University of Illinois at Chicago
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<i>Quiet Urgency</i>
No full textThis photograph, captured near the Ilulissat Glacier in Greenland, reflects a moment during our Arctic research expedition. My work focuses on understanding how climate change affects biogeochemical processes in the Arctic Ocean, specifically how increased freshwater inputs from sea ice, rivers, and glaciers influence phytoplankton production. By studying these processes, I aim to uncover the cascading effects of freshwater inputs on Arctic ecosystems. This month-long trip spanned Alaska to Greenland, allowing us to witness the glacier's breathtaking scale and beauty before heading home. In this image, my colleague reflects on the glacier's immense scale and serene surroundings. We described the sound of the ice melting as the most peaceful we had ever heard—a moment of tranquility that highlighted the importance of our work. The Ilulissat Glacier, one of the fastest-melting glaciers in Greenland, retreats at an astounding rate of up to 100 feet per day, making it a stark symbol of accelerating climate change. This experience deepened my understanding of the interconnectedness of climate systems and strengthened my commitment to addressing the challenges posed by climate change. I am truly grateful to UIC for supporting me and the opportunity to explore and contribute to preserving the Arctic’s delicate ecosystem.</p
<i>We’re stardust, remember?</i>
No full textLooking through the microscope, the vastness of the cosmos stares back at me. Although greatly differing in size, our brain and the universe are more alike than you think. The intricate patterns of vibrant cyan astrocytes stretch out like delicate star-shaped filaments. Grey orbs—the nuclei—drift as silent moons, while magenta nucleoli pulse like quasars, radiating energy at the heart of creation. Golden puncta, scattered like stardust, are RNA—the molecular messengers of life, shining with purpose. This image captures the cellular architecture of the hippocampus, a key brain region for memory and learning, with sub-cellular resolution. At the center of the image lies the pyramidal layer of the hippocampus, where neurons are densely packed in an arc, resembling the swirling core of a galaxy. The improvement in the image resolution was achieved by physically expanding the brain tissue by embedding it in a swellable hydrogel. This imaging technique called expansion microscopy allows us to visualize nanoscale protein structures and RNA simultaneously in the brain tissue. Like the universe, the brain holds infinite mysteries waiting to be explored, and evolving microscopy techniques are pushing us closer to illuminating its vast complexity.</p
Role of GALC in Adult Brain Myelination
No full textKrabbe Disease (KD) is a demyelinating leukodystrophy instigated by various mutations in the GALC gene. KD has multiple subtypes, but the most common and most aggressive variant is lethal within the first years of life without treatment. The GALC enzyme is responsible for catabolism of galactosphingolipids, particularly galactosylceramide and psychosine. Psychosine is cytotoxic and its accumulation leads to widespread pathology, particularly demyelination. KD is studied through animal models, particularly the Twitcher (TWI, GALC -/-) mouse model that features a nonsense mutation leading to no functional GALC enzyme.
A previous study from this lab treated TWI with an adeno-associated virus (AAV) with a GALC transgene (TWI-AAV). This therapy increased survival, reduced signs of disease, increased GALC activity to supraphysiologic levels, and reduced pathology. However, the protective effect of the AAV waned over time such that GALC activity decreased and psychosine increased.
Chapter II examines the aged TWI-AAV as compared to WT, untreated TWI, and younger TWI-AAV. The aged TWI-AAV have multi-focal demyelination, specifically in the brain, as compared to the widespread demyelination of untreated TWI. The demyelinated lesions mostly resembled untreated TWI with no GALC mRNA, no GALC enzyme, and microgliosis. However, the demyelinated lesions also had novel pathology, previously not documented in untreated TWI, including blood brain barrier disruptions and fibrinogen extravasation. This pathology has however been documented in Multiple Sclerosis (MS), for which GALC is a known risk factor. Furthermore, certain proteins related to MS pathology were also elevated in the aged TWI-AAV brain.
Chapter III investigates the episome dilution hypothesis as the cause for why the AAV treatment efficacy declined over time. Upon transducing cells, the DNA within AAV is known to primarily exist as non-replicating extrachromosomal episomes. The demyelinated lesions of aged TWI-AAV were shown to have actively replicating oligodendrocyte precursor cells (OPC). Furthermore, the OPCs specifically within the lesions did not express GALC in contrast to OPCs in other regions. In vitro and in vivo experiments provided evidence in support of the episome dilution hypothesis. AAV DNA and GALC transgene were shown to decrease over time in TWI neuroglial cells, inversely proportional to total cell count. GFP fluorescence, from AAV encoded GFP, diminished over time in WT mouse brains. Together, this data shows it is highly likely the AAV treatment efficacy declined over time due to episomal dilution and eventual exhaustion.
Chapter IV explores the role of GALC in adulthood, particularly its role in myelination, through the tamoxifen (TMX) inducible GALC knockout GFPC model. Adult GALC loss within oligodendrocytes (OG) lead to mild to moderate dysmyelination and locomotor impairment, particularly in complex tasks requiring balance and coordination. The mice were then challenged with an additional demyelinating insult in the form of experimental autoimmune encephalitis (EAE), a model of MS, to examine if the GALC deficiency made them more vulnerable to secondary demyelination. The GALC deficiency and EAE were additive in worsening signs of disease, significantly decreasing median survival, associated demyelination, gliosis, microgliosis, decreasing GALC activity, and increasing psychosine. GALC deletion and EAE demonstrated an additive effect showing that GALC loss sensitizes myelin to further demyelinating insults.
Lastly, Chapter V summarizes the findings of this thesis. The main findings of this thesis being that episomal AAV DNA is lost through continuous cellular replication as defined in the episomal dilution hypothesis and GALC is required for myelin maintenance throughout life. The gradual dilution of episomal AAV DNA leads to focal loss of therapeutic episome with reversion to an untreated state over time in regions with suspected higher basal rates of cellular replication. GALC being required for myelin maintenance throughout life is a novel finding, this highlights how a successful therapy for KD will need to continuously supply GALC throughout life for it to be successful. Lastly, the conclusion discusses the limitations of the experiments in this thesis and ideas for future experimentation to address unanswered questions
Modeling Phase Transformation Induced Shear Failure in Geomaterial
No full textOne hypothesized mechanism that triggers deep-focus earthquakes in oceanic subducting slabs below ~300 km depth is transformational faulting due to the olivine-to-spinel phase transition. This study develops high-fidelity numerical models to investigate phase transformation-induced stress redistribution and material weakening in olivine. A thermodynamically consistent constitutive model is formulated and implemented in finite element modeling, incorporating viscoplastic behavior, thermo-mechanical coupling, and multiscale material features, including polycrystalline structures and mesoscale heterogeneity.
Simulation results reveal that spinel formation under pressure initiates near inclusions and grain boundaries, aligning with experimental observations. At lower rates, thin spinel bands form diagonally to the compression direction, correlating with high pressure regions and suggesting fault initiation. At higher transformation rates and temperatures, more extensive spinel formation leads to ductile behavior. Overall, the numerical model captures mechanical features similar to laboratory experiments including spinel band formation and stress softening behavior. Further analyses on local stress-strain relationships and distributions also offer insights into the underlying mechanisms, demonstrating a reduction in material strength due to transformation and shedding light on fault initiation processes.
To overcome conventional finite element method (FEM) limitations in capturing localized spinel bands, a Shearing Particle Method (SPM) in the framework of the Reproducing Kernel Particle Method (RKPM) is introduced. The SPM sharpens stress and strain localization by incorporating shear discontinuous enrichment functions. Comparisons with extended FEM (XFEM) model results show the SPM's enhanced ability to model localized spinel bands and provide insights into fault initiation mechanisms
Structural and Functional Explorations of Novel Ribosome-Targeting Antibacterials
No full textProtein synthesis is vital for cell survival. Ribosomes, the site of protein synthesis, are known to serve as targets for approx. half of the clinically useful antibiotics. The emergence of drug resistance in bacteria, however, creates dire need for new antibiotics. One approach to addressing this crisis is the discovery of novel chemical scaffolds. Alternatively, optimizing existing antibacterial drugs through chemical modifications can improve potency, enhance target affinity, or alter their mechanism of action for improved efficacy. In this work, we explored the mechanisms of under studied or “forgotten” ribosome targeting antibacterial compounds namely thermorubin, sparsomycin and bottromycin A2 which are naturally occurring secondary metabolites, and CAM BER, a semi-synthetic derivative of chloramphenicol. Varied in form yet unified in function, these compounds—despite their diverse sizes, chemical structures, and physical properties—converge on a common target i.e. protein synthesis. To establish each compound’s mode and mechanism of action, we used microbiological, biochemical, and structural methods. Using high-resolution X-ray crystallography, CryoEM, and primer extension inhibition (toe printing) assays, we demonstrated that thermorubin inhibits translation elongation, thereby disproving the prior hypothesis that it is a bona fide inhibitor of translation initiation. CAM-BER, a berberine analog of chloramphenicol, binds the ribosome 40X more strongly than its parent compound. Interestingly, our X-ray crystal structure demonstrated that CAM-BER binding causes a previously unseen rearrangement of 23S rRNA nucleotide A2059. Based on our structure, we predicted that CAM-BER should inhibit translation initiation, unlike elongation inhibitor chloramphenicol. Our toe-printing data supports this hypothesis. CAM-BER’s altered mechanism may help it bypass certain resistance pathways evolved against chloramphenicol. Sparsomycin's clinical use is limited by its broad activity, inhibiting translation not only in bacteria but also in archaea and eukarya. Structurally understanding sparsomycin’s mode of binding in a physiologically relevant complex is the key to designing effective derivatives. To this end, we first conducted toe-printing assays to identify the ideal stalling complex for crystallization. We report the first X-ray crystal structure of sparsomycin bound to the Thermus 70S ribosome with mRNA and full-length tRNA, resolving previous discrepancies and unambiguously establishing its binding mode in bacteria. Despite its discovery seventy years ago, the binding site and mechanism of bottromycin A2 remain unidentified. Significance of studying bottromycin A2 lies in the fact that it exhibits antibacterial activity against MRSA (Methicillin-resistant Staphylococcus aureus) and VRE (Vancomycin-resistant Enterococci), which pose serious threat to public health. Leveraging our toolkit of various in vivo and in vitro techniques, we demonstrated that bottromycin A2 inhibits translation elongation in a context-dependent manner. We also showed that the binding site of this drug likely resides near A2602 in the ribosome's catalytic center. Our efforts to determine its mode of binding in the ribosome using cryo EM are currently underway
Numerical and Experimental Study of Electrohydrodynamic Flow For A Pin-to-Plane Electrostatic Atomizer
No full textThis dissertation investigates electrohydrodynamic (EHD) flows in pin-to-plane electrostatic atomizers through numerical, analytical, and experimental approaches. The research addresses challenges in optimizing electrostatic atomizer designs for charge injection for use in industrial applications.
The study begins with a numerical evaluation of electric field and potential distributions for various geometric configurations, highlighting the dominant role of sharp curvatures and relative proximity of electrode structures to the counter electrode.
Analytical solutions for a hyperbolic paraboloid geometry model further explores the interplay between normal and tangential electric field components. It reveals the dominance of the normal electric field components, despite the curvature inducing tangential field components; diminishing the significance of the tangential component as a potential driving mechanism for EHD flows.
A comprehensive numerical parametric analysis examines the effects Reynolds number, mobility, charge injection level, and charge injection area on flow structures; identifying conditions that may lead to unsteady flow patterns. Response surface methodology and multivariate statistical analysis quantify parameter interdependencies and their influence on charge profiles, peak velocities, and impingement pressures.
Experimentally, a multi-scale, dual-domain Particle Image Velocimetry (PIV) study was conducted to capture high-resolution local and bulk flow dynamics at applied voltages ranging from 4 to 12 kV. The results reveal correlations between applied potential, flow velocity, and emergent flow structures, including a novel pattern of interlocking vortices.
This work advances the understanding of EHD phenomena in pin-to-plane configurations and provides actionable guidelines for optimizing electrostatic atomizer designs. The findings and methodologies contribute to the development of more efficient and versatile systems tailored to diverse industrial needs
Exploring Ricci Curvature and Ricci Flow in Social and Biological Graphs and Hypergraphs
No full textThis thesis leverages algorithmic and graph-theoretic tools to gain new insights into complex
networks, focusing on network shape measures, particularly Ricci curvature, and its discrete
adaptations. The research spans multiple applications, including networks of functional correlations
in brain regions, where we investigate structural changes in ADHD-diseased brain networks.
By introducing and comparing Forman-Ricci and Ollivier-Ricci curvatures, we demonstrate
their distinct contributions and limitations, showing that one cannot substitute for the
other. In ADHD networks, for instance, we identify seven critical edges supported by neuroscience
findings.
The thesis also provides foundational work on applying Ollivier-Ricci curvature to complex
networked systems, establishing theoretical bounds for exact and approximate computations.
This analysis enhances our understanding of how curvature can capture underlying structures
that elude more conventional metrics. Additionally, we generalize these approaches to hypergraphs,
which model higher-order interactions in social and biological networks. Using a
novel curvature-guided diffusion process coupled with topological surgery and edge-weight renormalization,
we identify influential cores in directed and undirected hypergraphs, validated
on metabolic and co-authorship networks
Empathy Cause Identification: Towards Unveiling Empathic Triggers in Online Interactions
No full textThe study of empathy and its triggers is an emerging area in natural language processing (NLP), offering vital insights for creating empathetic and emotionally intelligent technologies. This thesis addresses a gap in research by focusing on empathy cause identification—a challenging task aimed at pinpointing the specific triggers prompting empathetic responses in communicative settings.
To advance this field, this work introduces a novel dataset annotated specifically for empathy cause identification and explores various models designed to evaluate and demonstrate the dataset’s applicability. This research not only contributes to the understanding of empathy in textual communication but also paves the way for the development of AI systems capable of more nuanced and supportive interactions.
The dataset AcnEmpathize used to create the new dataset, received a letter of non-determination, see the Appendix, from the Institutional Review Board (IRB) at the University of Illinois
Chicago (UIC) and was determined not to constitute human subjects research
Exploring the Links Between Masculinities and Sexual Consent Through the Lens of Social Work
No full textThis dissertation includes three articles studying masculinities and sexual consent acquisition. The first article explores masculinities research in the field of social work through a systematic mapping review. Results from this study indicated that social work research on masculinities has grown significantly over the past several decades, focused on men's self-reported behaviors and attitudes, but could benefit from future exploration of broader constructs of masculinity beyond traditional conceptions. The second and third articles explore masculinities and sexual consent using quantitative data. In the second article, multinomial regressions were conducted to evaluate the relationships between the construct of masculinity and sexual consent acquisition style. Findings indicated that internalized and externalized masculinity factors are significantly associated with sexual consent acquisition style, with isolation, socialization, and hegemonic masculinity norms playing key roles. In article three, multinomial regressions were employed to assess the relationships between perceived disadvantages related to masculinity and consent acquisition style. Results from this study indicated that men facing negative societal pressure due to their masculinity are more likely to have ambiguous acquisition style, while those with sexual insecurities have concrete acquisition style, suggesting a complex relationship between perceived disadvantage, privilege, and masculinity in shaping consent attitudes. The dissertation results provide a valuable addition to the masculinities research conducted by social work researchers. This dissertation provides implications for social work practice when working with those experiencing masculinities and consent violations, research on masculinities, and policy related to gender and patriarchy
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