Browsing by Subject "Inhibitors"

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Perspectives from long-tenured superintendents of color: enablers and inhibitors of superintendent longevity
(2023-12) Montelongo, Bardo Alberto; Woulfin, Sarah; Reyes, Pedro; DeMatthews, David; San Miguel, Trinidad
Superintendent longevity contributes to organizational success, while superintendent turnover creates academic instability and organizational dysfunction. Yet superintendent longevity continues to be a worrisome issue in education. The current turnover rate of superintendencies ranges from 14% to 20% annually, and superintendent tenure in districts with the highest percentage of low-income students is 3.5 years shorter than in districts with the lowest poverty levels. The concern becomes urgent when considering the direct correlation between superintendent longevity and district effectiveness. In contrast, frequent superintendent turnover has been linked to unsustainable district improvement efforts and less overall growth. Adding to the concern is the demographic imbalance between superintendents and the students they serve, with the low representation of people of color in superintendencies remaining problematic. Superintendents today are expected to function as agents of change who address head-on the increased state and federal accountability pressures, and who strive to level the field and yield excellent and equitable educational outcomes for all students. These transformative outcomes require innovative solutions, continuity of vision, and systemic reform resulting from sustained and focused leadership. This study sought to document how long-tenured superintendents of color in Texas perceived the enablers and inhibitors to their longevity and the strategies they deployed to remain in the role. By adopting a qualitative research design to examine the perspectives of 12 long-tenured superintendents of color regarding their lived experiences in the superintendency, the study aimed to represent and uplift the voices and experiences of those typically underrepresented in research. The findings revealed three enabling factors of superintendent longevity for which it is possible to articulate a subset of strategies deployed by participants to sustain their longevity in the role. The three enablers identified were 1) purpose-driven leadership, 2) a healthy relationship with the school board, and 3) establishing trust as a leader. Finally, the study provides recommendations to current and aspiring superintendents, school boards, and superintendent preparation programs in the hope it can enhance the design of more efficacious supports to help retain superintendents and provide concrete strategies to sustain their longevity in the superintendency.
Progress in the search for ricin A chain and shiga toxin inhibitors
(2009-12) Bai, Yan, 1977-; Robertus, Jon D.
Ricin and Shiga toxin type 1 are potent cytotoxins known as ribosome inhibition proteins, abbreviated RIPs. Proteins of this family shut down protein synthesis by removing a critical adenine in the conserved stem-loop structure of 28S rRNA. Due to its exquisite cytotoxicity, the plant toxin ricin has been used as a biological warfare agent. Although great achievement has been made on ricin research, including catalytic mechanism and structure analysis, there is still no specific treatment available for ricin exposure. In addition, ricin A chain inhibitors may also be useful against the homologous bacterial proteins shiga toxins, which are responsible for dysentery, and diseases related to food poisoning, including hemolytic uremic syndrome. Previous study on RTA inhibitor search has provided a number of substrate analog inhibitors, all of which, however, are weaker inhibitors. Therefore, the goal of this work is to improve the binding affinity of known inhibitors and to discovery new scaffolds for inhibitor discovery and development. In this work, multiple approaches were employed for this purpose, including optimizing known inhibitors and searching new inhibitors by Virtual Drug Screening (VDS) and High Throughput Screening (HTS). A number of new RTA inhibitors were discovered by these strategies, which provide a variety of pharmacophores for RTA inhibitor design, and also added a new line of evidence for VDS as an advanced technology for drug discovery and development.
Synthesis and optimization of a library of small molecule inhibitors of ricin toxin A
(2012-05) Pruet, Jeffrey Michael; Anslyn, Eric V., 1960-
Ricin is a potent cyctotoxin with no known antidote. Chapter 1 provides background and context for this thesis, which is primarily focused on probing the active site of Ricin toxin A (RTA). Relevant information about Ricin, its use, method of action, and noteworthy contributions towards the discovery of Ricin A chain inhibitors are provided. Furthermore, a brief description of the assays used by our collaborators to monitor RTA inhibition is provided. Additionally, a great deal of this thesis pertains to a particular heterocycle, pterin, and thus the remainder of Chapter 1 is dedicated to pterins, their physical properties, biological relevance, and selected reports of pterin chemistry. Chapter 2 details preliminary research focused on the use of nucleic acid-based platforms as RTA inhibitors. Two specific nucleic acids were chosen, adenine and guanine, and the chapter is split to address them individually. Rational for their use is provided, as well as the synthetic strategies investigated. Both platforms showed significant interference with the analysis assay, most pronounced for the adenine series. A primary goal throughout this thesis is the identification of a simple, rapid method to provide a library of new compounds. To this end, discussion of improved synthetic routes are provided within the section dedicated to guanines. Initial investigation into pterins as a platform for RTA inhibitors is provided in Chapter 3. Much of this chapter is concerned with hurtles encountered while dealing with the poor solubility of pterins, purification, and limits in reaction scope. Finally this chapter details a significant discovery in pterin's utility, both in terms of synthetic ease and preference towards one regioisomer over another. A variety of amides are initially used to probe the active site for significant interactions to the pterin pendents. Chapter 4 builds off the discoveries detailed within the previous chapter. Efforts to optimize the preliminary amide series from Chapter 3 are described, leading to a significant enhancement in activity. Additionally, Chapter 4 describes a synthetic breakthrough which greatly enhanced the speed of synthesis and complexity of the designed pterin inhibitors. Building upon the goal to map the RTA active site, a description of various peptide conjugated pterins is provided, as well as efforts to arrive at optimized isosteres of the most promising peptide derivatives.