全文获取类型
收费全文 | 13347篇 |
免费 | 1057篇 |
国内免费 | 2篇 |
专业分类
14406篇 |
出版年
2023年 | 69篇 |
2022年 | 156篇 |
2021年 | 270篇 |
2020年 | 160篇 |
2019年 | 192篇 |
2018年 | 259篇 |
2017年 | 253篇 |
2016年 | 411篇 |
2015年 | 666篇 |
2014年 | 766篇 |
2013年 | 922篇 |
2012年 | 1253篇 |
2011年 | 1159篇 |
2010年 | 701篇 |
2009年 | 620篇 |
2008年 | 892篇 |
2007年 | 929篇 |
2006年 | 776篇 |
2005年 | 757篇 |
2004年 | 669篇 |
2003年 | 638篇 |
2002年 | 630篇 |
2001年 | 107篇 |
2000年 | 77篇 |
1999年 | 104篇 |
1998年 | 144篇 |
1997年 | 88篇 |
1996年 | 75篇 |
1995年 | 70篇 |
1994年 | 71篇 |
1993年 | 72篇 |
1992年 | 52篇 |
1991年 | 47篇 |
1990年 | 42篇 |
1989年 | 26篇 |
1988年 | 24篇 |
1987年 | 23篇 |
1986年 | 23篇 |
1985年 | 16篇 |
1984年 | 22篇 |
1983年 | 19篇 |
1982年 | 8篇 |
1981年 | 17篇 |
1980年 | 14篇 |
1979年 | 10篇 |
1978年 | 11篇 |
1975年 | 8篇 |
1971年 | 11篇 |
1969年 | 8篇 |
1966年 | 8篇 |
排序方式: 共有10000条查询结果,搜索用时 17 毫秒
101.
Complement inhibition is to a large extent achieved by proteolytic degradation of activated complement factors C3b and C4b by factor I (FI). This reaction requires a cofactor protein that binds C3b/C4b. We found that the cofactor activity of C4b-binding protein towards C4b/C3b and factor H towards C3b increase at micromolar concentrations of Zn(2+) and are abolished at 2 mM Zn(2+) and above. 65Zn(2+) bound to C3b and C4b molecules but not the cofactors or FI when they were immobilized in a native form on a nitrocellulose membrane. Zn(2+) binding constants for C3met (0.2 microM) and C4met (0.1 microM) were determined using fluorescent chelator. It appears that higher cofactor activity at low zinc concentrations is due to an increase of affinity between C4b/C3b and cofactor proteins as assessed by surface plasmon resonance. Inhibition of the reaction seen at higher concentrations is due to aggregation of C4b/C3b. 相似文献
102.
103.
Stefan Balabanov Thomas Wilhelm Simone Venz Gunhild Keller Christian Scharf Heike Pospisil Melanie Braig Christine Barett Carsten Bokemeyer Reinhard Walther Tim H. Brümmendorf Andreas Schuppert 《PloS one》2013,8(1)
In drug discovery, the characterisation of the precise modes of action (MoA) and of unwanted off-target effects of novel molecularly targeted compounds is of highest relevance. Recent approaches for identification of MoA have employed various techniques for modeling of well defined signaling pathways including structural information, changes in phenotypic behavior of cells and gene expression patterns after drug treatment. However, efficient approaches focusing on proteome wide data for the identification of MoA including interference with mutations are underrepresented. As mutations are key drivers of drug resistance in molecularly targeted tumor therapies, efficient analysis and modeling of downstream effects of mutations on drug MoA is a key to efficient development of improved targeted anti-cancer drugs. Here we present a combination of a global proteome analysis, reengineering of network models and integration of apoptosis data used to infer the mode-of-action of various tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) cell lines expressing wild type as well as TKI resistance conferring mutants of BCR-ABL. The inferred network models provide a tool to predict the main MoA of drugs as well as to grouping of drugs with known similar kinase inhibitory activity patterns in comparison to drugs with an additional MoA. We believe that our direct network reconstruction approach, demonstrated on proteomics data, can provide a complementary method to the established network reconstruction approaches for the preclinical modeling of the MoA of various types of targeted drugs in cancer treatment. Hence it may contribute to the more precise prediction of clinically relevant on- and off-target effects of TKIs. 相似文献
104.
Jens Buchholz Andreas Schwentner Britta Brunnenkan Christina Gabris Simon Grimm Robert Gerstmeir Ralf Takors Bernhard J. Eikmanns Bastian Blombach 《Applied and environmental microbiology》2013,79(18):5566-5575
Exchange of the native Corynebacterium glutamicum promoter of the aceE gene, encoding the E1p subunit of the pyruvate dehydrogenase complex (PDHC), with mutated dapA promoter variants led to a series of C. glutamicum strains with gradually reduced growth rates and PDHC activities. Upon overexpression of the l-valine biosynthetic genes ilvBNCE, all strains produced l-valine. Among these strains, C. glutamicum aceE A16 (pJC4 ilvBNCE) showed the highest biomass and product yields, and thus it was further improved by additional deletion of the pqo and ppc genes, encoding pyruvate:quinone oxidoreductase and phosphoenolpyruvate carboxylase, respectively. In fed-batch fermentations at high cell densities, C. glutamicum aceE A16 Δpqo Δppc (pJC4 ilvBNCE) produced up to 738 mM (i.e., 86.5 g/liter) l-valine with an overall yield (YP/S) of 0.36 mol per mol of glucose and a volumetric productivity (QP) of 13.6 mM per h [1.6 g/(liter × h)]. Additional inactivation of the transaminase B gene (ilvE) and overexpression of ilvBNCD instead of ilvBNCE transformed the l-valine-producing strain into a 2-ketoisovalerate producer, excreting up to 303 mM (35 g/liter) 2-ketoisovalerate with a YP/S of 0.24 mol per mol of glucose and a QP of 6.9 mM per h [0.8 g/(liter × h)]. The replacement of the aceE promoter by the dapA-A16 promoter in the two C. glutamicum
l-lysine producers DM1800 and DM1933 improved the production by 100% and 44%, respectively. These results demonstrate that C. glutamicum strains with reduced PDHC activity are an excellent platform for the production of pyruvate-derived products. 相似文献
105.
Lee D. Major Thomas S. Partridge Joy Gardner Stephen J. Kent Robert de Rose Andreas Suhrbier Wayne A. Schroder 《PloS one》2013,8(2)
SerpinB2, also known as plasminogen activator inhibitor type 2, is a major product of activated monocytes/macrophages and is often strongly induced during infection and inflammation; however, its physiological function remains somewhat elusive. Herein we show that SerpinB2 is induced in peripheral blood mononuclear cells following infection of pigtail macaques with CCR5-utilizing (macrophage-tropic) SIVmac239, but not the rapidly pathogenic CXCR4-utilizing (T cell-tropic) SHIVmn229. To investigate the role of SerpinB2 in lentiviral infections, SerpinB2−/− mice were infected with EcoHIV, a chimeric HIV in which HIV gp120 has been replaced with gp80 from ecotropic murine leukemia virus. EcoHIV infected SerpinB2−/− mice produced significantly lower anti-gag IgG1 antibody titres than infected SerpinB2+/+ mice, and showed slightly delayed clearance of EcoHIV. Analyses of published microarray studies showed significantly higher levels of SerpinB2 mRNA in monocytes from HIV-1 infected patients when compared with uninfected controls, as well as a significant negative correlation between SerpinB2 and T-bet mRNA levels in peripheral blood mononuclear cells. These data illustrate that SerpinB2 can be induced by lentiviral infection in vivo and support the emerging notion that a physiological role of SerpinB2 is modulation of Th1/Th2 responses. 相似文献
106.
107.
Andreas Becker Jana F. Liewald Gerhard Wegener 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》1998,168(3):159-167
Hypertrehalosaemic hormones stimulate trehalogenesis while inhibiting glycolysis in cockroach fat body. Signal transduction
of the hypertrehalosaemic peptide Bld HrTH was examined in isolated fat body of the Argentine cockroach Blaptica dubia with respect to its effects on the increase in trehalose production and decrease in the content of the glycolytic activator
fructose 2,6-bisphosphate in the tissue. Cyclic AMP does not seem to be involved in these processes as the cAMP analogue cpt-cAMP
and the phosphodiesterase inhibitor IBMX, which both permeate cell membranes, had no effect on either parameter. Octopamine
at physiological concentrations (10−7 mol · l−1) was also ineffective, but at 10−5 mol · l−1 or above, octopamine stimulated trehalose production although the content of fructose 2,6-bisphosphate in fat body was not
affected. Both calcium entry and the release of Ca2+ from intracellular stores seem to be involved in the action of the hormone. If Ca2+ was omitted from the incubation medium, the hormone stimulated trehalose production less, though still significantly, whereas
the hormone effect on fructose 2,6-bisphosphate was completely abolished in the absence of extracellular Ca2+. With Ca2+ present in the medium, the effect of the hormone on fructose 2,6-bisphosphate could be fully mimicked by the calcium ionophore
A23187, suggesting that calcium entry is a␣decisive step in this signalling pathway. Trehalose production, on the other hand,
was increased by thimerosal and thapsigargin which increase cytosolic Ca2+ from intracellular stores, whereas thimerosal in the absence of extracellular Ca2+ increased rather than decreased the content of fructose 2,6-bisphosphate, thus dissociating the two effects, which are normally
coordinated by the hormone. Trehalose production and the content of fructose 2,6-bisphosphate were not significantly affected
by mepacrine and mellitin, which are known to inhibit, respectively stimulate, phospholipase A2. Our data suggest that the effects of Bld HrTH on the stimulation of trehalose production and reduction of fructose 2,6-bisphosphate
content in fat body are mediated by Ca2+, but that different signalling pathways are involved, suggesting that the two processes, although they are functionally linked,
could be regulated separately.
Accepted: 10 November 1997 相似文献
108.
109.
Nogueira-Ferreira Rita Ferreira Rita Padrão Ana Isabel Oliveira Paula Santos Manuel Kavazis Andreas N. Vitorino Rui Moreira-Gonçalves Daniel 《Journal of physiology and biochemistry》2019,75(4):561-572
Journal of Physiology and Biochemistry - Aerobic exercise training induces a unique cardioprotective phenotype, but it is becoming clear that it does not promote the same structural, functional,... 相似文献
110.
Oesterhelt C Klocke S Holtgrefe S Linke V Weber AP Scheibe R 《Plant & cell physiology》2007,48(9):1359-1373
Redox modulation is a general mechanism for enzyme regulation, particularly for the post-translational regulation of the Calvin cycle in chloroplasts of green plants. Although red algae and photosynthetic protists that harbor plastids of red algal origin contribute greatly to global carbon fixation, relatively little is known about post-translational regulation of chloroplast enzymes in this important group of photosynthetic eukaryotes. To address this question, we used biochemistry, phylogenetics and analysis of recently completed genome sequences. We studied the functionality of the chloroplast enzymes phosphoribulokinase (PRK, EC 2.7.1.19), NADP-dependent glyceraldehyde 3-phosphate dehydrogenase (NADP-GAPDH, GapA, EC 1.2.1.13), fructose 1,6-bisphosphatase (FBPase, EC 3.1.3.11) and glucose 6-phosphate dehydrogenase (G6PDH, EC 1.1.1.49), as well as NADP-malate dehydrogenase (NADP-MDH, EC 1.1.1.37) in the unicellular red alga Galdieria sulphuraria (Galdieri) Merola. Despite high sequence similarity of G. sulphuraria proteins to those of other photosynthetic organisms, we found a number of distinct differences. Both PRK and GAPDH co-eluted with CP12 in a high molecular weight complex in the presence of oxidized glutathione, although Galdieria CP12 lacks the two cysteines essential for the formation of the N-terminal peptide loop present in higher plants. However, PRK inactivation upon complex formation turned out to be incomplete. G6PDH was redox modulated, but remained in its tetrameric form; FBPase was poorly redox regulated, despite conservation of the two redox-active cysteines. No indication for the presence of plastidic NADP-MDH (and other components of the malate valve) was found. 相似文献