全文获取类型
收费全文 | 208篇 |
免费 | 26篇 |
出版年
2023年 | 2篇 |
2022年 | 2篇 |
2021年 | 7篇 |
2020年 | 3篇 |
2019年 | 2篇 |
2018年 | 10篇 |
2017年 | 6篇 |
2016年 | 6篇 |
2015年 | 22篇 |
2014年 | 6篇 |
2013年 | 13篇 |
2012年 | 14篇 |
2011年 | 16篇 |
2010年 | 9篇 |
2009年 | 14篇 |
2008年 | 10篇 |
2007年 | 11篇 |
2006年 | 10篇 |
2005年 | 11篇 |
2004年 | 12篇 |
2003年 | 3篇 |
2002年 | 11篇 |
2001年 | 3篇 |
2000年 | 2篇 |
1999年 | 2篇 |
1998年 | 2篇 |
1997年 | 2篇 |
1996年 | 2篇 |
1994年 | 1篇 |
1993年 | 3篇 |
1992年 | 4篇 |
1991年 | 1篇 |
1988年 | 4篇 |
1986年 | 1篇 |
1984年 | 3篇 |
1983年 | 1篇 |
1977年 | 2篇 |
1975年 | 1篇 |
排序方式: 共有234条查询结果,搜索用时 328 毫秒
101.
102.
Tous M Ribas V Escolà-Gil JC Blanco-Vaca F Calpe-Berdiel L Coll B Ferré N Alonso-Villaverde C Rull A Camps J Joven J 《Cytokine》2006,34(3-4):224-232
There are increasing evidences showing that inflammation participates in atherosclerosis. Therefore, the therapeutic use of anti-inflammatory agents should be considered. We have induced chronic, aseptic inflammation upon the injection of turpentine and tested the effect of dexamethasone on lipoprotein metabolism and, consequently, atherosclerosis in apolipoprotein E-deficient mice. Aseptic inflammation caused a significant decrease in hyperlipidemia. Treatment with dexamethasone elicited the opposite effect increasing hyperlipidemia through mechanisms related to the increase in the synthesis of triglyceride-rich lipoproteins. Changes in plasma lipids correlated with those observed in the size of atherosclerotic lesions. Our data suggest the presence of a common mechanism present in both observations and which is probably related to the cytokine secretion. Among the candidates, we chose to test the effect of interleukin-6 because it is involved in both processes, atherosclerosis and inflammation, and its expression is efficiently repressed by corticosteroids. The injection of recombinant interleukin-6 in our mice elicited the same effects observed in our model of inflammation. We conclude that manipulation of inflammation-related mechanisms modulates lipid homeostasis and development of atherosclerotic plaque in rodents. 相似文献
103.
Small molecule inhibitors of Apaf-1-related caspase- 3/-9 activation that control mitochondrial-dependent apoptosis 总被引:1,自引:0,他引:1
Malet G Martín AG Orzáez M Vicent MJ Masip I Sanclimens G Ferrer-Montiel A Mingarro I Messeguer A Fearnhead HO Pérez-Payá E 《Cell death and differentiation》2006,13(9):1523-1532
Apoptosis is a biological process relevant to human disease states that is strongly regulated through protein-protein complex formation. These complexes represent interesting points of chemical intervention for the development of molecules that could modulate cellular apoptosis. The apoptosome is a holoenzyme multiprotein complex formed by cytochrome c-activated Apaf-1 (apoptotic protease-activating factor), dATP and procaspase-9 that link mitochondria disfunction with activation of the effector caspases and in turn is of interest for the development of apoptotic modulators. In the present study we describe the identification of compounds that inhibit the apoptosome-mediated activation of procaspase-9 from the screening of a diversity-oriented chemical library. The active compounds rescued from the library were chemically optimised to obtain molecules that bind to both recombinant and human endogenous Apaf-1 in a cytochrome c-noncompetitive mechanism that inhibits the recruitment of procaspase-9 by the apoptosome. These newly identified Apaf-1 ligands decrease the apoptotic phenotype in mitochondrial-mediated models of cellular apoptosis. 相似文献
104.
105.
Gemma Navarro Marisol S. Aymerich Daniel Marcellino Antoni Cort��s Vicent Casad�� Josefa Mallol Enric I. Canela Luigi Agnati Amina S. Woods Kjell Fuxe Carmen Llu��s Jose Luis Lanciego Sergi Ferr�� Rafael Franco 《The Journal of biological chemistry》2009,284(41):28058-28068
The Ca2+-binding protein calmodulin (CaM) has been shown to bind directly to cytoplasmic domains of some G protein-coupled receptors, including the dopamine D2 receptor. CaM binds to the N-terminal portion of the long third intracellular loop of the D2 receptor, within an Arg-rich epitope that is also involved in the binding to Gi/o proteins and to the adenosine A2A receptor, with the formation of A2A-D2 receptor heteromers. In the present work, by using proteomics and bioluminescence resonance energy transfer (BRET) techniques, we provide evidence for the binding of CaM to the A2A receptor. By using BRET and sequential resonance energy transfer techniques, evidence was obtained for CaM-A2A-D2 receptor oligomerization. BRET competition experiments indicated that, in the A2A-D2 receptor heteromer, CaM binds preferentially to a proximal C terminus epitope of the A2A receptor. Furthermore, Ca2+ was found to induce conformational changes in the CaM-A2A-D2 receptor oligomer and to selectively modulate A2A and D2 receptor-mediated MAPK signaling in the A2A-D2 receptor heteromer. These results may have implications for basal ganglia disorders, since A2A-D2 receptor heteromers are being considered as a target for anti-parkinsonian agents.G-protein-coupled receptors are able to form homo- and hetero-oligomers with unique biochemical and functional characteristics (1–7), and they are easily detected in vitro by using biophysical techniques (8–10). Heteromers of adenosine A2A and dopamine D2 receptors were one of the first G-protein-coupled receptor heteromers to be described (11). A close physical interaction between both receptors was shown using co-immunoprecipitation and co-localization assays (11) and fluorescence and bioluminescence resonance energy transfer (FRET2 or BRET) techniques (12–14). At the biochemical level, two types of antagonistic A2A-D2 receptor interactions have been discovered that may explain the A2A-D2 receptor interactions described both at the neuronal and behavioral level (11, 15–18). First, by means of an allosteric interaction in the receptor heteromer, stimulation of A2A receptor decreases the affinity of D2 receptor for their agonists (12). Second, the stimulation of the Gi/o-protein-coupled D2 receptor inhibits the cAMP accumulation induced by the stimulation of the Gs/olf-protein-coupled A2A receptor (11, 17, 18). In view of the well known role of dopamine in Parkinson disease, schizophrenia, and drug addiction, it has been suggested that the A2A-D2 receptor interactions in the central nervous system may provide new therapeutic approaches to combat these disorders (16, 19).An epitope-epitope electrostatic interaction between an Arg-rich epitope of the N terminus of the third intracellular loop (3IL) of the D2 receptor and an epitope containing a phosphorylated Ser localized in the distal part of the C terminus of the A2A receptor is involved in A2A-D2 receptor heteromer interface (14, 20, 21). The same Arg-rich epitope of the D2 receptor is able to interact with CaM (22–25). In the absence of phosphorylated residues, adjacent aspartates or glutamates, which are abundant in CaM, may also form non-covalent complexes with Arg-rich epitopes (26). Therefore, CaM can potentially convey a Ca2+ signal to the D2 receptor through direct binding to the 3IL of the D2 receptor (22). Mass spectrometry data have shown that bovine CaM can form multiple non-covalent complexes with an Arg-rich peptide corresponding to the N-terminal region of the 3IL of the D2 receptor (VLRRRRKRVN) (24) as well as a peptide from the proximal C terminus of the A2A receptor (24). This epitope, whose sequence is 291RIREFRQTFR300 in the human A2A receptor, also contains several Arg residues. Since the suspected interaction between the A2A receptor and CaM was awaiting confirmation by assays using complete proteins, the present study was undertaken to demonstrate the existence of interactions between the A2A receptor and CaM both in a recombinant protein expression cell system and in the brain. A proteomics approach was used for the discovery of protein-protein interactions between the A2A receptor and CaM in rat brain, whereas BRET in transfected cells demonstrated a direct interaction between CaM and this receptor. Furthermore, by using BRET and sequential resonance energy transfer (SRET) techniques and analyzing MAPK signaling in transfected cells, evidence was obtained for CaM-A2A-D2 receptor oligomerization and a selective Ca2+-mediated modulation of A2A and D2 receptor function in the A2A-D2 receptor heteromer. 相似文献
106.
107.
Gemma Navarro Sergi Ferré Arnau Cordomi Estefania Moreno Josefa Mallol Vicent Casadó Antoni Cortés Hanne Hoffmann Jordi Ortiz Enric I. Canela Carme Lluís Leonardo Pardo Rafael Franco Amina S. Woods 《The Journal of biological chemistry》2010,285(35):27346-27359
G protein-coupled receptor (GPCR) heteromers are macromolecular complexes with unique functional properties different from those of its individual protomers. Little is known about what determines the quaternary structure of GPCR heteromers resulting in their unique functional properties. In this study, using resonance energy transfer techniques in experiments with mutated receptors, we provide for the first time clear evidence for a key role of intracellular domains in the determination of the quaternary structure of GPCR heteromers between adenosine A2A, cannabinoid CB1, and dopamine D2 receptors. In these interactions, arginine-rich epitopes form salt bridges with phosphorylated serine or threonine residues from CK1/2 consensus sites. Each receptor (A2A, CB1, and D2) was found to include two evolutionarily conserved intracellular domains to establish selective electrostatic interactions with intracellular domains of the other two receptors, indicating that these particular electrostatic interactions constitute a general mechanism for receptor heteromerization. Mutation experiments indicated that the interactions of the intracellular domains of the CB1 receptor with A2A and D2 receptors are fundamental for the correct formation of the quaternary structure needed for the function (MAPK signaling) of the A2A-CB1-D2 receptor heteromers. Analysis of MAPK signaling in striatal slices of CB1 receptor KO mice and wild-type littermates supported the existence of A1-CB1-D2 receptor heteromer in the brain. These findings allowed us to propose the first molecular model of the quaternary structure of a receptor heteromultimer. 相似文献
108.
Naima Boughalleb Ibtissem Ben Salem Roberto Beltrán Antonio Vicent Ana Pérez Sierra Paloma Abad‐Campos José García‐Jiménez Josep Armengol 《Journal of Phytopathology》2010,158(3):137-142
Surveys of 11 watermelon fields throughout production areas of this crop in southern and central regions in Tunisia were conducted in 2007 to determine the aetiology and distribution of watermelon vine decline. Monosporascus cannonballus was isolated from diseased roots in all surveyed fields. All the isolates were identified according to morphological features and confirmed by amplification of a fragment of the ITS region with specific primers. Ascospores of M. cannonballus were recovered from soil in all watermelon fields surveyed and the average population densities ranged from 3.65 to 10.14 ascospores per g of soil. Multiple linear regression analysis revealed that only four of the crop and soil factors evaluated had a significant correlation with ascospore density at the end of the growing season: vertisol vs. other soils, disease incidence, percentage of clay and pH. The pH of the soil showed a strong significant negative linear relationship with ascospore density, while the other three factors correlated positively. 相似文献
109.
Matthew R. McLennan Benjamin Hintz Vicent Kiiza Jacqueline Rohen Georgia A. Lorenti Kimberley J. Hockings 《African Journal of Ecology》2021,59(1):17-28
Endangered wildlife increasingly inhabits human‐dominated landscapes outside protected areas. Large‐bodied mammals require large spaces, and their ranging may be especially impacted by landscape modifications including farming, road development and urbanisation. We studied the Wagaisa community of chimpanzees (Pan troglodytes) in Uganda, which inhabit a landscape characterised by high human population density, widespread deforestation, and rapid agricultural and infrastructural development. We aimed to assess whether this dynamic, fragmented environment constrains the chimpanzees’ ranging, and to identify critical habitat patches to aid their conservation. During March–May 2018, we assessed range use from locations of direct observations and indirect signs, corroborated by longer‐term behavioural monitoring of the chimpanzees (June 2018–December 2019). No evidence of limited ranging was found. The Wagaisa chimpanzees used an area measuring ≥ 43 km2 (100% MCP) and ranged extensively in the anthropogenic matrix. Most frequently used parts of the range (‘core habitat areas’) centred around small (5–20 acres), widely dispersed remnant forest patches and exotic eucalyptus plantations. Forty per cent of chimpanzee nests were constructed in eucalyptus trees, suggesting a behavioural adjustment to landscape changes. Actions to facilitate conservation of these ‘village chimpanzees’ and others surviving in transformed human‐dominated habitat need not conflict with the sustainable development of the region. 相似文献
110.
Sofia Cristóvão-Ferreira Gemma Navarro Marc Brugarolas Kamil Pérez-Capote Sandra H. Vaz Giorgia Fattorini Fiorenzo Conti Carmen Lluis Joaquim A. Ribeiro Peter J. McCormick Vicent Casadó Rafael Franco Ana M. Sebastião 《Purinergic signalling》2013,9(3):433-449
Astrocytes play a key role in modulating synaptic transmission by controlling extracellular gamma-aminobutyric acid (GABA) levels via GAT-1 and GAT-3 GABA transporters (GATs). Using primary cultures of rat astrocytes, we show here that a further level of regulation of GABA uptake occurs via modulation of the GATs by the adenosine A1 (A1R) and A2A (A2AR) receptors. This regulation occurs through A1R–A2AR heteromers that signal via two different G proteins, Gs and Gi/0, and either enhances (A2AR) or inhibits (A1R) GABA uptake. These results provide novel mechanistic insight into how GPCR heteromers signal. Furthermore, we uncover a previously unknown mechanism where adenosine, in a concentration-dependent manner, acts via a heterocomplex of adenosine receptors in astrocytes to significantly contribute to neurotransmission at the tripartite (neuron–glia–neuron) synapse. 相似文献