Lysosomal Membrane Permeabilization Induces Cell Death in a Mitochondrion-dependent Fashion

A number of diseases are due to lysosomal destabilization, which results in damaging cell loss. To investigate the mechanisms of lysosomal cell death, we characterized the cytotoxic action of two widely used quinolone antibiotics: ciprofloxacin (CPX) or norfloxacin (NFX). CPX or NFX plus UV light (NFX*) induce lysosomal membrane permeabilization (LMP), as detected by the release of cathepsins from lysosomes. Inhibition of the lysosomal accumulation of CPX or NFX suppresses their capacity to induce LMP and to kill cells. CPX- or NFX-triggered LMP results in caspase-independent cell death, with hallmarks of apoptosis such as chromatin condensation and phosphatidylserine exposure on the plasma membrane. LMP triggers mitochondrial membrane permeabilization (MMP), as detected by the release of cytochrome c. Both CPX and NFX* cause Bax and Bak to adopt their apoptotic conformation and to insert into mitochondrial membranes. Bax−/− Bak−/− double knockout cells fail to undergo MMP and cell death in response to CPX- or NFX-induced LMP. The single knockout of Bax or Bak (but not Bid) or the transfection-enforced expression of mitochondrion-targeted (but not endoplasmic reticulum–targeted) Bcl-2 conferred protection against CPX (but not NFX*)-induced MMP and death. Altogether, our data indicate that mitochondria are indispensable for cell death initiated by lysosomal destabilization

Anelastic Limits for Euler Type Systems

In this paper, we present rigorous derivations of anelastic limits for compressible Euler type systems when the Mach (or Froude) number tends to zero. The first and main part is to prove local existence and uniqueness of strong solution together with uniform estimates on a time interval independent of the small parameter. The key new remark is that the systems under consideration can be written in a form where ideas from \cite{MS} can be adapted. The second part of the analysis is to pass to the limit as the parameter tends to zero. In this context, the main problem is to study the averaged effect of fast acoustic waves on the slow incompressible motion. In some cases, the averaged system is completely decoupled from acoustic waves. The first example studied in this paper enters this category: it is a shallow-water type system with topography and the limiting system is the inviscid lake equation (rigid lid approximation). This is similar to the low Mach limit analysis for prepared data, following the usual terminology, where the acoustic wave disappears in a pure pressure term for the limit equation. The decoupling also occurs in infinite domains where the fast acoustic waves are rapidly dispersed at infinity and therefore have no time to interact with the slow motion (see \cite{Sc,MS, Al}). In other cases, and this should be expected in general for bounded domains or periodic solutions, this phenomenon does not occur and the acoustic waves leave a nontrivial averaged term in the limit fluid equation, which cannot be incorporated in the pressure term. In this case, the limit system involves a fluid equation, coupled to a nontrivial infinite dimensional system of differential equations which models the energy exchange between the fluid and some remanent acoustic energy. This was suspected for the periodic low Mach limit problem for nonisentropic Euler equations in \cite{MeSc} and proved for finite dimensional models. The second example treated in this paper, namely Euler type system with heterogeneous barotropic pressure law, is an example where this scenario is rigorously carried out. To the authors' knowledge, this is the first example in the literature where such a coupling is mathematically justified

Recent mathematical results and open problems about shallow water equations. Analysis and simulation of fluid dynamic

International audienceThe purpose of this work is to present recent mathematical results about the shallow water model. We will also mention related open problems of high mathematical interest

Mesures couplées de vitesse et de température par IRM pour l'étude de la convection de Rayleigh Benard

International audienceL'étude des transferts thermiques par conduction et convection représente un vaste champ d'applications industrielles et environnementales. L'apparition et l'évolution des instabilités thermo-convectives ainsi que leur dynamique représentent un intérêt majeur car les transferts thermiques sont améliorés lors du passage du régime conductif au régime convectif. Dans cette étude, la configuration étudiée est celle de Rayleigh-Bénard, pour laquelle l'origine de l'instabilité convective est due à un gradient vertical de température entre deux plaques horizontales. Lorsque la différence de température est faible et le fluide visqueux, le régime est purement conductif et il n'y a pas d'écoulement du fluide. Passé une certaine différence de température, des structures convectives se forment et l'écoulement démarre. Du fait de la possibilité de cartographier avec la même technique différentes grandeurs physiques, l'IRM s'avère un outil intéressant pour étudier ce phénomène. Cependant, si la mesure de vitesse d'écoulement par IRM est une technique fréquemment utilisée en mécanique des fluides et donne de bons résultats dans nos systèmes, la mesure de température est plus délicate. Nous avons comparé les principales techniques de thermométrie IRM : cartographie de la phase du signal, du coefficient de diffusion ou des temps de relaxation. Cette dernière technique semble être la plus adaptée dans le cas du glycérol et la carte obtenue est parfaitement en accord avec les mesures de vitesse. La méthode a aussi été utilisée sur un fluide rhéofluidifiant, le xanthane. Si la mesure de vitesse reste satisfaisante, des difficultés apparaissent lorsque l'écart de température devient trop élevé. Cela semble lié aux valeurs des temps de relaxation beaucoup plus long dans le cas du xanthane que du glycérol. La méthode a aussi été utilisée sur un fluide rhéofluidifiant, le xanthane. Si la mesure de vitesse reste satisfaisante, des difficultés apparaissent lorsque l’écart de température devient trop élevé. Cela semble lié aux valeurs des temps de relaxation beaucoup plus long dans le cas du xanthane que du glycérol

Magnetic Resonance Imaging of Convection in Phase Changing Materials

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Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion

A number of diseases are due to lysosomal destabilization, which results in damaging cell loss. To investigate the mechanisms of lysosomal cell death, we characterized the cytotoxic action of two widely used quinolone antibiotics: ciprofloxacin (CPX) or norfloxacin (NFX). CPX or NFX plus UV light (NFX*) induce lysosomal membrane permeabilization (LMP), as detected by the release of cathepsins from lysosomes. Inhibition of the lysosomal accumulation of CPX or NFX suppresses their capacity to induce LMP and to kill cells. CPX- or NFX-triggered LMP results in caspase-independent cell death, with hallmarks of apoptosis such as chromatin condensation and phosphatidylserine exposure on the plasma membrane. LMP triggers mitochondrial membrane permeabilization (MMP), as detected by the release of cytochrome c. Both CPX and NFX* cause Bax and Bak to adopt their apoptotic conformation and to insert into mitochondrial membranes. Bax−/− Bak−/− double knockout cells fail to undergo MMP and cell death in response to CPX- or NFX-induced LMP. The single knockout of Bax or Bak (but not Bid) or the transfection-enforced expression of mitochondrion-targeted (but not endoplasmic reticulum–targeted) Bcl-2 conferred protection against CPX (but not NFX*)-induced MMP and death. Altogether, our data indicate that mitochondria are indispensable for cell death initiated by lysosomal destabilization

Immunosurveillance against tetraploidization-induced colon tumorigenesis

<p>Circumstantial evidence suggests that colon carcinogenesis can ensue the transient tetraploidization of (pre-)malignant cells. In line with this notion, the tumor suppressors APC and TP53, both of which are frequently inactivated in colon cancer, inhibit tetraploidization in vitro and in vivo. Here, we show that-contrarily to their wild-type counterparts-Tp53(-/-) colonocytes are susceptible to drug-induced or spontaneous tetraploidization in vitro. Colon organoids generated from tetraploid Tp53(-/-) cells exhibit a close-to-normal morphology as compared to their diploid Tp53(-/-) counterparts, yet the colonocytes constituting these organoids are characterized by an increased cell size and an elevated expression of the immunostimulatory protein calreticulin on the cell surface. The subcutaneous injection of tetraploid Tp53(-/-) colon organoids led to the generation of proliferating tumors in immunodeficient, but not immunocompetent, mice. Thus, tetraploid Tp53(-/-) colonocytes fail to survive in immunocompetent mice and develop neoplastic lesions in immunocompromised settings only. These results suggest that tetraploidy is particularly oncogenic in the context of deficient immunosurveillance.</p>

Sofosbuvir-Daclatasvir Is Suboptimal in Patients with Genotype 2 Chronic Hepatitis C Infection: Real-life Experience from the HEPATHER ANRS CO22 Cohort

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