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A conserved element in the first intron of Cd4 has a lineage specific, TCR signal-responsive, canonical enhancer function that matches the timing of cell surface CD4 upregulation required to prevent lineage choice error
(Frontiers in Immunology) Swan, Gregory A; Fujii, Chika; Guzynski, Mia E; Page, Sheridan M; Meyers, Isabelle V; Penev, Yordan P; Littleton, Sejiro; Azzahra, Adinda; Richardson, Christine; Sarafova, Sophia D
IntroductionThe regulation of Cd4 expression during T-cell development and immune responses is essential for proper lineage commitment and function in the periphery. However, the mechanisms of genetic and epigenetic regulation are complex, and their interplay not entirely understood. Previously, we demonstrated the need for CD4 upregulation during positive selection to ensure faithful commitment of MHC-II-restricted T cells to the CD4 lineage. In this study, we investigate whether a conserved region, here called NCE, that is proximal to the Cd4 silencer and contains E4m has the required developmental-stage-specific canonical enhancer function and TCR responsiveness to mediate the CD4 upregulation required to prevent lineage errors.MethodsTo investigate the role of NCE, transient transfection of reporter plasmids was performed in thymoma cell lines arrested at the double-positive (DP, CD4+CD8+) and intermediate (INT, CD4+CD8lo) stages of development. CRISPR/Cas9-mediated deletion of the coreNCE/E4m region was carried out in these cell lines to assess its impact on CD4 surface expression, re-expression rates, and TCR signaling responsiveness. To avoid developmental alterations from direct manipulation of the endogenous Cd4 locus in vivo, BAC-transgenic reporter mice were generated with the locus modified to express EGFP in the presence or absence of NCE. EGFP mRNA levels were measured via RT-qPCR, and EGFP fluorescence was analyzed in post-selection thymocytes.ResultsOur in vitro experiments demonstrate that NCE by itself can function as an enhancer at the INT, but not the DP stage of development. Furthermore, CRISPR/Cas9-mediated deletion of coreNCE/E4m resulted in reduced CD4 surface levels, slower re-expression rates, and reduced TCR signaling responsiveness in INT cells, but not in DP cells. In vivo, NCE-sufficient transgenic mice exhibited upregulation of Cd4 reporter EGFP mRNA levels at the INT stage and a corresponding upregulation of EGFP fluorescence, whereas NCE-deficient mice showed a significant loss of Cd4 reporter EGFP mRNA and no detectable EGFP production in any post-selection thymocytes.DiscussionThis study demonstrates that the canonical enhancer function of coreNCE/E4m is essential for CD4 upregulation following positive selection. The NCE region, with its developmental-stage-specific activity and its known epigenetic regulatory capabilities, ensures faithful lineage commitment to the CD4 lineage.
Climate Risk and Resilience: Industry’s Challenges and CIRCAD’s Role
Ferris, William; Mehrotra, Sarthak
In Fall 2024, the Center for Innovation in Risk Analysis for Climate Adaptation and Decision-making hosted industry attendees at its 2024 Climate Risk and Resilience summit, with the goal of identifying what the insurance and reinsurance sectors need to lead efforts to address society’s climate risk and resilience challenges. Attendee insight, collected via a brief survey, suggested the main concerns to be related to data and risk modeling, and other concerns to be related to financial and insurance issues, as well as needs for greater collaboration. Respondents identified that a center like CIRCAD would be capable of providing modeling and research support and supporting organizations’ convening and communication needs.
Duke Research at Pickett: The Evolution of a Free-standing Research Site Partnering with Communities Toward Health Equity Advancement
(Journal of Clinical and Translational Science, 2024-01-01) Van Althuis, L; Taylor, S; Freeman, D; Freel, S; Sutton, L; Bethea, K; Martin, L; McMillan, A; Garber, DW; Bentley-Edwards, K; Barrett, N; Snyder, DC; Naggie, S
While clinical research intends to improve health outcomes for all, access to research participation is often limited and inequitable. Geographic proximity is a recognized barrier, thus, systemic infrastructure solutions through federal programs including General Clinical Research Centers and Clinical and Translational Science Awards have sought to improve accessibility. Even with such support, academic medical centers often have limited clinical research-dedicated space apart from shared exam rooms in difficult-to-navigate hospitals or clinics. In 2019, the Duke University School of Medicine looked beyond its medical center campus to identify freestanding sites within Durham communities for participant study visits. Catalyzed by the COVID-19 pandemic, Duke Research at Pickett, a 22 000-square-foot building with a laboratory, 30 exam rooms, and onsite parking, opened in October 2020 to support vaccine and treatment trials. Upon the lifting of many COVID-19 restrictions, and in partnership with the Research Equity and Diversity Initiative (READI) Community Advisory Council, the building was transformed to encourage community gatherings, education, and training programs. To date, Duke Research at Pickett has hosted 2692 participants in 78 research trials and 14 community-engaged activities.
The Tragedy of Vortigern
(2024-11-11) Smith, Benjamin
Traditionally, the understanding of the history of Britain in Late Antiquity and into the Early Medieval period—a period which saw significant socio-political change in the island following the departure of the Roman Empire and the subsequent collapse in central authority and which also saw the arrival of the Anglo-Saxons—is composed of few facts but many theories. There are no surviving textual witnesses to this period. The closest, the 6th century De Excidio, has been built upon subsequently in the 8th century Historia Ecclesiastica gentis Anglorum and the 9th century Historia Brittonum, to form a literary tradition which has greatly influenced the view of the period and colors it with figures of history and legend, such as Vortigern. This project approaches this literary tradition to understand what a close reading of these narratives can teach us about the ways that authors of the past engage with history and legend in order to make sense of their own present. This project begins by providing historical background for the texts, and then analyzing them in reverse-chronological order, and then reaching conclusions on relationship of history and legend in early medieval British literature. The second half of the project offers a creative piece which was inspired by the texts and influenced by my analysis on them.
Concomitant Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma and Non-Immunoglobulin M Plasma Cell Neoplasm.
(Archives of pathology & laboratory medicine, 2025-01) Zhao, Yue; Petersen, Philip; Stuart, Sophie; He, Jiaqi; Ju, Yaping; Carrillo, Luis F; Carlsen, Eric D; Xie, Yi; Ghezavati, Alireza; Siddiqi, Imran; Zhang, Ling; Wang, Endi