全文获取类型
收费全文 | 1249篇 |
免费 | 111篇 |
专业分类
1360篇 |
出版年
2023年 | 16篇 |
2022年 | 18篇 |
2021年 | 49篇 |
2020年 | 22篇 |
2019年 | 32篇 |
2018年 | 34篇 |
2017年 | 42篇 |
2016年 | 52篇 |
2015年 | 78篇 |
2014年 | 90篇 |
2013年 | 85篇 |
2012年 | 118篇 |
2011年 | 95篇 |
2010年 | 72篇 |
2009年 | 64篇 |
2008年 | 63篇 |
2007年 | 70篇 |
2006年 | 51篇 |
2005年 | 51篇 |
2004年 | 46篇 |
2003年 | 41篇 |
2002年 | 51篇 |
2001年 | 21篇 |
2000年 | 12篇 |
1999年 | 10篇 |
1998年 | 9篇 |
1997年 | 6篇 |
1996年 | 6篇 |
1995年 | 5篇 |
1993年 | 4篇 |
1992年 | 3篇 |
1991年 | 5篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1985年 | 3篇 |
1984年 | 5篇 |
1983年 | 4篇 |
1982年 | 3篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1977年 | 1篇 |
1973年 | 1篇 |
1971年 | 1篇 |
1969年 | 2篇 |
1962年 | 1篇 |
1959年 | 1篇 |
1957年 | 1篇 |
排序方式: 共有1360条查询结果,搜索用时 0 毫秒
971.
Linking the Rb and polycomb pathways 总被引:9,自引:0,他引:9
Polycomb group (PcG) proteins associate to form complexes that repress Hox genes, thereby imposing the patterning of Hox expression required for development. However, these proteins have a second Hox-independent role in regulating cell proliferation. Our results suggest that association between Rb and PcG proteins forms a repressor complex that blocks entry of cells into mitosis. Also, we provide evidence that Rb colocalizes with nuclear PcG complexes and is important for association of PcG complexes with nuclear targets. The Rb-PcG complex may provide a means to link cell cycle arrest to differentiation events leading to embryonic pattern formation. 相似文献
972.
973.
Molina J Landa A Bautista G Martínez M Córdoba F 《Biochimica et biophysica acta》2004,1674(3):299-304
Corn coleoptile lectin is present with beta-glucosidase (EC. 3.2.1.2.1) in a single tightly bound molecular association complex (88.7 kDa). SDS-PAGE of the molecular complex dissociates into two main components. Of these, at a concentration of 75%, the corn coleoptile beta-glucosidase (60 kDa) is identified by enzymatic activity, with two 16-amino acid tryptic peptides displaying close homology with the primary structure of the enzyme. In separate experiments, we isolated homogenous monomeric enzyme of corn coleoptile. This allowed us to conclude that lectin properties like erythrocyte agglutination, found in the (88.7 kDa) molecular complex, is not due to the beta-glucosidase bound in it. Another protein (30 kDa) dissociated from the same SDS-PAGE gels rendered several tryptic peptides, including a 20-amino acid sequence V(L)GP(Q)W(A)GGSGGSPVDITAEPQR closely homologous to the putative beta-glucosidase aggregating factor (BGAF) precursor described recently. Tryptic peptide SAFTE(A)WN(V)ELK(V) was also present in the BGAF precursor. KFHEQR peptide was not present in BGAF precursor or any other protein sequence examined. Tryptic peptide TYGPFGA showed good homology with the BGAF precursor protein, FEGLYLFHTPLGSGAN peptide displayed identity with the BGAF precursor sequence. Thus, the 30 kDa protein does not appear to be identical to BGAF, but is rather a similar molecule which could be endowed with the lectin properties of the 88.7 kDa molecular complex. 相似文献
974.
975.
Wu CC MacCoss MJ Mardones G Finnigan C Mogelsvang S Yates JR Howell KE 《Molecular biology of the cell》2004,15(6):2907-2919
The Golgi complex functions to posttranslationally modify newly synthesized proteins and lipids and to sort them to their sites of function. In this study, a stacked Golgi fraction was isolated by classical cell fractionation, and the protein complement (the Golgi proteome) was characterized using multidimensional protein identification technology. Many of the proteins identified are known residents of the Golgi, and 64% of these are predicted transmembrane proteins. Proteins localized to other organelles also were identified, strengthening reports of functional interfacing between the Golgi and the endoplasmic reticulum and cytoskeleton. Importantly, 41 proteins of unknown function were identified. Two were selected for further analysis, and Golgi localization was confirmed. One of these, a putative methyltransferase, was shown to be arginine dimethylated, and upon further proteomic analysis, arginine dimethylation was identified on 18 total proteins in the Golgi proteome. This survey illustrates the utility of proteomics in the discovery of novel organellar functions and resulted in 1) a protein profile of an enriched Golgi fraction; 2) identification of 41 previously uncharacterized proteins, two with confirmed Golgi localization; 3) the identification of arginine dimethylated residues in Golgi proteins; and 4) a confirmation of methyltransferase activity within the Golgi fraction. 相似文献
976.
Inducible clustering of membrane-targeted SH3 domains of the adaptor protein Nck triggers localized actin polymerization 总被引:8,自引:0,他引:8
BACKGROUND: SH2/SH3 adaptor proteins play a critical role in tyrosine kinase signaling pathways, regulating essential cell functions by increasing the local concentration or altering the subcellular localization of downstream effectors. The SH2 domain of the Nck adaptor can bind tyrosine-phosphorylated proteins, while its SH3 domains can modulate actin polymerization by interacting with effectors such as WASp/Scar family proteins. Although several studies have implicated Nck in regulating actin polymerization, its role in living cells is not well understood. RESULTS: We used an antibody-based system to experimentally modulate the local concentration of Nck SH3 domains on the plasma membrane of living cells. Clustering of fusion proteins containing all three Nck SH3 domains induced localized polymerization of actin, including the formation of actin tails and spots, accompanied by general cytoskeletal rearrangements. All three Nck SH3 domains were required, as clustering of individual SH3 domains or a combination of the two N-terminal Nck SH3 domains failed to promote significant local polymerization of actin in vivo. Changes in actin dynamics induced by Nck SH3 domain clustering required the recruitment of N-WASp, but not WAVE1, and were unaffected by downregulation of Cdc42. CONCLUSIONS: We show that high local concentrations of Nck SH3 domains are sufficient to stimulate localized, Cdc42-independent actin polymerization in living cells. This study provides strong evidence of a pivotal role for Nck in directly coupling ligand-induced tyrosine phosphorylation at the plasma membrane to localized changes in organization of the actin cytoskeleton through a signaling pathway that requires N-WASp. 相似文献
977.
The population structure of the edible Atlanto-Mediterranean sea urchin Paracentrotus lividus is described by analysing sequence variation in a fragment of the mitochondrial gene cytochrome c oxidase subunit I in 127 individuals from 12 localities across south-west Europe. The study revealed high levels of genetic diversity but low levels of genetic structure, suggesting a large degree of gene flow between populations and panmixis within each, the Mediterranean and Atlantic basins. However, we found significant genetic differentiation between the two basins probably due to restricted gene flow across the geographical boundary imposed by the area of the Strait of Gibraltar. Populations of P. lividus appeared to have experienced a recent demographic expansion in the late Pleistocene. We provide new evidence on the population structure of this commercial species, predicting a healthy stock of this sea urchin on the Mediterranean and Atlantic coasts. 相似文献
978.
Dunham CM Dioum EM Tuckerman JR Gonzalez G Scott WG Gilles-Gonzalez MA 《Biochemistry》2003,42(25):7701-7708
To evaluate the contributions of the G(beta)-2 arginine to signal transduction in oxygen-sensing heme-PAS domains, we replaced this residue with alanine in Bradyrhizobium japonicum FixL and examined the results on heme-domain structure, ligand binding, and kinase regulation. In the isolated R220A BjFixL heme-PAS domain, the iron-histidine bond was increased in length by 0.31 A, the heme flattened even without a ligand, and the interaction of a presumed regulatory loop (the FG loop) with the helix of heme attachment was weakened. Binding of carbon monoxide was similar for ferrous BjFixL and R220A BjFixL. In contrast, the level of binding of oxygen was dramatically lower (K(d) approximately 1.5 mM) for R220A BjFixL, and this was manifested as 60- and 3-fold lower on- and off-rate constants, respectively. Binding of cyanide followed the same pattern as binding of oxygen. The catalytic activity was 3-4-fold higher in the "on-state" unliganded forms of R220A BjFixL than in the corresponding BjFixL species. Cyanide regulation of this activity was strongly impaired, but some inhibition was nevertheless preserved. Carbon monoxide and nitric oxide regulation, although weak in BjFixL, were abolished from R220A BjFixL. We conclude that the G(beta)-2 arginine assists in the binding of oxygen to BjFixL but does not accomplish this by stabilizing the oxy form. This arginine is not absolutely required for regulation, although it is important for shifting a pre-existing kinase equilibrium toward the inactive state on binding of regulatory ligands. These findings support a regulatory model in which the heme-PAS domain operates as an ensemble that couples to the kinase rather than a mechanism driven by a single central switch. 相似文献
979.
Natsch A Gfeller H Gygax P Schmid J Acuna G 《The Journal of biological chemistry》2003,278(8):5718-5727
Human axillary odor is known to be formed upon the action of Corynebacteria sp. on odorless axilla secretions. The known axilla odor determinant 3-methyl-2-hexenoic acid was identified in hydrolyzed axilla secretions along with a chemically related compound, 3-hydroxy-3-methylhexanoic acid. The natural precursors of both these acids were purified from non-hydrolyzed axilla secretions. From liquid chromatography/mass spectrometry analysis, it appeared that the acids are covalently linked to a glutamine residue in fresh axilla secretions, and the corresponding conjugates were synthesized for confirmation. Bacterial isolates obtained from the human axilla and belonging to the Corynebacteria were found to release the acids from these odorless precursors in vitro. A Zn(2+)-dependent aminoacylase mediating this cleavage was purified from Corynebacterium striatum Ax20, and the corresponding gene agaA was cloned and heterologously expressed in Escherichia coli. The enzyme is highly specific for the glutamine residue but has a low specificity for the acyl part of the substrate. agaA is closely related to many genes coding for enzymes involved in the cleavage of N-terminal acyl and aryl substituents from amino acids. This is the first report of the structure elucidation of precursors for human body odorants and the isolation of the bacterial enzyme involved in their cleavage. 相似文献
980.
Torres GE Carneiro A Seamans K Fiorentini C Sweeney A Yao WD Caron MG 《The Journal of biological chemistry》2003,278(4):2731-2739
The dopamine transporter (DAT) is a presynaptic plasma membrane protein responsible for the termination of dopaminergic neurotransmission in the central nervous system. While most studies have focused on structure/function analysis, much less information is available regarding the assembly and the trafficking of this protein. To address this problem, we performed a mutational analysis of the DAT protein, combined with biochemical, immunological, and functional approaches. In mammalian cells co-expressing differentially tagged DAT molecules, HA-tagged DAT co-purified with 6His-tagged DAT demonstrating a physical interaction between transporter proteins. Evidence for the functional oligomerization of DAT was obtained using dominant-negative mutants of DAT. Two loss-of-function mutant transporters (Y335A and D79G) that were targeted to the cell surface inhibited wild-type DAT uptake activity without affecting the membrane targeting of the wild-type transporter. Moreover, non-functional amino and carboxyl termini-truncated mutants of DAT inhibited wild-type DAT function by interfering with the normal processing of the wild-type transporter to the cell membrane. Mutations in the leucine repeat of the second transmembrane domain of the transporter could eliminate the dominant-negative effect of all these mutants. In addition, a small fragment comprising the first two transmembrane domains of DAT inhibited wild-type transporter function but not when the leucine repeat motif was mutated. Taken together, our results suggest that the assembly of DAT monomers plays a critical role in the expression and function of the transporter. 相似文献