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BACKGROUND: Long non-coding RNAs (LncRNAs) have been implicated as critical regulators of cancer tumorigenesis and progression. However, their functions and molecular mechanisms in colorectal cancer (CRC) still remain to be further elucidated. METHODS: LINC00460 was identified by differential analysis between human CRC and normal tissues and verified by in situ hybridization (ISH) and qRT-PCR. We investigated the biological functions of LINC00460 in CRC by in vitro and in vivo experiments. We predicted the mechanism and downstream functional molecules of LINC00460 by bioinformatics analysis, and confirmed them by dual luciferase reporter gene assay, RNA immunoprecipitation (RIP), RNA pull-down, etc. RESULTS: LINC00460 was found to be significantly overexpressed in CRC and associated with poor prognosis. Overexpression of LINC00460 promoted CRC cell immune escape and remodeled a suppressive tumor immune microenvironment, thereby promoting CRC proliferation and metastasis. Mechanistic studies showed that LINC00460 served as a molecular sponge for miR-186-3p, and then promoted the expressions of MYC, CD47 and PD-L1 to facilitate CRC cell immune escape. We also demonstrated that MYC upregulated LINC00460 expression at the transcriptional level and formed a positive feedback loop. CONCLUSIONS: The LINC00460/miR-186-3p/MYC feedback loop promotes CRC cell immune escape and subsequently facilitates CRC proliferation and metastasis. Our findings provide novel insight into LINC00460 as a CRC immune regulator, and provide a potential therapeutic target for CRC patients.
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Antígeno B7-H1 , Antígeno CD47 , Neoplasias Colorretais , MicroRNAs , RNA Longo não Codificante , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/imunologia , MicroRNAs/genética , Antígeno CD47/metabolismo , Antígeno CD47/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Camundongos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Animais , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Evasão Tumoral/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Masculino , Feminino , Proliferação de Células , Retroalimentação Fisiológica , Prognóstico , Camundongos NusRESUMO
BACKGROUND: A balanced protein homeostasis network helps cholangiocarcinoma (CCA) maintain their oncogenic growth, and disrupting proteostasis therapeutically will induce proteotoxic stress. Phosphatase and tensin homolog (PTEN) have been reported to be involved in proteostasis, and PTEN-associated pathways are commonly altered in CCA. Celastrol, a triterpene from plants, exhibits cytotoxic effects in various types of cancer. However, the underlying mechanisms remain unclear. PURPOSE: We investigated the therapeutic effect of celastrol in CCA and identified the molecular characteristics of tumors that were sensitive to celastrol. The target of celastrol was explored. We then evaluated the candidate combination therapeutic strategy to increase the effectiveness of celastrol in celastrol-insensitive CCA tumors. METHODS: Various CCA cells were categorized as either celastrol-sensitive or celastrol-insensitive based on their response to celastrol. The molecular characteristics of cells from different groups were determined by RNA-seq. PTEN status and its role in proteasome activity in CCA cells were investigated. The CMAP analysis, molecular docking, and functional assay were performed to explore the effect of celastrol on proteasome activities. The correlation between PTEN status and clinical outcomes, as well as proteasomal activity, were measured in CCA patients. The synergistic therapeutic effect of autophagy inhibitors on celastrol-insensitive CCA cells were measured. RESULTS: Diverse responses to celastrol were observed in CCA cells. PTEN expression varied among different CCA cells, and its status could impact cell sensitivity to celastrol: PTENhigh tumor cells were resistant to celastrol, while PTENlow cells were more sensitive. Celastrol induced proteasomal dysregulation in CCA cells by directly targeting PSMB5. Cells with low PTEN status transcriptionally promoted proteasome subunit expression in an AKT-dependent manner, making these cells more reliant on proteasomal activities to maintain proteostasis. This caused the PTENlow CCA cells sensitive to celastrol. A negative correlation was found between PTEN levels and the proteasome signature in CCA patients. Moreover, celastrol treatment could induce autophagy in PTENhigh CCA cells. Disrupting the autophagic pathway in PTENhigh CCA cells enhanced the cytotoxic effect of celastrol. CONCLUSION: PTEN status in CCA cells determines their sensitivity to celastrol, and autophagy inhibitors could enhance the anti-tumor effect in PTENhigh CCA.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , PTEN Fosfo-Hidrolase , Triterpenos Pentacíclicos , Triterpenos , Colangiocarcinoma/tratamento farmacológico , Triterpenos Pentacíclicos/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Humanos , Linhagem Celular Tumoral , Neoplasias dos Ductos Biliares/tratamento farmacológico , Triterpenos/farmacologia , Simulação de Acoplamento Molecular , Tripterygium/química , Antineoplásicos Fitogênicos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Bortezomib/farmacologiaRESUMO
INTRODUCTION: This study delineated the interrelationships between subclinical alterations in the left heart, cerebrospinal fluid (CSF), Alzheimer's disease (AD) biomarkers, and cognition. METHODS: Multiple linear regressions were conducted in 1244 cognitively normal participants (mean age = 65.5; 43% female) who underwent echocardiography (left atrial [LA] and left ventricular [LV] morphologic or functional parameters) and CSF AD biomarkers measurements. Mediating effects of AD pathologies were examined. Differences in cardiac parameters across ATN categories were tested using analysis of variance (ANOVA) and logistic regressions. RESULTS: LA or LV enlargement (characterized by increased diameters and volumes) and LV hypertrophy (increased interventricular septal or posterior wall thickness and ventricular mass) were associated with higher CSF phosphorylated (p)-tau and total (t)-tau levels, and poorer cognition. Tau pathologies mediated the heart-cognition relationships. Cardiac parameters were higher in stage 2 and suspected non-Alzheimer's pathology groups than controls. DISCUSSION: These findings suggested close associations of subclinical cardiac changes with tau pathologies and cognition. HIGHLIGHTS: Various subclinical alterations in the left heart related to poorer cognition. Subclinical cardiac changes related to tau pathologies in cognitively normal adults. Tau pathologies mediated the heart-cognition relationships. Subclinical cardiac changes related to the AD continuum, especially to stage 2. The accumulation of cardiac alterations magnified their damage to the brain.
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Doença de Alzheimer , Biomarcadores , Ecocardiografia , Proteínas tau , Humanos , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Feminino , Masculino , Biomarcadores/líquido cefalorraquidiano , Idoso , Proteínas tau/líquido cefalorraquidiano , Pessoa de Meia-Idade , Cognição/fisiologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologiaRESUMO
BACKGROUND: Cardiometabolic multimorbidity is associated with an increased risk of dementia, but the pathogenic mechanisms linking them remain largely undefined. We aimed to assess the associations of cardiometabolic multimorbidity with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology to enhance our understanding of the underlying mechanisms linking cardiometabolic multimorbidity and AD. METHODS: This study included 1464 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Cardiometabolic diseases (CMD) are a group of interrelated disorders such as hypertension, diabetes, heart diseases (HD), and stroke. Based on the CMD status, participants were categorized as CMD-free, single CMD, or CMD multimorbidity. CMD multimorbidity is defined as the coexistence of two or more CMDs. The associations of cardiometabolic multimorbidity and CSF biomarkers were examined using multivariable linear regression models with demographic characteristics, the APOE ε4 allele, and lifestyle factors as covariates. Subgroup analyses stratified by age, sex, and APOE ε4 status were also performed. RESULTS: A total of 1464 individuals (mean age, 61.80 years; age range, 40-89 years) were included. The markers of phosphorylated tau-related processes (CSF P-tau181: ß = 0.165, P = 0.037) and neuronal injury (CSF T-tau: ß = 0.065, P = 0.033) were significantly increased in subjects with CMD multimorbidity (versus CMD-free), but not in those with single CMD. The association between CMD multimorbidity with CSF T-tau levels remained significant after controlling for Aß42 levels. Additionally, significantly elevated tau-related biomarkers were observed in patients with specific CMD combinations (i.e., hypertension and diabetes, hypertension and HD), especially in long disease courses. CONCLUSIONS: The presence of cardiometabolic multimorbidity was associated with tau phosphorylation and neuronal injury in cognitively normal populations. CMD multimorbidity might be a potential independent target to alleviate tau-related pathologies that can cause cognitive impairment.
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Doença de Alzheimer , Diabetes Mellitus , Hipertensão , Adulto , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Apolipoproteína E4/líquido cefalorraquidiano , Multimorbidade , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidianoRESUMO
BACKGROUND: Liver cirrhosis (LC) is the highest risk factor for hepatocellular carcinoma (HCC) development worldwide. The efficacy of the guideline-recommended surveillance methods for patients with LC remains unpromising. METHODS: A total of 4367 LCs not previously known to have HCC and 510 HCCs from 16 hospitals across 11 provinces of China were recruited in this multi-center, large-scale, cross-sectional study. Participants were divided into Stage â cohort (510 HCCs and 2074 LCs) and Stage â ¡ cohort (2293 LCs) according to their enrollment time and underwent Tri-phasic CT/enhanced MRI, US, AFP, and cell-free DNA (cfDNA). A screening model called PreCar Score was established based on five features of cfDNA using Stage â cohort. Surveillance performance of PreCar Score alone or in combination with US/AFP was evaluated in Stage â ¡ cohort. FINDINGS: PreCar Score showed a significantly higher sensitivity for the detection of early/very early HCC (Barcelona stage A/0) in contrast to US (sensitivity of 51.32% [95% CI: 39.66%-62.84%] at 95.53% [95% CI: 94.62%-96.38%] specificity for PreCar Score; sensitivity of 23.68% [95% CI: 14.99%-35.07%] at 99.37% [95% CI: 98.91%-99.64%] specificity for US) (P < 0.01, Fisher's exact test). PreCar Score plus US further achieved a higher sensitivity of 60.53% at 95.08% specificity for early/very early HCC screening. INTERPRETATION: Our study developed and validated a cfDNA-based screening tool (PreCar Score) for HCC in cohorts at high risk. The combination of PreCar Score and US can serve as a promising and practical strategy for routine HCC care. FUNDING: A full list of funding bodies that contributed to this study can be found in Acknowledgments section.
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Carcinoma Hepatocelular , Ácidos Nucleicos Livres , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/epidemiologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/epidemiologia , alfa-Fetoproteínas , Estudos Transversais , Detecção Precoce de Câncer/métodos , Ultrassonografia/métodos , Cirrose Hepática/diagnóstico , Cirrose Hepática/complicações , Biomarcadores TumoraisRESUMO
Endoplasmic reticulum (ER) stress plays a key role in the pathogenesis of several organ damages. Studies show that excessive ER stress (ERS) can destroy cellular homeostasis, causing cell damage and physiological dysfunction in various organs. In recent years, Sirtuin1 (SIRT1) has become a research hotspot on ERS. Increasing evidence suggests that SIRT1 plays a positive role in various ERS-induced organ damage via multiple mechanisms, including inhibiting cellular apoptosis and promoting autophagy. SIRT1 can also alleviate liver, heart, lung, kidney, and intestinal damage by inhibiting ERS. We discuss the possible mechanism of SIRT1, explore potential therapeutic targets of diseases, and provide a theoretical basis for treating ERS-related diseases.
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Estresse do Retículo Endoplasmático , Sirtuína 1 , Tecidos , Apoptose , Humanos , Animais , Tecidos/metabolismo , Tecidos/patologiaRESUMO
To alleviate the growth inhibition, and intestinal damage of Chinese mitten crab (Eriocheir sinensis) induced by low fishmeal diets (LF), an 8-week feeding trial was conducted to evaluate the addition of dietary soybean-derived bioactive peptides (SBP) in LF diets on the regulation of growth, digestion and intestinal health. The crabs were fed isonitrogenous and isoenergetic conventional diet and LF diets (10 % fishmeal replaced by soybean meal, LF) supplemented with 0, 1 %, 2 %, 4 % and 6 % SBP, respectively. The results showed that LF diet inhibited growth while inclusion of SBP quadratically remitted the growth inhibition induced by LF. For digestive function, increasing addition level of SBP quadratically improved the α-amylase and trypsin activities. For antioxidant function, LF group significantly increased the malondialdehyde content, while SBP linearly decreased the malondialdehyde level and cubically increased the anti-superoxide anion activity and total antioxidant capacity level. For intestinal health, the peritrophic membrane (PM) almost completely separated from the inner wall of the intestinal lumen, the epithelial cells reduced, the muscularis became thinner and the apoptotic signals increased in LF group; with SBP addition, the intestinal morphology was improved, with the PM adhering to the inner wall of the intestinal lumen, an increase in the number of epithelial cells and an increase in the thickness of the muscularis. Additionally, there was a decrease in apoptotic signals. Dietary SBP also increased the expression of PT and Crustin1 quadratically and decreased the expression of ALF1 linearly, ALF3 and ILF2 quadratically.
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Antioxidantes , Glycine max , Antioxidantes/metabolismo , Imunidade Inata , Dieta/veterinária , Peptídeos/farmacologia , Malondialdeído , Ração Animal/análiseRESUMO
BACKGROUND: Myocardial infarction (MI) is one of the common causes of hospitalization and death all over the world. Maresin2 (MaR2), a specialized pro-solving mediator of inflammation, has been consolidated to be a novel cytokine fine-tuning inflammatory cascade. However, the precise mechanism is still unknown. Here, we demonstrated that maresin2 relieved myocardial damage via ULK1 O-GlcNAc modification during MI. METHODS: The myocardial infarction model was established by ligating the left anterior descending artery (LAD). Echocardiography, histopathology, transmission electron microscope, and Western blot were used to evaluate cardiac function and remodeling. Furthermore, primary neonatal rat cardiomyocytes (NRCMs) were cultivated, and immunoprecipitation (IP) assays were performed to explore the specific mechanism. RESULTS: As suggested, maresin2 treatment protected cardiac function and ameliorated adverse cardiac remodeling. Furthermore, we found that maresin2 facilitated autophagy and inhibited apoptosis under the modulation of O-GlcNAcylation-dependent ULK1 activation. Meanwhile, we discovered that maresin2 treatment ameliorated the inflammation of myocardial cells by inhibiting the interaction of TAK1 and TAB1. CONCLUSIONS: Maresin2 is likely to promote autophagy while relieving apoptosis and inflammation of myocardial cells, thereby exerting a protective effect on the heart after MI.
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Infarto do Miocárdio , Ratos , Animais , Infarto do Miocárdio/patologia , Miocárdio/patologia , Miócitos Cardíacos , Vasos Coronários/patologia , Inflamação/patologia , Remodelação Ventricular , Proteína Homóloga à Proteína-1 Relacionada à AutofagiaRESUMO
Studies have shown that multimorbidity may be associated with the Alzheimer's disease (AD) stages, but it has not been fully characterized in patients without dementia. A total of 1402 Han Chinese older adults without dementia from Chinese Alzheimer's Biomarker and LifestylE (CABLE) study were included and grouped according to their multimorbidity patterns, defined by the number of chronic disorders and cluster analysis. Multivariable linear regression models were used to detect the associations with AD-related cerebrospinal fluid (CSF) biomarkers. Multimorbidity and severe multimorbidity (≥4 chronic conditions) were significantly associated with CSF amyloid and tau levels (pFDR < 0.05). Metabolic patterns were significantly associated with higher levels of CSF Aß40 (ß = 0.159, pFDR = 0.036) and tau (P-tau: ß = 0.132, pFDR = 0.035; T-tau: ß = 0.126, pFDR = 0.035). The above associations were only significant in the cognitively normal (CN) group. Multimorbidity was associated with brain AD pathology before any symptomatic evidence of cognitive impairment. Identifying such high-risk groups might allow tailored interventions for AD prevention.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Doença de Alzheimer/diagnóstico , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Multimorbidade , Disfunção Cognitiva/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Estilo de Vida , Fragmentos de Peptídeos/líquido cefalorraquidianoRESUMO
Based on observations in China's east coastal oceans, we conducted a preliminary assessment of 16 sets of carbonic acid dissociation constants (K1* and K2*) by comparing spectrophotometrically measured pH values at 25 °C with those calculated from total alkalinity and dissolved inorganic carbon. We obtained that K1* and K2* often performed differently within different salinity ranges, and that the constants of Millero et al. (2002) (M02) demonstrated the best performance for the salinity range of 24-35. In contrast, the often recommended constants of Mehrbach et al. (1973) refit by Dickson and Millero (1987) (DM87-M) and Lucker et al. (2000) (L00) would underestimate pH at salinities of 24-30. This was mainly associated with the higher product of K1* and K2* by DM87-M and L00 than by M02 at this salinity range. Also, we found almost no differences between pH values calculated with DM87-M and L00.
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Carbono , Ácido Carbônico , Oceanos e Mares , Carbono/análise , Salinidade , ChinaRESUMO
BACKGROUND: Anaerobic fungi are effective fibre-degrading microorganisms in the digestive tract of horses. However, our understanding of their diversity and community structure is limited, especially in different parts of the gastrointestinal tract. RESULTS: For the first time, high-throughput sequencing technology was used to analyse and predict fungal microbial diversity in different parts of the gastrointestinal tract of Mongolian horses. The results revealed that the richness and diversity of fungi in the hindgut of Mongolian horses were much higher than those in the foregut. The foregut was dominated by Basidiomycota and Ascomycota, whereas the hindgut was dominated by Neocallimastigomycota and Basidiomycota. At the genus level, the relative abundance of many pathogenic fungi (Cryptococcus, Cladosporium, Alternaria, and Sarocladium) in the foregut was significantly higher than that in the posterior gut, indicating that Mongolian horses have strong disease resistance. The prediction of fungal function also showed significant differences in the fungal flora between the foregut and the hindgut. The fungi in Mongolian horses' foreguts were mainly pathologically nutritive and contained many animal and plant pathogens, particularly in the small intestine (jejunum and ileum). This indicates that the foregut may be the most important immune site in the digestive system of Mongolian horses, which explains the high disease resistance of Mongolian horses. The number of unassigned functional groups in the posterior gut was significantly higher than that in the anterior gut, indicating that the functions of fungal groups in the posterior gut have not been fully explored, and further studies are required in the future. CONCLUSIONS: Analysis of high-throughput sequencing results revealed that the fungal composition varied greatly among different gastrointestinal tract segments in Mongolian horses, whose hindgut contains many anaerobic fungi involved in plant cellulose degradation. This provides important basic data for studying fungal diversity in the digestive system of healthy horses, which can be used for the health assessment of horses and provides clues for further research on the disease resistance and digestive capacity of horses, as well as a reference for the early diagnosis of intestinal diseases and innovative treatment methods.
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Micobioma , Cavalos , Animais , Resistência à Doença , Íleo , Jejuno , DigestãoRESUMO
Introduction: Candida utilis (C. utilis) has been extensively utilized as human food or animal feed additives. With its ability to support heterologous gene expression, C. utilis proves to be a valuable platform for the synthesis of proteins and metabolites that possess both high nutritional and economic value. However, there remains a dearth of research focused on the characteristics of C. utilis through genomic, transcriptomic and metabolic approaches. Methods: With the aim of unraveling the molecular mechanism and genetic basis governing the biological process of C. utilis, we embarked on a de novo sequencing endeavor to acquire comprehensive sequence data. In addition, an integrated transcriptomic and metabolic phenotype analysis was performed to compare the wild-type C. utilis (WT) with a genetically engineered strain of C. utilis that harbors the heterologous δ-zein gene (RCT). Results: δ-zein is a protein rich in methionine found in the endosperm of maize. The integrated analysis of transcriptomic and metabolic phenotypes uncovered significant metabolic diversity between the WT and RCT C. utilis. A total of 252 differentially expressed genes were identified, primarily associated with ribosome function, peroxisome activity, arginine and proline metabolism, carbon metabolism, and fatty acid degradation. In the experimental setup using PM1, PM2, and PM4 plates, a total of 284 growth conditions were tested. A comparison between the WT and RCT C. utilis demonstrated significant increases in the utilization of certain carbon source substrates by RCT. Gelatin and glycogen were found to be significantly utilized to a greater extent by RCT compared to WT. Additionally, in terms of sulfur source substrates, RCT exhibited significantly increased utilization of O-Phospho-L-Tyrosine and L-Methionine Sulfone when compared to WT. Discussion: The introduction of δ-zein gene into C. utilis may lead to significant changes in the metabolic substrates and metabolic pathways, but does not weaken the activity of the strain. Our study provides new insights into the transcriptomic and metabolic characteristics of the genetically engineered C. utilis strain harboring δ-zein gene, which has the potential to advance the utilization of C. utilis as an efficient protein feed in agricultural applications.
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Effective condition monitoring and fault diagnosis of bearings can not only maximize the life of rolling bearings and prevent unexpected shutdowns caused by equipment failures but also eliminate unnecessary costs and waste caused by excessive maintenance. However, the existing deep-learning-based bearing fault diagnosis models have the following defects. First of all, these models have a large demand for fault data. Second, the previous models only consider that single-scale features are generally less effective in diagnosing bearing faults. Therefore, we designed a bearing fault data collection platform based on the Industrial Internet of Things, which is used to collect bearing status data from sensors in real time and feed it back into the diagnostic model. On the basis of this platform, we propose a bearing fault diagnosis model based on deep generative models with multiscale features (DGMMFs) to solve the above problems. The DGMMF model is a multiclassification model, which can directly output the abnormal type of the bearing. Specifically, the DGMMF model uses 4 different variational autoencoder models to augment the bearing data and integrates features of different scales. Compared with single-scale features, these multiscale features contain more information and can perform better. Finally, we conducted a large number of related experiments on the real bearing fault datasets and verified the effectiveness of the DGMMF model using multiple evaluation metrics. The DGMMF model has achieved the highest value under all metrics, among which the value of precision is 0.926, the value of recall is 0.924, the value of accuracy is 0.926, and the value of F1 score is 0.925.
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In the present study, the contents of seven active components [genipinic acid(GA), protocatechuic acid(PCA), neochlorogenic acid(NCA), chlorogenic acid(CA), cryptochlorogenic acid(CCA),(+)-pinoresinol di-O-ß-D-glucopyranosid(PDG), and(+)-pinoresinol 4'-O-ß-D-glucopyranoside(PG)] of Eucommiae Cortex in aortic vascular endothelial cells of spontaneously hypertensive rats(SHR) were simultaneously determined by ultra-high liquid chromatography-triple quadrupole mass spectrometry(UPLC-MS/MS). The qualified SHR models were selected. The primary aortic endothelial cells(VECs) of rats were separated and cultured by ligation and adherence, followed by subculture. After successful identification, an UPLC-MS/MS method for simultaneously determining the contents of GA, PCA, NCA, CA, CCA, PDG, PG in seven components of Eucommiae Cortex in VECs was established, including specificity, linearity, matrix effect, recovery, accuracy, precision and stability. The established method had the lo-west limit of quantification of 0.97-4.95 µg·L~(-1), accuracy of 87.26%-109.6%, extraction recovery of 89.23%-105.3%, matrix effect of 85.86%-106.2%, and stability of 86.00%-112.5%. Therefore, the established accurate UPLC-MS/MS method could rapidly and simultaneously determine the contents of the seven active components of Eucommiae Cortex in VECs of SHRs, which provided a refe-rence for the study of cellular pharmacokinetics of active components of Eucommiae Cortex extract.
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Células Endoteliais , Espectrometria de Massas em Tandem , Ratos , Animais , Ratos Endogâmicos SHR , Cromatografia Líquida , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodosRESUMO
In this work, an effective approach based on a nonlinear output frequency response function (NOFRF) and improved convolution neural network is proposed for analog circuit fault diagnosis. First, the NOFRF spectra, rather than the output of the system, are adopted as the fault information of the analog circuit. Furthermore, to further improve the accuracy and efficiency of analog circuit fault diagnosis, the batch normalization layer and the convolutional block attention module (CBAM) are introduced into the convolution neural network (CNN) to propose a CBAM-CNN, which can automatically extract the fault features from NOFRF spectra, to realize the accurate diagnosis of the analog circuit. The fault diagnosis experiments are carried out on the simulated circuit of Sallen-Key. The results demonstrate that the proposed method can not only improve the accuracy of analog circuit fault diagnosis, but also has strong anti-noise ability.
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Reservoir operation is an important part of basin water resources management. The rational use of reservoir operation scheme can not only enhance the capacity of flood control and disaster reduction in the basin, but also improve the efficiency of water use and give full play to the comprehensive role the reservoir. The conventional decision-making method of reservoir operation scheme is computationally large, subjectivity and difficult to capture the nonlinear relationship. To solve these problems, this paper proposes a reservoir operation scheme decision-making model IWGAN-IWOA-CNN based on artificial intelligence and deep learning technology. In view of the lack of data in the original reservoir operation scheme and the limited improvement of data characteristics by the traditional data augmentation algorithm, an improved generative adversarial network algorithm (IWGAN) is proposed. IWGAN uses the loss function which integrates Wasserstein distance, gradient penalty and difference item, and dynamically adds random noise in the process of model training. The whale optimization algorithm is improved by introducing Logistic chaotic mapping to initialize population, non-linear convergence factor and adaptive weights, and Levy flight perturbation strategy. The improved whale optimization algorithm (IWOA) is used to optimize hyperparameters of convolutional neural networks (CNN), so as to obtain the best parameters for model prediction. The experimental results show that the data generated by IWGAN has certain representation ability and high quality; IWOA has faster convergence speed, higher convergence accuracy and better stability; IWGAN-IWOA-CNN model has higher prediction accuracy and reliability of scheme selection.
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BACKGROUND: Cerebral small vessel disease (CSVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). OBJECTIVE: This study aimed to comprehensively investigated the associations of CSVD burden with cognition and AD pathologies. METHODS: A total of 546 non-demented participants (mean age, 72.1 years, range, 55-89; 47.4% female) were included. The longitudinal neuropathological and clinical correlates of CSVD burden were assessed using linear mixed-effects and Cox proportional-hazard models. Partial least squares structural equation model (PLS-SEM) was used to assess the direct and indirect effects of CSVD burden on cognition. RESULTS: We found that higher CSVD burden was associated with worse cognition (MMSE, ß=â-0.239, pâ=â0.006; MoCA, ß=â-0.493, pâ=â0.013), lower cerebrospinal fluid (CSF) Aß level (ß=â-0.276, pâ<â0.001) and increased amyloid burden (ß=â0.048, pâ=â0.002). In longitudinal, CSVD burden contributed to accelerated rates of hippocampus atrophy, cognitive decline, and higher risk of AD dementia. Furthermore, as the results of PLS-SEM, we observed both significant direct and indirect impact of advanced age (direct, ß=â-0.206, pâ<â0.001; indirect, ß=â-0.002, pâ=â0.043) and CSVD burden (direct, ß=â-0.096, pâ=â0.018; indirect, ß=â-0.005, pâ=â0.040) on cognition by Aß-p-tau-tau pathway. CONCLUSION: CSVD burden could be a prodromal predictor for clinical and pathological progression. Simultaneously, we found that the effects were mediated by the one-direction-only sequence of pathological biomarker changes starting with Aß, through abnormal p-tau, and neurodegeneration.
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Doença de Alzheimer , Doenças de Pequenos Vasos Cerebrais , Disfunção Cognitiva , Humanos , Feminino , Idoso , Masculino , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Disfunção Cognitiva/metabolismo , Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/metabolismo , Biomarcadores/líquido cefalorraquidiano , Progressão da DoençaRESUMO
BACKGROUND: Glucocorticoid-induced osteoporosis is the most common secondary cause of osteoporosis, which increases the risk of fracture. Long non-coding RNA telomerase RNA elements (TERC) has been proven to be closely related to osteoporosis. However, the role of TERC in glucocorticoid-induced osteoporosis and its underlying molecular mechanism remains unclear. METHODS: The in vitro model of osteoporosis was established after bone marrow mesenchymal stem cells (BMSCs) were exposed to dexamethasone (DEX). The cell viability, alkaline phosphatase (ALP) activity and mineralized nodules of BMSCs were evaluated. The messenger RNA and protein levels were detected by quantitative real-time polymerase chain reaction and Western blot. The interaction between TERC, enhancer of zeste homolog 2 (EZH2) and dickkopf-1 (DKK1) was confirmed by chromatin immunoprecipitation and RNA immunoprecipitation assays. RESULTS: Bone marrow mesenchymal stem cells were isolated, identified and induced osteogenic differentiation. The findings showed that the levels of osteogenic marker genes, including ALP, Runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN) in BMSCs were increased dependent on the osteogenic induction time. Similarly, TERC was significantly increased, but DKK1 was significantly decreased during BMSC osteogenic differentiation. Functional research showed that TERC overexpression promoted cell viability, ALP activity and mineralized nodules of BMSCs and increased the levels of osteogenic differentiation-related genes (ALP, RUNX2 and OCN), and TERC overexpression increased EZH2 protein level. Moreover, the decrease of cell viability, ALP activity and mineralized nodules induced by DEX was reversed by TERC overexpression. Furthermore, TERC inhibited DKK1 expression by promoting the histone modification of DKK1, and TERC overexpression alleviated DEX suppressed osteogenic differentiation of BMSCs by interaction with EZH2 to regulate DKK1. CONCLUSION: Our findings illustrated that TERC overexpression alleviated DEX-induced osteoporosis by recruiting EZH2 to regulate DKK1. Our research provided a novel direction for the treatment of glucocorticoid-induced osteoporosis.
Assuntos
MicroRNAs , Osteoporose , RNA Longo não Codificante , Humanos , Glucocorticoides/efeitos adversos , MicroRNAs/genética , RNA Longo não Codificante/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Osteogênese , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Osteoporose/induzido quimicamente , Osteoporose/genética , Diferenciação Celular , Células Cultivadas , Peptídeos e Proteínas de Sinalização Intercelular/genéticaRESUMO
BACKGROUND: In randomized studies, the strategy of pulmonary vein antral isolation (PVI) plus linear ablation has failed to increase success rates for persistent atrial fibrillation (PeAF) ablation when compared with PVI alone. Peri-mitral reentry related atrial tachycardia due to incomplete linear block is an important cause of clinical failures of a first ablation procedure. Ethanol infusion (EI) into the vein of Marshall (EI-VOM) has been demonstrated to facilitate a durable mitral isthmus linear lesion. OBJECTIVE: This trial is designed to compare arrhythmia-free survival between PVI and an ablation strategy termed upgraded '2C3L' for the ablation of PeAF. STUDY DESIGN: The PROMPT-AF study (clinicaltrials.gov 04497376) is a prospective, multicenter, open-label, randomized trial using a 1:1 parallel-control approach. Patients (n = 498) undergoing their first catheter ablation of PeAF will be randomized to either the upgraded '2C3L' arm or PVI arm in a 1:1 fashion. The upgraded '2C3L' technique is a fixed ablation approach consisting of EI-VOM, bilateral circumferential PVI, and 3 linear ablation lesion sets across the mitral isthmus, left atrial roof, and cavotricuspid isthmus. The follow-up duration is 12 months. The primary end point is freedom from atrial arrhythmias of >30 seconds, without antiarrhythmic drugs, in 12 months after the index ablation procedure (excluding a blanking period of 3 months). CONCLUSIONS: The PROMPT-AF study will evaluate the efficacy of the fixed '2C3L' approach in conjunction with EI-VOM, compared with PVI alone, in patients with PeAF undergoing de novo ablation.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Humanos , Fibrilação Atrial/cirurgia , Veias Pulmonares/cirurgia , Estudos Prospectivos , Átrios do Coração/cirurgia , Etanol , Ablação por Cateter/métodos , Resultado do Tratamento , RecidivaRESUMO
BACKGROUND: There are controversies surrounding the effects of lung function decline on cognitive impairment and dementia. OBJECTIVE: We conducted a meta-analysis and systematic review to explore the associations of lung function decline with the risks of cognitive impairment and dementia. METHODS: The PubMed, EMBASE, and the Cochrane Library were searched to identify prospective studies published from database inception through January 10, 2023. We pooled relative risk (RR) and 95% confidence intervals (CI) using random-effects models. The Egger test, funnel plots, meta-regression, sensitivity, and subgroup analyses were conducted to detect publication bias and investigate the source of heterogeneity. RESULTS: Thirty-three articles with a total of 8,816,992 participants were subjected to meta-analysis. Poorer pulmonary function was associated with an increased risk of dementia (FEV: RRâ=â1.25 [95% CI, 1.17-1.33]; FVC: RRâ=â1.40 [95% CI, 1.16-1.69]; PEF: RRâ=â1.84 [95% CI, 1.37-2.46]). The results of the subgroup analyses were similar to the primary results. Individuals with lung diseases had a higher combined risk of dementia and cognitive impairment (RRâ=â1.39 [95% CI, 1.20-1.61]). Lung disease conferred an elevated risk of cognitive impairment (RRâ=â1.37 [95% CI, 1.14-1.65]). The relationship between lung disease and an increased risk of dementia was only shown in total study participants (RRâ=â1.32 [95% CI, 1.11-1.57]), but not in the participants with Alzheimer's disease (RRâ=â1.39 [95% CI, 1.00-1.93]) or vascular dementia (RRâ=â2.11 [95% CI, 0.57-7.83]). CONCLUSION: Lung function decline was significantly associated with higher risks of cognitive impairment and dementia. These findings might provide implications for the prevention of cognitive disorders and the promotion of brain health.