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231.
The activation of seven-transmembrane receptors (7TMRs) allows cells to sense their environment and convert extracellular signals (like hormone binding) into intracellular signals (through G protein-coupled and/or β arrestin-coupled pathways). A single 7TMR is capable of transducing a wide spectrum of physiological responses inside a cell by coupling to these pathways. This intracellular pleiotropic action is enabled by multiple conformations exhibited by these receptors. Developments in membrane protein structure determination technologies have led to a rapid increase in crystal structures for many 7TMRs. Majority of these receptors have been crystallized in their inactive conformation and, for some, one of the many active conformations has also been crystallized. Given the topological constraints of a lipid bilayer that results in a single fold of seven almost parallel TM helices connected by mostly unstructured loops, these structures exhibit a diversity of conformations not only across the receptors but also across the different functional forms for receptors with structures for one of the functionally active conformations. Here we present a method to characterize this conformational diversity in terms of transmembrane helix topology (TMHTOP) parameters and how to use these helix orientation parameters to predict functionally-distinct multiple conformations for these receptors. The TMHTOP parameters enable a quantification of the structural changes that underlie 7TMR activation and also sheds a unique mechanistic light on the pleiotropic nature of these receptors. It provides a common language to describe the 7TMR activation mechanisms as well as differences across many receptors in terms of visually intuitive structural parameters. Protein structure prediction methods can use these parameters to describe 7TMR conformational ensembles, which coupled to experimental data can be used to develop testable hypotheses for the structural basis of 7TMR functions. 相似文献
232.
Kausch KD Sobolev AP Goyal RK Fatima T Laila-Beevi R Saftner RA Handa AK Mattoo AK 《Amino acids》2012,42(2-3):843-856
Exogenous treatment with jasmonates (JA) has been shown to reduce the levels of polyamines in many plants. But the role of endogenous JA on polyamine biosynthesis or other cellular metabolites has thus far remained uninvestigated. We developed transgenic tomato (Solanum lycopersicum L.) having severely reduced methyl JA levels by silencing a fruit ripening-associated lipoxygenase (LOX), SlLoxB, using a truncated LOX gene under the control of the constitutive CaMV35S promoter. The LOX suppressed and MeJA-deficient fruits had lowered polyamine levels. Thus, these transgenic fruits were used as a plant model to evaluate the effects of reduced endogenous MeJA on cellular metabolites in ripening tomato fruits using NMR spectroscopy. During on-shelf ripening, transgenic fruits were significantly reduced in the content of 19 out of 30 metabolites examined, including Ile, Val, Ala, Thr, Asn Tyr, Glu, Gln, His, Phe, Trp, GABA, citrate, succinate, myo-inositol, unidentified compound B, nucleic acid compound Nucl1, choline, and trigonelline as compared to the wild-type azygous counterparts. A significant increase in β-glucose levels in transgenic fruits was observed at the pink stage. The transgenic fruits were equivalent to the wild type in lycopene level and chlorophyll degradation rates. Taken together, these results show that intracellular MeJA significantly regulates overall primary metabolism, especially aminome (amino acids and polyamines) of ripening fruits. 相似文献
233.
Florentinus AK Bowden P Sardana G Diamandis EP Marshall JG 《Journal of Proteomics》2012,75(4):1303-1317
The proteins secreted by prostate cancer cells (PC3(AR)6) were separated by strong anion exchange chromatography, digested with trypsin and analyzed by unbiased liquid chromatography tandem mass spectrometry with an ion trap. The spectra were matched to peptides within proteins using a goodness of fit algorithm that showed a low false positive rate. The parent ions for MS/MS were randomly and independently sampled from a log-normal population and therefore could be analyzed by ANOVA. Normal distribution analysis confirmed that the parent and fragment ion intensity distributions were sampled over 99.9% of their range that was above the background noise. Arranging the ion intensity data with the identified peptide and protein sequences in structured query language (SQL) permitted the quantification of ion intensity across treatments, proteins and peptides. The intensity of 101,905 fragment ions from 1421 peptide precursors of 583 peptides from 233 proteins separated over 11 sample treatments were computed together in one ANOVA model using the statistical analysis system (SAS) prior to Tukey-Kramer honestly significant difference (HSD) testing. Thus complex mixtures of proteins were identified and quantified with a high degree of confidence using an ion trap without isotopic labels, multivariate analysis or comparing chromatographic retention times. 相似文献
234.
We examined the effect of Pb(2+) (8 and 40?mg?l(-1)) on reactive oxygen species generation and alterations in antioxidant enzymes in hydroponically grown wheat at 24, 72, and 120?h after exposure. Pb(2+) toxicity was more pronounced on root growth, and it correlated with the greater Pb accumulation in roots. Pb exposure (40?mg?l(-1)) enhanced superoxide anion, H(2)O(2), and MDA content in wheat roots by 1.9- to 2.2-folds, 56-255%, and 41-90%, respectively, over the control. Pb-induced loss of membrane integrity was confirmed by the enhanced electrolyte leakage and in vivo histochemical localization. Activities of scavenging enzymes, superoxide dismutases and catalases, enhanced in Pb-treated wheat roots by 1.4- to 5.7-folds over that in the control. In contrast, the activities of ascorbate and guaiacol peroxidases and glutathione reductases decreased significantly, suggesting their non-involvement in detoxification process. The study concludes that Pb(2+)-induced oxidative damage in wheat roots involve greater H(2)O(2) accumulation and the deactivation of the related scavenging enzymes. 相似文献
235.
Kaur S Singh HP Batish DR Negi A Mahajan P Rana S Kohli RK 《Biological trace element research》2012,146(3):360-368
The present study investigated the effect of Arsenic (As; 5, 10, 50 μM) on protein and sugar metabolism vis-à-vis oxidative
damage during early germination process and radicle emergence (at 12, 24 and 48 h stage) in Phaseolus aureus. As-exposure (50 μM) significantly enhanced protein content (by 40–60%), whereas carbohydrate content declined (by 31–44%)
over that in the control. It was associated with a decline in the activities of proteases (47–53%), and increase in the activities
of α- and β-amylases, starch phosphorylases, and acid invertases by 3.0, 2.6, 4.8, and 1.7 times after 48 h exposure to 50 μM
As. The alteration in protein and carbohydrate metabolic machinery was also accompanied by As-induced reactive oxygen species
(ROS)-mediated oxidative damage. As treatment enhanced malondialdehyde and hydrogen peroxide content by 46–252% and 23–216%,
and hydroxyl and superoxide ion generation by 15–104% and 17–278%, respectively. As-induced lipid peroxidation and membrane
disruption was confirmed by enhanced electrolyte leakage (by 49%) and reduced cell viability (by 43%). Furthermore, in response
to 50 μM As, the activities of superoxide dismutases, catalases, ascorbate peroxidases, guaiacol peroxidases, and glutathione
reductases increased by 77%, 70%, 116%, 43% and 120%, respectively, in radicles at 48 h stage over that in the control. The
study concludes that As inhibits radicle emergence and elongation in germinating P. aureus seeds by altering biochemical processes related to sugar metabolism and inducing an ROS-mediated oxidative damage. 相似文献
236.
Annaba F Sarwar Z Gill RK Ghosh A Saksena S Borthakur A Hecht GA Dudeja PK Alrefai WA 《American journal of physiology. Gastrointestinal and liver physiology》2012,302(10):G1216-G1222
Apical sodium-dependent bile acid transporter (ASBT) is responsible for the absorption of bile acids from the intestine. A decrease in ASBT function and expression has been implicated in diarrhea associated with intestinal inflammation. Whether infection with pathogenic microorganisms such as the enteropathogenic Escherichia coli (EPEC) affect ASBT activity is not known. EPEC is a food-borne enteric pathogen that translocates bacterial effector molecules via type three secretion system (TTSS) into host cells and is a major cause of infantile diarrhea. We investigated the effects of EPEC infection on ileal ASBT function utilizing human intestinal Caco2 cells and HEK-293 cells stably transfected with ASBT-V5 fusion protein (2BT cells). ASBT activity was significantly inhibited following 60 min infection with EPEC but not with nonpathogenic E. coli. Mutations in bacterial escN, espA, espB, and espD, the genes encoding for the elements of bacterial TTSS, ablated EPEC inhibitory effect on ASBT function. Furthermore, mutation in the bacterial BFP gene encoding for bundle-forming pili abrogated the inhibition of ASBT by EPEC, indicating the essential role for bacterial aggregation and the early attachment. The inhibition by EPEC was associated with a significant decrease in the V(max) of the transporter and a reduction in the level of ASBT on the plasma membrane. The inhibition of ASBT by EPEC was blocked in the presence of protein tyrosine phosphatase inhibitors. Our studies provide novel evidence for the alterations in the activity of ASBT by EPEC infection and suggest a possible effect for EPEC in influencing intestinal bile acid homeostasis. 相似文献
237.
Ali MA Ismail R Choon TS Elumalai M Kumar S Osman H Govidasamy J Yadav R Yadav G Kour R Vyas S 《Journal of enzyme inhibition and medicinal chemistry》2012,27(1):155-159
A series of 6,7-dimethoxy-3-(4-pyridyl)-2,3,3a,4-tetrahydroindeno[1,2-c]pyrazol-2-yl-4-substituted phenylmethanone/ethanone derivatives were synthesized and in vitro activity against mycobacterium tuberculosis (MTB) and INHR-MTB were carried out. Among the synthesized compounds, compound (4h) 6,7-dimethoxy-3-(4-pyridyl)-2,3,3a,4-tetrahydroindeno[1,2-c]pyrazol-2-yl-4-pyridyl methanone was found to be the most active agent against MTB and INHR-MTB with a minimum inhibitory concentration of 0.22 μM. 相似文献
238.
The effects of electromagnetic field (EMF) exposure on biological systems have been studied for many years, both as a source of medical therapy and also for potential health risks. In particular, the mechanisms of EMF absorption in the human or animal body is of medical/engineering interest, and modern modelling techniques, such as the Finite Difference Time Domain (FDTD), can be utilized to simulate the voltages and currents induced in different parts of the body. The simulation of one particular component, the spinal cord, is the focus of this article, and this study is motivated by the fact that the spinal cord can be modelled as a linear conducting structure, capable of generating a significant amount of voltage from incident EMF. In this article, we show, through a FDTD simulation analysis of an incoming electromagnetic field (EMF), that the spinal cord acts as a natural antenna, with frequency dependent induced electric voltage and current distribution. The multi-frequency (100-2400?MHz) simulation results show that peak voltage and current response is observed in the FM radio range around 100?MHz, with significant strength to potentially cause changes in the CNS. This work can contribute to the understanding of the mechanism behind EMF energy leakage into the CNS, and the possible contribution of the latter energy leakage towards the weakening of the blood brain barrier (BBB), whose degradation is associated with the progress of many diseases, including Acquired Immuno-Deficiency Syndrome (AIDS). 相似文献
239.
240.
We previously identified Bud23 as the methyltransferase that methylates G1575 of rRNA in the P-site of the small (40S) ribosomal subunit. In this paper, we show that Bud23 requires the methyltransferase adaptor protein Trm112 for stability in vivo. Deletion of Trm112 results in a bud23Δ-like mutant phenotype. Thus Trm112 is required for efficient small-subunit biogenesis. Genetic analysis suggests the slow growth of a trm112Δ mutant is due primarily to the loss of Bud23. Surprisingly, suppression of the bud23Δ-dependent 40S defect revealed a large (60S) biogenesis defect in a trm112Δ mutant. Using sucrose gradient sedimentation analysis and coimmunoprecipitation, we show that Trm112 is also involved in 60S subunit biogenesis. The 60S defect may be dependent on Nop2 and Rcm1, two additional Trm112 interactors that we identify. Our work extends the known range of Trm112 function from modification of tRNAs and translation factors to both ribosomal subunits, showing that its effects span all aspects of the translation machinery. Although Trm112 is required for Bud23 stability, our results suggest that Trm112 is not maintained in a stable complex with Bud23. We suggest that Trm112 stabilizes its free methyltransferase partners not engaged with substrate and/or helps to deliver its methyltransferase partners to their substrates. 相似文献