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A histochemical approach to activity-based copper sensing reveals cuproplasia-dependent vulnerabilities in cancer
No full textThis article was originally published in Proceedings of the National Academy of Sciences. The version of record is available at: https://doi.org/10.1073/pnas.2412816122.
© 2025 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution- NonCommercial-NoDerivatives License 4.0 (CC BY- NC- ND).Significance
Copper is an essential element for life, where it mediates copper-dependent cell growth and proliferation (cuproplasia) and cell death (cuproptosis) processes that underpin health and disease. We present a histochemical activity-based sensing strategy that enables systematic profiling of bioavailable copper levels, termed the labile copper pool, across many cell lines in parallel to assess their copper dependencies. We identified that cancer cells with heightened activation of the antioxidant response transcription factor NRF2 have reciprocally lower levels of labile Cu(I). In turn, these cells are more susceptible to cell death induced by copper chelation. By revealing a cuproplasia-dependent vulnerability in cancer, this work showcases the utility of chemical copper detection methods for studying metals in biology and medicine.
Abstract
Copper is an essential nutrient for sustaining vital cellular processes spanning respiration, metabolism, and proliferation. However, loss of copper homeostasis, particularly misregulation of loosely bound copper ions which are defined as the labile copper pool, occurs in major diseases such as cancer, where tumor growth and metastasis have a heightened requirement for this metal. To help decipher the role of copper in the etiology of cancer, we report a histochemical activity-based sensing approach that enables systematic, high-throughput profiling of labile copper status across many cell lines in parallel. Coppermycin-1 reacts selectively with Cu(I) to release puromycin, which is then incorporated into nascent peptides during protein translation, thus leaving a permanent and dose-dependent marker for labile copper that can be visualized with standard immunofluorescence assays. We showcase the utility of this platform for screening labile Cu(I) pools across the National Cancer Institute’s 60 (NCI-60) human tumor cell line panel, identifying cell types with elevated basal levels of labile copper. Moreover, we use Coppermycin-1 to show that lung cancer cells with heightened activation of nuclear factor-erythroid 2-related factor 2 (NRF2) possess lower resting labile Cu(I) levels and, as a result, have reduced viability when treated with a copper chelator. This work establishes that methods for labile copper detection can be used to assess cuproplasia, an emerging form of copper-dependent cell growth and proliferation, providing a starting point for broader investigations into the roles of transition metal signaling in biology and medicine.We thank the NIH (R01 GM 79465, R01 GM 139245, and R01 ES 28096 to C.J.C. and R01 NIAMS AR077578 to T.P.B.), the Florida Department of Health (9BC07 to G.M.D), and the Agilent Biodesign Program (to C.J.C.) for research support. M.S.M. thanks the UC President's Postdoctoral Fellowship Program, Chinook-Berkeley Postdoctoral Fellowship Program, and an NIH MOSAIC K99/R00 (K99GM143573, R00GM143573) award for funding. J.O. thanks the Japan Society for the Promotion of Science for postdoctoral funding. C.J.C. is a CIFAR Fellow. Parts of the figures were prepared using Bio-Render. High-throughput imaging experiments reported in this publication were supported by the Office of the Director, NIH, under Award Number S10OD021828. We thank Beverly Teicher and Nathan Coussens at the NCI for help with sample preparation and experimental guidance; the content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank Willie S. Hercule and Sara E. Sosa (University of California, Berkeley Tissue Culture Facility) for expert technical assistance. We thank Mary G. West, Deepa Sridharan, and Pingping He at the QB3 High-Throughput Screening Facility at UC Berkeley for their guidance in organizing the logistics and in data analysis for the high-throughput imaging experiments. We thank Dr. Hasan Celik and UC Berkeley's NMR facility in the College of Chemistry (CoC-NMR) for spectroscopic assistance. Instruments in the CoC-NMR are supported in part by NIH S10OD024998. ICP-MS measurements were performed in the OHSU Elemental Analysis Core with partial support from NIH S10OD028492. We thank Dr. Jessica Sampson and the UD High-Throughput Experimentation (HTE) Laboratory for LC-MS assistance. Instruments in the UD HTE are supported by NIH P20 GM1104316, Unidel-18D, and NSF CHE-2404894. Figure diagrams were created using BioRender
A Flexible Hybrid Site-Specific Integration-Based Expression System in CHO Cells for Higher-Throughput Evaluation of Monoclonal Antibody Expression Cassettes
No full textThis article was originally published in Biotechnology Journal. The version of record is available at: https://doi.org/10.1002/biot.202400520.
© 2025 The Author(s). Biotechnology Journal published by Wiley-VCH GmbH.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.The implementation of site-specific integration (SSI) systems in Chinese hamster ovary (CHO) cells for the production of monoclonal antibodies (mAbs) can alleviate concerns associated with production instability and reduce cell line development timelines. SSI cell line performance is driven by the interaction between genomic integration location, clonal background, and the transgene expression cassette, requiring optimization of all three parameters to maximize productivity. Systematic comparison of these parameters has been hindered by SSI platforms involving low-throughput enrichment strategies, such as cell sorting. This study presents a recombinase-mediated cassette exchange (RMCE)-capable SSI system that uses only chemical selection to enrich for transgene-expressing RMCE pools in less than one month. The system was used to compare eight mAb expression cassettes containing two novel genetic regulatory elements, the Azin1 CpG island and the Piggybac transposase 5’ terminal repeat, in various orientations to improve the expression of two therapeutic mAbs from two genomic loci. Similar patterns of productivity and mRNA expression were observed across sites and mAbs, and the best performing cassette universally increased mAb productivity by 7- to 11-fold. This flexible system allows for higher-throughput comparison of expression cassettes from a consistent clonal and transcriptional background to optimize RMCE-derived cell lines for industrial production of mAbs.This work was supported by funding from the National Science Foundation under grants 1624698 and 2100502, and in part by the financial assistance award 70NANB17H002 from the U.S. Department of Commerce National Institutes of Standards and Technology
Wood duck reproductive success and brood ecology from artificial nest boxes in the Delmarva Peninsula
No full textWilliams, Christopher K.Wood Ducks (Aix sponsa) nesting in artificial nest boxes have received considerable research attention throughout the last century. However, spatial and habitat differences among these studies have confounded results and necessitate further study, particularly in the Mid-Atlantic where data is limited and both inland forested wetlands and coastal open marsh habitats support populations of Wood Ducks. I analyzed nesting records from 2020–2023 and assessed the relative influence that 22 box physical characteristics and surrounding habitat attributes had in determining nest box use, nest parasitism, and nest success. During 2023–2024 I deployed 79 GPS-UHF-VHF transmitters on hen Wood Ducks and 237 VHF prong and suture transmitters on ducklings to monitor third-order habitat selection, movement behavior, and 30-day duckling survival in both habitat types. Boxes in the Inland habitat that had 60–70 cm2 entrance areas and were placed in areas with >30 cm of water received the most use and attributes that made boxes more likely to be used also increased the probability that nests within them were parasitized. Parasitism did not have a severe impact on nest success and clutch size was strongly related to the probability of success in the Inland habitat. Newer boxes placed in >75 cm of water, with entrances > 2 m above water, and that were >200 m from another box were used the most in the Coastal habitat. Boxes that were more visible were more likely to be parasitized in the Coastal habitat, and Coastal boxes that were older, in deeper water, and had greater separation from neighboring boxes were most likely to have successful nests. Broods in both habitats sought out wetland areas with abundant emergent aquatic vegetation and water depths of ~30 cm. Inland broods preferred areas with less canopy cover and Coastal broods opted for areas with lower levels of salinity. Inland broods traveled to more distinct wetlands throughout brood rearing, but Coastal broods moved greater distances on a daily basis. Thirty-day duckling survival was 0.15 (CI 0.08–0.28) in the Inland habitat and 0.21 (CI 0.12–0.37) in the Coastal habitat. Rainfall had the largest impact on duckling mortality in both habitats where more precipitation increased mortality. Lower minimum daily temperatures also increased hazard rate in the Inland habitat. Coastal duckling mortality increased with advancing Julian Date of nest hatch and with larger brood sizes. Although the influence of metrics related to nest and brood success varied between habitats, both can generally be managed with consideration of the same biological principles. Nest boxes should be conspicuous but not visible from neighboring boxes, have small entrance areas, be placed in water to deter nest predation, and be placed in or near wetlands with abundant emergent vegetation. Depending on metrics used to quantify parasitism and success, intraspecific nest parasitism may not appear to be detrimental to Wood Duck nesting but likely has negative implications on duckling survival. The extent of nest parasitism should therefore be closely monitored and discouraged when possible.University of Delaware, Department of Entomology and Wildlife EcologyM.S
Efficient, consistent, and persistent visual-inertial navigation
No full textHuang, GuoquanThe use of visual-inertial navigation systems (VINS) has become ubiquitous due to their ability to provide high quality 3D motion tracking and has continued to be at the center of simultaneous localization and mapping (SLAM) research. Deployment platforms continue to reduce in cost and miniaturize to further enable mass production to consumers (e.g., smartphones, virtual and augmented-reality headsets, and micro-aerial vehicles (MAV)). A key barrier that prevents the wider deployment of VINS is the accuracy and computational demands for long-term persistent state estimation (e.g., hours of continuous operation in a common global frame). Development of computationally efficient VINS which can efficiently incorporate loop-closure information to reduce estimator drift and increase accuracy over long-term estimation periods with persistent maps remains a crucial challenge, which this thesis looks to address. ☐ We first introduce a state-of-the-art open-sourced filter-based VINS research framework, termed OpenVINS, which leverages cutting edge extended Kalman filter (EKF) estimator techniques and demonstrates accurate and consistent state estimation where both the mean and uncertainty of the state are recovered at each timestep. We then focus on how to improve this visual-inertial odometry (VIO) to include further loop-closure information by tracking large environmental plane geometric primitives in an efficient manner leveraging a novel minimal plane representation termed the Closest Point (CP) plane. We show that the inclusion of such CP planes, which can be tracked for significant periods due to their large spatial nature and the proposed novel tracking algorithm, reduces the long-term drift in both simulation and real-world experiments. We then focus on the visual-inertial simultaneous localization and mapping (VI-SLAM) task and how we can perform consistent long-term persistent localization without causing computational complexity to explode over time. We show that the Schmidt-Kalman filter (SKF) methodology can be leveraged in conjunction with two different measurement models, including a novel 2D-to-2D method for indirect loop-closure to historical poses, to bound long-term drift which only increases complexity linearly in terms of size of the historical map. We then show that the proposed Schmidt-EKF for VI-SLAM (SEVIS) can be coupled with a secondary optimization thread, which enables relinearization, to perform large-scale estimation. We finally apply the learned loop-closure and measurement constraint techniques to the distributed multi-robot cooperative localization (CL) case. We show that covariance intersection (CI) can be efficiently leveraged for distributed VI-SLAM and we can limit long-term drift while also not requiring robots to simultaneously visit locations for cross-robot constraints. This novel distributed CL estimator shows state-of-the-art accurate, consistent, and efficient performance both in simulation and real-world experiments.University of Delaware, Department of Computer and Information SciencesPh.D
Engineering multimodal nanoparticles to combat triple-negative breast cancer
No full textDay, Emily S.Triple-negative breast cancer (TNBC) is an aggressive subtype of cancer that accounts for about 15-20% of all breast cancer cases and has a poorer short-term prognosis when compared to other subtypes. Many current chemotherapeutics used to treat TNBC are nonspecific, and, therefore, cause off-target effects and fail to elicit a robust tumor response, which results in higher mortality and recurrence rates. Targeted therapy enabled by nanoparticle (NP)-based drug carriers may prove more effective against TNBC. One promising target for TNBC is the Wnt pathway, which is a known developmental pathway that encourages cell proliferation, migration, and cell fate determination and then transitions to mostly stem cell maintenance in adults. Unfortunately, many cancers, including TNBC, have found ways to upregulate the canonical, β-catenin dependent Wnt pathway in order to promote cell proliferation, migration, chemoresistance, and other oncogenic behaviors. Accordingly, Wnt hyperactivity is strongly correlated with recurrence and metastasis. One method to both target and therapeutically manipulate TNBC cells is by coating NPs with antibodies against Frizzled7 (FZD7) receptors in the Wnt pathway, which are overexpressed in ~70% of TNBC cases but minimally expressed by other cells in the body. When antibody nanoconjugates bind FZD7 receptors, it prevents their activation by extracellular Wnt ligands, leading to downstream inhibition of the Wnt signaling pathway. As TNBC lacks targeted treatment options, the ability to use FZD7-targeted NPs to specifically target and eliminate TNBC cells is particularly appealing. This thesis develops methods to coat NPs with FZD7 antibodies and demonstrates their utility in delivering chemotherapeutic agents or small interfering ribonucleic acid (siRNA) therapeutics to TNBC cells. ☐ The first aim of this thesis focused on developing NPs coated with anti-FZD7 antibodies and/or siRNA targeting β-catenin, a downstream protein in the Wnt pathway that is a key mediator in TNBC’s oncogenesis. The goal of this aim was to investigate optimal parameters for modifying the surface of poly(lactic-co-glycolic acid) (PLGA) NPs with either antibodies, siRNA, or both. The second aim of this dissertation investigated the role of FZD7 targeting on the delivery and efficacy of an encapsulated drug, doxorubicin (DOX). The ability of FZD7-targeted, DOX-loaded NPs to inhibit TNBC cell viability was evaluated in vitro and compared against the effects of DOX delivered freely or in non-targeted NPs. Finally, the third aim of this thesis utilized PLGA NPs to carry both FZD7 antibodies and β-catenin siRNAs to inhibit the Wnt pathway in TNBC cells at both the receptor and effector levels. The RNA interference effects of this platform were assessed through in vitro assays that measured TNBC cell viability, migration, drug resistance, and spheroid formation in response to various treatments. ☐ Collectively, this work demonstrates that antibody-modified polymer NPs can be designed to target FZD7 receptors that are overexpressed on TNBC cells and provide specific delivery of diverse therapeutic cargo including chemotherapeutics and siRNAs. Future research in this field should continue to tailor NP design parameters to achieve optimal efficacy and safety and validate therapeutic potential in in vivo models of TNBC.University of Delaware, Department of Biomedical EngineeringPh.D
Methodologies, tools, and techniques for developing and optimizing applications in science and engineering
No full textEigenmann, RudolfIn the realm of computational and data-driven research applications, the quest to increase the quality and efficiency of such applications stood as a paramount challenge for researchers. This dissertation is driven by the objective of improving these two key aspects through the development of innovative methodologies, tools, and techniques. Enhancing the quality of CDI applications leads to more accurate research outcomes and more reliable research findings, which are essential for building upon previous work and advancing the field. Meanwhile, improving the efficiency of CDI applications enables researchers to complete tasks and experiments more quickly, ultimately boosting their research progress and overall productivity. This increased efficiency also results in the more effective utilization of system resources. By collectively improving both the quality and efficiency of CDI applications, this work accelerates the pace of scientific discovery and innovation, leading to the development of more effective solutions for some of the world's most pressing challenges. ☐ This research integrates best practices into the CDI development process to elevate the quality of applications. Furthermore, it identifies parallelization techniques and optimization methodologies that result in the creation of tools to streamline and accelerate the optimization process, thereby improving the efficiency of scientific applications. The projects in this work form a cohesive whole, each building upon the previous one to significantly advance the field. ☐ To enhance application quality, the Xpert Network was initiated to identify and compile a set of guidelines for the development of CDI applications, drawing from the collective experience of professionals in the field. The ATOM Project followed, implementing these practices in real-world settings to evaluate their effectiveness and practicality, which also identified additional practices along the way for addressing evolving requirements of funding agencies for software sustainability. Together, these efforts produced a set of guidelines aimed at improving the quality, reliability, and maintainability of CDI applications. To further assess the effectiveness and practicality of these practices, surveys were distributed to a diverse group of researchers to gather a broad range of perspectives. The results confirmed the high impact and usability of the guidelines, demonstrating their value in improving the quality of CDI applications in real-world settings. Findings from these projects resulted in a set of best practices for CDI application development providing a valuable resource for CDI practitioners. ☐ On the efficiency front, to identify effective techniques for optimizing scientific applications beyond those currently offered by automatic parallelizers, a comparative analysis of auto-parallelized and manually parallelized codes was conducted. This study uncovered key optimization strategies where manual parallelization consistently outperformed automatic parallelization methods, highlighting areas where existing auto-parallelization tools can be improved. These findings offer the potential for implementing more efficient parallelization techniques in auto-parallelizers. Furthermore, the code sections that revealed these differences will be used in future studies to test and validate newly developed methods and tools. ☐ Recognizing the need for faster iterative optimization cycles — particularly for long-running CDI applications, as highlighted by the comparative study — the CaRV (Capture, Replay, and Validate) methodology and tool were developed. CaRV accelerates the optimization process by running only the specific code sections undergoing optimization, rather than re-running the entire application, while simultaneously validating these optimized code sections for both performance and correctness. Evaluation results demonstrated that CaRV significantly reduced execution time, proving its effectiveness in optimizing code segments within long-running CDI applications. ☐ To further accelerate the optimization process of scientific applications and increase the efficiency of CDI applications, we developed iCetus, an interactive parallelizer designed to support users through the entire optimization cycle. Integrated with CaRV, the tool enabled a dual approach: CaRV accelerates the optimization process while validating both performance improvements and correctness, and iCetus automates the optimization workflow by incorporating multiple underlying tools. The integration of iCetus and CaRV leverages the strengths of both tools, enabling use cases that were not previously supported, such as applying manual or AI-generated optimizations, while delivering rapid feedback on their effectiveness and correctness. This integration provided significant performance improvements during the development process across a wide range of application sizes. This integration marked the culmination of our efforts to improve the efficiency of scientific applications by enhancing their performance. ☐ By introducing tools, techniques, and methodologies that enhance the efficiency of CDI applications, this research benefits practitioners involved in the development and optimization of these applications. It facilitates faster execution, accelerates research progress, expedites research outcomes, increases researcher productivity, and promotes more resource-efficient solutions.University of Delaware, Department of Electrical and Computer EngineeringPh.D
Primary Care Physicians in Delaware 2024
No full textSince 1995, the Primary Cary Physicians in Delaware Survey Report has provided updates to the primary care profession across Delaware. The 2024 report marks the tenth iteration of the survey, building upon the 2021 publication. While the State of Delaware maintains records of licensed physicians, this report supplements that information by focusing on physicians actively delivering direct patient care, detailing their practice characteristics and demographic profiles. Regular updates on these data offer a comprehensive overview of the physician landscape in Delaware. These insights can be utilized by local and state governments, employers, and educational institutions to plan for the future and ensure an adequate supply of health care professionals in Delaware.Office of Healthcare Provider Resources, Delaware Division of Public Healt
A vision for divergent thinking in the Fashion Design and Product Innovation program at the University of Delaware
No full textRutherford, TeomaraCreativity is essential to success in fashion design, yet many fashion design programs, including the Fashion Design and Product Innovation (FDPI) program at the University of Delaware, do not explicitly emphasize creative thinking skills, like divergent thinking (DT), within their curricula. Instead, creativity is often fostered indirectly through convergent thinking methods that focus on technical proficiency and industry readiness. This ELP examines how one fashion design education program can better integrate DT instruction in ways that align with academic objectives and industry needs. Through a literature review, content analysis of internal program documents, and interviews with FDPI faculty, this study examined faculty perceptions of creativity and the presence of DT instruction in the curriculum. Findings revealed limited formal emphasis on DT, a lack of shared definitions of creativity, and an opportunity to enhance student learning by developing measurable DT skills, including fluency, flexibility, originality, and elaboration. Based on these findings, this ELP proposes integrating structured DT teaching materials into existing courses to nurture creative capacity in future fashion designers more effectively.University of Delaware, School of EducationD.Ed
EAST GAY STREET, A PEDESTRIAN PLAZA
No full textPROJECT MISSION
This project will re-imagine West Chester as a pedestrian oriented town reflective of its summer schedule along East Gay Street. From Matlack to New Street, East Gay Street will provide a space for businesses, vendors, visitors, and students to gather as a community. This project will encourage safe pedestrian traffic, urban greening, and year-round use. I want to create a space that acts as an extension of what is already there, a place for the residents and visitors to experience the already thriving business, restaurants, and shops in a safe, sustainable and accommodating environment.
GOALS & OBJECTIVES:
1. Create gathering spaces for year-round use
Road Redesign / Closing
Adding site elements and spaces to accommodate users
2. Encourage safe pedestrian traffic
Road Diets
Material changes to promote safety
3. Design for urban greening
Bioretention areas for water filtering
Saving existing trees / proposing new treesWik, AnnaZimmerman, Jame