全文获取类型
收费全文 | 1233篇 |
免费 | 70篇 |
出版年
2021年 | 13篇 |
2020年 | 14篇 |
2018年 | 12篇 |
2017年 | 14篇 |
2016年 | 19篇 |
2015年 | 20篇 |
2014年 | 32篇 |
2013年 | 79篇 |
2012年 | 47篇 |
2011年 | 53篇 |
2010年 | 27篇 |
2009年 | 26篇 |
2008年 | 49篇 |
2007年 | 64篇 |
2006年 | 56篇 |
2005年 | 52篇 |
2004年 | 68篇 |
2003年 | 47篇 |
2002年 | 61篇 |
2001年 | 51篇 |
2000年 | 52篇 |
1999年 | 36篇 |
1998年 | 10篇 |
1997年 | 10篇 |
1996年 | 15篇 |
1995年 | 13篇 |
1994年 | 8篇 |
1993年 | 7篇 |
1992年 | 25篇 |
1991年 | 33篇 |
1990年 | 23篇 |
1989年 | 31篇 |
1988年 | 28篇 |
1987年 | 27篇 |
1986年 | 20篇 |
1985年 | 24篇 |
1984年 | 14篇 |
1983年 | 8篇 |
1982年 | 9篇 |
1980年 | 14篇 |
1979年 | 17篇 |
1978年 | 10篇 |
1977年 | 7篇 |
1976年 | 8篇 |
1975年 | 6篇 |
1974年 | 6篇 |
1972年 | 4篇 |
1968年 | 4篇 |
1967年 | 4篇 |
1965年 | 4篇 |
排序方式: 共有1303条查询结果,搜索用时 15 毫秒
71.
Hersleth HP Uchida T Røhr AK Teschner T Schünemann V Kitagawa T Trautwein AX Görbitz CH Andersson KK 《The Journal of biological chemistry》2007,282(32):23372-23386
High resolution crystal structures of myoglobin in the pH range 5.2-8.7 have been used as models for the peroxide-derived compound II intermediates in heme peroxidases and oxygenases. The observed Fe-O bond length (1.86-1.90 A) is consistent with that of a single bond. The compound II state of myoglobin in crystals was controlled by single-crystal microspectrophotometry before and after synchrotron data collection. We observe some radiation-induced changes in both compound II (resulting in intermediate H) and in the resting ferric state of myoglobin. These radiation-induced states are quite unstable, and compound II and ferric myoglobin are immediately regenerated through a short heating above the glass transition temperature (<1 s) of the crystals. It is unclear how this influences our compound II structures compared with the unaffected compound II, but some crystallographic data suggest that the influence on the Fe-O bond distance is minimal. Based on our crystallographic and spectroscopic data we suggest that for myoglobin the compound II intermediate consists of an Fe(IV)-O species with a single bond. The presence of Fe(IV) is indicated by a small isomer shift of delta = 0.07 mm/s from M?ssbauer spectroscopy. Earlier quantum refinements (crystallographic refinement where the molecular-mechanics potential is replaced by a quantum chemical calculation) and density functional theory calculations suggest that this intermediate H species is protonated. 相似文献
72.
One of the water stress-specific cDNA clones of rice characterisedpreviously, wsi18, was selected for further study. The wsi18gene can be induced by water stress conditions such as mannitol,NaCl, and dryness, but not by ABA, cold, or heat. A genomicclone for wsi18, pwsi18, contained about 1.7 kbp of the 5' upstreamsequence, two introns, and the full coding sequence. The 5'-upstreamsequence of pwsi18 contained putative cis-acting elements, namelyan ABA-responsive element (ABRE), three G-boxes, three E-boxes,a MEF-2 sequence, four direct and two inverted repeats, andfour sequences similar to DRE, which is involved in the dehydrationresponse of Arabi-dopsis genes. The gusA reporter gene underthe control of the pwsi18 promoter showed transient expressionin response to water stress. Deletion of the downstream DRE-likesequence between the distal G-boxes-2 and -3 resulted in ratherlow GUS expression. (Received March 27, 1997; Accepted November 5, 1997) 相似文献
73.
Conformational change of myoglobin (Mb) accompanied by binding of a ligand was investigated with 244 nm excited ultraviolet resonance Raman Spectroscopy (UVRR). The UVRR spectra of native sperm whale (sw) and horse (h) Mbs and W7F and W14F swMb mutants for the deoxy and CO-bound states enabled us to reveal the UVRR spectra of Trp7, Trp14, and Tyr151 residues, separately. The difference spectra between the deoxy and CO-bound states reflected the environmental or structural changes of Trp and Tyr residues upon CO binding. The W3 band of Trp7 near the N-terminus exhibited a change upon CO binding, while Trp14 did not. Tyr151 in the C-terminus also exhibited a definite change upon CO binding, but Tyr103 and Tyr146 did not. The spectral change of Tyr residues was characterized through solvent effects of a model compound. The corresponding spectral differences between CO- and n-butyl isocyanide-bound forms were much smaller than those between the deoxy and CO-bound forms, suggesting that the conformation change in the C- and N-terminal regions is induced by the proximal side of the heme through the movement of iron. Although the swinging up of His64 upon binding of a bulky ligand is noted by X-ray crystallographic analysis, UVRR spectra of His for the n-butyl isocyanide-bound form did not detect the exposure of His64 to solvent. 相似文献
74.
Yasuda S Kitagawa H Ueno M Ishitani H Fukasawa M Nishijima M Kobayashi S Hanada K 《The Journal of biological chemistry》2001,276(47):43994-44002
Ceramide produced at the endoplasmic reticulum (ER) is transported to the lumen of the Golgi apparatus for conversion to sphingomyelin (SM). N-(3-Hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12) is a novel analog of ceramide. Metabolic labeling experiments showed that HPA-12 inhibits conversion of ceramide to SM, but not to glucosylceramide, in Chinese hamster ovary cells. Cultivation of cells with HPA-12 significantly reduced the content of SM. HPA-12 did not inhibit the activity of SM synthase. The inhibition of SM formation by HPA-12 was abrogated when the Golgi apparatus was made to merge with the ER by brefeldin A. Moreover, HPA-12 inhibited redistribution of a fluorescent analog of ceramide, N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)-d-erythro-sphingosine (C(5)-DMB-Cer), from intracellular membranes to the Golgi region. Among four stereoisomers of the drug, (1R,3R)-HPA-12, which resembles natural ceramide stereochemically, was found to be the most active, although (1R,3R)-HPA-12 did not affect ER-to-Golgi trafficking of protein. Interestingly, (1R,3R)-HPA-12 inhibited conversion of ceramide to SM little in mutant cells defective in an ATP- and cytosol-dependent pathway of ceramide transport. These results indicated that (1R,3R)-HPA-12 inhibits ceramide trafficking from the ER to the site of SM synthesis, possibly due to an antagonistic interaction with a ceramide-recognizing factor(s) involved in the ATP- and cytosol-dependent pathway. 相似文献
75.
Yagyu K Kitagawa K Irie T Wu B Zeng XT Hattori N Inagaki C 《Journal of neurochemistry》2001,78(3):569-576
Cl(-)-ATPase in the CNS is a candidate for an outwardly directed neuronal Cl(-) transporter requiring phosphatidylinositol-4-phosphate (PI4P) for its optimal activity. To test its pathophysiological changes in a phosphatidylinositol (PI) metabolism disorder, the effects of neurotoxic factors in Alzheimer's disease (AD), amyloid beta proteins (Abetas), on the Cl(-)-ATPase activity were examined using primary cultured rat hippocampal neurons. Amyloid beta proteins (1-40, 1-42 and 25-35) concentration-dependently (1-100 nM) and time-dependently (from 1 h to 6 day) decreased Cl(-)-ATPase activity and elevated intracellular Cl(-) concentrations ([Cl(-)]i), Abeta25-35 being the most potent. Addition of inositol or 8-Br-cyclic GMP completely reversed these Abeta-induced changes. The recoveries in enzyme activity were attenuated by an inhibitor of PI 4-kinase, 10 microM wortmannin or 20 microM quercetin, but not by a PI 3-kinase inhibitor, 50 nM wortmannin or 10 microM LY294002. The PI, PIP and PIP2 levels of the plasma membrane-rich fraction were lower in the Abeta-treated cells as compared with each control. In the Abeta-exposed culture, but not in control, stimulation by 10 microM glutamate for 10 min significantly increased fragmentation of DNA and decreased cell viability. Addition of inositol or 8-Br-cyclic GMP prevented the effect of Abeta-treatment on the neurotoxicity of glutamate. Thus, Abetas reduce neuronal Cl(-)-ATPase activity, resulting in an increase in [Cl(-)]i probably by lowering PI4P levels, and this may reflect a pre-apoptotic condition in early pathophysiological profiles of AD. 相似文献
76.
Yutaka Tokiwa Masaru Kitagawa Hong Fan Tetsuji Yokochi Takao Raku Yoichi Hiraguri Shigeo Shibatani Yoshihiko Maekawa Naoki Kashimura Ryuichiro Kurane 《Biotechnology Techniques》1999,13(8):563-566
The transesterification of divinyladipate with adenosine in DMF containing 20% (v/v) DMSO was catalyzed by Streptomyces sp. alkaline protease and esterification occurred exclusively at the 3-position of hydroxyl group of ribofuranose in adenosine to give 3-O-vinyladipoyl adenosine without other products. 相似文献
77.
Yagita Y Kitagawa K Taguchi A Ohtsuki T Kuwabara K Mabuchi T Matsumoto M Yanagihara T Hori M 《Journal of neurochemistry》1999,72(4):1544-1551
78.
An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin 总被引:15,自引:0,他引:15 下载免费PDF全文
Kitagawa M Hatakeyama S Shirane M Matsumoto M Ishida N Hattori K Nakamichi I Kikuchi A Nakayama K Nakayama K 《The EMBO journal》1999,18(9):2401-2410
beta-catenin plays an essential role in the Wingless/Wnt signaling cascade and is a component of the cadherin cell adhesion complex. Deregulation of beta-catenin accumulation as a result of mutations in adenomatous polyposis coli (APC) tumor suppressor protein is believed to initiate colorectal neoplasia. beta-catenin levels are regulated by the ubiquitin-dependent proteolysis system and beta-catenin ubiquitination is preceded by phosphorylation of its N-terminal region by the glycogen synthase kinase-3beta (GSK-3beta)/Axin kinase complex. Here we show that FWD1 (the mouse homologue of Slimb/betaTrCP), an F-box/WD40-repeat protein, specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC. Mutations at the signal-induced phosphorylation site of beta-catenin inhibited its association with FWD1. FWD1 facilitated ubiquitination and promoted degradation of beta-catenin, resulting in reduced cytoplasmic beta-catenin levels. In contrast, a dominant-negative mutant form of FWD1 inhibited the ubiquitination process and stabilized beta-catenin. These results suggest that the Skp1/Cullin/F-box protein FWD1 (SCFFWD1)-ubiquitin ligase complex is involved in beta-catenin ubiquitination and that FWD1 serves as an intracellular receptor for phosphorylated beta-catenin. FWD1 also links the phosphorylation machinery to the ubiquitin-proteasome pathway to ensure prompt and efficient proteolysis of beta-catenin in response to external signals. SCFFWD1 may be critical for tumor development and suppression through regulation of beta-catenin protein stability. 相似文献
79.
Identification of the mouse H-ficolin gene as a pseudogene and orthology between mouse ficolins A/B and human L-/M-ficolins 总被引:8,自引:0,他引:8
Ficolin is a collagenous lectin which plays a crucial role in innate immunity. Three and two ficolins have been identified in human and mice, respectively. To identify the mouse homologue of human H-ficolin and to elucidate the orthology between mouse ficolins A/B and human L-/M-ficolins, the gene structures were explored. The mouse homologue of the H-ficolin gene was identified as a pseudogene on chromosome 4. The mouse ficolin A gene was located far from the ficolin B gene on chromosome 2, whereas the human L-ficolin and M-ficolin genes were close in the region homologous to the ficolin B locus. Together with the exon-intron structures and the phylogenetic tree, these results suggest that ficolin B is the mouse orthologue of M-ficolin and that the genes encoding serum-type ficolins, ficolin A and L-ficolin, were generated independently from the ficolin B/M-ficolin lineage each in mice and primates. 相似文献
80.