全文获取类型
收费全文 | 639篇 |
免费 | 50篇 |
专业分类
689篇 |
出版年
2023年 | 5篇 |
2022年 | 16篇 |
2021年 | 14篇 |
2020年 | 13篇 |
2019年 | 9篇 |
2018年 | 14篇 |
2017年 | 11篇 |
2016年 | 13篇 |
2015年 | 30篇 |
2014年 | 31篇 |
2013年 | 45篇 |
2012年 | 60篇 |
2011年 | 52篇 |
2010年 | 17篇 |
2009年 | 26篇 |
2008年 | 27篇 |
2007年 | 37篇 |
2006年 | 24篇 |
2005年 | 18篇 |
2004年 | 29篇 |
2003年 | 18篇 |
2002年 | 16篇 |
2001年 | 18篇 |
2000年 | 13篇 |
1999年 | 19篇 |
1998年 | 3篇 |
1997年 | 4篇 |
1996年 | 9篇 |
1995年 | 3篇 |
1992年 | 10篇 |
1991年 | 6篇 |
1990年 | 6篇 |
1989年 | 7篇 |
1988年 | 12篇 |
1987年 | 6篇 |
1986年 | 10篇 |
1985年 | 10篇 |
1984年 | 5篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1981年 | 1篇 |
1980年 | 4篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1975年 | 1篇 |
1974年 | 3篇 |
1973年 | 3篇 |
1971年 | 2篇 |
排序方式: 共有689条查询结果,搜索用时 15 毫秒
121.
122.
Minh V. Huynh Derek Parsonage Tom E. Forshaw Venkat R. Chirasani G. Aaron Hobbs Hanzhi Wu Jingyun Lee Cristina M. Furdui Leslie B. Poole Sharon L. Campbell 《The Journal of biological chemistry》2022,298(8)
The recent development of mutant-selective inhibitors for the oncogenic KRASG12C allele has generated considerable excitement. These inhibitors covalently engage the mutant C12 thiol located within the phosphoryl binding loop of RAS, locking the KRASG12C protein in an inactive state. While clinical trials of these inhibitors have been promising, mechanistic questions regarding the reactivity of this thiol remain. Here, we show by NMR and an independent biochemical assay that the pKa of the C12 thiol is depressed (pKa ∼7.6), consistent with susceptibility to chemical ligation. Using a validated fluorescent KRASY137W variant amenable to stopped-flow spectroscopy, we characterized the kinetics of KRASG12C fluorescence changes upon addition of ARS-853 or AMG 510, noting that at low temperatures, ARS-853 addition elicited both a rapid first phase of fluorescence change (attributed to binding, Kd = 36.0 ± 0.7 μM) and a second, slower pH-dependent phase, taken to represent covalent ligation. Consistent with the lower pKa of the C12 thiol, we found that reversible and irreversible oxidation of KRASG12C occurred readily both in vitro and in the cellular environment, preventing the covalent binding of ARS-853. Moreover, we found that oxidation of the KRASG12C Cys12 to a sulfinate altered RAS conformation and dynamics to be more similar to KRASG12D in comparison to the unmodified protein, as assessed by molecular dynamics simulations. Taken together, these findings provide insight for future KRASG12C drug discovery efforts, and identify the occurrence of G12C oxidation with currently unknown biological ramifications. 相似文献
123.
Huynh TP Mah V Sampson VB Chia D Fishbein MC Horvath S Alavi M Wu DC Harper J Sarafian T Dubinett SM Langhans SA Goodglick L Rajasekaran AK 《American journal of physiology. Lung cellular and molecular physiology》2012,302(11):L1150-L1158
Diminished Na,K-ATPase expression has been reported in several carcinomas and has been linked to tumor progression. However, few studies have determined whether Na,K-ATPase function and expression are altered in lung malignancies. Because cigarette smoke (CS) is a major factor underlying lung carcinogenesis and progression, we investigated whether CS affects Na,K-ATPase activity and expression in lung cell lines. Cells exposed to CS in vitro showed a reduction of Na,K-ATPase activity. We detected the presence of reactive oxygen species (ROS) in cells exposed to CS before Na,K-ATPase inhibition, and neutralization of ROS restored Na,K-ATPase activity. We further determined whether Na,K-ATPase expression correlated with increasing grades of lung adenocarcinoma and survival of patients with smoking history. Immunohistochemical analysis of lung adenocarcinoma tissues revealed reduced Na,K-ATPase expression with increasing tumor grade. Using tissue microarray containing lung adenocarcinomas of patients with known smoking status, we found that high expression of Na,K-ATPase correlated with better survival. For the first time, these data demonstrate that CS is associated with loss of Na,K-ATPase function and expression in lung carcinogenesis, which might contribute to disease progression. 相似文献
124.
125.
Huynh Vu Pradeep Singh Laurie Lewis Joseph G. Zendegui Krishna Jayaraman 《Nucleosides, nucleotides & nucleic acids》2013,32(8):853-864
Abstract DMT-Cholesteryl succinylamino solid supports (CPG, loading: 33 μmole/gram and TentaGel loading: 152 μmole/gram) and DMT-cholesteryl phosphoramidite were prepared for use in automated DNA synthesis of cholesteryl modified TFOs in the synthesis scales from 0.2 to 300 μmole. The modified TFOs were found to have a 5 to 50 fold increase in their uptake properties. 相似文献
126.
Influence of a freeze-thaw cycle on the stress-stretch curves of tissues of porcine abdominal organs
NH Nguyn MT D Ng TN Trn PT Phạm O Grottke R Tolba M Staat 《Journal of biomechanics》2012,45(14):2382-2386
The paper investigates both fresh porcine spleen and liver and the possible decomposition of these organs under a freeze-thaw cycle. The effect of tissue preservation condition is an important factor which should be taken into account for protracted biomechanical tests. In this work, tension tests were conducted for a large number of tissue specimens from twenty pigs divided into two groups of 10. Concretely, the first group was tested in fresh state; the other one was tested after a freeze-thaw cycle which simulates the conservation conditions before biomechanical experiments. A modified Fung model for isotropic behavior was adopted for the curve fitting of each kind of tissues. Experimental results show strong effects of the realistic freeze-thaw cycle on the capsule of elastin-rich spleen but negligible effects on the liver which virtually contains no elastin. This different behavior could be explained by the autolysis of elastin by elastolytic enzymes during the warmer period after thawing. Realistic biomechanical properties of elastin-rich organs can only be expected if really fresh tissue is tested. The observations are supported by tests of intestines. 相似文献
127.
Thu P. Huynh Sonali P. Barwe Seung J. Lee Ryan McSpadden Omar E. Franco Simon W. Hayward Robert Damoiseaux Stephen S. Grubbs Nicholas J. Petrelli Ayyappan K. Rajasekaran 《PloS one》2015,10(4)
Glucocorticoids are commonly used as palliative or chemotherapeutic clinical agents for treatment of a variety of cancers. Although steroid treatment is beneficial, the mechanisms by which steroids improve outcome in cancer patients are not well understood. Na,K-ATPase beta-subunit isoform 1 (NaK-β1) is a cell-cell adhesion molecule, and its expression is down-regulated in cancer cells undergoing epithelial-to mesenchymal-transition (EMT), a key event associated with cancer progression to metastatic disease. In this study, we performed high-throughput screening to identify small molecules that could up-regulate NaK-β1 expression in cancer cells. Compounds related to the glucocorticoids were identified as drug candidates enhancing NaK-β1 expression. Of these compounds, triamcinolone, dexamethasone, and fluorometholone were validated to increase NaK-β1 expression at the cell surface, enhance cell-cell adhesion, attenuate motility and invasiveness and induce mesenchymal to epithelial like transition of renal cell carcinoma (RCC) cells in vitro. Treatment of NaK-β1 knockdown cells with these drug candidates confirmed that these compounds mediate their effects through up-regulating NaK-β1. Furthermore, we demonstrated that these compounds attenuate tumor growth in subcutaneous RCC xenografts and reduce local invasiveness in orthotopically-implanted tumors. Our results strongly indicate that the addition of glucocorticoids in the treatment of RCC may improve outcome for RCC patients by augmenting NaK-β1 cell-cell adhesion function. 相似文献
128.
129.
le TM Vien NN Minh TC Thuong HD Khuong TV Nga C Thompson JI Campbell M de Jong JJ Farrar C Schultsz HR van Doorn S Baker 《PloS one》2012,7(8):e42919
Antimicrobial consumption is one of the major contributing factors facilitating the development and maintenance of bacteria exhibiting antimicrobial resistance. Plasmid-mediated quinolone resistance (PMQR) genes, such as the qnr family, can be horizontally transferred and contribute to reduced susceptibility to fluoroquinolones. We performed an observational study, investigating the copy number of PMQR after antimicrobial therapy. We enrolled 300 children resident in Ho Chi Minh City receiving antimicrobial therapy for acute respiratory tract infections (ARIs). Rectal swabs were taken on enrollment and seven days subsequently, counts for Enterobacteriaceae were performed and qnrA, qnrB and qnrS were quantified by using real-time PCR on metagenomic stool DNA. On enrollment, we found no association between age, gender or location of the participants and the prevalence of qnrA, qnrB or qnrS. Yet, all three loci demonstrated a proportional increase in the number of samples testing positive between day 0 and day 7. Furthermore, qnrB demonstrated a significant increase in copy number between paired samples (p<0.001; Wilcoxon rank-sum), associated with non-fluoroquinolone combination antimicrobial therapy. To our knowledge, this is the first study describing an association between the use of non-fluoroquinolone antimicrobials and the increasing relative prevalence and quantity of qnr genes. Our work outlines a potential mechanism for the selection and maintenance of PMQR genes and predicts a strong effect of co-selection of these resistance determinants through the use of unrelated and potentially unnecessary antimicrobial regimes. 相似文献
130.
Singh SK Yang K Karthikeyan S Huynh T Zhang X Phillips MA Zhang H 《The Journal of biological chemistry》2004,279(13):13166-13173
The thrH gene product of Pseudomonas aeruginosa has been shown to complement both homoserine kinase (thrB gene product) and phosphoserine phosphatase (serB gene product) activities in vivo. Sequence comparison has revealed that ThrH is related to phosphoserine phosphatases (PSP, EC 3.1.3.3) and belongs to the l-2-haloacid dehalogenase-like protein superfamily. We have solved the crystal structures of ThrH in the apoform and in complex with a bound product phosphate. The structure confirms an overall fold similar to that of PSP. Most of the catalytic residues of PSP are also conserved in ThrH, suggesting that similar catalytic mechanisms are used by both enzymes. Spectrophotometry-based in vitro assays show that ThrH is indeed a phosphoserine phosphatase with a K(m) of 0.207 mm and k(cat) of 13.4 min(-1), comparable with those of other PSPs. More interestingly, using high pressure liquid chromatography-based assays, we have demonstrated that ThrH is able to further transfer the phosphoryl group to homoserine using phosphoserine as the phosphoryl group donor, indicating that ThrH has a novel phosphoserine:homoserine phosphotransferase activity. 相似文献