全文获取类型
收费全文 | 4566篇 |
免费 | 415篇 |
国内免费 | 1篇 |
专业分类
4982篇 |
出版年
2023年 | 21篇 |
2022年 | 47篇 |
2021年 | 83篇 |
2020年 | 58篇 |
2019年 | 66篇 |
2018年 | 66篇 |
2017年 | 64篇 |
2016年 | 132篇 |
2015年 | 215篇 |
2014年 | 231篇 |
2013年 | 319篇 |
2012年 | 419篇 |
2011年 | 370篇 |
2010年 | 248篇 |
2009年 | 241篇 |
2008年 | 299篇 |
2007年 | 311篇 |
2006年 | 298篇 |
2005年 | 290篇 |
2004年 | 271篇 |
2003年 | 253篇 |
2002年 | 277篇 |
2001年 | 44篇 |
2000年 | 23篇 |
1999年 | 46篇 |
1998年 | 72篇 |
1997年 | 39篇 |
1996年 | 33篇 |
1995年 | 37篇 |
1994年 | 23篇 |
1993年 | 26篇 |
1992年 | 17篇 |
1991年 | 6篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1988年 | 3篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1982年 | 2篇 |
1981年 | 1篇 |
1978年 | 1篇 |
1976年 | 1篇 |
1974年 | 4篇 |
1972年 | 3篇 |
1971年 | 5篇 |
1970年 | 1篇 |
1969年 | 2篇 |
1967年 | 1篇 |
1965年 | 1篇 |
1923年 | 1篇 |
排序方式: 共有4982条查询结果,搜索用时 0 毫秒
11.
Zhu YF Wang XC Connors P Wilcoxen K Gao Y Gross R Strack N Gross T McCarthy JR Xie Q Ling N Chen C 《Bioorganic & medicinal chemistry letters》2003,13(11):1931-1934
4-benzylquinolines 5, based on a series of isoquinolines 1, were prepared and tested as inhibitors of the IGF/IGFBP-3 complex based on their ability to displace IGF-I from its binding to IGF-binding protein-3. SAR studies on the 6,7-dihydroxy moiety of the quinoline 5a showed that the catecol moiety could be replaced with other functional groups. Computational modeling of the 5a/mini-IGFBP-5 complex revealed the possible binding site of 5a on IGFBP-5. 相似文献
12.
Pascreau G Delcros JG Morin N Prigent C Arlot-Bonnemains Y 《Developmental biology》2008,317(2):523-530
Xenopus laevis Aurora-A is phosphorylated in vivo onto three amino acids: Ser53, Thr295 and Ser349. The activation of the kinase depends on its autophosphorylation on Thr295 within the T-loop. The phosphorylation of Ser53 by still unknown kinase(s) prevents its degradation. The present work focused on the regulation of Aurora-A function via Ser349 phosphorylation. Mutagenesis of Ser349 to alanine (S349A) had few impact in vitro on the capability of the kinase to autophosphorylate as well as on its activity. These data in addition to in gel kinase assays and site-specific proteolytic digestion experiments prove that Ser349 is clearly neither a primary autophosphorylation site, nor an autophosphorylation site depending on the priming phosphorylation of Thr295. Using specific antibodies, we also show that the phosphorylation of Aurora-A Ser349 is a physiological event during Xenopus oocyte maturation triggered by progesterone. A peak of phosphorylation paralleled the decrease of Aurora activity observed between meiosis I and II. In response to progesterone, X. laevis stage VI oocytes microinjected with the Aurora-A S349A mutant proceeded normally to germinal vesicle breakdown (GVBD), but degenerated rapidly soon after. Since phosphorylation of Ser349 is responsible for a decrease in kinase activity, our results suggest that a down-regulation of Aurora-A activity involving Ser349 phosphorylation is required in the process of maturation. 相似文献
13.
Toby J. Lloyd-Jones Mark V. Roberts E. Charles Leek Nathalie C. Fouquet Ewa G. Truchanowicz 《PloS one》2012,7(11)
Little is known about the timing of activating memory for objects and their associated perceptual properties, such as colour, and yet this is important for theories of human cognition. We investigated the time course associated with early cognitive processes related to the activation of object shape and object shape+colour representations respectively, during memory retrieval as assessed by repetition priming in an event-related potential (ERP) study. The main findings were as follows: (1) we identified a unique early modulation of mean ERP amplitude during the N1 that was associated with the activation of object shape independently of colour; (2) we also found a subsequent early P2 modulation of mean amplitude over the same electrode clusters associated with the activation of object shape+colour representations; (3) these findings were apparent across both familiar (i.e., correctly coloured – yellow banana) and novel (i.e., incorrectly coloured - blue strawberry) objects; and (4) neither of the modulations of mean ERP amplitude were evident during the P3. Together the findings delineate the timing of object shape and colour memory systems and support the notion that perceptual representations of object shape mediate the retrieval of temporary shape+colour representations for familiar and novel objects. 相似文献
14.
Devos N Deflorian G Biemar F Bortolussi M Martial JA Peers B Argenton F 《Mechanisms of development》2002,115(1-2):133-137
We have identified the cDNAs of two new zebrafish preprosomatostatins, PPSS1 and PPSS3, in addition to the previously cloned PPSS2 (Argenton et al., 1999). PPSS1 is the orthologue of mammalian PPSSs, with a conserved C-terminal SS-14 sequence, PPSS2 is a divergent SS precursor and PPSS3 is a cortistatin-like prohormone. Using whole-mount in situ hybridisation, we have analysed the expression of PPSS1 and PPSS2 in zebrafish embryos up to 5 days post fertilisation. PPSS1 was expressed in the developing pancreas and central nervous system (CNS), whereas PPSS2 expression was exclusively pancreatic. In the CNS, PPSS1 was detected in several areas, in particular in the vagal motor nucleus and in cells that pioneer the tract of the postoptic commissure. PPSS1 was also expressed transiently in the telencephalon and spinal motor neurons. In all areas but the telencephalon PPSS1 was coexpressed with islet-1. 相似文献
15.
The rotational dynamics of short DNA fragments with or without intrinsic curvature were studied using time-resolved phase fluorimetry of intercalated ethidium with detection of the anisotropy. Parameters determined were the spinning diffusion coefficient of the DNA fragments about the long axis and the zero-time ethidium fluorescence anisotropy. We find a significant decrease in the spinning diffusion coefficient for all curved fragments compared to the straight controls. This decrease is likewise evident in rotational diffusion coefficients computed from DNA structures obtained by a curvature prediction program for these sequences. Using a hinged-cylinder model, we can identify the change in rotational diffusion coefficient with a permanent bend of 13-16 degrees per helix turn for the sequences studied. Moreover, for some of the curved fragments an increased flexibility has to be assumed in addition to the permanent bend in order to explain the data. 相似文献
16.
Research on the angiotensin-converting enzyme (ACE) in insects has substantially advanced during the recent decade. The cloning of this enzyme in many insect species, the determination of the 3D-structure and several molecular and physiological studies have contributed to the characterization of insect ACE as we know it today: a functional enzyme with a putative role in reproduction, development and defense. The discovery of the endothelin-converting enzyme in insects occurred more recently and cloning of the corresponding cDNA has been carried out in only one insect species so far. However, activity studies and analysis of insect genomes indicate that this enzyme is also widely distributed among insect species. Making hypotheses about its putative function would be preliminary, but its wide tissue distribution suggests a major and diverse biological role. 相似文献
17.
Colitis induced by proteinase-activated receptor-2 agonists is mediated by a neurogenic mechanism 总被引:6,自引:0,他引:6
Nguyen C Coelho AM Grady E Compton SJ Wallace JL Hollenberg MD Cenac N Garcia-Villar R Bueno L Steinhoff M Bunnett NW Vergnolle N 《Canadian journal of physiology and pharmacology》2003,81(9):920-927
Proteinase-activated receptor-2 (PAR2) activation induces colonic inflammation by an unknown mechanism. We hypothesized that PAR2 agonists administered intracolonically in mice induce inflammation via a neurogenic mechanism. Pretreatment of mice with neurokinin-1 and calcitonin-gene-related peptide (CGRP) receptor antagonists or with capsaicin showed attenuated PAR2-agonist-induced colitis. Immunohistochemistry demonstrated a differential expression of a marker for the type-1 CGRP receptor during the time course of PAR2-agonist-induced colitis, further suggesting a role for CGRP. We conclude that PAR2-agonist-induced intestinal inflammation involves the release of neuropeptides, which by acting on their receptors cause inflammation. These results implicate PAR2 as an important mediator of intestinal neurogenic inflammation. 相似文献
18.
Javelle A Rodríguez-Pastrana BR Jacob C Botton B Brun A André B Marini AM Chalot M 《FEBS letters》2001,505(3):393-398
Heterologous expression of the yeast triple Mep mutant has enabled the first molecular characterization of AMT/MEP family members in an ectomycorrhizal fungus. External hyphae, which play a key role in nitrogen nutrition of trees, are considered as the absorbing structure of the ectomycorrhizal symbiosis and therefore molecular studies on ammonium transport in hyphae are urgently needed. The kinetic properties of AMT2 and AMT3 from Hebeloma cylindrosporum were studied in Saccharomyces cerevisiae. Expression of HcAmts in the yeast triple Mep mutant restored ammonium retention within cells. The HcAmts did not complement the ammonium sensing defect phenotype of Mep2Delta cells during pseudohyphal differentiation. Northern blot analysis in H. cylindrosporum showed that the HcAMTs were up-regulated upon nitrogen deprivation and down-regulated by ammonium. 相似文献
19.
Swayne BG Kawata A Behan NA Williams A Wade MG Macfarlane AJ Yauk CL 《Mutation research》2012,748(1-2):1-7
The cytokinesis-block micronucleus cytome (CBMN-Cyt) assay was originally developed as an ideal system for measuring DNA damage, cytostasis and cytotoxicity. The objective of the present study is to simultaneously evaluate the background levels of micronuclei (MN), nucleoplasmic bridges (NPBs), nuclear buds (NBUDs), cell death (necrosis or apoptosis) and nuclear division index (NDI) in the peripheral blood lymphocytes of non-occupationally exposed, healthy subjects living in the city of Kayseri in Turkey. We used the CBMN-Cyt assay, taking into account factors - age, gender, and smoking habits - that might affect MN frequency and also other CBMN-Cyt assay parameters. Ninety-six healthy subjects (48 female and 48 male) were selected with ages varying between 21 and 60 years. The parameters, except for the number of binucleated (BN) cells with NPBs, showed no statistically significant difference between smokers and non-smokers. There were significant differences between female and male groups in MN frequency (higher in females) and in the number of NPBs (lower in females), while the other parameters were not significantly different between genders. The correlations between years of age and MN frequency, number of NPBs and the frequency of necrotic cells were statistically significant, while the correlations between the years of age and the other parameters were not. The results of the correlation analysis between years of smoking and MN frequency were positive, although no statistically significant correlation was found between the years of smoking and the other parameters. Among the smokers, no correlation was found either between the pack-years of smoking and the parameters assessed in this group. The results of the present study provide evidence of increasing MN frequency, number of NPBs and frequency of necrotic cells with increasing age in the peripheral blood lymphocytes of healthy individuals and influencing MN frequency and number of NPBs by gender. 相似文献
20.
γ-secretase, which assembles as a tetrameric complex, is an aspartyl protease that proteolytically cleaves substrate proteins within their membrane-spanning domain; a process also known as regulated intramembrane proteolysis (RIP). RIP regulates signaling pathways by abrogating or releasing signaling molecules. Since the discovery, already > 15 years ago, of its catalytic component, presenilin, and even much earlier with the identification of amyloid precursor protein as its first substrate, γ-secretase has been commonly associated with Alzheimer's disease. However, starting with Notch and thereafter a continuously increasing number of novel substrates, γ-secretase is becoming linked to an equally broader range of biological processes. This review presents an updated overview of the current knowledge on the diverse molecular mechanisms and signaling pathways controlled by γ-secretase, with a focus on organ development, homeostasis and dysfunction. This article is part of a Special Issue entitled: Intramembrane Proteases. 相似文献