The GEOPRAS consortium comprises seven partners that have been involved for several years in coastal archaeology. Our programme studies the coastal societies of recent Prehistory (Mesolithic and Neolithic) on the French Atlantic shores in order to understand their social and economic organization and the role they play in broader historical dynamics such as neolithization. Characteristics such as the accumulation of goods through storage, specialised modes of production, and the emergence of a social hierarchy or a sedentary lifestyle are often attributed to these coastal populations, on the basis of ethnographic documents from the last two centuries. However, each of these social manifestations must be described according to regional environmental variables, without evolutionary preconceptions. Our research hypothesis is that environmental dynamics have greatly facilitated certain forms of historical evolution. This encourages us to determine with greater precision the nature of these environmental transformations, then to analyse human networks at the continent-ocean interface. The first task will be to restore the environmental benchmarks. During the Mesolithic and Neolithic periods, most coastal landscapes were radically transformed by the sea-level rise and the associated processes of erosion and sedimentation. The coastal environments of the past will be reproduced through a three-level approach combining a large scale (region) with an intermediate scale (nearby landscape) and a local scale (archaeological site). Our consortium proposes a combination of methods suited to different geographical conditions (dunes, rocky coasts, marshlands) around the Bay of Biscay, testing the limits of several of them. To gain the best possible understanding of an "archaeological signal", the GEOPRAS project will focus on developing rapid intervention and rescue methods for archaeology and geoarchaeology. We intend to apply these methods to sites currently being excavated or whose exploration is planned as part of the project, such as foreshore and marshland sites and shell middens. Optimal integrated methods and procedures will be developed for the recording of archaeological remains, which are often ephemeral on foreshores, as well as for sampling, particularly in shell middens. These procedures include geophysical surveys, archaeozoology, micromorphology, geochemistry, taphonomy, metagenomic approaches, and OSL datings. The second task is to study how human societies have managed the land-sea interface. Shell middens have become the emblematic nodes of these coastal Holocene settlements because they contain an abundance of bio-archaeological data. They will be analysed to judge biodiversity as well as food practices. The third task is to understand the specific features of technical systems in a maritime context, especially seafaring. This technical field is at the heart of all the questions raised about the relationships between coastal areas, as well as the decisive features of the various technical systems developed in these areas. To overcome the lack of knowledge of prehistoric watercraft, we suggest an approach, based on three disciplinary poles in permanent interaction: 1) ethnographic and historical references, 2) technological and use-wear analyses of lithic and bone tools, 3) experimentation. In addition to proposing methodological developments, we aim to lay down the conceptual, methodological and technical foundations of a maritime prehistory with procedures adapted to coastal heritage. The results will be included in a handbook of maritime prehistory, to be published in French and English. The involvement of amateur archaeologists, observers, tourists and other citizens in scientific tasks will be anticipated and coordinated by inviting them to take part in the main scientific meetings and, of course, in field operations such as surveys, excavations and experiments.

Chaperone-Mediated Autophagy (CMA) is a major pathway of lysosomal proteolysis recognized as a key player of the control of intermediary metabolism. To date, this cellular function is presumed to be restricted to mammals and birds, due the absence of an identifiable LAMP2A, a limiting and essential protein for CMA, in phylogenetically earlier species. However, we recently identified the existence of lamp2a in several fish species. In this context, we propose to define for the first time whether or not a CMA (or a CMA-like) process is ancestral to mammalian/bird species and determine the physiological relevance of the newly identified lamp2a homolog in fish with respect to that process. To address this issue, our strategy will be based on two complementary approaches. We will first characterize the repertoire and the expression of genes involved in CMA in a large number of fish species of agronomical, ecological and scientific interest. The growing number of fish species whose genome was completely sequenced as well as our advances in transcriptome analysis allows including in our study a large number of fish species and thus to provide a comprehensive picture of the “genetic structure” of CMA in fish. Secondly, we will decipher the physiological role of the newly identified lamp2a homolog in fish. Recently, we have generated knockout medaka (Oryzias latipes) for the corresponding lamp2a splice variant of the lamp2 gene, by using the genome-editing tool CRISPR-Cas9. We will therefore perform an exhaustive phenotyping of the lamp2a mutant medaka (at both histological, biochemical and molecular levels) in order to determine the metabolic changes induced by the deletion of lamp2a and the possible existence of a CMA activity in medaka. This project gathers two partners (UMR1419 NuMeA and UR1037 LPGP) with highly complementary expertise and skills in autophagy, fish genomics, gene editing technology and fish metabolism. A major aim of the team members is to put together and mutually benefit from complementary scientific as well as technical expertise of each one of the scientists involved in this project. The present consortium has thus the required complementarity and added value to successfully carry out the present project. The involvement of a PhD student in the present project will also strengthen the cohesion of the consortium. Overall this project, which does not present any particular risk, will demonstrate the existence of a CMA activity - not yet suspected - in fish. Addressing the role of lamp2a and the possible existence of CMA activity in fish will represent a major breakthrough in our understanding of the mechanisms involved in the control of metabolism in these species and provide the necessary fundamental knowledge to cope with the challenges of aquaculture. Moreover, the comparative functional genomics approach across phylogenetical distant species will provide an entirely new aspect of the autophagy research by exploring the extent to which the CMA network has diverged during vertebrate evolution. Finally, the national and international partnership network of the members involved in this project will guarantee an effective dissemination of the obtained results to both the aquaculture industry and the academic partners.

Disorders of sex development (DSD) are very heterogeneous and despite intensive research over the last 30 years, only about 50% of DSDs can be explained on the molecular level. This highlights that our knowledge on mechanisms governing sex determination is still fragmented. In the project SexDiff, we will use mouse and human genetics in combination with transcriptomic analyses and bio-informatics to clarify how sex determination is driven. Sex determination is a developmental process allowing the differentiation of a bipotential precursor in two completely different organs, the testis or the ovary. This decision is driven by the paternal transmission of the Y-linked gene SRY which eventually initiates testicular development by up-regulating the transcription factor SOX9. In absence of SRY, R-spondin1 (RSPO1), an activator of the WNT/?-catenin signalling pathway, initiates ovarian differentiation. Both pathways antagonize each other, and sexual differentiation is determined by the dominant pathway. We have a long-standing interest in mechanisms of mammalian sex determination and have contributed to understanding of function of key genes such as SOX9 and RSPO1 and how these genes promote one sexual fate and repress the other. Despite recent advances our understanding of genetic components and mechanisms of sex determination remain limited. Discovery of novel factors and mechanisms involved in the process is of vital interest as mutations in yet to be discovered genes may be a cause of human reproductive pathologies, particularly DSD. The Wilms’ tumour suppressor WT1 is essential for the differentiation of the gonad. Different variants of WT1 exist and the imbalance of the ratio between the alternative spliced isoforms +KTS/-KTS are the cause of the male-to-female sex reversal in the Frasier syndrome. Recently discovered mutations impacting specifically the 4th DNA binding Zinc finger promote female-to-male sex reversal. This positions WT1 at the crossroad of the cell fate decision during sexual development. In this project we aim to decipher the role of these isoforms/variant in the differentiation of the gonad using mouse models and modified induced pluripotent stem cells (iPSC) and to uncover novel signalling networks regulated by WT1 during gonadal differentiation. We believe that it is important because these newly identified factors may provide a valuable diagnostic tool to understand the aetiology of idiopathic cases of human disorders of sex development. In contrast to testis, much less is known about the mechanisms of ovarian development in mammals. We have recently established that ovarian differentiation is decided before the first signs of sexual differentiation, a concept that breaks with the present view of sex determination. During the course of SexDiff, we will further explore this and characterize the molecular function of Rspo1 and identify new actors of ovarian differentiation using our Rspo1 loss-of-function mutants. These newly identified factors will then be further characterised to establish their causality and contribution to errors of ovarian development in human using the combinatorial approach involving genomics, in-silico, in-vitro, ex-vivo and cellular reprogramming approaches. To achieve these goals, we will employ a whole range of state-of the art techniques including single-cell RNA-Sequencing, cellular reprogramming (using iPSCs) and targeted mutagenesis by CRISPR/Cas9. Using the concerted approaches involving mouse models, human patients, cellular models and in–silico analyses, SexDiff will contribute to an in-depth understanding of the normal and pathogenic development of the gonads. This is envisaged to contribute and enhance our understanding of the aetiology of errors in gonad development in human and pave way for a better diagnosis. SexDiff, therefore, is of interest not only for enhancing our knowledge of fundamental biology but has an implicit clinical application.

Robot-assisted surgery, allowing surgeons to perform complex surgeries through tiny incisions, has been significantly increasing in popularity worldwide. However, surgical safety is still a major concern in the high-risk operating environment and remains a threat to the quality of surgical outcome. As global statistics, millions of surgeries per year would encounter safety-critical intraoperative adverse events, most of which were otherwise avoidable if the surgeon can be timely aware of the potential risks in operation. In this project, we aim to introduce smart context-awareness into robot- assisted surgery, by developing novel artificial intelligence techniques to provide automatic cognitive assistance for surgeons during critical moments of the procedure, in order to improve surgical safety and quality. The use case of this project will be robot-assisted hysterectomy, which is the most common gynecological procedure performed on women diagnosed with uterine fibroids or cervical cancer. Both Hong Kong and French teams will explore together innovative multimodal machine learning methods, based on available synchronized clinical video and kinematic data, which will be more advanced and clinically relevant than all existing methods that only used visual perception. Based on our pilot studies, we have identified a set of critical intraoperative scenarios to address avoidable adverse events in hysterectomy, such as injury of the pelvic ureter during both the coagulation of the uterus pedicle and adnexectomy. To achieve our goal, we will solve the following key challenges: 1) How to yield precise and real-time recognition of the surgical context, i.e., surgical workflow, operation actions, surgical instruments, anatomical tissues and the reconstructed 3D surgical environments. 2) How to conduct automatic assessment of the identified critical-context-of-safety (CCS), and further provide informed decision-making support to surgeons for their best practice to avoid safety risks. By a research collaboration between world-class teams with complementary expertise and already-available clinical and annotated data, the i-SaferS project will generate outputs that provide fundamentally new and generic solutions and impactful references to the field. The project outcomes will significantly contribute to the emerging field of intelligent robotic surgery, and further strengthen the leading competitiveness of both partners in this field nationally and internationally.

This project aims at studying the "digital turn", that is, the transition of a cultural realm defined by the presence of physically available media content to a world where digitized media, that is likely to deeply reconfigure our ways of being in the world. In order to analyze this "digital revolution", we will focus on artistic contexts, and, more specifically, on music in everyday life, and its socio-technical reconfiguration. We have chosen this relatively narrow subject to conduct our investigations for a series of reasons. Firstly, music consumption is a widely shared social experience in which technological innovation - Acetate to Mp3 - is a key element in the transformation. Second, illegal downloading and peer to peer file sharing have become major issues of public debate, legislation and intervention. Finally, our everyday experience of music is not limited to listening, but engages our identities, our conception of time, our emotions and attachments, our ways of understanding and articulating public and private space, etc., in short, it constitutes a very complete social experience.Furthermore, we are seeing since the early 2000s a turning point where the model of the music business goes through an almost uninterrupted market recession, while simultaneously, the digital music sales expand significantly. Indeed, digitization of content - what Fabien Granjon and Clément Combes have named the "digitamorphosis," succeeding Antoine Hennion’s "discomorphosis", drives a shift in the way amateurs relate to musical content. The rules of listening and interpretation are not immutable. An entire century of music recordings and experiments has already transformed what we expect from music, its creative processes, and the soundscapes and formats that make our everyday musical experience. However, these changes depend on discrete value alterations accumulating over time, and, among other things, on a standardization of traditional codes and more recent practices. In short, as digital schemes develop, the limits of what is acceptable are modified: listening, possessing, sharing or archiving are experiences that are evolving due to streaming technologies, the co-existence of multiple listening devices (personal computer, home stereos, portable music players), and the presence of musical content in social networks. Thus, digitization of music subverts the dominant paradigm of media and medium as a merged whole (tape, acetate, CD), suggesting then the possibility of a new paradigm: that of music as a service and not just a data. We could be going from a product-based society to a society of experience. In order to carry out this project in which cultural sociologists, ethnomusicologists and computer science specialists participate from three partner laboratories (Atlantic Centre of Philosophy at the University of Nantes, Nantes Computing Laboratory ; Arts and Language Research Center at EHESS), we will set three goals: first, to establish a chronological sequence of the "digital turn", bringing about simultaneously a reflective analysis on what it means to take a socio-historical approach on this type of transformation. Second, we seek to understand how the shift from an analog culture to a digital one, as well as the appearance of a “native-digital” generation, may transform our every day musical experience. Finally, we will consider the hypothesis of digital technology (and especially social networks) as a lever of transformation of the traditional paradigms that shape our present understanding of musical taste, legal frameworks for musical consumption and political ideals of democracy through the Internet.