全文获取类型
收费全文 | 399篇 |
免费 | 23篇 |
专业分类
422篇 |
出版年
2023年 | 5篇 |
2022年 | 6篇 |
2021年 | 7篇 |
2020年 | 5篇 |
2019年 | 17篇 |
2018年 | 7篇 |
2017年 | 17篇 |
2016年 | 17篇 |
2015年 | 18篇 |
2014年 | 37篇 |
2013年 | 40篇 |
2012年 | 37篇 |
2011年 | 34篇 |
2010年 | 20篇 |
2009年 | 21篇 |
2008年 | 25篇 |
2007年 | 15篇 |
2006年 | 11篇 |
2005年 | 12篇 |
2004年 | 19篇 |
2003年 | 5篇 |
2002年 | 14篇 |
2001年 | 4篇 |
2000年 | 2篇 |
1999年 | 3篇 |
1998年 | 2篇 |
1997年 | 2篇 |
1994年 | 1篇 |
1993年 | 1篇 |
1991年 | 2篇 |
1990年 | 1篇 |
1989年 | 7篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1978年 | 1篇 |
1975年 | 1篇 |
1972年 | 1篇 |
1969年 | 1篇 |
1968年 | 1篇 |
排序方式: 共有422条查询结果,搜索用时 0 毫秒
71.
Venkatraman S Njoroge FG Wu W Girijavallabhan V Prongay AJ Butkiewicz N Pichardo J 《Bioorganic & medicinal chemistry letters》2006,16(6):1628-1632
Prolonged hepatitis C infection is the leading cause for cirrhosis of the liver and hepatocellular carcinoma. The etiological agent HCV virus codes a single polyprotein of approximately 3000 amino acids that is processed with the help of a serine protease NS3A to produce structural and non-structural proteins required for viral replication. Inhibition of NS3 protease can potentially be used to develop drugs for treatment of HCV infections. Herein, we report the development of a series of novel NS3 serine protease inhibitors derived from 2-aza-bicyclo[2.2.1]-heptane carboxylic acid with potential therapeutic use for treatment of HCV infections. 相似文献
72.
Mohammed Afzal Azam Srikanth Jupudi 《Journal of receptor and signal transduction research》2017,37(5):522-534
The discovery of clinically relevant inhibitors against MurF enzyme has proven to be a challenging task. In order to get further insight into the structural features required for the MurF inhibitory activity, we performed pharmacophore and atom-based three-dimensional quantitative structure–activity relationship studies for novel thiophene-3-carbonitriles based MurF inhibitors. The five-feature pharmacophore model was generated using 48 inhibitors having IC50 values ranging from 0.18 to 663?μm. The best-fitted model showed a higher coefficient of determination (R2?=?0.978), cross-validation coefficient (Q2?=?0.8835) and Pearson coefficient (0.9406) at four component partial least-squares factor. The model was validated with external data set and enrichment study. The effectiveness of the docking protocol was validated by docking the co-crystallized ligand into the catalytic pocket of MurF enzyme. Further, binding free energy calculated by the molecular mechanics generalized Born surface area approach showed that van der Waals and non-polar solvation energy terms are the main contributors to ligand binding in the active site of MurF enzyme. A 10-ns molecular dynamic simulation was performed to confirm the stability of the 3ZM6-ligand complex. Four new molecules are also designed as potent MurF inhibitors. These results provide insights regarding the development of novel MurF inhibitors with better binding affinity. 相似文献
73.
74.
Sen U Givvimani S Abe OA Lederer ED Tyagi SC 《American journal of physiology. Cell physiology》2011,300(1):C155-C163
Elevated level of homocysteine (Hcy) induces chronic inflammation in vascular bed, including glomerulus, and promotes glomerulosclerosis. In this study we investigated in vitro mechanism of Hcy-mediated monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) induction and determined the regulatory role of hydrogen sulfide (H?S) to ameliorate inflammation. Mouse glomerular mesangial cells (MCs) were incubated with Hcy (75 μM) and supplemented with vehicle or with H?S (30 μM, in the form of NaHS). Inflammatory molecules MCP-1 and MIP-2 were measured by ELISA. Cellular capability to generate H?S was measured by colorimetric chemical method. To enhance endogenous production of H?S and better clearance of Hcy, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) genes were delivered to the cells. Oxidative NAD(P)H p47(phox) was measured by Western blot analysis and immunostaining. Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH?-terminal kinase (JNK1/2) were measured by Western blot analysis. Our results demonstrated that Hcy upregulated inflammatory molecules MCP-1 and MIP-2, whereas endogenous production of H?S was attenuated. H?S treatment as well as CBS and CSE doubly cDNA overexpression markedly reduced Hcy-induced upregulation of MCP-1 and MIP-2. Hcy-induced upregulation of oxidative p47(phox) was attenuated by H?S supplementation and CBS/CSE overexpression as well. In addition to that we also detected Hcy-induced MCP-1 and MIP-2 induction was through phosphorylation of ERK1/2 and JNK1/2. Either H?S supplementation or CBS and CSE doubly cDNA overexpression attenuated Hcy-induced phosphorylation of these two signaling molecules and diminished MCP-1 and MIP-2 expressions. Similar results were obtained by inhibition of ERK1/2 and JNK1/2 using pharmacological and small interferring RNA (siRNA) blockers. We conclude that H?S plays a regulatory role in Hcy-induced mesangial inflammation and that ERK1/2 and JNK1/2 are two signaling pathways involved this process. 相似文献
75.
QSAR studies on series of pyrrolo[2,3-d]pyrimidine nucleoside analogues were performed for their adenosine kinase (AK) inhibitory activity using the Hansch approach. Significant correlations were obtained with hydrophobic parameter at position 'X'. Electronic and steric parameters on pyrimidine and pyrrole rings found to play an important role in the ligand-receptor interactions with the active sites of the enzyme. Presence of bulkier groups at 'X' and 'Y' positions seems to protect the title compounds from biodegradation, as is evident from their positive sterimol steric parameter B1 at these positions. 相似文献
76.
Saurav Prasad Katla Srikanth Anil M. Limaye Senthilkumar Sivaprakasam 《Biotechnology letters》2014,36(6):1303-1307
Casein whey permeate (CWP), a lactose-enriched dairy waste effluent, is a viable feed stock for the production of value-added products. Two lactic acid bacteria were cultivated in a synthetic casein whey permeate medium with or without pH control. Lactobacillus lactis ATCC 4797 produced d-lactic acid (DLA) at 12.5 g l?1 in a bioreactor. The values of Leudking–Piret model parameters suggested that lactate was a growth-associated product. Batch fermentation was also performed employing CWP (35 g lactose l?1) with casein hydrolysate as a nitrogen supplement in a bioreactor. After 40 h, L. lactis produced 24.3 g lactic acid l?1 with an optical purity >98 %. Thus CWP may be regarded as a potential feed-stock for DLA production. 相似文献
77.
Jayanthi Santhanam Lars R?berg Andrew F. Read Nicholas Jon Savill 《PLoS computational biology》2014,10(1)
Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter , the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery. 相似文献
78.
Barbara A. Miller Nicholas E. Hoffman Salim Merali Xue-Qian Zhang JuFang Wang Sudarsan Rajan Santhanam Shanmughapriya Erhe Gao Carlos A. Barrero Karthik Mallilankaraman Jianliang Song Tongda Gu Iwona Hirschler-Laszkiewicz Walter J. Koch Arthur M. Feldman Muniswamy Madesh Joseph Y. Cheung 《The Journal of biological chemistry》2014,289(11):7615-7629
Cardiac TRPM2 channels were activated by intracellular adenosine diphosphate-ribose and blocked by flufenamic acid. In adult cardiac myocytes the ratio of GCa to GNa of TRPM2 channels was 0.56 ± 0.02. To explore the cellular mechanisms by which TRPM2 channels protect against cardiac ischemia/reperfusion (I/R) injury, we analyzed proteomes from WT and TRPM2 KO hearts subjected to I/R. The canonical pathways that exhibited the largest difference between WT-I/R and KO-I/R hearts were mitochondrial dysfunction and the tricarboxylic acid cycle. Complexes I, III, and IV were down-regulated, whereas complexes II and V were up-regulated in KO-I/R compared with WT-I/R hearts. Western blots confirmed reduced expression of the Complex I subunit and other mitochondria-associated proteins in KO-I/R hearts. Bioenergetic analyses revealed that KO myocytes had a lower mitochondrial membrane potential, mitochondrial Ca2+ uptake, ATP levels, and O2 consumption but higher mitochondrial superoxide levels. Additionally, mitochondrial Ca2+ uniporter (MCU) currents were lower in KO myocytes, indicating reduced mitochondrial Ca2+ uptake was likely due to both lower ψm and MCU activity. Similar to isolated myocytes, O2 consumption and ATP levels were also reduced in KO hearts. Under a simulated I/R model, aberrant mitochondrial bioenergetics was exacerbated in KO myocytes. Reactive oxygen species levels were also significantly higher in KO-I/R compared with WT-I/R heart slices, consistent with mitochondrial dysfunction in KO-I/R hearts. We conclude that TRPM2 channels protect the heart from I/R injury by ameliorating mitochondrial dysfunction and reducing reactive oxygen species levels. 相似文献
79.
Tyrosinase is the key enzyme involved in the human pigmentation process, as well as the undesired browning of fruits and vegetables. Compounds inhibiting tyrosinase catalytic activity are an important class of cosmetic and dermatological agents which show high potential as depigmentation agents used for skin lightening. The multi-step protocol employed for the identification of novel tyrosinase inhibitors incorporated the Shape Signatures computational algorithm for rapid screening of chemical libraries. This algorithm converts the size and shape of a molecule, as well its surface charge distribution and other bio-relevant properties, into compact histograms (signatures) that lend themselves to rapid comparison between molecules. Shape Signatures excels at scaffold hopping across different chemical families, which enables identification of new actives whose molecular structure is distinct from other known actives. Using this approach, we identified a novel class of depigmentation agents that demonstrated promise for skin lightening product development. 相似文献
80.
Srikanth Kudithipudi Denis Kusevic Sara Weirich Albert Jeltsch 《Journal of visualized experiments : JoVE》2014,(93)
Lysine methylation is an emerging post-translation modification and it has been identified on several histone and non-histone proteins, where it plays crucial roles in cell development and many diseases. Approximately 5,000 lysine methylation sites were identified on different proteins, which are set by few dozens of protein lysine methyltransferases. This suggests that each PKMT methylates multiple proteins, however till now only one or two substrates have been identified for several of these enzymes. To approach this problem, we have introduced peptide array based substrate specificity analyses of PKMTs. Peptide arrays are powerful tools to characterize the specificity of PKMTs because methylation of several substrates with different sequences can be tested on one array. We synthesized peptide arrays on cellulose membrane using an Intavis SPOT synthesizer and analyzed the specificity of various PKMTs. Based on the results, for several of these enzymes, novel substrates could be identified. For example, for NSD1 by employing peptide arrays, we showed that it methylates K44 of H4 instead of the reported H4K20 and in addition H1.5K168 is the highly preferred substrate over the previously known H3K36. Hence, peptide arrays are powerful tools to biochemically characterize the PKMTs. 相似文献