6 research outputs found
A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction
K+ channels containing Kv1.1 α subunits, which become prevalent at internodes in demyelinated axons, may underlie their dysfunctional conduction akin to muscle weakness in multiple sclerosis. Small inhibitors were sought with selectivity for the culpable hyper-polarizing K+ currents. Modeling of interactions with the extracellular pore in a Kv1.1-deduced structure identified diaryldi(2-pyrrolyl)methane as a suitable scaffold with optimized alkyl ammonium side chains. The resultant synthesized candidate [2,2âČ-((5,5âČ(di-p-topyldiaryldi(2-pyrrolyl)methane)bis(2,2âČcarbonyl)bis(azanediyl)) diethaneamine·2HCl] (8) selectively blocked Kv1.1 channels (IC50 â 15 ÎŒM) recombinantly expressed in mammalian cells, induced a positive shift in the voltage dependency of K+ current activation, and slowed its kinetics. It preferentially inhibited channels containing two or more Kv1.1 subunits regardless of their positioning in concatenated tetramers. In slices of corpus callosum from mice subjected to a demyelination protocol, this novel inhibitor improved neuronal conduction, highlighting its potential for alleviating symptoms in multiple sclerosis
DomPepâA General Method for Predicting Modular Domain-Mediated Protein-Protein Interactions
Protein-protein interactions (PPIs) are frequently mediated by the binding of a modular domain in one protein to a short, linear peptide motif in its partner. The advent of proteomic methods such as peptide and protein arrays has led to the accumulation of a wealth of interaction data for modular interaction domains. Although several computational programs have been developed to predict modular domain-mediated PPI events, they are often restricted to a given domain type. We describe DomPep, a method that can potentially be used to predict PPIs mediated by any modular domains. DomPep combines proteomic data with sequence information to achieve high accuracy and high coverage in PPI prediction. Proteomic binding data were employed to determine a simple yet novel parameter Ligand-Binding Similarity which, in turn, is used to calibrate Domain Sequence Identity and Position-Weighted-Matrix distance, two parameters that are used in constructing prediction models. Moreover, DomPep can be used to predict PPIs for both domains with experimental binding data and those without. Using the PDZ and SH2 domain families as test cases, we show that DomPep can predict PPIs with accuracies superior to existing methods. To evaluate DomPep as a discovery tool, we deployed DomPep to identify interactions mediated by three human PDZ domains. Subsequent in-solution binding assays validated the high accuracy of DomPep in predicting authentic PPIs at the proteome scale. Because DomPep makes use of only interaction data and the primary sequence of a domain, it can be readily expanded to include other types of modular domains
Rhéa : entrepÎt de données et aide à la décision pour les services de réanimation
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A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction
K<sup>+</sup> channels containing
Kv1.1 α subunits, which
become prevalent at internodes in demyelinated axons, may underlie
their dysfunctional conduction akin to muscle weakness in multiple
sclerosis. Small inhibitors were sought with selectivity for the culpable
hyper-polarizing K<sup>+</sup> currents. Modeling of interactions
with the extracellular pore in a Kv1.1-deduced structure identified
diaryldiÂ(2-pyrrolyl)Âmethane as a suitable scaffold with optimized
alkyl ammonium side chains. The resultant synthesized candidate [2,2âČ-((5,5âČ(di-<i>p</i>-topyldiaryldiÂ(2-pyrrolyl)Âmethane)ÂbisÂ(2,2âČcarbonyl)ÂbisÂ(azanediyl))
diethaneamine·2HCl] (<b>8</b>) selectively blocked Kv1.1
channels (IC<sub>50</sub> â 15 ÎŒM) recombinantly expressed
in mammalian cells, induced a positive shift in the voltage dependency
of K<sup>+</sup> current activation, and slowed its kinetics. It preferentially
inhibited channels containing two or more Kv1.1 subunits regardless
of their positioning in concatenated tetramers. In slices of corpus
callosum from mice subjected to a demyelination protocol, this novel
inhibitor improved neuronal conduction, highlighting its potential
for alleviating symptoms in multiple sclerosis
Améliorer sa récupération en sport
En quelques dĂ©cennies, la rĂ©cupĂ©ration du sportif de haut niveau s'est dĂ©finitivement imposĂ©e comme un enjeu majeur. D'une part parce qu'il est essentiel de prĂ©server la santĂ© de l'athlĂšte, d'autre part parce que la rĂ©itĂ©ration de la performance, parfois sur de trĂšs courts laps de temps, requiert une parfaite rĂ©cupĂ©ration entre les Ă©preuves. Aux mĂ©thodes de rĂ©cupĂ©ration parfois anciennes - certaines d'entre elles remontent...Ă l'AntiquitĂ© ! - viennent s'ajouter des techniques particuliĂšrement innovantes. Ă tel point que l'encadrement mĂ©dical d'un athlĂšte dispose Ă prĂ©sent d'un vaste panel de mĂ©thodes : rĂ©cupĂ©ration active ou passive, Ă©tirements, massages, Ă©lectrostimulation, luminothĂ©rapie, aromathĂ©rapie, application de chaud ou de froid, cryothĂ©rapie, hydrothĂ©rapie, sauna, hammam, infrarouges, nutrition et rĂ©hydratation⊠Pour autant, il n'est pas toujours facile de distinguer les mĂ©thodes vĂ©ritablement efficaces des chimĂšres dont certaines peuvent s'avĂ©rer inopĂ©rantes, voire contre-productives lorsqu'elles sont mal employĂ©es. L'INSEP propose donc aujourd'hui un nouvel ouvrage, essentiel pour comprendre ces diffĂ©rentes techniques, et qui permettra aux athlĂštes, Ă leurs entraĂźneurs et Ă leur encadrement mĂ©dical de vĂ©ritablement mettre en Ćuvre des politiques de rĂ©cupĂ©ration efficaces et adaptĂ©es aux spĂ©cificitĂ©s de l'athlĂšte, mais aussi Ă celles de son sport et de son calendrier sportif. PrĂšs de 1 650 articles scientifiques du monde entier ont ainsi Ă©tĂ© analysĂ©s et synthĂ©tisĂ©s afin d'offrir au lecteur des informations fiables, loin de l'empirisme ou des effets de mode qui ne garantissent Ă©videmment pas toujours la rĂ©ussite... Du haut de ses vingt-trois chapitres, cet ouvrage nous invite Ă une nouvelle orientation dans la comprĂ©hension des processus de rĂ©cupĂ©ration chez le sportif. En complĂ©ment de cette analyse pertinente des diffĂ©rentes mĂ©thodes de rĂ©cupĂ©ration, quelques Ă©tudes de cas mettant le sportif au cĆur du dispositif de rĂ©cupĂ©ration, viennent Ă©clairer nos zones d'ombre et ainsi amĂ©liorer notre connaissance de la rĂ©cupĂ©ration en sport