Solvent vapours in incubators: a source of exposure among neonates?

Hygiene practices in neonatal units require the use of disinfecting solutions containing ethanol or isopropanol. Newly disinfected hands or soaked swabs introduced inside the incubators may emit vapours leading to alcohol exposures to the neonates. Alcohol emissions from hands and other occasional sources (e.g. soaked disinfecting swabs) lead to measurable levels of vapours inside incubators. Average isopropanol and ethanol concentrations ranging from 33.1 to 171.4 mg/m(3) (13.8 to 71.4 ppm) and from 23.5 to more than 146 mg/m3 (9.8 to > 6 ppm) respectively were measured inside occupied incubators (n = 11, measurement time about 230 min) in a neonatal unit of the Centre Hospitalier Universitaire Vaudois in Lausanne during regular activity. Exposure concentrations in a wide range of possible situations were then investigated by modeling using the one-box dispersion model. Theoretical modeling suggested typical isopropanol peaks and average concentrations ranging between 10(2) and 10(3) mg/m(3) (4.10(1) to 4.10(2)ppm), and 10(1) to 10(2) mg/m(3) (4 to 4.10(1) ppm), respectively. Based on our results we suggest several preventive measures to reduce the neonates' exposures to solvent vapours.

Edar/Eda interactions regulate enamel knot formation in tooth morphogenesis.

tabby and downless mutant mice have apparently identical defects in teeth, hair and sweat glands. Recently, genes responsible for these spontaneous mutations have been identified. downless (Dl) encodes Edar, a novel member of the tumour necrosis factor (TNF) receptor family, containing the characteristic extracellular cysteine rich fold, a single transmembrane region and a death homology domain close to the C terminus. tabby (Ta) encodes ectodysplasin-A (Eda) a type II membrane protein of the TNF ligand family containing an internal collagen-like domain. As predicted by the similarity in adult mutant phenotype and the structure of the proteins, we demonstrate that Eda and Edar specifically interact in vitro. We have compared the expression pattern of Dl and Ta in mouse development, taking the tooth as our model system, and find that they are not expressed in adjacent cells as would have been expected. Teeth develop by a well recorded series of epithelial-mesenchymal interactions, similar to those in hair follicle and sweat gland development, the structures found to be defective in tabby and downless mice. We have analysed the downless mutant teeth in detail, and have traced the defect in cusp morphology back to initial defects in the structure of the tooth enamel knot at E13. Significantly, the defect is distinct from that of the tabby mutant. In the tabby mutant, there is a recognisable but small enamel knot, whereas in the downless mutant the knot is absent, but enamel knot cells are organised into a different shape, the enamel rope, showing altered expression of signalling factors (Shh, Fgf4, Bmp4 and Wnt10b). By adding a soluble form of Edar to tooth germs, we were able to mimic the tabby enamel knot phenotype, demonstrating the involvement of endogenous Eda in tooth development. We could not, however, reproduce the downless phenotype, suggesting the existence of yet another ligand or receptor, or of ligand-independent activation mechanisms for Edar. Changes in the structure of the enamel knot signalling centre in downless tooth germs provide functional data directly linking the enamel knot with tooth cusp morphogenesis. We also show that the Lef1 pathway, thought to be involved in these mutants, functions independently in a parallel pathway.

Geochemical and H-O-Sr-Nd isotope evidence for magmatic processes and meteoric-water interactions in the basal complex of La Gomera, Canary Islands

The plutonic rocks of the Basal Complex of La Gomera, Canary Islands, Spain, were studied by means of major and trace element contents and by H-O-Sr-Nd isotope compositions in order to distinguish primary magmatic characteristics and late-stage alteration products. Deciphering the effects of alteration allowed us to determine primary, plume-related compositions that indicated D- and (18)O-depletion relative to normal upper mantle, supporting the conclusions of earlier studies on the plutonic rocks of Fuerteventura and La Palma. Late-stage alteration took place during the formation of the intrusive series induced by interaction with meteoric water. Inferred isotopic compositions of the meteoric water indicate that the water infiltrated into the rock edifice at a height of about 1500 m above sea level, suggesting the existence of a subaerial volcano which was active during the intrusive activity and that it has been either distroyed or remain buried by later volcanic and landslide events.

Analysis of an iterative deconvolution approach for estimating the source wavelet during waveform inversion of crosshole ground-penetrating radar data

A major issue in the application of waveform inversion methods to crosshole georadar data is the accurate estimation of the source wavelet. Here, we explore the viability and robustness of incorporating this step into a time-domain waveform inversion procedure through an iterative deconvolution approach. Our results indicate that, at least in non-dispersive electrical environments, such an approach provides remarkably accurate and robust estimates of the source wavelet even in the presence of strong heterogeneity in both the dielectric permittivity and electrical conductivity. Our results also indicate that the proposed source wavelet estimation approach is relatively insensitive to ambient noise and to the phase characteristics of the starting wavelet. Finally, there appears to be little-to-no trade-off between the wavelet estimation and the tomographic imaging procedures.

Stable alpha-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones.

α-Synuclein aggregation and accumulation in Lewy bodies are implicated in progressive loss of dopaminergic neurons in Parkinson disease and related disorders. In neurons, the Hsp70s and their Hsp40-like J-domain co-chaperones are the only known components of chaperone network that can use ATP to convert cytotoxic protein aggregates into harmless natively refolded polypeptides. Here we developed a protocol for preparing a homogeneous population of highly stable β-sheet enriched toroid-shaped α-Syn oligomers with a diameter typical of toxic pore-forming oligomers. These oligomers were partially resistant to in vitro unfolding by the bacterial Hsp70 chaperone system (DnaK, DnaJ, GrpE). Moreover, both bacterial and human Hsp70/Hsp40 unfolding/refolding activities of model chaperone substrates were strongly inhibited by the oligomers but, remarkably, not by unstructured α-Syn monomers even in large excess. The oligomers acted as a specific competitive inhibitor of the J-domain co-chaperones, indicating that J-domain co-chaperones may preferably bind to exposed bulky misfolded structures in misfolded proteins and, thus, complement Hsp70s that bind to extended segments. Together, our findings suggest that inhibition of the Hsp70/Hsp40 chaperone system by α-Syn oligomers may contribute to the disruption of protein homeostasis in dopaminergic neurons, leading to apoptosis and tissue loss in Parkinson disease and related neurodegenerative diseases.

Post-Plutonic Magmatism: from the Source to the Emplacement of an Upper Crustal Dyke Swarm, Adamello Massif, Italy

Magmas of the arc-tholeiitic and calc-alkaline differentiation suites contribute substantially to the formation of continental crust in subduction zones. Different geochemical-petrological models have been put forward to achieve evolved magmas forming large volumes of tonalitic to granitic plutons, building an important part of the continental crust. Primary magmas produced in the mantle wedge overlying the subducted slab migrate through the mantle and the crust. During the transfer, magma can accumulate in intermediate reservoirs at different levels where crystallization leads to differentiation and the heat transfer from the magma, together with gained heat from solidification, lead to partial melting of the crust. Partial melts can be assimilated and mix with more primitive magma. Moreover, already formed crystal cumulates or crystal mushes can be recycled and reactivated to transfer to higher crustal levels. Magma transport in the crust involves fow through fractures within a brittle elastic rock. The solidified magma filled crack, a dyke, can crosscut previously formed geological structures and thus serves as a relative or absolute time marker. The study area is situated in the Adamello massif. The Adamello massif is a composite of plutons that were emplaced between 42 and 29 million years. A later dyke swarm intruded into the southern part of the Adamello Batholith. A fractionation model covering dyke compositions from picrobasalts to dacites results in the cummulative crystallization of 17% olivine, 2% Cr-rich spinel, 18% clinopyroxene, 41% amphibole, 4% plagioclase and 0.1% magnetite to achieve an andesitic composition out of a hydrous primitive picrobasalt. These rocks show a similar geochemical evolution as experimental data simulating fractional crystallization and associated magma differentiation at lower crustal depth (7-10 kbar). The peraluminous, corundum normative composition is one characteristic of more evolved dacitic magmas, which has been explained in a long lasting debate with two di_erent models. Melting of mafic crust or politic material provides one model, whereas an alternative is fractionation from primary mantle derived melts. Amphibole occurring in basaltic-andesitic and andesitic dyke rocks as fractionating cumulate phase extracted from lower crustal depth (6-7.5 kbar) is driving the magmas to peraluminous, corundum normative compositions, which are represented by tonalites forming most of the Adamello Batholith. Most primitive picrobasaltic dykes have a slightly steepened chondrite normalized rare earth elements (REE) pattern and the increased enrichment of light-REE (LREE) for andesites and dacites can be explained by the fractional crystallization model originating from a picrobasalt, taking the changing fractionating phase assemblage and temperature into account. The injection of hot basaltic magma (~1050°C) in a closely spaced dyke swarm increases the surface of the contact to the mainly tonalitic wallrock. Such a setting induces partial melting of the wall rock and selective assimilation. Partial melting of the tonalite host is further expressed through intrusion breccias from basaltic dykes. Heat conduction models with instantaneous magma injection for such a dyke swarm geometry can explain features of partial melting observed in the field. Geochemical data of minerals and bulk rock further underline the selective or bulk assimilation of the tonalite host rock at upper crustal levels (~2-3 kbar), in particular with regard to light ion lithophile elements (LILE) such as Sr, Ba and Rb. Primitive picrobasalts carry an immiscible felsic assimilant as enclaves that bring along refractory rutile and zircon with textures typically found in oceanic plagiogranites or high pressure/low-temperature metamorphic rocks in general. U-Pb data implies a lower Cretaceous age for zircon not yet described as assimilant in Eocene to Oligocene magmatic rocks of the Central Southern Alps. The distribution of post-plutonic dykes in large batholiths such as the Adamello is one of the key features for understanding the regional stress field during the post-batholith emplacement cooling history. The emplacement of the regional dyke swarm covering the southern part of the Adamello massif was associated with consistent left lateral strike-slip movement along magma dilatation planes, leading to en echelon segmentation of dykes. Through the dilation by magma of pre-existing weaknesses and cracks in an otherwise uniform host rock, the dyke propagation and according orientation in the horizontal plane adjusted continuously perpendicular to least compressive remote stress σ3, resulting in an inferred rotation of the remote principal stress field. Les magmas issus des zones de subduction contribuent substantiellement à la formation de la croûte continentale. Les plutons tonalitiques et granitiques représentent, en effet, une partie importante de la croûte continentale. Des magmas primaires produits dans le 'mantle wedge ', partie du manteau se trouvant au-dessus de la plaque plongeante dans des zones de subduction, migrent à travers le manteau puis la croûte. Pendant ce transfert, le magma peut s'accumuler dans des réservoirs intermédiaires à différentes profondeurs. Le stockage de magma dans ces réservoirs engendre, d'une part, la différentiation des magmas par cristallisation fractionnée et, d'autre part, une fusion partielle la croûte continentale préexistante associée au transfert de la chaleur des magmas vers l'encaissant. Ces liquides magmatiques issus de la croûte peuvent, ensuite, se mélanger avec des magmas primaires. Le transport du magma dans la croûte implique notamment un flux de magma à travers différentes fractures recoupant les roches encaissantes élastiques. Au cours de ce processus de migration, des cumulats de cristaux ou des agrégats de cristaux encore non-solidifiés, peuvent être recyclés et réactivés pour être transportés à des niveaux supérieures de la croûte. Le terrain d'étude est situé dans le massif d'Adamello. Celui-ci est composé de plusieurs plutons mis en place entre 42 et 29 millions d'années. Dans une phase tardive de l'activité magmatique liée à ce batholite, une série de filons de composition variable allant de picrobasalte à des compositions dacitiques s'est mise en place la partie sud du massif. Deux modèles sont proposés dans la littérature, pour expliquer la formation des magmas dacitiques caractérisés par des compositions peralumineux (i.e. à corindon normatif). Le premier modèle propose que ces magmas soient issus de la fusion de matériel mafique et pélitique présent dans la partie inférieur de la croûte, alors que le deuxième modèle suggère une évolution par cristallisation fractionnée à partir de liquides primaires issus du manteau. Un modèle de cristallisation fractionnée a pu être développé pour expliquer l'évolution des filons de l'Adamello. Ce modèle explique la formation des filons dacitiques par la cristallisation fractionnée de 17% olivine, 2% spinelle riche en Cr, 18% clinopyroxène, 41% amphibole, 4% plagioclase et 0.1% magnetite à partir de liquide de compositions picrobasaltiques. Ce modèle prend en considération les contraintes pétrologiques déduites de l'observation des différents filons ainsi que du champ de stabilité des différentes phases en fonction de la température. Ces roches montrent une évolution géochimique similaire aux données expérimentales simulant la cristallisation fractionnée de magmas évoluant à des niveaux inférieurs de la croûte (7-10 kbar). Le modèle montre, en particulier, le rôle prépondérant de l'amphibole, une phase qui contrôle en particulier le caractère peralumineux des magmas différentiés ainsi que leurs compositions en éléments en traces. Des phénomènes de fusion partielle de l'encaissant tonalitique lors de la mise en place de _lons mafiques sont observée sur le terrain. L'injection du magma basaltique chaud (~1050°C) sous forme de filons rapprochés augmente la surface du contact avec l'encaissante tonalitique. Une telle situation produit la fusion partielle des roches encaissantes nécessaire à l'incorporation d'enclaves mafiques observés au sein des tonalites. Pour comprendre les conditions nécessaires pour la fusion partielle des roches encaissantes, des modèles de conduction thermique pour une injection simultanée d'une série de filons ont été développées. Des données géochimiques sur les minéraux et sur les roches totales soulignent qu'au niveau supérieur de la croûte, l'assimilation sélective ou totale de l'encaissante tonalitique modifie la composition du liquide primaire pour les éléments lithophiles tel que le Sr, Ba et Rb. Un autre aspect important concernant la pétrologie des filons de l'Adamello est la présence d'enclaves felsiques dans les filons les plus primitifs. Ces enclaves montrent, en particulier, des textures proches de celles rencontrées dans des plagiogranites océaniques ou dans des roches métamorphiques de haute pression/basse température. Ces enclaves contiennent du zircon et du rutile. La datations de ces zircons à l'aide du géochronomètre U-Pb indique un âge Crétacé inférieur. Cet âge est important, car aucune roche de cet âge n'a été considérée comme un assimilant potentiel pour des roches magmatiques d'âge Eocène à Oligocène dans les Alpes Sud Centrales. La réparation spatiale des filons post-plutoniques dans des grands batholites tel que l'Adamello, est une caractéristique clé pour la compréhension des champs de contraintes lors du refroidissement du batholite. L'orientation des filons va, en particulier, indiqué la contrainte minimal au sein des roches encaissante. La mise en place de la série de filon recoupant la partie Sud du massif de l'Adamello est associée à un décrochement senestre, un décrochement que l'on peut lié aux contraintes tectoniques régionales auxquelles s'ajoutent l'effet de la dilatation produite par la mise en place du batholite lui-même. Ce décrochement senestre produit une segmentation en échelon des filons.

Tuning the immune response of dendritic cells to surface-assembled poly(I:C) on microspheres through synergistic interactions between phagocytic and TLR3 signaling.

The artificial dsRNA polyriboinosinic acid-polyribocytidylic acid, poly(I:C), is a potent adjuvant candidate for vaccination, as it strongly drives cell-mediated immunity. However, because of its effects on non-immune bystander cells, poly(I:C) administration may bear danger for the development of autoimmune diseases. Thus poly(I:C) should be applied in the lowest dose possible. We investigated microspheres carrying surface-assembled poly(I:C) as a two-in-one adjuvant formulation to stimulate maturation of monocyte-derived dendritic cells (MoDCs). Negatively charged polystyrene microspheres were equipped with a poly(ethylene glycol) corona through electrostatically driven surface assembly of a library of polycationic poly(l-lysine)-graft-poly(ethylene glycol) copolymers, PLL-g-PEG. Stable surface assembly of poly(I:C) was achieved by incubation of polymer-coated microspheres in an aqueous poly(I:C) solution. Surface-assembled poly(I:C) exhibited a strongly enhanced efficacy to stimulate maturation of MoDCs by up to two orders of magnitude, as compared to free poly(I:C). Multiple phagocytosis events were the key factor to enhance the efficacy. The cytokine secretion pattern of MoDCs after exposure to surface-assembled poly(I:C) differed from that of free poly(I:C), while their ability to stimulate T cell proliferation was similar. Overall, phagocytic signaling plays an important role in defining the resulting immune response to such two-in-one adjuvant formulations.

Mechanosensory interactions drive collective behaviour in Drosophila.

Collective behaviour enhances environmental sensing and decision-making in groups of animals. Experimental and theoretical investigations of schooling fish, flocking birds and human crowds have demonstrated that simple interactions between individuals can explain emergent group dynamics. These findings indicate the existence of neural circuits that support distributed behaviours, but the molecular and cellular identities of relevant sensory pathways are unknown. Here we show that Drosophila melanogaster exhibits collective responses to an aversive odour: individual flies weakly avoid the stimulus, but groups show enhanced escape reactions. Using high-resolution behavioural tracking, computational simulations, genetic perturbations, neural silencing and optogenetic activation we demonstrate that this collective odour avoidance arises from cascades of appendage touch interactions between pairs of flies. Inter-fly touch sensing and collective behaviour require the activity of distal leg mechanosensory sensilla neurons and the mechanosensory channel NOMPC. Remarkably, through these inter-fly encounters, wild-type flies can elicit avoidance behaviour in mutant animals that cannot sense the odour--a basic form of communication. Our data highlight the unexpected importance of social context in the sensory responses of a solitary species and open the door to a neural-circuit-level understanding of collective behaviour in animal groups.

Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety.

BACKGROUND AND PURPOSE: The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored. EXPERIMENTAL APPROACH: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg x kg(-1)) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed. KEY RESULTS: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone C(max) was correlated with SPT assessment (rho(S)= 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers. CONCLUSIONS AND IMPLICATIONS: The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism.

Interactions of Ly49 family receptors with MHC class I ligands in trans and cis.

The Ly49A NK cell receptor interacts with MHC class I (MHC-I) molecules on target cells and negatively regulates NK cell-mediated target cell lysis. We have recently shown that the MHC-I ligand-binding capacity of the Ly49A NK cell receptor is controlled by the NK cells' own MHC-I. To see whether this property was unique to Ly49A, we have investigated the binding of soluble MHC-I multimers to the Ly49 family receptors expressed in MHC-I-deficient and -sufficient C57BL/6 mice. In this study, we confirm the binding of classical MHC-I to the inhibitory Ly49A, C and I receptors, and demonstrate that detectable MHC-I binding to MHC-I-deficient NK cells is exclusively mediated by these three receptors. We did not detect significant multimer binding to stably transfected or NK cell-expressed Ly49D, E, F, G, and H receptors. Yet, we identified the more distantly related Ly49B and Ly49Q, which are not expressed by NK cells, as two novel MHC-I receptors in mice. Furthermore, we show using MHC-I-sufficient mice that the NK cells' own MHC-I significantly masks the Ly49A and Ly49C, but not the Ly49I receptor. Nevertheless, Ly49I was partly masked on transfected tumor cells, suggesting that the structure of Ly49I is compatible in principal with cis binding of MHC-I. Finally, masking of Ly49Q by cis MHC-I was minor, whereas masking of Ly49B was not detected. These data significantly extend the MHC-I specificity of Ly49 family receptors and show that the accessibility of most, but not all, MHC-I-binding Ly49 receptors is modulated by the expression of MHC-I in cis.