ThediscoveryofmicroRNAshasrevealedanunexpectedandspectacularadditional levelof?netuningofthegenomeandhowgenesareusedagainandagainin differentcombinationstogeneratethecomplexitythatunderliesforinstancethe brain. SincetheinitialstudiesperformedinC. elegans,wegavegoneafarwayto begintounderstandhowmicroRNApathwayscanhaveanimpactonhealthand diseaseinhuman. AlthoughmicroRNAsareabundantlyexpressedinthebrain, relativelylittleisknownaboutthemultiplefunctionsoftheseRNAmoleculesinthe nervous system. Nevertheless,we knowalready that microRNA pathways play majorrolesintheproliferation,differentiation,functionandmaintenanceofneu- nalcells. SeveralintriguingstudieshavelinkedmicroRNAsasmajorregulatorsof theneuronalphenotype,andhaveimplicatedspeci?cmicroRNAsintheregulation ofsynapseformationandplasticity. DysfunctionofmicroRNApathwaysisalso slowlyemergingasapotentialimportantcontributortothepathogenesisofmajor neurodegenerativedisorderssuchasAlzheimer'sdiseaseandParkinson'sdisease. Thesenovelinsightsappeartobeparticularpromisingfortheunderstandingofthe veryfrequentandbadlyunderstoodsporadicformsofthesediseasesascomparedto thegeneticforms. Thus,thebetterunderstandingoftheimplicationsofthisnovel ?eldofmolecularbiologyiscrucialforthebroadareaofneurosciences,fromthe fundamentalaspectstotheclinic,andfromnoveldiagnostictopotentiallythe- peuticapplicationsforsevereneurologicalandmaybepsychiatricdiseases. The presentvolumegatherscontributionstotheColloqueMe'decineetRechercheonthe implicationsofmicroRNAsinneuroscienceorganizedbytheFondationIpsen,in Paris,onApril20,2009. Ithadasobjectivetobringtogetherneuroscientistsfrom differentareasofresearchtodiscusstheircurrentinsightsintothewonderfulworld ofmicroRNAs,andtohearanddiscusstheirresearchandviewsaboutmicroRNA biologyinneuronalprocessesandinbraindisorders. BartdeStrooper YvesChristen v Acknowledgments The editors wish to thank Jacqueline Mervaillie and Sonia Le Cornec for the organizationofthemeetingandMaryLynnGagefortheeditingofthebook. vii Contents Pro?lingthemicroRNAs ...1 KennethS. Kosik,ThalesPapagiannakopoulos,NaXu, KawtherAbu-Elneel,TsunglinLiu,andMinJeongKye TheWideVarietyofmiRNAExpressionPro?les intheDevelopingandMatureCNS ...9 MarikaKapsimali InteractionsbetweenmicroRNAsandTranscription FactorsintheDevelopmentandFunction oftheNervousSystem ...19 DavidJ. Simon AmicroRNAFeedbackCircuitinMidbrainDopamineNeurons ...27 AsaAbeliovich Fine-tuningmRNATranslationatSynapseswithmicroRNAs ...35 GerhardM. Schratt NeuronalP-bodiesandTransportofmicroRNA-Repressed mRNAs ...4 5 FlorenceRage CrosstalkbetweenmicroRNAandEpigeneticRegulation inStemCells ...57 KeithSzulwach,ShuangChang,andPengJin microRNAsinCNSDevelopmentandNeurodegeneration: InsightsfromDrosophilaGenetics ...69 StephenM. Cohen ix x Contents DrosophilaasaModelforNeurodegenerativeDisease: RolesofRNAPathwaysinPathogenesis ...79 NancyM. Bonini microRNAsinSporadicAlzheimer'ThediscoveryofmicroRNAshasrevealedanunexpectedandspectacularadditional levelof?netuningofthegenomeandhowgenesareusedagainandagainin differentcombinationstogeneratethecomplexitythatunderliesforinstancethe brain. SincetheinitialstudiesperformedinC. elegans,wegavegoneafarwayto begintounderstandhowmicroRNApathwayscanhaveanimpactonhealthand diseaseinhuman. AlthoughmicroRNAsareabundantlyexpressedinthebrain, relativelylittleisknownaboutthemultiplefunctionsoftheseRNAmoleculesinthe nervous system. Nevertheless,we knowalready that microRNA pathways play majorrolesintheproliferation,differentiation,functionandmaintenanceofneu- nalcells. SeveralintriguingstudieshavelinkedmicroRNAsasmajorregulatorsof theneuronalphenotype,andhaveimplicatedspeci?cmicroRNAsintheregulation ofsynapseformationandplasticity. DysfunctionofmicroRNApathwaysisalso slowlyemergingasapotentialimportantcontributortothepathogenesisofmajor neurodegenerativedisorderssuchasAlzheimer'sdiseaseandParkinson'sdisease. Thesenovelinsightsappeartobeparticularpromisingfortheunderstandingofthe veryfrequentandbadlyunderstoodsporadicformsofthesediseasesascomparedto thegeneticforms. Thus,thebetterunderstandingoftheimplicationsofthisnovel ?eldofmolecularbiologyiscrucialforthebroadareaofneurosciences,fromthe fundamentalaspectstotheclinic,andfromnoveldiagnostictopotentiallythe- peuticapplicationsforsevereneurologicalandmaybepsychiatricdiseases. The presentvolumegatherscontributionstotheColloqueMe'decineetRechercheonthe implicationsofmicroRNAsinneuroscienceorganizedbytheFondationIpsen,in Paris,onApril20,2009. Ithadasobjectivetobringtogetherneuroscientistsfrom differentareasofresearchtodiscusstheircurrentinsightsintothewonderfulworld ofmicroRNAs,andtohearanddiscusstheirresearchandviewsaboutmicroRNA biologyinneuronalprocessesandinbraindisorders. BartdeStrooper YvesChristen v Acknowledgments The editors wish to thank Jacqueline Mervaillie and Sonia Le Cornec for the organizationofthemeetingandMaryLynnGagefortheeditingofthebook. vii Contents Pro? lingthemicroRNAs ...1 KennethS. Kosik,ThalesPapagiannakopoulos,NaXu, KawtherAbu-Elneel,TsunglinLiu,andMinJeongKye TheWideVarietyofmiRNAExpressionPro?les intheDevelopingandMatureCNS ...9 MarikaKapsimali InteractionsbetweenmicroRNAsandTranscription FactorsintheDevelopmentandFunction oftheNervousSystem ...19 DavidJ. Simon AmicroRNAFeedbackCircuitinMidbrainDopamineNeurons ...27 AsaAbeliovich Fine-tuningmRNATranslationatSynapseswithmicroRNAs ...35 GerhardM. Schratt NeuronalP-bodiesandTransportofmicroRNA-Repressed mRNAs ...45 FlorenceRage CrosstalkbetweenmicroRNAandEpigeneticRegulation inStemCells ...57 KeithSzulwach,ShuangChang,andPengJin microRNAsinCNSDevelopmentandNeurodegeneration: InsightsfromDrosophilaGenetics ...69 StephenM. Cohen ix x Contents DrosophilaasaModelforNeurodegenerativeDisease: RolesofRNAPathwaysinPathogenesis ...79 NancyM. Bonini microRNAsinSporadicAlzheimer'sDiseaseandRelated Dementias ...91 Se'bastienS. He'bert,WimMandemakers,AikateriniS. Papadopoulou, andBartDeStrooper microRNADysregulationinPsychiatricDisorders ...99 BinXu,JosephA. Gogos,andMariaKarayiorgou Index ...1 19 Contributors Abeliovich Asa Columbia University Medical Center, 630 West 168th Street, Room15-405,NewYork,NY10032,USA,aa900@columbia. edu Abu-ElneelKawther NeuroscienceResearchInstitute,DepartmentofMolecular CellularandDevelopmentalBiology,UniversityofCaliforniaSantaBarbara,USA BoniniNancyM. UniversityofPennsylvania,306LeidyLaboratories,Depa- mentofBiology,Philadelphia,PA19104,USA,nbonini@sas. upenn. edu Chang Shuang Department of Human Genetics, Emory University School of Medicine,Atlanta,GA30322,USA CohenStephenM. TemasekLifeSciencesLaboratoryLimited,1ResearchLink National University of Singapore, 117604 Singapore, SINGAPORE, steve@ tll. org. sg DeStrooperBart Centerforhumangenetics,K. U. LeuvenandDepartmentof molecularanddevelopmentalgenetics,VIBLeuven,BELGIUM GogosJosephA. DepartmentofPhysiology&CellularBiophysicsandDepa- mentofNeuroscience,ColumbiaUniversity,NewYork,USA He'bert Se'bastien S. Centre de Recherche du CHUQ (CHUL), Axe Neur- ciences,Universite'Laval,De'partementdeBiologieme'dicale,2705Boul. Laurier, LocalRC-9800,Que'bec,Qc,Canada,sebastien. hebert@crchul. ulaval. ca JinPeng DepartmentofHumanGeneticsandGraduatePrograminGeneticsand MolecularBiology,EmoryUniversitySchoolofMedicine,Atlanta,GA30322, USA,pjin@genetics. emory. edu ' ' ' ' KapsimaliMarika INSERMU784,GenetiqueMoleculaireduDeveloppement, ' Ecole Normale Superieure, 46 rue d'Ulm, 75230 PARIS Cedex 05 FRANCE, kapsimal@biologie. ens. fr xi xii Contributors Karayiorgou Maria Columbia University, Department of Psychiatry, 1051 RiversideDrive,Unit#28,NewYorkNY10032,USA,mk2758@columbia. edu Kosik Kenneth S. Neuroscience Research Institute, Department of Molecular Cellular and Developmental Biology, University of California Santa Barbara, BiologyII,Room6139A,SantaBarbara,CA93106,USA,kosik@lifesci. ucsb.

Recent developments in stem cell biology have opened new directions in cell therapy. This book provides the state-of-the-art developments in using biomaterials as artificial niches for engineering stem cells, both for the purpose of better understanding their biology under 3D biomimetic conditions as well as for developing new strategies for efficient long term maintenance and directed differentiation of stem cells into various therapeutic lineages. Animal and human stem cells of both embryonic and adult origin are discussed with applications ranging from nerve regeneration, orthopedics, cardiovascular therapy, blood cell generation and cancer therapy. Both synthetic and natural biomaterials are reviewed with emphasis on how material-stem cell interactions direct specific signaling pathways and ultimately modulate the cell fate. This book is valuable for biomaterial scientists, tissue engineers, clinicians as well as stem cell biologists involved in basic research and applications of adult and embryonic stem cells.

This manual offers detailed protocols for fluorescence in situ hybridization (FISH) and comparative genomic hybridization approaches, which have been successfully used to study various aspects of genomic behavior and alterations. Methods using different probe and cell types, tissues and organisms, such as mammalians, fish, amphibians (including lampbrush-chromosomes), insects, plants and microorganisms are described in 57 chapters. In addition to multicolor FISH procedures and special applications such as the characterization of marker chromosomes, breakpoints, cryptic aberrations, nuclear architectures and epigenetic changes, as well as comparative genomic hybridization studies, this 2nd edition describes how FISH can be combined with other techniques. The latter include immunostaining, electron microscopy, single cell electrophoresis and microdissection. This well-received application guide provides essential protocols for beginning FISHers and FISH experts alike working in the fields of human genetics, microbiology, animal and plant sciences.

White moves from a simple proposition maintaining that all individuals seek suitable surroundings to propose a provocative approach to social and political action. Rooting his position in modern life sciences and particularly in sociobiology and neurobiology, he establishes an "IMPish" model that is "interactional," "mentalist," and "populational." Interactional in that both heredity and environment are credited for due influence on individuals' traits; mentalist in that individuals' actions can be purposeful rather than simply determined; and populational in his insistence that the unique persona must not be slighted in the rush to fashion statistics. Applying his behavioral principles most notably relevant to self-selection and using examples derived from modern political action, White examines the importance of these fundamental orientations in the social and political orders. The work has implications for policy assessment and re-formulation. It constitutes a challenge to much of the widely accepted contemporary political theory and public policy approaches.

For all introductory genetics courses. Concepts of Genetics emphasises the fundamental ideas of genetics, while exploring modern techniques and applications of genetic analysis. This best-selling text continues to provide understandable explanations of complex, analytical topics and recognises the importance of teaching students how to become effective problem solvers. The 12th Edition has been extensively updated to provide comprehensive coverage of important, emerging topics such as CRISPR-Cas and the study of posttranscriptional gene regulation in eukaryotes. An expanded emphasis on ethical considerations that genetics is bringing into everyday life is addressed in Genetics, Ethics, and Society and Case Study features.

This is a reference handbook for young researchers exploring gene and cell therapy. Gene therapy could be defined as a set of strategies modifying gene expression or correcting mutant/defective genes through the administration of DNA (or RNA) to cells, in order to treat disease. Important advances like the discovery of RNA interference, the completion of the Human Genome project or the development of induced pluripotent stem cells (iPSc) and the basics of gene therapy are covered. This is a great book for students, teachers, biomedical researchers delving into gene/cell therapy or researchers borrowing skills from this scientific field.

Advances in genetics have begun to deliver on their promise of new and improved approaches to the prevention and treatment of human disease, including the gene-based therapeutics. The international sports community has begun to recognize the potential harmful use of gene transfer technology by athletes. The task of monitoring and controlling sports doping must be a truly cooperative effort, involving the cooperation of a range of local, national, and international organizations. There are very serious broad social and ethical issues at stake that relate to our definition of sports and its role in our society, as well as the social and ethical principles that are challenged or breached through sport doping, determining which forms of performance enhancement - in sport or any other realm of human activity - are acceptable, and what makes the enhancement of sport performance different from enhancement in other areas of human activity (e.g., cosmetic surgery, mood and learning enhancement through drugs, and drug-based "treatment" of physical and intellectual changes in normal aging process). This book tackles all these issues and more, serving as the first such focused treatment of this increasingly important topic, which has broad-based implications for science, medicine, sports, and society.

This volume offers an analysis of the scale and nature of the immunological issues facing regenerative medicine, drawing on the expertise of laboratories around the world who have taken up the challenge of applying their expertise in immunology to the vagaries of stem cell biology. In Part I, we explore the extent to which the principles of allograft rejection, learned over several decades from our experiences of whole organ transplantation, apply within the unique context of cell replacement therapy. Part II discusses various innovative ways of addressing the issues of immunogenicity, while, in Part III, we focus exclusively on the induction of immunological tolerance through a variety of novel approaches. It is our hope that this systematic analysis of the current state of the field will galvanise efforts to solve an issue which has so far remained intractable.

Genetic engineering and biotechnology along with conventional breeding have played an important role in developing superior cultivars by transferring economically important traits from distant, wild and even unrelated species to the cultivated varieties which otherwise could not have been possible with conventional breeding. There is a vast amount of literature pertaining to the genetic improvement of crops over last few decades. However, the wonderful results achieved by crop scientists in food legumes' research and development over the years are scattered in different journals of the World. The two volumes in the series 'Alien Gene Transfer in Crop Plants' address this issue and offer a comprehensive reference on the developments made in major food crops of the world. These volumes aim at bringing the contributions from globally renowned scientists at one platform in a reader-friendly manner. The second volume entitled, "Alien Gene Transfer in Crop Plants: Achievements and Impact" will deal more with the practical aspects. This volume will cover achievements of alien gene transfer in major food crops of the world and their impact on development of newer genetic variability and additional avenues for selection; development of superior cultivars for increased yield, resistance to biotic and abiotic stresses, improved nutritional and industrial quality; innovation of new techniques and positive as well as negative environmental implications. This volume has been divided into four groups with an aim to cover all major cereals, pulses, oilseeds and other crops (vegetable and horticultural crops) which are of economic importance.

The critically acclaimed laboratory standard for more than fifty years, Methods in Enzymology is one of the most highly respected publications in the field of biochemistry. Since 1955, each volume has been eagerly awaited, frequently consulted, and praised by researchers and reviewers alike. Now with over 400 volumes (all of them still in print), the series contains much material still relevant today truly an essential publication for researchers in all fields of life sciences. This new volume presents methods related to the use of bacterial genetics for genomic engineering. The book includes sections on strain collections and genetic nomenclature; transposons; and phage.

The discovery of stem and progenitor cells in the adult mammalian CNS challenged the long standing no new neuron doctrine and opened the door to the potential for cell replacement therapy. The process from discovery to clinical applications can be long and tortuous, requiring rigorous steps involving standardized and precise protocols. "Neural Progenitor Cells: Methods and Protocols "is a collection of practical articles describing techniques used to study neural stem and progenitor cells. The volume also highlights the promise of stem cell-based therapeutic applications for CNS disorders. Written in the successful "Methods in Molecular Biology" series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible protocols, and notes on troubleshooting and avoiding known pitfalls.

Authoritative and easily accessible, "Neural Progenitor Cells: Methods and Protocols "serves both professionals and novices with its well-honed methodologies. "

This book deals with the paradoxical role of autophagy in tumor suppression and tumor promotion in cancer cells. Autophagy plays opposing, context-dependent roles in tumors; accordingly, strategies based on inhibiting or stimulating autophagy could offer as potential cancer therapies. The book elucidates the physiological role of autophagy in modulating cancer metastasis, which is the primary cause of cancer-associated mortality. Further, it reviews its role in the differentiation, development, and activation of multiple immune cells, and its potential applications in tumor immunotherapy. In addition, it examines the effect of epigenetic modifications of autophagy-associated genes in regulating tumor growth and therapeutic response and summarizes autophagy's role in the development of resistance to a variety of anti-cancer drugs in cancer cells. In closing, it assesses autophagy as a potential therapeutic target for cancer treatment. Given its scope, the book offers a valuable asset for all oncologists and researchers who wish to understand the potential role of autophagy in tumor biology.

In an attempt to cover modern aspects of thin films, this series has moved beyond the basic physics. This volume addresses the important aspects of both inorganic and organic thin films, both their theoretical as well as technological aspects.

Are you your genes? De-Sequencing: Identity Work with Genes explores this perplexing question, showing how different forms of knowledge must be contextualized to become meaningful. It is generally assumed that the genomic sequence adds up to the identity-forming material life is made of. Yet identity cannot itself adopt the form of a sequence. As the authors in this volume show, the genome must be 'de-sequenced' by human language to render it interpretable and meaningful in a social context. The book unpacks this type of 'sequence-speech' in engaging detail, adopting a personal, social, cultural, and bio-political approach to examine the transformation of human identity and reflexivity in the era of genetic citizenship.

Regulation of gene expression, a major determinant of gene activity, occupies a central place in molecular biology. Yeast Genetic Networks: Methods and Protocols covers approaches to the systems biological analysis of small-scale gene networks in yeast. Divided into four convenient sections, this detailed volume discusses the methods used to analyze gene expression quantitatively, presents a collection of mathematical and computational tools to analyze stochasticity, adaptation, sensitivity in signal transmission, and oscillations in gene expression, provides instructional methods on how to utilize the tools of quantitative genetics to identify genes that regulate stochasticity and oscillations in gene expression, and concludes with a section devoted to the analysis of conserved gene expression systems and networks in different fungal species. Written in the highly successful Methods in Molecular Biology (TM) series format, chapters contain introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and notes on troubleshooting and avoiding known pitfalls. Authoritative and accessible, Yeast Genetic Networks: Methods and Protocols serves as an ideal and valuable resource for both novices and experienced researchers.

Adult Stem Cells, second edition, takes a critical look at issues concerning the developmental or differentiation potential for a variety of tissue types and for specific adult stem cell types. Since the first edition appeared a decade ago, our understanding of adult stem cells, and more specifically tissue-specific adult stem cells, has advanced tremendously. And an increased interest in regenerative medicine and potential stem cell applications has driven a quest for better understanding of stem cell biology. In turn, this has spawned much activity on generation and utilization of more and better reagents to identify and isolate stem cells and stem cell-like subpopulations, and on assays elucidating their developmental or differentiation potential and functional integration with host tissues and organs. In this fully updated new edition, chapters cover topics ranging from signaling pathways maintaining stemness in hematopoietic cells to regeneration after injury and endocrine mechanisms underlying the stem cell theory of aging. Other chapters cover stem cells by organ or system including pituitary, cardiac, epithelial, teeth, lung, ovary, prostate, liver, and many more. Importantly, the authors of the chapters have not only summarized their successes, but have also summarized some of the difficulties that each particular field is still facing with respect to maximizing the utility of stem cells in clinical settings. Collectively, they impart both the excitement and challenges facing stem cell utilization for repair and regeneration making this book essential reading for those involved in stem cell research as well as those involved in clinical assays.

Fungal pathogens pose an on-going and serious threat for poikilotherms and homeotherms, and can cause a broad spectrum of diseases ranging from innocuous to life-threatening. In addition, long-term exposure to some mycotoxigenic moulds can lead to mycotoxicoses in human and animals. Given the expanding population of immune compromised hosts, the list of fungal opportunists grows longer every year. Moreover, antifungal resistance, drug-related toxicity and our limited arsenal of antifungals have exacerbated the situation. To address these problems, strategies such as the identification of novel targets, use of the structure-activity relationship in rational drug design, development of new formulations, modification of existing antifungals to combat resistance, and bioavailability enhancement are called for. For the reader's convenience, this book has been divided into three sections. The first six chapters of Section I provide a timely review of mycoses, from endemic to cosmopolitan and from generalized to specific, while both chapters of Section II focus on risks associated with mycotoxins. In closing, the two chapters of Section III describe potential antifungal leads and drug candidates based on phytochemicals and coumarin scaffold.

Great disparities exist between organisms with regard to the relative ease of chromosomal mutagenesis and manipulation. In Chromosomal Mutagenesis, a team of experts provide a variety of chromosomal manipulation techniques, including insertional gene disruptions, gene knockouts, stimulated homologous recombination techniques and other novel tools, for both prokaryotic and eukaryotic organisms, and attempt to expand the genetic toolbox beyond model organisms. Following the format of the highly successful Methods in Molecular Biology format, each chapter offers step-by-step laboratory instructions, lists of the necessary equipment and reagents, and tips on troubleshooting and avoiding known pitfalls.

Comprehensive and cutting-edge, Chromosomal Mutagenesis covers state-of-the-art techniques that are staged to expand, if not revolutionize, genetic analysis in the long neglected and relevant cell types.

There has been no mechanistic explanation for evolutionary change consistent with phylogeny in the 150 years since the publication of 'Origins'. As a result, progress in the field of evolutionary biology has stagnated, relying on descriptive observations and genetic associations rather testable scientific measures. This book illuminates the need for a larger evolutionary-based platform for biology. Like physics and chemistry, biology needs a central theory in order to frame the questions that arise, the way hypotheses are tested, and how to interpret the data in the context of a continuum.The reduction of biology to its self-referential, self-organized properties provides the opportunity to recognize the continuum from the Singularity/Big Bang to Consciousness based on cell-cell communication for homeostasis.

This volume is aimed in general at scientists who have an interest in deciphering the molecular mechanisms for sequence recognition of DNA. The methods have general applicability to small molecules as well as oligomers and proteins, while the examples provide general principles involved in sequence recognition.

This book provides readers with an overview of the frequent occurrence of asymmetric cell division. Employing a broad range of examples, it highlights how this mode of cell division constitutes the basis of multicellular organism development and how its misregulation can lead to cancer. To underline such developmental correlations, readers will for example gain insights into stem cell fate and tumor growth. In turn, subsequent chapters include descriptions of asymmetric cell division from unicellular organisms to humans in both physiological and pathological conditions. The book also illustrates the importance of this process for evolution and our need to understand the background mechanisms, offering a valuable guide not only for students in the field of developmental biology but also for experienced researchers from neighboring fields.