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81.
82.
Howard Sankey 《Studies in history and philosophy of science》2012,43(1):182-190
This article explores the relationship between epistemic relativism and Pyrrhonian scepticism. It is argued that a fundamental argument for contemporary epistemic relativism derives from the Pyrrhonian problem of the criterion. Pyrrhonian scepticism is compared and contrasted with Cartesian scepticism about the external world and Humean scepticism about induction. Epistemic relativism is characterized as relativism due to the variation of epistemic norms, and is contrasted with other forms of cognitive relativism, such as truth relativism, conceptual relativism and ontological relativism. An argument from the Pyrrhonian problem of the criterion to epistemic relativism is presented, and is contrasted with three other arguments for epistemic relativism. It is argued that the argument from the criterion is the most fundamental argument for epistemic relativism. Finally, it is noted how the argument of the present paper fits with the author’s previous suggestion that a particularist response to the Pyrrhonian sceptic may be combined with a naturalistic view of epistemic warrant to meet the challenge of epistemic relativism. 相似文献
83.
The microtubule cytoskeleton is a dynamic structure in which the lengths of the microtubules are tightly regulated. One regulatory mechanism is the depolymerization of microtubules by motor proteins in the kinesin-13 family. These proteins are crucial for the control of microtubule length in cell division, neuronal development and interphase microtubule dynamics. The mechanism by which kinesin-13 proteins depolymerize microtubules is poorly understood. A central question is how these proteins target to microtubule ends at rates exceeding those of standard enzyme-substrate kinetics. To address this question we developed a single-molecule microscopy assay for MCAK, the founding member of the kinesin-13 family. Here we show that MCAK moves along the microtubule lattice in a one-dimensional (1D) random walk. MCAK-microtubule interactions were transient: the average MCAK molecule diffused for 0.83 s with a diffusion coefficient of 0.38 microm2 s(-1). Although the catalytic depolymerization by MCAK requires the hydrolysis of ATP, we found that the diffusion did not. The transient transition from three-dimensional diffusion to 1D diffusion corresponds to a "reduction in dimensionality" that has been proposed as the search strategy by which DNA enzymes find specific binding sites. We show that MCAK uses this strategy to target to both microtubule ends more rapidly than direct binding from solution. 相似文献
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86.
Thrombospondin binds falciparum malaria parasitized erythrocytes and may mediate cytoadherence 总被引:8,自引:0,他引:8
D D Roberts J A Sherwood S L Spitalnik L J Panton R J Howard V M Dixit W A Frazier L H Miller V Ginsburg 《Nature》1985,318(6041):64-66
Plasmodium falciparum infected erythrocytes containing mature trophozoites and schizonts sequester along venular endothelium and are not in the peripheral circulation of patients with malaria. Knobs appear on infected erythrocytes and are the points of attachment to endothelium. Sequestration may protect the parasite from splenic destruction and may play a role in the pathogenesis of cerebral malaria. Correlates of sequestration have been developed in vitro using cultured human endothelium and an amelanotic melanoma cell line. Knobless strains (K-) of P. falciparum fail to sequester in vivo and to bind to cells in vitro. We now present evidence that the receptor for cytoadherence is the glycoprotein, thrombospondin. Aotus monkey or human erythrocytes containing knobby (K+) but not Aotus erythrocytes containing knobless strains of P. falciparum bind to immobilized thrombospondin. Neither binds to the adhesive proteins laminin, fibronectin, factor VIII/von Willebrand factor or vitronectin. Both soluble thrombospondin and anti-thrombospondin antibodies inhibit binding of parasitized Aotus erythrocytes to immobilize thrombospondin and to melanoma cells which secrete thrombospondin. 相似文献
87.
Burnett C Valentini S Cabreiro F Goss M Somogyvári M Piper MD Hoddinott M Sutphin GL Leko V McElwee JJ Vazquez-Manrique RP Orfila AM Ackerman D Au C Vinti G Riesen M Howard K Neri C Bedalov A Kaeberlein M Soti C Partridge L Gems D 《Nature》2011,477(7365):482-485
Overexpression of sirtuins (NAD(+)-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae), Caenorhabditis elegans and Drosophila melanogaster. Studies of the effects of genes on ageing are vulnerable to confounding effects of genetic background. Here we re-examined the reported effects of sirtuin overexpression on ageing and found that standardization of genetic background and the use of appropriate controls abolished the apparent effects in both C. elegans and Drosophila. In C. elegans, outcrossing of a line with high-level sir-2.1 overexpression abrogated the longevity increase, but did not abrogate sir-2.1 overexpression. Instead, longevity co-segregated with a second-site mutation affecting sensory neurons. Outcrossing of a line with low-copy-number sir-2.1 overexpression also abrogated longevity. A Drosophila strain with ubiquitous overexpression of dSir2 using the UAS-GAL4 system was long-lived relative to wild-type controls, as previously reported, but was not long-lived relative to the appropriate transgenic controls, and nor was a new line with stronger overexpression of dSir2. These findings underscore the importance of controlling for genetic background and for the mutagenic effects of transgene insertions in studies of genetic effects on lifespan. The life-extending effect of dietary restriction on ageing in Drosophila has also been reported to be dSir2 dependent. We found that dietary restriction increased fly lifespan independently of dSir2. Our findings do not rule out a role for sirtuins in determination of metazoan lifespan, but they do cast doubt on the robustness of the previously reported effects of sirtuins on lifespan in C. elegans and Drosophila. 相似文献
88.
McDermott-Roe C Ye J Ahmed R Sun XM Serafín A Ware J Bottolo L Muckett P Cañas X Zhang J Rowe GC Buchan R Lu H Braithwaite A Mancini M Hauton D Martí R García-Arumí E Hubner N Jacob H Serikawa T Zidek V Papousek F Kolar F Cardona M Ruiz-Meana M García-Dorado D Comella JX Felkin LE Barton PJ Arany Z Pravenec M Petretto E Sanchis D Cook SA 《Nature》2011,478(7367):114-118
Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy. 相似文献
89.
Welsh WF Orosz JA Carter JA Fabrycky DC Ford EB Lissauer JJ Prša A Quinn SN Ragozzine D Short DR Torres G Winn JN Doyle LR Barclay T Batalha N Bloemen S Brugamyer E Buchhave LA Caldwell C Caldwell DA Christiansen JL Ciardi DR Cochran WD Endl M Fortney JJ Gautier TN Gilliland RL Haas MR Hall JR Holman MJ Howard AW Howell SB Isaacson H Jenkins JM Klaus TC Latham DW Li J Marcy GW Mazeh T Quintana EV Robertson P Shporer A Steffen JH Windmiller G Koch DG Borucki WJ 《Nature》2012,481(7382):475-479
Most Sun-like stars in the Galaxy reside in gravitationally bound pairs of stars (binaries). Although long anticipated, the existence of a 'circumbinary planet' orbiting such a pair of normal stars was not definitively established until the discovery of the planet transiting (that is, passing in front of) Kepler-16. Questions remained, however, about the prevalence of circumbinary planets and their range of orbital and physical properties. Here we report two additional transiting circumbinary planets: Kepler-34 (AB)b and Kepler-35 (AB)b, referred to here as Kepler-34 b and Kepler-35 b, respectively. Each is a low-density gas-giant planet on an orbit closely aligned with that of its parent stars. Kepler-34 b orbits two Sun-like stars every 289?days, whereas Kepler-35 b orbits a pair of smaller stars (89% and 81% of the Sun's mass) every 131?days. The planets experience large multi-periodic variations in incident stellar radiation arising from the orbital motion of the stars. The observed rate of circumbinary planets in our sample implies that more than ~1% of close binary stars have giant planets in nearly coplanar orbits, yielding a Galactic population of at least several million. 相似文献
90.
Two Earth-sized planets orbiting Kepler-20 总被引:1,自引:0,他引:1
Fressin F Torres G Rowe JF Charbonneau D Rogers LA Ballard S Batalha NM Borucki WJ Bryson ST Buchhave LA Ciardi DR Désert JM Dressing CD Fabrycky DC Ford EB Gautier TN Henze CE Holman MJ Howard A Howell SB Jenkins JM Koch DG Latham DW Lissauer JJ Marcy GW Quinn SN Ragozzine D Sasselov DD Seager S Barclay T Mullally F Seader SE Still M Twicken JD Thompson SE Uddin K 《Nature》2012,482(7384):195-198
Since the discovery of the first extrasolar giant planets around Sun-like stars, evolving observational capabilities have brought us closer to the detection of true Earth analogues. The size of an exoplanet can be determined when it periodically passes in front of (transits) its parent star, causing a decrease in starlight proportional to its radius. The smallest exoplanet hitherto discovered has a radius 1.42 times that of the Earth's radius (R(⊕)), and hence has 2.9 times its volume. Here we report the discovery of two planets, one Earth-sized (1.03R(⊕)) and the other smaller than the Earth (0.87R(⊕)), orbiting the star Kepler-20, which is already known to host three other, larger, transiting planets. The gravitational pull of the new planets on the parent star is too small to measure with current instrumentation. We apply a statistical method to show that the likelihood of the planetary interpretation of the transit signals is more than three orders of magnitude larger than that of the alternative hypothesis that the signals result from an eclipsing binary star. Theoretical considerations imply that these planets are rocky, with a composition of iron and silicate. The outer planet could have developed a thick water vapour atmosphere. 相似文献