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991.
Hamilton JA 《Progress in lipid research》2004,43(3):177-199
The interactions of fatty acids with proteins have been studied by a variety of conventional approaches for decades. However, only limited aspects of fatty acid-protein interactions have been elucidated, even with the integration of information gleaned from the many techniques. Judgments must be made about what information is most reliable, particularly when derivatives of fatty acids are substituted for natural fatty acids. In recent years, the application of techniques of structural biology has brought about dramatic advances in this important area of lipid research. High-resolution crystallographic and NMR structures of several proteins with bound fatty acids reveal the complete tertiary structure of the protein and molecular details of fatty acid-protein interactions. The examples presented include most of the known structures of (non-enzymatic) proteins that bind fatty acids. The proteins are found in very different compartments of cells and organisms: the plasma compartment (human serum albumin); the cytosolic compartment of mammalian cells (fatty acid- binding proteins); the cytosol of plant cells (nonspecific lipid-transfer protein); the nucleus of mammalian cells (peroxisome proliferator-activated receptor and hepatic nuclear factor 4); and a bacterial membrane (halorhodopsin). This review discusses the structural features of these proteins and their binding pocket(s) and compares the specific modes of their interactions with fatty acids. 相似文献
992.
993.
Hamilton CJ Saravanamuthu A Fairlamb AH Eggleston IM 《Bioorganic & medicinal chemistry》2003,11(17):3683-3693
The synthesis and evaluation of 3,5-disubstituted benzofuran derivatives as time-dependent inhibitors of the protozoan oxidoreductase trypanothione reductase are reported. These molecules were designed as simplified mimetics of the naturally occurring spermidine-bridged macrocyclic alkaloid lunarine 1, a known time-dependent inhibitor of trypanothione reductase. In this series of compounds the bis-polyaminoacrylamide derivatives 2-4 were all shown to be competitive inhibitors, but only the bis-4-methyl-piperazin-1-yl-propylacrylamide derivative 4 displayed time-dependent activity. The kinetics of time dependent inactivation of trypanothione reductase by 1 and 4 have been determined and are compared and discussed herein. 相似文献
994.
Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed,oncogene-transformed,and human cancer cells 总被引:1,自引:0,他引:1 下载免费PDF全文
Law BK Chytil A Dumont N Hamilton EG Waltner-Law ME Aakre ME Covington C Moses HL 《Molecular and cellular biology》2002,22(23):8184-8198
Transforming growth factor beta (TGF-beta) induces cell cycle arrest of most nontransformed epithelial cell lines. In contrast, many human carcinomas are refractory to the growth-inhibitory effect of TGF-beta. TGF-beta overexpression inhibits tumorigenesis, and abolition of TGF-beta signaling accelerates tumorigenesis, suggesting that TGF-beta acts as a tumor suppressor in mouse models of cancer. A screen to identify agents that potentiate TGF-beta-induced growth arrest demonstrated that the potential anticancer agent rapamycin cooperated with TGF-beta to induce growth arrest in multiple cell lines. Rapamycin also augmented the ability of TGF-beta to inhibit the proliferation of E2F1-, c-Myc-, and (V12)H-Ras-transformed cells, even though these cells were insensitive to TGF-beta-mediated growth arrest in the absence of rapamycin. Rapamycin potentiation of TGF-beta-induced growth arrest could not be explained by increases in TGF-beta receptor levels or rapamycin-induced dissociation of FKBP12 from the TGF-beta type I receptor. Significantly, TGF-beta and rapamycin cooperated to induce growth inhibition of human carcinoma cells that are resistant to TGF-beta-induced growth arrest, and arrest correlated with a suppression of Cdk2 kinase activity. Inhibition of Cdk2 activity was associated with increased binding of p21 and p27 to Cdk2 and decreased phosphorylation of Cdk2 on Thr(160). Increased p21 and p27 binding to Cdk2 was accompanied by decreased p130, p107, and E2F4 binding to Cdk2. Together, these results indicate that rapamycin and TGF-beta cooperate to inhibit the proliferation of nontransformed cells and cancer cells by acting in concert to inhibit Cdk2 activity. 相似文献
995.
Boulanger N Munks RJ Hamilton JV Vovelle F Brun R Lehane MJ Bulet P 《The Journal of biological chemistry》2002,277(51):49921-49926
The gut epithelium is an essential interface in insects that transmit parasites. We investigated the role that local innate immunity might have on vector competence, taking Stomoxys calcitrans as a model. S. calcitrans is sympatric with tsetse flies, feeds on many of the same vertebrate hosts, and is thus regularly exposed to the trypanosomes that cause African sleeping sickness and nagana. Despite this, S. calcitrans is not a cyclical vector of these trypanosomes. Trypanosomes develop exclusively in the lumen of digestive organs, and so epithelial immune mechanisms, and in particular antimicrobial peptides (AMPs), may be the prime determinants of the fate of an infection. To investigate why S. calcitrans is not a cyclical vector of trypanosomes, we have looked in its midgut for AMPs with trypanolytic activity. We have identified a new AMP of 42 amino acids, which we named stomoxyn, constitutively expressed and secreted exclusively in the anterior midgut of S. calcitrans. It displays an amphipathic helical structure and exhibits a broad activity spectrum affecting the growth of microorganisms. Interestingly, this AMP exhibits trypanolytic activity to Trypanosoma brucei rhodesiense. We argue that stomoxyn may help to explain why S. calcitrans is not a vector of trypanosomes causing African sleeping sickness and nagana. 相似文献
996.
Papineni RV O'Connell KM Zhang H Dirksen RT Hamilton SL 《The Journal of biological chemistry》2002,277(51):49167-49174
Apocalmodulin and Ca(2+) calmodulin bind to overlapping sites on the ryanodine receptor skeletal form, RYR1, but have opposite functional effects on channel activity. Suramin, a polysulfonated napthylurea, displaces both forms of calmodulin, leading to an inhibition of activity at low Ca(2+) and an enhancement of activity at high Ca(2+). Calmodulin binding motifs on RYR1 are also able to directly interact with the carboxy-terminal tail of the transverse tubule dihydropyridine receptor (DHPR) (Sencer, S., Papineni, R. V., Halling, D. B., Pate, P., Krol, J., Zhang, J. Z., and Hamilton, S. L. (2001) J. Biol. Chem. 276, 38237-38241). Suramin binds directly to a peptide that corresponds to the calmodulin binding site of RYR1 (amino acids 3609-3643) and blocks the interaction of this peptide with both calmodulin and the carboxyl-terminal tail of the DHPR alpha(1)-subunit. Suramin, added to the internal solution of voltage-clamped skeletal myotubes, produces a concentration-dependent increase in the maximal magnitude of voltage-gated Ca(2+) transients without significantly altering L-channel Ca(2+) channel conducting activity. Together, these results suggest that an interaction between the carboxyl-terminal tail of the DHPR alpha(1)-subunit with the calmodulin binding region of RYR1 serves to limit sarcoplasmic reticulum Ca(2+) release during excitation-contraction coupling and that suramin-induced potentiation of voltage-gated Ca(2+) release involves a relief of this inhibitory interaction. 相似文献
997.
Molecular genecology is the study of geographical clines in frequencies of molecular markers and their relationship to ecological clines in environmental conditions. This study outlines the principles underlying the selection of populations, focusing on avoiding 'false positives'- noncausal correlations between allele frequency and the environment. The principles are illustrated by identifying a set of populations of Lolium perenne for the study of temperature responses. The selected set of populations encompasses a 20 degrees C range in mean January temperature. Their freezing tolerance shows a linear trend with winter temperature, LT50 decreasing by 0.25 degrees C for each 1 degrees C reduction in mean January temperature. 相似文献
998.
Improved winter hardiness is an important breeding objective in the forage grass Lolium perenne. This is a complex trait with several components, including the ability to survive and grow at low temperature, to acclimate to cold, tolerate wind, snow cover and ice encasement. Marker-assisted selection has the potential to increase the efficiency of breeding for improved cold tolerance. Here we describe a genecological approach to identifying molecular markers that are associated with adaptation to low winter temperatures. AFLP was used to assess the genetic diversity in 29 wild populations of ryegrass (Lolium perenne) representing a pan-European temperature cline in terms of their geographical origin. A further 18 populations from a temperature cline in Bulgaria were also analysed. In addition, two varieties and five populations representing parents of mapping families currently in use at IGER were included in the analysis. Principal coordinate (PCoA) and cluster analyses of the molecular marker data showed that the Bulgarian altitude cline populations could be distinguished clearly from the other populations. Two regression analyses were carried out; one to identify AFLP markers that correlated in frequency with low mean January temperature of the geographical origin of the population, and another to identify AFLP markers correlating in frequency with the cold tolerance phenotype of the populations, as determined by LT50 values in freezing tests. In the first analysis six AFLP markers showed significant type II trends with mean January temperature, and in the second analysis 28 bands had a significant univariate relationship with the LT50 value of the accessions. In steps 2 and 3 of the stepwise analysis a further 4 and 5 bands, respectively, improved the fit significantly. The results of the two types of regression analysis are discussed in relation to ecogeography and cold tolerance phenotype of the populations. 相似文献
999.
1000.
Hamilton JA 《Prostaglandins, leukotrienes, and essential fatty acids》2002,67(2-3):65-72
The interactions of fatty acids with proteins have been probed with a great variety of techniques and strategies. Many approaches have substituted covalently labeled fatty acids or structurally related molecules. Information from such studies ultimately requires validation by studies with natural fatty acids. However, even the best conventional approaches with natural fatty acids generally have revealed only limited aspects of fatty acid-protein interactions. In contrast, recent crystallographic and NMR studies of several proteins with bound fatty acids provide complete three-dimensional structures with molecular details of these interactions. This presentation reviews three examples of proteins that are indirectly or directly involved in cell signaling: a protein in the plasma compartment (human serum albumin); a protein family in the cytosolic compartment of mammalian cells (fatty-acid-binding proteins), and a nuclear protein (peroxisome proliferator-activated receptor): it also discusses the structures of these proteins and their binding pocket(s), compares their specific modes of interactions with fatty acids, and discusses established and potential roles of fatty acid-protein interactions in cell signaling. 相似文献