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Development of a pH-Sensitive Probe for in vivo Cerenkov Imaging of the Tumor Microenvironment
No full textAcidity in the tumor microenvironment (TME) is related to invasion, metastasis, and chemotherapeutic resistance, all of which are contributors to poor prognoses in cancer patients. In this thesis, we propose the application of Cerenkov radiation as a tool for imaging pH in vivo through the measurement of Selective Bandwidth Quenching (SBQ) and Cerenkov Radiation Energy Transfer (CRET) in triple negative human breast cancer models MDA-MB-231 and 4175-Luc+. To test the hypothesis that SBQ and CRET signals could provide measurements of TME pH in vivo, a Cerenkov-active molecule, NFbD, was conjugated and chelated with 68Ga. Cerenkov imaging was performed with NFbD-Ga in vitro to construct pH titration curves, later used to interpolate in vivo Cerenkov pH values. In vivo Cerenkov imaging was performed on athymic nude mice bearing 4175-Luc+ triple negative breast cancer xenografts after intratumoral injections of NFbD-Ga (40 μCi). CRET values obtained from in vivo Cerenkov imaging were used to estimate TME pH values, which were validated by 31P Magnetic Resonance Spectroscopy (31P MRS) following i.p. injection of 3-APP. Tissue scattering, and absorption effects were evaluated in vitro with tissue phantoms. NFbD maintained its pH-sensitivity after conjugation (pKa = 7.8, λex = 599 nm, λem = 669 nm at pH 9). SBQ and CRET were observed in vitro inter-and intramolecularly, at 600 nm and 700 nm, respectively. SBQ and CRET were also observed in vivo. CRET measurements following intratumoral injections of NFbD-Ga yielded a tumor pHCerenkov = 6.90 ± 0.16, 31P-MRS on the same tumors yielded a pHMRS = 6.92 ± 0.04. Chicken tissue phantoms provided insight on tissue attenuation effects, showing that 1 mm of tissue can attenuate 64% of the Cerenkov signal, in the absence of naphthofluorescein and further attenuation to 17% is achieved with the addition of naphthofluorescein. The synthesis and development of this Cerenkov-active, pH sensitive probe for the determination of TME pH provided detectable CRET signals in vivo, allowing Cerenkov to be used as a potential technique for non-invasive pH imaging
Narratives of Islamic Self-Making: Black Muslim Youth in a Philadelphia Public School
No full textThe phenomenon I trace throughout this dissertation is how West African and African American Muslim youth navigate the complicated terrain of racial, ethnic, and religious identities within the localized context of their school, a charter school in Southwest Philadelphia named Honors Academy. I investigate the puzzle of how, given historical contestations among African immigrants and African American Black Muslims in the US, these youth, in interacting everyday with each other at school, make sense of the differences that become salient in school in their processes of becoming Black Muslims in the US. I consider the role the school and varied spaces in the school play in this process. How can we understand what sociocultural influences become salient within different contexts in the school and how these influences shape what aspects of being Black, Muslim, and ethnic become most significant within these youth’s interactions and discourses? I argue that Black Muslim youth at Honors engage in Islamic self-making, which is the process of engaging in diverse practices of religious self-fashioning, including but not limited to religious technologies. Black Muslim youth engage in Islamic self-making through praying, fasting, and dressing modestly, through making claims to public spaces, through market strategies such as selling Islamic themed products, and through creating religious material inscriptions. Islamic space-making, a form of Islamic self-making, takes place within the context of an increasingly market-driven public education and is embedded within larger social processes such as racialization, racial formations, and ethnicization. Specifically, within US Muslim communities, ethnoreligious hegemonies, a privileging of Arab, South Asian, and immigrant Islams over Black Islamic forms, operate alongside and work within US racial formations to maintain the logic of white supremacy. I note how ethnoreligious hegemonies shape Islamic self-making practices amongst Honors students and how differences between Black Muslim youth played a prominent role despite the MSA and Honor’s attempts to cultivate unity amongst their students. Islamic self-making emphasizes that there are multiple means through which Islamic selves can be cultivated and that this process is mediated differently across spaces. My spaces of investigation are identity affirming contexts, such as the Muslim Students’ Association (MSA) and African American History (AAH) class, which are grounded within a limited multicultural ideology at Honors but also occasionally creating alternative openings for religious expressions. Through each of these spaces, which include an afterschool club, classrooms, hallways, and a mosque, I consider specifically: How do religion, ethnic and family histories, and racial formations mediate forms of Islamic self-making for Black Muslim youth, within a racist, Islamophobic, and capitalist US context? This ethnographic account acknowledges the diversity of Black youth’s identities and counters the essentialization of Black experiences, while also investigating the link between religious expressions and racial formations
Barriers to Entry for Black Pre-Service Teachers
No full textFor decades, calls for an increase in the number of minority teachers have led local, state, and federal policy conversations. However, specific barriers to entry into the teaching profession for Black pre-service teachers have received less attention. Moreover, the minimally existing research on the topic is mixed. Despite being the most affected by barriers to entry into the teaching profession, little research has investigated how barriers specifically impact Black pre-service teachers during the teacher training or Educator Preparation Provider (EPP) process. This study examines one possible cause: licensure exams, of which Black test-takers have had the lowest pass rates of all racial or ethnic demographic groups since the inception of the exam. First, this study will thoroughly review existing literature on the various theoretical barriers to entry for Black pre-service teachers, including coursework, field experiences, and licensure exams. Next, the impact of a licensure exam policy change on Black test taker pass rates in Arkansas will be assessed using various descriptive data and the difference-in-differences estimator methodology. This study hypothesizes a change in licensure exam type has negatively impacted the Black teacher workforce in Arkansas, specifically elementary school teachers. Finally, recommendations for state and federal policy and practice will be discussed
Leading through Uncertainty: Exploring How Senior Leaders Experience Uncertainty in a Knowledge-Intensive Organization
No full textLeading through uncertainty is a prevailing experience for leaders in today’s organizations. Past research related to uncertainty and leadership used a cognitive, one-dimensional conceptualization of uncertainty and focused on its negative implications for employees. The purpose of this research study was to gain a deep understanding and contribute insights into the lived experience of uncertainty from the perspective of senior leaders in a knowledge-intensive organization. A qualitative phenomenological approach was used to explore and interpret the meaning of uncertainty as experienced by 20 senior leaders in a knowledge-intensive organization. Qualitative data was analyzed through a deductive and inductive thematic analysis process, applying van Manen\u27s lifeworld existentials to guide the data reflection and analysis. This study contributes and expands the current literature on leadership and uncertainty by describing how leaders experience uncertainty intrapersonally and interpersonally. While further study is warranted, the findings suggest that uncertainty is mostly an emotional and physical experience, advancing the traditional conceptualization of uncertainty as a purely cognitive phenomenon. In doing so, this study offers a multidimensional and dynamic understanding of the experience of uncertainty. The findings also indicate that the most effective and adaptive way for leaders to deal with the experience of uncertainty is through adopting a relational approach including establishing trust, embracing not knowing, engaging in dialogue, and distributing power. Finally, this study contributes to the emerging body of literature uncertainty that suggests that uncertainty can lead to positive outcomes at an individual, team, and organizational level
Disorderly and Inhumane: Explaining Government-Sponsored Mass Expulsion, 1900–2020
No full textSince 2015 over two million people have been expelled, en masse, around the world. Mass expulsion is a major international issue that threatens peace and security around the globe. This dissertation examines why and how governments expel ethnic groups en masse. What motivates them to implement an expulsion policy and why don’t more governments do the same? By isolating policies of intentional group-based population removal—distinct from genocide, massacre, and coercive assimilation—I show that the motivations of expulsionist governments are informed by the phase of nation-building and the perceived threat of the target group. The four clusters of motivations are: fifth column, anti-colonialism, nativism, and counterinsurgency/reprisal. Since not all governments with one of the identified motivations to expel go on to remove populations en masse, I also identify important constraints on governments’ strategic choices. Through four paired-comparison case studies of similarly motivated governments with different outcomes (expulsion or non-expulsion), I show that alliances, target group homeland state(s), and the international community are the key contributing factors that enable or deter mass expulsion policies. The evidence is drawn from archival research conducted at the United Nations High Commissioner for Refugees, the International Committee of the Red Cross, and the League of Nations archives in Geneva, Switzerland, as well as from other primary sources, secondary historical sources, and extant datasets. This dissertation contributes to the field of ethnic conflict and exclusionary politics. It fills a gap in the literature by systematically examining mass expulsion policies that intentionally remove ethnic groups over the longue durée. The argument expands existing explanations beyond war and security threats to highlight an entire class of expulsions that target economic threats, which requires scholarly and international policy attention. The dissertation also deepens our understanding of critical atrocity constraints and proposes tangible policy recommendations for deterring its use
Elucidating the Role of Hepatic FOXO1 Signaling in the Regulation of Adipose Tissue Biology
No full textThe 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
Structural Studies of TRPV5 Modulation
No full textCalcium homeostasis is a highly regulated process in the body. Transient receptor potential vanilloid 5 (TRPV5) is a calcium selective ion channel that is responsible for the regulation of calcium reabsorption in the kidney. TRPV5 has been shown to be the essential for maintaining this calcium homeostasis and is implicated in disorders including hypercalciuria and kidney stone disease. However, little is known about the structural basis for mechanisms of TRPV5 regulation. Therefore, we aimed to address questions surrounding TRPV5 structure and regulation by solving cryo-electron microscopy (cryo-EM) structures of TRPV5 under various conditions. Specifically, we focused on regulation by low pH and phosphorylation by protein kinase A (PKA) that inhibit and activate TRPV5 respectively. Employing cryo-EM, we were able to structurally evaluate TRPV5 under several low pH conditions along with the activating phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). The structures resolved conformational changes elicited by low pH conditions. Next, we solved the cryo-EM structures of TRPV5 to investigate the effect of PKA phosphorylation. TRPV5 was investigated using a phosphomimic mutation to simulate TRPV5 phosphorylation. Overall, the phosphorylation had little effect on channel structure, but we found that phosphorylation decreases calmodulin (CaM) mediated inactivation. These findings provide a better picture of TRPV5 modulation and will be helpful in the development of therapeutics aimed to address calcium centric pathologies
Topic Modeling: Optimal Estimation, Statistical Inference, and Beyond
No full textWith the development of computer technology and the internet, increasingly large amounts of textual data are generated and collected every day. It is a significant challenge to analyze and extract meaningful and actionable information from vast amounts of unstructured textual data. This thesis explores several problems in topic modelings and provides new algorithms with theoretical guarantees. The first part of this thesis aims to develop an optimality theory for unsupervised topic modeling under the probabilistic latent semantic indexing (pLSI) model. Novel and computationally fast algorithms for estimation and inference of both the word-topic matrix and the topic-document matrix are proposed and their theoretical properties are investigated. Moreover, a refitting algorithm is proposed to establish asymptotic normality and construct valid confidence intervals for the individual entries of the word-topic and topic-document matrices. In the second part, we study supervised topic modeling, which jointly considers a collection of documents and their paired side information. To take account of the compositional nature of the topic-document matrix, we adapt the log-contrast model and introduce a novel bias-adjusted algorithm to investigate the regression coefficients in the generalized linear model. In addition, a de-biased procedure is proposed to establish an asymptotically unbiased and normally distributed estimator, and hence valid confidence intervals are constructed for the individual entries of regression coefficients. We also investigate the errors-in-variables models under the generalized linear model framework in the third part. We proposed an estimator when the measurement error is small
Corporate Criminal Liability in India: A Pressing Issue
Get PDFA company is regarded as a distinct legal body from its owners. It may be characterized as a group of people working towards a single purpose, typically commercial. The degree to which a firm, as a distinct organization, is accountable for the actions of its workers is defined by Corporate Criminal Liability under Indian criminal law. The two main questions raised about corporate liability are whether a company can commit a crime, and whether it is legally accountable for the alleged criminal conduct.
This paper analyzes the history of the concept of Corporate Criminal Liability around the world, its background and development in India, and how it has evolved over the years. Through case studies, this paper attempts to study how the concept applies to the Indian judicial system and lists the shortcomings that need to be addressed. In the end, the research suggests how Corporate Criminal Liability laws and their applications can be improved to hold corporations more accountable, and ultimately, safeguard the public
Essays On Macroeconomics
Get PDFThis dissertation consists of two chapters. In the first chapter, we propose a protocol of repeated bargaining where occasional periods of increased outside opportunities yield improved outcomes but also higher breakout probabilities, yet there is a lot of risk sharing. Crucially, we only look at the Markov perfect equilibria which dispenses us from both having non payoff relevant state variables that are costly to compute nor contrived process of equilibrium selection. Using the negotiation protocol proposed in the first chapter, I study the welfare-maximizing income tax progressivity when married couples file jointly as is the U.S. income tax system. To see how progressive income tax impacts household formation and intra-household allocations, I construct a life-cycle model to study how changes in tax policy affect labor supply --- especially those of secondary earners in married households --- and household formation/dissolution. Married households make allocation decisions jointly without being able to commit future arrangements. With this model, I find the sensitivity of the marriage patterns to the tax code: changing tax unit from a household to an individual increases the number of married households by 3\%, mainly via a reduction of the marriage age coming from reduced rewards to search for advantageous tax partners. I also consider the same policy reform but abstracting the responses of marriage/divorce decisions and intra-household sharing rules to show how those are quantitatively important. We then use the model to compute the optimal income tax progressivity that maximizes welfare under two scenarios; (i) married couples filing jointly and (ii) individual taxation. In Scenario (i), the optimal progressivity for married couples is lower. At the same time, that of singles is slightly higher than the current U.S. tax code. In comparison, the optimal progressivity in Scenario (ii) is much higher than the current U.S. single income tax schedule