Influence of the live cell DNA marker DRAQ5 on chromatin-associated processes

In the last decade, live cell fluorescence microscopy experiments have revolutionized cellular and molecular biology, enabling the localization of proteins within cellular compartments to be analysed and to determine kinetic parameters of enzymatic reactions in living nuclei to be measured. Recently, in vivo DNA labelling by DNA-stains such as DRAQ5, has provided the opportunity to measure kinetic reactions of GFP-fused proteins in targeted areas of the nucleus with different chromatin compaction levels. To verify the suitability of combining DRAQ5-staining with protein dynamic measurements, we have tested the cellular consequences of DRAQ5 DNA intercalation. We show that DRAQ5 intercalation rapidly modifies both the localization and the mobility properties of several DNA-binding proteins such as histones, DNA repair, replication and transcription factors, by stimulating a release of these proteins from their substrate. Most importantly, the effect of DRAQ5 on the mobility of essential cellular enzymes results in a potent inhibition of the corresponding cellular functions. From these observations, we suggest that great caution must be used when interpreting live cell data obtained using DRAQ5

Determinants of maternal pregnancy one-carbon metabolism and newborn human DNA methylation profiles

Maternal one-carbon (1-C) metabolism provides methylgroups for fetal development and programing by DNA methylation as one of the underlying epigenetic mechanisms. We aimed to investigate maternal 1-C biomarkers, folic acid supplement use, and MTHFR C677T genotype as determinants of 1-C metabolism in early pregnancy in association with newborn DNA methylation levels of fetal growth and neurodevelopment candidate genes. The participants were 463 mother-child pairs of Dutch national origin from a large populationbased birth cohort in Rotterdam, The Netherlands. In early pregnancy (median 13.0 weeks, 90% range 10.4-17.1), we assessed the maternal folate and homocysteine blood concentrations, folic acid supplement use, and the MTHFR C677T genotype in mothers and newborns. In newborns, DNA methylation was measured in umbilical cord blood white blood cells at 11 regions of the seven genes: NR3C1, DRD4, 5-HTT, IGF2DMR, H19, KCNQ1OT1, and MTHFR. The associations between the 1-C determinants and DNA methylation were examined using linear mixed models. An association was observed between maternal folate deficiency and lower newborn DNA methylation, which attenuated after adjustment for potential confounders. The maternal MTHFR TT genotype was significantly associated with lower DNA methylation. However, maternal homocysteine and folate concentrations, folic acid supplement use, and the MTHFR genotype in the newborn were not associated with newborn DNA methylation. The maternal MTHFR C677T genotype, as a determinant of folate status and 1-C metabolism, is associated with variations in the epigenome of a selection of genes in newborns. Research on the implications of these variations in methylation on gene expression and health is recommended

Prenatal parental tobacco smoking, gene specific DNA methylation, and newborns size: the Generation R study

Background: Deleterious effects of prenatal tobacco smoking on fetal growth and newborn weight are well-established. One of the proposed mechanisms underlying this relationship is alterations in epigenetic programming. We selected 506 newborns from a population-based prospective birth cohort in the Netherlands. Prenatal parental tobacco smoking was assessed using self-reporting questionnaires. Information on birth outcomes was obtained from medical records. The deoxyribonucleic acid (DNA) methylation of the growth genes IGF2DMR and H19 was measured in newborn umbilical cord white blood cells. Associations were assessed between parental tobacco smoking and DNA methylation using linear mixed models and adjusted for potential confounders. Results: The DNA methylation levels of IGF2DMR and H19 in the non-smoking group were median (90 % range), 54.0 % (44.6–62.0), and 30.0 % (25.5–34.0), in the first trimester only smoking group 52.2 % (44.5–61.1) and 30.8 % (27.1–34.1), and in the continued smoking group 51.6 % (43.9–61.3) and 30.2 % (23.7–34.8), respectively. Continued prenatal maternal smoking was inversely associated with IGF2DMR methylation (β = −1.03, 95 % CI −1.76; −0.30) in a dose-dependent manner (P-trend = 0.030). This association seemed to be slightly more profound among newborn girls (β = −1.38, 95 % CI −2.63; −0.14) than boys (β = −0.72, 95 % CI −1.68; 0.24). H19 methylation was also inversely associated continued smoking <5 cigarettes/day (β = −0.96, 95 % CI −1.78; −0.14). Moreover, the association between maternal smoking and newborns small for gestational age seems to be partially explained by IGF2DMR methylation (β = −0.095, 95 % CI −0.249; −0.018). Among non-smoking mothers, paternal tobacco smoking was not associated with IGF2DMR or H19 methylation. Conclusions: Maternal smoking is inversely associated with IGF2DMR methylation in newborns, which can be one of the underlying mechanisms through which smoking affects fetal growth

Scales, Implicatures, and in fact, if not, and let alone Constructions.

太田朗先生傘寿記念論文

Future mmVLBI Research with ALMA: A European vision

Very long baseline interferometry at millimetre/submillimetre wavelengths (mmVLBI) offers the highest achievable spatial resolution at any wavelength in astronomy. The anticipated inclusion of ALMA as a phased array into a global VLBI network will bring unprecedented sensitivity and a transformational leap in capabilities for mmVLBI. Building on years of pioneering efforts in the US and Europe the ongoing ALMA Phasing Project (APP), a US-led international collaboration with MPIfR-led European contributions, is expected to deliver a beamformer and VLBI capability to ALMA by the end of 2014 (APP: Fish et al. 2013, arXiv:1309.3519). This report focuses on the future use of mmVLBI by the international users community from a European viewpoint. Firstly, it highlights the intense science interest in Europe in future mmVLBI observations as compiled from the responses to a general call to the European community for future research projects. A wide range of research is presented that includes, amongst others: - Imaging the event horizon of the black hole at the centre of the Galaxy - Testing the theory of General Relativity an/or searching for alternative theories - Studying the origin of AGN jets and jet formation - Cosmological evolution of galaxies and BHs, AGN feedback - Masers in the Milky Way (in stars and star-forming regions) - Extragalactic emission lines and astro-chemistry - Redshifted absorption lines in distant galaxies and study of the ISM and circumnuclear gas - Pulsars, neutron stars, X-ray binaries - Testing cosmology - Testing fundamental physical constantsComment: Replaced figures 2 and 3: corrected position SRT. Corrected minor typo in 5.

Knotty inflation and the dimensionality of spacetime

We suggest a structure for the vacuum comprised of a network of tightly knotted/linked flux tubes formed in a QCD-like cosmological phase transition and show that such a network can drive cosmological inflation. As the network can be topologically stable only in three space dimensions, this scenario provides a dynamical explanation for the existence of exactly three large spatial dimensions in our Universe

Identification et caractérisation de nouveaux gènes impliqués dans la réponse cellulaire aux inhibiteurs d'ADN topoisomérases

Les inhibiteurs d'ADN topoisomérases sont des agents anti-cancéreux couramment utilisés en chimiothérapie. La réponse cellulaire à ces drogues est étroitement liée à l'équilibre qui existe entre les gènes de résistance, et les gènes de sensibilité. En utilisant la méthode de sélection d'éléments génétiques suppresseurs nous avons caractérisé deux gènes impliqués dans la sensibilité aux inhibiteurs de topoisomérases. L'un code une nouvelle protéine arginine méthyl transférase (PRMT7) et altère la réponse cellulaire aux inhibiteurs de topoisomérases I par un mécanisme intervenant en aval de l'interaction de la drogue avec sa cible. L'autre est un nouveau gène que nous avons appelé P40. Ce gène est impliqué dans la sensibilité aux inhibiteurs de topoisomérases II. Ce gène code une nouvelle protéine cytoplasmique qui peut moduler la réponse cellulaire aux agents endommageant l'ADN en participant à des complexes multi-protéiques impliquant l'alpha et la beta-caténine.DNA topoisomerase inhibitors are anticancer agents widely used in chemotherapy. Their cytotoxic activity depends on the balance between the genes of sensitivity and the genes of resistance. Using a selection of genetic suppressor elements, we characterized genes that can modulate the cellular sensitivity to topoisomerase inhibitors. One is coding for a new protein arginin methyl transferase (PRMT7) which repression confers hypersensitivity to topo1 inhibitors without altering the enzyme activity. The other is a new gene, that we called P40, and is involved in the sensitivity to topo2 inhibitors. Its product is a new cytoplasmic protein that could modulate cell response to DNA damaging agents by its participation to multi-protein complexes involving alpha and beta-catenins.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Faraday Effect in Stacks of Aromatic Molecules

© 2017 American Chemical Society. The effects of stacking aromatic units on the Verdet constant are analyzed by employing quantum chemistry calculations and are compared to the effects of oligomerization. Building stacked oligomers leads to enhanced Verdet constants, but still smaller than in the corresponding linear oligomers. Further enhancements appear when going from simple to fused-ring polyaromatic compounds.status: publishe