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941.
Valentina Gallo Evelin Schwarzer Stefan Rahlfs R. Heiner Schirmer Rob van Zwieten Dirk Roos Paolo Arese Katja Becker 《PloS one》2009,4(10)
In Plasmodium falciparum-infected red blood cells (RBCs), the flavoenzyme glutathione reductase (GR) regenerates reduced glutathione, which is essential for antioxidant defense. GR utilizes NADPH produced in the pentose phosphate shunt by glucose-6-phosphate dehydrogenase (G6PD). Thus, conditions affecting host G6PD or GR induce increased sensitivity to oxidants. Hereditary G6PD deficiency is frequent in malaria endemic areas and provides protection against severe malaria. Furthermore, GR deficiency resulting from insufficient saturation of the enzyme with its prosthetic group FAD is common. Based on these naturally occurring phenomena, GR of malaria parasites and their host cells represent attractive antimalarial drug targets. Recently we were given the opportunity to examine invasion, growth, and drug sensitivity of three P. falciparum strains (3D7, K1, and Palo Alto) in the RBCs from three homozygous individuals with total GR deficiency resulting from mutations in the apoprotein. Invasion or growth in the GR-deficient RBCs was not impaired for any of the parasite strains tested. Drug sensitivity to chloroquine, artemisinin, and methylene blue was comparable to parasites grown in GR-sufficient RBCs and sensitivity towards paraquat and sodium nitroprusside was only slightly enhanced. In contrast, membrane deposition of hemichromes as well as the opsonizing complement C3b fragments and phagocytosis were strongly increased in ring-infected RBCs of the GR-deficient individuals compared to ring-infected normal RBCs. Also, in one of the individuals, membrane-bound autologous IgGs were significantly enhanced. Thus, based on our in vitro data, GR deficiency and drug-induced GR inhibition may protect from malaria by inducing enhanced ring stage phagocytosis rather than by impairing parasite growth directly. 相似文献
942.
943.
Vera Kozjak-Pavlovic Elke A. Dian-Lothrop Michael Meinecke Oliver Kepp Katharina Ross Krishnaraj Rajalingam Anke Harsman Eva Hauf Volker Brinkmann Dirk Günther Ines Herrmann Robert Hurwitz Joachim Rassow Richard Wagner Thomas Rudel 《PLoS pathogens》2009,5(10)
The bacterial PorB porin, an ATP-binding β-barrel protein of pathogenic Neisseria gonorrhoeae, triggers host cell apoptosis by an unknown mechanism. PorB is targeted to and imported by host cell mitochondria, causing the breakdown of the mitochondrial membrane potential (ΔΨm). Here, we show that PorB induces the condensation of the mitochondrial matrix and the loss of cristae structures, sensitizing cells to the induction of apoptosis via signaling pathways activated by BH3-only proteins. PorB is imported into mitochondria through the general translocase TOM but, unexpectedly, is not recognized by the SAM sorting machinery, usually required for the assembly of β-barrel proteins in the mitochondrial outer membrane. PorB integrates into the mitochondrial inner membrane, leading to the breakdown of ΔΨm. The PorB channel is regulated by nucleotides and an isogenic PorB mutant defective in ATP-binding failed to induce ΔΨm loss and apoptosis, demonstrating that dissipation of ΔΨm is a requirement for cell death caused by neisserial infection. 相似文献
944.
Marieke Koopmans Dirk Martens Rene H. Wijffels 《Marine biotechnology (New York, N.Y.)》2010,12(3):340-349
To obtain more knowledge about carbon requirements for growth by sponges, the growth rate, respiration rate, and clearance
rate was measured in situ in Haliclona oculata. We found that only 34% of the particulate carbon pumped through the sponge was used for both respiration and growth. The
net growth efficiency, being the ratio of carbon incorporated in biomass and the total carbon used by the sponge for respiration
and growth, was found to be 0.099 ± 0.013. Thus, about 10% of the total used carbon was fixed in biomass, and over 90% was
used for generating energy for growth, maintenance, reproduction, and pumping. H. oculata had 2.5 μmol C available for every micromole O2 consumed. A value of 0.75 for respiratory quotient (RQ in micromole CO2 micromole O2−1) was used for H. oculata, which is the average value reported in literature for different marine invertebrates. Thus, carbon was available
in excess to meet the respiratory demand. Oxygen was found not to be the limiting factor for growth, since only 3.3% of the
oxygen pumped through the sponge body was used. Our results indicate that both oxygen and carbon availability are not limiting.
The low growth efficiency agrees with the low growth rates found for the species used in this study. 相似文献
945.
Naarmann IS Harnisch C Müller-Newen G Urlaub H Ostareck-Lederer A Ostareck DH 《RNA (New York, N.Y.)》2010,16(11):2189-2204
Erythroid precursor cells lose the capacity for mRNA synthesis due to exclusion of the nucleus during maturation. Therefore, the stability and translation of mRNAs that code for specific proteins, which function in late stages of maturation when reticulocytes become erythrocytes, are controlled tightly. Reticulocyte 15-lipoxygenase (r15-LOX) initiates the breakdown of mitochondria in mature reticulocytes. Through the temporal restriction of mRNA translation, the synthesis of r15-LOX is prevented in premature cells. The enzyme is synthesized only in mature reticulocytes, although r15-LOX mRNA is already present in erythroid precursor cells. Translation of r15-LOX mRNA is inhibited by hnRNP K and hnRNP E1, which bind to the differentiation control element (DICE) in its 3' untranslated region (3'UTR). The hnRNP K/E1-DICE complex interferes with the joining of the 60S ribosomal subunit to the 40S subunit at the AUG. We took advantage of the inducible human erythroid K562 cell system that fully recapitulates this process to identify so far unknown factors, which are critical for DICE-dependent translational regulation. Applying RNA chromatography with the DICE as bait combined with hnRNP K immunoprecipitation, we specifically purified the DEAD-box RNA helicase 6 (DDX6) that interacts with hnRNP K and hnRNP E1 in a DICE-dependent manner. Employing RNA interference and fluorescence in situ hybridization, we show that DDX6 colocalizes with endogenous human (h)r15-LOX mRNA to P-body-like RNP granules, from which 60S ribosomal subunits are excluded. Our data suggest that in premature erythroid cells translational silencing of hr15-LOX mRNA is maintained by DDX6 mediated storage in these RNP granules. 相似文献
946.
Dirk Repsilber Sabine Kern Anna Telaar Gerhard Walzl Gillian F Black Joachim Selbig Shreemanta K Parida Stefan HE Kaufmann Marc Jacobsen 《BMC bioinformatics》2010,11(1):27
Background
For heterogeneous tissues, such as blood, measurements of gene expression are confounded by relative proportions of cell types involved. Conclusions have to rely on estimation of gene expression signals for homogeneous cell populations, e.g. by applying micro-dissection, fluorescence activated cell sorting, or in-silico deconfounding. We studied feasibility and validity of a non-negative matrix decomposition algorithm using experimental gene expression data for blood and sorted cells from the same donor samples. Our objective was to optimize the algorithm regarding detection of differentially expressed genes and to enable its use for classification in the difficult scenario of reversely regulated genes. This would be of importance for the identification of candidate biomarkers in heterogeneous tissues. 相似文献947.
Jelley RA Elliott J Gibson KR Harrison T Beher D Clarke EE Lewis HD Shearman M Wrigley JD 《Bioorganic & medicinal chemistry letters》2006,16(14):3839-3842
Previously, chemistry effort on the gem-cyclohexane series of gamma-secretase inhibitors has focused on the 4-position of the cyclohexane ring. Recently chemistry has been directed towards the 3-position and substitution here has also provided compounds with high gamma-secretase activity. 相似文献
948.
Churcher I Beher D Best JD Castro JL Clarke EE Gentry A Harrison T Hitzel L Kay E Kerrad S Lewis HD Morentin-Gutierrez P Mortishire-Smith R Oakley PJ Reilly M Shaw DE Shearman MS Teall MR Williams S Wrigley JD 《Bioorganic & medicinal chemistry letters》2006,16(2):280-284
The protease gamma-secretase plays a pivotal role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease (AD). Here, we report a further extension to a series of cyclohexyl sulfone-based gamma-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Abeta(40) lowering in vivo (e.g., compound 32, MED 1mg/kg p.o. in APP-YAC mice). 相似文献
949.
Frederik A. R. Muylle Dirk Adriaensen Wim De Coen Jean-Pierre Timmermans Ronny Blust 《Biometals》2006,19(4):437-450
Intracellular zinc levels are homeostatically regulated and although most is bound, a pool of labile Zn(II) is present in
cells. We show here that the zinc probe FluoZin-3 is useful to monitor zinc fluxes during fluorescent imaging of the trout
hepatic cell line D11. Nuclei and bulk cytosol appeared to lack detectable labile zinc, while the punctuate staining pattern
colocalized with a lysosome-specific probe. Applying extracellular zinc alone resulted in vesicular sequestration of the metal
ion. Together with Na-pyrithione a delayed and toxic rise in cellular fluorescence was triggered. When using another ionophore,
4-Br A23187, a zinc buffering effect of the vesicular pools was evident. Secondly, N-ethylmaleimide induced a homogeneous fluorescence rise, which was strongly enhanced by addition of Zn-pyrithione and disappeared
after TPEN washing. This suggests the involvement of thiol residues in controlling available cytosolic zinc. Our observations
have implications for the interpretation of calculated intracellular Zn2+ concentrations. 相似文献
950.
The catalytic domain of a mosquitocidal toxin prolonged by a C-terminal 44 residue linker connecting to four ricin B-like domains was crystallized. Three crystal structures were established at resolutions between 2.5A and 3.0A using multi-wavelength and single-wavelength anomalous X-ray diffraction as well as molecular replacement phasing techniques. The chainfold of the toxin fragment corresponds to those of ADP-ribosylating enzymes. At pH 4.3 the fragment is associated in a C(7)-symmetric heptamer in agreement with an aggregate of similar size observed by size-exclusion chromatography. In two distinct crystal forms, the heptamers formed nearly spherical, D(7)-symmetric tetradecamers. Another crystal form obtained at pH 6.3 contained a recurring C(2)-symmetric tetramer, which, however, was not stable in solution. On the basis of the common chainfold and NAD(+)-binding site of all ADP-ribosyl transferases, the NAD(+)-binding site of the toxin was assigned at a high confidence level. In all three crystal forms the NAD(+) site was occupied by part of the 44 residue linker, explaining the known inhibitory effect of this polypeptide region. The structure showed that the cleavage site for toxin activation is in a highly mobile loop that is exposed in the monomer. Since it contains the inhibitory linker as a crucial part of the association contact, the observed heptamer is inactive. Moreover, the heptamer cannot be activated by proteolysis because the activation loop is at the ring center and not accessible for proteases. Therefore the heptamer, or possibly the tetradecamer, seems to represent an inactive storage form of the toxin. 相似文献