Elevation of IL-8 secretion induced by PEDV infection via NF-κB signaling pathway.

Porcine epidemic diarrhea virus (PEDV) is associated with severe enteritis, which contributes to high mortality in piglets. The aim of this study was to describe molecular mechanisms associated with proinflammatory cytokine(s) production during PEDV infection. We showed that infection of porcine intestine epithelial cell clone J2 (IPEC-J2) with PEDV induces a gradual increase in interleukin 8 (IL-8) production at different time points, as well as infection of Vero E6 with PEDV. The secretion of IL-8 in these two cell lines infected with PEDV is related to the activation of NF-κB. Furthermore, the cells expressing PEDV M or E protein can induce the upregulation of IL-8. These findings suggest that the IL-8 production can be the initiator of inflammatory response by the host cells upon PEDV infection.

ERK5 promotes autocrine expression to sustain mitogenic balance for cell fate specification in human pluripotent stem cells.

The homeostasis of human pluripotent stem cells (hPSCs) requires the signaling balance of extracellular factors. Exogenous regulators from cell culture medium have been widely reported, but little attention has been paid to the autocrine factor from hPSCs themselves. In this report, we demonstrate that extracellular signal-related kinase 5 (ERK5) regulates endogenous autocrine factors essential for pluripotency and differentiation. ERK5 inhibition leads to erroneous cell fate specification in all lineages even under lineage-specific induction. hPSCs can self-renew under ERK5 inhibition in the presence of fibroblast growth factor 2 (FGF2) and transforming growth factor ß (TGF-ß), although NANOG expression is partially suppressed. Further analysis demonstrates that ERK5 promotes the expression of autocrine factors such as NODAL, FGF8, and WNT3. The addition of NODAL protein rescues NANOG expression and differentiation phenotypes under ERK5 inhibition. We demonstrate that constitutively active ERK5 pathway allows self-renewal even without essential growth factors FGF2 and TGF-ß. This study highlights the essential contribution of autocrine pathways to proper maintenance and differentiation.

Enhancing the production of reactive oxygen species in the rhizosphere to promote contaminants degradation in sediments by electrically strengthening microbial extracellular electron transfer.

The production of reactive oxygen species (ROS) in the rhizosphere is limited by the low extracellular electron transfer capacity of indigenous microorganisms. In the present study, electrical stimulation was used to promote the generation of rhizospheric ROS by accelerating extracellular electron transfer. The result showed that •OH concentrations in the electrically stimulated group (ES group) exceeded the control group by 15.76 %. Accordingly, the removal rate of the target pollutant (i.e., 2,4-dichlorophenol, and sulfamethoxazole) was 20.01 %-24.80 % higher in the ES group than in the control group. The sediment of the ES group had a higher capacity (30.55 %) and a lower electrical resistance (29.15 %) compared to the control group, which subsequently promoted the dissimilatory iron reduction to produce Fe(II) for triggering a Fenton-like process. The increased extracellular respiratory capacity under electrical stimulation could be attributed to the polarization of C-N and CO bonds, which provided more electron storage sites and thus participated in proton-coupled electron transfer. In addition, the concentration of ATP and co-enzymes (NADH/NAD+ and Complex I/Complex III), reflecting electron exchange within respiratory chains, increased distinctly under electrical stimulation. Applying electrical stimulation seemed feasible to increase ROS production and contaminant degradation in the rhizosphere, deepening the understanding of electrical stimulation to promote the production of ROS in the natural system.

Integrated Cyano Groups into the Skeleton of Conjugated Polymers to Activate Molecular Oxygen for Boosting Photocatalytic H2O2 Efficiency.

Conjugated polymers (CPs) have shown promising potential in the field of hydrogen peroxide (H2O2) photosynthesis. However, a deeper understanding of the interactions between building units and specific functional groups within the molecular skeleton is necessary to elucidate the mechanisms driving H2O2 generation. Herein, a series of typical donor-acceptor (D-A) conjugated polymers (B-B, B-CN, B-DCN) were synthesized by introducing different amounts of cyano groups (-CN) into the molecular skeleton. The strong electron withdrawing properties of cyano can greatly promote the effective separation and transfer of photogenerated charges between building units, resulting in an impressive efficiency of H2O2 generation (2128.5 µmol g-1 h-1) for B-DCN, representing a 96-fold enhancement compared to B-B. More importantly, experimental results and theoretical calculations further revealed that the introduction of -CN can markedly reduce the adsorption energy (Ead) of O2, while serving as an active site to induce the conversion of crucial intermediate superoxide anions (.O2-) into singlet oxygen (1O2), achieving dual-channel H2O2 generation (O2→.O2-→H2O2, O2→.O2-→1O2→H2O2). This work provides valuable insights into the design of efficient H2O2 photosynthesis materials.

KLF9 regulates osteogenic differentiation of mesenchymal stem cells.

Osteoporosis is a progressive skeletal disease which is characterized by reduced bone mass and degradation of bone microstructure. Mesenchymal stem cells (MSCs) have the potential to inhibit osteoporosis since they are multipotent stem cells that can differentiate into multiple types of cells including osteoblasts. Hence the mechanism of osteogenic differentiation of MSCs deserves comprehensive study. Here we report that KLF9 is a novel regulator in osteogenic differentiation of MSCs. We observed that depletion of KLF9 can largely compromise the osteogenic differentiation ability of MSCs. In addition, we revealed that inhibition of the PI3K-Akt pathway could also affect osteogenic differentiation since KLF9 depletion inhibits PI3K expression. Finally, we discovered that KLF9 expression can be induced by dexamethasone which is an essential component in osteogenic induction medium. Taken together, our study provides new insights into the regulatory role of KLF9 in osteogenic differentiation of MSCs.

Deprivation of methionine inhibits osteosarcoma growth and metastasis via C1orf112-mediated regulation of mitochondrial functions.

Osteosarcoma is a malignant bone tumor that primarily inflicts the youth. It often metastasizes to the lungs after chemotherapy failure, which eventually shortens patients' lives. Thus, there is a dire clinical need to develop a novel therapy to tackle osteosarcoma metastasis. Methionine dependence is a special metabolic characteristic of most malignant tumor cells that may offer a target pathway for such therapy. Herein, we demonstrated that methionine deficiency restricted the growth and metastasis of cultured human osteosarcoma cells. A genetically engineered Salmonella, SGN1, capable of overexpressing an L-methioninase and hydrolyzing methionine led to significant reduction of methionine and S-adenosyl-methionine (SAM) specifically in tumor tissues, drastically restricted the growth and metastasis in subcutaneous xenograft, orthotopic, and tail vein-injected metastatic models, and prolonged the survival of the model animals. SGN1 also sharply suppressed the growth of patient-derived organoid and xenograft. Methionine restriction in the osteosarcoma cells initiated severe mitochondrial dysfunction, as evident in the dysregulated gene expression of respiratory chains, increased mitochondrial ROS generation, reduced ATP production, decreased basal and maximum respiration, and damaged mitochondrial membrane potential. Transcriptomic and molecular analysis revealed the reduction of C1orf112 expression as a primary mechanism underlies methionine deprivation-initiated suppression on the growth and metastasis as well as mitochondrial functions. Collectively, our findings unraveled a molecular linkage between methionine restriction, mitochondrial function, and osteosarcoma growth and metastasis. A pharmacological agent, such as SGN1, that can achieve tumor specific deprivation of methionine may represent a promising modality against the metastasis of osteosarcoma and potentially other types of sarcomas as well.

Application and progress of new technologies and new materials in the treatment of pathological scar.

Pathological scars (PS), including hypertrophic scars (HTS) and keloids, are a common complication of poor wound healing that significantly affects patients' quality of life. Currently, there are several treatment options for PS, including surgery, drug therapy, radiation therapy, and biological therapy. However, these treatments still face major challenges such as low efficacy, high side effects, and a high risk of recurrence. Therefore, the search for safer and more effective treatments is particularly urgent. New materials often have less immune rejection, good histocompatibility, and can reduce secondary damage during treatment. New technology can also reduce the side effects of traditional treatments and the recurrence rate after treatment. Furthermore, derivative products of new materials and biomaterials can improve the therapeutic effect of new technologies on PS. Therefore, new technologies and innovative materials are considered better options for enhancing PS. This review concentrates on the use of two emerging technologies, microneedle (MN) and photodynamic therapy (PDT), and two novel materials, photosensitizers and exosomes (Exos), in the treatment of PS.

Fermented bile acids improved growth performance and intestinal health by altering metabolic profiles and intestinal microbiome in Micropterus salmoides.

A type of fermented bile acids (FBAs) has been produced through a biological method, and its effects on growth performance, metabolism, and intestinal microbiota in largemouth bass were investigated. The results demonstrated that incorporating 0.03 %-0.05 % FBAs diet could improve the final weight, weight gain and specific growth rate, and decrease the feed conversion ratio. Dietary FBAs did not significantly affect the levels of high-density lipoprotein, low-density lipoprotein, and triglycerides, but decreased the activities of α-amylase in most groups. Adding FBAs to the diet significantly increased the integrity of the microscopic structure of the intestine, thickened the muscular layer of the intestine, and notably enhanced its intestinal barrier function. The addition of FBAs to the diet increased the diversity of the gut microbiota in largemouth bass. At the phylum level, there was an increase in the abundance of Proteobacteria, Firmicutes, Tenericutes and Cyanobacteria and a significant decrease in Actinobacteria and Bacteroidetes. At the genus level, the relative abundance of beneficial bacteria Mycoplasma in the GN6 group and Coprococcus in the GN4 group significantly increased, while the pathogenic Enhydrobacter was inhibited. Meanwhile, the highest levels of AKP and ACP were observed in the groups treated with 0.03 % FBAs, while the highest levels of TNF-α and IL-10 were detected in the group treated with 0.04 % FBAs. Additionally, the highest levels of IL-1ß, IL-8T, GF-ß, IGF-1, and IFN-γ were noted in the group treated with 0.06 % FBAs. These results suggested that dietary FBAs improved growth performance and intestinal wall health by altering lipid metabolic profiles and intestinal microbiota in largemouth bass.

Dynamic Mechanical Properties and Modified Johnson-Cook Model Considering Recrystallization Softening for Nickel-Based Powder Metallurgy Superalloys.

The material undergoes high temperature and high strain rate deformation process during the cutting process, which may induce the dynamic recrystallization behavior and result in the evolution of dynamic mechanical properties of the material to be machined. In this paper, the modified Johnson-Cook (J-C) model for nickel-based powder metallurgy superalloy considering dynamic recrystallization behavior in high strain rate and temperature is proposed. The dynamic mechanical properties of the material under different strain rates and temperature conditions are obtained by quasi-static compression test and split Hopkinson pressure bar (SHPB) test. The coefficients of the modified J-C model are obtained by the linear regression method. The modified model is verified by comparison with experimental and model prediction results. The results show that the modified J-C model proposed in this paper can accurately describe the mechanical properties of nickel-based powder metallurgy superalloys at high temperatures and high strain rates. This provides help for studying the cutting mechanism and finite element simulation of nickel-based powder metallurgy superalloy.

Assessment of Changes in Body Composition After 3 Months of Dulaglutide Treatment.

Background: Changes in body composition accompanied by glucagon-like peptide 1 receptor agonist (GLP-1RA) induced weight loss have drawn much attention. However, fewer studies have reported body composition changes in patients receiving dulaglutide therapy in Chinese population. Methods: A total of 70 overweight/obese type 2 diabetes mellitus (T2DM) patients who received dulaglutide therapy were included. Clinical data were collected. Visceral fat area (VFA) and body composition were also measured. Changes in clinical indicators and body composition of patients before and after intervention were also analyzed. Correlation analysis and multiple linear regression model were used to evaluate the association between hemoglobin A1C (HbA1c) and body composition. Results: The results showed that body weight (BW), VFA, body fat (BF), lean body mass (LBM), skeletal muscle mass (SMM) and water content were reduced after 3 months dulaglutide intervention. The lean body mass percentage (LBMP) and skeletal muscle mass percentage (SMMP) significantly increased. Moreover, there was no significant difference in bone mineral quality (BMQ) after the intervention. The multiple linear regression model revealed that the % change in BF was independently associated with % change in HbA1c (ß = 0.449, t = 3.148, p=0.002). Conclusion: These results indicate that dulaglutide intervention does not cause muscle and bone mass loss while inducing weight loss, and % change in BF was independently associated with improved glucose control during dulaglutide therapy. This study offers some positive results to support the clinical application of dulaglutide.

POZ/BTB and AT hook containing zinc finger 1 (PATZ1) suppresses differentiation and regulates metabolism in human embryonic stem cells.

Human embryonic stem cells (hESCs) can proliferate infinitely (self-renewal) and give rise to almost all types of somatic cells (pluripotency). Hence, understanding the molecular mechanism of pluripotency regulation is important for applications of hESCs in regenerative medicine. Here we report that PATZ1 is a key factor that regulates pluripotency and metabolism in hESCs. We found that depletion of PATZ1 is associated with rapid downregulation of master pluripotency genes and prominent deceleration of cell growth. We also revealed that PATZ1 regulates hESC pluripotency though binding the regulatory regions of OCT4 and NANOG. In addition, we demonstrated PATZ1 is a key node in the OCT4/NANOG transcriptional network. We further revealed that PATZ1 is essential for cell growth in hESCs. Importantly, we discovered that depletion of PATZ1 drives hESCs to exploit glycolysis which energetically compensates for the mitochondrial dysfunction. Overall, our study establishes the fundamental role of PATZ1 in regulating pluripotency in hESCs. Moreover, PATZ1 is essential for maintaining a steady metabolic homeostasis to refine the stemness of hESCs.

Conserved mechanisms of self-renewal and pluripotency in mouse and human ESCs regulated by simulated microgravity using a 3D clinostat.

Embryonic stem cells (ESCs) exhibit unique attributes of boundless self-renewal and pluripotency, making them invaluable for fundamental investigations and clinical endeavors. Previous examinations of microgravity effects on ESC self-renewal and differentiation have predominantly maintained a descriptive nature, constrained by limited experimental opportunities and techniques. In this investigation, we present compelling evidence derived from murine and human ESCs, demonstrating that simulated microgravity (SMG)-induced stress significantly impacts self-renewal and pluripotency through a previously unidentified conserved mechanism. Specifically, SMG induces the upregulation of heat shock protein genes, subsequently enhancing the expression of core pluripotency factors and activating the Wnt and/or LIF/STAT3 signaling pathways, thereby fostering ESC self-renewal. Notably, heightened Wnt pathway activity, facilitated by Tbx3 upregulation, prompts mesoendodermal differentiation in both murine and human ESCs under SMG conditions. Recognizing potential disparities between terrestrial SMG simulations and authentic microgravity, forthcoming space flight experiments are imperative to validate the impact of reduced gravity on ESC self-renewal and differentiation mechanisms.

POU Class 2 Homeobox Associating Factor 1, as a Hub Candidate Gene in OP, Relieves Osteoblast Apoptosis.

Increasing evidence suggests that osteoblast apoptosis contributes to the pathogenesis of postmenopausal osteoporosis (PMOP). This study aimed to identify a hub gene associated with osteoporosis (OP) progression and its functions. We utilized the GSE68303 expression dataset from GEO database and conducted weighted gene co-expression network analysis (WGCNA) to investigate changes in co-expressed genes between sham and ovariectomy (OVX) groups. Differentially expressed genes (DEGs) were identified using the "limma" R package on GSE68303 dataset. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the DAVID database. A protein-protein interaction (PPI) network was constructed using the STRING database, which was visualized by Cytoscape software. The top ten hub genes were screened using the Cytohubba plugin, among which POU class 2 homeobox associating factor 1 (POU2AF1), an OP-related hub gene, showed a significant increase in OVX-induced mouse model based on immunohistochemical staining. Inhibition of POU2AF1 suppressed cell viability, induced cell cycle arrest at the G1 phase, and promoted osteoblast apoptosis as demonstrated by CCK-8 assay, flow cytometry analysis, and TUNEL assay. Moreover, overexpression of POU2AF1 decreased cleaved caspase-3/-8/-9 expression while increasing cyclinD1 and Ki67 expression in MC3T3-E1 and hFOB1.19 cells. Therefore, POU2AF1 may serve as a potential diagnostic biomarker for slowing down the progression of OP.

New insights into inhibition of high Fe(III) content on anaerobic digestion of waste-activated sludge.

The impacts of the increased iron in the waste-activated sludge (WAS) on its anaerobic digestion were investigated. It was found that low Fe(III) content (< 750 mg/L) promoted WAS anaerobic digestion, while the continual increase of Fe(III) inhibited CH4 production and total chemical oxygen demand (TCOD) removal. As the Fe(III) content increased to 1470 mg/L, methane production has been slightly inhibited about 5 % compared with the group containing 35 mg/L Fe(III). Particularly, as Fe(III) concentration was up to 2900 mg/L, CH4 production, and TCOD removal decreased by 43.6 % and 37.5 %, respectively, compared with the group with 35 mg/L Fe(III). Furthermore, the percentage of CO2 of the group with 2900 mg/L Fe(III) decreased by 52.8 % compared with the group containing 35 mg/L Fe(III). It indicated that Fe(II) generated by the dissimilatory iron reduction might cause CO2 consumption, which was confirmed by X-ray diffraction that siderite (FeCO3) was generated in the group with 2900 mg/L Fe(III). Further study revealed that Fe(III) promoted the WAS solubilization and hydrolysis, but inhibited acidification and methane production. The methanogenesis test with H2/CO2 as a substrate showed that CO2 consumption weakened hydrogenotrophic methanogenesis and then increased H2 partial pressure, further causing VFA accumulation. Microbial community analysis indicated that the abundance of hydrogen-utilizing methanogens decreased with the high Fe(III) content. Our study suggested that the increase of Fe(III) in sludge might inhibit methanogenesis by consuming or precipitating CO2. To achieve maximum bioenergy conversion, the iron content should be controlled to lower than 750 mg/L. The study may provide new insights into the mechanistic understanding of the inhibition of high Fe(III) content on the anaerobic digestion of WAS.

Prognosis prediction based on methionine metabolism genes signature in gliomas.

BACKGROUND: Glioma cells have increased intake and metabolism of methionine, which can be monitored with 11 C-L-methionine. However, a short half-life of 11 C (~ 20 min) limits its application in clinical practice. It is necessary to develop a methionine metabolism genes-based prediction model for a more convenient prediction of glioma survival. METHODS: We evaluated the patterns of 29 methionine metabolism genes in glioma from the Cancer Genome Atlas (TCGA). A risk model was established using Lasso regression analysis and Cox regression. The reliability of the prognostic model was validated in derivation and validation cohorts (Chinese Glioma Genome Atlas; CGGA). GO, KEGG, GSEA and ESTIMATE analyses were performed for biological functions and immune characterization. RESULTS: Our results showed that a majority of the methionine metabolism genes (25 genes) were involved in the overall survival of glioma (logrank p and Cox p < 0.05). A 7-methionine metabolism prognostic signature was significantly related to a poor clinical prognosis and overall survival of glioma patients (C-index = 0.83). Functional analysis revealed that the risk model was correlated with immune responses and with epithelial-mesenchymal transition. Furthermore, the nomogram integrating the signature of methionine metabolism genes manifested a strong prognostic ability in the training and validation groups. CONCLUSIONS: The current model had the potential to improve the understanding of methionine metabolism in gliomas and contributed to the development of precise treatment for glioma patients, showing a promising application in clinical practice.

BRD9-mediated control of the TGF-ß/Activin/Nodal pathway regulates self-renewal and differentiation of human embryonic stem cells and progression of cancer cells.

Bromodomain-containing protein 9 (BRD9) is a specific subunit of the non-canonical SWI/SNF (ncBAF) chromatin-remodeling complex, whose function in human embryonic stem cells (hESCs) remains unclear. Here, we demonstrate that impaired BRD9 function reduces the self-renewal capacity of hESCs and alters their differentiation potential. Specifically, BRD9 depletion inhibits meso-endoderm differentiation while promoting neural ectoderm differentiation. Notably, supplementation of NODAL, TGF-ß, Activin A or WNT3A rescues the differentiation defects caused by BRD9 loss. Mechanistically, BRD9 forms a complex with BRD4, SMAD2/3, ß-CATENIN and P300, which regulates the expression of pluripotency genes and the activity of TGF-ß/Nodal/Activin and Wnt signaling pathways. This is achieved by regulating the deposition of H3K27ac on associated genes, thus maintaining and directing hESC differentiation. BRD9-mediated regulation of the TGF-ß/Activin/Nodal pathway is also demonstrated in the development of pancreatic and breast cancer cells. In summary, our study highlights the crucial role of BRD9 in the regulation of hESC self-renewal and differentiation, as well as its participation in the progression of pancreatic and breast cancers.

Extracellular vesicles from bone marrow mesenchymal stem cells alleviate osteoporosis in mice through USP7-mediated YAP1 protein stability and the Wnt/ß-catenin pathway.

Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) have emerged as promising tools for promoting bone regeneration. This study investigates the functions of EVs derived from bone marrow-derived MSCs (BMSCs) in osteoporosis (OP) and the molecular mechanism. EVs were isolated from primary BMSCs in mice. A mouse model with OP was induced by ovariectomy. Treatment with EVs restored bone mass and strength, attenuated trabecular bone loss and cartilage damage, and increased osteogenesis while suppressing osteoclastogenesis in ovariectomized mice. In vitro, the EVs treatment improved the osteogenic differentiation of MC-3T3 while inhibiting osteoclastic differentiation of RAW264.7 cells. Microarray analysis revealed a significant upregulation of ubiquitin specific peptidase 7 (USP7) expression in mouse bone tissues following EV treatment. USP7 was found to interact with Yes1 associated transcriptional regulator (YAP1) and stabilize YAP1 protein through deubiquitination modification. YAP1-related genes were enriched in the Wnt/ß-catenin signaling, and overexpression of YAP1 promoted the nuclear translocation of ß-catenin. Functional experiments underscored the critical role of maintaining USP7, YAP1, and ß-catenin levels in the pro-osteogenic and anti-osteoclastogenic properties of the BMSC-EVs. In conclusion, this study demonstrates that USP7, delivered by BMSC-derived EVs, stabilizes YAP1 protein, thereby ameliorating bone formation in OP through the Wnt/ß-catenin activation.