The ecology of the sewer systems: Microbial composition, function, assembly, and network in different spatial locations.

Microbial induced concrete corrosion (MICC) is the primary deterioration affecting global sewers. Disentangling ecological mechanisms in the sewer system is meaningful for implementing policies to protect sewer pipes using trenchless technology. It is necessary to understand microbial compositions, interaction networks, functions, alongside assembly processes in sewer microbial communities. In this study, sewer wastewater samples and microbial samples from the upper part (UP), middle part (MP) and bottom part (BP) of different pipes were collected for 16S rRNA gene amplicon analysis. It was found that BP harbored distinct microbial communities and the largest proportion of unique species (1141) compared to UP and MP. The community in BP tended to be more clustered. Furthermore, significant differences in microbial functions existed in different spatial locations, including the carbon cycle, nitrogen cycle and sulfur cycle. Active microbial sulfur cycling indicated the corrosion risk of MICC. Among the environmental factors, the oxidation‒reduction potential drove changes in BP, while sulfate managed changes in UP and BP. Stochasticity dominated community assembly in the sewer system. Additionally, the sewer microbial community exhibited numerous positive links. BP possessed a more complex, modular network with higher modularity. These deep insights into microbial ecology in the sewer system may guide engineering safety and disaster prevention in sewer infrastructure.

Multiphase comparative study for WHO/ISUP nuclear grading diagnostic model based on enhanced CT images of clear cell renal cell carcinoma.

To compare and analyze the diagnostic value of different enhancement stages in distinguishing low and high nuclear grade clear cell renal cell carcinoma (ccRCC) based on enhanced computed tomography (CT) images by building machine learning classifiers. A total of 51 patients (Dateset1, including 41 low-grade and 10 high-grade) and 27 patients (Independent Dateset2, including 16 low-grade and 11 high-grade) with pathologically proven ccRCC were enrolled in this retrospective study. Radiomic features were extracted from the corticomedullary phase (CMP), nephrographic phase (NP), and excretory phase (EP) CT images, and selected using the recursive feature elimination cross-validation (RFECV) algorithm, the group differences were assessed using T-test and Mann-Whitney U test for continuous variables. The support vector machine (SVM), random forest (RF), XGBoost (XGB), VGG11, ResNet18, and GoogLeNet classifiers are established to distinguish low-grade and high-grade ccRCC. The classifiers based on CT images of NP (Dateset1, RF: AUC = 0.82 ± 0.05, ResNet18: AUC = 0.81 ± 0.02; Dateset2, XGB: AUC = 0.95 ± 0.02, ResNet18: AUC = 0.87 ± 0.07) obtained the best performance and robustness in distinguishing low-grade and high-grade ccRCC, while the EP-based classifier performance in poorer results. The CT images of enhanced phase NP had the best performance in diagnosing low and high nuclear grade ccRCC. Firstorder_Kurtosis and firstorder_90Percentile feature play a vital role in the classification task.

Deubiquitination of CDC6 by OTUD6A promotes tumour progression and chemoresistance.

BACKGROUND: CDC6 is an oncogenic protein whose expression level fluctuates during the cell cycle. Although several E3 ubiquitin ligases responsible for the ubiquitin-mediated proteolysis of CDC6 have been identified, the deubiquitination pathway for CDC6 has not been investigated. METHODS: The proteome-wide deubiquitinase (DUB) screening was used to identify the potential regulator of CDC6. Immunofluorescence, protein half-life and deubiquitination assays were performed to determine the protein stability of CDC6. Gain- and loss-of-function experiments were implemented to analyse the impacts of OUTD6A-CDC6 axis on tumour growth and chemosensitivity in vitro. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced conditional Otud6a knockout (CKO) mouse model and tumour xenograft model were performed to analyse the role of OTUD6A-CDC6 axis in vivo. Tissue specimens were used to determine the association between OTUD6A and CDC6. RESULTS: OTUD6A interacts with, depolyubiquitinates and stabilizes CDC6 by removing K6-, K33-, and K48-linked polyubiquitination. Moreover, OTUD6A promotes cell proliferation and decreases sensitivity to chemotherapy by upregulating CDC6. CKO mice are less prone to BCa tumorigenesis induced by BBN, and knockdown of OTUD6A inhibits tumour progression in vivo. Furthermore, OTUD6A protein level has a positive correlation with CDC6 protein level, and high protein levels of OTUD6A and CDC6 are associated with poor prognosis in patients with bladder cancer. CONCLUSIONS: We reveal an important yet missing piece of novel DUB governing CDC6 stability. In addition, our findings propose a model for the OTUD6A-CDC6 axis that provides novel insights into cell cycle and chemosensitivity regulation, which may become a potential biomarker and promising drug target for cancer treatment.

Prognosis of Peritoneal Dialysis Patients with Different Peritoneal Transport Characteristics: A Retrospective Cohort Study.

INTRODUCTION: We aimed to examine the clinical characteristics of peritoneal dialysis (PD) patients with different baseline peritoneal transport characteristics and the effect of peritoneal transport characteristics on the prognosis of PD patients. METHODS: Patients who received PD for more than 3 months were included. Clinical characteristics, risk factors for high peritoneal transport, and risk factors for death and technique failure were examined. All patients were treated with glucose-containing peritoneal dialysis solution, and the peritoneal dialysis protocol was either day ambulatory peritoneal dialysis (DAPD) or continuous ambulatory peritoneal dialysis (CAPD). RESULTS: A total of 351 patients were enrolled, comprising 70 in the low transport group, 149 in the low average transport group, 88 in the high average transport group, and 44 in the high transport group. Multivariate logistic regression analysis showed that a high Charlson's comorbidity index (CCI) and low albumin were risk factors for a high baseline transport status. In the nonhigh transport group, the proportion of patients with albumin less than 30 g/L, who developed high transport status, was higher than those with albumin more than 30 g/L (P = .029). The survival rate in the high transport group was significantly lower than that in the other three groups (P < .001). Multivariate Cox regression analysis showed that age, systolic blood pressure, CCI, C-reactive protein (CRP) and high transport were independent risk factors for all-cause mortality. Male sex, triglycerides and CRP were independent risk factors for technique failure. CONCLUSION: High peritoneal transport status is an independent risk factor for death. High CCI and low albumin are determinants of baseline high peritoneal transport. To avoid development of a high transport state, serum albumin should be increased to more than 30 g/L.  DOI: 10.52547/ijkd.7617.

Study on Vertical Bearing Capacity of Pile Foundation with Distributed Geopolymer Post-Grouting on Pile Side.

To study the applicability of the new geopolymer grouting material for super-long and large-diameter post-grouting bored piles in silty fine sand geology, this paper compares the bearing capacity of two grouting materials, geopolymer and normal Portland cement, and different grouting volume pile side-distributed grouting piles in silty fine sand based on field model tests are analyzed through the diffusion forms of the two materials in silty fine sand through the morphology of the grouted body after excavation. The results show that the ultimate bearing capacities of P0 (ungrouted pile), P1 (8 kg cement grouted pile), P2 (6 kg geopolymer-grouted pile), P3 (8 kg geopolymer-grouted pile) and P4 (10 kg geopolymer-grouted pile) are 5400 N, 8820 N, 9450 N, 11,700 N and 12,600 N, respectively, and that the ultimate bearing capacity of the grouted pile is improved compared with that of the ungrouted pile since, under the same grouting amount, the maximum bearing capacity of the pile using geopolymer grouting is increased by 133% compared with that of the pile with cement grouting. This further verifies the applicability of the geopolymer grouting material for the post-grouting of the pile foundation in silty fine sand. Under the action of the ultimate load, the pile side friction resistance of P1, P2, P3 and P4 is increased by 200%, 218%, 284% and 319% compared with that of P0. In addition, the excavation results show that the geopolymer post-grouting pile forms the ellipsoidal consolidation body at the pile side grouting location, which mainly comprises extrusion diffusion with a small amount of infiltration diffusion, and the cement grouting pile forms a sheet-like consolidation body at the lower grouting location, which primarily comprises split diffusion. This study can provide a reference basis for the theoretical and engineering application of post-grouting piles using geopolymers.

Research and Application Progress of Vegetation Porous Concrete.

Vegetation porous concrete is a novel material that integrates concrete technology with plant growth, offering excellent engineering applicability and environmental friendliness. This material is mainly utilized in eco-engineering projects such as riverbank protection, architectural greening, and slope protection along roads. This paper systematically reviews the current research progress of vegetation porous concrete by collecting and analyzing the relevant literature from both domestic and international sources. It covers several aspects including the material components of vegetation porous concrete, such as aggregates, cementitious materials, chemical admixtures, and plant species, as well as aspects like mix design, workability, porosity, pH value, mechanical strength, and vegetative performance. Furthermore, the application of vegetation porous concrete in riverbank protection, slope protection along highways, and urban architecture is discussed, along with a prospective outlook on future research directions for vegetation porous concrete.

Gut microbiome in men with chronic prostatitis/chronic pelvic pain syndrome: profiling and its predictive significance.

PURPOSE: To investigate the difference in gut microbiome composition between patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and healthy controls, and to assess the potential of gut microbiota as predictive markers for CP/CPPS risk. METHODS: The present study included 41 CP/CPPS patients and 43 healthy controls in China. Fecal specimen data were obtained and analysed using 16S rRNA gene sequencing. Alpha and beta-diversity indices, relative microbiome abundances, cluster analysis, and linear discriminant analysis effect size (LEfSe) were employed. Microbial biomarkers were selected for the development of a diagnostic classification model, and the functional prediction was conducted using PICRUSt2. RESULTS: Alpha-diversity measures revealed no statistically significant difference in bacterial community structure between CP/CPPS patients and controls. However, significant differences were observed in the relative abundances of several bacterial genera. Beta-diversity analysis revealed a distinct separation between the two groups. Significant inter-group differences were noted at various taxonomic levels, with specific bacterial genera being significantly different in abundance. The LEfSe analysis indicated that three bacterial species were highly representative and seven bacterial species were low in CP/CPPS patients as compared to the control group. A diagnostic model for CP/CPPS based on microbial biomarkers exhibited good performance. PICRUSt2 functional profiling indicated significant differences in the development and regeneration pathway. CONCLUSION: Significant differences in the gut microbiome composition were found between groups. The study provided a novel diagnostic model for CP/CPPS based on microbiota, presenting promising potential for future therapeutic targets and non-invasive diagnostic biomarkers for CP/CPPS patients.

Knockdown of AK142426 suppresses M2 macrophage polarization and inflammation in peritoneal fibrosis via binding to c-Jun.

BACKGROUND: Peritoneal fibrosis is a common complication of peritoneal dialysis, which may lead to ultrafiltration failure and ultimately treatment discontinuation. LncRNAs participate in many biological processes during tumorigenesis. We investigated the role of AK142426 in peritoneal fibrosis. METHODS: The AK142426 level in peritoneal dialysis (PD) fluid was detected by quantitative real-time-PCR assay. The M2 macrophage distribution was determined by flow cytometry. The inflammatory cytokines of TNF-α and TGF-ß1 were measured by ELISA assay. The direct interaction between AK142426 and c-Jun was evaluated by RNA pull-down assay. In addition, the c-Jun and fibrosis related proteins were assessed by western blot analysis. RESULTS: The PD-induced peritoneal fibrosis mouse model was successfully established. More importantly, PD treatment induced M2 macrophage polarization and the inflammation in PD fluid, which might be associated with exosome transmission. Fortunately, AK142426 was observed to be upregulated in PD fluid. Mechanically, knockdown of AK142426 suppressed M2 macrophage polarization and inflammation. Furthermore, AK142426 could upregulate c-Jun through binding c-Jun protein. In rescue experiments, overexpression of c-Jun could partially abolish the inhibitory effect of sh-AK142426 on the activation of M2 macrophages and inflammation. Consistently, knockdown of AK142426 alleviated peritoneal fibrosis in vivo. CONCLUSIONS: This study demonstrated that knockdown of AK142426 suppressed M2 macrophage polarization and inflammation in peritoneal fibrosis via binding to c-Jun, suggesting that AK142426 might be a promising therapeutic target for patients of peritoneal fibrosis.

A supramolecular assembly strategy for hydrophilic drug delivery towards synergistic cancer treatment.

To improve the drug loading, tumor targeting, and delivery simplicity of hydrophilic drugs, we propose a supramolecular assembly strategy that potentially benefits a wide range of hydrophilic drug delivery. Firstly, we choose a hydrophilic drug (tirapazamine) as a model drug to directly co-assemble with chlorin e6 (Ce6) at different molar ratios, and systematically evaluate the resultant Ce6-tirapazamine nanoparticles (CT NPs) in aspects of size distribution, polydispersity, morphology, optical properties and molecular dynamics simulation. Based on the assembling facts between Ce6 and tirapazamine, we summarize a plausible rule of the supramolecular assembly for hydrophilic drugs. To validate our findings, more drugs with increasing hydrophilicity, such as temozolomide, gemcitabine hydrochloride and 5-azacytidine, successfully co-assemble with Ce6 into nanostructures by following similar assembling behaviors, demonstrating that our assembling rule may guide a wide range of hydrophilic drug delivery. Next, the combination of Ce6 and tirapazamine was chosen as the representative to investigate the anti-tumor activities of the supramolecular assemblies. CT NPs showed synergistic anti-tumor efficacy, increased tumor accumulation and significant tumor progression and metastasis inhibition in tumor-bearing mice. We anticipate that the supramolecular assembly mechanism will provide broad guidance for developing easy-to-make but functional nanomedicines. STATEMENT OF SIGNIFICANCE: Although thousands of nanomedicines have been developed, only a few have been approved for clinical use. The manufacturing complexity significantly hinders the "bench-to-bed" translation of nanomedicines. Hence, we need to rethink how to conduct research on translational nanomedicines by avoiding more and more complex chemistry and complicated nanostructures. Here, we summarize a plausible rule according to multiple supramolecular assembly pairs and propose a supramolecular assembly strategy that can improve the drug loading, tumor targeting, and manufacturing simplicity of nanomedicine for hydrophilic drugs. The supramolecular assembly strategy would guide a broader range of drug delivery to provide a new paradigm for developing easy-to-make but multifunctional nanoformulations for synergistic cancer treatment.

Pain Trajectory after Short-Stay Anorectal Surgery: A Prospective Observational Study.

The evolution of pain after anorectal surgery has not been well characterized. The main objective of this study is to evaluate patterns in acute postoperative pain in patients undergoing short-stay anorectal surgery. A total of 217 patients were included in the study, which used group-based trajectory modeling to estimate postoperative pain and then examined the relationships between sociodemographic or surgical factors and pain trajectories. Three distinct postoperative pain trajectories were determined: hemorrhoidectomy (OR, 0.15), higher anxiety (OR, 3.26), and a higher preoperative pain behavior score (OR, 3.15). In multivariate analysis, they were associated with an increased likelihood of being on the high pain trajectory. The pain trajectory group was related to postoperative analgesic use (p < 0.001), with the high-low group needing more nonsteroidal analgesics. The study showed that there were three obvious pain trajectories after anorectal surgery, including an unreported low-moderate-low type. More than 60% of patients maintained moderate to severe pain within 7 days after the operation. These postoperative pain trajectories were predominantly defined by surgery factors and patient factors.

Effects of acute normovolemic hemodilution on allogeneic blood transfusion & coagulation in orthognathic surgery: A randomized study.

BACKGROUND: Acute normovolemic hemodilution (ANH) is one of the important techniques predominantly used in cardiac, hepatic, and vascular surgery for decreasing allogeneic blood transfusion. However, the effect of ANH in orthognathic surgery has been rarely studied. Therefore, this study aims to assess the ANH-mediated reduction in the allogeneic red blood cell transfusion for orthognathic surgery patients. STUDY DESIGN AND METHODS: In this single-center study, 18-80 years old patients were recruited. Patients with hemoglobin ≥11 g/dL and normal coagulation function were randomly divided into ANH or standard treatment group. RESULTS: Ninety six patients underwent ANH, and 101 patients received standard treatment. No differences in demographic or major pre-operative characteristics were observed between the two groups. One patient in the ANH and three patients in the standard treatment group received allogeneic blood [3(2.97%) vs. 1(1.16%), control vs. ANH, p = .395]. Multivariate logistic regression analysis revealed that ANH treatment was not associated with transfusion of allogeneic blood (p = .763). After retransfusing autologous blood, PT and APTT in the ANH group significantly increased compared to standard treatment group (PT: -1.73 ± 1.09 vs. -2.15 ± 1.06, p = .035; APTT: -6.39 ± 5.76 vs. -8.16 ± 5.70, p = .031; control vs. ANH). No significant differences between the two groups were observed for changes in coagulation parameters at first postoperative day. However, platelet counts in the ANH group decreased compared to the standard group. No significant difference in major adverse outcomes was observed between the two groups. CONCLUSION: ANH did not reduce the incidence of allogeneic transfusion in patients undergoing orthognathic surgery.

Assessment of Two-Vehicle and Multi-Vehicle Freeway Rear-End Crashes in China: Accommodating Spatiotemporal Shifts.

Accounting for the growing numbers of injuries, fatalities, and property damage, rear-end crashes are an urgent and serious topic nowadays. The vehicle number involved in one crash significantly affected the injury severity outcomes of rear-end crashes. To examine the transferability and heterogeneity across crash types (two-vehicle versus multi-vehicle) and spatiotemporal stability of determinants affecting the injury severity of freeway rear-end crashes, this study modeled the data of crashes on the Beijing-Shanghai Freeway and Changchun-Shenzhen Freeway across 2014-2019. Accommodating the heterogeneity in the means and variances, the random parameters logit model was proposed to estimate three potential crash injury severity outcomes (no injury, minor injury, and severe injury) and identify the determinants in terms of the driver, vehicle, roadway, environment, temporal, spatial, traffic, and crash characteristics. The likelihood ratio tests revealed that the effects of factors differed significantly depending on crash type, time, and freeway. Significant variations were observed in the marginal effects of determinants between two-vehicle and multi-vehicle freeway rear-end crashes. Then, spatiotemporal instability was reported in several determinants, including trucks early morning. In addition, the heterogeneity in means and variances of the random parameters revealing the interactions of random parameters and other insignificant variables suggested the higher risk of determinants including speeding indicators, early morning, evening time, and rainy weather conditions. The current finding accounting for spatiotemporal instability could help freeway designers, decision-makers, management strategies to understand the contributing mechanisms of the factors to develop effective management strategies and measurements.

Role of IGF-1R in epithelial-mesenchymal transdifferentiation of human peritoneal mesothelial cells.

BACKGROUND: Peritoneal fibrosis (PF) is caused by epithelial-mesenchymal transdifferentiation (EMT) in the peritoneum under high glucose (HG) conditions. The study aimed to explored the role of Insulin-like growth factor 1 receptor (IGF-1R) in the regulation of EMT in human peritoneal mesothelial cells (HPMCs). METHODS: We used HG peritoneal dialysis fluid (PDF) to induce in vivo PF in mice, and treated HPMCs with HG in vitro to stimulate EMT. RESULTS: In the mice, the higher the glucose concentration in the dialysate, the more obvious the peritoneal tissue thickening and the more that collagen was deposited. The in vitro study indicated that the expression of IGF-1R, α-SMA, vimentin was upregulated, while the expression of occludin, ZO-1, and E-cadherin was downregulated in HPMCs under HG and IGF-1R overexpression conditions. Conversely, the expression of IGF-1R, α-SMA, and vimentin was downregulated, while the expression of occludin, ZO-1, and E-cadherin was upregulated in IGF-1R-underexpressed HPMCs under HG conditions. The cell migration abilities were increased, while the cell adhesion abilities were reduced in HPMCs under HG and IGF-1R overexpression conditions. In contrast, cell migration abilities were reduced, while cell adhesion abilities were increased in IGF-1Runderexpressed HPMCs under HG conditions. CONCLUSIONS: Targeting at IGF-1R may provide novel insights into the prevention and treatment of PF.

Comprehensive analysis of N6-methyladenosine regulators with the tumor immune landscape and correlation between the insulin-like growth factor 2 mRNA-binding protein 3 and programmed death ligand 1 in bladder cancer.

BACKGROUND: N6-methyladenosine (m6A) is one of the most abundant post-transcriptional modifications of RNA. However, there is limited information about the potential roles of m6A regulators in tumor immunity. Therefore, in this study, we aimed to testify the functions of m6A regulators in bladder cancer as well as their association with the tumor immune landscape. METHODS: We reported the variation and expression levels of m6A regulators in the TCGA database and GTEx database of bladder cancer. Clusters, risk score patterns, and nomograms were constructed to evaluate the function and prognostic value of m6A regulators. Furthermore, we constructed nomogram to evaluate the prognosis of the individual patients. The correlation between insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and programmed cell death ligand 1 (PD-L1) was evaluated both in vitro and in vivo. RESULTS: We found that the tumor grade and DNA damage pathways were strongly correlated with distinct clusters. Furthermore, two risk score groups with six m6A regulators were identified using the least absolute shrinkage and selection operator (LASSO) and multivariable Cox regression analysis, which could be regarded as independent prognostic markers in patients with bladder cancer. The risk score pattern was linked to the tumor immune landscape, indicating a correlation between immune checkpoints and m6A regulators. Moreover, an m6A regulator, IGF2BP3, was found to be highly expressed in the tumor samples, regulating both the total and membrane-bound PD-L1 expression levels. CONCLUSIONS: The results of this study revealed that the m6A clusters and patterns play crucial roles in the regulation of tumor immunity, which may be used to develop comprehensive treatment strategies for the management of bladder cancer.

Associations Between Obesity and Kidney Disease in Chinese Men and Women With Type 2 Diabetes: A Retrospective Cohort Study.

BACKGROUND: Our aim in this study was to explore the risk factors for kidney disease in Chinese men and women with type 2 diabetes (T2D) and to clarify the relationship between obesity and the risk of chronic kidney disease (CKD). METHODS: This retrospective study included 3,194 patients with T2D. Among 2,574 T2D patients without CKD at baseline, 753 with follow-up records of at least 12 months were included in the retrospective cohort. Logistic regression and Cox regression were used to evaluate the risk for CKD in men and women. A restricted cubic spline model was used to analyze the association of body mass index (BMI) and waist circumference (WC) with CKD risk. RESULTS: Multivariate logistic regression analysis suggested that obesity was a risk factor for T2D with CKD in men but not in women. After a median follow-up period of 2.8 years, the incidence of CKD in men with obesity was significantly higher than that in men with obesity with T2D (p=0.039), but there was no statistically significant difference between women with obesity and women without obesity with T2D (p=0.825). In the restricted cubic spline model analysis, BMI and WC were associated with CKD risk in a nonlinear fashion in males and females. The risk of CKD was higher in males with a BMI of ≥29.5 kg/m2 or a WC of ≥100 cm, whereas there was no difference observed in females. CONCLUSIONS: Obesity was strongly related to T2D with CKD in men. Male diabetes patients with obesity, especially abdominal obesity, are more likely to develop CKD.

Core-Shell MOF-in-MOF Nanopore Bifunctional Host of Electrolyte for High-Performance Solid-State Lithium Batteries.

Solid-state lithium-ion batteries with high safety are the encouraging next-generation rechargeable electrochemical energy storage devices. Yet, low Li+ conductivity of solid electrolyte and instability of solid-solid interface are the key issues hampering the practicability of the solid electrolyte. In this research, core-shell MOF-in-MOF nanopores UIO-66@67 are proposed as a unique bifunctional host of ionic liquid (IL) to fabricate core-shell ionic liquid-solid electrolyte (CSIL). In the current design of CSIL, the shell structure (UIO-67) has a large pore size and a high specific surface area, boosting the absorption amount of ionic liquid electrolyte, thus increasing the ionic conductivity. Nevertheless, the core structure (UIO-66) has a small pore size compared to the ionic liquid, which can confine the large ions, decreasing their mobility, and selectively boost the transport of Li+ . The CSIL solid electrolyte exhibits considerable enhancement in the lithium transference number (tLi + ) and ionic conductivity compared to the homogenous porous host (pure UIO-66 and UIO-67). Additionally, the Li|CSIL|Li symmetric batteries maintain a stable polarization of less than 28 mV for more than 1000 h at 1000 µA cm-2 . Overall, the results demonstrate the concept of core-shell MOF-in-MOF nanopores as a promising bifunctional host of electrolytes for solid-state or quasi-solid-state rechargeable batteries.

Macrophages regulates the transition of pericyte to peritoneal fibrosis through the GSDMD/IL-1ß axis.

BACKGROUND: End stage renal disease (ESRD) has caused public health problem with high prevalence worldwide. Peritoneum from peritoneal dialysis patients with ESRD can induce pathological changes of the peritoneum, including fibrosis. The trans-differentiation of pericytes has been found to be closely associated with inflammatory diseases, such as organ fibrosis. However, the function of macrophages in regulating the transition of pericyte to peritoneal fibrosis is unclear. METHODS: Histological examination was conducted using Hematoxylin and eosin (HE) staining and Masson's trichrome staining. The protein levels were determined via western blot. Enzyme-linked immunosorbent assay (ELISA) was used to examine IL-1ß concentrations. Gasdermin D (GSDMD) was knocked out in mice by Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-Associated 9 (CRISPR-Cas9). RESULTS: Mice receiving dextrose peritoneal dialysate displayed mesothelial cell monolayer loss and thickness of submesothelial compact zone increase. Moreover, dextrose peritoneal dialysate treatment up-regulated GSDMD expression. GSDMD knockdown inhibited IL-1ß production in macrophages. Further, pericytes were treated with cultural supernatant from macrophages. We found that GSDMD knockdown suppressed fibrosis and vascular endothelial growth factor (VEGF)/phosphoinositide 3-kinase (PI3K) pathway in pericytes. In addition, GSDMD were knocked out in mice using CRISPR/Cas9. The histological examinations revealed that GSDMD-/- alleviated the damage of peritoneal tissue and thickness of submesothelial compact zone. GSDMD-/- attenuated interleukin-1beta (IL-1ß) level and peritoneal fibrosis induced by dextrose peritoneal dialysate treatment in pericytes in vivo. CONCLUSION: These results demonstrated that macrophages can regulate the transition of pericyte to peritoneal fibrosis via the GSDMD/IL-1ß axis, which provides a new therapeutic target.

Identification of a Nuclear Mitochondrial-Related Multi-Genes Signature to Predict the Prognosis of Bladder Cancer.

INTRODUCTION: Bladder cancer (BC) is one of the most prevalent urinary cancers, and its management is still a problem causing recurrence and progression, elevating mortality. MATERIALS AND METHODS: We aimed at the nuclear mitochondria-related genes (MTRGs), collected from the MITOMAP: A Human Mitochondrial Genome Database. Meanwhile, the expression profiles and clinical information of BC were downloaded from the Cancer Genome Atlas (TCGA) as a training group. The univariate, multivariate, and the least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to construct a nuclear mitochondrial-related multi-genes signature and the prognostic nomogram. RESULTS: A total of 17 nuclear MTRGs were identified to be correlated with the overall survival (OS) of BC patients, and a nuclear MTRGs signature based on 16 genes expression was further determined by the LASSO Cox regression analysis. Based on a nuclear MTRGs scoring system, BC patients from the TCGA cohort were divided into high- and low- nuclear MTRGs score groups. Patients with a high nuclear MTRGs score exhibited a significantly poorer outcome (median OS: 92.90 vs 20.20 months, p<0.0001). The nuclear MTRGs signature was further verified in three independent datasets, namely, GSE13507, GSE31684, and GSE32548, from the Gene Expression Omnibus (GEO). The BC patients with a high nuclear MTRGs score had significantly worse survival (median OS in GSE13507: 31.52 vs 98.00 months, p<0.05; GSE31684: 32.85 months vs unreached, p<0.05; GSE32548: unreached vs unreached, p<0.05). Furthermore, muscle-invasive bladder cancer (MIBC) patients had a significantly higher nuclear MTRGs score (p<0.05) than non-muscle-invasive bladder cancer (NMIBC) patients. The integrated signature outperformed each involved MTRG. In addition, a nuclear MTRGs-based nomogram was constructed as a novel prediction prognosis model, whose AUC values for OS at 1, 3, 5 years were 0.76, 0.75, and 0.75, respectively, showing the prognostic nomogram had good and stable predicting ability. Enrichment analyses of the hallmark gene set and KEGG pathway revealed that the E2F targets, G2M checkpoint pathways, and cell cycle had influences on the survival of BC patients. Furthermore, the analysis of tumor microenvironment indicated more CD8+ T cells and higher immune score in patients with high nuclear MTRGs score, which might confer sensitivity to immune checkpoint inhibitors. CONCLUSIONS: Not only could the signature and prognostic nomogram predict the prognosis of BC, but it also had potential therapeutic guidance.

Nrf2 attenuates ferroptosis-mediated IIR-ALI by modulating TERT and SLC7A11.

Acute lung injury (ALI) carries a mortality rate of ~50% and is a hot topic in the world of critical illness research. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical modulator of intracellular oxidative homeostasis and serves as an antioxidant. The Nrf2-related anti-oxidative stress is strongly associated with ferroptosis suppression. Meanwhile, telomerase reverse transcriptase (TERT), the catalytic portion of the telomerase protein, is reported to travel to the mitochondria to alleviate ROS. In our study, we found that TERT was significantly reduced in lung tissue of Nrf2-/- mice in the model of intestinal ischemia/reperfusion-induced acute lung injury (IIR-ALI). In addition, MDA levels showed marked increase, whereas GSH and GPX4 levels fell drastically in ALI models. Moreover, typical-related structural changes were observed in the type II alveolar epithelial cells in the IIR model. We further employed the scanning transmission X-ray microscopy (STXM) to examine Fe levels and distribution within cells. Based on our observations, massive aggregates of Fe were found in the MLE-12 cells upon OGD/R (oxygen and glucose deprivation/reperfusion) induction. Additionally, Nrf2 silencing dramatically reduced TERT and SLC7A11 levels, and further exacerbated cellular injuries. In contrast, TERT-overexpressing cells exhibited marked elevation in SLC7A11 levels and thereby inhibited ferroptosis. Collectively, these data suggest that Nrf2 can negatively regulate ferroptosis via modulation of TERT and SLC7A11 levels. The conclusion from this study brings insight into new candidates that can be targeted in future IIR-ALI therapy.