Objectives/Goals: The bromodomain PHD finger transcription factor (BPTF) is an oncogenic driver of neuroblastoma. Our objective is to pioneer the discovery of the first class of chemical compounds that engage the PHD finger of BPTF and inhibit its biological function in cellulo, thereby establishing first-in-class chemical probes for this epigenetic reader. Methods/Study Population: Our previous work has identified a collection of small molecules that engage BPTF PHD in vitro. Following structure–activity relationships analysis, candidates will be used in a neuroblastoma cell model to validate BPTF PHD interaction in cellulo and predict therapeutic potential. Nanoluciferase bioluminescence resonance energy transfer (NanoBRET) will be used to confirm BPTF PHD engagement by compounds. Selective toxicity in neuroblastoma cells upon inhibitor treatment will be gauged by comparing cell growth and viability in the IMR-32 cell line against the HEK293 cell line. Treated HEK293 cells will be subjected to the assay for transposase-accessible chromatin (ATAC) and RNA sequencing methods to monitor changes in chromatin structure and transcriptional signatures against untreated cells. Results/Anticipated Results: We hypothesize that compounds with low micromolar potency for BPTF PHD in vitro will engage the target in cellulo and displace NanoLuciferase tagged protein from its HaloTagged® peptide binding partner. Additionally, we anticipate that our inhibitors will show cytotoxicity for IMR-32 cells with limited effects on HEK293 cells. We envision that inhibitor treatment in HEK293 cells will correlate with reduced chromatin exposure, suggesting that blocking the BPTF–histone interaction via PHD finger inhibition hinders the remodeling of transcriptionally silent heterochromatin into a transcriptionally active state. Finally, we expect that inhibitor treatment will result in diminished gene expression of oncogenic transcription factors, including N-Myc, a biomarker of neuroblastoma. Discussion/Significance of Impact: These first-in-class chemical probes for BPTF PHD will enable further investigation of BPTF and high-risk neuroblastoma progression, as well as its role in other diseases. In addition, these compounds will serve as a platform for the development of new anticancer agents that may improve outcomes for children that suffer from high-risk neuroblastoma.

Accelerating COVID-19 Treatment Interventions and Vaccines (ACTIV) was initiated by the US government to rapidly develop and test vaccines and therapeutics against COVID-19 in 2020. The ACTIV Therapeutics-Clinical Working Group selected ACTIV trial teams and clinical networks to expeditiously develop and launch master protocols based on therapeutic targets and patient populations. The suite of clinical trials was designed to collectively inform therapeutic care for COVID-19 outpatient, inpatient, and intensive care populations globally. In this report, we highlight challenges, strategies, and solutions around clinical protocol development and regulatory approval to document our experience and propose plans for future similar healthcare emergencies.

This manuscript addresses a critical topic: navigating complexities of conducting clinical trials during a pandemic. Central to this discussion is engaging communities to ensure diverse participation. The manuscript elucidates deliberate strategies employed to recruit minority communities with poor social drivers of health for participation in COVID-19 trials. The paper adopts a descriptive approach, eschewing analysis of data-driven efficacy of these efforts, and instead provides a comprehensive account of strategies utilized. The Accelerate COVID-19 Treatment Interventions and Vaccines (ACTIV) public–private partnership launched early in the COVID-19 pandemic to develop clinical trials to advance SARS-CoV-2 treatments. In this paper, ACTIV investigators share challenges in conducting research during an evolving pandemic and approaches selected to engage communities when traditional strategies were infeasible. Lessons from this experience include importance of community representatives’ involvement early in study design and implementation and integration of well-developed public outreach and communication strategies with trial launch. Centralization and coordination of outreach will allow for efficient use of resources and the sharing of best practices. Insights gleaned from the ACTIV program, as outlined in this paper, shed light on effective strategies for involving communities in treatment trials amidst rapidly evolving public health emergencies. This underscores critical importance of community engagement initiatives well in advance of the pandemic.

Background: In September 2022, UNC Hospitals was awarded a Regional Emerging Special Pathogens Treatment Center (RESPTC) grant by the U.S. Department of Health and Human Services Administration for Strategic Preparedness and Response (ASPR) to care for up to two patients with viral hemorrhagic fever, or similar pathogen, and up to ten patients with novel respiratory pathogens. Intensive infection prevention efforts and timely multidisciplinary commitment was required to develop the Space, Strategy, Staff, and Stuff needed to care for patients with a special pathogen. Methods: Multiple space needs assessments were undertaken to acquire spaces for the care of patients, simulation training, and a dedicated laboratory. Strategies for developing the response plan required collaboration with hospital executives, nursing leadership, public health leaders, and regional partners. Staff were recruited across various disciplines to join the response team and were provided hands-on skills training which was assessed by post-training surveys. Specialized ‘stuff’ (i.e., PPE, training equipment, and waste management devices) were researched and procured for use by the team. Results: Patient care and dedicated laboratory space was identified within existing infrastructure, and renovation plans were developed to adapt the space for these specialized activities. A waste management plan that benefits the hospital for routine waste and allows for Category A waste management was approved. Fifty-three staff members were recruited from 3 main disciplines (RNs, MDs, Paramedics), and across numerous settings (Medicine Acute Care & ICU, Pediatric ICU & Stepdown, Air Care/Transport, Burn ICU, Surgery Stepdown, Emergency Medicine, Infection Prevention, Infectious Disease) were trained during five 4-hour training sessions, culminating in an exercise involving transporting a rule–out Ebola patient to the hospital’s special pathogens unit. Post-training evaluations demonstrated a very high level of confidence (‘strongly agree’) in staffs’ knowledge about the RESPTC site (92.3%), special pathogens (80.8%), collaboration needed for managing patient care (80.8%), and in their comfort with special PPE donning and doffing (73.1%). Conclusions: Using a systematic approach to develop Space, Strategy, Staff, and Stuff, a large academic hospital readied itself to become a new RESPTC site. Key lessons learned include the importance of a multidisciplinary response team; local, state, and regional coordination for care planning and delivery; and early community partnership development. Logistical infrastructure and waste management challenges continue to require partnership with hospital leadership to optimize workflows and patient care. Holistic decision-making around infrastructure has led to changes that benefit all hospital patients and offer efficiencies to

Disclosure: William Fischer: Consultant - Roche, Merck, Inhalon Biopharma; Speaker for ACGME - IMG. David J Weber: Consultant on vaccines: Pfizer; DSMB chair: GSK; Consultant on disinfection: BD, GAMA, PDI, Germitec

A theoretical and experimental framework for novel metamaterial with programmable damping properties is presented. This material system is able to switch between elastic-dominated and damping-dominated regimes with different overall stiffness under dynamic loading depending on the external stimulus. The unit cell combines an auxetic and a bellow-like layer separated by an interface through which the amount of media flow can be tuned depending on the lateral strain. A simplified analytical model is derived to analyse the programmable damping effect. The model is further extended with a fluid-dynamics approach to link the effective damping properties with geometrical parameters to aid with the practical design of the metamaterial. Afterward, experiments are conducted on a macroscopic level using laser-sintered unit cells to validate the functionality of the concept both with air and water as media within the unit cells. To conclude the work, initial results on microscopic-level unit cells fabricated by two-photon lithography are introduced to showcase the scalability of the concept. This work provides an experimentally validated theoretical framework for future investigations to design unit cells with programmable damping on different length scales for applications requiring tailored dynamic energy dissipation.

Economists have for decades recommended that carbon dioxide and other greenhouse gases be taxed – or otherwise priced – to provide incentives for their reduction. The USA does not have a federal carbon tax; however, many state and federal programs to reduce carbon emissions effectively price carbon – for example, through cap-and-trade systems or regulations. There are also programs that subsidize reductions in carbon emissions. At the 2022 meetings of the American Economic Association, the Society for Benefit-Cost Analysis brought together five well-known economists – Joe Aldy, Dallas Burtraw, Carolyn Fischer, Meredith Fowlie, and Rob Williams – to discuss how the USA does, in fact, price carbon and how it could price carbon. Maureen Cropper chaired the panel. This paper summarizes their remarks.

In this review article, we discuss selected developments regarding the role of the equation of state in simulations of core-collapse supernovae. There are no first-principle calculations of the state of matter under supernova conditions since a wide range of conditions is covered, in terms of density, temperature, and isospin asymmetry. Instead, model equation of state are commonly employed in supernova studies. These can be divided into regimes with intrinsically different degrees of freedom: heavy nuclei at low temperatures, inhomogeneous nuclear matter where light and heavy nuclei coexist together with unbound nucleons, and the transition to homogeneous matter at high densities and temperatures. In this article, we discuss each of these phases with particular view on their role in supernova simulations.

Nitric oxide (NO) activates soluble guanylyl cyclase (sGC) and the resulting increase in cyclic guanosine monophosphate (cGMP) is an important intracellular signalling pathway in the vertebrate retina. Immunocytochemical detection of cGMP following exposure to NO donors has proven an effective method of identifying cells that express sGC. While such an approach has proven useful for the study of several vertebrate retinas, it has not been applied to the well-characterized teleost retina. Therefore, in the present study, we have applied this approach to the retina of the goldfish (Carassius auratus). In the presence of the phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX), incubation of goldfish eyecups in Ringer's solution containing (±)-S-nitroso-N-acetylpenicillamine (SNAP) increased cGMP-like immunoreactivity (cG-ir) in bipolar, horizontal, amacrine, and ganglion cells and in ganglion cell axons and optic nerve. Weak labeling was observed in horizontal cells but no change in cG-ir was noted within photoreceptors. The NO donor-stimulated increases of cG-ir in horizontal, bipolar, amacrine, and ganglion cells are consistent with known physiological effects of NO on these neurons. The physiological significance of NO action at the level of optic nerve is not known. The lack of an effect of SNAP on cG-ir in photoreceptors was unexpected, as there are known physiological actions of NO, mediated by cGMP, on these neurons. Although this may be due to insufficient sensitivity of immunolabeling, this result may indicate a difference between isoforms of sGC or cGMP PDE in these neurons, compared to neurons where exogenous NO increased cG-ir.