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991.
Tanaka K 《Bioscience, biotechnology, and biochemistry》2010,74(12):2367-2373
There is mounting evidence that replication defects are the major source of spontaneous genomic instability in cells, and that S-phase checkpoints are the principal defense against such instability. The S-phase checkpoint mediator protein Mrc1/Claspin mediates the checkpoint response to replication stress by facilitating phosphorylation of effector kinase by a sensor kinase. In this review, the multiple functions and the regulation of the S-phase checkpoint mediator are discussed. 相似文献
992.
Makoto Tanaka Kunikazu Tanji Motoko Niida Tetsu Kamitani 《Histochemistry and cell biology》2010,133(3):273-284
The RING-finger protein Ro52/TRIM21 is known as an autoantigen and is recognized by anti-Ro/SSA antibodies, which are commonly found in patients with Sjögren’s syndrome and systemic lupus erythematosus. Recently, Ro52 has been shown to localize to distinct structures called cytoplasmic bodies and function as an E3 ubiquitin ligase. However, the Ro52 cytoplasmic bodies have not been well characterized. In this study, we investigated the Ro52 cytoplasmic bodies using fluorescence microscopy. This analysis revealed that the Ro52 cytoplasmic bodies are diffusely located in the cytoplasm and exist independently of TRIM5α cytoplasmic bodies. Our results further showed that the Ro52 cytoplasmic bodies are not stained with MitoTracker dye and are not colocalized with the proteasome subunit Rpt5, the caveolae component caveolin-1, the endosome markers (EEA1, Rab5, and Rab7), and the lysosome marker LAMP2. These results indicate that the Ro52 cytoplasmic bodies are not mitochondria, proteasome-enriched structures, caveolae, endosomes, or lysosomes. Importantly, the Ro52 cytoplasmic bodies are highly motile and are located along the microtubule network. These results suggest that the Ro52 cytoplasmic bodies are unidentified structures that are transported along the microtubule network. 相似文献
993.
The RING-finger protein Ro52/TRIM21 is known to be an autoantigen and is recognized by anti-Ro/SSA antibodies, which are commonly found in patients with Sjögren’s syndrome and systemic lupus erythematosus. We recently showed that Ro52 is an E3 ubiquitin ligase and localizes to cytoplasmic bodies that are highly motile along the microtubule network. To expand our knowledge of Ro52, we searched partners co-operating with Ro52. We performed a yeast two-hybrid screening of a human brain cDNA library with Ro52 as bait. This screening identified several genes encoding Ro52-interacting proteins, including the apoptosis-related proteins, Daxx and FLASH. Further yeast two-hybrid assays revealed that Daxx binds to the B30.2 domain of Ro52 and that FLASH binds to coiled-coil domains of Ro52 through its death-effector domain-recruiting domain. These results suggest that Ro52, Daxx, and FLASH form heteromeric protein complexes. Indeed, this was supported by results of immunoprecipitation experiments in which we found that Daxx is co-immunoprecipitated with Ro52 in the presence of overexpressed FLASH. Importantly, our fluorescence microscopy revealed that, although Daxx is predominantly located in the nucleus, overexpression of both Ro52 and FLASH leads to relocation of Daxx into the cytoplasm. Thus, Ro52 seems to co-operate with FLASH to induce cytoplasmic localization of Daxx in cells. 相似文献
994.
Osami Shoji Takashi Fujishiro Shingo Nagano Shota Tanaka Takuya Hirose Yoshitsugu Shiro Yoshihito Watanabe 《Journal of biological inorganic chemistry》2010,15(8):1331-1339
Cytochrome P450BSβ, a H2O2-dependent cytochrome P450 catalyzing the hydroxylation of long-alkyl-chain fatty acids, lacks the general acid–base residue
around the heme, which is indispensable for the efficient generation of the active species using H2O2. On the basis of the crystal structure of the palmitic acid bound form of cytochrome P450BSβ, it was suggested that the role of the general acid–base function was provided by the carboxylate group of fatty acids. The
participation of the carboxylate group of the substrate was supported by the fact that cytochrome P450BSβ can catalyze oxidations of nonnatural substrates such as styrene and ethylbenzene in the presence of a series of short-alkyl-chain
carboxylic acids as a dummy molecule of fatty acid. We refer to a series of short-alkyl-chain carboxylic acids as a “decoy
molecule”. As shown here, we have clarified the crystal structure of the decoy-molecule-bound form and elucidated that the
location of its carboxylate group is virtually the same as that of palmitic acid in the heme cavity, indicating that the carboxylate
group of the decoy molecule serves as the general acid–base catalyst. This result further confirms that the role of the acid–base
function is satisfied by the carboxylate group of the substrates. In addition, the structure analysis of the substrate-free
form has clarified that no remarkable structural change is induced by the binding of the decoy molecule as well as fatty acid.
Consequently, whether the carboxylate group is positioned in the active site provides the switching mechanism of the catalytic
cycle of cytochrome P450BSβ. 相似文献
995.
996.
Objectives: Mathematical models are useful for studying vascular and avascular tumours, because these allow for more logical experimental design and provide valuable insights into the underlying mechanisms of their growth and development. The processes of avascular tumour growth and the development of capillary networks through tumour‐induced angiogenesis have already been extensively investigated, albeit separately. Despite the clinical significance of vascular tumours, few studies have combined these approaches to develop a single comprehensive growth and development model. Materials and methods: We develop a continuum‐based mathematical model of vascular tumour growth. In the model, angiogenesis is initiated through the release of angiogenic growth factors (AGFs) by cells in the hypoxic regions of the tumour. The nutrient concentration within the tumour reflects the influence of capillary growth and invasion induced by AGF. Results and conclusions: Parametric and sensitivity studies were performed to evaluate the influence of different model parameters on tumour growth and to identify the parameters with the most influence, which include the rates of proliferation, apoptosis and necrosis, as well as the diffusion of sprout tips and the size of the region affected by angiogenesis. An optimization was performed for values of the model parameters that resulted in the best agreement with published experimental data. The resulting model solution matched the experimental data with a high degree of correlation (r = 0.85). 相似文献
997.
Hiroki Shimizu Shinji Tanaka Tadashi Toki Isao Yasumatsu Toshihiko Akimoto Kaoru Morishita Tomonori Yamasaki Takanori Yasukochi Shin Iimura 《Bioorganic & medicinal chemistry letters》2010,20(17):5113-5118
Imidazo[1,2-b]pyridazine derivatives from high-throughput screening were developed as IKKβ inhibitors. By the optimization of the 3- and 6-position of imidazo[1,2-b]pyridazine scaffold, cell-free IKKβ inhibitory activity and TNFα inhibitory activity in THP-1 cell increased. Also, these compounds showed high kinase selectivity. The structure–activity relationship was revealed and the interaction model of imidazo[1,2-b]pyridazine compounds with IKKβ was constructed. 相似文献
998.
Tadao Takada Chie Tanaka Mitsunobu Nakamura Kazushige Yamana 《Bioorganic & medicinal chemistry letters》2010,20(3):994-996
The DNA base stack provides unique features for the efficient long-range charge transfer. For the purpose of investigating excess electron transfer process through DNA, we developed a new method for fluorescence analysis of excess electron transfer based on reductive cleavage of a disulfide bond and a thiol-specific fluorescent probe. Excess electron transfer was detected by monitoring the fluorescence of emissive pyrene monomer generated by the reaction of pyrene maleimides with the cleaved disulfide bond (thiols). Mechanism of reductive cleavage of disulfides through excess electron transfer and subsequent reaction with the fluorescent probes were discussed. This facile and sensitive detection by fluorescence method can be applied for mechanistic study of excess electron transfer. 相似文献
999.
Masaki Asada Tetsuo Obitsu Atsushi Kinoshita Yoshihiko Nakai Toshihiko Nagase Isamu Sugimoto Motoyuki Tanaka Hiroya Takizawa Ken Yoshikawa Kazutoyo Sato Masami Narita Shuichi Ohuchida Hisao Nakai Masaaki Toda 《Bioorganic & medicinal chemistry letters》2010,20(8):2639-2643
A series of novel N-acylsulfonamide analogs were synthesized and evaluated for their binding affinity and antagonist activity for the EP3 receptor subtype. Representative compounds were also evaluated for their inhibitory effect on PGE2-induced uterine contraction in pregnant rats. Among those tested, a series of N-acylbenzenesulfonamide analogs were found to be more potent than the corresponding carboxylic acid analogs in both the in vitro and in vivo evaluations. The structure activity relationships (SAR) are also discussed. 相似文献
1000.
Nobuhisa Ozaki Arigala Uma Ravi Sankar Mitsuji Yamashita Takashi Aoki Yasutaka Tanaka Motohiko Kimura Mitsuo Toda Michio Fujie Yasuo Takehara Harumi Sakahara 《Bioorganic & medicinal chemistry letters》2010,20(3):932-934
A new type of dendritic molecules Gd-DTPA-XDA-D1-Glc(OH), which work as a functionalized ligand coordinating gadolinium(III) ion at the center of their frameworks with two glucose moieties on the molecular surfaces, were readily synthesized with high yield. The structures were established by IR, 1H, 13C NMR, and mass spectral studies. Its bio-distribution patterns were evaluated on rats. 相似文献