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Nasal immunity: from understanding CD8+ T cell accumulation following vaccination to exploring the role of nociceptors in nasal infection
No full textMany respiratory pathogens first take their foothold in the nasal mucosa (NM), from which they can replicate, disseminate, and cause life-threatening complications. Having a strong line of defense at this primary site of infection can substantially help curb disease severity. The barrier function of the nasal mucosa rests on several actors from innate and adaptive immune cells to structural cells and secreted factors. In an effort to better understand nasal immunity and develop strategies to enhance immune defense at this site, we first explore how long term CD8+ T cell mediated immunity is established in the nose and in a second chapter ask the question of whether sensory neurons, particularly nociceptors, participate in nasal immune defense.
Tissue resident adaptive immune cells, particularly CD8+ Tissue resident memory (TRM) T cells, have been shown to provide rapid pathogen control upon infection. However, current clinical peripheral vaccination strategies do not elicit strong CD8+ TRM responses in barrier tissues. Here, using model antigen ovalbumin with adjuvant poly(I:C), we describe a peripheral vaccination strategy coupled to a noninvasive intranasal engagement step that allows the formation of CD8+ TRMs capable of significantly reducing viral burden following Influenza A virus (IAV) infection. We dissect the steps leading to robust effector CD8+ T cell accumulation starting with the recruitment of a small population of antigen-specific effector CD8+ T cells to the non-inflamed nasal mucosa, which we call pioneer cells. We show that following antigen delivery pioneer cells produce IFNγ leading to CXCL9 and CXCL10 production by neighboring cells, which allows further recruitment of effector CD8+ T cells. We also show that blocking α4 integrin prevented recruitment of pioneer cells to the nasal mucosa. We further investigate the molecular identity of peripheral cells generated following vaccination using single cell RNA sequencing and identify a putative pioneer cell population characterized by high Itgb4, Itgb1, as well as Runx1 expression and transcriptional activity.
In the next chapter, we examine the role of nociceptors, which have increasingly been shown to modulate host defense in other barrier tissues, in nasal host defense. We first characterize sensory neuron populations in the nasal mucosa, showing dense nociceptive innervation in the respiratory tissue, as well as around the Nasal-Associated Lymphoid Tissue (NALT) and sparser nociceptive innervation in the olfactory tissue. We address the role of nociceptors in shaping nasal immunity by using genetic, systemic or local depletion of nociceptors and follow up with nasal infection models using IAV or Streptococcus pneumoniae. Following nasal influenza infection, there was no difference in viral titers between wild-type and nociceptor-ablated mice but there were trends towards more neutrophils and macrophages in nociceptor-ablated mice. However, following S. pneumoniae infection, we obtained mixed results with several independent experiments showing significantly lower bacterial burden in nociceptor depleted animals (locally and systemically), reminiscent of studies in the lungs and meninges, while more recent experiments show no difference in titers despite successful nociceptor ablation.
Overall, this investigation into two very different aspects of nasal immunity revealed in one part that boosting existing known effectors of host defense namely CD8+ TRMs can be crucial against viral pathogens while in a second part showed that although the nasal tissue is densely innervated by somatosensory neurons, the role of nociceptive fibers in nasal host defense remains to be ascertained and perhaps needs to be evaluated while accounting for variables such as their interactions with olfactory neurons, or the microbial communities of the nasal cavity.Immunolog
Probing Muon + b-Jet Resonances in pp Collisions with the ATLAS Detector
No full textProbing heavy resonances in collider physics has been a longstanding and fruitful endeavor. Despite well-motivated candidates like leptoquarks and their role in grand unified theories, direct experimental searches for lepton–quark resonances in proton–proton collisions are relatively scarce. Cross-generational lepton–quark resonances have received even less experimental attention. This thesis presents an ATLAS search for one such under-represented resonance: the muon and b-jet resonance. The search leverages the full Run 2 and partial Run 3 datasets at √s = 13 TeV and √s = 13.6 TeV, respectively. For a measure of sensitivity, a benchmark leptoquark model with only muon and b-quark Yukawa couplings is used. Using the CLs statistical method, the analysis improves upon prior leptoquark mass exclusion limits for couplings above ~1.Physic
Investigating the Assumptions in Current Methods of Observing and Modeling Tropical Vertical Motion Profiles
No full textThis thesis investigates tropical vertical motion profiles using both observations and modelling work. Firstly, we investigate if we can use in-situ observations of heavy-water isotopologues in rainfall to understand vertical motion profiles in the tropics. Next, this thesis will also systematically investigate the different methodologies used to parameterize the large-scale tropical circulation in idealized small-domain simulations, and the differences between them, and whether we can assume that these different schemes are interchangeable. Lastly, I also discuss what these different parametrizations can tell us about convective organization in idealized large-domain simulations, and also within the tropics.
Previous work has provided proof-of-concept in using in-situ observations of depletion of heavy-water isotopologues to understand vertical motion profiles in the tropical East Pacific. Using station observational data collected around the time of the OTREC field campaign and after, we show that top-heavy convection results in rainfall that is more depleted in heavy-water isotopologues such as HDO and HO. However, these trends of depletion are not spatially consistent, resulting in rainfall that may be more enriched in one location compared to other locations despite having similar rainfall rate and vertical-motion structure. We verify these results using realistic WRF simulations, and based on our results, we provide another metric to measure top-heaviness, one that is also partially dependent on vertical moisture advection.
Next, we discuss how large-scale vertical motion profiles are parameterized in idealized small-domain models using the WTG framework. Ever since the canonical formulation of the WTG, adjustment schemes utilizing its explicit and implicit forms have become ubiquitous when modelling tropical convection in small-domain simulations. However, despite the prevalence of these schemes in modelling work for tropical climate, they often produce noticeably different vertical motion structures. For example, the original Weak Temperature Gradient formulation of Raymond and Zeng [2005] is known to produce vertical-motion structures that are more top-heavy than the Damped Gravity Wave formulation of Kuang [2008] and Blossey et al. [2009]. We show that the differences observed when using different WTG-adjustment schemes are often more pronounced under more idealized conditions, and can be traced back to how different WTG-adjustment schemes treat the different vertical modes.
Lastly, most past research surrounding small-domain simulations in the WTG framework have focused on the analogues to the wet- and dry-regimes of self-aggregation in large-domain simulations. My work also shows that the WTG framework is potentially able to attain analogues to convectively-coupled waves (CCWs) in small domain simulations. Model runs in large-domain simulations are able to replicate these CCWs regardless of radiative scheme. We note that despite prevalence of convective organization in the form of CCWs across all large-domain simulations we have run, it is still a somewhat overlooked aspect of convective organization, as current work on this field predominantly focuses on self-aggregation of convection.Earth and Planetary Science
Taking Care: Home Cooking and Community in the Late 19th and Early 20th Century Chinese Diaspora
No full textHow did members of the late nineteenth and early twentieth century Chinese diaspora care for spatially extended communities? Taking Care uses multiple methodologies from archaeology, ethnography, and history to investigate the complex, circulatory web of relations that shifted the social organization of food production and consumption across the Chinese diaspora. This dissertation explores different spatial and social configurations of home cooking, their impact on social experience at the time, and their influence on contemporary Chinese American conceptions of food’s connection with community care. I argue that home cooking was a primary means of care in northern California and the Guangdong Province. Home cooking is a flexible concept encompassing the places and care practices of feeding oneself and one’s intimate community. Recovering cooking practices at residential institutions, ephemeral homes of itinerant laborers, and family configurations, I re-site the locus of inquiry from the use of material food evidence for reifying race or labor-based identities (e.g., Chinese Railroad Worker, Chinese Miner, Chinese Farmer, etc.) to exploring the lived experiences—the structures, patterns, and material choices of daily life—of people who could, at any given moment, labor in any number of different ways and not once consider that type of work constitutive of their identity. Instead, investigating the care provided by home cooking offers an approach for understanding how communities form and maintain collective memories and identity.Anthropolog
Generation of genotypes and phenotypes from sequencing data
No full textDNA sequencing of hundreds of thousands of human samples has become a component of research biobanks over the last several years. Unlike previous efforts using genotyping arrays and whole exome sequencing, whole genome sequencing imposes no prior expectation on captured genetic information. Whole genome sequencing thus allows for the characterization of novel human polymorphisms such as large structural variation and for the identification of incidentally captured DNA sequences that are non-human in origin. When performed at scale, human structural variation can be associated with phenotypes and the presence of non-human sequences can be considered phenotypes to then be associated with human genotypes. These concepts have been employed in separate lines of work spanning retrotransposons, human DNA viruses, and the oral microbiome.
Retrotransposons comprise about 45% of the human genome, but their contributions to human trait variation and evolution are only beginning to be explored. Here, we find that a sequence of SVA retrotransposon insertions in an early intron of the ASIP (agouti signaling protein) gene has probably shaped human pigmentation several times. In the UK Biobank (n = 169,641), a recent 3.3-kb SVA insertion polymorphism associated strongly with lighter skin pigmentation (0.22 [0.21–0.23] s.d.; P = 2.8 × 10−351) and increased skin cancer risk (odds ratio = 1.23 [1.18–1.27]; P = 1.3 × 10−28), appearing to underlie one of the strongest common genetic influences on these phenotypes within European populations. ASIP expression in skin displayed the same association pattern, with the SVA insertion allele exhibiting 2.2-fold (1.9–2.6) increased expression. This effect had an unusual apparent mechanism: an earlier, nonpolymorphic, human-specific SVA retrotransposon 3.9 kb upstream appeared to have caused ASIP hypofunction by nonproductive splicing, which the new (polymorphic) SVA insertion largely eliminated. Extended haplotype homozygosity indicated that the insertion allele has risen to allele frequencies up to 11% in European populations over the past several thousand years. These results indicate that a sequence of retrotransposon insertions contributed to a species-wide increase, then a local decrease, of human pigmentation.
It is largely unknown which human genetic variants shape a person’s oral microbiome and potentially promote its dysbiosis. We characterized the oral microbiomes of 12,519 people by analyzing whole-genome sequencing reads from previously sequenced saliva-derived DNA. Human genetic variation at 11 loci (10 novel) associated with differences in oral microbiome composition. Nearly all of these associations implicated candidate genes with readily interpretable functions, several related to carbohydrate availability. The strongest association (p=3.0x10-188) involved the common FUT2 W154X loss-of-function variant, which associated with the abundances of 32 bacterial species. Human host genetics also appeared to powerfully shape within-species genetic variation in oral bacteria. Variation at the 11 human loci associated with variation in gene dosages in 68 regions of bacterial genomes. Several such associations implicated interactions of bacterial proteins with histo-blood group antigens presented on host mucosal cell surfaces and salivary proteins. Common, multi-allelic copy-number variation of AMY1, which encodes salivary amylase, associated with oral microbiome composition (p=1.5x10-53) and with dentures use in UK Biobank (p=5.9x10-35, n=418k), suggesting that amylase abundance impacts oral health by influencing the oral microbiome. Two other microbiome composition-associated loci, FUT2 and PITX1, also significantly associated with dentures risk, collectively nominating numerous microbial taxa that might contribute to tooth decay.
Many viruses have adapted to persist in infected humans for life. Variable host control of their abundance (or load) can lead to clearance or disease. Here, we analyzed the viral load of 31 DNA viruses in human blood and saliva using whole-genome sequencing data from UK Biobank (n=490,401), SPARK (n=12,519), and All of Us (n=414,817). Viral load varied markedly with age, time of day, and season, and was higher in men than women for most viruses. Human genetic variation at dozens of genomic loci associated with load of seven viruses: Epstein-Barr virus (EBV, 45 loci), human herpesvirus 7 (HHV-7, 24 loci), HHV-6B, Merkel cell polyomavirus, and three anelloviruses. Variation at the human leukocyte antigen (HLA) complex generated the strongest associations (p = 1.1×10-8 to 9.1×10-851). Effects of HLA alleles exhibited specificity to different viruses and varied by age and body site, and HLA-B*08:01 also exhibited a host-virus genetic interaction with EBV subtype (p = 2.3×10-44). Other human genetic effects involved genes encoding proteins that process peptides for antigen presentation, such as ERAP1 (HHV-7, p = 2.7×10-78) and ERAP2 (EBV, p = 4.6×10-111). Mendelian randomization analyses indicated that although EBV infection strongly increases risk of multiple sclerosis (MS), EBV DNA load is unlikely to further modulate risk of MS (p = 0.52). In contrast, EBV viral load exhibited a strong causal effect on increased risk of Hodgkin lymphoma (OR = 19.81 [3.04–129] per s.d. increase in EBV load, p = 1.8×10-3). This suggests that higher chronic EBV viral load increases lymphoma risk, whereas associations of EBV infection with autoimmune conditions reflect host immune responses to particular viral epitopes.Biomedical Informatic
T cell evolution in the blood and organs during acute graft-versus-host disease
No full textHematopoietic Stem Cell Transplantation (HSCT) can be curative for a variety of diseases, including hematologic malignancies, immunodeficiencies, and bone marrow failure syndromes. Graft-Versus-Host Disease (GVHD) remains one of the deadliest complications of HSCT. Even with the use of current GVHD prophylaxis regimens, which are broadly acting, non-targeted agents, GVHD still occurs in 50-80% of allogeneic transplant recipients. There is a need for more selective therapies to prevent GVHD while still preserving the protective effects of the immune system. T cells are the main instigators of acute GVHD (aGVHD), given that their removal ameliorates this disease. However, their removal does not decrease transplant mortality, due to diminished engraftment, increased relapse, and higher risks of infection. Considering the essential protective effects of T cells as well as their role in GVHD, better understanding and targeting of alloreactive T cells while preserving non-pathogenic T cells will be important for the future of HSCT.
Chapter two describes our investigations into T cell programming changes that occur in the liver and lungs during aGVHD in non-human primates (NHP) and identified organ-specific gene expression programs specific to the lung and liver. We demonstrated how these programs developed through clonal expansion of the T cells within the organ-microenvironment in an antigen-independent manner. These discoveries laid a foundation for better targeted and possible organ-specific treatment development for aGVHD in the future.
Chapter three describes our investigation of candidate GVHD-modifying gene edits in a xenogeneic model of aGVHD, using CRISPR/Cas9-edited human T cells transplanted into immunodeficient (NSG) mice. We edited target genes that were implicated in aGVHD T cell pathogenesis and evaluated how their deletion affected aGVHD development in the model. We focused on RGS1 for its role in aGVHD development, with results suggesting that knocking out RGS1 could decrease aGVHD.
Chapter four describes our evaluation of the differences in T cell reconstitution after clinical HSCT in two cohorts of patients treated with distinct GVHD prophylaxis regimens: tacrolimus and methotrexate (Tac/MTX) compared to post-transplant cyclophosphamide, tacrolimus and MMF (PT-Cy). Additionally, we evaluated the differences in T cell gene expression programs when patients developed aGVHD in the two cohorts. We found evidence for wholesale T cell depletion with PT-Cy, resulting in long term deficits in TCR diversity, relative enriched contributions of host-derived cells, and prolonged deficits in naïve T cells compared to patients receiving Tac/MTX. T cell subsets in patients who developed aGVHD in either cohort demonstrated distinct immune activation patterns.
The data presented in this thesis evaluate T cell reconstitution in the blood and organs of two model systems, mice and NHP, as well as human clinical trial samples, to further understand how T cells evolve throughout HSCT and the development of aGVHD. These discoveries have implications for the efficacy and toxicity of current aGVHD prophylaxis regimens, as well as for developing aGVHD prevention and treatment using targeted agents in the future.Immunolog
Topics in Privacy, Data Privacy and Differential Privacy
No full textIn an era of unprecedented data availability and analytic capacity, the protection of individuals' privacy in statistical data releases is becoming an increasingly difficult problem. This dissertation contributes to the theoretical and methodological foundations of statistical data privacy, largely focusing on differential privacy (DP). We begin with a multifaceted investigation into privacy from legal, economic, social, and philosophical standpoints, before turning to a formal system of DP specifications built around five core building blocks found throughout the literature: the domain, multiverse, input premetric, output premetric, and protection loss budget. This system is applied to statistical disclosure control (SDC) mechanisms used in the US Decennial Census, analyzing both the traditional method of data swapping and the contemporary TopDown Algorithm. Beyond these case studies, this dissertation explores the inferential limitations posed by DP and Pufferfish privacy in both frequentist and Bayesian settings, establishing general bounds under mild assumptions. It further addresses the challenges of applying DP to complex survey pipelines, incorporating issues such as sampling, weighting, and imputation. Finally, it contextualizes DP within broader frameworks of data privacy, namely the Five Safes and contextual integrity, advocating for a more integrated approach to privacy that respects statistical utility, transparency, and societal norms.Statistic
Remembering the Enslaved and the Emancipated in Latin Verse Epitaphs, Epigrams, and Poems of Consolation
No full textIn this dissertation, I examine the extant Latin poetry written to commemorate enslaved and emancipated persons in the ancient Roman world. My study engages with two bodies of evidence. The first comprises the 243 surviving Latin verse epitaphs inscribed on the gravestones of persons from these social groups: these epitaphs date from the first century BCE to the fourth century CE and originate from across the Roman empire. The second body of evidence comprises the poems within the Latin literary canon (that is, the texts circulated in manuscript form rather than being incised on stone) that were written to commemorate enslaved and emancipated persons and/or to console someone on the loss of one such person. 19 poems of this nature survive: one by Lucilius, 14 by Martial, and four by Statius, ranging in length from two lines to 234. These forms of sepulchral poetry, I argue, not only served to honor deceased individuals, but also provided a space in which contrasting perspectives on slavery, including both positive and negative sentiments, could be expressed.
In Chapters 1 and 2, I demonstrate that, when slaveholders commemorate their enslaved and emancipated dependents (which is the case in all of the canonical texts and some of the inscribed epitaphs), they tend to depict slavery as benevolent and paternalistic and to position themselves as central to their dependents’ social and professional lives. In Chapter 1, I analyze how these tendencies are manifested in the inscribed verse epitaphs; in Chapter 2, I consider how they are manifested in two canonical genres of poetry (namely, the epigram and the poem of consolation).
In Chapters 3 and 4, I examine how, when enslaved and emancipated persons memorialize themselves, or are memorialized by their family and friends (which is the case in most of the inscribed epitaphs), they often challenge or reframe this worldview. In Chapter 3, I examine cases where this is done overtly, including an epitaph from Gaul that describes enslavement as traumatic, and a group of epitaphs, two from Carthage and one from Italy, that equate death with liberation from bondage. As I demonstrate in Chapter 4, enslaved and emancipated persons could also engage in more subtle modes of resistance. Many of them, when writing their own epitaphs or those of their family members, choose to tell their life stories in ways that conflict with the picture presented by the slaveholders: for instance, they may foreground their family and community rather than their relationship with their slaveholder.
Finally, in Chapter 5, I underscore the subjectivity of sepulchral poetry, and its capacity to shape perceptions of particular social groups, by examining the extant poems, both canonical and epigraphic, for a more complex social group: namely, alumni, meaning children born to enslaved or emancipated parents and ‘fostered’ by their slaveholder. These alumni may be represented in different ways (e.g., as ordinary household slaves or as adoptive children) according to the perspective and agenda of their commemorator(s).
Overall, therefore, these poems enabled persons from various social backgrounds not just to mourn their deceased loved ones, but also to participate in a broader dialogue on slavery and to shape the ways in which the experiences of enslavement and emancipation were remembered.Classic
Essays on the Economics of Social Insurance and Labor Markets
No full textThis dissertation investigates the labor market and fiscal consequences of social insurance reforms, drawing on large-scale administrative data from Germany. Across three chapters, I examine how programs designed to insure against economic risk - whether through wage subsidies, public insurance expansions, or regulatory wage floors - affect employment, workforce composition, and broader economic outcomes.
The first chapter analyzes the employment effects of Germany’s Short-Time Work (Kurzarbeit) program during the COVID-19 crisis. Using matched administrative data on program participation and the universe of Social Security records, I show that while Short-Time Work mitigated immediate job losses in 2020, participating firms experienced persistently lower employment growth through 2022. Instrumental variables estimates suggest that extensive program use led to substantial job hoarding, merely delaying, but not averting, adjustments. These findings highlight the short-run benefits and long-run costs of broad-based job retention subsidies.
The second chapter evaluates the impact of Germany’s 2022 Healthcare Development Act, which introduced wage floors in long-term care (LTC). Using a difference-in-differences design comparing LTC nurses to hospital nurses, I find that the reform raised wages particularly at the bottom, without reducing employment or firm entry. Wage compression resulted from both genuine wage gains and positive selection, as lower-paid workers were more likely to exit and newly hired staff experienced accelerated wage growth.
The third chapter studies the long-run labor market effects of Germany’s 1995 introduction of universal LTC insurance. Leveraging regional variation in pre-reform coverage and rich individual work histories, I show that the insurance expansion spurred large-scale job creation in nursing homes without displacing employment in other sectors. Employment gains were concentrated among lower-skilled workers, and local unemployment declined. A structural model reveals that the fiscal and welfare effects depend critically on pre-existing labor market frictions and tax wedges, with the reform effectively paying for itself through fiscal spillovers.
Together, these studies offer empirical evidence on how well-designed social insurance programs can support vulnerable workers, stimulate labor demand, and shape earnings distributions, underscoring the importance of targeting and institutional context for ensuring long-run efficiency.Public Polic
Evaluating the Effectiveness of the Higg Materials Sustainability Index Through Stakeholder Perception Assessment
No full textThe textile industry greatly impacts the environment, contributing to climate change by releasing 1.2 billion tons of greenhouse gas emissions (GHGs) annually with the potential to increase by 60% by 2030. In addition, water use, water pollution and loss of biodiversity from dyeing and finishing of textiles accounts for 17-20% of all industrial pollution (Global Fashion Agenda, 2019), and depletes non-renewable resources. For instance, popular materials such as polyester and cotton have negative environmental and social impact, because polyester required large amounts of fossil fuels and non-renewable resources, and conventional cotton requires fertilizers and pesticides and large amounts of water (Ellen MacArthur Foundation, 2017). These are just two examples indicating that selection of materials, specificity of item design and innovation, can contribute to more efficient use of resources, and eventually lead to waste reduction.
The Higg Materials Sustainability Index (MSI) is a tool that is designed to help apparel and footwear companies to explore new fibers and finishes. It provides guidance in selecting materials with lower environmental impact, thus making the industry more sustainable and more transparent. The purpose of my research was to establish an understanding of how Sustainable Apparel Coalition (SAC) stakeholders perceive the Higg MSI textile material scoring. My main research questions were to determine if the textile materials’ Higg MSI scores aligned with stakeholders’ perceptions, and if the Higg MSI was an effective tool helping SAC internal stakeholders to make informed decisions.
I hypothesized that by analyzing survey responses I would find insignificant inconsistencies between respondents’ perceptions and the existing scoring. Furthermore, I hypothesized that the Higg MSI scoring methodology was a trusted decision-making tool effectively used in the textile industry. To test my hypotheses, I developed three complementary surveys to collect data for the analysis. I wanted to learn how well SAC members understood and what beliefs they have about the environmental impact of selected textile materials. After collecting all responses, I aggregated the data and conducted analysis to establish variability and central tendency. I found a lot of variability in responses per material and detected misalignment between the Higg MSI scoring and the modal values of the responses. Next, I grouped analyzed materials based on their origins and looked for trends in responses. The analysis demonstrated that respondents expected natural materials to perform better than synthetic materials. In addition, I determined that the environmental performance of synthetic materials was not well understood by respondents.
As a result, I determined that SAC stakeholders disagreed with some of the Higg MSI scoring due to lack of information, unclear methodology and plausibility of data used in establishing aggregated scores. I compiled these findings and outlined possible solutions needed to address this emergent misalignment between members’ perceptions and the Higg MSI methodology.Extension Studie