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171.
Kahle KT Wilson FH Leng Q Lalioti MD O'Connell AD Dong K Rapson AK MacGregor GG Giebisch G Hebert SC Lifton RP 《Nature genetics》2003,35(4):372-376
A key question in systems biology is how diverse physiologic processes are integrated to produce global homeostasis. Genetic analysis can contribute by identifying genes that perturb this integration. One system orchestrates renal NaCl and K+ flux to achieve homeostasis of blood pressure and serum K+ concentration. Positional cloning implicated the serine-threonine kinase WNK4 in this process; clustered mutations in PRKWNK4, encoding WNK4, cause hypertension and hyperkalemia (pseudohypoaldosteronism type II, PHAII) by altering renal NaCl and K+ handling. Wild-type WNK4 inhibits the renal Na-Cl cotransporter (NCCT); mutations that cause PHAII relieve this inhibition. This explains the hypertension of PHAII but does not account for the hyperkalemia. By expression in Xenopus laevis oocytes, we show that WNK4 also inhibits the renal K+ channel ROMK. This inhibition is independent of WNK4 kinase activity and is mediated by clathrin-dependent endocytosis of ROMK, mechanisms distinct from those that characterize WNK4 inhibition of NCCT. Most notably, the same mutations in PRKWNK4 that relieve NCCT inhibition markedly increase inhibition of ROMK. These findings establish WNK4 as a multifunctional regulator of diverse ion transporters; moreover, they explain the pathophysiology of PHAII. They also identify WNK4 as a molecular switch that can vary the balance between NaCl reabsorption and K+ secretion to maintain integrated homeostasis. 相似文献
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Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome 总被引:36,自引:0,他引:36
Eriksson M Brown WT Gordon LB Glynn MW Singer J Scott L Erdos MR Robbins CM Moses TY Berglund P Dutra A Pak E Durkin S Csoka AB Boehnke M Glover TW Collins FS 《Nature》2003,423(6937):293-298
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q-the inheritance of both copies of this material from one parent-and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders, revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo (that is, newly arisen and not inherited) single-base substitution, G608G(GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing. 相似文献
175.
Kappelman J Rasmussen DT Sanders WJ Feseha M Bown T Copeland P Crabaugh J Fleagle J Glantz M Gordon A Jacobs B Maga M Muldoon K Pan A Pyne L Richmond B Ryan T Seiffert ER Sen S Todd L Wiemann MC Winkler A 《Nature》2003,426(6966):549-552
Afro-Arabian mammalian communities underwent a marked transition near the Oligocene/Miocene boundary at approximately 24 million years (Myr) ago. Although it is well documented that the endemic paenungulate taxa were replaced by migrants from the Northern Hemisphere, the timing and evolutionary dynamics of this transition have long been a mystery because faunas from about 32 to 24 Myr ago are largely unknown. Here we report a late Oligocene fossil assemblage from Ethiopia, which constrains the migration to postdate 27 Myr ago, and yields new insight into the indigenous faunal dynamics that preceded this event. The fauna is composed of large paenungulate herbivores and reveals not only which earlier taxa persisted into the late Oligocene epoch but also demonstrates that one group, the Proboscidea, underwent a marked diversification. When Eurasian immigrants entered Afro-Arabia, a pattern of winners and losers among the endemics emerged: less diverse taxa such as arsinoitheres became extinct, moderately species-rich groups such as hyracoids continued into the Miocene with reduced diversity, whereas the proboscideans successfully carried their adaptive radiation out of Afro-Arabia and across the world. 相似文献
176.
Medicine: silencing viruses with RNA 总被引:19,自引:0,他引:19
Carmichael GG 《Nature》2002,418(6896):379-380
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Gordon R. Richards 《Journal of forecasting》2004,23(8):586-601
Financial market time series exhibit high degrees of non‐linear variability, and frequently have fractal properties. When the fractal dimension of a time series is non‐integer, this is associated with two features: (1) inhomogeneity—extreme fluctuations at irregular intervals, and (2) scaling symmetries—proportionality relationships between fluctuations over different separation distances. In multivariate systems such as financial markets, fractality is stochastic rather than deterministic, and generally originates as a result of multiplicative interactions. Volatility diffusion models with multiple stochastic factors can generate fractal structures. In some cases, such as exchange rates, the underlying structural equation also gives rise to fractality. Fractal principles can be used to develop forecasting algorithms. The forecasting method that yields the best results here is the state transition‐fitted residual scale ratio (ST‐FRSR) model. A state transition model is used to predict the conditional probability of extreme events. Ratios of rates of change at proximate separation distances are used to parameterize the scaling symmetries. Forecasting experiments are run using intraday exchange rate futures contracts measured at 15‐minute intervals. The overall forecast error is reduced on average by up to 7% and in one instance by nearly a quarter. However, the forecast error during the outlying events is reduced by 39% to 57%. The ST‐FRSR reduces the predictive error primarily by capturing extreme fluctuations more accurately. Copyright © 2004 John Wiley & Sons, Ltd. 相似文献