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Author |
David Roche; Debora Gil; Jesus Giraldo |
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Title |
Assessing agonist efficacy in an uncertain Em world |
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Conference Article |
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Year |
2012 |
Publication |
40th Keystone Symposia on mollecular and celular biology |
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Pages |
79 |
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Abstract |
The operational model of agonism has been widely used for the analysis of agonist action since its formulation in 1983. The model includes the Em parameter, which is defined as the maximum response of the system. The methods for Em estimation provide Em values not significantly higher than the maximum responses achieved by full agonists. However, it has been found that that some classes of compounds as, for instance, superagonists and positive allosteric modulators can increase the full agonist maximum response, implying upper limits for Em and thereby posing doubts on the validity of Em estimates. Because of the correlation between Em and operational efficacy, τ, wrong Em estimates will yield wrong τ estimates.
In this presentation, the operational model of agonism and various methods for the simulation of allosteric modulation will be analyzed. Alternatives for curve fitting will be presented and discussed. |
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Fairmont Banff Springs, Banff, Alberta, Canada |
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Keystone Symposia |
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Keystone Symposia |
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A. Christopoulus and M. Bouvier |
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english |
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english |
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Keystone Symposia |
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KSMCB |
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IAM |
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Call Number  |
IAM @ iam @ RGG2012 |
Serial |
1855 |
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Author |
David Roche; Debora Gil; Jesus Giraldo |
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Title |
Multiple active receptor conformation, agonist efficacy and maximum effect of the system: the conformation-based operational model of agonism, |
Type |
Journal Article |
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Year |
2013 |
Publication |
Drug Discovery Today |
Abbreviated Journal |
DDT |
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Volume |
18 |
Issue |
7-8 |
Pages |
365-371 |
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Abstract |
The operational model of agonism assumes that the maximum effect a particular receptor system can achieve (the Em parameter) is fixed. Em estimates are above but close to the asymptotic maximum effects of endogenous agonists. The concept of Em is contradicted by superagonists and those positive allosteric modulators that significantly increase the maximum effect of endogenous agonists. An extension of the operational model is proposed that assumes that the Em parameter does not necessarily have a single value for a receptor system but has multiple values associated to multiple active receptor conformations. The model provides a mechanistic link between active receptor conformation and agonist efficacy, which can be useful for the analysis of agonist response under different receptor scenarios. |
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Elsevier |
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IAM; 600.057; 600.054 |
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Call Number |
IAM @ iam @ RGG2013a |
Serial |
2190 |
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Author |
David Roche; Debora Gil; Jesus Giraldo |
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Title |
Mechanistic analysis of the function of agonists and allosteric modulators: Reconciling two-state and operational models |
Type |
Journal Article |
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Year |
2013 |
Publication |
British Journal of Pharmacology |
Abbreviated Journal |
BJP |
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Volume |
169 |
Issue |
6 |
Pages |
1189-202 |
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Abstract |
Two-state and operational models of both agonism and allosterism are compared to identify and characterize common pharmacological parameters. To account for the receptor-dependent basal response, constitutive receptor activity is considered in the operational models. By arranging two-state models as the fraction of active receptors and operational models as the fractional response relative to the maximum effect of the system, a one-by-one correspondence between parameters is found. The comparative analysis allows a better understanding of complex allosteric interactions. In particular, the inclusion of constitutive receptor activity in the operational model of allosterism allows the characterization of modulators able to lower the basal response of the system; that is, allosteric modulators with negative intrinsic efficacy. Theoretical simulations and overall goodness of fit of the models to simulated data suggest that it is feasible to apply the models to experimental data and constitute one step forward in receptor theory formalism. |
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IAM; 600.044; 605.203 |
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Call Number |
IAM @ iam @ RGG2013b |
Serial |
2195 |
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Author |
David Roche; Debora Gil; Jesus Giraldo |
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Title |
Mathematical modeling of G protein-coupled receptor function: What can we learn from empirical and mechanistic models? |
Type |
Book Chapter |
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Year |
2014 |
Publication |
G Protein-Coupled Receptors – Modeling and Simulation Advances in Experimental Medicine and Biology |
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Volume |
796 |
Issue |
3 |
Pages |
159-181 |
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Keywords |
β-arrestin; biased agonism; curve fitting; empirical modeling; evolutionary algorithm; functional selectivity; G protein; GPCR; Hill coefficient; intrinsic efficacy; inverse agonism; mathematical modeling; mechanistic modeling; operational model; parameter optimization; receptor dimer; receptor oligomerization; receptor constitutive activity; signal transduction; two-state model |
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Abstract |
Empirical and mechanistic models differ in their approaches to the analysis of pharmacological effect. Whereas the parameters of the former are not physical constants those of the latter embody the nature, often complex, of biology. Empirical models are exclusively used for curve fitting, merely to characterize the shape of the E/[A] curves. Mechanistic models, on the contrary, enable the examination of mechanistic hypotheses by parameter simulation. Regretfully, the many parameters that mechanistic models may include can represent a great difficulty for curve fitting, representing, thus, a challenge for computational method development. In the present study some empirical and mechanistic models are shown and the connections, which may appear in a number of cases between them, are analyzed from the curves they yield. It may be concluded that systematic and careful curve shape analysis can be extremely useful for the understanding of receptor function, ligand classification and drug discovery, thus providing a common language for the communication between pharmacologists and medicinal chemists. |
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Springer Netherlands |
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ISSN |
0065-2598 |
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978-94-007-7422-3 |
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IAM; 600.075 |
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Call Number |
IAM @ iam @ RGG2014 |
Serial |
2197 |
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Author |
Oriol Rodriguez-Leor; Josefina Mauri; Eduard Fernandez-Nofrerias; M. Gomez; Antonio Tovar; L. Cano; C. Diego; Carme Julia; Vicente del Valle; Debora Gil; Petia Radeva |
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Title |
Ecografia Intracoronària: Segmentació Automàtica de area de la llum |
Type |
Conference Article |
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Year |
2002 |
Publication |
XXXVIII Congreso Nacional de la Sociedad Española de Cardiología. |
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IAM;ADAS;MILAB |
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Call Number |
IAM @ iam @ RMF2002 |
Serial |
1638 |
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Author |
Oriol Rodriguez-Leor; Josefina Mauri; Eduard Fernandez-Nofrerias; C. Garcia; R. Villuendas; Vicente del Valle; Debora Gil; Petia Radeva |
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Title |
Reconstruction of a spatio-temporal model of the intima layer from intravascular ultrasound sequences |
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Journal Article |
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Year |
2003 |
Publication |
European Heart Journal |
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ESC Congress |
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IAM;MILAB |
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IAM @ iam @ RMF2003c |
Serial |
1641 |
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Author |
Oriol Rodriguez-Leor; Josefina Mauri; Eduard Fernandez-Nofrerias; Antonio Tovar; Vicente del Valle; Aura Hernandez-Sabate; Debora Gil; Petia Radeva |
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Title |
Utilización de la Estructura de los Campos Vectoriales para la Detección de la Adventicia en Imágenes de Ecografía Intracoronaria |
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Journal Article |
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2004 |
Publication |
Revista Internacional de Enfermedades Cardiovasculares Revista Española de Cardiología |
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57 |
Issue |
2 |
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100 |
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IAM;MILAB |
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IAM @ iam @ RMF2004 |
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1642 |
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Author |
Debora Gil; Aura Hernandez-Sabate; Antoni Carol; Oriol Rodriguez; Petia Radeva |
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Title |
A Deterministic-Statistic Adventitia Detection in IVUS Images |
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Conference Article |
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Year |
2005 |
Publication |
3rd International workshop on International Workshop on Functional Imaging and Modeling of the Heart |
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65-74 |
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Keywords |
Electron microscopy; Unbending; 2D crystal; Interpolation; Approximation |
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Abstract |
Plaque analysis in IVUS planes needs accurate intima and adventitia models. Large variety in adventitia descriptors difficulties its detection and motivates using a classification strategy for selecting points on the structure. Whatever the set of descriptors used, the selection stage suffers from fake responses due to noise and uncompleted true curves. In order to smooth background noise while strengthening responses, we apply a restricted anisotropic filter that homogenizes grey levels along the image significant structures. Candidate points are extracted by means of a simple semi supervised adaptive classification of the filtered image response to edge and calcium detectors. The final model is obtained by interpolating the former line segments with an anisotropic contour closing technique based on functional extension principles. |
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Barcelona; June 2005 |
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FIMH |
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IAM;MILAB |
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IAM @ iam @ RMF2005 |
Serial |
1524 |
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Author |
Debora Gil; Aura Hernandez-Sabate; Antoni Carol; Oriol Rodriguez; Petia Radeva |
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Title |
A Deterministic-Statistic Adventitia Detection in IVUS Images |
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Conference Article |
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2005 |
Publication |
ESC Congress |
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Electron microscopy; Unbending; 2D crystal; Interpolation; Approximation |
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Abstract |
Plaque analysis in IVUS planes needs accurate intima and adventitia models. Large variety in adventitia descriptors difficulties its detection and motivates using a classification strategy for selecting points on the structure. Whatever the set of descriptors used, the selection stage suffers from fake responses due to noise and uncompleted true curves. In order to smooth background noise while strengthening responses, we apply a restricted anisotropic filter that homogenizes grey levels along the image significant structures. Candidate points are extracted by means of a simple semi supervised adaptive classification of the filtered image response to edge and calcium detectors. The final model is obtained by interpolating the former line segments with an anisotropic contour closing technique based on functional extension principles. |
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Stockholm; Sweden; September 2005 |
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ESC |
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IAM;MILAB |
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IAM @ iam @ RMF2005a |
Serial |
1523 |
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Author |
Oriol Rodriguez-Leor; Josefina Mauri; Eduard Fernandez-Nofrerias; Vicente de Valle; E. Garcia; A. Barrios; Debora Gil; Petia Radeva |
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Title |
Analysis of the changes in angiography local grey-level values to determine myocardial perfusion |
Type |
Conference Article |
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Year |
2006 |
Publication |
World Congress of Cardiology |
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862 |
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Barcelona (Spain) |
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IAM;MILAB |
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IAM @ iam @ RMF2006 |
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1644 |
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