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471.
A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease 总被引:50,自引:0,他引:50
Janus C Pearson J McLaurin J Mathews PM Jiang Y Schmidt SD Chishti MA Horne P Heslin D French J Mount HT Nixon RA Mercken M Bergeron C Fraser PE St George-Hyslop P Westaway D 《Nature》2000,408(6815):979-982
Much evidence indicates that abnormal processing and extracellular deposition of amyloid-beta peptide (A beta), a proteolytic derivative of the beta-amyloid precursor protein (betaAPP), is central to the pathogenesis of Alzheimer's disease (reviewed in ref. 1). In the PDAPP transgenic mouse model of Alzheimer's disease, immunization with A beta causes a marked reduction in burden of the brain amyloid. Evidence that A beta immunization also reduces cognitive dysfunction in murine models of Alzheimer's disease would support the hypothesis that abnormal A beta processing is essential to the pathogenesis of Alzheimer's disease, and would encourage the development of other strategies directed at the 'amyloid cascade'. Here we show that A beta immunization reduces both deposition of cerebral fibrillar A beta and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of A beta in the brain. This implies that either a approximately 50% reduction in dense-cored A beta plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic A beta species. 相似文献
472.
Pani A Batetta B Putzolu M Sanna F Spano O Piras S Mulas MF Bonatesta RR Amat di S Filippo C Vargiu L Marceddu T Sanna L La Colla P Dessì S 《Cellular and molecular life sciences : CMLS》2000,57(7):1094-1102
The product of the MDR1 gene (P-gp) has been implicated in the transport of cholesterol from plasma membrane to endoplasmic reticulum for esterification.
In previous studies on leukemia cell lines, we suggested that cholesterol esterification may regulate the rate of cell growth
and that the MDR1 gene might be involved in this process by modulating intracellular cholesterol esters levels. To further investigate this
matter, the rate of cell growth, cholesterol metabolism, expression of the MDR1 gene, and P-gp activity were compared in KB cell lines displaying differences in expression and function of P-gp (drug-sensitive
phenotype versus MDR phenotype). The rate of cell growth correlated with cholesterol esterification in all KB cell lines,
whereas the over-expression of MDR1 observed in the MDR cell lines was not always associated with an increased capacity of cells to esterify cholesterol. Two
known inhibitors of P-gp activity, progesterone and verapamil, strongly inhibited both cholesterol esterification and cell
proliferation in all KB cell lines, but they affected intracellular accumulation of labeled vinblastine only in MDR cell lines.
These results further support a role for cholesterol esters in the regulation of cell growth and suggest that the P-gp expressed
in MDR KB cells is not involved in the general process leading to cholesterol esterification.
Received 14 February 2000; received after revision 10 April 2000; accepted 8 May 2000 相似文献
473.
Calvete JJ Costa FH Saker-Sampaio S Murciano MP Nagano CS Cavada BS Grangeiro TB Ramos MV Bloch C Silveira SB Freitas BT Sampaio AH 《Cellular and molecular life sciences : CMLS》2000,57(2):343-350
The primary structure of a lectin isolated from the red alga Bryothamnion triquetrum was established by combination of Edman degradation of sets of overlapping peptides and mass spectrometry. It contains 91 amino acids and two disulphide bonds. The primary structure of the B. triquetrum lectin does not show amino acid sequence similarity with known plant and animal lectin structures. Hence, this protein may be the paradigm of a novel lectin family. 相似文献
474.
Roest Crollius H Jaillon O Bernot A Dasilva C Bouneau L Fischer C Fizames C Wincker P Brottier P Quétier F Saurin W Weissenbach J 《Nature genetics》2000,25(2):235-238
The number of genes in the human genome is unknown, with estimates ranging from 50,000 to 90,000 (refs 1, 2), and to more than 140,000 according to unpublished sources. We have developed 'Exofish', a procedure based on homology searches, to identify human genes quickly and reliably. This method relies on the sequence of another vertebrate, the pufferfish Tetraodon nigroviridis, to detect conserved sequences with a very low background. Similar to Fugu rubripes, a marine pufferfish proposed by Brenner et al. as a model for genomic studies, T. nigroviridis is a more practical alternative with a genome also eight times more compact than that of human. Many comparisons have been made between F. rubripes and human DNA that demonstrate the potential of comparative genomics using the pufferfish genome. Application of Exofish to the December version of the working draft sequence of the human genome and to Unigene showed that the human genome contains 28,000-34,000 genes, and that Unigene contains less than 40% of the protein-coding fraction of the human genome. 相似文献
475.
Marine iguanas shrink to survive El Niño 总被引:3,自引:0,他引:3
476.
Single-molecule studies of the effect of template tension on T7 DNA polymerase activity 总被引:8,自引:0,他引:8
T7 DNA polymerase catalyses DNA replication in vitro at rates of more than 100 bases per second and has a 3'-->5' exonuclease (nucleotide removing) activity at a separate active site. This enzyme possesses a 'right hand' shape which is common to most polymerases with fingers, palm and thumb domains. The rate-limiting step for replication is thought to involve a conformational change between an 'open fingers' state in which the active site samples nucleotides, and a 'closed' state in which nucleotide incorporation occurs. DNA polymerase must function as a molecular motor converting chemical energy into mechanical force as it moves over the template. Here we show, using a single-molecule assay based on the differential elasticity of single-stranded and double-stranded DNA, that mechanical force is generated during the rate-limiting step and that the motor can work against a maximum template tension of approximately 34 pN. Estimates of the mechanical and entropic work done by the enzyme show that T7 DNA polymerase organizes two template bases in the polymerization site during each catalytic cycle. We also find a force-induced 100-fold increase in exonucleolysis above 40 pN. 相似文献
477.
NO is necessary and sufficient for egg activation at fertilization 总被引:14,自引:0,他引:14
Kuo RC Baxter GT Thompson SH Stricker SA Patton C Bonaventura J Epel D 《Nature》2000,406(6796):633-636
The early steps that lead to the rise in calcium and egg activation at fertilization are unknown but of great interest--particularly with the advent of in vitro fertilization techniques for treating male infertility and whole-animal cloning by nuclear transfer. This calcium rise is required for egg activation and the subsequent events of development in eggs of all species. Injection of intact sperm or sperm extracts can activate eggs, suggesting that sperm-derived factors may be involved. Here we show that nitric oxide synthase is present at high concentration and active in sperm after activation by the acrosome reaction. An increase in nitrosation within eggs is evident seconds after insemination and precedes the calcium pulse of fertilization. Microinjection of nitric oxide donors or recombinant nitric oxide synthase recapitulates events of egg activation, whereas prior injection of oxyhaemoglobin, a physiological nitric oxide scavenger, prevents egg activation after fertilization. We conclude that nitric oxide synthase and nitric-oxide-related bioactivity satisfy the primary criteria of an egg activator: they are present in an appropriate place, active at an appropriate time, and are necessary and sufficient for successful fertilization. 相似文献
478.
Lubowich DA Pasachoff JM Balonek TJ Millar TJ Tremonti C Roberts H Galloway RP 《Nature》2000,405(6790):1025-1027
The Galactic Centre is the most active and heavily processed region of the Milky Way, so it can be used as a stringent test for the abundance of deuterium (a sensitive indicator of conditions in the first 1,000 seconds in the life of the Universe). As deuterium is destroyed in stellar interiors, chemical evolution models predict that its Galactic Centre abundance relative to hydrogen is D/H = 5 x 10(-12), unless there is a continuous source of deuterium from relatively primordial (low-metallicity) gas. Here we report the detection of deuterium (in the molecule DCN) in a molecular cloud only 10 parsecs from the Galactic Centre. Our data, when combined with a model of molecular abundances, indicate that D/H = (1.7 +/- 0.3) x 10(-6), five orders of magnitude larger than the predictions of evolutionary models with no continuous source of deuterium. The most probable explanation is recent infall of relatively unprocessed metal-poor gas into the Galactic Centre (at the rate inferred by Wakker). Our measured D/H is nine times less than the local interstellar value, and the lowest D/H observed in the Galaxy. We conclude that the observed Galactic Centre deuterium is cosmological, with an abundance reduced by stellar processing and mixing, and that there is no significant Galactic source of deuterium. 相似文献
479.
Macilwain C 《Nature》2000,406(6793):221-222
480.