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BACKGROUND: Harel-Yoon syndrome is a disease caused by variants in the ATAD3A gene, which manifest as global developmental delay, hypotonia, intellectual disability, and axonal neuropathy. The aim of this study is to summarize the clinical and gene mutation characteristics of a child with refractory epilepsy caused by ATAD3A gene mutation. METHODS: The whole-exome sequencing combined with copy number variation analysis could help to understand the genetic diversity and underlying disease mechanisms in ATAD3A gene mutation. RESULTS: We report a Chinese boy with Harel-Yoon syndrome presenting with refractory epilepsy, hypotonia, global developmental delay, and congenital cataract through whole-exome sequencing. Genetic analysis showed a missense mutation, c.251T>C(p.Thr84Met) in the ATAD3A gene (NM_001170535.1). Further copy number variation analysis identified a novel heterozygous deletion on chromosome1p36.33, which spans ATAD3A exon 1 and 2 regions. Multiple antiepileptic drugs failed to control his seizures. Eventually, seizure was controlled through ketogenic diet (KD). CONCLUSION: Our case shows the potential diagnostic role of whole-exome sequencing in Harel-Yoon syndrome and expands the ATAD3A gene mutation spectrum. Multiple antiepileptic drugs failed to control refractory epilepsy in Harel-Yoon syndrome. The KD therapy may be effective for patients with refractory epilepsy who carry the ATAD3A variants.
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Dieta Cetogénica , Epilepsia Refractaria , Malformaciones del Sistema Nervioso , Masculino , Niño , Humanos , Hipotonía Muscular/genética , Epilepsia Refractaria/complicaciones , Epilepsia Refractaria/genética , Anticonvulsivantes , Variaciones en el Número de Copia de ADN , Convulsiones , Mutación , ATPasas Asociadas con Actividades Celulares Diversas/genética , Proteínas de la Membrana/genética , Proteínas Mitocondriales/genéticaRESUMEN
This article investigates the asymptotic stability of a general class of fractional-order multiple delayed systems to evaluate the delay robustness. We establish a one-to-one spectral connection between the original fractional-order system and the transformed one under the power mapping. The applicability of the Cluster Treatment of Characteristic Roots paradigm to the transformed dynamics is proved by this connection. Then, we utilize the Dixon resultant-based frequency sweeping framework to create the complete stability map. The results demonstrate that the order adjustment control significantly enhances the control flexibility and brings unlimited possibilities for the improvement of the delay robustness. Finally, we inspect the stability preservation problem when using the integer-order approximations for practical implementation.
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N6-methyladenosine (m6A), the most abundant modification in mRNAs, has been defined as a crucial modulator in the progression of acute myelogenous leukemia (AML). Identification of the key regulators of m6A modifications in AML could provide further insights into AML biology and uncover more effective therapeutic strategies for patients with AML. Here, we report overexpression of YTHDF1, an m6A reader protein, in human AML samples at the protein level with enrichment in leukemia stem cells (LSC). Whereas YTHDF1 was dispensable for normal hematopoiesis in mice, depletion of YTHDF1 attenuated self-renewal, proliferation, and leukemic capacity of primary human and mouse AML cells in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of cyclin E2 in an m6A-dependent manner. Structure-based virtual screening of FDA-approved drugs identified tegaserod as a potential YTHDF1 inhibitor. Tegaserod blocked the direct binding of YTHDF1 with m6A-modified mRNAs and inhibited YTHDF1-regulated cyclin E2 translation. Moreover, tegaserod reduced the viability of patient-derived AML cells in vitro and prolonged survival in patient-derived xenograft models. Together, our study defines YTHDF1 as an integral regulator of AML progression by regulating the expression of m6A-modified mRNAs, which might serve as a potential therapeutic target for AML. SIGNIFICANCE: The m6A reader YTHDF1 is required for progression of acute myelogenous leukemia and can be targeted with the FDA-approved drug tegaserod to suppress leukemia growth.
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Leucemia Mieloide Aguda , ARN , Humanos , Animales , Ratones , ARN Mensajero/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Adenosina , Ciclinas , Proteínas de Unión al ARN/genéticaRESUMEN
Brombuterol, a new ß-adrenergic agonist to enhance animal growth and increase feeding efficiency, is forbidden as an additive in animal feed for livestock production due to its adverse effects on consumers. In this study, a highly specific and sensitive monoclonal antibody was obtained and an indirect competitive monoclonal ELISA was developed to detect brombuterol, with an IC50 value of 0.1 µg/kg (µg/L) and no cross-reactivity to other structurally related ß-adrenergic agonists. The average recovery of brombuterol using the icELISA method ranged from 72.9% to 106.4% with the coefficient of variation lower than 18.9%, which was determined by analysing spiked animal feed, swine urine, pork and liver samples (n = 5). Finally, the icELISA gave results having a good correlation with those obtained by liquid chromatography-tandem mass spectrometry. These results demonstrated that the developed icELISA for the detection of brombuterol is highly specific, sensitive, and reliable, indicating good potential for use in the area of food safety to improve consumer protection.
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Compuestos de Anilina/análisis , Anticuerpos Monoclonales/inmunología , Ensayo de Inmunoadsorción Enzimática , Etanolaminas/análisis , Análisis de los Alimentos , Contaminación de Alimentos/análisis , Alimentación Animal/análisis , Animales , Hígado/química , Estructura Molecular , Carne de Cerdo/análisis , PorcinosRESUMEN
MicroRNA (miRNA) mimics or antagomirs hold great promise for asthma treatment compared with glucocorticoids as mainstay therapy for asthma. But the role of miRNA in regulating asthmatic inflammation is largely unclear. We previously reported that miR-3162-3p in the peripheral blood of children with asthma was obviously upregulated compared to that in healthy children. This study aimed to elucidate the role of miR-3162-3p in pulmonary inflammation in normal and asthmatic mice as well as preliminarily explore the potential of miR-3162-3p antagomir in asthma treatment. A noninvasive whole-body plethysmograph measured airway responsiveness. Both qRT-PCR and Western blot were used to detect the expression of miRNA, mRNA, or protein. Cells in bronchoalveolar lavage fluid were counted by platelet counting and Wright's staining. Inflammatory infiltration and mucus secretion were identified by hematoxylin and eosin and periodic acid-Schiff staining, respectively. Cytokines in the lungs were detected by ELISA. The miR-3162-3p mimic intraperitoneally administered to normal mice decreased ß-catenin levels in the lungs without obviously altering the lung histology and cytokine levels. Antagonizing miR-3162-3p in ovalbumin-induced asthmatic mice effectively alleviated the typical features of asthma, such as airway hyper-responsiveness, airway inflammation, and Th1/Th2 cytokine imbalance, and concomitantly rescued the total and active ß-catenin expression. Collectively, we discovered divergent roles of miR-3162-3p in lung inflammation between normal and asthmatic mice. The anti-inflammatory effects of the miR-3162-3p antagomir were comparable to those of glucocorticoid treatment. Our study helped in understanding the contribution of miRNAs to the pathogenesis of asthma.
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Antagomirs/genética , Asma/genética , Pulmón/metabolismo , MicroARNs/genética , Neumonía/genética , Alérgenos/inmunología , Animales , Niño , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Pulmón/patología , Ratones , Ovalbúmina/inmunología , Hipersensibilidad Respiratoria , Células TH1/inmunología , Células Th2/inmunología , beta Catenina/metabolismoRESUMEN
Particulate matter with a diameter of less than 2.5⯵m (PM2.5) easily deposits on lung alveoli and degrades human health. Surfactant protein A (SP-A) is the most abundant pulmonary surfactant protein stored in lamellar bodies (LBs) of alveolar epithelial type II cells. The impacts of PM2.5 on SP-A are multifaceted and intractable, and the underlying mechanism remains unclear. In this study, the expression and distribution of SP-A in Balb/c mice and A549 cells under PM2.5 exposure were investigated. The results showed that the low and medium concentration of PM2.5 gradually enhanced SP-A protein and mRNA expression, whereas the high concentration of PM2.5 conspicuously decreased SP-A protein but not its mRNA compared with the control. The trafficking of SP-A to LBs was gradually disturbed, and concomitantly, the lesions of LBs responsible for the transport and storage of SP-A protein were exacerbated with increased PM2.5 concentration. Reactive oxygen species production abundantly increased upon PM2.5 exposure, and it was antagonized by the oxidant inhibitor N-acetylcysteine. Subsequently, the injured LBs and the decrease in SP-A expression under exposure to the high concentration of PM2.5 were well rescued. The present study provides a new perspective to investigate the adverse effects of PM2.5 or diesel exhaust particles on other proteins transported to and stored in LBs.