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BackgroundThe upper-airway microbiome is involved in asthma exacerbations despite inhaled corticosteroid (ICS) treatment. Although human genetics regulates microbiome composition, its influence on asthma-related airway bacteria remains unknown.ObjectiveWe sought to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response.MethodsSaliva, nasal, and pharyngeal samples from 257 European patients with asthma were analyzed. The association of 6,296,951 genetic variants with exacerbation-related microbiome traits despite ICS treatment was tested through microbiome genome-wide association studies. Variants with 1 × 10-4 -6 were examined in gene-set enrichment analyses. Significant results were sought for replication in 114 African American and 158 Latino children with and without asthma. ICS-response-associated single nucleotide polymorphisms reported in the literature were evaluated as microbiome quantitative trait loci. Multiple comparisons were adjusted by the false discovery rate.ResultsGenes associated with exacerbation-related airway-microbiome traits were enriched in asthma comorbidities development (ie, reflux esophagitis, obesity, and smoking), and were likely regulated by trichostatin A and the nuclear factor-κB, the glucocorticosteroid receptor, and CCAAT/enhancer-binding protein transcription factors (7.8 × 10-13 ≤ false discovery rate ≤ 0.022). Enrichment in smoking, trichostatin A, nuclear factor-κB, and glucocorticosteroid receptor were replicated in the saliva samples from diverse populations (4.42 × 10-9 ≤ P ≤ .008). The ICS-response-associated single nucleotide polymorphisms rs5995653 (APOBEC3B-APOBEC3C), rs6467778 (TRIM24), and rs5752429 (TPST2) were identified as microbiome quantitative trait loci of Streptococcus, Tannerella, and Campylobacter in the upper airway (0.027 ≤ false discovery rate ≤ 0.050).ConclusionsGenes associated with asthma exacerbation-related microbiome traits might influence asthma comorbidities. We reinforced the therapeutic interest of trichostatin A, nuclear factor-κB, the glucocorticosteroid receptor, and CCAAT/enhancer-binding protein in asthma exacerbations.

The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized. Here we show that human respiratory bronchioles contain a unique secretory cell population that is distinct from cells in larger proximal airways. Organoid modelling reveals that these respiratory airway secretory (RAS) cells act as unidirectional progenitors for alveolar type 2 cells, which are essential for maintaining and regenerating the alveolar niche. RAS cell lineage differentiation into alveolar type 2 cells is regulated by Notch and Wnt signalling. In chronic obstructive pulmonary disease, RAS cells are altered transcriptionally, corresponding to abnormal alveolar type 2 cell states, which are associated with smoking exposure in both humans and ferrets. These data identify a distinct progenitor in a region of the human lung that is not found in mouse that has a critical role in maintaining the gas-exchange compartment and is altered in chronic lung disease.

Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease disrupting lung health throughout the life of an individual and that is increasing in incidence. The TGF-[beta] superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that TGFbr2 is critical for alveolar epithelial (AT1) cell fate maintenance and function. Loss of TGFbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analyses reveal the necessity of TGFbr2 expression in AT1 cells for extracellular matrix production. Moreover, TGF-[beta] signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGF-[beta] signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome., Introduction Bronchopulmonary dysplasia (BPD) is a lung disease that disproportionately affects infants born at less than 28 weeks gestation, the threshold for extreme prematurity (1). Despite multiple medical advances including [...]

BackgroundSevere asthma exacerbations are a major cause of asthma morbidity and increased healthcare costs. Several studies have shown racial and ethnic differences in asthma exacerbation rates. We aimed to identify genetic variants associated with severe exacerbations in two high-risk populations for asthma.MethodsA genome-wide association study of asthma in children and youth with severe exacerbations was performed in 1283 exacerbators and 2027 controls without asthma of Latino ancestry. Independent suggestive variants (P ≤ 5 × 10-6 ) were selected for replication in 448 African Americans exacerbators and 595 controls. Case-only analyses were performed comparing the exacerbators with additional 898 Latinos and 524 African Americans asthma patients without exacerbations, while adjusting by treatment category as a proxy of asthma severity. We analyzed the functionality of associated variants with in silico methods and by correlating genotypes with methylation levels in whole blood in a subset of 473 Latinos.ResultsWe identified two genome-wide significant associations for susceptibility to asthma with severe exacerbations, including a novel locus located at chromosome 2p21 (rs4952375, odds ratio = 1.39, P = 3.8 × 10-8 ), which was also associated with asthma exacerbations in a case-only analysis (odds ratio = 1.25, P = 1.95 × 10-3 ). This polymorphism is an expression quantitative trait locus of the long intergenic non-protein coding RNA 1913 (LINC01913) in lung tissues (P = 1.3 × 10-7 ) and influences methylation levels of the protein kinase domain-containing cytoplasmic (PKDCC) gene in whole-blood cells (P = 9.8 × 10-5 ).ConclusionWe identified a novel susceptibility locus for severe asthma exacerbations in Hispanic/Latino and African American youths with functional effects in gene expression and methylation status of neighboring genes.

Several studies have shown that the airways of asthma patients contain higher diversity of bacteria and are enriched in pathogenic species. However, sampling the airways in children is challenging. Here we aimed to identify differences in the salivary bacterial composition between African Americans children with and without asthma. Saliva samples from 57 asthma cases and 57 healthy controls were analyzed by means of 16S ribosomal RNA amplicon profiling. Measurements of bacterial diversity and genus relative abundance were compared between cases and controls using the nonparametric Wilcoxon test and multivariate regression models. A total of five phyla and a mean of 56 genera were identified. Among them, 15 genera had a relative abundance greater than 1%, being Prevotella, Haemophilus, Streptococcus, and Veillonella the most abundant genera. Differences between cases and controls were found in terms of diversity, as well as in relative abundance for Streptococcus genus (13.0% in cases vs 18.3% in controls; P = .003) and Veillonella genus (11.1% in cases vs 8.0% in controls; P = .002). These differences remained significant after correction for multiple comparisons and when potential confounders were taken into account in logistic regression models. In conclusion, we identified changes in the salivary microbiota associated with asthma among African Americans.

Cold supply chains of food and beverage sectors represent one of the main drivers of the EU total final energy consumption. Within this context, food quality losses, changes in temperature regimes, energy use, environmental burdens, and the economic viability of energy efficiency measures are essential aspects to consider for improving cold supply chains’ overall sustainability. This paper presents a dedicated toolbox, developed within the Horizon 2020 project ICCEE, for supporting decision-making and actors to assess energy efficiency path within a specific type of food cold-supply (i.e., meat, fish, milk and cheese products, fruits, and vegetables). More in specific the toolbox offers support for decision-makers to understand and minimize the specific energy consumption, to decrease the overall environmental impact even including non-energy benefit evaluation many times underestimated. The six separated tools merged within a unique toolbox consider different methodological approaches such as: assessment of the whole energy requirements in stock and flows considering the storage impact, the logistics and quality losses over time, implementation of Life Cycle Assessment and Life Cycle costs within the environmental and financial assessment of energy efficiency measures, based on a benchmarking approach. Finally, a specific approach implementing Multi Criteria Analysis was developed on selected key performance indicators such as specific and cumulated energy consumptions, quality losses and environmental burdens (i.e., global warming potential and water scarcity). The latest version of the ICCEE toolbox is available as free downloadable package on the ICCEE website.

The Colombian energy matrix faces significant changes toward meeting its energy needs while fulfilling its pledges in the Intended National Determined Contributions linked to the Paris Agreement. The country has developed a plan for energy transition with a 2050 horizon, a strategy reflected and supported by new legislative packages. Within its design, biomass and biomass waste play a vital role in bioenergy production; however, the benefits of deploying new bioenergy production facilities have not been fully accounted for, including only an economic and climate change perspective. In this work, a Life Cycle Sustainability Assessment of a potential bioenergy plant for industrial symbiosis with the largest landfill in the country is undertaken, avoiding environmental burden shifting between environmental damage categories and exposing the social potential of such projects. The results show how these types of projects are economically feasible and have the potential to boost the sustainable development of local communities, which under the Colombian context, have been structurally relegated from conventional economic growth for decades.

The Bacillus Calmette Guerin (BCG) vaccine has been shown to induce nonspecific protection against diseases other than tuberculosis in vaccinated individuals, attributed to the induction of trained immunity. We have previously demonstrated that BCG administration induces innate immune training in mixed peripheral blood mononuclear cells and monocytes in calves. Gamma Delta (gd) T cells are non-conventional T cells that exhibit innate and adaptive immune system features. They are in higher proportion in the peripheral blood of cattle than humans or rodents and play an essential role in bovine immune response to pathogens. In the current study, we determined if BCG administration induced innate immune training in bovine gd T cells. A group of 16 pre-weaned Holstein calves (2-4 d age) were enrolled in the study and randomly assigned to vaccine and control groups (n=8/group). The vaccine group received two doses of 106 colony forming units (CFU) BCG Danish strain subcutaneously, separated by 2 weeks. The control group remained unvaccinated. Gamma delta T cells were purified from peripheral blood using magnetic cell sorting three weeks after receiving the 1st BCG dose. We observed functional changes in the gd T cells from BCG-treated calves shown by increased IL-6 and TNF-a cytokine production in response to in vitro stimulation with Escherichia coli LPS and PAM3CSK4. ATAC-Seq analysis of 78,278 regions of open chromatin (peaks) revealed that gd T cells fromBCGtreated calves had an altered epigenetic status compared to cells from the control calves. Differentially accessible peaks (DAP) found near the promoters of innate immunity-related genes like Siglec14, Irf4, Ifna2, Lrrfip1, and Tnfrsf10d were 1 to 4-fold more accessible in cells from BCG-treated calves. MOTIF enrichment analysis of the sequences within DAPs, which explores transcription factor binding motifs (TFBM) upstream of regulatory elements, revealed TFBM for Eomes and IRF-5 were among the most enriched transcription factors. GO enrichment analysis of genes proximal to the DAPs showed enrichment of pathways such as regulation of IL-2 production, T-cell receptor signaling pathway, and other immune regulatory pathways. In conclusion, our study shows that subcutaneous BCG administration in preweaned calves can induce innate immune memory in the form of trained immunity in gd T cells. This memory is associated with increased chromatin accessibility of innate immune response-related genes, thereby inducing a functional trained immune response evidenced by increased IL-6 and TNF-α cytokine production. [ABSTRACT FROM AUTHOR]

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.

It is expected that Cross-laminated timber (CLT) and other engineered wood products will experience rapid growth in the coming years. Global population growth is requiring more housing units, at the same time the negative impact of construction industry cannot stay in the same level as today. Alternatives for concrete and steel reinforced structures are being explored. CLT has proven to be an excellent substitution for concrete regarding construction of buildings up to eight storeys high. In addition to much lower environmental impact, construction process using CLT takes significantly less time due to pre-cut shapes required for specific project. Despite mentioned benefits, there are considerable amount of CLT cuttings generated in this process. Due to irregular shape and small dimensions of these cuttings they are useless for further use in construction. By applying re-processing technology described in this paper, around 70 % of generated cuttings can be re-processed into new CLT panels. In this paper we are evaluating the environmental benefits of re-processing these cuttings into new CLT panels versus business-as-usual scenario with waste disposal. Life cycle assessment results showed significant reduction of environmental impact for the scenario of CLT cutting re-processing.

Circular economy and industrial symbiosis represent a production and consumption model involving sharing, lending, reusing, and recycling existing materials and products in the most efficient way to increase sustainability and reduce or eliminate waste. Beef production has a high impact on the environment in different impact categories, especially those activities related to livestock breeding and feeding. In this study, a life cycle assessment and a life cycle cost evaluation are carried out investigating potential energy efficiency measures to promote industrial symbiosis scenarios referring to a proposed baseline scenario. Three main potential measures are evaluated: energy recovery from waste via anaerobic digestion, integration of renewable sources at warehouses, including solar PV panels, and the replacement of auxiliary equipment at the retailer. It was found that energy reconversion of food waste through anaerobic digestion and cogeneration provides the most valuable benefits to the supply chain. From the economic perspective, using a conventional life cycle cost assessment, the energy production from the use of wastes for anaerobic digestion proved to be the best potential option.

New district heating system technologies have arisen in the last years to deliver economic and environmental benefits to residential and commercial buildings. The extensive ranges of equipment, energy sources, temperature profile configurations, size of the network, energy demand, and many other intrinsic variables, make it difficult to identify if a determined district heating option is potentially better than another in environmental terms. As for the economic evaluation, there are several tools decision-makers can rely on to assess environmental performance. The main challenge is to provide a holistic point of view for which lifespan and complexity of implementable, new technological systems can be an obstacle. For this reason, in this paper, a Life Cycle Assessment is performed upon a technical evaluation of several district heating configuration options for the Gulbene region in Latvia, where DH systems in most of the assessed parishes are already operating under medium temperature regimes, also known as third-generation district heating. The goal of the study is to understand the environmental impact of moving from the current DH system to a low temperature one. Results show a considerable environmental benefit if low-temperature profiles, combined with the use of renewable energy sources are adopted in the current DH systems. A hotspot analysis is also performed showing the use stage is the one carrying most of the burden across the project’s lifetime, followed by infrastructure construction; also showing that the refurbishment of buildings does not play a major role in the total environmental impact contribution.

In the past few years, Colombia has begun to implement new laws according to new global trends, however, carbon dioxide emissions have not decreased despite country commitments according to the Paris agreement and other international treaties. In this paper, a pathway to achieve full decarbonization of the energy system of the country has been analysed using a multi-criteria analysis tool and considering several options from previous studies, evaluating three different abatement scenarios obtained by different models. Then, a Strength, Weakness, Opportunities and Threats (SWOT) analysis is conducted in order to propose a set of environmental policies that aid in seeking greater reduction of greenhouse gas emissions (GHG) in sectors as agriculture, forestry, land use and transport. This set of measures is then summarized, and their abatement costs and GHG reduction potential are displayed. The outcomes show the country has great potential to exploit its renewable natural resources and indicates how a new electricity mix may not only decrease GHG emissions but also reduce the levelized cost of electricity for the end users.

The transcription factor GATA6 has been shown to be important for lung development and branching morphogenesis in mouse models, but its role in human lung development is largely unknown. Here, we studied the role of GATA6 during lung differentiation using human pluripotent stem cells. We found that the human stem cell lines most efficient at generating [NKX2.1.sup.+] lung progenitors express lower endogenous levels of GATA6 during endoderm patterning and that knockdown of GATA6 during endoderm patterning increased the generation of these cells. Complete ablation of GATA6 resulted in the generation of lung progenitors displaying increased cell proliferation with up to a 15-fold expansion compared with control cells, whereas the null cell line displayed a defect in further development into mature lung cell types. Furthermore, transgenic expression of GATA6 at the endoderm anteriorization stage skewed development toward a liver fate at the expense of lung progenitors. Our results suggest a critical dosage effect of GATA6 during human endoderm patterning and a later requirement during terminal lung differentiation. These studies offer an approach of modulating GATA6 expression to enhance the production of lung progenitors from human stem cell sources., Introduction Embryonic lung development can be divided into 4 stages: embryonic, pseudoglandular, canalicular, and saccular (1). Several transcription factors have been implicated during these stages in the early embryo, including [...]