全文获取类型
收费全文 | 1581篇 |
免费 | 97篇 |
国内免费 | 1篇 |
专业分类
1679篇 |
出版年
2021年 | 22篇 |
2019年 | 12篇 |
2018年 | 23篇 |
2017年 | 19篇 |
2016年 | 37篇 |
2015年 | 60篇 |
2014年 | 81篇 |
2013年 | 71篇 |
2012年 | 107篇 |
2011年 | 105篇 |
2010年 | 56篇 |
2009年 | 49篇 |
2008年 | 98篇 |
2007年 | 87篇 |
2006年 | 72篇 |
2005年 | 65篇 |
2004年 | 67篇 |
2003年 | 73篇 |
2002年 | 50篇 |
2001年 | 50篇 |
2000年 | 51篇 |
1999年 | 22篇 |
1998年 | 19篇 |
1997年 | 19篇 |
1996年 | 11篇 |
1995年 | 9篇 |
1994年 | 14篇 |
1993年 | 8篇 |
1992年 | 12篇 |
1991年 | 18篇 |
1990年 | 24篇 |
1989年 | 18篇 |
1988年 | 12篇 |
1987年 | 16篇 |
1986年 | 12篇 |
1985年 | 13篇 |
1984年 | 13篇 |
1983年 | 8篇 |
1982年 | 9篇 |
1979年 | 8篇 |
1977年 | 10篇 |
1976年 | 11篇 |
1975年 | 14篇 |
1973年 | 11篇 |
1972年 | 12篇 |
1971年 | 12篇 |
1970年 | 9篇 |
1969年 | 9篇 |
1968年 | 8篇 |
1967年 | 9篇 |
排序方式: 共有1679条查询结果,搜索用时 15 毫秒
51.
Cell-based assays for G-protein-coupled receptor (GPCR) activation applied in high-throughput screening (HTS) monitor various readouts for second messengers or intracellular effectors. Recently, our understanding of diverging signaling pathways downstream of receptor activation and the capability of small molecules to selectively modulate signaling routes has increased substantially, underlining the importance of selecting appropriate readouts in cellular functional screens. To minimize the rate of false negatives in large-scale screening campaigns, it is crucial to maximize the chance of a ligand being detected, and generally applicable methods for detecting multiple analytes from a single well might serve this purpose. The few assays developed so far based on multiplexed GPCR readouts are limited to only certain applications and usually rely on genetic manipulations hindering screening in native or native-like cellular systems. Here we describe a more generally applicable and HTS-compatible homogeneous assay based on the combination of fluorometric detection of [Ca2+] with subsequent homogeneous time-resolved fluorescence (HTRF) cAMP readout in the same well. Besides describing development and validation of the assay, using a cell line recombinantly expressing the human PTH1 receptor screening of a small library is also presented, demonstrating the robustness and HTS compatibility of the novel paradigm. 相似文献
52.
Phosphorylation of the activation loop in RAF kinases has been suggested to be critical for changes in activity. The extent to which the activation segment is phosphorylated, the specific structural consequences, and the in vivo relevance have however remained elusive. In this issue of the The EMBO Journal, Köhler et al (2015) addressed these questions by generating a knock‐in mouse expressing a B‐Raf mutant with a non‐phosphorylatable activation loop. The mutant causes a range of developmental phenotypes; intriguingly, it also impairs the tumorigenic potential of a subset of BRAF mutants, suggesting potential new strategies for RAF inhibition. 相似文献
53.
Relationships between wild bees,hoverflies and pollination success in apple orchards with different landscape contexts 下载免费PDF全文
Ádám Kőrösi László Somay Zoltán Elek Viktor Markó Miklós Sárospataki Réka Bakos Ákos Varga Katinka Nyisztor András Báldi 《Agricultural and Forest Entomology》2016,18(1):68-75
54.
A novel type of lipid droplet/lipoprotein (LD/LP) particle from Thermoplasma acidophilum has been identified recently, and based on biochemical evidences, it was named Thermoplasma Quinone Droplet (TaQD). The major components of TaQDs are menaquinones, and to some extent polar lipids, and the 153 amino acid long Ta0547 vitellogenin‐N domain protein. In this paper, the aim is to identify TaQD proteome components with 1D‐SDS‐PAGE/LC–MS/MS and cross reference them with Edman degradation. TaQD samples isolated with three different purification methods—column chromatography, immunoprecipitation, and LD ultracentrifugation—are analyzed. Proteins Ta0093, Ta0182, Ta0337, Ta0437, Ta0438, Ta0547, and Ta1223a are identified as constituents of the TaQD proteome. The majority of these proteins is uncharacterized and has low molecular weight, and none of them is predicted to take part in lipid metabolism. Bioinformatics analyses does not predict any interaction between these proteins, however, there are indications of interactions with proteins taking part in lipid metabolism. Whether if TaQDs provide platform for lipid metabolism and the interactions between TaQD proteins and lipid metabolism proteins occur in the reality remain for further studies. 相似文献
55.
Miklos Szucs Peter Osvath Attila Jakab Daniel Varga Balazs Varga Bela Juhasz 《Reproductive biology》2019,19(1):38-44
The relationship between overweight and male fertility is well studied, still the correlation of obesity and decreased sperm quality is a subject to debate. The widely used conventional spermatological examinations alone seem to be inadequate to assess fertilization potential. Hyaluronan Binding Assay (HBA®) is one of the available validated tests that allows the functional examination of sperm. Data of 72 male patients (mean age 33.9 (24–43) years) from infertile couples were analysed. Body Mass Index (BMI) determination, conventional semen analysis and HBA were performed. Additionally, a relatively new Hyaluronan Bound Matured Sperm Count (HB-MaSC) -index, first introduced by the authors in 2015, was calculated. This index reflects fertilization potential of sperm more precisely. With the increase of BMI, sperm count decreased significantly until about 25?kg/m2, above 25?kg/m2 no further decrease was observed, although sperm count remained permanently low. Greater body weight (in the 70–90?kg range) was observed to have a significant negative effect only on the progressive sperm motility. In addition to sperm concentration and motility, sperm fertilization potential is also negatively affected by obesity, but is irrespective of body weight, as evaluated using BMI + HB-MaSC linear regression analyses adjusted for age and weight. This correlation between male BMI and sperm fertilization potential – as opposed to the conventional correlations with sperm concentration or motility – appears to provide more helpful information in the identification of real capability for fertilization. 相似文献
56.
Jieyan He Tianshu Li Tomasz Próchnicki Gabor Horvath Eicke Latz Shinji Takeoka 《Biochemistry and Biophysics Reports》2019
Lysine (K) type cationic lipid with a propyl spacer and ditetradecyl hydrophobic moieties composing liposomes, K3C14, previously studied for gene delivery, were reported to activate the NLRP3 inflammasomes in human macrophages via the conventional phagolysosomal pathway. In this study, K3C16, a propyl spacer bearing lysine type lipids with dihexadecyl moieties (an extension of two hydrocarbon tail length) were compared with K3C14 as liposomes. Such a small change in tail length did not alter the physical properties such as size distribution, zeta potential and polydispersity index (PDI). The NLRP3 activation potency of K3C16 was shown to be 1.5-fold higher. Yet, the toxicity was minimal, whereas K3C14 has shown to cause significant cell death after 24 h incubation. Even in the presence of endocytosis inhibitors, cytochalasin D or dynasore, K3C16 continued to activate the NLRP3 inflammasomes and to induce IL-1β release. To our surprise, K3C16 liposomes were confirmed to fuse with the plasma membrane of human macrophages and CHO-K1 cells. It is demonstrated that the change in hydrophobic tail length by two hydrocarbons drastically changed a cellular entry route and potency in activating the NLRP3 inflammasomes. 相似文献
57.
Varga B Barabás O Kovári J Tóth J Hunyadi-Gulyás E Klement E Medzihradszky KF Tölgyesi F Fidy J Vértessy BG 《FEBS letters》2007,581(24):4783-4788
Human dUTPase, essential for DNA integrity, is an important survival factor for cancer cells. We determined the crystal structure of the enzyme:alpha,beta-imino-dUTP:Mg complex and performed equilibrium binding experiments in solution. Ordering of the C-terminus upon the active site induces close juxtaposition of the incoming nucleophile attacker water oxygen and the alpha-phosphorus of the substrate, decreasing their distance below the van der Waals limit. Complex interactions of the C-terminus with both substrate and product were observed via a specifically designed tryptophan sensor, suitable for further detailed kinetic and ligand binding studies. Results explain the key functional role of the C-terminus. 相似文献
58.
59.
60.
Although three-dimensional electron microscopy (3D-EM) permits structural characterization of macromolecular assemblies in distinct functional states, the inability to classify projections from structurally heterogeneous samples has severely limited its application. We present a maximum likelihood-based classification method that does not depend on prior knowledge about the structural variability, and demonstrate its effectiveness for two macromolecular assemblies with different types of conformational variability: the Escherichia coli ribosome and Simian virus 40 (SV40) large T-antigen. 相似文献