The Experts below are selected from a list of 352212 Experts worldwide ranked by ideXlab platform
John G Partridge - One of the best experts on this subject based on the ideXlab platform.
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utilizing gcamp transgenic mice to monitor endogenous gq 11 coupled receptors
Frontiers in Pharmacology, 2015Co-Authors: John G PartridgeAbstract:The family of GCaMPs are engineered proteins that contain Ca2+ binding motifs within a circularly permutated variant of Aequorea Victoria green fluorescent protein (cp-GFP). The rapidly advancing field of utilizing GCaMP reporter constructs represents a major step forward in our ability to monitor intracellular Ca2+ dynamics. With the use of these Genetically encoded Ca2+ sensors, investigators have studied activation of endogenous Gq types of G-protein coupled receptors (GPCRs) and subsequent rises in intracellular calcium. Escalations in intracellular Ca2+ from GPCR activation can be faithfully monitored in space and time as an increase in fluorescent emission from these proteins. Further, transgenic mice are now commercially available that express GCaMPs in a Cre recombinase dependent fashion. These GCaMP reporter mice can be bred to distinct Cre recombinase driver mice to direct expression of this sensor in unique populations of cells. Concerning the central nervous system (CNS), sources of calcium influx, including those arising from Gq activation can be observed in targeted cells types like neurons or astrocytes. This powerful Genetic Method allows simultaneous monitoring of the activity of dozens of cells upon activation of endogenous Gq-coupled GPCRs. Therefore, in combination with pharmacological tools, this strategy of monitoring GPCR activation is amenable to high throughput analysis of orthosteric and allosteric ligands of Gq coupled receptors in their endogenous environments.
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Utilizing GCaMP transgenic mice to monitor endogenous Gq/11 coupled receptors
Frontiers Media S.A., 2015Co-Authors: John G PartridgeAbstract:The family of GCaMPs are engineered proteins that contain Ca2+ binding motifs within a circularly permutated variant of Aequorea Victoria green fluorescent protein (cp-GFP). The rapidly advancing field of utilizing GCaMP reporter constructs represents a major step forward in our ability to monitor intracellular Ca2+ dynamics. With the use of these Genetically encoded Ca2+ sensors, investigators have studied activation of endogenous Gq types of G-protein coupled receptors (GPCRs) and subsequent rises in intracellular calcium. Escalations in intracellular Ca2+ from GPCR activation can be faithfully monitored in space and time as an increase in fluorescent emission from these proteins. Further, transgenic mice are now commercially available that express GCaMPs in a Cre recombinase dependent fashion. These GCaMP reporter mice can be bred to distinct Cre recombinase driver mice to direct expression of this sensor in unique populations of cells. Concerning the central nervous system (CNS), sources of calcium influx, including those arising from Gq activation can be observed in targeted cells types like neurons or astrocytes. This powerful Genetic Method allows simultaneous monitoring of the activity of dozens of cells upon activation of endogenous Gq-coupled GPCRs. Therefore, in combination with pharmacological tools, this strategy of monitoring GPCR activation is amenable to high throughput analysis of orthosteric and allosteric ligands of Gq coupled receptors in their endogenous environments
Claudia Bank - One of the best experts on this subject based on the ideXlab platform.
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an experimental evaluation of drug induced mutational meltdown as an antiviral treatment strategy
Evolution, 2016Co-Authors: Claudia Bank, Nicholas Renzette, Ping Liu, Sebastian Matuszewski, Hyunjin Shim, Matthieu FollAbstract:The rapid evolution of drug resistance remains a critical public health concern. The treatment of influenza A virus (IAV) has proven particularly challenging, due to the ability of the virus to develop resistance against current antivirals and vaccines. Here, we evaluate a novel antiviral drug therapy, favipiravir, for which the mechanism of action in IAV involves an interaction with the viral RNA-dependent RNA polymerase resulting in an effective increase in the viral mutation rate. We used an experimental evolution framework, combined with novel population Genetic Method development for inference from time-sampled data, to evaluate the effectiveness of favipiravir against IAV. Evaluating whole genome polymorphism data across 15 time points under multiple drug concentrations and in controls, we present the first evidence for the ability of IAV populations to effectively adapt to low concentrations of favipiravir. In contrast, under high concentrations, we observe population extinction, indicative of mutational meltdown. We discuss the observed dynamics with respect to the evolutionary forces at play and emphasize the utility of evolutionary theory to inform drug development.
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an experimental evaluation of drug induced mutational meltdown as an antiviral treatment strategy
bioRxiv, 2016Co-Authors: Claudia Bank, Nicholas Renzette, Ping Liu, Sebastian Matuszewski, Hyunjin Shim, Matthieu Foll, Daniel N Bolon, Konstantin B Zeldovich, Timothy F Kowalik, Robert W FinbergAbstract:The rapid evolution of drug resistance remains a critical public health concern. The treatment of influenza A virus (IAV) has proven particularly challenging, due to the ability of the virus to develop resistance against current antivirals and vaccines. Here we evaluate a novel antiviral drug therapy, favipiravir, for which the mechanism of action in IAV involves an interaction with the viral RNA- dependent RNA polymerase resulting in an effective increase in the viral mutation rate. We utilize an experimental evolution framework, combined with novel population Genetic Method development for inference from time-sampled data, in order to evaluate the effectiveness of favipiravir against IAV. Evaluating whole genome polymorphism data across fifteen time points under multiple drug concentrations and in controls, we present the first evidence for the ability of viral populations to effectively adapt to low concentrations of favipiravir. In contrast, under high concentrations, we observe population extinction, indicative of mutational meltdown. We discuss the observed dynamics with respect to the evolutionary forces at play and emphasize the utility of evolutionary theory to inform drug development.
Matthieu Foll - One of the best experts on this subject based on the ideXlab platform.
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an experimental evaluation of drug induced mutational meltdown as an antiviral treatment strategy
Evolution, 2016Co-Authors: Claudia Bank, Nicholas Renzette, Ping Liu, Sebastian Matuszewski, Hyunjin Shim, Matthieu FollAbstract:The rapid evolution of drug resistance remains a critical public health concern. The treatment of influenza A virus (IAV) has proven particularly challenging, due to the ability of the virus to develop resistance against current antivirals and vaccines. Here, we evaluate a novel antiviral drug therapy, favipiravir, for which the mechanism of action in IAV involves an interaction with the viral RNA-dependent RNA polymerase resulting in an effective increase in the viral mutation rate. We used an experimental evolution framework, combined with novel population Genetic Method development for inference from time-sampled data, to evaluate the effectiveness of favipiravir against IAV. Evaluating whole genome polymorphism data across 15 time points under multiple drug concentrations and in controls, we present the first evidence for the ability of IAV populations to effectively adapt to low concentrations of favipiravir. In contrast, under high concentrations, we observe population extinction, indicative of mutational meltdown. We discuss the observed dynamics with respect to the evolutionary forces at play and emphasize the utility of evolutionary theory to inform drug development.
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an experimental evaluation of drug induced mutational meltdown as an antiviral treatment strategy
bioRxiv, 2016Co-Authors: Claudia Bank, Nicholas Renzette, Ping Liu, Sebastian Matuszewski, Hyunjin Shim, Matthieu Foll, Daniel N Bolon, Konstantin B Zeldovich, Timothy F Kowalik, Robert W FinbergAbstract:The rapid evolution of drug resistance remains a critical public health concern. The treatment of influenza A virus (IAV) has proven particularly challenging, due to the ability of the virus to develop resistance against current antivirals and vaccines. Here we evaluate a novel antiviral drug therapy, favipiravir, for which the mechanism of action in IAV involves an interaction with the viral RNA- dependent RNA polymerase resulting in an effective increase in the viral mutation rate. We utilize an experimental evolution framework, combined with novel population Genetic Method development for inference from time-sampled data, in order to evaluate the effectiveness of favipiravir against IAV. Evaluating whole genome polymorphism data across fifteen time points under multiple drug concentrations and in controls, we present the first evidence for the ability of viral populations to effectively adapt to low concentrations of favipiravir. In contrast, under high concentrations, we observe population extinction, indicative of mutational meltdown. We discuss the observed dynamics with respect to the evolutionary forces at play and emphasize the utility of evolutionary theory to inform drug development.
Sebastian Matuszewski - One of the best experts on this subject based on the ideXlab platform.
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an experimental evaluation of drug induced mutational meltdown as an antiviral treatment strategy
Evolution, 2016Co-Authors: Claudia Bank, Nicholas Renzette, Ping Liu, Sebastian Matuszewski, Hyunjin Shim, Matthieu FollAbstract:The rapid evolution of drug resistance remains a critical public health concern. The treatment of influenza A virus (IAV) has proven particularly challenging, due to the ability of the virus to develop resistance against current antivirals and vaccines. Here, we evaluate a novel antiviral drug therapy, favipiravir, for which the mechanism of action in IAV involves an interaction with the viral RNA-dependent RNA polymerase resulting in an effective increase in the viral mutation rate. We used an experimental evolution framework, combined with novel population Genetic Method development for inference from time-sampled data, to evaluate the effectiveness of favipiravir against IAV. Evaluating whole genome polymorphism data across 15 time points under multiple drug concentrations and in controls, we present the first evidence for the ability of IAV populations to effectively adapt to low concentrations of favipiravir. In contrast, under high concentrations, we observe population extinction, indicative of mutational meltdown. We discuss the observed dynamics with respect to the evolutionary forces at play and emphasize the utility of evolutionary theory to inform drug development.
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an experimental evaluation of drug induced mutational meltdown as an antiviral treatment strategy
bioRxiv, 2016Co-Authors: Claudia Bank, Nicholas Renzette, Ping Liu, Sebastian Matuszewski, Hyunjin Shim, Matthieu Foll, Daniel N Bolon, Konstantin B Zeldovich, Timothy F Kowalik, Robert W FinbergAbstract:The rapid evolution of drug resistance remains a critical public health concern. The treatment of influenza A virus (IAV) has proven particularly challenging, due to the ability of the virus to develop resistance against current antivirals and vaccines. Here we evaluate a novel antiviral drug therapy, favipiravir, for which the mechanism of action in IAV involves an interaction with the viral RNA- dependent RNA polymerase resulting in an effective increase in the viral mutation rate. We utilize an experimental evolution framework, combined with novel population Genetic Method development for inference from time-sampled data, in order to evaluate the effectiveness of favipiravir against IAV. Evaluating whole genome polymorphism data across fifteen time points under multiple drug concentrations and in controls, we present the first evidence for the ability of viral populations to effectively adapt to low concentrations of favipiravir. In contrast, under high concentrations, we observe population extinction, indicative of mutational meltdown. We discuss the observed dynamics with respect to the evolutionary forces at play and emphasize the utility of evolutionary theory to inform drug development.
Hyunjin Shim - One of the best experts on this subject based on the ideXlab platform.
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an experimental evaluation of drug induced mutational meltdown as an antiviral treatment strategy
Evolution, 2016Co-Authors: Claudia Bank, Nicholas Renzette, Ping Liu, Sebastian Matuszewski, Hyunjin Shim, Matthieu FollAbstract:The rapid evolution of drug resistance remains a critical public health concern. The treatment of influenza A virus (IAV) has proven particularly challenging, due to the ability of the virus to develop resistance against current antivirals and vaccines. Here, we evaluate a novel antiviral drug therapy, favipiravir, for which the mechanism of action in IAV involves an interaction with the viral RNA-dependent RNA polymerase resulting in an effective increase in the viral mutation rate. We used an experimental evolution framework, combined with novel population Genetic Method development for inference from time-sampled data, to evaluate the effectiveness of favipiravir against IAV. Evaluating whole genome polymorphism data across 15 time points under multiple drug concentrations and in controls, we present the first evidence for the ability of IAV populations to effectively adapt to low concentrations of favipiravir. In contrast, under high concentrations, we observe population extinction, indicative of mutational meltdown. We discuss the observed dynamics with respect to the evolutionary forces at play and emphasize the utility of evolutionary theory to inform drug development.
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an experimental evaluation of drug induced mutational meltdown as an antiviral treatment strategy
bioRxiv, 2016Co-Authors: Claudia Bank, Nicholas Renzette, Ping Liu, Sebastian Matuszewski, Hyunjin Shim, Matthieu Foll, Daniel N Bolon, Konstantin B Zeldovich, Timothy F Kowalik, Robert W FinbergAbstract:The rapid evolution of drug resistance remains a critical public health concern. The treatment of influenza A virus (IAV) has proven particularly challenging, due to the ability of the virus to develop resistance against current antivirals and vaccines. Here we evaluate a novel antiviral drug therapy, favipiravir, for which the mechanism of action in IAV involves an interaction with the viral RNA- dependent RNA polymerase resulting in an effective increase in the viral mutation rate. We utilize an experimental evolution framework, combined with novel population Genetic Method development for inference from time-sampled data, in order to evaluate the effectiveness of favipiravir against IAV. Evaluating whole genome polymorphism data across fifteen time points under multiple drug concentrations and in controls, we present the first evidence for the ability of viral populations to effectively adapt to low concentrations of favipiravir. In contrast, under high concentrations, we observe population extinction, indicative of mutational meltdown. We discuss the observed dynamics with respect to the evolutionary forces at play and emphasize the utility of evolutionary theory to inform drug development.