全文获取类型
收费全文 | 1764篇 |
免费 | 162篇 |
专业分类
1926篇 |
出版年
2024年 | 2篇 |
2023年 | 7篇 |
2022年 | 15篇 |
2021年 | 29篇 |
2020年 | 27篇 |
2019年 | 16篇 |
2018年 | 26篇 |
2017年 | 20篇 |
2016年 | 43篇 |
2015年 | 82篇 |
2014年 | 90篇 |
2013年 | 118篇 |
2012年 | 161篇 |
2011年 | 150篇 |
2010年 | 85篇 |
2009年 | 106篇 |
2008年 | 118篇 |
2007年 | 140篇 |
2006年 | 99篇 |
2005年 | 101篇 |
2004年 | 106篇 |
2003年 | 88篇 |
2002年 | 81篇 |
2001年 | 14篇 |
2000年 | 18篇 |
1999年 | 17篇 |
1998年 | 27篇 |
1997年 | 12篇 |
1996年 | 17篇 |
1995年 | 16篇 |
1994年 | 14篇 |
1993年 | 15篇 |
1992年 | 7篇 |
1991年 | 7篇 |
1990年 | 4篇 |
1989年 | 5篇 |
1988年 | 5篇 |
1987年 | 3篇 |
1986年 | 2篇 |
1985年 | 5篇 |
1984年 | 3篇 |
1983年 | 6篇 |
1982年 | 4篇 |
1980年 | 3篇 |
1978年 | 2篇 |
1977年 | 3篇 |
1976年 | 2篇 |
1975年 | 1篇 |
1974年 | 2篇 |
1969年 | 1篇 |
排序方式: 共有1926条查询结果,搜索用时 0 毫秒
81.
Floxed allele for conditional inactivation of the GABAB(1) gene 总被引:3,自引:0,他引:3
Haller C Casanova E Müller M Vacher CM Vigot R Doll T Barbieri S Gassmann M Bettler B 《Genesis (New York, N.Y. : 2000)》2004,40(3):125-130
GABA(B) receptors are the G-protein-coupled receptors for the neurotransmitter GABA. GABA(B) receptors are broadly expressed in the nervous system. Their complete absence in mice causes premature lethality or--when mice are viable--epilepsy, impaired memory, hyperalgesia, hypothermia, and hyperactivity. A spatially and temporally restricted loss of GABA(B) function would allow addressing how the absence of GABA(B) receptors leads to these diverse phenotypes. To permit a conditional gene inactivation, we flanked critical exons of the GABA(B(1)) gene with lox511 sites. GABA(B(1)) (lox511/lox511) mice exhibit normal levels of GABA(B(1)) protein, are fertile, and do not display any behavioral phenotype. We crossed GABA(B(1)) (lox511/lox511) with Cre-deleter mice to produce mice with an unrestricted GABA(B) receptor elimination. These GABA(B(1)) (-/-) mice no longer synthesize GABA(B(1)) protein and exhibit the expected behavioral abnormalities. The conditional GABA(B(1)) allele described here is therefore suitable for generating mice with a site- and time-specific loss of GABA(B) function. 相似文献
82.
Early steps in the development of the forebrain 总被引:2,自引:0,他引:2
The tremendous complexity of the adult forebrain makes it a challenging task to elucidate how this structure forms during embryonic development. Nevertheless, we are beginning to understand how a simple epithelial sheet of ectoderm gives rise to the labyrinthine network of cells that constitutes the functional forebrain. Here, we discuss early events in forebrain development--those that lead to the establishment of the anterior neural plate and the regional subdivision of this territory into the different domains of the prospective forebrain. 相似文献
83.
The structural study of transient nucleoprotein complexes by electron microscopy is hampered by the coexistence of multiple interaction states leading to an heterogeneous image population. To tackle this problem, we have investigated the controlled immobilization of double stranded DNA molecules and of nucleoprotein complexes onto a support suitable for cryo-electron microscopy observation. The DNA was end-labeled with a biotin moiety in order to decorate, or to be incorporated into, two-dimensional streptavidin crystals formed in contact of a biotinylated lipid layer. The binding specificity and efficiency were examined by radioactively labeled oligonucleotides and by direct visualization of unstained and hydrated nucleic acid molecules in cryo-electron microscopy. By using RNA polymerase we further show that, once immobilized, femtomolar amounts of DNA template are suitable to interact with the enzyme. The image analysis of the RNA polymerase-DNA complexes showed that a three-dimensional model can be retrieved from such samples. 相似文献
84.
85.
Guillerm G Guillerm D Vandenplas-Vitkowski C Glapski C De Clercq E 《Bioorganic & medicinal chemistry letters》2003,13(10):1649-1652
Synthesis of 5'-S-vinyl-5'-thioadenosine 5, 5'-S-ethynyl-5'-thioadenosine 7 and 5'-S-cyano-5'-thioadenosine 9 is described. Incubation of AdoHcy hydrolase with 5, 7 and 9 resulted in time- and concentration-dependent inactivation of the enzyme and partial depletion of its NAD(+) content. From these results and characterisation of metabolites released during the inactivation process, hypothetical mechanisms are suggested. The antiviral activity of 5, 7 and 9 was examined. Significant activities were noted with 5 against Vaccinia, Junin and Taccaribe viruses. 相似文献
86.
87.
Merkulova-Rainon T England P Ding S Demerens C Tobelem G 《The Journal of biological chemistry》2003,278(39):37400-37408
Hepatocyte growth factor (HGF) is a pleiotropic factor that plays an important role in complex biological processes such as embryogenesis, tissue regeneration, cancerogenesis, and angiogenesis. HGF promotes cell proliferation, survival, motility, and morphogenesis through binding to its receptor, a transmembrane tyrosine kinase encoded by the MET proto-oncogene (c-met). Structurally speaking, HGF is a polypeptide related to the enzymes of the blood coagulation cascade. Thus, it comprises kringle domains that in some other proteins have been shown to be responsible for the anti-angiogenic activity. To check whether the isolated kringles of HGF were able to inhibit angiogenesis, we produced them as recombinant proteins and compared their biological activity with that of the recombinant HGF N-terminal domain (N). We showed that (i) none of the isolated HGF kringle exhibits an anti-angiogenic activity; (ii) N is a new anti-angiogenic polypeptide; (iii) the inhibitory action of N is not specific toward HGF, because it antagonized the angiogenic activity of other growth factors, such as fibroblast growth factor-2 and vascular endothelial growth factor; and (iv) in contrast with full-length HGF, N does not bind to the c-met receptor in vitro, but fully retains its heparin-binding capacity. Our results suggest that N inhibits angiogenesis not by disrupting the HGF/c-met interaction but rather by interfering with the endothelial glycosaminoglycans, which are the secondary binding sites of HGF. 相似文献
88.
Chazaud B Sonnet C Lafuste P Bassez G Rimaniol AC Poron F Authier FJ Dreyfus PA Gherardi RK 《The Journal of cell biology》2003,163(5):1133-1143
Once escaped from the quiescence niche, precursor cells interact with stromal components that support their survival, proliferation, and differentiation. We examined interplays between human myogenic precursor cells (mpc) and monocyte/macrophages (MP), the main stromal cell type observed at site of muscle regeneration. mpc selectively and specifically attracted monocytes in vitro after their release from quiescence, chemotaxis declining with differentiation. A DNA macroarray-based strategy identified five chemotactic factors accounting for 77% of chemotaxis: MP-derived chemokine, monocyte chemoattractant protein-1, fractalkine, VEGF, and the urokinase system. MP showed lower constitutive chemotactic activity than mpc, but attracted monocytes much strongly than mpc upon cross-stimulation, suggesting mpc-induced and predominantly MP-supported amplification of monocyte recruitment. Determination of [3H]thymidine incorporation, oligosomal DNA levels and annexin-V binding showed that MP stimulate mpc proliferation by soluble factors, and rescue mpc from apoptosis by direct contacts. We conclude that once activated, mpc, which are located close by capillaries, initiate monocyte recruitment and interplay with MP to amplify chemotaxis and enhance muscle growth. 相似文献
89.
Pruitt WM Karnoub AE Rakauskas AC Guipponi M Antonarakis SE Kurakin A Kay BK Sondek J Siderovski DP Der CJ 《Biochimica et biophysica acta》2003,1640(1):61-68
Intersectin-long (ITSN-L) contains the invariant Dbl homology (DH) and pleckstrin homology (PH) domain structure characteristic of the majority of Dbl family proteins. This strict domain topography suggests that the PH domain serves an essential, conserved function in the regulation of the intrinsic guanine nucleotide exchange activity of the DH domain. We evaluated the role of the PH domain in regulating the DH domain function of ITSN-L. Surprisingly, we found that the PH domain was dispensable for guanine nucleotide exchange activity on Cdc42 in vitro, yet the PH domain enhanced the ability of the DH domain to activate Cdc42 signaling in vivo. PH domains can interact with phosphoinositide substrates and products of phosphatidylinositol 3-kinase (PI3K). However, PI3K activation did not modulate ITSN-L DH domain function in vivo. 相似文献
90.
Debierre-Grockiego F Desaint C Fuentes V Poussin M Socié G Azzouz N Schwarz RT Prin L Gouilleux-Gruart V 《FEBS letters》2003,540(1-3):111-116
MIST (mast cell immunoreceptor signal transducer; also termed Clnk) is an adaptor protein structurally related to SLP-76-family hematopoietic cell-specific adaptor proteins. We demonstrate here that two major MIST-associated phosphoproteins expressed in mast cell lines are SLAP-130 and SKAP55, adaptors known to interact with the Src-homology (SH) 2 domain of Src-family protein tyrosine kinases (PTKs). MIST directly associated with SLAP-130 via its SH2 domain, and collaboration of SLAP-130 with SKAP55 was required for the recruitment of MIST to Lyn. Furthermore, MIST was preferentially recruited to Fyn rather than Lyn, which is regulated by higher affinity binding of SLAP-130 and SKAP55 with the Fyn-SH2 domain than the Lyn-SH2 domain. Our results suggest that the MIST–SLAP-130–SKAP55 adaptor complex functions downstream of high-affinity IgE receptor-associated Src-PTKs in mast cells. 相似文献