Mind4Stormwater aims to help cities achieve sustainable management of their “stormwater control measures” (SCMs). These nature-based solutions (e.g. wetlands, swales, infiltration trenches, bioretention systems) have emerged worldwide in the last few decades, meaning that their long-term management is far from assured. Operational and research questions have so far largely focused on optimising hydrologic, hydraulic and water quality performance. However, there is a growing concern regarding sustainable long-term management, and its impact on performance and cost. Such concern will likely limit application and development of SCMs. On the other hand, SCM operation and maintenance could create new business opportunities related to sensors, monitoring and asset management. According to the UN, investing US$188 billion to manage stormwater and preserve water quality in the US could generate US$265 billion in economic activity and create nearly 1.9 million jobs. The situation is likely very similar with the 600,000 direct jobs in the EU water services sector. Mind4Stormwater will adapt existing low-cost technology sensors to the specific context of SCMs, and develop an innovative Expert System to guide the utility manager in selecting the best O&M actions for each SCM. The Expert System will be developed on an Australian case-study with an asset base of 500 SCMs. It will then be adapted for French cities and an adaptation draft for European cities will be developed. Mind4Stormwater tackles a major problem that is emerging worldwide. This novel research will establish the researcher and both organisations as leaders in the emerging research topic of integrated monitoring and asset management of stormwater control measures. It will reinforce their international recognition and increase opportunities to host excellent researchers. A series of outreach activities will also deliver public education and awareness of the major importance of integrated urban water management.

Osteolytic bone metastases are responsible for long bone fracture leading to restricted mobility, surgery, or medullar compression that severely alter quality of life and have a huge socio-economic impact. Current fragility scores to estimate the fracture risk in patients with metastatic femur are based on qualitative evaluation from Quantitative Computed Tomography (QCT) scans and lack sensitivity and specificity. Efforts are now made towards the development of patient-specific finite element models to assess the strength of tumoral bone segments, but their accuracy is hampered by several limitations, including limited knowledge of metastatic bone mechanical properties, simulations performed only for single stance loading condition, and simulations providing a global failure criteria. The aim of METABONE is, therefore, to use a novel approach to better predict the fracture risk of metastatic femur. A patient-specific finite element model will be developed based on QCT scans, which will include the real material properties of ex vivo human metastatic bone determined experimentally in the first part of the project. The composition and mechanical behaviour of diseased bone tissue are hypothesised to be rather different from healthy tissue and influential of femoral strength. This model will be used clinically on patients with osteolytic lesions located in proximal femur to assess the fracture risk during daily life activities, using a local failure criteria and a range of different loading conditions. This novel methodology, combining experimental and numerical approaches, is expected to significantly improve the accuracy of fracture risk prediction. Successful completion of METABONE will have the potential to guide clinical decision making, by providing clinicians with a more accurate tool to optimize locomotor strategy and oncology program, in order to prevent bone fracture, improve survival and quality of life of the patients.

The proper function of neuronal circuits in the adult brain relies heavily on glucose metabolism to ensure energy-demanding neuronal functions such as synaptic activity or long distance axonal transport. Deregulation of the energetic metabolism is strongly associated to many neurodegenerative diseases and has been linked to some neuropsychiatric diseases such as schizophrenia. However our current understanding of metabolic regulation in the developing brain and in particular in rapidly growing neurons is still fragmental. I recently identified a novel function for the kinase LKB1 in the control of axon outgrowth and terminal branching in the mouse cortex (Courchet et al. Cell 2013). This novel function of LKB1 involves the kinase NUAK1/ARK5, a poorly studied kinase related to the metabolic regulator AMPK. Furthermore our work uncovered a completely novel mechanism by which LKB1 and NUAK1 control terminal axon branching through the capture of mitochondria at nascent presynaptic sites. However the roles of presynaptic mitochondria in developing neurons and how they contribute to axon morphogenesis remain an open question. In this project I will to study how the regulation of glucose metabolism and mitochondria function by LKB1 and NUAK1 underlie neuron development and circuit formation in the neocortex. We will develop techniques combining live imaging of fluorescent metabolic reporters, functional metabolomics and in vivo manipulation of gene expression in mouse models to identify the relationship between glucose metabolism and axon development. My experimental plan will revolve around three independent aims that will tackle this question from a subcellular scale to circuits in vivo. Overall, this project will provide new insights into the molecular mechanisms underlying the development of the neocortex and will point out some of the consequences of metabolic imbalance on the development of the brain, a question that has many important implications for public health.

Most of the muscular dystrophies (MDs) are due to defects the trans-membrane protein complex called Dystro-Glycan Complex, which is a structural and functional bridge between myofiber contractile apparatus and extracellular matrix (ECM).MD research is focused upon the cellular mechanisms of the pathology and there is a lack of information about how ECM molecules can affect MDs, although alteration in ECM composition is acknowledged since fibrosis is an important bad outcome in the patients.Our hypothesis is that alterations in dystrophic muscle ECM directly account for mechanisms which negatively affect skeletal muscle homeostasis.The goal of the project is to identify alterations in ECM compromised by muscular dystrophy and to investigate their effects on cell behavior.Mdx mouse (model for Duchenne Muscular Dystrophy) and Sarcoglycan-β-null mouse (model for Limb Girdle Muscular Dystrophy 2E) will be used.To obtain the ECMs we will take advantage of decellularization approach that removes the cellular components while maintaining the molecular and structural features as closer as possible to the native ECM.In tissue engineering the use of ECM biomaterials demonstrated that ECM plays a fundamental, active role in tissue remodeling by growth factors release and ECM degradation product action.Molecular alterations in the ECM composition will be investigated by proteomics that assures an accurate and exhaustive characterization.ECM will be used as 3D environment to study its functions in the behavior of primary cells involved in the pathology: myogenic stem cells, endothelial cells, fibro-adipogenic precursors and macrophages.Discovering how alterations in dystrophic muscle ECM affect myogenesis, angiogenesis, fibrosis and inflammatory response will be of paramount importance for a better understanding of MDs.Changing the focus of the research from the cells to the ECM, this study will provide a new point of view and could contribute to identify new therapeutic targets.

Acetylcholine receptor is an essential component of central and peripheral nervous systems which plays a key role in numerous physiological and pathological processes. In particular, acetylcholine receptor is responsible for the coupling between nervous and muscular system at the neuromuscular junction as they are activated following acetylcholine release from neurons to triggers muscle contraction. Despite extensive work to decipher the molecular properties of the receptor itself, how the activity of the receptor and the signal following its activation are modulated is still poorly understood. This is yet an important question to address as impairment in acetylcholine receptor-associated signalling is involved in neuromuscular pathologies such as myasthenia gravis or congenital myasthenic syndrome. Here, we propose to use the genetic animal model Caenorhabditis elegans to study the dynamic regulation of acetylcholine receptors. This nematode is a powerful tool to study acetylcholine receptor as this animal also uses acetylcholine as an excitatory neurotransmitter at the neuromuscular junction. In nematode, acetylcholine receptors are sensitive to levamisole, a specific agonist. Prolonged exposure to levamisole leads to hypercontraction of the worms and finally to their paralysis. However, mutations in genes associated to acetylcholine receptor activity or biosynthesis enable the worms to adapt to levamisole. In this project, using proteomic and genetic approaches based on levamisole adaptation, we will identify several new regulators of acetylcholine receptor and of the associated signalling pathway. Deeper functional characterization will be performed on the new regulators evolutionary conserved that then may be involved in some neuromuscular pathologies. This research will give new insights into functional dynamic of acetylcholine receptor and may then shed a new light on the cause of impaired functioning of acetylcholine receptor in diseases.