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  • 1
    Publication Date: 2008-09-23
    Description: Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine kinase that participates in numerous signalling pathways involved in diverse physiological processes. Several of these pathways are implicated in disease pathogenesis, which has prompted efforts to develop GSK3-specific inhibitors for therapeutic applications. However, before now, there has been no strong rationale for targeting GSK3 in malignancies. Here we report pharmacological, physiological and genetic studies that demonstrate an oncogenic requirement for GSK3 in the maintenance of a specific subtype of poor prognosis human leukaemia, genetically defined by mutations of the MLL proto-oncogene. In contrast to its previously characterized roles in suppression of neoplasia-associated signalling pathways, GSK3 paradoxically supports MLL leukaemia cell proliferation and transformation by a mechanism that ultimately involves destabilization of the cyclin-dependent kinase inhibitor p27(Kip1). Inhibition of GSK3 in a preclinical murine model of MLL leukaemia provides promising evidence of efficacy and earmarks GSK3 as a candidate cancer drug target.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4084721/" 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/PMC4084721/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Zhong -- Smith, Kevin S -- Murphy, Mark -- Piloto, Obdulio -- Somervaille, Tim C P -- Cleary, Michael L -- CA116606/CA/NCI NIH HHS/ -- CA55029/CA/NCI NIH HHS/ -- R01 CA055029/CA/NCI NIH HHS/ -- R01 CA116606/CA/NCI NIH HHS/ -- England -- Nature. 2008 Oct 30;455(7217):1205-9. doi: 10.1038/nature07284. Epub 2008 Sep 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18806775" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Division ; Cell Line, Transformed ; Cell Line, Tumor ; Cell Proliferation ; *Cell Transformation, Neoplastic ; Cyclin-Dependent Kinase Inhibitor p27 ; Disease Models, Animal ; G1 Phase ; Glycogen Synthase Kinase 3/antagonists & ; inhibitors/deficiency/genetics/*metabolism ; Histone-Lysine N-Methyltransferase ; Humans ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors/metabolism ; Isoenzymes/metabolism ; Leukemia, Lymphoid/*drug therapy/enzymology/metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Mice, SCID ; Myeloid Progenitor Cells/enzymology/metabolism/pathology ; Myeloid-Lymphoid Leukemia Protein/*metabolism ; Precursor Cells, B-Lymphoid/enzymology/metabolism/pathology
    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: 2008-03-21
    Description: Equal amounts of matter and antimatter are predicted to have been produced in the Big Bang, but our observable Universe is clearly matter-dominated. One of the prerequisites for understanding this elimination of antimatter is the nonconservation of charge-parity (CP) symmetry. So far, two types of CP violation have been observed in the neutral K meson (K(0)) and B meson (B(0)) systems: CP violation involving the mixing between K(0) and its antiparticle (and likewise for B(0) and ), and direct CP violation in the decay of each meson. The observed effects for both types of CP violation are substantially larger for the B(0) meson system. However, they are still consistent with the standard model of particle physics, which has a unique source of CP violation that is known to be too small to account for the matter-dominated Universe. Here we report that the direct CP violation in charged B(+/-)--〉K(+/-)pi(0) decay is different from that in the neutral B(0) counterpart. The direct CP-violating decay rate asymmetry, (that is, the difference between the number of observed B(-)--〉K(-)pi(0) event versus B(+)--〉K(+) pi(0) events, normalized to the sum of these events) is measured to be about +7%, with an uncertainty that is reduced by a factor of 1.7 from a previous measurement. However, the asymmetry for versus B(0)--〉K(+)pi(-) is at the -10% level. Although it is susceptible to strong interaction effects that need further clarification, this large deviation in direct CP violation between charged and neutral B meson decays could be an indication of new sources of CP violation-which would help to explain the dominance of matter in the Universe.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Belle Collaboration -- Lin, S-W -- Unno, Y -- Hou, W-S -- Chang, P -- Adachi, I -- Aihara, H -- Akai, K -- Arinstein, K -- Aulchenko, V -- Aushev, T -- Aziz, T -- Bakich, A M -- Balagura, V -- Barberio, E -- Bay, A -- Bedny, I -- Bitenc, U -- Bondar, A -- Bozek, A -- Bracko, M -- Browder, T E -- Chang, M-C -- Chao, Y -- Chen, A -- Chen, K-F -- Chen, W T -- Cheon, B G -- Chiang, C-C -- Chistov, R -- Cho, I-S -- Choi, S-K -- Choi, Y -- Choi, Y K -- Cole, S -- Dalseno, J -- Danilov, M -- Dash, M -- Drutskoy, A -- Eidelman, S -- Epifanov, D -- Fratina, S -- Fujikawa, M -- Furukawa, K -- Gabyshev, N -- Goldenzweig, P -- Golob, B -- Ha, H -- Haba, J -- Hara, T -- Hayasaka, K -- Hayashii, H -- Hazumi, M -- Heffernan, D -- Hokuue, T -- Hoshi, Y -- Hsiung, Y B -- Hyun, H J -- Iijima, T -- Ikado, K -- Inami, K -- Ishikawa, A -- Ishino, H -- Itoh, R -- Iwabuchi, M -- Iwasaki, M -- Iwasaki, Y -- Kah, D H -- Kaji, H -- Kataoka, S U -- Kawai, H -- Kawasaki, T -- Kibayashi, A -- Kichimi, H -- Kikutani, E -- Kim, H J -- Kim, S K -- Kim, Y J -- Kinoshita, K -- Korpar, S -- Kozakai, Y -- Krizan, P -- Krokovny, P -- Kumar, R -- Kuo, C C -- Kuzmin, A -- Kwon, Y-J -- Lee, M J -- Lee, S E -- Lesiak, T -- Li, J -- Liu, Y -- Liventsev, D -- Mandl, F -- Marlow, D -- McOnie, S -- Medvedeva, T -- Mimashi, T -- Mitaroff, W -- Miyabayashi, K -- Miyake, H -- Miyazaki, Y -- Mizuk, R -- Mori, T -- Nakamura, T T -- Nakano, E -- Nakao, M -- Nakazawa, H -- Nishida, S -- Nitoh, O -- Noguchi, S -- Nozaki, T -- Ogawa, S -- Ogawa, Y -- Ohshima, T -- Okuno, S -- Olsen, S L -- Ozaki, H -- Pakhlova, G -- Park, C W -- Park, H -- Peak, L S -- Pestotnik, R -- Peters, M -- Piilonen, L E -- Poluektov, A -- Sahoo, H -- Sakai, Y -- Schneider, O -- Schumann, J -- Schwartz, A J -- Seidl, R -- Senyo, K -- Sevior, M E -- Shapkin, M -- Shen, C P -- Shibuya, H -- Shidara, T -- Shinomiya, S -- Shiu, J-G -- Shwartz, B -- Singh, J B -- Sokolov, A -- Somov, A -- Stanic, S -- Staric, M -- Sumisawa, K -- Sumiyoshi, T -- Suzuki, S -- Tajima, O -- Takasaki, F -- Tamura, N -- Tanaka, M -- Tawada, M -- Taylor, G N -- Teramoto, Y -- Tikhomirov, I -- Trabelsi, K -- Uehara, S -- Ueno, K -- Uglov, T -- Uno, S -- Urquijo, P -- Ushiroda, Y -- Usov, Y -- Varner, G -- Varvell, K E -- Vervink, K -- Villa, S -- Wang, C C -- Wang, C H -- Wang, M-Z -- Watanabe, Y -- Wedd, R -- Wicht, J -- Won, E -- Yabsley, B D -- Yamaguchi, A -- Yamashita, Y -- Yamauchi, M -- Yoshida, M -- Yuan, C Z -- Yusa, Y -- Zhang, C C -- Zhang, Z P -- Zhilich, V -- Zhulanov, V -- Zupanc, A -- England -- Nature. 2008 Mar 20;452(7185):332-5. doi: 10.1038/nature06827.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physics, National Taiwan University, Taipei, 106, Taiwan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18354478" target="_blank"〉PubMed〈/a〉
    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: 2008-05-03
    Description: The identification of untranslated regions, introns, and coding regions within an organism remains challenging. We developed a quantitative sequencing-based method called RNA-Seq for mapping transcribed regions, in which complementary DNA fragments are subjected to high-throughput sequencing and mapped to the genome. We applied RNA-Seq to generate a high-resolution transcriptome map of the yeast genome and demonstrated that most (74.5%) of the nonrepetitive sequence of the yeast genome is transcribed. We confirmed many known and predicted introns and demonstrated that others are not actively used. Alternative initiation codons and upstream open reading frames also were identified for many yeast genes. We also found unexpected 3'-end heterogeneity and the presence of many overlapping genes. These results indicate that the yeast transcriptome is more complex than previously appreciated.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951732/" 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/PMC2951732/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nagalakshmi, Ugrappa -- Wang, Zhong -- Waern, Karl -- Shou, Chong -- Raha, Debasish -- Gerstein, Mark -- Snyder, Michael -- P50 HG002357/HG/NHGRI NIH HHS/ -- P50 HG002357-10/HG/NHGRI NIH HHS/ -- R01 CA077808/CA/NCI NIH HHS/ -- R01 CA077808-12/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2008 Jun 6;320(5881):1344-9. doi: 10.1126/science.1158441. Epub 2008 May 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18451266" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Codon, Initiator ; Computational Biology ; DNA, Complementary ; DNA, Intergenic ; *Gene Expression Profiling ; Genes, Fungal ; *Genome, Fungal ; Genomics ; Introns ; Open Reading Frames ; RNA, Fungal/genetics ; Saccharomyces cerevisiae/*genetics ; *Sequence Analysis, RNA ; *Transcription, Genetic ; Untranslated Regions
    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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  • 4
    Publication Date: 2008-01-07
    Print ISSN: 1550-7998
    Electronic ISSN: 1550-2368
    Topics: Physics
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  • 5
    Publication Date: 2008-11-13
    Print ISSN: 1550-7998
    Electronic ISSN: 1550-2368
    Topics: Physics
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  • 6
    Publication Date: 2008-02-27
    Print ISSN: 1550-7998
    Electronic ISSN: 1550-2368
    Topics: Physics
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  • 7
    Publication Date: 2008-03-12
    Print ISSN: 0031-9007
    Electronic ISSN: 1079-7114
    Topics: Physics
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  • 8
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  • 10
    Publication Date: 2022-05-26
    Description: Author Posting. © Elsevier B.V., 2008. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Earth and Planetary Science Letters 269 (2008): 508-517, doi:10.1016/j.epsl.2008.03.010.
    Description: A model of coupled He production/diffusion is used to constrain the question of whether Earth’s peridotitic mantle contains ubiquitous mesoscale veins or slabs of other lithologies. The high diffusion rates of helium preclude survival of He isotope heterogeneities on scales smaller than a few tens of meters, especially if they represent long term in-growth of 4He in the mantle. For 1.5 Gy residence times, and a diffusion coefficient of 10-10 m2/sec, 0.5 km slabs or 2 km cylinders will lose 〉90% of in-grown 4He. However, substantial 3He/4He variations may persist in slabs or be induced in adjacent mantle, depending on initial He, U and Th contents. We have modeled three cases of 3He/4He equilibration between mantle domains: an ocean crust (OC) slab in depleted upper mantle (DMM) or in enriched mantle (BSE), and a BSE slab in DMM. For a 1 km OC slab in DMM (8 Ra today), the slab today will have 3He/4He of only 3 Ra, and will have influenced the surrounding mantle with 4He for 〉7 km on either side. The average 3He/4He of this mixed zone will be 〈7 Ra, even when sampled by melts over a total width of 20-50 km. For the case of a 1 km BSE slab in DMM (8 Ra today), the slab will be 37 Ra today, and will have infected a mantle domain 〉16 km wide. Even with a 60 km melt sampling width, the average 3He/4He will be 〉15 Ra. Slabs may lose their He signature by diffusion, but their presence will be recorded in the surrounding mantle. We have evaluated 3 along-axis N-MORB ridge-crest data sets in this context (MAR 25.7-26.5°S; EPR 19-23°S; SWIR 16-24°E), with a view to defining scale-lengths of He isotope variability. The average 3He/4He variability for these 3 areas is very small, and independent of spreading rate: 0.13, 0.19 and 0.21 Ra (±1σ). Since these ridges range from ultraslow to very fast-spreading, the variability in size of along-axis magma chambers will lead inevitably to various scales of melt averaging. We conclude that these ridge areas are not sampling mantle that contains enriched veins or recycled oceanic crust slabs of significant size (〉 tens of meters). It appears difficult to sustain a view of the upper mantle as a ubiquitous mixture of veins and depleted matrix, with MORB always representing an averaging of this mixture.
    Description: We are grateful for the consistent support of NSF that made this work possible (EAR - 0509891 to SRH; OCE - 0525864 to MDK).
    Repository Name: Woods Hole Open Access Server
    Type: Preprint
    Format: application/pdf
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