In humans, evolution is not only biological but also cultural: humans develop new technologies, modify their diet, control their reproduction, build up complex social organizations etc. Biologists and social scientists have become all the more interested into this double evolution since there is growing evidence that biological and cultural processes interact. Among all cultural traits, social organization is of particular interest to biologists since it conditions when, where and with whom men and women reproduce and raise their children. Social organization is therefore a key factor influencing genes transmission to the next generation and their dispersal within and between populations. Its understanding is therefore crucial to understand gene pool evolution. Ethnologists have described the impressive complexity of social organizations in human populations, and in particular the complex rules of alliance (which determine mate choice), rules of descent (which affiliate individuals to kin groups), and rules of residence (which indicate where just married couples should settle down). For the past ten years, geneticists have intended to understand how these rules affect the genetic diversity of human populations at local and global scales. However, such ethnogenetic studies have focused on a small number of populations and on a limited number of genetic markers, mostly uniparentally inherited Y chromosome and mtDNA. Moreover, there is a lack of data regarding the impact of social organization on demographic traits (fertility, survival, migrations), which may in turn influence gene pool evolution. Consequently, there is a need for a more comprehensive understanding of the extent to which social organization influences demographic traits and genome-wide diversity among humans. We propose to collect new multidisciplinary data from South-East Asian populations, which exhibit a wide range of social organizations (patrilineal, matrilineal, cognatic descents, with different degrees of endogamy and different residence rules). We will collect not only genetic data (saliva) but also demographic and ethnological data at the individual level, in order to investigate the impact of social processes on biological processes at a fine scale. Moreover, we will sample data for trios (mother, father, child) rather than unrelated individuals, in order to investigate the influence of alliance rules on genetic diversity, and to infer phased haplotypes and perform linkage disequilibrium analyses. In addition to the classically studied Y chromosome and mtDNA, we will genotype ~550,000 genetic markers evenly spaced throughout the genome. Such multidisciplinary data will allow us to i) explore, at the population level and at the kin group level, the impact of social organization on neutral and counter selected genome wide diversity, ii) explore which demographic traits (fertility, survival, migrations) are most affected by social organization, iii) then develop new methodological tools for the field of ethnogenetics: in particular we will develop new multidisciplinary models, taking into account ethnological and demographic traits, and aiming at investigating to which extent some aspects of past and present social organization may be inferred from genetic data and possibly detect past transitions in social organization.

In a general context in which many African languages are still poorly documented and strongly endangered, the general goal of this project is to update and complement the documentation of the languages of Senegal (and thereby of the Niger-Congo family) in order to bring a substantial contribution to (1) the preservation of Senegal's linguistic and cultural heritage and (2) the typological description of the languages. In particular, the project will first prioritise descriptive and supportive efforts for the endangered languages of this country. In addition, the project will considerably advance the knowledge of Senegalese languages through the linguistic description of little or not at all known languages. Finally, the project will result in rendering the linguistic inheritance of the country accessible by creating documentary corpora of primary data on as many languages as possible. The project has four main components. The first component consists in the documentation of Senegalese languages. The documentation for language endangerment will depend on the compiled electronic corpora and video films produced by professionals in collaboration with the researchers. The data on Senegalese minority and endangered languages will be transcribed, interlinearised and annotated. For other languages, only audio-video will be compiled. The second component is based on the description of Senegalese languages. The results will be achieved through work on existing sources as well as fieldwork in order to identify and classify the languages that are not covered by existing inventories and obtain updated information on language endangerment. This component will consist in the gathering and summarization of linguistics data for Atlantic languages for which we have some documentation. Fieldwork will be planned for some of these languages, if necessary. The linguistic application TOOLBOX will be used for analysing and working with data. It is also planned to archive all texts in audio/video format with time-aligned transcriptions and annotations and to make them accessible via the internet. The third component will establish a typology of some characteristics of Atlantic languages. These analyses are closely linked with the descriptions and the compilations of descriptions produced in the previous component. Three books based on three linguistic features are planned: the nominal classification; the verbal system and the verbal derivation. The relevance of this step of the project consists, on the one hand, in the fact that it will provide and synthesize new data on the Atlantic family; on the other hand, these features are also specific of the Niger-Congo phylum. The scope of these analyses exceeds the framework of the description of the Atlantic languages. The fourth and last component 'filing' plans the preservation in sound-text files and the setting on line of the collected data. All the components of the project rely on an intense collaboration of the parties involved. All participants will conduct fieldwork in Senegal. Additionally, regular progress meetings will be organised and alternate between Dakar and Paris. Both the linguistic inventory and the electronic corpora will constitute important data bases for a number of different disciplines in the humanities and social sciences (sociologists, anthropologists, specialists on oral literature and history, etc.) and for futher analysis in linguistic typology; they will allow a revision of the genetic classification of the Atlantic group, grounded on a qualitatively and quantitatively outstanding documentation.

The complex and dynamic network of interactions between cellular macromolecules plays an essential role in the regulation of important physiological behaviour in both prokaryotes and eukaryotes. The main aim of this project is to combine the expertise of three research groups, to further step into detailed characterization of interactions of important bacterial chromatin regulatory proteins with their interacting components including proteins and nucleic acid fragments. We will thus unravel the underlying mechanism of a major, if not the major, regulatory network for gene silencing in bacteria and thus open the possibility of elucidating the control of pathogenicity in a range of key microorganisms. The approaches used by the teams in the consortium are highly complementary. Partner 1 will bring its expertise in nucleoprotein complex formation in vivo to identify H-NS partners and in the kinetics of transcription initiation to investigate the action of the nucleoprotein complexes on target genes transcription initiation both in vitro. Partner 2 will extend the ground breaking observations made by her team concerning the mode of specific action of H-NS towards a deeper mechanistic analysis of H-NS regulation and also identify key partners in H-NS nucleoprotein complexes in vivo. Partner 2 will define model for H-NS specific nucleoprotein complex that can be validated. Partner 3 will validate their model for H-NS action in different, and especially plant pathogenic, strains thus providing an important model for developing drugs against pathogenic related diseases. Partner 3 will use plasmids bearing promoters of representative E. chrysanthemi gene(s) and the corresponding protein preparations to elucidate the mechanism of the regulators and to define the conditions that will be used by Partner 1 for the nucleoprotein complex characterization. Partner 3 will also use its expertise in genetic, biochemistry and molecular biology to functionally characterize the partners of H-NS and PecT. Partner 3 will provide partner 1 with the required strains, proteins and DNA templates for in vitro kinetic analysis of the formation of nucleoprotein complexes and the analysis of potential partners in specific nucleoprotein complexes.

During DNA synthesis, replication fork progression can be compromised by replication fork barriers (RFBs) which can results from various situations (DNA damage, DNA/protein complexes, DNA secondary structures...). Depending on the nature of the replication block, multiple pathways can be employed to restart fork progression: homologous recombination, template switch and trans-lesion synthesis. Failures in these pathways can results in inability to resume correctly DNA replication and genetic instability. While many factors are involved in the restart or protection of arrested fork, how they help to bypass or correct the causative problem and what are exactly their precise functions at stalled forks is largely unknown. In addition, homologous recombination can also be deleterious during DNA replication and specific pathways are involved in the avoidance of improperly processed recombination intermediates that are toxic for cells. To get insight into the understanding of those mechanisms, we intend to develop methodologies to visualize and to characterize (at both qualitative and quantitative levels) replication and recombination intermediates formed both in vivo and in vitro. To date, it is clear that only physical analyses and sophisticated imaging of replication and recombination intermediates will allow a deeper investigation of their DNA structures. Such interdisciplinary goals can be achieved by joining biological laboratories disposing of elegant model systems with molecular imaging laboratories disposing of powerful techniques allowing deep and precise investigations of physical characteristics of DNA structures. Therefore, we propose to combine molecular biology (such as 2D-gel and DNA combing), and biochemistry with molecular imaging such as electronic microscopy, AFM and fluorescent microscopy. The development of new tools from molecular imaging techniques to study and characterize replication and recombination intermediates at the molecular level is at the heart of this project. Our proposal aims at the emergence of new concepts relative to fundamental biological processes such as DNA replication and recombination and to the development of new methodologies allowing DNA species to be analyzed in a great number of organisms.

Cytokines are small size proteins that, by diffusing in the extracellular space carry distinct signals (activation, inhibition, proliferation, differentiation), and provide cells a system to communicate. Current research increasingly shows that most cytokines, in addition to their specific receptors, bind to a class of molecules, collectively known as glycosaminoglycans, and in particular to one of them called heparan sulfate (HS). These long, unbranched polysaccharides are near ubiquitous constituents of cell surfaces, and are carried by a specialized family of glycoprotein: the proteoglycans. Cytokine-HS interactions importantly regulate cytokine-receptor binding and activation, signaling, storage and stabilization in the extracellular space, and/or induce structural changes that modify cytokines activity. Interactions with HS are thus crucial and impact the dynamic of the cytokines at the cell surface or in the extracellular matrix and thus, their proper tissue localization and many of their biological functions. Given the importance of HS-cytokine interactions both in normal and pathologic states, understanding the mechanism and the structural bases that drive these interactions and their functions represent an important issue. However, progresses in that field have been hampered by the extraordinary complexity of HS. In particular, the characterization of the protein-HS interface, the isolation of the corresponding binding domains, and the elucidation of the mechanism by which HS regulate cytokine activity and dynamic remain particularly challenging. Based on a preliminary determination of the structure that a cytokine: interferon-gamma (IFNg), recognizes along the HS chain, a set of glycoconjugate mimetics has been synthesized, and evaluated for their ability to interact with the protein. One of these molecules, composed of two N-sulfated octasaccharides (dp8), linked to each other through a 5 nm long spacer displays high affinity for the cytokine. This molecule, termed 2O10 inhibits the binding of IFNg to HS with an IC50 of 35-40 nM, and most interestingly also blocks the binding of the cytokine to its cell surface receptor. This achievement represented the first synthetic HS-like molecule that targets a cytokine, and provides a potentially powerful strategy to inhibit IFNg. Although this molecule enables us to define the structural organization of the binding site (i.e. two binding octasaccharides spaced apart by an internal domain of appropriate length), the sulfation profile of each of the dp8 (currently homogeneously sulfated) has not been address yet. Our working hypothesis, supported by preliminary results recently obtained, is that only a selected (and specific) number of sulfate groups are actually engaged in the complex with IFNg. By combining structural, chemical, analytical and biological approaches, the goal of our proposal is to characterize the molecular determinants involved in the interaction of IFNg with HS, and to investigate, at the cellular level, the biological relevance of this interaction. In particular, this project should significantly contribute to outline the importance of the sulfation profile within the octasaccharides that interact with IFNg. This important point has never been addressed before, due to the structural heterogeneity of natural HS molecules, but is now possible in the context of the 2O10 template that can be obtained in pure form and large amount by chemical synthesis. Based on these results, we want to enhance the affinity and specificity of such glycoconjugates towards IFNg. An ultimate goal of this work will be the development of an inhibitor of the cytokine, which could be then evaluated in a number of pathology in which the cytokine has been identified as a target. The new knowledge generated in this complex field of biology will be the basis of the development of new therapeutic strategies based on the use of 'small glycanic drugs' to control a fundamental immunologic process. This project results from a long-term and sustained collaboration carried out by partners 1 (glycobiologist) and 2 (organic chemist) in the investigation of the IFNg/HS interaction, bringing together structure/function analysis in the field of protein-HS interaction and HS carbohydrate chemistry. Coupled to partner 3 (mass spectrometry specialist), it will lead to a further step in the characterization of the IFNg/HS complex. Such knowledge and collaboration are shared and mastered by only a very small number of groups over the world. In this regard, the collaboration between the 3 partners, on which this proposal is based is rather unique and has already allowed addressing important issues in the field.