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INTEGRATIVE LEARNING OF CELLULAR SYSTEMS AND NETWORKS
Get PDFThesis (Ph.D.)--Michigan State University. Computational Mathematics, Science and Engineering - Doctor of Philosophy, 2024Advances in omics technologies have led to an abundance of comprehensive biomolecular information of biological systems, down to single-cell resolution. With omics data, biologists can gain a deeper understanding of the complex-hierarchical networks that constitute an organism. To this end, deep learning methods are often applied to assist in discovering meaningful patterns and relationships from omics data. Though deep learning methods can offer high performance on many complex tasks, some challenges arise with omics-based tasks: (1) Omics data are often high-dimensional with low-sample size and/or high levels of sparsity, with complex dependency structures between and within omics data types. (2) There is an imbalance of annotated data across different species and environments. These difficulties make desirable the integration of omics data across different modalities, group samples, and platforms, as well as environments and species. This thesis examines, builds and implements approaches to address these challenges through Integrative Learning techniques, which I use as a general term to encompass techniques that incorporate multiple sources of related data for improved learning (e.g., transfer learning, multi-task learning, and multi-modal data integration). In this work I highlight and address these challenges in different omics-based tasks. In addition to applied methods development, I provide probabilistic and mathematical frameworks that underpin many of these applied problems in omics analysis. Lastly, I showcase some of my more current experiments in deconvolution. Though these experiments are prelimary, often through toy examples, they demonstrate some possible future directions I want to consider.Description based on online resource. Title from PDF t.p. (Michigan State University Fedora Repository, viewed ).Includes bibliographical references
Role and membrane location of HIV gp41 hairpin in fusion
Get PDFThesis (Ph.D.)--Michigan State University. Chemistry - Doctor of Philosophy, 2024The primary cause of acquired immunodeficiency syndrome (AIDS) is the human immunodeficiency virus (HIV), which infects target white blood cells by connecting (fusion) the membranes of the host cell and HIV, causing the viral nucleocapsid to deposit in the cytoplasm. HIV's Gp41, a single-pass integral viral membrane protein with a 150-residue soluble domain outside the virus, is involved in fusion catalysis. This soluble ectodomain (SE) adopts a hairpin structure that contains N-helix-turn-C-helix, and two helices align themselves antiparallelly and there is van der Waals contact between them. The final fusion structure also consists of three hairpins joining together to form a six-helix bundle. There are competing hypotheses about the catalytic role in HIV/cell fusion of the SE hairpin structure. One hypothesis is that the hairpin is a \u201cpost-fusion\u201d structure with no role in catalysis, whereas another hypothesis postulates an important role for the hairpin in catalysis which is associated with binding to the membrane. The latter hypothesis is supported by rapid vesicle fusion induced by the hairpin under some conditions. Further, mixtures of WT and V513E proteins of a large HIV gp41 ectodomain construct with final trimer of-hairpins structure exhibit V513E (gp41 V2E in absence of gp120)-dominant reduction of vesicle fusion that is quantitatively similar to that for gp160 (glycoprotein 160, which is a precursor protein that gets cleaved into two smaller proteins: gp120 and gp41) fusion and infection. Vesicle fusion and helicity were measured for FP_HM (fusion peptide (FP)+hairpin (H)+membrane proximal external region (MPER)) using trimers with different fractions (f\u2019s) of WT and V2E proteins. Correlation between low helicity vs. fusion of V2E was also found in this study. Reductions in FP_HM fusion and helicity vs. fV2E were quantitatively-similar to those for gp160-mediated fusion and infection. Global fitting of all V2E data supports 6 WT gp41 (2 trimers) required for fusion. These data are understood by a model in which the ~25 kcal/mol free energy for initial membrane apposition is compensated by the thermostable hairpin between the Fp in target membrane and Mper/transmembrane domain in virus membrane. The data support a structural model for V2E dominance with a membrane-bound Fp with antiparallel \u3b2 sheet and interleaved strands from the two trimers. This increased distance is the hypothesized reason for reduced fusion and infection. Role of hairpin and correlation between helicity vs. fusion further studied through characterization and fusion of G10V_FPHM and L9R_FPHM, respectively. Results established the less helicity in V2E/L9R than WT vs. less fusion in V2E/L9R than WT and similar helicity in WT/G10V vs. similar fusion in WT/G10V. Position of hairpin in membrane could be better understanding of membrane apposition (viral and host membrane) during fusion because deep SE insertion indicates the close membrane apposition and surface insertion predicts far membrane apposition. Moreover, a hairpin contribution to catalysis of membrane fusion is most straightforwardly understood if there is deep insertion as the locations of the surrounding lipid molecules in the membrane would likely be very different than their energetically stable positions in an unperturbed bilayer. We used either 13C-glucose or 13C-glycerol to express a large soluble ectodomain in a minimum medium, with a dilution of the 13C labeling accomplished by mixing with unlabeled glucose or by selectively labeled glycerol. The proximity of protein with 13C-labeled and lipid with 2H labeled positioned either in middle /periphery/ in between of middle and periphery of the membrane were measured using the rotational-echo double-resonance (REDOR) solid-state NMR technique. The production of 13C proteins used a variety of carbon sources, and as a result, various labeled carbon peak assignments on the side chains of amino acids were observed in NMR. There was a significant REDOR dephasing for samples from different carbon sources, which shows that the soluble ectodomain has mostly peripheral location in the membrane.Description based on online resource. Title from PDF t.p. (Michigan State University Fedora Repository, viewed ).Includes bibliographical references
INVESTIGATION OF OXIDATION OF AMMONIA TO MOLECULAR NITROGEN WITH RUTHENIUM AND OSMIUM COMPLEXES
No full textThesis (Ph.D.)--Michigan State University. Chemistry - Doctor of Philosophy, 2024This thesis describes a strategy for deciphering the mechanism for Ru and Os polypyridyl complexes in electrocatalytic ammonia oxidation, a field with significant potential for the future of electrochemistry. Utilizing ammonia as an H2 storage medium and a power source to drive ammonia fuel cells is a promising avenue, but the sluggish reaction kinetics and high overpotentials of electrocatalytic ammonia oxidation reactions present significant obstacles. Overcoming these challenges by developing efficient catalysts will be a milestone in accelerating the adoption of large-scale applications. Mechanism study is key, allowing us to identify favorable pathways and optimize reaction conditions. Understanding how the structure of the catalyst influences its performance and activity will serve as a blueprint for designing the next generation of molecular catalysts. Building on our group's success in using Ru polypyridyl ammine complexes as homogeneous electrocatalysts for ammonia oxidation, we extend this framework to explore insight stoichiometry and prepare Os complexes described in this dissertation. The first chapter introduces the importance of ammonia and the motivation behind developing catalysts for its oxidation. The second chapter details our stoichiometric study for [RuIII(tpy)(dmabpy)NH3]3+, leading to the identification of new intermediates and the proposal of a HAT disproportion mechanism. The third chapter exhibits stoichiometry of [RuIII(tpy)(dmabpy)NH3]3+ derivatives, which strongly support our proposed mechanism. In the fourth chapter, we study the complexes that do not bear coordinated NH3 on polypyridyl complexes, where we learn more about the structure and activity in the stoichiometric aspect, which will be valuable knowledge to electrochemistry. The fifth chapter marks the beginning of our work in using molecular osmium complexes for ammonia oxidation catalysis. Two Osmium polypyridyl complexes were prepared, and their stoichiometries were deeply studied to unveil possible reaction pathways and obstacles in electrochemistry and to understand the influence of chemical structures (metal centers and ligands) in catalytic activity and performance.Description based on online resource. Title from PDF t.p. (Michigan State University Fedora Repository, viewed ).Includes bibliographical references
Translational Improvements in Blood Banking and Development of an Auxiliary Therapeutic for Type 1 Diabetes
Get PDFThesis (Ph.D.)--Michigan State University. Biomedical Engineering - Doctor of Philosophy, 2024With over 10.5 million units of red blood cells (RBCs) transfused in 2021 in the United States alone, blood transfusions are one of the most common hospital procedures. These life-saving interventions are necessary to treat a variety of conditions that result in decreased hemoglobin levels. Common causes include anemia, hemoglobinopathy, cancer, chemotherapy, radiotherapy, and blood loss from trauma or major surgeries.Despite centuries of research into the storage of RBCs for transfusion, current methods cannot prevent degradation of these cells. Detrimental biochemical and physical changes occur after even short periods of storage. This collection of harmful storage-induced changes is known as the storage lesion. The storage lesion can be broadly categorized into oxidative damages and metabolic impairments. Oxidative damages include generation of reactive oxygen species, lipid and protein oxidation, and degradation of cellular structure leading to severe morphological changes. Metabolic impairments lead to accumulation of lactate, acidifying the cellular milieu, and decreases in adenosine triphosphate (ATP) and 2,3-diphosphoglycerate levels. Transfusion of RBCs significantly impacted by the storage lesion raises questions of patient safety. Though contemporary transfusion medicine has mitigated clinical complications from these procedures, they are not without risk. Complications range from transfusion-transmitted infections to fatal acute reactions, such as transfusion-associated circulatory overload. Minimizing the number of transfusions required is a key objective in blood banking research. This may be achieved by improving the efficacy of transfusions through reduction of the storage lesion. Here, this is addressed through the use of modified additive solutions, which are used to prolong viability of RBCs in storage, and investigation of post-storage cellular rejuvenation. The additive solutions used today contain extreme amounts of glucose, ranging from 45 mmol L 121 to 111 mmol L 121. Such hyperglycemic conditions have been implicated in the development of various aspects of the storage lesion. Previous reports have demonstrated that a normoglycemic additive solution containing just 5.5 mmol L 121 glucose is effective in reducing oxidative stress and osmotic fragility in stored RBCs as well as increasing ATP release and cellular deformability. As glucose is metabolized throughout storage, an RBC feeding system was previously developed to automate maintenance of normoglycemic conditions. However, aspects of the design of this system limited experimental control and regulatory compliance, and therefore translational potential. Here, a second-generation RBC feeding system is developed and employed in additional normoglycemic RBC storage studies. Beyond validating the performance of this system, benefits of normoglycemic storage such as reduced cellular glycation and hemolysis are confirmed. Expanding on previous reports, rejuvenation of RBCs stored under these conditions via post-storage washing is investigated. This rejuvenation results in significant improvements to the health of stored RBCs. Both cellular deformability and morphology were consistently restored to near-normal. Next, the rejuvenation potential of C-peptide, a pancreatic hormone, is reviewed. There is a significant overlap between certain aspects of the storage lesion and the dysfunction of RBCs from people with type 1 diabetes (T1D). This includes reduced cellular deformability and ATP release, increased glycation and oxidative stress, and morphological changes. Consistent exposure to hyperglycemic environments may be responsible for these mutual impairments. Extensive study has shown this proinsulin-derived peptide to interact with RBCs, eliciting beneficial effects. Reports include improvements to cellular deformability, glucose metabolism, and ATP release, including enhanced RBC function in vivo. Thus, C-peptide may be an excellent candidate not just as an auxiliary therapeutic for T1D, but as a rejuvenating agent for RBC storage as well. A comprehensive review of the applications of a functional C-peptide formulation is provided. Preclinical development of this product is initiated, including studies into the efficacy of the proposed formulation. Inconsistencies in C-peptide function then lead to a thorough investigation to identify key developmental roadblocks. A resolution is offered, and a path toward successful in vivo clinical studies is laid out.Description based on online resource. Title from PDF t.p. (Michigan State University Fedora Repository, viewed ).Includes bibliographical references
High-Performance Data-driven Safe Autonomous Control Design
No full textThesis (Ph.D.)--Michigan State University. Electrical and Computer Engineering - Doctor of Philosophy, 2024This dissertation develops high-performance safe control algorithms for autonomous systems under deterministic and stochastic uncertainties. The research is divided into two main parts: deterministic and stochastic control systems.We focus on constructing safety certificates for unknown linear and nonlinear optimal control systems in the deterministic domain. We introduce an online method to develop control barrier certificates (CBCs) that expand the domain of attraction (DoA) without compromising performance. By formulating a feasible optimization problem using a relaxed algebraic Riccati equation (ARE) for linear systems and a relaxed Hamilton-Jacobi-Bellman (HJB) equation for nonlinear systems, alongside safety constraints, we identify the maximum barrier-certified region\u2014called safe optimal DoA\u2014where stability and safety coexist. To address the need for complete system dynamics knowledge, we propose an online data-driven approach employing a safe off-policy reinforcement learning algorithm, which learns a safe optimal policy while using a different exploratory policy for data collection.Building upon these results, we incorporate disturbances using the control framework to attenuate unknown disturbances while ensuring safety and optimality. We unify the robustness of CBCs with control methods to construct a robust and safe optimal DoA. A feasible optimization problem is developed using the relaxed game algebraic Riccati equation (GARE), solved iteratively via a sum-of-squares (SOS)-based safe policy iteration algorithm. To demonstrate practical applicability, we develop a LiDAR-based model predictive control (MPC) framework that incorporates control barrier functions (CBFs). We reduce computational complexity by synthesizing CBFs from clustered LiDAR data and integrating them into the MPC framework while ensuring safety and recursive feasibility. We validate this approach through simulations and experiments on a unicycle-type robot.In the stochastic domain, we synthesize risk-aware safe optimal controllers for partially unknown linear systems under additive Gaussian noise. By utilizing Conditional Value-at-Risk (CVaR) in the one-step cost function, we account for extremely low-probability events without excessive conservatism. Safety is guaranteed with high probability by imposing chance constraints. An online data-driven quadratic programming optimization simultaneously and safely learns the unknown dynamics and controls the system, tightening safety constraints as model confidence increases. We extend this framework to a fully risk-aware MPC for chance-constrained discrete-time linear systems with process noise, incorporating CVaR in both constraints and cost function. This approach ensures constraint satisfaction and performance optimization across the spectrum of risk assessments in stochastic environments. Recursive feasibility and risk-aware exponential stability are established through theoretical analysis.Finally, we present a data-driven risk-aware MPC framework where the mean and covariance of the noise are unknown and estimated online. We provide a computationally efficient solution to the multi-stage CVaR optimization problem using dual representations and data-driven ambiguity sets, casting it as a tractable semidefinite programming (SDP) problem. Recursive feasibility and risk-aware exponential stability are demonstrated, with numerical examples illustrating the efficacy of the proposed methods.Overall, this dissertation addresses challenges in unknown dynamics, disturbances, risk assessment, and computational tractability, providing robust and efficient solutions for safe optimal control in both deterministic and stochastic settings.Description based on online resource. Title from PDF t.p. (Michigan State University Fedora Repository, viewed ).Includes bibliographical references
A LATENT PROFILE PERSPECTIVE ON EMOTIONAL DEMANDS MANAGEMENT VIA EMOTION REGULATION AND JOB CRAFTING BEHAVIORS
Get PDFThesis (Ph.D.)--Michigan State University. Psychology - Doctor of Philosophy, 2024This study sought to integrate emotion regulation theory and job crafting theory to argue these phenomena function as parallel processes to manage emotional demands in the workplace. A latent profile analysis (LPA) was conducted using indicators that included every emotion regulation strategy from Gross\u2019s (1998; 2008) process model of emotion regulation and approach-avoidance oriented styles of relationship, skill, task, and cognitive job crafting to form profiles. Four profiles were hypothesized to emerge along a 2 (proactive vs. reactive) x 2 (approach-oriented vs. avoidance oriented) framework of distinct emotional demands management styles. Two studies were conducted each using a sample of paid participants from an online participant pool. Study 1 (N = 469) supported the four-profile hypothesis but not in the framework as expected. However, profiles\u2019 emotion regulation behaviors conformed to their relative proactivity and temperament scores. Study 2 (N = 370) is a two-time point study that replicated a four-profile structure across time using participant-matched data separated by 2 weeks. Similar to study 1, the framework did not emerge as expected but profiles\u2019 behaviors conformed to relative proactive and temperament scores. Moreover, profiles showed distinct patterns of emotion regulation behaviors and differences in well-being, disposition, demands and resource values that correspond to the JDR model of burnout (Demerouti & Bakker, 2001). The implication of these profiles\u2019 emergence on further integrating emotion regulation theory and job crafting theory and the application of LPA for synthesizing phenomena are discussed.Description based on online resource. Title from PDF t.p. (Michigan State University Fedora Repository, viewed ).Includes bibliographical references
INSTITUTIONAL LOGICS AND NORTH/SOUTH PARTNERSHIPS IN HIGHER EDUCATION : A NEW ANALYTICAL FRAMEWORK FOR PRACTICE
No full textThis dissertation explores North/South partnerships in higher education, shedding light on their practices and underlying logics. Recognizing the growing importance of these collaborations in addressing global challenges, universities are actively working to strengthen these ties. However, concerns about the potential replication of imperialistic structures in North/South partnerships necessitate a critical examination. This study is a response to these concerns, presenting a new analytical framework for the analysis of collaborative practice within this context that is rooted in the institutional logics perspective. My findings suggest that North/South partnerships are made up of multiple coexisting and competing practice conventions and logics that, once identified, bring the complex social dynamics and cultural contestations of this global academic field to the fore. The study has a twofold purpose: an empirical inquiry into international partnership practices in published articles on North/South collaborations, and a theoretical exploration of the logics underpinning these practices. Analyzing 58 articles published in 2022, the study captures the institutional logics employed by higher education actors to reason different types of partnership practices. Utilizing a constitutive approach within institutional logics and a focus on field-level communication, the study responds to calls by critical scholars to explore how broader cultural structures influences practice, identifying the specific logics and cultural content that define the field. This study makes notable contributions to organizational theory by elucidating the intricate cultural interplay within North/South partnerships and challenges prevailing assumptions of unidirectional trajectories toward cultural hegemony. The findings unveil distinct reasoning schemas and logic-practice combinations, offering a fresh lens to understand the cultural dynamics of North/South partnerships. The proposed analytical framework emerges as a potentially valuable tool for higher education actors seeking to develop more effective strategies for navigating the complexities of these types of collaborations. In the concluding chapter, evidence and practical recommendations tailored for diverse stakeholders are presented, emphasizing the importance of discerning nuanced differences among similar practices and fostering diversity, equity, and innovation. In essence, this dissertation goes beyond a mere exploration of North/South partnership practices; it uncovers a rich tapestry of practices, reasoning schema, logics, and cultural interplay. My findings underscore the spectrum of choices and considerations available to field participants when navigating practice and its expression. The new framework prompts participants to critically reflect on how the language used to explain or reason a practice constitutes its meaning and, consequently, its potential impact. It emphasizes the importance of scrutinizing practice choices, including those often taken for granted. These insights contribute to a nuanced understanding of North/South partnerships in higher education, reconceptualizing them from potential tools of imperialism into a space for actors to collaboratively create more effective partnerships. The outlined analytical framework for practice provides compelling tools to foster a more inclusive and mutually beneficial global higher education landscape.Thesis (Ph.D.)--Michigan State University. Higher, Adult, and Lifelong Education - Doctor of Philosophy, 2024Includes bibliographical reference
UNVEILING THE THERAPEUTIC POTENTIAL OF PERIVASCULAR ADIPOSE TISSUE (PVAT) : A SOURCE of VASOACTIVE COMPOUNDS
No full textABSTRACT The interplay between perivascular adipose tissue (PVAT), \u201cthe obesity triad\u201d (hypoxia, inflammation, oxidative stress), and the resulting atherosclerosis is gaining a large body of knowledge, but many questions remain to be answered. The state of the adipose tissue surrounding vessels has a significant role in the health of the vascular tissue and cardiovascular function. PVAT is not simply a structure that holds vasculature in place, but rather an active endocrine tissue with many functions including a role in vascular tone and atherogenesis. Recently, there has been growing consensus with evidence to support that high cholesterol levels are not necessarily where the focus should be when addressing atherosclerosis and cardiovascular disease. Recent evidence suggests that an increase in the quantity of adipose tissue (vis-a-vis obesity) negatively affects the composition of PVAT and leads to increases in oxidative stress, decreased blood flow, and increases in immunological activity, increasing inflammatory mediators. These inflammatory mediators are likely more important in forming atherosclerotic plaques than cholesterol. More data-gathering is indicated to find more of those molecules and to understand more deeply how obesity degrades PVAT.Keywords: Perivascular adipose tissue, white adipose tissue, brown adipose tissue,atherosclerosis, PCSK-9, atherogenesis, obesity, monoclonal antibody, inflammationThesis (M.S.)--Michigan State University. Basic Medical Science - Master of Science, 2024Includes bibliographical reference
IRIDIUM CATALYZED C\u2013H BORYLATION OF ARENES WITH N,B-TYPE DIBORON SPECIES AND Ir(I) ANIONIC COMPLEXES
No full textAryl boronic esters serve as synthetic intermediates for diverse applications in natural products, agrochemicals, and pharmaceuticals due to the abundance of transformations C\u2013B bonds can undergo. These compounds are commonly synthesized in an atom-economical way by directly converting C(sp2)\u2013H bonds into C\u2013B bonds using Ir-catalyzed C\u2013H borylation (CHB) chemistry. Traditionally, this process favors the C\u2013H bond in the least sterically congested position on substituted (hetero)aromatic ring systems. The work described here unveils novel CHB methods that are competent in targeting specific C\u2013H bonds, thereby enabling the synthesis of a diverse set of compounds. In recent years, a N,B-type dimeric pre-ligand (BB) emerged as the first spectator boryl species capable of steric-directed CHB using a 2:1 ratio of pre-ligand to Ir. Chapter 2 describes how this system was modified to direct borylation ortho to directing groups such as amides and esters by decreasing the ligand to metal ratio to 0.5:1, respectively. Additionally, it was found that maintaining the ligand to metal ratio at 2:1 while switching the Ir(I) pre-catalyst from [Ir(OMe)cod]2 to [IrCl(cod)]2 also led to the generation of chelate-directed products. These methods represent the first instances in which regiochemical switching is achieved by altering the reaction conditions as opposed to the ligand system. The synthesis of the hypothesized pre-assembled catalyst, representing the system where BB loadings are decreased, was isolated and resulted in an Ir(III) cationic species ion pairing with [IrCl2(cod)] as the counteranion. Chapter 3 studies the role of this Ir(I) anionic species in catalysis, detailing a new mode of Ir-catalyzed CHB. This system demonstrates [IrCl2(cod)][NBu4] as a competent catalyst for the transformation of C\u2013H to C\u2013B bonds, independent of external ligand or substrates bearing a directing group. Furthermore, it was found that the site of C\u2013H activation is influenced by the length of the alkyl chain in the ammonium cation, where [NPr4]+ increased the amount of ortho borylated product. Mechanistic experiments suggest this occurring through a heterogenous process that is distinct from classical homogenous CHB reactions that proceed via an Ir(III)/Ir(V) catalytic cycle.Thesis (Ph.D.)--Michigan State University. Chemistry - Doctor of Philosophy, 2024Includes bibliographical reference
Mapping the "Complex of Dialogues" : Institutional Ethnography of Mid-Level Administrators' Experience with Sexual Violence Policy
No full textScholarship on sexual violence rarely originates from scholars in the field of writing studies and/or addresses the issue in intersectionally Feminist ways. To address this gap, this study seeks to account for the complexities and interconnections between mid-level university administrators, their practices, guiding texts, and their institutions. Mid-level administrators are defined in this study to be administrators that are in charge of units and personnel but housed under larger organizational structures and colleges. Examples of such mid-level administrators would be Department Chairs, Resource Center Directors, Writing Program or Center Administrators, Title IX Coordinators, etc., but this study does not include individuals such as individual teachers, students, provosts, deans. To specifically center on the experiences of mid-level administrators and their embodied nature, this study uses institutional ethnography as the methodology. This project draws on various methods of textual analysis, storying, site observations, and interviews within this methodology. The dissertation maps how texts, social relationships, and policy all interact with one another to create everyday practices, such as how these mid-level administrators support survivors and train staff within their organization to report instances of violence. The findings illustrate that (1) universities\u2019 values and missions do not always align with their actions and (2) administrators want to enact care-based practices to care for students, yet they feel they are not provided with the necessary tools to do that work. This dissertation concludes by offering tangible suggestions and changes\u2014such as recommendations for intersectional praxis, development of care-plans and climate assessments, and creation of spaces and avenues of support for mid-level administrators\u2014that can serve as a starting place for universities to enact a care-based, intersectional approach to sexual violence prevention and response.Thesis (Ph.D.)--Michigan State University. Rhetoric and Writing - Doctor of Philosophy, 2024Includes bibliographical reference