Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4

Cancer cells rely on dysregulated gene expression. This establishes specific transcriptional addictions that may be therapeutically exploited. Yet, the mechanisms that are ultimately responsible for these addictions are poorly understood. Here, we investigated the transcriptional dependencies of transformed cells to the transcription factors YAP and TAZ. YAP/TAZ physically engage the general coactivator bromodomain-containing protein 4 (BRD4), dictating the genome-wide association of BRD4 to chromatin. YAP/TAZ flag a large set of enhancers with super-enhancer-like functional properties. YAP/TAZ-bound enhancers mediate the recruitment of BRD4 and RNA polymerase II at YAP/TAZ-regulated promoters, boosting the expression of a host of growth-regulating genes. Treatment with small-molecule inhibitors of BRD4 blunts YAP/TAZ pro-tumorigenic activity in several cell or tissue contexts, causes the regression of pre-established, YAP/TAZ-addicted neoplastic lesions and reverts drug resistance. This work sheds light on essential mediators, mechanisms and genome-wide regulatory elements that are responsible for transcriptional addiction in cancer and lays the groundwork for a rational use of BET inhibitors according to YAP/TAZ biology

Music processing in preterm and full-term newborns: A psychophysiological interaction (PPI) approach in neonatal fMRI

Neonatal Intensive Care Units (NICU) provide special equipment designed to give life support for the increasing number of prematurely born infants and assure their survival. More recently NICU's strive to include developmentally oriented care and modulate sensory input for preterm infants. Music, among other sensory stimuli, has been introduced into NICUs, but without knowledge on the basic music processing in the brain of preterm infants. In this study, we explored the cortico-subcortical music processing of different types of conditions (Original music, Tempo modification, Key transposition) in newborns shortly after birth to assess the effective connectivity of the primary auditory cortex with the entire newborn brain. Additionally, we investigated if early exposure during NICU stay modulates brain processing of music in preterm infants at term equivalent age. We approached these two questions using Psychophysiological Interaction (PPI) analyses. A group of preterm infants listened to music (Original music) starting from 33 weeks postconceptional age until term equivalent age and were compared to two additional groups without music intervention; preterm infants and full-term newborns. Auditory cortex functional connectivity with cerebral regions known to be implicated in tempo and familiarity processing were identified only for preterm infants with music training in the NICU. Increased connectivity between auditory cortices and thalamus and dorsal striatum may not only reflect their sensitivity to the known music and the processing of its tempo as familiar, but these results are also compatible with the hypothesis that the previously listened music induces a more arousing and pleasant state. Our results suggest that music exposure in NICU's environment can induce brain functional connectivity changes that are associated with music processing

How to measure the effectiveness of an intervention from an ecological perspective. Multiple single cases in children with autism spectrum disorder

Introduction Démontrer l’efficacité des pratiques orthophoniques est un enjeu important. Des approches méthodologiques adaptées à l’étude des cas uniques, comme le recours aux lignes de base, sont depuis longtemps utilisées pour la rééducation des troubles du langage oral ou des troubles d’apprentissage. Dans le domaine du handicap, la mesure de l’efficacité de l’intervention est plus complexe à mettre en œuvre et paraît difficilement conciliable avec le caractère écologique et fonctionnel des interventions proposées. Objectif La présente communication illustre la mesure de l’efficacité d’une intervention basée sur l’introduction d’un outil de communication augmentative et alternative (CAA) technologique, appelé Tiwouh, chez de jeunes enfants présentant un trouble du spectre autistique (TSA). Méthode Quatre jeunes patients TSA ont été entrainés via la plateforme Tiwouh à un outil CAA numérisé. Les comportements communicatifs de ces enfants ont été évalués lors de situation de lecture de livres avec leurs mamans, en comparant des livres entrainés ou non entrainés, avec ou sans le support CAA. Résultats Grâce aux différentes conditions de la même tâche (lecture de livres) ayant servi de lignes de base, il a été possible de mettre en évidence des effets spécifiques d’entrainement et de généralisation (à des livres non travaillés pendant la prise en charge) chez certains enfants. Ces données permettront d’aider à identifier les enfants qui bénéficieront le plus de ce type d’intervention. Conclusion Ce travail suggère que mesurer l’efficacité d’une intervention peut se faire quel que soit l’objectif thérapeutique visé, dans des situations variées et avec des patients au profil langagier hétérogène, en utilisant des mesures fonctionnelles et écologiques proches des besoins des patients.Introduction Establishing the effectivenss of speech-therapy interventions is a critical issue. Methodological approaches fitted for single-case studies, such as observation baselines, have been used for a long time in interventions addressing oral language or learning impairments. However, when targeting disabled populations, measuring the intervention efficacy is much harder, especially due to their ecological and functional aspects. Objective This work illustrates the efficacy assessment of an intervention based on a technological tool of Alternative and Augmentative Communication (AAC) – named Tiwouh – among children with autism spectrum disorder (ASD). Method Four young participants with ASD have been trained on the Tiwouh AAC plate-form. Their communication behaviors have been evaluated during the activity of reading book with their parents, comparing trained and non-trained books, with or without the support of the AAC tool. Results Thanks to the different experimental conditions of the same task (reading book) implemented as baselines, specific intervention effects have been highlighted. Moreover, some participants actually generalized these benefits to untrained books. Such data will help identifying participants’ profile that can benefit the most from these interventions. Conclusion The present work suggests measuring the effectiveness of an intervention can be achieved regardless of the therapeutic objective, in various situations and with patients exhibiting heterogeneous language profile, by using functional and ecological measures close to the population needs

Dispersion of Heat Flux Sensors Manufactured in Silicon Technology

In this paper, we focus on the dispersion performances related to the manufacturing process of heat flux sensors realized in CMOS (Complementary metal oxide semi-conductor) compatible 3-in technology. In particular, we have studied the performance dispersion of our sensors and linked these to the physical characteristics of dispersion of the materials used. This information is mandatory to ensure low-cost manufacturing and especially to reduce production rejects during the fabrication process. The results obtained show that the measured sensitivity of the sensors is in the range 3.15 to 6.56 μV/(W/m2), associated with measured resistances ranging from 485 to 675 kΩ. The dispersions correspond to a Gaussian-type distribution with more than 90% determined around average sensitivity S e ¯ = 4.5 µV/(W/m2) and electrical resistance R ¯ = 573.5 kΩ within the interval between the average and, more or less, twice the relative standard deviation

High plasma concentrations of sclerostin, an inhibitor of the Wnt signaling pathway in young horses affected by osteochondrosis

peer reviewedOsteochondrosis (OC) is a developmental disease in horses with a significant impact on the horse’s welfare and performance. The early disturbance of enchondral ossification progresses to inflammatory and healing process in older horses. Metabolic pathway analysis showed an obvious dysregulation of several signaling pathways related to cartilage formation and cartilage repair such as Wnt/β-catenin, Indian hedgehog and TGF-β signaling pathways. Other regulated genes appeared to be involved in high carbohydrate diet, abnormal insulin metabolism or inflammation. Sclerostin is an osteocyte-secreted soluble antagonist of the Wnt/β-catenin signaling pathway. It is crucial for osteoblast development and activity and is increased in naturally occurring lesions of equine osteochondrosis. The aim of this study is to compare the circulating sclerostin levels between OC-affected (n = 20) and healthy horses (n = 19). A significant linear regression between plasma sclerostin and age is observed especially in the healthy young horses. The mean plasma sclerostin concentration is significantly higher in young horses suffering from osteochondrosis compared to the control horses. These results reinforce the possible role of the Wnt/β-catenin signaling pathway in the OC pathogeny. The inhibition of this essential pathway could disturb the osteo-chondral differentiation. More studies are currently needed to define the eventual clinic interest of plasma sclerostin as future biomarker in bone and cartilage diseases.Soutien à la filière équin

La tomographie électrique au service de la recherche. Exemple en Montagne de Reims

Séminaire : Mouvement de Terrain et karst en Montagne de Reims, apport de la tomographie électriqueInternational audienceLe karst est les mouvements de terrain sont des phénomènes naturels connus depuis longtemps en Montagne de Reims. Le premier exemple de relation entre ses deux entités est observé dès les années 2000 au-dessus de Verzy, au niveau du système karstique associé à la fosse Martin-Godard (Lejeune, 2000). Ce cas est demeuré unique jusqu’à la réalisation d’une campagne de LiDAR aéroporté en 2018 qui a permis de multiplier par 5 le nombres de phénomènes exokarstiques connus sur ce secteur (750 dolines). Cette nouvelle base de données a permis de mettre en évidence deux types de relation entre le karst et les mouvements de terrain. Dans un cas, les dolines sont alimentées par l’impluvium formé par le mouvement de terrain. Dans un second temps, le mouvement de terrain conserve son activité car le karst permet l’absorption progressive du bourrelet frontal de sa coulée. Le mouvement de terrain est alors en déséquilibre permanent. Ces relations fortuites sont visibles lorsque l’exokarst trépane une coulée d’un mouvement de terrain.Néanmoins, l’observation du liseré karstique du massif permet de poser une hypothèse supplémentaire : existent-il un karst actif ou non sous les mouvements de terrain qui ne présente pas de manifestation de surface ?Pour répondre à cette question, la tomographie électrique semble être un outil adapté. Une campagne a été réalisée sur le mouvement de terrain dit du Curabilly (bassin de la Lingonne). Les conditions géomorphologiques sont idéales au développement de karst (gradient hydraulique, géologie propice…). Toutefois, il n’existe pas de formes exokarstiques détectables. Deux profils géophysiques ont donc été réalisés. Les résultats ont permis de décrire le volume du mouvement de terrain permettant de le caractériser comme un glissement de type Ay (Bollot, 2014). Plusieurs zones présentent des réponses difficiles à interpréter, ses zones correspondent également à des zones potentiellement karstiques, Il semble donc pertinent de poursuivre les investigations en affinant les mesures sur les secteurs à réponses particulières afin d’espérer répondre totalement à la problématique

Maternal Nutrition during Pregnancy Affects Testicular and Bone Development, Glucose Metabolism and Response to Overnutrition in Weaned Horses Up to Two Years.

INTRODUCTION: Pregnant mares and post-weaning foals are often fed concentrates rich in soluble carbohydrates, together with forage. Recent studies suggest that the use of concentrates is linked to alterations of metabolism and the development of osteochondrosis in foals. The aim of this study was to determine if broodmare diet during gestation affects metabolism, osteoarticular status and growth of yearlings overfed from 20 to 24 months of age and/or sexual maturity in prepubertal colts. MATERIAL AND METHODS: Twenty-four saddlebred mares were fed forage only (n = 12, group F) or cracked barley and forage (n = 12, group B) from mid-gestation until foaling. Colts were gelded at 12 months of age. Between 20 and 24 months of age, all yearlings were overfed (+140% of requirements) using an automatic concentrate feeder. Offspring were monitored for growth between 6 and 24 months of age, glucose homeostasis was evaluated via modified frequently sampled intra veinous glucose tolerance test (FSIGT) at 19 and 24 months of age and osteoarticular status was investigated using radiographic examinations at 24 months of age. The structure and function of testicles from prepubertal colts were analyzed using stereology and RT-qPCR. RESULTS: Post-weaning weight growth was not different between groups. Testicular maturation was delayed in F colts compared to B colts at 12 months of age. From 19 months of age, the cannon bone was wider in B vs F yearlings. F yearlings were more insulin resistant at 19 months compared to B yearlings but B yearlings were affected more severely by overnutrition with reduced insulin sensitivity. The osteoarticular status at 24 months of age was not different between groups. CONCLUSION: In conclusion, nutritional management of the pregnant broodmare and the growing foal may affect sexual maturity of colts and the metabolism of foals until 24 months of age. These effects may be deleterious for reproductive and sportive performances in older horses