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61.
Wendel HG De Stanchina E Fridman JS Malina A Ray S Kogan S Cordon-Cardo C Pelletier J Lowe SW 《Nature》2004,428(6980):332-337
Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro. Nevertheless, how Akt disables apoptosis and its contribution to clinical drug resistance are unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's action in tumorigenesis and drug resistance, but is unable to confer sensitivity to rapamycin and chemotherapy. These results establish Akt signalling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity in a genotype-dependent manner. 相似文献
62.
Finger-length ratios and sexual orientation 总被引:1,自引:0,他引:1
Williams TJ Pepitone ME Christensen SE Cooke BM Huberman AD Breedlove NJ Breedlove TJ Jordan CL Breedlove SM 《Nature》2000,404(6777):455-456
63.
Foreshock sequences and short-term earthquake predictability on East Pacific Rise transform faults 总被引:3,自引:0,他引:3
East Pacific Rise transform faults are characterized by high slip rates (more than ten centimetres a year), predominantly aseismic slip and maximum earthquake magnitudes of about 6.5. Using recordings from a hydroacoustic array deployed by the National Oceanic and Atmospheric Administration, we show here that East Pacific Rise transform faults also have a low number of aftershocks and high foreshock rates compared to continental strike-slip faults. The high ratio of foreshocks to aftershocks implies that such transform-fault seismicity cannot be explained by seismic triggering models in which there is no fundamental distinction between foreshocks, mainshocks and aftershocks. The foreshock sequences on East Pacific Rise transform faults can be used to predict (retrospectively) earthquakes of magnitude 5.4 or greater, in narrow spatial and temporal windows and with a high probability gain. The predictability of such transform earthquakes is consistent with a model in which slow slip transients trigger earthquakes, enrich their low-frequency radiation and accommodate much of the aseismic plate motion. 相似文献
64.
Mackay TF Richards S Stone EA Barbadilla A Ayroles JF Zhu D Casillas S Han Y Magwire MM Cridland JM Richardson MF Anholt RR Barrón M Bess C Blankenburg KP Carbone MA Castellano D Chaboub L Duncan L Harris Z Javaid M Jayaseelan JC Jhangiani SN Jordan KW Lara F Lawrence F Lee SL Librado P Linheiro RS Lyman RF Mackey AJ Munidasa M Muzny DM Nazareth L Newsham I Perales L Pu LL Qu C Ràmia M Reid JG Rollmann SM Rozas J Saada N Turlapati L Worley KC Wu YQ Yamamoto A Zhu Y Bergman CM Thornton KR 《Nature》2012,482(7384):173-178
A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to dissect the genotype-phenotype map were based on incomplete genotypic information. Here, we describe the Drosophila melanogaster Genetic Reference Panel (DGRP), a community resource for analysis of population genomics and quantitative traits. The DGRP consists of fully sequenced inbred lines derived from a natural population. Population genomic analyses reveal reduced polymorphism in centromeric autosomal regions and the X chromosome, evidence for positive and negative selection, and rapid evolution of the X chromosome. Many variants in novel genes, most at low frequency, are associated with quantitative traits and explain a large fraction of the phenotypic variance. The DGRP facilitates genotype-phenotype mapping using the power of Drosophila genetics. 相似文献
65.
Takeda Y Costa S Delamarre E Roncal C Leite de Oliveira R Squadrito ML Finisguerra V Deschoemaeker S Bruyère F Wenes M Hamm A Serneels J Magat J Bhattacharyya T Anisimov A Jordan BF Alitalo K Maxwell P Gallez B Zhuang ZW Saito Y Simons M De Palma M Mazzone M 《Nature》2011,479(7371):122-126
PHD2 serves as an oxygen sensor that rescues blood supply by regulating vessel formation and shape in case of oxygen shortage. However, it is unknown whether PHD2 can influence arteriogenesis. Here we studied the role of PHD2 in collateral artery growth by using hindlimb ischaemia as a model, a process that compensates for the lack of blood flow in case of major arterial occlusion. We show that Phd2 (also known as Egln1) haplodeficient (Phd2(+/-)) mice displayed preformed collateral arteries that preserved limb perfusion and prevented tissue necrosis in ischaemia. Improved arteriogenesis in Phd2(+/-) mice was due to an expansion of tissue-resident, M2-like macrophages and their increased release of arteriogenic factors, leading to enhanced smooth muscle cell (SMC) recruitment and growth. Both chronic and acute deletion of one Phd2 allele in macrophages was sufficient to skew their polarization towards a pro-arteriogenic phenotype. Mechanistically, collateral vessel preconditioning relied on the activation of canonical NF-κB pathway in Phd2(+/-) macrophages. These results unravel how PHD2 regulates arteriogenesis and artery homeostasis by controlling a specific differentiation state in macrophages and suggest new treatment options for ischaemic disorders. 相似文献
66.
Lindblad-Toh K Garber M Zuk O Lin MF Parker BJ Washietl S Kheradpour P Ernst J Jordan G Mauceli E Ward LD Lowe CB Holloway AK Clamp M Gnerre S Alföldi J Beal K Chang J Clawson H Cuff J Di Palma F Fitzgerald S Flicek P Guttman M Hubisz MJ Jaffe DB Jungreis I Kent WJ Kostka D Lara M Martins AL Massingham T Moltke I Raney BJ Rasmussen MD Robinson J Stark A Vilella AJ Wen J Xie X Zody MC;Broad Institute Sequencing Platform Whole Genome Assembly Team Baldwin J Bloom T Chin CW Heiman D Nicol R 《Nature》2011,478(7370):476-482
The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ~4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ~60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease. 相似文献
67.
68.
Ferreira MA O'Donovan MC Meng YA Jones IR Ruderfer DM Jones L Fan J Kirov G Perlis RH Green EK Smoller JW Grozeva D Stone J Nikolov I Chambert K Hamshere ML Nimgaonkar VL Moskvina V Thase ME Caesar S Sachs GS Franklin J Gordon-Smith K Ardlie KG Gabriel SB Fraser C Blumenstiel B Defelice M Breen G Gill M Morris DW Elkin A Muir WJ McGhee KA Williamson R MacIntyre DJ MacLean AW St CD Robinson M Van Beck M Pereira AC Kandaswamy R McQuillin A Collier DA Bass NJ Young AH Lawrence J Ferrier IN 《Nature genetics》2008,40(9):1056-1058
To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder. 相似文献
69.
Recent evidence has revived the idea that translocations of macromolecules between nucleus and cytoplasm may be regulated via expansion and contraction of the entire diameter of the nuclear pore complex. The present investigation does not support this hypothesis. 相似文献
70.
Jordan Bell 《Archive for History of Exact Sciences》2010,64(3):301-373
In this article, we give a summary of Leonhard Euler’s work on the pentagonal number theorem. First we discuss related work
of earlier authors and Euler himself. We then review Euler’s correspondence, papers and notebook entries about the pentagonal
number theorem and its applications to divisor sums and integer partitions. In particular, we work out the details of an unpublished
proof of the pentagonal number theorem from Euler’s notebooks. As we follow Euler’s discovery and proofs of the pentagonal
number theorem, we pay attention to Euler’s ideas about when we can consider a mathematical statement to be true. Finally,
we discuss related results in the theory of analytic functions. 相似文献