全文获取类型
收费全文 | 847篇 |
免费 | 54篇 |
出版年
2022年 | 7篇 |
2021年 | 6篇 |
2020年 | 6篇 |
2019年 | 3篇 |
2018年 | 8篇 |
2017年 | 9篇 |
2016年 | 17篇 |
2015年 | 25篇 |
2014年 | 21篇 |
2013年 | 68篇 |
2012年 | 37篇 |
2011年 | 50篇 |
2010年 | 22篇 |
2009年 | 23篇 |
2008年 | 45篇 |
2007年 | 49篇 |
2006年 | 49篇 |
2005年 | 49篇 |
2004年 | 58篇 |
2003年 | 52篇 |
2002年 | 51篇 |
2001年 | 19篇 |
2000年 | 15篇 |
1999年 | 12篇 |
1998年 | 13篇 |
1997年 | 10篇 |
1995年 | 9篇 |
1994年 | 4篇 |
1993年 | 11篇 |
1992年 | 10篇 |
1991年 | 12篇 |
1990年 | 8篇 |
1989年 | 12篇 |
1988年 | 8篇 |
1987年 | 4篇 |
1986年 | 7篇 |
1985年 | 6篇 |
1984年 | 5篇 |
1983年 | 5篇 |
1982年 | 9篇 |
1981年 | 6篇 |
1980年 | 5篇 |
1979年 | 6篇 |
1978年 | 16篇 |
1977年 | 3篇 |
1974年 | 5篇 |
1972年 | 6篇 |
1971年 | 3篇 |
1970年 | 4篇 |
1965年 | 2篇 |
排序方式: 共有901条查询结果,搜索用时 31 毫秒
91.
Takada E Shimo K Hata K Abiake M Mukai Y Moriyama M Heasley L Mizuguchi J 《Experimental cell research》2005,304(2):518-530
Type I interferon (IFN)-induced antitumor action is due in part to apoptosis, but the molecular mechanisms underlying IFN-induced apoptosis remain largely unresolved. In the present study, we demonstrate that IFN-beta induced apoptosis and the loss of mitochondrial membrane potential (delta psi m) in the murine CH31 B lymphoma cell line, and this was accompanied by the up-regulation of CD95, but not CD95-ligand (CD95-L), tumor necrosis factor (TNF), or TNF-related apoptosis-inducing ligand (TRAIL). Pretreatment with anti-CD95-L mAb partially prevented the IFN-beta-induced loss of delta psi m, suggesting that the interaction of IFN-beta-up-regulated CD95 with CD95-L plays a crucial role in the induction of fratricide. IFN-beta induced a sustained activation of c-Jun NH2-terminal kinase 1 (JNK1), but not extracellular signal-regulated kinases (ERKs). The IFN-beta-induced apoptosis and loss of delta psi m were substantially compromised in cells overexpressing a dominant-negative form of JNK1 (dnJNK1), and it was slightly enhanced in cells carrying a constitutively active JNK construct, MKK7-JNK1 fusion protein. The IFN-beta-induced up-regulation of CD95 together with caspase-8 activation was also abrogated in the dnJNK1 cells while it was further enhanced in the MKK7-JNK1 cells. The levels of cellular FLIP (c-FLIP), competitively interacting with caspase-8, were down-regulated by stimulation with IFN-beta but were reversed by the proteasome inhibitor lactacystin. Collectively, the IFN-beta-induced sustained activation of JNK mediates apoptosis, at least in part, through up-regulation of CD95 protein in combination with down-regulation of c-FLIP protein. 相似文献
92.
Kimura T Hosoda Y Sato Y Kitamura Y Ikeda T Horibe T Kikuchi M 《The Journal of biological chemistry》2005,280(36):31438-31441
We previously reported that the reductive activities of yeast protein-disulfide isomerase (PDI) family proteins did not completely explain their contribution to the viability of Saccharomyces cerevisiae (Kimura, T., Hosoda, Y., Kitamura, Y., Nakamura, H., Horibe, T., and Kikuchi, M. (2004) Biochem. Biophys. Res. Commun. 320, 359-365). In this study, we examined oxidative refolding activities and found that Mpd1p, Mpd2, and Eug1p exhibit activities of 13.8, 16.0, and 2.16%, respectively, compared with Pdi1p and that activity for Eps1p is undetectable. In analyses of interactions between yeast PDI proteins and endoplasmic reticulum molecular chaperones, we found that Mpd1p alone does not have chaperone activity but that it interacts with and inhibits the chaperone activity of Cne1p, a homologue of mammalian calnexin, and that Cne1p increases the reductive activity of Mpd1p. These results suggest that the interface between Mpd1p and Cne1p is near the peptide-binding site of Cne1p. In addition, Eps1p interacts with Pdi1p, Eug1p, Mpd1p, and Kar2p with dissociation constants (KD) in the range of 10(-7) to 10(-6). Interestingly, co-chaperone activities were completely suppressed in Eps1p-Pdi1p and Eps1p-Mpd1p complexes, although only Eps1p and Pdi1p have chaperone activity. The in vivo consequences of these results are discussed. 相似文献
93.
Kao MC Di Bernardo S Nakamaru-Ogiso E Miyoshi H Matsuno-Yagi A Yagi T 《Biochemistry》2005,44(9):3562-3571
The ND6 subunit is one of seven mitochondrial DNA-encoded subunits of the proton-translocating NADH-quinone oxidoreductase (complex I). Physiological importance of the ND6 subunit is becoming increasingly apparent because a number of mutations leading to amino acid changes in this subunit have been found to be associated with known mitochondrial diseases. Using the Escherichia coli enzyme (NDH-1), we have investigated the NuoJ subunit (the E. coli counterpart of ND6) by employing a chromosomal DNA manipulation technique. A series of point mutations was constructed directly on the nuoJ gene in the chromosome targeting at highly conserved residues. Analyses with blue-native gel electrophoresis and immunological methods revealed that, in all point mutants, the assembly of NDH-1 was normal and that the deamino-NADH-K(3)Fe(CN)(6) reductase activity of the membrane was essentially the same as that of the wild-type. However, energy-coupled NDH-1 activities were affected to varied extents. Among them, mutants of the Val-65 residue that is located in the most conserved transmembrane segment significantly lost the coupled electron-transfer activities and exhibited diminished membrane potential and proton translocation. This may suggest that Val-65 or the area around it is important for energy transduction of the coupling site 1. Together with the results on mutations related to human diseases, possible functional roles of the NuoJ subunit have been discussed. 相似文献
94.
Yamashita T Ino T Miyoshi H Sakamoto K Osanai A Nakamaru-Ogiso E Kita K 《Biochimica et biophysica acta》2004,1608(2-3):97-103
The components and organization of the respiratory chain in helminth mitochondria vary remarkably depending upon the stage of the life cycle. Mitochondrial complex I in the parasitic helminth Ascaris suum uses ubiquinone-9 (UQ(9)) and rhodoquinone-9 (RQ(9)) under aerobic and anaerobic conditions, respectively. In this study, we investigated structural features of the quinone reduction site of A. suum complex I using a series of quinazoline-type inhibitors and also by the kinetic analysis of rhodoquinone-2 (RQ(2)) and ubiquinone-2 (UQ(2)) reduction. Structure-activity profiles of the inhibition by quinazolines were comparable, but not completely identical, between NADH-RQ(2) and NADH-UQ(2) oxidoreductase activities. However, the inhibitory mechanism of quinazolines was competitive and partially competitive against RQ(2) and UQ(2), respectively. The pH profiles of both activities differed remarkably; NADH-RQ(2) oxidoreductase activity showed an optimum pH at 7.6, whereas NADH-UQ(2) oxidoreductase activity showed two optima pH at 6.4 and 7.2. Our results indicate that although A. suum complex I uses both RQ(2) and UQ(2) as an electron acceptor, the manner of reaction (or binding) of the two quinones differs. 相似文献
95.
Fujikura J Hosoda K Iwakura H Tomita T Noguchi M Masuzaki H Tanigaki K Yabe D Honjo T Nakao K 《Cell metabolism》2006,3(1):59-65
To investigate the precise role of Notch/Rbp-j signaling in the pancreas, we inactivated Rbp-j by crossing Rbp-j floxed mice with Pdx.cre or Rip.cre transgenic mice. The loss of Rbp-j at the initial stage of pancreatic development induced accelerated alpha and PP cell differentiation and a concomitant decrease in the number of Neurogenin3 (Ngn3)-positive cells at E11.5. Then at E15, elongated tubular structures expressing ductal cell markers were evident; however, differentiation of acinar and all types of endocrine cells were reduced. During later embryonic stages, compensatory acinar cell differentiation was observed. The resultant mice exhibited insulin-deficient diabetes with both endocrine and exocrine pancreatic hypoplasia. In contrast, the loss of Rbp-j specifically in beta cells did not affect beta cell number and function. Thus, our analyses indicate that Notch/Rbp-j signaling prevents premature differentiation of pancreatic progenitor cells into endocrine and ductal cells during early development of the pancreas. 相似文献
96.
Daisuke Iyaguchi Susumu Kawano Kazuki Takada Eiko Toyota 《Bioorganic & medicinal chemistry》2010,18(6):2076-2080
The crystal structures of the complexes of bovine trypsin with m-guanidinosalicylidene-l-alaninato(aqua)copper(II) hydrochloride (inhibitor 1), [N,N′-bis(m-guanidinosalicylidene)ethylenediaminato]copper(II) (inhibitor 2), and [N,N′-bis(m-amidinosalicylidene)ethylenediaminato]copper(II) (inhibitor 4) have been determined. The guanidine-containing trypsin-inhibitors (1 and 2) bind to the trypsin active site in a manner similar to that previously reported for amidine-containing inhibitors, for example, m-amidinosalicylidene-l-alaninato(aqua)copper(II) hydrochloride (inhibitor 3). However, the binding mode of the guanidino groups of inhibitors 1 and 2 to Asp189 in the S1 pocket of trypsin was found to be markedly different from that of the amidino group of inhibitor 3. The present X-ray analyses revealed that the interactions of the metal ion of the inhibitors with the active site residues of trypsin play a crucial role in the binding affinity to the trypsin molecule. These structural information and inhibitory activity data for amidine- and guanidine-containing Schiff base metal chelate inhibitors provide new avenues for designing novel inhibitors against physiologically important trypsin-like serine proteases. 相似文献
97.
Eiko Nakamaru-Ogiso Mou-Chieh Kao Han Chen Subhash C. Sinha Takao Yagi Tomoko Ohnishi 《The Journal of biological chemistry》2010,285(50):39070-39078
Complex I pumps protons across the membrane by using downhill redox energy. Here, to investigate the proton pumping mechanism by complex I, we focused on the largest transmembrane subunit NuoL (Escherichia coli ND5 homolog). NuoL/ND5 is believed to have H+ translocation site(s), because of a high sequence similarity to multi-subunit Na+/H+ antiporters. We mutated thirteen highly conserved residues between NuoL/ND5 and MrpA of Na+/H+ antiporters in the chromosomal nuoL gene. The dNADH oxidase activities in mutant membranes were mostly at the control level or modestly reduced, except mutants of Glu-144, Lys-229, and Lys-399. In contrast, the peripheral dNADH-K3Fe(CN)6 reductase activities basically remained unchanged in all the NuoL mutants, suggesting that the peripheral arm of complex I was not affected by point mutations in NuoL. The proton pumping efficiency (the ratio of H+/e−), however, was decreased in most NuoL mutants by 30–50%, while the IC50 values for asimicin (a potent complex I inhibitor) remained unchanged. This suggests that the H+/e− stoichiometry has changed from 4H+/2e− to 3H+ or 2H+/2e− without affecting the direct coupling site. Furthermore, 50 μm of 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), a specific inhibitor for Na+/H+ antiporters, caused a 38 ± 5% decrease in the initial H+ pump activity in the wild type, while no change was observed in D178N, D303A, and D400A mutants where the H+ pumping efficiency had already been significantly decreased. The electron transfer activities were basically unaffected by EIPA in both control and mutants. Taken together, our data strongly indicate that the NuoL subunit is involved in the indirect coupling mechanism. 相似文献
98.
An agar-degrading bacterium, strain SA7, was isolated from plant roots cultivated in soil. Analysis of the 16S rDNA sequence showed that strain SA7 is affiliated with the genus Asticcacaulis. Strain SA7 produced extracellular agarase, and grew utilizing agar in the culture medium as sole carbon source. Zymogram analysis showed that strain SA7 extracellularly secreted single agarase protein (about 70 kDa). 相似文献
99.
Nakajima T Hasegawa G Kamiuchi K Fukui M Yamasaki M Tominaga M Asano M Hosoda H Yoshikawa T Nakamura N 《Redox report : communications in free radical research》2006,11(5):223-230
Advanced diabetic nephropathy is characterized by abnormal synthesis of extracellular matrix (ECM) proteins, such as collagen I (COL I). The present experiments were designed to test the hypothesis that the presence of abnormal ECM proteins may be responsible for increased generation of reactive oxygen species (ROS) that are thought to have an important role in the pathogenesis of diabetic nephropathy. SV40 MES 13 murine mesangial cells were plated on COL I or collagen IV (COL IV) for 3 h at 5.5 or 25 mM D-glucose concentration. Increased intracellular ROS generation and reduced intracellular nitric oxide (NO) production was measured in cells attached to COL I compared with cells attached to COL IV. Treatment with N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME), an inhibitor of NO synthase, reduced this difference in ROS generation between cells attached to either COL I or IV. The results using antibodies against integrins also indicated that an alpha(2) integrin-mediated pathway was involved in the different response in ROS generation caused by ECM proteins. These results suggest that contact between altered ECM proteins that are present in advanced diabetic nephropathy and mesangial cells has the potential to increase intracellular oxidative stress, leading to progressive glomerular damage. 相似文献
100.
MICROTUBULE ORGANIZATION 1 regulates structure and function of microtubule arrays during mitosis and cytokinesis in the Arabidopsis root
下载免费PDF全文
![点击此处可从《Plant physiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Kawamura E Himmelspach R Rashbrooke MC Whittington AT Gale KR Collings DA Wasteneys GO 《Plant physiology》2006,140(1):102-114
MICROTUBULE ORGANIZATION 1 (MOR1) is a plant member of the highly conserved MAP215/Dis1 family of microtubule-associated proteins. Prior studies with the temperature-sensitive mor1 mutants of Arabidopsis (Arabidopsis thaliana), which harbor single amino acid substitutions in an N-terminal HEAT repeat, proved that MOR1 regulates cortical microtubule organization and function. Here we demonstrate by use of live cell imaging and immunolabeling that the mor1-1 mutation generates specific defects in the microtubule arrays of dividing vegetative cells. Unlike the universal cortical microtubule disorganization in elongating mor1-1 cells, disruption of mitotic and cytokinetic microtubule arrays was not detected in all dividing cells. Nevertheless, quantitative analysis identified distinct defects in preprophase bands (PPBs), spindles, and phragmoplasts. In nearly one-half of dividing cells at the restrictive temperature of 30 degrees C, PPBs were not detected prior to spindle formation, and those that did form were often disrupted. mor1-1 spindles and phragmoplasts were short and abnormally organized and persisted for longer times than in wild-type cells. The reduced length of these arrays predicts that the component microtubule lengths are also reduced, suggesting that microtubule length is a critical determinant of spindle and phragmoplast structure, orientation, and function. Microtubule organizational defects led to aberrant chromosomal arrangements, misaligned or incomplete cell plates, and multinucleate cells. Antiserum raised against an N-terminal MOR1 sequence labeled the full length of microtubules in interphase arrays, PPBs, spindles, and phragmoplasts. Continued immunolabeling of the disorganized and short microtubules of mor1-1 at the restrictive temperature demonstrated that the mutant mor1-1(L174F) protein loses function without dissociating from microtubules, providing important insight into the mechanism by which MOR1 may regulate microtubule length. 相似文献