全文获取类型
收费全文 | 3875篇 |
免费 | 227篇 |
国内免费 | 205篇 |
专业分类
4307篇 |
出版年
2023年 | 57篇 |
2022年 | 77篇 |
2021年 | 114篇 |
2020年 | 100篇 |
2019年 | 147篇 |
2018年 | 156篇 |
2017年 | 105篇 |
2016年 | 87篇 |
2015年 | 78篇 |
2014年 | 248篇 |
2013年 | 292篇 |
2012年 | 252篇 |
2011年 | 235篇 |
2010年 | 160篇 |
2009年 | 161篇 |
2008年 | 150篇 |
2007年 | 186篇 |
2006年 | 166篇 |
2005年 | 146篇 |
2004年 | 102篇 |
2003年 | 125篇 |
2002年 | 74篇 |
2001年 | 59篇 |
2000年 | 59篇 |
1999年 | 42篇 |
1998年 | 40篇 |
1997年 | 55篇 |
1996年 | 37篇 |
1995年 | 26篇 |
1994年 | 23篇 |
1993年 | 26篇 |
1992年 | 46篇 |
1991年 | 44篇 |
1990年 | 29篇 |
1989年 | 22篇 |
1988年 | 25篇 |
1987年 | 26篇 |
1985年 | 47篇 |
1984年 | 80篇 |
1983年 | 54篇 |
1982年 | 51篇 |
1981年 | 44篇 |
1980年 | 56篇 |
1979年 | 44篇 |
1978年 | 24篇 |
1977年 | 29篇 |
1976年 | 24篇 |
1975年 | 24篇 |
1974年 | 16篇 |
1973年 | 17篇 |
排序方式: 共有4307条查询结果,搜索用时 0 毫秒
991.
992.
Vanina E. AlvarezGabriela T. Niemirowicz Juan J. Cazzulo 《Biochimica et Biophysica Acta - Proteins and Proteomics》2012,1824(1):195-206
Trypanosoma cruzi, the agent of the American Trypanosomiasis, Chagas disease, contains cysteine, serine, threonine, aspartyl and metallo peptidases. The most abundant among these enzymes is cruzipain, a cysteine proteinase expressed as a mixture of isoforms, some of them membrane-bound. The enzyme is an immunodominant antigen in human chronic Chagas disease and seems to be important in the host/parasite relationship. Inhibitors of cruzipain kill the parasite and cure infected mice, thus validating the enzyme as a very promising target for the development of new drugs against the disease. In addition, a 30 kDa cathepsin B-like enzyme, two metacaspases and two autophagins have been described. Serine peptidases described in the parasite include oligopeptidase B, a member of the prolyl oligopeptidase family involved in Ca2+-signaling during mammalian cell invasion; a prolyl endopeptidase (Tc80), against which inhibitors are being developed, and a lysosomal serine carboxypeptidase. Metallopeptidases homologous to the gp63 of Leishmania spp. are present, as well as two metallocarboxypeptidases belonging to the M32 family, previously found only in prokaryotes. The proteasome has properties similar to those of other eukaryotes, and its inhibition by lactacystin blocks some differentiation steps in the life cycle of the parasite. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome. 相似文献
993.
Sandoval CM Baker SL Jansen K Metzner SI Sousa MC 《Journal of molecular biology》2011,409(3):348-39121
Folding and insertion of integral β-barrel proteins in the outer membrane (OM) is an essential process for Gram-negative bacteria that requires the β-barrel assembly machinery (BAM). Efficient OM protein (OMP) folding and insertion appears to require a consensus C-terminal signal in OMPs characterized by terminal F or W residues. The BAM complex is embedded in the OM and, in Escherichia coli, consists of the β-barrel BamA and four lipoproteins BamBCDE. BamA and BamD are broadly distributed across all species of Gram-negative bacteria, whereas the other components are present in only a subset of species. BamA and BamD are also essential for viability, suggesting that these two proteins constitute the functional core of the bacterial BAM complex. Here, we present the crystal structure of BamD from the thermophilic bacteria Rhodothermus marinus refined to 2.15 Å resolution. The protein contains five tetratricopeptide repeats (TPRs) organized into two offset tandems, each capped by a terminal helix. The N-terminal domain contains three TPRs and displays remarkable structural similarity with proteins that recognize targeting signals in extended conformations. The C-terminal domain harbors the remaining two TPRs and previously described mutations that impair binding to other BAM components map to this domain. Therefore, the structure suggests a model where the C-terminal domain provides a scaffold for interaction with BAM components, while the N-terminal domain participates in interaction with the substrates, either recognizing the C-terminal consensus sequence or binding unfolded OMP intermediates. 相似文献
994.
We earlier showed that vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit increased expression of Gi proteins. Since the levels of endothelin-1 (ET-1) are enhanced in VSMC from SHR, we undertook the present study to examine the implication of endogenous ET-1 and the underlying mechanisms in the enhanced expression of Giα proteins in VSMC from SHR. The enhanced expression of Giα-2 and Giα-3 proteins in VSMC from SHR was inhibited by ETA and ETB receptor antagonists, BQ123 and BQ788 respectively. In addition, these antagonists also attenuated the enhanced inhibition of forskolin-stimulated adenylyl cyclase activity by low concentrations of GTPγS and by inhibitory hormones in VSMC from SHR compared to WKY. Furthermore, AG1295, AG1024 and PP2, inhibitors of platelet derived growth factor receptor (PDGFR), insulin-like growth factor 1 receptor (IGF-1R) and c-Src respectively, inhibited the enhanced expression of Giα protein and the enhanced phosphorylation of PDGFR and IGF-1R in VSMC from SHR to WKY levels. In addition, NAD(P)H oxidase inhibitor DPI and N-acetylcysteine (NAC), a scavenger of superoxide anion (O2−) also inhibited the enhanced phosphorylation of PDGFR and IGF-1R and c-Src in VSMC from SHR to control levels. Furthermore, the augmented phosphorylation of ERK1/2 in VSMC from SHR was attenuated by BQ123 and BQ788, growth factor receptors inhibitors and PP2. These results suggest that the enhanced levels of endogenous ET-1 in VSMC from SHR increase oxidative stress, which through c-Src-mediated activation of growth factor receptors and associated MAP kinase signaling, contribute to the enhanced expression of Giα proteins. 相似文献
995.
Bridget J. Powell Kevin J. Purdy Ian P. Thompson Mark J. Bailey 《FEMS microbiology ecology》1993,12(3):195-206
Abstract The presence of transfer proficient plasmids in bacteria isolated from the leaves of sugar beet ( Beta vulgaris L.) was studied. Of 435 bacteria sampled 79 (18%) contained plasmids. Pseudomonads (30%), Erwinia (12%) and Klebsiella (9%) were the largest populations sampled of which 22%, 33% and 29%, respectively, contained plasmids. The ability of these plasmids to self-transfer or mediate the mobilization of the tra− mob+ broad host range IncQ plasmid R300B was determined. R300B was maintained in 61/79 natural plasmid containing isolates, the Gram positive isolates could not support R300B. Pseudomonas aureofaciens SBW25, isolated from sugar beet leaves, was chromosomally marked with a tetracycline resistance gene and used as a recipient (SBW25ETc). Five isolates of Erwinia herbicola and one of Erwinia salicis containing natural plasmids were able to mobilize R300B into the recombinant, SBW25ETc. These mobolizing ( tra+ ) plasmids were not maintained in transconjugant SBW25 cells. Analysis of the fragment patterns of Pst I digested plasmid DNA demonstrated that four (pSB139, pSB140, pSB142, pSB146; 110 kb) were identical, one (pSB153; 65 kb) was common to a subset of fragments in these four and another (pSB169; 100 kb) was unique. Other natural isolates were able to transfer copper resistance ( Erwinia rhapontici , 2 strains) or mercury resistance ( Pseudomonas fluorescens SBW340) to a rifampicin resistant recipient Pseudomonas putida UWC1 but not to SBW25ETc. These self-transferable plasmids were not able to mobilize R300B. These data demonstrate that the phyllosphere supports indigenous microbial populations which have the capacity to transfer genetic material between bacteria of different genera. 相似文献
996.
Zhiqiang Wang Shimeng Liu Miyo Kakizaki Yuuki Hirose Yukiko Ishikawa Hiromasa Funato Masashi Yanagisawa Yonghao Yu Qinghua Liu 《The Journal of biological chemistry》2014,289(46):31950-31959
The lack of the neuropeptide orexin, also known as hypocretin, results in narcolepsy, a chronic sleep disorder characterized by frequent sleep/cataplexy attacks and rapid eye movement sleep abnormalities. However, the downstream pathways of orexin signaling are not clearly understood. Here, we show that orexin activates the mTOR pathway, a central regulator of cell growth and metabolism, in the mouse brain and multiple recombinant cell lines that express the G protein-coupled receptors (GPCRs), orexin 1 receptor (OX1R) or orexin 2 receptor (OX2R). This orexin/GPCR-stimulated mTOR activation is sensitive to rapamycin, an inhibitor of mTOR complex 1 (mTORC1) but is independent of two well known mTORC1 activators, Erk and Akt. Rather, our studies indicate that orexin activates mTORC1 via extracellular calcium influx and the lysosome pathway involving v-ATPase and Rag GTPases. Moreover, a cytoplasmic calcium transient is sufficient to mimic orexin/GPCR signaling to mTORC1 activation in a v-ATPase-dependent manner. Together, our studies suggest that the mTORC1 pathway functions downstream of orexin/GPCR signaling, which plays a crucial role in many physiological and metabolic processes. 相似文献
997.
Differential regulation of high-affinity agonist binding to muscarinic sites in the rat heart, cerebellum, and cerebral cortex 总被引:1,自引:0,他引:1
T W Vickroy H I Yamamura W R Roeske 《Biochemical and biophysical research communications》1983,116(1):284-290
The muscarinic agonist [3H]cismethyldioxolane ([3H]CD) was used to characterize the effects of regulators upon high-affinity agonist binding sites of the rat heart, cerebral cortex and cerebellum. Comparative studies with sodium ions (Na+), magnesium ions (Mg++), N-ethylmaleimide (NEM) and the guanine nucleotide Gpp(NH)p revealed tissue-specific effects. Mg++ preferentially enhanced while Gpp(NH)p and NEM reduced high-affinity [3H]CD binding in the heart and cerebellum. By comparison NEM enhanced high-affinity agonist binding in the cerebral cortex while Gpp(NH)p and Mg++ had little or no effect. Kinetic studies support an allosteric mechanism for these effects and provide further evidence for muscarinic receptor subtypes in mammalian tissues. 相似文献
998.
999.
The formation of Cu(II)-bleomycin complexes as a function of pH has been studied using circular dichroism, absorption, electron paramagnetic resonance spectroscopy, and potentiometric titration. Our data support the following points: the formation of Cu(II)-bleomycin complexes occurs in a three-step process: a first complex (I) is formed at pH 1.2, which most probably involves the pyrimidine nitrogen, the secondary amine nitrogen, and two water molecules as the four in-plane ligands of copper. A second complex (II) is formed at pH 2.5, through the further coordination of the peptide nitrogen of histidine residue, and histidine imidazole nitrogen giving rise to the release of two protons. The fixation, in apical position, of the alpha-amino nitrogen of beta-aminoalanine occurs in a last step through the release of one additional proton. A value of 2.7 has been obtained for the pK of formation of this third complex, which is the species present at physiological pH. In the Cu(II)-depbleomycin system only one complex (II') has been detected. 相似文献
1000.
Hendrickson Dean A. Norris Steven M. Schmitter-Soto Juan Jacobo 《Reviews in Fish Biology and Fisheries》2002,12(2-3):113-118
Reviews in Fish Biology and Fisheries - 相似文献