全文获取类型
收费全文 | 1060篇 |
免费 | 76篇 |
出版年
2023年 | 4篇 |
2022年 | 9篇 |
2021年 | 20篇 |
2020年 | 12篇 |
2019年 | 18篇 |
2018年 | 21篇 |
2017年 | 12篇 |
2016年 | 28篇 |
2015年 | 41篇 |
2014年 | 48篇 |
2013年 | 72篇 |
2012年 | 84篇 |
2011年 | 76篇 |
2010年 | 50篇 |
2009年 | 38篇 |
2008年 | 58篇 |
2007年 | 74篇 |
2006年 | 69篇 |
2005年 | 57篇 |
2004年 | 48篇 |
2003年 | 41篇 |
2002年 | 38篇 |
2001年 | 25篇 |
2000年 | 17篇 |
1999年 | 24篇 |
1998年 | 15篇 |
1997年 | 9篇 |
1996年 | 12篇 |
1995年 | 9篇 |
1994年 | 4篇 |
1993年 | 3篇 |
1992年 | 6篇 |
1991年 | 9篇 |
1990年 | 12篇 |
1989年 | 4篇 |
1988年 | 6篇 |
1987年 | 6篇 |
1986年 | 7篇 |
1985年 | 6篇 |
1984年 | 3篇 |
1983年 | 7篇 |
1982年 | 4篇 |
1981年 | 3篇 |
1980年 | 4篇 |
1979年 | 2篇 |
1977年 | 2篇 |
1973年 | 4篇 |
1972年 | 3篇 |
1971年 | 3篇 |
1969年 | 2篇 |
排序方式: 共有1136条查询结果,搜索用时 15 毫秒
31.
Manpreet Kaur Rawal Mohammad Firoz Khan Khyati Kapoor Neha Goyal Sobhan Sen Ajay Kumar Saxena Andrew M. Lynn Joel D. A. Tyndall Brian C. Monk Richard D. Cannon Sneha Sudha Komath Rajendra Prasad 《The Journal of biological chemistry》2013,288(34):24480-24493
The fungal ATP-binding cassette (ABC) transporter Cdr1 protein (Cdr1p), responsible for clinically significant drug resistance, is composed of two transmembrane domains (TMDs) and two nucleotide binding domains (NBDs). We have probed the nature of the drug binding pocket by performing systematic mutagenesis of the primary sequences of the 12 transmembrane segments (TMSs) found in the TMDs. All mutated proteins were expressed equally well and localized properly at the plasma membrane in the heterologous host Saccharomyces cerevisiae, but some variants differed significantly in efflux activity, substrate specificity, and coupled ATPase activity. Replacement of the majority of the amino acid residues with alanine or glycine yielded neutral mutations, but about 42% of the variants lost resistance to drug efflux substrates completely or selectively. A predicted three-dimensional homology model shows that all the TMSs, apart from TMS4 and TMS10, interact directly with the drug-binding cavity in both the open and closed Cdr1p conformations. However, TMS4 and TMS10 mutations can also induce total or selective drug susceptibility. Functional data and homology modeling assisted identification of critical amino acids within a drug-binding cavity that, upon mutation, abolished resistance to all drugs tested singly or in combinations. The open and closed Cdr1p models enabled the identification of amino acid residues that bordered a drug-binding cavity dominated by hydrophobic residues. The disposition of TMD residues with differential effects on drug binding and transport are consistent with a large polyspecific drug binding pocket in this yeast multidrug transporter. 相似文献
32.
AimsThe aim of the present investigation was to develop a nanoemulsion (NE) gel formulation for the transdermal delivery of meloxicam (MLX) in order to ensure maximum controlled and sustained drug release capacity.Main methodsThe MLX containing NE gel was prepared and characterized for particle size, zeta potential, pH, rheology, in vitro drug release, in vitro skin permeation, and in vitro hemolysis. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) of MLX-NE gel treated rat skin was performed to investigate the skin permeation mechanism of meloxicam from NE gel. Skin permeation potential of the developed gel formulation was assessed using confocal laser scanning microscopy (CLSM). The in vivo toxicity of MLX-NE gel was assessed by histopathological examination in rat. The rat paw edema test was performed to evaluate the anti-inflammatory activity of MLX-NE gel.Key findingsPercutaneous absorption studies demonstrated a higher permeation of meloxicam from NE gel, than the drug solution. FTIR and DSC studies supported stratum corneum lipid extraction as a possible penetration enhancer mechanism for MLX-NE gel. CLSM studies confirmed the permeation of the NE gel formulation to the deeper layers of the skin (up to 130 μm). MLX-NE gel turned out to be non-irritant, biocompatible, and provided maximum inhibition of paw edema in rats over 24 h in contrast to MLX solution.SignificanceThe nanoemulsion gel formulation may hold promise as an effective alternative for the transdermal delivery of meloxicam. 相似文献
33.
Saurabh Sudha Dhiman Dayanand Kalyani Sujit Sadashiv Jagtap Jung-Rim Haw Yun Chan Kang Jung-Kul Lee 《Applied microbiology and biotechnology》2013,97(3):1081-1091
Enhanced catalytic activities of different lignocellulases were obtained from Armillaria gemina under statistically optimized parameters using a jar fermenter. This strain showed maximum xylanase, endoglucanase, cellobiohydrolase, and β-glucosidase activities of 1,270, 146, 34, and 15 U mL?1, respectively. Purified A. gemina xylanase (AgXyl) has the highest catalytic efficiency (k cat/K m?=?1,440 mg?mL?1?s?1) ever reported for any fungal xylanase, highlighting the significance of the current study. We covalently immobilized the crude xylanase preparation onto functionalized silicon oxide nanoparticles, achieving 117 % immobilization efficiency. Further immobilization caused a shift in the optimal pH and temperature, along with a fourfold improvement in the half-life of crude AgXyl. Immobilized AgXyl gave 37.8 % higher production of xylooligosaccharides compared to free enzyme. After 17 cycles, the immobilized enzyme retained 92 % of the original activity, demonstrating its potential for the synthesis of xylooligosaccharides in industrial applications. 相似文献
34.
35.
36.
37.
Poulami Das Akanksha Bansal Sudha Narayan Rao Kedar Deodhar Umesh Mahantshetty Shyam K. Shrivastava Karthikeyan Sivaraman Rita Mulherkar 《PloS one》2016,11(11)
There are very few reports that describe the mutational landscape of cervical cancer, one of the leading cancers in Indian women. The aim of the present study was to investigate the somatic mutations that occur in cervical cancer. Whole exome sequencing of 10 treatment naïve tumour biopsies with matched blood samples, from a cohort of Indian patients with locally advanced disease, was performed. The data revealed missense mutations across 1282 genes, out of 1831 genes harbouring somatic mutations. These missense mutations (nonsynonymous + stop-gained) when compared with pre-existing mutations in the COSMIC database showed that 272 mutations in 250 genes were already reported although from cancers other than cervical cancer. More than 1000 novel somatic variations were obtained in matched tumour samples. Pathways / genes that are frequently mutated in various other cancers were found to be mutated in cervical cancers. A significant enrichment of somatic mutations in the MAPK pathway was observed, some of which could be potentially targetable. This is the first report of whole exome sequencing of well annotated cervical cancer samples from Indian women and helps identify trends in mutation profiles that are found in an Indian cohort of cervical cancer. 相似文献
38.
39.
Comparative analyses of quaternary arrangements in homo‐oligomeric proteins in superfamilies: Functional implications
下载免费PDF全文
![点击此处可从《Proteins》网站下载免费的PDF全文](/ch/ext_images/free.gif)
A comprehensive analysis of the quaternary features of distantly related homo‐oligomeric proteins is the focus of the current study. This study has been performed at the levels of quaternary state, symmetry, and quaternary structure. Quaternary state and quaternary structure refers to the number of subunits and spatial arrangements of subunits, respectively. Using a large dataset of available 3D structures of biologically relevant assemblies, we show that only 53% of the distantly related homo‐oligomeric proteins have the same quaternary state. Considering these homologous homo‐oligomers with the same quaternary state, conservation of quaternary structures is observed only in 38% of the pairs. In 36% of the pairs of distantly related homo‐oligomers with different quaternary states the larger assembly in a pair shows high structural similarity with the entire quaternary structure of the related protein with lower quaternary state and it is referred as “Russian doll effect.” The differences in quaternary state and structure have been suggested to contribute to the functional diversity. Detailed investigations show that even though the gross functions of many distantly related homo‐oligomers are the same, finer level differences in molecular functions are manifested by differences in quaternary states and structures. Comparison of structures of biological assemblies in distantly and closely related homo‐oligomeric proteins throughout the study differentiates the effects of sequence divergence on the quaternary structures and function. Knowledge inferred from this study can provide insights for improved protein structure classification and function prediction of homo‐oligomers. Proteins 2016; 84:1190–1202. © 2016 Wiley Periodicals, Inc. 相似文献
40.
B. Sudha Kalyani P.S. Krishna K. Sreenivasulu 《Saudi Journal of Biological Sciences》2019,26(7):1655-1660
Actinobacteria, which are the prolific producers of antibiotics and significant suppliers to the pharmaceutical industry, can produce a wide variety of bioactive metabolites. An actinomycete strain designated NLKPB45 was isolated from mangrove soils samples of Nellore coastal regions Andhra Pradesh and assessed for antibiotic production and activity against pathogenic bacteria. From a total of 9 mangrove soil samples, 143 acinomycetes were isolated. Among the isolated them 6 actinomycetes strains showed potential antibacterial activity against at two tested pathogens gram positive and gram negative bacteria E. coli and S. aureus. The potent strain NLKPB45 was identified by 16S gene isolation and sequencing to the Streptomyces genus. The ethyl acetate extracts also as shown excellent antimicrobial activity against Salmonella sp., staphylococcus aureus, E. coli, and B. subtilus were detected in both the supernatant extract samples from fermentations of culture NLKPB45. The anticancer activity of extracts in the HeLa with IC50 value of 37.1924 μg/ml, MCF-7 IC50 value of 40.9177 μg/ml and HT 29 IC50 value of 43.3758 μg/ml. 相似文献