全文获取类型
收费全文 | 2683篇 |
免费 | 139篇 |
国内免费 | 3篇 |
专业分类
2825篇 |
出版年
2023年 | 21篇 |
2022年 | 39篇 |
2021年 | 78篇 |
2020年 | 50篇 |
2019年 | 54篇 |
2018年 | 71篇 |
2017年 | 70篇 |
2016年 | 88篇 |
2015年 | 140篇 |
2014年 | 114篇 |
2013年 | 207篇 |
2012年 | 196篇 |
2011年 | 200篇 |
2010年 | 134篇 |
2009年 | 99篇 |
2008年 | 126篇 |
2007年 | 134篇 |
2006年 | 121篇 |
2005年 | 105篇 |
2004年 | 78篇 |
2003年 | 76篇 |
2002年 | 73篇 |
2001年 | 39篇 |
2000年 | 29篇 |
1999年 | 31篇 |
1998年 | 14篇 |
1997年 | 19篇 |
1995年 | 15篇 |
1992年 | 14篇 |
1991年 | 18篇 |
1990年 | 19篇 |
1989年 | 16篇 |
1988年 | 16篇 |
1987年 | 14篇 |
1986年 | 12篇 |
1985年 | 16篇 |
1984年 | 22篇 |
1983年 | 16篇 |
1982年 | 20篇 |
1981年 | 12篇 |
1979年 | 14篇 |
1977年 | 13篇 |
1976年 | 13篇 |
1975年 | 14篇 |
1974年 | 12篇 |
1972年 | 14篇 |
1971年 | 11篇 |
1968年 | 11篇 |
1967年 | 11篇 |
1966年 | 10篇 |
排序方式: 共有2825条查询结果,搜索用时 0 毫秒
101.
Monika Chaudhary Neeraj Kumar Ashish Baldi Ramesh Chandra M. Arockia Babu 《Journal of biomolecular structure & dynamics》2020,38(1):200-218
AbstractWith an endeavor to develop novel curcumin analogs as potential anti-cancer agents, we designed and synthesized a series of Knoevenagel condensates by clubbing pyrazole carbaldehydes at the active methylene carbon atom of the curcumin backbone. Molecular docking studies were carried out to target the proposed derivatives on human kinase β (IKKβ), a potential anti-cancer target. The chloro derivative displayed five hydrogen bond interactions with a docking score of ?11.874?kcal/mol higher than curcumin (docking score =??7.434?kcal/mol). This was supported by the fact that the propellant shaped derivatives fitted aptly into the binding pocket. Molecular simulations studies were also conducted on the lead molecule and the results figured out that the stable complexes were developed as the minimal deviations per residue of protein within the range of 0.11–0.92 Å. The screened compounds were synthesized, characterized and evaluated in vitro for cytotoxicity against cervical cancer cell line, HeLa using standard cell proliferation assay. Chloro derivative and bromo analog demonstrated IC50 (half maximal inhibitory concentration) value of 14.2 and 18.6 µg/ml, respectively, significantly lower than 42.4 µg/ml of curcumin and higher than 0.008 µg/ml of paclitaxel. Induction of apoptosis was evaluated in the terms of cleavage of caspase-3 enzyme and they also exhibited 69.6 and 65.4% of apoptosis significantly higher than 19.9% induced by curcumin. In conclusion, chloro and bromo derivatives must be evaluated under a set of stringent in vitro and in vivo parameters for translating in to a clinically viable product.Communicated by Ramaswamy H. Sarma 相似文献
102.
Marcus J. G.W. Ladds Gergana Popova Andrs Pastor-Fernndez Srinivasaraghavan Kannan Ingeborg M.M. van Leeuwen Maria Hkansson Bjrn Walse Fredrik Tholander Ravi Bhatia Chandra S. Verma David P. Lane Sonia Laín 《The Journal of biological chemistry》2020,295(52):17935
The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static. 相似文献
103.
104.
Krishna Kumar Natarajan Amaresan Someshwar Bhagat Kutthum Madhuri Palaniswamy Udhayaraj Ramesh Chandra Srivastava 《Archives Of Phytopathology And Plant Protection》2013,46(14):1399-1409
In this study, the in vitro potential of 42 Trichoderma spp. were evaluated against four isolates of soil borne phytopathogenic fungi viz., Rhizoctonia solani, Macrophomina sp., Sclerotium rolfsii and Pythium aphanidermatum in dual culture techniques and through production of volatile and non-volatile inhibitors. In vitro screening results showed that the proportion of isolates with antagonistic activities was highest for the S. rolfsii followed by R. solani, Macrophomina sp. and P. aphanidermatum, respectively. The isolates TNT1, TNP2 and TWP1 showed consistent results in volatile and non-volatile activity in vitro against any of the two pathogens tested. Based on genomic finger prints, potential isolates showed no particular correlation between the origin of the isolates and the Random Amplified Polymorphic DNA (RAPD) groups could not be established. However, the polymorphism shown by the isolates did not correlate to their level of antagonism. Whereas, in physiology studies using BIOLOG (microbial identification system), three groups were formed, one group consists with 14 different Trichoderma species and two groups with two isolates each comprised of only T. koningii and T. viride. 相似文献
105.
Yasuhiro Suzuki Chandra Nath Roy Warunya Promjunyakul Hiroyasu Hatakeyama Kohsuke Gonda Junji Imamura Biju Vasudevanpillai Noriaki Ohuchi Makoto Kanzaki Hideo Higuchi Mitsuo Kaku 《Molecular and cellular biology》2013,33(15):3036-3049
The mechanisms underlying the cellular entry of the HIV-1 Tat protein transduction domain (TatP) and the molecular information necessary to improve the transduction efficiency of TatP remain unclear due to the technical limitations for direct visualization of TatP''s behavior in cells. Using confocal microscopy, total internal reflection fluorescence microscopy, and four-dimensional microscopy, we developed a single-molecule tracking assay for TatP labeled with quantum dots (QDs) to examine the kinetics of TatP initially and immediately before, at the beginning of, and immediately after entry into living cells. We report that even when the number of multivalent TatP (mTatP)-QDs bound to a cell was low, each single mTatP-QD first locally induced the cell''s lateral transport machinery to move the mTatP-QD toward the center of the cell body upon cross-linking of heparan sulfate proteoglycans. The centripetal and lateral movements were linked to the integrity and flow of actomyosin and microtubules. Individual mTatP underwent lipid raft-mediated temporal confinement, followed by complete immobilization, which ultimately led to endocytotic internalization. However, bivalent TatP did not sufficiently promote either cell surface movement or internalization. Together, these findings provide clues regarding the mechanisms of TatP cell entry and indicate that increasing the valence of TatP on nanoparticles allows them to behave as cargo delivery nanomachines. 相似文献
106.
Catechins, the flavonoids found in abundance in green tea, have many beneficial health effects such as antioxidative, anticarcinogenic, anti-inflammatory, antiallergic, and hypotensive properties. However, flavonoids have antithyroid/goitrogenic effect, although less information is available about the effect of pure catechin on thyroid physiology. The present investigation has been undertaken to explore the effect of catechin administration on thyroid physiology in rat model. For the in vivo experiment catechin was injected intraperitoneally (i.p.) at doses of 10, 20 and 30 mg/kg body to male albino rats for 15 and 30 days, respectively, and thyroid activities were evaluated with respect to determination of serum levels of thyroid hormones, thyroid peroxidase, 5′-deiodinase I (5′-DI), and Na+, K+-ATPase activities that are involved in the synthesis of thyroid hormone. Catechin decreased the activities of thyroid peroxidase and thyroidal 5′-deiodinase I, while Na+, K+-ATPase activity significantly increased in dose-dependent manner; substantial decrease in serum T3 and T4 levels coupled with significant elevation of serum TSH were also noted. Histological examinations of the thyroid gland revealed marked hypertrophy and/or hyperplasia of the thyroid follicles with depleted colloid content. In in vitro study, short-term exposure of rat thyroid tissue to catechin at the concentrations of 0.10, 0.20, and 0.30 mg/ml leads to decrease in the activities of thyroid peroxidase and 5′-deiodinase I, while the activity of thyroidal Na+, K+-ATPase remains unaltered even at high concentration of catechin treatment. The present study reinforces the concept that catechin, tea flavonoids possess potent antithyroid activity as evidenced from in vivo and in vitro studies. 相似文献
107.
108.
Gloria Fuentes Antonio Ballesteros Chandra S. Verma 《Journal of biomolecular structure & dynamics》2013,31(2):145-155
Abstract Transesterification of sucrose with fatty acids catalyzed by subtilisin Carlsberg occurs with regioselectivity that is different from that in lipases. Thermomyces lanuginosus lipase (TlL) and Candida antarctica lipase B (CALB) catalyze synthesis at positions 6 and 6′, with differing abilities, while subtilisin catalysis leads to the l′-acylated sucrose. The catalytic machinery in lipases is approximately mirrored in subtilisins but different pocket morphologies including size, shape, and rearrangement of the catalytic elements underlies the differing regioselectivities. The thermodynamic consequences of these differences on the above reactions have been explored systematically using computational methods, determining the free energies of interaction of the putative transition-state adducts. Analysis of the conformers with the lowest transition state energies (protein-ligand interactions and vibrational entropy contributions) indicates that enthalpic factors control specificities in lipases while entropic factors are more important in subtilisin. 相似文献
109.
Excessive and indiscriminate use of antibiotics to treat bacterial infections has lead to the emergence of multiple drug resistant strains. Most infectious diseases are caused by bacteria which proliferate within quorum sensing (QS) mediated biofilms. Efforts to disrupt biofilms have enabled the identification of bioactive molecules produced by prokaryotes and eukaryotes. These molecules act primarily by quenching the QS system. The phenomenon is also termed as quorum quenching (QQ). In addition, synthetic compounds have also been found to be effective in QQ. This review focuses primarily on natural and synthetic quorum sensing inhibitors (QSIs) with the potential for treating bacterial infections. It has been opined that the most versatile prokaryotes to produce QSI are likely to be those, which are generally regarded as safe. Among the eukaryotes, certain legumes and traditional medicinal plants are likely to act as QSIs. Such findings are likely to lead to efficient treatments with much lower doses of drugs especially antibiotics than required at present. 相似文献
110.
Manoj Cheriyan Chandra Sekhar Pedamallu Kazuo Tori Francine Perler 《The Journal of biological chemistry》2013,288(9):6202-6211
Inteins are naturally occurring intervening sequences that catalyze a protein splicing reaction resulting in intein excision and concatenation of the flanking polypeptides (exteins) with a native peptide bond. Inteins display a diversity of catalytic mechanisms within a highly conserved fold that is shared with hedgehog autoprocessing proteins. The unusual chemistry of inteins has afforded powerful biotechnology tools for controlling enzyme function upon splicing and allowing peptides of different origins to be coupled in a specific, time-defined manner. The extein sequences immediately flanking the intein affect splicing and can be defined as the intein substrate. Because of the enormous potential complexity of all possible flanking sequences, studying intein substrate specificity has been difficult. Therefore, we developed a genetic selection for splicing-dependent kanamycin resistance with no significant bias when six amino acids that immediately flanked the intein insertion site were randomized. We applied this selection to examine the sequence space of residues flanking the Nostoc punctiforme Npu DnaE intein and found that this intein efficiently splices a much wider range of sequences than previously thought, with little N-extein specificity and only two important C-extein positions. The novel selected extein sequences were sufficient to promote splicing in three unrelated proteins, confirming the generalizable nature of the specificity data and defining new potential insertion sites for any target. Kinetic analysis showed splicing rates with the selected exteins that were as fast or faster than the native extein, refuting past assumptions that the naturally selected flanking extein sequences are optimal for splicing. 相似文献