758 research outputs found

    Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

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    Increasing evidence highlights that senescence plays an important role in idiopathic pulmonary fibrosis (IPF). This study delineates the specific contribution of mitochondria and the superoxide they form to the senescent phenotype of lung fibroblasts from IPF patients (IPF-LFs). Primary cultures of IPF-LFs exhibited an intensified DNA damage response (DDR) and were more senescent than age-matched fibroblasts from control donors (Ctrl-LFs). Furthermore, IPF-LFs exhibited mitochondrial dysfunction, exemplified by increases in mitochondrial superoxide, DNA, stress and activation of mTORC1. The DNA damaging agent etoposide elicited a DDR and augmented senescence in Ctrl-LFs, which were accompanied by disturbances in mitochondrial homoeostasis including heightened superoxide production. However, etoposide had no effect on IPF-LFs. Mitochondrial perturbation by rotenone involving sharp increases in superoxide production also evoked a DDR and senescence in Ctrl-LFs, but not IPF-LFs. Inhibition of mTORC1, antioxidant treatment and a mitochondrial targeting antioxidant decelerated IPF-LF senescence and/or attenuated pharmacologically induced Ctrl-LF senescence. In conclusion, increased superoxide production by dysfunctional mitochondria reinforces lung fibroblast senescence via prolongation of the DDR. As part of an auto-amplifying loop, mTORC1 is activated, altering mitochondrial homoeostasis and increasing superoxide production. Deeper understanding the mechanisms by which mitochondria contribute to fibroblast senescence in IPF has potentially important therapeutic implications

    Resonances in the dynamics of ϕ4\phi^4 kinks perturbed by ac forces

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    We study the dynamics of ϕ4\phi^4 kinks perturbed by an ac force, both with and without damping. We address this issue by using a collective coordinate theory, which allows us to reduce the problem to the dynamics of the kink center and width. We carry out a careful analysis of the corresponding ordinary differential equations, of Mathieu type in the undamped case, finding and characterizing the resonant frequencies and the regions of existence of resonant solutions. We verify the accuracy of our predictions by numerical simulation of the full partial differential equation, showing that the collective coordinate prediction is very accurate. Numerical simulations for the damped case establish that the strongest resonance is the one at half the frequency of the internal mode of the kink. In the conclusion we discuss on the possible relevance of our results for other systems, especially the sine-Gordon equation. We also obtain additional results regarding the equivalence between different collective coordinate methods applied to this problem.Comment: 23 pages, 7 figures, REVTeX, accepted for publication in Phys. Rev.
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