The central nervous control of walking in the locust, Schistocerca Americana

Rhythmic motor behaviors in all animals appear to be under the control of "central pattern generator" circuits, neural circuits which can produce output patterns appropriate for behavior even when isolated from their normal peripheral inputs. Insects have been a useful model system in which to study the control of legged terrestrial locomotion. Much is known about walking in insects at the behavioral level, but to date there has been no clear demonstration that a central pattern generator for walking exists. The focus of this thesis is to explore the central neural basis for locomotion in the locust, Schistocerca americana.

Rhythmic motor patterns could be evoked in leg motor neurons of isolated thoracic ganglia of locusts by the muscarinic agonist pilocarpine. These motor patterns would be appropriate for the movement of single legs during walking. Rhythmic patterns could be evoked in all three thoracic ganglia, but the segmental rhythms differed in their sensitivities to pilocarpine, their frequencies, and the phase relationships of motor neuron antagonists. These different patterns could be generated by a simple adaptable model circuit, which was both simulated and implemented in VLSI hardware. The intersegmental coordination of leg motor rhythms was then examined in preparations of isolated chains of thoracic ganglia. Correlations between motor patterns in different thoracic ganglia indicated that central coupling between segmental pattern generators is likely to contribute to the coordination of the legs during walking.

The work described here clearly demonstrates that segmental pattern generators for walking exist in insects. The pattern generators produce motor outputs which are likely to contribute to the coordination of the joints of a limb, as well as the coordination of different limbs. These studies lay the groundwork for further studies to determine the relative contributions of central and sensory neural mechanisms to terrestrial walking.

Cytokine control of neuronal phenotype

Diffusible proteins regulate neural development at a variety of stages. Using a novel neuronal culture assay, I have identified several cytokines that regulate the expression of neurotransmitters and neuropeptides in sympathetic neurons. These cytokines fall into two families. The first group is termed the neuropoietic cytokines, while including CDF/LIF, CNTF, OSM and GPA, induces expression of the same set of neuropeptide mRNAs in cultured sympathetic neurons. These four factors not only exhibit similar biological activities; they also share a predicted secondary structure and bind to a signal-transducing receptor subunit in common with IL-6 and IL-11. The latter two cytokines display a weaker activity in this assay. In addition, I find that several members of the TGF-β superfamily, activin A, BMP-2, and BMP-6, have a selective overlap with the neuropoietic family in the spectrum of neuropeptides that these cytokines induce in sympathetic neurons. Different patterns of neuropeptides induced by the TGF-β family members, however, demonstrate that the activities of these cytokines are distinct from those of the neuropoietic family. Another 30 cytokines are without detectable effect in this neuronal assay.

Activin A induces a set of neurotransmitters and neuropeptides that is somewhat similar to the phenotype of sympathetic neurons innervating sweat glands in rat footpads. In situ hybridization and RNase protection were carried out to test whether activins were involved in the phenotypic transition when sympathetic neurons contact sweat glands. I find that activin mRNA is present in both cholinergic and noradrenergic targets. Moreover, homogenates of footpads do not contain activin-like activity in the neuronal assay in vitro. Taken together, these data do not support activins as the best candidates for the sweat gland factor.

Several novel factors that regulate neuropeptide expression exist in heart cell conditioned medium. I attempted to purify these factors in collaboration with Dr. Jane Talvenheimo. Our results suggest that these factors are sensitive to the storage conditions used. Several modifications of purification strategy are discussed.

Neuronal mechanism of state control in Drosophila melanogaster

The changes in internal states, such as fear, hunger and sleep affect behavioral responses in animals. In most of the cases, these state-dependent influences are “pleiotropic”: one state affects multiple sensory modalities and behaviors; “scalable”: the strengths and choices of such modulations differ depending on the imminence of demands; and “persistent”: once the state is switched on the effects last even after the internal demands are off. These prominent features of state-control enable animals to adjust their behavioral responses depending on their internal demands. Here, we studied the neuronal mechanisms of state-controls by investigating energy-deprived state (hunger state) and social-deprived state of fruit flies, Drosophila melanogaster, as prototypic models. To approach these questions, we developed two novel methods: a genetically based method to map sites of neuromodulation in the brain and optogenetic tools in Drosophila.

These methods, and genetic perturbations, reveal that the effect of hunger to alter behavioral sensitivity to gustatory cues is mediate by two distinct neuromodulatory pathways. The neuropeptide F (NPF) – dopamine (DA) pathway increases sugar sensitivity under mild starvation, while the adipokinetic hormone (AKH)- short neuropeptide F (sNPF) pathway decreases bitter sensitivity under severe starvation. These two pathways are recruited under different levels of energy demands without any cross interaction. Effects of both of the pathways are mediated by modulation of the gustatory sensory neurons, which reinforce the concept that sensory neurons constitute an important locus for state-dependent control of behaviors. Our data suggests that multiple independent neuromodulatory pathways are underlying pleiotropic and scalable effects of the hunger state.

In addition, using optogenetic tool, we show that the neural control of male courtship song can be separated into probabilistic/biasing, and deterministic/command-like components. The former, but not the latter, neurons are subject to functional modulation by social experience, supporting the idea that they constitute a locus of state-dependent influence. Interestingly, moreover, brief activation of the former, but not the latter, neurons trigger persistent behavioral response for more than 10 min. Altogether, these findings and new tools described in this dissertation offer new entry points for future researchers to understand the neuronal mechanism of state control.

Phase-matching control of high-order harmonic generation in a two-color laser field

The phase-matching condition of high-order harmonic generation driven by intense few-cycle pulses could be controlled by adding second-harmonic pulses to change the ionization fraction of the gaseous medium. The harmonic generation efficiency could be improved by moving the phase-matching point with an all-optical control of the ionization fraction or a proper change of the confocal parameter. A specific order of harmonics could be easily controlled to reach phase matching at a fixed higher gas pressure by adding second-harmonic pulses with a suitable intensity. Such an all-optical phase-matching control was demonstrated to be dependent upon the temporal delay between the fundamental-wave and second harmonic pulses.

Robust Control of Evolutionary Dynamics

The application of principles from evolutionary biology has long been used to gain new insights into the progression and clinical control of both infectious diseases and neoplasms. This iterative evolutionary process consists of expansion, diversification and selection within an adaptive landscape - species are subject to random genetic or epigenetic alterations that result in variations; genetic information is inherited through asexual reproduction and strong selective pressures such as therapeutic intervention can lead to the adaptation and expansion of resistant variants. These principles lie at the center of modern evolutionary synthesis and constitute the primary reasons for the development of resistance and therapeutic failure, but also provide a framework that allows for more effective control.

A model system for studying the evolution of resistance and control of therapeutic failure is the treatment of chronic HIV-1 infection by broadly neutralizing antibody (bNAb) therapy. A relatively recent discovery is that a minority of HIV-infected individuals can produce broadly neutralizing antibodies, that is, antibodies that inhibit infection by many strains of HIV. Passive transfer of human antibodies for the prevention and treatment of HIV-1 infection is increasingly being considered as an alternative to a conventional vaccine. However, recent evolution studies have uncovered that antibody treatment can exert selective pressure on virus that results in the rapid evolution of resistance. In certain cases, complete resistance to an antibody is conferred with a single amino acid substitution on the viral envelope of HIV.

The challenges in uncovering resistance mechanisms and designing effective combination strategies to control evolutionary processes and prevent therapeutic failure apply more broadly. We are motivated by two questions: Can we predict the evolution to resistance by characterizing genetic alterations that contribute to modified phenotypic fitness? Given an evolutionary landscape and a set of candidate therapies, can we computationally synthesize treatment strategies that control evolution to resistance?

To address the first question, we propose a mathematical framework to reason about evolutionary dynamics of HIV from computationally derived Gibbs energy fitness landscapes -- expanding the theoretical concept of an evolutionary landscape originally conceived by Sewall Wright to a computable, quantifiable, multidimensional, structurally defined fitness surface upon which to study complex HIV evolutionary outcomes.

To design combination treatment strategies that control evolution to resistance, we propose a methodology that solves for optimal combinations and concentrations of candidate therapies, and allows for the ability to quantifiably explore tradeoffs in treatment design, such as limiting the number of candidate therapies in the combination, dosage constraints and robustness to error. Our algorithm is based on the application of recent results in optimal control to an HIV evolutionary dynamics model and is constructed from experimentally derived antibody resistant phenotypes and their single antibody pharmacodynamics. This method represents a first step towards integrating principled engineering techniques with an experimentally based mathematical model in the rational design of combination treatment strategies and offers predictive understanding of the effects of combination therapies of evolutionary dynamics and resistance of HIV. Preliminary in vitro studies suggest that the combination antibody therapies predicted by our algorithm can neutralize heterogeneous viral populations despite containing resistant mutations.

A control of gas-vacuolate cyanobacteria

The cyanobacteria that cause problems in water supply are principally the colonial forms that are buoyed up by gas vesicles. The success of these organisms is due, in part, to their gas vesicles, which enable them to perform vertical migrations or to maintain themselves in the euphotic zone. The gas vesicles are also the root cause of the problems. In calm periods they cause the cyanobacteria to float to the water surface forming noxious scums, and they may prevent the colonies from sedimenting in water treatment plants. Gas vesicles are hollow, gas-filled structures; they are rigid but can be collapsed by the application of pressure. Their critical collapse pressure is influenced by their dimensions, which vary in different organisms. Gas vesicles are formed by the assembly of two types of protein, which determine their mechanical and physical properties. Methods for collapsing gas vesicles in natural populations of cyanobacteria will be considered. They may have application to the control of cyanobacteria in water supply.

Fast and Efficient Neural Conversion of Human Hematopoietic Cells

Neurons obtained directly from human somatic cells hold great promise for disease modeling and drug screening. Available protocols rely on overexpression of transcription factors using integrative vectors and are often slow, complex, and inefficient. We report a fast and efficient approach for generating induced neural cells (iNCs) directly from human hematopoietic cells using Sendai virus. Upon SOX2 and c-MYC expression, CD133-positive cord blood cells rapidly adopt a neuroepithelial morphology and exhibit high expansion capacity. Under defined neurogenic culture conditions, they express mature neuronal markers and fire spontaneous action potentials that can be modulated with neurotransmitters. SOX2 and c-MYC are also sufficient to convert peripheral blood mononuclear cells into iNCs. However, the conversion process is less efficient and resulting iNCs have limited expansion capacity and electrophysiological activity upon differentiation. Our study demonstrates rapid and efficient generation of iNCs from hematopoietic cells while underscoring the impact of target cells on conversion efficiency.

Aspects of quality control of wind profiler measurements in complex topography

It is well known in the scientific community that some remote sensing instruments assume that sample volumes present homogeneous conditions within a defined meteorological profile. At complex topographic sites and under extreme meteorological conditions, this assumption may be fallible depending on the site, and it is more likely to fail in the lower layers of the atmosphere. This piece of work tests the homogeneity of the wind field over a boundary layer wind profiler radar located in complex terrain on the coast under different meteorological conditions. The results reveal the qualitative importance of being aware of deviations in this homogeneity assumption and evaluate its effect on the final product. Patterns of behavior in data have been identified in order to simplify the analysis of the complex signal registered. The quality information obtained from the homogeneity study under different meteorological conditions provides useful indicators for the best alternatives the system can offer to build wind profiles. Finally, the results are also to be considered in order to integrate them in a quality algorithm implemented at the product level.

Model-based control of a Rijke tube combustion instability

A Rijke tube is used to demonstrate model-based control of a combustion instability, where controller design is based on measurement of the unstable system. The Rijke tube used was of length 0.75m and had a grid-stabilised laminar flame in its lower half. A microphone was used as a sensor and a loudspeaker as an actuator for active control. The open loop transfer function (OLTF) required for controller design was that from the actuator to the sensor. This was measured experimentally by sending a signal with two components to the actuator. The first was a control component from an empirically designed controller, which was used to stabilise the system, thus eliminating the non-linear limit cycle. The second was a high bandwidth signal for identification of the OLTF. This approach to measuring the OLTF is generic and can be applied to large-scale combustors. The measured OLTF showed that only the fundamental mode of the tube was unstable; this was consistent with the OLTF predicted by a mathematical model of the tube, involving 1-D linear acoustic waves and a time delay heat release model. Based on the measured OLTF, a controller to stabilise the instability was designed using Nyquist techniques. This was implemented and was seen to result in an 80dB reduction in the microphone pressure spectrum. A robustness study was performed by adding an additional length to the top of the Rijke tobe. The controller was found to achieve control up to an increase in tube length of 19%. This compared favourably with the empirical controller, which lost control for an increase in tube length of less than 3%.

Active control of sound radiated by a submarine hull in bending vibration using inertial actuators

Submarines are efficient sources of low frequency radiated noise due to the vibrations induced by the rotation of the propeller in a non uniform wake. In this work the possibility of using inertial actuators to reduce the far field sound pressure is investigated. The submerged vessel is modelled as a cylindrical shell with two conical end caps. Complicating effects such as ring stiffeners, bulkheads and the fluid loading are taken into account. A harmonic radial force is transmitted from the propeller to the hull through the stern end cone and it is tonal at the blade passing frequency (rotational speed of the shaft multiplied by the number of blades). The actuators are attached at the inside of the prow end cone to form a circumferential array. Both Active Vibration Control (AVC) and Active Structural Acoustic Control (ASAC) are analysed and it is shown that the inertial actuators can significantly reduce the far field sound pressure.

Hybrid model predictive control applied to switching control of burner load for a compact marine boi

This paper discusses the application of hybrid model predictive control to control switching between different burner modes in a novel compact marine boiler design. A further purpose of the present work is to point out problems with finite horizon model predictive control applied to systems for which the optimal solution is a limit cycle. Regarding the marine boiler control the aim is to find an optimal control strategy which minimizes a trade-off between deviations in boiler pressure and water level from their respective setpoints while limiting burner switches.The approach taken is based on the Mixed Logic Dynamical framework. The whole boiler systems is modelled in this framework and a model predictive controller is designed. However to facilitate on-line implementation only a small part of the search tree in the mixed integer optimization is evaluated to find out whether a switch should occur or not. The strategy is verified on a simulation model of the compact marine boiler for control of low/high burner load switches. It is shown that even though performance is adequate for some disturbance levels it becomes deteriorated when the optimal solution is a limit cycle. Copyright © 2007 International Federation of Automatic Control All Rights Reserved.

Passive control of combustion instability in a low emissions aeroderivative gas turbine

This paper describes the conceptual ideas, the theoretical validation, the laboratory testing and the field trials of a recently patented fuel-air mixing device for use in high-pressure ratio, low emissions, gaseous-fueled gas turbines. By making the fuel-air mixing process insensitive to pressure fluctuations in the combustion chamber, it is possible to avoid the common problem of positive feedback between mixture strength and the unsteady combustion process. More specifically, a mixing duct has been designed such that fuel-air ratio fluctuations over a wide range of frequencies can be damped out by passive design means. By scaling the design in such a way that the range of damped frequencies covers the frequency spectrum of the acoustic modes in the combustor, the instability mechanism can be removed. After systematic development, this design philosophy was successfully applied to a 35:1 pressure ratio aeroderivative gas turbine yielding very low noise levels and very competitive NOx and CO measurements. The development of the new premixer is described from conceptual origins through analytic and CFD evaluation to laboratory testing and final field trials. Also included in this paper are comments about the practical issues of mixing, flashback resistance and autoignition.

Active control of sound radiated by a submarine hull in axisymmetric vibration using inertial actuators

This paper investigates the use of inertial actuators to reduce the sound radiated by a submarine hull under excitation from the propeller. The axial forces from the propeller are tonal at the blade passing frequency. The hull is modeled as a fluid-loaded cylindrical shell with ring stiffeners and equally spaced bulkheads. The cylinder is closed at each end by circular plates and conical end caps. The forces from the propeller are transmitted to the hull by a rigid foundation connected to the propeller shaft. Inertial actuators are used as the structural control inputs. The actuators are arranged in circumferential arrays and attached to the internal end plates of the hull. Two active control techniques corresponding to active vibration control and discrete structural acoustic sensing are implemented to attenuate the structural and acoustic responses of the submarine. In the latter technique, error information on the radiated sound fields is provided by a discrete structural acoustic sensor. An acoustic transfer function is defined to estimate the far field sound pressure from a single point measurement on the hull. The inertial actuators are shown to provide control forces with a magnitude large enough to reduce the sound due to hull vibration. © 2012 American Society of Mechanical Engineers.

Control of a shock-wave/boundary-layer interaction and subsequent subsonic diffuser using a combination of vortex generators and bleed

An experimental investigation has been undertaken in which vortex generators (VGs) have been employed to inhibit boundary-layer separation produced by the combined adversepressure- gradient of a terminal shock-wave and subsonic diffuser. This setup has been developed as part of a program to produce a more inlet relevant flow-field using a small-scale wind tunnel than previous studies. The resulting flow is dominated by large-scale separation, and as such, is thought to be a good test-bed for flow control. In this investigation, VGs have been added to determine their potential for shock-induced separation mitigation. In line with previous studies, it was observed that the application of VGs alone was not able to significantly alleviate separation overall, because enlarged corner separations was observed. Only when control of the corner separations using corner bleed was employed alongside centre-span control using VGs was a significant improvement in both wall pressure recovery (6% increase) and stagnation pressure recovery (2.4% increase) observed. Copyright © 2012 by the American Institute of Aeronautics and Astronautics, Inc.

Fabrication and control of miniature McKibben actuators

This paper investigates the development of miniature McKibben actuators. Due to their compliancy, high actuation force, and precision, these actuators are on the one hand interesting for medical applications such as prostheses and instruments for surgery and on the other hand for industrial applications such as for assembly robots. During this research, pneumatic McKibben actuators have been miniaturized to an outside diameter of 1.5 mm and a length ranging from 22 mm to 62 mm. These actuators are able to achieve forces of 6 N and strains up to about 15% at a supply pressure of 1 MPa. The maximal actuation speed of the actuators measured during this research is more than 350 mm/s. Further, positioning experiments with a laser interferometer and a PI controller revealed that these actuators are able to achieve sub-micron positioning resolution. © 2010 Published by Elsevier B.V. All rights reserved.