Empirical model-based identification of critical quality attributes in the preclinical design of nanostructured lipid carriers

International audienceIn this study, an empirical modelling-based method is proposed and implemented to identify the critical quality attributes and speed up the formulation optimization of a nanostructured lipid carrier. Design of experiments. A mixture design with five factors, each associated with the nanoparticle formulation, was used: cationic lipid concentration (X1), fusogenic lipid concentration (X2), PEG surfactant concentration (X3), lecithin concentration (X4) and the hydrodynamic diameter (X5). The first four factors are dependant of each other and obey to a constraint equation about the nanoparticle composition. The nanoparticle properties considered were polydispersity (Y1), stability (Y2) and transfection efficacies on the Hela (Y3) and PC3 cell lines (Y4). Rational methodology of nanoparticle design. The empirical modelling methodology was split up into three consecutive steps. In the first part, we show that only the hydrodynamic diameter of the nanoparticle has a significant influence on the polydispersity response and we deduce its design space. In the second step, an empirical model of the nanoparticle stability is obtained, which allows us to identify two main contributors: the nanoparticle size and the concentration of surfactant PEG. A stability region in the (X3, X5) space is derived from this model. In the final part of this study, two response surface models are computed from the experimental data and are used to determine the optimal values of three formulation factors of the nanostructured lipid carrier.Results. Two different formulations have been synthetized and their in vitro properties have corroborated the predicted values provided by the previous models. This study confirms that a rational and rigorous engineering of nanoparticles is possible, owing to statistical design of experiments and empirical modelling techniques. Such approaches can drastically reduce the preclinical development duration of nanotechnologies in medical applications

The development of high quality seals for silicon patch-clamp chips.

International audiencePlanar patch-clamp is a two-dimensional variation of traditional patch-clamp. By contrast to classical glass micropipette, the seal quality of silicon patch-clamp chips (i.e. seal resistance and seal success rate) have remained poor due to the planar geometry and the nature of the substrate and thus partially obliterate the advantages related to planar patch-clamp. The characterization of physical parameters involved in seal formation is thus of major interest. In this paper, we demonstrate that the physical characterization of surfaces by a set of techniques (Atomic Force Microscopy (AFM), Scanning Electron Microscopy (SEM), X-ray Photoelectron Spectroscopy (XPS), surface energy (polar and dispersive contributions), drop angles, impedance spectroscopy, combined with a statistical design of experiments (DOE)) allowed us discriminating chips that provide relevant performances for planar patch-clamp analysis. Analyses of seal quality demonstrate that dispersive interactions and micropore size are the most crucial physical parameters of chip surfaces, by contrast to surface roughness and dielectric membrane thickness. This multi-scale study combined with electrophysiological validation of chips on a diverse set of cell-types expressing various ion channels (IRK1, hERG and hNa(v)1.5 channels) unveiled a suitable patch-clamp chip candidate. This original approach may inspire novel strategies for selecting appropriate surface parameters dedicated to biochips

Discussion du huitième projet pour le remplacement de la gabelle portant sur le paiements des débets et le rapprochement de l'arriéré, lors de la séance du 22 mars 1790

Crécy Ferdinand Denis, comte de, Dupont de Nemours Pierre Samuel, Devillas Jean-Baptiste, Buzot François-Nicolas. Discussion du huitième projet pour le remplacement de la gabelle portant sur le paiements des débets et le rapprochement de l'arriéré, lors de la séance du 22 mars 1790. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XII - Du 2 mars au 14 avril 1790. Paris : Librairie Administrative P. Dupont, 1881. p. 297

Discussion du huitième projet pour le remplacement de la gabelle portant sur le paiements des débets et le rapprochement de l'arriéré, lors de la séance du 22 mars 1790

Crécy Ferdinand-Denis, comte de, Dupont de Nemours Pierre Samuel, Devillas Jean-Baptiste, Buzot François-Nicolas. Discussion du huitième projet pour le remplacement de la gabelle portant sur le paiements des débets et le rapprochement de l'arriéré, lors de la séance du 22 mars 1790. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) sous la direction de Jérôme Mavidal et Emile Laurent. Tome XII - Du 2 mars au 14 avril 1790. Paris : Librairie Administrative P. Dupont, 1881. p. 297

Thermal Effects of Silicon Thickness in 3-D ICs: Measurements and Simulations

International audienceThis paper presents the impact of silicon thickness on the temperature and the thermal resistance in a 3-D stack integrated circuits. This paper uses electrical measurements thanks to embedded in situ sensors and numerical design of experiments (DOEs). The primary objective is to provide the sensitivity of modeling factors by analyzing the variance on the basis of Sobol indices through DOE. The results show a strong influence of the silicon thickness and of the position of the hot spots with respect to the sensors on the maximum temperature and the thermal resistance of the total stack. The boundary conditions, in particular the heat-transfer coefficient of the bottom surface of the wafer, are also identified as significant factors. Therefore, simulation results and measurement approaches are compared. The measurements are carried out with embedded in situ sensors in the bottom die at wafer level. The results show a significant increase in temperature while decreasing the silicon thickness

Discussion sur le projet de décret de M. le baron de Menou sur la constitution militaire, lors de la séance du 28 février 1790

Boussay Jacques-François de Menou, baron de, abbé Maury, Lameth Alexandre Théodore Victor, chevalier de, Dubois de Crancé Edmond Louis, Tracy Antoine Louis Claude Destutt, comte de, Sérent Armand Sigismond, comte de, Virieu François Henri, comte de, Le Chapelier Isaac René Guy, Montmorency-Laval Mathieu Jean Félicité, duc de, Montlosier François Dominique de Reynaud, comte de, Noailles Louis Marie Marc Antoine, vicomte de, Liancourt François Alexandre Frédéric, duc de La Rochefoucauld, La Rochefoucauld-Liancourt François Alexandre, duc de, Lameth Charles Malo, comte de, La Galissonnière Augustin Félix Barrin, comte de, Montesquiou Fezensac François Xavier, abbé et duc de, Barnave Antoine, Ruffo de Bonneval Sixte Louis Constant, Target Guy Jean-Baptiste, Bouthillier-Chavigny de Beaujeu Charle-Léon, marquis de, Crécy Ferdinand Denis, comte de, Toulongeon Emmanuel François, vicomte de. Discussion sur le projet de décret de M. le baron de Menou sur la constitution militaire, lors de la séance du 28 février 1790. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XI - Du 24 décembre 1789 au 1er mars 1790. Paris : Librairie Administrative P. Dupont, 1880. pp. 738-741

Discussion sur le projet de décret de M. le baron de Menou sur la constitution militaire, lors de la séance du 28 février 1790

Menou Jacques François de Boussay, baron de, abbé Maury, Lameth Alexandre Théodore Victor, chevalier de, Dubois de Crancé Edmond Louis, Tracy Antoine-Louis-Claude Destutt, comte de, Sérent Armand Sigismond, comte de, Virieu François-Henri, comte de, Le Chapelier Isaac-René-Guy, Montmorency-Laval Mathieu-Jean, comte de, Montlosier François Dominique de Reynaud de, Noailles Louis Marie Marc Antoine, vicomte de, Liancourt François Alexandre Frédéric, duc de La Rochefoucauld, La Rochefoucauld-Liancourt François Alexandre, duc de, Lameth Charles Malo, comte de, Barrin de la Galissonnière Augustin-Félix, comte, Montesquiou Fezensac François Xavier, abbé et duc de, Barnave Antoine, Bonneval Sixte-Louis de, Target Guy-Jean-Baptiste, Bouthillier de Beaujeu Charles-Léon, marquis de, Crécy Ferdinand-Denis, comte de, Toulongeon Emmanuel-François, vicomte de. Discussion sur le projet de décret de M. le baron de Menou sur la constitution militaire, lors de la séance du 28 février 1790. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XI - Du 24 décembre 1789 au 1er mars 1790. Paris : Librairie Administrative P. Dupont, 1880. pp. 738-741

Reconstruction of the evolution of translation-related gene set in mollicutes.

<p>Ancestral gene content at each node of the phylogenetic tree was inferred using the posterior probabilities calculated from the birth-and death model implemented in the COUNT program. Genes gained and lost are framed and highlighted with colors corresponding to gene categories, respectively. Very similar results were obtained using Wagner parsimony method with a gain penalty of 4. The phylogenetic tree was inferred using the maximum likelihood method from the concatenated multiple alignments of 79 proteins encoded by genes present at one copy in each genome. The phylogenetic groups are indicated: S for Spiroplasma, H for Hominis, P for Pneumoniae and AAP. The non-cultivated <i>Mollicutes</i> are framed by a red dashed line.</p

Total number of proteins involved in translation for each <i>Mollicutes</i> species.

<p>The number of proteins involved in translation for each <i>Mollicutes</i> species was tabulated in reference to the number found for the two model bacteria <i>E. coli</i> (Ec) and <i>B. subtilis</i> (Bs). The numbering of species is the same as in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004363#pgen-1004363-g001" target="_blank">Figure 1</a>. The data corresponding to non-cultivated <i>Mollicutes</i> are framed with a red dashed line as in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004363#pgen-1004363-g001" target="_blank">Figure 1</a>. The horizontal blue dashed line indicates 104, which correspond to the core of translation proteins shared by all <i>Mollicutes.</i></p