HIV-1 infection of microglial cells in a reconstituted humanized mouse model and identification of compounds that selectively reverse HIV latency.

Most studies of HIV latency focus on the peripheral population of resting memory T cells, but the brain also contains a distinct reservoir of HIV-infected cells in microglia, perivascular macrophages, and astrocytes. Studying HIV in the brain has been challenging, since live cells are difficult to recover from autopsy samples and primate models of SIV infection utilize viruses that are more myeloid-tropic than HIV due to the expression of Vpx. Development of a realistic small animal model would greatly advance studies of this important reservoir and permit definitive studies of HIV latency. When radiation or busulfan-conditioned, immune-deficient NSG mice are transplanted with human hematopoietic stem cells, human cells from the bone marrow enter the brain and differentiate to express microglia-specific markers. After infection with replication competent HIV, virus was detected in these bone marrow-derived human microglia. Studies of HIV latency in this model would be greatly enhanced by the development of compounds that can selectively reverse HIV latency in microglial cells. Our studies have identified members of the CoREST repression complex as key regulators of HIV latency in microglia in both rat and human microglial cell lines. The monoamine oxidase (MAO) and potential CoREST inhibitor, phenelzine, which is brain penetrant, was able to stimulate HIV production in human microglial cell lines and human glial cells recovered from the brains of HIV-infected humanized mice. The humanized mice we have developed therefore show great promise as a model system for the development of strategies aimed at defining and reducing the CNS reservoir

On the collapse pressure of armored bubbles and drops

International audienceDrops and bubbles wrapped in dense monolayers of hydrophobic particles are known to sustain a significant decrease of their internal pressure. Through dedicated experiments we investigate the collapse behavior of such armored water drops as a function of the particle-to-drop size ratio in the range 0.02-0.2. We show that this parameter controls the behavior of the armor during the deflation: at small size ratios the drop shrinkage proceeds through the soft crumpling of the monolayer, at intermediate ratios the drop becomes faceted, and for the largest studied ratios the armor behaves like a granular arch. The results show that each of the three morphological regimes is characterized by an increasing magnitude of the collapse pressure. This increase is qualitatively modeled thanks to a mechanism involving out-of-plane deformations and particle disentanglement in the armor

Weighted Minimum-Length Rearrangement Scenarios

We present the first known model of genome rearrangement with an arbitrary real-valued weight function on the rearrangements. It is based on the dominant model for the mathematical and algorithmic study of genome rearrangement, Double Cut and Join (DCJ). Our objective function is the sum or product of the weights of the DCJs in an evolutionary scenario, and the function can be minimized or maximized. If the likelihood of observing an independent DCJ was estimated based on biological conditions, for example, then this objective function could be the likelihood of observing the independent DCJs together in a scenario. We present an O(n^4)-time dynamic programming algorithm solving the Minimum Cost Parsimonious Scenario (MCPS) problem for co-tailed genomes with n genes (or syntenic blocks). Combining this with our previous work on MCPS yields a polynomial-time algorithm for general genomes. The key theoretical contribution is a novel link between the parsimonious DCJ (or 2-break) scenarios and quadrangulations of a regular polygon. To demonstrate that our algorithm is fast enough to treat biological data, we run it on syntenic blocks constructed for Human paired with Chimpanzee, Gibbon, Mouse, and Chicken. We argue that the Human and Gibbon pair is a particularly interesting model for the study of weighted genome rearrangements

Buckling Cascade of Thin Plates: Forms, Constraints and Similarity

We experimentally study compression of thin plates in rectangular boxes with variable height. A cascade of buckling is generated. It gives rise to a self-similar evolution of elastic reaction of plates with box height which surprisingly exhibits repetitive vanishing and negative stiffness. These features are understood from properties of Euler's equation for elastica

Macroscopic behavior of bidisperse suspensions of noncolloidal particles in yield stress fluids

We study both experimentally and theoretically the rheological behavior of isotropic bidisperse suspensions of noncolloidal particles in yield stress fluids. We focus on materials in which noncolloidal particles interact with the suspending fluid only through hydrodynamical interactions. We observe that both the elastic modulus and yield stress of bidisperse suspensions are lower than those of monodisperse suspensions of same solid volume fraction. Moreover, we show that the dimensionless yield stress of such suspensions is linked to their dimensionless elastic modulus and to their solid volume fraction through the simple equation of Chateau et al.[J. rheol. 52, 489-506 (2008)]. We also show that the effect of the particle size heterogeneity can be described by means of a packing model developed to estimate random loose packing of assemblies of dry particles. All these observations finally allow us to propose simple closed form estimates for both the elastic modulus and the yield stress of bidisperse suspensions: while the elastic modulus is a function of the reduced volume fraction $\phi/\phi_m$ only, where $\phi_m$ is the estimated random loose packing, the yield stress is a function of both the volume fraction $\phi$ and the reduced volume fraction

Multiscale approach of mechanical behaviour of SiC/SiC composites: Elastic behaviour at the scale of the tow

SiC/SiC composites are candidates for structural applications at elevated temperatures in the context of the development of the 4th generation of nuclear reactors. A multiscale approach is under development to construct a predictive modelling of their complex mechanical behaviour due to their heterogeneous microstructure. This approach is based on two scale transitions: from the fibres/matrix microstructure to the tow and from the tow to the woven composite, each scale presenting a significant residual porosity. This paper focuses on the first scale transition and on the modelling of the elastic behaviour of the tow at room temperature. A microstructural investigation of several tows in a 2D SiC/SiC specimen has been conducted using scanning electron microscopy to get statistical data on microstructural characteristics by image analysis in order to generate a virtual microstructure. The elastic problem of homogenisation is numerically solved by means of finite element techniques. The simulations performed on various volumes show noticeable fluctuations of the apparent behaviour: so separation of length scales is not satisfied in this material. Nevertheless, this problem is neglected in a first approximation and the homogeneous equivalent behaviour is evaluated by averaging the apparent behaviours of several volume elements – smaller than the Representative Volume Element (RVE) – called Statistical Volume Elements (SVEs). Finally, influence of porosity and pores’ morphology is quantified

Hamster and Murine Models of Severe Destructive Lyme Arthritis

Arthritis is a frequent complication of infection in humans with Borrelia burgdorferi. Weeks to months following the onset of Lyme borreliosis, a histopathological reaction characteristic of synovitis including bone, joint, muscle, or tendon pain may occur. A subpopulation of patients may progress to a chronic, debilitating arthritis months to years after infection which has been classified as severe destructive Lyme arthritis. This arthritis involves focal bone erosion and destruction of articular cartilage. Hamsters and mice are animal models that have been utilized to study articular manifestations of Lyme borreliosis. Infection of immunocompetent LSH hamsters or C3H mice results in a transient synovitis. However, severe destructive Lyme arthritis can be induced by infecting irradiated hamsters or mice and immunocompetent Borrelia-vaccinated hamsters, mice, and interferon-gamma- (IFN-γ-) deficient mice with viable B. burgdorferi. The hamster model of severe destructive Lyme arthritis facilitates easy assessment of Lyme borreliosis vaccine preparations for deleterious effects while murine models of severe destructive Lyme arthritis allow for investigation of mechanisms of immunopathology