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排序方式: 共有290条查询结果,搜索用时 31 毫秒
1.
Mullighan CG Goorha S Radtke I Miller CB Coustan-Smith E Dalton JD Girtman K Mathew S Ma J Pounds SB Su X Pui CH Relling MV Evans WE Shurtleff SA Downing JR 《Nature》2007,446(7137):758-764
Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer. 相似文献
2.
Lord C Bhandari D Menon S Ghassemian M Nycz D Hay J Ghosh P Ferro-Novick S 《Nature》2011,473(7346):181-186
How the directionality of vesicle traffic is achieved remains an important unanswered question in cell biology. The Sec23p/Sec24p coat complex sorts the fusion machinery (SNAREs) into vesicles as they bud from the endoplasmic reticulum (ER). Vesicle tethering to the Golgi begins when the tethering factor TRAPPI binds to Sec23p. Where the coat is released and how this event relates to membrane fusion is unknown. Here we use a yeast transport assay to demonstrate that an ER-derived vesicle retains its coat until it reaches the Golgi. A Golgi-associated kinase, Hrr25p (CK1δ orthologue), then phosphorylates the Sec23p/Sec24p complex. Coat phosphorylation and dephosphorylation are needed for vesicle fusion and budding, respectively. Additionally, we show that Sec23p interacts in a sequential manner with different binding partners, including TRAPPI and Hrr25p, to ensure the directionality of ER-Golgi traffic and prevent the back-fusion of a COPII vesicle with the ER. These events are conserved in mammalian cells. 相似文献
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Extended megadroughts in the southwestern United States during Pleistocene interglacials 总被引:1,自引:0,他引:1
Fawcett PJ Werne JP Anderson RS Heikoop JM Brown ET Berke MA Smith SJ Goff F Donohoo-Hurley L Cisneros-Dozal LM Schouten S Sinninghe Damsté JS Huang Y Toney J Fessenden J WoldeGabriel G Atudorei V Geissman JW Allen CD 《Nature》2011,470(7335):518-521
The potential for increased drought frequency and severity linked to anthropogenic climate change in the semi-arid regions of the southwestern United States (US) is a serious concern. Multi-year droughts during the instrumental period and decadal-length droughts of the past two millennia were shorter and climatically different from the future permanent, 'dust-bowl-like' megadrought conditions, lasting decades to a century, that are predicted as a consequence of warming. So far, it has been unclear whether or not such megadroughts occurred in the southwestern US, and, if so, with what regularity and intensity. Here we show that periods of aridity lasting centuries to millennia occurred in the southwestern US during mid-Pleistocene interglacials. Using molecular palaeotemperature proxies to reconstruct the mean annual temperature (MAT) in mid-Pleistocene lacustrine sediment from the Valles Caldera, New Mexico, we found that the driest conditions occurred during the warmest phases of interglacials, when the MAT was comparable to or higher than the modern MAT. A collapse of drought-tolerant C(4) plant communities during these warm, dry intervals indicates a significant reduction in summer precipitation, possibly in response to a poleward migration of the subtropical dry zone. Three MAT cycles ~2?°C in amplitude occurred within Marine Isotope Stage (MIS) 11 and seem to correspond to the muted precessional cycles within this interglacial. In comparison with MIS 11, MIS 13 experienced higher precessional-cycle amplitudes, larger variations in MAT (4-6?°C) and a longer period of extended warmth, suggesting that local insolation variations were important to interglacial climatic variability in the southwestern US. Comparison of the early MIS 11 climate record with the Holocene record shows many similarities and implies that, in the absence of anthropogenic forcing, the region should be entering a cooler and wetter phase. 相似文献
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Vitart V Rudan I Hayward C Gray NK Floyd J Palmer CN Knott SA Kolcic I Polasek O Graessler J Wilson JF Marinaki A Riches PL Shu X Janicijevic B Smolej-Narancic N Gorgoni B Morgan J Campbell S Biloglav Z Barac-Lauc L Pericic M Klaric IM Zgaga L Skaric-Juric T Wild SH Richardson WA Hohenstein P Kimber CH Tenesa A Donnelly LA Fairbanks LD Aringer M McKeigue PM Ralston SH Morris AD Rudan P Hastie ND Campbell H Wright AF 《Nature genetics》2008,40(4):437-442
Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes. 相似文献
7.
Greenway MJ Andersen PM Russ C Ennis S Cashman S Donaghy C Patterson V Swingler R Kieran D Prehn J Morrison KE Green A Acharya KR Brown RH Hardiman O 《Nature genetics》2006,38(4):411-413
We recently identified angiogenin (ANG) as a candidate susceptibility gene for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by adult-onset loss of motor neurons. We now report the finding of seven missense mutations in 15 individuals, of whom four had familial ALS and 11 apparently 'sporadic' ALS. Our findings provide further evidence that variations in hypoxia-inducible genes have an important role in motor neuron degeneration. 相似文献
8.
Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band 总被引:8,自引:0,他引:8
We report a new mechanism in carcinogenesis involving coordinate long-range epigenetic gene silencing. Epigenetic silencing in cancer has always been envisaged as a local event silencing discrete genes. However, in this study of silencing in colorectal cancer, we found common repression of the entire 4-Mb band of chromosome 2q.14.2, associated with global methylation of histone H3 Lys9. DNA hypermethylation within the repressed genomic neighborhood was localized to three separate enriched CpG island 'suburbs', with the largest hypermethylated suburb spanning 1 Mb. These data change our understanding of epigenetic gene silencing in cancer cells: namely, epigenetic silencing can span large regions of the chromosome, and both DNA-methylated and neighboring unmethylated genes can be coordinately suppressed by global changes in histone modification. We propose that loss of gene expression can occur through long-range epigenetic silencing, with similar implications as loss of heterozygosity in cancer. 相似文献
9.
Sayer JA Otto EA O'Toole JF Nurnberg G Kennedy MA Becker C Hennies HC Helou J Attanasio M Fausett BV Utsch B Khanna H Liu Y Drummond I Kawakami I Kusakabe T Tsuda M Ma L Lee H Larson RG Allen SJ Wilkinson CJ Nigg EA Shou C Lillo C Williams DS Hoppe B Kemper MJ Neuhaus T Parisi MA Glass IA Petry M Kispert A Gloy J Ganner A Walz G Zhu X Goldman D Nurnberg P Swaroop A Leroux MR Hildebrandt F 《Nature genetics》2006,38(6):674-681
10.
Penstemon palmeri is a short-lived perennial herb colonizing disturbed sites in semiarid habitats in the western USA. In this study seed was harvested from six native and four seeded populations during two consecutive years. In laboratory germination trials at constant 15 C, considerable between-lot variation in primary dormancy and light requirement was observed. Four weeks of moist chilling (1 C) induced secondary dormancy at 15 C. Cold-induced secondary dormancy was reversed by one week of dark incubation at 30 C. This warm incubation treatment also reduced the light requirement of unchilled, after-ripened seed. Fluctuations in dormancy and light requirement of buried seeds have been linked to seasonal changes in soil temperature. Penstemon palmeri germination responses to temperature appear to be similar to those of facultative winter annuals. 相似文献