全文获取类型
收费全文 | 7784篇 |
免费 | 690篇 |
国内免费 | 1篇 |
出版年
2023年 | 27篇 |
2022年 | 71篇 |
2021年 | 155篇 |
2020年 | 92篇 |
2019年 | 117篇 |
2018年 | 156篇 |
2017年 | 119篇 |
2016年 | 255篇 |
2015年 | 434篇 |
2014年 | 474篇 |
2013年 | 518篇 |
2012年 | 682篇 |
2011年 | 733篇 |
2010年 | 501篇 |
2009年 | 379篇 |
2008年 | 539篇 |
2007年 | 515篇 |
2006年 | 454篇 |
2005年 | 433篇 |
2004年 | 412篇 |
2003年 | 350篇 |
2002年 | 379篇 |
2001年 | 73篇 |
2000年 | 44篇 |
1999年 | 74篇 |
1998年 | 88篇 |
1997年 | 60篇 |
1996年 | 48篇 |
1995年 | 22篇 |
1994年 | 29篇 |
1993年 | 25篇 |
1992年 | 23篇 |
1991年 | 22篇 |
1990年 | 14篇 |
1989年 | 17篇 |
1988年 | 15篇 |
1985年 | 8篇 |
1984年 | 12篇 |
1983年 | 10篇 |
1982年 | 5篇 |
1981年 | 10篇 |
1980年 | 6篇 |
1977年 | 6篇 |
1976年 | 6篇 |
1975年 | 5篇 |
1974年 | 5篇 |
1973年 | 5篇 |
1969年 | 4篇 |
1968年 | 4篇 |
1967年 | 7篇 |
排序方式: 共有8475条查询结果,搜索用时 49 毫秒
911.
Tatjana Krama Arnis Bērzi?? Seppo Rytk?nen Markus J. Rantala David Wheatcroft Indrikis Krams 《Acta ethologica》2012,15(1):127-134
In habitats where the density of breeding individuals is higher, breeding success has been shown to increase with the number
of close conspecific and heterospecific neighbours. However, the mechanisms linking habitat quality, group size of prey individuals
and offspring defence are poorly known. In this field study, we examined the relationships between habitat quality and parental
nest defence behaviour in the pied flycatcher (Ficedula hypoleuca). We found that mobbing is more intense in unmanaged forests where birds breed in more dense and diverse communities than
in heavily managed young forests where heterospecific densities are lower. We also found that the mobbing activities of pied
flycatchers breeding in unmanaged mature boreal forests attracted more neighbouring prey individuals than in nearby managed
forests. This study shows that habitat quality-mediated effects might be responsible for the decreased group size of mobbing
birds in managed forests, which may lead to less effective communal defence. 相似文献
912.
Grosse J Wehland M Pietsch J Ma X Ulbrich C Schulz H Saar K Hübner N Hauslage J Hemmersbach R Braun M van Loon J Vagt N Infanger M Eilles C Egli M Richter P Baltz T Einspanier R Sharbati S Grimm D 《FASEB journal》2012,26(2):639-655
This study focused on the effects of short-term microgravity (22 s) on the gene expression and morphology of endothelial cells (ECs) and evaluated gravisensitive signaling elements. ECs were investigated during four German Space Agency (Deutsches Zentrum für Luft- und Raumfahrt) parabolic flight campaigns. Hoechst 33342 and acridine orange/ethidium bromide staining showed no signs of cell death in ECs after 31 parabolas (P31). Gene array analysis revealed 320 significantly regulated genes after the first parabola (P1) and P31. COL4A5, COL8A1, ITGA6, ITGA10, and ITGB3 mRNAs were down-regulated after P1. EDN1 and TNFRSF12A mRNAs were up-regulated. ADAM19, CARD8, CD40, GSN, PRKCA (all down-regulated after P1), and PRKAA1 (AMPKα1) mRNAs (up-regulated) provide a very early protective mechanism of cell survival induced by 22 s microgravity. The ABL2 gene was significantly up-regulated after P1 and P31, TUBB was slightly induced, but ACTA2 and VIM mRNAs were not changed. β-Tubulin immunofluorescence revealed a cytoplasmic rearrangement. Vibration had no effect. Hypergravity reduced CARD8, NOS3, VASH1, SERPINH1 (all P1), CAV2, ADAM19, TNFRSF12A, CD40, and ITGA6 (P31) mRNAs. These data suggest that microgravity alters the gene expression patterns and the cytoskeleton of ECs very early. Several gravisensitive signaling elements, such as AMPKα1 and integrins, are involved in the reaction of ECs to altered gravity. 相似文献
913.
Burgoyne JR Haeussler DJ Kumar V Ji Y Pimental DR Zee RS Costello CE Lin C McComb ME Cohen RA Bachschmid MM 《FASEB journal》2012,26(2):832-841
Here we demonstrate a new paradigm in redox signaling, whereby oxidants resulting from metabolic stress directly alter protein palmitoylation by oxidizing reactive cysteine thiolates. In mice fed a high-fat, high-sucrose diet and in cultured endothelial cells (ECs) treated with high palmitate and high glucose (HPHG), there was decreased HRas palmitoylation on Cys181/184 (61±24% decrease for cardiac tissue and 38±7.0% in ECs). This was due to oxidation of Cys181/184, detected using matrix-assisted laser desorption/ionization time of flight (MALDI TOF)-TOF. Decrease in HRas palmitoylation affected its compartmentalization and Ras binding domain binding activity, with a shift from plasma membrane tethering to Golgi localization. Loss of plasma membrane-bound HRas decreased growth factor-stimulated ERK phosphorylation (84±8.6% decrease) and increased apoptotic signaling (24±6.5-fold increase) after HPHG treatment that was prevented by overexpressing wild-type but not C181/184S HRas. The essential role of HRas in metabolic stress was made evident by the similar effects of expressing an inactive dominant negative N17-HRas or a MEK inhibitor. Furthermore, the relevance of thiol oxidation was demonstrated by overexpressing manganese superoxide dismutase, which improved HRas palmitoylation and ERK phosphorylation, while lessening apoptosis in HPHG treated ECs. 相似文献
914.
Reiter V Matschkal DM Wagner M Globisch D Kneuttinger AC Müller M Carell T 《Nucleic acids research》2012,40(13):6235-6240
The unusual cyclin-dependent protein kinase 5 (CDK5) was discovered based on its sequence homology to cell cycle regulating CDKs. CDK5 was found to be active in brain tissues, where it is not involved in cell cycle regulation but in the regulation of neuronal cell differentiation and neurocytoskeleton dynamics. An aberrant regulation of CDK5 leads to the development of various neurodegenerative diseases including Alzheimer's disease. Although CDK5 is not regulated by cyclins, its activity does depend on the association with a protein activator and the presence or absence of further inhibitory factors. Recently, CDK5RAP1 was discovered to inhibit the active CDK5 kinase. Here, we show that CDK5RAP1 is a radical SAM enzyme, which postsynthetically converts the RNA modification N6-isopentenyladenosine (i(6)A) into 2-methylthio-N6-isopentenyladenosine (ms(2)i(6)A). This conversion is surprisingly not limited to mitochondrial tRNA, where the modification was known to exist. Instead, CDK5RAP1 introduces the modification also into nuclear RNA species establishing a link between postsynthetic kinase-based protein modification and postsynthetic RNA modification. 相似文献
915.
Banjac A Zimmermann MO Boeckler FM Kurz U Schultz A Schultz JE 《Cellular signalling》2012,24(3):629-634
The dimeric mammalian phosphodiesterases (PDEs) are regulated by N-terminal domains. In PDE5, the GAF-A subdomain of a GAF-tandem (GAF-A and -B) binds the activator cGMP and in PDE10 GAF-B binds cAMP. GAF-tandem chimeras of PDE5 and 10 in which the 36 aa linker helix between GAF-A and -B was swapped lost allosteric regulation of a reporter adenylyl cyclase. In 16 consecutive constructs we substituted the PDE10 linker with that from PDE5. An initial stretch of 10 amino acids coded for isoform specificity. A C240Y substitution uncoupled cyclase activity from regulation, whereas C240F, L or G did not. The C240Y substitution increased basal activity to stimulated levels. Notably, over the next 12 substitutions basal cyclase activity decreased linearly.Further targeted substitutions were based on homology modeling using the PDE2 structure. No combination of substitutions within the initial 10 linker residues caused loss of regulation. The full 10 aa stretch was required. Modeling indicated a potential interaction of the linker with a loop from GAF-A. To interrupt H-bonding a glycine substitution of the loop segment was generated. Despite reduction of basal activity, loss of regulation was maintained. Possibly, the orientation of the linker helix is determined by formation of the dimer at the initial linker segment. Downstream deflections of the linker helix may have caused loss of regulation. 相似文献
916.
In vertebrates, collagen tissues are the main component responsible for force transmission. In spite of the physiological importance of these phenomena, force transmission mechanisms are still not fully understood, especially at smaller scales, including in particular collagen molecules and fibrils. Here we investigate the mechanism of molecular sliding between collagen molecules within a fibril, by shearing a central molecule in a hexagonally packed bundle mimicking the collagen microfibril environment, using varied lateral distance between the molecules in both dry and solvated conditions. In vacuum, the central molecule slides under a stick-slip mechanism that is due to the characteristic surface profile of collagen molecules, enhanced by the breaking and reformation of H-bonds between neighboring collagen molecules. This mechanism is consistently observed for varied lateral separations between molecules. The high shearing force (>7 nN) found for the experimentally observed intermolecular distance (≈1.1 nm) suggests that in dry samples the fibril elongation mechanism relies almost exclusively on molecular stretching, which may explain the higher stiffnesses found in dry fibrils. When hydrated, the slip-stick behavior is observed only below 1.3 nm of lateral distance, whereas above 1.3 nm the molecule shears smoothly, showing that the water layer has a strong lubricating effect. Moreover, the average force required to shear is approximately the same in solvated as in dry conditions (≈2.5 nN), which suggests that the role of water at the intermolecular level includes the transfer of load between molecules. 相似文献
917.
Bayer RG Stael S Rocha AG Mair A Vothknecht UC Teige M 《Journal of experimental botany》2012,63(4):1713-1723
918.
Mehlmer N Parvin N Hurst CH Knight MR Teige M Vothknecht UC 《Journal of experimental botany》2012,63(4):1751-1761
Calcium has long been acknowledged as one of the most important signalling components in plants. Many abiotic and biotic stimuli are transduced into a cellular response by temporal and spatial changes in cellular calcium concentration and the calcium-sensitive protein aequorin has been exploited as a genetically encoded calcium indicator for the measurement of calcium in planta. The objective of this work was to generate a compatible set of aequorin expression plasmids for the generation of transgenic plant lines to measure changes in calcium levels in different cellular subcompartments. Aequorin was fused to different targeting peptides or organellar proteins as a means to localize it to the cytosol, the nucleus, the plasma membrane, and the mitochondria. Furthermore, constructs were designed to localize aequorin in the stroma as well as the inner and outer surface of the chloroplast envelope membranes. The modular set-up of the plasmids also allows the easy replacement of targeting sequences to include other compartments. An additional YFP-fusion was included to verify the correct subcellular localization of all constructs by laser scanning confocal microscopy. For each construct, pBin19-based binary expression vectors driven by the 35S or UBI10 promoter were made for Agrobacterium-mediated transformation. Stable Arabidopsis lines were generated and initial tests of several lines confirmed their feasibility to measure calcium signals in vivo. 相似文献
919.
Heiko Kroth Annalisa Ansaloni Yvan Varisco Asad Jan Nampally Sreenivasachary Nasrollah Rezaei-Ghaleh Valérie Giriens Sophie Lohmann María Pilar López-Deber Oskar Adolfsson Maria Pihlgren Paolo Paganetti Wolfgang Froestl Luitgard Nagel-Steger Dieter Willbold Thomas Schrader Markus Zweckstetter Andrea Pfeifer Hilal A. Lashuel Andreas Muhs 《The Journal of biological chemistry》2012,287(41):34786-34800
Increasing evidence implicates Aβ peptides self-assembly and fibril formation as crucial events in the pathogenesis of Alzheimer disease. Thus, inhibiting Aβ aggregation, among others, has emerged as a potential therapeutic intervention for this disorder. Herein, we employed 3-aminopyrazole as a key fragment in our design of non-dye compounds capable of interacting with Aβ42 via a donor-acceptor-donor hydrogen bond pattern complementary to that of the β-sheet conformation of Aβ42. The initial design of the compounds was based on connecting two 3-aminopyrazole moieties via a linker to identify suitable scaffold molecules. Additional aryl substitutions on the two 3-aminopyrazole moieties were also explored to enhance π-π stacking/hydrophobic interactions with amino acids of Aβ42. The efficacy of these compounds on inhibiting Aβ fibril formation and toxicity in vitro was assessed using a combination of biophysical techniques and viability assays. Using structure activity relationship data from the in vitro assays, we identified compounds capable of preventing pathological self-assembly of Aβ42 leading to decreased cell toxicity. 相似文献
920.
Prage EB Morgenstern R Jakobsson PJ Stec DF Voehler MW Armstrong RN 《Biochemistry》2012,51(11):2348-2356
Microsomal prostaglandin E synthase 1 (MPGES1) is an enzyme that produces the pro-inflammatory molecule prostaglandin E(2) (PGE(2)). Effective inhibitors of MPGES1 are of considerable pharmacological interest for the selective control of pain, fever, and inflammation. The isoprostane, 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), a naturally occurring degradation product of prostaglandin D(2), is known to have anti-inflammatory properties. In this paper, we demonstrate that 15d-PGJ(2) can inhibit MPGES1 by covalent modification of residue C59 and by noncovalent inhibition through binding at the substrate (PGH(2)) binding site. The mechanism of inhibition is dissected by analysis of the native enzyme and the MPGES1 C59A mutant in the presence of glutathione (GSH) and glutathione sulfonate. The location of inhibitor adduction and noncovalent binding was determined by triple mass spectrometry sequencing and with backbone amide H/D exchange mass spectrometry. The kinetics, regiochemistry, and stereochemistry of the spontaneous reaction of GSH with 15d-PGJ(2) were determined. The question of whether the anti-inflammatory properties of 15d-PGJ(2) are due to inhibition of MPGES1 is discussed. 相似文献