Ea of the nucleus that is seen in cancer cells. Hence, it is important to know if the 15900046 oscillation pattern is modified by changes in nuclear transport. The summary shows that the change in the oscillation pattern due to changes in the nuclear transport is different from that seen in changes of the N/C ratio (Figure 4A). By changing the nuclear transport, all characterizing parameters are altered. Changes in f and A0 are positively correlated with nuclear transport (Figure 4B and C). In contrast, tfp, td, and tp are negatively correlated with increasing nuclear transport (Figure 4 D and E). We also ran simulations by changing 
inward or outward nuclear transport separately. The results show large changes in the oscillation pattern. In addition, the oscillation change is not simple but shows biphasic alterations (Figure S2). In summary, the change in the nuclear transport altered f, tfp, tp and td greatly, while the change 1326631 in A0 is not large.Localized IKK activation does not alter the oscillation patternIn the control condition, IKK is activated in all cytoplasmic compartments. However, if we changed this global spatial condition to localized IKK activation, the oscillation pattern might change. We ran simulations that kept the spatially integrated rate of IKK activation ABBV-075 unchanged but changed the locus of activation. Unexpectedly, we cannot see any change in the oscillation pattern (Figure S4). Even in the most extreme cases where IKK is activated at a single plasma-membrane compartment (Figure S4A, middle), the oscillations almost perfectly overlapped to the control conditions. Thus, the locus and distribution of IKK activation do not change the oscillation pattern in our simulation conditions.Diffusion coefficient alters the oscillation patternThe diffusion coefficient is thought to be inherent to each protein. However, its effective value will be changed by changes in the density, volume, or surface area of the mitochondria, ER, and other organelles. The diffusion coefficient shows significant effect on the oscillation pattern (Figure 5A). While f stays unchanged with D in the middle range, it is increased or decreased at lower or higher values outside this range (Figure 5B). A0 increases with increases in D until D reaches 10212 m2/s and stays almost unchanged at larger values (Figure 5C). The Thiazole Orange site parameter tfp stays almost unchanged at lower D, then increases abruptly at higher Ds (Figure 5D). Both td and tp become larger with increasing D (Figure 5E). Thus, larger values of D result in prolonged oscillation. In summary, the diffusion coefficient 
affects theCharacterizing parameter has different sensitivities to different spatial parametersSensitivity analysis is a valuable analytical method to see the effectiveness of parameter changes on the phenomenon of interest [63]. We performed sensitivity analysis at several points on N/C ratio, nuclear transport, and D (Figure 7A). Positive and negative sensitivities are shown in reddish and bluish colors, respectively, with deeper colors for larger sensitivities. The numbers shown on the right to the color bar are sensitivities calculated by Eq. 1 (see Materials and Methods). Hatched regions indicate no available data.3D Spatial Effect on Nuclear NF-kB OscillationFigure 3. The oscillation pattern is altered by the change in N/C ratios. (A) Oscillation time courses are plotted for varying N/C ratios from 2.9 to 19 with the amplitude shown in color for higher and lower in red and blue, respectivel.Ea of the nucleus that is seen in cancer cells. Hence, it is important to know if the 15900046 oscillation pattern is modified by changes in nuclear transport. The summary shows that the change in the oscillation pattern due to changes in the nuclear transport is different from that seen in changes of the N/C ratio (Figure 4A). By changing the nuclear transport, all characterizing parameters are altered. Changes in f and A0 are positively correlated with nuclear transport (Figure 4B and C). In contrast, tfp, td, and tp are negatively correlated with increasing nuclear transport (Figure 4 D and E). We also ran simulations by changing inward or outward nuclear transport separately. The results show large changes in the oscillation pattern. In addition, the oscillation change is not simple but shows biphasic alterations (Figure S2). In summary, the change in the nuclear transport altered f, tfp, tp and td greatly, while the change 1326631 in A0 is not large.Localized IKK activation does not alter the oscillation patternIn the control condition, IKK is activated in all cytoplasmic compartments. However, if we changed this global spatial condition to localized IKK activation, the oscillation pattern might change. We ran simulations that kept the spatially integrated rate of IKK activation unchanged but changed the locus of activation. Unexpectedly, we cannot see any change in the oscillation pattern (Figure S4). Even in the most extreme cases where IKK is activated at a single plasma-membrane compartment (Figure S4A, middle), the oscillations almost perfectly overlapped to the control conditions. Thus, the locus and distribution of IKK activation do not change the oscillation pattern in our simulation conditions.Diffusion coefficient alters the oscillation patternThe diffusion coefficient is thought to be inherent to each protein. However, its effective value will be changed by changes in the density, volume, or surface area of the mitochondria, ER, and other organelles. The diffusion coefficient shows significant effect on the oscillation pattern (Figure 5A). While f stays unchanged with D in the middle range, it is increased or decreased at lower or higher values outside this range (Figure 5B). A0 increases with increases in D until D reaches 10212 m2/s and stays almost unchanged at larger values (Figure 5C). The parameter tfp stays almost unchanged at lower D, then increases abruptly at higher Ds (Figure 5D). Both td and tp become larger with increasing D (Figure 5E). Thus, larger values of D result in prolonged oscillation. In summary, the diffusion coefficient affects theCharacterizing parameter has different sensitivities to different spatial parametersSensitivity analysis is a valuable analytical method to see the effectiveness of parameter changes on the phenomenon of interest [63]. We performed sensitivity analysis at several points on N/C ratio, nuclear transport, and D (Figure 7A). Positive and negative sensitivities are shown in reddish and bluish colors, respectively, with deeper colors for larger sensitivities. The numbers shown on the right to the color bar are sensitivities calculated by Eq. 1 (see Materials and Methods). Hatched regions indicate no available data.3D Spatial Effect on Nuclear NF-kB OscillationFigure 3. The oscillation pattern is altered by the change in N/C ratios. (A) Oscillation time courses are plotted for varying N/C ratios from 2.9 to 19 with the amplitude shown in color for higher and lower in red and blue, respectivel.
