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101.
Discovery of novel dihydro-9,10-ethano-anthracene carboxamides as glucocorticoid receptor modulators
Bingwei V. Yang Wayne Vaccaro Arthur M. Doweyko Lidia M. Doweyko Tram Huynh David Tortolani Steven G. Nadler Lorraine McKay John Somerville Deborah A. Holloway Sium Habte David S. Weinstein Joel C. Barrish 《Bioorganic & medicinal chemistry letters》2009,19(8):2139-2143
A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities. 17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays. A hypothetical binding mode is provided which accounts for the induction of functional activity by a bridgehead methyl group. 相似文献
102.
Tran Cong Toai Huynh Duy Thao Nguyen Phuong Thao Ciro Gargiulo Phan Kim Ngoc Pham Hung Van D. Michael Strong 《Cell and tissue banking》2010,11(3):269-280
It is well accepted that human umbilical cord blood (UCB) is a source of mesenchymal stem cells (MSCs) which are able to differentiate
into different cell phenotypes such as osteoblasts, chondrocytes, adipocytes, myocytes, cardiomyocytes and neurons. The aim
of this study was to isolate MSCs from human UCB to determine their osteogenic potential by using different kinds of osteogenic
medium. Eventually, only those MSCs cultured in osteogenic media enriched with vitamin D2 and FGF9, were positive for osteocalcin by RT-PCR. All these cells were positive for alizarin red, alkaline phosphatase and
Von Kossa. The results obtained from RT-PCR have confirmed that osteogenesis is complete by expression of the osteocalcin
marker. In conclusion, vitamin D2, at least in vitro, may replace vitamin D3 as an osteogenic stimulator factor for MSC differentiation. 相似文献
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104.
Regulation of TFEB and V-ATPases by mTORC1 总被引:2,自引:0,他引:2
Peña-Llopis S Vega-Rubin-de-Celis S Schwartz JC Wolff NC Tran TA Zou L Xie XJ Corey DR Brugarolas J 《The EMBO journal》2011,30(16):3242-3258
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107.
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
108.
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
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110.
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