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991.
Bungard CJ Hartman GD Manikowski JJ Perkins JJ Bai C Brandish PE Euler DH Hershey JC Schmidt A Fang Y Norcross RT Rushmore TH Thompson CD Meissner RS 《Bioorganic & medicinal chemistry》2011,19(24):7374-7386
A series of partial agonists of the Glucocorticoid Receptor were prepared targeting reduced transactivation activity, while maintaining significant transrepression activity. Incorporation of an ortho-aryl amide produced compounds with the desired in vitro profile. Bioreactors consisting of Suspension cultures of Sf21 cells co expressing a CYP3A4 and NADPH-cytochrome P450 oxireductase were used to prepare the major metabolites of these compounds and revealed that oxidative N-dealkylation provided a pathway for formation of metabolites that were more agonistic than the parent partial agonists. Oxidative N-dealkylation was blocked in a new series of compounds, however oxidation alone was capable of producing full agonist metabolites. Incorporation of an ortho-primary amide and utilization of fluorine to modulate agonism afforded partial agonist MK-5932. Synthesis of the major metabolites of MK-5932 using bioreactor technology revealed that no significant GR-active metabolites were formed. Orally administered MK-5932 displayed anti-inflammatory efficacy in a Rat Oxazolone-induced chronic dermatitis model, while sparing plasma insulin. 相似文献
992.
993.
Habitat structural complexity mediates food web dynamics in a freshwater macrophyte community 总被引:2,自引:0,他引:2
A considerable amount of research has investigated the influence of habitat structure on predator success, yet few studies have explored the implications for community structure and food-web dynamics. The relative importance of macrophyte structure and fish predation on the composition of the macroinvertebrate and periphyton communities in a lowland river was investigated using a multifactorial caging experiment. We hypothesised that: (1) fish predators are less effective in a more structurally complex macrophyte analogue; (2) strong direct and indirect effects of fish predators (e.g. trophic cascades) are less likely to occur in a structurally complex habitat; and (3) the strength of these patterns is influenced by the composition of the prevailing community assemblage. We measured the abundance and composition of the macroinvertebrate and periphyton communities associated with three different-shaped macrophyte analogues, under different fish predator treatments and at different times. Macrophyte analogue architecture had strong, consistent effects on both the macroinvertebrate and periphyton communities; both were most abundant and diverse on the most structurally complex plant analogue. In contrast, the fish predators affected only a subset of the macroinvertebrate community and there was a suggestion of minor indirect effects on periphyton community composition. Contrary to expectations, the fish predators had their strongest effects in the most structurally complex macrophyte analogue. We conclude that in this system, macrophyte shape strongly regulates the associated freshwater assemblage, resulting in a diverse community structure less likely to exhibit strong effects of fish predation. 相似文献
994.
Bioluminescence and bioluminescence resonance energy transfer (BRET) are two naturally occurring light emission phenomena that have been adapted to a wide variety of important research applications including in vivo imaging and enzyme assays. The luciferase enzyme from the North American firefly, which produces yellow-green light, is a key component of many of these applications. Recognizing the heightened interest in the potential of near-infrared (nIR) light to improve these technologies, we have demonstrated that spectral emissions with maxima of 705 and 783 nm can be efficiently produced by a firefly luciferase variant covalently labeled with nIR fluorescent dyes. In one case, an outstanding BRET ratio of 34.0 was achieved emphasizing the importance of selective labeling with fluorescent dyes and the efficiency provided by the intramolecular BRET process. Additionally, we constructed a biotinylated fusion protein that similarly produced nIR light. This novel material was immobilized on solid supports containing streptavidin, demonstrating, in principle, that it may be used for receptor-based imaging. Also, the matrix-bound labeled fusion protein was used to measure factor Xa activity at physiological concentrations in blood. We believe this to be the first report of bright nIR light sources produced by chemical modification of a beetle luciferase. 相似文献
995.
Danielle M. Wilson Dustin L. Dalluge Marjorie Rover Emily A. Heaton Robert C. Brown 《Bioenergy Research》2013,6(1):103-113
Although upgrading bio-oil from fast pyrolysis of biomass is an attractive pathway for biofuel production, nitrogen (N) and mineral matter carried over from the feedstock to the bio-oil represents a serious contaminant in the process. Reducing the N and ash content of biomass feedstocks would improve process reliability and reduce production costs of pyrolytic biofuels. This study investigated: (1) How does switchgrass harvest date influence the yield, N concentration ([N]), and ash concentration of biomass and fast pyrolysis products? and (2) Is there a predictive relationship between [N] of switchgrass biomass and [N] of fast pyrolysis products? Switchgrass from five harvest dates and varying [N] from central Iowa were pyrolyzed using a free-fall reactor. Harvestable biomass peaked in August (8.6 Mg ha?1), dropping significantly by November (6.7 Mg ha?1, P?=?0.0027). Production of bio-oil per unit area mirrored that of harvested biomass at each harvest date; however, bio-oil yield per unit dry biomass increased from 46.6 % to 56.7 % during the season (P?=?0.0018). Allowing switchgrass to senesce lowered biomass [N] dramatically, by as much as 68 % from June to November (P?<?0.0001). Concurrently, bio-oil [N] declined from 0.51 % in June to 0.17 % by November (P?<?0.0001). Significant reductions in ash concentration were also observed in biomass and char. Finally, we show for the first time that the [N] of switchgrass biomass is a strong predictor of the [N] of bio-oil, char, and non-condensable gas with R 2 values of 0.89, 0.94, and 0.88, respectively. 相似文献
996.
Micheline Kézia Cordeiro‐Araújo Maria do Carmo Bittencourt‐Oliveira 《Phycological Research》2013,61(1):1-6
The active release of microcystins in cyanobacterium Microcystis aeruginosa (Kützing) Kützing, strain BCCUSP232 was confirmed. The microcystin release is controlled by an endogenous rhythm, pointing to a biosynthetic pattern of toxins in cyanobacteria. Proofing tests for this active release were carried out by experiments at two independent 24 h cycles, light : dark and continuous light (12:12 h) along the exponential growing phase. Cultivation samples at light, temperature and photoperiod controlled conditions were collected in 2‐h intervals. Microcystin concentrations from the pellet aliquots (intracellular microcystin per cell‐quota –IMC) and supernatant (extracellular microcystin per equivalent cell‐quota – EMC) were quantified with enzyme linked immunosorbent assay. The IMC concentrations showed increases and decreases in both cycles. Decreases of IMC clearly demonstrate that the toxin was actively released to the surrounding medium and not by cell lysis. The total microcystins concentrations (IMC and EMC) between the light : dark and continuous light cycles presented similar variations between the same hours. 相似文献
997.
Interaction between wall deposition and cell elongation in dark-grown hypocotyl cells in Arabidopsis
A central problem in plant biology is how cell expansion is coordinated with wall synthesis. We have studied growth and wall deposition in epidermal cells of dark-grown Arabidopsis hypocotyls. Cells elongated in a biphasic pattern, slowly first and rapidly thereafter. The growth acceleration was initiated at the hypocotyl base and propagated acropetally. Using transmission and scanning electron microscopy, we analyzed walls in slowly and rapidly growing cells in 4-d-old dark-grown seedlings. We observed thick walls in slowly growing cells and thin walls in rapidly growing cells, which indicates that the rate of cell wall synthesis was not coupled to the cell elongation rate. The thick walls showed a polylamellated architecture, whereas polysaccharides in thin walls were axially oriented. Interestingly, innermost cellulose microfibrils were transversely oriented in both slowly and rapidly growing cells. This suggested that transversely deposited microfibrils reoriented in deeper layers of the expanding wall. No growth acceleration, only slow growth, was observed in the cellulose synthase mutant cesA6(prc1-1) or in seedlings, which had been treated with the cellulose synthesis inhibitor isoxaben. In these seedlings, innermost microfibrils were transversely oriented and not randomized as has been reported for other cellulose-deficient mutants or following treatment with dichlorobenzonitrile. Interestingly, isoxaben treatment after the initiation of the growth acceleration in the hypocotyl did not affect subsequent cell elongation. Together, these results show that rapid cell elongation, which involves extensive remodeling of the cell wall polymer network, depends on normal cellulose deposition during the slow growth phase. 相似文献
998.
Leal DB Streher CA Neu TN Bittencourt FP Leal CA da Silva JE Morsch VM Schetinger MR 《Biochimica et biophysica acta》2005,1721(1-3):9-15
Human lymphocytes contain NTPDase (NTPDase-1; ecto-apyrase; ecto-diphosphohydrolase; CD39; EC 3.6.1.5), a cation-dependent enzyme that hydrolyzes ATP and ADP and also other di- and triphosphate nucleosides, acting at an optimum pH of 8.0. A significant inhibition of ATP and ADP hydrolysis (P<0.05) was observed in the presence of 20 mM sodium azide. NTPDase inhibitors, 20 mM sodium fluoride, 0.2 mM trifluoperazine and 0.3 mM suramin, significantly decreased ATP and ADP hydrolysis (P<0.05) and ADP hydrolysis was only inhibited by 0.5 mM orthovanadate (P<0.05). ATP and ADP hydrolysis was not inhibited in the presence of 0.01 mM Ap5A (P1,P5-di(adenosine-5')pentaphosphate), 0.1 mM ouabain, 1 mM levamisole, 2 microg/mL oligomycin, 0.1 mM N-ethylmaleimide (NEM), or 5 mM sodium azide. With respect to kinetic behavior, apparent K(m) values of 77.6+/-10.2 and 106.8+/-21.0 microM, and V(max) values of 68.9+/-8.1 and 99.4+/-8.5 (mean+/-S.E., n=3) nmol Pi/min/mg protein were obtained for ATP and ADP, respectively. A Chevilard plot demonstrated that only one enzymatic site is responsible for the hydrolysis of ATP and ADP. The presence of CD39 was determined by flow cytometry, showing a low density of 2.72+/-0.24% (mean+/-S.E.; n=30) in human peripheral lymphocytes. The study of NTPDase activity in human lymphocytes may be important to determine the immune response status against infectious agents related to ATP and ADP hydrolysis. 相似文献
999.
Chloe L. Edridge Alison J. Dunkley Danielle H. Bodicoat Tanith C. Rose Laura J. Gray Melanie J. Davies Kamlesh Khunti 《PloS one》2015,10(6)
Objective
To collate and evaluate the current literature reporting the prevalence and incidence of hypoglycaemia in population based studies of type 2 diabetes.Research Design and Methods
Medline, Embase and Cochrane were searched up to February 2014 to identify population based studies reporting the proportion of people with type 2 diabetes experiencing hypoglycaemia or rate of events experienced. Two reviewers independently screened studies for eligibility and extracted data for included studies. Random effects meta-analyses were carried out to calculate the prevalence and incidence of hypoglycaemia.Results
46 studies (n = 532,542) met the inclusion criteria. Prevalence of hypoglycaemia was 45% (95%CI 0.34,0.57) for mild/moderate and 6% (95%CI, 0.05,0.07) for severe. Incidence of hypoglycaemic episodes per person-year for mild/moderate and for severe was 19 (95%CI 0.00, 51.08) and 0.80 (95%CI 0.00,2.15), respectively. Hypoglycaemia was prevalent amongst those on insulin; for mild/moderate episodes the prevalence was 50% and incidence 23 events per person-year, and for severe episodes the prevalence was 21% and incidence 1 event per person-year. For treatment regimes that included a sulphonylurea, mild/moderate prevalence was 30% and incidence 2 events per person-year, and severe prevalence was 5% and incidence 0.01 events per person-year. A similar prevalence of 5% was found for treatment regimes that did not include sulphonylureas.Conclusions
Current evidence shows hypoglycaemia is considerably prevalent amongst people with type 2 diabetes, particularly for those on insulin, yet still fairly common for other treatment regimens. This highlights the subsequent need for educational interventions and individualisation of therapies to reduce the risk of hypoglycaemia. 相似文献1000.
Luciferases have proven to be useful tools in advancing our understanding of biologic processes. Having a multitude of bioluminescent reporters with different properties is highly desirable. We characterized codon-optimized thermostable green- and red-emitting luciferase variants from the Italian firefly Luciola italica for mammalian gene expression in culture and in vivo. Using lentivirus vectors to deliver and stably express these luciferases in mammalian cells, we showed that both variants displayed similar levels of activity and protein half-lives as well as similar light emission kinetics and higher stability compared to the North American firefly luciferase. Further, we characterized the red-shifted variant for in vivo bioluminescence imaging. Intramuscular injection of tumor cells stably expressing this variant into nude mice yielded a robust luciferase activity. Light emission peaked at 10 minutes post-d-luciferin injection and retained > 60% of signal at 1 hour. Similarly, luciferase activity from intracranially injected glioma cells expressing the red-shifted variant was readily detected and used as a marker to monitor tumor growth over time. Overall, our characterization of these codon-optimized luciferases lays the groundwork for their further use as bioluminescent reporters in mammalian cells. 相似文献