Centre de Gestion Scientifique

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. METHODS: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). FINDINGS: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6-58·8) of global deaths and 41·2% (39·8-42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. INTERPRETATION: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. FUNDING: Bill & Melinda Gates Foundation.

This paper presents cosmological results based on full-mission Planck observations of temperature and polarization anisotropies of the cosmic microwave background (CMB) radiation. Our results are in very good agreement with the 2013 analysis of the Planck nominal-mission temperature data, but with increased precision. The temperature and polarization power spectra are consistent with the standard spatially-flat 6-parameter ΛCDM cosmology with a power-law spectrum of adiabatic scalar perturbations (denoted “base ΛCDM” in this paper). From the Planck temperature data combined with Planck lensing, for this cosmology we find a Hubble constant, H0 = (67.8 ± 0.9) km s-1Mpc-1, a matter density parameter Ωm = 0.308 ± 0.012, and a tilted scalar spectral index with ns = 0.968 ± 0.006, consistent with the 2013 analysis. Note that in this abstract we quote 68% confidence limits on measured parameters and 95% upper limits on other parameters. We present the first results of polarization measurements with the Low Frequency Instrument at large angular scales. Combined with the Planck temperature and lensing data, these measurements give a reionization optical depth of τ = 0.066 ± 0.016, corresponding to a reionization redshift of zre=8.8-1.4+1.7. These results are consistent with those from WMAP polarization measurements cleaned for dust emission using 353-GHz polarization maps from the High Frequency Instrument. We find no evidence for any departure from base ΛCDM in the neutrino sector of the theory; for example, combining Planck observations with other astrophysical data we find Neff = 3.15 ± 0.23 for the effective number of relativistic degrees of freedom, consistent with the value Neff = 3.046 of the Standard Model of particle physics. The sum of neutrino masses is constrained to ∑ mν < 0.23 eV. The spatial curvature of our Universe is found to be very close to zero, with | ΩK | < 0.005. Adding a tensor component as a single-parameter extension to base ΛCDM we find an upper limit on the tensor-to-scalar ratio of r0.002< 0.11, consistent with the Planck 2013 results and consistent with the B-mode polarization constraints from a joint analysis of BICEP2, Keck Array, and Planck (BKP) data. Adding the BKP B-mode data to our analysis leads to a tighter constraint of r0.002 < 0.09 and disfavours inflationarymodels with a V(φ) ∝ φ2 potential. The addition of Planck polarization data leads to strong constraints on deviations from a purely adiabatic spectrum of fluctuations. We find no evidence for any contribution from isocurvature perturbations or from cosmic defects. Combining Planck data with other astrophysical data, including Type Ia supernovae, the equation of state of dark energy is constrained to w = −1.006 ± 0.045, consistent with the expected value for a cosmological constant. The standard big bang nucleosynthesis predictions for the helium and deuterium abundances for the best-fit Planck base ΛCDM cosmology are in excellent agreement with observations. We also constraints on annihilating dark matter and on possible deviations from the standard recombination history. In neither case do we find no evidence for new physics. The Planck results for base ΛCDM are in good agreement with baryon acoustic oscillation data and with the JLA sample of Type Ia supernovae. However, as in the 2013 analysis, the amplitude of the fluctuation spectrum is found to be higher than inferred from some analyses of rich cluster counts and weak gravitational lensing. We show that these tensions cannot easily be resolved with simple modifications of the base ΛCDM cosmology. Apart from these tensions, the base ΛCDM cosmology provides an excellent description of the Planck CMB observations and many other astrophysical data sets.

Phylogenetic analyses are central to many research areas in biology and typically involve the identification of homologous sequences, their multiple alignment, the phylogenetic reconstruction and the graphical representation of the inferred tree. The Phylogeny.fr platform transparently chains programs to automatically perform these tasks. It is primarily designed for biologists with no experience in phylogeny, but can also meet the needs of specialists; the first ones will find up-to-date tools chained in a phylogeny pipeline to analyze their data in a simple and robust way, while the specialists will be able to easily build and run sophisticated analyses. Phylogeny.fr offers three main modes. The 'One Click' mode targets non-specialists and provides a ready-to-use pipeline chaining programs with recognized accuracy and speed: MUSCLE for multiple alignment, PhyML for tree building, and TreeDyn for tree rendering. All parameters are set up to suit most studies, and users only have to provide their input sequences to obtain a ready-to-print tree. The 'Advanced' mode uses the same pipeline but allows the parameters of each program to be customized by users. The 'A la Carte' mode offers more flexibility and sophistication, as users can build their own pipeline by selecting and setting up the required steps from a large choice of tools to suit their specific needs. Prior to phylogenetic analysis, users can also collect neighbors of a query sequence by running BLAST on general or specialized databases. A guide tree then helps to select neighbor sequences to be used as input for the phylogeny pipeline. Phylogeny.fr is available at: http://www.phylogeny.fr/

Geant4 is a software toolkit for the simulation of the passage of particles through matter. It is used by a large number of experiments and projects in a variety of application domains, including high energy physics, astrophysics and space science, medical physics and radiation protection. Over the past several years, major changes have been made to the toolkit in order to accommodate the needs of these user communities, and to efficiently exploit the growth of computing power made available by advances in technology. The adaptation of Geant4 to multithreading, advances in physics, detector modeling and visualization, extensions to the toolkit, including biasing and reverse Monte Carlo, and tools for physics and release validation are discussed here.

Abstract. The Model for Ozone and Related chemical Tracers, version 4 (MOZART-4) is an offline global chemical transport model particularly suited for studies of the troposphere. The updates of the model from its previous version MOZART-2 are described, including an expansion of the chemical mechanism to include more detailed hydrocarbon chemistry and bulk aerosols. Online calculations of a number of processes, such as dry deposition, emissions of isoprene and monoterpenes and photolysis frequencies, are now included. Results from an eight-year simulation (2000–2007) are presented and evaluated. The MOZART-4 source code and standard input files are available for download from the NCAR Community Data Portal (http://cdp.ucar.edu).

We present the global general circulation model IPSL-CM5 developed to study the long-term response of the climate system to natural and anthropogenic forcings as part of the 5th Phase of the Coupled Model Intercomparison Project (CMIP5). This model includes an interactive carbon cycle, a representation of tropospheric and stratospheric chemistry, and a comprehensive representation of aerosols. As it represents the principal dynamical, physical, and bio-geochemical processes relevant to the climate system, it may be referred to as an Earth System Model. However, the IPSL-CM5 model may be used in a multitude of configurations associated with different boundary conditions and with a range of complexities in terms of processes and interactions. This paper presents an overview of the different model components and explains how they were coupled and used to simulate historical climate changes over the past 150 years and different scenarios of future climate change. A single version of the IPSL-CM5 model (IPSL-CM5A-LR) was used to provide climate projections associated with different socio-economic scenarios, including the different Representative Concentration Pathways considered by CMIP5 and several scenarios from the Special Report on Emission Scenarios considered by CMIP3. Results suggest that the magnitude of global warming projections primarily depends on the socio-economic scenario considered, that there is potential for an aggressive mitigation policy to limit global warming to about two degrees, and that the behavior of some components of the climate system such as the Arctic sea ice and the Atlantic Meridional Overturning Circulation may change drastically by the end of the twenty-first century in the case of a no climate policy scenario. Although the magnitude of regional temperature and precipitation changes depends fairly linearly on the magnitude of the projected global warming (and thus on the scenario considered), the geographical pattern of these changes is strikingly similar for the different scenarios. The representation of atmospheric physical processes in the model is shown to strongly influence the simulated climate variability and both the magnitude and pattern of the projected climate changes.

Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved the ability to interact with a diverse chemical environment, as shown by large expansions in odorant and gustatory receptors, as well as P450 and other detoxification enzymes. Development in Tribolium is more representative of other insects than is Drosophila, a fact reflected in gene content and function. For example, Tribolium has retained more ancestral genes involved in cell–cell communication than Drosophila, some being expressed in the growth zone crucial for axial elongation in short-germ development. Systemic RNA interference in T. castaneum functions differently from that in Caenorhabditis elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control. The red flour beetle Tribolium castaneum is a common pest: a type of 'bran bug', it targets cereal products, including grain, flour and rice bran. It is also a commonly used laboratory model, combining the ease of systematic RNA interference experiments such as those used with the nematode worm C. elegans with a biology that is more representative of most insects than even Drosophila. This weeks sees the publication by the Tribolium Genome Sequencing Consortium of the genomic sequence of T. castaneum. This is the first beetle genome to be published, and it will be a valuable resource for insect development studies and pest biology. The beetle Tribolium castaneum is a commonly used laboratory model, combining the ease of systematic RNAi experiments like those in Caenorhabditis elegans, with biology that is more representative of most insects than Drosophila melanogaster. A large consortium has sequenced and analysed the genome of the red flour beetle, creating a resource for biologists everywhere.

We propose a novel and fast multiscale feature detection and description approach that exploits the benefits of nonlinear scale spaces. Previous attempts to detect and describe features in nonlinear scale spaces such as KAZE [1] and BFSIFT [6] are highly time consuming due to the computational burden of creating the nonlinear scale space. In this paper we propose to use recent numerical schemes called Fast Explicit Diffusion (FED) [3, 4] embedded in a pyramidal framework to dramatically speed-up feature detection in nonlinear scale spaces. In addition, we introduce a Modified-Local Difference Binary (M-LDB) descriptor that is highly efficient, exploits gradient information from the nonlinear scale space, is scale and rotation invariant and has low storage requirements. Our features are called Accelerated-KAZE (A-KAZE) due to the dramatic speed-up introduced by FED schemes embedded in a pyramidal framework.

In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today's technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics.

The Pierre Auger Observatory, located on a vast, high plain in western Argentina, is the world's largest cosmic ray observatory. The objectives of the Observatory are to probe the origin and characteristics of cosmic rays above 10 17 eV and to study the interactions of these, the most energetic particles observed in nature. The Auger design features an array of 1660 water Cherenkov particle detector stations spread over 3000 km 2 overlooked by 24 air fluorescence telescopes. In addition, three high elevation fluorescence telescopes overlook a 23.5 km 2 , 61-detector infilled array with 750 m spacing. The Observatory has been in successful operation since completion in 2008 and has recorded data from an exposure exceeding 40,000 km 2 sr yr. This paper describes the design and performance of the detectors, related subsystems and infrastructure that make up the Observatory.

Correct expression of the genetic code at translation is directly correlated with tRNA identity. This survey describes the molecular signals in tRNAs that trigger specific aminoacylations. For most tRNAs, determinants are located at the two distal extremities: the anticodon loop and the amino acid accepting stem. In a few tRNAs, however, major identity signals are found in the core of the molecule. Identity elements have different strengths, often depend more on k cat effects than on K m effects and exhibit additive, cooperative or anti-cooperative interplay. Most determinants are in direct contact with cognate synthetases, and chemical groups on bases or ribose moieties that make functional interactions have been identified in several systems. Major determinants are conserved in evolution; however, the mechanisms by which they are expressed are species dependent. Recent studies show that alternate identity sets can be recognized by a single synthetase, and emphasize the importance of tRNA architecture and anti-determinants preventing false recognition. Identity rules apply to tRNA-like molecules and to minimalist tRNAs. Knowledge of these rules allows the manipulation of identity elements and engineering of tRNAs with switched, altered or multiple specificities.

Obesity is globaLy prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined aSociations betwEn body maS index and ĝ̂1/42.8 miLion SNPs in up to 123,865 individuals with targeted foLow up of 42 SNPs in up to 125,931 aDitional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci aSociated with body maS index (P < 5-10 -8 ), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly aSociated loci may provide new insights into human body weight regulation. © 2010 Nature America, Inc. All rights reserved.

We have studied the apoptotic response of poly(ADP-ribose) polymerase (PARP)−/− cells to different inducers and the consequences of the expression of an uncleavable mutant of PARP on the apoptotic process. The absence of PARP drastically increases the sensitivity of primary bone marrow PARP−/− cells to apoptosis induced by an alkylating agent but not by a topoisomerase I inhibitor CPT-11 or by interleukin-3 removal. cDNA of wild type or of an uncleavable PARP mutant (D214A-PARP) has been introduced into PARP−/− fibroblasts, which were exposed to anti-CD95 or an alkylating agent to induce apoptosis. The expression of D214A-PARP results in a significant delay of cell death upon CD95 stimulation. Morphological analysis shows a retarded cell shrinkage and nuclear condensation. Upon treatment with an alkylating agent, expression of wild-type PARP cDNA into PARP-deficient mouse embryonic fibroblasts results in the restoration of the cell viability, and the D214A-PARP mutant had no further effect on cell recovery. In conclusion, PARP−/− cells are extremely sensitive to apoptosis induced by triggers (like alkylating agents), which activates the base excision repair pathway of DNA, and the cleavage of PARP during apoptosis facilitates cellular disassembly and ensures the completion and irreversibility of the process. We have studied the apoptotic response of poly(ADP-ribose) polymerase (PARP)−/− cells to different inducers and the consequences of the expression of an uncleavable mutant of PARP on the apoptotic process. The absence of PARP drastically increases the sensitivity of primary bone marrow PARP−/− cells to apoptosis induced by an alkylating agent but not by a topoisomerase I inhibitor CPT-11 or by interleukin-3 removal. cDNA of wild type or of an uncleavable PARP mutant (D214A-PARP) has been introduced into PARP−/− fibroblasts, which were exposed to anti-CD95 or an alkylating agent to induce apoptosis. The expression of D214A-PARP results in a significant delay of cell death upon CD95 stimulation. Morphological analysis shows a retarded cell shrinkage and nuclear condensation. Upon treatment with an alkylating agent, expression of wild-type PARP cDNA into PARP-deficient mouse embryonic fibroblasts results in the restoration of the cell viability, and the D214A-PARP mutant had no further effect on cell recovery. In conclusion, PARP−/− cells are extremely sensitive to apoptosis induced by triggers (like alkylating agents), which activates the base excision repair pathway of DNA, and the cleavage of PARP during apoptosis facilitates cellular disassembly and ensures the completion and irreversibility of the process. Apoptosis or programmed cell death is a fundamental biological process that plays an important role in early development, cell homeostasis, and in diseases such as neurodegenerative disorders and cancer (1Kerr J.F.R. Winterford C.M. Harmon B.V. Cancer. 1994; 73: 2013-2026Crossref PubMed Scopus (2167) Google Scholar, 2Kusiak J.W. Izzo J.A. Zhao B. Mol. Chem. Neuropathol. 1996; 28: 153-162Crossref PubMed Scopus (33) Google Scholar, 3Jacobson M.D. Weill M. Raff M.C. Cell. 1997; 88: 347-354Abstract Full Text Full Text PDF PubMed Scopus (2415) Google Scholar). Programmed cell death can occur in response to many stimuli such as genotoxic insult when DNA repair is saturated, removal of growth factors, or activation of the CD95 antigen by CD95 ligand or anti-CD95 antibodies. Morphologically it is characterized by the appearance of membrane blebbing, cell shrinkage, chromatin condensation, and DNA cleavage, and finally the cell is fragmented into membrane-bound apoptotic bodies. At the biochemical level, there is increasing evidence for a central role of the family of cysteine proteases, the caspases, in the pathway that mediates the highly ordered process leading to cell death (4Nicholson D. Thornberry N. Trends Biochem. Sci. 1997; 22: 299-306Abstract Full Text PDF PubMed Scopus (2187) Google Scholar). Caspases have been identified as the enzymes responsible for the proteolysis of key proteins to be selectively cleaved at the onset of apoptosis. It appears that the role of these proteases in cell suicide is to disable critical homeostatic and repair enzymes as well as key structural components. A discrete but increasing number of specific proteins appears to be targeted for proteolytic cleavage during apoptosis, including poly(ADP-ribose) polymerase (PARP, 1The abbreviations used are: PARP, poly(ADP-ribose) polymerase; MEF, mouse embryonic fibroblast; PBS, phosphate-buffered saline; MMS, N-methylmethanesulfonate; MNU, methylnitrosourea; wt, wild-type; X-gal, 5-bromo-4-chloro-3-indolyl β-d-galactopyranoside; BM, bone marrow; BER, base excision repair; GFP, green fluorescence protein. EC 2.4.2.30), which was first described in Ref. 5Lazebnik Y.A. Kaufmann S.H. Desnoyers S. Poirier G.G. Earnshaw W.C. Nature. 1994; 371: 346-347Crossref PubMed Scopus (2351) Google Scholar. In the last years, cleavage of PARP has been used extensively as a marker of apoptosis. However, the reason for the cell to inactivate this protein during the execution phase of apoptosis is not fully understood. PARP is a nuclear zinc finger DNA-binding protein that detects and binds to DNA strand breaks. PARP has a modular organization comprising a NH2-terminal DNA-binding domain, a central regulatory domain, and a COOH-terminal catalytic domain. At a site of DNA breakage, PARP catalyzes the transfer of the ADP-ribose moiety from its substrate, NAD+, to a limited number of protein acceptors (heteromodification) involved in chromatin architecture (histones H1 and H2B, lamin B) or in DNA metabolism (topoisomerases, DNA replication factors) including PARP itself (automodification) (6Althaus F.R. Richter C. Mol. Biol. Biochem. Biophys. 1987; 37: 1-237PubMed Google Scholar, 7de Murcia G. Ménissier-de Murcia J. Trends Biochem. Sci. 1994; 19: 172-176Abstract Full Text PDF PubMed Scopus (763) Google Scholar, 8Lautier D. Hoflack J.C. Kirkland J.B. Poirier D. Poirier G.G. Biochim. Biophys. Acta. 1994; 1221: 215-220Crossref PubMed Scopus (18) Google Scholar, 9Oei S. Griesenbeck J. Schweiger M. Rev. Physiol. Biochem. Pharmacol. 1997; 131: 4135-4137Google Scholar). Mice lacking PARP have been generated by homologous recombination to assess the biological consequences of PARP deficiency (10Wang Z.Q. Auer B. Stingl L. Berghammer H. Haidacher D. Schweiger M. Wagner E.W. Genes Dev. 1995; 9: 509-520Crossref PubMed Scopus (715) Google Scholar, 11Ménissier de Murcia J. Niedergang C. Trucco C. Ricoul M. Dutrillaux B. Mark M. Oliver F.J. Masson M. Dierich A. LeMeur M. Walztinger C. Chambon P. de Murcia G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 7303-7307Crossref PubMed Scopus (968) Google Scholar, 12Wang Z.-Q. Stingl L. Morrison C. Jantsch M. Marek L. Schulze-Ostoff K. Wagner E. Genes Dev. 1997; 18: 2347-2358Crossref Scopus (517) Google Scholar). We have reported that PARP−/− mice are hypersensitive to genotoxic agents, like γ-rays and monofunctional alkylating agents, compared with their +/+ litter mates. Mutant mice displayed genomic instability as shown by an increased rate of sister chromatid exchanges and an increased occurrence of chromosomal breaks in their bone marrow cells. Using PARP−/− mice-derived cells, we and others have established that apoptosis occurs in the absence of PARP (11Ménissier de Murcia J. Niedergang C. Trucco C. Ricoul M. Dutrillaux B. Mark M. Oliver F.J. Masson M. Dierich A. LeMeur M. Walztinger C. Chambon P. de Murcia G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 7303-7307Crossref PubMed Scopus (968) Google Scholar, 12Wang Z.-Q. Stingl L. Morrison C. Jantsch M. Marek L. Schulze-Ostoff K. Wagner E. Genes Dev. 1997; 18: 2347-2358Crossref Scopus (517) Google Scholar, 13Leist M. Single B. Künstle G. Volbracht C. Hentze H. Nicotera P. Biochem. Biophys. Res. Commun. 1997; 233: 518-522Crossref PubMed Scopus (135) Google Scholar). However, we have shown that PARP−/− splenocytes exposed to a monofunctional alkylating agent underwent much more rapid apoptosis than wild-type (wt) cells (11Ménissier de Murcia J. Niedergang C. Trucco C. Ricoul M. Dutrillaux B. Mark M. Oliver F.J. Masson M. Dierich A. LeMeur M. Walztinger C. Chambon P. de Murcia G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 7303-7307Crossref PubMed Scopus (968) Google Scholar). In the present report, we have studied the specificity of the response to different inducers of apoptosis of PARP null cells and the biological meaning of PARP cleavage during apoptosis. To that purpose, we generated a mutant of PARP in which the specific caspase-3 cleavage site 211DEVD214 has been mutated. A fully active, nuclear, and uncleavable protein has been produced and when expressed in PARP−/− cells delays loss of cell viability and the morphological changes associated with apoptosis upon activation of the CD95 receptor. Immortalized mouse embryonic fibroblasts (MEFs) from either PARP+/+ or PARP−/− mice were cultured at 37 °C (5% CO2) in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum, 0.5% gentamicin (Sigma), 4.5 g/liter glucose. Bone marrow cells were isolated and maintained in the same culture medium (Dulbecco's modified Eagle's medium with 4.5 mg/ml glucose) containing 10 ng/ml recombinant interleukin-3 (IL-3). The BS(−) SHT construct bearing the full-length human PARP sequence (14Giner H. Simonin F. de Murcia G. Ménissier-de Murcia J. Gene (Amst.). 1992; 114: 279-283Crossref PubMed Scopus (60) Google Scholar) was used to generate the mutation D214A. The sequence of the oligonucleotide is 5′-GCCACTTCATCCACGCCGGCCACCTCATCGC-3′. The new restriction site NaeI (underlined) generated allowed us to verify the presence of the mutation in further subcloning. Oligonucleotide-directed mutagenesis was performed essentially according to the Amersham kit. After mutagenesis, cDNA was sequenced by the dideoxynucleotide chain termination method. The mutant sequence was recloned in the prokaryotic expression vector pTG 161 PARP, which expressed the wt PARP (15Simonin F. Poch O. Delarue M. de Murcia G. J. Biol. Chem. 1993; 268: 8529-8535Abstract Full Text PDF PubMed Google Scholar) by replacing theBssHII-NcoI wt fragment by the mutated one resulting in pTG 161 D214A-PARP. These vectors were used directly for transformation of the Escherichia coli TGE 900 strain (16Courtney M. Jallat S. Tessier L.H. Benavente A. Crystal R.G. Lecocq J.P. Nature. 1985; 313: 149-151Crossref PubMed Scopus (93) Google Scholar). A fragment PstI-PstI containing the whole cDNA from the PARP and D214A-PARP was introduced into theXhoI site of the eucaryotic expression vector pECV (17Belt P.B. Groeneveld H. Teubel W.J. Van der Putte P. Backendorf C. Gene (Amst.). 1989; 84: 407-417Crossref PubMed Scopus (55) Google Scholar) withPstI-XhoI adapters resulting either in pECV PARP or pECV D214A-PARP, respectively. This was done essentially as described by Schreiber et al. (18Schreiber V. de Murcia G. Ménissier-de Murcia J. Médecine/Sciences. 1992; 8: 134-139Crossref Scopus (3) Google Scholar). Briefly, cells grown on coverslips were washed three times with PBS and fixed with methanol/acetone (v/v) for 10 min at 4 °C. After washing three times with PBS supplemented with Tween 0.1% (v/v), cells were incubated overnight at 4 °C with polyclonal anti-PARP antibody (1:100 dilution). After washing, the coverslips were incubated with a secondary antibody (Texas Red-conjugated) for 4 h at room temperature. Immunofluorescence was evaluated using a Zeiss Axioplan microscope equipped with a wt PARP and D214A-PARP were by in using the with BS(−) PARP, and BS(−) D214A-PARP. In PARP D214A-PARP of a of the were incubated with of caspase-3 from at different times at 37 °C in a containing 10 and 10 These were from PARP−/− splenocytes with during h reported S. J.C. J. 1995; PubMed Scopus Google Scholar). The the in PARP and D214A-PARP of of the of mg/ml and 4 of the 10 10 and of PARP was as described V. M. Ménissier-de Murcia M. de Murcia G. 1997; PubMed Scopus Google Scholar). to of wild-type or mutant PARP proteins were incubated for 10 min at °C in of 4 DNA, NAD+, and The was by of of 10% and the was in a C. H. P. J. Biochem. PubMed Scopus Google Scholar). were by with of vector V. de Murcia G. Ménissier-de Murcia J. Gene (Amst.). 1994; PubMed Scopus Google Scholar) and of wt PARP, D214A-PARP, or the vector were induced to apoptosis by anti-CD95 or h were fixed with in PBS for 10 min at 4 °C and with X-gal, and in PBS for After the number of and cells was cells treatment were as a of cells E. L. M. J. 1997; PubMed Scopus Google Scholar). of the nuclear of apoptosis, were in and by the of a for the green fluorescence protein and 10 of pECV PARP, or were were with anti-CD95 h of apoptotic was performed according to et al. M.D. J.C. Raff M.C. Nature. 1993; PubMed Scopus Google Scholar). Briefly, the cells were fixed in for 10 min at room incubated for 10 min with at and with in PBS containing A for min at 37 °C. The cells were with and with a Zeiss fluorescence bone marrow cells were with for and incubated in were at different times and with for min at 4 °C. at cell and The was with (v/v), and the phase was with and on bone marrow cells are a to biochemical leading to apoptosis by growth removal G. M. A. J. 9: PubMed Scopus Google Scholar). cells were isolated from PARP+/+ and PARP−/− mice (11Ménissier de Murcia J. Niedergang C. Trucco C. Ricoul M. Dutrillaux B. Mark M. Oliver F.J. Masson M. Dierich A. LeMeur M. Walztinger C. Chambon P. de Murcia G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 7303-7307Crossref PubMed Scopus (968) Google Scholar) and maintained in culture in the presence of inducers of apoptosis, the genotoxic agent MNU, which activates the catalytic of PARP, the topoisomerase I inhibitor a and the removal of have been DNA induced by activates the base excision repair pathway the genotoxic effect produced by CPT-11 not this the apoptosis is of DNA and of from the N. A. M. J. 1996; PubMed Scopus Google Scholar). We have compared the of cells of to these inducers of apoptosis by of DNA into shown in primary cultured bone marrow cells exposed to apoptosis much more than their In PARP−/− cells an increased sensitivity to as by a effect on cell we induced DNA by not base excision we a effect on DNA of the cell when the cells were of there were no significant in the appearance of DNA These cells were sensitive to the induced by activation of the CD95 and in the presence of results have been described using primary Z.-Q. Stingl L. Morrison C. Jantsch M. Marek L. Schulze-Ostoff K. Wagner E. Genes Dev. 1997; 18: 2347-2358Crossref Scopus (517) Google Scholar) or M. Single B. Künstle G. Volbracht C. Hentze H. Nicotera P. Biochem. Biophys. Res. Commun. 1997; 233: 518-522Crossref PubMed Scopus (135) Google Scholar) from PARP null that the presence of PARP is not an for completion of apoptosis. In a more on the role of during apoptosis, that the absence of PARP the cells to cell death CD95 treatment C.M. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This from the of of PARP−/− in the which the to these results that PARP-deficient cells have a apoptotic when the is a agent the such as the alkylating agent apoptosis PARP is cleaved to of and of the fragment that cleavage occurs and Y.A. Kaufmann S.H. Desnoyers S. Poirier G.G. Earnshaw W.C. Nature. 1994; 371: 346-347Crossref PubMed Scopus (2351) Google Scholar) the nuclear of PARP (18Schreiber V. de Murcia G. Ménissier-de Murcia J. Médecine/Sciences. 1992; 8: 134-139Crossref Scopus (3) Google leading to a loss of it has been that the is the for and (4Nicholson D. Thornberry N. Trends Biochem. Sci. 1997; 22: 299-306Abstract Full Text PDF PubMed Scopus (2187) Google Scholar). To further the biological consequences of PARP cleavage on apoptosis, the at was to an in the caspase-3 cleavage to the mutant D214A-PARP the mutation in the nuclear the of the mutated protein was this purpose, PARP−/− cells were with D214A-PARP and the expressed protein was using a polyclonal antibody the whole protein. We that D214A-PARP protein was nuclear, that the is not involved in the nuclear of PARP cells with D214A-PARP cDNA were for poly(ADP-ribose) treatment with as by using an antibody not The same specific was for wt PARP and D214A-PARP in V. M. Ménissier-de Murcia M. de Murcia G. 1997; PubMed Scopus Google Scholar) that the mutation in the NH2-terminal of PARP not the catalytic of the protein as C. E. S. de Murcia G. Ménissier-de Murcia J. 1996; PubMed Scopus Google Scholar). the mutation to a protein was by an in cleavage using human caspase-3 and the PARP by in PARP with caspase-3 in the cleavage of the PARP into the to that during apoptosis. the mutant D214A-PARP with caspase-3 mutant D214A-PARP was to the cleavage by a from PARP−/− splenocytes induced to apoptosis by treatment with MNU, which is a of apoptosis in these cells (11Ménissier de Murcia J. Niedergang C. Trucco C. Ricoul M. Dutrillaux B. Mark M. Oliver F.J. Masson M. Dierich A. LeMeur M. Walztinger C. Chambon P. de Murcia G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 7303-7307Crossref PubMed Scopus (968) Google that mutation the cleavage by caspase-3 and during apoptosis. PARP has been shown to be an important for caspase-3 M. K. Desnoyers S. Poirier G.G. Cell. 1995; Full Text PDF PubMed Scopus Google activation of which is for apoptosis V. G. J. 1997; Scopus Google Scholar). CD95 is a cell that to the family N. S. A. M. S. M. A. S. Cell. Full Text PDF PubMed Scopus Google Scholar) in Ref. S. Cell. 1997; 88: Full Text Full Text PDF PubMed Scopus Google Scholar). the CD95 by either or by the CD95 ligand apoptosis. CD95 is directly to which and activates a responsible for the execution phase of apoptosis (4Nicholson D. Thornberry N. Trends Biochem. Sci. 1997; 22: 299-306Abstract Full Text PDF PubMed Scopus (2187) Google Scholar). the upon activation of caspase-3 by PARP protein is L. Thornberry A. J. 1996; PubMed Scopus Google Scholar). PARP cleavage a of programmed cell To the presence of an uncleavable PARP mutant is during the to apoptosis, we have different to induce apoptosis in treatment of the cells with either a CD95 of DNA or with the alkylating agent MMS, to DNA are by and PARP PARP−/− were with the with the vectors the wt PARP or the D214A-PARP mutant or the Apoptosis was in cells either an anti-CD95 treatment or to an alkylating A shows that h anti-CD95 treatment cells were of wt PARP not to cell However, cells the uncleavable PARP mutant a significant delay of 10 h in the loss of cell viability, that PARP cleavage is for the cell to the apoptotic in To that loss of cell viability was of activation of apoptosis, a specific inhibitor of A. Thornberry J.P. M. M. Y.A. Nature. 1995; PubMed Scopus Google was of cells with this inhibitor at cell death B) as has been shown V. G. J. 1997; Scopus Google Scholar). In PARP null cells are more sensitive to apoptosis induced by a monofunctional alkylating agent, and the of wt PARP the viability of PARP−/− cells that the absence of PARP is directly responsible for the of cells to DNA with the D214A-PARP mutant are the of and the sensitivity of PARP−/− cells to the same as wt PARP in this the absence of PARP cleavage not to the of cell To at which the of PARP with the apoptotic we have the of apoptotic PARP−/− cells during anti-CD95 this purpose, were with vectors the wt or the uncleavable PARP and a the green fluorescence protein as described and We established three different of cells GFP, according to the of the and cells 4 cells with but 4 and cells with a 4 the cells in the had the membrane according to morphological In wt PARP, were cells, and apoptotic cells had the nuclear 4 In cells the D214A-PARP mutant were much more to were cells, and the of apoptotic cells with nuclear was compared with their In conclusion, the of PARP not the nuclear of apoptosis but with the leading to cell membrane blebbing, as by the number of cells at this from different have the role of PARP in the apoptotic We have shown that splenocytes isolated from PARP−/− mice programmed cell death much more than their when with an alkylating agent (11Ménissier de Murcia J. Niedergang C. Trucco C. Ricoul M. Dutrillaux B. Mark M. Oliver F.J. Masson M. Dierich A. LeMeur M. Walztinger C. Chambon P. de Murcia G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 7303-7307Crossref PubMed Scopus (968) Google Scholar). These with in that PARP−/− cells are sensitive to DNA are by base excision but are sensitive to inducers of apoptosis that not this pathway Z.-Q. Stingl L. Morrison C. Jantsch M. Marek L. Schulze-Ostoff K. Wagner E. Genes Dev. 1997; 18: 2347-2358Crossref Scopus (517) Google Scholar, 13Leist M. Single B. Künstle G. Volbracht C. Hentze H. Nicotera P. Biochem. Biophys. Res. Commun. 1997; 233: 518-522Crossref PubMed Scopus (135) Google Scholar). To this specific we have to into that PARP in the pathway in with DNA polymerase and K. S. P. S. Res. 1996; PubMed Scopus Google Scholar, F. de Murcia G. Ménissier-de Murcia J. Res. Scopus Google Scholar, M. Niedergang C. Schreiber V. S. Ménissier-de Murcia J. de Murcia G. Mol. Cell. Biol. 18: PubMed Scopus Google Scholar) and in the organization of chromatin architecture the of Murcia G. A. Poirier G.G. Biochem. Biol. Google Scholar, A. de Murcia G. S. M. L. D. Poirier G.G. J. Biol. Chem. 1989; Full Text PDF PubMed Google Scholar). The reason these cells lacking PARP are much more and programmed cell death than cells be by the of DNA of the absence of which the cell to and the apoptotic pathway to of DNA to a new of cells. This is by the that PARP−/− cells have of DNA as by the C. Oliver F.J. N. V. de Murcia G. Ménissier-de Murcia J. Res. PubMed Scopus Google Scholar) and an increased of in PARP null splenocytes (11Ménissier de Murcia J. Niedergang C. Trucco C. Ricoul M. Dutrillaux B. Mark M. Oliver F.J. Masson M. Dierich A. LeMeur M. Walztinger C. Chambon P. de Murcia G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 7303-7307Crossref PubMed Scopus (968) Google Scholar) upon treatment with an alkylating A biochemical of apoptosis is the proteolytic cleavage and of PARP in the execution phase of cell in apoptosis is by of PARP cleavage is to is the cell to of this protein to apoptosis. of chromatin is a key of the apoptotic process. DNA during apoptosis is produced by in the of chromatin M. C. J. Res. 1993; PubMed Scopus Google and PARP with DNA breaks E. F. Ménissier-de Murcia J. J.A. A. V. B. E. de Murcia G. J. Mol. Biol. 1994; PubMed Scopus Google Scholar). this PARP facilitates the and of the proteins to repair of PARP by apoptotic to a disable key of the genomic with L. Thornberry A. J. 1996; PubMed Scopus Google to DNA repair during chromatin and the of to chromatin and nuclear In of it has been shown that of PARP by to the cells results in an increased of to chromatin M. Res. 1994; Google Scholar). The of PARP in the of the nuclear F. de Murcia G. Ménissier-de Murcia J. Res. Scopus Google Scholar) that its cleavage during apoptosis in nuclear disassembly and facilitates which are retarded upon expression of the uncleavable PARP In the uncleavable PARP mutant for the of PARP which cell viability upon anti-CD95 stimulation. The morphological consequences of uncleavable of on apoptosis have been for lamin L. D. E. J. Biol. 1996; PubMed Scopus Google Scholar) and 1997; PubMed Scopus Google Scholar). Mutant cells no of chromatin or nuclear shrinkage and during apoptosis membrane cell blebbing, the nuclear were of PARP cleavage has consequences at the and nuclear We have in a delay in cell and in chromatin in cells D214A-PARP anti-CD95 These on cell are to of proteases with specific These of the apoptotic such as the of and nuclear but not of cell N. M. C. G. J. Biol. 1997; PubMed Scopus Google Scholar). PARP cleavage is not to apoptosis as and cell PARP cleavage loss of cell viability proteolytic of cell leading to cell This of apoptosis upon uncleavable PARP PARP as a key targeted for early in the apoptotic process. In the results in this that PARP is not a but plays a role the cell not to apoptosis when the cell is to repair the cleavage be a that the cell is to with a DNA from either chromatin or an genotoxic We are to E. for to for the of to for and to for critical of the

Linguistic analyses suggest that sentences are not mere strings of words but possess a hierarchical structure with constituents nested inside each other. We used functional magnetic resonance imaging (fMRI) to search for the cerebral mechanisms of this theoretical construct. We hypothesized that the neural assembly that encodes a constituent grows with its size, which can be approximately indexed by the number of words it encompasses. We therefore searched for brain regions where activation increased parametrically with the size of linguistic constituents, in response to a visual stream always comprising 12 written words or pseudowords. The results isolated a network of left-hemispheric regions that could be dissociated into two major subsets. Inferior frontal and posterior temporal regions showed constituent size effects regardless of whether actual content words were present or were replaced by pseudowords (jabberwocky stimuli). This observation suggests that these areas operate autonomously of other language areas and can extract abstract syntactic frames based on function words and morphological information alone. On the other hand, regions in the temporal pole, anterior superior temporal sulcus and temporo-parietal junction showed constituent size effect only in the presence of lexico-semantic information, suggesting that they may encode semantic constituents. In several inferior frontal and superior temporal regions, activation was delayed in response to the largest constituent structures, suggesting that nested linguistic structures take increasingly longer time to be computed and that these delays can be measured with fMRI.

Abstract: We review the physics opportunities of the Future Circular Collider, covering its e+e-, pp, ep and heavy ion programmes. We describe the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions, the top quark and flavour, as well as phenomena beyond the Standard Model. We highlight the synergy and complementarity of the different colliders, which will contribute to a uniquely coherent and ambitious research programme, providing an unmatchable combination of precision and sensitivity to new physics.

Gamma-ray bursts (GRBs) are highly energetic explosions signaling the death of massive stars in distant galaxies. The Gamma-ray Burst Monitor and Large Area Telescope onboard the Fermi Observatory together record GRBs over a broad energy range spanning about 7 decades of gammaray energy. In September 2008, Fermi observed the exceptionally luminous GRB 080916C, with the largest apparent energy release yet measured. The high-energy gamma rays are observed to start later and persist longer than the lower energy photons. A simple spectral form fits the entire GRB spectrum, providing strong constraints on emission models. The known distance of the burst enables placing lower limits on the bulk Lorentz factor of the outflow and on the quantum gravity mass.

Abstract: In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100 km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100 TeV. Its unprecedented centre of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries.

INTRODUCTION Control of mosquito vectors has historically proven to be an effective means of eliminating malaria. Human malaria is transmitted only by mosquitoes in the genus Anopheles , but not all species within the genus, or even all members of each vector species, are efficient malaria vectors. Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. RATIONALE This variation in vectorial capacity suggests an underlying genetic/genomic plasticity that results in variation of key traits determining vectorial capacity within the genus. Sequencing the genome of Anopheles gambiae , the most important malaria vector in sub-Saharan Africa, has offered numerous insights into how that species became highly specialized to live among and feed upon humans and how susceptibility to mosquito control strategies is determined. Until very recently, similar genomic resources have not existed for other anophelines, limiting comparisons to individual genes or sets of genomic markers with no genome-wide data to investigate attributes associated with vectorial capacity across the genus. RESULTS We sequenced and assembled the genomes and transcriptomes of 16 anophelines from Africa, Asia, Europe, and Latin America, spanning ~100 million years of evolution and chosen to represent a range of evolutionary distances from An. gambiae , a variety of geographic locations and ecological conditions, and varying degrees of vectorial capacity. Genome assembly quality reflected DNA template quality and homozygosity. Despite variation in contiguity, the assemblies were remarkably complete and searches for arthropod-wide single-copy orthologs generally revealed few missing genes. Genome annotation supported with RNA sequencing transcriptomes yielded between 10,738 and 16,149 protein-coding genes for each species. Relative to Drosophila, the closest dipteran genus for which equivalent genomic resources exist, Anopheles exhibits a dynamic genomic evolutionary profile. Comparative analyses show a fivefold faster rate of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses in Anopheles . Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. We also document evidence of variation in important reproductive phenotypes, genes controlling immunity to Plasmodium malaria parasites and other microbes, genes encoding cuticular and salivary proteins, and genes conferring metabolic insecticide resistance. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts. CONCLUSIONS Anopheline mosquitoes exhibit a molecular evolutionary profile very distinct from Drosophila , and their genomes harbor strong evidence of functional variation in traits that determine vectorial capacity. These 16 new reference genome assemblies provide a foundation for hypothesis generation and testing to further our understanding of the diverse biological traits that determine vectorial capacity. Geography, vector status, and molecular phylogeny of the 16 newly sequenced anopheline mosquitoes and selected other dipterans. The maximum likelihood molecular phylogeny of all sequenced anophelines and two mosquito outgroups was constructed from the aligned protein sequences of 1085 single-copy orthologs. Shapes between branch termini and species names indicate vector status and are colored according to geographic ranges depicted on the map.

17 páginas, 11 figuras, 4 tablas.-- El Pdf del artículo es la versión pre-print: arXiv:0910.4279v1.-- et al.

Preeclampsia is a persistent hypertensive gestational disease characterized by high blood pressure and proteinuria, which presents from the second trimester of pregnancy. At the cellular level, preeclampsia has largely been associated with the release of free radicals by the placenta. Placenta-borne oxidative and nitrosative stresses are even sometimes considered as the major molecular determinants of the maternal disease. In this review, we present the recent literature evaluating free radical production in both normal and pathological placentas (including preeclampsia and other major pregnancy diseases), in humans and animal models. We then assess the putative effects of these free radicals on the placenta and maternal endothelium. This analysis was conducted with regard to recent papers and possible therapeutic avenues.