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Targeting LNK (SH2B3) to Expand Healthy and Fanconi Anemia Human Hematopoietic Stem and Progenitor Cells
No full textThe transfusion of healthy hematopoietic cells is required to treat diseases of and injury to the hematopoietic system. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for a variety of both malignant and non-malignant hematological disorders arising from dysfunction of hematopoietic stem cells (HSCs). HSCT is limited by our inability to robustly expand human HSCs ex vivo, especially for autologous gene therapy-based HSCT for monogenic disorders. Therefore, developing strategies that expand HSCs could greatly improve HSCT, particularly for gene therapy approaches for bone marrow failure (BMF) syndromes with defective HSCs such as Fanconi Anemia (FA). This thesis investigates the role of the adaptor protein LNK (SH2B3) in human hematopoiesis and whether depletion of LNK in human hematopoietic stem and progenitor cells (HSPCs) would expand human HSCs to improve HSCT. LNK is an established negative regulator of cytokine signaling in murine hematopoietic HSPCs and its deficiency potentiates activation of JAK2. As a result, mice genetically deficient for Lnk have an expanded pool of HSCs with enhanced self-renewal. Here, we demonstrate that depletion of LNK via lentiviral expression of miR30-based short hairpin RNAs (shRNAs) resulted in robust expansion of transplantable human HSCs that provided balanced multilineage reconstitution xenotransplant without evidence of malignant transformation. Importantly, LNK depletion enhanced cytokine mediated JAK/STAT activation in CD34+ HSPCs. Moreover, we demonstrate that LNK depletion expands primary HSPCs associated with FA using FA-like stem cell models and primary patient derived FA HSCs. In addition, we show that genetic deletion of LNK in human pluripotent stem cells increases their production of hematopoietic cells in growth factor driven differentiation protocols. Together, these results demonstrate the potential of targeting LNK to expand HSCs to improve HSCT, HSCT-based gene therapy and potentially other hematopoietic cell therapies
Overcoming Barriers to Women’s Participation in Water Supply through Innovative Technology
Get PDFResearch from the global development sector repeatedly shows that convenient access to safe water improves women’s quality of life. Similarly, digital technology is increasingly highlighted as an essential component for increasing women’s educational, economic, and civic opportunities—yet a gender divide exists. As digital technology becomes more prevalent in managing effective and reliable safe water services, the water sector has the opportunity to both create new channels for women to engage with technology and use technology to make safe water supply more responsive to women’s needs. In this article, we will explore how technology is deployed within the small water enterprise (SWE) value chain to produce benefits for women beyond immediate safe water access. Using Safe Water Network’s experience in India, where it launched a program with Honeywell Hometown Solutions to center women as safe water suppliers, as well as Saha Global’s program in Ghana, we will highlight how technology advances women’s roles as active participants in the local economy through their responsibilities as SWE managers and operators
Auctioning Annuities
Get PDFIn this paper, we empirically analyze a market for annuity contracts. To this end, we use multi-stage and multi-attribute auctions, where life insurance companies that have private information about their annuitization costs compete for retirees\u27 savings by offering pensions and bequests, and retirees choose \winners that maximize their expected present discounted utilities. We establish the identification of our model parameters and estimate them using rich administrative data from Chile. Our estimates suggest that (i) retirees with lowest savings quintiles value firms\u27 risk ratings (e.g., AAA, AA) the most, while the high savers do not; (ii) almost half the retirees who choose an annuity do not value bequest, and (iii) firms are more likely to have low annuitization cost for retirees in the top-two savings quintiles. Counterfactuals show that private information about costs harms only these high savers, and simplifying the current mechanism by using English auctions and \shutting-down risk ratings lead to higher pensions in equilibrium, but only for the high savers
The Great Transition: Kuznets Facts for Family-Economists
Get PDFThe 20th century beheld a dramatic transformation of the family. Some Kuznets style facts regarding structural change in the family are presented. Over the course of the 20th century in the United States fertility declined, educational attainment waxed, housework fell, leisure increased, jobs shifted from blue to white collar, and marriage waned. These trends are also observed in the cross-country data. A model is developed, and then calibrated, to address the trends in the US data. The calibration procedure is closely connected to the underlying economic logic. Three drivers of the great transition are considered: neutral technological progress, skill-biased technological change, and drops in the price of labor-saving household durables
Eleanor Allen: On a Mission to Provide Safe Water for Everyone, Forever
Get PDFEleanor Allen is a global water expert dedicated to helping millions of people access the safe and sustainable water and sanitation services needed to save lives, stay healthy, earn more money, and thrive. Eleanor is fiercely passionate about improving the state of the world with respect to water and sanitation. She has dedicated her career to this goal, first as a Peace Corps volunteer in the Dominican Republic, then as a consulting engineer (at CH2M/Jacobs and Arcadis), and now as the CEO of Water For People. Eleanor has lived and worked all over the world. As a professional civil engineer, business executive, and CEO, she has led large global and regional operations, managed projects and programs, developed business and raised funds, and designed water and wastewater treatment plants. Eleanor believes that societal change can be accelerated through social entrepreneurship and the efforts of organizations like Water For People. This article tells the story of Eleanor’s inspirational life and career journey, provides technical aspects of her current work, and shares her encouraging message on living life with a purpose to young water enthusiasts
Shoring Up Shortfalls: Women, Retirement and the Growing GigSupp Economy
Get PDFIn recent years, high-profile Silicon Valley firms have engineered billion-dollar IPOs through developing online and app-based platforms that connect service providers and sellers with customers and process their payments (the “online platform economy”). Today, millions of Americans earn income using platforms developed by Uber, Etsy, and Airbnb; and research has identified the limitations of existing federal tax rules to facilitate tax compliance of these workers and considered the consequences of their failure to pay self-employment taxes. However, questions remain as to the changing demographics and motivations of online platform economy workers and their retirement income security. Titled, Shoring Up Shortfalls: Women, Retirement and the Growing Gig Economy, we propose to identify and analyze: (i) the existing demographic data on this workforce; (ii) their economic motivations and retirement income needs; and (iii) the federal tax, retirement policy, and financial literacy proposals that would enable the gig economy workforce to support itself in retirement
Rejecting Ingrid Robeyns’ Defense of Limitarianism
Get PDFThis paper critically evaluates the argument put forth by the philosopher Ingrid Robeyns in her work entitled What, if Anything, is Wrong with Extreme Wealth. Robeyns holds the Chair Ethics of Institutions at Utrecht University, and her academic research focuses on issues pertaining to contemporary political philosophy and applied ethics. In her aforementioned publication, Robeyns defends the political theory called limitarianism, which holds that there should be an upper limit to the amount of income that an individual can hold. Limitarianism, like many other political philosophies, presents a view of how resources ought to be distributed in society based, in part, on certain ethical principles. Robeyns explicitly outlines two arguments in support of limitarianism as a political philosophy: (1) by eliminating excess wealth, limitarianism prevents the super-rich from undermining political equality and (2) by redistributing this excess wealth, there will be more resources available to address any urgent unmet needs or collective action problems in society. This paper carefully reviews and ultimately rejects Robeyns’ defense of limitarianism as a theory of political philosophy. This paper sets out to highlight both the flaws in the basic premises of limitarianism as a theory as well as the shortcomings of the specific arguments that Robeyns’ constructs in support of the theory itself
Scribes and Soldiers: A Brief Introduction to Seventeenth-Century Military Manuscripts
Get PDFThe history of early-modern European manuscripts has rarely focused on the use of manuscripts in armies. Some historians have even presented early-modern armies as unconcerned with daily records of the common soldiers under their command. Others have used early-modern handwritten documents as sources of information, without examining them as artifacts. But these documents are interesting works of vernacular art, created under difficult circumstances. They also provide clues to things like the literacy rate of some common soldiers. This article introduces early-modern military manuscripts. The focus is on the army of Electoral Saxony during the Thirty Years War (1618-1648)
Demands for “Sisterly” Love: Exploring the Hyperpenalization of Black Girls in the School District of Philadelphia
Get PDFAn immense amount of research, memos, and scholarship has surfaced in the last decade considering the school-to-prison pipeline and Black boys’ involuntary participation in it. Various education scholars have presented data emphasizing how Black male students are disproportionately punished–notably in ways that negatively impact their prospects for educational attainment, social mobility, and long-term empowerment. Many, however, fail to consider their close counterparts: Black girls. This thesis expands upon the Crenshaw, Ocen, and Nanda (2015) report to see if Black girls are also disproportionately penalized in Philadelphia public schools within the School District of Philadelphia (SDP) at higher rates relative to female students of other races. The thesis also employs relative risk ratios to determine, through an intra-gender analysis between Black and white students, if Black girls are disproportionately penalized at higher rates relative to Black boys.
The aforementioned scholars created a report on school discipline within Boston and New York City Public Schools. Their intra-gender analyses found that Black girls had a statistically greater risk of experiencing suspension and expulsion relative to female students of other races. This paper applies quantitative research methods through disciplinary data collection from the Civil Rights Data Collection Tool via the Department of Education. Additionally, the project weaves together education policy and political theory to investigate (1) how discourses of power, marginality, and intersectionality inform hyperpenalization; and (2) existing alternatives to current punitive paradigmatic practices
