Molecular placement of rutin in MNV-1 RdRp

<p>Rutin conformation in MNV-1 RdRp (3UPF) after 50ns molecular dynamic simulation starting from the XP pose.</p

Approche théorique de la réactivité des isonitriles en chimie organique

Les isonitriles sont des espèces connues depuis longtemps, mais étudiées depuis peu. Une approche théorique a permis de s'intéresser en détails aux réactions de Nef et de Ugi. Nous nous sommes tout d'abord focalisés sur la première. Après en avoir élucidé le mécanisme, nous avons étudié l'effet du solvant et nous avons proposé de nouvelles conditions expérimentales. Nous avons ensuite étudié l'influence des groupements de l'acyl, de l'isonitrile et du groupe partant. L'ensemble des variations considérées a pu être rationalisé en reliant l'énergie d'activation au pKa du groupe partant. En parallèle, nous avons étudié la réaction de Ugi. Le mécanisme proposé par Ugi pour cette réaction complexe n'avait toujours pas été vérifié 50 ans après sa découverte. Une étude quasi-exhaustive des différents mécanismes possibles a été menée, en utilisant une approche originale mêlant théorie et expériences. Le mécanisme de cette réaction a ainsi été démontré, tant dans le méthanol que dans le toluène. Les étapes cinétiquement déterminantes et les forces motrices ont été mises en lumière et diffèrent de celles proposées par Ugi. Une variation de la réaction de Ugi est le couplage Ugi-Smiles pour lequel de nombreux résultats expérimentaux n'ont toujours pas trouvé d'explications. Nous nous sommes donc intéressés au réarrangement de Smiles. Nous avons montré l'importance d'une liaison hydrogène intramoléculaire sur la faisabilité de la réaction, et nous avons étendu cette observation aux réactions intermoléculaires. Nous avons également étudié l'influence des substituants des quatre réactifs sur les barrières afin de construire un modèle prédictif.Isocyanides are known for a long time, but have been studied only recently. A theoretical approach allowed us to investigate in details the Nef and the Ugi reactions. We first focused on the former. After elucidating its mechanism, we studied solvent effects and proposed new experimental conditions. We then studied the acyl moiety and isocyanide influences, such as the leaving group one. All the variations were rationalized by linking the activation energy to the leaving group pKa. Simultaneously, we studied the Ugi reaction. The mechanism proposed by Ugi for this complex reaction was still unverified 50 years after its discovery. A thorough and quasi-complete study of all the possible mechanisms were lead, using a mixed theoretical and experimental approach. The mechanism of this reaction was demonstrated, in both methanol and toluene. Rate determining steps and driving forces were highlighted and differ from those proposed by Ugi. A variation of the Ugi reaction is the Ugi-Smiles coupling, for which numerous experimental results are still unexplained. We thus studied the Smiles rearrangement. We showed the key-role of an intramolecular hydrogen bond on the reaction feasibility, and extended this observation to intermolecular reactions. We also studied the four substituent influence on the barrier, aiming to build a predictive model.LYON-ENS Sciences (693872304) / SudocSudocFranceF

On Protein Preferential Solvation in Water:Glycerol Mixtures

For proteins in solvent mixtures, the relative abundances of each solvent in their solvation shell have a critical impact on their properties. Preferential solvation of a series of proteins in water-glycerol mixtures is studied here over a broad range of solvent compositions via classical molecular dynamics simulations. Our simulation results reveal that the differences between shell and bulk compositions exhibit dramatic changes with solvent composition, temperature and protein nature. In contrast with the simple and widely used picture where glycerol is completely excluded from the protein interface, we show that for aqueous solutions with less than 50% glycerol in volume, protein solvation shells have approximately the same composition as the bulk solvent and proteins are in direct contact with glycerol. We further demonstrate that at high glycerol concentration, glycerol depletion from the solvation shell is largely due to an entropic factor arising from the reduced accessibility of bulky glycerol molecules in protein cavities. The resulting molecular picture is important to understand protein activity and cryopreservation in mixed aqueous solvents.<br /

Characterization of the metabolomic response of freshwater periphytic biofilm exposed to a serial dilution of glyphosate

International audienceGlyphosate is a widely used herbicide detected ubiquitously in European freshwaters. However, there still is a lack of knowledge about its impact on aquatic ecosystems. To fill this gap, periphytic community playing a pivotal role in ecosystem functions, is a relevant model. Also, untargeted meta-metabolomics is an approach of choice through its ability to sensitively characterize the molecular/biochemical phenotype of the community. In this context, this study aims to characterize the meta-metabolome response of periphytic biofilm exposed during 14 days to different concentrations of glyphosate (0.1-150 µg.L-1). The meta-metabolome was characterized by an untargeted approach on a UPLC-HRMS-TOF system. Acquired data were processed in W4M and further analyzed with various chemometric methods. In particular, DROMICS was used to characterize trend (U, Bell, Increase, Decrease) and sensitivity (BMD1sd) of each metabolomic features as well as their aggregated response. Finally, the signals of interest were annotated by combining MS-DIAL and SIRIUS5. Chemometrics revealed that 7276 features reacted to glyphosate. Only 2288 could be annotated. Among them alkaloids (n=662) and amino acids and peptides (n=952) classes were the more reactive. Surprisingly, low effect of glyphosate was noted on the shikimates while this herbicide targets their biosynthesis. DROMICS showed no discrepancy in the proportion of each trend and the sensitivity to glyphosate between the classes. However, the strengh of the response (i.e. fold change) slightly change between the classes, as terpenoids and amino-acids were the most down-regulated classes. Altogether, our results higlighted a complex metabolic response of periphyton to glyphosate that questions potential impairment of ecological functions of these communities

Effect of high pressure homogenization on the structure and the interfacial and emulsifying properties of β-lactoglobulin

International audienceThe effect of high pressure homogenization (HPH) on the structure of β-lactoglobulin (β lg) was studied by combining spectroscopic, chromatographic, and electrophoretic methods. The consequences of the resulting structure modifications on oil/water (O/W) interfacial properties were also assessed. Moderated HPH treatment (100 MPa/4 cycles) showed no significant modification of protein structure and interfacial properties. However, a harsher HPH treatment (300 MPa/5 cycles) induced structural transformation, mainly from β sheets to random coils, wide loss in lipocalin core, and protein aggregation via intermolecular disulfide bridges. HPH-modified β lg displayed higher surface hydrophobicity leading to a faster adsorption rate at the interface and an earlier formation of an elastic interfacial film at Cβ-lg = 0.1 wt%. However, no modification of the interfacial properties was observed at Cβ-lg = 1 wt%. At this protein concentration, the prior denaturation of β lg by HPH did not modify the droplet size of nanoemulsions prepared with these β lg solutions as the aqueous phases. A slightly increased creaming rate was however observed. The effects of HPH and heat denaturations appeared qualitatively similar, but with differences in their extent

Rare earth elements and neodymium isotopes in sedimentary organic matter

We report rare earth element (REE) and neodymium (Nd) isotope data for the organic fraction of sediments collected from various depositional environments, i.e. rivers (n=25), estuaries (n=18), open-ocean settings (n=15), and cold seeps (n=12). Sedimentary Organic Matter (SOM) was extracted using a mixed hydrogen peroxide/nitric acid solution (20%-H2O2 – 0.02M-HNO3), after removal of carbonate and oxy-hydroxide phases with dilute hydrochloric acid (0.25M-HCl). A series of experimental tests indicate that extraction of sedimentary organic compounds using H202 may be complicated occasionally by partial dissolution of sulphide minerals and residual carbonates. However, this contamination is expected to be minor for REE because measured concentrations in H2O2 leachates are about two-orders of magnitude higher than in the above mentioned phases. The mean REE concentrations determined in the H2O2 leachates for samples from rivers, estuaries, coastal seas and open-ocean settings yield relatively similar levels, with ΣREE = 109 ± 86 ppm (mean ± s; n=58). The organic fractions leached from cold seep sediments display even higher concentration levels (285 ± 150 ppm; mean ± s; n=12). The H2O2 leachates for most sediments exhibit remarkably similar shale-normalized REE patterns, all characterized by a mid-REE enrichment compared to the other REE. This suggests that the distribution of REE in leached sedimentary organic phases is controlled primarily by biogeochemical processes, rather than by the composition of the source from which they derive (e.g. pore, river or sea- water). The Nd isotopic compositions for organic phases leached from river sediments are very similar to those for the corresponding detrital fractions. In contrast, the SOM extracted from marine sediments display εNd values that typically range between the εNd signatures for terrestrial organic matter (inferred from the analysis of the sedimentary detrital fractions) and marine organic matter (inferred from the analysis of local surface seawater). A notable exception is the case of organic matter (OM) fractions leached from cold seep sediment samples, which sometimes exhibit εNd values markedly different from both terrigenous and surface seawater signatures. This suggests that a significant fraction of organic compounds in these sediments may be derived from chemosynthetic processes, recycling pore water REE characterized by a distinct isotopic composition. Overall, our results confirm that organic matter probably plays an important role in the oceanic REE budget, through direct scavenging and remineralization within the water column. Both the high REE abundances and the shape of shale-normalized patterns for leached SOM also suggest that OM degradation in sub-surface marine sediments during early diagenesis could control, to a large extent, the distribution of REE in pore waters. Benthic fluxes of organic-bound REE could hence substantially contribute to the exchange processes between particulates and seawater that take place at ocean margins. Neodymium isotopes could provide useful information for tracing the origin (terrestrial versus marine) and geographical provenance of organic matter, with potential applications in paleoceanography. In particular, future studies should further investigate the potential of Nd isotopes in organic compounds preserved in sedimentary records for reconstructing past variations of surface ocean circulation

Healthcare trajectory of children with rare bone disease attending pediatric emergency departments

International audienceAbstract Background Children with rare bone diseases (RBDs), whether medically complex or not, raise multiple issues in emergency situations. The healthcare burden of children with RBD in emergency structures remains unknown. The objective of this study was to describe the place of the pediatric emergency department (PED) in the healthcare of children with RBD. Methods We performed a retrospective single-center cohort study at a French university hospital. We included all children under the age of 18 years with RBD who visited the PED in 2017. By cross-checking data from the hospital clinical data warehouse, we were able to trace the healthcare trajectories of the patients. The main outcome of interest was the incidence (IR) of a second healthcare visit (HCV) within 30 days of the index visit to the PED. The secondary outcomes were the IR of planned and unplanned second HCVs and the proportion of patients classified as having chronic medically complex (CMC) disease at the PED visit. Results The 141 visits to the PED were followed by 84 s HCVs, giving an IR of 0.60 [95% CI: 0.48–0.74]. These second HCVs were planned in 60 cases (IR = 0.43 [95% CI: 0.33–0.55]) and unplanned in 24 (IR = 0.17 [95% CI: 0.11–0.25]). Patients with CMC diseases accounted for 59 index visits (42%) and 43 s HCVs (51%). Multivariate analysis including CMC status as an independent variable, with adjustment for age, yielded an incidence rate ratio (IRR) of second HCVs of 1.51 [95% CI: 0.98–2.32]. The IRR of planned second HCVs was 1.20 [95% CI: 0.76–1.90] and that of unplanned second HCVs was 2.81 [95% CI: 1.20–6.58]. Conclusion An index PED visit is often associated with further HCVs in patients with RBD. The IRR of unplanned second HCVs was high, highlighting the major burden of HCVs for patients with chronic and severe disease