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INTRODUCTION: The bidirectional relationship between the brain cortex and cardiovascular diseases (CVDs) remains inadequately explored. METHODS: This study used bidirectional Mendelian randomization (MR) analysis to explore the interactions between nine phenotypes associated with hypertension, heart failure, atrial fibrillation (AF), and coronary heart disease (CHD), and brain cortex measurements. These measurements included total surface area (SA), average thickness (TH), and the SA and TH of 34 regions defined by the Desikan-Killiany atlas. The nine traits were obtained from sources such as the UK Biobank and FinnGen, etc., while MRI-derived traits of cortical structure were sourced from the ENIGMA Consortium. The primary estimate was obtained using the inverse-variance weighted approach. A false discovery rate adjustment was applied to the p-values (resulting in q-values) in the analyses of regional cortical structures. RESULTS: A total of 1,260 two-sample MR analyses were conducted. Existing CHD demonstrated an influence on the SA of the banks of the superior temporal sulcus (bankssts) (q=0.018) and the superior frontal lobe (q=0.018), while hypertension was associated with changes in the TH of the lateral occipital region (q=0.02). Regarding the effects of the brain cortex on CVD incidence, total SA was significantly associated with the risk of CHD. Additionally, 16 and 3 regions exhibited significant effects on blood pressure and AF risk, respectively (q<0.05). These regions were primarily located in the frontal, temporal, and cingulate areas, which are associated with cognitive function and mood regulation. CONCLUSION: The detection of cortical changes through MRI could aid in screening for potential neuropsychiatric disorders in individuals with established CVD. Moreover, abnormalities in cortical structure may predict future CVD risk, offering new insights for prevention and treatment strategies.
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Noradrenaline belongs to the monoamine system and is involved in cognition and emotional behaviors. Phox2a and Phox2b play essential but non-redundant roles during development of the locus coeruleus (LC), the main noradrenergic (NA) neuron center in the mammalian brain. The ubiquitin E3 ligase Rnf220 and its cofactor Zc4h2 participate in ventral neural tube patterning by modulating Shh/Gli signaling, and ZC4H2 mutation is associated with intellectual disability, although the mechanisms for this remain poorly understood. Here, we report that Zc4h2 and Rnf220 are required for the development of central NA neurons in the mouse brain. Both Zc4h2 and Rnf220 are expressed in developing LC-NA neurons. Although properly initiated at E10.5, the expression of genes associated with LC-NA neurons is not maintained at the later embryonic stages in mice with a deficiency of either Rnf220 or Zc4h2 In addition, we show that the Rnf220/Zc4h2 complex monoubiquitylates Phox2a/Phox2b, a process required for the full transcriptional activity of Phox2a/Phox2b. Our work reveals a role for Rnf220/Zc4h2 in regulating LC-NA neuron development, and this finding may be helpful for understanding the pathogenesis of ZC4H2 mutation-associated intellectual disability.
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Neuronas Adrenérgicas/fisiología , Proteínas de Homeodominio/metabolismo , Péptidos y Proteínas de Señalización Intracelular/fisiología , Neurogénesis/fisiología , Proteínas Nucleares/fisiología , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/fisiología , Ubiquitinación/genética , Neuronas Adrenérgicas/metabolismo , Animales , Diferenciación Celular/genética , Embrión de Pollo , Embrión de Mamíferos , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Transgénicos , Norepinefrina/metabolismoRESUMEN
Soma spacing and dendritic arborization during brain development are key events for the establishment of proper neural circuitry and function. Transcription factor Satb2 is a molecular node in regulating the development of the cerebral cortex, as shown by the facts that Satb2 is required for the regionalization of retrosplenial cortex, the determination of callosal neuron fate, and the regulation of soma spacing and dendritic self-avoidance of cortical pyramidal neurons. In this study, we explored downstream effectors that mediate the Satb2-implicated soma spacing and dendritic self-avoidance. First, RNA-seq analysis of the cortex revealed differentially expressed genes between control and Satb2 CKO mice. Among them, EphA7 transcription was dramatically increased in layers II/III of Satb2 CKO cortex. Overexpression of EphA7 in the late-born cortical neurons of wild-type mice via in utero electroporation resulted in soma clumping and impaired self-avoidance of affected pyramidal neurons, which resembles the phenotypes caused by knockdown of Satb2 expression. Importantly, the phenotypes by Satb2 knockdown was rescued by reducing EphA7 expression in the cortex. Finally, ChIP and luciferase reporter assays indicated a direct suppression of EphA7 expression by Satb2. These findings provide new insights into the complexity of transcriptional regulation of the morphogenesis of cerebral cortex.
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Corteza Cerebral , Neuronas , Animales , Cuerpo Celular/metabolismo , Corteza Cerebral/metabolismo , Proteínas de Unión a la Región de Fijación a la Matriz , Ratones , Neuronas/metabolismo , Células Piramidales/metabolismo , Receptor EphA7 , Factores de Transcripción/metabolismoRESUMEN
PURPOSE: We investigated whether increased expression of activated mitogen-activated protein kinase (MAPK) kinases 1 (MEK1) restores ischemic post-conditioning (IPostC) protection in hypertrophic myocardium following ischemia/reperfusion (I/R) injury. METHODS: C57Bl/6 mice received recombinant adeno-associated virus type 9 (rAAV9)-mediated activated MEK1 gene delivery systemically, then following the induction of cardiac hypertrophy via transverse aortic constriction for 4 weeks. In a Langendorff model, hypertrophic hearts were subjected to 40 min/60 min I/R or with IPostC intervention consisting of 6 cycles of 10 s reperfusion and 10 s no-flow before a 60-min reperfusion. Hemodynamics, infarct size (IS), myocyte apoptosis and changes in expression of reperfusion injury salvage kinase (RISK) pathway were examined. RESULTS: rAAV9-MEK1 gene delivery led to a 4.3-fold and 2.7-fold increase in MEK1 mRNA and protein expression in the heart versus their control values. I/R resulted in a larger IS in hypertrophic than in non-hypertrophic hearts (52.3 ± 4.7% vs. 40.0 ± 2.5%, P < 0.05). IPostC mediated IS reduction in non-hypertrophic hearts (27.6 ± 2.6%, P < 0.05), while it had no significant effect in hypertrophic hearts (46.5 ± 3.1%, P=NS) compared with the IS in non-hypertrophic or hypertrophic hearts subjected to I/R injury only, respectively. Hemodynamic decline induced by I/R was preserved by IPostC in non-hypertrophic hearts but not in hypertrophic hearts. rAAV9-MEK1 gene delivery restored IPostC protection in hypertrophic hearts evidenced by reduced IS (32.0 ± 2.8% vs. 46.5 ± 3.1%) and cardiac cell apoptosis and largely preserved hemodynamic parameters. These protective effects were associated with significantly increased phosphorylation of ERK1/2 and ribosomal protein S6 kinases (p70S6K), but it had no influence on Akt and glycogen synthase kinase-3ß. CONCLUSION: These results demonstrated that rAAV9-mediated activated MEK1 expression restores IPostC protection in the hypertrophic heart against I/R injury through the activation of ERK pathway.
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Dependovirus/genética , Técnicas de Transferencia de Gen , Vectores Genéticos , Hipertrofia Ventricular Izquierda/terapia , Poscondicionamiento Isquémico , MAP Quinasa Quinasa 1/biosíntesis , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/enzimología , Animales , Apoptosis , Modelos Animales de Enfermedad , Inducción Enzimática , Hipertrofia Ventricular Izquierda/enzimología , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/patología , Preparación de Corazón Aislado , MAP Quinasa Quinasa 1/genética , Masculino , Ratones Endogámicos C57BL , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Infarto del Miocardio/enzimología , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/enzimología , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/patología , Miocardio/patología , Fosforilación , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismoRESUMEN
OBJECTIVE: To investigate the use of antibiotics in children with community-acquired pneumonia (CAP) in multiple regions of China, and to provide a reference for CAP standard treatment and rational antibiotic use in children. METHODS: The medical data of 1 383 children with CAP who were hospitalized in the department of pediatrics in 10 grade A tertiary hospitals from 9 cities between April 14, 2014 and January 1, 2016 were reviewed, to analyze the status of antibiotic use in hospitalized children in North China, Northeast China, East China, and South China. RESULTS: The overall rate of antibiotic use in children with CAP was 89.08%, with 88.7% in North China, 95.5% in Northeast China, 83.3% in East China, and 86.6% in South China. The main types of antibiotics used were cephalosporins, macrolides, compound preparations of ß-lactam antibiotics, polyphosphoric broad-spectrum antibiotics and other ß-lactam antibiotics. The selection of antibiotics was generally rational, but antibiotics were still used in some patients with viral infection alone or a combined use of ≥2 kinds of antibiotics were noted in some patients with infection caused by one kind of pathogen. Irrational antibiotic use was observed in 131 children (10.63%). CONCLUSIONS: There are high rates of antibiotic use and irrational use of antibiotics among children with CAP. Standard management of antibiotic use in children with CAP should be strengthened.
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Infecciones Comunitarias Adquiridas , Antibacterianos/uso terapéutico , Niño , Niño Hospitalizado , China , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , HumanosRESUMEN
BACKGROUND: In animal models, secreted frizzled related protein 1 (Sfrp1) inhibition of the Wnt signaling pathway is beneficial because Sfrp1 reduces myocardial apoptosis and prevents heart failure. The mechanisms mediating the cellular survival effect of Sfrp1 has not been completely elucidated. The present study was designed to investigate the possible protective actions of Sfrp1 on cardiac muscle cells using an in vitro model of ischemia/reperfusion, and to evaluate the possible involvement of the Wnt signaling pathway. METHODS: We used a recombinant AAV9 vector to deliver the Sfrp1 gene into H9C2 rat cardiomyoblasts and adopted an in vitro model of ischemia/reperfusion. Cell vitality was measured by CKK-8 and the trypan blue exclusion assay. Western blot was used to evaluate the expression of Dvl-1, ß-catenin, c-Myc, Bax, and Bcl-2. Flow cytometry analysis of cardiomyocyte apoptosis was performed. RESULTS: We confirmed that Sfrp1 significantly increased cell viability (assayed by trypan blue and CKK-8) and decreased apoptosis (assayed by flow cytometry analysis and the Bax/Bcl-2 ratio). These effects were partly attributable to the ability of Sfrp1 to down-regulate Wnt signaling pathway (assayed by Western blot to evaluate the expression of Dvl-1, ß-catenin, and c-Myc). Indeed, reactivation of the Wnt signaling pathway activity with the specific activator, Licl, reduced Sfrp1-induced cardioprotection during hypoxia and reoxygenation. CONCLUSIONS: The present study demonstrated that Sfrp1 directly protected H9C2 cells from hypoxia and reoxygenation-induced reperfusion injury and apoptosis through inhibition of the Wnt signaling pathway, and added new mechanistic insight regarding the cardioprotective role of Sfrp1 on ischemic damage.
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Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de la Membrana/metabolismo , Miocardio/metabolismo , Vía de Señalización Wnt , Animales , Apoptosis , Hipoxia de la Célula/fisiología , Línea Celular , Supervivencia Celular , Regulación de la Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de la Membrana/genética , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/citología , Miocardio/patología , Ratas , Proteína X Asociada a bcl-2/metabolismo , beta Catenina/metabolismoRESUMEN
Adeno-associated virus (AAV) has become one of the most promising gene transfer tools for gene therapy. This work aims to evaluate tropism, gene transfer efficiency and safety of AAV9 vectors produced with recombinant baculovirus (rBac)-based system. AAV9-CMV-GFP and AAV9-CBA-GFP were produced using a rBac system, 1 × 10(11) particles of each vectors were administered intravenously (i.v.) into mice and animals were killed at 1, 2, 3, 4, 5 and 8 weeks after administration. The GFP expression in different organs was analyzed by fluorescence imaging and Western blot. Viral genomic quantities were measured using qPCR. In vitro transduction efficiency of AAV9 vectors in primary cardiomyocytes and hepatocytes was determined by flow cytometry. Toxicity of AAV9 vectors was evaluated by determining certain cardiac and liver injury biomarkers and renal function test in vivo and TUNEL analysis in vitro. The data showed that AAV9 viral particles packaged by the rBac system were fully functional in vivo and in vitro. The CMV promoter predominantly induced higher cardiac GFP transgene expression and DNA copy numbers while the CBA promoter resulted in robust GFP expression and high vector DNA copy numbers in mouse liver, both in a time-dependent increased manner. Such distinct preferential effects were also observed in the heart and liver as early as 3 and 5 days after co-infection. Both the AAV9-CMV and AAV9-CBA viral packages did not induce heart, liver and renal damage and cell apoptosis. These results indicated that AAV9-CMV can efficiently and safely direct cardiac gene transfer, whereas AAV9-CBA is preferential for liver gene delivery.
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Dependovirus/genética , Hepatocitos/metabolismo , Miocitos Cardíacos/metabolismo , Regiones Promotoras Genéticas/genética , Transducción Genética/métodos , Transgenes/genética , Actinas/genética , Animales , Apoptosis/genética , Pollos/genética , Citomegalovirus/genética , Dependovirus/fisiología , Vectores Genéticos/genética , Hepatocitos/citología , Hepatocitos/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/citología , Miocitos Cardíacos/virología , Seguridad , Tropismo ViralAsunto(s)
Asma , Leucocitos Mononucleares , Alérgenos , Humanos , Células Asesinas Naturales , Análisis de Secuencia de ARNRESUMEN
BACKGROUND: Changes of miRNAs in exosome have been reported in different disease diagnosis and provided as potential biomarkers. In this study, we compared microRNA profile in exosomes in 5 MHFMD and 5 ESHFMD as well as in 5 healthy children. METHODS: Different expression of miRNAs in exosomes across all the three groups were screened using miRNA microarray method. Further validated test was conducted through quantitative real-time PCR assays with 54 exosome samples (18 ESHFMD, 18 MHFMD, and 18 healthy control). The judgment accuracy was then estimated by the receiver operating characteristic (ROC) curve analysis; and the specificity and sensitivity were evaluated by the multiple logistic regression analysis. RESULTS: There were 11 different miRNAs in exosomes of MHFMD and ESHFMD compared to healthy children, of which 4 were up-regulated and 7 were down-regulated. Further validation indicated that the 4 significant differentially expressed candidate miRNAs (miR-671-5p, miR-16-5p, miR-150-3p, and miR-4281) in exosome showed the same changes as in the microarray analysis, and the expression level of three miRNAs (miR-671-5p, miR-16-5p, and miR-150-3p) were significantly different between MHFMD or ESHFMD and the healthy controls. The accuracy of the test results were high with the under curve (AUC) value range from 0.79 to 1.00. They also provided a specificity of 72%-100% and a sensitivity of 78%-100%, which possessed ability to discriminate ESHFMD from MHFMD with the AUC value of 0.76-0.82. CONCLUSIONS: This study indicated that the exosomal miRNA from patients with different condition of HFMD express unique miRNA profiles. Exosomal miRNA expression profiles may provide supplemental biomarkers for diagnosing and subtyping HFMD infections.
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Exosomas/metabolismo , Enfermedad de Boca, Mano y Pie/diagnóstico , MicroARNs/genética , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Diagnóstico Diferencial , Exosomas/genética , Ontología de Genes , Enfermedad de Boca, Mano y Pie/sangre , Enfermedad de Boca, Mano y Pie/genética , Humanos , MicroARNs/sangre , Anotación de Secuencia Molecular , Curva ROC , Reacción en Cadena en Tiempo Real de la Polimerasa , Índice de Severidad de la Enfermedad , Transcriptoma , Regulación hacia ArribaRESUMEN
BACKGROUND: The optimal cutoff of the waist-to-hip ratio (WHR) among Han adults in Xinjiang, which is located in the center of Asia, is unknown. We aimed to examine the relationship between different WHRs and cardiovascular risk factors among Han adults in Xinjiang, and determine the optimal cutoff of the WHR. METHODS: The Cardiovascular Risk Survey was conducted from October 2007 to March 2010. A total of 14618 representative participants were selected using a four-stage stratified sampling method. A total of 5757 Han participants were included in the study. The present statistical analysis was restricted to the 5595 Han subjects who had complete anthropometric data. The sensitivity, specificity, and distance on the receiver operating characteristic (ROC) curve in each WHR level were calculated. The shortest distance in the ROC curves was used to determine the optimal cutoff of the WHR for detecting cardiovascular risk factors. RESULTS: In women, the WHR was positively associated with systolic blood pressure, diastolic blood pressure, and serum concentrations of serum total cholesterol. The prevalence of hypertension and hypertriglyceridemia increased as the WHR increased. The same results were not observed among men. The optimal WHR cutoffs for predicting hypertension, diabetes, dyslipidemia and ≥ two of these risk factors for Han adults in Xinjiang were 0.92, 0.92, 0.91, 0.92 in men and 0.88, 0.89, 0.88, 0.89 in women, respectively. CONCLUSIONS: Higher cutoffs for the WHR are required in the identification of Han adults aged ≥ 35 years with a high risk of cardiovascular diseases in Xinjiang.
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Pueblo Asiatico , Enfermedades Cardiovasculares/etnología , Obesidad/diagnóstico , Obesidad/etnología , Relación Cintura-Estatura , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Biomarcadores/sangre , Presión Sanguínea , China/epidemiología , Femenino , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/etnología , Hipertensión/diagnóstico , Hipertensión/etnología , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/etnología , Lípidos/sangre , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Factores de Riesgo , Factores SexualesRESUMEN
OBJECTIVE: This study aimed to identify the best predictor of metabolic syndrome (MetS) by comparing the predicting ability of various anthropometric and atherogenic parameters in the Chinese Han population in Xinjiang. METHODS: A representative, cross-sectional sample of 5,757 Chinese Han adults were selected from the Cardiovascular Risk Survey conducted from October 2007 to March 2010. MetS prevalence, area under the curve (AUC), distance on the receiver operating characteristic curve and the cut-offs of each variable were compared for the presence of MetS. RESULTS: According to the criteria of the International Diabetes Federation (IDF), the Joint Interim Statement (JIS) and the Third Adult Treatment Panel (ATPIII), 32.1, 48.5, 39.3% of men and 38.0, 45.1, 44.9% of women had MetS in Xinjiang. According to the IDF criteria, the waist-to-height ratio (WHtR) had the highest AUC value in men (0.836) and women (0.837), with the optimal cut-off of 0.54 in men and 0.53 in women. According to both the JIS and ATPIII criteria, triglycerides/high-density lipoprotein cholesterol TG/HDL-C had the highest AUC value in men (0.830 and 0.833, respectively) and women (0.832 and 0.827, respectively), with the optimal cut-offs being 1.6 and 1.2 in men and 1.1 and 1.1 in women, respectively. CONCLUSION: WHtR was the best predictor of MetS according to the IDF criteria while TG/HDL-C was the best predictor of MetS according to the JIS and ATPIII criteria.
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Antropometría , Síndrome Metabólico/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Pueblo Asiatico/estadística & datos numéricos , Aterosclerosis/complicaciones , Aterosclerosis/diagnóstico , China/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prevalencia , Factores de Riesgo , Población Rural/estadística & datos numéricos , Factores Sexuales , Relación Cintura-EstaturaRESUMEN
BACKGROUND: To clarify the molecular mechanisms that participate in the severe hand, foot and mouth disease (HFMD) infected by Enterovirus 71 and to detect any related protein biomarkers, we performed proteomic analysis of protein extracts from 5 extremely severe HFMD children and 5 healthy children. METHODS: The protein profiles of them were compared using two-dimensional electrophoresis. Differentially expressed proteins were identified using mass spectrometry. Functional classifications of these proteins were based on the PANTHER. The interaction network of the differentially expressed protein was generated with Pathway Studio. RESULTS: A total of 38 differentially expressed proteins were identified. Functional classifications of these proteins indicated a series of altered cellular processes as a consequence of the severe HFMD. These results provided not only new insights into the pathogenesis of severe HFMD, but also implications of potential therapeutic designs. CONCLUSIONS: Our results suggested the possible pathways that could be the potential targets for novel therapy: viral protection, complement system and peroxide elimination.
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Enterovirus Humano A/aislamiento & purificación , Enfermedad de Boca, Mano y Pie/sangre , Proteoma/análisis , Proteínas Sanguíneas/análisis , Western Blotting , Electroforesis en Gel Bidimensional , Humanos , Mapas de Interacción de Proteínas , Proteómica , Reproducibilidad de los Resultados , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
BACKGROUND: Community-acquired pneumonia in children is common in China. To understand current clinical characteristics and practice, we conducted a cross-sectional study to analyze quality of care on childhood pneumonia in eight eastern cities in China. METHODS: Consecutive hospital records between January 1, 2010 and December 31, 2010 were collected from 13 traditional Chinese medicine (TCM) and western medicine (WM) hospitals in February, May, August, and November (25 cases per season, 100 cases over the year), respectively. A predesigned case report form was used to extract data from the hospital medical records. RESULTS: A total of 1298 cases were collected and analyzed. Symptoms and signs upon admission at TCM and WM hospitals were cough (99.3% vs. 98.6%), rales (84.8% vs. 75.0%), phlegm (83.3% vs. 49.1%), and fever (74.9% vs. 84.0%) in frequency. Patients admitted to WM hospitals had symptoms and signs for a longer period prior to admission than patients admitted to TCM hospitals. Testing to identify etiologic agents was performed in 1140 cases (88.4%). Intravenous antibiotics were administered in 99.3% (595/598) of cases in TCM hospitals and in 98.6% (699/700) of cases in WM hospitals. Besides, Chinese herbal extract injection was used more frequently in TCM hospitals (491 cases, 82.1%) than in WM hospitals (212 cases, 30.3%) (p < 0.01). At discharge, 818 cases (63.0%) were clinically cured, with a significant difference between the cure rates in TCM (87.6%) and WM hospitals (42.0%) (OR = 9.8, 95% confidence interval (CI): 7.3 ~ 12.9, p < 0.01). Pathogen and previous medical history were more likely associated with the disappearance of rales (OR = 7.2, 95% CI: 4.8 ~ 10.9). Adverse effects were not reported from the medical records. CONCLUSIONS: Intravenous use of antibiotics is highly prevalent in children with community-acquired pneumonia regardless of aetiology. There was difference between TCM and WM hospitals with regard to symptom profile and the use of antibiotics. Intravenous use of herbal injection was higher in TCM hospitals than in WM hospitals. Most of the cases were diagnosed based on clinical signs and symptoms without sufficient confirmation of aetiology. Audit of current practice is urgently needed to improve care.
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Infecciones Comunitarias Adquiridas/epidemiología , Hospitalización/estadística & datos numéricos , Medicina Tradicional China/métodos , Neumonía Bacteriana/epidemiología , Adolescente , Antibacterianos/uso terapéutico , Niño , Preescolar , China , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/microbiología , Estudios Transversales , Medicamentos Herbarios Chinos/uso terapéutico , Femenino , Hospitales , Humanos , Lactante , Masculino , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Resultado del TratamientoRESUMEN
To establish functional circuitry, neurons settle down in a particular spatial domain by spacing their cell bodies, which requires proper positioning of the soma and establishing of a zone with unique connections. Deficits in this process are implicated in neurodevelopmental diseases. In this study, we examined the function of EphB6 in the development of cerebral cortex. Overexpression of EphB6 via in utero electroporation results in clumping of cortical neurons, while reducing its expression has no effect. In addition, overexpression of EphrinB2, a ligand of EphB6, also induces soma clumping in the cortex. Unexpectedly, the soma clumping phenotypes disappear when both of them are overexpressed in cortical neurons. The mutual inhibitory effect of EphB6/ EphrinB2 on preventing soma clumping is likely to be achieved via interaction of their specific domains. Thus, our results reveal a combinational role of EphrinB2/EphB6 overexpression in controlling soma spacing in cortical development.
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Efrina-B2 , Receptor EphB6 , Receptor EphB6/metabolismo , Efrina-B2/genética , Efrina-B2/metabolismo , Cuerpo Celular/metabolismo , Neuronas/metabolismoRESUMEN
Brain community detection is an efficient method to represent the communities of brain networks. However, time-variable functions of the brain and the intricate brain community structure impose a great challenge on it. In this paper, a time-sequential graph adversarial learning (TGAL) framework is proposed to detect brain communities and characterize the structure of communities from brain networks. In the framework, a novel time-sequential graph neural network is designed as an encoder to extract efficient graph representations by spatio-temporal attention mechanism. Since it is difficult to capture the community structure, the measurable modularity loss is used to optimize by maximizing the modularity of the community. In addition, the framework employs an adversarial scheme to guide the learning of representation. The effectiveness of our model is shown through experiments on the real-world brain network datasets, and the great performance of brain community detection demonstrates the advantage of the proposed framework.
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Encéfalo , Aprendizaje , Encéfalo/diagnóstico por imagen , Redes Neurales de la ComputaciónRESUMEN
The accurate expression of postsynaptic AMPA receptors (AMPARs) is critical for information processing in the brain, and ubiquitination is a key regulator for this biological process. However, the roles of E3 ubiquitin ligases in the regulation of AMPARs are poorly understood. Here, we find that RNF220 directly interacts with AMPARs to meditate their polyubiquitination, and RNF220 knockout specifically increases AMPAR protein levels, thereby enhancing basal synaptic activity while impairing synaptic plasticity. Moreover, depending on its E3 ubiquitin ligase activity, RNF220 represses AMPAR-mediated excitatory synaptic responses and their neuronal surface expression. Furthermore, learning and memory are altered in forebrain RNF220-deficient mice. In addition, two neuropathology-related RNF220 variants fail to repress excitatory synaptic activity because of the incapability to regulate AMPAR ubiquitination due to their attenuated interaction. Together, we identify RNF220 as an E3 ubiquitin ligase for AMPARs and establish its substantial role in excitatory synaptic transmission and brain function.
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OBJECTIVES: Despite of strenuous research in the past decades, the etiology of schizophrenia (SCZ) still remains incredibly controversial. Previous genetic analysis has uncovered a close association of Unc-51 like kinase 4 (ULK4), a family member of Unc-51-like serine/threonine kinase, with SCZ. However, animal behavior data which may connect Ulk4 deficiency with psychiatric disorders, particularly SCZ are still missing. METHODS: We generated Emx1-Cre:Ulk4flox/flox conditional knockout (CKO) mice, in which Ulk4 was deleted in the excitatory neurons of cerebral cortex and hippocampus. RESULTS: The cerebral cellular architecture was maintained but the spine density of pyramidal neurons was reduced in Ulk4 CKO mice. CKO mice showed deficits in the spatial and working memories and sensorimotor gating. Levels of p-Akt and p-GSK-3α/ß were markedly reduced in the CKO mice indicating an elevation of GSK-3 signaling. Mechanistically, Ulk4 may regulate the GSK-3 signaling via putative protein complex comprising of two phosphatases, protein phosphatase 2A (PP2A) and 1α (PP1α). Indeed, the reduction of p-Akt and p-GSK-3α/ß was rescued by administration of inhibitor acting on PP2A and PP1α in CKO mice. CONCLUSIONS: Our data identified potential downstream signaling pathway of Ulk4, which plays important roles in the cognitive functions and when defective, may promote SCZ-like pathogenesis and behavioral phenotypes in mice.
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Proteínas Serina-Treonina Quinasas , Esquizofrenia , Animales , Cognición , Eliminación de Gen , Glucógeno Sintasa Quinasa 3/metabolismo , Ratones , Ratones Noqueados , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Esquizofrenia/genética , Esquizofrenia/patología , Transducción de SeñalRESUMEN
BACKGROUND: Strict countermeasures for coronavirus disease (COVID-19) were undertaken in China without knowing their influence on asthma. OBJECTIVE: To investigate the associations between the frequencies of asthma exacerbations and respiratory infections and air pollutants before and during the COVID-19 pandemic, which were direct consequences of countermeasures undertaken for the pandemic. METHODS: Asthma exacerbations and respiratory infections among hospitalized children in the permanent population of Guangzhou City, China, from February to June 2016-2019 (before the pandemic) to February to June 2020 (during the pandemic) were collected in this cross-sectional study in Guangzhou. RESULTS: The number of asthma exacerbation cases per month documented in the Guangzhou Women and Children's Hospital before (median: 13.5; range: 0-48) and during (median: 20; range: 0-34) the mitigative response to the COVID-19 pandemic was similar. The frequency of severe asthma exacerbation cases per month decreased, whereas that of mild asthma exacerbation cases per year increased (p = .004). The number of patients hospitalized with infectious respiratory diseases decreased from 146 (range: 90-172) per month before the pandemic to 42 (range: 33-57) per month during the pandemic (p = .004). Most pathogens and air pollutants decreased during the COVID-19 pandemic. The frequency of severe asthma exacerbations positively correlated to that of respiratory infections in children, but did not correlate to air pollutants. CONCLUSION: Strict countermeasures undertaken for the pandemic were associated with a decreased the frequency of infectious respiratory diseases and severe asthma exacerbations among urban children.
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Asma/epidemiología , COVID-19/epidemiología , SARS-CoV-2 , Adolescente , Contaminantes Atmosféricos , COVID-19/prevención & control , Niño , Preescolar , China/epidemiología , Estudios Transversales , Progresión de la Enfermedad , Femenino , Hospitalización , Hospitales Pediátricos , Humanos , Masculino , PandemiasRESUMEN
The present paper mainly reports a new method to synthesize long afterglow photoluminescent material BaAl2O4:Eu2+, Dy3+. Al(NO3)3.9H2O, Ba(NO3)2, urea, RE(NO3) 3(RE==Eu, Dy) were employed as raw materials, the admixture of H2O/n-butanol and H2O/n-butanol/SBS were used as medium, then BaAl2O4:Eu2+, Dy3+ phosphor was achieved by calcining the precursor, which was synthesized by hydrothermal method, at 130 degrees C under reduction atmosphere. The TEM and SEM were used to analyse the morphology and BaAl2O4:Eu2+, Dy3+ synthesized by annealing at 1300 degrees C are all nanorods. The excitation and emission spectra of the phosphor indicated that all of them are broad band, and the main emission peak is around 498 nm, which is due to 5d-->4f transition of Eu2+. The state-solid synthesis of the long afterglow phosphor BaAl2O4:Eu2+, Dy3+ generally requires a high calcination temperature, so the products are easily agglomerated, and in this paper the hydrothermal solvothermal synthesis was used, so the synthesized products calcined at 130 degrees degrees C still present well-dispersed rod structure, need not milling, and display well luminescence performance. The authors compared the two different conditions of experiment, and found that under the condition without surfactant the authors can still get well-dispersed rod structure of BaAl2O4:Eu2+, Dy3+. The method is hopeful to be used in synthesizing other alkali-earth aluminate and silicate and other luminescent materials.
RESUMEN
The retrosplenial cortex (Rsp) is a transitional cortex located between the neocortex and archicortex, but the molecular mechanism specifying Rsp from the archicortex remains elusive. We here report that the transcription factor Satb2 is required for specifying Rsp identity during its morphogenesis. In Satb2 CKO mice, the boundary between the Rsp and archicortex [i.e., subiculum (SubC)] disappears as early as E17.5, and Rsp efferent projection is aberrant. Rsp-specific genes are lost, whereas SubC-specific genes are ectopically expressed in Rsp of Satb2 CKO mice. Furthermore, cell-autonomous role of Satb2 in maintaining Rsp neuron identity is revealed by inactivation of Satb2 in Rsp neurons. Finally, Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development.