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Design, synthesis and evaluation of the first 2-alkynyl(aza)indole F probe targeting α-synuclein aggregates
No full textInternational audienceBackground/Objectives: The role of α-synuclein (α-syn) in the pathogenesis of Parkinson's disease (PD) or neurodegenerative diseases such as Lewy body dementia (LBD) and multiple system atrophy (MSA) is commonly accepted. Through different physiological dysfunctions, abnormal forms of α-syn are generated. These abnormal aggregates accumulate and alter pre-and postsynaptic transmission, in particular that of dopamine. Thus, the development of a diagnostic biomarker of synucleinopathies remains crucial and challenging. The development of an α-syn positron emission tomography (PET) radiopharmaceutical may be suitable to early diagnose and stratify patients, follow up disease progression, and evaluate future therapies. Methods: To develop a selective α-syn PET tracer, we synthesized an original series based on alkynyl(aza)indoles. Fifteen final ligands were synthesized bearing indoles or azaindoles from one side of the alkyne and a substituted phenyl ring for the opposite side of the alkyne. The final ligands were tested to determine Ki and/or Kd toward α-syn, tau, and Aβ. Results: The SAR showed that the indole series exhibited moderate to low affinity for α-syn and, moreover, lower Ki toward Aβ and tau (i.e., compound 39, Ki (αsyn) 21.7 nM, Ki (Aβ) 64.4 nM, Ki (Tau) 27.6 nM), highlighting the low potency of these series to afford an α-syn tracer. The introduction of a nitrogen on the different positions of the phenyl to obtain the corresponding azaindoles resulted for most of the compounds in better affinity for α-syn and selectivity towards Aβ compared to the indole analogs (i.e., compound 43, Ki (αsyn) 4.7 nM, Ki (Aβ) 24.4 nM, and Ki (Tau) 4.61 nM). A fluorinated azaindole derivative was prepared with a view to obtaining a 18 F tracer and exhibited the highest affinity for α-syn but without selectivity against tau and Aβ. The radiosynthesis of [ 18 F]45 was performed in a two-step procedure starting from the tosylated and protected precursor. [ 18 F]45 was obtained in 85 ± 5 min with a radiochemical yield of 32 ± 3%. Molar activity, determined from a calibration with stable 45, was around 130 GBq/µmole. The dynamic PET imaging showed that [ 18 F]45 was able to cross the blood-brain barrier, but non-specific uptake was observed, confirming the in vitro results. Conclusions: Although promising nanomolar affinity for the target, the new tracer showed mainly non-specific in vivo uptake in the rat brain, indicating that further pharmacomodulations on the azaindole series are required
Etude d’un lot métallurgique (creusets et alliages) issu des fouilles du château de Blain
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Initial experimental approaches concerning copper production structures at Viña del Cerro (AD 1200-1536)
No full textInternational audienceMetallurgy in the Copiapó Valley has a long history that begins in the Formative Period with the Molle society, around 2,000 years ago (Niemeyer 1998; Plaza and Garrido 2024). During this time, the first sedentary villages practicing agriculture emerged, where metals became a significant component of burial offerings, particularly in association with infants.Archaeological evidence indicates that specific locations with strong natural winds were used for copper smelting, together with high grade copper ores (malachite and brochantite) finally crushed (Plaza and Garrido 2024). This local technology persisted over time, continuing through the Late Intermediate Period and the Late Horizon, during the Inca expansion into the Copiapó Valley (Garrido and Plaza 2020; Plaza et al. 2023). Despite changes in the scale of production introduced by the Incas, there is clear technological continuity where metallurgists managed ancient local techniques throughout the entire pre-Hispanic cultural sequence of the region.As part of the Fondecyt 1230614 project, we are investigating the long history of mining in the southern Atacama Desert over the past 2,000 years. This research includes the study of the social organization of mining production, the architecture and settlement patterns of local mining camps, lapidary and pigment production, and ancient metallurgical practices. Regarding the latter, we are conducting archaeological excavations, analytical research, and have also initiated an experimental phase to better understand the processes involved in ancient metallurgy in the Copiapó region. Focusing on Viña del Cerro, the principal metallurgical site active before and during the Inca expansion, one of our main objectives is to reconstruct local metallurgical technologies for primary smelting — particularly because they represent a distinct tradition from those identified farther north in the central Andes
Coin moulds of the 3rd century AD from Charleville-Mézières (Ardennes, France): From identification to experimentation
No full textInternational audienceThe excavation of the copper cementation workshop at Le Clos-Paul site in Charleville-Mézières, Ardennes, France revealed forty-three fragments of coin moulds. Dating from to the end of the 3rd century AD, they are the only evidence of an opportunistic counterfeit production not directly linked to the metallurgical activity of the site. After studying the copied coins, metrological and structural observations allowed us to resume the study of the modus operandi of this counterfeiting process, continuing the work of Hans Drescher
Développement d'un nouvel outil de conception in silico de ligands par fragments avec une stratégie de repositionnement
No full textFragment-Based Ligand Design (FBLD) is a widely adopted approach in academic laboratories and pharmaceutical companies. Frags2Drugs (F2D), an innovative in silico FBLD tool aimed at designing novel protein kinase inhibitors, was previously developed. However, its applicability domain is limited solely to protein kinases, restricting its widespread adoption.This thesis proposes universal Frags2Drugs (uF2D), a structure-based molecular generator which expands the applicability domain of F2D to encompass the entire proteome.The uF2D methodology comprises two distinct components: a fragment hit identification tool and a linker generator. For fragment hit identification, an existing computational FBLD tool named CrystalDock, originally designed for fragment-to-lead optimization, has been thoroughly evaluated, re-implemented, and adapted. Fragment hits are identified by repositioning fragments with similar protein local environment found in cocrystallized protein-ligand complex structures. Multiple datasets have been compiled to systematically evaluate the performance of CrystalDock across varying levels of difficulty. A deep learning-based linker generator, DiffLinker, has also been evaluated.Although the program still requires refinement and parameter optimization, a prototype version of uF2D has been proposed, laying the foundation for future FBLD methodology development.La conception de ligands par fragments (FBLD) est une approche largement adoptée dans les laboratoires académiques et les entreprises pharmaceutiques. Frags2Drugs (F2D), un outil in silico innovant visant à concevoir de nouveaux inhibiteurs de protéines kinases et basé sur l'information structurale de fragments, a déjà été développé. Cependant, son domaine d'application est restreint aux protéines kinases, ce qui limite sa généralisation. Cette thèse propose universal Frags2Drugs (uF2D), un générateur de molécules bioactives tenant compte des structures de protéines, ce qui étend le domaine d'application de F2D à l'ensemble du protéome. La méthodologie uF2D comprend deux composants distincts : un outil d'identification des fragments hits et un générateur de liaisons. Pour l'identification des fragment hits, un outil FBLD computationnel existant, CrystalDock, initialement conçu pour l'optimisation fragment-to-lead, a été évalué, réimplémenté et adapté. Les fragments sont identifiés en repositionnant des fragments présentant un environnement protéique local similaire, présents dans des structures co-cristallisées de complexes protéine-ligand. Plusieurs jeux de données ont été compilés afin d'évaluer systématiquement les performances de CrystalDock à différents niveaux de difficulté. DiffLinker, un générateur de liaisons (linker) basé sur l'apprentissage profond, a également été évalué. Bien que le programme nécessite encore des améliorations et une optimisation de ses paramètres, une version prototype d'uF2D a été présentée, posant les bases du développement futur de la méthodologie FBLD
Time Series for QFFE: Special Issue of the Journal of Time Series Analysis
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Establishing a European Heliophysics Community (EHC)
No full textInternational audienceEurope hosts a large and highly active community of scientists working in the broad domain of Heliophysics. This broad discipline addresses plasmas in the regions of space and atmosphere influenced by the Sun and solar wind. However, this community has historically been fragmented, both geographically and thematically, which has limited the potential for strategic coordination, collaboration, and growth. This has recently prompted a grass-roots community-building effort to foster communication and in-teractions within the European Heliophysics Community (EHC). This white paper outlines the motivation, priorities, and initial steps towards establishing the EHC, and presents a vision for the future of Heliophysics in Europe. As a crucial first step of this endeavour, a dedicated EHC website is now available: https://www.heliophysics
L’emploi du fer dans les maçonneries de Notre-Dame de Paris. L’exemple des agrafes des murs gouttereaux
No full textNational audienceL’incendie survenu le 15 avril 2019 qui a détruit l’entièreté de la charpente de la cathédrale a contribué à mettre au jour des structures métalliques auparavant inconnues sur l’édifice. Les travaux du groupe de recherche Métal du chantier scientifique CNRS/Ministère de la Culture s’intéressent à ces armatures en fer dans une perspective interdisciplinaire. Comprendre la mise en œuvre de ce matériau dans l’assemblage des pierres, son rôle structurel, mais aussi appréhender les modalités de sa remise en œuvre dans la restauration en cours sont des réflexions auxquelles nous invite le chantier de rénovation de Notre-Dame de Paris aujourd’hui
Reaction of OH Radicals with C 2 H 4 : Kinetics, Products, Temperature, and Pressure Dependence
No full textInternational audienceThe kinetics and products of the reaction of OH radicals with ethylene were studied using a low-pressure discharge-flow reactor combined with modulated molecular beam mass spectrometry. The total rate constant of the reaction (k1) was determined as a function of pressure (0.4–20 Torr of helium) and temperature (240–1000 K). The title reaction was found to proceed through two channels: adduct forming and H atom abstraction. For the addition channel, the high- and low-pressure limit rate coefficient were extracted from a global fit of the fall off curves observed at different temperatures (present low pressure and available in the literature high-pressure data for the reaction rate constant) with the two-parameter expression. Moreover, this parametrization was found to reasonably reproduce existing measurements of k1 with N2 bath gas down to 69 K. The hydrogen atom abstraction channel was found to be the only important reaction pathway at T > 700 K. The rate constant of this reaction channel was determined in the temperature range 375–1000 K, as being equal to the overall rate constant at T > 700 K, and through the measurements of the yield of the reaction product, C2H3 radical, at T = 375–690 K: k1b = (1.43 ± 0.10) × 10–14 (T/298)3.96 ± 0.09 cm3 molecule–1 s–1. This expression was found to describe well earlier shock tube measurements at high temperatures (up to 1930 K) and can be recommended for use in the temperature range 375–1930 K. The rate constants measured in this study for both addition and abstraction channels are in good agreement with available theoretical calculations