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  • 1
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 1993-03-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yeates, T O -- Zhang, K Y -- New York, N.Y. -- Science. 1993 Mar 19;259(5102):1771-2.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17816893" target="_blank"〉PubMed〈/a〉
    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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  • 2
    Publication Date: 2010-09-09
    Description: B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts. Toxicology studies confirmed a wide safety margin consistent with the high degree of selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032 (ref. 5). In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumour regressions. At higher drug exposures afforded by a new amorphous drug formulation, greater than 80% inhibition of ERK phosphorylation in the tumours of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily. These data demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase activity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948082/" 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/PMC2948082/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bollag, Gideon -- Hirth, Peter -- Tsai, James -- Zhang, Jiazhong -- Ibrahim, Prabha N -- Cho, Hanna -- Spevak, Wayne -- Zhang, Chao -- Zhang, Ying -- Habets, Gaston -- Burton, Elizabeth A -- Wong, Bernice -- Tsang, Garson -- West, Brian L -- Powell, Ben -- Shellooe, Rafe -- Marimuthu, Adhirai -- Nguyen, Hoa -- Zhang, Kam Y J -- Artis, Dean R -- Schlessinger, Joseph -- Su, Fei -- Higgins, Brian -- Iyer, Raman -- D'Andrea, Kurt -- Koehler, Astrid -- Stumm, Michael -- Lin, Paul S -- Lee, Richard J -- Grippo, Joseph -- Puzanov, Igor -- Kim, Kevin B -- Ribas, Antoni -- McArthur, Grant A -- Sosman, Jeffrey A -- Chapman, Paul B -- Flaherty, Keith T -- Xu, Xiaowei -- Nathanson, Katherine L -- Nolop, Keith -- K24 CA097588/CA/NCI NIH HHS/ -- P50 CA093372/CA/NCI NIH HHS/ -- P50 CA093372-01/CA/NCI NIH HHS/ -- R01 CA118871/CA/NCI NIH HHS/ -- R01 CA118871-01A1/CA/NCI NIH HHS/ -- England -- Nature. 2010 Sep 30;467(7315):596-9. doi: 10.1038/nature09454.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA. gbollag@plexxikon.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20823850" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Dogs ; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/metabolism ; Humans ; Indoles/administration & dosage/adverse effects/chemistry/*therapeutic use ; MAP Kinase Signaling System/drug effects ; Macaca fascicularis ; Melanoma/*drug therapy/*enzymology/genetics/pathology ; Models, Molecular ; Mutant Proteins/antagonists & inhibitors/chemistry/genetics/metabolism ; Mutation/*genetics ; Neoplasm Metastasis ; Phosphorylation/drug effects ; Positron-Emission Tomography ; Proto-Oncogene Proteins B-raf/*antagonists & ; inhibitors/chemistry/genetics/metabolism ; Rats ; Substrate Specificity ; Sulfonamides/administration & dosage/adverse effects/chemistry/*therapeutic use ; Xenograft Model Antitumor Assays
    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: 2020
    Print ISSN: 1754-2189
    Electronic ISSN: 1750-2799
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 4
    Publication Date: 2015-01-10
    Description: To find signature features shared by various ncRNA sub-types and characterize novel ncRNAs, we have developed a method, RNAfeature , to investigate 〉600 sets of genomic and epigenomic data with various evolutionary and biophysical scores. RNAfeature utilizes a fine-tuned intra-species wrapper algorithm that is followed by a novel feature selection strategy across species. It considers long distance effect of certain features (e.g. histone modification at the promoter region). We finally narrow down on 10 informative features (including sequences, structures, expression profiles and epigenetic signals). These features are complementary to each other and as a whole can accurately distinguish canonical ncRNAs from CDSs and UTRs (accuracies: 〉92% in human, mouse, worm and fly). Moreover, the feature pattern is conserved across multiple species. For instance, the supervised 10-feature model derived from animal species can predict ncRNAs in Arabidopsis (accuracy: 82%). Subsequently, we integrate the 10 features to define a set of noncoding potential scores, which can identify, evaluate and characterize novel noncoding RNAs. The score covers all transcribed regions (including unconserved ncRNAs), without requiring assembly of the full-length transcripts. Importantly, the noncoding potential allows us to identify and characterize potential functional domains with feature patterns similar to canonical ncRNAs (e.g. tRNA, snRNA, miRNA, etc) on ~70% of human long ncRNAs (lncRNAs).
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 5
    Publication Date: 2014-10-22
    Description: The modular structure of many protein families, such as β-propeller proteins, strongly implies that duplication played an important role in their evolution, leading to highly symmetrical intermediate forms. Previous attempts to create perfectly symmetrical propeller proteins have failed, however. We have therefore developed a new and rapid computational approach to...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 6
    Publication Date: 2019
    Description: 〈p〉The valley degree of freedom of electrons in two-dimensional transition metal dichalcogenides has been extensively studied by theory (〈cross-ref type="bib" refid="R1"〉〈i〉1〈/i〉〈/cross-ref〉–〈cross-ref type="bib" refid="R4"〉〈i〉4〈/i〉〈/cross-ref〉), optical (〈cross-ref type="bib" refid="R5"〉〈i〉5〈/i〉〈/cross-ref〉–〈cross-ref type="bib" refid="R9"〉〈i〉9〈/i〉〈/cross-ref〉), and optoelectronic (〈cross-ref type="bib" refid="R10"〉〈i〉10〈/i〉〈/cross-ref〉–〈cross-ref type="bib" refid="R13"〉〈i〉13〈/i〉〈/cross-ref〉) experiments. However, generation and detection of pure valley current without relying on optical selection have not yet been demonstrated in these materials. Here, we report that valley current can be electrically induced and detected through the valley Hall effect and inverse valley Hall effect, respectively, in monolayer molybdenum disulfide. We compare temperature and channel length dependence of nonlocal electrical signals in monolayer and multilayer samples to distinguish the valley Hall effect from classical ohmic contributions. Notably, valley transport is observed over a distance of 4 μm in monolayer samples at room temperature. Our findings will enable a new generation of electronic devices using the valley degree of freedom, which can be used for future novel valleytronic applications.〈/p〉
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 7
    Electronic Resource
    Electronic Resource
    Copenhagen : International Union of Crystallography (IUCr)
    Acta crystallographica 49 (1993), S. 213-222 
    ISSN: 1399-0047
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Notes: The constraints of correct electron-density distribution, solvent flatness, correct local shape of the electron density and equal molecules are combined in an integrated procedure for macromolecular phase refinement and extension. These constraints on electron densities are satisfied simultaneously by solving a system of non-linear equations. The electron-density solution is further filtered by a phase combination procedure. The non-crystallographic symmetry operations are refined by a rotation and translation space search and a least-squares minimization method, thereby reducing the chance of introducing systematic phase errors during averaging. The effect of each constraint on phase refinement and extension is examined. The constraints are found to work synergistically in phase improvement. Test results on 2Zn insulin are presented.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Copenhagen : International Union of Crystallography (IUCr)
    Acta crystallographica 50 (1994), S. 258-262 
    ISSN: 1399-0047
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Notes: The crystal structure is described of ribulose 1,5-bisphosphate carboxylase/oxygenase in a new crystal form. This new form (form V) was obtained from a previously known crystal form (form III) through a solid-state phase transition. The solid-state phase transition was brought about by transferring the crystal from a high-salt low-pH mother liquor to a low-salt high-pH synthetic mother liquor. The interplay of electrostatic repulsion and osmotic pressure induced a unit-cell shrinkage of 24 Å along the c axis and expansion of 4 Å along the a and b axes. The space group also changed from I422 to I4. The new crystal form was shown to be more resistant to X-ray radiation damage, which suggests the effect of crystal stabilization by non-penetrating molecules. The structure of ribulose 1,5-bisphosphate carboxylase/oxygenase in the new crystal form is compared with that of the old crystal form.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Physics Letters A 120 (1987), S. 353-355 
    ISSN: 0375-9601
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    [S.l.] : International Union of Crystallography (IUCr)
    Acta crystallographica 46 (1990), S. 41-46 
    ISSN: 1600-5724
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Notes: A new density modification technique - histogram matching - is being developed with encouraging results. Its application to the known structure of pig 2Zn insulin refines the 6500 1.9 Å MIR phases from a mean error of 60° to one of 46°. With these refined phases as a starting point for phase extension to 1.5 Å, the mean error for the final 13 000 phases is 46°. The original 1.9 Å phases continue to refine during the phase extension to a final mean error of 40°. A comparison is made with similar calculations already published.
    Type of Medium: Electronic Resource
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