全文获取类型
收费全文 | 6265篇 |
免费 | 440篇 |
国内免费 | 4篇 |
专业分类
6709篇 |
出版年
2023年 | 23篇 |
2022年 | 82篇 |
2021年 | 158篇 |
2020年 | 73篇 |
2019年 | 98篇 |
2018年 | 137篇 |
2017年 | 121篇 |
2016年 | 201篇 |
2015年 | 290篇 |
2014年 | 326篇 |
2013年 | 420篇 |
2012年 | 529篇 |
2011年 | 603篇 |
2010年 | 318篇 |
2009年 | 280篇 |
2008年 | 371篇 |
2007年 | 435篇 |
2006年 | 365篇 |
2005年 | 328篇 |
2004年 | 305篇 |
2003年 | 315篇 |
2002年 | 302篇 |
2001年 | 54篇 |
2000年 | 28篇 |
1999年 | 42篇 |
1998年 | 47篇 |
1997年 | 43篇 |
1996年 | 32篇 |
1995年 | 31篇 |
1994年 | 18篇 |
1993年 | 21篇 |
1992年 | 15篇 |
1991年 | 14篇 |
1989年 | 12篇 |
1988年 | 9篇 |
1987年 | 8篇 |
1985年 | 8篇 |
1984年 | 11篇 |
1982年 | 11篇 |
1981年 | 10篇 |
1980年 | 12篇 |
1977年 | 21篇 |
1976年 | 18篇 |
1975年 | 12篇 |
1973年 | 9篇 |
1972年 | 12篇 |
1969年 | 10篇 |
1968年 | 13篇 |
1967年 | 7篇 |
1966年 | 11篇 |
排序方式: 共有6709条查询结果,搜索用时 0 毫秒
91.
Stepan A. Kremis Dmitry S. Baev Alla V. Lipeeva Elvira E. Shults Tatiana G. Tolstikova Olga I. Sinitsyna Alexey V. Kochetov Tatiana S. Frolova 《Journal of biochemical and molecular toxicology》2019,33(11)
The furocoumarin backbone is a promising platform for chemical modifications aimed at creating new pharmaceutical agents. However, the high level of biological activity of furocoumarins is associated with a number of negative effects. For example, some of the naturally occurring ones and their derivatives can show genotoxic and mutagenic properties as a result of their forming crosslinks with DNA molecules. Therefore, a particularly important area for the chemical modification of natural furocoumarins is to reduce the negative aspects of their bioactivity. By studying a group of 21 compounds—1,2,3‐triazolyl modified derivatives of furocoumarin and peucedanin—using the SOS chromotest, the Ames test, and DNA‐comet assays, we revealed modifications that can neutralize the structure's genotoxic properties. Theoretical aspects of the interaction of the compound library were studied using molecular modeling and this identified the leading role of the polyaromatic molecular core that takes part in stacking‐interactions with the pi‐systems of the nitrogenous bases of DNA. 相似文献
92.
Basu U Gyrd-Hansen M Baby SM Lozynska O Krag TO Jensen CJ Frödin M Khurana TS 《FEBS letters》2007,581(22):4153-4158
Utrophin is the autosomal homolog of dystrophin, the product of the Duchenne's muscular dystrophy (DMD) locus. Utrophin is of therapeutic interest since its over-expression can compensate dystrophin's absence. Utrophin is enriched at neuromuscular junctions due to heregulin-mediated utrophin-A promoter activation. We demonstrate that heregulin activated MSK1/2 and phosphorylated histone H3 at serine 10 in cultured C2C12 muscle cells, in an ERK-dependent manner. MSK1/2 inhibition suppressed heregulin-mediated utrophin-A activation. MSK1 over-expression potentiated heregulin-mediated utrophin-A activation and chromatin remodeling at the utrophin-A promoter. These results identify MSK1/2 as key effectors modulating utrophin-A expression as well as identify novel targets for DMD therapy. 相似文献
93.
To probe the size of the ion channel formed by Pseudomonas syringae lipodepsipeptide syringomycin E, we use the partial blockage of ion current by penetrating poly(ethylene glycol)s. Earlier experiments with symmetric application of these polymers yielded a radius estimate of approximately 1 nm. Now, motivated by the asymmetric non-ohmic current-voltage curves reported for this channel, we explore its structural asymmetry. We gauge this asymmetry by studying the channel conductance after one-sided addition of differently sized poly(ethylene glycol)s. We find that small polymers added to the cis-side of the membrane (the side of lipodepsipeptide addition) reduce channel conductance much less than do the same polymers added to the trans-side. We interpret our results to suggest that the water-filled pore of the channel is conical with cis- and trans-radii differing by a factor of 2-3 and that the smaller cis-radius is in the 0.25-0.35 nm range. In symmetric, two-sided addition, polymers entering the pore from the larger opening dominate blockage. 相似文献
94.
Gene duplication can occur on two scales: whole-genome duplications (WGD) and smaller-scale duplications (SSD) involving individual genes or genomic segments. Duplication may result in functionally redundant genes or diverge in function through neofunctionalization or subfunctionalization. The effect of duplication scale on functional evolution has not yet been explored, probably due to the lack of global knowledge of protein function and different times of duplication events. To address this question, we used integrated Bayesian analysis of diverse functional genomic data to accurately evaluate the extent of functional similarity and divergence between paralogs on a global scale. We found that paralogs resulting from the whole-genome duplication are more likely to share interaction partners and biological functions than smaller-scale duplicates, independent of sequence similarity. In addition, WGD paralogs show lower frequency of essential genes and higher synthetic lethality rate, but instead diverge more in expression pattern and upstream regulatory region. Thus, our analysis demonstrates that WGD paralogs generally have similar compensatory functions but diverging expression patterns, suggesting a potential of distinct evolutionary scenarios for paralogs that arose through different duplication mechanisms. Furthermore, by identifying these functional disparities between the two types of duplicates, we reconcile previous disputes on the relationship between sequence divergence and expression divergence or essentiality. 相似文献
95.
Sun Y Breydo L Makarava N Yang Q Bocharova OV Baskakov IV 《The Journal of biological chemistry》2007,282(12):9090-9097
Despite the ability of most proteins to form amyloid, very little is know about amyloid fibril structures and the factors that govern their stability. Using amyloid fibrils produced from full-length prion protein (PrP), we describe a reliable approach for determining both site-specific and global conformational stability of the fibrillar form. To measure site-specific stability, we produced six variants of PrP by replacing the residues at positions 88, 98, 127, 144, 196, and 230 with cysteine, labeled the new cysteines with the fluorescent dye acrylodan, and investigated their conformational status within the amyloid form in guanidine hydrochloride-induced denaturation experiments. We found that the fibrils labeled at positions 127, 144, 196, and 230 displayed cooperative unfolding and showed a very high C1/2 value similar to that observed for the global unfolding of the amyloid structure. The unfolding at residue 98 was also cooperative; however, it showed a C1/2 value substantially lower than that of global unfolding, whereas the unfolding of fibrils labeled at residue 88 was non-cooperative. These data illustrate that there are at least two independent cooperative folding domains within the amyloid structure of the full-length PrP. In addition, kinetic experiments revealed only a partial overlap between the region that constituted the fibrillar cross-beta core and the regions that were involved in nucleation. This result illustrates that separate PrP regions accounted for the nucleation and for the formation of the conformationally most stable fibrillar core. 相似文献
96.
Venegas-Calerón M Beaudoin F Sayanova O Napier JA 《The Journal of biological chemistry》2007,282(5):2996-3003
The marine parasitic protozoon Perkinus marinus synthesizes the polyunsaturated fatty acid arachidonic acid via the unusual alternative Delta8 pathway in which elongation of C18 fatty acids generates substrate for two sequential desaturations. Here we have shown that genes encoding the three P. marinus activities responsible for arachidonic acid biosynthesis (C18 Delta9-elongating activity, C20 Delta8 desaturase, C20 Delta5 desaturase) are genomically clustered and co-transcribed as an operon. The acyl elongation reaction, which underpins this pathway, is catalyzed by a FAE1 (fatty acid elongation 1)-like 3-ketoacyl-CoA synthase class of condensing enzyme previously only reported in higher plants and algae. This is the first example of an elongating activity involved in the biosynthesis of a polyunsaturated fatty acid that is not a member of the ELO/SUR4 family. The P. marinus FAE1-like elongating activity is sensitive to the herbicide flufenacet, similar to some higher plant 3-ketoacyl-CoA synthases, but unable to rescue the yeast elo2Delta/elo3Delta mutant consistent with a role in the elongation of polyunsaturated fatty acids. P. marinus represents a key organism in the taxonomic separation of the single-celled eukaryotes collectively known as the alveolates, and our data imply a lineage in which ancestral acquisition of plant-like genes, such as FAE1-like 3-ketoacyl-CoA synthases, occurred via endosymbiosis. The P. marinus FAE1-like elongating activity is also indicative of the independent evolution of the alternative Delta8 pathway, distinct from ELO/SUR4-dependent examples. 相似文献
97.
98.
Dong A Xu X Edwards AM;Midwest Center for Structural Genomics;Structural Genomics Consortium Chang C Chruszcz M Cuff M Cymborowski M Di Leo R Egorova O Evdokimova E Filippova E Gu J Guthrie J Ignatchenko A Joachimiak A Klostermann N Kim Y Korniyenko Y Minor W Que Q Savchenko A Skarina T Tan K Yakunin A Yee A Yim V Zhang R Zheng H Akutsu M Arrowsmith C Avvakumov GV Bochkarev A Dahlgren LG Dhe-Paganon S Dimov S Dombrovski L Finerty P Flodin S Flores A Gräslund S Hammerström M Herman MD Hong BS 《Nature methods》2007,4(12):1019-1021
We tested the general applicability of in situ proteolysis to form protein crystals suitable for structure determination by adding a protease (chymotrypsin or trypsin) digestion step to crystallization trials of 55 bacterial and 14 human proteins that had proven recalcitrant to our best efforts at crystallization or structure determination. This is a work in progress; so far we determined structures of 9 bacterial proteins and the human aminoimidazole ribonucleotide synthetase (AIRS) domain. 相似文献
99.
Tatiana B. Feldman Oleksandr I. Ivankov Alexander I. Kuklin Tatiana N. Murugova Marina A. Yakovleva Olga A. Smitienko Irina B. Kolchugina Adam Round Valentin I. Gordeliy Alexander V. Belushkin Mikhail A. Ostrovsky 《生物化学与生物物理学报:生物膜》2019,1861(10):183000
The supramolecular organization of the visual pigment rhodopsin in the photoreceptor membrane remains contentious. Specifically, whether this G protein-coupled receptor functions as a monomer or dimer remains unknown, as does the presence or absence of ordered packing of rhodopsin molecules in the photoreceptor membrane. Completely opposite opinions have been expressed on both issues. Herein, using small-angle neutron and X-ray scattering approaches, we performed a comparative analysis of the structural characteristics of the photoreceptor membrane samples in buffer, both in the outer segment of photoreceptor cells, and in the free photoreceptor disks. The average distance between the centers of two neighboring rhodopsin molecules was found to be ~5.8 nm in both cases. The results indicate an unusually high packing density of rhodopsin molecules in the photoreceptor membrane, but molecules appear to be randomly distributed in the membrane without any regular ordering. 相似文献
100.
Plant and Soil - Citrate secretion is a kind of typical strategy for plant against aluminum (Al) toxicity. However, the signaling process in Al-activated citrate secretion needs to be clarified.... 相似文献