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101.
A patient studied at autopsy was found to have a post-operative wound infection with Aspergillus flavus in which there was the formation of fungal structures resembling sclerotia. The ability of Aspergillus to form sclerotia in tissue appears to be rare and is related to the strain of Aspergillus flavus. Since sclerotia are considered as structures capable of withstanding dramatic shifts in the environment, the production of these in tissue may affect the efficacy of antifungal therapy. 相似文献
102.
Ryan H. S. Hutchins Suzanne E. Tank David Olefeldt William L. Quinton Christopher Spence Nicole Dion Cristian Estop‐Aragons Samson G. Mengistu 《Global Change Biology》2020,26(4):2304-2319
Despite occupying a small fraction of the landscape, fluvial networks are disproportionately large emitters of CO2 and CH4, with the potential to offset terrestrial carbon sinks. Yet the extent of this offset remains uncertain, because current estimates of fluvial emissions often do not integrate beyond individual river reaches and over the entire fluvial network in complex landscapes. Here we studied broad patterns of concentrations and isotopic signatures of CO2 and CH4 in 50 streams in the western boreal biome of Canada, across an area of 250,000 km2. Our study watersheds differ starkly in their geology (sedimentary and shield), permafrost extent (sporadic to extensive discontinuous) and land cover (large variability in lake and wetland extents). We also investigated the effect of wildfire, as half of our study streams drained watersheds affected by megafires that occurred 3 years prior. Similar to other boreal regions, we found that stream CO2 concentrations were primarily associated with greater terrestrial productivity and warmer climates, and decreased downstream within the fluvial network. No effects of recent wildfire, bedrock geology or land cover composition were found. The isotopic signatures suggested dominance of biogenic CO2 sources, despite dominant carbonate bedrock in parts of the study region. Fluvial CH4 concentrations had a high variability which could not be explained by any landscape factors. Estimated fluvial CO2 emissions were 0.63 (0.09–6.06, 95% CI) and 0.29 (0.17–0.44, 95% CI) g C m?2 year?1 at the landscape scale using a stream network modelling and a mass balance approach, respectively, a small but potentially important component of the landscape C balance. These fluvial CO2 emissions are lower than in other northern regions, likely due to a drier climate. Overall, our study suggests that fluvial CO2 emissions are unlikely to be sensitive to altered fire regimes, but that warming and permafrost thaw will increase emissions significantly. 相似文献
103.
Claire Bourdin Christopher McGuigan Andrea Brancale Stanley Chamberlain John Vernachio Jeff Hutchins Elena Gorovits Alexander Kolykhalov Jerry Muhammad Joseph Patti Geoffrey Henson Blair Bleiman K. Dawn Bryant Babita Ganguly Damound Hunley Aleksandr Obikhod C. Robin Walters Jin Wang C. Srivinas Rao 《Bioorganic & medicinal chemistry letters》2013,23(7):2260-2264
7-Deazapurines are known to possess broad antiviral activity, however the 2′-C-methylguanosine analogue displays poor cell permeation and limited phosphorylation, thus is not an efficient inhibitor of hepatitis C virus (HCV) replication. We previously reported the 6-O-methyl entity as a prodrug moiety to increase liphophilicity of guanine nucleosides and the ProTide approach applied to 2′-C-methyl-6-O-methylguanosine has lead to potent HCV inhibitors now in clinical trials. In this Letter, we report the synthesis and biological evaluation of 2′-C-methyl-6-O-methyl-7-deaza guanosine and ProTide derivatives. In contrast to prior studies, removal of the N-7 of the nucleobase entirely negates anti-HCV activity compared to the 2′-C-methyl-6-O-methylguanosine analogues. To understand better this significant loss of activity, enzymatic assays and molecular modeling were carried out and suggested 2′-C-methyl-6-O-methyl-7-deaza guanosine and related ProTides do not act as efficient prodrugs of the free nucleotide, in marked contrast to the case of the parent guanine analogue. 相似文献
104.
Wang M Gao M Miller KD Sledge GW Hutchins GD Zheng QH 《Bioorganic & medicinal chemistry letters》2011,21(1):245-249
SB-216763 is a novel, potent and selective glycogen synthase kinase-3 (GSK-3) inhibitor with an IC50 value of 34 nM. [11C]SB-216763 (3-(2,4-dichlorophenyl)-4-(1-[11C]methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione), a new potential PET agent for imaging of GSK-3, was first designed and synthesized in 20-30% decay corrected radiochemical yield and 370-555 GBq/μmol specific activity at end of bombardment (EOB). The synthetic strategy was to prepare a carbon-11-labeled maleic anhydride intermediate followed by the conversion to maleimide. 相似文献
105.
Nandedkar SD Weihrauch D Xu H Shi Y Feroah T Hutchins W Rickaby DA Duzgunes N Hillery CA Konduri KS Pritchard KA 《Journal of lipid research》2011,52(3):499-508
Asthma is characterized by oxidative stress and inflammation of the airways. Although proinflammatory lipids are involved in asthma, therapies targeting them remain lacking. Ac-DWFKAFYDKVAEKFKEAFNH(2) (4F) is an apolipoprotein (apo)A-I mimetic that has been shown to preferentially bind oxidized lipids and improve HDL function. The objective of the present study was to determine the effects of 4F on oxidative stress, inflammation, and airway resistance in an established murine model of asthma. We show here that ovalbumin (OVA)-sensitization increased airway hyperresponsiveness, eosinophil recruitment, and collagen deposition in lungs of C57BL/6J mice by a mechanism that could be reduced by 4F. OVA sensitization induced marked increases in transforming growth factor (TGF)β-1, fibroblast specific protein (FSP)-1, anti-T15 autoantibody staining, and modest increases in 4-hydroxynonenal (4-HNE) Michael's adducts in lungs of OVA-sensitized mice. 4F decreased TGFβ-1, FSP-1, anti-T15 autoantibody, and 4-HNE adducts in the lungs of the OVA-sensitized mice. Eosinophil peroxidase (EPO) activity in bronchial alveolar lavage fluid (BALF), peripheral eosinophil counts, total IgE, and proinflammatory HDL (p-HDL) were all increased in OVA-sensitized mice. 4F decreased BALF EPO activity, eosinophil counts, total IgE, and p-HDL in these mice. These data indicate that 4F reduces pulmonary inflammation and airway resistance in an experimental murine model of asthma by decreasing oxidative stress. 相似文献
106.
Although LDL is rendered proatherogenic by various experimental treatments (e.g., acetylation), the exact structural changes that drive LDL transformation in vivo remain enigmatic. Among the many hypothesized targets of oxidative modification are cholesterol esters (CE). This family of neutral lipids, which carries a highly unsaturated pool of fatty acyl groups, is the main component of both LDL particles and atherosclerotic plaques. Tandem mass spectrometry (MS/MS) was employed to reveal abundant and diverse oxidized CEs (oxCE), including novel oxidation products, within human peripheral vascular lesions. These oxCE species composed up to 40% of the total CE pool, with cholesteryl linoleate being oxidized to the greatest extent. Imaging mass spectrometry studies showed that oxCE was entirely confined within the plaque, along with unmodified CE and triacylglyceride (TAG). Interestingly, we found no evidence for TAG oxidation, although polyunsaturated species were abundant. Enzymatic oxidation of cholesteryl linoleate by 15-lipoxygenase (15-LO), an enzyme often invoked in CE oxidation, initially results in a regio- and stereospecific product. Analysis of intact cholesteryl hydroxyoctadecadienoate isomers in human atheromata revealed no regio- or stereospecificity, indicating 15-LO was either not a major source of oxCE or nonenzymatic processes had eroded any product specificity. 相似文献
107.
108.
Biological N2 fixation is the dominant supply of new nitrogen (N) to the oceans, but is often inhibited in the presence of fixed N sources such as nitrate (NO3
−). Anthropogenic fixed N inputs to the ocean are increasing, but their effect on marine N2 fixation is uncertain. Thus, global estimates of new oceanic N depend on a fundamental understanding of factors that modulate N source preferences by N2-fixing cyanobacteria. We examined the unicellular diazotroph Crocosphaera watsonii (strain WH0003) to determine how the light-limited growth rate influences the inhibitory effects of fixed N on N2 fixation. When growth (µ) was limited by low light (µ = 0.23 d−1), short-term experiments indicated that 0.4 µM NH4
+ reduced N2-fixation by ∼90% relative to controls without added NH4
+. In fast-growing, high-light-acclimated cultures (µ = 0.68 d−1), 2.0 µM NH4
+ was needed to achieve the same effect. In long-term exposures to NO3
−, inhibition of N2 fixation also varied with growth rate. In high-light-acclimated, fast-growing cultures, NO3
− did not inhibit N2-fixation rates in comparison with cultures growing on N2 alone. Instead NO3
− supported even faster growth, indicating that the cellular assimilation rate of N2 alone (i.e. dinitrogen reduction) could not support the light-specific maximum growth rate of Crocosphaera. When growth was severely light-limited, NO3
− did not support faster growth rates but instead inhibited N2-fixation rates by 55% relative to controls. These data rest on the basic tenet that light energy is the driver of photoautotrophic growth while various nutrient substrates serve as supports. Our findings provide a novel conceptual framework to examine interactions between N source preferences and predict degrees of inhibition of N2 fixation by fixed N sources based on the growth rate as controlled by light. 相似文献
109.
Zheng QH Liu X Fei X Wang JQ Mock BH Glick-Wilson BE Sullivan ML Hutchins GD 《Bioorganic & medicinal chemistry letters》2003,13(10):1787-1790
[11C]Edrophonium and its analogues have been synthesized for evaluation as new potential positron emission tomography (PET) imaging agents for heart acetylcholinesterase. The tracers were prepared by N-[11C]methylation of precursors using [11C]methyl triflate and isolated by solid-phase extraction (SPE) purification procedure in 50-65% radiochemical yields. 相似文献