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MuhammadM. Khalifa Bruno Martorelli Di Genova Sarah G. McAlpine Gina M. Gallego-Lopez David M. Stevenson Soren D. Rozema Neil P. Monaghan James C. Morris Laura J. Knoll Jennifer E. Golden 《ACS medicinal chemistry letters》2020,11(12):2382
Toxoplasma gondii causes a prevalent human infection for which only the acute stage has an FDA-approved therapy. To find inhibitors of both the acute stage parasites and the persistent cyst stage that causes a chronic infection, we repurposed a compound library containing known inhibitors of parasitic hexokinase, the first step in the glycolysis pathway, along with a larger collection of new structural derivatives. The focused screen of 22 compounds showed a 77% hit rate (>50% multistage inhibition) and revealed a series of aminobenzamide-linked picolinic acids with submicromolar potency against both T. gondii parasite forms. Picolinic acid 23, designed from an antiparasitic benzamidobenzoic acid class with challenging ADME properties, showed 60-fold-enhanced solubility, a moderate LogD7.4, and a 30% improvement in microsomal stability. Furthermore, isotopically labeled glucose tracing revealed that picolinic acid 23 does not function by hexokinase inhibition. Thus, we report a new probe scaffold to interrogate dual-stage inhibition of T. gondii. 相似文献
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Ian Glynn Davies Toni Blackham Agnieszka Jaworowska Catherine Taylor Matthew Ashton Leonard Stevenson 《International journal of food sciences and nutrition》2016,67(3):217-224
The aim of the study was to analyze the saturated fatty acid (SFA) and trans-fatty acid (TFA) contents of popular takeaway foods in the UK (including English, pizza, Chinese, Indian and kebab cuisine). Samples of meals were analyzed by an accredited public analyst laboratory for SFA and TFA. The meals were highly variable for SFA and TFA. English and Pizza meals had the highest median amount of SFA with 35.7?g/meal; Kebab meals were high in TFA with up to 5.2?g/meal. When compared to UK dietary reference values, some meals exceeded SFA and TFA recommendations from just one meal. Takeaway food would be an obvious target to reduce SFA and TFA contents and increase the potential of meeting UK recommendations. Strategies such as reformulation and smaller takeaway portion sizes warrant investigation. 相似文献
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Marilyn Katz Nicole Silverstein Patrick Coll Gail Sullivan Eric M. Mortensen Adam Sachs Jeffrey B. Gross Eric Girard Joy Liang Benjamin T. Ristau Christina Stevenson Phillip P. Smith Brian D. Shames Ryan Millea Irfan Ali Constantine M. Poulos Akila B. Ramaraj Azuka Onye Otukoya David W. McFadden 《Current problems in surgery》2019,56(7):260-329
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Jared M. Weiss MD Nathan Pennell MD PhD Allison M. Deal MS Daniel Morgensztern MD Daniel S. Bradford MD Jeffrey Crane MD Howard Jack West MD Carrie Lee MD Chad Pecot MD James P. Stevenson MD William Irvin MD Mark Socinski MD Tom Stinchcombe MD Liza C. Villaruz MD Hyman B. Muss MD 《Cancer》2020,126(5):1060-1067
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Edward T. Tipper Emily I. Stevenson Victoria Alcock Alasdair C. G. Knight J. Jotautas Baronas Robert G. Hilton Mike J. Bickle Christina S. Larkin Linshu Feng Katy E. Relph Genevieve Hughes 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(1)
Rivers carry the dissolved and solid products of silicate mineral weathering, a process that removes from the atmosphere and provides a key negative climate feedback over geological timescales. Here we show that, in some river systems, a reactive exchange pool on river suspended particulate matter, bonded weakly to mineral surfaces, increases the mobile cation flux by 50%. The chemistry of both river waters and the exchange pool demonstrates exchange equilibrium, confirmed by Sr isotopes. Global silicate weathering fluxes are calculated based on riverine dissolved sodium (Na+) from silicate minerals. The large exchange pool supplies Na+ of nonsilicate origin to the dissolved load, especially in catchments with widespread marine sediments, or where rocks have equilibrated with saline basement fluids. We quantify this by comparing the riverine sediment exchange pool and river water chemistry. In some basins, cation exchange could account for the majority of sodium in the river water, significantly reducing estimates of silicate weathering. At a global scale, we demonstrate that silicate weathering fluxes are overestimated by 12 to 28%. This overestimation is greatest in regions of high erosion and high sediment loads where the negative climate feedback has a maximum sensitivity to chemical weathering reactions. In the context of other recent findings that reduce the net consumption through chemical weathering, the magnitude of the continental silicate weathering fluxes and its implications for solid Earth degassing fluxes need to be further investigated.For decades, silicate weathering has been postulated to provide the negative climate feedback on Earth that prevents a runaway greenhouse climate like on Venus (1). Silicate mineral dissolution with carbonic acid converts atmospheric into carbonate, and releases essential nutrients to the terrestrial and marine biosphere (2). There have been many attempts to quantify the silicate weathering flux (3), mostly assuming that riverine dissolved sodium () is derived only from silicate minerals and rock salt. Here we show that there is a major addition of nonsilicate to the critical zone from ancient seawater, weakly bonded to sedimentary rocks and supplied to waters via the cation exchange process. The implication is not only that the silicate weathering flux is overestimated at a global scale, but that this nonsilicate is most important in regions previously thought to have the highest silicate weathering fluxes (so called weathering-limited regions) and greatest climate sensitivity.Cation exchange is a rapid chemical reaction between cations in the dissolved phase and mineral surfaces, particularly clays (4). Major and trace cations such as calcium (), magnesium (), sodium (), potassium (), and strontium () form the cation exchange pool, which balances negative charges on river-borne clay particle surfaces. This exchange takes place on interlayer sites, between the tetrahedral and octahedral layers, or on exposed surfaces (4). The importance of the cation exchange pool is well recognized in soils and aquifers (4, 5), has significant implications for enhanced weathering (6), and has been proposed as an important mechanism for buffering the composition of river waters (7–9). However, data on the riverine exchange pool are only available for two large river systems [Amazon and Ganges-Brahmaputra (10, 11)], despite its significance in providing a source of elements that are immediately bioavailable (12), and their potential for biasing the quantification of silicate weathering (9).It is increasingly recognized that rapidly reactive phases have a strong influence on the chemistry of river waters (13, 14). Cation exchange is a rapid reaction occurring continuously in soils, as riverine freshwaters evolve downstream interacting with particulate matter, and when they mix with seawater (15, 16). Important examples of cation exchange are the “swapping” of divalent cations and with , in particular when there is a major change in water composition such as when fluvial clays reach the ocean,[1]As a result, marine sediments have an exchange pool that is dominated by (17). Subsequently, these marine sediments are uplifted and emplaced on the continents where in the exchange pool is released by cation exchange with Ca-rich fresh waters (9). This has major implications for estimates of silicate weathering fluxes and associated consumption, because they are calculated using the content of rivers (3). Cerling et al. (9) proposed that the -rich exchange pool exerts an important control on natural waters, based on charge balance arguments from river water chemistry, but this hypothesis has never been rigorously tested (18) by determining the flux and composition of the exchange pool of rivers around the world.In this contribution, we present a large dataset of fluvial sediment cation exchange capacity (CEC) and composition in several of the world’s largest river basins. By comparing with the concomitant dissolved load chemistry, we demonstrate that 1) the exchange pool in river sediments is in equilibrium with the river water; 2) the fraction of mobile elements in the exchange pool relative to the dissolved pool can be significant, particularly in rapidly eroding, weathering-limited catchments; and 3) given reasonable inferences on the composition of old marine sedimentary rocks, modern-day silicate weathering has been overestimated and carbonate weathering has been underestimated. The results reduce the estimated magnitude of the silicate weathering flux, but increase the supply of base cations (e.g., , which can be a limiting nutrient) to the biosphere, suggesting a greater role of organic carbon burial compared with silicate weathering for the long-term atmospheric sink. 相似文献