全文获取类型
收费全文 | 860篇 |
免费 | 48篇 |
专业分类
908篇 |
出版年
2022年 | 4篇 |
2021年 | 10篇 |
2018年 | 9篇 |
2016年 | 16篇 |
2015年 | 21篇 |
2014年 | 23篇 |
2013年 | 44篇 |
2012年 | 42篇 |
2011年 | 37篇 |
2010年 | 18篇 |
2009年 | 26篇 |
2008年 | 40篇 |
2007年 | 38篇 |
2006年 | 39篇 |
2005年 | 49篇 |
2004年 | 45篇 |
2003年 | 57篇 |
2002年 | 53篇 |
2001年 | 27篇 |
2000年 | 29篇 |
1999年 | 21篇 |
1998年 | 13篇 |
1997年 | 16篇 |
1996年 | 10篇 |
1995年 | 10篇 |
1994年 | 12篇 |
1993年 | 11篇 |
1992年 | 17篇 |
1991年 | 16篇 |
1990年 | 11篇 |
1989年 | 13篇 |
1988年 | 12篇 |
1987年 | 4篇 |
1986年 | 7篇 |
1985年 | 8篇 |
1984年 | 4篇 |
1983年 | 9篇 |
1982年 | 4篇 |
1980年 | 7篇 |
1979年 | 7篇 |
1978年 | 7篇 |
1975年 | 8篇 |
1974年 | 5篇 |
1973年 | 4篇 |
1972年 | 4篇 |
1971年 | 4篇 |
1970年 | 4篇 |
1969年 | 3篇 |
1967年 | 5篇 |
1965年 | 4篇 |
排序方式: 共有908条查询结果,搜索用时 0 毫秒
121.
Yoshinaga T Nakatome K Nozaki J Naitoh M Hoseki J Kubota H Nagata K Koizumi A 《Biological chemistry》2005,386(11):1077-1085
A single mutation (C96Y) in the Ins2 gene, which disrupts the A7-B7 disulfide bond, causes the diabetic phenotype in Akita mice. We biochemically analyzed the conformation of wild-type and Akita mutant recombinant proinsulins. Gel filtration chromatography and dynamic light scattering revealed that the apparent size of the mutant proinsulin molecules was significantly larger than that of wild-type proinsulin, even in the absence of intermolecular disulfide bonds. Titration with a hydrophobic probe, 1-anilinonaphthalene-8-sulfonate, demonstrated that the mutant proinsulin was more hydrophobic than the wild type. In addition, circular dichroism studies revealed that the conformation of the mutant proinsulin was less stable than the wild type, which is consistent with the observation that hydrophobic residues are exposed on the surface of the proinsulin molecules. Studies with antiserum against the C-peptide of proinsulin indicated that the mutant proinsulin had an immunoreactivity that was at least one-tenth weaker than wild-type proinsulin, suggesting that the C-peptide of mutant proinsulin is buried inside the aggregate of the proinsulin molecule. These findings indicate that increased hydrophobicity of mutant proinsulin facilitates aggregate formation, providing a clue to the dominant negative effect in the Akita mouse. 相似文献
122.
Essential role of GATA3 for the maintenance of type 2 helper T (Th2) cytokine production and chromatin remodeling at the Th2 cytokine gene loci 总被引:6,自引:0,他引:6
Yamashita M Ukai-Tadenuma M Miyamoto T Sugaya K Hosokawa H Hasegawa A Kimura M Taniguchi M DeGregori J Nakayama T 《The Journal of biological chemistry》2004,279(26):26983-26990
GATA3 expression is essential for type-2 helper T (Th2) cell differentiation. GATA3-mediated chromatin remodeling at the Th2 cytokine gene loci, including Th2-specific long range histone hyperacetylation of the interleukin (IL)-13/IL-4 gene loci, occurs in developing Th2 cells. However, little is known about the role of GATA3, if any, in the maintenance of established remodeled chromatin at the Th2 cytokine gene loci. Here, we established a Cre/LoxP-based site-specific recombination system in cultured CD4 T cells using a unique adenovirus-mediated gene transfer technique. This system allowed us to investigate the effect of loss of GATA3 expression in in vitro differentiated Th2 cells. After ablation of GATA3, we detected reduced production of all Th2 cytokines, increased DNA methylation at the IL-4 gene locus, and decreased histone hyperacetylation at the IL-5 gene locus but not significantly so at the IL-13/IL-4 gene loci. Thus, GATA3 plays important roles in the maintenance of the Th2 phenotype and continuous chromatin remodeling of the specific Th2 cytokine gene locus through cell division. 相似文献
123.
Shishido T Nozaki N Takahashi H Arimoto T Niizeki T Koyama Y Abe J Takeishi Y Kubota I 《Biochemical and biophysical research communications》2006,345(4):1446-1453
Background
It is now evident that inflammation after vascular injury has significant impact on the restenosis after revascularization procedures such as angioplasty, stenting, and bypass grafting. However, the mechanisms that regulate inflammation and repair after vascular injury are incompletely understood. Here, we report that vascular injury-mediated cytokine expression, reactive oxygen species (ROS) production, as well as subsequent neointimal formation requires Toll-like receptor-2 (TLR-2) mediated signaling pathway in vivo.Methods and results
Vascular injury was induced by cuff-placement around the femoral artery in non-transgenic littermates (NLC) and TLR-2 knockout (TLR-2KO) mice. After cuff-placement in NLC mice, expression of TLR-2 was significantly increased in both smooth muscle medial layer and adventitia. Interestingly, we found that inflammatory genes expression such as tumor necrosis factor-α, interleukin-1β (IL-1β), IL-6, and monocyte chemoattractant protein-1 were markedly decreased in TLR-2KO mice compared with NLC mice. In addition, ROS production after vascular injury was attenuated in TLR-2KO mice compared with NLC mice. Since we observed the significant role of endogenous TLR-2 activation in regulating inflammatory responses and ROS production after vascular injury, we determined whether inhibition of endogenous TLR-2 activation can inhibit neointimal proliferation after vascular injury. Neointimal hyperplasia was markedly suppressed in TLR-2KO mice compared with WT mice at both 2 and 4 weeks after vascular injury.Conclusions
These findings suggested that endogenous TLR-2 activation might play a central role in the regulation of vascular inflammation as well as subsequent neointimal formation in injured vessels. 相似文献124.
Z Fu T Nakayama N Sato Y Izumi Y Kasamaki A Shindo M Ohta M Soma N Aoi M Sato Y Ozawa Y Ma 《Hereditas》2012,149(3):91-98
CYP4A11, which is a member of the cytochrome P450 family, acts mainly as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite involved in the maintenance of cardiovascular health. Recently, it was reported that many subfamilies of CYP genes have an association with myocardial infarction (MI). The aim of the present study was to assess the association between the human CYP4A11 gene and MI, using a haplotype-based case-control study with a separate analysis of the gender groups. A total of 239 MI patients and 285 controls were genotyped for 3 single-nucleotide polymorphisms (SNPs) of the human CYP4A11 gene (rs2269231, rs1126742, rs9333025). The data obtained via haplotype-based case-control studies were assessed for 3 separate groups: total subjects, men, and women. For the total, men and women groups, the distribution of the genotypes and alleles of the 3 SNPs did not show any significant difference between the MI patients and the control subjects. For the total and the men groups, the overall distribution of the haplotypes constructed with the 3 SNPs significantly differed between the MI patients and control subjects (P < 0.001). Also, for the total and for the men, the frequency of the T-T-A haplotype constructed with the 3 SNPs was significantly lower for the MI patients than for the control subjects (both P 0.001). The T-T-A haplotype constructed with the 3 SNPs appears to be a protective genetic marker for MI in Japanese men. 相似文献
125.
Ishimura A Ishige K Taira T Shimba S Ono S Ariga H Tezuka M Ito Y 《Neurochemistry international》2008,52(4-5):776-785
Several studies have indicated that lipid peroxidation often occurs in response to oxidative stress, and that many aldehydic products including 4-hydroxy-2-nonenal (HNE) are formed when lipid hydroperoxides break down. In order to clarify the mechanism of oxidative stress-induced neuronal death in the nervous system, we investigated H(2)O(2)- and HNE-induced cell death pathways in HT22 cells, a mouse hippocampal cell line, under the same experimental conditions. Treatment with H(2)O(2) and HNE decreased the viability of these cells in a time- and concentration-dependent manner. In the cells treated with H(2)O(2), significant increases in the immunoreactivities of DJ-1 and nuclear factor-kappaB (NF-kappaB) subunits (p65 and p50) were observed in the nuclear fraction. H(2)O(2) also induced an increase in the intracellular concentration of Ca(2+), and cobalt chloride (CoCl(2)), a Ca(2+) channel inhibitor, suppressed the H(2)O(2)-induced cell death. In HNE-treated cells, none of these phenomena were observed; however, HNE adduct proteins were formed after exposure to HNE, but not to H(2)O(2). N-Acetyl-L-cysteine (NAC) suppressed both HNE-induced cell death and HNE-induced expression of HNE adduct proteins, whereas H(2)O(2)-induced cell death was not affected. These findings suggest that the mechanisms of cell death induced by H(2)O(2) different from those induced by HNE in HT22 cells, and that HNE adduct proteins play an important role in HNE-induced cell death. It is also suggested that the pathway for H(2)O(2)-induced cell death in HT22 cells does not involve HNE production. 相似文献
126.
Shingo Ichimiya Takashi Kojima Hiroyuki Momota Nobuhiko Kondo Toshinori Ozaki Akira Nakagawara María Luisa Toribio Masakatsu Imamura Noriyuki Sato 《The journal of histochemistry and cytochemistry》2002,50(4):455-462
The thymus is a heterogeneous immune organ in which immature T-cells develop and eventually specialize to make certain immune responses of their own. Among various types of stromal cells in the thymus, thymic epithelial cells (TECs) have a crucially important function for presenting self-antigens and secreting cytokines to thymocytes for their maturation into T-cells. In this study we show that the p73 gene, a homologue of the tumor suppressor gene p53, was expressed in the nucleus of the human TEC in vivo and in TEC lines in vitro. Because p73 has the capacity to be a transactivator like p53, it may contribute to T-cell development in the context of TEC biology as regulated in the cell cycle and apoptosis. 相似文献
127.
Tsuda E Yang H Nishimura T Uehara Y Sakai T Furutani M Koshiba T Hirose M Nozaki H Murphy AS Hayashi K 《The Journal of biological chemistry》2011,286(3):2354-2364
Polar auxin movement is a primary regulator of programmed and plastic plant development. Auxin transport is highly regulated at the cellular level and is mediated by coordinated transport activity of plasma membrane-localized PIN, ABCB, and AUX1/LAX transporters. The activity of these transporters has been extensively analyzed using a combination of pharmacological inhibitors, synthetic auxins, and knock-out mutants in Arabidopsis. However, efforts to analyze auxin-dependent growth in other species that are less tractable to genetic manipulation require more selective inhibitors than are currently available. In this report, we characterize the inhibitory activity of 5-alkoxy derivatives of indole 3-acetic acid and 7-alkoxy derivatives of naphthalene 1-acetic acid, finding that the hexyloxy and benzyloxy derivatives act as potent inhibitors of auxin action in plants. These alkoxy-auxin analogs inhibit polar auxin transport and tropic responses associated with asymmetric auxin distribution in Arabidopsis and maize. The alkoxy-auxin analogs inhibit auxin transport mediated by AUX1, PIN, and ABCB proteins expressed in yeast. However, these analogs did not inhibit or activate SCF(TIR1) auxin signaling and had no effect on the subcellular trafficking of PIN proteins. Together these results indicate that alkoxy-auxins are inactive auxin analogs for auxin signaling, but are recognized by PIN, ABCB, and AUX1 auxin transport proteins. Alkoxy-auxins are powerful new tools for analyses of auxin-dependent development. 相似文献
128.
Masakatsu Kamiya Keisuke Oyauchi Yoshinori Sato Takuya Yokoyama Mofei Wang Tomoyasu Aizawa Yasuhiro Kumaki Mineyuki Mizuguchi Kunio Imai Makoto Demura Koichi Suzuki Keiichi Kawano 《Journal of peptide science》2010,16(5):242-248
We previously reported that yamamarin, a pentapeptide with an amidated C‐terminus (DILRG‐NH2) isolated from larvae of the silkmoth, and its palmitoylated analog (C16‐DILRG‐NH2) suppressed proliferation of rat hepatoma (liver cancer) cells. In this study, we investigated the structure–activity relationship of yamamarin by in vitro assay and spectroscopic methods (CD and NMR) for various analogs. The in vitro assay results demonstrated that the chemical structure of the C‐terminal part (‐RG‐NH2) of yamamarin is essential for its activity. The CD and NMR results indicated that yamamarin and its analog adopt predominantly a random coil conformation. Moreover, a comparison of NMR spectra of DILRG‐NH2 and C16‐DILRG‐NH2 revealed that the N‐terminal palmitoyl group of C16‐DILRG‐NH2 did not affect the conformation of the C‐terminal part, which is essential for activity. Together, these results should assist in the design of more sophisticated anticancer drugs. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
129.
Hayashi K Hashimoto K Kusaka N Yamazoe A Fukaki H Tasaka M Nozaki H 《Bioorganic & medicinal chemistry letters》2006,16(9):2470-2474
Two new types of caged gene-inducers, caged 17beta-estradiol and caged dexamethazone, were synthesized. Caged gene-inducers were applied to transgenic Arabidopsis plants carrying a steroid hormone-inducible transactivation system. Light uncaged caged gene-inducers and controlled spatial and temporal expression of transgene in the transgenic plant. Furthermore, caged gene-inducers enabled the control of root development by light. 相似文献
130.
In the enantioselective hydrolysis of the di-O-acetyl derivatives of meso-1,3-diol catalyzed by lipases, racemization of the monoacetate products occurs due to non-enzymatic general base-catalyzed acyl migration. The rate of acyl migration increases with increase of pH and buffer concentration. A mechanism of the migration has been proposed to proceed through a six-member ring transition that accounts for the experimental results. The acyl migration, however, was not observed in the enantioselective transesterification of meso-1,3-diols in neutral organic solvents. 相似文献