全文获取类型
收费全文 | 2186篇 |
免费 | 129篇 |
国内免费 | 3篇 |
出版年
2021年 | 16篇 |
2020年 | 14篇 |
2019年 | 16篇 |
2018年 | 21篇 |
2017年 | 18篇 |
2016年 | 43篇 |
2015年 | 41篇 |
2014年 | 61篇 |
2013年 | 130篇 |
2012年 | 111篇 |
2011年 | 113篇 |
2010年 | 87篇 |
2009年 | 76篇 |
2008年 | 112篇 |
2007年 | 106篇 |
2006年 | 94篇 |
2005年 | 123篇 |
2004年 | 124篇 |
2003年 | 134篇 |
2002年 | 132篇 |
2001年 | 54篇 |
2000年 | 53篇 |
1999年 | 56篇 |
1998年 | 28篇 |
1997年 | 32篇 |
1996年 | 22篇 |
1995年 | 12篇 |
1994年 | 12篇 |
1993年 | 18篇 |
1992年 | 39篇 |
1991年 | 44篇 |
1990年 | 36篇 |
1989年 | 30篇 |
1988年 | 35篇 |
1987年 | 24篇 |
1986年 | 27篇 |
1985年 | 18篇 |
1984年 | 12篇 |
1983年 | 10篇 |
1982年 | 15篇 |
1981年 | 15篇 |
1980年 | 13篇 |
1979年 | 19篇 |
1978年 | 11篇 |
1976年 | 12篇 |
1974年 | 12篇 |
1973年 | 12篇 |
1972年 | 9篇 |
1971年 | 12篇 |
1969年 | 10篇 |
排序方式: 共有2318条查询结果,搜索用时 15 毫秒
951.
Watanabe T Otsu K Takeda T Yamaguchi O Hikoso S Kashiwase K Higuchi Y Taniike M Nakai A Matsumura Y Nishida K Ichijo H Hori M 《Biochemical and biophysical research communications》2005,333(2):562-567
The molecular basis of myocardial cell death in the ischemia-reperfused heart still remains to be clarified. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in stress-induced apoptosis. We studied ASK1(-/-) mice to examine the role of ASK1 in ischemia-reperfusion injury. In the wild-type heart, ischemia-reperfusion resulted in necrotic injury, whereas infarct size was drastically reduced in the ASK1(-/-) heart. The necrotic injury was not accompanied with any evidence of apoptosis such as an increase in TUNEL-positive cells, DNA fragmentation or the activation of caspase-3. ASK1(-/-) cardiomyocytes were more resistant to H(2)O(2)- or Ca(2+)-induced apoptotic and non-apoptotic cell death compared with wild-type cells. These data suggest that ASK1 is involved in necrosis as well as apoptosis and that ASK1-dependent necrosis is likely to contribute to myocardial cell death in the ischemia-reperfused heart. 相似文献
952.
Osaterone acetate (17 alpha-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione; OA) is a steroidal antiandrogen. In order to clarify the species differences, metabolites of OA were examined in plasma, urine, and feces of dogs and humans after oral administration of OA. Eleven metabolites in plasma, urine, and feces were identified by their spectral properties and comparison to appropriate standards. The primary routes of OA metabolism involve 11 beta-, 15 beta- and 21-hydroxylation, 17 alpha-deacetylation, and dechlorination. Other metabolites arise from combinations of these pathways to form multiple oxidized metabolites. All metabolites observed in humans occurred in dogs. 11 beta-Hydroxylated metabolites (11 beta-OH OA and 11-oxo OA) were found in the plasma and urine of dogs, but there was no evidence of their presence in humans. 11 beta-Hydroxylation of exogenous steroids represents a distinctive biotransformation pathway. 相似文献
953.
Nakai Y Shiratsuchi A Manaka J Nakayama H Takio K Zhang JT Suganuma T Nakanishi Y 《Experimental cell research》2005,309(1):137-148
We previously isolated a monoclonal antibody named PH2 that inhibits phosphatidylserine-mediated phagocytosis of apoptotic cells by macrophages. We report here the identification of the cognate antigen. A protein bound by PH2 in Western blotting was identified as the 170-kDa subunit of eukaryotic translation initiation factor 3 (eIF3 p170/eIF3a). When eIF3a was expressed in a culture cell line as a protein fused to green fluorescence protein, the fusion protein was detected at the cell surface only after the induction of apoptosis. The same phenomenon was seen when the localization of endogenous eIF3a was determined using anti-eIF3a antibody, and eIF3a seemed to be partially degraded during apoptosis. Furthermore, bacterially expressed N-terminal half of eIF3a fused to glutathione S-transferase bound to the surface of macrophages and inhibited phagocytosis of apoptotic cells by macrophages when it was added to phagocytosis reactions. These results collectively suggest that eIF3a translocates to the cell surface upon apoptosis, probably after partial degradation, and bridges apoptotic cells and macrophages to enhance phagocytosis. 相似文献
954.
Tanaka N Shinkyo R Sakaki T Kasamastu M Imaoka S Funae Y Yokota H 《Biochimica et biophysica acta》2005,1726(2):194-205
Only one isoform of cytochrome P450 (CYP) 2E subfamily was known in human and various animals. Three cDNAs corresponding to CYP 2E subfamily members (CYP2E-a, CYP2E-b and CYP2E-c) were obtained from feline liver. These cDNAs each had a 1488-bp nucleotide coding region encoding a predicted amino acid sequence of 495 residues. Eleven amino acid substitutions were observed between CYP2E-a and CYP2E-b, but only one substitution between CYP2E-b and CYP2E-c. The CO difference spectrums about 450 nm wave length and similar values of Vmax and Km of 6-hydoxygenase activity toward chlorzoxazone were observed in all three isoforms expressed in AH22 yeast cells. By PCR-RFLP, mRNA of the CYP2E-a was found to be expressed in liver, mononuclear cells, kidney, lung, stomach, intestine and pancreas, whereas CYP2E-b and CYP2E-c were expressed mainly in the liver and mononuclear cells. Expression of CYP2E-a was observed in the livers of all felines tested, but CYP2E-b and CYP2E-c were not expressed in all cats. The sequences of two different introns between exons I and II and between exons VII and VIII were obtained in genomic DNA from the feline liver. Based on these results, we conclude that cats have two highly similar CYP2E genes. 相似文献
955.
Enomoto Y Sugita M Matsunaga I Naka T Sato A Kawashima T Shimizu K Takahashi H Norose Y Yano I 《Biochemical and biophysical research communications》2005,337(2):452-456
Mycolic acids are long chain fatty acids that constitute the lipid-rich cell wall framework of mycobacteria. Upon infection, mycobacteria begin to synthesize glucose monomycolate (GMM), a glucosylated species of mycolic acids, by utilizing host-derived glucose as sugar source. Accordingly, GMM production serves as a good indicator for local invasion of mycobacteria, and its detection by the host immune system would favor efficient monitoring of mycobacterial infection. Here, we found that GMM was produced abundantly at 30 degrees C rather than at 37 degrees C and recognized by a GMM-specific, CD1-restricted T cell line that was isolated from mycobacteria-infected human skin. Since the common portal sites for mycobacterial infection include ventilating alveoli of the lung and the externally exposed skin that often render invading microbes survive at reduced temperature, sampling GMM by CD1 lipid antigen-presenting molecules may allow the host to detect mycobacterial infection at its early phases. 相似文献
956.
Changes in endothelin-1 (ET-1)-induced contraction and activation of RhoA in bronchial smooth muscle of repeatedly antigen-challenged rats, which exhibit marked airway hyperresponsiveness (AHR), were examined. The ET-1-induced contraction of bronchial smooth muscle was significantly enhanced in the repeatedly antigen-challenged group. In normal control animals, ET-1 induced time- and concentration-dependent translocation of RhoA to the plasma membrane, indicating activation of RhoA by ET-1 in rat bronchial smooth muscle. The level of ET-1-induced RhoA translocation was increased much more markedly in the AHR group than in the control animals. It is suggested that the augmented activation of RhoA observed in the hyperresponsive bronchial smooth muscle might be responsible for the enhanced ET-1-induced contraction of bronchial smooth muscle in AHR rats. 相似文献
957.
Resistance to viral infection by intraepithelial lymphocytes in HIV-1 P18-I10-specific T-cell receptor transgenic mice 总被引:2,自引:0,他引:2
Kuribayashi H Wakabayashi A Shimizu M Kaneko H Norose Y Nakagawa Y Wang J Kumagai Y Margulies DH Takahashi H 《Biochemical and biophysical research communications》2004,316(2):356-363
For the analysis of mucosal immunity to HIV-1, we have recently established a line of transgenic (Tg) mice expressing the TCRalpha and TCRbeta genes of the murine CTL clone RT1 specific for P18-I10 (RGPGRAFVTI), an immunodominant gp160 envelope-derived epitope of IIIB isolate, restricted by the H-2D(d) MHC-I molecule. Here we examine those cells bearing specific TCR among the intraepithelial lymphocytes (IELs), with flow cytometric analysis using H-2D(d)/P18-I10 tetramers. We observed three distinct CD3(+), tetramer positive populations among the IELs: extra-thymic CD8alphabeta(+), alphabetaTCR T-cells; CD8 alphaalpha+, gammadeltaTCR T-cells; and thymus-derived CD8alphabeta+, alphabetaTCR T-cells. Challenge of these Tg mice with P18-I10 encoded by a vaccinia virus vector, either intrarectally (i.r.) or intraperitoneally (i.p.), revealed that the intraepithelial compartment seems to be a major site for prevention of the spread of viral infection. Such immunity appears due to the thymus-derived, CD8alphabeta+ antigen-specific CTLs together with CD8alphaalpha+ gammadelta cells, which regulate virus spread. This model system for studying CTL based immunity at mucosal sites should prove helpful in developing rational approaches for HIV control. 相似文献
958.
Kubo T Maezawa N Osada M Katsumura S Funae Y Imaoka S 《Biochemical and biophysical research communications》2004,318(4):1006-1011
Bisphenol A (BpA), an endocrine-disrupting chemical, is known to be a xenoestrogen and to affect the reproductive functions of animals. Recent reports have documented BpA-induced developmental abnormalities in the neuronal systems of humans and animals, and these effects appear to be non-estrogenic. In this study, we found that BpA inhibited the hypoxic response of human hepatoma cells. The expression of hypoxic response genes such as the erythropoietin (EPO) gene is done via a hypoxia inducible factor 1 (HIF-1)-dependent signaling pathway. To investigate possible structural requirements for this inhibitory effect, several BpA analogs were synthesized and added to this system. The blocking of two phenol groups in BpA did not change the effect, but the inhibition completely disappeared by the removal of two central methyl groups in BpA (the resulting compound is designated BpF). BpA, but not BpF, promoted degradation of the HIF-1alpha protein, which is a component of HIF-1, followed by inhibition of EPO induction. An immunoprecipitation assay indicated that BpA dissociated heat shock protein 90 (Hsp90) from HIF-1alpha and destabilized HIF-1alpha protein. HIF-1alpha is usually degraded first by ubiquitination and then by the proteasome pathway. Cobalt ion inhibits ubiquitination of HIF-1alpha and stabilizes it. In the present study, BpA promoted HIF-1alpha degradation in the presence of cobalt and in the presence of proteasome inhibitor. These results suggest that BpA degraded HIF-1alpha via a currently unknown pathway, and that this phenomenon required two methyl groups in BpA. 相似文献
959.
Maruyama M Nishio T Kato T Yoshida T Ishida C Watanabe Y Nishikawa M Kaneda Y Takakura Y 《Journal of cellular physiology》2004,201(1):117-125
We have recently demonstrated that when IFN-beta was exogenously expressed in epithelial cells, transiently expressed IFN-beta was predominantly secreted from the cell side to which the transfection was performed, while stably expressed one was almost equally secreted to the apical and basolateral sides. In the present study, we analyzed the subcellular transport of IFN-beta using confocal imaging with green fluorescent protein (GFP)-tagged IFN-beta in Madin-Darby canine kidney (MDCK) cells. Stably expressed and transiently expressed human IFN-beta (HuIFN-beta)-GFPs were seen in upper regions of the nucleus. In stable HuIFN beta-GFP-producing transformants, transiently expressed mouse IFN-beta (MuIFN-beta) was apparently co-localized with the bulk of the constitutive HuIFN beta-GFP proteins at TGN, and a significant quantity of them then appeared to pass into distinct post-TGN vesicles, accepting either type of IFN. Meanwhile, when cells were co-transfected with both expression vectors, transiently expressed both IFNs tended to co-localize not only at TGN but in post-TGN vesicles. These results suggest that stably and transiently expressed IFN-betas, albeit co-localized at TGN, were transported through apparently discriminated post-TGN routes. 相似文献
960.
Ameloblastin is a cell adhesion molecule required for maintaining the differentiation state of ameloblasts 总被引:14,自引:0,他引:14
Fukumoto S Kiba T Hall B Iehara N Nakamura T Longenecker G Krebsbach PH Nanci A Kulkarni AB Yamada Y 《The Journal of cell biology》2004,167(5):973-983
Tooth morphogenesis results from reciprocal interactions between oral epithelium and ectomesenchyme culminating in the formation of mineralized tissues, enamel, and dentin. During this process, epithelial cells differentiate into enamel-secreting ameloblasts. Ameloblastin, an enamel matrix protein, is expressed by differentiating ameloblasts. Here, we report the creation of ameloblastin-null mice, which developed severe enamel hypoplasia. In mutant tooth, the dental epithelium differentiated into enamel-secreting ameloblasts, but the cells were detached from the matrix and subsequently lost cell polarity, resumed proliferation, and formed multicell layers. Expression of Msx2, p27, and p75 were deregulated in mutant ameloblasts, the phenotypes of which were reversed to undifferentiated epithelium. We found that recombinant ameloblastin adhered specifically to ameloblasts and inhibited cell proliferation. The mutant mice developed an odontogenic tumor of dental epithelium origin. Thus, ameloblastin is a cell adhesion molecule essential for amelogenesis, and it plays a role in maintaining the differentiation state of secretory stage ameloblasts by binding to ameloblasts and inhibiting proliferation. 相似文献