Fluorescence has become an essential observable in Biology and Medicine. The discrimination of a fluorescent label usually relies on optimizing its brightness and its spectral properties. Despite its widespread use, this approach still suffers from important limitations. First, extraction of a fluorescent signal is challenging in light-scattering and autofluorescent samples. Second, spectral deconvolution of overlapping absorption and emission bands can only discriminate a few labels, which strongly limits the discriminative power of emerging genetic engineering strategies, and falls short from the several tens needed for advanced bioimaging and highly multiplexed diagnostic assays. Our consortium of chemists, physicists, and biologists introduces the HIGHLIGHT concept (PHase-sensItive imaGing of reversibly pHotoswitchable Labels after modulatIon of activatinG ligHT) to achieve chromatic aberration-free highly multiplexed fluorescence imaging with only single and dual wavelength channels in emission and excitation. HIGHLIGHT aims at expanding the discriminative dimensions of fluorophore sets much beyond spectral and concentration information such as classically implemented in multicolor labeling approaches. In HIGHLIGHT, label discrimination will not necessitate anymore singular spectroscopic signatures, sophisticated reading-out instruments, or delicate data processing for signal unmixing. In contrast, it shifts towards designing reactive schemes and observables to selectively promote and retrieve the response of a targeted label. HIGHLIGHT exploits reversibly photoswitchable fluorescent proteins (RSFPs) as labels. Increasingly exploited in super-resolution microscopy and dynamic contrast, they are not only fluorescent but as well engaged in rich photocycles. The HIGHLIGHT protocols exploit their specific fluorescence responses to light modulation under well-designed conditions, which provides several dimensions of dynamic contrast to overcome the limitations encountered with spectral discrimination; These responses will serve as readouts either alone or combined using statistical machine learning strategies, which will enable us to perform real time multiplexed imaging of more than ten spectrally similar fluorescent labels and discriminate more than one hundred hues created by mixing these labels in variable amounts and cell territories. As a proof of principle, we propose to challenge HIGHLIGHT in two types of contexts where the paucity of spectrally distinct fluorescent markers has until now been a major hindrance: the analysis of the lineage of retinal cell subtypes and that of their connectivity. In this project, we will namely (i) design and implement a suite of transgenic tools enabling to express varied combinations of 6-12 RSFPs within a population of cells; (ii) design HIGHLIGHT protocols for wide-field and scanning microscopies as well as relevant barcoding strategies to discriminate different cells; (iii) evaluate the photoswitching properties of several tens of RSFPs with one- and two-photon excitation under various environments; (iv) validate HIGHLIGHT for its implementation in a commercial confocal microscope and in state-of-the art Single Plane Illumination scanning Microscopes to push forward acquisition depth and speed; and eventually (v) perform multiplexed clonal analysis in the vertebrate retina, and single-neuron tracing and analysis of axonal convergence. Eventually, the tools and protocols introduced in this project will have near-universal applicability in Biology for multiplexed fluorescence-based observations within biological samples.

The project ” Regulators and explicit formulae ” aims at drawing together a group of mathematicians working on various aspects of regulator maps : analytic issues, motivic and K- theoretic problems, explicit formulae and reciprocity laws, links with L-functions, geometric interpretations via Arakelov theory. The main themes of the project are: - Motivic cohomology - Arakelov theory and explicit formulae - L-functions of number fields and elliptic curves. Polylogarithms

In global geodynamics, one of the most striking events is the transition from continental rifting to oceanic spreading, as most of the involved parameters fundamentally change (rift to drift, mantle source of magmas, nature of the lithosphere, magmatic plumbing system architecture, hydrothermal system). Despite their importance for the Earth geodynamics, the processes that govern the initiation of oceanic spreading and the associated production of juvenile magmatic crust remain first order open questions for the international geo-community. Few quantitative constraints exist on how magmatic spreading initiates to form steady MOR? In other words: How and when typical magmato/tectonic processes of oceanic spreading are gradually emplaced during Ocean Continent Transition (OCT) stage? Ultimately, why, at a certain moment, continental thinning switch to magmatic accretion and initiates the break-up? These fundamental questions could be tackled either by models (numerical or analogic) or following quantitative documentation of processes on fossil OCT and/or on active mature rifts, that can be viewed as nascent MOR. The Afar region at the northern end of the East African Rift system is the unique place on Earth where magmatic continental rifting and associated ongoing break-up processes are exposed onshore. This magmatic rift system is dissecting a Large Igneous Province and is connected laterally to the Red Sea and Gulf of Aden oceanic spreading ridges. This system presents the key advantage to expose extensional structures considered at ocean-continent transition with magmatic segments characterized by contrasted morphologies, magmato-tectonic styles, and maturity that have tentatively been assimilated to proto-spreading centers. The main working hypothesis of this project is that Afar is presently experiencing the final stage of continental break-up and progressive onset of steady magmatic spreading (process already completed in the lateral Red Sea and Gulf of Aden). The three main active, contrasted and complementary magmatic segments of Afar (Erta Ale, Dabbahu-Manda Hararo, Assal) offer the opportunity to study mantle and crustal processes in order to decipher fundamental parameters that control focussing of tectonic and magmatic activity until complete removal of continental lithosphere. The MAGMAFAR project is designed to make a breakthrough into this key and first order fundamental scientific issue of continental break-up in magmatic context, and rift transition to the onset of MOR. We will particularly focus on: (i) how do magmatic and tectonic processes control the styles and morphologies of magmatic segments? what are the parameters responsible for the characteristics of proto, steady-state spreading processes? (ii) why and how stable magma production and organized/focussed transfer to the crust start and led to break-up? Along the active magmatic segments of Afar we still need to understand precisely: how magmas are generated? how they are transferred to the crust? how they interact and are controlled by other forcing parameters (in particular, the mechanical behavior of the lithosphere)? We elaborated a general strategy that will combine high resolution quantification of both tectonic and igneous processes in the (i) active and (ii) plio-quaternary natural systems, which will serve in turn to calibrate (iii) an integrated thermo-mechanical modelling. Such an integrated and multidisciplinary approach, based on the combination of numerous complementary skills (petrology / geochemistry / geochronology / remote-sensing / structural geology / thermomechanical modelling), will be focused on the comprehensive description of these unique active segments, in order to bridge timescales and processes across the entire Afar Rift System. The MAGMAFAR project will produce a significant number of deliverables that will gradually cover the description and understanding of magmatic OCT from individual processes to general models.

The interstitial fibrosis is a major health problem because it causes dysfunction of many organs and is responsible for a high degree of morbidity and mortality due to organ injury. The frequency of pathologies with fibrosis increases progressively due to aging of the population and increase in risk factors due to occidental way of life. In this way, chronic kidney disease (CKD) is one of the pathologies associated with fibrosis, leading to renal dysfunction and to end stage renal disease. However, until now, no specific biomarker and no treatment are available,requiring to further study the molecular regulation of renal fibrosis. Our hypothesis is that soluble CD146 (sCD146), a new growth factor secreted abundantly during CKD, is involved in the development of interstitial fibrosis. The objective of our project will thus be to delineate the contribution of sCD146 to kidney fibrosis development, to evaluate its diagnostic interest as a biomarker, and to test newly generated anti-sCD146 antibodies as a new therapeutic approach.

A key problem in Mental Health is that up to one third of patients suffering from major mental disorders develop resistance against drug therapy. However, patients showing early signs of treatment resistance (TR) do not receive adequate early intensive pharmacological treatment but instead they undergo a stepwise trial-and-error treatment approach. This situation originates from three major knowledge and translation gaps: i.) we lack effective methods to identify individuals at risk for TR early in the disease process, ii.) we lack effective, personalized treatment strategies grounded in insights into the biological basis of TR, and iii.) we lack efficient processes to translate scientific insights about TR into clinical practice, primary care and treatment guidelines. It is the central goal of PSYCH-STRATA to bridge these gaps and pave the way for a shift towards a treatment decision-making process tailored for the individual at risk for TR. To that end, we aim to establish evidence-based criteria to make decisions of early intense treatment in individuals at risk for TR across the major psychiatric disorders of schizophrenia, bipolar disorder and major depression. PSYCH-STRATA will i.) dissect the biological basis of TR and establish criteria to enable early detection of individuals at risk for TR based on the integrated analysis of an unprecedented collection of genetic, biological, digital mental health, and clinical data. ii.) Moreover, we will determine effective treatment strategies of individuals at risk for TR early in the treatment process, based on pan-European clinical trials in SCZ, BD and MDD. These efforts will enable the establishment of novel multimodal machine learning models to predict TR risk and treatment response. Lastly, iii.) we will enable the translation of these findings into clinical practice by prototyping the integration of personalized treatment decision support and patient-oriented decision-making mental health boards.