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Lowered availability of oxygen in the micro-environment of cells perturbs metabolic and signaling pathways. It affects proliferation, tissue morphology, and differentiation. Leukemia impairs maturation of hematopoietic progenitors: the immune system, healing, and erythropoiesis are weakened, thereby perturbing iron homeostasis and further lowering oxygen provision to tissues. Here, the time-dependent molecular consequences of sudden hypoxia were studied in the KG1a model of immature hematopoietic progenitors. The oxygen tension of KG1a cells was abruptly lowered from the experimentally usual ca. 20% to 1%. Growth and key hubs of signaling, metabolism, and iron homeostasis were monitored by a combination of immunological methods and functional assays. The collapse of oxygen availability stopped proliferation after one generation. The number of cells then remained approximately constant over several days, including after anaerobic changes of the culture medium. Lowered oxygen resulted in transient increase of the hypoxia inducible factor 1α and of its REDD1 target, inhibition of mTOR, decreased autophagy, altered cap-dependent translation, and minimal repression of the already weak oxidative phosphorylation. These adjustments did not trigger important cellular iron fluxes since the cells relied on their internal iron stores to survive. In conclusion, the response of the KG1a cells to stringent hypoxia is varied, with some established hypoxia-sensitive pathways exhibiting activation whereas others were unaffected. The results draw attention to the flexibility of the environmental adaptation of cancer cells. They suggest that thorough characterization of early leukemic blasts is warranted to propose informed treatments to patients.

Pseudomonas aeruginosa (P.a) is one of the most critical antibiotic resistant bacteria in the world and is the most prevalent pathogen in cystic fibrosis (CF), causing chronic lung infections that are considered one of the major causes of mortality in CF patients. Although several studies have contributed to understanding P.a within-host adaptive evolution at a genomic level, it is still difficult to establish direct relationships between the observed mutations, expression of clinically relevant phenotypes, and clinical outcomes. Here, we performed a comparative untargeted LC/HRMS-based metabolomics analysis of sequential isolates from chronically infected CF patients to obtain a functional view of P.a adaptation. Metabolic profiles were integrated with expression of bacterial phenotypes and clinical measurements following multiscale analysis methods. Our results highlighted significant associations between P.a &ldquo, metabotypes&rdquo, expression of antibiotic resistance and virulence phenotypes, and frequency of clinical exacerbations, thus identifying promising biomarkers and therapeutic targets for difficult-to-treat P.a infections

Introduction Les Unites de Reconstitutions Centralisees des Chimiotherapies (URCC) sont concernees au quotidien par le probleme de la contamination de l’environnement de travail par les medicaments anticancereux (MAC). Cette contamination expose le personnel des URCC principalement par voie cutanee. L’objectif etait de decrire la contamination des surfaces par les MAC au sein d’URCC et sur la surface des poches de chimiotherapies qui y sont fabriquees. Materiel et methode Le kit de prelevements de surface developpe par le CHU de Bordeaux a permis de detecter et quantifier par UHPLC-MS/MS plusieurs MAC (n = 15) : 112 prelevements ont ete realises dans 3 URCC : dans l’enceinte de protection collective utilisee pour les preparations (isolateur ou PSMII), sur la surface des poches et leurs suremballages, dans l’environnement immediat de l’enceinte de preparation (paillasses, poignees de porte, materiel informatique), dans les pieces contigues (zone administrative). Resultats L’ensemble des prelevements de surface des 3 URCC (n = 51) est contamine et de 2 a 12 MAC ont ete detectes sur 1 meme prelevement. Avec une concentration mediane [C]med de 900 ng/compresse (cp) (n = 17 ; 6,6-32700 ng/cp, min-max), tous MAC confondus, l’interieur des enceintes de preparation est la zone la plus contaminee suivie de l’environnement immediat de la zone de preparation ([C]med = 2 ng/cp ; 0,0295-430 ng/cp, min-max, n = 29) dont le materiel informatique et telephone avec une [C]med de 64 ng/cp (n = 8). Dans les pieces contigues, une [C]med 6,6 fois plus faible (0,3 ng/c ; 0,12-1,2 ng/cp, min-max, n = 5) a ete detectee (bureaux, souris d’ordinateur, poignees). L’ensemble des poches (n = 29) est contamine et 90,6 % des suremballages (n = 29/32). Les [C]med sont de 4 ng/cp sur les poches (0,05–1 500 ng/cp, min-max) et 10 fois plus faible (0,4 ng/cp ; Conclusion Ces resultats montrent une contamination de l’environnement de travail des URCC pour l’ensemble des surfaces dont les pieces contigues aux salles de preparation dans lesquelles le port d’equipements de protection n’est pas preconise. La contamination de la surface des poches et leurs suremballages expose egalement les coursiers et les personnels des services de soins. Ce travail permet de rendre visible l’invisible pour sensibiliser le personnel quant a leur exposition et a la necessite de renforcer les procedures de nettoyage des locaux. Des etudes sont en cours sur les procedes de decontamination des surfaces pour abaisser les niveaux de contamination aussi bas que possible et reduire l’exposition professionnelle.

Bien avant le cadrage reglementaire prevoyant la pluridisciplinarite en sante au travail dans la fonction publique hospitaliere, le CHU de Bordeaux s’est engage de maniere volontariste dans le dimensionnement pluridisciplinaire de son service de sante au travail. En effet, en 2007, afin de renforcer et d’elargir l’action medicale sur le champ de risques psychosociaux, le service de sante au travail du CHU de Bordeaux a integre une competence en psychologie de la sante au travail. Depuis, l’hygiene et securite puis l’ergonomie sont venues elargir le champ disciplinaire et d’action de l’equipe. Cette demarche innovante etayee par une posture reflexive constante assuree avec les medecins sur l’activite de chacun, est a l’origine d’une charte interne au CHU pour la prevention et la gestion des risques psychosociaux (RPS) puis d’une seconde concernant les missions de l’equipe pluridisciplinaire. En 2012, la soumission et l’obtention d’un contrat local d’amelioration des conditions de travail (CLACT) sur la prevention conjointe des troubles musculosquelettiques et des risques psychosociaux a permis d’eprouver une methode d’intervention en binome ergonome et psychologue en sante au travail. Des seances d’analyse des pratiques ont permis de mettre en debat les logiques disciplinaires, croisant celles de l’hygiene et securite, de l’ergonomie et de la psychologie puis de les articuler avec celles de l’activite et du pilotage medical. En consequence, l’organisation de travail en equipe a ete consolidee permettant la construction d’un veritable collectif de travail pluridisciplinaire pilote par les medecins du travail. De maniere operationnelle, trois modalites organisationnelles ont ete posees. Tout d’abord, la mise en place de staffs mensuels dans lesquels les intervenants en prevention des risques professionnels (IPRP) et medecins du travail de secteur se concertent sur les demandes et s’entendent sur une conduite a tenir. Puis la creation une mission de coordination de l’equipe IPRP qui se positionne en appui et management de l’equipe IPRP au quotidien. Enfin, toujours dans une logique d’echange des pratiques et de co-construction des interventions entre chaque discipline, un staff hebdomadaire entre IPRP est anime par le coordonnateur. Ce travail d’equipe permet au service de sante au travail de mieux repondre a ses missions, par le renforcement de l’expertise medicale et le developpement des actions sur le terrain tant sur le plan individuel que collectif.

In the spinal nerve ligation (SNL) model of neuropathic pain, synaptic plasticity shifts the excitation/inhibition balance toward excitation in the spinal dorsal horn. We investigated the deregulation of the synaptogenic neuroligin (NL) molecules, whose NL1 and NL2 isoforms are primarily encountered at excitatory and inhibitory synapses, respectively. In the dorsal horn of SNL rats, NL2 was overexpressed whereas NL1 remained unchanged. In control animals, intrathecal injections of small interfering RNA (siRNA) targeting NL2 increased mechanical sensitivity, which confirmed the association of NL2 with inhibition. By contrast, siRNA application produced antinociceptive effects in SNL rats. Regarding NL partners, expression of the excitatory postsynaptic scaffolding protein PSD95 unexpectedly covaried with NL2 overexpression, and NL2/PSD95 protein interaction and colocalization increased. Expression of the inhibitory scaffolding protein gephyrin remained unchanged, indicating a partial change in NL2 postsynaptic partners in SNL rats. This phenomenon appears to be specific to the NL2(−) isoform. Our data showed unexpected upregulation and pronociceptive effects of the “inhibitory” NL2 in neuropathic pain, suggesting a functional shift of NL2 from inhibition to excitation that changed the synaptic ratio toward higher excitation.

Chronic pain states are characterized by long-term sensitization of spinal cord neurons that relay nociceptive information to the brain. Among the mechanisms involved, up-regulation of Cav1.2-comprising L-type calcium channel (Cav1.2-LTC) in spinal dorsal horn have a crucial role in chronic neuropathic pain. Here, we address a mechanism of translational regulation of this calcium channel. Translational regulation by microRNAs is a key factor in the expression and function of eukaryotic genomes. Because perfect matching to target sequence is not required for inhibition, theoretically, microRNAs could regulate simultaneously multiple mRNAs. We show here that a single microRNA, miR-103, simultaneously regulates the expression of the three subunits forming Cav1.2-LTC in a novel integrative regulation. This regulation is bidirectional since knocking-down or over-expressing miR-103, respectively, up- or down-regulate the level of Cav1.2-LTC translation. Functionally, we show that miR-103 knockdown in naive rats results in hypersensitivity to pain. Moreover, we demonstrate that miR-103 is down-regulated in neuropathic animals and that miR-103 intrathecal applications successfully relieve pain, identifying miR-103 as a novel possible therapeutic target in neuropathic chronic pain.

The maintenance of chronic pain states requires the regulation of gene expression, which relies on an influx of calcium. Calcium influx through neuronal L-type voltage-gated calcium channels (LTCs) plays a pivotal role in excitation–transcription coupling, but the involvement of LTCs in chronic pain remains unclear. We used a peptide nucleic acid (transportan 10-PNA conjugates)-based antisense strategy to investigate the role of the LTC subtypes CaV1.2 and CaV1.3 in long-term pain sensitization in a rat model of neuropathy (spinal nerve ligation). Our results demonstrate that specific knockdown of CaV1.2 in the spinal dorsal horn reversed the neuropathy-associated mechanical hypersensitivity and the hyperexcitability and increased responsiveness of dorsal horn neurons. Intrathecal application of anti-CaV1.2 siRNAs confirmed the preceding results. We also demonstrated an upregulation of CaV1.2 mRNA and protein in neuropathic animals concomitant to specific CaV1.2-dependent phosphorylation of the cAMP response element (CRE)-binding protein (CREB) transcription factor. Moreover, spinal nerve ligation animals showed enhanced transcription of the CREB/CRE-dependent gene COX-2 (cyclooxygenase 2), which also depends strictly on CaV1.2 activation. We propose that L-type calcium channels in the spinal dorsal horn play an important role in pain processing, and that the maintenance of chronic neuropathic pain depends specifically on channels comprising CaV1.2.

The 29/30 amino acid neuropeptide galanin has been implicated in pain processing at the spinal level and local dorsal horn neurons expressing the Gal(1) receptor may play a critical role. In order to determine the transmitter identity of these neurons, we used immunohistochemistry and antibodies against the Gal(1) receptor and the three vesicular glutamate transporters (VGLUTs), as well as in situ hybridization, to explore a possible glutamatergic phenotype. Gal(1) protein, which could not be demonstrated in Gal(1) knockout mice, colocalized with VGLUT2 protein, but not with glutamate decarboxylase, in many nerve endings in lamina II. Moreover, Gal(1) and VGLUT2 transcripts were often found in the same cell bodies in laminae I-IV. Gal(1)-protein and galanin-peptide showed an overlapping distribution but were not colocalized. Gal(1) staining did not appear to be affected by dorsal rhizotomy. Taken together, these findings provide strong evidence that Gal(1) is a heteroreceptor expressed on excitatory glutamatergic dorsal horn interneurons. Activation of such Gal(1) receptors may thus decrease the inhibitory tone in the superficial dorsal horn, and possibly cause antinociception.

International audience; This article gives an account of the remains of a cooking area discovered inside a building interpreted as a tower, situated in the villa of Saint Bézard (Aspiran). After an overview of the present research on cooking spaces in the central part of Narbonensis, the building is described, inside a vast agricultural and craft establishment organized around a villa. Following is the chronology of the tower (1st c. to 4th c. AD) with its architectural and functional characteristics. The cooking space and devices are analysed in detail as well as the finds, notably the plant remains which bring definite results allowing to situate a bakery area. Finally, the question of the place of bread consumption in rural context is raised, underlining the importance of the spread of rotary-querns or water mills devoted to flour production, between the 1st century and the 3rd century AD.; Cette contribution concerne les vestiges d’un espace culinaire mis au jour à l’intérieur d’un bâtiment interprété comme une tour, située dans l’emprise de la villa de Saint Bézard (Aspiran, Hérault). Après une introduction présentant un bref état de la recherche sur les espaces culinaires en Narbonnaise centrale, l’étude commence par une présentation de cet édifice inclus dans un vaste complexe agricole et artisanal organisé autour d’une villa. La chronologie de la tour (Ier-IVe s.) et ses caractéristiques architecturales et fonctionnelles sont ensuite abordées. La pièce culinaire et ses aménagements internes sont présentés en détail, tout comme les mobiliers associés, notamment les carporestes dont l’analyse apporte des éléments décisifs permettant de localiser ici une activité de boulangerie. In fine, on s’interroge sur la place de la consommation de pain en contexte rural en soulignant l’importance de la diffusion des moulins à sang ou hydrauliques, destinés à la production de farine panifiable, entre le Ier s. et le IIIe s. apr. J.-C.

Chronic pain states are characterized by long-term sensitization of spinal cord neurons that relay nociceptive information to the brain. Among the mechanisms involved, up-regulation of Cav1.2-comprising L-type calcium channel (Cav1.2-LTC) in spinal dorsal horn have a crucial role in chronic neuropathic pain. Here, we address a mechanism of translational regulation of this calcium channel. Translational regulation by microRNAs is a key factor in the expression and function of eukaryotic genomes. Because perfect matching to target sequence is not required for inhibition, theoretically, microRNAs could regulate simultaneously multiple mRNAs. We show here that a single microRNA, miR-103, simultaneously regulates the expression of the three subunits forming Cav1.2-LTC in a novel integrative regulation. This regulation is bidirectional since knocking-down or over-expressing miR-103, respectively, up- or down-regulate the level of Cav1.2-LTC translation. Functionally, we show that miR-103 knockdown in naive rats results in hypersensitivity to pain. Moreover, we demonstrate that miR-103 is down-regulated in neuropathic animals and that miR-103 intrathecal applications successfully relieve pain, identifying miR-103 as a novel possible therapeutic target in neuropathic chronic pain.

Functional cross-talk between structurally unrelated P2X ATP receptors and members of the 'cys-loop' receptor-channel superfamily represents a recently-discovered mechanism for rapid modulation of information processing. The extent and the mechanism of the inhibitory cross-talks between these two classes of ionotropic receptors remain poorly understood, however. Both ionic and molecular coupling were proposed to explain cross-inhibition between P2X subtypes and GABA(A) receptors, suggesting a P2X subunit-dependent mechanism. We show here that cross-inhibition between neuronal P2X(3) or P2X(2+3) and GABA(A) receptors does not depend on chloride and calcium ions. We identified an intracellular QST(386-388) motif in P2X(3) subunits which is required for the functional coupling with GABA(A) receptors. Moreover the cross-inhibition between native P2X(3) and GABA receptors in cultured rat dorsal root ganglia (DRG) neurons is abolished by infusion of a peptide containing the QST motif as well as by viral expression of the main intracellular loop of GABA(A)beta3 subunits. We provide evidence that P2X(3) and GABA(A) receptors are colocalized in the soma and central processes of nociceptive DRG neurons, suggesting that specific intracellular P2X(3)-GABA(A) subunit interactions underlie a pre-synaptic cross-talk that might contribute to the regulation of sensory synaptic transmission in the spinal cord.

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In the middle of the Vth century BC, east-central France is characterized by the production of open annular ornaments whose buffers adopted specific shapes: either a series of small mouldings or a truncated ellipsoid with rim. The available documentation, mainly from funeral contexts, has made it possible to collect a corpus of 82 objects distributed between the Langres plateau and the Jura Mountain. Based on several discriminating criteria analysed by a statistical approach, a morphological classification of these ornaments and micro-regional trends can be proposed., Au milieu du Ve siècle av. J.-C., le Centre-est de la France est caractérisé par la production de parures annulaires ouvertes dont les extrémités en petits tampons adoptent des formes spécifiques : soit un enchaînement de petites moulures, soit un ellipsoïde tronqué à rebord, plus rarement un tronc de cône. La documentation disponible, essentiellement issue de contextes funéraires, a permis de réunir un corpus de 82 objets répartis entre le plateau de Langres et le Massif du Jura. À partir de plusieurs critères discriminants analysés par une approche statistique, une classification morphologique de ces parures et des tendances micro-régionales peuvent être proposées.