New Features of Laboratory-Generated EPFRs from 1,2-Dichlorobenzene (DCB) and 2-Monochlorophenol (MCP).

The present research is primarily focused on investigating the characteristics of environmentally persistent free radicals (EPFRs) generated from commonly recognized aromatic precursors, namely, 1,2-dichlorobenzene (DCB) and 2-monochlorophenol (MCP), within controlled laboratory conditions at a temperature of 230 °C, termed as DCB230 and MCP230 EPFRs, respectively. An intriguing observation has emerged during the creation of EPFRs from MCP and DCB utilizing a catalyst 5% CuO/SiO2, which was prepared through various methods. A previously proposed mechanism, advanced by Dellinger and colleagues (a conventional model), postulated a positive correlation between the degree of hydroxylation on the catalyst's surface (higher hydroxylated, HH and less hydroxylated, LH) and the anticipated EPFR yields. In the present study, this correlation was specifically confirmed for the DCB precursor. Particularly, it was observed that increasing the degree of hydroxylation at the catalyst's surface resulted in a greater yield of EPFRs for DCB230. The unexpected finding was the indifferent behavior of MCP230 EPFRs to the surface morphology of the catalyst, i.e., no matter whether copper oxide nanoparticles are distributed densely, sparsely, or completely agglomerated. The yields of MCP230 EPFRs remained consistent regardless of the catalyst type or preparation protocol. Although current experimental results confirm the early model for the generation of DCB EPFRs (i.e., the higher the hydroxylation is, the higher the yield of EPFRs), it is of utmost importance to closely explore the heterogeneous alternative mechanism(s) responsible for generating MCP230 EPFRs, which may run parallel to the conventional model. In this study, detailed spectral analysis was conducted using the EPR technique to examine the nature of DCB230 EPFRs and the aging phenomenon of DCB230 EPFRs while they exist as surface-bound o-semiquinone radicals (o-SQ) on copper sites. Various aspects concerning bound radicals were explored, including the hydrogen-bonding tendencies of o-semiquinone (o-SQ) radicals, the potential reversibility of hydroxylation processes occurring on the catalyst's surface, and the analysis of selected EPR spectra using EasySpin MATLAB. Furthermore, alternative routes for EPFR generation were thoroughly discussed and compared with the conventional model.

Inhalation of particulate matter containing environmentally persistent free radicals induces endothelial dysfunction mediated via AhR activation at the air-blood interface.

Particulate matter (PM) containing environmentally persistent free radicals (EPFR) is formed by the incomplete combustion of organic wastes, resulting in the chemisorption of pollutants to the surface of PM containing redox-active transition metals. In prior studies in mice, EPFR inhalation impaired endothelium-dependent vasodilation. These findings were associated with aryl hydrocarbon receptor (AhR) activation in the alveolar type-II (AT-II) cells that form the air-blood interface in the lung. We thus hypothesized that AhR activation in AT-II cells promotes the systemic release of mediators that promote endothelium dysfunction peripheral to the lung. To test our hypothesis, we knocked down AhR in AT-II cells of male and female mice and exposed them to 280 µg/m3 EPFR lo (2.7e + 16 radicals/g) or EPFR (5.5e + 17 radicals/g) compared with filtered air for 4 h/day for 1 day or 5 days. AT-II-AhR activation-induced EPFR-mediated endothelial dysfunction, reducing endothelium-dependent vasorelaxation by 59%, and eNOS expression by 50%. It also increased endothelin-1 mRNA levels in the lungs and peptide levels in the plasma in a paracrine fashion, along with soluble vascular cell adhesion molecule-1 and iNOS mRNA expression, possibly via NF-kB activation. Finally, AhR-dependent increases in antioxidant response signaling, coupled to increased levels of 3-nitrotyrosine in the lungs of EPFR-exposed littermate control but not AT-II AhR KO mice suggested that ATII-specific AhR activation promotes oxidative and nitrative stress. Thus, AhR activation at the air-blood interface mediates endothelial dysfunction observed peripheral to the lung, potentially via release of systemic mediators.

Updates in Air Pollution: Current Research and Future Challenges.

Background: The United Nations has declared that humans have a right to clean air. Despite this, many deaths and disability-adjusted life years are attributed to air pollution exposure each year. We face both challenges to air quality and opportunities to improve, but several areas need to be addressed with urgency. Objective: This paper summarises the recent research presented at the Pacific Basin Consortium for Environment and Health Symposium and focuses on three key areas of air pollution that are important to human health and require more research. Findings and conclusion: Indoor spaces are commonly places of exposure to poor air quality and are difficult to monitor and regulate. Global climate change risks worsening air quality in a bi-directional fashion. The rising use of electric vehicles may offer opportunities to improve air quality, but it also presents new challenges. Government policies and initiatives could lead to improved air and environmental justice. Several populations, such as older people and children, face increased harm from air pollution and should become priority groups for action.

Identification of a Chondrocyte-Specific Enhancer in the Hoxc8 Gene.

Hox genes encode transcription factors whose roles in patterning animal body plans during embryonic development are well-documented. Multiple studies demonstrate that Hox genes continue to act in adult cells, in normal differentiation, in regenerative processes, and, with abnormal expression, in diverse types of cancers. However, surprisingly little is known about the regulatory mechanisms that govern Hox gene expression in specific cell types, as they differentiate during late embryonic development, and in the adult organism. The murine Hoxc8 gene determines the identity of multiple skeletal elements in the lower thoracic and lumbar region and continues to play a role in the proliferation and differentiation of cells in cartilage as the skeleton matures. This study was undertaken to identify regulatory elements in the Hoxc8 gene that control transcriptional activity, specifically in cartilage-producing chondrocytes. We report that an enhancer comprising two 416 and 224 bps long interacting DNA elements produces reporter gene activity when assayed on a heterologous transcriptional promoter in transgenic mice. This enhancer is distinct in spatial, temporal, and molecular regulation from previously identified regulatory sequences in the Hoxc8 gene that control its expression in early development. The identification of a tissue-specific Hox gene regulatory element now allows mechanistic investigations into Hox transcription factor expression and function in differentiating cell types and adult tissues and to specifically target these cells during repair processes and regeneration.

Two-pore potassium channel TREK-1 (K2P2.1) regulates NLRP3 inflammasome activity in macrophages.

Because of the importance of potassium efflux in inflammasome activation, we investigated the role of the two-pore potassium (K2P) channel TREK-1 in macrophage inflammasome activity. Using primary alveolar macrophages (AMs) and bone marrow-derived macrophages (BMDMs) from wild-type (wt) and TREK-1-/- mice, we measured responses to inflammasome priming [using lipopolysaccharide (LPS)] and activation (LPS + ATP). We measured IL-1ß, caspase-1, and NLRP3 via ELISA and Western blot. A membrane-permeable potassium indicator was used to measure potassium efflux during ATP exposure, and a fluorescence-based assay was used to assess changes in membrane potential. Inflammasome activation induced by LPS + ATP increased IL-1ß secretion in wt AMs, whereas activation was significantly reduced in TREK-1-/- AMs. Priming of BMDMs using LPS was not affected by either genetic deficiency or pharmacological inhibition of TREK-1 with Spadin. Cleavage of caspase-1 following LPS + ATP treatment was significantly reduced in TREK-1-/- BMDMs. The intracellular potassium concentration in LPS-primed wt BMDMs was significantly lower compared with TREK-1-/- BMDMs or wt BMDMs treated with Spadin. Conversely, activation of TREK-1 with BL1249 caused a decrease in intracellular potassium in wt BMDMs. Treatment of LPS-primed BMDMs with ATP caused a rapid reduction in intracellular potassium levels, with the largest change observed in TREK-1-/- BMDMs. Intracellular K+ changes were associated with changes in the plasma membrane potential (Em), as evidenced by a more depolarized Em in TREK-1-/- BMDMs compared with wt, and Em hyperpolarization upon TREK-1 channel opening with BL1249. These results suggest that TREK-1 is an important regulator of NLRP3 inflammasome activation in macrophages.NEW & NOTEWORTHY Because of the importance of potassium efflux in inflammasome activation, we investigated the role of the two-pore potassium (K2P) channel TREK-1 in macrophage inflammasome activity. Using primary alveolar macrophages and bone marrow-derived macrophages from wild-type and TREK-1-/- mice, we measured responses to inflammasome priming (using LPS) and activation (LPS + ATP). Our results suggest that TREK-1 is an important regulator of NLRP3 inflammasome activation in macrophages.

Household characteristics associated with environmentally persistent free radicals in house dust in two Australian locations.

The association between air pollution and adverse health outcomes has been extensively studied, and while oxidative stress in likely to be involved, the underlying mechanism(s) remain unclear. Recent studies propose environmentally persistent free radicals (EPFRs) as the missing connection between air pollution and detrimental health impacts. However, the indoor environment is rarely considered in EPFR research. We measured EPFRs in household dust from two locations in Australia and investigated household characteristics associated with EPFRs. Random forest models were built to identify important household characteristics through variable importance plots and the associations were analysed using Spearman's rho test. We found that age of house, type of garage, house outer wall material, heating method used in home, frequency of extractor fan use when cooking, traffic related air pollution, frequency of cleaning and major house renovation were important household characteristics associated with EPFRs in Australian homes. The direction of association between household characteristics and EPFRs differ between the locations. Hence, further research is warranted to determine the generalisability of our results.

International Pediatric COVID-19 Severity Over the Course of the Pandemic.

Importance: Multiple SARS-CoV-2 variants have emerged over the COVID-19 pandemic. The implications for COVID-19 severity in children worldwide are unclear. Objective: To determine whether the dominant circulating SARS-CoV-2 variants of concern (VOCs) were associated with differences in COVID-19 severity among hospitalized children. Design, Setting, and Participants: Clinical data from hospitalized children and adolescents (younger than 18 years) who were SARS-CoV-2 positive were obtained from 9 countries (Australia, Brazil, Italy, Portugal, South Africa, Switzerland, Thailand, UK, and the US) during 3 different time frames. Time frames 1 (T1), 2 (T2), and 3 (T3) were defined to represent periods of dominance by the ancestral virus, pre-Omicron VOCs, and Omicron, respectively. Age groups for analysis were younger than 6 months, 6 months to younger than 5 years, and 5 to younger than 18 years. Children with an incidental positive test result for SARS-CoV-2 were excluded. Exposures: SARS-CoV-2 hospitalization during the stipulated time frame. Main Outcomes and Measures: The severity of disease was assessed by admission to intensive care unit (ICU), the need for ventilatory support, or oxygen therapy. Results: Among 31 785 hospitalized children and adolescents, the median age was 4 (IQR 1-12) years and 16 639 were male (52.3%). In children younger than 5 years, across successive SARS-CoV-2 waves, there was a reduction in ICU admission (T3 vs T1: risk ratio [RR], 0.56; 95% CI, 0.42-0.75 [younger than 6 months]; RR, 0.61, 95% CI; 0.47-0.79 [6 months to younger than 5 years]), but not ventilatory support or oxygen therapy. In contrast, ICU admission (T3 vs T1: RR, 0.39, 95% CI, 0.32-0.48), ventilatory support (T3 vs T1: RR, 0.37; 95% CI, 0.27-0.51), and oxygen therapy (T3 vs T1: RR, 0.47; 95% CI, 0.32-0.70) decreased across SARS-CoV-2 waves in children 5 years to younger than 18 years old. The results were consistent when data were restricted to unvaccinated children. Conclusions and Relevance: This study provides valuable insights into the impact of SARS-CoV-2 VOCs on the severity of COVID-19 in hospitalized children across different age groups and countries, suggesting that while ICU admissions decreased across the pandemic in all age groups, ventilatory and oxygen support generally did not decrease over time in children aged younger than 5 years. These findings highlight the importance of considering different pediatric age groups when assessing disease severity in COVID-19.

The fungal intestinal microbiota predict the development of bronchopulmonary dysplasia in very low birthweight newborns.

RATIONALE: Bronchopulmonary dysplasia (BPD) is the most common morbidity affecting very preterm infants. Gut fungal and bacterial microbial communities contribute to multiple lung diseases and may influence BPD pathogenesis. METHODS: We performed a prospective, observational cohort study comparing the multikingdom fecal microbiota of 144 preterm infants with or without moderate to severe BPD by sequencing the bacterial 16S and fungal ITS2 ribosomal RNA gene. To address the potential causative relationship between gut dysbiosis and BPD, we used fecal microbiota transplant in an antibiotic-pseudohumanized mouse model. Comparisons were made using RNA sequencing, confocal microscopy, lung morphometry, and oscillometry. RESULTS: We analyzed 102 fecal microbiome samples collected during the second week of life. Infants who later developed BPD showed an obvious fungal dysbiosis as compared to infants without BPD (NoBPD, p = 0.0398, permutational multivariate ANOVA). Instead of fungal communities dominated by Candida and Saccharomyces, the microbiota of infants who developed BPD were characterized by a greater diversity of rarer fungi in less interconnected community architectures. On successful colonization, the gut microbiota from infants with BPD augmented lung injury in the offspring of recipient animals. We identified alterations in the murine intestinal microbiome and transcriptome associated with augmented lung injury. CONCLUSIONS: The gut fungal microbiome of infants who will develop BPD is dysbiotic and may contribute to disease pathogenesis.

Environmentally persistent free radicals: Methods for combustion generation, whole-body inhalation and assessing cardiopulmonary consequences.

Particulate matter (PM) containing environmentally persistent free radicals (EPFRs) results from the incomplete combustion of organic wastes which chemisorb to transition metals. This process generates a particle-pollutant complex that continuously redox cycles to produce reactive oxygen species. EPFRs are well characterized, but their cardiopulmonary effects remain unknown. This publication provides a detailed approach to evaluating these effects and demonstrates the impact that EPFRs have on the lungs and vasculature. Combustion-derived EPFRs were generated (EPFR lo: 2.1e-16 radical/g, EPFR hi: 5.5e-17 radical/g), characterized, and verified as representative of those found in urban areas. Dry particle aerosolization and whole-body inhalation were established for rodent exposures. To verify that these particles and exposures recapitulate findings relevant to known PM-induced cardiopulmonary effects, male C57BL6 mice were exposed to filtered air, ∼280 µg/m3 EPFR lo or EPFR hi for 4 h/d for 5 consecutive days. Compared to filtered air, pulmonary resistance was increased in mice exposed to EPFR hi. Mice exposed to EPFR hi also exhibited increased plasma endothelin-1 (44.6 vs 30.6 pg/mL) and reduced nitric oxide (137 nM vs 236 nM), suggesting vascular dysfunction. Assessment of vascular response demonstrated an impairment in endothelium-dependent vasorelaxation, with maximum relaxation decreased from 80% to 62% in filtered air vs EPFR hi exposed mice. Gene expression analysis highlighted fold changes in aryl hydrocarbon receptor (AhR) and antioxidant response genes including increases in lung Cyp1a1 (8.7 fold), Cyp1b1 (9 fold), Aldh3a1 (1.7 fold) and Nqo1 (2.4 fold) and Gclc (1.3 fold), and in aortic Cyp1a1 (5.3 fold) in mice exposed to EPFR hi vs filtered air. We then determined that lung AT2 cells were the predominate locus for AhR activation. Together, these data suggest the lung and vasculature as particular targets for the health impacts of EPFRs and demonstrate the importance of additional studies investigating the cardiopulmonary effects of EPFRs.

Associations of COVID-19 Hospitalizations, ICU Admissions, and Mortality with Black and White Race and Their Mediation by Air Pollution and Other Risk Factors in the Louisiana Industrial Corridor, March 2020-August 2021.

Louisiana ranks among the bottom five states for air pollution and mortality. Our objective was to investigate associations between race and Coronavirus Disease 2019 (COVID-19) hospitalizations, intensive care unit (ICU) admissions, and mortality over time and determine which air pollutants and other characteristics may mediate COVID-19-associated outcomes. In our cross-sectional study, we analyzed hospitalizations, ICU admissions, and mortality among positive SARS-CoV-2 cases within a healthcare system around the Louisiana Industrial Corridor over four waves of the pandemic from 1 March 2020 to 31 August 2021. Associations between race and each outcome were tested, and multiple mediation analysis was performed to test if other demographic, socioeconomic, or air pollution variables mediate the race-outcome relationships after adjusting for all available confounders. Race was associated with each outcome over the study duration and during most waves. Early in the pandemic, hospitalization, ICU admission, and mortality rates were greater among Black patients, but as the pandemic progressed, these rates became greater in White patients. However, Black patients were disproportionately represented in these measures. Our findings imply that air pollution might contribute to the disproportionate share of COVID-19 hospitalizations and mortality among Black residents in Louisiana.

Environmentally persistent free radicals enhance SARS-CoV-2 replication in respiratory epithelium.

Epidemiological evidence links lower air quality with increased incidence and severity of COVID-19; however, mechanistic data have yet to be published. We hypothesized air pollution-induced oxidative stress in the nasal epithelium increased viral replication and inflammation. Nasal epithelial cells (NECs), collected from healthy adults, were grown into a fully differentiated epithelium. NECs were infected with the ancestral strain of SARS-CoV-2. An oxidant combustion by-product found in air pollution, the environmentally persistent free radical (EPFR) DCB230, was used to mimic pollution exposure four hours prior to infection. Some wells were pretreated with antioxidant, astaxanthin, for 24 hours prior to EPFR-DCB230 exposure and/or SARS-CoV-2 infection. Outcomes included viral replication, epithelial integrity, surface receptor expression (ACE2, TMPRSS2), cytokine mRNA expression (TNF-α, IFN-ß), intracellular signaling pathways, and oxidative defense enzymes. SARS-CoV-2 infection induced a mild phenotype in NECs, with some cell death, upregulation of the antiviral cytokine IFN-ß, but had little effect on intracellular pathways or oxidative defense enzymes. Prior exposure to EPFR-DCB230 increased SARS-CoV-2 replication, upregulated TMPRSS2 expression, increased secretion of the proinflammatory cytokine TNF-α, inhibited expression of the mucus producing MUC5AC gene, upregulated expression of p21 (apoptosis pathway), PINK1 (mitophagy pathway), and reduced levels of antioxidant enzymes. Pretreatment with astaxanthin reduced SARS-CoV-2 replication, downregulated ACE2 expression, and prevented most, but not all EPFR-DCB230 effects. Our data suggest that oxidant damage to the respiratory epithelium may underly the link between poor air quality and increased COVID-19. The apparent protection by antioxidants warrants further research.

Environmental Impacts on COVID-19: Mechanisms of Increased Susceptibility.

Background: Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in >554M cases and >6.3M deaths worldwide. The disease caused by SARS-CoV-2, COVID-19, has resulted in a broad range of clinical symptoms differing in severity. Initially, the elderly were identified as particularly susceptible to severe COVID-19, with children experiencing less severe disease. However, as new variants arise, the epidemiology of SARS-CoV-2 infection is changing, and the disease severity in children is increasing. While environmental impacts on COVID-19 have been described, the underlying mechanisms are poorly described. Objective: The Pacific Basin Consortium for Environment and Health (PBC) held meeting on September 16, 2021, to explore environmental impacts on infectious diseases, including COVID-19. Methods: The PBC is an international group of environmental scientists and those interested in health outcomes. The PBC met to present preliminary data and discuss the role of exposures to airborne pollutants in enhancing susceptibility to and severity of respiratory tract viral infections, including COVID-19. Findings: Analysis of the literature and data presented identified age as an important factor in vulnerability to air pollution and enhanced COVID-19 susceptibility and severity. Mechanisms involved in increasing severity of COVID-19 were discussed, and gaps in knowledge were identified. Conclusions: Exposure to particulate matter (PM) pollution enhanced morbidity and mortality to COVID-19 in a pediatric population associated with induction of oxidative stress. In addition, free radicals present on PM can induce rapid changes in the viral genome that can lead to vaccine escape, altered host susceptibility, and viral pathogenicity. Nutritional antioxidant supplements have been shown to reduce the severity of viral infections, inhibit the inflammatory cytokine storm, and boost host immunity and may be of benefit in combating COVID-19.

Absence of antibody responses to SARS-CoV-2 N protein in COVID-19 vaccine breakthrough cases.

Understanding the risk factors for breakthrough coronavirus disease 2019 (COVID-19) (BC19) is critical to inform policy. Herein, we assessed Delta (Lineage B.1.617.2) variant-specific effectiveness of the BNT162b2 (Pfizer) vaccine and characterized Delta-driven BC19 cases (fully vaccinated individuals who get infected) with known-time-since-vaccination. In this longitudinal prospective study (January 21-October 30, 2021), 90 naïve and 15 convalescent individuals were enrolled at the initiation of vaccination. Samples from 27 unvaccinated individuals with previous laboratory-confirmed COVID-19 diagnosis were collected at a single time point. Longitudinal serology profile (antibodies against severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] S and N proteins) and live-virus-based neutralization capacities were assessed while controlling for age. Sex, age, history of reactions to the COVID-19 vaccine, and viral neutralization capacities were identified as significant risk factors for breakthrough COVID-19. At 8 months postvaccination, male sex, individuals ⩾65 years of age, and individuals who experienced noticeable side effects with the COVID-19 vaccine were at 5.47 (p-value = 0.0102), 4.33 (p-value = 0.0236), and 4.95 (p-value = 0.0159) fold greater risk of BC19 as compared to their peers, respectively. Importantly, every five-fold increase in viral neutralization capacities (by live-virus-based assays) was significantly associated with ~4-fold reduction in the risk occurrence of breakthrough COVID-19 (p-value = 0.045). Vaccine boosting remarkably increased these viral neutralization capacities by 16.22-fold (p- value = 0.0005), supporting the importance of the BNT162b2 booster in efforts to control the incursion of future variants into the population at large. Strikingly, BC19 cases exhibited a delayed/absent antibody response to the N protein, suggesting limited exposure to the virus. Since antibodies against N protein are widely used to evaluate the extent of virus spread in communities, our finding has important implications on the utility of existing serological diagnostic and surveillance for COVID-19.

Beyond the Unknown: A Broad Framing for Preparedness for Emerging Infectious Threats.

There have been multiple instances of novel pathogen emergence that have affected the health and security of the global community. To highlight that these novel pathogens presented a clear danger to public health, the WHO included "Disease X" on their list of priority pathogens in 2018. Indeed, since the emergence of SARS-CoV-2, Disease X has been pointed to as the looming threat of "the next big thing." However, developing surveillance and preparedness plans with Disease X as the linchpin is too narrow and ignores a large swath of potential threats from already identified, often neglected diseases. We propose instead the idea of "Disease f(x)" as a preferred call to arms with which to prioritize research and programmatic development. The common mathematical notation f(x) represents the knowledge that outbreaks are a function of many variables that define the transmission trajectory of that pathogen. Disease f(x) exploits commonalities across pathogen groupings while recognizing that emergences and outbreaks are fluid and that responses need to be agile and progressively tailored to specific pathogens with cultural and regional context. Adoption of this mindset across sectors, including biotechnology, disaster management, and epidemiology, will allow us to develop more efficient and effective responses to address the next major infectious threat.

Genomic Basis for Individual Differences in Susceptibility to the Neurotoxic Effects of Diesel Exhaust.

Air pollution is a known environmental health hazard. A major source of air pollution includes diesel exhaust (DE). Initially, research on DE focused on respiratory morbidities; however, more recently, exposures to DE have been associated with neurological developmental disorders and neurodegeneration. In this study, we investigated the effects of sub-chronic inhalation exposure to DE on neuroinflammatory markers in two inbred mouse strains and both sexes, including whole transcriptome examination of the medial prefrontal cortex. We exposed aged male and female C57BL/6J (B6) and DBA/2J (D2) mice to DE, which was cooled and diluted with HEPA-filtered compressed air for 2 h per day, 5 days a week, for 4 weeks. Control animals were exposed to HEPA-filtered air on the same schedule as DE-exposed animals. The prefrontal cortex was harvested and analyzed for proinflammatory cytokine gene expression (Il1ß, Il6, Tnfα) and transcriptome-wide response by RNA-seq. We observed differential cytokine gene expression between strains and sexes in the DE-exposed vs. control-exposed groups for Il1ß, Tnfα, and Il6. For RNA-seq, we identified 150 differentially expressed genes between air and DE treatment related to natural killer cell-mediated cytotoxicity per Kyoto Encyclopedia of Genes and Genomes pathways. Overall, our data show differential strain-related effects of DE on neuroinflammation and neurotoxicity and demonstrate that B6 are more susceptible than D2 to gene expression changes due to DE exposures than D2. These results are important because B6 mice are often used as the default mouse model for DE studies and strain-related effects of DE neurotoxicity warrant expanded studies.

Metal-Free Biomass-Derived Environmentally Persistent Free Radicals (Bio-EPFRs) from Lignin Pyrolysis.

To assess contribution of the radicals formed from biomass burning, our recent findings toward the formation of resonantly stabilized persistent radicals from hydrolytic lignin pyrolysis in a metal-free environment are presented in detail. Such radicals have particularly been identified during fast pyrolysis of lignin dispersed into the gas phase in a flow reactor. The trapped radicals were analyzed by X-band electron paramagnetic resonance (EPR) and high-frequency (HF) EPR spectroscopy. To conceptualize available data, the metal-free biogenic bulky stable radicals with extended conjugated backbones are suggested to categorize as a new type of metal-free environmentally persistent free radicals (EPFRs) (bio-EPFRs). They can be originated not only from lignin/biomass pyrolysis but also during various thermal processes in combustion reactors and media, including tobacco smoke, anthropogenic sources and wildfires (forest/bushfires), and so on. The persistency of bio-EPFRs from lignin gas-phase pyrolysis was outlined with the evaluated lifetime of two groups of radicals being 33 and 143 h, respectively. The experimental results from pyrolysis of coniferyl alcohol as a model compound of lignin in the same fast flow reactor, along with our detailed potential energy surface analyses using high-level DFT and ab initio methods toward decomposition of a few other model compounds reported earlier, provide a mechanistic view on the formation of C- and O-centered radicals during lignin gas-phase pyrolysis. The preliminary measurements using HF-EPR spectroscopy also support the existence of O-centered radicals in the radical mixtures from pyrolysis of lignin possessing a high g value (2.0048).

Risk factors among Black and White COVID-19 patients from a Louisiana Hospital System, March, 2020 - August, 2021.

Objectives: To investigate relationships between race and COVID-19 hospitalizations, intensive care unit (ICU) admissions, and mortality over time and which characteristics, may mediate COVID-19 associations. Methods: We analyzed hospital admissions, ICU admissions, and mortality among positive COVID-19 cases within the ten-hospital Franciscan Ministries of Our Lady Health System around the Mississippi River Industrial Corridor in Louisiana over four waves of the pandemic from March 1, 2020 - August 31, 2021. Associations between race and each outcome were tested, and multiple mediation analysis was performed to test if other demographic, socioeconomic, or air pollution variables mediate the race-outcome relationships. Results: Race was associated with each outcome over the study duration and during most waves. Early in the pandemic, hospitalization, ICU admission, and mortality rates were greater among Black patients, but as the pandemic progressed these rates became greater in White patients. However, Black patients were still disproportionately represented in these measures. Age was a significant mediator for all outcomes across waves, while comorbidity and emissions of naphthalene and chloroprene acted as mediators for the full study period. Conclusions: The role of race evolved throughout the pandemic in Louisiana, but Black patients bore a disproportionate impact. Naphthalene and chloroprene air pollution partially explained the long-term associations. Our findings imply that air pollution might contribute to the increased COVID-19 hospitalizations and mortality among Black residents in Louisiana but likely do not explain most of the effect of race.

IL-1ß Promotes Expansion of IL-33+ Lung Epithelial Stem Cells after Respiratory Syncytial Virus Infection during Infancy.

Respiratory syncytial virus (RSV)-induced immunopathogenesis and disease severity in neonatal mice and human infants have been related to elevated pulmonary IL-33. Thus, targeting IL-33 has been suggested as a potential therapy for respiratory viral infections. Yet, the regulatory mechanisms on IL-33 during early life remain unclear. Here, using a neonatal mouse model of RSV, we demonstrate that IL-1ß positively regulates but is not required for RSV-induced expression of pulmonary IL-33 in neonatal mice early after the initial infection. Exogenous IL-1ß upregulates RSV-induced IL-33 expression by promoting the proliferation of IL-33+ lung epithelial stem/progenitor cells. These cells are exclusively detected in RSV-infected neonatal rather than adult mice, partially explaining the IL-1ß-independent IL-33 expression in RSV-infected adult mice. Furthermore, IL-1ß aggravates IL-33-mediated T-helper cell type 2-biased immunopathogenesis upon reinfection. Collectively, our study demonstrates that IL-1ß exacerbates IL-33-mediated RSV immunopathogenesis by promoting the proliferation of IL-33+ epithelial stem/progenitor cells in early life.

Increased alveolar epithelial TRAF6 via autophagy-dependent TRIM37 degradation mediates particulate matter-induced lung metastasis.

Epidemiological and clinical studies have shown that exposure to particulate matter (PM) is associated with an increased incidence of lung cancer and metastasis. However, the underlying mechanism remains unclear. Here, we demonstrated the central role of PM-induced neutrophil recruitment in promoting lung cancer metastasis. We found that reactive oxygen species (ROS)-mediated alveolar epithelial macroautophagy/autophagy was essential for initiating neutrophil chemotaxis and pre-metastatic niche formation in the lungs in response to PM exposure. During PM-induced autophagy, the E3 ubiquitin ligase TRIM37 was degraded and protected TRAF6 from proteasomal degradation in lung epithelial cells, which promoted the NFKB-dependent production of chemokines to recruit neutrophils. Importantly, ROS blockade, autophagy inhibition or TRAF6 knockdown abolished PM-induced neutrophil recruitment and lung metastasis enhancement. Our study indicates that host lung epithelial cells and neutrophils coordinate to promote cancer metastasis to the lungs in response to PM exposure and provides ideal therapeutic targets for metastatic progression.Abbreviations: ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ATII: alveolar type II; Cho-Traf6 siRNA: 5'-cholesterol-Traf6 siRNA; EMT: epithelial-mesenchymal transition; HBE: human bronchial epithelial; HCQ: hydroxychloroquine; MAPK: mitogen-activated protein kinase; NAC: N-acetyl-L-cysteine; NFKB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NS: normal saline; PM: particulate matter; ROS: reactive oxygen species; TRAF6: TNF receptor-associated factor 6; TRIM37: tripartite motif-containing 37.