全文获取类型
收费全文 | 342篇 |
免费 | 46篇 |
出版年
2022年 | 3篇 |
2021年 | 4篇 |
2020年 | 3篇 |
2018年 | 4篇 |
2016年 | 13篇 |
2015年 | 9篇 |
2014年 | 10篇 |
2013年 | 16篇 |
2012年 | 18篇 |
2011年 | 12篇 |
2010年 | 10篇 |
2009年 | 11篇 |
2008年 | 13篇 |
2007年 | 12篇 |
2006年 | 12篇 |
2005年 | 16篇 |
2004年 | 10篇 |
2003年 | 12篇 |
2002年 | 12篇 |
2001年 | 9篇 |
2000年 | 5篇 |
1999年 | 3篇 |
1998年 | 6篇 |
1997年 | 3篇 |
1993年 | 9篇 |
1992年 | 7篇 |
1991年 | 8篇 |
1990年 | 9篇 |
1989年 | 5篇 |
1988年 | 5篇 |
1987年 | 5篇 |
1986年 | 6篇 |
1985年 | 3篇 |
1984年 | 7篇 |
1983年 | 5篇 |
1982年 | 4篇 |
1981年 | 3篇 |
1979年 | 3篇 |
1978年 | 3篇 |
1976年 | 3篇 |
1972年 | 4篇 |
1961年 | 3篇 |
1936年 | 4篇 |
1929年 | 3篇 |
1924年 | 2篇 |
1914年 | 7篇 |
1913年 | 4篇 |
1912年 | 2篇 |
1909年 | 2篇 |
1908年 | 2篇 |
排序方式: 共有388条查询结果,搜索用时 46 毫秒
51.
52.
E. S. Castle 《The Journal of general physiology》1934,17(6):751-762
For the growing cell of Phycomyces, a difference in the phototropic effect of light is described depending on its plane of polarization with reference to the axis of the cell. The difference which is found is primarily due to differences in the reflection losses at the cell surface. The magnitude of the effect approximates that deduced from the theory of phototropism suggested for this system. No specific effect of plane polarized light on the growth processes of the cell need be postulated. 相似文献
53.
Secretory carrier membrane protein 2 (SCAMP2) functions in late steps of membrane fusion in calcium-dependent granule exocytosis. A basic/hydrophobic peptide segment within SCAMP2 (SCAMP2 E: CWYRPIYKAFR) has been implicated in this function and shown to bind and sequester phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2 or PIP2] within membranes through an electrostatic mechanism. We now show that alanine substitution of tryptophan W2 within SCAMP2 E substantially weakens peptide binding to negatively charged liposomes; other substitutions for arginine R4 and lysine K8 have only limited effects on binding. Electron paramagnetic resonance analysis of liposomes containing spin-labeled PIP2 shows that R4 but not K8 is critical for SCAMP E binding to PIP2. The interfacial locations of SCAMP E and its structural variants within lipid bicelles measured by oxygen enhancement of nuclear relaxation are all similar. Corresponding point mutations within full-length SCAMP2 (SC2-R204A, SC2-K208A, and SC2-W202A) have been analyzed for biological effects on dense core vesicle exocytosis in neuroendocrine PC12 cells. With the same level of overexpression, SC2-R204A but not SC2-K208A inhibited secretion of cotransfected human growth hormone and of noradrenalin. Inhibition by SC2-R204A was the same as or greater than previously observed for SC2-W202A. Analysis of noradrenalin secretion by amperometry showed that inhibitory mutants of SCAMP2 decrease the probability of fusion pore opening and the stability of initially opened but not yet expanded fusion pores. The strong correlation between SCAMP2 E interactions with PIP2 and inhibition of exocytosis, particularly by SC2-R204A, led us to propose that SCAMP2 interaction with PIP2 within the membrane interface regulates fusion pore formation during exocytosis. 相似文献
54.
Bernard Barlaam Sabina Cosulich Martina Fitzek Hervé Germain Stephen Green Lyndsey L. Hanson Craig S. Harris Urs Hancox Kevin Hudson Christine Lambert-van der Brempt Maryannick Lamorlette Françoise Magnien Gilles Ouvry Ken Page Linette Ruston Lara Ward Bénédicte Delouvrié 《Bioorganic & medicinal chemistry letters》2017,27(13):3030-3035
We report the discovery of a novel aminopyrazine series of PI3Kα inhibitors, designed by hybridizing two known scaffolds of PI3K inhibitors. We describe the progress achieved from the first compounds plagued with poor general kinase selectivity to compounds showing high selectivity for PI3Kα over PI3Kβ and excellent general kinase selectivity. This effort culminated with the identification of compound 5 displaying high potency and selectivity, and suitable physiochemical and pharmacokinetic properties for oral administration. In vivo, compound 5 showed good inhibition of tumour growth (86% tumour growth inhibition at 50 mg/kg twice daily orally) in the MCF7 xenograft model in mice. 相似文献
55.
Lewis LM Sheffler D Williams R Bridges TM Kennedy JP Brogan JT Mulder MJ Williams L Nalywajko NT Niswender CM Weaver CD Conn PJ Lindsley CW 《Bioorganic & medicinal chemistry letters》2008,18(3):885-890
This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a novel series of selective M1 mAChR antagonists for the potential treatment of Parkinson's disease, dystonia and other movement disorders. Compounds in this series possess M1 antagonist IC(50)s in the 441nM-19microM range with 8- to >340-fold functional selectivity versus rM2-rM5. 相似文献
56.
57.
Luís Jaime Mota Amy E. Ramsden Mei Liu J. David Castle David W. Holden 《Cellular microbiology》2009,11(8):1236-1253
Salmonella enterica are facultative intracellular bacterial pathogens that proliferate within host cells in a membrane-bounded compartment, the Salmonella -containing vacuole (SCV). Intracellular replication of Salmonella is mediated by bacterial effectors translocated on to the cytoplasmic face of the SCV membrane by a type III secretion system. Some of these effectors manipulate the host endocytic pathway, resulting in the formation in epithelial cells of tubules enriched in late endosomal markers, known as Salmonella -induced filaments (SIFs). However, much less is known about possible interference of Salmonella with the secretory pathway. Here, a small-interference RNA screen revealed that secretory carrier membrane proteins (SCAMPs) 2 and 3 contribute to the maintenance of SCVs in the Golgi region of HeLa cells. This is likely to reflect a function of SCAMPs in vacuolar membrane dynamics. Moreover, SCAMP3, which accumulates on the trans -Golgi network in uninfected cells, marked tubules induced by Salmonella effectors that overlapped with SIFs but which also comprised distinct tubules lacking late endosomal proteins. We propose that SCAMP3 tubules reflect a manipulation of specific post-Golgi trafficking that might allow Salmonella to acquire nutrients and membrane, or to control host immune responses. 相似文献
58.
John C. Castle Yoshikazu Hara Christopher K. Raymond Philip Garrett-Engele Kenji Ohwaki Zhengyan Kan Jun Kusunoki Jason M. Johnson 《PloS one》2009,4(2)
Acetyl-CoA carboxylases ACC1 and ACC2 catalyze the carboxylation of acetyl-CoA to malonyl-CoA, regulating fatty-acid synthesis and oxidation, and are potential targets for treatment of metabolic syndrome. Expression of ACC1 in rodent lipogenic tissues and ACC2 in rodent oxidative tissues, coupled with the predicted localization of ACC2 to the mitochondrial membrane, have suggested separate functional roles for ACC1 in lipogenesis and ACC2 in fatty acid oxidation. We find, however, that human adipose tissue, unlike rodent adipose, expresses more ACC2 mRNA relative to the oxidative tissues muscle and heart. Human adipose, along with human liver, expresses more ACC2 than ACC1. Using RT-PCR, real-time PCR, and immunoprecipitation we report a novel isoform of ACC2 (ACC2.v2) that is expressed at significant levels in human adipose. The protein generated by this isoform has enzymatic activity, is endogenously expressed in adipose, and lacks the N-terminal sequence. Both ACC2 isoforms are capable of de novo lipogenesis, suggesting that ACC2, in addition to ACC1, may play a role in lipogenesis. The results demonstrate a significant difference in ACC expression between human and rodents, which may introduce difficulties for the use of rodent models for development of ACC inhibitors. 相似文献
59.
Prabhaker N Castle SJ Naranjo SE Toscano NC Morse JG 《Journal of economic entomology》2011,104(3):773-781
Two systemic neonicotinoids, imidacloprid and thiamethoxam, are widely used for residual control of several insect pests in cotton (Gossypium spp.), vegetables, and citrus (Citrus spp.). We evaluated their impact on six species of beneficial arthropods, including four parasitoid species--Aphytis melinus Debach, Gonatocerus ashmeadi Girault, Eretmocerus eremicus Rose & Zolnerowich, and Encarsia formosa Gahan--and two generalist predators--Geocoris punctipes (Say) and Orius insidiosus (Say)--in the laboratory by using a systemic uptake bioassay. Exposure to systemically treated leaves of both neonicotinoids had negative effects on adult survival in all four parasitoids, with higher potency against A. melinus as indicated by a low LC50. Mortality was also high for G. ashmeadi, E. eremicus, and E. formosa after exposure to both compounds but only after 48 h posttreatment. The two predators G. punctipes and O. insidiosus were variably susceptible to imidacloprid and thiamethoxam after 96-h exposure. However, toxicity to these predators may be related to their feeding on foliage and not just contact with surface residues. Our laboratory results contradict suggestions of little impact of these systemic neonicotinoids on parasitoids or predators but field studies will be needed to better quantify the levels of such impacts under natural conditions. 相似文献
60.
Lyndsey M. Vivian Robert C. Godfree Matthew J. Colloff C. Ellery Mayence David J. Marshall 《Plant Ecology》2014,215(9):997-1011
An important characteristic of many wetland plants in semi-arid regions is their capacity to withstand fluctuations between extended dry phases and floods. However, anthropogenic river regulation can reduce natural flow variability in riverine wetlands, causing a decline in the frequency and duration of deep flooding as well as extended droughts, and an increase in shallow flooding and soil saturation. Our aim in this paper was to use an experimental approach to examine whether reductions in flooding and drought disadvantage species adapted to both these extremes, and favours those with water requirements that match the new regime of frequent low-level flooding. We compared the growth characteristics and biomass allocation of three native Australian aquatic macrophytes (Pseudoraphis spinescens, Juncus ingens and Typha domingensis), which co-occur at Barmah Forest, south-eastern Australia, under three water treatments: drought, soil saturation and deep flooding. The responses of species to the treatments largely reflected changes in their relative abundance at Barmah Forest since river regulation. Typha domingensis, which has remained uncommon, performed relatively poorly in all treatments, while J. ingens, which has increased its range, exhibited more vigorous growth under soil saturation. Pseudoraphis spinescens, which was once widespread but has declined markedly in its distribution, grew strongly under all water treatments. These findings suggest that a return to more natural, variable river flow regimes can potentially be an important conservation and restoration strategy in ecosystems characterised by species that have adaptations to extreme hydrological growing conditions. 相似文献