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  • 1
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    A Ctf4 trimer couples the CMG helicase to DNA polymerase alpha in the eukaryotic replisome (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-05-09
    Description: Efficient duplication of the genome requires the concerted action of helicase and DNA polymerases at replication forks to avoid stalling of the replication machinery and consequent genomic instability. In eukaryotes, the physical coupling between helicase and DNA polymerases remains poorly understood. Here we define the molecular mechanism by which the yeast Ctf4 protein links the Cdc45-MCM-GINS (CMG) DNA helicase to DNA polymerase alpha (Pol alpha) within the replisome. We use X-ray crystallography and electron microscopy to show that Ctf4 self-associates in a constitutive disk-shaped trimer. Trimerization depends on a beta-propeller domain in the carboxy-terminal half of the protein, which is fused to a helical extension that protrudes from one face of the trimeric disk. Critically, Pol alpha and the CMG helicase share a common mechanism of interaction with Ctf4. We show that the amino-terminal tails of the catalytic subunit of Pol alpha and the Sld5 subunit of GINS contain a conserved Ctf4-binding motif that docks onto the exposed helical extension of a Ctf4 protomer within the trimer. Accordingly, we demonstrate that one Ctf4 trimer can support binding of up to three partner proteins, including the simultaneous association with both Pol alpha and GINS. Our findings indicate that Ctf4 can couple two molecules of Pol alpha to one CMG helicase within the replisome, providing a new model for lagging-strand synthesis in eukaryotes that resembles the emerging model for the simpler replisome of Escherichia coli. The ability of Ctf4 to act as a platform for multivalent interactions illustrates a mechanism for the concurrent recruitment of factors that act together at the fork.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059944/" 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/PMC4059944/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Simon, Aline C -- Zhou, Jin C -- Perera, Rajika L -- van Deursen, Frederick -- Evrin, Cecile -- Ivanova, Marina E -- Kilkenny, Mairi L -- Renault, Ludovic -- Kjaer, Svend -- Matak-Vinkovic, Dijana -- Labib, Karim -- Costa, Alessandro -- Pellegrini, Luca -- 084279/Wellcome Trust/United Kingdom -- Wellcome Trust/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2014 Jun 12;510(7504):293-7. doi: 10.1038/nature13234. Epub 2014 May 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK [2]. ; 1] Clare Hall Laboratories, Cancer Research UK London Research Institute, London EN6 3LD, UK [2]. ; 1] Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK [2] Imperial College, South Kensington, London SW7 2AZ, UK (R.L.P.); Cancer Research UK London Research Institute, London WC2A 3LY, UK (M.E.I.). ; Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK. ; MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. ; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK. ; Clare Hall Laboratories, Cancer Research UK London Research Institute, London EN6 3LD, UK. ; Protein purification, Cancer Research UK London Research Institute, London WC2A 3LY, UK. ; Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805245" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Catalytic Domain ; Conserved Sequence ; Crystallography, X-Ray ; DNA Helicases/chemistry/*metabolism/ultrastructure ; DNA Polymerase I/chemistry/*metabolism/ultrastructure ; *DNA Replication ; DNA-Binding Proteins/*chemistry/*metabolism/ultrastructure ; DNA-Directed DNA Polymerase/*chemistry/*metabolism ; Microscopy, Electron ; Minichromosome Maintenance Proteins/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Multienzyme Complexes/*chemistry/*metabolism ; Nuclear Proteins/chemistry/metabolism ; Protein Binding ; *Protein Multimerization ; Protein Structure, Quaternary ; Protein Subunits/chemistry/metabolism ; Saccharomyces cerevisiae/*chemistry/ultrastructure ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism/ultrastructure
    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
    Electronic Resource
    Electronic Resource
    The efficacy of a transdermal formulation of clonidine in mild to moderate hypertension and its effects on the arterial and venous vasculature of the forearm (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 111-114 
    Details
    ISSN: 1432-1041
    Keywords: clonidine ; hypertension ; transdermal administration ; baroreflex ; arterial compliance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the efficacy of clonidine hydrochloride administered transdermally once a week for 9 to 15 weeks in 12 patients with mild to moderate hypertension. Clonidine reduced both supine and standing blood pressures on average, but only 8 subjects were responders, i.e. had a decrease in supine diastolic blood pressure to below 90 mm Hg or more than 10% from baseline. Supine heart rate was unchanged, but in the responders the orthostatic increase in heart rate was reduced by clonidine from baseline (p〈0.05). Moreover, in all the patients the change in the orthostatic increase in heart rate was correlated with the change in supine diastolic pressure (p〈0.05). Brachial artery blood flow, forearm arterial compliance, vascular resistance, and venous tone were not affected by clonidine. Thus, transdermal clonidine reduced blood pressure, probably by a baroreflex-mediated effect, but did not affect the vasculature of the forearm.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544552
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    Paper (German National Licenses)
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  • 3
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    Structural basis of differential ligand recognition by two classes of bis-(3'-5')-cyclic dimeric guanosine monophosphate-binding riboswitches (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-04-25
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Confined growth of multicellular spheroids [Cell Biology] (2013)
    National Academy of Sciences
    Details
    Publication Date: 2013-09-11
    Description: Deciphering the multifactorial determinants of tumor progression requires standardized high-throughput preparation of 3D in vitro cellular assays. We present a simple microfluidic method based on the encapsulation and growth of cells inside permeable, elastic, hollow microspheres. We show that this approach enables mass production of size-controlled multicellular spheroids. Due to...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    Giant Kiruna-type deposits form by efficient flotation of magmatic magnetite suspensions (2015)
    Geological Society of America (GSA)
    In: Geology
    Details
    Publication Date: 2015-06-23
    Description: Kiruna-type iron oxide–apatite (IOA) deposits are an important source of Fe ore, and two radically different processes are being actively investigated for their origin. One hypothesis invokes direct crystallization of immiscible Fe-rich melt that separated from a parent silicate magma, while the other hypothesis invokes deposition of Fe-oxides from hydrothermal fluids of either magmatic or crustal origin. Here, we present a new model based on Fe and O stable isotopes and trace and major element geochemistry data of magnetite from the ~350 Mt Fe Los Colorados IOA deposit in the Chilean iron belt that merges these divergent processes into a single sequence of events that explains all characteristic features of these curious deposits. We propose that concentration of magnetite takes place by the preferred wetting of magnetite, followed by buoyant segregation of these early-formed magmatic magnetite-bubble pairs, which become a rising magnetite suspension that deposits massive magnetite in regional-scale transcurrent faults. Our data demonstrate an unambiguous magmatic origin, consistent with the namesake IOA analogue in the Kiruna district, Sweden. Further, our model explains the observed coexisting purely magmatic and hydrothermal-magmatic features and allows a genetic connection between Kiruna-type IOA and iron oxide–copper–gold deposits, contributing to a global understanding valuable to exploration efforts.
    Print ISSN: 0091-7613
    Electronic ISSN: 1943-2682
    Topics: Geosciences
    Published by Geological Society of America (GSA)
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  • 6
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    Structural basis of differential ligand recognition by two classes of bis-(3'-5')-cyclic dimeric guanosine monophosphate-binding riboswitches [Biochemistry] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-05-11
    Description: The bis-(3′-5′)-cyclic dimeric guanosine monophosphate (c-di-GMP) signaling pathway regulates biofilm formation, virulence, and other processes in many bacterial species and is critical for their survival. Two classes of c-di-GMP-binding riboswitches have been discovered that bind this second messenger with high affinity and regulate diverse downstream genes, underscoring the importance of RNA receptors in this pathway. We have solved the structure of a c-di-GMP-II riboswitch, which reveals that the ligand is bound as part of a triplex formed with a pseudoknot. The structure also shows that the guanine bases of c-di-GMP are recognized through noncanonical pairings and that the phosphodiester backbone is not contacted by the RNA. Recognition is quite different from that observed in the c-di-GMP-I riboswitch, demonstrating that at least two independent solutions for RNA second messenger binding have evolved. We exploited these differences to design a c-di-GMP analog that selectively binds the c-di-GMP-II aptamer over the c-di-GMP-I RNA. There are several bacterial species that contain both types of riboswitches, and this approach holds promise as an important tool for targeting one riboswitch, and thus one gene, over another in a selective fashion.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 7
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    First Use of High Charge States for Mass Measurements of Short-Lived Nuclides in a Penning Trap (2011)
    American Physical Society (APS)
    Details
    Publication Date: 2011-12-30
    Description: Author(s): S. Ettenauer, M. C. Simon, A. T. Gallant, T. Brunner, U. Chowdhury, V. V. Simon, M. Brodeur, A. Chaudhuri, E. Mané, C. Andreoiu, G. Audi, J. R. Crespo López-Urrutia, P. Delheij, G. Gwinner, A. Lapierre, D. Lunney, M. R. Pearson, R. Ringle, J. Ullrich, and J. Dilling [Phys. Rev. Lett. 107, 272501] Published Thu Dec 29, 2011
    Keywords: Nuclear Physics
    Print ISSN: 0031-9007
    Electronic ISSN: 1079-7114
    Topics: Physics
    Published by American Physical Society (APS)
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  • 8
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    TRACE ELEMENT SIGNATURE OF PYRITE FROM THE LOS COLORADOS IRON OXIDE-APATITE (IOA) DEPOSIT, CHILE: A MISSING LINK BETWEEN ANDEAN IOA AND IRON OXIDE COPPER-GOLD SYSTEMS? (2016)
    Society of Economic Geologists (SEG)
    Details
    Publication Date: 2016-04-09
    Description: Although studies have proposed that iron oxide-apatite (IOA) deposits may represent the deeper roots of some Andean iron oxide copper-gold (IOCG) systems, their genetic links remain obscure and controversial. A key question when considering an integrated genetic model is whether a magmatic-hydrothermal fluid that precipitates massive magnetite will continue transporting significant amounts of dissolved Fe, Cu, and Au after IOA precipitation. Here we provide new geochemical data for accessory pyrite from the Los Colorados IOA deposit in the Chilean iron belt that confirm the role of this sulfide as a relevant repository for economic metals in IOA deposits. Pyrite occurs at Los Colorados as disseminated grains and as veinlets associated with magnetite and actinolite that postdate the main igneous magnetite stage. Electron probe microanalysis (EPMA) data for pyrite show anomalously high Co and Ni concentrations (up ~3.9 and ~1.5 wt %, respectively) and relatively high As contents (100s of ppm to a maximum of ~2,000 ppm). When combined with results from secondary ion mass spectrometry (SIMS) spot analyses, pyrite data show significant amounts of Cu that range from sub-ppm values (~100 ppb) up to 1,000s of ppm, plus nonnegligible concentrations of Zn, Pb, Cd, Sb, Se, and Te (up to ~100 ppm). The highest contents of Cu measured (wt % level) most likely record the presence of Cu-bearing submicron-sized mineral inclusions. Contents of Au and Ag are up to ~1 and 10 ppm, respectively, with maximum concentrations that can rise up to ~800 ppm Au and ~300 ppm Ag due to the presence of submicron-sized inclusions. The high Co/Ni ratios of pyrite from Los Colorados are consistent with a magmatic-hydrothermal origin associated with a greater mafic affinity, compared to pyrite from porphyry Cu deposits. Furthermore, the geochemical signature of Los Colorados pyrite shares important similarities of composition and microtexture with the few published data for pyrite from IOCG deposits (e.g., Ernest Henry, Australia, and Manto Verde, Chile). These findings, combined with recent geochemical and isotopic studies that support an igneous origin for the dike-shaped magnetite orebodies at Los Colorados, point to a magmatic source of mafic to intermediate composition for the contained metals, and support the hypothesis that IOA systems can source Fe-Cu-Au-rich fluids. Based on experimental studies, these IOA-derived fluids may continue transporting significant amounts of metals to form IOCG mineralization at shallower levels in the crust.
    Print ISSN: 0361-0128
    Topics: Geosciences
    Published by Society of Economic Geologists (SEG)
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  • 9
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    TRACE ELEMENT SIGNATURE OF PYRITE FROM THE LOS COLORADOS IRON OXIDE-APATITE (IOA) DEPOSIT, CHILE: A MISSING LINK BETWEEN ANDEAN IOA AND IRON OXIDE COPPER-GOLD SYSTEMS? (2016)
    Society of Economic Geologists (SEG)
    Details
    Publication Date: 2016-04-15
    Description: Although studies have proposed that iron oxide-apatite (IOA) deposits may represent the deeper roots of some Andean iron oxide copper-gold (IOCG) systems, their genetic links remain obscure and controversial. A key question when considering an integrated genetic model is whether a magmatic-hydrothermal fluid that precipitates massive magnetite will continue transporting significant amounts of dissolved Fe, Cu, and Au after IOA precipitation. Here we provide new geochemical data for accessory pyrite from the Los Colorados IOA deposit in the Chilean iron belt that confirm the role of this sulfide as a relevant repository for economic metals in IOA deposits. Pyrite occurs at Los Colorados as disseminated grains and as veinlets associated with magnetite and actinolite that postdate the main igneous magnetite stage. Electron probe microanalysis (EPMA) data for pyrite show anomalously high Co and Ni concentrations (up ~3.9 and ~1.5 wt %, respectively) and relatively high As contents (100s of ppm to a maximum of ~2,000 ppm). When combined with results from secondary ion mass spectrometry (SIMS) spot analyses, pyrite data show significant amounts of Cu that range from sub-ppm values (~100 ppb) up to 1,000s of ppm, plus nonnegligible concentrations of Zn, Pb, Cd, Sb, Se, and Te (up to ~100 ppm). The highest contents of Cu measured (wt % level) most likely record the presence of Cu-bearing submicron-sized mineral inclusions. Contents of Au and Ag are up to ~1 and 10 ppm, respectively, with maximum concentrations that can rise up to ~800 ppm Au and ~300 ppm Ag due to the presence of submicron-sized inclusions. The high Co/Ni ratios of pyrite from Los Colorados are consistent with a magmatic-hydrothermal origin associated with a greater mafic affinity, compared to pyrite from porphyry Cu deposits. Furthermore, the geochemical signature of Los Colorados pyrite shares important similarities of composition and microtexture with the few published data for pyrite from IOCG deposits (e.g., Ernest Henry, Australia, and Manto Verde, Chile). These findings, combined with recent geochemical and isotopic studies that support an igneous origin for the dike-shaped magnetite orebodies at Los Colorados, point to a magmatic source of mafic to intermediate composition for the contained metals, and support the hypothesis that IOA systems can source Fe-Cu-Au-rich fluids. Based on experimental studies, these IOA-derived fluids may continue transporting significant amounts of metals to form IOCG mineralization at shallower levels in the crust.
    Print ISSN: 0361-0128
    Topics: Geosciences
    Published by Society of Economic Geologists (SEG)
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  • 10
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    Iron and Oxygen Isotope Signatures of the Pea Ridge and Pilot Knob Magnetite-Apatite Deposits, Southeast Missouri, USA (2016)
    Society of Economic Geologists (SEG)
    Details
    Publication Date: 2016-11-18
    Description: New O and Fe stable isotope ratios are reported for magnetite samples from high-grade massive magnetite of the Mesoproterozoic Pea Ridge and Pilot Knob magnetite-apatite ore deposits and these results are compared with data for other iron oxide-apatite deposits to shed light on the origin of the southeast Missouri deposits. The 18 O values of magnetite from Pea Ridge ( n = 12) and Pilot Knob ( n = 3) range from 1.0 to 7.0 and 3.3 to 6.7, respectively. The 56 Fe values of magnetite from Pea Ridge ( n = 10) and Pilot Knob ( n = 6) are 0.03 to 0.35 and 0.06 to 0.27, respectively. These 18 O and the 56 Fe values suggest that magnetite crystallized from a silicate melt (typical igneous 56 Fe ranges 0.06–0.49) and grew in equilibrium with a magmatic-hydrothermal aqueous fluid. We propose that the 18 O and 56 Fe data for the Pea Ridge and Pilot Knob magnetite-apatite deposits are consistent with the flotation model recently proposed by Knipping et al. (2015a) , which invokes flotation of a magmatic magnetite-fluid suspension and offers a plausible explanation for the igneous (i.e., up to ~15.9 wt % TiO 2 in magnetite) and hydrothermal features of the deposits.
    Print ISSN: 0361-0128
    Topics: Geosciences
    Published by Society of Economic Geologists (SEG)
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