Graph contrastive learning as a versatile foundation for advanced scRNA-seq data analysis.

Single-cell RNA sequencing (scRNA-seq) offers unprecedented insights into transcriptome-wide gene expression at the single-cell level. Cell clustering has been long established in the analysis of scRNA-seq data to identify the groups of cells with similar expression profiles. However, cell clustering is technically challenging, as raw scRNA-seq data have various analytical issues, including high dimensionality and dropout values. Existing research has developed deep learning models, such as graph machine learning models and contrastive learning-based models, for cell clustering using scRNA-seq data and has summarized the unsupervised learning of cell clustering into a human-interpretable format. While advances in cell clustering have been profound, we are no closer to finding a simple yet effective framework for learning high-quality representations necessary for robust clustering. In this study, we propose scSimGCL, a novel framework based on the graph contrastive learning paradigm for self-supervised pretraining of graph neural networks. This framework facilitates the generation of high-quality representations crucial for cell clustering. Our scSimGCL incorporates cell-cell graph structure and contrastive learning to enhance the performance of cell clustering. Extensive experimental results on simulated and real scRNA-seq datasets suggest the superiority of the proposed scSimGCL. Moreover, clustering assignment analysis confirms the general applicability of scSimGCL, including state-of-the-art clustering algorithms. Further, ablation study and hyperparameter analysis suggest the efficacy of our network architecture with the robustness of decisions in the self-supervised learning setting. The proposed scSimGCL can serve as a robust framework for practitioners developing tools for cell clustering. The source code of scSimGCL is publicly available at https://github.com/zhangzh1328/scSimGCL.

A generalizable framework to comprehensively predict epigenome, chromatin organization, and transcriptome.

Many deep learning approaches have been proposed to predict epigenetic profiles, chromatin organization, and transcription activity. While these approaches achieve satisfactory performance in predicting one modality from another, the learned representations are not generalizable across predictive tasks or across cell types. In this paper, we propose a deep learning approach named EPCOT which employs a pre-training and fine-tuning framework, and is able to accurately and comprehensively predict multiple modalities including epigenome, chromatin organization, transcriptome, and enhancer activity for new cell types, by only requiring cell-type specific chromatin accessibility profiles. Many of these predicted modalities, such as Micro-C and ChIA-PET, are quite expensive to get in practice, and the in silico prediction from EPCOT should be quite helpful. Furthermore, this pre-training and fine-tuning framework allows EPCOT to identify generic representations generalizable across different predictive tasks. Interpreting EPCOT models also provides biological insights including mapping between different genomic modalities, identifying TF sequence binding patterns, and analyzing cell-type specific TF impacts on enhancer activity.

ABLE-SCORE, a simplified risk score for major adverse cardiovascular outcomes in left ventricular hypertrabeculation: a multicenter longitudinal cohort study.

BACKGROUND: Left ventricular hypertrabeculation (LVHT) is a heterogeneous entity with life-threatening complications and variable prognosis. However, there are limited prediction models available to identify individuals at high risk of adverse outcomes, and the current risk score in LVHT is comparatively complex for clinical practice. This study aimed to develop and validate a simplified risk score to predict major adverse cardiovascular events (MACE) in LVHT. METHODS: This multicenter longitudinal cohort study consecutively enrolled morphologically diagnosed LVHT patients between January 2009 and December 2020 at Fuwai Hospital (derivation cohort, n = 300; internal validation cohort, n = 129), and between January 2014 and December 2022 at two national-level medical centers (external validation cohort, n = 95). The derivation/internal validation cohorts and the external validation cohort were followed annually until December 2022 and December 2023, respectively. MACE was defined as a composite of all-cause mortality, heart transplantation/left ventricular assist device implantation, cardiac resynchronization therapy, malignant ventricular arrhythmia, and thromboembolism. A simplified risk score, the ABLE-SCORE, was developed based on independent risk factors in the multivariable Cox regression predictive model for MACE, and underwent both internal and external validations to confirm its discrimination, calibration, and clinical applicability. RESULTS: A total of 524 LVHT patients (43.5 ± 16.6 years, 65.8% male) were included in the study. The ABLE-SCORE was established using four easily accessible clinical variables: age at diagnosis, N-terminal pro-brain natriuretic peptide levels, left atrium enlargement, and left ventricular ejection fraction ≤ 40% measured by echocardiography. The risk score showed excellent performance in discrimination, with Harrell's C-index of 0.821 [95% confidence interval (CI), 0.772-0.869], 0.786 (95%CI, 0.703-0.869), and 0.750 (95%CI, 0.644-0.856) in the derivation, internal validation, and external validation cohort, respectively. Calibration plots of the three datasets suggested accurate agreement between the predicted and observed 5-year risk of MACE in LVHT. According to decision curve analysis, the ABLE-SCORE displayed greater net benefits than the existing risk score for LVHT, indicating its strength in clinical applicability. CONCLUSIONS: A simplified and efficient risk score for MACE was developed and validated using a large LVHT cohort, making it a reliable and convenient tool for the risk stratification and clinical management of patients with LVHT.

Associations of 50 modifiable risk factors with atrial fibrillation using Mendelian randomization analysis.

BACKGROUND: Substantial focus has been placed on atrial fibrillation (AF) treatment and associated stroke prevention rather than preventing AF itself. We employed Mendelian randomization (MR) approach to examine the causal relationships between 50 modifiable risk factors (RFs) and AF. METHODS: Instrumental variables for genetically predicted exposures were derived from corresponding genome-wide association studies (GWASs). Summary-level statistical data for AF were obtained from a GWAS meta-analysis (discovery dataset, N = 1,030,836) and FinnGen (validation dataset, N = 208,594). Univariable and multivariable MR analyses were performed, primarily using inverse variance weighted method with a series of robust sensitivity analyses. RESULTS: Genetic predisposition to insomnia, daytime naps, apnea, smoking initiation, moderate to vigorous physical activity and obesity traits, including body mass index, waist-hip ratio, central and peripheral fat/fat-free mass, exhibited significant associations with an increased risk of AF. Coffee consumption and ApoB had suggestive increased risks. Hypertension (odds ratio (OR) 95% confidence interval (CI): 5.26 (4.42, 6.24)), heart failure (HF) (OR 95% CI, 4.77 (2.43, 9.37)) and coronary artery disease (CAD) (OR 95% CI: 1.20 (1.16, 1.24)) were strongly associated with AF, while college degree, higher education attachment and HDL levels were associated with a decreased AF risk. Reverse MR found a bidirectional relationship between genetically predicted AF and CAD, HF and ischemic stroke. Multivariable analysis further indicated that obesity-related traits, systolic blood pressure and lower HDL levels independently contributed to the development of AF. CONCLUSIONS: This study identified several lifestyles and cardiometabolic factors that might be causally related to AF, underscoring the importance of a holistic approach to AF management and prevention.

Association between Hematocrit and Acute Kidney Injury in Patients with Acute Myocardial Infarction.

Backgrounds: Hematocrit is found an independent risk factor for acute kidney injury (AKI) in certain patients, but this effect in patients with acute myocardial infarction (AMI) is unclear. We aim to identify the relationship between hematocrit and AKI in patients with AMI. Methods: The patient data for the discovery and validation cohorts were extracted from the electronic Intensive Care Unit database and the Medical Information Mart for Intensive Care III database, respectively, to identify the relationship between hematocrit and AKI. With normal hematocrit as the reference, patients were divided into five groups based on the initial hematocrit value. The primary outcome was AKI during hospitalization. A multivariable logistic regression and a marginal effect analysis were used to evaluate the relationship between hematocrit and AKI. Results: In this study, a total of 9692 patients diagnosed with AMI were included, with 7712 patients in the discovery cohort and 1980 patients in the validation cohort. In the discovery cohort, hematocrit in 30-33%, 27-30% or < 27% were independent risk factors for AKI in the multivariate logistic analysis, with odds ratio (OR) of 1.774 (95% confidence interval [CI]: 1.203-2.617, p = 0.004), 1.834 (95% CI: 1.136-2.961, p = 0.013) and 2.577 (95% CI: 1.510-4.397, p < 0.001), respectively. Additionally, in the validation cohort, low hematocrit levels independently contributed to an increased risk of AKI among patients with AMI. During the analysis of marginal effects, a significant negative linear relationship between hematocrit levels and AKI was observed. Conclusions: Decreased hematocrit was an independent risk factor for AKI in patients with AMI. The relationship between hematocrit and AKI was negative linear.

Sex Differences in the Epidemiology, Risk Factors, and Prognosis of Malignant Ventricular Arrhythmias in Sepsis Patients.

Background: Women are frequently underrepresented in clinical trials and databases focusing on ventricular arrhythmias (VAs). However, understanding sex-based differences in risk factors and the prognosis of VAs is essential for tailoring personalized prevention and treatment strategies. This study aimed to investigate sex differences in the epidemiology, risk factors, and prognosis of VAs in patients with sepsis. Methods: We conducted a comprehensive analysis of 27,139 sepsis patients (mean [SD] age, 66.6 [16.2] years; 15,626 [57.6%] male), among whom 1136 (4.2%) developed VAs during their hospitalization. We evaluated VAs incidence and potential risk elements in both male and female patients, along with in-hospital mortality. Results: Men had a significantly higher likelihood of developing VAs compared to women (odds ratio [OR]: 1.70, 95% confidence interval [CI]: 1.50-1.94, p < 0.001). In the case of non-ischemic cardiomyopathy (NICM), the association with VAs was stronger in men than in women (relative risk ratio [RRR] = 1.63, 95% CI: 1.10-2.40, interaction p = 0.014). Furthermore, we observed significant sex-specific interactions in the relationship between incident VAs, congestive heart failure (CHF) (RRR = 1.35, 95% CI: 1.03-1.76, interaction p = 0.031), and pneumonia (RRR = 1.33, 95% CI: 1.02-1.74, interaction p = 0.036) when considering the adjusted model. The presence of VAs was associated with a nearly twofold increase in the risk of in-hospital mortality, a result that was observed in both sexes. Conclusions: In sepsis patients, the emergence of VAs independently escalates the risk of in-hospital mortality, with a notable correlation between male sex and an increased VAs risk. The impacts of CHF, NICM and pneumonia on incident VAs were significantly influenced by sex.

Association of stress hyperglycemia ratio and mortality in patients with sepsis: results from 13,199 patients.

BACKGROUND: The stress hyperglycemia ratio (SHR), adjusted for average glycemic status, is suggested for assessing actual blood glucose levels. Its link with adverse outcomes is known in certain populations, yet its impact on sepsis patients' prognosis is unclear. This study explores the association between SHR and mortality in sepsis. METHODS: We included 13,199 sepsis patients in this study and categorized SHR into distinct groups. Additionally, we utilized restricted cubic spline analysis to evaluate the correlation between SHR as a continuous variable and mortality. The primary outcome was 1-year all-cause mortality. Logistic regression and Cox proportional hazards models were employed to assess the associations between the SHR and both in-hospital mortality and 1-year mortality, respectively. RESULTS: Among the study participants, 4,690 (35.5%) patients died during the 1-year follow-up. After adjusting for confounding variables, we identified a U-shaped correlation between SHR and 1-year mortality. Using an SHR of 0.99 as the reference point, the hazard ratio for predicted 1-year mortality increased by 1.17 (95% CI 1.08 to 1.27) per standard deviation above 0.99, whereas each standard deviation increase predicted the hazard ratio of 0.52 (95% CI 0.39 to 0.69) below 0.99. Furthermore, we found that SHR could enhance the predictive performance of conventional severity scores. CONCLUSION: There exists a U shaped association between SHR and mortality in sepsis patients, where both low and high SHR values are associated with an increased risk of poor outcomes.

Catheter ablation of ventricular tachycardia in patients with arrhythmogenic right ventricular cardiomyopathy and biventricular involvement.

AIMS: Catheter ablation of ventricular tachycardia (VT) improves VT-free survival in 'classic' arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to investigate electrophysiological features and ablation outcomes in patients with ARVC and biventricular (BiV) involvement. METHODS AND RESULTS: We assembled a retrospective cohort of definite ARVC cases with sustained VTs. Patients were divided into the BiV (BiV involvement) group and the right ventricular (RV) (isolated RV involvement) group based on the left ventricular systolic function detected by cardiac magnetic resonance. All patients underwent electrophysiological mapping and VT ablation. Acute complete success was non-inducibility of any sustained VT, and the primary endpoint was VT recurrence. Ninety-eight patients (36 ± 14 years; 87% male) were enrolled, including 50 in the BiV group and 48 in the RV group. Biventricular involvement was associated with faster clinical VTs, a higher VT inducibility, and more extensive arrhythmogenic substrates (all P < 0.05). Left-sided VTs were observed in 20% of the BiV group cases and correlated with significantly reduced left ventricular systolic function. Catheter ablation achieved similar acute efficacy between these two groups, whereas the presence of left-sided VTs increased acute ablation failure (40 vs. 5%, P = 0.012). Over 51 ± 34 months [median, 48 (22-83) months] of follow-up, cumulative VT-free survival was 52% in the BiV group and 58% in the RV group (P = 0.353). A multivariate analysis showed that younger age, lower RV ejection fraction (RVEF), and non-acute complete ablation success were associated with VT recurrence in the BiV group. CONCLUSION: Biventricular involvement implied a worse arrhythmic phenotype and increased the risk of left-sided VTs, while catheter ablation maintained its efficacy for VT control in this population. Younger age, lower RVEF, and non-acute complete success predicted VT recurrence after ablation.

NOTCH Signaling in Osteosarcoma.

The combination of neoadjuvant chemotherapy and surgery has been promoted for the treatment of osteosarcoma; however, the local recurrence and lung metastasis rates remain high. Therefore, it is crucial to explore new therapeutic targets and strategies that are more effective. The NOTCH pathway is not only involved in normal embryonic development but also plays an important role in the development of cancers. The expression level and signaling functional status of the NOTCH pathway vary in different histological types of cancer as well as in the same type of cancer from different patients, reflecting the distinct roles of the Notch pathway in tumorigenesis. Studies have reported abnormal activation of the NOTCH signaling pathway in most clinical specimens of osteosarcoma, which is closely related to a poor prognosis. Similarly, studies have reported that NOTCH signaling affected the biological behavior of osteosarcoma through various molecular mechanisms. NOTCH-targeted therapy has shown potential for the treatment of osteosarcoma in clinical research. After the introduction of the composition and biological functions of the NOTCH signaling pathway, the review paper discussed the clinical significance of dysfunction in osteosarcoma. Then the paper reviewed the recent relevant research progress made both in the cell lines and in the animal models of osteosarcoma. Finally, the paper explored the potential of the clinical application of NOTCH-targeted therapy for the treatment of osteosarcoma.

2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis.

BACKGROUND: Osteosarcoma is a malignant bone tumor that usually affects adolescents aged 15-19 y. The DNA damage response (DDR) is significantly enhanced in osteosarcoma, impairing the effect of systemic chemotherapy. Targeting the DDR process was considered a feasible strategy benefitting osteosarcoma patients. However, the clinical application of DDR inhibitors is not impressive because of their side effects. Chinese herbal medicines with high anti-tumor effects and low toxicity in the human body have gradually gained attention. 2-Hydroxy-3-methylanthraquinone (HMA), a Chinese medicine monomer found in the extract of Oldenlandia diffusa, exerts significant inhibitory effects on various tumors. However, its anti-osteosarcoma effects and defined molecular mechanisms have not been reported. METHODS: After HMA treatment, the proliferation and metastasis capacity of osteosarcoma cells was detected by CCK-8, colony formation, transwell assays and Annexin V-fluorescein isothiocyanate/propidium iodide staining. RNA-sequence, plasmid infection, RNA interference, Western blotting and immunofluorescence assay were used to investigate the molecular mechanism and effects of HMA inhibiting osteosarcoma. Rescue assay and CHIP assay was used to further verified the relationship between MYC, CHK1 and RAD51. RESULTS: HMA regulate MYC to inhibit osteosarcoma proliferation and DNA damage repair through PI3K/AKT signaling pathway. The results of RNA-seq, IHC, Western boltting etc. showed relationship between MYC, CHK1 and RAD51. Rescue assay and CHIP assay further verified HMA can impair homologous recombination repair through the MYC-CHK1-RAD51 pathway. CONCLUSION: HMA significantly inhibits osteosarcoma proliferation and homologous recombination repair through the MYC-CHK1-RAD51 pathway, which is mediated by the PI3K-AKT signaling pathway. This study investigated the exact mechanism of the anti-osteosarcoma effect of HMA and provided a potential feasible strategy for the clinical treatment of human osteosarcoma.

Prognostic significance of the stress hyperglycemia ratio in critically ill patients.

BACKGROUND: The stress hyperglycemia ratio (SHR) has demonstrated a noteworthy association with unfavorable cardiovascular clinical outcomes and heightened in-hospital mortality. Nonetheless, this relationship in critically ill patients remains uncertain. This study aims to elucidate the correlation between SHR and patient prognosis within the critical care setting. METHODS: A total of 8978 patients admitted in intensive care unit (ICU) were included in this study. We categorized SHR into uniform groups and assessed its relationship with mortality using logistic or Cox regression analysis. Additionally, we employed the restricted cubic spline (RCS) analysis method to further evaluate the correlation between SHR as a continuous variable and mortality. The outcomes of interest in this study were in-hospital and 1-year all-cause mortality. RESULTS: In this investigation, a total of 825 (9.2%) patients experienced in-hospital mortality, while 3,130 (34.9%) individuals died within the 1-year follow-up period. After adjusting for confounding variables, we identified a U-shaped correlation between SHR and both in-hospital and 1-year mortality. Specifically, within the SHR range of 0.75-0.99, the incidence of adverse events was minimized. For each 0.25 increase in the SHR level within this range, the risk of in-hospital mortality rose by 1.34-fold (odds ratio [OR]: 1.34, 95% CI: 1.25-1.44), while a 0.25 decrease in SHR within 0.75-0.99 range increased risk by 1.38-fold (OR: 1.38, 95% CI: 1.10-1.75). CONCLUSION: There was a U-shaped association between SHR and short- and long-term mortality in critical ill patients, and the inflection point of SHR for poor prognosis was identified at an SHR value of 0.96.

Prognostic value of high-sensitivity C-reactive protein in patients undergoing percutaneous coronary intervention with different glycemic metabolism status.

BACKGROUND: High-sensitivity C-reaction protein (hsCRP), a biomarker of residual inflammatory risk, has been demonstrated with poor cardiovascular outcomes. We aimed to investigate the prognostic value of hsCRP in patients undergoing percutaneous coronary intervention (PCI) with or without diabetes mellitus (DM). METHODS: In this large-scale, prospective cohort study, we enrolled 8050 consecutive patients who underwent PCI for coronary artery stenosis. All subjects were stratified as high hsCRP (> 3 mg/L) and low hsCRP (≤ 3 mg/L) and were divided into four groups (hsCRP-L/non-DM, hsCRP-H/non-DM, hsCRP-L/DM, hsCRP-H/DM). The primary endpoint of the study was major adverse cardiovascular events (MACEs), including all-cause mortality, myocardial infarction, stroke, and unplanned vessel revascularization, evaluated at a 3 year follow-up. RESULTS: After 35.7 months (interquartile range: 33.2 to 36.0 months) of median follow-up time, 674 patients suffered from MACEs. We found elevated hsCRP was highly associated with an increased risk of MACEs in both diabetic (hazard ratio [HR] = 1.68, 95% confidence interval CI 1.29-2.19, P < 0.001) and non-diabetic patients (HR = 1.31, 95% CI: 1.05-1.62, P = 0.007) after adjustment for other confounding factors. Kaplan-Meier survival analysis showed the highest incidence of MACEs in hsCRP-H/DM (P < 0.001). In addition, the results of the restricted cubic spline analysis suggested a positive linear relationship between hsCRP and MACEs. CONCLUSION: Elevated hsCRP is an independent risk factors of MACEs in patients undergoing PCI irrespective of glycemic metabolism status.

Biomimetic and Multifunctional Hemostatic Hydrogel with Rapid Thermoresponsive Gelation and Robust Wet Adhesion for Emergency Hemostasis: A Rational Design Based on Photo-Cross-Linking Coordinated Hydrophilic-Hydrophobic Balance Strategies.

Uncontrolled bleeding in emergency situations is a great threat to both military and civilian lives, and an ideal hemostat for effectively controlling prehospital hemorrhage is urgently needed but still lacking. Although hemostatic hydrogels are promising for emergency hemostasis, they are currently challenged by either the mutual exclusion between a short gelation time and strong adhesive network or the insufficient functionality of ingredients and complicated operations for in situ curing. Herein, an extracellular matrix biopolymer-based and multifunctional hemostatic hydrogel that simultaneously integrates rapid thermoresponsive gelation, robust wet adhesion, and ease of use in emergencies is rationally engineered. This hydrogel can be conveniently used via simple injection and achieves instant sol-gel phase transition at body temperature. Its comprehensive performance could be facilely regulated by tuning the proportions of components, and the optimal performance (gelation time 6-8 s, adhesion strength 125 ± 3.6 kPa, burst pressure 282 ± 4.1 mmHg) is established due to the coordinated enhancement of the photo-cross-linking pretreatment and the hydrophilic-hydrophobic balance among various interactions in the hydrogel system. Additionally, it exhibits significant coagulation effect in vitro and enables effective hemostasis and wound healing in vivo. This work provides a promising platform for versatile applications of hydrogel-based materials, including emergency hemostasis.

Characterizing collaborative transcription regulation with a graph-based deep learning approach.

Human epigenome and transcription activities have been characterized by a number of sequence-based deep learning approaches which only utilize the DNA sequences. However, transcription factors interact with each other, and their collaborative regulatory activities go beyond the linear DNA sequence. Therefore leveraging the informative 3D chromatin organization to investigate the collaborations among transcription factors is critical. We developed ECHO, a graph-based neural network, to predict chromatin features and characterize the collaboration among them by incorporating 3D chromatin organization from 200-bp high-resolution Micro-C contact maps. ECHO predicted 2,583 chromatin features with significantly higher average AUROC and AUPR than the best sequence-based model. We observed that chromatin contacts of different distances affected different types of chromatin features' prediction in diverse ways, suggesting complex and divergent collaborative regulatory mechanisms. Moreover, ECHO was interpretable via gradient-based attribution methods. The attributions on chromatin contacts identify important contacts relevant to chromatin features. The attributions on DNA sequences identify TF binding motifs and TF collaborative binding. Furthermore, combining the attributions on contacts and sequences reveals important sequence patterns in the neighborhood which are relevant to a target sequence's chromatin feature prediction.

Outcomes of catheter ablation in high-risk patients with Brugada syndrome refusing an implantable cardioverter defibrillator implantation.

AIMS: The aim of this study was to investigate the outcomes of catheter ablation (CA) in preventing arrhythmic events among patients with symptomatic Brugada syndrome (BrS) who declined implantable cardioverter defibrillator (ICD) implantation. METHODS AND RESULTS: A total of 40 patients with symptomatic BrS were included in the study, of which 18 refused ICD implantation and underwent CA, while 22 patients received ICD implantation. The study employed substrate modification (including endocardial and epicardial approaches) and ventricular fibrillation (VF)-triggering pre-mature ventricular contraction (PVC) ablation strategies. The primary outcomes were a composite endpoint consisting of episodes of VF and sudden cardiac death during the follow-up period. The study population had a mean age of 43.8 ± 9.6 years, with 36 (90.0%) of them being male. All patients exhibited the typical Type 1 BrS electrocardiogram pattern, and 16 (40.0%) were carriers of an SCN5A mutation. The Shanghai risk scores were comparable between the CA and the ICD groups (7.05 ± 0.80 vs. 6.71 ± 0.86, P = 0.351). Ventricular fibrillation-triggering PVCs were ablated in 3 patients (16.7%), while VF substrates were ablated in 15 patients (83.3%). Epicardial ablation was performed in 12 patients (66.7%). During a median follow-up of 46.2 (17.5-73.7) months, the primary outcomes occurred more frequently in the ICD group than in the CA group (5.6 vs. 54.5%, Log-rank P = 0.012). CONCLUSION: Catheter ablation is an effective alternative therapy for improving arrhythmic outcomes in patients with symptomatic BrS who decline ICD implantation. Our findings support the consideration of CA as an alternative treatment option in this population.

The causal associations of non-alcoholic fatty liver disease with blood pressure and the mediating effects of cardiometabolic risk factors: A Mendelian randomization study.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is prevalent in hypertensive people, but the causal effect remains unclear. We employed Mendelian randomization (MR) approach to assess the causality between NAFLD and different blood pressure (BP) parameters. METHOD AND RESULTS: Instrumental variables for genetically predicted NAFLD, including chronically elevated serum alanine aminotransferase levels (cALT) and imaging and biopsy-confirmed NAFLD, were obtained from a genome-wide association study (N = 164,197). Multiple MR methods were implemented, including Inverse variance weighted, MR-Egger, Maximum likelihood, Weighted median, Simple median, Penalised weighted median, MR-RAPS, and cML-MA. Outliers were detected using MR-PRESSO, and pleiotropy was assessed using MR-Egger intercept and Phenoscanner. Heterogeneity was quantified using Cochran's Q and Rucker's Q' tests. Potential shared risk factors were analyzed to reveal the mediating effect. A higher genetic predisposition to cALT was causally associated with an increased risk of elevated BP levels, resulting in 0.65 mmHg (95% CI, 0.42-0.87), 0.38 mmHg (95% CI, 0.25-0.50) and 0.33 mmHg (95% CI, 0.22-0.44) higher for systolic BP, diastolic BP and pulse pressure, respectively. When more stringent criteria were used, imaging and biopsy-confirmed NAFLD showed a 1.12 mmHg (95% CI, 0.94-1.30) increase in SBP and a 0.55 mmHg (95% CI, 0.39-0.70) increase in DBP. Risk factor and mediation analyses suggested type 2 diabetes and fasting insulin levels might mediate the causal relationship between NAFLD and BP. CONCLUSION: The two-sample MR analyses showed robust causal effects of genetically predicted NAFLD on 3 different BP indices. The shared genetic profile between NAFLD and BP may suggest important therapeutic targets and early interventions for cardiometabolic risk factors.

Development and Validation of Machine Learning-Based Models to Predict In-Hospital Mortality in Life-Threatening Ventricular Arrhythmias: Retrospective Cohort Study.

BACKGROUND: Life-threatening ventricular arrhythmias (LTVAs) are main causes of sudden cardiac arrest and are highly associated with an increased risk of mortality. A prediction model that enables early identification of the high-risk individuals is still lacking. OBJECTIVE: We aimed to build machine learning (ML)-based models to predict in-hospital mortality in patients with LTVA. METHODS: A total of 3140 patients with LTVA were randomly divided into training (n=2512, 80%) and internal validation (n=628, 20%) sets. Moreover, data of 2851 patients from another database were collected as the external validation set. The primary output was the probability of in-hospital mortality. The discriminatory ability was evaluated by the area under the receiver operating characteristic curve (AUC). The prediction performances of 5 ML algorithms were compared with 2 conventional scoring systems, namely, the simplified acute physiology score (SAPS-II) and the logistic organ dysfunction system (LODS). RESULTS: The prediction performance of the 5 ML algorithms significantly outperformed the traditional models in predicting in-hospital mortality. CatBoost showed the highest AUC of 90.5% (95% CI 87.5%-93.5%), followed by LightGBM with an AUC of 90.1% (95% CI 86.8%-93.4%). Conversely, the predictive values of SAPS-II and LODS were unsatisfactory, with AUCs of 78.0% (95% CI 71.7%-84.3%) and 74.9% (95% CI 67.2%-82.6%), respectively. The superiority of ML-based models was also shown in the external validation set. CONCLUSIONS: ML-based models could improve the predictive values of in-hospital mortality prediction for patients with LTVA compared with traditional scoring systems.

FAM19A5/S1PR1 signaling pathway regulates the viability and proliferation of mantle cell lymphoma.

Several intracellular pathological processes have been reported to be regulated by the FAM19A5/S1PR1 signaling pathway. However, the role of FAM19A5/S1PR1 signaling pathway in the viability and proliferation of mantle cell lymphoma is not been completely understood. The task of this study is to explore the influence of FAM19A5/S1PR1 signaling pathway in affecting the survival and growth of mantle cell lymphoma. shRNAs against FAM19A5 or S1PR1 were transfected into mantle cell lymphom. Cell viability and proliferation were measured through MTT assay and CCK8 assay, respectively. Our results demonstrated that loss of FAM19A5 significantly reduced the viability of mantle cell lymphom, an effect that was followed by a drop in cell proliferation capacity. Besides, inhibition of S1PR1 also impairs cell survival and interrupt mantle cell lymphom proliferation in vitro. Taken together, our results illustrate that FAM19A5/S1PR1 signaling pathway is associated with the regulation of mantle cell lymphom viability and proliferation. This finding will provide a potential target for the treatment of malignant lymphoma in the clinical practice.

Quercetin encapsulated in folic acid-modified liposomes is therapeutic against osteosarcoma by non-covalent binding to the JH2 domain of JAK2 Via the JAK2-STAT3-PDL1.

Osteosarcoma (OS) is a malignant solid tumor prone to lung metastasis that occurs in adolescents aged 15-19 years. Neoadjuvant chemotherapy and surgical treatment aimed at curing OS have gained limited progress over the last 30 years. Exploring new effective second-line therapies for OS patients is a serious challenge for researchers. Quercetin, a multiple biologically active polyphenolic flavonoid, has been used in tumor therapy. However, the exact mechanism of quercetin is still unknown, which limits the application of quercetin. In the current study, we found that quercetin could inhibit JAK2 through the JH2 domain in a non-covalent manner, resulting in the inhibition of OS proliferation and immune escape via the JAK2-STAT3-PD-L1 signaling axis. More importantly, to overcome the shortcomings of quercetin, including low water solubility and low oral availability, we encapsulated it with folic acid-modified liposomes. The transportation of quercetin by folic acid-modified liposomes may provide a feasible strategy to cure OS.

Discovery of 4-(phenoxymethyl)-1H-1,2,3-triazole derivatives as novel xanthine oxidase inhibitors.

A series of 4-(phenoxymethyl)-1H-1,2,3-triazole derivatives were designed, synthesized, and evaluated for their xanthine oxidase (XO) inhibitory activities. Among these compounds, 9m emerged as the most effective XO inhibitor with an IC50 value of 0.70 µM, which was approximately 14-fold more potent than allopurinol. Additionally, compound 9m displayed favorable drug-like properties with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.33 and 3.41, respectively. We further explored the binding mode of 9m in complex with XO by molecular docking and molecular dynamics studies. In vivo hypouricemic studies also suggested that 9m could effectively lower the serum uric acid levels of rat. In summary, compound 9m could be a promising lead for further development of XO inhibitors.