Lignes ferroviaires à grande vitesse et dynamiques locales : une analyse comparée de la littérature

Dans ce contexte, cette communication s'intéresse spécifiquement au rôle des lignes ferroviaires à grande vitesse (LGV) sur les dynamiques économiques locales. Cette question est en effet d'actualité compte tenu des nombreux projets de lignes à grande vitesse au niveau mondial (USA, Brésil, Chine, etc.) et européen (Portugal, Espagne, France, etc.) et de la diversité des attentes qu'ils suscitent (dynamisme économique général, attractivité de nouvelles entreprises ou de ménages (qui bénéficieraient de nouvelles opportunités en matière de mobilité domicile/travail), développement de programmes immobiliers résidentiels ou de centres d'affaires autour des gares, développement du tourisme, renouvellement de l'identité urbaine, etc.). Cette communication se propose d'inviter à la prudence quant à cette liaison en mettant en évidence les écarts entre ces attentes exprimées dans la littérature grise ex ante à l'échelle nationale et internationale et les résultats de cette littérature ex post (1). Si l'existence de tels écarts renforce l'hypothèse selon laquelle des conditions doivent être réunies pour que d'éventuels effets se produisent, nous montrerons que ces conditions énoncées précisément dans la littérature académique, ne sont reprises que partiellement dans la littérature grise (2). Or ces conditions permettent de montrer que les effets sont toujours le produit d'une confrontation singulière entre une desserte, un contexte territorial spécifique et des jeux d'acteurs particuliers ; une reproduction à l'identique de cas particuliers de success stories est alors nécessairement illusoire.Infrastructures de transport ; Développement local ; Ligne ferroviaire à grande vitesse ; Effets structurants

Cross metathesis for the synthesis of HDAC inhibitors. Potential in multitarget drug design

Histone deacetylases represent a family of eleven zinc-dependant enzymes. Their over expression has been correlated to several human diseases, in particular cancers. The search for compounds able to selectively inhibit one of these HDAC is of high importance to obtain less side effect during treatment as well as avoiding of target effects. In this work we have designed a series of inhibitors using an asymmetric cross metathesis approach. We present the synthesis, some molecular modelling and the biological activities of the prepared compounds.Link ka Knjizi sažetaka se nalazi ovde - http://www.mutalig.eu/2017/06/2nd-annual-meeting-porto-september-21-24-2017

Heterogeneous RNA editing and influence of ADAR2 on mesothelioma chemoresistance and the tumor microenvironment

We previously observed increased levels of adenosine-deaminase-acting-on-dsRNA (Adar)-dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR-dependent RNA editing in mesothelioma. We found that tumors and mesothelioma primary cultures have higher ADAR-mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1-associated protein 1 wild-type tumors, with corresponding changes in RNA editing in transcripts and 3'UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment, and type-1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also in chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures

Ecofriendly recycled aggregate concrete and bioreceptivity

Nowadays, it becomes essential to limit environmental impact of building materials and to consider the life cycle of materials used. Recycling of materials from demolition has the dual objective of preserving natural resources and limiting the number of storage sites. The study presented here aims to develop the use of recycled aggregate issued of concrete in total replacement of natural materials (sand and gravel). This work has to be done upstream the studies on bio-corrosion or bio-receptivity of these concrete composed of recycled aggregates. Following an experimental analysis of physical, mechanical and mineralogical properties of recycled aggregates,the influence of these characteristics on choosing formulation parameters of concrete and mortar was studied. It was shown that the use of superplasticizers is necessary to reach satisfactory properties of concrete. The next step of this work will be toanalyse the bio-receptivity of these concrete and compatibilitywith bio-admixture used to decrease bio-receptivity and bio-corrosion; and to develop bio-superplasticizers to replace chemical ones

Phylogenetic estimation of the viral fitness landscape of HIV-1 set-point viral load

Set-point viral load (SPVL), a common measure of human immunodeficiency virus (HIV)-1 virulence, is partially determined by viral genotype. Epidemiological evidence suggests that this viral property has been under stabilising selection, with a typical optimum for the virus between 10$^{4}$ and 10$^{5}$ copies of viral RNA per ml. Here we aimed to detect transmission fitness differences between viruses from individuals with different SPVLs directly from phylogenetic trees inferred from whole-genome sequences. We used the local branching index (LBI) as a proxy for transmission fitness. We found that LBI is more sensitive to differences in infectiousness than to differences in the duration of the infectious state. By analysing subtype-B samples from the Bridging the Evolution and Epidemiology of HIV in Europe project, we inferred a significant positive relationship between SPVL and LBI up to approximately 10$^{5}$ copies/ml, with some evidence for a peak around this value of SPVL. This is evidence of selection against low values of SPVL in HIV-1 subtype-B strains, likely related to lower infectiousness, and perhaps a peak in the transmission fitness in the expected range of SPVL. The less prominent signatures of selection against higher SPVL could be explained by an inherent limit of the method or the deployment of antiretroviral therapy

Viral genetic variation accounts for a third of variability in HIV-1 set-point viral load in Europe

HIV-1 set-point viral load-the approximately stable value of viraemia in the first years of chronic infection-is a strong predictor of clinical outcome and is highly variable across infected individuals. To better understand HIV-1 pathogenesis and the evolution of the viral population, we must quantify the heritability of set-point viral load, which is the fraction of variation in this phenotype attributable to viral genetic variation. However, current estimates of heritability vary widely, from 6% to 59%. Here we used a dataset of 2,028 seroconverters infected between 1985 and 2013 from 5 European countries (Belgium, Switzerland, France, the Netherlands and the United Kingdom) and estimated the heritability of set-point viral load at 31% (CI 15%-43%). Specifically, heritability was measured using models of character evolution describing how viral load evolves on the phylogeny of whole-genome viral sequences. In contrast to previous studies, (i) we measured viral loads using standardized assays on a sample collected in a strict time window of 6 to 24 months after infection, from which the viral genome was also sequenced; (ii) we compared 2 models of character evolution, the classical "Brownian motion" model and another model ("Ornstein-Uhlenbeck") that includes stabilising selection on viral load; (iii) we controlled for covariates, including age and sex, which may inflate estimates of heritability; and (iv) we developed a goodness of fit test based on the correlation of viral loads in cherries of the phylogenetic tree, showing that both models of character evolution fit the data well. An overall heritability of 31% (CI 15%-43%) is consistent with other studies based on regression of viral load in donor-recipient pairs. Thus, about a third of variation in HIV-1 virulence is attributable to viral genetic variation.Peer reviewe

Phylogenetic estimation of the viral fitness landscape of HIV-1 set-point viral load

Set-point viral load (SPVL), a common measure of human immunodeficiency virus (HIV)-1 virulence, is partially determined by viral genotype. Epidemiological evidence suggests that this viral property has been under stabilising selection, with a typical optimum for the virus between 104 and 105 copies of viral RNA per ml. Here we aimed to detect transmission fitness differences between viruses from individuals with different SPVLs directly from phylogenetic trees inferred from whole-genome sequences. We used the local branching index (LBI) as a proxy for transmission fitness. We found that LBI is more sensitive to differences in infectiousness than to differences in the duration of the infectious state. By analysing subtype-B samples from the Bridging the Evolution and Epidemiology of HIV in Europe project, we inferred a significant positive relationship between SPVL and LBI up to approximately 105 copies/ml, with some evidence for a peak around this value of SPVL. This is evidence of selection against low values of SPVL in HIV-1 subtype-B strains, likely related to lower infectiousness, and perhaps a peak in the transmission fitness in the expected range of SPVL. The less prominent signatures of selection against higher SPVL could be explained by an inherent limit of the method or the deployment of antiretroviral therapy.Peer Reviewe

Easy and accurate reconstruction of whole HIV genomes from short-read sequence data with shiver

Studying the evolution of viruses and their molecular epidemiology relies on accurate viral sequence data, so that small differences between similar viruses can be meaningfully interpreted. Despite its higher throughput and more detailed minority variant data, next-generation sequencing has yet to be widely adopted for HIV. The difficulty of accurately reconstructing the consensus sequence of a quasispecies from reads (short fragments of DNA) in the presence of large between-and within-host diversity, including frequent indels, may have presented a barrier. In particular, mapping (aligning) reads to a reference sequence leads to biased loss of information; this bias can distort epidemiological and evolutionary conclusions. De novo assembly avoids this bias by aligning the reads to themselves, producing a set of sequences called contigs. However contigs provide only a partial summary of the reads, misassembly may result in their having an incorrect structure, and no information is available at parts of the genome where contigs could not be assembled. To address these problems we developed the tool shiver to pre-process reads for quality and contamination, then map them to a reference tailored to the sample using corrected contigs supplemented with the user's choice of existing reference sequences. Run with two commands per sample, it can easily be used for large heterogeneous data sets. We used shiver to reconstruct the consensus sequence and minority variant information from paired-end short-read whole-genome data produced with the Illumina platform, for sixty-five existing publicly available samples and fifty new samples. We show the systematic superiority of mapping to shiver's constructed reference compared with mapping the same reads to the closest of 3,249 real references: median values of 13 bases called differently and more accurately, 0 bases called differently and less accurately, and 205 bases of missing sequence recovered. We also successfully applied shiver to whole-genome samples of Hepatitis C Virus and Respiratory Syncytial Virus. shiver is publicly available from https://github.com/ChrisHIV/shiver.Peer reviewe

A highly virulent variant of HIV-1 circulating in the Netherlands

We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log(10) increase (i.e., a similar to 3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV-CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences-is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination. with increased transmissibility and an unfamiliar molecular mechanism of virulence

Etude des modifications post-traductionnelles du Peroxisome Proliferator Activated Receptor Alpha (PPAR Alpha) et de leurs conséquences sur les fonctions biologiques de ce récepteur nucléaire

PPARa appartient à la superfamille des récepteurs nucléaires (RN). C'est un facteur de transcription activé par des ligands. PPARa est impliqué dans la régulation du métabolisme des lipides et des lipoprotéines ainsi que dans le contrôle de la réponse inflammatoire. Ces différentes fonctions lui confèrent un rôle protecteur contre l athérosclérose. Le but de nos travaux a été de mettre en évidence diverses modifications post-traductionnelles de PPARa ainsi que de définir leurs conséquences sur les fonctions de ce RN. Ainsi, nous avons montré que la protéine PPARa est ubiquitinée, ce qui conduit à sa dégradation par le système ubiquitine-protéasome. Nous avons également mis en évidence que les ligands de PPARa diminuent son ubiquitination le protégeant ainsi de la dégradation. Enfin, nous avons montré que le système ubiquitine-protéasome est impliqué dans la régulation de l'expression des gènes cibles de PPARa dans des cellules hépatiques humaines en contrôlant le taux intracellulaire de ce RN. Comme il a été décrit dans la littérature, PPARa est une protéine phosphorylée. Nous avons alors étudié le rôle des protéines kinases C (PKC) dans la régulation de l'activité de PPARa. De manière originale, nos résultats montrent que l activité des PKC est nécessaire à l'obtention d'une activation optimale des propriétés transactivatrices de PPARa par ses ligands dans les cellules hépatiques humaines. Nous avons également observé que les PKC diminuent les propriétés de transrépression de ce RN. Nos résultats mettent ainsi en évidence l'existence d'un mécanisme de contrôle des propriétés de transactivation et de transrepression de PPARa par les PKC. Enfin, nous avons montré que l'inhibition des PKC dans les cellules hépatiques humaines diminue la phosphorylation de PPARa et que ce RN est phosphorylé par les PKC classiques in vitro. En conclusion, nos travaux ont permis de mettre en évidence deux nouvelles voies de régulation de l'activité de PPARa par des modifications post-traductionnelles, le système ubiquitine-protéasome et la voie des PKC.PPARa belong to the nuclear receptor (NR) superfamily. This NR is a transcription factor activated by ligands. PPARa is implicated in the regulation of the lipid and lipoprotein metabolism and in the control of the inflammatory response. These functions confer anti-atherogenic properties to PPARa. The aim of our work was to identified new post-translational modifications of PPARa and to determine their consequences on the functions of this NR. In a first study, we have shown that PPARa is ubiquitinated, which lead to the degradation of this NR by the ubiquitin-proteasome pathway. We shown too that the PPARa ligands protect this NR from degradation by decreasing its ubiquitination. Finally, we have demonstrated that the ubiquitin-proteasome pathway is implicated in the control of PPARa target genes expression by regulating its intracellular level. As it was already described in the literature, PPARa is a phosphoprotein. Then, in a second study, we have evaluated the role of the protein kinases C (PKC) in the regulation of the PPARa activities. Our results demonstrate that PKC activity is necessary to obtain an optimal induction of the PPARa transcriptional activity by its ligands. We have observed too that PKC decrease the transrepression properties of PPARa. Our results describe a new control mechanism of the PPARa transactivation and transrepression functions by the PKC. Finally, we have shown that PKC inhibition decreases the PPARa phosphorylation and that this nuclear receptor is phosphorylated by the classical PKC in vitro. In conclusion, our work describe two new regulation mechanisms of the PPARa functions by post-tranlational modifications, the ubiquitin-proteasome system and the PKC signalling pathway.LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF