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  • 1
    Publication Date: 2014-10-10
    Description: Non-homologous end-joining (NHEJ) and homologous recombination (HR) are the two prominent pathways responsible for the repair of DNA double-strand breaks (DSBs). NHEJ is not restricted to a cell-cycle stage, whereas HR is active primarily in the S/G2 phases suggesting there are cell cycle-specific mechanisms that play a role in the choice between NHEJ and HR. Here we show NHEJ is attenuated in S phase via modulation of the autophosphorylation status of the NHEJ factor DNA-PKcs at serine 2056 by the pro-HR factor BRCA1. BRCA1 interacts with DNA-PKcs in a cell cycle-regulated manner and this interaction is mediated by the tandem BRCT domain of BRCA1, but surprisingly in a phospho-independent manner. BRCA1 attenuates DNA-PKcs autophosphorylation via directly blocking the ability of DNA-PKcs to autophosphorylate. Subsequently, blocking autophosphorylation of DNA-PKcs at the serine 2056 phosphorylation cluster promotes HR-required DNA end processing and loading of HR factors to DSBs and is a possible mechanism by which BRCA1 promotes HR.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 2
    Publication Date: 2012-07-28
    Description: Shear failure is the dominant mode of earthquake-causing rock failure along faults. High fluid pressure can also potentially induce rock failure by opening cavities and cracks, but an active example of this process has not been directly observed in a fault zone. Using borehole array data collected along the low-stress Chelungpu fault zone, Taiwan, we observed several small seismic events (I-type events) in a fluid-rich permeable zone directly below the impermeable slip zone of the 1999 moment magnitude 7.6 Chi-Chi earthquake. Modeling of the events suggests an isotropic, nonshear source mechanism likely associated with natural hydraulic fractures. These seismic events may be associated with the formation of veins and other fluid features often observed in rocks surrounding fault zones and may be similar to artificially induced hydraulic fracturing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ma, Kuo-Fong -- Lin, Yen-Yu -- Lee, Shiann-Jong -- Mori, Jim -- Brodsky, Emily E -- New York, N.Y. -- Science. 2012 Jul 27;337(6093):459-63. doi: 10.1126/science.1222119.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Earth Sciences, and Institute of Geophysics, National Central University, Taiwan, Republic of China. fong@ncu.edu.tw〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22837526" 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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  • 3
    Publication Date: 2013-02-09
    Description: The 2011 moment magnitude 9.0 Tohoku-Oki earthquake produced a maximum coseismic slip of more than 50 meters near the Japan trench, which could result in a completely reduced stress state in the region. We tested this hypothesis by determining the in situ stress state of the frontal prism from boreholes drilled by the Integrated Ocean Drilling Program approximately 1 year after the earthquake and by inferring the pre-earthquake stress state. On the basis of the horizontal stress orientations and magnitudes estimated from borehole breakouts and the increase in coseismic displacement during propagation of the rupture to the trench axis, in situ horizontal stress decreased during the earthquake. The stress change suggests an active slip of the frontal plate interface, which is consistent with coseismic fault weakening and a nearly total stress drop.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, Weiren -- Conin, Marianne -- Moore, J Casey -- Chester, Frederick M -- Nakamura, Yasuyuki -- Mori, James J -- Anderson, Louise -- Brodsky, Emily E -- Eguchi, Nobuhisa -- Expedition 343 Scientists -- New York, N.Y. -- Science. 2013 Feb 8;339(6120):687-90. doi: 10.1126/science.1229379.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Kochi Institute for Core Sample Research, Japan Agency for Marine-Earth Science and Technology, Nankoku, Japan. lin@jamstec.go.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23393262" 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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  • 4
    Publication Date: 2013-12-07
    Description: The frictional resistance on a fault during slip controls earthquake dynamics. Friction dissipates heat during an earthquake; therefore, the fault temperature after an earthquake provides insight into the level of friction. The Japan Trench Fast Drilling Project (Integrated Ocean Drilling Program Expedition 343 and 343T) installed a borehole temperature observatory 16 months after the March 2011 moment magnitude 9.0 Tohoku-Oki earthquake across the fault where slip was ~50 meters near the trench. After 9 months of operation, the complete sensor string was recovered. A 0.31 degrees C temperature anomaly at the plate boundary fault corresponds to 27 megajoules per square meter of dissipated energy during the earthquake. The resulting apparent friction coefficient of 0.08 is considerably smaller than static values for most rocks.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fulton, P M -- Brodsky, E E -- Kano, Y -- Mori, J -- Chester, F -- Ishikawa, T -- Harris, R N -- Lin, W -- Eguchi, N -- Toczko, S -- Expedition 343, 343T, and KR13-08 Scientists -- New York, N.Y. -- Science. 2013 Dec 6;342(6163):1214-7. doi: 10.1126/science.1243641.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Earth and Planetary Sciences, University of California, Santa Cruz, CA, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24311684" 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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  • 5
    Publication Date: 2013-07-03
    Description: Permeability controls fluid flow in fault zones and is a proxy for rock damage after an earthquake. We used the tidal response of water level in a deep borehole to track permeability for 18 months in the damage zone of the causative fault of the 2008 moment magnitude 7.9 Wenchuan earthquake. The unusually high measured hydraulic diffusivity of 2.4 x 10(-2) square meters per second implies a major role for water circulation in the fault zone. For most of the observation period, the permeability decreased rapidly as the fault healed. The trend was interrupted by abrupt permeability increases attributable to shaking from remote earthquakes. These direct measurements of the fault zone reveal a process of punctuated recovery as healing and damage interact in the aftermath of a major earthquake.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xue, Lian -- Li, Hai-Bing -- Brodsky, Emily E -- Xu, Zhi-Qing -- Kano, Yasuyuki -- Wang, Huan -- Mori, James J -- Si, Jia-Liang -- Pei, Jun-Ling -- Zhang, Wei -- Yang, Guang -- Sun, Zhi-Ming -- Huang, Yao -- New York, N.Y. -- Science. 2013 Jun 28;340(6140):1555-9. doi: 10.1126/science.1237237.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Earth and Planetary Sciences, University of California, Santa Cruz, CA 95064, USA. lxue3@ucsc.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23812711" target="_blank"〉PubMed〈/a〉
    Keywords: China ; *Disasters ; *Earthquakes ; *Groundwater
    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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  • 6
    Publication Date: 2013-12-07
    Description: Large coseismic slip was thought to be unlikely to occur on the shallow portions of plate-boundary thrusts, but the 11 March 2011 Tohoku-Oki earthquake [moment magnitude (Mw) = 9.0] produced huge displacements of ~50 meters near the Japan Trench with a resultant devastating tsunami. To investigate the mechanisms of the very large fault movements, we conducted high-velocity (1.3 meters per second) friction experiments on samples retrieved from the plate-boundary thrust associated with the earthquake. The results show a small stress drop with very low peak and steady-state shear stress. The very low shear stress can be attributed to the abundance of weak clay (smectite) and thermal pressurization effects, which can facilitate fault slip. This behavior provides an explanation for the huge shallow slip that occurred during the earthquake.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ujiie, Kohtaro -- Tanaka, Hanae -- Saito, Tsubasa -- Tsutsumi, Akito -- Mori, James J -- Kameda, Jun -- Brodsky, Emily E -- Chester, Frederick M -- Eguchi, Nobuhisa -- Toczko, Sean -- Expedition 343 and 343T Scientists -- New York, N.Y. -- Science. 2013 Dec 6;342(6163):1211-4. doi: 10.1126/science.1243485.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24311683" 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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  • 7
    Publication Date: 2013-12-07
    Description: The mechanics of great subduction earthquakes are influenced by the frictional properties, structure, and composition of the plate-boundary fault. We present observations of the structure and composition of the shallow source fault of the 2011 Tohoku-Oki earthquake and tsunami from boreholes drilled by the Integrated Ocean Drilling Program Expedition 343 and 343T. Logging-while-drilling and core-sample observations show a single major plate-boundary fault accommodated the large slip of the Tohoku-Oki earthquake rupture, as well as nearly all the cumulative interplate motion at the drill site. The localization of deformation onto a limited thickness (less than 5 meters) of pelagic clay is the defining characteristic of the shallow earthquake fault, suggesting that the pelagic clay may be a regionally important control on tsunamigenic earthquakes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chester, Frederick M -- Rowe, Christie -- Ujiie, Kohtaro -- Kirkpatrick, James -- Regalla, Christine -- Remitti, Francesca -- Moore, J Casey -- Toy, Virginia -- Wolfson-Schwehr, Monica -- Bose, Santanu -- Kameda, Jun -- Mori, James J -- Brodsky, Emily E -- Eguchi, Nobuhisa -- Toczko, Sean -- Expedition 343 and 343T Scientists -- New York, N.Y. -- Science. 2013 Dec 6;342(6163):1208-11. doi: 10.1126/science.1243719.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Tectonophysics, Department of Geology and Geophysics, Texas A&M University, College Station, TX 77843, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24311682" 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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  • 8
    Publication Date: 2013-05-21
    Description: Huntington's disease (HD) is a fatal neurodegenerative disease characterized by abnormal motor coordination, cognitive decline and psychiatric disorders. This disease is caused by an expanded CAG trinucleotide repeat in the gene encoding the protein huntingtin. Reduced levels of brain-derived neurotrophic factor (BDNF) in the brain, which results from transcriptional inhibition and axonal transport deficits mediated by mutant huntingtin, have been suggested as critical factors underlying selective neurodegeneration in both HD patients and HD mouse models. BDNF activates its high-affinity receptor TrkB and promotes neuronal survival; restoring BDNF signaling is thus of particular therapeutic interest. In the present study, we evaluated the ability of a small-molecule TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and its synthetic derivative 4'-dimethylamino-7,8- dihydroxyflavone (4'-DMA-7,8-DHF) to protect neurons in the well-characterized N171-82Q HD mouse model. We found that chronic administration of 7, 8-DHF (5 mg/kg) or 4'-DMA-7,8-DHF (1 mg/kg) significantly improved motor deficits, ameliorated brain atrophy and extended survival in these N171-82Q HD mice. Moreover, 4'-DMA-7,8-DHF preserved DARPP32 levels in the striatum and rescued mutant huntingtin-induced impairment of neurogenesis in the N171-82Q HD mice. These data highlight consideration of TrkB as a therapeutic target in HD and suggest that small-molecule TrkB agonists that penetrate the brain have high potential to be further tested in clinical trials of HD.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 9
    Publication Date: 2013-10-23
    Description: Mincle [macrophage inducible Ca2+-dependent (C-type) lectin; CLEC4E] and MCL (macrophage C-type lectin; CLEC4D) are receptors for the cord factor TDM (trehalose-6,6′-dimycolate), a unique glycolipid of mycobacterial cell-surface components, and activate immune cells to confer adjuvant activity. Although it is known that receptor–TDM interactions require both sugar and lipid moieties of...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 10
    Publication Date: 2012-02-28
    Description: Synthetic scaffolds that permit spatial and temporal organization of enzymes in living cells are a promising post-translational strategy for controlling the flow of information in both metabolic and signaling pathways. Here, we describe the use of plasmid DNA as a stable, robust and configurable scaffold for arranging biosynthetic enzymes in the cytoplasm of Escherichia coli . This involved conversion of individual enzymes into custom DNA-binding proteins by genetic fusion to zinc-finger domains that specifically bind unique DNA sequences. When expressed in cells that carried a rationally designed DNA scaffold comprising corresponding zinc finger binding sites, the titers of diverse metabolic products, including resveratrol, 1,2-propanediol and mevalonate were increased as a function of the scaffold architecture. These results highlight the utility of DNA scaffolds for assembling biosynthetic enzymes into functional metabolic structures. Beyond metabolism, we anticipate that DNA scaffolds may be useful in sequestering different types of enzymes for specifying the output of biological signaling pathways or for coordinating other assembly-line processes such as protein folding, degradation and post-translational modifications.
    Keywords: Synthetic Biology and Assembly Cloning
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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