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International audience; Real-time globally consistent GPS tracking is critical for an accurate localization and is crucial for applications such as autonomous navigation or multi-robot mapping. However, under challenging environment conditions such as indoor/outdoor transitions, GPS signals are partially available or not consistent over time. In this paper, a real-time tracking system for continuously locating emergency response agents in challenging conditions is presented. A cooperative localization method based on Laser-Visual-Inertial (LVI) and GPS sensors is achieved by communicating optimization events between a LiDAR-Inertial-SLAM (LI-SLAM) and Visual-Inertial-SLAM (VI-SLAM) that operate simultaneously. The estimation of the pose assisted by multiple SLAM approaches provides the GPS localization of the agent when a stand-alone GPS fails. The system has been tested under the terms of the MALIN Challenge, which aims to globally localize agents across outdoor and indoor environments under challenging conditions (such as smoked rooms, stairs, indoor/outdoor transitions, repetitive patterns, extreme lighting changes) where it is well known that a stand-alone SLAM will not be enough to maintaining the localization. The system achieved Absolute Trajectory Error of 0.48%, with a pose update rate between 15 and 20 Hz. Furthermore, the system is able to build a global consistent 3D LiDAR Map that is post-processed to create a 3D reconstruction at different level of details.

The aims of the present study were to characterize the mechanical output of final road sprints of an elite sprinter during international competitions in relation to his power-velocity-endurance characteristics, and to investigate the relationship between this sprint performance and the power produced during preceding phases of the race. The sprinter performed a set of short and long sprints (5 to 15 s) on a cycle ergometer to determine his maximal power-velocity-endurance profile. Based on eleven races, the distribution of power throughout each race, peak and mean power (Ppeak and Pmean ) and associated pedalling rates (vPpeak and vPmean ) during the final sprint were analyzed. The power-velocity-endurance profile of the sprinter indicated that his mean maximal power and corresponding optimal pedalling rate ranged from 20.1 W.kg-1 (124 rpm) for a 1-s sprint to 15.2 W.kg-1 (112 rpm) for 20 s. Race data showed that final road sprints were mainly performed on the ascending limb of the power-velocity relationship (vPpeak , 104±8 and vPmean , 101±8 rpm). Additionally, Ppeak and Pmean were lower than the theoretical maximal power determined from the power-velocity-endurance profile (10.4±7.0% and 11.2±9.2%, respectively), which highlighted a significant state of fatigue induced by the race. Finally, sprint power exhibited a high variability between races and was strongly related to the level of power produced during the last minute before the sprint. These findings show the importance of considering both the power-velocity-endurance qualities and the power demand of the last lead-up phase before the sprint in order to optimize final sprint performance.

International audience; Hemiindigoids comprise a range of natural and synthetic scaffolds that share the same aromatic hydrocarbon backbone as well as promising biological and optical properties. The encouraging therapeutic potential of these scaffolds has been unraveled by many studies over the past years and uncovered representants with inspiring pharmacophoric features such as the acetylcholinesterase inhibitor donezepil and the tubulin polymerization inhibitor indanocine. In this review, we summarize the last advances in the medicinal potential of hemiindigoids, with a special attention to molecular design, structure–activity relationship, ligand-target interactions, and mechanistic explanations covering their effects. As their strong fluorogenic potential and photoswitch behavior recently started to be highlighted and explored in biology, giving rise to the development of novel fluorescent probes and photopharmacological agents, we also discuss these properties in a medicinal chemistry perspective.

International audience; Despite being extensively studied for several decades, the microtubule-associated protein Tau has not finished revealing its secrets. For long, Tau has been known for its ability to promote microtubule assembly. A less known feature of Tau is its capability to bind to cancer-related protein kinases, suggesting a possible role of Tau in modulating microtubule-independent cellular pathways that are associated with oncogenesis. With the intention of finding new therapeutic targets for cancer, it appears essential to examine the interaction of Tau with these kinases and their consequences. This review aims at collecting the literature data supporting the relationship between Tau and cancer with a particular focus on glioblastoma tumors in which the pathological significance of Tau remains largely unexplored. We will first treat this subject from a mechanistic point of view showing the pivotal role of Tau in oncogenic processes. Then, we will discuss the involvement of Tau in dysregulating critical pathways in glioblastoma. Finally, we will outline promising strategies to target Tau protein for the therapy of glioblastoma.

Pyomelanin is a brown-black phenolic polymer and results from the oxidation of homogentisic acid (HGA) in the L-tyrosine pathway. As part of the research for natural and active ingredients issued from realistic bioprocesses, this work re-evaluates the HGA pigment and makes an updated inventory of its syntheses, microbial pathways, and properties, with tracks and recent advances for its large-scale production. The mechanism of the HGA polymerization is also well documented. In alkaptonuria, pyomelanin formation leads to connective tissue damage and arthritis, most probably due to the ROS issued from HGA oxidation. While UV radiation on human melanin may generate degradation products, pyomelanin is not photodegradable, is hyperthermostable, and has other properties better than L-Dopa melanin. This review aims to raise awareness about the potential of this pigment for various applications, not only for skin coloring and protection but also for other cells, materials, and as a promising (semi)conductor for bioelectronics and energy.

International audience; In chlordecone (CLD)-contaminated soils of the French West Indies, if microbial remediation or a physicochemical remediation process, e.g., in situ chemical reduction, is implemented, concentrations of degradation byproducts, such as hydrochlordecones, are expected to increase in the ecosystems. To study their impact in mixtures with CLD, bioassays were carried out. They consisted in evaluating the regenerative capacity of hydra polyps, from a clone whose phylogenetic analysis confirmed that it belonged to the species Hydra vulgaris Pallas, 1766. Hydra gastric sections were exposed to CLD alone or CLD plus dechlorinated byproducts (CLD-BP) for 96 h to assess regeneration. Based on chromatographic analysis, the CLD-BP mix was composed of the 5-monohydrochlordecone isomer (CAS nomenclature), four dihydrochlordecone isomers, and one trihydrochlordecone isomer representing 50%, 47%, and 3% of the total chromatographic area, respectively. A total of 18 mixtures of CLD and CLD-BP were tested. Six environmental concentrations of CLD (2.10 −4 μM to 4.10 −2 μM) and a similar range of CLD-BP were used. Results from exposures to CLD alone showed the following: (i) a significant decrease in the regenerative capacity of hydra, except at the lowest concentration (2.10 −4 μM); (ii) a concentration-independent deleterious effect. The regeneration scores obtained after the exposure to the addition of CLD-BP were not significantly different from those obtained after exposure to CLD alone. Using an experimental design, a modeling of the regeneration scores of hydra exposed to mixtures is proposed. Interpreted carefully, since they are limited to only one type of bioassay, the present results suggest that the situation in the aquatic environments should not become worse in terms of toxicity, if soil remediation programs resulting in the formation of hydrochlordecones are put in place.; Dans les sols des Antilles françaises contaminés par la chlordécone (CLD), si une remédiation microbienne ou un processus de remédiation physico-chimique, par exemple une réduction chimique in situ, est mise en œuvre, on s'attend à ce que les concentrations de sous-produits de dégradation, tels que les hydrochlordécones, augmentent dans les écosystèmes. Pour étudier leur impact dans les mélanges avec la CLD, des bio-essais ont été réalisés. Ils ont consisté à évaluer la capacité de régénération de polypes d'hydre, à partir d'un clone dont l'analyse phylogénétique a confirmé l'appartenance à l'espèce Hydra vulgaris Pallas, 1766. Des sections gastriques d'hydres ont été exposées à la CLD seule ou à la CLD plus des sous-produits déchlorés (CLD-BP) pendant 96 h pour évaluer la régénération. D'après l'analyse chromatographique, le mélange CLD-BP était composé de l'isomère 5-monohydrochlordécone (nomenclature CAS), de quatre isomères dihydrochlordécone et d'un isomère trihydrochlordécone représentant respectivement 50 %, 47 % et 3 % de la surface chromatographique totale. Au total, 18 mélanges de CLD et de CLD-BP ont été testés. Six concentrations environnementales de CLD (2.10-4 μM à 4.10-2 μM) et une gamme similaire de CLD-BP ont été utilisées. Les résultats des expositions à la CLD seule ont montré ce qui suit : (i) une diminution significative de la capacité de régénération de l'hydre, sauf à la plus faible concentration (2.10-4 μM) ; (ii) un effet délétère indépendant de la concentration. Les scores de régénération obtenus après l'exposition à l'ajout de CLD-BP n'étaient pas significativement différents de ceux obtenus après l'exposition à la CLD seule. À l'aide d'un plan expérimental, une modélisation des scores de régénération des hydres exposés à des mélanges est proposée. Interprétés avec précaution, car limités à un seul type de bioessai, les présents résultats suggèrent que la situation des milieux aquatiques ne devrait pas s'aggraver en termes de toxicité, si des programmes de dépollution des sols entraînant la formation d'hydrochlordécones sont mis en place.

Chlordecone (CLD), an obsolete insecticide, used in the French West Indies between 1972 and 1993, is persistent in the environment but can be dechlorinated either chemically or under the action of microorganisms. Therefore, if soil remediation programs based on these processes are implemented in areas still contaminated today, those will see their concentrations of dechlorinated derivatives increase and these compounds will be also found in freshwater by streaming, leaching and erosion processes. The purpose of the present study was to evaluate, at environmental concentrations, the toxic effects of mixtures of chlordecone and a three-chlorine substituted byproduct. A hydra clone, which has been confirmed to be Hydra vulgaris Pallas, 1766 has been retained for bioassays where the toxicity has been evaluated by regeneration capacity during exposure. Exposure to mixtures is complex to investigate by classical methods, therefore, an experimental design associated to a mathematical model has been used to predict the effects of all the mixtures and to detect the toxic influence of each compound. The predictive model is discussed regarding the stochastic “endocrine disruptor effect” of CLD. At probable environmental concentrations of the compounds in the mixture, results show that impairment of regeneration capacity is explained mostly by the presence of CLD in the mixtures and support the implementation of remediation programs aimed at dechlorination of this persistent organochlorine pesticide.

International audience; La chlordécone (CLD) est un insecticide organochloré obsolète qui a été utilisé aux Antilles françaisesde 1972 à 1993. Elle est persistante dans l’environnement et se transforme très lentement pardéchloration. En conséquence, elle est encore présente dans les sols mais aussi dans les écosystèmesd’eau douce suite au lessivage, la lixiviation et l’érosion des sols sous l’action des pluies. Dans la mesureoù des programmes de remédiation des sols seraient mis en place dans des zones encore contaminéesaujourd’hui, la concentration des dérivés déchlorés augmenterait alors que celle en CLD diminuerait.L’objet du présent travail est d’évaluer la toxicité de mélanges de CLD et d’un dérivé déchloré, à desconcentrations susceptibles d’être retrouvées dans les eaux de surface, envers un invertébré d’eaudouce modèle. Le dérivé déchloré choisi ici correspond à une tri-hydrochlordécone (CLD-3Cl) qui seforme au cours du procédé de remédiation ISCR (In Situ Chemical Reduction) testé avec succès par leBRGM à l’échelle de la parcelle (Mouvet et al., 2020, https://doi.org/10.1007/s11356-020-07603-z).Pour les essais biologiques de toxicité, le cnidaire Hydra vulgaris a été choisi comme invertébrémodèle. Ces bioessais ont consisté à évaluer la capacité de régénération de cette hydre d’eau douceaprès 96 h d’exposition au mélange CLD + CLD-3Cl. L’impact des mélanges étant complexes à étudierpar les méthodes classiques, la méthode des plans d’expériences a été utilisée pour réduire le nombred’expériences à réaliser sur la plage de concentrations étudiées (0 à 20 μg/L équivalent CLD) sansperdre d’informations et de détecter d’éventuelles interactions entre les composés. Un modèleprédictif de la toxicité du mélange en fonction des différents niveaux de concentrations possibles estproposé ici. Celui-ci permet de conforter le fait que la molécule déchlorée est moins toxique que laCLD et que la présence de dérivés déchlorés en mélange avec cette dernière ne devrait pas engendrerune toxicité supérieure à la CLD seule. Nos résultats montrent que les plans d’expériences sont desoutils très utiles en écotoxicologie et toxicologie environnementale pour évaluer les effets de mélangescomplexes avec de faibles concentrations de xénobiotiques.

Pyomelanin is a polymer of homogentisic acid synthesized by microorganisms. This work aimed to develop a production process and evaluate the quality of the pigment. Three procedures have been elaborated and optimized, (1) an HGA-Mn2+ chemical autoxidation (PyoCHEM yield 0.317 g/g substrate), (2) an induced bacterial culture of Halomonas titanicae through the 4-hydroxyphenylacetic acid-1-hydroxylase route (PyoBACT, 0.55 g/L), and (3) a process using a recombinant laccase with the highest level produced (PyoENZ, 1.25 g/g substrate) and all the criteria for a large-scale prototype. The chemical structures had been investigated by 13C solid-state NMR (CP-MAS) and FTIR. Car-Car bindings predominated in the three polymers, Car-O-Car (ether) linkages being absent, proposing mainly C3-C6 (β-bindings) and C4-C6 (α-bindings) configurations. This work highlighted a biological decarboxylation by the laccase or bacterial oxidase(s), leading to the partly formation of gentisyl alcohol and gentisaldehyde that are integral parts of the polymer. By comparison, PyoENZ exhibited an Mw of 5,700 Da, was hyperthermostable, non-cytotoxic even after irradiation, scavenged ROS induced by keratinocytes, and had a highly DPPH-antioxidant and Fe3+-reducing activity. As a representative pigment of living cells and an available standard, PyoENZ might also be useful for applications in extreme conditions and skin protection.

International audience; This paper introduces a Wearable SLAM system that performs indoor and outdoor SLAM in real time. The related project is part of the MALIN challenge which aims at creating a system to track emergency response agents in complex scenarios (such as dark environments, smoked rooms, repetitive patterns, building floor transitions and doorway crossing problems), where GPS technology is insufficient or inoperative. The proposed system fuses different SLAM technologies to compensate the lack of robustness of each, while estimating the pose individually. LiDAR and visual SLAM are fused with an inertial sensor in such a way that the system is able to maintain GPS coordinates that are sent via radio to a ground station, for real-time tracking. More specifically, LiDAR and monocular vision technologies are tested in dynamic scenarios where the main advantages of each have been evaluated and compared. Finally, 3D reconstruction up to three levels of details is performed.

International audience; This paper presents a use case for SLAM techniques applied to real time localization and detailed mapping for emergency response personnel in non cooperative environments. Such environments tend to defeat conventional localization approaches, therefore we must ensure continuous operation of our localization and mapping regardless of the difficulties encountered (lack of GPS signals, lighting conditions, smoke, etc.). The proposed system fuses two SLAM algorithms, a LiDAR-based and a camera-based. Since LiDAR-based SLAM uses dense 3D measurements, it is well suited to the construction of a detailed map, while the visual SLAM allows to quickly recognize already visited places in order to apply loop closure corrections, by using a key frames graph. The currently proposed system allows collaboration between these two SLAMs through pose sharing and relocalization.

Chlordecone (CLD) is an organochlorine pesticide widely used in the past to control pest insects in banana plantations in the French West Indies. Due to its persistence in the environment, CLD has contaminated the soils where it has been spread, as well as the waters, and is still present in them. The objective of our study was to evaluate the effects of chronic exposure to environmentally relevant CLD concentrations in an animal model, the freshwater hydra (Hydra circumcincta). In a multi-marker approach, we have studied the expression of some target stress genes, the morphology, and the asexual reproduction rates. Our data showed that exposure to low concentrations of chlordecone leads to (i) a modulation of the expression of target genes involved in oxidative stress, detoxification, and neurobiological processes, and (ii) morphological damages and asexual reproduction impairment. We have observed non-monotonic dose-response curves, which agree with endocrine-disrupting chemical effects. Thus, "U-shaped" dose-response curves were observed for SOD, GRed, Hym355, and potentially GST gene expressions; inverted "U-shaped" curves for GPx and CYP1A gene expressions and reproductive rates; and a biphasic dose-response curve for morphological damages. Therefore, in the range of environmental concentrations tested, very low concentrations of CLD can produce equally or more important deleterious effects than higher ones. Finally, to our knowledge, this study is the first one to fill the lack of knowledge concerning the effects of CLD in Hydra circumcincta and confirms that this diploblastic organism is a pertinent freshwater model in the risk assessment.

The biological activities of berberine, a natural plant molecule, are known to be affected by structural modifications, mostly at position 9 and/or 13. A series of new 13-substituted berberine derivatives were synthesized and evaluated in term of antimicrobial activity using various microorganisms associated to human diseases. Contrarily to the original molecule berberine, several derivatives were found strongly active in microbial sensitivity tests against Mycobacterium, Candida albicans and Gram-positive bacteria, including na&iuml, ve or resistant Bacillus cereus, Staphylococcus aureus and Streptococcus pyogenes with minimal inhibitory concentration (MIC) of 3.12 to 6.25 &micro, M. Among the various Gram-negative strains tested, berberine&rsquo, s derivatives were only found active on Helicobacter pylori and Vibrio alginolyticus (MIC values of 1.5&ndash, 3.12 &micro, M). Cytotoxicity assays performed on human cells showed that the antimicrobial berberine derivatives caused low toxicity resulting in good therapeutic index values. In addition, a mechanistic approach demonstrated that, contrarily to already known berberine derivatives causing either membrane permeabilization, DNA fragmentation or interacting with FtsZ protein, active derivatives described in this study act through inhibition of the synthesis of peptidoglycan or RNA. Overall, this study shows that these new berberine derivatives can be considered as potent and safe anti-bacterial agents active on human pathogenic microorganisms, including ones resistant to conventional antibiotics.

Sunscreen oil-in-water emulsions containing few ingredients and two EU-authorized organic filters had been developed in an eco-friendly approach. Based on their photostability, spectroscopic features, and the lack of data on toxicity, BEMT (UVA/B range; bis-ethylhexyloxyphenol methoxyphenyl triazine) and DHHB (UVA; diethylamino hydroxybenzoylhexyl benzoate) were selected and incorporated at minimal concentrations to reduce the risk of impact on human health and coastal marine ecosystems. Despite the inconclusive results previously reported, the use of the w-soluble and largely available Na-lignosulfonate (LiS) had been reconsidered with success. Since BEMT and DHHB alone or in combination were not able to higher the sun protection factor (SPF) value at 50, results showed that it becomes possible by supplementing with LiS at 5% (w/w), ensuring stability, antiradical property, and a non-toxicity of the sun emulsion. After defining the range doses for the three components, minimizing concentrations was achieved by experimental design studies using a response surface methodology in which SPF values before and after irradiation has been considered. Consequently, an SPF30 and SPF50 emulsions containing only 9 and 12% total filter respectively and 5% LiS each had been developed. This high boosting effect led to discussions on how LiS interacts, suggesting the involvement of J aggregation, the formation of LiS micelles that would partly encapsulate the o-soluble filters, and the mode of adsorption at the solid-liquid interface of the poly(methyl-methacrylate) plate or the skin.

International audience; A series of new hybrid 2-(diethoxyphosphoryl)-N-(benzylidene)propan-2-amine oxide derivatives with different aromatic substitution (PPNs) were synthesized. These molecules were evaluated for their EPR spin trapping potential on eleven different radicals and NO-donation properties in vitro, cytotoxicity and vasoprotective effect on precontracted rat aortic rings. A subfamily of the new PPNs featured an antioxidant moiety occurring in natural phenolic acids. From the experimental screening of these hydroxyphenyl- and methoxyphenyl-substituted PPNs, biocompatible nitrones 4d, and 4g−4i deriving from caffeic, gallic, ferulic and sinapic acids, which combined improved EPR probing of ROS formation, vasorelaxant action and antioxidant potency, might be potential drug candidate alternatives to PBN and its analogues.

Rationale: Monocytes play critical roles in the pathogenesis of arthritis by contributing to the inflammatory response and bone erosion. Among genes involved in regulating monocyte functions, miR-146a negatively regulates the inflammatory response and osteoclast differentiation of monocytes. It is also the only miRNA reported to differentially regulate the cytokine response of the two classical Ly6Chigh and non-classical Ly6Clow monocyte subsets upon bacterial challenge. Although miR-146a is overexpressed in many tissues of arthritic patients, its specific role in monocyte subsets under arthritic conditions remains to be explored. Methods: We analyzed the monocyte subsets during collagen-induced arthritis (CIA) development by flow cytometry. We quantified the expression of miR-146a in classical and non-classical monocytes sorted from healthy and CIA mice, as well as patients with rheumatoid arthritis (RA). We monitored arthritis features in miR-146a-/- mice and assessed in vivo the therapeutic potential of miR-146a mimics delivery to Ly6Chigh monocytes. We performed transcriptomic and pathway enrichment analyses on both monocyte subsets sorted from wild type and miR-146a-/- mice. Results: We showed that the expression of miR-146a is reduced in the Ly6Chigh subset of CIA mice and in the analogous monocyte subset (CD14+CD16-) in humans with RA as compared with healthy controls. The ablation of miR-146a in mice worsened arthritis severity, increased osteoclast differentiation in vitro and bone erosion in vivo. In vivo delivery of miR-146a to Ly6Chigh monocytes, and not to Ly6Clow monocytes, rescues bone erosion in miR-146a-/- arthritic mice and reduces osteoclast differentiation and pathogenic bone erosion in CIA joints of miR-146a+/+ mice, with no effect on inflammation. Silencing of the non-canonical NF-κB family member RelB in miR-146a-/- Ly6Chigh monocytes uncovers a role for miR-146a as a key regulator of the differentiation of Ly6Chigh, and not Ly6Clow, monocytes into osteoclasts under arthritic conditions. Conclusion: Our results show that classical monocytes play a critical role in arthritis bone erosion. They demonstrate the theranostics potential of manipulating miR-146a expression in Ly6Chigh monocytes to prevent joint destruction while sparing inflammation in arthritis.

International audience; Native from Africa, Dialium guineense Willd. Parkia biglobosa R. Br. Ex Benth. And Tamarindus indica L. grow in tropical regions, and are very widespread in West Africa, particularly in Benin. They are simultaneously used in the traditional healing of infectious diseases but there is a lack on their bioactive compounds description. This work places a special emphasis on inventory of known bioactives compounds from the three plants and their mechanism of action in order to identify the need for further research. It emerges from this work that numerous studies confirm the biological activities of the plants extracts. Nevertheless, few bioactive molecules are described as well as the mode of action of the active extracts.

Many carbonyl species from either lipid peroxidation or glycoxidation are extremely reactive and can disrupt the function of proteins and enzymes. 4-hydroxynonenal and methylglyoxal are the most abundant and toxic lipid-derived reactive carbonyl species. The presence of these toxics leads to carbonyl stress and cause a significant amount of macromolecular damages in several diseases. Much evidence indicates trapping of reactive carbonyl intermediates may be a useful strategy for inhibiting or decreasing carbonyl stress-associated pathologies. There is no rapid and convenient analytical method available for the assessment of direct carbonyl scavenging capacity, and a very limited number of carbonyl scavengers have been identified to date, their therapeutic potential being highlighted only recently. In this context, we have developed a new and rapid sensitive fluorimetric method for the assessment of reactive carbonyl scavengers without involvement glycoxidation systems. Efficacy of various thiol- and non-thiol-carbonyl scavenger pharmacophores was tested both using this screening assay adapted to 96-well microplates and in cultured cells. The scavenging effects on the formation of Advanced Glycation End-product of Bovine Serum Albumin formed with methylglyoxal, 4-hydroxynonenal and glucose-glycated as molecular models were also examined. Low molecular mass thiols with an α-amino-β-mercaptoethane structure showed the highest degree of inhibitory activity toward both α,β-unsaturated aldehydes and dicarbonyls. Cysteine and cysteamine have the best scavenging ability toward methylglyoxal. WR-1065 which is currently approved for clinical use as a protective agent against radiation and renal toxicity was identified as the best inhibitor of 4-hydroxynonenal., Graphical abstract Reaction of carbonyl compounds with NBD-H to form highly fluorescent derivatives. Fluorescence is strongly inhibited by carbonyl scavengers such as thiols with an α-amino-β-mercaptoethane structure., Highlights • We describe a rapid method for assessment of reactive carbonyl scavengers. • We evaluated the carbonyl scavenger activity of various pharmacophores. • α-amino-β-mercaptoethane structure showed the highest degree of activity.

In our search for potent anti-HIV and antiplasmodial agents, novel series of flavonoid derivatives and their chalcone intermediates were synthesized and evaluated for inhibition of HIV multiplication and antiproliferative activity on Plasmodium falciparum parasites. Chalcones exhibited a more selective antiplasmodial activity than flavonoids. Methoxyflavone 7e was the only one compound active in both P. falciparum and HIV-1 whereas aminomethoxyflavones showed activity against HIV-2. Para substitution on the B ring seemed to increase HIV-2 potency.

Haspin is a serine/threonine kinase required for completion of normal mitosis that is highly expressed during cell proliferation, including in a number of neoplasms. Consequently, it has emerged as a potential therapeutic target in oncology. A high throughput screen of approximately 140,000 compounds identified an acridine analog as a potent haspin kinase inhibitor. Profiling against a panel of 270 kinases revealed that the compound also exhibited potent inhibitory activity for DYRK2, another serine/threonine kinase. An optimization study of the acridine series revealed that the structure–activity relationship (SAR) of the acridine series for haspin and DYRK2 inhibition had many similarities. However, several structural differences were noted that allowed generation of a potent haspin kinase inhibitor (33, IC50

Five new 9‐(N‐substituted)‐acridinamines (7–11), have been synthesized from allyl 4‐(9‐chloro‐7‐methoxy‐2‐acridinyl)‐butanoate (6). The structure of these new acridine derivatives was determined using and 1H, 13C, and 2D nuclear magnetic resonance (NMR) spectroscopy.

The (1)H and (13)C NMR resonances for forty-three 2-aryl and 2-N-arylamino benzothiazole derivatives were completely assigned using a concerted application of one- and two-dimensional experiments (DEPT, gs-COSY, gs-HMQC and gs-HMBC).

Malaria is a major health concern particularly in Africa which has about 90% of the worldwide annual clinical cases. The increasing number of drug-resistantPlasmodium falciparumjustifies the search for new drugs in this field. Antimalarial activity of 2-substituted 6-nitro- and 6-amino-benzothiazoles and their anthranilic acids has been tested. Anin vitrostudy has been performed on W2 and 3D7 strains ofP. falciparumand on clinical isolates from malaria-infected patients. Toxicity has been assessed on THP1 human monocytic cells. For the most active drug candidates, thein vitrostudy was followed byin vivoassaysonP. berghei-infected mice and byin vitroassays in order to determine the stage-dependency and the mechanism of action. Of 39 derivatives testedin vitro, 2 had specific antimalarial properties. Each compound was active on all stages of the parasite, but one was markedly active on mature schizonts, while the other was more active on young schizont forms. Both drugs were also active on mitochondrial membrane potential.In vivodata confirmed efficiency with a sustained decrease of parasitaemia. Products A12 and C7 may be considered as potential antimalarial worthy of further chemical and biological research.

The analogs of the Troger’s base, 7,17-methano-6,7,16,17-tetrahydrodiacridino-[3,4-b:3’,4’-f][1,5]-diazocine was prepared starting from 2-aminoacridine instead of 3-aminoacridine. The new compound, 7,17-methano-6,7,16,17-tetrahydro-diacridino-[2,1-b:2’,1’-f]-[1,5]-diazocine, has been fully characterized by Hand CNMR spectroscopies using monoand bi-dimensional techniques. Other aminoacridine derivatives failed to afford Troger’s bases.

Novel 7,8,9,10-tetrahydrothiazolo[5,4-a]acridine and 1,2,3,4-tetrahydro-12H-benzothiazolo[2,3-b]-quinazolin-12-one derivatives were synthesized in one step from the corresponding benzothiazoles. These two new tetracyclic skeletons were unambiguously characterized and are presently in pharmacological tests.

The 1H and 13C NMR resonances for 18 tetracyclic acridines 9-substituted on the acridine ring with Cl, NH2 and AMS [N-(4-amino-3-methoxyphenyl)1methanesulfonamide] groups were completely and unequivocally assigned by the concerted application of gs-HMQC and gs-HMBC experiments. For NH2 and AMS substituents, the potential amino–imino tautomerism is completely shifted towards the imino tautomer. Copyright © 2001 John Wiley & Sons, Ltd.

We have synthesized quinolinones with potential antiparasitic and anti-HIV activities by an original two-step method involving microwave irradiation and have evaluated their activities against Plasmodium falciparum, Leishmania donovani, Trichomonas vaginalis, and HIV. None of the tested compounds had been previously described using this method of synthesis. One of the compounds had interesting antiparasitic and anti-HIV activity, which could be improved by substitution with different radicals.

International audience; A series of mitochondria targeted α-aminophosphonatescombining a diethoxyphosphoryl group and analkyl chain-connected triphenylphosphonium bromide tailwere designed and synthesized, and their pH-sensitive 31PNMR properties and biological activities in vitro and in vivowere evaluated. The results showed a number of these mitoaminophosphonatesexhibiting pKa values fitting the mitochondrialpH range, short relaxation, and chemical shift parameterscompatible with sensitive 31P NMR detection, and lowcytotoxicity on green algae and murine fibroblasts cell cultures.Of these, two selected compounds demonstrated to distribute at NMR detectable levels within the cytosolic and mitochondrialsites following their perfusion to isolated rat livers, with no detrimental effects on cell energetics and aerobic respiration. Thisstudy provided a new molecular scaffold for further development of in situ spectroscopic real-time monitoring of mitochondrion/cytosol pH gradients.

The absence of Klotho (KL) from mice causes the development of disorders associated with human aging and decreased longevity, whereas increased expression prolongs lifespan. With age, KL protein levels decrease, and keeping levels consistent may promote healthier aging and be disease-modifying. Using the KL promoter to drive expression of luciferase, we conducted a high-throughput screen to identify compounds that activate KL transcription. Hits were identified as compounds that elevated luciferase expression at least 30%. Following validation for dose-dependent activation and lack of cytotoxicity, hit compounds were evaluated further in vitro by incubation with opossum kidney and Z310 rat choroid plexus cells, which express KL endogenously. All compounds elevated KL protein compared with control. To determine whether increased protein resulted in an in vitro functional change, we assayed FGF23 (fibroblast growth factor 23) signalling. Compounds G–I augmented ERK (extracellular-signal-regulated kinase) phosphorylation in FGFR (fibroblast growth factor receptor)-transfected cells, whereas co-transfection with KL siRNA (small interfering RNA) blocked the effect. These compounds will be useful tools to allow insight into the mechanisms of KL regulation. Further optimization will provide pharmacological tools for in vivo studies of KL.

The complete 1H and 13C NMR assignment of 9 acetamidochalcones, 18 acetamidoflavones, 18 aminoflavones, 9 acetamidoflavonols and 9 aminoflavonols has been performed using one- and two-dimensional NMR techniques including COSY, HMQC and HMBC experiments. Copyright © 2010 John Wiley & Sons, Ltd.

New acridine derivatives have been prepared via Ullman condensation involving benzoxazole (5) and 2-bromo-benzoic acid. Linear products were obtained. The structure of oxazolo[4,5-b]acridine was determined by NMR spectroscopy.

Novel 7,8,9,10-tetrahydrothiazolo[5,4-a]acridine and 1,2,3,4-tetrahydro-12H-benzothiazolo[2,3-b]-quinazolin-12-one derivatives were synthesized in one step from the corresponding benzothiazoles. These two new tetracyclic skeletons were unambiguously characterized and are presently in pharmacological tests.

International audience; Hydrosoluble sesame oil fatty acid transesters having enhanced antioxidant activities were synthesizedin a two-step process. The key step involved the biocatalyzed (lipase from Candida antarctica)acylation of sesame oil methanolic ester with either vanillyl (VNA) or piperonyl benzylic alcohols, or5-hydroxymethyl resorcinol (5-HMR). These substrates were selected to introduce phenolic orsesamol structurally related frameworks. The VNA and 5-HMR-derived transesters were obtainedwith 20-40% yields and retained the starting proportions of sesame oil linoleic, oleic, and saturatedacids, these fatty acids also being the only constituents of the nonesterified fraction. The VNAderivedtransester showed the best antioxidant capacity in standard assays and was processed asthe unique lipid phase of spray-dried emulsions containing a high level of linoleic acid phenolic ester.These emulsions provided a high degree of protection to UV-irradiated fibroblasts, through thepotential synergy between VNA antioxidant action and replenishment of damaged membranes byunsaturated fatty acids.

Dry sesamol emulsions were synthesized from several combinations of saccharose with hydroxypropylmethylcellulose (HPMC) or sodium caseinate (SC) using spray-drying techniques at 120° to 180°C, or freeze-drying. On the basis of physical characteristics such as droplet size distribution, residual moisture, and microscopic structure, the best material was obtained when spray-drying was applied at either 150° or 180°C with SC or HPMC as excipients, respectively. The extent to which the antioxidant properties of free sesamol towards a set of free radicals (galvinoxyl, diphenylpicrylhydrazyl, superoxide, and hydroxyl) were altered in the starting and reconstituted liquid emulsions submitted to normal storage or pre-exposed to a flux hydroxyl radicals was investigated. Emulsions were further evaluated for their antioxidant properties in cultured 3T3 murine fibroblasts and in an ex vivo model of ultraviolet irradiated rat skin. It was found that, in the material having the best physical properties, encapsulation was decisive in: (1) improving the overall antioxidant behavior of reconstituted versus starting liquid emulsions: (2) sparing sesamol consumption due to free radical attack; and (3) significantly protecting cells and skin against free radical- or irradiation-induced enzymatic release and/or lipid peroxidation. Demonstrating a high activity at high dilutions where interactions of excipient become negligible, the new emulsions could be of great interest in sesamol-based pharmacology or topical applications. Drug Dev Res 69:251–266, 2008. © 2008 Wiley-Liss, Inc.

This paper deals with recent advances in acoustic experimental methods and especially acoustic imaging. The paper covers two areas of interest to acousticians. In the first part, it is explained how near-field acoustic holography (NAH) can be extended with beamforming in the near-field, focalization. The combination of the two methods is providing now a source localization solution with a good spatial resolution over the complete frequency range without the burden of measuring a large number of points as would be required if only NAH was used. In the second part of the paper, a method is described that goes one step beyond source localization. It is interesting to locate the noise sources, but from an engineering standpoint it is even more interesting to know the internal sources/forces causing these noise sources. In this part is explained how source localization techniques in conjunction with artificial excitation of the structure can provide information on the internal sources of the structure.