全文获取类型
收费全文 | 27641篇 |
免费 | 97篇 |
国内免费 | 111篇 |
专业分类
系统科学 | 122篇 |
丛书文集 | 451篇 |
教育与普及 | 36篇 |
理论与方法论 | 90篇 |
现状及发展 | 12141篇 |
研究方法 | 1263篇 |
综合类 | 13275篇 |
自然研究 | 471篇 |
出版年
2013年 | 215篇 |
2012年 | 424篇 |
2011年 | 893篇 |
2010年 | 172篇 |
2008年 | 489篇 |
2007年 | 601篇 |
2006年 | 534篇 |
2005年 | 570篇 |
2004年 | 616篇 |
2003年 | 496篇 |
2002年 | 531篇 |
2001年 | 861篇 |
2000年 | 824篇 |
1999年 | 587篇 |
1992年 | 559篇 |
1991年 | 386篇 |
1990年 | 420篇 |
1989年 | 410篇 |
1988年 | 404篇 |
1987年 | 413篇 |
1986年 | 454篇 |
1985年 | 580篇 |
1984年 | 403篇 |
1983年 | 333篇 |
1982年 | 294篇 |
1981年 | 320篇 |
1980年 | 370篇 |
1979年 | 871篇 |
1978年 | 679篇 |
1977年 | 655篇 |
1976年 | 522篇 |
1975年 | 513篇 |
1974年 | 773篇 |
1973年 | 641篇 |
1972年 | 707篇 |
1971年 | 768篇 |
1970年 | 1080篇 |
1969年 | 842篇 |
1968年 | 724篇 |
1967年 | 748篇 |
1966年 | 712篇 |
1965年 | 530篇 |
1964年 | 180篇 |
1959年 | 267篇 |
1958年 | 526篇 |
1957年 | 361篇 |
1956年 | 279篇 |
1955年 | 255篇 |
1954年 | 297篇 |
1948年 | 186篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
961.
Monoclonal antibody and ligand binding sites of the T cell erythrocyte receptor (CD2) 总被引:4,自引:0,他引:4
The human T cell erythrocyte receptor (CD2 antigen) allows thymocytes and mature T cells to adhere to thymic epithelium and target cells through a cell surface protein, LFA-3 (refs 1-6). Monoclonal antibodies recognizing CD2 can either block adhesion or, in certain combinations, induce an antigen-independent T cell activation. We have identified the binding sites for 16 monoclonal antibodies against CD2 by a rapid and generally applicable mutational analysis. The binding sites fall in three discrete regions: antibodies that participate in activation and block erythrocyte adhesion bind to the first region; antibodies that block adhesion bind to the second region; and antibodies that participate in activation but do not block adhesion bind to the third region. A large number of mutations selected for loss of antibody reactivity in the first two regions also weaken the CD2-LFA-3 interaction. Good agreement was observed between mutational lesions blocking LFA-3 binding and lesions blocking binding by activating antibodies, which supports the view that such antibodies induce T cell activation by mimicking the effect of LFA-3 binding. CD2 sequences that participate in LFA-3 binding correspond to immunoglobulin variable region hypervariable sequences when the homologous domains are aligned. 相似文献
962.
Cloning of decay-accelerating factor suggests novel use of splicing to generate two proteins 总被引:9,自引:0,他引:9
Decay-accelerating factor (DAF), a glycoprotein that is anchored to the cell membrane by phosphatidylinositol, binds activated complement fragments C3b and C4b, thereby inhibiting amplification of the complement cascade on host cell membranes. Here, we report the molecular cloning of human DAF from HeLa cells. Analysis of DAF complementary DNAs revealed two classes of DAF messenger RNA, one apparently derived from the other by a splicing event that causes a coding frameshift near the C terminus. The apparent 'intron' sequence contains an Alu family member and encodes contiguous protein sequence. Two DAF proteins are therefore possible, having divergent C-terminal domains which differ in their hydrophobicity. Both mRNAs are found on polysomes, suggesting that both are translated. We propose that the major (90%) spliced DAF mRNA encodes membrane-bound DAF whereas the minor (10%) unspliced DAF mRNA may encode secreted DAF and we present expression data supporting this. The deduced DAF sequence contains four repeating units homologous to a consensus repeat found in a recently described family of complement proteins. 相似文献
963.
The activation of a guanine nucleotide binding (G) protein is an essential step in coupling certain receptors to the inhibition of voltage-activated calcium channels. We have previously observed that analogues of GTP potentiate the effect of receptor agonists and inhibit calcium currents in cultured dorsal root ganglion (DRG) neurones. A residual sustained 'L-type' component of the calcium channel current is resistant to inhibition by internal guanosine 5'-O-3-thiotriphosphate (GTP-gamma-S). Because calcium channel antagonists such as D600, nifedipine and diltiazem inhibit L currents, we examined their effect on GTP-gamma-S-modified currents. These compounds all produced a rapid and very marked potentiation of calcium channel currents in the presence of internal GTP-gamma-S and this effect was prevented by pertussis toxin which ADP ribosylates the G proteins Gi/Go (for review see ref. 10). We suggest that this potentiation indicates that activated G protein can interact with the calcium channel, and that this enhances the action of calcium channel ligands at their agonist sites on the channel in its resting state. These results represent the first electrophysiological evidence that guanine nucleotides are able to influence cellular responses to calcium channel ligands. 相似文献
964.
An AIDS-related cytotoxic autoantibody reacts with a specific antigen on stimulated CD4+ T cells 总被引:2,自引:0,他引:2
R B Stricker T M McHugh D J Moody W J Morrow D P Stites M A Shuman J A Levy 《Nature》1987,327(6124):710-713
Patients with the acquired immune deficiency syndrome (AIDS) and AIDS-related conditions are known to have abnormalities of T cell subpopulations, including a decreased helper/inducer (bearing the CD4 antigen) to suppressor/cytotoxic (bearing the CD8 antigen) T cell ratio and decreased absolute numbers of T cells with the CD4+ phenotype. Infection of T cells with a retrovirus, termed human immunodeficiency virus (HIV), is thought to be important in these abnormalities. HIV infection alone does not adequately explain the CD4+ T-cell abnormalities seen in AIDS, however, and the nature of T-cell destruction in this disease remains poorly characterized. Here we describe an AIDS-related serum autoantibody that reacts with an antigen of relative molecular mass 18,000 (Mr 18K) restricted to lectin-stimulated or HIV-infected CD4+ T cells. The antibody also suppresses proliferation of CD4+ T cells in vitro and induces cytotoxicity of these cells in the presence of complement. Its role in the development of AIDS merits attention. 相似文献
965.
N E Simpson K K Kidd P J Goodfellow H McDermid S Myers J R Kidd C E Jackson A M Duncan L A Farrer K Brasch 《Nature》1987,328(6130):528-530
Multiple endocrine neoplasis type 2A (MEN2A) is one of several kinds of cancers that appear to be inherited in an autosomally dominant fashion. We have assigned the MEN2A locus to chromosome 10 by linkage with a new DNA marker (D10S5). The linkage led us to investigate other chromosome 10 markers and demonstrate linkage between the disease locus and the interstitial retinol-binding protein (IRBP) gene. The D10S5 locus was sublocalized to 10q21.1 by hybridization in situ and the IRBP gene to p11.2----q11.2 with a secondary site at q24----q25. The linkages were established using 292 members of five families, three different restriction fragment length polymorphisms (RFLPs) at D10S5 and two RFLPs recognized by the IRBP probe. The recombination frequencies from pairwise linkage analysis between the disease and two marker loci D10S5 and IRBP were 0.19 and 0.11, with maximum lod scores of 3.6 and 8.0 respectively. Ordering of the three loci by multipoint analysis placed the IRBP gene approximately midway between the disease and D10S5 loci. 相似文献
966.
M Manning J P Przybylski A Olma W A Klis M Kruszynski N C Wo G H Pelton W H Sawyer 《Nature》1987,329(6142):839-840
Early reports that acyclic analogues of oxytocin and vasopressin (AVP) have drastically reduced agonistic activities established as dogma that an intact hexapeptide ring structure is essential for the pharmacological activities of analogues of neurohypophysial hormones. Thus, virtually all the many hundreds of agonistic and antagonistic analogues of the neurohypophysial peptides that have been reported contain an intact ring. Here we report that an intact ring is not essential for binding of antagonistic AVP analogues to vasopressor (V1) or antidiuretic (V2) AVP receptors. In fact, one acyclic AVP analogue seems to be about as potent as any previously reported cyclic V2 antagonist. This finding suggests new possibilities for the design of AVP analogues as pharmacological probes and for therapeutic use. Similar modifications might be useful in the design of analogues of other cyclic peptides, such as calcitonin, somatostatin and the atrial natriuretic factors. 相似文献
967.
The genetic defect in familial Alzheimer's disease is not tightly linked to the amyloid beta-protein gene 总被引:1,自引:0,他引:1
R E Tanzi P H St George-Hyslop J L Haines R J Polinsky L Nee J F Foncin R L Neve A I McClatchey P M Conneally J F Gusella 《Nature》1987,329(6135):156-157
Amyloid beta-protein (AP) is a peptide of relative molecular mass (Mr) 42,000 found in the senile plaques, cerebrovascular amyloid deposits, and neurofibrillary tangles of patients with Alzheimer's disease and Down's syndrome (trisomy 21). Recent molecular genetic evidence has indicated that AP is encoded as part of a larger protein by a gene on chromosome 21 (refs 5-7). The defect in the inherited autosomal dominant form of Alzheimer's disease, familial Alzheimer's disease (FAD), has been mapped to the same approximate region of chromosome 21 by genetic linkage to anonymous DNA markers, raising the possibility that this gene product, which could be important in the pathogenesis of Alzheimer's disease, is also the site of the inherited defect in FAD (ref. 5). We have determined the pattern of segregation of the AP gene in FAD pedigrees using restriction fragment length polymorphisms. The detection of several recombination events with FAD suggests that the AP gene is not the site of the inherited defect underlying this disorder. 相似文献
968.
The expression of hybrid HIV:Ty virus-like particles in yeast 总被引:3,自引:0,他引:3
969.
Y Y Toyoshima S J Kron E M McNally K R Niebling C Toyoshima J A Spudich 《Nature》1987,328(6130):536-539
The rotating crossbridge model for muscle contraction proposes that force is produced by a change in angle of the crossbridge between the overlapping thick and thin filaments. Myosin, the major component of the thick filament, is comprised of two heavy chains and two pairs of light chains. Together they form two globular heads, which give rise to the crossbridge in muscle, and a coiled-coil rod, which forms the shaft of the thick filament. The isolated head fragment, subfragment-1 (S1), contains the ATPase and actin-binding activities of myosin (Fig. 1). Although S1 seems to have the requisite enzymatic activity, direct evidence that S1 is sufficient to drive actin movement has been lacking. It has long been recognized that in vitro movement assays are an important approach for identifying the elements in muscle responsible for force generation. Hynes et al. showed that beads coated with heavy meromyosin (HMM), a soluble proteolytic fragment of myosin consisting of a part of the rod and the two heads, can move on Nitella actin filaments. Using the myosin-coated surface assay of Kron and Spudich, Harada et al. showed that single-headed myosin filaments bound to glass support movement of actin at nearly the same speed as intact myosin filaments. These studies show that the terminal portion of the rod and the two-headed nature of myosin are not required for movement. To restrict the region responsible for movement further, we have modified the myosin-coated surface assay by replacing the glass surface with a nitrocellulose film. Here we report that myosin filaments, soluble myosin, HMM or S1, when bound to a nitrocellulose film, support actin sliding movement (Fig. 2). That S1 is sufficient to cause sliding movement of actin filaments in vitro gives strong support to models of contraction that place the site of active movement in muscle within the myosin head. 相似文献
970.
Expression and functional characterization of artificial mutants of interleukin-2 receptor 总被引:1,自引:0,他引:1
The physiological proliferation of T lymphocytes (T cells) requires interaction between the humoral growth factor, interleukin 2 (IL-2) and its cell-surface receptor. Studies of IL-2 binding to the IL-2 receptor (IL-2R) on T cells have revealed that there are two distinct species of IL-2R, one with high and one with low affinity. Isolation and characterization of cDNA for the human IL-2R made it possible to deduce the complete primary sequence (251 residues) of the receptor protein. However, expression of IL-2R alone is not sufficient for either growth signal transduction or high-affinity site formation: another lymphocyte-specific molecule called converter seems to be required for the biological activity of IL-2R. We found that the converter did not form a stable complex with IL-2R unless the receptor bound the ligand (the 'affinity conversion' model). To discover which are the functionally important parts of the human IL-2R we have constructed artificial mutant cDNAs encoding the receptor. The mutant receptors produced from them had deletions or substitutions in the cytoplasmic region (13 residues), the transmembrane region (19 residues) or the carboxy-terminal portion of the extracellular region (219 residues). All were active in growth signal transduction, efficient internalization and high-affinity site formation in two mouse T-cell lines, suggesting that the extracellular region of IL-2R and the converter may be responsible for growth signal transduction. 相似文献