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  • 1
    Electronic Resource
    Electronic Resource
    Cadomian terranes, wrench faulting and thrusting in the central Europe Variscides: geophysical and geological evidence (1995)
    Springer
    Geologische Rundschau 84 (1995), S. 412-432 
    Details
    ISSN: 0016-7835
    Keywords: Key words Cadomian terranes ; Wrench faults ; European Variscides ; DEKORP ; gravity-magnetism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Geosciences
    Notes: Abstract  Sixty five per cent of the Paleozoic basement of western and central Europe is hidden by a sedimentary cover and/or sea. This work aims to remove that blanket to detect new structures which could used to build a more comprehensive model of the Variscan orogeny. It is based on the interpretation of various forms of data: (a) published gravity maps corrected for the effects of the crust–mantle boundary topography and light sedimentary basins; (b) aeromagnetic maps; (c) measurements of densities; and (d) induced and remanent magnetizations on rocks from Paleozoic outcrops of the upper Rhenish area. From the northern Bohemian Massif to the eastern Paris Basin, the Saxothuringian is characterized by a 500 km long belt of gravity highs, the most important being the Kraichgau high. Most of the corresponding heavy bodies are buried under a post-early Viséan cover. They are interpreted as relics of Late Proterozoic terranes overlain by an Early to Middle Paleozoic sequence, equivalent to the Bohemian terrane in the Bohemian Massif. The most probable continuation of these dense Bohemian terranes toward the west is the Southern Channel–Northern Brittany Cadomian terrane. The gravity lows are correlated with Variscan granites and pre- and early Variscan metagranites. Gravity and magnetic maps demonstrate large-scale displacement in Devonian–Early Carboniferous times along the parallel and equidistant, NW–SE striking, Vistula, Elbe, Bavarian, Bray and South Armorican dextral wrench faults. In the Vosges–Schwarzwald and Central Massif the faults continue with the east–west striking Lalaye-Lubine–Baden-Baden and Marche faults and with south vergent thrusts. The Bavarian faults shift the Kraichgau terrane by 150 km relative to the Bohemian terrane, whereas the offset of the Northern Brittany Cadomian relative to the Northern Vosges–Kraichgau terranes is estimated at 400 km along the Bray fault. Sinistral wrench faults are the NE–SW striking Sillon Houiller, Rheingraben, Rodl, Vitis and Diendorf faults. The southern Vosges–Schwarzwald Devonian–Dinantian basin is interpreted as a pull-apart basin at the south-easterly extremity of the Bray fault. The Bohemian and Kraichgau body form allochthonous terranes which were thrust over the Saxothuringian crust. Thrusting to the north-west was accompanied by back-thrusting and led to the formation of pop-up structures. Contemporaneous dextral and sinistral wrench faulting resulted in transpressive strain during collision. The zonal structure of the Variscides in the sense of Kossmat (1927) is relevant only to the Rhenohercynian Foreland Belt. Kossmat (1927) already spoke of a Moldanubian Region because it displays no real zonal structure. The Saxothuringian Zone was formed by terrane accretion. Their apparent zonal structure is not a pre-collisional feature, but only the result of accretion and collision.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00260450
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  • 2
    Electronic Resource
    Electronic Resource
    Cadomian terranes, wrench faulting and thrusting in the central Europe Variscides: geophysical and geological evidence (1995)
    Springer
    International journal of earth sciences 84 (1995), S. 412-432 
    Details
    ISSN: 1437-3262
    Keywords: Cadomian terranes ; Wrench faults ; European Variscides ; DEKORP ; gravity-magnetism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Geosciences
    Notes: Abstract Sixty five per cent of the Paleozoic basement of western and central Europe is hidden by a sedimentary cover and/or sea. This work aims to remove that blanket to detect new structures which could used to build a more comprehensive model of the Variscan orogeny. It is based on the interpretation of various forms of data: (a) published gravity maps corrected for the effects of the crust-mantle boundary topography and light sedimentary basins; (b) aeromagnetic maps; (c) measurements of densities; and (d) induced and remanent magnetizations on rocks from Paleozoic outcrops of the upper Rhenish area. From the northern Bohemian Massif to the eastern Paris Basin, the Saxothuringian is characterized by a 500 km long belt of gravity highs, the most important being the Kraichgau high. Most of the corresponding heavy bodies are buried under a post-early Viséan cover. They are interpreted as relics of Late Proterozoic terranes overlain by an Early to Middle Paleozoic sequence, equivalent to the Bohemian terrane in the Bohemian Massif. The most probable continuation of these dense Bohemian terranes toward the west is the Southern Channel-Northern Brittany Cadomian terrane. The gravity lows are correlated with Variscan granites and pre- and early Variscan metagranites. Gravity and magnetic maps demonstrate large-scale displacement in Devonian-Early Carboniferous times along the parallel and equidistant, NW-SE striking, Vistula, Elbe, Bavarian, Bray and South Armorican dextral wrench faults. In the Vosges-Schwarzwald and Central Massif the faults continue with the east-west striking Lalaye-Lubine-Baden-Baden and Marche faults and with south vergent thrusts. The Bavarian faults shift the Kraichgau terrane by 150 km relative to the Bohemian terrane, whereas the offset of the Northern Brittany Cadomian relative to the Northern Vosges-Kraichgau terranes is estimated at 400 km along the Bray fault. Sinistral wrench faults are the NE-SW striking Sillon Houiller, Rheingraben, Rodl, Vitis and Diendorf faults. The southern Vosges-Schwarzwald Devonian-Dinantian basin is interpreted as a pull-apart basin at the south-easterly extremity of the Bray fault. The Bohemian and Kraichgau body form allochthonous terranes which were thrust over the Saxothuringian crust. Thrusting to the north-west was accompanied by back-thrusting and led to the formation of pop-up structures. Contemporaneous dextral and sinistral wrench faulting resulted in transpressive strain during collision. The zonal structure of the Variscides in the sense of Kossmat (1927) is relevant only to the Rhenohercynian Foreland Belt. Kossmat (1927) already spoke of a Moldanubian Region because it displays no real zonal structure. The Saxothuringian Zone was formed by terrane accretion. Their apparent zonal structure is not a pre-collisional feature, but only the result of accretion and collision.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00260450
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  • 3
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    Endocranial capacity in an early hominid cranium from Sterkfontein, South Africa (1998)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1998-06-20
    Description: Two- and three-dimensional computer imaging shows that endocranial capacity in an approximately 2.8- to 2.6-million-year-old early hominid cranium (Stw 505) from Sterkfontein, South Africa, tentatively assigned to Australopithecus africanus, is approximately 515 cubic centimeters. Although this is the largest endocranial capacity recorded for this species, it is still markedly less than anecdotal reports of endocranial capacity exceeding 600 cubic centimeters. No australopithecine has an endocranial capacity approaching, let alone exceeding, 600 cubic centimeters. Some currently accepted estimates of early hominid endocranial capacity may be inflated, suggesting that the tempo and mode of early hominid brain evolution may need reevaluation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Conroy, G C -- Weber, G W -- Seidler, H -- Tobias, P V -- Kane, A -- Brunsden, B -- New York, N.Y. -- Science. 1998 Jun 12;280(5370):1730-1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Anatomy and Neurobiology and Department of Anthropology, Washington University School of Medicine, St. Louis, MO 63110, USA. conroyg@thalamus.wustl.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9624045" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Brain/*anatomy & histology ; Computer Simulation ; *Fossils ; History, Ancient ; Hominidae/*anatomy & histology ; Humans ; Image Processing, Computer-Assisted ; *Models, Anatomic ; Skull/*anatomy & histology ; South Africa ; Tomography, X-Ray Computed
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    Macromolecular architecture in eukaryotic cells visualized by cryoelectron tomography (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-11-09
    Description: Electron tomography of vitrified cells is a noninvasive three-dimensional imaging technique that opens up new vistas for exploring the supramolecular organization of the cytoplasm. We applied this technique to Dictyostelium cells, focusing on the actin cytoskeleton. In actin networks reconstructed without prior removal of membranes or extraction of soluble proteins, the cross-linking of individual microfilaments, their branching angles, and membrane attachment sites can be analyzed. At a resolution of 5 to 6 nanometers, single macromolecules with distinct shapes, such as the 26S proteasome, can be identified in an unperturbed cellular environment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Medalia, Ohad -- Weber, Igor -- Frangakis, Achilleas S -- Nicastro, Daniela -- Gerisch, Gunther -- Baumeister, Wolfgang -- New York, N.Y. -- Science. 2002 Nov 8;298(5596):1209-13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Biochemistry, D-82152 Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12424373" target="_blank"〉PubMed〈/a〉
    Keywords: Actin Cytoskeleton/chemistry/metabolism/*ultrastructure ; Actins/ultrastructure ; Animals ; Binding Sites ; Cell Membrane/metabolism/ultrastructure ; Cell Movement ; Dictyostelium/chemistry/physiology/*ultrastructure ; Endoplasmic Reticulum, Rough/ultrastructure ; Freezing ; *Image Processing, Computer-Assisted ; Macromolecular Substances ; Microfilament Proteins/*ultrastructure ; Organelles/*ultrastructure ; Peptide Hydrolases/ultrastructure ; *Proteasome Endopeptidase Complex ; Proteome ; Protozoan Proteins/ultrastructure ; Ribosomes/ultrastructure ; Tomography/*methods
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity (2000)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2000-02-05
    Description: Cell-mediated (type-1) immunity is necessary for immune protection against most intracellular pathogens and, when excessive, can mediate organ-specific autoimmune destruction. Mice deficient in Eta-1 (also called osteopontin) gene expression have severely impaired type-1 immunity to viral infection [herpes simplex virus-type 1 (KOS strain)] and bacterial infection (Listeria monocytogenes) and do not develop sarcoid-type granulomas. Interleukin-12 (IL-12) and interferon-gamma production is diminished, and IL-10 production is increased. A phosphorylation-dependent interaction between the amino-terminal portion of Eta-1 and its integrin receptor stimulated IL-12 expression, whereas a phosphorylation-independent interaction with CD44 inhibited IL-10 expression. These findings identify Eta-1 as a key cytokine that sets the stage for efficient type-1 immune responses through differential regulation of macrophage IL-12 and IL-10 cytokine expression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ashkar, S -- Weber, G F -- Panoutsakopoulou, V -- Sanchirico, M E -- Jansson, M -- Zawaideh, S -- Rittling, S R -- Denhardt, D T -- Glimcher, M J -- Cantor, H -- AI12184/AI/NIAID NIH HHS/ -- AI37833/AI/NIAID NIH HHS/ -- CA76176/CA/NCI NIH HHS/ -- etc. -- New York, N.Y. -- Science. 2000 Feb 4;287(5454):860-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Skeletal Disorders and Rehabilitation, Department of Orthopedic Surgery, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10657301" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD44/metabolism ; Granuloma/immunology ; Herpes Simplex/immunology ; Herpesvirus 1, Human/immunology ; Hypersensitivity, Delayed ; Interferon-gamma/biosynthesis ; Interleukin-10/*biosynthesis ; Interleukin-12/*biosynthesis ; Keratitis, Herpetic/immunology ; Listeriosis/immunology ; Lymphocyte Activation ; Macrophages/*immunology ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Nude ; Osteopontin ; Phosphorylation ; Receptors, Vitronectin/metabolism ; Sialoglycoproteins/*immunology/metabolism/pharmacology ; T-Lymphocytes/*immunology/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
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    Inactivation of misselected CD8 T cells by CD8 gene methylation and cell death (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-05-15
    Description: Misselected CD8 cells that express T cell receptors (TCRs) that do not recognize class I major histocompatibility complex (MHC) protein can emerge from thymic selection. A postthymic quality control mechanism that purges these cells from the repertoire is defined here. The failure of mature CD8 cells to simultaneously engage their TCR and CD8 coreceptor triggers an activation process that begins with inhibition of CD8 gene expression through remethylation and concludes with up-regulation of surface Fas and Fas ligand and cellular apoptosis. Thus, inhibition of a death signal through continued TCR-CD8 coengagement of MHC molecules is a key checkpoint for the continued survival of correctly selected T cells. Molecular defects that prevent delivery of the death signal to mistakenly selected T cells underlie the expansion of double-negative T cells, which is the cellular signature of a subset of systemic autoimmune diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pestano, G A -- Zhou, Y -- Trimble, L A -- Daley, J -- Weber, G F -- Cantor, H -- AI 13600/AI/NIAID NIH HHS/ -- AI 37833/AI/NIAID NIH HHS/ -- CA76176/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 1999 May 14;284(5417):1187-91.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10325233" target="_blank"〉PubMed〈/a〉
    Keywords: Adoptive Transfer ; Animals ; Antigens, CD8/*genetics ; Antigens, CD95/genetics ; *Apoptosis ; CD8-Positive T-Lymphocytes/*cytology/*immunology ; *DNA Methylation ; Fas Ligand Protein ; Gene Expression Regulation ; Granzymes ; Histocompatibility Antigens Class I/immunology ; Kruppel-Like Transcription Factors ; Lymphocyte Count ; Membrane Glycoproteins/genetics ; Mice ; Mice, Inbred C57BL ; Receptors, Antigen, T-Cell/genetics/immunology ; Serine Endopeptidases/genetics ; Thymus Gland/immunology ; Trans-Activators/genetics ; Up-Regulation
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
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    Fibroblasts transformed with v-src show enhanced formation of an inositol tetrakisphosphate (1989)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1989-10-06
    Description: The tyrosine kinase pp60v-src, encoded by the v-src oncogene, seems to regulate phosphatidylinositol metabolism. The effect of pp60v-src on control points in inositol phosphate production was examined by measuring the amounts of inositol polyphosphates in Rat-1 cells expressing wild-type or mutant forms of the protein. Expression of v-src-resulted in a five- to sevenfold elevation in the steady-state amount of an isomer of inositol tetrakisphosphate, whereas the concentrations of inositol trisphosphates or other inositol tetrakisphosphates were not affected. The activity of a key enzyme in the formation of inositol tetrakisphosphates, inositol (1,4,5)-trisphosphate 3-kinase, was increased six- to eightfold in cytosolic extracts prepared from the v-src-transformed cells, suggesting that this enzyme may be one target for the pp60v-src kinase and that it may participate in the synthesis of novel, higher order inositol phosphates.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Johnson, R M -- Wasilenko, W J -- Mattingly, R R -- Weber, M J -- Garrison, J C -- CA-39076/CA/NCI NIH HHS/ -- CA-40042/CA/NCI NIH HHS/ -- DK-19952/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 1989 Oct 6;246(4926):121-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of Virginia School of Medicine, Charlottesville 22908.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/2506643" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Transformed ; Fibroblasts/metabolism ; Inositol Phosphates/*metabolism ; Isomerism ; Oncogene Protein pp60(v-src) ; Protein-Tyrosine Kinases/metabolism ; Rats ; Retroviridae Proteins/*physiology ; Sugar Phosphates/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
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    MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade (1998)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1998-09-11
    Description: Signal transduction is controlled both by regulation of enzyme activation and by organization of enzymatic complexes with nonenzymatic adapters, scaffolds, and anchor proteins. The extracellular signal-regulated kinase (ERK) cascade is one of several evolutionarily conserved mitogen-activated protein (MAP) kinase cascades important in the regulation of growth, apoptosis, and differentiation. A two-hybrid screen was conducted to identify nonenzymatic components of this signaling cascade that might be important in regulating its activity. A protein called MP1 (MEK Partner 1) was identified that bound specifically to MEK1 and ERK1 and facilitated their activation. When overexpressed in cultured cells, MP1 enhanced activation of ERK1 and activation of a reporter driven by the transcription factor Elk-1. Expression of MP1 in cells increased binding of ERK1 to MEK1. MP1 apparently functions as an adapter to enhance the efficiency of the MAP kinase cascade.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schaeffer, H J -- Catling, A D -- Eblen, S T -- Collier, L S -- Krauss, A -- Weber, M J -- CA39076/CA/NCI NIH HHS/ -- GM47332/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1998 Sep 11;281(5383):1668-71.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Cancer Center, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9733512" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium-Calmodulin-Dependent Protein Kinases/*metabolism ; Carrier Proteins/*metabolism ; Cell Line ; *DNA-Binding Proteins ; Enzyme Activation ; MAP Kinase Kinase 1 ; MAP Kinase Kinase 2 ; Mitogen-Activated Protein Kinase 1 ; Mitogen-Activated Protein Kinase 3 ; *Mitogen-Activated Protein Kinase Kinases ; *Mitogen-Activated Protein Kinases ; Molecular Sequence Data ; Phosphorylation ; Protein-Serine-Threonine Kinases/*metabolism ; Protein-Tyrosine Kinases/*metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-raf/metabolism ; Recombinant Fusion Proteins/metabolism ; *Signal Transduction ; *Transcription Factors ; Transcriptional Activation ; Transfection ; ets-Domain Protein Elk-1
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
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    Polar patterns of driven filaments (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-09-03
    Description: The emergence of collective motion exhibited by systems ranging from flocks of animals to self-propelled microorganisms to the cytoskeleton is a ubiquitous and fascinating self-organization phenomenon. Similarities between these systems, such as the inherent polarity of the constituents, a density-dependent transition to ordered phases or the existence of very large density fluctuations, suggest universal principles underlying pattern formation. This idea is followed by theoretical models at all levels of description: micro- or mesoscopic models directly map local forces and interactions using only a few, preferably simple, interaction rules, and more macroscopic approaches in the hydrodynamic limit rely on the systems' generic symmetries. All these models characteristically have a broad parameter space with a manifold of possible patterns, most of which have not yet been experimentally verified. The complexity of interactions and the limited parameter control of existing experimental systems are major obstacles to our understanding of the underlying ordering principles. Here we demonstrate the emergence of collective motion in a high-density motility assay that consists of highly concentrated actin filaments propelled by immobilized molecular motors in a planar geometry. Above a critical density, the filaments self-organize to form coherently moving structures with persistent density modulations, such as clusters, swirls and interconnected bands. These polar nematic structures are long lived and can span length scales orders of magnitudes larger than their constituents. Our experimental approach, which offers control of all relevant system parameters, complemented by agent-based simulations, allows backtracking of the assembly and disassembly pathways to the underlying local interactions. We identify weak and local alignment interactions to be essential for the observed formation of patterns and their dynamics. The presented minimal polar-pattern-forming system may thus provide new insight into emerging order in the broad class of active fluids and self-propelled particles.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schaller, Volker -- Weber, Christoph -- Semmrich, Christine -- Frey, Erwin -- Bausch, Andreas R -- England -- Nature. 2010 Sep 2;467(7311):73-7. doi: 10.1038/nature09312.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lehrstuhl fur Biophysik-E27, Technische Universitat Munchen, 85748 Garching, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20811454" target="_blank"〉PubMed〈/a〉
    Keywords: Actin Cytoskeleton/*metabolism ; Animals ; Cytoskeleton/*chemistry ; Microtubules/chemistry ; *Models, Biological ; Myosin Subfragments/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
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    A new class of anthelmintics effective against drug-resistant nematodes (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-03-14
    Description: Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics--the benzimidazoles, imidazothiazoles and macrocyclic lactones--has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaminsky, Ronald -- Ducray, Pierre -- Jung, Martin -- Clover, Ralph -- Rufener, Lucien -- Bouvier, Jacques -- Weber, Sandra Schorderet -- Wenger, Andre -- Wieland-Berghausen, Susanne -- Goebel, Thomas -- Gauvry, Noelle -- Pautrat, Francois -- Skripsky, Thomas -- Froelich, Olivier -- Komoin-Oka, Clarisse -- Westlund, Bethany -- Sluder, Ann -- Maser, Pascal -- England -- Nature. 2008 Mar 13;452(7184):176-80. doi: 10.1038/nature06722.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Novartis Centre de Recherche Sante Animale, CH-1566 St Aubin (FR), Switzerland. ronald.kaminsky@novartis.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18337814" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Amino Acid Sequence ; Aminoacetonitrile/adverse effects/*analogs & ; derivatives/pharmacokinetics/*pharmacology ; Animals ; Anthelmintics/chemistry/*classification/pharmacokinetics/*pharmacology ; Caenorhabditis elegans/drug effects/genetics/metabolism ; Caenorhabditis elegans Proteins/chemistry/genetics/metabolism ; Cattle ; Cattle Diseases/drug therapy/parasitology ; *Drug Resistance/genetics ; Larva/drug effects/genetics ; Molecular Sequence Data ; Nematoda/*drug effects/genetics/physiology ; Parasitic Diseases, Animal/drug therapy/*parasitology ; Receptors, Nicotinic/chemistry/genetics/metabolism ; Sheep/parasitology ; Sheep Diseases/drug therapy/parasitology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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