RESUMEN
INTRODUCTION AND OBJECTIVES: Acute liver injury (ALI) is characterized by massive hepatocyte death with high mortality and poor prognosis. Hepatocyte pyroptosis plays a key role in the physiopathological processes of ALI, which can damage mitochondria and release NLRP3 inflammasome particles, causing systemic inflammatory responses. Z-DNA Binding Protein 1 (ZBP1) is a sensor that induces cell death. Here, we investigated whether ZBP1 participates in hepatocyte pyroptosis and explored the possible pathogenesis of ALI. MATERIALS AND METHODS: Hepatocyte pyrotosis was induced with lipopolysaccharide (LPS) and nigericin (Nig), and the expression of Zbp1 (ZBP1) was examined by western blot analysis and RT-qPCR. Further, we transfected AML-12 (LO2 and HepG2) cell lines with Zbp1 (ZBP1) siRNA. After ZBP1 was silenced, LDH release and flow cytometry were used to measure the cell death; Western blot analysis and RT-qPCR were used to detect the marker of NLRP3 inflammasome activation and pyroptosis. We also detected the expression of mitochondrial linear rupture marker phosphoglycerate mutase family member 5 (PGAM5) using western blot analysis and reactive oxygen species (ROS) using the DCFH-DA method. RESULTS: The expression of ZBP1 was up-regulated in LPS/Nig-induced hepatocytes. Si-Zbp1 (Si-ZBP1) inhibited NLRP3 inflammasome activation and pyroptosis in LPS/Nig-induced hepatocytes. Moreover, ZBP1 silencing inhibited the expression of PGAM5 by reducing ROS production. CONCLUSIONS: ZBP1 promotes hepatocellular pyroptosis by modulating mitochondrial damage, which facilitates the extracellular release of ROS.
Asunto(s)
Hepatocitos , Lipopolisacáridos , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Especies Reactivas de Oxígeno , Animales , Humanos , Células Hep G2 , Hepatocitos/metabolismo , Hepatocitos/patología , Inflamasomas/metabolismo , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Nigericina/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Fosfoproteínas Fosfatasas , Especies Reactivas de Oxígeno/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Transducción de SeñalRESUMEN
BACKGROUND: The majority of HBeAg-positive mothers with chronic hepatitis B have high levels of viremia and inactive disease with normal alanine aminotransferase (ALT) during pregnancy. In addition, postpartum disease activation and ALT flare have been reported in the range of 15 - 35%. However, the current International Association Guidelines have not provided clear recommendations and a risk-stratified monitoring schedule. Furthermore, data are lacking on the definition of normal ALT in the postpartum period in mothers with chronic hepatitis B. The clinical features and ALT flare patterns in HBeAg-positive mothers versus HBeAg-negative mothers are not fully explored. Thus, we design a cohort study to investigate the aforementioned area and generate data to assist healthcare providers in better managing mothers with hepatitis B. We aim to assess the frequency of postpartum ALT flares and predictors for such events. METHOD: This study is a single-center and prospective cohort study (n = 360) that consists of two groups of patients including HBsAg-positive mothers (n = 120) and healthy mothers without HBV infection (n = 240). In HBeAg-positive mothers, antiviral therapy during late pregnancy is permitted to prevent Mother-to-child transmission (MTCT) but discontinued at delivery if there is no further indication for the treatment. Mothers are enrolled at the gestational weeks of 12-24. After delivery, both mothers and their infants will be followed up until postpartum week 24. Clinical and laboratory data are collected every 4 weeks during the study except there are no follow-up visits at the postpartum weeks 16 and 20. The primary objective is the proportion of patients with postpartum ALT flares. The secondary objectives are independent risk factors during pregnancy for predicting postpartum ALT flares and the normal range of postpartum ALT levels in healthy mothers. DISCUSSION: The current study focuses on the incidence of postpartum ALT flares in mothers with chronic hepatitis B including subgroup analysis based on HBeAg status. The data will have several clinical implications, such as providing evidence for an appropriate monitoring schedule in CHB mothers after delivery. Further analyses on predictors of such events may assist clinicians in identifying mothers who might develop severe postpartum ALT flares. The data generated from healthy mothers have the potential to identify the patterns of ALT changes during pregnancy and postpartum, so we can gain a better understanding of the normal range of ALT in this subpopulation. TRIAL REGISTRATION NUMBER AT THE CHINESE CLINICAL TRIAL REGISTRY: ChiCTR2200061130.
Asunto(s)
Hepatitis B Crónica , Lactante , Embarazo , Humanos , Femenino , Hepatitis B Crónica/epidemiología , Hepatitis B Crónica/tratamiento farmacológico , Estudios Prospectivos , Alanina Transaminasa , Antivirales/uso terapéutico , Antígenos e de la Hepatitis B , Estudios de Cohortes , Incidencia , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Periodo Posparto , Virus de la Hepatitis B/genética , ADN ViralRESUMEN
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread to many countries around the world. In addition to lung disease, severe cases also displayed varying degrees of liver injury. This article will describe the latest developments regarding coronavirus and the pathogenesis of liver injury, the prone population and clinical characteristics of these patients, as well as providing some suggestions for clinical treatment.
Asunto(s)
COVID-19/complicaciones , Hepatopatías/etiología , SARS-CoV-2 , Antivirales/efectos adversos , Antivirales/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Femenino , Humanos , Incidencia , Hepatopatías/diagnóstico , Hepatopatías/terapia , Masculino , Medicina Tradicional China/efectos adversosRESUMEN
BACKGROUND: Streptococcus agalactiae (GBS) is the causative pathogen of puerperal sepsis in pregnant women and pneumonia, sepsis and meningitis in infants. Infection of GBS is responsible for the increased morbidity in pregnant women and the elderly, and bring challenges to clinical diagnosis and treatment. However, culture-based approaches to detect S.agalactiae is time-consuming with limited sensitivity. Besides, real-time quantitative PCR demands expensive instruments with tedious steps. Thus, we aim to establish a new detection method for more accurate and rapid detection of S.agalactiae. RESULTS: The ddPCR primer targeted the CpsE gene showed better amplified efficiency in the reaction. The limit of detection for GBS DNA with ddPCR was able to reach 5 pg/µL. Moreover, no positive amplified signals could be detected in the reactions which served 11 non-GBS strains DNA as templates. Furthermore, the coefficient of variation of this method was 4.5%, indicating excellent repeatability of ddPCR assay. CONCLUSIONS: In our study, ddPCR was performed as a rapid detection of S.agalactiae with high sensitivity and specificity. This technique can promote the accuracy of the diagnosis of GBS infection and provide a scientific basis for clinical treatment.
Asunto(s)
Proteínas Bacterianas/genética , Reacción en Cadena de la Polimerasa/métodos , Infecciones Estreptocócicas/diagnóstico , Streptococcus agalactiae/aislamiento & purificación , Cartilla de ADN/genética , Diagnóstico Precoz , Humanos , Límite de Detección , Streptococcus agalactiae/genéticaRESUMEN
BACKGROUND: Neisseria meningitidis is a major cause of bacterial meningitis, and these infections are associated with a high mortality rate. Rapid and reliable diagnosis of bacterial meningitis is critical in clinical practice. However, this disease often occurs in economically depressed areas, so an inexpensive, easy to use, and accurate technology is needed. We performed a pooled-analysis to assess the potential of the recently developed loop-mediated isothermal amplification (LAMP) assay for detection of meningococcus. METHODS: Pubmed, Embase, and Web of Science were searched to identify original studies that used the LAMP assay to detect meningococcus. After pooling of data, the sensitivity and specificity were calculated, a summary receiver operating characteristic (SROC) curve was determined, and the area under the SROC curve was computed to determine diagnostic accuracy. Publication bias was assessed using Deek's funnel plot. RESULTS: We examined 14 studies within 6 publications. The LAMP assay had high sensitivity (94%) and specificity (100%) in the detection of meningococcus in all studies. The area under the SROC curve (0.980) indicated high overall accuracy of the LAMP assay. There was no evidence of publication bias. DISCUSSION: The LAMP assay has accuracy comparable to bacterial culture and PCR for detection of meningococcus, but is less expensive and easier to use. We suggest the adoption of the LAMP assay to detect meningococcus, especially in economically depressed areas.
Asunto(s)
Meningitis Meningocócica/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Neisseria meningitidis/genética , Técnicas de Amplificación de Ácido Nucleico/métodos , Exactitud de los Datos , Humanos , Meningitis Meningocócica/microbiología , Técnicas de Diagnóstico Molecular/economía , Técnicas de Amplificación de Ácido Nucleico/economía , Reacción en Cadena de la Polimerasa/economía , Reacción en Cadena de la Polimerasa/métodos , Curva ROC , Sensibilidad y EspecificidadRESUMEN
An amendment to this paper has been published and can be accessed via the original article.
RESUMEN
BACKGROUND: Detection of hepatitis B virus (HBV) is vital for the diagnosis of hepatitis B infection. A novel test loop-mediated isothermal amplification (LAMP) has been successfully applied to detect various pathogens. However, the accuracy of LAMP in diagnosing HBV remains unclear. Therefore, in the present study, the accuracy of LAMP for HBV detection was evaluated systematically. METHODS: Embase, Cochrane Library, and PubMed databases were searched for studies using LAMP to detect HBV. Then, two researchers extracted data and assessed the quality of literature using the QUADAS-2 tool independently. I2 statistic and chi-square test were analyzed to investigate the heterogeneity, and Deek's funnel plot assessed the publication bias. The pooled sensitivity (SEN), specificity (SPE), positive LR (PLR), negative LR (NLR), diagnostic odds ratio (DOR), and 95% confidence intervals were displayed in forest plots. We calculated the area under the curve (AUC) to assess the overall efficiency of LAMP for HBV detection. RESULTS: A total of nine studies with 1298 samples were finally included in this evaluation. The pooled sensitivity and specificity of HBV detection were 0.91 (95% CI: 0.89 ~ 0.92) and 0.97 (95% CI: 0.94 ~ 0.99), respectively. The PLR, NLR, and DOR were 16.93 (95% CI: 6.15 ~ 46.55), 0.08 (95% CI: 0.05 ~ 0.14), and 397.57 (95% CI: 145.41 ~ 1087.07). Besides, the AUC was 0.9872, and Deek's plot suggested that there existed publication bias in the studies. CONCLUSION: Compared with PCR, LAMP is a simple, rapid, and effective assay to diagnose HBV. However, additional evidence is essential to confirm that LAMP can replace other methods in diagnosing HBV infection.
Asunto(s)
Hepatitis B/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificación de Ácido Nucleico/métodos , Hepatitis B/sangre , Humanos , Control de Calidad , Sensibilidad y EspecificidadRESUMEN
Novel antibacterial agents are urgently needed to address the infections caused by multi-drug resistant bacteria. Urinary tract infections are common infectious diseases in clinical. Most of these infections are caused by drug-resistant uropathogenic Escherichia coli. PPK1 is an essential kinase for bacterial motility, biofilm formation, quorum sensing, and virulence factors in the expression of uropathogenic E. coli. In the present study, two small molecules potentially targeting PPK1 were discovered through virtual screening and biological assays. The in vitro and in vivo results suggested that the interaction of these compounds with PPK1 can disrupt biofilm formation of uropathogenic E. coli and reduce invasive ability and resistance to oxidative stress of this strain. Moreover, the compounds exhibit good antibacterial bacterial activity in the mice with urinary tract infection. Taken together, our findings could provide a new chemotype for the development of antibacterials targeting PPK1.
Asunto(s)
Antibacterianos/farmacología , Descubrimiento de Drogas , Proteínas Quinasas/metabolismo , Infecciones Urinarias/tratamiento farmacológico , Escherichia coli Uropatógena/efectos de los fármacos , Antibacterianos/aislamiento & purificación , Biopelículas/efectos de los fármacos , Humanos , Infecciones Urinarias/microbiologíaRESUMEN
The present study was to investigate clinical significance, biological functions and underlying mechanisms of BTB Domain and CNC Homolog 1(BACH1) deregulation in human colorectal cancer (CRC). The result showed that BACH1 upregulation was significantly associated with enhanced tumor invasion (Pâ¯=â¯0.014) and gender (Pâ¯=â¯0.028) of CRC patients. Kaplan-Meier method results showed that the overall survival of CRC patients with high BACH1 mRNA expression was markedly shorter than those with low expression (Pâ¯=â¯0.015), and multivariate analyzes results showed that BACH1 was an independent prognostic predictor for CRC patients (Pâ¯=â¯0.049). In vitro studies revealed that BACH1 efficiently promoted invasion and migration of CRC cell line. In vitro studies proved that the HCT116â¯cell stably expressing BACH1 formed significantly larger tumor nodules and remarkably accelerated tumor xenografts growth. In addition, Immunohistochemical scores of CD31 and Vimentin were significantly higher than those of the control group. Finally, correlation analysis indicated that BACH1 expression was positively correlated with C-X-C Motif Chemokine Receptor 4(CXCR4) in tumor tissues and cell lines. Together, BACH1 serves as an oncogene to promote CRC progression and an independent prognostic factor for survival and metastasis. BACH1 may inhibit the progression of CRC through BACH1/CXCR4 pathway.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Receptores CXCR4/metabolismo , Transducción de Señal , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Colorrectales/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Modelos de Riesgos Proporcionales , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores CXCR4/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The homeoprotein Bapx1 is an important regulator of gastroduodenal tract morphogenesis. Here, we investigated how Bapx1 influences gastric cancer (GC) prognosis and elucidated the underlying mechanisms. Bapx1 expression was greater in GC tissues compared to adjacent non-tumor tissues and expression was positively correlated with mortality, lymph node and distance metastasis. Silencing Bapx1 diminished cell invasion/migration and decreased mesenchymal phenotypes. Transforming growth factor-ß (TGF-ß) induced Bapx1 expression and epithelial-mesenchymal transition (EMT) in GC cells. However, down-regulated Bapx1 reversed TGF-ß induced invasion, migration, morphological changes, and EMT. In summary, Bapx1 indicates poor prognosis for GC by promoting tumor migration and invasion via TGF-ß-induced EMT.
Asunto(s)
Carcinoma/genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/genética , Neoplasias Gástricas/genética , Factores de Transcripción/genética , Factor de Crecimiento Transformador beta/farmacología , Anciano , Antígenos CD , Cadherinas/genética , Cadherinas/metabolismo , Carcinoma/diagnóstico , Carcinoma/mortalidad , Carcinoma/cirugía , Línea Celular , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Femenino , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Proteínas de Homeodominio/antagonistas & inhibidores , Proteínas de Homeodominio/metabolismo , Humanos , Metástasis Linfática , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/cirugía , Análisis de Supervivencia , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Vimentina/genética , Vimentina/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
The total internal reflection (TIR) effect in conventional electroluminescent devices causes a large amount of light energy trapped in the devices and result in heat energy that adversely affects the performance of the device. In order to enhance the light out-coupling efficiency without sacrificing the electrical properties, a micro-rod array (MRA) structure fabricated by a femtosecond laser was demonstrated. Green, blue, and red organic light-emitting diodes were employed to verify the effect of the proposed method, which increases out-coupling efficiencies by a factor of 1.9, 1.7, and 1.82, respectively, compared with conventional devices. This highly effective method is compatible with current device fabrication processes and is applicable to full-color electroluminescent devices.
RESUMEN
A high directional backlight system that combined a composite microstructure light guide plate (LGP) with a collimated light source was proposed for eco-displays. The collimated planar light was expanded from a point light source and guided towards the normal direction by utilizing the micro-prism array on LGP. High uniformity of spatial luminous, 91%, with a narrow viewing cone of ± 4° can be achieved without additional optical films. Moreover, compared to the conventional backlight, only 5% of power consumption was needed to keep the same luminance, hence, the optical efficiency increased by a factor of 1.47.
RESUMEN
Postpartum elevation of alanine aminotransferase (ALT) in mothers with chronic hepatitis B (CHB) presents a significant clinical challenge. However, the existing literature demonstrates inconsistencies regarding its incidence and predictors in mothers infected with the hepatitis B virus (HBV). Recent advancements in antiviral prophylaxis against mother-to-child transmission of HBV and postpartum cessation of antiviral therapy further complicate this issue. Our literature review, spanning PubMed, and two Chinese-language databases (CNKI and Wanfang) from 1 January 2000 to 31 December 2023 aimed to consolidate and analyse available data on the frequency and severity of postpartum ALT flares, identify risk factors, and propose a management algorithm. Data from 23 eligible studies involving 8,077 pregnant women revealed an overall incidence of postpartum ALT elevation: 25.7% for mild cases, 4.4% for moderate cases, and 1.7% for severe cases. In the subgroup of mothers who were HBeAg-positive and on antiviral prophylaxis for preventing mother-to-child transmission, postpartum intermediate and severe ALT elevations were reported with pooled rates of 5.9% and 0.8%, respectively. Importantly, none resulted in mortality or necessitated liver transplantation. Identified risk factors for postpartum ALT flares in mothers with CHB included HBV DNA levels, ALT levels during pregnancy, postpartum cessation of antiviral treatment, and HBeAg status. By leveraging this evidence and recent data on predictors of intermediate or severe postpartum ALT flares, we propose a risk-stratified algorithm for managing postpartum ALT elevation and selecting therapy in mothers with CHB, tailoring different approaches for treatment-naive vs treatment-experienced populations. These recommendations aim to provide guidance for clinical decision-making and enhance patient outcomes.
RESUMEN
BACKGROUND: Radiofrequency ablation (RFA) is an effective therapy for hepatocellular carcinoma (HCC). However, incomplete radiofrequency ablation (IRFA) can promote the progression of residual cancer cells, which is a serious problem in the clinical application of RFA. Therefore, it is of great significance to explore the mechanism and countermeasures of the progression of residual tumors after IRFA. Our previous study confirmed that IRFA can activate the hypoxia/ autophagy pathway of residual tumors in mice and then induce the proliferation of residual tumor cells. Additionally, we found a metal ruthenium complex [Ru(bpy)2(ipad)](ClO4)2 (Ru, where bpy = 2,2'-bipyridine and ipad = 2-(anthracene-9,10-dione-2-yl)imidazo[4,5-f][1,10]phenanthroline) can effectively inhibit hypoxia-inducible factor (HIF-1α) and has good anti-tumor effect in a hypoxic environment; however, whether Ru could suppress the proliferation of residual tumor cells after IRFA is unknown. OBJECTIVE: This study intends to evaluate the effect of Ru in suppressing the proliferation of residual hepatocellular carcinoma after IRFA in a mice model. METHODS: The Hepa1-6 xenograft mouse model was established in C57BL/6 mice to simulate clinical IRFA. H&E staining was used to evaluate the biosafety of major organs in the treated mice. TUNEL assay was employed to assess the antitumor effect. Immunohistochemically and immunofluorescence staining was performed to detect the expression of HIF-1α and autophagy-related proteins. The ELISA assay was used to examine the cytokines of interferon-gamma (IFN-γ) and interleukin 10 (IL-10). RESULTS: Our findings revealed that the residual tumor relapsed via the HIF-1α/LC3B/P62 autophagy- related pathway after IRFA, while Ru could suppress this process. In addition, it was demonstrated that Ru could effectively activate the immune system of the mice and reverse the tumor immune suppression microenvironment after IRFA. CONCLUSION: The ruthenium complex Ru could suppress the proliferation of residual hepatocellular carcinoma cells after IRFA in the mice model. This study introduces a novel approach that combines the use of ruthenium complexes with IRFA, offering a potential solution to address the reoccurrence of residual liver cancer following IRFA in clinical settings.
RESUMEN
Scrub typhus (ST) is an acute focal infectious disease that is caused by Orientia tsutsugamushi. The Asia-Pacific region is an area of relatively high incidence. There is a high incidence in China, principally owing to the disease being endemic in the south of the country. The main source of ST infection is rats, which act as reservoirs of infection after being bitten by the chigger mite, and the human population is generally susceptible to the disease. ST can be controlled and treated successfully if antibiotics are administered in a timely manner. However, because it does not have a specific clinical manifestation, it is difficult to distinguish ST from other febrile diseases in clinical practice. Therefore, rapid diagnostic methods are still needed to help clinicians make a timely diagnosis. Here, we share three cases of patients with ST who experienced hemorrhage, but did not have typical skin lesions, such as eschar and ulcer, early in the course of their disease, and review the relevant literature regarding ST. We conclude that clinicians should pay attention to the risk of hemorrhage associated with this disease, and emphasize the importance of making an early diagnosis.
Asunto(s)
Orientia tsutsugamushi , Tifus por Ácaros , Enfermedades Vasculares , Humanos , Animales , Ratas , Tifus por Ácaros/complicaciones , Tifus por Ácaros/diagnóstico , Tifus por Ácaros/tratamiento farmacológico , Hemorragia/complicaciones , Asia , Enfermedades Vasculares/complicacionesRESUMEN
Acute liver failure (ALF) is a severe liver disease caused by disruptions in the body's immune microenvironment. In the early stages of ALF, Kupffer cells (KCs) become depleted and recruit monocytes derived from the bone marrow or abdomen to replace the depleted macrophages entering the liver. These monocytes differentiate into mature macrophages, which are activated in the immune microenvironment of the liver and polarized to perform various functions. Macrophage polarization can occur in two directions: pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. Controlling the ratio and direction of M1 and M2 in ALF can help reduce liver injury. However, the liver damage caused by pyroptosis should not be underestimated, as it is a caspase-dependent form of cell death. Inhibiting pyroptosis has been shown to effectively reduce liver damage induced by ALF. Furthermore, macrophage polarization and pyroptosis share common binding sites, signaling pathways, and outcomes. In the review, we describe the role of macrophage polarization and pyroptosis in the pathogenesis of ALF. Additionally, we preliminarily explore the relationship between macrophage polarization and pyroptosis, as well as their effects on ALF.
Asunto(s)
Fallo Hepático Agudo , Piroptosis , Humanos , Hepatocitos/metabolismo , Fallo Hepático Agudo/patología , Macrófagos del Hígado , MacrófagosRESUMEN
BACKGROUND: Cerebral malaria (CM) is a manifestation of malaria caused by plasmodium infection. It has a high mortality rate and severe neurological sequelae, existing a significant research gap and requiring further study at the molecular level. METHODS: We downloaded the GSE117613 dataset from the Gene Expression Omnibus (GEO) database to determine the differentially expressed genes (DEGs) between the CM group and the control group. Weighted gene coexpression network analysis (WGCNA) was applied to select the module and hub genes most relevant to CM. The common genes of the key module and DEGs were selected to perform further analysis. The least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine recursive feature elimination (SVM-RFE) were applied to screen and verify the diagnostic markers of CM. Eventually, the hub genes were validated in the external dataset. Gene set enrichment analysis (GSEA) was applied to investigate the possible roles of the hub genes. RESULTS: The GO and KEGG results showed that DEGs were enriched in some neutrophil-mediated pathways and associated with some lumen structures. Combining LASSO and the SVM-RFE algorithms, LEF1 and IRAK3 were identified as potential hub genes in CM. Through the GSEA enrichment results, we found that LEF1 and IRAK3 participated in maintaining the integrity of the blood-brain barrier (BBB), which contributed to improving the prognosis of CM. CONCLUSIONS: This study may help illustrate the pathophysiology of CM at the molecular level. LEF1 and IRAK3 can be used as diagnostic biomarkers, providing new insight into the diagnosis and prognosis prediction in pediatric CM.
Asunto(s)
Malaria Cerebral , Niño , Humanos , Malaria Cerebral/diagnóstico , Malaria Cerebral/genética , África , Algoritmos , Aprendizaje Automático , BiomarcadoresRESUMEN
Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 (DNAH10) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.
Asunto(s)
Trastornos de la Motilidad Ciliar , Semen , Humanos , Masculino , Animales , Ratones , Semen/metabolismo , Dineínas/genética , Dineínas/metabolismo , Cilios/genética , Cilios/metabolismo , Mutación , Trastornos de la Motilidad Ciliar/genéticaRESUMEN
Background: Drug exposure during gestation or in prematurely born children represents a significant risk to congenital heart disease (CHD). Amantadine is an antiviral agent also effective in the treatment of Parkinson's disease. However, while its potential side effects associated with tetralogy of fallot (ToF) and birth defects were implicated, its underlying etiologic mechanisms of action remain unknown. Here, we report teratogenic effects of amantadine drug during early cardiogenesis through developing a novel zebrafish (Danio rerio) knock-in (KI) animal model and explore the underlying mechanisms. Methods: Homologous recombination (HR) pathway triggered by CRISPR/Cas9 system was utilized to generate an enhanced green fluorescent protein (EGFP) KI zebrafish animal model. Dynamic fluorescence imaging coupled with a whole-mount in-situ hybridization (WISH) assay was employed to compare the spatial and temporal expression patterns of the EGFP reporter in the KI animal model with the KI-targeted endogenous gene. Heart morphology and EGFP expression dynamics in the KI animal models were monitored to assess cardiac side effects of different doses of amantadine hydrochloride. Expression of key genes required for myocardium differentiation and left-right (LR) asymmetry was analyzed using WISH and quantitative reverse transcription-PCR (RT-PCR). Results: A novel EGFP KI line targeted at the ventricular myosin heavy chain (vmhc) gene locus was successfully generated, in which EGFP reporter could faithfully recapitulate the endogenous expression dynamics of the ventricle chamber-specific expression of the vmhc gene. Amantadine drug treatment-induced ectopic expression of vmhc gene in the atrium and caused cardiac-looping or LR asymmetry defects to dose-dependently during early cardiogenesis, concomitant with dramatically reduced expression levels of key genes required for myocardium differentiation and LR asymmetry. Conclusion: We generated a novel zebrafish KI animal model in which EGFP reports the ventricle chamber-specific expression of vmhc gene dynamics that is useful to effectively assess drug safety on the cardiac morphology in vivo. Specifically, this study identified teratogenic effects of amantadine drug during early cardiogenesis dose dependent, which could be likely conveyed by inhibiting expression of key genes required for cardiac myocardium differentiation and LR asymmetry.
RESUMEN
Xpert Xpress Flu/RSV is a fast and automated real-time nucleic acid amplification tool for detecting influenza virus and respiratory syncytial virus (RSV). The aim of this study was to verify the accuracy of Xpert Xpress Flu/RSV for detecting influenza virus and RSV. PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched up to October 2020. The quality of the original research was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 guidelines. Meta-DiSc 1.4 software was used to analyze the sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and summary receiver operating characteristic curve. Deek's funnel plot asymmetry test was used to evaluate the publication bias using the Stata 12.0 software. Ten studies with 25 fourfold tables were included in the analysis. The sensitivity of Xpert Xpress Flu/RSV for detecting influenza A, influenza B, and RSV were 0.97, 0.98, and 0.96, respectively, and the specificities were 0.97, 1.00, and 1.00, respectively. Compared with other common clinical real-time reverse transcription-polymerase chain reaction (RT-PCR), Xpert Xpress Flu/RSV is a valuable tool for diagnosing influenza virus and RSV with high sensitivity and specificity.