全文获取类型
收费全文 | 2322篇 |
免费 | 233篇 |
国内免费 | 5篇 |
出版年
2023年 | 12篇 |
2022年 | 30篇 |
2021年 | 44篇 |
2020年 | 21篇 |
2019年 | 24篇 |
2018年 | 42篇 |
2017年 | 34篇 |
2016年 | 66篇 |
2015年 | 97篇 |
2014年 | 100篇 |
2013年 | 115篇 |
2012年 | 184篇 |
2011年 | 164篇 |
2010年 | 113篇 |
2009年 | 115篇 |
2008年 | 113篇 |
2007年 | 118篇 |
2006年 | 81篇 |
2005年 | 77篇 |
2004年 | 96篇 |
2003年 | 76篇 |
2002年 | 65篇 |
2001年 | 81篇 |
2000年 | 65篇 |
1999年 | 59篇 |
1998年 | 21篇 |
1997年 | 22篇 |
1996年 | 18篇 |
1995年 | 11篇 |
1994年 | 14篇 |
1993年 | 17篇 |
1992年 | 41篇 |
1991年 | 27篇 |
1990年 | 28篇 |
1989年 | 43篇 |
1988年 | 30篇 |
1987年 | 28篇 |
1986年 | 14篇 |
1985年 | 26篇 |
1984年 | 20篇 |
1983年 | 14篇 |
1982年 | 15篇 |
1981年 | 15篇 |
1980年 | 22篇 |
1979年 | 35篇 |
1978年 | 20篇 |
1977年 | 11篇 |
1976年 | 11篇 |
1974年 | 24篇 |
1973年 | 14篇 |
排序方式: 共有2560条查询结果,搜索用时 15 毫秒
211.
Among 21 human strains of Laribacter hongkongensis, small plasmids were observed in four strains, and large ones in six strains. The smallest, 3264-bp plasmid, pHLHK19, has only one ORF that encodes a putative replication initiator protein and a predicted origin of replication (ori) with a DnaA box, three 18-bp direct repeats and five pairs of inverted repeats. An Escherichia coli-L. hongkongensis shuttle vector was constructed by ligating the HindIII-digested pHLHK19, containing the replication initiator protein and ori of pHLHK19, to HindIII-digested pBK-CMV. This shuttle vector can propagate in E. coli and L. hongkongensis with good transformation efficiencies. 相似文献
212.
Chen YX Man K Ling GS Chen Y Sun BS Cheng Q Wong OH Lo CK Ng IO Chan LC Lau GK Lin CL Huang F Huang FP 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(9):6009-6015
The dendritic cell (DC)-based tumor immunotherapy has been a new promise of cure for cancer patients, but animal studies and clinical trials have thus far only shown limited success, especially in treating established tumors. Certain immunosuppressive mechanisms triggered by tumor cells or the derivatives are believed to be a major obstacle. We studied the role of DC-derived IL-10 and its negative impact on vaccine efficacy in mouse models. Liver tumor cells were injected via the portal vein, giving rise to disseminated intrahepatic tumors, or s.c. to form solid but extrahepatic tumors. Bone marrow-derived DCs were generated from normal or IL-10-deficient mice and used as the vector to deliver tumor Ags. We demonstrate here that DCs devoid of IL-10, a potent immunosuppressive cytokine, are superior over conventional DCs in triggering antitumor immunity. The IL-10(-/-)DCs were highly immunogenic, expressed enhanced levels of surface MHC class II molecules, and secreted increased amounts of Th1-related cytokines. By inducing tumor-specific killing and through the establishment of immunological memory, the vaccines delivered by IL-10(-/-)DCs could evoke strong therapeutic and protective immunity against hepatocellular carcinoma in the mouse models. These findings will have great clinical impact once being translated into the treatment of malignant, and potentially infectious, diseases in humans. 相似文献
213.
214.
215.
The β-sheet plaques that are the most obvious pathological feature of Alzheimer's disease are composed of amyloid-β peptides and are highly enriched in the metal ions Zn, Fe and Cu. The interaction of the full-length amyloid peptide, Aβ(1-42), with phospholipid lipid bilayers was studied in the presence of the metal-chelating drug, Clioquinol (CQ). The effect of cholesterol and metal ions was also determined using solid-state 31P and 2H NMR. CQ modulated the effect of metal ions on the integrity of the bilayer and although CQ perturbed the phospholipid membrane, the bilayer integrity was maintained. Model membranes enriched in cholesterol were studied under conditions of peptide association and incorporation. Solid-state NMR showed that the bilayer integrity was preserved in cholesterol-enriched membranes in comparison to phosphatidylcholine-phosphatidylserine bilayers. Changes in peptide structure, consistent with an increase in β-sheet, were observed using specifically 13C-labelled Aβ(1-42) by magic angle spinning NMR. Results using aligned phosphatidylcholine bilayers and completely 15N-labelled peptide indicated that the peptide aggregated. The results are consistent with oligomeric β-sheet structured peptides only partially penetrating the bilayer and cholesterol reducing the membrane disruption. 相似文献
216.
Teng M Johnson MD Thomas C Kiel D Lakis JN Kercher T Aytes S Kostrowicki J Bhumralkar D Truesdale L May J Sidelman U Kodra JT Jørgensen AS Olesen PH de Jong JC Madsen P Behrens C Pettersson I Knudsen LB Holst JJ Lau J 《Bioorganic & medicinal chemistry letters》2007,17(19):5472-5478
Following our previous publication describing the biological profiles, we herein describe the structure-activity relationships of a core set of quinoxalines as the hGLP-1 receptor agonists. The most potent and efficacious compounds are 6,7-dichloroquinoxalines bearing an alkyl sulfonyl group at the C-2 position and a secondary alkyl amino group at the C-3 position. These findings serve as a valuable starting point for the discovery of more drug-like small molecule agonists for the hGLP-1 receptor. 相似文献
217.
Parker MF Barten DM Bergstrom CP Bronson JJ Corsa JA Deshpande MS Felsenstein KM Guss VL Hansel SB Johnson G Keavy DJ Lau WY Mock J Prasad CV Polson CT Sloan CP Smith DW Wallace OB Wang HH Williams A Zheng M 《Bioorganic & medicinal chemistry letters》2007,17(16):4432-4436
A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity. 相似文献
218.
Wang X Kolasa T El Kouhen OF Chovan LE Black-Shaefer CL Wagenaar FL Garton JA Moreland RB Honore P Lau YY Dandliker PJ Brioni JD Stewart AO 《Bioorganic & medicinal chemistry letters》2007,17(15):4303-4307
Our HTS effort yielded a preferential mGluR1 pyrimidinone antagonist 1 with lead-like characteristics. Rapid hit to lead (HTL) study identified compounds with improved functional activity and selectivity such as 1b with little improvements in ADME properties. Addition of an aminosulfonyl group on the N-1 aromatic ring led to 2f, a compound with similar in vitro biochemical profiles as those of 1b but drastically improved in vitro ADME properties. These improvements were paralleled by rat PK study characterized by low clearance and quantitative bioavailability. Compound 2f represented a true lead-like molecule that is amenable for further lead optimization (LO) evaluation. 相似文献
219.
Lo YM Tsui NB Chiu RW Lau TK Leung TN Heung MM Gerovassili A Jin Y Nicolaides KH Cantor CR Ding C 《Nature medicine》2007,13(2):218-223
Current methods for prenatal diagnosis of chromosomal aneuploidies involve the invasive sampling of fetal materials using procedures such as amniocentesis or chorionic villus sampling and constitute a finite risk to the fetus. Here, we outline a strategy for fetal chromosome dosage assessment that can be performed noninvasively through analysis of placental expressed mRNA in maternal plasma. We achieved noninvasive prenatal diagnosis of fetal trisomy 21 by determining the ratio between alleles of a single-nucleotide polymorphism (SNP) in PLAC4 mRNA, which is transcribed from chromosome 21 and expressed by the placenta, in maternal plasma. PLAC4 mRNA in maternal plasma was fetal derived and cleared after delivery. The allelic ratios in maternal plasma correlated with those in the placenta. Fetal trisomy 21 was detected noninvasively in 90% of cases and excluded in 96.5% of controls. 相似文献
220.
PIAS1 interacts with and represses SOX9 transactivation activity 总被引:1,自引:0,他引:1