The Experts below are selected from a list of 288 Experts worldwide ranked by ideXlab platform
Arthur J Atkinson - One of the best experts on this subject based on the ideXlab platform.
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chapter 3 compartmental analysis of drug distribution
Principles of Clinical Pharmacology (Second Edition), 2007Co-Authors: Arthur J AtkinsonAbstract:Publisher Summary This chapter discusses the compartmental analysis of drug distribution. Drug distribution can be defined as the postabsorptive transfer of a drug from one location in the body to another. Drug transfer between Compartments is characterized by “intercompartmental clearance,” a term to describe the volume-independent parameter that quantifies the rate of analyte transfer between the Compartments of a kinetic model. The central compartment of a pharmacokinetic (PK) model usually is the only one that is directly accessible to sampling. When attempting to identify this compartment as intravascular space, the erythrocyte/plasma partition ratio must be incorporated in comparisons of central compartment volume with expected blood volume if plasma levels, rather than whole blood levels are used for PK analysis. The physiological basis for the transfer of drugs and other compounds among Compartments can only be inferred for mammillary systems in which the central compartment represents intravascular space and intercompartmental clearance can be equated with transcapillary exchange. The mechanism of transcapillary exchange is elaborated in the chapter.
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CHAPTER 3 – Compartmental Analysis of Drug Distribution
Principles of Clinical Pharmacology, 2007Co-Authors: Arthur J AtkinsonAbstract:Publisher Summary This chapter discusses the compartmental analysis of drug distribution. Drug distribution can be defined as the postabsorptive transfer of a drug from one location in the body to another. Drug transfer between Compartments is characterized by “intercompartmental clearance,” a term to describe the volume-independent parameter that quantifies the rate of analyte transfer between the Compartments of a kinetic model. The central compartment of a pharmacokinetic (PK) model usually is the only one that is directly accessible to sampling. When attempting to identify this compartment as intravascular space, the erythrocyte/plasma partition ratio must be incorporated in comparisons of central compartment volume with expected blood volume if plasma levels, rather than whole blood levels are used for PK analysis. The physiological basis for the transfer of drugs and other compounds among Compartments can only be inferred for mammillary systems in which the central compartment represents intravascular space and intercompartmental clearance can be equated with transcapillary exchange. The mechanism of transcapillary exchange is elaborated in the chapter.
Lakshminarayanan Mahadevan - One of the best experts on this subject based on the ideXlab platform.
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Spatial control of irreversible protein aggregation.
eLife, 2019Co-Authors: Christoph Weber, Thomas C. T. Michaels, Lakshminarayanan MahadevanAbstract:Liquid cellular Compartments form in the cyto- or nucleoplasm and can regulate aberrant protein aggregation. Yet, the mechanisms by which these Compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid Compartments. We find that even for weak interactions aggregates strongly partition into the liquid compartment. Aggregate partitioning is caused by a positive feedback mechanism of aggregate nucleation and growth driven by a flux maintaining the phase equilibrium between the compartment and its surrounding. Our model establishes a link between specific aggregating systems and the physical conditions maximizing aggregate partitioning into the compartment. The underlying mechanism of aggregate partitioning could be used to confine cytotoxic protein aggregates inside droplet-like Compartments but may also represent a common mechanism to spatially control irreversible chemical reactions in general.
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Spatial control of irreversible protein aggregation.
arXiv: Biological Physics, 2018Co-Authors: Christoph Weber, Thomas C. T. Michaels, Lakshminarayanan MahadevanAbstract:Liquid cellular Compartments spatially segregate from the cytoplasm and can regulate aberrant protein aggregation, a process linked to several medical conditions, including Alzheimer's and Parkinson's diseases. Yet the mechanisms by which these droplet-like Compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid Compartments. We find that, even for weak interactions between the compartment constituents and the aggregating monomers, aggregates are strongly enriched inside the liquid compartment relative to the surrounding cytoplasm. We show that this enrichment is caused by a positive feedback mechanism of aggregate nucleation and growth which is mediated by a flux maintaining the phase equilibrium between the compartment and the cytoplasm. Our model predicts that the compartment volume that maximizes aggregate enrichment in the compartment is determined by the reaction orders of aggregate nucleation. The underlying mechanism of aggregate enrichment could be used to confine cytotoxic protein aggregates inside droplet-like Compartments suggesting potential new avenues against aberrant protein aggregation. Our findings could also represent a common mechanism for the spatial control of irreversible chemical reactions in general.
Jen Jen Yeh - One of the best experts on this subject based on the ideXlab platform.
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de novo compartment deconvolution and weight estimation of tumor samples using decoder
Nature Communications, 2019Co-Authors: Xianlu Laura Peng, Richard A Moffitt, Robert J Torphy, Keith E Volmar, Jen Jen YehAbstract:Tumors are mixtures of different Compartments. While global gene expression analysis profiles the average expression of all Compartments in a sample, identifying the specific contribution of each compartment remains a challenge. With the increasing recognition of the importance of non-neoplastic components, the ability to breakdown the gene expression contribution of each is critical. Here, we develop DECODER, an integrated framework which performs de novo deconvolution and single-sample compartment weight estimation. We use DECODER to deconvolve 33 TCGA tumor RNA-seq data sets and show that it may be applied to other data types including ATAC-seq. We demonstrate that it can be utilized to reproducibly estimate cellular compartment weights in pancreatic cancer that are clinically meaningful. Application of DECODER across cancer types advances the capability of identifying cellular Compartments in an unknown sample and may have implications for identifying the tumor of origin for cancers of unknown primary. Separating different cell Compartments from bulk gene expression data can be challenging. Here the authors present DECODER, which can perform de novo deconvolutions on non-negative matrices including microarray, RNA-seq and ATAC-seq data sets.
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de novo compartment deconvolution and weight estimation of tumor samples decoder
bioRxiv, 2019Co-Authors: Xianlu Laura Peng, Richard A Moffitt, Robert J Torphy, Keith E Volmar, Jen Jen YehAbstract:Abstract Tumors are mixtures of different Compartments. While global gene expression analysis profiles the average expression of all Compartments in a sample, identifying the specific contribution of each compartment remains a challenge. With the increasing recognition of the importance of non-neoplastic components, the ability to breakdown the gene expression contribution of each is critical. To this end, we developed DECODER, an integrated framework which performs de novo deconvolution, and compartment weight estimation for a single sample. We use DECODER to deconvolve 33 TCGA tumor RNA-seq datasets and show that it may be applied to other data types including ATAC-seq. We demonstrate that it can be utilized to reproducibly estimate cellular compartment weights in pancreatic cancer that are clinically meaningful. Application of DECODER across cancer types advances the capability of identifying cellular Compartments in an unknown sample and may have implications for identifying the tumor of origin for cancers of unknown primary.
Dong Woo Lim - One of the best experts on this subject based on the ideXlab platform.
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Oppositely Charged, Stimuli-Responsive Anisotropic Nanoparticles for Colloidal Self-Assembly
2019Co-Authors: Eun Young Hwang, Jae Sang Lee, Dong Woo LimAbstract:Anisotropic nanoparticles (ANPs) composed of distinct Compartments are of interest as advanced materials because they offer unique physicochemical properties controlled by polymer composition, distribution of functional groups, and stimuli responsiveness of each compartment. Furthermore, colloidal self-assembly of ANPs via noncovalent interactions between Compartments can create superstructures with additional functionality. In this study, ANPs with two Compartments composed of oppositely charged and thermally responsive ternary copolymers were prepared using electrohydrodynamic cojetting. One compartment was composed of poly(N-isopropylacrylamide-co-stearyl acrylate-co-allylamine), which is positively charged in aqueous solution at pH 7, and the other compartment was composed of poly(N-isopropylacrylamide-co-stearyl acrylate-co-acrylic acid), which is negatively charged. The ANPs were stabilized in aqueous solution by physical cross-linking because of hydrophobic interactions between the 18-carbon alkyl chains of their stearyl acrylate moieties and self-assembled into supracolloidal nanostructures via electrostatic interactions. Colloidal self-assembly and thermal responsiveness were controlled by compartment charge density and solution ionic strength. The supracolloidal nanostructures exhibited both the intrinsic temperature-responsive properties of the ANPs and collective properties from self-assembly. These multifunctional, stimuli-responsive nanostructures will be useful in a variety of applications, including switchable displays, drug delivery carriers, and ion-sensitive gels
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Thermally-Induced Actuations of Stimuli-Responsive, Bicompartmental Nanofibers for Decoupled Drug Release
Frontiers Media S.A., 2019Co-Authors: Chan Woo Jung, Eun Young Hwang, Jae Sang Lee, Ghulam Jalani, Dong Woo LimAbstract:Stimuli-responsive anisotropic microstructures and nanostructures with different physicochemical properties in discrete Compartments, have been developed as advanced materials for drug delivery systems, tissue engineering, regenerative medicine, and biosensing applications. Moreover, their stimuli-triggered actuations would be of great interest for the introduction of the functionality of drug delivery reservoirs and tissue engineering scaffolds. In this study, stimuli-responsive bicompartmental nanofibers (BCNFs), with completely different polymer compositions, were prepared through electrohydrodynamic co-jetting with side-by-side needle geometry. One compartment with thermo-responsiveness was composed of methacrylated poly(N-isopropylacrylamide-co-allylamine hydrochloride) (poly(NIPAM-co-AAh)), while the counter compartment was made of poly(ethylene glycol) dimethacrylates (PEGDMA). Both methacrylated poly(NIPAM-co-AAh) and PEGDMA in distinct Compartments were chemically crosslinked in a solid phase by UV irradiation and swelled under aqueous conditions, because of the hydrophilicity of both poly(NIPAM-co-AAh) and PEGDMA. As the temperature increased, BCNFs maintained a clear interface between Compartments and showed thermally-induced actuation at the nanoscale due to the collapsed poly(NIPAM-co-AAh) compartment under the PEGDMA compartment of identical dimensions. Different model drugs, bovine serum albumin, and dexamethasone phosphate were alternately loaded into each compartment and released at different rates depending on the temperature and molecular weight of the drugs. These BCNFs, as intelligent nanomaterials, have great potential as tissue engineering scaffolds and multi-modal drug delivery reservoirs with stimuli-triggered actuation and decoupled drug release
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Table_1_Thermally-Induced Actuations of Stimuli-Responsive, Bicompartmental Nanofibers for Decoupled Drug Release.docx
2019Co-Authors: Chan Woo Jung, Eun Young Hwang, Jae Sang Lee, Ghulam Jalani, Dong Woo LimAbstract:Stimuli-responsive anisotropic microstructures and nanostructures with different physicochemical properties in discrete Compartments, have been developed as advanced materials for drug delivery systems, tissue engineering, regenerative medicine, and biosensing applications. Moreover, their stimuli-triggered actuations would be of great interest for the introduction of the functionality of drug delivery reservoirs and tissue engineering scaffolds. In this study, stimuli-responsive bicompartmental nanofibers (BCNFs), with completely different polymer compositions, were prepared through electrohydrodynamic co-jetting with side-by-side needle geometry. One compartment with thermo-responsiveness was composed of methacrylated poly(N-isopropylacrylamide-co-allylamine hydrochloride) (poly(NIPAM-co-AAh)), while the counter compartment was made of poly(ethylene glycol) dimethacrylates (PEGDMA). Both methacrylated poly(NIPAM-co-AAh) and PEGDMA in distinct Compartments were chemically crosslinked in a solid phase by UV irradiation and swelled under aqueous conditions, because of the hydrophilicity of both poly(NIPAM-co-AAh) and PEGDMA. As the temperature increased, BCNFs maintained a clear interface between Compartments and showed thermally-induced actuation at the nanoscale due to the collapsed poly(NIPAM-co-AAh) compartment under the PEGDMA compartment of identical dimensions. Different model drugs, bovine serum albumin, and dexamethasone phosphate were alternately loaded into each compartment and released at different rates depending on the temperature and molecular weight of the drugs. These BCNFs, as intelligent nanomaterials, have great potential as tissue engineering scaffolds and multi-modal drug delivery reservoirs with stimuli-triggered actuation and decoupled drug release.
Christoph Weber - One of the best experts on this subject based on the ideXlab platform.
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Spatial control of irreversible protein aggregation.
eLife, 2019Co-Authors: Christoph Weber, Thomas C. T. Michaels, Lakshminarayanan MahadevanAbstract:Liquid cellular Compartments form in the cyto- or nucleoplasm and can regulate aberrant protein aggregation. Yet, the mechanisms by which these Compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid Compartments. We find that even for weak interactions aggregates strongly partition into the liquid compartment. Aggregate partitioning is caused by a positive feedback mechanism of aggregate nucleation and growth driven by a flux maintaining the phase equilibrium between the compartment and its surrounding. Our model establishes a link between specific aggregating systems and the physical conditions maximizing aggregate partitioning into the compartment. The underlying mechanism of aggregate partitioning could be used to confine cytotoxic protein aggregates inside droplet-like Compartments but may also represent a common mechanism to spatially control irreversible chemical reactions in general.
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Spatial control of irreversible protein aggregation.
arXiv: Biological Physics, 2018Co-Authors: Christoph Weber, Thomas C. T. Michaels, Lakshminarayanan MahadevanAbstract:Liquid cellular Compartments spatially segregate from the cytoplasm and can regulate aberrant protein aggregation, a process linked to several medical conditions, including Alzheimer's and Parkinson's diseases. Yet the mechanisms by which these droplet-like Compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid Compartments. We find that, even for weak interactions between the compartment constituents and the aggregating monomers, aggregates are strongly enriched inside the liquid compartment relative to the surrounding cytoplasm. We show that this enrichment is caused by a positive feedback mechanism of aggregate nucleation and growth which is mediated by a flux maintaining the phase equilibrium between the compartment and the cytoplasm. Our model predicts that the compartment volume that maximizes aggregate enrichment in the compartment is determined by the reaction orders of aggregate nucleation. The underlying mechanism of aggregate enrichment could be used to confine cytotoxic protein aggregates inside droplet-like Compartments suggesting potential new avenues against aberrant protein aggregation. Our findings could also represent a common mechanism for the spatial control of irreversible chemical reactions in general.
