The search for the genetic factors underlying complex neuropsychiatric disorders has proceeded apace in the past decade. Despite some advances in identifying genetic variants associated with psychiatric disorders, most variants have small individual contributions to risk. By contrast, disease risk increase appears to be less subtle for disease-predisposing environmental insults. In this study, we sought to identify associations between environmental pollution and risk of neuropsychiatric disorders. We present exploratory analyses of 2 independent, very large datasets: 151 million unique individuals, represented in a United States insurance claims dataset, and 1.4 million unique individuals documented in Danish national treatment registers. Environmental Protection Agency (EPA) county-level environmental quality indices (EQIs) in the US and individual-level exposure to air pollution in Denmark were used to assess the association between pollution exposure and the risk of neuropsychiatric disorders. These results show that air pollution is significantly associated with increased risk of psychiatric disorders. We hypothesize that pollutants affect the human brain via neuroinflammatory pathways that have also been shown to cause depression-like phenotypes in animal studies.

Voltage‐gated Na+ current is reduced by acid solution. Protons reduce peak Na+ conductance by lowering single channel conductance and shift the voltage range of gating by neutralizing surface charges. Structure‐function studies identify six carboxyls and a lysine in the channel's outer vestibule. We examined the roles of the superficial ring of carboxyls in acid block of Nav1.4 (the rat skeletal muscle Na+ channel isoform) by measuring the effects of their neutralization or their substitution by lysine on sensitivity to acid solutions, using the two‐micropipette voltage clamp in Xenopus oocytes. Alteration of the outer ring of carboxylates had little effect on the voltage for half‐activation of Na+ current, as if they are distant from the channels' voltage sensors. The mutations did not abolish proton block; rather, they all shifted the pKa (‐log of the dissociation constant) in the acid direction. Effects of neutralization on pKa were not identical for different mutations, with E758Q > D1241A > D1532N > E403Q. E758K showed double the effect of E758Q, and the other lysine mutations all produced larger effects than the neutralizing mutations. Calculation of the electrostatic potential produced by these carboxylates using a pore model showed that the pKa values of carboxylates of Glu‐403, Glu‐758, and Asp‐1532 are shifted to values similar to the experimentally measured pKa. Calculations also predict the experimentally observed changes in pKa that result from mutational neutralization or introduction of a positive charge. We propose that proton block results from partial protonation of these outer ring carboxylates and that all of the carboxylates contribute to a composite Na+ site.

Protons are potent physiological modifiers of voltage-gated Na + channels, shifting the voltage range of channel gating and reducing current magnitude (pK a ∼6). We recently showed that proton block of the skeletal muscle isoform (Na V 1.4) resulted from protonation of the four superficial carboxylates in the outer vestibule of the channel. We concluded that the large local negative electrostatic field shifted the outer vestibule carboxylate pK a into the physiological range. However, block was not complete; the best-fit titration curves yielded an acid pH asymptote of 10-15%, suggesting that the selectivity filter carboxylates may not be protonated. Using HEK 293 cells stably expressing different isoforms, each with varying channel density, we demonstrate that a pH-independent current is found in Na V 1.4, but not in the cardiac isoform (Na V 1.5). Mutational studies showed that absence of the pH-independent current in Na V 1.5 could be ascribed to the cysteine in domain I, just above the selectivity filter aspartate (Cys373). We suggest that this cysteine can be protonated in acid solution to produce a positive charge that blocks the pore. Competition between protons and Na + did not exist for Na + concentrations between 1 and 140 mM. The residual current in acid solution, when the cysteine is absent, confirms that over the range of pH values that can be achieved physiologically, the selectivity filter carboxylates are not protonated. The pH-independent current helps to protect activation of skeletal muscle during the acidosis that occurs during exercise.

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BackgroundInjection drug use is a growing major public health concern. Injection drug users (IDUs) have a higher incidence of co-morbidities including HIV, Hepatitis, and other infections. An effective humoral response is critical for optimal homeostasis and protection from infection; however, the impact of injection heroin use on humoral immunity is poorly understood. We hypothesized that IDUs have altered B cell and antibody profiles.Methods and FindingsA comprehensive systems biology-based cross-sectional assessment of 130 peripheral blood B cell flow cytometry- and plasma- based features was performed on HIV-/Hepatitis C-, active heroin IDUs who participated in a syringe exchange program (n = 19) and healthy control subjects (n = 19). The IDU group had substantial polydrug use, with 89% reporting cocaine injection within the preceding month. IDUs exhibited a significant, 2-fold increase in total B cells compared to healthy subjects, which was associated with increased activated B cell subsets. Although plasma total IgG titers were similar between groups, IDUs had significantly higher IgG3 and IgG4, suggestive of chronic B cell activation. Total IgM was also increased in IDUs, as well as HIV Envelope-specific IgM, suggestive of increased HIV exposure. IDUs exhibited numerous features suggestive of systemic inflammation, including significantly increased plasma sCD40L, TNF-α, TGF-α, IL-8, and ceramide metabolites. Machine learning multivariate analysis distilled a set of 10 features that classified samples based on group with absolute accuracy.ConclusionsThese results demonstrate broad alterations in the steady-state humoral profile of IDUs that are associated with increased systemic inflammation. Such dysregulation may impact the ability of IDUs to generate optimal responses to vaccination and infection, or lead to increased risk for inflammation-related co-morbidities, and should be considered when developing immune-based interventions for this growing population.