全文获取类型
收费全文 | 2566篇 |
免费 | 133篇 |
国内免费 | 2篇 |
出版年
2019年 | 18篇 |
2018年 | 26篇 |
2017年 | 25篇 |
2016年 | 39篇 |
2015年 | 53篇 |
2014年 | 74篇 |
2013年 | 161篇 |
2012年 | 131篇 |
2011年 | 130篇 |
2010年 | 90篇 |
2009年 | 76篇 |
2008年 | 126篇 |
2007年 | 129篇 |
2006年 | 102篇 |
2005年 | 137篇 |
2004年 | 135篇 |
2003年 | 137篇 |
2002年 | 129篇 |
2001年 | 57篇 |
2000年 | 59篇 |
1999年 | 61篇 |
1998年 | 31篇 |
1997年 | 29篇 |
1996年 | 21篇 |
1994年 | 18篇 |
1993年 | 17篇 |
1992年 | 41篇 |
1991年 | 41篇 |
1990年 | 34篇 |
1989年 | 26篇 |
1988年 | 41篇 |
1987年 | 26篇 |
1986年 | 33篇 |
1985年 | 24篇 |
1984年 | 23篇 |
1983年 | 23篇 |
1982年 | 17篇 |
1981年 | 23篇 |
1980年 | 17篇 |
1979年 | 24篇 |
1978年 | 20篇 |
1977年 | 25篇 |
1975年 | 19篇 |
1974年 | 19篇 |
1973年 | 29篇 |
1972年 | 15篇 |
1971年 | 18篇 |
1969年 | 21篇 |
1968年 | 15篇 |
1966年 | 16篇 |
排序方式: 共有2701条查询结果,搜索用时 46 毫秒
991.
Tani K Naganawa A Ishida A Egashira H Odagaki Y Miyazaki T Hasegawa T Kawanaka Y Sagawa K Harada H Ogawa M Maruyama T Nakai H Ohuchida S Kondo K Toda M 《Bioorganic & medicinal chemistry》2002,10(6):1883-1894
A series of 9-halo PGF analogues 1-2 and 5-13 were synthesized and biologically evaluated. Among the compounds, 2 was the best EP2-receptor agonist. A practical method of synthesizing 2 via the Julia olefination of an aldehyde 3 with an optically active sulfone 4, which was prepared by Sharpless asymmetric epoxidation of 15, was developed. Other 9-halogenated PGF analogues were synthesized essentially by the same procedure and evaluated. The absolute configuration of 16-OH of 2 was determined as S by the X-ray analysis of a salt consisting of a 1/1 molar ratio of 2 and L-lysine. 相似文献
992.
RecQ DNA helicases from many organisms have been indicated to function in the maintenance of genomic stability. In human cells, mutation in the WRN helicase, a RecQ-like DNA helicase, results in the Werner syndrome (WS), a genetic disorder characterized by genomic instability and premature ageing. Similarly, mutation in SGS1, the RECQ homologue in budding yeast, results in genomic instability and accelerated ageing. We previously demonstrated that mouse WRN interacts physically with a novel, highly conserved protein that we named WHIP, and that in budding yeast cells, simultaneous deletion of WHIP/MGS1 and SGS1 results in slow growth and shortened life span. Here we show by using genetic analysis in Saccharomyces cerevisiae that mgs1Delta sgs1Delta cells have increased rates of terminal G2/M arrest, and show elevated rates of spontaneous sister chromatid recombination (SCR) and rDNA array recombination. Finally, we report that complementation of the synthetic relationship between SGS1 and WHIP/MGS1 requires both the helicase and Top3-binding activities of Sgs1, as well as the ATPase activity of Mgs1. Our results suggest that Whip/Mgs1 is implicated in DNA metabolism, and is required for normal growth and cell cycle progression in the absence of Sgs1. 相似文献
993.
994.
995.
996.
Sofia Zanin Christian Borgo Cristina Girardi Sean E. O'Brien Yoshihiko Miyata Lorenzo A. Pinna Arianna Donella-Deana Maria Ruzzene 《PloS one》2012,7(11)
CK2 is a pleiotropic protein kinase, which regulates many survival pathways and plays a global anti-apoptotic function. It is highly expressed in tumor cells, and is presently considered a promising therapeutic target. Among the many inhibitors available for this kinase, the recently developed CX-4945 and CX-5011 have proved to be very potent, selective and effective in inducing cell death in tumor cells; CX-4945 has recently entered clinical trials. However, no data are available on the efficacy of these compounds to overcome drug resistance, a major reasons of cancer therapy failure. Here we address this point, by studying their effects in several tumor cell lines, each available as variant R resistant to drug-induced apoptosis, and normal-sensitive variant S. We found that the inhibition of endogenous CK2 was very similar in S and R treated cells, with more than 50% CK2 activity reduction at sub-micromolar concentrations of CX-4945 and CX-5011. A consequent apoptotic response was induced both in S and R variants of each pairs. Moreover, the combined treatment of CX-4945 plus vinblastine was able to sensitize to vinblastine R cells that are otherwise almost insensitive to this conventional antitumor drug. Consistently, doxorubicin accumulation in multidrug resistant (MDR) cells was greatly increased by CX-4945.In summary, we demonstrated that all the R variants are sensitive to CX-4945 and CX-5011; since some of the treated R lines express the extrusion pump Pgp, often responsible of the MDR phenotype, we can also conclude that the two inhibitors can successfully overcome the MDR phenomenon. 相似文献
997.
Akari Takahashi Toshihiko Torigoe Yasuaki Tamura Takayuki Kanaseki Tomohide Tsukahara Yasushi Sasaki Hidekazu Kameshima Tetsuhiro Tsuruma Koichi Hirata Takashi Tokino Yoshihiko Hirohashi Noriyuki Sato 《Cell stress & chaperones》2012,17(6):757-763
Focal inflammation causes systemic fever. Cancer hyperthermia therapy results in shrinkage of tumors by various mechanisms, including induction of adaptive immune response. However, the physiological meaning of systemic fever and mechanisms of tumor shrinkage by hyperthermia have not been completely understood. In this study, we investigated how heat shock influences the adaptive immune system. We established a cytotoxic T lymphocyte (CTL) clone (#IM29) specific for survivin, one of the tumor-associated antigens (TAAs), from survivin peptide-immunized cancer patients’ peripheral blood, and the CTL activities were investigated in several temperature conditions (37–41 °C). Cytotoxicity and IFN-γ secretion of CTL were greatest under 39 °C condition, whereas they were minimum under 41 °C. To address the molecular mechanisms of this phenomenon, we investigated the apoptosis status of CTLs, expression of CD3, CD8, and TCRαβ by flow cytometry, and expression of perforin, granzyme B, and Fas ligand by western blot analysis. The expression of perforin and granzyme B were upregulated under temperature conditions of 39 and 41 °C. On the other hand, CTL cell death was induced under 41 °C condition with highest Caspase-3 activity. Therefore, the greatest cytotoxicity activity at 39 °C might depend on upregulation of cytotoxic granule proteins including perforin and granzyme B. These results suggest that heat shock enhances effector phase of the adaptive immune system and promotes eradication of microbe and tumor cells.
Electronic supplementary material
The online version of this article (doi:10.1007/s12192-012-0348-0) contains supplementary material, which is available to authorized users. 相似文献998.
Hiroyuki Iketani Hironori Katayama Chiyomi Uematsu Nobuko Mase Yoshihiko Sato Toshiya Yamamoto 《Plant Systematics and Evolution》2012,298(9):1689-1700
By use of Bayesian statistical inference and allelic data for 18 microsatellite loci, we analyzed the genetic structure of Chinese, Korean, and Japanese pear cultivars and of native populations of Pyrus ussuriensis. Although Japanese pear cultivars had a simple genetic structure, Chinese and Korean pear cultivars were admixures of Japanese pear and native P. ussuriensis from the Asian continent. Genetic differentiation between groups of native populations and those of cultivars was high, but cultivars were not well differentiated from each other. Chinese and Korean cultivars, which have traditionally been classified as either P. ussuriensis, P. bretschneideri, or P. pyrifolia, were much closer to Japanese cultivars, which have traditionally been classified as P. pyrifolia, than to native P. ussuriensis. We propose a new classification of cultivars by using the Group concept in accordance with the International Nomenclature for Cultivated Plants, namely, the Pyrus Ussurian pear group, the Pyrus Chinese white pear group, the Pyrus Chinese sand pear group, and the Pyrus Japanese pear group. 相似文献
999.
Akihiro WatariKiyohito Yagi Masuo Kondoh 《Biochemical and biophysical research communications》2012,426(4):454-460
Claudin-4, a member of a tetra-transmembrane protein family that comprises 27 members, is a key functional and structural component of the tight junction-seal in mucosal epithelium. Modulation of the claudin-4-barrier for drug absorption is now of research interest. Disruption of the claudin-4-seal occurs during inflammation. Therefore, claudin-4 modulators (repressors and inducers) are promising candidates for drug development. However, claudin-4 modulators have never been fully developed. Here, we attempted to design a screening system for claudin-4 modulators by using a reporter assay. We prepared a plasmid vector coding a claudin-4 promoter-driven luciferase gene and established stable reporter gene-expressing cells. We identified thiabendazole, carotene and curcumin as claudin-4 inducers, and potassium carbonate as a claudin-4 repressor by using the reporter cells. They also increased or decreased, respectively, the integrity of the tight junction-seal in Caco-2 cells. This simple reporter system will be a powerful tool for the development of claudin-4 modulators. 相似文献
1000.
Yoshizaki T Kusunoki C Kondo M Yasuda M Kume S Morino K Sekine O Ugi S Uzu T Nishio Y Kashiwagi A Maegawa H 《Biochemical and biophysical research communications》2012,417(1):352-357
Autophagy is an essential process for both the maintenance and the survival of cells, with homeostatic low levels of autophagy being critical for intracellular organelles and proteins. In insulin resistant adipocytes, various dysfunctional/damaged molecules, organelles, proteins, and end-products accumulate. However, the role of autophagy (in particular, whether autophagy is activated or not) is poorly understood. In this study we found that in adipose tissue of insulin resistant mice and hypertrophic 3T3-L1 adipocytes autophagy was suppressed. Also in hypertrophic adipocytes, autophagy-related gene expression, such as LAMP1, LAMP2, and Atg5 was reduced, whereas gene expression in the inflammatory-related genes, such as MCP-1, IL-6, and IL-1β was increased. To find out whether suppressed autophagy was linked to inflammation we used the autophagy inhibitor, 3-methyladenine, to inhibit autophagy. Our results suggest that such inhibition leads to an increase in inflammatory gene expression and causes endoplasmic reticulum (ER) stress (which can be attenuated by treatment with the ER stress inhibitor, Tauroursodeoxycholic Acid). Conversely, the levels of inflammatory gene expression were reduced by the activation of autophagy or by the inhibition of ER stress. The results indicate that the suppression of autophagy increases inflammatory responses via ER stress, and also defines a novel role of autophagy as an important regulator of adipocyte inflammation in systemic insulin resistance. 相似文献