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Abstract Under the next cycle of target setting under the Paris Agreement, countries will be updating and submitting new nationally determined contributions (NDCs) over the coming year. To this end, there is a growing need for the United States to assess potential pathways toward a new, maximally ambitious 2035 NDC. In this study, we use an integrated assessment model with state-level detail to model existing policies from both federal and non-federal actors, including the Inflation Reduction Act, Bipartisan Infrastructure Law, and key state policies, across all sectors and gases. Additionally, we develop a high-ambition scenario, which includes new and enhanced policies from these actors. We find that existing policies can reduce net greenhouse gas (GHG) emissions by 44% (with a range of 37% to 52%) by 2035, relative to 2005 levels. The high-ambition scenario can deliver net GHG reductions up to 65% (with a range of 59% to 71%) by 2035 under accelerated implementation of federal regulations and investments, as well as state policies such as renewable portfolio standards, EV sales targets, and zero-emission appliance standards. This level of reductions would provide a basis for continued progress toward the country’s 2050 net-zero emissions goal.

Abstract Objective In patients with Dravet syndrome (DS), fenfluramine reduced convulsive seizure frequency and provided clinical benefit in nonseizure endpoints (e.g., executive function, survival). In zebrafish mutant scn1 DS models, chronic fenfluramine treatment preserved neuronal cytoarchitecture prior to seizure onset and prevented gliosis; here, we extend these findings to a mammalian model of DS (Scn1a+/− mice) by evaluating the effects of fenfluramine on neuroinflammation (degenerated myelin, activated microglia) and survival. Methods Scn1a+/− DS mice were treated subcutaneously once daily with fenfluramine (15 mg/kg) or vehicle from postnatal day (PND) 7 until 35‐37. Sagittal brain sections were processed for immunohistochemistry using antibodies to degraded myelin basic protein (D‐MBP) for degenerated myelin, or CD11b for activated (inflammatory) microglia; sections were scored semi‐quantitatively. Apoptotic nuclei were quantified by TUNEL assay. Statistical significance was evaluated by 1‐way ANOVA with post‐hoc Dunnett's test (D‐MBP, CD11b, and TUNEL) or Logrank Mantel‐Cox (survival). Results Quantitation of D‐MBP immunostaining per 0.1 mm2 unit area of the parietal cortex and hippocampus CA3 yielded significantly higher spheroidal and punctate myelin debris counts in vehicle‐treated DS mice than in wild‐type mice. Fenfluramine treatment in DS mice significantly reduced these counts. Activated CD11b + microglia were more abundant in DS mouse corpus callosum and hippocampus than in wild‐type controls. Fenfluramine treatment of DS mice resulted in significantly fewer activated CD11b + microglia than vehicle‐treated DS mice in these brain regions. TUNEL staining in corpus callosum was increased in DS mice relative to wild‐type controls. Fenfluramine treatment in DS mice lowered TUNEL staining relative to vehicle‐treated DS mice. By PND 35‐37, 55% of control DS mice had died, compared with 24% of DS mice receiving fenfluramine treatment (P = 0.0291). Significance This is the first report of anti‐neuroinflammation and pro‐survival after fenfluramine treatment in a mammalian DS model. These results corroborate prior data in humans and animal models and suggest important pharmacological activities for fenfluramine beyond seizure reduction. Plain Language Summary Dravet syndrome is a severe epilepsy disorder that impairs learning and causes premature death. Clinical studies in patients with Dravet syndrome show that fenfluramine reduces convulsive seizures. Additional studies suggest that fenfluramine may have benefits beyond seizures, including promoting survival and improving control over emotions and behavior. Our study is the first to use a Dravet mouse model to investigate nonseizure outcomes of fenfluramine. Results showed that fenfluramine treatment of Dravet mice reduced neuroinflammation significantly more than saline treatment. Fenfluramine‐treated Dravet mice also lived longer than saline‐treated mice. These results support clinical observations that fenfluramine may have benefits beyond seizures.

Abstract We present a variable‐resolution global chemistry‐climate model (AM4VR) developed at NOAA's Geophysical Fluid Dynamics Laboratory (GFDL) for research at the nexus of US climate and air quality extremes. AM4VR has a horizontal resolution of 13 km over the US, allowing it to resolve urban‐to‐rural chemical regimes, mesoscale convective systems, and land‐surface heterogeneity. With the resolution gradually reducing to 100 km over the Indian Ocean, we achieve multi‐decadal simulations driven by observed sea surface temperatures at 50% of the computational cost for a 25‐km uniform‐resolution grid. In contrast with GFDL's AM4.1 contributing to the sixth Coupled Model Intercomparison Project at 100 km resolution, AM4VR features much improved US climate mean patterns and variability. In particular, AM4VR shows improved representation of: precipitation seasonal‐to‐diurnal cycles and extremes, notably reducing the central US dry‐and‐warm bias; western US snowpack and summer drought, with implications for wildfires; and the North American monsoon, affecting dust storms. AM4VR exhibits excellent representation of winter precipitation, summer drought, and air pollution meteorology in California with complex terrain, enabling skillful prediction of both extreme summer ozone pollution and winter haze events in the Central Valley. AM4VR also provides vast improvements in the process‐level representations of biogenic volatile organic compound emissions, interactive dust emissions from land, and removal of air pollutants by terrestrial ecosystems. We highlight the value of increased model resolution in representing climate–air quality interactions through land‐biosphere feedbacks. AM4VR offers a novel opportunity to study global dimensions to US air quality, especially the role of Earth system feedbacks in a changing climate.