全文获取类型
收费全文 | 225篇 |
免费 | 9篇 |
出版年
2023年 | 2篇 |
2022年 | 5篇 |
2021年 | 7篇 |
2020年 | 3篇 |
2019年 | 3篇 |
2018年 | 5篇 |
2017年 | 4篇 |
2016年 | 5篇 |
2015年 | 8篇 |
2014年 | 10篇 |
2013年 | 20篇 |
2012年 | 17篇 |
2011年 | 13篇 |
2010年 | 13篇 |
2009年 | 6篇 |
2008年 | 9篇 |
2007年 | 13篇 |
2006年 | 13篇 |
2005年 | 11篇 |
2004年 | 8篇 |
2003年 | 12篇 |
2002年 | 6篇 |
2001年 | 1篇 |
1999年 | 1篇 |
1996年 | 5篇 |
1995年 | 3篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1992年 | 2篇 |
1990年 | 3篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1985年 | 1篇 |
1984年 | 3篇 |
1982年 | 3篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1976年 | 1篇 |
1975年 | 2篇 |
1974年 | 3篇 |
1970年 | 1篇 |
排序方式: 共有234条查询结果,搜索用时 31 毫秒
161.
162.
Chantal Le Bouguenec Thea Horaud Gilda Bieth R. Colimon C. Dauguet 《Molecular & general genetics : MGG》1984,194(3):377-387
Summary Wild-type strain A454 (Streptococcus pyogenes) transferred en bloc its erythromycin (Em) and tetracycline (Tc) resistance markers into several plasmid-free streptococcal recipients. No plasmid DNA was detected in either the wild-type or the transconjugant strains. Crosses were performed between A454 and S. faecalis Rec+ or Rec- recipients carrying hemolysin-bacteriocin plasmids, pIP964 or pAD1. The Em Tc-resistant transconjugants obtained harbored either the parental plasmid or an Em Tc resistance plasmid derived from pIP964 or pAD1. The restriction endonuclease analysis of 12 derivative plasmids showed insertions of various sizes into different fragments of pIP964 or pAD1. A454 and the Em Tc-resistant plasmid-free transconjugants were found to contain two EcoRI DNA fragments, that shared homology with 32P-labeled pIP1077, one of the Em Tc resistance derivative plasmids, but not with 32P-labeled pIP964. No homology was detected between pIP1077 and the cellular DNA of the antibiotic-susceptible recipients.Previously Thea Horodniceanu 相似文献
163.
164.
David Tyssen Scott A. Henderson Adam Johnson Jasminka Sterjovski Katie Moore Jennifer La Mark Zanin Secondo Sonza Peter Karellas Michael P. Giannis Guy Krippner Steve Wesselingh Tom McCarthy Paul R. Gorry Paul A. Ramsland Richard Cone Jeremy R. A. Paull Gareth R. Lewis Gilda Tachedjian 《PloS one》2010,5(8)
Background
Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published.Methods and Findings
Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations) and surface groups. Antiviral activity was determined in cell culture assays. Time-of-addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA) and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115) and fourth generation (SPL7013) DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina.Conclusions
Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is formulated as VivaGel® and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides. 相似文献165.
Nusco GA Chun JT Ercolano E Lim D Gragnaniello G Kyozuka K Santella L 《Biochemical and biophysical research communications》2006,348(1):109-114
Cofilin is a small protein that belongs to the family of actin-depolymerizing factors (ADF). The main cellular function of cofilin is to change cytoskeletal dynamics and thus to modulate cell motility and cytokinesis. We have recently demonstrated that the actin cytoskeleton is involved in the modulation of Ca(2+) signalling in starfish oocytes. To extend these observations, we have explored whether cofilin influences Ca(2+) signalling in the oocytes. Here we show that microinjection of the functionally active cofilin alters the Ca(2+) signalling mediated by the three major second messengers, InsP(3), NAADP, and cADPr. Cofilin intensifies the Ca(2+) signals induced by InsP(3) and NAADP, and delays those induced by cADPr. Furthermore, the injection of cofilin increases the Ca(2+) signals during hormone-induced oocyte maturation and fertilization. The results suggest that the dynamic regulation of F-actin by its binding proteins may play an important role in the modulation of intracellular Ca(2+) signalling. 相似文献
166.
Structure and Dynamics of a Benthic Invertebrate Community in an Intertidal Area of the Tagus Estuary, Western Portugal: A Six Year Data Series 总被引:1,自引:0,他引:1
Gilda Silva José Lino Costa Pedro Raposo de Almeida Maria José Costa 《Hydrobiologia》2006,572(1):115-128
A predictive model, incorporating macroinvertebrate and environmental data, similar to that developed for Australian rivers
(AUSRIVAS) and British rivers (RIVPACS) was constructed using a dataset collected from 23 reference (least altered) wetlands
on the Swan Coastal Plain, Western Australia, sampled in summer and spring, 1989 and spring, 1990. Four main groups of reference
wetlands were identified by UPGMA classification (using the Bray–Curtis dissimilarity measure). Distinguishing environmental
variables identified by Stepwise Multiple Discriminant Function Analysis were: calcium, colour (gilvin), latitude, longitude,
sodium and organic carbon. Observed to expected ratios of taxa with a >50% chance of occurrence (OE50) derived from the model
for a suite of 23 test wetlands sampled in spring, 1997, were significantly correlated with pH and the depth of the sampling
sites. Greater discrimination between the test wetlands was provided by the OE50 ratios than either raw richness (number of
families) or a biotic index (SWAMPS). Results obtained for a subset of 11 test wetlands sampled with both a rapid bioassessment
protocol (incorporating field picking of 200 invertebrates collected in 2 min sweeps from selected habitats) and a semi-quantitative
protocol (incorporating laboratory picking of all invertebrates collected in sweeps along 10 m transects at randomly allocated
sites) were not significantly different, indicating that the former could be used to reduce the time and costs associated
with macroinvertebrate-based wetland monitoring programs. In addition to providing an objective method of assessing wetland
condition, predictive modelling provides a list of taxa expected to occur under reference conditions, which can be used as
a target in wetland restoration programs. The probable impediment to widespread adoption of predictive modelling for wetland
bioassessment is the need to produce models tailored to specific geographic regions and specific climatic conditions. This
may incur significant costs in countries, such as Australia, which span a wide range of climatic zones. 相似文献
167.
168.
Abstract The 11.6-megadalton (MDa) plasmid pIP955, encoding resistance to macrolides and related drugs and chloramphenicol, harbored by Streptococcus pyogenes strain A449, transferred only by filter mating and only into Streptococcus sanguis strain Challis recipient. This transfer was completely inhibited by low concentrations of deoxyribonuclease I and occurred even if the donor strain had been killed. 相似文献
169.
Sara Sigismund Veronica Algisi Gilda Nappo Alexia Conte Roberta Pascolutti Alessandro Cuomo Tiziana Bonaldi Lisette G G C Verhoef Elena Maspero Fabrizio Bianchi Andrea Ciliberto Simona Polo Pier Paolo Di Fiore 《The EMBO journal》2013,32(15):2140-2157
How the cell converts graded signals into threshold‐activated responses is a question of great biological relevance. Here, we uncover a nonlinear modality of epidermal growth factor receptor (EGFR)‐activated signal transduction, by demonstrating that the ubiquitination of the EGFR at the PM is threshold controlled. The ubiquitination threshold is mechanistically determined by the cooperative recruitment of the E3 ligase Cbl, in complex with Grb2, to the EGFR. This, in turn, is dependent on the simultaneous presence of two phosphotyrosines, pY1045 and either one of pY1068 or pY1086, on the same EGFR moiety. The dose–response curve of EGFR ubiquitination correlate precisely with the non‐clathrin endocytosis (NCE) mode of EGFR internalization. Finally, EGFR‐NCE mechanistically depends on EGFR ubiquitination, as the two events can be simultaneously re‐engineered on a phosphorylation/ubiquitination‐incompetent EGFR backbone. Since NCE controls the degradation of the EGFR, our findings have implications for how the cell responds to increasing levels of EGFR signalling, by varying the balance of receptor signalling and degradation/attenuation. 相似文献
170.
Henriques ST Huang YH Rosengren KJ Franquelim HG Carvalho FA Johnson A Sonza S Tachedjian G Castanho MA Daly NL Craik DJ 《The Journal of biological chemistry》2011,286(27):24231-24241
Cyclotides, a large family of cyclic peptides from plants, have a broad range of biological activities, including insecticidal, cytotoxic, and anti-HIV activities. In all of these activities, cell membranes seem likely to be the primary target for cyclotides. However, the mechanistic role of lipid membranes in the activity of cyclotides remains unclear. To determine the role of lipid organization in the activity of the prototypic cyclotide, kalata B1 (kB1), and synthetic analogs, their bioactivities and affinities for model membranes were evaluated. We found that the bioactivity of kB1 is dependent on the lipid composition of target cell membranes. In particular, the activity of kB1 requires specific interactions with phospholipids containing phosphatidylethanolamine (PE) headgroups but is further modulated by nonspecific peptide-lipid hydrophobic interactions, which are favored in raft-like membranes. Negatively charged phospholipids do not favor high kB1 affinity. This lipid selectivity explains trends in antimicrobial and hemolytic activities of kB1; it does not target bacterial cell walls, which are negatively charged and lacking PE-phospholipids but can insert in the membranes of red blood cells, which have a low PE content and raft domains in their outer layer. We further show that the anti-HIV activity of kB1 is the result of its ability to target and disrupt the membranes of HIV particles, which are raft-like membranes very rich in PE-phospholipids. 相似文献