Abstract Atherosclerosis is a chronic inflammatory disease characterized with innate and adaptive immunity but also involves pyroptosis. Few studies have explored the role of pyroptosis in advanced atherosclerotic plaques from different vascular beds. Here we try to identify the different underlying function of pyroptosis in the progression of atherosclerosis between carotid arteries and femoral. arteries. We extracted gene expression levels from 55 advanced carotid or femoral atherosclerotic plaques. The pyroptosis score of each sample was calculated by single-sample-gene-set enrichment analysis (ssGSEA). We then divided the samples into two clusters: high pyroptosis scores cluster (PyroptosisScoreH cluster) and low pyroptosis scores cluster (PyroptosisScoreL cluster), and assessed functional enrichment and immune cell infiltration in the two clusters. Key pyroptosis related genes were identified by the intersection between results of Cytoscape and LASSO (Least Absolute Shrinkage and Selection Operator) regression analysis. Finally, all key pyroptosis related genes were validated in vitro. We found all but one of the 29 carotid plaque samples belonged to the PyroptosisScoreH cluster and the majority (19 out of 26) of femoral plaques were part of the PyroptosisScoreL cluster. Atheromatous plaque samples in the PyroptosisScoreL cluster had higher proportions of gamma delta T cells, M2 macrophages, myeloid dendritic cells (DCs), and cytotoxic lymphocytes (CTLs), but lower proportions of endothelial cells (ECs). Immune full-activation pathways (e.g., NOD-like receptor signaling pathway and NF-kappa B signaling pathway) were highly enriched in the PyroptosisScoreH cluster. The key pyroptosis related genes GSDMD, CASP1, NLRC4, AIM2, and IL18 were upregulated in advanced carotid atherosclerotic plaques. We concluded that compared to advanced femoral atheromatous plaques, advanced carotid atheromatous plaques were of higher grade of pyroptosis. GSDMD, CASP1, NLRC4, AIM2, and IL18 were the key pyroptosis related genes, which might provide a new sight in the prevention of fatal strokes in advanced carotid atherosclerosis.
To explore the correlation between F10 gene mutation and its phenotype in a Chinese pedigree affected with FX deficiency.Prothrombin time(PT), activated partial thromboplastin time(APTT), fibrinogen, FII activity(FII:C), FVII activity(FVII:C), FIX activity (FIX:C), FX activity(FX:C) were determined with a one-stage clotting assay. The FX antigen(FX:Ag) was detected with an enzyme linked immunosorbent assay(ELISA). The 8 exons, introns and 5' and 3' untranslated regions(UTR) of the F10 gene of the proband and her family members were subjected to PCR amplification and Sanger sequencing. Suspected mutation was confirmed by reverse sequencing. Polymorphisms were excluded by direct sequencing of 100 healthy individuals.The PT and APTT of the proband have prolonged to 16.1 s and 49.0 s, respectively. Her FX:C and FX:Ag were reduced by 27% and 56%, and her mother's PT, APTT, FX:C and FX:Ag were 14.8 s, 37.4 s, 44%, 34%, respectively. Her grandmother's PT, APTT, FX:C and FX:Ag were 15.8 s, 42.2 s, 31%, 45%, respectively. The results of her father and other family members were all within the normal range. Genetic analysis has revealed a heterozygous G to A mutation in the proband at position 28076 in exon 8 of the F10 gene, which resulted in a p.Gly363Ser substitution. The same mutation was also found in her mother and grandmother. No mutation of the F10 gene was found in her father. Gly363Ser may result in changes in the secondary structure of the FX protein and reduction of its activity.The g.28076G to A(p.Gly363Ser) mutation of the F10 gene probably underlies the FX deficiency in this pedigree. The mutation was discovered for the first time in Chinese patients.
To investigate the phenotype and genotype defect characteristics of a Chinese patient with hereditary factor XI deficiency.The activated partial thromboplastin time (APTT), prothrombin time (PT), FXI activity (FXI:C) of the proband and his relatives were measured by a clotting method using automatic coagulation analyzer. FXI antigen (FXI:Ag) was assayed by enzyme-linked immunosorbent assay (ELISA). Fifteen exons of the F11 gene were amplified by PCR and sequenced. Pymol software was used to analyze the novel mutations.The APTT of the proband was significantly prolonged (70.3 s, reference 34.5 s) with decreased FXI activity (6%, reference 50%-150%) and FXI antigen (1.9%, reference 50%-150%). The FXI activity and FXI antigen of his son was 31% and 39%, respectively. Two heterozygous F11 mutations were identified in the proband, which included a G to T substitution at nucleotide 1296 in exon 11 resulting in substitution of glycine by valine at codon 400 (p.Gly400Val) and a A to T substitution at nucleotide 1691 in exon 14 resulting in substitution of arginine (AGA) by a termination codon (TGA) at codon 532 (p.Arg532Ter). Analysis using Pymol indicated that the number of hydrogen bonds has changed, which led to a transformation of the structure of the FXI protein. The son of the proband was found to be heterozygous for the c.1296G to T (p.Gly400Val) mutation. NM_13142 c.1691A to T (p.Arg532Ter) is a novel mutation based on HGMD professional 2016.4. Based on 2015 Guidelines of ACMG, it is PVS1 (very strong pathogenicity).The compound heterozygous mutations of F11 NM_13142 c.1296G to T (p.Gly400Val) and F11 NM_13142 c.1691A to T(p.Arg532Ter) probably underlies the FXI deficiency in the proband.
To carry out phenotypic and genotypic analysis for two Chinese pedigrees affected with coagulation factor XII (F XII) deficiency.Plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), thrombin time (TT), and blood coagulation factor VIII, IX, XI, XII activity (FVIII:C, FIX:C, FXI:C, FXII:C) were determined with one stage clotting assay on a STAGO coagulation analyzer. FXII antigen was determined with an enzyme linked immunosorbent assay (ELISA). The 14 exons and their flanking sequences of the F12 gene were subjected to PCR amplification and Sanger sequencing. The conservation and structure of mutant protein were analyzed with MegAlign software and PYMOL software.The APTT of the probands was significantly prolonged, while their FXII:C and FXII:Ag were significantly reduced. Genetic analysis of the proband has revealed three novel mutations in the F12 gene, including g.5972G>A splice site mutation in intron 5, g.8810_8814delGTCTA in exon 14, and g.6259G>A (p.Pro182Leu) in exon 7. In addition, a previously known mutation IVS13-1G>A has been found.Four mutations have been identified in the two Chinese pedigrees, among which three were novel. Above mutations probably played a role in the defect of FXII in the two pedigrees.
Background: In operable chronic thromboembolic pulmonary hypertension (CTEPH) patients, the utilization of bridging therapy with targeted medications prior to pulmonary endarterectomy (PEA) remains a topic of controversy, despite being common in cases of severe hemodynamic impairment. This study aims to assess the impact of riociguat as a bridging therapy on postoperative hemodynamics and outcomes. Methods: We conducted a retrospective study involving patients undergoing PEA from December 2016 to November 2023. Patients were categorized into two groups based on the use of riociguat before PEA. Pulmonary vascular resistance (PVR) following riociguat administration was assessed pre-PEA. Postoperative outcomes, including mortality, complications, and hemodynamics, were compared, employing propensity score matching analysis. Results: Among the patients, 41.8% (n=56) received riociguat as bridging therapy. In patients with PVR ≥800 dynes·sec·cm−5, riociguat resulted in a reduction in PVR {1,207 [974–1,698] vs. 1,125 [928–1,486] dynes·sec·cm−5, P<0.01}, while no significant difference was observed in patients with PVR <800 dynes·sec·cm−5 {641 [474–740] vs. 600 [480–768] dynes·sec·cm−5, P=0.46}. After propensity score matching, each group included 26 patients. The overall perioperative mortality rate was 2.6%. Postoperative PVR {326 [254–398] vs. 361 [290–445] dynes·sec·cm−5, P=0.35} was similar in the riociguat group compared to the control group. The incidence of residual pulmonary hypertension (PH) and other postoperative outcomes were also comparable. Conclusions: The use of riociguat as bridging therapy demonstrated hemodynamic improvement before PEA in patients with high preoperative PVR. However, no additional benefits in postoperative mortality or hemodynamics were observed.
Background: Identifying effective pharmacological interventions to prevent the progressive enlargement and rupture of aortic aneurysms (AAs) is critical. Previous studies have suggested links between metformin use and a decreased incidence of AAs. In this study, we employed Mendelian randomization (MR) to investigate causal effects of metformin's targets on AA risk and to explore the underlying mechanisms underlying these effects. Methods: To examine the relationship between metformin use and AA risk, we implemented both two-sample MR and multivariable MR analyses. Utilizing genetic instrumental variables, we retrieved cis-expression quantitative trait loci (cis-eQTL) data for potential targets of metformin from the Expression Quantitative Trait Loci Genetics Consortium (eQTLGen) Consortium and Genotype-Tissue Expression (GTEx) project. Colocalization analysis was employed to ascertain the probability of shared causal genetic variants between single nucleotide polymorphisms (SNPs) associated with eQTLs and AA. Results: Our findings reveal that metformin use reduces AA risk, exhibiting a protective effect with an odds ratio (OR) of 4.88 × 10-3 (95% confidence interval [CI]: 7.30 × 10-5–0.33, p = 0.01). Furthermore, the protective effect of type 2 diabetes on AA risk appears to be driven by metformin use (ORMVMR = 1.34 × 10-4, 95% CI: 3.97 × 10-8–0.45, p = 0.03). Significant Mendelian randomization (MR) results were observed for the expression of two metformin-related genes in the bloodstream: NADH:ubiquinone oxidoreductase subunit A6 (NDUFA6) and cytochrome b5 type B (CYB5B), across two independent datasets (ORCYB5B = 1.35, 95% CI: 1.20–1.51, p = 2.41 × 10-7; ORNDUFA6 = 1.12; 95% CI: 1.07–1.17, p = 1.69 × 10-6). The MR analysis of tissue-specific expression also demonstrated a positive correlation between increased NDUFA6 expression and heightened AA risk. Lastly, NDUFA6 exhibited evidence of colocalization with AA. Conclusions: Our study suggests that metformin may play a significant role in lowering the risk of AA. This protective effect could potentially be linked to the mitigation of mitochondrial and immune dysfunction. Overall, NDUFA6 has emerged as a potential mechanism through which metformin intervention may confer AA protection.
Abstract Background Anxiety, an important factor that affects the therapeutic effect and preservation rate of methadone maintenance treatment, has a high prevalence among MMT patients. This study aims to investigate the effects of treatment status and life quality on anxiety in MMT patients. Methods One hundred and Seventy-seven methadone maintenance treatment users in Guangzhou, China were evaluated. The socio-demographic, duration and MMT-related characteristics were documented. Anxiety level and quality of life were evaluated by Beck Anxiety inventory (BAI) and the Quality of Life-Drug Addiction (QOL-DA) respectively. The correlation between different factors and BAI score was also analyzed. Results The BAI total score and the QOL-DA score were 7.1±8.2, 163.5±21.4 respectively. 30.5% of the subjects showed mild to severe anxiety. Treatment interruption and QOL-DA score had strong correlations with the score of BAI, with correlation coefficients of 0.17 and − 0.08 respectively. Conclusions Anxiety symptoms were commonly presented in MMT patients. Treatment interruption and quality of life are two major factors affecting anxiety of MMT patients.
High-density genetic maps (HDGMs) are very useful for genomic studies and quantitative trait loci (QTL) mapping. However, the low frequency of DNA polymorphisms in peanut has limited the quantity of available markers and hindered the construction of a HDGM. This study generated a peanut genetic map with the highest number of high-quality SNPs based on SLAF-seq technology and a newly constructed RIL population ('ZH16' × 'sd-H1'). The constructed HDGM included 3,630 SNP markers belonging to 2,636 bins on 20 linkage groups (LGs), and it covers 2,098.14 cM in length, with an average marker distance of 0.58 cM. This HDGM was applied for the following collinear comparison, scaffold anchoring and analysis of genomic characterization including recombination rates and segregation distortion in peanut. For QTL mapping of investigated 14 yield-related traits, a total of 62 QTLs were detected on 12 chromosomes across 3 environments, and the co-localization of QTLs was observed for these traits which were significantly correlated on phenotype. Two stable co-located QTLs for seed- and pod-related traits were significantly identified in the chromosomal end of B06 and B07, respectively. The construction of HDGM and QTL analysis for yield-related traits in this study provide useful information for fine mapping and functional analysis of genes as well as molecular marker-assisted breeding.
We aimed to determine whether the use of pulmonary nodule diameter and CTR predicts lymph nodes (LNs) metastasis for early-stage (cT1N0M0) lung adenocarcinoma.We retrospectively analyzed 433 consecutive patients who underwent therapeutic surgical resection in our hospital. Information about age, sex, history of malignancy, smoking index, high-resolution computed tomography (HRCT) imaging information, pathologic findings, and status of LNs metastasis were collected.A total of 433 patients were included 277 women and 156 men, with a median age of 58.09±9.41 years. On univariate and multivariate analysis, visceral pleural invasion (VPI) (P=0.005), the diameter of nodule measured by postoperative pathology (DP) (P=0.011), the largest axial diameter of the lesion on the mediastinal window (DM) (P<0.001), the ratio of the maximum diameter of consolidation relative to the maximum tumor diameter from the lung window (CTR) (P=0.01), and total dissected LNs number (P=0.005) categories were independent facto for LNs metastasis. The receiver operating characteristic (ROC) curve showed that DM ≥11.81 cm, or CTR ≥79.50%, or VPI indicated LNs metastasis. LNs metastasis patients could be better predicted by a total dissected LNs number with a cutoff point of 13.5 for lung cancer.VPI, DP, DM, CTR, and total dissected LNs number categories were independent factors for LNs metastasis. If DM ≥11.81 cm, or CTR ≥79.50%, or VPI systemic lymphadenectomy was recommended. We suggested 14 LNs as the cut point for the evaluation LNs examination.
Abstract Background The aim of the study was to explore the mechanism of mesenchymal human umbilical cord msenchymal stem cells derived exosomes (MSC-EXO) against experimental pulmonary artery hypertension (PAH) pulmonary vascular remodeling . Methods and results After PAH model was successful established, the animals received tail vein injections of MSC-EXO. Post-operation, the pulmonary artery pressure was measured, and the lung tissues were stained to evaluate the pulmonary vascular remodeling. Our results showed that MSC-EXO could significantly inhibit the pulmonary arterial hypertension, attenuate pulmonary vascular remodeling and lung fibrosis in vivo . Furthermore, the hypoxia-induced pulmonary artery endothelial cell (PAEC) model was used in vitro . Our results showed the expression of CD31, V-Ecadherin, Wnt5a, Wnt11, BMPR2 and Smad1/5/8 were significantly higher, but the expression of alpha smooth muscle actin (a-SMA), β-catenin, cyclin D1 and Smad2/3 were significantly lower in in MSC-EXO administration group then that in MCT or hypoxia group. Moreover, the present study found that BMP signaling suppressed obviously when the cells were transfection with Wnt5a siRNA. Conclusion In conclusion, these results suggested that MSC-EXO could protect PAH vascular remodeling through regulation of Wnt/BMP signaling pathway.
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