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  • 1
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    Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-beta (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-06-05
    Description: Extracellular plaques of amyloid-beta and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer's disease. Plaques comprise amyloid-beta fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of Alzheimer's disease. Despite the importance of plaques to Alzheimer's disease, oligomers are considered to be the principal toxic forms of amyloid-beta. Interestingly, many adverse responses to amyloid-beta, such as cytotoxicity, microtubule loss, impaired memory and learning, and neuritic degeneration, are greatly amplified by tau expression. Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-beta are strongly associated with Alzheimer's disease, are more toxic than amyloid-beta, residues 1-42 (Abeta(1-42)) and Abeta(1-40), and have been proposed as initiators of Alzheimer's disease pathogenesis. Here we report a mechanism by which pE-Abeta may trigger Alzheimer's disease. Abeta(3(pE)-42) co-oligomerizes with excess Abeta(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Abeta(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% Abeta(3(pE)-42) plus 95% Abeta(1-42) (5% pE-Abeta) seed new cytotoxic LNOs through multiple serial dilutions into Abeta(1-42) monomers in the absence of additional Abeta(3(pE)-42). LNOs isolated from human Alzheimer's disease brain contained Abeta(3(pE)-42), and enhanced Abeta(3(pE)-42) formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. We conclude that Abeta(3(pE)-42) confers tau-dependent neuronal death and causes template-induced misfolding of Abeta(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Abeta(3(pE)-42) acts similarly at a primary step in Alzheimer's disease pathogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367389/" 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/PMC3367389/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nussbaum, Justin M -- Schilling, Stephan -- Cynis, Holger -- Silva, Antonia -- Swanson, Eric -- Wangsanut, Tanaporn -- Tayler, Kaycie -- Wiltgen, Brian -- Hatami, Asa -- Ronicke, Raik -- Reymann, Klaus -- Hutter-Paier, Birgit -- Alexandru, Anca -- Jagla, Wolfgang -- Graubner, Sigrid -- Glabe, Charles G -- Demuth, Hans-Ulrich -- Bloom, George S -- GM008136/GM/NIGMS NIH HHS/ -- P50 AG016573/AG/NIA NIH HHS/ -- P50AG16573/AG/NIA NIH HHS/ -- R01 AG033069/AG/NIA NIH HHS/ -- R01AG033069/AG/NIA NIH HHS/ -- T32 GM008136/GM/NIGMS NIH HHS/ -- T32 GM008136-25/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 May 2;485(7400):651-5. doi: 10.1038/nature11060.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, University of Virginia, Charlottesville, Virginia 22904, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22660329" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/metabolism ; Amyloid/chemistry/drug effects/metabolism/*toxicity ; Amyloid beta-Peptides/*chemistry/genetics/metabolism/toxicity ; Animals ; Disease Models, Animal ; Glutamic Acid/chemistry/*metabolism ; Humans ; Mice ; Mice, Transgenic ; Mutant Proteins/*chemistry/genetics/metabolism/*toxicity ; Peptide Fragments/*chemistry/genetics/metabolism/toxicity ; Prions/chemistry/*metabolism/toxicity ; tau Proteins/deficiency/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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    Dissecting the genomic complexity underlying medulloblastoma (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-07-27
    Description: Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662966/" 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/PMC3662966/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jones, David T W -- Jager, Natalie -- Kool, Marcel -- Zichner, Thomas -- Hutter, Barbara -- Sultan, Marc -- Cho, Yoon-Jae -- Pugh, Trevor J -- Hovestadt, Volker -- Stutz, Adrian M -- Rausch, Tobias -- Warnatz, Hans-Jorg -- Ryzhova, Marina -- Bender, Sebastian -- Sturm, Dominik -- Pleier, Sabrina -- Cin, Huriye -- Pfaff, Elke -- Sieber, Laura -- Wittmann, Andrea -- Remke, Marc -- Witt, Hendrik -- Hutter, Sonja -- Tzaridis, Theophilos -- Weischenfeldt, Joachim -- Raeder, Benjamin -- Avci, Meryem -- Amstislavskiy, Vyacheslav -- Zapatka, Marc -- Weber, Ursula D -- Wang, Qi -- Lasitschka, Barbel -- Bartholomae, Cynthia C -- Schmidt, Manfred -- von Kalle, Christof -- Ast, Volker -- Lawerenz, Chris -- Eils, Jurgen -- Kabbe, Rolf -- Benes, Vladimir -- van Sluis, Peter -- Koster, Jan -- Volckmann, Richard -- Shih, David -- Betts, Matthew J -- Russell, Robert B -- Coco, Simona -- Tonini, Gian Paolo -- Schuller, Ulrich -- Hans, Volkmar -- Graf, Norbert -- Kim, Yoo-Jin -- Monoranu, Camelia -- Roggendorf, Wolfgang -- Unterberg, Andreas -- Herold-Mende, Christel -- Milde, Till -- Kulozik, Andreas E -- von Deimling, Andreas -- Witt, Olaf -- Maass, Eberhard -- Rossler, Jochen -- Ebinger, Martin -- Schuhmann, Martin U -- Fruhwald, Michael C -- Hasselblatt, Martin -- Jabado, Nada -- Rutkowski, Stefan -- von Bueren, Andre O -- Williamson, Dan -- Clifford, Steven C -- McCabe, Martin G -- Collins, V Peter -- Wolf, Stephan -- Wiemann, Stefan -- Lehrach, Hans -- Brors, Benedikt -- Scheurlen, Wolfram -- Felsberg, Jorg -- Reifenberger, Guido -- Northcott, Paul A -- Taylor, Michael D -- Meyerson, Matthew -- Pomeroy, Scott L -- Yaspo, Marie-Laure -- Korbel, Jan O -- Korshunov, Andrey -- Eils, Roland -- Pfister, Stefan M -- Lichter, Peter -- P30 HD018655/HD/NICHD NIH HHS/ -- R01 CA109467/CA/NCI NIH HHS/ -- England -- Nature. 2012 Aug 2;488(7409):100-5. doi: 10.1038/nature11284.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22832583" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/genetics ; Amino Acid Sequence ; Cell Transformation, Neoplastic ; Cerebellar Neoplasms/classification/diagnosis/*genetics/pathology ; Child ; Chromatin/metabolism ; Chromosomes, Human/genetics ; DEAD-box RNA Helicases/genetics ; DNA Helicases/genetics ; DNA-Binding Proteins/genetics ; Genome, Human/*genetics ; Genomics ; Hedgehog Proteins/metabolism ; High-Throughput Nucleotide Sequencing ; Histone Demethylases/genetics ; Humans ; Medulloblastoma/classification/diagnosis/*genetics/pathology ; Methylation ; Mutation/genetics ; Mutation Rate ; Neoplasm Proteins/genetics ; Nuclear Proteins/genetics ; Oncogene Proteins, Fusion/genetics ; Phosphoprotein Phosphatases/genetics ; Polyploidy ; Receptors, Cell Surface/genetics ; Sequence Analysis, RNA ; Signal Transduction ; T-Box Domain Proteins/genetics ; Transcription Factors/genetics ; Wnt Proteins/metabolism ; beta Catenin/genetics
    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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    Signatures of mutational processes in human cancer (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-08-16
    Description: All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776390/" 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/PMC3776390/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alexandrov, Ludmil B -- Nik-Zainal, Serena -- Wedge, David C -- Aparicio, Samuel A J R -- Behjati, Sam -- Biankin, Andrew V -- Bignell, Graham R -- Bolli, Niccolo -- Borg, Ake -- Borresen-Dale, Anne-Lise -- Boyault, Sandrine -- Burkhardt, Birgit -- Butler, Adam P -- Caldas, Carlos -- Davies, Helen R -- Desmedt, Christine -- Eils, Roland -- Eyfjord, Jorunn Erla -- Foekens, John A -- Greaves, Mel -- Hosoda, Fumie -- Hutter, Barbara -- Ilicic, Tomislav -- Imbeaud, Sandrine -- Imielinski, Marcin -- Jager, Natalie -- Jones, David T W -- Jones, David -- Knappskog, Stian -- Kool, Marcel -- Lakhani, Sunil R -- Lopez-Otin, Carlos -- Martin, Sancha -- Munshi, Nikhil C -- Nakamura, Hiromi -- Northcott, Paul A -- Pajic, Marina -- Papaemmanuil, Elli -- Paradiso, Angelo -- Pearson, John V -- Puente, Xose S -- Raine, Keiran -- Ramakrishna, Manasa -- Richardson, Andrea L -- Richter, Julia -- Rosenstiel, Philip -- Schlesner, Matthias -- Schumacher, Ton N -- Span, Paul N -- Teague, Jon W -- Totoki, Yasushi -- Tutt, Andrew N J -- Valdes-Mas, Rafael -- van Buuren, Marit M -- van 't Veer, Laura -- Vincent-Salomon, Anne -- Waddell, Nicola -- Yates, Lucy R -- Australian Pancreatic Cancer Genome Initiative -- ICGC Breast Cancer Consortium -- ICGC MMML-Seq Consortium -- ICGC PedBrain -- Zucman-Rossi, Jessica -- Futreal, P Andrew -- McDermott, Ultan -- Lichter, Peter -- Meyerson, Matthew -- Grimmond, Sean M -- Siebert, Reiner -- Campo, Elias -- Shibata, Tatsuhiro -- Pfister, Stefan M -- Campbell, Peter J -- Stratton, Michael R -- 088340/Wellcome Trust/United Kingdom -- 093867/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- T32 CA009216/CA/NCI NIH HHS/ -- England -- Nature. 2013 Aug 22;500(7463):415-21. doi: 10.1038/nature12477. Epub 2013 Aug 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23945592" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/genetics ; Algorithms ; Cell Transformation, Neoplastic/*genetics/pathology ; Cytidine Deaminase/genetics ; DNA/genetics/metabolism ; DNA Mutational Analysis ; Humans ; Models, Genetic ; Mutagenesis/*genetics ; Mutagenesis, Insertional/genetics ; Mutagens/pharmacology ; Mutation/*genetics ; Neoplasms/enzymology/*genetics/pathology ; Organ Specificity ; Reproducibility of Results ; Sequence Deletion/genetics ; Transcription, Genetic/genetics
    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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  • 4
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    Combining transcription factor binding affinities with open-chromatin data for accurate gene expression prediction (2017)
    Oxford University Press
    Details
    Publication Date: 2017-01-10
    Description: The binding and contribution of transcription factors (TF) to cell specific gene expression is often deduced from open-chromatin measurements to avoid costly TF ChIP-seq assays. Thus, it is important to develop computational methods for accurate TF binding prediction in open-chromatin regions (OCRs). Here, we report a novel segmentation-based method, TEPIC, to predict TF binding by combining sets of OCRs with position weight matrices. TEPIC can be applied to various open-chromatin data, e.g. DNaseI-seq and NOMe-seq. Additionally, Histone-Marks (HMs) can be used to identify candidate TF binding sites. TEPIC computes TF affinities and uses open-chromatin/HM signal intensity as quantitative measures of TF binding strength. Using machine learning, we find low affinity binding sites to improve our ability to explain gene expression variability compared to the standard presence/absence classification of binding sites. Further, we show that both footprints and peaks capture essential TF binding events and lead to a good prediction performance. In our application, gene-based scores computed by TEPIC with one open-chromatin assay nearly reach the quality of several TF ChIP-seq data sets. Finally, these scores correctly predict known transcriptional regulators as illustrated by the application to novel DNaseI-seq and NOMe-seq data for primary human hepatocytes and CD4+ T-cells, respectively.
    Keywords: Protein-nucleic acid interaction, Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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