全文获取类型
收费全文 | 256篇 |
免费 | 15篇 |
出版年
2022年 | 4篇 |
2021年 | 6篇 |
2020年 | 5篇 |
2019年 | 6篇 |
2018年 | 1篇 |
2017年 | 4篇 |
2016年 | 8篇 |
2015年 | 17篇 |
2014年 | 11篇 |
2013年 | 22篇 |
2012年 | 17篇 |
2011年 | 19篇 |
2010年 | 13篇 |
2009年 | 6篇 |
2008年 | 12篇 |
2007年 | 14篇 |
2006年 | 11篇 |
2005年 | 9篇 |
2004年 | 15篇 |
2003年 | 13篇 |
2002年 | 8篇 |
2001年 | 5篇 |
2000年 | 2篇 |
1999年 | 1篇 |
1998年 | 1篇 |
1996年 | 1篇 |
1995年 | 1篇 |
1994年 | 2篇 |
1992年 | 5篇 |
1991年 | 2篇 |
1990年 | 1篇 |
1989年 | 3篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1985年 | 1篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1980年 | 3篇 |
1979年 | 1篇 |
1975年 | 6篇 |
1974年 | 1篇 |
1972年 | 2篇 |
1971年 | 2篇 |
1970年 | 1篇 |
1966年 | 1篇 |
1961年 | 1篇 |
排序方式: 共有271条查询结果,搜索用时 15 毫秒
111.
Carotti A Altomare C Catto M Gnerre C Summo L De Marco A Rose S Jenner P Testa B 《化学与生物多样性》2006,3(2):134-149
A series of coumarin derivatives (1-22), bearing at the 7-position ether, ketone, ester, carbamate, or amide functions of varying size and lipophilicity, were synthesized and investigated for their in vitro monoamine oxidase-A and -B (MAO-A and -B) inhibitory activities. Most of the compounds acted preferentially as MAO-B inhibitors, with IC(50) values in the micromolar to low-nanomolar range. A structure-activity-relationship (SAR) study highlighted lipophilicity as an important property modulating the MAO-B inhibition potency of 7-substituted coumarins, as shown by a linear correlation (n=20, r(2)=0.72) between pIC(50) and calculated log P values. The stability of ester-containing coumarin derivatives in rat plasma provided information on factors that either favor (lipophilicity) or decrease (steric hindrance) esterase-catalyzed hydrolysis. Two compounds (14 and 22) were selected to investigate how lipophilicity and enzymatic stability may affect in vivo MAO activities, as assayed ex vivo in rat. The most-potent and -selective MAO-B inhibitor 22 (=7-[(3,4-difluorobenzyl)oxy]-3,4-dimethyl-1-benzopyran-2(2H)-one) within the examined series significantly inhibited (>60%) ex vivo rat-liver and striatal MAO-B activities 1 h after intraperitoneal administration of high doses (100 and 300 mumol kg(-1)), revealing its ability to cross the blood-brain barrier. At the same doses, liver and striatum MAO-A was less inhibited in vivo, somehow reflecting MAO-B selectivity, as assessed in vitro. In contrast, the metabolically less stable derivative 14, bearing an isopropyl ester in the lateral chain, had a weak effect on hepatic MAO-B activity in vivo, and none on striatal MAO-B, but, surprisingly, displayed inhibitory effects on MAO-A in both peripheral and brain tissues. 相似文献
112.
Giovannoni MP Vergelli C Cilibrizzi A Crocetti L Biancalani C Graziano A Dal Piaz V Loza MI Cadavid MI Díaz JL Gavaldà A 《Bioorganic & medicinal chemistry》2010,18(22):7890-7899
A series of pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones was synthesized and tested in radioligand binding assays to determine their affinities for the human adenosine A(1), A(2A), A(2B) and A(3) receptors. Results indicated that this scaffold is appropriate for adenosine receptor subtype A(1) ligands and that the best arranged groups around this scaffold are 3- and 4-pyridinyl at position 1, benzyl at position 3, hydrogen at position 6 and 3-thienyl or phenyl at position 9. The most interesting compounds showed K(i) for A1 in the nanomolar range and an appreciable selectivity for other receptor subtypes. 相似文献
113.
Lorella Pasquinucci Orazio Prezzavento Agostino Marrazzo Emanuele Amata Simone Ronsisvalle Zafiroula Georgoussi Danai-Dionysia Fourla Giovanna M. Scoto Carmela Parenti Giuseppina Aricò Giuseppe Ronsisvalle 《Bioorganic & medicinal chemistry》2010,18(14):4975-4982
6,7-Benzomorphan derivatives, exhibiting different μ, δ, and κ receptor selectivity profiles depending on the N-substituent, represent a useful skeleton for the synthesis of new and better analgesic agents. In this work, an aromatic ring and/or alkyl residues have been used with an N-propanamide or N-acetamide spacer for the synthesis of a new series of 5,9-dimethyl-2′-hydroxy-6,7-benzomorphan derivatives (12–22). Data obtained by competition binding assays showed that the μ opioid receptor seems to prefer an interaction with the 6,7-benzomorphan ligands having an N-substituent with a propanamide spacer and less hindered amide. Highly stringent features are required for δ receptor interaction, while an N-acetamide spacer and/or bulkier amide could preferentially lead to κ receptor selectivity. In the propanamide series, compound 12 (named LP1) displayed high μ affinity (Ki = 0.83 nM), good δ affinity (Ki = 29 nM) and low affinity for the κ receptor (Ki = 110 nM), with a selectivity ratio δ/μ and κ/μ of 35.1 and 132.5, respectively. Further, in the adenylyl cyclase assay, LP1 displayed a μ/δ agonist profile, with IC50 values of 4.8 and 12 nM at the μ and δ receptors, respectively. The antinociceptive potency of LP1 in the tail-flick test after sc administration in rat was comparable with the potency of morphine (ED50 = 2.03 and 2.7 mg/kg, respectively), and was totally reversed by naloxone. LP1, possessing a μ/δ agonist profile, could represent a lead in further developing benzomorphan-based ligands with potent in vivo analgesic activity and a reduced tendency to induce side effects. 相似文献
114.
Michela Visani Dario de Biase Gianluca Marucci Cristian Taccioli Agostino Baruzzi Annalisa Pession the PERNO Study group 《PloS one》2013,8(1)
Glioblastoma is the most aggressive brain tumor that may occur in adults. Regardless of the huge improvements in surgery and molecular therapy, the outcome of neoplasia remains poor. MicroRNAs are small molecules involved in several cellular processes, and their expression is altered in the vast majority of tumors. Several studies reported the expression of different miRNAs in glioblastoma, but one of the most critical point in understanding glioblastoma miRNAs profile is the comparison of these studies. In this paper, we focused our attention on the non-neoplastic references used for determining miRNAs expression. The aim of this study was to investigate if using three different non-neoplastic brain references (normal adjacent the tumor, commercial total RNA, and epileptic specimens) could provide discrepant results. The analysis of 19 miRNAs was performed using Real-Time PCR, starting from the set of samples described above and the expression values compared. Moreover, the three different normal RNAs were used to determine the miRNAs profile in 30 glioblastomas. The data showed that different non-neoplastic controls could lead to different results and emphasize the importance of comparing miRNAs profiles obtained using the same experimental condition. 相似文献
115.
T. M. Golas H. van de Geest J. Gros A. Sikkema N. D’Agostino J. P. Nap C. Mariani J. J. H. M. Allefs I. Rieu 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2013,126(1):59-68
Phytophthora infestans, the causal agent of late blight, remains the main threat to potato production worldwide. Screening of 19 accessions of Solanum dulcamara with P. infestans isolate Ipo82001 in detached leaf assays revealed strong resistance in an individual belonging to accession A54750069-1. This plant was crossed with a susceptible genotype, and an F1 population consisting of 63 individuals was obtained. This population segregated for resistance in 1:1 ratio, both in detached leaf assays and in an open-field experiment. Presence of the formerly mapped Rpi-dlc1 gene as the cause of the observed segregating resistance could be excluded. Subsequently, AFLP analyses using 128 primer combinations enabled identification of five markers linked to a novel resistance gene named Rpi-dlc2. AFLP markers did not show sequence similarity to the tomato and potato genomes, hampering comparative genetic positioning of the gene. For this reason we used next-generation mapping (NGM), an approach that exploits direct sequencing of DNA (in our case: cDNA) pools from bulked segregants to calculate the genetic distance between SNPs and the locus of interest. Plotting of these genetic distances on the tomato and potato genetic map and subsequent PCR-based marker analysis positioned the gene on chromosome 10, in a region overlapping with the Rpi-ber/ber1 and -ber2 loci from S. berthaultii. Pyramiding of Rpi-dlc2 and Rpi-dlc1 significantly increased resistance to P. infestans, compared with individuals containing only one of the genes, showing the usefulness of this strategy to enhance resistance against Phytophthora. 相似文献
116.
Giovanna Flaim Federica Camin Agostino Tonon Ulrike Obertegger 《Biogeochemistry》2013,116(1-3):187-198
Altitude encompasses broad environmental gradients that influence the isotopic composition of lake water. We selected 55 lakes in the Eastern Alps along an altitudinal gradient [214–2,532 m above sea level (a.s.l.)] to model the isotopic signal of surface water dependent on intrinsic (lake geomorphometry) and extrinsic (air temperature, precipitation) factors. Ordinary and generalised least squared regression were used for statistical analysis. The isotope signal of lake water was lower in spring than in summer and decreased with altitude (?0.21 δ18O ‰/100 m; ?1.5 δ2H ‰/100 m). This pattern largely depended on temperature and a pseudo-latitude effect. The isotopic signal in monthly precipitation (12 stations; altitudinal gradient 90–2,730 m a.s.l.) generally showed the expected pattern of less enriched values with altitude; however, unusual values were related to weather anomalies. The local meteoric water line was similar to the global meteoric water line as shown by overlapping confidence intervals. By discriminating different elevational bands, we could show that high elevation lakes (>1,500 m a.s.l.) experience different patterns of evaporation with respect to low elevation lakes (<1,500 m a.s.l.). Our study showed that lakes have a unique isotopic fingerprint along an altitudinal gradient, potentially useful for tracing ecological processes and for paleoclimatic studies. 相似文献
117.
Abstract Puccinellia festucaeformis (Host) Parl.: germination and early growth on different salt substrates. Germination behaviour of Puccinellia festucaeformis seeds and early growth of seedlings at different experimental conditions was analysed. The following growth substrates were utilized: NaCl, KCl, KNO3, MgCl2, MgSO4, Na2SO4, NaNO3, CaCl2 at the decreasing concentrations of 0.50, 0.25, 0.12, 0.06M. Caryopses were allowed to imbibe and grow at alternating temperatures (10°-20°C or 20°-30°C) in the dark for 3 days. Seedling were grown for 15 days, at controlled light and temperature conditions, in the same nutrient substrates as those used for the germination experiments. The germination experiments showed a high tolerance to salts up to 0.25M solution and for the whole range of MgSO4 concentrations. High growth temperatures increased the depressive effects of salt concentrations. Seedling growth was highly reduced when salt concentration was higher than 0.12M. High salt tolerance - maximum shoot and root growth - was showed by seedling allowed to grow on 0.50M MgSO4. Germination and growth condition of Puccinellia festucaeformis is discussed in relation to the ecological features of this species and to its possible importance as bioindicator of MgSO4 rich natural substrates. 相似文献
118.
F Fausti S Di Agostino M Cioce P Bielli C Sette P P Pandolfi M Oren M Sudol S Strano G Blandino 《Cell death and differentiation》2013,20(11):1498-1509
Werner syndrome (WS) results from dysfunction of the WRN protein, and is associated with premature aging and early death. Here we report that loss of WRN function elicits accumulation of the Yes-associated protein (YAP protein), a major effector of the Hippo tumor suppressor pathway, both experimentally and in WS-derived fibroblasts. YAP upregulation correlates with slower cell proliferation and accelerated senescence, which are partially mediated by the formation of a complex between YAP and the PML protein, whose activity promotes p53 activation. The ATM kinase is necessary for YAP and PML accumulation in WRN-depleted cells. Notably, the depletion of either YAP or PML partially impairs the induction of senescence following WRN loss. Altogether, our findings reveal that loss of WRN activity triggers the activation of an ATM-YAP-PML-p53 axis, thereby accelerating cellular senescence. The latter has features of SASP (senescence-associated secretory phenotype), whose protumorigenic properties are potentiated by YAP, PML and p53 depletion. 相似文献
119.
Szabo M Agostino M Malone DT Yuriev E Capuano B 《Bioorganic & medicinal chemistry letters》2011,21(22):6782-6787
We have synthesised an extensive series of URB602 analogues as inhibitors of monoacylglycerol lipase (MAGL), which is the major enzyme responsible for metabolising the endocannabinoid 2-arachidonylglycerol. The recently identified crystal structure of MAGL was used in the design strategy and revealed three possible binding sites for URB602 and the proposed analogues. A test series of carbamate analogues were docked into the identified sites to predict the most favourable binding location. The synthesised analogues of URB602 explored the biological effects of isosteric replacement, ring size and substitution, para substitution of the biphenyl moiety and the incorporation of a bicyclic element. The compounds were tested for their ability to inhibit human MAGL. The carbamate analogue 16 displayed the most significant inhibitory activity, reducing MAGL activity to 26% of controls at 100 μM compared to 73% for the parent compound URB602. 相似文献
120.
Hênio Henrique Arag?o Rêgo Lidia A. Braunstein Gregorio D′Agostino H. Eugene Stanley Sasuke Miyazima 《PloS one》2014,9(10)
In linguistic studies, the academic level of the vocabulary in a text can be described in terms of statistical physics by using a “temperature” concept related to the text''s word-frequency distribution. We propose a “comparative thermo-linguistic” technique to analyze the vocabulary of a text to determine its academic level and its target readership in any given language. We apply this technique to a large number of books by several authors and examine how the vocabulary of a text changes when it is translated from one language to another. Unlike the uniform results produced using the Zipf law, using our “word energy” distribution technique we find variations in the power-law behavior. We also examine some common features that span across languages and identify some intriguing questions concerning how to determine when a text is suitable for its intended readership. 相似文献