Rapidly Progressive Glomerulonephritis (RPGN) is a class of acquired renal disease that remains one of few human autoimmune diseases representing an acute threat to survival. Focal necrotizing crescentic GN is the renal lesion typically associated with the clinical syndrome of RPGN and is a medical emergency that requires side-effect prone immunosuppressive therapies. Untreated RPGN progresses rapidly to renal insufficiency. During crescent formation in experimental RPGN in mice, podocytes assume a migratory phenotype and proliferate. Immune-mediated glomerulonephritis can also develop chronically. IgA nephropathy (IgAN) is the most common primary GN. The realization that around 30% of patients with this apparently benign condition progress to end-stage renal disease revealed IgAN to be a major health problem. It thus appears that a sub-group of IgAN patients undergo a phenotypic switch to accelerated disease progression and poor outcome. The basis for this switch is poorly understood, yet common pathological features between RPGN and severe IgAN may suggest that a second insult could convert IgAN to an RPGN-like phenotype, begging the question of what such an insult would be, and whether there is mechanistic convergence in the pathogenesis of the two diseases. This project relies on two recent findings in our laboratories: 1/ We demonstrated de novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in podocytes from both mice and humans with RPGN. Such induction correlated with increased phosphorylation of EGFR in podocytes from mice with anti-GBM disease. Glomerular EGFR activation was absent and the course of RPGN markedly improved in HB-EGF-deficient mice. Moreover, conditional deletion of the Egfr gene from podocytes or administration of a clinically available EGFR inhibitor both markedly alleviate RPGN in mice. 2/ With the aim of identifying the pathogenic molecular pathways involved in mesangial cell transformation in IgAN, we performed a gene expression screen to identify genes induced by IgA1-complexes in human mesangial cells (HMC). HMC were stimulated by IgA1 complexes purified from IgAN patients or by serum IgA1 purified from normal subjects. HB-EGF was one of the most prominent genes up-regulated in HMC stimulated with patient-derived IgA1 complexes. These observations suggest that engagement of EGFR by HB-EGF constitutes a pathogenic switch in RPNG that may also be common to IgAN. We will first address whether the EGFR is a pathogenic mediator common to inflammatory GN. We then aim to identify pathological conversions and signaling pathways upstream of EGFR and determine to what extent they are shared in RPGN and IgAN. We are interested in defining points of mechanistic convergence between the two disease forms in attempt do identify a pathogenic switch that can convert relatively benign chronic GN such as IgAN to a rapidly progressing form of the disease. We postulate that engagement of EGFR signaling might constitute such a switch. To test this hypothesis, will first use transgenic models to address whether expression of EGFR and its ligands is sufficient to either trigger RPGN or convert IgAN to RPGN. As we anticipate that an additional insult will be required, we will then seek to identify upstream pathways and events that may elicit EGFR signaling, potentially by release of ligands such as HB-EGF. Transactivation of EGFR by G-protein-coupled receptors (GPCRs), also implicated in GN, has been documented. This interaction allows GPCRs to take advantage of pathways downstream of EGFR to influence cell function. Seeking to identify GPCRs that may engage the EGFR pathway, we focus on GPCR families likely to be engaged in both RPGN and IgAN due to dysfunction of the capillary barrier, including protease-activated receptors (PARs) and endothelin receptors (ETA and ETB). We hope to identify dominant signaling pathways of EGFR and additional targets.

Verifying correctness and robustness of programs and systems is a major challenge in a society which relies more and more on safety-critical systems controlled by embedded software. This issue is even more critical when the computations involve floating-point number arithmetic, an arithmetic known for its quite unusual behaviors, and which is increasingly used in embedded software. Note for example the "catastrophic cancellation" phenomenon where most of the significant digits of a result are cancelled or, numerical sequences whose limit is very different over the real numbers and over the floating-point numbers. A more important problem arises when we want to analyse the relationship between floating-point computations and an "idealized" computation that would be carried out with real numbers, the reference in the design of the program. The point is that for some input values, the control flow over the real numbers can go through one conditional branch while it goes through another one over the floating-point numbers. Certifying that a program, despite some control flow divergences, computes what it is actually expected to compute with a minimum error is the subject of the robustness or continuity analysis. Providing a set of techniques and tools for verifying the accuracy, correctness and robustness for critical embedded software is a major challenge. The aim of this project is to address this challenge by exploring new methods based on a tight collaboration between abstract interpretation (IA) and constraint programming (CP). In other words, the goal is to push the limits of these two techniques for improving accuracy analysis, to enable a more complete verification of programs using floating point computations, and thus, to make critical decisions more robust. The cornerstone of this project is the combination of the two approaches to increase the accuracy of the proof of robustness by using PPC techniques, and, where appropriate, to generate non-robust test cases. The goal is to benefit from the strengths of both techniques: PPC provides powerful but computationally expensive algorithms to reduce domains with an arbitrary given precision whereas AI does not provide fine control over domain precision, but has developed many abstract domains that quickly capture program invariants of various forms. Incorporating some PPC mechanisms (search tree, heuristics) in abstract domains would enable, in the presence of false alarms, to refine the abstract domain by using a better accuracy. The first problem to solve is to set the theoretical foundations of an analyser based on two substantially different paradigms. Once the interactions between PPC and IA are well formalized, the next issue is to handle constraints of general forms and potentially non-linear abstract domains. Last but not least, an important issue concerns the robustness analysis of more general systems than programs, like hybrid systems which are modeling control command programs. Research results will be evaluated on realistic benchmarks coming from industrial companies, in order to determine their benefits and relevance. For the explored approaches, using realistic examples is a key point since the proposed techniques often only behave in an acceptable manner on a given sub classes of problems (if we consider the worst-case computational complexity all these problems are intractable). That's why many solutions are closely connected to the target problems.

Nature does nothing uselessly (Aristotle: I.1253a8). This is also true for our human body, although it is highly complex and built up by highly synchronized sub-systems and a huge number of individual cells. When a body tissue or cells are placed in a dish, a flask or a multi-well plate, they undergo substantial changes of the cellular microenvironment, including extracellular matrix, soluble factors and cell-cell contacts. Such changes should have important consequences on the performance of cell-based assays, tissue engineering and regenerative medicine. Although a huge amount of research work has been done to improve the in-vitro culture conditions, it is still far way to approach the real in-vivo cellular microenvironments. One of the reasons is the lack of general platforms which allow high precision regulation of cellular microenvironments. Microengineering techniques are now widely used to fabricate surface texted culture substrates or synthetic extracellular matrix on one hand, and microfluidic devices for dynamic control of soluble factors on another hand. In this project, we propose a systematic investigation of cell migration and differentiation on patterned micro and nanopillars arrays, with or without integration into microfluidic devices. By changing the geometrical parameters of the pillars, we will particularly focus on the role of substrate stiffness cell migration and differentiation. Previously, the most of investigations in this field were done with over simplified pattern design and fabrication. For example, micropillars of large diameters were produced using elastomer such as PDMS, which are suited for the cell force measurement but not for the control of cell migration and related applications. In this project, we plan to fabricate pillars with much small diameters, down to 100 nanometers, in order to cover a large range of pillar diameters which are required for controlled cell migration studies. We will also produce oblique pillars for directed cell migration under different assay configurations. Furthermore, we will design and generate a variety of pillar arrays varying in pillar diameter, spacing and height, in order to create stiffness gradients for durotaxis studies. Finally, we will propose a two-level patterning approach to create quasi three-dimensional features in order to achieve a new freedom in designing synthetic cellular microenvironment. Each type of the pillars will be evaluated by cell migration recordings. After optimization, the pillar arrays will be integrated into microfluidic devices to perform the same experiment under microflow conditions at a higher throughput. The final gold of this project is to assess the market potential of the proposed assays. Therefore, we propose a multidisciplinary consortium composed by three academic research teams (one from ENS specialized in nanofabrication technologies for cell biology, one from Curie Institute specialized in cell polarity and migration on patterned surface, and another from the University of Paris-Diderot (Institut Jacques Monod) specialized in biophysics of cell-based assays) and a start-up company (Elvesys) specialized in microfluidic instrumentation. Although our demonstration example will be done with micro and nanopillars, other types of patterns can also be produced in a similar manner. The fabricated samples can also be useful for other types of cell-based assays, including adhesion, proliferation, differentiation, and apoptosis etc. As the fabrication technology we proposed can be used for large scale manufacturing, it will be easy to convert our prototype devices into industrial production. To this end, we anticipate a number of clinic applications of such products including tissue engineering, wound healing, etc.

The scientific and technological interest in Graphene has recently exploded due to its unique properties, promising many exciting applications in optics, mechanics and electronics. However many challenges remain before graphene can be integrated into sophisticated devices. The electronic states of graphene are strongly affected by surface charges, and the presence of surface contaminants dramatically degrades the film properties, especially the electronic mobility. Therefore, a key point in all graphene-based technology is the development of cleaning techniques, which can selectively etch surface contaminants. However, no such technology exists at present. For nano-electronic applications the opening of an electronic band gap is another challenge. This could be achieved either by substitutional doping or by edge patterning of graphene nano-ribbons, but mo mature processes have been developed. This project will address these issues by developing innovative plasma processes. Plasma surface processing is universally used for integrated circuit fabrication. However, plasma processing of graphene remains marginal, with only a few papers published in 2012. This is mainly because conventional plasma sources are too aggressive for atomically thin layers, usually causing damage the basal plane of graphene. However, we will investigate the use of novel low ion energy plasma sources which have recently been developed for the microelectronic and photovoltaic industries to reduce plasma induced damage and allow controlled atomic-scale etching. The goal of this project is to evaluate two new plasma sources (Pulsed ICP plasmas at LTM and TVWP at LPP/LPICM) to clean, dope and pattern graphene layers in a controlled way, opening the possibility for graphene device manufacturing. These plasma sources have demonstrated remarkable capabilities in 2012 to etch and deposit ultrathin layers. In particular, H2 plasmas are promising for graphene cleaning (H atoms can etch amorphous hydrocarbons while preserving the integrity of the graphene), while Cl2, N2 and BCl3 are interesting for graphene doping. Efficient process development will be achieved using the following strategy: 1) Molecular Dynamic simulations (MD) to predict the necessary flux and energy of particles to the surface; 2) Plasma diagnostics to control the flux and energy of incident particles; 3) Surface diagnostics to monitor the effect of the plasma treatment. Several powerful surface analysis techniques (XPS, Raman, XPEEM, µ-Auger) will be used to characterize the effect of plasma treatment on the film structure, composition and electronic properties. Finally, we plan to fabricate and electrically characterize real electronic devices in graphene. Our success will repose upon the complementary skills of the five partners in graphene devices, in plasma processing and in surface characterization. I-Néel has expertise in the CVD growth of high mobility graphene on large area substrates and the fabrication and electrical characterization of graphene electronic devices. LTM, LPP and LPICM are specialized in the characterization and development of plasma processes for microelectronic and photovoltaic applications, respectively. They have recently developed the two new plasma sources at the heart of this project. Finally, CEA-LETI has the expertise in photoelectron spectromicroscopy (XPEEM) combined with scanning probes and Auger microscopies. XPEEM provides direct, spatially-resolved information on the surface chemical properties and band structure of graphene relevant to doping and cleaning (Dirac point and Fermi level positions). This tool will guide the development of plasma cleaning, doping and etching of graphene. Thanks to our complementary expertise, we aim to achieve technological breakthroughs in the fabrication of graphene devices, which will be of great utility to the entire national graphene community

This project will focus on the synthesis and properties of ternary carbides or nitrides called MAX phases. These phases have a Mn+1AXn composition, where n = 1, 2 or 3, M being an early transition metal, A is an A-group element and X is either C or N. They are layered and hexagonal, with Mn+1Xn layers interleaved with layers of pure A. To summarize the properties of these phases as a class of materials, one can write that they combine some of the best properties of ceramics (low density and high stiffness, fatigue resistance,...) and metals (high thermal and electrical conductivity, high fracture toughness and damage tolerance, hardness, …). The MAX materials can be elaborated by conventional ceramic processes (reactive sintering, HIP, CVD…). Furthermore, many of the MAX phases have a high oxidation resistance. Two industrials (ACERDE and MECACHROME) associated with three laboratories (CEA/DEN, LEM and LMP) are joining efforts to synthesize and to develop MAX phases for structural applications. The main goal of this project is to evaluate this family of compounds for such applications by studying some « 312 » (Ti3SiC2, Ti3AlC2) and « 211 »( Ti2AlC, Ti2AlN) phases. Particular efforts will be concentrated on two major challenges, corresponding to problems that have not been completely understood up to now : • to obtain high purity MAX phases (i.e. without secondary phases and oxygen free), which requires a better understanding of chemical reactions and their kinetics during synthesis; • to maintain good mechanical properties under various conditions (chemical environment, irradiation effects), In the framework of this project, different techniques will be used for the processing of MAX phases either in the form of monolithic pieces and of coatings: - Physical Vapour Deposition (PVD) - Chemical Vapour Deposition (CVD) - Synthesis of nanoparticles by laser pyrolysis method and subsequent shaping by conventional powder metallurgy technique Concerning medium term applications, emphasis will be put on high performance motor compounds like pistons and valves, as well as on cutting tools. Structural compounds for generation IV reactor cores are rather a target for long term applications.