Theoretical study on the regulation of circadian rhythms by RNA methylation

Gibo, Shingo; Kurosawa, Gen

doi:10.1016/j.jtbi.2019.110140

Cited by 6 publications

(4 citation statements)

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“…Previous research on coupled Goodwin oscillators focused in particular on the coupling of gene regulatory pathways across cells that are putatively involved in establishing a molecular circadian ”clock” (e.g., Refs. [ 36 , 49 ]). However, oscillatory signaling pathways have been identified also in other contexts.…”

Section: Discussionmentioning

confidence: 99%

“…2 and 4 have been limited to discuss oscillatory systems described by second-order and third-order differential equations. However, in general, and, in particular, in the context of the Goodwin oscillator, fourth-order differential equations [ 36 , 49 ] and higher order differential equations [ 65 ] describing oscillatory units have been used in the literature. Therefore, the current study may open a new avenue to identify the underlying, essential low-dimensional dynamics of such high-dimensional oscillatory models.…”

Section: Discussionmentioning

confidence: 99%

“…( 62 )–( 67 ) for , , , and which implies and such that the inequality ( 72 ) was satisfied like . Since the Goodwin oscillator has been frequently discussed in the context of circadian rhythmic activity on the cellular level that is autonomous (and not driven by the day–night cycle) [ 36 , 46 , 49 ], we selected the parameter k as /d, such that the model produced oscillations with a period of approximately 1 day. Finally, the following initial conditions were used: and , , .…”

Section: Further Applicationsmentioning

confidence: 99%

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Unstable eigenvectors and reduced amplitude spaces specifying limit cycles of coupled oscillators with simultaneously diagonalizable matrices: with applications from electric circuits to gene regulation

Mongkolsakulvong

Frank

2022

Eur. Phys. J. B

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A fascinating phenomenon is the self-organization of coupled systems to a whole. This phenomenon is studied for a particular class of coupled oscillatory systems exhibiting so-called simultaneously diagonalizable matrices. For three exemplary systems, namely, an electric circuit, a coupled system of oscillatory neurons, and a system of coupled oscillatory gene regulatory pathways, eigenvectors and amplitude equations are derived. It is shown that for all three systems, only the unstable eigenvectors and their amplitudes matter for the dynamics of the systems on their respective limit cycle attractors. A general class of coupled second-order dynamical oscillators is presented in which stable limit cycles emerging via Hopf bifurcations are solely specified by appropriately defined unstable eigenvectors and their amplitudes. While the eigenvectors determine the orientation of limit cycles in state spaces, the amplitudes determine the evolution of states along those limit cycles. In doing so, it is shown that the unstable eigenvectors define reduced amplitude spaces in which the relevant long-term dynamics of the systems under consideration takes place. Several generalizations are discussed. First, if stable and unstable system parts exhibit a slow-fast dynamics, the fast variables may be eliminated and approximative descriptions of the emerging limit cycle dynamics in reduced amplitude spaces may be again obtained. Second, the principle of reduced amplitude spaces holds not only for coupled second-order oscillators, but can be applied to coupled third-order and higher order oscillators. Third, the possibility to apply the approach to multifrequency limit cycle attractors and other types of attractors is discussed. Graphic abstract

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Further Applicationsmentioning

confidence: 99%

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Unstable eigenvectors and reduced amplitude spaces specifying limit cycles of coupled oscillators with simultaneously diagonalizable matrices: with applications from electric circuits to gene regulation

Mongkolsakulvong

Frank

2022

Eur. Phys. J. B

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“…GHA was conducted as previously described for the studies of music and circadian rhythms (Terada et al, 1994) (Gibo & Kurosawa, 2020). GHA is a method in signal processing to quantify periodic components within a certain frequency range, so-called "dominant period" by estimating the most fitted summation of trigonometric functions for given time series (Terada et al, 1994).…”

Section: Quantification Of Body Temperature Fluctuationmentioning

confidence: 99%

Op0011 highly Differentiated Cd4 and Cd8 T Effector Memory Cells Re-Expressing Cd45ra (Temra) Are Associated With Active Disease Refractory to Anti-TNF Therapy in Rheumatoid Arthritis

et al. 2022

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BackgroundHighly differentiated T cells have been reported to be enriched in rheumatoid arthritis (RA) compared to healthy individuals1. The role of terminally differentiated T effector memory re-expressing CD45RA (Temra) in RA pathogenesis and disease activity is still unclear, including whether they can be used as a marker of sustained disease activity in RA patients receiving anti-TNF therapy.ObjectivesTo investigate whether the frequency of peripheral blood Temra can be used as a biomarker to identify disease refractory to anti-TNF therapy in RA, if they correlate with inflammation in anti-TNF treated patients, and whether they associate with a flare following tapering anti-TNF.MethodsRA patients on anti-TNF therapy were recruited from rheumatology clinic (cross-sectional cohort). Clinical data and whole blood were collected. Patients were stratified based on disease activity. Remission was defined as no recorded DAS28-CRP≥2.4, no swollen joints, no C-reactive protein (CRP) of >5mg/L, and on a stable DMARD dose and no reported disease flare/loss of remission in the 6 months prior. Non-remission was defined as any other disease activity which does not fulfil the remission definition. Patients on abatacept, or methotrexate monotherapy and healthy volunteers were recruited as comparison groups. A separate cohort of anti-TNF patients (longitudinal cohort) who have been in remission on a stable dose of anti-TNF for ≥6 months and no use of corticosteroids in the last 6 months, was also recruited. Whole blood was obtained prior to dose tapering (dose halving) and at the point of a flare. Whole blood was processed by gradient centrifugation to obtain peripheral blood mononuclear cells (PBMC). PBMC were stained with fluorochrome-conjugated antibodies for multi-parameter flow cytometry. Analysis was performed on live lymphocytes using FlowJo software version 10.8. Two-tailed Mann-Whitney U test or unpaired t-test were used to obtain unadjusted values, analysis of variance (ANOVA) of log-transformed data was used to obtain age-adjusted values, Spearman’s rank correlation was used to compare correlation between Temra and CRP.ResultsRA patients (36 anti-TNF, 12 abatacept, 16 methotrexate monotherapy) and 14 healthy individuals were recruited. There was a higher proportion of CD4 (age-adjusted p = 0.004) and CD8 Temra (age-adjusted p = 0.0007) in RA patients on anti-TNF with persistent disease activity compared to those who had achieved remission. These differences were confirmed when analysing absolute numbers of CD4 and CD8 Temra. Unexpectedly, the difference in Temra frequency between remission and non-remission RA was not observed in patients treated with methotrexate or abatacept. The median CD4 and CD8 Temra frequencies in RA patients in remission with all treatments studied were similar to healthy individuals.Temra were not observed to increase with age in the anti-TNF, abatacept, or methotrexate cohorts in contrast to previous reports in healthy individuals2. The frequency of CD4 and CD8 Temra correlated with CRP only in patients on anti-TNF (CD4 Temra Spearman r = 0.5185, p = 0.001, and CD8 Temra Spearman r = 0.5040, p = 0.005).There was an increase in CD4 (p = 0.003) but not CD8 Temra at 3 months in patients who flared on tapering anti-TNF compared to those who remained in remission (Figure 1).ConclusionIncreased CD4 and CD8 Temra frequency were associated with persistent disease activity in anti-TNF treated patients but not with other DMARD therapies (abatacept and methotrexate). CD4 Temra increased in those who flared on tapering anti-TNF. These results suggest that Temra may play a role in driving persistent disease activity refractory to anti-TNF therapy rather than merely a marker of inflammation.References[1]Weyand CM, Yang Z, Goronzy JJ. T-cell aging in rheumatoid arthritis. Curr Opin Rheumatol. 2014;26(1):93-100.[2]Callender LA, Carroll EC, Bober EA, et al. Mitochondrial mass governs the extent of human T cell senescence. Aging Cell. 2020;19(2):e13067.AcknowledgementsSAY is funded by research grants by Versus Arthritis, Royal College of Physicians/Rosetrees Trust, NIHR University College London Hospitals Biomedical Research Centre and UCLH Charities.Disclosure of InterestsSu-Ann Yeoh: None declared, James Kimpton: None declared, Muhammad Shipa: None declared, Eleanor Hawkins: None declared, Arne Akbar Grant/research support from: AA has received funding from the Leo Skin Foundation (Denmark), Michael Ehrenstein Consultant of: MRE has received consultancy fees from Galapagos and Sanofi., Grant/research support from: MRE has received financial grants from GlaxoSmithKline.

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Frequency-modulated timer regulates torpor–arousal cycles during hibernation in distinct small mammalian hibernators

Gibo,

Yamaguchi,

Gracheva

et al. 2024

npj Biol Timing Sleep

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Hibernation allows mammals to endure harsh seasons by reducing their basal metabolism and body temperature (Tb) to minimize energy expenditure. During hibernation in small animals such as Syrian hamsters and 13-lined ground squirrels, Tb decreases to an ambient level ( < 5 °C) and remains constant for days to weeks in a physiological condition termed deep torpor. Torpor is interrupted by periods of arousal, during which Tb recovers to a euthermic level (approximately 37 °C), and these torpor–arousal cycles are repeated multiple times during hibernation. However, little is known about the mechanisms governing Tb fluctuations during hibernation. In this study, we employed an unbiased model selection approach to Tb data and revealed that a model incorporating frequency modulation quantitatively reproduced Tb fluctuation during hibernation in Syrian hamsters. We found that an unexpectedly long period of 120–430 days modulates a shorter period of several days. In addition, the aforementioned model reproduced Tb fluctuation in 13-lined ground squirrels, which can undergo repeated hibernation according to intrinsic circannual rhythms in constant laboratory conditions. This is the first quantitative study to demonstrate the concerted action of two endogenous periods, one lasting a few days and the other lasting a year, in the torpor–arousal cycles of distinct mammalian hibernators. We anticipate that our theoretical analysis of Tb fluctuation will be a starting point for quantitative comparisons of hibernation patterns across various hibernating species. Furthermore, quantification of Tb data using models will foster our understanding of the molecular mechanisms of hibernation by revealing the biological processes operating within these periods.

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Theoretical study on the regulation of circadian rhythms by RNA methylation

Cited by 6 publications

References 36 publications

Unstable eigenvectors and reduced amplitude spaces specifying limit cycles of coupled oscillators with simultaneously diagonalizable matrices: with applications from electric circuits to gene regulation

Unstable eigenvectors and reduced amplitude spaces specifying limit cycles of coupled oscillators with simultaneously diagonalizable matrices: with applications from electric circuits to gene regulation

Op0011 highly Differentiated Cd4 and Cd8 T Effector Memory Cells Re-Expressing Cd45ra (Temra) Are Associated With Active Disease Refractory to Anti-TNF Therapy in Rheumatoid Arthritis

Frequency-modulated timer regulates torpor–arousal cycles during hibernation in distinct small mammalian hibernators

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