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961.
Nagula Shankaraiah 《Tetrahedron letters》2009,50(5):520-1992
A concise enantioselective strategy for the synthesis of key PDE5 inhibitor 2 was developed in 5 and 6 steps using asymmetric hydrogenation and one-pot chiral auxiliary approaches, respectively. The synthesis features the use of imine 6 obtained through Bischler-Napieralsky reaction from amide 5. Absolute R configuration was introduced in (+)-7 by asymmetric transfer-hydrogenation reaction with Ru(II) catalyst followed by establishing the tricyclic pyrroloquinalone core using the Winterfeldt oxidation. Another alternative synthetic approach for the introduction of chirality in the molecule employed imine 6 and chloroformates of different chiral auxiliaries, which achieved N-acyliminium ion intermediates that were reduced in situ using PdCl2/Et3SiH protocol. These synthetic routes were applied in the total synthesis of promising male erectile dysfunction (MED) PDE5 inhibitor 1. 相似文献
962.
Claudia Cafarchia Domenico Otranto Stefania Weigl Bronwyn E. Campbell Antonio Parisi Cinzia Cantacessi Francesca Mancianti Patrizia Danesi Robin B. Gasser 《Electrophoresis》2009,30(20):3555-3564
Dermatophytes are fungi that can be contagious and cause infections in the keratinized skin of mammals, including humans. The etiological diagnosis of dermatophytosis relies on a combination of in vitro‐culture and microscopic methods. Effective molecular tools could overcome the limitations of conventional methods of identification. In the present study, following phenetic identification as M. canis, M. fulvum, M. gypseum, T. mentagrophytes and T. terrestre, we genetically characterized key dermatophytes, employing the sequences of the first and second internal transcribed spacers of nuclear ribosomal DNA as well as part of the chitin synthase‐1 gene, and assessed the utility of these DNA regions (based on levels of nucleotide variation within and among species/taxa) as markers for the classification of species and genotypes. Employing partial chitin synthase‐1 gene as the marker, we also established a PCR‐coupled SSCP approach as a diagnostic/analytical mutation‐scanning tool. This tool should facilitate fundamental investigations of the ecology, epidemiology and population genetics of dermatophytes and, importantly, should assist in allowing a more rapid diagnosis of dermatophytoses in humans and other animals, thus overcoming the significant delays in targeted chemotherapy following diagnosis using conventional methods. (Nucleotide sequence data reported in this paper are available in the EMBL, GenBank and DDJB datadases under accession numbers FJ897707–FJ897713 (ITS‐1), FJ897714–FJ897720 (ITS‐2) and FJ897700–FJ897706 (pchs‐1)). 相似文献
963.
Sameer Kawatkar Hongming Wang Ryszard Czerminski Diane Joseph-McCarthy 《Journal of computer-aided molecular design》2009,23(8):527-539
Fragment-based drug discovery approaches allow for a greater coverage of chemical space and generally produce high efficiency
ligands. As such, virtual and experimental fragment screening are increasingly being coupled in an effort to identify new
leads for specific therapeutic targets. Fragment docking is employed to create target-focussed subset of compounds for testing
along side generic fragment libraries. The utility of the program Glide with various scoring schemes for fragment docking
is discussed. Fragment docking results for two test cases, prostaglandin D2 synthase and DNA ligase, are presented and compared
to experimental screening data. Self-docking, cross-docking, and enrichment studies are performed. For the enrichment runs,
experimental data exists indicating that the docking decoys in fact do not inhibit the corresponding enzyme being examined.
Results indicate that even for difficult test cases fragment docking can yield enrichments significantly better than random.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
964.
Ji Ae Lee Ha Yong Song Sung Mi Ju Su Jin Lee Hyung-Joo Kwon Won Sik Eum Sang Ho Jang Soo Young Choi Jinseu Park 《Experimental & molecular medicine》2009,41(9):629-637
Inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) have been known to be involved in various pathophysiological processes such as inflammation. This study was performed to determine the regulatory function of superoxide dismutase (SOD) on the LPS-induced expression of iNOS, and COX-2 in RAW 264.7 cells. When a cell-permeable SOD, Tat-SOD, was added to the culture medium of RAW 264.7 cells, it rapidly entered the cells in a dose-dependent manner. Treatment of RAW 264.7 cells with Tat-SOD led to decrease in LPS-induced ROS generation. Pretreatment with Tat-SOD significantly inhibited LPS-induced expression of iNOS and NO production but had no effect on the expression of COX-2 and PGE2 production in RAW 264.7 cells. Tat-SOD inhibited LPS-induced NF-κB DNA binding activity, IκBα degradation and activation of MAP kinases. These data suggest that SOD differentially regulate expression of iNOS and COX-2 in LPS-stimulated RAW 264.7 cells. 相似文献
965.
966.
967.
<正>A convenient method for the synthesis of ezetimibe analogs as cholesterol absorption inhibitors was described.The key step in the synthesis was the intramolecular ring formation through Mitsunobu reaction.Furthermore,a new series of analogs was designed and synthesized. 相似文献
968.
建立了尿中2,4-滴(2,4-D)、2,4-滴丙酸(2,4-DP)2、甲4氯(MCPA)和2甲4氯丙酸(MCPP)4种苯氧羧酸类除草剂的气相色谱-质谱(GC-MS)分析方法。尿样加氯化钠饱和,酸化后用乙醚萃取,萃取物进行特丁二甲硅烷基(TBDMS)衍生化后分析。尿中4种除草剂的浓度在3~3 000 ng/mL范围内工作曲线的线性关系良好,检出限在1 ng/mL以下,3、100和1 000 ng/mL水平加标回收率在97.0%~102.2%之间,精密度在6.2%~14.2%之间。该法灵敏,可用于中毒者和职业接触者尿中苯氧羧酸类除草剂的分析。 相似文献
969.
970.
Kyeong-Min Lee Hye-Young Seo Mi-Kyung Kim Ae-Kyung Min Seong-Yeol Ryu Yoon-Nyun Kim Young Joo Park Hueng-Sik Choi Ki-Up Lee Wan-Ju Park Keun-Gyu Park In-Kyu Lee 《Experimental & molecular medicine》2010,42(1):21-29
Angiotensin II is a major effector molecule in the development of cardiovascular disease. In vascular smooth muscle cells (VSMCs), angiotensin II promotes cellular proliferation and extracellular matrix accumulation through the upregulation of plasminogen activator inhibitor-1 (PAI-1) expression. Previously, we demonstrated that small heterodimer partner (SHP) represses PAI-1 expression in the liver through the inhibition of TGF-β signaling pathways. Here, we investigated whether SHP inhibited angiotensin II-stimulated PAI-1 expression in VSMCs. Adenovirus-mediated overexpression of SHP (Ad-SHP) in VSMCs inhibited angiotensin II- and TGF-β-stimulated PAI-1 expression. Ad-SHP also inhibited angiotensin II-, TGF-β- and Smad3-stimulated PAI-1 promoter activity, and angiotensin II-stimulated AP-1 activity. The level of PAI-1 expression was significantly higher in VSMCs of SHP-/- mice than wild type mice. Moreover, loss of SHP increased PAI-1 mRNA expression after angiotensin II treatment. These results suggest that SHP inhibits PAI-1 expression in VSMCs through the suppression of TGF-β/Smad3 and AP-1 activity. Thus, agents that target the induction of SHP expression in VSMCs might help prevent the development and progression of atherosclerosis. 相似文献