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  • 1
    Publication Date: 2010-01-15
    Description: In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901986/" 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/PMC2901986/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jianming -- Adrian, Francisco J -- Jahnke, Wolfgang -- Cowan-Jacob, Sandra W -- Li, Allen G -- Iacob, Roxana E -- Sim, Taebo -- Powers, John -- Dierks, Christine -- Sun, Fangxian -- Guo, Gui-Rong -- Ding, Qiang -- Okram, Barun -- Choi, Yongmun -- Wojciechowski, Amy -- Deng, Xianming -- Liu, Guoxun -- Fendrich, Gabriele -- Strauss, Andre -- Vajpai, Navratna -- Grzesiek, Stephan -- Tuntland, Tove -- Liu, Yi -- Bursulaya, Badry -- Azam, Mohammad -- Manley, Paul W -- Engen, John R -- Daley, George Q -- Warmuth, Markus -- Gray, Nathanael S -- R01 CA130876/CA/NCI NIH HHS/ -- R01 CA130876-03/CA/NCI NIH HHS/ -- England -- Nature. 2010 Jan 28;463(7280):501-6. doi: 10.1038/nature08675. Epub 2010 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Harvard Medical School, Department of Cancer Biology, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20072125" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/*chemistry/metabolism/*pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; Benzamides ; Binding Sites ; Bone Marrow Transplantation ; Cell Line, Tumor ; Crystallization ; Disease Models, Animal ; Drug Resistance, Neoplasm/*drug effects ; Female ; Fusion Proteins, bcr-abl/*chemistry/genetics/metabolism ; Humans ; Imatinib Mesylate ; Inhibitory Concentration 50 ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug ; therapy/enzymology/*metabolism ; Male ; Mass Spectrometry ; Mice ; Models, Molecular ; Mutation/genetics ; Piperazines/chemistry/pharmacology ; Protein Structure, Tertiary ; Pyrimidines/chemistry/metabolism/pharmacology ; Transplantation, Heterologous
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-04-15
    Description: Languages vary widely but not without limit. The central goal of linguistics is to describe the diversity of human languages and explain the constraints on that diversity. Generative linguists following Chomsky have claimed that linguistic diversity must be constrained by innate parameters that are set as a child learns a language. In contrast, other linguists following Greenberg have claimed that there are statistical tendencies for co-occurrence of traits reflecting universal systems biases, rather than absolute constraints or parametric variation. Here we use computational phylogenetic methods to address the nature of constraints on linguistic diversity in an evolutionary framework. First, contrary to the generative account of parameter setting, we show that the evolution of only a few word-order features of languages are strongly correlated. Second, contrary to the Greenbergian generalizations, we show that most observed functional dependencies between traits are lineage-specific rather than universal tendencies. These findings support the view that-at least with respect to word order-cultural evolution is the primary factor that determines linguistic structure, with the current state of a linguistic system shaping and constraining future states.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dunn, Michael -- Greenhill, Simon J -- Levinson, Stephen C -- Gray, Russell D -- England -- Nature. 2011 May 5;473(7345):79-82. doi: 10.1038/nature09923. Epub 2011 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Psycholinguistics, Post Office Box 310, 6500 AH Nijmegen, The Netherlands. michael.dunn@mpi.nl〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21490599" target="_blank"〉PubMed〈/a〉
    Keywords: *Biological Evolution ; Cultural Evolution ; Humans ; *Language ; *Linguistics ; Phylogeny
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-05-04
    Description: The mTOR complex 1 (mTORC1) kinase nucleates a pathway that promotes cell growth and proliferation and is the target of rapamycin, a drug with many clinical uses. mTORC1 regulates messenger RNA translation, but the overall translational program is poorly defined and no unifying model exists to explain how mTORC1 differentially controls the translation of specific mRNAs. Here we use high-resolution transcriptome-scale ribosome profiling to monitor translation in mouse cells acutely treated with the mTOR inhibitor Torin 1, which, unlike rapamycin, fully inhibits mTORC1 (ref. 2). Our data reveal a surprisingly simple model of the mRNA features and mechanisms that confer mTORC1-dependent translation control. The subset of mRNAs that are specifically regulated by mTORC1 consists almost entirely of transcripts with established 5' terminal oligopyrimidine (TOP) motifs, or, like Hsp90ab1 and Ybx1, with previously unrecognized TOP or related TOP-like motifs that we identified. We find no evidence to support proposals that mTORC1 preferentially regulates mRNAs with increased 5' untranslated region length or complexity. mTORC1 phosphorylates a myriad of translational regulators, but how it controls TOP mRNA translation is unknown. Remarkably, loss of just the 4E-BP family of translational repressors, arguably the best characterized mTORC1 substrates, is sufficient to render TOP and TOP-like mRNA translation resistant to Torin 1. The 4E-BPs inhibit translation initiation by interfering with the interaction between the cap-binding protein eIF4E and eIF4G1. Loss of this interaction diminishes the capacity of eIF4E to bind TOP and TOP-like mRNAs much more than other mRNAs, explaining why mTOR inhibition selectively suppresses their translation. Our results clarify the translational program controlled by mTORC1 and identify 4E-BPs and eIF4G1 as its master effectors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347774/" 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/PMC3347774/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thoreen, Carson C -- Chantranupong, Lynne -- Keys, Heather R -- Wang, Tim -- Gray, Nathanael S -- Sabatini, David M -- CA103866/CA/NCI NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA103866-08/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA129105-05/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 2;485(7396):109-13. doi: 10.1038/nature11083.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana Farber Cancer Institute, 250 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22552098" target="_blank"〉PubMed〈/a〉
    Keywords: 5' Untranslated Regions/genetics ; Animals ; Base Sequence ; Cell Line, Tumor ; Eukaryotic Initiation Factor-4E/metabolism ; Eukaryotic Initiation Factor-4G/metabolism ; *Gene Expression Regulation/drug effects ; Humans ; Male ; Mice ; *Models, Biological ; Multiprotein Complexes ; Naphthyridines/pharmacology ; Nucleotide Motifs ; Phosphorylation ; Prostatic Neoplasms/genetics/pathology ; Protein Binding ; *Protein Biosynthesis/drug effects ; Proteins/antagonists & inhibitors/*metabolism ; RNA, Messenger/genetics/metabolism ; Ribosomes/metabolism ; TOR Serine-Threonine Kinases
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2012-12-04
    Description: Cryptophyte and chlorarachniophyte algae are transitional forms in the widespread secondary endosymbiotic acquisition of photosynthesis by engulfment of eukaryotic algae. Unlike most secondary plastid-bearing algae, miniaturized versions of the endosymbiont nuclei (nucleomorphs) persist in cryptophytes and chlorarachniophytes. To determine why, and to address other fundamental questions about eukaryote-eukaryote endosymbiosis, we sequenced the nuclear genomes of the cryptophyte Guillardia theta and the chlorarachniophyte Bigelowiella natans. Both genomes have 〉21,000 protein genes and are intron rich, and B. natans exhibits unprecedented alternative splicing for a single-celled organism. Phylogenomic analyses and subcellular targeting predictions reveal extensive genetic and biochemical mosaicism, with both host- and endosymbiont-derived genes servicing the mitochondrion, the host cell cytosol, the plastid and the remnant endosymbiont cytosol of both algae. Mitochondrion-to-nucleus gene transfer still occurs in both organisms but plastid-to-nucleus and nucleomorph-to-nucleus transfers do not, which explains why a small residue of essential genes remains locked in each nucleomorph.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Curtis, Bruce A -- Tanifuji, Goro -- Burki, Fabien -- Gruber, Ansgar -- Irimia, Manuel -- Maruyama, Shinichiro -- Arias, Maria C -- Ball, Steven G -- Gile, Gillian H -- Hirakawa, Yoshihisa -- Hopkins, Julia F -- Kuo, Alan -- Rensing, Stefan A -- Schmutz, Jeremy -- Symeonidi, Aikaterini -- Elias, Marek -- Eveleigh, Robert J M -- Herman, Emily K -- Klute, Mary J -- Nakayama, Takuro -- Obornik, Miroslav -- Reyes-Prieto, Adrian -- Armbrust, E Virginia -- Aves, Stephen J -- Beiko, Robert G -- Coutinho, Pedro -- Dacks, Joel B -- Durnford, Dion G -- Fast, Naomi M -- Green, Beverley R -- Grisdale, Cameron J -- Hempel, Franziska -- Henrissat, Bernard -- Hoppner, Marc P -- Ishida, Ken-Ichiro -- Kim, Eunsoo -- Koreny, Ludek -- Kroth, Peter G -- Liu, Yuan -- Malik, Shehre-Banoo -- Maier, Uwe G -- McRose, Darcy -- Mock, Thomas -- Neilson, Jonathan A D -- Onodera, Naoko T -- Poole, Anthony M -- Pritham, Ellen J -- Richards, Thomas A -- Rocap, Gabrielle -- Roy, Scott W -- Sarai, Chihiro -- Schaack, Sarah -- Shirato, Shu -- Slamovits, Claudio H -- Spencer, David F -- Suzuki, Shigekatsu -- Worden, Alexandra Z -- Zauner, Stefan -- Barry, Kerrie -- Bell, Callum -- Bharti, Arvind K -- Crow, John A -- Grimwood, Jane -- Kramer, Robin -- Lindquist, Erika -- Lucas, Susan -- Salamov, Asaf -- McFadden, Geoffrey I -- Lane, Christopher E -- Keeling, Patrick J -- Gray, Michael W -- Grigoriev, Igor V -- Archibald, John M -- BB/G00885X/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Dec 6;492(7427):59-65. doi: 10.1038/nature11681. Epub 2012 Nov 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23201678" target="_blank"〉PubMed〈/a〉
    Keywords: Algal Proteins/genetics/metabolism ; Alternative Splicing/genetics ; Cell Nucleus/*genetics ; Cercozoa/cytology/*genetics/metabolism ; Cryptophyta/cytology/*genetics/metabolism ; Cytosol/metabolism ; *Evolution, Molecular ; Gene Duplication/genetics ; Gene Transfer, Horizontal/genetics ; Genes, Essential/genetics ; Genome/*genetics ; Genome, Mitochondrial/genetics ; Genome, Plant/genetics ; Genome, Plastid/genetics ; Molecular Sequence Data ; *Mosaicism ; Phylogeny ; Protein Transport ; Proteome/genetics/metabolism ; Symbiosis/*genetics ; Transcriptome/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2013-04-19
    Description: Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703927/" 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/PMC3703927/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Howe, Kerstin -- Clark, Matthew D -- Torroja, Carlos F -- Torrance, James -- Berthelot, Camille -- Muffato, Matthieu -- Collins, John E -- Humphray, Sean -- McLaren, Karen -- Matthews, Lucy -- McLaren, Stuart -- Sealy, Ian -- Caccamo, Mario -- Churcher, Carol -- Scott, Carol -- Barrett, Jeffrey C -- Koch, Romke -- Rauch, Gerd-Jorg -- White, Simon -- Chow, William -- Kilian, Britt -- Quintais, Leonor T -- Guerra-Assuncao, Jose A -- Zhou, Yi -- Gu, Yong -- Yen, Jennifer -- Vogel, Jan-Hinnerk -- Eyre, Tina -- Redmond, Seth -- Banerjee, Ruby -- Chi, Jianxiang -- Fu, Beiyuan -- Langley, Elizabeth -- Maguire, Sean F -- Laird, Gavin K -- Lloyd, David -- Kenyon, Emma -- Donaldson, Sarah -- Sehra, Harminder -- Almeida-King, Jeff -- Loveland, Jane -- Trevanion, Stephen -- Jones, Matt -- Quail, Mike -- Willey, Dave -- Hunt, Adrienne -- Burton, John -- Sims, Sarah -- McLay, Kirsten -- Plumb, Bob -- Davis, Joy -- Clee, Chris -- Oliver, Karen -- Clark, Richard -- Riddle, Clare -- Elliot, David -- Threadgold, Glen -- Harden, Glenn -- Ware, Darren -- Begum, Sharmin -- Mortimore, Beverley -- Kerry, Giselle -- Heath, Paul -- Phillimore, Benjamin -- Tracey, Alan -- Corby, Nicole -- Dunn, Matthew -- Johnson, Christopher -- Wood, Jonathan -- Clark, Susan -- Pelan, Sarah -- Griffiths, Guy -- Smith, Michelle -- Glithero, Rebecca -- Howden, Philip -- Barker, Nicholas -- Lloyd, Christine -- Stevens, Christopher -- Harley, Joanna -- Holt, Karen -- Panagiotidis, Georgios -- Lovell, Jamieson -- Beasley, Helen -- Henderson, Carl -- Gordon, Daria -- Auger, Katherine -- Wright, Deborah -- Collins, Joanna -- Raisen, Claire -- Dyer, Lauren -- Leung, Kenric -- Robertson, Lauren -- Ambridge, Kirsty -- Leongamornlert, Daniel -- McGuire, Sarah -- Gilderthorp, Ruth -- Griffiths, Coline -- Manthravadi, Deepa -- Nichol, Sarah -- Barker, Gary -- Whitehead, Siobhan -- Kay, Michael -- Brown, Jacqueline -- Murnane, Clare -- Gray, Emma -- Humphries, Matthew -- Sycamore, Neil -- Barker, Darren -- Saunders, David -- Wallis, Justene -- Babbage, Anne -- Hammond, Sian -- Mashreghi-Mohammadi, Maryam -- Barr, Lucy -- Martin, Sancha -- Wray, Paul -- Ellington, Andrew -- Matthews, Nicholas -- Ellwood, Matthew -- Woodmansey, Rebecca -- Clark, Graham -- Cooper, James D -- Tromans, Anthony -- Grafham, Darren -- Skuce, Carl -- Pandian, Richard -- Andrews, Robert -- Harrison, Elliot -- Kimberley, Andrew -- Garnett, Jane -- Fosker, Nigel -- Hall, Rebekah -- Garner, Patrick -- Kelly, Daniel -- Bird, Christine -- Palmer, Sophie -- Gehring, Ines -- Berger, Andrea -- Dooley, Christopher M -- Ersan-Urun, Zubeyde -- Eser, Cigdem -- Geiger, Horst -- Geisler, Maria -- Karotki, Lena -- Kirn, Anette -- Konantz, Judith -- Konantz, Martina -- Oberlander, Martina -- Rudolph-Geiger, Silke -- Teucke, Mathias -- Lanz, Christa -- Raddatz, Gunter -- Osoegawa, Kazutoyo -- Zhu, Baoli -- Rapp, Amanda -- Widaa, Sara -- Langford, Cordelia -- Yang, Fengtang -- Schuster, Stephan C -- Carter, Nigel P -- Harrow, Jennifer -- Ning, Zemin -- Herrero, Javier -- Searle, Steve M J -- Enright, Anton -- Geisler, Robert -- Plasterk, Ronald H A -- Lee, Charles -- Westerfield, Monte -- de Jong, Pieter J -- Zon, Leonard I -- Postlethwait, John H -- Nusslein-Volhard, Christiane -- Hubbard, Tim J P -- Roest Crollius, Hugues -- Rogers, Jane -- Stemple, Derek L -- 095908/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- 1 R01 DK55377-01A1/DK/NIDDK NIH HHS/ -- P01 HD022486/HD/NICHD NIH HHS/ -- P01 HD22486/HD/NICHD NIH HHS/ -- R01 GM085318/GM/NIGMS NIH HHS/ -- R01 OD011116/OD/NIH HHS/ -- R01 RR010715/RR/NCRR NIH HHS/ -- R01 RR020833/RR/NCRR NIH HHS/ -- England -- Nature. 2013 Apr 25;496(7446):498-503. doi: 10.1038/nature12111. Epub 2013 Apr 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23594743" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chromosomes/genetics ; Conserved Sequence/*genetics ; Evolution, Molecular ; Female ; Genes/genetics ; Genome/*genetics ; Genome, Human/genetics ; Genomics ; Humans ; Male ; Meiosis/genetics ; Molecular Sequence Annotation ; Pseudogenes/genetics ; Reference Standards ; Sex Determination Processes/genetics ; Zebrafish/*genetics ; Zebrafish Proteins/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2013-06-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pybus, Oliver G -- Gray, Rebecca R -- England -- Nature. 2013 Jun 20;498(7454):310-1. doi: 10.1038/498310b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23783626" target="_blank"〉PubMed〈/a〉
    Keywords: Africa ; Animals ; Asia ; Chiroptera/*virology ; Hepacivirus/*classification/*isolation & purification ; Hepatitis C/transmission/virology ; Humans ; Phylogeny ; Rodentia/*virology ; Zoonoses/transmission/*virology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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