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1.
Arhamatoulaye Ma?ga Jon Merlin Elodie Marcon Céline Rouget Maud Larregola Bernard Gilquin Carole Fruchart-Gaillard Evelyne Lajeunesse Charles Marchetti Alain Lorphelin Laurent Bellanger Roger J. Summers Dana S. Hutchinson Bronwyn A. Evans Denis Servent Nicolas Gilles 《PloS one》2013,8(7)
ρ-Da1a is a three-finger fold toxin from green mamba venom that is highly selective for the α1A-adrenoceptor. This toxin has atypical pharmacological properties, including incomplete inhibition of 3H-prazosin or 125I-HEAT binding and insurmountable antagonist action. We aimed to clarify its mode of action at the α1A-adrenoceptor. The affinity (pKi 9.26) and selectivity of ρ-Da1a for the α1A-adrenoceptor were confirmed by comparing binding to human adrenoceptors expressed in eukaryotic cells. Equilibrium and kinetic binding experiments were used to demonstrate that ρ-Da1a, prazosin and HEAT compete at the α1A-adrenoceptor. ρ-Da1a did not affect the dissociation kinetics of 3H-prazosin or 125I-HEAT, and the IC50 of ρ-Da1a, determined by competition experiments, increased linearly with the concentration of radioligands used, while the residual binding by ρ-Da1a remained stable. The effect of ρ-Da1a on agonist-stimulated Ca2+ release was insurmountable in the presence of phenethylamine- or imidazoline-type agonists. Ten mutations in the orthosteric binding pocket of the α1A-adrenoceptor were evaluated for alterations in ρ-Da1a affinity. The D1063.32A and the S1885.42A/S1925.46A receptor mutations reduced toxin affinity moderately (6 and 7.6 times, respectively), while the F862.64A, F2886.51A and F3127.39A mutations diminished it dramatically by 18- to 93-fold. In addition, residue F862.64 was identified as a key interaction point for 125I-HEAT, as the variant F862.64A induced a 23-fold reduction in HEAT affinity. Unlike the M1 muscarinic acetylcholine receptor toxin MT7, ρ-Da1a interacts with the human α1A-adrenoceptor orthosteric pocket and shares receptor interaction points with antagonist (F862.64, F2886.51 and F3127.39) and agonist (F2886.51 and F3127.39) ligands. Its selectivity for the α1A-adrenoceptor may result, at least partly, from its interaction with the residue F862.64, which appears to be important also for HEAT binding. 相似文献
2.
Agnès Méreau Vincent Anquetil Marie Cibois Maud Noiret Aline Primot Audrey Vallée Luc Paillard 《Nucleic acids research》2009,37(19):e126
Several different mRNAs can be produced from a given pre-mRNA by regulated alternative splicing, or as the result of deregulations that may lead to pathological states. Analysing splicing patterns is therefore of importance to describe and understand developmental programs, cellular responses to internal or external cues, or human diseases. We describe here a method, Pyrosequencing Analysis of Splicing Patterns (PASP), that combines RT–PCR and pyrosequencing of PCR products. We demonstrated that: (i) Ratios of two pure RNAs mixed in various proportions were accurately measured by PASP; (ii) PASP can be adapted to virtually any splicing event, including mutually exclusive exons, complex patterns of exon skipping or inclusion, and alternative 3′ terminal exons; (iii) In extracts from different organs, the proportions of RNA isoforms measured by PASP reflected those measured by other methods. The PASP method is therefore reliable for analysing splicing patterns. All steps are done in 96-wells microplates, without gel electrophoresis, opening the way to high-throughput comparisons of RNA from several sources. 相似文献
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Comparison of control strategies against animal infectious diseases allows determining optimal strategies according to their epidemiological and/or economic impacts. However, in real life, the choice of a control strategy does not always obey a pure economic or epidemiological rationality. The objective of this study was to analyze the choice of a foot and mouth disease (FMD) control strategy as a decision-making process in which the decision-maker is influenced by several stakeholders (government, agro-food industries, public opinion). For each of these, an indicator of epizootic impact was quantified to compare seven control strategies. We then determined how, in France, the optimal control strategy varied according to the relative weights of stakeholders and to the perception of risk by the decision-maker (risk-neutral/risk-averse). When the scope of decision was national, whatever their perception of risk and the stakeholders'' weights, decision-makers chose a strategy based on vaccination. This consensus concealed marked differences between regions, which were connected with the regional breeding characteristics. Vaccination-based strategies were predominant in regions with dense cattle and swine populations, and in regions with a dense population of small ruminants, combined with a medium density of cattle and swine. These differences between regions suggested that control strategies could be usefully adapted to local breeding conditions. We then analyzed the feasibility of adaptive decision-making processes depending on the date and place where the epizootic starts, or on the evolution of the epizootic over time. The initial conditions always explained at least half of the variance of impacts, the remaining variance being attributed to the variability of epizootics evolution. However, the first weeks of this evolution explained a large part of the impacts variability. Although the predictive value of the initial conditions for determining the optimal strategy was weak, adaptive strategies changing dynamically according to the evolution of the epizootic appeared feasible. 相似文献
5.
C. Langton Hewer 《BMJ (Clinical research ed.)》1937,2(3996):274-276
6.
C. Langton Hewer 《BMJ (Clinical research ed.)》1937,1(3971):360-361
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Maud Martin Ilse Geudens Jonathan Bruyr Michael Potente Anouk Bleuart Marielle Lebrun Nicolas Simonis Christophe Deroanne Jean‐Claude Twizere Philippe Soubeyran Paul Peixoto Denis Mottet Veerle Janssens Wolf‐Karsten Hofmann Filip Claes Peter Carmeliet Richard Kettmann Holger Gerhardt Franck Dequiedt 《The EMBO journal》2013,32(18):2491-2503
10.
Audrey M. Neyrinck Maud Alligier Patrick B. Memvanga Elodie Névraumont Yvan Larondelle Véronique Préat Patrice D. Cani Nathalie M. Delzenne 《PloS one》2013,8(11)