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The new LIBER Strategy for the period 2023-2027. This five-year period promises to bring radical changes in the research landscape. The Strategy focuses on those developments where a leading role of LIBER will bring the most added value.

International audience; Polystyrene (PS) is a major commodity polymer widely used in various applications ranging from packaging to insulation thanks to its low cost, high stiffness, and transparency as well as its relatively high softening temperature. Similarly to all polymers prepared by radical polymerization, PS is constituted of a C–C backbone and thus is not degradable. To confer degradability to such materials, the copolymerization of vinyl monomers with a cyclic monomer that could undergo radical ring-opening is an efficient method to introduce purposely cleavable bonds into the polymer backbone. Dibenzo[c,e]-oxepane-5-thione (DOT) is a cyclic thionolactone monomer known for its efficient copolymerization with acrylate derivatives but so far could not be incorporated into PS backbones. From a theoretical study combining density functional theory (DFT) and kinetic models using the PREDICI software, we showed that the modification of experimental conditions could overcome these limitations and that high molar mass degradable polystyrene (Mw close to 150 000 g·mol–1) could be prepared via statistical insertion of thioester groups into the polymer backbone. This copolymerization process is compatible with conventional free radical polymerization and reversible deactivation radical polymerization (RDRP) techniques such as nitroxide mediated polymerization (NMP). Thanks to favorable reactivity ratios allowing only a few mol % of thioester units to be randomly incorporated, there was no major modification of the thermal and mechanical properties of the PS. The degradation of such PS could be performed in tetrahydrofuran (THF) at room temperature (RT) in 1 h using 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as a base, leading to oligomers with Mn close to 2000 g·mol–1. We successfully demonstrate further applicability of these copolymerization systems for the phototriggered decomposition of PS in solution as well as the synthesis of cross-linked PS networks degradable into soluble side products.

Disrupted-in-Schizophrenia-1 (DISC1) is a scaffold protein of significant importance for neurodevelopment and a prominent candidate protein in the etiology of mental disorders. In this work, we investigate the role of conformational heterogeneity and local structural disorder in the oligomerization pathway of the full-length DISC1 and of two truncation variants. Through extensive coarse-grained molecular dynamics simulations with a predictive energy landscape based model, we reveal the general mechanistic principles of DISC1 oligomerization. We found that both conformational heterogeneity and structural disorder play an important role in the dimerization pathway of DISC1. This study sheds light on the differences in oligomerization pathways of the full-length protein compared to the truncated variants produced by a chromosomal translocation associated with schizophrenia.

The pathogenesis of Alzheimer's disease is characterized by the aggregation and fibrillation of amyloid peptides Aβ(1-40) and Aβ(1-42) into amyloid plaques. Despite strong potential therapeutic interest, the structural pathways associated with the conversion of monomeric Aβ peptides into oligomeric species remain largely unknown. In particular, the higher aggregation propensity and associated toxicity of Aβ(1-42) compared to that of Aβ(1-40) are poorly understood. To explore in detail the structural propensity of the monomeric Aβ(1-40) and Aβ(1-42) peptides in solution, we recorded a large set of nuclear magnetic resonance (NMR) parameters, including chemical shifts, nuclear Overhauser effects (NOEs), and J couplings. Systematic comparisons show that at neutral pH the Aβ(1-40) and Aβ(1-42) peptides populate almost indistinguishable coil-like conformations. Nuclear Overhauser effect spectra collected at very high resolution remove assignment ambiguities and show no long-range NOE contacts. Six sets of backbone J couplings ((3)JHNHα, (3)JC'C', (3)JC'Hα, (1)JHαCα, (2)JNCα, and (1)JNCα) recorded for Aβ(1-40) were used as input for the recently developed MERA Ramachandran map analysis, yielding residue-specific backbone ϕ/ψ torsion angle distributions that closely resemble random coil distributions, the absence of a significantly elevated propensity for β-conformations in the C-terminal region of the peptide, and a small but distinct propensity for αL at K28. Our results suggest that the self-association of Aβ peptides into toxic oligomers is not driven by elevated propensities of the monomeric species to adopt β-strand-like conformations. Instead, the accelerated disappearance of Aβ NMR signals in D2O over H2O, particularly pronounced for Aβ(1-42), suggests that intermolecular interactions between the hydrophobic regions of the peptide dominate the aggregation process.

In addition to encoding RNA primary structures, genomes also encode RNA secondary and tertiary structures that play roles in gene regulation and, in the case of RNA viruses, genome replication. Methods for the identification of functional RNA structures in genomes typically rely on scanning analysis windows, where multiple partially-overlapping windows are used to predict RNA structures and folding metrics to deduce regions likely to form functional structure. Separate structural models are produced for each window, where the step size can greatly affect the returned model. This makes deducing unique local structures challenging, as the same nucleotides in each window can be alternatively base paired. In the presented approach, all base pairs from all analysis windows are considered and weighted by favorable folding metrics throughout all windows. This results in unique base pairing throughout the genome and the generation of local regions/structures that can be ranked by their propensity to form unusually thermodynamically stable folds. This approach was applied to the Zika virus (ZIKV) genome. ZIKV is linked to a variety of neurological ailments including microcephaly and Guillain-Barré syndrome and its (+)-sense RNA genome encodes two, previously described, functionally essential structured RNA regions. Our approach is able to successfully identify and model the structures of these regions, while also finding additional regions likely to form functional RNA structures throughout the viral polyprotein coding region. All data for the ZIKV genome have been archived at the RNAStructuromeDB, a repository of RNA folding data for humans and their pathogens.

LILLIAD Innovation Learning Centre is a new building, incorporating a refurbishment of the former Central Library of Lille University of Science and Technologies, France, and an extension. It has been a project developed over ten years and opened in September 2016. Three hubs have been created inside the new building : the library, the research showcase and the events facilities.; LILLIAD Learning center innovation est né de la rénovation de l'ancienne bibliothèque centrale de l'Université de Lille - Science et Technologies, à laquelle a été ajoutée une extension. Projet mené sur 10 ans, le nouveau bâtiment a ouvert ses portes en septembre 2016. Trois espaces ont été créés à l'intérieur du nouveau bâtiment : une bibliothèque, une vitrine de la recherche menée au sein de l'université et enfin un complexe événementiel.

With the development of science, people's demand for the technique of query is gradually increased. Especially, the emergency of new terms proposed more demand for query techniques. Therefore, the accuracy of semantic similarity calculation is more important in searching of terms. Now, the hybrid semantic similarity calculation method has been more popular. However, when the expert calculates the semantic similarity, weight values determined are based on expert's experience which has a certain degree of subjectivity and affect the accuracy and objectivity of the semantic similarity calculation. Therefore, this paper proposed an improved hybrid semantic similarity algorithm based on the fuzzy optimization methods. This algorithm could avoid subjectivity for the determined weights and make weights more scientific. In this paper, an example is given for demonstrate how this algorithm can be used for calculating the semantic similarity of volcano terms. Comparing with the old methods, this algorithm can improve query accuracy.

Using high-pressure NMR spectroscopy and differential scanning calorimetry, we investigate the folding landscape of the mature HIV-1 protease homodimer. The cooperativity of unfolding was measured in the absence or presence of a symmetric active site inhibitor for the optimized wild type protease (PR), its inactive variant PRD25N, and an extremely multidrug-resistant mutant, PR20. The individual fit of the pressure denaturation profiles gives rise to first order, ∆GNMR, and second order, ∆VNMR (the derivative of ∆GNMR with pressure); apparent thermodynamic parameters for each amide proton considered. Heterogeneity in the apparent ∆VNMR values reflects departure from an ideal cooperative unfolding transition. The narrow to broad distribution of ∆VNMR spanning the extremes from inhibitor-free PR20D25N to PR-DMP323 complex, and distinctively for PRD25N-DMP323 complex, indicated large variations in folding cooperativity. Consistent with this data, the shape of thermal unfolding transitions varies from asymmetric for PR to nearly symmetric for PR20, as dimer-inhibitor ternary complexes. Lack of structural cooperativity was observed between regions located close to the active site, including the hinge and tip of the glycine-rich flaps, and the rest of the protein. These results strongly suggest that inhibitor binding drastically decreases the cooperativity of unfolding by trapping the closed flap conformation in a deep energy minimum. To evade this conformational trap, PR20 evolves exhibiting a smoother folding landscape with nearly an ideal two-state (cooperative) unfolding transition. This study highlights the malleability of retroviral protease folding pathways by illustrating how the selection of mutations under drug pressure remodels the free-energy landscape as a primary mechanism.

A new and convenient method, named ARTSY-J, is introduced that permits extraction of the 3 J HNHα couplings in proteins from the relative intensities in a pair of 15 N– 1 H TROSY-HSQC spectra. The pulse scheme includes 3 J HNHα dephasing of the narrower TROSY 1 H N –{ 15 N} doublet component during a delay, integrated into the regular two-dimensional TROSY-HSQC pulse scheme, and compares the obtained intensity with a reference spectrum where 3 J HNHα dephasing is suppressed. The effect of passive 1 H α spin flips downscales the apparent 3 J HNHα coupling by a uniform factor that depends approximately linearly on both the duration of the 3 J HNHα dephasing delay and the 1 H– 1 H cross relaxation rate. Using such a correction factor, which accounts for the effects of both inhomogeneity of the radiofrequency field and 1 H α spin flips, agreement between prior and newly measured values for the small model protein GB3 is better than 0.3 Hz. Measurement for the HIV-1 protease homodimer (22 kDa) yields 3 J HNHα values that agree to better than 0.7 Hz with predictions made on the basis of a previously parameterized Karplus equation. Although for Gly residues the two individual 3 J HNHα couplings cannot be extracted from a single set of ARTSY-J spectra, the measurement provides valuable ϕ angle information.

Provided that care is taken in adjusting the WATERGATE element of a (1)H-(15)N TROSY-HSQC experiment, such that neither the water magnetization nor the (1)H(α) protons are inverted by its final 180° pulse, (3)JHNHα couplings can be measured directly from splittings in the (1)H dimension of the spectrum. With band-selective (1)H decoupling, very high (15)N resolution can be achieved. A complete set of (3)JHNHα values, ranging from 3.4 to 10.1 Hz was measured for the 56-residue third domain of IgG-binding protein G (GB3). Using the H-N-C(α)-H(α) dihedral angles extracted from a RDC-refined structure of GB3, (3)JHNHα values predicted by a previously parameterized Karplus equation agree to within a root-mean-square deviation (rmsd) of 0.37 Hz with the experimental data. Values measured for the Alzheimer's implicated Aβ(1-40) peptide fit to within an rmsd of 0.45 Hz to random coil (3)JHNHα values.

The way in which the network of intramolecular interactions determines the cooperative folding and conformational dynamics of a protein remains poorly understood. High-pressure NMR spectroscopy is uniquely suited to examine this problem because it combines the site-specific resolution of the NMR experiments with the local character of pressure perturbations. Here we report on the temperature dependence of the site-specific volumetric properties of various forms of staphylococcal nuclease (SNase), including three variants with engineered internal cavities, as measured with high-pressure NMR spectroscopy. The strong temperature dependence of pressure-induced unfolding arises from poorly understood differences in thermal expansion between the folded and unfolded states. A significant inverse correlation was observed between the global thermal expansion of the folded proteins and the number of strong intramolecular hydrogen bonds, as determined by the temperature coefficient of the backbone amide chemical shifts. Comparison of the identity of these strong H-bonds with the co-evolution of pairs of residues in the SNase protein family suggests that the architecture of the interactions detected in the NMR experiments could be linked to a functional aspect of the protein. Moreover, the temperature dependence of the residue-specific volume changes of unfolding yielded residue-specific differences in expansivity and revealed how mutations impact intramolecular interaction patterns. These results show that intramolecular interactions in the folded states of proteins impose constraints against thermal expansion and that, hence, knowledge of site-specific thermal expansivity offers insight into the patterns of strong intramolecular interactions and other local determinants of protein stability, cooperativity, and potentially also of function.

Flexibility of the glycine-rich flaps is known to be essential for catalytic activity of the HIV-1 protease, but their exact conformations at the different stages of the enzymatic pathway remain subject to much debate. Although hundreds of crystal structures of protease-inhibitor complexes have been solved, only about a dozen inhibitor-free protease structures have been reported. These latter structures reveal a large diversity of flap conformations, ranging from closed to semi-open to wide open. To evaluate the average structure in solution, we measured residual dipolar couplings (RDCs) and compared these to values calculated for crystal structures representative of the closed, semi-open, and wide-open states. The RDC data clearly indicate that the inhibitor-free protease, on average, adopts a closed conformation in solution that is very similar to the inhibitor-bound state. By contrast, a highly drug-resistant protease mutant, PR20, adopts the wide-open flap conformation.

It has been known for nearly 100 years that pressure unfolds proteins, yet the physical basis of this effect is not understood. Unfolding by pressure implies that the molar volume of the unfolded state of a protein is smaller than that of the folded state. This decrease in volume has been proposed to arise from differences between the density of bulk water and water associated with the protein, from pressure-dependent changes in the structure of bulk water, from the loss of internal cavities in the folded states of proteins, or from some combination of these three factors. Here, using 10 cavity-containing variants of staphylococcal nuclease, we demonstrate that pressure unfolds proteins primarily as a result of cavities that are present in the folded state and absent in the unfolded one. High-pressure NMR spectroscopy and simulations constrained by the NMR data were used to describe structural and energetic details of the folding landscape of staphylococcal nuclease that are usually inaccessible with existing experimental approaches using harsher denaturants. Besides solving a 100-year-old conundrum concerning the detailed structural origins of pressure unfolding of proteins, these studies illustrate the promise of pressure perturbation as a unique tool for examining the roles of packing, conformational fluctuations, and water penetration as determinants of solution properties of proteins, and for detecting folding intermediates and other structural details of protein-folding landscapes that are invisible to standard experimental approaches.

The ionization of internal groups in proteins can trigger conformational change. Despite this being the structural basis of most biological energy transduction, these processes are poorly understood. Small angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR) spectroscopy experiments at ambient and high hydrostatic pressure were used to examine how the presence and ionization of Lys-66, buried in the hydrophobic core of a stabilized variant of staphylococcal nuclease, affect conformation and dynamics. NMR spectroscopy at atmospheric pressure showed previously that the neutral Lys-66 affects slow conformational fluctuations globally, whereas the effects of the charged form are localized to the region immediately surrounding position 66. Ab initio models from SAXS data suggest that when Lys-66 is charged the protein expands, which is consistent with results from NMR spectroscopy. The application of moderate pressure (

La cartographie des densites spectrales a differentes valeurs d'induction magnetique est certainement la meilleure methode pour decrire le comportement dynamique d'une proteine en solution, a travers l'analyse des parametres de relaxation heteronucleaire 15 N. Cependant, de telles analyses ne sont que rarement reportees dans la litterature, probablement parce que cette methode est excessivement consommatrice de temps machine. En effet, si l'on utilise n valeurs differentes de champs magnetiques, l'echantillonnage discret de la fonction de densite spectrale par 2n + 1 points demande la mesure de 3n parametres de relaxation (n R 1 , n R 2 et n 15 N{ 1 H}NOEs), dans l'hypothese de validite de l'approximation des hautes frequences. Nous avons propose une nouvelle strategie qui permet de decrire la fonction densite spectrale par n + 2 points en ne mesurant qu'un total de n +2 parametres de relaxation heteronucleaire, moyennant quelques approximations dont nous avons verifie la validite par simulation. Appliquee a l'analyse de la proteine C12A-pB MTCP1 a cinq inductions differentes de champ magnetique, cette approche permet de diviser au minimum par deux le temps de mesure experimentale, sans alterer l'interpretation dynamique des fonctions de densite spectrale par le modele de Lipari-Szabo.

A design of a 3.3 Volts BiCMOS buffer with current consumption and linearity control is presented. This buffer with a low output impedance is fully differential and designed to be used with RF (radio frequency) mixer in low IF (intermediate frequency) architecture. The proposed buffer is directly connected to the output of the RF mixer and designed to drive off- chip low impedance load as SAW (surface acoustic wave) or discrete differential filters. A good flexibility is obtained about the control of the linearity performance with the possibility to adjust the power consumption. The linearity and current consumption are independently adjustable and an optimum of the 3rd order linearity performance is achieved for each current consumption value. A schematic of the differential Bi-CMOS 3.3 volts buffer is proposed and some linearity simulation results are presented and discussed in terms of output IM3 level and current consumption. The results show a saving of half power in comparison with a buffer with no linearity control for the same output IM3 level.

The first step of HIV infection involves the fusion of the viral and target cell membranes, a process mediated by the viral envelope glycoproteins, gp120 and gp41. The binding of gp120 to the cell surface receptors CD4 triggers a cascade of conformational changes that disrupt the gp41-gp120 interactions and allows the insertion of the N-terminal fusion peptide of gp41 into the host cell membrane. The gp41 trimer then rapidly folds into a 6-helix bundle that pulls together the fusion peptide, inserted in the host cell membrane and the transmembrane domain, located in the viral membrane. Very little structural information is known about the pre-fusion state of gp41 notwithstanding its critical importance for the design of fusion inhibitors. To investigate the dynamics and structural properties of such metastable states, we designed a set of protein constructs mimicking the extracellular ectodomain of gp41. We found that the secondary structure of gp41 ectodomain is pronouncedly impacted by the presence of phospholipid vesicles or detergents containing phosphatidyl choline head groups. Our NMR and multi-angle light scattering data attribute these changes to the transition between a trimer in the absence of detergent to a monomer in the presence of a membrane-mimicking environment. The structure of gp41 in a monomeric state was determined by state-of-the-art NMR techniques, including measurements of NOE distance restraints and residual dipolar couplings in weakly aligned solutions. 15N relaxation data provided a detailed view at the backbone dynamics of both the trimeric and monomeric conformations. This stable monomeric state may represent a crucial structural intermediate facilitating both the gp41 conformational change during fusion and the local apposition of the viral and cellular membranes.