Induced pluripotent stem cells were created from a pancreas agenesis patient with a mutation in GATA6. Using genome-editing technology, additional stem cell lines with mutations in both GATA6 alleles ...were generated and demonstrated a severe block in definitive endoderm induction, which could be rescued by re-expression of several different GATA family members. Using the endodermal progenitor stem cell culture system to bypass the developmental block at the endoderm stage, cell lines with mutations in one or both GATA6 alleles could be differentiated into β-like cells but with reduced efficiency. Use of suboptimal doses of retinoic acid during pancreas specification revealed a more severe phenotype, more closely mimicking the patient’s disease. GATA6 mutant β-like cells fail to secrete insulin upon glucose stimulation and demonstrate defective insulin processing. These data show that GATA6 plays a critical role in endoderm and pancreas specification and β-like cell functionality in humans.
•GATA6 is required for definitive endoderm specification in human ES/iPS cells•Bypassing the endoderm defect allows GATA6 mutants to generate β-like cells•Suboptimal retinoic acid signaling blocks pancreas specification in GATA6 mutants•GATA6 is critical for human β cell function in vitro
In this study, Gadue and colleagues studied GATA6 mutant pluripotent stem cells and demonstrate that GATA6 is necessary for human definitive endoderm specification. GATA6 also plays an important role in pancreas specification which could be partially bypassed by retinoic acid signaling. Furthermore, derivative β cells lacked glucose responsiveness in vitro, showing that GATA6 is vital for appropriate human pancreas development.
The objective of the present study was to measure emissions of N₂O from fertilized grazed grassland that can be used to add valuable information to the limited existing data on N₂O fluxes from grazed ...grassland and aid the development of new country-specific EFs for direct emissions from soils in the UK. This was done by evaluating the effect on N₂O emissions of inorganic fertiliser N applied to grazed grassland soils over the range of N inputs 0-350kgha⁻¹. Nitrous oxide fluxes were measured using closed static chambers at 3 sites in England and Wales over a two-year period. Cumulative fluxes were calculated and the total emission regressed against applied inorganic fertiliser N in order to estimate the emission factor for N₂O emissions from soils. The data showed that, the emission factor for N₂O from inorganic fertiliser applied to grazed grassland soils in the UK differs from the IPCC default value of 1.25%. A nonlinear response of N₂O emissions to fertiliser N application rates was observed. Annual emissions of N₂O were estimated from a modelled function fitted to the measured data and after subtraction of the background flux resulted in emissions of 0.5 and 3.9kgN₂O-Nha⁻¹ yr⁻¹ for an application of 100kg N for three locations in the UK, one in the East and the other two in the West of the UK (after combining the data from two sites), respectively.
The role of beef in human diets has been questioned over the last few decades, due largely to its typically high mass-based carbon footprint. However, recent advancements in sustainability literature ...challenge this paradigm based on the new theory that climate impacts of food commodities should be measured relative to their overall nutritional value rather than their nominal mass. This shift has opened a new opportunity for the global beef industry, and especially for pasture-based systems that can avoid food-feed competition for land and other resources, as beef is a nutritionally dense food. Nonetheless, the sector’s true capability to supply a wide range of nutrients for humans, consistently across multiple systems under multiple weather patterns, has not been well-documented. Using whole-system datasets from the North Wyke Farm Platform in the South West of England, we investigated the nutritional value of beef produced from the three most common pasture systems in temperate regions: permanent pasture (PP), grass and white clover (GWC) and a short-term monoculture grass ley (MG). Beef produced from these three pasture systems was analysed for key nutrients (fatty acids, minerals and vitamin E) over three production cycles (2015–2017) to determine potential differences between systems. Fatty acid, mineral and vitamin E profiles of the pasture and silage fed to each group were also assessed, with subtle differences between pastures reported. For beef, subtle differences were also observed between systems, with GWC having higher omega-6 polyunsaturated fatty acid (PUFA) concentrations than PP and MG. However, the overall nutritional quality of beef was found to be largely comparable across all systems, suggesting that temperate pasture-based beef can be classified as a single commodity in future sustainability assessments, regardless of specific sward types. A 100 g serving of temperate pasture-based beef was found to be a high source (>20% recommended daily intake: RDI) of protein, monounsaturated fatty acids, saturated fatty acids, vitamins – B2, B3, B12 and minerals – Fe, P, Zn; a good source (10–19% RDI) of vitamin – B6 and mineral – K; and a complementary source (5–9% RDI) of omega-3 PUFA, vitamin – B9 and minerals – Cu, Mg, Se. The nutritional value of a food item should be used in defining its environmental cost (e.g. carbon footprint) to make fair comparisons across different food groups (e.g. protein sources). Here, we showed that pasture-based beef had a nutrient indexed carbon footprint of between 0.19 and 0.23 Kg CO2-eq/1% RDI of key nutrients.
Non-alcoholic fatty liver disease (NAFLD) affects over 30% of adults in the United States. Bone morphogenetic protein (BMP) signaling is known to contribute to hepatic fibrosis, but the role of BMP ...signaling in the development of NAFLD is unclear. In this study, treatment with either of two BMP inhibitors reduced hepatic triglyceride content in diabetic (db/db) mice. BMP inhibitor-induced decrease in hepatic triglyceride levels was associated with decreased mRNA encoding Dgat2, an enzyme integral to triglyceride synthesis. Treatment of hepatoma cells with BMP2 induced DGAT2 expression and activity via intracellular SMAD signaling. In humans we identified a rare missense single nucleotide polymorphism in the BMP type 1 receptor ALK6 (rs34970181;R371Q) associated with a 2.1-fold increase in the prevalence of NAFLD. In vitro analyses revealed R371Q:ALK6 is a previously unknown constitutively active receptor. These data show that BMP signaling is an important determinant of NAFLD in a murine model and is associated with NAFLD in humans.
The environmental performance of urban neighbourhoods is a crucial indicator to measure the sustainability of the built urban form, especially as cities face increased urbanisation and densified ...development. With new construction contributing significantly to global carbon emissions, there is a need to understand how modifications in the urban form can affect its environmental performance at the scale of the neighbourhood. This research addresses this need by developing a Planning Support System workflow to aid decision-making in urban planning in order to analyse environmental performance, focusing on thermal comfort and solar energy potential. It explores the relationship between urban form and the selected environmental performance indicators while utilising freely available 3D geoinformation data of the Netherlands. It develops simplified workflows using established plug-ins and open-source 3D software that can be replicated by smaller municipalities with resource constraints, thus removing barriers to 3D-data based data-driven decision making for sustainable and informed urban planning.
This paper introduces new insights into the integration of thermostatically controlled loads (TCLs) as hybrid energy sources for grid ancillary and demand response services. Leveraging a generalized ...virtual battery (VB) model emerges as an effective approach to determine maximum reserve capacity of these aggregated devices. Our research extends the VB model and endeavors to establish a pragmatic framework for EWH control for peak shaving and managing the payback effect. The importance of aggregator capacity in mitigating the impacts of TCL external control, such as customer comfort and safety, is emphasized. Electric water heaters (EWHs) are used as the residential TCL device given their extensive availability and thermal capacity. Two TCL control scenarios, OFF control and ON/OFF control are compared using the Model Predictive Control (MPC) method. The ON/OFF control was found to improve peak shaving capability by approximately 47% when compared to the more rudimentary OFF control mechanism. The main contributions of this study are threefold: assessment of maximum reserve capacity using a modified VB model, creation of a reference control signal based on this result, and development of effective control strategies for managing the payback effect when maximal reserves are utilized. The robustness of the maximum capacity estimation is analyzed through a sensitivity analysis mainly driven by variations in hot water consumption and communication loss. Comprehensive and comparative simulation results show improved capabilities in the utilization of the maximum reserved energy of loads, minimizing the expected payback to avoid additional energy peaks and assessing the impacts of external factors that can affect the expected maximum capacity of the VB.
Alveolar epithelial type 2 (AT2) cells harbor the facultative progenitor capacity in the lung alveolus to drive regeneration after lung injury. Using single-cell transcriptomics, software-guided ...segmentation of tissue damage, and in vivo mouse lineage tracing, we identified the grainyhead transcription factor cellular promoter 2-like 1 (Tfcp2l1) as a regulator of this regenerative process. Tfcp2l1 loss in adult AT2 cells inhibits self-renewal and enhances AT2-AT1 differentiation during tissue regeneration. Conversely, Tfcp2l1 blunts the proliferative response to inflammatory signaling during the early acute injury phase. Tfcp2l1 temporally regulates AT2 self-renewal and differentiation in alveolar regions undergoing active regeneration. Single-cell transcriptomics and lineage tracing reveal that Tfcp2l1 regulates cell fate dynamics across the AT2-AT1 differentiation and restricts the inflammatory program in murine AT2 cells. Organoid modeling shows that Tfcp2l1 regulation of interleukin-1 (IL-1) receptor expression controlled these cell fate dynamics. These findings highlight the critical role Tfcp2l1 plays in balancing epithelial cell self-renewal and differentiation during alveolar regeneration.
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•Tfcp2l1 maintains temporal and spatial AT2 self-renewal during lung regeneration•Tfcp2l1 regulates AT2-AT1 cell differentiation in regional zones of active regeneration•Tfcp2l1 dampens the early response to the inflammatory milieu through control of Il1r1
Cardenas-Diaz et al. use single-cell transcriptomics, software-guided segmentation of tissue damage, and mouse lineage tracing to interrogate the role of Tfcp2l1 in alveolar type 2 cells during lung regeneration. Tfcp2l1 regulates cell fate dynamics across AT2-AT1 differentiation and restricts the inflammatory program in murine AT2 cells.
•Urinary nitrogen concentrations were lowest on animals consuming high sugar grasses.•However, soil under high sugar grasses recorded the highest N2O emissions.•Synthetic urine generated N2O ...emissions inconsistent with locally collected urine.•Differences in emissions amongst systems were explained by gene abundance ratios.•Results indicate the importance of soil-pasture-animal-microbiome interactions.
Pasture-based livestock farming contributes considerably to global emissions of nitrous oxide (N2O), a powerful greenhouse gas approximately 265 times more potent than carbon dioxide. Traditionally, the estimation of N2O emissions from grasslands is carried out by means of plot-scale experiments, where externally sourced animal excreta are applied to soils to simulate grazing conditions. This approach, however, fails to account for the impact of different sward types on the composition of excreta and thus the functionality of soil microbiomes, creating unrealistic situations that are seldom observed under commercial agriculture. Using three farming systems under contrasting pasture management strategies at the North Wyke Farm Platform, an instrumented ruminant grazing trial in Devon, UK, this study measured N2O emissions from soils treated with cattle urine and dung collected within each system as well as standard synthetic urine shared across all systems, and compared these values against those from two forms of controls with and without inorganic nitrogen fertiliser applications. Soil microbial activity was regularly monitored through gene abundance to evaluate interactions between sward types, soil amendments, soil microbiomes and, ultimately, N2O production. Across all systems, N2O emissions attributable to cattle urine and standard synthetic urine were found to be inconsistent with one another due to discrepancy in nitrogen content. Despite previous findings that grasses with elevated levels of water-soluble carbohydrates tend to generate lower levels of N2O, the soil under high sugar grass monoculture in this study recorded higher emissions when receiving excreta from cattle fed the same grass. Combined together, our results demonstrate the importance of evaluating environmental impacts of agriculture at a system scale, so that the feedback mechanisms linking soil, pasture, animals and microbiomes are appropriately considered.
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