In Love with a Corporation without Knowing It: An Asymetrical Relationship

International audienceMost areas of the law rely on the assumption on free will, which manifests in the expression of consent. We examine the nature of human emotions toward fictional characters and social robots, and question the concept of consent in the context of these unreciprocated fictional relationships. We conclude that policies need to regulate the use of social robots in order to protect consumers, and especially vulnerable ones, from an asymmetry of power between them and robotic companies. We propose different statutory and design-based solutions depending on the purpose of the robots and the type of users

Données nouvelles sur l’habitat du Néolithique final en marge du Grand-Pressigny : les apports du site du Fond d’Arrêt et de la Pierre Levée (Pussigny, Indre-et-Loire)

International audienceLe site du « Fond d’Arrêt et de la Pierre Levée » est localisé au sud-ouest de la commune de Pussigny (Indre-et- Loire) en périphérie de la région du Grand-Pressigny. L’occupation du Néolithique final est marquée par de nombreux trous de poteaux conservés principalement dans deux micro-vallons qui traversent l’emprise de fouille. Ils sont accompagnés par un riche mobilier composé essentiellement de céramique et de lithique. L’organisation spatiale des trous de poteaux a permis d’envisager un minimum de neuf bâtiments. Ce sont des architectures en abside à deux nefs marquées par une ligne de poteaux centrale. Si le contexte chronoculturel du site reste difficile à définir, les différentes études de mobilier démontrent un contact entre le site et les ateliers de taille pressigniens. Ainsi, le site conserve des vestiges rares sur les habitats de la fin du Néolithique dans le sud de la Touraine et apporte des éléments de réflexions sur la caractérisation des occupations domestiques autour de la région du Grand-Pressigny

A novel inhibitor of the mitochondrial respiratory complex I with uncoupling properties exerts potent antitumor activity

International audienceCancer cells are highly dependent on bioenergetic processes to support their growth and survival. Disruption of metabolic pathways, particularly by targeting the mitochondrial electron transport chain complexes (ETC-I to V) has become an attractive therapeutic strategy. As a result, the search for clinically effective new respiratory chain inhibitors with minimized adverse effects is a major goal. Here, we characterize a new OXPHOS inhibitor compound called MS-L6, which behaves as an inhibitor of ETC-I, combining inhibition of NADH oxidation and uncoupling effect. MS-L6 is effective on both intact and sub-mitochondrial particles, indicating that its efficacy does not depend on its accumulation within the mitochondria. MS-L6 reduces ATP synthesis and induces a metabolic shift with increased glucose consumption and lactate production in cancer cell lines. MS-L6 either dose-dependently inhibits cell proliferation or induces cell death in a variety of cancer cell lines, including B-cell and T-cell lymphomas as well as pediatric sarcoma. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI-1) partially restores the viability of B-lymphoma cells treated with MS-L6, demonstrating that the inhibition of NADH oxidation is functionally linked to its cytotoxic effect. Furthermore, MS-L6 administration induces robust inhibition of lymphoma tumor growth in two murine xenograft models without toxicity. Thus, our data present MS-L6 as an inhibitor of OXPHOS, with a dual mechanism of action on the respiratory chain and with potent antitumor properties in preclinical models, positioning it as the pioneering member of a promising drug class to be evaluated for cancer therapy. MS-L6 exerts dual mitochondrial effects: ETC-I inhibition and uncoupling of OXPHOS. In cancer cells, MS-L6 inhibited ETC-I at least 5 times more than in isolated rat hepatocytes. These mitochondrial effects lead to energy collapse in cancer cells, resulting in proliferation arrest and cell death. In contrast, hepatocytes which completely and rapidly inactivated this molecule, restored their energy status and survived exposure to MS-L6 without apparent toxicity

Seuils, Thresholds, Soglitudes

Ce numéro consacré  à l’étude de la notion de seuil ouvre le champ de la recherche pluridisciplinaire à une approche innovante et propose à la fois une lecture possible des systèmes, des notions et des textes produits par les sciences humaines et une nouvelle manière de penser, créer et produire. La notion de « soglitude » est inspirée du mot italien « soglia » qui désigne le seuil et l’état solitaire de l’homme qui ne l’est finalement pas complètement, puisque le seuil ouvre et lie, sépare et joint, arrête et situe dans le continu tout le flux de la pensée, de la perception des événements, et de la mémoire. Les textes réunis dans ce numéro proposent une première approche de la méthode de la pensée des seuils. Non seulement état-charnière, transition, le seuil est lui-même à la fois une métaphore et une réalité dans les domaines représentés ici : la photographie, le film, l’anthropologie, l’histoire, la philosophie, l’histoire de l’art et la poésie où chacun dit à sa façon comment le seuil apporte une approche plus souple, une recherche plus nuancée, un flux de la réflexion qui s’arrête seulement pour repartir sur d’autres seuils, d’autres rives. A travers des exemples parfois très concrets, les auteurs montrent que la « soglitude » est une méthode à part entière qui peut s’appliquer à des domaines de recherches très divers. Un deuxième numéro est en préparation qui se consacrera à l’application concrète de cette méthode

The TLR3 L412F polymorphism prevents TLR3-mediated tumor cell death induction in pediatric sarcomas

Abstract Toll-like receptor 3 (TLR3) is a pattern recognition receptor mainly known for its role in innate immune response to infection. Indeed, binding of double-stranded RNA (dsRNA) to TLR3 triggers a pro-inflammatory cascade leading to cytokine release and immune cell activation. Its anti-tumoral potential has emerged progressively, associated with a direct impact on tumor cell death induction and with an indirect action on immune system reactivation. Accordingly, TLR3 agonists are currently being tested in clinical trials for several adult cancers. Meanwhile, TLR3 variants have been linked to auto-immune disorders, and as risk factors of viral infection and cancers. However, aside from neuroblastoma, TLR3 role in childhood cancers has not been evaluated. Here, by integrating public transcriptomic data of pediatric tumors, we unveil that high TLR3 expression is largely associated with a better prognosis in childhood sarcomas. Using osteosarcomas and rhabdomyosarcomas as models, we show that TLR3 efficiently drives tumor cell death in vitro and induces tumor regression in vivo. Interestingly, this anti-tumoral effect was lost in cells expressing the homozygous TLR3 L412F polymorphism, which is enriched in a rhabdomyosarcomas cohort. Thus, our results demonstrate the therapeutic potential associated with the targeting of TLR3 in pediatric sarcomas, but also the need to stratify patients eligible for this clinical approach with respect to the TLR3 variants expressed

BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas

Pediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded by ACVR1. However, the potential impact of the BMP pathway in tumors non-mutated for ACVR1 is less clear. By integrating bulk, single-cell and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels between ACVR1 wild type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the BMP/K27M crosstalk

Fusion-negative Rhabdomyosarcoma 3D-organoids as an innovative model to predict resistance to cell death inducers

Rhabdomyosarcoma (RMS) is the main form of soft-tissue sarcoma in children and adolescents. For 20 years, and despite international clinical trials, its cure rate has not really improved, and remains stuck at 20% in case of relapse. The definition of new effective therapeutic combinations is hampered by the lack of reliable models, which complicate the transposition of promising results obtained in pre-clinical studies into efficient solutions for young patients. Inter-patient heterogeneity, particularly in the so-called fusion-negative group (FNRMS), adds an additional level of difficulty in optimizing the clinical management of children and adolescents with RMS. Here, we describe an original 3D-organoid model derived from relapsed FNRMS and show that it finely mimics the characteristics of the original tumor, including inter- and intra-tumoral heterogeneity. Moreover, we have established the proof-of-concept of their preclinical potential by re-evaluating the therapeutic opportunities of targeting apoptosis in FNRMS from a streamlined approach based on the exploitation of bulk and single-cell omics data

Fusion-negative rhabdomyosarcoma 3D organoids to predict effective drug combinations: A proof-of-concept on cell death inducers

International audienceHighlights d Relapsed rhabdomyosarcoma (RMS) 3D organoids can be derived from needle biopsies d RMS 3D organoids finely preserve inter-and intra-tumor heterogeneity d Transcriptomic approach reveals Survivin as a key apoptosis blockage point in RMS d RMS 3D organoids are powerful tools to design and/or reexplore drug combinations Author

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

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