Antibacterial activity of extracts and neolignans from Piper regnellii (Miq.) C. DC. var. pallescens (C. DC.) Yunck

The evaluation of the activity of the aqueous and ethyl acetate extracts of the leaves of Piper regnellii was tested against gram-positive and gram-negative bacteria. The aqueous extractdisplayed a weak activity against Staphylococcus aureus and Bacillus subtilis with minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of 1000 ��g/ml. The ethyl acetate extract presented a good activity against S. aureus and B. subtilis with MIC and MBC at 15.62 ��g/ml. In contrast to the relative low MICs for gram-positive bacteria, gram-negative bacteria were not inhibited by the extracts at concentrations < 1000 mg/ml. The ethyl acetate extract was fractionated on silica gel into nine fractions. The hexane and chloroform fractions were active against S. aureus (MIC at 3.9 ��g/ml) and B. subtilis (MIC at 3.9 and 7.8 ��g/ml, respectively). Using bioactivity-directed fractionation, the hexane fraction was rechromatographed to yield the antimicrobial compounds 1, 2, 5, and 6identified as eupomatenoid-6, eupomatenoid-5, eupomatenoid-3, and conocarpan, respectively. The pure compounds 1 and 2 showed a good activity against S. aureus with MIC of 1.56 ��g/ml and 3.12 ��g/ml, respectively. Both compounds presented MIC of 3.12 ��g/ml against B. subtilis. The pure compound 6 named as conocarpan was quite active against S. aureus and B. subtilis with MIC of 6.25 ��g/ml. The antibacterial properties of P. regnellii justify its use in traditional medicine for the treatment of wounds, contaminated through bacteria infections.

Extensive remodeling of DC function by rapid maturation-induced transcriptional silencing.

The activation, or maturation, of dendritic cells (DCs) is crucial for the initiation of adaptive T-cell mediated immune responses. Research on the molecular mechanisms implicated in DC maturation has focused primarily on inducible gene-expression events promoting the acquisition of new functions, such as cytokine production and enhanced T-cell-stimulatory capacity. In contrast, mechanisms that modulate DC function by inducing widespread gene-silencing remain poorly understood. Yet the termination of key functions is known to be critical for the function of activated DCs. Genome-wide analysis of activation-induced histone deacetylation, combined with genome-wide quantification of activation-induced silencing of nascent transcription, led us to identify a novel inducible transcriptional-repression pathway that makes major contributions to the DC-maturation process. This silencing response is a rapid primary event distinct from repression mechanisms known to operate at later stages of DC maturation. The repressed genes function in pivotal processes--including antigen-presentation, extracellular signal detection, intracellular signal transduction and lipid-mediator biosynthesis--underscoring the central contribution of the silencing mechanism to rapid reshaping of DC function. Interestingly, promoters of the repressed genes exhibit a surprisingly high frequency of PU.1-occupied sites, suggesting a novel role for this lineage-specific transcription factor in marking genes poised for inducible repression.

In vitro anti-microbial activity of the Cuban medicinal plants Simarouba glauca DC, Melaleuca leucadendron L and Artemisia absinthium L

In the present study, an extensive in vitro antimicrobial profiling was performed for three medicinal plants grown in Cuba, namely Simarouba glauca, Melaleuca leucadendron and Artemisia absinthium. Ethanol extracts were tested for their antiprotozoal potential against Trypanosoma b. brucei, Trypanosoma cruzi, Leishmania infantum and Plasmodium falciparum. Antifungal activities were evaluated against Microsporum canis and Candida albicans whereas Escherichia coli and Staphylococcus aureus were used as test organisms for antibacterial activity. Cytotoxicity was assessed against human MRC-5 cells. Only M. leucadendron extract showed selective activity against microorganisms tested. Although S. glauca exhibited strong activity against all protozoa, it must be considered non-specific. The value of integrated evaluation of extracts with particular reference to selectivity is discussed.

Dectin-1 and DC-SIGN polymorphisms associated with invasive pulmonary Aspergillosis infection.

The recognition of pathogen-derived structures by C-type lectins and the chemotactic activity mediated by the CCL2/CCR2 axis are critical steps in determining the host immune response to fungi. The present study was designed to investigate whether the presence of single nucleotide polymorphisms (SNPs) within DC-SIGN, Dectin-1, Dectin-2, CCL2 and CCR2 genes influence the risk of developing Invasive Pulmonary Aspergillosis (IPA). Twenty-seven SNPs were selected using a hybrid functional/tagging approach and genotyped in 182 haematological patients, fifty-seven of them diagnosed with proven or probable IPA according to the 2008 EORTC/MSG criteria. Association analysis revealed that carriers of the Dectin-1(rs3901533 T/T) and Dectin-1(rs7309123 G/G) genotypes and DC-SIGN(rs4804800 G), DC-SIGN(rs11465384 T), DC-SIGN(7248637 A) and DC-SIGN(7252229 C) alleles had a significantly increased risk of IPA infection (OR = 5.59 95%CI 1.37-22.77; OR = 4.91 95%CI 1.52-15.89; OR = 2.75 95%CI 1.27-5.95; OR = 2.70 95%CI 1.24-5.90; OR = 2.39 95%CI 1.09-5.22 and OR = 2.05 95%CI 1.00-4.22, respectively). There was also a significantly increased frequency of galactomannan positivity among patients carrying the Dectin-1(rs3901533_T) allele and Dectin-1(rs7309123_G/G) genotype. In addition, healthy individuals with this latter genotype showed a significantly decreased level of Dectin-1 mRNA expression compared to C-allele carriers, suggesting a role of the Dectin-1(rs7309123) polymorphism in determining the levels of Dectin-1 and, consequently, the level of susceptibility to IPA infection. SNP-SNP interaction (epistasis) analysis revealed significant interactions models including SNPs in Dectin-1, Dectin-2, CCL2 and CCR2 genes, with synergistic genetic effects. Although these results need to be further validated in larger cohorts, they suggest that Dectin-1, DC-SIGN, Dectin-2, CCL2 and CCR2 genetic variants influence the risk of IPA infection and might be useful in developing a risk-adapted prophylaxis.

La dona a Roma (del segle IV aC al segle III dC)

Estudi interdisciplinari de la dona romana entre els segles IV aC i III dC. El treball s'ha basat en estudis monogr��fics, justificats i comprovats mitjan��ant la lectura i l'examen de fonts de l'��poca.

The role of dentritic cells in leishmania infection : use of novel DC lines for the development of monoclonal antibodies

Les cellules dendritiques (DCs) sont des cellules multifonctionnelles qui font le lien entre le syt��me immunitaire inn�� et adaptatif chez les mammif��res. Il existe plusieurs sous-types de DCs bas��s sur leurs fonctions et l'endroit o�� elles se situent dans le corps. Dans le cadre de cette th��se, nous avons ��tudi�� le r��le de ces cellules face �� une infection parasitaire. La Leishmania est un parasite causant une maladie appel��e Leishmaniose, maladie end��mique de l'Afrique, de l'Asie et de certaines r��gions de l'Am��rique du Sud. Certaines esp��ces causent des l��sions cutan��es, alors que d'autres causent des l��sions dans les muqueuses ou dans les organes internes. Le syst��me immunitaire r��pond en g��n��rant une r��ponse inflammatoire qui ��limine l'infection. Lors d'une r��ponse non-inflammatoire (de type cytokines, chemokines), cela va amener �� une persistance du parasite sur le long terme. Les DC s'activant en pr��sence du parasite dans la peau, vont le transporter vers un ganglion. A cet endroit, se trouvent diff��rents sous-types de DC qui ont la particularit�� de pr��senter l'antig��ne (sp��cifique �� la Leishmaniose) aux lymphocytes T, ce qui va alors amener �� une r��ponse immunitaire puissante contre le parasite. Nous avons compar�� diff��rentes esp��ces de Leishmaniose dans leur fa��on d'activer les DC et diff��rents mod��les de souris ont ��t�� utilis�� dans ce but-l��. Les souris du type C57BL/6 sont connues pour ��tre r��sistantes �� L. major et sensibles �� L. mexicana, alors qu'au contraire, les souris Balb/c sont connues pour ��tre sensibles �� ces deux esp��ces. En utilisant des parasites fluorescents transg��niques, nous avons compar�� ces deux esp��ces de parasites (L. major et L. mexicana) en recherchant quelles cellules elles sont capables d'infecter in-vivo dans un mod��le murin. Le r��le g��n��ral des DC dans une infection �� L. major a d��j�� ��t�� d��crit. Dans notre ��tude, nous avons ��tudi�� le besoin en DC CD8a+ dans les ganglions afin d'engendrer une r��ponse face �� une infection �� L. major. Les souris qui n'ont pas ce sous-type de DC sont beaucoup plus sensibles �� l'infection : elles ont des marqueurs inflammatoires plus bas et des l��sions plus grandes. Nous avons ��galement remarqu�� que les DC CD8a+ jouent un r��le crucial dans une phase plus avanc��e de l'infection. Dans notre laboratoire, nous avons la chance d'avoir une source illimit��e de DCs de sous-type CD8a+ provenant d'une souris g��n��tiquement modifi��e par nos soin. Gr��ce �� cela, nous avons utilis�� ces cellules CD8a+ pour immuniser des rats afin de produire des anticorps monoclonaux ayant des propri��t��s sp��cifiques comme l'identification de prot��ines uniques pr��sentes �� la surface des DC et qui ensuite, modulent une r��ponse immunitaire in-vivo. Nous sommes actuellement en phase de caract��risation de plus de 750 hybridomes g��n��r��s dans notre laboratoire. - Les cellules dendritiques (DCs) constituent le lien entre le syst��me inn�� et adaptatif de la r��ponse immunitaire, car elles sont capables de pr��senter l'antig��ne, de donner la co- stimulation et de rel��cher des cytokines et chimokines. Au cours de cette th��se, nous avons explor�� diff��rentes familles de DC lors d'infections parasitaires, telles que la Leishmaniose, parasite intracellulaire qui infecte les mammif��res. La plupart des l��sions cutan��es r��sistantes sont caract��ris��es par une r��ponse pro-inflammatoire g��n��r��e par l'IL-12. A l'inverse, pour la forme non r��sistante, la r��ponse est g��n��r��e par l'IL-4 et l'IL-10, dans les mod��les murins vuln��rables. L'infection avec Lmajor a ��t�� caract��ris��e chez la souris C57BL/6 (Thl) et chez la souris Balb/c (Th2). Chez la souris C57BL/6 la l��sion gu��rit, alors que chez la souris Balb/c, la l��sion est au contraire non-cicatrisante. Nous avons compar�� l'activation caus��e dans l'ensemble des DC par diff��rentes esp��ces de Leishmania, et plus sp��cifiquement dans les DC CD8a+ pr��sentes dans les ganglions lymphatiques et leur r��le dans la vuln��rabilit�� �� L. major. Ces cellules sont sp��cialis��es dans la pr��sentation crois��e d'antig��nes exog��nes par le CMH-I et le haut taux de production d'IL-12 apr��s activation. En utilisant des DC d��riv��es de moelle osseuse, nous avons constat�� que L. guyanensis V+ (transportant un retrovirus) ��tait le plus efficace pour l'activation des DC in-vitro compar�� �� L. major, L. mexicana et L. guyanensis (V-). Toutefois, in-vivo, les souris infect��es avec L. major ont vu la taille de leur ganglions lymphatiques drainants augment��e, 3-6 semaines apr��s l'infection dans les deux esp��ces de souris (les C57BL/6 r��sistantes et les Balb/c sensibles). En utilisant un parasite fluorescent transg��nique, nous avons trouv�� que les souris C57BL/6 sensibles �� Lmexicana ont un nombre plus important de cellules &#914; infect��es et un plus petit nombre de DC d��riv��es des monocytes inflammatoires, compar�� au souris infect��es avec L. major. Les cons��quences de ces observations sont encore �� l'��tude. Des souris d��ficientes en CD8ct+DC et CD103+ sont plus sensibles �� L. major que les souris WT: leurs l��sions sont plus grandes et la charge parasitaire est plus importante. Nous avons g��n��r�� une chim��re de moelles osseuse CD11-DTR et Batf3-/- en m��langeant les moelles de ces deux souris, afin de d��terminer le temps apr��s infection o�� le manque de DC's CD8a+ contribue le plus �� l'augmentation de la vuln��rabilit�� chez la souris KO. Ces souris produisent plus d'IgG1 et IgE, font une r��ponse Th2 plus forte et Thl moins forte. Nous avons constat�� que les souris d��ficientes en DC CD8a+ au d��but de la r��ponse immunitaire adaptive (trois semaines apr��s injection) maintiennent un haut taux de l��sions de grande taille, semblable �� celui des souris chez qui les cellules ont ��t�� d��pl��t��es avant l'injection. Cela indique que les DC CD8a+ sont n��cessaires pour l'efficacit�� de l'immunit�� dans la phase chronique de l'infection �� L. major. Parall��lement �� cela, nous avons aussi commenc�� une g��n��ration d'anticorps monoclonaux dirig��s contre les DC CD8a+ activ��s en utilisant des souches ��tablies dans notre laboratoire. En partant d'une librairie de 763 hybridomes, nous avons identifi�� plusieurs clones dignes d'int��r��t avec une capacit�� fonctionnelle �� moduler la prolif��ration et la s��cr��tion de cytokines des cellules T, ainsi que les mol��cules de co-stimulation pr��sentes �� la surface des DC activ��es elle-m��me. - Dendritic cells (DCs) are the bridge between the innate and the adaptive arms of the immune systems. They are professional antigen presentation cells and have important cytokine/chemokine release functions. In this dissertation we have focussed on the study of the different subsets of DCs in parasitic infection immunity. Leishmania are intra-cellular parasites of many different species that infect mammals. Most cutaneous lesions that are self- healing are characterized with a pro-inflammatory response with IL-12 while high levels of cytokines such as IL-4 and IL-10 characterized in susceptible mouse models. In mice L. major infection has been well characterized in C57BL/6 mice (Thl) that form healing lesions while Balb/c mice (Th2) form non-healing lesions. This thesis is focussed on comparing DC activation at large by different strains of Leishmania and more specifically, dLN resident CD8a+ DCs and their role in L. major susceptibility. This subset is specialized in cross- presentation of exogenous antigens in the MHC-I pathway and produce high levels of EL-12. Using bone marrow derived DCs we found that L. guyanensis V+ (carrying a retro-virus) was the most efficient at activating DCs in-vitro. In-vivo however L. major infected mice had the largest dLNs 3-6 weeks after infection in both genetically resistant C57BL/6 and susceptible Balb/c mice. Using transgenic fluorescent parasites, we found that C57BL/6 mice which are susceptible to L. mexicana had more number of infected &#914; cells and fewer number of infected inflammatory monocyte derived DCs in contrast to L. major infection. Using mice deficient in CD8a+ DCs, we found that these mice were more susceptible to L. major than their WT counterparts. They made larger lesions, had higher parasite burdens, higher levels of Th2 indicating immunolgloblins as measured by higher serie IgE levels and lower CD4+ IFNy+ cells. A mixed bone marrow chimera system of CDllc-DTR and Batf3~'~ was generated to determine the time point at which the lack of CD8a+ DCs most contributes to the increased susceptibility in KO mice. We found that mice depleted of CD8a+ DCs at the advent of the adaptive response (3 weeks after infection) maintained the significantly higher lesion size similar to mice whose cells were depleted from the onset of infection. This indicates that CD8a+ DCs are required for effective immunity in the chronic phase of L. major infection. We also began the generation of a valuable tool of monoclonal antibodies against activated CD8a+ DCs using our in-house DC line. From a library of 763 hybridomas we have identified several interesting clones with a functional ability to modulate &#932; cell proliferation and cytokine secretion as well as down-modulating co-stimulatory molecules on activated DC cells themselves.

Globalization and the Symphony of the New (Post-modern) World: From Westphalia to Maastricht���passing by Washington DC

Taking on the challenge of understanding and explaining the Symphony of (today���s) New World in realistic terms (not realist), this essay aims to analyse the Post-Cold war era by devising a multi-conceptual framework that combines different theoretical contributions not yet linked in a fully explanatory way. This paper suggests two inter-related analytical contexts (or background melodies) to understand Dvorak��s "New World���. First, the socio-economic structural context that falls under the controversial category of Globalization and, second, the post-modern political structural context that is built on Robert Cooper���s threefold analysis (Pre-modern, Modern and Post-modern) of today���s world [Cooper, R: 1997, 1999]. Lastly, the closing movement (allegro con fuoco) enters the normative arena to assess American foreign policy options in the light of the theoretical framework devised in the first part of the essay.

L'��mbit urb�� i periurb�� de Rhode entre el 195 aC i el segle II dC

Aquest projecte de recerca es planteja, com a objectiu principal, elaborar una contextualitzaci�� de Rhode entre el 195 aC i mitjan segle II dC. Es tracta d���assolir noves hip��tesis sobre el final relativament sobtat que pateix la fundaci�� massaliota, quin s��n els motius del seu abandonament, si aquest es produeix totalment, quins fets porten a la recuperaci�� d���aquest espai i quin paper pot jugar l'��mbit periurb�� de Rhode durant tot aquest per��ode. Alhora, es cerca posar en relaci�� els esdeveniments que passen a Rhode amb el proc��s de romanitzaci�� que pateix el territori

Allemagne, occupation d��c. 1918, Bingen sur Rhin, un remorqueur, sur la montagne la statue colossale repr��sentant la victoire de l'Allemagne en 1870 : [photographie de presse] / [Agence Rol]

R��f��rence bibliographique : Rol, 57263

Allemagne, occupation, d��c. 1919, Bingen sur Rhin, flotte marchande en rade attendant le d��part pour Mayence : [photographie de presse] / [Agence Rol]

R��f��rence bibliographique : Rol, 57260

The evolutionary history of the CD209 (DC-SIGN) family in humans and non-human primates

The CD209 gene family that encodes C-type lectins in primates includes CD209 (DC-SIGN), CD209L (L-SIGN) and CD209L2. Understanding the evolution of these genes can help understand the duplication events generating this family, the process leading to the repeated neck region and identify protein domains under selective pressure. We compiled sequences from 14 primates representing 40 million years of evolution and from three non-primate mammal species. Phylogenetic analyses used Bayesian inference, and nucleotide substitutional patterns were assessed by codon-based maximum likelihood. Analyses suggest that CD209 genes emerged from a first duplication event in the common ancestor of anthropoids, yielding CD209L2 and an ancestral CD209 gene, which, in turn, duplicated in the common Old World primate ancestor, giving rise to CD209L and CD209. K(A)/K(S) values averaged over the entire tree were 0.43 (CD209), 0.52 (CD209L) and 0.35 (CD209L2), consistent with overall signatures of purifying selection. We also assessed the Toll-like receptor (TLR) gene family, which shares with CD209 genes a common profile of evolutionary constraint. The general feature of purifying selection of CD209 genes, despite an apparent redundancy (gene absence and gene loss), may reflect the need to faithfully recognize a multiplicity of pathogen motifs, commensals and a number of self-antigens

Comparative Study of Chemoembolization, Loadable Beads: In vitro Drug Release and Physical Properties of DC Bead and Hepasphere, Loaded with Doxorubicin and Irinotecan

Purpose To characterize in vitro the loadability, physical properties, and release of irinotecan and doxorubicin from two commercially available embolization microspheres. Materials and Methods DC Bead (500-700 &#956;m) and Hepasphere (400-600 &#956;m) microspheres were loaded with either doxorubicin or irinotecan solutions. Drug amount was quantified with spectrophotometry, bead elasticity was measured under compression, and bead size and loading homogeneity were assessed with microscopy image analysis. Drug release was measured over 1-week periods in saline by using a pharmacopeia flow-through method. Results Almost complete drug loading was obtained for both microsphere types and drugs. Doxorubicin-loaded DC Beads maintained their spherical shape throughout the release. In contrast, Hepaspheres showed less homogeneous doxorubicin loading and, after release, some fractured microspheres. Incomplete doxorubicin release was observed in saline over 1 week (27% �� 2 for DC beads and 18% �� 7 for Hepaspheres; P = .013). About 75% of this amount was released within 2.2 hours for both beads. For irinotecan, complete release was obtained for both types of beads, in a sustained manner over 2-3 hours for DC Beads, and in a significantly faster manner as a 7-minute burst for Hepaspheres. Conclusions The two drug-eluting microspheres could be efficiently loaded with both drugs. Incomplete doxorubicin release was attributed to strong drug-bead ionic interactions. Weaker interactions were observed with irinotecan, which led to faster drug release.