University of California Research Initiatives

Abstract: Structure elucidation plays a critical role across the landscape of medicinal chemistry, including medicinal inorganic chemistry. Herein, we discuss the importance of structure elucidation in drug development and then provide three vignettes that capture key instances of its relevance in the development of biologically active inorganic compounds. In the first, we describe the exploration of the biological activity of the trinuclear Ru compound called ruthenium red and the realization that this activity derived from a dinuclear impurity. We next explore the development of Au‐based antitubercular and antiarthritic drugs, which features a key step whereby ligands were discovered to bind to Au through S atoms. The third exposition traces the development of As‐based antiparasitic drugs, a key step of which was the realization that the reaction of arsenic acid and aniline does not produce an anilide of arsenic acid, as originally thought, but rather an amino arsonic acid. These case studies provide the motivation for an outlook in which the development of Sb‐based antiparasitic drugs is described. Although antileishmanial pentavalent antimonial drugs remain in widespread use to this day, their chemical structures remain unknown.

Abstract: Glioblastoma multiforme (GBM) is the most aggressive primary malignant brain tumor in adults, with a poor prognosis that highlights a dire clinical need for innovative therapeutic interventions. Despite significant advances in diagnoses and multimodality therapies, the overall prognosis for patients with GBM remains poor, with a median survival time of 15-18 months. Therefore, there is an unmet medical need to develop alternative treatment strategies to improve clinical outcomes. Dysregulation of post-transcriptional control and translational machinery have been implicated in malignant tumor development. Cytoplasmic polyadenylation element binding proteins (CPEB1-CPEB4) are RNA-binding proteins that regulate poly(A) tail elongation of target mRNAs and subsequently contribute to phenotypic changes in cancer cells. Notably, a self-cleaving ribozyme was identified in the CPEB3 gene, but its role in cancer is wholly unexplored. Considering the role of CPEB3 as a tumor suppressor gene and the promotion of cancer progression through the downregulation of CPEB3, our hypothesis is that the CPEB3 ribozyme regulates CPEB3 expression, and its activity contributes to the progression of tumors. Using antisense oligonucleotides (ASOs) as an approach, we demonstrated that inhibition of CPEB3 ribozyme resulted in an increase of CPEB3 mRNA and protein expression. Blocking the CPEB3 ribozyme led to a significant reduction in cell proliferation, migration, and invasion in GBM cell lines. Gene set enrichment analysis (GSEA) revealed the downregulation of epithelial-mesenchymal transition (EMT), angiogenesis, and hypoxia gene sets in GBM cells treated with ASO compared to Ctrl-ASO. We further measured VEGFA mRNA and protein expression and found that ASO-treated GBM cells secreted significantly less VEGF in conditioned media. Inhibition of the CPEB3 ribozyme also mitigated the EMT process in GBM cells. Subsequently, ASO strategies were applied to patient-derived glioma stem cells (GSCs), representing a clinically relevant model for pre-clinical therapeutic intervention. We found that treatment of CPEB3 ribozyme ASO up-regulated CPEB3 mRNA and inhibited cell proliferation in GSCs. Furthermore, the combination of ASO and temozolomide chemotherapy exhibited a more pronounced decrease in GSCs proliferation compared to individual treatment alone. Collectively, this study highlights the significance of the CPEB3 ribozyme in GBM and explores therapeutic approaches focused on targeting CPEB3 in cancer. Citation Format: Claire Chen, Eric Wang, Lily Tong, Mehran Nikan, Daniela A. Bota, Claudia Benavente, Andrej Luptak. Suppression of the CPEB3 ribozyme modulates the progression of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3180.

Abstract: The urbanization process substantially alters every aspect of the soil environment. In this study, we compared soil microclimate, chemistry, and physical characteristics of unmanaged natural soils with managed soils of three common urban land uses (stormwater natural treatment systems, ornamentally landscaped areas, and lawns) across three University of California campuses. Over the course of 1-year, average monthly soil temperatures among land uses showed fewer than expected differences. Average monthly soil moisture reflected wet and dry seasonal changes, but this pattern was muted in managed land uses compared to natural soils due to irrigation. From April through December, lawns and landscaped areas were significantly wetter than natural soils (e.g. 1.5–3 times higher in August and September). Soil organic matter, total carbon, and total nitrogen were significantly higher in lawns compared to other land uses, while their bulk density was significantly lower. Principle component analysis confirmed that natural and lawn soil properties were distinct from each other. These differences in the managed soils, particularly lawns, are attributable to typical urban land management practices such as fertilization, irrigation, and the installation of organic-rich sod. As urbanization continues to change the native landscape of semi-arid regions, these changes to soil microclimate, chemistry, and physical characteristics are important to consider for urban best practices and sustainable development.

Are voters as polarized as political leaders when it comes to their preferences about how to cast their ballots in November 2020 and their policy positions on how elections should be run in light of the COVID-19 outbreak? Prior research has shown little party divide on voting by mail, with nearly equal percentages of voters in both parties choosing to vote this way where it is an option. Has a divide opened up this year in how voters aligned with the Democratic and Republican parties prefer to cast a ballot? We address these questions by presenting the findings of an online survey of a nationally diverse sample of 5,612 eligible voters, fielded from April 8-10, with an embedded experiment providing treated respondents with scientific projections about the COVID-19 outbreak. We find an eight-percentage point difference between Democrats and Republicans in their preference for voting by mail in the control group, but this party divide doubles in the treatment group. We also find that exposure to scientific projections about the outbreak increases support for vote-by-mail legislation and confidence in vote-by-mail election integrity for both Democrats and Republicans.

We report findings from a mixed-methods study analyzing the networks of a group of Multiple-Subject pre-service teachers (PSTs) along two social dimensions:1) close friendship and 2) equity conversation networks. Our research was guided by the following questions: Do PSTs have equity conversations with those they are close to? Why or why not? We find 1.7% of PSTs have equity conversations with those they are close to. We found that some students sought relationships with those who share similar commitments towards social justice whereas other students had close relationships with a focus on engaging in social activities. These findings have implications for the ways in which administrators and teacher educators design programs to foster cohesive networks.

To inform the vital conversation among the nation’s political leaders, elections administrators, and scholars about how to hold a safe, accessible, and fair election in November, this paper reports how a sample of 5,612 eligible American voters, surveyed April 8-10, want to see the election run during the COVID-19 crisis. We embed a randomized experiment presenting respondents with truthful summaries of the projections of two teams of scientists about the pandemic. Our descriptive findings show that four in ten eligible voters would prefer to cast their ballot by mail rather than in person this November and that a majority of respondents favor policies expanding mail voting. Our experimental findings show that respondents who read the scientific projections were more likely to prefer voting by mail, were more likely to trust that a mail ballot would be counted accurately, and were more likely to favor holding the election entirely by mail.