全文获取类型
收费全文 | 11217篇 |
免费 | 825篇 |
国内免费 | 6篇 |
出版年
2024年 | 13篇 |
2023年 | 49篇 |
2022年 | 139篇 |
2021年 | 238篇 |
2020年 | 172篇 |
2019年 | 203篇 |
2018年 | 327篇 |
2017年 | 293篇 |
2016年 | 481篇 |
2015年 | 679篇 |
2014年 | 810篇 |
2013年 | 856篇 |
2012年 | 1031篇 |
2011年 | 1012篇 |
2010年 | 661篇 |
2009年 | 567篇 |
2008年 | 749篇 |
2007年 | 668篇 |
2006年 | 567篇 |
2005年 | 519篇 |
2004年 | 500篇 |
2003年 | 406篇 |
2002年 | 344篇 |
2001年 | 156篇 |
2000年 | 119篇 |
1999年 | 104篇 |
1998年 | 60篇 |
1997年 | 52篇 |
1996年 | 32篇 |
1995年 | 25篇 |
1994年 | 18篇 |
1993年 | 18篇 |
1992年 | 23篇 |
1991年 | 29篇 |
1990年 | 25篇 |
1989年 | 25篇 |
1988年 | 13篇 |
1987年 | 6篇 |
1986年 | 6篇 |
1985年 | 15篇 |
1984年 | 10篇 |
1983年 | 2篇 |
1982年 | 3篇 |
1979年 | 2篇 |
1978年 | 3篇 |
1977年 | 2篇 |
1975年 | 3篇 |
1974年 | 4篇 |
1972年 | 2篇 |
1966年 | 1篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
231.
Non hemolytic short peptidomimetics as a new class of potent and broad-spectrum antimicrobial agents
Ravichandran N. Murugan Binu Jacob Eun-Hee Kim Mija Ahn Hoik Sohn Ji-Hyung Seo Chaejoon Cheong Jae-Kyung Hyun Kyung S. Lee Song Yub Shin Jeong Kyu Bang 《Bioorganic & medicinal chemistry letters》2013,23(16):4633-4636
Since the bacterial resistance to antibiotics is increasing rapidly, numerous studies have contributed to the design and synthesis of potent synthetic mimics of antimicrobial peptides (AMPs). In an attempt to find the pharmacophore of short antimicrobial peptidomimetics through systematic tuning of hydrophobic and hydrophilic patterns, we have identified a set of short histidine-derived antimicrobial peptides (SAMPs) with potent and broad-spectrum activity. A combination of high antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), without hemolytic activity and proteolytic stability makes these molecules promising candidates for novel antimicrobial therapeutics. 相似文献
232.
Seong Rim Byeon Hyunjin Vincent Kim Mijin Jeon Young Gil Ahn Maeng Sup Kim Jae Yang Kong Hye Yun Kim Young Soo Kim Dong Jin Kim 《Bioorganic & medicinal chemistry letters》2013,23(11):3467-3469
Alzheimer’s disease drug discovery regarding exploration into the molecules and processes has focused on the intrinsic causes of the brain disorder correlated with the accumulation of amyloid-β. An anti-amyloidogenic bis-styrylbenzene derivative, KMS80013, showed excellent oral bioavailability (F = 46.2%), facilitated brain penetration (26%, iv) in mouse and target specific in vivo efficacy in acute AD mouse model attenuating the cognitive deficiency in Y-maze test. Acute toxicity (LD50 >2000 mg/kg) and hERG channel inhibition (14% at 10 μM) results indicated safety of KMS80013. 相似文献
233.
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
234.
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
235.
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
236.
We herein report a peptide receptor-based bioelectronic nose (PRBN) that can determine the quality of seafood in real-time through measuring the amount of trimethylamine (TMA) generated from spoiled seafood. The PRBN was developed using single walled-carbon nanotube field-effect transistors (SWNT-FETs) functionalized with olfactory receptor-derived peptides (ORPs) which can recognize TMA and it allowed us to sensitively and selectively detect TMA in real-time at concentrations as low as 10fM. Utilizing these properties, we were able to not only determine the quality of three kinds of seafood (oyster, shrimp, and lobster), but were also able to distinguish spoiled seafood from other types of spoiled foods without any pretreatment processes. Especially, the use of small synthetic peptide rather than the whole protein allowed PRBNs to be simply manufactured through a single-step process and to be reused with high reproducibility due to no requirement of lipid bilayers. Furthermore, the PRBN was produced on a portable scale making it effectively useful for the food industry where the on-site measurement of seafood quality is required. 相似文献
237.
Hae Woong Park Myoung Rae Cho Taek Jun Kang Seung-Joon Ahn Sung Wook Jeon 《Biocontrol Science and Technology》2013,23(6):637-645
Infectivity of entomopathogenic nematode (EPN) Steinernema carpocapsae Pocheon strain on the green peach aphid Myzus persicae and its parasitic wasps (e.g., Aphidius colemani, Aphidius gifuensis and Diaeretiella rapae) was evaluated under laboratory conditions. Infective juveniles (IJs) of S. carpocapsae Pocheon strain had low infectivity against nymph and adult stages of M. persicae, showing 2% and 6.7% of mortality, respectively. Application of the EPNs had little effect on mummies caused by the three parasitoid species, allowing them to remain intact. No IJ invaded the host, regardless of EPN application rate. The parasitoid emergence from mummies ranged from 80% to 85% in the presence of EPN while 79–86% was recorded in the absence of EPN. However, the presence of the IJs reduced oviposition by the three parasitoid species, decreasing the rate up to 59% when the nematodes were applied before parasitoid release, while little difference in oviposition was observed when nematodes were applied after parasitoid release. 相似文献
238.
Tae Young Shin Won Woo Lee Seung Hyun Ko Jae Bang Choi Sung Min Bae Jae Young Choi 《Biocontrol Science and Technology》2013,23(3):288-304
We investigated the occurrence of entomopathogenic fungi in 1080 soil samples representing multiple locations and conditions in Korea. Entomopathogenic fungi were isolated from soils using a selective medium containing dodine and antibiotics. Following an initial identification based on morphology, the fungal isolates were more precisely identified by the sequence of their nuclear ribosomal RNA (rRNA) internal transcribed spacer (ITS) regions. As a result, entomopathogenic fungi were found to occur in 32% (342 isolates) of the soil samples studied. The most abundant species were Beauveria spp. (125 isolates) and Metarhizium spp. (82 isolates). Entomopathogenic fungi were more often recovered from natural mountain and riparian soils than from agricultural habitats. The pathogenicity of isolated fungi was evaluated by using wax moth Galleria mellonella L. (Lepidoptera: Pyralidae) larvae. It was determined that 60% (207 isolates) of the isolates were pathogenic using this model. These entomopathogenic fungi may, therefore, have potential use against a variety of agricultural pests. This is the first study of the isolation and distribution of entomopathogenic fungi in representative sampling locations throughout Korea. 相似文献
239.
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
240.
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