by Genetic Engineering 211 Resistance to Viruses 215 Host-induced Gene Silencing 218 Insect and Disease Control 218 Improving Nutritional Values 219 Secondary Metabolites 220 Perspectives 220 References 222 Index 229

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Book SynopsisOxidative Stress and Antioxidant Protection: The Science of Free Radical Biology and< Disease provides an overview of the basic principles of free radical formation. The text delves into free radical formation in molecular biology and its effect on subcellular damage, as well as the role of antioxidant reserves as a protective mechanism. Oxidative Stress and Antioxidant Protection begins with a historical perspective of pioneers in oxidative stress with an introductory section that explains the basic principles related to oxidative stress in biochemistry and molecular biology, demonstrating both pathways and biomarkers. This section also covers diagnostic imaging and differential diagnostics. The following section covers psychological, physiologic, pharmacologic and pathologic correlates. This section addresses inheritance, gender, nutrition, obesity, family history, behavior modification, natural herbal-botanical products, and supplementation in the treatment oTable of ContentsList of Contributors ix Special Recognition xiii Foreword xv Preface xvii Section 1: Introduction 1 Introduction to Free Radicals, Inflammation, and Recycling 3 Donald Armstrong 2 Diagnostic Imaging and Differential Diagnosis 11 Robert D. Stratton Section 2: Clinical Correlations on Acute and Chronic Diseases 3 Free Radicals: Their Role in Brain Function and Dysfunction 23 Natan Gadoth 4 Mediators of Neuroinflammation 39 Rajiv Tikamdas, Ping Zhang, and Bin Liu 5 Oxidative and Nitrative Stress in Schizophrenia 57 Anna Dietrich-Muszalska 6 The Effects of Hypoxia, Hyperoxia, and Oxygen Fluctuations on Oxidative Signaling in the Preterm Infant and on Retinopathy of Prematurity 77 M. Elizabeth Hartnett 7 Oxidative Damage in the Retina 93 Robert D. Stratton 8 The Role of Oxidative Stress in Hearing Loss 115 Colleen G. Le Prell and Josef M. Miller 9 Disorders of Children 133 Hirokazu Tsukahara and Masato Yashiro 10 Oxidative Stress in Oral Cavity: Interplay between Reactive Oxygen Species and Antioxidants in Health, Inflammation, and Cancer 155 Maurizio Battino, Maria Greabu and Bogdan Calenic 11 Oxidative Stress and the Skin 167 Christina L. Mitchell 12 Oxidative Stress in Osteoarticular Diseases 183 María José Alcaraz, Sergio Portal-Núñez, Juan A. Ardura and Pedro Esbrit 13 Gene Therapy to Reduce Joint Inflammation in Horses 193 Patrick Colahan, Rachael Watson, and Steve Ghivizzani 14 Muscle and Oxidative Stress 205 Reza Ghiasvand and Mitra Hariri 15 Role of Oxidants and Antioxidants in Male Reproduction 221 Ashok Agarwal, Hanna Tadros, Aaron Panicker and Eva Tvrdá 16 Role of Oxidants and Antioxidants in Female Reproduction 253 Ashok Agarwal, Hanna Tadros and Eva Tvrdá 17 Reactive Oxygen Species, Oxidative Stress, and Cardiovascular Diseases 281 Fatemeh Sharifpanah and Heinrich Sauer 18 Oxidative Stress and Antioxidant Imbalance: Respiratory Disorders 307 Surinder K. Jindal 19 Oxidative Stress and Type 1 Diabetes 319 Chao Liu, Clayton E. Mathews, and Jing Chen 20 Metabolic Syndrome, Inflammation, and Reactive Oxygen Species in Children and Adults, 329 William E. Winter and Janet H. Silverstein 21 Oxidative Stress in Chronic Pancreatitis 339 Shweta Singh and Bechan Sharma 22 Wound Healing and Hyperbaric Oxygen Therapy Physiology: Oxidative Damage and Antioxidant Imbalance 347 James R. Wilcox and D. Scott Covington 23 Radiobiology and Radiotherapy 357 Justin Wray and Judith Lightsey 24 Chemotherapy-Mediated Pain and Peripheral Neuropathy: Impact of Oxidative Stress and Inflammation 367 Hassan A.N. El-Fawal, Robert Rembisz, Ryyan Alobaidi, and Shaker A. Mousa 25 Grape Polyphenol-rich Products with Antioxidant and Anti-inflammatory Properties 389 Eduarda Fernandes, Marisa Freitas, Renan C. Chisté, Elena Falqué, and Herminia Domínguez 26 Isotonic Oligomeric Proanthocyanidins 403 Hanbo Hu and Donald Armstrong 27 Superoxide Dismutase Mimics and Other Redox-active Therapeutics 415 Ines Batinic-Haberle and Artak Tovmasyan 28 Herbal Medicine: Past, Present, and Future with Emphasis on the Use of Some Common Species 471 Aneela Afzal and Mohammad Afzal 29 Ayurvedic Perspective on Oxidative Stress Management 483 Priyanka M. Jadhav 30 Clinical Trials and Antioxidant Outcomes 493 Carlos Palacio and Arshag D. Mooradian 31 Statistical Approaches to Make Decisions in Clinical Experiments 507 Albert Vexler and Xiwei Chen Index 561

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Book SynopsisIn vitro fertilization (IVF) and other assisted reproductive technologies (ART) have become a significant part of human reproduction, with already one in 50 children worldwide being born through ART and the demand steadily increasing. To accommodate the various kinds of infertility problems, new methods have been developed to increase IVF and ART success rates and it has also become possible to treat sperm, eggs, and embryos in culture to improve reproductive success, to increase the health state of an embryo, and to prevent disease in the developing child. Human Reproduction: Updates and New Horizons focuses on recent developments and new approaches to study egg and sperm cells and embryo development, as well as addressing the increasing demand for IVF and ART to overcome infertility problems of various kinds that are encountered by an increasing number of couples worldwide. The book includes 10 chapters written by experts in their specific fields to provide informatiTable of ContentsList of Contributors xv 1 Sperm Selection Techniques and their Relevance to ART 1Luke Simon, Monis B. Shamsi, and Douglas T. Carrell 1.1 Introduction 1 1.2 Need of Sperm Selection in ART 2 1.3 Methodology of Sperm Selection 3 1.4 Electrophoretic Sperm Separation 14 1.5 Zeta Test 18 1.6 Microelectrophoresis Sperm Selection 21 1.7 Raman Spectroscopy 24 1.8 Hyaluronic Acid Binding Assay 27 1.9 Future Perspective 30 References 31 2 In Vitro Maturation of Human Oocytes: Current Practices and Future Promises 45Catherine M.H. Combelles 2.1 Introduction 45 2.2 Clinical Indications for IVM 46 2.3 Ovarian Stimulation Approaches for the Retrieval of Immature Oocytes 51 2.4 Maternal Conditions that may Influence IVM 54 2.5 Follicular Origins of Immature Oocytes for IVM 55 2.6 Clinical Safety of IVM 57 2.7 Concluding Remarks towards the Optimization of IVM 58 References 61 3 Molecular Biology of Endometriosis 71Jayasree Sengupta, G. Anupa, Muzaffer Ahmed Bhat, and Debabrata Ghosh 3.1 Introduction 71 3.2 Brief Background 71 3.3 Genetic Basis of Endometriosis 76 3.4 Molecular Mechanisms of Endometriosis 77 3.5 Molecular Etiopathological Basis of Endometriosis: Leads in Genomics Era 83 3.6 Molecular Etiopathological Basis of Endometriosis: Leads in the Post-Genomics Era 99 3.7 Future Targets 113 Acknowledgments 115 Conflicts of Interest 116 References 116 4 Novel Immunological Aspects for the Treatment of Age-induced Ovarian and Testicular Infertility, Other Functional Diseases, and Early and Advanced Cancer Immunotherapy 143Antonin Bukovsky 4.1 Introduction 143 4.2 Ovarian Infertility 145 4.3 Novel In Vitro Proposals for Ovarian Infertility Treatment 163 4.4 Novel In Vivo Proposal for Ovarian and Testicular Infertility Treatment 170 4.5 Systemic Treatment of Other Functional Diseases by Tissue Rejuvenation 174 4.6 Advantages of Local and Systemic Use of Honey Bee Propolis and Cayenne Pepper 175 4.7 The Promise of Pyramid Healing Systems 180 4.8 Raw Shiitake Causes Early Neoplasia Regression and Malignancy Recurrence Prevention 180 4.9 Immune Modulation for the Treatment of an Advanced Cancer 182 4.10 Advanced Ovarian Cancer Regression Case Report 184 4.11 Discussion 187 4.12 Conclusions 192 Abbreviations 193 Competing Interests 193 Author Contribution 193 References 194 5 Mitochondrial Manipulation for Infertility Treatment and Disease Prevention 205Tetsuya Ishii 5.1 Introduction 205 5.2 The Roles of Mitochondria in Fertilization, Embryonic Development, and Disease 206 5.3 The Genetics of Mitochondria and Mitochondrial Diseases 209 5.4 Ooplasmic Transfer to Treat Infertility 210 5.5 Pronuclear Transfer to Achieve Pregnancy 214 5.6 Germinal Vesicle Transfer to Restore the Viability of Oocytes 216 5.7 Mitochondrial Diseases and Prevention of their Inheritance 217 5.8 Mitochondrial Replacement by Transferring Pronuclei and MII Spindle 218 5.9 Discussion 220 Acknowledgments 222 References 223 6 Novel Imaging Techniques to Assess Gametes and Preimplantation Embryos 231Jason E. Swain 6.1 Introduction 231 6.2 Light and Impact on Mammalian Gametes and Embryos 232 6.3 Novel Imaging Approaches for Gametes and Embryos 233 6.4 Conclusion 255 References 256 7 Clinical Application of Methods to Select In Vitro Fertilized Embryos 267Kirstine Kirkegaard, Thomas F. Dyrlund, and Hans Jakob Ingerslev 7.1 Introduction 267 7.2 Morphological Assessment 268 7.3 Genomic and Transcriptomic Analysis 279 7.4 Analysis of Conditioned Culture Medium 285 7.5 Summary 294 References 295 8 New Horizons/Developments in Time-Lapse Morphokinetic Analysis of Mammalian Embryos 313Munevver Serdarogullari, Necati Findikli, and Mustafa Bahcecî 8.1 Introduction 313 8.2 Utilization of Time-Lapse Morphokinetics in Mammalian Embryos: A Historical Perspective 314 8.3 What is TLM? 315 8.4 What are the Benefits of TLM? 316 8.5 Application of TLM in Human ART Practice 318 8.6 The Possible Utilization of TLM Analysis in Aneuploidy Detection 324 8.7 Expected Contributions of TLM Technology in the Future of Mammalian Embryology 327 References 328 9 The Non-Human Primate Model for Early Human Development 339Stuart Meyers and Renee Riejo-Pera 9.1 Introduction 339 9.2 Why Primate Models Are Critical to Understanding Human Development and Subfertility 340 9.3 NHP Model of Assisted Reproductive Technology (ART) 342 9.4 NHP Model of Early Embryo Development 343 9.5 Research Perspective on NHP Embryo Development 345 9.6 Summary 347 References 348 10 Cytoskeletal Functions, Defects, and Dysfunctions Affecting Human Fertilization and Embryo Development 355Heide Schatten and Qing-Yuan Sun 10.1 Introduction 355 10.2 Components of the Cytoskeleton and their Important Functions in Reproductive Biology 356 10.3 The Role of the Cytoskeleton in Oocyte Maturation 360 10.4 Maturation Failures and Oocyte Aging 369 10.5 Fertilization and First Mitosis/Cell Division 371 10.6 Cellular Differentiation/Polarization During Pre-Implantation Embryo Development/Compaction Stage 374 10.7 Perspectives and Future Directions 380 References 381 Index 399

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Book SynopsisTechnology Platforms for 3D Cell Culture: A Users Guide points to the options available to perform 3D culture, shows where such technology is available, explains how it works, and reveals how it can be used by scientists working in their own labs.Table of ContentsList of contributors, vii Preface, xi List of abbreviations, xiv 1 An introduction to the third dimension for routine cell culture, 1Antonio Romo‐Morales and Stefan Przyborski Part I: Aggregate‐based technologies 2 Gravity‐enforced microtissue engineering, 23Randy Strube, Johannes Haugstetter, Markus Furter, Andreia Fernandez, David Fluri and Jens M. Kelm 3 Physiologically relevant spheroid models for three‐dimensionalcell culture, 50Nicole A. Slawny and MaryAnn Labant 4 NanoCulture Plate: A scaffold‐based high‐throughput three‐dimensional cell culture system suitable for live imaging and co‐culture, 74Manabu Itoh, Kazuya Arai, Hiromi Miura and M. Mamunur Rahman 5 Micro‐moulded non‐adhesive hydrogels to form multicellular microtissues – the 3D Petri Dish®, 97Elizabeth Leary, Sean Curran, Michael Susienka, Kali L. Manning, Andrew M. Blakely and Jeffrey R. Morgan 6 Organotypic microtissues on an air‐liquid interface, 123Lars E. Sundstrom, Igor Charvet and Luc Stoppini Part II: Hydrogels 7 Materials and assay systems used for three‐dimensional cell culture, 145Suparna Sanyal and Marshall Kosovsky 8 HyStem®, a customisable hyaluronan‐based hydrogel matrix for 3D cell culture, 173T. I. Zarembinski, B. J. Engel, N. J. Doty, P. E. Constantinou, M. V. Onorato, I. E. Erickson, E. L. S. Fong, M. Martinez, R. L. Milton, B. P. Danysh, N. A. Delk, D. A. Harrington, M. C. Farach‐Carson and D. D. Carson 9 3‐D Life biomimetic hydrogels: A modular system for cell environment design, 197Brigitte M. Angres and Helmut Wurst Part III: Scaffolds 10 Alvetex®, a highly porous polystyrene scaffold for routine three‐dimensional cell culture, 225Antonio Romo‐Morales, Eleanor Knight and Stefan Przyborski 11 CelluSponge™ and Go Matrix as innovative three‐dimensional cell culture platforms, 250Bramasta Nugraha 12 Mimetix® electrospun scaffold: An easy‐to‐use tool for 3D cell culture in drug discovery and regenerative medicine, 284Robert J. McKean and Elena Heister Part IV: 3D bioreactor technologies 13 Quasi Vivo® bioreactor technology, 305J. Malcolm Wilkinson 14 Three‐dimensional cell‐based assays in hollow fibre bioreactors, 327John J. S. Cadwell and William G. Whitford 15 Three‐dimensional engineered tissues for high‐throughput compound screening: Mechanical properties of skin and ageing, 351Michael Conway, Ayla Annac and Tetsuro Wakatsuki 16 Three‐dimensional cell culture in the Rotary Cell Culture System™, 370Stephen S. Navran Glossary, 386 Index, 393

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Book SynopsisThis book combines recent information and discoveries in the field of human molecular biology and human molecular evolution. It provides an interdisciplinary approach drawing together data from various diverse disciplines to address both the more classical anthropological content and the current more contemporary molecular focus of courses. Chapters include a history of human evolutionary genetics; the human genome structure and function; population structure and variability; gene and genomic dynamics; culture; health and disease; bioethics; future.Table of ContentsPreface, ix 1 The history of human evolutionary genetics, 1 World views, 1 Science and philosophy, 1 The biology of mankind: anatomy and physiology in a historical context (up to the 16th century), 3 Beginnings of the present scientific model, 4 Biological evolution and genetic foundations: the brilliant quartet, 5 Nineteenth century: cytology, embryology, and reproduction, 9 Twentieth century, the century of genetics, 10 The synthetic theory of evolution, 11 Bacterial and molecular genetics, 11 Parallel developments: paleoanthropology, 12 Technical and methodological developments, 13 Conclusions, 14 Review questions and exercises, 14 References, 14 2 The human genome: structure, function, and variation, 16 Science, politics, and ethics, 16 Structural aspects, 17 Normal and abnormal phenotype distribution, 19 Function, 21 Sex chromosomes, 23 Paleogenomics, 25 Variability: mtDNA, 28 Nuclear variability, 28 Exomes and proteomes, 30 Selection or drift? History, 31 Selection or drift? Methods, 32 Selection or drift? Analyses, 34 Nervous system and culture, 37 Conclusions, 37 Review questions and exercises, 37 References, 38 3 Population structure, 42 DNA-based marker systems, 42 SNPs, STRs, and Indels as DNA markers, 45 Population genetic tools for analyzing population structure, 49 Forces affecting population dynamics, structure, and evolution, 55 Applications of population genetics, 60 From populations to races and species, 62 Review questions and exercises, 64 References, 65 4 Genetic variability, 68 On the nature of variability, 68 Mechanisms responsible for generating genetic variability, 69 Randomness of mutations, 71 Inheritance and environment, 75 Selection works on the phenotype, 76 The impact of selection, 77 Cultural expressions as markers of ancestry, 79 Congruency among marker systems, 80 Does junk DNA exist?, 80 How genetic diversity is studied?, 82 Epigenetic diversity, 84 Review questions and exercises, 85 References, 86 5 Gene and genomic dynamics, 87 Molecular evidence for punctuated equilibrium and gradualism, 88 Next-generation sequencing, 90 Genetic variation, 92 Variation, population structure, and effective population size, 94 Recombination and its effect on variation, 94 Linkage equilibrium and disequilibrium, 95 Forces leading to linkage disequilibrium, 98 Linkage disequilibrium and SNP haplotypes, 99 Linkage disequilibrium in humans, 100 Genome structural variations, 102 CNV classifications and formation mechanisms, 102 Methods used to detect CNVs, 103 CNVs associated with human phenotypes, 105 CNVs and evolution, 106 CNV in primates, 107 Chromosome rearrangements and selfish genetic elements, 108 Transposable elements, 109 Population dynamics of transposable elements, 110 Transposons in human evolution, 111 Selfish genetic elements in evolution, 113 Genome-wide association studies, 113 Concerns over the effective use of GWAS, 117 Conclusions, 117 Review questions and exercises, 118 References, 119 6 Human origins and early diasporas, 124 The on switch to humanity, 124 Early hominins, 128 Emerging themes and variations in hominin evolution, 130 The first hominin migrants, 134 The emergence of modern humans, 135 The Saharan pump, 135 Early migrations, 136 Neanderthals prevailed, 136 Review questions and exercises, 138 References, 139 7 Culture, 141 Concept, 141 Origin and development, 141 Factors that could condition cultural evolution, 142 Biology–culture interaction, 145 Language, 146 Domestication, 148 Art, 151 Free will, morality, and religion, 153 Conclusions, 155 Review questions and exercises, 155 References, 155 8 Health and disease, 158 Hopes and reality, 158 Concept of health and methods of study, 158 Darwinian medicine, 160 Parent–offspring conflict, 161 Pathogen history, 161 Evolution of infectious diseases, 162 DNA damage, mutagenesis, and teratogenesis, 163 What is better, more or less gene product?, 165 Genetic manipulation of animals to study health and disease, 166 Reproductive fitness and health, 167 Consanguinity, 168 Violence, 168 Cancer, 171 Degenerative diseases, 172 Ecogenetics, pharmacogenetics, and pharmacogenomics, 174 Detection of genetic diseases, 176 Genetic counseling, 176 Treatment, 178 Conclusions, 179 Review questions and exercises, 179 References, 180 9 Recent human evolution: an integrative approach, 182 Recent human evolution, 182 Out of Africa, 184 Back to Africa, 188 Beyond Arabia, 190 The Asian agricultural revolution and the Austronesian expansion, 194 Evidence from plants and animals, 198 Contacts between South America and Polynesia, 200 Review questions and exercises, 202 References, 203 10 Bioethics: consequences and implications of genetic technology on human evolution, 206 Social and biological evolution, 207 Overview of ethics and philosophical influences on Western ethics, 207 Evolution of ethics and morality, 212 The history and beginning of modern-day bioethics, 213 Reproductive technologies and the new eugenics: unnatural selection?, 216 Enhancement through IVF, PGD, and CRISPR, 219 Ethical issues associated with medical technology, 220 Gene therapy, 220 Stem cell therapy, 222 Biosimilars, 222 Genetic privacy, 222 Genetic testing, 223 DNA profiling, 224 Conclusions, 227 Review questions and exercises, 227 References, 228 11 Future of human evolution, 230 Gene and culture coevolution, 231 Life expectancy and population growth: past, present, and future, 231 Mutation rates and future evolution, 232 The evolution of new genes, 234 Climate change, 234 Diet, 235 Sex selection, 236 Artificial selection, 236 Transhumanism and artificial intelligence, 237 Conclusions, 238 Review questions and exercises, 239 References, 239 Appendix, 241 Index, 249

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Book SynopsisThe third edition of this best-selling book continues to offer a user-friendly, step-by-step introduction to all the key processes involved in bringing a drug to the market, including the performance of pre-clinical studies, the conduct of human clinical trials, regulatory controls, and even the manufacturing processes for pharmaceutical products. Concise and easy to read, Drugs: From Discovery to Approval, Third Edition quickly introduces basic concepts, then moves on to discuss target selection and the drug discovery process for both small and large molecular drugs. The third edition incorporates the latest developments and updates in the pharmaceutical community, provides more comprehensive coverage of topics, and includes more materials and case studies suited to college and university use. Biotechnology is a dynamic field with changes across R&D, clinical trials, manufacturing and regulatory processes, and the third edition of the text provides timely updates for thoTable of ContentsPreface xv 1 Introduction 1 1.1 Aim of this Book 1 1.2 An Overview of the Drug Discovery to Approval Process 2 1.3 The Pharmaceutical Industry 6 1.4 Economics of Drug Discovery and Development 11 1.5 Trends in Drug Discovery and Development 13 1.6 Case Study #1.1 15 1.7 Case Study #1.2 17 1.8 Summary of Important Points 20 1.9 Review Questions 20 1.10 Brief Answers and Explanations 21 1.11 Further Reading 22 2 Drug Discovery: Targets and Receptors 23 2.1 Drug Discovery Processes 23 2.2 Medical Needs 24 2.3 Target Identification 26content 2.4 Target Validation 33 2.5 Drug Interactions with Targets or Receptors 36 2.6 Enzymes 40 2.7 Receptors and Signal Transduction 42 2.8 Assay Development 52 2.9 Case Study #2.1 52 2.10 Case Study #2.2 53 2.11 Summary of Important Points 57 2.12 Review Questions 57 2.13 Brief Answers and Explanations 58 2.14 Further Reading 58 3 Drug Discovery: Small Molecule Drugs 61 3.1 Introduction 61 3.2 Irrational Approach 62 3.3 Rational Approach 67 3.4 Antisense Approach 85 3.5 RNA Interference Approach 88 3.6 Chiral Drugs 91 3.7 Closing Remarks 92 3.8 Case Study #3.1 94 3.9 Case Study #3.2 96 3.10 Summary of Important Points 98 3.11 Review Questions 99 3.12 Brief Answers and Explanations 99 3.13 Further Reading 100 4 Drug Discovery: Large Molecule Drugs 103 4.1 Introduction 103 4.2 Vaccines 105 4.3 Antibodies 117 4.4 Cytokines 128 4.5 Hormones 134 4.6 Gene Therapy 137 4.7 Stem Cells and Cell Therapy 139 4.8 Case Study #4.1 141 4.9 Case Study #4.2 144 4.10 Summary of Important Points 146 4.11 Review Questions 147 4.12 Brief Answers and Explanations 148 4.13 Further Reading 148 5 Drug Development and Preclinical Studies 151 5.1 Introduction 151 5.2 Pharmacodynamics 154 5.3 Pharmacokinetics 158 5.4 Toxicology 168 5.5 Animal Tests, In Vitro Assays, and In Silico Methods 172 5.6 Formulations and Delivery Systems 175 5.7 Nanotechnology 183 5.8 Case Study #5.1 184 5.9 Case Study #5.2 185 5.10 Summary of Important Points 187 5.11 Review Questions 188 5.12 Brief Answers and Explanations 188 5.13 Further Reading 189 6 Clinical Trials 191 6.1 Definition of Clinical Trial 191 6.2 Ethical Considerations 192 6.3 Clinical Trials 195 6.4 Regulatory Requirements for Clinical Trials 204 6.5 Clinical Data Management 215 6.6 Role of Regulatory Authorities 218 6.7 Gene Therapy Clinical Trial 218 6.8 Adaptive Clinical Trial 220 6.9 Meta-Analysis 221 6.10 Case Study #6.1 222 6.11 Case Study #6.2 226 6.12 Summary of Important Points 227 6.13 Review Questions 228 6.14 Brief Answers and Explanations 228 6.15 Further Reading 229 7 Regulatory Authorities 231 7.1 Role of Regulatory Authorities 231 7.2 US Food and Drug Administration 233 7.3 European Medicines Agency 236 7.4 Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) 238 7.5 China Food and Drug Administration 240 7.6 India’s Central Drugs Standard Control Organization 240 7.7 Australia’s Therapeutic Goods Administration 241 7.8 Canada’s Health Canada 243 7.9 Other Regulatory Authorities 243 7.10 Authorities other than Drug Regulatory Agencies 243 7.11 International Conference on Harmonization 244 7.12 World Health Organization 245 7.13 Pharmaceutical Inspection Cooperation Scheme 246 7.14 Case Study # 7.1 246 7.15 Case Study # 7.2 249 7.16 Summary of Important Points 250 7.17 Review Questions 251 7.18 Brief Answers and Explanations 251 7.19 Further Reading 252 8 Regulatory Applications 253 8.1 Introduction 253 8.2 United States 254 8.3 European Union 272 8.4 Japan 280 8.5 China 282 8.6 India 287 8.7 Australia 287 8.8 Canada 287 8.9 Case Study #8.1 290 8.10 Case Study #8.2 292 8.11 Summary of Important Points 294 8.12 Review Questions 299 8.13 Brief Answers and Explanations 299 8.14 Further Reading 300 9 Good Manufacturing Practice: Regulatory Requirements 301 9.1 Introduction 301 9.2 United States 302 9.3 Europe 308 9.4 International Conference on Harmonization (ICH) 309 9.5 Pharmaceutical Inspection Cooperation Scheme (PIC/S) 311 9.6 Selected Core Elements of GMP 312 9.7 Selected GMP Systems 335 9.8 New cGMP Initiatives 350 9.9 Case Study #9.1 352 9.10 Case Study #9.2 358 9.11 Summary of Important Points 362 9.12 Review Questions 363 9.13 Brief Answers and Explanations 363 9.14 Further Reading 364 10 Good Manufacturing Practice: Drug Manufacturing 367 10.1 Introduction 367 10.2 GMP Manufacturing 371 10.3 GMP Inspection 372 10.4 Manufacture of Small Molecule APIs (Chemical Synthesis Methods) 379 10.5 Manufacture of Large Molecule APIs (Recombinant DNA Methods) 385 10.6 Finished Dosage Forms 394 10.7 Product Quality Review 398 10.8 Manufacturing Variations 399 10.9 Case Study #10.1 400 10.10 Case Study #10.2 404 10.11 Summary of Important Points 407 10.12 Review Questions 408 10.13 Brief Answers and Explanations 408 10.14 Further Reading 408 11 Future Perspectives 411 11.1 Past Advances and Future Challenges 411 11.2 Small Molecule Pharmaceutical Drugs 412 11.3 Large Molecule Biopharmaceutical Drugs 414 11.4 Traditional Medicine 414 11.5 Personalized Medicine 419 11.6 Gene Therapy 420 11.7 Cloning and Stem Cells 420 11.8 Old Age Diseases and Aging 423 11.9 Lifestyle Drugs 423 11.10 Performance-Enhancing Drugs 428 11.11 Chemical and Biological Terrorism 428 11.12 Transgenic Animals and Plants 432 11.13 Antibiotics Drug Resistance 433 11.14 Regulatory Issues 435 11.15 Intellectual Property Rights and Marketing Exclusivities 437 11.16 Bioethics 440 11.17 Concluding Remarks 442 11.18 Case Study #11.1 445 11.19 Case Study #11.2 447 11.20 Further Reading 449 Appendix 1 History of Drug Discovery and Development 451 A1.1 Early History of Medicine 451 A1.2 Drug Discovery and Development in the Middle Ages 453 A1.3 Foundation of Current Drug Discovery and Development 454 A1.4 Beginnings of Modern Pharmaceutical Industry 454 A1.5 Evolution of Drug Products 455 A1.6 Further Reading 456 Appendix 2 Cells, Nucleic Acids, Genes, and Proteins 457 A2.1 Cells 457 A2.2 Nucleic Acids 460 A2.3 Genes and Proteins 462 A2.4 Further Reading 468 Appendix 3 Selected Drugs and Their Mechanisms Of Action 469 Appendix 4 A DHFR Plasmid Vector 481 Appendix 5 Vaccine Production Methods 483 Appendix 6 Vaccines Approved By FDA 485 Appendix 7 Pharmacology/Toxicology Review Format 489 Appendix 8 Examples of General Biomarkers 495 Appendix 9 Toxicity Grading 499 Appendix 10 Health Systems in Selected Countries 505 Acronyms 509 Glossary 515 Index 519

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Book SynopsisFor nearly a decade, scientists, educators and policy makers have issued a call to college biology professors to transform undergraduate life sciences education. As a gateway science for many undergraduate students, biology courses are crucial to addressing many of the challenges we face, such as climate change, sustainable food supply and fresh water and emerging public health issues. While canned laboratories and cook-book approaches to college science education do teach students to operate equipment, make accurate measurements and work well with numbers, they do not teach students how to take a scientific approach to an area of interest about the natural world. Science is more than just techniques, measurements and facts; science is critical thinking and interpretation, which are essential to scientific research. Discovery-Based Learning in the Life Sciences presents a different way of organizing and developing biology teaching laboratories, to promote both dTable of ContentsAcknowledgments xiii 1 The New Life Sciences 1 The Challenges We Face in Teaching the New Biology 2 Visions of Change 5 Need for Structural Change 6 Conceptual Organization of Introductory Biology 8 Learning and Mastering 10 Further Reading 13 2 Changing Goals and Outcomes in Introductory Life Science Course Laboratories 15 The Introductory Science Course Experience That We Have 15 How Science is Actually Done 15 Challenges to Successful Science Teaching 18 Pre-College Preparation Disparities 18 Avoiding the Textbook as the Organizer of Your Course 18 Weaning Away from Content-Heavy Lectures 20 The Elements of Successful Science Learning 21 Student Autonomy 21 Relevance 21 Student Investment 21 Sustained Engagement 22 Understanding Through Teaching 23 Two Re-organizational Schemes for an Introductory Biology Course 23 Re-organizational Scheme 1: Putting the Classroom First 23 Re-organizational Scheme 2: Putting the Laboratory First 26 Example Topic: Biological Arms Races (Conceptual Areas: Structure and Function, Information Storage and Transfer, Evolution, Systems) 27 What Do These Scenarios have in Common? What is Going on? 28 Classroom Support for the Laboratory Work 29 Summary 30 Further Reading 31 3 Incorporating Discovery-Based Laboratory Experiences at the Introductory Level 33 The Reality of Introductory Biology Laboratories 37 Converting the Survey Approach to Biology Techniques into Discovery-Based Experiences that Emphasize Concepts 38 Module I: What are the Effects of Different Aspects of Climate Change or Other Anthropogenic Changes on Plant Primary Productivity? 41 Weeks 1 and 2: Observing Plant Cells and Measuring Plant Primary Productivity –Two Laboratory Weeks 42 Simple Assays of Photosynthesis/Primary Productivity 44 Week 3: Designing Independent Experiments to Explore the Effects of Climate Change on Primary Productivity in Green Plants 46 Week 4 and 5: Student-designed Discovery-based Experiments and Data Analysis 46 Week 6: Field Observations of Plant Communities in Areas Exposed to Fertilizer Run-off or Other Human Activity such as Road Salt Application in the Winter 47 Assessments 47 Module 2: How Does Antibiotic Resistance Develop? 48 Week 1: Observing cell division; Measuring bacterial Growth and Introduction to Sterile Techniques 49 Week 2: Plate Assay or Turbidity Measurements to Examine Antibiotic Resistance, Design of Selection Experiments 50 Weeks 3–5: Independent Experiments Examining Antibiotic Resistance 52 Week 6–7: Continued Experiments if Time Permits 54 Assessments 54 Module 3: Self-Discovery Explorations of Human Diseases Caused by Single Nucleotide Polymorphisms 54 Week 1: Student Investigation Specific Aims and Goals –Use of Bioinformatics to Explore Genetic Diseases Associated with SNPs 56 Weeks 2 and 3: SNP Analysis for TASR 38 or cdk3 Using Polymerase Chain Reaction 58 Assessment Ideas 58 Summary 60 Further Reading 60 4 The Constraints and Realities of Discovery-Based Laboratories 63 Instructor Expertise 63 Time 65 Preparation Time 66 Student Time In and Out of the Laboratory 66 Time for Class and Laboratory –the Schedule of Classes 68 Time of Academic Year 69 The Physical Arrangement of the Teaching Laboratory 70 Class Size 71 Number of Laboratory Sections 72 Resources for Discovery-Based Laboratories 72 Organisms 73 Equipment 76 Safety Considerations for Independent Projects 76 Transportation for Field-Based Studies 76 Preparatory Staff 77 Student Interns/TAs 78 Summary 78 Further Reading 78 5 A Model Introductory Biology Course 81 Instructor Group Meetings 81 Shared Course Materials 82 Flexible Design Allows for the Introduction of New Modules 82 Overall Conceptual Organization 83 Laboratory Modules for the First Edition of “Introduction to Biological Investigation” 84 Module 1: Caenorhabditis elegans: From Genes to Behavior 84 Module 2: Cyanogenic Clover: Genetic Variation and Natural Selection 89 Module 3: Biodiversity and Soil Microbial Ecology 93 Additional Laboratory Modules 95 Module 4: Personal Genomics: Understanding Individual Genetic Variation 96 Module 5: Behavioral Variations Within a Species 97 Assessment of Learning of Core Concepts and Skills 99 Student Evaluation of the Course 99 Faculty Concerns and Discomforts 100 Further Reading 101 6 Two Model Scenarios for an Intermediate-Level Life Science Course 103 Model 1: Exploration of Gerontogenes and Behavior 105 Assessment of Skills and Student Learning 107 Model 2: How do Common Lawn Chemicals Affect the Behavior and the Nervous System of C. elegans? 107 Summary of the Format 110 Assessment of Student Learning 110 Goal 1: Achieve a Solid Foundation in the Experimental Approaches to a Variety of Current Research Questions in Neuroscience and Behavior 111 Goal 2: Achieve a Sophisticated Ability to Read and Interpret the Primary Experimental Literature 111 Goal 3: Formulate a Hypothesis, Design and Conduct a Multilevel Experimental Project Over SeveralWeeks to Discover New Information About the Relationship Between Genes and Behavior 111 Goal 4: Perform and Understand Appropriate Statistical Analysis of Behavioral Data, Gain Confidence in the Use and Limitations of Model Organisms, Computational and Bioinformatics Approaches to Examining Complex Relationships Between Genes and Behavior 112 Goal 5: Become Facile in the “Language” of Neuroscience and Behavior, with a Thorough Mastery of our Chosen Subtopics, asWell as a Keen Ability to Speak and Write on the Discipline 112 Further Reading 113 7 Assessments and Why They Are Important 115 What is Assessment? 115 Student Learning Assessments 116 Course-Based Assessments 120 Example 1: Assessment of Discovery-Based Introductory Biology Course 122 Example 2: Assessment of a Redesigned Introductory Cell Biology Course Using Pretesting and Post-Testing 124 Instructor Quality Assessments 126 Interpreting the Data 127 What to do with the Data? 128 Further Reading 129 8 Fully Incorporating Vision and Change 131 The Anthropocene and the Importance of Biology Literacy 131 Limited Resources Constrain the Discovery Laboratory for All 132 Alternative Approaches 133 Envisioning Introductory Biology for the Science-Literate Citizen 134 Introductory Life Sciences: The Discovery-Based Classroom 135 Organizing the Discovery-Based Classroom: An Introductory Life Science Course for All Students 137 Unit One: Food and Energy 137 Unit Two: Climate Change and Other Human Impacts 140 Unit Three: Health and Disease 142 Summary of This Chapter 143 Combining Science Literacy Training with Science Career Training 144 Concluding Thoughts 145 Further Reading 146 Appendix A: Laboratory Instructions for Behavioral Experiments Using Caenorhabditis elegans 149 Learning Goals and Expectations 150 Part 1: Initial Behavioral Observations ofWild-Type and MutantWorms 150 Workshop 1A: Mechanosensory Behavior Experiments and Statistical Analysis 150 Workshop 1B: Chemosensory Behavioral Experiment and Statistical Analysis 153 Appendix B: Instructions for Microscopy Workshop 157 Assignment forWorkshop 2 158 Procedure for Preparing Wet Mounts of C. elegans 158 Index 161

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Book SynopsisMoonlighting Proteins: Novel Virulence Factors in Bacterial Infections is a complete examination of the ways in which proteins with more than one unique biological action are able to serve as virulence factors in different bacteria. The book explores the pathogenicity of bacterial moonlighting proteins, demonstrating the plasticity of protein evolution as it relates to protein function and to bacterial communication. Highlighting the latest discoveries in the field, it details the approximately 70 known bacterial proteins with a moonlighting function related to a virulence phenomenon. Chapters describe the ways in which each moonlighting protein can function as such for a variety of bacterial pathogens and how individual bacteria can use more than one moonlighting protein as a virulence factor. The cutting-edge research contained here offers important insights into many topics, from bacterial colonization, virulence, and antibiotic resistance, to protein structure andTable of ContentsList of Contributors xv Preface xix About the Editor xxiii Part I Overview of Protein Moonlighting 1 1 What is Protein Moonlighting and Why is it Important? 3 Constance J. Jeffery 1.1 What is Protein Moonlighting? 3 1.2 Why is Moonlighting Important? 5 1.2.1 Many More Proteins Might Moonlight 5 1.2.2 Protein Structure/Evolution 5 1.2.3 Roles in Health and Disease 8 1.2.3.1 Humans 8 1.2.3.2 Bacteria 10 1.3 Current questions 11 1.3.1 How Many More Proteins Moonlight? 11 1.3.2 How Can We Identify Additional Proteins That Moonlight and all the Moonlighting Functions of Proteins? 11 1.3.3 In Developing Novel Therapeutics, How Can We Target the Appropriate Function of a Moonlighting Protein and Not Affect Other Functions of the Protein? 12 1.3.4 How do Moonlighting Proteins get Targeted to More Than One Location in the Cell? 12 1.3.5 What Changes in Expression Patterns Have Occurred to Enable the Protein to be Available in a New Time and Place to Perform a New Function? 12 1.4 Conclusions 13 References 13 2 Exploring Structure–Function Relationships in Moonlighting Proteins 21 Sayoni Das, Ishita Khan, Daisuke Kihara, and Christine Orengo 2.1 Introduction 21 2.2 Multiple Facets of Protein Function 22 2.3 The Protein Structure–Function Paradigm 23 2.4 Computational Approaches for Identifying Moonlighting Proteins 25 2.5 Classification of Moonlighting Proteins 26 2.5.1 Proteins with Distinct Sites for Different Functions in the Same Domain 27 2.5.1.1 α‐Enolase, Streptococcus pneumonia 27 2.5.1.2 Albaflavenone monooxygenase, Streptomyces coelicolor A3(2) 29 2.5.1.3 MAPK1/ERK2, Homo sapiens 30 2.5.2 Proteins with Distinct Sites for Different Functions in More Than One Domain 30 2.5.2.1 Malate synthase, Mycobacterium tuberculosis 31 2.5.2.2 BirA, Escherichia coli 31 2.5.2.3 MRDI, Homo sapiens 33 2.5.3 Proteins Using the Same Residues for Different Functions 33 2.5.3.1 GAPDH E. coli 33 2.5.3.2 Leukotriene A4 hydrolase, Homo sapiens 33 2.5.4 Proteins Using Different Residues in the Same/Overlapping Site for Different Functions 34 2.5.4.1 Phosphoglucose isomerase, Oryctolagus cuniculus, Mus musculus, Homo sapiens 34 2.5.4.2 Aldolase, Plasmodium falciparum 36 2.5.5 Proteins with Different Structural Conformations for Different Functions 36 2.5.5.1 RfaH, E. coli 36 2.6 Conclusions 37 References 39 Part II Proteins Moonlighting in Prokarya 45 3 Overview of Protein Moonlighting in Bacterial Virulence 47 Brian Henderson 3.1 Introduction 47 3.2 The Meaning of Bacterial Virulence and Virulence Factors 47 3.3 Affinity as a Measure of the Biological Importance of Proteins 49 3.4 Moonlighting Bacterial Virulence Proteins 50 3.4.1 Bacterial Proteins Moonlighting as Adhesins 52 3.4.2 Bacterial Moonlighting Proteins That Act as Invasins 59 3.4.3 Bacterial Moonlighting Proteins Involved in Nutrient Acquisition 59 3.4.4 Bacterial Moonlighting Proteins Functioning as Evasins 60 3.4.5 Bacterial Moonlighting Proteins with Toxin‐like Actions 63 3.5 Bacterial Moonlighting Proteins Conclusively Shown to be Virulence Factors 64 3.6 Eukaryotic Moonlighting Proteins That Aid in Bacterial Virulence 66 3.7 Conclusions 67 References 68 4 Moonlighting Proteins as Cross‐Reactive Auto‐Antigens 81 Willem van Eden 4.1 Autoimmunity and Conservation 81 4.2 Immunogenicity of Conserved Proteins 82 4.3 HSP Co‐induction, Food, Microbiota, and T-cell Regulation 84 4.3.1 HSP as Targets for T‐Cell Regulation 85 4.4 The Contribution of Moonlighting Virulence Factors to Immunological Tolerance 87 References 88 Part III Proteins Moonlighting in Bacterial Virulence 93 Part 3.1 Chaperonins: A Family of Proteins with Widespread Virulence Properties 95 5 Chaperonin 60 Paralogs in Mycobacterium tuberculosis and Tubercle Formation 97 Brian Henderson 5.1 Introduction 97 5.2 Tuberculosis and the Tuberculoid Granuloma 97 5.3 Mycobacterial Factors Responsible for Granuloma Formation 98 5.4 Mycobacterium tuberculosis Chaperonin 60 Proteins, Macrophage Function, and Granuloma Formation 100 5.4.1 Mycobacterium tuberculosis has Two Chaperonin 60 Proteins 100 5.4.2 Moonlighting Actions of Mycobacterial Chaperonin 60 Proteins 101 5.4.3 Actions of Mycobacterial Chaperonin 60 Proteins Compatible with the Pathology of Tuberculosis 102 5.4.4 Identification of the Myeloid‐Cell‐Activating Site in M. tuberculosis Chaperonin 60.1 105 5.5 Conclusions 106 References 106 6 Legionella pneumophila Chaperonin 60, an Extra‐ and Intra‐Cellular Moonlighting Virulence‐Related Factor 111 Karla N. Valenzuela‐Valderas, Angela L. Riveroll, Peter Robertson, Lois E. Murray, and Rafael A. Garduno 6.1 Background 111 6.2 HtpB is an Essential Chaperonin with Protein‐folding Activity 112 6.3 Experimental Approaches to Elucidate the Functional Mechanisms of HtpB 112 6.3.1 The Intracellular Signaling Mechanism of HtpB in Yeast 113 6.3.2 Yeast Two‐Hybrid Screens 118 6.4 Secretion Mechanisms Potentially Responsible for Transporting HtpB to Extracytoplasmic Locations 120 6.4.1 Ability of GroEL and HtpB to Associate with Membranes 121 6.4.2 Ongoing Mechanistic Investigations on Chaperonins Secretion 122 6.5 Identifying Functionally Important Amino Acid Positions in HtpB 124 6.5.1 Site‐Directed Mutagenesis 125 6.6 Functional Evolution of HtpB 126 6.7 Concluding Remarks 127 References 129 Part 3.2 Peptidylprolyl Isomerases, Bacterial Virulence, and Targets for Therapy 135 7 An Overview of Peptidylprolyl Isomerases (PPIs) in Bacterial Virulence 137 Brian Henderson 7.1 Introduction 137 7.2 Proline and PPIs 137 7.3 Host PPIs and Responses to Bacteria and Bacterial Toxins 138 7.4 Bacterial PPIs as Virulence Factors 138 7.4.1 Proposed Mechanism of Virulence of Legionella pneumophila Mip 140 7.5 Other Bacterial PPIs Involved in Virulence 140 7.6 Conclusions 142 References 142 Part 3.3 Glyceraldehyde 3‐Phosphate Dehydrogenase (GAPDH): A Multifunctional Virulence Factor 147 8 GAPDH: A Multifunctional Moonlighting Protein in Eukaryotes and Prokaryotes 149 Michael A. Sirover 8.1 Introduction 149 8.2 GAPDH Membrane Function and Bacterial Virulence 150 8.2.1 Bacterial GAPDH Virulence 151 8.2.2 GAPDH and Iron Metabolism in Bacterial Virulence 153 8.3 Role of Nitric Oxide in GAPDH Bacterial Virulence 153 8.3.1 Nitric Oxide in Bacterial Virulence: Evasion of the Immune Response 154 8.3.2 Formation of GAPDHcys‐NO by Bacterial NO Synthases 155 8.3.3 GAPDHcys‐NO in Bacterial Virulence: Induction of Macrophage Apoptosis 155 8.3.4 GAPDHcys‐NO in Bacterial Virulence: Inhibition of Macrophage iNOS Activity 156 8.3.5 GAPDHcys‐NO in Bacterial Virulence: Transnitrosylation to Acceptor Proteins 157 8.4 GAPDH Control of Gene Expression and Bacterial Virulence 158 8.4.1 Bacterial GAPDH Virulence 159 8.5 Discussion 160 Acknowledgements 162 References 162 9 Streptococcus pyogenes GAPDH: A Cell‐Surface Major Virulence Determinant 169 Vijay Pancholi 9.1 Introduction and Early Discovery 169 9.2 GAS GAPDH: A Major Surface Protein with Multiple Binding Activities 170 9.3 AutoADP‐Ribosylation of SDH and Other Post‐Translational Modifications 172 9.4 Implications of the Binding of SDH to Mammalian Proteins for Cell Signaling and Virulence Mechanisms 173 9.5 Surface Export of SDH/GAPDH: A Cause or Effect? 178 9.6 SDH: The GAS Virulence Factor‐Regulating Virulence Factor 180 9.7 Concluding Remarks and Future Perspectives 183 References 183 10 Group B Streptococcus GAPDH and Immune Evasion 195 Paula Ferreira and Patrick Trieu‐Cuot 10.1 The Bacterium GBS 195 10.2 Neonates are More Susceptible to GBS Infection than Adults 195 10.3 IL‐10 Production Facilitates Bacterial Infection 196 10.4 GBS Glyceraldehyde‐3‐Phosphate Dehydrogenase Induces IL‐10 Production 197 10.5 Summary 199 References 200 11 Mycobacterium tuberculosis Cell‐Surface GAPDH Functions as a Transferrin Receptor 205 Vishant M. Boradia, Manoj Raje, and Chaaya Iyengar Raje 11.1 Introduction 205 11.2 Iron Acquisition by Bacteria 206 11.2.1 Heme Uptake 206 11.2.2 Siderophore‐Mediated Uptake 207 11.2.3 Transferrin Iron Acquisition 207 11.3 Iron Acquisition by Intracellular Pathogens 207 11.4 Iron Acquisition by M. tb 208 11.4.1 Heme Uptake 208 11.4.2 Siderophore‐Mediated Iron Acquisition 209 11.4.3 Transferrin‐Mediated Iron Acquisition 209 11.5 Glyceraldehyde‐3‐Phosphate Dehydrogenase (GAPDH) 210 11.6 Macrophage GAPDH and Iron Uptake 210 11.6.1 Regulation 210 11.6.2 Mechanism of Iron Uptake and Efflux 211 11.6.3 Role of Post‐Translational Modifications 211 11.7 Mycobacterial GAPDH and Iron Uptake 212 11.7.1 Regulation 212 11.7.2 Mechanism of Iron Uptake 215 11.7.3 Uptake by Intraphagosomal M. tb 216 11.8 Conclusions and Future Perspectives 216 Acknowledgements 218 References 219 12 GAPDH and Probiotic Organisms 225 Hideki Kinoshita 12.1 Introduction 225 12.2 Probiotics and Safety 225 12.3 Potential Risk of Probiotics 227 12.4 Plasminogen Binding and Enhancement of its Activation 228 12.5 GAPDH as an Adhesin 229 12.6 Binding Regions 232 12.7 Mechanisms of Secretion and Surface Localization 234 12.8 Other Functions 235 12.9 Conclusion 236 References 237 Part 3.4 Cell‐Surface Enolase: A Complex Virulence Factor 245 13 Impact of Streptococcal Enolase in Virulence 247 Marcus Fulde and Simone Bergmann 13.1 Introduction 247 13.2 General Characteristics 248 13.3 Expression and Surface Exposition of Enolase 249 13.4 Streptococcal Enolase as Adhesion Cofactor 252 13.4.1 Enolase as Plasminogen‐Binding Protein 252 13.4.1.1 Plasminogen‐Binding Sites of Streptococcal Enolases 253 13.4.2 Role of Enolase in Plasminogen‐Mediated Bacterial‐Host Cell Adhesion and Internalization 254 13.4.3 Enolase as Plasminogen‐Binding Protein in Non‐Pathogenic Bacteria 255 13.5 Enolase as Pro‐Fibrinolytic Cofactor 256 13.5.1 Degradation of Fibrin Thrombi and Components of the Extracellular Matrix 257 13.6 Streptococcal Enolase as Cariogenic Factor in Dental Disease 258 13.7 Conclusion 258 Acknowledgement 259 References 259 14 Streptococcal Enolase and Immune Evasion 269 Masaya Yamaguchi and Shigetada Kawabata 14.1 Introduction 269 14.2 Localization and Crystal Structure 271 14.3 Multiple Binding Activities of α‐Enolase 273 14.4 Involvement of α‐Enolase in Gene Expression Regulation 276 14.5 Role of Anti‐α‐Enolase Antibodies in Host Immunity 277 14.6 α‐Enolase as Potential Therapeutic Target 279 14.7 Questions Concerning α‐Enolase 281 References 281 15 Borrelia burgdorferi Enolase and Plasminogen Binding 291 Catherine A. Brissette 15.1 Introduction to Lyme Disease 291 15.2 Life Cycle 292 15.3 Borrelia Virulence Factors 292 15.4 Plasminogen Binding by Bacteria 293 15.5 B. burgdorferi and Plasminogen Binding 294 15.6 Enolase 295 15.7 B. burgdorferi Enolase and Plasminogen Binding 297 15.8 Concluding Thoughts 301 Acknowledgements 301 References 301 Part 3.5 Other Glycolytic Enzymes Acting as Virulence Factors 309 16 Triosephosphate Isomerase from Staphylococcus aureus and Plasminogen Receptors on Microbial Pathogens 311 Reiko Ikeda and Tomoe Ichikawa 16.1 Introduction 311 16.2 Identification of Triosephosphate Isomerase on S. aureus as a Molecule that Binds to the Pathogenic Yeast C. neoformans 312 16.2.1 Co‐Cultivation of S. aureus and C. neoformans 312 16.2.2 Identification of Adhesins on S. aureus and C. neoformans 312 16.2.3 Mechanisms of C. neoformans Cell Death 313 16.3 Binding of Triosephosphate Isomerase with Human Plasminogen 314 16.4 Plasminogen‐Binding Proteins on Trichosporon asahii 314 16.5 Plasminogen Receptors on C. neoformans 316 16.6 Conclusions 316 References 317 17 Moonlighting Functions of Bacterial Fructose 1,6‐Bisphosphate Aldolases 321 Neil J. Oldfield, Fariza Shams, Karl G. Wooldridge, and David P.J. Turner 17.1 Introduction 321 17.2 Fructose 1,6‐bisphosphate Aldolase in Metabolism 321 17.3 Surface Localization of Streptococcal Fructose 1,6‐bisphosphate Aldolases 322 17.4 Pneumococcal FBA Adhesin Binds Flamingo Cadherin Receptor 323 17.5 FBA is Required for Optimal Meningococcal Adhesion to Human Cells 324 17.6 Mycobacterium tuberculosis FBA Binds Human Plasminogen 325 17.7 Other Examples of FBAs with Possible Roles in Pathogenesis 326 17.8 Conclusions 327 References 327 Part 3.6 Other Metabolic Enzymes Functioning in Bacterial Virulence 333 18 Pyruvate Dehydrogenase Subunit B and Plasminogen Binding in Mycoplasma 335 Anne Gründel, Kathleen Friedrich, Melanie Pfeiffer, Enno Jacobs, and Roger Dumke 18.1 Introduction 335 18.2 Binding of Human Plasminogen to M. pneumoniae 337 18.3 Localization of PDHB on the Surface of M. pneumoniae Cells 340 18.4 Conclusions 343 References 344 Part 3.7 Miscellaneous Bacterial Moonlighting Virulence Proteins 349 19 Unexpected Interactions of Leptospiral Ef‐Tu and Enolase 351 Natália Salazar and Angela Barbosa 19.1 Leptospira –Host Interactions 351 19.2 Leptospira Ef‐Tu 352 19.3 Leptospira Enolase 353 19.4 Conclusions 354 References 354 20 Mycobacterium tuberculosis Antigen 85 Family Proteins: Mycolyl Transferases and Matrix‐Binding Adhesins 357 Christopher P. Ptak, Chih‐Jung Kuo, and Yung‐Fu Chang 20.1 Introduction 357 20.2 Identification of Antigen 85 358 20.3 Antigen 85 Family Proteins: Mycolyl Transferases 359 20.3.1 Role of the Mycomembrane 359 20.3.2 Ag85 Family of Homologous Proteins 359 20.3.3 Inhibition and Knockouts of Ag85 360 20.4 Antigen 85 Family Proteins: Matrix‐Binding Adhesins 361 20.4.1 Abundance and Location 361 20.4.2 Ag85 a Fibronectin‐Binding Adhesin 362 20.4.3 Ag85 an Elastin‐Binding Adhesin 363 20.4.4 Implication in Disease 364 20.5 Conclusion 365 Acknowledgement 365 References 365 Part 3.8 Bacterial Moonlighting Proteins that Function as Cytokine Binders/Receptors 371 21 Miscellaneous IL‐1β‐Binding Proteins of Aggregatibacter actinomycetemcomitans 373 Riikka Ihalin 21.1 Introduction 373 21.2 A. actinomycetemcomitans Biofilms Sequester IL‐1β 374 21.3 A. actinomycetemcomitans Cells Take in IL‐1β 375 21.3.1 Novel Outer Membrane Lipoprotein of A. actinomycetemcomitans Binds IL‐1β 375 21.3.2 IL‐1β Localizes to the Cytosolic Face of the Inner Membrane and in the Nucleoids of A. actinomycetemcomitans 377 21.3.3 Inner Membrane Protein ATP Synthase Subunit β Binds IL‐1β 377 21.3.4 DNA‐Binding Histone‐Like Protein HU Interacts with IL‐1β 378 21.4 The Potential Effects of IL‐1β on A. actinomycetemcomitans 379 21.4.1 Biofilm Amount Increases and Metabolic Activity Decreases 379 21.4.2 Potential Changes in Gene Expression 380 21.5 Conclusions 381 References 382 Part 3.9 Moonlighting Outside of the Box 387 22 Bacteriophage Moonlighting Proteins in the Control of Bacterial Pathogenicity 389 Janine Z. Bowring, Alberto Marina, José R. Penadés, and Nuria Quiles‐Puchalt 22.1 Introduction 389 22.2 Bacteriophage T4 I‐TevI Homing Endonuclease Functions as a Transcriptional Autorepressor 391 22.3 Capsid Psu Protein of Bacteriophage P4 Functions as a Rho Transcription Antiterminator 394 22.4 Bacteriophage Lytic Enzymes Moonlight as Structural Proteins 398 22.5 Moonlighting Bacteriophage Proteins De‐Repressing Phage‐Inducible Chromosomal Islands 398 22.6 dUTPase, a Metabolic Enzyme with a Moonlighting Signalling Role 401 22.7 Escherichia coli Thioredoxin Protein Moonlights with T7 DNA Polymerase for Enhanced T7 DNA Replication 404 22.8 Discussion 404 References 406 23 Viral Entry Glycoproteins and Viral Immune Evasion 413 Jonathan D. Cook and Jeffrey E. Lee 23.1 Introduction 413 23.2 Enveloped Viral Entry 414 23.3 Moonlighting Activities of Viral Entry Glycoproteins 415 23.3.1 Viral Entry Glycoproteins Moonlighting as Evasins 416 23.3.2 Evading the Complement System 417 23.3.3 Evading Antibody Surveillance 419 23.3.3.1 The Viral Glycan Shield 419 23.3.3.2 Shed Viral Glycoproteins: An Antibody Decoy 421 23.3.3.3 Antigenic Variations in Viral Glycoproteins 421 23.3.3.4 Shed Viral Glycoproteins and Immune Signal Modulation 423 23.3.4 Evading Host Restriction Factors 423 23.3.5 Modulation of Other Immune Pathways 424 23.4 Viral Entry Proteins Moonlighting as Saboteurs of Cellular Pathways 427 23.4.1 Sabotaging Signal Transduction Cascades 427 23.4.2 Host Surface Protein Sabotage 428 23.5 Conclusions 429 References 429 Index 439

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Book SynopsisA thought-provoking exploration of deleterious mutations in the human genome and their effects on human health and wellbeing Despite all of the elaborate mechanisms that a cell employs to handle its DNA with the utmost care, a newborn human carries about 100 new mutations, originated in their parents, about 10 of which are deleterious. A mutation replacing just one of the more than three billion nucleotides in the human genome may lead to synthesis of a dysfunctional protein, and this can be inconsistent with life or cause a tragic disease. Several percent of even young people suffer from diseases that are caused, exclusively or primarily, by pre]existing and new mutations in their genomes, including both a wide variety of genetically simple Mendelian diseases and diverse complex diseases such as birth anomalies, diabetes, and schizophrenia. Milder, but still substantial, negative effects of mutations are even more pervasive. As of now, we possess no means of reducingTable of ContentsPreface ix 1 Genotypes and Phenotypes 1 1.1 DNA is a Text 1 1.2 Genomes Small and Large 6 1.3 Genes and Intergenic Regions 7 1.4 Cells, Mitosis, and Meiosis 14 1.5 From Genotype to Phenotype 17 Further Reading 21 2 Mendelian Inheritance and Population Genetics 23 2.1 Inheritance is Discrete 23 2.2 Populations are Genetically Variable 27 2.3 Loci and Genes 33 2.4 Effects of Alleles on Phenotypes 37 2.5 Mendelian Traits and Diseases 43 Further Reading 46 3 Complex Traits and Their Inheritance 49 3.1 Complex Inheritance of Phenotypes 49 3.2 Properties of a Complex Trait 52 3.3 Complex Traits in Populations 55 3.4 Effects of Heredity and Environment on Complex Traits 60 3.5 Polymorphic Loci Behind Complex Variation 64 Further Reading 68 4 Unavoidable Mutation 71 4.1 Phenomenon of Mutation 71 4.2 Kinds of Mutations 73 4.3 Spontaneous Mutation 75 4.4 Evolution of Mutation Rates 77 4.5 Artificial Mutagenesis and Antimutagenesis 79 Further Reading 81 5 Struggle for Fidelity 83 5.1 Fidelity of DNA Replication 83 5.2 Cleaning Up After the Replisome 88 5.3 Dealing with DNA Damages 91 5.4 Harms of Broken Maintenance 96 5.5 Mechanisms of Mutation 100 Further Reading 104 6 Mutation Rates 107 6.1 Measuring Mutation Rates 107 6.2 Data on Mutation Rates 109 6.3 Guilty Older Men 112 6.4 Rates of Phenotypically Drastic Mutations 114 6.5 Mild Mutations and Mutational Pressures 118 Further Reading 121 7 Natural Selection 123 7.1 Vulnerable Adaptations and Their Evolutionary Origin 123 7.2 Two Basic Characteristics of Selection 127 7.3 Measuring Natural Selection 129 7.4 Selection at a Polymorphic Locus 132 7.5 Selection on a Quantitative Trait 135 Further Reading 138 8 Functioning DNA and Junk DNA 141 8.1 Selective Neutrality and Random Drift 141 8.2 Effective Population Size 144 8.3 Junk DNA Provides the Simplest Evidence for Evolution 144 8.4 Finding Functioning Genome Segments 145 8.5 The Genomic Rate of Deleterious Mutations 147 Further Reading 148 9 It Takes All the Running You Can Do 149 9.1 Middle Class Neighborhood for Drosophila 149 9.2 Selection Against Deleterious Alleles 153 9.3 Mutation–Selection Equilibrium 155 9.4 Inbreeding Depression 158 9.5 Dangerous Slightly Deleterious Alleles 160 Further Reading 162 10 Phenomenon of Imperfection 165 10.1 Phenotypic and Genotypic Imperfection 165 10.2 Five Evolutionary Causes of Imperfection 168 10.3 Weakly Perfect Human Genotypes and Phenotypes 171 10.4 Native, Novel, and Optimal Environments 173 10.5 Factors, Exacerbating Mutation Imperfection 175 Further Reading 176 11 Our Imperfect Fitness 177 11.1 Properties of an Allele 177 11.2 Human Derived Alleles 180 11.3 Average Imperfection of a Genotype 186 11.4 Variation Among Genotypes 190 11.5 Selection in Modern Human Populations 192 Further Reading 197 12 Our Imperfect Wellness 199 12.1 Qualitative Characteristics of Wellness 199 12.2 Quantitative Traits 206 12.3 Contributions of Heredity and Environment 208 12.4 Wellness‐impairing Alleles 211 12.5 Genetic Architecture of Wellness 215 Further Reading 217 13 Mutational Pressure on Our Species 219 13.1 Mutational Pressure on Diseases 219 13.2 Mutational Pressure on Quantitative Traits 225 13.3 Possible Increase of the Mutational Pressure 226 13.4 De Novo Mutations and Human Wellness 228 13.5 Optimistic and Pessimistic Scenarios 230 Further Reading 231 14 Ethical Issues 233 14.1 Lessons from History 233 14.2 Modern Practices 237 14.3 Humanist Ethics and the Main Concern 241 14.4 The Main Concern and Ethical Dilemmas 244 14.5 Role of Scientists 247 Further Reading 250 15 What to Do? 253 15.1 Conditionally Beneficial or Unconditionally Deleterious? 253 15.2 Mutationless Utopia: What Could It Be? 257 15.3 Mutationless Utopia: Is It Ever Going to Happen? 261 15.4 What Can I Do Without Germline Genotype Modification? 265 15.5 Prognosis 268 Further Reading 269 Index 271

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Book SynopsisAn authoritative overview of the ecological activities of microbes in the biosphere Environmental Microbiology and Microbial Ecologypresents a broad overview of microbial activity and microbes' interactions with their environments and communities. Adopting an integrative approach, this text covers both conventional ecological issues as well as cross-disciplinary investigations that combine facets of microbiology, ecology, environmental science and engineering, molecular biology, and biochemistry. Focusing primarily on single-cell forms of prokaryotes and cellular forms of algae, fungi, and protozoans this book enables readers to gain insight into the fundamental methodologies for the characterization of microorganisms in the biosphere. The authors draw from decades of experience to examine the environmental processes mediated by microorganisms and explore the interactions between microorganisms and higher life forms. Highly relevant to modern readers, this book examines topics incTable of ContentsPreface xv 1 Introduction to Microorganisms and Their Activities 1 1.1 Central Themes of Environmental Microbiology and Microbial Ecology 1 1.2 Are the Terms Prokaryotes or Eukaryotes Relevant? 1 1.2.1 Intracellular Membranes in Prokaryotes 2 1.2.2 Compartmentalized Heterotrophic Bacterial Cells 3 1.2.3 The Universal Tree of Life: Rooted or Unrooted 4 1.2.4 What About the Giant Viruses? 4 1.3 Major Approach to Study Microorganisms 5 1.3.1 Application of Genomics, Metagenomics, and Proteomics 6 1.3.2 Biochemical and Physiological Analysis 7 1.4 The Impact of Horizontal Gene Transfer Between Microorganisms 7 1.4.1 Genetic Islands 9 1.4.2 Risks from Genetically Modified Organisms 10 1.4.3 Microbial Viruses and Gene Transfer Agents 10 1.5 What Determines Which Microorganisms are Present? 12 1.5.1 Metabolism as a Basis of Selection 13 1.5.2 Is Persistence of Microorganisms Dependent Only on Spore Production? 14 1.6 Is the Size and Shape of a Prokaryotic Cell Important? 19 1.6.1 Nanobacteria 19 1.6.2 Ultramicroscopic Bacteria 21 1.6.3 Very Large Bacteria 21 1.6.4 Influence of Diffusion on Bacterial Cell Form 22 1.6.5 Features of a Specific Cell Form 22 1.6.5.1 Coccus Form 22 1.6.5.2 Rod Form 22 1.6.5.3 Curved Rod or Spirochete Form 23 1.6.5.4 Unusual Forms 23 1.7 Microbial Predation 23 1.7.1 Bacteria as Prey 23 1.7.2 Bacteria as Trackers and Predators 24 1.8 Summary 25 Discussion Questions 25 References 26 Further Reading 31 2 Microbes in the Biosphere: Examination, Cultivation, and Communities 33 2.1 Overview and Focus 33 2.2 Microscopy to Study Environmental Microbes 33 2.2.1 Light Supported Microscopy 34 2.2.2 Fluorescence Microscopy 35 2.2.3 Scanning Confocal Laser Microscopy 37 2.2.4 High Resolution by Electron Microscopy 37 2.3 Internal Structures in Prokaryotes 41 2.3.1 Gas Vacuoles 41 2.3.2 Sulfur Globules 41 2.3.3 Polymeric Carbon Reserves 42 2.3.4 Polyphosphate Granules 43 2.3.5 Metallic Nanoparticles 43 2.4 Strategies for Culturing Microorganisms 44 2.4.1 Overview 44 2.4.2 Approaches for Isolation of Microorganisms 45 2.4.3 Establishing Microbial Communities 45 2.4.4 The iChip and Growing Uncultured Bacteria 46 2.5 Molecular Detection 49 2.5.1 Characterization of Microorganisms Using Genomics and Metagenomics 49 2.5.2 Physiological Analysis Using Metatranscriptomics and Metaproteomics 53 2.5.3 Lipid Biomarker Profiles 54 2.6 Examining Bacteria that Do Not Grow as Pure Cultures in the Laboratory 56 2.6.1 Host‐dependent Microorganisms 56 2.6.1.1 Bacteria as Obligate Pathogens 56 2.6.1.2 Bacteria as Endosymbionts 57 2.6.1.3 The Nanoarchaeum–Ignicoccus Relationship 58 2.6.2 Molecular Analysis of Uncultivable Bacteria 58 2.7 Microbial Community Structures 59 2.7.1 Primary Production and Microbial Communities 59 2.7.2 Biofilms 62 2.7.3 Role of Quorum Sensing 64 2.8 Summary 67 Discussion Questions 68 References 68 Further Reading 75 3 Terrestrial Systems: Soil and Subsurface Environments 77 3.1 Overview and Focus 77 3.2 Soil: An Environment for Microorganisms 77 3.2.1 Soil Horizons 78 3.2.2 Soil Organic Matter (SOM) 78 3.3 Soil Microbiology 80 3.3.1 Soil Prokaryotes 80 3.3.2 Soil Fungi 82 3.3.3 Soil Crusts 83 3.3.4 Soil Invertebrates and Burrowing Animals 83 3.3.5 The Rhizosphere and Associated Bacteria 83 3.4 Understanding Soil Ecosystems 85 3.4.1 The Carbon : Nitrogen Ratio 85 3.4.2 The Fungi : Bacteria Ratio 85 3.4.3 SOM and Soil Food Webs 86 3.4.4 Influence of Agricultural Management on the Soil Microbe Community 89 3.4.5 Impact of Viruses on the Soil Microbiota 90 3.5 Subsurface Microbiology 90 3.5.1 Groundwater 90 3.5.2 Cave Water 92 3.5.3 Deep Subsurface Aquifers 92 3.5.3.1 Aquifer in a Coal‐bearing Basin 92 3.5.3.2 Deep Granitic Aquifer 93 3.5.3.3 Anaerobic, Alkaline Aquifer 94 3.5.3.4 Saline Hydrothermal Aquifer 94 3.6 Deep Subsurface Microbiology 95 3.6.1 Marine Sediment Microbiology 96 3.6.2 Deep Mines and Boreholes 97 3.6.3 Deep Subsea Floor 98 3.6.4 Deep Subsurface Storage Sites 98 3.6.4.1 Storage of Nuclear Fuel Waste 98 3.6.4.2 Underground Storage for H 2 and CH 4 100 3.6.4.3 Underground Storage for CO 2 101 3.6.4.4 Geothermal Energy Production 102 3.6.5 Endolithic Microorganisms 102 3.7 Life in Deep Subsurfaces 103 3.7.1 Adjusting to a Subsurface Diet 103 3.7.2 Energy Sources in the Deep Biosphere 103 3.7.3 The Benefit of Living Together 105 3.8 Geomicrobiology 106 3.8.1 Rock and Mineral Weathering 106 3.8.2 Mineral Transformations 107 3.8.3 Microbial Metal Binding 109 3.8.4 Microbiota of Subsurface Crystals 109 3.9 Summary 110 Discussion Questions 111 References 111 Further Reading 116 4 Aquatic Surface Environments: Freshwater, Marine, and Wastewater 117 4.1 Overview and Focus 117 4.2 Water as Relevant to Microbial Growth 117 4.2.1 Water Activity 118 4.3 Marine Environments and Associated Microbiomes 119 4.3.1 Marine Primary Productivity 120 4.3.2 Marine Heterotrophs 122 4.3.3 Bacterial Symbionts and Marine Hosts 123 4.3.4 Microbial EPSs, Marine Snow, and Marine Gel Particles 125 4.3.5 Brackish Water and Intertidal Zones 127 4.3.6 Coral Reefs 128 4.4 Freshwater Environments and Associated Microbiomes 131 4.4.1 Lakes and Rivers 132 4.4.2 Wetlands 137 4.4.3 The Snow and Glacier Ice Ecosystems 139 4.4.4 Microbiota of Cold and Hot Springs 140 4.4.5 Microbial Mats 142 4.5 Maintaining Populations in Low Nutrient Environments 144 4.6 Aquaculture Wastewater 148 4.7 Hormone Degradation in Fresh Water 149 4.8 Human Activities and Influence on Microbial Ecology 150 4.9 Drinking Water 151 4.10 Municipal Water Treatment 151 4.11 Wastewater Treatment Systems 152 4.11.1 Septic Tanks 152 4.11.2 Municipal Wastewater Treatment 152 4.11.2.1 Primary Treatment 153 4.11.2.2 Secondary Treatment 153 4.12 Alternative Approaches for Wastewater Treatment 154 4.13 Coliforms and Other Indicator Organisms 155 4.14 Viruses in Aquatic Environments: Diversity and Activity 156 4.15 Summary 158 Discussion Questions 159 References 159 Further Reading 166 5 Life in Extreme Environments 167 5.1 Overview 167 5.2 Sampling in Extreme Environments 168 5.3 Extreme Temperature Environments 173 5.3.1 Psychrophiles 174 5.3.2 Thermophiles 176 5.3.2.1 Alpine Environment – Yellowstone National Park 176 5.3.2.2 Hydrothermal Vent Communities 179 5.3.2.3 The Guaymas Basin 180 5.4 Xerophiles 180 5.5 Piezophiles 182 5.6 Acidophiles 183 5.7 Alkaliphiles 187 5.8 Halophiles and Chaophiles 189 5.9 Radioresistant Microorganisms 194 5.10 Membrane Adaptations to Extreme Conditions 195 5.10.1 Low Temperatures 195 5.10.2 High Temperatures 196 5.10.3 pH Extremes: Low and High 196 5.11 Astrobiology 197 5.12 Nutrient Limited Environments 198 5.13 Volcanic Surfaces 200 5.14 Summary 202 Discussion Questions 202 References 202 Further Reading 209 6 Mutualism: Microorganisms and Terrestrial Plants 211 6.1 Overview and Focus 211 6.2 Cyanobacteria and the Chloroplast Ancestor 211 6.3 Lichens: Cyanobacteria/Algae–Fungi Mutualism 217 6.3.1 Distribution and Organization 217 6.3.2 Natural Products of Lichens 219 6.4 Mutualisms with Cyanobacteria as Intracellular or Epiphytic Organisms 220 6.4.1 Bryophytes 220 6.4.2 Mosses 221 6.4.3 Azolla 221 6.4.4 Gunnera 222 6.4.5 Cycads 222 6.4.6 Geosiphon 222 6.4.7 Diatoms 224 6.5 Rhizobia–Legume Symbiosis 224 6.5.1 Bacterial Species Involved 224 6.5.2 Rhizospheric Rhizobia 225 6.5.3 The Root Nodulation Process 226 6.5.4 Nodules on Plant Stems 230 6.6 Frankia and the Non‐legume Nitrogen‐fixing Nodule 231 6.7 Mycorrhizae 233 6.7.1 Arbuscular Mycorrhizae (AM) 235 6.7.2 Ectomycorrhiza (EcM) 236 6.8 Patterns of Regulation for Plant–Microbe Mutualism 237 6.9 Bacterial‐Fungal Interactions 238 6.9.1 Direct Effects 238 6.9.2 Plant Growth‐promoting Bacteria 239 6.9.3 Systemic Induction of Plant Immunity 239 6.10 Endophytic Microorganisms 240 6.11 Microbiology of the Phyllosphere 241 6.12 Summary 242 Discussion Questions 243 References 243 Further Reading 247 7 Mutualism: Microorganisms and Animals 249 7.1 Overview and Focus 249 7.2 Building a Microbial Community – The Role of the Host 249 7.2.1 Microbiology and Innate Immunity 249 7.2.2 Microbiology and Adaptive Immunity 250 7.3 Host Models to Study Parasite Relationships 251 7.3.1 Germ‐free Animals 251 7.3.2 Caenorhabditis elegans 251 7.3.3 Drosophila melanogaster 252 7.3.4 Galleria mellonella 252 7.4 Digestive Tract Environment 252 7.4.1 Omnivores 253 7.4.2 Carnivores 254 7.4.3 Herbivores 255 7.4.3.1 Bacteria and Archaea 257 7.4.3.2 Anaerobic Protozoa 257 7.4.3.3 Anaerobic Fungi 258 7.4.3.4 Probiotics and Methane Mitigation Strategies 260 7.5 The Human Microbiome 260 7.5.1 Skin 260 7.5.2 Oral Microorganisms 261 7.5.3 Intestinal Microbiome 263 7.5.3.1 Establishment of Intestinal Flora 263 7.5.3.2 The Healthy Gut 264 7.5.3.3 Influence of the Intestine on Human Health 265 7.5.3.4 Obesity, Diabetes, and Health Issues 266 7.5.3.5 Probiotics 269 7.6 Gut Microbiota across the Animal World 269 7.6.1 Systems of Maternal Transmission 270 7.6.2 Microbiota of Ruminates and Hindgut Fermenters 270 7.6.3 Gut Microbiota of Bears 275 7.6.4 Microbiota of Birds 275 7.6.5 Intestinal Bacteria of Fish 278 7.7 Insect–Fungus Symbiosis 279 7.7.1 Scale Insects and Septobasidium 279 7.7.2 Attine Ant–Fungus Symbiosis 279 7.7.3 Woodwasp–Fungus Symbiosis 280 7.7.4 Ambrosia Beetles–Fungus 281 7.7.5 Termite–Fungus 281 7.8 Mutualisms Involving Insects and Bacteria 282 7.8.1 Aphids–Buchnera and Endosymbionts 282 7.8.2 Wolbachia–Insects 283 7.8.3 Mealybug–Bacteria 283 7.8.4 Termite Gut–Bacteria 284 7.9 Mutualisms Involving Invertebrates 285 7.9.1 Microbiome of Marine Worms 285 7.9.2 Squid (Euprymna)–Vibrio fischeri Symbiosis 286 7.9.3 Medicinal Leech–Aeromonas sp. and Rikenella‐like Bacteria 287 7.9.4 Nematode–Bacteria 288 7.10 Summary 288 Discussion Questions 289 References 290 Further Reading 295 8 Microbes Driving the Nutrient Cycles 297 8.1 Overview and Focus 297 8.2 Nutrient Cycles and What Drives Them 297 8.3 The Aerobic Environment 299 8.3.1 The “Great Oxidation Event” 299 8.3.2 Oxygen Cycle 300 8.3.3 Hydrogen Peroxide and ROS 303 8.4 Carbon – A Renewable Resource 304 8.4.1 Carbon Dioxide Fixation and Carbonate Reduction 305 8.4.2 Methanogenesis, Methanotrophy, and Methylotrophy 306 8.4.3 Mineralization of Carbon Compounds 308 8.4.4 Production and Utilization of CO 311 8.4.5 Production and Utilization of Hydrogen Cyanide 312 8.5 Nitrogen for Biosynthesis and Energy 312 8.5.1 Nitrification 314 8.5.2 Denitrification 314 8.5.3 Nitrate Reduction 315 8.5.4 Nitrite Reductase 316 8.5.5 Metabolism of NO and N 2 O 316 8.5.6 Production of NO by NOS 317 8.5.7 Respiratory Ammonification 317 8.5.8 Anammox Reaction 318 8.5.9 Assimilation of Nitrogen 318 8.5.10 Dinitrogen Fixation 318 8.6 Sulfur Cycling 319 8.6.1 Oxidation of Hydrogen Sulfide 320 8.6.2 Oxidation of Elemental Sulfur 321 8.6.3 Dissimilative S 0 Reduction 321 8.6.4 Dissimilative Sulfate Reduction 322 8.6.5 Assimilatory Sulfate Reduction 322 8.6.6 Production of H 2 S and Dimethyl Sulfide 322 8.6.6.1 Hydrogen Sulfide 322 8.6.6.2 Dimethyl Sulfide 323 8.7 Cycling of Trace Elements 324 8.7.1 Iron 324 8.7.2 Manganese 326 8.8 Phosphorus Cycling 328 8.9 Selenium Cycling 330 8.10 Cycling Toxic Elements 331 8.10.1 Mercury 331 8.10.2 Arsenic 332 8.11 Summary 335 Discussion Questions 335 References 336 Further Reading 340 9 Bioremediation Using Microorganisms 341 9.1 Overview and Focus 341 9.2 Microbial Bioremediation: Strategies and Applications 341 9.2.1 Biostimulation 343 9.2.2 Bioaugmentation 344 9.2.2.1 Indigenous Bacteria 344 9.2.2.2 Genetically Modified Organisms 344 9.2.3 Intrinsic Bioremediation 345 9.2.4 Microbial Consortium 345 9.2.5 Co‐metabolism 346 9.3 Organic Compounds and Xenobiotics Degraded 347 9.3.1 Pesticides 347 9.3.2 Chlorinated Organic Compounds 348 9.3.2.1 Chloroethylenes 349 9.3.2.2 Chloromethanes 350 9.3.2.3 Polychlorinated Biphenyl Compounds 351 9.3.3 Population Dynamics in Degradation of Hydrocarbons 352 9.3.3.1 Oil Spills 352 9.3.3.2 Fuel Hydrocarbons 353 9.3.3.3 Polyaromatic Hydrocarbons 355 9.3.3.4 Azo Dyes 357 9.3.4 Explosives 357 9.3.4.1 Trinitrotoluene 357 9.3.4.2 RDX and HMX 359 9.3.4.3 Perchlorate 359 9.3.5 Bioremediation and Detoxification of Metal(loid)s 359 9.3.5.1 Dissimilatory Metal(loid) Reduction 360 9.3.5.2 Methylation Reactions 361 9.4 Design of Systems for Bioremediation 362 9.4.1 In Situ vs Ex Situ 362 9.4.2 Bioreactors 363 9.4.3 Biofarming 363 9.4.4 Permeable Reactive Barriers 363 9.4.5 Groundwater and Lagoon Treatment 363 9.4.6 Bioventing 364 9.5 Summary 364 Discussion Questions 364 References 365 Further Reading 370 10 Biocorrosion and Geomicrobiology 371 10.1 Overview and Focus 371 10.2 Microbially Influenced Corrosion (MIC) of Ferrous Metals 371 10.2.1 Current Theories of Biocorrosion 371 10.2.1.1 Emic 373 10.2.1.2 Cmic 374 10.2.1.3 Iron Sulfide Crusts 374 10.2.1.4 Biofilms and Extracellular Matrix 374 10.2.2 Biocorrosion of Nonferrous Materials 375 10.2.3 Control of Biocorrosion 376 10.3 Bioalteration of Rocks, Monuments, and Other Surfaces 376 10.3.1 Biofilms on Rocks and Buildings 376 10.3.2 Biodegradation of Art Objects 377 10.3.2.1 Marble Statues in Italy 377 10.3.2.2 Paintings in the Lascaux Cave in France 377 10.3.2.3 Mogao Grottoes in China 378 10.3.2.4 Damage to Frescoes 378 10.3.3 Biotechnology for Restoration of Artworks and Historic Stones 378 10.4 Biodeterioration of Concrete 380 10.5 Mineral Interaction and Biomineralization 382 10.5.1 Iron Hydroxides 382 10.5.2 Magnetic Mineral Crystals 383 10.5.3 Manganese Oxides 383 10.5.4 Carbonates 384 10.5.5 Phosphates 384 10.5.6 Sulfates 385 10.5.7 Sulfides 385 10.5.8 Clays 385 10.5.9 Uranium Precipitate and Crystals 386 10.5.10 Gold Grains 386 10.6 Interactions with Transition and Rare Earth Elements 387 10.6.1 Transition Elements 387 10.6.2 Rare Earth Elements 388 10.7 Toxic Elements 389 10.7.1 Mercury 389 10.7.2 Chromium 389 10.7.3 Arsenic 390 10.7.4 Selenium 390 10.8 Metallic and Metalloid Nanoparticles of Microbial Origin 391 10.9 Summary 393 Discussion Questions 393 References 394 Further Reading 398 11 Microbial Communities and Metabolic Networks 399 11.1 Overview and Focus 399 11.2 Examples of Succession of Populations 399 11.2.1 Development of Coral Black Band Disease 400 11.2.2 Population Succession in Production of Dairy Products 400 11.2.3 Population Dynamics in Fermentation of Non‐dairy Foods 401 11.2.3.1 Kimchi 401 11.2.3.2 Coffee 401 11.2.3.3 Cocoa 402 11.2.3.4 Chinese Soy Sauce 402 11.2.4 Composting Plant Material 403 11.3 Impact of Climate Change on Microorganisms 403 11.3.1 Marine Environment 403 11.3.2 Soil Environment 404 11.4 Syntrophy and Co‐metabolism 406 11.5 Ecosystem Created by Hydraulic Fracturing in Shale 408 11.6 Extracellular Electron Transport 408 11.6.1 Membrane‐bound Proteins 409 11.6.2 Electron Shuttling 409 11.6.3 Nanowires 410 11.6.4 Extracellular Electron Movement in Biofilms 410 11.7 Cross‐talk: Interkingdom Signaling 410 11.7.1 Microbial Endocrinology 411 11.7.2 Cross‐signaling in Nonhuman Systems 412 11.8 Evolving Systems of Interest 412 11.8.1 Polyploidy in Bacteria 412 11.8.2 Impact of Viruses and CRISPR‐cas Systems 414 11.8.3 Impact of Outer Membrane Vesicles 416 11.8.4 Atmospheric Microbiology 420 11.8.5 Long‐distance Electron Transfer 423 11.9 Summary 424 Discussion Questions 425 References 425 Further Reading 433 Index 435

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Book SynopsisPublished with the New York Academy of Sciences A timely, broad-ranging exploration of the neurobiological basis and molecular mechanisms of migraines Migraines impact the lives of a significant portion of the world's population, afflicting sufferers with severe pain, nausea, and often visual impairment.Table of ContentsList of Contributors xv Foreword xxi Part I Anatomy and physiology 1 1 Functional anatomy of trigeminovascular pain 3Karl Messlinger and Mária Dux 1.1 Anatomy of the trigeminovascular system 3 1.2 Trigeminal ganglion 9 1.3 Trigeminal brainstem nuclear complex 12 2 Physiology of the meningeal sensory pathway 31Andrew Strassman and Agustin Melo-Carrillo 2.1 Anatomy of the trigeminovascular system 31 2.2 Nociceptive response properties of peripheral and central neurons in the meningeal sensory pathway 32 2.3 Activity of neurons in the meningeal sensory pathway under conditions associated with headache: CSD and nitroglycerin 36 2.4 Role of blood vessels in activation of the meningeal sensory pathway 38 2.5 Unique neuronal properties of the meningeal sensory pathway 39 2.6 Intracranial vs extracranial mechanisms of migraine: new findings 40 References 41 3 Meningeal afferent ion channels and their role in migraine 49Gregory Dussor PhD 3.1 Meningeal afferents and migraine pain 49 3.2 Transient receptor potential (TRP) channels and headache 49 3.3 Acid-sensing ion channels 54 3.4 Glutamate-gated channels 55 3.5 ATP-gated channels 55 3.6 K+ channels 56 3.7 Other ion channels that may contribute to dural afferent signaling 57 3.8 Conclusions 57 3.9 Acknowledgements 58 References 58 4 Functional architecture of central pain pathways: focus on the trigeminovascular system 69Rodrigo Noseda and Luis Villanueva 4.1 Introduction 69 4.2 Ascending trigeminal nociceptive pathways 69 4.3 Trigeminovascular pain is subject to descending control 77 4.4 Conclusions 82 References 83 Part II Special features of migraine pain 91 5 Visceral pain 93Michael S. Gold and G.F. Gebhart 5.1 Organization of innervation 93 5.2 Common features of visceral pain and headache 96 5.3 Summary and conclusions 101 5.4 Acknowledgement 101 References 102 6 Meningeal neurogenic inflammation and dural mast cells in migraine pain 107Dan Levy PhD 6.1 Introduction 107 6.2 The neurogenic inflammation hypothesis of migraine 108 6.3 Meningeal neurogenic plasma protein extravasation and migraine 108 6.4 Meningeal neurogenic vasodilatation and migraine 110 6.5 Neurogenic mast cell activation in migraine 111 6.6 Endogenous events that could promote meningeal NI in migraine 113 6.7 Anti-migraine drugs and meningeal NI 113 6.8 Is meningeal NI a pro-nociceptive event in migraine? 114 6.9 Conclusions 115 References 116 7 Sensitization and photophobia in migraine 125Aaron Schain and Rami Burstein 7.1 Introduction 125 7.2 Experimental activation of trigeminovascular pathways 125 7.3 Peripheral sensitization 127 7.4 Central sensitization: medullary dorsal horn 127 7.5 Central sensitization: thalamus 129 7.6 Temporal aspects of sensitization and their implications to triptan therapy 129 7.7 Modulation of central sensitization 131 7.8 Neural substrate of migraine-type photophobia 133 References 135 8 Central circuits promoting chronification of migraine 139Christopher W. Atcherley, Kelsey Nation, Milena De Felice, Jennifer Y. Xie, Michael H. Ossipov, David W. Dodick and Frank Porreca 8.1 Introduction 139 8.2 Pharmacotherapy of migraine 140 8.3 Medication overuse headache (MOH) and migraine chronification 141 8.4 Central circuits modulating pain 143 8.5 Evaluation of descending modulation: diffuse noxious inhibitory controls and conditioned pain modulation 145 8.6 Conclusions 148 References 149 9 Triptans to calcitonin gene-related peptide modulators – small molecules to antibodies – the evolution of a new migraine drug class 157Richard J Hargreaves 9.1 Introduction 157 9.2 Trigeminovascular system – migraine physiology and pharmacology 157 9.3 Small molecule CGRP receptor antagonists 159 9.4 Current status of small molecule CGRP receptor antagonist programs 161 9.5 Unraveling the site of action of small molecule CGRP receptor antagonists using clinical pharmacology and brain imaging 162 9.6 Biologic approaches to CGRP modulation 163 9.7 Summary and conclusion 167 References 168 10 Lessons learned from CGRP mutant mice 175Levi P. Sowers, Annie E. Tye and Andrew F. Russo 10.1 Introduction 175 10.2 Modeling migraine 175 10.3 Calcitonin gene-related peptide (CGRP) in migraine 176 10.4 What has CGRP manipulation in mice taught us about migraine? 177 10.5 Conclusions 183 References 183 Part III Clinical characteristics of migraine 189 11 The clinical characteristics of migraine 191F. Michael Cutrer MD, Ryan Smith MD and David W. Dodick MD 11.1 Overview of migraine 191 11.2 Migraine prodrome 191 11.3 The migraine headache is the centerpiece of the syndrome 192 11.4 Migraine aura 194 11.5 Proposed aura types 197 11.6 Postdrome 198 11.7 Status migrainosus 199 Summary 199 References 199 12 The premonitory phase of migraine 201Michele Viana and Peter J. Goadsby 12.1 What is the premonitory phase? Towards a definition 201 12.2 How common are premonitory symptoms? 202 12.3 Do premonitory symptoms reliably predict a migraine attack? 202 12.4 Premonitory symptoms in individuals 203 12.5 Intra-patient variability of the premonitory phase 203 12.6 Difference between patients with and without premonitory symptoms 204 12.7 Premonitory symptoms in children 204 12.8 Premonitory symptoms and migraine triggers 204 12.9 Premonitory symptoms and pathophysiological studies 205 12.10 Treatment during the premonitory phase 206 12.11 Conclusion 206 References 207 Part IV Migraine genetics and CSD 209 13 The genetic borderland of migraine and epilepsy 211Isamu Aiba and Jeffrey Noebels 13.1 Introduction 211 13.2 Gene-linked comorbidity 211 13.3 The challenge of dissecting seizure and aura excitability defects 212 13.4 Clinical overlap of migraine with aura and epilepsy phenotypes 214 13.5 Acquired and genetic etiologies of migraine with aura and epilepsies 216 13.6 Migraine aura is linked to specific genes with locus and allelic heterogeneity 218 13.7 Correspondence of regional brain susceptibility for migraine in genetic epilepsy syndromes 219 13.8 Are SD thresholds progressive? 220 13.9 Spreading depolarization in cardiorespiratory brainstem regions, a candidate mechanism of SUDEP 221 13.10 Brainstem SD is a “second hit” leading to SUDEP 222 13.11 Tau ablation prevents seizures, SUDEP and brainstem SD threshold in models of SUDEP 223 13.12 Conclusion 223 13.13 Acknowledgements 223 References 223 14 Genetics of monogenic and complex migraine 233Else A. Tolner, Else Eising, Gisela M. Terwindt, Michel D. Ferrari and Arn M.J.M. van den Maagdenberg 14.1 Migraine is a genetic disease 233 14.2 How to identify genes for migraine? 234 14.3 Gene identification in monogenic Familial Hemiplegic Migraine 234 14.4 Functional studies of gene mutations in monogenic familial hemiplegic migraine 236 14.5 Genetic studies in monogenic disorders in which migraine is a prominent part of the clinical phenotype 239 14.6 Genome-wide association studies in common polygenic migraine 240 14.7 Future directions in genetic migraine research 241 References 243 15 Lessons from familial hemiplegic migraine and cortical spreading depression 251Daniela Pietrobon 15.1 Introduction 251 15.2 FHM genes and functional consequences of FHM mutations 252 15.3 Insights into the mechanisms underlying susceptibility to cortical spreading depression and initiation of migraine attacks from the functional analysis of FHM mouse models 255 15.4 Acknowledgements 260 References 260 16 From cortical spreading depression to trigeminovascular activation in migraine 267Turgay Dalkara and Michael A. Moskowitz 16.1 CSD causes the visual aura 267 16.2 SD may underlie transient neurological dysfunctions preceding attacks 269 16.3 Does SD cause headache? 270 16.4 Human data supporting the parenchymal inflammatory signaling 274 16.5 Meningeal neurogenic inflammation amplifies the parenchymal signal 275 16.6 Understanding human CSD and migraine without aura 276 16.7 Potential of CSD models to understand migraine and drug development 278 References 278 Part V Modeling and imaging in migraine 285 17 Mathematical modeling of human cortical spreading depression 287Markus A. Dahlem 17.1 Introduction 287 17.2 Microscopic models: cellular and cytoarchitectonic detail 288 17.3 Computational models 291 17.4 Macroscopic models: large scale spatiotemporal phenomenology 292 References 301 18 Tools for high-resolution in vivo imaging of cellular and molecular mechanisms in cortical spreading depression and spreading depolarization 307K;;v;;lc;;m K;;l;;ç, Hana Uhlirova, Peifang Tian, Payam A. Saisan, Mohammad Abbas Yaseen, Jonghwan Lee, Sergei A. Vinogradov, David A. Boas, Sava Sakadžic and Anna Devor ´ 18.1 Introduction 307 18.2 Large-scale imaging of vascular dynamics with microscopic resolution 308 18.3 Combining measurements of single-vessel diameter with imaging and quantification of intracellular Ca2+ in neurons and astrocytes 309 18.4 NADH autofluorescence: an endogenous marker of energy metabolism 311 18.5 Direct imaging of molecular O2 in blood and tissue 312 18.6 Employing optogenetics to study inter-cellular communication 314 18.7 Conclusions and outlook 314 References 315 19 Animal models of migraine aura 321Shih-Pin Chen, Jeremy Theriot, Cenk Ayata and KC Brennan 19.1 Introduction: spreading depression and migraine 321 19.2 In vivo and in vitro models of SD susceptibility 322 19.3 Experimental preparations 324 19.4 Methods to trigger SD 327 19.5 Methods to detect CSD 329 19.6 SD susceptibility attributes 331 19.7 Recommended quality measures for experimental models of migraine aura 333 19.8 Future directions 334 References 335 20 Human models of migraine 347Jakob Møller Hansen MD, PhD and Messoud Ashina MD, PhD, DMSc 20.1 Introduction 347 20.2 The first steps: GTN and the NO-hypothesis 347 20.3 Calcitonin gene-related peptide (CGRP) 351 20.4 Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) 353 20.5 Can we gain from the use of experimental models to study functional consequences of migraine mutations? 354 20.6 Conclusion 355 References 355 21 Imaging pain and headache 363Duncan J. Hodkinson, Sophie L. Wilcox and David Borsook 21.1 Introduction 363 21.2 Functional brain changes in migraine 363 21.3 Structural brain changes in migraine 367 21.4 Insights from orofacial pain 370 21.5 Conclusions 371 References 372 Index 377

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Book SynopsisThrough eight successful editions, and over nearly 40 years, Biogeography: An Ecological and Evolutionary Approach has provided a thorough and comprehensive exploration of the varied scientific disciplines and research that are essential to understanding the subject. The text has been praised for its solid background in historical biogeography and basic biology, that is enhanced and illuminated by discussions of current research. This new edition incorporates the exciting changes of the recent years, and presents a thoughtful exploration of the research and controversies that have transformed our understanding of the biogeography of the world. It also clearly identifies the three quite different arenas of biogeographical research: continental biogeography, island biogeography and marine biogeography. It is the only current textbook with full coverage of marine biogeography. It reveals how the patterns of life that we see today have been created by the twoTable of ContentsPreface xi Acknowledgements xiii 1 The History of Biogeography 1 Lessons from the Past 1 Ecological versus Historical Biogeography, and Plants versus Animals 3 Biogeography and Creation 4 The Distribution of Life Today 5 Evolution – a Flawed and Dangerous Idea! 7 Enter Darwin – and Wallace 8 World Maps: Biogeographical Regions of Plants and Animals 10 Getting around the World 12 The Origins of Modern Historical Biogeography 16 The Development of Ecological Biogeography 19 Living Together 20 Marine Biogeography 23 Island Biogeography 24 Biogeography Today 26 SECTION I: The Challenge of Existing 31 2 Patterns of Distribution: Finding a Home 33 Limits of Distribution 37 The Niche 38 Overcoming the Barriers 39 Climatic Limits: The Palms 41 A Successful Family: The Daisies (Asteraceae) 42 Patterns among Plovers 46 Magnolias: Evolutionary Relicts 49 The Strange Case of the Testate Amoeba 50 Climatic Relicts 52 Topographical Limits and Endemism 59 Physical Limits 60 Species Interaction: A Case of the Blues 66 Competition 69 Reducing Competition 71 Predators and Prey, Parasites and Hosts 73 Migration 76 Invasion 79 3 Communities and Ecosystems: Living Together 89 The Community 89 The Ecosystem 92 Ecosystems and Species Diversity 95 Biotic Assemblages on a Global Scale 98 Mountain Biomes 103 Global Patterns of Climate 106 Climate Diagrams 109 Modelling Biomes and Climate 112 4 Patterns of Biodiversity 117 How Many Species are There? 118 Latitudinal Gradients of Diversity 123 Is Evolution Faster in the Tropics? 131 The Legacy of Glaciation 132 Latitude and Species Ranges 133 Diversity and Altitude 134 Biodiversity Hotspots 136 Diversity in Space and Time 139 Intermediate Disturbance Hypothesis 141 Dynamic Biodiversity and Neutral Theory 142 SECTION II: THE ENGINES OF THE PLANET 147 5 Plate Tectonics 149 The Evidence for Plate Tectonics 149 Changing Patterns of Continents 154 How Plate Tectonics affects the Living World, Part I: Events on Land 154 How Plate Tectonics affects the Living World, Part II: Events in the Oceans 156 Islands and Plate Tectonics 162 Terranes 164 6 Evolution, the Source of Novelty 169 The Mechanism of Evolution: The Genetic System 172 From Populations to Species 173 Sympatry versus Allopatry 176 Defining the Species 179 A Case Study: Darwin’s Finches 180 Controversies and Evolution 183 Charting the Course of Evolution 188 SECTION III: ISLAND BIOGEOGRAPHY 193 7 Life, Death and Evolution on Islands 195 Types of Island 196 Getting There: The Challenges of Arriving 196 Dying There: Problems of Survival 197 Adapting and Evolving 199 The Hawaiian Islands 201 Integrating the Data: The Theory of Island Biogeography 208 Modifying the Theory 212 The General Dynamic Model for Oceanic Island Biogeography 214 Nestedness 216 Living Together: Incidence and Assembly Rules 216 Building an Ecosystem: The History of Rakata 218 SECTION IV: PATTERNS OF LIFE 229 8 From Evolution to Patterns of Life 231 Dispersal, Vicariance and Endemism 231 Methods of Analysis 232 Event]Based Biogeography 236 Reticulate Patterns 239 The Molecular Approach to Historical Biogeography 245 Molecules and the More Distant Past 250 9 Patterns in the Oceans 255 Zones in the Ocean and on the Seafloor 257 Basic Biogeography of the Seas 260 The Open]Sea Environment 261 The Ocean Floor 268 The Shallow]Sea Environment 273 10 Patterns in the Past 291 Early Land Life on the Moving Continents 292 One World – for a While 295 Biogeography of the Earliest Mammals 298 Early History of the Flowering Plants 303 Reconstructing Early Biomes 305 11 Setting the Scene for Today 315 The Biogeographical Regions Today 315 The Basis of Mammal Biogeography 317 Patterns of Distribution Today, I: The Mammals 319 Patterns of Distribution Today, II: The Flowering Plants 322 History of Today’s Biogeographical Regions 323 The Old World Tropics: Africa, India and South]East Asia 324 Australia 331 New Caledonia 334 New Zealand 335 The West Indies 336 South America 341 The Northern Hemisphere: Holarctic Mammals and Boreal Plants 346 12 Ice and Change 353 Climatic Wiggles 354 Interglacials and Interstadials 356 Biological Changes in the Pleistocene 358 The Last Glacial 361 Causes of Glaciation 370 The Current Interglacial: A False Start 375 Forests on the Move 377 The Dry Lands 381 Changing Sea Levels 383 A Time of Warmth 384 Climatic Cooling 386 Recorded History 388 Atmosphere and Oceans: Short]Term Climate Change 388 The Future 390 SECTION V: PEOPLE AND PROBLEMS 397 13 The Human Intrusion 399 The Emergence of Humans 399 Modern Humans and the Megafaunal Extinctions 406 Plant Domestication and Agriculture 409 Animal Domestication 414 Diversification of Homo sapiens 415 The Biogeography of Human Parasitic Diseases 417 Environmental Impact of Early Human Cultures 420 14 Conservation Biogeography 425 Welcome to the Anthropocene 425 Less, and Less Interesting 429 What is behind the Biodiversity Crisis? 430 Crisis Management: Responding to Biodiversity Loss 435 The Birth of Conservation Biogeography 437 The Scope of Conservation Biogeography 438 Conservation Biogeography in Action 443 The Future is Digital 446 Conclusions 449 Glossary 455 Index 469 Colour plates between pages 146 and 147

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Book SynopsisThrough eight successful editions, and over nearly 40 years, Biogeography: An Ecological and Evolutionary Approach has provided a thorough and comprehensive exploration of the varied scientific disciplines and research that are essential to understanding the subject.Table of ContentsPreface xi Acknowledgements xiii 1 The History of Biogeography 1 Lessons from the Past 1 Ecological versus Historical Biogeography, and Plants versus Animals 3 Biogeography and Creation 4 The Distribution of Life Today 5 Evolution – a Flawed and Dangerous Idea! 7 Enter Darwin – and Wallace 8 World Maps: Biogeographical Regions of Plants and Animals 10 Getting around the World 12 The Origins of Modern Historical Biogeography 16 The Development of Ecological Biogeography 19 Living Together 20 Marine Biogeography 23 Island Biogeography 24 Biogeography Today 26 SECTION I: THE CHALLENGE OF EXISTING 31 2 Patterns of Distribution: Finding a Home 33 Limits of Distribution 37 The Niche 38 Overcoming the Barriers 39 Climatic Limits: The Palms 41 A Successful Family: The Daisies (Asteraceae) 42 Patterns among Plovers 46 Magnolias: Evolutionary Relicts 49 The Strange Case of the Testate Amoeba 50 Climatic Relicts 52 Topographical Limits and Endemism 59 Physical Limits 60 Species Interaction: A Case of the Blues 66 Competition 69 Reducing Competition 71 Predators and Prey, Parasites and Hosts 73 Migration 76 Invasion 79 3 Communities and Ecosystems: Living Together 89 The Community 89 The Ecosystem 92 Ecosystems and Species Diversity 95 Biotic Assemblages on a Global Scale 98 Mountain Biomes 103 Global Patterns of Climate 106 Climate Diagrams 109 Modelling Biomes and Climate 112 4 Patterns of Biodiversity 117 How Many Species are There? 118 Latitudinal Gradients of Diversity 123 Is Evolution Faster in the Tropics? 131 The Legacy of Glaciation 132 Latitude and Species Ranges 133 Diversity and Altitude 134 Biodiversity Hotspots 136 Diversity in Space and Time 139 Intermediate Disturbance Hypothesis 141 Dynamic Biodiversity and Neutral Theory 142 SECTION II: THE ENGINES OF THE PLANET 147 5 Plate Tectonics 149 The Evidence for Plate Tectonics 149 Changing Patterns of Continents 154 How Plate Tectonics affects the Living World, Part I: Events on Land 154 How Plate Tectonics affects the Living World, Part II: Events in the Oceans 156 Islands and Plate Tectonics 162 Terranes 164 6 Evolution, the Source of Novelty 169 The Mechanism of Evolution: The Genetic System 172 From Populations to Species 173 Sympatry versus Allopatry 176 Defining the Species 179 A Case Study: Darwin’s Finches 180 Controversies and Evolution 183 Charting the Course of Evolution 188 SECTION III: ISLAND BIOGEOGRAPHY 193 7 Life, Death and Evolution on Islands 195 Types of Island 196 Getting There: The Challenges of Arriving 196 Dying There: Problems of Survival 197 Adapting and Evolving 199 The Hawaiian Islands 201 Integrating the Data: The Theory of Island Biogeography 208 Modifying the Theory 212 The General Dynamic Model for Oceanic Island Biogeography 214 Nestedness 216 Living Together: Incidence and Assembly Rules 216 Building an Ecosystem: The History of Rakata 218 SECTION IV: PATTERNS OF LIFE 229 8 From Evolution to Patterns of Life 231 Dispersal, Vicariance and Endemism 231 Methods of Analysis 232 Event‐Based Biogeography 236 Reticulate Patterns 239 The Molecular Approach to Historical Biogeography 245 Molecules and the More Distant Past 250 9 Patterns in the Oceans 255 Zones in the Ocean and on the Seafloor 257 Basic Biogeography of the Seas 260 The Open‐Sea Environment 261 The Ocean Floor 268 The Shallow‐Sea Environment 273 10 Patterns in the Past 291 Early Land Life on the Moving Continents 292 One World – for a While 295 Biogeography of the Earliest Mammals 298 Early History of the Flowering Plants 303 Reconstructing Early Biomes 305 11 Setting the Scene for Today 315 The Biogeographical Regions Today 315 The Basis of Mammal Biogeography 317 Patterns of Distribution Today, I: The Mammals 319 Patterns of Distribution Today, II: The Flowering Plants 322 History of Today’s Biogeographical Regions 323 The Old World Tropics: Africa, India and South‐East Asia 324 Australia 331 New Caledonia 334 New Zealand 335 The West Indies 336 South America 341 The Northern Hemisphere: Holarctic Mammals and Boreal Plants 346 12 Ice and Change 353 Climatic Wiggles 354 Interglacials and Interstadials 356 Biological Changes in the Pleistocene 358 The Last Glacial 361 Causes of Glaciation 370 The Current Interglacial: A False Start 375 Forests on the Move 377 The Dry Lands 381 Changing Sea Levels 383 A Time of Warmth 384 Climatic Cooling 386 Recorded History 388 Atmosphere and Oceans: Short‐Term Climate Change 388 The Future 390 SECTION V: PEOPLE AND PROBLEMS 397 13 The Human Intrusion 399 The Emergence of Humans 399 Modern Humans and the Megafaunal Extinctions 406 Plant Domestication and Agriculture 409 Animal Domestication 414 Diversification of Homo sapiens 415 The Biogeography of Human Parasitic Diseases 417 Environmental Impact of Early Human Cultures 420 14 Conservation Biogeography 425 Welcome to the Anthropocene 425 Less, and Less Interesting 429 What is behind the Biodiversity Crisis? 430 Crisis Management: Responding to Biodiversity Loss 435 The Birth of Conservation Biogeography 437 The Scope of Conservation Biogeography 438 Conservation Biogeography in Action 443 The Future is Digital 446 Conclusions 449 Glossary 455 Index 469 Colour plates between pages 146 and 147

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