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Is Aggregate-Dependent Yeast Aging Fortuitous

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1 Is Aggregate-Dependent Yeast Aging Fortuitous
Is Aggregate-Dependent Yeast Aging Fortuitous? A Model of Damage Segregation and Aggregate Dynamics  Martín Andrade-Restrepo  Biophysical Journal  Volume 113, Issue 11, Pages (December 2017) DOI: /j.bpj Copyright © 2017 Biophysical Society Terms and Conditions

2 Figure 1 The passive-only model. (A and B) Schematic representations of the model’s short-term and long-term components. (C and D) Snapshot of the model’s single-division cycle simulation. (E) Example of a crossing of the neck. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2017 Biophysical Society Terms and Conditions

3 Figure 2 MSD of aggregates in the passive-only model. (A and B) Log-log plot of the MSD of one aggregate (top) and the volume of the same aggregate for which the MSD was computed (bottom). (Dashed lines) Shown here is the unconstrained MSD of an aggregate of radius ria (top) and to the volume of one aggregate with initial radius ria in the absence of fusion events (bottom). (C) Same as Fig. 2 A. (D) Same as Fig. 2 C for different rates of appearance and growth of aggregates. (E) Log-log plot of the MSD of a particle in 2D undergoing unconstrained diffusion 〈r2(t)〉u, diffusion inside an empty cell 〈r2(t)〉d, or diffusion inside a cell with a vacuole 〈r2(t)〉a. In all three cases, D = 1 × 10−3. In (A) to (C), N = 5, δt = 0.1 s, τm = 12 min, and τd = 120 min. In (D), N = 1 and δt = 0.25 s; all other parameters were set to the values in Table S1. Results were averaged over 1024 realizations. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2017 Biophysical Society Terms and Conditions

4 Figure 3 Aggregate kinetics from the short-term component of the passive-only model. (A–C) Total aggregate volume, fraction of the total aggregate volume, and number of aggregates inside the mother (dark shaded) and the daughter cell (light shaded). (Continuous line) Shown here is the analytical prediction when numerically integrating Eq. S2 in the Supporting Material. (Dotted line) Numerical average from the stochastic simulations of the short-term component of the model. (D and E) Same as (B) and (C) for different rates of appearance and growth of aggregates. (A–C) N = 5, δt = 0.1 s, τm = 12 min, and τd = 120 min. In (D) and (E), N = 1 and δt = 0.25 s; all other parameters were set to the values in Table S1. Results were averaged over 1024 realizations. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2017 Biophysical Society Terms and Conditions

5 Figure 4 Differences between the outputs of the passive-only model and experimental observations. (A) Histogram of the total number of cross-compartment crossing events from mother to bud (M > B) and from bud to mother (B > M). (A) (Inset) Fraction of total cross-compartment events in each direction. (B) Average number of crossing events M > B (line) and B > M (dashed line) after a cell division cycle as a function of the parameter τm. (C) Logarithm of the diffusion rate of an aggregate with radius ria (top), number of crossing events from mother to daughter (middle), and from daughter to mother (bottom) for different values of β and γ after a cell division cycle. In (A), N = 5, δt = 0.1 s, τm = 12 min, and τd = 120 min. In (B) and (C), N = 1, δt = 0.25 s, and τm = 12 min; in (C), τd = 120 min; all other parameters were set to the values in Table S1. Results were averaged over 1024 realizations. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2017 Biophysical Society Terms and Conditions

6 Figure 5 Long-term dynamics of the model. (A–D) Number of aggregates and total aggregate volume inside the mother cell (top) and inside the daughter cell (bottom) at the end of the cell division. (E) Fraction of total aggregate volume inside the daughter cell at the end of cell division. Error bars correspond to the SE. In all simulations, δt = 0.5 s; all other parameters were set to the values in Table S1. Results were averaged over 1024 realizations. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2017 Biophysical Society Terms and Conditions

7 Figure 6 Long-term aggregate dynamics. (A) Total aggregate volume inside the mother cell at the end of the 28th division. (Inset) Same as in (A), but in log-log scale. (B–D) Number of crossing events from mother to bud (continuous line) and from bud to mother (dotted line); probability of inheritance of at least one aggregate by the daughter cell at the end of cell division (C); and probability of inheritance of the largest aggregate by the daughter cell, if it exists (D), as a function of the mother’s age (in generations) for different rates of appearance and growth of aggregates. Error bars correspond to the SE. In all simulations, δt = 0.5; all other parameters were set to the values in Table S1. Results were averaged over 1024 realizations. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2017 Biophysical Society Terms and Conditions

8 Figure 7 Short-term results from the AQC variants of the passive-only model. (A) Log-log plot for the MSD of an aggregate (top) and the volume of the same aggregate for which the MSD was computed (bottom). (Dashed light lines) Given here is the unconstrained MSD of an aggregate of radius ria (top) and of the volume of one aggregate with initial radius ria in the absence of fusion events. (B) Average number of crossing events from mother to bud (M > B) and from bud to mother (B > M). (Inset) Proportion of crossing events in both directions. N = 5 and δt = 0.1 s; all other parameters were set to the values in Table S1. Results were averaged over 1024 realizations. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2017 Biophysical Society Terms and Conditions

9 Figure 8 Long-term results from the AQC variants of the passive-only model. (A) Total aggregate volume inside the mother cell at the end of the 28th division. (B) Average number of crossing events from mother to bud (continuous line) and from bud to mother (dotted line). (C and D) Total number of aggregates and the total aggregate volume inside the mother cell (top) and inside the daughter cell (bottom). (E) Probability of inheritance of at least one aggregate by the daughter cell at the end of cell division. (F) Probability of inheritance of the largest aggregate, if it exists, by the daughter cell. Error bars correspond to the SE. In all simulations, δt = 0.5, τm = 100 min, and τd = 1000 min; all other parameters were set to the values in Table S1. Results were averaged over 1024 realizations. Biophysical Journal  , DOI: ( /j.bpj ) Copyright © 2017 Biophysical Society Terms and Conditions


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