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71.
Ding L Ley TJ Larson DE Miller CA Koboldt DC Welch JS Ritchey JK Young MA Lamprecht T McLellan MD McMichael JF Wallis JW Lu C Shen D Harris CC Dooling DJ Fulton RS Fulton LL Chen K Schmidt H Kalicki-Veizer J Magrini VJ Cook L McGrath SD Vickery TL Wendl MC Heath S Watson MA Link DC Tomasson MH Shannon WD Payton JE Kulkarni S Westervelt P Walter MJ Graubert TA Mardis ER Wilson RK DiPersio JF 《Nature》2012,481(7382):506-510
Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions. 相似文献
72.
Mariathasan S Weiss DS Newton K McBride J O'Rourke K Roose-Girma M Lee WP Weinrauch Y Monack DM Dixit VM 《Nature》2006,440(7081):228-232
A crucial part of the innate immune response is the assembly of the inflammasome, a cytosolic complex of proteins that activates caspase-1 to process the proinflammatory cytokines interleukin (IL)-1beta and IL-18. The adaptor protein ASC is essential for inflammasome function, binding directly to caspase-1 (refs 3, 4), but the triggers of this interaction are less clear. ASC also interacts with the adaptor cryopyrin (also known as NALP3 or CIAS1). Activating mutations in cryopyrin are associated with familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, diseases that are characterized by excessive production of IL-1beta. Here we show that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels. The release of IL-1beta in response to nigericin, a potassium ionophore, and maitotoxin, a potent marine toxin, was also found to be dependent on cryopyrin. In contrast to Asc-/- macrophages, cells deficient in the gene encoding cryopyrin (Cias1-/-) activated caspase-1 and secreted normal levels of IL-1beta and IL-18 when infected with Gram-negative Salmonella typhimurium or Francisella tularensis. Macrophages exposed to Gram-positive Staphylococcus aureus or Listeria monocytogenes, however, required both ASC and cryopyrin to activate caspase-1 and secrete IL-1beta. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes. 相似文献
73.
In this paper we develop a version of the Jackknife which seems especially suited for Multidimensional Scaling. It deletes one stimulus at a time, and combines the resulting solutions by a least squares matching method. The results can be used for stability analysis, and for purposes of cross validation. 相似文献
74.
G. Renaud Jacqueline Marais R. Infante 《Cellular and molecular life sciences : CMLS》1980,36(6):642-643
Summary After 24-h fasting, when the recovery of plasma membrane protein isolated from rat liver was unchanged, the enrichment in 5-nucleotidase was decreased by 16%. Modifications of the lipid composition were also observed and resulted in a 27% decrease of the cholesterol/phospholipid molar ratio. 相似文献
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77.
A substantial uncertainty in the Earth's global geochemical water cycle is the amount of water that enters the deep mantle through the subduction and recycling of hydrated oceanic lithosphere. Here we address the question of recycling of water into the deep mantle by characterizing the volatile contents of different mantle components as sampled by ocean island basalts and mid-ocean-ridge basalts. Although all mantle plume (ocean island) basalts seem to contain more water than mid-ocean-ridge basalts, we demonstrate that basalts associated with mantle plume components containing subducted lithosphere--'enriched-mantle' or 'EM-type' basalts--contain less water than those associated with a common mantle source. We interpret this depletion as indicating that water is extracted from the lithosphere during the subduction process, with greater than 92 per cent efficiency. 相似文献
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79.
Gibbons RJ Pellagatti A Garrick D Wood WG Malik N Ayyub H Langford C Boultwood J Wainscoat JS Higgs DR 《Nature genetics》2003,34(4):446-449
Inherited mutations of specific genes have elucidated the normal roles of the proteins they encode by relating specific mutations to particular phenotypes. But many potentially informative mutations in such genes are lethal early in development. Consequently, inherited mutations may not reflect all the functional roles of such proteins. Acquired, somatic defects should reflect a wider spectrum of mutations because they are not prone to negative selection in development. It has been difficult to identify such mutations so far, but microarray analysis provides a new opportunity to do so. Using this approach, we have shown that in individuals with myelodysplasia associated with alpha-thalassemia (ATMDS), somatic mutations of the gene encoding the chromatin remodeling factor ATRX cause an unexpectedly severe hematological phenotype compared with the wide spectrum of inherited mutations affecting this gene. These findings cast new light on this pleiotropic cofactor, which appears to be an essential component rather than a mere facilitator of globin gene expression. 相似文献
80.
Dodé C Levilliers J Dupont JM De Paepe A Le Dû N Soussi-Yanicostas N Coimbra RS Delmaghani S Compain-Nouaille S Baverel F Pêcheux C Le Tessier D Cruaud C Delpech M Speleman F Vermeulen S Amalfitano A Bachelot Y Bouchard P Cabrol S Carel JC Delemarre-van de Waal H Goulet-Salmon B Kottler ML Richard O Sanchez-Franco F Saura R Young J Petit C Hardelin JP 《Nature genetics》2003,33(4):463-465
We took advantage of overlapping interstitial deletions at chromosome 8p11-p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males. 相似文献