Since the early 50s, paracetamol (acetaminophen) is very popular among non-prescription painkillers, which is why it is one of the most widely used drugs in the world. Of particular concern in the context of this application is that more than half of pregnant women in the Western world report intake of mild analgesics, especially acetaminophen, for treatment of pain and fever. During pregnancy, only paracetamol is recommended for the treatment of pain and fever. However, recommendations for the use of analgesics family of non-steroidal anti-inflammatory drugs for the treatment of these symptoms during the first trimester of pregnancy are more flexible, although organogenesis begins. A large body of evidence argues for a fetal origin of reproductive disorders observed in adulthood. These disorders, grouped under the terms “Testis dysgenesis syndrome” and “Ovarian dysgenesis Syndrome”, include congenital malformations of the male genital tract like cryptorchidism and hypospadias, increased incidence of infertility and of testicular cancers in the male, and increased incidence of infertility, endometriosis, disorders of the uterus and of the ovary such as premature ovarian failure and polycystic ovarian syndrome in the female. Analgesics have recently been identified as a new family of endocrine disruptors in the male, as evidenced by epidemiological and in utero and ex vivo experiments in rats. We have identified that several analgesics (paracetamol, aspirin, indomethacin) disturbed ex vivo the endocrine capabilities of the human fetal testis. However, if the risk is now established in the male, to date, the risk assessment of analgesic consumption during pregnancy on the development of fetal ovary has not been investigated. Other families of endocrine disruptive compounds, such as Bisphenol A, have been shown to modify the endocrine capabilities of the fetal testis but to impact the germ cell lineage in the ovary. Indeed, the human fetal ovary undergoes major morphogenetic events in the germ cell lineage including mitosis, meiosis, and epigenetic programming during the first and second trimesters of pregnancy. Altogether, these data urge for an investigation on the effects of analgesics on the development of human fetal ovaries, with a special emphasis on the germline. The specific aims of this proposal are i) to enlarge risk assessment of mild-analgesic exposure on the development of the human fetal ovary, ii) to finely characterize the effects of these molecules, for instance in terms of dose, duration of exposure and windows of sensitivity, on the fetal ovary and iii) to understand their mechanism(s) of action at the ovarian level. The experimental strategy of this proposal is to i) investigate the impact of analgesic on the development of human ovaries during the first trimester of pregnancy, when the germ line switches from mitosis to meiosis, ii) address whether windows of sensitivity exist by using in utero exposure in the rat experimental model and xenografting of human fetal ovaries into nude mice, iii) investigate what are the intimate mechanisms of action of analgesics at the RNA level by using high throughput sequencing, and iv) address possible silent long-lasting effect of analgesics at the DNA level. The ACETAMINOV proposal contributes to the exploration of the physiological and pathological ovarian differentiation, especially during the vulnerable phase of fetal life, thus integrating to public health policies.

Pain is one of the most distressing symptoms during the early postoperative period. Pain also occurs when rigid sealants are employed to stick tissues or close wounds as they hurt fragile tissues. To the best of our knowledge there is yet no sealant able to connect tissues in a soft manner. In this context, our project aims to develop original “soft glues” to efficiently connect tissues without mechanical constraints. SoftGlue will be elaborated in a one-step, easy to be scaled-up method, in water, at room temperature and without the need of organic solvents. In vitro studies will be carefully designed to minimize animal experiments, better understand the mechanisms of action of SoftGlue and optimize the formulations. First, in vitro sealing properties of SoftGlue will be assessed and compared to commercial products. Mechanical properties will be characterized using a set of standard procedures. In addition, we will develop an original method to study the bioadhesive properties, using an optical device to visualize SoftGlue in tissues under mechanical stresses (effect of thermo - mechanical solicitations) mimicking in vivo bonding wounds, blood flow, etc. After in vitro evaluations, selected few (3-4) SoftGlue will be evaluated in vivo. Tissue regeneration will be evaluated and neovessels formation will be investigated. Cell proliferation and migration will be assessed. Finally, a detailed diagram of the possible in vitro and in vivo toxic and genotoxic effects will be established. This project is a real opportunity to develop a long-term collaboration between complementary teams and to get this consortium persisting beyond scope of the project. SoftGlue is an ambitious interdisciplinary project dealing with an important societal need.

"With the ""Short Forms Beyond Borders (SFBB)"" project, we intend to work collaboratively on short forms as a tool for cultural, educational and social mediation in Europe. The relevance of short forms is becoming more and more visible in today's society. Brevity is becoming a way of doing things, a question of time and style, indeed of thinking (as in Twitter). Examples of short forms include short videos, text messages, short stories, Instagram stories, sound fragments, television series, short speeches, sales pitches, news briefs, slogans etc. “Short forms” is an innovative concept that can reach many targeted audiences. The present project aims to develop teaching approaches and pedagogical tools and programmes for adolescents and young adults, with a particular focus on the definition and use of short forms for cultural, educational and social mediation in Europe (literary, artistic, cultural, communicational, journalistic, social for example). Our project aims to both instruct these young people and eventually help respond to the needs of young migrants to find their place in European culture. Short forms become a means to develop and affirm social connections and cohesion, and also encourage the expression of individual and cultural identity. Based on our expertise in the area of short forms, we are interested in creating tools that develop and promote this potential for intercultural communication and societal cohesion.These tools will be contribute to activities that foster a sense of belonging (students belonging to Europe, the integration of migrants, the exploration of foreign spaces in the context of tourism), while taking into consideration individual and national identities.Specialists will consolidate skills and tools and will share competencies with a growing audience of teaching professionals who wish to develop the use of short forms tools for cultural, linguistic and pedagogical mediation.PARTNERS:Specialists of short forms from six European universities (Angers, France; Athens, Greece; Szeged, Hungary; Santiago de Compostela, Spain; Giessen, Germany; Leuven, Belgium) and a private firm, Baludik (Nantes), will work together to develop short forms as both tools and objects of pedagogical innovation and cultural mediation. Baludik develops a smartphone application to create educational and touristic itineraries (https://baludik.fr/). The tool will be used in the context of the project for pedagogical experimentations and tests.PROJECT ACTIVITIES:If European funds are obtained, the project will begin in October 2020 and will end in late August 2022. We will organize 6 meetings throughout the two years of the project (October, March, and June). These meetings will allow the members to coordinate their activities, and will also involve teaching sessions for professionals and students. The project will involve the mobility of professors and students (Masters and Doctoral). The indirect audiences of the tools in the project will be secondary school classes, and, if possible, young migrants. Tourists and amateurs of culture might also be interested in cultural products created by students in the context of the project. Short forms will be studied, created, used as tools and integrated into European programmes as a means to negotiate not only linguistic and cultural issues, but also social issues and questions of identity in Europe. They will be approached as tools for mediation in a perspective combining education, research and innovation that will focus on both the use and production of short forms. The first axis of the project will involve developing clear definitions for use by teaching professionals. We will also conduct surveys in the partner institutions to understand how short forms are currently being used in classrooms. A survey of online resources in the area of short forms will also take place during this first phase and will be pursued throughout the project. We will also create a website to be used for the full duration of the project. Its database will be accessible and contributed to by partners and participants during the project; the resources will be made widely available after the end of the project.In the third axis of the project we will develop pedagogical toolkits designed for intercultural and language learning.The last axis of the project will involve organizing these tools to develop innovative teaching sequences and modules that could be integrated into Masters and Doctoral programmes at European universities. Sequences for use in training secondary school teachers will also be developed. POTENTIAL LONG TERM BENEFITS:- Original pedagogical modules, that are “ready to use,” will be made available for integration into existing Masters and Doctoral programmes. These modules will follow the model of ""flash trainings""- An Erasmus Mundus application will be submitted for the creation of a European Short Forms Masters Degree."

The conserved 3’-5’ exoribonuclease EXOSC10 (Rrp6 in yeast) is essential for early embryogenesis, development of the forebrain and red blood cells, gametogenesis and cancer cell division. Among the protein’s best-studied substrates are ribosomal RNAs (rRNAs) and small nucleolar RNAs (snoRNAs) important for ribosome biogenesis, and long non-coding RNAs (lncRNAs) involved in B-cell enhancer activity and double strand break (DSB) repair. Our key goal is to understand how the stability of human 3’-5’ exoribonuclease EXOSC10 is regulated, and if external cues such as physical and chemical stress impair ribosome biogenesis and translation elongation by altering the protein’s cellular concentration, hence activity. We hypothesize that EXOSC10 is targeted by the anaphase promoting complex/cyclosome (APC/C)-proteasome pathway and thereby constitutes a molecular link between external cues and effects on ribosome biogenesis and function. Our model predicts that EXOSC10 alleles with altered stability and/or activity may be at the origin of certain ribosomopathies, which are defined as diseases caused by altered structural RNA/protein components of ribosomes or gene products required for ribosome biogenesis. Given that the anti-cancer drug 5-fluorouracil (5-FU) reduces the enzymatic activity of EXOSC10 via substrate inhibition, mutant alleles showing increased stability in cancer cells may also contribute to cancer cell survival and ultimately drug resistance via a compensatory mechanism. Our key objectives are to (1) demonstrate that yeast Rrp6 and mammalian EXOSC10 are extensively regulated at the post-translational level via environmental cues, (2) test our hypothesis that the APC/C-proteasome pathway plays a critical and evolutionarily conserved role in controlling EXOSC10/Rrp6 stability, (3) determine if abnormally stable EXOSC10 alleles alter a cancer cell’s ability to progress through the mitotic cell cycle and to respond to drug treatment, and (4) identify amino acids within the predicted destruction boxes and any of the modified residues in EXOSC10 have been mutated in cancer patients, and study the effect of these alterations on cell division and drug resistance in cultured cells. The project will lead to insight into the regulatory mechanisms that govern EXOSC10 stability and thereby help better understand how nutritional, physical and chemical stress influences ribosome biogenesis and protein translation. The outcome of the proposed work is thus not only of cell- and developmental biological interest but will likely also help improve cancer prognosis and drug treatment and efforts to elucidate molecular mechanisms underlying ribosomopathies in molecular oncology and the field of human developmental disorders.