PDE4 as a target in preterm labour

Cyclic nucleotide phosphodiesterases (PDE) are the enzymes catalyzing the hydrolysis and inactivation of the second messengers, cAMP and cGMP. Eleven PDE families are described to date, and selective inhibitors of some PDEs families are currently used in clinic for treating cardiovascular disorders, erectile dysfunction, and pulmonary hypertension. Isoforms of the PDE4 family are involved in smooth muscle contraction and inflammation. PDE4 selective inhibitors are currently in clinical trials for the treatment of diseases related to inflammatory disorders. Because of their myorelaxant properties, we first examined their expression in human myometrium and uncover an increased expression of one specific isoform, PDE4B2, in the near-term myometrium as compared to myometrium in the nonpregnant state. Using human myometrial cells in culture, we demonstrated that PDE4B2 can be induced by its own substrate, under the control of one of the major utero-contractile agonists, PGE2, itself upregulated by the proinflammatory cytokine IL-1β. Functionally, augmentation of global PDE4 activity decreases the ability of β-adrenergic agonists (the most commonly used tocolytic drugs) to inhibit myometrial contraction at the end of pregnancy and during pathophysiological situations, such as persistent intrauterine inflammation which is a major cause of very preterm delivery. Currently exploring the anti-inflammatory properties of PDE4 inhibitors in gestational tissues, we recently demonstrated the ability of these drugs to block a persistent inflammatory response of the foetal membranes in Humans and to prevent inflammation-driven preterm delivery and foetal demise in mice. These data open up a new therapeutical strategy to prevent inflammation-induced preterm delivery and its sequelae in very preterm infants

Velocity Correlations in Driven Two-Dimensional Granular Media

Simulations of volumetrically forced granular media in two dimensions produce s tates with nearly homogeneous density. In these states, long-range velocity correlations with a characteristic vortex structure develop; given sufficient time, the correlations fill the entire simulated area. These velocity correlations reduce the rate and violence of collisions, so that pressure is smaller for driven inelastic particles than for undriven elastic particles in the same thermodynamic state. As the simulation box size increases, the effects of veloc ity correlations on the pressure are enhanced rather than reduced.Comment: 12 pages, 6 figures, 21 reference

MPGDs in Compton imaging with liquid-xenon

The interaction of radiation with liquid xenon, inducing both scintillation and ionization signals, is of particular interest for Compton-sequences reconstruction. We report on the development and recent results of a liquid-xenon time-projection chamber, dedicated to a novel nuclear imaging technique named "3 gamma imaging". In a first prototype, the scintillation is detected by a vacuum photomultiplier tube and the charges are collected with a MICROMEGAS structure; both are fully immersed in liquid xenon. In view of the final large-area detector, and with the aim of minimizing dead-zones, we are investigating a gaseous photomultiplier for recording the UV scintillation photons. The prototype concept is presented as well as preliminary results in liquid xenon. We also present soft x-rays test results of a gaseous photomultiplier prototype made of a double Thick Gaseous Electron Multiplier (THGEM) at normal temperature and pressure conditions.Comment: presented at MPGD09, CRETE, June 2009; to be published in JINST Proceedings, PDF, 10 pages, 11 figure

Shocks in supersonic sand

We measure time-averaged velocity, density, and temperature fields for steady granular flow past a wedge and calculate a speed of granular pressure disturbances (sound speed) equal to 10% of the flow speed. The flow is supersonic, forming shocks nearly identical to those in a supersonic gas. Molecular dynamics simulations of Newton's laws and Monte Carlo simulations of the Boltzmann equation yield fields in quantitative agreement with experiment. A numerical solution of Navier-Stokes-like equations agrees with a molecular dynamics simulation for experimental conditions excluding wall friction.Comment: 4 pages, 5 figure

Geometric origin of mechanical properties of granular materials

Some remarkable generic properties, related to isostaticity and potential energy minimization, of equilibrium configurations of assemblies of rigid, frictionless grains are studied. Isostaticity -the uniqueness of the forces, once the list of contacts is known- is established in a quite general context, and the important distinction between isostatic problems under given external loads and isostatic (rigid) structures is presented. Complete rigidity is only guaranteed, on stability grounds, in the case of spherical cohesionless grains. Otherwise, the network of contacts might deform elastically in response to load increments, even though grains are rigid. This sets an uuper bound on the contact coordination number. The approximation of small displacements (ASD) allows to draw analogies with other model systems studied in statistical mechanics, such as minimum paths on a lattice. It also entails the uniqueness of the equilibrium state (the list of contacts itself is geometrically determined) for cohesionless grains, and thus the absence of plastic dissipation. Plasticity and hysteresis are due to the lack of such uniqueness and may stem, apart from intergranular friction, from small, but finite, rearrangements, in which the system jumps between two distinct potential energy minima, or from bounded tensile contact forces. The response to load increments is discussed. On the basis of past numerical studies, we argue that, if the ASD is valid, the macroscopic displacement field is the solution to an elliptic boundary value problem (akin to the Stokes problem).Comment: RevTex, 40 pages, 26 figures. Close to published paper. Misprints and minor errors correcte

Numerical model for granular compaction under vertical tapping

A simple numerical model is used to simulate the effect of vertical taps on a packing of monodisperse hard spheres. Our results are in agreement with an experimantal work done in Chicago and with other previous models, especially concerning the dynamics of the compaction, the influence of the excitation strength on the compaction efficiency, and some ageing effects. The principal asset of the model is that it allows a local analysis of the packings. Vertical and transverse density profiles are used as well as size and volume distributions of the pores. An interesting result concerns the appearance of a vertical gradient in the density profiles during compaction. Furthermore, the volume distribution of the pores suggests that the smallest pores, ranging in size between a tetrahedral and an octahedral site, are not strongly affected by the tapping process, in contrast to the largest pores which are more sensitive to the compaction of the packing.Comment: 8 pages, 15 figures (eps), to be published in Phys. Rev. E. Some corrections have been made, especially in paragraph IV

Theory of Stellar Population Synthesis with an application to N-Body simulations

Aims. We present here a new theoretical approach to population synthesis. The aim is to predict colour magnitude diagrams (CMDs) for huge numbers of stars. With this method we generate synthetic CMDs for N-body simulations of galaxies. Sophisticated hydrodynamic N-body models of galaxies require equal quality simulations of the photometric properties of their stellar content. The only prerequisite for the method to work is very little information on the star formation and chemical enrichment histories, i.e. the age and metallicity of all star-particles as a function of time. The method takes into account the gap between the mass of real stars and that of the star-particles in N-body simulations, which best correspond to the mass of star clusters with different age and metallicity, i.e. a manifold of single stellar sopulations (SSP). Methods. The theory extends the concept of SSP to include the phase-space (position and velocity) of each star. Furthermore, it accelerates the building up of simulated CMD by using a database of theoretical SSPs that extends to all ages and metallicities of interest. Finally, it uses the concept of distribution functions to build up the CMD. The technique is independent of the mass resolution and the way the N-body simulation has been calculated. This allows us to generate CMDs for simulated stellar systems of any kind: from open clusters to globular clusters, dwarf galaxies, or spiral and elliptical galaxies. Results. The new theory is applied to an N-body simulation of a disc galaxy to test its performance and highlight its flexibility.Comment: accepted for publication in A&