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991.
Homocysteine (Hcy) metabolites, Hcy-thiolactone and N-Hcy-proteins, have been linked to the pathology of human cardiovascular and neurodegenerative diseases. Hcy-thiolactone is
generated in an error-editing reaction in protein biosynthesis when Hcy is selected in place of methionine by methionyl-tRNA
synthetase. N-Hcy-protein, in which Hcy is linked via isopeptide bond to ε-amino group of a protein lysine residue, forms in a post-translational
reaction of Hcy-thiolactone with proteins. Here, we identify a novel metabolite, Nε-Hcy-Lys, in human and mouse plasma, and show that this metabolite is elevated in genetic (cystathionine β-synthase deficiency
in humans and mice, methylenetetrahydrofolate reductase deficiency in mice) or dietary (high Met diet in mice) deficiencies
in Hcy metabolism. We also show that Nε-Hcy-Lys is generated by proteolytic degradation of N-Hcy-protein in mouse liver extracts. Our data indicate that free Nε-Hcy-Lys is an important pathology-related component of Hcy metabolism in humans and mice. 相似文献
992.
Song JK Kannan R Merdes G Singh J Mlodzik M Giniger E 《Development (Cambridge, England)》2010,137(21):3719-3727
Abl is an essential regulator of cell migration and morphogenesis in both vertebrates and invertebrates. It has long been speculated that the adaptor protein Disabled (Dab), which is a key regulator of neuronal migration in the vertebrate brain, might be a component of this signaling pathway, but this idea has been controversial. We now demonstrate that null mutations of Drosophila Dab result in phenotypes that mimic Abl mutant phenotypes, both in axon guidance and epithelial morphogenesis. The Dab mutant interacts genetically with mutations in Abl, and with mutations in the Abl accessory factors trio and enabled (ena). Genetic epistasis tests show that Dab functions upstream of Abl and ena, and, consistent with this, we show that Dab is required for the subcellular localization of these two proteins. We therefore infer that Dab is a bona fide component of the core Abl signaling pathway in Drosophila. 相似文献
993.
994.
Navjot S. Sodhi Tien Ming Lee Cagan H. Sekercioglu Edward L. Webb Dewi M. Prawiradilaga David J. Lohman Naomi E. Pierce Arvin C. Diesmos Madhu Rao Paul R. Ehrlich 《Biodiversity and Conservation》2010,19(4):1175-1188
Garnering support from local people is critical for maintaining ecologically viable and functional protected areas. However,
empirical data illustrating local people’s awareness of the importance of nature’s services is limited; hence possibly impeding
effective ecosystem (environmental)-services based conservation efforts. Using data from five protected forests in four developing
Southeast Asian countries, we provide evidence that local people living near parks value a wide range of environmental services,
including cultural, provisioning, and regulating services, provided by the forests. Local people with longer residency valued
environmental services more. Educated as well as poor people valued forest ecosystem services more. Conservation education
has some influence on people’s environmental awareness. For conservation endeavors to be successful, large-scale transmigration
programs should be avoided and local people must be provided with alternative sustenance opportunities and basic education
in addition to environmental outreach to reduce their reliance on protected forests and to enhance conservation support. 相似文献
995.
Edward W. Lowe Alysia Ferrebee Alice L. Rodriguez P. Jeffrey Conn Jens Meiler 《Bioorganic & medicinal chemistry letters》2010,20(19):5922-5924
Positive allosteric modulation of the metabotropic glutamate receptor subtype 5 was studied by conducting a comparative molecular field analysis on 118 benzoxazepine derivatives. The model with the best predictive ability retained significant cross-validated correlation coefficients of q2 = 0.58 (r2 = 0.81) yielding a standard error of 0.20 in pEC50 for this class of compounds. The subsequent contour maps highlight the structural features pertinent to the bioactivity values of benzoxazepines. 相似文献
996.
Bin Ma Kevin M. Guckian Edward Yin-Shiang Lin Wen-Cherng Lee Daniel Scott Gnanasambandam Kumaravel Timothy L. Macdonald Kevin R. Lynch Cheryl Black Sowmya Chollate Kyungmin Hahm Gregg Hetu Ping Jin Yi Luo Ellen Rohde Anthony Rossomando Robert Scannevin Joy Wang Chunhua Yang 《Bioorganic & medicinal chemistry letters》2010,20(7):2264-2269
Modifying FTY720, an immunosuppressant modulator, led to a new series of well phosphorylated tetralin analogs as potent S1P1 receptor agonists. The stereochemistry effect of tetralin ring was probed, and (?)-(R)-2-amino-2-((S)-6-octyl-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol was identified as a good SphK2 substrate and potent S1P1 agonist with good oral bioavailability. 相似文献
997.
Robert M. Tynebor Meng-Hsin Chen Swaminathan R. Natarajan Edward A. O’Neill James E. Thompson Catherine E. Fitzgerald Stephen J. O’Keefe James B. Doherty 《Bioorganic & medicinal chemistry letters》2010,20(9):2765-2769
The development and synthesis of potent p38α MAP kinase inhibitors containing a 2H-quinolizin-2-one platform is described. Evolution of the 2H-quinolizin-2-one series from an early lead to solving off target activity and pharmacokinetic issues is also discussed. 相似文献
998.
Robert R. Singhaus Ronald C. Bernotas Robert Steffan Edward Matelan Elaine Quinet Ponnal Nambi Irene Feingold Christine Huselton Anna Wilhelmsson Annika Goos-Nilsson Jay Wrobel 《Bioorganic & medicinal chemistry letters》2010,20(2):521-525
Replacement of a quinoline with an imidazo[1,2-a]pyridine in a series of liver X receptor (LXR) agonists incorporating a [3-(sulfonyl)aryloxyphenyl] side chain provided high affinity LXR ligands 7. In functional assays of LXR activity, good agonist potency and efficacy were found for several analogs. 相似文献
999.
Morshed A. Chowdhury Khaled R.A. Abdellatif Ying Dong Gang Yu Zhangjian Huang Moshfiqur Rahman Dipankar Das Carlos A. Velázquez Mavanur R. Suresh Edward E. Knaus 《Bioorganic & medicinal chemistry letters》2010,20(4):1324-1329
A new group of hybrid nitric oxide (NO) releasing anti-inflammatory (AI) coxib prodrugs (NO-coxibs) wherein the para-tolyl moiety present in celecoxib was replaced by a N-(4-nitrooxybutyl)piperidyl 15a–b, or N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl 17a–b, NO-donor moiety was synthesized. All compounds released a low amount of NO upon incubation with phosphate buffered saline (PBS) at pH 7.4 (2.4–5.8% range). In comparison, the percentage NO released was higher (3.1–8.4% range) when these nitrate prodrugs were incubated in the presence of l-cysteine. In vitro COX-1/COX-2 isozyme inhibition studies showed this group of compounds are moderately more potent, and hence selective, inhibitors of the COX-2 relative to the COX-1 enzyme. AI structure–activity relationship data acquired showed that compounds having a MeSO2 COX-2 pharmacophore exhibited superior AI activity compared to analogs having a H2NSO2 substituent. Compounds having a MeSO2 COX-2 pharmacophore in conjunction with a N-(4-nitrooxybutyl)piperidyl (ED50 = 132.4 mg/kg po), or a N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl (ED50 = 118.4 mg/kg po), moiety exhibited an AI potency profile that is similar to aspirin (ED50 = 128.7 mg/kg po) but lower than ibuprofen (ED50 = 67.4 mg/kg po). 相似文献
1000.
Edward G. Robins Yongjun Zhao Imtiaz Khan Anthony Wilson Sajinder K. Luthra Erik Årstad 《Bioorganic & medicinal chemistry letters》2010,20(5):1749-1751
Two S-[18F]fluoroalkylated diarylguanidines were synthesized and evaluated in vitro as potential tracers for imaging of N-methyl-d-aspartate receptors (NMDARs) with positron emission tomography (PET). [18F]1 and [18F]10 were synthesized by [18F]fluoroethylation and [18F]fluoromethylation of the thiol precursor 6, respectively. [18F]1 is a promising candidate NMDAR PET tracer, with low nanomolar affinity for the NMDA PCP-site, high selectivity and moderate lipophilicity. 相似文献