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Evaluation of dual-function molecules containing both Zn-Ionophore and aggregation inhibition moieties for mutant p53 protein reactivation
No full textInternational audienceThe p53 protein plays an important role in preventing cancer and is critical in inducing an antiproliferative response. Unfortunately, the p53 pathway is compromised in almost all cancers, and mutations to p53 lead to loss of function due to protein unfolding, compromised Zn2+ binding, aggregation and amyloid formation. Herein, two new multidentate N,O donor ligands LI-A and LH-A were tested to potentially restore Zn2+ binding to mutant p53, while also inhibiting protein aggregation. The design of these ligands centered on combining an iminodiacetate (IDA) metal binding moiety which was previously determined to exhibit favourable Zn2+ binding affinity and Cu2+/Zn2+ selectivity ratio, with a benzothiazole unit that has been demonstrated to limit mutant p53 protein aggregation. The new ligands were shown to exhibit Zn2+ Kd values in the low nM range based on a fluorophore competition assay, while also inhibiting mutant p53 aggregation via a Thioflavin-T (ThT) assay. In cell-based assays and NCI-60 screening, neither of the new ligands displayed significant cytotoxicity. A reactive oxygen species (ROS) assay showed that neither of the new ligands increased intracellular ROS, however, the previously studied LI compound did show an increase in ROS, providing further information on the mechanism of action of this class of compounds. The current results highlight that the dipicolylamine (DPA) unit is important for anticancer activity, and that phenolate substitution has an important role in dictating the mechanism of cytotoxicity
One pot-synthesis, crystal structure , DFT studies, in silico molecular docking studies of Novel Mannich bases from p-methoxythymol
No full textInternational audienceThis work was designed to synthesize Mannich base compounds starting from naturally occurring p-methoxythymol. This end was isolated from the wood of Tetraclinis Articulata and involved in a three-component Mannich reaction with formaldehyde and various secondary acyclic and cyclic amines. All targeted compounds 1a-e were fully identified based on their 1H and13C Nuclear magnetic resonance (NMR) spectral data. The structures of 1a, 1d and 1e were confirmed by X-ray diffraction (XRD) analysis showing that the molecules are associated by C—H···O and C—H···π interactions forming a supramolecular network. The Hirshfeld surface indicate that the H···H (75.5–81.5 %) interactions are significantly higher than the others interactions. Further, density functional theory calculations have been used to analyze the electronic and geometric frontier molecular orbital and molecular electrostatic map analyses of the compounds to predict the reactive site. Molecular docking studies performed against apoptotic and anti-apoptotic proteins BAX, BCL2, and Caspase-3 demonstrated that compound 1e had the highest binding affinity of -24.0, -24.5, and -24.8 kJ/mol than the piperine (-20.2, -28.4, -27.6 kJ/mol) which was used as standard inhibitor. At the end, in silico Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) predictions found all compounds to have a favorable drug-like profile, predicted Central Nervous System (CNS) permeability, and low toxicity. Conclusively, the results suggest that the newly synthesized Mannich base derivatives of p-methoxythymol have promising applications as lead compounds for anticancer drug development
Input-to-state stability of infinite-dimensional systems: Foundations and present-day developments
No full textInternational audienceInput-to-state stability (ISS) unifies the stability and robustness in one notion, and serves as a basis for broad areas of nonlinear control theory. In this contribution, we covered the most fundamental facts in the infinite-dimensional ISS theory with a stress on Lyapunov methods. We consider various applications given by different classes of infinite-dimensional systems. Finally, we discuss a Lyapunov-based small-gain theorem for stability analysis of an interconnection of two ISS systems
Réactiver l'opéra au XXIe siècle. Correction de l'interprétation et efficacité de l'activation
No full textNational audienceUsant de mises en scène récentes d'opéras, on examine le concept goodmanien d'activation, en distinguant interprétation et activation, activation d'une œuvre et activation d'un genre. On montre que la norme de la correction de l'interprétation, et la norme d'efficacité de l'activation, se contrarient, ce qui contrevient à la tentative d'interpréter Goodman en termes réalistes et essentialistes
Imperfect condition-based maintenance policy for stochastic degradation systems in dynamic environments
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Compréhension de la nucléophilie des anilines para-substituées dans le méthanol: réactivité et analyses computationnelles
No full textInternational audienceWe investigated the nucleophilic reactivity of a series of para-substituted anilines 2a-2e through a combined kinetic and theoretical approach, employing their reactions with thiophenes 1a-1c as electrophilic references in methanol at 20 °C. The satisfactorily correlations observed between the reaction rates and the oxidation potentials of the anilines provide compelling evidence for a single-electron transfer (SET) mechanism. Nucleophilicity parameters (N, sN) were determined in methanol following Mayr's empirical equation. A particularly compelling finding of our study is the good correlation observed between the nucleophilicity parameters (N) of anilines 2a-2e measured in methanol and those reported by Mayr in acetonitrile, demonstrating the role of solvent polarity in nucleophilic reactivity.Utilizing this correlation and the established relationship between N and the Hammett constant (σp), we predicted N values for five additional 4-X-anilines 2f-2j (X = NO₂, CN, CF₃, F, and N(CH₃)₂). Furthermore, density functional theory (DFT) calculations were conducted to explore relationships between N and various reactivity descriptors, including the nucleophilicity index (ω -1 ), dipole moment (μ), polarizability (α), and hyperpolarizability (β) for the ten para-X-substituted anilines 2a-2j. The data reveal a clear structure-property framework for tuning the NLO response of substituted anilines. Molecules substituted with strong EWGs are superior candidates for NLO applications due to their high dipole moments, elevated polarizabilities, and exceptionally large hyperpolarizabilities.</div
Immersive Environments
No full textInternational audienceImmersive environments present significant management opportunities for businesses, enabling innovative approaches toemployee engagement, customer interactions, and operational efficiency. Through the integration of virtual and augmented realitytechnologies, organizations can enhance training programs, improve workplace safety, and optimize operational support in sectorssuch as manufacturing and engineering. Additionally, immersive environments facilitate remote collaboration, talent acquisition,and the creation of engaging work environments, addressing the challenges of a competitive job market. Looking forward,advancements in technology and user experience will drive the widespread adoption of immersive environments, fosteringinterdisciplinary collaboration to create personalized and interactive experiences. As immersive technologies become moreaccessible and widespread, accompanied by supplementary tools and techniques, they hold immense potential to revolutionizeindustries beyond entertainment, including healthcare and education. The trajectory of immersive environments points towardscontinued growth, innovation, and enhanced human engagement across various sectors, signaling a transformative shift in howbusinesses operate and interact with their stakeholders. Also, we propose the holistic framework for immersive environments,comprising three interconnected elements: immersive technology, environment, and experiences. These elements collectively shapeand define the nature of immersive environments, influencing their creation, deployment, and impac
Trajectories and turning points: Objects of intermediation for generalisation
No full textInternational audienceWe introduce generalisation as an intermediated trajectory to explain how system innovations, like alternative food systems, diffuse. While existing literature on diffusion and scaling focuses on human agency and steady progression, we propose a relational, object-oriented approach that highlights the role of situated intermediation punctuating/disrupting trajectories of generalisation. We identify four key objects of intermediation-knowledge, value(s), infrastructures, and rules-and demonstrate their role in reconfiguring actor networks and redirecting transformative trajectories. Through three empirical cases (natural wine, sustainable apiculture, and participatory research in France), we demonstrate how intermediation around these objects resolves challenges (interdependencies, uncertainties, complexities, controversies) and creates turning points that redirect transformative pathways. Our framework integrates the trajectory-turning point model to identify four conditions for transformative change: stability, resistance, identity transformation, and role commitment. Findings reveal that generalisation is dynamic and intermediated, whereby objects and actors collaboratively reconfigure networks, institutional contexts, and innovation objectives. The original contribution of this meso-level perspective lies in theorising generalisation as an intermediated trajectory, emphasising the material and relational work of objects alongside human agency. This reframing advances transition studies and innovation policy research by shifting focus from diffusion mechanisms to the situated, iterative processes that enable systems transformation
A Note on Pareto-Optimal Taxation Mechanism in Noncooperative Strategic Bilateral Exchange
No full textInternational audienceThis paper investigates the taxation mechanism implemented in strategic bilateral exchange by Gabszewicz and Grazzini (JPET, 1999). These authors show that endowment taxation with transfers can implement a Pareto-optimal allocation when the preferences of traders are represented by some specific homothetic utility functions. We show that this taxation mechanism can also implement a Pareto-optimal allocation when the preferences of traders are represented by non homothetic utility functions. To this end, we consider a class of quasi-linear utility functions. Furthermore, we illustrate that, with quasi-linear utility functions, by introducing heterogeneity between traders, there are other environments in which this taxation mechanism implements a Pareto-optimal outcome
Lire les romans rustiques à la lumière de Marcel Mauss : Sand et la sociologie du don
No full textInternational audienceL'article montre la fécondité d'une lecture des romans "rustiques" ou "champêtres" de Sand (La Mare au diable, François le Champi, La Petite Fadette) à la lumière de l'Essai sur le don de Marcel Mauss et de de la sociologie du don défendue par le mouvement anti-utilitariste dans les sciences sociales (MAUSS)