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71.
Herman J. Kempen Monica Gomaraschi S. Eralp Bellibas Stephanie Plassmann Brad Zerler Heidi L. Collins Steven J. Adelman Laura Calabresi Peter L. J. Wijngaard 《Journal of lipid research》2013,54(9):2341-2353
MDCO-216, a complex of dimeric recombinant apoA-IMilano (apoA-IM) and palmitoyl-oleoyl-phosphatidylcholine (POPC), was administered to cynomolgus monkeys at 30, 100, and 300 mg/kg every other day for a total of 21 infusions, and effects on lipids, (apo)lipoproteins, and ex-vivo cholesterol efflux capacity were monitored. After 7 or 20 infusions, free cholesterol (FC) and phospholipids (PL) were strongly increased, and HDL-cholesterol (HDL-C), apoA-I, and apoA-II were strongly decreased. We then measured short-term effects on apoA-IM, lipids, and (apo)lipoproteins after the first or the last infusion. After the first infusion, PL and FC went up in the HDL region and also in the LDL and VLDL regions. ApoE shifted from HDL to LDL and VLDL regions, while ApoA-IM remained located in the HDL region. On day 41, ApoE levels were 8-fold higher than on day 1, and FC, PL, and apoE resided mostly in LDL and VLDL regions. Drug infusion quickly decreased the endogenous cholesterol esterification rate. ABCA1-mediated cholesterol efflux on day 41 was markedly increased, whereas scavenger receptor type B1 (SRB1) and ABCG1-mediated effluxes were only weakly increased. Strong increase of FC is due to sustained stimulation of ABCA1-mediated efflux, and drop in HDL and formation of large apoE-rich particles are due to lack of LCAT activation. 相似文献
72.
Steven Rockman Lorena E. Brown Ian G. Barr Brad Gilbertson Sue Lowther Anatoly Kachurin Olga Kachurina Jessica Klippel Jesse Bodle Martin Pearse Deborah Middleton 《Journal of virology》2013,87(6):3053-3061
In preparing for the threat of a pandemic of avian H5N1 influenza virus, we need to consider the significant delay (4 to 6 months) necessary to produce a strain-matched vaccine. As some degree of cross-reactivity between seasonal influenza vaccines and H5N1 virus has been reported, this was further explored in the ferret model to determine the targets of protective immunity. Ferrets were vaccinated with two intramuscular inoculations of trivalent inactivated split influenza vaccine or subcomponent vaccines, with and without adjuvant, and later challenged with a lethal dose of A/Vietnam/1203/2004 (H5N1) influenza virus. We confirmed that vaccination with seasonal influenza vaccine afforded partial protection against lethal H5N1 challenge and showed that use of either AlPO4 or Iscomatrix adjuvant with the vaccine resulted in complete protection against disease and death. The protection was due exclusively to the H1N1 vaccine component, and although the hemagglutinin contributed to protection, the dominant protective response was targeted toward the neuraminidase (NA) and correlated with sialic acid cleavage-inhibiting antibody titers. Purified heterologous NA formulated with Iscomatrix adjuvant was also protective. These results suggest that adjuvanted seasonal trivalent vaccine could be used as an interim measure to decrease morbidity and mortality from H5N1 prior to the availability of a specific vaccine. The data also highlight that an inducer of cross-protective immunity is the NA, a protein whose levels are not normally monitored in vaccines and whose capacity to induce immunity in recipients is not normally assessed. 相似文献
73.
Andrew Koo David Nordsletten Renato Umeton Beracah Yankama Shiva Ayyadurai Guillermo García-Carde?a C.?Forbes Dewey Jr. 《Biophysical journal》2013,104(10):2295-2306
Nitric oxide (NO) produced by vascular endothelial cells is a potent vasodilator and an antiinflammatory mediator. Regulating production of endothelial-derived NO is a complex undertaking, involving multiple signaling and genetic pathways that are activated by diverse humoral and biomechanical stimuli. To gain a thorough understanding of the rich diversity of responses observed experimentally, it is necessary to account for an ensemble of these pathways acting simultaneously. In this article, we have assembled four quantitative molecular pathways previously proposed for shear-stress-induced NO production. In these pathways, endothelial NO synthase is activated 1), via calcium release, 2), via phosphorylation reactions, and 3), via enhanced protein expression. To these activation pathways, we have added a fourth, a pathway describing actual NO production from endothelial NO synthase and its various protein partners. These pathways were combined and simulated using CytoSolve, a computational environment for combining independent pathway calculations. The integrated model is able to describe the experimentally observed change in NO production with time after the application of fluid shear stress. This model can also be used to predict the specific effects on the system after interventional pharmacological or genetic changes. Importantly, this model reflects the up-to-date understanding of the NO system, providing a platform upon which information can be aggregated in an additive way. 相似文献
74.
Leyi Gong Xiaochun Han Tania Silva Yun-Chou Tan Bindu Goyal Parch Tivitmahaisoon Alejandra Trejo Wylie Palmer Heather Hogg Alam Jahagir Muzaffar Alam Paul Wagner Karin Stein Lubov Filonova Brad Loe Ferenc Makra David Rotstein Lubica Rapatova David Goldstein 《Bioorganic & medicinal chemistry letters》2013,23(12):3565-3569
A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties. 相似文献
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77.
Brad S. Coates Holly Johnson Kyung‐Seok Kim Richard L. Hellmich Craig A. Abel Charles Mason Thomas W. Sappington 《Ecology and evolution》2013,3(8):2459-2470
Female European corn borer, Ostrinia nubilalis, produce and males respond to sex pheromone blends with either E‐ or Z‐Δ11‐tetradecenyl acetate as the major component. E‐ and Z‐race populations are sympatric in the Eastern United States, Southeastern Canada, and the Mediterranean region of Europe. The E‐ and Z‐pheromone races of O. nubilalis are models for incipient species formation, but hybridization frequencies within natural populations remain obscure due to lack of a high‐throughput phenotyping method. Lassance et al. previously identified a pheromone gland‐expressed fatty‐acyl reductase gene (pgfar) that controls the ratio of Δ11‐tetradecenyl acetate stereoisomers. We identified three single nucleotide polymorphism (SNP) markers within pgfar that are differentially fixed between E‐ and Z‐race females, and that are ≥98.2% correlated with female pheromone ratios measured by gas chromatography. Genotypic data from locations in the United States demonstrated that pgfar‐z alleles were fixed within historically allopatric Z‐pheromone race populations in the Midwest, and that hybrid frequency ranged from 0.00 to 0.42 within 11 sympatric sites where the two races co‐occur in the Eastern United States (mean hybridization frequency or heterozygosity (HO) = 0.226 ± 0.279). Estimates of hybridization between the E‐ and Z‐races are important for understanding the dynamics involved in maintaining race integrity, and are consistent with previous estimates of low levels of genetic divergence between E‐ and Z‐races and the presence of weak prezygotic mating barriers. 相似文献
78.
Rebecca C. Jones Dorothy A. Steane Martyn Lavery René E. Vaillancourt Brad M. Potts 《Ecology and evolution》2013,3(1):1-17
Forest trees frequently form species complexes, complicating taxonomic classification and gene pool management. This is certainly the case in Eucalyptus, and well exemplified by the Eucalyptus globulus complex. This ecologically and economically significant complex comprises four taxa (sspp. bicostata, globulus, maidenii, pseudoglobulus) that are geographically and morphologically distinct, but linked by extensive “intergrade” populations. To resolve their genetic affinities, nine microsatellites were used to genotype 1200 trees from throughout the natural range of the complex in Australia, representing 33 morphological core and intergrade populations. There was significant spatial genetic structure (FST = 0.10), but variation was continuous. High genetic diversity in southern ssp. maidenii indicates that this region is the center of origin. Genetic diversity decreases and population differentiation increases with distance from this area, suggesting that drift is a major evolutionary process. Many of the intergrade populations, along with other populations morphologically classified as ssp. pseudoglobulus or ssp. globulus, belong to a “cryptic genetic entity” that is genetically and geographically intermediate between core ssp. bicostata, ssp. maidenii, and ssp. globulus. Geography, rather than morphology, therefore, is the best predictor of overall genetic affinities within the complex and should be used to classify germplasm into management units for conservation and breeding purposes. 相似文献
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80.
Annick?Nembot-Simo Jinko?Graham Brad?McNeneyEmail author 《Source code for biology and medicine》2013,8(1):5