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The inhalation of fine particulate matter (PM 2.5 ) is a major contributor to adverse health effects from air pollution worldwide. An important toxicity pathway is thought to follow oxidative stress from the formation of exogenous reactive oxygen species (ROS) in the body, a proxy of which is oxidative potential (OP). As redox-active transition metals and organic species are important drivers of OP in urban environments, we investigate how seasonal changes in emission sources, aerosol chemical composition, acidity, and metal dissolution influence OP dynamics. Using a kinetic model of the lung redox chemistry, we predicted ROS (O 2 •- , H 2 O 2 , • OH) formation with input parameters comprising the ambient concentrations of PM 2.5 , water-soluble Fe and Cu, secondary organic matter, nitrogen dioxide, and ozone across two years and two urban sites in Canada. Particulate species were the largest contributors to ROS production. Soluble Fe and Cu had their highest and lowest values in summer and winter, and changes in Fe solubility were closely linked to seasonal variations in chemical aging, the acidity of aerosol, and organic ligand levels. The results indicate three conditions that influence OP across various seasons: (a) low aerosol pH and high organic ligand levels leading to the highest OP in summer, (b) opposite trends leading to the lowest OP in winter, and (c) intermediate conditions corresponding to moderate OP in spring and fall. This study highlights how atmospheric chemical aging modifies the oxidative burden of urban air pollutants, resulting in a seasonal cycle with a potential effect on population health., Competing Interests: The authors declare no competing financial interest., (Crown © 2024. Published by American Chemical Society.)

Air pollution causes morbidity and excess mortality. In the epithelial lining fluid of the respiratory tract, air pollutants trigger a chemical reaction sequence that causes the formation of noxious hydroxyl radicals that drive oxidative stress. For hitherto unknown reasons, individuals with pre-existing inflammatory disorders are particularly susceptible to air pollution. Through detailed multiphase chemical kinetic analysis, we show that the commonly elevated concentrations of endogenous nitric oxide in diseased individuals can increase the production of hydroxyl radicals via peroxynitrite formation. Our findings offer a molecular rationale of how adverse health effects and oxidative stress caused by air pollutants may be exacerbated by inflammatory disorders.

The adverse health effects of air pollution around the world have been associated with the inhalation of fine particulate matter (PM 2.5 ). Such outcomes are thought to be related to the induction of oxidative stress due to the excess formation of reactive oxygen species (ROS) in the respiratory and cardiovascular systems. The ability of airborne chemicals to deplete antioxidants and to form ROS is known as oxidative potential (OP). Here we studied the influence of aerosol acidity and organic ligands on the solubility of transition metals, in particular iron (Fe) and copper (Cu), and on the OP of PM 2.5 from Canadian National Air Pollution Surveillance urban sites in Toronto, Vancouver, and Hamilton. Using chemical assays and model simulations of the lung redox chemistry, we quantified ROS formation in the lung lining fluid, targeting superoxide anion (O 2 •- ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radical ( • OH), as well as the PM 2.5 redox potential (RP). Experimental • OH formation (OP OH ) showed high correlations with RP and model-predicted ROS metrics. Both aerosol acidity and oxalate content enhanced the solubility of transition metals, with oxalate showing a stronger association. While experimental OP metrics were primarily associated with species of primary origin such as elemental carbon, Fe, and Cu, model-predicted ROS were associated with secondary processes including proton- and ligand-mediated dissolution of Fe. Model simulations showed that water-soluble Cu was the main contributor to O 2 •- formation, while water-soluble Fe dominated the formation of highly reactive • OH radical, particularly at study sites with highly acidic aerosol and elevated levels of oxalate. This study underscores the importance of reducing transition metal emissions in urban environments to improve population health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Exposure to ambient air pollution is a major risk factor for human health. Inhalation of air pollutants can enhance the formation of reactive species in the epithelial lining fluid (ELF) of the respiratory tract and can lead to oxidative stress and oxidative damage. Here, we investigate the chemical modification of proteins by reactive species from air pollution and endogenous biological sources using an extended version of the multiphase chemical kinetic model KM-SUB-ELF 2.0 with a detailed mechanism of protein modification. Fine particulate matter (PM 2.5 ) and nitrogen dioxide ( • NO 2 ) act synergistically and increase the formation of nitrotyrosine (Ntyr), a common biomarker of oxidative stress. Ozone (O 3 ) is found to be a burden on the antioxidant defense system but without substantial influence on the Ntyr concentration. In simulations with low levels of air pollution, the Ntyr concentration in the ELF is consistent with the range of literature values for bronchoalveolar lavage fluid from healthy individuals. With high levels of air pollution, however, we obtain strongly elevated Ntyr concentrations. Our model analysis shows how chemical reactions of air pollutants can modify proteins and thus their functionality in the human body, elucidating a molecular pathway that may explain air pollutant effects on human health.

Redox-active substances in fine particulate matter (PM) contribute to inhalation health risks through their potential to generate reactive oxygen species in epithelial lung lining fluid (ELF). The ELF's air-liquid interface (ALI) can play an important role in the phase transfer and multi-phase reactions of redox-active PM constituents. We investigated the influence of interfacial processes and properties by scrubbing of coated nano-particles with simulated ELF in a nebulizing mist chamber. Weakly water-soluble redox-active organics abundant in ambient fine PM were reproducibly loaded into ELF via ALI mixing. The resulting oxidative potential (OP) of selected quinones and other PAH derivatives were found to exceed the OP resulting from bulk mixing of the same amounts of redox-active substances and ELF. Our results indicate that the OP of PM components depends not only on the PM substance properties but also on the ELF interface properties and uptake mechanisms. OP measurements based on bulk mixing of phases may not represent the effective OP in the human lung., (© 2022. The Author(s).)

Air pollution is a major risk factor for human health. Chemical reactions in the epithelial lining fluid (ELF) of the human respiratory tract result in the formation of reactive oxygen species (ROS), which can lead to oxidative stress and adverse health effects. We use kinetic modeling to quantify the effects of fine particulate matter (PM2.5), ozone (O 3 ), and nitrogen dioxide (NO 2 ) on ROS formation, interconversion, and reactivity, and discuss different chemical metrics for oxidative stress, such as cumulative production of ROS and hydrogen peroxide (H 2 O 2 ) to hydroxyl radical (OH) conversion. All three air pollutants produce ROS that accumulate in the ELF as H 2 O 2 , which serves as reservoir for radical species. At low PM2.5 concentrations (<10 μg m -3 ), we find that less than 4% of all produced H 2 O 2 is converted into highly reactive OH, while the rest is intercepted by antioxidants and enzymes that serve as ROS buffering agents. At elevated PM2.5 concentrations (>10 μg m -3 ), however, Fenton chemistry overwhelms the ROS buffering effect and leads to a tipping point in H 2 O 2 fate, causing a strong nonlinear increase in OH production. This shift in ROS chemistry and the enhanced OH production provide a tentative mechanistic explanation for how the inhalation of PM2.5 induces oxidative stress and adverse health effects.

Objective: Gout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout., Methods: Variant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout., Results: We identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher's exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71×10 -5 ). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry., Conclusion: Here, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis., Competing Interests: Competing interests: ND reports grants from Health Research Council of New Zealand, during the conduct of the study; grants and personal fees from AstraZeneca, grants from Amgen, personal fees from Horizon, personal fees from Selecta, personal fees from Janssen, personal fees from Abbvie, personal fees from Kowa, personal fees from Dyve BioSciences, personal fees from Arthrosi, outside the submitted work. LABJ reports to be Scientific Advisory Board member of Olatec Therapeutics LLC. A-KT reports personal fees from Speakers fees for Novartis Pharma, Ardea Biosience, Astra Zeneca, Gruenenthal, Berlin Chemie Menarini, outside the submitted work., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Cerium oxide nanoparticles (CeNPs) have been shown to exhibit antioxidant capabilities, but their efficiency in scavenging reactive oxygen species (ROS) and the underlying mechanisms are not yet well understood. In this study, cerium dioxide nanoparticles (CeNPs) and nanorods (CeNRs) were found to exhibit much stronger scavenging activity than ·OH generation in phosphate buffered saline (PBS) and surrogate lung fluid (SLF). The larger surface area and higher defect density of CeNRs may lead to higher ·OH scavenging activity than for CeNPs. These insights are important to understand the redox activity of cerium nanomaterials and provide clues to the role of CeNPs in biological and environmental processes., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article.

Introduction: A minority of patients with sporadic early-onset Alzheimer's disease (AD) exhibit de novo germ line mutations in the autosomal dominant genes such as APP, PSEN1, or PSEN2. We hypothesized that negatively screened patients may harbor somatic variants in these genes., Methods: We applied an ultrasensitive approach based on single-molecule molecular inversion probes followed by deep next generation sequencing of 11 genes to 100 brain and 355 blood samples from 445 sporadic patients with AD (>80% exhibited an early onset, <66 years)., Results: We identified and confirmed nine somatic variants (allele fractions: 0.2%-10.8%): two APP, five SORL1, one NCSTN, and one MARK4 variants by independent amplicon-based deep sequencing., Discussion: Two of the SORL1 variant might have contributed to the disease, the two APP variants were interpreted as likely benign and the other variants remained of unknown significance. Somatic variants in the autosomal dominant AD genes may not be a common cause of sporadic AD, including early onset cases., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

In a Dutch consanguineous family with recessively inherited nonsyndromic hearing impairment (HI), homozygosity mapping combined with whole-exome sequencing revealed a MPZL2 homozygous truncating variant, c.72del (p.Ile24Metfs ∗ 22). By screening a cohort of phenotype-matched subjects and a cohort of HI subjects in whom WES had been performed previously, we identified two additional families with biallelic truncating variants of MPZL2. Affected individuals demonstrated symmetric, progressive, mild to moderate sensorineural HI. Onset of HI was in the first decade, and high-frequency hearing was more severely affected. There was no vestibular involvement. MPZL2 encodes myelin protein zero-like 2, an adhesion molecule that mediates epithelial cell-cell interactions in several (developing) tissues. Involvement of MPZL2 in hearing was confirmed by audiometric evaluation of Mpzl2-mutant mice. These displayed early-onset progressive sensorineural HI that was more pronounced in the high frequencies. Histological analysis of adult mutant mice demonstrated an altered organization of outer hair cells and supporting cells and degeneration of the organ of Corti. In addition, we observed mild degeneration of spiral ganglion neurons, and this degeneration was most pronounced at the cochlear base. Although MPZL2 is known to function in cell adhesion in several tissues, no phenotypes other than HI were found to be associated with MPZL2 defects. This indicates that MPZL2 has a unique function in the inner ear. The present study suggests that deleterious variants of Mplz2/MPZL2 affect adhesion of the inner-ear epithelium and result in loss of structural integrity of the organ of Corti and progressive degeneration of hair cells, supporting cells, and spiral ganglion neurons., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The present study assessed the reoccurrence of myocardial ischemia after withholding electrical neurostimulation. After randomization, in the study or withdrawal group, spinal cord stimulation (SCS) was set active during the first 4 weeks, followed by 4 weeks of withholding stimulation. In the control group, SCS was switched off during 4 weeks before the end of the study. The control group had no crossover period. Measurements were done at baseline, then after 4 and 8 weeks. The first periods at 4 weeks of each sequence of both groups were compared. In addition, a comparison of clinical variables was performed between the study group 4 weeks after withholding stimulation and the control group 4 weeks following randomization. A total number of 24 patients with refractory angina and an implanted spinal cord stimulator were included in the study (n = 12) and control group. Angina pectoris complaints, nitroglycerin intake, ischemia, and heart rate variability using 48-hour ambulatory electrocardiographic monitoring were assessed. In addition, neurohormonal status and symptom-limited aerobic capacity were evaluated. There was no increase of anginal complaints or ischemia after withholding stimulation. Neurohormonal levels and aerobic capacity were not altered. We conclude that there is no adverse clinical rebound phenomenon after withholding neurostimulation in patients with refractory angina pectoris.