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151.
Michael Cowley Alastair S. Garfield Marta Madon-Simon Marika Charalambous Richard W. Clarkson Matthew J. Smalley Howard Kendrick Anthony R. Isles Aled J. Parry Sara Carney Rebecca J. Oakey Lora K. Heisler Kim Moorwood Jason B. Wolf Andrew Ward 《PLoS biology》2014,12(2)
Developmental programming links growth in early life with health status in adulthood. Although environmental factors such as maternal diet can influence the growth and adult health status of offspring, the genetic influences on this process are poorly understood. Using the mouse as a model, we identify the imprinted gene Grb10 as a mediator of nutrient supply and demand in the postnatal period. The combined actions of Grb10 expressed in the mother, controlling supply, and Grb10 expressed in the offspring, controlling demand, jointly regulate offspring growth. Furthermore, Grb10 determines the proportions of lean and fat tissue during development, thereby influencing energy homeostasis in the adult. Most strikingly, we show that the development of normal lean/fat proportions depends on the combined effects of Grb10 expressed in the mother, which has the greater effect on offspring adiposity, and Grb10 expressed in the offspring, which influences lean mass. These distinct functions of Grb10 in mother and pup act complementarily, which is consistent with a coadaptation model of imprinting evolution, a model predicted but for which there is limited experimental evidence. In addition, our findings identify Grb10 as a key genetic component of developmental programming, and highlight the need for a better understanding of mother-offspring interactions at the genetic level in predicting adult disease risk. 相似文献
152.
The structural, dynamical, and thermodynamic properties of a model potassium channel are studied using molecular dynamics simulations. We use the recently unveiled protein structure for the KcsA potassium channel from Streptomyces lividans. Total and free energy profiles of potassium and sodium ions reveal a considerable preference for the larger potassium ions. The selectivity of the channel arises from its ability to completely solvate the potassium ions, but not the smaller sodium ions. Self-diffusion of water within the narrow selectivity filter is found to be reduced by an order of magnitude from bulk levels, whereas the wider hydrophobic section of the pore maintains near-bulk self-diffusion. Simulations examining multiple ion configurations suggest a two-ion channel. Ion diffusion is found to be reduced to approximately (1)/(3) of bulk diffusion within the selectivity filter. The reduced ion mobility does not hinder the passage of ions, as permeation appears to be driven by Coulomb repulsion within this multiple ion channel. 相似文献
153.
Structural studies of innervation on nonpregnant rat uterus 总被引:1,自引:0,他引:1
154.
155.
E. Garfield 《BMJ (Clinical research ed.)》1996,313(7054):411-413
Impact factors are widely used to rank and evaluate journals. They are also often used inappropriately as surrogates in evaluation exercises. The inventor of the Science Citation Index warns against the indiscriminate use of these data. Fourteen year cumulative impact data for 10 leading medical journals provide a quantitative indicator of their long term influence. In the final analysis, impact simply reflects the ability of journals and editors to attract the best papers available. 相似文献
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158.
Facundo Davaro Sorcha D. Forde Mark Garfield Zhaozhao Jiang Kristen Halmen Nelsy Depaula Tamburro Evelyn Kurt-Jones Katherine A. Fitzgerald Douglas T. Golenbock Donghai Wang 《The Journal of biological chemistry》2014,289(23):16214-16222
Multiple clinical trials have shown that the 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors known as statins have anti-inflammatory effects. However, the underlying molecular mechanism remains unclear. The proinflammatory cytokine interleukin-1β (IL-1β) is synthesized as a non-active precursor. The 31-kDa pro-IL-1β is processed into the 17-kDa active form by caspase-1-activating inflammasomes. Here, we report a novel signaling pathway induced by statins, which leads to processing of pro-IL-1β into an intermediate 28-kDa form. This statin-induced IL-1β processing is independent of caspase-1- activating inflammasomes. The 28-kDa form of IL-1β cannot activate interleukin-1 receptor-1 (IL1R1) to signal inflammatory responses. Instead, it interferes with mature IL-1β signaling through IL-1R1 and therefore may dampen inflammatory responses initiated by mature IL-1β. These results may provide new clues to explain the anti-inflammatory effects of statins. 相似文献
159.
Richard J. Chen Guofeng Zhang Susan H. Garfield Yi-Jun Shi Kevin G. Chen Pamela G. Robey Richard D. Leapman 《PloS one》2015,10(11)
Human pluripotent stem cells (hPSCs) represent very promising resources for cell-based regenerative medicine. It is essential to determine the biological implications of some fundamental physiological processes (such as glycogen metabolism) in these stem cells. In this report, we employ electron, immunofluorescence microscopy, and biochemical methods to study glycogen synthesis in hPSCs. Our results indicate that there is a high level of glycogen synthesis (0.28 to 0.62 μg/μg proteins) in undifferentiated human embryonic stem cells (hESCs) compared with the glycogen levels (0 to 0.25 μg/μg proteins) reported in human cancer cell lines. Moreover, we found that glycogen synthesis was regulated by bone morphogenetic protein 4 (BMP-4) and the glycogen synthase kinase 3 (GSK-3) pathway. Our observation of glycogen bodies and sustained expression of the pluripotent factor Oct-4 mediated by the potent GSK-3 inhibitor CHIR-99021 reveals an altered pluripotent state in hPSC culture. We further confirmed glycogen variations under different naïve pluripotent cell growth conditions based on the addition of the GSK-3 inhibitor BIO. Our data suggest that primed hPSCs treated with naïve growth conditions acquire altered pluripotent states, similar to those naïve-like hPSCs, with increased glycogen synthesis. Furthermore, we found that suppression of phosphorylated glycogen synthase was an underlying mechanism responsible for altered glycogen synthesis. Thus, our novel findings regarding the dynamic changes in glycogen metabolism provide new markers to assess the energetic and various pluripotent states in hPSCs. The components of glycogen metabolic pathways offer new assays to delineate previously unrecognized properties of hPSCs under different growth conditions. 相似文献
160.
DE Runcie DA Garfield CC Babbitt JA Wygoda S Mukherjee GA Wray 《Molecular ecology》2012,21(18):4547-4562
Stress responses play an important role in shaping species distributions and robustness to climate change. We investigated how stress responses alter the contribution of additive genetic variation to gene expression during development of the purple sea urchin, Strongylocentrotus purpuratus, under increased temperatures that model realistic climate change scenarios. We first measured gene expression responses in the embryos by RNA‐seq to characterize molecular signatures of mild, chronic temperature stress in an unbiased manner. We found that an increase from 12 to 18 °C caused widespread alterations in gene expression including in genes involved in protein folding, RNA processing and development. To understand the quantitative genetic architecture of this response, we then focused on a well‐characterized gene network involved in endomesoderm and ectoderm specification. Using a breeding design with wild‐caught individuals, we measured genetic and gene–environment interaction effects on 72 genes within this network. We found genetic or maternal effects in 33 of these genes and that the genetic effects were correlated in the network. Fourteen network genes also responded to higher temperatures, but we found no significant genotype–environment interactions in any of the genes. This absence may be owing to an effective buffering of the temperature perturbations within the network. In support of this hypothesis, perturbations to regulatory genes did not affect the expression of the genes that they regulate. Together, these results provide novel insights into the relationship between environmental change and developmental evolution and suggest that climate change may not expose large amounts of cryptic genetic variation to selection in this species. 相似文献