全文获取类型
收费全文 | 14993篇 |
免费 | 1392篇 |
国内免费 | 2308篇 |
出版年
2024年 | 28篇 |
2023年 | 257篇 |
2022年 | 384篇 |
2021年 | 977篇 |
2020年 | 778篇 |
2019年 | 877篇 |
2018年 | 756篇 |
2017年 | 585篇 |
2016年 | 775篇 |
2015年 | 1105篇 |
2014年 | 1360篇 |
2013年 | 1364篇 |
2012年 | 1671篇 |
2011年 | 1589篇 |
2010年 | 960篇 |
2009年 | 807篇 |
2008年 | 885篇 |
2007年 | 749篇 |
2006年 | 622篇 |
2005年 | 461篇 |
2004年 | 338篇 |
2003年 | 317篇 |
2002年 | 225篇 |
2001年 | 100篇 |
2000年 | 105篇 |
1999年 | 113篇 |
1998年 | 88篇 |
1997年 | 69篇 |
1996年 | 58篇 |
1995年 | 48篇 |
1994年 | 41篇 |
1993年 | 29篇 |
1992年 | 35篇 |
1991年 | 34篇 |
1990年 | 22篇 |
1989年 | 16篇 |
1988年 | 12篇 |
1987年 | 7篇 |
1986年 | 3篇 |
1985年 | 19篇 |
1984年 | 5篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1978年 | 2篇 |
1975年 | 1篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1965年 | 1篇 |
1938年 | 1篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Interferon- (IFN),4 a cytokine with modulatory activities on many cell types, is useful for treating many types of cancer and infectious diseases. This study investigates whether modification of a protein, using IFN as an example, with a lipophilic group can alter its distribution and kinetic properties in the body. Ser163 of IFN2a was mutated to Cys to generate a free sulfhydryl group for site-specific chemical modification. IFN2a(S163C) was conjugated by iodoacetamide derivatives of varying lengths, and the modified IFN2a was purified by gel filtration chromatography. The biological activities of IFN2a(S163C) and lipophilized IFN2a(S163C) were similar to that of IFN2a, as evidenced by their inhibitory effects on the growth of Daudi cells and on the replication of vesicular stomatitis virus in Madin-Darby bovine kidney cells. Lipophilized IFN2a(S163C) bound to human serum albumin and cell membranes more readily than did IFN2a. Future experiments will investigate whether lipophilized IFN2a(S163C) has improved pharmacokinetic properties. 相似文献
992.
Zhao L Cuff CA Moss E Wille U Cyrus T Klein EA Praticò D Rader DJ Hunter CA Puré E Funk CD 《The Journal of biological chemistry》2002,277(38):35350-35356
Targeted gene disruption or overexpression of 12/15-lipoxygenase in mice on the genetic background of apolipoprotein E or low density lipoprotein-receptor (LDL-R) deficiency has implicated 12/15-lipoxygenase in atherogenesis. The data support indirectly a role for 12/15-lipoxygenase in the oxidative modification of low density lipoprotein. In this study we set out to explore other potential mechanisms for 12/15-lipoxygenase in atherosclerosis using apolipoprotein B mRNA editing catalytic polypeptide-1/LDL-R double-deficient mice, a model highly related to the human condition of familial hypercholesterolemia. 12/15-Lipoxygenase deficiency in this strain led to approximately 50% decrease in aortic lesions in male and female mice at 8 months on a chow diet in the absence of cholesterol differences. While studying 12/15-lipoxygenase-deficient macrophages in culture, we discovered a remarkable selective defect (75-90% decrease) in interleukin-12 production but not in tumor necrosis factor-alpha or nitric oxide release, in response to lipopolysaccharide in the presence or absence of interferon-gamma priming. The lipopolysaccharide/interferon-gamma response was associated with a 33-50% decrease in nuclear interferon consensus sequence-binding protein, which is consistent with interferon consensus sequence-binding protein containing protein complex-dependent regulation of the interleukin-12 p40 gene. The decrease in interleukin-12 production was recapitulated in vivo in mouse aortas of the triple knockout group and was reflected in a marked decrease in interferon-gamma expression. The data provide support for a novel mechanism linking the 12/15-lipoxygenase pathway to a known immunomodulatory Th1 cytokine in atherogenesis. 相似文献
993.
994.
BLAST++ is a tool that is integrated with NCBI BLAST, allowing multiple, say K, queries to be searched against a database concurrently. The results obtained by BLAST++ are identical to that obtained by executing BLAST on each of the K queries, but BLAST++ completes the processing in a much shorter time. AVAILABILITY: http://xena1.ddns.comp.nus.edu.sg/~genesis/blast++ Supplementary information: http://xena1.ddns.comp.nus.edu.sg/~genesis/blast++ 相似文献
995.
Molecular anatomy of the DNA damage and replication checkpoints 总被引:12,自引:0,他引:12
Cell cycle checkpoints are signal transduction pathways that enforce the orderly execution of the cell division cycle and arrest the cell cycle upon the occurrence of undesirable events, such as DNA damage, replication stress, and spindle disruption. The primary function of the cell cycle checkpoint is to ensure that the integrity of chromosomal DNA is maintained. DNA lesions and disrupted replication forks are thought to be recognized by the DNA damage checkpoint and replication checkpoint, respectively. Both checkpoints initiate protein kinase-based signal transduction cascade to activate downstream effectors that elicit cell cycle arrest, DNA repair, or apoptosis that is often dependent on dose and cell type. These actions prevent the conversion of aberrant DNA structures into inheritable mutations and minimize the survival of cells with unrepairable damage. Genetic components of the damage and replication checkpoints have been identified in yeast and humans, and a working model is beginning to emerge. We summarize recent advances in the DNA damage and replication checkpoints and discuss the essential functions of the proteins involved in the checkpoint responses. 相似文献
996.
Twelve 17-(2'-oxazolyl)- and 17-(2'-thiazolyl)-androsta-5,16-diene derivatives were designed and synthesized from 3 beta-acetoxy-pregna-5,16-dien-20-one (1b) as inhibitors of 17 alpha-hydroxylase-C(17,20)-lyase (P450(17 alpha)). Potent inhibitors of this enzyme could be of value as treatment of prostate cancer. Two substituents (methyl and phenyl) were introduced either at their 4'- or 5'-position in order to investigate their structure-activity relationship. Due to the 16,17-double bond, 17-thiazoles were generally obtained in low yield. The pharmacological results showed that the compounds containing 17-(2'-oxazolyl) (14c) and 17-(2'-thiazolyl) (8c) (41.5%) demonstrated reasonable inhibition against P450(17 alpha). Their 3-acetate (13c and 7c) were less potent than their 3-OH counterparts. The introduction of a phenyl or methyl group generally decreased inhibitory activity. Surprisingly, 17-(5'-methyl-2'-thiazolyl) (12a) was the most potent compound in this series and was almost as potent as L-39, which has good antitumor activity. 相似文献
997.
998.
999.
Phytase enzymology, applications, and biotechnology 总被引:13,自引:1,他引:12
Phytases are phosphohydrolases that initiate the step-wise removal of phosphate from phytate. These enzymes have been widely used in animal feeding to improve phosphorus nutrition and to reduce phosphorus pollution of animal waste. The potential of phytases in improving human nutrition of essential trace minerals in plant-derived foods is being explored. This review covers the basic biochemistry and application of phytases, and emphasizes the emerging biotechnology used for developing new effective phytases with improved properties. 相似文献
1000.
Li Y Yu WH Ren J Chen W Huang L Kharbanda S Loda M Kufe D 《Molecular cancer research : MCR》2003,1(10):765-775
The DF3/MUC1 transmembrane oncoprotein is aberrantly overexpressed in most human breast carcinomas and interacts with the Wnt effector gamma-catenin. Here, we demonstrate that MUC1 associates constitutively with ErbB2 in human breast cancer cells and that treatment with heregulin/neuregulin-1 (HRG) increases the formation of MUC1-ErbB2 complexes. The importance of the MUC1-ErbB2 interaction is supported by the demonstration that HRG induces binding of MUC1 and gamma-catenin and targeting of the MUC1-gamma-catenin complex to the nucleolus. Significantly, nucleolar localization of gamma-catenin in response to HRG is dependent on MUC1 expression. Moreover, mutation of a RRK motif in the MUC1 cytoplasmic domain abrogates HRG-induced nucleolar localization of MUC1 and gamma-catenin. In concert with these results, we show nucleolar localization of MUC1 and gamma-catenin in human breast carcinomas but not in normal mammary ductal epithelium. These findings demonstrate that MUC1 functions in cross talk between ErbB2 and Wnt pathways by acting as a shuttle for HRG-induced nucleolar targeting of gamma-catenin. 相似文献