Mrc1+ macrophage-derived IGF1 mitigates crystal nephropathy by promoting renal tubule cell proliferation via the AKT/Rb signaling pathway.

Rationale: The present understanding of the cellular characteristics and communications in crystal nephropathy is limited. Here, molecular and cellular studies combined with single-cell RNA sequencing (scRNA-seq) were performed to investigate the changes in cell components and their interactions in glyoxylate-induced crystallized kidneys to provide promising treatments for crystal nephropathy. Methods: The transcriptomes of single cells from mouse kidneys treated with glyoxylate for 0, 1, 4, or 7 days were analyzed via 10× Genomics, and the single cells were clustered and characterized by the Seurat pipeline. The potential cellular interactions between specific cell types were explored by CellChat. Molecular and cellular findings related to macrophage-to-epithelium crosstalk were validated in sodium oxalate (NaOx)-induced renal tubular epithelial cell injury in vitro and in glyoxylate-induced crystal nephropathy in vivo. Results: Our established scRNA atlas of glyoxylate-induced crystalline nephropathy contained 15 cell populations with more than 40000 single cells, including relatively stable tubular cells of different segments, proliferating and injured proximal tubular cells, T cells, B cells, and myeloid and mesenchymal cells. In this study, we found that Mrc1+ macrophages, as a subtype of myeloid cells, increased in both the number and percentage within the myeloid population as crystal-induced injury progresses, and distinctly express IGF1, which induces the activation of a signal pathway to dominate a significant information flow towards injured and proliferating tubule cells. IGF1 promoted the repair of damaged tubular epithelial cells induced by NaOx in vitro, as well as the repair of damaged tubular epithelial cells and the recovery of disease outcomes in glyoxylate-induced nephrolithic mice in vivo. Conclusion: After constructing a cellular atlas of glyoxylate-induced crystal nephropathy, we found that IGF1 derived from Mrc1+ macrophages attenuated crystal nephropathy through promoting renal tubule cell proliferation via the AKT/Rb signaling pathway. These findings could lead to the identification of potential therapeutic targets for the treatment of crystal nephropathy.

Airway acidification impaired host defense against Pseudomonas aeruginosa infection by promoting type 1 interferon ß response.

Airway microenvironment played an important role in the progression of chronic respiratory disease. Here we showed that standardized pondus hydrogenii (pH) of exhaled breath condensate (EBC) of bronchiectasis patients was significantly lower than that of controls and was significantly correlated with bronchiectasis severity index (BSI) scores and disease prognosis. EBC pH was lower in severe patients than that in mild and moderate patients. Besides, acidic microenvironment deteriorated Pseudomonas aeruginosa (P. aeruginosa) pulmonary infection in mice models. Mechanistically, acidic microenvironment increased P. aeruginosa outer membrane vesicles (PA_OMVs) released and boosted it induced the activation of interferon regulatory factor3 (IRF3)-interferonß (IFN-ß) signalling pathway, ultimately compromised the anti-bacteria immunity. Targeted knockout of IRF3 or type 1 interferon receptor (IFNAR1) alleviated lung damage and lethality of mice after P. aeruginosa infection that aggravated by acidic microenvironment. Together, these findings identified airway acidification impaired host resistance to P. aeruginosa infection by enhancing it induced the activation of IRF3-IFN-ß signalling pathway. Standardized EBC pH may be a useful biomarker of disease severity and a potential therapeutic target for the refractory P. aeruginosa infection. The study also provided one more reference parameter for drug selection and new drug discovery for bronchiectasis.

Combined toxicity of polystyrene microplastics and ammonium perfluorooctanoate to Daphnia magna: Mediation of intestinal blockage.

Microplastics (MPs) have worldwide accumulated in aquatic environments and coexisted with various water contaminants including perfluorinated compounds (PFCs) that are frequently detected. The adverse effects of individual MPs or PFCs on aquatic organisms have been extensively reported; however, the combined toxicity of MPs and PFCs remains unknown. This study evaluated the combined toxicity of MPs [pristine and aged polystyrene (PS)] and a PFC [ammonium perfluorooctanoate (APFO)] to Daphnia magna under different concentration ratios by three classic methods: toxicity unit, additive index, and mixed toxicity index. The adsorption kinetics of APFO on MPs, aggregation of MPs in exposure medium, MP gut fullness of daphnids, intestinal histology, and lipid peroxidation were analyzed to reveal the mechanism underlying the combined toxicity. Our results showed that the combined toxic modes varied with the concentration ratios of MPs to APFO (antagonism at 4:1 and 1:4, synergism at 3:1, 1:2, and 1:3, and partial addition/antagonism at 2:1 and 1:1 for pristine PS + APFO; antagonism at all ratios except partial addition/antagonism at 3:1 and 1:3 for aged PS + APFO), which could be attributed to the alteration of MP aggregation and thus MP gut fullness in the daphnids. The combined toxicity was further confirmed to occur in the daphnid's gut, which was reflected in physiological and biochemical responses mediated by intestinal blockage. Observable intestinal damages under co-exposures at µg•L-1 levels indicated the risks from future long-term exposure to MPs and PFCs in aquatic environments. This work demonstrates the necessity of assessing combined toxicity with different concentration ratios and provides new insights into the potential risks of MPs in aquatic environments.

In-situ sludge reduction performance and mechanism in an anoxic/aerobic process coupled with alternating aerobic/anaerobic side-stream reactor.

Activated sludge process with anaerobic side-stream reactors (SR) in the sludge recirculation can achieve in-situ sludge reduction, but sludge reduction efficiency is limited with the low hydraulic retention time (HRT) of SR. An anoxic/aerobic (AO) process, AO coupled with anaerobic SR and AO coupled with alternating aerobic/anaerobic side-stream reactor (AO-OASR) were operated to investigate enhancing effects of alternative aerobic and anaerobic condition (AltOA) in SR on sludge reduction and pollutants removal performance. The AltOA was firstly proposed into SR with a low HRT during the long-term continuous operation. The results showed that AO-OASR presented a lower effluent COD concentration (29.6%) with no adverse effect on nitrogen removal, compared to AO, owing to the intensified refractory carbon reuse in the mainstream aerobic tank. The sludge yield in AO-OASR (0.240 g SS/g COD) was 39.7% lower than that in AO. The OASR accelerated sludge lysis and particle organic matter hydrolysis due to the weakened network strength of flocs, leading to an enhanced increase (17.3 mg/L) of dissolved organic matter (DOM), especially for the fraction of molecular weight (MW) < 25 kDa. The OASR reduced the adenosine triphosphate (ATP) content for heterotrophic anabolism in the mainstream reactor by 42.9%, compared to the ASR. MW < 25 kDa of DOM caused the disturbance of oxidative phosphorylation with a decreasing ATP synthase activity under high-level electronic transport system, leading to ATP dissipation. The cooperation interaction of predator (norank_Chitinophagales), hydrolytic/fermentative bacteria (unclassified_Bacteroidia and Delftia), and slow grower (Trichococcus) played a key role in improving the sludge reduction and carbon reuse in AO-OASR. The results provided an efficient and cost-saving technology for sludge reduction with modified SR under low HRT, which is meaningful to overcome the present bottleneck of deficient reduction efficiency for application in wastewater treatment plants.