A new large area MCP-PMT for high energy detection.

20-inch Large area photomultiplier tube based on microchannel plate (MCP-PMT) is newly developed in China. It is widely used in high energy detection experiments such as Jiangmen Underground Neutrino Observatory (JUNO), China JinPing underground Laboratory (CJPL) and Large High Altitude Air Shower Observatory (LHAASO). To overcome the poor time performance of the existing MCP-PMT, a new design of large area MCP-PMT is proposed in this paper. Three-dimensional models are developed in CST Studio Suite to validate its feasibility. Effects of the size and bias voltage of the focusing electrodes and MCP configuration on the collection efficiency (CE) and time performance are studied in detail using the finite integral technique and Monte Carlo method. Based on the simulation results, the optimized operating and geometry parameters are chosen. Results show that the mean ratio of photoelectrons landing on the MCP active area is 97.5%. The acceptance fraction of the impinging photoelectrons is close to 100% due to the emission of multiple secondary electrons when hitting the MCP top surface. The mean transit time spread (TTS) of the photoelectrons from the photocathode is 1.48 ns.

Bioinformatics and functional experiments reveal that MRC2 inhibits atrial fibrillation via the PPAR signaling pathway.

Background: Atrial fibrillation (AF) is a prevalent cardiac arrhythmia that requires improved clinical markers to increase diagnostic accuracy and provide insight into its pathogenesis. Although some biomarkers are available, new ones need to be discovered to better capture the complex physiology of AF. However, their limitations are still not fully addressed. Bioinformatics and functional studies can help find new clinical markers and improve the understanding of AF, meeting the need for early diagnosis and individualized treatment. Methods: To identify AF-related differentially expressed genes (DEGs), We applied the messenger RNA (mRNA) expression profile retrieved in Series Matrix File format from the GSE143924 microarray dataset obtained from the Gene Expression Omnibus (GEO) database, and then used weighted gene co-expression network analysis (WGCNA) to identify the overlapping genes. These genes were analyzed by enrichment analysis, expression analysis and others to obtain the hub gene. Additionally, the potential signaling pathway of hub gene in AF was explored and verified by functional experiments, like quantitative real-time polymerase chain reaction (qRT-PCR), cell counting kit-8 (CCK-8), flow cytometry, and Western blotting (WB) assay. Results: From the GSE143924 data (410 DEGs) and tan module (57 genes), 10 overlapping genes were identified. A central down-regulated gene in AF, MRC2, was identified through bioinformatics analysis. based on these results, it was hypothesized that the PPAR signaling pathway is related to the mechanism of action of MRC2 in AF. Moreover, over-MRC2 markedly reduced the growth speed of angiotensin II (Ang II)-induced human cardiac fibroblasts (HCFs) and increased apoptosis. Conversely, knockdown of MRC2 promoted HCFs cell proliferation number. Additionally, MRC2 over-expression increased the protein expression level of PPARα, PPARγ, CPT-1, and SIRT3 in Ang II-induced HCFs. Conclusions: While meeting the need for new biomarkers in the diagnosis and prognosis of AF, this study reveals the inherent limitations of current biomarkers. We identified MRC2 as a key player as an inhibitory gene in AF, highlighting its role in suppressing AF progression through the PPAR signaling pathway. MRC2 may not only serve as a diagnostic indicator, but also as a promising therapeutic target for patients with AF, which is expected to be applied in clinical practice and open up new avenues for individualized interventions.

Exosomal PGAM1 promotes prostate cancer angiogenesis and metastasis by interacting with ACTG1.

Tumor-derived exosomes and their contents promote cancer metastasis. Phosphoglycerate mutase 1 (PGAM1) is involved in various cancer-related processes. Nevertheless, the underlying mechanism of exosomal PGAM1 in prostate cancer (PCa) metastasis remains unclear. In this study, we performed in vitro and in vivo to determine the functions of exosomal PGAM1 in the angiogenesis of patients with metastatic PCa. We performed Glutathione-S-transferase pulldown, co-immunoprecipitation, western blotting and gelatin degradation assays to determine the pathway mediating the effect of exosomal PGAM1 in PCa. Our results revealed a significant increase in exosomal PGAM1 levels in the plasma of patients with metastatic PCa compared to patients with non-metastatic PCa. Furthermore, PGAM1 was a key factor initiating PCa cell metastasis by promoting invadopodia formation and could be conveyed by exosomes from PCa cells to human umbilical vein endothelial cells (HUVECs). In addition, exosomal PGAM1 could bind to γ-actin (ACTG1), which promotes podosome formation and neovascular sprouting in HUVECs. In vivo results revealed exosomal PGAM1 enhanced lung metastasis in nude mice injected with PCa cells via the tail vein. In summary, exosomal PGAM1 promotes angiogenesis and could be used as a liquid biopsy marker for PCa metastasis.

Determining effect of seagrass-mediated CO2 flux on the atmospheric cooling potential of a subtropical intertidal seagrass meadow.

Atmospheric greenhouse gas (GHG) emissions from seagrass meadows that determine the ecosystem atmospheric cooling effect have rarely been quantified. This study measured the simultaneous fluxes direct to the atmosphere of three GHGs (CO2, CH4 and N2O) within a Halophila beccarii seagrass meadow and an adjacent unvegetated bare intertidal flat, and their relationships to seagrass abundance and relevant soil parameters. The results showed that seasonal variation in seagrass abundance was strongly linked with the CO2 exchange rate. The CH4 and N2O fluxes were similarly low at both sites and comparable between winter and summer. The global warming potential of CH4 and N2O reduced the ecosystem CO2 uptake by only 5 % at the seagrass site. The results indicated that the H. beccarii meadow had a stronger atmospheric cooling effect than the bare flat and that the seagrass-mediated CO2 flux in this oligotrophic seagrass meadow primarily determined the atmospheric cooling effect.

Celastrol inhibits pathologic neovascularization in oxygen-induced retinopathy by targeting the miR-17-5p/HIF-1α/VEGF pathway.

Retinopathy of prematurity (ROP), which is characterized by retinal neovascularization (RNV), is a major cause of neonatal blindness. The primary treatment for ROP is anti-vascular endothelial growth factor (VEGF) therapy, which is costly and can rapidly lead to desensitization. Celastrol, a bioactive compound extracted from Tripterygium wilfordii Hook F. ("Thunder of God Vine"), has been shown to exert anticancer and anti-inflammatory effects. However, whether celastrol has antiangiogenic activity and can suppress inflammation to inhibit ROP progression is unclear. This was investigated in the present study in vitro as well as in vivo using a mouse model of oxygen-induced retinopathy (OIR). Our results showed that celastrol treatment reduced neovascular and avascular areas in the retina and inhibited microglia activation and inflammation in OIR mice. Celastrol also inhibited proliferation, migration, and tube formation in cultured human retinal microvascular endothelial cells, and reversed the activation of the microRNA (miR)-17-5p/hypoxia-inducible factor (HIF)-1α/VEGF pathway in the retina of OIR mice. These results indicate that celastrol alleviates pathologic RNV in the retina by protecting neuroglia and suppressing inflammation via inhibition of miR-17-5p/HIF-1α/VEGF signaling, and thus has therapeutic potential for the prevention and treatment of ROP.Abbreviations: BSA, bovine serum albumin; COX2, cyclooxygenase 2; ECM, endothelial cell medium; FBS, fetal bovine serum; HDAC, histone deacetylase; HIF-1, hypoxia-inducible factor 1; HRMEC, human retinal microvascular endothelial cell; Hsp70, heat shock protein; IB4, isolectin B4; ICAM-1, intercellular adhesion molecule 1; IL-1ß/6, interleukin 1 beta/6; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein 1; miRNA, microRNA; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa B; OIR, oxygen-induced retinopathy; PBS, phosphate-buffered saline; PCNA, proliferating cell nuclear antigen; PI3K, phosphatidylinositol-3-kinase; qRT-PCR, quantitative real-time PCR; RNV, retinal neovascularization; ROP, retinopathy of prematurity; RTCA, real-time cell analyzer; RVO, retinal vaso-obliteration; TNF-α, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor.

A five-pseudouridylation-associated-LncRNA classifier for primary prostate cancer prognosis prediction.

Background: Prostate cancer (PCa) is one of the most common cancers in males around the globe, and about one-third of patients with localized PCa will experience biochemical recurrence (BCR) after radical prostatectomy or radiation therapy. Reportedly, a proportion of patients with BCR had a poor prognosis. Cumulative studies have shown that RNA modifications participate in the cancer-related transcriptome, but the role of pseudouridylation occurring in lncRNAs in PCa remains opaque. Methods: Spearman correlation analysis and univariate Cox regression were utilized to determine pseudouridylation-related lncRNAs with prognostic value in PCa. Prognostic pseudouridylation-related lncRNAs were included in the LASSO (least absolute shrinkage and selection operator) regression algorithm to develop a predictive model. KM (Kaplan-Meier) survival analysis and ROC (receiver operating characteristic) curves were applied to validate the constructed model. A battery of biological cell assays was conducted to confirm the cancer-promoting effects of RP11-468E2.5 in the model. Results: A classifier containing five pseudouridine-related lncRNAs was developed to stratify PCa patients on BCR and named the "ψ-lnc score." KM survival analysis showed patients in the high ψ-lnc score group experienced BCR more than those in the low ψ-lnc score group. ROC curves demonstrated that ψ-lnc score outperformed other clinical indicators in BCR prediction. An external dataset, GSE54460, was utilized to validate the predictive model's efficacy and authenticity. A ceRNA (competitive endogenous RNA) network was constructed to explore the model's potential molecular functions and was annotated through GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses. RP11-468E2.5 was picked for further investigation, including pan-cancer analysis and experimental validation. Preliminarily, RP11-468E2.5 was confirmed as a tumor promoter. Conclusion: We provide some evidence that pseudouridylation in lncRNA played a role in the development of PCa and propose a novel prognostic classifier for clinical practice.

Symptoms of Dry Eye Disease in Hospitalized Patients with Coronavirus Disease 2019 (COVID-19).

BACKGROUND: We aimed to investigate the symptoms of the dry eye disease (DED) of hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: This cross-sectional, observational study analysis included 91 hospitalized patients with confirmed COVID-19 in Wuhan, China. The Ocular Surface Disease Index (OSDI) and the five-item Dry Eye Questionnaire (DEQ-5) were used to assess the severity of DED symptoms in the patients, and the analysis of variance was used to determine the factors associated with DED. RESULTS: A total of 42 patients consented to complete the investigation (response rate 46.15%). There were 26 (61.90%) patients who were diagnosed with DED symptoms by OSDI, and there were 28 (66.67%) patients with DED symptoms who were diagnosed by DEQ-5 score. For the biochemical tests, the patients with DED symptoms had lower aspartate aminotransferase (AST) levels compared to those with no DED symptoms (20.86 vs. 42.14, p=0.04). Further analysis showed that a previous history of cardiac or stroke disease (p=0.02) and typical symptoms of muscle soreness (p=0.03) were significantly different among the four DED symptoms groups on the basis of OSDI scores. The contributing factors of OSDI were mainly focused on visual function and environmental triggers. CONCLUSION: The incidence of DED symptoms is higher in hospitalized patients with COVID-19. The serum AST levels, history of cardiac or stroke disease, and the typical symptoms of muscle soreness may be the main impact factors on DED symptoms. We also need to pay more attention to the visual function and environmental triggers of hospitalized patients with COVID-19.

5-Methylcytosine RNA Methyltransferases-Related Long Non-coding RNA to Develop and Validate Biochemical Recurrence Signature in Prostate Cancer.

The effects of 5-methylcytosine in RNA (m5C) in various human cancers have been increasingly studied recently; however, the m5C regulator signature in prostate cancer (PCa) has not been well established yet. In this study, we identified and characterized a series of m5C-related long non-coding RNAs (lncRNAs) in PCa. Univariate Cox regression analysis and least absolute shrinkage and selector operation (LASSO) regression analysis were implemented to construct a m5C-related lncRNA prognostic signature. Consequently, a prognostic m5C-lnc model was established, including 17 lncRNAs: MAFG-AS1, AC012510.1, AC012065.3, AL117332.1, AC132192.2, AP001160.2, AC129510.1, AC084018.2, UBXN10-AS1, AC138956.2, ZNF32-AS2, AC017100.1, AC004943.2, SP2-AS1, Z93930.2, AP001486.2, and LINC01135. The high m5C-lnc score calculated by the model significantly relates to poor biochemical recurrence (BCR)-free survival (p < 0.0001). Receiver operating characteristic (ROC) curves and a decision curve analysis (DCA) further validated the accuracy of the prognostic model. Subsequently, a predictive nomogram combining the prognostic model with clinical features was created, and it exhibited promising predictive efficacy for BCR risk stratification. Next, the competing endogenous RNA (ceRNA) network and lncRNA-protein interaction network were established to explore the potential functions of these 17 lncRNAs mechanically. In addition, functional enrichment analysis revealed that these lncRNAs are involved in many cellular metabolic pathways. Lastly, M AFG-AS1 was selected for experimental validation; it was upregulated in PCa and probably promoted PCa proliferation and invasion in vitro. These results offer some insights into the m5C's effects on PCa and reveal a predictive model with the potential clinical value to improve the prognosis of patients with PCa.

Comparison of Various Strategies for the Prognosis and Outcomes of Ischaemic Dilated Cardiomyopathy in Smokers: Complete Revascularisation and Smoking Cessation Produces a Superior Outcome.

BACKGROUND: Various therapies have been used to improve the symptoms and prognosis of patients with coronary artery disease. However, comparative studies showing more suitable choices for patients with ischaemic dilated cardiomyopathy (IDCM) and who smoke cigarettes are lacking. METHODS: A total of 338 patients were divided into four groups according to whether they received complete revascularisation (CR), and/or underwent smoking cessation (SC). They were followed prospectively for 12 months. The major adverse cardiac and cerebrovascular events (MACCEs: all-cause mortality, non-fatal MI, non-fatal stroke, repeat revascularisation, and AHF) were the primary endpoint, and decompensation necessitating hospitalisation and the combined endpoint thereof were secondary endpoints. RESULTS: During a mean follow-up of 12 months, the prevalence of MACCEs was significantly lower in patients receiving CR plus SC (CRSC) than in patients receiving CR only (CR), SC only (SC), and neither R nor SC (NoRSC) (CRSC 4.4% vs. CR 11.9, p<0.05; vs. SC 26.5%, p<0.001; vs. NoRSC 34.5%, p<0.001, respectively). At 12 months, CR plus SC induced the greatest clinical benefits of the secondary outcomes in the CRSC group (49.1% relative increase in LVEF; 89.8% decrease in NT-proBNP level; 30.9% decrease in LVEDD; 38.3% decrease in LVESD; 51.4% decrease in LVEDVi; 51.2% decrease in LVESVi; 96.4% decrease in hs-cTnT level; 93.5% decrease in CK-MB level; 91.1% decrease in hs-CRP level; 94.0% decrease in IL-6 level; 1.9-fold increase in eNOS level; 1.8-fold increase in NO level; 1.3-fold increase in NOS level, all p<0.001). Absence of revascularisation brought about fewer benefits, and those who continued smoking had worse outcomes. CONCLUSIONS: The combination of CR and SC could be an optimal therapeutic regimen for patients with IDCM who smoke because it improves myocardial blood perfusion and endothelial function.

A novel PITX2c loss­of­function mutation underlies lone atrial fibrillation.

Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia responsible for substantial morbidity and significantly increased mortality rates. A growing body of evidence documents the important role of genetic defects in the pathogenesis of AF. However, AF is a heterogeneous disease and the genetic determinants for AF in an overwhelming majority of patients remain unknown. In the present study, a cohort of 100 unrelated patients with lone AF and a total of 200 unrelated, ethnically matched healthy individuals used as controls, were recruited. The whole coding exons and splice junctions of the pituitary homeobox 2c (PITX2c) gene, which encodes a paired­like homeobox transcription factor required for normal cardiovascular morphogenesis, were sequenced in the 100 patients and 200 control subjects. The causative potential of the identified mutation of PITX2c was predicted by MutationTaster and PolyPhen­2. The functional characteristics of the PITX2c mutation were assayed using a dual­luciferase reporter assay system. Based on the results, a novel heterozygous PITX2c mutation (p.T97A) was identified in a patient with AF. The missense mutation was absent in the 400 reference chromosomes and was automatically predicted to be disease­causing. Multiple alignments of PITX2c protein sequences across species revealed that the altered amino acid was completely conserved evolutionarily. Functional analysis demonstrated that the mutant PITX2c protein was associated with significantly decreased transcriptional activity when compared with its wild­type counterpart. The findings of the present study firstly link the PITX2c loss­of­function mutation to lone AF, and provide novel insight into the molecular mechanisms underlying AF, suggesting the potential implications for the early prophylaxis and allele­specific therapy of this common type of arrhythmia.