全文获取类型
收费全文 | 1598篇 |
免费 | 146篇 |
出版年
2023年 | 4篇 |
2022年 | 9篇 |
2021年 | 28篇 |
2020年 | 16篇 |
2019年 | 19篇 |
2018年 | 31篇 |
2017年 | 23篇 |
2016年 | 53篇 |
2015年 | 72篇 |
2014年 | 95篇 |
2013年 | 100篇 |
2012年 | 146篇 |
2011年 | 123篇 |
2010年 | 88篇 |
2009年 | 79篇 |
2008年 | 120篇 |
2007年 | 126篇 |
2006年 | 101篇 |
2005年 | 104篇 |
2004年 | 75篇 |
2003年 | 72篇 |
2002年 | 91篇 |
2001年 | 16篇 |
2000年 | 14篇 |
1999年 | 19篇 |
1998年 | 31篇 |
1997年 | 11篇 |
1996年 | 12篇 |
1995年 | 8篇 |
1994年 | 6篇 |
1993年 | 14篇 |
1992年 | 6篇 |
1991年 | 6篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1987年 | 3篇 |
1986年 | 4篇 |
1982年 | 2篇 |
1980年 | 1篇 |
1977年 | 1篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1971年 | 1篇 |
1969年 | 2篇 |
1968年 | 1篇 |
排序方式: 共有1744条查询结果,搜索用时 15 毫秒
991.
992.
Silke Fuchs William T. Garrood Anna Beber Andrew Hammond Roberto Galizi Matthew Gribble Giulia Morselli Tin-Yu J. Hui Katie Willis Nace Kranjc Austin Burt Andrea Crisanti Tony Nolan 《PLoS genetics》2021,17(10)
CRISPR-based homing gene drives can be designed to disrupt essential genes whilst biasing their own inheritance, leading to suppression of mosquito populations in the laboratory. This class of gene drives relies on CRISPR-Cas9 cleavage of a target sequence and copying (‘homing’) therein of the gene drive element from the homologous chromosome. However, target site mutations that are resistant to cleavage yet maintain the function of the essential gene are expected to be strongly selected for. Targeting functionally constrained regions where mutations are not easily tolerated should lower the probability of resistance. Evolutionary conservation at the sequence level is often a reliable indicator of functional constraint, though the actual level of underlying constraint between one conserved sequence and another can vary widely. Here we generated a novel adult lethal gene drive (ALGD) in the malaria vector Anopheles gambiae, targeting an ultra-conserved target site in a haplosufficient essential gene (AGAP029113) required during mosquito development, which fulfils many of the criteria for the target of a population suppression gene drive. We then designed a selection regime to experimentally assess the likelihood of generation and subsequent selection of gene drive resistant mutations at its target site. We simulated, in a caged population, a scenario where the gene drive was approaching fixation, where selection for resistance is expected to be strongest. Continuous sampling of the target locus revealed that a single, restorative, in-frame nucleotide substitution was selected. Our findings show that ultra-conservation alone need not be predictive of a site that is refractory to target site resistance. Our strategy to evaluate resistance in vivo could help to validate candidate gene drive targets for their resilience to resistance and help to improve predictions of the invasion dynamics of gene drives in field populations. 相似文献
993.
Suhling Frank Befeld Silke Häusler Matthias Katzur Katrin Lepkojus Sigrit Mesléard Francois 《Hydrobiologia》2000,431(1):69-79
The density of 23 macroinvertebrate species and the total macroinvertebrate biomass were compared between rice-fields treated with lindane and diazinon in June and alphamethine in August and untreated controls. The macroinvertebrates could be divided into four groups: (1) Taxa, in which the densities were lower in the insecticide treatment in July and August than in the non-insecticide treatment. (2) The Culicidae which occurred in the insecticide treatment in significantly lower density in July, but in significantly higher density in August. (3) Ischnura elegans (Vander L.) which was found in July after the lindane application in significantly higher numbers in the insecticide treatments, but in significantly lower numbers in the insecticide treatment in August after the application of the pyrethroid. In these three groups, we assumed that direct effects due to the insecticides toxicity were the reason for the differences in density. (4) The fourth group included three taxa in which the densities were significantly higher in the insecticide treatment in July and August than in the control. For this, indirect effects due to reduced biotic interactions may be responsible. The biomass was higher in the insecticide treatments in July, mainly because of a high increase in gastropod density, during the rest of the season it was similar between treatments and controls. 相似文献
994.
995.
996.
Annette V. Jacobsen Catia L. Pierotti Kym N. Lowes Amanda E. Au Ying Zhang Nima Etemadi Cheree Fitzgibbon Wilhelmus J. A. Kersten Andr L. Samson Mark F. van Delft David C. S. Huang Hlne Jousset Sabroux Guillaume Lessene John Silke James M. Murphy 《Cell death & disease》2022,13(4)
Necroptosis is a form of caspase-independent programmed cell death that arises from disruption of cell membranes by the mixed lineage kinase domain-like (MLKL) pseudokinase after its activation by the upstream kinases, receptor interacting protein kinase (RIPK)-1 and RIPK3, within a complex known as the necrosome. Dysregulated necroptosis has been implicated in numerous inflammatory pathologies. As such, new small molecule necroptosis inhibitors are of great interest, particularly ones that operate downstream of MLKL activation, where the pathway is less well defined. To better understand the mechanisms involved in necroptosis downstream of MLKL activation, and potentially uncover new targets for inhibition, we screened known kinase inhibitors against an activated mouse MLKL mutant, leading us to identify the lymphocyte-specific protein tyrosine kinase (Lck) inhibitor AMG-47a as an inhibitor of necroptosis. We show that AMG-47a interacts with both RIPK1 and RIPK3, that its ability to protect from cell death is dependent on the strength of the necroptotic stimulus, and that it blocks necroptosis most effectively in human cells. Moreover, in human cell lines, we demonstrate that AMG-47a can protect against cell death caused by forced dimerisation of MLKL truncation mutants in the absence of any upstream signalling, validating that it targets a process downstream of MLKL activation. Surprisingly, however, we also found that the cell death driven by activated MLKL in this model was completely dependent on the presence of RIPK1, and to a lesser extent RIPK3, although it was not affected by known inhibitors of these kinases. Together, these results suggest an additional role for RIPK1, or the necrosome, in mediating human necroptosis after MLKL is phosphorylated by RIPK3 and provide further insight into reported differences in the progression of necroptosis between mouse and human cells.Subject terms: Kinases, Necroptosis 相似文献
997.
Modelling complexation and electrostatic attraction in heavy metal biosorption by Sargassum biomass 总被引:5,自引:0,他引:5
Silke Schiewer 《Journal of applied phycology》1999,11(1):79-87
Biosorption, the passive accumulation of metal ions by biomass, can be used for purifying metal bearing wastewater. Seaweeds
represent a readily available source of biosorbent material that possesses a high metal binding capacity. For example, Sargassum
can accumulate 2 mequiv of Cd per gram of biomass i.e. 10% of its dry weight. Binding of Cd and Cu by Sargassum is an ion
exchange process involving both covalent and ionic bonds. The amount of cations bound covalently or by complexation can be
predicted using multi-component sorption isotherms involving 2 types of binding sites, carboxyl and sulphate. A Donnan model
was used to account for the effect of ionic strength and electrostatic attraction. The use of a multi-component isotherm that
included one term for Na binding was less appropriate than the Donnan model for modelling ionic strength effects. It was possible
to predict metal and proton binding as a function of the pH value, metal concentration and ionic strength of the solution.
This revised version was published online in June 2006 with corrections to the Cover Date. 相似文献
998.
A recombinant strain of Escherichia coli was used to produce poly(4-hydroxybutyric acid), P(4HB), homopolyester by fed-batch culture in M9 mineral salts medium containing glucose and 4-hydroxybutyric acid as carbon sources. The final cell dry weight, P(4HB) concentration and P(4HB) content were 12.6 g/l, 4.4 g/l, and 36% of cell dry weight, respectively, in a 27-l stirred and aerated fermenter after 60 h of fed-batch fermentation at constant pH. 相似文献
999.
Sequence Variations in Human Immunodeficiency Virus Type 1 Nef Are Associated with Different Stages of Disease 总被引:5,自引:0,他引:5
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Frank Kirchhoff Philippa J. Easterbrook Nigel Douglas Maxine Troop Thomas C. Greenough Jonathan Weber Silke Carl John L. Sullivan Rod S. Daniels 《Journal of virology》1999,73(7):5497-5508
nef alleles derived from a large number of individuals infected with human immunodeficiency virus type 1 (HIV-1) were analyzed to investigate the frequency of disrupted nef genes and to elucidate whether specific amino acid substitutions in Nef are associated with different stages of disease. We confirm that deletions or gross abnormalities in nef are rarely present. However, a comparison of Nef consensus sequences derived from 41 long-term nonprogressors and from 50 individuals with progressive HIV-1 infection revealed that specific variations are associated with different stages of infection. Five amino acid variations in Nef (T15, N51, H102, L170, and E182) were more frequently observed among nonprogressors, while nine features (an additional N-terminal PxxP motif, A15, R39, T51, T157, C163, N169, Q170, and M182) were more frequently found in progressors. Strong correlations between the frequency of these variations in Nef and both the CD4(+)-cell count and the viral load were observed. Moreover, analysis of sequential samples obtained from two progressors revealed that several variations in Nef, which were more commonly observed in patients with low CD4(+)-T-cell counts, were detected only during or after progression to immunodeficiency. Our results indicate that sequence variations in Nef are associated with different stages of HIV-1 infection and suggest a link between nef gene function and the immune status of the infected individual. 相似文献
1000.
Silke Heising Lothar Richter Wolfgang Ludwig B. Schink 《Archives of microbiology》1999,172(2):116-124
A green phototrophic bacterium was enriched with ferrous iron as sole electron donor and was isolated in defined coculture
with a spirilloid chemoheterotrophic bacterium. The coculture oxidized ferrous iron to ferric iron with stoichiometric formation
of cell mass from carbon dioxide. Sulfide, thiosulfate, or elemental sulfur was not used as electron donor in the light. Hydrogen
or acetate in the presence of ferrous iron increased the cell yield of the phototrophic partner, and hydrogen could also be
used as sole electron source. Complexed ferric iron was slowly reduced to ferrous iron in the dark, with hydrogen as electron
source. Similar to Chlorobium limicola, the phototrophic bacterium contained bacteriochlorophyll c and chlorobactene as photosynthetic pigments, and also resembled representatives of this species morphologically. On the
basis of 16S rRNA sequence comparisons, this organism clusters with Chlorobium, Prosthecochloris, and Pelodictyon species within the green sulfur bacteria phylum. Since the phototrophic partner in the coculture KoFox is only moderately
related to the other members of the cluster, it is proposed as a new species, Chlorobium ferrooxidans. The chemoheterotrophic partner bacterium, strain KoFum, was isolated in pure culture with fumarate as sole substrate. The
strain was identified as a member of the ɛ-subclass of the Proteobacteria closely related to “Geospirillum arsenophilum” on the basis of physiological properties and 16S rRNA sequence comparison. The “Geospirillum” strain was present in the coculture only in low numbers. It fermented fumarate, aspartate, malate, or pyruvate to acetate,
succinate, and carbon dioxide, and could reduce nitrate to dinitrogen gas. It was not involved in ferrous iron oxidation but
possibly provided a thus far unidentified growth factor to the phototrophic partner.
Received: 17 November 1998 / Accepted: 26 April 1999 相似文献