Books by Subject

all 180 titles

Biology

  • Digital
    Julie Marie Granka.
    Organismic evolution involves both selective and neutral forces, although their relative contributions are often unknown. This thesis proposes novel statistical methods for analyzing genetic data from a variety of organisms, including yeast, Mycobacterium tuberculosis, and humans. The chapters of this thesis provide complimentary perspectives on the relative roles of selection and neutrality, from the molecular to the population level, and present various statistical tools for genetic data analysis. Chapter 2 proposes a maximum-likelihood based method with which to classify and identify interactions, or epistasis, between pairs of genes. Chapter 3 details a study of genetic data from Mycobacterium tuberculosis isolated from human Aboriginal Canadian communities; our analyses suggest that the bacterium spread to these communities via the Canadian fur trade in the 18th and 19th centuries. Chapter 4 discusses the detection of signatures of natural selection in the genomes of 12 diverse African human populations, and proposes novel considerations for identifying biological functions under selection and for comparing signals of selection between populations. Finally, Chapter 5 details the inference of the genetic basis and evolutionary history of light skin pigmentation and short stature in the genetically diverse [not equal to sign] Khomani Bushmen of the Kalahari Desert of South Africa, believed to be one of the world's most ancient human populations. These chapters emphasize that a more complete understanding of the evolutionary history of humans and other organisms requires not only the consideration of neutral and selective processes, but also both phenotypic and genetic information. The statistical methods and approaches presented in the following chapters have the potential to improve inferences of natural selection and demography from genetic data, as well as provide insight into the relative roles of both.
  • Digital
    Susan Masino, Detlev Boison, editors.
    Springer2013
    Adenosine and Metabolism--A Brief Historical Note / Bertil B. Fredholm -- Adenosine Metabolism, Adenosine Kinase, and Evolution / Jaoek Park and Radhey S. Gupta -- Adenosine and Energy Metabolism--Relationship to Brain Bioenergetics / Xuesong Chen, Liang Hui and Jonathan D. Geiger -- Adenosine and Autocrine Metabolic Regulation of Neuronal Activity / Masahito Kawamura Jr. and David N. Ruskin -- Physiologic and Metabolic Regulation of Adenosine: Mechanisms / Chris G. Dulla and Susan A. Masino -- The Double-Edged Sword: Gaining Adenosine at the Expense of ATP. How to Balance the Books / Stephanie zur Nedden, Alexander S. Doney and Bruno G. Frenguelli -- Downstream Pathways of Adenosine / Ana M. Sebastião, Sofia Cristóvão-Ferreira and Joaquim A. Ribeiro -- Astrocytic ATP Release / Dustin J. Hines and Philip G. Haydon -- Role of Striatal A2A Receptor Subpopulations in Neurological Disorders / Sergi Ferré, César Quiroz, Marco Orrú, Xavier Guitart and Seema Gulyani, et al. -- Sleep and Adenosine: Human Studies / Tarja Porkka-Heiskanen -- Adenosine and Other Purinergic Products in Circadian Timing / Christine Muheim and Steven A. Brown -- Adenosine in the Immune System / György Hask, Balázs Koscsó́ and Balázs Csóka -- The Bioenergetic Network of Adenosine in Hibernation, Sleep, and Thermoregulation / Kelly L. Drew and Tulasi R. Jinka -- Adenosine and Stroke / Felicita Pedata, Anna Maria Pugliese, Francesca Corti and Alessia Melani -- The Many Roles of Adenosine in Traumatic Brain Injury / Patrick M. Kochanek, Jonathan D. Verrier, Amy K. Wagner and Edwin K. Jackson -- Therapeutic Perspectives of Adenosine Receptor Compounds in Functional Restitution After Spinal Cord Injury / Kwaku D. Nantwi -- Adenosine and Pain / Jana Sawynok -- Symptomatic and Neuroprotective Effects of A2A Receptor Antagonists in Parkinson's Disease / Annalisa Pinna, Nicola Simola, Lucia Frau and Micaela Morelli -- Adenosine Receptors and Alzheimer's Disease / David Blum, Ursula Sandau, Cyril Laurent, Vânia Batalha and Antoine Leboucher, et al. -- Adenosine Receptors in Huntington's Disease / David Blum, Alberto Martire, Sylvie Burnouf, Bernard Sablonnière and Pierre Krystkowiak, et al. -- Adenosine and Multiple Sclerosis / Maria Victoria Sánchez-Gómez, Estibaliz González-Fernández, Rogelio O. Arellano and Carlos Matute -- Adenosinergic Perspectives on Schizophrenia: Opportunity for an Integrative Synthesis / Benjamin K. Yee, Philipp Singer and Detlev Boison -- The Role of Adenosine in the Ventral Striatal Circuits Regulating Behavioral Activation and Effort-Related Decision Making: Importance for Normal and Pathological Aspects of Motivation / John D. Salamone, Merce Correa, Patrick A. Randall, Eric J. Nunes and Marta Pardo, et al. -- Adenosine and Autism: Physiological Symptoms and Metabolic Opportunities / Julia Svedova, Inge-Marie Eigsti and Susan A. Masino -- Stress, Brain Adenosine Signaling, and Fatigue-Related Behavioral Processes / Traci N. Plumb, Sarah R. Sterlace, Kelly A. Cavanaugh and Thomas R. Minor -- Disruption of Adenosine Homeostasis in Epilepsy and Therapeutic Adenosine Augmentation / Detlev Boison -- Ketogenic Diet and Epilepsy: The Role of Adenosine / Jong M. Rho, Beth Zupec-Kania and Susan A. Masino -- Silk: A Biocompatible and Biodegradable Biopolymer for Therapeutic Adenosine Delivery / Eleanor M. Pritchard, Detlev Boison and David L. Kaplan -- Anatomical Distribution of Nucleoside System in the Human Brain and Implications for Therapy / Zsolt Kovács and Arpád Dobolyi.
  • Digital/Print
    Igor I. Goryanin, Andrew B. Goryachev, editors.
    Digital : Springer2012
    Print2012
    Part 1. Multiscale biological networks: identification, modeling and analysis -- Modular Analysis of Biological Networks / Hans-Michael Kaltenbach and Jörg Stelling -- Modeling Signaling Networks Using High-throughput Phospho-proteomics / Camille Terfve and Julio Saez-Rodriguez -- An Integrated Bayesian Framework for Identifying Phosphorylation Networks in Stimulated Cells / Tapesh Santra, Boris Kholodenko and Walter Kolch -- Signaling Cascades: Consequences of Varying Substrate and Phosphatase Levels / Elisenda Feliu, Michael Knudsen and Carsten Wiuf -- Heterogeneous Biological Network Visualization System: Case Study in Context of Medical Image Data / Erno Lindfors, Jussi Mattila, Peddinti V. Gopalacharyulu, Antti Pesonen and Jyrki Lötjönen, et al. -- Evolution of the Cognitive Proteome: From Static to Dynamic Network Models / J. Douglas Armstrong and Oksana Sorokina -- Molecular Systems Biology of Sic1 in Yeast Cell Cycle Regulation Through Multiscale Modeling / Matteo Barberis -- Proteome-Wide Screens in Saccharomyces cerevisiae Using the Yeast GFP Collection / Yolanda T. Chong, Michael J. Cox and Brenda Andrews -- Unraveling the Complex Regulatory Relationships Between Metabolism and Signal Transduction in Cancer / Michelle L. Wynn, Sofia D. Merajver and Santiago Schnell -- Part 2. Cellular decision making: adaptation, differentiation and death -- The Cell as a Thermostat: How Much does it Know? / Dennis Bray -- Stem Cell Differentiation as a Renewal-Reward Process: Predictions and Validation in the Colonic Crypt / Kiran Gireesan Vanaja, Andrew P. Feinberg and Andre Levchenko -- A Dynamic Physical Model of Cell Migration, Differentiation and Apoptosis in Caenorhabditis elegans / Antje Beyer, Ralf Eberhard, Nir Piterman, Michael O. Hengartner and Alex Hajnal, et al. -- A Modular Model of the Apoptosis Machinery / E. O. Kutumova, I. N. Kiselev, R. N. Sharipov, I. N. Lavrik and Fedor A. Kolpakov -- An Ensemble Approach for Inferring Semi-quantitative Regulatory Dynamics for the Differentiation of Mouse Embryonic Stem Cells Using Prior Knowledge / Dominik Lutter, Philipp Bruns and Fabian J. Theis -- Cell Death and Life in Cancer: Mathematical Modeling of Cell Fate Decisions / Andrei Zinovyev, Simon Fourquet, Laurent Tournier, Laurence Calzone and Emmanuel Barillot -- Theoretical Aspects of Cellular Decision-Making and Information-Processing / Tetsuya J. Kobayashi and Atsushi Kamimura -- Zooming in on Yeast Osmoadaptation / Clemens Kühn and Edda Klipp -- Part 3. Spatial and temporal dymensions of intracellular dynamics -- Receptor Dynamics in Signaling / Verena Becker, Jens Timmer and Ursula Klingmüller -- A Systems-Biology Approach to Yeast Actin Cables / Tyler Drake, Eddy Yusuf and Dimitrios Vavylonis -- Modeling Morphodynamic Phenotypes and Dynamic Regimes of Cell Motion / Mihaela Enculescu and Martin Falcke -- Time-Structure of the Yeast Metabolism In vivo / Kalesh Sasidharan, Masaru Tomita, Miguel Aon, David Lloyd and Douglas B. Murray -- Coarse Graining Escherichia coli Chemotaxis: From Multi-flagella Propulsion to Logarithmic Sensing / Tine Curk, Franziska Matthäus, Yifat Brill-Karniely and Jure Dobnikar -- Self-Feedback in Actin Polymerization / Anders E. Carlsson -- Part 4. Computational tools, algorithms and theoretical methods for systems biology -- Global Optimization in Systems Biology: Stochastic Methods and Their Applications / Eva Balsa-Canto, J. R. Banga, J. A. Egea, A. Fernandez-Villaverde and G. M. de Hijas-Liste -- Mathematical Modeling of the Human Energy Metabolism Based on the Selfish Brain Theory / Matthias Chung and Britta Göbel -- Identification of Sensitive Enzymes in the Photosynthetic Carbon Metabolism / Renato Umeton, Giovanni Stracquadanio, Alessio Papini, Jole Costanza and Pietro Liò, et al. -- Formal Methods for Checking the Consistency of Biological Models / Allan Clark, Vashti Galpin, Stephen Gilmore, Maria Luisa Guerriero and Jane Hillston -- Global Parameter Identification of Stochastic Reaction Networks from Single Trajectories / Christian L. Müller, Rajesh Ramaswamy and Ivo F. Sbalzarini -- A Systems Biology View of Adaptation in Sensory Mechanisms / Pablo A. Iglesias -- Leveraging Modeling Approaches: Reaction Networks and Rules / Michael L. Blinov and Ion I. Moraru -- Part 5. Applications of systems biology in medicine, biotechnology and pharmaceutical industry -- Why and How to Expand the Role of Systems Biology in Pharmaceutical Research and Development / Robert D. Phair -- Multiscale Mechanistic Modeling in Pharmaceutical Research and Development / Lars Kuepfer, Jörg Lippert and Thomas Eissing -- Re-analysis of Bipolar Disorder and Schizophrenia Gene Expression Complements the Kraepelinian Dichotomy / Kui Qian, Antonio Di Lieto, Jukka Corander, Petri Auvinen and Dario Greco -- Bringing Together Models from Bottom-Up and Top-Down Approaches: An Application for Growth of Escherichia coli on Different Carbohydrates / Andeas Kremling -- A Differential Equation Model to Investigate the Dynamics of the Bovine Estrous Cycle / H. M. T. Boer, C. Stötzel, S. Röblitz and H. Woelders -- Reducing Systems Biology to Practice in Pharmaceutical Company Research; Selected Case Studies / N. Benson, L. Cucurull-Sanchez, O. Demin, S. Smirnov and P. van der Graaf -- System-Scale Network Modeling of Cancer Using EPoC / Tobias Abenius, Rebecka Jörnsten, Teresia Kling, Linnéa Schmidt and José Sánchez, et al. -- Early Patient Stratification and Predictive Biomarkers in Drug Discovery and Development / Daphna Laifenfeld, David A. Drubin, Natalie L. Catlett, Jennifer S. Park and Aaron A. Van Hooser, et al. -- Biomedical Atlases: Systematics, Informatics and Analysis / Richard A. Baldock and Albert Burger.
  • Digital
    Arun Devabhaktuni.
    Tandem mass spectrometry (MS/MS) enables the high-throughput identification and characterization of complex protein mixtures, and depends critically on bioinformatics tools to interpret mass spectra as peptide sequences. There exist two general techniques for the interpretation of mass spectra: de novo sequencing and database search. In de novo sequencing, a mass spectrum is directly interpreted as a protein sequence. In database search, a mass spectrum is identified from its best match in an existing sequence or spectrum database. Though more unbiased and less restrictive than database search algorithms, de novo sequencing algorithms are less popular due to their relatively lower accuracy and lack of automated statistical validation tools. However, database search algorithms suffer greatly in both speed and sensitivity as database search spaces increase through the addition of protein sequences and post-translational modifications. To able to apply MS/MS to more diverse systems, I developed the de novo sequencing algorithm Label Assisted De novo Sequencing (LADS). LADS utilizes chemical strategies to bolster introduce signatures into mass spectra which improve sequencing accuracy, and employs a support vector machine-based model to discriminate true from false identifications. I also developed a method by which to empirically estimate false discovery rates (FDRs) from any de novo sequencing algorithm. In the last stage of my PhD, I developed TagGraph, an unrestricted database search tool able to match peptides to mass spectra from sequence databases without assuming any protease specificity or requiring a user-specified set of modifications. I demonstrate the utility of TagGraph on the recently published human proteome dataset, matching over four million spectra to modified peptides, and identifying new functional roles and disease associations for protein hydroxylation. Both TagGraph and the de novo FDR calibration technology described herein have the potential to greatly extend the scope and depth of tandem MS analyses.
  • Digital
    Attila Magyar, Gábor Szederkényi, Katalin M. Hangos.
    ScienceDirect2018
    Analysis and Control of Polynomial Dynamic Models with Biological Applications synthesizes three mathematical background areas (graphs, matrices and optimization) to solve problems in the biological sciences (in particular, dynamic analysis and controller design of QP and polynomial systems arising from predator-prey and biochemical models). The book puts a significant emphasis on applications, focusing on quasi-polynomial (QP, or generalized Lotka-Volterra) and kinetic systems (also called biochemical reaction networks or simply CRNs) since they are universal descriptors for smooth nonlinear systems and can represent all important dynamical phenomena that are present in biological (and also in general) dynamical systems.
  • Digital
    Mark A. McElwain.
    Only a few signaling pathways control the majority of biological processes throughout animal development and homeostasis, indicating that each pathway regulates multiple processes. The Wnt family of secreted ligands is one interesting and important example of this paradigm. Evidence abounds that Wnt signaling impacts numerous biological events including embryonic patterning, stem cell self- renewal, cell proliferation, and tissue regeneration. While only a few Wnt proteins have been extensively characterized, it is likely that each family member signals to control a variety of critical biological processes; therefore, it is clear that by understanding the signaling mechanism used by a single Wnt protein, we can understand how many aspects of biology are regulated. WntD is one of 7 Wnt homologs encoded by the Drosophila genome. While most of these Wnt proteins likely signal through a pathway dependent on the [Beta]-catenin homolog Armadillo (Arm), WntD very likely utilizes an Arm-independent mechanism to control embryonic dorsal/ventral (D/V) patterning, migration of the primordial germ cells (PGC) to the embryonic gonad, and the innate immune response. It is therefore of great interest to identify genes involved in this signal transduction pathway and better characterize the effect WntD has on these important biological processes. To this end, a suppressor/enhancer deficiency screen based upon the role of WntD in D/V patterning was previously performed in the laboratory. From this screen, 30 strong candidates for suppressors and 13 strong candidates for enhancers were identified. Here, I present further characterization of two candidate WntD pathway members identified in the screen: Fz4, a likely WntD receptor and Dcerk, a lipid kinase. I show by both in vitro and in vivo assays that both Fz4 and Dcerk function in the WntD signal transduction pathway, and present evidence suggesting that this WntD-Fz4-Dcerk signaling cassette is utilized during both D/V patterning and PGC migration, yet another instance of a single signaling cascade mediating multiple developmental events. Interestingly, I show that both of these novel WntD signal transducers appear to act redundantly with a homologous protein: in both D/V patterning and PGC migration, WntD likely signals through Fz3 and Fz4 receptors to activate the lipid kinases Dcerk and Dmulk. I further show, in collaboration with the Saba Laboratory at Children's Hospital Oakland Research Institute, that these kinases are necessary for wild-type ceramide-1-phosphate (C1P) levels in the adult, and either is sufficient to increase embryonic C1P levels, suggesting that both Dcerk and Dmulk are bona fide ceramide kinases. My data linking WntD-ceramide kinase signaling to PGC migration is consistent with a model in which WntD signaling is responsible for generation of optimal levels of embryonic C1P, which is likely to be the long-undiscovered substrate that is formed into a gradient by the lipid phosphate phosphatases encoded by Wunen and Wunen2. Future experiments will be required to further test this model. Importantly, these results may suggest a mechanism for the regulation of a broad range of migratory cell types, including other cells that migrate to generate a specific tissue or organ during embryonic development, and immune cells that must travel long distances to fight off infections.
  • Digital
    Stephanie Marie Melillo.
    Striding bipedalism is a mode of locomotion that defines our lineage. Bipedality freed the hands, arms and shoulders from the mechanical constraints of locomotion, an evolutionary innovation that has had an obvious impact on our species' fitness. As I will discuss in this dissertation, the shoulder blade (scapula) is shaped to optimize use of the upper limb in certain positions. Our closest living relatives (chimpanzees and gorillas) possess adaptations that likely increase efficiency in overhead use of the arms, as in forearm suspension or vertical climbing. The modern human shoulder, on the other hand, lacks such adaptations. This difference may reflect an evolutionary change in shape that occurred as our ancestors transitioned to a terrestrial way of life and became increasingly dexterous, eventually losing ancestral adaptations. On the other hand, recent discoveries suggest our lineage may have never possessed adaptations to suspension. Fossils from the shoulder of our early human ancestors are scarce. A recently discovered partial skeleton from Woranso-Mille (Afar Depression, Ethiopia), KSD-VP-1/1, preserves the oldest and most complete scapula of an adult Australopithecus afarensis individual. The intended contribution of this dissertation is to provide a comparative description of the new scapula (KSD-VP-1/1g) and to detail its implications for our understanding of anatomy and adaptation in the Australopithecus shoulder, and the evolutionary history of the modern human shoulder more generally.
  • Digital
    edited by Darcia Narvaez, Kristin Valentino, Agustin Fuentes, James J. McKenna and Peter Gray.
    OSO2014
    1. Children's development in light of evolution and culture / Darcia Narvaez [and four others] -- 2. Epigenetics of mammalian parenting / Frances A. Champagne. Commentary. As time goes by, a touch is more than just a touch / Eric E. Nelson -- 3. Nonhuman primate models of mental health : early life experiences affect developmental trajectories / Amanda M. Dettmer, Stephen J. Suomi, and Katie Hinde. Commentary. Look how far we have come : a bit on consilience in elucidating the role of caregivers in relationship to their developing primate infants and children / James J. McKenna -- 4. Relationships and resource uncertainty : cooperative development of Efe hunter-gatherer infants and toddlers / Gilda Morelli, Paula Ivey Henry, and Steffen Foerster. Commentary. Social connectedness versus mothers on their own : research on hunter-gatherer tribes highlights the lack of support mothers and babies receive in the United States / Kathleen Kendall-Tackett -- 5. Batek childrearing and morality / Karen L. Endicott and Kirk M. Endicott. Commentary. Parenting in the modern jungle / Michael Jindra -- 6. Cosleeping beyond infancy : culture, ecology, and evolutionary biology of bed sharing among Aka foragers and Ngandu farmers of Central Africa / Barry S. Hewlett and Jennifer W. Roulette. Commentary. Intertwining the influences of culture and ecology broadens a definition of the importance of closeness in care / Wendy Middlemiss -- 7. Environment of evolutionary adaptedness, rough-and-tumble play, and the selection of restraint in human aggression / Douglas P. Fry. Commentary. Evolutionary adaptation and violent aggression : from myths to realities / Riane Eisler -- 8. Play theory of hunter-gatherer egalitarianism / Peter Gray. Commentary. Comparative studies of social play, fairness, and fitness : what we know and where we should be heading / Marc Bekoff -- 9. Incentives in the family I : the family firm, an evolutionary/economic theory for parent-offspring relations / Joan Roughgarden and Zhiyuan Song -- 10. Preliminary steps toward addressing the role of nonadult individuals in human evolution / Agustín Fuentes. Commentary. Conflict and evolution / Melvin Konner -- 11. Child maltreatment and early mother-child interactions / Kristin Valentino, Michelle Comas, and Amy K. Nuttall. Commentary. Ancestral attachment : how the evolutionary foundation of attachment informs our understanding of child maltreatment interventions / Alyssa N. Crittenden -- 12. Importance of the developmental perspective in evolutionary discussions of post-traumatic stress disorder / Robyn Bluhm and Ruth A. Lanius. Commentary. Modeling of complex post-traumatic stress disorder can benefit from careful integration of evolutionary and developmental accounts / Pierre Lienard -- 13. From the emergent drama of interpretation to enscreenment / Eugene Halton. Commentary. Darwinism and children / Jonathan Marks -- 14. Childhood environments and flourishing / Tracy R. Gleason and Darcia Narvaez -- 15. Postscript. Back to the future / James J. McKenna.
  • Digital
    Diane Tseng.
    Mobilization of the T cell response against cancer has the potential to achieve long-lasting cures. However, it is not known how to optimally harness antigen presenting cells to achieve an effective anti-tumor T cell response. In this study, we show that anti-CD47 antibody-mediated phagocytosis of cancer by macrophages can initiate an anti-tumor T cell immune response. Using the ovalbumin model antigen system, anti-CD47 antibody-mediated phagocytosis of cancer cells by macrophages resulted in increased priming of OT-I T cells (CD8+), but did not prime OT-II T cells (CD4+). The CD4+ T cell response was characterized by a reduction in Foxp3+ regulatory T cells. Macrophages following anti-CD47-mediated phagocytosis primed CD8+ T cells to exhibit cytotoxic effector function in vivo, protecting animals from tumor challenge. We conclude that anti-CD47 antibody treatment not only enables macrophage phagocytosis of cancer, but can also initiate an anti-tumor cytotoxic T cell immune response. Anti-CD47-mediated phagocytosis of cancer cells by macrophages leads to priming of a predominant CD8+ T cell response without priming of CD4+ T cells, demonstrating differential priming of T cell responses by macrophages. Priming of effector CD8+ T cells is difficult to achieve with existing vaccines for cancer and infectious diseases. Anti-CD47-based vaccination strategies serve as a promising new strategy for overcoming this challenge for treating or preventing human disease.
  • Digital
    by Giovanni Boniolo.
    Springer2012
    Deliberation and Democracy -- Plato Was Not So Far Wrong: Recalling Athenian Democracy -- A Reappraisal of the Medieval Approach Will Lead to Excellent Deliberators -- Beware of Those Who Think They Possess the Truth! -- Let Us Learn How to Deliberate before Deliberating! -- Between Ethics and Biomedicine.
  • Print
    Cigall Kadoch.
  • Digital
    Xinhong Lim.
    The skin is a classical example of a tissue maintained by stem cells, but the identity of the stem cells that maintain the different epidermal compartments and the signaling mechanisms that control their activity remain unclear. Using lineage tracing and quantitative clonal analyses, we show that the Wnt-target gene Axin2 marks epidermal stem cells that compete neutrally and require Wnt/[beta]-catenin signaling to proliferate. By RNA in situ hybridization, we show that the Axin2-expressing stem cells produce their own self-renewal signals in the form of Wnt proteins. These cells also express secreted Wnt inhibitors, including Dkks, which accumulate at high levels around more differentiated cells. We propose a new model for skin maintenance, in which epidermal stem cells produce short-range Wnt signals to maintain their own identity and function, while simultaneously secreting longer-range inhibitors that suppress Wnt signaling to promote differentiation of the stem cell progeny.
  • Print
    Robert M. Sapolsky.
    Status: Not Checked OutLane Catalog Record
    Why do we do the things we do? Stanford professor Robert Sapolsky attempts to answer that question as fully as possible, looking at it from every angle. Sapolsky starts by examining the factors that bear on a person's reaction in the precise moment a behavior occurs, and then hops back in time from there, in stages, ultimately ending up at the deep history of our species and its evolutionary legacy.-- Provided by publisher.
  • Digital
    George Ellis and Mark Solms.
    Cambridge2017
    1. Introduction -- 2. The mind and the brain -- 3. Hierarchy, modularity, and development -- 4. Claims of innate modularity -- 5. The mind and emotions -- 6. A realistic view of evolution, development, and emotions -- 7. Conclusion -- Appendix. Language infinities -- References -- Index.
  • Digital
    Gandhy Pierre-Louis.
    Epithelial cells sometimes display polarity along the axis orthogonal to the apicobasal axis -- a phenomenon referred to as planar cell polarity (PCP). This polarization biases organization of the cytoskeleton, and is required for a range of fundamental processes including, but not limited to, oriented cell division, polarized function of cilia, and the control of collective cell migration events during development. Consequently, deregulation or dysfunction of PCP genes has been linked to disorders including deafness as a result of misorientation of inner ear cells, neural tube closure defects because of a failure to execute convergent & extension, and tumor invasiveness. Despite having identified some of the key proteins required to achieve PCP, much is still unknown about their molecular functions. Evolutionarily conserved proteins, known as the core PCP proteins, are distributed asymmetrically within wing epithelial cells and form complexes within the proximal or distal cortical domains. Here, we demonstrate that these diametrically opposed complexes participate in a bi-directional negative feedback loop that simultaneously produces their asymmetric distribution within cells and reinforces the orientation of polarity to neighbors by transmitting polarity information intercellularly. We found that one of the core PCP proteins, Prickle (Pk), is important for negative feedback as it is required to mediate the exclusion of distal and proximal complexes from the plasma membrane during acquisition of asymmetry. Moreover, we found that the level of Pk is regulated by the Cullin1 (Cul1)/SkpA/Supernumerary limbs (Slimb) E3 ubiquitin ligase complex. Our observations lead us to believe that loss of, or excess, Pk perturbs PCP signaling through the disruption of feedback. Ultimately, these results highlight an underlying molecular mechanism for the generation of planar polarity. Finally, the approaches presented in this monograph can further help elucidate the molecular functions of the other core PCP proteins.
  • Digital
    by Theresa Overfield.
    TandFonline2017
  • Print
    Ludwig von Bertalanffy.
    Status: Not Checked OutLane Catalog Record
  • Digital
    edited by Ajaykumar Vishwakarma, Jeffrey M. Karp.
    ScienceDirect2017
    I. Biology of stem cell niches and molecular mechanisms -- The need to study, mimic, and target stem cell niches -- Harnessing the biology of stem cells' niche -- Pluripotent stem cell microenvironment -- Regulation of hematopoietic stem cell dynamics by molecular niche signaling -- HSC niche: regulation of mobilization and homing -- Neuronal stem cells niches of the brain -- Cardiovascular stem cell niche -- Intestinal epithelial Lgr5+ stem cell niche and organoids -- The epithelial stem cell niche in skin -- The satellite cell niche in skeletal muscle -- The cancer stem cell niche -- Cellular senescence and stem cell niche -- Biochemical and physical cues in the stem cell niche directing cell fate -- Matrix chemistry controlling stem cell behavior -- Matrix growth factor and surface ligand presentation -- Effects of matrix mechanical forces and geometry on stem cell behavior -- Wettability effect on stem cell behavior -- Fluid flow control of stem cells with investigation of mechanotransduction pathways -- Hypoxia regulation of stem cell: mechanisms, biological properties, and applications -- III. Designing smart biomaterials to mimic and control stem cell niche -- Polymer design and development -- Design and development of ceramics and glasses -- Surface functionalization of biomaterials -- Biofunctional hydrogels for three-dimensional stem cell culture -- Technologies to engineer cell substrate mechanics in hydrogels -- Micro- and nanosurface patterning technologies -- Self-assembled nanostructures (SANs) -- Biometric nanofibers as artificial stem cell niche -- IV. Bioengineering strategies to model synthetic stem cell niches -- Employing microfluidic devices to induce concentration gradients -- Engineering niches for embryonic and induced pluripotent stem cells -- Engineering niches for cardiovascular tissue regeneration -- Engineering niches for blood vessel regeneration -- Engineering niches for bone tissue regeneration -- Engineering vascular niche for bone tissue regeneration -- Engineering niches for cartilage tissue regeneration -- Engineering niches for stem and progenitor cell differentiation into immune cells -- Engineering niches for skin and wound healing -- Designing stem cell niche for liver development and regeneration -- Engineering the niche for intestinal regeneration.
  • Print
    Weinberg, Robert A.
    Status: Not Checked OutLane Catalog Record
    Thoroughly updated and incorporating the most important advances in the fast-growing field of cancer biology, This book is a textbook for students studying the molecular and cellular bases of cancer at the undergraduate, graduate, and medical school levels. The principles of cancer biology are presented in an organized, cogent, and in-depth manner. The clarity of writing, supported by an extensive full-color art program and numerous pedagogical features, makes the book accessible and engaging. The information unfolds through the presentation of key experiments that give readers a sense of discovery and provide insights into the conceptual foundation underlying modern cancer biology. Besides its value as a textbook, this book is a useful reference for individuals working in biomedical laboratories and for clinical professionals. Every copy of the book comes with an updated DVD-ROM containing the book's art program, a selection of movies, audio file mini-lectures, Supplementary Sidebars, and a Media Guide.
  • Digital
    Elizabeth Choe Yu.
    Cardiomyopathies are diseases of the myocardium resulting in heart failure, arrhythmia, and sudden death. Cardiomyopathies represent a major cause of morbidity and mortality in all age groups and recent application of human genomic technologies has revealed thousands of gene mutations that cause inherited and sporadic cardiomyopathies. Many mutations in the beta-cardiac myosin heavy chain (beta-MHC) gene, which encodes the motor that powers ventricular contraction, have been identified to cause inherited cardiomyopathies, including dilated cardiomyopathy (DCM). However, the molecular mechanisms by which these mutations alter the force generation and kinetic properties of the myosin molecule have not been elucidated. As a result, there are no available therapies targeted toward treating the underlying cause of these diseases to date. We have successfully adapted a system to produce recombinant human cardiac myosin motor domain, known as subfragment-1 (S1), using a mammalian myoblast cell line. This technique has allowed us to obtain significant quantities of highly purified recombinant human beta-cardiac myosin S1 for in-depth functional analyses of wild type and DCM-causing mutants. Characterization of biomechanical properties of DCM causing human beta-cardiac S1 demonstrated that DCM mutations results in an overall hypo-contractile state, although the fundamental mechanistic changes that lead to decreased power output vary. In the future, more complex systems can be analyzed by performing assays with regulated thin filaments instead of actin and double-headed myosin motors to gain further insights into the effects of beta-MHC mutations on cardiac myosin function. Furthermore, using emerging induced pluripotent stem cell (iPSC) technology, insights into the effects of these mutations of myosin biomechanical function in vitro can be correlated with their effects on cardiomyocyte function at the cellular level. Further understanding of these mechanisms can guide the search for specific therapeutic targets and lead to the development of small molecules to modulate the effects of the DCM-causing mutations and potentially prevent or reverse this clinically devastating disease.
  • Digital
    John Golbeck, Art van der Est, editors.
    Springer2014
    "The volume is intended as an introduction to the physical principles governing the main processes that occur in photosynthesis, with emphasis on the light reactions and electron transport chain. A unique feature of the photosynthetic apparatus is the fact that the molecular structures are known in detail for essentially all of its major components. The availability of this data has allowed their functions to be probed at a very fundamental level to discover the design principles that have guided evolution. Other volumes on photosynthesis have tended to focus on single components or on a specific set of biophysical techniques, and the authors' goal is to provide new researchers with an introduction to the overall field of photosynthesis. The book is divided into sections, each dealing with one of the main physical processes in photosynthetic energy conversion. Each section has several chapters each describing the role that a basic physical property, such as charge or spin, plays in governing the process being discussed. The chapters proceed in an orderly fashion from a quantum mechanical description of early processes on an ultrafast timescale to a classical treatment of electron transfer and catalysis on a biochemical timescale culminating in evolutionary principles on a geological timescale."--Publisher's website.
  • Digital
    edited by Takeshi Furuichi and Jo Thompson.
    Springer2008
    The bonobo's adaptive potential : social relations under captive conditions / Jeroen M.G. Stevens, Hilde Vervaecke and Linda Van Elsacker -- What does agonistic dominance imply in bonobos? / Tommaso Paoli and Elisabetta Palagi -- Social play in bonobos : not only an immature matter / Elisabetta Palagi and Tommaso Paoli -- Gestures and multimodal signaling in bonobos / Amy S. Pollick, Annette Jeneson and Frans B.M. de Waal -- Longitudinal structure of a unit-group of bonobos : male philopatry and possible fusion of unit-groups / Chie Hashimoto ... [et al.] -- Seasonal changes in fruit production and party size of bonobos at Wamba / Mbangi Mulavwa ... [et al.] -- Relationships among fruit abundance, ranging rate, and party size and composition of bonobos at Wamba / Takeshi Furuichi ... [et al.] -- Bonobo (Pan paniscus) density estimation in the SW-Salonga National Park, Democratic Republic of Congo : common methodology revisited / Meike Mohneke and Barbara Fruth -- Ecological factors influencing bonobo density and distribution in the Salonga National Park : applications for population assessment / Gay Edwards Reinartz ... [et al.] -- Range occupation and population estimates of bonobos in the Salonga National Park : application to large-scale surveys of bonobos in the Democratic Republic of Congo / Falk Grossmann ... [et al.] -- Traditional land-use practices for bonobo conservation / Jo Myers Thompson, Lubuta Mbokoso Nestor and Richard Bovundja Kabanda -- Human hunting and its impact on bonobos in the Salonga National Park, Democratic Republic of Congo / John A. Hart ... [et al.] -- The bonobos of the Lake Tumba-Lake Maindombe hinterland : threats and opportunities for population conservation / Bila-Isia Inogwabini ... [et al.] -- Changes in the status of bonobos, their habitat, and the situation of humans at Wamba in the Luo Scientific Reserve, Democratic Republic of Congo / Gen'ichi Idani ... [et al.] -- The conservation value of Lola ya Bonobo sanctuary / Claudine André ... [et al.].
  • Digital
    Andrew B. Hellman.
    The nervous system is comprised of a complex network of neurons that are connected by specialized structures called synapses. Each synapse contains a myriad of proteins that fulfill different functions, ranging from the release and reception of neurotransmitters to the maintenance and strengthening of the signals between neurons. Given the multitude of proteins present at the synapse, one question is how do they arrive and remain there? In my thesis, I use Caenorhabditis elegans to explore the cellular processes that contribute to the proper localization of important presynaptic proteins. In the first part of my thesis, I explored how presynaptic proteins are properly localized to the signal-sending process, called the axon, and excluded from the signal receiving process, called the dendrite. In the motor neuron DA9, synaptic vesicles localize in a stereotyped region of the axon, but in cdk-5 mutants, 40% of the vesicle material is mislocalized to the dendrite. Chan-Yen Ou, a postdoctoral fellow in the lab, isolated a mutant that suppressed cdk-5, suggesting that the gene acts downstream or parallel to cdk-5. I mapped this mutant to the unc-101 locus, which encodes the [Mu]-subunit of the AP1 complex. AP complexes are players in clathrin-mediated endocytosis, and the [Mu]-subunit is the cargo recognition molecule within the complex. The AP1 complex plays a well-established role at the trans-golgi network in the cell body, but we present three results that suggest UNC-101 also acts at presynapses. The first result is the strong localization of UNC-101 at the synapse. The second result is that disrupting synaptic vesicle endocytosis (SVE) using genetic mutations causes a v similar phenotype as unc-101 mutations; animals mutant for unc-57/endophilin, unc- 26/synaptojanin, or dyn-1/dynamin 1 also suppress the cdk-5 dendritic phenotype. The third result is that the transport of synaptic vesicles from the synaptic region towards the dendrite decreases in an unc-101; cdk-5 double mutant compared to the cdk-5 single mutant, suggesting that UNC-101 is preventing retrograde flow from the synapses. While these results suggest a synaptic role for UNC-101, they do not exclude the possibility that UNC-101 also acts at the cell body. Indeed, I also show that UNC-101 affects the localization of postsynaptic proteins, which may occur by sorting proteins at the cell body. Additionally, postsynaptic proteins are unaffected by unc-57, suggesting an SVE-independent role for unc-101. Thus, I provide evidence that the AP1 subunit UNC-101 acts at presynapses and contributes to the molecular polarity of the DA9 motor neuron. The second part of my thesis contains my findings regarding a new system that I established to study synapse formation: the AFD thermosensory neuron. I found that the synaptic pattern in AFD is highly stereotyped, and I also isolated a mutant from a forward genetic screen that I mapped to the tax-4 locus. tax-4 and tax-2 encode two subunits of a cyclic nucleotide-gated channel that is necessary for sensory activity in AFD. When the genes are mutated, the localization of multiple presynaptic proteins is disrupted. Interestingly, they are not all similarly affected. Clusters of synaptic vesicles and the active zone protein SYD-2/liprin-[Alpha] are dimmer and more numerous in tax-4 and tax-2 than wild-type animals. While SAD-1/SAD kinase clusters are also dimmer, there are fewer in tax-4 and tax-2 than wild-type animals. These results suggest that sensory activity can have different effects depending on the presynaptic vi protein. Thus, for the second part of my thesis, I describe the establishment of a new system to study synapse development, the results of a screen, and a link between neural activity and the localization of presynaptic proteins.
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    Evan Lloyd Guiney.
    In response to hyperosmotic shock, cells of the budding yeast Saccharomyces cerevisiae lose up to 50% of their volume. This drastic decrease in cell size results in excess plasma membrane, which forms large infoldings that must be quickly removed. How these plasma membrane invaginations are resolved to restore the cell surface is not well understood. We show that hyperosmotic shock activates calcineurin, the Ca2+/calmodulin-dependent protein phosphatase, leading to restoration of normal membrane morphology. During hyperosmotic stress, actin patches (sites of endocytosis) become depolarized; we find that under these conditions calcineurin accumulates at sites of polarized growth and promotes actin patch repolarization. Hyperosmotic stress causes calcineurin to bind to the yeast synaptojanin Inp53/Sjl3 and dephosphorylate its proline rich tail. Dephosphorylation by calcineurin activates Inp53, which in turn dephosphorylates PI(4,5)P2 at the plasma membrane and promotes repolarization of the actin cytoskeleton. Consistently, cells lacking the partially redundant synaptojanins Inp51/Sjl1 and Inp52/Sjl2 require calcineurin for growth even in the absence of hyperosmotic stress, and display abnormal plasma membrane morphology when calcineurin activation of Inp53 is blocked. Finally, we find that calcineurin binding to Inp53 stimulates its association with the yeast amphiphysin Rvs167, suggesting model where calcineurin stimulates Inp53 and Rvs167 mediated membrane scission, promoting recovery from excess membrane stress and allowing resumption of polarized growth. In neurons, periods of intense synaptic vesicle release also result in excess membrane, and calcineurin stimulates association of synaptojanin with amphiphysin to promote synaptic vesicle endocytosis. Our findings in yeast suggest that stimulation of endocytic complex formation by Ca2+/calcineurin is a fundamental and conserved feature of the eukaryotic response to excess plasma membrane.
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    Craig Patrick Giacomini.
    Recurrent gene fusions and chromosomal translocations have long been recognized for their roles in oncogenesis. This dissertation employs genomic approaches to discover and characterize novel gene fusions in several cancer types. First we developed a "breakpoint analysis" pipeline for gene fusion discovery and applied this method to a collection of nearly 1,000 human cancer samples profiled on DNA microarrays. This approach led to the discovery and characterization of twelve new gene fusions in diverse cancer types including angiosarcoma, pancreatic cancer, and colon cancer. Separately, we performed RNA Sequencing on a series of 36 breast cancer specimens and used a suite of computational tools developed in-house to discover ~350 candidate gene rearrangements. Notably, we discovered recurrent fusions of the sterile 20 (STE20)-like kinase TAOK1, and functional studies suggest that these fusions encode potent oncoproteins that drive breast carcinogenesis. Many of the alterations discovered in this dissertation represent the first gene fusions reported to date in the corresponding cancer type, and many represent potentially druggable targets with therapeutic implications for patients.
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    Mogens L. Glass, Stephen C. Wood, editors.
    Springer2009
    Overview of the respiratory system / S.C. Wood -- Control of respiration in aquatic vertebrates: Gas transport and gill function in water-breathing fish / S.F. Perry ... [et al.]. Patterns of acid-base regulation during exposure to hypercarbia in fishes / C.J. Brauner and D.W. Baker. Buoyancy control in aquatic vertebrates / B. Pelster. Gas exchange and control of respiration in air-breathing teleost fish / M.L. Glass and F.T. Rantin. Effects of temperature on cardiac function in teleost fish / A.L. Kalinin ... [et al.]. Physiological evidence indicates lungfish as a sister group to the land vertebrates / M.L. Glass. Aestivation in amphibians, reptiles, and lungfish / M.L. Glass, J. Amin-Naves, and G.S.F. da Silva -- Evolution of pulmonary mechaincs and respiratory control: Trade-offs in the evolution of the respiratory apparatus of chordates / S.F. Perry, W. Klein, and J.R. Codd. Environmental selection pressures shaping the pulmonary surfactant system of adult and developing lungs / S. Orgeig and C.B. Daniels. Midbrain structures and control of ventilation in amphibians / L.H. Gargaglioni and L.G.S. Branco. Comparative aspects of hypoxia tolerance of the ectothermic vertebrate heart / H. Gesser and J. Overgaard. Control of the heart and of cardiorespiratory interactions in ectothermic vertebrates / E.W. Taylor and T. Wang. The endocrine-paracrine control of the cardiovascular system / B. Tota and M.C. Cerra. Stoking the brightest fires of life among vertebrates / Raul K. Suarez and Kenneth C. Welch -- Respiratory physiology of birds : metabolic control: Prenatal development of cardiovascular regulation in avian species / J. Altimiras, D.A. Crossley II, and E. Villamor. Control of breathing in birds : implications for high-altitude flight / G.R. Scott and W.K. Milsom -- Mammalian and human physiology: Peripheral chemoreceptors in mammals : structure, function and transduction / P. Kumar. Central chemosensitivity in mammals / L.K. Hartzler and R.W. Putnam. Human exercise physiology / S. Volianitis and Niels H. Secher.
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    Maria Lynn Spletter.
    The brain is a complex organ formed from billions of neurons. There are thousands of types of neurons, each with a unique morphology, function, gene expression profile and pattern of connectivity. This structure poses a very interesting developmental challenge: how do neurons acquire unique identities and connect to specific partner neurons during development? The Drosophila antennal lobe presents an attractive genetic model system in which to investigate these questions. In the antennal lobe, olfactory receptor neuron (ORN) axons project to glomeruli where they synapse with their partner projection neuron (PN) dendrites. These connections are highly stereotyped, as ORNs expressing the same odorant receptor converge on the same glomerulus and all PNs of the same class send their dendrites to the same glomerulus. Cell surface molecules are known to be crucial to instructing this specific wiring during development, and a transcriptional code likely dictates which cells express a particular cell surface molecule. However, the identities of many of these cell surface molecules and transcription factors remain unknown, and it is possible that additional cell types also inform the specific wiring of PNs and ORNs. In this thesis, I present work that furthers our understanding of the development and function of the fly olfactory circuit. First, I discuss a detailed characterization of local interneurons in the antennal lobe, dramatically expanding our basic knowledge of the types of cells present during development as well as central to information processing in the antennal lobe. Second, I present my work on the transcription factor longitudinals lacking (lola) that plays a role both in fate determination and wiring specificity of olfactory projection neurons, the second order cells that relay olfactory information to higher brain centers. Finally, I present an analysis of the regulatory elements driving expression of the projection neuron marker GH146 as a first step in defining transcriptional regulatory modules and identifying factors that may direct fate and wiring decisions in PNs.
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    Weizhe Hong.
    Neurons are interconnected with extraordinary precision to allow proper propagation and integration of neural activities. The organization of these specific connections emerges from sequential developmental events, including axon guidance, target selection, and synapse formation. Compared to axon guidance, little is known about how selection and matching between pre- and post-synaptic partners are achieved. To ensure the proper relay of olfactory information in flies, axons of ~50 classes of olfactory receptor neurons (ORNs) form one-to-one connections with dendrites of ~50 classes of projection neurons (PNs). Previous developmental analysis has shown that PN dendrites first target to specific areas within the developing antennal lobe to create a proto-map. This is followed by ORN axon invasion into the antennal lobe. However, it is unclear (1) how PNs target their dendrites to specific areas and (2) how ORN axons subsequently recognize PN dendrites to form highly specific one-to-one connections. To address the first question, I conducted a genetic screen to identify new genes involved in PN dendrite targeting. I identified Capricious, a leucine-rich repeat transmembrane protein that is differentially expressed in different PN classes. Loss- and gain-of-function studies indicate that Capricious instructs the segregation of Capricious-positive and negative PN dendrites to discrete glomerular targets. Moreover, the function of Capricious in regulating PN dendrite targeting is independent of pre-synaptic ORNs. The closely related protein Tartan plays a partially redundant function with Capricious. Therefore, these leucine-rich repeat proteins instruct targeting of PN dendrites to discrete glomeruli in the antennal lobe. To address the second question, we designed highly sensitive and robust assays to examine the matching and mismatching between PNs and ORNs. This allowed me to perform two unbiased screens, which independently identified two Teneurins, Ten-m and Ten-a, as synaptic matching molecules. Teneurins are EGF repeat-containing transmembrane proteins that are evolutionarily conserved from worms to mammals. Drosophila Teneurins, Ten-m and Ten-a, are highly expressed in select PN and ORN matching pairs. Loss- and gain-of-function of Teneurins cause specific mismatching of ORN axons and PN dendrites. Moreover, Teneurins promote homophilic interactions in vitro, and homophilically mediate trans-cellular interactions to promote PN-ORN attraction in vivo. Therefore, I propose that Teneurins instruct synaptic matching specificity between PNs and ORNs through homophilic attraction. The identification of Teneurins reveals a general mechanism for determining synapse specificity directly between pre- and post-synaptic neurons. In summary, I have identified two major mechanisms for the stepwise assembly of the olfactory circuit. In the first step, PN dendrites target to specific, discrete glomerular locations in the antennal lobe through a pair of leucine-rich repeat transmembrane proteins, Capricious and Tartan. Subsequently, ORN axons arrive at the antennal lobe, and recognize PN dendrites through homophilic attractions mediated by a pair of EGF repeat-containing transmembrane proteins, Ten-m and Ten-a. These molecules and underlying mechanisms not only help mechanistically understand the olfactory circuit assembly but also elucidate the general principles by which wiring specificity is established.
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    Springerv. 5-, 2002-
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    Timothy Richard Stowe.
    Centrosomes and cilia are evolutionarily conserved organelles with important functions in cell signaling, organismal development and disease. Defects in centrosome and cilium function are associated with a set of phenotypically-related syndromes called ciliopathies. To discover new centrosome/cilium components, candidate genes were identified by virtue of their transcriptional upregulation in multiciliated tracheal epithelial cells and selected for further study based on their subcellular localization. Using this approach, Cep72 was identified as a component of centriolar satellites - poorly understood centrosome-associated structures defined by the protein PCM1. A subset of ciliopathy-associated proteins that includes BBS4, Cep290 and OFD1 associate with centriolar satellites, yet how this association affects their function is unknown. Cep72 was determined to be a PCM1-interacting protein and its association with centriolar satellites was characterized in detail. Cep72 was found to interact with Cep290 and overexpression/depletion experiments demonstrated that Cep72 facilitates recruitment of Cep290, but not BBS4, to centriolar satellites. Loss of satellites by depletion of PCM1 resulted in cytoplasmic disperal of BBS4 and redistribution of Cep72 and Cep290 from centriolar satellites to the centrosome. In contrast to the reported function of centriolar satellites in facilitating the localization of proteins to the centrosome, the effects of PCM1 depletion on Cep72 and Cep290 localization suggest that association with centriolar satellites can also restrict centrosomal localization for some proteins. During ciliogenesis, BBS4 transitions from centriolar satellites to the primary cilium, however regulation of this transition is not understood. Depletion of Cep72 or Cep290 prevented transition of BBS4 localization, causing BBS4 to remain localized to centriolar satellites in ciliated cells. Depletion of PCM1 or Cep72 in developing zebrafish embryos resulted in phenotypes consistent with centrosome/cilium defects, suggesting centriolar satellites influence cilium function during development. Given these results, we propose that centriolar satellites function in modulating the ciliary localization of BBS4 and possibly other ciliogenesis factors, via a mechanism that involves Cep290 as an effector of that regulation. The distribution of centriolar satellites around the centrosome during interphase requires microtubules and dynein. During the cellular stress response to misfolded proteins, protein aggregates are transported in a microtubule and dynein-dependent manner to structures surrounding the centrosome referred to as aggresomes. We observed PCM1-dependent recruitment of centriolar satellite proteins to aggresomes, which prompted further investigation of the potential involvement of PCM1 in aggresome formation. Depletion of PCM1 had modest effects on aggresome formation and cell viability in response to misfolded proteins. However the influence of PCM1 on centrosome function and microtubule organization could not be ruled out as possible explanation for these effects.
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    Joshua Martin Santé.
    The Chibby protein antagonizes Wnt/Beta-Catenin signaling, a prominent regulator pathway of development, via direct interaction with the transcriptional activator domain of Beta-Catenin. Chibby mutant mice have a defect in the formation of motile cilia in the airway epithelium. The centrosome is the major microtubule organizing center of animal cells and includes two centrioles, termed mother and the daughter based on their age and replicative history. The mother harbors subdistal and distal appendages, which, respectively, anchor the interphase microtubule array and are required for ciliation. Several lines of published evidence suggest a link between the primary cilium, a single, non-motile structure found on many cells, and Wnt/Beta-Catenin signaling. Based on this evidence I investigated Chibby, and related members of the Chibby protein family, to determine its role in centrosome and cilium structure and function. I report here that the Chibby family of proteins is associated physically and functionally with the centrioles of the centrosome in mammalian cells. The Chibby family consists of Chibby (Cby1), Nurit/Cby2, and the previously uncharacterized, Chibby3 (Cby3). Fluorescence microscopy revealed that Cby1 localized to the mother centriole of the centrosome, and that this localization was partially shared with Nurit/Cby2 and Cby3. Cby1 colocalizes at the mother centriole with phospho-Beta-Catenin, a modified form of Beta-Catenin that, in some contexts it is targeted for proteasome-mediated degradation. I also found that Cby1 partially colocalized with phospho-Beta-Catenin at a ring-like structure at the midbody during cytokinesis, where they might regulate abscission. The localization of Cby1 to the mother centriole was similar to that described for proteins for the distal appendages of the mother centriole. I found that Cby1 colocalized with, and exhibited cell cycle dynamics similar to, Cep164, a known distal appendage protein that is required for primary cilium formation. Consistent with a role for Cby1 in these centriolar structures, Cby1-/- mouse embryonic fibroblasts exhibited a strong reduction in primary cilium formation that could be complemented by expression of the wild-type Cby1 protein. Remarkably, overexpression of either GFP-tagged Beta-Catenin or GFP-Cby1 in hTERT-RPE1 cells resulted in fewer, but longer, cilia than controls suggesting that both of these proteins are important for structure and function of the primary cilium. In summary, I propose that Cby1 is associated with the distal appendages of the mother centriole, that defects in those structures are the likely cause of the failure of cilium formation in cells lacking Cby1, and that both primary and motile cilia display this requirement for Cby1.
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    Michelle Kathryn Zeman.
    Accurate maintenance and transmission of DNA from one cell to another is crucial for the propagation of a species, as accumulation of random mutations can result in loss of critical cellular functions. During DNA replication, DNA lesions encountered by the replication machinery cannot be repaired, as unwinding of the parental DNA separates the damaged DNA from the undamaged template which would normally be used for repair. These replication-blocking lesions can be seriously detrimental to the cell, as stalled replication forks can collapse into double-stranded DNA breaks and lead to genomic rearrangements. To prevent the accumulation of stalled and collapsed forks, the cell uses DNA damage tolerance (DDT) pathways to bypass the DNA lesion and complete replication. There are two known DDT pathways -- translesion synthesis, which uses specialized translesion synthesis polymerases to replicate directly over a DNA lesion, and template switching, which promotes invasion into the sister chromatid and extrusion of the newly synthesized strand for use as a template. These processes rely on a series of E3 ubiquitin ligases in mammalian cells, including Rad18, SHPRH, and HLTF. As a result, we wished to examine the role of ubiquitin modification, and ubiquitin-related SUMO modification, on the control of DDT. Together, the data presented here provide important new insight into how cells control the response to DNA damage and, importantly, how this response is repressed in the absence of damage. As misregulation of Rad18 and SHPRH, as well as several other DDT components, has been implicated in cancer development and progression, knowing more about this regulation may help us understand how cells avoid the generation of mutations, and ultimately the development of disease.
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    Veronica Graciela Beaudry.
    Desmosomes are multi-protein cell-cell adhesion junctions found throughout stratified squamous epithelia and the myocardium. These specialized adhesion complexes maintain the structural integrity of these tissues, which are continuously exposed to mechanical stress. Perturbations in desmosome structure and function lead to clinical symptoms associated with a variety of human skin and heart disorders. While the molecular basis for these phenotypes is mainly attributable to the role of the desmosome in resisting mechanical stress, emerging roles for this complex in cellular signaling, apoptosis, and tissue morphogenesis are accumulating. Understanding the molecular mechanisms of desmosome function in both normal tissue homeostasis and disease will bring new insights into these complex biological processes. Loss of cellular adhesion junctions is a common feature of epithelial cancer progression. However, the specific contribution of how desmosome function affects this disease has not been looked at in great detail. In the first two chapters, we examined the consequences of desmosome loss to tumor formation using mice deficient for the desmosomal protein Perp. In-depth analyses focusing on Perp's mechanism of action revealed new insights into the role of Perp and the desmosome in adhesion, apoptosis, and inflammation. In the second part of my thesis, we investigated the role of the desmosome in epithelial wound healing and in Ankyloblepharon Ectodermal Dysplasia and Cleft Lip/Palate (AEC), a human skin disease characterized by severe craniofacial abnormalities, skin erosions, and alopecia. We first showed that proper desmosome function is essential for efficient wound healing in vivo. Lastly, we investigated whether some of the clinical symptoms associated with AEC were attributable to defects in Perp function. We identified a subset of AEC derived p63 mutants that were capable of transactiving Perp expression, despite being previously characterized as inactive for other p63 target genes. Analysis of skin biopsies revealed disrupted Perp expression in a subset of AEC patients, further corroborating a role for Perp dysfunction in the pathogenesis of this disease. Together these studies have uncovered important roles for Perp and the desmosome in maintaining proper skin homeostasis and insights into the mechanisms of how Perp loss and desmosome disruption contributes to disease progression in a variety of contexts.
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    Laura Elizabeth Sanman.
    Macrophages are immune cells that inhabit almost every tissue of the body and work to maintain organismal homeostasis. They recognize a broad range of deviations from normal (e.g., metabolic imbalance, presence of pathogens, tissue damage) and tailor their responses to return the body to normal. Macrophages are remarkably plastic in their signaling state, which allows them to respond to homeostatic disruptions in a rapid and appropriate manner. Due to this rapid adaptation to new environments, the ability to perturb and observe macrophage signaling in a temporally defined manner is key. Chemical tools allow such rapid manipulation and observation and, in this thesis, I will describe our use of chemical tools such as small molecule inhibitors and optical probes to dissect dynamic macrophage signaling. One mechanism through which macrophages respond to danger is by initiating the formation of protein complexes called inflammasomes. These complexes facilitate activation of the pro-inflammatory cytokines IL-1β and IL-18 and rapid pyroptotic cell death. This causes inflammation, the goal of which is to identify and combat the source(s) of danger. Inflammasome signaling is beneficial for fighting pathogenic bacteria, fungi, and viruses, but aberrant or excessive inflammasome signaling can damage tissues. Chapters 2 and 4 describe the application of small molecule inhibitors to dissect the cellular signals that lead to formation of a specific inflammasome, the NLRP3 inflammasome, which is implicated in the response to bacterial pathogens and is also overactive in metabolic and genetic autoinflammatory disease. Our work in Chapter 2 describes the identification of a small molecule activator of the NLRP3 inflammasome. By characterizing the mechanism of action of this small molecule, we found that disruption of glycolytic metabolism drives NLRP3 inflammasome formation and pyroptotic cell death in macrophages. We find that this mechanism of NLRP3 inflammasome activation is used by host macrophages to sense and react to the intracellular bacterial pathogen Salmonella typhimurium. In Chapter 4, we discuss the development of a live-cell imaging-based screening method that enables comprehensive identification of small molecules that modulate NLRP3 inflammasome formation and pyroptotic cell death. The goals of this project are to further knowledge of cellular signals leading to NLRP3 activation and to identify therapeutic leads for combatting aberrant NLRP3-driven inflammation. Just as macrophages have evolved many ways of recognizing pathogens, pathogens have also evolved many methods of evading detection and can even successfully colonize and replicate within macrophages. For example, Salmonella typhimurium lives in specialized endosomes and lysosomes in host macrophages. In Chapter 3, we describe the development of optical probes that we use to characterize the interplay of endolysosomal Salmonella with host macrophages' endolysosomal enzymes. We focus on a specific family of enzymes, the cysteine cathepsins, because they fulfill anti-bacterial and pro-bacterial functions depending on their localization. We find that upon initial colonization of macrophages, cathepsins can access Salmonella in early endosome-like compartments. In contrast, at later time-points after colonization, Salmonella cause an elevation in endolysosomal pH that impairs cathepsin protease activity and prevents cathepsins from accessing their replicative niche. Taken together, these data convey a complex and changing equilibrium between a bacterial pathogen and the cells that it colonizes.
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    Ramona Hoh.
    Multiciliated cells of the respiratory epithelium are unique in that they generate hundreds of modified centrioles called basal bodies per cell. Each basal body anchors a motile cilium at the cell apical surface, and coordinated beating of motile cilia is vital for protecting from airway infection and for respiratory function. We used mice expressing GFP from the promoter of a ciliated cell-specific gene, FOXJ1, to obtain sorted populations of ciliating cells for transcriptional analysis. In addition to successfully identifying candidates found in other proteomics and genomics studies of motile and nonmotile cilia, approximately half of the significantly upregulated genes identified here have not yet been linked to cilia, and of those a third of are currently uncharacterized. We identified several genes associated with human diseases. These include FTO, which has been linked to human obesity, and DYX1C1, which is a candidate gene for developmental dyslexia. Interestingly, FTO localizes to cilia and Dyx1c1-GFP localizes to cilia and centrosomes, establishing novel links between cilia and two genetic diseases with poorly understood cellular and molecular etiology. Finally, we identified a number of transcription factors that are differentially expressed in ciliating mouse tracheal epithelial cells, including the proto-oncogene c-myb. We show that C-myb is expressed specifically in ciliating cells, and that this expression is temporally restricted to early in the differentiation process. These results suggest a role for the leukemogenic transcription factor C-myb in ciliated cell differentiation.
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    Achim Kramer, Martha Merrow, editors.
    Springer2013
    Molecular and cellular basis of circadian clocks -- Molecular components of the mammalian circadian clock / Ethan D. Buhr and Joseph S. Takahashi -- The epigenetic language of circadian clocks / Saurabh Sahar and Paolo Sassone-Corsi -- Peripheral circadian oscillators in mammals / Steven A. Brown and Abdelhalim Azzi -- Cellular mechanisms of circadian pacemaking: beyond transcriptional loops / John S. O'Neill, Elizabeth S. Maywood, and Michael H. Hastings -- The clock in the brain: neurons, glia, and networks in daily rhythms / Emily Slat, G. Mark Freeman Jr., and Erik D. Herzog -- Circadian control of physiology and behavior -- Circadian clocks and metabolism / Biliana Marcheva, Kathryn M. Ramsey, Clara B. Peek, Alison Affinati, Eleonore Maury, and Joseph Bass -- The circadian control of sleep / Simon P. Fisher, Russell G. Foster, and Stuart N. Peirson -- Daily regulation of hormone profiles / Andries Kalsbeek and Eric Fliers -- Circadian clocks and mood-related behaviors / Urs Albrecht -- Chronopharmacology and chronotherapy -- Molecular clocks in pharmacology / Erik S. Musiek and Garret A. FitzGerald -- Cancer chronotherapeutics: experimental, theoretical,and clinical aspects / E. Ortiz-Tudela, A. Mteyrek, A. Ballesta, P.F. Innominato, and F. Lévi -- Pharmacological modulators of the circadian clock as potential therapeutic drugs: focus on genotoxic/anticancer therapy / Marina P. Antoch and Roman V. Kondratov -- Light and the human circadian clock / Till Roenneberg, Thomas Kantermann, Myriam Juda, Ceéline Vetter, and Karla V. Allebrandt -- Systems biology of circadian clocks -- Mathematical modeling in chronobiology / G. Bordyugov, P.O. Westermark, A. Korenčič, S. Bernard, and H. Herzel -- Mammalian circadian clock: the roles of transcriptional repression and delay / Yoichi Minami, Koji L. Ode, and Hiroki R. Ueda -- Genome-wide analyses of circadian systems / Akhilesh B. Reddy -- Proteomic approaches in circadian biology / Maria S. Robles and Matthias Mann.
  • Digital/Print
    edited by Michael W. Young.
    Digital : ScienceDirect2005
    Print2005
    Genetic approaches to circadian clocks -- Tracking circadian control of gene activity -- Molecular cycles : clock protein rhythms -- Anatomical representation of neural clocks -- Mosaic circadian systems -- Peripheral circadian clocks -- Cell and tissue culture system -- Intercellular signaling -- Photoresponsive clocks -- Sleeping flies -- Circadian biology of populations -- Circadian clocks affecting noncircadian biology.
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    Maureen M. Dawson, Brian A. Dawson, Joyce A. Overfield.
    Status: Not Checked OutLane Catalog Record
    Communication skills in science -- Using scientific literature -- Essay writing -- Writing practical reports -- The project report -- Scientific posters -- Oral presentations -- Preparing a curriculum vitae and job application.
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    Tiara Lynn Aiko Kawahara.
    Aging is a degenerative process accompanied by tissue deterioration, decline in function and increased susceptibility to disease. It is now understood to be a genetically and environmentally regulated process, rather than simply the result of wear and tear. We developed a systematic approach to identify combinatorial cis-regulatory motifs that drive age-dependent gene expression across different tissues and organisms, and identified the transcription factor NF-[kappa]B as a candidate regulator of aging. Using multiple independent models, we show a role for NF-[kappa]B in regulating transcriptional programs of aging. First, we found that aged mice subjected to NF-[kappa]B blockade for two weeks exhibit reversion of the tissue characteristics and global gene expression programs to those of young mice. Next, we detected deregulated transcriptional activity of NF-[kappa]B in Sirt6-deficient mice, which exhibit premature aging-like symptoms. We show that Sirt6 interacts with the NF-[kappa]B RelA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-[kappa]B target gene promoters. Computational genomics analyses revealed increased activity of NF-[kappa]B-driven gene expression programs in multiple Sirt6-deficient tissues in vivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of Sirt6-deficient mice, suggesting that hyperactive NF-[kappa]B-dependent transcription in the absence of Sirt6 promotes premature aging-like syndromes. Finally, we performed a genome-scale survey of RelA and Sirt6 location on chromatin in mouse embryonic fibroblasts (MEFs) via chromatin immunoprecipiation (ChIP)-on-chip to understand to what extent Sirt6 and RelA act coordinately to regulate gene expression. These results indicate that RelA and Sirt6 co-occupy the promoters of a large population of genes at sites less than 500kb apart and/or require RelA to enable binding of Sirt6. Expression analysis of these shared targets reveals direct regulation of 301 promoters, including genes such as Shc1 (encoding p66), Cdkn2a (encoding p16), Wnt2 and Jmjd3, which have been separately implicated in the aging process. We propose that hyperactive NF-[kappa]B signaling contributes to premature and normal aging.
  • Digital
    William Rowland Goodyer.
    To meet host metabolic demands after birth, organs like pancreatic islets increase their physiological function and mass. Compared to fetal islet development, however, little is known about mechanisms governing neonatal islet maturation and expansion. Here I demonstrate calcineurin/Nuclear Factor of Activated T-cells (Cn/NFAT) signaling regulates both [beta]-cell maturation and proliferation in neonatal mice and humans. Inactivation of the gene encoding the calcineurin phosphatase regulatory subunit, calcineurin b1 (Cnb1), in mouse islets resulted in defective dense core granule biogenesis, impaired insulin secretion, and reduced neonatal [beta]-cell proliferation and mass, culminating in lethal, early-onset diabetes. [beta]-cells lacking Cnb1 failed to express genes required for insulin storage and secretion, as well as neonatal replication. Tacrolimus, a calcineurin inhibitor and widely used immunosuppressant, reduces human [beta]-cell secretion and promotes diabetes, toxicities without a clear molecular basis. Exposure of mouse and human islets to tacrolimus reduced expression of genes encoding factors essential for insulin dense core granule formation and secretion, and neonatal [beta]-cell proliferation consistent with our genetic studies. Chromatin immunoprecipitation and other molecular studies revealed these genes as novel, direct NFAT targets in neonatal mouse and human islets. Thus, calcineurin/NFAT signaling coordinately regulates factors that govern [beta]-cell maturation and proliferation, revealing unique models for the pathogenesis and therapy of diabetes mellitus and diverse human islet diseases.
  • Digital
    Anna D. Cunningham.
    G6PD deficiency, an enzymopathy affecting 7% of the world population, is caused by over 160 different amino acid variants in glucose-6-phosphate dehydrogenase (G6PD). This essential enzyme plays a critical role in maintaining redox homeostasis, and while variants that reduce activity are protective against malaria, complete loss of G6PD activity is lethal. G6PD deficiency is a major risk factor for hyperbilirubinemia and kernicterus, and may contribute to many health conditions including neurodegenerative diseases, heart disease, diabetes, and aging. The clinical presentation of G6PD deficiency is diverse, likely due to the broad distribution of variants across the protein and the potential for multidimensional biochemical effects -- previously characterized G6PD variants have been shown to affect catalytic activity, thermostability, and protein folding. However, the relationship between the structural, biochemical, and phenotypic effects of a G6PD variant remains largely unexplored. Recent developments in the fields of bioinformatics and genome sequencing have allowed us to combine existing phenotypic, biochemical, and genomic information about G6PD to develop new hypotheses about its evolution, structure, and function. In this study, we use existing databases of characterized and uncharacterized G6PD variants to interpret the importance of various structural regions of G6PD. Using biochemical analyses, we identify a trade-off between protein stability and catalytic activity as a major determinant of a G6PD variant's clinical phenotype. Additionally, we examine the evolution of G6PD using a recently developed sequence coevolution analysis method. We identify three coevolving sectors of amino acids that are enriched in different classes of G6PD variants; these three sectors also correspond to functionally characterized structural regions. Based on two sectors that span multiple structural regions, we develop novel hypotheses about conformational and allosteric regulation of G6PD. This work expands the current understanding of the structural and biochemical underpinnings of G6PD variant pathogenicity, and suggests a promising avenue for correcting G6PD deficiency by targeting essential structural features of G6PD.
  • Digital
    Bonifacino, Juan S.
  • Digital
    edited by V. S. Chandrasekhar Pammi, Narayanan Srinivasan.
    ScienceDirect2013
    This well-established international series examines major areas of basic and clinical research within neuroscience, as well as emerging and promising subfields.This volume explores interdisciplinary research on decision making taking a neural and behavioural approach *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
    Erica Swesey Savig.
    While undergoing medical treatment for life-threatening illnesses, patients - and their family members - often experience emotional and psychological distress. This is particularly true during pediatric stem cell transplantation, where hospital isolation restrictions further impact normal childhood and family functioning. Many experience the extremes of anxiety, depression, or post-traumatic stress symptoms. In this dissertation, we take a human-centered design needfinding approach to identify the internal "core needs" of children and their family members that are heightened during pediatric stem cell transplantation. Importantly, we learn how these needs are affected by their isolation environment, including the social milieu and hospital organization. The emotional and psychological vulnerability of the population demanded a finely crafted sensitive interview style, to help the interviewees comfortably reflect on their difficult past experiences. This resulted in the design of new activity-based tools and techniques that elicit deeply emotional stories and offer opportunities for positively transforming them. Interviews were also conducted with the interdisciplinary care team. Overall, five common core needs were identified: emotional and mental strength, social relatedness, autonomy, connectedness, and normalcy. By honing in on these core needs, new supportive care programs, interventions, hospital policies, clinical operations and care practices may be designed with the patient's and family's well-being in mind.
  • Digital
    Graham A. Anderson.
    Developing animal embryos have fascinated scientists for centuries. Their morphology and dynamic behaviors are some of the most beautiful phenomena in all of biology, and their task of converting a single cell into a functional animal seems miraculous. This dissertation is an effort to understand the early embryonic cell division patterns that appear in diverse animal embryos using the frog Xenopus laevis as a model for embryogenesis. We characterized the timing and geometry of multiple waves that move throughout the embryo. By using a temperature gradient to perturb endogenous cell division timing, we found that these dazzling waves are caused by a simple and autonomous mechanism: the variance of intrinsic cell cycle period along the embryonic axes. Again using a temperature gradient, we found that relative cell division synchrony before the mid-blastula transition is required for normal mesodermal induction. Amazingly, desynchronized embryos with mesoderm induction defects go on to become healthy tadpoles. This suggests the existence of a previously unknown synchronizing mechanism during the developmental process of involution. The early X. laevis embryo is at once simple in its design, yet robust to perturbation. We hope others use this dissertation to aid in further understanding of the dynamic processes of early animal embryos.
  • Digital
    Alexey Melkikh, Maria Sutormina.
    Springer2013
    Understanding the general laws of an effective system for the transport of substances in cells is an important goal of systems and synthetic biology and will help us to answer why the transport subsystem of a cell is arranged as it is. In addition, the construction of models for optimizing transport systems is of considerable importance in the early stages in the development of a functioning protocell. The aim of this book is to describe the latest techniques for the calculation of the optimal parameters of the transport subsystem of a cell at its maximum efficiency.
  • Digital
    Ukrae Cho.
    One of the fundamental experimental strategies of modern biology is "perturb and observe". Investigators perturb a complex biological system and, by observing the consequences of their experimental change, infer the function of the perturbed component(s). In order for researchers to be confident in their conclusions, perturbation and observation should have sufficient levels of specificity and sensitivity. Here, I describe two chemical technologies -- one observational and the other perturbational -- that enable better studies of biomolecules in whole-body organisms by making possible the selective visualization of lanthanide luminescence and the pharmacological control of protein stability. In chapter 1 and 2, I discuss a next-generation system for time-resolved lanthanide imaging. As luminescent lanthanide complexes have emission lifetimes that are > 100,000-fold longer than those of organic fluorophores, they can be selectively detected over fluorescent background by time-gating, enabling autofluorescence-free micrographs. However, the optical microscopy of lanthanide probes has not yet achieved detection limits and acquisition speed suitable for most biological applications. I describe three factors that have been impeding the efficient visualization of lanthanide luminescence, and present simple but powerful solutions to the respective problems. I also show novel imaging applications of lanthanide complexes that exploit unique chemical and photophysical properties of these organometallic probes. In chapter 3, I discuss the development of destabilizing domains (DDs) that allow rapid, reversible, and tunable control of protein levels in model organisms that thrive best at 20-25 °C. By genetically appending our DD to a protein of interest, the expression level of resulting fusion protein was successfully modulated by a small molecule ligand in C. elegans.
  • Digital/Print
    edited by R. Jeroen Pasterkamp, Marten P. Smidt, J. Peter H. Burbach.
    Digital : Springer2009
    Print2009
    Development of the dopamine systems in zebrafish / Jørn Schweitzer and Wolfgang Driever -- Dopamine systems in the forebrain / John W. Cave and Harriet Baker -- The role of Otx genes in progenitor domains of ventral midbrain / Antonio Simeone ... [et al.] -- Terminal differentiation of mesodiencephalic dopaminergic neurons : the role of Nurr1 and Pitx3 / Marten P. Smidt and J. Peter H. Burbach -- Foxa1 and Foxa2 transcription factors regulate differentiation of midbrain dopaminergic neurons / Siew-Lan Ang -- Transcriptional regulation of their survival : the engrailed homeobox genes / Horst H. Simon and Kambiz N. Alavian -- Neurotrophic support of midbrain dopaminergic neurons / Oliver von Bohlen und Halbach and Klaus Unsicker -- TGF in dopamine neuron development, maintenance, and neuroprotection / Eleni Roussa, Oliver von Bohlen und Halbach, and Kerstin Krieglstein -- Axon guidance in the dopamine system / Asheeta A. Prasad and R. Jeroen Pasterkamp -- Protocols for generating ES-cell-derived dopamine neurons / Sonja Kriks and Lorenz Studer -- Molecular and cellular determinants for generating ES-cell-derived dopamine neurons for cell therapy / -- Jan Pruszak and Ole Isacson.
  • Digital
    Kyle M. Loh.
    One aspiration of regenerative medicine has been to produce pure populations of human tissue progenitors from differentiating pluripotent stem cells, potentially providing limitless tissues for patients-in-need. Yet, the developmental process through which pluripotent cells become diversified into a broad array of human tissue progenitors in vivo remains poorly ambiguous. Consequently in vitro stem-cell differentiation often generates an impure mixture of cell-types poorly suited for therapeutic purposes. To more accurately guide stem-cell differentiation, I have systematically mapped the pairwise lineage choices through which pluripotent cells become diversified into a broad array of derivatives belonging to the human endoderm germ layer (which gives rise to lungs, liver, pancreas, intestines and so forth) and mesoderm germ layer (which yields bone, heart and blood amongst other cell-types). At each binary lineage choice, I determined the signals that drove cells to one fate or the other. By providing the inductive signals to steer stem cells towards one lineage while inhibiting the repressive signals that instead instructed alternate fates, I could "force" pluripotent stem cells to differentiate into a pure population of a single cell-type at each lineage juncture. This approach of logically guiding stem-cell differentiation by inhibiting alternate lineage choices yielded highly pure populations of transplantable human liver progenitors, bone progenitors and heart progenitors that could each engraft in vivo in respective animal models, providing the starting point for future cell replacement therapy. Moreover by profiling transcriptional and chromatin changes between purified populations of different human endoderm and mesoderm progenitors, I defined stepwise changes in gene expression and revealed opening and closing of chromatin elements at each developmental step. Collectively, I have reconstituted aspects of human development in culture, providing a versatile platform to produce purified populations of tissue progenitors for regenerative medicine, to systematically identify the positive and negative signals that guide cell-fate choice at each lineage transition, and to understand the molecular underpinnings of human development. Akin to the relationship of biochemistry to genetics, the ability to synthetically reconstitute a process in a reductionist system demonstrates a causal understanding of how the process naturally works, and these are the goals of pluripotent stem cell differentiation as pertains to developmental biology; to artificially reconstitute complex developmental processes in a dish, to causally understand development at increasingly-higher resolution; and ultimately to achieve precise control over stem-cell differentiation to realize a new era of regenerative medicine.
  • Digital
    Tiffany Hung.
    Recent advances in transcriptome analysis have revealed a large number of non-protein coding transcripts that have previously been uncharacterized. A subset of these molecules, termed long noncoding RNAs (lncRNAs), has been implicated in the regulation of chromatin states. Here, we detail a journey of lncRNA discovery and analysis, beginning from the de novo discovery of lncRNAs within the promoters of cell cycle genes, followed by the functional characterization of select candidates. We characterize two examples that regulate the p53-mediated DNA damage response. LncRNA PANDA blocks the apoptosis pathway by inhibiting the transcription factor NF-YA, and lncRNA DINO regulates the p53 transcriptional response by regulating SET7-mediated post-translational modification. Altogether, these studies support a model whereby pervasive lncRNA transcripts, previously discarded as transcriptional byproducts, function through diverse mechanisms as critical regulators of biological pathways.
  • Digital
    Jan Bruin, Leo P.S. van der Geest, editors.
    Springer2009
  • Digital
    Michael L. Arnold.
    OSO2015
    Genetic exchange : an historical consideration -- Genetic exchange and species concepts -- Testing for genetic exchange -- Genetic exchange, reproductive barriers, and the mosaic genome -- Genetic exchange and fitness -- Evolutionary outcomes of genetic exchange -- Genetic exchange and conservation -- Genetic exchange and humans.
  • Digital
    [edited by] Esther Lubzens, Joan Cerdà, Melody Clark.
    Springer2010
    Many organisms have evolved the ability to enter into and revive from a dormant state. They can survive for long periods in this state (often even months to years), yet can become responsive again within minutes or hours. This is often, but not necessarily, associated with desiccation. Preserving one 's body and reviving it in future generations is a dream of mankind. To date, however, we have failed to learn how cells, tissues or entire organisms can be made dormant or be effectively revived at ambient temperatures. In this book studies on organisms, ranging from aquatic cyanobacteria that produce akinetes to hibernating mammals, are presented, and reveal common but also divergent physiological and molecular pathways for surviving in a dormant form or for tolerating harsh environments. Attempting to learn the functions associated with dormancy and how they are regulated is one of the great future challenges. Its relevance to the preservation of cells and tissues is one of the key concerns of this book
  • Digital
    Jing Shan Lim.
    Developmental pathways are frequently re-activated and implicated during tumorigenesis. During lung development, Notch signaling inhibits the formation of pulmonary neuroendocrine cells, which are the adult epithelial cells of origin for small cell lung cancer (SCLC), the most aggressive and lethal subtype of lung cancer. This inhibitory role of Notch in neuroendocrine differentiation suggested that Notch activity might be tumor suppressive in SCLC. Consistent with this, genomic studies revealed inactivating mutations in the NOTCH receptors in ~15-25% of SCLC tumors. Ectopic Notch activation also inhibited tumor initiation in a mouse model for SCLC, suppressed the proliferation of neuroendocrine SCLC cells in culture and induced a differentiation switch to a non-neuroendocrine cell fate. Surprisingly, however, we identified a subset (~25%) of cells (Notch+ cells) in SCLC tumors that activate endogenous Notch signaling. These cells are non-neuroendocrine, proliferate slower than the Notch-, neuroendocrine tumor cells and are generated from the neuroendocrine cells, thus establishing a level of intratumoral heterogeneity generated by the bulk tumor cells themselves. Notch+ cells promote the proliferation of neuroendocrine cells, and Notch inhibition cooperates with chemotherapy to inhibit SCLC growth. These data show that the Notch pathway can be both tumor suppressive and oncogenic in SCLC; Notch inhibits the proliferation and differentiation of neuroendocrine cells but also promotes their growth in a paracrine manner. Downstream of Notch, we identified Rest/Nrsf, a transcriptional repressor that typically acts to restrict the expression of neuronal genes, as a target of Notch that mediates its inhibition of neuroendocrine cell fate. Thus, the Notch pathway has complex roles in SCLC and is able to modulate both tumor growth as well as its neuroendocrine differentiation.
  • Digital/Print
    Arthur N. Popper, Anthony Hawkins, editors.
    Digital : Springer2012
    Print2012
    Part I. Introduction -- Part II. Sound Detection by Aquatic Animals -- Part III. Sound Production by Aquatic Animals -- Part IV. Physiological Effects of Sounds -- Part V. Anthropogenic Sounds and Behavior -- Part VI. Population Effects -- Part VII. Anthropogenic Sound Sources and Their Measurement -- Part VIII. Science, Regulation and Sound Exposure Criteria -- Part IX. Monitoring, Management and Mitigation -- Part X. Workshops and Concluding Remarks.
  • Digital/Print
    Arthur N. Popper, Anthony Hawkins, editors.
    Digital : Springer2016
    Print2016
    The meeting of Aquatic Noise 2013 will introduce participants to the most recent research data, regulatory issues and thinking about effects of man-made noise and will foster critical cross-disciplinary discussion between the participants. Emphasis will be on the cross-fertilization of ideas and findings across species and noise sources. As with its predecessor, The Effects of Noise on Aquatic Life: 3rd International Conference will encourage discussion of the impact of underwater sound, its regulation and mitigation of its effects. With over 100 contributions from leading researchers, a wide range of sources of underwater sound will be considered.
  • Print
    compiled by A.F. Dorian.
    Status: Not Checked OutLane Catalog Record
    pt. A. General medicine -- pt. B. Anatomy -- pt. C. Biology, genetics and biochemistry -- pt. D. Therapeutic substances.
  • Digital
    Michelle Renee Marques.
    Ewing's sarcoma is the second most common malignant bone cancer in children. The prominent defining feature of Ewing's sarcoma is a translocation event between a member of the FET family of RNA binding proteins and a member of the Ets transcription factor family. The majority of patients have a translocation event between the EWSR1 gene and the FLI1 gene. The EWS-FLI1 translocation was first discovered in 1992 and to date, the mechanism by which EWS-FLI1 induces the formation of Ewing's sarcomas remains unclear. Understanding the role of EWS-FLI1 in oncogenesis is critical for Ewing's sarcoma and would have broad implications for other cancers as well. Translocations involving members of the FET or Ets families are also found in leukemia, prostate cancer and other sarcomas. A primary goal of my graduate work has been to develop tools to express EWS-FLI1 in primary human cells as well as in genetically engineered mice to understand how EWS-FLI1 induces oncogenesis and determine the cell of origin in Ewing's sarcoma. As recent work suggested that Ewing's sarcomas arise from a mesenchymal stem/progenitor cell (MSC), we examined the effects of EWS-FLI1 expression in primary human MSCs. We isolated MSCs from pediatric patients at Lucile Packard Children's Hospital to establish human bone marrow derived MSC lines (which we call HBMs). Through a series of experiments, we learned that the precise expression levels of EWS-FLI1 were critical in determining the effect of this oncogene on primary cells. High expression of EWS-FLI1 was not tolerated in HBMs. In contrast, when expressed at lower levels, stable EWS-FLI1 expression was maintained in HBMs. To elucidate transcriptional targets of EWS-FLI1 in HBMs, we used next-generation sequencing (RNAseq) to identify genes dysregulated by EWS-FLI1. Using this approach we identified 170 targets that constitute an EWS-FLI1 expression signature, including novel target genes. Expression of a subset of these genes was dependent on EWS-FLI1 expression in Ewing's sarcoma cell lines, validating their regulation by EWS-FLI1. The majority of these target genes were required for growth in soft agar of Ewing's sarcoma cell lines and some also showed an effect on cell growth. Among these EWS-FLI1 target genes we focused on a novel long non-coding RNA, lnc277, which is induced and regulated by EWS-FLI1 in Ewing's sarcoma cell lines and in other human cell lines ectopically expressing EWS-FLI1. Expression of lnc277 is highly specific to Ewing's sarcoma and is required for cell growth and transformation by EWS-FLI1. To decipher a mechanism for how lnc277 functions in Ewing's sarcoma cells, we have used protein arrays to identify interacting proteins. Lnc277 appears to interact with several proteins involved in transcription, splicing, RNA stability and translation, including STAU1, HNRPK1 and several others. Additionally, we performed RNAseq analysis of lnc277 knock-down to identify specific genes whose expression is altered upon depletion of lnc277. To elucidate the cell of origin for Ewing's sarcoma and create a model that can be used to test novel strategies for treatment, we have genetically engineered mice to conditionally express the EWS-FLI1 translocation from the endogenous EWSR1 locus. We have generated mice that contain lox sites within both the EWSR1 locus and the FLI1 locus such that upon Cre recombinase expression, some cells will undergo a reciprocal recombination event, generating both the EWS-FLI1 and FLI1-EWS chromosomes. We have genomic DNA and mRNA confirmation that this recombination occurs in vitro and in vivo after expression of Cre recombinase. This is the first example to our knowledge of a mouse model that faithfully recapitulates a translocation mechanism in a solid tumor. The reciprocal translocation model relies on two chromosomes recombining with each other, an event that we have found to be highly rare with these two chromosomes in the mouse. Therefore, we focused our efforts on a second mouse model where the recombination event occurs much more efficiently, our EWS-FLI1-V5 mouse model. The EWS-FLI1-V5 mouse model expresses a V5-epitope tagged version of EWS-FLI1 also from the EWSR1 locus. To create this model, a FLI1 cDNA was introduced downstream of the EWSR1 gene on the same chromosome. The expression of Cre recombinase results in the formation of the translocation by splicing the N-terminal EWSR1 exons to a FLI1 cDNA containing the C-terminal exons. This model leads to expression of EWS-FLI1-V5 in the majority of cells where Cre is expressed. We have carried out in vitro studies expressing EWS-FLI1-V5 in mouse embryo fibroblasts (MEFs) and mouse MSCs. Whereas EWS-FLI1-V5 expression inhibits proliferation in MEFs, MSCs expressing EWS-FLI1-V5 continue to proliferate. We have demonstrated that several of the new target genes identified in the human system were also regulated by EWS-FLI1-V5 in mouse cells. We have crossed both our Ewing's sarcoma mouse models to four Cre strains that express Cre recombinase in mesenchymal tissues as well as one that expresses Cre recombinase in the neural crest lineage. Mice from the reciprocal translocation model failed to develop tumors, most likely because the translocation event was so rare either no cell recombined the EWSR1 and FLI1 loci or that EWS-FLI1 expression was not tolerated in the cells that did recombine the loci. The EWS-FLI1-V5 mice expressing EWS-FLI1 in the mesenchymal lineage using Dermo1-Cre, Col1[alpha]2-Cre, Prx1-Cre or Sox9-Cre died embryonically. Interestingly, we only obtained mice that could potentially be expressing EWS-FLI1-V5 in the neural crest lineage using P0-Cre, suggesting the expression of EWS-FLI1-V5 in these cells was not toxic or that other cells can compensate for loss of the cells expressing EWS-FLI1-V5. Whether these adult mice actually express EWS-FLI1-V5 in the tissues derived from the neural crest lineage and whether these mice are tumor prone are areas for future study. Through this thesis work, we have used a combined approach that leverages both human and mouse model systems to create an in vivo model of Ewing's sarcomagenesis. These models could be used to define the cell of origin for Ewing's sarcoma and gain an understanding of the genetic requirements for oncogenesis downstream of EWS-FLI1. Through our studies of pediatric human mesenchymal stem cells expressing EWS-FLI1 in Chapters 2 and 3, we have discovered a number of novel EWS-FLI1 target genes and identified a lncRNA that is highly specific to and required for EWS-FLI1 mediated oncogenesis. In Chapters 4 and 5, two novel transgenic mouse strains were generated to express the EWS-FLI1 gene fusion from the endogenous EWSR1 locus in a way that is physiologically relevant to Ewing's sarcoma. These tools should help define the effects of EWS-FLI1 expression in primary and cancer cells and hopefully result in new therapies to benefit children diagnosed with this disease.
  • Digital
    Wiley1999-
    A fully searchable, working editorial site of articles by scientists and scientific historians in the fields of biochemistry and physiology, cell biology, developmental biology, ecology, evolution, genetics, immunology, molecular biology, neuroscience, microbiology and virology, plant science, structural biology, and science and society.
  • Digital
    Kapa Lenkov.
    The ability of an animal to change quickly in response to its surroundings is essential to its survival and in some species, individuals respond by changing phenotype. The studies in this thesis focus on the molecular mechanisms through which environmental information can affect changes in phenotype in an African cichlid fish, Astatotilapia burtoni. This species is particularly useful for this study, as adult male burtoni assume one of two distinct, reversible, behavioral and physiological phenotypes. Dominant (D) males are brightly colored, reproductively capable and engage in mating and aggressive territorial behaviors while non-dominant (ND) males are drably colored, reproductively incapable, and are behaviorally passive. Importantly, the transition from ND to D or the reverse can occur in a matter of minutes and is triggered solely by external social cues. How such external information is translated into phenotypic changes on the molecular level is the focus of these experiments and my data suggest an epigenetic mechanism may regulate this transition. The specific epigenetic mechanism assessed here is DNA methylation, which is the covalent attachment of a methyl group to the cytosine nucleotide of DNA, which can lead to changes in expression. First, I showed that DNA methylation is present in A. burtoni, as not all animals utilize this mechanism. I used immunohistochemistry to demonstrate that high levels of global methylation are present in the nuclei of all cells examined, most likely bound with the highest frequency to heterochromatin, to suppress transcription of specific transcribed regions. However, there were no differences detected between behavioral states using these methods. Next I demonstrated that epigenetic mechanisms play a role during the determination of social status by treating juvenile males with epigenetic modifiers that either promote or interfere with DNA methyltransferase (DNMT). Animals injected with zebularine, which blocks the activity of DNMT, were statistically unlikely to ascend to D status, while those injected with methionine, which acts as a methyl donor, were statistically likely to become D males. Once a potential role for DNA methylation in social status determination was found, I surveyed potential sites of action on the GnRH1 gene, a key regulator of reproductive behavior, for variations in methylation on the single nucleotide level. I found that fully established Ds and NDs do not have differences in methylation levels in any on the individual nucleotides assayed on the GnRH1 promoter or coding region; however, juvenile males have lower levels of methylation than Ds at some sites on the promoter, while males transitioning to D status have lower average promoter methylation, but higher average coding region methylation than D males. Furthermore, ND animals injected with zebularine have higher average levels of methylation on both the promoter and coding region than control ND males. In order to better understand the context of the methylation changes during sexual maturation, methylation levels on the GnRH1 gene were measured during normal development. GnRH1 methylation levels remain constant between two and four weeks of age but increase significantly at several sites between 4 and 6 weeks of age. Furthermore, crowding mothers during the brooding stage and raising young in crowded tanks results in lower methylation levels at both 2 and 6 weeks of age, as well as causing delayed growth at the 6 week stage. Finally, I measured GnRH1 methylation in a non-reproductive context. Since GnRH agonists can interfere with short-term memory in humans, I measured changes in methylation in the GnRH1 gene during memory formation and storage. Animals who successfully learned a memory task showed a correlation with higher methylation at sites in the GnRH1 coding region than non-learners. Learners were successfully able to recall their training after three months; however, the increased methylation in the coding region was no longer present. In summary, DNA methylation is present in A. burtoni and increases on the GnRH1 gene promoter and coding sequence during transitions in development and sexual maturation. As GnRH1 expression levels are known to increase in these cases, increased methylation is not acting canonically as a repressor of expression on GnRH1. During short-term learning, higher methylation is limited to only the coding region of GnRH1, indicating that there may be several different epigenetic regulatory pathways involving this gene. Furthermore, the observation that there are no differences in GnRH1 methylation between stable D and ND males, or, in the long-term, between learners and non-learners, suggests that methylation in this location may be transitory and used as a short-term marker for other regulatory mechanisms.
  • Digital
    Seumas Miller, Michael J. Selgelid.
    Springer2008
  • Digital
    Yi Alicia Yin.
    Telomerase is up-regulated in 90% of human tumors where it confers cellular immortality. Gliomas, melanomas, and cancers of the liver, bladder and thyroid, sustain highly recurrent mutations in the promoter of the gene encoding telomerase reverse transcriptase (TERT), whose transcription controls telomerase expression. These proximal promoter mutations, C124T and C146T, are the most common noncoding mutations in the human cancer genome. Each mutation creates a new DNA binding consensus site for ETS transcription factor GABP, but the requirement for GABP in telomerase function and cell immortalization remains unknown. In a larger context, transcriptional activation of TERT in cancers without promoter mutations has remained an intractable mystery. A detailed understanding of how TERT regulation in cancer compares to that in normal cells is also lacking. Closing these gaps of knowledge would greatly advance our understanding of the immortalization process and provide insights into therapeutic designs targeting telomerase in cancer. The work described here aims to answer the fundamental questions regarding the mechanisms governing telomerase reactivation in cancer. Using CRISPR mediated genome editing, here we show that GABP is not only indispensible for telomerase expression and immortality in TERT mutant cancers, but also necessary for TERT activation in TERT WT cancers. GABP activates wild type TERT promoter by binding to a conserved ETSbox. In TERT promoter mutant cancers, cooperation between ETSbox and the de novo ETS site is crucial in allowing heterotetramer formation of GABP. Furthermore, we demonstrate that GABP is not only required for TERT transcription in cancers but also in human and mouse embryonic stem cells. We propose that an evolutionarily conserved role of GABP in regulating TERT promoter in telomerase positive cells, and TERT promoter mutations operate by potentiating this mechanism through allowing heterotetramer formation and therefore stronger effects of GABP.
  • Digital
    Roger Jankowski.
    Springer2013
    The primary nose and palate in evolution -- The primary nose and palate in human embryo development -- Parallels between evolution and development of the nose -- The seemingly simple formation of the secondary palate and nose in the human embryo -- The complex formation of the secondary palate and nose in evolution -- A theory of secondary palate formation -- Primary and secondary palates : primary and secondary nasal fossae -- Olfactory and respiratory nasal fossae -- Is the human ethmoid labyrinth a sinus? -- Understanding the anatomy of the human nose -- Formation of the paranasal air sinues -- The nose in midface development -- Reminder of the normal embryologic development of the human brain -- Phylogenetic origins of the visual and olfactory organs -- Lessons from midface malformations associated to holoprosencephaly -- The evo-devo scenario of nose and midface formation -- A help to teaching anatomy -- Medical hypothesis and perspectives -- Evolutionary and develomental (evo-devo) medicine.
  • Digital
    meeting organized by Bruce Stillman, David Stewart, and Jan Witkowski.
    Cold Spring Harb Lab Press2009
  • Digital
    Henry Joseph Folse III.
    In the first chapter, we argue that an individual organism ought not to be defined in terms of genetic homogeneity, but rather by the evolutionary criteria of the alignment of fitness interests, the export of fitness due to interdependence for survival and reproduction, and adaptive functional organization. We consider how these concepts apply to various putative individual organisms, review the costs and benefits of intraorganismal genetic heterogeneity, and demonstrate that high relatedness is neither necessary nor sufficient for individuality. In the second chapter, we model the benefits and costs of genetic mosaicism for a long-lived tree in coevolution with a short-lived pest. We demonstrate benefits of mosaicism for trees at both the individual and population levels when somatic mutation introduces new defenses. In the third chapter, we develop a game theoretic model of the decision to reject or fuse with a potential partner in a colonial ascidian, based on weighing costs and benefits of fusion. We find that once fused, the interactions between cell lineages are cooperative in the soma, but competitive in the germline.
  • Digital
    Elisabeth A. Murray, Steven P. Wise, Kim S. Graham.
    OSO2017
    Current theories about human memory have been shaped by clinical observations and animal experiments. This doctrine holds that the medial temporal lobe subserves one memory system for explicit or declarative memories, while the basal ganglia subserves a separate memory system for implicit or procedural memories, including habits. Cortical areas outside the medial temporal lobe are said to function in perception, motor control, attention, or other aspects of executive function, but not in memory. The Evolution of Memory Systems' advances dramatically different ideas on all counts. It proposes that several memory systems arose during evolution and that they did so for the same general reason: to transcend problems and exploit opportunities encountered by specific ancestors at particular times and places in the distant past. Instead of classifying cortical areas in terms of mutually exclusive perception, executive, or memory functions, the authors show that all cortical areas contribute to memory and that they do so in their own ways-using specialized neural representations. The book also presents a proposal on the evolution of explicit memory. According to this idea, explicit (declarative) memory depends on interactions between a phylogenetically ancient navigation system and a representational system that evolved in humans to represent one's self and others. As a result, people embed representations of themselves into the events they experience and the facts they learn, which leads to the perception of participating in events and knowing facts.The Evolution of Memory Systems' is an important new work for students and researchers in neuroscience, psychology, and biology.
  • Digital
    edited by Pierre Pontarotti.
    Springer2008
    I. Modelization of Evolution -- Rate of Adaptation of Large Populations / Feng Yu and Alison Etheridge, p. 3-27 -- A Phylogenetic Mixture Model for Heterotachy / Andrew Meade and Mark Pagel, p. 29-41 -- II. Concepts in Evolutionary Biology -- Accelerated Evolution of Genes of Recent Origin / Macarena Toll-Riera, Jose Castresana and M. Mar Albà, p. 45-59 -- Life-Cycle Features of Tumour Cells / Jekaterina Erenpreisa and Mark S. Cragg, 61-71 -- General Evolutionary Regularities of Organic and Social Life / Valeria I. Mikhalevich, p. 73-94 -- Old and New Concepts in EvoDevo / Margherita Raineri, p. 95-114 -- III. Knowledge -- Overturning the Prejudices about Hydra and Metazoan Evolution / Hiroshi Shimizu, p. 117-134 -- The Search for the Origin of Cnidarian Nematocysts in Dinoflagellates / Jung Shan Hwang, Satoshi Nagai, Shiho Hayakawa, Yasuharu Takaku and Takashi Gojobori, p. 135-152 -- IV. Applied Evolutionary Biology -- A Possible Relationship Between the Phylogenetic Branch Lengths and the Chaetognath rRNA Paralog Gene Functionalities: Ubiquitous, Tissue-Specific or Pseudogenes / Roxane-Marie Barthélémy, Michel Grino, Pierre Pontarotti, Jean-Paul Casanova and Eric Faure, p. 155-164 -- Mode and Tempo of matK : Gene Evolution and Phylogenetic Implications / Khidir W. Hilu and Michelle M. Barthet, p. 165-179 -- Phylogeography and Conservation of the Rare South African Fruit Chafer Ichnestoma stobbiai (Coleoptera: Scarabaeidae) / Ute Kryger and Clarke H. Scholtz, p. 181-196 -- Nothing in Medicine Makes Sense Except in the Light of Evolution: A Review / Bernard Swynghedauw, p. 197-207 -- An Overview of Evolutionary Biology Concepts for Functional Annotation: Advances and Challenges / Anthony Levasseur and Pierre Pontarotti, p. 209-215.
  • Digital/Print
    Orkun S. Soyer, editor.
    Digital : Springer2012
    Print2012
  • Print
    Jonathan Orsay.
    Status: Not Checked OutLane Catalog Record
  • Print
    Jonathan Orsay.
    Status: Not Checked OutLane Catalog Record
  • Digital
    Melissa Gale Works.
    Stroke is the fourth leading cause of death in industrialized countries and is a major cause of disability in the United States. Protein therapy shows promise for the reduction of brain damage following stroke; however, current delivery methods lack the ability to efficiently deliver therapeutic proteins to the brain without invasive methods. It is possible to exploit normal inflammation in the brain, and the resultant immune cell migration following stroke, by injecting modified leukocytes such as dendritic cells that act as carriers of protective transgenes in a non-invasive, ischemia-targeted manner. With this solution in mind, my thesis focused on investigating the mechanisms of ex vivo-derived dendritic cell (exDC) migration to the stroke brain and using exDCs as vehicles for the delivery of anti-inflammatory proteins. I determined that the number of exDCs that migrate to the brain after stroke is positively correlated with the level of inflammation 6 hour after stroke. Tissue damage is also positively correlated with inflammation at this same time point. Finally, I investigated whether exDCs could be modified to deliver anti-inflammatory therapy after stroke. ExDCs were successfully transduced to constitutively express soluble TNF receptor 1 (sTNFR1) secrete functional protein that does not alter the phenotype or migratory ability of the cells. Importantly, when sTNFR1-exDCs are delivered after stroke they reduce inflammation and damage in vivo. These studies indicate that the use of cell-mediated protein delivery may be a promising new approach to reduce brain damage following acute neurological insult.
  • Digital
    edited by David O. Carter, Jeffery K. Tomberlin, M. Eric Benbow, Jessica L. Metcalf.
    Wiley2017
    Forensic Microbiology focuses on newly emerging areas of microbiology relevant to medicolegal and criminal investigations: postmortem changes, establishing cause of death, estimating postmortem interval, and trace evidence analysis. Recent developments in sequencing technology allow researchers, and potentially practitioners, to examine microbial communities at unprecedented resolution and in multidisciplinary contexts. This detailed study of microbes facilitates the development of new forensic tools that use the structure and function of microbial communities as physical evidence. Chapters cover: -Experiment design -Data analysis -Sample preservation -The influence of microbes on results from autopsy, toxicology, and histology -Decomposition ecology -Trace evidence This diverse, rapidly evolving field of study has the potential to provide high quality microbial evidence which can be replicated across laboratories, providing spatial and temporal evidence which could be crucial in a broad range of investigative contexts. This book is intended as a resource for students, microbiologists, investigators, pathologists, and other forensic science professionals.
  • Digital
    David M. Williams, Malte C. Ebach ; foreword by Gareth Nelson.
    Springer2008
    Introduction: Systematics, evolution, and classification -- Systematics as problem solving -- The archetype -- Ernest Haeckel and systematische phylogenie -- The German development of morphology: from Ernest Haeckel to Willie Hanning -- Pattern Cladistics -- Homologues and homology -- Discovering homologues -- Homology and systematics -- Homology and transformation -- Character conflict -- The analyses of relationships -- Biogeograhical relationships, evolution, and classification.
  • Digital
    Barry Halliwell, B.A. (Oxon), D. Phil. (Oxon), D. Sc (LOND), and John M.C. Gutteridge, PHD (LOND), D.Sc (LOND).
    OSO2015
    Oxygen: boon yet bane, introducing oxygen toxicity and reactive species -- Redox chemistry: the essentials -- Antioxidant defences synthesized in vivo -- Antioxidants from the diet -- Oxidative stress and redox regulation: adaptation, damage, repair, senescence, and death -- Measurement of reactive species -- Reactive species can pose special problems needing special solutions: some examples -- Reactive species can be useful -- Reactive species can be poisonous -- Reactive species in disease: friends or foes? -- Ageing, nutrition, disease, and therapy: a role for antioxidants?.
  • Digital
    Francisco Javier Piña.
    Calcineurin is a Ca2+/calmodulin-dependent serine/threonine protein phosphatase conserved from yeast to mammals required for cell survival during environmental stress in yeast. It dephosphorylates several proteins located in different cellular compartments. Hph1 is a substrate of calcineurin that together with Hph2, its homolog, is also required for cellular adaptation to environmental stress. Hph1 and Hph2 are novel proteins of unknown function. Hph1 and Hph2 are tail-anchored integral ER-membrane proteins and have no identifiable homologs of in other organisms, except closely related yeast species. The goal of this work was to identify proteins that interact with Hph1 and Hph2 to help us identify their biological function. We show that Hph1 and Hph2 interact with the post-translational translocation machinery and are required for Vph1 stability, suggesting that they function in post-translational translocation at the ER. We have found several additional phenotypes for cells lacking HPH1 and HPH2 that overlap with the phenotypes observed for cells that have defects in vacuolar acidification. Hph1, but not Hph2, interacts with Vam6, a guanine-nucleotide-exchange factor, that regulates homotypic vacuolar fusion (through Ypt7) and TORC1 activation (through Gtr1). Interestingly, hph1[Delta] hph2[Delta] cells are resistant to rapamycin, further suggesting a role for these proteins in nutrient signaling. Structure-function analyses revealed that the coiled-coil motif is required for proper Hph1 localization and function, whereas the transmembrane domain is dispensable. This study has advanced our understanding of Hph1 and calcineurin function in regulating the cell's response to environmental stress and paves the way for a mechanistic understanding of Hph1 and Hph2 function in yeast.
  • Digital
    edited by Mark P. Running.
    Springer Protocols2013
    Remarkably, while G protein-coupled receptors (GPCRs) are highly prevalent in animals and yeast, very few candidate GPCRs have been identified in plants. In G Protein-Coupled Receptor Signaling in Plants: Methods and Protocols, experts in the field describe techniques used in the study of small GTPases and related proteins. Beginning with a chapter on bioinformatics approaches for GPCR discovery, this detailed volume continues with chapters on heterotrimeric G protein subunits, Rab-GTPases, as well as lipid modifications, including myristoylation, acylation, and prenylation. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Practical and dependable, G Protein-Coupled Receptor Signaling in Plants: Methods and Protocols aims to aid further studies into the roles of small GTPases which will help elucidate numerous key processes in plants.
  • Digital
    Xiao Xu.
    Stress is a fundamental aspect of aging as accumulated damage from a lifetime of stress can limit lifespan, and protective responses to stress can extend lifespan. In this study, we identify a conserved C. elegans GATA transcription factor, egl-27, that is involved in several stress responses and aging. We found that overexpression of egl-27 extends the lifespan of wild-type animals. Furthermore, egl-27 is required for the pro-longevity effects from impaired insulin/IGF-1 like signaling (IIS), as reduced egl-27 activity fully suppresses the longevity of worms that are mutant for the IIS receptor, daf-2. egl-27 expression is inhibited by daf-2 and activated by pro-longevity factors daf-16/FOXO and elt-3/GATA, suggesting that egl-27 acts at the intersection of IIS and GATA pathways to extend lifespan. Consistent with its role in IIS signaling, we found that egl-27 is involved in stress response pathways. egl-27 expression is induced in the presence of multiple stresses, its targets are significantly enriched for many types of stress genes, and altering levels of egl-27 itself affects survival to heat and oxidative stress. Finally, we found that egl-27 expression increases between young and old animals, suggesting that increased levels of egl-27 in aged animals may act to promote stress resistance. These results identify egl-27 as a novel factor that links stress and aging pathways.
  • Digital
    Dennis Jacob Bua.
    The physiological state of the genome is chromatin. Chromatin is a dynamic polymer composed of genomic DNA, histone proteins, and other factors. Dysregulation of chromatin homeostasis can lead to diverse human pathologies including cancer. This work focuses on chromatin-based mechanisms of gene regulation; more specifically the (1) targeting and (2) stabilization of gene-regulatory proteins on the chromatin template. In regard to chromatin targeting, not much is known about how gene-regulatory proteins selectively associate with their targets. Herein we detail the discovery of a new targeting factor, the nuclear phospholipid phosphatidylinositol-5-phosphate (PtdIns(5)P). PtdIns(5)P directly interacts with the tumor suppressor ING2 (inhibitor of growth family member 2) in the nucleus to coordinate gene expression of select ING2 targets. In regard to chromatin stabilization, lysine methylation is a principle mechanism for retaining chromatin-effector modules at discrete chromatin zones. Numerous lysine methylation events have been discovered on the major protein component of chromatin, histones, but relatively few specific modules have been characterized to sense these modifications. We screened through a library of putative methyl-lysine binding domains, which resulted in the identification of three novel chromatin binding modules. Taken together these data shed insight into the molecular modes of action of gene regulation by chromatin and phosphoinositide pathways.
  • Digital
    Erika L. Bustamante.
    In humans, the hormones insulin and glucagon are the principal regulators of blood sugar homeostasis. In the fruit fly, Drosophila melanogaster, the regulation of circulating sugar levels is similarly controlled by insulin-like and glucagon-like factors. Insulin signaling in Drosophila has been studied intensively; by contrast, relatively little is known about the genetic regulation of Drosophila Adipokinetic hormone (Akh), the polypeptide with glucagon-like functions, and the corpora cardiaca (CC) cells that produce Akh. Here I describe the use of an enhancer trap screen that led to the identification of a novel regulator of CC function, the homeodomain transcription factor unplugged (unpg). Knocking down unpg in the CC cells results in decreased Akh transcript levels and reduced circulating glucose and trehalose. I also describe the identification of a number of enhancer traps that are capable of driving GFP expression in the CC cells, suggesting a role for the associated genes in CC cell function. As in human diabetes, insulin deficiency in the fruit fly elevates circulating glucose levels and impairs triglyceride regulation. Reduced insulin signaling in Drosophila also increases expression of the adipokine Akh, a phenotype reminiscent of the excessive glucagon signaling that accompanies human diabetes. Thus, it remains unclear if insulin deficiency or adipokine excess is the primary basis for diabetic phenotypes in flies lacking insulin-producing cells. Here I show that simultaneous targeted ablation of cells producing Drosophila insulin and adipokinetic hormone results in hypoglycemia. Mutation of the gene encoding the Akh receptor (Akhr) reduces circulating glucose levels in adult Drosophila lacking insulin, arguing that excessive Akh signaling is the basis for hyperglycemia in insulin-deficient flies. Simultaneous attenuation of insulin and Akh synthesis also produced hypoglycemic flies. Similar approaches revealed triglyceride imbalance from insulin deficiency requires Akh. Thus adipokines like Akh, not insulin, may be the principal hormonal regulators of glucose and lipid balance in some non-mammalian animal classes and states of insulin deficiency.
  • Digital
    Vishvanath Nene, Chittaranjan Kole, editors.
    Springer2009
  • Digital
    Wayne Hunter, Chittaranjan Kole (editors).
    Springer2008
    Honeybee / D. Schlipalius, P.R. Ebert, G.J. Hunt -- Bumblebee / L. Wilfert, P. Schmid-Hempel, J. Gadau -- The jewel wasp - Nasonia / J. Gadau ... [et al.] -- Silkworm / Y. Yasukochi, H. Fujii, M.R. Goldsmith -- Pea aphid / J.A. Brisson, G.K. Davis -- Mosquito / D.W. Severson -- Hessian fly / J.J. Stuart, M.-S. Chen, M.O. Harris -- Tick / A.J. Ullmann, J.J. Stuart, C.A. Hill.
  • Digital
    Thomas D. Kocher, Chittaranjan Kole (editors).
    Springer2008
  • Digital
    editors Scott Johnson, Hefin Jones.
    Wiley2017
    This book presents a comprehensive overview of the latest scientific knowledge and contemporary theory relating to global climate change and terrestrial invertebrates. Featuring contributions from top international experts, this book explores how changes to invertebrate populations will affect human decision making processes across a number of crucial issues, including agriculture, disease control, conservation planning, and resource allocation. Topics covered include methodologies and approaches to predict invertebrate responses, outcomes for disease vectors and ecosystem service providers, underlying mechanisms for community level responses to global climate change, evolutionary consequences and likely effects on interactions among organisms, and many more. Timely and thought-provoking, Global Climate Change and Terrestrial Invertebrates offers illuminating insights into the profound influence the simplest of organisms may have on the very future of our fragile world.
  • Digital
    Shawn Fletcher Sorrells.
    Glucocorticoids (GCs) are stress hormones that are well-known for their potent and pleiotropic anti-inflammatory effects. In the injured CNS, their anti-inflammatory properties could be particularly beneficial due to the often detrimental effects of excessive inflammation in the brain. In more recent years, however, it has become clear that GCs do not always decrease inflammation and can even augment aspects of the immune response. The research presented in this doctoral dissertation describes the impact of this increased inflammatory response in the CNS using animal models of excitotoxicity and hypoxia/ischemia. Specifically, both exogenous GC treatments and the endogenously released GCs post-injury were found to increase immune cell activation (both in phenotype and in p65 nuclear translocation) in both rat and mouse models of excitotoxic hippocampal neuron death and in a mouse MCAO stroke model. These increased inflammatory responses are likely to be mediated by an unexpected GC-suppression of several anti-inflammatory cytokines including CX3CL1 and CD22 and failure of GCs to activate some of their normal anti-inflammatory targets like IkBa, IL-1ra, and MKP-1. Furthermore, these GC-augmented inflammatory responses are necessary for GCs to make more neurons die from either of these injuries. Taken together, this work demonstrates that cellular inflammation is not kept in check by GCs in the forebrain; instead, GCs worsen hippocampal and cortical neuron death, at least in part, by increasing the neurotoxicity of CNS inflammation.
  • Digital
    Vladimir Parpura, Arne Schousboe, Alexei Verkhratsky, editors.
    Springer2014
    1. Glutamate and ATP: The Crossroads of Signaling and Metabolism in the Brain -- 2. Glutamate Metabolism in the Brain Focusing on Astrocytes -- 3. Glycogenolysis and Purinergic Signaling -- 4. Purinergic and Glutamatergic Receptors on Astroglia -- 5. Regulated Exocytosis in Astrocytes Is as Slow as the Metabolic Availability of Gliotransmitters: Focus on Glutamate and ATP -- 6. Adenosine and Glutamate in Neuroglial Interaction: Implications for Circadian Disorders and Alcoholism -- 7. Purinergic Receptor Stimulation Decreases Ischemic Brain Damage By Energizing Astrocyte Mitochondria -- 8. Excitotoxicity and Mitochondrial Dysfunction Underlie Age-dependent Ischemic White Matter Injury -- 9. Role of Astrocytes in Delayed Neuronal Death: GLT-1 and its Novel Regulation by MicroRNAs -- 10. Ca2+ Signaling in Astrocytes and its Role in Ischemic Stroke -- 11. Pathological Potential of Astroglial Purinergic Receptors.
  • Digital
    Arne Schousboe, Ursula Sonnewald, editors.
    Springer2016
    Introduction to the Glutamate-Glutamine cycle -- Glucose, lactate, β-hydroxybutyrate, acetate, GABA, and succinate as substrates for synthesis of glutamate and GABA in the glutamine-glutamate/GABA cycle -- Anaplerosis for glutamate synthesis in the neonate and in adulthood -- Enzyme complexes important for the glutamate-glutamine cycle -- BCAA metabolism and NH3 homeostasis -- Glutaminases Vesicular Glutamate Uptake -- The glutamine transporters and their role in the Glutamate/GABA-Glutamine Cycle -- Glutamine Metabolism in Gliomas -- Oligodendrocytes: development, physiology and glucose metabolism -- Dysregulation of glutamate cycling mediates methylmercury-induced neurotoxicity -- Astroglia, glutamatergic transmission and psychiatric diseases -- Glutamine Synthetase: Role in Neurological Disorders -- The Glutamate -- Glutamine Cycle in Epilepsy -- Index.
  • Digital
    edited by Gary W. Barrett, George A. Feldhamer.
    Springer2008
    The golden mouse : a levels-of-organization perspective / Gary W. Barrett -- The golden mouse : taxonomy and natural history / George A. Feldhamer and Donald W. Linzey -- Population ecology of the golden mouse / Robert K. Rose -- Community ecology of the golden mouse / Cory C. Christopher and Guy N. Cameron -- Ecosystem ecology of the golden mouse / Steven W. Seagle -- Landscape ecology of the golden mouse / Jerry O. Wolff and Gary W. Barrett -- Relative abundance and conservation : is the golden mouse a rare species? / George A. Feldhamer and Anita T. Morzillo -- The golden mouse : a model of energetic efficiency / John D. Peles and Gary W. Barrett -- Nesting ecology of the golden mouse : an oikos engineer / Thomas M. Luhring and Gary W. Barrett -- Ectoparasites, bots, and vector-borne diseases associated with the golden mouse / Lance A. Durden -- Aesthetic landscapes of the golden mouse / Terry L. Barrett and Gary W. Barrett -- Future challenges and research opportunities : what do we really know? / Gary W. Barrett and George A. Feldhamer.
  • Digital
    Thomas D. Glenn.
    The scope and complexity of the vertebrate nervous system requires the rapid transmission of neural impulses over long distances. The myelin sheath is an evolutionary adaptation that allows axons to rapidly propagate action potentials. Schwann cells in the peripheral nervous system (PNS) and oligodendrocytes in the central nervous system (CNS) form myelin by wrapping their cell membranes around axons to form a multilayered membranous sheath that insulates and supports axons. Voltage gated sodium channels cluster at the unmyelinated gaps between myelin segments--the nodes of Ranvier. Depolarization of the axonal membrane at the nodes allows action potentials to propagate in a saltatory manner. Diseases of myelin, including multiple sclerosis in the CNS, and Charcot-Marie-Tooth disease in the PNS, underscore its clinical importance. In this dissertation, I focus on the mechanisms controlling the initiation and maturation of myelin in the PNS, as well as the role of Schwann cells in regulating sodium channel clustering at the nodes of Ranvier. Schwann cells arise from the neural crest in a series of developmental stages and depend upon axonal signals, such as Neuregulin 1 type III (Nrg1-III), for their survival and differentiation into myelinating Schwann cells. Nrg1-III signals control almost every aspect of Schwann cell development, but it has been proposed that other signaling pathways, such as those mediated by cyclic adenosine monophosphate (cAMP), may intersect with the Nrg1 pathway to affect a Schwann cell's response to Nrg1. In Chapter 2, I describe the identification of an orphan adhesion G protein-coupled receptor (GPCR), Gpr126, that was identified in a forward genetic screen in zebrafish. Gpr126 is essential for Schwann cells to initiate myelination, and gpr126 mutant zebrafish are devoid of PNS myelin. I show that Gpr126 is required cell-autonomously in Schwann cells to initiate myelination, and that elevating cAMP by drug treatment rescues myelination in gpr126 mutants in vivo. These results provide strong evidence that Gpr126 is the receptor that activates cAMP signaling to initiate myelination in Schwann cells in vivo. In Chapter 3, I demonstrate that although Gpr126 is essential for the initiation of myelination, it is no longer required for the maturation or maintenance of the myelin sheath. Notably, although Gpr126 signaling is required for the expression of the promyelinating transcription factor Krox20 during the initiation of myelination, Gpr126 signaling is dispensable for the maintenance of Krox20 expression. I further demonstrate that expression of activated protein kinase A (PKA) in Schwann cells is sufficient to rescue myelination in gpr126 mutants in vivo, but that over-expression of Nrg1-III in neurons is not. These results show that Gpr126 has a specific function during the initiation of myelination, and suggest that Gpr126 signaling functions in parallel to Nrg1 signaling. In chapter 4, I describe a novel role for Schwann cells in inhibiting the clustering of axonal sodium channels at the internodes, thereby confining sodium channel clustering to the nodes of Ranvier. Taken together, the findings described in this dissertation identify an orphan adhesion GPCR that regulates the initiation of myelination in Schwann cells, as well as define a novel role for Schwann cells in the regulation of sodium channel clustering.
  • Digital
    edited by José M. Causadias, Eva H. Telzer, Nancy A. Gonzales.
    Wiley2018
    Part I. General Issues in Culture and Biology Interplay -- Part II. Animal Culture -- Part III. Cultural Genomics -- Part IV. Cultural Neurobiology -- Part V. Cultural Neuroscience.
  • Digital
    edited by Ronald Ross Watson.
    Springer2013
    Research and clinical application of vitamin D has increased dramatically over the past decade stimulated by novel health promotion discoveries and documentation. This book brings together key researchers with their views focusing on the health promotion role of vitamin D. Such information is vital to clinicians, users of vitamin D supplements of all ages and those interested in public policy. The authors document and define many of the key health related roles of vitamin D. Its traditional application in bone and muscle health as well as therapy of arthritis is expanded and clarified with new research. A better understanding of the effects of vitamin D inadequacy is modelled using problems ranging from infant growth retardation to chronic kidney and periodontal disease. Uniquely the vitamin?s role in resistance and treatment of infectious diseases is shown in examples ranging from HIV/AIDS to tuberculosis. Mechanistic understanding of vitamin D's actions is enhanced by looking into its effects on immune modulation and inflammation. Expansion of the role of sunlight in stimulating vitamin D production is discussed relative to the reduction in a variety of cancers. Clearly vitamin D is like a two edged sword with great benefits but also some risks. This book provides carefully defined examples of both situations.
  • Digital
    Emily C. Piccione.
    The epidermal growth factor receptor (EGFR) is essential to multiple physiologic and neoplastic processes via signaling by its tyrosine kinase domain and subsequent activation of transcription factors. We identified a novel splice variant of the EGFR called mini-LEEK (mLEEK) which represents a deletion of exons 2-22 but maintains the open reading frame and generates a novel glycine codon at the junction. This variant deletes the extracytoplasmic domain, transmembrane region, and most of the tyrosine kinase domain of the EGFR. mLEEK is localized to the nucleus in most cells and since it contains a previously characterized strong transactivation domain, we hypothesized that mLEEK functions to regulate transcription. Microarray studies revealed upregulation of several molecular chaperone proteins, including GRP78 (also known as BiP) and GRP94, in response to mLEEK expression. Overexpression of mLEEK resulted in increased transcription from GRP78 and GRP94 luciferase reporter plasmids as well as an increase in endogenous GRP78 and GRP94 protein levels, suggesting a direct effect on transcription. Furthermore, mLEEK utilizes the cis-regulatory ER stress response element (ERSE) found in both the GRP78 and GRP94 promoters to activate transcription as mutation of the ERSE elements in the GRP78 promoter abolishes the activation of transcription by mLEEK. Chromatin immunoprecipitation experiments demonstrate that mLEEK physically interacts in a complex with the ERSE-containing region of the GRP78 promoter. Additionally, mLEEK co-precipitates with ATF6, a transcription factor known to be part of the ERSE-mediated activation of chaperones. Molecular chaperone transcription is induced as a downstream effector of the unfolded protein response (UPR). The UPR is a mechanism that increases the cellular capacity for protein folding. Cellular demands for protein folding increase upon physiological conditions that create endoplasmic reticulum (ER) stress. Interestingly, mLEEK specifically upregulates molecular chaperones required for the UPR and does not activate other arms of the UPR. Splicing of XBP1 precursor mRNA, which is uniquely triggered upon ER stress, was reduced in cells overexpressing mLEEK. Another molecular readout for UPR induction is the activation of CHOP transcription. Cells overexpressing mLEEK demonstrated reduced activation of CHOP transcription in the presence of ER stress inducing agents. Moreover, knockdown of mLEEK results in enhanced sensitivity to ER stress. Collectively, these data suggest that expression of mLEEK and the subsequent upregulation molecular chaperones primes cells to accommodate the increased need for protein folding upon ER stress and prevents induction of the UPR. mLEEK is also essential for cell viability, as mLEEK knockdown lead to reduced viability and increased activation of caspases. We found that mLEEK is present at the RNA and protein level in a high percentage of tumors relative to normal tissue. Preliminary data suggest that mLEEK expression does not lead to transformation of NIH3T3 cells. The potential contribution of mLEEK to tumorigenesis will be revisited in the future using knockdown strategies that were subsequently developed. Other preliminary data have shown that mLEEK is secreted into the media and taken up by neighboring cells, leading to increased GRP94 transcription in recipient cells. Collectively, our work describes the discovery and characterization of a novel EGFR variant. These findings reveal an unexpected function for an EGFR variant and represent a new mechanism for the upregulation of molecular chaperones required for the UPR that could be exploited for therapeutic purposes. Our findings also suggest a potential role for mLEEK in cancer and a novel method of cell communication mediated by a secreted protein. These possibilities await future studies.
  • Digital
    Dara P. Dowlatshahi.
    The covalent attachment of ubiquitin (Ub), a 76-amino-acid protein, to another protein is a highly occurring and conserved post-translational modification. Ub functions in a plethora of diverse signaling pathways including proteasomal degradation, endocytosis and trafficking of membrane receptors and DNA repair when conjugated to substrate proteins. Ub is unique in that it can also be conjugated to itself to create an assortment of polyubiquitin chains, through either its amino terminus or any of its seven internal lysines, where a large part of its diverse signaling is ascribed to these polyubiquitin chains. Previous work has identified proteins, which specifically recognize these different types of Ub linkages to contain domains or motifs termed Ub binding domains (UBDs). Studies on the various and diverse roles of Ub signaling along with its own diversity of conjugates present on substrates and their recognition by UBDs have uncovered the existence of a Ub syntax or code. The main goal of the work entailed in this thesis was to contribute to decryption of this code by identifying new linkage specific polyubiquitin binding proteins and characterizing their function and mechanism of polyubiquitin recognition. We developed and used a K63 linkage specific polyubiquitin affinity reagent in conjunction with shotgun LC-MS/MS to identify novel polyubiquitin binding proteins. We found that the majority of polyubiquitin dependent identified proteins were previously known Ub binders as well as a few previously unidentified Ub interacting proteins, demonstrating this as a valid approach for the identification of polyubiquitin binding proteins. One such previously unidentified protein we identified was ALIX, a a component of the Endosomal Sorting Complex Required for Transport (ESCRT) machinery known to be involved in Human Immunodeficiency Virus (HIV) budding. We characterized ALIX and found that it binds directly and selectively to K63-linked polyubiquitin via two potential Ub binding sites on a single [alpha]-helical surface within a coiled-coil region, where mutation of these sites impaired retroviral release. Our study demonstrates ALIX as the first example of a K63 chain specific polyubiquitin receptor in the endosomal sorting pathway that supplies evidence for a functional link between K63 polyubiquitin binding and ESCRT function, specifically in retrovirus budding. In summary the findings in our study contribute to the understanding of the role of K63-linked polyubiquitin in the ESCRT pathway. Our work also demonstrates the power of using unbiased affinity capture and tandem mass spectrometry to identify polyubiquitin receptor proteins to further decryption of the Ub code.
  • Digital
    edited by Holger Heine.
    Springer2008
    Evolution of resistance genes in plants / Shunyuan Xiao, Wenming Wang, Xiaohua Yang -- The path less explored: innate immune reactions in Cnidarians / Thomas C. G. Bosch -- Bug versus bug : humoral immune responses in Drosophila melanogaster / Deniz Ertürk-Hasdemir ... [et al.] -- Cellular immune responses in Drosophila melanogaster / Adrienne Ivory, Katherine Randle, Louisa Wu -- Immune reactions in the vertebrates' closest relatives, the urochordates / Konstantin Khalturin, Ulrich Kürn, Thomas C. G. Bosch -- Innate immune system of the zebrafish, Danio rerio / Con Sullivan, Carol H. Kim -- Toll-like receptors in the mammalian innate immune system / Andrei E. Medvedev, Stefanie N. Vogel -- NLRs : a cytosolic armory of microbial sensors linked to human diseases / Mathias Chamaillard -- Antimicrobial peptides as first-line effector molecules of the human innate immune system / Regine Gläser, Jürgen Harder, Jens-Michael Schröder -- The complement system in innate immunity / K. R. Mayilyan ... [et al.].
  • Digital
    edited by Dr. Robert G. Foottit, Professor Peter H. Adler.
    Wiley2017
    Introduction -- The importance of insects -- Insect biodiversity : regional examples -- Insect biodiversity in the nearctic region -- Amazonian rainforests and their richness and abundance of terrestrial arthropods on the edge of extinction : abiotic-biotic players in the critical zone -- Insect biodiversity in the afrotropical region -- Biodiversity of australasian insects -- Insect biodiversity in the palearctic region -- Insect biodiversity : taxon examples -- Biodiversity of aquatic insects -- Biodiversity of diptera -- Biodiversity of heteroptera -- Biodiversity of coleoptera -- Biodiversity of hymenoptera -- Diversity and significance of lepidoptera : a phylogenetic perspective -- Insect biodiversity : tools and approaches -- The science of insect taxonomy : prospects and needs -- Insect species, concepts and practice -- Molecular dimensions of insect taxonomy in the genomics era -- Dna barcodes and insect biodiversity -- Insect biodiversity informatics -- Parasitoid biodiversity and insect pest management -- Taxonomy of crop pests : the aphids -- Adventive (non-native) insects and the consequences for science and society of species that become invasive -- Biodiversity of blood-sucking flies : implications for humanity -- Reconciling ethical and scientific issues for insect conservation -- Taxonomy and management of insect biodiversity -- Insect biodiversity, millions and millions.
  • Digital/Print
    edited by Steeve Hervé Thany.
    Digital : Springer2010
    Print2010
    Identification of cholinergic synaptic transmission in the insect nervous system / Steeve Hervé Thany, Hélène Tricoire-Leignel, and Bruno Lapied -- The evolution of pentameric ligand-gated ion channels / Joseph A. Dent -- Diversity of insect nicotinic acetylcholine receptor subunits / Andrew K. Jones and David B. Sattelle -- Identification of critical elements determining toxins and insecticide affinity, ligand binding domains, and channel properties / Hélène Tricoire-Leignel and Steeve Hervé Thany -- Electrophysiological studies and pharmacological properties of insect native nicotinic acetylcholine receptors / Steeve Hervé Thany -- Characterisation of insect nicotinic acetylcholine receptors by heterologous expression / Neil S. Millar and Stuart J. Lansdell -- Neonicotinoid insecticides : historical evolution and resistance mechanisms / Steeve Hervé Thany -- Ecotoxicity of neonicotinoid insecticides to bees / Axel Decourtye and James Devillers -- State of the art on insect nicotinic acetylcholine receptor function in learning and memory / Monique Gauthier.
  • Digital
    Alan Edward Rorie.
    The work presented in this dissertation primarily focuses on decision-related activity in the lateral intraparietal area (LIP) and, secondarily, the dorsolateral prefrontal cortex (DLPFC). In Chapter 1 we review the previous independent investigations indicating that these areas are separately modulated by sensory information, value information and choice appropriate to represent decisions. We argue that when both sensory and value information must be simultaneously integrated to make choices, it is unknown, if, how and when these areas integrate these factors. We present a behavioral paradigm in which animal subjects must combine sensory and value information, on a trial-to-trial basis, to make optimal choices. This paradigm is based on a well-known motion discrimination task; however, in our task the magnitude of the reward associated with each option varies from trial to trial. On some trials both options are worth equally large or small rewards. On other trials one option's reward is greater than that of the other. In Chapter 2, we demonstrate that in the unequal reward conditions subjects' choices are consistently biased towards the greater magnitude option. Additionally, we will show that this bias is independent of the motion stimulus strength and its magnitude is nearly optimal. In Chapter 3, we observe that single neurons in cortical area LIP consistently, simultaneously and dynamically represent both sensory and value information. We will argue that this representation supports an integrator model of decision making, in which sensory information is accumulated until the decision is resolved by a threshold crossing. Our results support an interpretation of this model in which value information adjusts the likelihood of a threshold crossing by iv raising or lowering the accumulator's initial state. In Chapter 4, we present a preliminary comparison between LIP and DLPFC activity, under identical conditions, suggesting they play fundamentally different roles in decision making. In Chapter 5, we discuss future lines of research.
  • Digital
    Zhengqing Ouyang.
    High-throughput genomics has been increasingly generating the massive amount of genome-wide data. With proper modeling methodologies, we can expect to archive a more comprehensive understanding of the regulatory mechanisms of biological systems. This work presents integrative approaches for the modeling and analysis of gene regulatory systems. In mammals, gene expression regulation is combinatorial in nature, with diverse roles of regulators on target genes. Microarrays (such as Exon Arrays) and RNA-Seq can be used to quantify the whole spectrum of RNA transcripts. ChIP-Seq is being used for the identification of transcription factor (TF) binding sites and histone modification marks. RNA interference (RNAi), coupled with gene expression profiles, allow perturbations of gene regulatory systems. Our approaches extract useful information from those genome-wide measurements for effectively modeling the logic of gene expression regulation. We present a predictive model for the prediction of gene expression from ChIP-Seq signals, based on quantitative modeling of regulator-gene association strength, principal component analysis, and regression-based model selection. We demonstrate the combinatorial regulation of TFs, and their power for explaining genome-wide gene expression variation. We also illustrate the roles of covalent histone modification marks on predicting gene expression and their regulation by TFs. We present a dynamical model of gene expression profiling, and derive the perturbed behaviors of the ordinary differential equation (ODE) system. Based on that, we present a regularized multivariate regression method for inferring the gene regulatory network of a stable cell type. We model the sparsity and stability of the network by a regularization approach. We applied the approaches to both a simulation data set and the RNAi perturbation data in mouse embryonic stem cells.
  • Digital
    Natasha Mahealani Flores.
    Regeneration is a process that requires tightly regulated proliferation, differentiation, and tissue remodeling. Classical model organisms such as C. elegans, D. melanogaster, and M. musculus have limited regenerative capabilities therefore we present the freshwater planarian Schmidtea mediterranea, which provides an ideal system to study the role of stem cells in regeneration. This immortal adult organism boasts excellent regenerative capabilities driven by a stem cell population called neoblasts. The neoblast population is the only mitotically active cell type in planarians and can be easily manipulated without concern for embryonic requirements. This unique model also allows for the study of human embryonic stem cell genes in a simpler in vivo system. Thus S. mediterranea offers the opportunity to accelerate the studies and understanding of stem cell biology and regeneration in the environment of a living organism. GATA transcription factors are DNA binding proteins that are well-known master regulators of development. Through the activation and repression of transcription, these factors direct cellular differentiation toward lineage specification. Here we used loss-of-function experiments to understand the role of the GATA4/5/6 subfamily in the differentiation of neoblasts. S. mediterranea has a single homolog of mammalian GATA-4, -5, and -6, Smed-gata4/5/6, which is expressed primarily in the planarian intestine and in some neoblasts. Smed-gata4/5/6 knockdown results in perturbed homeostasis and regeneration, eventually leading to planarian death. Loss of Smed-gata4/5/6 disrupts intestinal differentiation and also affects non-intestinal lineages. During late time points of regeneration, Smed-gata4/5/6 loss leads to decreased neoblast proliferation and gene expression of neoblast subpopulations. These data support the conserved role of Smed-gata4/5/6 in intestinal differentiation and indicate the intestine may act as a neoblast niche. Our preliminary work on Experimental Evolution through irradiation exposure shows a sub-lethal dose of irradiation eliminates neoblast expression after 24 hours and expression recovery occurs after 3-4 weeks. This demonstrates S. mediterranea is a malleable model organism that can be used to study the link between regeneration and cancer.
  • Digital
    Ye Emily Wu.
    Nervous system function requires the structural and functional integrity of chemical synapses, the fundamental units of neural communication. Synapse formation requires the packaging of synaptic vesicle (SV) and active zone (AZ) proteins into vesicular cargoes in the cell soma, their long-distance microtubule-dependent transport down the axon and finally, their clustering and assembly into functional complexes at specific sites. The subcellular localization, size, and number of synapses diverse greatly between different types of neurons and are critical determinants of the identity and strength of neural connections. Compared to our knowledge of extrinsic signals and cell-surface molecules that regulate synapse formation and synaptic specificity, less is known about the intrinsic regulatory mechanisms that regulate presynaptic protein transport and assembly to achieve proper spatial distribution of synapses. We have taken advantage of the powerful genetics in Caenorhabditis elegans to investigate this question. Using in vivo time-lapse fluorescence microscopy in a motor neuron DA9 in C. elegans, we show that SV and AZ proteins exhibit extensive co-trafficking and undergo frequent pauses during axonal transport. At the pause sites, the balance between the capture and dissociation of mobile transport packets determines the extent of presynaptic protein clustering. Through forward genetic screens, we identified a molecular regulatory network that controls the capture and dissociation events to dictate the spatial distribution of presynaptic specializations. First, we identified an Arf-like small G protein, ARL-8, that regulates synapse distribution by inhibiting premature clustering of presynaptic cargoes during axonal transport. arl-8 mutants accumulate presynaptic specializations within the proximal axon of several neuronal classes, with a corresponding failure to assemble presynapses distally. Time-lapse imaging analysis revealed that presynaptic cargoes in arl-8 mutants exhibit a decreased tendency to dissociate from immotile clusters and an increased probability of being captured by immotile clusters. We further performed genetic suppressor screens to isolate molecules that functionally interact with arl-8 in presynaptic patterning. We report that loss-of-function mutations in a JKK-1/JNK-1 MAP kinase pathway and several active zone assembly proteins strongly and partially suppress the abnormal distribution of presynaptic proteins in arl-8 mutants. Time-lapse imaging analysis demonstrated that the JNK kinase pathway and active zone assembly molecules inhibit presynaptic protein dissociation. In addition, we found that the kinesin motor UNC-104/KIF1A controls the capture efficiency. Furthermore, UNC-104/KIF1A functions as an effector of ARL-8 by binding specifically to the GTP-bound form of ARL-8. Together, these findings revealed novel intrinsic mechanisms that control the subcellular localization, size, and number of synapses by coordinating axonal transport with presynaptic assembly.
  • Digital/Print
    edited by Terence D. Allen.
    Digital : ScienceDirect2008
    Print2008
  • 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.
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    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.
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    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-
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    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.
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    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.
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    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.
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    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-
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    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.
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    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.
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    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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