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A detailed knowledge of the cracking mechanisms of crude oils should highly improve the understanding of geochemical reactions involved in hydrocarbon degradation into lighter oil and gas and consequently the applicability of kinetic models currently used for prediction of gas formation. Although the mechanisms of cracking are well known for several model compounds or simple mixtures, there is, to date, no available method to model complex mixtures, especially when they contain heavy compounds, except by using empirical approaches. During thermal cracking, oil will produce both lighter and heavier molecules than those present in the initial sample. Thus, the pyrolysate will be a mixture of both new compounds and compounds not yet degraded. In order to discriminate between reactants and products, we have chosen to fractionate each oil into two classes : the first one (distillate 300-) comprising light hydrocarbons ranging from C6 to C16 the second one (residue 300+) comprising both hydrocarbons and polar compounds. For simulation of thermal evolution of crude oils, about 100 experiments were carried out on two oils (Boscan and Pematang), in a closed pyrolysis system, over a wide range of heating times (few minutes to 1 month) and temperatures (335 to 500°C). The pyrolysate is represented by 10 chemical fractions (C1, C2, C3-C5, C6-C13 saturates, benzene + toluene + xylenes + naphthalene, C9-C13 alkyl aromatics, C14+ saturates, C14+ condensed aromatics, C14+ alkyl and/or naphtheno aromatics + resins + asphaltenes and coke). For kinetic modeling, the degradation of each fraction, except for C1, C6-C13 aromatic mixture comprising benzene, toluene, xylenes and naphthalene, and coke considered as stable compounds, is described by a balanced elementary reaction governed by first order kinetics and obeying Arrhenius law. For a given oil, the kinetic parameters of the model (apparent activation energies Ei, preexponential factor A and stoichiometric coefficients alphaij) were optimized with reference to a dataset comprising the final compositions resulting from oil pyrolysis experiments. This optimization was carried out successively on each distillate and each residue, on both distillate and residue from the same oil, then on the two distillates and two residues altogether. The model accounts satisfactorily for the specific kinetics of cracking of both each oil and of the two oils together, suggesting that it is now possible to predict the thermal behavior of a given oil provided the proportions of the ten fractions selected for the model are known. The wide temperature range in which the model is valid, supports its extrapolation to the temperature range of sedimentary basins. Une meilleure connaissance des mécanismes du craquage thermique des huiles doit permettre de mieux comprendre leur évolution naturelle dans les bassins sédimentaires et donc d'améliorer les modèles actuels utilisés pour prédire la formation du gaz. Bien que les mécanismes de craquage soient bien connus pour des composés modèles ou des mélanges simples d'hydrocarbures, il n'existe pas à l'heure actuelle, à l'exception des modèles empiriques, de méthode pour rendre compte de la dégradation thermique des mélanges complexes, surtout, lorsque ces derniers sont enrichis en produits lourds. Au cours du craquage thermique, une huile produira à la fois des composés plus légers et des composés plus lourds que la charge initiale. En conséquence, les produits de pyrolyse seront un mélange complexe contenant des produits nouveaux et des composés non encore dégradés. Afin de pouvoir faire la distinction entre réactifs et produits, nous avons choisi de fractionner chaque huile en deux grandes fractions : la première (distillat 300- ) contenant des hydrocarbures légers de C6 à C16 et la seconde (résidu 300+) contenant des hydrocarbures et des produits polaires. Afin de simuler l'évolution thermique des huiles, nous avons réalisé une centaine d'expériences de pyrolyse en milieu fermé sur deux huiles; l'une enrichie en composés aromatiques (Boscan) et l'autre enrichie en structures aliphatiques (Pematang). La gamme de température explorée est comprise entre 335 et 540°C et celle des temps de séjour entre quelques minutes et quelques semaines. Les huiles, ainsi que les produits de pyrolyse sont représentés par 10 classes chimiques (C1, C2, C3-C5, C6-C13 saturés, benzène + toluène + xylènes + naphtalène, C9-C13 aromatiques alkylés, C14+ saturés, C14+ aromatiques condensés, C14+ alkyl et/ou naphténo aromatiques + résines + asphaltènes et coke). Pour les modèles cinétiques, le craquage de chacune des fractions, à l'exception du méthane, du mélange aromatique comprenant le benzène, le toluène, les xylènes et le naphtalène et du coke considérés comme produits stables, est décrit par une réaction élémentaire pondérée, gouvernée par une cinétique d'ordre 1 et obéissant à la loi d'Arrhénius. Pour chaque huile étudiée, les paramètres cinétiques (énergies d'activation apparentes Ei, facteur préexponentiel A et coefficients stoechiométriques alphaij) sont optimisés à partir d'un jeu de données expérimentales sur la composition des produits finaux résultant des expériences. Cette optimisation a été réalisée successivement sur chaque distillat et sur chaque résidu, sur le distillat et sur le résidu provenant d'une même huile, puis sur l'ensemble des deux distillats et des résidus. Les modèles obtenus rendent compte de façon satisfaisante de la cinétique de craquage de chacune des 2 huiles modélisées séparément ainsi que de la cinétique de craquage de l'ensemble des 2 huiles. En conséquence, il semble possible maintenant de prédire à priori le comportement thermique d'une huile donnée, à condition de connaître au départ, les proportions respectives des 10 classes chimiques définies pour la modélisation. Par ailleurs, la large gamme de températures explorées dans laquelle ces modèles sont valables, a permis leur extrapolation dans la gamme de températures des bassins sédimentaires.

Cleft lip and palate are one of the most common congenital craniofacial malformations. As an initial treatment, presurgical orthopedics is considered standard treatment at many cleft centers. Digital impressions are becoming feasible in cleft care. Computer-aided design (CAD) and three-dimensional (3D) printing are manufacturing standards in dentistry. The assimilation of these technologies has the potential to alter the traditional workflow for the fabrication of customized presurgical orthopedic plates. We present a digital workflow comprising three steps: 3D digital image acquisition with an intraoral scanner, open-source CAD modeling, and point-of-care 3D printing for the fabrication of personalized passive presurgical plates for newborns with cleft lip and palate. The digital workflow resulted in patient-related benefits, such as no risk of airway obstruction with quicker data acquisition (range 1-2.5 min). Throughput time was higher in the digital workflow 260-350 min compared to 135 min in the conventional workflow. The manual and personal intervention time was reduced from 135 min to 60 min. We show a clinically useful digital workflow for presurgical plates in cleft treatment. Once care providers overcome procurement costs, digital impressions, and point-of-care 3D printing will simplify these workflows and have the potential to become standard for cleft care.

Asymmetric division of neural precursor cells contributes to the generation of a variety of neuronal types. Asymmetric division is mediated by the asymmetric inheritance of fate determinants by the two daughter cells. In vertebrates, asymmetric fate determinants, such as Par3 and Mib, are only now starting to be identified. Here we show that, during mitosis of neural precursors in zebrafish, directional trafficking of Sara endosomes to one of the daughters can function as such a determinant. In asymmetric lineages, where one daughter cell becomes a neuron (n cell) whereas the other divides again to give rise to two neurons (p cell), we found that the daughter that inherits most of the Sara endosomes acquires the p fate. Sara endosomes carry an endocytosed pool of the Notch ligand DeltaD, which is thereby itself distributed asymmetrically. Sara and Notch are both essential for cell fate assignation within asymmetric lineages. Therefore, the Sara endosome system determines the fate decision between neuronal differentiation and mitosis in asymmetric lineages and thereby contributes to controlling the number of neural precursors and differentiated neurons during neurogenesis in a vertebrate.

Despite therapeutic advances multiple myeloma remains largely incurable, and novel therapeutic concepts are needed. The Hsp90-chaperone is a reasonable therapeutic target, because it maintains oncogenic signaling of multiple deregulated pathways. However, in contrast to promising preclinical results, only limited clinical efficacy has been achieved through pharmacological Hsp90 inhibition. Because Hsp70 has been described to interact functionally with the Hsp90-complex, we analyzed the suitability of Hsp72 and Hsp73 as potential additional target sites. Expression of Hsp72 and Hsp73 in myeloma cells was analyzed by immunohistochemical staining and western blotting. Short interfering RNA-mediated knockdown or pharmacological inhibition of Hsp72 and Hsp73 was performed to evaluate the role of these proteins in myeloma cell survival and for Hsp90-chaperone function. Furthermore, the role of PI3K-dependent signaling in constitutive and inducible Hsp70 expression was investigated using short interfering RNA-mediated and pharmacological PI3K inhibition. Hsp72 and Hsp73 were frequently overexpressed in multiple myeloma. Knockdown of Hsp72 and/or Hsp73 or treatment with VER-155008 induced apoptosis of myeloma cells. Hsp72/Hsp73 inhibition decreased protein levels of Hsp90-chaperone clients affecting multiple oncogenic signaling pathways, and acted synergistically with the Hsp90 inhibitor NVP-AUY922 in the induction of death of myeloma cells. Inhibition of the PI3K/Akt/GSK3β pathway with short interfering RNA or PI103 decreased expression of the heat shock transcription factor 1 and down-regulated constitutive and inducible Hsp70 expression. Treatment of myeloma cells with a combination of NVP-AUY922 and PI103 resulted in additive to synergistic cytotoxicity. In conclusion, Hsp72 and Hsp73 sustain Hsp90-chaperone function and critically contribute to the survival of myeloma cells. Translation of Hsp70 inhibition into the clinic is therefore highly desirable. Treatment with PI3K inhibitors might represent an alternative therapeutic strategy to target Hsp70.