52 research outputs found
Light-Management Strategies for Thin-Film Silicon Multijunction Solar Cells
Light management is of crucial importance to reach high efficiencies with thin-film silicon multijunction solar cells. In this contribution, we present light-management strategies that we recently developed. This includes high quality absorber materials, low-refractive index intermediate reflectors, and highly transparent multiscale electrodes. Specifically, we show the fabrication of high-efficiency tandem devices with a certified stabilized efficiency of 12.6%, triple-junction solar cells with a stabilized efficiency of 12.8%, recently developed smoothening intermediate reflector layers based on silicon dioxide nanoparticles, and periodic-on-random multiscale textures
Structural activation of the transcriptional repressor EthR from Mycobacterium tuberculosis by single amino acid change mimicking natural and synthetic ligands
Ethionamide is an antituberculous drug for the treatment of multidrug-resistant Mycobacterium tuberculosis. This antibiotic requires activation by the monooxygenase EthA to exert its activity. Production of EthA is controlled by the transcriptional repressor EthR, a member of the TetR family. The sensitivity of M. tuberculosis to ethionamide can be artificially enhanced using synthetic ligands of EthR that allosterically inactivate its DNA-binding activity. Comparison of several structures of EthR co-crystallized with various ligands suggested that the structural reorganization of EthR resulting in its inactivation is controlled by a limited portion of the ligand-binding-pocket. In silico simulation predicted that mutation G106W may mimic ligands. X-ray crystallography of variant G106W indeed revealed a protein structurally similar to ligand-bound EthR. Surface plasmon resonance experiments established that this variant is unable to bind DNA, while thermal shift studies demonstrated that mutation G106W stabilizes EthR as strongly as ligands. Proton NMR of the methyl regions showed a lesser contribution of exchange broadening upon ligand binding, and the same quenched dynamics was observed in apo-variant G106W. Altogether, we here show that the area surrounding Gly106 constitutes the molecular switch involved in the conformational reorganization of EthR. These results also shed light on the mechanistic of ligand-induced allosterism controlling the DNA binding properties of TetR family repressors
New therapeutic approaches by a boosting strategy of antituberculosis nicotinamide analogues
Les antibiotiques reprĂ©sentent Ă lâheure actuelle le seul moyen de lutte efficace contre la tuberculose. Parmi eux, lâĂ©thionamide (ETH) est lâun des antituberculeux les plus efficaces. Il pose cependant des problĂšmes dâeffets indĂ©sirables non nĂ©gligeables ce qui relĂšgue son utilisation en seconde ligne de traitement. Ces inconvĂ©nients aboutissent frĂ©quemment Ă une inobservance au traitement, Ă lâorigine du dĂ©veloppement de souches rĂ©sistantes.LâETH, Ă lâinstar dâautres composĂ©s antimycobactĂ©riens, est une pro-drogue nĂ©cessitant son activation mĂ©tabolique par une enzyme produite par la mycobactĂ©rie elle-mĂȘme. Il a Ă©tĂ© montrĂ© que cette bio-activation intra-bactĂ©rienne est exercĂ©e par la mono-oxygĂ©nase EthA dont la production est rĂ©primĂ©e par le rĂ©gulateur transcriptionnel EthR. Lors de travaux prĂ©cĂ©dents, des inhibiteurs de EthR ont Ă©tĂ© dĂ©veloppĂ©s dans le but de stimuler la bioactivation de lâETH par EthA. Ces molĂ©cules de synthĂšse ont permis de potentialiser lâefficacitĂ© de lâETH dâun facteur trois sur un modĂšle murin dâinfection tuberculeuse. Toutefois, bien quâactifs chez lâanimal, cette premiĂšre sĂ©rie de composĂ©s possĂšde des propriĂ©tĂ©s pharmacocinĂ©tiques et pharmacodynamiques (PK/PD) insuffisantes pour une utilisation en clinique humaine. Le premier objectif de ce travail a donc Ă©tĂ© de dĂ©finir un « profil minimum acceptable » nĂ©cessaire Ă la rĂ©alisation dâĂ©tudes prĂ©-cliniques. LâĂ©valuation systĂ©matique des performances de plus de 500 composĂ©s a menĂ© Ă lâidentification de leads compatibles avec le profil dĂ©fini. Notre deuxiĂšme objectif a Ă©tĂ© dâĂ©valuer lâintĂ©rĂȘt de la stratĂ©gie de potentialisation de lâETH dans la problĂ©matique de la prise en charge de la tuberculose multi-rĂ©sistante (MDR-TB). Ainsi, dans 80% des cas, lâusage de nos inhibiteurs dâEthR a permis dâabaisser significativement la concentration minimale inhibitrice dâETH.ParallĂšlement, tirant profit de la quantitĂ© importante de composĂ©s gĂ©nĂ©rĂ©s lors de ce programme dâoptimisation, une Ă©tude fondamentale des interactions entre inhibiteurs et EthR a Ă©tĂ© menĂ©e. De cette maniĂšre, nous avons pu identifier une rĂ©gion restreinte de la poche dâinteraction de EthR avec ses inhibiteurs/ligands, nĂ©cessaire et suffisante Ă la rĂ©organisation spatiale menant Ă une forme inactive du rĂ©presseur. Pour la premiĂšre fois dans cette famille de rĂ©presseur de type TetR, nous avons montrĂ© que la modification dâun seul acide aminĂ© dans cette rĂ©gion de la protĂ©ine provoque les mĂȘmes phĂ©nomĂšnes allostĂ©riques que ceux induits par la fixation des inhibiteurs/ligands. De façon inattendue, le programme dâoptimisation des inhibiteurs nous a menĂ© Ă lâidentification dâune nouvelle famille de molĂ©cules capables de potentialiser lâETH alors quâelles ont perdu leur capacitĂ© dâinteragir avec EthR. Des expĂ©riences de transcriptomique et de RMN ont rĂ©vĂ©lĂ© que ces composĂ©s inhibent une voie de bio-activation de lâETH indĂ©pendante de EthA. Cette voie ouvre des perspectives extraordinaires de traitement puisque ces inhibiteurs augmentent significativement lâefficacitĂ© de la prodrogue, non seulement sur les souches cliniques MDR-TB, mais Ă©galement sur les souches cliniques rĂ©sistantes Ă lâETH. Notre dernier objectif a Ă©tĂ© de calquer cette stratĂ©gie de potentialisation Ă lâantituberculeux le plus utilisĂ© dans le monde, lâisoniazide (INH). Tout comme lâETH, lâINH est une pro-drogue. Sa bio-activation est tributaire de la catalase-peroxydase KatG dont le niveau dâexpression est sous dĂ©pendance du rĂ©gulateur transcriptionnel FurA. Notre objectif a donc Ă©tĂ© dâobtenir des inhibiteurs spĂ©cifiques de FurA. En lâabsence de structure cristallographique de FurA nous empĂȘchant une approche par chimie raisonnĂ©e sur cible, nous avons basĂ© notre stratĂ©gie sur un criblage Ă haut dĂ©bit de vastes chimiothĂšques. Les premiers hits et leur partielle optimisation sont discutĂ©s dans ce travail.Antibiotics are currently the only effective means of control against tuberculosis. Among them, ethionamide (ETH) is one of the most effective. However it is responsible for significant side effects that relegate the ETH use to a second-line. These events often lead to non-compliance with treatment promoting many cases of multidrug resistant-tuberculosis (MDR-TB). Like other antimycobacterial compounds, ETH is a prodrug that requires bioactivation by an enzyme produced by the mycobacteria. It has been shown that the intrabacterial bioactivation of the prodrug by the monooxygenase EthA is controled by the mycobacterial repressor EthR. In previous studies, our group has developped EthR inhibitors shown to stimulate the bioactivation of ETH by EthA. These synthetic compounds led to boost the ETH efficacy three-fold in a M. tuberculosis-infected mice model. However, although active in animals, these compounds possess insufficient pharmacokinetic and pharmacodynamic (PK/PD) properties for envisaging human clinical evaluation. The first objective of this work was therefore to define a âminimum acceptable profileâ required for initiating pre-clinical studies. Systematic evaluation of the performance of more than 500 compounds led to the identification of leads compatible with the defined profile. Our second objective was to evaluate the benefit of the ETH boosting strategy in the management of MDR-TB. In 80% of cases, the use of our EthR inhibitors drastically decreased the minimum inhibitory concentration of ETH.In parallel, we conducted a fundamental study on the interactions between inhibitors and EthR by exploiting the large amount of compounds generated during the optimization blueprint. This way, we have identified a narrow region of the binding pocket of EthR that interacts in all cases with its inhibitors/ligands. For the first time in this TetR family of repressors, we have shown that this portion of the ligand-binding site is necessary and sufficient for the structural reorganization of the repressor. As such, the modification of a single amino acid in this region of the protein caused the same allosteric phenomena as those induced by inhibitors/ligands, which led to the inactive form of EthR.Unexpectedly, the optimization blueprint of EthR inhibitors led to the identification of a new family of compounds able to boost ETH in spite of their loss of interaction with EthR. Transcriptomics and NMR experiments showed that these compounds inhibit the ETH bioactivation independently of EthA. This novel pathway opens up extraordinary opportunities for TB treatment since these compounds significantly increase the effectiveness of ETH, not only against clinical MDR-TB strains, but also against clinical isolates resistant to ETH.The last objective was to transpose this boosting strategy to isoniazid (INH), the most commonly used antituberculosis drug. As ETH, INH is a prodrug. Its bioactivation depends on the catalase-peroxidase KatG whose level of expression is controlled by the transcriptional regulator FurA. Our objective was therefore to obtain specific FurA inhibitors. Due to the absence of crystallographic structure of FurA, which preclude a target based approach, our strategy was based on high-throughput screening of large chemical libraries. The first hits and their partial optimization are discussed in this work
Fabrication of Functional Plastic Parts Using Nanostructured Steel Mold Inserts
We report on the fabrication of sub-micro and nanostructured steel mold inserts for the replication of nanostructured immunoassay biochips. Planar and microstructured stainless steel inserts were textured at the sub-micron and nanoscale by combining nanosphere lithography and electrochemical etching. This allowed the fabrication of structures with lateral dimensions of hundreds of nanometers and aspect ratios of up to 1:2. Nanostructured plastic parts were produced by means of hot embossing and injection molding. Surface nanostructuring was used to control wettability and increase the sensitivity of an immunoassay
IntĂ©rĂȘt du monitorage des concentrations sĂ©riques des bĂȘta-lactamines chez le patient de rĂ©animation
LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF
Recherches sur les conditionnements spĂ©cifiques dâĂ©lĂ©ments sĂ©parĂ©s
De nouvelles matrices de conditionnement permettant dâassurer, sur de trĂšs longues pĂ©riodes en conditions de stockage, un confinement de radionuclĂ©ides Ă vie longue (I, Cs, Actinides mineurs) aprĂšs sĂ©paration poussĂ©e, ont Ă©tĂ© Ă©tudiĂ©es dans le cadre de la loi de 1991. Elles sont une solution alternative Ă la solution de rĂ©fĂ©rence sĂ©paration poussĂ©e - transmutation et permettent aussi le stockage des radionuclĂ©ides non transmutables. Le dĂ©veloppement de ces matrices a fait lâobjet de travaux importants entre le CEA et le milieu acadĂ©mique dans le cadre du GDR NOMADE (NOuveaux MAteriaux pour les DEchets)
Do Anti-Biofilm Antibiotics Have a Place in the Treatment of Diabetic Foot Osteomyelitis?
The choice of antibiotic regimens for use in patients presenting with diabetic foot osteomyelitis and their duration differs according to the situation. Antibiotics play a more important role in the medical option where no infected bone has been resected, while their role is reduced but not negligible in the case of surgical options. Some studies have reported the presence of biofilm structures in bone samples taken from patients with diabetic foot osteomyelitis, which raises the question of the place of anti-biofilm antibiotic regimens in this setting. During the last two decades, clinical studies have suggested a potential benefit for anti-biofilm antibiotics, mainly rifampicin against staphylococci and fluoroquinolones against gram-negative bacilli. However, no data from randomized controlled studies have been reported so far. The present work provides a summary of the available data on the question of the place of anti-biofilm antibiotics for the treatment of diabetic foot osteomyelitis, but also the potential limitations of such treatments
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