Identification du rôle de la mélanotransferrine dans l'activation du plasminogène : implication dans la dégradation de la matrice extracellulaire et l'invasion tumorale

L'activation du plasminogène est importante dans les phénomènes liés au cancer. Ma thèse démontre que la mélanotransferrine agit comme accélérateur dans l'activation du plasminogène avec ses deux activateurs : l'uPA, lié au cancer et le tPA, lié à la fibrinolyse. Son action ambivalente, à la fois protumorale et antitumorale, est caractérisée par son site d'action au niveau cellulaire. La mélanotransferrine membranaire agit comme un catalyseur pour amplifier l'activation du plasminogène à la membrane, tandis que la forme soluble de la mélanotransferrine entre en compétition avec la mélanotransferrine membranaire\ud pour inhiber son effet. Dans la présente étude, nous avons découvert que deux composantes du\ud système plasminolytique : le pro-uPA, précurseur de l'uPA et le plasminogène interagissent avec la mélanotransferrine. L'interaction de la mélanotransferrine avec le système plasminolytique stimule l'activation du plasminogène par ses\ud deux activateurs. Nous démontrons également avec un anticorps dirigé contre la mélanotransferrine ou par l'inhibition de son expression par un siRNA que la mélanotransferrine intervient dans le processus menant aux métastases par l'inhibition de la migration cellulaire. De plus, nous démontrons que la\ud mélanotransferrine module la dissolution de caillots de fibrine dépendante du tPA ou de l'uPA, une composante importante de la matrice provisoire extracellulaire impliquée dans la dispersion des métastases. Dans un modèle où le dépôt de\ud fibrine provoqué par le facteur tissulaire (TF) stimule l'invasion des cellules de mélanome (SK-Mel-28), nous démontrons une inhibition de l'invasion induite par le TF dans le poumon lorsque l'expression de la mélanotransferrine est inhibée\ud par un siRNA. Ces résultats suggèrent que la mélanotransferrine est directement impliquée dans la propagation des métastases des mélanomes qui l'expriment fortement. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Activation du plasminogène, Invasion tumorale, Migration, Fibrinolyse, uPA, tPA

Real-time pollen monitoring using digital holography

We present the first validation of the SwisensPoleno, currently the only operational automatic pollen mon-itoring system based on digital holography. The device pro-vides in-flight images of all coarse aerosols, and here wedevelop a two-step classification algorithm that uses theseimages to identify a range of pollen taxa. Deterministiccriteria based on the shape of the particle are applied toinitially distinguish between intact pollen grains and othercoarse particulate matter. This first level of discriminationidentifies pollen with an accuracy of 96 %. Thereafter, in-dividual pollen taxa are recognized using supervised learn-ing techniques. The algorithm is trained using data obtainedby inserting known pollen types into the device, and out ofeight pollen taxa six can be identified with an accuracy ofabove 90 %. In addition to the ability to correctly identifyaerosols, an automatic pollen monitoring system needs to beable to correctly determine particle concentrations. To fur-ther verify the device, controlled chamber experiments us-ing polystyrene latex beads were performed. This providedreference aerosols with traceable particle size and numberconcentrations in order to ensure particle size and samplingvolume were correctly characterized

Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency

Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient's cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient's cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Global warming of the mantle at the origin of flood basalts over supercontinents.

International audienc

A gyro-kinetic model for trapped electron and ion modes

Équipe 107 : Physique des plasmas chaudsInternational audienceIn tokamak plasmas, it is recognized that ITG (ion temperature gradient instability) and trapped electron modes (TEM) are held responsible for turbulence giving rise to anomalous transport. The present work focuses on the building of a model including trapped kinetic ions and trapped kinetic electrons. For this purpose, the dimensionality is reduced by averaging the motion over the cyclotron motion and the ``banana'' orbits, according to the fact that the instabilities are characterized by frequencies of the order of the low trapped particle precession frequency. Moreover, a set of action-angle variables is used. The final model is 4D (two-dimensional phase space parametrized by the two first adiabatic invariants namely the particle energy and the trapping parameter). In this paper, the trapped ion and electron modes (TIM and TEM) are studied by using a linear analysis of the model. This work is currently performed in order to include trapped electrons in an existing semi lagrangian code for which TIM modes are already taken into account. This study can be considered as a first step in order to include kinetic trapped electrons in the 5D gyrokinetic code GYSELA

Modelling plant diseases impact with the Belgium Crop Growth Monitoring System.

peer reviewe

Expression of melanotransferrin isoforms in human serum: relevance to Alzheimer's disease.

Levels of soluble melanotransferrin in serum have been reported to be higher in patients with Alzheimer's disease than in control subjects. The present study investigated melanotransferrin in human body fluids in the light of these findings. To clarify the correlation between melanotransferrin and Alzheimer's disease, the melanotransferrin content was determined by non-reducing, denaturing SDS/PAGE and Western blotting. Under these conditions, serum melanotransferrin migrated at 79 and 82 kDa. Melanotransferrin antigenicity and the relative proportions of the two forms were very sensitive to factors that altered its conformation, including disulphide bridges, pH and bivalent cations. Serum melanotransferrin levels were not significantly different between control subjects and patients with Alzheimer's disease using whole serum, EDTA-supplemented serum or serum immunoglobulin-depleted by Protein G-Sepharose and enriched by affinity precipitation with the lectin from Asparagus pea. Glycosylated forms of serum melanotransferrin bound to Asparagus lectin manifested similar patterns on two-dimensional gel electrophoresis in samples from controls and Alzheimer's disease subjects. Melanotransferrin was also present in saliva and at a high level in urine, but contents were similar in controls and patients with Alzheimer's disease. Together, these results demonstrate that serum melanotransferrin exists in various conformations depending on the binding of bivalent cations or following post-translational modification. These data also indicate that human serum melanotransferrin levels are unchanged in subjects with Alzheimer's disease

Gyrokinetic modelling: a multi water bag approach

International audiencePredicting turbulent transport in nearly collisionless fusion plasmas requires one to solve kinetic (or, more precisely, gyrokinetic) equations. In spite of considerable progress, several pending issues remain; although more accurate, the kinetic calculation of turbulent transport is much more demanding in computer resources than fluid simulations. An alternative approach is based on a water-bag representation of the distribution function that is not an approximation but rather a special class of initial conditions, allowing one to reduce the full kinetic Vlasov equation into a set of hydrodynamic equations while keeping its kinetic character. The main result for the water-bag model is a lower cost in the parallel velocity direction since no differential operator associated with some approximate numerical scheme has to be carried out on this variable v∥. Indeed, a small bag number is sufficient to correctly describe the ion temperature gradient instability