Heterogeneous N2O5 Uptake During Winter: Aircraft Measurements During the 2015 WINTER Campaign and Critical Evaluation of Current Parameterizations

Nocturnal dinitrogen pentoxide (N2O5) heterogeneous chemistry impacts regional air quality and the distribution and lifetime of tropospheric oxidants. Formed from the oxidation of nitrogen oxides, N2O5 is heterogeneously lost to aerosol with a highly variable reaction probability, γ(N2O5), dependent on aerosol composition and ambient conditions. Reaction products include soluble nitrate (HNO3 or NO3−) and nitryl chloride (ClNO2). We report the first‐ever derivations of γ(N2O5) from ambient wintertime aircraft measurements in the critically important nocturnal residual boundary layer. Box modeling of the 2015 Wintertime INvestigation of Transport, Emissions, and Reactivity (WINTER) campaign over the eastern United States derived 2,876 individual γ(N2O5) values with a median value of 0.0143 and range of 2 × 10−5 to 0.1751. WINTER γ(N2O5) values exhibited the strongest correlation with aerosol water content, but weak correlations with other variables, such as aerosol nitrate and organics, suggesting a complex, nonlinear dependence on multiple factors, or an additional dependence on a nonobserved factor. This factor may be related to aerosol phase, morphology (i.e., core shell), or mixing state, none of which are commonly measured during aircraft field studies. Despite general agreement with previous laboratory observations, comparison of WINTER data with 14 literature parameterizations (used to predict γ(N2O5) in chemical transport models) confirms that none of the current methods reproduce the full range of γ(N2O5) values. Nine reproduce the WINTER median within a factor of 2. Presented here is the first field‐based, empirical parameterization of γ(N2O5), fit to WINTER data, based on the functional form of previous parameterizations

Sources and Secondary Production of Organic Aerosols in the Northeastern United States during WINTER

Most intensive field studies investigating aerosols have been conducted in summer, and thus, wintertime aerosol sources and chemistry are comparatively poorly understood. An aerosol mass spectrometer was flown on the National Science Foundation/National Center for Atmospheric Research C‐130 during the Wintertime INvestigation of Transport, Emissions, and Reactivity (WINTER) 2015 campaign in the northeast United States. The fraction of boundary layer submicron aerosol that was organic aerosol (OA) was about a factor of 2 smaller than during a 2011 summertime study in a similar region. However, the OA measured in WINTER was almost as oxidized as OA measured in several other studies in warmer months of the year. Fifty‐eight percent of the OA was oxygenated (secondary), and 42% was primary (POA). Biomass burning OA (likely from residential heating) was ubiquitous and accounted for 33% of the OA mass. Using nonvolatile POA, one of two default secondary OA (SOA) formulations in GEOS‐Chem (v10‐01) shows very large underpredictions of SOA and O/C (5×) and overprediction of POA (2×). We strongly recommend against using that formulation in future studies. Semivolatile POA, an alternative default in GEOS‐Chem, or a simplified parameterization (SIMPLE) were closer to the observations, although still with substantial differences. A case study of urban outflow from metropolitan New York City showed a consistent amount and normalized rate of added OA mass (due to SOA formation) compared to summer studies, although proceeding more slowly due to lower OH concentrations. A box model and SIMPLE perform similarly for WINTER as for Los Angeles, with an underprediction at ages \u3c6 hr, suggesting that fast chemistry might be missing from the models

Anthropogenic Control over Wintertime Oxidation of Atmospheric Pollutants

Anthropogenic air pollutants such as nitrogen oxides (NO(x) = NO + NO(2)), sulfur dioxide (SO(2)), and volatile organic compounds (VOC), among others, are emitted to the atmosphere throughout the year from energy production and use, transportation, and agriculture. These primary pollutants lead to the formation of secondary pollutants such as fine particulate matter (PM(2.5)) and ozone (O(3)) and perturbations to the abundance and lifetimes of short-lived greenhouse gases. Free radical oxidation reactions driven by solar radiation govern the atmospheric lifetimes and transformations of most primary pollutants and thus their spatial distributions. During winter in the mid and high latitudes, where a large fraction of atmospheric pollutants are emitted globally, such photochemical oxidation is significantly slower. Using observations from a highly instrumented aircraft, we show that multi-phase reactions between gas-phase NO(x) reservoirs and aerosol particles, as well as VOC emissions from anthropogenic activities, lead to a suite of atypical radical precursors dominating the oxidizing capacity in polluted winter air, and thus, the distribution and fate of primary pollutants on a regional to global scale

Memantine increases NMDA receptor level in the prefrontal cortex but fails to reverse apomorphine-induced conditioned place preference in rats

Studies have shown that inflammation and neurodegeneration may accompany the development of addiction to apomorphine and that the glutamate NMDA receptor antagonist, memantine, may be neuroprotective. The similarity between apomorphine and dopamine with regard to their chemical, pharmacological and toxicological properties provided a basis for investigating the mechanism of action of the former agent. In this study, we investigated whether memantine would suppress apomorphine-seeking behavior in rats subjected to apomorphine-induced place preference conditioning, through modulation of NMDA receptors in the prefrontal cortex. Repeated apomorphine (1 mg/kg) treatment induced conditioned place preference (CPP) and had no significant effect on NMDA receptor levels in the prefrontal cortex. Prior treatment with memantine (5 mg/kg or 10 mg/kg) increased the levels of NMDA receptors in the prefrontal cortex but did not suppress CPP induced by apomorphine. These data give further support to the addictive effect of apomorphine and demonstrate that blockade of NMDA receptors by memantine is unable to suppress apomorphine-seeking behavior

An odd oxygen framework for wintertime ammonium nitrate aerosol pollution in urban areas: NOx and VOC control as mitigation strategies

Wintertime ammonium nitrate aerosol pollution is a severe air quality issue affecting both developed and rapidly urbanizing regions from Europe to East Asia. In the US, it is acute in western basins subject to inversions that confine pollutants near the surface. Measurements and modeling of a wintertime pollution episode in Salt Lake City, Utah demonstrates that ammonium nitrate is closely related to photochemical ozone through a common parameter, total odd oxygen, Ox,total. We show that the traditional NOx‐VOC framework for evaluating ozone mitigation strategies also applies to ammonium nitrate. Despite being nitrate‐limited, ammonium nitrate aerosol pollution in Salt Lake City is responsive to VOC control and, counterintuitively, not initially responsive to NOx control. We demonstrate simultaneous nitrate limitation and NOx saturation and suggest this phenomenon may be general. This finding may identify an unrecognized control strategy to address a global public health issue in regions with severe winter aerosol pollution

Autoradiographic quantification of muscarinic cholinergic synaptic markers in bat, shrew, and rat brain

We employed radioligand binding autoradiography to determine the distributions of pre- and postsynaptic cholinergic radioligand binding sites in the brains of two species of bat, one species of shrew, and the rat. High affinity choline uptake sites were measured with [ 3 H]hemicholinium, and presynaptic cholinergic vesicles were identified with [ 3 H]vesamicol. Muscarinic cholinergic receptors were determined with [ 3 H]scopolamine. The distribution patterns of the three cholinergic markers were similar in all species examined, and identified known major cholinergic pathways on the basis of enrichments in both pre- and postsynaptic markers. In addition, there was excellent agreement, both within and across species, in the regional distributions of the two presynaptic cholinergic markers. Our results indicate that pharmacological identifiers of cholinergic pathways and synapses, including the cholinergic vesicle transport site, and the organizations of central nervous system cholinergic pathways are phylogenetically conserved among eutherian mammals.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45409/1/11064_2004_Article_BF00971334.pd

Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease

We investigated the effects of glial cell line-derived neurotrophic factor (GDNF) in Parkinson’s disease, using intermittent intraputamenal convection-enhanced delivery via a skull-mounted transcutaneous port as a novel administration paradigm to potentially afford putamen-wide therapeutic delivery. This was a single-centre, randomized, double-blind, placebo-controlled trial. Patients were 35–75 years old, had motor symptoms for 5 or more years, and presented with moderate disease severity in the OFF state [Hoehn and Yahr stage 2–3 and Unified Parkinson’s Disease Rating Scale motor score (part III) (UPDRS-III) between 25 and 45] and motor fluctuations. Drug delivery devices were implanted and putamenal volume coverage was required to exceed a predefined threshold at a test infusion prior to randomization. Six pilot stage patients (randomization 2:1) and 35 primary stage patients (randomization 1:1) received bilateral intraputamenal infusions of GDNF (120 mg per putamen) or placebo every 4 weeks for 40 weeks. Efficacy analyses were based on the intention-to-treat principle and included all patients randomized. The primary outcome was the percentage change from baseline to Week 40 in the OFF state (UPDRS-III). The primary analysis was limited to primary stage patients, while further analyses included all patients from both study stages. The mean OFF state UPDRS motor score decreased by 17.3 17.6% in the active group and 11.8 15.8% in the placebo group (least squares mean difference: 4.9%, 95% CI: 16.9, 7.1, P = 0.41). Secondary endpoints did not show significant differences between the groups either. A post hoc analysis found nine (43%) patients in the active group but no placebo patients with a large clinically important motor improvement (510 points) in the OFF state (P = 0.0008). 18F-DOPA PET imaging demonstrated a significantly increased uptake throughout the putamen only in the active group, ranging from 25% (left anterior putamen; P = 0.0009) to 100% (both posterior putamina; P50.0001). GDNF appeared to be well tolerated and safe, and no drug-related serious adverse events were reported. The study did not meet its primary endpoint. 18F-DOPA imaging, however, suggested that intermittent convection-enhanced delivery of GDNF produced a putamen-wide tissue engagement effect, overcoming prior delivery limitations. Potential reasons for not proving clinical benefit at 40 weeks are discussed

Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson's Disease

Background: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every 4 weeks to patients with moderately advanced Parkinson’s disease, did not show significant clinical improvements against placebo at 40 weeks, although it significantly increased [18F]DOPA uptake throughout the entire putamen. Objective: This open-label extension study explored the effects of continued (prior GDNF patients) or new (prior placebo patients) exposure to GDNF for another 40 weeks. Methods: Using the infusion protocol of the parent study, all patients received GDNF without disclosing prior treatment allocations (GDNF or placebo). The primary outcome was the percentage change from baseline to Week 80 in the OFF state Unified Parkinson’s Disease Rating Scale (UPDRS) motor score. Results: All 41 parent study participants were enrolled. The primary outcome decreased by 26.7±20.7% in patients on GDNF for 80 weeks (GDNF/GDNF; N = 21) and 27.6±23.6% in patients on placebo for 40 weeks followed by GDNF for 40 weeks (placebo/GDNF, N = 20; least squares mean difference: 0.4%, 95% CI: –13.9, 14.6, p = 0.96). Secondary endpoints did not show significant differences between the groups at Week 80 either. Prespecified comparisons between GDNF/GDNF at Week 80 and placebo/GDNF at Week 40 showed significant differences for mean OFF state UPDRS motor (–9.6±6.7 vs. –3.8±4.2 points, p = 0.0108) and activities of daily living score (–6.9±5.5 vs. –1.0±3.7 points, p = 0.0003). No treatment-emergent safety concerns were identified. Conclusions: The aggregate study results, from the parent and open-label extension suggest that future testing with GDNF will likely require an 80- rather than a 40-week randomized treatment period and/or a higher dose

Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits

Background Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation. Objective The present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry. Results The effects of accumbens DA depletions on food-seeking behavior are critically dependent upon the work requirements of the task. Lever pressing schedules that have minimal work requirements are largely unaffected by accumbens DA depletions, whereas reinforcement schedules that have high work (e.g., ratio) requirements are substantially impaired by accumbens DA depletions. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related decision making. Rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead, these rats select a less-effortful type of food-seeking behavior. Conclusions Along with prefrontal cortex and the amygdala, nucleus accumbens is a component of the brain circuitry regulating effort-related functions. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue, or anergia in depression