全文获取类型
收费全文 | 108篇 |
免费 | 13篇 |
出版年
2024年 | 1篇 |
2016年 | 1篇 |
2015年 | 3篇 |
2014年 | 4篇 |
2013年 | 1篇 |
2012年 | 4篇 |
2011年 | 5篇 |
2010年 | 6篇 |
2009年 | 5篇 |
2008年 | 5篇 |
2007年 | 16篇 |
2006年 | 5篇 |
2005年 | 5篇 |
2004年 | 4篇 |
2003年 | 3篇 |
2002年 | 7篇 |
2001年 | 3篇 |
2000年 | 1篇 |
1999年 | 1篇 |
1998年 | 4篇 |
1996年 | 1篇 |
1995年 | 1篇 |
1994年 | 2篇 |
1992年 | 3篇 |
1991年 | 3篇 |
1990年 | 4篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1985年 | 1篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1981年 | 1篇 |
1978年 | 2篇 |
1975年 | 1篇 |
1970年 | 1篇 |
1942年 | 1篇 |
1941年 | 1篇 |
1940年 | 1篇 |
1925年 | 1篇 |
1924年 | 1篇 |
排序方式: 共有121条查询结果,搜索用时 15 毫秒
61.
Ken C.N. Chang Yihe Wang Peter V.N. Bodine Sunil Nagpal Barry S. Komm 《The Journal of steroid biochemistry and molecular biology》2010,118(1-2):117-124
Bazedoxifene (BZA), a new selective estrogen receptor modulator (SERM) was recently approved in Europe for the prevention and treatment of postmenopausal osteoporosis. Combination therapy using BZA and conjugated estrogens (CE) is currently in late stage development representing a new paradigm for the treatment of menopausal symptoms and prevention of osteoporosis. A GeneChip microarray study was designed to compare gene expression profiles of BZA to that of other SERMs, raloxifene (RAL) and lasofoxifene (LAS). In addition, we compared the gene expression profiles of the three SERMs in combination with CE, a mixture of 10 most abundant estrogens present in Premarin. According to the hierarchical clustering heat map analysis, gene clusters that specifically responded to CE treatments or SERM treatments were identified and gene lists sorted based on a set of cutoff filters. A group of genes differentially regulated by CE were also identified to be antagonized by BZA when comparing CE with the BZA + CE treatment. All three SERMs showed significant antagonistic effect against CE-stimulated cell proliferation, based on the MCF-7 cell proliferation assay and GeneChip data, with the order of antagonist activity being BZA > RAL > LAS. These results indicate that SERMs in combination with CE exhibit differential pharmacology, and therefore, combinations of other SERMs and estrogen preparations may not yield the same effects that are observed in clinic by pairing BZA with CE. 相似文献
62.
Plantevin Krenitsky V Nadolny L Delgado M Ayala L Clareen SS Hilgraf R Albers R Hegde S D'Sidocky N Sapienza J Wright J McCarrick M Bahmanyar S Chamberlain P Delker SL Muir J Giegel D Xu L Celeridad M Lachowitzer J Bennett B Moghaddam M Khatsenko O Katz J Fan R Bai A Tang Y Shirley MA Benish B Bodine T Blease K Raymon H Cathers BE Satoh Y 《Bioorganic & medicinal chemistry letters》2012,22(3):1433-1438
In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF. 相似文献
63.
64.
Hwee DT Gomes AV Bodine SC 《American journal of physiology. Endocrinology and metabolism》2011,301(5):E967-E977
Muscle ring finger-1 (MuRF1) is a muscle-specific E3 ubiquitin ligase that has been implicated in the regulation of cardiac mass through its control of the ubiquitin proteasome system. While it has been suggested that MuRF1 is required for cardiac atrophy, a resting cardiac phenotype has not been reported in mice with a null deletion [knockout (KO)] of MuRF1. Here, we report that MuRF1 KO mice have significantly larger hearts than age-matched wild-type (WT) littermates at ≥ 6 mo of age and that loss of cardiac mass can occur in the absence of MuRF1. The objective of this study was to determine whether changes in proteasome activity were responsible for the cardiac phenotypes observed in MuRF1 KO mice. Cardiac function, architecture, and proteasome activity were analyzed at rest and following 28 days of dexamethasone (Dex) treatment in 6-mo-old WT and MuRF1 KO mice. Echocardiography demonstrated normal cardiac function in the enlarged hearts in MURF1 KO mice. At rest, heart mass and cardiomyocyte diameter were significantly greater in MuRF1 KO than in WT mice. The increase in cardiac size in MuRF1 KO mice was related to a decrease in proteasome activity and an increase in Akt signaling relative to WT mice. Dex treatment induced a significant loss of cardiac mass in MuRF1 KO, but not WT, mice. Furthermore, Dex treatment resulted in an increase in proteasome activity in KO, but a decrease in WT, mice. In contrast, Akt/mammalian target of rapamycin signaling decreased in MuRF1 KO mice and increased in WT mice in response to Dex treatment. These findings demonstrate that MuRF1 plays an important role in regulating cardiac size through alterations in protein turnover and that MuRF1 is not required to induce cardiac atrophy. 相似文献
65.
66.
Background
The attenuated Yellow fever (YF) 17D vaccine virus is one of the safest and most effective viral vaccines administered to humans, in which it elicits a polyvalent immune response. Herein, we used the YF 17D backbone to express a Trypanosoma cruzi CD8+ T cell epitope from the Amastigote Surface Protein 2 (ASP-2) to provide further evidence for the potential of this virus to express foreign epitopes. The TEWETGQI CD8+ T cell epitope was cloned and expressed based on two different genomic insertion sites: in the fg loop of the viral Envelope protein and the protease cleavage site between the NS2B and NS3. We investigated whether the site of expression had any influence on immunogenicity of this model epitope.Results
Recombinant viruses replicated similarly to vaccine virus YF 17D in cell culture and remained genetically stable after several serial passages in Vero cells. Immunogenicity studies revealed that both recombinant viruses elicited neutralizing antibodies to the YF virus as well as generated an antigen-specific gamma interferon mediated T-cell response in immunized mice. The recombinant viruses displayed a more attenuated phenotype than the YF 17DD vaccine counterpart in mice. Vaccination of a mouse lineage highly susceptible to infection by T. cruzi with a homologous prime-boost regimen of recombinant YF viruses elicited TEWETGQI specific CD8+ T cells which might be correlated with a delay in mouse mortality after a challenge with a lethal dose of T. cruzi.Conclusions
We conclude that the YF 17D platform is useful to express T. cruzi (Protozoan) antigens at different functional regions of its genome with minimal reduction of vector fitness. In addition, the model T. cruzi epitope expressed at different regions of the YF 17D genome elicited a similar T cell-based immune response, suggesting that both expression sites are useful. However, the epitope as such is not protective and it remains to be seen whether expression of larger domains of ASP-2, which include the TEWETGQI epitope, will elicit better T-CD8+ responses to the latter. It is likely that additional antigens and recombinant virus formulations will be necessary to generate a protective response. 相似文献67.
68.
69.
A pregnant Holstein cow was experimentally inoculated with bovine parvovirus. Approximately five weeks after the last of three injections, the animal aborted a fetus which showed signs of mummification. Virus particles similar to bovine parvovirus were identified by electron microscopy from fetal lung tissue and intestinal contents. Five months after the abortion, the experimental animal died of a corynebacterial metritis and septicemia. Immunofluorescence tests were performed on representative tissues obtained at necropsy. Of all tissues examined only the uterus showed a positive response to the immunofluorescence assay, indicating that the viral antigen persisted in the uterine environment long after its elimination from the systemic circulation. 相似文献
70.
Lowering of extracellular Ca2+ levels will reversibly arrest the growth of human fibroblasts (WI38). Simian virus40(SV40)-transformed WI38 cells do not exhibit this Ca2+-dependent arrest. One possibility for this difference in Ca2+ requirement is that extracellular or surface membrane-bound Ca2+ may be required for growth factor receptor-mediated endocytosis and this Ca2+ requirement may differ in normal versus transformed cells. In this study we have evaluated the role of Ca2+ in the binding, internalization, and degradation of epidermal growth factor (EGF) in the WI38 and SV40 WI38 cell. The binding of [125I]EGF to the cell surface is not significantly altered by lowering of Ca2+ to 10?5-M levels in either the normal or transformed cell. At this Ca2+ level, growth of the normal cell is inhibited. The subsequent internalization of EGF is reduced nearly threefold in the normal cell but not in the transformed cell following Ca2+ deprivation. Degradation of the EGF-receptor complex is also sensitive to Ca2+. A twofold reduction in the rate of release of acid-soluble 125I occurs in the normal but not the transformed cell under conditions of lowered medium Ca2+. In contrast, 2-chloro-10-3-aminopropyl phenothiazine (CP), an inhibitor of the Ca2+-dependent regulator protein calmodulin, causes an inhibition of [125I]EGF internalization and degradation in both the normal and transformed WI38 cell, and a marked inhibition of [125I]EGF binding to the cell surface receptor of the transformed cell but not the normal cell. 相似文献