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Metabolic processes can transform a drug into metabolites with different properties that may affect its efficacy and safety. Therefore, investigation of the metabolic fate of a drug candidate is of great significance for drug discovery. Computational methods have been developed to predict drug metabolites, but most of them suffer from two main obstacles: the lack of model generalization due to restrictions on metabolic transformation rules or specific enzyme families, and high rate of false-positive predictions. Here, we presented MetaPredictor, a rule-free, end-to-end and prompt-based method to predict possible human metabolites of small molecules including drugs as a sequence translation problem. We innovatively introduced prompt engineering into deep language models to enrich domain knowledge and guide decision-making. The results showed that using prompts that specify the sites of metabolism (SoMs) can steer the model to propose more accurate metabolite predictions, achieving a 30.4% increase in recall and a 16.8% reduction in false positives over the baseline model. The transfer learning strategy was also utilized to tackle the limited availability of metabolic data. For the adaptation to automatic or non-expert prediction, MetaPredictor was designed as a two-stage schema consisting of automatic identification of SoMs followed by metabolite prediction. Compared to four available drug metabolite prediction tools, our method showed comparable performance on the major enzyme families and better generalization that could additionally identify metabolites catalyzed by less common enzymes. The results indicated that MetaPredictor could provide a more comprehensive and accurate prediction of drug metabolism through the effective combination of transfer learning and prompt-based learning strategies.
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Simulação por Computador , Aprendizado Profundo , Humanos , Preparações Farmacêuticas/metabolismo , Preparações Farmacêuticas/química , Biologia Computacional/métodos , Descoberta de Drogas/métodos , Software , AlgoritmosRESUMO
In the heterostructure of two-dimensional (2D) materials, many novel physics phenomena are strongly dependent on the Moiré superlattice. How to achieve the continuous manipulation of the Moiré superlattice in the same sample is very important to study the evolution of various physical properties. Here, in minimally twisted monolayer-multilayer graphene, we found that bubble-induced strain has a huge impact on the Moiré superlattice. By employing the AFM tip to dynamically and continuously move the nanobubble, we realized the modulation of the Moiré superlattice, like the evolution of regular triangular domains into long strip domain structures with single or double domain walls. We also achieved controllable modulation of the Moiré superlattice by moving multiple nanobubbles and establishing the coupling of nanobubbles. Our work presents a flexible method for continuous and controllable manipulation of Moiré superlattices, which will be widely used to study novel physical properties in 2D heterostructures.
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Topological defects are widely recognized as effective active sites toward a variety of electrochemical reactions. However, the role of defect curvature is still not fully understood. Herein, carbon nanomaterials with rich topological defect sites of tunable curvature is reported. The curved defective surface is realized by controlling the high-temperature pyrolytic shrinkage process of precursors. Theoretical calculations demonstrate bending the defect sites can change the local electronic structure, promote the charge transfer to key intermediates, and lower the energy barrier for oxygen reduction reaction (ORR). Experimental results convince structural superiority of highly-curved defective sites, with a high kinetic current density of 22.5 mA cm-2 at 0.8 V versus RHE for high-curvature defective carbon (HCDC), ≈18 times that of low-curvature defective carbon (LCDC). Further raising the defect densities in HCDC leads to the dual-regulated products (HCHDC), which exhibit exceptionally outstanding ORR activity in both alkaline and acidic media (half-wave potentials: 0.88 and 0.74 V), outperforming most of the reported metal-free carbon catalysts. This work uncovers the curvature-activity relationship in carbon defect for ORR and provides new guidance to design advanced catalysts via curvature-engineering.
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An effective palladium nanocatalyst (Fe3O4@SiO2-FPBA-DTPA-Pd) was proposed and prepared, which was immobilized on magnetic silica with ethylenediamine pentaacetic acid and formylphenylboronic acid as biligands. A series of characterizations showed that Fe3O4@SiO2-FPBA-DTPA-Pd was 5-15 nm and contained 1.44 mmol/g Pd2+/Pd0. It was stable below 232.7 °C, and its saturation magnetization value was 21.17 emu/g which was easily recycled by a magnet. Its catalytic ability was evaluated through 7 Suzuki reactions and 15 Heck reactions. Results showed that the yields of 14 reactions catalyzed by Fe3O4@SiO2-FPBA-DTPA-Pd were more than 90%, while were better than those of the other two immobilized Pd catalysts on a single diethyltriamine pentaacetic acid (DTPA) group or boronic acid group. Moreover, Fe3O4@SiO2-FPBA-DTPA-Pd showed good reusability in both Suzuki and Heck reactions. In two model Suzuki and Heck reactions, after seven cycles, its yields were still above 95% without significant loss, which exceeded those of many reported catalysts; therefore, it has great potential in future large-scale industrial production.
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BACKGROUND: Cardiovascular magnetic resonance (cardiac MR) reference ranges in Chinese children are lacking. PURPOSE: To establish age- and sex-specific reference ranges for cardiac MR parameters in a cohort of healthy Chinese children. STUDY TYPE: Retrospective. SUBJECTS: One hundred ninety-six healthy children (mean age 9.5 ± 3.6 years, 111 boys). FIELD STRENGTH/SEQUENCE: 1.5 T; balanced steady-state free precession. ASSESSMENT: Biventricular volume and ejection fractions (EF), left atrial (LA) volume, right atrial (RA) area, left ventricular (LV) mass and thickness, aortic root (AR), and main pulmonary artery (MPA) dimensions were measured. Parameters were compared between age groups and sex. The relationships between parameters and age, body mass index (BMI) and body surface area (BSA) were investigated. STATISTICAL TESTS: Independent-samples t tests; Pearson's correlation. A P value <0.05 was considered statistically significant. RESULTS: Generally, boys exhibited greater absolute measurements of LV volume (end-diastolic: 94.4 ± 29.5 vs. 81.3 ± 31.0 mL), LA volume (end-diastolic: 42.6 ± 13.4 vs. 38.0 ± 13.3 mL), RA area (end-diastolic: 11.6 ± 2.5 vs. 10.8 ± 2.6 cm2), LV thickness (base: 4.4 ± 1.1 vs. 3.8 ± 0.9 mm), AR dimensions (annuls: 16.3 ± 2.7 vs. 15.0 ± 2.8 mm), and MPA dimensions (14.3 ± 2.3 vs. 13.1 ± 2.4 mm) than girls did. However, these differences were not observed when the measurements were normalized to BSA (LV volume: 75.3 ± 11.7 vs. 71.9 ± 12.3 mL/m2, P = 0.052; LA volume: 34.8 ± 8.9 vs. 34.5 ± 7.6 mL/m2, P = 0.783; RA area: 9.7 ± 2.3 vs. 10.2 ± 2.3 cm2/m2, P = 0.107; LV thickness: 3.6 ± 0.7 vs. 3.6 ± 0.9 mm/m2, P = 0.990; AR: 13.6 ± 2.7 vs. 14.3 ± 3.4 mm/m2, P = 0.108; MPA: 11.9 ± 2.3 vs. 12.4 ± 2.4 mm/m2, P = 0.118). Boys had greater RV volume (end-diastolic: 98.7 ± 33.5 vs. 82.7 ± 33.1 mL) and LV mass (52.6 ± 20.2 vs. 41.4 ± 16.0 g) compared to girls, irrespective of whether the values were indexed or not for BSA. Additionally, there were significant associations between age, BMI, and BSA with biventricular volume, LA volume, RA area, LV mass and thickness, AR and MPA dimensions in both boys and girls. DATA CONCLUSION: This study suggests reference ranges at 1.5 T for Chinese children. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.
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Background: The previous studies have demonstrated that patients with Crohn's disease in remission (CD-R) have abnormal alterations in brain function. However, whether brain function changes in patients with Crohn's disease in activity (CD-A) and the relationship with CD-R are still unclear. In this study, we aimed to investigate whether the different levels of disease activity may differentially affect the brain function and to find the brain functional biomarker distinguishing patients with different disease stages by measuring the amplitude of low frequency fluctuations (ALFF). Methods: 121 patients with CD and 91 healthy controls (HCs) were recruited. The clinical and psychological assessment of participants were collected. The criteria for the disease activity were the Crohn's disease activity index (CDAI) scores. CD-R refers to CD patients in remission which the CDAI score is less than 150. Conversely, CD-A refers to CD patients in activity which the CDAI score is ≥150. The ALFF was compared among three groups by performing one-way analysis of variance, followed by a post hoc two-sample t-test. Differences among the groups were selected as seeds for functional connectivity analyses. We also investigated the correlation among clinical, psychological scores and ALFF. Binary logistic regression analysis was used to examine the unique contribution of the ALFF characteristics of the disease stages. Results: There were widespread differences of ALFF values among the 3 groups, which included left frontal pole (FP_L), right supramarginal gyrus (SG_R), left angular gyrus (AG_L), right cingulate gyrus (CG_R), right intracalcarine cortex (IC_R), right parahippocampal gyrus (PG_R), right lingual gyrus (LG_R), right precuneous cortex (PC_R), left occipital fusiform gyrus (OFG_L). Significant brain regions showing the functional connections (FC) increased in FP_L, SG_R, PC_R and OFG_L between CD-A and HCs. The erythrocyte sedimentation rate had a negative correlation with the ALFF values in PC_R in the patients with CD. The phobic anxiety values had a negative correlation with the ALFF values in OFG_L. The psychoticism values had a negative correlation with ALFF values in the IC_R. And the hostility values had a positive correlation with the ALFF values in CG_R. Significant brain regions showing the FC increased in FP_L, SG_R, CG_R, PG_R, LG_R and OFG_L between CD-R and HCs. In binary logistic regression models, the LG_R (beta = 5.138, p = 0.031), PC_R (beta = 1.876, p = 0.002) and OFG_L (beta = 3.937, p = 0.044) was disease stages predictors. Conclusion: The results indicated the significance of the altered brain activity in the different disease stages of CD. Therefore, these findings present a potential identify neuroimaging-based brain functional biomarker in CD. Additionally, the study provides a better understanding of the pathophysiology of CD.
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Rationale and objectives: To investigate alterations in the brain structure in patients with Crohn's disease in activity (CD-A) and in remission (CD-R) compared to healthy controls (HCs) and explore the relationship between gray matter volume (GMV) and psychological disorders. Materials and methods: A total of 127 CD patients (62 CD-A, 65 CD-R) and 92 healthy controls (HCs) were enrolled and analyzed in this study. The Crohn's disease activity index (CDAI) was used as the grouping criteria. Voxel-based morphometry (VBM) was applied to investigate gray matter volume (GMV), white matter volume (WMV) and global cerebrospinal fluid (CSF) volume alterations. Pearson correlation analysis was used to evaluate the relationships. Results: The CSF volume was negatively correlated with the disease duration in CD-R. Increased GMV of CD was observed in the parahippocampal gyrus, precentral gyrus, precuneous cortex, and subcallosal cortex, decreased was located in the occipital pole, precentral gyrus, inferior temporal gyrus, middle frontal gyrus, angular gyrus, frontal pole, lateral occipital cortex, and lingual gyrus. The GMV in the right temporal pole, left precuneous cortex, and left cingulate gyrus had a positive correlation with erythrocyte and hemoglobin in CD groups. The GMV in the right frontal pole, right postcentral gyrus, and left cingulate gyrus had a negative correlation with somatization in the CD groups. The GMV in the right temporal pole had a negative correlation with psychoticism and other in the CD groups. The GMV in the left cingulate gyrus was positive with bowel symptoms and systemic symptoms in the CD groups. Conclusion: Alterations of GMV in CD-A and CD-R and associated correlation with psychological disorders may provide evidence for possible neuro-mechanisms of CD with psychological disorders.
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Phylogenetic relationships among Holometabola have been the subject of controversy. The value of the wing base structure in phylogenetic analysis has been demonstrated but remains largely underexplored and scarce in studies of Holometabola. We studied the phylogenetic relationships among Holometabola (excluding Siphonaptera), focusing exclusively on wing base structure. Cladistic assessments were conducted using 53 morphological data points derived from the bases of both the forewing and hindwing. The results of wing base data revealed a sister relationship between Hymenoptera and remaining orders. The sister-group relationships between Strepsiptera and Coleoptera, Mecoptera and Diptera, Trichoptera and Lepidoptera, and Neuropterida and Coleopterida were corroborated. In Neuropterida, our results recovered the sister relationship between Megaloptera and Neuroptera, as well as the monophyly of Megaloptera.
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Nanopolystyrene (NP) and phoxim (PHO) are common environmental pollutants in aquatic systems. We evaluated the toxic effects of exposure to ambient concentrations of NP and/or PHO in the intestines of the Chinese mitten crab (Eriocheir sinensis). Our study showed that histopathological changes were observed in the intestines. Specifically, NP and/or PHO exposure increased intraepithelial lymphocytes. Furthermore, NP and/or PHO exposure induced oxidative stress, as evidenced by a significant decrease in superoxide dismutase activity (SOD), peroxidase activity (POD), and total antioxidant capacity (T-AOC). Pro-inflammatory gene expression and transcriptome analysis demonstrated that NP and/or PHO exposure induced the intestinal inflammatory response. Transcriptome results showed that NP and/or PHO exposure upregulated the NF-κB signaling pathway, which is considered a key pathway in the inflammatory response. Additionally, the expression of pro-inflammatory genes significantly increased after a single exposure to NP or PHO, but it exhibited a significant decrease after the co-exposure. The downregulation of these genes in the co-exposure group likely suggested that the co-exposure mitigated intestinal inflammation response in E. sinensis. Collectively, our findings mainly showed that NP and/or PHO exposure at ambient concentrations induces oxidative stress and inflammatory response in the intestines of E. sinensis.
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Braquiúros , Compostos Organotiofosforados , Estresse Oxidativo , Animais , Antioxidantes/metabolismo , Intestinos , Inflamação/induzido quimicamente , Braquiúros/metabolismoRESUMO
Nanopolystyrene (NP) and cadmium (Cd) are ubiquitous contaminants in aquatic systems. The present study aimed to investigate the toxic effects of exposure to ambient concentrations of NP and/or Cd on the intestinal tract of the Chinese mitten crab (Eriocheir sinensis). Exposure to NP and/or Cd induced oxidative stress, as evidenced by a significant increase in lipid peroxide content (LPO), total antioxidant capacity (T-AOC), and peroxidase activity (POD), and significant decreases in superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities in E. sinensis. In addition, exposure to NP and/or Cd imbalanced the homeostasis of the intestinal microbiota, as demonstrated by the significantly increased abundance of Spiroplasma. Transcriptomic and metabolomic analyses were performed to investigate the mechanisms underlying intestinal toxicity. Our results showed that ferroptosis, ABC transporters, phosphotransferase system, apoptosis, and leukocyte transendothelial migration were disturbed after exposure to NP and/or Cd. In particular, Cd exposure affected mucin type O-glycan biosynthesis, purine metabolism, and neuroactive ligand-receptor interaction. Intriguingly, co-exposure to NP and Cd might mitigate intestinal toxicity by decreasing oxidative stress and affecting these pathways. Taken together, our study clearly demonstrates that exposure to NP and/or Cd at environmentally relevant concentrations causes intestinal toxicity in E. sinensis.
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Braquiúros , Cádmio , Animais , Cádmio/toxicidade , Antioxidantes/metabolismo , Estresse Oxidativo , Intestinos , Braquiúros/metabolismoRESUMO
Circular RNA (circRNA) forms closed loops via back-splicing in precursor mRNA, resisting exonuclease degradation. In higher eukaryotes, protein-coding genes create circRNAs through exon back-splicing. Unlike mRNAs, circRNAs possess unique production and structural traits, bestowing distinct cellular functions and biomedical potential. In this review, we explore the pivotal roles of viral circRNAs and associated RNA in various biological processes. Analysing the interactions between viral circRNA and host cellular machinery yields fresh insights into antiviral immunity, catalysing the development of potential therapeutics. Furthermore, circRNAs serve as enduring biomarkers in viral diseases due to their stable translation within specific tissues. Additionally, a deeper understanding of translational circRNA could expedite the establishment of circRNA-based expression platforms, meeting the rising demand for broad-spectrum viral vaccines. We also highlight the applications of circular RNA in biomarker studies as well as circRNA-based therapeutics. Prospectively, we expect a technological revolution in combating viral infections using circRNA.
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MicroRNAs , Viroses , Humanos , RNA Circular/genética , RNA Circular/metabolismo , RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Splicing de RNA , RNA Viral/genética , RNA Viral/metabolismo , Viroses/diagnóstico , Viroses/genética , Viroses/terapia , MicroRNAs/genéticaRESUMO
OBJECTIVES: This study aims to assess the relative of social support and psychological distress in disease activity among patients with Crohn's disease (CD) in China, and explore whether sex moderates the relationship between disease activity and social support and psychological distress in CD. DESIGN: Our study has a cross-sectional design. SETTING: This was a single-centre study, which was conducted in Wuhan, China. PARTICIPANTS: A total of 184 patients with CD at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology were enrolled in this study; of these,162 patients were included in the final analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: The main study outcome was the CD patients' clinical and questionnaire data. The association of disease activity, social support and psychological distress with patients with CD was also evaluated based on the collected data. RESULTS: A total of 162 patients with CD were enrolled. Compared with patients with CD in remission (CD-R), the patients with CD in activity (CD-A) had higher C reactive protein (CRP) (p=0.001), anaemia (p<0.001) and relapse rates in the last year (p<0.001). Independent samples t-tests indicated that the CD-A group reported lower Social Support Rating Scale scores and higher Symptom Checklist-90 scores than the CD-R group. Moreover, men with CD had lower somatisation (p=0.030) and anxiety (p=0.050) scores than women. In binary logistic regression models, the subjective support (beta=0.903, p=0.013), the clinical factors of CRP (beta=1.038, p=0.001) and psychological distress factors of anxiety (beta=1.443, p=0.008) and other (beta=1.235, p=0.042) were disease activity predictors. CONCLUSION: The findings highlight the importance of the psychological distress and social support factors that may play a role in CD patients' health. Interventions to address these issues should be part of management in CD.
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Doença de Crohn , Angústia Psicológica , Masculino , Humanos , Feminino , Doença de Crohn/complicações , Doença de Crohn/psicologia , Estudos Transversais , Estresse Psicológico/epidemiologia , Estresse Psicológico/etiologia , Estresse Psicológico/psicologia , Proteína C-Reativa , Hospitais , Apoio SocialRESUMO
Since the 1960 s, our health has been compromised by exposure to over 350,000 newly introduced toxic substances, contributing to the current pandemic in allergic, autoimmune and metabolic diseases. The "Epithelial Barrier Theory" postulates that these diseases are exacerbated by persistent periepithelial inflammation (epithelitis) triggered by exposure to a wide range of epithelial barrier-damaging substances as well as genetic susceptibility. The epithelial barrier serves as the body's primary physical, chemical, and immunological barrier against external stimuli. A leaky epithelial barrier facilitates the translocation of the microbiome from the surface of the afflicted tissues to interepithelial and even deeper subepithelial locations. In turn, opportunistic bacterial colonization, microbiota dysbiosis, local inflammation and impaired tissue regeneration and remodelling follow. Migration of inflammatory cells to susceptible tissues contributes to damage and inflammation, initiating and aggravating many chronic inflammatory diseases. The objective of this review is to highlight and evaluate recent studies on epithelial physiology and its role in the pathogenesis of chronic diseases in light of the epithelial barrier theory.
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Hipersensibilidade , Doenças Metabólicas , Microbiota , Humanos , Inflamação , Doença Crônica , DisbioseRESUMO
Objectives: Tumor grading is important for prognosis of pancreatic ductal adenocarcinoma (PDAC). In this study, we developed preoperative clinical-radiomics nomograms using features from contrast-enhanced CT (CECT), to discriminate high-grade and low-grade PDAC and predict overall survival (OS). Methods: In this single-center, retrospective study conducted from February 2014 to April 2021, consecutive PDAC patients who underwent CECT and had pathologically identified grading were randomized to training (n=200) and test (n=84) cohorts for development of model to predict histological grade based on radiomics scores from CECT (HGrad). Another 42 patients were used as external validation cohort of HGrad. A nomogram (HGnom) was constructed using radiomics score, CA12-5 and smoking to predict histological grade. A second nomogram (Pnom) was constructed using radiomics score, CA12-5, TNM, adjuvant treatment, resection margin and microvascular invasion to predict OS in radical resection patients (217 of 284). Results: Among 326 patients, 122 were high-grade (120 poorly differentiated and 2 undifferentiated). The HGrad yielded AUCs of 0.75 (95% CI: 0.64, 0.85) and 0.76 (95% CI: 0.60, 0.91) in test and validation cohorts. The HGnom achieved AUCs of 0.77 (95% CI: 0.66, 0.87), and the predicted grades calibrated well with actual grades (P=.13). OS was different between the grades predicted by radiomics scores (P=.01). The integrated AUC of the Pnom for predicting OS was 0.80 (95% CI: 0.75, 0.88). Conclusion: Compared with the HGrad using features from CECT, the HGnom demonstrated higher performance for predicting histological grade. The Pnom helped identify patients with high survival outcome in pancreatic ductal adenocarcinoma.
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Indoleamine 2,3-dioxygenase 1 (IDO1) is viewed as an extremely promising target for cancer immunotherapy. Here, we proposed a two-layer stacking ensemble model, IDO1Stack, that can efficiently predict IDO1 inhibitors. First, we constructed a series of classification models based on five machine learning algorithms and eight molecular characterization methods. Then, a stacking ensemble model was built using the top five models as the base classifier and logistic regression as the meta-classifier. The areas under the receiver operating characteristic curve (AUC) of IDO1Stack on the test set and external validation set were 0.952 and 0.918, respectively. Furthermore, we computed the applicability domain and privileged substructures of the model and interpreted the model using SHapley Additive exPlanations (SHAP). It is expected that IDO1Stack can well study the interaction between target and ligand, providing practitioners with a reliable tool for rapid screening and discovery of IDO1 inhibitors.
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Indolamina-Pirrol 2,3,-Dioxigenase , Aprendizado de Máquina , Indolamina-Pirrol 2,3,-Dioxigenase/química , Imunoterapia , Algoritmos , LigantesRESUMO
Oxidative stress (OS) is a key factor involved in the initiation and development of chronic diseases. Despite its widespread acceptance as an antioxidant, the effects of ginseng on OS in human clinical trials have not been comprehensively analyzed. Therefore, this study aimed to synthesize the results of previous randomized clinical trials (RCTs) examining the impact of ginseng consumption on OS indicators. PubMed, Web of Science, Scopus, and Cochrane databases were searched for articles on the effects of ginseng consumption on oxidative stress markers up to March 20, 2023. Standardized mean difference (SMD) and 95% confidence intervals (CIs) were used to assess effect sizes. Twelve RCTs with 15 effect sizes revealed that the effects of ginseng lowered serum malondialdehyde (MDA) levels (SMD = 0.45, 95% CI: -0.87, -0.08; p = 0.03) and significantly increased the serum total antioxidant capacity (TAC) (SMD = 0.23, 95% CI: 0.01, 0.45; p = 0.04), oxidative dismutase (SOD) (SMD = 0.39, 95% CI: 0.21, 0.57; p < 0.0001), glutathione (GSH) (SMD = 0.36; 95% CI: 0.11, 0.61; p = 0.005), and glutathione reductase (GR) (SMD = 0.56; 95% CI: 0.31, 0.81; p < 0.0001) levels compared to the effects of placebo. However, the effects on serum glutathione peroxidase (GPx) and catalase (CAT) were not significant. Moreover, subgroup analysis based on intervention duration showed that ginseng consumption increased GPx (SMD = 0.91, 95% CI: 0.05, 1.78; p = 0.039) and CAT (SMD = 0.74, 95% CI: 0.27, 1.21; p = 0.002) levels after more than 4 weeks of intervention. According to the results of this meta-analysis, ginseng supplementation dramatically reduced MDA levels and increased TAC, SOD, GSH, and GR levels. Our results open up a new line of defense against oxidative stress-induced diseases.
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Antioxidantes , Panax , Humanos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Suplementos Nutricionais , Panax/metabolismo , Estresse Oxidativo , Biomarcadores , Glutationa Peroxidase , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND: It is well established that obesity is associated with the risk of heart failure (HF). However, the data about relationship between visceral fat and the risk of HF are limited. AIMS: We aim to evaluate the association between visceral obesity assessed by visceral adiposity index (VAI) and incident HF and left ventricular (LV) structure and function in Atherosclerosis Risk in Communities (ARIC) study. METHODS: We included 12 161 participants (aged 54.1 ± 5.8 years) free of history of HF and coronary heart disease at baseline (1987-89) in ARIC study. We used multivariable Cox hazard regression models to assess the association between the VAI and incident HF. We further explored the effects of the VAI on LV geometry and function among 4817 participants with echocardiographic data using multivariable linear regression analysis and multinomial logistic regression. RESULTS: During a median follow-up of 22.5 years, a total of 1904 (15.7%) participants developed HF. After adjustment for traditional HF risk factors, 1 unit increase in the baseline VAI was associated with an 8% higher risk of incident HF [hazard ratio (HR): 1.08, 95% confidence interval (CI): 1.06-1.11]. Results were similar when participants were categorized by VAI tertiles. Compared with participants in the lowest tertile of VAI, those in the second tertile and third tertile had a greater risk of incident HF [HR (95% CI): 1.19 (1.05-1.34) and 1.42 (1.26-1.61), respectively]. For the analyses of the HF subtypes, the higher VAI was only associated with the risk of HF with preserved ejection fraction, not with HF with reduced ejection fraction. In addition, the greater VAI was associated with worse LV diastolic function and abnormal LV geometry including concentric remodelling, concentric hypertrophy, and eccentric hypertrophy. CONCLUSION: This study shows that higher VAI was independently associated with the increased risk of incident HF and abnormal LV geometry and LV diastolic dysfunction.
We investigated the relationship between visceral adiposity index (VAI) and incident heart failure (HF) in 12 161 participants and further evaluated the possible effect of the VAI on late-life left ventricular (LV) structure and function in 4817 participants who underwent echocardiography examination at Visit 5 in Atherosclerosis Risk in Communities study.Our study found that VAI, a simple alternative indicator of visceral obesity, was positively associated with the risk of HF.Our results shown that VAI was significantly associated with abnormal LV geometry and worse LV diastolic function in late life.
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Aterosclerose , Insuficiência Cardíaca , Disfunção Ventricular Esquerda , Humanos , Obesidade Abdominal/complicações , Adiposidade , Estudos Prospectivos , Hipertrofia/complicações , Fatores de RiscoRESUMO
Rhinoviruses and allergens, such as house dust mite are major agents responsible for asthma exacerbations. The influence of pre-existing airway inflammation on the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. We analyse mechanisms of response to viral infection in experimental in vivo rhinovirus infection in healthy controls and patients with asthma, and in in vitro experiments with house dust mite, rhinovirus and SARS-CoV-2 in human primary airway epithelium. Here, we show that rhinovirus infection in patients with asthma leads to an excessive RIG-I inflammasome activation, which diminishes its accessibility for type I/III interferon responses, leading to their early functional impairment, delayed resolution, prolonged viral clearance and unresolved inflammation in vitro and in vivo. Pre-exposure to house dust mite augments this phenomenon by inflammasome priming and auxiliary inhibition of early type I/III interferon responses. Prior infection with rhinovirus followed by SARS-CoV-2 infection augments RIG-I inflammasome activation and epithelial inflammation. Timely inhibition of the epithelial RIG-I inflammasome may lead to more efficient viral clearance and lower the burden of rhinovirus and SARS-CoV-2 infections.
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Fatores de Restrição Antivirais , Asma , COVID-19 , Proteína DEAD-box 58 , Inflamassomos , Rhinovirus , Humanos , Fatores de Restrição Antivirais/genética , Fatores de Restrição Antivirais/metabolismo , Asma/genética , Asma/imunologia , COVID-19/genética , COVID-19/imunologia , Proteína DEAD-box 58/metabolismo , Infecções por Enterovirus/genética , Infecções por Enterovirus/imunologia , Inflamassomos/genética , Inflamassomos/metabolismo , Inflamação , Interferon Tipo I , Infecções por Picornaviridae/genética , Infecções por Picornaviridae/imunologia , Rhinovirus/metabolismo , Rhinovirus/patogenicidade , SARS-CoV-2RESUMO
Chemical mutagenicity is a serious issue that needs to be addressed in early drug discovery. Over a long period of time, medicinal chemists have manually summarized a series of empirical rules for the optimization of chemical mutagenicity. However, given the rising amount of data, it is getting more difficult for medicinal chemists to identify more comprehensive chemical rules behind the biochemical data. Herein, we integrated a large Ames mutagenicity data set with 8576 compounds to derive mutagenicity transformation rules for reversing Ames mutagenicity via matched molecular pairs analysis. A well-trained consensus model with a reasonable applicability domain was constructed, which showed favorable performance in the external validation set with an accuracy of 0.815. The model was used to assess the generalizability and validity of these mutagenicity transformation rules. The results demonstrated that these rules were of great value and could provide inspiration for the structural modifications of compounds with potential mutagenic effects. We also found that the local chemical environment of the attachment points of rules was critical for successful transformation. To facilitate the use of these mutagenicity transformation rules, we integrated them into ADMETopt2 ( http://lmmd.ecust.edu.cn/admetsar2/admetopt2/ ), a free web server for optimization of chemical ADMET properties. The above-mentioned approach would be extended to the optimization of other toxicity endpoints.