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Roles of CpsA and SLAMF1 in the innate immune response to Mycobacterium tuberculosis
No full textMycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), possesses an arsenal of virulence factors to evade host immunity. Not only is Mtb able to evade innate immunity, but adaptive immunity also often fails to adequately control Mtb infection. A mechanistic understanding of how Mtb establishes infection and evades immunity is critical to the development of a protective vaccine and novel therapeutics. The Mtb protein CpsA protects Mtb against the host NADPH oxidase and LC3-asociated phagocytosis of the innate immune system. Consequently, a ΔcpsA mutant is initially attenuated in vivo but eventually reaches the same bacterial burden in the lungs as wild type (WT) Mtb. Using flow cytometry, we found that CpsA promotes dissemination of Mtb from alveolar macrophages and the airways into recruited myeloid cells in the lung interstitium, which promotes priming of naïve T cells. Because it elicits a delayed adaptive immune response, the ΔcpsA mutant experiences a more permissive environment, allowing it to ultimately achieve the same bacterial burden as WT Mtb. Our studies reveal that a more effective innate immune response against Mtb can be undermined by a corresponding delay in the adaptive immune response. CD4+ T cells are crucial for protective immunity to Mtb. A direct cognate interaction between CD4+ T cells and infected macrophages is important for control of Mtb; however, the mechanism has been elusive. We found that in Mtb-infected mice and macaques, SLAMF1 expression was induced in diverse myeloid cells specifically by the combination of Mtb infection and T cells and depended, in part, on autophagy. Moreover, when we infected Slamf1-/- mice, we found they had higher Mtb burdens, dysregulated inflammatory responses, and more rapid disease progression than wild type mice. In macaques, macrophage SLAMFI expression was highest in protective granulomas and after highly-protective intravenous BCG vaccination. Together, these data demonstrate that SLAMF1 is a T cell contact-dependent factor in macrophages that contributes to host protection from TB. Overall, these findings provide insight into the protective immune response to Mtb and the virulence strategies of Mtb that must be overcome by an effective vaccine
A Novel Way of Conceptualizing and Measuring Situation Selection
No full textSituation selection is a form of emotion regulation where people approach or avoid certain things, places, or objects to proactively regulate their emotions. Though it is the only strategy that occurs before encountering emotion-eliciting events, situation selection remains understudied. The present research proposes a new measure of Day Recollection Situation Selection (DRSS) in which participants are prompted to recall the day\u27s events before reporting their approach and avoidance behaviors. Across two studies, we aimed to: (1) develop the DRSS measure, (2) compare it to existing measures of situation selection and well-being, (3) examine within- and between-person variability, and (4) compare baseline DRSS to daily means and variability. In one age-diverse survey, and a separate daily diary survey, the DRSS revealed 3 subscales: prohedonic approach, prohedonic avoidance, and contrahedonic behaviors. While the first two subscales aligned with existing measures of approach and avoidance, the contrahedonic subscale was uniquely captured by the DRSS and predicted lower well-being. Approximately half of the variability of the DRSS came at the within-person level. Baseline DRSS predicted greater daily use of all three forms of situation selection, but baseline contrahedonic behaviors were uniquely predictive of variability in daily life. These findings highlight the prohedonic and contrahedonic behaviors of situation selection, with the latter being less frequent but impactful for well-being. Our findings suggest that situation selection can be both prohedonic and contrahedonic. These findings underscore the multi-faceted nature of situation selection as a form of emotion regulation, highlighting that while prohedonic behaviors are more common, the less frequent contrahedonic behaviors have important implications for shaping well-being in daily life
Examining emotion regulation in individuals with social anxiety disorder using nomothetic and idiographic approaches
No full textSocial anxiety disorder (SAD) is frequently linked to difficulties with emotion regulation. One family of emotion regulation strategies is situation selection, which largely involves approaching or avoiding a situation based on how someone anticipates they might feel in that situation. Despite group-level SAD research about the use of avoidance as a situation selection strategy, there is limited idiographic research about how people with SAD use situational avoidance to regulate their emotions. There is also a dearth of research about the use of other situation selection strategies, including approach, at both the individual and group level. As such, the goal of this dissertation was to examine idiographic and nomothetic relationships between anxiety and the use of avoidance and approach in people with and without SAD. Participants (N = 20) were asked to complete brief surveys four times a day for 30 days using a smartphone application. The longitudinal data were analyzed using residual multilevel dynamic structural equation models and multilevel models to examine individual- and group-level differences in dynamic relationships between anxiety, approach, and avoidance. The findings indicated that individuals did not vary significantly in the relationships between these variables and that there were no significant differences between the SAD and control groups in the relationships between anxiety and situation selection strategy use. Group-level results did reveal some important autoregressive effects in people on the average. Evidence from the nomothetic approach also provided mixed support that people may use similar strategies to regulate themselves and others. Importantly, the data suggest that some people may not often engage in situational avoidance or approach, as very few study participants endorsed using these strategies to regulate themselves or others. Directions for future research and implications for intervention are discussed
The Witten Deformation and Proper Cocompact Lie Group Actions
Get PDFWe study the interactions between the Witten deformation of the de Rham exterior differentiation and topological invariants in two scenarios of proper Lie group actions. In the first scenario, we work on a closed oriented manifold admitting an action by a compact connected Lie group. Using a special Morse-Bott function invariant under the group action, we deform the de Rham exterior derivative and get the associated Witten Laplacian. Applying asymptotic analysis, we localize the kernel of the Witten Laplacian around the critical components of the invariant Morse-Bott function. Finally, we build the chain isomorphism between the invariant Thom-Smale complex and the invariant Witten instanton complex. In the second scenario, we work on an oriented noncompact manifold admitting a proper cocompact action by a Lie group. First, through the generalized mod 2 index map between real KK-groups, we deform the Dirac type operator associated with the de Rham exterior derivative and find the appropriate Witten deformation of the de Rham exterior derivative. Then, we show that the invariant cohomology associated with this Witten deformation can be used to compute the semi-characteristic of the manifold. Finally, we prove that the semi-characteristic vanishes when there are two independent invariant vector fields on the manifold
Investigating the Roles of SOX10 and ETV4 in Melanocyte and Melanoma Development
Get PDFThe neural crest is a transient, multipotent cell population unique to vertebrates that gives rise to diverse lineages, including craniofacial cartilage, peripheral neurons, glia, and pigment-producing melanocytes. Proper specification and differentiation of neural crest derivatives are orchestrated by tightly regulated gene regulatory networks, and disruption of these developmental programs can lead to congenital disorders and malignancies. Melanocytes, derived from the neural crest, are best known for their role in skin pigmentation but also contribute to homeostasis and specialized functions in the eye, ear, and heart. These cells produce melanin to protect tissues from ultraviolet radiation and oxidative damage, and they play key roles in immune signaling, tissue structure, and sensory function. However, melanocytes are also highly responsive to environmental stress and intrinsically vulnerable to transformation. In melanoma, the most aggressive form of skin cancer, melanocytes acquire oncogenic mutations and reactivate neural crest-associated gene programs that promote dedifferentiation, invasion, and therapeutic resistance. This dissertation investigates the molecular underpinnings of melanocyte development and melanoma progression, with a focus on two transcription factors, SOX10 and ETV4, that regulate neural crest and melanocyte biology. SOX10, a core component of the melanocyte lineage gene regulatory network, is indispensable for melanocyte specification, survival, and pigment gene expression. Beyond its developmental roles, SOX10 functions as a major lineage dependency in melanoma, maintaining proliferative identity, promoting phenotypic plasticity, and contributing to drug resistance. To define the molecular mechanisms underlying SOX10 function, this work employs proximity-dependent biotinylation (miniTurbo) to map the human SOX10 interactome in melanoma cells, revealing novel co-regulators and chromatin-associated partners that support its oncogenic activity. ETV4, a member of the ETS family of transcription factors, is broadly expressed in embryogenesis and cancer but has not been well studied in melanocyte lineages. Using a zebrafish model of melanoma, this dissertation shows that etv4 overexpression delays melanocyte differentiation during development and suppresses melanoma formation in adults. Together, these studies illuminate the roles of SOX10 and ETV4 in melanocyte biology and melanoma progression. By uncovering lineage-specific transcriptional mechanisms and protein interactions, this work contributes to a deeper understanding of melanocyte plasticity and identifies potential targets for therapeutic intervention in melanoma and pigmentary disorders
Effective and Efficient Graph Foundation Model
Get PDFGraph data has emerged as a central component in numerous real-world applications, spanning recommender systems, drug discovery, social networking, and traffic forecasting. While traditional and modern graph learning techniques—ranging from graph kernels to Graph Neural Networks (GNNs) and graph transformers—have achieved significant success, their task-specific nature and reliance on supervised learning limit their adaptability to new, unseen tasks. This rigidity becomes especially problematic in dynamic environments where retraining for every new task is costly and often infeasible. Inspired by the transformative impact of foundation models in natural language processing, this thesis explores the feasibility of developing a graph foundation model—a single, unified model capable of generalizing across diverse graph tasks and domains. Such a model would not only address conventional challenges like node classification and link prediction but also extend to emerging tasks involving information retrieval, reasoning, and structural querying over graphs. To realize this vision, the thesis identifies and tackles three key challenges: (1) domain heterogeneity in graph data representations, (2) task inflexibility stemming from human-designed prediction heads, and (3) the computational and structural complexity intrinsic to graphs. The thesis is structured around three main contributions: Chapter 2 introduces a unified model capable of learning across multiple graph domains; Chapter 3 expands on this foundation to build a more generalizable and versatile graph model; and Chapter 4 investigates the fundamental properties of graph learning to enhance the efficiency and scalability of the proposed models. Together, these contributions represent a step toward building general-purpose graph models that mirror the flexibility and transferability of language foundation models, laying the groundwork for more adaptive and scalable graph-based machine learning systems
From the Amazon to the Andes: Paleoclimatic and Paleoenvironmental Changes Recorded by Sedimentary Biomarkers Since the Late Pleistocene
No full textThe South American tropics encompass some of Earth\u27s most diverse and dynamic landscapes, from tropical glaciers and arid deserts to savannahs, shrublands, and the planet’s largest and most biodiverse rainforest—spread across a vast climatic and topographic gradient. These biomes provide vital natural resources that sustain communities, bolster economies, and serve as key components of the global hydrologic and carbon cycles. Despite their environmental and socioeconomic importance, these tropical systems are highly vulnerable to contemporary and future climate change and its cascading impacts. Adding to this challenge, the scarcity and short duration of instrumental climate records from this region pose major challenges to quantifying hydroclimate and environmental responses to anthropogenic climate change. Proxy-based paleoclimate reconstructions are therefore essential for understanding pre-industrial climate variability, offering critical insights into past hydroclimate and environmental change. Yet paradoxically, high-resolution paleoclimate records from the South American tropics remain limited, especially in comparison to the northern high latitudes. This dissertation addresses that gap by presenting high-resolution local- to regional-scale reconstructions of hydroclimate and environmental change from eastern Amazonia and the Eastern Cordillera of the Colombian Andes over the past 20,000 years, using organic geochemical proxies preserved in lacustrine sediments. I first develop plant wax n-alkane δ2H and δ13C records from Lago Caranã, Brazil, to evaluate eastern Amazonian precipitation and vegetation dynamics over the past ~5600 years. I then apply the same tools to sediments from Lago de Tota, Colombia, to investigate the dynamics of the Intertropical Convergence Zone (ITCZ) and South American Summer Monsoon (SASM), and their influence on the understudied northern tropics of South America over the past ~19,300 years. Finally, I develop a method that leverages the DionexTM accelerated solvent extraction (ASE) 350 system for the selective sequential extraction and chromatographic separation of sedimentary n-alkyl lipids and polycyclic aromatic hydrocarbons (PAHs), which I apply to the Lago Caranã sediments to reconstruct late Holocene fire activity in the region. On centennial timescales, I find that expansions and contractions of the ITCZ’s seasonal range, driven by Atlantic sea surface temperature variability, may have enhanced moisture transport into eastern Amazonia throughout the late Holocene. The legacy of pre-Columbian Indigenous land use is recorded in Caranã’s n-alkane δ13C record through changes in vegetation composition and forest canopy structure, driven by both local and regional fire activity as indicated by sedimentary charcoal and PAH data. On millennial timescales, shifts in the mean position of the ITCZ, driven by variations in the Atlantic Meridional Overturning Circulation (AMOC) and intensification of austral summer insolation, increased precipitation and convection over the northern South American lowlands during the late Pleistocene and Holocene. Together, these records offer new insights into the nuanced drivers of hydroclimate and environmental change in the South American tropics, enhancing our understanding of how tropical systems respond to both natural and anthropogenic climate forcing
Acquisition Algorithms for Protein Mass Spectrometry and Their Application to Clinical Proteomics
No full textBottom-up protein mass spectrometry aims for the identification and quantification of protein species by proxy of their proteolytic peptides. This dissertation presents methodological advances in three areas of protein mass spectrometry: acquisition methods, clinical appli- cations, and data analysis algorithms. The second chapter presents an optimized internal standard-triggered parallel reaction monitoring (OIS-PRM) method and demonstrates its application to study prognostic biomarkers in head and neck squamous cell carcinoma (HN- SCC). OIS-PRM uses intelligent scan scheduling and real-time monitoring of peptide elution profiles to reduce cycle-times and improve quantitative precision and accuracy. The assay measured NRF2 activation in both cell lines and formalin-fixed paraffin-embedded tumor samples, and it also quantified differences in T-cell marker expression between HPV-positive and HPV-negative tumors. The clinical applications demonstrated here may also help guide treatment decisions for HNSCC patients based on molecular signatures of NRF2 activity and inflammation. The third chapter introduces Pioneer and Altimeter, open-source tools for the analysis of data-independent acquisition (DIA) mass spectrometry data. Pioneer implements several innovations. These include an intensity-aware fragment indexing algorithm, robust spectral deconvolution using pseudo-Huber loss, and modeling of quadrupole transmission effects on fragment isotope patterns. Altimeter generates collision energy-specific spectral predictions using B-spline functions. This enables a single library to accommodate different instruments and methods. Across multiple benchmarks using different mass analyzers and experimental conditions, Pioneer demonstrates 3-15 times faster processing speeds and comparable or superior proteome coverage and quantitative precision compared to a state-of-the-art analysis tool, DIA-NN. Together, these tools improve DIA analyses and establish a new computational framework that can adapt to emerging experimental techniques
Correcting Misinformation in Online Groups
No full textThe spread of misinformation, especially within online clusters of like-minded individuals, poses a critical threat to democracies, increasingly leading to radicalization and mobilized violence worldwide. How can we dispel misinformation within online groups? Extending works on group norms and social identity to online groups, I argue that corrections delivered by users within an online group can reduce group members’ misperceptions. Using four original studies from South Korea, I provide observational and experimental evidence that confirms the prevalence of peer corrections, the existence of bias in favor of online ingroup, and the effectiveness of ingroup peer corrections in reducing misperceptions. These results highlight the importance of leveraging the influence of online groups to correct misinformation, offering a potentially scalable solution to combat misinformation in the digital age. This study contributes to our understanding of digital publics and their effects on attitude change and persuasion
Échos culturels : Dynamique et évolution de la langue française dans les œuvres littéraires et cinématographiques francophones de la Louisiane et de l’Afrique, du XIXe siècle à nos jours
No full textFrancophone studies have long recognized the well-established literary connections between African and diasporic Caribbean literatures. However, the ties between Louisiana and African Francophone literary traditions remain understudied. This research interrogates the corpus of Francophone Louisiana and Francophone African writings from the 19th century to the present, employing a comparative framework to juxtapose the smallest Francophone region (Louisiana) with the largest (Francophone Africa). By analyzing the evolution of the French language and its cinematic representations across these regions, this study elucidates distinct yet interrelated linguistic phenomena that have emerged since the 19th century, thereby constructing a theoretical framework for understanding the trajectory of French in these contexts. The comparative approach emphasizes the regionalization of French through processes of Africanization and Creolization, revealing the profound sociolinguistic transformations shaped by historical, cultural, and social forces. This perspective enables a transdisciplinary examination of linguistic and literary legacies, bridging Francophone Louisiana and Francophone Africa while engaging with broader questions of language evolution, identity formation, and lived experiences. Crucially, this study establishes connections between these regions not only through their shared histories of transatlantic slavery but also through the African linguistic foundations of Louisiana Creole, thereby contributing to a more nuanced understanding of Francophone cultural and literary intersections