Lysosomal Storage Diseases: How Gene-Targeted Therapies are Changing What is Treatable

Lysosomal storage diseases (LSDs) are a set of inborn errors of metabolism characterized by deficiencies in acid hydrolases that lead to substrate accumulation in cells and decreased or absent formation of downstream products. Substrate buildup can result in a wide range of symptoms affecting multiple peripheral organ systems and the central nervous system. Disease onset is commonly observed in infancy or childhood, but adult-onset forms also occur. Current treatments include enzyme replacement therapy and substrate reduction therapy, which are effective in the short term, but gene therapies are emerging as a potential long-term and efficacious treatment option. Delivery of gene therapy is accomplished by using adeno-associated viruses, specifically serotypes 9 and 10, and lentiviruses due to their ability to reach the central nervous system. Modifications to these vectors and intracerebroventricular, intrathecal, or intravenous delivery can maximize transgene expression in affected tissues. Results from animal studies show the promise of these therapies to treat Krabbe, Fabry, and Gaucher disease. Early treatment administration showed the best outcomes for increasing life span and clearance of accumulated substrates. Combination therapy shows promising results when gene therapies were given in addition to bone marrow transplants in animal models. Next-generation sequencing technology allows for the reliable identification of pathogenic variants that can lead to LSDs and successful gene therapy experiments in animal models reveal the potential for clinical application

Extensible Knowledge Representation: the Case of Description Reasoners

This paper offers an approach to extensible knowledge representation and reasoning for a family of formalisms known as Description Logics. The approach is based on the notion of adding new concept constructors, and includes a heuristic methodology for specifying the desired extensions, as well as a modularized software architecture that supports implementing extensions. The architecture detailed here falls in the normalize-compared paradigm, and supports both intentional reasoning (subsumption) involving concepts, and extensional reasoning involving individuals after incremental updates to the knowledge base. The resulting approach can be used to extend the reasoner with specialized notions that are motivated by specific problems or application areas, such as reasoning about dates, plans, etc. In addition, it provides an opportunity to implement constructors that are not currently yet sufficiently well understood theoretically, but are needed in practice. Also, for constructors that are provably hard to reason with (e.g., ones whose presence would lead to undecidability), it allows the implementation of incomplete reasoners where the incompleteness is tailored to be acceptable for the application at hand

Civil Interests, The Social Contract, and The Conditions of Political Legitimacy

This dissertation explores the idea of civil interests, and considers how civil interests constrain the legitimate exercise of political authority. John Locke presents the concept of civil interests in A Letter Concerning Toleration as the legitimate object of political authority’s concern. First, I identify the idea of civil interests and its relationship with the social contract in Locke’s Letter. I argue for the prominence of Locke’s contractarian line of argument in his case for toleration. Second, I trace the idea of civil interests through the historical social contract arguments of Locke’s Second Treatise, Thomas Hobbes’ Leviathan, and Immanuel Kant’s major political works. I demonstrate the utility of analyzing the social contract in light of the idea of civil interests by clarifying puzzling features of each theory, specifically Hobbes’ conflicting remarks on religious liberty, and Kant’s elusive notion of possible consent. Third, I abstract the social contract argument for identifying persons’ civil interests from its historical expression to argue that persons’ civil interests, consist of their lives and liberty. I additionally justify my appeal to the social contract, and specify its details for the purpose of my argument. Finally, I apply the social contract argument centred on the concept of civil interests to argue against legal moralism as theory of criminalization and criminal law. I argue that instrumental legal moralism is conceptually untenable, and non-instrumental legal moralism provides an illegitimate justification for criminalization and the criminal law

Design Clarity in Public Outreach Documents: A Guidebook for a First Detector Volunteer Network

We established a first detectors network by inviting woodland owners to monitor for invasive pests on their property as volunteers. Accessible outreach materials are necessary to communicate volunteer responsibilities. A professional graphic design firm provided a series of design and layout techniques, including font size, font style, spacing, color palette, backgrounds, and figures, that improved our instructional guidebook. The guidebook was received positively in anonymous volunteer evaluations and in face-to-face discussion. The techniques may be useful in the development of materials for other outreach programs