HAL Portal ESPCI (Ecole Supérieure de Physique et de Chimie Industrielles)
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The genetic architecture of HIV-1 virulence
No full textInternational audienceThe virulence of Human Immunodeficiency Virus-1 (HIV-1) is partly determined by viral genetic variation. Finding individual genetic variants affecting virulence is important for our understanding of HIV pathogenesis and evolution of virulence; however, very few have been identified. To this end, within the “Bridging the Evolution and Epidemiology of HIV in Europe” (BEEHIVE) collaboration, we produced whole-genome HIV sequence data for 2294 seroconverters from European countries for a genome-wide association study (GWAS). We considered two phenotypes: (i) set-point viral load (SPVL), the approximately stable viral load from 6 to 24 months after infection, and (ii) the rate of CD4 cell count decline. We developed a GWAS method that corrects for population structure with random effects, accounts for two or more alleles at each locus, and tests for the effect of multiple genetic variants including single-nucleotide polymorphisms (SNPs), k-mers, insertions and deletions, within-host variant frequency, the number of rare point mutations, and drug resistance. We confirmed with this new approach that viral genomes explained 26% [95% CI 17%–35%] of the variance in SPVL, while they explained only 0.9% [0.0%–2.1%] of the variance in the rate of CD4 cell count decline. After correction for multiple testing, among all tested variants, only two significantly explained SPVL: an epitope mutation allowing escape from the host HLA-B*57 allele and lowering SPVL by −0.26 copies/ml and an epitope mutation allowing escape from the host HLA-B*35 allele and increasing SPVL by +0.22 copies/ml. We attempted to replicate these two large effects in two additional independent datasets together encompassing 2445 seroconverters, with mixed results. Overall, the inferred effects of all SNPs and amino-acid variants weakly correlated (R2 ranging from 0.08 to 0.87%, P-values from 0.001 to 0.32) between our main dataset and these two additional datasets. Lastly, a lasso regression of phenotypes on genetic variants confirmed the heritability of SPVL and explained up to 6% of variance in SPVL in cross-validation datasets. These findings suggest that HIV SPVL is determined by viral genomes through HLA escape variants with potentially large, host-dependent effects that may not always be detected at the population level and many other variants with effects too weak to reach genome-wide significance in our GWAS
A Microporous Bimetallic Aluminum-Copper-Carboxylate-Pyrazolate MOF for CO2 Capture
No full textHerein, we present a novel bimetallic hetero-functional ultra-microporous MOF, labelled MIP-212(Al/Cu) (MIP stands for Materials from Institute of Porous Materials of Paris), designed based on Hard and Soft Acids and Bases (HSAB) principle. This MOF is constructed from Al3+ and Cu2+ ions together with the carboxylate-pyrazolate ligand (PyC), that endows the structure with two types of narrow tunnel-like pores decorated with either μ2-OH groups or Cu(II) open metal sites. While the structure shows a slight breathing behaviour depending on pore’s content, the confinement effect, in combination with open metal sites generated upon activation, leads to a remarkably high CO2 uptake capacity at ambient temperature and low pressure (ca. 2.30 mmol/g at 0.15 bar), comparable to benchmark MOFs, with a good CO2/N2 IAST estimated selectivity of ca. 30 at 1 bar. The calculated Qst (CO2) of -36.8 kJ·mol-1 suggests a relatively low energy demand for its regeneration process. Finally, dynamic breakthrough measurements conducted under binary gas mixture conditions of CO2:N2 (15:85) prompts MIP-212(Al/Cu) as a promising post-combustion CO2 capture adsorbent, when employed in a typical temperature swing adsorption (TSA) process, as predicted by process, techno-economics and environmental Key Performance Indicator
Correlative Near-Field Characterizations with KPFM, sMIM and SCM to Characterize the Geometry of a N-Channel Failed SiC JFET
No full textInternational audienceAbstract The growing demand for high-performance power electronic devices in a variety of applications has led to a need for efficient, compact designs with increasingly complex architectures. To achieve this, precise and accurate analysis of the local electrical properties at the nanoscale is required to confirm the doping layer geometries at the end of the process. This study employs non-destructive nanoscale characterization techniques to investigate the local properties of designed and fabricated Silicon Carbide (SiC) power devices based on lateral Junction Field-Effect Transistors (JFETs). The SiC sample under study comprises failed n-type lateral JFET channels fabricated with multiple SiC layers in a mesa structure, featuring varying doping levels and several SiC homojunctions. Various electrical modes based on Atomic Force Microscopy (AFM), including the well-known Kelvin Probe Force Microscopy (KPFM), as well as advanced Scanning Capacitance Microscopy (SCM) and scanning Microwave Impedance Microscopy (sMIM) modes, were employed. These three AFM electrical modes enable the mapping of electrical properties, the identification of junctions and the local doping geometries, which are all crucial for device operation and performance. These approaches are highly effective in resolving small-scale variations within multilayers and in providing clear information on doping concentrations, types and work function differences. Mappings from the three modes are compared in terms of sensitivity and signal-to-noise ratio. The impact of the applied VDC during SCM mode on the characterization of SiC junctions is also highlighted
Proteins and Water Control the Stability of the Intracellular Amorphous Calcium Carbonate Inclusions Formed by Cyanobacteria
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Astrocyte-to-neuron H2O2 signalling supports long-term memory formation in Drosophila and is impaired in an Alzheimer’s disease model
No full textInternational audienceAstrocytes help protect neurons from potential damage caused by reactive oxygen species (ROS). While ROS can also exert beneficial effects, it remains unknown how neuronal ROS signalling is activated during memory formation, and whether astrocytes play a role in this process. Here we discover an astrocyte-to-neuron H 2 O 2 signalling cascade in Drosophila that is essential for long-term memory formation. Stimulation of astrocytes by acetylcholine induces an increase in intracellular calcium ions, which triggers the generation of extracellular superoxide (O 2 • – ) by astrocytic NADPH oxidase. Astrocyte-secreted superoxide dismutase 3 (Sod3) converts O 2 • – to hydrogen peroxide (H 2 O 2 ), which is imported into neurons of the olfactory memory centre, the mushroom body, as revealed by in vivo H 2 O 2 imaging. Notably, Sod3 activity requires copper ions, which are supplied by neuronal amyloid precursor protein. We also find that human amyloid-β peptide, implicated in Alzheimer’s disease, inhibits the nAChRα7 astrocytic cholinergic receptor and impairs memory formation by preventing H 2 O 2 synthesis. These findings may have important implications for understanding the aetiology of Alzheimer’s disease
Label‐Free Machine Learning Prediction of Chemotherapy on Tumor Spheroids Using a Microfluidics Droplet Platform
No full textInternational audienceAn integrated approach is proposed to rapidly evaluate the effects of anticancer treatments in 3D models, combining a droplet‐based microfluidic platform for spheroid formation and single‐spheroid chemotherapy application, label‐free morphological analysis, and machine learning to assess treatment response. Morphological features of spheroids, such as size and color intensity, are extracted and selected using the multivariate information‐based inductive causation algorithm, and used to train a neural network for spheroid classification into viability classes, derived from metabolic assays performed within the same platform as a benchmark. The model is tested on Ewing sarcoma cell lines and patient‐derived xenograft (PDX) cells, demonstrating robust performance across datasets. It accurately predicts spheroid viability, used to generate dose‐response curves and to determine half maximal inhibitory concentration (IC50) values comparable to traditional biochemical assays. Notably, a model trained on cell line spheroids successfully classifies PDX spheroids, highlighting its adaptability. Compared to convolutional neural network‐based approaches, this method works with smaller training datasets and provides greater interpretability by identifying key morphological features. The droplet platform further reduces cell requirements, while single‐spheroid confinement enhances classification quality. Overall, this label‐free experimental and analytical platform is confirmed as a scalable, efficient, and dynamic tool for drug screening
Electrodeposition and soft oxidation of nickel‑iron hydroxides: An efficient two-step approach for the synthesis of highly active and stable iron-rich NiFe-LDHs with controlled Ni/Fe composition for oxygen evolution reaction
No full textInternational audienceNickel‑iron layered double hydroxides (NiFe-LDHs) are promising low-cost and active electrocatalysts for the alkaline oxygen evolution reaction (OER), yet conventional synthesis methods face two key limitations: (i) poor control over the Ni/Fe atomic ratio and (ii) difficulty in producing active, stable iron-rich NiFe-LDHs due to the formation of inactive iron hydroxide phases. Given iron's higher abundance and lower cost compared to nickel, developing iron-rich NiFe-LDHs is highly desirable. In this study, we present a two-step synthesis approach to overcome these challenges: first, rapid cathodic electrodeposition (<1 min) of NiFe(OH)2 onto an electrode, followed by controlled ambient oxidation of Fe2+ to Fe3+, yielding phase-pure NiFe-LDH. By adjusting the electrodeposition potential, we achieve precise control of the Ni/Fe ratio in the film, matching the precursor solution composition. SEM-EDS analysis confirms this correlation for films electrodeposited at −2.0 V vs. Ag/AgCl (3 M KCl) across a broad Ni/Fe range. The oxidation step integrates iron (as Fe2+ and Fe3+) into the LDH lattice without forming inactive iron oxide phases. XPS analysis reveals a consistent M3+/M2+ ratio (∼1/3, M = Ni and Fe), consistent with the hydrotalcite (honessite) structure, indicating Fe oxidation is governed by the LDH structure. Electrochemical testing in 1 M aqueous KOH demonstrates outstanding performance: a NiFe-LDH with 35.1 ± 2.0 at. % Fe exhibits an overpotential of 167 ± 22 mV at 30 mA·cm−2, while a 76.6 ± 4.0 at. % Fe film requires 249 ± 10 mV. Both catalysts maintain stability over 100 h at 100 mA·cm−2, surpassing previously reported NiFe-LDHs with comparable Fe content in activity and durability. This work provides a scalable route to iron-rich NiFe-LDHs synthesis with controlled composition and high catalytic performance
Conception et synthèse de dérivés du ganglioside GM3 en tant que candidats vaccins anticancéreux
No full textGlycosylation is a prevalent post-translational modification of cell-surface proteins and lipids, essential for cellular recognition, signaling, and immune modulation. In cancer, glycosylation patterns are often dysregulated, leading to the overexpression of tumor-associated carbohydrate antigens (TACAs). These aberrant structures provide targets for synthetic vaccine development, aiming to induce immune memory and improve tumor recognition. Advances in glycan synthesis have significantly enhanced the design and immunogenicity of carbohydrate-based cancer vaccines. Ganglioside GM3 (Neu5Ac-α2,3-Gal-β1,4-Glc-β1-ceramide) is widely distributed in neuronal and epithelial membranes and regulates cell growth, adhesion, apoptosis, and signaling. Notably, GM3 is overexpressed in various tumors, including melanoma, breast cancer, and lung cancer. It is also one of the nine TACAs that have been progressed into clinical trials by the FDA. In our previous studies, a series of GM3 analogues were synthesized by replacing the glycosidic units excluding sialic acid. These non-natural glycan structures demonstrated promising anti-tumor activities by in vitro assays. In this study, a series of allyl glycosides (glucose, galactose, mannose, and lactose) were synthesized. Selective protection strategies were applied to expose either the C-3 or C-6 hydroxyl groups to serve as acceptors for sialylation. The key glycosylation step employed sialyl xanthate as glycosylation donor to afford six products in good yields (41~65%). Side reactions arising from allyl electrophilic addition were minimized by careful control of promoter addition. All new compounds were purified by chromatography and fully characterized using high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) spectroscopy. Subsequently, the allyl glycosides were converted to their corresponding glycolaldehydes via ozonolysis and conjugated to carrier protein BSA and KLH. The conjugation degree was determined using MALDI-TOF-MS or specific colorimetric assays. Notably, even among structural isomers, significant differences in conjugation efficiency were observed. To further investigate this phenomenon, α- and β-glycolaldehyde glycosides of five biologically relevant monosaccharides (Man, Glc, Gal, GlcNAc, and GalNAc) were synthesized and conjugated to proteins at a fixed sugar-to-protein molar ratio. Continuous kinetic monitoring revealed that anomeric configuration markedly influences both reaction rates and final sugar loading: α-Man > β-Man; β-Gal/GalNAc > their α-counterparts; Glc and GlcNAc showed no significant anomeric differences. NMR analysis identified cyclic intermediates that reduce the effective concentration of reactive aldehyde, while DFT calculations provided complementary insight into anomer-specific electrophilic character. This work presents a systematic study on the synthesis of GM3 derivatives and the conjugation of glycolaldehyde to protein, providing valuable information for design, synthesis, and conjugation of GM3 analogues and their vaccine application.La glycosylation est une modification post-traductionnelle fréquente des protéines et lipides membranaires, essentielle à la reconnaissance cellulaire, à la signalisation et à la modulation immunitaire. Dans les cancers, les profils de glycosylation sont souvent altérés, conduisant à la surexpression d'antigènes tumoraux glucidiques (TACAs). Ces structures aberrantes constituent des cibles pour le développement de vaccins synthétiques, visant à induire une mémoire immunitaire et à améliorer la reconnaissance tumorale. Les avancées en synthèse glycannique ont considérablement renforcé la conception et l'immunogénicité des vaccins anticancéreux à base de glucides. Le ganglioside GM3 (Neu5Ac-α2,3-Gal-β1,4-Glc-β1-céramide) est largement distribué dans les membranes neuronales et épithéliales, où il régule la croissance cellulaire, l'adhésion, l'apoptose et la signalisation. Il est notoirement surexprimé dans divers types de tumeurs, notamment le mélanome, le cancer du sein et le cancer du poumon. GM3 fait également partie des neuf TACAs ayant atteint les essais cliniques approuvés par la FDA. Dans nos travaux précédents, une série d'analogues de GM3 a été synthétisée par remplacement des unités glycosidiques autres que l'acide sialique. Ces structures glycosidiques non naturelles ont démontré une activité antitumorale prometteuse lors de tests in vitro. Dans cette étude, une série de glycosides allyliques (glucose, galactose, mannose et lactose) a été synthétisée. Des stratégies de protection sélective ont été appliquées pour exposer sélectivement les groupes hydroxyles en C-3 ou C-6 servant de récepteurs à la sialylation. L'étape clé de glycosylation a utilisé un donneur sialyl xanthate permettant d'obtenir six produits avec de bons rendements (41-65%). Les réactions secondaires impliquant l'addition électrophile sur le groupement allyle ont été minimisées par un contrôle rigoureux de l'addition du promoteur. Tous les nouveaux composés ont été purifiés par chromatographie et pleinement caractérisés par spectrométrie de masse à haute résolution (HRMS) et spectroscopie RMN. Les glycosides allyliques ont ensuite été convertis en leurs dérivés glycolaldéhydiques par ozonolyse, puis conjugués aux protéines porteuses BSA et KLH. Le degré de conjugaison a été déterminé par MALDI-TOF-MS ou par des dosages colorimétriques spécifiques. Il est à noter que, même entre isomères de structure, des différences significatives d'efficacité de conjugaison ont été observées. Afin d'explorer plus en détail ce phénomène, des glycosides glycolaldéhydiques α et β de cinq monosaccharides d'importance biologique (Man, Glc, Gal, GlcNAc et GalNAc) ont été synthétisés et conjugués à des protéines selon un rapport molaire sucre/protéine fixe. Un suivi cinétique en continu a révélé que la configuration anomérique influençait fortement à la fois la vitesse de réaction et la charge finale en sucres : α-Man > β-Man ; β-Gal/GalNAc > leurs α-contreparties; Glc et GlcNAc ne montraient pas de différence anomérique significative. L'analyse RMN a mis en évidence des intermédiaires cycliques réduisant la concentration effective en aldéhyde réactif, tandis que des calculs DFT ont apporté un éclairage complémentaire sur le caractère électrophile spécifique à chaque anomère. Ce travail présente une étude systématique sur la synthèse de dérivés de GM3 et la conjugaison de glycolaldéhydes à des protéines, apportant des informations utiles pour la conception, la synthèse et l'application vaccinale d'analogues de GM3
Ramollissement élastique et compaction simultanée induits par les ondes de cisaillement dans les milieux granulaires denses : expérimentation et modélisation
No full textPropriétés et rhéologie de milieux hétérogènes; GAPSUS - Acoustique Physique, Sous-Marine et Ultra-SonoreNational audienceDans cette étude, nous analysons le ramollissement élastique et la compaction simultanée d'un milieu granulaire dense à l'aide d'expériences de résonance acoustique. Le ramollissement élastique se manifeste par une diminution de la vitesse des ondes de cisaillement lorsque l'amplitude des ondes dépasse un certain seuil. Toutefois, aucun réarrangement macroscopique des grains ni dilatation n'est observé. En revanche, ce ramollissement élastique s'accompagne d'une compaction légère, mais observable à l’échelle des aspérités des grains. Nous expliquons ces résultats apparemment contradictoires en utilisant un modèle théorique basé sur les zones de transformation par cisaillement (STZs, shear transformation zones), qui correspondent à des régions molles ou à des contacts glissants entre grains. Ce modèle prédit une réponse linéaire entre la contrainte et la déformation de cisaillement dans le cas d'une oscillation acoustique de faible amplitude, où la déformation macro-plastique reste négligeable. Cependant, ces ondes peuvent également réduire le frottement entre les grains ainsi que la raideur tangentielle des contacts, par un mécanisme de lubrification acoustique, tel que prédit par le modèle de Hertz-Mindlin. Ce phénomène entraîne une augmentation de la fluidité et du désordre structural, ce qui conduit à un affaiblissement du module dynamique du milieu. La compaction observée, associée à cette diminution du frottement microscopique, est confirmée par des simulations numériques et s’avère également cohérente avec la prédiction d’une corrélation de type Ising entre les STZs, qui se manifeste en dessous du seuil de rupture
Déviation d’onde et le spectre de dispersion observable
No full textOndes guidées; GAPSUS - Acoustique Physique, Sous-Marine et Ultra-SonoreNational audienceLes ondes guidées dans les plaques sont souvent mesurées le long d’une ligne en s’éloignant de la source. Une transformée de Fourier spatio-temporelle fournit le spectre de dispersion dans le domaine fréquence- nombre d’onde. Pour les plaques anisotropes, il est possible d’observer dans le spectre plusieurs contributions d’un même mode. Cet effet s’explique par l’angle de déviation, qui est l’angle entre le vecteur d’onde et le vecteur d’énergie associé. Nous montrons que les ondes guidées proches des résonances à vitesse de groupe nulle présentent des angles de déviation compris entre 0° et 360°. En introduisant le concept de « points de phase stationnaire », nous modélisons précisément le spectre observé, même dans le cas où l’angle de déviation couvre 360°. Nos résultats sont confirmés sur une plaque de silicium par des mesures ultrasons-laser