Research Triangle Park Foundation

Adeno-associated virus (AAV) vectors are promising platforms used in a growing number of approved gene therapy (GT) products across diverse therapeutic areas. Due to the potential safety and efficacy concerns associated with AAV-based immune responses, patients with pre-existing anti-AAV antibodies (Abs) are routinely excluded from GT trials to prevent treatment of patients who are hypothesized to have potentially higher risk and/or little or no benefit. However, the exclusion of seropositive patients without prior GT exposure is not based on data-driven Ab titer cut-offs, and diagnostics to identify levels of pre-existing immunity have not been standardized, precluding data generation that would substantiate or reject this hypothesis. There are also significant gaps in clinical data comparing the impact of pre-existing immunity with treatment-induced immune responses for a variety of disease states. This review aims to address these gaps by examining the impact of pre-existing anti-AAV Abs on the safety and efficacy of approved and failed GT products and ongoing clinical trials. Together, these data suggest that pre-existing immunity may not be the principal determinant of GT success. Therefore, to expand the number of patients eligible for treatment, novel AAV GTs should be optimized to mitigate against the effects of anti-AAV Abs and avoid the need for exclusionary screening; in turn, including both seronegative and seropositive patients in clinical trials will enable characterization of the clinical relevance of anti-AAV Abs. Strategies to prevent an undesirable immune response to GT, including immunosuppressive regimens and modifications to GT manufacturing, design and delivery, are presented for consideration in future GT trials.

Sea level rise (SLR) threatens coastal ecosystems, which are critical for sequestering carbon (C), providing habitat, and reducing storm surge. Mangrove forests are particularly efficient in C sequestration and host a variety of dependent species. Using United States (U.S.) National Oceanic Atmospheric Administration data, we estimated future mangrove inundation from SLR at 0.3, 0.61, and 3.0 m in the U.S. By 3.0 m of SLR (around the middle of next century), we estimate mangrove area loss to be almost half of current areas, or 47.4% of the approximately 266.7 thousand ha currently present. To estimate C sequestration and ecosystem service loss, we compared scenarios where inundated mangrove areas convert to saltmarsh vs open ocean. We estimate sequestration loss to be approximately 30–199 thousand metric tons C y–1 from 3.0 m of SLR. Combined with decreases in other ecosystem services, this represents an annual loss of $5.8 billion (in USD and Int$) per meter of SLR. Migration poleward, although unlikely in areas with coastal development, may reduce some impacts in select locations. Overall, we conclude mangrove areas and their accompanying ecosystem services are likely to be greatly reduced by SLR in the future.

Abstract Background Fendioxypyracil is a novel protoporphyrinogen oxidase (PPO)–inhibiting herbicide (HRAC Group 14) developed to address the increasing prevalence of herbicide-resistant weeds and to expand available weed control options. PPO inhibitors disrupt chlorophyll biosynthesis by blocking the conversion of protoporphyrinogen IX to protoporphyrin IX, resulting in light-promoted formation of reactive oxygen species and rapid plant necrosis. Building on established PPO chemistry, fendioxypyracil incorporates a pyridine-based core and an aryloxy sidechain designed to enhance binding affinity and post-emergence activity. Results Greenhouse evaluations demonstrated high efficacy of fendioxypyracil against key grass weeds, including wild oat ( Avena fatua ), crabrass ( Digitaria Sanginalis ), goosegrass ( Eleusina indica ) and barnyard grass ( Echinochloa crus-galli ), as well as strong control of major broadleaf species. Physiological characterization and enzyme inhibition assays confirmed PPO as the primary site and mode of action, with IC₅₀ values lower than those of the commercial standard saflufenacil for both PPO isoforms. Conclusion Fendioxypyracil represents a next-generation PPO inhibitor with broad-spectrum and systemic activity, offering a valuable new tool for integrated weed management. Its high biological activity and efficacy across multiple weed taxa supports its potential to enhance on-farm weed control strategies and contributes to resistance management programs.

IntroductionAnimal studies have historically informed toxicological testing and safety assessments. However, assessment of the variability in both quantitative and qualitative results has been limited. Biological variability, experimental differences, interpretation of categorical endpoints, and data availability and curation approaches all contribute to the quantified variability.MethodsA literature review was conducted to identify publications describing variability analyses for in vivo toxicology studies. Variability analyses were evaluated and summarized for a variety of toxicological endpoints: ocular irritation, dermal sensitization and irritation, acute oral and inhalation lethality, subchronic and chronic toxicity, carcinogenicity, neurotoxicity including DNT, endocrine, and genotoxicity.ResultsThis review summarizes published investigations of variability within mammalian toxicological studies that have been largely conducted in accordance with health effects test guidelines. The results of this review suggest that replicability of in vivo toxicological guideline studies varies widely by study type, endpoint complexity, and classification approach.DiscussionWhile any test system will have inherent variability, understanding its sources and impact on study interpretation will help ensure that appropriate confidence is applied when using the test method. Furthermore, such information aids in establishing relevant metrics to serve as baselines for informing performance characterization of new approach methodologies (NAMs). Future evaluation of NAMs should be contextualized using estimates of uncertainty and variance of the traditional study data to demonstrate “better” performance compared to traditional testing approaches. Robust understanding of guideline study performance is important for risk assessments, where it is important to find species-relevant NAMs that can perform at least as well as existing bioassays.

Fire whirls, a combustion-intensifying phenomenon, offer potential for cleaner, more efficient burns with reduced emissions in environmental applications like oil spill remediation. While most knowledge of fire whirls stems from laboratory-scale experiments, and only a limited subset of these experiments has captured emissions, this study addresses a critical research gap by conducting one of the largest controlled fire whirl experiments to date, focusing on enhancing in-situ burning. Using a 1.5-meter diameter crude oil pool with 15 mm and 40 mm slick thicknesses on an open water surface, fire whirls were successfully generated within a 5-meter-tall three-wall structure under the influence of various wind conditions. Measurements of flame geometry, flow velocity, temperature profiles, heat flux, mass consumption, and emissions were compared to pool fires. Results revealed that fire whirls, with mean flame heights nearly double those of pool fires, increased burning rates by 40% and reduced soot emissions by 40%. The highest fuel consumption efficiency of 95% was achieved in a 15 mm slick thickness fire whirl experiment, while in other fire whirl experiments, especially those with 40 mm slick thickness, premature extinguishment was observed lowering ultimate fuel consumption efficiencies. Enhanced performance compared to traditional pool fires suggests that fire whirls might be more effective for in-situ burning, however this efficiency is currently only achieved under calm ambient conditions. This study discusses the potential interactive effects of ambient conditions, configuration sizing, and boilover phenomenon on fire whirl dynamics, highlighting the need of continued research across scales to optimize configurations and mitigate detrimental emissions, thereby enhancing the efficacy of in-situ burning in large-scale oil spill scenarios.