全文获取类型
收费全文 | 5731篇 |
免费 | 371篇 |
出版年
2023年 | 20篇 |
2022年 | 26篇 |
2021年 | 60篇 |
2020年 | 43篇 |
2019年 | 40篇 |
2018年 | 93篇 |
2017年 | 99篇 |
2016年 | 156篇 |
2015年 | 285篇 |
2014年 | 293篇 |
2013年 | 383篇 |
2012年 | 462篇 |
2011年 | 406篇 |
2010年 | 242篇 |
2009年 | 195篇 |
2008年 | 344篇 |
2007年 | 345篇 |
2006年 | 297篇 |
2005年 | 271篇 |
2004年 | 244篇 |
2003年 | 243篇 |
2002年 | 259篇 |
2001年 | 92篇 |
2000年 | 95篇 |
1999年 | 73篇 |
1998年 | 43篇 |
1997年 | 29篇 |
1996年 | 28篇 |
1995年 | 33篇 |
1994年 | 37篇 |
1993年 | 31篇 |
1992年 | 48篇 |
1991年 | 54篇 |
1990年 | 53篇 |
1989年 | 46篇 |
1988年 | 41篇 |
1987年 | 54篇 |
1986年 | 35篇 |
1985年 | 43篇 |
1984年 | 51篇 |
1983年 | 33篇 |
1982年 | 21篇 |
1981年 | 28篇 |
1980年 | 24篇 |
1979年 | 21篇 |
1978年 | 24篇 |
1974年 | 22篇 |
1973年 | 36篇 |
1972年 | 24篇 |
1971年 | 23篇 |
排序方式: 共有6102条查询结果,搜索用时 15 毫秒
991.
Mario M. Müller Esther Klaile Olga Vorontsova Bernhard B. Singer Bj?rn ?brink 《The Journal of cell biology》2009,187(4):569-581
Carcinoembryonic antigen (CEA)–related cell adhesion molecule 1 (CAM1 [CEACAM1]) mediates homophilic cell adhesion and regulates signaling. Although there is evidence that CEACAM1 binds and activates SHP-1, SHP-2, and c-Src, knowledge about the mechanism of transmembrane signaling is lacking. To analyze the regulation of SHP-1/SHP-2/c-Src binding, we expressed various CFP/YFP-tagged CEACAM1 isoforms in epithelial cells. The supramolecular organization of CEACAM1 was examined by cross-linking, coclustering, coimmunoprecipitation, and fluorescence resonance energy transfer. SHP-1/SHP-2/c-Src binding was monitored by coimmunoprecipitation and phosphotyrosine-induced recruitment to CEACAM1-L in cellular monolayers. We find that trans-homophilic CEACAM1 binding induces cis-dimerization by an allosteric mechanism transmitted by the N-terminal immunoglobulin-like domain. The balance of SHP-2 and c-Src binding is dependent on the monomer/dimer equilibrium of CEACAM1-L and is regulated by trans-binding, whereas SHP-1 does not bind under physiological conditions. CEACAM1-L homodimer formation is reduced by coexpression of CEACAM1-S and modulated by antibody ligation. These data suggest that transmembrane signaling by CEACAM1 operates by alteration of the monomer/dimer equilibrium, which leads to changes in the SHP-2/c-Src–binding ratio. 相似文献
992.
Macarena Marín Dirk W. Heinz Dietmar H. Pieper Bj?rn U. Klink 《The Journal of biological chemistry》2009,284(47):32709-32716
When methyl-substituted aromatic compounds are degraded via ortho (intradiol)-cleavage of 4-methylcatechol, the dead-end metabolite 4-methylmuconolactone (4-ML) is formed. Degradation of 4-ML has only been described in few bacterial species, including Pseudomonas reinekei MT1. The isomerization of 4-ML to 3-methylmuconolactone (3-ML) is the first step required for the mineralization of 4-ML and is catalyzed by an enzyme termed 4-methylmuconolactone methylisomerase (MLMI). We identified the gene encoding MLMI in P. reinekei MT1 and solved the crystal structures of MLMI in complex with 3-ML at 1.4-Å resolution, with 4-ML at 1.9-Å resolution and with a MES buffer molecule at 1.45-Å resolution. MLMI exhibits a ferredoxin-like fold and assembles as a tight functional homodimeric complex. We were able to assign the active site clefts of MLMI from P. reinekei MT1 and of the homologous MLMI from Cupriavidus necator JMP134, which has previously been crystallized in a structural genomics project. Kinetic and structural analysis of wild-type MLMI and variants created by site-directed mutagenesis indicate Tyr-39 and His-26 to be the most probable catalytic residues. The previously proposed involvement of Cys-67 in covalent catalysis can now be excluded. Residue His-52 was found to be important for substrate affinity, with only marginal effect on catalytic activity. Based on these results, a novel catalytic mechanism for the isomerization of 4-ML to 3-ML by MLMI, involving a bislactonic intermediate, is proposed. This broadens the knowledge about the diverse group of proteins exhibiting a ferredoxin-like fold. 相似文献
993.
?yvind Halskau Jr. Ming Ying Anne Baumann Rune Kleppe David Rodriguez-Larrea Bj?rg Alm?s Jan Haavik Aurora Martinez 《The Journal of biological chemistry》2009,284(47):32758-32769
Tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines, is activated by phosphorylation-dependent binding to 14-3-3 proteins. The N-terminal domain of TH is also involved in interaction with lipid membranes. We investigated the binding of the N-terminal domain to its different partners, both in the unphosphorylated (TH-(1–43)) and Ser19-phosphorylated (THp-(1–43)) states by surface plasmon resonance. THp-(1–43) showed high affinity for 14-3-3 proteins (Kd ∼ 0.5 μm for 14-3-3γ and -ζ and 7 μm for 14-3-3η). The domains also bind to negatively charged membranes with intermediate affinity (concentration at half-maximal binding S0.5 = 25–58 μm (TH-(1–43)) and S0.5 = 135–475 μm (THp-(1–43)), depending on phospholipid composition) and concomitant formation of helical structure. 14-3-3γ showed a preferential binding to membranes, compared with 14-3-3ζ, both in chromaffin granules and with liposomes at neutral pH. The affinity of 14-3-3γ for negatively charged membranes (S0.5 = 1–9 μm) is much higher than the affinity of TH for the same membranes, compatible with the formation of a ternary complex between Ser19-phosphorylated TH, 14-3-3γ, and membranes. Our results shed light on interaction mechanisms that might be relevant for the modulation of the distribution of TH in the cytoplasm and membrane fractions and regulation of l-DOPA and dopamine synthesis. 相似文献
994.
Hunting for willow ptarmigan (Lagopus lagopus) is a popular recreational activity in Norway, but studies of the hunters are limited. While large game management in Norway
is based on sound models and research, management of small game hunters and hunting have not been subject to the same rigour.
Compared to the extensive body of knowledge about ptarmigan behaviour and habitat preferences, the knowledge base on ptarmigan
hunters is very limited. We surveyed the habitat preferences of 3,056 hunters to identify preferred landscape categories using
pictures covering a range of landscape types. We also examined to which extent residence types and forms of hunting were related
to habitat preferences. Through factor analysis, we identified three categories of hunting habitat; mountain forest, low alpine
and high alpine. Mode of hunting is more important than residence status in terms of preferred habitat. Hunters using dogs
preferred mountain forest and low alpine habitats more than hunters without dogs. Hunters without dogs had a higher preference
than dog hunters for high alpine habitats. Hunters with mixed modes of hunting have wider habitat preferences. Residence status
only affects the perception of the mountain forest habitat. The results may have implications for management as land use and
place-based meanings are currently changing in many natural and rural landscapes, and hunting needs to be integrated with
other recreational uses. 相似文献
995.
Kristian Björnstad Olof Beck Anders Helander 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2009,877(11-12):1162-1168
A sensitive and specific LC–MS/MS method for simultaneous detection of 10 plant-derived psychoactive substances (atropine, N,N-dimethyltryptamine, ephedrine, harmaline, harmine, ibogaine, lysergic acid amide, psilocin, scopolamine and yohimbine) in urine was developed. Direct injection of urine diluted with 3 deuterated internal standards allowed for a readily accessible method suitable for application in clinical intoxication cases. Separation was achieved using reversed phase chromatography and gradient elution with a total analysis time of 14 min. Electrospray ionization was used and ions were monitored in the positive selected reaction monitoring mode. The calibration curves were linear (r2 > 0.999) and the total imprecision at high (1000 μg/L) and low (50 μg/L) substance concentrations were 4.9–13.8% and 8.3–26%, respectively. Infusing the analytes post column and injecting matrix samples showed limited influence by ion suppression. The multi-component method proved to be useful for investigation of authentic cases of intoxication with plant-derived psychoactive drugs and was indicated to cover the clinically relevant concentration ranges. 相似文献
996.
Björn Schwanhäusser Manfred Gossen Gunnar Dittmar Matthias Selbach Dr. 《Proteomics》2009,9(1):205-209
Current methods for system‐wide gene expression analysis detect changes in mRNA abundance, but neglect regulation at the level of translation. Pulse labeling with stable isotopes has been used to measure protein turnover rates, but this does not directly provide information about translation rates. Here, we developed pulsed stable isotope labeling by amino acids in cell culture (pSILAC) with two heavy isotope labels to directly quantify protein translation on a proteome‐wide scale. We applied the method to cellular iron homeostasis as a model system and demonstrate that it can confidently identify proteins that are translationally regulated by iron availability. 相似文献
997.
Sperm ultrastructure of several species in each of the two suborders of Thysanoptera Tubulifera and Terebrantia shows a distinctive and unusual architecture. Members of the whole order share a bizarre axoneme consisting of 27 microtubular elements derived from the amalgamation of 3 (9+0) axonemes present in each spermatid at the beginning of spermiogenesis. The reciprocal shifting of these axonemes along the length of the sperm, together with their possible shortening and overlapping for short distances, could explain why in some species it is never possible to observe the complete set of 27 microtubular elements in any one cross section. Tubuliferan sperm have a small elliptical (in cross section) acrosome extending the length of the sperm. In Bolothrips insularis and Compsothrips albosignatus this structure is larger and is associated with an external, flattened vesicle throughout its length. Terebrantian sperm lack an acrosome, but display for half their length a dense body running parallel to the nucleus. The sperm, in members of this suborder, are also characterized by possession of a small mitochondrion and by the unusual bilobed outline of cross sections through the anterior sperm region, with the nucleus located in one of the two lobes. Structures serving to anchor sperm to the inner surface of the cyst cell have been observed at their anterior tips in the testes of tubuliferans. In B. insularis, an anterior appendage is formed in immature sperm and is maintained in the mature spermatozoon parallel to its long axis in the most anterior region. Such an anchoring structure has not been observed in sperm of the terebrantian species examined, probably because the testis of terebrantians contains only a single cyst of developing gametes. 相似文献
998.
Background
Molecular signatures are sets of genes, proteins, genetic variants or other variables that can be used as markers for a particular phenotype. Reliable signature discovery methods could yield valuable insight into cell biology and mechanisms of human disease. However, it is currently not clear how to control error rates such as the false discovery rate (FDR) in signature discovery. Moreover, signatures for cancer gene expression have been shown to be unstable, that is, difficult to replicate in independent studies, casting doubts on their reliability. 相似文献999.
Rasmus Skern-Mauritzen Petter Frost Sussie Dalvin Bj?rn Olav Kvamme Ingunn Sommerset Frank Nilsen 《BMC molecular biology》2009,10(1):44
Background
Trypsin-like serine proteases are involved in a large number of processes including digestive degradation, regulation of developmental processes, yolk degradation and yolk degradome activation. Trypsin like peptidases considered to be involved in digestion have been characterized in Lepeophtheirus salmonis. During these studies a trypsin-like peptidase which differed in a number of traits were identified. 相似文献1000.