Ultrashort pulse laser cutting of glass by controlled fracture propagation

International audienceLaser induced controlled fracture propagation has great potential in cutting brittle materials such as glass or sapphire. In this paper we demonstrate that the use of ultrashort pulse laser sources may be advantageous since it allows to overcome several restrictions of the convenient method

Analysis of three-dimensional transonic compressors

A method for computing the three-dimensional transonic flow around the blades of a compressor or of a propeller is given. The method is based on the use of the velocity potential, on the hypothesis that the flow is inviscid, irrotational and isentropic. The equation of the potential is solved in a transformed space such that the surface of the blade is mapped into a plane where the periodicity is implicit. This equation is in a nonconservative form and is solved with the help of a finite difference method using artificial time. A computer code is provided and some sample results are given in order to demonstrate the influence of three-dimensional effects and the blade's rotation

Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules:Synthesis, electrochemical and SAR study

International audienceTo study the antiparasitic 8-nitroquinolin-2(1H)-one pharmacophore, a series of 31 derivatives was synthesized in 1-5 steps and evaluated in vitro against both Leishmania infantum and Trypanosoma brucei brucei. In parallel, the reduction potential of all molecules was measured by cyclic voltammetry. Structure-activity relationships first indicated that antileishmanial activity depends on an intramolecular hydrogen bond (described by X-ray diffraction) between the lactam function and the nitro group, which is responsible for an important shift of the redox potential (+0.3 V in comparison with 8-nitroquinoline). With the assistance of computational chemistry, a set of derivatives presenting a large range of redox potentials (from -1.1 to -0.45 V) was designed and provided a list of suitable molecules to be synthesized and tested. This approach highlighted that, in this series, only substrates with a redox potential above -0.6 V display activity toward L. infantum. Nevertheless, such relation between redox potentials and in vitro antiparasitic activities was not observed in T. b. brucei. Compound 22 is a new hit compound in the series, displaying both antileishmanial and antitrypanosomal activity along with a low cytotoxicity on the human HepG2 cell line. Compound 22 is selectively bioactivated by the type 1 nitroreductases (NTR1) of L. donovani and T. brucei brucei. Moreover, despite being mutagenic in the Ames test, as most of nitroaromatic derivatives, compound 22 was not genotoxic in the comet assay. Preliminary in vitro pharmacokinetic parameters were finally determined and pointed out a good in vitro microsomal stability (half-life > 40 min) and a 92% binding to human albumin

Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1H)-one Scaffold Using Palladium-Catalysed Cross-Coupling Reactions

International audienceAn antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.56 V) than the initial hit (-0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC50 =1.5 μm) and low cytotoxicity on the human HepG2 cell line (CC50 =120 μm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action

Inférence des acteurs de la régulation des expressions géniques

The increasing amount of available data is a source of many issues in bioinformatics such that the development of new methods of treatments and efficient analysis of data. Especially, regulatory networks are at the heart of many projects. Also, in order to understand regulatory systems, it appears to be necessary to characterize and to understand actors of these systems such as RNA and pseudogenes. We develop a new method to compare a query RNA with a static set of target RNAs. Our method is based on (i) a preliminary indexing of the sequence/structure seeds of the target RNAs, (ii) searching the potentially homolog RNAs by detecting seeds of the query present in targets, chaining these seeds, then (iii) completing the alignment using an anchor-based exact alignment algorithm. We apply our method on the benchmark Bralibase2.1. We compare our method accuracy and efficiency with the exact method LocARNA and its recent seeds-based speed-up ExpLocP. Our pipeline RNA-unchained greatly improves computation time of LocARNA and is comparable to the one of ExpLocP, while improving the overall accuracy of the final alignments.Moreover, we develop a new method, PseudOE, to detect and to characterize the pseudome of one genome, and to analyse by comparison two genomes at least. This method allows to analyse the pan-pseudome of two distantly related Oenococcus oeni strains with opposite oenological properties. Quite interestingly, with 8.5% of pseudogenes for a compact 1.8Mb genome, O. oeni appeared to be prone to pseudogenization compared to other bacteria. A great proportion of pseudogenes were found to come from mutational degradation suggesting a relatively recent origin that could illustrate the natural propensity of O. oeni for hypermutability. In addition, we identify a spatial organization of pseudogenes into dedicated chromosomal territories. These analysis illustrate peculiar properties of O. oeni pseudogenes, providing additional insights of gene/genome evolution from which future genome annotation will benefit.La quantité croissante de données générées est à l’origine de nombreuses problématiques en bioinformatique telles que le développement de nouvelles méthodes de traitement et d’analyse efficaces de ces données. Plus particulièrement, les réseaux de régulation des fonctions cellulaires sont au coeur de nombreux projets aujourd’hui. Il est donc nécessaire, afin d’appréhender correctement ces systèmes de régulation, de comprendre l’origine et de caractériser les acteurs de ces systèmes tels que les ARN et les pseudogènes.Nous avons établi une nouvelle méthode de comparaison d’une séquence ARN requête avec un jeu de séquences ARN cibles. Notre méthode se base sur (i) l’indexation préalable des graines en séquence/structure des ARN du jeu cible, (ii) la recherche des ARN cibles par détection des graines de la séquence requête présentes également dans le jeu de données cible et le chainage de ces graines, puis (iii) la complétion de l’alignement obtenu à l’aide d’un algorithme d’alignement exact incorporant des contraintes d’alignement. Cette méthode a été appliquée sur le jeu de données de BraliBase2.1. L’exactitude des résultats obtenus et l’efficacité de la méthode ont alors été comparés à la méthode d’alignement exact LocARNA et à son filtre basé sur un algorithme de chainage de graines récemment développé, ExpLocP. Notre méthode RNA-unchained permet d’améliorer significativement les temps de calcul de LocARNA et présente des temps de calcul similaires à ExpLocP, tout en améliorant l’exactitude des alignements finaux.De plus, nous avons développé une méthode, PseudOE, de détection et de caractérisation du pseudome au sein d’un génome et d’analyse comparative de ce pseudome entre plusieurs génomes. Cette méthode a ainsi permis de réaliser l’analyse du panpseudome de deux souches relativement distantes de l’espèce Oenococcus oeni et qui présentent des propriétés oenologiques opposées. On observe dans ces génomes compacts, de 1,8Mb, 8,5% de pseudogènes. Par comparaison aux autres génomes bactériens, les génomes d’O. oeni semblent sensibles à la pseudogénisation. La majorité des pseudogènes détectés ont pour origine des mutations de leur séquence et sont présents uniquement dans l’un des génomes, ce qui soutient l’hypothèse d’une origine récente de ces séquences et qui illustre la tendance des O. oeni à l’hypermutabilité. De plus, l’analyse des données fournies par PseudOE a permis la mise en évidence d’une organisation spatiale des pseudogènes au sein de territoires spécifiques du chromosome. L’ensemble de ces analyses illustre les particularités des pseudogènes chez O. oeni et apporte des informations supplémentaires concernant l’évolution des gènes/génomes dont les annotations de génomes pourraient retirer des bénéfices

Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity

Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 mu M) alongside good antileishmanial activities (IC50 = 1-2.1 mu M) against L. donovani, L. infantum, and L. major; and good antitrypanosomal activities (IC50 = 1.3-2.2 mu M) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC50 = 0.6 to 13.3 mu M). Molecule 5, presenting a low reduction potential (E degrees = -0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making 5 a good candidate for further in vivo studies