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61.
Ko M Huang Y Jankowska AM Pape UJ Tahiliani M Bandukwala HS An J Lamperti ED Koh KP Ganetzky R Liu XS Aravind L Agarwal S Maciejewski JP Rao A 《Nature》2010,468(7325):839-843
TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs. 相似文献
62.
Generalization of the linguistic aggregation operator and its application in decision making 下载免费PDF全文
A generalization of the linguistic aggregation functions (or operators) is presented by using generalized and quasiarithmetic means.Firstly,the linguistic weighted generalized mean (LWGM) and the linguistic generalized ordered weighted averaging (LGOWA) operator are introduced.These aggregation functions use linguistic information and generalized means in the weighted average (WA) and in the ordered weighted averaging (OWA) function.They are very useful for uncertain situations where the available information cannot be assessed with numerical values but it is possible to use linguistic assessments.These aggregation operators generalize a wide range of aggregation operators that use linguistic information such as the linguistic generalized mean (LGM),the linguistic OWA (LOWA) operator and the linguistic ordered weighted quadratic averaging (LOWQA) operator.We also introduce a further generalization by using quasi-arithmetic means instead of generalized means obtaining the quasi-LWA and the quasi-LOWA operator.Finally,we develop an application of the new approach where we analyze a decision making problem regarding the selection of strategies. 相似文献
63.
64.
Natural variation for sulfate content in Arabidopsis thaliana is highly controlled by APR2 总被引:2,自引:0,他引:2
Loudet O Saliba-Colombani V Camilleri C Calenge F Gaudon V Koprivova A North KA Kopriva S Daniel-Vedele F 《Nature genetics》2007,39(7):896-900
Most agronomic traits of importance, whether physiological (such as nutrient use efficiency) or developmental (such as flowering time), are controlled simultaneously by multiple genes and their interactions with the environment. Here, we show that variation in sulfate content between wild Arabidopsis thaliana accessions Bay-0 and Shahdara is controlled by a major quantitative trait locus that results in a strong interaction with nitrogen availability in the soil. Combining genetic and biochemical results and using a candidate gene approach, we have cloned the underlying gene, showing how a single-amino acid substitution in a key enzyme of the assimilatory sulfate reduction pathway, adenosine 5'-phosphosulfate reductase, is responsible for a decrease in enzyme activity, leading to sulfate accumulation in the plant. This work illustrates the potential of natural variation as a source of new alleles of known genes, which can aid in the study of gene function and metabolic pathway regulation. Our new insights on sulfate assimilation may have an impact on sulfur fertilizer use and stress defense improvement. 相似文献
65.
Sobacchi C Frattini A Guerrini MM Abinun M Pangrazio A Susani L Bredius R Mancini G Cant A Bishop N Grabowski P Del Fattore A Messina C Errigo G Coxon FP Scott DI Teti A Rogers MJ Vezzoni P Villa A Helfrich MH 《Nature genetics》2007,39(8):960-962
Autosomal recessive osteopetrosis is usually associated with normal or elevated numbers of nonfunctional osteoclasts. Here we report mutations in the gene encoding RANKL (receptor activator of nuclear factor-KB ligand) in six individuals with autosomal recessive osteopetrosis whose bone biopsy specimens lacked osteoclasts. These individuals did not show any obvious defects in immunological parameters and could not be cured by hematopoietic stem cell transplantation; however, exogenous RANKL induced formation of functional osteoclasts from their monocytes, suggesting that they could, theoretically, benefit from exogenous RANKL administration. 相似文献
66.
本文应用系统仿真原理和GPSS(General Purpose Simulation System——通用仿真系统)仿真语言构造了大型水利枢纽混凝土工程的运输浇筑系统的GPSS模型,并通过计算机运行对该系统进行了仿真研究,得出了具有一定实用价值的结果,为大型水利枢纽的可行性研究、设计、施工提供了参考. 相似文献
67.
Gandin V Miluzio A Barbieri AM Beugnet A Kiyokawa H Marchisio PC Biffo S 《Nature》2008,455(7213):684-688
Cell growth and proliferation require coordinated ribosomal biogenesis and translation. Eukaryotic initiation factors (eIFs) control translation at the rate-limiting step of initiation. So far, only two eIFs connect extracellular stimuli to global translation rates: eIF4E acts in the eIF4F complex and regulates binding of capped messenger RNA to 40S subunits, downstream of growth factors, and eIF2 controls loading of the ternary complex on the 40S subunit and is inhibited on stress stimuli. No eIFs have been found to link extracellular stimuli to the activity of the large 60S ribosomal subunit. eIF6 binds 60S ribosomes precluding ribosome joining in vitro. However, studies in yeasts showed that eIF6 is required for ribosome biogenesis rather than translation. Here we show that mammalian eIF6 is required for efficient initiation of translation, in vivo. eIF6 null embryos are lethal at preimplantation. Heterozygous mice have 50% reduction of eIF6 levels in all tissues, and show reduced mass of hepatic and adipose tissues due to a lower number of cells and to impaired G1/S cell cycle progression. eIF6(+/-) cells retain sufficient nucleolar eIF6 and normal ribosome biogenesis. The liver of eIF6(+/-) mice displays an increase of 80S in polysomal profiles, indicating a defect in initiation of translation. Consistently, isolated hepatocytes have impaired insulin-stimulated translation. Heterozygous mouse embryonic fibroblasts recapitulate the organism phenotype and have normal ribosome biogenesis, reduced insulin-stimulated translation, and delayed G1/S phase progression. Furthermore, eIF6(+/-) cells are resistant to oncogene-induced transformation. Thus, eIF6 is the first eIF associated with the large 60S subunit that regulates translation in response to extracellular signals. 相似文献
68.
Mitochondria are cellular organelles of crucial importance, playing roles in cellular life and death. In certain cell types, such as neurons, mitochondria must travel long distances so as to meet metabolic demands of the cell. Mitochondrial movement is essentially microtubule (MT) based and is executed by two main motor proteins, Dynein and Kinesin. The organization of the cellular MT network and the identity of motors dictate mitochondrial transport. Tight coupling between MTs, motors, and the mitochondria is needed for the organelle precise localization. Two adaptor proteins are involved directly in mitochondria-motor coupling, namely Milton known also as TRAK, which is the motor adaptor, and Miro, which is the mitochondrial protein. Here, we discuss the active mitochondria transport process, as well as motor–mitochondria coupling in the context of MT organization in different cell types. We focus on mitochondrial trafficking in different cell types, specifically neurons, migrating cells, and polarized epithelial cells. 相似文献
69.
The metal powder direct and rapid prototyping technology is one of the most developing methods in the laser rapid prototyping technique. The coaxial powder delivery system is the key technique. The purpose of this paper is to introduce a new type of coaxial powder delivery system and simulate the metal powder and shield gas flow in the powder nozzle. 2-D and 3-D model of the new coaxial powder delivery system are established. Then gas-solid two-phase flow model and the k-ε turbulent model are selected to simulate the flow of metal powder in powder nozzle. The Euler-Lagrange method is used in the simulating computation. The results show that the new coaxial powder delivery system has stable performance, uniform powder flux, high cooling efficiency, and long useful life. 相似文献
70.
Remco van Horssen Marieke Willemse Anna Haeger Francesca Attanasio Tuba Güneri Albrecht Schwab Christian M. Stock Roberto Buccione Jack A. M. Fransen Bé Wieringa 《Cellular and molecular life sciences : CMLS》2013,70(12):2175-2190
Oncogenic transformation involves reprogramming of cell metabolism, whereby steady-state levels of intracellular NAD+ and NADH can undergo dramatic changes while ATP concentration is generally well maintained. Altered expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD+-salvage, accompanies the changes in NAD(H) during tumorigenesis. Here, we show by genetic and pharmacological inhibition of NAMPT in glioma cells that fluctuation in intracellular [NAD(H)] differentially affects cell growth and morphodynamics, with motility/invasion capacity showing the highest sensitivity to [NAD(H)] decrease. Extracellular supplementation of NAD+ or re-expression of NAMPT abolished the effects. The effects of NAD(H) decrease on cell motility appeared parallel coupled with diminished pyruvate-lactate conversion by lactate dehydrogenase (LDH) and with changes in intracellular and extracellular pH. The addition of lactic acid rescued and knockdown of LDH-A replicated the effects of [NAD(H)] on motility. Combined, our observations demonstrate that [NAD(H)] is an important metabolic component of cancer cell motility. Nutrient or drug-mediated modulation of NAD(H) levels may therefore represent a new option for blocking the invasive behavior of tumors. 相似文献