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Single-nucleotide variations in C13orf31 (LACC1) that encode p.C284R and p.I254V in a protein of unknown function (called 'FAMIN' here) are associated with increased risk for systemic juvenile idiopathic arthritis, leprosy and Crohn's disease. Here we set out to identify the biological mechanism affected by these coding variations. FAMIN formed a complex with fatty acid synthase (FASN) on peroxisomes and promoted flux through de novo lipogenesis to concomitantly drive high levels of fatty-acid oxidation (FAO) and glycolysis and, consequently, ATP regeneration. FAMIN-dependent FAO controlled inflammasome activation, mitochondrial and NADPH-oxidase-dependent production of reactive oxygen species (ROS), and the bactericidal activity of macrophages. As p.I254V and p.C284R resulted in diminished function and loss of function, respectively, FAMIN determined resilience to endotoxin shock. Thus, we have identified a central regulator of the metabolic function and bioenergetic state of macrophages that is under evolutionary selection and determines the risk of inflammatory and infectious disease.
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Artritis Juvenil/genética , Enfermedad de Crohn/genética , Infecciones/genética , Lepra/genética , Macrófagos/inmunología , Proteínas/genética , Choque Séptico/genética , Adenosina Trifosfato/metabolismo , Animales , Bacteriólisis , Células Cultivadas , Metabolismo Energético , Acido Graso Sintasa Tipo I/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Inflamasomas/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Metabolismo de los Lípidos/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , NADPH Oxidasas/metabolismo , Oxidación-Reducción , Polimorfismo de Nucleótido Simple , RiesgoRESUMEN
Covalent organic frameworks (COFs) are a family of engaging membrane materials for molecular separation, which remain challenging to fabricate in the form of thin-film composite membranes due to slow crystal growth and insoluble powder. Here, an additive approach is presented to construct COF-based thin-film composite membranes in 10 min via COF oligomer coating onto poly(ether ether ketone) (PEEKï¼ultrafiltration membranes. By the virtue of ultra-thin liquid phase and liquid-solid interface-confined assembly, the COF oligomers are fast stacked up and grow along the interface with the solvent evaporation. Benefiting from the low out-plane resistance of COFs, COF@PEEK composite membranes exhibit high solvent permeances in a negative correlation with solvent viscosity. The well-defined pore structures enable high molecular sieving ability (Mw = 300 g mol-1 ). Besides, the COF@PEEK composite membranes possess excellent mechanical integrities and steadily operate for over 150 h in the condition of high-pressure cross flow. This work not only exemplifies the high-efficiency and scale-up preparation of COF-based thin-film composite membranes but also provides a new strategy for COF membrane processing.
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BACKGROUND: The Corona Virus Disease 2019 (COVID-19) pandemic has raised concerns regarding its potential impact on male reproductive health. However, the impact of COVID-19 on sperm quality remains uncertain. This retrospective study aimed to investigate the short-term and relatively long-term effects of COVID-19 infection on sperm quality. METHODS: A total of 85 males with fertility requirements, who underwent semen evaluation at Guilin People's Hospital between June 2022 and July 2023, were included in the study. Changes in semen parameters were analyzed across three specific timeframes: within 6 months before COVID-19 infection, within 3 months after COVID-19 infection, and 3-6 months after COVID-19 recovery. RESULTS: The results revealed that the sperm concentration and total sperm number were significantly lower after infection compared to before, while in the recovery period, the sperm concentration, total sperm count, progressive motility, and normal morphology significantly increased. Comparing the three periods, the most significant difference was observed in sperm concentration, which exhibited a significant decrease after infection but returned to normal levels after recovery from COVID-19. CONCLUSIONS: These findings suggest that COVID-19 may exert some impact on sperm quality, particularly evidenced by decreased sperm concentration post-infection. Fortunately, these effects on semen parameters appear to be temporary, with gradual restoration of semen parameters within 3-6 months after recovery. However, further research is needed to explore the underlying mechanisms and long-term implications of these observed changes in semen parameters.
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COVID-19 , Semen , Masculino , Humanos , Estudios Retrospectivos , Espermatozoides , HospitalesRESUMEN
Addressing global carbon inequality constitutes an important task for both international negotiations on climate-change mitigation and the achievement of sustainable development goals. Soaring international trade might become a vigorous modifier for reducing global carbon inequality through production reallocation and economic boosts in different countries. However, this effect remains largely unexplored, not only because of little awareness of the windfall benefits from international trade but also because of debates on quantifying global carbon inequality from both production- and consumption-based perspectives. To avoid incomplete implications from a single perspective, this study first adapted a producer-consumer shared responsibility to evaluate global carbon inequality using the technology-adjusted consumption-based accounting method for 189 countries from 2006 to 2016. A dynamic panel data model was developed to examine the different channels through which international trade affects global carbon inequality in developed and developing countries. The results demonstrate that even with increasing carbon emissions, less global carbon inequality was witnessed from 2006 to 2016. International trade plays an important role in reducing global carbon inequality, mostly by stimulating the economy and increasing household income in developing countries. However, production reallocation via international trade fails in reducing the emission responsibilities of developed countries, rendering this futile in alleviating global carbon inequality. Carbon leakage that transfers carbon-intensive production across borders can lead to this unintended result, and more stringent cross-border regulations such as the carbon border adjustment mechanism can be effective. This study not only highlights the pivotal role of international trade in reducing global carbon inequality but also the future direction of international cooperation on climate change mitigation in a globalized world.
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Carbono , Comercio , Internacionalidad , Dióxido de Carbono , Cambio Climático , Desarrollo EconómicoRESUMEN
Here we describe an asymmetric [3,3]-sigmatropic rearrangement of aryl iodanes that enables the enantioselective α-arylation of chiral 2-oxazolines, thereby producing valuable chiral α-aryl carbonyl compounds. The success of this protocol hinges on the selective assembly of aryl iodanes with 2-oxazolines and the smooth deprotonation of the in situ-generated iodonium-imine species. The nearly neutral and mild conditions of the reaction allow it to tolerate a wide variety of functional groups. Moreover, the remaining iodine atom in the products not only provides a versatile platform for further elaboration of such molecules but also supplies the asymmetric hypervalent iodine chemistry with a new class of chiral scaffolds.
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BACKGROUND: Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood. METHODS: We used a combination of metabolomics, transcriptomics, bioinformatics, and microscopy to elucidate a potential mechanism by which MYC regulates FAO in TNBC. RESULTS: We propose that MYC induces a multigenic program that involves changes in intracellular calcium signalling and fatty acid metabolism. We determined key roles for fatty acid transporters (CD36), lipases (LPL), and kinases (PDGFRB, CAMKK2, and AMPK) that each contribute to promoting FAO in human mammary epithelial cells that express oncogenic levels of MYC. Bioinformatic analysis further showed that this multigenic program is highly expressed and predicts poor survival in the claudin-low molecular subtype of TNBC, but not other subtypes of TNBCs, suggesting that efforts to target FAO in the clinic may best serve claudin-low TNBC patients. CONCLUSION: We identified critical pieces of the FAO machinery that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype.
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Claudinas/metabolismo , Ácidos Grasos/metabolismo , Metabolómica/métodos , Proteínas Proto-Oncogénicas c-myc/genética , Neoplasias de la Mama Triple Negativas/genética , Línea Celular Tumoral , Proliferación Celular , Transición Epitelial-Mesenquimal , Femenino , Humanos , TransfecciónRESUMEN
We achieve automated and reliable annotation of lipid species and their molecular structures in high-throughput data from chromatography-coupled tandem mass spectrometry using decision rule sets embedded in Lipid Data Analyzer (LDA; http://genome.tugraz.at/lda2). Using various low- and high-resolution mass spectrometry instruments with several collision energies, we proved the method's platform independence. We propose that the software's reliability, flexibility, and ability to identify novel lipid molecular species may now render current state-of-the-art lipid libraries obsolete.
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Cromatografía Liquida/métodos , Lípidos/análisis , Lípidos/química , Espectrometría de Masas en Tándem/métodos , Algoritmos , Animales , Hígado/química , Ratones , Estructura Molecular , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Ureaplasma urealyticum (UU) infection, as well as asymptomatic leukocytospermia, whether it has effect on semen parameters and whether it needs screening and treatment is still a confusing and controversial topic for clinicians. METHODS: Among 1530 adult males who visited Guilin People's Hospital due to infertility, 295 were diagnosed with asymptomatic leukocytospermia, and 95 were further screened for UU-positive. 81 UU-positive asymptomatic leukocytospermia patients received 7-day or 14-day treatment plan with doxycycline, and 70 cases were cured. The semen parameters of non-leukocytospermia, leukocytospermia, UU-positive leukocytospermia and UU-negative leukocytospermia groups were compared, and the differences between the two treatment plans and the semen parameters before UU treatment and 1 month after UU-cured were compared. RESULTS: Compared with non-leukocytospermia patients, the sperm concentration, progressive motility (PR), and normal morphology of patients with leukocytospermia decreased, while those with UU-positive leukocytospermia performed more significantly. The PR, total motility, and normal morphology of UU-positive leukocytospermia patients were significantly lower than those of UU-negative leukocytospermia patients (all p < 0.001). The UU cure rates of the 7-day and 14-day treatment plan with doxycycline was 84.62% and 89.66% (p = 0.738), respectively, and the sperm concentration, PR, total motility, and normal morphology of the cured UU-positive leukocytospermia patients were all increased after 1 month (p = 0.001, p = 0.022, p = 0.004 and p = 0.008, respectively). CONCLUSIONS: It is significant to screen and treat UU infection in asymptomatic leukocytospermia for improving sperm quality. Where appropriate, the 7-day treatment plan with doxycycline may be a good choice.
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Leucocitos , Análisis de Semen , Semen/citología , Infecciones por Ureaplasma/diagnóstico , Infecciones por Ureaplasma/tratamiento farmacológico , Ureaplasma urealyticum , Adulto , Enfermedades Asintomáticas , Estudios de Casos y Controles , Humanos , Masculino , Estudios Retrospectivos , Infecciones por Ureaplasma/complicacionesRESUMEN
BACKGROUND: MicroRNAs play a vital role in coronary artery disease. Abnormal expression of microRNAs has been found to be associated with the occurrence of CAD. METHODS: We identified significantly differentially expressed microRNAs in plasma between 40 patients with CAD and 10 controls with NCA using RNA sequencing. The differentially expressed microRNAs were analyzed for Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. RESULTS: Fifty cDNA libraries were constructed and sequenced, and a total of 1871.82 M raw reads were obtained, and 2135 microRNAs were found. Compared to the expressed microRNAs of NCA controls, 159 microRNAs were differentially expressed in CAD patients, including 119 upregulated microRNAs and 40 downregulated microRNAs. The top 10 upregulated miRNAs were miR-144-3p, miR-34a-5p, miR-15b-3p, miR-22-3p, miR-29b-3p, miR-1270, miR-6891-5p, miR-106a-5p, miR-15b-5p, and hsa-miR-499b-3p. The top ten downregulated miRNAs were miR-4437, miR-6842-3p, miR-4664-3p, miR-671-3p, miR-219a-1-3p, miR-7848-3p, miR-664a-3p, miR-1284, miR-361-3p, and miR-6780a-5p. The target genes of differentially expressed microRNAs were related to many basic biological terms, such as biological process, cellular component, and molecular function. According to the KEGG pathway analysis, the most enriched pathways of the differentially expressed microRNAs were endocytosis, focal adhesion, axon guidance, and so on. Furthermore, six upregulated and two downregulated microRNAs were detected by qRT-PCR (Quantitative Real-time PCR) and ROC analysis for diagnosing CAD. CONCLUSION: The results suggest that the expression levels of some microRNAs may play a vital role in the physiological and pathological course of CAD. Our study may provide useful information for the diagnosis and treatment of CAD.
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MicroARN Circulante/genética , Biología Computacional , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Análisis de Secuencia de ARN , Estudios de Casos y Controles , Femenino , Ontología de Genes , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Reproducibilidad de los Resultados , Regulación hacia Arriba/genéticaRESUMEN
OBJECTIVE: Acute Myocardial Infarction (AMI) is the most severe type of coronary atherosclerotic heart diseases. MiRNA is a class of endogenous noncoding small molecule RNA, which plays an important regulatory role in the development of some diseases. METHODS: We examined the miRNA expression profiles in 16 patients with AMI compared with 6 non-AMI controls using RNA sequencing. RESULTS: Compared with the miRNA expression profiles of non-AMI controls, a total of 181 differentially expressed miRNAs were discriminated in AMI patients, of which 96 upregulated miRNAs and 85 downregulated miRNAs. The top ten upregulated miRNAs were as follows: miR-449a-5p, miR-126-5p, miR-93-5p, miR-199a-3p, miR-4454, miR-6880-3p, miR-3135a, miR-548ad-5p, miR-4508, and miR-556-5p; while the top ten downregulated were as follows: miR-6805-5p, miR-1228-5p, miR-939-5p, miR-615-3p, miR-6780a-5p, miR-6857-3p, miR-5088-55p, miR-7155-3p, miR-184, and miR-4525. And the qRT-PCR results of differentially expressed miRNAs showed the same result as high-throughput sequencing data. For these 181 differentially expressed miRNAs, 19 841 target genes were predicted by GO analysis. The enrichment analysis revealed 2061 involved in biological processes, 353 in molecular function and 303 in cellular components. To identify biological pathways in AMI as compared to non-AMI, the target genes of differentially expressed miRNAs were mapped to the classical signal transduction pathway in KEGG, indicating that 214 classes were enriched. ROC analysis showed that the circulating miRNAs had the important value for AMI diagnosis and supported the previous conclusions that circulating miRNAs were effective to diagnose the AMI as a novel biomarker. CONCLUSIONS: Our findings require further research to confirm. It may provide a meaningful reference for the diagnosis and treatment of AMI.
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MicroARN Circulante/sangre , MicroARN Circulante/genética , Biología Computacional , Perfilación de la Expresión Génica , Infarto del Miocardio/sangre , Infarto del Miocardio/genética , Área Bajo la Curva , Análisis por Conglomerados , Regulación hacia Abajo/genética , Femenino , Ontología de Genes , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Reproducibilidad de los Resultados , Regulación hacia Arriba/genéticaRESUMEN
Mobile manipulation has a broad range of applications in robotics. However, it is usually more challenging than fixed-base manipulation due to the complex coordination of a mobile base and a manipulator. Although recent works have demonstrated that deep reinforcement learning is a powerful technique for fixed-base manipulation tasks, most of them are not applicable to mobile manipulation. This paper investigates how to leverage deep reinforcement learning to tackle whole-body mobile manipulation tasks in unstructured environments using only on-board sensors. A novel mobile manipulation system which integrates the state-of-the-art deep reinforcement learning algorithms with visual perception is proposed. It has an efficient framework decoupling visual perception from the deep reinforcement learning control, which enables its generalization from simulation training to real-world testing. Extensive simulation and experiment results show that the proposed mobile manipulation system is able to grasp different types of objects autonomously in various simulation and real-world scenarios, verifying the effectiveness of the proposed mobile manipulation system.
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Aprendizaje Profundo , Robótica , Algoritmos , Calibración , Simulación por Computador , Percepción VisualRESUMEN
BACKGROUND: The adverse effect of low-dose CT on image quality may be mitigated using iterative reconstructions. The purpose of this study was to evaluate the performance of the full model-based iterative reconstruction (MBIR) and adaptive statistical reconstruction (ASIR) algorithms in low radiation dose and low contrast dose abdominal contrast-enhanced CT (CECT) in children. METHODS: A total of 59 children (32 males and 27 females) undergoing low radiation dose (100kVp) and low contrast dose (270 mgI/ml) abdominal CECT were enrolled. The median age was 4.0 years (ranging from 0.3 to 13 years). The raw data were reconstructed with MBIR, ASIR and filtered back-projection (FBP) algorithms into 6 groups (MBIR, 100%ASIR, 80%ASIR, 60%ASIR, 40%ASIR and FBP). The CT numbers, standard deviations, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of liver, pancreas, kidney and abdominal aorta were measured. Two radiologists independently evaluated the subjective image quality including the overall image noise and structure display ability on a 4-point scale with 3 being clinically acceptable. The measurements among the reconstruction groups were compared using one-way ANOVA. RESULTS: The overall image noise score and display ability were 4.00 ± 0.00 and 4.00 ± 0.00 with MBIR and 3.27 ± 0.33 and 3.25 ± 0.43 with ASIR100%, respectively, which met the diagnostic requirement; other reconstructions couldn't meet the diagnostic requirements. Compared with FBP images, the noise of MBIR images was reduced by 62.86-65.73% for the respective organs (F = 48.15-80.47, P < 0.05), and CNR increased by 151.38-170.69% (F = 22.94-38.02, P < 0.05). CONCLUSIONS: MBIR or ASIR100% improves the image quality of low radiation dose and contrast dose abdominal CT in children to meet the diagnostic requirements, and MBIR has the best performance.
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Abdomen/diagnóstico por imagen , Algoritmos , Medios de Contraste/administración & dosificación , Procesamiento de Imagen Asistido por Computador/métodos , Tomografía Computarizada por Rayos X/métodos , Adolescente , Análisis de Varianza , Aorta Abdominal/diagnóstico por imagen , Niño , Preescolar , Femenino , Humanos , Lactante , Riñón/diagnóstico por imagen , Hígado/diagnóstico por imagen , Masculino , Páncreas/diagnóstico por imagen , Dosis de Radiación , Estudios Retrospectivos , Relación Señal-Ruido , Tomografía Computarizada por Rayos X/estadística & datos numéricos , Ácidos Triyodobenzoicos/administración & dosificaciónRESUMEN
BACKGROUND: T cells are key regulators of immunity and one of the cells recruited in atherosclerosis and participated in various stages of the development of atherosclerosis. Characterizing T-cell receptor (TCR) repertoires is a priority of great scientific interest and potential clinical utility for the early diagnosis, risk stratification and prognostic evaluation of acute myocardial infarction (AMI). METHODS: The TCR repertoires in 21 subjects including 7 patients with non-ST-segment elevation myocardial infarction (NSTEMI), 6 patients with ST-segment elevation myocardial infarction (STEMI) and 8 subjects with normal coronary artery (NCA) as control were characterized by using high-throughput sequencing. Bioinformatics analysis were performed. RESULTS: Patients with NSTEMI displayed more diverse TCR sequences than NCA controls, but they had lower percentage of top 200 TCR sequences. However, no significant differences were observed between the patients with STEMI and NCA controls, but STEMI group had lower percentage of top 200 TCR sequences. T cells from patients with AMI and NCA controls showed a differential V and J gene usage, especially, significant difference was observed in frequencies of V gene (TRBV2, TRBV29-1, TRBV30 and TRBV12-3) and J gene (TRBJ2-1) usage. Furthermore, significantly differences in average overlap was observed in groups of AMI and NCA control. The results showed that patients with AMI had distinct TCR repertoires which revealed the association between cardiovascular condition and T-cell clonotypes. CONCLUSIONS: Our findings revealed the differences of TCR repertoires between patients with AMI and NCA controls, which might be potential biomarkers for evaluating risk stratification or diagnosis of acute coronary syndrome.
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Secuenciación de Nucleótidos de Alto Rendimiento , Infarto del Miocardio/genética , Infarto del Miocardio/inmunología , Receptores de Antígenos de Linfocitos T/genética , Adulto , Anciano , Secuencia de Aminoácidos , Células Clonales , Análisis por Conglomerados , Regiones Determinantes de Complementariedad/química , Regiones Determinantes de Complementariedad/metabolismo , Vasos Coronarios/patología , Femenino , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Despite significant advances in the management of acute coronary syndromes (ACS), there are still plenty of patients undergoing percutaneous coronary intervention (PCI) and stent implantation suffered poor prognosis and high treatment expenditure. Evidence increasingly suggests that the ratio of low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio might be a novel marker for the risk of atherosclerotic cardiovascular disease, but the impact of LDL-C/HDL-C ratio on 1-year prognosis of drug-eluting stent (DES) implantation patients after PCI is still not reported. Our aim of the study was to investigate the impact of LDL-C/HDL-C ratio on 1-year prognosis of DES implantation patients after PCI. METHODS: Between May 2014 and July 2016, 1937 patients who were underwent primary PCI and DES implantation and achieving LDL-C with statins were enrolled and divided into two groups based on the ratio of LDL-C/HDL-C. RESULTS: The entire occurrence of adverse cardiovascular events according to the ratio of LDL-C/HDL-C showed that there were no significant differences in 1-year cardiovascular death (hazard ratio [HR]: 1.97, 95% confidence interval [CI]: 0.49 to 7.84, P = 0.329), myocardial infarction (MI) (HR: 1.66, 95% CI: 0.84 to 3.28, P = 0.172) and bleeding events (HR: 1.08, 95% CI: 0.83 to 1.41, P = 0.598) The cumulative incidence of target lesion revascularization (TLR) (HR: 1.43, 95% CI: 1.10 to 1.86, P = 0.007), stent thrombosis (ST) (HR: 2.04, 95% CI: 1.06 to 3.93, P = 0.037) and major adverse cardiac events (MACE) (HR: 1.54, 95% CI: 1.24 to 1.91, P < 0.001) were significantly higher in high group than in low group. Multivariate Cox regression analysis revealed that age (HR: 1.556, 95%, CI: 1.198 to 2.021, P < 0.001), together with diabetes mellitus (HR: 1.490, 95% CI: 1.142 to 1.945, P = 0.003), and ratio of LDL-C/HDL-C (HR: 1.638, 95% CI: 1.260 to 2.218, P < 0.001) were independent predictors of 1-year MACE. The Kaplan-Meier cumulative MACE-free survival curves with a log-rank test showed that the presence of high ratio of LDL-C/HDL-C was associated with higher incidences of MACE after PCI with DES implantation. CONCLUSIONS: The high LDL-C/HDL-C ratio was associated with cardiovascular events in patients with ACS after PCI and DES implantation.
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Síndrome Coronario Agudo/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/mortalidad , Síndrome Coronario Agudo/cirugía , Anciano , Prótesis Vascular , Implantación de Prótesis Vascular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/epidemiología , Pronóstico , Modelos de Riesgos Proporcionales , Resultado del TratamientoRESUMEN
Herein we describe the dearomatization of aryl iodanes through an unprecedented "rearrangement/addition" sequence. The process consists of two stages. First, a rapid [3,3] sigmatropic rearrangement of the aryl iodane with an α-stannyl nitrile affords a highly electrophilic dearomatized intermediate at -78 °C. A low-temperature rearrangement then enables the unstable dearomatized species to be trapped in situ with various nucleophiles. As a consequence, the reaction not only breaks the aromaticity of the aryl iodane but also sequentially installs two different functional groups, thus resulting in a polysubstituted alicyclic product.
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In patients with asthma or chronic obstructive pulmonary disease, rhinovirus (RV) infections can provoke acute worsening of disease, and limited treatment options exist. Viral replication in the host cell induces significant remodeling of intracellular membranes, but few studies have explored this mechanistically or as a therapeutic opportunity. We performed unbiased lipidomic analysis on human bronchial epithelial cells infected over a 6 h period with the RV-A1b strain of RV to determine changes in 493 distinct lipid species. Through pathway and network analysis, we identified temporal changes in the apparent activities of a number of lipid metabolizing and signaling enzymes. In particular, analysis highlighted FA synthesis and ceramide metabolism as potential anti-rhinoviral targets. To validate the importance of these enzymes in viral replication, we explored the effects of commercially available enzyme inhibitors upon RV-A1b infection and replication. Ceranib-1, D609, and C75 were the most potent inhibitors, which confirmed that FAS and ceramidase are potential inhibitory targets in rhinoviral infections. More broadly, this study demonstrates the potential of lipidomics and pathway analysis to identify novel targets to treat human disorders.
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Bronquios/citología , Células Epiteliales/metabolismo , Células Epiteliales/virología , Metabolismo de los Lípidos , Terapia Molecular Dirigida , Rhinovirus/fisiología , Replicación Viral , Antivirales/farmacología , Células HeLa , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Rhinovirus/efectos de los fármacosRESUMEN
Autotaxin (ATX; also known as ENPP2), the lysophospholipase responsible for generating the lipid receptor agonist lysophosphatidic acid (LPA), is a secreted enzyme. Here we show that, once secreted, ATX can bind to the surface of cell-secreted exosomes. Exosome-bound ATX is catalytically active and carries generated LPA. Once bound to a cell, through specific integrin interactions, ATX releases the LPA to activate cell surface G-protein-coupled receptors of LPA; inhibition of signalling by the receptor antagonist Ki1642 suggests that these receptors are LPAR1 and LPAR3. The binding stimulates downstream signalling, including phosphorylation of AKT and mitogen-activated protein kinases, the release of intracellular stored Ca2+ and cell migration. We propose that exosomal binding of LPA-loaded ATX provides a means of efficiently delivering the lipid agonist to cell surface receptors to promote signalling. We further propose that this is a means by which ATX-LPA signalling operates physiologically.
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Exosomas/metabolismo , Hidrolasas Diéster Fosfóricas/metabolismo , Receptores del Ácido Lisofosfatídico/metabolismo , Vesículas Secretoras/metabolismo , Transducción de Señal , Animales , Centrifugación por Gradiente de Densidad , Fraccionamiento Químico , Medios de Cultivo Condicionados/farmacología , ADN/biosíntesis , Exosomas/efectos de los fármacos , Exosomas/ultraestructura , Células HEK293 , Humanos , Laminina/metabolismo , Lisofosfolípidos/metabolismo , Espectrometría de Masas , Ratones , Cuerpos Multivesiculares/metabolismo , Cuerpos Multivesiculares/ultraestructura , Células 3T3 NIH , Transporte de Proteínas/efectos de los fármacos , Vesículas Secretoras/efectos de los fármacos , Vesículas Secretoras/ultraestructura , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND AND OBJECTIVES: The objective of this study is to evaluate the effects of cytochrome P450 2C19 (CYP2C19) polymorphism on adverse cardiovascular events (MACE) in Hakka patients with acute coronary syndrome (ACS) receiving clopidogrel who had undergone coronary drug-eluting stent placement after percutaneous coronary intervention (PCI) in southern China. METHODS: Genotyping of CYP2C19 and MACE of 934 ACS patients with PCI on clopidogrel maintenance therapy were analyzed. Patients who carried loss-of-function CYP2C19 were treated with a 150-mg maintenance dose of clopidogrel or 90 mg of ticagrelor antiplatelet therapy, and patients who were non-carriers received clopidogrel therapy daily at a maintenance dose of 75 mg and the patients were followed-up for at least 12 months. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, and target vessel revascularization and stroke. RESULTS: The allelic frequency of CYP2C19*2 and CYP2C19*3 of Hakka patients in the current study was 31.64 and 5.19%, respectively. The CYP2C19 wild-type homozygotes (*1/*1) were the most predominant among the patients (40.36%), followed by the CYP2C19*2 heterozygotes (*1/*2) (40.26%). The distribution of CYP2C19 phenotypes was divided into extensive metabolizers (EM; 40.36%), intermediate metabolizers (IM; 45.61%), and poor metabolizers (PM; 14.03%). Based on the genotype-guided antiplatelet therapy, there was no significant association between the carrier status and the clinical outcome at 1, 6, and 12 months. In addition, no significant difference in the rates of bleeding was found among the three groups. After logistic regression analysis, hypertension was the only independent predictor of cardiovascular events (relative risk, 1.501; 95% CI, 1.011 to 2.229; P = 0.044). CONCLUSIONS: Our results shed new light on the important benefit of testing CYP2C19 polymorphisms before prescribing clopidogrel in patients treated with drug-eluting stent implantation after PCI. The testing may help to optimize pharmacotherapy effectiveness by providing individualized treatment to the Chinese population. Our findings mandate further studies aimed at initiating genome-based personalized antiplatelet therapy in a Hakka population in southern China.
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Síndrome Coronario Agudo/terapia , Citocromo P-450 CYP2C19/genética , Stents Liberadores de Fármacos , Infarto del Miocardio/genética , Intervención Coronaria Percutánea/instrumentación , Variantes Farmacogenómicas , Polimorfismo Genético , Accidente Cerebrovascular/genética , Ticlopidina/análogos & derivados , Síndrome Coronario Agudo/diagnóstico por imagen , Síndrome Coronario Agudo/mortalidad , Adenosina/análogos & derivados , Adenosina/uso terapéutico , Anciano , Pueblo Asiatico/genética , Distribución de Chi-Cuadrado , China , Toma de Decisiones Clínicas , Clopidogrel , Citocromo P-450 CYP2C19/metabolismo , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Hemorragia/inducido químicamente , Heterocigoto , Homocigoto , Humanos , Hipertensión/complicaciones , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/mortalidad , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/mortalidad , Farmacogenética , Fenotipo , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/farmacocinética , Medicina de Precisión , Estudios Retrospectivos , Factores de Riesgo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/mortalidad , Ticagrelor , Ticlopidina/efectos adversos , Ticlopidina/farmacocinética , Ticlopidina/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND Periprocedural myocardial injury (PMI) is known to be a predictor of postprocedural cardiovascular morbidity and mortality following a percutaneous coronary intervention (PCI). However, the correlation between low-density lipoprotein cholesterol and periprocedural myocardial injury in patients following elective PCI in southern China remains unclear. Therefore, we aimed to investigate the association of preoperative low-density lipoprotein cholesterol (LDL-C) levels with PMI in patients following elective PCI. MATERIAL AND METHODS This study included 1942 consecutive patients who received elective PCI. Cardiac troponin I (cTnI) was used to assess perioperative myocardial injury. The peak cTnI was measured within 24 h after PCI, and the correlation between the cTnI value and the preoperative LDL level was studied. RESULTS The data suggest that the PCI patients with preprocedural LDL-C <100 mg/dl were strongly and independently correlated with less risk of PMI. Univariate logistic regression indicated that patients with preprocedural LDL-C of 70~99 mg/dl were correlated with lower risk of postprocedural cTnI elevation above 3×ULN (odds ratio [OR]: 0.762; 95% [CI]: 0.603-0.965; P<0.024) up to 20×ULN (OR: 0.730; 95% CI: 0.576-0.924; P<0.000) compared to those with preprocedural LDL-C ≥100 mg/dl. Moreover, patients with preprocedural LDL-C of <70 mg/dl were more strongly correlated with lower risk of postprocedural cTnI elevation above 3×ULN (OR: 0.641; 95% CI: 0.436-0.936; P<0.021) up to 20×ULN (OR: 0.476; 95% CI: 0.316-0.717; P<0.000). CONCLUSIONS Our study demonstrated that PCI patients with lower preprocedural LDL-C were correlated with a lower risk of PMI in southern China.
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LDL-Colesterol/análisis , Infarto del Miocardio/mortalidad , Intervención Coronaria Percutánea/efectos adversos , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , China/epidemiología , HDL-Colesterol/análisis , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Procedimientos Quirúrgicos Electivos , Femenino , Lesiones Cardíacas , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Intervención Coronaria Percutánea/mortalidad , Factores de Riesgo , Troponina IRESUMEN
BACKGROUND In southern China, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a significant health problem. The aim of this study was to investigate the molecular epidemiological characteristic of the G6PD gene among Chinese Hakka in southern Guangdong province. MATERIAL AND METHODS We screened 611 unrelated subjects for G6PD genetic polymorphism analyzed by a gene chip analysis for common Chinese G6PD mutations. G-6-PD enzyme activity was determined by use of the G-6-PD quantitative detection kit. RESULTS Seven mutation sites were detected from subjects in our study. G6PD Canton (c.1376 GâT)(33.06%), G6PD Kaiping (c.1388 GâA)(30.67%), and polymorphism (c.1311 CâT)(25.89%) account for 89.62% of mutations, followed by G6PD Gaohe (c.95 AâG)(5.97%), G6PD Chinese-5 (c.1024 CâT)(3.58%), G6PD Maewo (c.1360 CâT)(0.39%), and G6PD Viangchan (c.871GâA)(0.39%). CONCLUSIONS We studied the genetic polymorphisms and frequencies of G6PD gene in the Hakka population of Meizhou. Our results coincide with the results among the Chinese Jiangxi Hakka population. It was consistent with previous research reports on Chinese people. There were differences in the results of reports from some other Asian populations. Our results could be useful for future prevention and control of G6PD deficiency aimed at the Chinese Hakka population.