Exosomes Derived from Human Palatal Mesenchymal Cells Mediate Intercellular Communication During Palatal Fusion by Promoting Oral Epithelial Cell Migration.

Purpose: Exosomes are important "messengers" in cell-cell interactions, but their potential effects on palatal fusion are still unknown. This study aimed to explore the role and mechanism of exosomes derived from palatal mesenchymal cells in epithelial-mesenchymal communication during palatogenesis. Methods: The expression of exosome marker CD63 and CD81 in palatal cells during palatogenesis was detected by immunofluorescence staining. After being purified from the supernatant of human embryonic palatal mesenchymal (HEPM) cells, exosomes (HEPM-EXO) were characterized by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and Western blot. HEPM-EXO were co-cultured with human immortalized oral epithelial cells (HIOEC). The effects of HEPM-EXO on the cell proliferation, migration, apoptosis and epithelial-mesenchymal transition (EMT) of HIOEC were evaluated. The proteins encapsulated in HEPM-EXO were analyzed by proteomic analysis. Results: The extensive expression of CD63 and CD81 in palatal epithelial and mesenchymal cells were continuously detected during E12.5~E14.5, suggesting that exosomes were involved in the process of palatal fusion. The expression of CD63 was also observed in the acellular basement membrane between the palatal epithelium and the mesenchyme in vivo, and HEPM-EXO could be internalized by HIOEC in vitro, suggesting that exosomes are potent to diffuse through the cellular tissue boundary to mediate palatal cell-cell communication. Exposure of HEPM-EXO to HIOEC substantially inhibited the proliferation and stimulated the migration of HIOEC, but had no significant effect on cell apoptosis and EMT. Proteomic analysis revealed the basic characteristics of the proteins in HEPM-EXO and that exosomal THBS1 may potentially regulate the cell behaviors of HIOEC, which needs further verification. Gene ontology (GO) analysis uncovered that the proteins highly expressed in HEPM-EXO are closely related to wound healing, implying a promising therapeutic opportunity of HEPM-EXO in tissue injury treatment with future studies. Conclusion: HEPM-EXO mediated cell-cell communication by regulating cell proliferation and migration of oral epithelial cells during palatogenesis.

A Novel Nomogram for Predicting Early Rebleeding After Endoscopic Treatment of Esophagogastric Variceal Hemorrhage.

BACKGROUND: Early rebleeding is a significant complication of endoscopic treatment for esophagogastric variceal hemorrhage (EGVH). However, a reliable predictive model is currently lacking. AIMS: To identify risk factors for rebleeding within 6 weeks and establish a nomogram for predicting early rebleeding after endoscopic treatment of EVGH. METHODS: Demographic information, comorbidities, preoperative evaluation, endoscopic features, and laboratory tests were collected from 119 patients who were first endoscopic treatment for EGVH. Independent risk factors for early rebleeding were determined through least absolute shrinkage and selection operator logistic regression. The discrimination, calibration, and clinical utility of the nomogram were assessed and compared with the model for end-stage liver disease (MELD), Child-Pugh, and albumin-bilirubin (ALBI) scores using receiver-operating characteristic (ROC) curves, calibration plots, and decision curve analyses (DCA). RESULTS: Early rebleeding occurred in 39 patients (32.8%) within 6 weeks after endoscopic treatment. Independent early rebleeding factors included gastric variceal hemorrhage (GVH), concomitant hepatocellular carcinoma (HCC), international normalized ratio (INR), and creatinine. The nomogram demonstrated exceptional calibration and discrimination capability. The area under the curve for the nomogram was 0.758 (95% CI 0.668-0.848), and it was validated at 0.71 through cross-validation and bootstrapping validation. The DCA and ROC curves demonstrated that the nomogram outperformed the MELD, Child-Pugh, and ALBI scores. CONCLUSIONS: Compared with existing prediction scores, the nomogram demonstrated superior discrimination, calibration, and clinical applicability for predicting rebleeding in patients with EGVH after endoscopic treatment. Therefore, it may assist clinicians in the early implementation of aggressive treatment and follow-up.

Classification of Central Nervous System Tumors Histologically Diagnosed in a Single Center of China 2003-2019.

OBJECTIVE: The classification of central nervous system (CNS) tumors has changed greatly. The Central Brain Tumor Registry of the United States (CBTRUS) and other institutions have analyzed the incidence rate and characteristics of primary CNS tumors. However, there are limited studies analyzing the incidence rate and characteristics of CNS tumors in China. To better understand CNS tumors in China, we summarized all primary CNS tumors diagnosed pathologically in a single center from 2003 to 2019. METHODS: All patients with primary CNS tumors who underwent neurosurgery at our hospital from January 2003 to December 2019 were included in this study. The data were collected from the hospital information system, including diagnosis time, age, gender, anatomic sites, and pathologic results. RESULTS: A total of 17,226 cases of primary CNS tumors were retrospectively analyzed in this study. Among all cases, the major tumor types included meningiomas, tumors of neuroepithelial tissue, and pituitary adenomas. Most tumors of neuroepithelial tissue were glioblastoma and astrocytoma. Most tumors of neuroepithelial tissue were located in the frontal lobe. However, grade 4 tumors of neuroepithelial tissue were more common in the temporal lobe. The median age of all patients was 46 years. The incidence of CNS tumors was higher in women than in men. CONCLUSIONS: Based on this data set, we analyzed various parameters of CNS tumors and found that grade 4 tumors of neuroepithelial tissue were more common in the temporal lobe, which were rarely reported in previous articles.

Value of synthetic MRI quantitative parameters in preprocedural evaluation for TRUS/MRI fusion-guided biopsy of the prostate.

BACKGROUND: Transrectal ultrasonography (TRUS)/magnetic resonance imaging (MRI) fusion-guided biopsy has a high clinical application value. However, this technique has some limitations, which limit its use in routine clinical practice. Therefore, the selection of suitable proatate lesions for this technique is worthy of our attention. Synthetic MRI (SyMRI) is capable of quantifying multiple relaxation parameters, which might have potential value in preprocedural evaluation for TRUS/MRI fusion-guided biopsy of the prostate. The aim of our study is to examine the value of SyMRI quantitative parameters in preprocedural evaluation for TRUS/MRI fusion-guided biopsy of the prostate. METHODS: We prospectively selected 148 lesions in 137 patients who underwent prostate biopsy in our hospital. Next, 2-4 needles of TRUS/MRI fusion-guided biopsy combined with 10 needles of system biopsy (SB) were used as the protocol for prostate biopsy. Before biopsy, the MAGiC sequences of the MRI images of the enrolled patients underwent post-processing, and the longitudinal relaxation time (T1), transverse relaxation time (T2), and proton density (PD) were extracted. The biopsy pathology results were used as a gold standard to compare the differences in SyMRI quantitative parameters between benign and malignant prostate lesions in the peripheral and transitional zones. The receiver operating characteristic (ROC) curves were plotted to confirm the optimal SyMRI quantitative parameter for prostate lesion benignancy/malignancy performance, and the cutoff values of these parameters were used for grouping the lesions. The single-needle biopsy prostate cancer (PCa)-positivity rates (number of positive biopsy needles/total biopsy needles) and PCa overall detection rates by TRUS/MRI fusion-guided biopsy and SB were compared in different subgroups. RESULTS: The T1 and T2 values can determine the benignancy/malignancy of prostate transition lesions(p < 0.01), and the T2 value has a greater diagnostic performance (p = 0.0376). The T2 value can determine the benignancy/malignancy of prostate peripheral lesions. The optimal diagnostic cutoff values for T2 were 77 and 81 ms, respectively. The single-needle PCa positivity rate of TRUS/MRI fusion-guided biopsy was higher than SB for any prostate lesions in different subgroups (p < 0.01). However, only in the subgroup of transition zone lesions with T2 ≤ 77 ms, the PCa overall detection rate of TRUS/MRI fusion-guided biopsy was significantly higher than that of SB (p = 0.031). CONCLUSION: SyMRI-T2 value can provide a theoretical basis for the selection of suitable lesions for TRUS/MRI fusion-guided biopsy.

Deciphering prognostic value of CD22 and its contribution to suppression of proinflammatory cytokines production in patients with IgA nephropathy.

BACKGROUND: CD22, mainly expressed in mature B cells, could negatively regulate the function of B cells by binding to sialic acid-positive IgG (SA-IgG). Soluble CD22 (sCD22) is generated by the cleavage of the extracellular domain of CD22 on the membrane surface. However, the role of CD22 in IgA nephropathy (IgAN) remains unknown. METHODS: A total of 170 IgAN patients with a mean follow-up of 18 months were included in this study. The sCD22, TGF-ß, IL-6 and TNF-α were detected using commercial ELISA kits. SA-IgG were purified to stimulate peripheral blood mononuclear cells (PBMCs) from IgAN patients. RESULTS: The plasma levels of sCD22 were lower in IgAN patients in comparison with healthy control. Furthermore, CD22 mRNA levels in PBMCs from patients with IgAN were significantly lower than those of healthy controls. The plasma levels of sCD22 were positively correlated to the mRNA levels of CD22. We found that patients with higher sCD22 levels had a lower level of serum creatinine and a higher level of eGFR on the time of renal biopsy and a higher remission rate of proteinuria and a lower risk of kidney events at the end of follow-up. The logistic regression analysis showed sCD22 was associated with an increased odd of proteinuria remission after being adjusted for eGFR, proteinuria, and SBP. After adjusting for confounding variables, sCD22 was a borderline significant predictor of less kidney composite endpoint. In addition, the sCD22 levels were positively associated with SA-IgG in plasma. The experimental results in vitro showed that addition of SA-IgG enhanced the release of sCD22 in cell supernatant and the phosphorylation of CD22 in PBMCs, further inhibiting the production of IL-6, TNF-α, and TGF-ß in cell supernatant in a dose-dependent manner. Pretreatment with CD22-antibody significantly increased the expression of cytokines in PBMCs. CONCLUSIONS: This is the first study to demonstrate that lower plasma soluble CD22 in IgAN patients and high soluble CD22 levels are associated with an increased odd of proteinuria remission and a decreased odd of kidney endpoint. The interaction between CD22 and SA-IgG can inhibit proliferation and inflammation release in PBMCs from IgAN patients.

Wnt signaling regulates MFSD2A-dependent drug delivery through endothelial transcytosis in glioma.

BACKGROUND: Systemic delivery of anti-tumor therapeutic agents to brain tumors is thwarted by the blood-brain barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). A failure of pharmacological compounds to cross BBB is one culprit for the dismal prognosis of glioblastoma (GBM) patients. Identification of novel vascular targets to overcome the challenges posed by the BBB in tumors for GBM treatment is urgently needed. METHODS: Temozolomide (TMZ) delivery was investigated in CT2A and PDGFB-driven RCAS/tv-a orthotopic glioma models. Transcriptome analysis was performed on ECs from murine gliomas. Mfsd2a deficient, Cav1 deficient, and Mfsd2a EC-specific inducible mice were developed to study the underlying molecular mechanisms. RESULTS: We demonstrated that inhibiting Wnt signaling by LGK974 could increase TMZ delivery and sensitize glioma to chemotherapy in both murine glioma models. Transcriptome analysis of ECs from murine gliomas revealed that Wnt signaling inhibition enhanced vascular transcytosis as indicated by the upregulation of PLVAP and downregulation of MFSD2A. Mfsd2a deficiency in mice enhances TMZ delivery in tumors, whereas constitutive expression of Mfsd2a in ECs suppresses the enhanced TMZ delivery induced by Wnt pathway inhibition in murine glioma. In addition, Wnt signaling inhibition enhanced caveolin-1 (Cav1)-positive caveolae-mediated transcytosis in tumor ECs. Moreover, Wnt signaling inhibitor or Mfsd2a deficiency fails to enhance TMZ penetration in tumors from Cav1-deficient mice. CONCLUSIONS: These results demonstrated that Wnt signaling regulates MFSD2A-dependent TMZ delivery through a caveolae-mediated EC transcytosis pathway. Our findings identify Wnt signaling as a promising therapeutic target to improve drug delivery for GBM treatment.

Effects of sodium-glucose co-transporter-2 inhibitors on kidney, cardiovascular, and safety outcomes in patients with advanced chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials.

AIMS: The overall effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors in patients with advanced chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR), 15-30 ml/min per 1.73 m2) remain unclear, and we thus conducted a systematic review and meta-analysis to evaluate the effects of SGLT2 inhibitors on kidney, cardiovascular (CV), and safety outcomes in patients with advanced CKD. METHODS: The Medline, Embase, and Cochrane Library databases were systematically searched for randomized controlled trials (RCTs) published up to March 3, 2022, and reporting effects of SGLT2 inhibitors on kidney, CV, or safety outcomes in patients with advanced CKD. RESULTS: From 2675 records, six RCTs with 2167 participants were included in the quantitative analyses. In patients with advanced CKD, SGLT2 inhibitors reduced the risk of the primary kidney outcome (a composite of worsening kidney function, end-stage kidney disease (ESKD), or kidney death) by 23% (RR 0.77, 95% CI 0.61-0.98, p = 0.04, I2 = 0 for the heterogeneity) and slowed the annual decline in eGFR slope, with the difference between SGLT2 inhibitor group and placebo group being 1.24 mL/min/1.73m2 per year (95% CI 0.06-2.42, p = 0.04). SGLT2 inhibitors were also associated with a decreased risk of primary CV outcome (a composite of CV death or hospitalization for heart failure) (HR 0.71, 95% CI 0.53-0.96, p = 0.03, I2 = 0 for the heterogeneity) and with similar risks of adverse events (such as acute kidney injury, fracture, amputation, and urinary tract infection). CONCLUSIONS: Among patients with advanced CKD, SGLT2 inhibitors reduced the risks of primary kidney and CV outcomes and attenuated the progressive decrease in eGFR compared with placebo, with no evidence of additional safety concerns. These observed benefits may support continuing the use of SGLT2 inhibitors in patients with advanced CKD before initiating maintenance dialysis or kidney transplantation. Future large-scale RCTs are needed to confirm the robustness of these results.

SLC1A5 enhances malignant phenotypes through modulating ferroptosis status and immune microenvironment in glioma.

Glioma is the most common type of primary malignant tumor in the central nervous system with limited treatment satisfaction. Finding new therapeutic targets has remained a major challenge. Ferroptosis is a novel and distinct type of programmed cell death, playing a regulatory role in the progression of tumors. However, the role of ferroptosis or ferroptosis-related genes (FRGs) in glioma progression has not been extensively studied. In our study, a novel ferroptosis-related prognostic model, including 7 genes, was established, in which patients classified into the high-risk group had more immuno-suppressive status and worse prognosis. Among these 7 genes, we screened solute carrier family 1 member 5 (SLC1A5), an FRG, as a possible new target for glioma treatment. Our results showed that the expression of SLC1A5 was significantly upregulated in glioblastoma tissues compared with the low-grade gliomas. In addition, SLC1A5 knockdown could significantly inhibit glioma cell proliferation and invasion, and reduce the sensitivity of ferroptosis via the GPX4-dependent pathway. Furthermore, SLC1A5 was found to be related to immune response and SLC1A5 knockdown decreased the infiltration and M2 polarization of tumor-associated macrophages. Pharmacological inhibition of SLC1A5 by V9302 was confirmed to promote the efficacy of anti-PD-1 therapy. Overall, we developed a novel prognostic model for glioma based on the seven-FRGs signature, which could apply to glioma prognostic and immune status prediction. Besides, SLC1A5 in the model could regulate the proliferation, invasion, ferroptosis and immune state in glioma, and be applied as a prognostic biomarker and potential therapeutic target for glioma.

Magnetic Resonance Image Compilation Was Used in Conjunction with Prostate PI-RADS v2.1 Score Has Diagnostic Relevance for Benign and Malignant Prostate Lesions.

Objective: To assess the diagnostic usefulness of magic in conjunction with PI-RADS v2.1 for prostate cancer malignant foci. Methods: A total of 202 lesions (97 transitional zone lesions and 105 peripheral zone lesions) from 198 people were investigated retrospectively using traditional MRI and magic images. Each lesion has a unique pathological consequence. Lesions T1, T2, and PD values were employed as magic observation markers. The locations of the lesions were aggregated, and the paired t-test and receiver operating characteristic curve (ROC) were employed to find the indices with statistical significance in separating benign from malignant prostatic nodules (+1 point) and (-1 point) respectively. Draw a ROC curve and compare it to the PI-RADS v2.1 score using the magic positive and negative indices as well as the PI-RADS v2.1 score. By comparing the ROC curves scored separately, the diagnostic efficiency of the two scoring approaches for benign and malignant prostate lesions was investigated. Results: T2 value has the highest diagnostic efficiency among the magic observation indices. T2 value of 77 ms for transitional zone lesions and T2 value of 89 ms for peripheral zone lesions are positive indices, whereas T2 value >77 ms and T2 value >89 ms are negative indexes. PI-RADS v2.1 combines one score and magic. In the transitional zone, the sensitivity, specificity, positive predictive value, and negative predictive value of the two scoring methods were 57.52, 87.70, 76.70, and 74.6 percent and 82.50, 73.68, 95.5, and 74.7 percent, respectively, and the AUC values were 0.735 and 0.846, respectively (P = 0.004); in the peripheral zone, the AUC values were 86.15 percent, 68.42 percent, 82.4. Conclusions: Magic T2 value is a favorable sign for diagnosing benign and malignant prostate cancers when used in conjunction with PI-RADS v2.1. The end product exceeds PI-RADS v2.1 on its own, which is more useful in identifying benign and malignant prostate lesions, decreasing unnecessary puncture and alleviating patient pain.

Cardiac Function Assessment in Fetuses With Ductus Arteriosus Constriction: A Two-Dimensional Echocardiography and FetalHQ Study.

Background: Fetal ductal constriction (DC) is associated with excessive polyphenol-rich food (PRF) consumption during pregnancy. However, the effect of this hemodynamic change on fetal cardiac function still needs to be elucidated. Therefore, this study aimed to evaluate the cardiac function of fetuses with PRF-related DC and to describe serial observations of cardiac function changes. Methods: We compared the traditional echocardiographic indices, including morphological, hemodynamic, and functional parameters, between study fetuses and controls. For global and segmental deformation analysis of the left and right ventricles, fetalHQ with the speckle-tracking technique was used to calculate sphericity index (SI), global longitudinal strain (GLS), fractional shortening (FS), fractional area change (FAC), etc. In addition, follow-up data were compared with the generalized linear model. Results: A total of 60 DC fetuses and 60 gestational-matched controls were enrolled in our study, with 20 DC fetuses undertaking a follow-up echocardiogram after 2-3 weeks. Compared with controls, there was a distinct decrease in right ventricular GLS (RVGLS) (-13.39 ± 3.77 vs. -21.59 ± 2.51, p < 0.001), RVFAC (22.20 ± 9.56 vs. 36.01 ± 4.84, p < 0.001), left ventricular GLS (LVGLS) (-19.52 ± 3.24 vs. -23.81 ± 2.01 p < 0.001), and LVFAC (39.64 ± 7.32 vs. 44.89 ± 4.91, p = 0.004). For 24-segment FS analysis, DC fetuses showed lower FS in left ventricular (LV) segments 18-24, with no difference in LV segments 1-17. Right ventricular (RV) FS in segments 4-23 was also reduced in the DC group. The 24-segment SI analysis indicated significantly lower SI in DC than those in controls for LV segments 1-14 and RV segments 19-24. We found that the pulsatility index (PI) of ductus arteriosus (DA) was an independent variable for RVGLS (ß = -0.29, p = 0.04). In 20 DC fetuses with follow-up echocardiograms, no obvious difference in myocardial deformation was found between the initial examination and follow-up data. Conclusion: Left and right ventricular performances were both impaired in DC fetuses, along with a series of morphological and hemodynamic changes. Although the state of DA constriction improved on second examinations, cardiac function was not completely restored.

AtPRMT5-mediated AtLCD methylation improves Cd2+ tolerance via increased H2S production in Arabidopsis.

Arabidopsis (Arabidopsis thaliana) PROTEIN ARGININE METHYLTRANSFERASE5 (PRMT5), a highly conserved arginine (Arg) methyltransferase protein, regulates multiple aspects of the growth, development, and environmental stress responses by methylating Arg in histones and some mRNA splicing-related proteins in plants. Hydrogen sulfide (H2S) is a recently characterized gasotransmitter that also regulates various important physiological processes. l-cysteine desulfhydrase (LCD) is a key enzyme of endogenous H2S production. However, our understanding of the upstream regulatory mechanisms of endogenous H2S production is limited in plant cells. Here, we confirmed that AtPRMT5 increases the enzymatic activity of AtLCD through methylation modifications during stress responses. Both atprmt5 and atlcd mutants were sensitive to cadmium (Cd2+), whereas the overexpression (OE) of AtPRMT5 or AtLCD enhanced the Cd2+ tolerance of plants. AtPRMT5 methylated AtLCD at Arg-83, leading to a significant increase in AtLCD enzymatic activity. The Cd2+ sensitivity of atprmt5-2 atlcd double mutants was consistent with that of atlcd plants. When AtPRMT5 was overexpressed in the atlcd mutant, the Cd2+ tolerance of plants was significantly lower than that of AtPRMT5-OE plants in the wild-type background. These results were confirmed in pharmacological experiments. Thus, AtPRMT5 methylation of AtLCD increases its enzymatic activity, thereby strengthening the endogenous H2S signal and ultimately improving plant tolerance to Cd2+ stress. These findings provide further insights into the substrates of AtPRMT5 and increase our understanding of the regulatory mechanism upstream of H2S signals.

NEAT1/MALAT1/XIST/PKD--Hsa-Mir-101-3p--DLGAP5 Axis as a Novel Diagnostic and Prognostic Biomarker Associated With Immune Cell Infiltration in Bladder Cancer.

Background: The clinical value of the biomarkers of bladder cancer (BC) is limited due to their low sensitivity or specificity. As a biomarker, DLG associated protein 5 (DLGAP5) is a potential cell cycle regulator in cancer cell carcinogenesis. However, its functional part in BC remains unclear. Therefore, this study aims to identify DLGAP5 expression in BC and its potential diagnostic and prognostic values. Eventually, it predicts the possible RNA regulatory pathways of BC. Methods: Data on DLGAP5 expression levels in BC and normal bladder tissues were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. The receiver operating characteristic (ROC), Kaplan-Meier survival curves, and the univariate and multivariate Cox regression analysis determined the diagnostic and prognostic values of DLGAP5 in BC patients. Finally, the StarBase predicted the target RNAs and constructed networks using Cytoscape. Results: DLGAP5 expression was significantly upregulated in BC tissue, verified by the TCGA (p < 0.001), GSE3167, GSE7476, and GSE65635 datasets (p < 0.01). BC patients with increased DLGAP5 had poor overall survival (OS) (p = 0.01), disease specific survival (DSS) (p = 0.006) and progress free interval (DFI) (p = 0.007). The area under the ROC curve (AUC) was 0.913. The multivariate Cox analysis identified that lymphovascular invasion (p = 0.007) and DLGAP5 (p = 0.002) were independent prognostic factors. Conclusion: Increased DLGAP5 expression was closely associated with a poor prognosis in BC patients. In this case, DLGAP5 might be a diagnostic and prognostic biomarker for BC. DLGAP5 expression might be regulated by NEAT1/MALAT1/XIST/PKD--Hsa-mir-101-3p pathways.

The Potential Value of m6A RNA Methylation in the Development of Cancers Focus on Malignant Glioma.

N6-methyladenosine (m6A) RNA methylation is an epigenetic modification that has emerged in the last few years and has received increasing attention as the most abundant internal RNA modification in eukaryotic cells. m6A modifications affect multiple aspects of RNA metabolism, and m6A methylation has been shown to play a critical role in the progression of multiple cancers through a variety of mechanisms. This review summarizes the mechanisms by which m6A RNA methylation induced peripheral cancer cell progression and its potential role in the infiltration of immune cell of the glioblastoma microenvironment and novel immunotherapy. Assessing the pattern of m6A modification in glioblastoma will contribute to improving our understanding of microenvironmental infiltration and novel immunotherapies, and help in developing immunotherapeutic strategies.

Immune Gene Signatures and Immunotypes in Immune Microenvironment Are Associated With Glioma Prognose.

Glioma is the most common primary malignant brain tumor in adults with very poor prognosis. The limited new therapeutic strategies for glioma patients can be partially attributed to the complex tumor microenvironment. However, knowledge about the glioma immune microenvironment and the associated regulatory mechanisms is still lacking. In this study, we found that, different immune subtypes have a significant impact on patient survival. Glioma patients with a high immune response subtype had a shorter survival compared with patients with a low immune response subtype. Moreover, the number of B cell, T cell, NK cell, and in particular, the macrophage in the immune microenvironment of patients with a high immune response subtype were significantly enhanced. In addition, 132 genes were found to be related to glioma immunity. The functional analysis and verification of seven core genes showed that their expression levels were significantly correlated with the prognosis of glioma patients, and the results were consistent at tissue levels. These findings indicated that the glioma immune microenvironment was significantly correlated with the prognosis of glioma patients and multiple genes were involved in regulating the progression of glioma. The identified genes could be used to stratify glioma patients based on immune subgroup analysis, which may guide their clinical treatment regimen.

Singlet Oxygen and Mobile Hydroxyl Radicals Co-operating on Gas-Solid Catalytic Reaction Interfaces for Deeply Oxidizing NOx.

Learning from the important role of porphyrin-based chromophores in natural photosynthesis, a bionic photocatalytic system based on tetrakis (4-carboxyphenyl) porphyrin-coupled TiO2 was designed for photo-induced treating low-concentration NOx indoor gas (550 parts per billion), achieving a high NO removal rate of 91% and a long stability under visible-light (λ ≥ 420 nm) irradiation. Besides the great contribution of the conventional •O2- reactive species, a synergic effect between a singlet oxygen (1O2) and mobile hydroxyl radicals (•OHf) was first illustrated for removing NOx indoor gas (1O2 + 2NO → 2NO2, NO2 + •OHf → HNO3), inhibiting the production of the byproducts of NO2. This work is helpful for understanding the surface mechanism of photocatalytic NOx oxidation and provides a new perspective for the development of highly efficient air purification systems.

The prevalence and clinical correlates of medical disorders comorbidities in patients with bipolar disorder.

OBJECTIVE: Medical disorders in patients with bipolar disorder (BD) have attracted more and more attention. So far, there is still a lack of studies on this issue utilizing large sample sizes in the Chinese sample. Therefore, we conducted this study to explore the clinical characteristics of BD patients comorbid medical disorders in a relatively large Chinese sample. METHODS: This was a cross-sectional study including 1,393 BD patients (882 patients with medical disorders and 511 patients without medical disorders). Their demographic and clinical characteristics were obtained by the Hospital Information System and self-designed questionnaires. RESULTS: The comorbidity rate of medical disorders in BD was 63.32%. The average number of medical disorders for a BD patient was 2.69. The top five comorbid medical disorders in BD patients were circulatory system diseases (19%), nervous system diseases (18%), endocrine and metabolic diseases (17%), digestive system diseases (16%), and respiratory system diseases (8%). BD patients with comorbid medical disorders had an older average age, lower education level, longer illness course, later onset age, lower ratio of psychotic features, more admission numbers, higher ratio of smoking and drinking alcohol, more number of manic episodes (All P < 0.05). Smoking, numbers of depressive episode, onset age, and illness course were independent risk factors of comorbidities in BD patients (All P < 0.05). CONCLUSIONS: Medical disorders in Chinese BD patients are highly prevalent. The smoking, number of depressive episodes, onset age, illness course, are correlated with BD patients comorbid medical disorders. Clinicians should pay attention to the medical disorders comorbidities in BD patients, and take effective measures to improve treatment outcome and reduce the suffering. The integrative approach should be the imperative in clinical practice.

Mechanistic Insight into the Fragmentation of Type I Collagen Fibers into Peptides and Amino Acids by a Vibrio Collagenase.

Vibrio collagenases of the M9A subfamily are closely related to Vibrio pathogenesis for their role in collagen degradation during host invasion. Although some Vibrio collagenases have been characterized, the collagen degradation mechanism of Vibrio collagenase is still largely unknown. Here, an M9A collagenase, VP397, from marine Vibrio pomeroyi strain 12613 was characterized, and its fragmentation pattern on insoluble type I collagen fibers was studied. VP397 is a typical Vibrio collagenase composed of a catalytic module featuring a peptidase M9N domain and a peptidase M9 domain and two accessory bacterial prepeptidase C-terminal domains (PPC domains). It can hydrolyze various collagenous substrates, including fish collagen, mammalian collagens of types I to V, triple-helical peptide [(POG)10]3, gelatin, and 4-phenylazobenzyloxycarbonyl-Pro-Leu-Gly-Pro-o-Arg (Pz-peptide). Atomic force microscopy (AFM) observation and biochemical analyses revealed that VP397 first assaults the C-telopeptide region to dismantle the compact structure of collagen and dissociate tropocollagen fragments, which are further digested into peptides and amino acids by VP397 mainly at the Y-Gly bonds in the repeating Gly-X-Y triplets. In addition, domain deletion mutagenesis showed that the catalytic module of VP397 alone is capable of hydrolyzing type I collagen fibers and that its C-terminal PPC2 domain functions as a collagen-binding domain during collagenolysis. Based on our results, a model for the collagenolytic mechanism of VP397 is proposed. This study sheds light on the mechanism of collagen degradation by Vibrio collagenase, offering a better understanding of the pathogenesis of Vibrio and helping in developing the potential applications of Vibrio collagenase in industrial and medical areas. IMPORTANCE Many Vibrio species are pathogens and cause serious diseases in humans and aquatic animals. The collagenases produced by pathogenic Vibrio species have been regarded as important virulence factors, which occasionally exhibit direct pathogenicity to the infected host or facilitate other toxins' diffusion through the digestion of host collagen. However, our knowledge concerning the collagen degradation mechanism of Vibrio collagenase is still limited. This study reveals the degradation strategy of Vibrio collagenase VP397 on type I collagen. VP397 binds on collagen fibrils via its C-terminal PPC2 domain, and its catalytic module first assaults the C-telopeptide region and then attacks the Y-Gly bonds in the dissociated tropocollagen fragments to release peptides and amino acids. This study offers new knowledge regarding the collagenolytic mechanism of Vibrio collagenase, which is helpful for better understanding the role of collagenase in Vibrio pathogenesis and for developing its industrial and medical applications.

The Role of m6A Regulator-Mediated Methylation Modification and Tumor Microenvironment Infiltration in Glioblastoma Multiforme.

N6-methyladenosine (m6A) RNA methylation is an emerging epigenetic modification in recent years and epigenetic regulation of the immune response has been demonstrated, but the potential role of m6A modification in GBM tumor microenvironment (TME) cell infiltration and stemness remain unknown. The m6A modification patterns of 310 GBM samples were comprehensively evaluated based on 21 m6A regulators, and we systematically correlated these modification patterns with TME cell infiltration characteristics and stemness characteristics. Construction of m6Ascore to quantify the m6A modification patterns of individual GBM samples using a principal component analysis algorithm. We identified two distinct patterns of m6A modification. The infiltration characteristics of TME cells in these two patterns were highly consistent with the immunophenotype of the GBM, including the immune activation differentiation pattern and the immune desert dedifferentiation pattern. We also identified two modes of regulation of immunity and stemness by m6A methylation. Stromal activation and lack of effective immune infiltration were observed in the high m6Ascore subtype. Pan-cancer analysis results illustrate a significant correlation between m6AScore and tumor clinical outcome, immune infiltration, and stemness. Our work reveals that m6A modifications play an important role in the development of TME and stemness diversity and complexity. Patients with a low m6AScore showed significant therapeutic advantages and clinical benefits. Assessing the m6A modification pattern of individual tumors will help enhance our knowledge of TME infiltration and stemness characteristics, contribute to the development of immunotherapeutic strategies.

Value of Contrast-Enhanced Ultrasound in Adjusting the Classification of Chinese-TIRADS 4 Nodules.

OBJECTIVES: To explore the value of applying contrast-enhanced ultrasound (CEUS) in adjusting the classification of category 4 nodules in the Chinese-Thyroid Imaging Report and Data System (C-TIRADS). METHODS: The data of preoperative conventional ultrasound and CEUS examinations of 125 C-TIRADS 4 nodules in 109 patients were retrospectively analyzed. We divided the thyroid nodules into two groups based on whether recommend by the guide fine-needle aspiration (FNA). Group I included C-TIRADS 4A nodules with a maximum diameter ≤15 mm and C-TIRADS 4B and 4C nodules with a maximum diameter ≤10 mm, and Group II included C-TIRADS 4A nodules with a maximum diameter >15 mm and C-TIRADS 4B and 4C nodules with a maximum diameter >10 mm. In CEUS, thyroid nodules showing suspicious malignant features such as hypoenhancement or early washout were adjusted to a level higher in the C-TIRADS classification; thyroid nodules showing possible benign features such as iso- or hyperenhancement were adjusted to a level lower; and thyroid nodules showing no enhancement were adjusted to C-TIRADS 3. Taking the pathological results as the gold standard, the receiver operating characteristic (ROC) curves of the C-TIRADS classification before and after the adjustment based on CEUS were plotted, and the diagnostic efficiency was compared. RESULTS: The sensitivity, specificity, accuracy, and positive and negative predictive values of the C-TIRADS classification for the diagnosis of thyroid nodule malignancy before the adjustment based on the CEUS results were 83.6%, 63.8%, 74.4%, 72.7%, and 77.1%, respectively, and these values were 91.0%, 82.8%, 87.2%, 85.9%, and 88.9%, respectively, after the adjustment. The area under the ROC curve (AUC) was 0.737 and 0.869, respectively, showing a significant difference (Z = 3.288, P=0.001). The diagnostic efficiency of C-TIRADS classification after the adjustment based on the CEUS results in both groups was improved compared with the result before the adjustment, and the difference in Group II was significant (Z = 2.931, P=0.003). CONCLUSIONS: CEUS significantly improved the diagnostic performance in the adjustment of C-TIRADS 4 nodule classification, especially for the nodules which needs FNA recommended by the C-TIRADS.