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Biological and Health Sciences

Predoctoral fellows have been nominated by their programs and are selected through a competitive review process based on the creativity and impact of the research they are pursuing. The abstracts for recipients in the biological and health sciences describe the framework, aims, and significance of each fellow’s dissertation and demonstrate the breadth of Rackham doctoral programs.

Natural Variation and Microbial Interactions in Candida Albicans
Faith Anderson, Microbiology and Immunology

Candida albicans (C. albicans) is a fungus that commonly colonizes mucosal surfaces of healthy individuals; however, C. albicans has the capacity to cause both superficial mucosal and life-threatening disseminated infections. The fungal and host factors that govern the shift from a commensal to pathogenic state are unclear. I have examined natural genetic and phenotypic variations of colonizing C. albicans isolates to understand how commensal and pathogenic populations differ. Furthermore, I am determining how interactions with resident bacteria influence the virulence traits and immune recognition of C. albicans. Overall, my work will provide a greater insight as to how genetic variation, microbial interactions, and host immune recognition impact the ability of C. albicans to colonize commensally or cause disease.

Biophysical Characterization of the Carboxysome Positioning System
Christopher Azaldegui, Chemical Biology

Bacteria use the ParA family of ATPases to spatially organize various cellular cargoes. Recently, a ParA-like ATPase termed Maintenance of carboxysome distribution A (McdA) and its partner protein, McdB, were revealed to position carboxysomes, a bacterial microcompartment which accounts for a third of global carbon fixation. Using Halothiobacillus neapolitanus as a model organism and a suite of high-resolution biophysical imaging techniques, I am investigating the mechanism underlying carboxysome positioning. I have developed an experimental framework which includes quantitative fluorescence microscopy, single-molecule tracking, and quantitative image analysis to assess McdB phase separation and to investigate how the ATPase activity of McdA governs its motion in living cells. Finally, I am using correlative light and electron microscopies to reveal how mutations to the McdAB system alter the carboxysome ultrastructure and localization. Altogether, my work is revealing how bacterial microcompartments are spatially regulated and will further our understanding of subcellular biophysics.

RiPP’in it: Using Multi-Omics for Plant Cyclic Peptide Discovery for Drug Development
Desnor Chigumba, Chemical Biology

Cyclic plant peptides have diverse functions including anti-cancer, anti-bacterial, and anti-viral properties. Traditionally, these medicines have been discovered through bioactivity-guided fractionation. However, this approach has several limitations including re-discovery of known compounds, limited source materials, and largely non-specific chemical discovery. Recently, plant macrocyclic peptides with tryptophan crosslinks known as lyciumins, were characterized as ribosomally synthesized and post-translationally modified peptides (RiPPs) originating from plant-specific BURP domain-precursor peptides. I propose there is a large unknown diversity of sidechain-macrocyclic peptides derived from BURP domain precursor genes. This study uses a combination of plant genome mining and tandem mass spectrometry-based metabolomics as a discovery strategy for novel classes of macrocyclic peptides. I test these peptides against human disease models to characterize their targets. Proteomic characterization is employed to probe the mechanism of BURP domain mediated macro-cyclization. This approach overcomes the bottlenecks of bioactivity-guided fractionation and yields novel natural product lead structures for drug development.

Dissecting Proteostatic Regulation of CD8+ T-cell Immunity
Luis Correa, Immunology

CD8+ T-cells are critical players in immunity against intracellular pathogens and essential for the formation of immunologic memory. Upon activation, CD8+ T-cells undergo an increase in protein synthesis. Little is known about the mechanisms by which CD8+ T-cells maintain protein homeostasis (proteostasis) during T-cell differentiation and the role of proteostasis in T-cell persistence. Endoplasmic reticulum associated degradation (ERAD) pathway is critical to preserving proteostasis. ERAD complexes recognize misfolded proteins in the endoplasmic reticulum (ER) and facilitate their degradation. Our objective was to determine the role of Sel1L/ERAD in regulating CD8+ T-cell persistence and memory formation following acute viral infection. Using the murine model of acute viral infection (LCMV-Armstrong), we found that CD8+ T-cells experience ER stress over the course of infection. Furthermore, we find that Sel1L/ERAD is required for CD8+ T-cell function and memory formation. Mechanistically, Sel1L/ERAD is required for an oxidative phosphorylation metabolic program associated with CD8+ T-cell persistence.

Color Evolution Across Squamate Signaling Systems
John David Curlis, Ecology and Evolutionary Biology

Colorful signals among animals present a compelling example of phenotypic diversity found in nature. Because signals are often directly related to natural and sexual selection, the mechanisms underlying their evolution are important for understanding the maintenance of evolutionary diversity. I am directly testing how signal evolution is impacted by sensory drive, the idea that certain signals are most adaptive in ecological contexts in which they are most easily perceived. Using the slender anole, a small lizard that possesses a colorful throat fan (dewlap) used in signaling, I will test the hypothesis that different light environments drive differential selection pressures on signal color. I am monitoring transplanted populations of slender anoles on tiny islands in Panama and measuring changes in dewlap color over generations, as well as conducting behavioral experiments on anoles from the mainland. This research will lend valuable insights into the evolution of diversity across the tree of life.

Genetics and Evolution of the Gyromitrin Mycotoxin in False Morel Mushrooms
Alden Dirks, Ecology and Evolutionary Biology

Gyromitrin is a mycotoxin produced by false morel mushrooms (Gyromitra spp.). Paradoxically, gyromitrin-containing false morels are consumed as a delicacy in some parts of the world after detoxification. Care must be taken because poisoning can result in organ damage, and repeated exposure may induce neurodegenerative diseases. Despite false morels’ infamy as both delicacy and deadly poison, we have limited evidence concerning which false morels produce gyromitrin. The genes responsible for gyromitrin production and the evolutionary processes that gave rise to it are also unknown. My thesis explores the distribution, genetics, and evolution of gyromitrin using a novel chemical assay, next-generation sequencing, and genetic transformation. I sampled false morels from across North America and tested them for gyromitrin, which revealed a discontinuous and more limited distribution than expected. Ongoing transcriptomic, phylogenomic, and knockout studies aim to reveal the gyromitrin- producing genes and history of its evolution in false morels.

Determining the Thermodynamic Gain of Experimental Rotating Detonation Combustors
Alexander Feleo, Aerospace Engineering

To sustainably meet the growing energy needs of the world, alternatives to standard deflagration engines are required. Rotating detonation combustors (RDCs) are novel chemical-based devices that utilize detonation to provide a thermodynamic efficiency increase while being capable of safely operating with sustainably produced hydrogen, unlike standard deflagrative devices. The evaluation of the thermodynamic benefit of RDCs is experimentally challenging, due to the unsteady, non-uniform, and complex fluid flow. This work has redefined the performance metrics of interest for RDCs as well as identifying and quantifying some of the key loss mechanisms that detrimentally impact the performance, such as backflow into the inlet. The link between the details of the detonation wave(s) and performance is investigated. Overall, these findings will inform future designs of RDCs that can then achieve the reduction/elimination of carbon emissions from combustion-based power generation and propulsion systems.

Redox Chemistry Controls Coenzyme B12 Trafficking in Mitochondria
Harsha Gouda, Biological Chemistry

Coenzyme B12 (or AdoCbl) is used as a cofactor by human methylmalonyl-CoA mutase (MCM), which catalyzes the 1,2-rearrangment of methylmalonyl-CoA to succinyl-CoA. The synthesis of AdoCbl is carried out by ATP:cob(I)alamin adenosyltransferase (ATR), using ATP and cob(II)alamin as substrates. We have shown that ATR facilitates AdoCbl synthesis by controlling the 4-coordinate geometry of cob(II)alamin, which brings the cob(II)alamin/cob(I)alamin reduction potential within reach of biological reductants. In MCM, the occasional escape of the 5´-deoxyadenosyl moiety of AdoCbl, leaves cob(II)alamin stranded in the active site and prone to hyper-oxidation by molecular oxygen, forming a dead-end MCM•cofactor complex. We have discovered that this inactivation is prevented by the common metabolite, ADP, which helps preserve the cob(II)alamin redox state and promotes its repair. Crystallographic and EPR studies have identified that ADP uses bivalent molecular mimicry to seal off solvent access to the cofactor, thus preventing its hyperoxidation.

Spatial Metabolism Modeling of Sustainability, Resilience, and Justice Tradeoffs: The Case of Urban Agriculture
Jason Hawes, Resource Policy and Behavior

Cities are responding to climate change and urbanization by producing sustainability and resilience plans and announcing new justice initiatives. Yet, scholars and practitioners struggle to model synergies and tradeoffs between sustainability, resilience, and justice as cities grow and change. In this work, I apply a novel spatial metabolism modeling framework to urban agriculture (UA) as a case study for changing cities. UA is widely discussed as a key intervention for urban systems, however its multi-sectoral effects – food provision, community cohesion, mental health benefits, etc. – vary across space and time and have proven difficult to assess. This work will characterize the spatialized effects of UA expansion on material and social flows (i.e., spatial metabolism) by combining citizen-science data using a spatial planning framework. Results will outline the effects of UA on people, places, and planet and demonstrate how spatial metabolism can be used to track sustainability, resilience, and justice outcomes.

Determining the Role of Prefrontal and Parietal Cortex in Consciousness
Emma Huels, Neuroscience

This dissertation aims to inform a key controversy regarding the roles of prefrontal (PFC)
and parietal (PC) cortex in level (awake vs. unconscious) and content (i.e., qualitative experience) of consciousness using anesthesia and psychedelic-induced states as model systems in rats. Aim 1 tests the hypothesis that inactivation of PFC, but not PC, suppresses behavioral arousal by quantifying the effect of tetrodotoxin(TTX)-mediated inactivation of PFC/PC on anesthetic-induced loss/return of consciousness. Aim 2 tests whether interactions of PFC and PC mediate psychedelic-induced increases in Lempel-Ziv complexity (a proposed surrogate measure for changes in content of consciousness in humans) by determining 1) the changes in Lempel-Ziv complexity and directed connectivity during psychedelic administration, and 2) the causal influence of PC on PFC (and vice-versa) via changes in these measures following TTX-mediated inactivation of PC/PFC. These studies are expected to yield foundational knowledge for anesthesiology/neurology (monitoring level of consciousness) and psychiatry (psychosis).

Mobile Health Enabled, Patient-Centric Precision Dosing of Immunosuppression
Abbie Leino, Clinical Pharmacy Translational Sciences

The lifesaving potential of organ transplantation depends on the individualization of immunosuppressive drugs. Precision dosing is critical to prevent immune-mediated damage while minimizing toxicity. Precise dosing for these highly variable drugs requires multiple blood collections, which is challenging to implement. My work will develop a convenient method for the patient to self-collect blood microsamples at home for quantification and interpretation by the healthcare team. I have developed the first analytical procedure to simultaneously quantify tacrolimus and mycophenolate from a novel volumetric absorptive microsampling device, the Tasso-M20. The device painlessly obtains capillary blood by pressing a button. My ongoing work seeks to document the accuracy of Tasso-M20 samples in the real world and implement mobile health technology to increase patient acceptability and usability to facilitate the collection of repeated samples. Combining modern tools from various disciplines (analytical chemistry, pharmacometrics, and health behavior), I hope to support precision dosing and improve patient outcomes.

Supervisory and Time-Distributed Methods for Computationally Efficient Model Predictive Control
Jordan Leung, Aerospace Engineering

The need for reliable constrained control methodologies, such as Model Predictive Control (MPC), is constantly increasing due to the increased adoption of autonomous systems in our everyday lives (e.g., self-driving cars) and in advanced engineering challenges (e.g., reusable rockets). However, MPC can be difficult to implement in practice since control inputs are generated by solving a constrained Optimal Control Problem (OCP) at each timestep. Thus, onboard processors must be capable of solving these OCPs faster than the required sampling period of the controller. This dissertation proposes three approaches for reducing the computational cost of implementing MPC. System-theoretic analyses are performed for each approach to derive formal guarantees of safety (e.g., stability and constraint satisfaction). Moreover, case studies of automotive and aerospace control problems are used to demonstrate that the proposed approaches can safely control constrained dynamic systems at a low computational cost.

Computational Approaches for Modeling Cell Differentiation Using Single-Cell and Spatial Omics Data
Jialin Liu, Bioinformatics

Cell differentiation is the process in which cells develop into distinct types with specialized functions. This process is vital for the proper development, reproduction, growth, and longevity of multicellular organisms. Recent molecular biology techniques that measure the molecules within individual cells in their native tissue context hold tremendous potential to systematically and unbiasedly model the cell differentiation process. However, significant data analysis and modeling challenges must be overcome in order to define cellular identity from multiple protocols and quantify communication between cells. The goal of my thesis is to develop computational methods for defining cellular identity, detecting cell-cell communication, and predicting the dynamics of communications during cellular differentiation.

A Mixed Methods Approach to Understanding and Improving Hand Function in Older Adults
Rachel Logue, Movement Science

Aging is associated with a variety of sensorimotor changes that impact the function of the upper limbs, particularly the hands, making it difficult to complete daily activities and remain independent. Despite most activities requiring full use of the hands, aging and hand function remains understudied. Currently, there is limited understanding regarding the reliability of clinical hand assessments, the role older adults’ and physicians’ attitudes toward hand function play in the reporting and assessment of impairments, and interventions to improve function. The aims of the proposed dissertation are: 1) to evaluate grip strength, the most common assessment of hand function, as a predictor of hand impairments 2) to describe attitudes and behaviors regarding hand function expressed by older adults and clinicians 3) to implement an upper limb training intervention for older adults. Results from this dissertation will inform future clinical practice to better serve our aging population.

Modulation of Ubiquilin-2 by the Novel RTL8 Family of Proteins
Harihar Milaganur Mohan, Cellular and Molecular Biology

Maintaining protein quality control is essential for cell function. Ubiquilins (UBQLNs) are central to this process as they promote the clearance of defective proteins arising from genetic mutations or environmental stress. The most important UBQLN, UBQLN2, participates in cellular physiology, stress responses, and neurodegenerative disease processes through its interactions with various cellular proteins. Yet, many of these interactions and how they alter UBQLN2 function remain poorly understood. One example is the recently identified RTL8 family of proteins which are the strongest UBQLN2 interactors. My dissertation investigates how this novel class of proteins modulates UBQLN2 function. To date, I have uncovered the molecular basis of UBQLN2-RTL8 interactions and their effects on regulating abnormal proteins. I have also begun elucidating RTL8’s critical role in UBQLN2’s response to stress. My remaining thesis work will further establish RTL8 as a key regulator of UBQLN2-mediated protein quality control and potentially neurodegenerative disease processes.

Exploring Protein Dynamics Through Paradigms of Chaperone Action and Structural Disorder
Rishav Mitra, Molecular, Cellular and Developmental Biology

Protein folding and dynamics shape all aspects of biology. Decades of work has shown that far from being rigid structures, proteins are intrinsically dynamic and undergo motions at different time scales. Models have been used for decades to build frameworks for understanding complex biological phenomena. In particular, the cross-disciplinary fields of protein folding, and dynamics have benefited immensely by employing model proteins to establish mechanistic paradigms and theoretical models that collectively shape our ways of thinking about the biophysics of proteins. In this thesis I explore molecular chaperones and intrinsically disordered proteins as models where dynamics play an important role. Molecular chaperones are the main players in cellular protein quality control. They assist in protein folding, maintain native structures, and prevent protein aggregation. The first part of my thesis explores the mechanism of action of the small ATP-independent Escherichia coli chaperone Spy on a topologically complex client. In the second part of my thesis, I characterize the structure and dynamics of a highly conserved disordered protein, SERF, and explore the role of disorder in protein-RNA interactions. Collectively, the use of two unrelated systems offers insights into how the dynamically accessible conformational space of proteins determines their biological function.

Characterization of Regulation and Activities of ETS-Dependent ‘GGAA’ Repeat Enhancers in B-cell Acute Lymphoblastic Leukemia
Alexander Monovich, Molecular and Cellular Pathology

Atypical enhancer regulation plays critical roles in oncogenic gene expression programs. We have identified aberrant enhancer-like activation of ‘GGAA’ short tandem repeats (GGAA-reps) as a novel driver of gene expression signatures in the ETV6::RUNX1 and ETV6::RUNX1-like subtypes of B-cell acute lymphoblastic leukemia (B-ALL), the most common pediatric malignancy. GGAA-rep enhancer activity is facilitated by deficiency of the ETS repressor ETV6 and direct binding by the ETS activator ERG. Re-expression of ETV6 in ETV6::RUNX1-positive, ETV6-null B-ALL cells represses repeat enhancers and associated genes, and reduces leukemia fitness. Through a CRISPR-interference screen of GGAA-reps and ETV6 binding sites, I have additionally identified GGAA-reps that mediate growth-promoting expression of known oncogenes (e.g., MYC, PIM1, RUNX1) that may represent potential therapeutic targets in ETV6::RUNX1 and ETV6::RUNX1-like B-ALL. Future work will be focused on further validation and characterization of our screen hits in addition to determining mechanisms underlying GGAA-rep activity in ETV6-altered B-ALL.

Statistical Methods to Incorporate Information Theory in Causal Inference
Soumik Purkayastha, Biostatistics

Investigating public health disparities requires identifying underlying causal factors. This dissertation proposes novel and scalable analytic methods for causal discovery and inference with special emphasis on public health. Said methods bridge statistical and information theory for the sake of application to biomedical research. In chapter I, a framework for estimating and testing the significance of causal relationships in observational data is presented. In chapter II, a mediation model is proposed that can detect complex non-linear effects of multiple mediators on the association between exposure and outcome. Chapter III extends ideas proposed in earlier chapters to study the framework of instrumental variables, which are used to study causal relationships when controlled experiments are not feasible, or are improperly implemented. To solicit the interest of practitioners from diverse backgrounds, this thesis is accompanied by well-documented software to implement the proposed methods.

Defining the Nutrient Inputs that Support Pancreatic Cancer Metabolism
Peter Sajjakulnukit, Cancer Biology

Pancreatic ductal adenocarcinoma (PDA) is the deadliest major cancer. Metabolism is rewired in PDA to support growth in the nutrient deregulated tumor microenvironment, including the profile of nutrients utilized and the mechanisms by which these are accessed. To characterize the spectrum of nutrients that support PDA metabolism, we employed an arrayed nutrient screen of ~175 individual substrates and assayed for cellular reducing potential. We found that uridine is metabolized by PDA cells to support bioenergetics via uridine phosphorylase 1 (UPP1). UPP1 is regulated by mutant KRAS, the main oncogenic driver of PDA, and its knockout inhibits tumor growth. These findings identify uridine utilization as an important compensatory metabolic process in PDA, suggesting a novel metabolic axis for PDA therapy. Ongoing studies utilizing this screening technique are being performed to define the nitrogen inputs and the effect of lipids, and dipeptides in PDA.

Harnessing Compact Type I CRISPR Systems As Large-Scale Genome Editing Tools
Renke Tan, Biological Chemistry

CRISPR-Cas are adaptive immune systems in prokaryotes. CRISPR-Cas technology employs Cas9 enzyme for precise genome editing. Yet, the most abundant microbial adaptive immune system-Type I CRISPRs, are under-exploited for eukaryotic applications. The goal of my thesis is to harness compact Type I (CRISPR-Cas3) systems into robust genome editing tools. The first part introduces a CRISPR-Cas3 with high editing efficiency and compact size for use in mammalian cells. Secondly, my work uncovered that expressing a separately encoded NlaCas11 in human cells is the key to enable plasmid- and mRNA- based gene editing. Furthermore, I demonstrate that supplyingcas11is a universal strategy to systematically implement divergent CRISPR-Cas3 editors. The third part of this thesis focuses on profiling the genome editing outcomes for the compact CRISPR-Cas3 editors. Together, these findings greatly expand our ability to engineer long-range genome edits, paving the way for research and therapeutic applications.

Cumulative Loneliness and Memory Aging Among Middle-Aged and Older Men and Women in the United States
Xuexin Yu, Epidemiological Science

Although loneliness has been associated with increased risk of dementia, this dissertation will address several knowledge gaps for loneliness to become a practical public health intervention target to prevent and/or delay dementia onset at the population level. In Aim 1, a prospective cohort study will examine the association between cumulative loneliness and subsequent memory aging from a life course perspective. In Aim 2, a simulation study with quantitative probabilistic bias analyses will assess the potential impact of differential loneliness underreport across gender and age groups in the association studied in Aim 1. In Aim 3, a causal mediation analysis will be performed to investigate the mediating role of systemic inflammation in the loneliness-memory relationship, providing evidence on the potential biological mechanism in this association. Overall, this dissertation will contribute to understanding the loneliness-memory relationship among the US middle-aged and older adults.