全文获取类型
收费全文 | 12117篇 |
免费 | 776篇 |
国内免费 | 7篇 |
出版年
2024年 | 22篇 |
2023年 | 49篇 |
2022年 | 152篇 |
2021年 | 232篇 |
2020年 | 131篇 |
2019年 | 205篇 |
2018年 | 295篇 |
2017年 | 244篇 |
2016年 | 424篇 |
2015年 | 615篇 |
2014年 | 745篇 |
2013年 | 797篇 |
2012年 | 1066篇 |
2011年 | 1042篇 |
2010年 | 648篇 |
2009年 | 498篇 |
2008年 | 787篇 |
2007年 | 674篇 |
2006年 | 611篇 |
2005年 | 558篇 |
2004年 | 570篇 |
2003年 | 452篇 |
2002年 | 360篇 |
2001年 | 355篇 |
2000年 | 327篇 |
1999年 | 227篇 |
1998年 | 89篇 |
1997年 | 77篇 |
1996年 | 49篇 |
1995年 | 48篇 |
1994年 | 38篇 |
1993年 | 29篇 |
1992年 | 83篇 |
1991年 | 54篇 |
1990年 | 44篇 |
1989年 | 48篇 |
1988年 | 27篇 |
1987年 | 28篇 |
1986年 | 21篇 |
1985年 | 23篇 |
1984年 | 13篇 |
1983年 | 15篇 |
1982年 | 12篇 |
1981年 | 12篇 |
1980年 | 11篇 |
1979年 | 9篇 |
1978年 | 15篇 |
1975年 | 13篇 |
1974年 | 11篇 |
1970年 | 6篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
991.
Jeong-Mo Choi Adrian?W.R. Serohijos Sean Murphy Dennis Lucarelli Leo?L. Lofranco Andrew Feldman Eugene?I. Shakhnovich 《Biophysical journal》2015,108(4):795-798
It has long been known that solvation plays an important role in protein-protein interactions. Here, we use a minimalistic solvation-based model for predicting protein binding energy to estimate quantitatively the contribution of the solvation factor in protein binding. The factor is described by a simple linear combination of buried surface areas according to amino-acid types. Even without structural optimization, our minimalistic model demonstrates a predictive power comparable to more complex methods, making the proposed approach the basis for high throughput applications. Application of the model to a proteomic database shows that receptor-substrate complexes involved in signaling have lower affinities than enzyme-inhibitor and antibody-antigen complexes, and they differ by chemical compositions on interfaces. Also, we found that protein complexes with components that come from the same genes generally have lower affinities than complexes formed by proteins from different genes, but in this case the difference originates from different interface areas. The model was implemented in the software PYTHON, and the source code can be found on the Shakhnovich group webpage: http://faculty.chemistry.harvard.edu/shakhnovich/software. 相似文献
992.
Live cell imaging compatible immobilization of Chlamydomonas reinhardtii in microfluidic platform for biodiesel research 下载免费PDF全文
993.
Enhancing functional expression of heterologous proteins through random substitution of genetic codes in the 5' coding region 下载免费PDF全文
994.
Se Joon Choi Anne Panhelainen Yvonne Schmitz Kristin E. Larsen Ellen Kanter Min Wu David Sulzer Eugene V. Mosharov 《The Journal of biological chemistry》2015,290(11):6799-6809
1-Methyl-4-phenylpyridinium (MPP+), the active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, selectively kills dopaminergic neurons in vivo and in vitro via a variety of toxic mechanisms, including mitochondrial dysfunction, generation of peroxynitrite, induction of apoptosis, and oxidative stress due to disruption of vesicular dopamine (DA) storage. To investigate the effects of acute MPP+ exposure on neuronal DA homeostasis, we measured stimulation-dependent DA release and non-exocytotic DA efflux from mouse striatal slices and extracellular, intracellular, and cytosolic DA (DAcyt) levels in cultured mouse ventral midbrain neurons. In acute striatal slices, MPP+ exposure gradually decreased stimulation-dependent DA release, followed by massive DA efflux that was dependent on MPP+ concentration, temperature, and DA uptake transporter activity. Similarly, in mouse midbrain neuronal cultures, MPP+ depleted vesicular DA storage accompanied by an elevation of cytosolic and extracellular DA levels. In neuronal cell bodies, increased DAcyt was not due to transmitter leakage from synaptic vesicles but rather to competitive MPP+-dependent inhibition of monoamine oxidase activity. Accordingly, monoamine oxidase blockers pargyline and l-deprenyl had no effect on DAcyt levels in MPP+-treated cells and produced only a moderate effect on the survival of dopaminergic neurons treated with the toxin. In contrast, depletion of intracellular DA by blocking neurotransmitter synthesis resulted in ∼30% reduction of MPP+-mediated toxicity, whereas overexpression of VMAT2 completely rescued dopaminergic neurons. These results demonstrate the utility of comprehensive analysis of DA metabolism using various electrochemical methods and reveal the complexity of the effects of MPP+ on neuronal DA homeostasis and neurotoxicity. 相似文献
995.
Youngsil Choi Mi-Jung Kwon Yangmi Lim Ji-Hye Yun Weontae Lee Eok-Soo Oh 《The Journal of biological chemistry》2015,290(27):16943-16953
Syndecans, a family of transmembrane heparansulfate proteoglycans, are known to interact through their transmembrane domains to form non-covalently linked homodimers, a process essential for their individual functions. Because all syndecan transmembrane domains are highly conserved and thus might mediate interactions between different members of the syndecan family, we investigated syndecan interactions in detail. All recombinant syndecan-2 and -4 protein variants containing the transmembrane domain formed not only sodium dodecyl sulfate (SDS)-resistant homodimers but also SDS-resistant heterodimers. Biochemical and structural data revealed that recombinant syndecan-2 and -4 formed intermolecular interactions in vitro, and the GXXXG motif in transmembrane domain mediated this interaction. When exogenously expressed in rat embryonic fibroblasts, syndecan-2 interacted with syndecan-4 and vice versa. Furthermore, bimolecular fluorescence complementation-based assay demonstrated specific hetero-molecular interactions between syndecan-2 and -4, supporting hetero-oligomer formation of syndecans in vivo. Interestingly, hetero-oligomerization significantly reduced syndecan-4-mediated cellular processes such as protein kinase Cα activation and protein kinase Cα-mediated cell adhesion as well as syndecan-2-mediated tumorigenic activities in colon cancer cells such as migration and anchorage-independent growth. Taken together, these data provide evidence that hetero-oligomerization produces distinct syndecan functions and offer insights into the underlying signaling mechanisms of syndecans. 相似文献
996.
997.
Jun-Hyuk Choi So-Young Kim Sook-Kyung Kim Michael G. Kemp Aziz Sancar 《The Journal of biological chemistry》2015,290(48):28812-28821
DNA damage by UV and UV-mimetic agents elicits a set of inter-related responses in mammalian cells, including DNA repair, DNA damage checkpoints, and apoptosis. Conventionally, these responses are analyzed separately using different methodologies. Here we describe a unified approach that is capable of quantifying all three responses in parallel using lysates from the same population of cells. We show that a highly sensitive in vivo excision repair assay is capable of detecting nucleotide excision repair of a wide spectrum of DNA lesions (UV damage, chemical carcinogens, and chemotherapeutic drugs) within minutes of damage induction. This method therefore allows for a real-time measure of nucleotide excision repair activity that can be monitored in conjunction with other components of the DNA damage response, including DNA damage checkpoint and apoptotic signaling. This approach therefore provides a convenient and reliable platform for simultaneously examining multiple aspects of the DNA damage response in a single population of cells that can be applied for a diverse array of carcinogenic and chemotherapeutic agents. 相似文献
998.
Amrita Datta Chaudhuri Savan Kabaria Doo Chul Choi M. Maral Mouradian Eunsung Junn 《The Journal of biological chemistry》2015,290(19):12425-12434
Parkinson disease is associated with decreased activity of the mitochondrial electron transport chain. This defect can be recapitulated in vitro by challenging dopaminergic cells with 1-methyl-4-phenylpyridinium (MPP+), a neurotoxin that inhibits complex I of electron transport chain. Consequently, oxidative phosphorylation is blocked, and cells become dependent on glycolysis for ATP production. Therefore, increasing the rate of glycolysis might help cells to produce more ATP to meet their energy demands. In the present study, we show that microRNA-7, a non-coding RNA that protects dopaminergic neuronal cells against MPP+-induced cell death, promotes glycolysis in dopaminergic SH-SY5Y and differentiated human neural progenitor ReNcell VM cells, as evidenced by increased ATP production, glucose consumption, and lactic acid production. Through a series of experiments, we demonstrate that targeted repression of RelA by microRNA-7, as well as subsequent increase in the neuronal glucose transporter 3 (Glut3), underlies this glycolysis-promoting effect. Consistently, silencing Glut3 expression diminishes the protective effect of microRNA-7 against MPP+. Further, microRNA-7 fails to prevent MPP+-induced cell death when SH-SY5Y cells are cultured in a low glucose medium, as well as when differentiated ReNcell VM cells or primary mouse neurons are treated with the hexokinase inhibitor, 2-deoxy-d-glucose, indicating that a functional glycolytic pathway is required for this protective effect. In conclusion, microRNA-7, by down-regulating RelA, augments Glut3 expression, promotes glycolysis, and subsequently prevents MPP+-induced cell death. This protective effect of microRNA-7 could be exploited to correct the defects in oxidative phosphorylation in Parkinson disease. 相似文献
999.
Soo-A Jung Yong-Man Park Seung-Woo Hong Jai-Hee Moon Jae-Sik Shin Ha-Reum Lee Seung-Hee Ha Dae-Hee Lee Jeong Hee Kim Seung-Mi Kim Jeong Eun Kim Kyu-pyo Kim Yong Sang Hong Eun Kyung Choi Jung Shin Lee Dong-Hoon Jin TaeWon Kim 《The Journal of biological chemistry》2015,290(16):9974-9985
YM155, which blocks the expression of survivin, a member of the inhibitor of apoptosis (IAP) family, induces cell death in a variety of cancer types, including prostate, bladder, breast, leukemia, and non-small lung cancer. However, the mechanism underlying gastric cancer susceptibility and resistance to YM155 is yet to be specified. Here, we demonstrate that cIAP1 stability dictates resistance to YM155 in human gastric cancer cells. Treatment of human gastric cancer cells with YM155 differentially induced cell death dependent on the stability of cIAP1 as well as survivin. Transfection with cIAP1 expression plasmids decreased cell sensitivity to YM155, whereas knockdown of endogenous cIAP1 using RNA interference enhanced sensitivity to YM155. In addition, double knockdown of survivin and cIAP1 significantly induced cell death in the YM155-resistant cell line, MKN45. We also showed that YM155 induced autoubiquitination and proteasome-dependent degradation of cIAP1. Surprisingly, survivin affected the stability of cIAP1 through binding, contributing to cell sensitivity to YM155. Thus, our findings reveal that YM155 sensitizes human gastric cancer cells to apoptotic cell death by degrading cIAP1, and furthermore, cIAP1 in gastric cancer cells may act as a PD marker for YM155 treatment. 相似文献
1000.
Loss of mitofusin 2 links beta‐amyloid‐mediated mitochondrial fragmentation and Cdk5‐induced oxidative stress in neuron cells 下载免费PDF全文
Junghyung Park Hoonsung Choi Ju‐Sik Min Bokyung Kim Sang‐Rae Lee Jong Won Yun Myung‐Sook Choi Kyu‐Tae Chang Dong‐Seok Lee 《Journal of neurochemistry》2015,132(6):687-702
Mitochondrial dysfunction is implicated in age‐related degenerative disorders such as Alzheimer's disease (AD). Maintenance of mitochondrial dynamics is essential for regulating mitochondrial function. Aβ oligomers (AβOs), the typical cause of AD, lead to mitochondrial dysfunction and neuronal loss. AβOs have been shown to induce mitochondrial fragmentation, and their inhibition suppresses mitochondrial dysfunction and neuronal cell death. Oxidative stress is one of the earliest hallmarks of AD. Cyclin‐dependent kinase 5 (Cdk5) may cause oxidative stress by disrupting the antioxidant system, including Prx2. Cdk5 is also regarded as a modulator of mitochondrial fission; however, a precise mechanistic link between Cdk5 and mitochondrial dynamics is lacking. We estimated mitochondrial morphology and alterations in mitochondrial morphology‐related proteins in Neuro‐2a (N2a) cells stably expressing the Swedish mutation of amyloid precursor protein (APP), which is known to increase AβO production. We demonstrated that mitochondrial fragmentation by AβOs accompanies reduced mitofusin 1 and 2 (Mfn1/2) levels. Interestingly, the Cdk5 pathway, including phosphorylation of the Prx2‐related oxidative stress, has been shown to regulate Mfn1 and Mfn2 levels. Furthermore, Mfn2, but not Mfn1, over‐expression significantly inhibits the AβO‐mediated cell death pathway. Therefore, these results indicate that AβO‐mediated oxidative stress triggers mitochondrial fragmentation via decreased Mfn2 expression by activating Cdk5‐induced Prx2 phosphorylation.