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Patrick Steinhoff, Melanie Paul, Julian P Schroers, Michael E Tauchert
A series of zero-valent palladium complexes featuring diphosphinometal ligands is reported. The metalloligand in the PMP-type framework (M = LiI, CuI, ZnII) acts as a weak to medium acceptor ligand for palladium. A Pd0→ZnII bond was observed in the solid state and further confirmed by NBO analysis. The heterobimetallic Pd/Zn complex 2-Zn displayed excellent activity in chemoselective CO2 hydrosilylation producing silyl formate (TOF1/2 = 3000 h-1).
December 21, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Lionel Gellon, Simran Kaushal, Jorge Cebrián, Mayurika Lahiri, Sergei M Mirkin, Catherine H Freudenreich
Fork stabilization at DNA impediments is key to maintaining replication fork integrity and preventing chromosome breaks. Mrc1 and Tof1 are two known stabilizers that travel with the replication fork. In addition to a structural role, Mrc1 has a DNA damage checkpoint function. Using a yeast model system, we analyzed the role of Mrc1 and Tof1 at expanded CAG repeats of medium and long lengths, which are known to stall replication forks and cause trinucleotide expansion diseases such as Huntington's disease and myotonic dystrophy...
November 23, 2018: Nucleic Acids Research
Hai-Yan Liu, Tian-Jiao Xia, Ze-Zhang Zhu, Xing Zhao, Yue Qian, Zheng-Liang Ma, Xiao-Ping Gu
Transcranial electric motor evoked potentials (TCeMEPs) play an important role in reducing the risk of iatrogenic paraplegia. TCeMEPs could be obviously suppressed by neuromuscular blockade (NMB). The aims of this study were to examine the effects of NMB on TCeMEPs and to determine an appropriate level of partial neuromuscular blockade (pNMB) for TCeMEPs during surgical correction of idiopathic scoliosis under total intravenous anesthesia (TIVA). All patients were maintained with TIVA. The pNMB levels were classified into five phases: one or two train-of-four (TOF) counts (TOF1 ); three TOF counts, or T4 /T1 (TOFR, T1,4 , first or four twitch height of TOF) ≤ 15% (TOF2 ); TOFR at 16-25% (TOF3 ); TOFR at 26-50% (TOF4 ); and TOFR at 51-75% (TOF5 )...
July 20, 2018: Journal of Clinical Monitoring and Computing
Alison O'Mahony, Markus R John, Hannah Cho, Misato Hashizume, Ernest H Choy
BACKGROUND: Clinical trials have shown combinations of anti-tumor necrosis factor biologicals plus methotrexate (MTX) are more effective treatments for rheumatoid arthritis than biological monotherapies, based, in part, on the assumption that MTX reduces the immunogenicity of biologicals. However, co-treatment with the anti-interleukin-6 receptor-alpha antibody tocilizumab (TCZ) and MTX does not demonstrate the same level of incremental benefit over TCZ monotherapy. Using the human primary cell based BioMAP phenotypic profiling platform, we investigated the impact of TCZ, adalimumab (ADA), and the small molecule drug tofacitinib (TOF), alone and in combination with MTX, on translational biomarkers that could indicate unique pharmacodynamic interactions outside those of reduced immunogenicity...
June 7, 2018: Journal of Translational Medicine
Saima Wani, Neelam Maharshi, Deepash Kothiwal, Lakshmi Mahendrawada, Raju Kalaivani, Shikha Laloraya
Genomic stability is maintained by the concerted actions of numerous protein complexes that participate in chromosomal duplication, repair, and segregation. The Smc5/6 complex is an essential multi-subunit complex crucial for repair of DNA double-strand breaks. Two of its subunits, Nse1 and Nse3, are homologous to the RING-MAGE complexes recently described in human cells. We investigated the contribution of the budding yeast Nse1 RING-domain by isolating a mutant nse1-103 bearing substitutions in conserved Zinc-coordinating residues of the RING-domain that is hypersensitive to genotoxic stress and temperature...
June 2018: Current Genetics
Fabio Puddu, Israel Salguero, Mareike Herzog, Nicola J Geisler, Vincenzo Costanzo, Stephen P Jackson
Camptothecin-induced locking of topoisomerase 1 on DNA generates a physical barrier to replication fork progression and creates topological stress. By allowing replisome rotation, absence of the Tof1/Csm3 complex promotes the conversion of impending topological stress to DNA catenation and causes camptothecin hypersensitivity. Through synthetic viability screening, we discovered that histone H4 K16 deacetylation drives the sensitivity of yeast cells to camptothecin and that inactivation of this pathway by mutating H4 K16 or the genes SIR1-4 suppresses much of the hypersensitivity of tof1∆ strains towards this agent...
June 2017: EMBO Reports
Joseph T P Yeeles, Agnieska Janska, Anne Early, John F X Diffley
The eukaryotic replisome is a molecular machine that coordinates the Cdc45-MCM-GINS (CMG) replicative DNA helicase with DNA polymerases α, δ, and ε and other proteins to copy the leading- and lagging-strand templates at rates between 1 and 2 kb min-1 . We have now reconstituted this sophisticated machine with purified proteins, beginning with regulated CMG assembly and activation. We show that replisome-associated factors Mrc1 and Csm3/Tof1 are crucial for in vivo rates of replisome progression. Additionally, maximal rates only occur when DNA polymerase ε catalyzes leading-strand synthesis together with its processivity factor PCNA...
January 5, 2017: Molecular Cell
Maksym Shyian, Stefano Mattarocci, Benjamin Albert, Lukas Hafner, Aleksandra Lezaja, Michael Costanzo, Charlie Boone, David Shore
The Rif1 protein is a negative regulator of DNA replication initiation in eukaryotes. Here we show that budding yeast Rif1 inhibits DNA replication initiation at the rDNA locus. Absence of Rif1, or disruption of its interaction with PP1/Glc7 phosphatase, leads to more intensive rDNA replication. The effect of Rif1-Glc7 on rDNA replication is similar to that of the Sir2 deacetylase, and the two would appear to act in the same pathway, since the rif1Δ sir2Δ double mutant shows no further increase in rDNA replication...
November 2016: PLoS Genetics
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No abstract text is available yet for this article.
August 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
Deepak Bastia, Pankaj Srivastava, Shamsu Zaman, Malay Choudhury, Bidyut K Mohanty, Julien Bacal, Lance D Langston, Philippe Pasero, Michael E O'Donnell
Several important physiological transactions, including control of replicative life span (RLS), prevention of collision between replication and transcription, and cellular differentiation, require programmed replication fork arrest (PFA). However, a general mechanism of PFA has remained elusive. We previously showed that the Tof1-Csm3 fork protection complex is essential for PFA by antagonizing the Rrm3 helicase that displaces nonhistone protein barriers that impede fork progression. Here we show that mutations of Dbf4-dependent kinase (DDK) of Saccharomyces cerevisiae, but not other DNA replication factors, greatly reduced PFA at replication fork barriers in the spacer regions of the ribosomal DNA array...
June 28, 2016: Proceedings of the National Academy of Sciences of the United States of America
Dongqing Huang, Brian D Piening, Jacob J Kennedy, Chenwei Lin, Corey W Jones-Weinert, Ping Yan, Amanda G Paulovich
In response to replication stress, a phospho-signaling cascade is activated and required for coordination of DNA repair and replication of damaged templates (intra-S-phase checkpoint) . How phospho-signaling coordinates the DNA replication stress response is largely unknown. We employed state-of-the-art liquid chromatography tandem-mass spectrometry (LC-MS/MS) approaches to generate high-coverage and quantitative proteomic and phospho-proteomic profiles during replication stress in yeast, induced by continuous exposure to the DNA alkylating agent methyl methanesulfonate (MMS) ...
May 2016: Genetics
Demis Menolfi, Axel Delamarre, Armelle Lengronne, Philippe Pasero, Dana Branzei
The essential functions of the conserved Smc5/6 complex remain elusive. To uncover its roles in genome maintenance, we established Saccharomyces cerevisiae cell-cycle-regulated alleles that enable restriction of Smc5/6 components to S or G2/M. Unexpectedly, the essential functions of Smc5/6 segregated fully and selectively to G2/M. Genetic screens that became possible with generated alleles identified processes that crucially rely on Smc5/6 specifically in G2/M: metabolism of DNA recombination structures triggered by endogenous replication stress, and replication through natural pausing sites located in late-replicating regions...
December 17, 2015: Molecular Cell
Stephanie A Schalbetter, Sahar Mansoubi, Anna L Chambers, Jessica A Downs, Jonathan Baxter
Faithful genome duplication and inheritance require the complete resolution of all intertwines within the parental DNA duplex. This is achieved by topoisomerase action ahead of the replication fork or by fork rotation and subsequent resolution of the DNA precatenation formed. Although fork rotation predominates at replication termination, in vitro studies have suggested that it also occurs frequently during elongation. However, the factors that influence fork rotation and how rotation and precatenation may influence other replication-associated processes are unknown...
August 18, 2015: Proceedings of the National Academy of Sciences of the United States of America
Juergen Zech, Emma Louise Godfrey, Hisao Masai, Edgar Hartsuiker, Jacob Zeuthen Dalgaard
During S-phase replication forks can stall at specific genetic loci. At some loci, the stalling events depend on the replisome components Schizosaccharomyces pombe Swi1 (Saccharomyces cerevisiae Tof1) and Swi3 (S. cerevisiae Csm3) as well as factors that bind DNA in a site-specific manner. Using a new genetic screen we identified Mrc1 (S. cerevisiae Mrc1/metazoan Claspin) as a replisome component involved in replication stalling. Mrc1 is known to form a sub-complex with Swi1 and Swi3 within the replisome and is required for the intra-S phase checkpoint activation...
2015: PloS One
Sonya Dimitrova Uzunova, Alexander Stefanov Zarkov, Anna Marianova Ivanova, Stoyno Stefanov Stoynov, Marina Nedelcheva Nedelcheva-Veleva
BACKGROUND: The S-phase checkpoint aims to prevent cells from generation of extensive single-stranded DNA that predisposes to genome instability. The S. cerevisiae complex Tof1/Csm3/Mrc1 acts to restrain the replicative MCM helicase when DNA synthesis is prohibited. Keeping the replication machinery intact allows restart of the replication fork when the block is relieved. Although the subunits of the Tof1/Csm3/Mrc1 complex are well studied, the impact of every single subunit on the triple complex formation and function needs to be established...
2014: Cell Division
Hajime Murakami, Scott Keeney
It has been long appreciated that, during meiosis, DNA replication is coordinated with the subsequent formation of the double-strand breaks (DSBs) that initiate recombination, but a mechanistic understanding of this process was elusive. We now show that, in yeast, the replisome-associated components Tof1 and Csm3 physically associate with the Dbf4-dependent Cdc7 kinase (DDK) and recruit it to the replisome, where it phosphorylates the DSB-promoting factor Mer2 in the wake of the replication fork, synchronizing replication with an early prerequisite for DSB formation...
August 14, 2014: Cell
Nicolai B Larsen, Ehud Sass, Catherine Suski, Hocine W Mankouri, Ian D Hickson
Replication fork (RF) pausing occurs at both 'programmed' sites and non-physiological barriers (for example, DNA adducts). Programmed RF pausing is required for site-specific DNA replication termination in Escherichia coli, and this process requires the binding of the polar terminator protein, Tus, to specific DNA sequences called Ter. Here, we demonstrate that Tus-Ter modules also induce polar RF pausing when engineered into the Saccharomyces cerevisiae genome. This heterologous RF barrier is distinct from a number of previously characterized, protein-mediated, RF pause sites in yeast, as it is neither Tof1-dependent nor counteracted by the Rrm3 helicase...
2014: Nature Communications
Karsten H Wrede, Philipp Dammann, Christoph Mönninghoff, Sören Johst, Stefan Maderwald, I Erol Sandalcioglu, Oliver Müller, Neriman Özkan, Mark E Ladd, Michael Forsting, Marc U Schlamann, Ulrich Sure, Lale Umutlu
PURPOSE: To prospectively evaluate 7 Tesla time-of-flight (TOF) magnetic resonance angiography (MRA) in comparison to 1.5 Tesla TOF MRA and 7 Tesla non-contrast enhanced magnetization-prepared rapid acquisition gradient-echo (MPRAGE) for delineation of unruptured intracranial aneurysms (UIA). MATERIAL AND METHODS: Sixteen neurosurgical patients (male n = 5, female n = 11) with single or multiple UIA were enrolled in this trial. All patients were accordingly examined at 7 Tesla and 1...
2014: PloS One
Vanessa Borges, Duncan J Smith, Iestyn Whitehouse, Frank Uhlmann
Cohesion between sister chromatids, mediated by the chromosomal cohesin complex, is a prerequisite for their alignment on the spindle apparatus and segregation in mitosis. Budding yeast cohesin first associates with chromosomes in G1. Then, during DNA replication in S-phase, the replication fork-associated acetyltransferase Eco1 acetylates the cohesin subunit Smc3 to make cohesin's DNA binding resistant to destabilization by the Wapl protein. Whether stabilization of cohesin molecules that happen to link sister chromatids is sufficient to build sister chromatid cohesion, or whether additional reactions are required to establish these links, is not known...
March 2013: Chromosoma
Andrea R LeClere, John K Yang, David T Kirkpatrick
Double-stranded break (DSB) repair during meiotic recombination in yeast Saccharomyces cerevisiae leads to the formation of heteroduplex DNA, a hybrid DNA molecule composed of single strands from two homologous chromosomes. Differences in sequence between the strands within heteroduplex DNA generate mismatches or large unpaired loops that are substrates for repair. At least two pathways function to repair large loops that form within heteroduplex DNA: the RAD1-dependent large loop repair (LLR) pathway and another as yet uncharacterized RAD1-independent LLR pathway...
January 2013: Fungal Genetics and Biology: FG & B
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