A New Strategy to Preserve and Assess Oxygen Consumption in Murine Tissues

Mitochondrial dysfunctions are implicated in several pathologies, such as metabolic, cardiovascular, respiratory, and neurological diseases, as well as in cancer and aging. These metabolic alterations are usually assessed in human or murine samples by mitochondrial respiratory chain enzymatic assays, by measuring the oxygen consumption of intact mitochondria isolated from tissues, or from cells obtained after physical or enzymatic disruption of the tissues. However, these methodologies do not maintain tissue multicellular organization and cell-cell interactions, known to influence mitochondrial metabolism. Here, we develop an optimal model to measure mitochondrial oxygen consumption in heart and lung tissue samples using the XF24 Extracellular Flux Analyzer (Seahorse) and discuss the advantages and limitations of this technological approach. Our results demonstrate that tissue organization, as well as mitochondrial ultrastructure and respiratory function, are preserved in heart and lung tissues freshly processed or after overnight conservation at 4 °C. Using this method, we confirmed the repeatedly reported obesity-associated mitochondrial dysfunction in the heart and extended it to the lungs. We set up and validated a new strategy to optimally assess mitochondrial function in murine tissues. As such, this method is of great potential interest for monitoring mitochondrial function in cohort samples.     

New huprine derivatives functionalized at position 9 as highly potent acetylcholinesterase inhibitors

A series of 24 huprine derivatives diversely functionalized at position 9 have been synthesized and evaluated for their inhibitory activity against human recombinant acetylcholinesterase (AChE). These derivatives were prepared in one to five steps from huprine 1 bearing an ester function at position 9. Ten analogues ( 1 , 2 , 6 – 9 , 13 – 15 , and 23 ) are active in the low nanomolar range (IC₅₀ <5 nM ), very close to the parent compound huprine X. Compounds 2 , 6 , and 7 show a very good selectivity for AChE, with AChE inhibitory activities 700–1160‐fold higher than those for butyrylcholinesterase (BChE). The inhibitory potency of these compounds decreases with the steric bulk of the substituents at position 9. According to docking simulations, small substituents fit into the acyl‐binding pocket, whereas the larger ones stick out of the active site gorge of AChE. Determination of the kinetic parameters of three of the most potent huprines ( 2 , 6 , and 7 ) showed that most of the difference in K_D is accounted by a decrease in k_on, which is correlated to the increase of the substituent size. A first in vivo evaluation has been performed in mice for the most active compound 2 (IC₅₀=1.1 nM ) and showed a rather weak toxicity (LD₅₀=40 mg kg^?1) and an ability to cross the blood–brain barrier with doses above 15 mg kg^?1.     

Statistical prediction of fracture parameters of concrete and implications for choice of testing standard

This article shows how the fracture energy of concrete, as well as other fracture parameters such as the effective length of the fracture process zone, critical crack-tip opening displacement and the fracture toughness, can be approximately predicted from the standard compression strength, maximum aggregate size, water-cement ratio, and aggregate type (river or crushed). A database, consisting of 238 test data, is extracted from the literature and tabulated, and approximate mean prediction formulae calibrated by this very large data set are developed. A distinction is made between (a) the fracture energy, G_f, corresponding to the area under the initial tangent of the softening stress-separation curve of cohesive crack model, which governs the maximum loads of structures and is obtained by the size effect method (SEM) or related methods (Jenq-Shah two-parameter method and Karihaloo's effective crack model, ECM) and (b) the fracture energy, G_F, corresponding to the area under the complete stress-separation curve, which governs large postpeak deflections of structures and is obtained by the work-of-fracture method (WFM) proposed for concrete by Hillerborg. The coefficients of variation of the errors in the prediction formulae compared to the test data are calculated; they are 17.8% for G_f and 29.9% for G_F, the latter being 1.67 times higher than the former. Although the errors of the prediction formulae taking into account the differences among different concretes doubtless contribute significantly to the high values of these coefficients of variation, there is no reason for a bias of the statistics in favor of G_f or G_F. Thus, the statistics indicate that the fracture energy based on the measurements in the maximum load region is much less uncertain than that based on the measurement of the tail of the postpeak load-deflection curve. While both G_f and G_F are needed for accurate structural analysis, it follows that if the testing standard should measure, for the sake of simplicity, only one of these two fracture energies, then G_f is preferable.     

Carbon–polymer composites with extreme electrical conductivity

The aim of this study was to develop Carbon–polymer composites with extreme electrical conductivity (100 S/cm) combined with good flexural strength. Despite the many optimization methods described in the literature, no comprehensive optimization procedure was to be found because the formulation did not control by itself the final properties. This study showed the major influence of the processing conditions with these peculiar materials. A detailed study of the influence of the processing conditions on the microstructural and macroscopic properties was performed. We, thereby, proposed a comprehensive way to optimize the properties of the final product. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42274.     

Intermolecular versus Intramolecular Palladium‐Catalyzed Direct Arylations between 1‐(2‐Bromobenzyl)imidazoles and Aryl Bromides

Herein, we report on the sequential palladium‐catalyzed intermolecular followed by intramolecular direct arylations of 1‐(2‐bromobenzyl)imidazoles. We found that, in the presence of 1 mol% palladium acetate and potassium acetate as base, the intermolecular reaction between 1‐(2‐bromobenzyl)imidazole derivatives and electron‐deficient aryl bromides proceeded faster than the intramolecular reaction, allowing us to prepare medium‐size polycyclic imidazoles after a second Pd‐catalyzed intramolecular arylation. These iterative direct arylations allowed the synthesis of fused nitrogen‐containing heterocycles with a 5‐ or 7‐membered‐ring in only two steps. Some reactions have also been performed as a one‐pot procedure using 2 mol% of palladium acetate in the presence of a larger amount of base (3 equiv.).

     

Palladium‐Catalysed Regioselective Sequential C‐5 and C‐2 Direct Arylations of 3‐Acetylpyrroles with Aryl Bromides

The PdCl(C₃H₅)(dppb)/KOAc system was found to be effective for the direct regioselective C‐5 arylation of 3‐acetylpyrroles with ortho‐substituted aryl bromides. This procedure has been found to be tolerant to a variety of functional groups at C‐2 of the aryl bromide such as methyl, formyl, nitrile, nitro, hydroxymethyl, chloro, fluoro or trifluoromethyl. The sequential direct C‐5 arylation followed by C‐2 arylation of such 3‐substituted pyrroles allows the synthesis of 2,5‐diaryl‐3‐acetylpyrroles in high yields.