Lipid-driven interleaflet coupling of plasma membrane order regulates FcεRI signaling in mast cells.

Interleaflet coupling-the influence of one leaflet on the properties of the opposing leaflet-is a fundamental plasma membrane organizational principle. This coupling is proposed to participate in maintaining steady-state biophysical properties of the plasma membrane, which in turn regulates some transmembrane signaling processes. A prominent example is antigen (Ag) stimulation of signaling by clustering transmembrane receptors for immunoglobulin E (IgE), FcεRI. This transmembrane signaling depends on the stabilization of ordered regions in the inner leaflet for sorting of intracellular signaling components. The resting inner leaflet has a lipid composition that is generally less ordered than the outer leaflet and that does not spontaneously phase separate in model membranes. We propose that interleaflet coupling can mediate ordering and disordering of the inner leaflet, which is poised in resting cells to reorganize upon stimulation. To test this in live cells, we first established a straightforward approach to evaluate induced changes in membrane order by measuring inner leaflet diffusion of lipid probes by imaging fluorescence correlation spectroscopy, by imaging fluorescence correlation spectroscopy (ImFCS), before and after methyl-α-cyclodexrin (mαCD)-catalyzed exchange of outer leaflet lipids (LEX) with exogenous order- or disorder-promoting phospholipids. We examined the functional impact of LEX by monitoring two Ag-stimulated responses: recruitment of cytoplasmic Syk kinase to the inner leaflet and exocytosis of secretory granules (degranulation). Based on the ImFCS data in resting cells, we observed global increase or decrease of inner leaflet order when outer leaflet is exchanged with order- or disorder-promoting lipids, respectively. We find that the degree of both stimulated Syk recruitment and degranulation correlates positively with LEX-mediated changes of inner leaflet order in resting cells. Overall, our results show that resting-state lipid ordering of the outer leaflet influences the ordering of the inner leaflet, likely via interleaflet coupling. This imposed lipid reorganization modulates transmembrane signaling stimulated by Ag clustering of IgE-FcεRI.

Frequency spectrum of chemical fluctuation: A probe of reaction mechanism and dynamics.

Even in the steady-state, the number of biomolecules in living cells fluctuates dynamically, and the frequency spectrum of this chemical fluctuation carries valuable information about the dynamics of the reactions creating these biomolecules. Recent advances in single-cell techniques enable direct monitoring of the time-traces of the protein number in each cell; however, it is not yet clear how the stochastic dynamics of these time-traces is related to the reaction mechanism and dynamics. Here, we derive a rigorous relation between the frequency-spectrum of the product number fluctuation and the reaction mechanism and dynamics, starting from a generalized master equation. This relation enables us to analyze the time-traces of the protein number and extract information about dynamics of mRNA number and transcriptional regulation, which cannot be directly observed by current experimental techniques. We demonstrate our frequency spectrum analysis of protein number fluctuation, using the gene network model of luciferase expression under the control of the Bmal 1a promoter in mouse fibroblast cells. We also discuss how the dynamic heterogeneity of transcription and translation rates affects the frequency-spectra of the mRNA and protein number.

Super-Gaussian, superdiffusive transport of multimode active matter.

Living matter often exhibits multimode transport that switches between an active, self-propelled motion and a seemingly passive, random motion. Here, we investigate an exactly solvable model of multimode active matter, such as living cells and motor proteins, which alternatingly undergoes active and passive motion. Our model study shows that the reversible transition between a passive mode and an active mode causes super-Gaussian transport dynamics, observed in various experiments. We find the non-Gaussian character of the matter's displacement distribution is essentially determined by the population ratio between active and passive motion. Interestingly, under a certain population ratio of the active and passive modes, the displacement distribution changes from sub-Gaussian to super-Gaussian as time increases. The mean-square displacement of our model exhibits transient superdiffusive dynamics, yet recovers diffusive behavior at both the short- and long-time limits. We finally generalize our model to encompass complex, multimode active matter in an arbitrary spatial dimension.

The Chemical Fluctuation Theorem governing gene expression.

Gene expression is a complex stochastic process composed of numerous enzymatic reactions with rates coupled to hidden cell-state variables. Despite advances in single-cell technologies, the lack of a theory accurately describing the gene expression process has restricted a robust, quantitative understanding of gene expression variability among cells. Here we present the Chemical Fluctuation Theorem (CFT), providing an accurate relationship between the environment-coupled chemical dynamics of gene expression and gene expression variability. Combined with a general, accurate model of environment-coupled transcription processes, the CFT provides a unified explanation of mRNA variability for various experimental systems. From this analysis, we construct a quantitative model of transcription dynamics enabling analytic predictions for the dependence of mRNA noise on the mRNA lifetime distribution, confirmed against stochastic simulation. This work suggests promising new directions for quantitative investigation into cellular control over biological functions by making complex dynamics of intracellular reactions accessible to rigorous mathematical deductions.

Exchange symmetry, fluctuation-compressibility relation, and thermodynamic potentials of quantum liquids.

Liquid helium does not obey the Gibbs fluctuation-compressibility relation, which was noted more than six decades ago. However, still missing is a clear explanation of the reason for the deviation or the correct fluctuation-compressibility relation for the quantum liquid. Here we present the fluctuation-compressibility relation valid for any grand canonical system. Our result shows that the deviation from the Gibbs formula arises from a nonextensive part of thermodynamic potentials. The particle-exchange symmetry of many-body wave function of a strongly degenerate quantum gas is related to the thermodynamic extensivity of the system; a Bose gas does not always obey the Gibbs formula, while a Fermi gas does. Our fluctuation-compressibility relation works for classical systems as well as quantum systems. This work demonstrates that the application range of the Gibbs-Boltzmann statistical thermodynamics can be extended to encompass nonextensive open systems without introducing any postulate other than the principle of equal a priori probability.