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International audience; nhibiting receptor tyrosine kinases is commonly achieved by two main strategies targeting either the intracellular kinase domain by low molecular weight compounds or the extracellular ligand-binding domain by monoclonal antibodies. Identifying small molecules able to inhibit RTKs at the extracellular level would be highly desirable to gain exquisite selectivity but is believed to be challenging owing to the size of RTK endogenous ligands (cytokines, growth factors) and the topology of RTK extracellular domains. We here report the high-throughput screening of the French Chemical Library (48K compounds) for extracellular inhibitors of the Fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase, by a homogeneous time-resolved fluorescence competition assay. A total of 679 small molecular weight ligands (1.4%) were confirmed to strongly inhibit (>75%) the binding of the fluorescent labeled FLT3 ligand (FL cytokine) to FLT3 overexpressed in HEK-293 cells, at two different concentrations (5 and 20 μM). Concentration-response curves, obtained for 111 lead-like molecules, confirmed the unexpected tolerance of the FLT3 extracellular domain for low molecular weight druggable inhibitors exhibiting submicromolar potencies, chemical diversity, and promising pharmacokinetic properties. Further investigation of one hit confirmed inhibitory properties in dorsal root ganglia neurons and in a mouse model of neuropathic pain.

Opioid analgesia is counteracted on chronic use by tolerance and hyperalgesia inducing dose escalation and life-threatening overdoses. Mu opiate receptors (MOR) expressed in primary sensory neurons were recently found to control tolerance and hyperalgesia, but the underlying mechanisms remained elusive. Here we show that genetic inactivation offms-like tyrosine kinase receptor 3 (FLT3) receptor in sensory neurons abrogates morphine tolerance and hyperalgesia by preventing MOR-induced hyperactivation of the cAMP signaling pathway and subsequent excitatory adaptive processes. Moreover, the specific FLT3 inhibitor BDT001 potentiates morphine analgesia in acute and chronic pain models, without aggravating morphine adverse effects, and reverses tolerance and hyperalgesia once installed. Thus, FLT3 appears as a key regulator of the MOR signaling pathway and its pharmacological blockade shows promise to enhance chronic opioid analgesic efficacy.

Until the end of the 1940's, France leans very few on radiobroadcasting to enforce its hold on the colonized populations of sub-Saharan French Africa (AOF, AÉF and Madagascar). It's at the last moment that France managed to redress the situation. A radiobroadcasting network managed from Paris was built in a few years. This network has been entrusted to the Société de Radiodiffusion de la France d'outre-mer (SORAFOM), created in 1956 by Pierre Schaeffer, inventor of the “musique concrete”. This creation, so fragile in appearance, managed to resist decolonization. It even had its golden age during the 1960's. The activities of the Office de Coopération radiophonique (OCORA), witch replaced the SORAFOM in 1962, extended to television and all branches of radio: provision of programs, specialists, equipment, training of Africans in its Studio-École. The society founded by Pierre Schaeffer intervened even in more countries than before independence. France has thus succeeded in building a media empire in Africa whereas the formal empire collapsed. This PHD propose to enlighten this apparent paradox by relying on unpublished or little-used sources. Its proposes to answer some burning questions. Which stakeholders are at the origin of this empire? What were their intentions? Why the SORAFOM-OCORA has survived the independence of African countries? To what extent was this company a tool of French imperialism before and after independence ? What were the human and cultural consequences of the formation of this media empire?; Jusqu'à la fin des années 1940, la puissance coloniale française a peu compté sur la radio pour renforcer son pouvoir sur les populations colonisées d'Afrique sub-saharienne (AOF, AÉF et Madagascar). C'est in-extremis que la France est parvenue à redresser la situation en construisant en quelques années un réseau de radiodiffusion d'outre-mer dirigé depuis Paris alors même que l'empire était en train de se désagréger. Ce réseau est confié à la Société de radiodiffusion de la France d'outre-mer (SORAFOM), fondée en 1956 par Pierre Schaeffer, inventeur de la musique concrète. Cet édifice, en apparence fragile, parvient à résister aux décolonisations. Il connaît même son âge d'or pendant les années 1960. Les activités de l'Office de coopération radiophonique (OCORA), qui a remplacé la SORAFOM en 1962, s'étendent à la télévision et à toutes les branches de la radio : fourniture d'émissions, de spécialistes, de matériel et formation d'un personnel africain dans son Studio-École. La société fondée par Pierre Schaeffer intervient même dans plus de pays qu'au temps de la colonisation. La France a ainsi réussi a fonder un véritable « empire médiatique » dans le domaine de la radio alors même que l'empire formel s'était effondré. Cette thèse vise à éclairer ce paradoxe apparent en s'appuyant sur des archives inédites ou encore peu exploitées. Elle propose de répondre à des questions brulantes : quels acteurs ont été à l'origine de cet empire médiatique ? Avec quelles intentions ? Pourquoi la SORAFOM-OCORA a-t-elle survécu aux indépendances ? Jusqu'à quel point ces organisations ont été des outils de l'impérialisme français avant et après les indépendances ? Quelles ont été les conséquences humaines et culturelles de la formation de cet empire médiatique ?

Alors que la France developpe un veritable reseau de radiodiffusion dans ses colonies d’Afrique subsaharienne au cours des annees 1950, se pose la question de son equipement. Cet article defend l’idee que Pierre Schaeffer et les autres fondateurs de la Societe de radiodiffusion de la France d’Outre-Mer (SORAFOM) ont deliberement detourne les normes techniques de la Radio-television francaise pour creer un equipement adapte et une acoustique differente dans les radios africaines. Cet article croise trois champs de recherche : l’histoire de l’innovation, les Sound studies et enfin l’histoire des medias en Afrique. Il revele les raisons qui ont pousse a concevoir un materiel specifique. Il propose d’eclairer les pratiques et les representations qui ont guide la realisation de ces normes et de cet equipement mais aussi le resultat de ces efforts. Cet article est base sur l’exploitation d’archives inedites du ministere de la Cooperation et de temoignages rares d’anciens agents de la SORAFOM.

Introduction: The digitalized PREVED (PREgnancy, PreVention, Endocrine Disruptor) questionnaire was used in the clinical practices of health professionals (HP) who adhered to the MEDPREVED strategy. The objectives were to assess the strategy and to determine if it could improve access to endocrine disruptor (ED) exposure prevention. Methods: After having filled in the digital questionnaire in HP waiting rooms, patients were invited to talk about ED exposure during the consultation. HPs were previously trained in ED and had received a prevention kit for their patients. After the seven-month implementation phase, the evaluation phase consisted of five mixed assessments: interviews with: (i) patients who were young children’s parents; (ii) patients in the general population; (iii) paediatricians; (iv) midwives; and a quantitative study on GPs. Assessment concerned feasibility, accessibility, and usefulness of the strategy; we then used the Levesque model to evaluate how it could improve access to ED exposure prevention. Results: The study included 69 participants. The strategy appeared feasible for the filling-out step due to digital and environment access. However, it depended on patient and HP profiles. The strategy seemed useful insofar as it facilitated reflexive investment, an intention to healthy behaviour and, rather rarely, talk about ED exposure. The beginning of this discussion depended on time, prioritizing of the topic and HP profile. The strategy has confirmed the Levesque model’s limiting factors and levers to access ED prevention. Conclusions: The MEDPREVED strategy is feasible, accessible, and useful in clinical prevention practice. Further study is needed to measure the impact on knowledge, risk perception and behavior of beneficiaries of the MEDPREVED strategy in the medium and long term.

En 2012, l’historien anglais Simon Potter faisait paraître Broadcasting Empire. The BBC and the British World, 1922-1970. Jusqu’à présent, il ne semble pas que ce livre ait fait l’objet d’un compte rendu de lecture en français. Simon Potter est professeur d’Histoire contemporaine à l’Université de Bristol, spécialiste d’Histoire Impériale et d’histoire des médias (presse, radio, télévision). Il cherche à traiter en même temps ces champs de recherche et participe au groupe de recherche « Conne...

Acute pain events have been associated with persistent pain sensitization of nociceptive pathways increasing the risk of transition from acute to chronic pain. However, it is unclear whether injuryinduced persistent pain sensitization can promote long-term mood disorders. The receptor tyrosine kinase FLT3 is causally required for pain chronification after peripheral nerve injury, questioning its role in the development of pain-induced mood alterations. Here, we evaluated the emotional and sensorial components of pain after a single (SI) or double paw incision (DI). We then investigated the role of FLT3 either by inhibition using transgenic knock-out mice and functional antibodies or by activation with FLT3 ligand (FL) administrations.DI mice showed significant anxiodepressive-like and spontaneous pain behaviors as opposed to SI mice. DI also promoted and extended mechanical pain hypersensitivity compared to SI. This emotional and sensorial pain exaggeration correlated with spinal changes especially by increased microglia activation after DI versus SI. Intrathecal minocycline, a microglial inhibitor, specifically reversed DI inducedmechanical hypersensitivity in males. Repeated treatment with the microglia proliferation inhibitor GW2580 not only eliminated the exaggerated pain hypersensitivity produced by DI but also prevented anxiodepressive-related behaviors in DI animals. Finally, FL injections in naive animals provoked mechanical allodynia and anxiodepressive-like disorders concomitant with a strong microglial activation while Flt3 silencing in a genetic mouse line or FLT3 blocking via functional antibodies, blunted the development of persistent pain and depression after DI. Altogether our results show that the repetition of peripheral lesions facilitate not only exaggerated nociceptive behaviors but also induced anxiodepressive disorders supported by spinal central changes. The inhibition of FLT3 could thus become a promising therapy in the management of pain sensitization and related mood alterations.

Cet extrait du discours de Modibo Keita, prononcé le 4 septembre 1957 lors de l’inauguration de Radio-Bamako témoigne combien la radio, et plus largement les médias, furent considérés comme un enjeu de taille dans la période des décolonisations et de la première décennie des indépendances sur le continent africain... Lire la suite