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Christian MS Laskin OL Sharper V Hoberman A Stirling DI Latriano L 《Birth defects research. Part B, Developmental and reproductive toxicology》2007,80(3):188-207
BACKGROUND: Lenalidomide, a thalidomide analog, is indicated for treatment of patients with deletion-5q myelodysplastic syndromes or multiple myeloma. NZW rabbits were used because of sensitivity to thalidomide's teratogenicity. METHODS: Range-finding and pulse-dosing studies preceded a full developmental toxicity study in New Zealand white (NZW) rabbits (25/group) given lenalidomide (0, 3, 10, or 20 mg/kg/day) or thalidomide (180 mg/kg/day) by stomach tube on gestation days (GD) 7-19. Clinical signs, body weights, and feed consumption were recorded daily from GD 7. On GD 29, standard maternal necropsy, uterine content, and fetal evaluations were carried out. RESULTS: In all studies, thalidomide was selectively toxic to development. In the pulse-dosing study, lenalidomide did not affect development at 100 mg/kg/day. Increases in C(max) and AUC(0-24 hr) values for lenalidomide were slightly less than dose-proportional; lenalidomide occurred in the fetuses. At 10 and 20 mg/kg/day, lenalidomide was maternally toxic (reduced body weight gain and feed consumption; at 20 mg/kg/day, weight loss and one abortion). Developmental toxicity at 10 and 20 mg/kg/day included reduced fetal body weights and increased postimplantation losses and fetal variations (morbidity/purple-discolored skin, undeveloped intermediate lung lobe, irregular nasal-frontal suture, and delayed metacarpal ossification). Thalidomide selectively reduced fetal body weight, increased postimplantation loss and caused characteristic limb and other dysmorphology. CONCLUSIONS: The maternal and developmental NOAELs for lenalidomide are 3 mg/kg/day. Unlike thalidomide, lenalidomide affected embryo-fetal development only at maternally toxic dosages, confirming that structure-activity relationships may not predict maternal or developmental effects. No fetal malformations were attributable to lenalidomide. 相似文献
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Sren Toft Elsa Cuende Astrid Louise Olesen Anne Mathiesen Maria Meisner Larsen Kim Jensen 《Oikos》2019,128(10):1467-1477
Habitats vary in food resources with carnivores often being prey limited, but it is unclear whether habitats facilitate a nutritionally balanced diet. Two paradigms in nutritional ecology, ecological stoichiometry and nutritional geometry, predict that carnivores are limited mainly by protein or lipid, respectively. Using the carabid beetle Anchomenus dorsalis and 10 other predatory beetles from agricultural fields, we developed and tested two simple procedures for quantifying macronutrient‐specific habitat conditions without requiring information about the natural prey. Both procedures assume that predators forage for nutrients rather than specific prey. Our results show that 10 of 11 species were food limited. Five species were lipid limited and one species was protein limited in the field. Co‐existing predator species showed considerable segregation of fundamental macronutritional niches. A linear relationship between specific nutrient limitation and the target lipid:protein (L:P) intake ratio indicates that species with high L:P target are more protein limited while species with low L:P target are more lipid limited. The study illustrates how species within a natural assemblage vary in nutritional niche and in specific nutrient limitation. 相似文献
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Maud Chan-Yao-Chong Célia Deville Louise Pinet Carine van Heijenoort Dominique Durand Tâp Ha-Duong 《Biophysical journal》2019,116(7):1216-1227
Because of their large conformational heterogeneity, structural characterization of intrinsically disordered proteins (IDPs) is very challenging using classical experimental methods alone. In this study, we use NMR and small-angle x-ray scattering (SAXS) data with multiple molecular dynamics (MD) simulations to describe the conformational ensemble of the fully disordered verprolin homology domain of the neural Aldrich syndrome protein involved in the regulation of actin polymerization. First, we studied several back-calculation software of SAXS scattering intensity and optimized the adjustable parameters to accurately calculate the SAXS intensity from an atomic structure. We also identified the most appropriate force fields for MD simulations of this IDP. Then, we analyzed four conformational ensembles of neural Aldrich syndrome protein verprolin homology domain, two generated with the program flexible-meccano with or without NMR-derived information as input and two others generated by MD simulations with two different force fields. These four conformational ensembles were compared to available NMR and SAXS data for validation. We found that MD simulations with the AMBER-03w force field and the TIP4P/2005s water model are able to correctly describe the conformational ensemble of this 67-residue IDP at both local and global level. 相似文献
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Louise Isager Ahl Jozef Mravec Bodil Jrgensen Paula J. Rudall Nina Rnsted Olwen M. Grace 《Plant, cell & environment》2019,42(8):2458-2471
Plants have evolved a multitude of adaptations to survive extreme conditions. Succulent plants have the capacity to tolerate periodically dry environments, due to their ability to retain water in a specialized tissue, termed hydrenchyma. Cell wall polysaccharides are important components of water storage in hydrenchyma cells. However, the role of the cell wall and its polysaccharide composition in relation to drought resistance of succulent plants are unknown. We investigate the drought response of leaf‐succulent Aloe (Asphodelaceae) species using a combination of histological microscopy, quantification of water content, and comprehensive microarray polymer profiling. We observed a previously unreported mode of polysaccharide and cell wall structural dynamics triggered by water shortage. Microscopical analysis of the hydrenchyma cell walls revealed highly regular folding patterns indicative of predetermined cell wall mechanics in the remobilization of stored water and the possible role of homogalacturonan in this process. The in situ distribution of mannans in distinct intracellular compartments during drought, for storage, and apparent upregulation of pectins, imparting flexibility to the cell wall, facilitate elaborate cell wall folding during drought stress. We conclude that cell wall polysaccharide composition plays an important role in water storage and drought response in Aloe. 相似文献
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Anubama Rajan Felipe-Andrs Piedra Letisha Aideyan Trevor McBride Matthew Robertson Hannah L. Johnson Gina Marie Aloisio David Henke Cristian Coarfa Fabio Stossi Vipin Kumar Menon Harshavardhan Doddapaneni Donna Marie Muzny Sara Joan Javornik Cregeen Kristi Louise Hoffman Joseph Petrosino Richard A. Gibbs Vasanthi Avadhanula Pedro A. Piedra 《Journal of virology》2022,96(7)
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