Niche-Selective Inhibition of Pathogenic Th17 Cells by Targeting Metabolic Redundancy.

Targeting glycolysis has been considered therapeutically intractable owing to its essential housekeeping role. However, the context-dependent requirement for individual glycolytic steps has not been fully explored. We show that CRISPR-mediated targeting of glycolysis in T cells in mice results in global loss of Th17 cells, whereas deficiency of the glycolytic enzyme glucose phosphate isomerase (Gpi1) selectively eliminates inflammatory encephalitogenic and colitogenic Th17 cells, without substantially affecting homeostatic microbiota-specific Th17 cells. In homeostatic Th17 cells, partial blockade of glycolysis upon Gpi1 inactivation was compensated by pentose phosphate pathway flux and increased mitochondrial respiration. In contrast, inflammatory Th17 cells experience a hypoxic microenvironment known to limit mitochondrial respiration, which is incompatible with loss of Gpi1. Our study suggests that inhibiting glycolysis by targeting Gpi1 could be an effective therapeutic strategy with minimum toxicity for Th17-mediated autoimmune diseases, and, more generally, that metabolic redundancies can be exploited for selective targeting of disease processes.

Lactate activates the mitochondrial electron transport chain independently of its metabolism.

Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation.

The histone chaperone CAF-1 cooperates with the DNA methyltransferases to maintain Cd4 silencing in cytotoxic T cells.

The transcriptional repression of alternative lineage genes is critical for cell fate commitment. Mechanisms by which locus-specific gene silencing is initiated and heritably maintained during cell division are not clearly understood. To study the maintenance of silent gene states, we investigated how the Cd4 gene is stably repressed in CD8+ T cells. Through CRISPR and shRNA screening, we identified the histone chaperone CAF-1 as a critical component for Cd4 repression. We found that the large subunit of CAF-1, Chaf1a, requires the N-terminal KER domain to associate with the histone deacetylases HDAC1/2 and the histone demethylase LSD1, enzymes that also participate in Cd4 silencing. When CAF-1 was lacking, Cd4 derepression was markedly enhanced in the absence of the de novo DNA methyltransferase Dnmt3a but not the maintenance DNA methyltransferase Dnmt1. In contrast to Dnmt1, Dnmt3a deficiency did not significantly alter levels of DNA methylation at the Cd4 locus. Instead, Dnmt3a deficiency sensitized CD8+ T cells to Cd4 derepression mediated by compromised functions of histone-modifying factors, including the enzymes associated with CAF-1. Thus, we propose that the heritable silencing of the Cd4 gene in CD8+ T cells exploits cooperative functions among the DNA methyltransferases, CAF-1, and histone-modifying enzymes.

Retraction Note: DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions.

Change History: This Article has been retracted; see accompanying Retraction. Corrected online 20 January: In this Article, author Frank Rigo was incorrectly listed with a middle initial; this has been corrected in the online versions of the paper.

A comparative life cycle assessment of recycling waste concrete powder into CO2-Capture products.

Waste concrete powder (WCP), a byproduct of construction and demolition (C&D), currently has a low degree of recycling despite its potential for environmentally friendly applications. WCP can serve as a valuable substitute for cement, offering advantages for resource conservation and carbon sequestration. However, there are very few studies that quantitatively assess the environmental impact of incorporating WCP into the circular economy as a secondary material instead of disposing of it. The energy-intensive processing of WCP raises questions about the optimal carbonation time using available equipment. This study aims to fill this knowledge gap by employing carbon footprint and life cycle assessments (LCA) to optimize WCP recycling. Three recycling WCP scenarios are analyzed. The first scenario involved the conversion of WCP into compacts that absorb CO2 during the carbonation process. The results of the first scenario revealed that the optimal carbonation time for WCP compacts was 8 h, during which 42.7 kg CO2-e per tonne of WCP compacts was sequestered. The total global warming potential (GWP) was -4.22 kgCO2-e, indicating a carbon-negative recycling process. In the second and third scenarios, LCA was conducted to compare the use of carbonated and uncarbonated WCP as a partial replacement for cement in concrete. In these scenarios, it was found that uncarbonated WCP is a more effective solution for reducing the carbon footprint of traditional concrete mixes, achieving a significant 16% reduction of GWP when 20% of cement is replaced. Conversely, using carbonated WCP as a partial cement replacement in concrete mixtures shows limited potential for CO2 uptake. The sensitivity analysis reveals that the carbon footprint of the WCP compacts production process is strongly influenced by the electricity supplier used.

Coupled effects of elevated CO2 and biochar on microbial communities of vegetated soil.

Soil microbial communities are important for plant growth and establishing healthy ecosystems. Although biochar is widely adopted as a sustainable fertilizer, its influence on soil ecological functions is still unclear, especially under climate change such as elevated carbon dioxide concentration (eCO2). This study explores the coupled effects between eCO2 and biochar on microbial communities in soil planted with tree seedlings of Schefflera heptaphylla. Root characteristics and soil microbial communities were examined and interpreted with statistical analysis. Results show that biochar application at ambient carbon dioxide concentration (aCO2) always improves plant growth, which is further promoted under eCO2. Similarly, ß-glucosidase, urease and phosphatase activities are enhanced by biochar at aCO2 (p < 0.05). In contrast, only urease activity increases with biochar added at eCO2 (p < 0.05). The beneficial effects of biochar on soil enzyme activities become less significant at eCO2. Depending on biochar type, biochar can increase bacterial diversity and fungal richness at aCO2. However, at eCO2, biochar does not significantly affect microbial richness (p > 0.05) while microbial diversity is reduced by peanut shell biochar (p < 0.05). Owing to better plant growth under biochar application and eCO2, plants are likely to become more dominant in specializing the microbial communities that are favourable to them. In such community, the abundance of Proteobacteria is the greatest and increases after biochar addition at eCO2. The most abundant fungus also shifts from Rozellomycota to Ascomycota and Basidiomycota. These microbes can improve soil fertility. Even though the microbial diversity is reduced, using biochar at eCO2 can further promote plant growth, which in turn enhances carbon sequestration. Thus, biochar application can be an effective strategy to facilitate ecological restoration under climate change and relieve the problem of eCO2.

DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions.

T helper 17 (TH17) lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by RORγt, a ligand-regulated nuclear receptor. Here we identify the RNA helicase DEAD-box protein 5 (DDX5) as a RORγt partner that coordinates transcription of selective TH17 genes, and is required for TH17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with RORγt and coactivate its targets depends on intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA), Rmrp, which is mutated in patients with cartilage-hair hypoplasia. A targeted Rmrp gene mutation in mice, corresponding to a gene mutation in cartilage-hair hypoplasia patients, altered lncRNA chromatin occupancy, and reduced the DDX5-RORγt interaction and RORγt target gene transcription. Elucidation of the link between Rmrp and the DDX5-RORγt complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation, and provides new opportunities for therapeutic intervention in TH17-dependent diseases.

Regional citrate anti-coagulation dose titration: impact on dose of continuous renal replacement therapy.

BACKGROUND: Regional citrate anti-coagulation (RCA) is the recommended anti-coagulation for continuous renal replacement therapy (CRRT). Citrated replacement fluids provide convenience but may compromise effluent delivery when adjusted to maintain circuit ionised calcium levels (circuit-iCa). This study aims to evaluate the effect of RCA titration on the delivered CRRT effluent dose. METHODS: This prospective observational study evaluated patients on RCA-CRRT in continuous veno-venous hemodiafiltration mode. Citrated replacement fluid was titrated to target circuit-iCa 0.26-0.40 mmol/L. Patients were then stratified into 'reduced-dose' who required citrate down-titration and 'stable-dose' who did not. RESULTS: Data from 200 RCA-CRRT sessions were collected. The reduced-dose RCA group (n = 114) had higher median initial citrate dose (3.00 vs 2.50; P < 0.001) but lower time-averaged dose (2.49 vs 2.60; P < 0.001). In addition, median prescribed effluent dose was 33.3 mL/kg/h (28.6-39.2) but median delivered effluent dose was significantly lower at 29.9 mL/kg/h (25.4-36.9; P < 0.001). Mortality was higher in the reduced-dose RCA group (39.5% vs 25.6%; P = 0.022) and in patients with delivered-to-prescribed effluent dose ratio of < 0.9 vs ≥ 0.9 (51.3% vs 29.2%; P = 0.014). CONCLUSION: RCA titration can significantly impact delivered CRRT effluent dose. Measures should be taken to address the CRRT dose deficit and prevent poor outcomes due to inadequate dialysis.

Quality and yield of Pseudostellaria heterophylla treated with GGBS as pH adjuster against the toxicity of Cd and Cu.

The contamination of Cd and Cu in soil is a great threat to medicinal plant. Ground granulated blast furnace slag (GGBS) is a potential soil pH adjuster to reduce metal toxicity. However, how GGBS affects the quality and yield of herbal plants under the stress of Cd and Cu is not clear. This study aims to investigate the quality and yield of a medicinal plant (Pseudostellaria heterophylla) responding to GGBS treatment in Cd and Cu contaminated soil. GGBS with three mass percentages (0%, 3%, 5%) was added into contaminated lateritic soils for planting. Each condition had 21 replicated seedlings. The concentrations of Cd and Cu in plant, amounts of active ingredients (polysaccarides and saponins) in medicinal organ, and tuber properties were measured after harvest. The results showed that under 3% and 5% GGBS treatments, Cd and Cu accumulations in all plant organs (leaf, stem, root and tuber) were reduced by 69.4-86.0% and 10.3-30.1%, respectively. They were below the permissible limits (World Health Organization, WHO). Even though the concentrations of active ingredients in P. heterophylla tuber decreased by up to 35.8%, they still met Hong Kong Chinese Materia Medica standard. Besides, the biomass of root tuber increased by 9.8% and 46%, due to 3% and 5% GGBS treatments, respectively. The recommended 5% GGBS treatment in practice can balance the reduction of active ingredients and the increase of plant yield when minimizing Cd and Cu accumulation in tuber.