全文获取类型
收费全文 | 24014篇 |
免费 | 2221篇 |
国内免费 | 61篇 |
专业分类
26296篇 |
出版年
2022年 | 167篇 |
2021年 | 284篇 |
2020年 | 166篇 |
2019年 | 234篇 |
2018年 | 275篇 |
2017年 | 246篇 |
2016年 | 390篇 |
2015年 | 738篇 |
2014年 | 788篇 |
2013年 | 1185篇 |
2012年 | 1315篇 |
2011年 | 1327篇 |
2010年 | 833篇 |
2009年 | 791篇 |
2008年 | 1209篇 |
2007年 | 1214篇 |
2006年 | 1127篇 |
2005年 | 1137篇 |
2004年 | 1067篇 |
2003年 | 1031篇 |
2002年 | 1016篇 |
2001年 | 327篇 |
2000年 | 287篇 |
1999年 | 345篇 |
1998年 | 314篇 |
1997年 | 235篇 |
1996年 | 249篇 |
1995年 | 223篇 |
1994年 | 236篇 |
1993年 | 214篇 |
1992年 | 255篇 |
1991年 | 243篇 |
1990年 | 212篇 |
1989年 | 228篇 |
1988年 | 246篇 |
1987年 | 229篇 |
1986年 | 193篇 |
1985年 | 243篇 |
1984年 | 266篇 |
1983年 | 229篇 |
1982年 | 242篇 |
1981年 | 274篇 |
1980年 | 242篇 |
1979年 | 212篇 |
1978年 | 223篇 |
1977年 | 208篇 |
1976年 | 186篇 |
1975年 | 188篇 |
1974年 | 201篇 |
1973年 | 192篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Androgen receptor heterogeneity in LNCaP cells is caused by a hormone independent phosphorylation step 总被引:6,自引:0,他引:6
George G. J. M. Kuiper Petra E. de Ruiter Albert O. Brinkmann 《The Journal of steroid biochemistry and molecular biology》1992,41(3-8):697-700
Androgen receptor synthesis and modification were studied in the human LNCaP cell line. Immunoblotting showed that the androgen receptor migrated as a closely spaced 110–112 kDa doublet on SDS-PAGE gels. Most of the receptor protein is present in the higher molecular mass form. Labelling experiments with [35S]methionine showed that the androgen receptor is synthesized as a single 110 kDa protein which is rapidly converted to a 112 kDa protein. Upon alkaline phosphatase treatment a gradual elimination of the 112 kDa isoform with a concomitant increase of the 110 kDa isoform was seen, indicating that the observed 110 to 112 kDa upshift reflects androgen receptor phosphorylation. Furthermore, it is shown that both isoforms can bind hormone and undergo a hormone dependent transformation to a tight nuclear binding form, indicating that the 110 to 112 kDa conversion is not an obligatory step for hormone binding or receptor transformation. 相似文献
992.
An arctic river was fertilized continuously through the ice-free season with phosphoric acid beginning in 1983. The epilithic
diatom community increased in biomass in the first two years in response to the added limiting nutrient (Peterson et al., 1983). The diatom community switched from one dominated by Hannea arcus to one dominated by species of Achnanthes and Cymbella. The immediate responses to the P-addition were decreases in both
the Shannon diversity and evenness indices. By the second year, the community diversity increased downriver reaching maximal
species richness (110–127 spp). In 1985–1987, the epilithic algal biomass decreased an order of magnitude with both whole-river
PO4 (1985, 1987) and PO4 + NH4 addition (1986). In the 5th summer of fertilization, the reduction in biomass was clearly caused by a numerical increase
of grazing, refugia-building chironomids (Orthocladiinae, primarily) (Gibeau, 1991; Gibeau, Miller, Hershey, in prep.). We
assume the algal biomass reduction in the 3rd and 4th years was similarly caused by grazers with a two year time lag in the
numerical response of these monovoltine species. The evenness of the community increased in 1986 as if it might have been
grazed; however the number of immigrants was reduced. The community became dominated by Eunotia, Cymbella and Achnanthes,
species either fast growing or more prostrate, as the erect species of Hannea Diatoma, and Fragillaria declined. A detrended
correspondence analysis of the temporal and spatial diatom samples in species space (186 spp.) showed that the largest variation
in the community was between years and less variation was associated with river fertilization.
Samples from bioassay tubes run by Peterson et al. (1983) in the Kuparuk River showed P and N + P limitation as found in the river in 1983–84. Like the river samples, the
largest change in the diatom community occurred between 15 and 25 day samples, more than that induced by fertilization. Diatoms
sampled from all treatments taken at day 25 were more similar to one another than those sampled at day 15. Diatoms colonizing
glass slides used in the bioassay tubes were dominated by Achnanthes linearis and Cymbella minuta. Of the 84 species found in bioassays, 26 species were present in all river samples for 4 years. Differences in the communities
discriminated by multivariate methods were cause by changes in rare species and abundance patterns of common species. 相似文献
993.
Summary Bifunctional shuttle vector (pBN183) and recombinant plasmids (pDCO2 and pDCO3) carrying aStreptomyces cholesterol oxidase gene (choA) were deleted to varying degrees inStreptococcus thermophilus. Restriction mapping of the deleted plasmids led to the identification of deletion prone regions in the transforming DNAs. Sequence analysis revealed that direct repeats and hairpin structures occurred in these regions, suggesting that they are deleterious to the stability of plasmids inS. thermophilus. 相似文献
994.
An age-structured population dynamics model is presented that incorporates pheromone-trapping and food-trapping as control methods for an insect pest. The model yields the following results. Low rates of pest survivorship allow lower trapping rates for control. Species with long developmental periods are easier to control than those with shorter developmental periods (other factors being equal) due to lower net survival. The rates of pheromone trapping alone for effective control are usually very high. The combination of pheromone and food trapping allows control with much lower trapping rates than either method alone. Even small amounts of immigration of adult pests into the control area renders pheromone control ineffective, whereas food traps suppress both the immigrants and the resident population. Food- (or odor-) baited traps which attract both males and females are only somewhat more efficient than those which attract females alone. The existence of density-dependent population regulation assists the control program substantially, but this assistance declines as food trapping becomes a more important part of the control program. Larval competition strongly affects the required trapping rates for eradication; species in which all larvae exert strong competition are much easier to control than those in whic the younger larvae contribute little to the total competitive depression. 相似文献
995.
Mona F. Said Riham F. George Andrea Petreni Claudiu T. Supuran Nada M. Mohamed 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):701
In continuation of our previous studies to optimise potent carbonic anhydrase inhibitors, two new series of isatin N-phenylacetamide based sulphonamides were synthesised and screened for their human (h) carbonic anhydrase (EC 4.2.1.1) inhibitory activities against four isoforms hCA I, hCA II, hCA IX and hCA XII. The indole-2,3-dione derivative 2h showed the most effective inhibition profile against hCAI and hCA II (KI = 45.10, 5.87 nM) compared to acetazolamide (AAZ) as standard inhibitor. Moreover, 2h showed appreciable inhibition activity against the tumour-associated hCA XII, similar to AAZ showing KI of 7.91 and 5.70 nM, respectively. The analogs 3c and 3d showed good cytotoxicity effects, and 3c revealed promising selectivity towards lung cell line A549. Molecular docking was carried out for 2h and 3c to predict their binding conformations and affinities towards the hCA I, II, IX and XII isoforms. 相似文献
996.
Vronique Sauv George Sung Emma J MacDougall Guennadi Kozlov Anshu Saran Rayan Fakih Edward A Fon Kalle Gehring 《The EMBO journal》2022,41(12)
PINK1 and parkin constitute a mitochondrial quality control system mutated in Parkinson’s disease. PINK1, a kinase, phosphorylates ubiquitin to recruit parkin, an E3 ubiquitin ligase, to mitochondria. PINK1 controls both parkin localization and activity through phosphorylation of both ubiquitin and the ubiquitin‐like (Ubl) domain of parkin. Here, we observed that phospho‐ubiquitin can bind to two distinct sites on parkin, a high‐affinity site on RING1 that controls parkin localization and a low‐affinity site on RING0 that releases parkin autoinhibition. Surprisingly, ubiquitin vinyl sulfone assays, ITC, and NMR titrations showed that the RING0 site has higher affinity for phospho‐ubiquitin than phosphorylated Ubl in trans. We observed parkin activation by micromolar concentrations of tetra‐phospho‐ubiquitin chains that mimic mitochondria bearing multiple phosphorylated ubiquitins. A chimeric form of parkin with the Ubl domain replaced by ubiquitin was readily activated by PINK1 phosphorylation. In all cases, mutation of the binding site on RING0 abolished parkin activation. The feedforward mechanism of parkin activation confers robustness and rapidity to the PINK1‐parkin pathway and likely represents an intermediate step in its evolutionary development. 相似文献
997.
Anoek Friskes Lisa Koob Lenno Krenning Tesa M Severson Emma
S Koeleman Xabier Vergara Michael Schubert Jeroen van
den
Berg Bastiaan Evers Anna G Manjn Stacey Joosten Yongsoo Kim Wilbert Zwart Ren
H Medema 《Nucleic acids research》2022,50(17):9930
Cells respond to double-strand breaks (DSBs) by activating DNA damage response pathways, including cell cycle arrest. We have previously shown that a single double-strand break generated via CRISPR/Cas9 is sufficient to delay cell cycle progression and compromise cell viability. However, we also found that the cellular response to DSBs can vary, independent of the number of lesions. This implies that not all DSBs are equally toxic, and raises the question if the location of a single double-strand break could influence its toxicity. To systematically investigate if DSB-location is a determinant of toxicity we performed a CRISPR/Cas9 screen targeting 6237 single sites in the human genome. Next, we developed a data-driven framework to design CRISPR/Cas9 sgRNA (crRNA) pools targeting specific chromatin features. The chromatin context was defined using ChromHMM states, Lamin-B1 DAM-iD, DNAseI hypersensitivity, and RNA-sequencing data. We computationally designed 6 distinct crRNA pools, each containing 10 crRNAs targeting the same chromatin state. We show that the toxicity of a DSB is highly similar across the different ChromHMM states. Rather, we find that the major determinants of toxicity of a sgRNA are cutting efficiency and off-target effects. Thus, chromatin features have little to no effect on the toxicity of a single CRISPR/Cas9-induced DSB. 相似文献
998.
Marjolein Glas H. Bart van den Berg van Saparoea Stephen H. McLaughlin Winfried Roseboom Fan Liu Gregory M. Koningstein Alexander Fish Tanneke den Blaauwen Albert J. R. Heck Luitzen de Jong Wilbert Bitter Iwan J. P. de Esch Joen Luirink 《The Journal of biological chemistry》2015,290(35):21498-21509
Cell division in Escherichia coli involves a set of essential proteins that assembles at midcell to form the so-called divisome. The divisome regulates the invagination of the inner membrane, cell wall synthesis, and inward growth of the outer membrane. One of the divisome proteins, FtsQ, plays a central but enigmatic role in cell division. This protein associates with FtsB and FtsL, which, like FtsQ, are bitopic inner membrane proteins with a large periplasmic domain (denoted FtsQp, FtsBp, and FtsLp) that is indispensable for the function of each protein. Considering the vital nature and accessible location of the FtsQBL complex, it is an attractive target for protein-protein interaction inhibitors intended to block bacterial cell division. In this study, we expressed FtsQp, FtsBp, and FtsLp individually and in combination. Upon co-expression, FtsQp was co-purified with FtsBp and FtsLp from E. coli extracts as a stable trimeric complex. FtsBp was also shown to interact with FtsQp in the absence of FtsLp albeit with lower affinity. Interactions were mapped at the C terminus of the respective domains by site-specific cross-linking. The binding affinity and 1:1:1 stoichiometry of the FtsQpBpLp complex and the FtsQpBp subcomplex were determined in complementary surface plasmon resonance, analytical ultracentrifugation, and native mass spectrometry experiments. 相似文献
999.
1000.
A combined oral contraceptive affects mucosal SHIV susceptibility factors in a pigtail macaque (Macaca nemestrina) model 下载免费PDF全文