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International audience; Pseudohypoparathyroidism 1B (PHP1B) is caused by maternal epigenetic defects in the imprinted GNAS cluster. PHP1B can follow an autosomal dominant mode of inheritance or occur sporadically (spor-PHP1B). These latter patients present broad methylation changes of two or more differentially methylated regions (DMR) that, when mimicking the paternal allele, raises the suspicious of the occurrence of paternal uniparental disomy of chromosome 20 (upd(20)pat). A cohort of 33 spor-PHP1B patients was screened for upd(20)pat using comparative genomic hybridization with SNP-chip. Methylation analyses were assessed by methylation specific-multiplex ligation-dependent probe amplification. Upd(20)pat was identified in 6 patients, all exhibiting typical paternal methylation pattern compared to normal controls, namely a complete loss of methylation of GNAS A/B:TSS-DMR, negligible methylation at GNAS-AS1 :TSS-DMR and GNAS-XL:Ex1-DMR and complete gain of methylation at GNAS-NESP:TSS-DMR. The overall frequency of upd(20) is 18% in our cohort when searched considering both severe and partial loss of imprinting. However, twenty five patients displayed severe methylation pattern and the upd(20)pat frequency reaches 24% when searching in this group. Consequently, up to day, upd(20)pat is the most common anomaly than other genetic alterations in spor-PHP1B patients. Upd(20)pat occurrence is not linked to the parental age in contrast to upd(20)mat, strongly associated with an advanced maternal childbearing age. This study provides criteria to guide further investigations for upd(20)pat needed for an adequate genetic counseling.

International audience; 5-HT4 receptor (5-HT4R) activation and blockade of the 5-HT6 receptor (5-HT6R) are known to enhance the release of numerous neurotransmitters whose depletion is implicated in Alzheimer's disease (AD). Furthermore, 5-HT4R agonists seem to favor production of the neurotrophic soluble amyloid protein precursor alpha (sAPPα). Consequently, combining 5-HT4R agonist/5-HT6R antagonist activities in a single chemical compound would constitute a novel approach able to display both a symptomatic and disease-modifying effect in AD. Seventeen novel derivatives of RS67333 (1) were synthesized and evaluated as potential dual-target compounds. Among them, four agents showed nanomolar and submicromolar affinities toward 5-HT4R and 5-HT6R, respectively; one of them, 7m, was selected on the basis of its in vitro affinity (Ki5-HT4R = 5.3 nM, Ki5-HT6R = 219 nM) for further in vivo experiments, where 7m showed an antiamnesic effect in the mouse at 1 mg/kg ip

International audience; The low levels of antidepressants detected in surface waters currently raise concern about their potential long-term risks to nontarget aquatic organisms. We investigated the transgenerational effects of sertraline, a selective serotonin reuptake inhibitor, and venlafaxine, a serotonin-norepinephrine reuptake inhibitor, on the life traits of Daphnia magna over two generations under environmentally realistic concentrations. We also studied the reversibility of the effect using recovery experiments. We assessed daphnid survival, growth, and reproduction over 21 days and evidenced detectable effects of the antidepressants. Sertraline increased the F0-daphnid fecundity whereas it decreased the offspring number of F1-daphnids. Transfer to clean medium caused negative effects on the offspring of daphnids exposed to 0.3 μg L(–1), but improved the fecundity of offspring of daphnids exposed to 100 μg L(–1). Venlafaxine exposure decreased the offspring number of F0-daphnids and resulted in drug tolerance in the F1 generation. Sertraline, unlike venlafaxine, may turn out to be a true environmental threat due to its accumulation in algae and the physiological weakness observed over generations. These effects across generations point out to the need to perform multigeneration tests to assess the environmental risk of pharmaceuticals in nontarget organisms

Varroa destructor is the main concern related to the gradual decline of honeybees. Nowadays, among the various acaricides used in the control of V. destructor, most presents increasing resistance. An interesting alternative could be the identification of existent molecules as new acaricides with no effect on honeybee health. We have previously constructed the first 3D model of AChE for honeybee. By analyzing data concerning amino acid mutations implicated in the resistance associated to pesticides, it appears that pirimicarb should be a good candidate for varroacide. To check this hypothesis, we characterized the AChE gene of V. destructor. In the same way, we proposed a 3D model for the AChE of V. destructor. Starting from the definition of these two 3D models of AChE in honeybee and varroa, a comparison between the gorges of the active site highlighted some major differences and particularly different shapes. Following this result, docking studies have shown that pirimicarb adopts two distinct positions with the strongest intermolecular interactions with VdAChE. This result was confirmed with in vitro and in vivo data for which a clear inhibition of VdAChE by pirimicarb at 10 μM (contrary to HbAChE) and a 100% mortality of varroa (dose corresponding to the LD50 (contact) for honeybee divided by a factor 100) were observed. These results demonstrate that primicarb could be a new varroacide candidate and reinforce the high relationships between in silico, in vitro, and in vivo data for the design of new selective pesticides.

Currently, the hazard posed by pharmaceutical residues is a major concern of ecotoxicology. Most of the antidepressants belong to a family named the Cationic Amphipathic Drugs known to have specific interactions with cell membranes. The present study assessed the impact of eight antidepressants belonging to selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors by the combination of multi-approaches (in vivo, in vitro, in silico) and gives some insights on the mode of action for these molecules. Antidepressants were from the most to the least toxic compound for Daphnia magna: Sertraline (EC50=1.15 mg L(-1))>Clomipramine (2.74 mg L(-1))>Amitriptyline (4.82 mg L(-1))>Fluoxetine (5.91 mg L(-1))>Paroxetine (6.24 mg L(-1))>Mianserine (7.81 mg L(-1))>Citalopram (30.14 mg L(-1)) and Venlafaxine (141.28 mg L(-1)). These acute toxicities were found correlated to Log Kow coefficients (R=0.93, p

The work described herein aims at finding new potential ligands for the brain imaging of 5-HT(4) receptors (5-HT(4)Rs) using single-photon emission computed tomography (SPECT). Starting from the nonsubstituted phenanthridine compound 4a, exhibiting a K(i) value of 51 nM on the 5-HT(4)R, we explored the structure-affinity in this series. We found that substitution in position 4 of the tricycle with a fluorine atom gave the best result. Introduction of an additional nitrogen atom inside the tricyclic framework led to an increase of both the affinity and selectivity for 5-HT(4)R, suggesting the design of the antagonist 4v, exhibiting a high affinity of 0.04 nM. Several iodinated analogues were then synthesized as potential SPECT tracers. The iodinated compound 11d was able to displace the reference radioiodinated 5-HT(4)R antagonist (1-butylpiperidin-4-yl)methyl-8-amino-7-iodo[(123)I]-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate {[(123)I]1, [(123)I]SB 207710} both in vitro and in vivo in brain. Compound 11d was radiolabeled with [(125)I]iodine, providing a potential SPECT candidate for brain imaging of 5-HT(4)R.

Introduction Des mutations des genes CYP24A1 codant la vitamine D 24-hydroxylase, et plus recemment SLC34A1 et SLC34A3 codant les cotransporteurs renaux sodium-phosphate, ont ete associees au phenotype d’hypersensibilite a la vitamine D (HVD). Ce phenotype comprend une calcemie elevee et une PTH basse, des hypercalcemies aigues en cas de prise de vitamine D, des complications de l’hypercalciurie chronique (lithiase renale, nephrocalcinose). Objectifs Evaluer la contribution de ces genes au phenotype HVD et identifier un profil biologique specifique susceptible de guider l’analyse moleculaire. Patients et methodes Etude par NGS des genes CYP24A1, SLC34A1, SLC34A3 et SLC9A3R1 (lithiase renale avec hypophosphatemie) dans une cohorte de 185 patients presentant une hypercalcemie et/ou une hypercalciurie avec PTH Resultats Nous avons identifie 34 (18 %) patients avec mutations CYP24A1 (26 [14 %]) bialleliques et 8 ([4 %] heterozygotes), 18 (10 %) patients avec mutations SLC34A1 (5 [3 %]) bialleliques et 13 (7 %) heterozygotes), 13 (7 %) patients avec mutations SLC34A3 (6 [3 %]) bialleliques et 7 (4 %) heterozygotes), aucun patient avec mutation SLC9A3R1. Deux (1 %) patients presentent une double heterozygotie (SLC34A1/SLC34A3 et CYP24A1/SLC34A3). Parmi les patients avec mutation biallelique, les patients SLC34A3 presentent une calcemie et une phosphatemie plus basses. Les sujets heterozygotes pour ces 3 genes presentent des valeurs de 1,25-(OH)2D plus elevees que les patients avec mutation biallelique.

International audience; The hazards linked to pharmaceutical residues like antidepressants are currently a major concern of ecotoxicology because they may have adverse effects on non-target aquatic organisms. Our study assesses the ecotoxicity of three antidepressants (fluoxetine, sertraline and clomipramine) using a battery of marine and freshwater species representing different trophic levels, and compares the bioassay sensitivity levels. We selected the following bioassays: the algal growth inhibition test (Skeletonema marinoi and Pseudokirchneriella subcapitata), the microcrustacean immobilization test (Artemia salina and Daphnia magna), development and adult survival tests on Hydra attenuata, embryotoxicity and metamorphosis tests on Crassostrea gigas, and in vitro assays on primary cultures of Haliotis tuberculata hemocytes. The results showed high inter-species variability in EC50-values ranging from 43 to 15,600 µg/L for fluoxetine, from 67 to 4,400 µg/L for sertraline, and from 4.70 µg/L to more than 100,000 µg/L for clomipramine. Algae (S. marinoi and P. subcapitata) and the embryo-larval stages of the oyster C. gigas were the most sensitive taxa. This raises an issue due to their ecological and/or economic importance. The marine crustacean A. salina was the least sensitive species. This difference in sensitivity between bioassays highlights the importance of using a test battery.

A series of nitrated 2-substituted-quinolines was synthesized and evaluated in vitro toward Leishmania donovani promastigotes. In parallel, the in vitro cytotoxicity of these molecules was assessed on the murine J774 and human HepG2 cell lines. Thus, a very promising antileishmanial hit molecule was identified (compound 21), displaying an IC(50) value of 6.6 μM and CC(50) values ≥ 100 μM, conferring quite good selectivity index to this molecule, in comparison with 3 drug-compounds of reference (amphotericin B, miltefosine and pentamidine). Compound 21 also appears as an efficient in vitro antileishmanial molecule against both Leishmania infantum promastigotes and the intracellular L. donovani amastigotes (respective IC(50) = 7.6 and 6.5 μM). Moreover, hit quinoline 21 does not show neither significant antiplasmodial nor antitoxoplasmic in vitro activity and though, presents a selective antileishmanial activity. Finally, a structure-activity relationships study enabled to define precisely the antileishmanial pharmacophore based on this nitroquinoline scaffold: 2-hydroxy-8-nitroquinoline.

International audience; Sewage sludge and slurry are used as fertilisers on pastures grazed by ruminants. The former may be a source of Taenia saginata, which causes cysticercosis in cattle and taeniosis in man. The latter is a source of digestive tract-strongyles, a major helminth infection in cattle. The interest of application on pastures of these two biowastes is environmental (optimal recycling of biowastes) and agronomic (fertilisation). The parasitic risk and the fertilisation value of such applications on pastures were evaluated during one grazing season. Liquid sewage sludge did induce higher herbage biomass, which corresponded to higher liveweight gains during the first 2 months of grazing, compared to slurry spread pastures and calves grazing them. The sludge group of calves did not acquire live cysticerci and thus the risk was nil under the conditions of the study (delay of 6 weeks between application and grazing). The slurry group of calves did become lightly infected with digestive-tract strongyles, mostly Ostertagia ostertagi. Under the conditions of this experiment, a 6-week delay between application and grazing strongly reduced the risk of infection: it renders compatible the agronomic use and requirements of public or animal health.

International audience; Urban sewage production is increasing and its agronomical use as a fertiliser has been advocated. Considerable defiance is prevalent in consumers and among farmers on the use of such fertilisers due to unknown pathological or environmental risks. The aim of the present review was to consider which pathological risk is major. Cysticercosis due to Taenia saginata appears to be one of the major pathological threats when sewage sludge is used to fertilise cattle pastures in temperate areas. The situation is different in Africa (Taenia solium and T. saginata are both highly prevalent) and Asia (Taenia saginata-like are prevalent). The processing of sludge and the delay between its application onto a pasture and grazing are probably major risk factors. Little data are available on the influence of processing, delay between processing and the use of sludge on the pathogenic risk. Producers and consumers will be more confident on the use of sludge if objective data are gained on risk. Most of the cases of cysticercosis (North America, United-Kingdom, Germany or Denmark) are related to poor human hygiene or accidental overflooding of sewage plants onto pastures. The standard application of sludge on pastures is apparently at low risk. This low risk does not mean that surveillance should cease since outbreaks of cysticercosis have been reported. Future investigations should concentrate on the most sustainable means of reducing risk (length of storage before use, composting, other treatments).; L'utilisation des boues d'épuration urbaine sur les pâturages : le risque de cysticercose. La production de boues urbaines résiduaires est en augmentation. Leur emploi agronomique comme fertilisant a été proposé. Une méfiance profonde des consommateurs ou des exploitants agricoles quant à l'emploi des boues urbaines en tant que fertilisants est réelle, qu'il s'agisse de risque pathologique ou environnemental. Le but de cette synthèse est de déterminer quel est le risque pathologique majeur. L'infestation par Taenia saginata semble être le risque le plus important en relation avec l'application de boues d'épandages sur les pâturages bovins dans les régions tempérées. La situation est différente en Afrique (Taenia solium et T. saginata sont tous les deux très prévalents) et en Asie (les Taenia ressemblant à T. saginata ont un spectre d'hôtes herbivores assez large). Les processus de fabrication des boues et le délai entre le dépôt sur pâture et l'accès à la pâture sont sans doute des facteurs essentiels du risque. De rares données sont disponibles quant au délai et au traitement pour ce qui concerne leur pouvoir pathogène. Elles devraient être développées afin d'améliorer la confiance entre producteurs et consommateurs, sur des bases objectives. Le risque lié à l'épandage est faible comme le montrent des études aux USA, en Grande-Bretagne, Allemagne ou Danemark. La principale cause de risque repose sur un faible niveau d'hygiène humaine ou sur des mauvaises gestions des flux par les stations d'épuration qui déverseront sur des pâturages accidentellement des boues non traitées. Bien que le risque soit faible, la surveillance doit être maintenue car des épidémies locales ont été recensées. Les voies de recherches devraient être centrées sur les moyens durables de réduction du risque, à savoir, l'augmentation des durées de stockage des boues, leur compostage, ou d'autres traitements.

The synthesis of eighteen novel (thia)indanopyrazole derivatives was achieved starting from amino(thia)indanones. Some of them displayed a dual binding site acetylcholinesterase inhibition which makes them potentially interesting for Alzheimer's disease treatment.