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Description
A notable challenge when assembling synthetic gene circuits is that modularity often fails to function as intended. A crucial underlying reason for this modularity failure is the existence of competition for shared and limited gene expression resources. By designing a synthetic cascading bistable switches (Syn-CBS) circuit in a single strain

A notable challenge when assembling synthetic gene circuits is that modularity often fails to function as intended. A crucial underlying reason for this modularity failure is the existence of competition for shared and limited gene expression resources. By designing a synthetic cascading bistable switches (Syn-CBS) circuit in a single strain with two coupled self-activation modules to achieve successive cell fate transitions, nonlinear resource competition within synthetic gene circuits is unveiled. However, in vivo it can be seen that the transition path was redirected with the activation of one switch always prevailing over that of the other, contradictory to coactivation theoretically expected. This behavior is a result of resource competition between genes and follows a ‘winner-takes-all’ rule, where the winner is determined by the relative connection strength between the two modules. Despite investigation demonstrating that resource competition between gene modules can significantly alter circuit deterministic behaviors, how resource competition contributes to gene expression noise and how this noise can be controlled is still an open issue of fundamental importance in systems biology and biological physics. By utilizing a two-gene circuit, the effects of resource competition on protein expression noise levels can be closely studied. A surprising double-edged role is discovered: the competition for these resources decreases noise while the constraint on resource availability adds its own term of noise into the system, denoted “resource competitive” noise. Noise reduction effects are then studied using orthogonal resources. Results indicate that orthogonal resources are a good strategy for eliminating the contribution of resource competition to gene expression noise. Noise propagation through a cascading circuit has been considered without resource competition. It has been noted that the noise from upstream genes can be transmitted downstream. However, resource competition’s effects on this cascading noise have yet to be studied. When studied, it is found that resource competition can induce stochastic state switching and perturb noise propagation. Orthogonal resources can remove some of the resource competitive behavior and allow for a system with less noise.
ContributorsGoetz, Hanah Elizabeth (Author) / Tian, Xiaojun (Thesis advisor) / Wang, Xiao (Committee member) / Lai, Ying-Cheng (Committee member) / Arizona State University (Publisher)
Created2022
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Description
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is the 10th leading cause of death, worldwide. The prevalence of drug-resistant clinical isolates and the paucity of newly-approved antituberculosis drugs impedes the successful eradication of Mtb. Bacteria commonly use two-component systems (TCS) to sense their environment and genetically modulate adaptive responses.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is the 10th leading cause of death, worldwide. The prevalence of drug-resistant clinical isolates and the paucity of newly-approved antituberculosis drugs impedes the successful eradication of Mtb. Bacteria commonly use two-component systems (TCS) to sense their environment and genetically modulate adaptive responses. The prrAB TCS is essential in Mtb, thus representing an auspicious drug target; however, the inability to generate an Mtb ΔprrAB mutant complicates investigating how this TCS contributes to pathogenesis. Mycobacterium smegmatis, a commonly used M. tuberculosis genetic surrogate was used here. This work shows that prrAB is not essential in M. smegmatis. During ammonium stress, the ΔprrAB mutant excessively accumulates triacylglycerol lipids, a phenotype associated with M. tuberculosis dormancy and chronic infection. Additionally, triacylglycerol biosynthetic genes were induced in the ΔprrAB mutant relative to the wild-type and complementation strains during ammonium stress. Next, RNA-seq was used to define the M. smegmatis PrrAB regulon. PrrAB regulates genes participating in respiration, metabolism, redox balance, and oxidative phosphorylation. The M. smegmatis ΔprrAB mutant is compromised for growth under hypoxia, is hypersensitive to cyanide, and fails to induce high-affinity respiratory genes during hypoxia. Furthermore, PrrAB positively regulates the hypoxia-responsive dosR TCS response regulator, potentially explaining the hypoxia-mediated growth defects in the ΔprrAB mutant. Despite inducing genes encoding the F1F0 ATP synthase, the ΔprrAB mutant accumulates significantly less ATP during aerobic, exponential growth compared to the wild-type and complementation strains. Finally, the M. smegmatis ΔprrAB mutant exhibited growth impairment in media containing gluconeogenic carbon sources. M. tuberculosis mutants unable to utilize these substrates fail to establish chronic infection, suggesting that PrrAB may regulate Mtb central carbon metabolism in response to chronic infection. In conclusion, 1) prrAB is not universally essential in mycobacteria; 2) M. smegmatis PrrAB regulates genetic responsiveness to nutrient and oxygen stress; and 3) PrrAB may provide feed-forward control of the DosRS TCS and dormancy phenotypes. The data generated in these studies provide insight into the mycobacterial PrrAB TCS transcriptional regulon, PrrAB essentiality in Mtb, and how PrrAB may mediate stresses encountered by Mtb during the transition to chronic infection.
ContributorsMaarsingh, Jason (Author) / Haydel, Shelley E (Thesis advisor) / Roland, Kenneth (Committee member) / Sandrin, Todd (Committee member) / Bean, Heather (Committee member) / Arizona State University (Publisher)
Created2019
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Description
The research on the topology and dynamics of complex networks is one of the most focused area in complex system science. The goals are to structure our understanding of the real-world social, economical, technological, and biological systems in the aspect of networks consisting a large number of interacting units and

The research on the topology and dynamics of complex networks is one of the most focused area in complex system science. The goals are to structure our understanding of the real-world social, economical, technological, and biological systems in the aspect of networks consisting a large number of interacting units and to develop corresponding detection, prediction, and control strategies. In this highly interdisciplinary field, my research mainly concentrates on universal estimation schemes, physical controllability, as well as mechanisms behind extreme events and cascading failure for complex networked systems.

Revealing the underlying structure and dynamics of complex networked systems from observed data without of any specific prior information is of fundamental importance to science, engineering, and society. We articulate a Markov network based model, the sparse dynamical Boltzmann machine (SDBM), as a universal network structural estimator and dynamics approximator based on techniques including compressive sensing and K-means algorithm. It recovers the network structure of the original system and predicts its short-term or even long-term dynamical behavior for a large variety of representative dynamical processes on model and real-world complex networks.

One of the most challenging problems in complex dynamical systems is to control complex networks.

Upon finding that the energy required to approach a target state with reasonable precision

is often unbearably large, and the energy of controlling a set of networks with similar structural properties follows a fat-tail distribution, we identify fundamental structural ``short boards'' that play a dominant role in the enormous energy and offer a theoretical interpretation for the fat-tail distribution and simple strategies to significantly reduce the energy.

Extreme events and cascading failure, a type of collective behavior in complex networked systems, often have catastrophic consequences. Utilizing transportation and evolutionary game dynamics as prototypical

settings, we investigate the emergence of extreme events in simplex complex networks, mobile ad-hoc networks and multi-layer interdependent networks. A striking resonance-like phenomenon and the emergence of global-scale cascading breakdown are discovered. We derive analytic theories to understand the mechanism of

control at a quantitative level and articulate cost-effective control schemes to significantly suppress extreme events and the cascading process.
ContributorsChen, Yuzhong (Author) / Lai, Ying-Cheng (Thesis advisor) / Spanias, Andreas (Committee member) / Tepedelenlioğlu, Cihan (Committee member) / Ying, Lei (Committee member) / Arizona State University (Publisher)
Created2016
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Description
The purpose of information source detection problem (or called rumor source detection) is to identify the source of information diffusion in networks based on available observations like the states of the nodes and the timestamps at which nodes adopted the information (or called infected). The solution of the problem can

The purpose of information source detection problem (or called rumor source detection) is to identify the source of information diffusion in networks based on available observations like the states of the nodes and the timestamps at which nodes adopted the information (or called infected). The solution of the problem can be used to answer a wide range of important questions in epidemiology, computer network security, etc. This dissertation studies the fundamental theory and the design of efficient and robust algorithms for the information source detection problem.

For tree networks, the maximum a posterior (MAP) estimator of the information source is derived under the independent cascades (IC) model with a complete snapshot and a Short-Fat Tree (SFT) algorithm is proposed for general networks based on the MAP estimator. Furthermore, the following possibility and impossibility results are established on the Erdos-Renyi (ER) random graph: $(i)$ when the infection duration $<\frac{2}{3}t_u,$ SFT identifies the source with probability one asymptotically, where $t_u=\left\lceil\frac{\log n}{\log \mu}\right\rceil+2$ and $\mu$ is the average node degree, $(ii)$ when the infection duration $>t_u,$ the probability of identifying the source approaches zero asymptotically under any algorithm; and $(iii)$ when infection duration $
In practice, other than the nodes' states, side information like partial timestamps may also be available. Such information provides important insights of the diffusion process. To utilize the partial timestamps, the information source detection problem is formulated as a ranking problem on graphs and two ranking algorithms, cost-based ranking (CR) and tree-based ranking (TR), are proposed. Extensive experimental evaluations of synthetic data of different diffusion models and real world data demonstrate the effectiveness and robustness of CR and TR compared with existing algorithms.
ContributorsZhu, Kai (Author) / Ying, Lei (Thesis advisor) / Lai, Ying-Cheng (Committee member) / Liu, Huan (Committee member) / Shakarian, Paulo (Committee member) / Arizona State University (Publisher)
Created2015
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Description
The emergence of invasive non-Typhoidal Salmonella (iNTS) infections belonging to sequence type (ST) 313 are associated with severe bacteremia and high mortality in sub-Saharan Africa. Distinct features of ST313 strains include resistance to multiple antibiotics, extensive genomic degradation, and atypical clinical diagnosis including bloodstream infections, respiratory symptoms, and fever. Herein,

The emergence of invasive non-Typhoidal Salmonella (iNTS) infections belonging to sequence type (ST) 313 are associated with severe bacteremia and high mortality in sub-Saharan Africa. Distinct features of ST313 strains include resistance to multiple antibiotics, extensive genomic degradation, and atypical clinical diagnosis including bloodstream infections, respiratory symptoms, and fever. Herein, I report the use of dynamic bioreactor technology to profile the impact of physiological fluid shear levels on the pathogenesis-related responses of ST313 pathovar, 5579. I show that culture of 5579 under these conditions induces profoundly different pathogenesis-related phenotypes than those normally observed when cultures are grown conventionally. Surprisingly, in response to physiological fluid shear, 5579 exhibited positive swimming motility, which was unexpected, since this strain was initially thought to be non-motile. Moreover, fluid shear altered the resistance of 5579 to acid, oxidative and bile stress, as well as its ability to colonize human colonic epithelial cells. This work leverages from and advances studies over the past 16 years in the Nickerson lab, which are at the forefront of bacterial mechanosensation and further demonstrates that bacterial pathogens are “hardwired” to respond to the force of fluid shear in ways that are not observed during conventional culture, and stresses the importance of mimicking the dynamic physical force microenvironment when studying host-pathogen interactions. The results from this study lay the foundation for future work to determine the underlying mechanisms operative in 5579 that are responsible for these phenotypic observations.
ContributorsCastro, Christian (Author) / Nickerson, Cheryl A. (Thesis advisor) / Ott, C. Mark (Committee member) / Roland, Kenneth (Committee member) / Barrila, Jennifer (Committee member) / Arizona State University (Publisher)
Created2016
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Description
Conductance fluctuations associated with quantum transport through quantumdot systems are currently understood to depend on the nature of the corresponding classical dynamics, i.e., integrable or chaotic. There are a couple of interesting phenomena about conductance fluctuation and quantum tunneling related to geometrical shapes of graphene systems. Firstly, in graphene quantum-dot

Conductance fluctuations associated with quantum transport through quantumdot systems are currently understood to depend on the nature of the corresponding classical dynamics, i.e., integrable or chaotic. There are a couple of interesting phenomena about conductance fluctuation and quantum tunneling related to geometrical shapes of graphene systems. Firstly, in graphene quantum-dot systems, when a magnetic field is present, as the Fermi energy or the magnetic flux is varied, both regular oscillations and random fluctuations in the conductance can occur, with alternating transitions between the two. Secondly, a scheme based on geometrical rotation of rectangular devices to effectively modulate the conductance fluctuations is presented. Thirdly, when graphene is placed on a substrate of heavy metal, Rashba spin-orbit interaction of substantial strength can occur. In an open system such as a quantum dot, the interaction can induce spin polarization. Finally, a problem using graphene systems with electron-electron interactions described by the Hubbard Hamiltonian in the setting of resonant tunneling is investigated.

Another interesting problem in quantum transport is the effect of disorder or random impurities since it is inevitable in real experiments. At first, for a twodimensional Dirac ring, as the disorder density is systematically increased, the persistent current decreases slowly initially and then plateaus at a finite nonzero value, indicating remarkable robustness of the persistent currents, which cannot be discovered in normal metal and semiconductor rings. In addition, in a Floquet system with a ribbon structure, the conductance can be remarkably enhanced by onsite disorder.

Recent years have witnessed significant interest in nanoscale physical systems, such as semiconductor supperlattices and optomechanical systems, which can exhibit distinct collective dynamical behaviors. Firstly, a system of two optically coupled optomechanical cavities is considered and the phenomenon of synchronization transition associated with quantum entanglement transition is discovered. Another useful issue is nonlinear dynamics in semiconductor superlattices caused by its key potential application lies in generating radiation sources, amplifiers and detectors in the spectral range of terahertz. In such a system, transition to multistability, i.e., the emergence of multistability with chaos as a system parameter passes through a critical point, is found and argued to be abrupt.
ContributorsYing, Lei (Author) / Lai, Ying-Cheng (Thesis advisor) / Vasileska, Dragica (Committee member) / Chen, Tingyong (Committee member) / Yao, Yu (Committee member) / Arizona State University (Publisher)
Created2016
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Description
Invasive salmonellosis caused by Salmonella enterica serovar Typhimurium ST313 is a major health crisis in sub-Saharan Africa, with multidrug resistance and atypical clinical presentation challenging current treatment regimens and resulting in high mortality. Moreover, the increased risk of spreading ST313 pathovars worldwide is of major concern, given global public transportation

Invasive salmonellosis caused by Salmonella enterica serovar Typhimurium ST313 is a major health crisis in sub-Saharan Africa, with multidrug resistance and atypical clinical presentation challenging current treatment regimens and resulting in high mortality. Moreover, the increased risk of spreading ST313 pathovars worldwide is of major concern, given global public transportation networks and increased populations of immunocompromised individuals (as a result of HIV infection, drug use, cancer therapy, aging, etc). While it is unclear as to how Salmonella ST313 strains cause invasive disease in humans, it is intriguing that the genomic profile of some of these pathovars indicates key differences between classic Typhimurium (broad host range), but similarities to human-specific typhoidal Salmonella Typhi and Paratyphi. In an effort to advance fundamental understanding of the pathogenesis mechanisms of ST313 in humans, I report characterization of the molecular genetic, phenotypic and virulence profiles of D23580 (a representative ST313 strain). Preliminary studies to characterize D23580 virulence, baseline stress responses, and biochemical profiles, and in vitro infection profiles in human surrogate 3-D tissue culture models were done using conventional bacterial culture conditions; while subsequent studies integrated a range of incrementally increasing fluid shear levels relevant to those naturally encountered by D23580 in the infected host to understand the impact of biomechanical forces in altering these characteristics. In response to culture of D23580 under these conditions, distinct differences in transcriptional biosignatures, pathogenesis-related stress responses, in vitro infection profiles and in vivo virulence in mice were observed as compared to those of classic Salmonella pathovars tested.

Collectively, this work represents the first characterization of in vivo virulence and in vitro pathogenesis properties of D23580, the latter using advanced human surrogate models that mimic key aspects of the parental tissue. Results from these studies highlight the importance of studying infectious diseases using an integrated approach that combines actions of biological and physical networks that mimic the host-pathogen microenvironment and regulate pathogen responses.
ContributorsYang, Jiseon (Author) / Nickerson, Cheryl A. (Thesis advisor) / Chang, Yung (Committee member) / Stout, Valerie (Committee member) / Ott, C Mark (Committee member) / Roland, Kenneth (Committee member) / Barrila, Jennifer (Committee member) / Arizona State University (Publisher)
Created2015
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Description
This dissertation treats a number of related problems in control and data analysis of complex networks.

First, in existing linear controllability frameworks, the ability to steer a network from any initiate state toward any desired state is measured by the minimum number of driver nodes. However, the associated optimal control energy

This dissertation treats a number of related problems in control and data analysis of complex networks.

First, in existing linear controllability frameworks, the ability to steer a network from any initiate state toward any desired state is measured by the minimum number of driver nodes. However, the associated optimal control energy can become unbearably large, preventing actual control from being realized. Here I develop a physical controllability framework and propose strategies to turn physically uncontrollable networks into physically controllable ones. I also discover that although full control can be guaranteed by the prevailing structural controllability theory, it is necessary to balance the number of driver nodes and control energy to achieve actual control, and my work provides a framework to address this issue.

Second, in spite of recent progresses in linear controllability, controlling nonlinear dynamical networks remains an outstanding problem. Here I develop an experimentally feasible control framework for nonlinear dynamical networks that exhibit multistability. The control objective is to apply parameter perturbation to drive the system from one attractor to another. I introduce the concept of attractor network and formulate a quantifiable framework: a network is more controllable if the attractor network is more strongly connected. I test the control framework using examples from various models and demonstrate the beneficial role of noise in facilitating control.

Third, I analyze large data sets from a diverse online social networking (OSN) systems and find that the growth dynamics of meme popularity exhibit characteristically different behaviors: linear, “S”-shape and exponential growths. Inspired by cell population growth model in microbial ecology, I construct a base growth model for meme popularity in OSNs. Then I incorporate human interest dynamics into the base model and propose a hybrid model which contains a small number of free parameters. The model successfully predicts the various distinct meme growth dynamics.

At last, I propose a nonlinear dynamics model to characterize the controlling of WNT signaling pathway in the differentiation of neural progenitor cells. The model is able to predict experiment results and shed light on the understanding of WNT regulation mechanisms.
ContributorsWang, Lezhi (Author) / Lai, Ying-Cheng (Thesis advisor) / Wang, Xiao (Thesis advisor) / Papandreoou-Suppappola, Antonia (Committee member) / Brafman, David (Committee member) / Arizona State University (Publisher)
Created2017
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Description
In sub-Saharan Africa, an invasive form of nontyphoidal Salmonella (iNTS) belonging to sequence type (ST)313 has emerged as a major public health concern causing widespread bacteremia and mortality in children with malaria and adults with HIV. Clinically, ST313 pathovars are characterized by the absence of gastroenteritis, which is commonly found

In sub-Saharan Africa, an invasive form of nontyphoidal Salmonella (iNTS) belonging to sequence type (ST)313 has emerged as a major public health concern causing widespread bacteremia and mortality in children with malaria and adults with HIV. Clinically, ST313 pathovars are characterized by the absence of gastroenteritis, which is commonly found in “classical” nontyphoidal Salmonella (NTS), along with multidrug resistance, pseudogene formation, and chromosome degradation. There is an urgent need to understand the biological and physical factors that regulate the disease causing properties of ST313 strains. Previous studies from our lab using dynamic Rotating Wall Vessel (RWV) bioreactor technology and “classical” NTS strain χ3339 showed that physiological fluid shear regulates gene expression, stress responses and virulence in unexpected ways that are not observed using conventional shake and static flask conditions, and in a very different manner as compared to ST313 strain D23580. Leveraging from these findings, the current study was the first to report the effect of fluid shear on the pathogenesis-related stress responses of S. Typhimurium ST313 strain A130, which evolved earlier than D23580 within the ST313 clade. A130 displayed enhanced resistance to acid, oxidative and bile stresses when cultured in the high fluid shear (HFS) control condition relative to the low fluid shear (LFS) condition in stationary phase using Lennox Broth (LB) as the culture medium. The greatest magnitude of the survival benefit conferred by high fluid shear was observed in response to oxidative and acid stresses. No differences were observed for thermal and osmotic stresses. Based on previous findings from our laboratory, we also assessed how the addition of phosphate or magnesium ions to the culture medium altered the acid or oxidative stress responses of A130 grown in the RWV. Addition of either

phosphate or magnesium to the culture medium abrogated the fluid shear-related differences observed for A130 in LB medium for the acid or oxidative stress responses, respectively. Collectively, these findings indicate that like other Salmonella strains assessed thus far by our team, A130 responds to differences in physiological fluid shear, and that ion concentrations can modulate those responses.
ContributorsGutierrez-Jensen, Ami Dave (Author) / Nickerson, Cheryl A. (Thesis advisor) / Barrila, Jennifer (Thesis advisor) / Ott, C. M. (Committee member) / Roland, Kenneth (Committee member) / Arizona State University (Publisher)
Created2017
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Description
Online social media is popular due to its real-time nature, extensive connectivity and a large user base. This motivates users to employ social media for seeking information by reaching out to their large number of social connections. Information seeking can manifest in the form of requests for personal and time-critical

Online social media is popular due to its real-time nature, extensive connectivity and a large user base. This motivates users to employ social media for seeking information by reaching out to their large number of social connections. Information seeking can manifest in the form of requests for personal and time-critical information or gathering perspectives on important issues. Social media platforms are not designed for resource seeking and experience large volumes of messages, leading to requests not being fulfilled satisfactorily. Designing frameworks to facilitate efficient information seeking in social media will help users to obtain appropriate assistance for their needs

and help platforms to increase user satisfaction.

Several challenges exist in the way of facilitating information seeking in social media. First, the characteristics affecting the user’s response time for a question are not known, making it hard to identify prompt responders. Second, the social context in which the user has asked the question has to be determined to find personalized responders. Third, users employ rhetorical requests, which are statements having the

syntax of questions, and systems assisting information seeking might be hindered from focusing on genuine questions. Fouth, social media advocates of political campaigns employ nuanced strategies to prevent users from obtaining balanced perspectives on

issues of public importance.

Sociological and linguistic studies on user behavior while making or responding to information seeking requests provides concepts drawing from which we can address these challenges. We propose methods to estimate the response time of the user for a given question to identify prompt responders. We compute the question specific social context an asker shares with his social connections to identify personalized responders. We draw from theories of political mobilization to model the behaviors arising from the strategies of people trying to skew perspectives. We identify rhetorical questions by modeling user motivations to post them.
ContributorsRanganath, Suhas (Author) / Liu, Huan (Thesis advisor) / Lai, Ying-Cheng (Thesis advisor) / Tong, Hanghang (Committee member) / Vaculin, Roman (Committee member) / Arizona State University (Publisher)
Created2017