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101.
Regan CF Guo Z Chen Y Huang CQ Chen M Jiang W Rueter JK Coon T Chen C Saunders J Brown MS Betz SF Struthers RS Yang C Wen J Madan A Zhu YF 《Bioorganic & medicinal chemistry letters》2008,18(16):4503-4507
A novel series of potent zwitterionic uracil GnRH antagonists were discovered that showed reduced liability for CYP3A4 enzyme inhibition. 相似文献
102.
P. J. Smith D. Steinke S. M. Mcveagh A. L. Stewart C. D. Struthers C. D. Roberts 《Journal of fish biology》2008,73(5):1170-1182
Two regions of mtDNA, cytochrome b and cytochrome c oxidase subunit 1, were sequenced in nine species of Bathyraja from the Southern Ocean and New Zealand. Based on sequence divergence, the species that has been referred to as Bathyraja eatonii from the Antarctic continental shelf and slope is a species distinct from B. eatonii from the Kerguelen Plateau (the type locality) and is a new and undescribed species Bathyraja sp. (cf. eatonii). There was no sequence divergence among samples of Bathyraja sp. (dwarf) from the Ross Sea and the South Atlantic. However, for both Bathyraja sp. (cf. eatonii) and Bathyraja maccaini in the Ross Sea and the South Atlantic Ocean, the DNA sequence divergences indicate differentiation among ocean basins and within Bathyraja sp. (cf. eatonii) divergences are similar to those among recognized species of Bathyraja in the North Pacific Ocean. 相似文献
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Kandimalla ER Struthers M Bett AJ Wisniewski T Dubey SA Jiang W Precopio M Sun Z Wang H Lan T Agrawal S Casimiro DR 《Cellular immunology》2011,270(2):126-134
Single-stranded oligoribonucleotides (ORNs) stimulate innate immune responses through TLR7 and TLR8. Specific linkages and chemical modifications incorporated into synthetic ORN can greatly enhance nuclease stability, selectivity, and potency. In the present study, we have synthesized 15 ORN containing different sequence compositions and chemical modifications and studied their TLR7- and TLR8-mediated immune response profiles in HEK293 cells expressing human TLR7 or TLR8, human PBMCs, mDCs and pDCs, non-human primate (NHP) PBMCs, and in vivo in mice and NHPs. Based on the results obtained, eight of the ORNs containing specific chemical modifications induced immune responses through both TLR7 and TLR8, including activation of NF-κB in TLR7- and TLR8-transfected cell lines; induction of IFN-α, IL-6, TNF-α, IL-12, and IP-10 in human PBMCs; IFN-α induction in human pDCs; CD80 upregulation in human pDCs and mDCs; IL-12 induction following acute administration in mice; IFN-α, IP-10, IL-6, and IL-12 induction in NHP PBMCs; and IFN-α, IP-10, and IL-6 induction following acute administration in NHPs. Seven of the ORNs show selectivity for TLR8-induced responses; they specifically activate only TLR8-transfected cell lines, induce cytokines other than IFN-α in human and NHP PBMCs, activate mDCs more than pDCs, and do not induce IL-12 acutely in mice, consistent with the lack of functional TLR8 in mice. The novel TLR8-selective ORNs also induce cytokines other than IFN-α acutely in NHPs. In conclusion, we have designed and synthesized novel ORNs with varying sequence compositions and chemical modifications, which selectively act as agonists of TLR8 or dual agonists of TLR7 and TLR8. 相似文献
109.
Faca V Pitteri SJ Newcomb L Glukhova V Phanstiel D Krasnoselsky A Zhang Q Struthers J Wang H Eng J Fitzgibbon M McIntosh M Hanash S 《Journal of proteome research》2007,6(9):3558-3565
In-depth analysis of the serum and plasma proteomes by mass spectrometry is challenged by the vast dynamic range of protein abundance and substantial complexity. There is merit in reducing complexity through fractionation to facilitate mass spectrometry analysis of low-abundance proteins. However, fractionation reduces throughput and has the potential of diluting individual proteins or inducing their loss. Here, we have investigated the contribution of extensive fractionation of intact proteins to depth of analysis. Pooled serum depleted of abundant proteins was fractionated by an orthogonal two-dimensional system consisting of anion-exchange and reversed-phase chromatography. The resulting protein fractions were aliquotted; one aliquot was analyzed by shotgun LC-MS/MS, and another was further resolved into protein bands in a third dimension using SDS-PAGE. Individual gel bands were excised and subjected to in situ digestion and mass spectrometry. We demonstrate that increased fractionation results in increased depth of analysis based on total number of proteins identified in serum and based on representation in individual fractions of specific proteins identified in gel bands following a third-dimension SDS gel analysis. An intact protein analysis system (IPAS) based on a two-dimensional plasma fractionation schema was implemented that resulted in identification of 1662 proteins with high confidence with representation of protein isoforms that differed in their chromatographic mobility. Further increase in depth of analysis was accomplished by repeat analysis of aliquots from the same set of two-dimensional fractions resulting in overall identification of 2254 proteins. We conclude that substantial depth of analysis of proteins from milliliter quantities of serum or plasma and detection of isoforms are achieved with depletion of abundant proteins followed by two-dimensional protein fractionation and MS analysis of individual fractions. 相似文献
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