全文获取类型
收费全文 | 1105篇 |
免费 | 67篇 |
出版年
2022年 | 11篇 |
2021年 | 12篇 |
2020年 | 5篇 |
2019年 | 7篇 |
2018年 | 21篇 |
2017年 | 13篇 |
2016年 | 23篇 |
2015年 | 33篇 |
2014年 | 43篇 |
2013年 | 107篇 |
2012年 | 73篇 |
2011年 | 77篇 |
2010年 | 30篇 |
2009年 | 29篇 |
2008年 | 61篇 |
2007年 | 64篇 |
2006年 | 48篇 |
2005年 | 41篇 |
2004年 | 54篇 |
2003年 | 41篇 |
2002年 | 47篇 |
2001年 | 29篇 |
2000年 | 23篇 |
1999年 | 22篇 |
1998年 | 6篇 |
1996年 | 6篇 |
1995年 | 7篇 |
1993年 | 8篇 |
1992年 | 17篇 |
1991年 | 16篇 |
1990年 | 11篇 |
1989年 | 25篇 |
1988年 | 19篇 |
1987年 | 17篇 |
1986年 | 14篇 |
1985年 | 6篇 |
1984年 | 8篇 |
1983年 | 6篇 |
1982年 | 5篇 |
1980年 | 4篇 |
1979年 | 10篇 |
1977年 | 10篇 |
1976年 | 6篇 |
1975年 | 4篇 |
1974年 | 4篇 |
1973年 | 5篇 |
1972年 | 5篇 |
1971年 | 8篇 |
1970年 | 8篇 |
1966年 | 3篇 |
排序方式: 共有1172条查询结果,搜索用时 906 毫秒
961.
Kazuhiko Iikubo Kazuo Kurosawa Takahiro Matsuya Yutaka Kondoh Akio Kamikawa Ayako Moritomo Yoshinori Iwai Hiroshi Tomiyama Itsuro Shimada 《Bioorganic & medicinal chemistry》2019,27(8):1683-1692
Echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) is a valid therapeutic target for the treatment of EML4–ALK-positive non-small cell lung cancer (NSCLC). We discovered 12c as a novel and potent EML4–ALK inhibitor through structural optimization of 5a. In mice xenografted with 3T3 cells expressing EML4–ALK, oral administration of 12c demonstrated potent antitumor activity. This article describes the synthesis and biological evaluation of pyrazine-2-carboxamide derivatives along with studies of their structure–activity relationship (SAR) using computational modeling. 相似文献
962.
TNF-alpha drives human CD14+ monocytes to differentiate into CD70+ dendritic cells evoking Th1 and Th17 responses 总被引:3,自引:0,他引:3
Iwamoto S Iwai S Tsujiyama K Kurahashi C Takeshita K Naoe M Masunaga A Ogawa Y Oguchi K Miyazaki A 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(3):1449-1457
Many mechanisms involving TNF-alpha, Th1 responses, and Th17 responses are implicated in chronic inflammatory autoimmune disease. Recently, the clinical impact of anti-TNF therapy on disease progression has resulted in re-evaluation of the central role of this cytokine and engendered novel concept of TNF-dependent immunity. However, the overall relationship of TNF-alpha to pathogenesis is unclear. Here, we demonstrate a TNF-dependent differentiation pathway of dendritic cells (DC) evoking Th1 and Th17 responses. CD14(+) monocytes cultured in the presence of TNF-alpha and GM-CSF converted to CD14(+) CD1a(low) adherent cells with little capacity to stimulate T cells. On stimulation by LPS, however, they produced high levels of TNF-alpha, matrix metalloproteinase (MMP)-9, and IL-23 and differentiated either into mature DC or activated macrophages (M phi). The mature DC (CD83(+) CD70(+) HLA-DR (high) CD14(low)) expressed high levels of mRNA for IL-6, IL-15, and IL-23, induced naive CD4 T cells to produce IFN-gamma and TNF-alpha, and stimulated resting CD4 T cells to secret IL-17. Intriguingly, TNF-alpha added to the monocyte culture medium determined the magnitude of LPS-induced maturation and the functions of the derived DC. In contrast, the M phi (CD14(high)CD70(+)CD83(-)HLA-DR(-)) produced large amounts of MMP-9 and TNF-alpha without exogenous TNF stimulation. These results suggest that the TNF priming of monocytes controls Th1 and Th17 responses induced by mature DC, but not inflammation induced by activated M phi. Therefore, additional stimulation of monocytes with TNF-alpha may facilitate TNF-dependent adaptive immunity together with GM-CSF-stimulated M phi-mediated innate immunity. 相似文献
963.
Dynamic reorganization of photosystems I and II is suggested to occur in chloroplast thylakoid membranes to maintain the efficiency of photosynthesis under fluctuating light conditions. To directly observe the process in action, live-cell imaging techniques are necessary. Using live-cell imaging, we have shown that the fine thylakoid structures in the moss Physcomitrella patens are flexible in time. However, the spatiotemporal resolution of a conventional confocal microscopy limits more precise visualization of entire thylakoid structures and understanding of the structural dynamics. Here, we discuss the issues related to observing chlorophyll fluorescence at multiple spatiotemporal scales in vivo and in vitro. 相似文献
964.
Bent structures are formed in DNA by the binding of small molecules or proteins. We developed a chemical method to detect bent DNA structures. Oligonucleotide duplexes in which two mercaptoalkyl groups were attached to the positions facing each other across the major groove were prepared. When the duplex contained the cisplatin adduct, which was proved to induce static helix bending, interstrand disulfide bond formation under an oxygen atmosphere was detected by HPLC analyses, but not in the non-adducted duplex, when the two thiol-tethered nucleosides were separated by six base pairs. When the insert was five and seven base pairs, the disulfide bond was formed and was not formed, respectively, regardless of the cisplatin adduct formation. The same reaction was observed in the duplexes containing an abasic site analog and the (6–4) photoproduct. Compared with the cisplatin case, the disulfide bond formation was slower in these duplexes, but the reaction rate was nearly independent of the linker length. These results indicate that dynamic structural changes of the abasic site- and (6–4) photoproduct-containing duplexes could be detected by our method. It is strongly suggested that the UV-damaged DNA-binding protein, which specifically binds these duplexes and functions at the first step of global-genome nucleotide excision repair, recognizes the easily bendable nature of damaged DNA. 相似文献
965.
Large-scale synthesis of oligoribonucleotides has been performed successfully on a solid support by the phosphoramidite approach using levulinyl and tetrahydrofuranyl protection for the 5'- and 2'-hydroxyl groups respectively. A hexamer containing inosine and four fragments of a hammerhead-type ribozyme have been synthesized on a 10 mumol scale for structural studies by NMR spectroscopy and X-ray crystallography. 相似文献
966.
The amounts and isomeric structures of free oligosaccharides derived from N-linked sugar chains present in the cytosol fraction of perfused mouse liver were analyzed by tagging the reducing end with 2-aminopyridine followed by 2-dimensional HPLC mapping with standard sugar chains. Sixteen pyridylaminated (PA-) oligomannosides terminating with a PA-GlcNAc residue (GN1-type), three glucose-containing oligomannosides, and four oligomannosides terminating with a PA-di-N-acetylchitobiose (GN2-type) were detected. The total contents of the GN1- and GN2-type oligomannosides were 3. 4 and 0.5 nmol, respectively, per gram of wet tissue. Maltooligosaccharides (dimer to pentamer) were also detected, the total content of which was 13 nmol per gram of wet tissue. Besides these oligosaccharides, a PA-disialobiantennary sugar chain-the sole complex-type sugar chain-was also detected. All the oligomannosides identified had partial structures of Glc(3)Man(9)GlNAc(2)-p-p-dolichol, revealing that they were metabolic degradation products. Manalpha1-2Manalpha1-2Manalpha1-3(Manalpha1-6)++ +Manbeta1-4GlcNAc (M5B') was the major oligomannoside, suggesting that cytosolic endo-beta-N-acetylglucosaminidase and neutral alpha-mannosidase participate in the degradation, because these enzymes have suitable substrate specificities for the production of M5B'. Degradation by these enzymes seems to be the main pathway by which oligomannosides are degraded in mouse cytosol; however, small amounts of Manalpha1-6(Manalpha1-3)Manalpha1-6(Manalpha1-3) Manbeta1-4(GlcNAc)1-2 and related oligomannosides together with parts of their structures were also detected, suggesting that there is another minor route by which cytosolic free oligomannosides are produced. 相似文献
967.
968.
Keiichi Ikeda B Yukihiro Hiraoka Hideaki Iwai Takashi Matsumoto Reiko Mineki Hikari Taka Kenji Takamori Hideoki Ogawa Fumiyuki Yamakura 《Nitric oxide》2007,16(1):18-28
We have previously reported on the formation of 6-nitrotryptophan by the reaction of reactive nitrogen species with a tryptophan residue in human Cu, Zn-superoxide dismutase (SOD) (F. Yamakura et al., J. Biochem. 138 (2005) 57-69). Here, we report on the preparation of anti-6-nitrotryptophan antiserum by using synthesized 6-nitrotryptophan-conjugated keyhole limpet hemocyanin as an antigen and the purification of the antibody by using a 6-nitrotryptophan-conjugated affinity column. The purified antibody was immunoreactive with 6-nitrotryptophan residue containing Cu, Zn-SOD but not immunoreactive with Cu, Zn-SOD, Mn-SOD, bovine serum albumin, and 3-nitrotyrosine residue containing Mn-SOD. Nitro group of 6-nitrotryptophan was reduced by sodium hydrosulfite to form 6-aminotryptophan as a major product. The reduced 6-nitrotryptophan residues lost its immunoreactivity with the antibody. We detected different immunoreactive bands between using antibody for 6-nitrotryptophan residues and that for 3-nitrotyrosine residues in crude extracts of neuron-like PC12 cells treated with peroxynitrite by a Western blot analysis. Western blot analysis for two-dimensional gel electrophoresis showed nine intensively stained immunoreactive spots for 6-nitrotryptophan residues in the peroxynitrite-treated PC12 cells, which were subjected to trypsin digestion and LC-ESI-MS/MS analysis. We identified M2 pyruvate kinase, elongation factor 2, mitochondrial aconitase, pyruvate carboxylase, and heat shock protein HSP90alpha as candidates for 6-nitrotryptophan residues containing proteins, with peptide coverage over 10%, in crude extracts of peroxynitrite-treated PC12 cells. 相似文献
969.
Spontaneous arthritis was found in 19 of 55 Rowett hooded strain rats with rnu gene. Most cases were in the male rnu/rnu (15/19) but a few occurred in the male rnu/+ (3/10) and female rnu/rnu (1/8). The lesions were first noted as reddened swelling due to exudative inflammation of periarticular soft tissues including synovial membranes in the tarsal and/or carpal joints. Most of the affected animals cured leaving slight induration but in a few male rnu/rnu ankylosis with pannus formation and exostosis developed. No sign of mycoplasmal or bacterial infection was noticed in the colony. 相似文献
970.
Studies on nucleic acid interactions. I. Stabilities of mini-duplexes (dG2A4XA4G2-dC2T4YT4C2) and self-complementary d(GGGAAXYTTCCC) containing deoxyinosine and other mismatched bases. 总被引:19,自引:15,他引:4
下载免费PDF全文
![点击此处可从《Nucleic acids research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The thermal stability of DNA duplexes containing deoxyinosine in a pairing position in turn with each of the four major deoxynucleotides has been investigated by measuring ultraviolet-absorbance at different temperatures. d(G2A4 X A4G2) and d(C2T4YT4C2) were prepared by the solid-phase phosphotriester method. When X is deoxyinosine, the Tm values of the duplexes are in the order Y = dC greater than dA greater than dG greater than dT greater than dU. The Tm of other duplexes containing dG, dA and dT at X were also measured. Self-complementary duplexes d(GGGAAINTTCCC) showed the same order of stability with N being dC, dA, dG and dT. Thermal stabilities of duplexes containing dG instead of dI were compared with other matched and mismatched duplexes. The Tm values of sequence isomers containing purine-pyrimidine combinations were compared. Self-complementary duplexes containing G-C and A-T in the central positions showed Tm values ca. 10 degrees higher than those containing C-G and T-A in the same positions. Thermodynamic parameters and circular dichroism spectra of these oligonucleotides were compared. 相似文献