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Chronic inflammation is a common feature of obesity, with elevated cytokines such as interleukin-1 (IL-1) in the circulation and tissues. Here, we report an unconventional IL-1R-MyD88-IRAK2-PHB/OPA1 signaling axis that reprograms mitochondrial metabolism in adipocytes to exacerbate obesity. IL-1 induced recruitment of IRAK2 Myddosome to mitochondria outer membranes via recognition by TOM20, followed by TIMM50-guided translocation of IRAK2 into mitochondria inner membranes, to suppress oxidative phosphorylation and fatty acid oxidation, thereby attenuating energy expenditure. Adipocyte-specific MyD88 or IRAK2 deficiency reduced high-fat-diet-induced weight gain, increased energy expenditure and ameliorated insulin resistance, associated with a smaller adipocyte size and increased cristae formation. IRAK2 kinase inactivation also reduced high-fat diet-induced metabolic diseases. Mechanistically, IRAK2 suppressed respiratory super-complex formation via interaction with PHB1 and OPA1 upon stimulation of IL-1. Taken together, our results suggest that the IRAK2 Myddosome functions as a critical link between inflammation and metabolism, representing a novel therapeutic target for patients with obesity.
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Adipócitos/imunologia , Inflamação/imunologia , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-1/metabolismo , Membranas Mitocondriais/metabolismo , Obesidade/imunologia , Adipócitos/patologia , Animais , Células Cultivadas , Humanos , Quinases Associadas a Receptores de Interleucina-1/genética , Masculino , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Fosforilação Oxidativa , Proibitinas , Transporte Proteico , Receptores de Interleucina-1/metabolismo , Transdução de SinaisRESUMO
Mechanisms that degrade inflammatory mRNAs are well known; however, stabilizing mechanisms are poorly understood. Here, we show that Act1, an interleukin-17 (IL-17)-receptor-complex adaptor, binds and stabilizes mRNAs encoding key inflammatory proteins. The Act1 SEFIR domain binds a stem-loop structure, the SEFIR-binding element (SBE), in the 3' untranslated region (UTR) of Cxcl1 mRNA, encoding an inflammatory chemokine. mRNA-bound Act1 directs formation of three compartmentally distinct RNA-protein complexes (RNPs) that regulate three disparate events in inflammatory-mRNA metabolism: preventing mRNA decay in the nucleus, inhibiting mRNA decapping in P bodies and promoting translation. SBE RNA aptamers decreased IL-17-mediated mRNA stabilization in vitro, IL-17-induced skin inflammation and airway inflammation in a mouse asthma model, thus providing a therapeutic strategy for autoimmune diseases. These results reveal a network in which Act1 assembles RNPs on the 3' UTRs of select mRNAs and consequently controls receptor-mediated mRNA stabilization and translation during inflammation.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Inflamação/imunologia , Interleucina-17/metabolismo , Estabilidade de RNA/fisiologia , Transdução de Sinais/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Regulação da Expressão Gênica/imunologia , Inflamação/metabolismo , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Receptores de Interleucina-17/metabolismoRESUMO
Glassy polymers are generally stiff and strong yet have limited extensibility1. By swelling with solvent, glassy polymers can become gels that are soft and weak yet have enhanced extensibility1-3. The marked changes in properties arise from the solvent increasing free volume between chains while weakening polymer-polymer interactions. Here we show that solvating polar polymers with ionic liquids (that is, ionogels4,5) at appropriate concentrations can produce a unique class of materials called glassy gels with desirable properties of both glasses and gels. The ionic liquid increases free volume and therefore extensibility despite the absence of conventional solvent (for example, water). Yet, the ionic liquid forms strong and abundant non-covalent crosslinks between polymer chains to render a stiff, tough, glassy, and homogeneous network (that is, no phase separation)6, at room temperature. Despite being more than 54 wt% liquid, the glassy gels exhibit enormous fracture strength (42 MPa), toughness (110 MJ m-3), yield strength (73 MPa) and Young's modulus (1 GPa). These values are similar to those of thermoplastics such as polyethylene, yet unlike thermoplastics, the glassy gels can be deformed up to 670% strain with full and rapid recovery on heating. These transparent materials form by a one-step polymerization and have impressive adhesive, self-healing and shape-memory properties.
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Microglial activation is a critical factor in the pathogenesis and progression of neuroinflammatory diseases. Mild hypothermia, known for its neuroprotective properties, has been shown to alleviate microglial activation. In this study, we explore the differentially expressed (DE) mRNAs and long non-coding RNAs (lncRNAs) in BV-2 microglial cells under different conditions: normal temperature (CN), mild hypothermia (YT), normal temperature with lipopolysaccharide (LPS), and mild hypothermia with LPS (LPS + YT). Venn analysis revealed 119 DE mRNAs that were down-regulated in the LPS + YT vs LPS comparison but up-regulated in the CN vs LPS comparison, primarily enriched in Gene Ontology terms related to immune and inflammatory responses. Furthermore, through Venn analysis of YT vs CN and LPS + YT vs LPS comparisons, we identified 178 DE mRNAs and 432 DE lncRNAs. Among these transcripts, we validated the expression of Tent5c at the protein and mRNA levels. Additionally, siRNA-knockdown of Tent5c attenuated the expression of pro-inflammatory genes (TNF-α, IL-1ß, Agrn, and Fpr2), cellular morphological changes, NLRP3 and p-P65 protein levels, immunofluorescence staining of p-P65 and number of cells with ASC-speck induced by LPS. Furthermore, Tent5c overexpression further potentiated the aforementioned indicators in the context of mild hypothermia with LPS treatment. Collectively, our findings highlight the significant role of Tent5c down-regulation in mediating the anti-inflammatory effects of mild hypothermia.
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Hipotermia , RNA Longo não Codificante , Humanos , Lipopolissacarídeos/farmacologia , Regulação para Baixo , Microglia/metabolismo , Hipotermia/metabolismo , RNA Longo não Codificante/metabolismoRESUMO
The importance of the immune microenvironment in poorly cohesive carcinoma (PCC) has been highlighted due to its limited response rate to conventional therapy and emerging treatment resistance. A combination of clinical cohorts, bioinformatics analyses, and functional/molecular experiments revealed that high infiltration of Interferon Induced Protein with Tetratricopeptide Repeats 1 (IFIT1) + tumor-associated neutrophils (TANs) is a distinguishing feature of PCC patients. Upregulation of IFIT1 + TANs promote migration and invasion of gastric cancer (GC) cell lines (MKN45 and MKN74) and stimulates the growth of cell-derived xenograft models. Besides, by promoting macrophage secreted phosphoprotein 1 (SPP1) expression and facilitating cancer-associated fibroblast and endothelial cell recruitment and activation through TANs, IFIT1 promotes a mesenchymal phenotype, which is associated with a poor prognosis. Importantly, compared to non-PCC (NPCC), PCC tumors is more immunosuppressive. Mechanistically, IFIT1 can be stimulated by IFN-γ and contributes to the expression of Programmed Cell Death 1 Ligand (PDL1) in TANs. We demonstrated in mouse models that IFIT1 + PDL1 + TANs can induce acquired resistance to anti-PD-1 immunotherapy, which may be responsible for the difficulty of PCC patients to benefit from immunotherapy. This work highlights the role of IFIT1 + TANs in mediating the remodeling of the tumor immune microenvironment and immunotherapeutic resistance and introduces IFIT1 + TANs as a promising target for precision therapy of PCC.
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Proteínas Adaptadoras de Transdução de Sinal , Neutrófilos , Proteínas de Ligação a RNA , Humanos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Animais , Proteínas de Ligação a RNA/metabolismo , Linhagem Celular Tumoral , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Microambiente Tumoral/imunologia , Feminino , Antígeno B7-H1/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/imunologia , Masculino , Camundongos , Resistencia a Medicamentos Antineoplásicos , Movimento Celular , Tolerância Imunológica , Terapia de Imunossupressão , Regulação Neoplásica da Expressão Gênica , Invasividade Neoplásica , Camundongos Nus , Imunoterapia , Pessoa de Meia-IdadeRESUMO
Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial-mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity.
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Fibroblastos Associados a Câncer , Comunicação Celular , Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Microambiente Tumoral , Animais , Humanos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Transição Epitelial-Mesenquimal/genética , Junções Comunicantes/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Análise Espaço-Temporal , Junções Íntimas/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Autoantígenos/genética , Autoantígenos/metabolismoRESUMO
Horizontal gene transfer (HGT) is a major driving force in the evolution of prokaryotic and eukaryotic genomes. Despite recent advances in distribution and ecological importance, the extensive pattern, especially in seed plants, and post-transfer adaptation of HGT-acquired genes in land plants remain elusive. We systematically identified 1150 foreign genes in 522 land plant genomes that were likely acquired via at least 322 distinct transfers from nonplant donors and confirmed that recent HGT events were unevenly distributed between seedless and seed plants. HGT-acquired genes evolved to be more similar to native genes in terms of average intron length due to intron gains, and HGT-acquired genes containing introns exhibited higher expression levels than those lacking introns, suggesting that intron gains may be involved in the post-transfer adaptation of HGT in land plants. Functional validation of bacteria-derived gene GuaD in mosses and gymnosperms revealed that the invasion of foreign genes introduced a novel bypass of guanine degradation and resulted in the loss of native pathway genes in some gymnosperms, eventually shaping three major types of guanine metabolism in land plants. We conclude that HGT has played a critical role in land plant evolution.
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BACKGROUND: Sarcopenia is frequently found in patients with heart failure with reduced ejection fraction (HFrEF) and is associated with reduced exercise capacity, poor quality of life and adverse outcomes. Recent evidence suggests that axial thoracic skeletal muscle size could be used as a surrogate to assess sarcopenia in HFrEF. Since diabetes mellitus (DM) is one of the most common comorbidities with HFrEF, we aimed to explore the potential association of axial thoracic skeletal muscle size with left ventricular (LV) remodeling and determine its prognostic significance in this condition. METHODS: A total of 243 diabetes patients with HFrEF were included in this study. Bilateral axial thoracic skeletal muscle size was obtained using cardiac MRI. Patients were stratified by the tertiles of axial thoracic skeletal muscle index (SMI). LV structural and functional indices, as well as amino-terminal pro-B-type natriuretic peptide (NT-proBNP), were measured. The determinants of elevated NT-proBNP were assessed using linear regression analysis. The associations between thoracic SMI and clinical outcomes were assessed using a multivariable Cox proportional hazards model. RESULTS: Patients in the lowest tertile of thoracic SMI displayed a deterioration in LV systolic strain in three components, together with an increase in LV mass and a heavier burden of myocardial fibrosis (all P < 0.05). Moreover, thoracic SMI (ß = -0.25; P < 0.001), rather than body mass index (ß = -0.04; P = 0.55), was independently associated with the level of NT-proBNP. The median follow-up duration was 33.6 months (IQR, 20.4-52.8 months). Patients with adverse outcomes showed a lower thoracic SMI (40.1 [34.3, 47.9] cm2/m2 vs. 45.3 [37.3, 55.0] cm2/m2; P < 0.05) but a similar BMI (P = 0.76) compared with those without adverse outcomes. A higher thoracic SMI indicated a lower risk of adverse outcomes (hazard ratio: 0.96; 95% confidence interval: 0.92-0.99; P = 0.01). CONCLUSIONS: With respect to diabetes patients with HFrEF, thoracic SMI is a novel alternative for evaluating muscle wasting in sarcopenia that can be obtained by a readily available routine cardiac MRI protocol. A reduction in thoracic skeletal muscle size predicts poor outcomes in the context of DM with HFrEF.
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Diabetes Mellitus , Insuficiência Cardíaca , Sarcopenia , Disfunção Ventricular Esquerda , Humanos , Insuficiência Cardíaca/diagnóstico por imagem , Sarcopenia/diagnóstico por imagem , Sarcopenia/epidemiologia , Qualidade de Vida , Biomarcadores , Volume Sistólico/fisiologia , Peptídeo Natriurético Encefálico , Imageamento por Ressonância Magnética , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia , Fragmentos de Peptídeos , Músculo Esquelético/diagnóstico por imagem , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologiaRESUMO
BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is associated with a high rate of mortality and morbidity. Evidence has shown that sex differences may be an important contributor to phenotypic heterogeneity in patients with HFrEF. Although diabetes mellitus (DM) frequently coexists with HFrEF and results in a worse prognosis, there remains a need to identify sex-related differences in the characteristics and outcomes of this population. In this study, we aimed to investigate the between-sex differences in clinical profile, left ventricular (LV) remodeling, and cardiovascular risk factors and outcomes in patients with HFrEF concomitant with DM. METHODS: A total of 273 patients with HFrEF concomitant with DM who underwent cardiac MRI were included in this study. Clinical characteristics, LV remodeling as assessed by cardiac MRI, and cardiovascular risk factors and outcomes were compared between sexes. RESULTS: Women were older, leaner and prone to have anemia and hypoproteinemia but less likely to have ischemic etiology. Cardiac MRI revealed that despite similar LVEFs between the sexes, there was more LV concentric remodeling, less impaired global systolic peak strain in longitudinal and circumferential components and a decreased likelihood of late gadolinium enhancement presence in women than in men. During a median follow-up time of 34.6 months, women exhibited better overall survival than men did (log-rank P = 0.042). Multivariable Cox proportional hazards analysis indicated different risk factors for predicting outcomes between sexes, with hypertension [hazard ratio (HR) = 2.05, 95% confidence interval (CI) 1.05 to 4.85, P = 0.041] and hypoproteinemia (HR = 2.27, 95% CI 1.06 to 4.37, P = 0.039) serving as independent determinants of outcomes in women, whereas ischemic etiology (HR = 1.96, 95% CI 1.11 to 3.48, P = 0.021) and atrial fibrillation (HR = 1.86, 95% CI 1.02 to 3.41, P = 0.044) served as independent determinants of outcomes in men. CONCLUSIONS: Among patients with HFrEF concomitant with DM, women displayed different LV remodeling and risk factors and had better survival than men did. Sex-based phenotypic heterogeneity in patients with HFrEF in the context of DM should be addressed in clinical practice.
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Insuficiência Cardíaca , Volume Sistólico , Função Ventricular Esquerda , Remodelação Ventricular , Humanos , Feminino , Masculino , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/diagnóstico , Pessoa de Meia-Idade , Idoso , Fatores Sexuais , Prognóstico , Valor Preditivo dos Testes , Disparidades nos Níveis de Saúde , Fatores de Risco , Imagem Cinética por Ressonância Magnética , Fatores de Tempo , Estudos Retrospectivos , Imageamento por Ressonância Magnética , Medição de Risco , Diabetes Mellitus/mortalidade , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Fatores de Risco de Doenças CardíacasRESUMO
BACKGROUND: There is an urgent need to develop an efficient therapeutic strategy for heart failure with preserved ejection fraction (HFpEF), which is mediated by phenotypic changes in cardiac macrophages. We previously reported that vitamin B6 (VB6) inhibits macrophage-mediated inflammasome activation OBJECTIVE: We sought to examine whether the prophylactic use of VB6 prevents HFpEF METHODS: HFpEF model was elicited by a combination of high fat diet and Nω-nitro-l-arginine methyl ester in mice. Cardiac function was assessed using conventional echocardiography and Doppler imaging. Immunohistochemistry and immunoblotting were used to detect changes in the macrophage phenotype and myocardial remodeling-related molecules RESULTS: Co-administration of VB6 with HFpEF mice mitigated HFpEF phenotypes, including diastolic dysfunction, cardiac macrophage phenotypic shifts, fibrosis, and hypertrophy. Echocardiographic improvements were observed, with the E/E' ratio decreasing from 42.0 to 21.6 and the E/A ratio improving from 2.13 to 1.17. The exercise capacity also increased from 295.3 m to 657.7 m. However, these beneficial effects were negated in downstream of kinase 3 (DOK3)-deficient mice. Mechanistically, VB6 increased DOK3 protein levels and inhibited macrophage phenotypic changes, which were abrogated by an AMP-activated protein kinase inhibitor CONCLUSION: VB6 increases DOK3 signaling to lower the risk of HFpEF by inhibiting phenotypic changes in cardiac macrophages.
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BACKGROUND: The alteration of left atrial (LA) phasic function in subacute and chronic pulmonary embolism (PE) patients is unclear. PURPOSE: To investigate LA phasic strain and LA-right ventricular (RV) interaction in subacute and chronic PE patients with different degrees of obstruction by MRI-feature tracking (MRI-FT). STUDY TYPE: Retrospective. POPULATION: One hundred three PE patients (54 subacute [2 weeks to 3 months after initial symptoms], 49 chronic [>3 months after initial symptoms]) and 80 controls. FIELD STRENGTH/SEQUENCE: 3.0 T/balanced steady state free precession sequence. ASSESSMENT: Patients were divided into mild (pulmonary artery obstruction index [PAOI] < 30%, N = 57), moderate (30% ≤ PAOI < 50%, N = 27), and severe (50% ≥ PAOI, N = 19) PE subgroups. LA reservoir, conduit, and active pump longitudinal strains (εs, εe, and εa) and strain rates (SRs, SRe, and SRa) and biventricular global strains were measured. Determinants of LA strains were investigated. STATISTICAL TESTS: ANOVA, t-tests, Mann-Whitney U tests, linear regression. P < 0.05 was considered statistically significant. RESULTS: For both subacute and chronic PE patients, LA reservoir, conduit, and active pump strains and strain rates were significantly lower than in controls. However, there were no significant differences in LA strains between patients with subacute and chronic PE (P = 0.933, 0.625, and 0.630 for εs, εe, and εa). The severe PE subgroup had significantly higher εa and SRa than the mild and moderate PE subgroups. LA strains were significantly correlated with RV diameter and biventricular strains, and RV diameter (ß = -6.836, -4.084, and -1.899 for εs, εe, and εa) was independently associated with LA strains after adjustment for other factors (R2 = 0.627, 0.536, and 0.437 for εs, εe, and εa). DATA CONCLUSION: LA phasic function evaluated by MRI-FT was significantly impaired in subacute and chronic PE patients, and LA active pump function in the severe PE subgroup was higher than that in the mild and moderate PE subgroups. The independent association between RV diameter and LA strains demonstrates that RV diameter may be an important indicator for monitoring LA dysfunction in PE patients. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.
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BACKGROUND: Metabolic syndrome (MetS) is associated with worse prognosis in patients with myocardial infarction (MI). However, it is unclear how MetS in MI patients is associated with left atrial (LA) and left ventricular (LV) deformation. PURPOSE: To determine the effect of MetS on LA and LV deformation and atrioventricular interactions in MI patients. STUDY TYPE: Retrospective. POPULATION: One hundred eighty-one MI patients (73 MetS+ and 108 MetS-), 107 age- and sex-matched controls (49 MetS+ and 58 MetS-). FIELD STRENGTH/SEQUENCE: 3.0 T/balanced steady-state free precession (SSFP)/segmented phase-sensitive inversion recovery SSFP sequence. ASSESSMENT: LA strain and strain rates (reservoir, conduit, and active), left atrioventricular coupling index (LACI), and LV geometry and radial, circumferential and longitudinal global peak strains (PS) were compared among groups. STATISTICAL TESTS: Two-way analysis of variance, Spearman and Pearson's correlation coefficients, and multivariable linear regression analysis. P value <0.05 indicated statistical significance. RESULTS: Compared with controls, the MI patients with or without MetS showed impaired LA function (reservoir, conduit, and active) and LV deformation (radial, circumferential, and longitudinal PS) and higher LACI. The MetS+ group had lower LA reservoir and conduit function and LV deformation than MetS- group. The MetS-MI interaction was not statistically significant. Furthermore, multivariable linear regression showed that MetS was independently associated with LA and LV deformation (ß = -0.181 to -0.209) in MI patients; LA function was independently associated with LV circumferential PS (ß = 0.230 to 0.394) and longitudinal PS (ß = 0.189 to 0.420), and LA passive strain and strain rate were negatively associated with LV mass (ß = -0.178 and -0.298). DATA CONCLUSION: MetS may be associated with the LA and LV dysfunction in MI patients. Impaired LV deformation and LV hypertrophy are independently associated with LA dysfunction in MI patients, and the MI patients have higher LACI than controls, suggesting atrioventricular interaction alterations. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: 3.
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BACKGROUND: The impact of functional mitral regurgitation and type 2 mellitus diabetes (T2DM) on left ventricular (LV) strain in nonischemic dilated cardiomyopathy (NIDCM) patients remains unclear. PURPOSE: To evaluate the impact of mitral regurgitation severity on LV strain, and explore additive effect of T2DM on LV function across varying mitral regurgitation severity levels in NIDCM patients. STUDY TYPE: Retrospective. POPULATION: 352 NIDCM (T2DM-) patients (49.1 ± 14.6 years, 67% male) (207, 85, and 60 no/mild, moderate, and severe mitral regurgitation) and 96 NIDCM (T2DM+) patients (55.2 ± 12.4 years, 77% male) (47, 30, and 19 no/mild, moderate, and severe mitral regurgitation). FIELD STRENGTH/SEQUENCE: 3.0 T/balanced steady-state free precession sequence. ASSESSMENT: LV geometric parameters and strain were measured and compared among groups. Determinants of LV strain were investigated. STATISTICAL TEST: Student's t-test, Mann-Whitney U test, one-way ANOVA, Kruskal-Wallis test, univariable and multivariable linear regression. P < 0.05 was considered statistically significant. RESULTS: LV GLPS and longitudinal PDSR decreased gradually with increasing mitral regurgitation severity in NIDCM patients with T2DM(GLPS: -5.7% ± 2.1% vs. -4.3% ± 1.6% vs. -2.6% ± 1.3%; longitudinal PDSR:0.5 ± 0.2 sec-1 vs. 0.4 ± 0.2 sec-1 vs. 0.3 ± 0.1 sec-1). NIDCM (T2DM+) demonstrated decreased GCPS and GLPS in the no/mild subgroup, reduced LV GCPS, GLPS, and longitudinal PDSR in the moderate subgroup, and reduced GRPS, GCPS, GLPS, and longitudinal PDSR in the severe subgroup compared with NIDCM (T2DM-) patients. Multivariable regression analysis identified that mitral regurgitation severity (ß = -0.13, 0.15, and 0.25 for GRPS, GCPS, and GLPS) and the presence of T2DM (ß = 0.14 and 0.13 for GCPS and GLPS) were independent determinants of LV strains in NIDCM patients. DATA CONCLUSION: Increased mitral regurgitation severity is associated with reduced LV strains in NIDCM patients with T2DM. The presence of T2DM exacerbated the decline of LV function across various mitral regurgitation levels in NIDCM patients, resulting in reduced LV strains. TECHNICAL EFFICACY: Stage 3.
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BACKGROUND: Congenital unilateral renal agenesis (URA) is a kind of rare birth defect during fetal development with varies clinical phenotypes. The pathogenesis and the relationship between gene and phenotype are still unclear. METHODS: Ten URA fetuses were followed up after birth using postnatal renal ultrasound examination to confirm the diagnosis with nine children were URA and one was Renal Ectopy (RE). Trio- WES, CNV- seq were performed with the 10 children and their close relatives. RESULTS: There were 3 heterozygous variants of CHD7, PROKR2 and NRIP1 genes were identified in 3 children, respectively. CHD7 (c.2663T>C, p.M888T) is classified as likely pathogenic (LP), PROKR2 (c.685G>C, p.G229R) and NRIP1 (c.2705T>G, p.F902C) are classified as variants of uncertain significance (VUS). CHD7 (c.2663T>C, p.M888T) and PROKR2 (c.685G>C, p.G229R) as URA-related genes may be associated with idiopathic hypogonadotropic hypogonadism (IHH) or CHARGE syndrome (CS), and 3D-protein structure prediction revealed that the two variants may affect the stability in the CHD7 protein or PROKR2 protein, separately. The RE-related gene NRIP1 (c.2705T>G, p.F902C) may be causative of congenital anomalies of the kidneys and urinary tract (CAKUT). CONCLUSIONS: Identification of these variants can in exploring the etiology of URA or RE and improve the level of genetic counseling. IMPACTS: We performed trio-whole-exome sequencing (trio- WES) and copy number variation sequencing (CNV- seq) in 10 children, including 9 children with Unilateral Renal Agenesis and 1 with Renal Ectopy after birth. The possible pathogenic genes of URA can be screened using prenatal and postnatal diagnosis of URA fetuses and gene detection after birth. Future studies evaluating this association may lead to a better understanding of URA and elucidate exploring the etiology of URA or RE and improve the level of genetic counseling.
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Purinergic receptor P2Y11, a G protein-coupled receptor that is stimulated by extracellular ATP, has been demonstrated to be related to the chemotaxis of granulocytes, apoptosis of neutrophils, and secretion of cytokines in vitro. P2Y11 mutations were associated with narcolepsy. However, little is known about the roles of P2RY11 in the occurrence of narcolepsy and inflammatory response in vivo. In this study, we generated a zebrafish P2Y11 mutant using CRISPR/Cas9 genome editing and demonstrated that the P2Y11 mutant replicated the narcolepsy-like features including reduced HCRT expression and excessive daytime sleepiness, suggesting that P2Y11 is essential for HCRT expression. Furthermore, we accessed the cytokine expression in the mutant and revealed that the P2RY11 mutation disrupted the systemic inflammatory balance by reducing il4, il10 and tgfb, and increasing il6, tnfa, and il1b. In addition, the P2RY11-deficient larvae with caudal fin injuries exhibited significantly slower migration and less recruitment of neutrophils and macrophages at damaged site, and lower expression of anti-inflammatory cytokines during tissue damage. All these findings highlight the vital roles of P2RY11 in maintaining HCRT production and secreting anti-inflammatory cytokines in the native environment, and suggested that P2RY11-deficient zebrafish can serve as a reliable and unique model to further explore narcolepsy and inflammatory-related diseases with impaired neutrophil and macrophage responses.
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Citocinas , Inflamação , Macrófagos , Neutrófilos , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Neutrófilos/metabolismo , Neutrófilos/imunologia , Macrófagos/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Inflamação/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Citocinas/metabolismo , Mutação/genética , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2/deficiênciaRESUMO
BACKGROUND Sleep disorders are a common disease faced by people today and can lead to fatigue, lack of concentration, impaired memory, and even death. In recent years, the development of brain stimulation techniques has provided a new perspective for the treatment of sleep disorders. However, there is a lack of bibliometric analyses related to sleep disorders and brain stimulation techniques. Therefore, this study analyzed the application status and trend of brain stimulation technology in sleep disorder research. MATERIAL AND METHODS Articles and reviews published between 1999 and 2023 were retrieved from the Web of Science. CiteSpace was used to visually analyze the publications, countries, institutions, journals, authors, references, and keywords. RESULTS A total of 459 publications were obtained. The number of studies was shown to be on a general upward trend. The country with the largest number of publications was the United States; UDICE-French Research Universities had the highest number of publications; Neurology had the highest citation frequency; 90% of the top 10 references cited were from Journal Citation Reports Q1; Brigo was the author with the highest number of publications; and the most frequent keywords were "transcranial magnetic stimulation", "deep brain stimulation", and "Parkinson disease". CONCLUSIONS Our study used CiteSpace software to analyze 459 studies published since 1999 on brain stimulation techniques for the treatment of sleep disorders, revealing research trends and the current state of the field. Our results will help researchers to understand the existing research quickly and provide direction for future research.
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Bibliometria , Transtornos do Sono-Vigília , Humanos , Fadiga , Transtornos do Sono-Vigília/terapia , Tecnologia , EncéfaloRESUMO
BACKGROUND: Parentâchild communication in migrant families is essential to family bonds and the mental health of left-behind children (LBC). Little is known about the different patterns of communication between migrant parents and LBC and associated communication quality and mental health outcomes. METHODS: A sample of 2,183 Chinese children (mean age = 12.95 ± 1.29 years) from Anhui province, including LBC whose parents had both migrated (n = 1,025) and children whose parents had never migrated (never-LBC, n = 1,158), was analyzed. With the LBC sample, latent class analysis was applied to identify the patterns of parentâchild communication. Multinomial logistic regression analysis was conducted to assess the associations between the sociodemographic variables and class membership of LBC. Analysis of covariance and chi-square tests were used to compare communication quality and mental health outcome differences among the classes of LBC and between each of the classes and never-LBC. RESULTS: Five latent classes of communication formed through different media or channels between migrant parents and their LBC were identified. Higher household economic status (OR = 2.81, p < 0.05) was associated with adequate communication. LBC in Class 1, defined by frequent technologically-mediated and face-to-face communication, had a significantly higher quality of communication with their migrant parents (F = 8.92, p < 0.001) and better mental health than those in other latent classes; these children did not have significantly worse mental health outcomes compared to never -LBC. CONCLUSIONS: Facilitating multichannel parentâchild communication is a practical way of reducing mental health inequities between LBC and their peers.
Assuntos
Comunicação , Pais , Humanos , Criança , Adolescente , Relações Pais-Filho , China , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Entomopathogenic nematodes (EPNs) use the chemical cues emitted by insects and insect-damaged plants to locate their hosts. Steinernema carpocapsae, a species of EPN, is an established biocontrol agent used against insect pests. Despite its promising potential, the molecular mechanisms underlying its ability to detect plant volatiles remain poorly understood. In this study, we investigated the response of S. carpocapsae infective juveniles (IJs) to 8 different plant volatiles. Among these, carvone was found to be the most attractive volatile compound. To understand the molecular basis of the response of IJs to carvone, we used RNA-Seq technology to identify gene expression changes in response to carvone treatment. Transcriptome analysis revealed 721 differentially expressed genes (DEGs) between carvone-treated and control groups, with 403 genes being significantly upregulated and 318 genes downregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the responsive DEGs to carvone attraction were mainly involved in locomotion, localization, behavior, response to stimulus, and olfactory transduction. We also identified four upregulated genes of chemoreceptor and response to stimulus that were involved in the response of IJs to carvone attraction. Our results provide insights into the potential transcriptional mechanisms underlying the response of S. carpocapsae to carvone, which can be utilized to develop environmentally friendly strategies for attracting EPNs.
Assuntos
Monoterpenos Cicloexânicos , Insetos , Rabditídios , Animais , Rabditídios/fisiologiaRESUMO
Triadica sebifera (T. sebifera) has attracted much attention because of the high oil content in its seeds, but there are few systematic studies on the phenolic compounds of T. sebifera leaves (TSP). In this study, the extraction process of TSP was optimized by response surface methodology. The phenolic components of these extracts were analyzed by high-performance liquid chromatography (HPLC). Moreover, the effects of hot air drying (HD), vacuum drying (VD) and freeze drying (FD) on the antioxidant activity and characterization of T. sebifera leaf extract (TSLE) were evaluated. Under the conditions of ethanol concentration 39.8%, liquid-solid ratio (LSR) 52.1, extraction time 20.2 min and extraction temperature 50.6 °C, the maximum TSP yield was 111.46 mg GAE/g dw. The quantitative analysis and correlation analysis of eight compounds in TSP showed that the type and content of phenolic compounds had significant correlations with antioxidant activity, indicating that tannic acid, isoquercitrin and ellagic acid were the main components of antioxidant activities. In addition, through DPPH and ABTS determination, VD-TSLE and FD-TSLE showed strong scavenging ability, with IC50 values of 138.2 µg/mL and 135.5 µg/mL and 73.5 µg/mL and 74.3 µg/mL, respectively. Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) infrared spectroscopy revealed small differences in the extracts of the three drying methods. This study lays a foundation for the effective extraction process and drying methods of phenolic antioxidants from T. sebifera leaves, and is of great significance for the utilization of T. sebifera leaves.
Assuntos
Antioxidantes , Fenóis , Extratos Vegetais , Folhas de Planta , Folhas de Planta/química , Fenóis/química , Fenóis/isolamento & purificação , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Cromatografia Líquida de Alta PressãoRESUMO
A practical metal-free and additive-free approach for the synthesis of 6/7/8-membered oxacyclic ketone-fused isoxazoles/isoxazolines tetracyclic or tricyclic structures is reported through Csp3-H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones. This convenient approach enables the simultaneous formation of isoxazole/isoxazoline and 6/7/8-membered oxacyclic ketones to form polycyclic architectures by using tert-butyl nitrite (TBN) as a non-metallic radical initiator and N-O fragment donor.