全文获取类型
收费全文 | 3300篇 |
免费 | 184篇 |
国内免费 | 1篇 |
专业分类
3485篇 |
出版年
2022年 | 16篇 |
2021年 | 29篇 |
2020年 | 15篇 |
2019年 | 31篇 |
2018年 | 33篇 |
2017年 | 31篇 |
2016年 | 47篇 |
2015年 | 84篇 |
2014年 | 107篇 |
2013年 | 233篇 |
2012年 | 186篇 |
2011年 | 215篇 |
2010年 | 145篇 |
2009年 | 128篇 |
2008年 | 205篇 |
2007年 | 177篇 |
2006年 | 182篇 |
2005年 | 182篇 |
2004年 | 178篇 |
2003年 | 185篇 |
2002年 | 171篇 |
2001年 | 63篇 |
2000年 | 41篇 |
1999年 | 62篇 |
1998年 | 46篇 |
1997年 | 54篇 |
1996年 | 46篇 |
1995年 | 49篇 |
1994年 | 26篇 |
1993年 | 46篇 |
1992年 | 49篇 |
1991年 | 47篇 |
1990年 | 29篇 |
1989年 | 31篇 |
1988年 | 27篇 |
1987年 | 27篇 |
1986年 | 15篇 |
1985年 | 27篇 |
1984年 | 24篇 |
1983年 | 32篇 |
1982年 | 22篇 |
1981年 | 19篇 |
1980年 | 23篇 |
1978年 | 10篇 |
1977年 | 16篇 |
1976年 | 12篇 |
1975年 | 8篇 |
1973年 | 7篇 |
1972年 | 5篇 |
1970年 | 8篇 |
排序方式: 共有3485条查询结果,搜索用时 15 毫秒
131.
Yamamoto S Matsunaga N Hitaka T Yamada M Hara T Miyazaki J Santou T Kusaka M Yamaoka M Kanzaki N Furuya S Tasaka A Hamamura K Ito M 《Bioorganic & medicinal chemistry》2012,20(1):422-434
A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer. 相似文献
132.
Okamoto H Watanabe K Ikeuchi Y Suzuki T Endo Y Hori H 《The Journal of biological chemistry》2004,279(47):49151-49159
Transfer RNA (m7G46) methyltransferase catalyzes the methyl transfer from S-adenosylmethionine to N7 atom of the guanine 46 residue in tRNA. Analysis of the Aquifex aeolicus genome revealed one candidate open reading frame, aq065, encoding this gene. The aq065 protein was expressed in Escherichia coli and purified to homogeneity on 15% SDS-polyacrylamide gel electrophoresis. Although the overall amino acid sequence of the aq065 protein differs considerably from that of E. coli YggH, the purified aq065 protein possessed a tRNA (m7G46) methyltransferase activity. The modified nucleoside and its location were determined by liquid chromatography-mass spectroscopy. To clarify the RNA recognition mechanism of the enzyme, we investigated the methyl transfer activity to 28 variants of yeast tRNAPhe and E. coli tRNAThr. It was confirmed that 5'-leader and 3'-trailer RNAs of tRNA precursor are not required for the methyl transfer. We found that the enzyme specificity was critically dependent on the size of the variable loop. Experiments using truncated variants showed that the variable loop sequence inserted between two stems is recognized as a substrate, and the most important recognition site is contained within the T stem. These results indicate that the L-shaped tRNA structure is not required for methyl acceptance activity. It was also found that nucleotide substitutions around G46 in three-dimensional core decrease the activity. 相似文献
133.
Kato A Kawamata N Tamayose K Egashira M Miura R Fujimura T Murayama K Oshimi K 《The Journal of biological chemistry》2002,277(32):28934-28941
Modification of the cytoplasmic tails of the integrin alpha(IIb)beta(3) plays an important role in the signal transduction in platelets. We searched for proteins that bind to the alpha(IIb) cytoplasmic tail using the yeast two-hybrid assay with a cDNA library of the megakaryocyte-derived cell line and identified a protein, ancient ubiquitous protein 1 (Aup1), that is ubiquitously expressed in human cells. Observation of UT7/TPO cells expressing a red fluorescent protein-tagged Aup1 indicated its localization in the cytoplasm. Immunoprecipitation of UT7/TPO cells by an antibody for Aup1 revealed that approximately 40% of alpha(IIb) is complexed with Aup1. Binding study with an alpha(IIb) cytoplasmic tail peptide and glutathione S-transferase-Aup1 fusion protein revealed a low affinity (K(d) = 90 microm). Subsequent yeast two-hybrid assay indicated binding of Aup1 to cytoplasmic tails of other integrin alpha subunits. Binding study with the purified Aup1 and various glutathione S-transferase-alpha(IIb) cytoplasmic tail peptides revealed specific binding of Aup1 to the membrane-proximal sequence (KVGFFKR) that is conserved among the integrin alpha subunits and plays a crucial role in the alpha(IIb)beta(3) inside-out signaling. As Aup1 possesses domains related to signal transduction, these results suggest involvement of Aup1 in the integrin signaling. 相似文献
134.
MicroRNA-122 (miR-122), which is expressed at high levels in hepatocytes, is selectively stabilized by 3′-adenylation mediated by the cytoplasmic poly(A) polymerase GLD-2. Here, we report that poly(A)-specific ribonuclease (PARN) is responsible for the deadenylation and destabilization of miR-122. The 3′-oligoadenylated variant of miR-122 was detected in Huh7 cells when PARN was down-regulated. In addition, both the steady-state level and stability of miR-122 were increased in PARN knockdown cells. We also demonstrate that CUG-binding protein 1 (CUGBP1) specifically interacts with miR-122 and other UG-rich miRNAs, and promotes their destabilization. Overexpression of CUGBP1 or PARN in Huh7 cells reduced the steady-state levels of these miRNAs. Because CUGBP1 interacts directly with PARN, we hypothesized that it specifically recruits PARN to miR-122. In fact, CUGBP1 enhanced PARN-mediated deadenylation and degradation of miR-122 in a dose-dependent manner in vitro. These results indicate that the cellular level of miR-122 is determined by the balance between the opposing effects of GLD-2 and PARN/CUGBP1 on the metabolism of its 3′-terminus. 相似文献
135.
Takatoshi Murata Tsutomu Sato Takeshi Kamoda Hiromitsu Moriyama Yasuo Kumazawa Nobuhiro Hanada 《Experimental cell research》2014
Hydrogen sulfide (H2S) is a novel gasotransmitter that plays multiple biological roles in various body systems. In addition to its endogenous production, H2S is produced by bacteria colonizing digestive organs, including the oral cavity. H2S was previously shown to enhance pro-apoptotic effects in cancer cell lines, although the mechanisms involved remain unclear. To properly assess the anti-cancer effects of H2S, however, investigations of apoptotic effects in normal cells are also necessary. The aims of this study were (1) to compare the susceptibility to H2S-induced apoptosis between the oral cancer cell line Ca9-22 and oral keratinocytes that were derived from healthy gingiva, and (2) to identify candidate genes involved in the induction of apoptosis by H2S. The susceptibility to H2S-induced apoptosis in Ca9-22 cells was significantly higher than that in keratinocytes. H2S exposure in Ca9-22 cells, but not keratinocytes, enhanced the expression of pleckstrin homology-like domain, family A, member 1 (PHLDA1), which was identified through a differential display method. In addition, PHLDA1 expression increased during actinomycin D-induced apoptosis in Ca9-22 cells. Knockdown of PHLDA1 expression by small interfering RNA in Ca9-22 cells led to expression of active caspase 3, thus indicating apoptosis induction. The tongue cancer cell line SCC-25, which expresses PHLDA1 at a high level, showed similar effects. Our data indicate that H2S is an anti-cancer compound that may contribute to the low incidence of oral cancer. Furthermore, we demonstrated the role of PHLDA1 as an apoptosis suppressor. 相似文献
136.
Matsunaga Tadashi Tomoda Ryuzo Matsuda Hidemi 《Applied microbiology and biotechnology》1984,19(6):404-408
Summary A photomicrobial electrode, which uses the photosynthetic bacteria Chromatium sp. in conjunction with a hydrogen electrode, was developed for the determination of sulphide. The response time of the photomicrobial electrode was 5–10 min. A linear relationship was obtained between the current of the electrode and the sodium sulphide concentration below 3.5 mM. The minimum detectable concentration of sodium sulphide was 0.4 mM. Selectivity of the sensor is satisfactory. A good agreement was obtained between the photomicrobial electrode and the ethylene blue method (correlation coefficient: 0.90). 相似文献
137.
The maximum theanine production by Camellia sinensis cultured cells was achieved by culturing in the modified MS medium containing 2 mg/l indole-3-butyric acid, 0.1 mg/l kinetin, 0 mM NH4NO3 and 39.6 mM KNO3 with 40 mM ethylamine hydrochloride or 20 mM ethylamine hydrochloride and 10 mM L-glutamic acid. Other primary amines, such as methylamine, n-butylamine, 2-hydroxyethylamine, 2cyanoethylamine, aniline, benzylamine and phenylethylamine, were also biotransformed to N5-alkyl-L-glutamine derivatives by C. sinensis cultured cells.Abbreviations IBA
indole-3-butyric acid
- K
kinetin
- MS medium
Murashige and Skoog's basal medium (1962)
- NMR
nuclear magnetic resonance
Part 70 in the series Studies on Plant Tissue Culture. For Part 69 see Furuya et al. (1990). 相似文献
138.
Upon absorption of light, the retinal chromophore in rhodopsin isomerizes from the 11-cis to the trans configuration, initiating a photoreaction cycle. The primary photoreaction state, bathorhodopsin (BATHO), relaxes thermally through lumirhodopsin (LUMI) into a photoactive state, metarhodopsin (META), which stimulates the conjugated G-protein. Previous crystallographic studies of squid and bovine rhodopsins have shown that the structural change in the primary photoreaction of squid rhodopsin is considerably different from that observed in bovine rhodopsin. It would be expected that there is a fundamental difference in the subsequent thermal relaxation process between vertebrate and invertebrate rhodopsins. In this work, we performed crystallographic analyses of the LUMI state of squid rhodopsin using the P62 crystal. When the crystal was illuminated at 100 K with blue light, a half fraction of the protein was converted into BATHO. This reaction state relaxed into LUMI when the illuminated crystal was warmed in the dark to 170 K. It was found that, whereas trans retinal is largely twisted in BATHO, it takes on a more planar configuration in LUMI. This relaxation of retinal is accompanied by reorientation of the Schiff base NH bond, the hydrogen-bonding partner of which is switched to Asn185 in LUMI. Unlike bovine rhodopsin, the BATHO-to-LUMI transition in squid rhodopsin was accompanied by no significant change in the position/orientation of the beta-ionone ring of retinal. 相似文献
139.
A genomic clone for the cyc07 gene, which is expressed specifically at the S phase during the cell cycle in synchronous cultures of periwinkle (Catharanthus roseus) cells, was isolated. Determination of the nucleotide sequence of the clone revealed that the cyc07 gene consists of seven exons separated by six introns. Genomic Southern analysis indicated that the cyc07 gene is present as a single copy per haploid genome in periwinkle. Expression of related genes was detected in a wide range of other plants. Transgenic Arabidopsis plants were generated that expressed the gene for -glucuronidase (GUS) under the control of the promoter of the cyc07 gene. The tissue-specific pattern of expression directed by the promoter was investigated by analysis of GUS activity. Histochemical tests demonstrated that 589 bp of the 5-upstream sequence of the cyc07 gene could direct specifical expression of the GUS reporter gene in meristematic tissues in transgenic plants. The spatial pattern of expression directed by the promoter was closely correlated with meristematic activity and cell proliferation, suggesting an association between the function of the cyc07 gene and cell proliferation. 相似文献
140.
Treatment of Mid‐Pregnant Mice with KRN633, an Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase,Induces Abnormal Retinal Vascular Patterning in Their Newborn Pups 下载免费PDF全文
Akane Morita Tsutomu Nakahara Naomichi Abe Asami Mori Kenji Sakamoto Tohru Nagamitsu Kunio Ishii 《Birth defects research. Part B, Developmental and reproductive toxicology》2014,101(4):293-299
We previously reported that treatment of mid‐pregnant mice with KRN633, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, caused fetal growth restriction resulting from diminished vascularization in the placenta and fetal organs. In this study, we examined how the treatment of mid‐pregnant mice with KRN633 affects the development and morphology of vascular components (endothelial cells, pericytes, and basement membrane) in the retinas of their newborn pups. Pregnant mice were treated with KRN633 (5 mg/kg) once daily from embryonic day 13.5 until the day of delivery. Vascular components were examined using immunohistochemistry with specific markers for each component. Radial vascular growth in the retina was slightly delayed until postnatal day 4 (P4) in the newborn pups of KRN633‐treated mothers. On P8, compared with the pups of control mothers, the pups of KRN633‐treated mothers exhibited decreased numbers of central arteries and veins and abnormal branching of the central arteries. No apparent differences in pericytes or basement membrane were observed between the pups of control and KRN633‐treated mothers. These results suggest that a critical period for determining retinal vascular patterning is present at the earliest stages of retinal vascular development, and that the impaired vascular endothelial growth factor signaling during this period induces abnormal architecture in the retinal vascular network 相似文献