Background The novel human coronavirus disease 2019 (COVID-19) pandemic has claimed more than 600,000 lives worldwide, causing tremendous public health, social, and economic damages. While the risk factors of COVID-19 are still under investigation, environmental factors, such as urban air pollution, may play an important role in increasing population susceptibility to COVID-19 pathogenesis. Methods We conducted a cross-sectional nationwide study using zero-inflated negative binomial models to estimate the association between long-term (2010-2016) county-level exposures to NO 2 , PM 2.5 and O 3 and county-level COVID-19 case-fatality and mortality rates in the US. We used both single and multipollutant models and controlled for spatial trends and a comprehensive set of potential confounders, including state-level test positive rate, county-level healthcare capacity, phase-of-epidemic, population mobility, population density, sociodemographics, socioeconomic status, race and ethnicity, behavioral risk factors, and meteorology. Results 3,659,828 COVID-19 cases and 138,552 deaths were reported in 3,076 US counties from January 22, 2020 to July 17, 2020, with an overall observed case-fatality rate of 3.8%. County-level average NO 2 concentrations were positively associated with both COVID-19 case-fatality rate and mortality rate in single-, bi-, and tri-pollutant models. When adjusted for co-pollutants, per inter-quartile range (IQR) increase in NO 2 (4.6 ppb), COVID-19 case-fatality rate and mortality rate were associated with an increase of 11.3% (95% CI 4.9% to 18.2%) and 16.2% (95% CI 8.7% to 24.0%), respectively. We did not observe significant associations between COVID-19 case-fatality rate and long-term exposure to PM 2.5 or O 3 , although per IQR increase in PM 2.5 (2.6 ug/m 3 ) was marginally associated with 14.9% (95% CI: 0.0% to 31.9%) increase in COVID-19 mortality rate when adjusted for co-pollutants. Discussion Long-term exposure to NO 2 , which largely arises from urban combustion sources such as traffic, may enhance susceptibility to severe COVID-19 outcomes, independent of long-term PM 2.5 and O 3 exposure. The results support targeted public health actions to protect residents from COVID-19 in heavily polluted regions with historically high NO 2 levels. Continuation of current efforts to lower traffic emissions and ambient air pollution may be an important component of reducing population-level risk of COVID-19 case-fatality and mortality.

Background:The novel human coronavirus disease 2019 pandemic has claimed more than 240,000 lives worldwide, causing tremendous public health, social, and economic damages. While the risk factors of COVID-19 are still under investigation, environmental factors, such as urban air pollution, may play an important role in increasing population susceptibility to COVID-19 pathogenesis. Methods:We conducted a cross-sectional nationwide study using zero-inflated negative binomial models to estimate the association between long-term (2010-2016) county-level exposures to NO 2 , PM 2.5 and O 3 and county-level COVID-19 case-fatality and mortality rates in the US. We used both single and multipollutant models and controlled for spatial trends and a comprehensive set of potential confounders, including state-level test positive rate, county-level healthcare capacity, phase-of-epidemic, population mobility, sociodemographic, socioeconomic status, behavior risk factors, and meteorological factors.Results: 1,027,799 COVID-19 cases and 58,489 deaths were reported in 3,122 US counties from January 22, 2020 to April 29, 2020, with an overall observed case-fatality rate of 5.8%. Spatial variations were observed for both COVID-19 death outcomes and long-term ambient air pollutant levels. County-level average NO 2 concentrations were positively associated with both COVID-19 case-fatality rate and mortality rate in single-, bi-, and tri-pollutant models (p-values<0.05). Per inter-quartile range (IQR) increase in NO 2 (4.6 ppb), COVID-19 case-fatality rate and mortality rate were associated with an increase of 7.1% (95% CI 1.2% to 13.4%) and 11.2% (95% CI 3.4% to 19.5%), respectively. We did not observe significant associations between long-term exposures to PM 2.5 or O 3 and COVID-19 death outcomes (p-values>0.05), although per IQR increase in PM 2.5 (3.4 ug/m 3 ) was marginally associated with 10.8% (95% CI: -1.1% to 24.1%) increase in COVID-19 mortality rate. Discussions and Conclusions:Long-term exposure to NO 2 , which largely arises from urban combustion sources such as traffic, may enhance susceptibility to severe COVID-19 outcomes, independent of longterm PM 2.5 and O 3 exposure. The results support targeted public health actions to protect residents from COVID-19 in heavily polluted regions with historically high NO 2 levels. Moreover, continuation of current efforts to lower traffic emissions and ambient air pollution levels may be an important component of reducing population-level risk of COVID-19 deaths.

Using HRM, we identified and verified biological perturbations associated with primary traffic pollutant in panel-based setting with repeated measurement. Observed response was consistent with endogenous metabolic signaling related to oxidative stress, inflammation, and nucleic acid damage and repair. Collectively, the current findings provide support for the use of untargeted HRM in the development of metabolic biomarkers of traffic pollution exposure and response.

Background. Mechanisms underlying the effects of traffic-related air pollution on people with asthma remain largely unknown, despite the abundance of observational and controlled studies reporting associations between traffic sources and asthma exacerbation and hospitalizations. Objectives. To identify molecular pathways perturbed following traffic pollution exposures, we analyzed data as part of the Atlanta Commuters Exposure (ACE–2) study, a crossover panel of commuters with and without asthma. Methods. We measured 27 air pollutants and conducted high-resolution metabolomics profiling on blood samples from 45 commuters before and after each exposure session. We evaluated metabolite and metabolic pathway perturbations using an untargeted metabolome-wide association study framework with pathway analyses and chemical annotation. Results. Most of the measured pollutants were elevated in highway commutes (p < 0.05). From both negative and positive ionization modes, 17,586 and 9,087 metabolic features were extracted from plasma, respectively. 494 and 220 unique features were associated with at least 3 of the 27 exposures, respectively (p<0.05), after controlling confounders and false discovery rates. Pathway analysis indicated alteration of several inflammatory and oxidative stress related metabolic pathways, including leukotriene, vitamin E, cytochrome P450, and tryptophan metabolism. We identified and annotated 45 unique metabolites enriched in these pathways, including arginine, histidine, and methionine. Most of these metabolites were not only associated with multiple pollutants, but also differentially expressed between participants with and without asthma. The analysis indicated that these metabolites collectively participated in an interrelated molecular network centering on arginine metabolism, underlying the impact of traffic-related pollutants on individuals with asthma. Conclusions. We detected numerous significant metabolic perturbations associated with in-vehicle exposures during commuting and validated metabolites that were closely linked to several inflammatory and redox pathways, elucidating the potential molecular mechanisms of traffic-related air pollution toxicity. These results support future studies of metabolic markers of traffic exposures and the corresponding molecular mechanisms.

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Hypoxia administered after transient global cerebral ischemia (tGCI) has been shown to induce neuroprotection in adult rats, but the underlying mechanisms for this protection are unclear. Here, we tested the hypothesis that hypoxic postconditioning (HPC) induces neuroprotection through upregulation of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF), and that this involves phosphatidylinositol-3-kinase (PI3K), p38 mitogen-activated protein kinase (p38 MAPK), and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) pathways. The expression of HIF-1α, VEGF, and cleaved caspase-9 were determined by immunohistochemistry and Western blot. As pharmacologic interventions, the HIF-1α inhibitor 2-methoxyestradiol (2ME2), PI3K inhibitor LY294002, p38 MAPK inhibitor SB203580, and MEK inhibitor U0126 were administered before HPC or after tGCI. We found that HPC maintained the higher expression of HIF-1α and VEGF and decreased cleaved caspase-9 levels in CA1 after tGCI. These effects were reversed by 2ME2 administered before HPC, and the neuroprotection of HPC was abolished. LY294002 and SB203580 decreased the expression of HIF-1α and VEGF after HPC, whereas U0126 increased HIF-1α and VEGF after tGCI. These findings suggested that HIF-1α exerts neuroprotection induced by HPC against tGCI through VEGF upregulation and cleaved caspase-9 downregulation, and that the PI3K, p38 MAPK, and MEK pathways are involved in the regulation of HIF-1α and VEGF.

Autophagy disruption leads to neuronal damage in hypoxic-ischemic brain injury. Rab7, a member of the Rab GTPase superfamily, has a unique role in the regulation of autophagy. Hypoxic preconditioning (HPC) provides neuroprotection against transient global cerebral ischemia (tGCI). However, the underlying mechanisms remain poorly understood. Thus, the current study explored the potential molecular mechanism of the neuroprotective effect of HPC by investigating how Rab7 mediates autophagosome (AP) maturation after tGCI in adult rats. We found that HPC attenuated AP accumulation in the hippocampal CA1 region after tGCI via restoration of autophagic flux. We also confirmed that this HPC-induced neuroprotection was not caused by the increase in lysosomes or the improvement of lysosomal function after tGCI. Electron microscopic analysis then revealed an increase in autolysosomes in CA1 neurons of HPC rats. Moreover, the inhibition of autophagosome-lysosome fusion by chloroquine significantly aggravated neuronal death in CA1, indicating that AP maturation contributes to HPC-induced neuroprotection against neuronal injury after tGCI. Furthermore, the activation of Rab7 was found to be involved in the neuroprotective effect of AP maturation after HPC. At last, the knockdown of ultraviolet radiation resistance-associated gene (UVRAG) in vivo disrupted the interaction between Vps16 and Rab7, attenuated the activation of Rab7, interrupted autophagic flux, and ultimately abrogated the HPC-induced neuroprotection against tGCI. Our results indicated that AP maturation was enhanced by the activation of Rab7 via UVRAG-Vps16 interaction, which further demonstrated the potential neuroprotective role of Rab7 in HPC against tGCI-induced neuronal injury in adult rats.