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91.
Freezing the Dynamic Gap for Selectivity: Motion‐Based Design of Inhibitors of the Shikimate Kinase Enzyme 下载免费PDF全文
Verónica Prado Dr. Emilio Lence Paul Thompson Prof. Alastair R. Hawkins Prof. Concepción González‐Bello 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(50):17988-18000
Shikimate kinase (SK), the fifth enzyme of the aromatic amino acid biosynthesis, is a recognized target for antibiotic drug discovery. The potential of the distinct dynamic apolar gap, which isolates the natural substrate from the solvent environment for catalysis, and the motion of Mycobacterium tuberculosis and Helicobacter pylori SK enzymes, which was observed by molecular dynamics simulations, was explored for inhibition selectivity. The results of the biochemical and computational studies reveal that the incorporation of bulky groups at position C5 of 5‐aminoshikimic acid and the natural substrate enhances the selectivity for the H. pylori enzyme due to key motion differences in the shikimic acid binding domain (mainly helix α5). These studies show that the less‐exploited motion‐based design approach not only is an alternative strategy for the development of competitive inhibitors, but could also be a way to achieve selectivity against a particular enzyme among its homologues. 相似文献
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夏雪 《科技情报开发与经济》2012,22(12):122-123
通过对国家自然科学基金项目申报与立项因子的分析,提出了一些建议和看法,为今后申报国家自然科学基金项目提供借鉴。 相似文献
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分析农业资源利用的生产史、认识史和方法史的辩证发展过程,探讨在农业资源利用的现代化进程中,即从传统农业向现代综合生态化农业的转变过程中,农业地理学研究所面临的新任务与新要求,提出了发展农业地理学新的知识体系和研究方法及如何在具有鲜明综合性和区域性特点的现代农业资源高层次利用中发挥其作用等问题的若干思考。 相似文献
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本文研究了八种抗菌素(四环素、红霉素、卡那霉素、多粘菌素B、头孢霉素、抗霉素A、杆菌肽和博莱霉素)对明亮发光杆菌A_2(photobocterium phosphoreum A_2)发光的影响。其中四环素、抗霉素A和杆菌肽在低浓度时刺激细菌发光,然后随着作用时间的延长而逐渐抑制发光;较高浓度时则完全抑制发光,未见刺激发光。其余五种抗菌素则均表现为抑制细菌发光。抑制发光的程度随时间和所用浓度的高低而呈一定的依存关系。实验结果表明,抗菌素对发光细菌的影响作用还是跟它们各自的作用机制有关。本文还讨论了细胞质膜在细菌发光中的作用和呼吸抑制剂对细菌发光的影响的作用机制。 相似文献
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根据奶牛产后不同患病时期其生殖内分泌的机能状态,应用激素治疗途径人为调理下丘脑—垂体—性腺轴系与子宫的关系,增强病畜自我防卫能力,并与抗菌素相结合治疗73头子宫内膜炎奶牛。其中三合激素和土霉素结合治疗20头,治愈率为70%;雌激素、催产素和四环素结合治疗15头,治愈率为80%;雌激素和青、链霉素结合治疗21头,治愈率为76.19%;前列腺素和氯霉素结合治疗17头,治愈率为82.35%。 相似文献
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Aminoglycoside microarrays to explore interactions of antibiotics with RNAs and proteins 总被引:3,自引:0,他引:3
RNA is an important target for drug discovery efforts. Several clinically used aminoglycoside antibiotics bind to bacterial rRNA and inhibit protein synthesis. Aminoglycosides, however, are losing efficacy due to their inherent toxicity and the increase in antibiotic resistance. Targeting of other RNAs is also becoming more attractive thanks to the discovery of new potential RNA drug targets through genome sequencing and biochemical efforts. Identification of new compounds that target RNA is therefore urgent, and we report here on the development of rapid screening methods to probe binding of low molecular weight ligands to proteins and RNAs. A series of aminoglycosides has been immobilized onto glass microscope slides, and binding to proteins and RNAs has been detected by fluorescence. Construction and analysis of the arrays is completed by standard DNA genechip technology. Binding of immobilized aminoglycosides to proteins that are models for study of aminoglycoside toxicity (DNA polymerase and phospholipase C), small RNA oligonucleotide mimics of aminoglycoside binding sites in the ribosome (rRNA A-site mimics), and a large (approximately 400 nucleotide) group I ribozyme RNA is detected. The ability to screen large RNAs alleviates many complications associated with binding experiments that use isolated truncated regions from larger RNAs. These studies lay the foundation for rapid identification of small organic ligands from combinatorial libraries that exhibit strong and selective RNA binding while displaying decreased affinity to toxicity-causing proteins. 相似文献
100.
Antibiotics are precious resources in the fight to combat bacterial infections caused by pathogenic organisms. Vancomycin is one of the antibiotics of last resort in the treatment of life-threatening infections by gram-positive bacteria. The rules by which nature assembles the glycopeptide (vancomycin) and lipoglycopeptide (teicoplanin) antibiotics are becoming elucidated and verified: first amino acids are synthesized, then joined together and cross-linked. This knowledge opens up approaches for reprogramming strategies at the level of altered monomers, swapped assembly lines, and different post-assembly tailoring enzymes. 相似文献