19 research outputs found
QuadrilatĆØres et pentagones dans le graphe dāĆ©change
Les mutations successives faites sur un carquois Q sont rƩgies par
certaines relations. Dans cet article, on dƩmontre deux de ces relations tout
en donnant une application Ć lāĆ©tude des graphes dāĆ©changes
Bifunctional ligands of the bradykinin B2 and B1 receptors : an exercise in peptide hormone plasticity
Kinins are the small and fragile hydrophilic peptides related to bradykinin (BK) and derived from circulating kininogens via the action of kallikreins. Kinins bind to the preformed and widely distributed B2 receptor (B2R) and to the inducible B1 receptor (B1R). B2Rs and B1Rs are related G protein coupled receptors that possess natural agonist ligands of nanomolar affinity (BK and Lys BK for B2Rs, Lys-des-Arg9-BK for B1R). Decades of structure-activity exploration have resulted in the production of peptide analogs that are antagonists, one of which is clinically used (the B2R antagonist icatibant), and also non-peptide ligands for both receptor subtypes. The modification of kinin receptor ligands has made them resistant to extracellular or endosomal peptidases and/or produced bifunctional ligands, defined as agonist or antagonist peptide ligands conjugated with a chemical fluorophore (emitting in the whole spectrum, from the infrared to the ultraviolet), a drug-like moiety, an epitope, an isotope chelator/carrier, a cleavable sequence (thus forming a pro-drug) and even a fused protein. Dual molecular targets for specific modified peptides may be a source of side effects or of medically exploitable benefits. Biotechnological protein ligands for either receptor subtype have been produced: they are enhanced green fluorescent protein or the engineered peroxidase APEX2 fused to an agonist kinin sequence at their C-terminal terminus. Antibodies endowed with pharmacological actions (agonist, antagonist) at B2R have been reported, though not monoclonal antibodies. These findings define classes of alternative ligands of the kinin receptor of potential therapeutic and diagnostic value
A Novel Nonpeptide Antagonist of the Kinin B 1 Receptor: Effects at the Rabbit Receptor
ABSTRACT The kinin B 1 receptor (B 1 R) has attracted interest as a potential therapeutic target because this inducible G protein-coupled receptor is involved in sustained inflammation and inflammatory pain production. is a high-affinity nonpeptide antagonist for the human B 1 R, but it is potent at the rabbit B 1 R as well: its K i value for the inhibition of [ The kinin B 1 receptor (B 1 R) is a G protein-coupled receptor selectively stimulated by sequences related to bradykinin (BK) but not by BK itself. Instead, des-Arg 9 -BK, Lys-BK (kallidin) and Lys-des-Arg 9 -BK (des-Arg 1
Vascular smooth muscle contractility assays for inflammatory and immunological mediators
The blood vessels are one of the important target tissues for the mediators of inflammation and allergy; further cytokines affect them in a number of ways. We review the use of the isolated blood vessel mounted in organ baths as an important source of pharmacological information. While its use in the bioassay of vasoactive substances tends to be replaced with modern analytical techniques, contractility assays are effective to evaluate novel synthetic drugs, generating robust potency and selectivity data about agonists, partial agonists and competitive or insurmountable antagonists. For instance, the human umbilical vein has been used extensively to characterize ligands of the bradykinin B2 receptors. Isolated vascular segments are live tissues that are intensely reactive, notably with the regulated expression of gene products relevant for inflammation (e.g., the kinin B1 receptor and inducible nitric oxide synthase). Further, isolated vessels can be adapted as assays of unconventional proteins (cytokines such as interleukin-1, proteases of physiopathological importance, complement-derived anaphylatoxins and recombinant hemoglobin) and to the gene knockout technology. The well known cross-talks between different cell types, e.g., endothelium-muscle and nerve terminal-muscle, can be extended (smooth muscle cell interaction with resident or infiltrating leukocytes and tumor cells). Drug metabolism and distribution problems can be modeled in a useful manner using the organ bath technology, which, for all these reasons, opens a window on an intermediate level of complexity relative to cellular and molecular pharmacology on one hand, and in vivo studies on the other
Bradykinin receptors : agonists, antagonists, expression, signaling and adaptation to sustained stimulation
Bradykinin-related peptides, the kinins, are blood-derived peptides that stimulate 2 G proteinācoupled receptors, the
B1 and B2 receptors (B1R, B2R). The pharmacologic and molecular identities of these 2 receptor subtypes will be
succinctly reviewed, with emphasis on drug development, receptor expression, signaling, and adaptation to
persistent stimulation. Peptide and nonpeptide antagonists and fluorescent ligands have been produced for each
receptor. The B2R is widely and constitutively expressed in mammalian tissues, whereas the B1R is mostly inducible
under the effect of cytokines during infection and immunopathology. Both receptor subtypes mediate the vascular
aspects of inflammation (vasodilation, edema formation). On this basis, icatibant, a peptide antagonist of the B2R, is
approved in the management of hereditary angioedema attacks. Other clinical applications are still elusive despite
the maturity of the medicinal chemistry efforts applied to kinin receptors. While both receptor subtypes are mainly
coupled to the Gq protein and related second messengers, the B2R is temporarily desensitized by a cycle of
phosphorylation/endocytosis followed by recycling, whereas the nonphosphorylable B1R is relatively resistant to
desensitization and translocated to caveolae on activation
InfeĢrence bayeĢsienne sous un a priori normal-gamma dans diffeĢrents contextes et pour des fonctions de la moyenne et de la variance
Dans ce meĢmoire, on obtient diffeĢrents reĢsultats portant sur lāinfeĢrence bayeĢsienne de divers modeĢles. Des reĢsultats analytiques sont obtenus tout au long du meĢmoire. Le chapitre 1 servira dans un premier temps aĢ deĢmontrer dans quels contextes dāapplication les diffeĢrents modeĢles que lāon eĢtudiera peuvent servir. Dans un deuxieĢme temps, ce chapitre se verra eĢtre une introduction aĢ quelques distributions et fonctions speĢciales que lāon retrouve dans le reste du meĢmoire. On y preĢsentera eĢgalement quelques notions sur lāinfeĢrence preĢdictive. Le chapitre 2 porte sur lāinfeĢrence preĢdictive sous le modeĢle de loi multinormale aĢ variance connue ainsi que sous le modeĢle gamma aĢ parameĢtre dāeĢchelle inconnu. On exploitera une deĢcomposition faisant intervenir la loi a priori non informative. Plusieurs cas particuliers seront deĢtailleĢs. On terminera ce chapitre en faisant une analyse du modeĢle de loi normale avec (Īø, Ī·) ā¼ N G, cāest-aĢ-dire lāa priori normal-gamma. On discutera et interpreĢtera les lois a posteriori tout en abordant lāinfeĢrence preĢdictive sous ce modeĢle. Le chapitre 3 reprend le modeĢle normal-gamma, mais dans un contexte dāindeĢpendance pour la loi a priori. On eĢtudiera les marginales des deux composantes du modeĢle et cette contribution nous paraiĢt tout aĢ fait originale. Tout dāabord, on verra que la marginale a posteriori de la moyenne fait intervenir une convolution entre une loi normale centreĢe reĢduite et une loi student. On explorera par la suite diffeĢrentes proprieĢteĢs de cette densiteĢ, notamment sa forme, lāimpact du choix des diffeĢrents hyperparameĢtres, ainsi que son espeĢrance et sa variance. Quelques cas limites seront eĢgalement abordeĢs. Puis, de facĢ§on un peu plus concise, la meĢme approche sera utiliseĢe pour eĢtudier la marginale a posteriori de la variance. Enfin, le chapitre 4 preĢsente lāinfeĢrence bayeĢsienne lorsquāon consideĢre un quantile, un coefficient de variation (ainsi que son inverse) et un coefficient de discrimination. Lāapproche choisie ici est de consideĢrer tout dāabord un cadre geĢneĢral puis de sāinteĢresser au modeĢle normal-gamma. On donnera des formes ana- lytiques pour les fonctions de densiteĢ et de la reĢpartition, lāespeĢrance et la variance de ces fonctions lorsque ces quantiteĢs existeront. On y trouvera eĢgalement quelques exemples afin de pouvoir comprendre le roĢle des hyperparameĢtres du modeĢle choisi
InfeĢrence bayeĢsienne sous un a priori normal-gamma dans diffeĢrents contextes et pour des fonctions de la moyenne et de la variance
Dans ce meĢmoire, on obtient diffeĢrents reĢsultats portant sur lāinfeĢrence bayeĢsienne de divers modeĢles. Des reĢsultats analytiques sont obtenus tout au long du meĢmoire. Le chapitre 1 servira dans un premier temps aĢ deĢmontrer dans quels contextes dāapplication les diffeĢrents modeĢles que lāon eĢtudiera peuvent servir. Dans un deuxieĢme temps, ce chapitre se verra eĢtre une introduction aĢ quelques distributions et fonctions speĢciales que lāon retrouve dans le reste du meĢmoire. On y preĢsentera eĢgalement quelques notions sur lāinfeĢrence preĢdictive. Le chapitre 2 porte sur lāinfeĢrence preĢdictive sous le modeĢle de loi multinormale aĢ variance connue ainsi que sous le modeĢle gamma aĢ parameĢtre dāeĢchelle inconnu. On exploitera une deĢcomposition faisant intervenir la loi a priori non informative. Plusieurs cas particuliers seront deĢtailleĢs. On terminera ce chapitre en faisant une analyse du modeĢle de loi normale avec (Īø, Ī·) ā¼ N G, cāest-aĢ-dire lāa priori normal-gamma. On discutera et interpreĢtera les lois a posteriori tout en abordant lāinfeĢrence preĢdictive sous ce modeĢle. Le chapitre 3 reprend le modeĢle normal-gamma, mais dans un contexte dāindeĢpendance pour la loi a priori. On eĢtudiera les marginales des deux composantes du modeĢle et cette contribution nous paraiĢt tout aĢ fait originale. Tout dāabord, on verra que la marginale a posteriori de la moyenne fait intervenir une convolution entre une loi normale centreĢe reĢduite et une loi student. On explorera par la suite diffeĢrentes proprieĢteĢs de cette densiteĢ, notamment sa forme, lāimpact du choix des diffeĢrents hyperparameĢtres, ainsi que son espeĢrance et sa variance. Quelques cas limites seront eĢgalement abordeĢs. Puis, de facĢ§on un peu plus concise, la meĢme approche sera utiliseĢe pour eĢtudier la marginale a posteriori de la variance. Enfin, le chapitre 4 preĢsente lāinfeĢrence bayeĢsienne lorsquāon consideĢre un quantile, un coefficient de variation (ainsi que son inverse) et un coefficient de discrimination. Lāapproche choisie ici est de consideĢrer tout dāabord un cadre geĢneĢral puis de sāinteĢresser au modeĢle normal-gamma. On donnera des formes ana- lytiques pour les fonctions de densiteĢ et de la reĢpartition, lāespeĢrance et la variance de ces fonctions lorsque ces quantiteĢs existeront. On y trouvera eĢgalement quelques exemples afin de pouvoir comprendre le roĢle des hyperparameĢtres du modeĢle choisi
QuadrilatĆØres et pentagones dans le graphe dāĆ©change
Les mutations successives faites sur un carquois Q sont rƩgies par
certaines relations. Dans cet article, on dƩmontre deux de ces relations tout
en donnant une application Ć lāĆ©tude des graphes dāĆ©changes
Bradykinin receptors : agonists, antagonists, expression, signaling, and adaptation to sustained stimulation
Bradykinin-related peptides, the kinins, are blood-derived peptides that stimulate 2 G proteinācoupled receptors, the B1 and B2 receptors (B1R, B2R). The pharmacologic and molecular identities of these 2 receptor subtypes will be succinctly reviewed herein, with emphasis on drug development, receptor expression, signaling, and adaptation to persistent stimulation. Peptide and non-peptide antagonists and fluorescent ligands have been produced for each receptor. The B2R is widely and constitutively expressed in mammalian tissues, whereas the B1R is mostly inducible under the effect of cytokines during infection and immunopathology. The B2R is temporarily desensitized by a cycle of phosphorylation/endocytosis followed by recycling, whereas the nonphosphorylable B1R is relatively resistant to desensitization and translocated to caveolae on activation. Both receptor subtypes, mainly coupled to protein G Gq, phospholipase C and calcium signaling, mediate the vascular aspects of inflammation (vasodilation, edema formation). On this basis, icatibant, a peptide antagonist of the B2R, is approved in the management of hereditary angioedema attacks. This disease is the therapeutic showcase of the kallikrein-kinin system, with an orally bioavailable B2R antagonist under development, as well as other agents that inhibit the kinin forming protease, plasma kallikrein. Other clinical applications are still elusive despite the maturity of the medicinal chemistry efforts applied to kinin receptors