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Are Redox‐Active Centers Bridged by Saturated Flexible Linkers Systematically Electrochemically Independent?
No full textInternational audienceAbstract The extent to which electrophores covalently bridged by a saturated linker are electrochemically independent was investigated considering the charge/spin duality of the electron and functionality of the electrophore as a spin carrier upon reduction. By combining computational modeling with electrochemical experiments, we investigated the mechanism by which tethered electrophores react together within 4,4′‐oligo[ n ]methylene‐bipyridinium assemblies (with n =2 to 5). We show that native dicationic electrophores (redox state Z =+2) are folded prior to electron injection into the system, allowing the emergence of supra‐molecular orbitals (supra‐MOs) likely to support the process of the reductive σ bond formation giving cyclomers. Indeed, for Z =+2, London Dispersion (LD) forces contribute to flatten the potential energy surface such that all‐trans and folded conformers are approximately isoenergetic. Then, upon one‐electron injection, for radical cations ( Z =+1), LD forces significantly stabilize the folded conformers, except for the ethylene derivative deprived of supra‐MOs. For radical cations equipped with supra‐MOs, the unpaired electron is delocalized over both heterocycles through space. Cyclomer completion ( Z =0) upon the second electron transfer occurs according to the inversion of redox potentials. This mechanism explains why intramolecular reactivity is favored and why pyridinium electrophores are not independent
Transport of N -acetylchitooligosaccharides and fluorescent N-acetylchitooligosaccharide analogs into rat liver lysosomes
No full textInternational audienceFree polymannose-type oligosaccharides (fOS) are processed by cytosolic enzymes to generate Man5GlcNAc which is transferred to lysosomes and degraded. Lysosomal fOS import was demonstrated in vitro but is poorly characterized in part due to lack of convenient substrates. As chitooligosaccharides (COS, oligomers β1,4-linked GlcNAc) block [3H]Man5GlcNAc transport into lysosomes, we asked if COS are themselves transported and if so, can they be chemically modified to generate fluorescent substrates. We show that COS are degraded by lysosomal hydrolases to generate GlcNAc, and robust ATP-dependent transport of [3H]COS2/4 di and tetrasaccharides into intact rat liver lysosomes was observed only after blocking lysosomal [3H]GlcNAc efflux with cytochalasin B. As oligosaccharides with unmodified reducing termini are the most efficient inhibitors of [3H]COS2/4 and [3H]Man5GlcNAc transport, the non-reducing GlcNAc residue of COS2-4 was de-N-acetylated using Sinorhizobium meliloti NodB, and the resulting amine substituted with rhodamine B (RB) to yield RB-COS2-4. The fluorescent compounds inhibit [3H]Man5GlcNAc transport and display temperature-sensitive, ATP-dependent transport into a sedimentable compartment that is ruptured with the lysosomotropic agent L-methyl methionine ester. Once in this compartment, RB-COS3 is converted to RB-COS2 further identifying it as the lysosomal compartment. RB-COS2/3 and [3H]Man5GlcNAc transports are blocked similarly by competing sugars, and are partially inhibited by the vacuolar ATPase inhibitor bafilomycin and high concentrations of the P-type ATPase inhibitor orthovanadate. These data show that Man5GlcNAc, COS2/4 and RB-COS2/3 are transported into lysosomes by the same or closely related mechanism and demonstrate the utility of COS modified at their non-reducing terminus to study lysosomal oligosaccharide transport
Improved ACOM pattern matching in 4D-STEM through adaptive sub-pixel peak detection and image reconstruction
No full textInternational audienceThe technique known as 4D-STEM has recently emerged as a powerful tool for the local characterization of crystalline structures in materials, such as cathode materials for Li-ion batteries or perovskite materials for photovoltaics. However, the use of new detectors optimized for electron diffraction patterns and other advanced techniques requires constant adaptation of methodologies to address the challenges associated with crystalline materials. In this study, we present a novel image-processing method to improve pattern matching in the determination of crystalline orientations and phases. Our approach uses sub-pixel adaptive image processing to register and reconstruct electron diffraction signals in large 4D-STEM datasets. By using adaptive prominence and linear filters, we can improve the quality of the diffraction pattern registration. The resulting data compression rate of 10 3 is well-suited for the era of big data and provides a significant enhancement in the performance of the entire ACOM data processing method. Our approach is evaluated using dedicated metrics, which demonstrate a high improvement in phase recognition. Several features are extracted from the registered data to map properties such as the spot count, and various virtual dark fields, which are used to enhance the handling of the results maps. Our results demonstrate that this data preparation method not only enhances the quality of the resulting image but also boosts the confidence level in the analysis of the outcomes related to determining crystal orientation and phase. Additionally, it mitigates the impact of user bias that may occur during the application of the method through the manipulation of parameters
FRET-Sensing of Multivalent Protein Binding at the Interface of Biomimetic Microparticles Functionalized with Fluorescent Glycolipids
No full textInternational audienceCell adhesion is a fundamental phenomenon for cell communication and regulation. Adhesion sites are triggered by the binding of single ligand-receptor pairs that will initiate the formation of clusters of receptors. To study cell adhesion in live cells with microscopy techniques, there is a need of fluorescent particles targeted towards membrane receptors with a signal sensitive to the binding and movement of receptors and ligands at the interface. We propose new biomimetic fluorescent lipid microparticles for membrane receptor targeting and sensing. The particles are functionalized with tailor-made fluorescent lipids targeted towards lectins or biotin membrane receptor and can be specifically recognized and internalized by cells as evidenced by their phagocytosis in primary murine bone-marrow derived macrophages. By using a FRET pair of fluorescent mannolipids, it was possible to detect the presence of concanavalin A in solution by energy transfer showing that the particles can sense receptor binding at the interface and the associated movement of the ligands at the site of adhesion. Our results demonstrate that this biosensing platform can be specifically internalized by phagocytes, effectively mimicking a bacteria, and reveal short-range interactions of surface receptors via FRE
Challenges and Opportunities of Molecular Simulations for Negative Gas Adsorption
No full textInternational audienceNegative gas adsorption (NGA) is a particularly eye-catching phenomenon, involving the spontaneous desorption of gas upon pressure increase during adsorption in a flexible nanoporous material. The material undergoes a structural transition from an “open-pore” phase to a contracted “closed-pore” phase upon gas adsorption, leading to macroscopic gas desorption visible to the naked eye. It was initially evidenced experimentally in 2016 for the adsorption of methane and n-butane in the DUT-49 metal–organic framework (DUT = Dresden University of Technology) and later demonstrated to be a general phenomenon, occurring for different gases and in a variety of materials with the same topology. NGA materials belong to the category of metamaterials, displaying behavior that is not found (or rarely observed) in “natural” or simple materials. The negative adsorption transition takes place outside of thermodynamic equilibrium, and its characterization requires the use of many complementary experimental techniques (adsorption measurements, in situ X-ray diffraction, EXAFS, NMR, etc.), as well as molecular simulation techniques. In order to obtain a full and consistent picture of the NGA phenomenon, it is indeed necessary to combine computational modeling with a variety of methods, at different scales, in order to understand the microscopic behavior of the host framework and guest molecules to the macroscopic experimental results. At the smallest scale, density functional theory calculations have been used to understand the energetics and structure of the NGA materials, as well as the micromechanical properties of their organic linkers: the buckling of these linkers explains the large metastability of the open-pore phase and gives rise to the NGA transition. At a larger scale, classical grand canonical Monte Carlo simulations in the “rigid host” structures can predict the adsorption capacity of different phases, elucidating the driving force behind the structural transition. To explicitly couple the flexibility of the framework and the adsorption of guest molecules, molecular dynamics simulations (relying on a classical force field for the flexible metal–organic framework) can be coupled with free energy methods to investigate the thermodynamics of NGA, obtaining free energy profiles that determine the relative stability of different phases with varying amounts of adsorbed gas. Finally, mesoscopic-scale modeling methods are required in order to understand the phenomenon at a scale larger than one unit cell and explain experimental findings about the influence of crystal size effects on the NGA transition. This Account summarizes the computational approaches that have been used so far to better understand negative gas adsorption and highlights open questions and perspectives in this field of research
Understanding copper sulfide formation from layered template and their use as power electrode materials in aqueous electrolyte
No full textInternational audienceCopper sulfide has received increasing attention as an electrode material in past decades. In this study, we report the synthesis of copper sulfide with layered copper hydroxide salt (LHS) (Cu2(OH)3NO3) precursors using different protocols. X-ray diffraction suggests the presence of numerous non-stoichiometric phases (Cu1-xS) and not a pure covellite phase and SEM images show particles with flower-like shape but different in size. The solidstate kinetic parameters of the reaction refined by the JMAK method indicate a pseudomorphic transformation controlled by 1D diffusion, different in term of precursors phase, reagents and protocol applied. The microwave method needs less energy to achieve the transformation than the amine digestion (AD) method and the morphology of particles is also different. Tested in sodium acetate electrolyte, CuS provides a maximum capacity of 67 mAh/g for AD, which is much higher than for the commercial grade CuS. This is explained by the difference in nanostructuration of the flower-like shape particles obtained from the layered template. Finally, CuS is used as both a positive and negative electrode material in a complete aqueous battery system but its redox process, which is strongly diffusion limited especially in the lower potential domain, prevents the whole system from operating at high power
Capacitive-Controlled Prussian White with a Nickel Iron Hexacyanoferrate Composite Cathode for Rapid Sodium Diffusion
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High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design
No full textInternational audienceRational design of next-generation therapeutics can be facilitated by high-resolution structures of drug targets bound to small-molecule inhibitors. However, application of structure-based methods to macromolecules refractory to crystallization has been hampered by the often-limiting resolution and throughput of cryogenic electron microscopy (cryo-EM). Here, we use high-resolution cryo-EM to determine structures of the CDK-activating kinase, a master regulator of cell growth and division, in its free and nucleotide-bound states and in complex with 15 inhibitors at up to 1.8 Å resolution. Our structures provide detailed insight into inhibitor interactions and networks of water molecules in the active site of cyclin-dependent kinase 7 and provide insights into the mechanisms contributing to inhibitor selectivity, thereby providing the basis for rational design of next-generation therapeutics. These results establish a methodological framework for the use of high-resolution cryo-EM in structure-based drug design
Rare‐Earth‐Doped Y 2 SiO 5 Crystal Directly Bonded on Glass for Efficient Optical Quantum Technologies Platform
No full textInternational audienceFor high‐efficiency optical quantum technology platforms, bonding rare‐earth doped crystals on glass are of great interest, enabling the enhancement of the optical guided mode interaction with the active rare‐earth ions. Optical coherence lifetimes and stable operation are operated at very low temperature (3–4 K). Bonding should be preferably performed without adding any intermediate sticking layer in order not to hamper the optical mode distribution and propagation. Directly bonded Y 2 SiO 5 crystal on a borosilicate glass is shown and the bonding mechanisms are discussed
