Optimisation d’un système microfluidique pour le test d’agents thérapeutiques avec la radiothérapie

Au moins 60% des patients atteints de cancer vont recevoir de la radiothérapie (RT). L’efficacité de la radiothérapie dans le traitement du cancer est limitée par le phénomène de radiorésistance des cellules cancéreuses et par la toxicité des radiations sur les tissus sains. La découverte de nouveaux agents radiosensibilisants et radioprotecteurs permettrait de surmonter ces difficultés. Les modèles cellulaires 3D tels que les sphéroïdes, émergent motivés par le besoin de modèles précliniques plus proches des tumeurs in vivo. L’objectif du projet est d’optimiser un système microfluidique pour tester facilement et à faible coût des agents thérapeutiques avec la RT sur des sphéroïdes dans un contexte de repositionnement. Le système microfluidique développé permet la formation de 336 sphéroïdes homogènes en deux jours avec intervention minimale de l’utilisateur. Les sphéroïdes sont répartis dans 16 chambres de culture séparées par un système de valve magnétique pour éviter des effets bystander entre sphéroïdes irradiés et non-irradiés. Une nouvelle technique d’irradiation a été développée permettant d’exposer un système à 4 doses de radiation différentes. En tout, 4 doses de radiation et 4 concentrations d’agents thérapeutiques peuvent être testées par système. En utilisant cette approche, l’efficacité de trois agents avec la RT a été évaluée avec des tests de survie clonogénique. Nous avons démontré que le Talazoparib, un inhibiteur de PARP, radiosensibilise les cellules de sarcome de tissus mous (STS) cultivés en sphéroïdes à 2 Gy. Le système développé permet d’évaluer le potentiel d’agents thérapeutiques avec la RT et contribue à l’adoption des sphéroïdes comme modèle préclinique.At least 60% of cancer patients will receive radiotherapy (RT) as part of their treatment. The efficacy of radiotherapy in the treatment of cancer is limited by the phenomenon of radioresistance of cancer cells and by the toxicity of radiation on healthy tissues. The discovery of new radiosensitizers and radioprotectors is essential to overcome these challenges. 3D cellular models such as spheroids emerge motivated by the need for better preclinical models. The objective of the project was to optimize a microfluidic system for easy, fast and low-cost testing of therapeutic agents with RT on spheroids. The developed microfluidic system allows the formation of 336 homogeneous spheroids in two days with minimal user intervention. The spheroids are distributed in 16 culture chambers separated by a magnetic valve system to avoid bystander effects between irradiated and unirradiated spheroids. A new irradiation technique has been developed to expose a system with 4 different radiation doses. In total, 4 radiation doses and 4 concentrations of therapeutic agents can be tested per system. Using this approach, the efficacy of three agents with RT was evaluated with clonogenic assays. Radiosensitizing properties of Talazoparib, a PARP inhibitor, on soft tissue sarcoma (STS) cells cultured as spheroids at 2 Gy were demonstrated. The developed system enables the evaluation of therapeutic agents with RT and contributes to the wide adoption of spheroids as a preclinical model

Structuration du territoire bourguignon : de l’île à l’isthme

La structuration du territoire bourguignon est dominée par trois données majeures. Son organisation interne, avec la disposition périphérique de ses aires les plus actives, est assimilable à celle d’une île. Sa position au sein de l’espace national et européen en fait une aire de transitions multiples, au maillage instable, soumise à de vigoureuses forces centrifuges qui peuvent menacer son unité. Enfin, traversée depuis toujours par de permanents et très abondants transits, elle est un espace intermédiaire entre des pôles moteurs, puissamment marquée par les réseaux et trafics exogènes qui sillonnent son territoire.Three principles govern the structuration of the burgundian territory. Its internal organization, with the peripheral location of its most active areas, is similar to the organization of an island. Its situation within national and European space makes it an area of multiple transitions, an unsettled organization, submissive to strong centrifugal forces which can threaten its unity. Lastly, it has always been crossed by numerous links, it is an intermediate space between nodes, strongly marked with networks and exogenous traffic which criss-cross its territory.Die Entwicklung der räumlichen Strukturen in Burgund wird wesentlich durch drei Tatsachen bestimmt. Durch die periphere Lage der aktivsten Räume ist die innere Organisation der Struktur einer Insel ähnlich. Wegen ihrer Lage im nationalen und europäischen Raum bildet dieses ein Gebiet mit zahlreichen Übergängen, dessen Einheit von starken zentrifugalen Kräften gefährdet wird. Seit jeher gibt es einen permanenten und dichten Transitverkehr durch Burgund. Insofern bildet Burgund einen « Durchgangsraum » zwischen den Wirtschaftszentren

Fine-grained Simulation in the Design of Automotive Communication Systems

International audienceEarly in the design cycle, the two main approaches for verifying timing constraints and di- mensioning automotive embedded networks are worst-case schedulability analysis and simulation. The first aim of the paper is to demonstrate that both provide complementary results and that, most often, none of them alone is sufficient. In this paper, we present a simulation approach accounting for the clock drifts that occur on the network nodes at run- time and evaluate the extent to which the results ob- tained with this approach are relevant for the design- ers in order to validate the performances of a CAN- based communication system. One of the practical outcome of this study is to show that initial phasings between nodes, as well as the values of the clock drifts, do not significantly impact the frame response time distributions that can be observed on the long run

Multi-source and multicore automotive ECUs - OS protection mechanisms and scheduling

International audienceAs the demand for computing power is quickly increasing in the automotive domain, car manufacturers and tier-one suppliers are gradually introducing multicore ECUs in their electronic architectures. Additionally, these multicore ECUs offer new features such as higher levels of parallelism which ease the respect of the safety requirements such as the ISO 26262 and the implementation of other automotive use-cases. These new features involve also more complexity in the design, development and verification of the software applications. Hence, OEMs and suppliers will require new tools and methodologies for deployment and validation. In this paper, we review the operating system protection mechanisms (e.g., memory, timing), needed for multi-source software in a safety critical context, with a clear focus on AUTOSAR OS which is the upcoming de-facto standard for automotive ECUs. We then identify the main use cases for multicore ECUs and eventually focus on one of them. Precisely, we address the problem of scheduling numerous elementary software components, called runnables, on a limited set of identical cores. In the context of an automotive design, we assume the use of the static task partitioning scheme which provides simplicity and better predictability for the ECU designers by comparison with a global scheduling approach. We show how the global scheduling problem can be addressed as two sub-problems: partitioning the set of runnables and building the schedule on each core. Then, we prove that each of the sub-problems cannot be solved optimally due to their algorithmic complexity. We then present low complexity heuristics to partition and build a schedule of the runnable set on each core before discussing schedulability verification methods. Finally, we assess the performance of our approach on a case-study

A morphological model for sexing nestling peregrine falcons (Falco Peregrinus Macropus) verified through genetic analysis

Adult peregrine falcons (Falco peregrinus macropus) have monotypic plumage and display strong reversed sexual dimorphism, with females significantly larger than males. Reversed sexual dimorphism is measurable among nestlings in the latter stages of their development and can therefore be used to differentiate between sexes. In the early stages of development, however, nestlings cannot be sexed with any degree of certainty because morphological differentiation between the sexes is not well developed. During this study we developed a model for sexing younger nestlings based on genetic analysis and morphometric data collected as part of a long-term banding study of this species. A discriminant function model based on morphological characteristics was developed for determining the sex of nestlings (n = 150) in the field and was shown to be 96.0% accurate. This predictive model was further tested against an independent morphometric dataset taken from a second group of nestlings (n = 131). The model correctly allocated sex to 96.2% of this second group of nestlings. Sex can reliably be determined (98.6% accurate) for nestlings that have a wing length of at least 9 cm using this model. Application of this model, therefore, allows the banding of younger nestlings and, as such, significantly increases the period of time over which banding can occur. Another important implication of this model is that by banding nestlings earlier, they are less likely to jump from the nest, therefore reducing the risk of injury to both the brood and the bander.<br /

Deprotonation of large calixarenes-cation binding and conformations

© 2016 CSIRO. Single crystal X-ray studies of p-t-butylcalix[10]arene·2dmso·7H2O (1) and [NMe4][p-t-butylcalix[9]arene-H]·2dmso·H2O (2), provide new data on these large macrocycles and their conformations, that of 2 being the first where an encapsulated [NMe4]+ cation is present, while 1 contains the neutral ligand. Both were obtained as crystalline products of the reactions of the calixarenes with tetramethylammonium hydroxide after prolonged standing. The structure of [NEt4][calix[4]arene-H], in which the cation approaches inclusion in the shallow cone of the anion, is also defined and compared with various other alkylammonium derivatives of calixarenes as well as that of p-t-butylcalix[9]arene

Respiratory Paradoxical Adverse Drug Reactions Associated with Acetylcysteine and Carbocysteine Systemic Use in Paediatric Patients: A National Survey

OBJECTIVE: To report pediatric cases of paradoxical respiratory adverse drug reactions (ADRs) after exposure to oral mucolytic drugs (carbocysteine, acetylcysteine) that led to the withdrawal of licenses for these drugs for infants in France and then Italy. DESIGN: The study followed the recommendations of the European guidelines of pharmacovigilance for medicines used in the paediatric population. SETTING: Cases voluntarily reported by physicians from 1989 to 2008 were identified in the national French pharmacovigilance public database and in drug company databases. PATIENTS: The definition of paradoxical respiratory ADRs was based on the literature. Exposure to mucolytic drugs was arbitrarily defined as having received mucolytic drugs for at least 2 days (>200 mg) and at least until the day before the first signs of the suspected ADR. RESULTS: The non-exclusive paradoxical respiratory ADRs reported in 59 paediatric patients (median age 5 months, range 3 weeks to 34 months, 98% younger than 2 years old) were increased bronchorrhea or mucus vomiting (n = 27), worsening of respiratory distress during respiratory tract infection (n = 35), dyspnoea (n = 18), cough aggravation or prolongation (n = 11), and bronchospasm (n = 1). Fifty-one (86%) children required hospitalization or extended hospitalization because of the ADR; one patient died of pulmonary oedema after mucus vomiting. CONCLUSION: Parents, physicians, pharmacists, and drug regulatory agencies should know that the benefit risk ratio of mucolytic drugs is at least null and most probably negative in infants according to available evidence

Inter-Individual Variability and Conspecific Densities: Consequences for Population Regulation and Range Expansion

The presence of conspecifics can strongly modulate the quality of a breeding site. Both positive and negative effects of conspecifics can act on the same individuals, with the final balance between its costs and benefits depending on individual characteristics. A particular case of inter-individual variation found in many avian species is chromatic variability. Among birds, plumage coloration can co-vary with morphology, physiology and behavior as well as with age. These relationships suggest that cost-benefit balances of conspecific presence may be different for individuals with different colorations. We investigated whether inter-individual variability affects population regulation and expansion processes by analyzing potential differences in density-dependent productivity and settlement patterns in relation to plumage coloration in a population of a long-lived avian species recently undergoing a notable increase in numbers and distribution range. Our results show strong variation in the effect of density on productivity of breeding pairs depending on plumage coloration of their members. Productivity of dark birds decreased along the breeding density gradient while that of lighter breeders remained unchanged with conspecific density. In a similar way, our results showed an uneven occupation of localities by individuals with different plumage coloration in relation to local densities, with the breeding of lighter harriers more aggregated than that of dark-brown ones. At a population scale, darker birds had higher probability of colonization of the most isolated, empty sites. Explanations for species range expansion and population regulation usually make the inferred assumption that species traits are similar among individuals. However, in most species, there could be individual variation in niche requirements or dispersal propensities among individuals with different traits. Our results contribute to the growing appreciation that the individual traits, but not the average trait at the level of species, are important during population regulation and expansion processes

Les équipements de transports européens : travaux et projets

Bavoux Danièle, Bavoux Jean-Jacques. Les équipements de transports européens : travaux et projets . In: Annales de Géographie, t. 106, n°593-594, 1997. pp. 218-228