Etudes théoriques de dérivés (HqX) de la 8-hydroxyquinoléine : complexes Al(qX)3 et monocouches sur Al(111)

La 8-hydroxyquinoléine (Hq) et ses dérivés (Hq chimiquement modifiée) sont connus pour leur capacité à complexer des ions métalliques. Ils sont mis en oeuvre dans la dépollution des effluents aqueux, la conception de composants électroluminescents, et l’inhibition de la corrosion de surfaces métalliques. Les propriétés de ces molécules et des complexes formés avec des ions métalliques dépendent des modifications chimiques réalisées sur la Hq. Nous effectuons des études théoriques sur la Hq et deux de ses dérivés, la 5,7-dibromo-8-hydroxyquinoléine (HqBr) et l’acide 8 hydroxyquinoléine-5-sulfonique (HqSH), dans le cadre de la Théorie de la Fonctionnelle de la Densité et en prenant en compte les forces de dispersion (DFT-D). Dans un premier temps, nous avons déterminé les formes stables des complexes issus de l’interaction entre un cation Al3+ et les molécules Hq, HqBr et HqSH déprotonées, puis nous avons effectué des analyses topologiques (ELF et QTAIM) de la structure électronique de ces complexes. Des liaisons ionocovalentes sont formées entre les molécules et l’ion Al³. Puis, nous avons étudié l’adsorption des molécules Hq, HqBr et HqSH déshydrogénées sur une surface Al(111), dans le vide et en présence d’eau (modèle de solvant implicite). Les trois types de molécules peuvent former des couches stables compactes sur la surface Al(111). A contrario, les topologies d’adsorption d’une molécule isolée sont différentes pour la Hq, dont l’efficacité en tant qu’inhibiteur de la corrosion de l’aluminium a été démontré expérimentalement, et pour les HqBr et HqSH, qui ne démontrentaucune efficacité en tant qu’inhibiteurs de corrosion. Ces conformations différentes des molécules sur la surface Al(111) en début du processus de formation des couches organiques, pourraient jouer sur leur propriété de protection de l’aluminium contre la corrosion. Enfin, la formation de complexes directement sur la surface Al(111) a été étudiée par dynamique moléculaire ab initio afin d’explorer l’espace des conformations. De nombreuses géométries stables ont été déterminées et la formation d’un complexe sur la surface par adsorption de trois molécules déshydrogénées sur une surface Al(111) présentant un ad-atome est favorisée par rapport à la précipitation d’un complexe Alq3 préalablement formé dans le vide. Ainsi, nous présentons dans ce travail une description : i) de la nature précise des liaisons dans les complexes Alq3, ii) des géométries des dérivés de la Hq adsorbés sur une surface Al(111), iii) de la formation sur Al(111) de complexes de type Alq3 par adsorption de molécules Hq déshydrogénées sur une surface Al(111)

A New Parametrization for Independent Set Reconfiguration and Applications to RNA Kinetics

International audienceIn this paper, we study the Independent Set (IS) reconfiguration problem in graphs. An IS reconfiguration is a scenario transforming an IS L into another IS R, inserting/removing vertices one step at a time while keeping the cardinalities of intermediate sets greater than a specified threshold. We focus on the bipartite variant where only start and end vertices are allowed in intermediate ISs. Our motivation is an application to the RNA energy barrier problem from bioinformatics, for which a natural parameter would be the difference between the initial IS size and the threshold. We first show the para-NP hardness of the problem with respect to this parameter. We then investigate a new parameter, the cardinality range, denoted by ρ which captures the maximum deviation of the reconfiguration scenario from optimal sets (formally, ρ is the maximum difference between the cardinalities of an intermediate IS and an optimal IS). We give two different routes to show that this problem is in XP for ρ: The first is a direct O(n 2)-space, O(n 2ρ+2.5)-time algorithm based on a separation lemma; The second builds on a parameterized equivalence with the directed pathwidth problem, leading to a O(n ρ+1)-space, O(n ρ+2)-time algorithm for the reconfiguration problem through an adaptation of a prior result by Tamaki [20]. This equivalence is an interesting result in its own right, connecting a reconfiguration problem (which is essentially a connectivity problem within a reconfiguration network) with a structural parameter for an auxiliary graph. We demonstrate the practicality of these algorithms, and the relevance of our introduced parameter, by considering the application of our algorithms on random small-degree instances for our problem. Moreover, we reformulate the computation of the energy barrier between two RNA secondary structures, a classic hard problem in computational biology, as an instance of bipartite reconfiguration. Our results on IS reconfiguration thus yield an XP algorithm in O(n ρ+2) for the energy barrier problem, improving upon a partial O(n 2ρ+2.5) algorithm for the problem

Tree Diet: Reducing the Treewidth to Unlock FPT Algorithms in RNA Bioinformatics

Hard graph problems are ubiquitous in Bioinformatics, inspiring the design of specialized Fixed-Parameter Tractable algorithms, many of which rely on a combination of tree-decomposition and dynamic programming. The time/space complexities of such approaches hinge critically on low values for the treewidth tw of the input graph. In order to extend their scope of applicability, we introduce the Tree-Diet problem, i.e. the removal of a minimal set of edges such that a given tree-decomposition can be slimmed down to a prescribed treewidth tw\u27. Our rationale is that the time gained thanks to a smaller treewidth in a parameterized algorithm compensates the extra post-processing needed to take deleted edges into account. Our core result is an FPT dynamic programming algorithm for Tree-Diet, using 2^{O(tw)}n time and space. We complement this result with parameterized complexity lower-bounds for stronger variants (e.g., NP-hardness when tw\u27 or tw-tw\u27 is constant). We propose a prototype implementation for our approach which we apply on difficult instances of selected RNA-based problems: RNA design, sequence-structure alignment, and search of pseudoknotted RNAs in genomes, revealing very encouraging results. This work paves the way for a wider adoption of tree-decomposition-based algorithms in Bioinformatics

Automated Design of Dynamic Programming Schemes for RNA Folding with Pseudoknots

Despite being a textbook application of dynamic programming (DP) and routine task in RNA structure analysis, RNA secondary structure prediction remains challenging whenever pseudoknots come into play. To circumvent the NP-hardness of energy minimization in realistic energy models, specialized algorithms have been proposed for restricted conformation classes that capture the most frequently observed configurations. While these methods rely on hand-crafted DP schemes, we generalize and fully automatize the design of DP pseudoknot prediction algorithms. We formalize the problem of designing DP algorithms for an (infinite) class of conformations, modeled by (a finite number of) fatgraphs, and automatically build DP schemes minimizing their algorithmic complexity. We propose an algorithm for the problem, based on the tree-decomposition of a well-chosen representative structure, which we simplify and reinterpret as a DP scheme. The algorithm is fixed-parameter tractable for the tree-width tw of the fatgraph, and its output represents a ?(n^{tw+1}) algorithm for predicting the MFE folding of an RNA of length n. Our general framework supports general energy models, partition function computations, recursive substructures and partial folding, and could pave the way for algebraic dynamic programming beyond the context-free case

8-Hydroxyquinoline complexes (Alq3) on Al(111): atomic scale structure, energetics and charge distribution

8-Hydroxyquinoline (8Hq) is known to efficiently inhibit the corrosion of aluminium by forming metal–organic layers (8Hq forms complexes with aluminium atoms). In the present work, the atomic scale structure and the energetics of 8-hydroxyquinoline complexes (Alq3) adsorbed on an aluminium surface are investigated by dispersion-corrected DFT computations. Two scenarios are considered: (i) an Alq3 complex, previously formed in vacuum, is deposited on a flat Al(111) surface or (ii) three deprotonated 8Hq molecules (q) directly adsorb on a defective Al(111) surface presenting Al adatoms (Al–Al(111)). For the Alq3 formation in vacuum, each addition of a q molecule on the Al atom stabilises the system, the oxidation state of the Al atom evolving from AlI in Alq to AlIII in Alq2 and Alq3. The subsequent deposition of Alq3 on Al(111) leads to a strong bonding between the q molecules of the complex and the Al(111) surface, with a significant electron transfer occurring from the surface to the complexes (0.73 to 1.57 e). The formation on the metal surface of Alq3 complexes via the adsorption of q molecules on an Al adatom leads to more stable structures than the ones obtained from direct adsorption of Alq3 on Al(111). For the most stable adsorption conformation, the three q molecules are bonded to the Al adatom but only two are bonded to the aluminium surface. In that case, the total electron transfer from the Al–Al(111) surface to the q molecules is 4.40 e and the electron transfer from the Al(111) surface to the Alq3-like species is 2.04 e. The structure, energetics and charge distribution data demonstrate an iono-covalent bonding between the q molecules and the Al atoms, in the complex as well as on the aluminium surface

Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy

Mammalian target of rapamycin (mTOR) is a key regulator of cell growth that associates with raptor and rictor to form the mTOR complex 1 (mTORC1) and mTORC2, respectively. Raptor is required for oxidative muscle integrity, whereas rictor is dispensable. In this study, we show that muscle-specific inactivation of mTOR leads to severe myopathy, resulting in premature death. mTOR-deficient muscles display metabolic changes similar to those observed in muscles lacking raptor, including impaired oxidative metabolism, altered mitochondrial regulation, and glycogen accumulation associated with protein kinase B/Akt hyperactivation. In addition, mTOR-deficient muscles exhibit increased basal glucose uptake, whereas whole body glucose homeostasis is essentially maintained. Importantly, loss of mTOR exacerbates the myopathic features in both slow oxidative and fast glycolytic muscles. Moreover, mTOR but not raptor and rictor deficiency leads to reduced muscle dystrophin content. We provide evidence that mTOR controls dystrophin transcription in a cell-autonomous, rapamycin-resistant, and kinase-independent manner. Collectively, our results demonstrate that mTOR acts mainly via mTORC1, whereas regulation of dystrophin is raptor and rictor independent

Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy

mTor, acting mainly via mTORC1, controls dystrophin transcription in a raptor- and rictor-independent mechanism

Theoretical studies of the interactions of 8-hydroxyquinoline derivatives with aluminum

La 8-hydroxyquinoléine (Hq) et ses dérivés (Hq chimiquement modifiée) sont connus pour leur capacité à complexer des ions métalliques. Ils sont mis en oeuvre dans la dépollution des effluents aqueux, la conception de composants électroluminescents, et l’inhibition de la corrosion de surfaces métalliques. Les propriétés de ces molécules et des complexes formés avec des ions métalliques dépendent des modifications chimiques réalisées sur la Hq. Nous effectuons des études théoriques sur la Hq et deux de ses dérivés, la 5,7-dibromo-8-hydroxyquinoléine (HqBr) et l’acide 8 hydroxyquinoléine-5-sulfonique (HqSH), dans le cadre de la Théorie de la Fonctionnelle de la Densité et en prenant en compte les forces de dispersion (DFT-D). Dans un premier temps, nous avons déterminé les formes stables des complexes issus de l’interaction entre un cation Al3+ et les molécules Hq, HqBr et HqSH déprotonées, puis nous avons effectué des analyses topologiques (ELF et QTAIM) de la structure électronique de ces complexes. Des liaisons ionocovalentes sont formées entre les molécules et l’ion Al³. Puis, nous avons étudié l’adsorption des molécules Hq, HqBr et HqSH déshydrogénées sur une surface Al(111), dans le vide et en présence d’eau (modèle de solvant implicite). Les trois types de molécules peuvent former des couches stables compactes sur la surface Al(111). A contrario, les topologies d’adsorption d’une molécule isolée sont différentes pour la Hq, dont l’efficacité en tant qu’inhibiteur de la corrosion de l’aluminium a été démontré expérimentalement, et pour les HqBr et HqSH, qui ne démontrentaucune efficacité en tant qu’inhibiteurs de corrosion. Ces conformations différentes des molécules sur la surface Al(111) en début du processus de formation des couches organiques, pourraient jouer sur leur propriété de protection de l’aluminium contre la corrosion. Enfin, la formation de complexes directement sur la surface Al(111) a été étudiée par dynamique moléculaire ab initio afin d’explorer l’espace des conformations. De nombreuses géométries stables ont été déterminées et la formation d’un complexe sur la surface par adsorption de trois molécules déshydrogénées sur une surface Al(111) présentant un ad-atome est favorisée par rapport à la précipitation d’un complexe Alq3 préalablement formé dans le vide. Ainsi, nous présentons dans ce travail une description : i) de la nature précise des liaisons dans les complexes Alq3, ii) des géométries des dérivés de la Hq adsorbés sur une surface Al(111), iii) de la formation sur Al(111) de complexes de type Alq3 par adsorption de molécules Hq déshydrogénées sur une surface Al(111).The 8-hydroxyquinoline (Hq) and its derivatives (chemically modified Hq) are known for their ability to chelate metallic cations. They are used in applications such as depollution, light emitting devices, medicine and inhibition of the corrosion of metallic surfaces. The properties of these molecules and of their metal-organic complexes depend on the chemical modifications made on Hq. In the present work, in addition to Hq, two derivatives are studied: the 5,7-dibromo-8-hydroxyquinoline (HqBr) and the 8-hydroxyquinoline-5-sulfonic acid (HqSH). Our investigation is carried out in the framework of the dispersion corrected Density Functional Theory (DFT-D), and focuses on the study of the interactions of Hq, HqBr and HqSH species with aluminum. First, we investigate the geometries of the complexes formed by deprotonated Hq, HqBr and HqSH with an aluminum cation, and characterize the bonds formed between the molecules and the cation from ELF and QTAIM topological analyses of the electronic structure of the complexes. The three molecules form similar iono-covalent bonds with the Al³ ion. We then focus on the interaction of the dehydrogenated Hq, HqBr and HqSH species with an Al(111) surface, in vacuum and in water, to get insight on the adsorption properties of the three molecules. While all three molecule can form stable and compact layers on Al(111), the adsorption a single molecule is different for Hq, which has been shown experimentally to be an efficient corrosion inhibitor of aluminum, than for HqBr and HqSH, which have shown no inhibition efficiency against aluminum corrosion. These different geometries could influence the dynamics of the layer formation, and thus the protection of the aluminum surface against corrosion. Finally, the formation of Hq complexes, noted Alq3, on Al(111) is investigated, using ab initio molecular dynamics to explore the conformation space of the system. The work shows a large amount of possible stable geometries that could coexist. The formation of a complex on the surface by the adsorption of three dehydrogenated molecules on an Al adatom of the Al(111) surface is favored over the deposition of an Alq3 complex preformed in vacuum. This work gives: i) an accurate description of the nature of the bonding in aluminum complexes, in vacuum and solution, ii) an insight of the interactions of dehydrogenated Hq derivatives with the Al(111) surface, iii) new possible configurations of dehydrogenated Hq adsorbed on a defective Al(111) surface, forming Alq3-like complexes on the surface

Tree Diet: Reducing the Treewidth to Unlock FPT Algorithms in RNA Bioinformatics

International audienceHard graph problems are ubiquitous in Bioinformatics, inspiring the design of specialized Fixed-Parameter Tractable algorithms, many of which rely on a combination of tree-decomposition and dynamic programming. The time/space complexities of such approaches hinge critically on low values for the treewidth $tw$ of the input graph. In order to extend their scope of applicability, we introduce the TREE-DIET problem, i.e. the removal of a minimal set of edges such that a given tree-decomposition can be slimmed down to a prescribed treewidth $tw'$. Our rationale is that the time gained thanks to a smaller treewidth in a parameterized algorithm compensates the extra post-processing needed to take deleted edges into account. Our core result is an FPT dynamic programming algorithm for TREE-DIET, using $2^{O(tw)} n$ time and space. We complement this result with parameterized complexity lower-bounds for stronger variants (e.g., NP-hardness when tw or $tw−tw'$ is constant). We propose a prototype implementation for our approach which we apply on difficult instances of selected RNA-based problems: RNA design, sequence-structure alignment, and search of pseudoknotted RNAs in genomes, revealing very encouraging results. This work paves the way for a wider adoption of tree-decomposition-based algorithms in Bioinformatics

Tree Diet: Reducing the Treewidth to Unlock FPT Algorithms in RNA Bioinformatics

International audienceHard graph problems are ubiquitous in Bioinformatics, inspiring the design of specialized Fixed-Parameter Tractable algorithms, many of which rely on a combination of tree-decomposition and dynamic programming. The time/space complexities of such approaches hinge critically on low values for the treewidth $tw$ of the input graph. In order to extend their scope of applicability, we introduce the TREE-DIET problem, i.e. the removal of a minimal set of edges such that a given tree-decomposition can be slimmed down to a prescribed treewidth $tw'$. Our rationale is that the time gained thanks to a smaller treewidth in a parameterized algorithm compensates the extra post-processing needed to take deleted edges into account. Our core result is an FPT dynamic programming algorithm for TREE-DIET, using $2^{O(tw)} n$ time and space. We complement this result with parameterized complexity lower-bounds for stronger variants (e.g., NP-hardness when tw or $tw−tw'$ is constant). We propose a prototype implementation for our approach which we apply on difficult instances of selected RNA-based problems: RNA design, sequence-structure alignment, and search of pseudoknotted RNAs in genomes, revealing very encouraging results. This work paves the way for a wider adoption of tree-decomposition-based algorithms in Bioinformatics