Strong shift equivalence, algebraic K-theory, and isolating zero-dimensional dynamics on manifolds

We study the relations of shift equivalence and strong shift equivalence for matrices over a ring $\mathcal{R}$, and establish a connection between these relations and algebraic K-theory. We utilize this connection to obtain results in two areas where the shift and strong shift equivalence relations play an important role: the study of finite group extensions of shifts of finite type, and the Generalized Spectral Conjectures of Boyle and Handelman for nonnegative matrices over subrings of the real numbers. We show the refinement of the shift equivalence class of a matrix $A$ over a ring $\mathcal{R}$ by strong shift equivalence classes over the ring is classified by a quotient $NK_{1}(\mathcal{R}) / E(A,\mathcal{R})$ of the algebraic K-group $NK_{1}(\calR)$. We use the K-theory of non-commutative localizations to show that in certain cases the subgroup $E(A,\mathcal{R})$ must vanish, including the case $A$ is invertible over $\mathcal{R}$. We use the K-theory connection to clarify the structure of algebraic invariants for finite group extensions of shifts of finite type. In particular, we give a strong negative answer to a question of Parry, who asked whether the dynamical zeta function determines up to finitely many topological conjugacy classes the extensions by $G$ of a fixed mixing shift of finite type. We apply the K-theory connection to prove the equivalence of a strong and weak form of the Generalized Spectral Conjecture of Boyle and Handelman for primitive matrices over subrings of $\mathbb{R}$. We construct explicit matrices whose class in the algebraic K-group $NK_{1}(\mathcal{R})$ is non-zero for certain rings $\mathcal{R}$ motivated by applications. We study the possible dynamics of the restriction of a homeomorphism of a compact manifold to an isolated zero-dimensional set. We prove that for $n \ge 3$ every compact zero-dimensional system can arise as an isolated invariant set for a homeomorphism of a compact $n$-manifold. In dimension two, we provide obstructions and examples.

PHYSICAL FACTORS IN B CELL ACTIN DYNAMICS AND ACTIVATION

Cells adapt to their changing world by sensing environmental cues and responding appropriately. This is made possible by complex cascades of biochemical signals that originate at the cell membrane. In the last decade it has become apparent that the origin of these signals can also arise from physical cues in the environment. Our motivation is to investigate the role of physical factors in the cellular response of the B lymphocyte. B cells patrol the body for signs of invading pathogens in the form of antigen on the surface of antigen presenting cells. Binding of antigen with surface proteins initiates biochemical signaling essential to the immune response. Once contact is made, the B cell spreads on the surface of the antigen presenting cell in order to gather as much antigen as possible. The physical mechanisms that govern this process are unexplored. In this research, we examine the role of the physical parameters of antigen mobility and cell surface topography on B cell spreading and activation. Both physical parameters are biologically relevant as immunogens for vaccine design, which can provide laterally mobile and immobile antigens and topographical surfaces. Another physical parameter that influences B cell response and the formation of the cell-cell junction is surface topography. This is biologically relevant as antigen presenting cells have highly convoluted membranes, resulting in variable topography. We found that B cell activation required the formation of antigen-receptor clusters and their translocation within the attachment plane. We showed that cells which failed to achieve these mobile clusters due to prohibited ligand mobility were much less activation competent. To investigate the effect of topography, we use nano- and micro-patterned substrates, on which B cells were allowed to spread and become activated. We found that B cell spreading, actin dynamics, B cell receptor distribution and calcium signaling are dependent on the topographical patterning of the substrate. A quantitative understanding of cellular response to physical parameters is essential to uncover the fundamental mechanisms that drive B cell activation. The results of this research are highly applicable to the field of vaccine development and therapies for autoimmune diseases. Our studies of the physical aspects of lymphocyte activation will reveal the role these factors play in immunity, thus enabling their optimization for biological function and potentially enabling the production of more effective vaccines.

Guided Migration and Collective Behavior: Cell Dynamics during Cancer Progression

This dissertation focuses on gaining understanding of cell migration and collective behavior through a combination of experiment, analysis, and modeling techniques. Cell migration is a ubiquitous process that plays an important role during embryonic development and wound healing as well as in diseases like cancer, which is a particular focus of this work. As cancer cells become increasingly malignant, they acquire the ability to migrate away from the primary tumor and spread throughout the body to form metastatic tumors. During this process, changes in gene expression and the surrounding tumor environment can lead to changes in cell migration characteristics. In this thesis, I analyze how cells are guided by the texture of their environment and how cells cooperate with their neighbors to move collectively. The emergent properties of collectively moving groups are a particular focus of this work as collective cell dynamics are known to change in diseases such as cancer. The internal machinery for cell migration involves polymerization of the actin cytoskeleton to create protrusions that---in coordination with retraction of the rear of the cell---lead to cell motion. This actin machinery has been previously shown to respond to the topography of the surrounding surface, leading to guided migration of amoeboid cells. Here we show that epithelial cells on nanoscale ridge structures also show changes in the morphology of their cytoskeletons; actin is found to align with the ridge structures. The migration of the cells is also guided preferentially along the ridge length. These ridge structures are on length scales similar to those found in tumor microenvironments and as such provide a system for studying the response of the cells' internal migration machinery to physiologically relevant topographical cues. In addition to sensing surface topography, individual cells can also be influenced by the pushing and pulling of neighboring cells. The emergent properties of collectively migrating cells show interesting dynamics and are relevant for cancer progression, but have been less studied than the motion of individual cells. We use Particle Image Velocimetry (PIV) to extract the motion of a collectively migrating cell sheet from time lapse images. The resulting flow fields allow us to analyze collective behavior over multiple length and time scales. To analyze the connection between individual cell properties and collective migration behavior, we compare experimental flow fields with the migration of simulated cell groups. Our collective migration metrics allow for a quantitative comparison between experimental and simulated results. This comparison shows that tissue-scale decreases in collective behavior can result from changes in individual cell activity without the need to postulate the existence of subpopulations of leader cells or global gradients. In addition to tissue-scale trends in collective behavior, the migration of cell groups includes localized dynamic features such as cell rearrangements. An individual cell may smoothly follow the motion of its neighbors (affine motion) or move in a more individualistic manner (non-affine motion). By decomposing individual motion into both affine and non-affine components, we measure cell rearrangements within a collective sheet. Finally, finite-time Lyapunov exponent (FTLE) values capture the stretching of the flow field and reflect its chaotic character. Applying collective migration analysis techniques to experimental data on both malignant and non-malignant human breast epithelial cells reveals differences in collective behavior that are not found from analyzing migration speeds alone. Non-malignant cells show increased cooperative motion on long time scales whereas malignant cells remain uncooperative as time progresses. Combining multiple analysis techniques also shows that these two cell types differ in their response to a perturbation of cell-cell adhesion through the molecule E-cadherin. Non-malignant MCF10A cells use E-cadherin for short time coordination of collective motion, yet even with decreased E-cadherin expression, the cells remain coordinated over long time scales. In contrast, the migration behavior of malignant and invasive MCF10CA1a cells, which already shows decreased collective dynamics on both time scales, is insensitive to the change in E-cadherin expression.

Effects of Drive Speed Modulation on Dynamics of Slender Rotating Structures

Slender rotating structures are used in many mechanical systems. These structures can suffer from undesired vibrations that can affect the components and safety of a system. Furthermore, since some these structures can operate in a harsh environment, installation and operation of sensors that are needed for closed-loop and collocated control schemes may not be feasible. Hence, the need for an open-loop non-collocated scheme for control of the dynamics of these structures. In this work, the effects of drive speed modulation on the dynamics of slender rotating structures are studied. Slender rotating structures are a type of mechanical rotating structures, whose length to diameter ratio is large. For these structures, the torsion mode natural frequencies can be low. In particular, for isotropic structures, the first few torsion mode frequencies can be of the same order as the first few bending mode frequencies. These situations can be conducive for energy transfer amongst bending and torsion modes. Scenarios with torsional vibrations experienced by rotating structures with continuous rotor-stator contact occur in many rotating mechanical systems. Drill strings used in the oil and gas industry are an example of rotating structures whose torsional vibrations can be deleterious to the components of the drilling system. As a novel approach to mitigate undesired vibrations, the effects of adding a sinusoidal excitation to the rotation speed of a drill string are studied. A portion of the drill string located within a borewell is considered and this rotating structure has been modeled as an extended Jeffcott rotor and a sinusoidal excitation has been added to the drive speed of the rotor. After constructing a three-degree-of-freedom model to capture lateral and torsional motions, the equations of motions are reduced to a single differential equation governing torsional vibrations during continuous stator contact. An approximate solution has been obtained by making use of the Method of Direct Partition of Motions with the governing torsional equation of motion. The results showed that for a rotor undergoing forward or backward whirling, the addition of sinusoidal excitation to the drive speed can cause an increase in the equivalent torsional stiffness, smooth the discontinuous friction force at contact, and reduce the regions of negative slope in the friction coefficient variation with respect to speed. Experiments with a scaled drill string apparatus have also been conducted and the experimental results show good agreement with the numerical results obtained from the developed models. These findings suggest that the extended Jeffcott rotordynamics model can be useful for studies of rotor dynamics in situations with continuous rotor-stator contact. Furthermore, the results obtained suggest that the drive speed modulation scheme can have value for attenuating drill-string vibrations.

Guided Migration and Collective Behavior: Cell Dynamics during Cancer Progression

This dissertation focuses on gaining understanding of cell migration and collective behavior through a combination of experiment, analysis, and modeling techniques. Cell migration is a ubiquitous process that plays an important role during embryonic development and wound healing as well as in diseases like cancer, which is a particular focus of this work. As cancer cells become increasingly malignant, they acquire the ability to migrate away from the primary tumor and spread throughout the body to form metastatic tumors. During this process, changes in gene expression and the surrounding tumor environment can lead to changes in cell migration characteristics. In this thesis, I analyze how cells are guided by the texture of their environment and how cells cooperate with their neighbors to move collectively. The emergent properties of collectively moving groups are a particular focus of this work as collective cell dynamics are known to change in diseases such as cancer. The internal machinery for cell migration involves polymerization of the actin cytoskeleton to create protrusions that---in coordination with retraction of the rear of the cell---lead to cell motion. This actin machinery has been previously shown to respond to the topography of the surrounding surface, leading to guided migration of amoeboid cells. Here we show that epithelial cells on nanoscale ridge structures also show changes in the morphology of their cytoskeletons; actin is found to align with the ridge structures. The migration of the cells is also guided preferentially along the ridge length. These ridge structures are on length scales similar to those found in tumor microenvironments and as such provide a system for studying the response of the cells' internal migration machinery to physiologically relevant topographical cues. In addition to sensing surface topography, individual cells can also be influenced by the pushing and pulling of neighboring cells. The emergent properties of collectively migrating cells show interesting dynamics and are relevant for cancer progression, but have been less studied than the motion of individual cells. We use Particle Image Velocimetry (PIV) to extract the motion of a collectively migrating cell sheet from time lapse images. The resulting flow fields allow us to analyze collective behavior over multiple length and time scales. To analyze the connection between individual cell properties and collective migration behavior, we compare experimental flow fields with the migration of simulated cell groups. Our collective migration metrics allow for a quantitative comparison between experimental and simulated results. This comparison shows that tissue-scale decreases in collective behavior can result from changes in individual cell activity without the need to postulate the existence of subpopulations of leader cells or global gradients. In addition to tissue-scale trends in collective behavior, the migration of cell groups includes localized dynamic features such as cell rearrangements. An individual cell may smoothly follow the motion of its neighbors (affine motion) or move in a more individualistic manner (non-affine motion). By decomposing individual motion into both affine and non-affine components, we measure cell rearrangements within a collective sheet. Finally, finite-time Lyapunov exponent (FTLE) values capture the stretching of the flow field and reflect its chaotic character. Applying collective migration analysis techniques to experimental data on both malignant and non-malignant human breast epithelial cells reveals differences in collective behavior that are not found from analyzing migration speeds alone. Non-malignant cells show increased cooperative motion on long time scales whereas malignant cells remain uncooperative as time progresses. Combining multiple analysis techniques also shows that these two cell types differ in their response to a perturbation of cell-cell adhesion through the molecule E-cadherin. Non-malignant MCF10A cells use E-cadherin for short time coordination of collective motion, yet even with decreased E-cadherin expression, the cells remain coordinated over long time scales. In contrast, the migration behavior of malignant and invasive MCF10CA1a cells, which already shows decreased collective dynamics on both time scales, is insensitive to the change in E-cadherin expression.