全文获取类型
收费全文 | 2687篇 |
免费 | 290篇 |
出版年
2023年 | 12篇 |
2022年 | 31篇 |
2021年 | 50篇 |
2020年 | 24篇 |
2019年 | 36篇 |
2018年 | 47篇 |
2017年 | 44篇 |
2016年 | 79篇 |
2015年 | 112篇 |
2014年 | 119篇 |
2013年 | 125篇 |
2012年 | 157篇 |
2011年 | 178篇 |
2010年 | 104篇 |
2009年 | 103篇 |
2008年 | 123篇 |
2007年 | 174篇 |
2006年 | 143篇 |
2005年 | 141篇 |
2004年 | 121篇 |
2003年 | 117篇 |
2002年 | 133篇 |
2001年 | 68篇 |
2000年 | 61篇 |
1999年 | 60篇 |
1998年 | 32篇 |
1997年 | 30篇 |
1996年 | 26篇 |
1995年 | 18篇 |
1994年 | 24篇 |
1993年 | 20篇 |
1992年 | 36篇 |
1991年 | 27篇 |
1990年 | 28篇 |
1989年 | 24篇 |
1988年 | 28篇 |
1987年 | 26篇 |
1986年 | 18篇 |
1985年 | 27篇 |
1984年 | 19篇 |
1983年 | 17篇 |
1982年 | 16篇 |
1980年 | 12篇 |
1979年 | 12篇 |
1977年 | 14篇 |
1976年 | 12篇 |
1974年 | 13篇 |
1971年 | 14篇 |
1970年 | 11篇 |
1965年 | 8篇 |
排序方式: 共有2977条查询结果,搜索用时 15 毫秒
971.
Bratton LD Auerbach B Choi C Dillon L Hanselman JC Larsen SD Lu G Olsen K Pfefferkorn JA Robertson A Sekerke C Trivedi BK Unangst PC 《Bioorganic & medicinal chemistry》2007,15(16):5576-5589
In an effort to identify hepatoselective inhibitors of HMG-CoA reductase, two series of pyrroles were synthesized and evaluated. Efforts were made to modify (3R,5R)-7-[3-(4-fluorophenyl)-1-isopropyl-4-phenyl-5-phenylcarbamoyl-1H-pyrrol-2-yl]-3,5-dihydroxy-heptanoic acid sodium salt 30 in order to reduce its lipophilicity and therefore increase hepatoselectivity. Two strategies that were explored were replacement of the lipophilic 3-phenyl substituent with either a polar function (pyridyl series) or with lower alkyl substituents (lower alkyl series) and attachment of additional polar moieties at the 2-position of the pyrrole ring. One compound was identified to be both highly hepatoselective and active in vivo. We report the discovery, synthesis, and optimization of substituted pyrrole-based hepatoselective ligands as potent inhibitors of HMG-CoA reductase for reducing low density lipoprotein cholesterol (LDL-c) in the treatment of hypercholesterolemia. 相似文献
972.
The heterogametic sex tends to be rare, absent, sterile, or deformed in F1 hybrid crosses between species, a pattern called Haldane's rule (HR). The introgression of single genes or chromosomal regions from one drosophilid species into the genetic background of another have shown that HR is most often associated with fixed genetic differences in inter-specific crosses. However, because such introgression studies have involved species diverged several hundred thousand generations from a common ancestor, it is not clear whether HR attends the speciation process or results from the accumulation of epistatically acting genes postspeciation. We report the first evidence for HR prior to speciation in crosses between two populations of the red flour beetle, Tribolium castaneum, collected 931 km apart in Colombia and Ecuador. In this cross, HR is manifested as an increase in the proportion of deformed males compared to females and the expression of HR is temperature dependent. Neither population, when crossed to a geographically distant population from Japan, exhibits HR at any rearing temperature. Using joint-scaling analysis and additional data from backcrosses and F2's, we find that the hybrid incompatibilities and the emergence of HR are concurrent processes involving interactions between X-linked and autosomal genes. However, we also find many examples of incompatibilities manifest by F2 and backcross hybrids but not by F1 hybrids and most incompatibilities are not sex different in their effects, even when they involve both X-autosomal interactions and genotype-by-environment interactions. We infer that incipient speciation in flour beetles can occur with or without HR and that significant hybrid incompatibilities result from the accumulation of epistatically acting gene differences between populations without differentially affecting the heterogametic sex in F1 hybrids. The temperature dependence of the incompatibilities supports the inference that genotype-by-environment interactions and adaptation to different environments contribute to the genetic divergence important to postzygotic reproductive isolation. 相似文献
973.
Winterhalter WE Mousseau TA 《Evolution; international journal of organic evolution》2007,61(7):1520-1531
Phenotypic plasticity describes an organism's ability to produce multiple phenotypes in direct response to its environmental conditions. Over the past 15 years empiricists have found that this plasticity frequently exhibits geographic variation and often possesses a significant heritable genetic basis. However, few studies have examined both of these aspects of plasticity simultaneously. Here, we examined both the geographic and genetic variations of the plasticity for diapause incidence (the proportion of eggs that enter an arrested state of development capable of surviving over the winter) relative to temperatures and photoperiods associated with long and short season environments across six populations of the striped ground cricket, Allonemobius socius, using a half-sibling split brood quantitative genetic design. We found that plasticity, as measured by the slope of the reaction norm, was greater in the southern-low altitude region (where populations are bivoltine) relative to the southern-high and northern-low altitude regions (where populations are univoltine). However, the heritability of plasticity was only significantly different from zero in univoltine populations that experienced "intermediate" natal season lengths. These patterns suggest that selection may favor the plasticity of diapause incidence in bivoltine regions, but act against plasticity in regions in which populations are univoltine. Furthermore, our data suggest that under "intermediate" natal season length conditions, the interplay between local adaptation and gene flow may keep the plasticity of diapause incidence low (but still significant) while maintaining its genetic variation. As such, this study not only provides a novel observation into the geographic variation of phenotypic plasticity, but also provides much needed groundwork for tests of its adaptive significance. 相似文献
974.
Excised or intact inflorescences? Methodological effects on parasitoid wasp longevity 总被引:3,自引:1,他引:2
The development of accurate and repeatable experimental techniques is a cornerstone of any research program. Indeed, the first stage in developing a conservation biological control program typically involves ranking the suitability of various plant species as food resources for the target species of natural enemy in the laboratory or glasshouse. Herein the choice of flower presentation method is a highly relevant consideration. It is unclear whether excised flowers with their peduncles submerged in water will generate similar effects on the life history traits of a natural enemy compared with those using flowers remaining intact on a rooted plant. Either method has been used in 86 previous studies, yet none has quantified this effect. It is possible that both plant nectar content and production are altered as a result of changes in the physiological condition of the excised flowers. A laboratory test was designed to assess the influence of flower presentation method (excised or intact inflorescences) and different types of nectar (artificial and natural) on the longevity of the wasp Aphidius ervi, an important parasitoid of aphids. Distinct differences were revealed in the suitability of the nine flower species and three control treatments on parasitoid wasp longevity, with buckwheat being the most suitable plant. However, apart from coriander, flower presentation method and wasp gender generally did not affect parasitoid longevity for the set of species tested. As there was little evidence that parasitoid wasp longevity would be altered on excised flowers, and because of reasons pertaining to improved logistical and experimental requirements, the use of excised flowers is cautiously recommended to researchers for further laboratory evaluations of the effects of nectar provision on parasitoid fitness. 相似文献
975.
Dynamic regulation of the large exocytotic fusion pore in pancreatic acinar cells 总被引:1,自引:0,他引:1
下载免费PDF全文
![点击此处可从《Molecular biology of the cell》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Larina O Bhat P Pickett JA Launikonis BS Shah A Kruger WA Edwardson JM Thorn P 《Molecular biology of the cell》2007,18(9):3502-3511
Loss of granule content during exocytosis requires the opening of a fusion pore between the secretory granule and plasma membrane. In a variety of secretory cells, this fusion pore has now been shown to subsequently close. However, it is still unclear how pore closure is physiologically regulated and contentious as to how closure relates to granule content loss. Here, we examine the behavior of the fusion pore during zymogen granule exocytosis in pancreatic acinar cells. By using entry of high-molecular-weight dyes from the extracellular solution into the granule lumen, we show that the fusion pore has a diameter of 29-55 nm. We further show that by 5 min after granule fusion, many granules have a closed fusion pore with evidence indicating that pore closure is a prelude to endocytosis and that in granules with a closed fusion pore the chymotrypsinogen content is low. Finally, we show that latrunculin B treatment promotes pore closure, suggesting F-actin affects pore dynamics. Together, our data do not support the classical view in acinar cells that exocytosis ends with granule collapse. Instead, for many granules the fusion pore closes, probably as a transition to endocytosis, and likely involving an F-actin-dependent mechanism. 相似文献
976.
Locomotion over ballast surfaces provides a unique situation for investigating the biomechanics of gait. Although much research has focused on level and sloped walking on a smooth, firm surface in order to understand the common kinematic and kinetic variables associated with human locomotion, the literature currently provides few if any discussions regarding the dynamics of locomotion on surfaces that are either rocky or uneven. The purpose of this study was to investigate a method for using force plates to measure the ground reaction forces (GRFs) during gait on ballast. Ballast is a construction aggregate of unsymmetrical rock used in industry for the purpose of forming track bed on which railway ties are laid or in yards where railroad cars are stored. It is used to facilitate the drainage of water and to create even running surfaces. To construct the experimental ballast surfaces, 31.75 mm (1 1/4 in.) marble ballast at depths of approximately 63.5 mm (2.5 in.) or 101.6 mm (4 in.) were spread over a carpeted vinyl tile walkway specially designed for gait studies. GRF magnitudes and time histories from a force plate were collected under normal smooth surface and under both ballast surface conditions for five subjects. GRF magnitudes and time histories during smooth surface walking were similar to GRF magnitudes and time histories from the two ballast surface conditions. The data presented here demonstrate the feasibility of using a force plate system to expand the scope of biomechanical analyses of locomotion on ballast surfaces. 相似文献
977.
Fazel Shabanpoor Ross A D Bathgate Mohammed Akhter Hossain Eleni Giannakis John D Wade Richard A Hughes 《Journal of peptide science》2007,13(2):113-120
Insulin-like peptide 3 (INSL3) is a peptide hormone belonging to the relaxin-insulin superfamily of peptides that plays important roles in testes descent, oocyte maturation and the control of male germ cell apoptosis. These actions are mediated via a specific G-protein coupled receptor, LGR8. Previous structure-activity studies have shown that the key binding site of INSL3 is situated within its B-chain. Recent studies in our laboratory have led to the identification of a cyclic peptide mimetic 2 of the INSL3 B-chain, which we have shown to compete with the binding of [33P]-relaxin to LGR8 expressed in HEK293T cells, and to inhibit cAMP-mediated signaling in these cells, i.e. it is an antagonist of INSL3. In order to further define the structure-activity relationships of cyclic analogues of the INSL3 B-chain, we used a structure-based approach to design a series of cyclic, disulfide-constrained INSL3 B-chain mimetics. To do this, we first created a model of the 3D structure of INSL3 using the crystal structure of human relaxin as a template. This model of INSL3 was then used as a template to design a series of disulfide-constrained mimetics of the INSL3 B-chain. The peptides were synthesized by solid-phase peptide synthesis using pseudoproline dipeptides to improve the synthesis outcome. Of the seven prepared INSL3 B-chain mimetics, three compounds were found to have partial displacement activity, while four were able to completely displace [33P]-relaxin from LGR8, including compounds that were markedly shorter than compound 2. The best of these, mimetic 6, showed significantly greater affinity for LGR8 than compound 2, but still displayed around 1000-fold less affinity for LGR8 than native INSL3. Analysis of selected mimetics for their alpha-helical content using circular dichroism (CD) spectroscopy revealed that, generally, the mimetics showed less than expected helicity. The inability of the compounds to display true native INSL3 structure is likely contributing to their reduced receptor binding affinity. We are currently examining alternative INSL3 B-chain mimetics that might better present key receptor binding residues in the native INSL3-like conformation. 相似文献
978.
979.
The DNA damage response: ten years after 总被引:14,自引:0,他引:14
The DNA damage response (DDR), through the action of sensors, transducers, and effectors, orchestrates the appropriate repair of DNA damage and resolution of DNA replication problems, coordinating these processes with ongoing cellular physiology. In the past decade, we have witnessed an explosion in understanding of DNA damage sensing, signaling, and the complex interplay between protein phosphorylation and the ubiquitin pathway employed by the DDR network to execute the response to DNA damage. These findings have important implications for aging and cancer. 相似文献
980.