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Organophosphates (OPs) are either found in nature or synthetized for use as pesticides, flame retardants, neurotoxic warfare agents or drugs (cholinergic enhancers in Alzheimer's disease and myasthenia gravis, or inhibitors of lipases in metabolic diseases). Because of the central role of acetylcholinesterase cholinergic neurotransmission in humans, one of the main purposes for using OPs is inactivation of the enzyme by phosphorylation of the nucleophilic serine residue in the active center. However, hundreds of serine hydrolases are expressed in the human proteome, and many of them are potential targets for OP adduction. In this review, we first situate the α/β hydrolase fold proteins among the distinctively folded proteins known to interact with OPs, in particular the different lipases, peptidases, and enzymes hydrolyzing OPs. Second, we compile the human α/β hydrolases and review those that have been experimentally shown to interact with OPs. Among the 120 human α/β hydrolase fold proteins, 102 have a serine in the consensus GXSXG pentapeptide compatible with an active site, 6 have an aspartate or a cysteine as the active site nucleophile residue, and 12 evidently lack an active site. 76 of the 120 have been experimentally shown to bind an OP.

Butyrylcholinesterase (BChE) is an important enzyme for detoxication and metabolism of ester compounds. It also hydrolyzes the neurotransmitter acetylcholine (ACh) in pathological conditions and may play a role in Alzheimer's disease (AD). We here compared the learning ability and vulnerability to Aβ toxicity in male and female BChE knockout (KO) mice and their 129Sv wild-type (Wt) controls. Animals tested for place learning in the water-maze showed increased acquisition slopes and presence in the training quadrant during the probe test. An increased passive avoidance response was also observed for males. BChE KO mice therefore showed enhanced learning ability in spatial and non-spatial memory tests. Intracerebroventricular (ICV) injection of increasing doses of amyloid-β[25-35] (Aβ25-35) peptide oligomers resulted, in Wt mice, in learning and memory deficits, oxidative stress and decrease in ACh hippocampal content. In BChE KO mice, the Aβ25-35-induced deficit in place learning was attenuated in males and blocked in females. No change in lipid peroxidation or ACh levels was observed after Aβ25-35 treatment in male or female BChE KO mice. These data showed that the genetic invalidation of BChE in mice augmented learning capacities and lowered the vulnerability to Aβ toxicity.

L’histoire est un combat de l’esprit, une aventure, et, comme toutes les équipées humaines, ne connaît jamais que des succès partiels, tout relatifs, hors de proportion avec l’ambition initiale, comme de toute bagarre engagée avec les profondeurs déroutantes de l’être, l’homme en revient avec un sentiment aigu de ses limites, de sa faiblesse, de son humilité.Henri-Irénée Marrou, De la connaissance historique, Paris, 1954. En 1992, dans les Dialogues d’Histoire ancienne, Pierre Lévêque livrait...

À partir de la conquête arabo-musulmane du viie siècle, les chrétiens de tradition syriaque (araméen chrétien) sont peu à peu passés à l’usage courant de la langue arabe, dans un processus et à des époques qui ont varié selon les régions et les communautés. On voit ainsi apparaître des manuscrits en arabe écrits par des chrétiens. Certains ont plus tard mis au point un système d’écriture, le garshuni, qui consiste à écrire la langue arabe avec l’alphabet syriaque. Ce système, peu adapté puisque le syriaque n’a que 22 caractères pour noter les 28 de l’arabe, a été très largement utilisé, notamment dans les communautés syro-orthodoxe et maronite. Cette communication donne un aperçu du phénomène : chronologie, diffusion, modalité d’adaptation de l’écriture, place dans les manuscrits, et essaie d’expliquer les raisons qui ont poussé à la création de cette écriture.

Le dossier présenté ici rassemble des communications prononcées lors du colloque de Nîmes en 2014 consacré au thème « Langages et communication ». Ici, il est essentiellement question de l’écriture à travers une approche phénoménologique, en tant que moyen de communication affiché, mais aussi comme marqueur de prestige, d’identité, comme moyen de communication dans le choix même de la forme, au-delà même du contenu du message. Une écriture s’affirme comme une simple retranscription visuelle d...

International audience; The conversion of skeletal muscle into meat, i.e. maturation, is a complex process where muscle undergoes an energetic stress leading to different biochemical and physiological changes. In agronomic field, the study of these alterations is of particular interest, in order to improve the quality of meat.It is well established that the proteolytic events generated by the enzymes such as cathepsins, calpains and ubiquitin proteasome system are involved in skeletal muscle maturation. Recent data suggest that autophagy may also contribute to the post-mortem maturation, but how this process is regulated remains currently unknown.To evaluate the autophagic process during skeletal muscle post-mortem maturation, we designed a pilot study using 6 month-old mice within a 48h post-mortem time frame. We measured the expression of proteins involved in autophagic pathway, and the autophagic flux using the colchicine (an inhibitor of autophagy). The interaction between autophagy and myostatin, a negative regulator of skeletal muscle mass, was also analyzed during this post-mortem interval. In addition, the respective contribution of proteolysis mechanisms during skeletal muscle post-mortem maturation was assessed by following the degradation of targeted myofibrillar proteins (Desmin, Troponin T) in the context of autophagic flux inhibition in wild-type (WT) and myostatin knocked-out (Mstn KO) mice.Our data showed attenuation in AMPK and ULK (inducer of autophagy) activation associated to a reduced basal autophagic flux that remained low within the postmortem time frame in Mstn KO muscle. Futhermore, post-mortem myofibrillar proteolysis was more pronounced in Mstn KO muscle and is not altered with autophagic flux inhibition compared to WT muscle.In conclusion, our results showed a difference in the proteolytic profile between the two genotypes, with the absence of myostatin promoting a reduced level of autophagy during the post-mortem maturation of skeletal muscle. Previous studies described a positive relationship between autophagy and oxidative stress. Further studies are needed in order to demonstrate how the oxidative stress regulates autophagy in the context of myostatin inhibition.

Le dossier présenté ici rassemble des communications prononcées lors du colloque de Nîmes en 2014 consacré au thème « Langages et communication ». Ici, il est essentiellement question de l’écriture à travers une approche phénoménologique, en tant que moyen de communication affiché, mais aussi comme marqueur de prestige, d’identité, comme moyen de communication dans le choix même de la forme, au-delà même du contenu du message. Une écriture s’affirme comme une simple retranscription visuelle d’un message oral, selon un code commun entre le locuteur et le destinataire, et qui permet au message de défier les barrières de l’espace et du temps. Définie comme cela, elle semble un outil parfaitement neutre. Les communications ici rassemblées montrent qu’il n’en est rien et que tout un message implicite est présent également dans le choix même d’écrire, dans la forme dans laquelle se coule le message écrit et que sont à l’œuvre ici des choix qui n’ont rien de neutre.

B-cell activation yields abundant cell death in parallel to clonal amplification and remodeling of immunoglobulin (Ig) genes by activation-induced deaminase (AID). AID promotes affinity maturation of Ig variable regions and class switch recombination (CSR) in mature B lymphocytes. In the IgH locus, these processes are under control by the 3’ regulatory region (3’RR) super-enhancer, a region demonstrated in the mouse to be both transcribed and itself targeted by AID-mediated recombination. Alternatively to CSR, IgH deletions joining Sμ to “like-switch” DNA repeats that flank the 3’ super-enhancer can thus accomplish so-called “locus suicide recombination” (LSR) in mouse B-cells. We now show that AID-mediated LSR also actively occurs in humans, and provides an activation-induced cell death pathway in multiple conditions of B-cell activation. LSR deletions either focus on the functional IgH allele or are bi-allelic, since they can only be detected when they are ongoing and their signature vanishes from fully differentiated plasma cells or from “resting” blood memory B-cells, but readily reappears when such memory B-cells are re-stimulatedin vitro. Highly diversified breakpoints are distributed either within the upstream (3’RR1) or downstream (3’RR2) copies of the IgH 3’ super-enhancer and all conditions activating CSRin vitroalso seem to trigger LSR.Author SummaryClass switch recombination, initiated by the activation-induced deaminase enzyme rearranges immunoglobulin (Ig) genes in order to replace expression of IgM by IgG, IgA or IgE. A variant form of this event, locus suicide recombination (LSR), was previously reported in mouse B-lymphocytes and simply deletes all functional Ig constant genes, thus terminating B-cell function. This study first demonstrates that the structure of the human Ig heavy chain locus provides an ideal target for LSR, and is thus actively (but transiently) affected by this deletional process at the activated B-cell stage. LSR then yields recombined genes that do not support B-cell survival and which thus become undetectable among long-lived memory B-cells or plasma cells.

International audience

International audience; The conversion of skeletal muscle into meat, i.e. maturation, is a complex process where muscle undergoes different biochemical and physiological changes. In agronomic field, the study of these events is of particular interest, in order to improve the quality of meat.It is well established that the proteolytic events generated by the enzymes such as cathepsins, calpains and ubiquitine proteasome system are involved in skeletal muscle maturation. Recent data suggest that other mechanisms, such as apoptosis and autophagy, may also contribute to the post-mortem maturation. However, their intervention is not clearly described. We designed a pilot study using mice to evaluate the proteolytic mechanisms within a 48h post-mortem time frame and their interaction with myostatin, a negative regulator of skeletal muscle mass. We measured the proteolysis of myofibrillar proteins (filamin, desmin, troponin T), as well as the activation and the expression of proteins involved in autophagic pathways. Our data showed a significant progressive degradation of myofibrillar proteins over the 48h PM period. Moreover, it was more pronounced in the muscle of Mstn KO mice. AMPK activation was attenuated in Mstn KO mice and was associated to a lower activation of the protein kinase ULK (inducer of autophagy) which suggests a reduced autophagy in Mstn KO mice. Using colchicine (an inhibitor of autophagy), we showed in Mstn KO muscle a reduced basal autophagic flux that remained low within the postmortem time frame. In conclusion, our results showed a difference in the proteolytic profile between the two genotypes during the post-mortem maturation of skeletal muscle. The absence of myostatin promotes a faster degradation of myofibrillar proteins associated to a reduced level of autophagy. The mechanisms responsible for this difference between the two genotypes remain to be elucidated.

International audience; Dans le muscle des animaux producteurs de viande, un ensemble de processus enzymatiques et physicochimiques conduit à la transformation post-mortem du muscle en viande. Associés aux caractéristiques structurales et métaboliques du tissu musculaire, ces processus conditionnent in fine les qualités sensorielles de la viande. Il est clairement établi que les évènements de protéolyse générés par les groupes enzymatiques cathepsines, calpaïnes et protéasome contribuent à la transformation post-mortem du muscle et participent à l’acquisition d'une de ces qualités sensorielles : la tendreté (1). Des données antérieures (2,3) suggèrent que d'autres mécanismes tels l'apoptose et l'autophagie, pourraient également contribuer à la transformation postmortem du muscle. Leur cinétique d’apparition n’a cependant pas été clairement établie en parallèle des autres événements protéolytiques. Pour répondre à cette question nous avons mené une étude pilote de la maturation post-mortem du muscle chez la souris (souris contrôles et KO Myostatine). Nous avons suivi au cours d’une cinétique (0 à 48h post-mortem) des indicateurs de la maturation post-mortem du muscle (pH, dégradation des protéines myofibrillaires) et mesuré l’expression protéique et/ou l’activité de marqueurs et régulateurs de la protéolyse musculaire, de l’apoptose et de l’autophagie. Nos résultats préliminaires montrent une protéolyse significativement plus importante dans le muscle des souris KO Myostatine (représentatif d'un muscle plus tendre par analogie avec les muscles de bovins culards). L'apoptose est présente dans les deux génotypes mais rapidement atténuée dans le muscle KO Myostatine. L'autophagie basale est réduite dans le muscle KO Myostatine. Cependant, tout en restant inférieur au niveau basal d'autophagie du muscle contrôle, le flux autophagique est induit lors du processus de maturation dans le muscle KO Myostatine. Ainsi la contribution relative de l'autophagie et de l'apoptose dans la maturation postmortem du muscle est dépendante du génotype. Ces résultats restent à confirmer dans des échantillons de viande de bovins culards (ayant des mutations de myostatine) vs des bovins contrôles présentant des potentiels de tendreté différents. 1 - Guillemin et al., 2009 Inra Prod Anim2 - Ouali et al., 2013 Meat Sci3 - Garcia-Macia et al., 2014 Autophagy

International audience; d’une cinétique de temps (0 à 48h PM) des indicateurs de la maturation post-mortem du muscle (pH, dégradation des protéines myofibrillaires) et mesuré l’expression protéique et/ou l’activité de marqueurs et régulateurs de la protéolyse musculaire, de l’apoptose et de l’autophagie.Nos résultats préliminaires montrent une protéolyse significativement plus importante dans le muscle KO Myostatine (représentatif d'un muscle plus tendre par analogie avec les muscles de bovins culards). L'apoptose est présente dans les deux génotypes mais rapidement atténuée dans le muscle KO Myostatine. L'autophagie basale est réduite dans le muscle KO Myostatine. Cependant, tout en restant inférieur au niveau basal d'autophagie du muscle contrôle, le flux autophagique est induit lors du processus de maturation dans le muscle KO Myostatine. Ainsi la contribution relative de l'autophagie et de l'apoptose dans la maturation post-mortem du muscle est dépendante du génotype. restent à confirmer dans des échantillons de viande de bovins culards (ayant des mutations de myostatine) vs. bovins contrôles présentant des potentiels de tendreté différents.

In this work, the effects of kaolin silver complex (KAgC) have been evaluated to replace the use of SO2 for the control of spoilage microorganisms in the winemaking process. The results showed that KAgC at a dose of 1 g/L provided effective control against the development of B. bruxellensis and acetic acid bacteria. In wines artificially contaminated with an initial population of B. bruxellensis at 104 CFU/mL, a concentration proven to produce off flavors in wine, only residual populations of the contaminating yeast remained after 24 days of contact with the additive. Populations of acetic bacteria inoculated into wine at concentrations of 102 and 104 CFU/mL were reduced to negligible levels after 72 h of treatment with KAgC. The antimicrobial effect of KAgC against B. bruxellensis and acetic bacteria was also demonstrated in a wine naturally contaminated by these microorganisms, decreasing their population in a similar way to a chitosan treatment. Related to this effect, wines with KAgC showed lower concentrations of acetic acid and 4-ethyl phenol than wines without KAgC. The silver concentration from KAgC that remained in the finished wines was below the legal limits. These results demonstrated the effectiveness of KAgC to reduce spoilage microorganisms in winemaking.

International audience; This volume presents the inscriptions recorded in 2004 along the so-called Darb al-Bakrah, an ancient north–south caravan track connecting Hegra with Petra. The inscriptions were found at a number of sites along the track. They are carved in a variety of scripts and languages, among which are Imperial Aramaic, Nabataean, Nabataeo-Arabic, Palmyrene, Ancient South Arabian, Ancient North Arabian (Taymanitic, Dadanitic, Hismaic, Safaitic, Thamudic B, C, and D, etc.), and Greek. The Arabic inscriptions and the rock drawings will be published in separate volumes. The inscriptions are edited by six scholars specialised in the history and epigraphy of ancient Arabia.

The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 (hCB2R) represent promisingtargets for pharmacotherapy in the later stages of Alzheimer’s disease. We merged pharmacophores for both targets into small benzimidazole-based molecules, investigated SARs, and identified several dual-acting ligands with a balanced affinity/inhibitory activity and an excellent selectivity over both hCB1R and hAChE. A homology model for the hCB2R was developed based on the hCB1R crystal structure and used for molecular dynamics studies to investigate binding modes. In vitro studies proved hCB2R agonism. Unwanted μ-opioid receptor affinitycould be designed out. One well-balanced dual-acting and selective hBChE inhibitor/hCB2R agonist showed superior in vivo activity over the lead CB2 agonist with regards to cognition improvement. The data shows the possibility to combine a small molecule with selective and balanced GPCR-activity/enzyme inhibition and in vivo activity for the therapy of AD and may help to rationalize the development of other dual-acting ligands.

International audience; Molecular mechanisms underlying terminal differen­tiation of B cells into plasma cells are major determi­nants of adaptive immunity but remain only partially understood. Here we present the transcriptional and epigenomic landscapes of cell subsets arising from activation of human naive B cells and differenti­ation into plasmablasts. Cell proliferation of acti­vated B cells was linked to a slight decrease in DNA methylation levels, but followed by a committal step in which an S phase-synchronized differentia­tion switch was associated with an extensive DNA demethylation and local acquisition of 5-hydroxyme­thylcytosine at enhancers and genes related to plasma cell identity. Downregulation of both TGF­β1/SMAD3 signaling and p53 pathway supported this final step, allowing the emergence of a CD23­-negative subpopulation in transition from B cells to plasma cells. Remarkably, hydroxymethylation of PRDM1, a gene essential for plasma cell fate, was coupled to progression in S phase, revealing an intri­cate connection among cell cycle, DNA (hydroxy) methylation, and cell fate determination.

Il s’agit ici de la deuxieme livraison des « Notes d’epigraphie et de philologie pheniciennes » (voir Semitica & Classica 7, 2014, p. 183-189). Les notes publiees ici relevent essentiellement de la suite de notre etude des inscriptions pheniciennes de Chypre a l’epoque hellenistique ; elles concernent les epithetes divines, la translitteration des mots et titres grecs en caracteres pheniciens, les formules de datation, les noms de mois, la structure et l’interpretation de certains passages du trophee de Kition, l’onomastique et la forme des substantifs « roi » et « regne » en phenicien.

Nouvel examen de l’inscription phenicienne de Tartous, connue aussi sous le nom de « Premiere Aradienne » (RES 56). Elle commemore l’erection d’un monument funeraire. Le nom du defunt et celui du donateur sont grecs, transcrits en phenicien. Le patronyme du defunt est pour le moment inconnu, mais il n’est pas non plus phenicien. Cette inscription represente donc un temoignage original sur l’usage du grec et du phenicien au debut de l’epoque hellenistique.