In vivo imaging of pyrrole-imidazole polyamides with positron emission tomography

The biodistribution profiles in mice of two pyrrole-imidazole polyamides were determined by PET. Pyrrole-imidazole polyamides are a class of small molecules that can be programmed to bind a broad repertoire of DNA sequences, disrupt transcription factor-DNA interfaces, and modulate gene expression pathways in cell culture experiments. The 18F-radiolabeled polyamides were prepared by oxime ligation between 4-[18F]-fluorobenzaldehyde and a hydroxylamine moiety at the polyamide C terminus. Small animal PET imaging of radiolabeled polyamides administered to mice revealed distinct differences in the biodistribution of a 5-ring β-linked polyamide versus an 8-ring hairpin, which exhibited better overall bioavailability. In vivo imaging of pyrrole-imidazole polyamides by PET is a minimum first step toward the translation of polyamide-based gene regulation from cell culture to small animal studies

Double di ffential fragmentation cross sections measurements of 95 MeV/u 12C on thin targets for hadrontherapy

During therapeutic treatment with heavy ions like carbon, the beam undergoes nuclear fragmentation and secondary light charged particles, in particular protons and alpha particles, are produced. To estimate the dose deposited into the tumors and the surrounding healthy tissues, an accurate prediction on the fluences of these secondary fragments is necessary. Nowadays, a very limited set of double di ffential carbon fragmentation cross sections are being measured in the energy range used in hadrontherapy (40 to 400 MeV/u). Therefore, new measurements are performed to determine the double di ffential cross section of carbon on di erent thin targets. This work describes the experimental results of an experiment performed on May 2011 at GANIL. The double di ffential cross sections and the angular distributions of secondary fragments produced in the 12C fragmentation at 95 MeV/u on thin targets (C, CH2, Al, Al2O3, Ti and PMMA) have been measured. The experimental setup will be precisely described, the systematic error study will be explained and all the experimental data will be presented.Comment: Submitted to PR

Improved nuclear localization of DNA-binding polyamides

Regulation of endogenous genes by DNA-binding polyamides requires effective nuclear localization. Previous work employing confocal microscopy to study uptake of fluorophore-labeled polyamides has demonstrated the difficulty of predicting a priori the nuclear uptake of a given polyamide. The data suggest that dye identity influences uptake sufficiently such that a dye-conjugate cannot be used as a proxy for unlabeled analogs. Polyamides capable of nuclear localization unaided by fluorescent dyes are desirable due to size and other limitations of fluorophores. Recently, a polyamide-fluorescein conjugate targeted to the hypoxia response element (HRE) was found to inhibit vascular endothelial growth factor (VEGF) expression in cultured HeLa cells. The current study uses inhibition of VEGF expression as a biological read-out for effective nuclear localization of HRE-targeted polyamides. We synthesized a focused library of non-fluorescent, HRE-targeted polyamides in which the C-terminus ‘tail’ has been systematically varied. Members of this library bind the HRE with affinities comparable or superior to that of the fluorescein-labeled analog. Although most library members demonstrate modest or no biological activity, two non-fluorescent polyamides are reported with activity rivaling that of the previously reported fluorescein-labeled polyamide. We also show evidence that promoter occupancy by HIF-1, the transcription factor that binds the HRE, is inhibited by HRE-targeted polyamides

Comparison of two analysis methods for nuclear reaction measurements of 12C +12C interactions at 95 MeV/u for hadrontherapy

During therapeutic treatment with heavier ions like carbon, the beam undergoes nuclear fragmentation and secondary light charged particles, in particular protons and alpha particles, are produced. To estimate the dose deposited into the tumors and the surrounding healthy tissues, the accuracy must be higher than ($\pm$3% and$\pm$1 mm). Therefore, measurements are performed to determine the double differential cross section for different reactions. In this paper, the analysis of data from 12C +12C reactions at 95 MeV/u are presented. The emitted particles are detected with \DeltaEthin-\DeltaEthick-E telescopes made of a stack of two silicon detectors and a CsI crystal. Two different methods are used to identify the particles. One is based on graphical cuts onto the \DeltaE-E maps, the second is based on the so-called KaliVeda method using a functional description of \DeltaE versus E. The results of the two methods will be presented in this paper as well as the comparison between both

Accessibility of nuclear chromatin by DNA binding polyamides

Pyrrole-imidazole polyamides bind DNA with affinities comparable to those of transcriptional regulatory proteins and inhibit the DNA binding activities of components of the transcription apparatus. If polyamides are to be useful for the regulation of gene expression in cell culture experiments, one pivotal issue is accessibility of specific sites in nuclear chromatin. We first determined the kinetics of uptake and subcellular distribution of polyamides in lymphoid and myeloid cells using fluorescent polyamide-bodipy conjugates and deconvolution microscopy. Then cells were incubated with a polyamide-chlorambucil conjugate, and the sites of specific DNA cleavage in the nuclear chromatin were assayed by ligation-mediated PCR. In addition, DNA microarray analysis revealed that two different polyamides generated distinct transcription profiles. Remarkably, the polyamides affected only a limited number of genes

Small intestinal mucosa expression of putative chaperone fls485

<p>Abstract</p> <p>Background</p> <p>Maturation of enterocytes along the small intestinal crypt-villus axis is associated with significant changes in gene expression profiles. <it>fls485 </it>coding a putative chaperone protein has been recently suggested as a gene involved in this process. The aim of the present study was to analyze <it>fls48</it>5 expression in human small intestinal mucosa.</p> <p>Methods</p> <p><it>fls485 </it>expression in purified normal or intestinal mucosa affected with celiac disease was investigated with a molecular approach including qRT-PCR, Western blotting, and expression strategies. Molecular data were corroborated with several <it>in situ </it>techniques and usage of newly synthesized mouse monoclonal antibodies.</p> <p>Results</p> <p>fls485 mRNA expression was preferentially found in enterocytes and chromaffine cells of human intestinal mucosa as well as in several cell lines including Rko, Lovo, and CaCo2 cells. Western blot analysis with our new anti-fls485 antibodies revealed at least two fls485 proteins. In a functional CaCo2 model, an increase in fls485 expression was paralleled by cellular maturation stage. Immunohistochemistry demonstrated fls485 as a cytosolic protein with a slightly increasing expression gradient along the crypt-villus axis which was impaired in celiac disease Marsh IIIa-c.</p> <p>Conclusions</p> <p>Expression and synthesis of fls485 are found in surface lining epithelia of normal human intestinal mucosa and deriving epithelial cell lines. An interdependence of enterocyte differentiation along the crypt-villus axis and fls485 chaperone activity might be possible.</p

Capitalist Convergence? European (dis?)Integration and the Post-crash Restructuring of French and European Capitalisms

© 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group. This article critiques and builds upon first-wave (Höpner and Schäfer 2010. A new phase of European integration: organised capitalisms in post-Ricardian Europe. West European Politics, 33 (2), 344–368) and second-wave (Johnston and Regan 2018. Introduction: is the European Union capable of integrating diverse models of capitalism? New Political Economy, 23 (2), 145–159) European Integration and comparative capitalisms literatures which posit convergence towards a single model of capitalism or growth. It utilises the case study of France to explore the impact of European integration and disintegration on national models of capitalism in the post-crisis era. The article focuses on the impact of integrative and disintegrative dynamics on France’s ‘state-industry-finance nexus’, putting forward three core claims. First, French capitalism is not accurately captured by the above frameworks and remains better characterised by the concept of post-dirigisme. Indeed, comparative capitalisms debates must move beyond a simple bifurcation of capitalist types. Second, European integrative pressures must be viewed as fragmented, differentiating, mediated by domestic state actors and producing capitalist variegation and hybridisation. Countering functionalist tendencies within this literature, it shows how different conceptions of state-market relations crucially mediate the relationship between national capitalisms and European integration. Finally, in the context of Brexit, the dynamics of European disintegration–an issue not discussed so far in these debates–is contributing to a variegated and multi-directional process of capitalist restructuring in post-crisis France

178Hg and asymmetric fission of neutron-deficient pre-actinides

International audienceFission at low excitation energy is an ideal playground to probe the impact of nuclear structure on nuclear dynamics. While the importance of structural effects in the nascent fragments is well established in the (trans-)actinide region, the observation of asymmetric fission in several neutron-deficient pre-actinides can be explained by various mechanisms. To deepen our insight into that puzzle, an innovative approach based on inverse kinematics and an enhanced version of the VAMOS++ heavy-ion spectrometer was implemented at the GANIL facility, Caen. Fission of Hg178 was induced by fusion of Xe124 and Fe54. The two fragments were detected in coincidence using VAMOS++ supplemented with a new SEcond Detection arm. For the first time in the pre-actinide region, access to the pre-neutron mass and total kinetic energy distributions, and the simultaneous isotopic identification of one the fission fragment, was achieved. The present work describes the experimental approach, and discusses the pre-neutron observables in the context of an extended asymmetric-fission island located southwest of Pb208. A comparison with different models is performed, demonstrating the importance of this new asymmetric-fission island for elaborating on driving effects in fission

Search for 22^{22}Na in novae supported by a novel method for measuring femtosecond nuclear lifetimes

Classical novae are thermonuclear explosions in stellar binary systems, and important sources of $^{26}$Al and $^{22}$Na. While gamma rays from the decay of the former radioisotope have been observed throughout the Galaxy, $^{22}$Na remains untraceable. The half-life of $^{22}$Na (2.6 yr) would allow the observation of its 1.275 MeV gamma-ray line from a cosmic source. However, the prediction of such an observation requires good knowledge of the nuclear reactions involved in the production and destruction of this nucleus. The $^{22}$Na($p,\gamma$)$^{23}$Mg reaction remains the only source of large uncertainty about the amount of $^{22}$Na ejected. Its rate is dominated by a single resonance on the short-lived state at 7785.0(7) keV in $^{23}$Mg. In the present work, a combined analysis of particle-particle correlations and velocity-difference profiles is proposed to measure femtosecond nuclear lifetimes. The application of this novel method to the study of the $^{23}$Mg states, combining magnetic and highly-segmented tracking gamma-ray spectrometers, places strong limits on the amount of $^{22}$Na produced in novae, explains its non-observation to date in gamma rays (flux < 2.5x$10^{-4}$ ph/(cm$^2$s)), and constrains its detectability with future space-borne observatories.Comment: 18 pages, 3 figures, 1 tabl