全文获取类型
收费全文 | 3676篇 |
免费 | 226篇 |
出版年
2021年 | 36篇 |
2019年 | 18篇 |
2018年 | 39篇 |
2017年 | 35篇 |
2016年 | 52篇 |
2015年 | 89篇 |
2014年 | 99篇 |
2013年 | 219篇 |
2012年 | 162篇 |
2011年 | 172篇 |
2010年 | 97篇 |
2009年 | 90篇 |
2008年 | 171篇 |
2007年 | 156篇 |
2006年 | 142篇 |
2005年 | 169篇 |
2004年 | 158篇 |
2003年 | 164篇 |
2002年 | 157篇 |
2001年 | 142篇 |
2000年 | 128篇 |
1999年 | 124篇 |
1998年 | 58篇 |
1997年 | 45篇 |
1996年 | 47篇 |
1995年 | 55篇 |
1994年 | 36篇 |
1993年 | 37篇 |
1992年 | 99篇 |
1991年 | 72篇 |
1990年 | 76篇 |
1989年 | 66篇 |
1988年 | 67篇 |
1987年 | 69篇 |
1986年 | 52篇 |
1985年 | 48篇 |
1984年 | 39篇 |
1983年 | 39篇 |
1982年 | 35篇 |
1981年 | 28篇 |
1980年 | 19篇 |
1979年 | 27篇 |
1978年 | 32篇 |
1977年 | 23篇 |
1976年 | 23篇 |
1975年 | 29篇 |
1973年 | 20篇 |
1970年 | 21篇 |
1969年 | 17篇 |
1968年 | 18篇 |
排序方式: 共有3902条查询结果,搜索用时 15 毫秒
991.
Xu Z Vagnarelli P Ogawa H Samejima K Earnshaw WC 《The Journal of biological chemistry》2010,285(51):40163-40170
INCENP, Borealin, Survivin, and Aurora B kinase comprise the chromosomal passenger complex, an essential regulator of mitotic events. INCENP (inner centromere protein) binds and activates Aurora B through a feedback loop involving phosphorylation of a Thr-Ser-Ser (TSS) motif near the INCENP C terminus. Here, we have examined the role of the TSS motif in vertebrate cells using an DT40 INCENP(ON/OFF) conditional knock-out cell line in which mutants are expressed in the absence of wild-type INCENP. Our analysis confirms that regulated phosphorylation of the two serine residues (presumably by Aurora B) is critical for full activation of the kinase and is essential for cell viability. Cells expressing INCENP mutants bearing either phospho-null (TAA) or phospho-mimetic (TEE) mutations exhibit significant levels of Aurora B kinase activity but fail to undergo normal spindle elongation or complete cytokinesis. This work confirms previous suggestions that INCENP can act as a rheostat, with different INCENP mutants promoting differing degrees of kinase activation. Our results also reveal that mitotic progression is accompanied by a requirement for progressively higher levels of Aurora B kinase activity. 相似文献
992.
Tsuneo Ogawa Yurika Kawano Takuroh Imamura Kumiko Kawakita Mina Sagara Takeshi Matsuo Yousuke Kakitsubata Tadashi Ishikawa Kazuo Kitamura Kinta Hatakeyama Yujiro Asada Tatsuhiko Kodama 《Obesity (Silver Spring, Md.)》2010,18(9):1871-1874
Pentraxin 3 (PTX3) is an acute‐phase protein that shares structural homology with C‐reactive protein (CRP). PTX3 is produced in macrophages, endothelial cells, and adipocytes in response to inflammatory stimuli, whereas hepatocytes are the main source of CRP. Because obesity and metabolic syndrome (MetS) are considered chronic inflammatory states, PTX3 might be involved in the pathogenesis of obesity and MetS as well as CRP. Levels of CRP correlated positively with body weight, BMI, waist circumference (WC), fasting plasma glucose and interleukin (IL)‐6, and negatively with high‐density lipoprotein cholesterol and adiponectin in healthy males. In contrast, PTX3 correlated positively with adiponectin, and negatively with body weight, BMI, WC, and triglyceride. Plasma CRP significantly increased, whereas plasma PTX3 significantly decreased with increasing BMI. Plasma CRP and PTX3 levels were significantly higher and lower, respectively, in individuals who had more than one MetS component compared with those who had none. In conclusion, PTX3 and CRP antagonistically participate in the development of obesity or MetS. 相似文献
993.
Zhang Y Furuyama K Kaneko K Ding Y Ogawa K Yoshizawa M Kawamura M Takeda K Yoshida T Shibahara S 《The FEBS journal》2006,273(14):3136-3147
Heme oxygenase consists of two structurally related isozymes, heme oxygenase-1 and and heme oxygenase-2, each of which cleaves heme to form biliverdin, iron and carbon monoxide. Expression of heme oxygenase-1 is increased or decreased depending on cellular microenvironments, whereas little is known about the regulation of heme oxygenase-2 expression. Here we show that hypoxia (1% oxygen) reduces the expression levels of heme oxygenase-2 mRNA and protein after 48 h of incubation in human cell lines, including Jurkat T-lymphocytes, YN-1 and K562 erythroleukemia, HeLa cervical cancer, and HepG2 hepatoma, as judged by northern blot and western blot analyses. In contrast, the expression level of heme oxygenase-1 mRNA varies under hypoxia, depending on the cell line; it was increased in YN-1 cells, decreased in HeLa and HepG2 cells, and remained undetectable in Jurkat and K562 cells. Moreover, heme oxygenase-1 protein was decreased in YN-1 cells under the conditions used, despite the induction of heme oxygenase-1 mRNA under hypoxia. The heme oxygenase activity was significantly decreased in YN-1, K562 and HepG2 cells after 48 h of hypoxia. To explore the mechanism for the hypoxia-mediated reduction of heme oxygenase-2 expression, we showed that hypoxia shortened the half-life of heme oxygenase-2 mRNA (from 12 h to 6 h) in YN-1 cells, without affecting the half-life of heme oxygenase-1 mRNA (9.5 h). Importantly, the heme contents were increased in YN-1, HepG2 and HeLa cells after 48 h of incubation under hypoxia. Thus, the reduced expression of heme oxygenase-2 may represent an important adaptation to hypoxia in certain cell types, which may contribute to the maintenance of the intracellular heme level. 相似文献
994.
Inoue H Ogawa W Asakawa A Okamoto Y Nishizawa A Matsumoto M Teshigawara K Matsuki Y Watanabe E Hiramatsu R Notohara K Katayose K Okamura H Kahn CR Noda T Takeda K Akira S Inui A Kasuga M 《Cell metabolism》2006,3(4):267-275
STAT3 regulates glucose homeostasis by suppressing the expression of gluconeogenic genes in the liver. The mechanism by which hepatic STAT3 is regulated by nutritional or hormonal status has remained unknown, however. Here, we show that an increase in the plasma insulin concentration, achieved either by glucose administration or by intravenous insulin infusion, stimulates tyrosine phosphorylation of STAT3 in the liver. This effect of insulin was mediated by the hormone's effects in the brain, and the increase in hepatic IL-6 induced by the brain-insulin action is essential for the activation of STAT3. The inhibition of hepatic glucose production and of expression of gluconeogenic genes induced by intracerebral ventricular insulin infusion was impaired in mice with liver-specific STAT3 deficiency or in mice with IL-6 deficiency. These results thus indicate that IL-6-STAT3 signaling in the liver contributes to insulin action in the brain, leading to the suppression of hepatic glucose production. 相似文献
995.
Ando T Ichikawa J Wako M Hatsushika K Watanabe Y Sakuma M Tasaka K Ogawa H Hamada Y Yagita H Nakao A 《Arthritis research & therapy》2006,8(5):R146-10
Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), a member of the TNF family, is a multifunctional cytokine that regulates cell growth, migration, and survival principally through a TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14). However, its physiological roles in bone are largely unknown. We herein report various effects of TWEAK on mouse osteoblastic MC3T3-E1 cells. MC3T3-E1 cells expressed Fn14 and produced RANTES (regulated upon activation, healthy T cell expressed and secreted) upon TWEAK stimulation through PI3K-Akt, but not nuclear factor-kappaB (NF-kappaB), pathway. In addition, TWEAK inhibited bone morphogenetic protein (BMP)-2-induced expression of osteoblast differentiation markers such as alkaline phosphatase through mitogen-activated protein kinase (MAPK) Erk pathway. Furthermore, TWEAK upregulated RANKL (receptor activation of NF-kappaB ligand) expression through MAPK Erk pathway in MC3T3-E1 cells. All these effects of TWEAK on MC3T3-E1 cells were abolished by mouse Fn14-Fc chimera. We also found significant TWEAK mRNA or protein expression in osteoblast- and osteoclast-lineage cell lines or the mouse bone tissue, respectively. Finally, we showed that human osteoblasts expressed Fn14 and induced RANTES and RANKL upon TWEAK stimulation. Collectively, TWEAK/Fn14 interaction regulates RANTES production, BMP-2-induced differentiation, and RANKL expression in MC3T3-E1 cells. TWEAK may thus be a novel cytokine that regulates several aspects of osteoblast function. 相似文献
996.
Kiyoshi Ogawa Shigenori Nishimura Masamitsu Doi Hiroyuki Takashima Yoshinori Nishi Takuya Yoshida Tadayasu Ohkubo Yuji Kobayashi 《Journal of peptide science》2006,12(1):51-57
The solution conformation of human calcitonin in a mixture of 60% water and 40% trifluoroethanol has been determined by the combined use of 1H NMR spectroscopy and distance geometry calculations with a distributed computing technique. 1H NMR spectroscopy provided 195 distance constraints and 13 hydrogen bond constraints. The 20 best converged structures exhibit atomic rmsd of 0.43 A for the backbone atoms from the averaged coordinate position in the region of Asn3-Phe22. The conformation is characterized by a nearly amphiphilic alpha-helix domain that extends from Leu4 in the cyclic region to His20. There are no significant differences observed among the overall structures of a series of calcitonins obtained from ultimobranchial bodies, including those that possess 20- to 50-fold greater activity. Three aromatic amino acid residues, Tyr12, Phe16 and Phe19, form a hydrophobic surface of human calcitonin. Bulky side chains on the surface could interfere with the ligand-receptor interaction thereby causing its low activity, relative to those of other species. 相似文献
997.
Xue QG Waldrop GL Schey KL Itoh N Ogawa M Cooper RK Losso JN La Peyre JF 《Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology》2006,145(1):16-26
A serine protease inhibitor was purified from plasma of the eastern oyster, Crassostrea virginica. The inhibitor is a 7609.6 Da protein consisting of 71 amino acids with 12 cysteine residues that are postulated to form 6 intra-chain disulfide bridges. Sequencing of the cloned cDNA identified an open reading frame encoding a polypeptide of 90 amino acids, with the 19 N-terminal amino acids forming a signal peptide. No sequence similarity with known proteins was found in sequence databases. The protein inhibited the serine proteases subtilisin A, trypsin and perkinsin, the major extracellular protease of the oyster protozoan parasite, Perkinsus marinus, in a slow binding manner. The mechanism of inhibition involves a rapid binding of inhibitor to the enzyme to form a weak enzyme-inhibitor complex followed by a slow isomerization to form a very tight binding enzyme-inhibitor complex. The overall dissociation constants K(i) with subtilisin A, perkinsin and trypsin were 0.29 nM, 13.7 nM and 17.7 nM, respectively. No inhibition of representatives of the other protease classes was detected. This is the first protein inhibitor of proteases identified from a bivalve mollusk and it represents a new protease inhibitor family. Its tight binding to subtilisin and perkinsin suggests it plays a role in the oyster host defense against P. marinus. 相似文献
998.
Yamaguchi M Terao Y Ogawa T Takahashi T Hamada S Kawabata S 《Microbes and infection / Institut Pasteur》2006,8(12-13):2791-2796
Streptococcus sanguinis, a normal inhabitant of the human oral cavity, has low cariogenicity, though colonization on tooth surfaces by this bacterium initiates aggregation by other oral bacteria and maturation of dental plaque. Additionally, S. sanguinis is frequently isolated from infective endocarditis patients. We investigated the functions of sortase A (SrtA), which cleaves LPXTG-containing proteins and anchors them to the bacterial cell wall, as a possible virulence factor of S. sanguinis. We identified the srtA gene of S. sanguinis by searching a homologous gene of Streptococcus mutans in genome databases. Next, we constructed an srtA-deficient mutant strain of S. sanguinis by insertional inactivation and compared it to the wild type strain. In the case of the mutant strain, some surface proteins could not anchor to the cell wall and were partially released into the culture supernatant. Furthermore, adherence to saliva-coated hydroxyapatite beads and polystyrene plates, as well as adherence to and invasion of human epithelial cells were reduced significantly in the srtA-deficient strain when compared to the wild type. In addition, antiopsonization levels and bacterial survival of the srtA-deficient mutant were decreased in human whole blood. This is the first known study to report that SrtA contributes to antiopsonization in streptococci. Our results suggest that SrtA anchors surface adhesins as well as some proteins that function as antiopsonic molecules as a means of evading the human immune system. Furthermore, they demonstrate that SrtA of S. sanguinis plays important roles in bacterial colonization. 相似文献
999.
Ter-butyl hydroperoxide (TBH) induced microsomal lipid peroxidation has been measured by oxygen consumption and malonaldehyde (MDA) formation. It has been found that the singlet oxygen (1O2) trap 2,5 diphenylfuran depressed both oxygen consumption and MDA formation. In contrast, histidine, another 1O2 trap does not effect neither oxygen consumption, nor MDA production. On the other hand, β-carotene, a 1O2 quencher strongly depresses oxygen consumption but slightly affects MDA production. Such results are consistent with the generation of 1O2 as transient by product of peroxidative microsomal lipid decomposition. 相似文献
1000.
Both isomers of (E)-2,3-methanophenylalanine (EPhe), a sterically restricted amino acid, were incorporated into peptides in order to examine their possible enzyme inhibitory activity. Both (2R,3S)- and (2S,3R)-EPhe-Phe(or Leu)-OMe were found to inhibit effectively the hydrolysis of Ac-Tyr-OEt by chymotrypsin in a competitive manner. The ester groups of these dipeptides were quite resistant to chymotrypsin hydrolysis, and the EPhe-Phe peptide bond was also entirely stable. The inhibition constant (Ki) of the most potent dipeptide of H-(2R,3S)-EPhe-Phe-OMe was 0.16 mM at 25°C. The inhibitory action of Phe-containing peptides was found to depend on the configuration of the Phe residue. The electrophilic nature of the cyclopropane ring which is conjugated with both the phenyl ring and the ester carbonyl group appears to be relevant to the inhibitory activity. Fully irreversible inactivation of chymotrypsin was achieved by its incubation with H-(2R,3S)-EPhe-Leu-OMe. An enzyme carboxylate group is thought to be responsible for nucleophilic attack on the cyclopropane ring leading to irreversible inactivation. 相似文献