Books by Subject
- Adaptive and neutral evolutionary insights from statistical analyses of population genetic data — Innate immunity of plants, mammals, and humans (100)
- Insect nicotinic acetylcholine receptors — Trophic and guild interactions in biological control (100)
- Using artificial intelligence in chemistry and biology : a practical guide — Wistar Institute of Anatomy and Biology : history, organization, purposes, equipment. (11)
- 2013Julie 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.
- 2013 SpringerSusan Masino, Detlev Boison, editors.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.
- 2006 Springeredited by R. Jan Stevenson ... [et al.].
- 2012 SpringerIgor I. Goryanin, Andrew B. Goryachev, editors.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.
- 2007 Springeredited by J. Seckbach.
- 2006 Springeredited by Inderjit and K.G. Mukerji.
- 2006 SpringerRainer Flindt ; translated by Neil Solomon.
- Analysis of the WntD signaling pathway in inhibition of dorsal activity and in embryonic primordial germ cell guidance2011Mark 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.
- Anatomy of the Australopithecus scapula and evolution of the human shoulder : insights from a new fossil specimen, KSD-VP-1/1g2011Stephanie 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.
- Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective anti-tumor T cell response2013Diane 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.
- 2012 Springerby Giovanni Boniolo.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.
- ATP-dependent chromatin remodeling in human malignancy : identification and characterization of novel subunits of the mSWI/SNF-like BAF complex2012Cigall Kadoch.
- 2007 CRCnetBASEedited by Norman MacLeod.
- 2013Xinhong 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.
- 2006 Springereditor, David L.G. Noakes.
- 2007 CRCnetBASEedited by Gordon B. Curry, Chris J. Humphries.The global biodiversity information facility (GBIF) / Meredith A. Lane and James. L. Edwards -- The European network for biodiversity information / Wouter Los and Cees H.J. Hof -- Networking taxonomic concepts--uniting without 'unitary-ism' / Walter G. Berendsohn and Mark Geoffrey -- Networking biological collections databases : building a European infrastructure / Malcolm J. Scoble and Walter G. Berendsohn -- A comparison between morphometric and artifical neural network approaches to the automated species recognition problem in systematics / Norman MacLeod, M. O'Neill, and Steven A. Walsh -- Automated extraction of biodiversity data from taxonomic descriptions / Gordon B. Curry and Richard J. Connor -- The grid and biodiversity informatics / Andrew C. Jones -- LIAS--an interactive database system from structured descriptive data of ascomycetes / Dagmar Triebel ... [et al.] -- Linking biodiversity databases : preparing species diversity information sources by assembling, merging and linking databases / Richard J. White -- Priority areas for rattan conservation on Borneo / Jacob Andersen Sterling ... [et al].
- v. 1-, 1949-Ludwig von Bertalanffy.
- 2014Weinberg, Robert A.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.
- 2006 CRCnetBASEGeorge A. Knox.The southern ocean -- Phytoplankton and primary production -- Sea-ice microbial communities -- Zooplankton -- Krill -- Nekton -- Fish -- Seals -- Whales -- Birds -- Benthic communities -- The fast ice and ice shelves -- Ice-edge processes -- Decomposition and the roles of bacteria and protozoa -- Ecosystem dynamics -- Resource exploitation -- Ecosystem changes resulting from resource exploitation -- Management of living resources -- Ultraviolet radiation -- Global warming and Antarctic marine ecosystems -- Human impact.
- 2008 CRCnetBASEedited by Jeanette Wyneken, Matthew H. Godfrey, Vincent Bels.How the turtle gets its shell / Scott F. Gilbert, Judith A. Cebra-Thomas, and Ann C. Burke -- Comparative ontogenetic and phylogenetic aspects of Chelonian chondro-osseous growth and skeletochronology / Melissa L. Snover and Anders G.J. Rhodin -- Evolution and structure of the turtle shell / Peter C.H. Pritchard -- Long bone allometry in tortoises and turtles / Gustavo A. Llorente ... [et al.] -- Evolution of locomotion in aquatic turtles / Sabine Renous ... [et al.] -- Hindlimb function in turtle locomotion : limb movements and muscular activation across taxa, environment, and ontogeny / Richard W. Blob, Angela R.V. Rivera, and Mark W. Westneat -- Cervical anatomy and function in turtles / Anthony Herrel, Johan Van Damme, and Peter Aerts -- Functional evolution of feeding behavior in turtles / Vincent Bels ... [et al.] -- The structure of cardiopulmonary systems of turtles : implications for behavior / Jeanette Wyneken -- Reproductive structures and strategies of turtles / Jeffrey D. Miller and Stephen A. Dinkelacker -- Mixed and uniform brood sex ratio strategy in turtles : the facts, the theory, and their consequences / Vincent Hulin ... [et al.] -- The physiology and anatomy of anoxia tolerance in the freshwater turtle brain / Sarah L. Milton -- The relationships of turtles with amniotes / Olivier Rieppel.
- 2014 SpringerJohn Golbeck, Art van der Est, editors."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.
- 2008 Springeredited by Takeshi Furuichi and Jo Thompson.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.].
- 2011Andrew 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.
- Calcineurin regulates the yeast synaptojanin Inp53/Sjl3 to promote membrane recovery during hyperosmotic stress2013Evan 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.
- 2013Craig 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.
- 2009 SpringerMogens L. Glass, Stephen C. Wood, editors.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.
- 2009Maria 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.
- 2012Weizhe 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.
- v. 1-4, 1999-2002. Springer
- v. 5-, 2002- Springer
- Centrosomes, cilia and centriolar satellites : characterizing the role of Cep72 in centriolar satellite function2011Timothy 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.
- 2010Joshua 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.
- Characterizing multiple roles for ubiquitination and SUMOylation in the DNA damage tolerance pathways2013Michelle 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.
- 2010Veronica 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.
- 2006 ScienceDirectR.J.P.Williams and J.J.R. Fraústo da Silva.1. The evolution of earth-the geochemical partner of the global ecosystem (5 billion years of history) -- 2. Basic chemistry of the ecosystem -- 3. Energy, order and disorder, and organised systems -- 4. Outline of biological chemical principles : components, pathways and controls -- 5. First steps in evolution of prokaryotes : anaerobic chemotypes four to three billion years ago -- 6. The evolution of protoaerobic and aerobic prokaryote chemotypes (three to two billion years ago) -- 7. Unicellular eukaryotes chemotypes (about one and a half billion years ago?) -- 8. Multi-cellular eukaryote chemotypes (from one billion years ago) -- 9. The evolution of chemotypes with nerves and a brain (0.5 billion years ago to today) -- 10. Evolution due to mankind : a completely novel chemotype (less than one hundred thousand years ago) -- 11. Conclusion : the inevitable factors in evolution
- 2007 ebraryC. Ray Chandler, Lorne M. Wolfe, & Daniel E.L. Promislow.The academic job market -- Choosing a graduate program -- Prepare early for your job search -- Target your job search -- The application -- Preparing for the interview -- The interview -- The seminar -- Social time -- The negotiations -- All in the family.
- 2010Ramona 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.
- 2013 SpringerAchim Kramer, Martha Merrow, editors.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.
- 2005 ScienceDirectedited by Michael W. Young.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.Also available: Print – 2005
- 2009 CRCnetBASEGabriel Valiente.
- 2010Maureen M. Dawson, Brian A. Dawson, Joyce A. Overfield.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.
- 2006 Springeredited by Marc William Cadotte, Sean M. McMahon and Tadashi Fukami.
- 2010Tiara 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.
- 2013William 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.
- 2008 CRCnetBASEedited by John B. Dunning, Jr.
- 2002- Wileyeditorial board, Juan S. Bonifacino ... [et al.].ch. 1. Cell Culture -- ch. 2. Preparation and Isolation of Cells -- ch. 3. Subcellular Fractionation and Isolation of Organelles -- ch. 4. Microscopy -- ch. 5. Characterization of Cellular Proteins -- ch. 6. Electrophoresis and Immunoblotting -- ch. 7. Protein Labeling and Immunoprecipitation -- ch. 8. Cell Cycle Analysis -- ch. 9. Cell Adhesion -- ch. 10. Extracellular Matrix -- ch. 11. In Vitro Reconstitution -- ch. 12. Cell Motility -- ch. 13. Organelle Motility -- ch. 14. Signal Transduction: Protein Phosphorylation -- ch. 15. Protein Trafficking -- ch. 16. Antibodies as Cell Biological Tools -- ch. 17. Macromolecular Interactions in Cells -- ch. 18. Cellular Aging and Death -- ch. 19. Whole Organism and Tissue Analysis -- ch. 20. Expression and Introduction of Macromolecules into Cells -- ch. 21. Fluorescent Protein Technology -- ch. 22. Cell Biology of Chromosomes and Nuclei -- ch. 23. Stem Cells -- ch. 24. Lipids -- ch. 25. Nanotechnology -- ch. 26. Viruses -- ch. 27. RNA-Based Methods in Cell Biology -- Appendix 1. Useful Information and Data -- Appendix 2. Laboratory Stock Solutions and Equipment -- Appendix 3. Commonly Used Techniques -- Appendix. Suppliers.
- 2013 ScienceDirectedited by V. S. Chandrasekhar Pammi, Narayanan Srinivasan.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.
- Developing a national registry of pharmacologic and biologic clinical trials : workshop report (2006)2006 NAPCommittee on Clinical Trial Registries, Board on Health Sciences Policy.
- 2013 SpringerAlexey Melkikh, Maria Sutormina.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.
- 2009 Springeredited by R. Jeroen Pasterkamp, Marten P. Smidt, J. Peter H. Burbach.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.Also available: Print – 2009
- 2008 CRCnetBASEedited by John W. Blunt, Murray H. G. Munro.
- 2012Tiffany 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.
- 2009 SpringerJan Bruin, Leo P.S. van der Geest, editors.
- 2010 Springer[edited by] Esther Lubzens, Joan Cerdà, Melody Clark.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
- 2006 ScienceDirectTherese A. Markow, Patrick O'Grady.
- 2006 Springeredited by J. Eilenberg and H. M. T. Hokkanen.
- 2006 CRCnetBASEedited by Anthony Herrel, Thomas Speck, Nicolas P. Rowe.
- 2006 SpringerE. Granéli, J.T. Turner (eds.).
- 2012 SpringerArthur N. Popper, Anthony Hawkins, editors.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.
- 2016 SpringerArthur N. Popper, Anthony Hawkins, editors.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.Also available: Print – 2016
- Elsevier's Encyclopaedic dictionary of medicine : in five languages, English, French, German, Italian, and Spanishpt. A-<D>, 1987-<90>compiled by A.F. Dorian.pt. A. General medicine -- pt. B. Anatomy -- pt. C. Biology, genetics and biochemistry -- pt. D. Therapeutic substances.
- 2012Michelle 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.
- 2006 ScienceDirectJ. Ricard.Also available: Print – 2006
- 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.
- 2013Kapa 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.
- 2008 SpringerSeumas Miller, Michael J. Selgelid.
- 2013 SpringerRoger Jankowski.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.
- 2009 Cold Spring Harb Lab Pressmeeting organized by Bruce Stillman, David Stewart, and Jan Witkowski.
- 2011Henry 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.
- 2008 Springeredited by Pierre Pontarotti.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.
- Evolutionary computation, machine learning, and data mining in bioinformatics : 5th European Conference, EvoBIO 2007, Valencia, Spain, April 11-13, 2007 : proceedings2007 SpringerElena Marchiori, Jason H. Moore, Jagath C. Rajapakse (eds.).
- 2012 SpringerOrkun S. Soyer, editor.
- [v.1], 2014Jonathan Orsay.
- [v.2], 2014Jonathan Orsay.
- Exogenous migratory therapy : investigating ex vivo-derived dendritic cell migration and delivery of anti-inflammatory therapy after stroke2013Melissa 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.
- 2007 ScienceDirectedited by Fred A. Rainey and Aharon Oren.Also available: Print – 2006
- Field manual of techniques in invertebrate pathology : application and evaluation of pathogens for control of insects and other invertebrate pests. 2nd ed.2007 Springeredited by Lawrence A. Lacey and Harry K. Kaya.
- 2008 SpringerDavid M. Williams, Malte C. Ebach ; foreword by Gareth Nelson.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.
- Functional analyses of HPH1and HPH2 revealed roles in post-translational protein translocation and nutrient translocation and nutrient signaling2010Francisco 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.
- 2006 Springeredited by Vladimir Burdyuzha.
- 2013 Springer Protocolsedited by Mark P. Running.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.
- 2012Xiao 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.
- 2012Dennis 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.
- Genetic studies of endocrine function and metabolic regulation by the corpora cardiaca cells in Drosophila melanogaster2011Erika 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.
- 2009 SpringerVishvanath Nene, Chittaranjan Kole, editors.
- 2008 SpringerWayne Hunter, Chittaranjan Kole (editors).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.
- 2008 SpringerThomas D. Kocher, Chittaranjan Kole (editors).
- 2011Shawn 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.
- 2014 SpringerVladimir Parpura, Arne Schousboe, Alexei Verkhratsky, editors.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.
- 2005 Springeredited by John S. Axford.Also available: Print – 2005
- 2008 Springeredited by Gary W. Barrett, George A. Feldhamer.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.
- 2008 CRCnetBASED. Hank Ellison.
- 2013 Springeredited by Ronald Ross Watson.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.
- 2007 SpringerPeter M. Narins ... [et al.], editors.Hearing and sound communication in amphibians : prologue and prognostication / Peter M. Narins and Albert S. Feng -- An integrated phylogeny of Amphibia / David Cannatella -- The behavioral ecology of anuran communication / Kentwood D. Wells and Joshua J. Schwartz -- Call production and neural basis of vocalization / Wolfgang Walkowiak -- Recognition and localization of acoustic signals / H. Carl Gerhardt and Mark A. Bee -- Pathways for sound transmission to the inner ear in amphibians / Matthew J. Mason -- Anatomy, physiology, and function of auditory end organs in the frog inner ear / Dwayne D. Simmons, Sebastiaan W.F. Meenderink and Pantelis N. Vassilakis -- Central auditory pathways in anuran amphibians : the anatomical basis of hearing and sound communication / Walter Wilczynski and Heike Endepols -- Function of the amphibian central auditory system / Gary J. Rose and David M. Gooler -- Plasticity in the auditory system across metamorphosis / Andrea Megela Simmons and Seth S. Horowitz -- Sound processing in real-world environments / Albert S. Feng and Johannes Schul.
- 2007 Springeredited by René Bobe, Zeresenay Alemseged, Anna K. Behrensmeyer.Approaches to the analysis of faunal change during the East African Pliocene / A.K. Behrensmeyer, R. Bobe, and Z. Alemseged -- Environmental hypotheses of Pliocene human evolution / R. Potts -- African Pliocene and Pleistocene cercopithecid evolution and global climatic change / S.R. Frost -- Patterns of change in the Plio-Pleistocene carnivorans of eastern Africa : implications for hominin evolution / M.E. Lewis and L. Werdelin-- Stratigraphic variation in Suidae from the Shungura Formation and some coeval deposits / H.B.S. Cooke -- Patterns of abundance and diversity in late Cenozoic bovids from the Turkana and Hadar Basins, Kenya and Ethiopia / R. Bobe, A.K. Behrensmeyer, G.G. Eck, and J.M. Harris -- Comparability of fossil data and its significance for the interpretation of hominin environments : a case study in the lower Omo Valley, Ethiopia / Z. Alemseged, R. Bobe, and D. Geraads -- The effects of collection strategy and effort on faunal recovery : a case study of the American and French collections from the Shungura Formation, Ethiopia / G.G. Eck -- Serengeti micromammals and their implications for Olduvai paleoenvironments / D.N. Reed -- Taphonomy and paleoecological context of the upper Laetolil Beds (localities 8 and 9), Laetoli in northern Tanzania / C. Musiba, C. Magori, M. Stoller, T. Stein, S. Branting, M. Vogt, R. Tuttle, B. Hallgrímsson, S. Killindo, F. Mizambwa, F. Ndunguru, and A. Mabulla -- The paleoecology of the upper Laetolil Beds at Laetoli : a reconsideration of the large mammal evidence / D.F. Su and T. Harrison -- Fauna, taphonomy, and ecology of the Plio-Pleistocene Chiwondo Beds, northern Malawi / O. Sandrock, O. Kullmer, F. Schrenk, Y.M. Juwayeyi, and T.G. Bromage-- Investigating faunal evidence for hominin paleoecology in East Africa / A.K. Behrensmeyer, Z. Alemseged, and R. Bobe.
- 2006 Springeredited by David L. Hawksworth and Alan T. Bull.
- 2010Emily 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.
- Identification and characterization of a novel polyubiquitin binding protein involved in virus maturation2012Dara 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.
- 2008 Springeredited by Holger Heine.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.].
- Adaptive and neutral evolutionary insights from statistical analyses of population genetic data — Innate immunity of plants, mammals, and humans (100)
- Insect nicotinic acetylcholine receptors — Trophic and guild interactions in biological control (100)
- Using artificial intelligence in chemistry and biology : a practical guide — Wistar Institute of Anatomy and Biology : history, organization, purposes, equipment. (11)
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