全文获取类型
收费全文 | 9469篇 |
免费 | 668篇 |
国内免费 | 2篇 |
出版年
2022年 | 48篇 |
2021年 | 104篇 |
2020年 | 67篇 |
2019年 | 86篇 |
2018年 | 106篇 |
2017年 | 97篇 |
2016年 | 197篇 |
2015年 | 307篇 |
2014年 | 373篇 |
2013年 | 515篇 |
2012年 | 541篇 |
2011年 | 560篇 |
2010年 | 402篇 |
2009年 | 338篇 |
2008年 | 484篇 |
2007年 | 541篇 |
2006年 | 502篇 |
2005年 | 535篇 |
2004年 | 502篇 |
2003年 | 477篇 |
2002年 | 483篇 |
2001年 | 127篇 |
2000年 | 94篇 |
1999年 | 118篇 |
1998年 | 162篇 |
1997年 | 104篇 |
1996年 | 113篇 |
1995年 | 125篇 |
1994年 | 121篇 |
1993年 | 122篇 |
1992年 | 89篇 |
1991年 | 84篇 |
1990年 | 102篇 |
1989年 | 93篇 |
1988年 | 71篇 |
1987年 | 79篇 |
1986年 | 72篇 |
1985年 | 75篇 |
1984年 | 77篇 |
1983年 | 79篇 |
1982年 | 65篇 |
1981年 | 78篇 |
1980年 | 62篇 |
1979年 | 57篇 |
1978年 | 50篇 |
1977年 | 51篇 |
1976年 | 47篇 |
1975年 | 43篇 |
1974年 | 41篇 |
1973年 | 37篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
911.
912.
Furdas SD Shekfeh S Bissinger EM Wagner JM Schlimme S Valkov V Hendzel M Jung M Sippl W 《Bioorganic & medicinal chemistry》2011,19(12):3678-3689
We present a combination of database screening, synthesis and in vitro testing to identify novel histone acetyltransferase (HAT) inhibitors. The National Cancer Institute compound collection (NCI) and several commercial databases were filtered by similarity-based virtual screening to find new HAT inhibitors. Employing the recombinant HAT p300/CBP-associated factor (PCAF) and two different histone substrates for screening, pyridoisothiazolones were identified as inhibitors of human PCAF. Due to the limited solubility of the initial hits, we synthesized and tested them on PCAF. The compounds inhibit the proliferation of cancer cells. In summary, valuable chemical tools and potential lead candidates for new anticancer agents directed against HATs as new targets have been identified. 相似文献
913.
Balenga NA Aflaki E Kargl J Platzer W Schröder R Blättermann S Kostenis E Brown AJ Heinemann A Waldhoer M 《Cell research》2011,21(10):1452-1469
The directional migration of neutrophils towards inflammatory mediators, such as chemokines and cannabinoids, occurs via the activation of seven transmembrane G protein coupled receptors (7TM/GPCRs) and is a highly organized process. A crucial role for controlling neutrophil migration has been ascribed to the cannabinoid CB(2) receptor (CB(2)R), but additional modulatory sites distinct from CB(2)R have recently been suggested to impact CB(2)R-mediated effector functions in neutrophils. Here, we provide evidence that the recently de-orphanized 7TM/GPCR GPR55 potently modulates CB(2)R-mediated responses. We show that GPR55 is expressed in human blood neutrophils and its activation augments the migratory response towards the CB(2)R agonist 2-arachidonoylglycerol (2-AG), while inhibiting neutrophil degranulation and reactive oxygen species (ROS) production. Using HEK293 and HL60 cell lines, along with primary neutrophils, we show that GPR55 and CB(2)R interfere with each other's signaling pathways at the level of small GTPases, such as Rac2 and Cdc42. This ultimately leads to cellular polarization and efficient migration as well as abrogation of degranulation and ROS formation in neutrophils. Therefore, GPR55 limits the tissue-injuring inflammatory responses mediated by CB(2)R, while it synergizes with CB(2)R in recruiting neutrophils to sites of inflammation. 相似文献
914.
915.
Wollenhaupt K Reinke K Brüssow KP Kanitz W Tomek W 《Molecular reproduction and development》2011,78(12):895-905
The implantation of the blastocyst into the endometrium is an indispensable premise for successful embryonic development. This process is regulated by maternal and embryonic signals that influence gene expression at the translational level, among other processes. Recently, we have shown that proteolytical cleavage of the prototypical 25‐kDa, mRNA cap‐binding protein eIF4E produces a stable variant with a molecular mass of approximately 23 kDa exclusively in the porcine endometrium during implantation. This is accompanied by dephosphorylation and reduction of the abundant repressor 4E‐BP1. Here, we investigate the distribution of the truncated eIF4E and of 4E‐BP1 in the porcine uterine tissue, their binding in native samples, and we analyzed eIF4E‐, eIF4G‐, and 4E‐BP1‐specific proteolytic activities. Our results show that in pigs, the truncated eIF4E is located in the endometrial luminal epithelium during implantation. Neither glandulary tissue nor stroma expressed any truncated eIF4E. The reduced abundance of 4E‐BP1 during implantation is mainly the result of decay in the glandular epithelia. Moreover, steroid replacements, in vitro protease assays, and cell lysate fractionation showed that eIF4E cleavage and 4E‐BP1 decay both depended on the ovarian steroid hormones estradiol and progestrone, but these effects are the result of different proteolytic activities. Although eIF4G cleavage also depends on calcium, stimulation by these steroids could not be established. We propose that the translation initiation process in the endometrium is differently regulated by the truncated eIF4E, utilizing different abundances of 4E‐BP1 and binding dynamic of eIF4E/4E‐BP1 in distinct forms of implantation. Mol. Reprod. Dev. 78:895–905, 2011. © 2011 Wiley Periodicals, Inc. 相似文献
916.
Tobacco (Nicotiana tabacum) plants strictly adjust the contents of both ATP synthase and cytochrome b(6)f complex to the metabolic demand for ATP and NADPH. While the cytochrome b(6)f complex catalyzes the rate-limiting step of photosynthetic electron flux and thereby controls assimilation, the functional significance of the ATP synthase adjustment is unknown. Here, we reduced ATP synthase accumulation by an antisense approach directed against the essential nuclear-encoded γ-subunit (AtpC) and by the introduction of point mutations into the translation initiation codon of the plastid-encoded atpB gene (encoding the essential β-subunit) via chloroplast transformation. Both strategies yielded transformants with ATP synthase contents ranging from 100 to <10% of wild-type levels. While the accumulation of the components of the linear electron transport chain was largely unaltered, linear electron flux was strongly inhibited due to decreased rates of plastoquinol reoxidation at the cytochrome b(6)f complex (photosynthetic control). Also, nonphotochemical quenching was triggered at very low light intensities, strongly reducing the quantum efficiency of CO(2) fixation. We show evidence that this is due to an increased steady state proton motive force, resulting in strong lumen overacidification, which in turn represses photosynthesis due to photosynthetic control and dissipation of excitation energy in the antenna bed. 相似文献
917.
918.
Helmut Fuchs Valérie Gailus-Durner Thure Adler Juan Antonio Aguilar-Pimentel Lore Becker Julia Calzada-Wack Patricia Da Silva-Buttkus Frauke Neff Alexander Götz Wolfgang Hans Sabine M. Hölter Marion Horsch Gabi Kastenmüller Elisabeth Kemter Christoph Lengger Holger Maier Mikolaj Matloka Gabriele Möller Beatrix Naton Cornelia Prehn Martin Hrabě de Angelis 《Methods (San Diego, Calif.)》2011,53(2):120-135
Model organisms like the mouse are important tools to learn more about gene function in man. Within the last 20 years many mutant mouse lines have been generated by different methods such as ENU mutagenesis, constitutive and conditional knock-out approaches, knock-down, introduction of human genes, and knock-in techniques, thus creating models which mimic human conditions. Due to pleiotropic effects, one gene may have different functions in different organ systems or time points during development. Therefore mutant mouse lines have to be phenotyped comprehensively in a highly standardized manner to enable the detection of phenotypes which might otherwise remain hidden. The German Mouse Clinic (GMC) has been established at the Helmholtz Zentrum München as a phenotyping platform with open access to the scientific community (www.mousclinic.de; [1]). The GMC is a member of the EUMODIC consortium which created the European standard workflow EMPReSSslim for the systemic phenotyping of mouse models (http://www.eumodic.org/ [2]). 相似文献
919.
The shape and motion of cells can yield significant insights into the internal operation of a cell. We present a simple, yet versatile, framework that provides multiple metrics of cell shape and cell shape dynamics. Analysis of migrating Dictyostelium discoideum cells shows that global and local metrics highlight distinct cellular processes. For example, a global measure of shape shows rhythmic oscillations suggestive of contractions, whereas a local measure of shape shows wave-like dynamics indicative of protrusions. From a local measure of dynamic shape, or boundary motion, we extract the times and locations of protrusions and retractions. We find that protrusions zigzag, while retractions remain roughly stationary along the boundary. We do not observe any temporal relationship between protrusions and retractions. Our analysis framework also provides metrics of the boundary as whole. For example, as the cell speed increases, we find that the cell shape becomes more elongated. We also observe that while extensions and retractions have similar areas, their shapes differ. 相似文献
920.
Kudryashev M Cyrklaff M Alex B Lemgruber L Baumeister W Wallich R Frischknecht F 《Cellular microbiology》2011,13(5):731-741
Some Borrelia species are the causative agents of tick-borne Lyme disease responsible for different disabilities depending on species and hosts. Borrelia are highly motile bacterial cells, and light microscopy shows that these spirochetes can associate with each other during movement. Using cryo-electron tomography, we observed closely associated Borrelia cells. Some of these showed a single outer membrane surrounding two longitudinally arranged cytoplasmic cylinders. We also observed fusion of two cytoplasmic cylinders and differences in the surface layer density of fused spirochetes. These processes could play a role in the interaction of Borrelia species with the host's immune system. 相似文献