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Background: There is sufficient evidence that women with atrial fibrillation (AF) have a greater symptom burden than men with AF and are more likely to experience recurrence after catheter ablation. However, the mechanisms underlying these sex differences are unclear. Methods: We prospectively enrolled 125 consecutive patients, including 40 non-AF patients and 85 AF patients, who underwent high-density voltage mapping during sinus rhythm and AF patients who underwent first ablation. Results: Overall, 37 (44%) female patients with AF and 24 (60%) female non-AF patients with a mean age of 61.7 ± 11.6 years and 53.6 ± 16.7 years, respectively, were enrolled in this study. The results showed that the atrial voltage of female AF patients was significantly lower than that of male AF patients (1.11 ± 0.58 mV vs. 1.53 ± 0.65 mV; P = 0.003), while there were no significant sex differences in non-AF patients (3.02 ± 0.86 mV vs. 3.21 ± 0.84 mV; P = 0.498). Multiple linear regression analysis revealed that female sex (− 0.29, 95% confidence interval [CI] − 0.64 to − 0.13, P = 0.004) and AF type (− 0.32, 95% CI − 0.69 to − 0.13, P = 0.004) were the only factors independently associated with voltage. Compared with men, women in the paroxysmal AF group had a 3.5-fold greater incidence of recurrence (adjusted hazard ratio 4.49; 95% CI 1.101–18.332, P = 0.036). Both globally and regionally, the results showed that sex-related differences in voltage values occurred prominently in paroxysmal AF patients but not in nonparoxysmal AF patients. Conclusion: Sex-related differences in atrial substrates and arrhythmia-free survival were found in paroxysmal AF patients, suggesting the existence of sex-related pathophysiological factors. [ABSTRACT FROM AUTHOR]

Background: Broussonetia papyrifera is an economically significant tree with high utilization value, yet its cultivation is often constrained by soil contamination with heavy metals (HMs). Effective scientific cultivation management, which enhances the yield and quality of B. papyrifera, necessitates an understanding of its regulatory mechanisms in response to HM stress. Results: Twelve Metallothionein (MT) genes were identified in B. papyrifera. Their open reading frames ranged from 186 to 372 bp, encoding proteins of 61 to 123 amino acids with molecular weights between 15,473.77 and 29,546.96 Da, and theoretical isoelectric points from 5.24 to 5.32. Phylogenetic analysis classified these BpMTs into three subclasses: MT1, MT2, and MT3, with MT2 containing seven members and MT3 only one. The expression of most BpMT genes was inducible by Cd, Mn, Cu, Zn, and abscisic acid (ABA) treatments, particularly BpMT2e, BpMT2d, BpMT2c, and BpMT1c, which showed significant responses and warrant further study. Yeast cells expressing these BpMT genes exhibited enhanced tolerance to Cd, Mn, Cu, and Zn stresses compared to control cells. Yeasts harboring BpMT1c, BpMT2e, and BpMT2d demonstrated higher accumulation of Cd, Cu, Mn, and Zn, suggesting a chelation and binding capacity of BpMTs towards HMs. Site-directed mutagenesis of cysteine (Cys) residues indicated that mutations in the C domain of type 1 BpMT led to increased sensitivity to HMs and reduced HM accumulation in yeast cells; While in type 2 BpMTs, the contribution of N and C domain to HMs' chelation possibly corelated to the quantity of Cys residues. Conclusion: The BpMT genes are crucial in responding to diverse HM stresses and are involved in ABA signaling. The Cys-rich domains of BpMTs are pivotal for HM tolerance and chelation. This study offers new insights into the structure-function relationships and metal-binding capabilities of type-1 and − 2 plant MTs, enhancing our understanding of their roles in plant adaptation to HM stresses. [ABSTRACT FROM AUTHOR]

Background: Shikonin (SK), a naphthoquinone with anti-tumor effects, has been found to decrease production of tumor-associated exosomes (exo). This study aims to verify the treatment effect of SK on ovarian cancer (OC) cells, especially on the production of exo and their subsequent effect on macrophage polarization. Methods: OC cells SKOV3 and A2780 were treated with SK. The exo were isolated from OC cells with or without SK treatment, termed OC exo and SK OC exo, respectively. These exo were used to treat PMA-induced THP-1 cells (M0 macrophages). M2 polarization of macrophages was determined by measuring the M2 specific cell surface markers CD163 and CD206 as well as the secretion of M2 cytokine IL-10. The functions of galectin 3 (LGALS3/GAL3) and β-catenin in macrophage polarization were determined by gain- or loss-of-function assays. CB-17 SCID mice were subcutaneously injected with SKOV3 cells to generate xenograft tumors, followed by OC exo or SK OC exo treatment for in vivo experiments. Results: SK suppressed viability, migration and invasion, and apoptosis resistance of OC cells in vitro. Compared to OC exo, SK OC exo reduced the M2 polarization of macrophages. Regarding the mechanism, SK reduced exo production in cancer cells, and it decreased the protein level of GAL3 in exo and recipient macrophages, leading to decreased β-catenin activation. M2 polarization of macrophages was restored by LGALS3 overexpression but decreased again by the β-catenin inhibitor FH535. Compared to OC exo, the SK OC exo treatment reduced the xenograft tumor growth in mice, and it decreased the M2 macrophage infiltration within tumor tissues. Conclusion: This study suggests that SK reduces M2 macrophage population in OC by repressing exo production and blocking exosomal GAL3-mediated β-catenin activation. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is a common systemic inflammatory disease resulting from the activation of trypsinogen by various incentives in ICU. The annual incidence rate is approximately 30 out of 100,000. Some patients may progress to severe acute pancreatitis, with a mortality rate of up to 40%. Therefore, the goal of this article is to explore the key genes for effective diagnosis and treatment of AP. The analysis data for this study were merged from two GEO datasets. 1357 DEGs were used for functional enrichment and cMAP analysis, aiming to reveal the pathogenic genes and potential mechanisms of AP, as well as potential drugs for treating AP. Importantly, the study used LASSO and SVM-RFE machine learning to screen the most likely AP occurrence biomarker for Prdx4 among numerous candidate genes. A receiver operating characteristic of Prdx4 was used to estimate the incidence of AP. The ssGSEA algorithm was employed to investigate immune cell infiltration in AP. The biomarker Prdx4 gene exhibited significant associations with a majority of immune cells and was identified as being expressed in NKT cells, macrophages, granulocytes, and B cells based on single-cell transcriptome data. Finally, we found an increase in Prdx4 expression in the pancreatic tissue of AP mice through immunohistochemistry. After treatment with recombinant Prdx4, the pathological damage to the pancreatic tissue of AP mice was relieved. In conclusion, our study identified Prdx4 as a potential AP hub gene, providing a new target for treatment. [ABSTRACT FROM AUTHOR]

Sepsis remains a critical concern in intensive care units due to its high mortality rate. Early identification and intervention are paramount to improving patient outcomes. In this study, we have proposed predictive models for early sepsis prediction based on time-series data, utilizing both CNN-Transformer and LSTM-Transformer architectures. By collecting time-series data from patients at 4, 8, and 12 h prior to sepsis diagnosis and subjecting it to various network models for analysis and comparison. In contrast to traditional recurrent neural networks, our model exhibited a substantial improvement of approximately 20%. On average, our model demonstrated an accuracy of 0.964 (± 0.018), a precision of 0.956 (± 0.012), a recall of 0.967 (± 0.012), and an F1 score of 0.959 (± 0.014). Furthermore, by adjusting the time window, it was observed that the Transformer-based model demonstrated exceptional predictive capabilities, particularly within the earlier time window (i.e., 12 h before onset), thus holding significant promise for early clinical diagnosis and intervention. Besides, we employed the SHAP algorithm to visualize the weight distribution of different features, enhancing the interpretability of our model and facilitating early clinical diagnosis and intervention. [ABSTRACT FROM AUTHOR]

Background: To investigate the prevalence and evolution of Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) at commercial fattening pig farms, a total of 1397 clinical samples were collected from a single fattening cycle at seven pig farms in five provinces of China from 2020 to 2021. Results: The RT‒PCR results revealed that PRRSV was present on all seven farms, and the percentage of PRRSV-positive individuals was 17.54–53.33%. A total of 344 partial NSP2 gene sequences and 334 complete ORF5 gene sequences were obtained from the positive samples. The statistical results showed that PRRSV-2 was present on all seven commercial fattening farms, and PRRSV-1 was present on only one commercial fattening farm. A total of six PRRSV-2 subtypes were detected, and five of the seven farms had two or more PRRSV-2 subtypes. L1.8 (L1C) PRRSV was the dominant epidemic strain on five of the seven pig farms. Sequence analysis of L1.8 (L1C) PRRSV from different commercial fattening pig farms revealed that its consistency across farms varied substantially. The amino acid alignment results demonstrated that there were 131 aa discontinuous deletions in NSP2 between different L1.8 (L1C) PRRSV strains and that the GP5 mutation in L1.8 (L1C) PRRSV was mainly concentrated in the peptide signal region and T-cell epitopes. Selection pressure analysis of GP5 revealed that the use of the PRRSV MLV vaccine had no significant episodic diversifying effect on L1.8 (L1C) PRRSV. Conclusion: PRRSV infection is common at commercial fattening pig farms in China, and the percentage of positive individuals is high. There are multiple PRRSV subtypes of infection at commercial fattening pig farms in China. L1.8 (L1C) is the main circulating PRRSV strain on commercial fattening pig farms. L1.8 (L1C) PRRSV detected at different commercial fattening pig farms exhibited substantial differences in consistency but similar molecular characteristics. The pressure on the GP5 of L1.8 (L1C) PRRSV may not be directly related to the use of the vaccines. [ABSTRACT FROM AUTHOR]

Purpose: Recent technological advancements in data acquisition tools allowed neuroscientists to acquire different modality data to diagnosis Alzheimer's disease (AD). However, how to fuse these enormous amount different modality data to improve recognizing rate and find significance brain regions is still challenging. Methods: The algorithm used multimodal medical images [structural magnetic resonance imaging (sMRI) and positron emission tomography (PET)] as experimental data. Deep feature representations of sMRI and PET images are extracted by 3D convolution neural network (3DCNN). An improved Transformer is then used to progressively learn global correlation information among features. Finally, the information from different modalities is fused for identification. A model-based visualization method is used to explain the decisions of the model and identify brain regions related to AD. Results: The model attained a noteworthy classification accuracy of 98.1% for Alzheimer's disease (AD) using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Upon examining the visualization results, distinct brain regions associated with AD diagnosis were observed across different image modalities. Notably, the left parahippocampal region emerged consistently as a prominent and significant brain area. Conclusions: A large number of comparative experiments have been carried out for the model, and the experimental results verify the reliability of the model. In addition, the model adopts a visualization analysis method based on the characteristics of the model, which improves the interpretability of the model. Some disease-related brain regions were found in the visualization results, which provides reliable information for AD clinical research. [ABSTRACT FROM AUTHOR]

Background: High mobility group box-1 (HMGB1) is an endogenous danger signal that mediates activation of the innate immune response including NLR pyrin domain containing 3 (NLRP3) inflammasome activation and proinflammatory cytokine release. Although HMGB1 and NLRP3 have been implicated in the pathophysiology of seizures, the correlation between HMGB1 and NLRP3 expression has not been determined in children with febrile seizures (FS). To explore the relationship between extra-cellular HMGB1 and NLRP3 in children with FS, we analyzed serum HMGB1, NLRP3, caspase-1, and proinflammatory cytokines in patients with FS. Methods: Thirty children with FS and thirty age-matched febrile controls were included in this study. Blood was obtained from the children with FS within 1 h of the time of the seizure; subsequently, the serum contents of HMGB1, NLRP3, caspase-1, interleukin (IL)-1β, interleukin (IL)-6, and tumour necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. The Mann‒Whitney U test was used to compare serum cytokine levels between FS patients and controls. Spearman's rank correlation coefficient was calculated to detect significant correlations between cytokine levels. Results: Serum levels of HMGB1, NLRP3, caspase-1, IL-1β, IL-6, and TNF-α were significantly higher in FS patients than in febrile controls (p < 0.05). Serum levels of HMGB1 were significantly correlated with levels of NLRP3 and caspase-1 (both, p < 0.05). Serum levels of caspase-1 were significantly correlated with levels of IL-1β (p < 0.05). Serum levels of IL-1β were significantly correlated with levels of IL-6 and TNF-α (p < 0.05). Conclusions: HMGB1 is up-regulated in the peripheral serum of FS patients, which may be responsible, at least in part, for the increased expression of NLRP3 and Caspase-1. Increased expression of caspase-1 was significantly associated with elevated serum levels of IL-1β. Given that activated Caspase-1 directly regulates the expression of mature IL-1β and positively correlates with activation of the NLRP3 inflammasome, our data suggest that increased levels of peripheral HMGB1 possibly mediate IL-1β secretion through the activation of the NLRP3 inflammasome in children with FS. Thus, both HMGB1 and NLRP3 might be potential targets for preventing or limiting FS. [ABSTRACT FROM AUTHOR]

Background: To clarify the relationship between the PaO2/FiO2 and 28-day mortality in patients with sepsis. Methods: This was a retrospective cohort study regarding MIMIC-IV database. Nineteen thousand two hundred thirty-three patients with sepsis were included in the final analysis. PaO2/FiO2 was exposure variable, 28-day mortality was outcome variable. PaO2/FiO2 was log-transformed as LnPaO2/FiO2. Binary logistic regression was used to explore the independent effects of LnPaO2/FiO2 on 28-day mortality using non-adjusted and multivariate-adjusted models. A generalized additive model (GAM) and smoothed curve fitting was used to investigate the non-linear relationship between LnPaO2/FiO2 and 28-day mortality. A two-piecewise linear model was used to calculate the OR and 95% CI on either side of the inflection point. Results: The relationship between LnPaO2/FiO2 and risk of 28-day death in sepsis patients was U-shape. The inflection point of LnPaO2/FiO2 was 5.30 (95%CI: 5.21—5.39), which indicated the inflection point of PaO2/FiO2 was 200.33 mmHg (95%CI: 183.09 mmHg—219.20 mmHg). On the left of inflection point, LnPaO2/FiO2 was negatively correlated with 28-day mortality (OR: 0.37, 95%CI: 0.32—0.43, p < 0.0001). On the right of inflection point, LnPaO2/FiO2 was positively correlated with 28-day mortality in patients with sepsis (OR: 1.53, 95%CI: 1.31—1.80, p < 0.0001). Conclusions: In patients with sepsis, either a high or low PaO2/FiO2 was associated with an increased risk of 28-day mortality. In the range of 183.09 mmHg to 219.20 mmHg, PaO2/FiO2 was associated with a lower risk of 28-day death in patients with sepsis. [ABSTRACT FROM AUTHOR]

Background& Aims: Little is known on the gender-specific effect and potential role of non-linear associations between metabolic syndrome (MetS) components and liver cancer risk. We evaluated these associations based on the UK Biobank cohort.Methods: We included 474,929 individuals without previous cancer based on the UK Biobank cohort. Gender-specific hazard ratios (HRs) and 95% confidence interval (CIs) were calculated by Cox proportional hazards regression, adjusting for potential confounders. Non-linear associations for individual MetS components were assessed by the restricted cubic spline method.Results: Over a median follow-up of 6.6 years, we observed 276 cases of liver cancer (175 men, 101 women). MetS [HR 1.48, 95% CI 1.27-1.72] and central obesity [HR 1.65, 95% CI 1.18-2.31] were associated with higher risk of liver cancer in men but not in women. Participants with hyperglycaemia has higher risk of liver cancer. High waist circumference and blood glucose were dose-dependently associated with increased liver cancer risk in both genders. For high density lipoprotein (HDL) cholesterol (both genders) and blood pressure (women), U-shaped associations were observed. Low HDL cholesterol (< 1.35 mmol/L) in men and high HDL cholesterol in women (> 1.52 mmol/L) were associated with increased liver cancer risk.Conclusions: MetS components showed gender-specific linear or U- shaped associations with the risk of liver cancer. Our study might provide evidence for individualized management of MetS for preventing liver cancer. [ABSTRACT FROM AUTHOR]

Background: The anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have been administered to patients with ALK-positive non-small cell lung cancer for a long period of time and show a promising response. However, the differences in the toxicity profiles among these drugs are still unclear.Methods: We performed a comprehensive search of the MEDLINE, EMBASE, WEB OF SCIENCE and COCHRANE databases from the drugs' inception to May 2016 to identify clinical trials. Severe adverse events (AEs) (grade ≥ 3) based on the ALK-TKI type were analysed.Results: Seventeen trials published between 2011 and 2016, including a total of 1826 patients, were eligible for analysis. Patients in 10 trials (n = 1000) received crizotinib, patients in 5 trials (n = 601) received ceritinib and patients in 2 trials (n = 225) received alectinib. The overall frequencies of treatment-related death and AEs due to treatment withdrawal were 0.9% (12/1365) and 5.5% (85/1543), respectively. Moreover, the frequency of severe AEs in patients treated with ceritinib was significantly higher than patients treated with crizotinib or alectinib, especially for hepatotoxicity, fatigue and some of gastrointestinal symptoms. Additionally, significant difference in the elevated lipase and amylase levels (grade ≥ 3) were detected between ceritinib and crizotinib/alectinib, whereas neutropenia was less frequent.Conclusions: ALK-TKIs were safe for ALK-positive patients. Moreover, statistically significant differences in some severe AEs among ceritinib, crizotinib and alectinib were detected in present study. [ABSTRACT FROM AUTHOR]

Background: The global dementia prevalence is surging, necessitating research into contributing factors. We aimed to investigate the association between metabolic syndrome (MetS), its components, serum uric acid (SUA) levels, and dementia risk., Methods: Our prospective study comprised 466,788 participants without pre-existing MetS from the UK Biobank. We confirmed dementia diagnoses based on the ICD-10 criteria (F00-03). To evaluate the dementia risk concerning MetS, its components, and SUA levels, we applied Cox proportional hazards models, while adjusting for demographic factors., Results: Over a median follow-up of 12.7 years, we identified 6845 dementia cases. Individuals with MetS had a 25% higher risk of all-cause dementia (hazard ratio [HR] = 1.25, 95% confidence interval [CI] = 1.19-1.31). The risk increased with the number of MetS components including central obesity, dyslipidemia for high-density lipoprotein (HDL) cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides. Particularly for those with all five components (HR = 1.76, 95% CI = 1.51-2.04). Dyslipidemia for HDL cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides were independently associated with elevated dementia risk (p < 0.01). MetS was further linked to an increased risk of all-cause dementia (11%) and vascular dementia (VD, 50%) among individuals with SUA levels exceeding 400 μmol/L (all-cause dementia: HR = 1.11, 95% CI = 1.02-1.21; VD: HR = 1.50, 95% CI = 1.28-1.77)., Conclusions: Our study provides robust evidence supporting the association between MetS, its components, and dementia risk. These findings emphasize the importance of considering MetS and SUA levels in assessing dementia risk, offering valuable insights for prevention and management strategies., (© 2024. The Author(s).)