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排序方式: 共有293条查询结果,搜索用时 15 毫秒
81.
Washburn WN Harper TW Wu G Godfrey JD McCann P Girotra R Shao C Zhang H Gavai A Mikkilineni A Dejneka T Ahmed S Caringal Y Hangeland J Zhang M Cheng PT Russell AD Skwish S Slusarchyk DA Allen GT Frohlich BH Abboa-Offei BE Cap M Waldron TL George RJ Tesfamariam B Dickinson KE Seymour AA Sher PM 《Bioorganic & medicinal chemistry letters》2007,17(15):4290-4296
Utilization of N-substituted-4-hydroxy-3-methylsulfonanilidoethanolamines 1 as selective beta(3) agonists is complicated by their propensity to undergo metabolic oxidative N-dealkylation, generating 0.01-2% of a very potent alpha(1) adrenergic agonist 2. A summary of the SAR for this hepatic microsomal conversion precedes presentation of strategies to maintain the advantages of chemotype 1 while mitigating the consequences of N-dealkylation. This effort led to the identification of 4-hydroxy-3-methylsulfonanilidopropanolamines 15 for which the SAR for the unique stereochemical requirements for binding to the beta adrenergic receptors culminated in the identification of the potent, selective beta(3) agonist 15f. 相似文献
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Anderson K Sizovs A Cortez M Waldron C Haddleton DM Reineke TM 《Biomacromolecules》2012,13(8):2229-2239
In this study, we have synthesized six analogs of a trehalose-pentaethylenehexamine glycopolymer (Tr4) that contain (1A) adamantane, (1B) carboxy, (1C) alkynyl-oligoethyleneamine, (1D) azido trehalose, (1E) octyl, or (1F) oligoethyleneamine end groups and evaluated the effects of polymer end group chemistry on the ability of these systems to bind, compact, and deliver pDNA to cultured HeLa cells. The polymers were synthesized in one-pot azide-alkyne cycloaddition reactions with an adaptation of the Carothers equation for step-growth polymerization to produce a series of polymers with similar degrees of polymerization. An excess of end-capping monomer was added at the end of the polymerizations to maximize functionalization efficiency, which was evaluated with GPC, NMR, and MALDI-TOF. The polymers were all found to bind and compact pDNA at similarly low N/P ratios and form polyplexes with plasmid DNA. The effects of the different end group structures were most evident in the polyplex internalization and transfection assays in the presence of serum as determined by flow cytometry and luciferase gene expression, respectively. The Tr4 polymers end-capped with carboxyl groups (1B) (N/P = 7), octyne (1E) (N/P = 7), and oligoethyleneamine (1F) (N/P = 7), were taken into cells as polyplex and exhibited the highest levels of fluorescence, resulting from labeled plasmid. Similarly, the polymers end-functionalized with carboxyl groups (1E at N/P = 7), octyl groups (1E at N/P = 15), and in particular oligoethyleneamine groups (1F at N/P = 15) yielded dramatically higher reporter gene expression in the presence of serum. This study yields insight into how very subtle structural changes in polymer chemistry, such as end groups can yield very significant differences in the biological delivery efficiency and transgene expression of polymers used for pDNA delivery. 相似文献
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Disorders of the temporomandibular joint (TMJ), including TMJ osteoarthritis (TMJ OA), are the topic of intensive clinical research; however, this is not the case in the archaeological literature, with the majority of work on the subject ceasing with the early 1990s. The methods employed in the diagnosis of TMJ OA within the archaeological work appear nonrepresentative of the disease and may have led to erroneous assumptions about the pattern and prevalence of OA. This current work presents a new method for evaluating OA specifically for the TMJ, considering both the biomechanics of the joint and the mechanisms of the disease. Totally, 496 specimens (including a group of modern documented specimens) were analyzed for the presence of TMJ OA using the following criteria: eburnation, osteophytes (marginal and new bone on joint surface), porosity, and alteration to joint contour. The results suggest that eburnation occurs rarely in the TMJ, so should not be used as an exclusive criterion. Rather a combination of at least two of the other criteria should be used, with osteophytes and porosity occurring the most frequently on both the mandibular condyle and articular eminence. Additionally, the prevalence of TMJ OA in the modern assemblage was similar to that observed in current clinical research, suggesting that the method employed here was able to produce a reasonable approximation of what is found in contemporary living populations. 相似文献
89.
Composition of the adult digestive tract bacterial microbiome based on seven mouth surfaces, tonsils, throat and stool samples 总被引:1,自引:0,他引:1
Segata N Haake SK Mannon P Lemon KP Waldron L Gevers D Huttenhower C Izard J 《Genome biology》2012,13(6):R42-18
Background
To understand the relationship between our bacterial microbiome and health, it is essential to define the microbiome in the absence of disease. The digestive tract includes diverse habitats and hosts the human body's greatest bacterial density. We describe the bacterial community composition of ten digestive tract sites from more than 200 normal adults enrolled in the Human Microbiome Project, and metagenomically determined metabolic potentials of four representative sites.Results
The microbiota of these diverse habitats formed four groups based on similar community compositions: buccal mucosa, keratinized gingiva, hard palate; saliva, tongue, tonsils, throat; sub- and supra-gingival plaques; and stool. Phyla initially identified from environmental samples were detected throughout this population, primarily TM7, SR1, and Synergistetes. Genera with pathogenic members were well-represented among this disease-free cohort. Tooth-associated communities were distinct, but not entirely dissimilar, from other oral surfaces. The Porphyromonadaceae, Veillonellaceae and Lachnospiraceae families were common to all sites, but the distributions of their genera varied significantly. Most metabolic processes were distributed widely throughout the digestive tract microbiota, with variations in metagenomic abundance between body habitats. These included shifts in sugar transporter types between the supragingival plaque, other oral surfaces, and stool; hydrogen and hydrogen sulfide production were also differentially distributed.Conclusions
The microbiomes of ten digestive tract sites separated into four types based on composition. A core set of metabolic pathways was present across these diverse digestive tract habitats. These data provide a critical baseline for future studies investigating local and systemic diseases affecting human health. 相似文献90.
Martin AM Kuhlmann C Trossbach S Jaeger S Waldron E Roebroek A Luhmann HJ Laatsch A Weggen S Lessmann V Pietrzik CU 《The Journal of biological chemistry》2008,283(18):12004-12013
The low density lipoprotein receptor-related protein 1 (LRP1) emerges to play fundamental roles in cellular signaling pathways in the brain. One of its prominent ligands is the serine proteinase tissue-type plasminogen activator (tPA), which has been shown to act as a key activator of neuronal mitogen-activated protein kinase pathways via the N-methyl-D-aspartate (NMDA) receptor. However, here we set out to examine whether LRP1 and the NMDA receptor might eventually act in a combined fashion to mediate tPA downstream signaling. By blocking tPA from binding to LRP1 using the receptor-associated protein, we were able to completely inhibit NMDA receptor activation. Additionally, inhibition of NMDA receptor calcium influx with MK-801 resulted in dramatic reduction of tPA-mediated downstream signaling. This indicates a functional interaction between the two receptors, since both experimental approaches resulted in strongly reduced calcium influx and Erk1/2 phosphorylation. Additionally, we were able to inhibit Erk1/2 activation by competing for the LRP1 C-terminal binding motif with a truncated PSD95 construct resembling its PDZ III domain. Furthermore, we identified the distal NPXY amino acid motif in the C terminus of LRP1 as the crucial element for LRP1-NMDA receptor interaction via the adaptor protein PSD95. These results provide new insights into the mechanism of a tPA-induced, LRP1-mediated gating mechanism for NMDA receptors. 相似文献