Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Primary hepatocyte cultures are now considered as convenient models for in vitro analyzing liver drug transport. However, if primary human and rat hepatocytes have been well-characterized with respect to drug transporter expression and regulation, much less is known for primary mouse hepatocytes. The present study was therefore designed to gain insights about this point. The profile of sinusoidal and canalicular drug transporter mRNA expression in short time (4h)-cultured mouse hepatocytes was found to be highly correlated with that of freshly isolated hepatocytes; by contrast, those of counterparts cultured for a longer time (until 4days) either in monolayer configurations on plastic or collagen or in sandwich configuration with matrigel were profoundly altered: uptake drug transporters such as Oct1, Oatps and Oat2 were thus down-regulated, whereas most of efflux transporters such as Mdr1a/b, Mrp3, Mrp4 and Bcrp were induced. Moreover, short time-cultured hepatocytes exhibited the highest levels of sinusoidal influx transporter activities. Transporter-mediated drug secretion into canalicular networks was however only observed in sandwich-cultured hepatocytes. Mouse hepatocytes cultured either in monolayer or sandwich configurations were finally shown to exhibit up-regulation of referent transporters in response to exposure to prototypical activators of the drug sensing receptors pregnane X receptor, aryl hydrocarbon receptor or constitutive androstane receptor. Taken together, these data demonstrate the feasibility of using primary mouse hepatocytes for investigating potential interactions of xenobiotics with hepatic transporter activity or regulation, provided that adequate culture conditions are retained.
ISSN: 0928-0987

inserm-00823243
http://www.hal.inserm.fr/inserm-00823243
DOI : 10.1016/j.ejps.2013.01.013
PUBMED : 23396053

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
BACKGROUND: Mammalian spermatogenesis is a process that involves a complex expression program in both somatic and germ cells present in the male gonad. A number of studies have attempted to define the transcriptome of male meiosis and gametogenesis in rodents and primates. Few human transcripts, however, have been associated with testicular somatic cells and germ cells at different post-natal developmental stages and little is known about their level of germline-specificity compared with non-testicular tissues. METHODS: We quantified human transcripts using GeneChips and a total of 47 biopsies from prepubertal children diagnosed with undescended testis, infertile adult patients whose spermatogenesis is arrested at consecutive stages and fertile control individuals. These results were integrated with data from enriched normal germ cells, non-testicular expression data, phenotype information, predicted regulatory DNA-binding motifs and interactome data. RESULTS: Among 3580 genes for which we found differential transcript concentrations in somatic and germ cells present in human testis, 933 were undetectable in 45 embryonic and adult non-testicular tissues, including many that were corroborated at protein level by published gene annotation data and histological high-throughput protein immunodetection assays. Using motif enrichment analyses, we identified regulatory promoter elements likely involved in germline development. Finally, we constructed a regulatory disease network for human fertility by integrating expression signals, interactome information, phenotypes and functional annotation data. CONCLUSIONS: Our results provide broad insight into the post-natal human testicular transcriptome at the level of cell populations and in a global somatic tissular context. Furthermore, they yield clues for genetic causes of male infertility and will facilitate the identification of novel cancer/testis genes as targets for cancer immunotherapies.
ISSN: 0268-1161

hal-00877243
https://hal.archives-ouvertes.fr/hal-00877243
DOI : 10.1093/humrep/des301
PUBMED : 22926843

Éditeur(s) : HAL CCSD IGI Global
Résumé : International audience
Standard data mining techniques have been applied and adapted for eliciting knowledge from social networks, by achieving classical tasks such as classification, search for frequent patterns or link prediction. Most works have exploited only the network topological structure, and therefore cannot be used to answer questions involving nodes features. For instance, the frequent pattern discovery task generally refers to the search for sub-networks frequently found in a single network or in a set of networks. In the same area, this paper focuses on the concept of frequent link that stands as a regularity found in a network on links between node groups that share common characteristics. The extraction of such links from a social network is a particularly challenging and computationally intensive problem, since it is much dependent on the number of links and attributes. In this study, we propose a solution for reducing the search space of frequent links, by filtering the nodes features on a criterion of frequency. We make the assumption that frequent links occur between sets of features that are themselves frequent. This property is used to reduce the search space and speed up the extraction process. We empirically show that it is well founded. We discuss the efficiency of the solution in terms of computation time and number of frequent patterns found depending on several frequency thresholds.
ISSN: 1947-8186

hal-00786166
https://hal.archives-ouvertes.fr/hal-00786166

Résumé : Ifremer launched and coordinated the development of a strategy for the REBENT network (REseau BENThique) in 2000 to monitor the aftermath of the "Erika" oil spill in December 1999. Its aim is to provide consistent baseline knowledge about coastal benthic habitats and constitute a monitoring tool to detect changes at various scales over time and space. Sector-based seabed habitat mapping in shallow water (< 50 m deep), is currently being conducted throughout Brittany's coastal waters through a combination of geoacoustic marine systems and ground-truthing using biological grab sampling and seabed observations. Sedimentological and biological results on Glenan area emphasize a great diversity of subtidal habitats and marine species recognized. Sidescan imagery accentuates the complexity of the communities structure in a marine environment distinguished by strong and regulary roughness of the sea. Maerl biocenose is present at the nord-east of the archipelago. Progressively it gives way to mud sediment colonized by Amphiura filiformis and Haploops in the deeper channel. To the west and the south, substratum types are more coarse, occasionally mobiles, composed of essentially sand community with Nephtys and gravelly sand community with Branchiostoma lanceolatum.
Le Rebent (Réseau benthique), initié en 2000 à la suite de la catastrophe de l'Erika, a pour objectif de suivre les habitats benthiques côtiers et de détecter les changements à différentes échelles de temps et d'espace. L'approche sectorielle dans les petits fonds (< 50 m) des côtes bretonnes combine, des moyens de prospection acoustique, afin de délimiter les principaux types de substrats, avec des prélèvements et des observations biologiques pour caractériser les peuplements macrobenthiques. Les résultats des analyses sédimentologiques et faunistiques montrent autour de l'archipel des Glénan, une grande diversité d'habitats et d'espèces reconnues. L'imagerie acoustique fait ressortir la complexité de leur structuration dans un environnement marin soumis à de fortes et régulières périodes d'agitation. La biocénose de maërl occupe le nord-est de l'archipel. Elle laisse place progressivement aux sédiments envasés à Amphiura filiformis et aux vases à Haploops dans le fond du chenal. A l'ouest et au sud, les subtrats sont plus grossiers, essentiellement sableux à Nephtys et sablo-graveleux à Branchiostoma lanceolatum, épisodiquement mobiles.

Droits : info:eu-repo/semantics/openAccess
http://archimer.ifremer.fr/doc/2006/rapport-2301.pdf
http://archimer.ifremer.fr/doc/2006/sup-2301.pdf
http://archimer.ifremer.fr/doc/00000/2301/

Éditeur(s) : HAL CCSD Frontiers Media
Résumé : International audience
The yeast Candida glabrata has become the second cause of systemic candidemia in humans. However, relatively few genome-wide studies have been conducted in this organism and our knowledge of its transcriptional regulatory network is quite limited. In the present work, we combined genome-wide chromatin immunoprecipitation (ChIP-seq), transcriptome analyses, and DNA binding motif predictions to describe the regulatory interactions of the seven Yap (Yeast AP1) transcription factors of C. glabrata. We described a transcriptional network containing 255 regulatory interactions and 309 potential target genes. We predicted with high confidence the preferred DNA binding sites for 5 of the 7 CgYaps and showed a strong conservation of the Yap DNA binding properties between S. cerevisiae and C. glabrata. We provided reliable functional annotation for 3 of the 7 Yaps and identified for Yap1 and Yap5 a core regulon which is conserved in S. cerevisiae, C. glabrata, and C. albicans. We uncovered new roles for CgYap7 in the regulation of iron-sulfur cluster biogenesis, for CgYap1 in the regulation of heme biosynthesis and for CgYap5 in the repression of GRX4 in response to iron starvation. These transcription factors define an interconnected transcriptional network at the crossroads between redox homeostasis, oxygen consumption, and iron metabolism.
ISSN: 1664-302X

Droits : http://creativecommons.org/licenses/by/
hal-01323791
http://hal.upmc.fr/hal-01323791
http://hal.upmc.fr/hal-01323791/document
http://hal.upmc.fr/hal-01323791/file/fmicb-07-00645.pdf
DOI : 10.3389/fmicb.2016.00645

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
Cell proliferation is a hallmark of cancer and depends on complex signaling networks that are chiefly supported by protein kinase activities. Therapeutic strategies have been used to target specific kinases but new methods are required to identify combined targets and improve treatment. Here, we propose a small interfering RNA genetic screen and an integrative approach to identify kinase networks involved in the proliferation of cancer cells. The functional siRNA screen of 714 kinases in HeLa cells identified 91 kinases implicated in the regulation of cell growth, most of them never being reported in previous whole-genome siRNA screens. Based on gene ontology annotations, we have further discriminated between two classes of kinases that, when suppressed, result in alterations of the mitotic index and provoke cell-cycle arrest. Extinguished kinases that lead to a low mitotic index mostly include kinases implicated in cytosolic signaling. In contrast, extinguished kinases that result in a high mitotic index mostly include kinases implicated in cell division. By mapping hit kinases in the PhosphPOINT phosphoprotein database, we generated scale-free networks consisting of 449 and 661 protein-protein interactions for kinases from low MI and high MI groups, respectively. Further analyses of the kinase interactomes revealed specific modules such as FER- and CRKL-containing modules that connect three members of the epidermal growth factor receptor (EGFR) family, suggesting a tight control of the mitogenic EGF-dependent pathway. Based on experimental studies, we confirm the involvement of these two kinases in the regulation of tumor cell growth. Based on a combined approach of large kinome-wide siRNA screens and ontology annotations, our study identifies for the first time two kinase groups differentially implicated in the control of cell proliferation. We further demonstrate that integrative analysis of the kinase interactome provides key information which can be used to facilitate or optimize target design for new therapeutic strategies. The complete list of protein-protein interactions from the two functional kinase groups will provide a useful database for future investigations.
ISSN: 1471-2164

hal-01118475
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01118475
DOI : 10.1186/1471-2164-15-1169
PUBMED : 25540073

Éditeur(s) : HAL CCSD
Résumé : International audience
The SOX8 and SOX9 transcription factors are involved in, among others, sex differentiation, male gonad development and adult maintenance of spermatogenesis. Sox8(-/-) mice lacking Sox9 in Sertoli cells fail to form testis cords and cannot establish spermatogenesis. Although genetic and histological data show an important role for these transcription factors in regulating spermatogenesis, it is not clear which genes depend upon them at a genome-wide level. To identify transcripts that respond to the absence of Sox8 in all cells and Sox9 in Sertoli cells we measured mRNA concentrations in testicular samples from mice at 0, 6 and 18 days post-partum. In total, 621 and 629 transcripts were found at decreased or increased levels, respectively, at different time points in the mutant as compared to the control samples. These mRNAs were categorized as preferentially expressed in Sertoli cells or germ cells using data obtained with male and female gonad samples and enriched testicular cell populations. Five candidate genes were validated at the protein level. Furthermore, we identified putative direct SOX8 and SOX9 target genes by integrating predicted SOX-binding sites present in potential regulatory regions upstream of the transcription start site. Finally, we used protein network data to gain insight into the effects on regulatory interactions that occur when Sox8 and Sox9 are absent in developing Sertoli cells. The integration of testicular samples with enriched Sertoli cells, germ cells and female gonads enabled us to broadly distinguish transcripts directly affected in Sertoli cells from others that respond to secondary events in testicular cell types. Thus, combined RNA profiling signals, motif predictions and network data identified putative SOX8/SOX9 target genes in Sertoli cells and yielded insight into regulatory interactions that depend upon these transcription factors. In addition, our results will facilitate the interpretation of genome-wide in vivo SOX8 and SOX9 DNA binding data.
Andrology

hal-00877013
https://hal.archives-ouvertes.fr/hal-00877013
DOI : 10.1111/j.2047-2927.2012.00049.x
PUBMED : 23315995

Éditeur(s) : HAL CCSD
Résumé : In Martinique in the eighteenth century, the "free people of color", both those free by birth and freedmen, black or mixed race, form a legal category, which was distinct from those of whites and slaves. Comparative studies with Spanish or English territories show that no legal regulation formalized a shift - from the category of free colored people to that of White - in the French colonies between the late seventeenth century and the French Revolution. Also, this thesis proposes to show the informal process that enabled some people - the "assimilated" - to cross the color barrier. I analysed the color prejudice, a racist system, whose ideology, supported by local regulations, legitimized the collective construction of a public and social order. In a second step, I examined the development of the color bar. The free colored people were the first to bear the brunt of the impermeability of the demarcation line and of the problems posed by the purity of blood; but some whites, through interracial unions, and Native Americans have also been targeted. Finally I thought about what made the whiteness, and the strategies to achieve whiteness, change in status. Notarial acts and 33,000 acts of parish registers treaties led to the reconstitution of genealogies, in order to examine individuals and families over generations; I observed the importance of the phenotype, whitening, legitimacy relations, privileged partners, choice of networks, wealth levels and the use of space.
À la Martinique au XVIIIe siècle, les « libres de couleur », qu’ils soient nés libres ou affranchis, noirs ou métis, forment une catégorie juridique distincte des Blancs et des esclaves. L’étude comparée, avec les territoires espagnols ou anglais, montre qu’aucune réglementation légale n’a officialisé un passage de la catégorie Libre de couleur à celle de Blanc dans les colonies françaises de la fin du XVIIe siècle à la Révolution française. Aussi, cette thèse se propose de montrer les processus officieux qui ont permis à certaines personnes – les « assimilés » – de franchir la barrière de couleur. Une réflexion a été menée sur le préjugé de couleur, système raciste dont l’idéologie, soutenue par la réglementation locale, a légitimé la construction collective d’un ordre public et social. Puis, on a examiné l’élaboration de la barrière de couleur. Les libres de couleur ont été les premiers à faire les frais de l’imperméabilisation de la ligne de démarcation et des problèmes posés par la pureté de sang ; mais les Blancs mésalliés, dans le cadre d’unions interraciales, et les Amérindiens ont aussi été visés. Enfin nous avons réfléchi à ce qui faisait la blancheur et aux stratégies adoptées pour réussir ce changement de statut. Le notariat et les 33 000 actes des registres paroissiaux traités ont donné lieu à la reconstitution de généalogies pour examiner des individus et des familles sur plusieurs générations ; on a ainsi observé l’importance du phénotype, le blanchiment, la légitimité des relations, les conjoints privilégiés, le choix des réseaux, les niveaux de fortune et l’usage de l’espace.
https://tel.archives-ouvertes.fr/tel-01221063

NNT : 2015AGUY0847
tel-01221063
https://tel.archives-ouvertes.fr/tel-01221063
https://tel.archives-ouvertes.fr/tel-01221063/document
https://tel.archives-ouvertes.fr/tel-01221063/file/These_Pierre-Louis.pdf

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Children are exposed to toxic metals and metalloids via their diet and environment. Our objective was to assess the aggregate chronic exposure of children aged 3–6 years, living in France, to As, Cd, Cr, Cu, Mn, Pb, Sb, Sr, and V present in diet, tap water, air, soil and floor dust in the years 2007–2009. Dietary data came from the French Total Diet Study, while concentrations in residential tap water, soil and indoor floor dust came from the ‘Plomb-Habitat’ nationwide representative survey on children's lead exposure at home. Indoor air concentrations were assumed to be equal to outdoor air concentrations, which were retrieved from regulatory measurements networks. Human exposure factors were retrieved from literature. Data were combined with Monte Carlo simulations. Median exposures were 1.7, 0.3, 10.2, 34.1, 60.3, 0.7, 0.1, 44.3, 1.5 and 95th percentiles were 4.4, 0.5, 15.8, 61.3, 98.3, 2.5, 0.1, 111.1, 2.9 μg/kg bw/d for As, Cd, Cr, Cu, Mn, Pb, Sb, Sr, and V respectively. Dietary exposures dominate aggregate exposures, with the notable exception of Pb - for which soils and indoor floor dust ingestion contribute most at the 95th percentile. The strengths of this study are that it aggregates exposures that are often estimated separately, and uses a large amount of representative data. This assessment is limited to main diet and residential exposure, and does not take into account the relative bioavailability of compounds. These results could be used to help target prevention strategies.
ISSN: 0160-4120

inserm-01404061
http://www.hal.inserm.fr/inserm-01404061
http://www.hal.inserm.fr/inserm-01404061/document
http://www.hal.inserm.fr/inserm-01404061/file/rev1%20-%20MS%20Expo%20metals.pdf
DOI : 10.1016/j.envint.2016.10.009

Éditeur(s) : Université des Antilles Études caribéennes
Résumé : L’exploitation commerciale des produits forestiers non ligneux a animé et anime encore au plan international les débats sur la gestion durable des forêts, notamment par son apport en matière de conservation, d’amélioration des conditions d’existence des populations locales et de gestion participative. Cependant, l’exploitation commerciale des PFNL soulève la problématique de la durabilité tant au plan écologique, économique que sociopolitique. La présente recherche traite de cette problématique en prenant comme PFNL d’illustration le raphia dans la forêt marécageuse Hlanzoun. Elle vise à analyser la durabilité socio-économique et environnementale de l’exploitation du raphia dans la forêt marécageuse « Hlanzoun ». La méthodologie utilisée est une combinaison d’approches quantitatives et qualitatives. Les outils d’analyse de données utilisés sont entre autre, la statistique descriptive, l’analyse filière des revenus d’exploitation et des valeurs ajoutées et l’analyse du système socio-écologique. Nos résultats montrent que le raphia est une plante à usages multiples. Que ce soit les feuilles, les fibres, la sève ou le tronc, tout ou presque peut être valorisé sur le raphia. Au niveau des villages riverains du Hlanzoun l’exploitation de la sève du raphia et sa transformation en alcool alimentaire est de loin le type d’usage qui procure le plus de revenu malgré le fait que les autres types d’usages mobilisent un nombre plus important d’acteurs. L’exploitation commerciale de ce PFNL se déploie suivant une organisation relativement simple et avec des caractéristiques propres à la plupart des activités de la petite production marchande des économies sous-développées en crise. Cette exploitation est essentiellement articulée autour des coupeurs/collecteurs, des intermédiaires commerciaux, des agents de transformation/conditionnement et des consommateurs des produits finis. La contribution annuelle totale de la filière raphia au développement a été estimée à 192 429 633 Fr. CFA (environ 385 000 dollar) et les revenus d’exploitation de tous les acteurs ont un signe positif malgré le faible niveau de technologie et de formation. Le raphia apporte donc des revenus relativement importants aux divers acteurs en dépit des handicaps de la filière et du déficit d’équité dans la répartition des richesses produites. Au plan de la gouvernance, on note un déficit d’instances, de règles et de procédures, dont l’effectivité et la légitimité sont clairement établies. Cet état de chose laisse le parc à raphia dans un régime d’accès « libre » mais seulement pour les riverains ; nous nous retrouvons donc en présence d’un système de cueillette, caractérisé par l’exploitation de plants immatures et la surexploitation, mettant en péril la capacité de renouvellement de la ressource et même l’avenir de la filière. On note cependant un effort de contrôle de l’accès des non riverains et des tentatives d’adaptation des riverains. En effet, le nombre d’exploitants est passé de 148 à 92 entre 2008 et 2010 et le nombre de pieds de raphia saignés est passé de 15 452 à 8 832 durant la même période. Au total, l’exploitation du raphia dans le Hlanzoun s’inscrit dans un environnement défavorable par rapport aux exigences de développement durable d’une filière de PFNL. Mais les divers acteurs sont à présent conscients de la nécessité d’agir pour une meilleure réglementation de l’accès et de l’exploitation.
The commercial use of non woody forest products is a crucial issue in the international debate on the sustainable management of forests. These products are supposed to contribute to conservation by improving local populations’ livelihood and their involvement in forest management. This study lies within the scope of two South-South Cooperation projects (PSC 22P07 and PSC 03T08) implemented by the CEBEDES NGO with the financial support of the Kingdom of the Netherlands. It aims at analyzing the socioeconomic and environmental sustainability of the raffia stands management in the swamp forest "Hlanzoun ". This small forest is located in one of Benin southern Wetlands in the municipality of Zogbodomey.The methodology to assess raffia socioeconomic performances relies on the estimation of the values added within the raffia value chains. Stakeholders at every segment of the value chains have been surveyed on the incomes obtained out of raffia. The methodology to assess the sustainability of the management relies on a simple indicator measuring the ratio of younger to elder palms. Palms in stands have been counted according to their age group. The survey confirms that raffia is a multi-purpose plant used for its leaves, fibers, sap and trunk. In villages at the borders of the Hlanzoun forest, harvesting the raffia sap on standing palms and processing it into alcohol are a major income generating activity. Alcohol is then marketed through a network of collectors, wholesalers and petty traders up to the consumers. The contribution of raffia to local and regional development was estimated by the total incomes generated at 192.429.633 F CFA. All stakeholders earn positive and significant incomes in spite of the low level of technology and skills, but traders receive a large share of the wealth produced. As regard to governance, "free" access only concerns residents and efforts are made to control the access of non-residents. One notes a deficit of legitimated authorities, rules and procedures for a sustainable use: Restrictions on the harvest of immature palms are not anymore enforced and it endangers the renewal capacity of the resource. But at the same time, the number of operators seems to be decreasing (from 148 to 92 between 2008 and 2010, whereas the number of harvested raffia palms decreased from 15,452 to 8,832 during the same period). A self-regulation might occur, due to the fact that a livelihood of local people relies on a diversity of income generating activities. In total, the operation of Raffia in Hlazoun is in an unfavorable environment with the requirements of sustainable development in a sector of NTFF. But the various actors are now aware of the need for action to better regulate access and operation.
Bénin

Droits : info:eu-repo/semantics/openAccess
urn:doi:10.4000/etudescaribeennes.5556
http://journals.openedition.org/etudescaribeennes/5556

Résumé : Les graphes définis à partir de structures algébriques possèdent d’excellentes propriétés de symétries particulièrement intéressantes. L’exemple le plus flagrant est la notion de graphe de Cayley qui s’est révélée très riche non seulement du point de vue théorique mais aussi pratique par ses applications à de nombreux domaines incluant l’architecture des réseaux ou les machines parallèles. Néanmoins, la régularité des graphes de Cayley se révèle parfois être une limite étant donné qu’ils sont toujours sommet-transitifs et donc en particulier non pertinents pour générer des réseaux semiréguliers.Cette observation a motivé, en 2005, la définition d’une nouvelle classe de graphes définis à partir d’un groupe, appelés G-graphes. Ils possèdent aussi de nombreuses propriétés de régularité mais de manière moins restrictive.Cette thèse propose un nouveau regard sur cette classe de graphes par une approche plutôt orientée recherche opérationnelle alors que la grande majorité des études précédentes est dominée par des approches essentiellement algébriques. Nous-nous sommes alors intéressés à plusieurs questions :— La caractérisation des G-graphes : nous proposons des améliorations par rapport aux précédents résultats.— Identifier des classes de graphes comme des G-graphes grâce à des isomorphismes ou en utilisant le théorème de caractérisation.— Etudier la structure et les propriétés de ces graphes, en particulier pour de possibles applications aux réseaux : colorations semi-régulières, symétries et robustesse.— Une approche algorithmique pour la reconnaissance de cette classe avec notamment un premier exemple de cas polynomial lorsque le groupe est abélien.
Interactions between graph theory and group theory have already led to interesting results for both domains. Graphs defined from algebraic groups have highly symmetrical structure giving birth to interesting properties. The most famous example is Cayley graphs, which revealed to be particularly interesting both from a theoretical and a practical point of view due to their applications in several domains including network architecture or parallel machines. Nevertheless, the regularity of Cayley graphs is also a limit as they are always vertex-transitive and therefore not relevant to generate semi-regular networks. This observation motivated the definition, in 2005, of a new family of graphs defined from a group, called G-graphs. They also have many regular properties but are less restrictive. These graphs are in particular semi-regular k-partite, with a chromatic number k directly given in the group representation and they can be either transitive or not.This thesis proposes a new insight into this class of graphs using an approach based on operational research while most of previous studies have been so far dominated by algebraic approaches. Then, the thesis addresses different kind of questions:— Characterizing G-graphs: we propose improvements of previous results.— Identifying some classes of graphs as G-graphs through isomorphism or using the characterization theorem.— Studying the structure and properties of these graphs, in particular for possible applications to networks: semi-regular coloring, symmetries and robustness.— Algorithmic approach for recognizing this class with a first example of polynomial case when the group is abelian.

http://www.theses.fr/2014AGUY0787/document

Éditeur(s) : HAL CCSD Endocrine Society
Résumé : International audience
Transcriptional regulation by the estrogen receptor-alpha(ER) has been investigated mainly in breast cancer cell lines, but estrogens such as 17 beta-estradiol (E2) exert numerous extrareproductive effects, particularly in the liver, where E2 exhibits both protective metabolic and deleterious thrombotic actions. To analyze the direct and early transcriptional effects of estrogens in the liver, we determined the E2-sensitive transcriptome and ER cistrome in mice after acute administration of E2 or placebo. These analyses revealed the early induction of genes involved in lipid metabolism, which fits with the crucial role of ER in the prevention of liver steatosis. Characterization of the chromatin state of ER binding sites (BSs) in mice expressing or not ER demonstrated that ER is not required per se for the establishment and/or maintenance of chromatin modifications at the majority of its BSs. This is presumably a consequence of a strong overlap between ER and hepatocyte nuclear factor 4 alpha BSs. In contrast, 40% of the BSs of the pioneer factor forkhead box protein a (Foxa2) were dependent upon ER expression, and ER expression also affected the distribution of nucleosomes harboring dimethylated lysine 4 of Histone H3 around Foxa2 BSs. We finally show that, in addition to a network of liver-specific transcription factors including CCAAT/enhancer-binding protein and hepatocyte nuclear factor 4 alpha, ER might be required for proper Foxa2 function in this tissue.
ISSN: 0888-8809

hal-01357623
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01357623
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01357623/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01357623/file/Changes%20in%20gene%20expression%201%20and%20Estrogen%20Receptor_accepted.pdf
DOI : 10.1210/me.2015-1311

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
A hallmark of living systems is the management and the storage of information through genetic and epigenetic mechanisms. Although the notion of epigenetics was originally given to any regulation beyond DNA sequence, it has often been restricted to chromatin modifications, supposed to behave as cis-markers, specifying the sets of genes to be expressed or repressed. This definition does not take into account the initial view of epigenetics, based on nonlinear interaction networks whose "attractors" can remain stable without need for any chromatin mark. In addition, most chromatin modifications are the steady state resultants of highly dynamic modification and de-modification activities and, as such, seem poorly appropriate to work as long-term memory keepers. Instead, the basic support of epigenetic memory could remain the attractors, to which chromatin modifications belong as do many other components. The influence of chromatin modifications in memory is highly questionable when envisioned as static structural marks, but can be recovered under the dynamic circuitry perspective, thanks to their self-templating properties. Beside their standard repressive or permissive functions, chromatin modifications can also influence transcription in multiple ways such as: (1) by randomizing or inversely stabilizing gene expression, (2) by mediating cooperativity between pioneer and secondary transcription factors, and (3) in the hysteresis and the ultrasensitivity of gene expression switches, allowing the cells to take unambiguous transcriptional decisions.
ISSN: 1420-682X

hal-01063617
https://hal.archives-ouvertes.fr/hal-01063617
DOI : 10.1007/s00018-012-0923-7
PUBMED : 22331281

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Recently it has become clear that exposure to xenobiotics may result in various forms of cell death; not only passive cell deaths like necrosis, or programmed cell deaths such as apoptosis, but also regulated necrosis, autophagy, senescence, or mitotic catastrophe. Complex cell signaling networks influence the processing of cell death. Furthermore, recent research has revealed early complex molecular interactions between organelles prior to the final triggering of cell death. The plasma membrane may play an important role in the early cell death signaling events. Regarding this latter aspect, drugs and environmental pollutants have been reported to affect plasma membrane characteristics which may further affect cell fate. Changes in membrane fluidity or in composition and function of specialized membrane microdomains (plasma membrane remodeling) have been proven to be involved in the regulation of many important physiological signaling pathways, including cell death. Furthermore, it has been suggested that a crosstalk between chemical-induced cellular membrane effects and other organelles may be of vital importance to explain the final outcome of chemical exposure. Here, we review the effects of plasma membrane remodeling on cell survival and cell death; we describe how the cell signaling pathways activated by changes in plasma membrane characteristics may influence cell fate. Since plasma membrane function plays an important role in the regulation of a number of cellular responses, it has been implicated in the development or progress of several diseases. A better knowledge of the effects of various chemicals on plasma membrane remodeling may be important for understanding the pathogenesis of major diseases, and may assist in developing new therapeutic strategies.
ISSN: 0300-483X

inserm-00818916
http://www.hal.inserm.fr/inserm-00818916
DOI : 10.1016/j.tox.2012.12.014
PUBMED : 23287390

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Chromatin modification enzymes are important regulators of gene expression and some are evolutionarily conserved from yeast to human. Saccharomyces cerevisiae is a major model organism for genome-wide studies that aim at the identification of target genes under the control of conserved epigenetic regulators. Ume6 interacts with the upstream repressor site 1 (URS1) and represses transcription by recruiting both the conserved histone deacetylase Rpd3 (through the co-repressor Sin3) and the chromatin-remodeling factor Isw2. Cells lacking Ume6 are defective in growth, stress response, and meiotic development. RNA profiling studies and in vivo protein-DNA binding assays identified mRNAs or transcript isoforms that are directly repressed by Ume6 in mitosis. However, a comprehensive understanding of the transcriptional alterations, which underlie the complex ume6Δ mutant phenotype during fermentation, respiration, or sporulation, is lacking. We report the protein-coding transcriptome of a diploid MAT a/α wild-type and ume6/ume6 mutant strains cultured in rich media with glucose or acetate as a carbon source, or sporulation-inducing medium. We distinguished direct from indirect effects on mRNA levels by combining GeneChip data with URS1 motif predictions and published high-throughput in vivo Ume6-DNA binding data. To gain insight into the molecular interactions between successive waves of Ume6-dependent meiotic genes, we integrated expression data with information on protein networks. Our work identifies novel Ume6 repressed genes during growth and development and reveals a strong effect of the carbon source on the derepression pattern of transcripts in growing and developmentally arrested ume6/ume6 mutant cells. Since yeast is a useful model organism for chromatin-mediated effects on gene expression, our results provide a rich source for further genetic and molecular biological work on the regulation of cell growth and cell differentiation in eukaryotes.
ISSN: 1617-4615

hal-01151619
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01151619
DOI : 10.1007/s00438-015-1051-5
PUBMED : 25957495

Éditeur(s) : HAL CCSD Endocrine Society
Résumé : International audience
Sertoli cells (SCs), the only somatic cells within seminiferous tubules, associate intimately with developing germ cells. They not only provide physical and nutritional support but also secrete factors essential to the complex developmental processes of germ cell proliferation and differentiation. The SC transcriptome must therefore adapt rapidly during the different stages of spermatogenesis. We report comprehensive genome-wide expression profiles of pure populations of SCs isolated at 5 distinct stages of the first wave of mouse spermatogenesis, using RNA sequencing technology. We were able to reconstruct about 13 901 high-confidence, nonredundant coding and noncoding transcripts, characterized by complex alternative splicing patterns with more than 45% comprising novel isoforms of known genes. Interestingly, roughly one-fifth (2939) of these genes exhibited a dynamic expression profile reflecting the evolving role of SCs during the progression of spermatogenesis, with stage-specific expression of genes involved in biological processes such as cell cycle regulation, metabolism and energy production, retinoic acid synthesis, and blood-testis barrier biogenesis. Finally, regulatory network analysis identified the transcription factors endothelial PAS domain-containing protein 1 (EPAS1/Hif2α), aryl hydrocarbon receptor nuclear translocator (ARNT/Hif1β), and signal transducer and activator of transcription 1 (STAT1) as potential master regulators driving the SC transcriptional program. Our results highlight the plastic transcriptional landscape of SCs during the progression of spermatogenesis and provide valuable resources to better understand SC function and spermatogenesis and its related disorders, such as male infertility.
ISSN: 0888-8809

hal-01146846
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01146846
DOI : 10.1210/me.2014-1356
PUBMED : 25710594

Éditeur(s) : HAL CCSD
Résumé : Cell signaling contains the whole biological mecanisms allowing the response of a cell to its microenvironnement in an adapted way. Many extremely intertwinned biological reactions are involved in a network that behaves as a complex system. The understanding of cell response requires the development of data acquisition technics and methods to formalize data into models. This point is the main drive of this thesis. We present here two approaches in order to analyse different granularities of cell signaling. In the first one, we used differential model to study the role of a new component of TGF-β canonical pathway. In the second one, we explored the combinatorial complexity of cell signaling, developing a discrete formalism based on guarded transitions. In this approach, we interpreted the whole database Pathway Interaction Database into a single unified model of signal transduction. Simulation and analysis methods, such as reachability and invariance research, have been developed. The interests are presented through an application on cell cycle regulation by cell signaling, and a global analysis on the regulation of genes compared to experimental data.
La signalisation cellulaire regroupe l'ensemble des mécanismes biologiques permettant à une cellule de répondre de façon adaptée à son microenvironnement. Pour ce faire, de nombreuses réactions biologiques entrent en jeux avec un important enchevêtrement, créant ainsi un réseau dont le comportement s'apparente à un système complexe. Le compréhension de la réponse cellulaire à une stimulation passe par le développement conjoint des techniques d'acquisition de données, et des méthodes permettant de formaliser ces données dans un modèle. C'est sur ce dernier point que s'inscrivent les travaux exposés dans cette thèse. Nous présentons ici deux approches visant à répondre à des questions de natures différentes sur la signalisation cellulaire. Dans la première nous utilisons un modèle différentiel pour étudier le rôle d'un nouvel interactant dans la voie canonique du TGF-beta. Dans la seconde nous avons exploré la combinatoire de la signalisation cellulaire en développant un formalisme discret basé sur les transitions gardées. Cette approche regroupe l'interprétation de la base de données Pathway Interaction Database dans un unique modèle dynamique de propagation du signal. Des méthodes de simulations et d'analyses inspirées des techniques de vérification de modèles telles que l'atteignabilité et l'invariance ont été développées. En outre, nous avons étudié la régulation du cycle cellulaire en réponse à la signalisation, ainsi que la régulation des gènes de notre modèle en comparaison avec des données d'expressions.
https://tel.archives-ouvertes.fr/tel-00926487

Droits : info:eu-repo/semantics/OpenAccess
tel-00926487
https://tel.archives-ouvertes.fr/tel-00926487
https://tel.archives-ouvertes.fr/tel-00926487/document
https://tel.archives-ouvertes.fr/tel-00926487/file/AndrieuxThese.pdf

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Glioblastoma (GB), the most frequent primary tumor of the central nervous system, remains one of the most lethal human cancers despite intensive researches. Current paradigm in the study of GB has been focused on inter-patient variability and on trying to isolate new classification elements or prognostic factors. Here, using ICPL, a technique for protein relative quantification by mass spectrometry, we investigated protein expression between the four regions of GB on clinically relevant biopsies from 5 patients. We identified 584 non-redundant proteins and 31 proteins were found to be up-regulated in the tumor region compared to the peri-tumoral brain tissue, among which, 24 proteins belong to an interaction network linked to 4 biological processes. The core of this network is mainly constituted of interactions between beta-actin (ACTB) with heat shock proteins (HSP90AA1, HSPA8) and 14-3-3 proteins (YWHAZ, YWHAG, YWHAB). A cluster of three isoforms of the sodium pump α-subunit (ATP1A1, ATP1A2, ATP1A3) was also identified outside this network. The differential expression observed for ACTB and 14-3-3γ was further validated by western blot and/or immunohistochemistry. Our study confirms the identity of previously proposed molecular targets, highlights several functional processes altered in GB such as energy metabolism and synaptic transmission and could thus provide added value to new therapeutic trails.
ISSN: 1874-3919

hal-00877756
https://hal.archives-ouvertes.fr/hal-00877756
DOI : 10.1016/j.jprot.2012.04.034
PUBMED : 22575386

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
The regulatory mechanisms involved in the acquisition of thermal tolerance are unknown in insects. Reversible phosphorylation is a widespread post-translational modification that can rapidly alter proteins function(s). Here, we conducted a large-scale comparative screening of phosphorylation networks in adult Drosophila flies that were cold-acclimated versus control. Using a modified SIMAC method followed by a multiple MS analysis strategy, we identified a large collection of phosphopeptides (about 1600) and phosphoproteins (about 500) in both groups, with good enrichment efficacy (80%). The saturation curves from the four biological replicates revealed that the phosphoproteome was rather well covered under our experimental conditions. Acclimation evoked a strong phosphoproteomic signal characterized by large sets of unique and differential phosphoproteins. These were involved in several major GO superclusters of which cytoskeleton organization, positive regulation of transport, cell cycle, and RNA processing were particularly enriched. Data suggest that phosphoproteomic changes in response to acclimation were mainly localized within cytoskeletal network, and particularly within microtubule associated complexes. This study opens up novel research avenues for exploring the complex regulatory networks that lead to acquired thermal tolerance.
ISSN: 2045-2322

hal-01532256
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01532256
DOI : 10.1038/s41598-017-01974-z
PUBMED : 28490779

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: The TGF-β transforming growth factor is the most pleiotropic cytokine controlling a broad range of cellular responses that include proliferation, differentiation and apoptosis. The context-dependent multifunctional nature of TGF-β is associated with complex signaling pathways. Differential models describe the dynamics of the TGF-β canonical pathway, but modeling the non-canonical networks constitutes a major challenge. Here, we propose a qualitative approach to explore all TGF-β-dependent signaling pathways. RESULTS: Using a new formalism, CADBIOM, which is based on guarded transitions and includes temporal parameters, we have built the first discrete model of TGF-β signaling networks by automatically integrating the 137 human signaling maps from the Pathway Interaction Database into a single unified dynamic model. Temporal property-checking analyses of 15934 trajectories that regulate 145 TGF-β target genes reveal the association of specific pathways with distinct biological processes. We identify 31 different combinations of TGF-β with other extracellular stimuli involved in non-canonical TGF-β pathways that regulate specific gene networks. Extensive analysis of gene expression data further demonstrates that genes sharing CADBIOM trajectories tend to be co-regulated. CONCLUSIONS: As applied here to TGF-β signaling, CADBIOM allows, for the first time, a full integration of highly complex signaling pathways into dynamic models that permit to explore cell responses to complex microenvironment stimuli.
ISSN: 1752-0509

inserm-00978313
http://www.hal.inserm.fr/inserm-00978313
http://www.hal.inserm.fr/inserm-00978313/document
http://www.hal.inserm.fr/inserm-00978313/file/1752-0509-8-30.pdf
DOI : 10.1186/1752-0509-8-30