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Genomic studies of lung adenocarcinoma (LUAD) have advanced our understanding of the disease's biology and accelerated targeted therapy. However, the proteomic characteristics of LUAD remain poorly understood. We carried out a comprehensive proteomics analysis of 103 cases of LUAD in Chinese patients. Integrative analysis of proteome, phosphoproteome, transcriptome, and whole-exome sequencing data revealed cancer-associated characteristics, such as tumor-associated protein variants, distinct proteomics features, and clinical outcomes in patients at an early stage or with EGFR and TP53 mutations. Proteome-based stratification of LUAD revealed three subtypes (S-I, S-II, and S-III) related to different clinical and molecular features. Further, we nominated potential drug targets and validated the plasma protein level of HSP 90ß as a potential prognostic biomarker for LUAD in an independent cohort. Our integrative proteomics analysis enables a more comprehensive understanding of the molecular landscape of LUAD and offers an opportunity for more precise diagnosis and treatment.
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Adenocarcinoma del Pulmón/metabolismo , Neoplasias Pulmonares/metabolismo , Proteómica , Adenocarcinoma del Pulmón/genética , Pueblo Asiatico/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Sistemas de Liberación de Medicamentos , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Mutación/genética , Estadificación de Neoplasias , Fosfoproteínas/metabolismo , Análisis de Componente Principal , Pronóstico , Proteoma/metabolismo , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND & AIMS: Accumulating evidence has indicated the presence of mature microRNAs (miR) in the nucleus, but their effects on steatohepatitis remain elusive. We have previously demonstrated that the intranuclear miR-204-3p in macrophages protects against atherosclerosis, which shares multiple risk factors with metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we aimed to explore the functional significance of miR-204-3p in steatohepatitis. METHODS: miR-204-3p levels and subcellular localization were assessed in the livers and peripheral blood mononuclear cells of patients with MASLD. Wild-type mice fed high-fat or methionine- and choline-deficient diets were injected with an adeno-associated virus system containing miR-204-3p to determine the effect of miR-204-3p on steatohepatitis. Co-culture systems were applied to investigate the crosstalk between macrophages and hepatocytes or hepatic stellate cells (HSCs). Multiple high-throughput epigenomic sequencings were performed to explore miR-204-3p targets. RESULTS: miR-204-3p expression decreased in livers and macrophages in mice and patients with fatty liver. In patients with MASLD, miR-204-3p levels in peripheral blood mononuclear cells were inversely related to the severity of hepatic inflammation and damage. Macrophage-specific miR-204-3p overexpression reduced steatohepatitis in high-fat or methionine- and choline-deficient diet-fed mice. miR-204-3p-overexpressing macrophages inhibited TLR4/JNK signaling and pro-inflammatory cytokine release, thereby limiting fat deposition and inflammation in hepatocytes and fibrogenic activation in HSCs. Epigenomic profiling identified miR-204-3p as a specific regulator of ULK1 expression. ULK1 transcription and VPS34 complex activation by intranuclear miR-204-3p improved autophagic flux, promoting the anti-inflammatory effects of miR-204-3p in macrophages. CONCLUSIONS: miR-204-3p inhibits macrophage inflammation, coordinating macrophage actions on hepatocytes and HSCs to ameliorate steatohepatitis. Macrophage miR-204-3p may be a therapeutic target for MASLD. IMPACT AND IMPLICATIONS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic inflammatory disease ranging from simple steatosis to steatohepatitis. However, the molecular mechanisms underlying the progression of MASLD remain incompletely understood. Here, we demonstrate that miR-204-3p levels in circulating peripheral blood mononuclear cells are negatively correlated with disease severity in patients with MASLD. Nuclear miR-204-3p activates ULK1 transcription and improves autophagic flux, limiting macrophage activation and hepatic steatosis. Our study provides a novel understanding of the mechanism of macrophage autophagy and inflammation in steatohepatitis and suggests that miR-204-3p may act as a potential therapeutic target for MASLD.
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Hígado Graso , MicroARNs , Animales , Ratones , Homólogo de la Proteína 1 Relacionada con la Autofagia , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Hígado Graso/metabolismo , Hígado Graso/genética , Hígado Graso/etiología , Hepatocitos/metabolismo , Hígado/metabolismo , Hígado/patología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genéticaRESUMEN
PURPOSE OF REVIEW: The effect of continuous positive airway pressure (CPAP) on resistant hypertension in patients at high risk with obstructive sleep apnea (OSA) needs further investigation. We aimed to determine the effect of CPAP on blood pressure in patients with resistant hypertension and OSA. Databases including PubMed, EMBASE, MEDLINE, the Cochrane Library, and CMB were searched. Data were pooled using a random-effects or fixed-effects model to derive weighted mean differences (WMDs) and 95% confidence intervals (CIs). RECENT FINDINGS: A total of 12 trials and 718 participants were included. Compared with control, CPAP significantly reduced 24-h systolic blood pressure (SBP) (WMD: - 5.92 mmHg [ - 8.72, - 3.11]; Pï¼0.001), 24-h diastolic blood pressure (DBP) (WMD: - 4.44 mmHg [- 6.26 , - 2.62]; P ï¼0.001), daytime SBP (WMD: - 5.76 mmHg [ - 9.16, - 2.36]; P ï¼0.001), daytime DBP (WMD: - 3.92 mmHg [- 5.55, - 2.30]; nighttime SBP (WMD: - 4.87 mmHg [ - 7.96 , - 1.78]; P = 0.002), and nighttime DBP (WMD: - 2.05 mmHg [- 2.99, - 1.11]; Pï¼0.001) in patients with resistant hypertension and OSA. CPAP improved the blood pressure both in the short (ï¼3 months) and long term (≥ 3 months). No significant impact on mean heart rate was noted (WMD: -2.76 beats per min [- 7.50, 1.97]; P = 0.25). CPAP treatment was associated with BP reduction in patients with resistant hypertension and OSA.
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Presión Sanguínea , Presión de las Vías Aéreas Positiva Contínua , Hipertensión , Apnea Obstructiva del Sueño , Humanos , Apnea Obstructiva del Sueño/terapia , Apnea Obstructiva del Sueño/fisiopatología , Apnea Obstructiva del Sueño/complicaciones , Presión de las Vías Aéreas Positiva Contínua/métodos , Hipertensión/fisiopatología , Hipertensión/terapia , Presión Sanguínea/fisiología , Resultado del Tratamiento , Antihipertensivos/uso terapéuticoRESUMEN
Microorganisms in deep-sea hydrothermal vents provide valuable insights into life under extreme conditions. Mass spectrometry-based proteomics has been widely used to identify protein expression and function. However, the metaproteomic studies in deep-sea microbiota have been constrained largely by the low identification rates of protein or peptide. To improve the efficiency of metaproteomics for hydrothermal vent microbiota, we firstly constructed a microbial gene database (HVentDB) based on 117 public metagenomic samples from hydrothermal vents and proposed a metaproteomic analysis strategy, which takes the advantages of not only the sample-matched metagenome, but also the metagenomic information released publicly in the community of hydrothermal vents. A two-stage false discovery rate method was followed up to control the risk of false positive. By applying our community-supported strategy to a hydrothermal vent sediment sample, about twice as many peptides were identified when compared with the ways against the sample-matched metagenome or the public reference database. In addition, more enriched and explainable taxonomic and functional profiles were detected by the HVentDB-based approach exclusively, as well as many important proteins involved in methane, amino acid, sugar, glycan metabolism and DNA repair, etc. The new metaproteomic analysis strategy will enhance our understanding of microbiota, including their lifestyles and metabolic capabilities in extreme environments. The database HVentDB is freely accessible from http://lilab.life.sjtu.edu.cn:8080/HventDB/main.html.
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Respiraderos Hidrotermales/microbiología , Metagenoma , Metagenómica/métodos , Microbiota/genética , Péptidos/genética , Proteogenómica/métodos , Proteoma/genética , Secuencia de Aminoácidos/genética , ADN Ribosómico/genética , Bases de Datos Genéticas , Genes Microbianos , FilogeniaRESUMEN
OBJECTIVE: This study aims to investigate the association of lysine methyltransferase 2 C (MLL3) and transforming growth factor ß (TGF-ß) signaling-related gene polymorphisms with the susceptibility of Stanford type B aortic dissection (AD) and its clinical prognostic outcomes. The methods involved investigating the MLL3 (rs10244604, rs6963460, rs1137721), TGFß1 (rs1800469), TGFß2 (rs900), TGFR1 (rs1626340) and TGFR2 (rs4522809) gene polymorphisms. Logistic regression was performed to investigate the association between 7 single nucleotide gene polymorphisms (SNPs) and Stanford type B aortic dissection. The GMDR software was used to analyze gene-gene and gene-environment interactions. The odds ratio (OR) with a 95% confidence interval (CI) was employed to evaluate the association of genes and Stanford type B AD risk. RESULTS: Genotypes and allele distributions in the case and control groups showed significant differences (P < 0.05). Logistic regression has shown that the Stanford Type B AD risk was highest in individuals with the rs1137721 CT genotype (OR = 4.33, 95% CI = 1.51-12.40). Additionally, WBC, drinking, hypertension, triglycerides (TG), and low-density lipoprotein (LDL-C) were independent risk factors for Stanford Type B AD. Logistic regression showed that the Stanford Type B AD risk was highest in individuals with the MLL3 (rs1137721)-TT + CT and TGFß1 (rs4522809)-AA genotype (OR = 6.72, 95% CI = 1.56-29.84), and lowest in those with the MLL3 (rs1137721)-CC and TGFß1 (rs4522809)-AA + GG genotype (OR = 4.38, 95% CI = 0.92-20.83). However, the 55-month median long-term follow-up did not show statistical significance. CONCLUSION: Carriers of both TT + CT of MLL3 (rs1137721) and AA of TGFß1 (rs4522809) polymorphisms may be closely related to the development of Stanford type B AD. MLL3 (rs1137721), WBC, and TG/TC were found to be associated with the morbidity of Stanford type B AD. MLL3 (KMT2C) is associated with the TGF-ß signaling pathway protein. The risk of Stanford type B AD is related to the interactions of gene-gene and gene-environment.
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Disección Aórtica , Proteínas de Unión al ADN , Factor de Crecimiento Transformador beta1 , Humanos , Disección Aórtica/genética , Polimorfismo de Nucleótido Simple , Pronóstico , Transducción de Señal , Proteínas de Unión al ADN/genética , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
To investigate the association of myosin heavy chain protein 11 (MYH11) and transforming growth factor ß signaling-related gene polymorphisms with the susceptibility of DeBakey type III aortic dissection (AD) and its clinical outcomes. Four single-nucleotide polymorphism (SNPs) (MYH11 rs115364997, rs117593370, TGFB1 rs1800469, and TGFBR1 rs1626340) were analyzed in patients with DeBakey III AD (173) and healthy participants (335). Gene-gene and gene-environment interactions were evaluated using generalized multifactor dimensionality reduction. The patients were followed up for a median of 55.7 months. MYH11 rs115364997 G or TGFBR1 rs1626340 A carriers had an increased risk of DeBakey type III AD. MYH11, TGFB1, TGFBR1, and environment interactions contributed to the risk of DeBakey type III AD (cross-validation consistency = 10/10, P = 0.001). Dominant models of MYH11 rs115364997 AG + GG genotype (HR = 2.443; 95%CI: 1.096-5.445, P = 0.029), TGFB1 rs1800469 AG + GG (HR = 2.303; 95%CI: 1.069-4.96, P = 0.033) were associated with an increased risk of mortality in DeBakey type III AD. The dominant model of TGFB1 rs1800469 AG + GG genotype was associated with an increased risk of recurrence of chest pain in DeBakey type III AD (HR = 1.566; 95%CI: 1.018-2.378, P = 0.041). In conclusions, G carriers of MYH11 rs115364997 or TGFB1 rs1800469 may be the poor prognostic indicators of mortality and recurrent chest pain in DeBakey type III AD. The interactions of gene-gene and gene-environment are associated with the risk of DeBakey type III AD.
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Disección Aórtica , Cadenas Pesadas de Miosina/genética , Polimorfismo de Nucleótido Simple , Receptor Tipo I de Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta1/genética , Disección Aórtica/genética , Disección Aórtica/patología , Dolor en el Pecho/genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Cadenas Pesadas de Miosina/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
ABSTRACT: We aim to investigate whether genetic variants of the Fibrillin-1 (FBN1) gene were associated with DeBakey type III aortic dissection (AD) and its clinical prognosis in Chinese Han population. Three single-nucleotide polymorphisms (SNPs) (rs145233125, rs11070646, rs201170905) in FBN1 were analyzed in patients with DeBakey type III AD (159) and healthy subjects (216). Gene-environment interactions were evaluated to use generalized multifactor dimensionality reduction. Haplotype analysis of the 3 SNPs in the FBN1 gene was performed by Haploview software. Patients were followed up for average 4 years. G carriers of rs11070646 and rs201170905 in FBN1 have an increased risk of DeBakey type III AD. The interaction of FBN1 and environmental factors facilitated to the increased risk of DeBakey type III AD (cross-validation consistency = 10/10, P = 0.001). One of the most common haplotypes revealed an increased risk of DeBakey type III AD (CGG, P = 0.009). Recessive models of rs145233125 CC genotype ( P < 0.05) and rs201170905 GG genotype ( P < 0.001) were associated with an increased risk of death and recurrent chest pain of DeBakey type III AD. In conclusions, FBN1 gene polymorphisms contribute to DeBakey type III AD susceptibility. The interactions of gene and environment are related with the risk of DeBakey type III AD. C carriers of rs145233125 and G carriers of rs201170905 may be the adverse prognostic indicators of death and recurrent chest pain in DeBakey type III AD.
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Disección Aórtica , Fibrilina-1/genética , Predisposición Genética a la Enfermedad , Disección Aórtica/diagnóstico , Disección Aórtica/genética , Estudios de Casos y Controles , Dolor en el Pecho , China/epidemiología , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , PronósticoRESUMEN
BACKGROUND: It is unknown whether an abnormal level of von Willebrand factor (vWF) is correlated with the prognosis of patients with atrial fibrillation (AF) and current findings are controversial. This meta-analysis aimed to evaluate the association between vWF levels and the clinical prognosis of patients with AF. METHODS: We searched prospective cohort studies on PubMed, Embase, Web of Science, Cochrane Library and WanFang databases for vWF and adverse events of AF from inception of the databases to July 2019. The risk ratios of all-cause death, cardiovascular death, major adverse cardiac events (MACE), stroke and bleeding prognosis in patients with AF were analysed using a fixed-effects model or random-effects model, and all included studies were evaluated with heterogeneity and publication bias analysis. RESULTS: Twelve studies which included 7449 patients with AF were used in the meta-analysis. The average age was 71.3 years and the average follow-up time was 3.38 years. The analysis found that high vWF levels were associated with increased risks of all-cause death (RR 1.56; 95% CI 1.16 to 2.11, p=0.00400), cardiovascular death (RR 1.91; 95% CI 1.20 to 3.03, p=0.00600), MACE (RR 1.83; 95% CI 1.28 to 2.62, p=0.00090), stroke (RR 1.69; 95% CI 1.08 to 2.64, p=0.02000) and bleeding (RR 2.01; 95% CI 1.65 to 2.45, p<0.00001) in patients with AF. CONCLUSIONS: vWF is a risk factor for poor prognosis of AF, and patients with higher vWF levels have a higher risk of all-cause death, cardiovascular death, MACE, stroke and bleeding.
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Fibrilación Atrial/sangre , Factor de von Willebrand/análisis , Biomarcadores/análisis , Causas de Muerte , Humanos , Pronóstico , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Sedation with dexmedetomidine and propofol may cause hypotension or bradycardia. This study aimed to compare the effects of dexmedetomidine and propofol on hemodynamics and clinical outcomes in surgical intensive care unit (ICU) patients after major abdominal surgery. MATERIALS AND METHODS: Enrolled patients were randomly allocated to the dexmedetomidine or propofol group. Cardiac index was measured using a continuous noninvasive cardiac output monitor on the basis of chest bioreactance. Heart rate, blood pressure, opioid requirement, urine output, delirium incidence, ICU length of stay, and total hospital length of stay were compared between the two groups. The incidences of bradycardia, hypotension, and severe low cardiac index were compared. RESULTS: We enrolled 60 patients. Heart rate and mean arterial pressure were significantly lower in the dexmedetomidine group than in the propofol group. Cardiac index did not differ significantly between the two groups (dexmedetomidine group 3.1 L/min/m2, [95% confidence interval {95% CI} 2.8-3.3] versus propofol group 3.2 L/min/m2 [95% CI 2.9-3.5], P = 0.578). The incidences of bradycardia, hypotension, and severe low cardiac index did not differ significantly between the two groups. CONCLUSIONS: Cardiac index did not differ significantly between the dexmedetomidine and propofol groups in surgical ICU patients after major abdominal surgery.
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Dexmedetomidina/efectos adversos , Hemodinámica/efectos de los fármacos , Dolor Postoperatorio/tratamiento farmacológico , Propofol/efectos adversos , Procedimientos Quirúrgicos Operativos/efectos adversos , Anciano , Anciano de 80 o más Años , Analgésicos Opioides/uso terapéutico , Bradicardia/inducido químicamente , Bradicardia/epidemiología , Cuidados Críticos/métodos , Cuidados Críticos/estadística & datos numéricos , Enfermedad Crítica/terapia , Delirio/epidemiología , Delirio/etiología , Delirio/prevención & control , Femenino , Humanos , Hipotensión/inducido químicamente , Hipotensión/epidemiología , Incidencia , Unidades de Cuidados Intensivos/estadística & datos numéricos , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Manejo del Dolor/efectos adversos , Manejo del Dolor/métodos , Manejo del Dolor/estadística & datos numéricos , Dimensión del Dolor , Dolor Postoperatorio/diagnóstico , Dolor Postoperatorio/etiología , Cuidados Posoperatorios/efectos adversos , Cuidados Posoperatorios/métodos , Cuidados Posoperatorios/estadística & datos numéricos , Resultado del TratamientoRESUMEN
Static magnetic field (SMF) plays important roles in various biological processes of many organisms including plants, though the molecular mechanism remains largely unclear. Here in this study, we evaluated different magnetic setups to test their effects on growth and development on Arabidopsis (Arabidopsis thaliana), and discovered that plant growth was significantly enhanced by inhomogeneous SMF generated by a regular triangular prism magnet perpendicular to the direction of gravity. Comparative transcriptomic analysis revealed that auxin synthesis and signal transduction genes were upregulated by SMF exposure. SMF also facilitated plants to maintain the iron homeostasis. The expression of iron metabolism-related genes was downregulated by SMF, however, the iron content in plant tissues remains relatively unchanged. Furthermore, SMF exposure also helped the plants to reduce ROS level and synergistically maintain the oxidant balance by enhanced activity of antioxidant enzymes and accumulation of nicotinamide. Taken together, our data suggested that SMF is involved in regulating the growth and development of Arabidopsis thaliana through maintaining iron homeostasis and balancing oxidative stress, which could be beneficial for plant survival and growth. The work presented here would extend our understanding of the mechanism and the regulatory network of how magnetic field affects the plant growth, which would provide insights into the development of novel plant synthetic biology technologies to engineer stress-resistant and high-yielding crops.
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The objective of this study is to investigate whether common genetic variants of the LTBP4 gene are linked to the susceptibility of sudden cardiac death in individuals who have atherosclerotic coronary artery disease (SCD-CAD) in Chinese populations. A total of 208 SCD-CAD cases and 638 controls were included in the analysis, and logistic regression was employed to assess the association between a 4-bp insertion/deletion polymorphism (rs34005443) within LTBP4 and the susceptibility to SCD-CAD among Chinese individuals. Logistic regression analysis demonstrated a notable association between the insertion allele of rs34005443 and an escalated susceptibility to SCD-CAD [odds ratio (OR) = 1.434; 95 % confidence interval:1.14-1.80; P = 1.79 × 10-3]. Genotype-phenotype correlation analysis was performed using Genotype-Tissue expression (GTEx) database and further validated by human myocardium using qPCR. Correlation analysis revealed that LTBP4 expression level was lower in samples with the insertion allele. Furthermore, the dual-luciferase activity assays indicated that rs34005443 may play a regulatory role. Additionally, we predicted 30 transcription factors that are likely to bind to rs34005443 and its highly linked genetic variants via 3DSNP database. Subsequent GO and KEGG analysis indicated that these transcription factors have a significant function in regulating gene expression. Finally, PPI network analysis suggested a tight connection between LTBP4 proteins and TGFßs, highlighting these genes as potential hub genes in the context of SCD-CAD. In summary, our study revealed that rs34005443 might contribute to SCD-CAD susceptibility by regulating LTBP4 expression. These findings revealed that this indel could be a potentially functional marker for molecular diagnosis and risk stratification of SCD-CAD.
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Enfermedad de la Arteria Coronaria , Muerte Súbita Cardíaca , Predisposición Genética a la Enfermedad , Proteínas de Unión a TGF-beta Latente , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Alelos , Estudios de Casos y Controles , China/epidemiología , Enfermedad de la Arteria Coronaria/genética , Muerte Súbita Cardíaca/etiología , Pueblos del Este de Asia/genética , Estudios de Asociación Genética , Genotipo , Mutación INDEL , Proteínas de Unión a TGF-beta Latente/genética , Modelos LogísticosRESUMEN
Porcine reproductive and respiratory syndrome (PRRS) is an epidemic animal infectious disease worldwide, causing huge economic losses to the global swine industry. Fas-associated death domain (FADD) was previously reported to be an adaptor protein that functions in transferring the apoptotic signals regulated by the death receptors. In the current study, we unravel its unidentified role in promoting type I interferon (IFN) production during PRRS virus (PRRSV) infection. We identified that FADD inhibited PRRSV infection via promotion of type I IFN transcription. Overexpression of FADD suppressed the replication of PRRSV, while knockout of FADD increased viral titer and nucleocapsid protein expression. Mechanistically, FADD promoted mitochondrial antiviral signaling protein (MAVS)-mediated production of IFN-ß and some IFN-stimulated genes (ISGs). Furthermore, FADD exerted anti-PRRSV effects in a MAVS-dependent manner and increased the type I IFN signaling during PRRSV infection. This study highlights the importance of FADD in PRRSV replication, which may have implications for the future control of PRRS.
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Magnetic sense, or termed magnetoreception, has evolved in a broad range of taxa within the animal kingdom to facilitate orientation and navigation. MagRs, highly conserved A-type iron-sulfur proteins, are widely distributed across all phyla and play essential roles in both magnetoreception and iron-sulfur cluster biogenesis. However, the evolutionary origins and functional diversification of MagRs from their prokaryotic ancestor remain unclear. In this study, MagR sequences from 131 species, ranging from bacteria to humans, were selected for analysis, with 23 representative sequences covering species from prokaryotes to Mollusca, Arthropoda, Osteichthyes, Reptilia, Aves, and mammals chosen for protein expression and purification. Biochemical studies revealed a gradual increase in total iron content in MagRs during evolution. Three types of MagRs were identified, each with distinct iron and/or iron-sulfur cluster binding capacity and protein stability, indicating continuous expansion of the functional roles of MagRs during speciation and evolution. This evolutionary biochemical study provides valuable insights into how evolution shapes the physical and chemical properties of biological molecules such as MagRs and how these properties influence the evolutionary trajectories of MagRs.
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Proteínas Hierro-Azufre , Animales , Proteínas Hierro-Azufre/genética , Proteínas Hierro-Azufre/metabolismo , Proteínas Hierro-Azufre/química , Evolución Biológica , Evolución Molecular , Filogenia , Hierro/metabolismoRESUMEN
Lysophosphoglycerides (LPLs) have been reported to accumulate in myocardium and serve as a cause of arrhythmias in acute myocardial ischemia. However, in this study we found that LPLs level in the ventricular myocardium was decreased by the onset of acute myocardial ischemia in vivo in rats. Decreasing of LPLs level in left ventricular myocardium, but not right, was observed within 26 min of left myocardial ischemia, regardless of whether arrhythmias were triggered. Lower LPLs level in the ventricular myocardium was also observed in aconitine-simulated ventricular fibrillation (P < 0.0001) and ouabain-simulated III° atrioventricular block (P < 0.0001). Shot-lasting electric shock, e.g., ≤ 40 s, decreased LPLs level, while long-lasting, e.g., 5 min, increased it (fold change = 2.27, P = 0.0008). LPLs accumulation was observed in long-lasting myocardial ischemia, e.g., 4 h (fold change = 1.20, P = 0.0012), when caspase3 activity was elevated (P = 0.0012), indicating increased cell death, but not coincided with higher frequent arrhythmias. In postmortem human ventricular myocardium, differences of LPLs level in left ventricular myocardium was not observed among coronary artery disease- and other heart diseases-caused sudden death and non-heart disease caused death. LPLs level manifested a remarkable increasing from postmortem 12 h on in rats, thus abolishing the potential for serving as biomarkers of sudden cardiac death. Token together, in this study we found that LPLs in ventricular myocardium were initially decreased by the onset of ischemia, LPLs accumulation do not confer arrhythmogenesis during acute myocardial ischemia. It is necessary to reassess the roles of LPLs in myocardial infarction.
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Arritmias Cardíacas , Ventrículos Cardíacos , Isquemia Miocárdica , Miocardio , Animales , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patología , Ratas , Masculino , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/etiología , Humanos , Miocardio/metabolismo , Miocardio/patología , Fibrilación Ventricular/metabolismo , Fibrilación Ventricular/etiología , Fibrilación Ventricular/patología , Aconitina/análogos & derivados , Modelos Animales de Enfermedad , Ouabaína/farmacología , Ouabaína/metabolismoRESUMEN
OBJECTIVES: To evaluate the cardiovascular safety of COVID-19 vaccines in the real world. METHODS: Studies reported on any COVID-19 vaccine-related cardiovascular events in the population aged ≥12 years between 1 January 2020 and 15 June 2022 were included. RESULTS: A total of 42 studies were included in this meta-analysis. Myocarditis risk was mainly seen after the second (risk ratio [RR], 2.09; 95% confidence interval [CI]: 1.59-2.58) and third (RR, 2.02; 95% CI: 1.04-2.91) dose. A total of 5 vaccines were analyzed, among which mRNA-1273 (RR, 3.13; 95% CI: 2.11-4.14) and BNT162b2 (RR, 1.57; 95% CI: 1.30-1.85) vaccines were associated with myocarditis risk. No significant increase in risk of myocardial infarction (RR, 0.96) or arrhythmia (RR, 0.98) events was observed following vaccination. The risk of cardiovascular events (myocarditis, RR, 8.53; myocardial infarction, RR, 2.59; arrhythmia, RR, 4.47) after SARS-CoV-2 infection was much higher than after vaccination. CONCLUSIONS: The risk of myocarditis was observed after COVID-19 vaccination, but it was much lower than that following the SARS-CoV-2 infection. No significant increased risk of myocardial infarction or arrhythmia was found after COVID-19 vaccination.
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COVID-19 , Infarto del Miocardio , Miocarditis , Humanos , Vacunas contra la COVID-19 , Vacuna BNT162 , SARS-CoV-2 , VacunaciónRESUMEN
Objective: The effect of oxygen therapy on the prognosis of chronic obstructive pulmonary disease (COPD) with nocturnal hypoxemia (NOD) has been controversial. Therefore, this study systematically evaluated the relevant literature and included it into randomized controlled studies for meta-analysis to evaluate the efficacy and prognosis. Methods: We searched PubMed, EMBASE, web of science, Cochrane, China HowNet and Wanfang database for the literature on the prognosis of COPD patients with simple NOD from the establishment of the database to 30 June 2022. The outcome indicators were death and aggravation of the disease. The efficacy evaluation measures were pulmonary function and arterial blood gas results. The publication bias and heterogeneity of the included studies were evaluated. Results: A total of 621 patients from 5 studies were included in this meta-analysis, and there was no publication bias in the included studies. The total mortality of long-term oxygen therapy (LTOT) in COPD patients with simple NOD in oxygen therapy group (RR = 1.04; 95% CI: 0.81-1.33, p = 0.77), mortality (RR = 0.87; 95% CI: 0.58-1.31, p = 0.50), risk of progression to LTOT events (RR = 1.07; 95% CI: 0.76-1.51, p = 0.71). PaO2 in patients with COPD and simple NOD in oxygen therapy group was higher than that in non-oxygen therapy group (mean difference (MD) = 13.47; 95% CI: 3.49-23.46, p = 0.008), the decrease of PaCO2 level was not statistically significant (MD = -10.05; 95% CI: -26.36-6.27, p = 0.23). Conclusion: Oxygen therapy can improve the prognosis of blood oxygen partial pressure in COPD patients with simple NOD, but oxygen therapy has no significant effect on the survival rate, controlling the progression of the disease to LTOT and reducing the partial pressure of carbon dioxide.
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BACKGROUND: Alzheimer's disease (AD), a type of neurodegeneration disease, is characterized by Aß deposition and tangles of nerve fibers. Schisandrin is one of the main components of Fructus Schisandrae Chinensis. Researches showed that schisandrin can improve the cognitive impairment and memory of AD mice, but the specific mechanism has not been fully elucidated. PURPOSE: The purpose of this study is to investigate the possible mechanism of schisandrin in improving AD pathology. METHODS: The Morris water maze test was executed to detect spatial learning and memory. Ultra performance liquid chromatography-Triple time of flight mass spectrometry (UPLC-Triple-TOF/MS)-based plasma lipidomics was used to study the changes of plasma lipids. Moreover, we measured the levels of protein and mRNA expression of APOE and ABCA1 in the rat brains and in BV2 microglia. RESULTS: Our study found that schisandrin could improve learning and memory, and reduce Aß deposition in AD rats. Furthermore, we found that schisandrin can improve plasma lipid metabolism disorders. Therefore, we hypothesized schisandrin might act via LXR and the docking results showed that schisandrin interacts with LXRß. Further, we found schisandrin increased the protein and mRNA expression of LXR target genes APOE and ABCA1 in the brain of AD rats and in BV2 microglia. CONCLUSION: Our study reveals the neuroprotective effect and mechanism of schisandrin improves AD pathology by activating LXR to produce APOE and ABCA1.
RESUMEN
BACKGROUND: This study is aimed at investigating the association of Fibrillin-1 (FBN1) and transforming growth factor ß (TGF-ß) signaling-related gene polymorphisms with the susceptibility of Stanford type B aortic dissection (AD) and its clinical prognostic outcomes. METHODS: Five single-nucleotide polymorphism (SNPs) (FBN1rs 145233125, rs201170905, rs11070646, TGFB1rs1800469, and TGFB2rs900) were analyzed in patients with Stanford type B AD (164) and healthy controls (317). Gene-gene and gene-environment interactions were assessed by generalized multifactor dimensionality reduction. A 4-year follow-up was performed for all AD patients. RESULTS: G carriers of FBN1 rs201170905 and TGFB1 rs1800469 have an increased risk of Stanford type B AD. The interaction of FBN1, TGFB1, TGFB2 and environmental promoted to the increased risk of type B AD (cross-validation consistency = 10/10, P = 0.001). Dominant models of FBN1rs145233125 TC + CC genotype (P = 0.028), FBN1 rs201170905 AG + GG (P = 0.047) and TGFB1 rs1800469 AG + GG (P = 0.052) were associated with an increased risk of death of Stanford type B AD. The recessive model of FBN1 rs145233125 CC genotype (P < 0.001), FBN1rs201170905 GG (P < 0.001), TGFB1 rs1800469 AG + GG genotype (P = 0.011) was associated with an increased risk of recurrence of chest pain in Stanford type B AD. CONCLUSIONS: The interactions of gene-gene and gene-environment are related with the risk of Stanford type B AD. C carriers of rs145233125, G carriers of rs201170905 and G carriers of rs1800469 may be the poor clinical outcome indicators of mortality and recurrent chest pain in Stanford type B AD.
Asunto(s)
Disección Aórtica , Factor de Crecimiento Transformador beta , Disección Aórtica/genética , Dolor en el Pecho , Fibrilina-1/genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Pronóstico , Factor de Crecimiento Transformador beta/genéticaRESUMEN
The movement of the cervical spine should be restricted throughout the rehabilitation phase after it has been injured. Cervical orthosis is commonly utilized in clinical settings to guarantee cervical spine stability. However, to date, the investigations are limited to patient-specific cervical fixation orthoses. This study provides a new idea for making personalized orthoses. The CT data of the patient's cervical spine were collected, then mimics were used for reconstructing the skin of the cervical spine, the Geomagic Studio was used for surface fitting, the Inspire Studio was used for structural topology optimization, redundant structures were removed, the resulting orthotics were postprocessed, and finally, it was printed with a 3D printer. No signs of pain or discomfort were observed during the wearing. The cervical spine range of motion in flexion, extension, lateral flexion, and rotation is all less than 8° after using the device. Low cost, quick manufacturing time, high precision, attractive appearance, lightweight structure, waterproof design, and practical customized orthotics for patients are all advantages of 3D printing technology in the field of orthopedics. Many possible benefits of using 3D printing to build new orthotics include unique design, stiffness, weight optimization, and improved biomechanical performance, comfort, and fit. Personalized orthotics may be designed and manufactured utilizing 3D printing technology.
RESUMEN
Nonalcoholic steatohepatitis (NASH) is an advanced stage of nonalcoholic fatty liver disease (NAFLD) with serious consequences that currently lacks approved pharmacological therapies. Recent studies suggest the close relationship between the pathogenesis of NAFLD and the dysregulation of RNA splicing machinery. Here, we reveal death-associated protein kinase-related apoptosis-inducing kinase-2 (DRAK2) is markedly upregulated in the livers of both NAFLD/NASH patients and NAFLD/NASH diet-fed mice. Hepatic deletion of DRAK2 suppresses the progression of hepatic steatosis to NASH. Comprehensive analyses of the phosphoproteome and transcriptome indicated a crucial role of DRAK2 in RNA splicing and identified the splicing factor SRSF6 as a direct binding protein of DRAK2. Further studies demonstrated that binding to DRAK2 inhibits SRSF6 phosphorylation by the SRSF kinase SRPK1 and regulates alternative splicing of mitochondrial function-related genes. In conclusion, our findings reveal an indispensable role of DRAK2 in NAFLD/NASH and offer a potential therapeutic target for this disease.