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PILRα Sustains Microglial Capacity to Process Myelin in a Mouse Model of Demyelination
No full textAlzheimer\u27s disease (AD) is characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and neurodegeneration. Microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in AD pathogenesis by containing the spreading of Aβ plaques. Genetic studies have associated a variant of the receptor Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRα) with reduced risk for AD. PILRα is a receptor found on myeloid cells, such as microglia, that binds to endogenous cell surface glycoproteins and sends inhibitory signals within the cell. Additionally, it serves as an entry receptor for Herpes Simplex Virus 1. To elucidate the role of PILRα in microglial responses to brain pathology, here we used the cuprizone (CPZ) model of demyelination in Pilrα–/– mice. In this model, CPZ-fed mice experience oligodendrocyte death and demyelination of brain white matter, with microglia crucially clearing damaged myelin and promoting remyelination by oligodendrocyte progenitor cells (OPCs) after CPZ exposure ceases. Among mouse brain cells, PILRα expression was specifically observed in microglia. Deficiency of PILRα reduced microglia response to demyelination and myelin remodeling. This defect was associated with increased proliferation of OPCs. Co-immunoprecipitation experiments corroborated a direct interaction of PILRα with the inhibitory phosphatase SHP1. Hence, PILRα plays a key role in balancing the microglial response and promoting myelin regeneration by OPCs. This reveals an unexpected function in regulating repair mechanisms during brain pathology
The Hill We Climb: A Mixed Methods Exploration of Stress and Depression in a Community Sample
Get PDFWhile research on Black mental health has increased over the past decade, there remain strides to make with regard to the investigation of the relationship between stress and depression among Black Americans. For decades, stress process scholars have documented that negative, adverse experiences have consequences for mental health conditions, such as depression. Stress process theory predicts that greater exposure to stressors and limited access to coping resources increase the risk of poor mental health. Therefore, socially disadvantaged groups such as Black Americans would be expected to be at great risk of mental health conditions due to previous exposure to stressors. Nevertheless, epidemiological research indicates a paradox in which there is an equal or lower prevalence of mental conditions in Black individuals compared with White individuals. Guided by the life course perspective and stress process model, stress exposures (i.e., life stressors and stressful life events) among mid-to-older Black Americans were explored in this dissertation. Three empirical studies were comprised and drew upon from the St. Louis Personality and Aging Network (SPAN) Study. While investigating major stressors in life narratives, the first study employed a qualitative approach to explore these narratives and identified three predominant life stressors: illness, death of loved ones, and family. The second study used SPAN survey data to examine the association between stress exposure and depressive symptoms is a predictor. Consistent with prior research, I found that stress exposures were predictors of depressive symptoms. Finally, the third study explored the effects of stressful life events and depressive symptoms across three-time points. Approximately 90% of participants included in the study reported experiencing at least one stressful life event each wave and an increase in the number of stressful life events was significantly associated with an increase in depressive symptoms. Overall, the findings of this dissertation underscore the critical importance of accounting for the dimensions and frequency of stress exposure throughout the Black adult life course to better understand the nuances and context of their mental health experiences. Given the high risk for poor mental health among Black adults, public health researchers should further explore the link between stress and mental health among this population, especially as the U.S. aging population is growing and becoming increasingly diverse
Essays on securities fraud class actions
No full textThis piece argues that both the efficient market requirement and event study methodology—once the core of the fraud-on-the-market theory—have evolved in securities fraud class actions. It provides the first comprehensive analysis of fraud-on-the-market cases over the past fifty years and divides this evolution into five chronological stages
Safe Real-Time Obstacle Detection and Navigation Using CBF–CLF and CBF–PID Control
Get PDFTraditional robotic navigation pipelines typically follow a three stage architecture: obstacle detection, path planning, and low-level control for trajectory tracking. While effective in static environments, these methods often introduce latency and lack formal guarantees of safety in dynamic or unplanned for scenarios. Our work addresses these limitations by developing a real-time controller grounded in Control Barrier Functions (CBFs) and Control Lyapunov Functions (CLFs), unified through a Quadratic Program (QP). We first investigate a hybrid CBF-PID-QP controller on a 1/10 scale car, where the CBF serves as a real-time safety filter, modifying the PID output to prevent constraint violations. While this architecture guarantees safety, it can result in “sticking points” or equilibrium states where the control inputs satisfy safety constraints but fail to make progress toward the goal. This is particularly pronounced under unicycle dynamics, where steering inputs may not influence the CBF, making certain maneuvers infeasible. To overcome this, we transition to a full CLF-CBF-QP framework using single-integrator dynamics. This formulation eliminates the need for global path planning or prior exploration. The CLF ensures convergence to a goal position, while the CBF maintains safety, allowing the controller to generate control inputs that are both safe and goal oriented in real time. We further propose a novel modification to the CBF function that enables prioritization of obstacles directly in the robot’s path and vii ensures a non-vanishing gradient, effectively eliminating sticking points even in symmetric obstacle-goal configurations. This method is validated on the Unitree G1 humanoid. Across simulation and hardware experiments, we demonstrate that our formulation avoids sticking points and successfully handles both static and dynamic obstacles without relying on global planners or learning- based policies. This work highlights that real-time, low-level controllers can replace conventional planning stacks, providing safe, responsive, and mathematically grounded behavior in complex, dynamic environments
The response of mitochondrial position to glucose stimulation in the MIN6 model system
No full textThe compartmentalization of eukaryotic cells into membrane-bound organelles with specific subcellular positioning enables precise spatial and temporal control of cellular functions. While functionally significant mitochondrial localization has been demonstrated in cells such as neurons, it remains unclear how general these cell principles are. Here, we examine the spatial organization of mitochondria within MIN6 pancreatic beta cells under variable glucose conditions. We observe glucose-dependent redistributions of mitochondria, favoring peripheral localization at elevated glucose levels when insulin secretion is also elevated. Our results suggest that active mitochondrial transport along microtubules and calcium activity, but not ATP synthesis, are critical regulators of this redistribution. We derived a mathematical model that suggests that a putative affinity of the mitochondria with the membrane competes with mitochondrial microtubule attachment to play an important role in establishing the mitochondrial spatial patterns we observe. These results suggest that mitochondrial positioning may contribute to optimizing energy delivery in response to local demand, potentially representing a general regulatory mechanism across various cell types
Mechanism of unconventional IL-33 release in airway disease
Get PDFThe alarmin cytokine IL-33 is a strong inducer of type two inflammation and has been implicated in various chronic lung diseases. Although much work has been done to understand the inflammatory effects of extracellular IL-33, there is still a knowledge gap in understanding how this cytokine is secreted by airway epithelial cells in steady-state conditions. In the work laid out in this document, a COPD-disease associated isoform of IL-33, that has exons 3 and 4 (IL-3334) spliced out and is tonically secreted at baseline conditions. This IL-33 isoform is secreted from airway epithelial cells alongside, or as part of, extracellular vesicles that arise from nSmase2-driven ceramide generation at the endosomal membrane whose contents are then secreted upon fusion to the plasma membrane. The main goal of this project was to uncover the mechanism through which IL-3334 is recruited to the nSmase2-dependent exosome biogenesis pathway. HSP70, the stress induced molecular chaperone, binds to IL-33 and chaperones it to a secretory membranous compartment, reminiscent of a microautophagy mechanism. IL-3334 also binds to the negatively charged lipid phosphatidyl serine which HSP70 may potentiate or enhance. Outside of the cell, this HSP70/cytokine complex stabilizes IL-3334 by inhibiting oxidation/degradation, thereby enhancing IL-3334-receptor binding and activity. We find evidence that IL-33, HSP70, HSP90 and proteostasis chaperonin TCP-1 are dysregulated in human chronic airway disease biospecimens. A significant portion of this work also delved into developing the tools and methodology to study the contributions of extracellular vesicles in airway disease. This molecular chaperone dysregulation phenomenon is also reflected in the differential proteomics in diseased bronchial wash extracellular vesicles which opens opportunities to track EV-mediated communication in vivo and in human derived biospecimens. These platforms can be applied to interrogate the functional roles of EVs, molecular chaperones and noncanonical IL-33 signaling in modulating immune responses, propagating inflammation, or contributing to airway remodeling in chronic lung diseases such as asthma and COPD. This work confirms proteostasis intermediates, chiefly HSP70 as a chaperone for non-canonical IL-3334 secretion and activity that may be amenable for therapeutic targeting in chronic airway diseases such as asthma and COPD
The Effects of Habitat and Anthropogenic Disturbance on Western Lowland Gorillas (Gorilla gorilla gorilla), Central Chimpanzees (Pan troglodytes troglodytes), and Associated Mammal Community
No full textIn northern Congo, sympatric western lowland gorillas (Gorilla gorilla gorilla) and central chimpanzees (Pan troglodytes troglodytes) face many threats, including hunting, human-induced habitat disturbance, and infectious diseases. This research presents three projects that explore factors that can affect the transmission of pathogens and development of disease in western lowland gorillas and central chimpanzees. Information and data were collected at multiple scales and different conservation contexts, from the individual apes, to social dynamics of the groups in which they live, and to the mammalian communities in which they have long coexisted in the Congo Basin of which they are a part. The first chapter, Comparing the Life History and Demography of Sympatric Western Lowland Gorillas (Gorilla gorilla gorilla) and Central Chimpanzees (Pan troglodytes troglodytes) , details the life history and demography of the habituated western lowland gorillas and central chimpanzees in the Goualougo Triangle and Djéké Triangle in the Republic of Congo. We found that the gorillas and chimpanzees in our study had broadly similar demographic patterns, including life spans, birth rates, infant mortality, and the presence of a significant post-reproductive period. This confirmed the findings of previous research that the fruit-heavy diets of both western lowland gorillas and central chimpanzees lead to similarly slow life histories. Understanding the life history of a species provides insights into the range of effects a pathogen could have on a potential host of that species, and how the presence of that species in a broader community will affect the transmission of pathogens among sympatric species. These findings also contribute to remedying the scarcity of life history data and demographic data from chimpanzees and gorillas in this region which is essential for informing monitoring programs and conservation policy. Given the pristine nature of the protected forest in northern Congo where these habituated great apes live, our results indicate that intact forests, especially in protected areas, are important to the demographic stability of western lowland gorillas and central chimpanzees, and that habitat disturbance could be disruptive to the life histories of great apes living outside of protected areas. In the second chapter, Comparing Correlates of Clinical Signs of Disease in Sympatric Western Lowland Gorillas and Central Chimpanzees , data from those same habituated gorilla and chimpanzee groups were used to explore how social and environmental factors affect and are affected by respiratory illness, gastrointestinal distress, and lesion outbreaks among the habituated apes. This work built on previous health monitoring of the habituated gorilla groups in the Goualougo Triangle and Djéké Triangle and the empirical social networks studied in these habituated groups. Results indicated that the intersection of demography and environmental factors such as fruit availability, as well as the social interactions of gorillas and chimpanzees, were all predictors of great ape health, with variations between species and clinical sign. By understanding the effects of fruit availability, demography, and sociality on health, we explored how they can provide additional pathways through which habitat disturbance could further exacerbate the prevalence and severity of disease in great apes, and improve our understanding great ape health in the face of global change. The third chapter, Mammalian Biodiversity Estimates Across an Anthropogenic Disturbance Gradient in Central Africa , uses invertebrate derived environmental DNA to study the mammalian community in which these great apes exist across an anthropogenic disturbance gradient in northern Congo. The relationship between biodiversity and pathogen transmission is well studied and stridently debated, but for many zoonotic and anthropozoonotic pathogens, evidence has emerged that their transmission is negatively correlated with biodiversity, and that anthropogenic disturbance is an important mechanism mediating this relationship. The anthropogenic disturbance gradient studied here seeks to capture a variety of contexts where the connections between humans and wildlife can lead to higher transmission of zoonotic pathogens. Both distance from a village and distance from a road correspond to the level of human pressure and had significant effects on the distribution of mammals found in the areas around Nouabalé-Ndoki National Park. We also found that intact forests were important habitats for many animals in the region, including both western lowland gorillas and central chimpanzees. The results obtained from this environmental DNA survey differed in species composition from our previous work in the region using camera traps to study biodiversity, despite their similar species richnesses, showing the value of complementary methods for assessing biodiversity in the region
The Republic of Silence: Writing the Resistance Against Fascism, 1936-1945
No full textThe Republic of Silence, Writing the Resistance, 1936-1945 advances the claim that the historiography of the Resistance against Fascism has largely been a process of forgetting rather than remembering. In its instrumentalist framing of resistance, much of the historiography of the Resistance has occluded the sense of futility that members of the resistance grappled with. Writing, I argue, is a point in which the conflict between the obligation and futility of resistance plays out in its most dramatic form. Why risk one’s safety to write a work that won’t change the course of history, or even fail to find a readership? By centralizing literature in this history of the Resistance, this dissertation seeks to develop a historically-informed form of criticism that resists instrumentalist forms of judgement. With defeats in Spain and the fall of the Popular Front this era marks a phase in anti-Fascism in which politics had to be imagined in the face of defeat rather than advancing a specific future. The solidarity of the resistance, as the literature of the time reveals, was a solidarity emerging out of a shared experience of futility rather than a shared vision of the historical future. While the authors I focus on come from various nationalities (from H.D. to Albert Camus, Primo Levi to Marguerite Duras, Jean Cassou to George Orwell), their belonging to the dissertation hinges on their participation in resistance activities against Fascism in Europe during this period. Each chapter accordingly addresses a dilemma—such as whether to publish one’s writing or conceal it, to write clearly or in code, to give one’s work a narrative structure, etc.—and investigates how it this shaped the styles of authors engaged in resistance across national boundaries. This method is taken here so as to demonstrate how similar stylistic tendencies evolved in authors who were not causally affiliated with one another, indicating that the ways in which many features of resistance writings emerged from shared conditions rather than direct influence. Interrogating how futility shaped each of these lived dilemmas, I argue that futility can be experienced as the starting point of creative action rather than its termination
Multimodal Characterization of Systems-Level Robustness in the Cellular Organelle Network
No full textEukaryotic cells house mesoscopic and macroscopic complex systems that work in tandem for proper cellular function. A defining feature of eukaryotic cells is their mesoscopic network of membrane bound compartments called organelles. While each type of organelle has their own individual functions, there are vital cellular processes that come from the interactions between them, such as organelle biogenesis and metabolic regulation. A central question in cellular biophysics is to what degree is cellular function robust or fragile to breaks in the organelle network. These interactions can be explored by genetically deleting inter-organelle protein tethers called organelle contact sites. Here we examine this question focusing on organelle contact sites focused on the endoplasmic reticulum, a principal player in both lipid and protein synthesis in the cell. Specifically, we examine components of the OCS connecting the ER and plasma membrane, Scs2 and Scs22, as well as the ER/nuclear envelope and vacuole, Nvj1. Using hyperspectral confocal microscopy, mass spectrometry and RNA-sequencing, I aim to address the systems-level role organelle interactions have at multimodal scales. In both replete conditions and lower carbon availability, the mutant strains show insensitivity on a cellular level, yet form putative compensatory modes at the mesoscopic and microscopic scales. The organelle-scale level shows widespread changes to the endomembrane system with varying volume fractions of the endoplasmic reticulum, lipid droplets and Golgi compared to wildtype. Preliminary results from computational genome-scale metabolic models paired with mass spectrometry and RNA- sequencing experimental data support a model of lipid redirection from the endoplasmic reticulum that the organelle network works to process metabolically to maintain cellular-scale homeostasis
Sex, Stress and Hormones : The Role of Modifiable Risk Factors in the Kinetics of Alzheimer’s Disease
Get PDFAlzheimer’s Disease (AD) is a neurodegenerative disease hallmarked by the presence of amyloid- plaques and tau tangles in the brain. The process of the disease begins decades prior to the onset of symptoms and is thought to be driven first by a buildup of amyloid- peptide in the extracellular space, triggering a cascade of pathology and symptomology culminating in loss of cerebral volume and cognitive impairment. Women are diagnosed with AD at a rate 2/3 higher than their male counterparts, even when controlling for age. While most driving factors of the disease are thought to be genetic, roughly 40% of disease risk is tied to modifiable risk factors. These risk factors include obesity, traumatic brain injury, sleep, and most interestingly, stress. Women are also more likely to develop stress related disorders, such as depression, post-traumatic stress disorder, and anxiety. Additionally, past trials that examine the role of hormone replacement therapy (HRT) in protecting cognition during aging have yielded conflicting results, suggesting there are different impacts of the various factors surrounding HRTs roll in the prevention of AD. We aim to elucidate the role of stress in the pathogenesis of AD, as well as the role of hormone signaling in female animals, to understand the impact these potentially modifiable risk factors have on disease. We find that there is a differential relationship between estrogen and progesterone signaling in female animals, with estrogen leading to an increase in amyloid- and progesterone leading to a decrease in amyloid-, suggesting that each hormone plays a different part in protecting brain health, and that an estrogen only approach to HRT may not be helpful in the prevention of AD. To further understand the impact of modifiable risk factors, we aimed to uncover the role of stress in amyloid- and tau kinetics. Using in vivo microdialysis, we have shown that female, but not males, display an increase in extracellular amyloid- in response to stress that persist long after the removal of the stressor. Additionally, tau increases in both males and females after stress, with females showing a dramatic 100% sustained increase, and males showing a moderate 50% increase that stays elevated for over ten hours after the removal of stress. This finding suggests that there is a different pathway at play during stress in the kinetics of amyloid- and tau. We find that -arrestin plays a role in the chaperoning of CRF-R from the cell surface in males, leading to the blunted response of amyloid- in males after stress. The mechanism behind the increase in tau seen in both males and females remains unknown, but we speculate that it is due to separate pathways, as the increase in tau in response to corticosterone injection is not seen in amyloid-. These findings suggest that sex differences in signaling in both stress pathways and hormone pathways may provide insight into the sex disparities seen in AD