Nanonization of megestrol acetate by laser fragmentation in aqueous milieu

Faculté de PharmacieNanonization is a simple and effective method to improve dissolution rate and oral bioavailability of drugs with poor water solubility. There is growing interest to downscale the nanocrystal production to enable early preclinical evaluation of new drug candidates when compound availability is scarce. The purpose of the present study was to investigate laser fragmentation to form nanosuspensions in aqueous solution of the insoluble model drug megestrol acetate (MA) using very little quantities of the drug. Laser fragmentation was obtained by focusing a femtosecond (fs) or nanosecond (ns) laser radiation on a magnetically stirred MA suspension in water or aqueous solution of a stabilizing agent. The size distribution and physicochemical properties of the drug nanoparticles were characterized, and the in vitro dissolution and in vivo oral pharmacokinetics of a laser fragmented formulation were evaluated. A MA nanosuspension was also prepared by media milling for comparison purpose. For both laser radiations, smaller particles were obtained as the laser power was increased, but at a cost of higher degradation. Significant nanonization was achieved after a 30-min fs laser treatment at 250 mW and a 1-h ns laser treatment at 2500 mW. The degradation induced by the laser process of the drug was primarily oxidative in nature. The crystal phase of the drug was maintained, although partial loss of crystallinity was observed. The in vitro dissolution rate and in vivo bioavailability of the laser fragmented formulation were similar to those obtained with the nanosuspension prepared by media milling, and significantly improved compared to the coarse drug powder. It follows that this laser nanonization method has potential to be used for the preclinical evaluation of new drug candidates.IRSC - CRNS

Sculpting the disk around T Cha: an interferometric view

(Abridged) Circumstellar disks are believed to be the birthplace of planets and are expected to dissipate on a timescale of a few Myr. The processes responsible for the removal of the dust and gas will strongly modify the radial distribution of the dust and consequently the SED. In particular, a young planet will open a gap, resulting in an inner disk dominating the near-IR emission and an outer disk emitting mostly in the far-IR. We analyze a full set of data (including VLTI/Pionier, VLTI/Midi, and VLT/NaCo/Sam) to constrain the structure of the transition disk around TCha. We used the Mcfost radiative transfer code to simultaneously model the SED and the interferometric observations. We find that the dust responsible for the emission in excess in the near-IR must have a narrow temperature distribution with a maximum close to the silicate sublimation temperature. This translates into a narrow inner dusty disk (0.07-0.11 AU). We find that the outer disk starts at about 12 AU and is partially resolved by the Pionier, Sam, and Midi instruments. We show that the Sam closure phases, interpreted as the signature of a candidate companion, may actually trace the asymmetry generated by forward scattering by dust grains in the upper layers of the outer disk. These observations help constrain the inclination and position angle of the outer disk. The presence of matter inside the gap is difficult to assess with present-day observations. Our model suggests the outer disk contaminates the interferometric signature of any potential companion that could be responsible for the gap opening, and such a companion still has to be unambiguously detected. We stress the difficulty to observe point sources in bright massive disks, and the consequent need to account for disk asymmetries (e.g. anisotropic scattering) in model-dependent search for companions.Comment: Removed the word "first" in the abstract of the paper: "obtained with the first 4-telescope combiner (VLTI/Pionier)

Compositional meta-analysis of the nutrient profile of potato cultivars

While several potato (Solanum tuberosum L.) cultivars of different maturity groups (e.g. early, mid-season, late) are being selected each year as a result of successful breeding for disease resistance and market requirements, their nutrient management is based on past experience and few experiments. Nutrient profiles from leaf analysis can guide fertilization and liming programs of potato cultivars. Since leaf analytical data are strictly positive and compositional, nutrient profiling using raw data is spoiled by non normal distribution, resonance and spurious correlations. Compositional data analysis provides log ratio transformations that avoid such problems. Our objective was to derive nutrient profiles from tissue analysis using isometric log ratio (ilr) coordinates and meta-analysis for classification of cultivars into uniform nutrient management groups. The dataset comprised 678 potato fields producing more than 28.5 Mg marketable tuber ha-1, i.e. above Quebec average, of the early-, mid-, and late-season cultivars. The first mature leaf from top was sampled at the beginning of flowering for N, P, K, Ca, and Mg analysis. Anionic (N, P) and cationic (K, Ca, Mg) nutrients were arranged into binary partitions representing positive and negative nutrient interactions. Groups of cultivars were compared to ‘Superior’ using ilr mean and standard deviation in the mixed model of meta-analysis. We minimized the within-group heterogeneity (I2 value) by allocating cultivars iteratively between ilr groups. We derived group-specific ilr norms to compute the Aitchison distance. The critical value for nutrient imbalance was 0.38. To guide correcting nutrient deficiencies with appropriate nutrient management techniques, nutrient composition can be altered numerically by a perturbation vector on nutrients that lead to the largest and most negative ilr differences from ilr norms until the Aitchison distance falls below critical value

The Science Case for the Planet Formation Imager (PFI)

Among the most fascinating and hotly-debated areas in contemporary astrophysics are the means by which planetary systems are assembled from the large rotating disks of gas and dust which attend a stellar birth. Although important work has already been, and is still being done both in theory and observation, a full understanding of the physics of planet formation can only be achieved by opening observational windows able to directly witness the process in action. The key requirement is then to probe planet-forming systems at the natural spatial scales over which material is being assembled. By definition, this is the so-called Hill Sphere which delineates the region of influence of a gravitating body within its surrounding environment. The Planet Formation Imager project (PFI) has crystallized around this challenging goal: to deliver resolved images of Hill-Sphere-sized structures within candidate planet-hosting disks in the nearest star-forming regions. In this contribution we outline the primary science case of PFI. For this purpose, we briefly review our knowledge about the planet-formation process and discuss recent observational results that have been obtained on the class of transition disks. Spectro-photometric and multi-wavelength interferometric studies of these systems revealed the presence of extended gaps and complex density inhomogeneities that might be triggered by orbiting planets. We present detailed 3-D radiation-hydrodynamic simulations of disks with single and multiple embedded planets, from which we compute synthetic images at near-infrared, mid-infrared, far-infrared, and sub-millimeter wavelengths, enabling a direct comparison of the signatures that are detectable with PFI and complementary facilities such as ALMA. From these simulations, we derive some preliminary specifications that will guide the array design and technology roadmap of the facility.Comment: SPIE Astronomical Telescopes and Instrumentation conference, June 2014, Paper ID 9146-120, 13 pages, 3 Figure

Methicillin-Resistant Staphylococcus capitis with Reduced Vancomycin Susceptibility Causes Late-Onset Sepsis in Intensive Care Neonates

isolated from the blood of NICU infants and compared these data to adult patients. element, and constantly showed either vancomycin resistance (37.5%) or heteroresistance (62.5%). Conversely, the isolates that were collected outside of the NICU were genetically diverse and displayed much lower rates of vancomycin resistance and heteroresistance (7.7% and 23.1%, respectively). strains has spread into several French NICUs. These isolates exhibit reduced susceptibility to vancomycin, which is the most widely used antimicrobial agent in the NICU setting

Generation of redesigned homing endonucleases comprising DNA-binding domains derived from two different scaffolds

Homing endonucleases have become valuable tools for genome engineering. Their sequence recognition repertoires can be expanded by modifying their specificities or by creating chimeric proteins through domain swapping between two subdomains of different homing endonucleases. Here, we show that these two approaches can be combined to create engineered meganucleases with new specificities. We demonstrate the modularity of the chimeric DmoCre meganuclease previously described, by successfully assembling mutants with locally altered specificities affecting both I-DmoI and I-CreI subdomains in order to create active meganucleases with altered specificities. Moreover these new engineered DmoCre variants appear highly specific and present a low toxicity level, similar to I-SceI, and can induce efficient homologous recombination events in mammalian cells. The DmoCre based meganucleases can therefore offer new possibilities for various genome engineering applications

A combinatorial approach to create artificial homing endonucleases cleaving chosen sequences

Meganucleases, or homing endonucleases (HEs) are sequence-specific endonucleases with large (>14 bp) cleavage sites that can be used to induce efficient homologous gene targeting in cultured cells and plants. These findings have opened novel perspectives for genome engineering in a wide range of fields, including gene therapy. However, the number of identified HEs does not match the diversity of genomic sequences, and the probability of finding a homing site in a chosen gene is extremely low. Therefore, the design of artificial endonucleases with chosen specificities is under intense investigation. In this report, we describe the first artificial HEs whose specificity has been entirely redesigned to cleave a naturally occurring sequence. First, hundreds of novel endonucleases with locally altered substrate specificity were derived from I-CreI, a Chlamydomonas reinhardti protein belonging to the LAGLIDADG family of HEs. Second, distinct DNA-binding subdomains were identified within the protein. Third, we used these findings to assemble four sets of mutations into heterodimeric endonucleases cleaving a model target or a sequence from the human RAG1 gene. These results demonstrate that the plasticity of LAGLIDADG endonucleases allows extensive engineering, and provide a general method to create novel endonucleases with tailored specificities