Analysis and Control of Cellular Ensembles

Karsten Kuritz

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Karsten Kuritz, Analysis and Control of Cellular Ensembles (2020), Logos Verlag, Berlin, ISBN: 9783832586263

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Beschreibung / Abstract

An ensemble system is a collection of nearly identical dynamical systems which admit a certain degree of heterogeneity, and which are subject to the restriction that they may only be manipulated or observed as a whole. This thesis presents analysis and control methods for cellular ensembles by considering reduced 1-dimensional dynamics of biological processes in high-dimensional single-cell data and models.

To be more specific, we address the quest for real-time analysis of biological processes within single-cell data by introducing the measure-preserving map of pseudotime into real-time, in short MAPiT. MAPiT enables the reconstruction of temporal and spatial dynamics from single-cell snapshot experiments. In addition, we propose a PDE-constrained learning algorithm which allows for efficient inference of changes in cell cycle progression from time series single-cell snapshot data. The second part of this thesis, is devoted to controlling a heterogeneous cell population, in the sense, that we aim at achieving a desired distribution of cellular oscillators on their periodic orbit. A systems theoretic approach to the ensemble control problem provides novel necessary and sufficient conditions for the control of phase distributions in terms of the Fourier coefficients of the phase response curve.

This thesis establishes a connection between the previously separate areas of single cell analysis and ensemble control. Our holistic view opens new perspectives for theoretic concepts in basic research and therapeutic strategies in precision medicine.

Inhaltsverzeichnis

  • BEGINN
  • 1 Introduction
  • 1.1 Motivation and focus
  • 1.2 Contributions and Outline
  • 2 Reconstructing temporal and spatial dynamics from single-cell pseudotime
  • 2.1 Background and problem formulation
  • 2.2 MAPiT - MAP of pseudotime into real-Time
  • 2.3 Reconstructing spheroids with MAPiT
  • 2.4 Analysing cell cycle progression with MAPiT
  • 2.5 Summary and discussion
  • 3 Cell cycle analysis with ergodic principles and age-structured population models
  • 3.1 Background and problem formulation
  • 3.2 Age-structured population models
  • 3.3 Relationship between ergodic analysis and age-structure population models
  • 3.4 Cell cycle-dependent expression of Cyclin B1
  • 3.5 Summary and discussion
  • 4 Cell cycle progression inference
  • 4.1 Background and problem formulation
  • 4.2 Cell cycle progression inference with sensitivities
  • 4.3 Evaluation with in silico data
  • 4.4 Analysis of cell cycle progression
  • 4.5 Summary and discussion
  • 5 Passivity-based ensemble control for cell cycle synchronization
  • 5.1 Background and problem formulation
  • 5.2 Theoretical foundation
  • 5.3 Ensemble control for cell cycle synchronization
  • 5.4 Computational studies
  • 5.5 Summary and discussion
  • 6 Ensemble control for cellular oscillators
  • 6.1 Background and problem formulation
  • 6.2 Ensemble control for oscillator moments
  • 6.3 Computational studies
  • 6.4 Summary and discussion
  • 7 Conclusions
  • 7.1 Summary and discussion
  • 7.2 Outlook
  • Appendices
  • A Technical background
  • A.1 Dynamical systems and control theory
  • A.2 Weakly connected oscillators
  • A.3 Fourier coefficients and circular moments
  • B Experimental protocols and data preprocessing
  • B.1 Ordering cells in pseudotime
  • B.2 Establishment of NCI-H460/geminin cell line
  • B.3 Live cell microscopy
  • B.4 Flow cytometric analysis
  • B.5 Construction of the average cell cycle trajectory
  • B.6 Estimation of constant speed and noise from cell cycle lengths
  • C Spheroid growth model
  • D Cell cycle model
  • E Technical computations and proofs
  • E.1 Speed equation
  • E.2 Derivation of ODE for j : s 7! x
  • E.3 Calculation of division rate from cell cycle length distribution
  • E.4 Proof of Lemma 6.1
  • Bibliography
  • Publications of the Author

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