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981.
Guo T Gu H Hobbs DW Busler DE Rokosz LL 《Bioorganic & medicinal chemistry letters》2007,17(6):1718-1721
Melanin concentrating hormone (MCH) plays an important role in the regulation of food intake and energy balance in mammals. MCH-1 receptor (MCH1R) deficient mice are lean and resistant to diet-induced obesity. As such, MCH1R antagonists are believed to have potential as possible treatments for obesity. The discovery of a novel class of tetralin ureas as potent MCH1R antagonists is described herein. 相似文献
982.
Vajdos FF Hoth LR Geoghegan KF Simons SP LeMotte PK Danley DE Ammirati MJ Pandit J 《Protein science : a publication of the Protein Society》2007,16(5):897-905
Lasofoxifene is a new and potent selective estrogen receptor modulator (SERM). The structural basis of its interaction with the estrogen receptor has been investigated by crystallographic analysis of its complex with the ligand-binding domain of estrogen receptor alpha at a resolution of 2.0 A. As with other SERMs, lasofoxifene diverts the receptor from its agonist-bound conformation by displacing the C-terminal AF-2 helix into the site at which the LXXLL motif of coactivator proteins would otherwise be able to bind. Lasofoxifene achieves this effect by occupying the space normally filled by residue Leu 540, as well as by modulating the conformation of residues of helix 11 (His 524, Leu 525). A well-defined salt bridge between lasofoxifene and Asp 351 suggests that charge neutralization in this region of the receptor may explain the some of the antiestrogenic effects of lasofoxifene. The results suggest general features of ERalpha/SERM recognition, and add a new dimension to efforts to rationalize differences between the biological activity profiles exhibited by these important pharmacological agents. 相似文献
983.
When human cells are stressed during G2, they are delayed from entering mitosis via a checkpoint mediated by the p38 kinase, and this delay can be modeled by the selective activation of p38 with anisomycin. Here, we report, on the basis of live-cell studies, that 75 nM anisomycin transiently (1 hr) activates p38 which, in turn, rapidly and completely blocks entry into mitosis for at least 4 hr in all primary, telomerase- or spontaneously immortalized (p53+ and pRB+) human cells. However, the same treatment does not delay entry into mitosis in cancer cells, or the delay in entering mitosis is shortened, even though it induces a similar transient and comparable (or stronger) activation of p38. Because the primary substrate of p38, the MK2 kinase, is also transiently (1-2 hr) activated by anisomycin in both normal and cancer cells, checkpoint disruption in transformed cells occurs downstream of MK2. Finally, observations on isogenic lines reveal that the duration of the stress checkpoint is shortened in cells lacking both p53 and pRb and that the constitutive expression of an active H-Ras oncogene in these cells further attenuates the checkpoint via an ERK1/2-dependent manner. Thus, transformation leads to attenuation of the p38-mediated stress checkpoint. This outcome is likely selected for during transformation because it confers the ability to outgrow normal cells under stressful in vitro (culture) or in vivo (tumor) environments. Our data caution against using cancer cells to study how p38 produces a G2 arrest. 相似文献
984.
Dennis TE Rayner MJ Walker MM 《Proceedings. Biological sciences / The Royal Society》2007,274(1614):1153-1158
The influence of the Earth's magnetic field on locomotory orientation has been studied in many taxa but is best understood for homing pigeons (Columba livia). Effects of experimentally induced and naturally occurring perturbations in the geomagnetic field suggest that pigeons are sensitive to changes in geomagnetic parameters. However, whether pigeons use the Earth's magnetic field for position determination remains unknown. Here we report an apparent orientation to the intensity gradient of the geomagnetic field observed in pigeons homing from sites in and around a magnetic anomaly. From flight trajectories recorded by GPS-based tracking devices, we noted that many pigeons released at unfamiliar sites initially flew, in some cases up to several kilometres, in directions parallel and/or perpendicular to the bearing of the local intensity field. This behaviour occurred irrespective of the homeward direction and significantly more often than what was expected by random chance. Our study describes a novel behaviour which provides strong evidence that pigeons when homing detect and respond to spatial variation in the Earth's magnetic field--information of potential use for navigation. 相似文献
985.
Chazdon RL Letcher SG van Breugel M Martínez-Ramos M Bongers F Finegan B 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2007,362(1478):273-289
Rates of change in tree communities following major disturbances are determined by a complex set of interactions between local site factors, landscape history and structure, regional species pools and species life histories. Our analysis focuses on vegetation change following abandonment of agricultural fields or pastures, as this is the most extensive form of major disturbance in Neotropical forests. We consider five tree community attributes: stem density, basal area, species density, species richness and species composition. We describe two case studies, in northeastern Costa Rica and Chiapas, Mexico, where both chronosequence and annual tree dynamics studies are being applied. These case studies show that the rates of change in tree communities often deviate from chronosequence trends. With respect to tree species composition, sites of different ages differ more than a single site followed over time through the same age range. Dynamic changes in basal area within stands, on the other hand, generally followed chronosequence trends. Basal area accumulation was more linked with tree growth rates than with net changes in tree density due to recruitment and mortality. Stem turnover rates were poor predictors of species turnover rates, particularly at longer time-intervals. Effects of the surrounding landscape on tree community dynamics within individual plots are poorly understood, but are likely to be important determinants of species accumulation rates and relative abundance patterns. 相似文献
986.
Transition metal ions are required for many aspects of mitochondrial physiology. Copper, iron, manganese and zinc are cofactors
in metalloenzymes and metalloproteins within the organelle. Little is known how cells maintain optimal pools of these metal
ions for mitochondrial function. This review documents the available literature on mitochondrial metal ion pools and protein
metallation reactions. Upon perturbation in metal pools, mis-metallation reactions do occur. Thus, regulation of metal ion
accessibility and bioavailability must exist. 相似文献
987.
In vitro anti-mycobacterial activities of several 5-substituted acyclic pyrimidine nucleosides containing 1-(2-hydroxyethoxy)methyl and 1-[(2-hydroxy-1-(hydroxymethyl) ethoxy)methyl] acyclic moieties are investigated against three mycobacteria viz. Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium avium, which cause serious infections and mortality in healthy people as well as patients with AIDS. 1-(2-Hydroxyethoxy)methyl-5-(1-azido-2-haloethyl or 1-azidovinyl) analogs (4-7), 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-5-decynyluracil (37), and 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-5-dodecynyluracil (38) exhibited significant in vitro anti-tubercular activity against these mycobacteria. 相似文献
988.
989.
Modeling assisted rational design of novel, potent, and selective pyrrolopyrimidine DPP-4 inhibitors
Gao YD Feng D Sheridan RP Scapin G Patel SB Wu JK Zhang X Sinha-Roy R Thornberry NA Weber AE Biftu T 《Bioorganic & medicinal chemistry letters》2007,17(14):3877-3879
Molecular modeling was used to improve potency of the cyclohexylamine series. In addition, a 3-D QSAR method was used to gain insight for reducing off-target DPP-8/9 activities. Compounds 3, 4, and 5 were synthesized and found to be potent DPP-4 inhibitors, in particular 4 and 5 are designed to be highly selective against off-target DASH enzymes while maintaining potency on DPP-4. 相似文献
990.
Liang GB Qian X Feng D Fisher M Brown CM Gurnett A Leavitt PS Liberator PA Misura AS Tamas T Schmatz DM Wyvratt M Biftu T 《Bioorganic & medicinal chemistry letters》2007,17(13):3558-3561
Diaryl imidazo[1,2-a]pyridine derivatives, such as 6a and 7i, have been synthesized and found to be potent inhibitors of parasite PKG activity. The most potent compounds are the 7-isopropylaminomethyl analog 6a and 2-isopropylamino analog 7i. These compounds are also fully active in in vivo assay as anticoccidial agents at 25 ppm in feed. 相似文献