Bile, the central metabolic product of the liver, is secreted by hepatocytes into bile canaliculi (BC), tubular subcellular structures of 0.5-2 $mu$m diameter which are formed by the apical membranes of juxtaposed hepatocytes. BC interconnect to buil
d a highly ramified 3D network that collects and transports bile towards larger interlobular bile ducts (IBD). The transport mechanism of bile is of fundamental interest and the current text-book model of osmotic canalicular bile flow, i.e. enforced by osmotic water influx, has recently been quantitatively verified based on flux measurements and BC contractility (Meyer et al., 2017) but challenged in the article entitled Intravital dynamic and correlative imaging reveals diffusion-dominated canalicular and flow-augmented ductular bile flux (Vartak et al., 2020). We feel compelled to share a series of arguments that question the key conclusions of this study (Vartak et al., 2020), particularly because it risks to be misinterpreted and misleading for the field in view of potential clinical applications. We summarized the arguments in the following 8 points.
Endocytosis underlies many cellular functions including signaling and nutrient uptake. The endocytosed cargo gets redistributed across a dynamic network of endosomes undergoing fusion and fission. Here, a theoretical approach is reviewed which can ex
plain how the microscopic properties of endosome interactions cause the emergent macroscopic properties of cargo trafficking in the endosomal network. Predictions by the theory have been tested experimentally and include the inference of dependencies and parameter values of the microscopic processes. This theory could also be used to infer mechanisms of signal-trafficking crosstalk. It is applicable to in vivo systems since fixed samples at few time points suffice as input data.
Anaerobic glycolysis in yeast perturbed by the reduction of xenobiotic ketones is studied numerically in two models which possess the same topology but different levels of complexity. By comparing both models predictions for concentrations and fluxes
as well as steady or oscillatory temporal behavior we answer the question what phenomena require what kind of minimum model abstraction. While mean concentrations and fluxes are predicted in agreement by both models we observe different domains of oscillatory behavior in parameter space. Generic properties of the glycolytic response to ketones are discussed.
Spiral and antispiral waves are studied numerically in two examples of oscillatory reaction-diffusion media and analytically in the corresponding complex Ginzburg-Landau equation (CGLE). We argue that both these structures are sources of waves in osc
illatory media, which are distinguished only by the sign of the phase velocity of the emitted waves. Using known analytical results in the CGLE, we obtain a criterion for the CGLE coefficients that predicts whether antispirals or spirals will occur in the corresponding reaction-diffusion systems. We apply this criterion to the FitzHugh-Nagumo and Brusselator models by deriving the CGLE near the Hopf bifurcations of the respective equations. Numerical simulations of the full reaction-diffusion equations confirm the validity of our simple criterion near the onset of oscillations. They also reveal that antispirals often occur near the onset and turn into spirals further away from it. The transition from antispirals to spirals is characterized by a divergence in the wavelength. A tentative interpretaion of recent experimental observations of antispiral waves in the Belousov-Zhabotinsky reaction in a microemulsion is given.
We study a recent model for calcium signal transduction. This model displays spiking, bursting and chaotic oscillations in accordance with experimental results. We calculate bifurcation diagrams and study the bursting behaviour in detail. This behavi
our is classified according to the dynamics of separated slow and fast subsystems. It is shown to be of the Fold-Hopf type, a type which was previously only described in the context of neuronal systems, but not in the context of signal transduction in the cell.
Nonlinear waves emitted from a moving source are studied. A meandering spiral in a reaction-diffusion medium provides an example, where waves originate from a source exhibiting a back-and-forth movement in radial direction. The periodic motion of the
source induces a Doppler effect that causes a modulation in wavelength and amplitude of the waves (``superspiral). Using the complex Ginzburg-Landau equation, we show that waves subject to a convective Eckhaus instability can exhibit monotonous growth or decay as well as saturation of these modulations away from the source depending on the perturbation frequency. Our findings allow a consistent interpretation of recent experimental observations concerning superspirals and their decay to spatio-temporal chaos.
We study a model for a thin liquid film dewetting from a periodic heterogeneous substrate (template). The amplitude and periodicity of a striped template heterogeneity necessary to obtain a stable periodic stripe pattern, i.e. pinning, are computed.
This requires a stabilization of the longitudinal and transversal modes driving the typical coarsening dynamics during dewetting of a thin film on a homogeneous substrate. If the heterogeneity has a larger spatial period than the critical dewetting mode, weak heterogeneities are sufficient for pinning. A large region of coexistence between coarsening dynamics and pinning is found.
We analyze the Eckhaus instability of plane waves in the one-dimensional complex Ginzburg-Landau equation (CGLE) and describe the nonlinear effects arising in the Eckhaus unstable regime. Modulated amplitude waves (MAWs) are quasi-periodic solutions
of the CGLE that emerge near the Eckhaus instability of plane waves and cease to exist due to saddle-node bifurcations (SN). These MAWs can be characterized by their average phase gradient $ u$ and by the spatial period P of the periodic amplitude modulation. A numerical bifurcation analysis reveals the existence and stability properties of MAWs with arbitrary $ u$ and P. MAWs are found to be stable for large enough $ u$ and intermediate values of P. For different parameter values they are unstable to splitting and attractive interaction between subsequent extrema of the amplitude. Defects form from perturbed plane waves for parameter values above the SN of the corresponding MAWs. The break-down of phase chaos with average phase gradient $ u$ > 0 (``wound-up phase chaos) is thus related to these SNs. A lower bound for the break-down of wound-up phase chaos is given by the necessary presence of SNs and an upper bound by the absence of the splitting instability of MAWs.
The transition from phase chaos to defect chaos in the complex Ginzburg-Landau equation (CGLE) is related to saddle-node bifurcations of modulated amplitude waves (MAWs). First, the spatial period P of MAWs is shown to be limited by a maximum P_SN wh
ich depends on the CGLE coefficients; MAW-like structures with period larger than P_SN evolve to defects. Second, slowly evolving near-MAWs with average phase gradients $ u approx 0$ and various periods occur naturally in phase chaotic states of the CGLE. As a measure for these periods, we study the distributions of spacings p between neighboring peaks of the phase gradient. A systematic comparison of p and P_SN as a function of coefficients of the CGLE shows that defects are generated at locations where p becomes larger than P_SN. In other words, MAWs with period P_SN represent ``critical nuclei for the formation of defects in phase chaos and may trigger the transition to defect chaos. Since rare events where p becomes sufficiently large to lead to defect formation may only occur after a long transient, the coefficients where the transition to defect chaos seems to occur depend on system size and integration time. We conjecture that in the regime where the maximum period P_SN has diverged, phase chaos persists in the thermodynamic limit.
The mechanism for transitions from phase to defect chaos in the one-dimensional complex Ginzburg-Landau equation (CGLE) is presented. We introduce and describe periodic coherent structures of the CGLE, called Modulated Amplitude Waves (MAWs). MAWs of
various period P occur naturally in phase chaotic states. A bifurcation study of the MAWs reveals that for sufficiently large period P, pairs of MAWs cease to exist via a saddle-node bifurcation. For periods beyond this bifurcation, incoherent near-MAW structures occur which evolve toward defects. This leads to our main result: the transition from phase to defect chaos takes place when the periods of MAWs in phase chaos are driven beyond their saddle-node bifurcation.
