全文获取类型
收费全文 | 1846篇 |
免费 | 130篇 |
国内免费 | 45篇 |
出版年
2023年 | 17篇 |
2022年 | 38篇 |
2021年 | 47篇 |
2020年 | 38篇 |
2019年 | 47篇 |
2018年 | 47篇 |
2017年 | 36篇 |
2016年 | 62篇 |
2015年 | 56篇 |
2014年 | 85篇 |
2013年 | 84篇 |
2012年 | 63篇 |
2011年 | 111篇 |
2010年 | 54篇 |
2009年 | 79篇 |
2008年 | 97篇 |
2007年 | 106篇 |
2006年 | 82篇 |
2005年 | 93篇 |
2004年 | 88篇 |
2003年 | 67篇 |
2002年 | 63篇 |
2001年 | 40篇 |
2000年 | 45篇 |
1999年 | 53篇 |
1998年 | 47篇 |
1997年 | 43篇 |
1996年 | 51篇 |
1995年 | 40篇 |
1994年 | 44篇 |
1993年 | 39篇 |
1992年 | 36篇 |
1991年 | 22篇 |
1990年 | 21篇 |
1989年 | 7篇 |
1988年 | 3篇 |
1987年 | 6篇 |
1986年 | 4篇 |
1985年 | 4篇 |
1984年 | 5篇 |
1983年 | 3篇 |
1982年 | 6篇 |
1981年 | 5篇 |
1980年 | 23篇 |
1979年 | 1篇 |
1978年 | 5篇 |
1976年 | 2篇 |
1974年 | 2篇 |
1973年 | 1篇 |
1972年 | 2篇 |
排序方式: 共有2021条查询结果,搜索用时 31 毫秒
1.
2.
Rashi Verma Monika Yadav Rajabrata Bhuyan Shweta Aggarwal Arnab Nayek 《Journal of receptor and signal transduction research》2016,36(6):601-616
Computer-aided antibody engineering has been successful in the design of new biologics for disease diagnosis and therapeutic interventions. Interleukin-6 (IL-6), a well-recognized drug target for various autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and psoriasis, was investigated in silico to design potential lead antibodies. Here, crystal structure of IL-6 along with monoclonal antibody olokizumab was explored to predict antigen–antibody (Ag???Ab)-interacting residues using DiscoTope, Paratome, and PyMOL. Tyr56, Tyr103 in heavy chain and Gly30, Ile31 in light chain of olokizumab were mutated with residues Ser, Thr, Tyr, Trp, and Phe. A set of 899 mutant macromolecules were designed, and binding affinity of these macromolecules to IL-6 was evaluated through Ag???Ab docking (ZDOCK, ClusPro, and Rosetta server), binding free-energy calculations using Molecular Mechanics/Poisson Boltzman Surface Area (MM/PBSA) method, and interaction energy estimation. In comparison to olokizumab, eight newly designed theoretical antibodies demonstrated better result in all assessments. Therefore, these newly designed macromolecules were proposed as potential lead antibodies to serve as a therapeutics option for IL-6-mediated diseases. 相似文献
3.
CHRISTOPHE GONINDARD CATHERINE GOIGOUX ETIENNE HOLLANDE LUCIEN DUSSOURD D'HINTERLAND 《Pigment cell & melanoma research》1996,9(3):148-153
The injection of α-MSH or of one of its analogues ([Nle4-D.Phe7] α-MSH4–10) reduced, in vivo, the release of two cytokines (IL-1α and TNFα) involved in inflammation. The inflammatory state was induced in BALB/c mice by intraperitoneal injection of a sublethal dose of lipopolysaccharides (LPS). The assay of these cytokines by ELISA showed a reduction of 20% with α-MSH and between 30 and 60% with the α-MSH analogue. The α-MSH or the analogue was administered in one of two ways: intravenously or subcutaneously. The most efficient method seemed to be the subcutaneous one because it improved the activity 10,000 times more than the intravenous method. Moreover, the analogue induced a regression of mortality in the animals treated by the intravenous method. Our results show that α-MSH and one of its analogues inhibit IL-1α and TNFα, and can be used as anti-inflammatory molecules. 相似文献
4.
Saori Oka 《Biochemical and biophysical research communications》2010,395(2):232-7396
GPR35 is a rhodopsin-like G protein-coupled receptor identified in 1998. It has been reported that kynurenic acid, a tryptophan metabolite, may act as an endogenous ligand for GPR35. However, the concentrations of kynurenic acid required to elicit the cellular responses are usually high, raising the possibility that another endogenous ligand may exist. In this study, we searched for another endogenous ligand for GPR35. Finally, we found that the magnitude of the Ca2+ response induced by 2-acyl lysophosphatidic acid in the GPR35-expressing HEK293 cells was markedly greater than that in the vector-transfected control cells. Such a difference was not apparent in the case of 1-acyl lysophosphatidic acid. 2-Acyl lysophosphatidic acid also caused the sustained activation of RhoA and the phosphorylation of extracellular signal-regulated kinase, and triggered the internalization of the GPR35 molecule. These results strongly suggest that 2-acyl lysophosphatidic acid is an endogenous ligand for GPR35. 相似文献
5.
6.
Uptake ofl-[35S]cysteic acid (L-CA) in rat synaptic membrane vesicles was investigated. Preincubation with either 10 mMl-glutamic acid (L-Glu), 25 mM L-CA, 10 mMdl-homocysteic acid, or 25 mMdl-2-amino-4-phosphonobutyrate on membrane vesicles enhanced L-[35S]CA and L-[3H]Glu uptake. Na+ (5 mM) and omission of Cl– from the assay medium decreased L-[35S]CA uptake into both 10 mM L-Glu-loaded and non-loaded membrane vesicles. The anion transport blockers, 4-acetamide-4-isothiocyano-2,2-disulfonic acid stibene (SITS) and 4,4-diisothiocyano-2,2-disulfonic acid stilbene (DIDS), inhibited L-[35S]CA uptake in a dose-dependent manner. The maximal uptake rate for L-[35S]CA was decreased by 50 M SITS, while the apparent Km value of L-CA was not changed. SITS increased the EC50 value of Cl– for L-[35S]CA uptake from 5 mM to 10 mM with reduction of the maximal effect. These results suggested that L-[35S]CA uptake into synaptic membrane vesicles was mediated by a SITS-sensitive hetero-exchange transport with non-labeled substrates.Abbreviations SITS
4-Acetamide-4-isothiocyano-2,2-disulfonic acid stilbene
- DIDS
4,4-Diisothiocyano-2,2-disulfonic acid stilbene
- CA
Cysteic acid
- APB
2-Amino-4-phosphonobutyrate
- CSA
Cysteine sulfinic acid
- EGTA
Ethyleneglycol bis(aminoethylether) tetraacetate
- GABA
-Aminobutyric acid 相似文献
7.
Benoît Verjans Frederic Hollande Colette Moreau Claudine Lejeune Christophe Erneux 《Cellular signalling》1990,2(6):595-599
Inositol 1,4,5-trisphosphate 5-phosphatase catalyses the dephosphorylation of the phosphate in the 5-position from inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate. One particulate and two soluble enzymes were previously described in bovine brain. In this study, we have obtained a precipitating antiserum against soluble type I inositol 1,4,5-trisphosphate 5-phosphatase. The particulate, but not the soluble type II enzyme, was immunoprecipitated by the serum. Inositol 1,4,5-triphosphate 5-phosphatase activity from crude extracts of rat brain, human platelets and rat liver were immmunoprecipitated by the same antibodies, suggesting the existence of common antigenic determinant among inositol 1,4,5-trisphosphate 5-phosphatases of diverse sources. 相似文献
8.
Aspergillus versicolor, which has been isolated from several mould affected houses was shown by laboratory studies under axenic conditions to produce several specific volatile compounds on water agar. These compounds were not produced by the fungus when grown on a rich malt extract medium or on several synthetic media. The volatile compounds were analysed by GC-MS. The majority of the peaks represented aromatic compounds. A non-aromatic substance which previously has been revealed by us among prominent volatile compounds sampled from building materials from so-called mould houses was produced only on water agar. According to a comparison with the mass spectrum and retention time of pure reference compound this compound is ethylhexanol, a compound not previously reported as a mould metabolite. The presence of this compound was correlated with pungent odor in the cultures. 相似文献
9.
Howard R. Hubbell George D. Gibson Robert D. Bigler 《Cancer immunology, immunotherapy : CII》1992,34(4):259-264
Summary Lymphokine-activated killer (LAK) cell activity was measured in human peripheral blood mononuclear cells (PBMC) treated in vitro for 3 days with recombinant interleukin-2 (rIL-2) and mismatched double-stranded RNA (dsRNA). Lytic activity was measured utilizing K562 (NK-sensitive) and 786-0 (NK-resistant) target cells. PBMC cultured with rIL-2 (10–1000 BRMP U/ml) alone showed concentration-dependent lytic activity against the 786-0 target cells, while cells cultured in unsupplemented medium or medium supplemented with mismatched dsRNA (200 µg/ml) alone could not lyse the 786-0 targets. The combination of mismatched dsRNA with suboptimal concentrations of rIL-2 (10–30 U/ml) showed enhancement of both natural killer (NK) and LAK cell activities. The uptake of [3H]thymidine by treated effector cells was dependent on time and rIL-2 concentration and was not increased in the cells treated with low-dose rIL-2/mismatched dsRNA, compared to those treated with low-dose rIL-2 or mismatched dsRNA alone. Similarly, changes in the expression of CD3, CD4, CD8, CD57, CD16 and CD25 cell surface antigens were dependent on rIL-2 concentration and not altered by the presence of mismatched dsRNA. These results indicate that mismatched dsRNA can potentiate rIL-2-induced LAK cell activity by increasing the functional activity per cell, rather than by increasing the number of activated cells. 相似文献
10.
Aino Laatikainen Leslie Schultz-Suhonen Rauno Mäntyjärvi 《Cancer immunology, immunotherapy : CII》1992,35(3):205-210
Summary The effect of interferon (IFN) on the immunogenicity and immunosensitivity of mouse cell lines transformed by bovine papillomavirus type 1 (BPV1) DNA was examined in a syngeneic mouse model. The overnight incubation of BPV1-transformed cell lines with 100 IU/ml IFN did not affect their ability to induce the generation of cytotoxic effector cells but it clearly increased their sensitivity to lysis by interleukin-2-induced lymphokine-activated killer (LAK) cells and by nonspecific LAK-type effector cells induced by BPV-1-transformed cell lines. The treatment of two allogeneic lymphoid tumour cell lines, P815X2 and YAC-1, with IFN either decreased or had no effect on their sensitivity to LAK-cell-mediated lysis. 相似文献