The Holy Roman Empire, building tool of a European unity?

The European Union has been going through deep crises since its creation, bringing into question its foundations. The question of its essence has been a heated one for the past years, and some have turned to the past of the continent in order to find clues as to what the European Union is today. Resorting to past models of unity can prove a hazardous task if taken as such, but it can also provide interesting insights to understanding our contemporary reality. The Holy Roman Empire was a thousand-year-old Empire which constituted the political reality of many Europeans from the Middle-Ages until the 19th century. Its lifespan and its width raise the question as to how it was able to foster a certain degree of unity. Through its imperial narrative, gathering multiple religious and political fictions, the Empire endowed itself with an ambition of European unity. It tried to use its flexible feudal structure to achieve it, within and beyond its borders. And while it met some serious obstacles and eventually collapsed, the Holy Roman Empire remains a major figure in the attempts to form European unity

Formations et industries du Futur

L’industrie évolue, les métiers de l’industrie aussi. L’industrie évolue vers l’industrie du futur. Les compétences attendues des techniciens et des ingénieurs doivent donc évoluer ver la capacité : - A imaginer, concevoir, produire, maintenir et recycler les objets et les systèmes dans un environnement numérique - A prévoir par la simulation et les essais le comportement de systèmes pluri-technologiques de plus en plus complexes. - Et à en valider la pertinence et la durabilité dans un environnement de développement durable. Pour réaliser ces activités, les techniciens et les ingénieurs auront besoin de disposer d’une base de connaissances pluridisciplinaires, scientifiques et technologiques solide, actualisée et opérationnelle. Ils devront également avoir la capacité à contribuer avec une réelle maîtrise du réel à la réussite d’un produit commercialisable dans une équipe pluridisciplinaire et pluritechnologique. De plus les ingénieurs devront innover et animer des équipes. Dans cette perspective, cette session a pour objet de faire le point sur la prise en compte dans les formations de l’évolution des compétences attendues aujourd’hui et demain. Elle s’articulera autour de trois interventions industrielles et académiques et une table ronde ouverte à des échanges avec la salle réunissant des industriels, des responsables de formation et des formateurs. Les thèmes en seront : - Les besoins de l’industrie de demain - La formation en sections de techniciens supérieurs - La formation en IUT et en Licence - La formation en master et en école d’ingénieurf

Susceptibility of pediatric acute lymphoblastic leukemia to STAT3 inhibition depends on p53 induction

Advances in the clinical management of pediatric B cell Acute Lymphoblastic Leukemia (B-ALL) have dramatically improved outcomes for this disease. However, relapsed and high-risk disease still contribute to significant numbers of treatment failures. Development of new, broad range therapies is urgently needed for these cases. We previously reported the susceptibility of ETV6-RUNX1+ pediatric B-ALL to inhibition of signal transducer and activator of transcription 3 (STAT3) activity. In the present study, we demonstrate that pharmacological or genetic inhibition of STAT3 results in p53 induction and that CRISPR-mediated TP53 knockout substantially reverses susceptibility to STAT3 inhibition. Furthermore, we demonstrate that sensitivity to STAT3 inhibition in patient-derived xenograft (PDX) B-ALL samples is not restricted to any particular disease subtype, but rather depends on TP53 status, the only resistant samples being TP53 mutant. Induction of p53 following STAT3 inhibition is not directly dependent on MDM2 but correlates with degradation of MDM4. As such, STAT3 inhibition exhibits synergistic in vitro and in vivo anti-leukemia activity when combined with MDM2 inhibition. Taken together with the relatively low frequency of TP53 mutations in this disease, these data support the future development of combined STAT3/MDM2 inhibition in the therapy of refractory and relapsed pediatric B-ALL

Identification of a c-MYB-directed therapeutic for acute myeloid leukemia

A significant proportion of patients suffering from acute myeloid leukemia (AML) cannot be cured by conventional chemotherapy, relapsed disease being a common problem. Molecular targeting of essential oncogenic mediators is an attractive approach to improving outcomes for this disease. The hematopoietic transcription factor c-MYB has been revealed as a central component of complexes maintaining aberrant gene expression programs in AML. We have previously screened the Connectivity Map database to identify mebendazole as an anti-AML therapeutic targeting c-MYB. In the present study we demonstrate that another hit from this screen, the steroidal lactone withaferin A (WFA), induces rapid ablation of c-MYB protein and consequent inhibition of c-MYB target gene expression, loss of leukemia cell viability, reduced colony formation and impaired disease progression. Although WFA has been reported to have pleiotropic anti-cancer effects, we demonstrate that its anti-AML activity depends on c-MYB modulation and can be partially reversed by a stabilized c-MYB mutant. c-MYB ablation results from disrupted HSP/HSC70 chaperone protein homeostasis in leukemia cells following induction of proteotoxicity and the unfolded protein response by WFA. The widespread use of WFA in traditional medicines throughout the world indicates that it represents a promising candidate for repurposing into AML therapy

Hematopoietic stem cell quiescence and DNA replication dynamics maintained by the resilient β-catenin/Hoxa9/Prmt1 axis

Maintenance of quiescence and DNA replication dynamics are two paradoxical requirements for the distinct states of dormant and active hematopoietic stem cells (HSCs), which are required to preserve the stem cell reservoir and replenish the blood cell system in response to hematopoietic stress respectively. Here, we show that key self-renewal factors, β-catenin or Hoxa9, largely dispensable for HSC integrity in fact have dual functions in maintaining quiescence and enabling efficient DNA replication fork dynamics to preserve the functionality of hematopoietic stem and progenitor cells (HSPCs). While β-catenin or Hoxa9 single knockout (KO) exhibited mostly normal hematopoiesis, their co-inactivation led to severe hematopoietic defects stemmed from aberrant cell cycle, DNA replication and damage in HSPCs. Mechanistically, β-catenin and Hoxa9 function in a compensatory manner to sustain key transcriptional programs that converge on the pivotal downstream target and epigenetic modifying enzyme, Prmt1, which protects the quiescent state and ensures an adequate supply of DNA replication and repair factors to maintain robust replication fork dynamics. Inactivation of Prmt1 phenocopied both cellular and molecular phenotypes of β-catenin/Hoxa9 combined KO, which at the same time could also be partially rescued by Prmt1 expression. The discovery of the highly resilient β-catenin/Hoxa9/Prmt1 axis in protecting both quiescence and DNA replication dynamics essential for HSCs at different key states provides not only novel mechanistic insights into their intricate regulation but also a potential tractable target for therapeutic intervention

Cytogenetic and Molecular Predictors of Outcome in Acute Lymphocytic Leukemia: Recent Developments

During the last decade a tremendous technologic progress based on genome-wide profiling of genetic aberrations, structural DNA alterations, and sequence variations has allowed a better understanding of the molecular basis of pediatric and adult B/T- acute lymphoblastic leukemia (ALL), contributing to a better recognition of the biological heterogeneity of ALL and to a more precise definition of risk factors. Importantly, these advances identified novel potential targets for therapeutic intervention. This review will be focused on the cytogenetic/molecular advances in pediatric and adult ALL based on recently published articles

An inquiry into the nature and the foramtin of the economic magnetudes : the question of the value and its measure in economics

Envisager un travail de recherche relatif à la valeur, à la formation et à la nature des grandeurs économiques peut sembler inopportun, tant les notions d’échange, de prix, de marché, et bien d’autres encore, tombent sous l’évidence de notre environnement quotidien. Nous montrons dans cette étude que nombre de concepts en économie ne reçoivent qu’une définition incertaine et parfois inconsistante. C’est à ce titre, le discours économique qui s’en trouve fragilisé, à tel point qu’il en vienne à se prononcer sur ce qui n’existe pas, et laisse échapper son objet véritable.Dans nos économies salariales, la valeur est tantôt reçue tantôt dépensée dans la formation et dans la destruction d’un revenu. Celui-ci est monétaire, et est objectif dans le sens où il confère un pouvoir ferme d’acquisition de biens et de services. Nous vérifions alors que l’objet de la science économique est le revenu, et que celui-ci unit les deux actes antagoniques de la production et de la consommation. Nous nous assurons par suite qu’il ne peut être pensé en termes « réels » ; la valeur n’est pas cachée derrière les choses. Dans un second temps, nous voyons que le revenu procède d’une mesure, et que c’est de cette mesure qu’il tire son objectivité. La mesure en économie est singulière, elle ne peut être empruntée au domaine de la physique. Elle est monétaire et réalisée dans le versement des salaires. À la lumière irremplaçable de la théorie des émissions de B. Schmitt, nous montrons que tout produit naît dans sa mesure en unités de salaires, et parvenons à une conclusion forte : la répartition révise l’émission du revenu sans réviser sa mesure. Nous sommes parvenus à une théorie cohérente et complète de la valeur.To investigate on the question of the formation of the economic magnitudes, and on the question of value seems to be pointless, since those notions appear to be understood and to fall under the scope of our daily experiment. We show in the present work that several fundamental concepts and central notions do not receive a proper definition within our discipline. As a consequence, it is all the economic discourse that is weakened, at such a point that it talks about things that, actually, do not exist, but in the economist’s mind, and do not consider its true matter. In our wage economy, value is sometimes created sometimes destructed respectively in the formation and the destruction of income. The latter is an objective magnitude in the sense that it confers to its owner the tangible ability to buy goods and services. We thus make sure that income unifies the two opposite operations that are production and consumption, and that it is the true object of the economic science. We also insure that income is a monetary by naturee, and cannot be expressed in “real” terms; value is not hidden behind things. In a second time, we see that income is measured, and that its objectivity comes from the fact that it is measured. In economics, measure is specific since the unit of measurement is monetary and by no mean physical. The operation of measurement happens in the payment of wages to the benefit of the employees. By showing that product is “born” in the same operation by which it is measured, we are leading to a strong conclusion: all income is derived from wages

Is the IOC watching you in its sponsors’ services ? : Exploring the dark side of Event Specific Ambush Marketing Legislation, toward the end of the Orwellian atmosphere for Paris 2024 Olympic Games/Issue/Does the Event Specific Ambush Marketing legislat

Marketing and Event ManagementThis paper examines the emerging trend around ambush marketing, explaining it and finding that stakeholders might go too far in their fight against ambush marketing, passing too aggressive special legislation, thus possibly engendering counterproductive effect on the protection of their brand and their partners. After a brief review of literature on the issue of ambush marketing and on the apparition of Event Specific Ambush Marketing Legislation (ESAML), this paper will focus on the evolution of ESAML inside the Olympic environment. Thanks to an analysis of the special legislation enacted for the 2012 London Olympics particularly, its aftereffects on the Olympic brand and partners' image and a general review of the literature that led the change of direction, the aim of this paper is to lay the groundwork for the 2024 Paris Olympics and to understand how the special legislation passed in France in 2018 has been conceived. Event Specific Ambush Marketing Legislation raised many issues from both legal and business perspectives which will be discussed with French experts and different stakeholders of the Olympic environment, in order to examine whether the International Olympic Committee and Paris 2024 Organisational Committee for the Olympic Games might be compared to Big Brother

Etude de la reaction de deshydrogenation oxydante de l'acide isobutyrique sur phosphates de fer

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : T 77746 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc