Étude in vitro de l’implication des cytokines de type Th17 dans la fibrose hépatique

Introduction: L’activation des cellules stellaires hépatiques (CSHs) est un point clé du processus de fibrose hépatique. Les lymphocytes T CD4+ intra-hépatiques sont une source majeure de cytokines anti-inflammatoires comme l’IL-10 et pro-inflammatoire (IL-17A), hépatoprotectrice (IL-22) produites par les Th17. Les Th17 sont impliqués dans de nombreuses pathologies inflammatoires mais l’effet de ces cellules sur les CSHs n’est pas encore élucidé. Objectif: Comprendre le rôle des cytokines de type Th17 dans le processus d’activation des CSHs. Méthodes: La lignée de CSHs humaine LX2 a été stimulée par l’IL-17A ou l’IL-22 puis comparée à des cellules traitées par le TGF-b et le tampon phosphate salin (PBS). L’activation des CSHs a été évaluée en examinant les molécules profibrotique alpha-smooth muscle actin (a-SMA), collagène de type I (COL1A1) et inhibiteur produits par les tissus des métalloprotéases matricielles I (TIMP-I) par q-PCR. L’expression protéique a été validée par immunobuvardage ou coloration au rouge de picro Sirius. L’expression membranaire de l’IL-10Rb, du TGF-b-RII et de l’IL-17RA a été mesurée par cytométrie en flux. Résultats: L’IL-17A et l’IL-22 n’activent pas les cellules LX2, car aucune induction d’a-SMA, de COL1A1 et de TIMP-I n’a été observée. Cependant, l’IL-17A et l’IL-22 sensibilisent les CSHs à l’action du TGF-b, tel que démontré par une forte expression et production d’a-SMA, collagène type I et TIMP-I. L’IL-17A, mais pas l’IL-22, induit la surexpression à la surface cellulaire du TGF-b-RII et inhibe partiellement la baisse d’expression du TGF--RII après stimulation au TGF-b. Conclusion: Nos résultats démontrent une fonction pro-fibrotique de l’IL-17A et de l’IL-22, car les deux cytokines sensibilisent les CSHs à l’action du TGF-b. L’IL-17A agit via la surexpression et la stabilisation du TGF-b-RII tandis que l’IL-22 agit probablement par des mécanismes intracellulaires.

Lê Cycles and Milnor Classes of Compact Hypersurfaces

We determine the relation amongst the global Lê cycles and the Milnor classes of analytic hypersurfaces defined by a section of a very ample line bundle over a compact complex manifold. The key point is finding appropriate expressions for the global Lê cycles and for the Milnor classes in terms of polar varieties. Our starting points are an interpretation of the Lê cycles given by T. Gaffney and R. Gassler, a formula by A. Parusinski and P. Pragacz for the Milnor classes via McPherson’s functor, and a conjecture of J.-P. Brasselet, that we prove, stating that Milnor classes can be expressed in terms of polar varieties. We then use the work by R. Piegne for Mather classes, by J. Schürmann and M. Tibăr for MacPherson’s classes for constructible functions, and by D. Massey for an extension of the local Lê cycles for constructible sheaves.

46, XY gonadal dysgenesis: new SRY point mutation in two siblings with paternal germ line mosaicism.

Stoppa-Vaucher S, Ayabe T, Paquette J, Patey N, Francoeur D, Vuissoz J-M, Deladoëy J, Samuels ME, Ogata T, Deal CL. 46, XY gonadal dysgenesis: new SRY point mutation in two siblings with paternal germ line mosaicism. Familial recurrence risks are poorly understood in cases of de novo mutations. In the event of parental germ line mosaicism, recurrence risks can be higher than generally appreciated, with implications for genetic counseling and clinical practice. In the course of treating a female with pubertal delay and hypergonadotropic hypogonadism, we identified a new missense mutation in the SRY gene, leading to somatic feminization of this karyotypically normal XY individual. We tested a younger sister despite a normal onset of puberty, who also possessed an XY karyotype and the same SRY mutation. Imaging studies in the sister revealed an ovarian tumor, which was removed. DNA from the father's blood possessed the wild type SRY sequence, and paternity testing was consistent with the given family structure. A brother was 46, XY with a wild type SRY sequence strongly suggesting paternal Y-chromosome germline mosaicism for the mutation. In disorders of sexual development (DSDs), early diagnosis is critical for optimal psychological development of the affected patients. In this case, preventive karyotypic screening allowed early diagnosis of a gonadal tumor in the sibling prior to the age of normal puberty. Our results suggest that cytological or molecular diagnosis should be applied for siblings of an affected DSD individual.

« Et ils prophétiseront » : la prophétie de Jl 3,1-5 reprise en Ac 2, 17-21 : clé d'interprétation du phénomène pentecostal

Cette présente recherche vise à défendre le point de vue selon lequel le don de l’Esprit dans le récit de la Pentecôte (Ac 2, 1-13) s’interprète principalement comme l’investissement d’une puissance habilitant au témoignage. À cette fin, nous posons l’hypothèse que le contenu d’Ac 2, 17-21 est un axe fondamental de la théologie pneumatique de l’œuvre lucanienne, lequel interprète la manifestation pentecostale dans une perspective prophétique. La démonstration se fait par le biais d’une analyse rédactionnelle d’Ac 2, 17-21, une citation de Jl 3,1-5 insérée dans un discours explicatif de Pierre du phénomène pentecostal. Nous examinons d’abord le lieu d’inscription de ce passage dans l’œuvre lucanienne afin d’évaluer la valeur stratégique de son emplacement (chapitre 1). Nous étudions ensuite l’interprétation que fait Luc de cette prophétie pour en venir à la conclusion qu’il envisage l’intervention de l’Esprit essentiellement dans une perspective d’habilitation à la prophétie (chapitre 2). Nous vérifions cette première conclusion dans l’Évangile de Luc (chapitre 3); puis ensuite dans les Actes des Apôtres (chapitre 4). Nous en arrivons ainsi à établir un parallélisme entre les étapes initiatiques du ministère de Jésus dans le troisième évangile et celui des disciples dans les Actes, pour y découvrir que, dans les deux cas, l’effusion de l’Esprit habilite à l’activité prophétique. Le ministère des disciples s’inscrit de la sorte dans le prolongement de celui du Maître. Nous soutenons, en fait, que tout le discours pneumatique de l’Évangile de Luc converge vers l’effusion initiale de l’Esprit sur les disciples dans le récit pentecostal, d’une part, et que cette effusion jette un éclairage sur l’ensemble de l’œuvre missionnaire des Actes, d’autre part. Bref, le passage explicatif du phénomène pentecostal, en l’occurrence Ac 2, 17-21, met en lumière un axe central des perspectives de Luc sur l’Esprit : Il s’agit de l’Esprit de prophétie. Dans cette optique, l’effusion de l’Esprit à la Pentecôte s’interpréterait essentiellement comme l’investissement du croyant d’une puissance en vue du témoignage.

Plan exportador Comercializadora Point Ltda.

A lo largo de la historia los mercados poco a poco se fueron abasteciendo de productos que buscaban brindar beneficios extras a sus compradores, tales que pudieran verse reflejados ya sea en facilitar las tareas habituales de los seres humanos, o simplemente brindar satisfacción por su consumo o percepción; A partir del nuevo milenio y dadas las cualidades dinámicas del mercado, las tendencias de compra del mercado de los bienes para el consumo humano han venido teniendo una desviación un poco más naturista; esta consiste en la búsqueda de alimentos producidos bajo altos estándares de calidad, pero diferentes a los productos convencionales. Actualmente se han venido desarrollando nuevas prácticas agrícolas, para evitar contaminar la tierra y lograr obtener alimentos más sanos, todos estos se llaman productos orgánicos, y su principal cualidad es que son más saludables y de valor agregado, ya que no se cultivan con ningún tipo de producto de síntesis química, lo que permite una mayor fertilidad de los suelos e incremento de la biodiversidad. Por estas razones y agregando la globalización de los mercados mundiales, es que queremos desarrollar un plan de exportación de Café Orgánico mediante la comercializadora POINT LTDA, aprovechando además brindarle a la empresa las herramientas necesarias para una futura internacionalización, teniendo en cuenta las grandes oportunidades que hay en estos momentos de expandir y tener negocios rentables en todo el mundo.

Mineral composition and 40Ar-39Ar data of samples from Garnet Point, Aurora Peak, Correll Nunatak, Penguin Point and Horn Bluffs, East Antarctica

George V Land (Antarctica) includes the boundary between Late Archean-Paleoproterozoic metamorphic terrains of the East Antarctic craton and the intrusive and metasedimentary rocks of the Early Paleozoic Ross-Delamerian Orogen. This therefore represents a key region for understanding the tectono-metamorphic evolution of the East Antarctic Craton and the Ross Orogen and for defining their structural relationship in East Antarctica, with potential implications for Gondwana reconstructions. In the East Antarctic Craton the outcrops closest to the Ross orogenic belt form the Mertz Shear Zone, a prominent ductile shear zone up to 5 km wide. Its deformation fabric includes a series of progressive, overprinting shear structures developed under different metamorphic conditions: from an early medium-P granulite-facies metamorphism, through amphibolite-facies to late greenschist-facies conditions. 40Ar-39Ar laserprobe data on biotite in mylonitic rocks from the Mertz Shear Zone indicate that the minimum age for ductile deformation under greenschist-facies conditions is 1502 ± 9 Ma and reveal no evidence of reactivation processes linked to the Ross Orogeny. 40Ar-39Ar laserprobe data on amphibole, although plagued by excess argon, suggest the presence of a ~1.7 Ga old phase of regional-scale retrogression under amphibolite-facies conditions. Results support the correlation between the East Antarctic Craton in the Mertz Glacier area and the Sleaford Complex of the Gawler Craton in southern Australia, and suggest that the Mertz Shear Zone may be considered a correlative of the Kalinjala Shear Zone. An erratic immature metasandstone collected east of Ninnis Glacier (~180 km east of the Mertz Glacier) and petrographically similar to metasedimentary rocks enclosed as xenoliths in Cambro-Ordovician granites cropping out along the western side of Ninnis Glacier, yielded detrital white-mica 40Ar-39Ar ages from ~530 to 640 Ma and a minimum age of 518 ± 5 Ma. This pattern compares remarkably well with those previously obtained for the Kanmantoo Group from the Adelaide Rift Complex of southern Australia, thereby suggesting that the segment of the Ross Orogen exposed east of the Mertz Glacier may represent a continuation of the eastern part of the Delamerian Orogen.

A point mutation in the γ2 subunit of γ-aminobutyric acid type A receptors results in altered benzodiazepine binding site specificity

Benzodiazepines allosterically modulate γ-aminobutyric acid (GABA) evoked chloride currents of γ-aminobutyric acid type A (GABAA) receptors. Coexpression of either rat γ2 or γ3, in combination with α1 and β2 subunits, results both in receptors displaying high [3H]Ro 15-1788 affinity. However, receptors containing a γ3 subunit display a 178-fold reduced affinity to zolpidem as compared with γ2-containing receptors. Eight chimeras between γ2 and γ3 were constructed followed by nine different point mutations in γ2, each to the homologous amino acid residue found in γ3. Chimeric or mutant γ subunits were coexpressed with α1 and β2 in human embryonic kidney 293 cells to localize amino acid residues responsible for the reduced zolpidem affinity. Substitution of a methionine-to-leucine at position 130 of γ2 (γ2M130L) resulted in a 51-fold reduction in zolpidem affinity whereas the affinity to [3H]Ro 15-1788 remained unchanged. The affinity for diazepam was only decreased by about 2-fold. The same mutation resulted in a 9-fold increase in Cl 218872 affinity. A second mutation (γ2M57I) was found to reduce zolpidem affinity by about 4-fold. Wild-type and γ2M130L-containing receptors were functionally expressed in Xenopus oocytes. Upon mutation allosteric coupling between agonist and modulatory sites is preserved. Dose–response curves for zolpidem and for diazepam showed that the zolpidem but not the diazepam apparent affinity is drastically reduced. The apparent GABA affinity is not significantly affected by the γ2M130L mutation. The identified amino acid residues may define part of the benzodiazepine binding pocket of GABAA receptors. As the modulatory site in the GABAA receptor is homologous to the GABA site, and to all agonist sites of related receptors, γ2M130 may either point to a homologous region important for agonist binding in all receptors or define a new region not underlying this principle.

Point mutation of the autophosphorylation site or in the nuclear location signal causes protein kinase A RII beta regulatory subunit to lose its ability to revert transformed fibroblasts.

The RII beta regulatory subunit of cAMP-dependent protein kinase (PKA) contains an autophosphorylation site and a nuclear location signal, KKRK. We approached the structure-function analysis of RII beta by using site-directed mutagenesis. Ser114 (the autophosphorylation site) of human RII beta was replaced with Ala (RII beta-P) or Arg264 of KKRK was replaced with Met (RII beta-K). ras-transformed NIH 3T3 (DT) cells were transfected with expression vectors for RII beta, RII beta-P, and RII beta-K, and the effects on PKA isozyme distribution and transformation properties were analyzed. DT cells contained PKA-I and PKA-II isozymes in a 1:2 ratio. Over-expression of wild-type or mutant RII beta resulted in an increase in PKA-II and the elimination of PKA-I. Only wild-type RII beta cells demonstrated inhibition of both anchorage-dependent and -independent growth and phenotypic change. The growth inhibitory effect of RII beta overexpression was not due to suppression of ras expression but was correlated with nuclear accumulation of RII beta. DT cells demonstrated growth inhibition and phenotypic change upon treatment with 8-Cl-cAMP. RII beta-P or RII beta-K cells failed to respond to 8-Cl-cAMP. These data suggest that autophosphorylation and nuclear location signal sequences are integral parts of the growth regulatory mechanism of RII beta.

Swellable polymer films containing Au nanoparticles for point-of-care therapeutic drug monitoring using surface-enhanced Raman spectroscopy

Large (10 × 10 cm) sheets of surface-enhanced Raman spectroscopy (SERS) active polymer have been prepared by stabilising metal nanoparticle aggregates within dry hydroxyethylcellulose (HEC) films. In these films the aggregates are protected by the polymer matrix during storage but in use they are released when aqueous analyte droplets cause the films to swell to their gel form. The fact that these "Poly-SERS" films can be prepared in bulk but then cut to size and stored in air before use means that they provide a cost effective and convenient method for routine SERS analysis. Here we have tested both Ag and Au Poly-SERS films for use in point-of-care monitoring of therapeutic drugs, using phenytoin as the test compound. Phenytoin in water could readily be detected using Ag Poly-SERS films but dissolving the compound in phosphate buffered saline (PBS) to mimic body fluid samples caused loss of the drug signal due to competition for metal surface sites from Cl^- ions in the buffer solution. However, with Au Poly-SERS films there was no detectable interference from Cl^- and these materials allowed phenytoin to be detected at 1.8 mg L^-1, even in PBS. The target range of detection of phenytoin in therapeutic drug monitoring is 10-20 mg L^-1. With the Au Poly-SERS films, the absolute signal generated by a given concentration of phenytoin was lower for the films than for the parent colloid but the SERS signals were still high enough to be used for therapeutic monitoring, so the cost in sensitivity for moving from simple aqueous colloids to films is not so large that it outweighs the advantages which the films bring for practical applications, in particular their ease of use and long shelf life.

Ventilation behavior in trained and untrained men during incremental test: evidence of one metabolic transition point

This study aimed to describe and compare the ventilation behavior during an incremental test utilizing three mathematical models and to compare the feature of ventilation curve fitted by the best mathematical model between aerobically trained (TR) and untrained ( UT) men. Thirty five subjects underwent a treadmill test with 1 km.h(-1) increases every minute until exhaustion. Ventilation averages of 20 seconds were plotted against time and fitted by: bi-segmental regression model (2SRM); three-segmental regression model (3SRM); and growth exponential model (GEM). Residual sum of squares (RSS) and mean square error (MSE) were calculated for each model. The correlations between peak VO2 (VO2PEAK), peak speed (Speed(PEAK)), ventilatory threshold identified by the best model (VT2SRM) and the first derivative calculated for workloads below (moderate intensity) and above (heavy intensity) VT2SRM were calculated. The RSS and MSE for GEM were significantly higher (p < 0.01) than for 2SRM and 3SRM in pooled data and in UT, but no significant difference was observed among the mathematical models in TR. In the pooled data, the first derivative of moderate intensities showed significant negative correlations with VT2SRM (r = -0.58; p < 0.01) and Speed(PEAK) (r = -0.46; p < 0.05) while the first derivative of heavy intensities showed significant negative correlation with VT2SRM (r = -0.43; p < 0.05). In UT group the first derivative of moderate intensities showed significant negative correlations with VT2SRM (r = -0.65; p < 0.05) and Speed(PEAK) (r = -0.61; p < 0.05), while the first derivative of heavy intensities showed significant negative correlation with VT2SRM (r= -0.73; p < 0.01), Speed(PEAK) (r = -0.73; p < 0.01) and VO2PEAK (r = -0.61; p < 0.05) in TR group. The ventilation behavior during incremental treadmill test tends to show only one threshold. UT subjects showed a slower ventilation increase during moderate intensities while TR subjects showed a slower ventilation increase during heavy intensities.

Reactivity, photolability, and computational studies of the ruthenium nitrosyl complex with a substituted cyclam fac-[Ru(NO)Cl(2)(kappa(3)N(4),N(8),N(11)(1-carboxypropyl)cyclam)]Cl center dot H(2)O

Chemical reactivity, photolability, and computational studies of the ruthenium nitrosyl complex with a substituted cyclam, fac-[Ru(NO)Cl(2)(kappa(3)N(4),N(8),N(11)(1-carboxypropyl)cyclam)]Cl center dot H(2)O ((1-carboxypropyl) cyclam = 3-(1,4,8,11-tetraazacyclotetradecan-1-yl) propionic acid)), (I) are described. Chloride ligands do not undergo aquation reactions (at 25 degrees C, pH 3). The rate of nitric oxide (NO) dissociation (k(obs-NO)) upon reduction of I is 2.8 s(-1) at 25 +/- 1 degrees C (in 0.5 mol L(-1) HCl), which is close to the highest value found for related complexes. The uncoordinated carboxyl of I has a pK(a) of similar to 3.3, which is close to that of the carboxyl of the non coordinated (1-carboxypropyl) cyclam (pK(a) = 3.4). Two additional pK(a) values were found for I at similar to 8.0 and similar to 11.5. Upon electrochemical reduction or under irradiation with light (lambda(irr) = 350 or 520 nm; pH 7.4), I releases NO in aqueous solution. The cyclam ring N bound to the carboxypropyl group is not coordinated, resulting in a fac configuration that affects the properties and chemical reactivities of I, especially as NO donor, compared with analogous trans complexes. Among the computational models tested, the B3LYP/ECP28MDF, cc-pVDZ resulted in smaller errors for the geometry of I. The computational data helped clarify the experimental acid-base equilibria and indicated the most favourable site for the second deprotonation, which follows that of the carboxyl group. Furthermore, it showed that by changing the pH it is possible to modulate the electron density of I with deprotonation. The calculated NO bond length and the Ru/NO charge ratio indicated that the predominant canonical structure is [Ru(III)NO], but the Ru-NO bond angles and bond index (b.i.) values were less clear; the angles suggested that [Ru(II)NO(+)] could contribute to the electronic structure of I and b.i. values indicated a contribution from [Ru(IV)NO(-)]. Considering that some experimental data are consistent with a [Ru(II)NO(+)] description, while others are in agreement with [Ru(III)NO], the best description for I would be a linear combination of the three canonical forms, with a higher weight for [Ru(II)NO(+)] and [Ru(III)NO].

Shoulder Muscular Activity During Isometric Three-Point Kneeling Exercise on Stable and Unstable Surfaces

The purpose of this study was to determine if performing isometric 3-point kneeling exercises on a Swiss ball influenced the isometric force output and EMG activities of the shoulder muscles when compared with performing the same exercises on a stable base of support. Twenty healthy adults performed the isometric 3-point kneeling exercises with the hand placed either on a stable surface or on a Swiss ball. Surface EMG was recorded from the posterior deltoid, pectoralis major, biceps brachii, triceps brachii, upper trapezius, and serratus anterior muscles using surface differential electrodes. All EMG data were reported as percentages of the average root mean square (RMS) values obtained in maximum voluntary contractions for each muscle studied. The highest load value was obtained during exercise on a stable surface. A significant increase was observed in the activation of glenohumeral muscles during exercises on a Swiss ball. However, there were no differences in EMG activities of the scapulothoracic muscles. These results suggest that exercises performed on unstable surfaces may provide muscular activity levels similar to those performed on stable surfaces, without the need to apply greater external loads to the musculoskeletal system. Therefore, exercises on unstable surfaces may be useful during the process of tissue regeneration.

Quantum Hall Effect near the Charge Neutrality Point in a Two-Dimensional Electron-Hole System

We study the transport properties of HgTe-based quantum wells containing simultaneously electrons and holes in a magnetic field B. At the charge neutrality point (CNP) with nearly equal electron and hole densities, the resistance is found to increase very strongly with B while the Hall resistivity turns to zero. This behavior results in a wide plateau in the Hall conductivity sigma(xy) approximate to 0 and in a minimum of diagonal conductivity sigma(xx) at nu = nu(p) - nu(n) = 0, where nu(n) and nu(p) are the electron and hole Landau level filling factors. We suggest that the transport at the CNP point is determined by electron-hole ""snake states'' propagating along the nu = 0 lines. Our observations are qualitatively similar to the quantum Hall effect in graphene as well as to the transport in a random magnetic field with a zero mean value.

Mechanism of point-defect diffusion in a two-dimensional colloidal crystal

The dynamics and mechanism of migration of a vacancy point defect in a two-dimensional (2D) colloidal crystal are studied using numerical simulations. We find that the migration of a vacancy is always realized by topology switching between its different configurations. From the temperature dependence of the topology switch frequencies, we obtain the activation energies for possible topology transitions associated with the vacancy diffusion in the 2D crystal. (C) 2011 American Institute of Physics. [doi:10.1063/1.3615287]