We investigate the dynamics and stability of nonlinear time-delayed one-degree-of-freedom systems possessing quadratic and cubic nonlinearities and subjected to external and parametric disturbances. Due to the time-delay terms, the trivial solution of the unforced system undergoes Hopf bifurcations. We use the method of multiple scales to determine the normal forms of the Hopf bifurcations and hence determine whether they are locally supercritical or subcritical. Then, we use a combination of a path following scheme, the normal forms, and the method of harmonic balance to calculate and trace small- and large-amplitude limit cycles and use Floquet theory to ascertain their stability and hence generate global bifurcation diagrams. We validate these diagrams using numerical simulations. We apply the results to two important physical problems: machine-tool chatter in lathes and control of the sway of container cranes using time-delayed position feedback. We find that the Hopf bifurcations in machine tools are globally subcritical even when they are locally supercritical. We find multiple large-amplitude solutions coexisting with the linearly stable trivial solution. Consequently, there are three operating regions for machine tools: an unconditionally stable region, an unconditionally unstable region, and a conditionally stable region. In the latter region, the multiple responses lead to hysteresis. Then, we investigate the use of bifurcation control to transform the subcritical bifurcations into supercritical ones. We find that cubic-velocity feedback with appropriate gains can shrink or even eliminate the conditionally stable region. Then, we find that time-delayed acceleration feedback with an appropriate gain can completely eliminate the linear instability region. In contrast, we find that the Hopf bifurcations in controlled cranes are locally and globally supercritical. Finally, we investigate the effectiveness of time-delayed position feedback in rejecting external and parametric disturbances in ship-mounted cranes. / Ph. D.

Repetitive stress injuries are common in the workplace where workers perform repetitive tasks continuously throughout the day. Muscle fatigue may lead to injury either directly through muscle damage or indirectly through changes in coordination, development of muscle imbalances, kinematic and muscle activation variability, and/or movement instability. To better understand the role of muscle fatigue in changes in movement parameters, we studied how muscle fatigue and muscle imbalances affected the control of movement timing, variability, and stability during a repetitive upper extremity sawing task. Since muscle fatigue leads to delayed muscle and cognitive response times, we might expect the ability to maintain movement timing would decline with muscle fatigue. We compared timing errors pre- and post-fatigue as subjects performed this repetitive sawing task synchronized with a metronome using standard techniques and a goal-equivalent manifold (GEM) approach. No differences in basic performance parameters were found. Significant decreases in the temporal correlations of the timing errors and velocities indicated that subjects made more frequent corrections to their movements post-fatigue. Muscle fatigue may lead to movement instability through a variety of mechanisms including delayed muscle response times and muscle imbalances. To measure movement stability, we must first define a state space that describes the movement. We compared a variety of different state space definitions and found that state spaces composed of angles and velocities with little redundant information provide the most consistent results. We then studied the affect of fatigue on the shoulder flexor muscles and general fatigue of the arm on movement stability. Subjects were able to maintain stability in spite of muscle fatigue, shoulder strength imbalance and decreased muscle cocontraction. Little is known about the time course for adaptations in response to fatigue. We studied the effect of muscle fatigue on movement coordination, kinematic variability and movement stability while subjects performed the same sawing task at two work heights. Increasing the height of the task caused subjects to make more adjustments to their movement patterns in response to muscle fatigue. Subjects also exhibited some increases in kinematic variability at the shoulder but no changes in movement stability. These findings suggest that people alter their kinematic patterns in response to fatigue possibly to maintain stability at the expense of increased variability. / text

Human thiopurine methyltransferase (TPMT) is an enzyme involved in the metabolism of thiopurine drugs, which are widely used in leukemia and inflammatory bowel diseases such as ulcerative colitis and Crohn´s disease. Due to genetic polymorphisms, approximately 30 protein variants are present in the population, some of which have significantly lowered activity. TPMT *5 (Leu49Ser) is one of the protein variants with almost no activity. The mutation is positioned in the hydrophobic core of the protein, close to the active site. Hydrogen exchange rates measured with NMR spectroscopy for N-terminally truncated constructs of TPMT *5 and TPMT *1 (wild type) show that local stability and hydrogen bonding patterns are changed by the mutation Leu49Ser. Most residues exhibit faster exchange rates and a lower local stability in TPMT *5 in comparison with TPMT *1. Changes occur close to the active site but also throughout the entire protein. Calculated overall stability is similar for the two constructs, so the measured changes are due to local stability. Protein dynamics measured with NMR relaxation experiments show that both TPMT *5 and TPMT *1 are monomeric in solution. Millisecond dynamics exist in TPMT *1 but not in TPMT *5, even though a few residues exhibit a faster dynamic. Dynamics on nanosecond to picosecond time scale have changed but no clear trends are observable.

Amyotrophic lateral sclerosis (ALS) is a devastating and progressive disease that results in selective death of motor neurons in the cortex, brain stem and spinal cord. ALS is the most common adult onset motor neuron disease resulting in paralysis and death, commonly within 2 – 5 years of symptom onset, yet there remains no effective treatment for the disease. The majority of ALS cases show no hereditary link (referred to as sporadic ALS or sALS); however, ~10% of cases show a dominant pattern of inheritance (referred to as familial ALS or fALS). Over 170 different mutations in human Cu, Zn superoxide dismutase (SOD1) have been identified to account for ~20% of fALS. SOD1 is a ubiquitously expressed homodimeric antioxidant enzyme. It is widely accepted that mutations in SOD1 result in a gain of toxic function, rather than a loss of native function. A prominent hypothesis for the gain of function is the formation of protein aggregates, which have been shown to be toxic to motor neurons. Protein aggregation is observed in a number of neurodegenerative disorders, including Alzheimer’s, Huntington’s and Parkinson’s disease. Each β-rich monomer of SOD1 binds one catalytic Cu ion and one structural Zn ion. The metallation state of SOD1 significantly influences the structure, dynamics, activity, stability, and aggregation propensity. A similar trend has been observed in a number of metalloenzymes and as such a method to rapidly and accurately quantitate metal ions in proteins is of great importance. Here a review of previous methods using the chromogenic chelator PAR to quantitate metal ions in proteins is presented. Three methods are assessed for their accuracy, precision and ease of use. The methods vary in accuracy, which is highest only under the specific conditions it was designed for. A robust new method is presented here that uses spectral decomposition software to accurately resolve the absorption bands of Cu and Zn with high precision. This method may be successful as a more general method for metal analysis of proteins allowing for the quantitation of additional metal combinations (e.g. Zn/Co, Ni/Cu, Ni/Co). Thermodynamic stability has widely been implicated as playing a major role in the aggregation of globular proteins. Metal loss significantly decreases the global stability of SOD1 and as such metal-depleted (apo) forms of SOD1 have largely been the focus of SOD1 investigations. Recent studies, however, suggest that complete global unfolding is not required for protein aggregation. Local unfolding has been investigated and proposed to be sufficient to induce irreversible protein aggregation in the absence of global destabilization. Enhanced local unfolding has been observed in a number of disease-related proteins. Since SOD1 aggregation may occur from partially unfolded forms, NMR temperature dependence studies have been carried out on the most abundant form of SOD1 in vivo, the fully metallated (holo) dimer, to provide a residue specific picture of subglobal structural changes in SOD1 upon heating. Amide proton (N1H) temperature coefficients report on the hydrogen bonding status of a protein. A curved N1H temperature dependence indicates that the proton populates an alternative conformation generally within 5 kcal/mol of the ground state. NMR temperature dependence studies of pseudoWT indicate that the thermal unfolding process of holo pWT begins with “fraying” of the structure at its periphery. In particular, increased disorder is observed in edge strands β5 and β6, as well as surrounding the zinc binding site. The local stability and conformational heterogeneity of ALS-associated mutants G93A, E100G and V148I was also assessed. All mutants display similar local unfolding patterns to pseudoWT, but also show distinct differences in the hydrogen bonding network surrounding the mutation site. Interestingly, each mutation regardless of its structural context results in altered dynamics at the β-barrel plug, a key stabilizing element in SOD1. A significant proportion of residues (~30%) access alternative states in both pseudoWT and mutants, however, overall mutants appear to be able to access higher free energy alternative states compared to pseudoWT. The implications of these results for the mechanism of protein aggregation and disease are discussed.

In this thesis, we study the population dynamics of predator-prey interactions described by mathematical models with age/stage structures. We first consider fixed development times for predators and prey and develop a stage-structured predator-prey model with Holling type II functional response. The analysis shows that the threshold dynamics holds. That is, the predator-extinction equilibrium is globally stable if the net reproductive number of the predator $\mathcal{R}_0$ is less than $1$, while the predator population persists if $\mathcal{R}_0$ is greater than $1$. Numerical simulations are carried out to demonstrate and extend our theoretical results. A general maturation function for predators is then assumed, and an age-structured predator-prey model with no age structure for prey is formulated. Conditions for the existence and local stabilities of equilibria are obtained. The global stability of the predator-extinction equilibrium is proved by constructing a Lyapunov functional. Finally, we consider a special case of the maturation function discussed before. More specifically, we assume that the development times of predators follow a shifted Gamma distribution and then transfer the previous model into a system of differential-integral equations. We consider the existence and local stabilities of equilibria. Conditions for existence of Hopf bifurcation are given when the shape parameters of Gamma distributions are $1$ and $2$.

"Safety is a value, not just a Priority" Geomechanically stable underground excavations require continuous assessment of rock mass behavior for maximizing safety. Optimizing pillar design is essential for preventing hazardous incidents and improving production in room-and-pillar mines. Maintaining regional and global stability is complicated for underground carbonate or stone deposits, where extensive fracture networks and groundwater flow become leading factors for generating unsteady ground conditions including karsts. A sudden encounter with karst cavities during mine advance may lead to safety issues, including ground collapse and outflow of unconsolidated sediments and groundwater. The presence of these eroded zones in pillars may cause their failure and poses a risk to the lives of miners apart from disrupting the pre-planned mining operations. A pervasive presence of joints and fractures plays a primary role in promoting structurally controlled failures in stone mines, which accelerates upon interaction with the karst cavities. The prevalent empirical and analytical approaches for pillar design ignore the geotechnical complexities such as the spatial density of discontinuities, karst voids, and deviation from the design during short-range mine planning. With the increasing market demand for limestone products, mining organizations, as well as enforcement agencies, are investing in research for increasing the efficiency of extracting valuable resources. While economical productivity is essential, preventing risks and ensuring the safety of miners remains the cardinal objective of mining operations. According to the Mine Safety and Health Administration (MSHA), since 2000, about 31% of occupational fatalities at all underground mines in the United States are caused due to ground collapse, which rises to 39% for underground stone mines. The objective of this study is to provide a reliable and methodological approach for pillar design in underground room-and-pillar hard rock mines for safe and efficient ore recovery. The numerical modeling techniques, implemented for a case study stone mine, could provide a pragmatic framework to assess the effect of karsts on rock mass behavior, and design future pillars detected with voids. The research uses data acquired from using remote sensing techniques, such as LiDAR and Ground-penetrating Radar surveys, to map the excavation characteristics. Discontinuum modeling was valuable for analyzing the pillar strength in the presence of discontinuities and cavities, as well as estimating a safe design standard. Discrete Fracture Networks, created using statistical information from discontinuity mapping, were employed to simulate the joints pervading the rock mass. This proposed research includes the calibration of rock mass properties to translate the effect of discontinuities to continuum models. Continuum modeling proved effective in analyzing regional stability along with characterizing the redistributed stress regime by imitating the excavation sequence. The results from pillar-scale and local-scale analyses are converged to optimize pillar design on a global scale and estimate the feasibility of secondary recovery in stone mines with a dominating discontinuity network and karst terrane. Stochastic analysis using finite volume modeling helped evaluate the performance of modified pillars to assist production while maintaining safety standards. The proposed research is valuable for improving future design parameters, excavation practices, and maintaining a balance between an approach towards increased safety while enhancing production. / Doctor of Philosophy / "The most valuable resource to come back out of a mine is a miner" – Anonymous. The United States accounted for 27% of the global limestone market share which was valued at US$58.5 billion in 2020 [148]. It is projected to reach a target of US$65.3 billion in 2027, growing even in midst of the COVID-19. As surface reserves deplete, much of the mineral demand gap is supplemented by mining underground deposits. Underground mines extract minerals from deep within the earth compared to surface mines. As a result, the miners experience a greater number of accidents in a constricted environment because of roof/tunnel collapse, fewer escape routes, ventilation, explosions, or inundation. According to the Mine Safety and Health Administration (MSHA), about 15% of all underground mine injuries in the US were caused by rockfalls since 1983. The majority of underground stone deposits are mined using the room-and-pillar mining method, which resembles a chessboard design where the light squares are mined, and the dark squares are left as rock pillars to support the tunnels. Limestone, a carbonate rock, contains a lot of fractures and joints (discontinuities). Erosion of rocks due to continuous water flow through the fractures leads to the formation of cavities known as karsts. Interaction of karsts with the prevalent fracture network increases rockfall risk during mining. The collapse of voids along with an inrush of filled rock-clay-water sludge can harm miners' lives, damage machinery, and stop further operations. Literature is scarce on topics that quantify the risk and disruption posed by these cavities in underground mines. Most rock classification systems cannot classify their effect because of the unpredictability and extensive analysis required. The objective of this research is to provide a reliable and methodological approach for designing pillars in underground hard rock mines for ensuring a safe working environment and efficient mineral recovery. This research starts with analyzing the strength of pillars, in which karst cavities were discovered while mining. The safety concerns often lead the miners to not excavate around the cavities and leave valuable resources unmined. Data from ground-penetrating radar and laser scanning surveys were used to characterize the voids and map the discontinuities. Discrete-element numerical modeling was used to simulate the pillars as an assembly of blocks jointed by the discontinuities. The simulation results help us understand the instability issues in the karst-ridden pillars and ways to improve upon the existing design. The findings were used to modulate the parameters for regional-scale models using finite volume modeling for less computationally intensive analyses and simulating rock as a continuum. The continuum models were highly effective in analyzing the instability issues due to the prevalent karstic network. This helps understand any alternative scenario that could have been implemented to optimize ore recovery while preventing risks. The results from the single pillar and regional analyses are combined to optimize pillar design on a global mine scale. This dissertation focuses on improving hazard mitigation in mines with unpredicted anomalies like karsts. Although this research is based on a specific mine site, it empowers the operators to explore the presented techniques to increase safety in all underground mines. The suggested methodology will help devise better strategies for handling instability issues without jeopardizing the mine operations. The primary motivation is to keep the underground miners safe from hazardous situations while fulfilling the secondary objective of maximizing mineral production.

[Non fourni] / Acute Myeloid Leukemia (AML) is a cancer of white cells characterized by a quick proliferation of immature cells, that invade the circulating blood and become more present than mature blood cells. This thesis is devoted to the study of two mathematical models of AML. In the first model studied, the cell dynamics are represented by PDE’s for the phases G₀, G₁, S, G₂ and M. We also consider a new phase called Ğ₀, between the exit of the M phase and the beginning of the G₁ phase, which models the fast self-renewal effect of cancerous cells. Then, by analyzing the solutions of these PDE’s, the model has been transformed into a form of two coupled nonlinear systems involving distributed delays. An equilibrium analysis is done, the characteristic equation for the linearized system is obtained and a stability analysis is performed. The second model that we propose deals with a coupled model for healthy and cancerous cells dynamics in AML consisting of two stages of maturation for cancerous cells and three stages of maturation for healthy cells. The cell dynamics are modelled by nonlinear partial differential equations. Applying the method of characteristics enable us to reduce the PDE model to a nonlinear distributed delay system. For an equilibrium point of interest, necessary and sufficient conditions of local asymptotic stability are given. Finally, we derive stability conditions for both mathematical models by using a Lyapunov approach for the systems of PDEs that describe the cell dynamics.

<p><b>In this dissertation we present the quantitative response of an epidemic of the so-called SIR-type, in a population consisting of a local component and a migrant component. Each component can be divided into three classes, the susceptible individuals, usually denoted by S, who are uninfected but may contract the disease, infected individuals (I) who are infected and can spread the disease to the susceptible individuals and the class (R) of recovered individuals. If a susceptible individual becomes infected, it moves into the infected class. An infected individual, at recovery, moves to the class R. Firstly we develop a model describing two interacting populations with vaccination. Assuming the vaccination rate in both groups or components are constant, we calculate a threshold parameter and we call it a vaccination reproductive number. This invariant determines whether the disease will die out or becomes endemic on the (in particular, local) population. Then we present the stability analysis of equilibrium points and the effect of vaccination. Our primary finding is that the behaviour of the disease free equilibrium depend on the vaccination rates of the combined population. We show that the disease free equilibrium is locally asymptotically stable if the vaccination reproductive number is less than one. Also our stability analysis show that the global stability of the disease free equilibrium depends on the basic reproduction number, not the vaccination reproductive number. If the vaccination reproductive number is greater than one, then the disease free equilibrium is unstable and there exists three endemic equilibrium points in our model. Two of these three endemic equilibria are so-called boundary equilibrium points, which means that the infection is only in one group of the population. The third one which we focus on is the general endemic point for the whole system. We derive a threshold condition that determines whether the endemic equilibria is locally asymptotically stable or not. Secondly, by assuming that the rate of vaccination in the migrant population is constant, we apply optimal control theory to find an optimal vaccination strategy in the local population. Our numerical simulation shows the effectiveness of the control strategy. This model is suitable for modeling the real life situation to control many communicable diseases. Models similar to the model used in the main contribution of our dissertation do exist in the literature. In fact, our model can be regarded as being in-between those of [Jia et al., Theoretical Population Biology 73 (2008) 437-448] and [Piccolo and Billings, Mathematical and Computer Modeling 42 (2005) 291-299]. Nevertheless our stability analysis is original, and furthermore we perform an optimal control study whereas the two cited papers do not. The essence of chapter 5 and 6 of this dissertation is being prepared for publication.</b></p>

<p><b>In this dissertation we present the quantitative response of an epidemic of the so-called SIR-type, in a population consisting of a local component and a migrant component. Each component can be divided into three classes, the susceptible individuals, usually denoted by S, who are uninfected but may contract the disease, infected individuals (I) who are infected and can spread the disease to the susceptible individuals and the class (R) of recovered individuals. If a susceptible individual becomes infected, it moves into the infected class. An infected individual, at recovery, moves to the class R. Firstly we develop a model describing two interacting populations with vaccination. Assuming the vaccination rate in both groups or components are constant, we calculate a threshold parameter and we call it a vaccination reproductive number. This invariant determines whether the disease will die out or becomes endemic on the (in particular, local) population. Then we present the stability analysis of equilibrium points and the effect of vaccination. Our primary finding is that the behaviour of the disease free equilibrium depend on the vaccination rates of the combined population. We show that the disease free equilibrium is locally asymptotically stable if the vaccination reproductive number is less than one. Also our stability analysis show that the global stability of the disease free equilibrium depends on the basic reproduction number, not the vaccination reproductive number. If the vaccination reproductive number is greater than one, then the disease free equilibrium is unstable and there exists three endemic equilibrium points in our model. Two of these three endemic equilibria are so-called boundary equilibrium points, which means that the infection is only in one group of the population. The third one which we focus on is the general endemic point for the whole system. We derive a threshold condition that determines whether the endemic equilibria is locally asymptotically stable or not. Secondly, by assuming that the rate of vaccination in the migrant population is constant, we apply optimal control theory to find an optimal vaccination strategy in the local population. Our numerical simulation shows the effectiveness of the control strategy. This model is suitable for modeling the real life situation to control many communicable diseases. Models similar to the model used in the main contribution of our dissertation do exist in the literature. In fact, our model can be regarded as being in-between those of [Jia et al., Theoretical Population Biology 73 (2008) 437-448] and [Piccolo and Billings, Mathematical and Computer Modeling 42 (2005) 291-299]. Nevertheless our stability analysis is original, and furthermore we perform an optimal control study whereas the two cited papers do not. The essence of chapter 5 and 6 of this dissertation is being prepared for publication.</b></p>

The thesis is based on using dynamical systems theories and techniques to study the qualitative dynamics of herpes simplex virus type 2 (HSV-2), a sexually-transmitted disease of major public health significance. A deterministic model for the interaction of the virus with the immune system in the body of an infected individual (in vivo) is designed first of all. It is shown, using Lyapunov function and LaSalle's Invariance Principle, that the virus-free equilibrium of the model is globally-asymptotically stable whenever a certain biological threshold, known as the reproduction number, is less than unity. Furthermore, the model has at least one virus-present equilibrium when the threshold quantity exceeds unity. Using persistence theory, it is shown that the virus will always be present in vivo whenever the reproduction threshold exceeds unity. The analyses (theoretical and numerical) of this model show that a future HSV-2 vaccine that enhances cell-mediated immune response will be effective in curtailling HSV-2 burden in vivo. A new single-group model for the spread of HSV-2 in a homogenously-mixed sexually-active population is also designed. The disease-free equilibrium of the model is globally-asymptotically stable when its associated reproduction number is less than unity. The model has a unique endemic equilibrium, which is shown to be globally-stable for a special case, when the reproduction number exceeds unity. The model is extended to incorporate an imperfect vaccine with some therapeutic benefits. Using centre manifold theory, it is shown that the resulting vaccination model undergoes a vaccine-induced backward bifurcation (the epidemiological importance of the phenomenon of backward bifurcation is that the classical requirement of having the reproduction threshold less than unity is, although necessary, no longer sufficient for disease elimination. In such a case, disease elimination depends upon the initial sizes of the sub-populations of the model). Furthermore, it is shown that the use of such an imperfect vaccine could lead to a positive or detrimental population-level impact (depending on the sign of a certain threshold quantity). The model is extended to incorporate the effect of variability in HSV-2 susceptibility due to gender differences. The resulting two-group (sex-structured) model is shown to have essentially the same qualitative dynamics as the single-group model. Furthermore, it is shown that adding periodicity to the corresponding autonomous two-group model does not alter the dynamics of the autonomous two-group model (with respect to the elimination of the disease). The model is used to evaluate the impact of various anti-HSV control strategies. Finally, the two-group model is further extended to address the effect of risk structure (i.e., risk of acquiring or transmitting HSV-2). Unlike the two-group model described above, it is shown that the risk-structured model undergoes backward bifurcation under certain conditions (the backward bifurcation property can be removed if the susceptible population is not stratified according to the risk of acquiring infection). Thus, one of the main findings of this thesis is that risk structure can induce the phenomenon of backward bifurcation in the transmission dynamics of HSV-2 in a population.