The prodomain of Arabidopsis metacaspase 2 positively regulates immune signaling mediated by pattern-recognition receptors.

Metacaspases (MCs) are structural homologs of mammalian caspases found in plants, fungi, and protozoa. Type-I MCs carry an N-terminal prodomain, the function of which is unclear. Through genetic analysis of Arabidopsis mc2-1, a T-DNA insertion mutant of MC2, we demonstrated that the prodomain of metacaspase 2 (MC2) promotes immune signaling mediated by pattern-recognition receptors (PRRs). In mc2-1, immune responses are constitutively activated. The receptor-like kinases (RLKs) BAK1/BKK1 and SOBIR1 are required for the autoimmune phenotype of mc2-1, suggesting that immune signaling mediated by the receptor-like protein (RLP)-type PRRs is activated in mc2-1. A suppressor screen identified multiple mutations in the first exon of MC2, which suppress the autoimmunity in mc2-1. Further analysis revealed that the T-DNA insertion at the end of exon 1 of MC2 causes elevated expression of the MC2 prodomain, and overexpression of the MC2 prodomain in wild-type (WT) plants results in the activation of immune responses. The MC2 prodomain interacts with BIR1, which inhibits RLP-mediated immune signaling by interacting with BAK1, suggesting that the MC2 prodomain promotes plant defense responses by interfering with the function of BIR1. Our study uncovers an unexpected function of the prodomain of a MC in plant immunity.

Preparation and Formation Mechanism Study of Antibiofilm Coating Based on Phase Transition of Glutenin.

The surface of food processing equipment is easily affected by biofilm-forming bacteria, leading to cross-contamination and food safety hazards. The critical issue is how to endow the surface of contact materials with antibacterial and antibiofilm abilities. A sustainable, stable, and antibiofilm coating was prepared by phase transition of glutenin. The disulfide bonds in glutenin were reduced by tris(2-carboxyethyl)phosphine, triggering the phase transition of glutenin. Hydrophobic interactions and intermolecular disulfide bonds may be the primary forces. Furthermore, the phase-transited products formed a nanoscale coating on the surface of stainless steel and glass under their own adhesion force and gravity. The coating exhibited good stability in harsh environments. More importantly, after 3 h of direct contact, the colony of Escherichia coli and Staphylococcus aureus decreased by one logarithm. The amount of biofilm was observed to be significantly decreased through optical microscopy and scanning electron microscopy. This article provides a foundational module for developing novel coatings.

Palladium-Catalyzed C(sp3)-H Nitrooxylation of Aliphatic Carboxamides with Practical Oxidants.

Here we report the palladium-catalyzed ß-C(sp3)-H nitrooxylation of aliphatic carboxamides using a modified quinoline auxiliary. Notably, Al(NO3)3·9H2O was used as a nitrate source as well as a practical oxidant. The 5-chloro-8-aminoquinoline auxiliary was nitrated in situ during the reaction, which may enhance its directing ability and help its removal. The reaction has a broad substrate scope with a variety of aliphatic carboxamides. The multiple substituted auxiliary can be easily removed and recovered. Two C-H-insertion palladacycle intermediates were isolated and characterized to elucidate the mechanism.

Efficacy and safety of pulsed field ablation for accessory pathways: a pilot study.

AIMS: Radiofrequency ablation is used as a first-line therapy for accessory pathways (APs). However, data regarding the effects of pulsed field ablation (PFA) on APs are limited. We sought to evaluate the acute procedural and 6-month success and safety of PFA in a cohort of patients with APs. METHODS AND RESULTS: A focal contact force-sensing PFA catheter was used for patients with APs. Pulsed field ablation generator generated a bipolar and biphasic waveform (±1000 V) with a duration of 100 ms from the tip of the PFA catheter. A 100% acute procedural success was achieved in 10 conscious patients with APs (7 left anterolateral, 2 left inferolateral, and 1 right posteroseptal APs) including 6 (60%) patients after an initial application. The average total ablation time was 6.3 ± 4.9 s for 4.7 ± 1.8 ablation sites (ASs), including 3.1 ± 2.4 s at targets and 3.2 ± 2.9 s at 3.2 ± 2 bolus ASs. The mean skin-to-skin time was 59.3 ± 15.5 min, and PFA catheter dwell time was 29.4 ± 7.8 min. One patient encountered transient sinus arrest during PFA due to parasympathetic overexcitation. Sinus rhythm was restored in all patients without any significant adverse events during the short-term follow-up. CONCLUSION: Pulsed field ablation of APs was feasible, effective, and safe. Its efficiency was remarkable for its ultrarapid termination of AP conduction. Further studies are warranted to prove whether utilization of PFA with current parameters can extend to manifold AP ablation.

Association Study between SNPs in MST1 and MST2 and H. pylori Infection as well as Noncardia Gastric Carcinogenesis.

INTRODUCTION: Gastric cancer (GC) remains a global health challenge, and H. pylori infection is a main risk factor for noncardia GC. The present study aimed to investigate the association between single nucleotide polymorphisms (SNPs) in mammalian sterile 20-like kinase 1 (MST1) and MST2, H. pylori (H. pylori) infection, and the risk of noncardia gastric cancer (GC). METHODS: A case-control study was conducted using enzyme-linked immunosorbent assay (ELISA) and TaqMan method to detect the titer of anti-H. pylori antibody in normal human serum and genotype 9 SNPs of MST1 and MST2 genes among 808 samples. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between SNPs and H. pylori infection, as well as the risk of noncardia gastric cancer in codominant, dominant, overdominant, recessive, and log-additive genetic models. Haplotypes were constructed using the Haploview 4.2 software. RESULTS: The CC genotype of MST2 SNP rs10955176 was associated with a reduced risk of H. pylori infection compared to the TT + CT genotype. None of other SNPs were associated with H. pylori infection. The TT genotype of MST2 SNP rs7827435 was associated with a reduced risk of noncardia gastric cancer compared to the AA + AT genotype. None of the SNPs were associated with noncardia gastric cancer. There were no associations between haplotypes and H. pylori infection or the risk of noncardia gastric cancer. CONCLUSIONS: The CC genotype of rs10955176 and the TT genotype of rs7827435 may serve as protective factors against H. pylori infection and noncardia gastric cancer risk, respectively.

The effect of external fixator on bone metabolism in patients with open fracture of extremities.

This experiment aimed to explore the influence mechanism of external fixator on open fracture. A total of 128 patients with open tibiofibular fractures were included in this study. The patients were randomly divided into external fixator group (n=64) and control group (n=64) according to the order of admission. Double-blind controlled observation was used. The levels of osteocalcin (BGP), ß-CTX, P1 NP, BALP, including haptoglobin (Hp), ceruloplasmin (CER), serum adrenocorticotropic hormone (ACTH), cortisol (COR), C-reactive protein (CRP), white blood cell (WBC) and interleukin-6 (IL-6) were recorded in different groups. The postoperative VAS score and quality of life were recorded. Log-rank was used to analyze the difference in postoperative adverse reaction rates among different groups. External fixation stent treatment increased BGP, PINP, and BALP expression and decreased ß-CTX, Hp, CER, ACTH, COR, CRP, WBC, and IL-6 levels. Patients in the external fixation stent group had significantly lower VAS score quality of life scores and incidence of adverse events than the control group. External fixation stents protect open fracture patients by promoting bone metabolism.

Forsythoside B alleviates osteoarthritis through the HMGB1/TLR4/NF-κB and Keap1/Nrf2/HO-1 pathways.

Osteoarthritis (OA) is a joint pain and dysfunction syndrome resulting from severe joint degeneration. Inflammation and degeneration of the articular cartilage are two main features of OA and have tight interactions during OA progression. Conventional treatment with nonsteroidal anti-inflammatory drugs has been widely utilized clinically, whereas the side effects have restricted their application. Forsythoside B has been found with anti-inflammatory effects and antiapoptosis in inflammatory diseases, whereas in OA it remains poorly understood. Interleukin (IL)-1ß (10 ng/mL) was taken to induce an OA cell model on HC-A chondrocytes and an OA rat model was constructed for in vivo experiments. Forsythoside B was adopted to treat HC-A chondrocytes and OA rats. As shown by the data, Forsythoside B hampered IL-1ß-elicited rat chondrocyte apoptosis, oxidative stress, and facilitated proliferation. The profiles of inflammatory factors, NOD-like receptor family pyrin domain containing 3 inflammasomes, Kelch-like epichlorohydrin-associated protein-1 (Keap1), and nuclear factor-κB (NF-κB) phosphorylation were suppressed by Forsythoside B, whereas the nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels were promoted. Further, Forsythoside B mitigated cartilage damage and degeneration. Moreover, the oxidative stress and inflammation mediators in the cartilage tissue of OA rats were remarkably abated. Collectively, Forsythoside B hinders the NF-κB and Keap1/Nrf2/HO-1 pathways to curb IL-1ß-elicited OA rat oxidative stress and inflammation both in vivo and ex vivo, ameliorating OA development. All over, this study provides an underlying strategy for treating OA, which might help the clinical treatment of OA patients.

AKR1C2 genetic variants mediate tobacco carcinogens metabolism involving bladder cancer susceptibility.

Tobacco carcinogens metabolism-related genes (TCMGs) could generate reactive metabolites of tobacco carcinogens, which subsequently contributed to multiple diseases. However, the association between genetic variants in TCMGs and bladder cancer susceptibility remains unclear. In this study, we derived TCMGs from metabolic pathways of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines, and then explored genetic associations between TCMGs and bladder cancer risk in two populations: a Chinese population of 580 cases and 1101 controls, and a European population of 5930 cases and 5468 controls, along with interaction and joint analyses. Expression patterns of TCMGs were sourced from Nanjing Bladder Cancer (NJBC) study and publicly available datasets. Among 43 TCMGs, we observed that rs7087341 T > A in AKR1C2 was associated with a reduced risk of bladder cancer in the Chinese population [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.72-0.97, P = 1.86 × 10-2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (Pinteraction = 5.04 × 10-3), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (Ptrend < 0.001). Genetically, rs7087341 showed an allele-specific transcriptional regulation as located at DNA-sensitive regions of AKR1C2 highlighted by histone markers. Mechanistically, rs7087341 A allele decreased AKR1C2 expression, which was highly expressed in bladder tumors that enhanced metabolism of tobacco carcinogens, and thereby increased DNA adducts and reactive oxygen species formation during bladder tumorigenesis. These findings provided new insights into the genetic mechanisms underlying bladder cancer.

Evaluation of candidate International Standards for meningococcal capsular polysaccharide groups W and Y.

Two candidate International Standards for meningococcal capsular group W and Y (MenW and MenY, respectively) polysaccharides were assessed for their suitability as quantitative standards in various physicochemical assays. The study was designed to evaluate the intended purpose of these standards, namely, to standardize the quantification of the respective polysaccharide content in meningococcal polysaccharide and conjugate vaccines and their intermediate components. Twelve laboratories from eleven different countries participated in the collaborative study of candidate preparations for International Standards for MenW and MenY polysaccharide (coded 16/152 and 16/206, respectively). Unitage was assigned using the Resorcinol assay. Our proposals, on the basis of data from the Resorcinol assay were: 1) candidate standard for MenW polysaccharide (16/152) to be assigned a content of 1.015 ± 0.071 mg MenW polysaccharide per ampoule (expanded uncertainty with coverage factor k = 2.13, corresponding to a 95 % level of confidence) and 2) candidate standard for MenY polysaccharide (16/206) be assigned a content of 0.958 ± 0.076 mg MenY polysaccharide per ampoule (expanded uncertainty with coverage factor k = 2.26, corresponding to a 95 % level of confidence). The amount of polysaccharide per ampoule remained consistent under all stability conditions over a 36-month period.

Cigarette smoking combined with genetic variation regulates the m6A methylation of CRNKL1 and is associated with bladder cancer risk.

Cigarette smoking was known to accelerate the occurrence and development of bladder cancer by regulating RNA modification. However, the association between the combination of cigarette smoking and RNA modification-related single nucleotide polymorphisms (RNAm-SNPs) and bladder cancer risk remains unclear. In this study, 1681 participants, including 580 cases and 1101 controls, were recruited for genetic association analysis. In total, 1 287 990 RNAm-SNPs involving nine RNA modifications (m6A, m1A, m6Am, 2'-O-Me, m5C, m7G, A-to-I, m5U, and pseudouridine modification) were obtained from the RMVar database. The interactive effect of cigarette smoking and RNAm-SNPs on bladder cancer risk was assessed through joint analysis. The susceptibility analysis revealed that 89 RNAm-SNPs involving m6A, m1A, and A-to-I modifications were associated with bladder cancer risk. Among them, m6A-related rs2273058 in CRNKL1 was associated with bladder cancer risk (odds ratios (OR) = 1.35, padj = 1.78 × 10-4), and CRNKL1 expression was increased in bladder cancer patients (p = 0.035). Cigarette smoking combined with the A allele of rs2273058 increased bladder cancer risk compared with nonsmokers with the G allele of rs2273058 (OR = 2.40, padj = 3.11 × 10-9). Mechanistically, the A allele of rs2273058 endowed CRNKL1 with an additional m6A motif, facilitating recognition by m6A reader IGF2BP1, thereby promoting CRNKL1 expression under cigarette smoking (r = 0.142, p = 0.017). Moreover, elevated CRNKL1 expression may accelerate cell cycle and proliferation, thereby increasing bladder cancer risk. In summary, our study demonstrated that cigarette smoking combined with RNAm-SNPs contributes to bladder cancer risk, which provides a potential target for bladder cancer prevention.

Electroacupuncture in the treatment of IBS in rats: investigation of the mechanisms of CRH+ neurons in the paraventricular nucleus.

Electroacupuncture (EA) is well documented to treat irritable bowel syndrome (IBS). However, the mechanism of the central nervous system related to IBS and acupuncture stimulation is still not well known. In this study, a rat model of IBS was established by cold-restraint comprehensive stresses for 15 days, and it was found that the levels of corticotropin-releasing hormone (CRH), corticosterone (CORT), and adrenocorticotropic hormone (ACTH) in the peripheral serum were increased; the visceral sensitivity was enhanced; and the intestinal motility was accelerated, specifically, there was an enhancement in the discharge frequency of neurons in the paraventricular nucleus (PVN). EA treatment for 3 days, 20 min/day, alleviated the increase in the levels of CRH, CORT, and ACTH in the peripheral serum of rats, reduced the visceral sensitivity of IBS rats, and inhibited colon movement and discharge frequency of the neurons in the PVN. In addition, EA could reduce the excitability of CRH neurons and the expression of corticotropin-releasing hormone receptor 1 (CRHR1) and corticotropin-releasing hormone receptor 2 (CRHR2) in PVN. At the same time, the expression of CRH, CRHR1, and CRHR2 in the peripheral colon was decreased. Taken together, EA appears to regulate intestinal functional activity through the central CRH nervous system, revealing the central regulation mechanism of EA in IBS rats, and providing a scientific research basis for the correlation among the meridians, viscera, and brain.NEW & NOTEWORTHY The purpose of this research was to determine the central regulatory mechanism of electroacupuncture (EA) in rats with irritable bowel syndrome (IBS). Our results showed that combined with the serum changes in corticotropin-releasing hormone (CRH), corticosterone (CORT), and adrenocorticotropic hormone (ACTH), the improvement of IBS by EA was related to them. Furthermore, EA could regulate intestinal functional activity through the central CRH+ nervous system.

Multi-omics study identifies that PICK1 deficiency causes male infertility by inhibiting vesicle trafficking in Sertoli cells.

BACKGROUND: Infertility affects approximately 10-15% of reproductive-age men worldwide, and genetic causes play a role in one-third of cases. As a Bin-Amphiphysin-Rvs (BAR) domain protein, protein interacting with C-kinase 1 (PICK1) deficiency could lead to impairment of acrosome maturation. However, its effects on auxiliary germ cells such as Sertoli cells are unknown. PURPOSE: The present work was aimed to use multi-omics analysis to research the effects of PICK1 deficiency on Sertoli cells and to identify effective biomarkers to distinguish fertile males from infertile males caused by PICK1 deficiency. METHODS: Whole-exome sequencing (WES) was performed on 20 infertility patients with oligozoospermia to identify pathogenic PICK1 mutations. Multi-omics analysis of a PICK1 knockout (KO) mouse model was utilized to identify pathogenic mechanism. Animal and cell function experiments of Sertoli cell-specific PICK1 KO mouse were performed to verify the functional impairment of Sertoli cells. RESULTS: Two loss-of-function deletion mutations c.358delA and c.364delA in PICK1 resulting in transcription loss of BAR functional domain were identified in infertility patients with a specific decrease in serum inhibin B, indicating functional impairment of Sertoli cells. Multi-omics analysis of PICK1 KO mouse illustrated that targeted genes of differentially expressed microRNAs and mRNAs are significantly enriched in the negative regulatory role in the vesicle trafficking pathway, while metabolomics analysis showed that the metabolism of amino acids, lipids, cofactors, vitamins, and endocrine factors changed. The phenotype of PICK1 KO mouse showed a reduction in testis volume, a decreased number of mature spermatozoa and impaired secretory function of Sertoli cells. In vitro experiments confirmed that the expression of growth factors secreted by Sertoli cells in PICK1 conditional KO mouse such as Bone morphogenetic protein 4 (BMP4) and Fibroblast growth factor 2 (FGF2) were decreased. CONCLUSIONS: Our study attributed male infertility caused by PICK1 deficiency to impaired vesicle-related secretory function of Sertoli cells and identified a variety of significant candidate biomarkers for male infertility induced by PICK1 deficiency.

c-MYC mediates the crosstalk between breast cancer cells and tumor microenvironment.

The MYC oncogenic family is dysregulated in diverse tumors which is generally linked to the poor prognosis of tumors. The members in MYC family are transcription factors which are responsible for the regulation of various genes expression. Among them, c-MYC is closely related to the progression of tumors. Furthermore, c-MYC aberrations is tightly associated with the prevalence of breast cancer. Tumor microenvironment (TME) is composed of many different types of cellular and non-cellular factors, mainly including cancer-associated fibroblasts, tumor-associated macrophages, vascular endothelial cells, myeloid-derived suppressor cells and immune cells, all of which can affect the diagnosis, prognosis, and therapeutic efficacy of breast cancer. Importantly, the biological processes occurred in TME, such as angiogenesis, immune evasion, invasion, migration, and the recruition of stromal and tumor-infiltrating cells are under the modulation of c-MYC. These findings indicated that c-MYC serves as a critical regulator of TME. Here, we aimed to summarize and review the relevant research, thus to clarify c-MYC is a key mediator between breast cancer cells and TME. Video Abstract.

Homologous proteins SAPCD2X1 and SAPCD2 have significantly different carcinogenic capacities in human colorectal cancer cells based on structural prediction and functional verification.

We discussed the expression and biological functions of the SAPCD2X1 protein in the HCT116 CRC cell line by bioinformatics analysis and prediction, and biological function verification. Spatial conformation models of SAPCD2X1 and SAPCD2 were predicted using the threading method, ensemble method, and several other protein structure prediction approaches. The conformational similarity between SAPCD2X1 and SAPCD2 was studied, and their functions were predicted. The biological experiments showed that SAPCD2X1 and SAPCD2 were overexpressed in CRC cells. SAPCD2X1-specific antibodies were prepared. The expressions of SAPCD2X1 and SAPCD2 were localized in cells using the immunofluorescence assay. The SAPCD2 and SAPCD2X1 overexpression models were validated using Western Blot and RT-qPCR. We successfully predicted the structures of the SAPCD2X1 and SAPCD2 proteins, and visualized them using the VDM software. It was predicted that the tertiary structure of SAPCD2X1 changed significantly compared with SAPCD2. Alteration of the biological functions of SAPCD2X1 was also predicted due to the changes in the spatial conformation of the protein. Anti-SAPCD2X1 antibody and SAPCD2X1-EGFP and SAPCD2-EGFP recombinant plasmids were established. The overexpression of the two proteins was induced in HCT116 cells using the recombinant plasmids, and verified by RT-qPCR and Western Blot. Meanwhile, the anti-SAPCD2X1 antibody was proved to have a high specificity. The immunofluorescence assay showed that SAPCD2X1 and SAPCD2 are mainly expressed in the cytoplasm. SAPCD2X1 and SAPCD2 exhibited significantly different biological functions in HCT116 cells. SAPCD2 is a carcinogenic protein, while SAPCD2X1 does not affect the proliferation, invasion, and migration of human CRC HCT116 cells.

An integrative approach for identification of smoking-related genes involving bladder cancer.

Tobacco smoking is one of the most important environmental risk factors involving bladder tumorigenesis. However, smoking-related genes in bladder carcinogenesis and corresponding genetic effects on bladder cancer risk remain unclear. Weighted correlation network analysis (WGCNA) underlying transcriptome of bladder cancer tissues was applied to identify smoking-related genes. The logistic regression model was utilized to estimate genetic effects of single nucleotide polymorphisms (SNPs) in smoking-related genes on bladder cancer risk in the Chinese and European populations with a total of 6510 cases and 6569 controls, as well as the interaction with smoking status. Transcriptome of cells and tissues was used to profile the expression pattern of candidate genes and their genetic variants. Our results demonstrated that a total of 24 SNPs in 14 smoking-related genes were associated with the risk of bladder cancer, of which rs9348451 in CDKAL1 exhibited an interaction with smoking status (ORinteraction = 1.38, Pinteraction = 1.08 × 10-2) and tobacco smoking might combine with CDKAL1 rs9348451 to increase the risk of bladder cancer (Ptrend = 4.27 × 10-4). Moreover, rs9348451 was associated with CDKAL1 expression in bladder cancer, especially in smokers (P < 0.001). Besides, CDKAL1 was upregulated in bladder cancer compared to normal adjacent tissues, as well as upregulated via treatment of cigarette smoke extracts. This study highlights the important role of nurture and nature, as well as their interaction on tumorigenesis, which provides a new way to decipher the etiology of bladder cancer with smoking status.

Impact of visceral obesity on infectious complications after resection for colorectal cancer: a retrospective cohort study.

OBJECTIVES: To explore the impact of visceral obesity (VO) measured by preoperative abdominal computed tomography (CT) on postoperative infectious complications for colorectal cancer (CRC) patients and establish a predictive model. METHODS: Patients who underwent resection for colorectal cancer between January 2015 and January 2021 were enrolled in this study. All patients were measured for body mass index (BMI) and visceral fat area (VFA) preoperatively. Infectious complications were compared between the different groups according to BMI and VO categories. Univariate and multivariate logistic regression were used to analyze whether VO was an independent risk factor for postoperative infectious complications. According to the results of logistic regression, six machine learning approaches were used to establish predictive models and perform internal validation. The best-performing model was interpreted by the SHAPley Additive exPlanations value. RESULTS: Approximately 64.81% of 520 patients had VO. VO was significantly connected with postoperative infectious complications (P < 0.001), coronary heart disease (P = 0.004), cerebral infarction (P = 0.001), hypertension (P < 0.001), diabetes (P < 0.001), and fatty liver (P < 0.001). The rates of wound infection (P = 0.048), abdominal or pelvic infection (P = 0.006), and pneumonia (P = 0.008) increased obviously in patients with VO. Compared to the low BMI group, a high BMI was found to be significantly associated with hypertension (P=0.007), fatty liver (P＜0.001), and a higher rate of postoperative infection (P=0.003). The results of logistic regression revealed that VO (OR = 2.01, 95% CI 1.17 ~ 3.48, P = 0.012), operation time ≥ 4 h (OR = 2.52, 95% CI 1.60 ~ 3.97, P < 0.001), smoking (OR = 2.04, 95% CI 1.16 ~ 3.59, P = 0.014), ostomy (OR = 1.65, 95% CI 1.04 ~ 2.61, P = 0.033), and chronic obstructive pulmonary disease (COPD) (OR = 2.23, 95% CI 1.09 ~ 4.57, P = 0.029) were independent risk factors. The light gradient boosting machine (LGBM) model displayed the largest area under the receiver operating characteristic curve (AUC) (0.74, 95% CI 0.68 ~ 0.81). CONCLUSIONS: In this study, VO was superior to BMI in evaluating the influence of obesity on metabolic comorbidities and postoperative infectious complications in colorectal cancer patients.

Pan-cancer analysis of the DNA methylation patterns of long non-coding RNA.

Long non-coding RNA (lncRNA) regulated by abnormal DNA methylation (ADM-lncRNA) emerges as a biomarker for cancer diagnosis and treatment. This study comprehensively described the methylation patterns of lncRNA in pan-cancer using the cancer data set in The Cancer Genome Atlas (TCGA). Based on the cancer heterogeneity of ADM-lncRNA in pan-cancer, we constructed a co-expression network of pan-cancer ADM-lncRNA (pADM-lncRNA) in 10 cancers, highlighting the combined action mode of abnormal DNA methylation, and indicating the internal connection among different cancers. Functional analysis revealed the pan-carcinogenic pathway of pADM-lncRNA and suggested potential factors for cancer heterogeneity and tumor immune microenvironment changes. Survival analysis showed the potential of pADM-lncRNA-mRNA co-expression pair as cancer biomarkers. Revealing the action mode of lncRNA and DNA methylation in cancer may help understand the key molecular mechanisms of cell carcinogenesis.

Correlation between Serum Myosin Light Chain 4 Levels and Recurrence after Radiofrequency Ablation in Patients with Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia that is harmful to human health. This study aims to explore the relationship between myosin light chain 4 (MYL4) and AF recurrence after radiofrequency ablation (RFA). Patients with AF (n = 85) were enrolled, and healthy subjects (n = 90) with normal sinus rhythm and no previous history of AF were selected as controls. The serum levels of MYL4, transforming growth factor (TGF) -ß1, and procollagen type-I C-terminal propeptide (PICP) were determined. The correlation between MYL4 and atrial fibrosis remodeling indicators (TGF-ß1/PICP) and left atrial diameter (LAD) was analyzed. The influence of MYL4 on AF recurrence after RFA was evaluated, and the independent correlation between them was assessed. Patients with AF and the controls showed no significant differences in age, gender, body mass index, systolic blood pressure, diastolic blood pressure, left ventricular ejection fraction, triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, white blood cell count, neutrophil/lymphocyte ratio, brain natriuretic peptide, and history of smoking, drinking, hypertension, and diabetes (P > 0.05), but with increased LAD in patients with AF (P < 0.01). Serum MYL4 level was reduced in patients with AF (0.6 ± 0.2) compared with that of controls (0.1 ± 0.6) (P < 0.01), and it was negatively correlated with TGF-ß1, PICP, and LAD (r = -0.2389, P < 0.05; r = -0.5174, P < 0.01; r = -0.3191; P < 0.01). Low levels of MYL4 increased the risk of AF recurrence after RFA (χ2 = 16.64; P < 0.0001). A low MYL4 level in patients with AF showed a poorer prognosis. Serum MYL4 level and AF type were independent risk factors affecting AF recurrence after RFA.

Exosomal circLPAR1 functions in colorectal cancer diagnosis and tumorigenesis through suppressing BRD4 via METTL3-eIF3h interaction.

BACKGROUND: Exosomes have emerged as vital biomarkers of multiple cancers and contain abundant circular RNAs (circRNAs). However, the potential for exosomal circRNAs to be used in diagnostics and their molecular mechanism of action in colorectal cancer (CRC) remain unclear. METHODS: CRC-specific exosomal circRNAs were identified by RNA sequencing, exoRBase database and a tissue microarray. The diagnostic performance of plasma exosomal circRNAs was evaluated among cancer-free controls, precancer individuals, CRC patients, and patients with other types of cancer. The corresponding biological functions were mainly assessed using circRNA pull-down, proteomic analysis, and RNA immunoprecipitation assay underlying cellular and mouse models. RESULTS: CircLPAR1 was encapsulated in exosomes with high stability and detectability, and its expression in plasma exosomes was remarkably decreased during CRC development but recovered after surgery. Exosomal circLPAR1 showed cancer specificity in CRC diagnosis and increased the diagnostic performance to an area under the receiver operating characteristic curve of 0.875, as determined by analysing its performance in combination with common clinical biomarkers CEA and CA19-9. Additionally, circLPAR1 was downregulated in CRC tissues and was associated with overall survival. Mechanistically, exosomal circLPAR1 was internalized by CRC cells, and it suppressed tumor growth, likely because exosomal circLPAR1 directly bound with eIF3h specifically suppressed the METTL3-eIF3h interaction, decreasing the translation of oncogene BRD4. CONCLUSIONS: This comprehensive study highlights plasma exosomal circLPAR1 as a promising predictor in CRC diagnosis and describes its biological regulation of colorectal tumorigenesis. This study provides a new perspective on early diagnosis in the clinic and pathogenesis in disease development.

Utility of 7,8-dihydroxyflavone in preventing astrocytic and synaptic deficits in the hippocampus elicited by PTSD.

Astrocytic functions and brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) signaling pathways are impaired in stress-related neuropsychiatric diseases. Previous studies have reported neuroprotective effects of 7,8-dihydroxyflavone (7,8-DHF), a TrkB activator. Here, we investigated the molecular mechanisms underlying pathogenesis of post-traumatic stress disorder (PTSD) using a modified single-prolonged stress (SPS&S) model and the potential beneficial effects of 7,8-DHF. SPS&S reduced the hippocampal expression of glial fibrillary acidic protein (GFAP), a marker of astrocytes, and induced morphological changes in astrocytes. From the perspective of synaptic function, the SPS&S model displayed reduced expression of BDNF, p-TrkB, postsynaptic density protein 95 (PSD95), AMPA receptor subunit GluR1 (GluA1), NMDA receptor subunit N2A/N2B ratio, calpain-1, phosphorylated protein kinase B (Akt) and phosphorylated mammalian target of rapamycin (mTOR) and conversely, higher phosphatase and tension homolog (PTEN) expression in the hippocampus. Acute or continuous intraperitoneal administration of 7,8-DHF (5 mg/kg) after SPS&S procedures prevented SPS&S-induced fear memory generalization and anxiety-like behaviors as well as abnormalities of hippocampal oscillations. Most importantly, 7,8-DHF attenuated SPS&S-induced abnormal BDNF-TrkB signaling and calpain-1-dependent cascade of synaptic deficits. Furthermore, treatment with a TrkB inhibitor completely blocked while an mTOR inhibitor partially blocked the effects of 7,8-DHF on behavioral changes of SPS&S model mice. Our collective findings suggest that 7,8-DHF effectively alleviates PTSD-like symptoms, including fear generalization and anxiety-like behavior, potentially by preventing astrocytic and synaptic deficits in the hippocampus through targeting of TrkB.