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91.
Kwon YE Park JY No KT Shin JH Lee SK Eun JS Yang JH Shin TY Kim DK Chae BS Leem JY Kim KH 《Bioorganic & medicinal chemistry》2007,15(20):6596-6607
With the goal of developing Alzheimer's disease therapeutics, we have designed and synthesized new piperidine derivatives having dual action of acetylcholinesterase (AChE) and beta-amyloid peptide (Abeta) aggregation inhibition. For binding with the catalytic site of AChE, an ester with aromatic group was designed, and for the peripheral site, another aromatic group was considered. And for intercalating amyloid-beta oligomerization, long and linear conformation with a lipophilic group was considered. The synthetic methods employed for the structure with dual action depended on alcohols with an aromatic ring and the substituted benzoic acids, which are esterificated in the last step of the synthetic pathway. We screened these new derivatives through inhibition tests of acetylcholinesterase, butyrylcholinesterase (BChE), and Abeta(1-42) peptide aggregation, AChE-induced Abeta(1-42) aggregation. Our results displayed that compound 12 showed the best inhibitory potency and selectivity of AChE, and 29 showed the highest selectivity of BChE inhibition. Compounds 15 and 12 had inhibitory activities against Abeta(1-42) aggregation and AChE-induced Abeta aggregation. In the docking model, we confirmed that 4-chlorobenzene of 12 plays the parallel pi-pi stacking against the indole ring of Trp84 in the bottom gorge of AChE. Because the benzyhydryl moiety of 12 covered the peripheral site of AChE in a funnel-like shape, 12 showed good inhibitory potency against AChE and could inhibit AChE-induced Abeta(1-42) peptide aggregation. 相似文献
92.
Choi SH Chae A Chen CH Merki E Shaw PX Tsimikas S 《Current opinion in biotechnology》2007,18(1):73-82
The diagnosis of vulnerable plaques, which have the propensity to develop atherothrombosis, remains an elusive goal in clinical medicine. The most accepted features of vulnerable plaques, such as a large lipid core, increased inflammatory milieu and thin fibrous caps, have been well characterized through pathological studies. The ability to image a vulnerable plaque in susceptible patients would theoretically result in useful prognostic information that can be used to either monitor or treat patients at risk more aggressively. Several invasive techniques, such as integrated backscatter, virtual histology, palpography, optical coherence tomography and thermal heterogeneity, have been validated ex vivo and are now being evaluated in clinical studies. Non-invasive techniques, such as nuclear imaging, show promise in identifying increased metabolic activity and characteristic features of vulnerable plaques in patients. Natural history and intervention studies will need to be performed to determine whether identifying and treating vulnerable plaques will lead to improved clinical outcomes. 相似文献
93.
Kang NS Ahn JH Kim SS Chae CH Yoo SE 《Bioorganic & medicinal chemistry letters》2007,17(13):3716-3721
In order to obtain information regarding the design of selective DPP4 inhibitors, a 3D-QSAR study was conducted using DPP4, DPP8, and DPP9 inhibitors including newly synthesized six- and seven-membered cyclic hydrazine derivatives (KR64300, KR64301), which were evaluated in vitro for their inhibition of DPP4, DPP8, and DPP9. In this study, a highly predictive CoMFA model based on the fast-docking for DPP4, DPP8, and DPP9 inhibitors was obtained. This reliable model showed leave-one-out cross-validation q(2) and conventional r(2) values of 0.68 and 0.96 for the DPP4 inhibitors, 0.58 and 0.98 for the DPP8 inhibitors, and 0.68 and 0.97 for the DPP9 inhibitors, respectively. The validation of the CoMFA model was confirmed by the compounds in the test set, including the synthesized six- and seven-membered cyclic hydrazines. According to this study, to obtain selective DPP4 inhibitors compared to their isozymes, the interaction of the inhibitors with the S3 site and S1' site in DPP4 must be considered. The proposed newly synthesized compounds, KR64300 and KR64301, interact well with the sites mentioned above, showing excellent selectivity. 相似文献
94.
An endonuclease from Xanthomonas oryzae pathovar oryzae KACC 10331, XorII, was recombinantly produced in Escherichia coli using a T7 system. XorII was purified using a combination of ion exchange and immobilized metal affinity chromatography (IMAC). An optimized washing protocol was carried out on an IMAC in order to obtain a high purity product. The final amount of purified XorII was approximately 2.5 mg/L of LB medium. The purified recombinant XorII was functional and showed the same cleavage pattern as PvuI. The enzyme activity tested the highest at 25 degrees in 50 mM NaCl, 10 mM Tris-HCl, 10 mM MgCl2, and 1 mM dithiothreitol at a pH of 7.9. 相似文献
95.
Alzheimer's disease is a neurodegenerative disorder associated with progressive loss of cognitive function and memory. Amyloid beta peptide (Abeta) is the major component of senile plaques and is known to exert its cytotoxic effect mainly by producing H2O2. Vascular endothelial growth factor (VEGF) is elevated in the cerebrospinal fluid (CSF) and brain of AD patients, and H2O2 is one of the factors that induce VEGF. Therefore, we tested whether Abeta might be responsible for the increased VEGF synthesis. We found that Abeta induced the production of H2O2 in vitro. Comparison of the amount of H2O2 required to induce VEGF synthesis in HN33 cells and the amount of H2O2 produced by 10 muM Abeta1-42 in vitro suggested that a toxic concentration of Abeta might induce VEGF synthesis in these cells. However, toxic concentrations of Abeta failed to induce VEGF synthesis in several cell systems. They also had no effect on antioxidant enzymes such as glutathione peroxidase, catalase, and peroxiredoxin in HN33 cells. Cu2+, Zn2+ and Fe3+ are known to accumulate in the brains of AD patients and promote aggregation of Abeta, and Cu2+ by itself induces synthesis of VEGF. However, there was no synergistic effect between Cu2+ and Abeta1-42 in the induction of VEGF synthesis and Zn2+ and Fe3+ also had no effect on the synthesis of VEGF, alone or in combination with Abeta. 相似文献
96.
97.
Min BW Cho YN Song MJ Noh TK Kim BK Chae WK Park YS Choi YD Harn CH 《Plant cell reports》2007,26(3):337-344
A mannose selection system was adapted for use in the Agrobacterium-mediated transformation of Chinese cabbage. This system makes use of the pmi gene that encodes phosphomannose isomerase, which converts mannose-6-phosphate to fructose-6-phosphate. Hypocotyl explants
from 4–5-day-old seedlings of Chinese cabbage inbred lines were pre-cultured for 2–3 days and then infected with Agrobacterium. Two genes (l-guluno-γ-lactone oxidase, GLOase, and jasmonic methyl transferase, JMT) were transformed into Chinese cabbage using the transformation procedure developed in this study. We found that supplementing
the media with 7 g l−1 mannose and 2% sucrose provides the necessary conditions for the selection of transformed plants from nontransformed plants.
The transformation rates were 1.4% for GLOase and 3.0% for JMT, respectively. The Southern blot analysis revealed that several independent transformants (T
0) were obtained from each transgene. Three different inbred lines were transformed, and most of the T
1 plants had normal phenotypes. The transformation method presented here for Chinese cabbage using mannose selection is efficient
and reproducible, and it can be useful to introduce a desirable gene(s) into commercially useful inbred lines of Chinese cabbage. 相似文献
98.
Epidemiological studies suggest that elevated plasma fibrinogen levels are associated with an increased risk of cardiovascular disorders. Normal fibrinogen level is in the range of 1.5-4.5mg/mL, depending upon both genetic (intrinsic) and environmental (extrinsic) factors. An increase of 0.25mg/mL from the normal level can often be correlated with a high risk of cardiovascular disease. Thus, it is useful to monitor fibrinogen level in serum of a patient for clinical diagnosis. We report a regenerative biosensor that measures real-time fibrinogen levels in undiluted serum. The biosensor uses Surface Plasmon Resonance (SPR), highly sensitive optical technique. The biosensor does not use bio-receptors (i.e., antibodies, enzymes, DNA, etc.) unlike conventional biosensors, and deploys the nature of competitive adsorption of proteins to achieve selective detection of fibrinogen. We measured fibrinogen-spiked serum samples with a concentration of 1.5-4.5 mg/mL, and repeated six measurement trials to obtain statistical distribution of the measurements using the regeneration method of the sensing surface. The SPR biosensor has a sensitivity of 42 mDeg/(mg/mL) for a fibrinogen concentration in the range of 0.5-2.5 mg/mL, whereas it was hard to correlate the measurements to the spiked-fibrinogen samples of above 2.5 mg/mL. 相似文献
99.
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