全文获取类型
收费全文 | 2422篇 |
免费 | 157篇 |
出版年
2023年 | 5篇 |
2022年 | 24篇 |
2021年 | 51篇 |
2020年 | 30篇 |
2019年 | 39篇 |
2018年 | 57篇 |
2017年 | 35篇 |
2016年 | 78篇 |
2015年 | 115篇 |
2014年 | 104篇 |
2013年 | 185篇 |
2012年 | 216篇 |
2011年 | 181篇 |
2010年 | 101篇 |
2009年 | 97篇 |
2008年 | 156篇 |
2007年 | 133篇 |
2006年 | 135篇 |
2005年 | 113篇 |
2004年 | 124篇 |
2003年 | 104篇 |
2002年 | 99篇 |
2001年 | 28篇 |
2000年 | 17篇 |
1999年 | 17篇 |
1998年 | 29篇 |
1997年 | 13篇 |
1996年 | 21篇 |
1995年 | 13篇 |
1994年 | 21篇 |
1993年 | 27篇 |
1992年 | 18篇 |
1991年 | 15篇 |
1990年 | 26篇 |
1989年 | 7篇 |
1988年 | 13篇 |
1987年 | 8篇 |
1986年 | 8篇 |
1985年 | 20篇 |
1984年 | 8篇 |
1983年 | 8篇 |
1982年 | 8篇 |
1981年 | 13篇 |
1980年 | 8篇 |
1979年 | 14篇 |
1978年 | 8篇 |
1975年 | 4篇 |
1974年 | 7篇 |
1973年 | 3篇 |
1968年 | 3篇 |
排序方式: 共有2579条查询结果,搜索用时 15 毫秒
101.
Gabriella Guerrini Giovanna Ciciani Samuele Ciattini Letizia Crocetti Simona Daniele Claudia Martini 《Journal of enzyme inhibition and medicinal chemistry》2016,31(2):195-204
To investigate the binding affinity of GABAA receptor subtype, new pyrazolo [1,5-a]quinazolines were designed, synthesized, and in vitro evaluated. These compounds, 5-deaza analogues of pyrazolo[5,1-c][1,2,4]benzotriazine derivatives which were already studied in our research group, permit us to evaluate the relevance of the nitrogen or the oxygen atom at 5-position of the tricyclic scaffold. Molecular dynamic study was done on a set of the new and known ligands to rationalize and to explain the lack of affinity on the 4- or 5-substituted new derivative. In fact, from biological results, it can be found that the only 5-unsubstituted new derivative, compound 15, has receptor recognition (Ki?=?834.7?nM). 相似文献
102.
Maria Paola Giovannoni Igor A. Schepetkin Letizia Crocetti Giovanna Ciciani Agostino Cilibrizzi Gabriella Guerrini 《Journal of enzyme inhibition and medicinal chemistry》2016,31(4):628-639
Compounds that can effectively inhibit the proteolytic activity of human neutrophil elastase (HNE) represent promising therapeutics for treatment of inflammatory diseases. We present here the synthesis, structure–activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with a cinnoline scaffold. These compounds exhibited HNE inhibitory activity but had lower potency compared to N-benzoylindazoles previously reported by us. On the other hand, they exhibited increased stability in aqueous solution. The most potent compound, 18a, had a good balance between HNE inhibitory activity (IC50 value?=?56?nM) and chemical stability (t1/2?=?114?min). Analysis of reaction kinetics revealed that these cinnoline derivatives were reversible competitive inhibitors of HNE. Furthermore, molecular docking studies of the active products into the HNE binding site revealed two types of HNE inhibitors: molecules with cinnolin-4(1H)-one scaffold, which were attacked by the HNE Ser195 hydroxyl group at the amido moiety, and cinnoline derivatives containing an ester function at C-4, which is the point of attack of Ser195. 相似文献
103.
Absolute Configuration Assignment of a Paraconic Acid Derivative via Vibrational Circular Dichroism Spectroscopy and Density Functional Theory Calculation 下载免费PDF全文
Sara Meninno Paola Rizzo Sergio Abbate Giovanna Longhi Giuseppe Mazzeo Guglielmo Monaco Alessandra Lattanzi Riccardo Zanasi 《Chirality》2016,28(2):110-115
Density functional theory calculation of the vibrational circular dichroism spectrum was used to assign the absolute configuration of an all‐carbon quaternary β‐stereocenter of a γ‐butyrolactone recently synthesized through an asymmetric organocatalytic tandem aldol/lactonization sequence. Comparison with the experimental spectrum is satisfactory, on account of the fact that spectroscopic features are weak due to the presence of multiple conformers. As a result, the (R) absolute configuration was assigned to the (+) optical isomer. Chirality 28:110–115, 2016. © 2015 Wiley Periodicals, Inc. 相似文献
104.
Chouaibi Moncef Boussaid Amel Donsì Francesco Ferrari Giovanna Hamdi Salem 《International journal of peptide research and therapeutics》2019,25(4):1509-1521
International Journal of Peptide Research and Therapeutics - In this study, response surface methodology, based on Box-Behnken design, was used to optimize the extraction conditions of protein... 相似文献
105.
Domenico Rau Maria L. Murgia Monica Rodriguez Elena Bitocchi Elisa Bellucci Davide Fois Diego Albani Laura Nanni Tania Gioia Debora Santo Luca Marcolungo Massimo Delledonne Giovanna Attene Roberto Papa 《The Plant journal : for cell and molecular biology》2019,97(4):693-714
The complete or partial loss of shattering ability occurred independently during the domestication of several crops. Therefore, the study of this trait can provide an understanding of the link between phenotypic and molecular convergent evolution. The genetic dissection of ‘pod shattering’ in Phaseolus vulgaris is achieved here using a population of introgression lines and next‐generation sequencing techniques. The ‘occurrence’ of the indehiscent phenotype (indehiscent versus dehiscent) depends on a major locus on chromosome 5. Furthermore, at least two additional genes are associated with the ‘level’ of shattering (number of shattering pods per plant: low versus high) and the ‘mode’ of shattering (non‐twisting versus twisting pods), with all of these loci contributing to the phenotype by epistatic interactions. Comparative mapping indicates that the major gene identified on common bean chromosome 5 corresponds to one of the four quantitative trait loci for pod shattering in Vigna unguiculata. None of the loci identified comprised genes that are homologs of the known shattering genes in Glycine max. Therefore, although convergent domestication can be determined by mutations at orthologous loci, this was only partially true for P. vulgaris and V. unguiculata, which are two phylogenetically closely related crop species, and this was not the case for the more distant P. vulgaris and G. max. Conversely, comparative mapping suggests that the convergent evolution of the indehiscent phenotype arose through mutations in different genes from the same underlying gene networks that are involved in secondary cell‐wall biosynthesis and lignin deposition patterning at the pod level. 相似文献
106.
107.
Mohammad S Baldini G Granell S Narducci P Martelli AM Baldini G 《The Journal of biological chemistry》2007,282(7):4963-4974
Melanocortin-4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that binds alpha-melanocyte-stimulating hormone (alpha-MSH) and has a central role in the regulation of appetite and energy expenditure. Most GPCRs are endocytosed following binding to the agonist and receptor desensitization. Other GPCRs are internalized and recycled back to the plasma membrane constitutively, in the absence of the agonist. In unstimulated neuroblastoma cells and immortalized hypothalamic neurons, epitopetagged MC4R was localized both at the plasma membrane and in an intracellular compartment. These two pools of receptors were in dynamic equilibrium, with MC4R being rapidly internalized and exocytosed. In the absence of alpha-MSH, a fraction of cell surface MC4R localized together with transferrin receptor and to clathrin-coated pits. Constitutive MC4R internalization was impaired by expression of a dominant negative dynamin mutant. Thus, MC4R is internalized together with transferrin receptor by clathrin-dependent endocytosis. Cell exposure toalpha-MSH reduced the amount of MC4R at the plasma membrane by blocking recycling of a fraction of internalized receptor, rather than by increasing its rate of endocytosis. The data indicate that, in neuronal cells, MC4R recycles constitutively and that alpha-MSH modulates MC4R residency at the plasma membrane by acting at an intracellular sorting step. 相似文献
108.
Cutrona G Boffa LC Mariani MR Matis S Damonte G Millo E Roncella S Ferrarini M 《Oligonucleotides》2007,17(1):146-150
The present study aims to evaluate the antigenicity of a PNA complementary to the Emu sequence (PNAEmu) with cancer therapeutic potential properties in Burkitt's lymphoma (BL). In BL cells, the c-myc oncogene is repositioned next to the Emu enhancer of the immunoglobulin (Ig) locus, due to chromosomal translocation, and up-regulated. PNAEmu linked to a nuclear localization signal peptide was shown specifically to block c-myc hyperexpression by inhibiting cell growth in vitro and in vivo. Recently, we reported that the administration of PNAEmu to mice, following inoculation with BL cells, hinders tumor growth without toxic effects. To investigate the potential use of PNAEmu in clinical applications further, we tested its antigenicity. Mice were inoculated with an emulsion of free PNA or PNA crosslinked to the immunogenic carrier keyhole limpet hemocyanin (KLH) with Freund's adjuvant. Antibodies to free PNA were undetected, whereas both IgG and IgM antibodies to PNA-KLH were detected in mouse serum 28 and 38 days after inoculation. 相似文献
109.
Orefice Ida Di Dato Valeria Sardo Angela Lauritano Chiara Romano Giovanna 《Aquatic Ecology》2022,56(2):377-397
Aquatic Ecology - Diatoms are eukaryotic microalgae representing one of the major groups in the marine phytoplankton, accounting for up to 40% of annual productivity at sea. They are widely... 相似文献
110.
Giacomo Pozzoli Hany E. Marei Asma Althani Alma Boninsegna Patrizia Casalbore Lionel N. J. L. Marlier Giulia Lanzilli Manuela Zonfrillo Giovanna Petrucci Bianca Rocca Pierluigi Navarra Alessandro Sgambato Carlo Cenciarelli 《Journal of cellular physiology》2019,234(9):15459-15471
Several clinical studies indicated that the daily use of aspirin or acetylsalicylic acid reduces the cancer risk via cyclooxygenases (Cox-1 and Cox-2) inhibition. In addition, aspirin-induced Cox-dependent and -independent antitumor effects have also been described. Here we report, for the first time, that aspirin treatment of human glioblastoma cancer (GBM) stem cells, a small population responsible for tumor progression and recurrence, is associated with reduced cell proliferation and motility. Aspirin did not interfere with cell viability but induced cell-cycle arrest. Exogenous prostaglandin E2 significantly increased cell proliferation but did not abrogate the aspirin-mediated growth inhibition, suggesting a Cox-independent mechanism. These effects appear to be mediated by the increase of p21 waf1 and p27 Kip1, associated with a reduction of Cyclin D1 and Rb1 protein phosphorylation, and involve the downregulation of key molecules responsible for tumor development, that is, Notch1, Sox2, Stat3, and Survivin. Our results support a possible role of aspirin as adjunctive therapy in the clinical management of GBM patients. 相似文献