Rational design, synthesis, and evaluation of nanomolar type II dehydroquinase inhibitors

The in silico design, synthesis, and biological evaluation of ten potent type II dehydroquinase inhibitors are described. These compounds contain an anhydroquinate core, incorporated as a mimic of the enolate reaction intermediate. This substructure is attached by a variety of linking units to a terminal phenyl group that binds in an adjacent pocket. Inhibitors were synthesised from (-)-quinic acid using palladium-catalysed Stille and carboamidation chemistry. Several inhibitors exhibited nanomolar inhibition constants against type II dehydroquinases from Streptomyces coelicolor and Mycobacterium tuberculosis. These are among the most potent inhibitors of these enzymes reported to date.     

Tracking a new cell-penetrating (W/R) nonapeptide, through an enzyme-stable mass spectrometry reporter tag

We have designed a mass stable reporter (msr) tag with m/z over 500, trifluoroacetyl(alpha,alpha-diethyl)Gly-Lys(Nepsilonbiotin)-(D)Lys-Cys, for the quantification of the uptake and study of the degradation processes of cell-penetrating peptides (CPP), by matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. This tag was found stable in cell lysis conditions. Using a quantitative MALDI-TOF mass spectrometry analysis based method, an accurate tracking of a new CPP and of its degradation products could be done. (1) The new msr(W/R) nonapeptide (H-RRWWRRWRR-NH2) enters chinese hamster ovary (CHO) K1 cells with a kinetic reaching a steady state after 30-60 min of incubation. This plateau was stable for 4 h and decreased slowly afterward. (2) The peptide msr(W/R) nonapeptide was not cytotoxic over 48 h incubation with CHO cells. (3) After 1 h incubation, the msr(W/R) nonapeptide accumulated with a 3-fold higher concentration than the extracellularly added concentration (7.5 microM). (4) The intracellular quantification was accurate with less than 3% of the quantified peptide being potentially membrane-bound. (5) There was no leakage of the full-length CPP outside the cells. And, finally, (6) analysis of the degradation process of this new CPP suggests that the peptide did not traffick to lysosomes.     

Size-dependent properties of magnetic iron oxide nanocrystals

The fine control of iron oxide nanocrystal sizes within the nanometre scale (diameters range from 2.5 to 14 nm) allows us to investigate accurately the size-dependence of their structural and magnetic properties. A study of the growth conditions of these nanocrystals obtained by thermal decomposition of an iron oleate precursor in high-boiling point solvents has been carried out. Both the type of solvent used and the ligand/precursor ratio have been systematically varied, and were found to be the key parameters to control the growth process. The lattice parameters of all the nanocrystals deduced from X-ray diffraction measurements are consistent with a structure of the type Fe3-xO4, i.e. intermediate between magnetite and maghemite, which evolves toward the maghemite structure for the smallest sizes (x=1/3). The evolution of the magnetic behavior with nanoparticle sizes emphasizes clearly the influence of the surface, especially on the saturation magnetization Ms and the magneto-crystalline anisotropy K. Dipolar interactions and thermal dependence have been also taken into account in the study on the nanoscale size-effect of magnetic properties.     

Fish Oil and Microalga Omega-3 as Dietary Supplements: A Comparative Study on Cardiovascular Risk Factors in High-Fat Fed Rats

Dietary supplementation with marine omega‐3 polyunsaturated fatty acids (n‐3 PUFA) can have beneficial effects on a number of risk factors for cardiovascular disease (CVD). We compared the effects of two n‐3 PUFA rich food supplements (freeze‐dried Odontella aurita and fish oil) on risk factors for CVD. Male rats were randomly divided into four groups of six animals each and fed with the following diets: control group (C) received a standard diet containing 7 % lipids; second group (HF high fat) was fed with a high‐fat diet containing 40 % lipids; third group (HFFO high fat+fish oil) was fed with the high‐fat diet supplemented with 0.5 % fish oil; and fourth group (HFOA high fat+O. aurita) received the high‐fat diet supplemented with 12 % of freeze‐dried O. aurita. After 8 weeks rats fed with the high‐fat diet supplemented with O. aurita displayed a significantly lower bodyweight than those in the other groups. Both the microalga and the fish oil significantly reduced insulinemia and serum lipid levels. O. aurita was more effective than the fish oil in reducing hepatic triacyglycerol levels and in preventing high‐fat diet‐induced steatosis. O. aurita and fish oil also reduced platelet aggregation and oxidative status induced by high fat intake. After an OA supplementation, the adipocytes in the HFOA group were smaller than those in the HF group. Freeze‐dried O. aurita showed similar or even greater biological effects than the fish oil. This could be explained by a potential effect of the n‐3 PUFA but also other bioactive compounds of the microalgae.     

Effect of Internal Current Flow During the Sintering of Zirconium Diboride by Field Assisted Sintering Technology

Effect of electric current on sintering behavior and microstructure evolution of zirconium diboride (ZrB₂) was investigated using three different configurations of Field Assisted Sintering Technology/Spark Plasma Sintering. The current flow through the ZrB₂ compact was controlled by modifying the interface between the graphite punches and the electrical conductive powder. Boron nitride discs, graphite foils or direct contact with the graphite punches were the three different interfaces used in order to deflect, conduct or promote, respectively, the current during the sintering process of the electrically conductive ZrB₂ ceramics. The current flow during the sintering process triggered the elimination/reduction in B₂O₃, leading to faster diffusion rates at high temperatures and limiting the formation of B₄C secondary phase. This allows to control the final density, grain size (from 19.6 to 43.2 μm) and secondary phase formation (from 5.95 to 11.61 vol%) as well as the electrical resistivity (from 7.7 to 9.4 μΩ·cm) of the specimens.     

Site‐Specific Labeling of MicroRNA Precursors: A Structure–Activity Relationship Study

Functionalized oligoribonucleotides are essential tools in RNA chemical biology. Various synthetic routes have been developed over recent years to conjugate functional groups to oligoribonucleotides. However, the presence of the functional group on the oligoribonucleotide backbone can lead to partial or total loss of biological function. The limited knowledge concerning the positioning of functional groups therefore represents a hurdle for the development of oligoribonucleotide chemical tools. Here we describe a systematic investigation of site‐specific labeling of pre‐miRNAs to identify positions for the incorporation of functional groups, in order not to hinder their processing into active mature miRNAs.     

Oxygen atom density in capacitively coupled RF oxygen plasma

The density of neutral oxygen atoms was determined in a plasma reactor for surface functionalization of polymer materials. Plasma was created in a stainless steel chamber by capacitively coupled RF generator at 13.56 MHz and adjustable forward power up to 100 W. Measurements were performed with a classical nickel catalytic probe. Systematic measurements were performed at a constant pumping speed, different flow rates from 15 to 100 sccm corresponding to pressures between 30 and 110 Pa, different powers between 40 and 100 W and different probe positions in the discharge chamber. The results showed that the O atom density did not depend much on probe position as long as it was between the powered electrode and grounded housing facing the electrode. The O density depended rather linearly with power at fixed pressure. At low power, the O density did not depend much on pressure, but at high power, it was increasing with increasing pressure. The O density was of the order of 10¹⁹ m⁻³ and increased slightly over 10²⁰ m⁻³ at the highest power and pressure. The results were explained by gas phase and surface reactions.     

Two step sintering of cubic yttria stabilized zirconia using Field Assisted Sintering Technique/Spark Plasma Sintering

Starting from homogenous highly packed green bodies, two sintering methods have been combined in order to limit grain growth during the densification of fully stabilized zirconia. Densification behavior and microstructures in relation with green body shaping have been investigated. It could be shown that two step sintering schedules carried out by FAST/SPS are very effective in reducing both processing time and grain growth.     

Experimental study of the stacking sequence effect on polymer/composite multi-layers submitted to thermomechanical cyclic loadings

Fast filling of hydrogen pressure tank leads to thermomechanical stresses in vessel structure. In this paper, the aim is to study the thermomechanical behaviour of the material used in the vessel structure. Flat coupons made of the same constituents as the hydrogen tank materials and with different stacking sequences have been tested under quasi-static tensile tests and fatigue. Three types of fatigue tests have been performed in order to understand damage mechanisms due to interactions between thermal and mechanical stresses: thermomechanical fatigue, 1 Hz mechanical fatigue and mechanical fatigue with a constant stress level stage. Damage development has been followed by acoustic emission and microscopic observations. Results show that, whatever the applied loading, there is a significant influence of the stacking sequence of the composite part. Moreover, the comparison of the material response to the different types of fatigue has revealed the harmful role of coupled temperature/mechanical cyclic stresses.