Sex hormones regulate many autoimmune and inflammatory diseases, including asthma. As adults, asthma prevalence is 2-fold greater in women compared to men. The number of group 2 innate lymphoid cells ...(ILC2) is increased in patients with asthma, and we investigate how testosterone attenuates ILC2 function. In patients with moderate to severe asthma, we determine that women have an increased number of circulating ILC2 compared to men. ILC2 from adult female mice have increased IL-2-mediated ILC2 proliferation versus ILC2 from adult male mice, as well as pre-pubescent females and males. Further, 5α-dihydrotestosterone, a hormone downstream of testosterone, decreases lung ILC2 numbers and IL-5 and IL-13 expression from ILC2. In vivo, testosterone attenuated Alternaria-extract-induced IL-5+ and IL-13+ ILC2 numbers and lung eosinophils by intrinsically decreasing lung ILC2 numbers, as well as by decreasing expression of IL-33 and thymic stromal lymphopoietin (TSLP), ILC2-stimulating cytokines. Collectively, these findings provide a foundational understanding of sexual dimorphism in ILC2 function.
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•The number of ILC2 is increased in women with asthma compared to men with asthma•Sex hormones regulate IL-2-dependent ILC2 proliferation and cytokine expression•Testosterone intrinsically and extrinsically attenuates ILC2 airway inflammation
Women have higher asthma prevalence compared to men, and ILC2 are increased in patients with asthma. Cephus et al. show that women with asthma have higher circulating ILC2 numbers compared to men with asthma. Testosterone negatively regulates ILC2 proliferation and cytokine expression, as well as ILC2-mediated allergic airway inflammation.
Emamectin benzoate is used as an in-feed treatment for the control of sea lice parasites in all of the main farmed Atlantic salmon (Salmo salar) facilities worldwide (Norway, Chile, Scotland and ...Canada). Investigations into its effect on non-target benthic fauna resulting from its excretion from farmed fish and uneaten feed have been limited. This paper presents the findings from a study that intended to assess the impact of emamectin benzoate on benthic fauna using a new low detection method for emamectin benzoate. Eight fish farms in the Shetland Isles, Scotland were surveyed, with sediment sampled along transects radiating from the farms analysed for benthic ecology, sediment chemistry and sediment veterinary medicine residues (analysed for emamectin benzoate and teflubenzuron). Canonical Correspondence Analysis (CCA) and Generalised Linear Mixed Modelling (GLMM) were used to assess which environmental parameters observed during the survey had the biggest effect on benthic community composition and abundance, and more specifically crustacean abundance and richness. Emamectin benzoate was found in 97% of samples, demonstrating widespread dispersion in the sediments sampled. The CCA showed that species composition was predominantly ordinated along a gradient of particle size, with a secondary axis dominated by a change in emamectin benzoate and organic carbon enrichment. Peaks in abundance of crustacean species were predicted to be organised along a gradient of emamectin benzoate concentration. The GLMM corroborated this by showing that emamectin benzoate had the strongest negative effect on total crustacean abundance and species richness, though there was some degree of collinearity with organic carbon, that had a smaller effect. Overall, this study shows that, following its use as an in-feed treatment for sea lice, emamectin benzoate residues are more widely distributed in the benthic environment than previously thought, and have a statistically significant effect on benthic ecology at the concentrations observed in this study.
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•Emamectin benzoate (EmBz) was widely detected in benthic sediment during the survey.•Benthic community composition was secondarily ordinated along a gradient of EmBz.•EmBz had the biggest effect on benthic crustacean abundance and richness.•The distribution of EmBz beyond fish farms was linked to impacts on benthic ecology.
Serotonergic anorexigens are the primary pharmacologic risk factor associated with pulmonary arterial hypertension (PAH), and the resulting PAH is clinically indistinguishable from the heritable form ...of disease, associated with BMPR2 mutations. Both BMPR2 mutation and agonists to the serotonin receptor HTR2B have been shown to cause activation of SRC tyrosine kinase; conversely, antagonists to HTR2B inhibit SRC trafficking and downstream function. To test the hypothesis that a HTR2B antagonist can prevent BMRP2 mutation induced PAH by restricting aberrant SRC trafficking and downstream activity, we exposed BMPR2 mutant mice, which spontaneously develop PAH, to a HTR2B antagonist, SB204741, to block the SRC activation caused by BMPR2 mutation. SB204741 prevented the development of PAH in BMPR2 mutant mice, reduced recruitment of inflammatory cells to their lungs, and reduced muscularization of their blood vessels. By atomic force microscopy, we determined that BMPR2 mutant mice normally had a doubling of vessel stiffness, which was substantially normalized by HTR2B inhibition. SB204741 reduced SRC phosphorylation and downstream activity in BMPR2 mutant mice. Gene expression arrays indicate that the primary changes were in cytoskeletal and muscle contractility genes. These results were confirmed by gel contraction assays showing that HTR2B inhibition nearly normalizes the 400% increase in gel contraction normally seen in BMPR2 mutant smooth muscle cells. Heritable PAH results from increased SRC activation, cellular contraction, and vascular resistance, but antagonism of HTR2B prevents SRC phosphorylation, downstream activity, and PAH in BMPR2 mutant mice.
Annuloplasty ring dehiscence is a well described mode of mitral valve repair failure. Defining the mechanisms underlying dehiscence may facilitate its prevention.
Factors that govern suture ...dehiscence were examined with an ovine model. After undersized ring annuloplasty in live animals (n = 5), cyclic force (FC) that acts on sutures during cardiac contraction was measured with custom transducers. FC was measured at ten suture positions, throughout cardiac cycles with peak left ventricular pressure (LVPmax) of 100, 125, and 150 mm Hg. Suture pullout testing was conducted on explanted mitral annuli (n = 12) to determine suture holding strength at each position. Finally, relative collagen density differences at suture sites around the annulus were assessed by two-photon excitation fluoroscopy.
Anterior FC exceeded posterior FC at each LVPmax (eg, 2.8 ± 1.3 N versus 1.8 ± 1.2 N at LVPmax = 125 mm Hg, p < 0.01). Anterior holding strength exceeded posterior holding strength (6.4 ± 3.6 N versus 3.9 ± 1.6 N, p < 0.0001). On the basis of FC at LVPmax of 150 mm Hg, margin of safety before suture pullout was vastly higher between the trigones (exclusive) versus elsewhere (4.8 ± 0.9 N versus 1.9 ± 0.5 N, p < 0.001). Margin of safety exhibited strong correlation to collagen density (R(2) = 0.947).
Despite lower cyclic loading on posterior sutures, the weaker posterior mitral annular tissue creates higher risk of dehiscence, apparently because of reduced collagen content. Sutures placed atop the trigones are less secure than predicted, because of a combination of reduced collagen and higher overall rigidity in this region. These findings highlight the inter-trigonal tissue as the superior anchor and have implications on the design and implantation techniques for next-generation mitral prostheses.
Encapsulation of atoms or small molecules inside fullerenes provides a unique opportunity for study of the confined species in the isolated cavity, and the synthesis of closed C
or C
fullerenes with ...enclosed atoms or molecules has recently developed using the method of 'molecular surgery'; in which an open-cage intermediate fullerene is the host for encapsulation of a guest species, before repair of the cage opening. In this work we review the main methods for cage-opening and closure, and the achievements of molecular surgery to date.
•Understanding the factors that can sustainably enhance soybean yield is critical.•Higher microbial diversity promoted less soybean damage by insect herbivores.•Soybean exhibits high tolerance to ...herbivory regardless of microbial diversity.•Promoting microbial diversity may promote a sustainable agricultural economy.
Biodiversity within ecological communities has been shown to influence plant resistance and tolerance to herbivory, and may strongly interact with climate change. However, the effects of diversity within microbial symbionts on their plant hosts’ responses to herbivores is less well documented, particularly within the context of agricultural systems. Here we examine the interactive effects of rhizobial diversity and drought in promoting soybean resistance and tolerance to insect and mammalian herbivores in an outdoor pot experiment. We demonstrate that soybean plants provided with a diverse mixture of rhizobial strains experience 30% less damage by chewing insect herbivores under both drought (reduced watering and increased temperature) and ambient weather conditions, as well as half as much colonization by aphids under drought conditions. This effect was not due to the presence of any particularly beneficial rhizobial strain (i.e., not a selection effect), but rather due to an enhanced benefit provided by the rhizobial strains in combination (i.e., a complementarity effect). No effects of rhizobial diversity were observed on the rate of defoliation by rabbits. While rhizobial diversity did affect soybean resistance to insect herbivores, these differences in insect damage did not carry through to affect soybean growth or final yield. Thus, soybean plants exhibited high tolerance to herbivory regardless of our experimentally imposed rhizobial diversity or drought treatments. With future projections for increased pest outbreaks and drought, understanding the factors that can sustainably enhance agricultural yield is critical. Our results suggest that promoting rhizobial diversity within soybean agriculture may be one nature-based solution to promote the resistance of this critical crop to insect pests.
Pulmonary vascular disease is characterized by remodeling and loss of microvessels and is typically attributed to pathological responses in vascular endothelium or abnormal smooth muscle cell ...phenotypes. We have challenged this understanding by defining an adult pulmonary mesenchymal progenitor cell (MPC) that regulates both microvascular function and angiogenesis. The current understanding of adult MPCs and their roles in homeostasis versus disease has been limited by a lack of genetic markers with which to lineage label multipotent mesenchyme and trace the differentiation of these MPCs into vascular lineages. Here, we have shown that lineage-labeled lung MPCs expressing the ATP-binding cassette protein ABCG2 (ABCG2+) are pericyte progenitors that participate in microvascular homeostasis as well as adaptive angiogenesis. Activation of Wnt/β-catenin signaling, either autonomously or downstream of decreased BMP receptor signaling, enhanced ABCG2+ MPC proliferation but suppressed MPC differentiation into a functional pericyte lineage. Thus, enhanced Wnt/β-catenin signaling in ABCG2+ MPCs drives a phenotype of persistent microvascular dysfunction, abnormal angiogenesis, and subsequent exacerbation of bleomycin-induced fibrosis. ABCG2+ MPCs may, therefore, account in part for the aberrant microvessel function and remodeling that are associated with chronic lung diseases.
Reports about the relationship between soil water retention and organic carbon content are contradictory. We hypothesized that this relationship is affected by both proportions of textural components ...and amount of organic carbon. To test the hypothesis, we used the U.S. National Soil Characterization database and the database from pilot studies on soil quality as affected by long-term management. Regression trees and group method of data handling (GMDH) revealed a complex joint effect of texture and taxonomic order on water retention at −33 kPa. Adding information on taxonomic order and on taxonomic order and organic carbon content to the textural class brought 10% and 20% improvement in water retention estimation, respectively, as compared with estimation from the textural class alone. Using total clay, sand and silt along with organic carbon content and taxonomic order resulted in 25% improvement in accuracy over using textural classes. Similar but lower trends in accuracy were found for water retention at −1500 kPa and the slope of the water retention curve. At low organic carbon contents, the sensitivity of the water retention to changes in organic matter content was highest in sandy soils. Increase in organic matter content led to increase of water retention in sandy soils, and to a decrease in fine-textured soils. At high organic carbon values, all soils showed an increase in water retention. The largest increase was in sandy and silty soils. Results are expressed as equations that can be used to evaluate effect of the carbon sequestration and management practices on soil hydraulic properties.
Interleukin‐6 (IL‐6)–mediated hyperinflammation may contribute to the mortality of coronavirus disease 2019 (COVID‐19). The IL‐6 receptor–blocking monoclonal antibody tocilizumab has been repurposed ...for COVID‐19, but prospective trials and dose‐finding studies in COVID‐19 have not yet fully reported. We conducted a single‐arm phase II trial of low‐dose tocilizumab in nonintubated hospitalized adult patients with COVID‐19, radiographic pulmonary infiltrate, fever, and C‐reactive protein (CRP) ≥ 40 mg/L. We hypothesized that doses significantly lower than the emerging standards of 400 mg or 8 mg/kg would resolve clinical and laboratory indicators of hyperinflammation. A dose range from 40 to 200 mg was evaluated, with allowance for one repeat dose at 24 to 48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Thirty‐two patients received low‐dose tocilizumab, with the majority experiencing fever resolution (75%) and CRP decline consistent with IL‐6 pathway abrogation (86%) in the 24–48 hours following drug administration. There was no evidence of a relationship between dose and fever resolution or CRP decline over the dose range of 40–200 mg. Within the 28‐day follow‐up, 5 (16%) patients died. For patients who recovered, median time to clinical recovery was 3 days (interquartile range, 2–5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (16%) patients. Low‐dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with COVID‐19. Results of this trial provide rationale for a randomized, controlled trial of low‐dose tocilizumab in COVID‐19.
In recent years water companies have started to adopt catchment management to reduce diffuse pollution in drinking water supply areas. The heterogeneity of catchments and the range of pollutants that ...must be removed to meet the EU Drinking Water Directive (98/83/EC) limits make it difficult to prioritise areas of a catchment for intervention. Thus conceptual frameworks are required that can disaggregate the components of pollutant risk and help water companies make decisions about where to target interventions in their catchments to maximum effect. This paper demonstrates the concept of generalising pollutants in the same framework by reviewing key pollutant processes within a source-mobilisation-delivery context. From this, criteria are developed (with input from water industry professionals involved in catchment management) which highlights the need for a new water industry specific conceptual framework. The new CaRPoW (Catchment Risk to Potable Water) framework uses the Source-Mobilisation-Delivery concept as modular components of risk that work at two scales, source and mobilisation at the field scale and delivery at the catchment scale. Disaggregating pollutant processes permits the main components of risk to be ascertained so that appropriate interventions can be selected. The generic structure also allows for the outputs from different pollutants to be compared so that potential multiple benefits can be identified. CaRPow provides a transferable framework that can be used by water companies to cost-effectively target interventions under current conditions or under scenarios of land use or climate change.
•Water companies must mitigate multiple pollutant risks in water supply catchments.•A review of catchment processes highlights links between multiple pollutants.•No current framework is able to identify and compare multiple pollutant risks.•The new CaRPoW framework disaggregates and compares risks for measure selection.•CaRPoW allows water companies to more effectively select and target measures.
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