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Most murine models of fungal exposure are based on the delivery of uncharacterized extracts or liquid conidia suspensions using aspiration or intranasal approaches. Studies that model exposure to dry fungal aerosols using whole body inhalation have only recently been described. In this study, we aimed to characterize pulmonary immune responses following repeated inhalation of conidia utilizing an acoustical generator to deliver dry fungal aerosols to mice housed in a nose only exposure chamber. Immunocompetent female BALB/cJ mice were exposed to conidia derived from Aspergillus fumigatus wild-type (WT) or a melanin-deficient (Δalb1) strain. Conidia were aerosolized and delivered to mice at an estimated deposition dose of 1×105 twice a week for 4 weeks (8 total). Histopathological and immunological endpoints were assessed 4, 24, 48, and 72 hours after the final exposure. Histopathological analysis showed that conidia derived from both strains induced lung inflammation, especially at 24 and 48 hour time points. Immunological endpoints evaluated in bronchoalveolar lavage fluid (BALF) and the mediastinal lymph nodes showed that exposure to WT conidia led to elevated numbers of macrophages, granulocytes, and lymphocytes. Importantly, CD8+ IL17+ (Tc17) cells were significantly higher in BALF and positively correlated with germination of A. fumigatus WT spores. Germination was associated with specific IgG to intracellular proteins while Δalb1 spores elicited antibodies to cell wall hydrophobin. These data suggest that inhalation exposures may provide a more representative analysis of immune responses following exposures to environmentally and occupationally prevalent fungal contaminants.

Pregnancy is a vulnerable time with significant cardiovascular changes that can lead to adverse outcomes, which can extend into the postpartum window. Exposure to emissions from electronic cigarettes (Ecig), commonly known as “vaping,” has an adverse impact on cardiovascular function during pregnancy and post-natal life of offspring, but the postpartum effects on maternal health are poorly understood. We used a Sprague Dawley rat model, where pregnant dams are exposed to Ecigs between gestational day (GD)2-GD21 to examine postpartum consequences. Litter and dam health were monitored during the weaning period, and maternal vascular and endocrine function were assessed after weaning. Exposure to Ecig emissions during pregnancy led to fetal losses (i.e., reabsorption in utero) and reduced survival of pups during weaning compared to controls (air-exposed dams). We find that maternal vaping during pregnancy, with or without nicotine (or flavoring) results in maternal vascular and hormonal dysfunction (i.e., reduced prolactin, increased expression of sirtuin 1 deacetylase in the brain). Both 5 and 30W Ecig aerosol exposures resulted in significant impairment of middle cerebral artery reactivity to acetylcholine-mediated dilation (decreasing ~ 22 and ~ 50%, respectively). We also observed an increase in the number of extracellular vesicles (EVs) in plasma from 30-W group that persists up to 3-week postpartum and that these EVs impaired endothelial cell function when applied to in vitro and ex vivo assays. Our data suggest (1) Ecig vaping, even without nicotine or flavorings, during pregnancy alters maternal circulating factors that influence maternal and fetal health, (2) circulating EVs may contribute to the etiology of vascular dysfunction, and (3) that the window for recovery from vascular dysfunction in the dam is likely to be longer than the exposure window. Graphical Abstract

Background Involuntary cough is a classic symptom of many respiratory diseases. The act of coughing serves a variety of functions such as clearing the airways in response to respiratory irritants or aspiration of foreign materials. It has been pointed out that a cough results in substantial stresses on the body which makes voluntary cough a useful tool in physical diagnosis. Methods In the present study, fifty-two normal subjects and sixty subjects with either obstructive or restrictive lung disorders were asked to perform three individual voluntary coughs. The objective of the study was to evaluate if the airflow and sound characteristics of a voluntary cough could be used to distinguish between normal subjects and subjects with lung disease. This was done by extracting a variety of features from both the cough airflow and acoustic characteristics and then using a classifier that applied a reconstruction algorithm based on principal component analysis. Results Results showed that the proposed method for analyzing voluntary coughs was capable of achieving an overall classification performance of 94% and 97% for identifying abnormal lung physiology in female and male subjects, respectively. An ROC analysis showed that the sensitivity and specificity of the cough parameter analysis methods were equal at 98% and 98% respectively, for the same groups of subjects. Conclusion A novel system for classifying coughs has been developed. This automated classification system is capable of accurately detecting abnormal lung function based on the combination of the airflow and acoustic properties of voluntary cough.

Inhalation of ultrafine particles (UFP) mediates systemic vascular impairment which is, in part, driven by elevated rates of oxidant generation. One significant source of oxidant production in the vascular compartment is the purine catabolizing enzyme, xanthine oxidoreductase (XOR). However, mechanisms linking XOR and/or endothelial glycosaminoglycan (GAG)-sequestered XOR to vessel dysfunction allied to UFP inhalation remain underexplored. Based on known interactions between UFP and the liver, we hypothesized that exposure could lead to hepatic release of XOR to the circulation which subsequently contributes to vascular impairment. Utilizing our murine hepatocyte-specific XOR knockout (XOR ) model (loss of function) in conjunction with reintroducing exogenous XOR (restoration of function) we demonstrate a specific role for liver-derived XOR in the pathogenesis of UFP-induced vascular impairment. Exposure of mice as well as exposure of hepatocytes to our model UFP, nano titanium dioxide (nTiO ) results in the upregulation and active release of XOR. Drinking water supplemented with the XOR inhibitor febuxostat or nitrite ( ) partially prevented nTiO -induced impairment of vascular reactivity. Interestingly, nitrite appears to cause a down-regulation of hepatic XOR. XOR mice were partially protected against both impairment of endothelial dependent dilation and augmented angiotensin II constriction. To further demonstrate the role of circulating XOR in nTiO -induced impairment of vessel reactivity, XOR mice had circulating XOR restored by injection prior to exposure, which eliminated the protection of the hepatic knockout. It is important to note that acute restoration of intraluminal XOR in isolated vessels did not alter endothelial-dependent dilation or angiotensin II constriction. As such, we interrogated potential downstream mediators of XOR effects on endothelial function and found a decrease in the repressive trimethylation of lysine 9 on histone 3. Together these findings demonstrate that circulating XOR is a key contributor to endothelial dysfunction caused by UFP exposure. However, the impairment is not acute in nature and might involve epigenetic-mediated alterations in gene expression.

Most murine models of fungal exposure are based on the delivery of uncharacterized extracts or liquid conidia suspensions using aspiration or intranasal approaches. Studies that model exposure to dry fungal aerosols using whole body inhalation have only recently been described. In this study, we aimed to characterize pulmonary immune responses following repeated inhalation of conidia utilizing an acoustical generator to deliver dry fungal aerosols to mice housed in a nose only exposure chamber. Immunocompetent female BALB/cJ mice were exposed to conidia derived from Aspergillus fumigatus wild-type (WT) or a melanin-deficient ( Delta alb1) strain. Conidia were aerosolized and delivered to mice at an estimated deposition dose of 1105 twice a week for 4 weeks (8 total). Histopathological and immunological endpoints were assessed 4, 24, 48, and 72 hours after the final exposure. Histopathological analysis showed that conidia derived from both strains induced lung inflammation, especially at 24 and 48 hour time points. Immunological endpoints evaluated in bronchoalveolar lavage fluid (BALF) and the mediastinal lymph nodes showed that exposure to WT conidia led to elevated numbers of macrophages, granulocytes, and lymphocytes. Importantly, CD8+ IL17+ (Tc17) cells were significantly higher in BALF and positively correlated with germination of A. fumigatus WT spores. Germination was associated with specific IgG to intracellular proteins while Delta alb1 spores elicited antibodies to cell wall hydrophobin. These data suggest that inhalation exposures may provide a more representative analysis of immune responses following exposures to environmentally and occupationally prevalent fungal contaminants.

Receptor tyrosine kinase-like orphan receptors (ROR) 1 and 2 are atypical members of the receptor tyrosine kinase (RTK) family and have been associated with several human diseases. The vertebrate RORs contain an ATP binding domain that deviates from the consensus amino acid sequence, although the impact of this deviation on catalytic activity is not known and the kinase function of these receptors remains controversial. Recently, ROR2 was shown to signal through a Wnt responsive, β-catenin independent pathway and suppress a canonical Wnt/β-catenin signal. In this work we demonstrate that both ROR1 and ROR2 kinase domains are catalytically deficient while CAM-1, the C. elegans homolog of ROR, has an active tyrosine kinase domain, suggesting a divergence in the signaling processes of the ROR family during evolution. In addition, we show that substitution of the non-consensus residues from ROR1 or ROR2 into CAM-1 and MuSK markedly reduce kinase activity, while restoration of the consensus residues in ROR does not restore robust kinase function. We further demonstrate that the membrane-bound extracellular domain alone of either ROR1 or ROR2 is sufficient for suppression of canonical Wnt3a signaling, and that this domain can also enhance Wnt5a suppression of Wnt3a signaling. Based on these data, we conclude that human ROR1 and ROR2 are RTK-like pseudokinases.