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Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor (PTL). However, IUI does not invariably cause PTL. We hypothesized that quantitative and qualitative differences in immune response exist in subjects with or without PTL. To define the triggers for PTL, we developed rhesus macaque models of IUI driven by lipopolysaccharide (LPS) or live Escherichia coli . PTL did not occur in LPS challenged rhesus macaques, while E . coli– infected animals frequently delivered preterm. Although LPS and live E . coli both caused immune cell infiltration, E . coli– infected animals showed higher levels of inflammatory mediators, particularly interleukin 6 (IL-6) and prostaglandins, in the chorioamnion-decidua and amniotic fluid (AF). Neutrophil infiltration in the chorio-decidua was a common feature to both LPS and E . coli . However, neutrophilic infiltration and IL6 and PTGS2 expression in the amnion was specifically induced by live E . coli . RNA sequencing (RNA-seq) analysis of fetal membranes revealed that specific pathways involved in augmentation of inflammation including type I interferon (IFN) response, chemotaxis, sumoylation, and iron homeostasis were up-regulated in the E . coli group compared to the LPS group. Our data suggest that the intensity of the host immune response to IUI may determine susceptibility to PTL.

Summertime Arctic shipboard observations of oxygenated volatile organic compounds (OVOCs) such as organic acids, key precursors of climatically active secondary organic aerosol (SOA), are consistent with a novel source of OVOCs to the marine boundary layer via chemistry at the sea surface microlayer. Although this source has been studied in a laboratory setting, organic acid emissions from the sea surface microlayer have not previously been observed in ambient marine environments. Correlations between measurements of OVOCs, including high levels of formic acid, in the atmosphere (measured by an online high-resolution time-of-flight mass spectrometer) and dissolved organic matter in the ocean point to a marine source for the measured OVOCs. That this source is photomediated is indicated by correlations between the diurnal cycles of the OVOC measurements and solar radiation. In contrast, the OVOCs do not correlate with levels of isoprene, monoterpenes, or dimethyl sulfide. Results from box model calculations are consistent with heterogeneous chemistry as the source of the measured OVOCs. As sea ice retreats and dissolved organic carbon inputs to the Arctic increase, the impact of this source on the summer Arctic atmosphere is likely to increase. Globally, this source should be assessed in other marine environments to quantify its impact on OVOC and SOA burdens in the atmosphere, and ultimately on climate.

Despite growing evidence that the ocean is an important source of ice-nucleating particles (INPs) in the atmosphere, our understanding of the properties and concentrations of INPs in ocean surface waters remains limited. We have investigated INPs in sea surface microlayer and bulk seawater samples collected in the Canadian Arctic during the summer of 2016. Consistent with our 2014 studies, we observed that INPs were ubiquitous in the microlayer and bulk seawaters; heat and filtration treatments reduced INP activity, indicating that the INPs were likely heat-labile biological materials between 0.22 and 0.02 µm in diameter; there was a strong negative correlation between salinity and freezing temperatures; and concentrations of INPs could not be explained by chlorophyll a concentrations. Unique in the current study, the spatial distributions of INPs were similar in 2014 and 2016, and the concentrations of INPs were strongly correlated with meteoric water (terrestrial runoff plus precipitation). These combined results suggest that meteoric water may be a major source of INPs in the sea surface microlayer and bulk seawater in this region, or meteoric water may be enhancing INPs in this region by providing additional nutrients for the production of marine microorganisms. In addition, based on the measured concentrations of INPs in the microlayer and bulk seawater, we estimate that the concentrations of INPs from the ocean in the Canadian Arctic marine boundary layer range from approximately 10−4 to <10-6 L−1 at −10 ∘C.

The sea-surface microlayer and bulk seawater can contain ice-nucleating particles (INPs) and these INPs can be emitted into the atmosphere. Our current understanding of the properties, concentrations, and spatial and temporal distributions of INPs in the microlayer and bulk seawater is limited. In this study we investigate the concentrations and properties of INPs in microlayer and bulk seawater samples collected in the Canadian Arctic during the summer of 2014. INPs were ubiquitous in the microlayer and bulk seawater with freezing temperatures in the immersion mode as high as −14 °C. A strong negative correlation (R = −0. 7, p = 0. 02) was observed between salinity and freezing temperatures (after correction for freezing depression by the salts). One possible explanation is that INPs were associated with melting sea ice. Heat and filtration treatments of the samples show that the INPs were likely heat-labile biological materials with sizes between 0.02 and 0.2 µm in diameter, consistent with previous measurements off the coast of North America and near Greenland in the Arctic. The concentrations of INPs in the microlayer and bulk seawater were consistent with previous measurements at several other locations off the coast of North America. However, our average microlayer concentration was lower than previous observations made near Greenland in the Arctic. This difference could not be explained by chlorophyll a concentrations derived from satellite measurements. In addition, previous studies found significant INP enrichment in the microlayer, relative to bulk seawater, which we did not observe in this study. While further studies are needed to understand these differences, we confirm that there is a source of INP in the microlayer and bulk seawater in the Canadian Arctic that may be important for atmospheric INP concentrations.

IL6 signaling plays an important role in triggering labor and IL6 is an established biomarker of intrauterine infection/inflammation (IUI) driven preterm labor (PTL). The biology of IL6 during IUI at the maternal-fetal interface was investigated in samples from human subjects and non-human primates (NHP). Pregnant women with histologic chorioamnionitis diagnosed by placenta histology were recruited (n=28 term, n=43 for preterm pregnancies from 26-36 completed weeks of gestation). IUI was induced in Rhesus macaque by intraamniotic injection of lipopolysachharide (LPS, n=23). IL1 signaling was blocked using Anakinra (human IL-1 receptor antagonist, n=13), and Tumor necrosis factor (TNF) signaling was blocked by anti TNF-antibody (Adalimumab n=14). The blockers were given before LPS. All animals including controls (intraamniotic injection of saline n=27), were delivered 16h after LPS/saline exposure at about 80% gestation. IUI induced a robust expression of mRNAs in the fetal membranes (chorion-amnion-decidua tissue) both in humans (term and preterm) and NHP. The major sources of mRNA expression were the amnion mesenchymal cells (AMC) and decidua stroma cells. Additionally, during IUI in the NHP, (a protease that cleaves membrane bound IL6 receptor (IL6R) to release a soluble form) and mRNA increased in the fetal membranes, and the ratio of IL6 and soluble forms of IL6R, gp130 increased in the amniotic fluid signifying upregulation of IL6 trans-signaling. Both IL1 and TNF blockade suppressed LPS-induced mRNAs in the AMC and variably decreased elements of IL6 trans-signaling. These data suggest that IL1 and TNF blockers may be useful anti-inflammatory agents via suppression of IL6 signaling at the maternal-fetal interface.

Based on measurements from the WOCE/JGOFS global CO2 survey, the CLIVAR/CO2 Repeat Hydrography Program and the Canadian Line P survey, we have observed an average decrease of 0.34% yr−1 in the saturation state of surface seawater in the Pacific Ocean with respect to aragonite and calcite. The upward migrations of the aragonite and calcite saturation horizons, averaging about 1 to 2 m yr−1, are the direct result of the uptake of anthropogenic CO2 by the oceans and regional changes in circulation and biogeochemical processes. The shoaling of the saturation horizon is regionally variable, with more rapid shoaling in the South Pacific where there is a larger uptake of anthropogenic CO2. In some locations, particularly in the North Pacific Subtropical Gyre and in the California Current, the decadal changes in circulation can be the dominant factor in controlling the migration of the saturation horizon. If CO2 emissions continue as projected over the rest of this century, the resulting changes in the marine carbonate system would mean that many coral reef systems in the Pacific would no longer be able to sustain a sufficiently high rate of calcification to maintain the viability of these ecosystems as a whole, and these changes perhaps could seriously impact the thousands of marine species that depend on them for survival. Key Points The saturation state of surface waters decreased by an average of 0.34% per year The aragonite and calcite saturation horizons shoal an average of 1‐2 m per yr The shoaling of the saturation horizon is regionally variable

It is estimated that more than half of the world population has been infected with Helicobacter pylori . Most newly acquired H. pylori infections occur in children before 10 years of age. We hypothesized that early life H. pylori infection could influence the composition of the microbiome at mucosal sites distant to the stomach. To test this hypothesis, we utilized the infant rhesus macaque monkey as an animal model of natural H. pylori colonization to determine the impact of infection on the lung and oral microbiome during a window of postnatal development. From a cohort of 4–7 month-old monkeys, gastric biopsy cultures identified 44% of animals infected by H. pylori . 16S ribosomal RNA gene sequencing of lung washes and buccal swabs from animals showed distinct profiles for the lung and oral microbiome, independent of H. pylori infection. In order of relative abundance, the lung microbiome was dominated by the phyla Proteobacteria, Firmicutes, Bacteroidota, Fusobacteriota, Campilobacterota and Actinobacteriota while the oral microbiome was dominated by Proteobacteria, Firmicutes, Bacteroidota, and Fusobacteriota. In comparison to the oral cavity, the lung was composed of more genera and species that significantly differed by H. pylori status, with a total of 6 genera and species that were increased in H. pylori negative infant monkey lungs. Lung, but not plasma IL-8 concentration was also associated with gastric H. pylori load and lung microbial composition. We found the infant rhesus macaque monkey lung harbors a microbiome signature that is distinct from that of the oral cavity during postnatal development. Gastric H. pylori colonization and IL-8 protein were linked to the composition of microbial communities in the lung and oral cavity. Collectively, these findings provide insight into how H. pylori infection might contribute to the gut-lung axis during early childhood and modulate future respiratory health.

Accumulation of activated neutrophils at the feto-maternal interface is a defining hallmark of intrauterine inflammation (IUI) that might trigger an excessive immune response during pregnancy. Mechanisms responsible of this massive neutrophil recruitment are poorly investigated. We have previously showed that intraamniotic injection of LPS in rhesus macaques induced a neutrophil predominant inflammatory response similar to that seen in human IUI. Here, we demonstrate that anti-TNF antibody (Adalimumab) inhibited ~80% of genes induced by LPS involved in inflammatory signaling and innate immunity in chorio-decidua neutrophils. Consistent with the gene expression data, TNF-blockade decreased LPS-induced neutrophil accumulation and activation at the feto-maternal interface. We also observed a reduction in IL-6 and other pro-inflammatory cytokines but not prostaglandins concentrations in the amniotic fluid. Moreover, TNF-blockade decreased mRNA expression of inflammatory cytokines in the chorio-decidua but not in the uterus, suggesting that inhibition of TNF-signaling decreased the inflammation in a tissue-specific manner within the uterine compartment. Taken together, our results demonstrate a predominant role for TNF-signaling in modulating the neutrophilic infiltration at the feto-maternal interface during IUI and suggest that blockade of TNF-signaling could be considered as a therapeutic approach for IUI, the major leading cause of preterm birth.

Antenatal corticosteroids (ACS) are standard of care for women at risk of preterm delivery, although choice of drug, dose or route have not been systematically evaluated. Further, ACS are infrequently used in low resource environments where most of the mortality from prematurity occurs. We report proof of principle experiments to test betamethasone-phosphate (Beta-P) or dexamethasone-phosphate (Dex-P) given orally in comparison to the clinical treatment with the intramuscular combination drug beta-phosphate plus beta-acetate in a Rhesus Macaque model. First, we performed pharmacokinetic studies in non-pregnant monkeys to compare blood levels of the steroids using oral dosing with Beta-P, Dex-P and an effective maternal intramuscular dose of the beta-acetate component of the clinical treatment. We then evaluated maternal and fetal blood steroid levels with limited fetal sampling under ultrasound guidance in pregnant macaques. We found that oral Beta is more slowly cleared from plasma than oral Dex. The blood levels of both drugs were lower in maternal plasma of pregnant than in non-pregnant macaques. Using the pharmacokinetic data, we treated groups of 6-8 pregnant monkeys with oral Beta-P, oral Dex-P, or the maternal intramuscular clinical treatment and saline controls and measured pressure-volume curves to assess corticosteroid effects on lung maturation at 5d. Oral Beta-P improved the pressure-volume curves similarly to the clinical treatment. Oral Dex-P gave more variable and nonsignificant responses. We then compared gene expression in the fetal lung, liver and hippocampus between oral Beta-P and the clinical treatment by RNA-sequencing. The transcriptomes were largely similar with small gene expression differences in the lung and liver, and no differences in the hippocampus between the groups. As proof of principle, ACS therapy can be effective using inexpensive and widely available oral drugs. Clinical dosing strategies must carefully consider the pharmacokinetics of oral Beta-P or Dex-P to minimize fetal exposure while achieving the desired treatment responses.

The epithelium-associated cytokine thymic stromal lymphopoietin (TSLP) can induce OX40L and CCL17 expression by myeloid dendritic cells (mDCs), which contributes to aberrant Th2-type immune responses. Herein, we report that such TSLP-induced Th2-type immune response can be effectively controlled by Dectin-1, a C-type lectin receptor expressed by mDCs. Dectin-1 stimulation induced STAT3 activation and decreased the transcriptional activity of p50-RelB, both of which resulted in reduced OX40L expression on TSLP-activated mDCs. Dectin-1 stimulation also suppressed TSLP-induced STAT6 activation, resulting in decreased expression of the Th2 chemoattractant CCL17. We further demonstrated that Dectin-1 activation was capable of suppressing ragweed allergen (Amb a 1)-specific Th2-type T cell response in allergy patients ex vivo and house dust mite allergen (Der p 1)-specific IgE response in non-human primates in vivo . Collectively, this study provides a molecular explanation of Dectin-1-mediated suppression of Th2-type inflammatory responses and suggests Dectin-1 as a target for controlling Th2-type inflammation.