Development and validation of the UCSS score, a novel method to predict septic shock after PCNL.

OBJECTIVE: To develop an objective and easily recognizable model to predict septic shock following percutaneous nephrolithotomy (PCNL). SUBJECTS AND METHODS: First, we identified differences between 431 patients who underwent PCNL with or without septic shock. These data were used to develop existing models and examine their improvement. Multivariate analysis was applied to identify risk factors of septic shock after PCNL based on the scores allocated to the PCNL postoperative test indicators. Finally, we developed a predictive nomogram using the selected factors and compared its performance with that of the existing nomograms SOFA, qSOFA, and SIRS. RESULTS: Twelve (2.8%) of the patients met the criteria for postoperative septic shock after PCNL. Baseline data analysis revealed differences in sex, preoperative drainage, urinary culture, and urinary leukocyte between groups. After transforming patient data into measurement-level data, we investigated each index score in these conditions, and found that the incidence of septic shock generally increased with the score. Multivariate analysis and early optimization screening revealed that septic shock factors could be predicted using platelets, leukocytes, bilirubin, and procalcitonin levels. We further compared the prediction accuracy of urinary calculi-associated septic shock (UCSS), SOFA, qSOFA, and SIRS scores using the AUC of the ROC curve. As compared to SIRS [AUC 0.938 (95% CI 0.910-0.959)] and qSOFA [AUC 0.930 (95% CI 0.901-0.952)], UCSS [AUC 0.974 (95% Cl 0.954-0.987)] and SOFA [AUC 0.974 (95% CI 0.954-0.987)] scored better at discriminating septic shock after PCNL. We further compared the ROC curves of UCSS with SOFA (95% CI - 0.800 to 0.0808, P = 0.992), qSOFA (95% CI - 0.0611 to 0.0808, P = 0.409), and SIRS (95% CI - 0.0703 to 0.144, P = 0.502), finding that UCSS was non-inferior to these models. CONCLUSIONS: UCSS, a new convenient and cost-effective model, can predict septic shock following PCNL and provide more accurate discriminative and corrective capability than existing models by including only objective data. The predictive value of UCSS for septic shock after PCNL was greater than that of qSOFA or SIRS scores.

Orf virus induces complete autophagy to promote viral replication via inhibition of AKT/mTOR and activation of the ERK1/2/mTOR signalling pathway in OFTu cells.

Orf virus (ORFV) is the causative agent of contagious ecthyma, which is an important zoonotic pathogen with a widespread distribution affecting sheep, goats and humans. Our previous research showed that autophagy can be induced in host cells by ORFV infection. However, the exact mechanism of ORFV-induced autophagy remains unknown. In this study, we investigated the underlying mechanisms of autophagy induced by ORFV in OFTu cells and the impact of autophagy on ORFV replication. By using specific autophagy inhibitors and activators, Western blotting, immunofluorescence and transmission electron microscopy imaging, we confirmed that ORFV infection triggered intracellular autophagosome accumulation and the activation of autophagic flux. Moreover, ORFV-induced autophagic activity was found to rely on an increase in the phosphorylation of tuberous sclerosis complex 2 (TSC2) and a decrease in the phosphorylation of mammalian target of rapamycin (mTOR), which is mediated by the suppression of the PI3K/AKT/mTOR signalling pathway and activation of the ERK1/2/mTOR signalling pathway. Furthermore, we investigated the role of mTOR-mediated autophagy during ORFV replication using pharmacological agents and demonstrated that ORFV-induced autophagy correlated positively with viral replication. Taken together, our data reveal the pathways of ORFV-induced autophagy and the impact of autophagy on ORFV replication, providing new insights into ORFV pathogenesis.

Oxalate-induced apoptosis through ERS-ROS-NF-κB signalling pathway in renal tubular epithelial cell.

BACKGROUND: Kidney stones are composed of approximately 70-80% calcium oxalate. However, the exact mechanism of formation of calcium oxalate kidney stones remains unclear. In this study, we investigated the roles of endoplasmic reticulum stress (ERS), reactive oxygen species (ROS), and the NF-κB signalling pathway in the pathogenesis of oxalate-induced renal tubular epithelial cell injury and its possible molecular mechanisms. METHODS: We established a model to evaluate the formation of kidney stones by intraperitoneal injection of glyoxylic acid solution into mice and assessed cell morphology, apoptosis, and the expression levels of ERS, ROS, and NF-κB signalling pathway-related proteins in mouse renal tissues. Next, we treated HK-2 cells with potassium oxalate to construct a renal tubular epithelial cell injury model. We detected the changes in autophagy, apoptosis, and mitochondrial membrane potential and investigated the ultrastructure of the cells by transmission electron microscopy. Western blotting revealed the expression levels of apoptosis and autophagy proteins; mitochondrial structural and functional proteins; and ERS, ROS, and NF-κB (p65) proteins. Lastly, we studied the downregulation of NF-κB activity in HK-2 cells by lentivirus interference and confirmed the interaction between the NF-κB signalling and ERS/ROS pathways. RESULTS: We observed swelling of renal tissues, increased apoptosis of renal tubular epithelial cells, and activation of the ERS, ROS, and NF-κB signalling pathways in the oxalate group. We found that oxalate induced autophagy, apoptosis, and mitochondrial damage in HK-2 cells and activated the ERS/ROS/NF-κB pathways. Interestingly, when the NF-κB signalling pathway was inhibited, the ERS/ROS pathway was also inhibited. CONCLUSION: Oxalate induces HK-2 cell injury through the interaction between the NF-κB signalling and ERS/ROS pathways.

Complete genomic sequences and comparative analysis of two Orf virus isolates from Guizhou Province and Jilin Province, China.

Orf virus (ORFV, species Orf virus) belongs to the typical species of the Parapoxvirus genus of the family Poxviridae, which infects sheep, goats, and humans with worldwide distribution. Although outbreaks of Orf have been reported sequentially in several Chinese provinces, the epidemiology of Orf and genetic diversity of ORFV strains still needs to be further characterized. To further reveal the genomic organization of the ORFV-GZ18 and ORFV-CL18 isolates, the complete genome sequences of two recently obtained ORFV isolates were sequenced using the next-generation sequencing technology and analyzed, which had been deposited in the GenBank database under accession number MN648218 and MN648219, respectively. The complete genomic sequence of ORFV-CL18 was 138,495 bp in length, including 131 potential open reading frames (ORFs) flanked by inverted terminal repeats (ITRs) of 3481 bp at both ends, which has genomic structure typical Parapoxviruses. The overall genomic organization of the fully sequenced genome of ORFV-GZ18 was consistent with ORFV-CL18 genome, with a complete genome size of 138,446 nucleotides, containing 131 ORFs flanked by ITRs of 3469 bp. Additionally, the overall G + C contents of ORFV-GZ18 and ORFV-CL18 genome sequences were about 63.9% and 63.8%, respectively. The phylogenetic analysis showed that both ORFV-GZ18 and ORFV-CL18 were genetically closely related to ORFV-SY17 derived from sheep. In summary, the complete genomic sequences of ORFV-GZ18 and ORFV-CL18 are reported, with the hope it will be useful to investigate the host range, geographic distribution, and genetic evolution of the virus in Southern West and Northern East China.

E2F4 may be a core transcription factor in the lncRNA-TF regulatory network in cervical cancer.

BACKGROUND: Cervical cancer is the most common gynecological cancer worldwide and is associated with high morbidity and mortality. Despite improvements in therapeutic strategies, the network regulation mechanism remains unclear and the treatment effect is not satisfactory. Therefore, there is a need to continue studying the mechanism of cervical cancer to explore effective gene targets and precise targeted therapy drugs. METHODS: First, three paired tissues (cancer tissues and noncancerous tissues) from patients with cervical squamous cell carcinoma were collected, grouped, and analyzed by microarray. Second, differentially expressed mRNAs (DEMs) and differentially expressed lncRNAs (DELs) (|fold change| ≥ 2 and p < 0.05) between the two groups were screened. For DEMs, functional annotation and pathway analysis were performed using DAVID. Functional prediction of DELs was then performed and their cis-regulatory and trans-regulatory networks were explored. RESULTS: Function prediction of DELs (both up-regulated and down-regulated) shows that the highest frequency Cellular Component (CC) item is cytosol, the highest frequency Molecular function (MF) item is mitotic cell cycle and the highest frequency Biological Process (BP) item is protein binding. Through cis-regulation analysis of DELs, the cis-regulatory relationship of 96 DELs was predicted. The lncRNA-trans-regulation network analysis suggested that E2F4 may be the core transcription factor in the lncRNA-TF regulatory network in cervical cancer. CONCLUSIONS: The lncRNA-TF regulatory network plays an important role in the occurrence and progression of cervical cancer, and E2F4 may be a critical transcription factor in the regulatory network.

Performance of SOFA, qSOFA and SIRS to predict septic shock after percutaneous nephrolithotomy.

OBJECTIVE: The new clinical criteria termed SOFA and qSOFA were demonstrated to be more accurate than SIRS in screening patients at high risk of sepsis. We aim to evaluate the ability of SOFA, qSOFA and SIRS to predict septic shock after PCNL. PATIENTS AND METHODS: Consecutive patients undergoing PCNL were included to assess the performance of SOFA, qSOFA and SIRS in predicting septic shock, the AUC of ROC curve and decision curve analysis were used, and the optimal cutoff values and their achieving time were calculated. RESULTS: Of the 431 included patients, 12 (2.7%) cases developed septic shock. Compared with non-septic shock patients, patients with septic shock were more likely to be female, have positive history of urine culture and higher urine leukocyte count, and show increased postoperative serum creatinine, PCT and decreased leukocyte. The optimal cutoff of SOFA, qSOFA and SIRS was > 2, > 0 and > 1, respectively. All of the 12 patients with verified septic shock met SOFA and SIRS criteria, while only 11 cases met qSOFA criterion. SOFA had the identical highest sensitivity (100%) and greater specificity (87% vs. 81%) than SIRS. qSOFA had higher specificity (92%) than both SOFA and SIRS at the expense of lower sensitivity (92%). The AUC of SOFA (0.973) to predict septic shock was greater than that of qSOFA (0.928) and SIRS (0.935). When combined with SIRS, SOFA outperformed qSOFA for discrimination of septic shock (AUC 0.987 vs. 0.978). Decision curve analysis indicated SOFA was clearly superior to both qSOFA and SIRS with a higher net benefit and net reduction in intervention. The qSOFA achieved the best time-based predictive efficiency, with the shortest median time to meet its cutoff, followed by SOFA and SIRS. CONCLUSION: The performance of SOFA in predicting septic shock after PCNL was slightly greater than qSOFA and SIRS. The comprehensive application of various criteria is recommended to assist early detection of septic shock following PCNL.

Novel Long Non-coding RNA lncAMPC Promotes Metastasis and Immunosuppression in Prostate Cancer by Stimulating LIF/LIFR Expression.

Long non-coding RNAs (lncRNAs) participate in the development and progression of prostate cancer (PCa). We aimd to identify a novel lncRNA, named lncRNA activated in metastatic PCa (lncAMPC), and investigate its mechanisms and clinical significance in PCa. First, the biological capacity of lncAMPC in PCa was demonstrated both in vitro and in vivo. The lncAMPC was overexpressed in tumor tissue and urine of metastatic PCa patients and promoted PCa tumorigenesis and metastasis. Then, a mechanism study was conducted to determine how the lncAMPC-activated pathway contributed to PCa metastasis and immunosuppression. In the cytoplasm, lncAMPC upregulated LIF expression by sponging miR-637 and inhibiting its activity. In the nucleus, lncAMPC enhanced LIFR transcription by decoying histone H1.2 away from the upstream sequence of the LIFR gene. The lncAMPC-activated LIF/LIFR expressions stimulated the Jak1-STAT3 pathway to simultaneously maintain programmed death-ligand 1 (PD-L1) protein stability and promote metastasis-associated gene expression. Finally, the prognostic value of the expression of lncAMPC and its downstream genes in PCa patients was evaluated. High LIF/LIFR levels indicated shorter biochemical recurrence-free survival among patients who underwent radical prostatectomy. Therefore, the lncAMPC/LIF/LIFR axis plays a critical role in PCa metastasis and immunosuppression and may serve as a prognostic biomarker and potential therapeutic target.

Preparation of Highly Swelling/Antibacterial Cross-Linked N-Maleoyl-Functional Chitosan/Polyethylene Oxide Nanofiber Meshes for Controlled Antibiotic Release.

Due to the cell affinity of chitosan (CS) and the hydrophilicity of polyethylene oxide (PEO), CS/PEO composited nanofiber meshes (NFMs) have been extensively used as wound healing dressings for skin tissue regeneration. Nonetheless, numerous innate drawbacks of the NFM system such as the use of toxic spinning solvents and cross-linkers, moderate water regain capacity, and lack of triggered release function significantly hampered their biomedical applications. In order to enhance their performances in promoting cell growth and preventing bacterial infection, highly swelling cross-linked N-maleoyl-functional chitosan (MCS)/PEO NFMs have been developed as the next-generation CS/PEO NFM system through an acid-free electrospinning process and a UV-irradiated cross-linked treatment without the use of aldehyde-containing cross-linkers. With the simultaneous introduction of ethylene oxide chains and disulfide bonds in the cross-linkages, this new NFM system displays enhanced swelling capability, antibacterial ability, triggered antibiotic release, and high biocompatibility. These biomedical merits enable the new NFM systems to be utilized as tissue scaffolds, especially for functional wound healing dressings.

Risk factors for sepsis in patients with struvite stones following percutaneous nephrolithotomy.

PURPOSE: To describe the clinical characteristics of struvite stones and determine the preoperative predictors of sepsis in struvite patients undergoing percutaneous nephrolithotomy (PCNL). METHODS: A retrospective study of patients who underwent PCNL between April 2011 and March 2018 was performed. The data of the struvite stones and non-struvite stones groups were compared following propensity score matching. Subsequently, the struvite stones group was sub-divided for further analysis according to the Sepsis-3 definition: non-sepsis and sepsis groups. RESULTS: After matching based on age, gender, BMI, and number of access tracts, the comparative analysis showed that staghorn calculi and higher Guy's stone score were more frequently observed in non-struvite stone patients (n = 97), while a history of urolithiasis surgery (56.70%), preoperative broad-spectrum antibiotic therapy (53.61%), positive preoperative urine culture (55.67%), and sepsis (35.05%) after surgery were more common in patients (n = 97) with struvite stones (all P values < 0.05). Eighteen (18.56%) patients presented with multidrug-resistant (MDR) bacteriuria. Multivariate analysis demonstrated that the preoperative presence of MDR bacteriuria (OR = 3.203; P = 0.043) and increased serum creatinine (OR = 3.963; P = 0.010) were independent risk predictors of sepsis. The two factors were used to construct a nomogram to predict the probability of sepsis. The nomogram was well calibrated and had moderate discriminative ability (concordance index: 0.711). CONCLUSION: Our study revealed that patients with struvite stones were associated with a significantly high risk of calculi recurrence and sepsis after surgery. The presence of MDR bacteriuria preoperatively was a reliable factor to predict sepsis.

Testosterone induces renal tubular epithelial cell death through the HIF-1α/BNIP3 pathway.

BACKGROUND: The morbidity of nephrolithiasis is 2-3 times higher in males than in females, suggesting that androgen plays a key role in nephrolithiasis. The death of renal tubular epithelial cells (TECs) is an important pathophysiological process contributing to the development of nephrolithiasis. Therefore, the aim of this study is to investigate whether androgen directly induces TECs apoptosis and necrosis and its underlying mechanisms in kidney stone formation. MATERIALS AND METHODS: We compared serum testosterone level between male and female healthy volunteers and kidney stone patients. The in vivo nephrolithiasis model was established using glyoxylic acid, and calcium deposits were detected by van Kossa staining. In the in vitro study using mouse TECs (TCMK-1 cells) and human TECs (HK-2 cells), apoptosis, necrosis, and the expression of BH3-only protein Bcl-2-like 19 kDa-interacting protein 3 (BNIP3) were examined incubated with different doses of testosterone using flow cytometry. Levels of apoptosis-related proteins transfected with the BNIP3 siRNA were examined by western blotting. The mitochondrial potential (ΔΨm) was detected by JC-1 staining and flow cytometry. We monitored BNIP3 expression in the testosterone-induced TECs injury model after treatment with hypoxia inducible factor 1α (HIF-1α) and/or hypoxia inducible factor 2α (HIF-2α) inhibitors to determine the upstream protein regulating BNIP3 expression. Additionally, ChIP and luciferase assays were performed to confirm the interaction between HIF-1α and BNIP3. RESULTS: Both male and female patients have significantly higher testosterones compared with healthy volunteers. More calcium deposits in the medulla were detected in male mice compared to female and castrated male mice. Testosterone induced TECs apoptosis and necrosis and increased BNIP3 expression in a dose-dependent manner. Testosterone also increased Bax expression, decreased Bcl-2 expression and induced a loss of ΔΨm. This effect was reversed by BNIP3 knockdown. HIF-1α inhibition significantly decreased BNIP3 expression and protected TECs from testosterone-induced apoptosis and necrosis. HIF-2α inhibition, however, did not influence BNIP3 expression or TECs apoptosis or necrosis. Finally, HIF-1α interacted with the BNIP3 promoter region. CONCLUSION: Based on these results, testosterone induced renal TECs death by activating the HIF-1α/BNIP3 pathway.

Long noncoding RNA MRCCAT1 promotes metastasis of clear cell renal cell carcinoma via inhibiting NPR3 and activating p38-MAPK signaling.

BACKGROUND: Recent evidences showed that long noncoding RNAs (lncRNAs) are frequently dysregulated and play important roles in various cancers. Clear cell renal cell carcinoma (ccRCC) is one of the leading cause of cancer-related death, largely due to the metastasis of ccRCC. However, the clinical significances and roles of lncRNAs in metastatic ccRCC are still unknown. METHODS: lncRNA expression microarray analysis was performed to search the dysregulated lncRNA in metastatic ccRCC. quantitative real-time PCR was performed to measure the expression of lncRNAs in human ccRCC samples. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of lncRNAs on ccRCC cell proliferation, migration, invasion and in vivo metastasis. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and western blot were performed to explore the molecular mechanisms underlying the functions of lncRNAs. RESULTS: The microarray analysis identified a novel lncRNA termed metastatic renal cell carcinoma-associated transcript 1 (MRCCAT1), which is highly expressed in metastatic ccRCC tissues and associated with the metastatic properties of ccRCC. Multivariate Cox regression analysis revealed that MRCCAT1 is an independent prognostic factor for ccRCC patients. Overexpression of MRCCAT1 promotes ccRCC cells proliferation, migration, and invasion. Depletion of MRCCAT1 inhibites ccRCC cells proliferation, migration, and invasion in vitro, and ccRCC metastasis in vivo. Mechanistically, MRCCAT1 represses NPR3 transcription by recruiting PRC2 to NPR3 promoter, and subsequently activates p38-MAPK signaling pathway. CONCLUSIONS: MRCCAT1 is a critical lncRNA that promotes ccRCC metastasis via inhibiting NPR3 and activating p38-MAPK signaling. Our results imply that MRCCAT1 could serve as a prognostic biomarker and therapeutic target for ccRCC.

Androgen receptor regulated microRNA miR-182-5p promotes prostate cancer progression by targeting the ARRDC3/ITGB4 pathway.

MicroRNAs (miRNAs) are important endogenous gene regulators that play key roles in prostate cancer development and metastasis. However, specific miRNA expression patterns in prostate cancer tissues from Chinese patients remain largely unknown. In this study, we compared miRNA expression patterns in 65 pairs of prostate cancer and para-cancer tissues by RNA sequencing and found that miR-182-5p was the most up-regulated miRNA in prostate cancer tissues. The result was validated using realtime PCR in 18 pairs of prostate cancer and para-cancer tissues. In in vitro analysis, it was confirmed that miR-182-5p promotes prostate cancer cell proliferation, invasion and migration and inhibit apoptosis. In addition, the androgen receptor directly regulated the transcription of miR-182-5p, which could target to the 3'UTR of ARRDC3 mRNA and affect the expression of ARRDC3 and its downstream gene ITGB4. For the in vivo experiment, miR-182-5p overexpression also promoted the growth and progression of prostate cancer tumors. In this regard, we suggest that miR-182-5p may be a key androgen receptor-regulated factor that contributes to the development and metastasis of Chinese prostate cancers and may be a potential target for the early diagnosis and therapeutic studies of prostate cancer.

A novel urinary long non-coding RNA transcript improves diagnostic accuracy in patients undergoing prostate biopsy.

BACKGROUND: Long non-coding RNA (LncRNA) PCA3 has been a well-established urine biomarker for the detection of prostate cancer (PCa). Our previous study showed a novel LncRNA FR0348383 is up-regulated in over 70% of PCa compared with matched benign tissues. The aim of this study was to evaluate the diagnostic value of urinary FR0348383 for men undergoing prostate biopsy due to elevated PSA (PSA > 4.0 ng/ml) and/or abnormal digital rectal examination (DRE). METHODS: Post-DRE first-catch urine specimens prior to prostate biopsies were prospectively collected. After the whole transcriptome amplification, quantitative real time polymerase chain reaction was applied to quantify urine FR0348383 and PSA levels. The FR0348383 score was calculated as the ratio of PSA and FR0348383 mRNA (PSA mRNA/FR0348383 mRNA × 1000). The diagnostic value of FR0348383 score was evaluated by logistic regression and decision curve analysis. RESULTS: 213 cases with urine samples containing sufficient mRNA were included, 94 cases had serum PSA level 4.0-10.0 ng/ml. PCa was identified in 72 cases. An increasing FR0348383 score was correlated with an increasing probability of a positive biopsy (P < 0.001). Multivariable logistic analysis indicated FR0348383 score (P < 0.001), PSA (P = 0.004), age (P = 0.007), prostate volume (P < 0.001) were independent predictors of PCa. ROC analysis demonstrated FR0348383 score outperformed PSA, %free PSA, and PSA Density in the prediction of PCa in the subgroup of patients with grey area PSA (AUC: 0.815 vs. 0.562 vs. 0.599 vs. 0.645). When using a probability threshold of 30% in the grey zone cohort, The FR0348383 score would save 52.0% of avoidable biopsies without missing any high grade cancers. CONCLUSIONS: FR0348383 transcript in post-DRE urine may be a novel biomarker for detection of PCa with great diagnostic value, especially in the grey zone cohort. The application of FR0348383 score in clinical practice might avoid unnecessary prostate biopsies and increase the specificity of PCa diagnosis.

IgG4-related disease of the ureter mimicking malignant ureter tumor: a case report and experience sharing.

Background: Immunoglobulin G4-related disease (IgG4-RD) is an autoimmune disease that can affect any organ or tissue in the body, and is characterized by intensive infiltration of IgG4-positive plasma cells, and elevated serum IgG4 levels. IgG4-RD causes renal impairment of unknown pathogenesis that may progress to kidney failure. However, few case of IgG4-RD mimicking malignant ureter tumor leading to severe hydronephrosis. Case Description: This report describes a 38-year-old male patient who was hospitalized for sudden waist pain. Enhanced abdominal computed tomography (CT) revealed a mass involving the right ureter. He presented to the urologist with severe right hydronephrosis. Urinalysis revealed occult blood (3+), and atypical cells were observed in urine cytology, raising the possibility of a ureteral malignancy. After that, the patient underwent diagnostic ureteroscopy instead of direct nephroureterectomy and was found not to have any malignancy. The patient received laparoscopic partial ureteral resection and anastomosis. Histologically, there were observations of IgG4-positive plasma cell infiltration exceeding 10 cells per high-power field, as well as a high ratio of IgG4-positive/IgG-positive cells exceeding 40%. And histopathology revealed ureteral IgG4-related disease, with no evidence of urothelial carcinoma. Conclusions: IgG4-RD has previously been reported in lesions involving the ureters, but misdiagnosis and subsequent radical nephroureterectomy can cause lifelong regret for the patient in having lost one side of the urinary tract. To avoid such misdiagnoses, clinicians should consider IgG4-RD as a potential condition.

Well-defined asymmetric nitrogen/carbon-coordinated single metal sites for carbon dioxide conversion.

Asymmetric nitrogen/carbon-coordinated single metal sites (M-NxC4-x) outperform symmetric M-N4 sites in carbon dioxide (CO2) electroreduction. However, the challenge of crafting well-defined M-NxC4-x sites complicates the understanding of their structure-catalytic performance relationship. In this study, we employ metallized N-confused tetraphenylporphyrin (M-NCTPP) to investigate CO2 conversion on M-N3C1 sites using both density functional theory and experimental methods. The optimal cobalt (Co)-N3C1 site (Co-NCTPP) achieves a current density of 500 mA cm-2 and a carbon monoxide Faraday efficiency exceeding 90 % at -1.25 V vs. the reversible hydrogen electrode, surpassing the performance of Co-N4 (Co-TPP). This research introduces a novel approach for designing and synthesizing high-activity heteroatom-anchored single metal sites, advancing fundamental understanding in the field.

Genistein is effective in inhibiting Orf virus infection in vitro by targeting viral RNA polymerase subunit RPO30 protein.

Orf virus (ORFV), a typical member of the genus Parapoxvirus, Poxvirus family, causes a contagious pustular dermatitis in sheep, goats, and humans. Poxviruses encode a multisubunit DNA-dependent RNA polymerase (vRNAP) that carries out viral gene expression in the host cytoplasm, which is a viral factor essential to poxvirus replication. Due to its vital role in viral life, vRNAP has emerged as one of the potential drug targets. In the present study, we investigated the antiviral effect of genistein against ORFV infection. We provided evidence that genistein exerted antiviral effect through blocking viral genome DNA transcription/replication and viral protein synthesis and reducing viral progeny, which were dosedependently decreased in genistein-treated cells. Furthermore, we identified that genistein interacted with the vRNAP RPO30 protein by CETSA, molecular modeling and Fluorescence quenching, a novel antiviral target for ORFV. By blocking vRNAP RPO30 protein using antibody against RPO30, we confirmed that the inhibitory effect exerted by genistein against ORFV infection is mediated through the interaction with RPO30. In conclusion, we demonstrate that genistein effectively inhibits ORFV transcription in host cells by targeting vRNAP RPO30, which might be a promising drug candidate against poxvirus infection.

Lycopene from tomatoes and tomato products exerts renoprotective effects by ameliorating oxidative stress, apoptosis, pyroptosis, fibrosis, and inflammatory injury in calcium oxalate nephrolithiasis: the underlying mechanisms.

Several mechanisms underlying nephrolithiasis, one of the most common urological diseases, involve calcium oxalate formation, including oxidative stress, inflammatory reactions, fibrosis, pyroptosis, and apoptosis. Although lycopene has strong antioxidant activity, its protective effects against CaOx-induced injury have not yet been reported. This study aimed to systematically investigate the protective effects of lycopene and explore its mechanisms and molecular targets. Crystal deposition, renal function, oxidative stress, inflammatory response, fibrosis, pyroptosis, and apoptosis were assessed to evaluate the renoprotective effects of lycopene against crystal formation in a CaOx rat model and oxalate-stimulated NRK-52E and HK-2 cells. Lycopene markedly ameliorated crystal deposition, restored renal function, and suppressed kidney injury by reducing oxidative stress, apoptosis, inflammation, fibrosis, and pyroptosis in the rats. In cell models, lycopene pretreatment reversed reactive oxygen species increase, apoptotic damage, intracellular lactate dehydrogenase release, cytotoxicity, pyroptosis, and extracellular matrix deposition. Network pharmacology and proteomic analyses were performed to identify lycopene target proteins under CaOx-exposed conditions, and the results showed that Trappc4 might be a pivotal target gene for lycopene, as identified by cellular thermal shift assay and surface plasmon resonance analyses. Based on molecular docking, molecular dynamics simulations, alanine scanning mutagenesis, and saturation mutagenesis, we observed that lycopene directly interacts with Trappc4 via hydrophobic bonds, which may be attributed to the PHE4 and PHE142 residues, preventing ERK1/2 or elevating AMPK signaling pathway phosphorylation events. In conclusion, lycopene might ameliorate oxalate-induced renal tubular epithelial cell injury via the Trappc4/ERK1/2/AMPK pathway, indicating its potential for the treatment of nephrolithiasis.

Characteristics of aseptic meningitis-like attack-an underestimated phenotype of myelin oligodendrocyte glycoprotein antibody-associated disease.

INTRODUCTION: Aseptic meningitis was recently reported and recognized as a novel phenotype of Myelin oligodendrocyte glycoprotein antibody-associated disease (MOG-AD). However, the frequency and clinical features of this specific subtype remain unclear. METHODS: We reported sixteen MOG-AD cases with aseptic meningitis from June 2018 to June 2022. Moreover, systematic literature of 17 reported cases was conducted. RESULTS: Upon reviewing the records of 91 patients diagnosed with MOG-AD in our center, we identified 16 patients (17.6%; 9 men and 7 women) with aseptic meningitis-like MOG-AD. The median age at onset was 23.5 ± 15.7 years. The common clinical presentations were fever (87.5%), headache (75.0%) and seizure (18.8%). Most patients had leukocytosis (62.5%) and a significantly elevated neutrophil-lymphocyte ratio (NLR, ≥3.0). Cerebrospinal fluid showed elevated intracranial hypertension (43.8%), elevated leukocytes (100%) and protein (56.3%). Negative brain magnetic resonance images were observed in 6 patients and only meningeal enhancement was observed in 8 patients at first. Almost all patients had a prolonged fever (over 2 weeks) and ineffectual antibiotic treatment. All patients experienced an effective response to immunotherapy. The majority had a benign course (low Expanded Disability Status Scale score and relapsing rate). Five patients (31.3%) progressed and four patients (25.0%) experienced recurrence. Aseptic meningitis-like MOG-AD of 17 cases reported in previous studies showed similar clinical features to our cases. CONCLUSION: Aseptic meningitis could be an initial or isolated manifestation of MOG-AD. It is an underestimated phenotype of MOG-AD.

Long non-coding RNA ENST00000503625 is a potential prognostic biomarker and metastasis suppressor gene in prostate cancer.

BACKGROUND: Dysregulation of Long Non-coding RNAs (lncRNAs) emerges to be a hallmark of cancers. Metastatic prostate cancer and localized disease that recurs after treatment are clinical challenges, it remains unclear how lncRNA plays a role in those processes. METHODS: From previous RNA-Seq data on 65 prostate cancer and adjacent normal tissues. We identified a novel lncRNA ENST00000503625 down-regulated in prostate cancer and correlated with tumor progression characteristics. Public datasets were examined for associations between ENST00000503625 expression and clinical parameters and prognoses. Subsequently, we constructed and externally validated a nomogram for predicting biochemical recurrence (BCR). Finally, in vitro experiments were carried out to determine how ENST00000503625 functions biologically in prostate cancer. RESULTS: Low ENST00000503625 in tumor was associated with poor clinical features and prognoses. TCGA pan-cancer analysis found that ENST00000503625 was deregulated in a variety of tumors and correlated with overall survival, disease-specific survival, and progression-free survival. The nomogram for predicting BCR was constructed using TCGA data, which exhibited excellent accuracy in external validation with Chinese Prostate Cancer Genome and Epigenome Atlas data. Gene Ontology and KEGG pathway analysis found that genes related to ENST00000503625 were enriched in multiple tumor progression related pathways. When ENST00000503625 was knocked down in vitro, the epithelial-mesenchymal transition was induced, by which cancer cells migrated and invaded more readily. CONCLUSION: Our data suggested that ENST00000503625 may serve as a potential prognostic marker or a therapeutic target for prostate cancer metastases.