Benzophenone derivatives : From natural source to synthetic one. Synthesis and anti-AGEs activity

International audienc

Volatility forecasting for risk management

Recent research has suggested that forecast evaluation on the basis of standard statistical loss functions could prefer models which are sub-optimal when used in a practical setting. This paper explores a number of statistical models for predicting the daily volatility of several key UK financial time series. The out-of-sample forecasting performance of various linear and GARCH-type models of volatility are compared with forecasts derived from a multivariate approach. The forecasts are evaluated using traditional metrics, such as mean squared error, and also by how adequately they perform in a modern risk management setting. We find that the relative accuracies of the various methods are highly sensitive to the measure used to evaluate them. Such results have implications for any econometric time series forecasts which are subsequently employed in financial decisionmaking

An analysis of the relevance of off-balance sheet items in explaining productivity change in European banking

The 1990s have witnessed a significant growth in bank income generated through non-traditional activities, especially for large EU universal banking institutions. Using the non-parametric Malmquist methodology this study analyses the impact of the inclusion of off-balance sheet (OBS) business in the definition of banks' output when estimating total factor productivity change indexes. Whereas the results reinforce the prevalent view in the recent literature, indicating that the exclusion of non-traditional activities leads to a misspecification of banks' output, the impact of the inclusion of these activities varies. Overall, the inclusion of OBS items results in an increase in estimated productivity levels for all countries under study. However, the impact seems to be the biggest on technological change rather than efficiency change. © 2005 Taylor & Francis

Prediction of photoperiodic regulators from quantitative gene circuit models

Photoperiod sensors allow physiological adaptation to the changing seasons. The external coincidence hypothesis postulates that a light-responsive regulator is modulated by a circadian rhythm. Sufficient data are available to test this quantitatively in plants, though not yet in animals. In Arabidopsis, the clock-regulated genes CONSTANS (CO) and FLAVIN, KELCH, F-BOX (FKF1) and their lightsensitive proteins are thought to form an external coincidence sensor. We use 40 timeseries of molecular data to model the integration of light and timing information by CO, its target gene FLOWERING LOCUS T (FT), and the circadian clock. Among other predictions, the models show that FKF1 activates FT. We demonstrate experimentally that this effect is independent of the known activation of CO by FKF1, thus we locate a major, novel controller of photoperiodism. External coincidence is part of a complex photoperiod sensor: modelling makes this complexity explicit and may thus contribute to crop improvement

Réparation et rechargement par brasage-diffusion des alliages intermétalliques gamma TiAl au moyen de mélanges de poudres TiAl/TiCuNi : aspect microstructural et mécanique des assemblages

L'objectif de ce travail est de déterminer les paramètres opératoires du procédé de rechargement brasage-diffusion en vue de réparer ou de recharger des pièces massives en alliages intermétalliques gamma-TiAl. Ces alliages intermétalliques à base de TiAl présentent une faible densité et constituent une nouvelle classe de matériaux structuraux qui allie à température élevée résistance et ductilité. Le rechargement brasage-diffusion (RBD) est un procédé tout désigné pour la réparation de fissures, de criques, mais aussi pour la reconstruction de zones usées ou endommagées de ces aluminiures en cours de fonctionnement. La particularité du procédé RBD réside dans le fait que le métal d'apport est constitué d'un mélange de poudres préfritté ou non. Ce mélange de poudres est constitué d'une poudre appelée métal de base, de composition proche de celle de la pièce à réparer, soit Ti-48AL-2Cr-2Nb (%at.) et d'une autre poudre dénommée fondant ou métal d'apport, Ti-15Cu-15Ni (%mass.), dont la température de fusion est inférieure à la température de frittage ou de brasage.La première partie de la thèse a consisté dans l'étude de la réalisation de préformes frittées à partir demélanges de poudres TiAl/TiCuNi. Ces mélanges subissent un frittage-réactif en présence de phaseliquide et sont appelés "préfrittés" ou "préformes". Il s'agissait d'une part de comprendre et d'expliquer la formation de la microstructure de ces préformes en fonction de la température, du temps de palier isotherme et de la composition du mélange, et d'autre part de déterminer les paramètres opératoires quimènent à des mélanges homogènes et denses avec un retrait contrôlé.La deuxième partie de l'étude consistait à utiliser les préformes réalisées dans les conditions optimales,afin d'assembler par brasage-diffusion des pièces massives en TiAl. Les joints obtenus, formés d'une zonede réaction à l'interface avec le TiAl, ont fait l'objet de caractérisations microstructurales et mécaniques. Les résultats indiquent que les joints denses avec moins de 2% de porosité et dont la microstructure est homogène, atteignent des résistances en traction à 750°C de l'ordre de 80% de celle du TiAl massif

An extreme value theory approach to calculating minimum capital risk requirements

This paper investigates the frequency of extreme events for three LIFFE futures contracts for the calculation of minimum capital risk requirements (MCRRs). We propose a semiparametric approach where the tails are modelled by the Generalized Pareto Distribution and smaller risks are captured by the empirical distribution function. We compare the capital requirements form this approach with those calculated from the unconditional density and from a conditional density - a GARCH(1,1) model. Our primary finding is that both in-sample and for a hold-out sample, our extreme value approach yields superior results than either of the other two models which do not explicitly model the tails of the return distribution. Since the use of these internal models will be permitted under the EC-CAD II, they could be widely adopted in the near future for determining capital adequacies. Hence, close scrutiny of competing models is required to avoid a potentially costly misallocation capital resources while at the same time ensuring the safety of the financial system

Generation of a large volume of clinically relevant nanometre-sized ultra-high-molecular-weight polyethylene wear particles for cell culture studies.

It has recently been shown that the wear of ultra-high-molecular-weight polyethylene in hip and knee prostheses leads to the generation of nanometre-sized particles, in addition to micron-sized particles. The biological activity of nanometre-sized ultra-high-molecular-weight polyethylene wear particles has not, however, previously been studied due to difficulties in generating sufficient volumes of nanometre-sized ultra-high-molecular-weight polyethylene wear particles suitable for cell culture studies. In this study, wear simulation methods were investigated to generate a large volume of endotoxin-free clinically relevant nanometre-sized ultra-high-molecular-weight polyethylene wear particles. Both single-station and six-station multidirectional pin-on-plate wear simulators were used to generate ultra-high-molecular-weight polyethylene wear particles under sterile and non-sterile conditions. Microbial contamination and endotoxin levels in the lubricants were determined. The results indicated that microbial contamination was absent and endotoxin levels were low and within acceptable limits for the pharmaceutical industry, when a six-station pin-on-plate wear simulator was used to generate ultra-high-molecular-weight polyethylene wear particles in a non-sterile environment. Different pore-sized polycarbonate filters were investigated to isolate nanometre-sized ultra-high-molecular-weight polyethylene wear particles from the wear test lubricants. The use of the filter sequence of 10, 1, 0.1, 0.1 and 0.015 µm pore sizes allowed successful isolation of ultra-high-molecular-weight polyethylene wear particles with a size range of < 100 nm, which was suitable for cell culture studies

E. coli metabolic protein aldehydealcohol dehydrogenase-E binds to the ribosome: a unique moonlighting action revealed

It is becoming increasingly evident that a high degree of regulation is involved in the protein synthesis machinery entailing more interacting regulatory factors. A multitude of proteins have been identified recently which show regulatory function upon binding to the ribosome. Here, we identify tight association of a metabolic protein aldehyde-alcohol dehydrogenase E (AdhE) with the E. coli 70S ribosome isolated from cell extract under low salt wash conditions. Cryo-EM reconstruction of the ribosome sample allows us to localize its position on the head of the small subunit, near the mRNA entrance. Our study demonstrates substantial RNA unwinding activity of AdhE which can account for the ability of ribosome to translate through downstream of at least certain mRNA helices. Thus far, in E. coli, no ribosome-associated factor has been identified that shows downstream mRNA helicase activity. Additionally, the cryo-EM map reveals interaction of another extracellular protein, outer membrane protein C (OmpC), with the ribosome at the peripheral solvent side of the 50S subunit. Our result also provides important insight into plausible functional role of OmpC upon ribosome binding. Visualization of the ribosome purified directly from the cell lysate unveils for the first time interactions of additional regulatory proteins with the ribosom

Site-Specific Bioconjugation of a Murine Dihydrofolate Reductase Enzyme by Copper(I)-Catalyzed Azide-Alkyne Cycloaddition with Retained Activity

Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) is an efficient reaction linking an azido and an alkynyl group in the presence of copper catalyst. Incorporation of a non-natural amino acid (NAA) containing either an azido or an alkynyl group into a protein allows site-specific bioconjugation in mild conditions via CuAAC. Despite its great potential, bioconjugation of an enzyme has been hampered by several issues including low yield, poor solubility of a ligand, and protein structural/functional perturbation by CuAAC components. In the present study, we incorporated an alkyne-bearing NAA into an enzyme, murine dihydrofolate reductase (mDHFR), in high cell density cultivation of Escherichia coli, and performed CuAAC conjugation with fluorescent azide dyes to evaluate enzyme compatibility of various CuAAC conditions comprising combination of commercially available Cu(I)-chelating ligands and reductants. The condensed culture improves the protein yield 19-fold based on the same amount of non-natural amino acid, and the enzyme incubation under the optimized reaction condition did not lead to any activity loss but allowed a fast and high-yield bioconjugation. Using the established conditions, a biotin-azide spacer was efficiently conjugated to mDHFR with retained activity leading to the site-specific immobilization of the biotin-conjugated mDHFR on a streptavidin-coated plate. These results demonstrate that the combination of reactive non-natural amino acid incorporation and the optimized CuAAC can be used to bioconjugate enzymes with retained enzymatic activityope

Development of an artificial metalloenzyme from a nicotinamide-dependent enzymatic scaffold

Transfer hydrogenation reactions can yield a diverse range of chiral products to be used as such, or as building block for the synthesis of more complex molecules. Biocatalysts and artificial metalloenzymes (ArMs) are sustainable alternatives to chemical routes. ArMs are the result of the insertion of a metal ion or complex into a biological scaffold. Most of the ArMs use proteins as a biological hosts to provide a highly functionalised environment where reactants are brought together and activated in very specific ways. The incorporation of the metal catalyst provides a synthetic activity, not necessarily accessible by natural biocatalysts. Most of the ArMs are based on nonenzymatic scaffolds, containing large binding sites generally evolved to accommodate hydrophobic molecules. As such, their design requires efforts to improve the specific chemical reaction targeted. Here we present the development of new ArMs that could be used as a biocatalytic platform for transfer hydrogenation reactions. In previous work, our group generated an artificial mutant of Thermoanaerobacter brockii alcohol dehydrogenase (TbADH) by bioconjugation of a piano-stool rhodium catalyst to cysteine 37 in the active site. In the present work, a computational design approach was used to investigate more suitable positions for the catalyst to be anchored within the catalytic site of the enzyme, using a covalent anchoring strategy. Four positions were found where thiol sidechains would be more accessible than the reported labelled position 37. Single cysteine mutations were prepared at those positions and compared with two other protein variants, where all but one native cysteine residues in the binding pocket were removed. After optimisation of the bioconjugation process with three different ligands bearing a bidentate N-N motif, two enzymatic scaffolds were identified and used for the development of ArMs, using covalent anchoring of Rh and Ir complexes. Five different ArMs were subsequently created and their activity towards the regeneration of nicotinamide cofactors and derivatives was assessed. One mutant bearing a rhodium complex bound at position 243 showed catalytic activity for the reduction of nicotinamides, with a discrimination between the natural cofactors and their mimics. This ArM could potentially be used in a cofactor recycling system compatible with both nicotinamide cofactors. Whilst some of the ArMs suffered from the dissociation of the Cp*Rh functionality from its complex, resulting in unspecific binding and catalysis, one of the constructs, possessing a Cp*Rh(bipyridine) catalyst, showed very promising results for the recycling of NADPH and of benzyl nicotinamide. Besides a covalent anchoring approach, which requires tedious work for the development of ArMs, a supramolecular approach was also investigated, by taking advantage of one feature of ADH, their nicotinamide binding pocket. Benzyl nicotinamide derivatives were synthesised and their capacity to interact with two ADHs, in a similar fashion to their natural cofactor, was assessed with the aim of using these as anchors for synthetic metal catalysts into ADHs. The lack of interactions observed with both enzymes, TbADH and horse liver alcohol dehydrogenase (HLADH), suggested that more hydrophilic structures would be required to yield a suitable supramolecular anchor. To provide initial data for further investigation on the development of ArMs by supramolecular anchoring with ADH enzymatic scaffolds, two separate studies were performed in silico. The first one focused on the anchor structure and its capability to mimic interactions within the cofactor binding site and led to the design of three potential supramolecular anchors where the benzyl substituent was replaced with more hydrophilic functionalities. The second study focused on finding enzymatic scaffolds capable of accommodating the hydrophobic benzyl nicotinamide derivatives. This study led to three potential ADH candidates. To assess the validity of the computational models from the 2 studies, experimental work will be required