全文获取类型
收费全文 | 436篇 |
免费 | 36篇 |
出版年
2023年 | 3篇 |
2022年 | 5篇 |
2021年 | 18篇 |
2020年 | 5篇 |
2019年 | 9篇 |
2018年 | 10篇 |
2017年 | 6篇 |
2016年 | 14篇 |
2015年 | 35篇 |
2014年 | 27篇 |
2013年 | 29篇 |
2012年 | 34篇 |
2011年 | 51篇 |
2010年 | 26篇 |
2009年 | 22篇 |
2008年 | 28篇 |
2007年 | 17篇 |
2006年 | 13篇 |
2005年 | 10篇 |
2004年 | 25篇 |
2003年 | 17篇 |
2002年 | 16篇 |
2001年 | 4篇 |
2000年 | 10篇 |
1999年 | 8篇 |
1998年 | 4篇 |
1997年 | 4篇 |
1996年 | 1篇 |
1995年 | 3篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1988年 | 6篇 |
1987年 | 1篇 |
1985年 | 4篇 |
1983年 | 1篇 |
1981年 | 1篇 |
1977年 | 1篇 |
1976年 | 1篇 |
排序方式: 共有472条查询结果,搜索用时 31 毫秒
61.
In a screen to identify genes involved in synaptic function, we isolated mutations in Drosophila melanogaster straightjacket (stj), an alpha(2)delta subunit of the voltage-gated calcium channel. stj mutant photoreceptors develop normal synaptic connections but display reduced "on-off" transients in electroretinogram recordings, indicating a failure to evoke postsynaptic responses and, thus, a defect in neurotransmission. stj is expressed in neurons but excluded from glia. Mutants exhibit endogenous seizure-like activity, indicating altered neuronal excitability. However, at the synaptic level, stj larval neuromuscular junctions exhibit approximately fourfold reduction in synaptic release compared with controls stemming from a reduced release probability at these synapses. These defects likely stem from destabilization of Cacophony (Cac), the primary presynaptic alpha(1) subunit in D. melanogaster. Interestingly, neuronal overexpression of cac partially rescues the viability and physiological defects in stj mutants, indicating a role for the alpha(2)delta Ca(2+) channel subunit in mediating the proper localization of an alpha(1) subunit at synapses. 相似文献
62.
63.
Jill A. Jablonowski Kiev S. Ly Michael Bogenstaetter Curt A. Dvorak Jamin D. Boggs Lisa K. Dvorak Brian Lord Kirsten L. Miller Curt Mazur Sandy J. Wilson Timothy W. Lovenberg Nicholas I. Carruthers 《Bioorganic & medicinal chemistry letters》2009,19(3):903-907
A novel series of imidazole containing histamine H3 receptor ligands were investigated and found to be potent functional antagonists. After improving the stability of these molecules towards liver microsomes, these compounds were found to have no appreciable affinity for CYP P450s. Subsequent in vivo experiments showed significant brain uptake of (4-chloro-phenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone 22. 相似文献
64.
R. M. Belagaje S. G. Reams S. C. Ly W. F. Prouty 《Protein science : a publication of the Protein Society》1997,6(9):1953-1962
A general method for obtaining high-level production of low molecular weight proteins in Escherichia coli is described. This method is based on the use of a novel Met-Xaa-protein construction which is formed by insertion of a single amino acid residue (preferably Arginine or Lysine) between the N-terminal methionine and the protein of interest. The utility of this method is illustrated by examples for achieving high-level production of human insulin-like growth factor-1, human proinsulin, and their analogs. Furthermore, highly produced insulin-like growth factor-1 derivatives and human proinsulin analogs are converted to their natural sequences by removal of dipeptides with cathepsin C. 相似文献
65.
Imidazo[1,2‐c]pyrimidin‐5(6H)‐one as a novel core of cyclin‐dependent kinase 2 inhibitors: Synthesis,activity measurement,docking, and quantum mechanical scoring
下载免费PDF全文
![点击此处可从《Journal of molecular recognition : JMR》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Cemal Köprülüoğlu Pavel Hobza Vladimír Kryštof Antonín Lyčka Martin Lepsik 《Journal of molecular recognition : JMR》2018,31(9)
We report on the synthesis, activity testing, docking, and quantum mechanical scoring of novel imidazo[1,2‐c]pyrimidin‐5(6H)‐one scaffold for cyclin‐dependent kinase 2 (CDK2) inhibition. A series of 26 compounds substituted with aromatic moieties at position 8 has been tested in in vitro enzyme assays and shown to inhibit CDK2. 2D structure‐activity relationships have ascertained that small substituents at position 8 (up to the size of naphtyl or methoxyphenyl) generally lead to single‐digit micromolar IC50 values, whereas bigger substituents (substituted biphenyls) decreased the compounds' activities. The binding modes of the compounds obtained using Glide docking have exhibited up to 2 hinge‐region hydrogen bonds to CDK2 and differed in the orientation of the inhibitor core and the placement of the 8‐substituents. Semiempirical quantum mechanics‐based scoring identified probable favourable binding modes, which will serve for future structure‐based design and synthetic optimization of substituents of the heterocyclic core. In summary, we have identified a novel core for CDK2 inhibition and will explore it further to increase the potencies of the compounds and also monitor selectivities against other protein kinases. 相似文献
66.
67.
68.
Ly Na Huynh Adama Zan Diarra Quang Luan Pham Nhiem Le-Viet Jean-Michel Berenger Van Hoang Ho Xuan Quang Nguyen Philippe Parola 《PLoS neglected tropical diseases》2021,15(9)
Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been reported as a promising and reliable tool for arthropod identification, including the identification of alcohol-preserved ticks based on extracted leg protein spectra. In this study, the legs of 361 ticks collected in Vietnam, including 251 Rhiphicephalus sanguineus s.l, 99 Rhipicephalus (Boophilus) microplus, two Amblyomma varanensis, seven Dermacentor auratus, one Dermacentor compactus and one Amblyomma sp. were submitted for MALDI-TOF MS analyses. Spectral analysis showed intra-species reproducibility and inter-species specificity and the spectra of 329 (91%) specimens were of excellent quality. The blind test of 310 spectra remaining after updating the database with 19 spectra revealed that all were correctly identified with log score values (LSV) ranging from 1.7 to 2.396 with a mean of 1.982 ± 0.142 and a median of 1.971. The DNA of several microorganisms including Anaplasma platys, Anaplasma phagocytophilum, Anaplasma marginale, Ehrlichia rustica, Babesia vogeli, Theileria sinensis, and Theileria orientalis were detected in 25 ticks. Co-infection by A. phagocytophilum and T. sinensis was found in one Rh. (B) microplus. 相似文献
69.
Jae Min Cho SeulKi Park Rajeshwary Ghosh Kellsey Ly Caroline Ramous Lauren Thompson Michele Hansen Maria Sara de Lima Coutinho Mattera Karla Maria Pires Maroua Ferhat Sohom Mookherjee Kevin J. Whitehead Kandis Carter Mrcio Buffolo Sihem Boudina J. David Symons 《Aging cell》2021,20(10)
Protein quality control mechanisms decline during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age‐associated cardiac dysfunction. Macroautophagy is the process by which post‐mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late‐in‐life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs. adult mice. As expected, 24‐month‐old male C57BL/6J mice (old) exhibited repressed autophagosome formation and protein aggregate accumulation in the heart, systolic and diastolic dysfunction, and reduced exercise capacity vs. 8‐month‐old (adult) mice (all p < 0.05). To investigate the influence of late‐in‐life exercise training, additional cohorts of 21‐month‐old mice did (old‐ETR) or did not (old‐SED) complete a 3‐month progressive resistance treadmill running program. Body composition, exercise capacity, and soleus muscle citrate synthase activity improved in old‐ETR vs. old‐SED mice at 24 months (all p < 0.05). Importantly, protein expression of autophagy markers indicate trafficking of the autophagosome to the lysosome increased, protein aggregate clearance improved, and overall function was enhanced (all p < 0.05) in hearts from old‐ETR vs. old‐SED mice. These data provide the first evidence that a physiological intervention initiated late‐in‐life improves autophagic flux, protein aggregate clearance, and contractile performance in mouse hearts. 相似文献
70.
Jurre Y. Siegers Vijaykrishna Dhanasekaran Ruopeng Xie Yi-Mo Deng Sarika Patel Vanra Ieng Jean Moselen Heidi Peck Ammar Aziz Borann Sarr Savuth Chin Seng Heng Asheena Khalakdina Michael Kinzer Darapheak Chau Philomena Raftery Veasna Duong Ly Sovann Ian G. Barr Erik A. Karlsson 《Journal of virology》2021,95(24)