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Eduardo D. Sontag - One of the best experts on this subject based on the ideXlab platform.
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Chemical networks with inflows and outflows: a positive linear differential inclusions approach.
Biotechnology Progress, 2009Co-Authors: David Angeli, Patrick De Leenheer, Eduardo D. SontagAbstract:Certain mass-action kinetics models of biochemical reaction networks, although described by nonlinear differential equations, may be partially viewed as state-dependent linear time-varying systems, which in turn may be modeled by convex compact valued positive linear differential inclusions. A result is provided on asymptotic stability of such inclusions, and applied to a ubiquitous biochemical reaction network with inflows and outflows, known as the Futile Cycle. We also provide a characterization of exponential stability of general homogeneous switched systems which is not only of interest in itself, but also plays a role in the analysis of the Futile Cycle.
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Singularly Perturbed Monotone Systems and an Application to Double Phosphorylation Cycles
Journal of Nonlinear Science, 2008Co-Authors: Liming Wang, Eduardo D. SontagAbstract:The theory of monotone dynamical systems has been found very useful in the modeling of some gene, protein, and signaling networks. In monotone systems, every net feedback loop is positive. On the other hand, negative feedback loops are important features of many systems, since they are required for adaptation and precision. This paper shows that, provided that these negative loops act at a comparatively fast time scale, the main dynamical property of (strongly) monotone systems, convergence to steady states, is still valid. An application is worked out to a double-phosphorylation “Futile Cycle” motif which plays a central role in eukaryotic cell signaling.
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On the number of steady states in a multiple Futile Cycle
Journal of Mathematical Biology, 2008Co-Authors: Liming Wang, Eduardo D. SontagAbstract:The multisite phosphorylation-dephosphorylation Cycle is a motif repeatedly used in cell signaling. This motif itself can generate a variety of dynamic behaviors like bistability and ultrasensitivity without direct positive feedbacks. In this paper, we study the number of positive steady states of a general multisite phosphorylation–dephosphorylation Cycle, and how the number of positive steady states varies by changing the biological parameters. We show analytically that (1) for some parameter ranges, there are at least n + 1 (if n is even) or n (if n is odd) steady states; (2) there never are more than 2 n − 1 steady states (in particular, this implies that for n = 2, including single levels of MAPK cascades, there are at most three steady states); (3) for parameters near the standard Michaelis–Menten quasi-steady state conditions, there are at most n + 1 steady states; and (4) for parameters far from the standard Michaelis–Menten quasi-steady state conditions, there is at most one steady state.
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A remark on the number of steady states in a multiple Futile Cycle
arXiv: Quantitative Methods, 2007Co-Authors: Liming Wang, Eduardo D. SontagAbstract:The multisite phosphorylation-dephosphorylation Cycle is a motif repeatedly used in cell signaling. This motif itself can generate a variety of dynamic behaviors like bistability and ultrasensitivity without direct positive feedbacks. In this paper, we study the number of positive steady states of a general multisite phosphorylation-dephosphorylation Cycle, and how the number of positive steady states varies by changing the biological parameters. We show analytically that (1) for some parameter ranges, there are at least n+1 (if n is even) or n (if n is odd) steady states; (2) there never are more than 2n-1 steady states (in particular, this implies that for n=2, including single levels of MAPK cascades, there are at most three steady states); (3) for parameters near the standard Michaelis-Menten quasi-steady state conditions, there are at most n+1 steady states; and (4) for parameters far from the standard Michaelis-Menten quasi-steady state conditions, there is at most one steady state.
Francisco Pelegri - One of the best experts on this subject based on the ideXlab platform.
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localized products of Futile Cycle lrmp promote centrosome nucleus attachment in the zebrafish zygote
Current Biology, 2012Co-Authors: Robin E Lindeman, Francisco PelegriAbstract:Summary Background The centrosome has a well-established role as a microtubule organizer during mitosis and cytokinesis. In addition, it facilitates the union of parental haploid genomes following fertilization by nucleating a microtubule aster along which the female pronucleus migrates toward the male pronucleus. Stable associations between the sperm aster and the pronuclei are essential during this directed movement. Results Our studies reveal that the zebrafish gene Futile Cycle ( fue ) is required in the zygote for male pronucleus-centrosome attachment and female pronuclear migration. We show that fue encodes a novel, maternally-provided long form of lymphoid-restricted membrane protein (lrmp ), a vertebrate-specific gene of unknown function. Both maternal lrmp messenger RNA (mRNA) and protein are highly localized in the zygote, in a largely overlapping pattern at nuclear membranes, centrosomes, and spindles. Truncated Lrmp-EGFP fusion proteins identified subcellular targeting signals in the C terminus of Lrmp; however, endogenous mRNA localization is likely important to ensure strict spatial expression of the protein. Localization of both Lrmp protein and lrmp RNA is defective in fue mutant embryos, indicating that correct targeting of lrmp gene products is dependent on Lrmp function. Conclusions Lrmp is a conserved vertebrate gene whose maternally inherited products are essential for nucleus-centrosome attachment and pronuclear congression during fertilization. Precise subcellular localization of lrmp products also suggests a requirement for strict spatiotemporal regulation of their function in the early embryo.
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Localized products of Futile Cycle/lrmp promote centrosome-nucleus attachment in the zebrafish zygote.
Current Biology, 2012Co-Authors: Robin E Lindeman, Francisco PelegriAbstract:Summary Background The centrosome has a well-established role as a microtubule organizer during mitosis and cytokinesis. In addition, it facilitates the union of parental haploid genomes following fertilization by nucleating a microtubule aster along which the female pronucleus migrates toward the male pronucleus. Stable associations between the sperm aster and the pronuclei are essential during this directed movement. Results Our studies reveal that the zebrafish gene Futile Cycle ( fue ) is required in the zygote for male pronucleus-centrosome attachment and female pronuclear migration. We show that fue encodes a novel, maternally-provided long form of lymphoid-restricted membrane protein (lrmp ), a vertebrate-specific gene of unknown function. Both maternal lrmp messenger RNA (mRNA) and protein are highly localized in the zygote, in a largely overlapping pattern at nuclear membranes, centrosomes, and spindles. Truncated Lrmp-EGFP fusion proteins identified subcellular targeting signals in the C terminus of Lrmp; however, endogenous mRNA localization is likely important to ensure strict spatial expression of the protein. Localization of both Lrmp protein and lrmp RNA is defective in fue mutant embryos, indicating that correct targeting of lrmp gene products is dependent on Lrmp function. Conclusions Lrmp is a conserved vertebrate gene whose maternally inherited products are essential for nucleus-centrosome attachment and pronuclear congression during fertilization. Precise subcellular localization of lrmp products also suggests a requirement for strict spatiotemporal regulation of their function in the early embryo.
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the maternal effect gene Futile Cycle is essential for pronuclear congression and mitotic spindle assembly in the zebrafish zygote
Development, 2003Co-Authors: Marcus P S Dekens, Francisco Pelegri, Hansmartin Maischein, Christiane NussleinvolhardAbstract:Embryos have been successfully used for the general study of the cell Cycle. Although there are significant differences between the early embryonic and the somatic cell Cycle in vertebrates, the existence of specialised factors that play a role during the early cell Cycles has remained elusive. We analysed a lethal recessive maternal-effect mutant, Futile Cycle ( fue ), isolated in a maternal-effect screen for nuclear division defects in the zebrafish ( Danio rerio ). The pronuclei fail to congress in zygotes derived from homozygous fue mothers. In addition, a defect in the formation of chromosomal microtubules prevents mitotic spindle assembly and thus chromosome segregation in fue zygotes. However, centrosomal functions do not appear to be affected in fue embryos, suggesting this mutant blocks a subset of microtubule functions. Cleavage occurs normally for several divisions resulting in many anucleate cells, thus showing that nuclear- and cell division can be uncoupled genetically. Therefore, we propose that in mitotic spindle assembly chromosome-dependent microtubule nucleation is essential for the coupling of nuclear and cell division.
Tim Stearns - One of the best experts on this subject based on the ideXlab platform.
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Centriole triplet microtubules are required for stable centriole formation and inheritance in human cells
eLife, 2017Co-Authors: Jennifer T. Wang, Jadranka Lončarek, Dong Kong, Christian R. Hoerner, Tim StearnsAbstract:Centrioles are composed of long-lived microtubules arranged in nine triplets. However, the contribution of triplet microtubules to mammalian centriole formation and stability is unknown. Little is known of the mechanism of triplet microtubule formation, but experiments in unicellular eukaryotes indicate that delta-tubulin and epsilon-tubulin, two less-studied tubulin family members, are required. Here, we report that centrioles in delta-tubulin and epsilon-tubulin null mutant human cells lack triplet microtubules and fail to undergo centriole maturation. These aberrant centrioles are formed de novo each cell Cycle, but are unstable and do not persist to the next cell Cycle, leading to a Futile Cycle of centriole formation and disintegration. Disintegration can be suppressed by paclitaxel treatment. Delta-tubulin and epsilon-tubulin physically interact, indicating that these tubulins act together to maintain triplet microtubules and that these are necessary for inheritance of centrioles from one cell Cycle to the next.
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Centriole triplet microtubules are required for stable centriole formation and inheritance in human cells
2017Co-Authors: Jennifer T. Wang, Jadranka Lončarek, Dong Kong, Christian R. Hoerner, Tim StearnsAbstract:Centrioles are composed of long-lived microtubules arranged in nine triplets. In unicellular eukaryotes, loss of the noncanonical tubulins, delta-tubulin and epsilon-tubulin, result in loss of the triplet microtubule structure. However, the contribution of triplet microtubules to mammalian centriole formation and stability is unknown. Here, we report the first characterization of delta-tubulin and epsilon-tubulin null human cells. Centrioles in cells lacking either delta-tubulin or epsilon-tubulin lack triplet microtubules and fail to undergo centriole maturation. These aberrant centrioles are formed de novo each cell Cycle, but are unstable and do not persist to the next cell Cycle, leading to a Futile Cycle of centriole formation and disintegration. Disintegration can be suppressed by paclitaxel treatment. Delta-tubulin and epsilon-tubulin physically interact, indicating that these tubulins act together to maintain triplet microtubules and that these are necessary for inheritance of centrioles from one cell Cycle to the next.
Christiane Nussleinvolhard - One of the best experts on this subject based on the ideXlab platform.
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the maternal effect gene Futile Cycle is essential for pronuclear congression and mitotic spindle assembly in the zebrafish zygote
Development, 2003Co-Authors: Marcus P S Dekens, Francisco Pelegri, Hansmartin Maischein, Christiane NussleinvolhardAbstract:Embryos have been successfully used for the general study of the cell Cycle. Although there are significant differences between the early embryonic and the somatic cell Cycle in vertebrates, the existence of specialised factors that play a role during the early cell Cycles has remained elusive. We analysed a lethal recessive maternal-effect mutant, Futile Cycle ( fue ), isolated in a maternal-effect screen for nuclear division defects in the zebrafish ( Danio rerio ). The pronuclei fail to congress in zygotes derived from homozygous fue mothers. In addition, a defect in the formation of chromosomal microtubules prevents mitotic spindle assembly and thus chromosome segregation in fue zygotes. However, centrosomal functions do not appear to be affected in fue embryos, suggesting this mutant blocks a subset of microtubule functions. Cleavage occurs normally for several divisions resulting in many anucleate cells, thus showing that nuclear- and cell division can be uncoupled genetically. Therefore, we propose that in mitotic spindle assembly chromosome-dependent microtubule nucleation is essential for the coupling of nuclear and cell division.
Liming Wang - One of the best experts on this subject based on the ideXlab platform.
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Singularly Perturbed Monotone Systems and an Application to Double Phosphorylation Cycles
Journal of Nonlinear Science, 2008Co-Authors: Liming Wang, Eduardo D. SontagAbstract:The theory of monotone dynamical systems has been found very useful in the modeling of some gene, protein, and signaling networks. In monotone systems, every net feedback loop is positive. On the other hand, negative feedback loops are important features of many systems, since they are required for adaptation and precision. This paper shows that, provided that these negative loops act at a comparatively fast time scale, the main dynamical property of (strongly) monotone systems, convergence to steady states, is still valid. An application is worked out to a double-phosphorylation “Futile Cycle” motif which plays a central role in eukaryotic cell signaling.
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On the number of steady states in a multiple Futile Cycle
Journal of Mathematical Biology, 2008Co-Authors: Liming Wang, Eduardo D. SontagAbstract:The multisite phosphorylation-dephosphorylation Cycle is a motif repeatedly used in cell signaling. This motif itself can generate a variety of dynamic behaviors like bistability and ultrasensitivity without direct positive feedbacks. In this paper, we study the number of positive steady states of a general multisite phosphorylation–dephosphorylation Cycle, and how the number of positive steady states varies by changing the biological parameters. We show analytically that (1) for some parameter ranges, there are at least n + 1 (if n is even) or n (if n is odd) steady states; (2) there never are more than 2 n − 1 steady states (in particular, this implies that for n = 2, including single levels of MAPK cascades, there are at most three steady states); (3) for parameters near the standard Michaelis–Menten quasi-steady state conditions, there are at most n + 1 steady states; and (4) for parameters far from the standard Michaelis–Menten quasi-steady state conditions, there is at most one steady state.
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A remark on the number of steady states in a multiple Futile Cycle
arXiv: Quantitative Methods, 2007Co-Authors: Liming Wang, Eduardo D. SontagAbstract:The multisite phosphorylation-dephosphorylation Cycle is a motif repeatedly used in cell signaling. This motif itself can generate a variety of dynamic behaviors like bistability and ultrasensitivity without direct positive feedbacks. In this paper, we study the number of positive steady states of a general multisite phosphorylation-dephosphorylation Cycle, and how the number of positive steady states varies by changing the biological parameters. We show analytically that (1) for some parameter ranges, there are at least n+1 (if n is even) or n (if n is odd) steady states; (2) there never are more than 2n-1 steady states (in particular, this implies that for n=2, including single levels of MAPK cascades, there are at most three steady states); (3) for parameters near the standard Michaelis-Menten quasi-steady state conditions, there are at most n+1 steady states; and (4) for parameters far from the standard Michaelis-Menten quasi-steady state conditions, there is at most one steady state.
