A Question of Identity: Genes that Distinguish Motoneurons from Interneurons

The question of how a single cell can grow, divide, and ultimately acquire a distinct function within an adult animal is central to the field of developmental biology. An elegant way to address this question is by studying the specification of a specific cell type, for example, vertebrate motoneurons. For an animal to be able to move and behave appropriately, individual motoneurons (MNs) must correctly innervate specific muscles. For this to happen, MNs must first be specified and then must differentiate into distinct subtypes, each of which is classified in part by the muscle it innervates. MN subtype specification is dependent on both the acquisition of MN-specific characteristics as well as the failure to acquire characteristics specific to interneurons, cells that only innervate other neurons. The entire process of specification is initiated in progenitor cells and relies on the correct spatial and temporal expression of specific genes. Previous work in various vertebrate models has identified some of the key genes involved in MN specification, most notably transcription factors such as olig2, nkx6s, lhxs, mnxs, and islet1. In this dissertation, I use the zebrafish model to demonstrate novel roles in MN specification for two of these families of transcription factors - the lhxs and the mnxs. I provide evidence that both lhx3 and lhx4 are necessary for normal MN and ventral interneuron (IN) development and work by preventing MNs from expressing IN-specific characteristics. I also show that mnx1, mnx2a, and mnx2b are necessary in MNs both to promote the acquisition of some MN subtype-specific characteristics and to prevent the acquisition of some IN-specific characteristics and appear to be working in part through interactions with islet1. Finally, I identify an intermediate filament gene, inab, as being expressed in a subset of zebrafish MNs and a ventral IN and as having a potential role in the axon outgrowth of a specific MN subtype. Together, this work provides evidence for a mechanism of MN specification dependent on the expression of genes that both promote aspects of MN fate and inhibit aspects of IN fate. This dissertation includes previously unpublished co-authored material

Impacts of Subway System Modifications on Air Quality in Subway Platforms and Trains.

Subway PM₂.₅ can be substantially sourced from the operation of the system itself. Improvements in subway air quality may be possible by examining the potential to reduce these emissions. To this end, PM₂.₅ was measured on the trains and station platforms of the Toronto subway system. A comparison with previously published data for this system reveals significant changes in below ground platform PM₂.₅. A reduction of nearly one-third (ratio (95% CI): 0.69 (0.63, 0.75)) in PM₂.₅ from 2011 to 2018 appears to have resulted from a complete modernization of the rolling stock on one subway line. In contrast, below ground platform PM₂.₅ for another line increased by a factor of 1.48 (95% CI; 1.42, 1.56). This increase may be related to an increase in emergency brake applications, the resolution of which coincided with a large decrease in PM₂.₅ concentrations on that line. Finally, platform PM₂.₅ in two newly opened stations attained, within one year of operation, typical concentrations of the neighboring platforms installed in 1963. Combined, these findings suggest that the production of platform PM₂.₅ is localized and hence largely freshly emitted. Further, PM₂.₅ changed across this subway system due to changes in its operation and rolling stock. Thus, similar interventions applied intentionally may prove to be equally effective in reducing PM₂.₅. Moreover, establishing a network of platform PM₂.₅ monitors is recommended to monitor ongoing improvements and identify impacts of future system changes on subway air quality. This would result in a better understanding of the relationship between the operations and air quality of subways

Response to Comment on "following Molecular Mobility during Chemical Reactions: No Evidence for Active Propulsion" and "molecular Diffusivity of Click Reaction Components: The Diffusion Enhancement Question"

In their Comment (DOI: 10.1021/jacs.2c02965) on two related publications by our groups (J. Am. Chem. Soc. 2021, 143, 20884-20890; DOI: 10.1021/jacs.1c09455) and another (J. Am. Chem. Soc. 2022, 144, 1380-1388; DOI: 10.1021/jacs.1c11754), Huang and Granick discuss the diffusion NMR measurements of molecules during a copper-catalyzed azide-alkyne cycloaddition (CuAAC) "click"reaction. Here we respond to these comments and maintain that no diffusion enhancement was observed for any species during the reaction. We show that the relaxation agent does not interfere with the CuAAC reaction kinetics nor the diffusion of the molecules involved. Similarly, the gradient pulse length and diffusion time do not affect the diffusion coefficients. Peak overlap was completely removed in our study with the use of hydrazine as the reducing agent. The steady-state assumption does not hold for these diffusion measurements that take several minutes, which is the reason monotonic gradient orders are not suitable. Finally, we discuss the other reactions where similar changes in diffusion have been claimed. Our conclusions are fully supported by the results represented in our original JACS Article and the corresponding Supporting Information

Household determinants of biocontaminant exposures in Canadian homes

Exposure to biocontaminants, such as dust mites, animal dander, bacteria, and mold, is associated with a range of health effects. This study identified household characteristics associated with indoor biocontaminant loadings in four Canadian cities. Floor dust was collected in 290 Canadian homes in Edmonton, Halifax, Montreal, and Windsor. The dust samples were analyzed for house dust mite allergens (Der f 1 and Der p 1), cat allergen (Fel d 1), cockroach allergen (Bla g 1), beta-(1,3)-D-glucan, and endotoxin. Household information was obtained through questionnaires and home inspections. We performed univariate and multivariate analyses to identify household determinants of biocontaminant loadings and mold odor presence. We observed large regional variations for all biocontaminants, except for cockroach allergen. The ranges of the contaminants measured in loadings and concentrations were similar to that of previous Canadian studies. Household characteristics including presence of carpeting, low floor cleaning frequency, older home age, presence of pets, and indoor relative humidity above 45% were positively associated with the presence of multiple indoor biocontaminants. High floor cleaning frequency and use of dehumidifiers were negatively associated with the presence of multiple indoor biocontaminants. Mold odor was positively associated with older home age, past water damage, and visible mold growth

Predictors of Indoor Air Concentrations in Smoking and Non-Smoking Residences

Indoor concentrations of air pollutants (benzene, toluene, formaldehyde, acetaldehyde, acrolein, nitrogen dioxide, particulate matter, elemental carbon and ozone) were measured in residences in Regina, Saskatchewan, Canada. Data were collected in 106 homes in winter and 111 homes in summer of 2007, with 71 homes participating in both seasons. In addition, data for relative humidity, temperature, air exchange rates, housing characteristics and occupants’ activities during sampling were collected. Multiple linear regression analysis was used to construct season-specific models for the air pollutants. Where smoking was a major contributor to indoor concentrations, separate models were constructed for all homes and for those homes with no cigarette smoke exposure. The housing characteristics and occupants’ activities investigated in this study explained between 11% and 53% of the variability in indoor air pollutant concentrations, with ventilation, age of home and attached garage being important predictors for many pollutants

Spatiotemporal Variations in Ambient Ultrafine Particles and the Incidence of Childhood Asthma.

Rationale: Little is known regarding the impact of ambient ultrafine particles (UFPs; <0.1 μm) on childhood asthma development. Objectives: To examine the association between prenatal and early postnatal life exposure to UFPs and development of childhood asthma. Methods: A total of 160,641 singleton live births occurring in the City of Toronto, Canada between April 1, 2006, and March 31, 2012, were identified from a birth registry. Associations between exposure to ambient air pollutants and childhood asthma incidence (up to age 6) were estimated using random effects Cox proportional hazards models, adjusting for personal- and neighborhood-level covariates. We investigated both single-pollutant and multipollutant models accounting for coexposures to particulate matter ≤2.5 μm in aerodynamic diameter (PM2.5) and NO2. Measurements and Main Results: We identified 27,062 children with incident asthma diagnosis during the follow-up. In adjusted models, second-trimester exposure to UFPs (hazard ratio per interquartile range increase, 1.09; 95% confidence interval, 1.06-1.12) was associated with asthma incidence. In models additionally adjusted for PM2.5 and nitrogen dioxide, UFPs exposure during the second trimester of pregnancy remained positively associated with childhood asthma incidence (hazard ratio per interquartile range increase, 1.05; 95% confidence interval, 1.01-1.09). Conclusions: This is the first study to evaluate the association between perinatal exposure to UFPs and the incidence of childhood asthma. Exposure to UFPs during a critical period of lung development was linked to the onset of asthma in children, independent of PM2.5 and NO2

Barriers and enablers to implementing antenatal magnesium sulphate for fetal neuroprotection guidelines: a study using the theoretical domains framework

BACKGROUND: Strong evidence supports administration of magnesium sulphate prior to birth at less than 30 weeks' gestation to prevent very preterm babies dying or developing cerebral palsy. This study was undertaken as part of The WISH (Working to Improve Survival and Health for babies born very preterm) Project, to assess health professionals' self-reported use of antenatal magnesium sulphate, and barriers and enablers to implementation of 2010 Australian and New Zealand clinical practice guidelines. METHODS: Semi-structured, one-to-one interviews were conducted with obstetric and neonatal consultants and trainees, and midwives in 2011 (n = 24) and 2012-2013 (n = 21) at the Women's and Children's Hospital, South Australia. Transcribed interview data were coded using the Theoretical Domains Framework (describing 14 domains related to behaviour change) for analysis of barriers and enablers. RESULTS: In 2012-13, health professionals more often reported 'routinely' or 'sometimes' administering or advising their colleagues to administer magnesium sulphate for fetal neuroprotection (86% in 2012-13 vs. 46% in 2011). 'Knowledge and skills', 'memory, attention and decision processes', 'environmental context and resources', 'beliefs about consequences' and 'social influences' were key domains identified in the barrier and enabler analysis. Perceived barriers were the complex administration processes, time pressures, and the unpredictability of preterm birth. Enablers included education for staff and women at risk of very preterm birth, reminders and 'prompts', simplified processes for administration, and influential colleagues. CONCLUSIONS: This study has provided valuable data on barriers and enablers to implementing magnesium sulphate for fetal neuroprotection, with implications for designing and modifying future behaviour change strategies, to ensure optimal uptake of this neuroprotective therapy for very preterm infants.Emily Bain, Tanya Bubner, Pat Ashwood, Emer Van Ryswyk, Lucy Simmonds, Sally Reid, Philippa Middleton and Caroline A. Crowthe

High-resolution spatial and spatiotemporal modelling of air pollution using fixed site and mobile monitoring in a Canadian city.

The development of high-resolution spatial and spatiotemporal models of air pollutants is essential for exposure science and epidemiological applications. While fixed-site sampling has conventionally provided input data for statistical predictive models, the evolving mobile monitoring method offers improved spatial resolution, ideal for measuring pollutants with high spatial variability such as ultrafine particles (UFP). The Quebec Air Pollution Exposure and Epidemiology (QAPEE) study measured and modelled the spatial and spatiotemporal distributions of understudied pollutants, such as UFPs, black carbon (BC), and brown carbon (BrC), along with fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) in Quebec City, Canada. We conducted a combined fixed-site (NO2 and O3) and mobile monitoring (PM2.5, BC, BrC, and UFPs) campaign over 10-months. Mobile monitoring routes were monitored on a weekly basis between 8am-10am and designed using location/allocation modelling. Seasonal fixed-site sampling campaigns captured continuous 24-h measurements over two-week periods. Generalized Additive Models (GAMs), which combined data on pollution concentrations with spatial, temporal, and spatiotemporal predictor variables were used to model and predict concentration surfaces. Annual models for PM2.5, NO2, O3 as well as seven of the smallest size fractions in the UFP range, had high out of sample predictive accuracy (range r2: 0.54-0.86). Varying spatial patterns were observed across UFP size ranges measured as Particle Number Counts (PNC). The monthly spatiotemporal models for PM2.5 (r2 = 0.49), BC (r2 = 0.27), BrC (r2 = 0.29), and PNC (r2 = 0.49) had moderate or moderate-low out of sample predictive accuracy. We conducted a sensitivity analysis and found that the minimum number of 'n visits' (mobile monitoring sessions) required to model annually representative air pollution concentrations was between 24 and 32 visits dependent on the pollutant. This study provides a single source of exposure models for a comprehensive set of air pollutants in Quebec City, Canada. These exposure models will feed into epidemiological research on the health impacts of ambient UFPs and other pollutants

Sleep disturbances in women with polycystic ovary syndrome: prevalence, pathophysiology, impact and management strategies

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting the reproductive, metabolic and psychological health of women. Clinic-based studies indicate that sleep disturbances and disorders including obstructive sleep apnea and excessive daytime sleepiness occur more frequently among women with PCOS compared to comparison groups without the syndrome. Evidence from the few available population-based studies is supportive. Women with PCOS tend to be overweight/obese, but this only partly accounts for their sleep problems as associations are generally upheld after adjustment for body mass index; sleep problems also occur in women with PCOS of normal weight. There are several, possibly bidirectional, pathways through which PCOS is associated with sleep disturbances. The pathophysiology of PCOS involves hyperandrogenemia, a form of insulin resistance unique to affected women, and possible changes in cortisol and melatonin secretion, arguably reflecting altered hypothalamic-pituitary-adrenal function. Psychological and behavioral pathways are also likely to play a role, as anxiety and depression, smoking, alcohol use and lack of physical activity are also common among women with PCOS, partly in response to the distressing symptoms they experience. The specific impact of sleep disturbances on the health of women with PCOS is not yet clear; however, both PCOS and sleep disturbances are associated with deterioration in cardiometabolic health in the longer term and increased risk of type 2 diabetes. Both immediate quality of life and longer-term health of women with PCOS are likely to benefit from diagnosis and management of sleep disorders as part of interdisciplinary health care.Renae C Fernandez, Vivienne M Moore, Emer M Van Ryswyk, Tamara J Varcoe, Raymond J Rodgers, Wendy A March, Lisa J Moran, Jodie C Avery, R Doug McEvoy, Michael J Davie

Prairie strips improve biodiversity and the delivery of multiple ecosystem services from corn–soybean croplands

Loss of biodiversity and degradation of ecosystem services from agricultural lands remain important challenges in the United States despite decades of spending on natural resource management. To date, conservation investment has emphasized engineering practices or vegetative strategies centered on monocultural plantings of nonnative plants, largely excluding native species from cropland. In a catchment-scale experiment, we quantified the multiple effects of integrating strips of native prairie species amid corn and soybean crops, with prairie strips arranged to arrest run-off on slopes. Replacing 10% of cropland with prairie strips increased biodiversity and ecosystem services with minimal impacts on crop production. Compared with catchments containing only crops, integrating prairie strips into cropland led to greater catchment-level insect taxa richness (2.6-fold), pollinator abundance (3.5-fold), native bird species richness (2.1-fold), and abundance of bird species of greatest conservation need (2.1-fold). Use of prairie strips also reduced total water runoff from catchments by 37%, resulting in retention of 20 times more soil and 4.3 times more phosphorus. Corn and soybean yields for catchments with prairie strips decreased only by the amount of the area taken out of crop production. Social survey results indicated demand among both farming and nonfarming populations for the environmental outcomes produced by prairie strips. If federal and state policies were aligned to promote prairie strips, the practice would be applicable to 3.9 million ha of cropland in Iowa alone