全文获取类型
收费全文 | 3259篇 |
免费 | 224篇 |
国内免费 | 1篇 |
专业分类
3484篇 |
出版年
2024年 | 4篇 |
2023年 | 12篇 |
2022年 | 42篇 |
2021年 | 58篇 |
2020年 | 38篇 |
2019年 | 45篇 |
2018年 | 90篇 |
2017年 | 63篇 |
2016年 | 120篇 |
2015年 | 160篇 |
2014年 | 218篇 |
2013年 | 240篇 |
2012年 | 289篇 |
2011年 | 273篇 |
2010年 | 170篇 |
2009年 | 161篇 |
2008年 | 196篇 |
2007年 | 187篇 |
2006年 | 177篇 |
2005年 | 141篇 |
2004年 | 179篇 |
2003年 | 108篇 |
2002年 | 102篇 |
2001年 | 107篇 |
2000年 | 69篇 |
1999年 | 56篇 |
1998年 | 16篇 |
1997年 | 21篇 |
1996年 | 12篇 |
1995年 | 11篇 |
1994年 | 5篇 |
1993年 | 9篇 |
1992年 | 16篇 |
1991年 | 17篇 |
1990年 | 21篇 |
1989年 | 15篇 |
1988年 | 5篇 |
1987年 | 5篇 |
1986年 | 3篇 |
1985年 | 7篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1979年 | 2篇 |
1978年 | 3篇 |
1977年 | 1篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1966年 | 1篇 |
排序方式: 共有3484条查询结果,搜索用时 31 毫秒
91.
Zhirong Li Tae Kyu Ahn Thomas J. Avenson Matteo Ballottari Jeffrey A. Cruz David M. Kramer Roberto Bassi Graham R. Fleming Jay D. Keasling Krishna K. Niyogi 《The Plant cell》2009,21(6):1798-1812
Plants protect themselves from excess absorbed light energy through thermal dissipation, which is measured as nonphotochemical quenching of chlorophyll fluorescence (NPQ). The major component of NPQ, qE, is induced by high transthylakoid ΔpH in excess light and depends on the xanthophyll cycle, in which violaxanthin and antheraxanthin are deepoxidized to form zeaxanthin. To investigate the xanthophyll dependence of qE, we identified suppressor of zeaxanthin-less1 (szl1) as a suppressor of the Arabidopsis thaliana npq1 mutant, which lacks zeaxanthin. szl1 npq1 plants have a partially restored qE but lack zeaxanthin and have low levels of violaxanthin, antheraxanthin, and neoxanthin. However, they accumulate more lutein and α-carotene than the wild type. szl1 contains a point mutation in the lycopene β-cyclase (LCYB) gene. Based on the pigment analysis, LCYB appears to be the major lycopene β-cyclase and is not involved in neoxanthin synthesis. The Lhcb4 (CP29) and Lhcb5 (CP26) protein levels are reduced by 50% in szl1 npq1 relative to the wild type, whereas other Lhcb proteins are present at wild-type levels. Analysis of carotenoid radical cation formation and leaf absorbance changes strongly suggest that the higher amount of lutein substitutes for zeaxanthin in qE, implying a direct role in qE, as well as a mechanism that is weakly sensitive to carotenoid structural properties. 相似文献
92.
Ganipisetti Srinivasrao Jung-Eun Park Sungmin Kim Mija Ahn Chaejoon Cheong Ky-Youb Nam Pethaiah Gunasekaran Eunha Hwang Nam-Hyung Kim Song Yub Shin Kyung S. Lee Eunkyung Ryu Jeong Kyu Bang 《PloS one》2014,9(9)
Background
Polo-like kinase-1 (Plk1) plays a crucial role in cell proliferation and the inhibition of Plk1 has been considered as a potential target for specific inhibitory drugs in anti-cancer therapy. Several research groups have identified peptide-based inhibitors that target the polo-box domain (PBD) of Plk1 and bind to the protein with high affinity in in vitro assays. However, inadequate proteolytic resistance and cell permeability of the peptides hinder the development of these peptide-based inhibitors into novel therapeutic compounds.Methodology/Principal Findings
In order to overcome the shortcomings of peptide-based inhibitors, we designed and synthesized small molecule inhibitors. Among these molecules, bg-34 exhibited a high binding affinity for Plk1-PBD and it could cross the cell membrane in its unmodified form. Furthermore, bg-34-dependent inhibition of Plk1-PBD was sufficient for inducing apoptosis in HeLa cells. Moreover, modeling studies performed on Plk1-PBD in complex with bg-34 revealed that bg-34 can interact effectively with Plk1-PBD.Conclusion/Significance
We demonstrated that the molecule bg-34 is a potential drug candidate that exhibits anti-Plk1-PBD activity and possesses the favorable characteristics of high cell permeability and stability. We also determined that bg-34 induced apoptotic cell death by inhibiting Plk1-PBD in HeLa cells at the same concentration as PEGylated 4j peptide, which can inhibit Plk1-PBD activity 1000 times more effectively than bg-34 can in in vitro assays. This study may help to design and develop drug-like small molecule as Plk1-PBD inhibitor for better therapeutic activity. 相似文献93.
Xu Wang Yong-Mo Ahn Adam G. Lentscher Julia S. Lister Robert C. Brothers Malea M. Kneen Barbara Gerratana Helena I. Boshoff Cynthia S. Dowd 《Bioorganic & medicinal chemistry letters》2017,27(18):4426-4430
Nicotinamide adenine dinucleotide (NAD+) synthetase catalyzes the last step in NAD+ biosynthesis. Depletion of NAD+ is bactericidal for both active and dormant Mycobacterium tuberculosis (Mtb). By inhibiting NAD+ synthetase (NadE) from Mtb, we expect to eliminate NAD+ production which will result in cell death in both growing and nonreplicating Mtb. NadE inhibitors have been investigated against various pathogens, but few have been tested against Mtb. Here, we report on the expansion of a series of urea-sulfonamides, previously reported by Brouillette et al. Guided by docking studies, substituents on a terminal phenyl ring were varied to understand the structure–activity-relationships of substituents on this position. Compounds were tested as inhibitors of both recombinant Mtb NadE and Mtb whole cells. While the parent compound displayed very weak inhibition against Mtb NadE (IC50 = 1000 µM), we observed up to a 10-fold enhancement in potency after optimization. Replacement of the 3,4-dichloro group on the phenyl ring of the parent compound with 4-nitro yielded 4f, the most potent compound of the series with an IC50 value of 90 µM against Mtb NadE. Our modeling results show that these urea-sulfonamides potentially bind to the intramolecular ammonia tunnel, which transports ammonia from the glutaminase domain to the active site of the enzyme. This hypothesis is supported by data showing that, even when treated with potent inhibitors, NadE catalysis is restored when treated with exogenous ammonia. Most of these compounds also inhibited Mtb cell growth with MIC values of 19–100 µg/mL. These results improve our understanding of the SAR of the urea-sulfonamides, their mechanism of binding to the enzyme, and of Mtb NadE as a potential antitubercular drug target. 相似文献
94.
Su Jin Lee Geun-Young Sim Youngshim Lee Bong-Gyu Kim Joong-Hoon Ahn 《Journal of industrial microbiology & biotechnology》2017,44(11):1551-1560
Plants synthesize various phenol amides. Among them, hydroxycinnamoyl (HC) tryptamines and serotonins exhibit antioxidant, anti-inflammatory, and anti-atherogenic activities. We synthesized HC–tryptamines and HC–serotonin from several HCs and either tryptamine or serotonin using Escherichia coli harboring the 4CL (4-coumaroyl CoA ligase) and CaHCTT [hydroxycinnamoyl-coenzyme A:serotonin N-(hydroxycinnamoyl)transferase] genes. E. coli was engineered to synthesize N-cinnamoyl tryptamine from glucose. TDC (tryptophan decarboxylase) and PAL (phenylalanine ammonia lyase) along with 4CL and CaHCTT were introduced into E. coli and the phenylalanine biosynthetic pathway of E. coli was engineered. Using this strategy, approximately 110.6 mg/L of N-cinnamoyl tryptamine was synthesized. By feeding 100 μM serotonin into the E. coli culture, which could induce the synthesis of cinnamic acid or p-coumaric acid, more than 99 μM of N-cinnamoyl serotonin and N-(p-coumaroyl) serotonin were synthesized. 相似文献
95.
Tak H Jang E Kim SB Park J Suk J Yoon YS Ahn JK Lee JH Joe CO 《Cellular signalling》2007,19(11):2379-2387
The signal pathway by which 14-3-3epsilon inhibits cell migration induced by MAPK-activated protein kinase 5 (MK5) was investigated in cultured HeLa cells. Both in vivo and in vitro analyses have revealed that 14-3-3epsilon interacts with MK5. 14-3-3epsilon bound to MK5 inhibits the phosphorylation of HSP27, a known substrate of MK5. Disturbance of actin cytoskeleton organization by 14-3-3epsilon was shown in transfected cells transiently expressing 14-3-3epsilon as well as established cells stably expressing 14-3-3epsilon. Moreover, overexpression of 14-3-3epsilon resulted in the inhibition of cell migration induced by MK5 overexpression or TNFalpha treatment. Our results suggest that 14-3-3epsilon bound to MK5 inhibits cell migration by inhibiting the phosphorylation of HSP27 whose phosphorylation regulates F-actin polymerization, actin cytoskeleton organization and subsequent actinfilament dynamics. 相似文献
96.
New A-ring modified betulinic acid derivatives having small steric hindrance were prepared and tested for cytotoxic activity on 3 cancer cell lines: 10 compounds showed stronger cytotoxic activity than betulinic acid. Especially, the compounds bearing 1-ene-3-oxo with electron-withdrawing groups at C2 showed strong cytotoxicity. 相似文献
97.
Lee Jun-Won Oh Ji Eun Rhee Ki-Jong Yoo Byung-Su Eom Young Woo Park Sang Wook Lee Ji Hyun Son Jung-Woo Youn Young Jin Ahn Min-Soo Ahn Sung-Gyun Kim Jang-Young Lee Seung-Hwan Yoon Junghan 《Molecular and cellular biochemistry》2019,453(1-2):197-203
Molecular and Cellular Biochemistry - Electron transfer occurs through heme-Fe across the cytochrome c protein. The current models of long range electron transfer pathways in proteins include... 相似文献
98.
MHC-I molecules play a critical role in immune surveillance against viruses by presenting peptides to cytotoxic T lymphocytes. Although the mechanisms by which MHC-I molecules assemble and acquire peptides in the ER are well characterized, how MHC-I molecules traffic to the cell surface remains poorly understood. To identify novel proteins that regulate the intracellular transport of MHC-I molecules, MHC-I-interacting proteins were isolated by affinity purification, and their identity was determined by mass spectrometry. Among the identified MHC-I-associated proteins was Tmp21, the human ortholog of yeast Emp24p, which mediates the ER-Golgi trafficking of a subset of proteins. Here, we show that Tmp21 binds to human classical and non-classical MHC-I molecules. The Tmp21-MHC-I complex lacks Β(2)-microglobulin, and the number of the complexes is increased when free MHC-I heavy chains are more abundant. Taken together, these results suggest that Tmp21 is a novel protein that preferentially binds to Β(2)-microglobulin-free MHC-I heavy chains. 相似文献
99.
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
100.
We examined the elevational patterns of plant species along two transects on Mt Seorak, South Korea, and calculated four richness indices from field survey data: total number of species per 100 m elevational band; mean number of species per plot in each elevational band; total estimated number of species per elevational band; and beta diversity of each elevational band. We evaluated the effects of area, mean distance between plots, climatic variables (mean annual temperature and precipitation), and productivity on the richness patterns along the two transects. In total, 235 plant species belonging to 72 families and 161 genera were recorded from 130 plots along the two transects. The analyses revealed different patterns including monotonic decline, and unimodal and multimodal shapes for richness indices of total, woody, and herbaceous plants with the change in elevation along the two transects. The proportion of suitable area (as opposed to rocky areas) was the best predictor for total number of species per elevational band, mean number of species per plot, and total estimated number of species per elevational band of total and herbaceous plants along the two transects. Mean distance between plots was the most important variable for beta diversity of all plant groups. Although regional area, climatic variables, and productivity were important variables for predicting woody plant richness patterns, the effects were not consistent between the two transects. Our study suggests that elevational species richness patterns may differ not only among different plant groups, but also between nearby elevational transects, and that these differences are explained by differences in the underlying mechanisms shaping these patterns. 相似文献