全文获取类型
收费全文 | 278篇 |
免费 | 71篇 |
专业分类
349篇 |
出版年
2023年 | 2篇 |
2022年 | 5篇 |
2021年 | 3篇 |
2020年 | 5篇 |
2019年 | 6篇 |
2018年 | 4篇 |
2017年 | 6篇 |
2016年 | 8篇 |
2015年 | 6篇 |
2014年 | 14篇 |
2013年 | 8篇 |
2012年 | 16篇 |
2011年 | 9篇 |
2010年 | 11篇 |
2009年 | 11篇 |
2008年 | 17篇 |
2007年 | 11篇 |
2006年 | 11篇 |
2005年 | 18篇 |
2004年 | 16篇 |
2003年 | 15篇 |
2002年 | 8篇 |
2001年 | 10篇 |
2000年 | 10篇 |
1999年 | 13篇 |
1998年 | 10篇 |
1997年 | 5篇 |
1996年 | 4篇 |
1995年 | 9篇 |
1994年 | 3篇 |
1993年 | 4篇 |
1992年 | 11篇 |
1991年 | 9篇 |
1990年 | 10篇 |
1989年 | 7篇 |
1988年 | 6篇 |
1987年 | 4篇 |
1986年 | 3篇 |
1983年 | 7篇 |
1982年 | 5篇 |
1981年 | 1篇 |
1978年 | 1篇 |
1970年 | 1篇 |
1968年 | 1篇 |
1962年 | 1篇 |
1959年 | 1篇 |
1957年 | 2篇 |
1905年 | 1篇 |
排序方式: 共有349条查询结果,搜索用时 15 毫秒
61.
62.
63.
64.
IKKgamma/NEMO is a protein that is critical for the assembly of the high molecular weight IkappaB kinase (IKK) complex. To investigate the role of IKKgamma/NEMO in the assembly of the IKK complex, we conducted a series of experiments in which the chromatographic distribution of extracts prepared from cells transiently expressing epitope-tagged IKKgamma/NEMO and the IKKs were examined. When expressed alone following transfection, IKKalpha and IKKbeta were present in low molecular weight complexes migrating between 200 and 400 kDa. However, when coexpressed with IKKgamma/NEMO, both IKKalpha and IKKbeta migrated at approximately 600 kDa which was similar to the previously described IKK complex that is activated by cytokines such as tumor necrosis factor-alpha. When either IKKalpha or IKKbeta was expressed alone with IKKgamma/NEMO, IKKbeta but not IKKalpha migrated in the higher molecular weight IKK complex. Constitutively active or inactive forms of IKKbeta were both incorporated into the high molecular weight IKK complex in the presence of IKKgamma/NEMO. The amino-terminal region of IKKgamma/NEMO, which interacts directly with IKKbeta, was required for formation of the high molecular weight IKK complex and for stimulation of IKKbeta kinase activity. These results suggest that recruitment of the IKKs into a high molecular complex by IKKgamma/NEMO is a crucial step involved in IKK function. 相似文献
65.
Clutton-Brock TH Brotherton PN O'Riain MJ Griffin AS Gaynor D Sharpe L Kansky R Manser MB McIlrath GM 《Proceedings. Biological sciences / The Royal Society》2000,267(1440):301-305
Evolutionary explanations of cooperative breeding based on kin selection have predicted that the individual contributions made by different helpers to rearing young should be correlated with their degree of kinship to the litter or brood they are raising. In the cooperative mongoose or meerkat, Suricata suricatta, helpers babysit pups at the natal burrow for the first month of pup life and frequent babysitters suffer substantial weight losses over the period of babysitting. Large differences in contributions exist between helpers, which are correlated with their age, sex and weight but not with their kinship to the young they are raising. Provision of food to some group members raises the contributions of individuals to babysitting. We discuss the implications of these results for evolutionary explanations of cooperative behaviour. 相似文献
66.
67.
COPI-independent Anterograde Transport: Cargo-selective ER to Golgi Protein Transport in Yeast COPI Mutants 总被引:28,自引:1,他引:28 下载免费PDF全文
The coatomer (COPI) complex mediates Golgi to ER recycling of membrane proteins containing a dilysine retrieval motif. However, COPI was initially characterized as an anterograde-acting coat complex. To investigate the direct and primary role(s) of COPI in ER/Golgi transport and in the secretory pathway in general, we used PCR-based mutagenesis to generate new temperature-conditional mutant alleles of one COPI gene in Saccharomyces cerevisiae, SEC21 (γ-COP). Unexpectedly, all of the new sec21 ts mutants exhibited striking, cargo-selective ER to Golgi transport defects. In these mutants, several proteins (i.e., CPY and α-factor) were completely blocked in the ER at nonpermissive temperature; however, other proteins (i.e., invertase and HSP150) in these and other COPI mutants were secreted normally. Nearly identical cargo-specific ER to Golgi transport defects were also induced by Brefeldin A. In contrast, all proteins tested required COPII (ER to Golgi coat complex), Sec18p (NSF), and Sec22p (v-SNARE) for ER to Golgi transport. Together, these data suggest that COPI plays a critical but indirect role in anterograde transport, perhaps by directing retrieval of transport factors required for packaging of certain cargo into ER to Golgi COPII vesicles. Interestingly, CPY–invertase hybrid proteins, like invertase but unlike CPY, escaped the sec21 ts mutant ER block, suggesting that packaging into COPII vesicles may be mediated by cis-acting sorting determinants in the cargo proteins themselves. These hybrid proteins were efficiently targeted to the vacuole, indicating that COPI is also not directly required for regulated Golgi to vacuole transport. Additionally, the sec21 mutants exhibited early Golgi-specific glycosylation defects and structural aberrations in early but not late Golgi compartments at nonpermissive temperature. Together, these studies demonstrate that although COPI plays an important and most likely direct role both in Golgi–ER retrieval and in maintenance/function of the cis-Golgi, COPI does not appear to be directly required for anterograde transport through the secretory pathway. 相似文献
68.
White Nicholas J Ashley Elizabeth A Recht Judith Delves Michael J Ruecker Andrea Smithuis Frank M Eziefula Alice C Bousema Teun Drakeley Chris Chotivanich Kesinee Imwong Mallika Pukrittayakamee Sasithon Prachumsri Jetsumon Chu Cindy Andolina Chiara Bancone Germana Hien Tran T Mayxay Mayfong Taylor Walter RJ von Seidlein Lorenz Price Ric N Barnes Karen I Djimdé Abdoulaye ter Kuile Feiko Gosling Roly Chen Ingrid Dhorda Mehul J Stepniewska Kasia Guérin Philippe Woodrow Charles J Dondorp Arjen M Day Nicholas PJ Nosten Francois H 《Malaria journal》2014,13(1):1-14
Background
Effective mating between laboratory-reared males and wild females is paramount to the success of vector control strategies aiming to decrease disease transmission via the release of sterile or genetically modified male mosquitoes. However mosquito colonization and laboratory maintenance have the potential to negatively affect male genotypic and phenotypic quality through inbreeding and selection, which in turn can decrease male mating competitiveness in the field. To date, very little is known about the impact of those evolutionary forces on the reproductive biology of mosquito colonies and how they ultimately affect male reproductive fitness.Methods
Here several male reproductive physiological traits likely to be affected by inbreeding and selection following colonization and laboratory rearing were examined. Sperm length, and accessory gland and testes size were compared in male progeny from field-collected females and laboratory strains of Anopheles gambiae sensu stricto colonized from one to over 25 years ago. These traits were also compared in the parental and sequentially derived, genetically modified strains produced using a two-phase genetic transformation system. Finally, genetic crosses were performed between strains in order to distinguish the effects of inbreeding and selection on reproductive traits.Results
Sperm length was found to steadily decrease with the age of mosquito colonies but was recovered in refreshed strains and crosses between inbred strains therefore incriminating inbreeding costs. In contrast, testes size progressively increased with colony age, whilst accessory gland size quickly decreased in males from colonies of all ages. The lack of heterosis in response to crossing and strain refreshing in the latter two reproductive traits suggests selection for insectary conditions.Conclusions
These results show that inbreeding and selection differentially affect reproductive traits in laboratory strains overtime and that heterotic ‘supermales’ could be used to rescue some male reproductive characteristics. Further experiments are needed to establish the exact relationship between sperm length, accessory gland and testes size, and male reproductive success in the laboratory and field settings. 相似文献69.
70.
Reuben Ha Emilisa Frirdich David Sychantha Jacob Biboy Michael E. Taveirne Jeremiah G. Johnson Victor J. DiRita Waldemar Vollmer Anthony J. Clarke Erin C. Gaynor 《The Journal of biological chemistry》2016,291(43):22686-22702
Campylobacter jejuni is a leading cause of bacterial gastroenteritis in the developed world. Despite its prevalence, its mechanisms of pathogenesis are poorly understood. Peptidoglycan (PG) is important for helical shape, colonization, and host-pathogen interactions in C. jejuni. Therefore, changes in PG greatly impact the physiology of this organism. O-acetylation of peptidoglycan (OAP) is a bacterial phenomenon proposed to be important for proper cell growth, characterized by acetylation of the C6 hydroxyl group of N-acetylmuramic acid in the PG glycan backbone. The OAP gene cluster consists of a PG O-acetyltransferase A (patA) for translocation of acetate into the periplasm, a PG O-acetyltransferase B (patB) for O-acetylation, and an O-acetylpeptidoglycan esterase (ape1) for de-O-acetylation. In this study, reduced OAP in ΔpatA and ΔpatB had minimal impact on C. jejuni growth and fitness under the conditions tested. However, accumulation of OAP in Δape1 resulted in marked differences in PG biochemistry, including O-acetylation, anhydromuropeptide levels, and changes not expected to result directly from Ape1 activity. This suggests that OAP may be a form of substrate level regulation in PG biosynthesis. Ape1 acetylesterase activity was confirmed in vitro using p-nitrophenyl acetate and O-acetylated PG as substrates. In addition, Δape1 exhibited defects in pathogenesis-associated phenotypes, including cell shape, motility, biofilm formation, cell surface hydrophobicity, and sodium deoxycholate sensitivity. Δape1 was also impaired for chick colonization and adhesion, invasion, intracellular survival, and induction of IL-8 production in INT407 cells in vitro. The importance of Ape1 in C. jejuni biology makes it a good candidate as an antimicrobial target. 相似文献