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91.
Hana Nůsková Marek Vrbacký Zdeněk Drahota Josef Houštěk 《Journal of bioenergetics and biomembranes》2010,42(5):395-403
The mechanism of cyanide’s inhibitory effect on the mitochondrial cytochrome c oxidase (COX) as well as the conditions for its recovery have not yet been fully explained. We investigated three parameters
of COX function, namely electron transport (oxygen consumption), proton transport (mitochondrial membrane potential Δψ
m) and the enzyme affinity to oxygen (p
50
value) with regard to the inhibition by KCN and its reversal by pyruvate. 250 μM KCN completely inhibited both the electron
and proton transport function of COX. The inhibition was reversible as demonstrated by washing of mitochondria. The addition
of 60 mM pyruvate induced the maximal recovery of both parameters to 60–80% of the original values. When using low KCN concentrations
of up to 5 μM, we observed a profound, 30-fold decrease of COX affinity for oxygen. Again, this decrease was completely reversed
by washing mitochondria while pyruvate induced only a partial, yet significant recovery of oxygen affinity. Our results demonstrate
that the inhibition of COX by cyanide is reversible and that the potential of pyruvate as a cyanide poisoning antidote is
limited. Importantly, we also showed that the COX affinity for oxygen is the most sensitive indicator of cyanide toxic effects. 相似文献
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David Pincus Michael W. Chevalier Tomás Aragón Eelco van Anken Simon E. Vidal Hana El-Samad Peter Walter 《PLoS biology》2010,8(7)
The unfolded protein response (UPR) is an intracellular signaling pathway that counteracts variable stresses that impair protein folding in the endoplasmic reticulum (ER). As such, the UPR is thought to be a homeostat that finely tunes ER protein folding capacity and ER abundance according to need. The mechanism by which the ER stress sensor Ire1 is activated by unfolded proteins and the role that the ER chaperone protein BiP plays in Ire1 regulation have remained unclear. Here we show that the UPR matches its output to the magnitude of the stress by regulating the duration of Ire1 signaling. BiP binding to Ire1 serves to desensitize Ire1 to low levels of stress and promotes its deactivation when favorable folding conditions are restored to the ER. We propose that, mechanistically, BiP achieves these functions by sequestering inactive Ire1 molecules, thereby providing a barrier to oligomerization and activation, and a stabilizing interaction that facilitates de-oligomerization and deactivation. Thus BiP binding to or release from Ire1 is not instrumental for switching the UPR on and off as previously posed. By contrast, BiP provides a buffer for inactive Ire1 molecules that ensures an appropriate response to restore protein folding homeostasis to the ER by modulating the sensitivity and dynamics of Ire1 activity. 相似文献
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Toxoplasma is parasite of cats that uses any warm-blooded animals as intermediate hosts. It is known to induce shifts in behavior, physiology and even morphology of its intermediate hosts, including humans. The lower second to fourth digit ratio (2D:4D ratio) in infected man and women, and higher height in infected man suggest that sex steroid hormones like testosterone could play a role in these shifts. Here, we searched for another indirect indication for a higher postnatal testosterone level, i.e. increased perceived dominance and masculinity in infected men. We showed portrait pictures of 89 male students of which 18 were Toxoplasma-infected to 109 female students. When we statistically corrected for age, men with latent toxoplasmosis were perceived as more dominant (p=0.009) and masculine (p=0.052). These results support the idea that the higher level of testosterone could be responsible for at least some of the toxoplasmosis-associated shifts in human and animal behavior. 相似文献
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Baek JH Im H Kang UB Seong KM Lee C Kim J Yu MH 《Protein science : a publication of the Protein Society》2007,16(9):1842-1850
The native form of serpins (serine protease inhibitors) is a metastable conformation, which converts into a more stable form upon complex formation with a target protease. It has been suggested that movement of helix-F (hF) and the following loop connecting to strand 3 of beta-sheet A (thFs3A) is critical for such conformational change. Despite many speculations inferred from analysis of the serpin structure itself, direct experimental evidence for the mobilization of hF/thFs3A during the inhibition process is lacking. To probe the mechanistic role of hF and thFs3A during protease inhibition, a disulfide bond was engineered in alpha(1)-antitrypsin, which would lock the displacement of thFs3A from beta-sheet A. We measured the inhibitory activity of each disulfide-locked mutant and its heat stability against loop-sheet polymerization. Presence of a disulfide between thFs3A and s5A but not between thFs3A and s3A caused loss of the inhibitory activity, suggesting that displacement of hF/thFs3A from strand 5A but not from strand 3A is required during the inhibition process. While showing little influence on the inhibitory activity, the disulfide between thFs3A and s3A retarded loop-sheet polymerization significantly. This successful protein engineering of alpha(1)-antitrypsin is expected to be of value in clinical applications. Based on our current studies, we propose that the reactive-site loop of a serpin glides through between s5A and thFs3A for the full insertion into beta-sheet A while a substantial portion of the interactions between hF and s3A is kept intact. 相似文献