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1. Dissipative phases across the superconductor-to-insulator transition

Author

Couëdo, François, Crauste, Olivier, Drillien, Anne-Aëlle, Humbert, Vincent, Bergé, Laurent, Marrache-Kikuchi, Claire. A., and Dumoulin, Louis

Subjects
Condensed Matter - Superconductivity
Abstract

Competing phenomena in low dimensional systems can generate exotic electronic phases, either through symmetry breaking or a non-trivial topology. In two-dimensional (2D) systems, the interplay between superfluidity, disorder and repulsive interactions is especially fruitful in this respect although both the exact nature of the phases and the microscopic processes at play are still open questions. In particular, in 2D, once superconductivity is destroyed by disorder, an insulating ground state is expected to emerge, as a result of a direct superconductor-to-insulator quantum phase transition. In such systems, no metallic state is theoretically expected to survive to the slightest disorder. Here we map out the phase diagram of amorphous NbSi thin films as functions of disorder and film thickness, with two metallic phases in between the superconducting and insulating ones. These two dissipative states, defined by a resistance which extrapolates to a finite value in the zero temperature limit, each bear a specific dependence on disorder. We argue that they originate from an inhomogeneous destruction of superconductivity, even if the system is morphologically homogeneous. Our results suggest that superconducting fluctuations can favor metallic states that would not otherwise exist.

Published
2016
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2. LUMINEU: a search for neutrinoless double beta decay based on ZnMoO$_4$ scintillating bolometers

Author

Armengaud, E., Arnaud, Q., Augier, C., Benoit, A., Berge, L., Boiko, R. S., Bergmann, T., Blumer, J., Broniatowski, A., Brudanin, V., Camus, P., Cazes, A., Chapellier, M., Charlieux, F., Chernyak, D. M., Coron, N., Coulter, P., Danevich, F. A., de Boissiere, T., Decourt, R., De Jesus, M., Devoyon, L., Drillien, A. -A., Dumoulin, L., Eitel, K., Enss, C., Filosofov, D., Fleischmann, A., Foerster, N., Fourches, N., Gascon, J., Gastaldo, L., Gerbier, G., Giuliani, A., Gray, D., Gros, M., Hehn, L., Henry, S., Herve, S., Heuermann, G., Humbert, V., Ivanov, I. M., Juillard, A., Kefelian, C., Kleifges, M., Kluck, H., Kobychev, V. V., Koskas, F., Kozlov, V., Kraus, H., Kudryavtsev, V. A., Sueur, H. Le, Loidl, M., Magnier, P., Makarov, E. P., Mancuso, M., de Marcillac, P., Marnieros, S., Marrache-Kikuchi, C., Menshikov, A., Nasonov, S. G., Navick, X. -F., Nones, C., Olivieri, E., Pari, P., Paul, B., Penichot, Y., Pessina, G., Piro, M. C., Plantevin, O., Poda, D. V., Redon, T., Robinson, M., Rodrigues, M., Rozov, S., Sanglard, V., Schmidt, B., Shlegel, S. Scorza V. N., Siebenborn, B., Strazzer, O., Tcherniakhovski, D., Tenconi, M., Torres, L., Tretyak, V. I., Vagneron, L., Vasiliev, Ya. V., Velazquez, M., Viraphong, O., Walker, R. J., Weber, M., Yakushev, E., Zhang, X., and Zhdankov, V. N.

Subjects
Nuclear Experiment, Physics - Instrumentation and Detectors
Abstract

The LUMINEU is designed to investigate the possibility to search for neutrinoless double beta decay in $^{100}$Mo by means of a large array of scintillating bolometers based on ZnMoO$_4$ crystals enriched in $^{100}$Mo. High energy resolution and relatively fast detectors, which are able to measure both the light and the heat generated upon the interaction of a particle in a crystal, are very promising for the recognition and rejection of background events. We present the LUMINEU concepts and the experimental results achieved aboveground and underground with large-mass natural and enriched crystals. The measured energy resolution, the $\alpha/\beta$ discrimination power and the radioactive internal contamination are all within the specifications for the projected final LUMINEU sensitivity. Simulations and preliminary results confirm that the LUMINEU technology can reach zero background in the region of interest (around 3 MeV) with exposures of the order of hundreds kg$\times$years, setting the bases for a next generation $0\nu2\beta$ decay experiment capable to explore the inverted hierarchy region of the neutrino mass pattern., Comment: 5 pages, 3 figures, submitted as proceedings of the TAUP 2015 conference

Published
2016
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3. Proceedings of the third French-Ukrainian workshop on the instrumentation developments for HEP

Author

Alessio, F., Barsuk, S. Ya., Berge, L., Bezshyyko, O. A., Boiko, R. S., Chaikovska, I., Chapellier, M., Charles, G., Chaus, A., Chehab, R., Chernyak, D. M., Coron, N., Danevich, F. A., Delerue, N., Devoyon, L., Drillien, A. -A., Dumoulin, L., Enss, C., Fedorchuk, O., Fleischmann, A., Gastaldo, L., Giuliani, A., Gray, D., Gros, M., Herve, S., Humbert, V., Ivanov, I. M., Juillard, A., Kharchenko, D., Kharchenko, V., Khodnevych, V., Kobychev, V. V., Koskas, F., Kovalchuk, O., Levchuk, I. P., Loidl, M., Lysenko, I., Magnier, P., Makarov, E. P., Malovytsia, M., Mancuso, M., de Marcillac, P., Marnieros, S., Marrache-Kikuchi, C., Maslov, V. I., Momot, I., Navick, X. -F., Nones, C., Okhrimenko, O., Olivieri, E., Onishchenko, I. N., Paul, B., Penichot, Y., Pessina, G., Plantevin, O., Poda, D. V., Prezado, Y., Pugatch, V., Redon, T., Rodrigues, M., Shchagin, A. V., Shlegel, V. N., Shul'ga, N. F., Shul'ga, S. N., Strazzer, O., Tenconi, M., Titov, M., Torres, L., Tretyak, V. I., Trofymenko, S. V., Vasiliev, Ya. V., Velazquez, M., and Viraphong, O.

Subjects
Physics - Instrumentation and Detectors, High Energy Physics - Experiment, Nuclear Experiment
Abstract

The reports collected in these proceedings have been presented in the third French-Ukrainian workshop on the instrumentation developments for high-energy physics held at LAL, Orsay on October 15-16. The workshop was conducted in the scope of the IDEATE International Associated Laboratory (LIA). Joint developments between French and Ukrainian laboratories and universities as well as new proposals have been discussed. The main topics of the papers presented in the Proceedings are developments for accelerator and beam monitoring, detector developments, joint developments for large-scale high-energy and astroparticle physics projects, medical applications., Comment: 3rd French-Ukrainian workshop on the instrumentation developments for High Energy Physics, October 15-16, 2015, LAL, Orsay, France, 94 pages

Published
2015

4. Structural basis for allosteric regulation of Human Topoisomerase IIα

Author

Arnaud Vanden Broeck, Christophe Lotz, Robert Drillien, Léa Haas, Claire Bedez, and Valérie Lamour

Subjects
Science
Abstract

Type 2 DNA topoisomerases (Top2) regulates DNA topology during DNA replication, transcription, and chromosome segregation. Here the authors describe a complete structure of the catalytic core of the human Topo IIα bound to DNA and etoposide, providing insight into the regulation of Topo IIα activities and how opening of the DNA-gate is spatially connected to the ATPase domain.

Published
2021
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5. Scintillating bolometers based on ZnMoO$_4$ and Zn$^{100}$MoO$_4$ crystals to search for 0$\nu$2$\beta$ decay of $^{100}$Mo (LUMINEU project): first tests at the Modane Underground Laboratory

Author

Poda, D. V., Armengaud, E., Arnaud, Q., Augier, C., Benoît, A., Bergé, L., Boiko, R. S., Bergmann, T., Blümer, J., Broniatowski, A., Brudanin, V., Camus, P., Cazes, A., Censier, B., Chapellier, M., Charlieux, F., Chernyak, D. M., Coron, N., Coulter, P., Cox, G. A., Danevich, F. A., de Boissière, T., Decourt, R., De Jesus, M., Devoyon, L., Drillien, A. -A., Dumoulin, L., Eitel, K., Enss, C., Filosofov, D., Fleischmann, A., Fourches, N., Gascon, J., Gastaldo, L., Gerbier, G., Giuliani, A., Gros, M., Hehn, L., Henry, S., Hervé, S., Heuermann, G., Humbert, V., Ivanov, I. M., Juillard, A., Kéfélian, C., Kleifges, M., Kluck, H., Kobychev, V. V., Koskas, F., Kozlov, V., Kraus, H., Kudryavtsev, V. A., Sueur, H. Le, Loidl, M., Magnier, P., Makarov, E. P., Mancuso, M., de Marcillac, P., Marnieros, S., Marrache-Kikuchi, C., Menshikov, A., Nasonov, S. G., Navick, X-F., Nones, C., Olivieri, E., Pari, P., Paul, B., Penichot, Y., Pessina, G., Piro, M. C., Plantevin, O., Redon, T., Robinson, M., Rodrigues, M., Rozov, S., Sanglard, V., Schmidt, B., Shlegel, V. N., Siebenborn, B., Strazzer, O., Tcherniakhovski, D., Tenconi, M., Torres, L., Tretyak, V. I., Vagneron, L., Vasiliev, Ya. V., Velazquez, M., Viraphong, O., Walker, R. J., Weber, M., Yakushev, E., Zhang, X., and Zhdankov, V. N.

Subjects
Physics - Instrumentation and Detectors, Nuclear Experiment
Abstract

The technology of scintillating bolometers based on zinc molybdate (ZnMoO$_4$) crystals is under development within the LUMINEU project to search for 0$\nu$2$\beta$ decay of $^{100}$Mo with the goal to set the basis for large scale experiments capable to explore the inverted hierarchy region of the neutrino mass pattern. Advanced ZnMoO$_4$ crystal scintillators with mass of $\sim$~0.3 kg were developed and Zn$^{100}$MoO$_4$ crystal from enriched $^{100}$Mo was produced for the first time by using the low-thermal-gradient Czochralski technique. One ZnMoO$_4$ scintillator and two samples (59 g and 63 g) cut from the enriched boule were tested aboveground at milli-Kelvin temperature as scintillating bolometers showing a high detection performance. The first results of the low background measurements with three ZnMoO$_4$ and two enriched detectors installed in the EDELWEISS set-up at the Modane Underground Laboratory (France) are presented., Comment: 7 pages, 5 figures, Contribution to the proceedings of the 37th International Conference on High Energy Physics (ICHEP 2014), Valencia, Spain, 2-9 July 2014

Published
2015
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6. Observation of thermally activated glassiness and memory dip in a-NbSi insulating thin films

Author

Delahaye, Julien, Grenet, Thierry, Marrache-Kikuchi, C., Bergé, L., and Drillien, A. A.

Subjects
Condensed Matter - Disordered Systems and Neural Networks, Condensed Matter - Materials Science
Abstract

We present electrical conductance measurements on amorphous NbSi insulating thin films. These films display out-of equilibrium electronic features that are markedly different from what has been reported so far in disordered insulators. Like in the most studied systems (indium oxide and granular Al films), a slow relaxation of the conductance is observed after a quench to liquid helium temperature which gives rise to the growth of a memory dip in MOSFET devices. But unlike in these systems, this memory dip and the related conductance relaxations are still visible up to room temperature, with clear signatures of a temperature dependent dynamics.

Published
2014
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7. Efficient production of protein complexes in mammalian cells using a poxvirus vector

Author

Robert Drillien, Karine Pradeau-Aubreton, Julien Batisse, Joëlle Mezher, Emma Schenckbecher, Justine Marguin, Eric Ennifar, and Marc Ruff

Subjects
Medicine, Science
Abstract

The production of full length, biologically active proteins in mammalian cells is critical for a wide variety of purposes ranging from structural studies to preparation of subunit vaccines. Prior research has shown that Modified vaccinia virus Ankara encoding the bacteriophage T7 RNA polymerase (MVA-T7) is particularly suitable for high level expression of proteins upon infection of mammalian cells. The expression system is safe for users and 10–50 mg of full length, biologically active proteins may be obtained in their native state, from a few litres of infected cell cultures. Here we report further improvements which allow an increase in the ease and speed of recombinant virus isolation, the scale-up of protein production and the simultaneous synthesis of several polypeptides belonging to a protein complex using a single virus vector. Isolation of MVA-T7 viruses encoding foreign proteins was simplified by combining positive selection for virus recombinants and negative selection against parental virus, a process which eliminated the need for tedious plaque purification. Scale-up of protein production was achieved by infecting a BHK 21 suspension cell line and inducing protein expression with previously infected cells instead of virus, thus saving time and effort in handling virus stocks. Protein complexes were produced from infected cells by concatenating the Tobacco Etch Virus (TEV) N1A protease sequence with each of the genes of the complex into a single ORF, each gene being separated from the other by twin TEV protease cleavage sites. We report the application of these methods to the production of a complex formed on the one hand between the HIV-1 integrase and its cell partner LEDGF and on the other between the HIV-1 VIF protein and its cell partners APOBEC3G, CBFβ, Elo B and Elo C. The strategies developed in this study should be valuable for the overexpression and subsequent purification of numerous protein complexes.

Published
2022

8. Purification of molybdenum oxide, growth and characterization of medium size zinc molybdate crystals for the LUMINEU program

Author

Shlegel, V. N., Berge, L., Boiko, R. S., Chapellier, M., Chernyak, D. M., Coron, N., Danevich, F. A., Decourt, R., Degoda, V. Ya., Devoyon, L., Drillien, A., Dumoulin, L., Enss, C., Fleischmann, A., Gastaldo, L., Giuliani, A., Gros, M., Herve, S., Ivanov, I. M., Kobychev, V. V., Kogut, Ya. P., Koskas, F., Loidl, M., Magnier, P., Makarov, E. P., Mancuso, M., de Marcillac, P., Marnieros, S., Marrache-Kikuchi, C., Nasonov, S. G., Navick, X. F., Nones, C., Olivieri, E., Paul, B., Penichot, Y., Pessina, G., Plantevin, O., Poda, D. V., Redon, T., Rodrigues, M., Strazzer, O., Tenconi, M., Torres, L., Tretyak, V. I., Vasiliev, Ya. V., Velazquez, M., Viraphong, O., and Zhdankov, V. N.

Subjects
Physics - Instrumentation and Detectors, Nuclear Experiment
Abstract

The LUMINEU program aims at performing a pilot experiment on neutrinoless double beta decay of 100Mo using radiopure ZnMoO4 crystals operated as scintillating bolometers. Growth of high quality radiopure crystals is a complex task, since there are no commercially available molybdenum compounds with the required levels of purity and radioactive contamination. This paper discusses approaches to purify molybdenum and synthesize compound for high quality radiopure ZnMoO4 crystal growth. A combination of a double sublimation (with addition of zinc molybdate) with subsequent recrystallization in aqueous solutions (using zinc molybdate as a collector) was used. Zinc molybdate crystals up to 1.5 kg were grown by the low-thermal-gradient Czochralski technique, their optical, luminescent, diamagnetic, thermal and bolometric properties were tested., Comment: Contribution to Proc. of Int. Workshop on Radiopure Scintillators RPSCINT 2013, 17-20 September 2013, Kyiv, Ukraine; to be published in EPJ Web of Conferences; expected to be online in January 2014; 6 pages, 6 figures, and 3 tables

Published
2013
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9. Axion searches with the EDELWEISS-II experiment

Author

Armengaud, E., Arnaud, Q., Augier, C., Benoit, A., Bergé, L., Bergmann, T., Blümer, J., Broniatowski, A., Brudanin, V., Camus, P., Cazes, A., Censier, B., Chapellier, M., Charlieux, F., Couëdo, F., Coulter, P., Cox, G. A., de Boissière, T., De Jesus, M., Dolgorouky, Y., Drillien, A. A., Dumoulin, L., Eitel, K., Filosofov, D., Fourches, N., Gascon, J., Gerbier, G., Gros, M., Hehn, L., Henry, S., Hervé, S., Heuermann, G., Holtzer, N., Humbert, V., Juillard, A., Kéfélian, C., Kleifges, M., Kluck, H., Kozlov, V., Kraus, H., Kudryavtsev, V. A., Sueur, H. Le, Mancuso, M., Marrache-Kikuchi, C., Marnieros, S., Menshikov, A., Navick, X-F., Nones, C., Olivieri, E., Pari, P., Paul, B., Piro, M. C., Rigaut, O., Robinson, M., Rozov, S., Sanglard, V., Schmidt, B., Siebenborn, B., Tcherniakhovski, D., Tenconi, M., Vagneron, L., Walker, R. J., Weber, M., Yakushev, E., and Zhang, X.

Subjects
Astrophysics - Cosmology and Nongalactic Astrophysics, High Energy Physics - Phenomenology
Abstract

We present new constraints on the couplings of axions and more generic axion-like particles using data from the EDELWEISS-II experiment. The EDELWEISS experiment, located at the Underground Laboratory of Modane, primarily aims at the direct detection of WIMPs using germanium bolometers. It is also sensitive to the low-energy electron recoils that would be induced by solar or dark matter axions. Using a total exposure of up to 448 kg.d, we searched for axion-induced electron recoils down to 2.5 keV within four scenarios involving different hypotheses on the origin and couplings of axions. We set a 95% CL limit on the coupling to photons $g_{A\gamma}<2.13\times 10^{-9}$ GeV$^{-1}$ in a mass range not fully covered by axion helioscopes. We also constrain the coupling to electrons, $g_{Ae} < 2.56\times 10^{-11}$, similar to the more indirect solar neutrino bound. Finally we place a limit on $g_{Ae}\times g_{AN}^{\rm eff}<4.70 \times 10^{-17}$, where $g_{AN}^{\rm eff}$ is the effective axion-nucleon coupling for $^{57}$Fe. Combining these results we fully exclude the mass range $0.91\,{\rm eV}

Published
2013
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10. A search for low-mass WIMPs with EDELWEISS-II heat-and-ionization detectors

Author

EDELWEISS Collaboration, Armengaud, E., Augier, C., Benoît, A., Bergé, L., Bergmann, T., Blümer, J., Broniatowski, A., Brudanin, V., Censier, B., Chapellier, M., Charlieux, F., Couëdo, F., Coulter, P., Cox, G. A., Domange, J., Drillien, A. A., Dumoulin, L., Eitel, K., Filosofov, D., Fourches, N., Gascon, J., Gerbier, G., Gironnet, J., Gros, M., Heuermann, G., Henry, S., Hervé, S., Juillard, A., Kleifges, M., Kluck, H., Kozlov, V., Kraus, H., Kudryavtsev, V. A., Sueur, H. Le, Loaiza, P., Marnieros, S., Menshikov, A., Navick, X. -F., Nones, C., Olivieri, E., Pari, P., Paul, B., Robinson, M., Rozov, S., Sanglard, V., Schmidt, B., Siebenborn, B., Tcherniakhovski, D., Torrento-Coello, A. S., Vagneron, L., Walker, R. J., Weber, M., Yakushev, E., and Zhang, X.

Subjects
Astrophysics - Cosmology and Extragalactic Astrophysics, High Energy Physics - Experiment, Physics - Instrumentation and Detectors
Abstract

We report on a search for low-energy (E < 20 keV) WIMP-induced nuclear recoils using data collected in 2009 - 2010 by EDELWEISS from four germanium detectors equipped with thermal sensors and an electrode design (ID) which allows to efficiently reject several sources of background. The data indicate no evidence for an exponential distribution of low-energy nuclear recoils that could be attributed to WIMP elastic scattering after an exposure of 113 kg.d. For WIMPs of mass 10 GeV, the observation of one event in the WIMP search region results in a 90% CL limit of 1.0x10^-5 pb on the spin-independent WIMP-nucleon scattering cross-section, which constrains the parameter space associated with the findings reported by the CoGeNT, DAMA and CRESST experiments., Comment: PRD rapid communication accepted

Published
2012
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13. The production of recombinant platelet‐derived growth factor D using the second generation modified vaccinia Ankara viral system

Author

Abdo J. Najy, Tri Pham, Karine Pradeau‐Aubreton, Robert Drillien, and Hyeong‐Reh C. Kim

Subjects
Platelet-Derived Growth Factor, Mammals, Vaccinia, Humans, Animals, Vaccinia virus, Virus Replication, Molecular Biology, Biochemistry, Recombinant Proteins
Abstract

The vaccinia virus expression system is known for the efficient production of recombinant proteins with "appropriate" posttranslational modification using desired mammalian cell lines. However, being a replication competent virus, vaccinia virus poses a health threat to immunocompromised individuals and requires biosafety level 2 (BSL2) laboratory precautions, thereby restricting its use by the scientific community. Development of the host range restricted modified vaccinia Ankara (MVA) system has allowed researchers to work with a safer virus even at BSL1. Here, we report on the use of an improved second generation MVA viral system incorporating two selective markers and fluorescent proteins for easier recombinant virus identification. Notably, we demonstrate that this novel system is capable of producing secreted recombinant proteins, a finding not previously reported. Through purification and characterization of wild type and mutant platelet-derived growth factor D (PDGF D) dimer species, we demonstrate this system is capable of producing the latent full-length PDGF D dimer, partially processed intermediate dimer (hemidimer), as well as fully processed growth factor domain dimer that show chemical integrity and biological activity. Importantly, this system is amenable to scaling up for the mass production of recombinant PDGF D (rPDGF D) dimer species.

Published
2022
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15. Structural basis for allosteric regulation of Human Topoisomerase IIα

Author

Robert Drillien, Léa Haas, Arnaud Vanden Broeck, Christophe Lotz, Valérie Lamour, Claire Bedez, Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), univOAK, Archive ouverte, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Gene isoform, Models, Molecular, Science, Allosteric regulation, General Physics and Astronomy, Cleavage (embryo), DNA-binding protein, Biochemistry, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Allosteric Regulation, Transcription (biology), Catalytic Domain, DNA-binding proteins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Poly-ADP-Ribose Binding Proteins, Multidisciplinary, biology, Mesocricetus, Topoisomerase, Cryoelectron Microscopy, DNA replication, General Chemistry, DNA, Recombinant Proteins, Cell biology, Enzymes, 030104 developmental biology, DNA Topoisomerases, Type II, Nucleoproteins, chemistry, Enzyme mechanisms, biology.protein, Protein Processing, Post-Translational, 030217 neurology & neurosurgery
Abstract

The human type IIA topoisomerases (Top2) are essential enzymes that regulate DNA topology and chromosome organization. The Topo IIα isoform is a prime target for antineoplastic compounds used in cancer therapy that form ternary cleavage complexes with the DNA. Despite extensive studies, structural information on this large dimeric assembly is limited to the catalytic domains, hindering the exploration of allosteric mechanism governing the enzyme activities and the contribution of its non-conserved C-terminal domain (CTD). Herein we present cryo-EM structures of the entire human Topo IIα nucleoprotein complex in different conformations solved at subnanometer resolutions (3.6–7.4 Å). Our data unveils the molecular determinants that fine tune the allosteric connections between the ATPase domain and the DNA binding/cleavage domain. Strikingly, the reconstruction of the DNA-binding/cleavage domain uncovers a linker leading to the CTD, which plays a critical role in modulating the enzyme’s activities and opens perspective for the analysis of post-translational modifications., Type 2 DNA topoisomerases (Top2) regulates DNA topology during DNA replication, transcription, and chromosome segregation. Here the authors describe a complete structure of the catalytic core of the human Topo IIα bound to DNA and etoposide, providing insight into the regulation of Topo IIα activities and how opening of the DNA-gate is spatially connected to the ATPase domain.

Published
2021
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24. Structural basis for the allosteric regulation of Human Topoisomerase 2α

Author

Robert Drillien, Christophe Lotz, Claire Bedez, Valérie Lamour, and Arnaud Vanden Broeck

Subjects
Gene isoform, chemistry.chemical_classification, biology, Chemistry, Topoisomerase, Allosteric regulation, Cleavage (embryo), Nucleoprotein, chemistry.chemical_compound, Enzyme, Biophysics, biology.protein, Linker, DNA
Abstract

The human type IIA topoisomerases (Top2) are essential enzymes that regulate DNA topology and chromosome organization. The Top2α isoform is a prime target for antineoplastic compounds used in cancer therapy that form ternary cleavage complexes with the DNA. Despite extensive studies, structural information on this large dimeric assembly is limited to the catalytic domains, hindering the exploration of allosteric mechanism governing the enzyme activities and the contribution of its non-conserved C-terminal domain (CTD). Herein we present cryo-EM structures of the entire human Top2α nucleoprotein complex in different conformations solved at subnanometer resolutions. Our data unveils the molecular determinants that fine tune the allosteric connections between the ATPase domain and the DNA binding/cleavage domain. Strikingly, the reconstruction of the DNA-binding/cleavage domain uncovers a linker leading to the CTD, which plays a critical role in modulating the enzyme’s activities and opens perspective for the analysis of post-translational modifications.

Published
2020
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40. Structural features of the salivary gland hypertrophy virus of the tsetse fly revealed by cryo-electron microscopy and tomography

Author

Igor Orlov, Bruno P. Klaholz, Danièle Spehner, Adly M. M. Abd-Alla, Robert Drillien, Max Bergoin, Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institute of genetics and molecular and cellular biology-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Pathologie Comparée (LPC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Insect Pest Control Laboratories [Vienna, Austria], International Atomic Energy Agency [Vienna] (IAEA)-Joint FAO/IAEA Division of Nuclear Techniques in Food and Agriculture, This work was supported by the Centre National pour la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (Inserm), the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05-01, and Instruct as part of the European Strategy Forum on Research Infrastructures (ESFRI)., ANR-10-INBS-05-01/10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), European Project: 654213,H2020,H2020-INFRASUPP-2014-2,STR- ESFRI(2015), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Insect Pest Control Laboratory (IPC laboratory), Food and Agriculture Organization of the United Nations [Rome, Italie] (FAO)-International Atomic Energy Agency [Vienna] (IAEA), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), Klaholz, Bruno, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, Support to Reinforce the European Strategy Forum for Research Infrastructures - STR- ESFRI - - H20202015-03-01 - 2019-03-01 - 654213 - VALID, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
Male, 0301 basic medicine, Insect virus, Tsetse Flies, Cryo-electron microscopy, viruses, [SDV]Life Sciences [q-bio], Cytomegalovirus, Insect Viruses, Context (language use), Salivary gland hypertrophy virus, Virus, 03 medical and health sciences, Sterile insect technique, Viral life cycle, SGHV, Virology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Electron microscopy, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Hytrosaviridae, Cryo-electron tomography, Helix, biology, Trypanosomosis, Cryoelectron Microscopy, Virion, Tsetse fly, Virus structure, biology.organism_classification, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Salivary Gland Hypertrophy
Abstract

International audience; Glossina palipides salivary gland hypertrophy virus (GpSGHV) infects tsetse flies, which are vectors for African trypanosomosis. This virus represents a major challenge in insect mass rearing and has hampered the implementation of the sterile insect technique programs in the Member States of the International Atomic Energy Agency. GpSGHV virions consist of long rod-shaped particles over 9000Å in length, but little is known about their detailed structural organization. We show by cryo electron microscopy and cryo electron tomography that the GpSGHV virion has a unique, non-icosahedral helical structure. Its envelope exhibits regularly spaced spikes that protrude from the lipid bilayer and are arranged on a four-start helix. This study provides a detailed insight into the 3D architecture of GpSGHV, which will help to understand the viral life cycle and possibly allow the design of antiviral strategies in the context of tsetse fly infections.

Published
2018
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41. Structural and Functional Studies of Human Type II Topoisomerases and their Post-Translational Modifications

Author

Valérie Lamour, Claire Bedez, Arnaud Vanden Broeck, Robert Drillien, Marc Ruff, Christophe Lotz, Claire Batisse, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, Chemistry, [SDV]Life Sciences [q-bio], Topoisomerase, Biophysics, Computational biology, Human type, 010402 general chemistry, 01 natural sciences, 0104 chemical sciences, 03 medical and health sciences, Posttranslational modification, biology.protein, Functional studies, 030304 developmental biology
Abstract

International audience; Type II DNA Topoisomerases (Top2) are essential enzymes involved in DNA replication, DNA condensation and chromosome segregation. They remove topological stress that appear in the DNA duplex by releasing catenates, relaxing supercoils and removing knots through transient double strand breaks. This mechanism is currently targeted by compounds used in cancer chemotherapy, that prevent religation of DNA breaks and lead to cell death. The implication of these enzymes in the cell cycle raises the question of their regulation notably by post-translational modifications (PTM). Anti-cancer drugs such as doxorubicin and etoposide were shown to induce hyperphosphorylation or hypophosphorylation in cancer cells. However the role of PTM in the catalytic regulation of Top2 is not clearly understood.In this work, we have focused on the post-translational modifications of the human Top2. We have systematically identified the phosphorylation and acetylation sites in the Top2 isoforms, and observed a distinct distribution of both modifications. This identification allowed us to understand the role of a catalytic residue subject to an acetylation and the potential impact of this modification.

Published
2020
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42. An innovative combined immunization platform for personalized cancer immunotherapy

Author

Emilie Thiebault Peter, Tania Sorg, Robert Drillien, Jessica Matta, Ghina Bou About, Célia Matta, Jean-Marc Limacher, Benoit Petit-Demouliere, and David Moulaert

Subjects
Cancer Research, Immune system, Oncology, Cancer immunotherapy, Immunization, business.industry, medicine.medical_treatment, Immune checkpoint inhibitors, Immunology, medicine, Tumor specific, chemical and pharmacologic phenomena, business
Abstract

e14225 Background: Activity of immune checkpoint inhibitors relies mainly on the presence of an immune response directed against neoantigens resulting from tumor specific mutations. The induction and/or amplification of such an immune response is expected to increase the activity of these therapies. We describe here a novel immunization platform developed for the purpose of personalized cancer immunotherapy. This platform integrates a DNA vector coding for neoantigens, a live modified vaccinia of strain Ankara (MVA) used as a physiologic adjuvant and anti-CTLA-4 as a locally acting early immune checkpoint blocker. Methods: Immune potency was assessed in C57BL6 mice injected subcutaneously three times five days apart with an ovalbumine (OVA) expressing DNA vector (100 µg), either alone or in combination with increasing doses of MVA (up to 2.5x107 plaque forming units, pfu) and increasing doses of anti-CTLA-4 (up to 100 µg). OVA specific immune responses were measured by ELISpot. Anti-tumor efficacy was then investigated with a similar administration scheme in a therapeutic B16F10 mice melanoma model with a DNA vector coding for the B16F10-M30 tumor neoantigen. Results: At an optimal dose of 2.5x106 pfu, MVA significantly improved OVA specific immune response up to 10 times higher as compared to vector alone. Addition of CTLA-4 blockade further increased the magnitude of response, up to 30 times higher than with vector alone. Both MVA and CTLA-4 demonstrated a bell-shaped dose dependent effect. In tumor-bearing animals, 80% experienced durable tumor-free survival when treated with the combination therapy as compared to less than 20% in untreated animals or animals treated with each component independently. Treatment appeared feasible and well-tolerated. Conclusions: Neoantigen coding DNA vector, MVA and CTLA-4 immune checkpoint blockade, when co-administered in immunocompetent C57BL6 mice, acted synergistically to induce a cellular immune response. The same approach translated into a strong anti-tumoral response in an aggressive melanoma model. This combined immunization platform appears as a potential novel way to enhance clinical benefit from current immune checkpoint inhibitors.

Published
2019
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44. Development and underground test of radiopure ZnMoO4 scintillating bolometers for the LUMINEU 0 nu 2 beta project

Author

J. Gascon, R. J. Walker, O. Plantevin, A. A. Drillien, V.N. Shlegel, M. Gros, S. Marnieros, K. Eitel, V. Kozlov, Christian Enss, M. Kleifges, B. Paul, T. de Boissière, C. Nones, C. Augier, L. Hehn, E. Olivieri, E. Yakushev, P. Coulter, C. Kéfélian, V. Humbert, G. Gerbier, M. Rodrigues, M. Chapellier, N. Foerster, A. Giuliani, S. Scorza, V. B. Brudanin, G. Heuermann, T. Redon, F. Koskas, L. Dumoulin, P. de Marcillac, Claire A. Marrache-Kikuchi, P. Magnier, S. Hervé, N. Fourches, L. Vagneron, H. Kraus, V.N. Zhdankov, A. Menshikov, M.-C. Piro, Max Robinson, Y. Penichot, X-F. Navick, Matias Velázquez, I.M. Ivanov, V. V. Kobychev, P. Pari, A. Broniatowski, R. Decourt, A. Cazes, D. Filosofov, A. Fleischmann, Oudomsack Viraphong, O. Strazzer, Denis Tcherniakhovski, G. Pessina, D. Gray, L. Gastaldo, Noël Coron, M. Loidl, Ph. Camus, L. Bergé, Alain Benoit, E.P. Makarov, V. A. Kudryavtsev, D.M. Chernyak, S. Henry, E. Armengaud, L. Devoyon, B. Schmidt, F.A. Danevich, Ya.V. Vasiliev, J. Blümer, M. Mancuso, R.S. Boiko, M. De Jesus, M. Tenconi, S. V. Rozov, Marc Weber, D.V. Poda, V.I. Tretyak, H. Kluck, T. Bergmann, Q. Arnaud, H. Le Sueur, X. Zhang, V. Sanglard, B. Siebenborn, A. Juillard, S.G. Nasonov, F. Charlieux, L. Torres, Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut de Physique Nucléaire de Lyon (IPNL), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), Hélium : du fondamental aux applications (HELFA), Institut Néel (NEEL), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Centre de Sciences Nucléaires et de Sciences de la Matière (CSNSM), Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris-Sud - Paris 11 (UP11), Kiev Institute for Nuclear Research (KINR), Ukrainian Academy of Sciences, Karlsruhe Institute of Technology (KIT), Dzhelepov Laboratory of Nuclear Problems [Dubna] (DLNP), Joint Institute for Nuclear Research (JINR), Cryogénie (Cryo), Institut d'astrophysique spatiale (IAS), Université Paris-Sud - Paris 11 (UP11)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Oxford [Oxford], Institut de Chimie de la Matière Condensée de Bordeaux (ICMCB), Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Karlsruher Institut für Technologie (KIT), Kirchhoff Institute for Physics, Universität Heidelberg [Heidelberg], Nikolaev Institute of Inorganic Chemistry [Novosibirsk] (NIC), Siberian Branch of the Russian Academy of Sciences (SB RAS), University of Sheffield [Sheffield], Laboratoire National Henri Becquerel (LNHB), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Service de physique de l'état condensé (SPEC - UMR3680), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Istituto Nazionale di Fisica Nucleare, Sezione di Milano (INFN), Istituto Nazionale di Fisica Nucleare (INFN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université de Bordeaux (UB), CML Ltd, ANR-12-BS05-0004,LUMINEU,Expérience souterraine avec détecteurs luminescents de molybdate de zinc pour l'étude de la masse et la nature des neutrinos(2012), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Hélium : du fondamental aux applications (NEEL - HELFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Cryogénie (NEEL - Cryo), Université Paris-Sud - Paris 11 (UP11)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National d’Études Spatiales [Paris] (CNES), University of Oxford, Universität Heidelberg [Heidelberg] = Heidelberg University, Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Département d'instrumentation Numérique (DIN (CEA-LIST)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), HELFA - Hélium : du fondamental aux applications, Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CSNSM PS1, Centre de Spectrométrie Nucléaire et de Spectrométrie de Masse (CSNSM), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Centre de Sciences Nucléaires et de Sciences de la Matière (CSNSM), Laboratory of Particle Physics (JINR-DUBNA), Joint Institute for Nuclear Research, Cryo - Cryogénie, Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Technologique (CEA) (DRT (CEA)), Institut Rayonnement Matière de Saclay (IRAMIS), Istituto Nazionale di Fisica Nucleare [Milano] (INFN), Joint Institute for Nuclear Research - Dubna, ANR-12-BS05-004,LUMINEU,Luminescent Underground Molybdenum Investigation for NEUtrino mass and nature, Armengaud, E, Arnaud, Q, Augier, C, Benoit, A, Berge, L, Boiko, R, Bergmann, T, Blumer, J, Broniatowski, A, Brudanin, V, Camus, P, Cazes, A, Chapellier, M, Charlieux, F, Chernyak, D, Coron, N, Coulter, P, Danevich, F, De Boissiere, T, Decourt, R, Jesus, M, Devoyon, L, Drillien, A, Dumoulin, L, Eitel, K, Enss, C, Filosofov, D, Fleischmann, A, Foerster, N, Fourches, N, Gascon, J, Gastaldo, L, Gerbier, G, Giuliani, A, Gray, D, Gros, M, Hehn, L, Henry, S, Herve, S, Heuermann, G, Humbert, V, Ivanov, I, Juillard, A, Kefelian, C, Kleifges, M, Kluck, H, Kobychev, V, Koskas, F, Kozlov, V, Kraus, H, Kudryavtsev, V, Sueur, H, Loidl, M, Magnier, P, Makarov, E, Mancuso, M, De Marcillac, P, Marnieros, S, Marrache-Kikuchi, C, Menshikov, A, Nasonov, S, Navick, X, Nones, C, Olivieri, E, Pari, P, Paul, B, Penichot, Y, Pessina, G, Piro, M, Plantevin, O, Poda, D, Redon, T, Robinson, M, Rodrigues, M, Rozov, S, Sanglard, V, Schmidt, B, Scorza, S, Shlegel, V, Siebenborn, B, Strazzer, O, Tcherniakhovski, D, Tenconi, M, Torres, L, Tretyak, V, Vagneron, L, Vasiliev, Y, Velazquez, M, Viraphong, O, Walker, R, Weber, M, Yakushev, E, Zhang, X, and Zhdankov, V

Subjects
gas and liquid scintillators), Zinc molybdate, Cryogenic detector, EDELWEISS, Scintillator, 01 natural sciences, Nuclear physics, CRYSTAL SCINTILLATORS, chemistry.chemical_compound, Double beta decay, 0103 physical sciences, Dilution refrigerator, [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], [PHYS.COND]Physics [physics]/Condensed Matter [cond-mat], 010306 general physics, Instrumentation, GRADIENT CZOCHRALSKI TECHNIQUE, Mathematical Physics, Physics, TUNGSTATES, 010308 nuclear & particles physics, Hybrid detector, DOUBLE-BETA-DECAY, Hybrid detectors, Scintillators, scintillation and light emission processes (solid, gas and liquid scintillators), Double-beta decay detectors, Double-beta decay detector, DARK-MATTER SEARCH, scintillation and light emission processes (solid, RADIOACTIVE CONTAMINATION, Cryogenic detectors, chemistry, Scintillators, LUMINESCENCE, [PHYS.COND.CM-MS]Physics [physics]/Condensed Matter [cond-mat]/Materials Science [cond-mat.mtrl-sci], PARTICLE PHYSICS, GROWTH, SINGLE-CRYSTALS, Neutrino, Isotopes of thorium, Radioactive decay
Abstract

International audience; The LUMINEU (Luminescent Underground Molybdenum Investigation for NEUtrino mass and nature) project envisages a high-sensitivity search for neutrinoless double beta (0 nu 2 beta) decay of Mo-100 with the help of scintillating bolometers based on zinc molybdate (ZnMoO4) crystals. One of the crucial points for the successful performance of this experiment is the development of a protocol for producing high quality large mass ZnMoO4 crystal scintillators with extremely high internal radiopurity. Here we report a significant progress in the development of large volume ZnMoO4 crystalline boules (with mass up to 1 kg) from deeply purified materials. We present and discuss the results achieved with two ZnMoO4 samples (with mass of about 0.3 kg each): one is a precursor of the LUMINEU project, while the other one was produced in the framework of LUMINEU with an improved purification / crystallization procedure. The two crystals were measured deep underground as scintillating bolometers in the EDELWEISS dilution refrigerator at the Laboratoire Souterrain de Modane (France) protected by a rock overburden corresponding to 4800 m w.e. The results indicate that both tested crystals are highly radiopure. However, the advanced LUMINEU sample shows a clear improvement with respect to the precursor, exhibiting only a trace internal contamination related with Po-210 at the level of 1 mBq/kg, while the activity of Ra-226 and Th-228 is below 0.005 mBq/kg. This demonstrates that the LUMINEU purification and crystal-growth procedures are very efficient and leads to radiopurity levels which exceedingly satisfy not only the LUMINEU goals but also the requirements of a next-generation 0 nu 2 beta experiment.

Published
2015
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45. Low-Birthweight Children at Early School-Age: A Longitudinal Study.

Author

Drillien, C. M.

Abstract

Eighty-seven percent of a cohort of 299 low birthweight infants were examined at age 6 2/3 years, together with 111 control children. Primary school problems were related to social grade, early intrauterine insult, sex, postnatal complications, and neurological and developmental status in the infant's first year. Journal Availability: J. B. Lippincott Co., E. Washington Sq., Philadelphia, PA 19105. (Author/SBH)

Published
1980

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Author

Armengaud, E, Arnaud, Q, Augier, C, Benoit, A, Berge, L, Boiko, R, Bergmann, T, Blumer, J, Broniatowski, A, Brudanin, V, Camus, P, Cazes, A, Chapellier, M, Charlieux, F, Chernyak, D, Coron, N, Coulter, P, Danevich, F, De Boissiere, T, Decourt, R, Jesus, M, Devoyon, L, Drillien, A, Dumoulin, L, Eitel, K, Enss, C, Filosofov, D, Fleischmann, A, Foerster, N, Fourches, N, Gascon, J, Gastaldo, L, Gerbier, G, Giuliani, A, Gray, D, Gros, M, Hehn, L, Henry, S, Herve, S, Heuermann, G, Humbert, V, Ivanov, I, Juillard, A, Kefelian, C, Kleifges, M, Kluck, H, Kobychev, V, Koskas, F, Kozlov, V, Kraus, H, Kudryavtsev, V, Sueur, H, Loidl, M, Magnier, P, Makarov, E, Mancuso, M, De Marcillac, P, Marnieros, S, Marrache-Kikuchi, C, Menshikov, A, Nasonov, S, Navick, X, Nones, C, Olivieri, E, Pari, P, Paul, B, Penichot, Y, Pessina, G, Piro, M, Plantevin, O, Poda, D, Redon, T, Robinson, M, Rodrigues, M, Rozov, S, Sanglard, V, Schmidt, B, Scorza, S, Shlegel, V, Siebenborn, B, Strazzer, O, Tcherniakhovski, D, Tenconi, M, Torres, L, Tretyak, V, Vagneron, L, Vasiliev, Y, Velazquez, M, Viraphong, O, Walker, R, Weber, M, Yakushev, E, Zhang, X, Zhdankov, V, Armengaud E., Arnaud Q., Augier C., Benoit A., Berge L., Boiko R. S., Bergmann T., Blumer J., Broniatowski A., Brudanin V., Camus P., Cazes A., Chapellier M., Charlieux F., Chernyak D. M., Coron N., Coulter P., Danevich F. A., De Boissiere T., Decourt R., Jesus M. D., Devoyon L., Drillien A. -A., Dumoulin L., Eitel K., Enss C., Filosofov D., Fleischmann A., Foerster N., Fourches N., Gascon J., Gastaldo L., Gerbier G., Giuliani A., Gray D., Gros M., Hehn L., Henry S., Herve S., Heuermann G., Humbert V., Ivanov I. M., Juillard A., Kefelian C., Kleifges M., Kluck H., Kobychev V. V., Koskas F., Kozlov V., Kraus H., Kudryavtsev V. A., Sueur H. L., Loidl M., Magnier P., Makarov E. P., Mancuso M., De Marcillac P., Marnieros S., Marrache-Kikuchi C., Menshikov A., Nasonov S. G., Navick X. -F., Nones C., Olivieri E., Pari P., Paul B., Penichot Y., Pessina G., Piro M. C., Plantevin O., Poda D. V., Redon T., Robinson M., Rodrigues M., Rozov S., Sanglard V., Schmidt B., Scorza S., Shlegel V. N., Siebenborn B., Strazzer O., Tcherniakhovski D., Tenconi M., Torres L., Tretyak V. I., Vagneron L., Vasiliev Y. V., Velazquez M., Viraphong O., Walker R. J., Weber M., Yakushev E., Zhang X., Zhdankov V. N., Armengaud, E, Arnaud, Q, Augier, C, Benoit, A, Berge, L, Boiko, R, Bergmann, T, Blumer, J, Broniatowski, A, Brudanin, V, Camus, P, Cazes, A, Chapellier, M, Charlieux, F, Chernyak, D, Coron, N, Coulter, P, Danevich, F, De Boissiere, T, Decourt, R, Jesus, M, Devoyon, L, Drillien, A, Dumoulin, L, Eitel, K, Enss, C, Filosofov, D, Fleischmann, A, Foerster, N, Fourches, N, Gascon, J, Gastaldo, L, Gerbier, G, Giuliani, A, Gray, D, Gros, M, Hehn, L, Henry, S, Herve, S, Heuermann, G, Humbert, V, Ivanov, I, Juillard, A, Kefelian, C, Kleifges, M, Kluck, H, Kobychev, V, Koskas, F, Kozlov, V, Kraus, H, Kudryavtsev, V, Sueur, H, Loidl, M, Magnier, P, Makarov, E, Mancuso, M, De Marcillac, P, Marnieros, S, Marrache-Kikuchi, C, Menshikov, A, Nasonov, S, Navick, X, Nones, C, Olivieri, E, Pari, P, Paul, B, Penichot, Y, Pessina, G, Piro, M, Plantevin, O, Poda, D, Redon, T, Robinson, M, Rodrigues, M, Rozov, S, Sanglard, V, Schmidt, B, Scorza, S, Shlegel, V, Siebenborn, B, Strazzer, O, Tcherniakhovski, D, Tenconi, M, Torres, L, Tretyak, V, Vagneron, L, Vasiliev, Y, Velazquez, M, Viraphong, O, Walker, R, Weber, M, Yakushev, E, Zhang, X, Zhdankov, V, Armengaud E., Arnaud Q., Augier C., Benoit A., Berge L., Boiko R. S., Bergmann T., Blumer J., Broniatowski A., Brudanin V., Camus P., Cazes A., Chapellier M., Charlieux F., Chernyak D. M., Coron N., Coulter P., Danevich F. A., De Boissiere T., Decourt R., Jesus M. D., Devoyon L., Drillien A. -A., Dumoulin L., Eitel K., Enss C., Filosofov D., Fleischmann A., Foerster N., Fourches N., Gascon J., Gastaldo L., Gerbier G., Giuliani A., Gray D., Gros M., Hehn L., Henry S., Herve S., Heuermann G., Humbert V., Ivanov I. M., Juillard A., Kefelian C., Kleifges M., Kluck H., Kobychev V. V., Koskas F., Kozlov V., Kraus H., Kudryavtsev V. A., Sueur H. L., Loidl M., Magnier P., Makarov E. P., Mancuso M., De Marcillac P., Marnieros S., Marrache-Kikuchi C., Menshikov A., Nasonov S. G., Navick X. -F., Nones C., Olivieri E., Pari P., Paul B., Penichot Y., Pessina G., Piro M. C., Plantevin O., Poda D. V., Redon T., Robinson M., Rodrigues M., Rozov S., Sanglard V., Schmidt B., Scorza S., Shlegel V. N., Siebenborn B., Strazzer O., Tcherniakhovski D., Tenconi M., Torres L., Tretyak V. I., Vagneron L., Vasiliev Y. V., Velazquez M., Viraphong O., Walker R. J., Weber M., Yakushev E., Zhang X., and Zhdankov V. N.

Published
2015

48. KAY-2-41, a Novel Nucleoside Analogue Inhibitor of Orthopoxviruses In Vitro and In Vivo

Author

Sophie Duraffour, Dimitrios Topalis, Graciela Andrei, Jan Balzarini, Kazuhiro Haraguchi, Robert Drillien, Robert Snoeck, and Joost van den Oord

Subjects
Genotype, Camelpox virus, viruses, Vaccinia virus, Orthopoxvirus, Thiophenes, medicine.disease_cause, Antiviral Agents, Virus, chemistry.chemical_compound, medicine, Pharmacology (medical), Cowpox virus, Pharmacology, Molecular Structure, biology, Nucleoside analogue, biology.organism_classification, Virology, Infectious Diseases, Herpes simplex virus, chemistry, Thymidine kinase, Vaccinia, Thymidine, medicine.drug, Cidofovir
Abstract

The availability of adequate treatments for poxvirus infections would be valuable not only for human use but also for veterinary use. In the search for novel antiviral agents, a 1′-methyl-substituted 4′-thiothymidine nucleoside, designated KAY-2-41, emerged as an efficient inhibitor of poxviruses. In vitro , KAY-2-41 was active in the micromolar range against orthopoxviruses (OPVs) and against the parapoxvirus orf. The compound preserved its antiviral potency against OPVs resistant to the reference molecule cidofovir. KAY-2-41 had no noticeable toxicity on confluent monolayers, but a cytostatic effect was seen on growing cells. Genotyping of vaccinia virus (VACV), cowpox virus, and camelpox virus selected for resistance to KAY-2-41 revealed a nucleotide deletion(s) close to the ATP binding site or a nucleotide substitution close to the substrate binding site in the viral thymidine kinase (TK; J2R ) gene. These mutations resulted in low levels of resistance to KAY-2-41 ranging from 2.7- to 6.0-fold and cross-resistance to 5-bromo-2′-deoxyuridine (5-BrdU) but not to cidofovir. The antiviral effect of KAY-2-41 relied, at least in part, on activation (phosphorylation) by the viral TK, as shown through enzymatic assays. The compound protected animals from disease and mortality after a lethal challenge with VACV, reduced viral loads in the serum, and abolished virus replication in tissues. In conclusion, KAY-2-41 is a promising nucleoside analogue for the treatment of poxvirus-induced diseases. Our findings warrant the evaluation of additional 1′-carbon-substituted 4′-thiothymidine derivatives as broad-spectrum antiviral agents, since this molecule also showed antiviral potency against herpes simplex virus 1 in earlier studies.

Published
2014
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