全文获取类型
收费全文 | 1277篇 |
免费 | 53篇 |
国内免费 | 1篇 |
出版年
2021年 | 22篇 |
2020年 | 16篇 |
2019年 | 14篇 |
2018年 | 32篇 |
2017年 | 21篇 |
2016年 | 34篇 |
2015年 | 45篇 |
2014年 | 51篇 |
2013年 | 103篇 |
2012年 | 77篇 |
2011年 | 90篇 |
2010年 | 57篇 |
2009年 | 48篇 |
2008年 | 61篇 |
2007年 | 60篇 |
2006年 | 84篇 |
2005年 | 58篇 |
2004年 | 40篇 |
2003年 | 43篇 |
2002年 | 31篇 |
2001年 | 19篇 |
2000年 | 9篇 |
1999年 | 13篇 |
1998年 | 9篇 |
1997年 | 6篇 |
1996年 | 10篇 |
1995年 | 16篇 |
1994年 | 11篇 |
1993年 | 8篇 |
1992年 | 15篇 |
1991年 | 6篇 |
1989年 | 7篇 |
1988年 | 6篇 |
1985年 | 9篇 |
1984年 | 8篇 |
1982年 | 10篇 |
1981年 | 7篇 |
1979年 | 6篇 |
1978年 | 6篇 |
1976年 | 6篇 |
1975年 | 7篇 |
1967年 | 7篇 |
1961年 | 7篇 |
1959年 | 5篇 |
1958年 | 5篇 |
1957年 | 8篇 |
1956年 | 7篇 |
1928年 | 5篇 |
1927年 | 8篇 |
1917年 | 5篇 |
排序方式: 共有1331条查询结果,搜索用时 183 毫秒
61.
Jaroslav Pavel Zuzana Oroszova Ludmila Hricova Nadezda Lukacova 《Cellular and molecular neurobiology》2013,33(5):681-688
To clarify the role of angiotensin II (Ang II) in the regulation of sensory signaling, we studied the effect of subpressor dose (150 ng/kg/min) of Ang II on pain-related behavior in relation with neuronal injury and activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRGs) after chronic constriction injury (CCI). Systemic continuous delivery of Ang II induced the tactile, heat and cold hyperlagesia, when measured at 7 days ofpost-injury. Blockade of the AT1 receptor with losartan (2.5 mg/kg/day) prevented tactile hyperalgesia and attenuated cold hyperalgesia, but did not affect the response to noxious heat stimulus. A marked increase of large-sized injured primary afferent neurons, detected by ATF3 immunolabeling, was seen in lower lumbar DRGs on ipsilateral side after Ang II treatment. Subpressor dose of Ang II induced an increase of activated SGCs (detected by GFAP immunolabeling) enveloping large-diameter neurons. Our results suggested that Ang II through the AT1 receptor activation is an important regulatory factor in neuropathic pain perception and plays an important role in the injury of large-sized primary afferent neurons and activation of SGCs elicited by the CCI. 相似文献
62.
Miriam Rossi Francesco Caruso Erica J. Crespi Jens Z. Pedersen Gail Nakano Michelle Duong Celia Mckee Sharon Lee Manasi Jiwrajka Charles Caldwell Francis Baffour Dylan Alex Karlin Genevieve Lidoff Stefano Leone Valentina Balducci Jaroslav Miler Sandra Incerpi 《Biochimie》2013
In order to better understand the antioxidant behavior of a series of polyphenolic 2′-hydroxychalcones, we describe the results of several chemical and biological studies, in vitro and in vivo. Single crystal X-ray methods elucidated their molecular structures and important intermolecular interactions such as H-bonding and molecular stacking in the crystal structures that contribute to our knowledge in explaining antioxidant activity. The results of experiments using the 1,1-diphenyl-2-dipicrylhydrazyl (DPPH) UV–vis spectroscopic method indicate that a hydroxyl group in position 5′ induces the highest antioxidant activity. Consequently, 2,2′,5′-trihydroxychalcone was selected for further study in vitro towards ROS scavenging in L-6 myoblasts and THP-1 human monocytes, where it shows an excellent antioxidant activity in a concentration range lower than that reported by most studies of related molecules. In addition, this chalcone shows a very selective activity: it inhibits the proliferation of leukemic cells, but it does not affect the normal L-6 myoblasts and human fibroblasts. In studying 2,2′,5′-trihydroxychalcone's effect on weight gain and serum glucose and insulin levels in Zucker fatty (fa−/fa−) rats we found that supplementing the diet with a 10 mg/kg dose of this chalcone (3 times weekly) blunted the increase in glucose that co-occurs with weight gain over the 6-week treatment period. It is concluded that 2,2′,5′-trihydroxychalcone has the potential to serve as a protective agent for some debilitating diseases. 相似文献
63.
Jiřina Vávrová Lenka Zárybnická Emilie Lukášová Martina Řezáčová Eva Novotná Zuzana Šinkorová Aleš Tichý Jaroslav Pejchal Kamila Ďurišová 《Radiation and environmental biophysics》2013,52(4):471-479
We compared the effects of inhibitors of kinases ATM (KU55933) and ATR (VE-821) (incubated for 30 min before irradiation) on the radiosensitization of human promyelocyte leukaemia cells (HL-60), lacking functional protein p53. VE-821 reduces phosphorylation of check-point kinase 1 at serine 345, and KU55933 reduces phosphorylation of check-point kinase 2 on threonine 68 as assayed 4 h after irradiation by the dose of 6 Gy. Within 24 h after gamma-irradiation with a dose of 3 Gy, the cells accumulated in the G2 phase (67 %) and the number of cells in S phase decreased. KU55933 (10 μM) did not affect the accumulation of cells in G2 phase and did not affect the decrease in the number of cells in S phase after irradiation. VE-821 (2 and 10 μM) reduced the number of irradiated cells in the G2 phase to the level of non-irradiated cells and increased the number of irradiated cells in S phase, compared to irradiated cells not treated with inhibitors. In the 144 h interval after irradiation with 3 Gy, there was a considerable induction of apoptosis in the VE-821 group (10 μM). The repair of the radiation damage, as observed 72 h after irradiation, was more rapid in the group exposed solely to irradiation and in the group treated with KU55933 (80 and 77 % of cells, respectively, were free of DSBs), whereas in the group incubated with 10 μM VE-821, there were only 61 % of cells free of DSBs. The inhibition of kinase ATR with its specific inhibitor VE-821 resulted in a more pronounced radiosensitizing effect in HL-60 cells as compared to the inhibition of kinase ATM with the inhibitor KU55933. In contrast to KU55933, the VE-821 treatment prevented HL-60 cells from undergoing G2 cell cycle arrest. Taken together, we conclude that the ATR kinase inhibition offers a new possibility of radiosensitization of tumour cells lacking functional protein p53. 相似文献
64.
Richard Štefl Eva Fadrná Jaroslav Koča 《Journal of biomolecular structure & dynamics》2013,31(5):1087-1095
Abstract The conformational behavior of single strand (ss) TAT and ATA trimers of DNA have been studied by computational chemistry tools including CICADA software interfaced with AMBER molecular mechanics and dynamics. The Single-Coordinate-Driving (SCD) method has been used in conjunction with molecular dynamics simulated annealing. It has been revealed that the conformational flexibility of each sequence differs substantially from the other one. Four common conformational families have been found for both trimers. These are: helical, reverse-stacked (base 3), half-stacked (base 3), reverse-stacked (base 1). However, the energies of conformers representing the families are different for both the studied systems. An additional conformational family, bulged, has been found for ss(ATA), while ss(TAT) has been found also in half-stacked (base 1) conformation. In general, ss(TAT) exhibits a higher number of low energy conformations while ss(ATA) shows one interesting low energy conformational interconversion between reverse-stacked (A3) family and half-stacked (A3) family. The high conformational variability of the trimers has been confirmed by flexibility analysis and by molecular dynamics simulations, which have also shown the conformational stability of single conformational families. It has been concluded that the methodology used is able to provide a very detailed picture of the conformational space of these molecules. 相似文献
65.
Michal Otyepka Zdeněk Kříž Jaroslav Koča 《Journal of biomolecular structure & dynamics》2013,31(2):141-154
Abstract This article presents a molecular dynamics (MD) study of the cdk2 enzyme and its two complexes with the inhibitors isopentenyladenine and roscovitine using the Cornell et al. force field from the AMBER software package. The results show that inserting an inhibitor into the enzyme active site does not considerably change enzyme structure but it seemingly changes the distribution of internal motions. The inhibitor causes differences in the domain motions in free cdk2 and in its complexes. It was found out that repulsion of roscovitine N9 substituent causes conformational change on Lys 33 side chain. Isopentenyladenine forms with Lys 33 side chain terminal amino group a hydrogen bond. It implies that the cavity, where N9 substituent of roscovitine is buried, can adopt larger substituent due to Lys 33 side chain flexibility. The composition of electrostatic and van der Waals interactions between the inhibitor and the enzyme were also calculated along both cdk2/inhibitor MD trajectories together with MM-PB/GBSA analysis. These results show that isopentenyladenine-like inhibitors could be more effective after modifications leading to an increase in their van der Waals contact with the enzyme. We suggest that a way leading to better inhibitors occupying isopentenyladenine binding mode could be: to keep N9 and N7 purine positions free, to keep 3,3-dimethylallylamino group at C6 position, and to add, e.g., benzylamino group at C2 position. The results support the idea that the isopentenyladenine binding mode can be used for cdk2 inhibitors design and that all possibilities to improve this binding mode were not uncovered yet. 相似文献
66.
67.
Katarína Střelcová Daniel Kurjak Adriana Leštianska Dana Kovalčíková Ľubica Ditmarová Jaroslav Škvarenina Yousif Abdel-Rahman Ahmed 《Biologia》2013,68(6):1118-1122
The paper focuses on the evaluation of transpiration as a physiological process, which is very sensitive to drought stress. Reactions of 25-year-old Norway spruce (Picea abies (L.) Karst.) trees to drought were examined during 2009 summer. Sap flow rate (SF), meteorological and soil characteristics were measured continually. Vapour pressure deficit of the air (VPD) and cumulative transpiration deficit (KTD) was calculated. During the second half of the vegetation period, the decrease in soil water content was observed and irrigation was applied to a group of spruce trees, while the second group was treated under natural soil drought. On the days, when the differences in transpiration between irrigated (IR) and non-irrigated (NIR) trees were significant (21 days), transpiration of NIR trees was only 23% of the transpiration of IR trees. We found significant differences in transpiration when the soil water content (SWC) of NIR variant at a depth of 5–15 cm ranged from 10.4 to 13.7%. Under both regimes of water availability, daily transpiration significantly responded to atmospheric conditions. However, the influence of all assessed meteorological parameters on SF of NIR trees was significantly lower than on IR tree. The dependency of transpiration on evaporative demands of atmosphere decreased with the decreasing soil moisture. Cumulative transpiration deficit of the stand during the entire evaluated period was 50.9 mm. The difference between the transpiration of the mean NIR tree and of the mean IR tree was 278.8 L over the assessed period of 47 days (5.9 L per day). The transpiration of NIR trees was 40.3% from the transpiration of IR trees during this period. 相似文献
68.
69.
Zbigniew Zawada Martin Šafařík Eva Dvořáková Olga Janoušková Anna Březinová Ivan Stibor Karel Holada Petr Bouř Jan Hlaváček Jaroslav Šebestík 《Amino acids》2013,44(5):1279-1292
Quinacrine is a drug that is known to heal neuronal cell culture infected with prions, which are the causative agents of neurodegenerative diseases called transmissible spongiform encephalopathies. However, the drug fails when it is applied in vivo. In this work, we analyzed the reason for this failure. The drug was suggested to “covalently” modify the prion protein via an acridinyl exchange reaction. To investigate this hypothesis more closely, the acridine moiety of quinacrine was covalently attached to the thiol groups of cysteines belonging to prion-derived peptides and to the full-length prion protein. The labeled compounds were conveniently monitored by fluorescence and absorption spectroscopy in the ultraviolet and visible spectral regions. The acridine moiety demonstrated characteristic UV–vis spectrum, depending on the substituent at the C-9 position of the acridine ring. These results confirm that quinacrine almost exclusively reacts with the thiol groups present in proteins and peptides. The chemical reaction alters the prion properties and increases the concentration of the acridine moiety in the prion protein. 相似文献
70.
Jiří Emmer Andrea Vavrinská Vladimír Sychrovský Ladislav Benda Zdeněk Kříž Jaroslav Koča Rolf Boelens Vladimír Sklenář Lukáš Trantírek 《Journal of biomolecular NMR》2013,55(1):59-70
Density functional theory was employed to study the influence of O-phosphorylation of serine, threonine, and tyrosine on the amidic 15N chemical shielding anisotropy (CSA) tensor in the context of the complex chemical environments of protein structures. Our results indicate that the amidic 15N CSA tensor has sensitive responses to the introduction of the phosphate group and the phosphorylation-promoted rearrangement of solvent molecules and hydrogen bonding networks in the vicinity of the phosphorylated site. Yet, the calculated 15N CSA tensors in phosphorylated model peptides were in range of values experimentally observed for non-phosphorylated proteins. The extent of the phosphorylation induced changes suggests that the amidic 15N CSA tensor in phosphorylated proteins could be reasonably well approximated with averaged CSA tensor values experimentally determined for non-phosphorylated amino acids in practical NMR applications, where chemical surrounding of the phosphorylated site is not known a priori in majority of cases. Our calculations provide estimates of relative errors to be associated with the averaged CSA tensor values in interpretations of NMR data from phosphorylated proteins. 相似文献