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Article ; Online: A physiologically-based pharmacokinetic model for tuberculosis drug disposition at extrapulmonary sites.

Ramachandran, Aparna / Gadgil, Chetan J

CPT: pharmacometrics & systems pharmacology

2023 Volume 12, Issue 9, Page(s) 1274–1284

Abstract: Tuberculosis (TB) is a leading cause of mortality attributed to an infectious agent. TB primarily targets the lungs, but in about 16% cases can affect other organs as well, giving rise to extrapulmonary TB (EPTB). However, an optimal regimen for EPTB ... ...

Abstract	Tuberculosis (TB) is a leading cause of mortality attributed to an infectious agent. TB primarily targets the lungs, but in about 16% cases can affect other organs as well, giving rise to extrapulmonary TB (EPTB). However, an optimal regimen for EPTB treatment is not defined. Although the recommended treatment for most forms of EPTB is the same as pulmonary TB, the pharmacokinetics of EPTB therapy are not as well studied. To address this gap, we formulate a whole-body physiologically-based pharmacokinetic (PBPK) model for EPTB that for the first time includes the ability to simulate drug concentrations in the pleura and lymph node, the most commonly affected sites of EPTB. Using this model, we estimate the time-dependent concentrations, at potential EPTB infection sites, of the following four first-line anti-TB drugs: rifampicin, ethambutol, isoniazid, and pyrazinamide. We use reported plasma concentration kinetics data to estimate model parameters for each drug and validate our model using reported concentration data not used for model formulation or parameter estimation. Model predictions match the validation data, and reported pharmacokinetic parameters (maximum plasma concentration, time to reach maximum concentration) for the drugs. The model also predicts ethambutol, isoniazid, and pyrazinamide concentrations in the pleura that match reported experimental values from an independent study. For each drug, the predicted drug concentrations at EPTB sites are compared with their critical concentration. Simulations suggest that although rifampicin and isoniazid concentrations are greater than critical concentration values at most EPTB sites, the concentrations of ethambutol and pyrazinamide are lower than their critical concentrations at most EPTB sites.
MeSH term(s)	Humans ; Isoniazid ; Pyrazinamide ; Ethambutol ; Rifampin/pharmacokinetics ; Tuberculosis/drug therapy ; Antitubercular Agents
Chemical Substances	Isoniazid (V83O1VOZ8L) ; Pyrazinamide (2KNI5N06TI) ; Ethambutol (8G167061QZ) ; Rifampin (VJT6J7R4TR) ; Antitubercular Agents
Language	English
Publishing date	2023-07-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.13008
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Mathematical model of the multi-amino acid multi-transporter system predicts uptake flux in CHO cells

Sreejan, Ashley / Gadgil, Mugdha / Gadgil, Chetan J.

Journal of biotechnology. 2022 Jan. 20, v. 344

2022

Abstract: Supply and uptake of amino acids is of great importance to mammalian cell culture processes. Mammalian cells such as Chinese hamster ovary (CHO) cells express several amino acid (AA) transporters including uniporters and exchangers. Each transporter ... ...

Abstract	Supply and uptake of amino acids is of great importance to mammalian cell culture processes. Mammalian cells such as Chinese hamster ovary (CHO) cells express several amino acid (AA) transporters including uniporters and exchangers. Each transporter transports multiple AAs, making prediction of the effect of changed medium composition or transporter levels on individual AA transport rate challenging. A general kinetic model for such combinatorial amino acid transport, and a simplified analytical expression for the uptake rate as a function of amino acid concentrations and transporter levels is presented. From this general model, a CHO cell-specific AA transport model, to our knowledge the first such network model for any cell type, is constructed. The model is validated by its prediction of reported uptake flux and dependencies from experiments that were not used in model construction or parameter estimation. The model defines theoretical conditions for synergistic/repressive effect on the uptake rates of other AAs upon external addition of one AA. The ability of the CHO-specific model to predict amino acid interdependencies experimentally observed in other mammalian cell types suggests its robustness. This model will help formulate testable hypotheses of the effect of process changes on AA initial uptake, and serve as the AA transport component of kinetic models for cellular metabolism.
Keywords	Cricetulus griseus ; amino acids ; biotechnology ; cell culture ; kinetics ; mathematical models ; metabolism ; prediction
Language	English
Dates of publication	2022-0120
Size	p. 40-49.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	843647-2
ISSN	1873-4863 ; 0168-1656 ; 1389-0352
ISSN (online)	1873-4863
ISSN	0168-1656 ; 1389-0352
DOI	10.1016/j.jbiotec.2021.12.003
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Article ; Online: Mathematical model of the multi-amino acid multi-transporter system predicts uptake flux in CHO cells.

Sreejan, Ashley / Gadgil, Mugdha / Gadgil, Chetan J

Journal of biotechnology

2021 Volume 344, Page(s) 40–49

Abstract	Supply and uptake of amino acids is of great importance to mammalian cell culture processes. Mammalian cells such as Chinese hamster ovary (CHO) cells express several amino acid (AA) transporters including uniporters and exchangers. Each transporter transports multiple AAs, making prediction of the effect of changed medium composition or transporter levels on individual AA transport rate challenging. A general kinetic model for such combinatorial amino acid transport, and a simplified analytical expression for the uptake rate as a function of amino acid concentrations and transporter levels is presented. From this general model, a CHO cell-specific AA transport model, to our knowledge the first such network model for any cell type, is constructed. The model is validated by its prediction of reported uptake flux and dependencies from experiments that were not used in model construction or parameter estimation. The model defines theoretical conditions for synergistic/repressive effect on the uptake rates of other AAs upon external addition of one AA. The ability of the CHO-specific model to predict amino acid interdependencies experimentally observed in other mammalian cell types suggests its robustness. This model will help formulate testable hypotheses of the effect of process changes on AA initial uptake, and serve as the AA transport component of kinetic models for cellular metabolism.
MeSH term(s)	Amino Acid Transport Systems ; Amino Acids/metabolism ; Animals ; Biological Transport ; CHO Cells ; Cricetinae ; Cricetulus ; Models, Theoretical
Chemical Substances	Amino Acid Transport Systems ; Amino Acids
Language	English
Publishing date	2021-12-09
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	843647-2
ISSN	1873-4863 ; 0168-1656 ; 1389-0352
ISSN (online)	1873-4863
ISSN	0168-1656 ; 1389-0352
DOI	10.1016/j.jbiotec.2021.12.003
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Article ; Online: SUMOylation of Dorsal attenuates Toll/NF-κB signaling.

Hegde, Sushmitha / Sreejan, Ashley / Gadgil, Chetan J / Ratnaparkhi, Girish S

Genetics

2022 Volume 221, Issue 3

Abstract: In Drosophila, Toll/NF-κB signaling plays key roles in both animal development and in host defense. The activation, intensity, and kinetics of Toll signaling are regulated by posttranslational modifications such as phosphorylation, SUMOylation, or ... ...

Abstract	In Drosophila, Toll/NF-κB signaling plays key roles in both animal development and in host defense. The activation, intensity, and kinetics of Toll signaling are regulated by posttranslational modifications such as phosphorylation, SUMOylation, or ubiquitination that target multiple proteins in the Toll/NF-κB cascade. Here, we have generated a CRISPR-Cas9 edited Dorsal (DL) variant that is SUMO conjugation resistant. Intriguingly, embryos laid by dlSCR mothers overcome dl haploinsufficiency and complete the developmental program. This ability appears to be a result of higher transcriptional activation by DLSCR. In contrast, SUMOylation dampens DL transcriptional activation, ultimately conferring robustness to the dorso-ventral program. In the larval immune response, dlSCR animals show an increase in crystal cell numbers, stronger activation of humoral defense genes, and high cactus levels. A mathematical model that evaluates the contribution of the small fraction of SUMOylated DL (1-5%) suggests that it acts to block transcriptional activation, which is driven primarily by DL that is not SUMO conjugated. Our findings define SUMO conjugation as an important regulator of the Toll signaling cascade, in both development and host defense. Our results broadly suggest that SUMO attenuates DL at the level of transcriptional activation. Furthermore, we hypothesize that SUMO conjugation of DL may be part of a Ubc9-dependent mechanism that restrains Toll/NF-κB signaling.
MeSH term(s)	Animals ; Drosophila/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Signal Transduction ; Sumoylation
Chemical Substances	Drosophila Proteins ; NF-kappa B
Language	English
Publishing date	2022-05-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2167-2
ISSN	1943-2631 ; 0016-6731
ISSN (online)	1943-2631
ISSN	0016-6731
DOI	10.1093/genetics/iyac081
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Book ; Online: Mathematical model for autoregulated miRNA biogenesis

Nyayanit, Dimpal A / Gadgil, Chetan J

2020

Abstract: MicroRNAs are small non-coding nucleotide sequences that regulate target protein expression at post-transcriptional levels. Biogenesis of microRNA is a highly regulated multi-step pathway. Regulation of miRNA biogenesis can be caused directly by the ... ...

Abstract	MicroRNAs are small non-coding nucleotide sequences that regulate target protein expression at post-transcriptional levels. Biogenesis of microRNA is a highly regulated multi-step pathway. Regulation of miRNA biogenesis can be caused directly by the components of the biogenesis pathway or indirectly by other regulators. In this study, we have built a detailed mathematical model of microRNA biogenesis to investigate the regulatory role of biogenesis pathway components. We extended a previous model to incorporate Microprocessor regulation of DGCR8 synthesis, exportin-mediated transport to the cytoplasm, and positive auto-regulation catalysed by mature miRNA translocation into the nucleus. Our simulation results lead to three hypotheses (i) Biogenesis is robust to Dicer protein levels at higher Exportin protein levels; (ii) Higher miRNA transcript formation may lead to lower RISC levels: an optimal level of both precursor miRNA and Dicer is required for optimal miRNA formation at lower levels of Exportin protein; and (iii) The positive auto-regulation by mature miRNA translocation into the nucleus can decrease the net functional cytoplasmic miRNA. Wherever possible, we compare these results to experimental observations not used in the model construction or calibration.
Keywords	Quantitative Biology - Molecular Networks
Subject code	570
Publishing date	2020-01-30
Publishing country	us
Document type	Book ; Online
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Article ; Online: Kinetic model of GPCR-G protein interactions reveals allokairic modulation of signaling.

Culhane, Kelly J / Gupte, Tejas M / Madhugiri, Indrani / Gadgil, Chetan J / Sivaramakrishnan, Sivaraj

Nature communications

2022 Volume 13, Issue 1, Page(s) 1202

Abstract: Established models of ternary complex formation between hormone, G protein coupled receptor (GPCR), and G protein assume that all interactions occur under equilibrium conditions. However, recent studies have established that the lifetimes of these ... ...

Abstract	Established models of ternary complex formation between hormone, G protein coupled receptor (GPCR), and G protein assume that all interactions occur under equilibrium conditions. However, recent studies have established that the lifetimes of these interactions are comparable to the duration of hormone activated GPCR signaling. To simulate interactions during such non-equilibrium conditions, we propose a kinetic model wherein the receptor undergoes rate-limiting transitions between two hormone-bound active states. Simulations, using experimentally measured parameters, demonstrate transient states in ternary complex formation, and delineate the phenomenon of GPCR priming, wherein non-cognate G proteins substantially enhance cognate G protein signaling. Our model reveals that kinetic barriers of slow receptor interconversion can be overcome through allokairic modulation, a regulatory mechanism of ternary complex formation and downstream signaling.
MeSH term(s)	GTP-Binding Proteins/metabolism ; Hormones ; Kinetics ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction
Chemical Substances	Hormones ; Receptors, G-Protein-Coupled ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2022-03-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-28789-5
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Article: Method for identification of sensitive nodes in Boolean models of biological networks.

Dnyane, Pooja A / Puntambekar, Shraddha S / Gadgil, Chetan J

IET systems biology

2018 Volume 12, Issue 1, Page(s) 1–6

Abstract: Biological systems are often represented as Boolean networks and analysed to identify sensitive nodes which on perturbation disproportionately change a predefined output. There exist different kinds of perturbation methods: perturbation of function, ... ...

Abstract	Biological systems are often represented as Boolean networks and analysed to identify sensitive nodes which on perturbation disproportionately change a predefined output. There exist different kinds of perturbation methods: perturbation of function, perturbation of state and perturbation in update scheme. Nodes may have defects in interpretation of the inputs from other nodes and calculation of the node output. To simulate these defects and systematically assess their effect on the system output, two new function perturbations, referred to as 'not of function' and 'function of not', are introduced. In the former, the inputs are assumed to be correctly interpreted but the output of the update rule is perturbed; and in the latter, each input is perturbed but the correct update rule is applied. These and previously used perturbation methods were applied to two existing Boolean models, namely the human melanogenesis signalling network and the fly segment polarity network. Through mathematical simulations, it was found that these methods successfully identified nodes earlier found to be sensitive using other methods, and were also able to identify sensitive nodes which were previously unreported.
MeSH term(s)	Humans ; Models, Biological ; Signal Transduction
Language	English
Publishing date	2018-01-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2264538-X
ISSN	1751-8857 ; 1751-8849
ISSN (online)	1751-8857
ISSN	1751-8849
DOI	10.1049/iet-syb.2017.0039
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Article ; Online: Mathematical modeling of combinatorial regulation suggests that apparent positive regulation of targets by miRNA could be an artifact resulting from competition for mRNA.

Nyayanit, Dimpal / Gadgil, Chetan J

RNA (New York, N.Y.)

2015 Volume 21, Issue 3, Page(s) 307–319

Abstract: MicroRNAs bind to and regulate the abundance and activity of target messenger RNA through sequestration, enhanced degradation, and suppression of translation. Although miRNA have a predominantly negative effect on the target protein concentration, ... ...

Abstract	MicroRNAs bind to and regulate the abundance and activity of target messenger RNA through sequestration, enhanced degradation, and suppression of translation. Although miRNA have a predominantly negative effect on the target protein concentration, several reports have demonstrated a positive effect of miRNA, i.e., increase in target protein concentration on miRNA overexpression and decrease in target concentration on miRNA repression. miRNA-target pair-specific effects such as protection of mRNA degradation owing to miRNA binding can explain some of these effects. However, considering such pairs in isolation might be an oversimplification of the RNA biology, as it is known that one miRNA interacts with several targets, and conversely target mRNA are subject to regulation by several miRNAs. We formulate a mathematical model of this combinatorial regulation of targets by multiple miRNA. Through mathematical analysis and numerical simulations of this model, we show that miRNA that individually have a negative effect on their targets may exhibit an apparently positive net effect when the concentration of one miRNA is experimentally perturbed by repression/overexpression in such a multi-miRNA multitarget situation. We show that this apparent unexpected effect is due to competition and will not be observed when miRNA interact noncompetitively with the target mRNA. This result suggests that some of the observed unusual positive effects of miRNA may be due to the combinatorial complexity of the system rather than due to any inherently unusual positive effect of the miRNA on its target.
MeSH term(s)	Artifacts ; Gene Expression Regulation/genetics ; MicroRNAs/genetics ; Models, Theoretical ; Protein Biosynthesis/genetics ; RNA, Messenger/genetics
Chemical Substances	MicroRNAs ; RNA, Messenger
Language	English
Publishing date	2015-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.046862.114
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Article ; Online: Size-independent differences between the mean of discrete stochastic systems and the corresponding continuous deterministic systems.

Gadgil, Chetan J

Bulletin of mathematical biology

2009 Volume 71, Issue 7, Page(s) 1599–1611

Abstract: In this paper, it is shown that for a class of reaction networks, the discrete stochastic nature of the reacting species and reactions results in qualitative and quantitative differences between the mean of exact stochastic simulations and the prediction ...

Abstract	In this paper, it is shown that for a class of reaction networks, the discrete stochastic nature of the reacting species and reactions results in qualitative and quantitative differences between the mean of exact stochastic simulations and the prediction of the corresponding deterministic system. The differences are independent of the number of molecules of each species in the system under consideration. These reaction networks are open systems of chemical reactions with no zero-order reaction rates. They are characterized by at least two stationary points, one of which is a nonzero stable point, and one unstable trivial solution (stability based on a linear stability analysis of the deterministic system). Starting from a nonzero initial condition, the deterministic system never reaches the zero stationary point due to its unstable nature. In contrast, the result presented here proves that this zero-state is a stable stationary state for the discrete stochastic system, and other finite states have zero probability of existence at large times. This result generalizes previous theoretical studies and simulations of specific systems and provides a theoretical basis for analyzing a class of systems that exhibit such inconsistent behavior. This result has implications in the simulation of infection, apoptosis, and population kinetics, as it can be shown that for certain models the stochastic simulations will always yield different predictions for the mean behavior than the deterministic simulations.
MeSH term(s)	Algorithms ; Computer Simulation ; Kinetics ; Models, Biological ; Models, Chemical ; Models, Statistical ; Probability ; Stochastic Processes
Language	English
Publishing date	2009-10
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	184905-0
ISSN	1522-9602 ; 0007-4985 ; 0092-8240
ISSN (online)	1522-9602
ISSN	0007-4985 ; 0092-8240
DOI	10.1007/s11538-009-9415-9
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Article ; Online: Analysis of miRNA regulation suggests an explanation for 'unexpected' increase in target protein levels.

Gokhale, Sucheta A / Gadgil, Chetan J

Molecular bioSystems

2012 Volume 8, Issue 3, Page(s) 760–765

Abstract: MicroRNA (miRNA) has been mostly associated with decrease in target protein expression levels. Recently, 'unexpected' observations of increase in target protein expression attributed to microRNA regulation have been reported. We formulate a comprehensive ...

Abstract	MicroRNA (miRNA) has been mostly associated with decrease in target protein expression levels. Recently, 'unexpected' observations of increase in target protein expression attributed to microRNA regulation have been reported. We formulate a comprehensive model for regulation by miRNA that includes both reversible mRNA-miRNA binding and selective return of RNA. We use this mathematical model incorporating multiple individual steps in the regulation process to study the simultaneous effects of these steps on the target protein level. We show that four dimensionless numbers obtained from 12 rate constants are sufficient to define the relative change in steady state target protein levels. We quantify the range of these numbers for which such pleiotropic increase in protein levels is possible, and interpret the experimental findings in the framework of our model such that the results are no longer unexpected. Finally, we show through stochastic simulation that the nature of the target protein distribution remains unchanged and the relative steady state noise levels are also completely defined by the values of these dimensionless numbers, irrespective of the individual reaction rate constants.
MeSH term(s)	Algorithms ; Binding Sites ; MicroRNAs/metabolism ; Proteins/genetics ; Proteins/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
Chemical Substances	MicroRNAs ; Proteins ; RNA, Messenger
Language	English
Publishing date	2012-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2188635-0
ISSN	1742-2051 ; 1742-206X
ISSN (online)	1742-2051
ISSN	1742-206X
DOI	10.1039/c1mb05368j
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