Polydiacetylenic nanofibers as new siRNA vehicles for in vitro and in vivo delivery

Polydiacetylenic nanofibers (PDA-Nfs) obtained by photopolymerization of surfactant 1 were optimized for intracellular delivery of small interfering RNAs (siRNAs). PDA-Nfs/siRNA complexes efficiently silenced the oncogene Lim-1 in the renal cancer cells 786-O in vitro. Intraperitoneal injection of PDA-Nfs/siLim1 downregulated Lim-1 in subcutaneous tumor xenografts obtained with 786-O cells in nude mice. Thus, PDA-Nfs represent an innovative system for in vivo delivery of siRNAs

Photopolymerized micelles of diacetylene amphiphile: physical characterization and cell delivery properties:

A series of polydiacetylene (PDA) - based micelles were prepared from diacetylenic surfactant bearing polyethylene glycol, by increasing UV-irradiation times. These polymeric lipid micelles were analyzed by physicochemical methods, electron microscopy and NMR analysis. Cellular delivery of fluorescent dye suggests that adjusting the polymerization state is vital to reach the full in vitro potential of PDA-based delivery system

Inhibition of dengue virus infection by mannoside glycolipid conjugates

International audienceDengue virus (DENV), a mosquito-borne flavivirus, causes severe and potentially fatal symptoms in millions of infected individuals each year. Although dengue fever represents a major global public health problem, the vaccines or antiviral drugs proposed so far have not shown sufficient efficacy and safety, calling for new antiviral developments. Here we have shown that a mannoside glycolipid conjugate (MGC) bearing a trimannose head with a saturated lipid chain inhibited DENV productive infection. It showed remarkable cell promiscuity, being active in human skin dendritic cells, hepatoma cell lines and Vero cells, and was active against all four DENV serotypes, with an IC 50 in the low micromolar range. Time-of-addition experiments and structure-activity analyses revealed the importance of the lipid chain to interfere with an early viral infection step. This, together with a correlation between antiviral activity and membrane polarization by the lipid moiety indicated that the in-hibitor functions by blocking viral envelope fusion with the endosome membrane. These finding establish MGCs as a novel class of antivirals against the DENV

Managing formalization to increase global team effectiveness and meaningfulness of work in multinational organizations

Global teams may help to integrate across locations, and yet, with formalized rules and procedures, responsiveness to those locations’ effectiveness, and the team members’ experiences of work as meaningful may suffer. We employ a mixed-methods approach to understand how the level and content of formalization can be managed to resolve these tensions in multinationals. In a sample of global teams from a large mining and resources organization operating across 44 countries, interviews, observations, and a quantitative 2-wave survey revealed a great deal of variability between teams in how formalization processes were enacted. Only those formalization processes that promoted knowledge sharing were instrumental in improving team effectiveness. Implementing rules and procedures in the set-up of the teams and projects, rather than during interactions, and utilizing protocols to help establish the global team as a source of identity increased this knowledge sharing. Finally, we found members’ personal need for structure moderated the effect of team formalization on how meaningful individuals found their work within the team. These findings have significant implications for theory and practice in multinational organizations

From Romantic Gothic to Victorian Medievalism: 1817 and 1877

"The Cambridge History of the Gothic was conceived in 2015, when Linda Bree, then Editorial Director at Cambridge University Press, first suggested the idea to us

Isolation of antimicrobial substances from insects : chemical synthesis and preparation of structural analogs

Les insectes sont connus pour leur forte résistance aux microorganismes, ce qui est principalement dû à leur réponse immunitaire innée efficace mettant notamment en jeu différentes familles de peptides antimicrobiens. Nous avons recherché chez les insectes des molécules non-peptidiques antimicrobiennes qui pourraient compléter naturellement cette réponse immunitaire de l’insecte. Dans ce travail nous décrivons l’isolement par pharmacoguidage d’une substance naturelle antimicrobienne à partir de l’espèce Harmonia axyridis. Cette coccinelle biosynthétise le Z-1,17-diaminooctadéc-9-ène, également appelé harmonine, dont nous avons pour la première fois mis en évidence ses propriétés antimicrobiennes. Par une étude de la relation de structure-activité de diverses α,ω-diamines nous avons déterminé quels éléments structuraux sont essentiels à l’activité biologique de la diamine naturelle. Nous basant sur des degrés de liberté de substitution autour de cette molécule active nous avons conçu des polyamines originales, qui ont une activité biologique accrue par rapport à la diamine naturelle ; elles ont été construites autour d’un squelette hydrocarboné ramifié. Nous avons également conçu des analogues rigidifiés de ces polyamines, qui sont construites autour d’un cycle tétrahydrofurane central, des THF-polyamines. Elles gardent les mêmes activités antibactériennes que les polyamines les plus actives. Contrairement à celles-ci, elles ont perdu toutes leurs propriétés cytotoxiques, déterminées par des tests d’hémolyse. Ainsi nous avons pu augmenter l’indice thérapeutique de ces polyamines par rapport à celui de l’harmonine, diamine naturelle d’insecte.Insects are famous for their strong resistance against invading microorganisms. Their immune response is based on a diverse set of inducible antimicrobial peptides. We addressed the question of whether there are other non-peptidic antimicrobial molecules reinforcing the immune response of the insects. In this work we describe the characterization of an antimicrobial diamine, which was isolated using a bioassay guide, from the coccinellid species Harmonia axyridis. This beetle biosynthesises the Z-1,17-diaminooctadec-9-ene, also called ‘harmonine’. It is the first time that the antimicrobial activities of this substance have been described. The chemical synthesis of diverse α,ω-diamines allowed for a detailed analysis of the structure-activity relationship of this family of compounds. This study showed which structural elements are essential for their biological activity. We showed that the active molecules could be diversely substituted at their central part; leading from this, novel polyamines, based on a branched hydrocarbon skeleton, were designed. These have an increased activity compared to the isolated natural diamine. We also describe the novel construction and synthesis of rigidified analogues of the polyamines, which are based on a tetrahydrofuran heterocycle. These THF-amines are endowed with the same activities as the most potent polyamines of these series. Unlike the polyamines based on a branched hydrocarbon part, the THF-amines show no cytotoxic properties as proved by hemolytic tests. The therapeutic index of the polyamines is increased as compared to harmonine

Isolement de substances antimicrobiennes d'insectes (Synthèse chimique et préparation d'analogues structuraux)

Résumé français : notice = 7Ko MAXIMUM : résumé trop long empêche la validation : longueur = 1700 caractéresRésumé anglais : idemSTRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Design and evaluation of ionizable peptide amphiphiles for siRNA delivery

International audienceSmall interfering RNAs (siRNAs) can down-regulate the expression of a target mRNA molecule in a sequence-specific manner, making them an attractive new class of drugs with broad potential for the treatment of diverse human diseases. Here, we report the synthesis of a series of cationic amphiphiles which were obtained by the coupling of amino acids and dipeptides onto a lipidic double chain. The new amphiphiles presenting a peptidic motif on a short hydrophilic spacer group were evaluated for selective gene silencing through RNA interference. Our results show that tryptophan residues boost siRNA delivery in an unexpected manner. The silencing experiments performed with very low concentrations of siRNA showed that the best formulations could induce significant death of tumor cells after silencing of polo-like kinase 1 which is implicated in cell cycle progression. In addition, these Trp containing peptide amphiphiles were highly efficient siRNA delivery vectors even in presence of competing serum proteins

Design and evaluation of ionizable peptide amphiphiles for siRNA delivery

International audienceSmall interfering RNAs (siRNAs) can down-regulate the expression of a target mRNA molecule in a sequence-specific manner, making them an attractive new class of drugs with broad potential for the treatment of diverse human diseases. Here, we report the synthesis of a series of cationic amphiphiles which were obtained by the coupling of amino acids and dipeptides onto a lipidic double chain. The new amphiphiles presenting a peptidic motif on a short hydrophilic spacer group were evaluated for selective gene silencing through RNA interference. Our results show that tryptophan residues boost siRNA delivery in an unexpected manner. The silencing experiments performed with very low concentrations of siRNA showed that the best formulations could induce significant death of tumor cells after silencing of polo-like kinase 1 which is implicated in cell cycle progression. In addition, these Trp containing peptide amphiphiles were highly efficient siRNA delivery vectors even in presence of competing serum proteins