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261.
262.
van Montfort T Eggink D Boot M Tuen M Hioe CE Berkhout B Sanders RW 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(9):4676-4685
The natural function of dendritic cells (DCs) is to capture and degrade pathogens for Ag presentation. However, HIV-1 can evade viral degradation by DCs and hijack DCs for migration to susceptible CD4(+) T lymphocytes. It is unknown what factors decide whether a virus is degraded or transmitted to T cells. The interaction of DCs with HIV-1 involves C-type lectin receptors, such as DC-specific ICAM-3-grabbing nonintegrin, which bind to the envelope glycoprotein complex (Env), which is decorated heavily with N-linked glycans. We hypothesized that the saccharide composition of the Env N-glycans is involved in avoiding viral degradation and Ag presentation, as well as preserving infectious virus for the transmission to target cells. Therefore, we studied the fate of normally glycosylated virus versus oligomannose-enriched virus in DCs. Changing the heterogeneous N-linked glycan composition of Env to uniform oligomannose N-glycans increased the affinity of HIV-1 for DC-specific ICAM-3-grabbing nonintegrin and enhanced the capture of HIV-1 by immature DCs; however, it decreased the subsequent transmission to target cells. Oligomannose-enriched HIV-1 was directed more efficiently into the endocytic pathway, resulting in enhanced viral degradation and reduced virus transfer to target cells. Furthermore, Env containing exclusively oligomannose N-glycans was presented to Env-specific CD4(+) T cells more efficiently. Taken together, our results showed that the HIV-1 N-glycan composition plays a crucial role in the balance between DC-mediated Ag degradation and presentation and DC-mediated virus transmission to target cells. This finding may have implications for the early events in HIV-1 transmission and the induction of antiviral immune responses. 相似文献
263.
Nicolli Bellotti de Souza Isabel M de Andrade Paula F Carneiro Guilherme AM Jardim Isadora MM de Melo Eufranio N da Silva Júnior Antoniana Ursine Krettli 《Memórias do Instituto Oswaldo Cruz》2014,109(5):546-552
Due to the recent advances of atovaquone, a naphthoquinone, through clinical trials
as treatment for malarial infection, 19 quinone derivatives with previously reported
structures were also evaluated for blood schizonticide activity against the malaria
parasite Plasmodium falciparum. These compounds include 2-hydroxy-3-methylamino
naphthoquinones (2-9), lapachol (10), nor-lapachol (11), iso-lapachol (12), phthiocol
(13) and phenazines (12-20). Their cytotoxicities were also evaluated against human
hepatoma and normal monkey kidney cell lines. Compounds 2 and 5 showed the highest
activity against P. falciparum chloroquine-resistant blood-stage parasites (clone
W2), indicated by their low inhibitory concentration for 50% (IC50) of
parasite growth. The therapeutic potential of the active compounds was evaluated
according to the selectivity index, which is a ratio of the cytotoxicity minimum
lethal dose which eliminates 50% of cells and the in vitro IC50.
Naphthoquinones 2 and 5, with activities similar to the reference antimalarial
chloroquine, were also active against malaria in mice and suppressed parasitaemia by
more than 60% in contrast to compound 11 which was inactive. Based on their in vitro
and in vivo activities, compounds 2 and 5 are considered promising molecules for
antimalarial treatment and warrant further study. 相似文献
264.
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266.
Background
The type III secretion system (TTSS) is an important virulence determinant of Gram-negative bacterial pathogens. It enables the injection of effector proteins into the cytosol of eukaryotic cells. These effectors ultimately manipulate the cellular functions of the infected organism. Salmonella enterica serovar Typhimurium encodes two virulence associated TTSSs encoded by the Salmonella Pathogenicity Islands (SPI) 1 and 2 that are required for the intestinal and systemic phases of the infection, respectively. However, recent studies suggest that the roles of these TTSSs are not restricted to these compartments. The regulation of TTSSs in Salmonella is very complex with several regulators operating to activate or to repress expression depending on the environmental conditions. 相似文献267.
Stefan Legewie Jan Berkhout Thomas Maiwald Nikolai P Kaimachnikov Jens Timmer Jan B Hoek Boris N Kholodenko 《Molecular systems biology》2009,5(1)
Crosstalk mechanisms have not been studied as thoroughly as individual signaling pathways. We exploit experimental and computational approaches to reveal how a concordant interplay between the insulin and epidermal growth factor (EGF) signaling networks can potentiate mitogenic signaling. In HEK293 cells, insulin is a poor activator of the Ras/ERK (extracellular signal‐regulated kinase) cascade, yet it enhances ERK activation by low EGF doses. We find that major crosstalk mechanisms that amplify ERK signaling are localized upstream of Ras and at the Ras/Raf level. Computational modeling unveils how critical network nodes, the adaptor proteins GAB1 and insulin receptor substrate (IRS), Src kinase, and phosphatase SHP2, convert insulin‐induced increase in the phosphatidylinositol‐3,4,5‐triphosphate (PIP3) concentration into enhanced Ras/ERK activity. The model predicts and experiments confirm that insulin‐induced amplification of mitogenic signaling is abolished by disrupting PIP3‐mediated positive feedback via GAB1 and IRS. We demonstrate that GAB1 behaves as a non‐linear amplifier of mitogenic responses and insulin endows EGF signaling with robustness to GAB1 suppression. Our results show the feasibility of using computational models to identify key target combinations and predict complex cellular responses to a mixture of external cues. 相似文献
268.
Higher-primate phylogeny--why can't we decide? 总被引:2,自引:0,他引:2
At present, no definitive agreement on either the correct branching order
or differential rates of evolution among the higher primates exists,
despite the accumulated integration of decades of morphological,
immunological, protein and nucleic acid sequence data, and numerous
reasonable theoretical models for the analysis, interpretation, and
understanding of those data. Of the three distinct unrooted phylogenetic
trees, that joining human with chimpanzee and the gorilla with the
orangutan is currently favored, but the two alternatives that group humans
with either gorillas or the orangutan rather than with chimpanzees also
have support. This paper is a synthetic and critical review of the
methodological literature and isolates some 20 specific reasons why
uncertainty in the evolutionary understanding of our closest living
relatives persists. Many of the difficulties are eliminated or ameliorated
by Lake's new methods of phylogenetic invariants and operator metrics. In
the companion paper these new methods are used to analyze both the nuclear
and mitochondrial DNA of the higher primates.
相似文献
269.
The 5'-untranslated region (5'-UTR) is the most conserved part of the HIV-1 RNA genome, and it contains regulatory motifs that mediate various steps in the viral life cycle. Previous work showed that the 5'-terminal 290 nucleotides of HIV-1 RNA adopt two mutually exclusive secondary structures, long distance interaction (LDI) and branched multiple hairpin (BMH). BMH has multiple hairpins, including the dimer initiation signal (DIS) hairpin that mediates RNA dimerization. LDI contains a long distance base-pairing interaction that occludes the DIS region. Consequently, the two conformations differ in their ability to form RNA dimers. In this study, we have presented evidence that the full-length 5'-UTR also adopts the LDI and BMH conformations. The downstream 290-352 region, including the Gag start codon, folds differently in the context of the LDI and BMH structures. These nucleotides form an extended hairpin structure in the LDI conformation, but the same sequences create a novel long distance interaction with upstream U5 sequences in the BMH conformation. The presence of this U5-AUG duplex was confirmed by computer-assisted RNA structure prediction, biochemical analyses, and a phylogenetic survey of different virus isolates. The U5-AUG duplex may influence translation of the Gag protein because it occludes the start codon of the Gag open reading frame. 相似文献
270.