Towards comprehensive observing and modeling systems for monitoring and predicting regional to coastal sea level

A major challenge for managing impacts and implementing effective mitigation measures and adaptation strategies for coastal zones affected by future sea level (SL) rise is our limited capacity to predict SL change at the coast on relevant spatial and temporal scales. Predicting coastal SL requires the ability to monitor and simulate a multitude of physical processes affecting SL, from local effects of wind waves and river runoff to remote influences of the large-scale ocean circulation on the coast. Here we assess our current understanding of the causes of coastal SL variability on monthly to multi-decadal timescales, including geodetic, oceanographic and atmospheric aspects of the problem, and review available observing systems informing on coastal SL. We also review the ability of existing models and data assimilation systems to estimate coastal SL variations and of atmosphere-ocean global coupled models and related regional downscaling efforts to project future SL changes. We discuss (1) observational gaps and uncertainties, and priorities for the development of an optimal and integrated coastal SL observing system, (2) strategies for advancing model capabilities in forecasting short-term processes and projecting long-term changes affecting coastal SL, and (3) possible future developments of sea level services enabling better connection of scientists and user communities and facilitating assessment and decision making for adaptation to future coastal SL change.RP was funded by NASA grant NNH16CT00C. CD was supported by the Australian Research Council (FT130101532 and DP 160103130), the Scientific Committee on Oceanic Research (SCOR) Working Group 148, funded by national SCOR committees and a grant to SCOR from the U.S. National Science Foundation (Grant OCE-1546580), and the Intergovernmental Oceanographic Commission of UNESCO/International Oceanographic Data and Information Exchange (IOC/IODE) IQuOD Steering Group. SJ was supported by the Natural Environmental Research Council under Grant Agreement No. NE/P01517/1 and by the EPSRC NEWTON Fund Sustainable Deltas Programme, Grant Number EP/R024537/1. RvdW received funding from NWO, Grant 866.13.001. WH was supported by NASA (NNX17AI63G and NNX17AH25G). CL was supported by NASA Grant NNH16CT01C. This work is a contribution to the PIRATE project funded by CNES (to TP). PT was supported by the NOAA Research Global Ocean Monitoring and Observing Program through its sponsorship of UHSLC (NA16NMF4320058). JS was supported by EU contract 730030 (call H2020-EO-2016, “CEASELESS”). JW was supported by EU Horizon 2020 Grant 633211, Atlantos

Régulation phosphoinositide-dépendante de mTORC1 dans le muscle squelettique : voies moléculaires et implication dans la myopathie myotubulaire

Phosphoinositides are secondary lipids messenger involved in multiple cellular functions. The PI3P and PI(3,5)P2 are two substrates of a PI-3-phosphatase named the myotubularine or MTM1. Mutation in the MTM1 gene are at the origin of the X-linked Centronuclear Myopathy (XLCNM). It was shown that MTM1 loss induce the accumulation of PI3P, in muscle cells of MTM1-KO mice models. However, the molecular and physiopathological consequences of MTM1 substrates deregulation are unknown. Previous observations show an altered anabolism-catabolism balance in muscle cells depleted of MTM1 expression. In particular, the two major pathways of cellular degradation: UPS (ubiquitin proteasome system) and autophagy are deregulated in this model. A direct role of MTM1 in UPS component regulation has been proposed while its role in anabolism remains to be explored. In this context, the exploration of the major pathways of anabolism by a pharmacological screen on Mtm1-KO muscle cells has enabled my team to highlight a hyperactivation of the mTORC1 pathway (mamelian Taoget Rapamycin complex 1). It is a major complex that regulates cell growth and inhibits cell degradation by repressing autophagy. The team confirmed the overactivation of mTORC1 pathway in differentiated muscle cells (from mice and patients) but also in adult muscle from Mtm1-KO mouse model. Interestingly, the pharmalogical inhibition of this pathway has certain benefits on the differentiation of myotubes but also on muscle function, and survival of Mtm1-KO mice. Based on these findings, my thesis project aimed to determine the molecular link between Mtm1, these lipid substrates, and mTORC1. Thus we explored the key organelle of recruitment and activation of mTORC1, the lysosome, and we hypothesized that Mtm1 and its substrates act on the assembly of mTORC1 on this cellular compartment. The use of models of XLCNM supported by proteomics, metabolomics and lipidomics strategies at the lysosome scale allowed us to highlights a molecular link between PI3P and PI(3,5)P2 and the subcomplexe RAGULATOR(LAMTOR)-RagGTPase ; the axis of mTORC1 activation by amino acids. We have shown that the accumulation of PI3P and PI(3,5)P2 on the lysosome promotes the formation and stability of LAMTOR-RagGTPase complex and thus predisposes mTORC1 to permanent activation. Thus, a regulated level of PI3P and PI(3,5)P2 would serve as a plateform for LAMTOR-RagGTPase complex to allow activation of mTORC1 independently of nutrient fluxes. Nevertheless, an accumulation of these lipids induces an overactivation of mTORC1 with harmful repercussions on muscle differentiation and function. Finally, our study proposes the use of mTORC1 inhibitors as an interesting therapeutic tool against this myopathy which to date remains incurable.Les phosphoinositides (PI) sont des lipides seconds messagers impliqués dans de multiples fonctions cellulaires. Leur importance est soulignée par un grand nombre de pathologies liées à des mutations d'enzymes intervenants dans leur métabolisme. Parmi ces PIs, le PI3P et le PI(3,5)P2 sont deux substrats d'une PI-3-phosphatase nommée la myotubularine ou MTM1. Des mutations dans le gène MTM1 sont à l'origine de la myopathie centronucléaire liée à l'X (XLCNM). Il a été montré que la perte de MTM1 induit une accumulation de PI3P, dans les cellules musculaires de souris modèle Mtm1-KO. Cependant, les conséquences moléculaires et les retombées physiopathologiques de la dérégulation des substrats et des produits de MTM1 restent encore inconnues. Des observations antérieures montrent une altération de la balance anabolisme-catabolisme dans des cellules musculaires déplétées de l'expression de MTM1. En effet, les deux voies majeures de la dégradation cellulaire : l'UPS (ubiquitin proteasome system) et l'autophagie sont dérégulées dans ce modèle. Un rôle direct de MTM1 dans la régulation de composant de l'UPS a été proposé alors que son rôle dans l'anabolisme reste encore à explorer. Dans ce cadre, l'exploration des voies majeures de l'anabolisme par un crible pharmacologique sur des cellules musculaires Mtm1-KO a permis à mon équipe de mettre en évidence une hyperactivation de la voie mTORC1 (mamelian Target rapamycin complex 1). C'est un complexe majeur qui régit la croissance cellulaire et inhibe la dégradation cellulaire en réprimant l'autophagie. L'équipe a confirmé la suractivation de la voie mTORC1 dans les cellules musculaires différenciées (de souris et de patients) mais aussi dans le muscle adulte du modèle murin Mtm1-KO. De façon intéressante, l'inhibition pharmacologique de cette voie à des bénéfices certains sur la différenciation des myotubes mais aussi sur la fonction musculaire, et la survie des souris Mtm1-KO. Partant de ces constats, mon projet de thèse a eu pour objectif de déterminer le lien moléculaire entre Mtm1, ces substrats lipidiques et mTORC1. Ainsi nous avons exploré l'organelle clé de recrutement et de l'activation de mTORC1, le lysosome. Nous avons alors émis l'hypothèse que MTM1 et ses substrats agissent sur l'assemblage de mTORC1 sur ce compartiment cellulaire. L'utilisation des modèles cellulaires de XLCNM, appuyée par des stratégies de protéomique, métabolomique et lipidomique à l'échelle du lysosome, nous a permis de mettre en évidence un lien moléculaire entre le PI3P et le PI(3,5)P2 et le sous complexe RAGULATOR(LAMTOR)- RagGTPase: l'axe d'activation de mTORC1 par les acides aminés. Nous avons montré que l'accumulation du PI3P et le PI(3,5)P2 sur le lysosome favorise la formation et la stabilité du complexe LAMTOR-RagGTPase et ainsi prédispose mTORC1 à une activation permanente. Ainsi, un taux régulé de PI3P et le PI(3,5)P2 servirait de plateforme pour le complexe LAMTOR-RagGTPase pour permettre une activation de mTORC1 indépendamment des flux de nutriments. Néanmoins, une accumulation de ces lipides induit une suractivation de mTORC1 avec des retombées néfastes sur la différentiation et la fonction musculaire. Enfin ; notre étude propose l'utilisation d'inhibiteurs de mTORC1 comme un outil thérapeutique intéressant contre cette myopathie qui, à ce jour, reste incurable

Understanding the effect of phosphorous on the ion-irradiation behaviour of RPV model steels using atom probe tomography and nanoindentation

International audienc

Data from: Temporal dynamics of seed excretion by wild ungulates: implications for plant dispersal

Dispersal is a key process in metapopulation dynamics as it conditions species' spatial responses to gradients of abiotic and biotic conditions and triggers individual and gene flows. In the numerous plants that are dispersed through seed consumption by herbivores (endozoochory), the distance and effectiveness of dispersal is determined by the combined effects of seed retention time in the vector's digestive system, the spatial extent of its movements, and the ability of the seeds to germinate once released. Estimating these three parameters from experimental data is therefore crucial to calibrate mechanistic metacommunity models of plant–herbivore interactions. In this study, we jointly estimated the retention time and germination probability of six herbaceous plants transported by roe deer (Capreolus capreolus), red deer (Cervus elaphus), and wild boar (Sus scrofa) through feeding experiments and a Bayesian dynamic model. Retention time was longer in the nonruminant wild boar (>36 h) than in the two ruminant species (roe deer: 18–36 h, red deer: 3–36 h). In the two ruminants, but not in wild boar, small and round seeds were excreted faster than large ones. Low germination probabilities of the excreted seeds reflected the high cost imposed by endozoochory on plant survival. Trait-mediated variations in retention time and germination probability among animal and plant species may impact plant dispersal distances and interact with biotic and abiotic conditions at the release site to shape the spatial patterns of dispersed plant species

MTM1-mediated production of phosphatidylinositol 5-phosphate fuels the formation of podosome-like protrusions regulating myoblast fusion

International audienceMyogenesis is a multistep process that requires a spatiotemporal regulation of cell events resulting finally in myoblast fusion into multinucleated myotubes. Most major insights into the mechanisms underlying fusion seem to be conserved from insects to mammals and include the formation of podosome-like protrusions (PLPs) that exert a driving force toward the founder cell. However, the machinery that governs this process remains poorly understood. In this study, we demonstrate that MTM1 is the main enzyme responsible for the production of phosphatidylinositol 5-phosphate, which in turn fuels PI5P 4-kinase α to produce a minor and functional pool of phosphatidylinositol 4,5-bisphosphate that concentrates in PLPs containing the scaffolding protein Tks5, Dynamin-2, and the fusogenic protein Myomaker. Collectively, our data reveal a functional crosstalk between a PI-phosphatase and a PI-kinase in the regulation of PLP formation

Determination of dolutegravir's unbound fraction in human plasma using validated equilibrium dialysis and LC-MS/MS methods

International audienceAssessment of the unbound pharmacologically active fraction (fu; as the ratio of unbound to total concentration) of dolutegravir could improve therapeutic drug monitoring (TDM) in patients that experience virological failure or toxicity, despite receiving adequate total concentrations. This study evaluated (i) dolutegravir's fu through equilibrium dialysis (ED), (ii) the pre-analytical parameters that influence fu, and (iii) fu's inter-individual variability in HIV patients. Validation of the LC-MS/MS method followed FDA guidelines. The results, based on coefficients of variation (results from nominal concentrations <15%), allowed accurate measurement of unbound and total dolutegravir concentrations. Equilibrium during ED was obtained in 4h. Sparse non-specific binding (9%) was observed, allowing results interpretation without interference. Steps before analysis (e.g., conservation at +4°C, freeze/thaw cycles) did not influence fu, allowing easy integration of fu analysis within laboratory routines. Anticoagulants from samples (citrated versus heparinized; p<0.001) and hemolysis (p=0.007) influenced fu and could lead to misinterpretation. Developed was then performed to the HIV-patients' plasma (n=54). Results, expressed as median InterQuartileRange[25%;75%] were 0.45% IQR[0.38;0.55] for fu, 9.26μg/L IQR[4.62;15.14] for unbound, and 2035μg/L IQR[878.5;2640] for total concentration. The high inter-individual variability observed in the unbound form from HIV patients was a first step towards integrating dolutegravir TDM

Fibronectin amyloid-like aggregation alters its extracellular matrix incorporation and promotes a single and sparsed cell migration

International audienceFibronectin (Fn) is an extracellular matrix (ECM) multifunctional glycoprotein essential for regulating cells behaviors. Within ECM, Fn is found as polymerized fibrils. Apart from fibrils, Fn could also form other kind of supramolecular assemblies such as aggregates. To gain insight into the impact of Fn aggregates on cell behavior, we generated several Fn oligomeric assemblies. These assemblies displayed various amyloid-like properties but were not cytotoxic. In presence of the more amyloid-like structured assemblies of Fn, the cell-ECM networks were altered and the cell shapes shifted toward extended mesenchymal morphologies. Additionnaly, the Fn amyloid-like aggregates promoted a single-cell and sparsed migration of SKOV3 cancer cells, which was associated with a relocalization of αv integrins from plasma membrane to perinuclear vesicles. These data pointed out that the features of supramolecular Fn assemblies could represent a higher level of fine-tuning cell phenotype, and especially migration of cancer cells

Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy

International audiencePrevious studies from our group, focusing on neuro-glial remodelling in human temporal lobe epilepsy (TLE), have shown the presence of immature vascular cells in various areas of the hippocampus. Here, we investigated angiogenic processes in hippocampi surgically removed from adult patients suffering from chronic intractable TLE, with various aetiologies.We compared hippocampi fromTLE patients to hippocampi obtained after surgery or autopsy from non-epileptic patients (NE). We quantified the vascular density, checked for the expression of angiogenic factors and their receptors and looked for any blood^brain barrier (BBB) leakage.We used a relevant model of rat limbic epilepsy, induced by lithium-pilocarpine treatment, to understand the sequence of events. In humans, the vessel density was significantly higher inTLE than in NE patients.This was neither dependent on the aetiology nor on the degree of neuronal loss, but was positively correlated with seizure frequency. In the whole hippocampus, we observed many complex, tortuous microvessels. In the dentate gyrus, when the granular layer was dispersed, long microvessels appeared radially orientated.Vascular endothelial factor (VEGF) and tyrosine kinase receptors were detected in different types of cells. An impairment of the BBB was demonstrated by the loss of tight junctions and by Immunoglobulines G (IgG) leakage and accumulation in neurons. In the rat model of TLE,VEGF over-expression and BBB impairment occurred early after status epilepticus, followed by a progressive increase in vascularization. In humans and rodents, angiogenic processes and BBB disruption were still obvious in the chronic focus, probably activated by recurrent seizures.We suggest that the persistent leakage of serum IgG in the interstitial space and their uptake by neurons may participate in hypoperfusion and in neuronal dysfunction occurring inTLE