全文获取类型
收费全文 | 1011篇 |
免费 | 73篇 |
国内免费 | 3篇 |
出版年
2023年 | 4篇 |
2022年 | 15篇 |
2021年 | 10篇 |
2020年 | 13篇 |
2019年 | 20篇 |
2018年 | 23篇 |
2017年 | 26篇 |
2016年 | 22篇 |
2015年 | 40篇 |
2014年 | 44篇 |
2013年 | 63篇 |
2012年 | 75篇 |
2011年 | 79篇 |
2010年 | 45篇 |
2009年 | 43篇 |
2008年 | 44篇 |
2007年 | 60篇 |
2006年 | 60篇 |
2005年 | 44篇 |
2004年 | 70篇 |
2003年 | 57篇 |
2002年 | 64篇 |
2001年 | 10篇 |
2000年 | 12篇 |
1999年 | 17篇 |
1998年 | 17篇 |
1997年 | 15篇 |
1996年 | 20篇 |
1995年 | 6篇 |
1994年 | 5篇 |
1993年 | 7篇 |
1992年 | 8篇 |
1990年 | 7篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1984年 | 3篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1981年 | 5篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1976年 | 3篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1968年 | 1篇 |
1945年 | 2篇 |
1926年 | 1篇 |
1925年 | 1篇 |
排序方式: 共有1087条查询结果,搜索用时 28 毫秒
31.
David C. Kombo Terry A. Hauser Vladimir P. Grinevich Matthew S. Melvin Jon-Paul Strachan Serguei S. Sidach Joseph Chewning Nikolai Fedorov Kartik Tallapragada Scott R. Breining Craig H. Miller 《Bioorganic & medicinal chemistry letters》2013,23(5):1450-1455
We have carried out a pharmacological evaluation of arylmethylene quinuclidine derivatives interactions with human α3β4 nAChRs subtype, using cell-based receptor binding, calcium-influx, electrophysiological patch-clamp assays and molecular modeling techniques. We have found that the compounds bind competitively to the α3β4 receptor with micromolar affinities and some of the compounds behave as non-competitive antagonists (compounds 1, 2 and 3), displaying submicromolar IC50 values. These evidences suggest a mixed mode of action for these compounds, having interactions at the orthosteric site and more pronounced interactions at an allosteric site to block agonist effects. One of the compounds, 1-benzyl-3-(diphenylmethylene)-1-azoniabicyclo[2.2.2]octane chloride (compound 3), exhibited poorly reversible use-dependent block of α3β4 channels. We also found that removal of a phenyl group from compound 1 confers a partial agonism to the derived analog (compound 6). Introducing a hydrogen-bond acceptor into the 3-benzylidene quinuclidine derivative (compound 7) increases agonism potency at the α3β4 receptor subtype. Docking into the orthosteric binding site of a α3β4 protein structure derived by comparative modeling accurately predicted the experimentally-observed trend in binding affinity. Results supported the notion that binding requires a hydrogen bond formation between the ligand basic nitrogen and the backbone carbonyl oxygen atom of the conserved Trp-149. 相似文献
32.
Alina Grigor’eva Irina Saranina Nina Tikunova Alexey Safonov Nikolai Timoshenko Alexey Rebrov Elena Ryabchikova 《Biometals》2013,26(3):479-488
Silver nanoparticles possess antibacterial effect for various bacteria; however mechanisms of the interaction between Ag-NPs and bacterial cells remain unclear. The aim of our study was to obtain direct evidence of Ag-NPs penetration into cells of Gram-negative bacterium S. typhimurium and Gram-positive bacterium S. aureus, and to study cell responses to Ag-NPs. The Ag-NPs (most 8–10 nm) were obtained by gas-jet method. S. typhimurium (7.81 × 107 CFU), or S. aureus (8.96 × 107 CFU) were treated by Ag-NPs (0.05 mg/l of silver) in orbital shaker at 190 rpm, 37 °C. Bacteria were sampled at 0.5, 1, 1.5, 2, 5 and 23 h of the incubation for transmission electron microscopy of ultrathin sections. The Ag-NPs adsorbed on outer membrane of S. typhimurium and cell wall of S. auereus; penetrated and accumulated in cells without aggregation and damaging of neighboring cytoplasm. In cells of S. aureus Ag-NPs bound with DNA fibers. Cell responses to Ag-NPs differed morphologically in S. typhimurium and S. aureus, and mainly were presented by damage of cell structures. The cytoplasm of S. aureus became amorphous, while S. typhimurium showed lumping and lysis of cytoplasm which led to formation of “empty” cells. Other difference was fast change of cell shape in S. typhimurium, and late deformation of S. aureus cells. The obtained results showed how different could be responses induced by the same NPs in relatively simple prokaryotic cells. Evidently, Ag-NPs directly interact with macromolecular structures of living cells and are exert an active influence on their metabolism. 相似文献
33.
Renata Hordejuk Nikolai A. Lobanov Anna Kicinska Krzysztof Dolowy 《Molecular membrane biology》2013,30(5):307-313
We report here that large conductance K+ selective channel in adrenal chromaffin granules is controlled by pH. We measured electrogenic influx of 86Rb+ into chromaffin granules prepared from bovine adrenal gland medulla. The 86Rb+ influx was inhibited by acidic pH. Purified chromaffin granule membranes were also fused with planar lipid bilayer. A potassium channel with conductance of 432±9 pS in symmetric 450 mM KCl was observed after reconstitution into lipid bilayer. The channel activity was unaffected by charybdotoxin, a blocker of the Ca2+-activated K+ channel of large conductance. It was observed that acidification to pH 6.4 cis side of the membrane lowered the channel open probability and single channel conductance. Whereas only weak influence on the single channel current amplitude and open probability were observed upon lowering of the pH at the trans side. We conclude that a pH-sensitive large conductance potassium channel operates in the chromaffin granule membrane. 相似文献
34.
Nikolai M. Veter Larisa R. G. DeSantis Lindsey T. Yann Shelly L. Donohue Ryan J. Haupt Sarah E. Corapi Siobhan L. Fathel Emily K. Gootee Lucas F. Loffredo Jennifer L. Romer Stoycho M. Velkovsky 《Biology letters》2013,9(5)
Macroecology strives to identify ecological patterns on broad spatial and temporal scales. One such pattern, Rapoport''s rule, describes the tendency of species'' latitudinal ranges to increase with increasing latitude. Several mechanisms have been proposed to explain this rule. Some invoke climate, either through glaciation driving differential extinction of northern species or through increased seasonal variability at higher latitudes causing higher thermal tolerances and subsequently larger ranges. Alternatively, continental tapering or higher interspecific competition at lower latitudes may be responsible. Assessing the incidence of Rapoport''s rule through deep time can help to distinguish between competing explanations. Using fossil occurrence data from the Palaeobiology Database, we test these hypotheses by evaluating mammalian compliance with the rule throughout the Caenozoic of North America. Adherence to Rapoport''s rule primarily coincides with periods of intense cooling and increased seasonality, suggesting that extinctions caused by changing climate may have played an important role in erecting the latitudinal gradients in range sizes seen today. 相似文献
35.
Petrunenko Yury K. Seryodkin Ivan V. Bragina Eugenia V. Soutyrina Svetlana S. Mukhacheva Anna S. Rybin Nikolai N. Miquelle Dale G. 《Acta theriologica》2020,65(2):245-253
Mammal Research - The persistence of wildlife populations largely depends on females successfully rearing young through the earliest, most vulnerable period. During this period, mothers must... 相似文献
36.
Nikolai Siebert Christin Eger Diana Seidel Madlen Jüttner Maxi Zumpe Danilo Wegner 《MABS-AUSTIN》2016,8(3):604-616
Ch14.18 manufactured in Chinese hamster ovary (CHO) cells is currently being evaluated in clinical trials. Short-term infusion (STI) (8–20 h/day; 4–5 days) of 100 mg/m2 ch14.18/CHO (dinutiximab β) per cycle in combination with cytokines is standard treatment of neuroblastoma (NB) patients. As pain is a limiting factor, we investigated a novel delivery method by continuous long-term infusion (LTI) of 100 mg/m2 over 10 days. 53 NB patients were treated with 5–6 cycles of 6 × 106 IU/m2 subcutaneous interleukin-2 (d 1-5, 8-12), LTI of 100 mg/m2 ch14.18/CHO (d 8-18) and 160 mg/m2 oral 13-cis-retinoic acid (d 22-35). Human anti-chimeric antibody (HACA), antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity were determined. With LTI, we observed a maximum concentration of ch14.18/CHO (Cmax) of 12.56 ± 0.68 µg/ml and a terminal half-life time (t1/2 β) of 32.7 ± 16.2 d. The clearance values for LTI and STI of 0.54 ± 0.13 and 0.41 ± 0.29 L/d m2 and area under the serum concentration-time curve (AUC) values of 189.6 ± 41.4 and 284.8 ± 156.8 µg×d/ml, respectively, were not significantly different. Importantly, we detected ch14.18/CHO trough concentration of ≥ 1 µg/ml at time points preceding subsequent antibody infusions after cycle 1, allowing a persistent activation of antibody effector mechanisms over the entire treatment period of 6 months. HACA responses were observed in 10/53 (19%) patients, similar to STI (21%), indicating LTI had no effect on the immunogenicity of ch14.18/CHO. In conclusion, LTI of ch14.18/CHO induced effector mechanisms over the entire treatment period, and may therefore emerge as the preferred delivery method of anti-GD2 immunotherapy to NB patients. 相似文献
37.
Zhang Rui Parniakov Oleksii Grimi Nabil Lebovka Nikolai Marchal Luc Vorobiev Eugène 《Bioprocess and biosystems engineering》2019,42(2):173-186
Bioprocess and Biosystems Engineering - Microalgae of Nannochloropsis sp. present valuable source of bio-molecules (pigments, lipids, proteins) that have nutritional potential for the... 相似文献
38.
Kandul NP Lukhtanov VA Pierce NE 《Evolution; international journal of organic evolution》2007,61(3):546-559
That chromosomal rearrangements may play an important role in maintaining postzygotic isolation between well-established species is part of the standard theory of speciation. However, little evidence exists on the role of karyotypic change in speciation itself--in the establishment of reproductive barriers between previously interbreeding populations. The large genus Agrodiaetus (Lepidoptera: Lycaenidae) provides a model system to study this question. Agrodiaetus butterflies exhibit unusual interspecific diversity in chromosome number, from n= 10 to n= 134; in contrast, the majority of lycaenid butterflies have n= 23/24. We analyzed the evolution of karyotypic diversity by mapping chromosome numbers on a thoroughly sampled mitochondrial phylogeny of the genus. Karyotypic differences accumulate gradually between allopatric sister taxa, but more rapidly between sympatric sister taxa. Overall, sympatric sister taxa have a higher average karyotypic diversity than allopatric sister taxa. Differential fusion of diverged populations may account for this pattern because the degree of karyotypic difference acquired between allopatric populations may determine whether they will persist as nascent biological species in secondary sympatry. This study therefore finds evidence of a direct role for chromosomal rearrangements in the final stages of animal speciation. Rapid karyotypic diversification is likely to have contributed to the explosive speciation rate observed in Agrodiaetus, 1.6 species per million years. 相似文献
39.
Wang GL Shi X Salisbury E Sun Y Albrecht JH Smith RG Timchenko NA 《The Journal of biological chemistry》2007,282(2):1468-1478
40.
Akunevich Anastasia Aleksandrovna Khrustalev Vladislav Victorovich Khrustaleva Tatyana Aleksandrovna Poboinev Victor Vitoldovich Shalygo Nikolai Vladimirovich Stojarov Aleksander Nicolaevich Arutyunyan Alexander Migranovich Kordyukova Larisa Valentinovna Sapon Yehor Gennadyevich 《The protein journal》2022,41(2):245-259
The Protein Journal - An interplay between monomeric and dimeric forms of human epidermal growth factor (EGF) affecting its interaction with EGF receptor (EGFR) is poorly understood. While EGF... 相似文献