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  • 1
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    CLP1 links tRNA metabolism to progressive motor-neuron loss (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-03-12
    Description: CLP1 was the first mammalian RNA kinase to be identified. However, determining its in vivo function has been elusive. Here we generated kinase-dead Clp1 (Clp1(K/K)) mice that show a progressive loss of spinal motor neurons associated with axonal degeneration in the peripheral nerves and denervation of neuromuscular junctions, resulting in impaired motor function, muscle weakness, paralysis and fatal respiratory failure. Transgenic rescue experiments show that CLP1 functions in motor neurons. Mechanistically, loss of CLP1 activity results in accumulation of a novel set of small RNA fragments, derived from aberrant processing of tyrosine pre-transfer RNA. These tRNA fragments sensitize cells to oxidative-stress-induced p53 (also known as TRP53) activation and p53-dependent cell death. Genetic inactivation of p53 rescues Clp1(K/K) mice from the motor neuron loss, muscle denervation and respiratory failure. Our experiments uncover a mechanistic link between tRNA processing, formation of a new RNA species and progressive loss of lower motor neurons regulated by p53.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674495/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674495/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hanada, Toshikatsu -- Weitzer, Stefan -- Mair, Barbara -- Bernreuther, Christian -- Wainger, Brian J -- Ichida, Justin -- Hanada, Reiko -- Orthofer, Michael -- Cronin, Shane J -- Komnenovic, Vukoslav -- Minis, Adi -- Sato, Fuminori -- Mimata, Hiromitsu -- Yoshimura, Akihiko -- Tamir, Ido -- Rainer, Johannes -- Kofler, Reinhard -- Yaron, Avraham -- Eggan, Kevin C -- Woolf, Clifford J -- Glatzel, Markus -- Herbst, Ruth -- Martinez, Javier -- Penninger, Josef M -- K99NS077435-01A1/NS/NINDS NIH HHS/ -- NS038253/NS/NINDS NIH HHS/ -- P 19223/Austrian Science Fund FWF/Austria -- P 21667/Austrian Science Fund FWF/Austria -- R00 NS077435/NS/NINDS NIH HHS/ -- R01 NS038253/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Mar 28;495(7442):474-80. doi: 10.1038/nature11923. Epub 2013 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23474986" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis ; Animals ; Animals, Newborn ; Axons/metabolism/pathology ; Cell Death ; Diaphragm/innervation ; Embryo Loss ; Embryo, Mammalian/metabolism/pathology ; Exons/genetics ; Female ; Fibroblasts ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Motor Neurons/*metabolism/*pathology ; Muscular Atrophy, Spinal ; Neuromuscular Diseases/metabolism/pathology ; Oxidative Stress ; RNA Processing, Post-Transcriptional ; RNA, Transfer, Tyr/genetics/*metabolism ; Respiration ; Spinal Nerves/cytology ; Transcription Factors/deficiency/*metabolism ; Tumor Suppressor Protein p53/metabolism ; Tyrosine/genetics/metabolism
    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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  • 2
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    The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-02-21
    Description: Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paolino, Magdalena -- Choidas, Axel -- Wallner, Stephanie -- Pranjic, Blanka -- Uribesalgo, Iris -- Loeser, Stefanie -- Jamieson, Amanda M -- Langdon, Wallace Y -- Ikeda, Fumiyo -- Fededa, Juan Pablo -- Cronin, Shane J -- Nitsch, Roberto -- Schultz-Fademrecht, Carsten -- Eickhoff, Jan -- Menninger, Sascha -- Unger, Anke -- Torka, Robert -- Gruber, Thomas -- Hinterleitner, Reinhard -- Baier, Gottfried -- Wolf, Dominik -- Ullrich, Axel -- Klebl, Bert M -- Penninger, Josef M -- W 1101/Austrian Science Fund FWF/Austria -- England -- Nature. 2014 Mar 27;507(7493):508-12. doi: 10.1038/nature12998. Epub 2014 Feb 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria. ; Lead Discovery Center GmbH, D-44227 Dortmund, Germany. ; Medical University Innsbruck, 6020 Innsbruck, Austria. ; Department of Microbiology and Immunology, Brown University, Providence, Rhode Island 02912, USA. ; School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Perth, Australia. ; Max-Planck, Institute for Biochemistry, Department of Molecular Biology, D-82152 Martinsried, Germany. ; 1] Medical University Innsbruck, 6020 Innsbruck, Austria [2] Internal Medicine III, University Hospital Bonn, 53127 Bonn, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24553136" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/deficiency/genetics/*metabolism ; Animals ; Anticoagulants/pharmacology/therapeutic use ; Female ; Killer Cells, Natural/drug effects/*immunology/metabolism ; Male ; Mammary Neoplasms, Experimental/drug therapy/genetics/immunology/*pathology ; Melanoma, Experimental/drug therapy/genetics/immunology/*pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neoplasm Metastasis/drug therapy/*immunology/prevention & control ; Proto-Oncogene Proteins/antagonists & inhibitors/metabolism ; Proto-Oncogene Proteins c-cbl/deficiency/genetics/*metabolism ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors/*metabolism ; Ubiquitin-Protein Ligases/deficiency/genetics/*metabolism ; Ubiquitination ; Warfarin/pharmacology/therapeutic use
    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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  • 3
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    Mantle heterogeneity controls on small-volume basaltic volcanism: COMMENT (2015)
    Geological Society of America (GSA)
    In: Geology
    Details
    Publication Date: 2015-10-20
    Print ISSN: 0091-7613
    Electronic ISSN: 1943-2682
    Topics: Geosciences
    Published by Geological Society of America (GSA)
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  • 4
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    Impacts of catastrophic volcanic collapse on the erosion and morphology of a distal fluvial landscape: Hautapu River, Mount Ruapehu, New Zealand (2014)
    Geological Society of America (GSA)
    Details
    Publication Date: 2014-12-31
    Description: Debris avalanches caused by the collapse of volcanic flanks pose a great risk to inhabited areas and may permanently change the surrounding landscape and its drainage systems. In this research, we explored the interplay between a debris avalanche and a tectonically uplifting surrounding landscape, providing insights into the long-term consequences of volcanic edifice failures. Exposures of coarse volcaniclastic sediments along the Hautapu River ~50 km southeast of Mount Ruapehu, New Zealand, show evidence of the largest known collapse event of the stratovolcano, which was followed by a vigorous regrowth phase that produced numerous pyroclastic eruptions and pumice-rich lahars. Similar diamicton deposits are exposed within the river catchment adjacent to the west. Cover-bed stratigraphy and geochemical correlation of andesitic lava blocks within the debris-avalanche deposit with dated lavas exposed on the cone indicate that deposition occurred between 125 and 150 ka. The collapse took place during the shift from a glacial to an interglacial climate, when glaciers on the cone were in retreat, and high pore-water pressures combined with deep hydrothermal alteration weakened the cone. In addition, collapse may have been accompanied by magmatic unrest. The ~2–3 km 3 debris avalanche inundated an area of 〉260 km 2 and entered the proto-Hautapu catchment, where it was channelized within the deeply entrenched valley. Mass-wasting events associated with postcollapse volcanism continued to be channeled into the proto–Hautapu River for another ~10 k.y., producing long-runout lahars. Subsequently, the river catchment was isolated from the volcano by incision of the intervening Whangaehu River into the proximal volcaniclastic sediments, accompanied by regional faulting and graben deepening around Ruapehu. At present, the volcaniclastic deposits form a distinctive plateau on the highest topographic elevation within the Hautapu Valley, forming a reversed topography caused by preferred incision of the Hautapu River into softer Late Tertiary sediments concurrent with constant uplift.
    Print ISSN: 0016-7606
    Electronic ISSN: 1943-2674
    Topics: Geosciences
    Published by Geological Society of America (GSA)
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  • 5
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    Forecasting catastrophic stratovolcano collapse: A model based on Mount Taranaki, New Zealand (2012)
    Geological Society of America (GSA)
    In: Geology
    Details
    Publication Date: 2012-11-01
    Description: Regular large-scale edifice collapse and regrowth is a common pattern during the long lifespans of andesitic stratovolcanoes worldwide. The 〉130 k.y. history of Mount Taranaki, New Zealand, is punctuated by at least 14 catastrophic collapses, producing debris avalanche deposits of 1 to 〉7.5 km 3 . The largest of these sudden events removed as much as one-third of the present-day equivalent cone. The resulting deposits show similar sedimentary and geomorphic features, suggesting similar proto-edifice characteristics, failure trigger mechanisms, and runout path conditions. Each collapse was followed by sustained renewed volcanism and cone regrowth, although there are no matching stepwise geochemical changes in the magma erupted; instead a stable, slowly evolving magmatic system has prevailed. Last Glacial climatic variations are also uncorrelated with the timing or magnitudes of edifice collapse. We demonstrate here that, if the magmatic composition erupted from stratovolcanoes is constant and basement geology conditions are stable, large-scale edifice collapse and the generation of catastrophic debris avalanches will be governed by the magma supply rate. Using a mass balance approach, a volume-frequency model can be applied to forecasting both the probable timing and volume of future edifice failure of such stratovolcanoes. In the Mount Taranaki case, the maximum potential size of a present collapse is estimated to be 7.9 km 3 , while the maximum interval before the next collapse is 〈16.2 k.y. The current annual collapse probability is ~0.00018, with the most likely collapse being a small one (〈2 km 3 ).
    Print ISSN: 0091-7613
    Electronic ISSN: 1943-2682
    Topics: Geosciences
    Published by Geological Society of America (GSA)
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