全文获取类型
收费全文 | 1068篇 |
免费 | 54篇 |
出版年
2023年 | 6篇 |
2022年 | 14篇 |
2021年 | 28篇 |
2020年 | 24篇 |
2019年 | 11篇 |
2018年 | 20篇 |
2017年 | 18篇 |
2016年 | 43篇 |
2015年 | 60篇 |
2014年 | 57篇 |
2013年 | 61篇 |
2012年 | 102篇 |
2011年 | 86篇 |
2010年 | 68篇 |
2009年 | 42篇 |
2008年 | 55篇 |
2007年 | 64篇 |
2006年 | 49篇 |
2005年 | 44篇 |
2004年 | 40篇 |
2003年 | 35篇 |
2002年 | 28篇 |
2001年 | 15篇 |
2000年 | 11篇 |
1999年 | 9篇 |
1998年 | 12篇 |
1997年 | 8篇 |
1996年 | 12篇 |
1995年 | 8篇 |
1994年 | 7篇 |
1993年 | 11篇 |
1992年 | 16篇 |
1991年 | 5篇 |
1990年 | 3篇 |
1989年 | 3篇 |
1988年 | 6篇 |
1987年 | 6篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1979年 | 3篇 |
1977年 | 1篇 |
1976年 | 5篇 |
1975年 | 4篇 |
1973年 | 2篇 |
1972年 | 1篇 |
1971年 | 2篇 |
1970年 | 2篇 |
排序方式: 共有1122条查询结果,搜索用时 38 毫秒
301.
Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition 总被引:2,自引:0,他引:2
Ronis MJ Butura A Sampey BP Shankar K Prior RL Korourian S Albano E Ingelman-Sundberg M Petersen DR Badger TM 《Free radical biology & medicine》2005,39(5):619-630
The effects of the dietary antioxidant N-acetylcysteine (NAC) on alcoholic liver damage were examined in a total enteral nutrition (TEN) model of ethanol toxicity in which liver pathology occurs in the absence of endotoxemia. Ethanol treatment resulted in steatosis, inflammatory infiltrates, occasional foci of necrosis, and elevated ALT in the absence of increased expression of the endotoxin receptor CD 14, a marker of Kupffer cell activation by LPS. In addition, ethanol treatment induced CYP 2 E1 and increased TNFalpha and TGFbeta mRNA expression accompanied by suppressed hepatic IL-4 mRNA expression. Ethanol treatment also resulted in the hepatic accumulation of malondialdehyde (MDA) and hydroxynonenal (HNE) protein adducts, decreased antioxidant capacity, and increased antibody titers toward serum hydroxyethyl radical (HER), MDA, and HNE adducts. NAC treatment increased cytosolic antioxidant capacity, abolished ethanol-induced lipid peroxidation, and inhibited the formation of antibodies toward HNE and HER adducts without interfering with CYP 2 E1 induction. NAC also decreased ethanol-induced ALT release and inflammation and prevented significant loss of hepatic GSH content. However, the improvement in necrosis score and reduction of TNFalpha mRNA elevation did not reach statistical significance. Although a direct correlation was observed among hepatic MDA and HNE adduct content and TNFalpha mRNA expression, inflammation, and necrosis scores, no correlation was observed between oxidative stress markers or TNFalpha and steatosis score. These data suggest that ethanol-induced oxidative stress can contribute to inflammation and liver injury even in the absence of Kupffer cell activation by endotoxemia. 相似文献
302.
Venkatraman S Lim J Cramer M Gardner MF James J Alves K Lingham RB Mumford RA Munoz B 《Bioorganic & medicinal chemistry letters》2005,15(18):4053-4056
A series of VLA-4 antagonist were synthesized wherein carboxylic acid was replaced by various acid surrogates. The effect of these acid surrogates toward potency was evaluated in a binding assay. A number of acid surrogates were potent antagonist of VLA-4, albeit significantly less potent than the corresponding carboxylic acid. Heterocyclic acid surrogate, oxadiazolidinone 3, demonstrated an improved pharmacokinetic property when dosed intravenously. 相似文献
303.
Thompson CR Iyer SS Melrose N VanOosten R Johnson K Pitson SM Obeid LM Kusner DJ 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(6):3551-3561
Mycobacterium tuberculosis (M.tb) is a leading cause of global infectious mortality. The pathogenesis of tuberculosis involves inhibition of phagosome maturation, leading to survival of M.tb within human macrophages. A key determinant is M.tb-induced inhibition of macrophage sphingosine kinase (SK) activity, which normally induces Ca2+ signaling and phagosome maturation. Our objective was to determine the spatial localization of SK during phagocytosis and its inhibition by M.tb. Stimulation of SK activity by killed M.tb, live Staphylococcus aureus, or latex beads was associated with translocation of cytosolic SK1 to the phagosome membrane. In contrast, SK1 did not associate with phagosomes containing live M.tb. To characterize the mechanism of phagosomal translocation, live cell confocal microscopy was used to compare the localization of wild-type SK1, catalytically inactive SK1G82D, and a phosphorylation-defective mutant that does not undergo plasma membrane translocation (SK1S225A). The magnitude and kinetics of translocation of SK1G82D and SK1S225A to latex bead phagosomes were indistinguishable from those of wild-type SK1, indicating that novel determinants regulate the association of SK1 with nascent phagosomes. These data are consistent with a model in which M.tb inhibits both the activation and phagosomal translocation of SK1 to block the localized Ca2+ transients required for phagosome maturation. 相似文献
304.
Background
Ventricular tachycardia (VT) and ventricular fibrillation (VF) are ventricular cardiac arrhythmia that could be catastrophic and life threatening. Correct and timely detection of VT or VF can save lives. 相似文献305.
Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis
van der Helm-van Mil AH Verpoort KN Breedveld FC Toes RE Huizinga TW 《Arthritis research & therapy》2005,7(5):R949-R958
Antibodies to citrullinated proteins (anti-cyclic-citrullinated peptide [anti-CCP] antibodies) are highly specific for rheumatoid
arthritis (RA) and precede the onset of disease symptoms, indicating a pathogenetic role for these antibodies in RA. We recently
showed that distinct genetic risk factors are associated with either anti-CCP-positive disease or anti-CCP-negative disease.
These data are important as they indicate that distinct pathogenic mechanisms are underlying anti-CCP-positive disease or
anti-CCP-negative disease. Likewise, these observations raise the question of whether anti-CCP-positive RA and anti-CCP-negative
RA are clinically different disease entities. We therefore investigated whether RA patients with anti-CCP antibodies have
a different clinical presentation and disease course compared with patients without these autoantibodies. In a cohort of 454
incident patients with RA, 228 patients were anti-CCP-positive and 226 patients were anti-CCP-negative. The early symptoms,
tender and swollen joint count, and C-reactive protein level at inclusion, as well as the swollen joint count and radiological
destruction during 4 years of follow-up, were compared for the two groups. There were no differences in morning stiffness,
type, location and distribution of early symptoms, patients' rated disease activity and C-reactive protein at inclusion between
RA patients with and without anti-CCP antibodies. The mean tender and swollen joint count for the different joints at inclusion
was similar. At follow-up, patients with anti-CCP antibodies had more swollen joints and more severe radiological destruction.
Nevertheless, the distribution of affected joints, for swelling, bone erosions and joint space narrowing, was similar. In
conclusion, the phenotype of RA patients with or without anti-CCP antibodies is similar with respect to clinical presentation
but differs with respect to disease course. 相似文献
306.
MOTIVATION: Currently available methods for the prediction of subcellular location of mitochondrial proteins rely largely on the presence of mitochondrial targeting signals in the protein sequences. However, a large fraction of mitochondrial proteins lack such signals, making those tools ineffective for genome-scale prediction of mitochondria-targeted proteins. Here, we propose a method for genome-scale prediction of nucleus-encoded mitochondrial proteins. The new method, MITOPRED, is based on the Pfam domain occurrence patterns and the amino acid compositional differences between mitochondrial and non-mitochondrial proteins. RESULTS: MITOPRED could predict mitochondrial proteins with 100% specificity at a 44% sensitivity rate and with 67% specificity at 99% sensitivity. Additionally, it was sufficiently robust to predict mitochondrial proteins across different eukaryotic species with similar accuracy. Based on Matthews correlation coefficient measure, the prediction performance of MITOPRED is clearly superior (0.73) to those of the two popular methods TargetP (0.51) and PSORT (0.53). Using this method, we predicted the nucleus-encoded mitochondrial proteins from six complete genomes (three invertebrate, two vertebrate and one plant species) and estimated the total number in each genome. In human, our method estimated the existence of 1362 mitochondrial proteins corresponding to 4.8% of the total proteome. AVAILABILITY: MITOPRED program is freely accessible at http://mitopred.sdsc.edu. Source code is available on request from the authors. SUPPLEMENTARY INFORMATION: Training data sets are also available at http://mitopred.sdsc.edu 相似文献
307.
Shankar VN Propp AE Schroeder N Surber BW Makin HL Jones G 《Archives of biochemistry and biophysics》2001,387(2):297-306
The active vitamin D analog, 19-nor-1alpha,25-dihydroxyvitamin D2 (19-nor-1alpha,25-(OH)2D2), has a similar structure to the natural vitamin D hormone, 1a,25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3), but lacks the C10-19 methylene group and possesses an ergosterol/ vitamin D2 rather than a cholesterol/vitamin D3 side chain. We have used this analog to investigate whether any of these structural features has any effect upon the type and rate of in vitro metabolism observed. Using a vitamin D-target cell, the human keratinocyte, HPK1A-ras, we observed formation of a number of metabolites, three of which were purified by extensive HPLC and conclusively identified by a combination of GC-MS and chemical derivatization as 19-nor-1alpha,24,25-(OH) 3D2, 19-nor-1alpha,24,25,26-(OH) 4D2, and 19-nor-1alpha,24,25,28-(OH)4,D2. The first metabolite is probably a product of the vitamin D-inducible cytochrome P450, P450cc24 (CYP24), while the latter two metabolites are likely to be further metabolic products of 19-nor-1alpha,24,25-(OH)3D2. These hydroxylated metabolites resemble those identified by other workers as products of the metabolism of 1alpha,25-(OH)2D2 in the perfused rat kidney. It therefore appears from the similar metabolic fate of 19-nor-1alpha,25-(OH)2D2 and 1alpha,25-(OH)2D2 that the lack of the C10-19 methylene group has little effect upon the nature of the lipid-soluble metabolic products and the rate of formation of these products seems to be comparable to that of products of 1alpha,25-(OH)2D3 in vitamin D-target cells. We also found extensive metabolism of 19-nor-1alpha,25(OH)2D2 to water-soluble metabolites in HPK1A-ras, metabolites which remain unidentified at this time. When we incubated 19-nor-1alpha,25-(OH)2D2 with the liver cell line HepG2, we obtained only 19-nor-1alpha,24,25-(OH)3D2. We conclude that 19-nor-1alpha,25-(OH)2D2 is efficiently metabolized by both vitamin D-target cells and liver cells. 相似文献
308.
Sensitivity of duckweed (Lemna major) to ultraviolet-B radiation 总被引:2,自引:0,他引:2
Farooq M Suresh Babu G Ray RS Misra RB Shankar U Hans RK 《Biochemical and biophysical research communications》2000,276(3):970-973
The sensitivity of an important aquatic macrophyte, duckweed (Lemna major), to UV-B radiation was studied under experimental conditions at three different doses designated as no, mild, and severe injury dose by observing visible injury symptoms and estimating levels of chlorophyll, pheophytin, carotenoids, protein, starch, free sugar, and peroxidase activity. Laboratory-grown duckweed plants were exposed to UV-B radiation at 0.4 mW/cm(2) intensity for different time periods. Mild and severe injury were developed at 6.48 and 8.64 J, respectively. Peroxidase activity increased at all the exposure levels. Dose-dependent decrease in chlorophyll and starch with drastic depletion in protein and free sugar content were observed. Pheophytin and carotenoids content increased at no injury level, but decreased at higher exposure level. The results indicate that ambient UV-B radiation at the indicated level acts as a physiological stress in Lemna major. 相似文献
309.
Ellsworth M. Campbell Anthony Boyles Anupama Shankar Jay Kim Sergey Knyazev Roxana Cintron William M. Switzer 《PLoS computational biology》2021,17(9)
Outbreak investigations use data from interviews, healthcare providers, laboratories and surveillance systems. However, integrated use of data from multiple sources requires a patchwork of software that present challenges in usability, interoperability, confidentiality, and cost. Rapid integration, visualization and analysis of data from multiple sources can guide effective public health interventions. We developed MicrobeTrace to facilitate rapid public health responses by overcoming barriers to data integration and exploration in molecular epidemiology. MicrobeTrace is a web-based, client-side, JavaScript application (https://microbetrace.cdc.gov) that runs in Chromium-based browsers and remains fully operational without an internet connection. Using publicly available data, we demonstrate the analysis of viral genetic distance networks and introduce a novel approach to minimum spanning trees that simplifies results. We also illustrate the potential utility of MicrobeTrace in support of contact tracing by analyzing and displaying data from an outbreak of SARS-CoV-2 in South Korea in early 2020. MicrobeTrace is developed and actively maintained by the Centers for Disease Control and Prevention. Users can email vog.cdc@ecarteborcim for support. The source code is available at https://github.com/cdcgov/microbetrace. 相似文献
310.
Mariya Chavarha Hamed Khoojinian Leonard E. Schulwitz Jr. Samares C. Biswas Shankar B. Rananavare 《Biophysical journal》2010,98(8):1549-1557
The hydrophobic surfactant proteins SP-B and SP-C promote rapid adsorption of pulmonary surfactant to an air/water interface. Previous evidence suggests that they achieve this effect by facilitating the formation of a rate-limiting negatively curved stalk between the vesicular bilayer and the interface. To determine whether the proteins can alter the curvature of lipid leaflets, we used x-ray diffraction to investigate how the physiological mixture of these proteins affects structures formed by 1-palmitoyl-2-oleoyl phosphatidylethanolamine, which by itself undergoes the lamellar-to-inverse hexagonal phase transition at 71°C. In amounts as low as 0.03% (w:w) and at temperatures as low as 57°C, the proteins induce formation of bicontinuous inverse cubic phases. The proteins produce a dose-related shift of diffracted intensity to the cubic phases, with minimal evidence of other structures above 0.1% and 62°C, but no change in the lattice-constants of the lamellar or cubic phases. The induction of the bicontinuous cubic phases, in which the individual lipid leaflets have the same saddle-shaped curvature as the hypothetical stalk-intermediate, supports the proposed model of how the surfactant proteins promote adsorption. 相似文献