Books by Subject

Biology

  • Digital
    Liujing Xing.
    Ependymal cells in the adult mammalian spinal cord are thought to be a population of "latent neural stem cells" with more regenerative potential than any other cell types in the adult spinal cord. In spite of their unique functions, the molecular signals that regulate ependymal cells in the postnatal and adult spinal cord remain poorly understood. In addition, there remain many gaps in our knowledge about the developmental origin and the generation of spinal cord ependymal cells. In Chapter 3, I begin my investigation of the developmental origin of spinal cord ependymal cells by analyzing Wnt-responsive neural progenitor cells in the developing spinal cord and show that Wnt signaling activity is concentrated in the dorsal midline neural progenitor cells throughout embryogenesis. Ependymal cells appear to be generated in a ventral to dorsal direction, with the dorsal midline ependymal cells generated last. Indeed, they are derived from Wnt-responsive dorsal midline radial glial cells give rise to towards the end of embryogenesis. These results suggest an important role of Wnt signaling in ependymal cell generation and highlights a region-specific allocation of ependymal cells which is consistent with the process during both neurogenesis and gliogenesis. In Chapters 4-6, I demonstrate that ependymal cells in the postnatal and adult spinal cord continue to be dependent on Wnt-signaling. Inhibiting Wnt signaling results in impaired ependymal cell proliferation. Ependymal cells also produce Wnt ligands which are required for maintaining ependymal cell proliferation. In Chapter 7, I investigate another Wnt-responsive cell population in the developing and adult spinal cord -- astrocytes. I also show evidence suggesting that Wnt signaling may be enriching for a more proliferative population of astrocytes at the periphery of the white matter, which serve as a source of new astrocytes in the adult spinal cord. Lastly in Chapter 8, I describe our efforts in elucidating the contribution of Wnt-responsive cells to long term glial scar formation after spinal cord injury. Taken together, these studies highlight the importance of Wnt signaling in the ependymal cell population throughout development, postnatal growth and homeostasis. The results also provide insights into the involvement of Wnt signaling in astrocyte proliferation and scar formation after spinal cord injury.
  • Digital
    Bertrade Clemence Ange Mbom.
    [Beta]-Catenin is a multifunctional protein with critical roles in cell-cell adhesion, Wnt-signaling and the centrosome cycle. Whereas the roles of [beta]-catenin in adhesion and Wnt-signaling are well understood, how [beta]-catenin regulates the centrosome cycle is not. NIMA-related protein kinase 2 (Nek2), which stimulates centrosome separation, binds to and phosphorylates [beta]-catenin. Using in vitro and cell-based assays, we show that Nek2 phosphorylates the same regulatory sites as Glycogen Synthase Kinase 3[beta] (GSK3[beta]) in the N-terminus of [beta]-catenin (S33/S37/T41) as well as additional sites. Significantly, Nek2, not GSK3[beta], is responsible for phosphorylating [beta]-catenin at centrosomes. Nek2 binding promotes [beta]-catenin stability by inhibiting binding of the E3 ligase [beta]-TrCP to [beta]-catenin, thereby preventing [beta]-catenin ubiquitination and degradation. Thus, [beta]-catenin phosphorylated by Nek2 on S33/S37/T41 accumulates at centrosomes in mitosis. We further show that Plk1 regulates Nek2 activity in stabilizing [beta]-catenin. Taken together, these results identify a novel mechanism for regulating [beta]-catenin stability, and provide new insight into a pathway involving Plk1, Nek2 and [beta]-catenin that regulates the centrosome cycle.
  • Digital
    Jesper Hoffmeyer, editor.
    Springer2008
    Introduction: Bateson the precursor / Jesper Hoffmeyer -- Angels fear revisited: Gregory Bateson's cybernetic theory of mind applied to religion-science debates / Mary Catherine Bateson -- From thing to relation. On Bateson's bioanthropology / Jesper Hoffmeyer -- What connects the map to the territory? / Tyrone Cashman -- The pattern which connects pleroma to creatura: the autocell bridge from physics to life / Terrence Deacon and Jeremy Sherman -- Bateson's method: double description. What is it? How does it work? What do we learn? / Julie Hui, Tyrone Cashman, and Terrence Deacon -- Gregory Bateson's relevance to current molecular biology / Luis Emilio Bruni -- Process ecology: creatura at large in an open universe / Robert E. Ulanowicz -- Connections in action - bridging implicit and explicit domains / Teresa S.S. Shilhab and Christian Gerlach -- Bateson: biology with meaning / Brian Goodwin -- Gregory Bateson's "uncovery" of ecological aesthetics / Peter Harries-Jones -- Collapsing the wave function of meaning: the epistemological matrix of talk-in-interaction / Donald Favareau -- Re-enchanting evolution: transcending fundamentalisms through a mythopoetic epistemology / Gregory Mengel -- Bateson and Peirce on the pattern that connects and the sacred / Søren Brier -- Bateson, Peirce and the sign of the sacred / Deborah Eicher-Catt.
  • Digital
    edited by Eric J. Sargis and Marian Dagosto.
    Springer2008
    Earliest evidence of Deltatheroida (Mammalia: Metatheria) from the early Cretaceous of North America / Brian M. Davis, Richard L. Cifelli and Zofia Kielan-Jaworowska -- Evolution of hind limb proportions in kangaroos (Marsupialia: Macropodoidea) / Benjamin P. Kear ... [et al.] -- Changing views in paleontology : the story of a giant (Megatherium, Xenarthra) / Christine Argot -- Evolutionary morphology of the Tenrecoidea (Mammalia) forelimb skeleton / Justine A. Salton and Eric J. Sargis -- Postcranial morphology of Apheliscus and Haplomylus (Condylarthra, Apheliscidae) : evidence for a Paleocene Holarctic origin of Macroscelidea / Tonya A. Penkrot ... [et al.] -- Postcranial skeleton of the Upper Paleocene (Itaboraian) "Condylarthra" (Mammalia) of the Itaboraí Basin, Brazil / Lilian P. Berqvist -- Postcranial osteology of mammals from Salla, Bolivia (late Oligocene) : form, function, and phylogenetic implications / Bruce J. Shockey and Frederico Anaya -- Evolution of the proximal third phalanx in Oligocene-Miocene equids, and the utility of phalangeal indices in phylogeny reconstruction / Jay A. O'Sullivan -- Adaptive zones and the pinniped ankle : a three-dimensional quantitative analysis of carnivoran tarsal evolution / P. David Polly -- The biogeographic origins of Primates and Euprimates : east, west, north, or south of Eden? / Mary T. Silcox -- Evaluating the mitten-gliding hypothesis for Paromomyidae and Micromomyidae (Mammalia, "Plesiadapiformes") using comparative functional morphology of new Paleogene skeletons / Douglas M. Boyer and Jonathan I. Bloch -- Morphological diversity in the skulls of large adapines (Primates, Adapiformes) and its systematic implications / Marc Godinot and Sébastien Couette -- Primate tibiae from the middle Eocene Shanghuang fissure-fillings of eastern China / Marian Dagosto ... [et al.] -- Rooneyia, postorbital closure, and the beginnings of the age of Anthropoidea / Alfred L. Rosenberger, Russell Hogg and Sai Man Wong -- Epitensoric position of the chorda tympani in Anthropoidea : a new synapomorphic character, with remarks on the fissura Glaseri in Primates / Wolfgang Maier -- Evolutionary morphology of the guenon postcranium and its taxonomic implications / Eric J. Sargis, Carl J. Terranova and Daniel L. Gebo -- Analysis of selected hominoid joint surfaces using laser scanning and geometric morphometrics : a preliminary report / William E.H. Harcourt-Smith ... [et al.] -- Comparative primate bone microstructure: records of life history, function, and phylogeny / Johanna Warshaw.
  • Print
    edited by Alexander Stone Macnow, MD.
    Status: Not Checked OutLane Catalog Record
    The Cell -- Reproduction -- Embryogenesis and Development -- The Nervous System -- The Endocrine System -- The Respiratory System -- The Cardiovascular System -- The Immune System -- The Digestive System -- Homeostasis -- Musculoskeletal System -- Genetics and Evolution.
  • Digital/Print
    edited by James Inglese.
    Digital : ScienceDirect2006
    Print2006
  • Digital
    Blair Whitney Benham-Pyle.
    Mechanical strain regulates the development, organization and function of multicellular tissues, but mechanisms linking mechanical strain and cell-cell junction proteins to cellular responses are poorly understood. We showed that mechanical strain applied to quiescent epithelial cells induced rapid cell cycle re-entry, mediated by independent nuclear accumulation and transcriptional activity of first Yap1 and then β-catenin. Inhibition of Yap1- and β-catenin-mediated transcription blocked cell cycle re-entry and progression through G1 into S phase, respectively. Maintenance of quiescence, Yap1 nuclear exclusion and β-catenin transcriptional responses to mechanical strain required E-cadherin extracellular engagement. Our results indicate that activation of Yap1 and β-catenin is a master regulator of mechanical strain-induced cell proliferation, and cadherins are signaling centers required for cellular responses to externally applied force. While both mechanical force and Wnt Signaling activate β-catenin-mediated transcription to promote proliferation, it is unknown whether mechanical force and Wnt signaling act independently or synergize to activate β-catenin signaling and cell division. We showed that mechanical strain induced Src-dependent phosphorylation of Y654 β-catenin and β-catenin accumulation, increasing β-catenin-mediated transcription. Under these conditions, however, cells accumulated in S/G2 but did not divide. Blocking β-catenin degradation through Casein Kinase I inhibition or Wnt3A addition increased β-catenin-mediated transcription and strain-induced accumulation of S/G2 cells. Significantly, only the combination of mechanical strain and Wnt/β-catenin activation triggered S/G2 cells to divide. These results indicate that strain-induced Src phosphorylation of β-catenin and Wnt-dependent β-catenin stabilization can synergize to increase β-catenin-mediated transcription to a level required for mitosis. Thus local Wnt signaling may fine-tune the effects of global mechanical strain to restrict cell divisions and maintain tissue homeostasis.
  • Digital
    Brett Theodore Staahl.
    During the development of the vertebrate nervous system neural progenitors divide, generate progeny that exit mitosis and then migrate to sites where they elaborate specific morphologies and synaptic connections. Mitotic exit in neurons is accompanied by an essential switch in the Mammalian SWI/SNF (also called BAF) ATP-dependent chromatin regulatory complexes from the neural progenitor npBAF to neuron-specific nBAF complexes. We elucidated the mechanism of a microRNA/chromatin switch underlying the switch of the npBAF subunit, BAF53a for the nBAF subunit BAF53b. Recapitulating this microRNA/chromatin switch in fibroblasts leads to their direct conversion to neurons. We have defined the kinetics of nBAF complex assembly in the formation of induced neurons from ES cells or fibroblasts as well as normal neural differentiation and using proteomic analysis find that this switch also includes the removal of SS18 and its replacement by CREST at mitotic exit. We find that switching of chromatin remodeling mechanisms is highly correlated with a broad switch in the use of neurogenic transcription factors. Knockdown of SS18 in neural stem cells causes cell-cycle exit and failure to self-renew, while continued expression of SS18 in neurons blocks dendritic outgrowth underlining the importance of subunit switching. Recent whole genome sequencing studies show that dominant mutations in BAF subunits underlie widely different human neurologic diseases including mental retardation, microcephally, schizophrenia, sporadic mutations in autism as well as the neurodegenerative disease, amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig's disease. Using whole exome analysis of ALS trios (trio=two unaffected parents and affected child), we identified and functionally characterized two de novo mutations in CREST that function in a dominant negative mode to inhibit dendrite outgrowth in cortical and motor neurons. As the aforementioned neurological diseases arise in different neuronal types, our studies suggest that the characteristics of these diseases must be interpreted in the context of the different BAF assemblies in neurons rather than a singular mSWI/SNF complex.
  • Print
    Maryadele J. O'Neil, editor-in-chief ; Patricia E. Heckelman, senior associate editor ; Peter H. Dobbelaar, associate editor ; Kristin J. Roman, assistant editor ; Catherine M. Kenny, senior editorial assistant ; Linda S. Karaffa, technical assistant.
    Status: Not Checked OutLane Catalog Record
  • Digital
    edited by Prem Lal Kashyap, Alok Kumar Srivastava, Shree Prakash Tiwari, Sudheer Kumar.
    Wiley2018
    "Microbes and climate are major influences on crop growth, and therefore significantly influence the quality, productivity, and sustainability of food production systems. Global warming is projected to significantly impact agriculture in terms of temperature, precipitation, chilling and glacial run-off etc. Microbes can be both beneficial and detrimental in agriculture; the array of functions they perform under stressed/limited conditions are currently underestimated. Agriculture is affected by the crop microbiome, nutrient cycling microbes, endophytes, and mycorrhizae, as well as pests and disease. Agricultural sustainability has always been highly dependent on the relationships between these factors. Various microorganisms can thrive under extreme conditions - extreme temperatures, extreme pH, high saline concentrations and pressures, etc. As a result, they provide excellent models for understanding the stress tolerance, adaptation and response mechanisms that can be subsequently engineered into crop plants to cope with climate change induced stresses. Use of these microorganisms may alleviate stresses in crop plants, which in turn opens a new and emerging application in agriculture. While there is an abundance of information on this topic, there is not yet a comprehensive volume pulling current research together. This text will be authored by leaders in the field and edited to ensure conciseness and clarity. Chapters will cover a broad range of agriculturally important crops, impact of climate change on crops as well as biotechnologically and environmentally relevant microbes; the text will serve as a springboard for novel research findings and new applications in the field"--Provided by publisher.
  • Digital
    Patrice Dion, Chandra Shekhar Nautiyal, editors ; foreword by John D. Rummel.
    Springer2008
  • Digital
    David R. Anderson.
    Springer2008
  • Digital
    Sunny Shang Lou.
    Cell migration requires the large-scale coordination of force generation. This coordination can occur on a mechanical level by physical coupling of interconnected cytoskeletal components, and on a biochemical level by feedback interactions among the signaling molecules that direct actin polymerization. The study of large-scale coordination in cell motility has been hampered by the fact that the cell types best suited for experimental exploration by mechanical perturbations are usually not ideal for experimental exploration by molecular perturbations, and vice versa. Fish epidermal keratocytes have proved to be particularly useful for experimentation and modeling of the mechanics of large-scale coordination because of their simple and stereotyped shapes, their large uniform actin-rich protrusive lamellipodia, and their extremely rapid and persistent movement. However, molecular manipulations in these primary cells, typically cultured from adult members of fish species that have not been genetically well-characterized, have been limited. I have developed a new method for keratocyte culture from zebrafish embryos, enabling me to take full advantage of the molecular experimental methods including morpholino-based gene knockdown that are available for zebrafish, which also has a fully sequenced genome. Using this new molecularly tractable experimental system, I have identified a novel role for myosin light chain kinase in regulating overall cell polarization independently of previously known polarity regulators such as the small GTPase Rho and membrane tension. My investigations of the biology of embryonic zebrafish keratocytes have also shed new light on other aspects of large-scale cell movement coordination. For example, I have found that some zebrafish embryonic keratocytes exhibit an interesting traveling wave behavior, where an actin-rich protrusion appears to propagate laterally around the perimeter of the cell. While superficially similar behavior has been previously observed in keratocytes isolated from adults from other fish species when they are cultured on highly adhesive substrates, I have been able to demonstrate that the mechanism of wave propagation differs in the two cases. These observations have the potential to illuminate the biochemical feedback interactions that are most crucial for the rapid actin polymerization found in keratocytes and other fast-moving cell types. Finally, I have used the embryonic zebrafish keratocyte system to study the mechanical origin of the regular wrinkles that can form perpendicular to the leading edge in fish keratocyte lamellipodia, which were first described more than 90 years ago. I have found that characteristics of these wrinkles can be well explained by a physical model assuming that the mechanical coupling within the lamellipodial cytoskeleton involved in actin-based cell motility is characterized by largely elastic behavior, suggesting that forces exerted on one side of the cell are rapidly transmitted over the entire length of the lamellipod. This result stands in contrast to previous expectations based on observations in other cell types suggesting that the actin cytoskeleton behaves as a viscous fluid over the relatively slow time scales associated with whole-cell motility.
  • Digital
    Kartik Viswanathan.
    Pancreatic [Beta]-cells secrete insulin to maintain systemic glucose balance. In response to physiological or pathological stresses that increase insulin demand, [Beta]-cells proliferate and enhance insulin secretion to increase insulin output. However, the mechanisms that govern these facultative changes are unclear. In this thesis, I investigate two potential factors in achieving these essential adaptive changes -- hypoxia inducible factor 1 alpha (Hif1a) and prolactin receptor (Prlr). During pregnancy, a common acquire state with increased insulin demand, Hif1a and Hif1a target gene expression, including Vegfa, Glut1, Gck were increased in maternal islets. Using mouse genetics, conditional deletion of Hif1a in [Beta]-cells ([Beta]Hif1a KO) resulted in glucose intolerance in pregnant, but not virgin, mice. Pregnant [Beta]Hif1a KO mice had impaired target gene expression, defective islet insulin secretion, and reduced vascularity. Pregnant mice develop transient hyperlipidemia, and recapitulation of the hyperlipidemia with fat-challenge or lipid treament induced Hif1a, Vegfa, and Pgk1 expression. Similar to pregnant [Beta]Hif1a KO mice, fat-challenged [Beta]Hif1a KO developed hyperglycemia, hypoinsulinemia, and glucose intolerance. All three hyperlipidemic states show ER stress, and treatment of unstressed mouse or human islets with thapsigargin was sufficient to increase Hif1a and downstream targets. To assess the significance of prolactin signaling in [Beta]-cell function and proliferation in adaptive settings, I created a novel conditional Prlr mouse model. In non-pregnant mice with [Beta]-cell-specific deletion of Prlr ([Beta]Prlr KO), glucose homeostasis is normal. However, pregnant [Beta]Prlr KO mice developed significant glucose intolerance. Given the widespread effects of lactogens on [Beta]-cell physiology, I anticipate altered [Beta]-cell proliferation and secretion in [Beta]Prlr KO islets, and current studies are underway to address this hypothesis. Collectively, our work has revealed that in settings of insulin resistance, both Hif1a and Prlr signaling play important roles in regulating the physiological changes required for proper [Beta]-cell function.
  • Digital
    Wilhelm Foissner, Kuidong Xu.
    Springer2006
    vol. 1. Protospathidiidae, Arcuospathidiidae, Apertospathulidae --
  • Digital
    by John B. Silver.
    Springer2008
    Designing a mosquito sampling programme -- Sampling the egg population -- Sampling the larval population -- Sampling the emerging adult population -- Sampling the adult resting population -- Sampling adults by animal bait catches and by animal-baited traps -- Blood-feeding and its epidemiological significance -- Sampling adults with non-attractant traps -- Sampling adults with light-traps -- Sampling adults with carbon dioxide traps -- Sampling adults with visual attraction traps, sound traps, and other miscellaneous attraction traps -- Estimation of the mortalities of the immature stages -- Methods of age-grading adults and estimation of adult survival rates -- Estimating the size of the adult population -- Measuring adult dispersal -- Experimental hut techniques -- Indices of association and species diversity indices.
  • Digital
    Paolo Dell'Aversana.
    ScienceDirect2017
    I. Two (apparently) different worlds. The exploratory brain -- Cognitive geosciences -- II. Bridging the gap. Exploration -- Imaging -- Recognition -- Integration -- III. Brain-based-technologies and brain empowerment. Brain-based technologies -- Applications to education in geosciences -- From information to significance -- Neuroplasticity and brain empowerment in exploration geosciences -- Epilogue.
  • Digital
    David J. K. Balfour, Marcus R. Munafò, editors.
    Springer2015
    The primary purpose of this book and its companion volume The Neuropharmacology of Nicotine Dependence is to explore the ways in which recent studies on nicotine and its role in tobacco addiction have opened our eyes to the psychopharmacological properties of this unique and fascinating drug. While the present volume considers the molecular and genetic factors which influence behavioral responses to nicotine and how these may impact on the role of nicotine in tobacco dependence, the book The Neuropharmacology of Nicotine Dependence focuses on the complex neural and psychological mechanisms that mediate nicotine dependence in experimental animal models and their relationship to tobacco addiction in humans. These volumes will provide readers with a contemporary overview of current research on nicotine psychopharmacology and its role in tobacco dependence from leaders in this field of research and will hopefully prove valuable to those who are developing their own research programmes in this important topic. CTBN Vol 23 The Behavioral Genetics of Nicotine and Tobacco The primary purpose of this book and its companion volume The Neuropharmacology of Nicotine Dependence is to explore the ways in which recent studies on nicotine and its role in tobacco addiction have opened our eyes to the psychopharmacological properties of this unique and fascinating drug. While the present volume considers the molecular and genetic factors which influence behavioral responses to nicotine and how these may impact on the role of nicotine in tobacco dependence, the book The Neuropharmacology of Nicotine Dependence focuses on the complex neural and psychological mechanisms that mediate nicotine dependence in experimental animal models and their relationship to tobacco addiction in humans. These volumes will provide readers with a contemporary overview of current research on nicotine psychopharmacology and its role in tobacco dependence from leaders in this field of research and will hopefully prove valuable to those who are developing their own research programmes in this important topic.
  • Digital
    edited by Robbin Gibb, Bryan Kolb.
    ScienceDirect2018
    The Neurobiology of Brain and Behavioral Development provides an overview of the process of brain development, including recent discoveries on how the brain develops. This book collates and integrates these findings, weaving the latest information with core information on the neurobiology of brain development. It focuses on cortical development, but also features discussions on how the other parts of the brain wire into the developing cerebral cortex. A systems approach is used to describe the anatomical underpinnings of behavioral development, connecting anatomical and molecular features of brain development with behavioral development. The disruptors of typical brain development are discussed in appropriate sections, as is the science of epigenetics that presents a novel and instructive approach on how experiences, both individual and intergenerational, can alter features of brain development. What distinguishes this book from others in the field is its focus on both molecular mechanisms and behavioral outcomes. This body of knowledge contributes to our understanding of the fundamentals of brain plasticity and metaplasticity, both of which are also showcased in this book.
  • Digital
    Susan L. Andersen, Daniel S. Pine, editors.
    Springer2014
    "Brain development, whether typical or atypical, provides the foundation for all behavior and possible psychopathology. This volume takes a comprehensive and translational approach in describing how basic neuronal patterning occurs, organizes into systems, and forms functional and inter-connected networks. The role that hormones and genes play in influencing brain development is also described. The resultant emotional, cognitive, reward, and social systems show how typical development proceeds. The second part of the book describes when the process of development goes awry. Here, a number of childhood disorders are covered. Autism, ADHD, emotional syndromes of bipolar disorder and depression, oppositional defiant disorder and conduct disorder, and sleep and schizophrenia are included in this volume. Written by leading experts in their respective fields, this volume will be a valuable resource to mental health professionals as well as preclinical investigators hoping to gain additional understanding about the neurobiology of the developing brain."--Publisher's website.
  • Digital
    edited by Andries Kalsbeek, Martha Merrow, Till Roenneberg, and Russell G. Foster.
    ScienceDirect2012
    This issue of Progress in Brain Research reviews current knowledge and understanding, provides a starting point for researchers and practitioners entering the field, and builds a platform for further research and discovery. Leading authors review the state-of-the-art in their field of investigation, and provide their views and perspectives for future research Chapters are extensively referenced to provide readers with a comprehensive list of resources on the topics covered All chapters include comprehensive background information and are written in a clear form that is also accessible to the non-specialist.
  • Digital
    edited by Lisa Plitnick, Danuta Herzyk.
    ScienceDirect2013
    Machine generated contents note: I.Development of Biophar-Maceuticals Defined as Novel Biologics -- 1.Overview of Biopharmaceuticals and Comparison with Small-molecule Drug Development / Thomas R. Gelzleichter -- Introduction -- History and Evolution of Biopharmaceuticals -- Development of Diverse Biopharmaceutical Modalities -- Comparison of Small-Molecule Drugs to Biopharmaceuticals -- Summary -- References -- 2.Regulatory Guidelines and their Application in the Nonclinical Evaluation of Biological Medicines / Maggie Dempster -- Introduction -- Species Selection -- Study Design Considerations for Repeat-Dose Studies -- Immunogenicity -- Reproductive and Developmental Toxicity -- Genotoxicity and Carcinogenicity -- Special Considerations for Anticancer Drugs -- First-in-Human (Fih) Clinical Trial -- Summary -- References -- 3.Early De-risking Strategy for Novel Biotherapeutics / Beth Hinkle -- Introduction -- Establishing A Safety Profile for Biotherapeutics -- General Safety Considerations Related to Biotherapeutics -- Progress in Evaluation of Immunotoxicity -- Can We Better Address Potential Off-Target Toxicity? -- Summary -- References -- 4.Novel Biopharmaceuticals: Pharmacokinetics, Pharmacodynamics, and Bioanalytics / Wolfgang Seghezzi -- Introduction -- Absorption, Distribution and Elimination of Biopharmaceuticals -- Disposition of Modified Molecules -- "Metabolism" and Biodistribution for Biopharmaceuticals -- Immunogenicity and impacts on PK and biodistribution -- Pharmacokinetics and Pharmacodynamics -- Preclinical to Clinical Translation -- Bioanalytics -- Drug Assays -- Biomarkers: Target Engagement Assays -- Immunogenicity Assessment: ADA Assays -- Summary -- References -- II.Development of Biosimilars -- 5.Overview of Biosimilar Therapeutics / Danuta J. Herzyk -- Introduction -- The Concept of Biosimilars -- General Considerations for Development of Biosimilars -- Biosimilar Candidates Based on Modality and Therapeutic Class -- Summary -- References -- 6.Regulatory Standards for the Approval of Biosimilar Products: A Global Review / Barbara Mounho-Zamora -- Introduction -- European Union -- Pioneer for the First Regulatory Pathway for Biosimilar Products -- The World Health Organization Guidance on Biosimilars -- Regulatory Pathway for Biosimilar Products in the United States -- Biosimilar Pathways in Other Regions -- Summary -- References -- 7.Early Characterization of Biosimilar Therapeutics / Thomas R. Gelzleichter -- Introduction -- Recombinant Insulins -- Recombinant Human Growth Hormone -- Recombinant Erythropoietins -- Recombinant Granulocyte Colony-Stimulating Factor -- Recombinant Interferons -- Low Molecular Weight Heparins -- Monoclonal Antibodies -- Other Classes -- Summary -- References -- III.Vaccines -- 8.Introduction to Vaccines and Adjuvants / Deborah L. Novicki -- Introduction -- The History of Vaccines -- The Impact of Vaccines on Human Health -- Advancements in Vaccines Technologies -- Advancements in Adjuvant Technologies -- Approved Infectious Disease Vaccines and Diseases for Which Preventive Vaccines are Still Needed -- Therapeutic Vaccines -- Product Complexity From a Quality Perspective -- Nonclinical Testing -- Clinical Testing -- Vaccine Development Using the Animal Rule -- The Anti-Vaccines Movement and Misperceptions About Vaccines and Their Safety -- Summary -- References -- 9.Global Regulatory Guidelines for Vaccines / Lisa M. Plitnick -- Introduction -- Toxicity Assessment -- Additional Toxicity Assessments -- Special Considerations -- Formulation/Delivery Devices -- Alternate Routes of Administration -- Special Considerations for Particular Types of Vaccines -- Summary -- References -- 10.Special Considerations for the Nonclinical Safety Assessment of Vaccines / Jayanthi J. Wolf -- Introduction -- De-risking Strategies for Vaccines -- Pharmacokinetics and Pharmacodynamics Assessments -- Differences in the Nonclinical Safety Assessment of Vaccines and Biopharmaceutical Drugs -- Summary -- References -- IV.Specialty Biologics and Indications -- 11.Turning the Corner with Viral-based Gene Therapy -- Development of the Rogue Biopharmaceutical / Timothy K. Maclachlan -- Introduction -- A History and Primer of Gene Therapy -- The Process of Getting Genes into Cells -- Health Authority Regulation of Gene Therapy Products -- Nonclinical Safety Studies and Regulatory Guidance -- Summary -- References -- 12.Blood Products / Vikram Arora -- Introduction -- Plasma-Derived Blood Products -- Blood Products Derived from Recombinant Technologies -- Summary -- References -- 13.Biological Therapies for Cancer / Gautham K. Rao -- Introduction -- Global Regulatory Guidances -- General Principles of Toxicology Assessments -- Nonclinical Studies and Principles of Study Design -- Specialty Toxicology Assessments -- Pharmacokinetics, Immunogenicity, and Pharmacodynamics -- Nonclinical Development of Marketed Biologies -- Recombinant Analogs of Endogeneous Human Proteins (Interferons, Cytokines, Enzymes) -- Summary -- References -- 14.Nonclinical Development of Multi-targeting Biopharmaceuticals / Anu V. Connor -- Introduction -- Scientific Rationale for Multi-Targeting Biopharmaceuticals (MTBs) -- Evolution of Technology Platforms -- General Challenges and Considerations -- Summary of Challenges -- T Cell-Dependent Bispecific Antibody (TDB) Biotherapeutics -- Dual-Targeting Antibodies -- Summary -- References -- 15.Considerations in the Development of Pluripotent Stem Cell-based Therapies / Joy A. Cavagnaro -- Introduction -- Early Decisions -- Nonclinical Development -- Translating Preclinical Data to Clinical Application -- Global Regulatory Guidance -- Summary -- References.
  • Digital
    by Andrii Rozhok.
    Springer2008
  • Digital
    Giuseppe Valacchi, editor ; Paul A. Davis, co-editor.
    Springer2008
  • Digital/Print
    edited by Helmut Sies and Bernard Brüne.
    Digital : ScienceDirect2007
    Print2007
  • Digital
    edited by Lars Olof Björn.
    Springer2008
  • Digital
    John A. Fuerst, editor.
    Springer2013
    History, classification and cultivation of the planctomycetes / Cheryl Jenkins and James T. Staley -- Cell compartmentalization and endocytosis in planctomycetes: structure and function in complex bacteria / John A. Fuerst, Richard I. Webb, and Evgeny Sagulenko -- Structural aspects of MC proteins of PVC superphylum members / Damien P. Devos -- Cell biology of anaerobic ammonium-oxidizing bacteria: unique prokaryotes with an energy-conserving intracellular compartment / Sarah Neumann, Muriel C.F. van Teeseling and Laura van Niftrik -- Acidophilic planctomycetes: expanding the horizons of new planctomycete diversity / Svetlana N. Dedysh and Irina S. Kulichevskaya -- Toward the development of genetic tools for Planctomycetes / Mareike Jogler and Christian Jogler -- Genomics and bioinformatics of the PVC superphylum / Olga K. Kamneva, Daniel H. Haft, Stormy J. Knight, Davide A. Liberles, and Naomi L. Ward -- Distribution and evolution of C1 transfer enzymes and evolution of the planctomycetes / Ludmila Chistoserdova -- Unusual members of the PVC superphylum: the methanotrophic Verrucomicrobia genus "Methylacidiphilum" / Christine E. Sharp, Huub J.M. Op den Camp, Ivica Tamas, and Peter F. Dunfield -- Phyla related to Planctomycetes: members of phylum Chlamydiae and their implications for Planctomycetes cell biology / Claire Bertelli and Gilbert Greub -- Planctomycetes: their evolutionary implications for models for origins of eukaryotes and the eukaryote nucleus and endomembranes / John A. Fuerst and Evgeny Sagulenko -- Final word: the future of planctomycetology and related studies / John A. Fuerst -- Index.
  • Digital
    Berryman, A. A.; Berryman, A. A.; Kindlmann, Pavel.
    Springer2008
  • Digital
    Peter Gluckman, Alan Beedle, Tatjana Buklijas, Felicia Low, Mark Hanson.
    OSO2016
  • Digital
    Sara L. Prescott.
    Cis-regulatory changes play a central role in normal phenotypic variation within a species as well as in morphological divergence, yet the regulatory principles underlying emergence and modulation of human traits remain poorly understood. As part of my PhD work, I have used epigenomic profiling to annotate and explore the molecular effects of enhancer mutations using in vitro-derived neural crest cells. First, by exploiting high-frequency polymorphisms in human cell lines, we explored how mutations can cooperatively affect binding of key neural crest transcription factors at specific human enhancers. We then extended this analysis across species, using human and chimpanzee cranial neural crest cells to systematically and quantitatively annotate divergence of craniofacial cis-regulatory landscapes genome-wide. We found that epigenomic divergence is often attributable to genetic variation within TF motifs at orthologous enhancers, with a novel motif being most predictive of activity biases. We further explored the properties of this cis-regulatory change, revealing the role of particular retroelements, uncovering broad clusters of species-biased enhancers near genes associated with human facial variation, and demonstrating that cis-regulatory divergence is linked to quantitative expression differences of crucial neural crest regulators. This work provides a wealth of candidates for future studies on human craniofacial development and evolution, and demonstrates the value of "cellular anthropology, " a strategy of using in-vitro-derived embryonic cell types to elucidate both fundamental and evolving mechanisms underlying morphological variation in higher primates.
  • Digital
    ScienceDirectv. 2-15, 1995-2004.
  • Digital/Print
    Jaroslava Halper, editor.
    Digital : Springer2014
    Print2014
    This volume is a reference handbook focusing on diseases like Marfan syndrome, Ehlers-Danlos syndrome, Loeys-Dietz syndrome and other heritable soft connective tissue diseases. The book presents detailed information for both basic scientists and for clinicians seeing patients. It is also a stepping stone for new investigations and studies that goes beyond the facts about the composition and biochemistry of the connective tissue and extracellular matrix, as the authors connect individual components to specific aspects of various soft tissue disorders and to the actual or potential treatment of them. Progress in Heritable Soft Connective Tissue Diseases features very prominent physicians and scientists as contributors who bring their most recent discoveries to the benefit of readers. Their expertise will help clinicians with proper diagnosis of sometimes elusive and uncommon heritable diseases of soft connective tissues. This book also offers an update on the pathophysiology of these diseases, including an emphasis on unifying aspects such as connections between embryonic development of the different types of connective tissues and systems, and the role of TGF-beta in development and physiology of soft tissues. This new set of data explains, at least in part, why many of these disorders are interconnected, though the primary pathophysiological events, such as gene mutations, may be different for each disorder.
  • Digital
    J. Robin Harris, editor.
    Springer2012
    Introduction and technical survey: Protein aggregation and fibrillogenesis -- Fibril formation by short synthetic peptides -- In vitrooligomerization and fibrillogenesis of amyloid-beta peptides -- Tau fibrillogenesis -- Prion protein aggregation and fibrillogenesisin vitro -- Alpha-synuclein aggregation and modulating factors -- Pathological self-aggregation of [beta](2)-microglobulin: A challenge for protein biophysics -- Islet amyloid polypeptide: Aggregation and fibrillogenesisin vitroand its inhibition -- Mechanisms of transthyretin aggregation and toxicity -- Fibrillogenesis of huntingtin and other glutamine containing proteins -- Aggregation and fibrillogenesis of proteins not associated with disease: a few case studies -- Experimental inhibition of peptide fibrillogenesis by synthetic peptides, carbohydrates and drugs -- Experimental inhibition of fibrillogenesis and neurotoxicity by amyloid-beta (abeta) and other disease-related peptides/proteins by plant extracts and herbal compounds -- Alzheimer's disease -- Modeling the polyglutamine aggregation pathway in Huntington's disease: from basic studies to clinical applications -- Parkinson's disease -- Human prion diseases: From kuru to variant Creutzfeldt-Jakob disease -- Animal prion diseases -- [beta](2)-Microglobulin amyloidosis -- Systemic AA amyloidosis -- Familial amyloidotic polyneuropathy and transthyretin -- The challenge of systemic immunoglobulin light-chain amyloidosis (AL).
  • Digital
    edited by Mike S. Lee and Qin C. Ji.
    Wiley2017
    Contemporary Protein Analysis by Ion Mobility Mass Spectrometry / Johannes PC Vissers, James I Langridge -- High-Resolution Accurate Mass Orbitrap and Its Application in Protein Therapeutics Bioanalysis / Hongxia Wang, Patrick Bennett -- Current Methods for the Characterization of Posttranslational Modifications in Therapeutic Proteins Using Orbitrap Mass Spectrometry / Zhiqi Hao, Qiuting Hong, Fan Zhang, Shiaw-Lin Wu, Patrick Bennett -- Macro- to Micromolecular Quantitation of Proteins and Peptides by Mass Spectrometry / Suma Ramagiri, Brigitte Simons, Laura Baker -- Peptide and Protein Bioanalysis Using Integrated Column-to-Source Technology for High-Flow Nanospray / Shane R Needham, Gary A Valaskovic -- Targeting the Right Protein Isoform: Mass Spectrometry-Based Proteomic Characterization of Alternative Splice Variants / Jiang Wu -- The Application of Immunoaffinity-Based Mass Spectrometry to Characterize Protein Biomarkers and Biotherapeutics / Bradley L Ackermann, Michael J Berna -- Semiquantification and Isotyping of Antidrug Antibodies by Immunocapture-LC/MS for Immunogenicity Assessment / Jianing Zeng, Hao Jiang, Linlin Luo -- Mass Spectrometry-Based Assay for High-Throughput and High-Sensitivity Biomarker Verification / Xuejiang Guo, Keqi Tang -- Monitoring Quality of Critical Reagents Used in Ligand Binding Assays with Liquid Chromatography Mass Spectrometry (LC-MS) / Brian Geist, Adrienne Clements-Egan, Tong-Yuan Yang -- Application of Liquid Chromatography-High Resolution Mass Spectrometry in the Quantification of Intact Proteins in Biological Fluids / Stanley (Weihua) Zhang, Jonathan Crowther, Wenying Jian -- LC-MS/MS Bioanalytical Method Development Strategy for Therapeutic Monoclonal Antibodies in Preclinical Studies / Hongyan Li, Timothy Heath, Christopher A James -- Generic Peptide Strategies for LC-MS/MS Bioanalysis of Human Monoclonal Antibody Drugs and Drug Candidates / Michael T Furlong -- Mass Spectrometry-Based Methodologies for Pharmacokinetic Characterization of Antibody Drug Conjugate Candidates During Drug Development / Yongjun Xue, Priya Sriraman, Matthew V Myers, Xiaomin Wang, Jian Chen, Brian Melo, Martha Vallejo, Stephen E Maxwell, Sekhar Surapaneni -- Sample Preparation Strategies for LC-MS Bioanalysis of Proteins / Long Yuan, Qin C Ji -- Characterization of Protein Therapeutics by Mass Spectrometry / Wei Wu, Hangtian Song, Thomas Slaney, Richard Ludwig, Li Tao, Tapan Das.
  • Digital
    Dena S. Leeman.
    The stem cell pool of most organs contains quiescent and actively dividing (activated) populations. These populations face different challenges over the course of life, raising the question of whether they maintain homeostasis differently and age in different ways. In this work, I perform transcriptomic profiling on multiple populations of the brain's regenerative neural stem cell (NSC) pool from young and old mice to gain an unbiased overview of their differential homeostatic properties and their changes with age. Interestingly, I find that quiescent and activated NSC populations differ in their degree of transcriptome-wide change with age and express different transcriptional signatures for the three primary branches of protein homeostasis (proteostasis)—the proteasome, the lysosome, and molecular chaperones. Additionally, aspects of these divergent modes of proteostasis can be generalized to other organs' stem cells. I functionally validate that quiescent and activated NSC populations differ in their regulation of multiple branches of proteostasis. Intriguingly, the populations with less active proteasomes and lysosomes also have higher levels of protein aggregates and undergo a greater degree of transcriptional change with age. Additionally, I find that the genes most changed with age in each cell type are the genes that constitute that cell type's signature with regard to quiescence and activation. Together, these findings highlight novel differences in the proteostatic strategies used by different stem cell populations that could potentially contribute to their differential aging.
  • Digital
    Rosa Margesin ... [et. al.], editors.
    Springer2008
  • Digital
    Stefanie Duttler.
    One of the most critical times in the life of a protein is during its biogenesis at the ribosome. A nascent polypeptide cannot achieve its final fold while still bound to the ribosome, and is at risk of being accessed by the cellular quality control machinery. However, the extent to which cotranslational ubiquitination and degradation occur remains under debate. Conflicting reports exist, ranging from 40% of nascent chains being subject to cotranslational degradation to claims that nascent polypeptides are, on the contrary, protected from degradation. Here, we developed a direct and quantitative method to determine the extent of cotranslational ubiquitination using ribosome isolation coupled to ubiquitin-affinity purification. We find that cotranslational ubiquitination occurs at low levels, and that at least a fraction of ubiquitinated nascent chains is targeted to the proteasome for degradation. We determined which proteins are susceptible to cotranslational ubiquitination and find that intrinsic sequence features determine the cotranslational ubiquitination of a specific subset of proteins. These proteins are more aggregation-prone, highly expressed and longer than 400 amino acids. Short proteins seem to be protected from cotranslational ubiquitination. One such mechanism could be the cotranslational formation of folded structures, which lead us to disrupt cotranslational folding by deleting chaperones or through drugs such as azetidine-2-carboxylic acid (AZC). Both lead to an increase of cotranslational ubiquitination as observed by pulse-labeling as well as microarray analysis. Ribosome-associated chaperones and cotranslational folding seem to have evolved to prevent a high degree of nascent chain degradation/ubiquitination. Similarly to ribosome-associated chaperones, the ubiquitin-proteasome-system may also be able to access nascent protein chains, but rather target them for degradation. We therefore determined which parts of the UPS mediate cotranslational ubiquitination. A clear E2-E3 relationship could however not be established, possibly due to redundancy in the cellular ubiquitin ligase network. Finally, we find that disruption of mRNA quality control components also leads to enhanced ubiquitination of nascent chains, suggesting that cotranslational quality control serves to avoid the production of erroneous proteins and protect the cell from resulting toxicity.
  • Digital
    edited by Anne Charmantier, Dany Garant, Loeske E.B. Kruuk.
    OSO2014
    1. The study of quantitative genetics in wild populations -- 2. Four decades of estimating heritabilities in wild vertebrate populations -- 3. Quantitative genetic approaches to understanding sexual selection and mating system evolution in the wild -- 4. Individual behaviour : behavioural ecology meets quantitative genetics -- 5. The quantitative genetics of senescence in wild animals -- 6. The effects of others' genes : maternal and other indirect genetic effects -- 7. Dominance genetic variance and inbreeding in natural populations -- 8. Cross-pollination of plants and animals : wild quantitative genetics and plant evolutionary genetics -- 9. Quantitative genetics of wild populations of arthropods -- 10. Case study : quantitative genetics and sexual selection of weaponry in a wild ungulate -- 11. Epigenetic processes and genetic architecture in character origination and evolution -- 12. Evolutionary potential and constraints in wild populations -- 13. Molecular quantitative genetics -- 14. Bayesian approaches to the quantitative genetic analysis of natural populations -- 15. Evolutionary dynamics in response to climate change.
  • Digital
    edited by Adriana Fontes, Beate Saegesser Santos.
    Springer Protocols2014
  • Digital
    Joanna Rae Kovalski.
    Characterizing the protein interactome of difficult-to-drug oncogenes, such as Ras, may identify new cancer targets. We undertook live-cell proximity-dependent protein labeling with wild type (WT) and oncogenic mutant (MT) KRAS, NRAS and HRAS isoforms in their associated tumor types, postulating that proximity-dependent protein labeling could detect interactions mediating pro-cancer functions missed by conventional approaches. This identified known, direct Ras interactors, including Raf and PI3K, as well as 130 new Ras-proximal proteins. The interactome was enriched for well-known Ras regulated roles such as cytoskeletal organization, cell junction integrity and cytoplasmic signaling pathways as well as a surprising group of small molecule transport proteins. Moreover, each Ras isoform exhibited a unique set of biological process enrichments, shedding light on isoform specific the functional pathways. A CRISPR genetic screen in 10 cell types demonstrated that 17 of these novel candidates phenocopied oncogenic Ras loss, resulting in decreased proliferation. Combined genetic and proteomic analysis identified well know oncogenic Ras effectors, Raf and PI3K; however, mTOR was the top oncogenic Ras interactor. mTOR-oncogenic Ras interaction is direct and occurs in human mutant KRAS tumors. The interaction depends upon mTORC2 constituents Rictor and MAPKAP1, but not mTORC1 component Raptor. Disruption of the oncogenic Ras-mTORC2 interaction blocked Ras-driven tumorigenesis in vivo via transcriptional regulation of cell cycle progression. Proximity-dependent protein labeling and CRISPR genetics thus synergize to identify new targets in cancers driven by Ras and other dominant oncogenes.
  • Digital
    Samantha J. Richardson, Vivian Cody [editors].
    Springer2009
  • Digital
    Manuel Eduardo Lopez, Jr.
    Niemann-Pick disease type C (NPC) is a rare metabolic lysosomal storage disorder (LSD) marked by accumulation of large quantities of cholesterol, lipids and other metabolites in cells. Though the disorder has been extensively explored using various genetic animal models, an understanding of the molecular and cellular pathology of the disease remains limited. A cell-type-specific and regulable rescue mouse model of NPC disease was engineered in order to identify the therapeutically relevant cell type and ascertain the effect of inflammation on disease progression. With the current information presented in this dissertation, a probable road map of NPC disease pathology has been drawn. The road map for NPC may also be applicable to, or act as a template for, other lysosomal storage diseases and neurodegenerative disorders with similar pathologies.
  • Digital
    Jaclyn Geok Yueen Lim.
    Adult stem cells are undifferentiated cells that are capable of both self-renewal and differentiation into a variety of specialized cells. Adult stem cell lineages have been identified in several organs including skin, blood, breast, intestine, bladder, skeletal muscle, prostate, and the testes. The changes in homeostatic conditions in these organs caused by tissue turnover or injury rely heavily on the pool of adult stem cells for cell replenishment. Therefore, the activity of adult stem cells must be tightly controlled, and many of these regulations are orchestrated by the stem cell niche, the local microenvironment in which stem cells reside. The fast generation cycle and the genetic tractability of fruit flies make the Drosophila testis stem cell niche an ideal system for the study of adult stem cell regulation. The Drosophila testis maintains two types of stem cells: germline stem cells (GSCs) which give rise to sperm, and cyst stem cells (CySCs) which differentiate into cyst cells that encapsulate germ cells. The somatic cyst cell lineage has been implicated to be required at several stages of spermatogenesis and play pivotal roles in germline proliferation, survival, and differentiation. This dissertation focuses on understanding the role of the cyst cell lineage in GSC maintenance and investigating the mechanisms by which cyst cells direct early germ cell differentiation. Previously, it has been proposed that CySCs are the source of instructive self-renewal cues for GSCs. In contrast to this model, I showed that early germ cells with GSC characteristics can be maintained in the absence of CySCs and cyst cells. These germ cells failed to enter the transit-amplifying program, which is regarded as the first step of differentiation in many adult stem cell lineages. My observations suggest that cyst cells provide a pro-differentiation environment for GSCs, and that this mechanism(s) may be repressed in CySCs which indirectly allow for GSC self-renewal. Encapsulation of germ cells by cyst cells is one of the differentiation-promoting mechanisms imposed by the soma on the germline, and I have uncovered that this process requires activation of the EGFR-Ras-MEK-MAPK pathway in differentiated cyst cells. Furthermore, I also showed that repression of EGFR activation in CySCs is important in maintaining the population of GSCs and CySCs at the niche, as premature activation of the pathway resulted in displacement of GSCs from the hub by somatic cells. Preliminary studies revealed a STAT target gene, Socs36E as a negative regulator of the EGFR pathway in CySCs to prevent out-competition of GSCs by somatic cells. To understand how the somatic cyst cells germline differentiation, I performed two genetic screens: an RNAi screen of genes that caused premature germ cell differentiation when misexpressed in the soma, and a misexpression screen of genes predicted to be cell-surface and secreted proteins. Three promising candidates were identified through these screens: two ribosomal subunits, Rpl13A and RpS10a; and a septate junction component, Neurexin IV. The two ribosomal proteins may be involved in the soma to promote germ cell encapsulation. Neurexin IV however, operates non-cell autonomously in cyst cells to regulate germ cell differentiation into spermatocytes. Together, the results of this dissertation emphasize the importance and complexity of the interaction between adult stem cells and their microenvironment in maintaining tissue homeostasis.
  • Digital
    Yanyin Kimberle Shen.
    The central nervous system, composed of the brain and the spinal cord, is made up of two broad classes of cell types: neurons and glia. The interaction between glial cells and neurons is crucial for proper development and function of the nervous system. The first type of glial cells, macroglia, includes astrocytes and oligodendrocytes. Oligodendrocytes are the cells that form myelin, an evolutionary adaptation that allows rapid and efficient propagation of action potentials along axons. Diseases of myelin include multiple sclerosis, in which damage to the myelin sheath in the central nervous system disrupts flow of information between the brain and the body, often leading to debilitating symptoms. The second glia cell type, microglia, performs a variety of roles in the CNS including phagocytic clearance of dead neurons and debris. Microglia have been implicated in neurodegenerative diseases such as Alzheimer's Disease, which is characterized by memory loss, neuronal death and accumulation of abnormal amyloid plaques. By understanding the pathways that control microglia and oligodendrocyte development and function, novel therapies for CNS diseases may be developed by harnessing the capabilities of these cell types. In this dissertation, I focus on the roles of the Rag-Ragulator complex and other lysosomal-associated proteins in microglia and oligodendrocytes. In Chapter 2, I describe the identification of mutations that disrupt the Rag-Ragulator complex in a screen for myelin mutants. In mutants lacking RagA and Lamtor4, components of the Rag-Ragulator complex, myelinated axons are reduced compared to wildtype siblings, despite the presence of oligodendrocytes. The absence of Rag-Ragulator function prevents oligodendrocytes from maturing and ensheathing exons. These results point toward a key function of lysosomes in myelination. In Chapter 3, I describe the microglial function of the Rag-Ragulator complex. RagA and Lamtor4 mutants have a reduced number of microglia. The few microglia that are present have an expanded lysosomal compartment - yet are unable to properly clear debris that they have engulfed. In Chapter 4, I characterize Tcirg1b mutants, which exhibit a similar microglia phenotype to RagA mutants. Tcirg1b encodes a component of the vacuolar proton pump that acidifies the lysosome. Tcirg1b mutants have microglia that are engorged with undigested apoptotic neuronal debris. Together, this work defines new roles of lysosomal genes in oligodendrocytes and microglia, thereby highlighting the importance of lysosome function in different glial cell types.
  • Digital
    Daniel Richard Calnan.
    The FoxO family of transcription factors plays an important role in longevity and tumor suppression by regulating the expression of a wide range of target genes. FoxO3 has recently been found to be associated with extreme longevity in humans and to regulate the homeostasis of adult stem cell pools in mammals, which may contribute to longevity. The activity of FoxO3 is controlled by a variety of post-translational modifications that have been proposed to form a 'code' affecting FoxO3 subcellular localization, DNA binding ability, protein-protein interactions and protein stability. Lysine methylation is a key post-translational modification on histones that regulate chromatin accessibility and is a key part of the 'histone code'. However, whether lysine methylation plays a role in modulating FoxO3 activity has never been examined. I found that the methyltransferase Set9 directly methylates FoxO3 in vitro and in cells. Using a combination of tandem mass spectrometry and methyl-specific antibodies, I find that Set9 methylates FoxO3 at a single residue, lysine 271, a site previously known to be deacetylated by Sirt1. Methylation of FoxO3 by Set9 decreases FoxO3 protein stability, while slightly increasing FoxO3 transcriptional activity. The modulation of FoxO3 stability and activity by methylation may be critical for fine-tuning cellular responses to stress stimuli, which may in turn affect FoxO3's ability to promote tumor suppression and longevity. Post-translational modifications control many aspects of FoxO3 activity, including protein stability, subcellular localization and binding partner association. To analyze whether FoxO3 functions primarily alone, or in a complex with other factors, I used size exclusion chromatography to assess the size of the potential FoxO3 protein complexes in cellular extracts. I found that FoxO3 is present in fractions with a relative molecular weight larger ranging from 250 to 700 kDa. Interestingly, the cytoplasmic fraction of FoxO3 appears to be in a larger complex than the nuclear fraction, suggesting that FoxO3 is present in more than one protein complex in cells. To identify novel binding partners of FoxO3 that could be present in these large molecular-weight protein complexes, I conducted a tandem affinity purification (TAP) of dual tagged FoxO3 in HeLa S3 cells followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) of the elution from the immunoprecipitation. I identified over 1,000 potential FoxO3 binding partners that were not present in the control immunoprecipitation. These candidate binding partners included protein kinases (e.g. mTOR, MAPKs), other tumor suppressors (e.g. p65, p130) and oncogenes (e.g.Myb), as well as proteins that contain a methyl lysine (e.g. WDR17, PHF3) and acetyl lysine (e.g. BAZ2B, BRD1) binding domains. Taken together, these results suggest that FoxO3 functions in large protein complexes that could affect FoxO3 activity. The formation of FoxO3-containing complexes could be triggered by FoxO3 post-translational modifications. By increasing our understanding of the regulation of FoxO3, as well identifying possible interacting proteins, we further our knowledge of the pathways important for both longevity and age related diseases, including cancer.
  • Digital
    NAP2007
  • Digital
    Peggie Cheung.
    Epigenetics is the study of heritable changes in gene expression that occur independent of changes in the primary DNA sequence. Chromatin structure defines the state in which genetic information is organized in the cell. The organization of this structure greatly influences the abilities of genes to be activated or silenced. In eukaryotic cells, 146 base pairs of DNA is wrapped around the histone octamer (two H2A/H2B dimers and one H3/H4 tetramer) forming the nucleosomes, the basic unit of chromatin. The nucleosome cores are connected by linker DNA sequences to further package into higher-order chromatin structures. In addition to the core histones, each histone contains an unstructured N-terminal tail. The histone tails are the sites of most of the post-translational modifications (PTMs), such as acetylation, methylation and phosphorylation. These modifications regulate the structure and function of chromatin through two general mechanisms. In the first model, histone modifications may play a direct role in altering chromatin structure. For example, histone acetylation neutralizes the positive charge of lysine residues and thus, affecting the interactions of the histones with DNA, transcription factors and other nucleosomes. Secondly, histone modifications can indirectly affect chromatin functions by serving as a binding platform for modular proteins and complexes. For instance, the methylation of histone H3 at lysine 9 is recognized specifically by the chromatin organization modifier (Chromo) domain of heterochromatin protein 1 (HP1), which contributes to the induction and the propagation of heterochromatin structure. Ten years ago, Strahl and Allis proposed a general idea of "histone code" hypothesis, which states that histone modifications, distinct or in combination, to form a "code" to influence chromatin structure and lead to varied transcriptional outputs. In recent years, many chromatin regulators were identified, such as the proteins that "write" or "erase" or "read" the modifications. Some chromatin regulators are expressed in a tissue-specific manner and play important roles in physiology and disease pathogenesis. For instance, the H3K27 histone methyltransferase EZH2 is overexpressed in tumors such as prostate, breast, colon, skin and lung cancer. Disruption of normal patterns of covalent histone modifications is another hallmark of cancer. One of the most characterized examples is the global reduction of the trimethylation of H4K20 and acetylation of H4K16, along with hypomethylation, at repeat sequences in many tumors. Since post-translational modifications have been shown to be important for many biological processes such as gene expression, DNA damage and repair and apoptosis, disruption of these processes has been linked to carcinogenesis and other disease pathogenesis. The discovery of reversible mutations in the epigenetic machinery makes post-translational modifications as one of the most promising and expanding fields in the current biomedical research. Methylation does not neutralize the charge of the modified residue nor does addition of methyl groups add considerable bulk, this mark is believed to create a distinct molecular architecture on histones that is recognized by specialized binding domains present within chromatin-regulatory proteins. The proteins and domains that recognize histone modifications, named "effectors" or "readers", are thought to define the functional consequences of lysine methylation by transducing molecular events at chromatin into biological outcomes. Mutations in these "readers" proteins have been shown to link to many disease pathogenesis. However, relatively few effector domains have been identified in comparison to the number of modifications present on histones and non-histone proteins. Here we developed a human epigenome peptide microarray platform (HEMP) for high-throughput discovery of chromatin effectors. We probed this platform with modification-specific antibodies and known chromatin effector domains to test the integrity of the peptides on the slides. We also screened a library of Royal Domain family members and identified three effector proteins with novel modified-histone binding activity. Hence, the development of the HEMP facilitates the identification of effector proteins and understanding of chromatin signaling networks. Multiple Myeloma (MM) is a malignancy of bone marrow plasma cells that frequently results in bone marrow destruction, bone marrow failure and death. 15% of patients with multiple myeloma is diagnosed with an immunoglobin gene, t(4; 14), translocation. MM patients carrying the t(4; 14) translocation is associated with the overexpression of WHSC1/MMSET/NSD2. NSD2 is a protein lysine methylatransferase in the nuclear receptor binding SET domain protein family. However, the molecular mechanism by which NSD2 contributes to myeloma pathogenesis is not known. Here we show that the dimethylation of histone H3 at lysine 36 (H3K36) is the principal physiological activity of NSD2. In mammalian cells, H3K36me2 normally maps to gene bodies. In t(4; 14)+ myeloma cells, overexpression of NSD2 disrupts the physiologic genomic organization of H3K36me2 which is found being dispersed throughout the genome. NSD2 expression is linked to transcription activation and H3K36me2 location at gene bodies positively correlates with transcription levels. In Myeloma cells, NSD2-mediated localized elevation of H3K36me2 induces transcription at normally inert cancer-associated genes. Catalytic activity of NSD2 confers tumor formation in xenograft model and promotes oncogenic transformation of primary cells by regulating transcriptional programs that favor oncogenesis. The BAH domain is an evolutionarily conserved chromatin-associated motif. Utilizing the HEMP, we screened several BAH domains from yeast and human for binding activity. We found that the BAH domain of human ORC1 specifically bind to H4K20me2 peptides. Structural studies show that BAH domain has an aromatic dimethyl-lysine-binding cage that interacts with the bound peptide. ORC1 is dispensable for ORC complex assembly but is necessary for loading of the complex into chromatin. The ability of ORC1 BAH domain binding to H4K20me2 is required for the efficient stabilization of ORC complex at chromatin. H4K20me2 is enriched at replication origins. Abrogation in ORC1 and H4K20me2 interactions impairs cell-cycle progression. Mutations in ORC1 BAH domain have been implicated in aetiology of Meier-Gorlin syndrome (MGS), a form of primordial dwarfism. In a zebrafish model, orc1 morphants display an MGS-like dwarfism phenotype, which can be rescued by wild type Orc1 but not ORC1 binding mutants. Zebrafish depleted with H4K20me2 also displays the MGS-like phenotype. Together, our findings reveal a new function for histone methylation signaling at chromatin in the regulation of DNA replication and organismal growth. KDM2A is the first jumonjiC domain-containing demethylase identified. We solved the co-crystal structure of KDM2A and its substrate, H3K36me2. We found that KDM2A demethylation activity is required to maintain genomic stability. We also show that KDM2A is a tumor suppressor and its demethylation activity is required for suppressing cellular transformation.
  • Digital
    Kelly Elizabeth McCann.
    Efficient DNA double-strand break (DSB) repair is essential for maintaining the stability of the genome. A single long-lived DSB can cause cell lethality (Bennett et al., 1996). Humans with defects in DSB repair are sensitive to DNA damaging agents and are predisposed to developing cancers, as exemplified by such diseases as Nijmegan breakage syndrome, Ataxia telangiectasia, and breast cancer susceptibility in women with mutations in the BRCA1 and BRCA2 genes (Duker, 2002). Repair of DNA damage requires activation of cell cycle checkpoint controls, recruitment of repair proteins to DNA lesions, and transcriptional activation of relevant genes. As shown by our data, deletion of particular histone modification genes produces sensitivity to ionizing radiation in Saccharomyces cerevisiae, suggesting a role for chromatin modification enzymes in the repair process as well. Because damage recognition and repair of lesions are both influenced by chromatin structure, we began by studying the role of histone acetylation in the DNA damage response. Acetylation of the N-terminal tails of histone H4 opens the chromatin to allow repair enzymes to access broken DNA. Through a screen of the yeast deletion pool, we found that deletion of BRE1 and DOT1 genes causes sensitivity to ionizing radiation. Ubiquitination of H2B on lysine 123 (H2B-K123) by ubiquitin ligase Bre1 is necessary for methylation of H3 on lysine 79 (H3-K79) by Dot1. Through the histone modifications they catalyze, these proteins are involved in many aspects of the DNA repair response, as outlined in Sections C, D, and E. Our studies focused on homologous recombination repair defects, genome-wide expression patterns in BRE1 and DOT1 deletion mutants, an analysis of the data regarding proteins purported to bind to methylated H3-K79, and optimization of a protein purification strategy to find Dot1 binding partners. Our yeast deletion pool screen also predicted a role for N-terminal acetyltransferase complex NatB in DNA double-strand break repair. In Section F, we build a case for acetylation of DNA end-binding protein Mre11.
  • Digital
    Brian A. Baldo.
    Springer2016
    1: Approved Biologics Used For Therapy and their Adverse Effects -- 2: Monoclonal Antibodies: Introduction -- 3: Monoclonal Antibodies Approved for Cancer Therapy -- 4: Other Approved Therapeutic Monoclonal Antibodies -- 5: Cytokines -- 6: Fusion Proteins -- 7: Peptide Hormones -- 8: Glycoprotein Hormones -- 9: Enzymes Approved for Therapy -- 10: Blood Coagulation -- 11: Vaccines -- 12: Botulinum Neurotoxins -- 13: Biosimilars.
  • Digital
    Julie Rebecca Perlin.
    The nervous system connects cells throughout the body to coordinate actions and transmit signals. Critical to the nervous system are the neurons that extend axons to their targets and the glial cells that interact with these axons. Oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system wrap axons to make the myelin sheath. Myelin is critical for enhancing the speed of action potentials as well as providing support to axons. Myelin was a critical adaptation that has allowed vertebrates to increase in size, precision of movement, and complexity. Insults to myelin cause devastating diseases, and a better understanding of the normal development of myelinating glia is necessary for improving treatment of human neuropathies. In this dissertation I investigate both well-known and novel signaling pathways and their roles in Schwann cell migration and myelination in zebrafish peripheral nerves. Before making myelin, Schwann cells must migrate along and cover the surface of a bundle of axons. Here, I demonstrate that Neuregulin 1 type III (Nrg 1 type III) is required in neurons to signal through ErbB receptors in Schwann cells for Schwann cell migration along the posterior lateral line nerve, a mechanosensory nerve. Further, ectopic expression of this signal in all neurons is sufficient to attract peripheral Schwann cells into the spinal cord. There appears to be distinct regulation of Schwann cell migration in different nerves of the peripheral nervous system, as migration of Schwann cells in motor nerves requires ErbB receptors but not the Nrg 1 type III ligand. Nrg1 type III does, however, control myelination in both sensory and motor nerves. Schwann cell migration is not only important to properly localize Schwann cells, but also to localize the lateral line nerve itself, which begins in the epidermis but then transitions across a basement membrane to the subepidermal space. As they migrate, Schwann cells degrade the basement membrane beneath the skin, which allows the nerve to transition out of the epidermis, and then rebuild the basement membrane after the nerve has been repositioned and protected from the disorganization that otherwise would take place if it remained in the epidermis. Finally, through analysis of a mutation that was found in a forward genetic screen for genes essential in myelination, I also identify a novel regulator of Schwann cell myelination. Together this work elucidates new roles of known genes in Schwann cell and nerve development and also identifies a novel gene required for peripheral myelination.
  • Digital
    Sara Elaine Brownell.
    This thesis explores the use of small heat shock proteins as anti-inflammatory therapeutics in the context of neurological diseases, specifically multiple sclerosis (MS) and stroke. The family of small heat shock proteins (sHSPs) has been extensively studied as intracellular molecular chaperones. However, recent studies looking at the role of sHSPs in neurological diseases have demonstrated a near universal upregulation of certain sHSPs in damaged and diseased brains. Initially, it was thought that sHSPs are pathological in these disease states, but transgenic overexpression and exogenous administration of sHSPs in various experimental disease paradigms have shown just the contrary -- that sHSPs are protective, not pathological. In this thesis, I have found that members of the family of sHSPs are protective and therapeutic in mouse models of multiple sclerosis and stroke, experimental autoimmune encephalomyelitis (EAE) and middle cerebral artery occlusion (MCAO), respectively. Alpha B crystallin (cryab), a member of the sHSP family, is elevated in stroke and deficiency of cryab leads to worse disease outcome, illustrating the protective role of alpha B crystallin. Exogenous administration of small heat shock proteins, including alpha B crystallin, decreases disease severity by modulating the immune system. This leads to the conclusion that sHSPs are endogenous anti-inflammatory and neuroprotectant molecules produced after neurological disease, whose beneficial properties can be augmented when administered therapeutically.
  • Digital
    Eckart Eich.
    Springer2008
  • Digital
    Alexander Gray Vaughan.
    This thesis encompasses three projects at the intersection of genetics, behavior, and neurobiology in the fruitfly, Drosophila melanogaster. The major work presented is an investigation of the afferent auditory system in D. melanogaster. The afferent auditory system of D. melanogaster arises from the Johnston's Organ in the second antennal segment, from which mechanosensory neurons project to a protocerebral region known as the Antennomechanosensory and Motor Complex (AMMC). The antennal mechanosensory system in Drosophila is used in multiple contexts, including vestibular mechanosensation, wind sensitivity, and courtship hearing. During courtship, male flies present a stereotypic pulse song as well as a hum-like sine-song to female flies; these stimuli are species-specific and critical to female receptivity. Using a large enhancer-Gal4 collection, I identify 12 candidate cell types within the AMMC, divided into 7 types of projection neurons as well as 5 types of local AMMC interneurons. I tested each of these cell types for its effect on courtship hearing by testing the effect of neuronal silencing on a) female receptivity, and b) a male locomotor response (Song-Induced Locomotion). These tests reveal that the activity of one class of projection neuron (aPN1), and one class of local interneuron (aLN(al)) are critical to courtship hearing in both male and female flies. Other cell types appear to be dispensable for courtship hearing, and may play a role in non-courtship related mechanosensation. To help confirm that these phenotypes are not specific to neuronal silencing, I also hyperactivated each cell type using the temperature-sensitive dTrpA1 reagent; these results confirm that aPN1 and aLN(al) alone are necessary for courtship hearing. Overall this work identifies a set of parallel pathways from the AMMC leading to the ventrolateral protocerebrum (VLPR), but reveal that only one of these pathways is necessary for courtship hearing. The structure of this circuit is analogous to the multi-lineage projection identified in D. melanogaster olfaction, in which a parallel pathways share a common projection but carry independent information. In addition to this work, I also discuss an investigation of the role of abnormal-chemosensory jump 6 (acj6) on escape behaviors, as well as an investigation of the expression of doublesex (dsx) in the nervous system.
  • Print
    John S. Wilkins.
    In this comprehensive work, John S. Wilkins traces the history of the idea of "species" from antiquity to today, providing a new perspective on the relationship between philosophical and biological approaches.--[Book cover].
  • Digital/Print
    Digital : SpringerLink2005-
  • Digital
    Vanessa Marie Burns.
    Revolutionary methods developed in the last decade have yielded new insights into many biological systems. Despite these technological advances, many complicated structures such as the brain have continued to defy our understanding. In part, this veil exists because of the necessary trade-offs made by most methods, sacrificing resolution of some dimensions (e.g. functional, temporal) in order to more precisely measure others (e.g. structural, molecular). Recent methods for unbiased, whole-sample analysis with high resolution could eliminate some of these trade-offs and yield a more complete understanding of systems-level interactions in complex structures. In this thesis, I apply whole-system methodologies to characterize a behavioral neural network spanning multiple brain regions and a developmental process in an entire organ, the pancreas. In the first section of this work, I use a model organism, the larval zebrafish, to study the whole-brain response in passive coping. I develop a behavioral challenge protocol that induces passive coping in the larval zebrafish and perform brain-wide calcium imaging of neural activity during the behavioral transition. Recordings of neural activity reveal a slow but striking ramping of activity confined to the lateral habenula, as well as a gradual transition to a reduced level of activity in both the raphe nuclei and the dorsal thalamus. Additionally, I use optogenetic stimulation of the lateral habenula combined with brain-wide imaging to show that activation is sufficient to reduce mobility as well as reduce activity in the raphe. These results provide unbiased evidence of a critical role for the lateral habenula in regulating both immediate and prolonged effects of stress on action selection, whereby either synaptic or membrane properties of lateral habenula neurons encode both prior and on-going experiences. In the second section of this work, I adapt CLARITY, a tissue-clearing technique, to be easily compatible for clearing a variety of heterogeneous and soft tissues and for integration into a standard clinical workflow. After developing a biphasic hydrogel methodology and an automated analysis platform for high-throughput quantitative volumetric analysis of biological features, I validate and apply this approach in the examination of a variety of organs and diseased tissues with a specific focus on the dynamics of pancreatic innervation and islet development in laboratory mouse and human clinical samples. Together, these two sections demonstrate unbiased, whole-sample techniques for: (1) probing the brain-wide neural response in disease-relevant behaviors in a model organism; and (2) characterizing molecular-level phenotypes and development processes in a variety of intact systems.
  • Digital
    Kerri A. Spilker.
    Specification and assembly of synapses is a highly coordinated and regulated process. Knowledge of the position and connectivity of all C. elegans neurons makes it a highly useful organism for studying the underlying mechanisms that control synapse formation. Using cell-specific promoters and fluorescently-labeled synaptic vesicle proteins, we are able to monitor synapse formation in subsets of C. elegans neurons. Close observation of synapse formation in a single posterior motorneuron (DA9) led to the identification of a mutation in the alternative splicing regulator mbl-1 that changes the synaptic pattern. The cholinergic motorneuron DA9 is required for backwards locomotion and forms ~25 synapses onto both inhibitory neurons and body wall muscles in the dorsal nerve cord (DNC) of the worm. We found that the 10 most distal synapses of DA9 fail to form in mbl-1 mutants, visualized with the synaptic vesicle-associated protein RAB-3 and the active zone proteins SYD-2/liprin-[Alpha] and UNC-10/Rim. In addition, some RAB-3 mis-localizes to the dendrite of DA9 and animals have a backwards locomotion defect consistent with a loss of synapses onto dorsal body wall muscles. mbl-1 is a member of the conserved MBNL (Muscleblind like) family of CCCH zinc-finger RNA binding proteins that regulate alternative splicing of target genes by directly binding to target mRNA. In the human disease myotonic dystrophy type 1 (DM1), a progressive muscular dystrophy, sequestration of MBNL proteins in nuclear foci leads to altered splicing of downstream genes. Mis-splicing of several genes is responsible for the muscular and cardiac symptoms present in individuals with DM1. Most work on the MBNL proteins has focused on their role in muscle morphogenesis and maintenance. However, C. elegans mbl-1 is expressed in a subset of motorneurons including DA9 and is required cell autonomously in these neurons to regulate proper synapse formation. Post-synaptic and muscle markers were unaffected in mbl-1 mutant animals. Thus, our work demonstrates that mbl-1 also functions in neurons to regulate synapse formation. In a separate set of experiments, we identified a new mutation in the coding region of the touch cell-specific beta-tubulin, mec-7(wy116) that causes a defect in synapse formation in the mechanosensory neuron PLM. Previous studies have shown that mec-7 is expressed exclusively in the six touch neurons of C. elegans and is required for sensing light touch. Our mec-7 mutation leads to a loss of synaptic vesicle accumulation at PLM synaptic sites in the ventral nerve cord and synaptic vesicles are visible at ectopic locations along the lateral axon of PLM. Localization of the synaptic proteins VAMP and GIT-1 is also defective in our mutant, but neuronal morphology is wild-type. mec-7(wy116) is mildly Mec, but other alleles of mec-7 (e1506, e1527) do not phenocopy the synaptic vesicle localization defect. mec-7(wy116) is a missense mutation that alters a highly conserved Thr at position 409 to Ile. Crystal structures of tubulin indicate that this residue is on the face of tubulin that interacts with kinesin motor. Because we see synaptic vesicles along the lateral axon of PLM, we believe that kinesin-mediated vesicle transport is less efficient in mec-7(wy116) mutants.
  • Digital
    edited by Huimin Zhao.
    ScienceDirect2013
    Synthetic Biology provides a framework to examine key enabling components in the emerging area of synthetic biology. Chapters contributed by leaders in the field address tools and methodologies developed for engineering biological systems at many levels, including molecular, pathway, network, whole cell, and multi-cell levels. The book highlights exciting practical applications of synthetic biology such as microbial production of biofuels and drugs, artificial cells, synthetic viruses, and artificial photosynthesis. The roles of computers and computational design are discussed, as well as future prospects in the field, including cell-free synthetic biology and engineering synthetic ecosystems. Synthetic biology is the design and construction of new biological entities, such as enzymes, genetic circuits, and cells, or the redesign of existing biological systems. It builds on the advances in molecular, cell, and systems biology and seeks to transform biology in the same way that synthesis transformed chemistry and integrated circuit design transformed computing. The element that distinguishes synthetic biology from traditional molecular and cellular biology is the focus on the design and construction of core components that can be modeled, understood, and tuned to meet specific performance criteria and the assembly of these smaller parts and devices into larger integrated systems that solve specific biotechnology problems. Includes contributions from leaders in the field presents examples of ambitious synthetic biology efforts including creation of artificial cells from scratch, cell-free synthesis of chemicals, fuels, and proteins, engineering of artificial photosynthesis for biofuels production, and creation of unnatural living organisms. Describes the latest state-of-the-art tools developed for low-cost synthesis of ever-increasing sizes of DNA and efficient modification of proteins, pathways, and genomesHighlights key technologies for analyzing biological systems at the genomic, proteomic, and metabolomic levels which are especially valuable in pathway, whole cell, and multi-cell applications. Details mathematical modeling tools and computational tools which can dramatically increase the speed of the design process as well as reduce the cost of development.
  • Digital
    Aparna Bhaduri.
    Systems level approaches to understanding biology have expanded the breadth of how we can study processes such as cancer and differentiation. Here, we apply transcriptome analysis, genomic analysis, network biology, and metabolomics to further our knowledge of cancer biology and epidermal differentiation. In each case, a combination of informatic and experimental approaches yielded specific insights that may not have been possible without the systems level approaches that were used. First, we performed RNA-sequencing in Cutaneous T-Cell Lymphoma (CTCL) in order to identify novel RNA transcripts. We were able to identify several CTCL specific transcripts that may help explain the etiology of this unique disease. During this effort, we additionally designed an algorithm to identify non-human sequences in a computationally effective manner that successfully identified positive control virus sequences, but did not identify any viral sequences in our CTCL RNA-sequencing data. We additionally interrogated CTCL using whole exome sequencing followed by targeted re-sequencing. Using integrative genomic analysis workflows, we identified mutations and structural variations that implicated the T-cell activation and proliferation pathways as deranged in nearly 40% of CTCL patients. We additionally identified a recurrent point mutation in the gene TNFRSF1B as well as recurrent genomic amplifications of this gene that contribute to increased non-canonical NFKB signaling via NFKB2. A number of lesions described in this work are responsive to existing therapeutic strategies, expanding the treatment options for patients with this disease. Numerous workflows developed in this work were cross applied to cutaneous squamous cell carcinoma (cSCC) and identified recurrent point mutations in the gene KNSTRN that contribute to cSCC by disrupting chromatid cohesion and promoting aneuploidy. We additionally explored the nature of normal somatic differentiation through the study of epidermal differentiation. To better reconstruct expression networks that are not transcription factor centric, we developed proximity analysis, a network analysis method that faithfully recreates eukaryotic interaction networks. Using RNA-sequencing data from a timecourse of differentiation, we identified MPZL3 as a gene central to the epidermal differentiation transcriptional network. Knockdown experiments showed that MPZL3 is required for differentiation, and vicinal protein labeling followed by mass spectrometry identified a number of mitochondrial protein interaction partners. This interaction with FDXR, a mitochondrial gene required for iron cluster formation and reactive oxygen species (ROS) mediated apoptosis, was validated and FDXR depletion phenocopied MPZL3 knock-down mediated differentiation defects. MPZL3 and FDXR are required for the ROS mediated differentiation that occurs in epidermal differentiation, a process that is a function of FDXR enzymatic activity. Further examination of metabolomics during epidermal differentiation surprisingly implicated glucose as highly accumulated during the course of differentiation. This finding was orthogonally validated, and media glucose is required for keratinocyte differentiation, but not proliferation. No accumulation was seen in glucose metabolic pathway intermediates or outputs, and forced expression of key glucose metabolic enzymes (HK1, HK2, G6PD) depletes this pool of accumulated glucose and inhibits differentiation. Similar glucose accumulation was seen in additional models of somatic tissue differentiation, including osteoblasts, adipocytes, and myoblasts. Using systems level approaches, we have identified novel mechanisms of neoplastic transformation as well as somatic tissue differentiation.
  • Digital
    Michael G. Katze, editor.
    Springer2013
    First, systems biology is an inter-disciplinary approach, requiring the combined talents of biologists, mathematicians, and computer scientists. Second, systems biology is holistic, with the goal of obtaining a comprehensive understanding of the workings of biological systems. This is achieved through the acquisition of massive amounts of data by high-throughput technologies-oligonucleotide microarrays, mass spectrometry, and next-generation sequencing-and the analysis of this data through sophisticated mathematical algorithms.
  • Digital
    Choi, Sangdun.
    Springerv. 1-, 2010-
  • Digital
    Bor-Sen Chen.
    ScienceDirect2018
    Systems Evolutionary Biology: Biological Network Evolution Theory, Stochastic Evolutionary Game Strategies, and Applications to Systems Synthetic Biology discusses the evolutionary game theory and strategies of nonlinear stochastic biological networks under random genetic variations and environmental disturbances and their application to systematic synthetic biology design. The book provides more realistic stochastic biological system models to mimic the real biological systems in evolutionary process and then introduces network evolvability, stochastic evolutionary game theory and strategy based on nonlinear stochastic networks in evolution. Readers will find remarkable, revolutionary information on genetic evolutionary biology that be applied to economics, engineering and bioscience.
  • Digital
    edited by Dr. Naidong Weng and Dr. Wenying Jian, Janssen Research & Development, LLC.
    Wiley2017
    Title Page ; Copyright Page; Contents; List of Contributors; Preface; Abbreviations; Part 1 Overview; Chapter 1 Overview of Targeted Quantitation of Biomarkers and Its Applications; 1.1 Introduction; 1.2 Biomarker Definition; 1.3 Current Challenges of a Biomarker; 1.4 Biomarker Validation Process; 1.5 Current Regulatory Requirement for Target Biomarker Quantitation; 1.6 Challenges of Biomarker Quantitation; 1.7 Current Technologies for Biomarker Quantitation; 1.7.1 LC-MS; 1.7.2 GC-MS; 1.7.3 Ligand-Binding Assay ; 1.7.4 Flow Cytometry; 1.7.5 Quantitative PCR (qPCR). 1.8 Current Biomarker Quantitation Applications1.8.1 Protein Biomarkers; 1.8.2 Peptide Biomarkers; 1.8.3 RNA Biomarkers; 1.8.4 Nucleotide Biomarkers; 1.8.5 Small Molecule Biomarkers; 1.9 Conclusion and Future Perspective; References; Chapter 2 Translational Application of Biomarkers; 2.1 Introduction; 2.2 Translational Medicine; 2.3 Biomarkers; 2.4 Biomarker Categories; 2.5 Neurobiological Disorders; 2.6 Cardiovascular Disorders; 2.7 Chronic Obstructive Pulmonary Disease; 2.8 Oncology; 2.9 Biomarker Measurements and Regulatory Considerations; 2.10 Conclusions; Acknowledgment; References. Chapter 3 Current Regulatory Guidance Pertaining Biomarker Assay Establishment and Industrial Practice of Fit-for-Purpose and Tiered Approach 3.1 Introduction; 3.2 Current Regulatory Guidance and Interpretation; 3.3 Current Industrial Discussion and Recommendations; 3.4 Considerations for Assay Validation and Sample Analysis; 3.4.1 Sensitivity; 3.4.2 Specificity and Selectivity; 3.4.3 Matrix Effects and Sample Variables; 3.4.3.1 Authentic Analyte/Authentic Matrix Approach; 3.4.3.2 Surrogate Analyte/Authentic Matrix Approach; 3.4.3.3 Authentic Analyte/Surrogate Matrix Approach. 4.2.1 Importance of Separation4.2.2 Basic Principle of LC; 4.2.3 Major Modes of LC Used for Targeted Biomarker Quantitation; 4.2.4 Modern LC Technologies; 4.2.4.1 HPLC and UHPLC; 4.2.4.2 Miniaturized Column LC; 4.2.4.3 2D-LC ; 4.3 Mass Spectrometry; 4.3.1 Major Types of MS Used for Targeted Biomarker Quantitation; 4.3.2 Ionization Techniques; 4.3.3 Ion Mobility; 4.3.4 Fragmentation Mode; 4.3.5 Emerging MS Techniques; 4.3.5.1 MS Imaging; 4.3.5.2 Other Surface Analysis MS Techniques; 4.4 Summary and Future Perspectives; References.
  • Digital
    Kipp Weiskopf.
    Cancer cells develop mechanisms to avoid detection by the immune system, and therapeutic approaches aimed at overcoming these mechanisms form the basis of cancer immunotherapy. In this dissertation, I employed macrophages as effector cells by targeting the CD47/SIRPa axis, which is a critical regulator of macrophage activation. CD47 is highly expressed on many different types of cancer, and it transduces inhibitory signals through SIRPa, a receptor on macrophages and other myeloid cells. Thus, the CD47/SIRPa axis serves as a myeloid-specific immune checkpoint. To create next-generation CD47 antagonists, we engineered high-affinity SIRPa variants that exhibited ~50,000-fold higher affinity for human CD47 relative to wild-type SIRPa. When produced as high-affinity SIRPa-Fc fusion proteins, these therapeutics acted as single agents for cancer with moderate on-target toxicity to normal cells expressing CD47. When produced as 14 kDa high-affinity SIRPa monomers, the therapeutics had minimal activity as single agents but instead acted as universal adjuvants to anti-cancer antibodies. Therefore, CD47 blockade is not sufficient to induce macrophage phagocytosis, but instead lowers the threshold for phagocytosis in the presence of a separate, tumor-opsonizing antibody. I demonstrated these principles could be extended to models of small cell lung cancer (SCLC), and I identified additional therapeutic targets on the surface of SCLC cells. Last, I generated anti-SIRPa antibodies and characterized KWAR23 as a clone that binds and antagonizes SIRPa directly on macrophages. Therapies targeting the CD47/SIRPa axis are now under investigation in clinical trials. These agents may differ in their pharmacokinetic, pharmacodynamic, and toxicity profiles, raising important considerations for further development and clinical evaluation. Overall, the therapies developed in this dissertation could be broadly applied to cancer and may benefit many patients suffering from disease.
  • Digital
    An online journal and ebook service of the Thieme Publishing Group. The ebook package is also called Thieme Clinical Collections.
  • Digital
    Deborah Ruth Mary Caswell.
    Metastasis is a complex series of steps leading to the establishment of tumors at secondary sites separate from the primary tumor. Accumulating evidence supports the idea that the metastatic process varies in different cancers. Two main models of the metastatic process exist. The first is referred to as the linear progression model. In this model the primary tumor progresses to full malignancy before tumor cells disseminate from it to form metastases at secondary sites. In the other model, the parallel progression model, metastases seeded from early-disseminated tumor cells independently progress to a late stage in parallel to the primary tumor. Recently the parallel progression model has been shown to occur in both breast and pancreatic tumor mouse models. This work illustrates that in lung cancer, in opposition to breast and pancreatic cancer, dissemination and metastasis occurs at a late stage of tumor progression, after gaining specific alterations that allow tumor cells to metastasize. The exact alterations that allow tumor cells to disseminate and metastasize remain unclear, but in this work it is demonstrated that the lineage transcription factor Nkx2-1 activates a number of targets that are potentially important for metastatic ability. One in particular, Selenbp1, is shown to act in a positive feedback loop with Nkx2-1 to inhibit lung adenocarcinoma metastasis. Using well-established mouse models in combination with massively parallel sequencing this work begins to piece together parts of the metastatic process.
  • Digital
    Bronner, Felix; Farach-Carson, Mary C.
    Springerv. 2-, 2005-
  • Digital
    Sarah Trosin.
    The mammalian somatic cell cycle relies upon a complex network of core machinery, some of which have redundant or overlapping functions. That cyclins are essential components in the mitotic circuit has been well established, but many molecular and spatiotemporal requirements remain unknown. In this thesis, I present three lines of study in which we examined cyclin requirements for mitotic onset using mammalian tissue culture cells. These studies utilize diverse approaches to better understand requirements for cyclin synthesis, localization, and post-translational changes in regulating mitotic entry in the mammalian somatic cell cycle. In the first study, we show that G2-phase cyclin synthesis is not required for mitotic entry. Protein inhibition and cyclin perturbation studies spanning the last five decades have supported a requirement for G2-phase protein synthesis of cyclins and other pro-mitotic proteins for mitotic entry; however, previous protein inhibition approaches have relied on inhibiting protein synthesis using cycloheximide (CHX), which could constitute enough of a stress to activate a p38-mediated antephase checkpoint. The antephase checkpoint prevents G2-phase cells from entering mitosis in the face of a range of stress agents, thereby constituting a second possible interpretation for why CHX-treated cells arrest in G2 phase. Here we show that CHX-treated G2-phase cells are able to enter mitosis when administered a p38 inhibitor, demonstrating that CHX secondarily activates a p38-mediated antephase checkpoint, which is responsible for preventing CHX-treated cells from entering mitosis. Sufficient cyclin synthesis for mitotic onset is apparently completed earlier, by the end of S phase. Thus, the ~4--6 hours of G2 phase preceding mitotic entry is not due to cyclin and other pro-mitotic protein synthesis requirements as has been the classical view of the cell cycle field, but rather appears to be necessary for preparations necessary to satisfy checkpoint requirements and other preparations for mitosis. The subsequent studies presented pertain to regulatory aspects controlling cyclin A2's dual roles in S phase and mitosis. Cyclin A2, the somatic form of cyclin A, is implicated in two essential aspects of the cell cycle, DNA synthesis and mitosis, but it is not known how cyclin A2 coordinates these two distinct functions. A mainly nuclear protein, cyclin A2 also accumulates in the cytoplasm in late S phase and during G2 phase, and we show that this cytoplasmic pool is required for mitotic entry. In addition, we examined cyclin A2 phosphorylation in the context of cell cycle regulation, and preliminary data suggests that phosphorylation is a key regulatory mechanism capable of controlling cyclin A2 localization and therefore its function. Collectively, these studies contribute to our understanding of cyclin requirements for mitotic entry, describing how the mitotic onset is in part governed by preparatory activities including localization-dependent cyclin functions and those that satisfy late-stage checkpoint requirements.
  • Digital
    edited by Alessandro Minelli, Thomas Pradeu.
    OSO2014
    Is it possible to explain and predict the development of living things? What is development? Answers to these innocuous questions are far from straightforward. To date, no systematic, targeted effort has been made to construct a unifying theory of development. This text offers a unique exploration of the foundations of ontogeny by asking how the development of living things should be understood. It explores the key concepts of developmental biology, asks whether general principles of development can be discovered, and examines the role of models and theories. This book analyses a wealth of approaches to concepts, models and theories of development, such as gene regulatory networks, accounts based on systems biology and on physics of soft matter, the different articulations of evolution and development, symbiont-induced development, as well as the widely discussed concepts of positional information and morphogenetic field, the idea of a 'programme' of development and its critiques, and the long-standing opposition between preformationist and epigenetic conceptions of development.
  • Digital
    Brook Celia Barajas.
    Since the development of chromosome conformation capture (3C) by Job Dekker et al. in 2002, interrogation of enhancer-promoter interactions has led to an increased understanding of the vital role that three-dimensional structure plays in gene regulation. However, the technical difficulty of 3C and related assays, as well as the sequencing depth required to make quantitative comparisons between contact frequencies in HiC, have limited investigations of enhancer-promoter dynamics in differentiation and disease. Knowledge of the contact landscape is critical to our understanding of both human disease and normal tissue function. For example, the correlation of common genetic variation with associated diseases through genome-wide association studies (GWAS) has revealed many disease-associated polymorphisms outside annotated exons or promoter regions. This implies that much disease-relevant regulation may occur from distal regions that rely on three-dimensional contacts to target their associated genes. In this work, we describe two applications of chromosome conformation capture technology that expand our understanding of differentiation and disease. In the first section, we seek to understand and disrupt regulation of a single gene involved in therapeutic resistance in melanoma. In the second and third sections, we identify novel regulators of epidermal differentiation, then create a map of histone modification and contact dynamics during this process to understand how regulators interact with and alter the chromatin environment to facilitate terminal differentiation.
  • Digital
    Yasunori Sasakura, editor.
    Springer2018
    This book comprehensively describes the transgenesis techniques and applied experimental methods in ascidians including enthusiastically developed original devices in addition to concrete examples of developmental biology studies. Ascidians have been one of the most important model animals in developmental biology for studying molecular and cellular processes underlying formation of the chordate body plan. Transgenic techniques such as microinjection, electropolation, cis-element analysis and application, and TALENs and CRISPR/Cas9 have been developed in ascidians for more than 20 years, and now many applied methods, some of which are unique in ascidians, have been accumulated. Those extensive technological innovations, such as cell isolation, cell labeling, germ-line transformation, marker transgenic lines, and the experimental systems for studying notochord formation and nervous system, are exceptional particularly in marine invertebrates. This book is useful for ascidian researchers to quickly access the techniques in which they are interested as well as to compare each technology to become familiar with specialized tips, and for biologists of other organisms to learn the unique techniques and ingenious attempts specific to ascidians. Providing detailed and easily understandable descriptions of techniques, the book will inspire ascidian specialists to improve their techniques, encourage anyone wanting to begin studying ascidians, and enable readers to immediately apply the techniques to the organisms they research.
  • Digital
    Alan Hunter Shain.
    Pancreatic ductal adenocarcinoma, subsequently referred to as pancreatic cancer, is one of the most deadly cancers with a five-year survival of only 5%. Typical treatment regimens include surgery and chemotherapy while targeted therapies are lacking. A better understanding of the underlying cancer biology may yield novel therapeutic targets. The field of genomics has transformed our ability to study cancer. Over the past two decades, microarray and sequencing based innovations have enabled biology to be carried out at the --omic scale (discussed further in Chapter 1). This dissertation employs --omic level analysis to query the differences between the pancreatic cancer genome and the normal human genome. First, high throughput structural characterizations were performed in order to annotate the mutated, rearranged, deleted, and amplified genes across seventy pancreatic cancers. These assays identified hundreds of candidate cancer genes. Among these candidates, SMURF1 was validated to be an oncogene (Chapter 2). Furthermore, various subunits of the SWI/SNF chromatin remodeling complex were validated to be tumor suppressor genes (Chapter 3). While SMURF1 and SWI/SNF were validated individually, the other candidates from structural studies were evaluated in parallel shRNA competive growth screen. From this, we characterize nine genes further -- some previously known to play a role in cancer and some novel (Chapter 4). The sum total of all of this work is a much deeper understanding of the biology of pancreatic cancer, yielding many novel therapeutic targets and hopefully allowing scientists to gain a foothold in the fight against this disease.
  • Digital
    H.G. Stratmann.
    Springer2016
  • Digital
    Boris Bogdan, Ralph Villiger.
    Springer2008
  • Digital/Print
    Michael G. Rossmann, Venigalla B. Rao, editors.
    Digital : Springer2012
    Print2012
    Viruses: sophisticated biological machines / M.G. Rossmann and V.B. Rao -- F(1)-ATPase: A prototypical rotary molecular motor / K. Kinosita, Jr. -- Principles of virus structural organization / B.V. Prasad and M.F. Schmid -- Reconstructing virus structures from nanometer to near-atomic resolutions with cryo-electron microscopy and tomography / J. Chang ... [et al.] -- Contractile tail machines of bacteriophages / P.G. Leiman and M.M. Shneider -- Long noncontractile tail machines of bacteriophages / A.R. Davidson ... [et al.] -- Short noncontractile tail machines: adsorption and DNA delivery by podoviruses / S.R. Casjens and I.J. Molineux -- Infection of cells by alphaviruses / D.T. Brown and R. Hernandez -- Influenza virus entry / M. Luo -- Molecular mechanisms of HIV entry / C.B. Wilen, J.C. Tilton and R.W. Doms -- Bunyavirus: structure and replication / T.S. Guu, W. Zheng and Y.J. Tao -- Viral polymerases / K.H. Choi -- Chaperonin-mediated folding of viral proteins / Z.L. Hildenbrand and R.A. Bernal -- Building the machines: scaffolding protein functions during bacteriophage morphogenesis / P.E. Prevelige and B.A. Fane -- Bacteriophage HK97 capsid assembly and maturation / R.W. Hendrix and J.E. Johnson -- Lipid-containing viruses: Bacteriophage PRD1 assembly / S.J. Butcher, V. Manole and N.J. Karhu -- Assembly of large icosahedral double-stranded RNA viruses / M.M. Poranen and D.H. Bamford -- The papillomavirus virion: a machine built to hide molecular Achilles' heels / C.B. Buck and B.L. Trus -- Procapsid assembly, maturation, nuclear exit: dynamic steps in the production of infectious herpesvirions / G. Cardone ... [et al.] -- Assembly and architecture of HIV / B.K. Ganser-Pornillos, M. Yeager and O. Pornillos -- Condensed genome structure / L.W. Black and J.A. Thomas -- The bacteriophage DNA packaging machine / M. Feiss and V.B. Rao -- The dsDNA packaging motor in Bacteriophage o29 / M.C. Morais -- Single-molecule studies of viral DNA packaging / Y.R. Chemla and D.E. Smith -- Genome gating in tailed bacteriophage capsids / P. Tavares, S. Zinn-Justin and E.V. Orlova -- Packaging in dsRNA Viruses / L. Mindich -- Mechanism of RNA packaging motor / E.J. Mancini and R. Tuma -- Helical viruses / G. Stubbs and A. Kendall.
  • Digital
    Li Ling.
    The mammalian nervous system consists of billions of neurons arranged into complicated networks (neuronal circuits) that mediate all aspects of brain function and behavior. A fundamental goal of neuroscience is to describe the structure of neural circuits at the level of single cells and to understand how this structure enables information acquisition, processing, storage, and ultimately the control of behavior. Over the past hundred years, the cumulative efforts of many individuals have led to the development of a wide array of neuronal labeling tools. First, in this thesis, with the ultimate goal of further expanding genetically coded labeling tools to visualize the presynaptic distribution in single neurons within the mouse brain in vivo, I developed a new genetic synaptic labeling method and used it to analyze the spatial patterning of synapses in developing and mature cerebellar granule. Second, taking the advantage of the MADM system that allows gene knockout in single cells and simultaneously labeling the cells for morphology characterization, I also utilized MADM to study the function of the Rai1 gene, heterozygosity of which results in Smith-Magenis Syndrome in human.
  • Print
    Status: Not Checked OutLane Catalog Record
  • Digital
  • Digital
    Jun Aruga, editor.
    Springer2018
    Zic family in animal evolution and development. comparative genomics of the Zic family genes / Jun Aruga, Minoru Hatayama -- Cnidarian Zic genes / Michael J. Layden -- Odd-paired: the Drosophila Zic gene / Deborah A. Hursh, Brian G. Stultz -- Zic genes in nematodes: a role in nervous system development and Wnt signaling / Guillaume Bordet, Vincent Bertrand -- Lophotrochozoan Zic genes / Jun Aruga -- Ascidian Zic genes / Yutaka Satou, Kaoru S. Imai -- Amphibian Zic genes / Christa Merzdorf, Jennifer Forecki -- Zic genes in teleosts: their roles in dorsoventral patterning in the somite / Kota Abe, Toru Kawanishi, Hiroyuki Takeda -- Zebrafish Zic genes mediate developmental signaling / Cecilia Lanny Winata, Vladimir Korzh -- Overview of rodent Zic genes / Koula E. M. Diamand, Kristen S. Barratt, Ruth M. Arkell -- Rodent Zic genes in neural network wiring / Eloísa Herrera -- Zic family in medicine. Zic family proteins in emerging biomedical studies / Jun Aruga -- ZIC1 function in normal cerebellar development and human developmental pathology / Jun Aruga, Kathleen J. Millen -- ZIC2 in holoprosencephaly / Kristen S. Barratt, Ruth M. Arkell -- ZIC3 in Heterotaxy / Helen M. Bellchambers, Stephanie M. Ware -- Deregulation of ZIC family members in oncogenesis / Rob Houtmeyers, Jabob Souopgui, Sabine Tejpar -- Roles of ZIC2 in regulation of pluripotent stem cells / Hisato Kondoh -- Zic family in medicine / Role of Zic family proteins in transcriptional regulation and chromatin remodeling / Minoru Hatayama, Jun Aruga.

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A repository of medical knowledge from internal medicine, cardiology, genetics, pharmacy, diagnosis and management, basic sciences, patient care, and more.

Continuously expanding, all databases in the repository contain the latest editions of selected medical titles.

MicroMedex: Premier pharmaceutical information source containing multiple databases and drug reference tools. Of particular value is DRUGDEX Evaluations, one of the most comprehensive drug sources available.DynaMed Plus is a clinical information resource used to answer questions quickly at the point-of-care. Easy-to-interpret Levels of Evidence help clinicians rapidly determine the quality of the available evidence.

Biomedical and pharmacological abstracting and indexing database of published literature, by Elsevier. Embase® contains over 32 million records from over 8,500 currently published journals (1947-present) and is noteworthy for its extensive coverage of the international pharmaceutical and alternative/complementary medicine literature.

Scopus is the largest abstract and citation database of peer-reviewed literature: scientific journals, books and conference proceedings.A drug information resource containing: American Hospital Formulary System (AHFS), drug formulary for Lucile Packard Children's Hospital (LPCH) and Stanford Hospital & Clinics (SHC), Lexi-Drugs (adverse reactions, dosage and administration, mechanism of action, storage, use, and administration information), Lexi-Calc, Lexi-ID, Lexi-I.V. Compatibility (King Guide), Lexi-Interact, and Lexi-PALS.Cumulative Index to Nursing and Allied Health Literature (CINAHL) contains coverage of nursing and allied health literature.A knowledge database that provides access to topic reviews based on over 6000 clinically relevant articles. The evidence-based content, updated regularly, provides the latest practice guidelines in 59 medical specialties.Provides critical assessments of systematic reviews compiled from a variety of medical journals.Selects from the biomedical literature original studies and systematic reviews that are immediately clinically relevant and then summarizes these articles in an enhanced abstract with expert commentary.

Multidisciplinary coverage of over 10,000 high-impact journals in the sciences, social sciences, and arts and humanities, as well as international proceedings coverage for over 120,000 conferences.

Includes cited reference searching, citation maps, and an analyze tool.

Features systematic reviews that summarize the effects of interventions and makes a determination whether the intervention is efficacious or not.

Cochrane reviews are created through a strict process of compiling and analyzing data from multiple randomized control trials to ensure comprehensiveness and reliability.

Provides systematic coverage of the psychological literature from the 1800s to the present through articles, book chapters and dissertations.BMJ Clinical Evidence. A clinical information tool built around systematic reviews summarizing the current state of knowledge about prevention and treatment of clinical conditions.PIER (Physicians' Information and Education Resource) is a Web-based decision-support tool designed for rapid point-of-care delivery of up-to-date, evidence-based guidance for primary care physicians.Cochrane Central Register of Controlled Trials (CENTRAL) provides access to 300,000 controlled trials that have been identified the Cochrane Collaboration.Provides drug information targeted for patients.A continually updating drug monograph.The National Guideline Clearinghouse (NGC): A comprehensive database of evidence-based clinical practice guidelines and related documents.MedlinePlus: A repository of health information from the National Library of Medicine. Links are from trusted sites. No advertising, no endorsement of commercial companies or productsLPCH CareNotes via MicroMedex: Patient education handouts customized by LPCH clinical staffMicromedex Lab Advisor: Evidence based laboratory test informationA drug database organized by generic name, trade name and drug class.LPCH / Stanford Hospital Formulary.A goldmine of trusted consumer health information from the world's largest medical library.A trusted source of expert advice for and about kids, providing the information necessary to help patients and parents understand their unique needs.Provides patient handouts from the American Academy of Family Physician.Access to the Stanford Health Library for patients.Lane provides access to over 5,000 eBooks many of which provide helpful background material that will prepare you to better tackle primary literature.

Largest, broadest eBook package; covers all sciences, as well as technology (including software), medicine, and humanities.

In addition to covering Wiley and Springer, MyiLibrary is also the only provider for Oxford and Cambridge University Press titles. No seat restrictions.

A collection of biomedical books that can be searched directly by concept, and linked to terms in PubMed abstracts.

A web-based, decision support system for infectious diseases, epidemiology, microbiology and antimicrobial chemotherapy. The database, updated weekly, currently includes 337 diseases, 224 countries, 1,147 microbial taxa and 306 antibacterial (-fungal, -parasitic, -viral) agents and vaccines.

Over 10,000 notes outline the status of specific infections within each country.

Large number of high quality software and database programming titles from O'Reilly. Other software titles are also available from Sams and Prentice Hall. Limited to 7 concurrent users.Vast collection of software and database programming titles from multiple publishers, including Microsoft Press.Largest provider of engineering-related eBooks; includes titles in computer science and biomedical engineering.Over 4,000 full-text e-books covering scientific and technical information from CRC Press and others. Many handbooks and single volume reference sources.Includes peer-reviewed life science and biomedical research protocols compiled from Methods in Molecular Biology, Methods in Molecular Medicine, Methods in Biotechnology, Methods in Pharmacology and Toxicology, Neuromethods, the Biomethods Handbook, the Proteomics Handbook, and Springer Laboratory Manuals.Contains full text access to selected biomedical and nursing books.

Provides online, full-text access to Springer's journal titles as well as journals from other publishers.

Subjects include: life sciences, chemical sciences, environmental sciences, geosciences, computer science, mathematics, medicine, physics and astronomy, engineering and economics. Also includes eBooks.

Collection of over 8 thousand fulltext titles in engineering, math, and basic and applied biomedical research. Coverage is from 1967 to the present.A library of ebooks on a wide array of topics, digitized and made available online in conjunction with the original publishers.