全文获取类型
收费全文 | 184篇 |
免费 | 18篇 |
出版年
2023年 | 2篇 |
2021年 | 5篇 |
2020年 | 2篇 |
2018年 | 1篇 |
2016年 | 7篇 |
2015年 | 2篇 |
2014年 | 12篇 |
2013年 | 17篇 |
2012年 | 16篇 |
2011年 | 9篇 |
2010年 | 9篇 |
2009年 | 9篇 |
2008年 | 15篇 |
2007年 | 12篇 |
2006年 | 9篇 |
2005年 | 5篇 |
2004年 | 12篇 |
2003年 | 6篇 |
2002年 | 10篇 |
2001年 | 4篇 |
2000年 | 3篇 |
1999年 | 2篇 |
1998年 | 2篇 |
1997年 | 3篇 |
1996年 | 2篇 |
1995年 | 3篇 |
1994年 | 1篇 |
1992年 | 2篇 |
1991年 | 3篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1985年 | 2篇 |
1983年 | 2篇 |
1981年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1975年 | 2篇 |
1974年 | 2篇 |
排序方式: 共有202条查询结果,搜索用时 109 毫秒
81.
82.
Discovery and optimization of potent broad-spectrum arenavirus inhibitors derived from benzimidazole
Dongcheng Dai James R. Burgeson Dima N. Gharaibeh Amy L. Moore Ryan A. Larson Natasha R. Cerruti Sean M. Amberg Tove’ C. Bolken Dennis E. Hruby 《Bioorganic & medicinal chemistry letters》2013,23(3):744-749
A chemically diverse library of about 400,000 small molecules was screened for antiviral activity against lentiviral pseudotypes with the Lassa virus envelope glycoprotein (LASV GP) gene incorporated. High-throughput screening resulted in discovery of a hit compound (ST-37) possessing a benzimidazole core which led to a potent compound series. Herein, we report SAR studies which involved structural modifications to the phenyl rings and methylamino linker portion attached to the benzimidazole core. Many analogs in this study possessed single digit nanomolar potency against LASV pseudotypes. Compounds in this benzimidazole series also exhibited nanomolar antiviral activity against pseudotypes generated from other arenavirus envelopes indicating the potential for development of a broad-spectrum inhibitor. Ultimately, lead compound ST-193 was identified and later found to be efficacious in a lethal LASV guinea pig model showing superior protection compared to ribavirin treatment. 相似文献
83.
Synthesis,Enzymatic Resolution,and Stereochemical Characterization of Isoparaconic Acid Derivatives: A Combined Experimental and Theoretical Investigation
下载免费PDF全文
![点击此处可从《Chirality》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Fulvia Felluga Cristina Forzato Giuseppe Mazzeo Patrizia Nitti Giuliana Pitacco Stefano Superchi 《Chirality》2014,26(10):640-650
Enantiomerically enriched isoparaconic acid derivatives were obtained by kinetic enzymatic resolution. To explain the solvent dependence observed for their optical rotatory power a computational investigation of their chiroptical properties was performed. Chirality 26:640–650, 2014. © 2014 Wiley Periodicals, Inc. 相似文献
84.
Krzysztof Lacek Richard A. Urbanowicz Fulvia Troise Claudia De Lorenzo Valeria Severino Antimo Di Maro Alexander W. Tarr Francesca Ferrara Alexander Ploss Nigel Temperton Jonathan K. Ball Alfredo Nicosia Riccardo Cortese Antonello Pessi 《The Journal of biological chemistry》2014,289(50):35015-35028
The broadly neutralizing antibodies HIV 2F5 and 4E10, which bind to overlapping epitopes in the membrane-proximal external region of the fusion protein gp41, have been proposed to use a two-step mechanism for neutralization; first, they bind and preconcentrate at the viral membrane through their long, hydrophobic CDRH3 loops, and second, they form a high affinity complex with the protein epitope. Accordingly, mutagenesis of the CDRH3 can abolish their neutralizing activity, with no change in the affinity for the peptide epitope. We show here that we can mimic this mechanism by conjugating a cholesterol group outside of the paratope of an antibody. Cholesterol-conjugated antibodies bind to lipid raft domains on the membrane, and because of this enrichment, they show increased antiviral potency. In particular, we find that cholesterol conjugation (i) rescues the antiviral activity of CDRH3-mutated 2F5, (ii) increases the antiviral activity of WT 2F5, (iii) potentiates the non-membrane-binding HIV antibody D5 10–100-fold (depending on the virus strain), and (iv) increases synergy between 2F5 and D5. Conjugation can be made at several positions, including variable and constant domains. Cholesterol conjugation therefore appears to be a general strategy to boost the potency of antiviral antibodies, and, because membrane affinity is engineered outside of the antibody paratope, it can complement affinity maturation strategies. 相似文献
85.
86.
Optineurin increases cell survival and translocates to the nucleus in a Rab8-dependent manner upon an apoptotic stimulus 总被引:2,自引:0,他引:2
De Marco N Buono M Troise F Diez-Roux G 《The Journal of biological chemistry》2006,281(23):16147-16156
In glaucoma the retinal ganglion cells of the retina die through the induction of apoptosis leading to excavation of the optic nerve and blindness. Mutations in the optineurin (optic neuropathy inducing) protein were found associated with an adult form of glaucoma. To date, the role of optineurin in the neurodegeneration process that occurs during glaucoma is still unknown. We now report that in response to an apoptotic stimulus, optineurin changes subcellular localization and translocates from the Golgi to the nucleus. This translocation is dependent on the GTPase activity of Rab8, an interactor of optineurin. Furthermore, we demonstrate that the overexpression of optineurin protects cells from H2O2-induced cell death and blocks cytochrome c release from the mitochondria. A mutated form of optineurin, E50K, identified in normal tension glaucoma patients loses its ability to translocate to the nucleus and when overexpressed compromises the mitochondrial membrane integrity resulting in cells that are less fit to survive under stress conditions. The correlation between optineurin function and cell survival will be key to begin to understand retinal ganglion cell biology and signaling and to design general "survival" strategies to treat a disease of such a complex etiology as glaucoma. 相似文献
87.
Cenci S Mezghrani A Cascio P Bianchi G Cerruti F Fra A Lelouard H Masciarelli S Mattioli L Oliva L Orsi A Pasqualetto E Pierre P Ruffato E Tagliavacca L Sitia R 《The EMBO journal》2006,25(5):1104-1113
After few days of intense immunoglobulin (Ig) secretion, most plasma cells undergo apoptosis, thus ending the humoral immune response. We asked whether intrinsic factors link plasma cell lifespan to Ig secretion. Here we show that in the late phases of plasmacytic differentiation, when antibody production becomes maximal, proteasomal activity decreases. The excessive load for the reduced proteolytic capacity correlates with accumulation of polyubiquitinated proteins, stabilization of endogenous proteasomal substrates (including Xbp1s, IkappaBalpha, and Bax), onset of apoptosis, and sensitization to proteasome inhibitors (PI). These events can be reproduced by expressing Ig-mu chain in nonlymphoid cells. Our results suggest that a developmental program links plasma cell death to protein production, and help explaining the peculiar sensitivity of normal and malignant plasma cells to PI. 相似文献
88.
Neurons display a high degree of variability and diversity in the expression and regulation of their voltage-dependent ionic channels. Under low level of synaptic background a number of physiologically distinct cell types can be identified in most brain areas that display different responses to standard forms of intracellular current stimulation. Nevertheless, it is not well understood how biophysically different neurons process synaptic inputs in natural conditions, i.e., when experiencing intense synaptic bombardment in vivo. While distinct cell types might process synaptic inputs into different patterns of action potentials representing specific “motifs” of network activity, standard methods of electrophysiology are not well suited to resolve such questions. In the current paper we performed dynamic clamp experiments with simulated synaptic inputs that were presented to three types of neurons in the juxtacapsular bed nucleus of stria terminalis (jcBNST) of the rat. Our analysis on the temporal structure of firing showed that the three types of jcBNST neurons did not produce qualitatively different spike responses under identical patterns of input. However, we observed consistent, cell type dependent variations in the fine structure of firing, at the level of single spikes. At the millisecond resolution structure of firing we found high degree of diversity across the entire spectrum of neurons irrespective of their type. Additionally, we identified a new cell type with intrinsic oscillatory properties that produced a rhythmic and regular firing under synaptic stimulation that distinguishes it from the previously described jcBNST cell types. Our findings suggest a sophisticated, cell type dependent regulation of spike dynamics of neurons when experiencing a complex synaptic background. The high degree of their dynamical diversity has implications to their cooperative dynamics and synchronization. 相似文献
89.
Simona Bindi Daniele Fancelli Cristina Alli Daniela Berta Jay A. Bertrand Alexander D. Cameron Paolo Cappella Patrizia Carpinelli Giovanni Cervi Valter Croci Matteo D’Anello Barbara Forte M. Laura Giorgini Aurelio Marsiglio Juergen Moll Enrico Pesenti Valeria Pittalà Maurizio Pulici Federico Riccardi-Sirtori Fulvia Roletto Paola Vianello 《Bioorganic & medicinal chemistry》2010,18(19):7113-7120
A novel series of 3-amino-1H-thieno[3,2-c]pyrazole derivatives demonstrating high potency in inhibiting Aurora kinases was developed. Here we describe the synthesis and a preliminary structure–activity relationship, which led to the discovery of a representative compound (38), which showed low nanomolar inhibitory activity in the anti-proliferation assay and was able to block the cell cycle in HCT-116 cell line. This compound demonstrated favorable pharmacokinetic properties and good efficacy in the HL-60 xenograft tumor model. 相似文献
90.
Abhinav Parashar Ophélie Gourgas Kirk Lau Jingjing Li Lisa Muiznieks Simon Sharpe Elaine Davis Marta Cerruti Monzur Murshed 《Journal of structural biology》2021,213(1):107637
Medial calcification has been associated with diabetes, chronic kidney disease, and genetic disorders like pseudoxanthoma elasticum. Recently, we showed that genetic reduction of arterial elastin content reduces the severity of medial calcification in matrix Gla protein (MGP)-deficient and Eln haploinsufficient Mgp?/?;Eln+/? mice. This study suggests that there might be a direct effect of elastin amount on medial calcification. We studied this using novel in vitro systems, which are based on elastin or elastin-like polypeptides. We first examined the mineral deposition properties of a transfected pigmented epithelial cell line that expresses elastin and other elastic lamina proteins. When grown in inorganic phosphate-supplemented medium, these cells deposited calcium phosphate minerals, which could be prevented by an N’-terminal peptide of MGP (m3pS) carrying phosphorylated serine residues. We next confirmed these findings using a cell-free elastin-like polypeptide (ELP3) scaffold, where the peptide prevented mineral maturation. Overall, this work describes a novel cell culture model for elastocalcinosis and examines the inhibition of mineral deposition by the m3pS peptide in this and a cell-free elastin-based scaffold. Our study provides strong evidence suggesting the critical functional roles of MGP’s phosphorylated serine residues in the prevention of elastin calcification and proposes a possible mechanism of their action. 相似文献