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51.
W Zhou EA Otto A Cluckey R Airik TW Hurd M Chaki K Diaz FP Lach GR Bennett HY Gee AK Ghosh S Natarajan S Thongthip U Veturi SJ Allen S Janssen G Ramaswami J Dixon F Burkhalter M Spoendlin H Moch MJ Mihatsch J Verine R Reade H Soliman M Godin D Kiss G Monga G Mazzucco K Amann F Artunc RC Newland T Wiech S Zschiedrich TB Huber A Friedl GG Slaats JA Joles R Goldschmeding J Washburn RH Giles S Levy A Smogorzewska F Hildebrandt 《Nature genetics》2012,44(8):910-915
Chronic kidney disease (CKD) represents a major health burden. Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD. 相似文献
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Cooper GM Coe BP Girirajan S Rosenfeld JA Vu TH Baker C Williams C Stalker H Hamid R Hannig V Abdel-Hamid H Bader P McCracken E Niyazov D Leppig K Thiese H Hummel M Alexander N Gorski J Kussmann J Shashi V Johnson K Rehder C Ballif BC Shaffer LG Eichler EE 《Nature genetics》2011,43(9):838-846
To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ~14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders. 相似文献
53.
INTERMEDIUM-C, a modifier of lateral spikelet fertility in barley, is an ortholog of the maize domestication gene TEOSINTE BRANCHED 1 总被引:1,自引:0,他引:1
Ramsay L Comadran J Druka A Marshall DF Thomas WT Macaulay M MacKenzie K Simpson C Fuller J Bonar N Hayes PM Lundqvist U Franckowiak JD Close TJ Muehlbauer GJ Waugh R 《Nature genetics》2011,43(2):169-172
The domestication of cereals has involved common changes in morphological features, such as seed size, seed retention and modification of vegetative and inflorescence architecture that ultimately contributed to an increase in harvested yield. In barley, this process has resulted in two different cultivated types, two-rowed and six-rowed forms, both derived from the wild two-rowed ancestor, with archaeo-botanical evidence indicating the origin of six-rowed barley early in the domestication of the species, some 8,600-8,000 years ago. Variation at SIX-ROWED SPIKE 1 (VRS1) is sufficient to control this phenotype. However, phenotypes imposed by VRS1 alleles are modified by alleles at the INTERMEDIUM-C (INT-C) locus. Here we show that INT-C is an ortholog of the maize domestication gene TEOSINTE BRANCHED 1 (TB1) and identify 17 coding mutations in barley TB1 correlated with lateral spikelet fertility phenotypes. 相似文献
54.
2007年9月底的大潮和中潮期间,在长江口徐六泾处结合采用1台光学后散射浊度仪OBS3A和1台现场激光粒度仪LISST 100(B型)并同步现场采集含沙样本对悬浮泥沙浓度进行了定点现场观测.在对絮凝体中水的体积与絮凝体体积相等这一假设条件进行修正的基础上,利用现场观测得出的絮凝体粒径和有效密度之间的关系以及每个粒径范围的絮凝体所占整个絮凝体的权重,修正了利用单一絮凝体粒径的有效密度代表所有絮凝体的假设,最终得到了更为合理的悬浮泥沙现场沉降速度. 相似文献
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All mammals previously studied take maximal rest or sleep after birth, with the amount gradually decreasing as they grow to adulthood, and adult fruitflies and rats die if they are forcibly deprived of sleep. It has therefore been assumed that sleep is necessary for development and serves a vital function in adults. But we show here that, unlike terrestrial mammals, killer-whale and bottlenose-dolphin neonates and their mothers show little or no typical sleep behaviour for the first postpartum month, avoiding obstacles and remaining mobile for 24 hours a day. We find that neonates and their mothers gradually increase the amount of time they spend resting to normal adult levels over a period of several months, but never exceed these levels. Our findings indicate either that sleep behaviour may not have the developmental and life-sustaining functions attributed to it, or that alternative mechanisms may have evolved in cetaceans. 相似文献
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The functions of mammalian sleep remain unclear. Most theories suggest a role for non-rapid eye movement (NREM) sleep in energy conservation and in nervous system recuperation. Theories of REM sleep have suggested a role for this state in periodic brain activation during sleep, in localized recuperative processes and in emotional regulation. Across mammals, the amount and nature of sleep are correlated with age, body size and ecological variables, such as whether the animals live in a terrestrial or an aquatic environment, their diet and the safety of their sleeping site. Sleep may be an efficient time for the completion of a number of functions, but variations in sleep expression indicate that these functions may differ across species. 相似文献
59.
Kanasaki K Palmsten K Sugimoto H Ahmad S Hamano Y Xie L Parry S Augustin HG Gattone VH Folkman J Strauss JF Kalluri R 《Nature》2008,453(7198):1117-1121
Despite intense investigation, mechanisms that facilitate the emergence of the pre-eclampsia phenotype in women are still unknown. Placental hypoxia, hypertension, proteinuria and oedema are the principal clinical features of this disease. It is speculated that hypoxia-driven disruption of the angiogenic balance involving vascular endothelial growth factor (VEGF)/placenta-derived growth factor (PLGF) and soluble Fms-like tyrosine kinase-1 (sFLT-1, the soluble form of VEGF receptor 1) might contribute to some of the maternal symptoms of pre-eclampsia. However, pre-eclampsia does not develop in all women with high sFLT-1 or low PLGF levels, and it also occurs in some women with low sFLT-1 and high PLGF levels. Moreover, recent experiments strongly suggest that several soluble factors affecting the vasculature are probably elevated because of placental hypoxia in the pre-eclamptic women, indicating that upstream molecular defect(s) may contribute to pre-eclampsia. Here we show that pregnant mice deficient in catechol-O-methyltransferase (COMT) show a pre-eclampsia-like phenotype resulting from an absence of 2-methoxyoestradiol (2-ME), a natural metabolite of oestradiol that is elevated during the third trimester of normal human pregnancy. 2-ME ameliorates all pre-eclampsia-like features without toxicity in the Comt(-/-) pregnant mice and suppresses placental hypoxia, hypoxia-inducible factor-1alpha expression and sFLT-1 elevation. The levels of COMT and 2-ME are significantly lower in women with severe pre-eclampsia. Our studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder. 相似文献
60.
基于时变偏扰模型的间歇过程迭代学习控制 总被引:5,自引:0,他引:5
为了克服模型与过程间的偏差,提出了一个基于时变偏扰模型的间歇过程迭代学习控制方法.利用主元回归(principal component regression,PCR)和部分最小二乘(partial least squares,PLS)方法,可以得到过程对象在正常运行轨迹附近线性化的模型.前一批次的模型预报误差被用来修正当前批次的模型预报值.每完成一个批次就利用新得到的数据对模型进行更新,该更新的模型也是在前一批次的控制轨迹基础上进行线性化得到的.主元回归和部分最小二乘方法能克服批次内不同阶段的控制量存在的相关关系从而得到更准确的模型.仿真结果表明:基于PCR和PLS模型的控制效果要好于基于多元线性回归(MLR)模型的控制效果. 相似文献