全文获取类型
收费全文 | 9629篇 |
免费 | 1028篇 |
国内免费 | 4篇 |
出版年
2021年 | 110篇 |
2020年 | 82篇 |
2019年 | 77篇 |
2018年 | 115篇 |
2017年 | 100篇 |
2016年 | 179篇 |
2015年 | 321篇 |
2014年 | 338篇 |
2013年 | 426篇 |
2012年 | 514篇 |
2011年 | 488篇 |
2010年 | 349篇 |
2009年 | 305篇 |
2008年 | 462篇 |
2007年 | 456篇 |
2006年 | 363篇 |
2005年 | 353篇 |
2004年 | 367篇 |
2003年 | 330篇 |
2002年 | 355篇 |
2001年 | 264篇 |
2000年 | 228篇 |
1999年 | 249篇 |
1998年 | 140篇 |
1997年 | 106篇 |
1996年 | 105篇 |
1995年 | 83篇 |
1994年 | 84篇 |
1993年 | 106篇 |
1992年 | 169篇 |
1991年 | 160篇 |
1990年 | 150篇 |
1989年 | 158篇 |
1988年 | 135篇 |
1987年 | 117篇 |
1986年 | 102篇 |
1985年 | 139篇 |
1984年 | 107篇 |
1983年 | 91篇 |
1982年 | 93篇 |
1981年 | 89篇 |
1980年 | 71篇 |
1979年 | 94篇 |
1978年 | 81篇 |
1977年 | 82篇 |
1975年 | 65篇 |
1974年 | 73篇 |
1973年 | 80篇 |
1971年 | 67篇 |
1969年 | 69篇 |
排序方式: 共有10000条查询结果,搜索用时 421 毫秒
961.
Pickhardt M Larbig G Khlistunova I Coksezen A Meyer B Mandelkow EM Schmidt B Mandelkow E 《Biochemistry》2007,46(35):10016-10023
One of the key pathological features of Alzheimer's disease is the aggregation of tau protein. We are therefore searching for compounds capable of inhibiting this reaction. On the basis of an initial screen of 200000 compounds [Pickhardt, M., Gazova, Z., von Bergen, M., Khlistunova, I., Wang, Y., Hascher, A., Mandelkow, E. M., Biernat, J., and Mandelkow, E. (2005) Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells, J. Biol. Chem. 280, 3628-3635], we performed an in silico screen and predicted a new phenylthiazolyl-hydrazide (PTH) compound as a possible hit [Larbig, G., Pickhardt, M., Lloyd, D. G., Schmidt, B., and Mandelkow, E. (2007) Screening for inhibitors of tau protein aggregation into Alzheimer paired helical filaments: A ligand based approach results in successful scaffold hopping. Curr. Alzheimer Res. 4 (3), 315-323.]. Synthesis of this compound showed that it was indeed active in terms of inhibiting de novo tau aggregation and disassembling preformed aggregates (IC50 = 7.7 microM and DC50 = 10.8 microM). We have now synthesized 49 similar structures and identified the core of the PTHs to be crucial for activity, thus representing a lead structure. Analysis of the binding epitope by saturation transfer difference NMR shows strong interactions between the tau protein and the ligand in the aromatic regions of the inhibitor. By chemical variation of the core, we improved the inhibitory potency five-fold. The compounds showed a low toxicity as judged by an N2A cell model of tau aggregation and lend themselves for further development. 相似文献
962.
Our objective was to assess the potential of Cladocera from mountain lakes for climate reconstruction. We related Cladocera
from surface sediments of Alpine lakes (1,502–2,309 m asl) to 29 abiotic environmental variables using statistical methods.
The environmental dataset included water chemistry, lake depth, and bi-hourly water-temperature logs, which were used to assess
mean monthly water temperatures, dates of freezing and breakup, spring and autumn mixing. We found 14 different Cladocera
of the families Bosminidae, Daphniidae, and Chydoridae. Lakes without Cladocera (eight lakes) were cold and/or ultra-oligotrophic,
whereas lakes with planktonic and littoral Cladocera (19 lakes) were warmer and/or less oligotrophic. Lakes with only littoral
Cladocera (18 lakes) had intermediate water temperatures/trophy. Changes in Cladocera assemblages were related to changes
in climate, nutrients, and/or alkalinity. We found a climate threshold at which Bosminidae disappeared in 95% of the lakes.
For climate-change research, we propose studying Cladocera along transects that include climatic thresholds.
Guest editor: Piet Spaak
Cladocera: Proceedings of the 7th International Symposium on Cladocera 相似文献
963.
Evolution and functional characterization of the RH50 gene from the ammonia-oxidizing bacterium Nitrosomonas europaea 总被引:1,自引:0,他引:1 下载免费PDF全文
Cherif-Zahar B Durand A Schmidt I Hamdaoui N Matic I Merrick M Matassi G 《Journal of bacteriology》2007,189(24):9090-9100
The family of ammonia and ammonium channel proteins comprises the Amt proteins, which are present in all three domains of life with the notable exception of vertebrates, and the homologous Rh proteins (Rh50 and Rh30) that have been described thus far only in eukaryotes. The existence of an RH50 gene in bacteria was first revealed by the genome sequencing of the ammonia-oxidizing bacterium Nitrosomonas europaea. Here we have used a phylogenetic approach to study the evolution of the N. europaea RH50 gene, and we show that this gene, probably as a component of an integron cassette, has been transferred to the N. europaea genome by horizontal gene transfer. In addition, by functionally characterizing the Rh50Ne protein and the corresponding knockout mutant, we determined that NeRh50 can mediate ammonium uptake. The RH50Ne gene may thus have replaced functionally the AMT gene, which is missing in the genome of N. europaea and may be regarded as a case of nonorthologous gene displacement. 相似文献
964.
Performance of the translational apparatus varies with the ecological strategies of bacteria 下载免费PDF全文
Protein synthesis is the predominant activity of growing bacteria; the protein synthesis system accounts for more than one-half the cell's dry mass and consumes most of the cell's energy during rapid growth. Translation has been studied extensively using model organisms, and the translational apparatus is qualitatively similar in terms of structure and function across all known forms of life. However, little is known about variation between organisms in translational performance. Using measurements of macromolecular content in a phylogenetically diverse collection of bacteria with contrasting ecological strategies, we found that the translational power (the rate of protein synthesis normalized to the mass of the protein synthesis system) is three- to fourfold higher among bacteria that respond rapidly to nutrient availability than among bacteria that respond slowly. An analysis of codon use in completely sequenced bacterial genomes confirmed that the selective forces acting on translation vary with the ecological strategy. We propose that differences in translational power result from ecologically based variation among microbes in the relative importance of two competing benefits: reducing the biomass invested in the protein synthesis system and reducing the energetic expense of protein synthesis. 相似文献
965.
The variability of coupled rhythmic limb movements is assumed to be a consequence of the strength of a movement’s attractor
dynamic and a constant stochastic noise process that continuously perturbs the movement system away from this dynamic. Recently,
it has been suggested that the nonlinear technique of recurrence analysis can be used to index the effects of noise and attractor
strength on movement variability. To test this, three experiments were conducted in which the attractor strength of bimanual
wrist-pendulum movements (using coordination mode, movement frequency and detuning), as well as the magnitude of stochastic
perturbations affecting the variability of these movements (using a temporally fluctuating visual metronome) was manipulated.
The results of these experiments demonstrate that recurrence analysis can index parametric changes in the attractor strength
of coupled rhythmic limb movements and the magnitude of metronome induced stochastic perturbations independently. The results
of Experiments 1 and 2 also support the claim that differences between the variability of inphase and antiphase coordination,
and between slow and fast movement frequencies are due to differences in attractor strength. In contrast to the standard assumption
that the noise that characterizes interlimb coordination remains constant for different magnitudes of detuning (Δ ω) the results
of Experiment 3 suggest that the magnitude of noise increases with increases in |Δ ω|. 相似文献
966.
Sangild PT Malo C Schmidt M Petersen YM Elnif J Holst JJ Buddington RK 《American journal of physiology. Regulatory, integrative and comparative physiology》2007,293(6):R2179-R2184
Exogenous glucagon-like peptide 2 (GLP-2) prevents intestinal atrophy and increases nutrient absorption in term newborn pigs receiving total parenteral nutrition (TPN). We tested the hypothesis that the immature intestine of fetuses and preterm neonates has a diminished nutrient absorption response to exogenous GLP-2. This was accomplished using catheterized fetal pigs infused for 6 days (87-91% of gestation) with GLP-2 (25 nmol.kg(-1).day(-1) iv; n = 7) or saline (n = 7), and cesarean-delivered preterm pigs (92% of gestation) that received TPN with GLP-2 (25 nmol.kg(-1).day(-1) iv; n = 8) or saline (n = 7) for 6 days after birth. Responses to GLP-2 were assessed by measuring intestinal dimensions, absorption of nutrients (glucose, leucine, lysine, proline) by intact tissues and brush border membrane vesicles, and abundance of sodium-glucose cotransporter mRNA. Infusion of GLP-2 increased circulating GLP-2 levels in fetuses, but did not increase intestinal mass or absorption of nutrients by intact tissues and brush border membrane vesicles, except for lysine. Administration of exogenous GLP-2 to preterm TPN-fed pigs similarly did not increase rates of nutrient absorption, yet nutrient absorption capacities of the entire small intestine tended to increase (+10-20%, P < 0.10) compared with TPN alone due to increased intestinal mass (+30%, P < 0.05). GLP-2 infusion did not increase sodium-glucose cotransporter-1 mRNA abundance in fetuses or postnatal preterm pigs. Hence, the efficacy of exogenous GLP-2 to improve nutrient absorption by the intestine of fetal and preterm pigs is limited compared with term pigs and more mature animals and humans. 相似文献
967.
Schorkopf DL Jarau S Francke W Twele R Zucchi R Hrncir M Schmidt VM Ayasse M Barth FG 《Proceedings. Biological sciences / The Royal Society》2007,274(1611):895-898
Stingless bees of the species Trigona spinipes (Fabricius 1793) use their saliva to lay scent trails communicating the location of profitable food sources. Extracts of the cephalic labial glands of the salivary system (not the mandibular glands, however) contain a large amount (approx. 74%) of octyl octanoate. This ester is also found on the scent-marked substrates at the feeding site. We demonstrate octyl octanoate to be a single compound pheromone which induces full trail following behaviour. The identification of the trail pheromone in this widely distributed bee makes it an ideal organism for studying the mechanism of trail following in a day flying insect. 相似文献
968.
da Silva LE Joussef AC Pacheco LK da Silva DG Steindel M Rebelo RA Schmidt B 《Bioorganic & medicinal chemistry》2007,15(24):7553-7560
In the present paper 12 N-quinolin-8-yl-arylsulfonamides synthesized by coupling 8-aminoquinolines with various arylsulfonylchlorides were assayed in vitro against Leishmania amazonensis, Leishmania chagasi and Trypanosoma cruzi strains. This series of new compounds were found to be selective for Leishmania spp. promastigote and amastigote forms. The most active compound was the N-(8-quinolyl)-3,5-difluoro-benzenesulfonamide 10 with an IC50 against L. amazonensis and L. chagasi of 2.12 and 0.45 μM, respectively. The less cytotoxic biphenyl derivative 7 was very effective against intracellular L. amazonensis with a reduction of macrophage cell infection of 82.1% at 25 μM. In addition, a copper complex 17 of an inactive ligand was readily synthesized and showed high leishmanicidal and trypanocidal activity against both extra and intracellular forms. 相似文献
969.
Fluorescent human RAD51 reveals multiple nucleation sites and filament segments tightly associated along a single DNA molecule 总被引:3,自引:0,他引:3
Modesti M Ristic D van der Heijden T Dekker C van Mameren J Peterman EJ Wuite GJ Kanaar R Wyman C 《Structure (London, England : 1993)》2007,15(5):599-609
The DNA strand-exchange reactions defining homologous recombination involve transient, nonuniform allosteric interactions between recombinase proteins and their DNA substrates. To study these mechanistic aspects of homologous recombination, we produced functional fluorescent human RAD51 recombinase and visualized recombinase interactions with single DNA molecules in both static and dynamic conditions. We observe that RAD51 nucleates filament formation at multiple sites on double-stranded DNA. This avid nucleation results in multiple RAD51 filament segments along a DNA molecule. Analysis of fluorescent filament patch size and filament kinks from scanning force microscopy (SFM) images indicate nucleation occurs minimally once every 500 bp. Filament segments did not rearrange along DNA, indicating tight association of the ATP-bound protein. The kinetics of filament disassembly was defined by activating ATP hydrolysis and following individual filaments in real time. 相似文献
970.
Kamila Myszka Katarzyna Czaczyk Marcin T. Schmidt Anna M. Olejnik 《World journal of microbiology & biotechnology》2007,23(11):1605-1612
The purpose of these investigations was to evaluate the influence of limited nutrient availability in the culture medium on
Proteus vulgaris biofilm formation on surfaces of stainless steel. The relationship between the P. vulgaris adhesion to the abiotic surfaces, the cellular ATP levels, cell surface hydrophobicity and changes in the profiles of extracellular
proteins and lipopolysaccharides was examined. In all experimental variants the starvation conditions induced the bacterial
cells to adhere to the surfaces of stainless steel. Higher ATP content and lower cell surface hydrophobicity of P. vulgaris cells was observed upon nutrient-limited conditions. Under starvation conditions a reduction in the levels of extracellular
low molecular weight proteins was noticed. High molecular weight proteins formed the conditioning layer on stainless steel
plates, making the bacteria adhesion process more favorable. The production of low molecular weight carbohydrates promoted
more advanced stages of P. vulgaris biofilm formation process on the surfaces of stainless steel upon starvation. 相似文献