全文获取类型
收费全文 | 2313篇 |
免费 | 128篇 |
国内免费 | 8篇 |
专业分类
2449篇 |
出版年
2023年 | 38篇 |
2022年 | 54篇 |
2021年 | 69篇 |
2020年 | 53篇 |
2019年 | 56篇 |
2018年 | 69篇 |
2017年 | 80篇 |
2016年 | 96篇 |
2015年 | 131篇 |
2014年 | 120篇 |
2013年 | 168篇 |
2012年 | 180篇 |
2011年 | 188篇 |
2010年 | 89篇 |
2009年 | 112篇 |
2008年 | 109篇 |
2007年 | 112篇 |
2006年 | 78篇 |
2005年 | 75篇 |
2004年 | 49篇 |
2003年 | 50篇 |
2002年 | 44篇 |
2001年 | 33篇 |
2000年 | 35篇 |
1999年 | 29篇 |
1998年 | 18篇 |
1996年 | 8篇 |
1995年 | 16篇 |
1994年 | 13篇 |
1992年 | 10篇 |
1991年 | 11篇 |
1990年 | 17篇 |
1989年 | 17篇 |
1988年 | 10篇 |
1987年 | 12篇 |
1986年 | 10篇 |
1985年 | 14篇 |
1984年 | 22篇 |
1983年 | 9篇 |
1982年 | 7篇 |
1981年 | 8篇 |
1979年 | 11篇 |
1978年 | 8篇 |
1976年 | 6篇 |
1975年 | 7篇 |
1973年 | 7篇 |
1972年 | 9篇 |
1971年 | 9篇 |
1967年 | 6篇 |
1888年 | 6篇 |
排序方式: 共有2449条查询结果,搜索用时 15 毫秒
31.
Doan Minh Sang Ik Ho Na Dr. Duong Tien Anh Do Thi Mai Dung Nguyen Thi Thu Hang Nguyen T. Phuong-Anh Assoc. Prof. Dr. Pham-The Hai Assoc. Prof. Dr. Dao Thi Kim Oanh Dr. Truong Thanh Tung Soo Jung Lee Joo Hee Kwon Prof. Dr. Jong Soon Kang Prof. Dr. Sang-Bae Han Assoc. Prof. Dr. Dinh Thi Thanh Hai Prof. Dr. Nguyen-Hai Nam 《化学与生物多样性》2023,20(5):e202201030
Herein, we report the design, synthesis and evaluation of novel (E)-3-(3-oxo-4-substituted-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-N-hydroxypropenamides ( 4 a – i , 7 a – g ) targeting histone deacetylases. Three human cancer cell lines were used to test the cytotoxicity of the synthesized compounds (SW620, colon; PC-3, prostate; NCI−H23, lung cancer); inhibitory activity towards HDAC; anticancer activity; as well as their impact on the cell cycle and apoptosis. As a result, compounds 4 a – i bearing the alkyl substituents seemed to be less potent than the benzyl-containing compounds 7 a – g in all biological assays. Compounds 7 e – f were found to be the most active HDAC inhibitors with IC50 of 1.498±0.020 μM and 1.794±0.159 μM, respectively. In terms of cytotoxicity and anticancer assay, 7 e and 7 f also showed good activity with IC50 values in the micromolar range. In addition, the cell cycle and apoptosis of SW620 were affected by compound 7 f in almost a similar manner to that of reference compound SAHA. Docking assays were carried out for analysis the binding mode and selectivity of this compound toward 8 HDAC isoforms. Overall, our data confirmed that the inhibition of HDAC plays a pivotal role in their anticancer activity. 相似文献
32.
Manh Dat Hoang Dieu Thi Doan Marlen Schmidt Harald Kranz Andreas Kremling Anna-Lena Heins 《Engineering in Life Science》2023,23(1):e2100162
Biotechnological production processes are sustainable approaches for the production of biobased components such as amino acids for food and feed industry. Scale-up from ideal lab-scale bioreactors to large-scale processes is often accompanied by loss in productivity. This may be related to population heterogeneities of cells originating from isogenic cultures that arise due to dynamic non-ideal conditions in the bioreactor. To better understand this phenomenon, deeper insights into single-cell physiologies in bioprocesses are mandatory before scale-up. Here, a triple reporter strain (3RP) was developed by chromosomally integrating the fluorescent proteins mEmerald, CyOFP1, and mTagBFP2 into the L-phenylalanine producing Escherichia coli strain FUS4 (pF81kan) to allow monitoring of growth, oxygen availability, and general stress response of the single cells. Functionality of the 3RP was confirmed in well-mixed lab-scale fed-batch processes with glycerol as carbon source in comparison to the strain without fluorescent proteins, leading to no difference in process performance. Fluorescence levels could successfully reflect the course of related process state variables, revealed population heterogeneities during the transition between different process phases and potentially subpopulations that exhibit superior process performance. Furthermore, indications were found for noise in gene expression as regulation strategy against environmental perturbation. 相似文献
33.
Can the biotic nestedness matrix be used predictively? 总被引:3,自引:1,他引:3
The biotas of a suite of neighboring patches of remnant vegetation often form a series of nested sub-sets, in which the species present in species-poor patches are non-random sub-sets of those present in richer patches. There has been recent interest in ways in which this knowledge may be used to aid conservation. We focus here on whether nested patterns can be used predictively. If nestedness in a fragmented system increases over time through biotic relaxation, locations where particular species may become extinct or are likely to colonize might be predictable and this could be useful in threatened-species management. We used the Temperature Calculator of Atmar and Patterson (1995) to arrange a matrix of bird species' occurrences in a series of buloke Allocasuarina leuhmannii woodland remnants so that nestedness was maximized. Probability bands generated by the calculator were used to predict possible colonization and extinction events. We then re-surveyed the avifauna of the fragments after a seven-year interval to test these predictions. Although nestedness increased between the two survey periods, there was no linear relationship between the generated probability of extinctions or colonizations and the accuracy of the predictions. The predictions derived from the calculator were no more accurate than a second set of predictions generated by use of a simple non-nested model. Despite the increase in nestedness, the arrangement of sites in each of the two maximally packed matrices was substantially different. For the nestedness matrix to generate accurate predictions, an increase in nestedness must be due to a minimization of unexpected species presences and absences rather than an extensive redistribution of species among remnants, as we found. The potential utility of nested patterns in predicting systematic colonization and extinction events should be further evaluated in other, less dynamic, fragmented systems such as those undergoing biotic relaxation. 相似文献
34.
35.
Ruairí A. Mac Síomóin Noboru Nakata Tatuo Murai Masanosuke Yoshikawa Hiroyuki Tsuji & Chihiro Sasakawa 《Molecular microbiology》1996,19(3):599-609
The virulent phenotype of Shigella requires loci on the chromosome as well as on the large virulence plasmid, and is regulated via a complex web of interactions amongst various chromosomal and large plasmid genes. To further investigate the role of chromosomal loci in virulence, we performed random Tn 10 mutagenesis in Shigella flexneri YSH6000T, and isolated an avirulent mutant (V3404) incapable of spreading throughout an epithelial cell monolayer. Although V3404 initially spread intercellularly at the same rate as the wild-type, it gradually slowed down and ceased spreading as a result of increasing defects in cell division, leading to the formation of long filamentous bacteria lacking septa, trapped within cells. In addition, the mutation affected the ability of V3404 to polymerize actin, a prerequisite for intra- and inter-cellular spreading ability. Sequencing of Tn 10 -flanking DNA revealed that the mutated gene, designated ispA (intracellular septation), was equivalent to a previously sequenced but uncharacterised gene of Escherichia coli located between trp and tonB . Using E. coli sequence data, we cloned the ispA gene from the YSH6000T chromosome and found that it complemented the V3404 mutation. Nucleotide sequencing and in vitro expression experiments revealed that ispA coded for a small (21 kDa), very hydrophobic protein. These results thus show that ispA is an essential virulence gene affecting several functions of the virulence process. 相似文献
36.
Pham Thi Huan Rona Taylor Alf A. Lindberg Naresh K. Verma 《Microbiology and immunology》1995,39(7):467-472
The glucosyl transferase gene (gtr) from bacteriophage phage X (SfX) caused partial conversion of serotype Y (group antigen 3, 4) to X (group antigen 7, 8) when introduced into a candidate vaccine strain of Shigella flexneri serotype Y (SFL124). The gtr gene caused conversion of O-antigens but did not eliminate the adsorption of the corresponding phage SfX. The hybrid strain expressing both group antigens 7, 8 and 3, 4 showed 75% protection when immunized guinea pigs were challenged with a wild-type S. flexneri serotype X strain. No protection was observed against serotype Y challenge, although group antigen 3, 4 was detected in the LPS of the hybrid strain. This suggests the importance of O-antigen immunity in the host defense against shigellosis. 相似文献
37.
Le Van Phung Tran Thi Bich Chi Hisako Hotta Eiko Yabuuchi Ikuya Yano 《Microbiology and immunology》1995,39(2):105-116
Viet nam is known as an endemic area of melioidosis but its etiologic agent originated in Viet nam was not extensively studied. For the first time, we analyzed the cellular lipid and fatty acid compositions of 15 Vietnamese isolates of Burkholderia pseudomallei, 10 from humans and 5 from the environment. Cellular lipid compositions were analyzed by two-dimensional thin-layer chromatography on silica gel G plates. Cellular fatty acid methyl esters were analyzed by gas chromatography (GC) and gas chromatography/mass spectrometry (GC/MS). The major lipids in all the isolates were phosphatidylglycerol (PG), two forms of phosphatidylethanolamine (PE-1 and PE-2), and two forms of ornithine-containing lipid (OL-1 and OL-2). PE-1 contained non-hydroxy fatty acids at both sn-1 and ?2 positions, while PE-2 possessed 2-hydroxy fatty acids and non-hydroxy fatty acids in a ratio of 1: 1. Since snake venom phospholipase A2 digestion of PE-2 liberated 2-hydroxy fatty acids, it was confirmed that these acids are at the sn-2 position of glycerol moiety. In both OL-1 and OL-2, amide-linked fatty acid was 3-hydroxy palmitic acid (3-OH-C16: 0), while ester-linked fatty acids were non-hydroxy acids in OL-1 and 2-hydroxy acids in OL-2. The total cellular fatty acid compositions of the test strains were characterized by the presence of 2-hydroxy palmitic (2-OH-C16: 0), 2-hydroxy hexadecenoic (2-OH-C16: 1), 2-hydroxy octadecenoic (2-OH-C18: 1), 2-hydroxy methylene octadecanoic (2-OH-C19CPA), 3-hydroxy myristic (3-OH-C14: 0) and 3-hydroxy palmitic (3-OH-C16: 0) acids. There were significant differences in the concentration of hexadecenoic (C16: 1), methylene hexadecanoic (C17CPA), octadecenoic (C18: 1) and methylene octadecanoic (C19CPA) acids among the Vietnamese isolates of B. pseudomallei. However, no significant difference was observed in cellular lipid and fatty acid components between strains of human and environmental origins. 相似文献
38.
Summary A versatile, cheap and automated system is designed for the measurement of small gas flows produced in laboratory-scale fermentation processes. An automatic sampling device for programmed times is linked to the flow meter. The displacement of a liquid by the gas being measured is the principle on which both the meter and the sampling device are based. The operation of the system is controlled by a simple electronic circuit. 相似文献
39.
S Mac Neil S W Walker H J Senior A Pollock B L Brown S S Bleehen D S Munro S Tomlinson 《The Biochemical journal》1984,224(2):453-460
Calmodulin antagonists inhibited hormone-stimulated cyclic AMP accumulation in both cultured cells and cell lysates of mouse B16 melanoma. Particulate preparations of B16 melanoma contained 34-45% of total cell calmodulin, which could not be dissociated by extensive washing irrespective of the presence of EGTA in the buffer. The adenylate cyclase activity in such preparations was unaffected by the addition of exogenous calmodulin. However, the rare-earth-metal ion La3+, which can mimic or replace Ca2+ in many systems, produced an immediate inhibition of agonist-stimulated adenylate cyclase activity and preincubation of particulate preparations was La3+ followed by washing with La3+-free buffer dissociated calmodulin (96% loss) from particulate preparations. The loss of calmodulin from particulate preparations was associated with a decrease in agonist responsiveness (74%) and a marked change in the Ca2+-sensitivity of the enzyme, low concentrations of calcium (approx. 10 nM) now failing to stimulate enzyme activity, high concentrations of calcium (greater than or equal to 100 nM) producing greater-than-normal inhibition of enzyme activity. Direct activation of adenylate cyclase by the addition of pure calmodulin was now demonstrable in such calmodulin-depleted particulate preparations. Half-maximal stimulation of agonist-responsive adenylate cyclase occurred at 80 nM-calmodulin in the presence of 10 microM free Ca2+. Maximal stimulation by calmodulin (at 300-600 nM) restored enzyme activity to 89 +/- 5% (mean +/- S.E.M., n = 7) of the activity in untreated, calmodulin-intact, preparations. 相似文献
40.
Secretion of melanophore-stimulating hormone (MSH) in long-term cultures of pituitary neurointermediate lobes 总被引:1,自引:0,他引:1
Summary Neurointermediate lobes from pituitaries of the frog, Rana berlandieri forreri (Rana pipiens, sensu lato), were maintained in organ culture in media with and without serum for up to six months. The cultured tissues were examined periodically by light microscopy and transmission electron microscopy and by bioassay of the melanophore-stimulating hormone (MSH) secreted and present in the culture media. Light-microscopic observations revealed a high degree of preservation of the pars intermedia at four weeks with isolated areas of some glands maintaining histological integrity for the entire six months. Similarly, at the ultrastructural level the cells appeared morphologically intact and to be actively synthesizing and secreting hormone. Bioassays showed the glands to be continuously secreting MSH; however, larger yields of hormone were obtained in media lacking serum. No significant ultrastructural differences between cells grown in the presence or absence of serum were detected. The difference in concentration of MSH between the two groups therefore apparently results from enzymatic degradation of the hormone by the serum. Organ culture of the vertebrate neurointermediate lobe may provide a unique method for the production of large quantities of MSH and for the study of other melanotropic and opiate peptides as they may be synthesized and secreted by the pars intermedia. 相似文献