Communication Complexity and Intrinsic Universality in Cellular Automata

The notions of universality and completeness are central in the theories of computation and computational complexity. However, proving lower bounds and necessary conditions remains hard in most of the cases. In this article, we introduce necessary conditions for a cellular automaton to be "universal", according to a precise notion of simulation, related both to the dynamics of cellular automata and to their computational power. This notion of simulation relies on simple operations of space-time rescaling and it is intrinsic to the model of cellular automata. Intrinsinc universality, the derived notion, is stronger than Turing universality, but more uniform, and easier to define and study. Our approach builds upon the notion of communication complexity, which was primarily designed to study parallel programs, and thus is, as we show in this article, particulary well suited to the study of cellular automata: it allowed to show, by studying natural problems on the dynamics of cellular automata, that several classes of cellular automata, as well as many natural (elementary) examples, could not be intrinsically universal

Etude des différents signaux d'activation de l'inflammasome dans les monocytes/macrophages : implication dans la réponse inflammatoire vis-à-vis des nanotubes de carbone et de Leishmania infantum

La vision de l'immunité en tant qu'entité discriminant les éléments du soi à protéger et du non soi à combattre a évolué ces dernières années avec la découverte des signaux de dangers endogènes et certains de leurs récepteurs associés. Ainsi, toute condition pouvant être délétère pour l'hôte, associée à une émission de signaux de dangers endogènes, est susceptible de produire une réaction immunitaire mobilisant les acteurs capable de promouvoir un retour à l'homéostasie. La réponse inflammatoire est initiée par le système immunitaire inné suite à la reconnaissance de signaux de danger d'origines exogènes et endogènes. Les macrophages, de part l'expression d'un large spectre de récepteurs et leur position stratégique dans les tissus jouent un rôle prépondérant dans la mise en place de cette réponse. L'exposition répétée à des particules environnementales comme l'amiante se traduit par la mise en place d'une réaction inflammatoire stérile et chronique qui s'avère être extrêmement délétère pour l'organisme et dans laquelle les macrophages jouent un rôle à la fois d'initiation et d'entretiens. L'étude de l'impact de nanoparticules manufacturées, les DWCNTs, sur la réponse inflammatoire des macrophages nous a conduits à isoler un complexe cytoplasmique, l'inflammasome Nlrp3. L'activation de l'inflammasome Nlrp3 se traduit par l'activation de la protéase caspase-1 et conduit à la libération spécifique d'IL-1ß et d'IL-18, cytokines hautement inflammatoires. Nous avons ainsi isolé l'efflux de potassium, le processus de phagocytose, la maturation de phagosome et la cathepsine-B comme des signaux de dangers cellulaires responsables de l'activation de l'inflammasome Nlrp3 en réponse à ces nanoparticules. Ce travail est publié dans le journal Nanomedicine. Dans la seconde partie de ce travail, nous nous sommes intéressés aux mécanismes moléculaires d'activation de l'inflammasome par un agent pathogénique, le parasite Leishmania infantum(L.i) responsable de la Leishmaniose viscérale. Nos résultats démontrent que L.i est capable d'induire la sécrétion d'IL-ß selon un processus nécessitant la protéase caspase-1 via l'engagement du récepteur membranaire Lectine de type C, Dectine-1. Nous isolons ainsi la tyrosine kinase Syk, le processus de phagocytose et les ROS comme signaux de dangers capables d'induire l'activation de la caspase-1 et la sécrétion d'IL-1 beta. Ce travail est actuellement soumis pour publication. Au final, l'ensemble des données de ce manuscrit témoignent de la capacité originale de l'inflammasome à reconnaître des signaux de stress cellulaire induits par des éléments d'origine et de propriétés différentes. Cela se traduit par la libération d'IL-1 beta dans les macrophages et le développement d'une réponse inflammatoire.The vision of the immunity as whole discriminating elements of the self to protect and non-self to fight has evolved the last years with the discovery of endogenous danger signals. Thus, any condition that may be deleterious to the host, associated with an endogenous danger signal emission, is likely to produce an immune response able to mobilizing actors to promote homeostasis. The inflammatory response is initiated by the innate immune system following the recognition of exogenous and endogenous danger signals. Macrophages, due to the expression of a broad spectrum of receptors and their strategic position in the tissues play a key role in the development of this response. Repeated exposure to environmental particles such as asbestos results in the establishment of a sterile and chronic inflammatory response known to be extremely harmful to the body. The study of the impact of nanoparticles, the DWCNTs, on the inflammatory response of macrophages led us to isolate a cytoplasmic complex, Nlrp3 inflammasome. Formation of Nlrp3 inflammasome results in the activation of the protease caspase-1 and leads to the specific release of IL-1ß and IL-18, both highly inflammatory cytokines. We have isolated the efflux of potassium, the process of phagocytosis, phagosome maturation and cathepsin B as endogenous dangers signals responsible for the activation of Nlrp3 inflammasome. In the second part of this work, we investigated the molecular mechanisms of activation of the inflammasome by a pathogenic agent, the parasite Leishmania infantum (L.i) responsible of visceral leishmaniasis. Our results showed that L.i is able to promote the secretion of IL-ß in a process requiring C-type lectin receptor Dectine-1 engagement and protease caspase-1 activation. Thus, we isolated the tyrosine kinase Syk, phagocytosis process and ROS as cellular dangers signals involved in the caspase-1 activation and IL-1 beta release. To conclude, all these data show the original and unique capacity of the inflammasome to recognize cellular stress signals induced by features different by their chemical and structural structures. This results in the release of IL-1 beta by monocytes/macrophages and the development of an inflammatory response

Double-walled carbon nanotubes trigger IL-1β release in human monocytes through Nlrp3 inflammasome activation

Because of their outstanding physical properties, carbon nanotubes (CNTs) are promising new materials in the field of nanotechnology. It is therefore imperative to assess their adverse effects on human health. Monocytes/macrophages that recognize and eliminate the inert particles constitute the main target of CNTs. In this article, we report our finding that double-walled CNTs (DWCNTs) synergize with Tolllike receptor agonists to enhance IL-1β release in human monocytes. We show that DWCNTs–induced IL-1β secretion is exclusively linked to caspase-1 and to Nlrp3 inflammasome activation in human monocytes. We also establish that this activation requires DWCNTs phagocytosis and potassium efflux, but not reactive oxygen specied (ROS) generation. Moreover, inhibition of lysosomal acidification or cathepsin-B activation reduces DWCNT-induced IL-1β secretion, suggesting that Nlrp3 inflammasome activation occurs via lysosomal destabilization. Thus, DWCNTs present a health hazard due to their capacity to activate Nlrp3 inflammasome, recalling the inflammation caused by asbestos and hence demonstrating that they should be used with caution. From the Clinical Editor: This is a very important biosafety/toxicity study regarding double walled carbon nanotubes. The investigators demonstrate that such nanotubes do represent a health hazard due to their capacity to activate Nlrp3 inflammasome, resembling the inflammation caused by asbestos. While further study of this phenomenon is definitely needed, the above findings clearly suggest that special precautions need to be taken when applying these nanoparticles in human disease research

Apprentissage profond non supervisé fondé sur l'algorithme EM pour la segmentation du mouvement

International audienceThis paper presents a CNN-based fully unsupervised method for motion segmentation from optical flow. We assume that the input optical flow can be represented as a piecewise set of parametric motion models, typically, affine or quadratic motion models. The core idea of this work is to leverage the Expectation-Maximization (EM) framework. It enables us to design in a well-founded manner the loss function and the training procedure of our motion segmentation neural network. However, in contrast to the classical iterative EM, once the network is trained, we can provide a segmentation for any unseen optical flow field in a single inference step, with no dependence on the initialization of the motion model parameters since they are not estimated in the inference stage. Our method outperforms comparable unsupervised methods and is very efficient.Cet article présente une méthode entièrement non supervisée basée sur un réseau neuronal convolutionnel pour la segmentation du mouvement à partir du flot optique. Nous supposons que le flot optique d'entrée peut être représenté par un ensemble de modèles de mouvement paramétriques, typiquement des modèles de mouvement affines ou quadratiques. L'idée centrale de ce travail est d'exploiter le cadre de l'Espérance-Maximisation (EM). Il nous permet de concevoir d'une manière bien fondée la fonction de perte et la procédure d'apprentissage de notre réseau de neurones de segmentation du mouvement. Contrairement à la méthode EM itérative classique, une fois le réseau entraîné, nous pouvons fournir une segmentation pour tout nouveau champ de flot optique en une seule étape d'inférence et sans avoir avoir à estimer de modèles de mouvement. Notre méthode surpasse les méthodes non supervisées comparables et est très efficace en temps de calcul. Mots Clés Segmentation du mouvement, flot optique, réseau de neurones, algorithme EM

Transfer of Communication Skills to the Workplace during Clinical Rounds : Impact of a Program for Residents

peer reviewe

Toxicité des nanotubes de carbone envers l'homme et l'environnement

Du fait d'un nombre grandissant d'applications commerciales des nanotubes de carbone, les questions relatives à leur impact potentiel sur la santé humaine et sur l'environnement sont toujours d'actualité et font encore l'objet de recherches très actives. Cet article fait le point sur les connaissances actuelles en prenant en compte la diversité des nanoparticules qui se cachent sous la dénomination générale de "nanotubes de carbone". Il ambitionne de traiter la question de manière générale, de l’échelle cellulaire, sur cultures in vitro, à l’échelle complexe de l’écosystème par des approches simplifiées en micro et mésocosmes, notamment

Clostridium perfringens Epsilon Toxin Targets Granule Cells in the Mouse Cerebellum and Stimulates Glutamate Release

Epsilon toxin (ET) produced by C. perfringens types B and D is a highly potent pore-forming toxin. ET-intoxicated animals express severe neurological disorders that are thought to result from the formation of vasogenic brain edemas and indirect neuronal excitotoxicity. The cerebellum is a predilection site for ET damage. ET has been proposed to bind to glial cells such as astrocytes and oligodendrocytes. However, the possibility that ET binds and attacks the neurons remains an open question. Using specific anti-ET mouse polyclonal antibodies and mouse brain slices preincubated with ET, we found that several brain structures were labeled, the cerebellum being a prominent one. In cerebellar slices, we analyzed the co-staining of ET with specific cell markers, and found that ET binds to the cell body of granule cells, oligodendrocytes, but not astrocytes or nerve endings. Identification of granule cells as neuronal ET targets was confirmed by the observation that ET induced intracellular Ca2+ rises and glutamate release in primary cultures of granule cells. In cultured cerebellar slices, whole cell patch-clamp recordings of synaptic currents in Purkinje cells revealed that ET greatly stimulates both spontaneous excitatory and inhibitory activities. However, pharmacological dissection of these effects indicated that they were only a result of an increased granule cell firing activity and did not involve a direct action of the toxin on glutamatergic nerve terminals or inhibitory interneurons. Patch-clamp recordings of granule cell somata showed that ET causes a decrease in neuronal membrane resistance associated with pore-opening and depolarization of the neuronal membrane, which subsequently lead to the firing of the neuronal network and stimulation of glutamate release. This work demonstrates that a subset of neurons can be directly targeted by ET, suggesting that part of ET-induced neuronal damage observed in neuronal tissue is due to a direct effect of ET on neurons

Type-3 Secretion System-induced pyroptosis protects Pseudomonas against cell-autonomous immunity

Inflammasome-induced pyroptosis comprises a key cell-autonomous immune process against intracellular bacteria, namely the generation of dying cell structures. These so-called pore-induced intracellular traps (PITs) entrap and weaken intracellular microbes. However, the immune importance of pyroptosis against extracellular pathogens remains unclear. Here, we report that Type-3 secretion system (T3SS)-expressing Pseudomonas aeruginosa ( P. aeruginosa ) escaped PIT immunity by inducing a NLRC4 inflammasome-dependent macrophage pyroptosis response in the extracellular environment. To the contrary, phagocytosis of Salmonella Typhimurium promoted NLRC4-dependent PIT formation and the subsequent bacterial caging. Remarkably, T3SS-deficient Pseudomonas were efficiently sequestered within PIT-dependent caging, which favored exposure to neutrophils. Conversely, both NLRC4 and caspase-11 deficient mice presented increased susceptibility to T3SS-deficient P. aeruginosa challenge, but not to T3SS-expressing P. aeruginosa. Overall, our results uncovered that P. aeruginosa uses its T3SS to overcome inflammasome-triggered pyroptosis, which is primarily effective against intracellular invaders. Importance Although innate immune components confer host protection against infections, the opportunistic bacterial pathogen Pseudomonas aeruginosa ( P. aeruginosa ) exploits the inflammatory reaction to thrive. Specifically the NLRC4 inflammasome, a crucial immune complex, triggers an Interleukin (IL)-1β and -18 deleterious host response to P. aeruginosa . Here, we provide evidence that, in addition to IL-1 cytokines, P. aeruginosa also exploits the NLRC4 inflammasome-induced pro-inflammatory cell death, namely pyroptosis, to avoid efficient uptake and killing by macrophages. Therefore, our study reveals that pyroptosis-driven immune effectiveness mainly depends on P. aeruginosa localization. This paves the way toward our comprehension of the mechanistic requirements for pyroptosis effectiveness upon microbial infections and may initiate targeted approaches in order to ameliorate the innate immune functions to infections. Graphical abstract Macrophages infected with T3SS-expressing P. aeruginosa die in a NLRC4-dependent manner, which allows bacterial escape from PIT-mediated cell-autonomous immunity and neutrophil efferocytosis. However, T3SS-deficient P. aeruginosa is detected by both NLRC4 and caspase-11 inflammasomes, which promotes bacterial trapping and subsequent efferocytosis of P. aeruginosa -containing-PITs by neutrophils

Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model

The coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world’s population is currently unvaccinated or incompletely vaccinated and has limited access to approved treatments against COVID-19, there is an urgent need to continue research on treatment options, especially those at low cost and which are immediately available to patients, particularly in low- and middle-income countries. Prior in vitro and observational studies have shown that fluoxetine, possibly through its inhibitory effect on the acid sphingomyelinase/ceramide system, could be a promising antiviral and anti-inflammatory treatment against COVID-19. In this report, we evaluated the potential antiviral and anti-inflammatory activities of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and against variants of concern in vitro, i.e., SARS-CoV-2 ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 and Omicron BA.5. Fluoxetine, administrated after SARS-CoV-2 infection, significantly reduced lung tissue viral titres and expression of several inflammatory markers (i.e., IL-6, TNFα, CCL2 and CXCL10). It also inhibited the replication of all variants of concern in vitro. A modulation of the ceramide system in the lung tissues, as reflected by the increase in the ratio HexCer 16:0/Cer 16:0 in fluoxetine-treated mice, may contribute to explain these effects. Our findings demonstrate the antiviral and anti-inflammatory properties of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and its in vitro antiviral activity against variants of concern, establishing fluoxetine as a very promising candidate for the prevention and treatment of SARS-CoV-2 infection and disease pathogenesis