Herein we describe new frontiers in mathematical modeling and statistical analysis of oscillatory biomedical signals, motivated by our recent studies of network formation in the human brain during the early stages of life and studies forty years ago on cardiorespiratory patterns during sleep in infants and animal models. The frontiers involve new nonlinear-type time-frequency analysis of signals with multiple oscillatory components, and efficient particle filters for joint state and parameter estimators together with uncertainty quantification in hidden Markov models and empirical Bayes inference.

The stochasticity of gene expression is manifested in the fluctuations of mRNA and protein copy numbers within a cell lineage over time. While data of this type can be obtained for many generations, most mathematical models are unsuitable to interpret such data since they assume non-growing cells. Here we develop a theoretical approach that quantitatively links the frequency content of lineage data to subcellular dynamics. We elucidate how the position, height, and width of the peaks in the power spectrum provide a distinctive fingerprint that encodes a wealth of information about mechanisms controlling transcription, translation, replication, degradation, bursting, promoter switching, cell cycle duration, cell division, gene dosage compensation, and cell size homeostasis. Predictions are confirmed by analysis of single-cell Escherichia coli data obtained using fluorescence microscopy. Furthermore, by matching the experimental and theoretical power spectra, we infer the temperature-dependent gene expression parameters, without the need of measurements relating fluorescence intensities to molecule numbers.

Spontaneous emergence of cell polarity intrinsically lies at the localization of signaling molecules on a particular region of cell membrane. Such a process necessarily contains a positive feedback loop to amplify the localized cluster. To describe the polarizing process and explore different feedback functions involved, deterministic and stochastic models with non-local kinetics are discussed in this paper. Stochastic Simulation Algorithm (SSA) is used to numerically simulate the polarizing behavior and analytical analysis by the power spectrum is applied to approximate the parameter regime for the spontaneous emergence of cell polarity. Compared to the results from the deterministic model, we can understand how the stochastic effect extends the parameter regime for achieving cell polarization under different types of feedback, including the forms of quadratic function, linear function, and Hill function. Both deterministic and stochastic methods fail to yield the polarity at a low number of molecules. Our results suggest that the parameter region for cell polarization under the Hill function feedback is smaller than that with the quadratic function feedback. ©2021

Multistep cell fate transitions with stepwise changes of transcriptional profiles are common to many developmental, regenerative and pathological processes. The multiple intermediate cell lineage states can serve as differentiation checkpoints or branching points for channeling cells to more than one lineages. However, mechanisms underlying these transitions remain elusive. Here, we explored gene regulatory circuits that can generate multiple intermediate cellular states with stepwise modulations of transcription factors. With unbiased searching in the network topology space, we found a motif family containing a large set of networks can give rise to four attractors with the stepwise regulations of transcription factors, which limit the reversibility of three consecutive steps of the lineage transition. We found that there is an enrichment of these motifs in a transcriptional network controlling the early T cell development, and a mathematical model based on this network recapitulates multistep transitions in the early T cell lineage commitment. By calculating the energy landscape and minimum action paths for the T cell model, we quantified the stochastic dynamics of the critical factors in response to the differentiation signal with fluctuations. These results are in good agreement with experimental observations and they suggest the stable characteristics of the intermediate states in the T cell differentiation. These dynamical features may help to direct the cells to correct lineages during development. Our findings provide general design principles for multistep cell linage transitions and new insights into the early T cell development. The network motifs containing a large family of topologies can be useful for analyzing diverse biological systems with multistep transitions.

This study quantitatively validates the principle that the biological properties associated with a given genotype are determined by the distribution of amino acids. In order to visualize this central law of molecular biology, each protein was represented by a point in 250-dimensional space based on its amino acid distribution. Proteins from the same family are found to cluster together, leading to the principle that the convex hull surrounding protein points from the same family do not intersect with the convex hulls of other protein families. This principle was verified computationally for all available and reliable protein kinases and human proteins. In addition, we generated 2,328,761 figures to show that the convex hulls of different families were disjoint from each other. The classification performs well with high and robust accuracy (95.75% and 97.5%) together with reasonable phylogenetic trees validate our methods further.