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61.
Lafontaine JA Day RF Dibrino J Hadcock JR Hargrove DM Linhares M Martin KA Maurer TS Nardone NA Tess DA Dasilva-Jardine P 《Bioorganic & medicinal chemistry letters》2007,17(18):5245-5250
A novel series of heterocycle-based analogs were prepared and evaluated for their in vitro and in vivo biological activity as human beta(3)-adrenergic receptor (AR) agonists. Several analogs demonstrated potent agonist activity at the beta(3)-AR, functional selectivity against beta(1)- and beta(2)-ARs, and favorable pharmacokinetic profiles in vivo. Compound 17 increased oxygen consumption in rats, a measure of energy expenditure, with an ED(20%) of 2mg/kg. 相似文献
62.
Standley SM Mende I Goh SL Kwon YJ Beaudette TT Engleman EG Fréchet JM 《Bioconjugate chemistry》2007,18(1):77-83
The development of multicomponent biotherapeutic carriers is an important challenge in the field of drug delivery, particularly in the area of protein-based vaccines. While the delivery of protein antigens to antigen presenting cells (APCs) is crucial for this type of vaccination, the incorporation of additional adjuvants may be just as important in order to generate more potent immune responses. This article presents the synthesis and biological evaluation of carrier particles that both deliver a protein payload to APCs and display receptor ligands for the enhancement of APC immunostimulation. Particles displaying CpG oligonucleotide ligands for Toll-like receptor 9 were synthesized. The addition of CpG DNA to the particles led to a 45-fold increase in the secretion of interleukin-12, a cytokine that aids in T-cell activation, and a significant increase in the expression of costimulatory molecules by APCs. Moreover, vaccination with particles containing both ovalbumin (OVA) and CpG DNA induced a superior OVA-specific CD8 T-cell response in vivo, as measured by increased OVA-specific CD8 T-cell proliferation, secretion of the proinflammatory cytokine IFN-gamma, and the induction of OVA-specific cytotoxicity. 相似文献
63.
Lamarche F Mével M Montier T Burel-Deschamps L Giamarchi P Tripier R Delépine P Le Gall T Cartier D Lehn P Jaffrès PA Clément JC 《Bioconjugate chemistry》2007,18(5):1575-1582
The DNA compacting properties of polyamines (especially spermine) are well-known, hence the use of spermine as the cationic part in several synthetic DNA carriers. Here, we describe the synthesis of modified spermines, with a "lipophosphoramidate" as the lipidic part, and their use for efficient in vitro transfection. Physicochemical measurements (particle size, zeta potentials, pKa determination) and gel retardation assays were also performed. Theoretical membrane-disrupting ability was established by FRET. Taken together, our results indicate that lipophosphoramidates constitute an interesting alternative to "classical" lipidic parts of cationic lipids used as DNA carriers. 相似文献
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Patrilineal populations show more male transmission of reproductive success than cognatic populations in Central Asia,which reduces their genetic diversity 下载免费PDF全文
67.
Christoph Gerhardt Johanna Maria Lier Stephan Burmühl Andreas Struchtrup Kathleen Deutschmann Maik Vetter Tristan Leu Sandra Reeg Tilman Grune Ulrich Rüther 《The Journal of cell biology》2015,210(1):1027-1045
Mutations in RPGRIP1L result in severe human diseases called ciliopathies. To unravel the molecular function of RPGRIP1L, we analyzed Rpgrip1l−/− mouse embryos, which display a ciliopathy phenotype and die, at the latest, around birth. In these embryos, cilia-mediated signaling was severely disturbed. Defects in Shh signaling suggested that the Rpgrip1l deficiency causes an impairment of protein degradation and protein processing. Indeed, we detected a cilia-dependent decreased proteasomal activity in the absence of Rpgrip1l. We found different proteasomal components localized to cilia and identified Psmd2, a component of the regulatory proteasomal 19S subunit, as an interaction partner for Rpgrip1l. Quantifications of proteasomal substrates demonstrated that Rpgrip1l regulates proteasomal activity specifically at the basal body. Our study suggests that Rpgrip1l controls ciliary signaling by regulating the activity of the ciliary proteasome via Psmd2. 相似文献
68.
Sensitivity Analysis of Environmental Process Modeling in a Life Cycle Context: A Case Study of Hemp Crop Production 下载免费PDF全文
Andrianandraina Anne Ventura Tristan Senga Kiessé Bogdan Cazacliu Rachida Idir Hayo M. G. van der Werf 《Journal of Industrial Ecology》2015,19(6):978-993
The aim of this article is to develop a methodological approach allowing to assess the influence of parameters of one or more elementary processes in the foreground system, on the outcomes of a life cycle assessment (LCA) study. From this perspective, the method must be able to: (1) include foreground process modeling in order to avoid the assumption of proportionality between inventory data and reference flows; (2) quantify influences of foreground processes’ parameters (and, possibly, interactions between parameters); and (3) identify trends (either increasing or decreasing) for each parameter on each indicator in order to determine the most favorable direction for parametric variation. These objectives can be reached by combining foreground system modeling, a set of two different sensitivity analysis methods (each one providing different and complementary information), and LCA. The proposed method is applied to a case study of hemp‐based insulation materials for buildings. The present study will focus on the agricultural stage as a foreground system and as a first step encompassing the entire life cycle. A set of technological recommendations were identified for hemp farmers in order to reduce the crop's environmental impacts (from –11% to –89% according to the considered impact category). One of the main limitations of the approach is the need for a detailed model of the foreground process. Further, the method is, at present, rather time‐consuming. However, it offers long‐term advantages given that the higher level of model detail adds robustness to the LCA results. 相似文献
69.
Andrew C. Tolonen Tristan Cerisy Hafez El‐Sayyed Magali Boutard Marcel Salanoubat George M. Church 《Environmental microbiology》2015,17(8):2618-2627
Recycling of plant biomass by a community of bacteria and fungi is fundamental to carbon flow in terrestrial ecosystems. Here we report how the plant fermenting, soil bacterium Clostridium phytofermentans enhances growth on cellulose by simultaneously lysing and consuming model fungi from soil. We investigate the mechanism of fungal lysis to show that among the dozens of different glycoside hydrolases C. phytofermentans secretes on cellulose, the most highly expressed enzymes degrade fungi rather than plant substrates. These enzymes, the GH18 Cphy1799 and Cphy1800, synergize to hydrolyse chitin, a main component of the fungal cell wall. Purified enzymes inhibit fungal growth and mutants lacking either GH18 grow normally on cellulose and other plant substrates, but have a reduced ability to hydrolyse chitinous substrates and fungal hyphae. Thus, C. phytofermentans boosts growth on cellulose by lysing fungi with its most highly expressed hydrolases, highlighting the importance of fungal interactions to the ecology of cellulolytic bacteria. 相似文献
70.
Internalization of staphylococcal leukotoxins that bind and divert the C5a receptor is required for intracellular Ca2+ mobilization by human neutrophils 下载免费PDF全文
Mira Y. Tawk Gaëlle Zimmermann‐Meisse Jean‐Louis Bossu Cristina Potrich Tristan Bourcier Mauro Dalla Serra Bernard Poulain Gilles Prévost Emmanuel Jover 《Cellular microbiology》2015,17(8):1241-1257
A growing number of receptors, often associated with the innate immune response, are being identified as targets for bacterial toxins of the beta‐stranded pore‐forming family. These findings raise the new question of whether the receptors are activated or merely used as docking points facilitating the formation of a pore. To elucidate whether the Staphylococcus aureus Panton‐Valentine leukocidin and the leukotoxin HlgC/HlgB act through the C5a receptor (C5aR) as agonists, antagonists or differ from the C5a complement‐derived peptide, their activity is explored on C5aR‐expressing cells. Both leukotoxins equally bound C5aR in neutrophils and in stable transfected U937 cells and initiated mobilization of intracellular Ca2+. HlgC/HlgB requires the presence of robust intracellular acidic Ca2+ stores in order to evoke a rise in free [Ca2+]i, while the LukS‐PV/LukF‐PV directly altered reticular Ca2+ stores. Intracellular target specificity is conferred by the F‐subunit associated to the S‐subunit binding the receptor. Furthermore, internalization of the two leukotoxin components (S‐ and F‐subunits) associated to C5aR is required for the initiation of [Ca2+]i mobilization. Electrophysiological recordings on living cells demonstrated that LukS‐PV/LukF‐PV does not alter the membrane resistance of C5aR‐expressing cells. The present observations suggest that part of the pore‐forming process occurs in distinct intracellular compartments rather than at the plasma membrane. 相似文献