全文获取类型
收费全文 | 9006篇 |
免费 | 776篇 |
国内免费 | 2篇 |
出版年
2021年 | 86篇 |
2020年 | 55篇 |
2019年 | 66篇 |
2018年 | 101篇 |
2017年 | 96篇 |
2016年 | 131篇 |
2015年 | 205篇 |
2014年 | 257篇 |
2013年 | 504篇 |
2012年 | 413篇 |
2011年 | 429篇 |
2010年 | 247篇 |
2009年 | 228篇 |
2008年 | 395篇 |
2007年 | 420篇 |
2006年 | 400篇 |
2005年 | 417篇 |
2004年 | 385篇 |
2003年 | 370篇 |
2002年 | 381篇 |
2001年 | 324篇 |
2000年 | 367篇 |
1999年 | 337篇 |
1998年 | 110篇 |
1997年 | 93篇 |
1996年 | 98篇 |
1995年 | 99篇 |
1994年 | 85篇 |
1993年 | 110篇 |
1992年 | 274篇 |
1991年 | 185篇 |
1990年 | 197篇 |
1989年 | 199篇 |
1988年 | 303篇 |
1987年 | 176篇 |
1986年 | 149篇 |
1985年 | 131篇 |
1984年 | 103篇 |
1983年 | 85篇 |
1982年 | 57篇 |
1981年 | 58篇 |
1979年 | 74篇 |
1978年 | 56篇 |
1977年 | 38篇 |
1976年 | 42篇 |
1975年 | 42篇 |
1974年 | 57篇 |
1973年 | 42篇 |
1972年 | 49篇 |
1968年 | 37篇 |
排序方式: 共有9784条查询结果,搜索用时 46 毫秒
981.
Bessho M Ohnishi I Matsuyama J Matsumoto T Imai K Nakamura K 《Journal of biomechanics》2007,40(8):1745-1753
Hip fractures are the most serious complication of osteoporosis and have been recognized as a major public health problem. In elderly persons, hip fractures occur as a result of increased fragility of the proximal femur due to osteoporosis. It is essential to precisely quantify the strength of the proximal femur in order to estimate the fracture risk and plan preventive interventions. CT-based finite element analysis could possibly achieve precise assessment of the strength of the proximal femur. The purpose of this study was to create a simulation model that could accurately predict the strength and surface strains of the proximal femur using a CT-based finite element method and to verify the accuracy of our model by load testing using fresh frozen cadaver specimens. Eleven right femora were collected. The axial CT scans of the proximal femora were obtained with a calibration phantom, from which the 3D finite element models were constructed. Materially nonlinear finite element analyses were performed. The yield and fracture loads were calculated, while the sites where elements failed and the distributions of the principal strains were determined. The strain gauges were attached to the proximal femoral surfaces. A quasi-static compression test of each femur was conducted. The yield loads, fracture loads and principal strains of the prediction significantly correlated with those measured (r=0.941, 0.979, 0.963). Finite element analysis showed that the solid elements and shell elements in undergoing compressive failure were at the same subcapital region as the experimental fracture site. 相似文献
982.
Peripheral tolerance and the qualitative characteristics of autoreactive T cell clones in primary biliary cirrhosis 总被引:1,自引:0,他引:1
Kawano A Shimoda S Kamihira T Ishikawa F Niiro H Soejima Y Taketomi A Maehara Y Nakamura M Komori A Migita K Ishibashi H Azuma M Gershwin ME Harada M 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(5):3315-3324
Primary biliary cirrhosis is characterized by autoreactive T cells specific for the mitochondrial Ag PDC-E2(163-176). We studied the ability of eight T cell clones (TCC) specific for PDC-E2(163-176) to proliferate or become anergic in the presence of costimulation signals. TCC were stimulated with either human PDC-E2(163-176), an Escherichia coli 2-oxoglutarate dehydrogenase mimic (OGDC-E2(34-47)), or analogs with amino acid substitutions using HLA-matched allogeneic PBMC or mouse L-DR53 fibroblasts as APC. Based on their differential responses to these peptides (human PDC-E2(163-176), E. coli OGDC-E2(34-47)) in the different APC systems, TCC were classified as costimulation dependent or independent. Only costimulation-dependent TCC could become anergic. TCC with costimulation-dependent responses to OGDC-E2 become anergic to PDC-E2 when preincubated with mimic, even if costimulation is independent for PDC-E2(163-176). Anergic TCC produced IL-10. One selected TCC could not become anergic after preincubation with PDC-E2(163-176)-pulsed L-DR53 but became anergic using L-DR53 pulsed with PDC-E2 peptide analogs with a substitution at a critical TCR binding site. TCC that only respond to peptide-pulsed PBMC, but not L-DR53, proliferate with peptide-pulsed CD80/CD86-transfected L-DR53; however, anergy was not induced with peptide-pulsed L-DR53 transfected with only CD80 or CD86. These data highlight that costimulation plays a dominant role in maintaining peripheral tolerance to PBC-specific Ags. They further suggest that, under specific circumstances, molecular mimicry of an autoantigen may restore rather than break peripheral tolerance. 相似文献
983.
IL-28 elicits antitumor responses against murine fibrosarcoma 总被引:3,自引:0,他引:3
Numasaki M Tagawa M Iwata F Suzuki T Nakamura A Okada M Iwakura Y Aiba S Yamaya M 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(8):5086-5098
IL-28 is a recently described antiviral cytokine. In this study, we investigated the biological effects of IL-28 on tumor growth to evaluate its antitumor activity. IL-28 or retroviral transduction of the IL-28 gene into MCA205 cells did not affect in vitro growth, whereas in vivo growth of MCA205IL-28 was markedly suppressed along with survival advantages when compared with that of controls. When the metastatic ability of IL-28-secreting MCA205 cells was compared with that of controls, the expression of IL-28 resulted in a potent inhibition of metastases formation in the lungs. IL-28-mediated suppression of tumor growth was mostly abolished in irradiated mice, indicating that irradiation-sensitive cells, presumably immune cells, are primarily involved in the IL-28-induced suppression of tumor growth. In vivo cell depletion experiments displayed that polymorphonuclear neutrophils, NK cells, and CD8 T cells, but not CD4 T cells, play an equal role in the IL-28-mediated inhibition of in vivo tumor growth. Consistent with these findings, inoculation of MCA205IL-28 into mice evoked enhanced IFN-gamma production and cytotoxic T cell activity in spleen cells. Antitumor action of IL-28 is partially dependent on IFN-gamma and is independent of IL-12, IL-17, and IL-23. IL-28 increased the total number of splenic NK cells in SCID mice and enhanced IL-12-induced IFN-gamma production in vivo and expanded spleen cells in C57BL/6 mice. Moreover, IL-12 augmented IL-28-mediated antitumor activity in the presence or absence of IFN-gamma. These findings indicate that IL-28 has bioactivities that induce innate and adaptive immune responses against tumors. 相似文献
984.
Huang M Ida H Arima K Nakamura H Aramaki T Fujikawa K Tamai M Kamachi M Kawakami A Yamasaki H Origuchi T Eguchi K 《Life sciences》2007,81(19-20):1461-1466
Our recent report demonstrated that apoptosis-specific autoantibodies against granzyme B-induced cleavage fragments of SS-B (La) were found in the sera from patients with primary Sj?gren's syndrome. The objective of this study was identified by the intracellular redistribution of La autoantigen during granzyme B-induced apoptosis. We developed green fluorescence protein (GFP)-La and GFP-LaDelta220 (generation of granzyme B-specific cleavage of La protein) fusion proteins. GFP-La protein was localized in the nucleus, whereas the GFP-LaDelta220 protein predominantly existed in the cytoplasm in transformed A293T cells. Nuclear GFP-La protein was translocated to cytoplasm after granzyme B enriched YT cells incubation. La protein in human salivary grand HSG cells is cleaved and translocated from the nucleus to the cytoplasm after YT cell co-cultivation. These results suggest that La protein is cleaved by granzyme B and N-terminal La fragment (27 kD) translocated to the cytoplasm, thus leading to a novel autoantibody production during granzyme B-mediated cytotoxicity. 相似文献
985.
Latent TGF-beta-binding protein 2 binds to DANCE/fibulin-5 and regulates elastic fiber assembly 总被引:1,自引:0,他引:1
下载免费PDF全文
![点击此处可从《The EMBO journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Elastic fibers play the principal roles in providing elasticity and integrity to various types of human organs, such as the arteries, lung, and skin. However, the molecular mechanism of elastic fiber assembly that leads to deposition and crosslinking of elastin along microfibrils remains largely unknown. We have previously shown that developing arteries and neural crest EGF-like protein (DANCE) (also designated fibulin-5) is essential for elastogenesis by studying DANCE-deficient mice. Here, we report the identification of latent transforming growth factor-beta-binding protein 2 (LTBP-2), an elastic fiber-associating protein whose function in elastogenesis is not clear, as a DANCE-binding protein. Elastogenesis assays using human skin fibroblasts reveal that fibrillar deposition of DANCE and elastin is largely dependent on fibrillin-1 microfibrils. However, downregulation of LTBP-2 induces fibrillin-1-independent fibrillar deposition of DANCE and elastin. Moreover, recombinant LTBP-2 promotes deposition of DANCE onto fibrillin-1 microfibrils. These results suggest a novel regulatory mechanism of elastic fiber assembly in which LTBP-2 regulates targeting of DANCE on suitable microfibrils to form elastic fibers. 相似文献
986.
Senda M Ito A Tsuchida A Hagiwara T Kaneda T Nakamura Y Kasama K Kiso M Yoshikawa K Katagiri Y Ono Y Ogiso M Urano T Furukawa K Oshima S Furukawa K 《The Biochemical journal》2007,402(3):459-470
Although disialyl glycosphingolipids such as GD3 and GD2 have been considered to be associated with malignant tumours, whether branched-type disialyl glycosphingolipids show such an association is not well understood. We investigated the sialyltransferases responsible for the biosynthesis of DSGG (disialylgalactosylgloboside) from MSGG (monosialylgalactosylgloboside). Among six GalNAc:alpha2,6-sialyltransferases cloned to date, we focused on ST6GalNAc III, V and VI, which utilize sialylglycolipids as substrates. In vitro enzyme analyses revealed that ST6GalNAc III and VI generated DSGG from MSGG with V(max)/K(m) values of 1.91 and 4.16 respectively. Transfection of the cDNA expression vectors for these enzymes resulted in DSGG expression in a renal cancer cell line. Although both ST6GalNAc III and VI genes were expressed in normal kidney cells, the expression profiles of ST6GalNAc VI among 20 renal cancer cell lines correlated clearly with those of DSGG, suggesting that the sialyltransferase involved in the synthesis of DSGG in the kidney is ST6GalNAc-VI. ST6GalNAc-VI and DSGG were found in proximal tubule epithelial cells in normal kidney tissues, while they were downregulated in renal cancer cell lines and cancer tissues. All these findings indicated that DSGG was suppressed during the malignant transformation of the proximal tubules as a maturation arrest of glycosylation. 相似文献
987.
988.
Noncanonical function of MEKK2 and MEK5 PB1 domains for coordinated extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase signaling
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
MEKK2 and MEK5 encode Phox/Bem1p (PB1) domains that heterodimerize with one another. MEKK2, MEK5, and extracellular signal-related kinase 5 (ERK5) form a ternary complex through interactions involving the MEKK2 and MEK5 PB1 domains and a 34-amino-acid C-terminal extension of the MEK5 PB1 domain. This C-terminal extension encodes an ERK5 docking site required for MEK5 activation of ERK5. The PB1 domains bind in a front-to-back arrangement, with a cluster of basic amino acids in the front of the MEKK2 PB1 domain binding to the back-end acidic clusters of the MEK5 PB1 domain. The C-terminal moiety, including the acidic cluster of the MEKK2 PB1 domain, is not required for MEK5 binding and binds MKK7. Quiescent MEKK2 preferentially binds MEK5, and MEKK2 activation results in ERK5 activation. Activated MEKK2 binds and activates MKK7, leading to JNK activation. The findings define how the MEKK2 and MEK5 PB1 domains are uniquely used for differential binding of two mitogen-activated protein kinase kinases, MEK5 and MKK7, for the coordinated control of ERK5 and c-Jun N-terminal kinase activation. 相似文献
989.
Dietary flavonoid apigenin is a potential inducer of intracellular oxidative stress: the role in the interruptive apoptotic signal 总被引:1,自引:0,他引:1
Miyoshi N Naniwa K Yamada T Osawa T Nakamura Y 《Archives of biochemistry and biophysics》2007,466(2):274-282
Apigenin is a representative dietary flavone (2-phenyl-4H-1-benzopyran-4-one) inhibiting cancer cell growth both in cell culture systems and in vivo. The prooxidant potential of apigenin was confirmed by the observations using flowcytometric and immunoblotting techniques that the intracellular accumulations of reactive oxygen species (ROS) and protein carbonyls were detected in the cells treated with apigenin in a dose-dependent manner. Conversely, chrysin (5,7-dihydroxyflavone) did not show any prooxidant effect. A structure-activity relationship data thus indicated that a 4'-monohydroxyl group, which can be oxidized to semiquinone radical but not up to quinone-like metabolite, is essential for prooxidant effect. When HL-60 cells were treated with not only a heme synthesis inhibitor succinyl acetone (SA) but also myeloperoxidase (MPO) inhibitors, the ROS level enhanced by apigenin was significantly reduced. The gathered data suggested that peroxidase-catalyzed production of apigenin B-ring phenoxyl radicals might be responsible for the prooxidant effect. This is supported by the observation that MPO is able to catalyze production of apigenin phenoxyl radicals, detected by an electron spin resonance-spin trapping technique. We also reveal that both SA and alpha-tocopherol enhance cellular susceptibility to apoptosis-inducing stimuli by apigenin. In conclusion, the prooxidant effect of apigenin is likely to oxidize a variety of thiols through the formation of phenoxyl radicals and thus seems to play a significant role in the abortive apoptotic pathway switching to necrotic cell death. 相似文献
990.