Multiferroic films are increasingly being studied for applications in solar energy conversion because of their efficient ferroelectric polarization-driven carrier separation and above-bandgap ...generated photovoltages, which in principle can lead to energy conversion efficiencies beyond the maximum value (34%) reported in traditional silicon-based bipolar heterojunction solar cells. However, the efficiency reported so far is still too low (<2%) to be considered for commercialization. Here, we demonstrate a new approach to effectively tune the bandgap of double perovskite multiferroic oxides by engineering the cationic ordering for the case of Bi sub(2)FeCrO sub(6). Using this approach, we report a power conversion efficiency of 8.1% under AM 1.5G irradiation (100mWcm super(-2)) for Bi sub(2)FeCrO sub(6) thin-film solar cells in a multilayer configuration.
Thoracic aortic aneurysm (TAA) has been associated with mutations affecting members of the TGF-β signaling pathway, or components and regulators of the vascular smooth muscle cell (VSMC) actomyosin ...cytoskeleton. Although both clinical groups present similar phenotypes, the existence of potential common mechanisms of pathogenesis remain obscure. Here we show that mutations affecting TGF-β signaling and VSMC cytoskeleton both lead to the formation of a ternary complex comprising the histone deacetylase HDAC9, the chromatin-remodeling enzyme BRG1, and the long noncoding RNA MALAT1. The HDAC9-MALAT1-BRG1 complex binds chromatin and represses contractile protein gene expression in association with gain of histone H3-lysine 27 trimethylation modifications. Disruption of Malat1 or Hdac9 restores contractile protein expression, improves aortic mural architecture, and inhibits experimental aneurysm growth. Thus, we highlight a shared epigenetic pathway responsible for VSMC dysfunction in both forms of TAA, with potential therapeutic implication for other known HDAC9-associated vascular diseases.
Epithelial-mesenchymal interactions are critical in regulating many aspects of vertebrate embryo development, and for the maintenance of homeostatic equilibrium in adult tissues. The interactions ...between epithelium and mesenchyme are believed to be mediated by paracrine signals such as cytokines and extracellular matrix components secreted from fibroblasts that affect adjacent epithelia. In this study, we sought to identify the repertoire of microRNAs (miRNAs) in normal lung human fibroblasts and their potential regulation by the cytokines TNF-alpha, IL-1beta and TGF-beta.
MiR-155 was significantly induced by inflammatory cytokines TNF-alpha and IL-1beta while it was down-regulated by TGF-beta. Ectopic expression of miR-155 in human fibroblasts induced modulation of a large set of genes related to "cell to cell signalling", "cell morphology" and "cellular movement". This was consistent with an induction of caspase-3 activity and with an increase in cell migration in fibroblasts tranfected with miR-155. Using different miRNA bioinformatic target prediction tools, we found a specific enrichment for miR-155 predicted targets among the population of down-regulated transcripts. Among fibroblast-selective targets, one interesting hit was keratinocyte growth factor (KGF, FGF-7), a member of the fibroblast growth factor (FGF) family, which owns two potential binding sites for miR-155 in its 3'-UTR. Luciferase assays experimentally validated that miR-155 can efficiently target KGF 3'-UTR. Site-directed mutagenesis revealed that only one out of the 2 potential sites was truly functional. Functional in vitro assays experimentally validated that miR-155 can efficiently target KGF 3'-UTR. Furthermore, in vivo experiments using a mouse model of lung fibrosis showed that miR-155 expression level was correlated with the degree of lung fibrosis.
Our results strongly suggest a physiological function of miR-155 in lung fibroblasts. Altogether, this study implicates this miRNA in the regulation by mesenchymal cells of surrounding lung epithelium, making it a potential key player during tissue injury.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is an urgent need for antivirals to treat the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To identify new candidates, we screen a repurposing library of ∼3,000 ...drugs. Screening in Vero cells finds few antivirals, while screening in human Huh7.5 cells validates 23 diverse antiviral drugs. Extending our studies to lung epithelial cells, we find that there are major differences in drug sensitivity and entry pathways used by SARS-CoV-2 in these cells. Entry in lung epithelial Calu-3 cells is pH independent and requires TMPRSS2, while entry in Vero and Huh7.5 cells requires low pH and triggering by acid-dependent endosomal proteases. Moreover, we find nine drugs are antiviral in respiratory cells, seven of which have been used in humans, and three are US Food and Drug Administration (FDA) approved, including cyclosporine. We find that the antiviral activity of cyclosporine is targeting Cyclophilin rather than calcineurin, revealing essential host targets that have the potential for rapid clinical implementation.
Display omitted
•3,000 compounds screened in two cell types against SARS-CoV-2•Entry pathways are distinct in hepatocyte Huh7.5 and respiratory Calu-3 cells•Only nine compounds that are active in Huh7.5 cells are active in Calu-3 cells•Cyclosporin and cyclophilin inhibitors block SARS-CoV-2 infection in diverse cells
There is an urgent need for antivirals to treat the newly emerged SARS-CoV-2. Dittmar et al. find nine host-directed drugs are antiviral in respiratory cells, seven of which have been given to humans, and three are FDA approved. We show host targets that have the potential for rapid clinical implementation.
Given the paucity of effective treatments for idiopathic pulmonary fibrosis (IPF), new insights into the deleterious mechanisms controlling lung fibroblast activation, the key cell type driving the ...fibrogenic process, are essential to develop new therapeutic strategies. TGF-β (transforming growth factor-β) is the main profibrotic factor, but its inhibition is associated with severe side effects because of its pleiotropic role.
To determine if downstream noncoding effectors of TGF-β in fibroblasts may represent new effective therapeutic targets whose modulation may be well tolerated.
We investigated the whole noncoding fraction of TGF-β-stimulated lung fibroblast transcriptome to identify new genomic determinants of lung fibroblast differentiation into myofibroblasts. Differential expression of the long noncoding RNA (lncRNA) DNM3OS (dynamin 3 opposite strand) and its associated microRNAs (miRNAs) was validated in a murine model of pulmonary fibrosis and in IPF tissue samples. Distinct and complementary antisense oligonucleotide-based strategies aiming at interfering with DNM3OS were used to elucidate the role of DNM3OS and its associated miRNAs in IPF pathogenesis.
We identified DNM3OS as a fibroblast-specific critical downstream effector of TGF-β-induced lung myofibroblast activation. Mechanistically, DNM3OS regulates this process in
by giving rise to three distinct profibrotic mature miRNAs (i.e., miR-199a-5p/3p and miR-214-3p), which influence SMAD and non-SMAD components of TGF-β signaling in a multifaceted way.
, we showed that interfering with DNM3OS function not only prevents lung fibrosis but also improves established pulmonary fibrosis.
Pharmacological approaches aiming at interfering with the lncRNA DNM3OS may represent new effective therapeutic strategies in IPF.
Epithelial cell organoids have increased opportunities to probe questions on tissue development and disease in vitro and for therapeutic cell transplantation. Despite their potential, current ...protocols to grow these organoids almost exclusively depend on culture within 3D Matrigel, which limits defined culture conditions, introduces animal components, and results in heterogenous organoids (i.e., shape, size, composition). Here, a method is described that relies on hyaluronic acid hydrogels for the generation and expansion of lung alveolar organoids (alveolospheres). Using synthetic hydrogels with defined chemical and physical properties, human‐induced pluripotent stem cell (iPSC)‐derived alveolar type 2 cells (iAT2s) self‐assemble into alveolospheres and propagate in Matrigel‐free conditions. By engineering predefined microcavities within these hydrogels, the heterogeneity of alveolosphere size and structure is reduced when compared to 3D culture, while maintaining the alveolar type 2 cell fate of human iAT2‐derived progenitor cells. This hydrogel system is a facile and accessible system for the culture of iPSC‐derived lung progenitors and the method can be expanded to the culture of primary mouse tissue derived AT2 and other epithelial progenitor and stem cell aggregates.
Epithelial cell organoids provide a system to probe tissue development and disease in vitro and for cell transplantation. Within the lung field, alveolar organoids almost exclusively depend on Matrigel, which limits defined culture conditions. In this work, the design of an accessible hydrogel system with predefined microcavities to generate alveolar organoids through self‐assembly and maintenance of progenitor cell fate and function is described.
The regulation of gene expression in cells, including by microRNAs (miRNAs), is a dynamic process. Current methods for identifying miRNA targets by combining sequence and miRNA and mRNA expression ...data do not adequately use the temporal information and thus miss important miRNAs and their targets. We developed the MIRna Dynamic Regulatory Events Miner (mirDREM), a probabilistic modeling method that uses input–output hidden Markov models to reconstruct dynamic regulatory networks that explain how temporal gene expression is jointly regulated by miRNAs and transcription factors. We measured miRNA and mRNA expression for postnatal lung development in mice and used mirDREM to study the regulation of this process. The reconstructed dynamic network correctly identified known miRNAs and transcription factors. The method has also provided predictions about additional miRNAs regulating this process and the specific developmental phases they regulate, several of which were experimentally validated. Our analysis uncovered links between miRNAs involved in lung development and differentially expressed miRNAs in idiopathic pulmonary fibrosis patients, some of which we have experimentally validated using proliferation assays. These results indicate that some disease progression pathways in idiopathic pulmonary fibrosis may represent partial reversal of lung differentiation.
Urine patches and dung pats from grazing livestock create hotspots for production and emission of the greenhouse gas, nitrous oxide (N2O), and represent a large proportion of total N2O emissions in ...many national agricultural greenhouse gas inventories. As such, there is much interest in developing country specific N2O emission factors (EFs) for excretal nitrogen (EF3, pasture, range and paddock) deposited during gazing. The aims of this study were to generate separate N2O emissions data for cattle derived urine and dung, to provide an evidence base for the generation of a country specific EF for the UK from this nitrogen source. The experiments were also designed to determine the effects of site and timing of application on emissions, and the efficacy of the nitrification inhibitor, dicyandiamide (DCD) on N2O losses. This co-ordinated set of 15 plot-scale, year-long field experiments using static chambers was conducted at five grassland sites, typical of the soil and climatic zones of grazed grassland in the UK. We show that the average urine and dung N2O EFs were 0.69% and 0.19%, respectively, resulting in a combined excretal N2O EF (EF3), of 0.49%, which is <25% of the IPCC default EF3 for excretal returns from grazing cattle. Regression analysis suggests that urine N2O EFs were controlled more by composition than was the case for dung, whilst dung N2O EFs were more related to soil and environmental factors. The urine N2O EF was significantly greater from the site in SW England, and significantly greater from the early grazing season urine application than later applications. Dycandiamide reduced the N2O EF from urine patches by an average of 46%. The significantly lower excretal EF3 than the IPCC default has implications for the UK's national inventory and for subsequent carbon footprinting of UK ruminant livestock products.
Display omitted
•First co-ordinated experiments in UK to generate data for country specific grazing excretal N2O EF•Urine had a significantly greater average N2O EF (0.69%) than dung (0.19%).•The combined excretal N2O EF was 0.49%, <25% of the IPCC default value for cattle.•DCD reduced the N2O EF from urine patches by an average of 46%.•Urine N2O was controlled by its composition, dung N2O was related to soil and environmental factors.
Intensification of grasslands is necessary to meet the increasing demand of livestock products. The application of nitrogen (N) on grasslands affects the N balance therefore the nitrogen use ...efficiency (NUE). Emissions of nitrous oxide (N2O) are produced due to N fertilisation and low NUE. These emissions depend on the type and rates of N applied. In this study we have compiled data from 5 UK N fertilised grassland sites (Crichton, Drayton, North Wyke, Hillsborough and Pwllpeiran) covering a range of soil types and climates. The experiments evaluated the effect of increasing rates of inorganic N fertiliser provided as ammonium nitrate (AN) or calcium ammonium nitrate (CAN). The following fertiliser strategies were also explored for a rate of 320 kg N ha−1: using the nitrification inhibitor dicyandiamide (DCD), changing to urea as an N source and splitting fertiliser applications. We measured N2O emissions for a full year in each experiment, as well as soil mineral N, climate data, pasture yield and N offtake. N2O emissions were greater at Crichton and North Wyke whereas Drayton, Hillsborough and Pwllpeiran had the smallest emissions. The resulting average emission factor (EF) of 1.12% total N applied showed a range of values for all the sites between 0.6 and 2.08%. NUE depended on the site and for an application rate of 320 kg N ha−1, N surplus was on average higher than 80 kg N ha−1, which is proposed as a maximum by the EU Nitrogen Expert Panel. N2O emissions tended to be lower when urea was applied instead of AN or CAN, and were particularly reduced when using urea with DCD. Finally, correlations between the factors studied showed that total N input was related to Nofftake and Nexcess; while cumulative emissions and EF were related to yield scaled emissions.
Display omitted
•N2O emissions and NUE were measured at 5 UK grassland sites.•Different fertilisation rates and strategies were tested in all sites.•Average N2O emission factor was 1.12%, but ranged from 0.60% to 2.08%.•Using urea and urea with DCD reduced N2O emission factor.•Yield scaled emissions and emissions relative to herbage N content show similar trend.
PDF
