Non-homologous end-joining pathway associated with occurrence of myocardial infarction: gene set analysis of genome-wide association study data

<p>Purpose: DNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease (CVD). The hypothesis is that DNA damage accumulating with age may induce cell death, which promotes formation of unstable plaques. Defects in DNA repair mechanisms may therefore increase the risk of CVD events. We examined whether the joints effect of common genetic variants in 5 DNA repair pathways may influence the risk of CVD events.</p> <p>Methods: The PLINK set-based test was used to examine the association to myocardial infarction (MI) of the DNA repair pathway in GWAS data of 866 subjects of the GENetic DEterminants of Restenosis (GENDER) study and 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. We included the main DNA repair pathways (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end-joining (NHEJ)) in the analysis.</p> <p>Results: The NHEJ pathway was associated with the occurrence of MI in both GENDER (P = 0.0083) and PROSPER (P = 0.014). This association was mainly driven by genetic variation in the MRE11A gene (PGENDER = 0.0001 and PPROSPER = 0.002). The homologous recombination pathway was associated with MI in GENDER only (P = 0.011), for the other pathways no associations were observed.</p> <p>Conclusion: This is the first study analyzing the joint effect of common genetic variation in DNA repair pathways and the risk of CVD events, demonstrating an association between the NHEJ pathway and MI in 2 different cohorts.</p&gt

Pydna: a simulation and documentation tool for DNA assembly strategies using python

Background: Recent advances in synthetic biology have provided tools to efficiently construct complex DNA molecules which are an important part of many molecular biology and biotechnology projects. The planning of such constructs has traditionally been done manually using a DNA sequence editor which becomes error-prone as scale and complexity of the construction increase. A human-readable formal description of cloning and assembly strategies, which also allows for automatic computer simulation and verification, would therefore be a valuable tool.Results: We have developed pydna, an extensible, free and open source Python library for simulating basic molecular biology DNA unit operations such as restriction digestion, ligation, PCR, primer design, Gibson assembly and homologous recombination. A cloning strategy expressed as a pydna script provides a description that is complete, unambiguous and stable. Execution of the script automatically yields the sequence of the final molecule(s) and that of any intermediate constructs. Pydna has been designed to be understandable for biologists with limited programming skills by providing interfaces that are semantically similar to the description of molecular biology unit operations found in literature.Conclusions: Pydna simplifies both the planning and sharing of cloning strategies and is especially useful for complex or combinatorial DNA molecule construction. An important difference compared to existing tools with similar goals is the use of Python instead of a specifically constructed language, providing a simulation environment that is more flexible and extensible by the user.Thanks to Dr. Aric Hagberg Los Alamos National Laboratory, U.S.A and Sergio Simoes, Universidade de Sao Paulo, Brasil for help with NetworkX and graph theory in general. Thanks to Henrik Bengtsson, Dept of Epidemiology & Biostatistics, University of California San Francisco, U.S.A. for critical reading of the manuscript. Thanks to the 2013 Bioinformatics 6605 N4 students A. Coelho, A. Faria, A. Neves D. Yelshyna and E. Costa for testing. This work was supported by the Fundacao para a Ciencia e Tecnologia (FCT) [PTDC/AAC-AMB/120940/2010, EXPL/BBB-BIO/1772/2013]; and the FEDER POFC-COMPETE [PEst-C/BIA/UI4050/2011]. FA and GR were supported by FCT fellowships [SFRH/BD/80934/2011 and SFRH/BD/42565/2007, respectively].info:eu-repo/semantics/publishedVersio

Combination chemotherapy for choroidal melanoma: ex vivo sensitivity to treosulfan with gemcitabine or Cytosine arabinoside

Treatment of choroidal melanoma by chemotherapy is usually unsuccessful, with response rates of less than 1% reported for dacarbazine (DTIC)-containing regimens which show 20% or more response rates in skin melanoma. Recently, we reported the activity of several cytotoxic agents against primary choroidal melanoma in an ATP-based tumour chemosensitivity assay (ATP-TCA). In this study, we have used the same method to examine the sensitivity of choroidal melanoma to combinations suggested by our earlier study. Tumour material from 36 enucleated eyes was tested against a battery of single agents and combinations which showed some activity in the previous study. The combination of treosulfan with gemcitabine or cytosine arabinoside showed consistent activity in 70% and 86% of cases, respectively. Paclitaxel was also active, particularly in combination with treosulfan (47%) or mitoxantrone (33%). Addition of paclitaxel to the combination of treosulfan + cytosine analogue added little increased sensitivity. For treosulfan + cytosine arabinoside, further sequence and timing experiments showed that simultaneous administration gave the greatest suppression, with minor loss of inhibition if the cytosine analogue was given 24 h after the treosulfan. Administration of cytosine analogue 24 h before treosulfan produced considerably less inhibition at any concentration. While we have so far been unable to study metastatic tumour from choroidal melanoma patients, the combination of treosulfan with gemcitabine or cytosine arabinoside shows activity ex vivo against primary tumour tissue. Clinical trials are in progress. © 1999 Cancer Research Campaig

Measurement of the (90,91,92,93,94,96)Zr(n,gamma) and (139)La(n,gamma) cross sections at n_TOF

Open AccessNeutron capture cross sections of Zr and La isotopes have important implications in the field of nuclear astrophysics as well as in the nuclear technology. In particular the Zr isotopes play a key role for the determination of the neutron density in the He burning zone of the Red Giant star, while the (139)La is important to monitor the s-process abundances from Ba up to Ph. Zr is also largely used as structural materials of traditional and advanced nuclear reactors. The nuclear resonance parameters and the cross section of (90,91,92,93,94,96)Zr and (139)La have been measured at the n_TOF facility at CERN. Based on these data the capture resonance strength and the Maxwellian-averaged cross section were calculated

Measurements of high-energy neutron-induced fission of (nat)Pb and (209)Bi

This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial License 3.0, which permits unrestricted use, distribution, and reproduction in any noncommercial medium, provided the original work is properly citedThe CERN Neutron Time-Of-Flight (n_TOF) facility is well suited to measure low cross sections as those of neutron-induced fission in subactinides. The cross section ratios of (nat)Pb and (209)Bi relative to (235)U and (238)U were measured using PPAC detectors and a fragment coincidence method that allows us to identify the fission events. The present experiment provides first results for neutron-induced fission up to 1 GeV. Good agreement is found with previous experimental data below 200 MeV. The comparison with proton-induced fission indicates that the limiting regime where neutron-induced and proton-induced fission reach equal cross sections is close to 1 GeV

Measurement of the neutron capture cross section of the s-only isotope 204Pb from 1 eV to 440 keV

The neutron capture cross section of 204Pb has been measured at the CERN n_TOF installation with high resolution in the energy range from 1 eV to 440 keV. An R-matrix analysis of the resolved resonance region, between 1 eV and 100 keV, was carried out using the SAMMY code. In the interval between 100 keV and 440 keV we report the average capture cross section. The background in the entire neutron energy range could be reliably determined from the measurement of a 208Pb sample. Other systematic effects in this measurement could be investigated and precisely corrected by means of detailed Monte Carlo simulations. We obtain a Maxwellian average capture cross section for 204Pb at kT=30 keV of 79(3) mb, in agreement with previous experiments. However our cross section at kT=5 keV is about 35% larger than the values reported so far. The implications of the new cross section for the s-process abundance contributions in the Pb/Bi region are discussed.Comment: 8 pages, 3 figures, article submitted to Phys. Rev.

New measurement of neutron capture resonances of 209Bi

The neutron capture cross section of Bi209 has been measured at the CERN n TOF facility by employing the pulse-height-weighting technique. Improvements over previous measurements are mainly because of an optimized detection system, which led to a practically negligible neutron sensitivity. Additional experimental sources of systematic error, such as the electronic threshold in the detectors, summing of gamma-rays, internal electron conversion, and the isomeric state in bismuth, have been taken into account. Gamma-ray absorption effects inside the sample have been corrected by employing a nonpolynomial weighting function. Because Bi209 is the last stable isotope in the reaction path of the stellar s-process, the Maxwellian averaged capture cross section is important for the recycling of the reaction flow by alpha-decays. In the relevant stellar range of thermal energies between kT=5 and 8 keV our new capture rate is about 16% higher than the presently accepted value used for nucleosynthesis calculations. At this low temperature an important part of the heavy Pb-Bi isotopes are supposed to be synthesized by the s-process in the He shells of low mass, thermally pulsing asymptotic giant branch stars. With the improved set of cross sections we obtain an s-process fraction of 19(3)% of the solar bismuth abundance, resulting in an r-process residual of 81(3)%. The present (n,gamma) cross-section measurement is also of relevance for the design of accelerator driven systems based on a liquid metal Pb/Bi spallation target.Comment: 10 pages, 5figures, recently published in Phys. Rev.

Resonance capture cross section of 207Pb

The radiative neutron capture cross section of 207Pb has been measured at the CERN neutron time of flight installation n_TOF using the pulse height weighting technique in the resolved energy region. The measurement has been performed with an optimized setup of two C6D6 scintillation detectors, which allowed us to reduce scattered neutron backgrounds down to a negligible level. Resonance parameters and radiative kernels have been determined for 16 resonances by means of an R-matrix analysis in the neutron energy range from 3 keV to 320 keV. Good agreement with previous measurements was found at low neutron energies, whereas substantial discrepancies appear beyond 45 keV. With the present results, we obtain an s-process contribution of 77(8)% to the solar abundance of 207Pb. This corresponds to an r-process component of 23(8)%, which is important for deriving the U/Th ages of metal poor halo stars.Comment: 7 pages, 3 figures, to be published in Phys. Rev.

High-accuracy determination of the U 238 / U 235 fission cross section ratio up to ≈1 GeV at n-TOF at CERN

Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOIThe U238 to U235 fission cross section ratio has been determined at n-TOF up to ≈1 GeV, with two different detection systems, in different geometrical configurations. A total of four datasets has been collected and compared. They are all consistent to each other within the relative systematic uncertainty of 3-4%. The data collected at n-TOF have been suitably combined to yield a unique fission cross section ratio as a function of neutron energy. The result confirms current evaluations up to 200 MeV. Good agreement is also observed with theoretical calculations based on the INCL++/Gemini++ combination up to the highest measured energy. The n-TOF results may help solve a long-standing discrepancy between the two most important experimental datasets available so far above 20 MeV, while extending the neutron energy range for the first time up to ≈1 GeV.Peer reviewedFinal Published versio