RESUMEN
Pygopus (Pygo) has been identified as a specific nuclear co-activator of the canonical Wingless (Wg)/Wnt signaling pathway in Drosophila melanogaster. Pygo proteins consist of two conserved domains: an N-terminal homologous domain (NHD) and a C-terminal plant homologous domain (PHD). The PHD's ability to bind to di- and trimethylated lysine 4 of histone H3 (H3K4me2/3) appears to be independent of Wnt signaling. There is ongoing debate regarding the significance of Pygo's histone-binding capacity. Drosophila Pygo orthologs have a tryptophan (W) > phenylalanine (F) substitution in their histone pocket-divider compared to vertebrates, leading to reduced histone affinity. In this research, we utilized CRISPR/Cas9 technology to introduce the Pygo-F773W point mutation in Drosophila, successfully establishing a viable homozygous Pygo mutant line for the first time. Adult mutant flies displayed noticeable abnormalities in reproduction, locomotion, heart function, and lifespan. RNA-seq and cluster analysis indicated that the mutation primarily affected pathways related to immunity, metabolism, and posttranslational modification in adult flies rather than the Wnt signaling pathway. Additionally, a reduction in H3K9 acetylation levels during the embryonic stage was observed in the mutant strains. These findings support the notion that Pygo plays a wider role in chromatin remodeling, with its involvement in Wnt signaling representing only a specific aspect of its chromatin-related functions.
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Proteínas de Drosophila , Drosophila melanogaster , Péptidos y Proteínas de Señalización Intracelular , Vía de Señalización Wnt , Animales , Sistemas CRISPR-Cas , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Histonas/metabolismo , Histonas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , MutaciónRESUMEN
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are used to regenerate the myocardium during cardiac repair after myocardial infarction. However, the regulatory mechanism underlying their ability to form mesodermal cells and differentiate into cardiomyocytes remains unclear. Here, we established a human-derived MSCs line isolated from healthy umbilical cords and established a cell model of the natural state to examine the differentiation of hUC-MSCs into cardiomyocytes. Quantitative RT-PCR, western blotting, immunofluorescence, flow cytometry, RNA Seq, and inhibitors of canonical Wnt signalling were used to detect the germ-layer markers T and MIXL1; the markers of cardiac progenitor cells MESP1, GATA4, and NKX2.5 and the cardiomyocyte-marker cTnT to identify the molecular mechanism associated with PYGO2, a key component of the canonical Wnt signalling pathway that regulates the formation of cardiomyocyte-like cells. We demonstrated that PYGO2 promotes the formation of mesodermal-like cells and their differentiation into cardiomyocytes through the hUC-MSC-dependent canonical Wnt signalling by promoting the early-stage entry of ß-catenin into the nucleus. Surprisingly, PYGO2 did not alter the expression of the canonical-Wnt, NOTCH, or BMP signalling pathways during the middle-late stages. In contrast, PI3K-Akt signalling promoted hUC-MSCs formation and their differentiation into cardiomyocyte-like cells. To the best of our knowledge, this is the first study to demonstrate that PYGO2 uses a biphasic mechanism to promote cardiomyocyte formation from hUC-MSCs.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Humanos , Miocitos Cardíacos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Vía de Señalización Wnt , Diferenciación Celular , Cordón Umbilical , Péptidos y Proteínas de Señalización Intracelular/metabolismoRESUMEN
Ankyrin repeat and suppression-of-cytokine-signaling box (Asb) proteins, a subset of ubiquitin ligase E3, include Asb5 with six ankyrin-repeat domains. Zebrafish harbor two asb5 gene isoforms, asb5a and asb5b. Currently, the effects of asb5 gene inactivation on zebrafish embryonic development and heart function are unknown. Using CRISPR/Cas9, we generated asb5a-knockout zebrafish, revealing no abnormal phenotypes at 48 h post-fertilization (hpf). In situ hybridization showed similar asb5a and asb5b expression patterns, indicating the functional redundancy of these isoforms. Morpholino interference was used to target asb5b in wild-type and asb5a-knockout zebrafish. Knocking down asb5b in the wild-type had no phenotypic impact, but simultaneous asb5b knockdown in asb5a-knockout homozygotes led to severe pericardial cavity enlargement and atrial dilation. RNA-seq and cluster analyses identified significantly enriched cardiac muscle contraction genes in the double-knockout at 48 hpf. Moreover, semi-automatic heartbeat analysis demonstrated significant changes in various heart function indicators. STRING database/Cytoscape analyses confirmed that 11 cardiac-contraction-related hub genes exhibited disrupted expression, with three modules containing these genes potentially regulating cardiac contractile function through calcium ion channels. This study reveals functional redundancy in asb5a and asb5b, with simultaneous knockout significantly impacting zebrafish early heart development and contraction, providing key insights into asb5's mechanism.
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Proteínas de Pez Cebra , Pez Cebra , Animales , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Contracción Muscular , Organogénesis , Isoformas de Proteínas/metabolismoRESUMEN
Wnt/ß-catenin signaling plays a key role in pathological cardiac remodeling in adults. The identification of a tissue-specific Wnt/ß-catenin interaction factor may provide a tissue-specific clinical targeting strategy. Drosophila Pygo encodes the core interaction factor of Wnt/ß-catenin. Two Pygo homologs (Pygo1 and Pygo2) have been identified in mammals. Different from the ubiquitous expression profile of Pygo2, Pygo1 is enriched in cardiac tissue. However, the role of Pygo1 in mammalian cardiac disease is yet to be elucidated. In this study, we found that Pygo1 was upregulated in human cardiac tissues with pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy accompanied by declined cardiac function, increased heart weight/body weight and heart weight/tibial length ratios, and increased cell size. The canonical ß-catenin/T-cell transcription factor 4 (TCF4) complex was abundant in Pygo1-overexpressing transgenic (Pygo1-TG) cardiac tissue, and the downstream genes of Wnt signaling, that is, Axin2, Ephb3, and c-Myc, were upregulated. A tail vein injection of ß-catenin inhibitor effectively rescued the phenotype of cardiac failure and pathological myocardial remodeling in Pygo1-TG mice. Furthermore, in vivo downregulated pygo1 during cardiac hypertrophic condition antagonized agonist-induced cardiac hypertrophy. Therefore, our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/ß-catenin-dependent manner, which may provide new clues for tissue-specific clinical treatment via targeting this pathway.NEW & NOTEWORTHY In this study, we found that Pygo1 is associated with human pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy. Meanwhile, cardiac function was improved when expression of Pygo1 was interfered in hypertrophy-model mice. Our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/ß-catenin-dependent manner, which may provide new clues for a tissue-specific clinical treatment targeting this pathway.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Insuficiencia Cardíaca/metabolismo , Hipertrofia Ventricular Izquierda/metabolismo , Miocardio/metabolismo , Función Ventricular Izquierda , Remodelación Ventricular , Vía de Señalización Wnt , beta Catenina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteína Axina/genética , Proteína Axina/metabolismo , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/prevención & control , Hipertrofia Ventricular Izquierda/inducido químicamente , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/patología , Isoproterenol , Masculino , Ratones Transgénicos , Miocardio/patología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Ratas , Receptor EphB3/genética , Receptor EphB3/metabolismo , Tiazolidinas/farmacología , Factor de Transcripción 4/genética , Factor de Transcripción 4/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/antagonistas & inhibidoresRESUMEN
Background: Short tandem repeats (STRs) are powerful genetic markers widely used in human genetics. Population data and locus-specific mutation rates of STRs are crucial for the evaluation and interpretation of genetic evidence in forensic and population genetics.Aim: To investigate the mutation rates of 21 autosomal STRs in a population from central south China.Subjects and methods: This study analysed 3420 paternity cases with a Combined Paternity Index >10,000 from Han population in Hunan. A total of 68,743 meiotic transfers were analysed and 62 mutations were identified.Results: The overall mutation rate of STR loci was 0.9 × 10-3 (95% CI, 0.0007-0.0011) and the locus-specific mutation rates were estimated ranging from 0.0000-0.0023. Locus D1S1656 exhibited the highest mutation rate of 2.3 × 10-3 (95% CI, 0.0005-0.0006), followed by D12S391 with a mutation rate of 2.0 × 10-3 (95% CI, 0.0007-0.0044). No mutation was observed at TPOX, D2S1338 or Penta D. One-step mutation cases accounted for 96.77% of total mutations and the ratio of paternal vs maternal mutations was â¼4.85:1. Inter-population comparisons of locus-specific mutation rates of several STRs revealed significant differences between Han in Hunan and Han in other regions of China. Conclusion: The data justified the use of geographical data in further genetic applications.
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Cromosomas Humanos/genética , Etnicidad/genética , Frecuencia de los Genes , Repeticiones de Microsatélite , China , Humanos , Tasa de Mutación , PaternidadRESUMEN
BACKGROUND: Previous studies reported that Atorvastatin (ATOR) can improve the efficacy of Mesenchymal stem cells (MSCs) transplantation after acute myocardial infarction (AMI). However, the results of those studies were inconsistent. To clarify the beneficial effects of atorvastatin added to the cell therapy with MSCs in animal model of acute myocardial infarction (AMI), we performed a systematic review and meta-analysis of case-control studies. METHODS: Searches were performed using the PubMed database, the Excerpta Medica Database (Embase), the Science Citation Index, the China National Knowledge Information database, the Wanfang database, and the Chinese Scientific and Technological Journal Database (VIP database). The search term included "Atorvastatin (or Ator)", "Mesenchymal Stem Cells (or Mesenchymal Stem Cell or MSC or MSCs)" and "Acute Myocardial Infarction (or Myocardial Infarction or AMI or MI)". The endpoints were the left ventricular ejection fraction (LVEF) in animal model with AMI. RESULTS: In total, 5 studies were included in the meta-analysis. Pooled analysis indicated a significant LVEF difference at 4 weeks follow-up between MSCs + ATOR combine group and MSCs alone group (95 % CI, 9.09-13.62 %; P < 0.01) with heterogeneity (P = 0.28; P >0.05) and inconsistency (I(2): 22 %). CONCLUSIONS: Atorvastatin can enhance the existing effects of MSCs transplantation, and this combinational therapy is a superior cell/pharmacological therapeutic approach that merits future preclinical and clinical studies.
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Atorvastatina/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Trasplante de Células Madre Mesenquimatosas , Infarto del Miocardio/terapia , Miocardio/patología , Regeneración/efectos de los fármacos , Animales , Distribución de Chi-Cuadrado , Terapia Combinada , Modelos Animales de Enfermedad , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Recuperación de la Función , Volumen Sistólico/efectos de los fármacos , Factores de Tiempo , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
CXXC5 is a member of the CXXC-type zinc-finger domain containing protein family, which is suggested to function in gene transcription, cell adhesion and cytoskeleton organization. Previous studies have revealed that CXXC5 is expressed in skeletal muscle, but whether it regulates skeletal myogenesis is yet unknown. Here, we screened for the possible signaling pathways in which CXXC5 might participate using luciferase gene reporters. The results indicated that CXXC5 significantly increased the activities of the promoters of genes involved in skeletal muscle differentiation. We therefore studied the role of CXXC5 during skeletal myogenesis in C2C12 myoblasts. Our findings suggest that overexpression of CXXC5 in C2C12 myoblasts facilitated myocyte differentiation, while RNAi interference of CXXC5 significantly inhibited the differentiation of C2C12 myoblasts. This study suggests that CXXC5 plays a significant role in regulating skeletal myogenesis.
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Proteínas Portadoras/metabolismo , Células Musculares/citología , Células Musculares/metabolismo , Mioblastos/citología , Mioblastos/metabolismo , Proteínas Portadoras/genética , Diferenciación Celular/fisiología , Línea Celular , Proteínas de Unión al ADN , Células HEK293 , Humanos , Transducción de Señal , Factores de TranscripciónRESUMEN
Leucine-rich repeat (LRR) containing proteins play an essential role in signal transduction, cell adhesion, cell development, DNA repair and RNA processing. Here we cloned a novel gene, Spata34, encoding a LRR containing protein of 415 aa. Spata34 gene consisted of 9 exons and 8 introns and mapped to chromosome 3qA3. Spata34 is conserved across species in evolution. The Spata34 gene was expressed at various levels, faintly before first weeks postpartum and strongly from 2 weeks postpartum in adult testes. Western blot analysis showed that Spata34 protein was specially expressed in mouse testis. Immunohistochemical analysis revealed that Spata34 protein was most abundant in the cytoplasm of round spermatids and elongating spermatids within seminiferous tubules of the adult testis. Overexpression of Spata34 in COS7 cells inhibited the transcriptional activity of AP-1, p53 and p21 which suggested that Spata34 protein may act as a transcriptional repressor in p53 and p21 pathway.
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Células Germinativas/metabolismo , Proteínas de la Membrana/genética , Proteínas Represoras/genética , Espermátides/metabolismo , Espermatogénesis/genética , Secuencia de Aminoácidos , Animales , Células COS , Chlorocebus aethiops , Femenino , Regulación del Desarrollo de la Expresión Génica , Células Germinativas/crecimiento & desarrollo , Humanos , Masculino , Proteínas de la Membrana/biosíntesis , Ratones , Espermátides/crecimiento & desarrollo , Testículo/crecimiento & desarrollo , Testículo/metabolismo , Factor de Transcripción AP-1/biosíntesis , Factor de Transcripción AP-1/metabolismo , Proteína p53 Supresora de Tumor/biosíntesis , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The reprogramming of lipid metabolism serves an important role in occurrence and development of liver cancer. Fatty acid hydroxylase domain containing 2 (FAXDC2) is a hydroxylase involved in the synthesis of cholesterol and sphingomyelin and downregulated in various types of cancer. There are no reports on the relationship between FAXDC2 and liver carcinogenesis. The present study used multiple portals and publicly available tools to explore its correlation with liver cancer. The results showed that the expression of FAXDC2 decreased in liver cancer and the methylation level near the promoter increased. Patients with liver cancer and with low expression of FAXDC2 had a poor prognosis. Gain of function and loss of function strategies were performed to evaluate its roles in liver cancer cells. CCK-8 assay showed that overexpression of FAXDC2 inhibited the viability of liver cancer cells (HepG2). Flow cytometry analysis indicated that HepG2 cells with overexpressing FAXDC2 showed an S phase arrest, associated with cyclin-dependent kinase 2 decreased. Transwell experiments showed that increasing FAXDC2 inhibited HepG2 cell invasion ability, accompanied by the upregulation of E-cadherin. Notably, knockdown of FAXDC2 had no significant effect on cell cycle and invasion functions. Based on the cBioPortal platform, FAXDC2 was predicted to closely correlate to the ERK signal in tumorigenesis. Western blotting results showed that overexpression of FAXDC2 decreased the phosphorylation level of ERK in liver cancer cells. The present study first identified FAXDC2 as a liver cancer suppressor, which might inhibit the proliferation and invasion of liver cancer cells through the mechanism associated with ERK signaling. The present study provided a possible new target for the diagnosis and treatment of liver cancer.
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Distant hybridization is an important technique in fish genetic breeding. In this study, based on the establishment of an allodiploid fish lineage (BT, 2n=48, F1-F6) derived from distant hybridization between female Megalobrama amblycephala (BSB, 2n=48) and male Culter alburnus (TC, 2n=48), and the backcross progeny (BTB, 2n=48) derived by backcrossing female F1 of BT to male BSB, an improved hybrid bream (BTBB, 2n=48) was obtained by backcrossing BTB (â) to BSB (â). Moreover, the morphological and genetic characteristics of BTBB individuals were investigated; BTBB was similar to BSB in appearance but had a higher body height than BSB. The study results regarding chromosome numbers and DNA content indicated that BTBB is a diploid hybrid fish. The 5S rDNA and Hox gene of BTBB were inherited from the original parents. Gonadal development in BTBB was normal. On the other hand, BTBB had a faster growth rate, higher muscle protein level, and lower muscle carbohydrate level than BSB. Hence, bisexual fertile BTBB is promoted and can be applied as a high-quality fish, and it can also be used as a new fish germplasm resource to develop high-quality fish further. Thus, this study is of great significance for fish genetic breeding.
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Cyprinidae , Cipriniformes , Animales , Cromosomas , Cyprinidae/genética , Cipriniformes/genética , Diploidia , Femenino , Hibridación Genética , Masculino , PloidiasRESUMEN
Abnormal activation of the classical Wnt pathway has been reported in non-small-cell lung cancer (NSCLC) previously. Pygo family genes, the core regulators of Wnt/ß-catenin signaling, were also reported to be involved in tumorigenesis. However, the role of the homolog Pygo1 in human lung cancer remains unclear. In the current study, we demonstrated an association of increased Pygo1 expression with consistent high nuclear ß-catenin signals across pathological tissue samples of early-stage human NSCLC. Overexpression of Pygo1 in lung cancer cells resulted in enhanced G1/S cell phase transformation, reduced apoptosis, and increased cell proliferation. These changes were accompanied by the downregulation of cell cycle-related proteins, such as RB, p16, p53, and p27Kip1, and increased expression of CyclinE1. Migration, wound healing, and colony formation assays revealed that Pygo1 overexpression enhanced the invasion and migration of lung cancer cells, increased the formation of clones, and suppressed E-cadherin expression. In addition, overexpression of Pygo1 in lung cancer cells led to an increase of ß-catenin/TCF4 complex, as well as upregulated expression of target genes of ß-catenin. In vivo experiments also revealed that Pygo1 overexpression promoted the tumorigenicity of a xenograft tumor model, while Wnt inhibition partially blocked the effect of Pygo1 overexpression. In conclusion, Pygo1 affects human NSCLC via the canonical Wnt/ß-catenin pathway, which provides new clues for lung cancer pathology.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , beta Catenina/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Vía de Señalización Wnt/genéticaRESUMEN
Cardiovascular disease still has the highest mortality. Gene-modified mesenchymal stromal/stem cells could be a promising therapy. Pygo plays an important role in embryonic development and regulates life activities with a variety of regulatory mechanisms. Therefore, this study aimed to investigate whether the overexpression of the PYGO1 gene can promote the differentiation of human umbilical cord-derived mesenchymal stromal/stem cells (HUC-MSCs) into early cardiac lineage cells and to preliminary explore the relevant mechanisms. In this study, HUC-MSCs were isolated by the explant method and were identified by flow cytometry and differentiation assay, followed by transfected with lentivirus carrying the PYGO1 plasmid. In PYGO1 group (cells were incubated with lentiviral-PYGO1), the mRNA expressions of cardiac differentiation-specific markers (MESP1, NKX2.5, GATA4, MEF2C, ISL1, TBX5, TNNT2, ACTC1, and MYH6 genes) and the protein expressions of NKX2.5 and cTnT were significantly up-regulated compared with the NC group (cells were incubated with lentiviral-empty vector). In addition, the proportion of NKX2.5, GATA4, and cTnT immunofluorescence-positive cells increased with the inducement time. Overexpression of PYGO1 statistically significantly increased the relative luciferase expression level of Topflash plasmid, the protein expression level of ß-catenin and the mRNA expression level of CYCLIND1. Compared with the control group, decreased protein levels of NKX2.5 and cTnT were detected in PYGO1 group after application of XAV-939, the specific inhibitor of the canonical Wnt/ß-catenin pathway. Our study suggests that overexpression of PYGO1 significantly promotes the differentiation of HUC-MSCs into early cardiac lineage cells, which is regulated by the canonical Wnt/ß-catenin signaling.
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Células Madre Mesenquimatosas , beta Catenina , Diferenciación Celular/genética , Humanos , ARN Mensajero/metabolismo , Cordón Umbilical , Vía de Señalización Wnt/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Transmembrane protein 121 (TMEM121) is isolated from the chicken heart using subtraction hybridisation. A previous study by the authors indicated that TMEM121 is highly expressed in adult mouse hearts and acts as an inhibitor of pathological cardiac hypertrophy. In the present study, the association between TMEM121 and cancer was investigated using bioinformatics tools, including Tumour Immune Estimation Resource (TIMER) 2.0, cBioPortal, LinkedOmics analysis, Kaplan-Meier plotter and UALCAN analysis. The expression, genetic variation, gene interaction network and co-expression pattern of TMEM121 in tumours were analysed. The results revealed that TMEM121 was expressed in various tumours and significantly downregulated in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) when compared with its expression in paracancerous tissues, whereas the methylation level of its promoter was increased in tumour tissues. Additionally, associations between TMEM121 and the PI3K/AKT signalling pathway, as well as the expression of cancer-related molecules, were detected. The aforementioned bioinformatics analysis suggests that TMEM121 may be involved in the development of cervical cancer. Therefore, gain-of-function and loss-of-function experiments in HeLa cells were conducted to verify the role of TMEM121 in cervical cancer. The assay using Cell Counting Kit-8 (CCK-8) revealed that the cell viability of HeLa cells with TMEM121 overexpression was significantly reduced. High TMEM121 expression inhibited HeLa cell migration, as indicated by the decrease in the cell scratch healing rate. The western blot assay revealed that TMEM121 overexpression downregulated the expression of B-cell lymphoma 2 (BCL-2), cyclin D1, cyclin E2 and phosphorylated (p)-AKT, while upregulating that of p27, E-cadherin and p-p38. When TMEM121 was knocked down, retinoblastoma protein (RB), p53, p27, E-cadherin, p-JNK and p-p38 were inhibited, but cyclin E1 was promoted. By combining bioinformatics and experimental biology in the present study, the results demonstrated for the first time, to the best of our knowledge, that TMEM121 may be a novel inhibitor of cervical cancer that is linked to multiple signalling pathways, paving the way for the development of novel diagnostic and therapeutic strategies.
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Spring viremia of carp virus (SVCV) causes severe morbidity and mortality in grass carp (Ctenopharyngodon idellus) in Europe, America and several Asian countries. We found that FKBP5 (FK506-binding protein 5) is an SVCV infection response factor; however, its role in the innate immune mechanism caused by SVCV infection remains unknown. This study cloned gcFKBP5 (grass carp FKBP5) and made its mimic protein structure for function discussion. We found that gcFKBP5 expression in the primary innate immune organs of grass carp, including intestine, liver and spleen, was highly upregulated by SVCV in 24 h, with a similar result in fish cells by poly(I:C) treatment. gcFKBP overexpression aggravates viral damage to cells and increases viral replication. Furthermore, SVCV engages gcFKBP5 interacting with TRAF2 (tumour necrosis factor receptor-associated factor 2) to promote host cell apoptosis for supporting viral replication. The enhanced viral replication seems not to be due to the repression of IFN and other antiviral factors as expected. For the first time, these data show the pivotal role of gcFKBP5 in the innate immune response of grass carp to SVCV infection.
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Carpas , Enfermedades de los Peces , Infecciones por Rhabdoviridae , Rhabdoviridae , Proteínas de Unión a Tacrolimus , Replicación Viral , Animales , Apoptosis , Enfermedades de los Peces/metabolismo , Enfermedades de los Peces/virología , Proteínas de Peces/metabolismo , Rhabdoviridae/fisiología , Factor 2 Asociado a Receptor de TNF/genética , Proteínas de Unión a Tacrolimus/metabolismo , Viremia/metabolismo , Viremia/virologíaRESUMEN
In order to study the impalpable effect of GFP in homozygous heart-specific GFP-positive zebrafish during the early stage, the researchers analyzed the heart function of morphology and physiology at the first 3 days after fertilization. This zebrafish line was produced by a large-scale Tol2 transposon mediated enhancer trap screen that generated a transgenic zebrafish with a heart-specific expression of green fluorescent protein (GFP)-tagged under control of the nppa enhancer. In situ hybridization experiments showed that the nppa:GFP line faithfully recapitulated both the spatial and temporal expressions of the endogenous nppa. Green fluorescence was intensively and specifically expressed in the myocardial cells located both in the heart chambers and in the atrioventricular canal. The embryonic heart of nppa:GFP line developed normally compared with those in the wild type. There was no difference between the nappa:GFP and wild type lines with respect to heart rate, overall size, ejection volume, and fractional shortening. Thus the excess expression of GFP in this transgenic line seemed to exert no detrimental effects on zebrafish hearts during the early stages.
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Factor Natriurético Atrial/química , Factor Natriurético Atrial/genética , Proteínas Fluorescentes Verdes/biosíntesis , Corazón/embriología , Miocardio/metabolismo , Animales , Animales Modificados Genéticamente , Elementos de Facilitación Genéticos , Proteínas Fluorescentes Verdes/química , Corazón/fisiología , Hibridación in Situ , Modelos Genéticos , Fenotipo , ARN Mensajero/metabolismo , Transgenes , Pez CebraRESUMEN
SMYD1 is a heart and muscle specific SET-MYND domain containing protein, which functions as a histone methyltransferase and regulates downstream gene transcription. We demonstrated that the expression of SMYD1 is restricted in the heart and skeletal muscle tissues in human. To reveal the regulatory mechanisms of SMYD1 expression during myogenesis and cardiogenesis, we cloned and characterized the human SMYD1 promoter, which contains highly conserved serum response factor (SRF) and myogenin binding sites. Overexpression of SRF and myogenin significantly increased the endogenous expression level of Smyd1 in C2C12 cells, respectively. Deletion of Srf in the heart of mouse embryos dramatically decreased the expression level of Smyd1 mRNA and the expression of Smyd1 can be rescued by exogenous SRF introduction in SRF null ES cells during differentiation. Furthermore, we demonstrated that SRF binds to the CArG site and myogenin binds to the E-box element on Smyd1 promoter region using EMSA and ChIP assays. Moreover, forced expression of SMYD1 accelerates myoblast differentiation and myotube formation in C2C12 cells. Taken together, these studies demonstrated that SMYD1 is a key regulator of myogenic differentiation and acts as a downstream target of muscle regulatory factors, SRF and myogenin.
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Proteínas de Unión al ADN/genética , Proteínas Musculares/genética , Miogenina/metabolismo , Factor de Respuesta Sérica/metabolismo , Factores de Transcripción/genética , Animales , Sitios de Unión , Diferenciación Celular , Línea Celular , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Elementos E-Box , Embrión de Mamíferos/metabolismo , Humanos , Ratones , Ratones Noqueados , Desarrollo de Músculos , Proteínas Musculares/química , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Regiones Promotoras Genéticas , Estructura Terciaria de Proteína , Factor de Respuesta Sérica/genética , Factores de Transcripción/química , Factores de Transcripción/metabolismo , Activación TranscripcionalRESUMEN
Introducing a knowledge graph into a recommender system as auxiliary information can effectively solve the sparse and cold start problems existing in traditional recommender systems. In recent years, many researchers have performed related work. A recommender system with knowledge graph embedding learning characteristics can be combined with a recommender system of the following three forms: one-by-one learning, joint learning, and alternating learning. For current knowledge graph embedding, a deep learning framework only has one embedding mode, which fails to excavate the potential information from the knowledge graph thoroughly. To solve this problem, this paper proposes the Ripp-MKR model, a multitask feature learning approach for knowledge graph enhanced recommendations with RippleNet, which combines joint learning and alternating learning of knowledge graphs and recommender systems. Ripp-MKR is a deep end-to-end framework that utilizes a knowledge graph embedding task to assist recommendation tasks. Similar to the MKR model, in the Ripp-MKR model, two tasks are associated with cross and compress units, which automatically share latent features and learn the high-order interactions among items in recommender systems and entities in the knowledge graph. Additionally, the model borrows ideas from RippleNet and combines the knowledge graph with the historical interaction record of a user's historically clicked items to represent the user's characteristics. Through extensive experiments on real-world datasets, we demonstrate that Ripp-MKR achieves substantial gains over state-of-the-art baselines in movie, book, and music recommendations.
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Aprendizaje Automático , Reconocimiento de Normas Patrones Automatizadas , Humanos , Redes Neurales de la Computación , Literatura de Revisión como AsuntoRESUMEN
To alleviate the data sparsity and cold start problems for collaborative filtering in recommendation systems, side information is usually leveraged by researchers to improve the recommendation performance. The utility of knowledge graph regards the side information as part of the graph structure and gives an explanation for recommendation results. In this paper, we propose an enhanced multi-task neighborhood interaction (MNI) model for recommendation on knowledge graphs. MNI explores not only the user-item interaction but also the neighbor-neighbor interactions, capturing a more sophisticated local structure. Besides, the entities and relations are also semantically embedded. And with the cross&compress unit, items in the recommendation system and entities in the knowledge graph can share latent features, and thus high-order interactions can be investigated. Through extensive experiments on real-world datasets, we demonstrate that MNI outperforms some of the state-of-the-art baselines both for CTR prediction and top-N recommendation.
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Reconocimiento de Normas Patrones Automatizadas , Algoritmos , Conocimiento , Redes Neurales de la Computación , SemánticaRESUMEN
Since the word2vec model was proposed, many researchers have vectorized the data in the research field based on it. In the field of social network, the Node2Vec model improved on the basis of word2vec can vectorize nodes and edges in social networks, so as to carry out relevant research on social networks, such as link prediction, and community division. However, social network is a network with homogeneous structure. When dealing with heterogeneous networks such as knowledge graph, Node2Vec will lead to inaccurate prediction and unreasonable vector quantization data. Specifically, in the Node2Vec model, the walk strategy for homogeneous networks is not suitable for heterogeneous networks, because the latter has distinguishing features for nodes and edges. In this paper, a Heterogeneous Network vector representation method is proposed based on random walks and Node2Vec, called KG2vec (Heterogeneous Network to Vector) that solves problems related to the inadequate consideration of the full-text semantics and the contextual relations that are encountered by the traditional vector representation of the knowledge graph. First, the knowledge graph is reconstructed and a new random walk strategy is applied. Then, two training models and optimizing strategies are proposed, so that the contextual environment between entities and relations is obtained, semantically providing a full vector representation of the Heterogeneous Network. The experimental results show that the KG2VEC model solves the problem of insufficient context consideration and unsatisfactory results of one-to-many relationship in the vectorization process of the traditional knowledge graph. Our experiments show that KG2vec achieves better performance with higher accuracy than traditional methods.
Asunto(s)
Gráficos por Computador , Aprendizaje Profundo , Servicios de Información , Modelos Teóricos , Red Social , Exactitud de los Datos , Bases de Datos Factuales , Humanos , Reconocimiento de Normas Patrones Automatizadas/métodos , SemánticaRESUMEN
Required for meiotic nuclear division 5 homolog A (RMND5A) functions as an E3 ubiquitin ligase. To date, few studies have investigated the role of RMND5A in cancer. In the present study, the expression levels of RMND5A in multiple types of cancer were analyzed using the Gene Expression Profiling Interactive Analysis platform. The results revealed that RMND5A was highly expressed and associated with overall survival in patients with pancreatic adenocarcinoma (PAAD). A wound-healing assay revealed that RMND5A overexpression significantly increased cell migration in the PAAD cell lines AsPC-1 and PANC-1. In silico analysis predicted that RMND5A was a potential target of microRNA(miR)-590-5p. Further in vitro experiments demonstrated that overexpression of miR-590-5p downregulated the expression levels of RMND5A and decreased the migratory ability of the AsPC-1 and PANC-1 cell lines. In addition, overexpression of miR-590-5p attenuated the promoting effects of RMND5A on the migration of AsPC-1 and PANC-1 cells. The results of the present study may further elucidate the mechanisms underlying PAAD progression and provide novel targets for the treatment of PAAD.