Distinct photochemistry of adsorbed and coprecipitated dicarboxylates with ferrihydrite: Implications for iron reductive dissolution and carbon stabilization.

Although ligand-promoted photodissolution of ferrihydrite (FH) has long been known for low molecular weight organic acids (LMWOAs), such as oxalate (Oxa) and malonate (Mal), photochemistry of coprecipitated FH with Oxa and Mal remains unknown, despite the importance of these mineral-organic associations in carbon retention has been acknowledged recently. In this study, ferrihydrite-LMWOAs associations (FLAs) were synthesized under circumneutral conditions. Photo-dissolution kinetics of FLAs were compared with those of adsorbed LMWOAs on FH surface and dissolved Fe-LMWOAs complexes through monitoring Fe(II) formation and organic carbon decay. For aqueous Fe(III)-LMWOAs complexes, Fe(II) yield was controlled by the initial concentration of LMWOAs and nature of photochemically generated carbon-centered radicals. Inner-sphere mononuclear bidentate (MB) configuration dominated while LMWOAs were adsorbed on the FH surface. MB complex of FH-Oxa was more photoreactive, leading to the rapid depletion of Oxa. Oxa can be readsorbed but in the form of binuclear bidentate and outer-sphere complexation, with much lower photoreactivity. While LMWOAs was coprecipitated with FH, the combination mode of LMWOAs with FH includes surface adsorption with a mononuclear bidentate structure and internal physical inclusion. Higher content of LMWOAs in the FLAs promoted the photo-production of Fe(II) as compared to pure FH, while it was not the case for FLAs containing moderate amounts of LMWOAs. The distinct photochemistry of adsorbed and coprecipitated Fe-LMWOAs complexes is attributed to ligand availability and configuration patterns of LMWOAs on the surface or entrapped in the interior structure. The present findings have significant implications for understanding the photochemical redox cycling of iron across the interface of Fe-organic mineral associates.

Phosphate-mediated degradation of organic pollutants in water with peroxymonosulfate revisited: Radical or non-radical oxidation?

Whilst it is generally recognized that phosphate enables to promote the removal of some organic pollutants with peroxymonosulfate (PMS) oxidation, however, there is an ongoing debate as to whether free radicals are involved. By integrating different methodologies, here we provide new insights into the reaction mechanism of the binary mixture of phosphates (i.e., NaH2PO4, Na2HPO3, and NaH2PO2) with peroxymonosulfate (PMS) or hydrogen peroxide (H2O2). Enhanced degradation of organic pollutants and observation of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) adducts (i.e. DMPOOH and 5,5-dimethyl-2-oxopyrroline-1-oxyl (DMPOX)) with electron paramagnetic resonance (EPR) in most phosphates/PMS system seemly support a radical-dominant mechanism. However, fluorescence probe experiments confirm that no significant amount of hydroxyl radicals (•OH) are produced in such reaction systems. PMS in the phosphate solutions (without any organics) remains relatively stable, but is only consumed while organic substrates are present, which is distinct from a typical radical-dominant Co2+/PMS system where PMS is continuously decomposed. Through density functional theory (DFT) calculation, the energy barriers of the phosphates/PMS reaction processes are greatly decreased when non-radical mechanism dominates. Complementary evidence suggests that the reactive intermediates of PMS-phosphate complex, rather than the free radicals, are capable of oxidizing electron-rich substrates such as DMPO and organic pollutants. Taking the case of phosphate/PMS system as an example, this study demonstrates the necessity of acquisition of lines of evidence for resolving paradoxes in identifying EPR adducts.

Reproductive Outcomes of Conventional In Vitro Fertilization and Intracytoplasmic Sperm Injection in Patients with Non-Severe Male Infertility Across Poor and Different Sub-Optimal Ovarian Response Categories: A Cohort Study Based on 30,352 Fresh Cycles from 2009-2019.

Due to the influence of economic, social and many other factors, there are more and more reproductive problems. Originally introduced for managing male factor infertility, intracytoplasmic sperm injection had become the most commonly used fertilization treatment in the world, with broadened indications including low oocyte yield, prior fertilization failure with conventional in vitro fertilization etc. However, academic evidence for better live-birth outcomes of intracytoplasmic sperm injection over conventional in vitro fertilization is limited. Thus, we aimed to compare the reproductive outcomes of conventional in vitro fertilization and intracytoplasmic sperm injection in patients with non-severe male factor infertility across poor and different sub-optimal ovarian response categories. The fertility rate, implantation rate, clinical pregnancy rate, live birth rate and other obstetric outcomes were mainly compared. Our results showed that independent of the number of oocytes retrieved, intracytoplasmic sperm injection significantly increased the fertilization rate, while conventional in vitro fertilization cycles showed a higher implantation rate, clinical pregnancy rate, and live birth rate. No differences were observed in most obstetric outcomes. Our study indicates that poor ovarian response is not an indication for intracytoplasmic sperm injection in couples with non-severe male infertility.

The SOX4/EZH2/SLC7A11 signaling axis mediates ferroptosis in calcium oxalate crystal deposition-induced kidney injury.

Epigenetic regulation is reported to play a significant role in the pathogenesis of various kidney diseases, including renal cell carcinoma, acute kidney injury, renal fibrosis, diabetic nephropathy, and lupus nephritis. However, the role of epigenetic regulation in calcium oxalate (CaOx) crystal deposition-induced kidney injury remains unclear. Our study demonstrated that the upregulation of enhancer of zeste homolog 2 (EZH2)-mediated ferroptosis facilitates CaOx-induced kidney injury. CaOx crystal deposition promoted ferroptosis in vivo and in vitro. Usage of liproxstatin-1 (Lip-1), a ferroptosis inhibitor, mitigated CaOx-induced kidney damage. Single-nucleus RNA-sequencing, RNA-sequencing, immunohistochemical and western blotting analyses revealed that EZH2 was upregulated in kidney stone patients, kidney stone mice, and oxalate-stimulated HK-2 cells. Experiments involving in vivo EZH2 knockout, in vitro EZH2 knockdown, and in vivo GSK-126 (an EZH2 inhibitor) treatment confirmed the protective effects of EZH2 inhibition on kidney injury and ferroptosis. Mechanistically, the results of RNA-sequencing and chromatin immunoprecipitation assays demonstrated that EZH2 regulates ferroptosis by suppressing solute carrier family 7, member 11 (SLC7A11) expression through trimethylation of histone H3 lysine 27 (H3K27me3) modification. Additionally, SOX4 regulated ferroptosis by directly modulating EZH2 expression. Thus, this study demonstrated that SOX4 facilitates ferroptosis in CaOx-induced kidney injury through EZH2/H3K27me3-mediated suppression of SLC7A11.

BMAL1 inhibits renal fibrosis and renal interstitial inflammation by targeting the ERK1/2/ELK-1/Egr-1 axis.

RATIONALE: Renal fibrosis and renal interstitial inflammation due to hydronephrosis are associated with progressive chronic kidney disease (CKD). The clock gene BMAL1 is thought to be involved in various diseases, including hypertension, diabetes, etc. However, little is known about how BMAL1 regulates renal fibrosis and renal interstitial inflammation in obstructed kidneys. METHODS: The expression level of BMAL1 in UUO was examined using the GEO database. Lentivirus, siRNA and adeno-associated virus were used to modulate BMAL1 levels in HK-2 cells and mouse kidney. qRT-PCR, immunofluorescence staining, histological analysis, ELISA and Western blot were used to determine the level of fibrin deposition and the release of inflammatory factors. Immunofluorescence staining and western blotting were used to examine the interaction between BMAL1 and the ERK1/2/ELK-1/Egr-1 axis. RESULTS: Bioinformatics analysis and in vivo experiments in this study showed that the expression level of BMAL1 in UUO model kidneys was higher than that in normal kidneys. We then found that downregulation of BMAL1 promoted the production of extracellular matrix (ECM) proteins and proinflammatory factors in vivo and in vitro, whereas upregulation inhibited this process. In addition, we demonstrated that the ERK1/2/ELK-1/Egr-1 axis is an important pathway for BMAL1 to play a regulatory role, and the use of PD98059 abolished the promoting effect of down-regulation of BMAL1 on fibrosis and inflammation. CONCLUSIONS: Our findings suggest that BAML1 can target the ERK1/2/ELK-1/Egr-1 axis to suppress fibrotic progression and inflammatory events in obstructed kidneys, thereby inhibiting the development of CKD.

STAT6 promoting oxalate crystal deposition-induced renal fibrosis by mediating macrophage-to-myofibroblast transition via inhibiting fatty acid oxidation.

OBJECTIVE AND DESIGN: Kidney stones commonly occur with a 50% recurrence rate within 5 years, and can elevate the risk of chronic kidney disease. Macrophage-to-myofibroblast transition (MMT) is a newly discovered mechanism that leads to progressive fibrosis in different forms of kidney disease. In this study, we aimed to investigate the role of MMT in renal fibrosis in glyoxylate-induced kidney stone mice and the mechanism by which signal transducer and activator of transcription 6 (STAT6) regulates MMT. METHODS: We collected non-functioning kidneys from patients with stones, established glyoxylate-induced calcium oxalate stone mice model and treated AS1517499 every other day in the treatment group, and constructed a STAT6-knockout RAW264.7 cell line. We first screened the enrichment pathway of the model by transcriptome sequencing; detected renal injury and fibrosis by hematoxylin eosin staining, Von Kossa staining and Sirius red staining; detected MMT levels by multiplexed immunofluorescence and flow cytometry; and verified the binding site of STAT6 at the PPARα promoter by chromatin immunoprecipitation. Fatty acid oxidation (FAO) and fibrosis-related genes were detected by western blot and real-time quantitative polymerase chain reaction. RESULTS: In this study, we found that FAO was downregulated, macrophages converted to myofibroblasts, and STAT6 expression was elevated in stone patients and glyoxylate-induced kidney stone mice. The promotion of FAO in macrophages attenuated MMT and upregulated fibrosis-related genes induced by calcium oxalate treatment. Further, inhibition of peroxisome proliferator-activated receptor-α (PPARα) eliminated the effect of STAT6 deletion on FAO and fibrosis-associated protein expression. Pharmacological inhibition of STAT6 also prevented the development of renal injury, lipid accumulation, MMT, and renal fibrosis. Mechanistically, STAT6 transcriptionally represses PPARα and FAO through cis-inducible elements located in the promoter region of the gene, thereby promoting MMT and renal fibrosis. CONCLUSIONS: These findings establish a role for STAT6 in kidney stone injury-induced renal fibrosis, and suggest that STAT6 may be a therapeutic target for progressive renal fibrosis in patients with nephrolithiasis.

YAP/ACSL4 Pathway-Mediated Ferroptosis Promotes Renal Fibrosis in the Presence of Kidney Stones.

The potential association between calcium oxalate stones and renal fibrosis has been extensively investigated; however, the underlying mechanisms remain unclear. Ferroptosis is a novel form of cell death characterized by iron-dependent lipid peroxidation and regulated by acyl coenzyme A synthase long-chain family member 4 (ACSL4). Yes-associated protein (YAP), a transcriptional co-activator in the Hippo pathway, promotes ferroptosis by modulating ACSL4 expression. Nevertheless, the involvement of YAP-ACSL4 axis-mediated ferroptosis in calcium oxalate crystal deposition-induced renal fibrosis and its molecular mechanisms have not been elucidated. In this study, we investigated ACSL4 expression and ferroptosis activation in the kidney tissues of patients with calcium oxalate stones and in mice using single-cell sequencing, transcriptome RNA sequencing, immunohistochemical analysis, and Western blot analysis. In vivo and in vitro experiments demonstrated that inhibiting ferroptosis or ACSL4 mitigated calcium oxalate crystal-induced renal fibrosis. Furthermore, YAP expression was elevated in the kidney tissues of patients with calcium oxalate stones and in calcium oxalate crystal-stimulated human renal tubular epithelial cell lines. Mechanistically, in calcium oxalate crystal-stimulated human renal tubular epithelial cell lines, activated YAP translocated to the nucleus and enhanced ACSL4 expression, consequently inducing cellular ferroptosis. Moreover, YAP silencing suppressed ferroptosis by downregulating ACSL4 expression, thereby attenuating calcium oxalate crystal-induced renal fibrosis. Conclusively, our findings suggest that YAP-ACSL4-mediated ferroptosis represents an important mechanism underlying the induction of renal fibrosis by calcium oxalate crystal deposition. Targeting the YAP-ACSL4 axis and ferroptosis may therefore hold promise as a potential therapeutic approach for preventing renal fibrosis in patients with kidney stones.

Comprehensive analysis reveals XCL2 as a cancer prognosis and immune infiltration-related biomarker.

BACKGROUND: X-C Motif Chemokine Ligand 2 (XCL2) is a 114 amino acid, structurally conserved chemokine involved in activating cytotoxic T cells. However, the pathophysiological mechanisms of XCL2 protein in various disease conditions, particularly cancer, remain poorly understood. METHODS: Bioinformatics was used to detect the expression of XCL2, the relationship between survival time and XCL2 in BLCA patients, the mutational status of XCL2, the role of XCL2 in the tumor immune microenvironment, and the sensitivity of XCL2-targeted drugs in 33 cancers. In vitro experiments were conducted to investigate the chemotactic effects of XCL2 expression on M1-type macrophages in human specimens and in isolated cancer cells. RESULTS: XCL2 expression was downregulated in tumor tissues and closely associated with the prognosis of human cancers. Furthermore, XCL2 affects DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR) in human cancers. The expression level of XCL2 significantly correlated with infiltrated immune cells, immunological pathways, and other immune markers. More importantly, we found that XCL2 was positively associated with T lymphocytes and macrophages in the transcriptome and single-cell sequencing data. Using multiple immunofluorescence staining, we found that the expression level of XCL2 was upregulated in many cells in pan-cancer samples, and the number of M1 macrophage marker CD68 and INOS-positive cells increased. 786O, U251, and MDA-MB-231 cells could recruit more M1 macrophages in vitro after overexpressing XCL2. CONCLUSIONS: Our results reveal that XCL2 could act as a vital chemokine in pan-cancer and provide new targets and concepts for cancer treatment.

Prognostic and immunological roles of IL18RAP in human cancers.

Across several cancers, IL18 receptor accessory protein (IL18RAP) is abnormally expressed, and this abnormality is related to tumor immunity and heterogeneous clinical outcomes. In this study, based on bioinformatics analysis, we discovered that IL18RAP is related to the human tumor microenvironment and promotes various immune cells infiltration. Additionally, the multiple immunofluorescence staining revealed that with the increased expression of IL18RAP, the number of infiltrated M1 macrophages increased. This finding was confirmed by coculture migration analysis using three human cancer cell lines (MDA-MB-231, U251, and HepG2) with IL18RAP knockdown. We discovered a positive link between IL18RAP and the majority of immunostimulators, immunoinhibitors, major histocompatibility complex (MHC) molecules, chemokines, and chemokine receptor genes using Spearman correlation analysis. Additionally, functional IL18RAP's gene set enrichment analysis (GSEA) revealed that it is related to a variety of immunological processes, such as positive regulation of interferon gamma production and positive regulation of NK cell-mediated immunity. Moreover, we used single-cell RNA sequencing analysis to detect that IL18RAP was mainly expressed in immune cells, and HALLMARK analysis confirmed that the INF-γ gene set expression was upregulated in CD8Tex cells. In addition, in human and mouse cancer cohorts, we found that the level of IL18RAP can predict the immunotherapy response. In short, our study showed that IL18RAP is a new tumor biomarker and may become a potential immunotherapeutic target in cancer.

Biocompatibility and efficacy of prostatic urethral lift in benign prostate hyperplasia: an in vivo and in vitro study.

The study aimed to assess the biocompatibility and efficacy of a prostatic urethral lift (PUL) for benign prostatic hyperplasia (BPH). Human BPH-1 cells were co-cultured with implant anchors and sutures, and cytotoxicity was measured. Scanning electron microscopy (SEM) was used to observe adhesion and growth of cells and to evaluate implant biocompatibility. Fifteen male beagle dogs were randomly assigned to the surgical (n = 9) or sham-operated (n = 6) groups. The surgical group underwent cystotomy, and PUL was used to insert two implants in each lobe of the prostate to compress the enlarged prostate and dilate the urethra; the sham group underwent cystotomy without implant insertion. Compared with the control group, no significant difference in cell viability among the groups with different co-culture times of implant anchors and sutures (P > 0.05) was observed. SEM revealed good adhesion and growth of prostate cells on the implants. Improvements in urine flow rates remained stable at 7, 28, and 180 days after surgery, and the urethral diameter in the prostate region was significantly increased compared with that before surgery. PUL is a biocompatible and effective treatment for BPH, improving the urine flow rate without causing inflammation, tissue damage, or cytotoxic effects. Here, the basis for further PUL application was provided.

Clinical outcome of different embryo transfer strategies after late rescue ICSI procedure: a 10-year total fertilisation failure cohort study.

BACKGROUND: Late rescue intracytoplasmic sperm injection (r-ICSI) has not been widely accepted as an alternative solution for unexpected total fertilisation failure (TFF) after in vitro fertilisation (IVF), due to the time-dependent in vitro deterioration of oocyte quality and endometrial growth not being synchronised with embryo development. This study aimed to evaluate the safety profile and effectiveness of freeze-all blastocyst transfer in combination with late r-ICSI. METHODS: This was a retrospective cohort study carried out at the Reproductive Centre of Peking University Third Hospital, Beijing, China. All participants received treatment between 2009 and 2019. 2,270 patients in the aggregate encountered unexpected TFF during 149,054 cycles of IVF and adopted a late r-ICSI procedure. Among these patients, 263 women did not have cleavage-stage embryos available for evaluation. The remaining patients were grouped according to different embryo transfer (ET) strategies (926 women in Group 1 underwent fresh ET, 365 women in Group 2 underwent freeze-all ET, 716 women in Group 3 experienced blastulation failure). Patients received different ET strategies after r-ICSI, with the main outcome measures included live birth rate (LBR), cumulative live birth rate (cLBR), and conservative cLBR. RESULTS: TFF occurred in 7.4% of all IVF cycles. Group 1 tended to be older at oocyte retrieval, with more infertile years, higher follicle-stimulating hormone (FSH) levels, higher gonadotropin consumption, and fewer oocytes retrieved. Group 2 exhibited considerably better LBRs following the first ET cycle (37.53% vs. 4.64%) and cLBRs (52.60% vs. 8.21%). After adjustment for covariates using binary logistic regression analyses, Group 2 still showed better obstetric performance in LBRs [OR:11.77, 95% CI (8.42-16.45)], cLBRs (OR:11.29, 95% CI (7.84-16.27)], and conservative cLBRs (OR:2.55, 95% CI (1.83-3.55)]. Additionally, the two groups showed similar miscarriage rates, whilst no new-borns with malformations or congenital diseases were reported. CONCLUSIONS: Freeze-all blastocyst stage ET serves as an optimal strategy to support late r-ICSI. However, for women with limited oocytes available for r-ICSI use, weighing the benefits against the costs of the procedure might be prudent before implementing in vitro blastulation.

Overexpression of sirtuin 1 attenuates calcium oxalate-induced kidney injury by promoting macrophage polarization.

Sirtuin 1 (SIRT1) protein is involved in macrophage differentiation, while NOTCH signaling affects inflammation and macrophage polarization. Inflammation and macrophage infiltration are typical processes that accompany kidney stone formation. However, the role and mechanism of SIRT1 in renal tubular epithelial cell injury caused by calcium oxalate (CaOx) deposition and the relationship between SIRT1 and the NOTCH signaling pathway in this urological disorder are unclear. This study investigated whether SIRT1 promotes macrophage polarization to inhibit CaOx crystal deposition and reduce renal tubular epithelial cell injury. Public single-cell sequencing data, RT-qPCR, immunostaining approaches, and Western blotting showed decreased SIRT1 expression in macrophages treated with CaOx or exposed to kidney stones. Macrophages overexpressing SIRT1 differentiated towards the anti-inflammatory M2 phenotype, significantly inhibiting apoptosis and alleviating injury in the kidneys of mice with hyperoxaluria. Conversely, decreased SIRT1 expression in CaOx-treated macrophages triggered Notch signaling pathway activation, promoting macrophage polarization towards the pro-inflammatory M1 phenotype. Our results suggest that SIRT1 promotes macrophage polarization towards the M2 phenotype by repressing the NOTCH signaling pathway, which reduces CaOx crystal deposition, apoptosis, and damage in the kidney. Therefore, we propose SIRT1 as a potential target for preventing disease progression in patients with kidney stones.

p53 deacetylation alleviates calcium oxalate deposition-induced renal fibrosis by inhibiting ferroptosis.

Calcium oxalate (CaOx) stones are among the most common types of kidney stones and are associated with renal tubular damage, interstitial fibrosis, and chronic kidney disease. The mechanism of CaOx crystal-induced renal fibrosis remains unknown. Ferroptosis, a type of regulated cell death, is characterised by iron-dependent lipid peroxidation, and the tumour suppressor p53 is a key regulator of ferroptosis. In the present study, our results demonstrated that ferroptosis was significantly activated in patients with nephrolithiasis and hyperoxaluric mice as well as verified the protective effects of ferroptosis inhibition on CaOx crystal-induced renal fibrosis. Moreover, the single-cell sequencing database, RNA-sequencing, and western blot analysis revealed that the expression of p53 was increased in patients with chronic kidney disease and the oxalate-stimulated human renal tubular epithelial cell line, HK-2. Additionally, the acetylation of p53 was enhanced by oxalate stimulation in HK-2 cells. Mechanistically, we found that the induction of p53 deacetylation, owing to either the SRT1720-induced activation of deacetylase sirtuin 1 or the triple mutation of p53, inhibited ferroptosis and alleviated renal fibrosis caused by CaOx crystals. We conclude that ferroptosis is one of the critical mechanisms contributing to CaOx crystal-induced renal fibrosis, and the pharmacological induction of ferroptosis via sirtuin 1-mediated p53 deacetylation may be a potential target for preventing renal fibrosis in patients with nephrolithiasis.

Gut microbiota in patients with kidney stones: a systematic review and meta-analysis.

BACKGROUND: Mounting evidence indicates that the gut microbiome (GMB) plays an essential role in kidney stone (KS) formation. In this study, we conducted a systematic review and meta-analysis to compare the composition of gut microbiota in kidney stone patients and healthy individuals, and further understand the role of gut microbiota in nephrolithiasis. RESULTS: Six databases were searched to find taxonomy-based comparison studies on the GMB until September 2022. Meta-analyses were performed using RevMan 5.3 to estimate the overall relative abundance of gut microbiota in KS patients and healthy subjects. Eight studies were included with 356 nephrolithiasis patients and 347 healthy subjects. The meta-analysis suggested that KS patients had a higher abundance of Bacteroides (35.11% vs 21.25%, Z = 3.56, P = 0.0004) and Escherichia_Shigella (4.39% vs 1.78%, Z = 3.23, P = 0.001), and a lower abundance of Prevotella_9 (8.41% vs 10.65%, Z = 4.49, P < 0.00001). Qualitative analysis revealed that beta-diversity was different between the two groups (P < 0.05); Ten taxa (Bacteroides, Phascolarctobacterium, Faecalibacterium, Flavobacterium, Akkermansia, Lactobacillus, Escherichia coli, Rhodobacter and Gordonia) helped the detection of kidney stones (P < 0.05); Genes or protein families of the GMB involved in oxalate degradation, glycan synthesis, and energy metabolism were altered in patients (P < 0.05). CONCLUSIONS: There is a characteristic gut microbiota dysbiosis in kidney stone patients. Individualized therapies like microbial supplementation, probiotic or synbiotic preparations and adjusted diet patterns based on individual gut microbial characteristics of patients may be more effective in preventing stone formation and recurrence.

Corrigendum: Vestibular dysfunction is an important contributor to the aging of visuospatial ability in older adults-Data from a computerized test system.

[This corrects the article DOI: 10.3389/fneur.2022.1049806.].

Histone H3K27 methyltransferase EZH2 regulates apoptotic and inflammatory responses in sepsis-induced AKI.

Rationale: The role of histone methylation modifications in renal disease, particularly in sepsis-induced acute kidney injury (AKI), remains unclear. This study aims to investigate the potential involvement of the histone methyltransferase zeste homolog 2 (EZH2) in sepsis-induced AKI and its impact on apoptosis and inflammation. Methods: We first examined the expression of EZH2 in the kidney of sepsis-induced AKI (LPS injection) mice and LPS-stimulated tubular epithelial cells. We next constructed the EZH2 knockout mice to further confirm the effects of EZH2 on apoptosis and inflammatory response in AKI. And the inflammatory level of epithelial cells can be reflected by detecting chemokines and the chemotaxis of macrophages. Subsequently, we constructed the EZH2 knocked-down cells again and performed Chromatin Immunoprecipitation sequencing to screen out the target genes regulated by EZH2 and the enrichment pathway. Then we confirmed the EZH2 target gene and its regulatory pathway in vivo and in vitro experiments. Experimental results were finally confirmed using another in vivo model of sepsis-induced AKI (cecal perforation ligation). Results: The study found that EZH2 was upregulated in sepsis-induced AKI and that silencing EZH2 could reduce renal tubular injury by decreasing apoptosis and inflammatory response of tubular epithelial cells. EZH2 knockout mice showed significantly reduced renal inflammation and macrophage infiltration. Chromatin immunoprecipitation sequencing and polymerase chain reaction identified Sox9 as a target of EZH2. EZH2 was found to be enriched on the promoter of Sox9. Silencing EZH2 resulted in a significant increase in the transcriptional level of Sox9 and activation of the Wnt/ß-catenin signaling pathway. The study further reversed the effects of EZH2 silencing by silencing Sox9 or administering the Wnt/ß-catenin inhibitor icg001. It was also found that Sox9 positively regulated the expression of ß-catenin and its downstream pathway-related genes. Finally, the study showed that the EZH2 inhibitor 3-deazaneplanocin A significantly alleviated sepsis-induced AKI. Conclusion: Our results indicate that silencing EZH2 can protect renal function by relieving transcriptional inhibition of Sox9, activating the Wnt/ß-catenin pathway, and attenuating tubular epithelial apoptosis and inflammatory response of the renal interstitium. These results highlight the potential therapeutic value of targeting EZH2 in sepsis-induced AKI.

Vestibular cognition assessment system: Tablet-based computerized visuospatial abilities test battery.

Introduction: The vestibular system is anatomically connected to extensive regions of the cerebral cortex, hippocampus, and amygdala. However, studies focusing on the impact of vestibular impairment on visuospatial cognition ability are limited. This study aimed to develop a mobile tablet-based vestibular cognitive assessment system (VCAS), enhance the dynamic and three-dimensional (3D) nature of the test conditions, and comprehensively evaluate the visuospatial cognitive ability of patients with vestibular dysfunction. Materials and methods: First, the VCAS assessment dimensions (spatial memory, spatial navigation, and mental rotation) and test content (weeding, maze, card rotation, and 3D driving tests) were determined based on expert interviews. Second, VCAS was developed based on Unity3D, using the C# language and ILruntime hot update framework development technology, combined with the A* algorithm, prime tree algorithm, and dynamic route rendering. Further, the online test was built using relevant game business logic. Finally, healthy controls (HC) and 78 patients with vertigo (VP) were recruited for the VCAS test. The validity of VCAS was verified using the test results of random controls. Results: In the weeding test, the HC group had a significantly longer span and faster velocity backward than did the VP group. In the 12 × 12 maze, statistically significant differences in step and time were observed between the two groups, with VP taking longer time and more steps. In the mental rotation task, no significant difference was observed between the two groups. Similarly, no significant difference was found in the performance of the two groups on maps 2, 3, and 4 in the 3D driving task. Discussion: Thus, impaired visuospatial cognition in patients with vestibular dysfunction is primarily related to spatial memory and navigation. VCAS is a clinically applicable visuospatial cognitive ability test for VP.

Effect of transmembrane protein 100 on prostate cancer progression by regulating SCNN1D through the FAK/PI3K/AKT pathway.

The effects of transmembrane (TMEM) proteins in the progression of prostate cancer (PCa) remain unknown. This study aims to explore the functions of TMEM100 in PCa. To explore the expression, regulation, and effects of TMEM100 in PCa, two PCa cell lines and 30 PCa tissue samples with adjacent control tissues were examined. Online databases, immunohistochemistry, immunofluorescence, western blot, flow cytometry, colony formation, wound healing, transwell assays, and xenograft mouse models were used to explore effects of TMEM100 relevant to PCa. TMEM100 expression was shown to decrease in PCa patients, and low TMEM100 expression was associated with tumor stage and metastasis. Overexpression of TMEM100 suppressed PCa progression by inhibiting the FAK/PI3K/AKT signaling pathway. Tumor size was smaller in TMEM100 overexpressing PCa cells in xenograft mice than in control mice. We also found that TMEM100 could regulate SCNN1D by inhibiting FAK/PI3K/AKT signaling in PCa cell lines. Taken together, our findings indicate that TMEM100 is a tumor suppressor that plays a vital role in preventing PCa proliferation, migration, and invasion through inhibition of FAK/PI3K/AKT signaling. These studies suggest that TMEM100 can be used as a predictive biomarker and therapeutic target.

Vestibular dysfunction is an important contributor to the aging of visuospatial ability in older adults-Data from a computerized test system.

Background: A convergence of research supports a key role of the vestibular system in visuospatial ability. However, visuospatial ability may decline with age. This work aims to elucidate the important contribution of vestibular function to visuospatial ability in old adults through a computerized test system. Methods: Patients with a clinical history of recurrent vertigo and at least failed one vestibular test were included in this cross-sectional study. Healthy controls of three age groups: older, middle-aged, and young adults were also involved. Visuospatial cognitive outcomes including spatial memory, spatial navigation, and mental rotation of all the groups were recorded. Comparing the performance of the visuospatial abilities between patients and age-matched controls as well as within the controls. Results: A total of 158 individuals were enrolled. Results showed that patients performed worse than the age-matched controls, with the differences in the forward span (p < 0.001), the time of the maze 8 × 8 (p = 0.009), and the time of the maze 12 × 12 (p = 0.032) being significant. For the differences in visuospatial cognitive outcomes within the controls, the younger group had a significantly better performance than the other groups. The older group and the middle-aged group had comparable performances during all the tests. Conclusions: Older patients with vestibular dysfunction had more difficulties during visuospatial tasks than age-matched controls, especially in spatial memory and spatial navigation. Within the controls, younger adults did much better than other age groups, while older adults behaved similarly to middle-aged adults. It is a valuable attempt to computerize the administration of tests for visuospatial ability.

Comprehensive analysis of a homeobox family gene signature in clear cell renal cell carcinoma with regard to prognosis and immune significance.

The homeobox (HOX) family genes have been linked to multiple types of tumors, while their effect on malignant behaviors of clear cell renal cell carcinoma (ccRCC) and clinical significance remains largely unknown. Here, we comprehensively analyzed the expression profiles and prognostic value of HOX genes in ccRCC using datasets from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. We developed a prognostic signature comprising eight HOX genes (HOXB1, HOXA7, HOXB5, HOXD8, HOXD9, HOXB9, HOXA9, and HOXA11) for overall survival prediction in ccRCC and it allowed patients to be subdivided into high- and low-risk groups. Kaplan-Meier survival analysis in all the internal and external cohorts revealed significant difference in clinical outcome of patients in different risk groups, indicating the satisfactory predictive power of the signature. Additionally, we constructed a prognostic nomogram by integrating signature-derived risk score and clinical factors such as gender, age, T and M status, which might be helpful for clinical decision-making and designing tailored management schedules. Immunological analysis revealed that the regulatory T cells (Tregs) infiltrated differently between the two subgroups in both TCGA and ICGC cohorts. ssGSEA method showed that the enrichment scores for mast cells were significantly lower in high-risk group compared with the low-risk group, which was consistent in both TCGA and ICGC cohorts. As for the related immune function, the enrichment scores of APC co-inhibition, para-inflammation, and type II IFN response were consistently lower in high-risk group in both cohorts. Of the eight HOX genes, the mRNA and protein levels of HOXD8 were downregulated in ccRCC than that in normal tissues, and decreased expression of HOXD8 was associated with increased tumor grade and stage, and lymph node metastasis. Survival analysis revealed that lower expression of HOXD8 predicted worse overall survival in ccRCC. In conclusion, our HOX gene-based signature was a favorable indicator to predict the prognosis of ccRCC cases and associated with immune cell infiltration. HOXD8 might be a tumor suppressor gene in ccRCC and a potential predictor of tumor progression.