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| Foreword | |
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| Preface | |
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| Acknowledgments | |
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| Genome Sequences | |
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| What's Wrong with My Child? | |
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| First Patients | |
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| Clinical Presentation | |
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| Family Pedigree | |
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| Karyotyping and Linkage Analysis | |
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| DNA Sequence Analysis | |
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| Summary 1.1 | |
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| What Is an E-Value? | |
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| The Next Steps in Understanding the Disease | |
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| The Need for an Animal Model System | |
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| What Was the Other Protein that Gave Lots of BLASTp Hits? | |
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| Does Utrophin Play a Role in Muscular Dystrophy, Too? | |
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| What Does Dystrophin Do? | |
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| What's Special about This Graph? | |
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| Why Do DMD Patients' Muscles Deteriorate after the First Three Years? | |
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| Is It Possible to Have DMD and Be Wild-Type for Dystrophin? | |
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| How Can They Have Muscular Dystrophy if Their Dystrophin Genes Are Normal? | |
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| What Do You Mean by Highly Unlikely? | |
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| Where Is the Muscular Dystrophy Field Now? | |
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| Sixth International Conference on Molecular Causes of Muscular Dystrophies | |
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| The Meeting Begins | |
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| Structural Weaknesses | |
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| Nonfunctional Mutations | |
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| New Paradigms: Nonstructural Causes for Muscular Dystrophies | |
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| Final Presentation | |
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| Is cGMP Production Elevated? | |
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| Summary 1.2 | |
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| Chapter 1 Conclusions | |
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| References | |
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| Genome Sequence Acquisition | |
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| How Are Genomes Sequenced? | |
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| What Is Genomics? | |
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| How Are Whole Genomes Sequenced? | |
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| How Are Organisms Picked for Genome Sequencing? | |
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| What Can You Learn from a Dot Plot? | |
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| How Do You Find Motifs? | |
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| Can We Predict Protein Functions from DNA Sequence? | |
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| What Are "Positives" and What Do They Have to Do with E-values? | |
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| What Shapes Are the Proteins? | |
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| Does Structure Reveal Function? | |
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| Why Do the Databases Contain So Many Partial Sequences? | |
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| Which Sequencing Method Worked Better? | |
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| Annotated Genomes Online | |
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| How Many Proteins Can One Gene Make? | |
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| Can the Genome Alter Gene Expression Without Changing the DNA Sequence? | |
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| What Is the Fifth Base in DNA? Methyl-Cytosine | |
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| Imprinting, Methylation, and Cancer | |
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| Summary 2.1 | |
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| What Have We Learned from Unicellular Genomes? | |
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| Why Do I Get So Many Pimples? | |
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| Which Genes Cause Pimples? | |
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| Are All Bacteria Living in Us Bad for Us? | |
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| Can Microbial Genomes Become Dependent upon Human Genes? | |
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| What Is the Minimum Number of Genes Possible? | |
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| Are All Viral Genomes Smaller than All Bacterial Genomes? | |
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| Is Mimivirus Alive? | |
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| Do Genomes Reflect an Organism's Ecological Niche? | |
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| Can You Estimate the Number of Inversions in a Dot Plot? | |
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| Why Is MED4's Genome So Small? | |
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| How Many Genome Changes Are Required Before a New Species Is Created? | |
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| What Kind of Organism Causes Malaria? | |
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| What Sort of Genome Does Plasmodium Possess? | |
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| Is the Predicted Proteome Equally Bizarre? | |
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| Is There a Model Eukaryote Genome? | |
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| What Did the Investigators Predict for the Future of Genomics? | |
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| Epilog for the Yeast Genome | |
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| Summary 2.2 | |
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| What Have We Learned from Metazoan Genomes? | |
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| Are Animal Genomes Harder to Finish? | |
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| What Are Polythene Chromosomes? | |
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| What Makes a Fly Different from Other Eukaryotes? | |
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| Is the Fly Still a Good Model Organism? | |
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| Fly Genome Epilog | |
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| Do We Need Two Plant Genome Sequences? | |
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| Plants Seem Simpler than Animals, but Are Their Genomes? | |
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| Can We Draw Any Conclusions from Draft Sequences? | |
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| What Lessons Have We Learned? | |
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| Rice Epilog | |
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| What Can We Possibly Learn from a Puffer Fish Genome? | |
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| Did the Genome Reveal Any Surprises? | |
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| Are There More Big Lessons from Tetraodon? | |
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| What Makes Humans Different? | |
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| How Do You Fit a Line to Data? | |
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| Whose DNA Did We Sequence? | |
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| Can We Describe a Typical Human Gene? | |
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| Human Genome Epilog | |
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| What Is the Next Goal in Human Genomics? | |
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| Summary 2.3 | |
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| Chapter 2 Conclusions | |
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| References | |
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| Comparative Genomics in Evolution and Medicine | |
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| Comparative Genomics | |
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| How Can E. coli Be Lethal and in Our Intestines at the Same Time? | |
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| How Can You Tell if Base Compositions Are Different? | |
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| Two Hundred Genomes: What Can Comparative Genomics Tell Us about Prokaryotes? | |
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| Do All Prokaryotes Have One Circular Chromosome? | |
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| Are the Genomes Still Changing? | |
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| How Many Genomes Are There? | |
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| What Can We Learn by Comparing Many Whole Genomes? | |
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| What Can We See at the Chromosomal Perspective? | |
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| Summary 3.1 | |
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| Evolution of Genomes | |
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| What Organism Is the Root of the Tree of Life? | |
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| What Are the Origins of our Nuclear Genes? | |
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| Are the Hit Numbers Significantly Different | |
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| Is There Evidence of Intermediate Stages in Genomic Evolution? | |
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| Are You Going to Eat That? | |
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| A Missing Link of Biblical Proportions | |
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| Could Nuclei Evolve without Symbiosis? | |
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| Are We Related to Rats? | |
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| What Is the Origin of Our Species? | |
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| Are We All of African Descent? | |
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| How Do You Know if the Tree Is Correct? | |
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| Have We Stopped Evolving? | |
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| Summary 3.2 | |
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| Genomic Identifications | |
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| How Can We Identify Biological Weapons? | |
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| How Long Can DNA Survive? | |
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| How Did Tuberculosis Reach North America? | |
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| How Are Newly Emerging Diseases Identified? | |
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| What Other Outbreaks Are Coming? | |
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| Summary 3.3 | |
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| Biomedical Genome Research | |
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| Can We Use Genomic Sequences to Make New Vaccines? | |
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| Can We Make New Types of Antibiotics? | |
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| Can We Invent a New Class of Medication? | |
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| Is There an Alternative Way to Inhibit RNAs? | |
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| Are There More Stable RNA Genomes We Can Target? | |
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| Summary 3.4 | |
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| Chapter 3 Conclusions | |
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| References | |
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| Genomic Variations | |
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| Environmental Case Study | |
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| Can Genomic Diversity Affect Global Warming? | |
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| How Do You Measure Genetic Diversity? | |
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| How Do You Model Population Diversity? | |
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| Summary 4.1 | |
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| Human Genomic Variation | |
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| How Much Variation Is in the Human Genome? | |
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| What's the Difference Between a Mutation and an Allele? | |
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| Why Should We Care about NSPs? | |
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| Are All SNPs Really SNPs? | |
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| Do Any SNPs Produce Common Phenotypes? | |
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| Are There Vital SNPs That Can Surprise Me? | |
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| Patent Law and Genomics | |
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| Why the SNP Frenzy? Pharmacogenomics! | |
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| Summary 4.2 | |
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| The Ultimate Genomic Phenotype-Death? | |
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| Why Do We Age? | |
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| Are There Hidden Costs for a Prolonged Life? | |
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| Do Bacteria Experience Genomic Tradeoffs Too? | |
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| Summary 4.3 | |
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| Ethical Consequences of Genomic Variations | |
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| Are Genetically Modified Organisms Bad? | |
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| Is Genetic Testing Good? | |
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| What Does a Positive Test Result Really Mean? | |
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| Genomic Diversity Banks and Small Populations | |
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| Who Benefits from Genomic Medicine? | |
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| Are There Simple Applications for Complex Genomes? | |
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| Should I Get a Genetic Test? | |
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| Should Humans Be Cloned? | |
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| Summary 4.4 | |
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| Chapter 4 Conclusions | |
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| References | |
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| Genome Expression | |
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| Why Can't I Just Take a Pill to Lose Weight? | |
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| Hungry for Knowledge | |
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| Saturday, 21 October. 7:30 A.M. | |
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| Library Opens at 8:30 A.M. on Saturdays | |
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| Building a Model for Weight Homeostasis | |
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| Cloning the Leptin Gene | |
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| Functional Tests for Leptin | |
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| Time to Visit Grandma | |
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| Grandma Gives You Homework! | |
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| Chapter 5 Conclusions | |
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| References | |
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| Basic Research with DNA Microarrays | |
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| Introduction to Microarrays | |
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| What Happened to My Home Brew? | |
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| Where's the Probe? | |
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| Microarray Data Look Good, but Are They Real? | |
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| How Do You Analyze These Data? | |
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| Why Should You Log-Transform Microarray Data? | |
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| How Do You Measure Similarity between Expression Patterns? | |
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| How Do You Cluster Genes? | |
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| Can Chips Reveal Regulatory Sequences? | |
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| Can We Formulate Testable Predictions with These Data? | |
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| Microarrays Seem Too Good to Be True-Are They? | |
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| Why Did the Beer Blow? | |
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| What Can We Learn from Stressed-Out Yeast? | |
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| Do Fungi Feel Stress? | |
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| What Goes Up? | |
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| Why Are There So Many Copies of Some Genes but Not Others? | |
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| How Well Do Promoters Control Gene Expression? | |
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| Do Promoters Work in Reverse? | |
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| Summary 6.1 | |
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| Alternative Uses of DNA Microarrays | |
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| Why Do So Many Unrelated Genes Share the Same Expression Profile? | |
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| Is It Useful to Compare the Columns of a Gene Expression Matrix? | |
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| Can Cells Verify Their Own Genes? | |
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| Which Predicted Genes Are Real and Which Ones Aren't? | |
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| Can Microarrays Improve Annotations? | |
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| Could a Microarray Validate Annotation of an Entire Genome? | |
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| Summary 6.2 | |
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| Chapter 6 Conclusions | |
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| References | |
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| Applied Research with DNA Microarrays | |
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| Cancer and Genomic Microarrays | |
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| Are There Better Ways to Diagnose Cancer? | |
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| What Are Signature Genes, and How Do You Use Them? | |
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| Can Breast Cancer Be Categorized with Microarrays? | |
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| What Genomic Changes Occur in Cancer Cells? | |
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| Summary 7.1 | |
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| Improving Health Care with DNA Microarrays | |
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| Why Is the Tuberculosis Vaccine Less Effective Now? | |
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| Can We Choose the Most Effective Medication for Each Cancer? | |
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| Can We Predict Effectiveness of Chemotherapy? | |
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| What Happens When You Accumulate Fat? | |
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| What Effect Does Leptin Have on wt Adipose Tissue? | |
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| Summary 7.2 | |
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| Chapter 7 Conclusions | |
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| References | |
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| Proteomics | |
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| Introduction | |
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| What Do All These Proteins Do? | |
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| Where Are These Proteins Located? | |
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| Which Proteins Are Needed in Different Conditions? | |
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| How Do You Know if You Have Sampled Enough Cells? | |
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| Summary 8.1 | |
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| Protein 3D Structures | |
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| Does a Protein's Shape Reveal Its Function? | |
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| Can We Use Structures to Develop Better Drugs? | |
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| Can One Protein Kill You? | |
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| Summary 8.2 | |
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| Protein Interaction Networks | |
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| Which Proteins Interact with Each Other? | |
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| Can Sequence Analysis Uncover Interactions? | |
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| Can We Detect Protein Interactions? | |
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| Is Sup35 a Central Protein in the Network? | |
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| Is It Possible to Understand Proteome-Wide Interactions? | |
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| Summary 8.3 | |
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| Measuring Proteins | |
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| Which Proteins Are Present? | |
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| What Are 2D Gels? | |
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| What Proteins Do Our White Blood Cells Need to Kill a Pathogen? | |
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| How Do You Identify Proteins on 2D Gels? | |
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| How Much of Each Protein Is Present? | |
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| Can We Quantify Proteomes in Cultured Cells? | |
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| Can We Quantify Proteins in Any Cell? | |
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| Nice Idea, But Does ICAT Work? | |
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| Is the Last Unexplored Ecosystem on Earth Inside the Cell? | |
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| Can We Make Protein Microarrays? | |
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| Can Microarrays Detect Proteome Interactions? | |
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| Can Protein Microarrays Measure Kinase Activity? | |
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| Are All Cells Equal? | |
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| What Does a Proteome Produce? | |
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| Summary 8.4 | |
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| Chapter 8 Conclusions | |
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| References | |
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| Whole Genome Perspective | |
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| Why Can't We Cure More Diseases? | |
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| How Are New Medications Developed? | |
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| Location, Location, Location | |
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| Delivery Vehicles | |
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| Specificity | |
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| What's the Right Dose? | |
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| How Many Drugs Does It Take to Cure a Disease? | |
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| What Type of Drug Works Best? | |
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| Can Medication Do More than Simply Mask Symptoms? | |
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| Do We Know the Answers? | |
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| Chapter 9 Conclusions | |
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| References | |
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| Genomic Circuits in Single Genes | |
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| Dissecting a Gene's Circuitry | |
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| How Are Genes Regulated? | |
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| Molecular Dissection of Development | |
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| Expression of Endo16 | |
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| How Does a Gene Control Location, Timing, and Quantity of Transcription? | |
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| Which Modules Control Location? | |
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| Why Do Modules F, E, and DC Promote Expression in the Wrong Cells? | |
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| How Does Lithium Affect Transcription? | |
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| What Controls the Timing of Endo16 Transcription? | |
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| Does Module G Have a Function? | |
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| Can We Draw a Transcription Circuit for Endo16? | |
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| What Makes Module A So Special? | |
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| How Do Module A-Binding Proteins Work? | |
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| Which Module A Sites Respond to Repression by Modules DC, E, and F? | |
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| How Does Module A Interact with the Basic Promoter? | |
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| Are Genes Hard-Wired? | |
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| Do Genes Contain Miniature Computer Programs? | |
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| How Do You Make a Computer Understand Gene Regulation? | |
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| Summary 10.1 | |
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| Integrating Single-Gene Circuits | |
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| How Can We Describe to Others What We Know About a Genome Circuit? | |
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| Does Interactivity Enhance Understanding? | |
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| Technical Hints | |
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| Summary 10.2 | |
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| Chapter 10 Conclusions | |
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| References | |
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| Integrated Genomic Circuits | |
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| Natural Gene Circuits | |
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| Can Genes Form Toggle Switches and Make Choices? | |
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| How Do Toggle Switches Work? | |
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| What Effect Do Noise and Stochastic Behavior Have on a Cell? | |
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| How Are Stochastic Models Applied to Cellular Processes? | |
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| Theory Is Nice, but Do Toggle Switches Really Exist? | |
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| How Can Multicellular Organisms Develop with Noisy Circuits? | |
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| Redundancy: Does Gene Duplication Really Increase Genome Reliability? | |
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| Does Memory Formation Require Toggle Switches? | |
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| Are Simple Models of Complex Circuits Worthwhile? | |
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| How Much Math Is Required to Model Memory? | |
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| How Do You Build Complex Models? | |
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| Can a Transient Stimulus Produce Persistent Kinase Activation? | |
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| Why Does 100 Minutes of 5 nM EGF Achieve Long-Term Activation? | |
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| Is It Possible to Predict Steady-State Behavior? | |
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| Can the Modeled Circuit Accommodate Learning and Forgetting? | |
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| What Roles Do Other Integrated Circuits Play in LTP? | |
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| Do They Need a More Complex Model to Match Reality? | |
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| Are LTP and Long-Term Memory Related? | |
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| What Have We Learned (How Much LTP Have We Generated)? | |
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| Can We Understand Cancer Better by Visualizing Its Circuitry? | |
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| Summary 11.1 | |
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| Synthetic Biology | |
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| Can Humans Engineer a Genetic Toggle Switch? | |
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| How to Build a Toggle Switch | |
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| Can We Build a Synthetic Oscillating Clock? | |
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| How Can You Visualize Gene Regulation Logic? | |
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| Can Synthetic Devices Alter Gene Expression? | |
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| If Circuits Are Interconnected, Does Gene Order Matter? | |
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| Observational Approach | |
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| Computational Approach | |
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| Does Gene1 Have to Be First? | |
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| Summary 11.2 | |
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| Chapter 11 Conclusions | |
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| References | |
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| Modeling Whole-Genome Circuits | |
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| Is Genomics a New Perspective? | |
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| The People Involved: Who Is Doing Systems Biology? | |
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| The Quality of the Message: What Questions Do Systems Biologists Ask? | |
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| Can We Model Entire Eukaryotes with a Systems Approach? | |
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| Does the Proteome Respond Like the Transcriptome? | |
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| Can We Build a Systems Model? | |
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| Context of the Message: What Is the Impact of this Research? | |
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| Will Systems Biology Go Systemic? | |
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| Chapter 12 Conclusions | |
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| References | |
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| Glossary | |
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| Credits | |
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| Index | |