全文获取类型
收费全文 | 755篇 |
免费 | 48篇 |
出版年
2023年 | 4篇 |
2022年 | 9篇 |
2021年 | 22篇 |
2020年 | 11篇 |
2019年 | 15篇 |
2018年 | 16篇 |
2017年 | 20篇 |
2016年 | 26篇 |
2015年 | 40篇 |
2014年 | 41篇 |
2013年 | 54篇 |
2012年 | 62篇 |
2011年 | 56篇 |
2010年 | 34篇 |
2009年 | 34篇 |
2008年 | 30篇 |
2007年 | 42篇 |
2006年 | 38篇 |
2005年 | 31篇 |
2004年 | 34篇 |
2003年 | 22篇 |
2002年 | 20篇 |
2001年 | 18篇 |
2000年 | 11篇 |
1999年 | 15篇 |
1998年 | 12篇 |
1997年 | 6篇 |
1996年 | 5篇 |
1995年 | 4篇 |
1994年 | 2篇 |
1993年 | 2篇 |
1992年 | 3篇 |
1991年 | 2篇 |
1990年 | 7篇 |
1989年 | 4篇 |
1988年 | 2篇 |
1987年 | 4篇 |
1986年 | 6篇 |
1985年 | 3篇 |
1981年 | 2篇 |
1980年 | 5篇 |
1979年 | 3篇 |
1978年 | 3篇 |
1976年 | 2篇 |
1972年 | 2篇 |
1970年 | 4篇 |
1969年 | 3篇 |
1968年 | 2篇 |
1967年 | 1篇 |
1966年 | 1篇 |
排序方式: 共有803条查询结果,搜索用时 437 毫秒
141.
142.
Kasthuri Kannayiram Vidhya Rekha Umapathy Y Chamundeswari JH Fathima Ramajayam Govindan Chella Perumal Palanisamy Vishnu Priya Veeraraghavan Selvaraj Jayaraman Ponnulakshmi Rajagopal 《Bioinformation》2022,18(3):80
Diabetes mellitus is a group of metabolic disorders that has risen to become the third most common cause in humans in recent years. The development of new bioactive substances from natural sources is a relatively new area. Flavonoids are believed to have a variety of beneficial properties in nature, including anti-inflammatory, antimicrobial, anticancer, antioxidant, neuroprotective, and anti-HIV properties. 15 naturally occurring flavonoids docked with the selected target aldose reductase. We report the optimal binding of Acumitin, Agathisflavone, Agehoustin B, and alpha-Toxicarol with aldose reductase for further consideration in drug discovery for T2DM. 相似文献
143.
Genetic mapping of ripening and ethylene-related loci in tomato 总被引:5,自引:0,他引:5
J. Giovannoni H. Yen B. Shelton S. Miller J. Vrebalov P. Kannan D. Tieman R. Hackett D. Grierson H. Klee 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》1999,98(6-7):1005-1013
The regulation of tomato fruit development and ripening is influenced by a large number of loci as demonstrated by the number
of existing non-allelic fruit development mutations and a multitude of genes showing ripening-related expression patterns.
Furthermore, analysis of transgenic and naturally occurring tomato mutants confirms the pivotal role of the gaseous hormone
ethylene in the regulation of climacteric ripening. Here we report RFLP mapping of 32 independent tomato loci corresponding
to genes known or hypothesized to influence fruit ripening and/or ethylene response. Mapped ethylene-response sequences fall
into the categories of genes involved in either hormone biosynthesis or perception, while additional ripening-related genes
include those involved in cell-wall metabolism and pigment biosynthesis. The placement of ripening and ethylene-response loci
on the tomato RFLP map will facilitate both the identification and exclusion of candidate gene sequences corresponding to
identified single gene and quantitative trait loci contributing to fruit development and ethylene response.
Received: 26 October 1998 / Accepted: 13 November 1998 相似文献
144.
145.
Ao Zhang Aarya Venkat Rahil Taujale James L. Mull Atsuko Ito Natarajan Kannan Robert S. Haltiwanger 《The Journal of biological chemistry》2021,297(1)
Peters Plus Syndrome (PTRPLS OMIM #261540) is a severe congenital disorder of glycosylation where patients have multiple structural anomalies, including Peters anomaly of the eye (anterior segment dysgenesis), disproportionate short stature, brachydactyly, dysmorphic facial features, developmental delay, and variable additional abnormalities. PTRPLS patients and some Peters Plus-like (PTRPLS-like) patients (who only have a subset of PTRPLS phenotypes, have mutations in the gene encoding β1,3-glucosyltransferase [B3GLCT]). B3GLCT catalyzes the transfer of glucose to O-linked fucose on thrombospondin type-1 repeats. Most B3GLCT substrate proteins belong to the ADAMTS superfamily and play critical roles in extracellular matrix. We sought to determine whether the PTRPLS or PTRPLS-like mutations abrogated B3GLCT activity. B3GLCT has two putative active sites, one in the N-terminal region and the other in the C-terminal glycosyltransferase domain. Using sequence analysis and in vitro activity assays, we demonstrated that the C-terminal domain catalyzes transfer of glucose to O-linked fucose. We also generated a homology model of B3GLCT and identified D421 as the catalytic base. PTRPLS and PTRPLS-like mutations were individually introduced into B3GLCT, and the mutated enzymes were evaluated using in vitro enzyme assays and cell-based functional assays. Our results demonstrated that PTRPLS mutations caused loss of B3GLCT enzymatic activity and/or significantly reduced protein stability. In contrast, B3GLCT with PTRPLS-like mutations retained enzymatic activity, although some showed a minor destabilizing effect. Overall, our data supports the hypothesis that loss of glucose from B3GLCT substrate proteins is responsible for the defects observed in PTRPLS patients, but not for those observed in PTRPLS-like patients. 相似文献
146.
M. Kannan P. Manivel K. Geetha J. Muthukumaran H. Surya Prakash Rao R. Krishna 《Journal of chemical biology》2012,5(4):151-166
Anomalous action of human acetylcholinesterase (hAChE) in Alzheimer’s disease (AD) was restrained by various AChE inhibitors, of which the specific and potent lead candidate Donepezil is used for treating the disease AD. Besides the specificity, the observed undesirable side effects caused by Donepezil invoked the quest for new lead molecules with the increased potency and specificity for AChE. The present study elucidates the potency of six 1N-methyl-1S-methyl-2-nitroethylene (NMSM) derivatives to form a specific interaction with the peripheral anionic site and catalytic anionic subsite residues of hAChE. The NMSMs were prepared in good yield from 1,1-di(methylsulfanyl)-2-nitroethylene and primary amine (or) amino acid esters. In silico interaction analysis reveals specific and potent interactions between hAChE and selected ligand molecules. The site-specific interactions formed between these molecules also results in a conformational change in the orientation of active site residues of hAChE, which prevents them from being accessed by beta-amyloid protein (Aβ), which is a causative agent for amyloid plaque formation and acetylcholine (ACh). In silico interaction analysis between the ligand-bounded hAChE with Aß and ACh confirms this observation. The variation in the conformation of hAChE associated with the decreased ability of Aβ and ACh to access the respective functional residues of hAChE induced by the novel NMSMs favors their selection for in vivo analysis to present themselves as new members of hAChE inhibitors. 相似文献
147.
148.
Prickly ash trees with shortened internodes, proliferation of shoots, phyllody and witches' brooms were observed for the first time in Korea. A phytoplasma was detected in infected trees by polymerase chain reaction amplification of 16S rDNA, 16S–23S intergenic spacer region and the fragment of rp operon sequences. The 16S rDNA sequences exhibited maximum (99.6%) similarity with Iranian lettuce phytoplasma, and the sequences of rp operon exhibited maximum (100%) similarity with golden rain phytoplasma. Based on the sequence analysis and phylogenetic studies, it was confirmed that phytoplasma infecting prickly ash trees in Korea belongs to the aster yellows group (subgroup 16SrI‐B). 相似文献
149.
Vijeta Sharma Nagarjuna Amarnath Swapnil Shukla R. Ayana Naveen Kumar Nisha Yadav Deepika Kannan Seema Sehrawat Soumya Pati Bimlesh Lochab Shailja Singh 《Bioorganic & medicinal chemistry letters》2018,28(9):1629-1637
Development of new class of anti-malarial drugs is an essential requirement for the elimination of malaria. Bioactive components present in medicinal plants and their chemically modified derivatives could be a way forward towards the discovery of effective anti-malarial drugs. Herein, we describe a new class of compounds, 1,3-benzoxazine derivatives of pharmacologically active phytophenols eugenol (compound 3) and isoeugenol (compound 4) synthesised on the principles of green chemistry, as anti-malarials. Compound 4, showed highest anti-malarial activity with no cytotoxicity towards mammalian cells. Compound 4 induced alterations in the intracellular Na+ levels and mitochondrial depolarisation in intraerythrocytic Plasmodium falciparum leading to cell death. Knowing P-type cation ATPase PfATP4 is a regulator for sodium homeostasis, binding of compound 3, compound 4 and eugenol to PfATP4 was analysed by molecular docking studies. Compounds showed binding to the catalytic pocket of PfATP4, however compound 4 showed stronger binding due to the presence of propylene functionality, which corroborates its higher anti-malarial activity. Furthermore, anti-malarial half maximal effective concentration of compound 4 was reduced to 490?nM from 17.54?µM with nanomaterial graphene oxide. Altogether, this study presents anti-plasmodial potential of benzoxazine derivatives of phytophenols and establishes disruption of parasite sodium homeostasis as their mechanism of action. 相似文献
150.
Melody D. Fulton Laura E. Hanold Zheng Ruan Sneha Patel Aaron M. Beedle Natarajan Kannan Eileen J. Kennedy 《Bioorganic & medicinal chemistry》2018,26(6):1167-1173
Although EGFR is a highly sought-after drug target, inhibitor resistance remains a challenge. As an alternative strategy for kinase inhibition, we sought to explore whether allosteric activation mechanisms could effectively be disrupted. The kinase domain of EGFR forms an atypical asymmetric dimer via head-to-tail interactions and serves as a requisite for kinase activation. The kinase dimer interface is primarily formed by the H-helix derived from one kinase monomer and the small lobe of the second monomer. We hypothesized that a peptide designed to resemble the binding surface of the H-helix may serve as an effective disruptor of EGFR dimerization and activation. A library of constrained peptides was designed to mimic the H-helix of the kinase domain and interface side chains were optimized using molecular modeling. Peptides were constrained using peptide “stapling” to structurally reinforce an alpha-helical conformation. Peptide stapling was demonstrated to notably enhance cell permeation of an H-helix derived peptide termed EHBI2. Using cell-based assays, EHBI2 was further shown to significantly reduce EGFR activity as measured by EGFR phosphorylation and phosphorylation of the downstream signaling substrate Akt. To our knowledge, this is the first H-helix-based compound targeting the asymmetric interface of the kinase domain that can successfully inhibit EGFR activation and signaling. This study presents a novel, alternative targeting site for allosteric inhibition of EGFR. 相似文献