全文获取类型
收费全文 | 21981篇 |
免费 | 1501篇 |
国内免费 | 9篇 |
专业分类
23491篇 |
出版年
2024年 | 19篇 |
2023年 | 126篇 |
2022年 | 311篇 |
2021年 | 580篇 |
2020年 | 351篇 |
2019年 | 471篇 |
2018年 | 593篇 |
2017年 | 478篇 |
2016年 | 810篇 |
2015年 | 1218篇 |
2014年 | 1344篇 |
2013年 | 1661篇 |
2012年 | 1948篇 |
2011年 | 1892篇 |
2010年 | 1175篇 |
2009年 | 1018篇 |
2008年 | 1378篇 |
2007年 | 1288篇 |
2006年 | 1181篇 |
2005年 | 1084篇 |
2004年 | 981篇 |
2003年 | 929篇 |
2002年 | 753篇 |
2001年 | 122篇 |
2000年 | 108篇 |
1999年 | 141篇 |
1998年 | 127篇 |
1997年 | 116篇 |
1996年 | 90篇 |
1995年 | 87篇 |
1994年 | 93篇 |
1993年 | 90篇 |
1992年 | 55篇 |
1991年 | 58篇 |
1990年 | 62篇 |
1989年 | 48篇 |
1988年 | 53篇 |
1987年 | 38篇 |
1986年 | 43篇 |
1985年 | 52篇 |
1984年 | 39篇 |
1983年 | 44篇 |
1982年 | 32篇 |
1981年 | 42篇 |
1980年 | 27篇 |
1979年 | 34篇 |
1978年 | 32篇 |
1977年 | 29篇 |
1976年 | 25篇 |
1975年 | 22篇 |
排序方式: 共有10000条查询结果,搜索用时 8 毫秒
931.
Byth KF Cooper N Culshaw JD Heaton DW Oakes SE Minshull CA Norman RA Pauptit RA Tucker JA Breed J Pannifer A Rowsell S Stanway JJ Valentine AL Thomas AP 《Bioorganic & medicinal chemistry letters》2004,14(9):2249-2252
Modification of imidazo[1,2-a]pyridine CDK inhibitors lead to identification of less lipophilic imidazo[1,2-b]pyridazine series of CDK inhibitors. Although several equivalent compounds from these two series have similar structure and show similar CDK activity, the SAR of the two series differs significantly. Protein inhibitor structure determination has confirmed differences in binding mode and given some understanding of these differences in SAR. Potent and selective imidazo[1,2-b]pyridazine inhibitors of CDK2 have been identified, which show >1 microM plasma levels following a 2mg/kg oral dose to mice. 相似文献
932.
Cusack KP Arnold LD Barberis CE Chen H Ericsson AM Gaza-Bulseco GS Gordon TD Grinnell CM Harsch A Pellegrini M Tarcsa E 《Bioorganic & medicinal chemistry letters》2004,14(22):5503-5507
Compounds that contain an alpha,beta-unsaturated carbonyl moiety are often flagged as potential Michael acceptors. All alpha,beta-unsaturated carbonyl moieties are not equivalent, however, and we sought to better understand this system and its potential implications in drug-like molecules. Measurement of the (13)C NMR shift of the beta-carbon and correlation to in vitro results allowed compounds in our collection to be categorized as potential Michael acceptors, potential substrates for NADPH, or as photoisomerizable. 相似文献
933.
Werstuck GH Kim AJ Brenstrum T Ohnmacht SA Panna E Capretta A 《Bioorganic & medicinal chemistry letters》2004,14(22):5465-5467
A family of compounds based upon the chemical structure of valproate were synthesized and assayed for their ability to inhibit glycogen synthase kinase (GSK)-3 alpha and beta activity in vitro. This data is correlated to the known anti-convulsant properties of these compounds in order to determine the potential role of GSK-3 inhibition in the therapeutic efficacy of these drugs. 相似文献
934.
Marked inhibition of retinal neovascularization in rats following soluble-flt-1 gene transfer 总被引:5,自引:0,他引:5
Rota R Riccioni T Zaccarini M Lamartina S Gallo AD Fusco A Kovesdi I Balestrazzi E Abeni DC Ali RR Capogrossi MC 《The journal of gene medicine》2004,6(9):992-1002
BACKGROUND: In mouse models of retinopathy of prematurity (ROP) inhibitors of vascular endothelial growth factor (VEGF) functions administered systemically completely block retinal neovascularization. In contrast, selective ocular VEGF depletion has achieved an approx. 50% inhibition of retinal neovascular growth. It is unclear whether a more complete inhibition of new blood vessel development can be obtained with an anti-VEGF therapy localized to the eye. Therefore, the objective of the present study was to determine the effect of local anti-VEGF therapy in a different animal model which closely mimics human ROP. METHODS: Rats were exposed to alternating cycles of high and low levels of oxygen for 14 days immediately after birth; thereafter, they were intravitreally injected with an adenoviral vector expressing a secreted form of the VEGF receptor flt-1 (Ad.sflt), which acts by sequestering VEGF. Contralateral eyes were injected with the control vector carrying the reporter gene expressing beta-galactosidase (Ad.betaGal). RESULTS: At the peak of retinal neovascular growth, i.e. post-natal day 21 (P21), we observed up to 97.5% decrease in retinal neovascularization in animals injected with Ad.sflt. At the end of observation (P28), no significant difference in retinal vessel number was detected in both oxygen-injured and normoxic Ad.sflt-treated retinas compared with untreated or Ad.betaGal-treated retinas. CONCLUSION: Adenoviral-mediated sflt-1 gene transfer induces a near-complete inhibition of ischemia-induced retinal neovascularization in rats without affecting pre-existing retinal vessels. 相似文献
935.
Drp-1-dependent division of the mitochondrial network blocks intraorganellar Ca2+ waves and protects against Ca2+-mediated apoptosis 总被引:8,自引:0,他引:8
By transiently or stably overexpressing the mitochondrial fission factor dynamin-related protein-1 (Drp-1), we evaluated the role of mitochondrial division in organelle Ca2+ homeostasis and apoptotic signaling. Quantitative 3D digital microscopy revealed a split mitochondrial network in Drp-1-overexpressing cells without changes in cell viability. High-speed mitochondrial [Ca2+] ([Ca2+]m) imaging revealed propagating intramitochondrial Ca2+ waves in intact cells, which were blocked in the Drp-1-fragmented network, leaving a fraction of individual mitochondria without substantial [Ca2+]m elevation. Consequently, in Drp-1-expressing cells the apoptotic efficacy of ceramide, which causes a Ca2+-dependent perturbation of mitochondrial structure and function, was drastically reduced. Conversely, the sensitivity to staurosporine-induced apoptosis, previously shown to be directly triggered by Drp-1-dependent recruitment of proapoptotic proteins to mitochondria, was enhanced. These results demonstrate that the regulated process of mitochondrial fusion and fission controls the spatiotemporal properties of mitochondrial Ca2+ responses and, thus, physiological and pathological consequences of cellular Ca2+ signals. 相似文献
936.
Soluble intercellular adhesion molecule-1 (sICAM-1): an overview 总被引:10,自引:0,他引:10
Soluble intercellular adhesion molecule-1 (sICAM-1) represents a circulating form of ICAM-1 that is constitutively expressed or is inducible on the cell surface of different cell lines. It serves as a counter-receptor for the lymphocyte function-associated antigen (LFA-1). Interaction between ICAM-1, present on endothelial cells, and LFA-1 facilitates leukocyte adhesion and migration across the endothelium. ICAM-1 and its circulating form have been implicated in the development of any number of diseases. 相似文献
937.
Only neutral polymorphisms found in the TIGR/myocilin gene of 45 Polish patients with primary open-angle glaucoma 总被引:1,自引:0,他引:1
Krawczyński MR Czarny-Ratajczak M Pecold K Latos-Bieleńska A 《Journal of applied genetics》2004,45(2):275-279
The aim of the study was to identify mutations of the TIGR gene in Polish patients with primary open-angle glaucoma (POAG) and to define possible genotype-phenotype correlations. The study included 45 patients with a verified diagnosis of POAG. The PCR amplification of all three exons of the TIGR gene and screening for the sequence changes by CSGE analysis was done for every patient. The probes with identified heteroduplexes were sequenced. Altogether 315 PCR products were obtained. The CSGE analysis detected 60 possible changes of the sequence in 28 patients. 34 heteroduplexes were chosen for sequencing, including 29 unique changes and 5 changes representative of identical heteroduplexes. Direct sequencing enabled detection of only four different changes in the TIGR gene sequence. Three of them: 5'UTR -83G-->A (in 14 patients), +227 exon 1 G-->A, Arg76Lys (in 14 patients) and +311 exon 3 T-->C, Tyr347Tyr (in 4 patients) have already been described in the literature as neutral polymorphisms of the gene. Only one change in the promoter, 5'UTR -126T-->C (in 2 patients), has not been described in the literature to date. However, this change does not alter directly the sequence of amino acids in myocilin, so it is difficult to conclude on its pathogenetic role. Thus our study showed only neutral polymorphisms of the TIGR gene. This suggests that the patients probably have mutations in other genes, so other loci that predispose to POAG must be analyzed. 相似文献
938.
939.
Szczerkowska-Dobosz A Rebała K Szczerkowska Z Witkowska-Toboła A 《Journal of applied genetics》2004,45(4):473-476
Psoriasis is a common skin disease with a genetic background and significant human leukocyte antigen (HLA) associations. HLA-Cw6 is the most frequently described association, particularly with psoriasis of the early onset type. Few studies of its correlation with various psoriasis clinical phenotypes and severity of the disease have been published so far; none in the Polish population. In this study 78 patients with psoriasis vulgaris were evaluated clinically and subdivided according to the age of onset and the type of psoriasis. A system of disease severity evaluation was applied to each patient. All patients and the control group (70 unrelated persons) were typed for HLA-Cw*06. The results show that Cw*06 allele frequency was higher in psoriatics than in the control group. Our investigation confirms that the Cw*06 allele is positively associated with psoriasis vulgaris of the early onset type, with a positive family history and its more severe form. 相似文献
940.