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Elucidating The Role Of Hepatic Foxo1 Signaling In The Regulation Of Adipose Tissue Biology
Get PDFThe hepatic transcription factor forkhead box O1 (FOXO1) is a critical regulator of hepatic and systemic insulin sensitivity. Previous studies demonstrate that genetic inhibition of liver FOXO1 improves insulin sensitivity in both genetic and dietary mouse models of metabolic disease. Mechanistically, this is due in part to cell non-autonomous control of adipose tissue insulin sensitivity. However, the mechanisms mediating this liver-adipose tissue crosstalk remain ill-defined. This thesis work comprises of two studies that sought to determine the role of hepatic insulin signaling via FOXO1 regulation over adipose tissue biology. The brown adipose tissue’s (BAT) ability to increase energy expenditure has made it a potential target for combating obesity, diabetes, and associated diseases. However, significant gaps remain in our understanding of how metabolic organs, such as the liver, coordinate the supply of hepatokines and energy substrates that can activate and fuel BAT thermogenesis. In the first study, we identify a role for hepatic insulin signaling via AKT-FOXO1 in the adaptive response to acute cold stress. Mechanistically, inhibition of FOXO1 by AKT controls BAT thermogenesis by enhancing catecholamine-induced lipolysis in the white adipose tissue and increasing circulating fibroblast growth factor 21 (FGF21). These studies provide relevant and missing fundamental knowledge to the liver’s response to acute cold exposure, in addition to providing an understanding of the inter-organ communication system that mobilizes energy for heat production. In the second study, we investigated how the FOXO1-dependent hepatokine FGF21 regulates glucose homeostasis, insulin tolerance and adipocyte lipolysis. The pharmacological effect of FGF21 on metabolism has been fairly well-studied, however how hepatic insulin signaling contributes to the regulation of endogenous hepatic FGF21 expression and its physiological role as a FOXO1-dependent hepatokine in the regulation of metabolism is not completely understood. We demonstrated that acute deletion of FGF21 did not alter glucose tolerance, insulin tolerance, or adipocyte lipolysis suggesting a permissive role for endogenous FGF21 and that liver FOXO1 controls glucose homeostasis independently of liver-derived FGF21. Taken together, these two studies have developed a deeper understanding on the cell-autonomous and cell-nonautonomous regulation of liver hepatic insulin signaling via FOXO1
Riskless Business: Impact And Risk Measurement In The Impact Investing Industry
No full textAt its core, impact investing promises two measurable outcomes: financial returns and social or environmental impact. While established methods for measuring and managing risk are used in financial analysis, no analogue yet exists for social impact in the domain of social and environmental impact investing. How do investors keep their promise of creating, measuring, and communicating impact to stakeholders, without clear guidance or regulation about how to do so? This question guides the three essays in this dissertation. In Chapter 1, I draw on 135 interviews and 102 documents related to impact measurement to investigate how impact investors conceptualize and attend to the expectation that they measure their impact. Using grounded theory analysis, I find a marked difference between the practice and rhetoric of impact measurement. Unlike the conventional portrayal of decoupling as non-implementation of adopted policies, this decoupling reflects how individuals deviate from idealized practices while reinterpreting those practices to meet institutional expectations. Then, in Chapter 2, I employ a narrative theory approach to investigate how the impact investors interviewed for this project conceptualize, operationalize, and measure impact risk, including the risks to achieving stated impact or causing unintended harm. As a result of this qualitative analysis, I hypothesize and experimentally test the proposition that investors systematically avoid and discount impact risk-related information in investment decision making. Finally, in Chapter 3, I consider the normative implications of the win-win framing by focusing on one impact investment strategy: investing in women. I interrogate the assumptions underlying the win-win strategy for increasing gender diversity and suggest that these assumptions have the potential to reaffirm the very power structures that have historically excluded and undervalued women in business. I then present an alternative theory as a corrective: intersectionality. I articulate distinctions between instrumental and intersectional approaches to valuing diversity using examples from organizations, and I argue that an intersectional approach to valuing diversity may matter not merely discursively but also for material change
Will And Capability: Western Governments\u27 Response To Russian Disinformation Since 2013
Get PDFIn 2013, the Kremlin resourced and launched a multiyear global operation to subvert democracy. The operation’s main weapon was intentionally harmful information—disinformation—spread through networks of paid trolls, bot networks, and users around the world. The information was aimed at sowing division within democracies and between democracies, particularly in NATO and the European Union. Some governments chose stronger responses than others. What explains the variation in government responses? I argue that each democracy’s combination of will and capability determined its response and that states with similar endowments of will and capability chose similar policies. I conduct an in depth cross-national of thirteen Western democracies supported by two case studies of specific states: Finland and the United States. My findings show that Kremlin disinformation has repeatedly adapted to changing contexts over the last century, is likely to continue adapting, and that Kremlin tactics having shown effectiveness, have spread to more state governments and even domestic actors. Future attacks will likely follow similar themes and patterns, so the lessons learned in this dissertation can help inform future responses
The Mhcii-Restricted Presentation Of Hiv-1 Antigens By Cd4+ T Cells
No full textHIV-1-specific CD4+ T cells (TCD4+) play a critical role in controlling HIV-1 infection. Robust HIV-1-specific TCD4+ responses are associated with decreased viral load and increased antibody neutralization breadth, and thus understanding the processes that lead to successful HIV-1-specific TCD4+ activation is crucial. According to convention, TCD4+ activation is mediated by professional antigen-presenting cells (APCs), such as dendritic cells (DCs), macrophages, and B cells that: 1) take up extracellular antigen, such as whole virions, 2) proteolyze internalized virions into smaller peptides within the endocytic compartment, 3) load resulting peptides onto major histocompatibility complex class II (MHCII) molecules within the late endosome, and 4) transport the peptide:MHCII complexes to the plasma membrane, where they can provide activating signal to antigen-specific TCD4+. However, several alternative processing modes have been described. Endogenous processing, one of these alternatives, occurs when the APC becomes productively infected and nascent viral proteins are used as processing substrates for presentation on MHCII. However, the relative contributions of these pathways to the HIV-1-specific TCD4+ response are unknown. In addition, the cell types capable of MHCII-restricted presentation may be more complex than originally appreciated. Notably, TCD4+, which express MHCII upon activation and are HIV-1 host cells, might act as APCs during an HIV-1 infection. In this study, I used a lentiviral transduction system to achieve HIV-1-specificity in primary human TCD4+. I then assessed the ability of primary monocyte-derived DCs and activated TCD4+ to present HIV-1-derived antigen. I show that activated TCD4+ are highly effective at MHCII-restricted presentation of an immunodominant HIV-1-derived epitope due to the tropism of HIV-1 for TCD4+ and the efficiency of endogenous processing. Additionally, and unexpectedly, I found that MHCII-restricted TCD4+-to-TCD4+ presentation facilitates transfer of virus to HIV-1-specific TCD4+, providing both a potential explanation for the rapid spread of the virus to HIV-1-specific TCD4+ in vivo and a novel mechanism for compromising the host response
Of Mice, Ferrets, And Men: From Original Antigenic Sin To A New Universal Influenza Virus Vaccine Candidate
No full textInfluenza viruses continuously circulate in the human population. Acquired immunity through infection or vaccination can be long-lived, yet individuals experience reinfections with antigenically distinct viral strains and subtypes throughout their lives. Furthermore, reinfections can boost antibody responses against viral strains first encountered in childhood, a process termed original antigenic sin (OAS). It is unknown how initial childhood exposures affect the induction of antibodies against the hemagglutinin (HA) stalk domain of influenza viruses. This is an important consideration since broadly reactive HA stalk antibodies can protect against infection from various subtypes, and universal vaccine platforms are being developed to induce these antibodies. Here we show that experimentally infected ferrets and naturally infected humans establish strong “immunological imprints” against HA stalk antigens first encountered during primary influenza virus infections. By defining the antibody specificity through serological assays, we find that HA stalk antibodies are boosted upon subsequent infections with antigenically distinct influenza A virus subtypes. Paradoxically, these heterosubtypic-boosted HA stalk antibodies do not bind efficiently to the boosting influenza virus strain, an indication of OAS. Next, in an effort deliver a better immunological imprint, we design an mRNA vaccine encoding 20 different HAs. We then use mouse and ferret animal models to define the antibody specificity elicited by this vaccine. Our 20 HA mRNA vaccine is able to elicit both strain specific and cross reactive antibodies. Furthermore, it is able to provide in vivo protection from challenge with an influenza virus not directly encoded by the HA sequences included, suggestive of its ability to elicit broad and potent immunity. Overall, the work presented here provides evidence of an immunological bias towards the HA stalk portion of the influenza virus first encountered, but also introduces a solution that may provide a broader immunological imprint
User-Friendly, Low-Cost, Microfluidic Devices With Capillary Circuits For Multiplexed, Isothermal, Point-Of-Care, Nucleic Acid Amplification Tests
Get PDFRapid, sensitive, and specific detection of causative pathogens is key to personalized medicine and the prompt implementation of appropriate mitigation measures to reduce disease transmission, mortality, morbidity, and cost. Conventional molecular detection methods require trained personnel, sophisticated equipment, and specialized laboratories, which limits their use to centralized laboratories. To enable molecular diagnostics at the point of need and in resource-poor settings, inexpensive, simple devices that combine multiple unit operations and are capable of co-detecting endemic pathogens are needed.
In this work, I have developed microfluidic devices with capillary circuits to automate liquid distribution, eliminating the need for expensive equipment, sophisticated laboratory facilities, and skilled personnel to enable molecular diagnostics at the point of need. Capillary valves with different sizes were developed and implemented to aliquot samples and reagents to multiple reaction chambers and to enable draining liquids from supply lines without affecting liquids in the various reaction chambers, enabling bubble-free operation. The sealing of my microfluidic devices to prevent evaporation during incubation is facilitated with phase-change materials and capillary-induced motion. When my microfluidic chip is heated to its incubation temperature, the phase-change material melts and flows to seal ports of entry and air vent. Numerical simulations were carried out to assess the viability of on-chip, in-house developed, two-stage isothermal nucleic acid amplification in the presence of diffusion and advection. An Android-based smartphone application was developed to automate real-time signal monitoring, time series image analysis, and diagnostic result interpretation. Three 3D-printed, portable, microfluidic devices with capillary circuits were designed, fabricated, and tested for single-stage and two-stage, isothermal nucleic acid amplification with either liquid reagents or pre-stored dry reagents that do not require a cold chain. All devices have proved successful for rapid, sensitive, and specific multiplexed detections of human and animal pathogens
Exploring The Genetic Architecture Of Autism Spectrum Disorder
Get PDFAutism Spectrum Disorder (ASD) is a group of heterogeneous disorders associated with hundreds of susceptibility genes or genetic risk variants of varying frequency and inheritance patterns. The prevalence of ASD in the U.S. is 1 in 44 children, with two thirds of the ASD cases without intellectual disability (ID). Previous genetic studies were often conducted in samples with both ASD with and without ID participants, revealing different genetic architecture of ASD with and without ID: ASD with ID is more associated with de novo variants while ASD without ID has a higher heritability. In addition to ID, other comorbidities including sleep disturbances and metabolic dysfunction were reported in ASD. To further explore the genetic architecture of ASD, especially ASD without ID, we performed an integrative analysis to evaluate the joint contributions of common and rare single-nucleotide variants, small insertions and deletions, and rare copy number variants (CNVs) to the risk of ASD in a new Penn-based collection of ASD without ID probands and family members (Autism Spectrum Program of Excellence (ASPE) collection). We showed in ASPE families, both common and rare variants contributed to ASD and quantitative autistic traits measured by the Social Responsiveness Scale. We also explored a spectrum of phenotypes associated with NRXN1: a known ASD associated trans-synaptic gene. The analysis of the Penn Medicine Biobank identified NRXN1 CNV carriers and found preliminary evidence that NRXN1 CNVs are associated with decreased cholesterol level, which could help explain metabolic dysfunction in ASD. Finally, since mating pattern determines the genetic structure of a population, we investigated assortative mating in ASD with and without ID families in two ASD collections: Simons Foundation Powering Autism Research for Knowledge (SPARK) and the Simons Simplex Collection (SSC). We observed similar degree of positive assortative mating in SPARK and SSC families with and without ID. This work highlighted the joint contributions of different types of genetic variants in multiple genes to the risk of ASD and presented potential gene-gene interaction models that could be studied in future experiments
The Shadows Of The Sensorium: Synesthesia And Intermediality In German Romantic Literature
No full textAlthough the term synesthesia does not formally make its way into medical discourse until the late nineteenth century, a strong poetic and scientific interest in or desire for synesthetic experiences emerges in the period around 1800 to stage interventions in the era’s dominant philosophical impulses. In German Romantic literature, depictions of synesthetic experiences have significance beyond the mere reveries that the protagonists experience: they prove to be vital lenses through which one can explore and express uncertainty or discomfort with presumed epistemological conditions of the period more broadly and within the role of the literary medium and systems of representation and signification. This dissertation examines depictions of synesthetic experiences in German Romantic literature and thought, and the extent to which they interact with, emulate, or problematize the medial landscape at the time. By looking at these experiences through and in relation to Romantic interarts and intermediality, this project illustrates the different ways in which such experiences also undermine Idealist-inflected conceptions of art and the Absolute, and are imbricated in Romanticism’s crisis of media (Oesterle and Neumann). An analysis of key episodes from the works of Friedrich Schlegel, E.T.A. Hoffmann, Johann Wolfgang von Goethe, and Justinus Kerner reveals both continuities and disjunctions between different clusters of Romantic thinkers and plots a trajectory to rethink the bifurcation between early and late Romantic clusters. Turning to the ways in which each author’s treatment of perception is tied to their poetics reveals an ongoing materialization of perception through the ways each of these thinkers navigates tensions between the visual and the verbal, materialism and idealism, and the spatial and temporal influences on and origins of perception. The opposition of color/light or darkness/shadows visible throughout the works and thought of each thinker highlights on the one hand the ways in which illusions are constructed in the texts, and on the other, draws attention to the limits of perception, an aspiration of both synesthesia and intermediality
Walking On The World: Landscape And Geographic Microcosms In Roman Floor Mosaics
No full textThe question of how Romans understood the world around them has inspired vigorous debate. In one camp, some argue that, due to a dearth of cartographic evidence and the prevalence of written itineraries, only linear understandings of space were possible, while others argue for the possibility of map-conscious, cartographic understandings. My project brings new evidence to this debate, in the form of floor mosaics with landscape and geographic imagery, to demonstrate that cartographic understandings of space were possible and wide-ranging. These mosaics display varied places like labeled Mediterranean islands, wild hunting grounds, and the Christian Holy Land. They compress large landscapes and geographies into their relatively small interiors, making their rooms microcosms of the world out there. I explore case studies organized thematically, compiling mosaics depicting water, land, map-like depictions, allegorical representations of space, and finally combinations of those types in a single Sicilian villa. Using theories of space and place and phenomenology, I study closely both the iconography and the archaeological contexts of the mosaics, situating these microcosmic floors back in their original spaces. I assess their scales relative to the human body, possible routes around their imagery, and views at downward angles. Often understudied as physical floors, I show how the mosaics allowed their viewers to inhabit and engage with the microcosms they created, physically imparting or reinforcing particular understandings of the expanses they depict. I conclude that because most of these floors depict geographically specific and even labeled places, as well as faraway places, and because the majority of the floors were laid down well after the establishment of the Roman empire, they can reveal increased cartographic understandings of the world that came with Rome’s imperial project. Several important ideas about empire emerge, like connection across the Roman world and access to its many landscapes and resources. Compressing these landscapes and geographies, owning or funding them, and making them accessible to others could be a clear way for Romans to show power
Penn Library\u27s LJS 425 - Risālah-i Tawḍīḥ al-alḥān. = رساله توضيح الالحان. (Video Orientation)
No full texthttps://repository.upenn.edu/sims_video/1172/thumbnail.jp