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Regulation of enhancer activity is important for controlling gene expression programs. Here, we report that a biochemical complex containing a potential chromatin reader, RACK7, and the histone lysine 4 tri-methyl (H3K4me3)-specific demethylase KDM5C occupies many active enhancers, including almost all super-enhancers. Loss of RACK7 or KDM5C results in overactivation of enhancers, characterized by the deposition of H3K4me3 and H3K27Ac, together with increased transcription of eRNAs and nearby genes. Furthermore, loss of RACK7 or KDM5C leads to de-repression of S100A oncogenes and various cancer-related phenotypes. Our findings reveal a RACK7/KDM5C-regulated, dynamic interchange between histone H3K4me1 and H3K4me3 at active enhancers, representing an additional layer of regulation of enhancer activity. We propose that RACK7/KDM5C functions as an enhancer "brake" to ensure appropriate enhancer activity, which, when compromised, could contribute to tumorigenesis.
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Carcinogénesis , Elementos de Facilitación Genéticos , Regulación de la Expresión Génica , Histona Demetilasas/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Técnicas de Inactivación de Genes , Xenoinjertos , Humanos , Ratones , Trasplante de Neoplasias , Receptores de Cinasa C Activada , Proteínas S100/genética , Transcripción GenéticaRESUMEN
Transforming growth factor-ß (TGF-ß) and Hippo signaling are two critical pathways engaged in cancer progression by regulating both oncogenes and tumor suppressors, yet how the two pathways coordinately exert their functions in the development of hepatocellular carcinoma (HCC) remains elusive. In this study, we firstly conducted an integrated analysis of public liver cancer databases and our experimental TGF-ß target genes, identifying CYR61 as a pivotal candidate gene relating to HCC development. The expression of CYR61 is downregulated in clinical HCC tissues and cell lines than that in the normal counterparts. Evidence revealed that CYR61 is a direct target gene of TGF-ß in liver cancer cells. In addition, TGF-ß-stimulated Smad2/3 and the Hippo pathway downstream effectors YAP and TEAD4 can form a protein complex on the promoter of CYR61, thereby activating the promoter activity and stimulating CYR61 gene transcription in a collaborative manner. Functionally, depletion of CYR61 enhanced TGF-ß- or YAP-mediated growth and migration of liver cancer cells. Consistently, ectopic expression of CYR61 was capable of impeding TGF-ß- or YAP-induced malignant transformation of HCC cells in vitro and attenuating HCC xenograft growth in nude mice. Finally, transcriptomic analysis indicates that CYR61 can elicit an antitumor program in liver cancer cells. Together, these results add new evidence for the crosstalk between TGF-ß and Hippo signaling and unveil an important tumor suppressor function of CYR61 in liver cancer.
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Carcinoma Hepatocelular , Proteína 61 Rica en Cisteína , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Factor de Crecimiento Transformador beta , Proteínas Señalizadoras YAP , Animales , Humanos , Ratones , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Movimiento Celular , Proteína 61 Rica en Cisteína/metabolismo , Proteína 61 Rica en Cisteína/genética , Minería de Datos , Regulación Neoplásica de la Expresión Génica/genética , Vía de Señalización Hippo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Ratones Desnudos , Regiones Promotoras Genéticas , Transducción de Señal/genética , Proteína Smad2/metabolismo , Proteína Smad2/genética , Proteína smad3/metabolismo , Proteína smad3/genética , Factores de Transcripción de Dominio TEA/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/genética , Regulación hacia Arriba , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genéticaRESUMEN
Glutathione peroxisomal-5 (Gpx5) promotes the elimination of H2O2 or organic hydrogen peroxide, and plays an important role in the physiological process of resistance to oxidative stress (OS). To directly and better understand the protection of Gpx5 against OS in epididymal cells and sperm, we studied its mechanism of antioxidant protection from multiple aspects. To more directly investigate the role of Gpx5 in combating oxidative damage, we started with epididymal tissue morphology and Gpx5 expression profiles in combination with the mouse epididymal epithelial cell line PC1 (proximal caput 1) expressing recombinant Gpx5. The Gpx5 is highly expressed in adult male epididymal caput, and its protein signal can be detected in the sperm of the whole epididymis. Gpx5 has been shown to alleviate OS damage induced by 3-Nitropropionic Acid (3-NPA), including enhancing antioxidant activity, reducing mitochondrial damage, and suppressing cell apoptosis. Gpx5 reduces OS damage in PC1 and maintains the well-functioning extracellular vesicles (EVs) secreted by PC1, and the additional epididymal EVs play a role in the response of sperm to OS damage, including reducing plasma membrane oxidation and death, and increasing sperm motility and sperm-egg binding ability. Our study suggests that GPX5 plays an important role as an antioxidant in the antioxidant processes of epididymal cells and sperm, including plasma membrane oxidation, mitochondrial oxidation, apoptosis, sperm motility, and sperm-egg binding ability.
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Antioxidantes , Epidídimo , Vesículas Extracelulares , Glutatión Peroxidasa , Estrés Oxidativo , Espermatozoides , Animales , Masculino , Ratones , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular , Epidídimo/metabolismo , Epidídimo/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa/genética , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Nitrocompuestos , Estrés Oxidativo/efectos de los fármacos , Propionatos/farmacología , Motilidad Espermática/efectos de los fármacos , Espermatozoides/metabolismo , Espermatozoides/efectos de los fármacos , Ratones Endogámicos C57BL , Envejecimiento , Metabolismo de los LípidosRESUMEN
Fish typically adapt to their environment through evolutionary traits, and this adaptive strategy plays a critical role in promoting species diversity. Onychostoma macrolepis is a rare and endangered wild species that exhibits a life history of overwintering in caves and breeding in mountain streams. We analyzed the morphological characteristics, histological structure, and expression of circadian clock genes in O. macrolepis to elucidate its adaptive strategies to environmental changes in this study. The results showed that the relative values of O. macrolepis eye diameter, body height, and caudal peduncle height enlarged significantly during the breeding period. The outer layer of the heart was dense; the ventricular myocardial wall was thickened; the fat was accumulated in the liver cells; the red and white pulp structures of the spleen, renal tubules, and glomeruli were increased; and the goblet cells of the intestine were decreased in the breeding period. In addition, the spermatogenic cyst contained mature sperm, and the ovaries were filled with eggs at various stages of development. Throughout the overwintering period, the melano-macrophage center is located between the spleen and kidney, and the melano-macrophage center in the cytoplasm has the ability to synthesize melanin, and is arranged in clusters to form cell clusters or white pulp scattered in it. Circadian clock genes were identified in all organs, exhibiting significant differences between the before/after overwintering period and the breeding period. These findings indicate that the environment plays an important role in shaping the behavior of O. macrolepis, helping the animals to build self-defense mechanisms during cyclical habitat changes. Studying the morphological, histological structure and circadian clock gene expression of O. macrolepis during the overwintering and breeding periods is beneficial for understanding its unique hibernation behavior in caves. Additionally, it provides an excellent biological sample for investigating the environmental adaptability of atypical cavefish species.
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Adaptación Fisiológica , Relojes Circadianos , Cyprinidae , Relojes Circadianos/genética , Cyprinidae/anatomía & histología , Cyprinidae/genética , Cyprinidae/fisiología , Cruzamiento , Conducta Sexual Animal/fisiología , Adaptación Fisiológica/fisiología , Animales , Masculino , Femenino , Estaciones del Año , Hígado/metabolismo , Bazo , Riñón , Proteínas de Peces/genética , Expresión Génica/fisiologíaRESUMEN
OBJECTIVE: The study aimed to explore the effect of serum uric acid (SUA) level on the progression of kidney function in systemic lupus erythematosus (SLE) patients. METHODS: A total of 123 biopsy-proven lupus nephritis (LN) patients were included in this retrospective observational study. Cox proportional hazard regression analyses as well as restricted cubic spline analyses were performed to identify predictors of renal outcome in LN patients. We also performed a systematic review and meta-analysis for SUA and overall kidney outcomes in SLE patients. RESULTS: Based on the laboratory tests at renal biopsy, 72 (58.5%) of the 123 patients had hyperuricemia. The median (IQR) follow-up duration was 3.67 years (1.79-6.63 years), and a total of 110 (89.4%) patients experienced progression of LN. Increased serum uric acid level, whether analyzed as continuous or categorical variable, was associated with higher risk of LN progression in Cox proportional hazard regression model (hazard ratio [HR]: 1.003, 95% confidence interval [CI]: 1.001-1.005; HR: 1.780, 95% CI: 1.201-2.639, respectively). This relationship maintained in women (HR: 1.947, 95% CI: 1.234-3.074) but not men (HR: 2.189, 95% CI: 0.802-5.977). The meta-analysis showed a similar result that both continuous and categorical SUA were positively associated with the risk of kidney function progression in LN (weighted mean difference [WMD]: 1.73, 95% CI: 0.97-2.49; odds ratio [OR]: 1.55, 95% CI: 1.20-2.01, respectively). CONCLUSIONS: Our study found overall and especially in women that higher SUA in LN patients were associated with increased risk of renal progression. Meta-analysis yielded consistent results. Future studies are required to establish if uric acid can be used as a biomarker for risk assessment and/or as a novel therapeutic target in SLE.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Femenino , Humanos , Pueblos del Este de Asia , Riñón/patología , Nefritis Lúpica/complicaciones , Estudios Retrospectivos , Ácido ÚricoRESUMEN
BACKGROUND: Since dysregulation of total Interleukin (IL)-18 and IL-18 binding protein (IL-18BP) may participate in systemic lupus erythematosus (SLE) and contribute to the occurrence of non-autoimmune epilepsy, the aim of the current work is to investigate whether the interaction between IL-18 and IL-18BP plays any role in neuropsychiatric systemic lupus erythematosus related seizures. METHODS: Data from 137 SLE patients and 30 healthy controls (HC) were consecutively collected from 2020 to 2021. Serum levels of total IL-18 and IL-18BP for all patients and HC were measured by ELISA test. Free IL-18 was calculated based on the law of mass action. RESULTS: Among the 137 SLE patients, 103 had active disease and were classified into NPSLE (n = 50) and Non-NPSLE (n = 53) groups. Among the NPSLE patients, 16 had seizure disorders. Serum free IL-18 levels were increased in NPSLE (277.6 [150.9-428.8]pg/mL) and were correlated with disease activity (r = 0.268, p = 0.002). Moreover, serum free IL-18 levels in NPSLE patients with seizure disorders (350.9 [237.9-455.9]pg/mL) were significantly higher than the levels in those with other neuropsychiatric symptoms (237.7 [124.6-428.8] pg/mL). CONCLUSIONS: The expression of free IL-18 was increased in neuropsychiatric systemic lupus erythematosus(NPSLE), especially in NPSLE related seizures. Also, serum levels of free IL-18 were significantly increased in active SLE patients. In this regard, free IL-18 may be involved in the pathogenesis of NPSLE related seizures and associated with disease activity.
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Epilepsia , Lupus Eritematoso Sistémico , Vasculitis por Lupus del Sistema Nervioso Central , Humanos , Interleucina-18 , ConvulsionesRESUMEN
BS69 (also called ZMYND11) contains tandemly arranged PHD, BROMO, and PWWP domains, which are chromatin recognition modalities. Here, we show that BS69 selectively recognizes histone variant H3.3 lysine 36 trimethylation (H3.3K36me3) via its chromatin-binding domains. We further identify BS69 association with RNA splicing regulators, including the U5 snRNP components of the spliceosome, such as EFTUD2. Remarkably, RNA sequencing shows that BS69 mainly regulates intron retention (IR), which is the least understood RNA alternative splicing event in mammalian cells. Biochemical and genetic experiments demonstrate that BS69 promotes IR by antagonizing EFTUD2 through physical interactions. We further show that regulation of IR by BS69 also depends on its binding to H3K36me3-decorated chromatin. Taken together, our study identifies an H3.3K36me3-specific reader and a regulator of IR and reveals that BS69 connects histone H3.3K36me3 to regulated RNA splicing, providing significant, important insights into chromatin regulation of pre-mRNA processing.
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Empalme Alternativo , Proteínas Portadoras/metabolismo , Cromatina/metabolismo , Histonas/metabolismo , Precursores del ARN/genética , ARN Mensajero/genética , Secuencia de Bases , Proteínas Portadoras/genética , Proteínas de Ciclo Celular , Línea Celular Tumoral , Cromatina/genética , Proteínas Co-Represoras , Metilación de ADN/genética , Proteínas de Unión al ADN , Células HeLa , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/genética , Humanos , Intrones/genética , Lisina/genética , Lisina/metabolismo , Factores de Elongación de Péptidos/antagonistas & inhibidores , Factores de Elongación de Péptidos/genética , Factores de Elongación de Péptidos/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Interferencia de ARN , Procesamiento Postranscripcional del ARN/genética , ARN Interferente Pequeño , Ribonucleoproteína Nuclear Pequeña U5/antagonistas & inhibidores , Ribonucleoproteína Nuclear Pequeña U5/genética , Ribonucleoproteína Nuclear Pequeña U5/metabolismo , Análisis de Secuencia de ARN , Empalmosomas/genéticaRESUMEN
Health care users and patients are increasingly using online health communities to seek medical service, especially during the COVID-19 epidemic. The factors that determine the online trust between physicians and patients perplex the stakeholders for a long time. Based on the trust theory, this study explored the influence of physicians' personal quality and online reputation on patients' selection. A longitudinal panel data collection exercise, covering 11905 physicians on haodf. com, was conducted on May 20, 2018, May 22, 2019 and May 25, 2020. The random effect models are used to test our hypothesis. Results show that physicians' quality (competence, benevolence, and integrity) and online reputation (online reviews and online rating) can significantly affect patients' selection. Moreover, the physician's gender can enhance the influence of online reputation on patients' selection. As online healthcare community becomes an increasingly appealing channel for health, the frequency of the physician's quality information updating and the quality of online service are equally important to online physician-patient trust.
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DNA methylation at the 5 position of cytosine (5mC) in the mammalian genome is a key epigenetic event critical for various cellular processes. The ten-eleven translocation (Tet) family of 5mC-hydroxylases, which convert 5mC to 5-hydroxymethylcytosine (5hmC), offers a way for dynamic regulation of DNA methylation. Here we report that Tet1 binds to unmodified C or 5mC- or 5hmC-modified CpG-rich DNA through its CXXC domain. Genome-wide mapping of Tet1 and 5hmC reveals mechanisms by which Tet1 controls 5hmC and 5mC levels in mouse embryonic stem cells (mESCs). We also uncover a comprehensive gene network influenced by Tet1. Collectively, our data suggest that Tet1 controls DNA methylation both by binding to CpG-rich regions to prevent unwanted DNA methyltransferase activity, and by converting 5mC to 5hmC through hydroxylase activity. This Tet1-mediated antagonism of CpG methylation imparts differential maintenance of DNA methylation status at Tet1 targets, ultimately contributing to mESC differentiation and the onset of embryonic development.
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5-Metilcitosina/metabolismo , Citosina/análogos & derivados , Proteínas de Unión al ADN/metabolismo , Células Madre Embrionarias/enzimología , Regulación del Desarrollo de la Expresión Génica , Oxigenasas de Función Mixta/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Animales , Citosina/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , Estudio de Asociación del Genoma Completo , Ratones , Unión Proteica , Estructura Terciaria de ProteínaRESUMEN
The radiative forcing of black carbon aerosol (BC) is one of the largest sources of uncertainty in climate change assessments. Contrasting results of BC absorption enhancement ( Eabs) after aging are estimated by field measurements and modeling studies, causing ambiguous parametrizations of BC solar absorption in climate models. Here we quantify Eabs using a theoretical model parametrized by the complex particle morphology of BC in different aging scales. We show that Eabs continuously increases with aging and stabilizes with a maximum of â¼3.5, suggesting that previous seemingly contrast results of Eabs can be explicitly described by BC aging with corresponding particle morphology. We also report that current climate models using Mie Core-Shell model may overestimate Eabs at a certain aging stage with a rapid rise of Eabs, which is commonly observed in the ambient. A correction coefficient for this overestimation is suggested to improve model predictions of BC climate impact.
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Carbono , Hollín , Aerosoles , Modelos Teóricos , Luz SolarRESUMEN
BACKGROUND: Oral squamous cell carcinomas (OC) are life-threatening diseases emerging as major international health concerns. OBJECTIVE: Development of an efficient clinical strategy for early diagnosis of the disease is a key for reducing the death rate. Biomarkers are proven to be an effective approach for clinical diagnosis of cancer. Although mechanisms underlying regulation of oral malignancy are still unclear, microRNAs (miRNAs) as a group of small non-coded RNAs may be developed as the effective biomarkers used for early detection of oral cancer. METHODS: A literature search was conducted using the databases of PubMed, Web of Science, and the Cochrane Library. The following search terms were used: miRNAs and oral cancer or oral carcinoma. A critical appraisal of the included studies was performed with upregulated miRNAs and downregulated miRNAs in oral cancer. RESULTS: In this review, we summarize the research progress made in miRNAs for diagnosis of oral cancer. The involvement of miRNAs identified in signal transduction pathways in OC, including Ras/MAPK signaling, PI3K/AKT signaling, JAK/STAT signaling, Wnt/ß-catenin signaling, Notch signaling, and TGF-ß/SMAD signaling pathway. CONCLUSIONS: A number of studies demonstrated that miRNAs may be developed as an ideal set of biomarkers used for early diagnosis and prognosis of cancers because of the stability in human peripheral blood and body fluids and availability of non-invasive approaches being developed for clinical utility. CLINICAL RELEVANCE: These findings suggest that miRNAs as biomarkers may be useful for diagnosis of OC.
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Biomarcadores de Tumor/metabolismo , MicroARNs/metabolismo , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/metabolismo , Detección Precoz del Cáncer , HumanosRESUMEN
Nanocomposites of Molybdenum oxide (MoO3) and Titanium dioxide (TiO2) were synthesized with femtosecond laser ablation of the pelleted powder in water. The pressing with Cold Isostatic press (CIP) provides facile method for pelletization of the oxides mixture. With this method the nanocomposites can be synthesized without replacement of the target during laser ablation. After laser ablation in water the stable MoO3-TiO2 nanocomposites were synthesized. The morphology of the synthesized nanocomposites was investigated with transmission electron microscopy. While the band gap modifications of the synthesized nanocomposites were witnessed with UV-Visible diffuse reflectance spectroscopy analysis. Besides, the generated nanocomposites were used for photovoltaic and photocatalytic applications. The nanocomposites exhibit significant improvement in the rate of photo conversion and photodegradation as well.
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OBJECTIVES: To assess how the severity of hepatic encephalopathy (HE) affects perfusion and metabolic changes in cirrhotic patients and the association between severity and liver disease and anemia. METHODS: The study groups comprised 31 healthy subjects and 33 cirrhotic patients who underwent MR examinations, and blood and neuropsychological tests. Of the cirrhotic patients, 14 were unaffected, and 11 had covert HE (CHE) and 8 overt HE (OHE). Global cerebral blood flow (CBF), oxygen extraction fraction (OEF), and metabolic rate of oxygen (CMRO2) were noninvasively measured by phase-contrast and T2-relaxation-under-spin-tagging MRI. Correlations were performed between MR measurements, hematocrits, ammonia levels, Child-Pugh scores and neuropsychological test scores. RESULTS: Compared with the values in healthy subjects, CBF was higher in unaffected patients, the same in CHE patients and lower in OHE patients, OEF was higher in all patients, and CMRO2 was the same in unaffected and CHE patients and lower in OHE patients. Hematocrit was negatively correlated with CBF and OEF, but not with CMRO2. Ammonia level was negatively correlated with CBF and CMRO2, and Child-Pugh score was negatively correlated with CMRO2. CONCLUSIONS: The severity-associated alterations in cirrhotic patients indicate that homeostasis of oxygen delivery and oxidative metabolism in HE is regulated by multiple mechanisms. These physiological alterations appeared to be associated with the degree of anemia, ammonia level, and liver function. KEY POINTS: ⢠CBF, OEF and CMRO2 did not change monotonically with HE progression. ⢠Anemia possibly contributed to CBF and OEF changes in cirrhotic patients. ⢠Liver dysfunction mainly contributed to changes in CMRO2 in cirrhotic patients.
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Circulación Cerebrovascular/fisiología , Encefalopatía Hepática/fisiopatología , Cirrosis Hepática/fisiopatología , Consumo de Oxígeno/fisiología , Adulto , Anciano , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Estudios de Casos y Controles , Femenino , Encefalopatía Hepática/diagnóstico por imagen , Encefalopatía Hepática/etiología , Homeostasis/fisiología , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Oxígeno/sangre , Índice de Severidad de la EnfermedadRESUMEN
The polarization evolution and control of a femtosecond laser pulse in the wake of molecular alignment inside a laser filament was investigated. A weak probe pulse was delayed with respect to the field-free revivals of the pre-excited rotational wave-packets created by an infrared filamenting pulse in nitrogen gas. 30° was set between the pump and probe's initial linear polarization directions in order to control the output probe's polarization ellipse. The detailed physical response of the probe's polarization states was analyzed in the wake of alignment and dephasing of molecular N(2). The probe's polarization was modulated by varying the retarded time between the pump and probe pulses.
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The genome-wide distribution patterns of the '6th base' 5-hydroxymethylcytosine (5hmC) in many tissues and cells have recently been revealed by hydroxymethylated DNA immunoprecipitation (hMeDIP) followed by high throughput sequencing or tiling arrays. However, it has been challenging to directly compare different data sets and samples using data generated by this method. Here, we report a new comparative hMeDIP-seq method, which involves barcoding different input DNA samples at the start and then performing hMeDIP-seq for multiple samples in one hMeDIP reaction. This approach extends the barcode technology from simply multiplexing the DNA deep sequencing outcome and provides significant advantages for quantitative control of all experimental steps, from unbiased hMeDIP to deep sequencing data analysis. Using this improved method, we profiled and compared the DNA hydroxymethylomes of mouse ES cells (ESCs) and mouse ESC-derived neural progenitor cells (NPCs). We identified differentially hydroxymethylated regions (DHMRs) between ESCs and NPCs and uncovered an intricate relationship between the alteration of DNA hydroxymethylation and changes in gene expression during neural lineage commitment of ESCs. Presumably, the DHMRs between ESCs and NPCs uncovered by this approach may provide new insight into the function of 5hmC in gene regulation and neural differentiation. Thus, this newly developed comparative hMeDIP-seq method provides a cost-effective and user-friendly strategy for direct genome-wide comparison of DNA hydroxymethylation across multiple samples, lending significant biological, physiological and clinical implications.
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Citosina/análogos & derivados , Células Madre Embrionarias/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Inmunoprecipitación , Células-Madre Neurales/metabolismo , Análisis de Secuencia de ADN/métodos , 5-Metilcitosina/análogos & derivados , Animales , Linaje de la Célula , Células Cultivadas , Citosina/análisis , Citosina/metabolismo , Metilación de ADN , Células Madre Embrionarias/citología , Expresión Génica , Genoma , RatonesRESUMEN
UHRF1 (Ubiquitin-like, with PHD and RING finger domains 1) plays an important role in DNA CpG methylation, heterochromatin function and gene expression. Overexpression of UHRF1 has been suggested to contribute to tumorigenesis. However, regulation of UHRF1 is largely unknown. Here we show that the deubiquitylase USP7 interacts with UHRF1. Using interaction-defective and catalytic mutants of USP7 for complementation experiments, we demonstrate that both physical interaction and catalytic activity of USP7 are necessary for UHRF1 ubiquitylation and stability regulation. Mass spectrometry analysis identified phosphorylation of serine (S) 652 within the USP7-interacting domain of UHRF1, which was further confirmed by a UHRF1 S652 phosphor (S652ph)-specific antibody. Importantly, the S652ph antibody identifies phosphorylated UHRF1 in mitotic cells and consistently S652 can be phosphorylated by the M phase-specific kinase CDK1-cyclin B in vitro. UHRF1 S652 phosphorylation significantly reduces UHRF1 interaction with USP7 in vitro and in vivo, which is correlated with a decreased UHRF1 stability in the M phase of the cell cycle. In contrast, UHRF1 carrying the S652A mutation, which renders UHRF1 resistant to phosphorylation at S652, is more stable. Importantly, cells carrying the S652A mutant grow more slowly suggesting that maintaining an appropriate level of UHRF1 is important for cell proliferation regulation. Taken together, our findings uncovered a cell cycle-specific signaling event that relieves UHRF1 from its interaction with USP7, thus exposing UHRF1 to proteasome-mediated degradation. These findings identify a molecular mechanism by which cellular UHRF1 level is regulated, which may impact cell proliferation.
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Proteínas Potenciadoras de Unión a CCAAT/metabolismo , División Celular , Epigénesis Genética , Ubiquitina Tiolesterasa/metabolismo , Secuencia de Aminoácidos , Aminoácidos/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/química , Proteína Quinasa CDC2/metabolismo , Línea Celular , Cromatografía de Afinidad , Ciclina B/metabolismo , Estabilidad de Enzimas , Humanos , Datos de Secuencia Molecular , Fosforilación , Fosfoserina/metabolismo , Estructura Terciaria de Proteína , Ubiquitina Tiolesterasa/química , Ubiquitina-Proteína Ligasas , Peptidasa Específica de Ubiquitina 7 , UbiquitinaciónRESUMEN
OBJECTIVES: MicroRNAs(miRNAs) play important roles in tumor development and progression. The purposes of this study were to investigate the role of miR-31 in cervical cancer and clarified the regulation of ARID1A by miR-31. METHODS: Quantitative RT-PCR was used to examine miR-31 expression in cervical cancer cell lines and patient specimens. The clinicopathological significance of miR-31 upregulation was further analyzed. The MTT, colony formation, apoptosis, cell cycle, wound healing and Transwell invasion assays, and a xenograft model were performed. A luciferase reporter assay was conducted to confirm the target gene of miR-31, and the results were validated in cell lines and patient specimens. RESULTS: MiR-31 was significantly up-regulated in cervical cancer cell lines and clinical tissues. The high miR-31 level was significantly correlated with higher FIGO stage, node metastasis, vascular involvement and deep stromal invasion. Patients with high expression of miR-31 had poorer overall survival than patients with low expression. MiR-31 was an independent prognostic factor in cervical cancer in multivariate Cox regression analysis. Down-regulation of miR-31 impaired cell proliferation, colony formation, and cell migration and invasion in vitro, and inhibited xenograft tumor growth in vivo. ARID1A was verified as a direct target of miR-31, which was further confirmed by the inverse expression of miR-31 and ARID1A in patient specimens. CONCLUSIONS: The newly identified miR-31/ARID1A pathway provides insight into cervical cancer progression, and may represent a novel therapeutic target.
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MicroARNs/biosíntesis , Proteínas Nucleares/biosíntesis , Factores de Transcripción/biosíntesis , Neoplasias del Cuello Uterino/metabolismo , Adulto , Animales , Apoptosis/fisiología , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Movimiento Celular/fisiología , Proteínas de Unión al ADN , Progresión de la Enfermedad , Femenino , Células HEK293 , Células HeLa , Xenoinjertos , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , MicroARNs/metabolismo , Invasividad Neoplásica , Estadificación de Neoplasias , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Regulación hacia Arriba , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patologíaRESUMEN
Introduction: Understanding the relationship between parenting style and the non-cognitive development of high school students is crucial, particularly in rural China. Non-cognitive abilities, including traits such as emotional regulation, resilience, and interpersonal skills, play a significant role in students' overall development and future success. This study aims to investigate how different parenting styles impact non-cognitive abilities among high school students in rural China. Methods: This study surveyed 6,549 high school students and their primary caregivers in rural China. The students had an average age of 17.61 years, with 48% being male, and 62% of Han ethnicity. Primary caregivers self-reported their parenting styles, while the students' non-cognitive abilities were assessed using the Big Five Inventory-Short (BFI-S). The relationship between parenting style and non-cognitive development was analyzed using two distinct methods: two dimensions (authoritative and authoritarian) and four categories of parenting styles. Results: The study revealed that an authoritative parenting style had a positive impact on the non-cognitive abilities of students. Conversely, a negative association was observed between the authoritarian parenting style and the students' non-cognitive development. This association was more pronounced in the non-cognitive developmental scores of girls compared to boys. Additionally, parents from wealthier families or those with higher levels of education were more likely to adopt an authoritative parenting style rather than an authoritarian one. Discussion: The results of this study highlight the significant influence of parenting styles on the non-cognitive development of high school students in rural China. Authoritative parenting, characterized by warmth and structure, appears to foster better non-cognitive outcomes, while authoritarian parenting, marked by strictness and less warmth, is associated with poorer non-cognitive development. The gender differences observed suggest that girls may be more sensitive to variations in parenting style. Furthermore, the socioeconomic and educational background of parents plays a crucial role in determining the parenting style adopted. These findings underscore the importance of developing and implementing parenting training interventions in rural China, aimed at promoting authoritative parenting practices to enhance the non-cognitive development of students.
RESUMEN
Gastrointestinal surgery using a stapler is usually associated with tissue damage, anastomosis leakage, bleeding, and other complications, which is one of the effective methods for treating digestive tract cancer. The cutting properties of staples and the tissue damage occurring in the process of stapling porcine esophageal and gastric tissues have been evaluated and a new type of stapler has been designed. Since different structural and mechanical properties esophageal and gastric tissues layers, the puncturing force exhibits a fluctuating trend. Compressive stress caused by the bending of the staple legs can lead to the destruction of the vascular network inside the tissue, tissue deforms and tears. Finally, a staple with an internal incision arc (IIA) tip is designed, which meeting the performance requirements.
Asunto(s)
Procedimientos Quirúrgicos del Sistema Digestivo , Grapado Quirúrgico , Porcinos , Animales , Grapado Quirúrgico/efectos adversos , Grapado Quirúrgico/métodos , Tracto Gastrointestinal , Anastomosis Quirúrgica/métodos , Diseño de EquipoRESUMEN
Background and Aims: We asked if comprehensive bile acid profiling could provide insights into the physiopathology of ABCB4-mutated patients and evaluated the prognostic value of taurine-conjugated tetrahydroxylated bile acid (tauro-THBA) in cholestasis. Methods: Serum bile acid profiles were evaluated in 13 ABCB4-mutated patients with 65 healthy controls by ultra-high-performance liquid chromatography/multiple-reaction monitoring-mass spectrometry (UPLC/MRM-MS). The concentration of tauro-THBA was compared between ABCB4-mutated patients with different prognoses. The areas under the curve (AUCs) of tauro-THBA were compared between ABCB11-mutated patients with native liver survival and those who died or underwent liver transplantation before 3 years of age by receiver operating characteristic curve (ROC), with another patient cohort for further verification. Results: The overall hydrophobicity indices of bile acids in ABCB4-mutated patients (12.99±3.25 m) were significantly lower than those of healthy controls (14.02±1.74 m, p<0.000). That was due to markedly increased bile acid modifications including conjugation, sulfation, and ketonization. Differences in the tauro-THBA concentration in ABCB4-mutated patients with different prognoses were not significant. ROC analysis indicated that levels of tauro-THBA of <60 nM yielded an AUC of 0.900 with a sensitivity of 80% and specificity of 87.5% for ABCB11-mutated patients with different prognoses (p=0.0192). Of the 15 patients with good prognosis, 14 were classified correctly and four of the five patients with a poor prognosis were classified correctly (14:15 vs. 1:5, p=0.005) with tauro-THBA as a classifier. Conclusions: Tauro-THBA concentration may be a biomarker for predicting the clinical outcome in low gamma-glutamyl transferase intrahepatic cholestasis patients.