Analysis of human serum and urine for tentative identification of potentially carcinogenic pesticide-associated N-nitroso compounds using high-resolution mass spectrometry.

Human serum and urine samples were analyzed for a suite of nitrosatable pesticides and potentially carcinogenic pesticide-associated N-nitroso (PANN) compounds. Formation of PANN compounds may occur in vivo after consumption of food or water containing trace amounts of nitrosatable pesticide residues and nitrate. Using a modified version of the Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) method, nine nitrosatable pesticides and byproducts were extracted from serum and urine from 64 individuals from two different sample populations in Atlantic Canada: (i) Prince Edward Island, a region where nitrate and trace amounts of nitrosatable pesticides have been detected in groundwater; and (ii) Halifax, Nova Scotia, a non-agricultural urban area. Samples were then analyzed using ultra-high pressure liquid chromatography (UHPLC) coupled with high-resolution accurate mass (HRAM) single-stage orbitrap mass spectrometry (MS), which allows for semi-targeted analysis and tentative identification of a virtually limitless number of exposure biomarkers. Two nitrosatable target analytes, ethylenethiourea (ETU) and 3,5,6-trichloro-2-pyridinol (TCPy) were found in serum, while atrazine (ATR) and ETU were detected in urine. Five and six PANN compounds were tentatively identified in serum and urine, respectively. The two PANN compounds that were most frequently tentatively identified in serum were N-nitroso dimethoate (N-DIM) and N-nitroso omethoate (N-OME) with detection frequencies of 78% and 95%, respectively. This is the first biomonitoring study of its kind to investigate PANN compounds in human serum and urine.

Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease.

Defective mitochondrial distribution in neurons is proposed to cause ATP depletion and calcium-buffering deficiencies that compromise cell function. However, it is unclear whether aberrant mitochondrial motility and distribution alone are sufficient to cause neurological disease. Calcium-binding mitochondrial Rho (Miro) GTPases attach mitochondria to motor proteins for anterograde and retrograde transport in neurons. Using two new KO mouse models, we demonstrate that Miro1 is essential for development of cranial motor nuclei required for respiratory control and maintenance of upper motor neurons required for ambulation. Neuron-specific loss of Miro1 causes depletion of mitochondria from corticospinal tract axons and progressive neurological deficits mirroring human upper motor neuron disease. Although Miro1-deficient neurons exhibit defects in retrograde axonal mitochondrial transport, mitochondrial respiratory function continues. Moreover, Miro1 is not essential for calcium-mediated inhibition of mitochondrial movement or mitochondrial calcium buffering. Our findings indicate that defects in mitochondrial motility and distribution are sufficient to cause neurological disease.

Trajectories of the socioeconomic gradient of mental health: Results from the CLSA COVID-19 Questionnaire Study.

As the coronavirus disease (COVID-19) pandemic prolongs, documenting trajectories of the socioeconomic gradient of mental health is important. We describe changes in the prevalence and absolute and relative income-related inequalities of mental health between April and December 2020 in Canada. We used data from the Canadian Longitudinal Study on Aging (CLSA) COVID-19 Questionnaire Study and the pre-pandemic CLSA Follow-up 1. We estimated the prevalence proportion, the concentration index (relative inequality), and the generalized concentration index (absolute inequality) for anxiety and self-reported feeling generally unwell at multiple points in April-December 2020, overall, by sex and age group, by region, and among those who reported poor or fair overall health and mental health pre-pandemic. Overall, the prevalence of anxiety remained unchanged (22.45 to 22.10%, p = 0.231), but self-reported feeling generally unwell decreased (9.83 to 5.94%, p = 0.004). Relative and absolute income-related inequalities were unchanged for both anxiety and self-reported feeling generally unwell, with exceptions of an increased concentration of self-reported feeling generally unwell among the poor, measured by the concentration index, overall (-0.054 to -0.115, p = 0.004) and in Ontario (-0.035 to -0.123, p = 0.047) and British Columbia (-0.055 to -0.141, p = 0.044). The COVID-19 pandemic appeared to neither exacerbate nor ameliorate existing income-related inequalities in mental health among older adults in Canada between April and December 2020. Continued monitoring of inequalities is necessary.

Does the inclusion of vehicle impoundment in provincial short-term administrative driver's license suspension programs reduce total and alcohol-related fatal collisions in Canada?

Objectives: To determine (1) whether the implementation of vehicle impoundment as part of provincial short-term administrative driver licensing suspension (ADLS) programs significantly reduced total and alcohol-related collision fatalities, and (2) if provinces with vehicle impoundment as part of their short-term ADLS programs see greater reductions in total and alcohol-related fatal collisions when compared to provinces without a vehicle impoundment law.Methods: Data on monthly total and alcohol-related fatal collisions from January 2005 to December 2016 are drawn from British Columbia (BC), Alberta (AB), Saskatchewan (SK), Manitoba (MB) and Ontario (ON). Changepoint time series analysis of fatal crashes is employed to detect within-province differences after implementing short-term impoundment programs, and between province differences comparing provinces with short-term impoundment programs (BC, introduced October 2010; AB, introduced July 2012; and SK, introduced July 2014) and those without (ON and MB). Outcome measures are the monthly per capita total and alcohol-related fatal collisions.Results: A significant reduction in per-capita alcohol-related fatal crashes was observed in British Columbia (-47.4%) in the period following the adoption of vehicle impoundment in their short-term ADLS. A significant decrease was also observed in Alberta (-37.5%), though this trend began prior to policy change; no significant effect was observed in per capita alcohol-related fatal crashes rates in Saskatchewan (-6.1%) in the two years following the introduction of vehicle impoundment. Ontario and Manitoba, two provinces without mandatory vehicle impoundment laws, also experienced significant reductions in per-capita alcohol-related fatal crashes between 2005 and 2016 (-36.4% and -35%, respectively).Conclusions: While mandatory vehicle impoundment programs for driving in the "warn" range (0.05%-0.08% BAC) have shown success in reducing fatal crashes in British Columbia, similar reductions in two other provinces with short-term vehicle impoundment were not observed. Moreover, large reductions in fatal crashes were observed in two provinces without vehicle impoundment as part of their short-term ADLS programs. Collectively, these findings suggest that vehicle impoundment, alone, has limited impact on fatal crash rates and that other factors help to explain the observed trends. Further analysis of new vehicle impoundment programs is warranted.

Stress Granule-Inducing Eukaryotic Translation Initiation Factor 4A Inhibitors Block Influenza A Virus Replication.

Eukaryotic translation initiation factor 4A (eIF4A) is a helicase that facilitates assembly of the translation preinitiation complex by unwinding structured mRNA 5' untranslated regions. Pateamine A (PatA) and silvestrol are natural products that disrupt eIF4A function and arrest translation, thereby triggering the formation of cytoplasmic aggregates of stalled preinitiation complexes known as stress granules (SGs). Here we examined the effects of eIF4A inhibition by PatA and silvestrol on influenza A virus (IAV) protein synthesis and replication in cell culture. Treatment of infected cells with either PatA or silvestrol at early times post-infection resulted in SG formation, arrest of viral protein synthesis and failure to replicate the viral genome. PatA, which irreversibly binds to eIF4A, sustained long-term blockade of IAV replication following drug withdrawal, and inhibited IAV replication at concentrations that had minimal cytotoxicity. By contrast, the antiviral effects of silvestrol were fully reversible; drug withdrawal caused rapid SG dissolution and resumption of viral protein synthesis. IAV inhibition by silvestrol was invariably associated with cytotoxicity. PatA blocked replication of genetically divergent IAV strains, suggesting common dependence on host eIF4A activity. This study demonstrates that the core host protein synthesis machinery can be targeted to block viral replication.