全文获取类型
收费全文 | 5419篇 |
免费 | 387篇 |
国内免费 | 4篇 |
出版年
2023年 | 18篇 |
2021年 | 80篇 |
2020年 | 64篇 |
2019年 | 71篇 |
2018年 | 110篇 |
2017年 | 92篇 |
2016年 | 101篇 |
2015年 | 164篇 |
2014年 | 229篇 |
2013年 | 348篇 |
2012年 | 355篇 |
2011年 | 387篇 |
2010年 | 241篇 |
2009年 | 192篇 |
2008年 | 239篇 |
2007年 | 281篇 |
2006年 | 256篇 |
2005年 | 207篇 |
2004年 | 176篇 |
2003年 | 172篇 |
2002年 | 151篇 |
2001年 | 135篇 |
2000年 | 142篇 |
1999年 | 118篇 |
1998年 | 58篇 |
1997年 | 47篇 |
1996年 | 50篇 |
1995年 | 46篇 |
1994年 | 40篇 |
1993年 | 41篇 |
1992年 | 76篇 |
1991年 | 99篇 |
1990年 | 92篇 |
1989年 | 100篇 |
1988年 | 49篇 |
1987年 | 64篇 |
1986年 | 76篇 |
1985年 | 82篇 |
1984年 | 72篇 |
1983年 | 48篇 |
1982年 | 52篇 |
1981年 | 38篇 |
1980年 | 30篇 |
1979年 | 40篇 |
1978年 | 33篇 |
1977年 | 34篇 |
1976年 | 27篇 |
1975年 | 25篇 |
1974年 | 27篇 |
1972年 | 27篇 |
排序方式: 共有5810条查询结果,搜索用时 156 毫秒
991.
McKay GA Reddy R Arhin F Belley A Lehoux D Moeck G Sarmiento I Parr TR Gros P Pelletier J Far AR 《Bioorganic & medicinal chemistry letters》2006,16(5):1286-1290
Screening of a chemical library in a DNA helicase assay involving the Pseudomonas aeruginosa DnaB helicase provided a triaminotriazine inhibitor with good antibacterial activity but associated cytotoxicity toward mammalian cells. Synthesis of analogs provided a few inhibitors that retained antibacterial activity and demonstrated a significant reduction in cytotoxicity. The impact of serum and initial investigations toward a mode of action highlight several features of this class of compounds as antibacterials. 相似文献
992.
Madhavan GR Chakrabarti R Reddy KA Rajesh BM Balraju V Rao PB Rajagopalan R Iqbal J 《Bioorganic & medicinal chemistry》2006,14(2):584-591
2,4-Thiazolidinedione derivatives of 1,3-benzoxazinone were synthesized and evaluated for their PPAR-alpha and -gamma dual activation. DRF-2519, a compound obtained through SAR of TZD derivatives of benzoxazinone, has shown potent dual PPAR activation. In ob/ob mice, it showed better efficacy than the comparator molecules. In fat fed rat model, it showed significant improvement in lipid parameters, which was better than fibrates. 相似文献
993.
994.
The anthocyanins in native Cornus alternifolia, Cornus controversa, Cornus kousa and Cornus florida were quantified by HPLC and characterized by spectroscopic methods. The analyses of C. alternifolia and C. controversa revealed that both contained , and , respectively. Similarly, C. florida and C. kousa showed identical anthocyanin profiles with major anthocyanins as and cyanidin 3-O-glucoside (6), respectively. The amount of anthocyanins , and in C. alternifolia and C. controversa were 8.21, 8.44 and 0.02 mg; and 7.74, 5.92, and 0.02 mg/g of fresh fruits, respectively. The anthocyanins and in C. kousa and C. florida were 0.02 and 0.16 mg; and 0.62 and 0.03 mg/g fresh fruits, respectively. Anthocyanins and were not studied earlier for their inhibition of lipid peroxidation, cyclooxygenase enzymes (COX-1 and COX-2), and tumor cell proliferation. At 50 microg/mL, anthocyanins and inhibited lipid peroxidation by 71% and 68%, respectively. Similarly, they inhibited COX-1 enzymes by 39% and 49% and COX-2 enzyme by 54% and 48%, respectively, at 100 microg/mL. Anthocyanin displayed 50% growth inhibition (IC(50)) at 21, 25, 50, 60, and 75 microg/mL, against HCT-116 (colon), MCF-7 (breast), NCI-H460 (lung), SF-268 (central nervous system CNS), and AGS (stomach) human tumor cell lines, respectively. Similarly, IC(50) values for anthocyanin were 38, 30, 76, 100, and 100 microg/mL against HCT-116, MCF-7, NCI H460, SF-268, and AGS, respectively. This is the first report of the quantification and biological activities of anthocyanins in C. alternifolia, C. kousa and C. florida in addition to the anthocyanins not previously quantified in C. controversa. 相似文献
995.
Shilpi Dasgupta Pisapati V. S. Sirisha Kudugunti Neelaveni Kathragadda Anuradha Alla G. Reddy Kumarasamy Thangaraj B. Mohan Reddy 《PloS one》2010,5(8)
The present study was carried out to assess the role of androgen receptor CAG repeat polymorphism and X chromosome inactivation (XCI) pattern among Indian PCOS women and controls which has not been hitherto explored and also to test the hypothesis that shorter CAG alleles would be preferentially activated in PCOS. CAG repeat polymorphism and X chromosome methylation patterns were compared between PCOS and non-PCOS women. 250 PCOS women and 299 controls were included for this study. Androgen receptor CAG repeat sizes, XCI percentages, and clinical and biochemical parameters were measured. The mean CAG repeat number is similar between the cases (18.74±0.13) and controls (18.73±0.12). The obese PCOS women were significantly more frequent in the <18 and >20 CAG repeat category than the lean PCOS women, yielding a highly significant odds (p = 0.001). Among the women with non-random X-inactivation, alleles with <19 repeats were more frequently activated among cases than controls (p = 0.33). CAG repeat polymorphism by itself cannot be considered as a useful marker for discriminating PCOS. We observed a trend of preferential activation of the shorter allele among the PCOS cases with non random XCI pattern. In the obese PCOS women, this microsatellite variation may account for the hyperandrogenicity to a larger extent than the lean PCOS women. 相似文献
996.
997.
Background: CYP1A1 is one of the commonest genes which had been widely investigated to find the risk of various malignancies in different ethnic groups. The polymorphism in these genes with a combination of environmental exposure has been hypothesized to confer a differential risk of cancer for individuals carrying these genetic variants. Based on this model, individuals with higher CYP1A1 activity would be at increased risk of cancer when exposed to high levels of smoke components. The proposed mechanism involves cytochrome P450 1A1 (CYP1A1), a gene that is inducible by xenobiotics to produce genetic susceptibility for malignancies. Patients and procedures: We performed a case–control study in 205 cases with histopathologically confirmed squamous cell carcinoma of head and neck and reported habits of bidi or cigarettes smoking and 245 similar controls to investigate the role of CYP1A1 polymorphisms in the risk of head and neck cancers especially among smokers of Hyderabad Indian population. Venous blood samples (5 ml) were collected from patients and control groups; genomic DNA was extracted and used for polymerase chain reaction (PCR) to determine the genotypes. RFLP assays were designed to detect each of the variant CYP1A1 alleles. Results and discussion: CYP1A1m1/m1 genotype (OR = 8.12, 95% CI: 3.27–21.30) and CYP1A1w1/m1 showed elevated risk when compared with CYP1A1w1/w1. Similarly CYP1A1w2/m2 (OR = 1.58, 95% CI: 0.94–2.67) and CYP1A1m2/m2 (OR = 6.31, 95% CI: 2.74–18.69) genotypes also showed elevated risk when compared with CYP1A1w2/w2 genotype. This data demonstrated that smoking was a risk factor for head and neck cancers. The m2 mutations were in close linkage disequilibrium with the m1 mutations; 53% m1 mutants had the mutation in the m2 site. Conclusion: Those individuals carrying at least one CYP1A1 m1 or m2 variant allele were at a 2-fold elevated risk for head and neck cancer. Our data clearly demonstrates that CYP1A1 is an important determinant in susceptibility to tobacco-induced head and neck carcinogens and there is an association between genetic polymorphism in the CYP1A1 locus and elevated risk of the type of smoking among Indians. This appears to be a new and important prognostic and diagnostic marker for determining the risk of head and neck cancers genetically. 相似文献
998.
999.
Background
MHC-II restricted CD4+ T cells are dependent on antigen presenting cells (APC) for their activation. APC dysfunction in HIV-infected individuals could accelerate or exacerbate CD4+ T cell dysfunction and may contribute to increased levels of immunodeficiency seen in some patients regardless of their CD4+ T cell numbers. Here we test the hypothesis that APC from HIV-infected individuals have diminished antigen processing and presentation capacity.Methodology/Principal Findings
Monocytes (MN) were purified by immuno-magnetic bead isolation techniques from HLA-DR1.01+ or DR15.01+ HIV-infected and uninfected individuals. MN were analyzed for surface MHC-II expression and for antigen processing and presentation capacity after overnight incubation with soluble antigen or peptide and HLA-DR matched T cell hybridomas. Surface expression of HLA-DR was 20% reduced (p<0.03) on MN from HIV-infected individuals. In spite of this, there was no significant difference in antigen processing and presentation by MN from 14 HIV-infected donors (8 HLA-DR1.01+ and 6 HLA-DR15.01+) compared to 24 HIV-uninfected HLA-matched subjects.Conclusions/Significance
We demonstrated that MHC class II antigen processing and presentation is preserved in MN from HIV-infected individuals. This further supports the concept that this aspect of APC function does not further contribute to CD4+ T cell dysfunction in HIV disease. 相似文献1000.
Narendranath Reddy Chintagari Amarjit Mishra Lijing Su Yang Wang Sahlu Ayalew Steven D. Hartson Lin Liu 《PloS one》2010,5(2)
Lung surfactant reduces surface tension and maintains the stability of alveoli. How surfactant is released from alveolar epithelial type II cells is not fully understood. Vacuolar ATPase (V-ATPase) is the enzyme responsible for pumping H+ into lamellar bodies and is required for the processing of surfactant proteins and the packaging of surfactant lipids. However, its role in lung surfactant secretion is unknown. Proteomic analysis revealed that vacuolar ATPase (V-ATPase) dominated the alveolar type II cell lipid raft proteome. Western blotting confirmed the association of V-ATPase a1 and B1/2 subunits with lipid rafts and their enrichment in lamellar bodies. The dissipation of lamellar body pH gradient by Bafilomycin A1 (Baf A1), an inhibitor of V-ATPase, increased surfactant secretion. Baf A1-stimulated secretion was blocked by the intracellular Ca2+ chelator, BAPTA-AM, the protein kinase C (PKC) inhibitor, staurosporine, and the Ca2+/calmodulin-dependent protein kinase II (CaMKII), KN-62. Baf A1 induced Ca2+ release from isolated lamellar bodies. Thapsigargin reduced the Baf A1-induced secretion, indicating cross-talk between lamellar body and endoplasmic reticulum Ca2+ pools. Stimulation of type II cells with surfactant secretagogues dissipated the pH gradient across lamellar bodies and disassembled the V-ATPase complex, indicating the physiological relevance of the V-ATPase-mediated surfactant secretion. Finally, silencing of V-ATPase a1 and B2 subunits decreased stimulated surfactant secretion, indicating that these subunits were crucial for surfactant secretion. We conclude that V-ATPase regulates surfactant secretion via an increased Ca2+ mobilization from lamellar bodies and endoplasmic reticulum, and the activation of PKC and CaMKII. Our finding revealed a previously unrealized role of V-ATPase in surfactant secretion. 相似文献