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Oral Regeneration in Stentor coeruleus: Cytoskeletal Patterning and Cell Cycle Control
Get PDFRegeneration and wound healing are essential biological processes that restore cellular and tissue integrity following injury from external perturbations. Central to these processes is the interpretation of positional cues which include chemical or mechanical signals that instruct cells on what to rebuild and where to place structures. While the mechanisms underlying tissue and organ regeneration have been extensively studied, the molecular and spatial logic of regeneration at the subcellular level remains less understood. The giant single-celled ciliate Stentor coeruleus offers a powerful model for uncovering how cells interpret positional information to reconstruct complex intracellular architecture. With a highly polarized body plan, anterior-posterior axis, and an oral apparatus critical for feeding, Stentor can regenerate entire structures from fragments, provided a part of the macronucleus is intact.Here, we explore how cytoskeletal patterning and cell cycle regulators support regeneration in Stentor. The oral apparatus regenerates at a stereotyped location along the anterior-posterior axis, guided by visible cortical landmarks such as pigmented stripes and organized arrays of cytoskeletal fibers. We find that Sfi1 family proteins, which scaffold centrin-based cytoskeletal assemblies, are upregulated during regeneration and are essential for both oral primordium formation and contractility. RNAi-mediated depletion of Sfi1 genes impairs regeneration and anterior-posterior centrin patterning, suggesting that Sfi1 proteins establish cytoskeletal polarity necessary for morphogenesis. These proteins are recruited in a temporally ordered manner to the regenerating oral primordium, linking gene expression timing with spatial organization.Moreover, we show that regeneration utilizes components of the canonical cell cycle. Using transcriptional and phosphoproteomic analyses, we identify upregulation of cell cycle regulators including E2F, CDK4, Rb, and cyclins during regeneration. Inhibition of CDK4 with Palbociclib disrupts this pathway and suppresses regeneration, indicating that CDK4-mediated phosphorylation of Rb and subsequent activation of E2F target genes is required. Interestingly, the morphological stages of regeneration mirror those seen during cell division, including macronuclear condensation and elongation, suggesting shared regulatory mechanisms. Our results raise the possibility that regeneration in Stentor reflects a partial redeployment of the developmental program associated with cell division.Together, our findings reveal that Stentor regeneration depends on the integration of cytoskeletal patterning with conserved cell cycle signaling pathways. This model system provides insight into how cells use positional cues and multifunctional molecular machinery to rebuild complex structures with spatial precision. Our work highlights the convergence of regeneration and cell cycle regulation as a general principle of morphogenesis, even at the level of a single cell
Validation and Optimization of a Quantitative Susceptibility Mapping (QSM) Pipeline for Paramagnetic Rim Lesions in Multiple Sclerosis
Get PDFQuantitative Susceptibility Mapping (QSM) provides valuable sensitivity to paramagnetic rim lesions (PRLs) in multiple sclerosis, but the influence of algorithmic choices within the processing pipeline remains unclear. This study systematically compared two phase unwrapping methods (ROMEO and PRELUDE), two background field removal strategies (V-SHARP and RESHARP), and dipole inversion with iLSQR to assess their impact on lesion visibility and contrast stability.ROMEO achieved rapid phase unwrapping (20–40 seconds per dataset) compared to the several hours required by PRELUDE, yet PRELUDE produced clearer boundaries for small lesions, particularly in anatomically complex regions. For background field removal, V-SHARP provided greater global stability across brain regions, while RESHARP enhanced local lesion-to-background discrimination, especially within the corpus callosum and basal ganglia. Case-specific analyses further revealed that lesion distribution strongly influenced outcomes: when lesions were widely distributed across white matter, pipeline effects were minimal, whereas lesions clustered near iron-rich structures such as the basal ganglia amplified pipeline-dependent differences, yielding significant QSM-level effects.In summary, ROMEO offers major efficiency advantages, but PRELUDE remains essential for small-lesion analysis. Likewise, V-SHARP ensures stable global contrast, while RESHARP is more effective in certain anatomical contexts. These findings underscore the need for pipeline selection tailored to lesion characteristics and anatomical location
Brainstem circuits that control appetite
Get PDFNutrients are essential for sustaining life as we know it. Therefore, organisms, including humans, have evolved complex brain networks to control the decision to seek food, consume it, and when to stop eating. Importantly, the desire to overeat and store excess energy for scarce times must be weighed against the harmful effects of overloading our digestive systems.The satiation of hunger has traditionally been viewed as a gradual process triggered during a meal by gastrointestinal feedback, which is relayed by sensory nerves to the caudal brainstem to suppress appetite. Therefore, brainstem circuits – namely, the caudal nucleus of the solitary tract - are thought to be activated over tens of minutes to promote satiety. However, this assumption has not been directly tested due to the challenge of studying such a deep brain structure. To address this longstanding question, we developed new methods for recording the activity of distinct cell types in this brain region and determined that they regulate appetite on multiple timescales.Chapter one of this dissertation reviews our historical understanding of how the caudal brainstem controls hunger satiation. Chapter two explains how new studies have shaped our understanding of spinal sensory neurons and their importance to GI function. Chapter three describes the first in vivo recordings of caudal brainstem circuits during behavior, which revealed that one group of neurons is primarily activated by the taste of food and control the duration of seconds-timescale feeding bursts, while a second distinct group of neurons is activated by mechanical feedback from the gut and promoted satiety that lasted for tens of minutes. These experiments have revealed fundamental principles by which the brain monitors external and visceral sensory signals during a meal to dynamically control ingestive behavior and maintain physiological homeostasis
Resting state functional magnetic resonance imaging in presymptomatic and symptomatic genetic prion disease
Get PDFGenetic prion diseases (gPrDs) are rare, fatal neurodegenerative disorders caused by pathogenic variants in the PRNP gene. Identifying early markers of network dysfunction is critical for advancing early detection and intervention strategies. This study investigates default mode network (DMN) functional connectivity alterations in presymptomatic gPrD carriers, with a focus on differences between faster- and slower-progressing subgroups. Resting-state fMRI data was acquired from presymptomatic carriers, symptomatic participants, and matched healthy controls. Seed-to-voxel analyses were performed to compare DMN connectivity across groups, with statistical significance determined after correction for multiple comparisons. Presymptomatic carriers exhibited distinct connectivity alterations based on progression rate. Faster-progressing individuals showed reduced posterior DMN connectivity, centered in the posterior cingulate and precuneus, while slower-progressing carriers displayed increased anterior DMN connectivity within the medial prefrontal cortex. Symptomatic participants demonstrated widespread DMN disruption relative to controls, consistent with progressive network breakdown. Alterations in DMN connectivity are detectable before symptom onset and differ according to progression rate, supporting their potential as early biomarkers in gPrD. While constrained by sample size and limited longitudinal follow-up, these findings highlight the value of resting-state fMRI in presymptomatic stages and underscore the need for larger, multicenter, longitudinal studies to clarify the trajectory of functional network changes in gPrD
Exploring Molecular Glues for 14-3-3 Protein-Protein Interactions
Get PDF14-3-3 regulates the activity of thousands of client proteins in various biological pathways through physical occlusion, structural conformations, and scaffolding protein-protein interactions (PPIs). Utilizing the role of 14-3-3 to regulate client proteins, the Arkin lab has developed molecule glues (MGs) that stabilize native 14-3-3/client interactions, harnessing the negative regulatory interactions to “turn off” client proteins’ functions in disease. By targeting PPIs as opposed to singular proteins, selectivity can be enhanced through selective MGs that bind the unique composite interfaces for a PPI of interest. This also allows for unstructured proteins/regions that were previously difficult to target to gain new induced binding pockets for modulators for the development of novel therapeutics. The work presented in this dissertation showcases the work on exploring MGs for various 14-3-3/client interactions, with focus on the 14-3-3/ERα and 14-3-3/CRAF complexes. These client proteins represent crucial targets in cancer (ERα and CRAF) and in developmental RASopathies (CRAF) that have distinct functions and binding modes to 14-3-3. Capitalizing on the differences allowed for the development of selective MGs and assays to characterize the effects of stabilizing these 14-3-3/client interactions. Work along each step of the drug discovery and development for 14-3-3/client MGs is presented in this dissertation: screening and validation of stabilizing fragments, optimization of fragment hits into selective MGs, and characterization of cell-active MGs. The lessons learned in each chapter provide insight into 14- 3-3 biology in the regulation of transcription factors (ERα) and kinases (CRAF) as well as serving as building blocks to expand stabilization to other native or neomorphic PPIs
Density Functional Theory Study of Iron–Oxygen Divacancies in Magnetite (Fe3O4) and Hematite (Fe2O3)
Get PDFDensity functional theory (DFT) calculations are employed to investigate the formation energies, charge redistribution, and binding energies of iron-oxygen divacancies in magnetite (Fe3O4) and hematite (Fe2O3). For magnetite, we focus on the low-temperature phase to explore variations with local environments. Building on previous DFT calculations of the variations in formation energies for oxygen vacancies with local charge and spin order in magnetite, we extend this analysis to include octahedral iron vacancies before analyzing the iron-oxygen divacancies. We also assessed the relative stability of iron-oxygen divacancies by comparing their formation energies with those of individual vacancies. Our findings reveal a significant energetic driving force for the formation of divacancy clusters, particularly in magnetite, where divacancies in the +1 charge state exhibit formation energies comparable to those of neutral iron vacancies under oxidizing conditions. In hematite, the results indicate a strong tendency for oxygen vacancies to bind to iron vacancies. These results highlight the significance of iron-oxygen vacancy complexes in the transport properties of iron oxides, with particular relevance to diffusion mechanisms under irradiation conditions
Anyon superconductivity from topological criticality in a Hofstadter–Hubbard model
Get PDFWe argue that the combination of strong repulsive interactions and high magnetic fields can generate electron pairing and superconductivity. Inspired by the large lattice constants of moiré materials, which make large flux per unit cell accessible at laboratory fields, we study the triangular lattice Hofstadter-Hubbard model at one-quarter flux quantum per plaquette, where previous literature has argued that a chiral spin liquid separates a weak-coupling integer quantum Hall phase and a strong-coupling topologically trivial antiferromagnetic insulator at a density of one electron per site. We argue that topological superconductivity emerges upon doping in the vicinity of the integer quantum Hall to chiral spin liquid transition. We employ exact diagonalization and density matrix renormalization group methods to examine this theoretical scenario and find that electronic pairing indeed occurs on both sides of criticality over a remarkably broad range of interaction strengths. On the chiral spin liquid side, our results provide a concrete model realization of the long-hypothesized mechanism of anyon superconductivity. Our study thus establishes a beyond-Bardeen-Cooper-Schrieffer route to electron pairing in a well-controlled limit, relying crucially on the interplay between electron correlations and band topology
Unified Robustness in AI: From Symbolic Reasoning to Hardware Resilience
Get PDFModern AI systems achieve remarkable performance in controlled settings yet remain fragile in deployment, where sensor noise, distribution shift, adversarial manipulation, and non-ideal hardware routinely violate the mathematical assumptions under which models are designed. This dissertation develops a unified framework for robustness that spans algorithms, representations, and hardware. The central thesis is that dependable, efficient, and interpretable intelligence emerges by coupling (i) symbolic structure for constraint and explanation, (ii) high-dimensional (HD) representations with kernel-theoretic control of geometry, and (iii) hardware–algorithm co-design that aligns encoders with the native (often analog and nonlinear) operations of emerging accelerators.Concretely, the dissertation makes four contributions. First, it introduces HDGIM, a genomesequencing pipeline that embraces stochasticity in ferroelectric FET (FeFET) compute-inmemory (CiM) arrays and achieves reliable, high-throughput operation via noise-aware HD learning. Second, it develops a kernel-aware analysis of HD encoders (e.g., Fourier Holographic Reduced Representations), deriving closed-form gradients that explain resilience to random noise while exposing vulnerabilities to structured, kernel-aligned perturbations and enabling principled white-box attacks. Third, it proposes two co-design methods—Kernel Matching and Kernel Transfer Encoding—and a joint end-to-end objective that restore target similarity geometry on non-ideal substrates, yielding iso-accuracy with ideal software and preserving algebraic operations (e.g., binding) required for graph reasoning. Fourth, it demonstrates that neurosymbolic binding of interpretable texture/shape/color descriptors with neural embeddings in HD space provides compositional redundancy, improves adversarial robustness across threat models, and supplies actionable explanations of failure. Empirical evaluations span classification and reasoning tasks on standard benchmarks and physics-based FeFET models. Co-design reduces a ∼ 65% naive quality collapse for relational HD reasoning on CiM to ∼ 6% loss, and achieves software-level accuracy under realistic device non-idealities. Kernel-aligned attacks validate the analysis and guide defenses; increasing hypervector dimensionality systematically improves robustness with predictable computational cost. The resulting methodology enables interpretable, energy-efficient, and dependable AI on resource-constrained platforms, including intelligent sensing, CiM and photonic accelerators, and low-power edge devices. Overall, the dissertation shows that unified robustness is attainable when symbolic reasoning, HD representation, and hardware realities are treated not as separate layers but as a single, co-designed system
Similarity Reasoning in the Social Sciences
Get PDFModels are an essential tool of social scientific practice. However, notable shortcomings— such as the failure of macroeconomic models in predicting the 2008 financial crisis—have cast doubts about their epistemic status. This dissertation examines how similarity is used in reasoning from models in social scientific methodology. I focus on reasoning by similarity because the justifications for a model’s explanatory and/or predictive power is often taken to be—explicitly or implicitly—because the model is deemed relevantly similar to the target phenomenon. The dissertation consists of four chapters, each using scientifically informed philosophical analysis to provide insights into what kinds of similarity judgments are useful when reasoning from models
The Role of the SLC39A8 A391T Variant in Crohn's Disease: Implications for Selenium Metabolism
Get PDFCrohn’s disease (CD) is a complex inflammatory bowel disease characterized by mucosal immune dysregulation and gut microbiome imbalances. Among the over 200 genetic loci associated with CD susceptibility, the SLC39A8 A391T variant remains an understudied coding mutation with potential implications for disease pathogenesis. SLC39A8 encodes ZIP8, a divalent cation transporter essential for trace elements homeostasis, including zinc and selenium (Se).We hypothesize that the A391T variant contributes to CD by impairing Se uptake, disrupting selenoprotein function, and impairing the intestinal barrier. To investigate this, we developed a knock-in mouse model carrying the A391T-equivalent mutation (A393T). Our findings reveal that homozygous A393T mice exhibit reduced Se levels in the intestinal mucosa, accompanied by low-grade inflammation and increased intestinal permeability.Furthermore, A393T mice develop exacerbated NSAID-induced small intestinal injury. Ongoing studies aim to assess whether A393T has reduced selenoprotein function and whether Se supplementation can mitigate the effects of the variant by restoring selenoprotein activity and intestinal homeostasis. These findings highlight a previously unrecognized role for SLC39A8 in Se metabolism and small intestinal homeostasis, offering new insights into potential therapeutic strategies for CD