全文获取类型
收费全文 | 5186篇 |
免费 | 411篇 |
国内免费 | 4篇 |
出版年
2024年 | 4篇 |
2023年 | 19篇 |
2022年 | 13篇 |
2021年 | 120篇 |
2020年 | 98篇 |
2019年 | 112篇 |
2018年 | 169篇 |
2017年 | 136篇 |
2016年 | 227篇 |
2015年 | 338篇 |
2014年 | 411篇 |
2013年 | 377篇 |
2012年 | 450篇 |
2011年 | 434篇 |
2010年 | 308篇 |
2009年 | 265篇 |
2008年 | 371篇 |
2007年 | 339篇 |
2006年 | 230篇 |
2005年 | 260篇 |
2004年 | 249篇 |
2003年 | 226篇 |
2002年 | 192篇 |
2001年 | 44篇 |
2000年 | 28篇 |
1999年 | 39篇 |
1998年 | 25篇 |
1997年 | 20篇 |
1996年 | 13篇 |
1995年 | 3篇 |
1994年 | 10篇 |
1993年 | 5篇 |
1992年 | 6篇 |
1991年 | 8篇 |
1990年 | 6篇 |
1989年 | 4篇 |
1988年 | 3篇 |
1987年 | 2篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1983年 | 5篇 |
1982年 | 5篇 |
1981年 | 2篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1974年 | 2篇 |
1972年 | 1篇 |
1971年 | 3篇 |
排序方式: 共有5601条查询结果,搜索用时 281 毫秒
91.
Hye Ri Park Jiyoon Kim Taekeun Kim Seonmi Jo Miyoung Yeom Bongjin Moon Il Han Choo Jaeick Lee Eun Jeong Lim Ki Duk Park Sun-Joon Min Ghilsoo Nam Gyochang Keum C. Justin Lee Hyunah Choo 《Bioorganic & medicinal chemistry》2013,21(17):5480-5487
In Parkinson’s disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinson’s disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinson’s disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure–activity relationship study revealed that the piperidino group was the best choice for the R1 amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5 nM in IC50 values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC50 value of 26.5 nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives. 相似文献
92.
Phuong-Thao Tran Van-Hai Hoang Shivaji A. Thorat Sung Eun Kim Jihyae Ann Yu Jin Chang Dong Woo Nam Hyundong Song Inhee Mook-Jung Jiyoun Lee Jeewoo Lee 《Bioorganic & medicinal chemistry》2013,21(13):3821-3830
In an effort to design inhibitors of human glutaminyl cyclase (QC), we have synthesized a library of N-aryl N-(5-methyl-1H-imidazol-1-yl)propyl thioureas and investigated the contribution of the aryl region of these compounds to their structure–activity relationships as cyclase inhibitors. Our design was guided by the proposed binding mode of the preferred substrate for the cyclase. In this series, compound 52 was identified as the most potent QC inhibitor with an IC50 value of 58 nM, which was two-fold more potent than the previously reported lead 2. Compound 52 is a most promising candidate for future evaluation to monitor its ability to reduce the formation of pGlu-Aβ and Aβ plaques in cells and transgenic animals. 相似文献
93.
Jeong Ah Hwang Mun Kyung Hwang Yongwoo Jang Eun Jung Lee Jong-Eun Kim Mi Hyun Oh Dong Joo Shin Semi Lim Geun og Ji Uhtaek Oh Ann M. Bode Zigang Dong Ki Won Lee Hyong Joo Lee 《The Journal of nutritional biochemistry》2013,24(6):1096-1104
Abnormal regulation of Ca2+ mediates tumorigenesis and Ca2+ channels are reportedly deregulated in cancers, indicating that regulating Ca2+ signaling in cancer cells is considered as a promising strategy to treat cancer. However, little is known regarding the mechanism by which Ca2+ affects cancer cell death. Here, we show that 20-O-β-d-glucopyranosyl-20(S)-protopanaxadiol (20-GPPD), a metabolite of ginseng saponin, causes apoptosis of colon cancer cells through the induction of cytoplasmic Ca2+. 20-GPPD decreased cell viability, increased annexin V-positive early apoptosis and induced sub-G1 accumulation and nuclear condensation of CT-26 murine colon cancer cells. Although 20-GPPD-induced activation of AMP-activated protein kinase (AMPK) played a key role in the apoptotic death of CT-26 cells, LKB1, a well-known upstream kinase of AMPK, was not involved in this activation. To identify the upstream target of 20-GPPD for activating AMPK, we examined the effect of Ca2+ on apoptosis of CT-26 cells. A calcium chelator recovered 20-GPPD-induced AMPK phosphorylation and CT-26 cell death. Confocal microscopy showed that 20-GPPD increased Ca2+ entry into CT-26 cells, whereas a transient receptor potential canonical (TRPC) blocker suppressed Ca2+ entry. When cells were treated with a TRPC blocker plus an endoplasmic reticulum (ER) calcium blocker, 20-GPPD-induced calcium influx was completely inhibited, suggesting that the ER calcium store, as well as TRPC, was involved. In vivo mouse CT-26 allografts showed that 20-GPPD significantly suppressed tumor growth, volume and weight in a dose-dependent manner. Collectively, 20-GPPD exerts potent anticarcinogenic effects on colon carcinogenesis by increasing Ca2+ influx, mainly through TRPC channels, and by targeting AMPK. 相似文献
94.
Targeted delivery of a phosphopeptide prodrug inhibits the proliferation of a human glioma cell line
Peptides are ideal candidates for developing therapeutics. Polo-like kinase 1 is an important regulatory protein in the cell cycle and contains a C-terminal polo-box domain, which is the hallmark of this protein family. We developed a peptide inhibitor of polo-like kinase 1 that targets its polo-box domain. This new phosphopeptide, cRGDyK-S-S-CPLHSpT, preferentially penetrates the cancer cell membrane mediated by the integrin receptor, which is expressed at high levels by cancer cells. In the present study, using high performance liquid chromatography and mass spectroscopy, we determined the stability of cRGDyK-S-S-CPLHSpT and its cleavage by glutathione under typical conditions for cell culture. We further assessed the ability of the peptide to inhibit the proliferation of the U87MG glioma cell line. The phosphorylated peptide was stable, and the disulfide bond of cRGDyK-S-S-CPLHSpT was cleaved in 50 mM glutathione. This peptide inhibited the growth of cancer cells and changed their morphology. Therefore, we conclude that the phosphopeptide shows promise as a prodrug and has a high potential to act as an anticancer agent by inhibiting polo-like kinase 1 by binding its polo-box domain. These findings indicate the therapeutic potential of PLHSpT and peptides similarly targeted to surface receptors of cancer cells and to the functional domains of regulatory proteins. 相似文献
95.
Akira Sakurai Yukiharu Sato Keun Hyung Park Nobutaka Takahashi Naohiko Yanagishima Isao Banno 《Bioscience, biotechnology, and biochemistry》2013,77(6):1451-1453
The pullulanase gene (pul) of Klebsiella aerogenes was transferred in vivo to Escherichia coli by using RP4:: Mu cts. The pul gene was expressed in E. coli, although the level of pullulanase activity in E. coli was lower than that in K. aerogenes, and the Pul+ transconjugants were relatively unstable in an unselective medium. Production of pullulanase, which is used to make maltose from starch, was induced in E. coli by pullulan, waxy maize amylopectin, soluble starch and maltose. When the transconjugant cells of E. coli were grown with pullulan or maltose, most pullulanase was produced intracellularly, whereas K. aerogenes produced pullulanase extracellularly. Retransfer of the pulk gene from E. coli to K. aerogenes by conjugation resulted in an increase of the production of extracellular pullulanase. 相似文献
96.
Eun Sik Tak 《Bioscience, biotechnology, and biochemistry》2013,77(3):367-373
The coelomic cells of the earthworm consist of leukocytes, chlorogocytes, and coelomocytes, which play an important role in innate immunity reactions. To gain insight into the expression profiles of coelomic cells of the earthworm, Eisenia andrei, we analyzed 1151 expressed sequence tags (ESTs) derived from the cDNA library of the coelomic cells. Among the 1151 ESTs analyzed, 493 ESTs (42.8%) showed a significant similarity to known genes and represented 164 unique genes, of which 93 ESTs were singletons and 71 ESTs manifested as two or more ESTs. From the 164 unique genes sequenced, we found 24 immune-related and cell defense genes. Furthermore, real-time PCR analysis showed that levels of lysenin-related proteins mRNA in coelomic cells of E. andrei were upregulated after the injection of Bacillus subtilis bacteria. This EST data-set would provide a valuable resource for future researches of earthworm immune system. 相似文献
97.
Seongho Jang Eu Ddeum Park Hyung Joo Suh Sang Hun Lee Jin Soo Kim 《Bioscience, biotechnology, and biochemistry》2013,77(10):1716-1722
To investigate the activity of fermented deer antler on exercise endurance capacity, we evaluated endurance capacity in five-week-old male BALB/c mice by administering the fermented deer antler extract (FA) or the non-fermented deer antler extract (NFA) and then subjected the mice to exercise in the form of swimming. The mice administered 500?mg/kg/day of FA showed a significant increase in swimming time compared with mice administered placebo (16.55?min vs. 21.64?min, P?<?0.05). Serum lactate dehydrogenase (LDH), the marker of the liver and muscle damage, was significantly lower in FA groups. However, NFA groups did not show significantly different swimming time or serum LDH from that of the control group. Moreover, the FA-500 group had significantly higher hepatic superoxide dismutase (SOD) activity after forced swimming than the control and NFA groups (P?<?0.05). These findings suggest that fermentation may increase the exercise endurance capacity of the deer antler. 相似文献
98.
Eun Kyoung Hwang Yong Gun Gong Il-Ki Hwang Eun-Jeong Park Chan Sun Park 《Journal of applied phycology》2013,25(3):825-829
Ecklonia cava and Ecklonia stolonifera are perennial brown algae that form sea forests off the coast of Korea. Both species are cultured to supply a summer feed for the abalone industry. Recent expansion of the abalone industry in Korea has been bringing an increase in demand for fresh algal supply. Zoospores of the two algae were seeded in October 2006 on seed frames coiled with 100 m of seed fibers. After 2 months of indoor culture and 2 months of intermediate culture, growth and production of the two algae were compared during their main cultivation period from March 2007 to June 2008, in the culture ground in Wando, Korea (34°26′18.68″ N, 127°05′43.88″ E), in situ. Growth rate of E. cava and E. stolonifera was 1.058 and 3.089 mm day?1, respectively. The mean production of E. stolonifera obtained from the culture ropes was ca. 12 kg wet wt. m?1 of culture rope while production of E. cava was ca. 3 kg wet wt. m?1 of culture rope. The difference in production was attributed from the different growth strategies of the two algae, with only E. stolonifera being able to regenerate blades from the holdfast. The ability to regenerate blades from the holdfast therefore makes E. stolonifera the preferred species for biomass production for abalone feeds. In a 120-day feeding experiment, growth rate, weight gain, and survival rate of abalone showed that E. cava and E. stolonifera feeds could provide an alternative feed to Saccharina japonica during summer months. 相似文献
99.
100.
Due to the highly folded chromatin in human sperm, a proper nuclear swelling was highly required to localize certain DNA inside the sperm nuclei. Therefore, previous method for denaturation of sperm chromatin had to adopt chemical agents of decondensation treatment using Heparin/DTT or LIS, directly applied into the sperm cell before further examinations by FISH. Nevertheless, authors still had questions arising on the efficiency of decondensation process which is directly related to the quality of fluorescence signals, which, in turn, underlies the reliability of the results in frequencies and compositions as that still not a proper solution to overcome the major limitation in sperm studies. In this study, we approached a newly improved denaturation process of sperm chromatin without undergoing decondensation treatments that intact human sperms were used as the first time to localize examined DNA, and also two rounds of sequential FISH was carried out in the same sperm cell for the first time to investigate an idea of nullisomy of given chromosomes. From the results, all the variable centromeric compositions of sperm chromosomes 7, 8, and sex chromosomes revealed with significantly given frequencies of monosomy, disomy and nullisomy. Moreover, nullisomy was identified as a true absence of given chromosome rather than technical error of hybridization failure under decondensation. From the findings by our modified denaturation of human sperm chromatin without undergoing decondensation treatment, we strongly believe that more advanced and deep studies in human sperm of nuclear architecture and frequencies can be progressed with significantly reliable results. 相似文献