全文获取类型
收费全文 | 29811篇 |
免费 | 81篇 |
国内免费 | 127篇 |
专业分类
系统科学 | 135篇 |
丛书文集 | 293篇 |
教育与普及 | 75篇 |
理论与方法论 | 111篇 |
现状及发展 | 12667篇 |
研究方法 | 1328篇 |
综合类 | 14927篇 |
自然研究 | 483篇 |
出版年
2013年 | 233篇 |
2012年 | 461篇 |
2011年 | 907篇 |
2010年 | 195篇 |
2008年 | 588篇 |
2007年 | 618篇 |
2006年 | 630篇 |
2005年 | 617篇 |
2004年 | 597篇 |
2003年 | 570篇 |
2002年 | 528篇 |
2001年 | 973篇 |
2000年 | 921篇 |
1999年 | 615篇 |
1994年 | 358篇 |
1992年 | 570篇 |
1991年 | 404篇 |
1990年 | 510篇 |
1989年 | 441篇 |
1988年 | 431篇 |
1987年 | 473篇 |
1986年 | 463篇 |
1985年 | 631篇 |
1984年 | 467篇 |
1983年 | 384篇 |
1982年 | 376篇 |
1981年 | 342篇 |
1980年 | 358篇 |
1979年 | 934篇 |
1978年 | 690篇 |
1977年 | 643篇 |
1976年 | 582篇 |
1975年 | 614篇 |
1974年 | 757篇 |
1973年 | 694篇 |
1972年 | 691篇 |
1971年 | 790篇 |
1970年 | 1051篇 |
1969年 | 830篇 |
1968年 | 864篇 |
1967年 | 797篇 |
1966年 | 718篇 |
1965年 | 534篇 |
1959年 | 290篇 |
1958年 | 502篇 |
1957年 | 326篇 |
1956年 | 321篇 |
1955年 | 270篇 |
1954年 | 304篇 |
1948年 | 247篇 |
排序方式: 共有10000条查询结果,搜索用时 671 毫秒
881.
Stimulation of specific GTP binding and hydrolysis activities in lymphocyte membrane by interleukin-2 总被引:3,自引:0,他引:3
Interleukin-2 (IL-2) is a polypeptide growth factor which stimulates the proliferation and differentiation of T lymphocytes. The receptor for IL-2 is expressed on activated T lymphocytes, cloned IL-2 dependent cells and several other cell types. Analysis of the primary structure and of immune-precipitated receptor suggests that this molecule has no intrinsic signal transduction function, unlike other growth factors. IL-2 interaction with a high affinity receptor has been shown, however, to activate the calcium/phospholipid-dependent protein kinase C (PK-C) presumably via phosphoinositide hydrolysis. Members of a family of closely related guanine nucleotide binding proteins (G proteins) regulate a diverse group of metabolic events. Two of them, Gs and Gi, stimulate and inhibit adenylate cyclase activity respectively, and other G proteins are involved in diverse signal transduction system. Another member, Go, has no known function and activation of phospholipase C has been attributed to the action of an unidentified G protein, Gp. Since it has been observed that IL-2 inhibits the catalytic activity of adenylate cyclase and that agents such as PGE2 which stimulate adenylate cyclase activity inhibit the lymphoproliferative response to IL-2, association of GTP binding proteins with IL-2 signal transduction was investigated. In this report we describe for the first time the participation of a GTP binding protein in the action of a polypeptide growth factor, interleukin-2. 相似文献
882.
Mouse embryogenesis relies on the presence of both the maternal and the paternal genome for development to term. It has been proposed that specific modifications are imprinted onto the chromosomes during gametogenesis; these modifications are stably propagated, and their expression results in distinct and complementary contributions of the two parental genomes to the development of the embryo and the extraembryonic membranes. Genetic data further suggest that a substantial proportion of the genome could be subject to chromosomal imprinting, the molecular nature of which is unknown. We used random DNA insertions in transgenic mice to probe the genome for modified regions. The DNA methylation patterns of transgenic alleles were compared after transmission from mother or father in seven mouse strains carrying autosomal insertions of the same transgenic marker. One of these loci showed a clear difference in DNA methylation specific for its parental origin, with the paternally inherited copy being relatively undermethylated. This difference was observed in embryos on day 10 of gestation, but not in their extraembryonic membranes. Moreover, the methylation pattern was faithfully reversed upon each germline transmission to the opposite sex. Our findings provide evidence for heritable molecular differences between maternally and paternally derived alleles on mouse chromosomes. 相似文献
883.
Characterization and molecular cloning of a bovine lentivirus related to human immunodeficiency virus 总被引:8,自引:0,他引:8
M A Gonda M J Braun S G Carter T A Kost J W Bess L O Arthur M J Van der Maaten 《Nature》1987,330(6146):388-391
884.
Kinetics of smooth and skeletal muscle activation by laser pulse photolysis of caged inositol 1,4,5-trisphosphate 总被引:1,自引:0,他引:1
Inositol 1,4,5-trisphosphate (InsP3) can stimulate skinned smooth and skeletal muscle to contract by initiating Ca2+ release from the sarcoplasmic reticulum. Whether this process is an integral component of the in vivo muscle activation mechanism was tested by releasing InsP3 rapidly within skinned muscle fibers of rabbit main pulmonary artery and frog semitendinosus. InsP3 was liberated on laser pulse photolysis of a photolabile but biologically inactive precursor of InsP3 termed caged InsP3. Caged InsP3 is a mixture of compounds in which InsP3 is esterified with 1(2-nitrophenyl)diazoethane (probably at the P4- or P5-position). Photochemical release of InsP3 induced a full contraction in both muscles at physiological free Mg2+ concentrations, but only in the smooth muscle were the InsP3 concentration (0.5 microM) and the activation rate compatible with the in vivo physiological response. Endogenous InsP3-specific phosphatase activity was present in smooth muscle and had about 35-fold greater activity than that in the skeletal-muscle preparation. Caged InsP3 was not susceptible to phosphatases in either preparation. 相似文献
885.
Neurons in the visual cortex typically respond selectively to the orientation, and velocity and direction of movement, of moving-bar stimuli. These responses are generally thought to provide information about the orientation and position of lines and edges in the visual field. Some cells are also endstopped, that is selective for bars of specific lengths. Hubel and Wiesel first observed that endstopped hypercomplex cells could respond to curved stimuli and suggested they might be involved in detection of curvature, but the exact relationship between endstopping and curvature has never been determined. We present here a mathematical model relating endstopping to curvature in which the difference in response of two simple cells gives rise to endstopping and varies in proportion to curvature. We also provide physiological evidence that endstopped cells in area 17 of the cat visual cortex are selective for curvature, whereas non-endstopped cells are not, and that some are selective for the sign of curvature. The prevailing view of edge and curve determination is that orientations are selected locally by the class of simple cortical cells and then integrated to form global curves. We have developed a computational theory of orientation selection which shows that measurements of orientation obtained by simple cells are not sufficient because there will be strong, incorrect responses from cells whose receptive fields (RFs) span distinct curves (Fig. 1). If estimates of curvature are available, however, these inappropriate responses can be eliminated. Curvature provides the key to structuring the network that underlies our theory and distinguishes it from previous lateral inhibition schemes. 相似文献
886.
Strömberg P Svensson S Hedberg JJ Nordling E Höög JO 《Cellular and molecular life sciences : CMLS》2002,59(3):552-559
The human alcohol dehydrogenase system is comprised of multiple forms that catalyse the oxidation/reduction of a large variety of alcohols and aldehydes. A transition that results in an Ile308Val substitution was identified in the human ADH2 gene by single-strand conformation polymorphism analysis. Screening a Swedish population revealed that Val308 was the most frequent allele (73%), and site-directed mutagenesis was used to obtain both allelozymes, which were expressed in Escherichia coli for characterisation. Thermostability was assayed by activity measurements and circular dichroism spectroscopy. The results showed that the 308Val substitution decreases protein stability, as compared to the Ile308 variant, an effect also demonstrated during prolonged storage. Ethanol, octanol, 12-hydroxydodecanoic acid and all-trans retinol were used as model substrates and, generally, slightly higher Km values were observed with Val at position 308. Finally, homology modelling, from mouse ADH2, further supported the decreased stability of the Val308 variant and located position 308 in the subunit interface of the molecule and in the vicinity of the active-site pocket entrance. In conclusion, the Ile308Val substitution represents a novel functional polymorphism within the human alcohol dehydrogenase gene cluster that may affect the metabolism of ethanol and other substrates. 相似文献
887.
Protein kinases mediate nitric oxide-induced apoptosis in the insect cell line IPLB-LdFB 总被引:2,自引:0,他引:2
The involvement of protein kinases (PKA, PKC and PKB) in nitric oxide (NO)-induced apoptosis with sodium nitroprusside plus
N-acetyl-L-cysteine in the IPLB-LdFB cell line from the insect Lymantria dispar was investigated. The presence of protein kinase-like molecules was demonstrated by western blot analysis. The role of the
kinases in programmed cell death was analysed in cytofluorimetric experiments by incubating the insect cells with H-89 (a
specific inhibitor of PKA), calphostin C (an inhibitor of PKC) or wortmannin (an inhibitor of phosphatidylinositol 3-kinase).
The results show that PKA is correlated with the induction and PKC and PKB with the prevention of NO-induced insect cell death.
Moreover, NO-induced apoptosis involves the release of cytochrome c.
Received 15 March 2002; accepted 25 March 2002 相似文献
888.
RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease 总被引:19,自引:0,他引:19
Bucciarelli LG Wendt T Rong L Lalla E Hofmann MA Goova MT Taguchi A Yan SF Yan SD Stern DM Schmidt AM 《Cellular and molecular life sciences : CMLS》2002,59(7):1117-1128
Receptor for AGE (RAGE) is a member of the immunoglobulin superfamily that engages distinct classes of ligands. The biology of RAGE is driven by the settings in which these ligands accumulate, such as diabetes, inflammation, neurodegenerative disorders and tumors. In this review, we discuss the context of each of these classes of ligands, including advance glycation end-products, amyloid beta peptide and the family of beta sheet fibrils, S100/calgranulins and amphoterin. Implications for the role of these ligands interacting with RAGE in homeostasis and disease will be considered. 相似文献
889.
We compared the effects ofAlzheimer's peptide (Abeta1-42), a,-antichymotrypsin (ACT) and an ACT/Abeta1-42 mixture on human glioma DK-MG cells. The solution of Abeta (5 microM) formed by 2-h incubation at room temperature induced tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 levels by 55 and 45%, respectively, and increased gelatinase B activity by 67%, while exposure of cells to the ACT/Abeta1-42 mixture (1:10 molar ratio ACT: Abeta1-42) under the same experimental conditions showed no effect on IL-6 levels or gelatinase B activity, but strongly induced TNF-alpha (by 190%), compared to the controls. Stimulation of the cells with Abeta1-42 alone, but not with ACT, increased by about 20% low-density lipoprotein (LDL) uptake and mRNA levels for LDL receptor and HMG-CoA reductase, while the ACT/Abeta1-42 mixture significantly increased LDL uptake (by 50%), up-regulated mRNA levels for LDL receptor and HMG-CoA reductase by 48 and 63%, respectively, and increased lipid accumulation by about 20-fold. These data suggest a possible new role for Abeta in Alzheimer's disease through its interaction with the inflammatory reactant, ACT. 相似文献
890.
HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus 总被引:21,自引:0,他引:21
Altfeld M Allen TM Yu XG Johnston MN Agrawal D Korber BT Montefiori DC O'Connor DH Davis BT Lee PK Maier EL Harlow J Goulder PJ Brander C Rosenberg ES Walker BD 《Nature》2002,420(6914):434-439
Early treatment of acute HIV-1 infection followed by treatment interruptions has shown promise for enhancing immune control of infection. A subsequent loss of control, however, allows the correlates of protective immunity to be assessed. Here we show that sudden breakthrough of plasma viraemia occurred after prolonged immune containment in an individual infected with HIV-1 at a time when 25 distinct CD8+ T-cell epitopes in the viral proteins Gag, RT, Integrase, Env, Nef, Vpr, Vif and Rev were being targeted. Sequencing of the virus in plasma and cells showed that superinfection with a second clade-B virus was coincident with the loss of immune control. This sudden increase in viraemia was associated with a decline in half of the CD8+ T-cell responses. The declining CD8+ T-cell responses were coupled with sequence changes relative to the initial virus that resulted in impaired recognition. Our data show that HIV-1 superinfection can occur in the setting of a strong and broadly directed virus-specific CD8+ T-cell response. The lack of cross-protective immunity for closely related HIV-1 strains, despite persistent recognition of multiple CD8 epitopes, has important implications for public health and vaccine development. 相似文献