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961.
Jeonghyeon Park Keumhan Noh Hae Won Lee Mi-sun Lim Sook Jin Seong Jeong Ju Seo Eun-Jung Kim Wonku Kang Young-Ran Yoon 《PloS one》2013,8(4)
Drug-induced torsades de pointes (TdP), a life-threatening arrhythmia associated with prolongation of the QT interval, has been a significant reason for withdrawal of several medicines from the market. Prolongation of the QT interval is considered as the best biomarker for predicting the torsadogenic risk of a new chemical entity. Because of the difficulty assessing the risk for TdP during drug development, we evaluated the metabolic phenotype for predicting QT prolongation induced by sparfloxacin, and elucidated the metabolic pathway related to the QT prolongation. We performed electrocardiography analysis and liquid chromatography–mass spectroscopy-based metabolic profiling of plasma samples obtained from 15 guinea pigs after administration of sparfloxacin at doses of 33.3, 100, and 300 mg/kg. Principal component analysis and partial least squares modelling were conducted to select the metabolites that substantially contributed to the prediction of QT prolongation. QTc increased significantly with increasing dose (r = 0.93). From the PLS analysis, the key metabolites that showed the highest variable importance in the projection values (>1.5) were selected, identified, and used to determine the metabolic network. In particular, cytidine-5′-diphosphate (CDP), deoxycorticosterone, L-aspartic acid and stearic acid were found to be final metabolomic phenotypes for the prediction of QT prolongation. Metabolomic phenotypes for predicting drug-induced QT prolongation of sparfloxacin were developed and can be applied to cardiac toxicity screening of other drugs. In addition, this integrative pharmacometabolomic approach would serve as a good tool for predicting pharmacodynamic or toxicological effects caused by changes in dose. 相似文献
962.
Farina A Shin JH Kim DH Bermudez VP Kelman Z Seo YS Hurwitz J 《The Journal of biological chemistry》2008,283(30):20925-20936
Human ChlR1 (hChlR1), a member of the DEAD/DEAH subfamily of helicases, was shown to interact with components of the cohesin complex and play a role in sister chromatid cohesion. In order to study the biochemical and biological properties of hChlR1, we purified the protein from 293 cells and demonstrated that hChlR1 possesses DNA-dependent ATPase and helicase activities. This helicase translocates on single-stranded DNA in the 5' to 3' direction in the presence of ATP and, to a lesser extent, dATP. Its unwinding activity requires a 5'-singlestranded region for helicase loading, since flush-ended duplex structures do not support unwinding. The helicase activity of hChlR1 is capable of displacing duplex regions up to 100 bp, which can be extended to 500 bp by RPA or the cohesion establishment factor, the Ctf18-RFC (replication factor C) complex. We show that hChlR1 interacts with the hCtf18-RFC complex, human proliferating cell nuclear antigen, and hFen1. The interactions between Fen1 and hChlR1 stimulate the flap endonuclease activity of Fen1. Selective depletion of either hChlR1 or Fen1 by targeted small interfering RNA treatment results in the precocious separation of sister chromatids. These findings are consistent with a role of hChlR1 in the establishment of sister chromatid cohesion and suggest that its action may contribute to lagging strand processing events important in cohesion. 相似文献
963.
This report describes the optimization of culture conditions for coenzyme Q10 (CoQ10) production by Agrobacterium
tumefaciens KCCM 10413, an identified high-CoQ10-producing strain (Kim et al., Korean patent. 10-0458818, 2002b). Among the conditions tested, the pH and the dissolved oxygen (DO) levels were the key factors affecting CoQ10 production. When the pH and DO levels were controlled at 7.0 and 0–10%, respectively, a dry cell weight (DCW) of 48.4 g l−1 and a CoQ10 production of 320 mg l−1 were obtained after 96 h of batch culture, corresponding to a specific CoQ10 content of 6.61 mg g-DCW−1. In a fed-batch culture of sucrose, the DCW, specific CoQ10 content, and CoQ10 production increased to 53.6 g l−1, 8.54 mg g-DCW−1, and 458 mg l−1, respectively. CoQ10 production was scaled up from a laboratory scale (5-l fermentor) to a pilot scale (300 l) and a plant scale (5,000 l) using
the impeller tip velocity (V
tip) as a scale-up parameter. CoQ10 production at the laboratory scale was similar to those at the pilot and plant scales. This is the first report of pilot-
and plant-scale productions of CoQ10 in A. tumefaciens. 相似文献
964.
Ha SJ Kim SY Seo JH Moon HJ Lee KM Lee JK 《Applied microbiology and biotechnology》2007,76(1):109-116
The production yield of Coenzyme Q10 (CoQ10) from the sucrose consumed by Agrobacterium tumefaciens KCCM 10413 decreased, and high levels of exopolysaccharide (EPS) accumulated after switching from batch culture to fed-batch
culture. Therefore, we examined the effect of sucrose concentration on the fermentation profile by A. tumefaciens. In the continuous fed-batch culture with the sucrose concentration maintained constantly at 10, 20, 30, and 40 g l−1, the dry cell weight (DCW), specific CoQ10 content, CoQ10 production, and the production yield of CoQ10 from the sucrose consumed increased, whereas EPS production decreased as maintained sucrose concentration decreased. The
pH-stat fed-batch culture system was adapted for CoQ10 production to minimize the concentration of the carbon source and osmotic stress from sucrose. Using the pH-stat fed-batch
culture system, the DCW, specific CoQ10 content, CoQ10 production, and the product yield of CoQ10 from the sucrose consumed increased by 22.6, 13.7, 39.3, and 39.3%, respectively, whereas EPS production decreased by 30.7%
compared to those of fed-batch culture in the previous report (Ha SJ, Kim SY, Seo JH, Oh DK, Lee JK, Appl Microbiol Biotechnol,
74:974–980, 2007). The pH-stat fed-batch culture system was scaled up to a pilot scale (300 l), and the CoQ10 production results obtained (626.5 mg l−1 of CoQ10 and 9.25 mg g DCW−1 of specific CoQ10 content) were similar to those obtained at the laboratory scale. Thus, an efficient and highly competitive process for microbial
CoQ10 production is available. 相似文献
965.
Seo Young Kang Gi Jeong Cheon Maria Lee Hee Seung Kim Jae-Weon Kim Noh-Hyun Park Yong Sang Song Hyun Hoon Chung 《Translational oncology》2017,10(2):178-183
PURPOSE: To investigate the prognostic value of preoperative intratumoral 18F-FDG uptake heterogeneity (IFH) derived from positron emission tomography (PET)/computed tomography (CT) in patients with endometrioid endometrial cancer. METHODS: We retrospectively evaluated clinicopathological data from patients with pathologically proven endometrioid endometrial cancer who had undergone 18F-FDG PET/CT scans before surgery. Patients were divided into two groups according to their IFH. The main outcome measure was disease-free survival (DFS). RESULTS: Between January 2010 and January 2015, data from 72 patients were available for analysis. The median duration of DFS was 23 months (range, 6 to 57 months), and 4 (5.6%) patients experienced recurrence. There were significant differences in tumor size, IFH, and DFS between patients with and without recurrence. In regression analysis, high IFH value [P = .007, hazard ratio (HR) 2.545, 95% confidence interval (CI) 1.468-8.674] was the only independent risk factor for recurrence. The Kaplan-Meier survival graphs showed that DFS significantly differed in groups categorized based on IFH (P < .001, log-rank test). CONCLUSIONS: Preoperative IFH measured by 18F-FDG PET/CT was associated with recurrence of endometrioid endometrial cancer. The finding supports evidence that FDG-based heterogeneity can be a novel and useful predictor of endometrioid endometrial cancer recurrence. 相似文献
966.
967.
Insulin-like growth factor-I (IGF-I) plays important roles in survival of neurons. Caveolae, cholesterol-rich microdomains of plasma membrane, act as platforms for some neurotrophic factors. In this study, we examined a possible role of caveolae in IGF-I signal transduction in pheochromocytoma PC12 cells. IGF-I treatment attenuated serum withdrawal-induced apoptosis, which was reversed by treatment with methyl-beta-cyclodextrin (CD) that removes cholesterol from plasma membrane. Immunocytochemical and subcellular fractionation analyses revealed that IGF-I receptor (IGF-IR) was colocalized with caveolin-1, a major protein component in caveolae, and that CD treatment reduced IGF-IR contents in caveolae. Consistent with these findings, IGF-I phosphorylation of insulin receptor substrate-1 and Akt was impaired, and cholesterol supply restored the IGF-I action. Furthermore, experiments using small interfering RNA revealed that the reduction of caveolin-1 expression impaired the IGF-I action. In addition, the colocalization of IGF-IR with caveolin-1, and the caveolae-dependent IGF-I action were duplicated in primary culture of rat cerebellar granule neurons. These results demonstrate that the presence of IGF-IR in caveolae is required for the neuroprotective action of IGF-I. 相似文献
968.
969.
Young Seok Ju Dongwan Hong Sheehyun Kim Sung-Soo Park Sujung Kim Seungbok Lee Hansoo Park Jong-Il Kim Jeong-Sun Seo 《Nucleic acids research》2010,38(20):e190
Comparative genomic hybridization (CGH) microarrays have been used to determine copy number variations (CNVs) and their effects on complex diseases. Detection of absolute CNVs independent of genomic variants of an arbitrary reference sample has been a critical issue in CGH array experiments. Whole genome analysis using massively parallel sequencing with multiple ultra-high resolution CGH arrays provides an opportunity to catalog highly accurate genomic variants of the reference DNA (NA10851). Using information on variants, we developed a new method, the CGH array reference-free algorithm (CARA), which can determine reference-unbiased absolute CNVs from any CGH array platform. The algorithm enables the removal and rescue of false positive and false negative CNVs, respectively, which appear due to the effects of genomic variants of the reference sample in raw CGH array experiments. We found that the CARA remarkably enhanced the accuracy of CGH array in determining absolute CNVs. Our method thus provides a new approach to interpret CGH array data for personalized medicine. 相似文献
970.
Jenny Chan Haruka Yamazaki Noboru Ishiyama Min-Duk Seo Tapas K. Mal Takayuki Michikawa Katsuhiko Mikoshiba Mitsuhiko Ikura 《The Journal of biological chemistry》2010,285(46):36092-36099
The three isoforms of the inositol 1,4,5-trisphosphate receptor (IP3R) exhibit distinct IP3 sensitivities and cooperativities in calcium (Ca2+) channel function. The determinants underlying this isoform-specific channel gating mechanism have been localized to the N-terminal suppressor region of IP3R. We determined the 1.9 Å crystal structure of the suppressor domain from type 3 IP3R (IP3R3SUP, amino acids 1–224) and revealed structural features contributing to isoform-specific functionality of IP3R by comparing it with our previously determined structure of the type 1 suppressor domain (IP3R1SUP). The molecular surface known to associate with the ligand binding domain (amino acids 224–604) showed marked differences between IP3R3SUP and IP3R1SUP. Our NMR and biochemical studies showed that three spatially clustered residues (Glu-20, Tyr-167, and Ser-217 in IP3R1 and Glu-19, Trp-168, and Ser-218 in IP3R3) within the N-terminal suppressor domains of IP3R1SUP and IP3R3SUP interact directly with their respective C-terminal fragments. Together with the accompanying paper (Yamazaki, H., Chan, J., Ikura, M., Michikawa, T., and Mikoshiba, K. (2010) J. Biol. Chem. 285, 36081–36091), we demonstrate that the single aromatic residue in this region (Tyr-167 in IP3R1 and Trp-168 in IP3R3) plays a critical role in the coupling between ligand binding and channel gating. 相似文献