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Browsing by Author "Reisfeld, Brad, committee member"

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    Engineering in practice: from quantitative biology modeling to engineering education
    (Colorado State University. Libraries, 2024) Weber, Lisa, author; Munsky, Brian, advisor; Atadero, Rebecca, committee member; Prasad, Ashok, committee member; Reisfeld, Brad, committee member
    In quantitative analyses of biological processes, one may use many different scales of models (e.g., spatial or non-spatial, deterministic or stochastic, time-varying or at steady-state) or many different approaches to match models to experimental data (e.g., model fitting or parameter uncertainty/ sloppiness quantification with different experiment designs). These different analyses can lead to surprisingly different results, even when applied to the same data and the same model. In Chapters 2, a variety of modeling approaches that can be utilized in analyzing biological processes are explained, with examples included of how to mathematically represent a system in order to use these various modeling approaches. Many of these mechanistic modeling approaches are demonstrated in Chapter 3 when we use a simplified gene regulation model to illustrate many of the concerns regarding modeling approach differences; these include ODE analyses of deterministic processes, chemical master equation and finite state projection analyses of heterogeneous processes, and stochastic simulations. For each analysis, we consider a time-dependent input signal (e.g., a kinase nuclear translocation) and several model hypotheses, along with simulated single cell data, to illustrate different approaches (e.g., deterministic and stochastic) in the identification of mechanisms and parameters of the same model from the same simulated data. We also explore how uncertainty in parameter space varies with respect to the chosen analysis approach or specific experiment design, and conclude with a discussion of how our simulated results relate to the integration of experimental and computational investigations to explore signal-activated gene expression models in yeast [1] and human cells [2]. Different modeling approaches are used in Chapter 4 to build on the work of Scott, et al. (2018, 2019) [3, 4] to evaluate different model classes for DNA structural conformation changes, including the unwinding/rewinding dynamics of the double-stranded DNA (dsDNA) helical structure and subsequent binding interactions with complementary single-stranded oligonucleotides probes (oligos), in relation to different conditions: temperature, salt concentration, and the level of supercoiling of the DNA molecule. This is done to identify a class of models that best fit the DNA unwinding and subsequent oligo probe binding experimental data as a function of these three conditions. In this work, we demonstrate the use of additional quantitative modeling approaches, including a modified genetic algorithm along with the process of cross validation and Markov Chain Monte Carlo (MCMC) simulations with the Metropolis-Hastings (MH) algorithm [5] to explore parameter space. We also demonstrate many of the challenges that can be encountered when modeling complex biological phenomena with actual experimental data. Although much of the work described in Chapters 2 through 4 may appear to be, on the surface, just the use of various computational methods for biological processes to increase understanding of biological mechanisms, much of it also has a separate purpose. The structure of these works and an underlying aim of much of this work, namely Chapters 2 and 3, is to provide guidance with examples to make these computational approaches more accessible to scientists and engineers. Many of these approaches are included in a quantitative biology (UQ-bio) summer school that has been conducted for the last few years as well. Through the process of developing these works and seeking to make quantitative biology more accessible, a related goal manifested to improve the accessibility of engineering education as a whole, which is addressed in Chapter 5, specifically related to diversity, equity, and inclusion (DEI) in undergraduate engineering education. There have been efforts since Fall 2017 to increase the presence of DEI in the undergraduate CBE education using a bottom up approach. To date, various efforts have been incorporated into the first two years of the CBE program. In Chapter 5, these previous efforts, along with lessons learned, are detailed. A substantial, holistic approach to incorporating DEI throughout the CBE curriculum is proposed, based on a review of recent work by other engineering education researchers, to help the CBE department create a more inclusive educational experience for undergraduate students and better enable students to handle the complex challenges they may face in their careers.
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    Hybrid MBSE-DevOps model for implementation in very small enterprises
    (Colorado State University. Libraries, 2024) Simpson, Cailin R., author; Simske, Steven, advisor; Miller, Erika, committee member; Reisfeld, Brad, committee member; Sega, Ronald, committee member
    This work highlights the challenge of implementing digital engineering (DE) practices, specifically model-based systems engineering (MBSE) and DevOps, in very small entities (VSEs) that deliver software products. VSEs often face unique challenges due to their limited resources and project scale. Various organizations have authored strategies for DE advancement, such as the Department of Defense's Digital Engineering Strategy and INCOSE's System Engineering 2035 that highlight the need for improved DE practices across the engineering fields. This work proposes a hybrid methodology named FlexOps, combining MBSE and DevOps, to address these challenges. The authors highlight the challenges faced by VSEs and emphasize that MBSE and DevOps adoption in VSEs requires careful consideration of factors like cost, skill availability, and customer needs. The motivation for the research stems from the difficulties faced by VSEs in implementing processes designed for larger companies. The authors aim to provide a stepping stone for VSEs to adopt DE practices through the hybrid FlexOps methodology, leveraging existing MBSE and DevOps practices while accommodating smaller project scales. This work emphasizes that VSEs supporting government contracts must also adopt DE practices to meet industry directives. The implementation of FlexOps in two case studies highlights its benefits, such as offering a stepping stone to DE practices, combining Agile, MBSE, and DevOps strategies, and addressing VSE-specific challenges. The challenges faced by VSEs in adopting DE practices may be incrementally improved by adopting a hybrid method: FlexOps. FlexOps was designed to bridge the gap between traditional practices and DE for VSEs delivering software products.
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    Leveraging bio-based monomers, chemical recyclability, and sustainable polymerization techniques for sustainable polymer synthesis
    (Colorado State University. Libraries, 2024) Bernsten, Simone Noelle, author; Miyake, Garret, advisor; McNally, Andy, committee member; Reynolds, Melissa, committee member; Reisfeld, Brad, committee member
    Polymeric materials have become vital to everyday life since their commercialization. Although polymers are integral to many industries and consumers, their synthesis and use brings with them a myriad of environmental concerns. Unsustainability can arise even before polymer synthesis in that many synthetic polymers are made from petroleum-derived monomers which are inherently nonrenewable. Next, many polymers are synthesized using one or more unsustainable components such as precious metals including iridium and ruthenium. Finally, at the end of a polymer's useful life, options for recycling are limited by the inability to make virgin-quality materials that can be used for the same application as the original polymer. The work described in this thesis aims to address each of these issues. The polymerizations of several bio-based monomers are described. The use of organic photoredox catalysis to enable polymerization represents sustainable synthesis of polymers. Polymers exhibiting chemical recyclability are also investigated, wherein end-of-life materials can be depolymerized and used to produce virgin- quality materials. Ultimately, this work represents a diverse array of methodologies for increasing the overall sustainability of polymeric materials.
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    Metabolic engineering interventions for sustainable 2,3-butanediol production in gas fermenting Clostridium autoethanogenum
    (Colorado State University. Libraries, 2023) Ghadermazi, Parsa, author; Chan, Siu Hung, advisor; Wrighton, Kelly, committee member; Reisfeld, Brad, committee member
    Gas fermentation provides a promising platform to turn low-cost and readily available single-carbon waste gases into commodity chemicals such as 2,3-butanediol. Clostridium autoethanogenum is usually used as a robust and flexible chassis for gas fermentation. Here, we leveraged on constraints-based stoichiometric modeling and kinetic ensemble modeling of the C. autoethanogenum metabolic network to provide a systematic in silico analysis of metabolic engineering interventions for 2,3-butanediol overproduction and low carbon substrate loss in dissipated CO2. Our analysis allowed us to identify and to assess comparatively the expected performances for a wide range of single, double, and triple interventions. Our analysis managed to individuate bottleneck reactions in relevant metabolic pathways when suggesting intervening strategies. Besides recapitulating intuitive and/or previously attempted genetic modifications, our analysis neatly outlined that the interventions - at least partially - impinging on by-products branching from acetyl-CoA and pyruvate (acetate, ethanol, amino acids) offer valuable alternatives to the interventions focusing directly on the specific branch from pyruvate to 2,3-butanediol.
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    The design and synthesis of super reducing organic photocatalysts through mechanistic understanding with application towards unactivated arene activation
    (Colorado State University. Libraries, 2024) Green, Alexander Richard, author; Miyake, Garret, advisor; Paton, Robert, committee member; Bailey, Travis, committee member; Reisfeld, Brad, committee member
    The work described in this dissertation focuses on the understanding of an organic photocatalyst system through a degradation and mechanistic study, leading to development of a new class of organic photocatalyst and improved application. The design of new organic photocatalysts is crucial for eliminating the need to use rare and expensive ruthenium and iridium that have dominated the field of photoredox catalysis for the past decade. Additionally, most of the catalysts describe here-in operate through a unique two electron, one proton activation mechanism to generate a closed shell species which enables direct quenching towards unactivated arenes such as benzene, without the use of a stoichiometric amount of reductant such as solvated electrons coming from pyrophoric metals. The progress described within this dissertation provides a deeper understanding of tunable organic reductants and their function.
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    The systems engineering casualty analysis simulation (SE-CAS)
    (Colorado State University. Libraries, 2019) Creary, Andron Kirk, author; Sega, Ron, advisor; Reisfeld, Brad, committee member; Young, Peter, committee member; Bradley, Thomas, committee member
    In this dissertation, we illustrate the use of the systems engineering casualty analysis simulation (SE-CAS). SE-CAS, inspired by the Army's need to detect, identify and operate in areas contaminated by Chemical Warfare Agent (CWA), is a framework for creating chemical warfare simulations. As opposed to existing simulations which emulate simple cause-and-effect relationships, SE-CAS is developed using a systems thinking approach to dynamically represent interconnected elements during weaponized release of CWA. Through use of monte-carlo simulation methods, integrated dynamic analytic models, and NASA WorldWind® global display, SE-CAS provides the capability to visualize areas of chemical warfare agent dispersion, symptomology and exposure effects, and prescription of optimal survival factors within a common constructive environment. Supported by Colorado State University's Walter Scott Jr. School of Engineering and industry affiliates, SE-CAS is part of a larger research & development effort to expand industry modeling, simulation and analysis capabilities within Chemical, Biological, Radiological, Nuclear and Explosives (CBRN-E) discipline. SE-CAS is an open, parameterized simulation allowing the user to set initial conditions, simulation mode, parameters, and randomized inputs through a scenario editor. Inputs are passed through the simulation components and service layers. This includes: processor logic, simulation management, visualization and observer services. Data output is handled within the simulation display, as well as in text format for easy back-end analysis. The contributions of this dissertation: advanced the state of the systems engineering practice in modeling, simulation and analysis of chemical warfare agents during simulated military operations, created a robust systems engineering framework for creating chemical warfare simulations that is modular and customizable, developed a practical software solution to fill gaps in CBRN-E M&S tool offerings, integration of newly created dynamic models compatible with CBRN-E platforms, and formulated a roadmap for the application of Live, Virtual and Constructive training and operational planning for joint warfare integrated systems assessments.
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    Towards elucidating photochemical reaction pathways in nickel catalyzed cross coupling and organocatalyzed Birch reduction
    (Colorado State University. Libraries, 2021) Kudisch, Max, author; Miyake, Garret, advisor; Finke, Richard, committee member; Chung, Jean, committee member; Reisfeld, Brad, committee member
    Carbon-nitrogen (C─N) bond forming reactions to couple aryl halides with amines are essential for the discovery and production of medicinal compounds. The state-of-the-art method uses a precious metal palladium catalyst at high temperatures which poses sustainability concerns. Recently, a method was reported in which an iridium photocatalyst (PC) works in tandem with a nickel catalyst under blue light irradiation to achieve C─N bond formation at room temperature. Herein, it was discovered that the iridium PC could be omitted if 365 nm light is used, constituting a precious metal-free approach. This discovery suggests that a nickel-centered excited state can mediate C─N bond formation, raising the possibility of an energy transfer type pathway in dual catalytic systems. The nickel complexes formed were identified for the first time and mechanistic evidence was found that is consistent with energy transfer with both [Ru(bpy)3]2+ (bpy = 2,2'-bipyridine) and a phenoxazine PC. A series of [NiBr2(amine)n] complexes were isolated, characterized, and detected in C─N coupling reaction mixtures. A theoretical framework for predicting energy transfer rate constant ratios based on Förster theory and UV-visible spectroscopy was developed. The phenoxazine PC was both predicted and found to exhibit faster energy transfer and enhanced reaction performance when compared with [Ru(bpy)3]2+. In addition, a light-driven, organocatalyzed system for Birch reduction was developed. Historically, Birch reduction to reduce an arene to a 1,4-cyclohexadiene has been limited by the required use of alkali metals which are pyrophoric and can be explosive. Under violet light, a benzo[ghi]perylene imide PC was found to reduce challenging arenes such as benzene, constituting the first visible light driven approach capable of this reactivity. Mechanistic studies were performed that are consistent with a catalytic cycle involving addition of OH─ to the PC to form an adduct, [PC─OH]─. Photolysis of the adduct forms OH• and the PC radical anion which subsequently undergoes photoionization, ejecting a solvated electron that reduces the substrate.