全文获取类型
收费全文 | 814篇 |
免费 | 67篇 |
出版年
2021年 | 7篇 |
2018年 | 9篇 |
2017年 | 5篇 |
2016年 | 14篇 |
2015年 | 22篇 |
2014年 | 21篇 |
2013年 | 35篇 |
2012年 | 46篇 |
2011年 | 37篇 |
2010年 | 34篇 |
2009年 | 17篇 |
2008年 | 40篇 |
2007年 | 40篇 |
2006年 | 38篇 |
2005年 | 31篇 |
2004年 | 43篇 |
2003年 | 34篇 |
2002年 | 36篇 |
2001年 | 25篇 |
2000年 | 14篇 |
1999年 | 12篇 |
1998年 | 9篇 |
1997年 | 9篇 |
1996年 | 11篇 |
1995年 | 6篇 |
1994年 | 7篇 |
1993年 | 14篇 |
1992年 | 6篇 |
1991年 | 8篇 |
1990年 | 8篇 |
1988年 | 6篇 |
1987年 | 5篇 |
1986年 | 11篇 |
1985年 | 8篇 |
1984年 | 10篇 |
1983年 | 12篇 |
1982年 | 11篇 |
1981年 | 4篇 |
1980年 | 7篇 |
1977年 | 11篇 |
1973年 | 4篇 |
1965年 | 5篇 |
1937年 | 4篇 |
1936年 | 4篇 |
1935年 | 8篇 |
1932年 | 5篇 |
1931年 | 7篇 |
1930年 | 7篇 |
1929年 | 11篇 |
1927年 | 4篇 |
排序方式: 共有881条查询结果,搜索用时 15 毫秒
71.
Chromatin plays a fundamental role in eukaryotic genomic regulation, and the increasing awareness of the importance of epigenetic processes in human health and disease emphasizes the need for understanding the structure and function of the nucleosome. Recent advances in chromatin structural studies, including the first structures of nucleosomes containing the Widom 601 sequence and the structure of a chromatin protein-nucleosome assembly, have provided new insight into stretching of nucleosomal DNA, nucleosome positioning, binding of metal ions, drugs and therapeutic candidates to nucleosomes, and nucleosome recognition by nuclear proteins. These discoveries ensure promising future prospects for unravelling structural attributes of chromatin. 相似文献
72.
Rudolph DA Dvorak CA Dvorak L Nepomuceno D Bonaventure P Lovenberg TW Carruthers NI 《Bioorganic & medicinal chemistry letters》2011,21(1):42-44
The synthesis and SAR for a novel series of tetrahydropyrido[3,2-c]pyrroles is described. Optimization of the pendant aryl ring lead to high binding affinity at the 5-HT7 receptor when small lipophilic groups were placed in the para position. Modification of the N-benzyl group and secondary amine were not well tolerated. A representative set of compounds was shown to be functional antagonists of the 5-HT7 receptor. 相似文献
73.
ADP regulates SNF1, the Saccharomyces cerevisiae homolog of AMP-activated protein kinase 总被引:1,自引:0,他引:1
Mayer FV Heath R Underwood E Sanders MJ Carmena D McCartney RR Leiper FC Xiao B Jing C Walker PA Haire LF Ogrodowicz R Martin SR Schmidt MC Gamblin SJ Carling D 《Cell metabolism》2011,14(5):707-714
The SNF1 protein kinase complex plays an essential role in regulating gene expression in response to the level of extracellular glucose in budding yeast. SNF1 shares structural and functional similarities with mammalian AMP-activated protein kinase. Both kinases are activated by phosphorylation on a threonine residue within the activation loop segment of the catalytic subunit. Here we show that ADP is the long-sought metabolite that activates SNF1 in response to glucose limitation by protecting the enzyme against dephosphorylation by Glc7, its physiologically relevant protein phosphatase. We also show that the regulatory subunit of SNF1 has two ADP binding sites. The tighter site binds AMP, ADP, and ATP competitively with NADH, whereas the weaker site does not bind NADH, but is responsible for mediating the protective effect of ADP on dephosphorylation. Mutagenesis experiments suggest that the general mechanism by which ADP protects against dephosphorylation is strongly conserved between SNF1 and AMPK. 相似文献
74.
Li L Leedom TA Do J Huang H Lai J Johnson K Osothprarop TF Rizzo JD Doppalapudi VR Bradshaw CW Lappe RW Woodnutt G Levin NJ Pirie-Shepherd SR 《Translational oncology》2011,4(4):249-257
CVX-045 is produced by covalently attaching a thrombospondin 1 (TSP-1) mimetic comprising a peptidic sequence and a linker to the Fab binding site of a proprietary scaffold antibody. CVX-045 possesses the potency of the TSP-1-derived peptide, along with the advantageous pharmacokinetics of an antibody. Antitumor activity of CVX-045 was evaluated in human xenograft models alone and in combination with standard chemotherapies and targeted molecules. In A549 and A431 xenograft models, CVX-045 demonstrated significant (P < .05) antiangiogenic activity, reducing tumor microvessel density and increasing the levels of necrosis within treated tumors. In an HT-29 xenograft model, CVX-045 in combination with 5-fluorouracil significantly (P < .01) decreased tumor growth rate compared with vehicle, CVX-045, or 5-fluorouracil alone. Cotreatment of CVX-045 plus CPT-11 delayed progression of tumor growth from day 28 to 60. In contrast CVX-045 alone treatment did not delay the progression of tumor growth, and CPT-11 alone delayed progression of tumor growth to day 39. Cotreatment of CVX-045 with sunitinib extended the time to reach tumor load from day 26 to 40. In summary, CVX-045 exhibits significant antiangiogenic activity in several tumor models and enhances antitumor activity in combination with chemotherapy or targeted therapies. These data suggest future avenues for effective combination therapy in treating solid tumors. CVX-045 has recently completed a phase 1 trial in solid tumors where it has been well tolerated. 相似文献
75.
Sherrod M Davis DR Zhou X Cassell MD Sigmund CD 《American journal of physiology. Regulatory, integrative and comparative physiology》2005,289(6):R1763-R1769
Angiotensinogen (AGT) is mainly expressed in glial cells in close proximity to renin-expressing neurons in the brain. We previously reported that glial-specific overexpression of ANG II results in mild hypertension. Here, we tested the hypothesis that glial-derived AGT plays an important role in blood pressure regulation in hypertensive mice carrying human renin (hREN) and human AGT transgenes under the control of their own endogenous promoters. To perform a glial-specific deletion of AGT, we used an AGT transgene containing loxP sites (hAGT(flox)), so the gene can be permanently ablated in the presence of cre-recombinase expression, driven by the glial fibrillary acidic protein (GFAP) promoter. Triple transgenic mice (RAC) containing a: 1) systemically expressed hREN transgene, 2) systemically expressed hAGT(flox) transgene, and 3) GFAP-cre-recombinase were generated and compared with double transgenic mice (RA) lacking cre-recombinase. Liver and kidney hAGT mRNA levels were unaltered in RAC and RA mice, as was the level of hAGT in the systemic circulation, consistent with the absence of cre-recombinase expression in those tissues. Whereas hAGT mRNA was present in the brain of RA mice (lacking cre-recombinase), it was absent from the brain of RAC mice expressing cre-recombinase, confirming brain-specific elimination of AGT. Immunohistochemistry revealed a loss of AGT immunostaining glial cells throughout the brain in RAC mice. Arterial pressure measured by radiotelemetry was significantly lower in RAC than RA mice and unchanged from nontransgenic control mice. These data suggest that there is a major contribution of glial-AGT to the hypertensive state in mice carrying systemically expressed hREN and hAGT genes and confirm the importance of a glial source of ANG II substrate in the brain. 相似文献
76.
To better understand the development of ventral mesencephalic dopamine neurons, we performed subtractive hybridization screens to find ventral mesencephalic genes expressed at rat embryonic day 10 when these neurons begin to differentiate. The most commonly identified genes in these screens were members of the Bex (Brain expressed X-linked) gene family, rat Bex1 (Rex3), and a novel gene, rat Bex4. After identifying these genes, we then sought to characterize the Bex gene family. Two additional novel Bex genes (human Bex5 and mouse Bex6) were discovered through genomic databases. Bex5 is present in humans and monkeys, but not rodents, while Bex6 exists in mice, but not humans. Bex4 and Bex5 are localized to the X chromosome, are expressed in brain, and are similar in sequence. Bex4 and Bex5 are 54% and 56% identical to human Bex3 (pHGR74, NADE). Mouse Bex6 is on chromosome 16 and is 67% identical to mouse Bex4. Human Bex gene expression was studied with tissue expression arrays probed with specific oligonucleotides. Human Bex1 and Bex2 have similar expression patterns in the central nervous system with high levels in pituitary, cerebellum, and temporal lobe, and Bex1 is widely expressed outside of the central nervous system with high expression in the liver. Human Bex4 is highly expressed in heart, skeletal muscle, and liver, while Bex3 and Bex5 are more widely expressed. The subcellular localization of the Bex proteins varies from nuclear (rat Bex1) to cytoplasmic (rat Bex3, human Bex5, and mouse Bex6) and to both nuclear and cytoplasmic (rat Bex2 and rat Bex4). Rat Bex3, rat Bex4, human Bex5, and mouse Bex6 are degraded by the proteasome, while rat Bex1 or Bex2 are not. Rat Bex3 protein can likely bind transition metals through a histidine-rich domain. Because this gene family was originally named Bex and because these genes are unified by sequence similarity and gene structure, we believe the Bex nomenclature should prevail over nomenclature based on function (NADE) that has not been extended to the other Bex genes. We conclude that the Bex gene family members are highly homologous but differ in their expression patterns, subcellular localization, and degradation by the proteasome. 相似文献
77.
Haffner CD McDougald DL Reister SM Thompson BD Conlee C Fang J Bass J Lenhard JM Croom D Secosky-Chang MB Tomaszek T McConn D Wells-Knecht K Johnson PR 《Bioorganic & medicinal chemistry letters》2005,15(23):5257-5261
We report the synthesis and biological activity of a series of 2-cyano-4-fluoro-1-thiovalylpyrrolidine inhibitors of DPP-IV. Within this series, compound 19 provided a potent, selective, and orally active DPP-IV inhibitor which demonstrated a very long duration of action in both rat and dog. 相似文献
78.
79.
80.
Dellinger TA Youngman RR Laub CA Brewster CC Kuhar TP 《Journal of economic entomology》2005,98(1):72-81
Cultivars of glandular-haired alfalfa, Medicago sativa L., such as '54H69', are currently available and marketed as being resistant to potato leafhopper, Empoasca fabae (Harris). Between 2000 and 2002, studies were conducted to compare the effects of '54H69' and a standard, nonglandular-haired alfalfa cultivar, 'Choice', on alfalfa weevil, Hypera postica (Gyllenhal), and potato leafhopper populations at Campbell and Montgomery counties, Virginia. '54H69' had no effect on alfalfa weevil populations. At each location, densities of alfalfa weevil in '54H69' and 'Choice' were similar, but pest pressure was higher at Campbell Co. than at Montgomery Co. and always exceeded the economic threshold before insecticide was applied. Densities of potato leafhopper also did not differ between '54H69' and 'Choice' in any year at the two locations. Insecticide treatment effectively reduced potato leafhopper densities in the two cultivars, although populations were below the economic threshold at both locations when the insecticides were applied. Overall, postinsecticide treatment comparisons showed that the densities of alfalfa weevil and potato leafhoppers were similar or higher in untreated '54H69' compared with insecticide-treated 'Choice'. In addition, there were no differences in seasonal dry yields between '54H69' and 'Choice' in any year at either location. Our results indicate that the glandular-haired alfalfa '54H69' does not provide acceptable resistance to potato leafhopper and also does not offer a yield advantage to growers in Virginia. 相似文献