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The pathogenesis of hepatitis B virus ï¼HBVï¼-associated hepatocellular carcinoma ï¼HCCï¼ is complicated with the crosstalk of multiple factors and the multi-step processes. The main mechanisms underlying the HBV-induced HCC include:â integration of HBV DNA into the host hepatocyte genome to alter gene function at the insertion siteï¼resulting in host genome instability and expression of carcinogenic truncated proteins;â¡HBV gene mutations at Sï¼Cï¼and X coding regions in the genome;â¢HBV X gene-encoded HBx protein activates proto-oncogenes and inhibits tumor suppressor genesï¼leading to the HCC occurrence. In this articleï¼the recent research progress on the molecular mechanism of HBV-induced HCC is comprehensively reviewedï¼so as to provide insights into the preventionï¼early prediction and postoperative adjuvant therapy of HCC.
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Carcinoma Hepatocelular , Hepatitis B , Neoplasias Hepáticas , Hepatitis B/complicaciones , Virus de la Hepatitis B/genética , Hepatocitos , HumanosRESUMEN
Promyelocytic leukemia (PML) protein, a tumor suppressor, plays an important role in patients with acute promyelocytic leukemia (APL) receiving arsenic trioxide (As2O3) therapy. APL is a M3 subtype of acute myeloid leukemia (AML), which is characterized by expression of PML-RARα (P/R) fusion protein, leading to the oncogenesis. As2O3 is currently used as the first-line drug for patients with APL, and the mechanism may be:As2O3 directly binds to PML part of P/R protein and induces multimerization of related proteins, which further recruits different functional proteins to reform PML nuclear bodies (PML-NBs), and finally it degraded by SUMOylation and ubiquitination proteasomal pathway. Gene mutations may lead to relapse and drug resistance after As2O3 treatment. In this review, we discuss the structure and function of PML proteins; the pathogenesis of APL induced by P/R fusion protein; the involvement of PML protein in treatment of APL patient with As2O3; and explain how PML protein mutations could cause resistance to As2O3 therapy.
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Trióxido de Arsénico , Leucemia Promielocítica Aguda , Proteína de la Leucemia Promielocítica , Antineoplásicos/uso terapéutico , Trióxido de Arsénico/uso terapéutico , Resistencia a Antineoplásicos/genética , Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Mutación , Proteínas de Fusión Oncogénica/metabolismo , Proteína de la Leucemia Promielocítica/química , Proteína de la Leucemia Promielocítica/genética , Proteína de la Leucemia Promielocítica/metabolismoRESUMEN
OBJECTIVES: The development of the digital economy constitutes a key component of China's endeavors to advance towards "Digital China." The sports industry functions as a new catalyst for high-quality economic growth. This study systematically evaluated the integration between these two sectors. METHODS: First, we conducted two levels of grey relational analysis to assess their integration between 2016 and 2021. Second, we conducted a VAR analysis to determine whether their integration between 2009 and 2021 represents a causal relationship. RESULTS: At the macro level, the grey relational analysis reveals that the sports industry (grade = 0.770) ranked second among China's eight key economic sectors in terms of digital economy integration. At the meso level, a wide variation (ranging from 0.606 to 0.789) existed in the grade of integration between the digital economy and the sub-sectors of the sports industry. According to the VAR model, the digital economy does not Granger cause (p = 0.344) the growth of the sports industry. CONCLUSIONS: This study yielded two added values to the existing literature: First, there exists a sectoral imbalance in the digitization process; second, the explosive growth of the sports industry was not primarily caused by the digital economy. Accordingly, the "sports + digital" complex is still in the first wave of technological integration. We propose three policy recommendations, namely, sectoral synergistic development, overtaking via esports IP, and new economy and new regulation. Collectively, these findings provide updated insights for the digital transformation towards "building a leading sports nation" and "Digital China."
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Deportes , China , Humanos , Desarrollo Económico , Industrias/economía , Modelos EconómicosRESUMEN
OBJECTIVE: Notch-1 is a signal regulatory protein with extensive effects in myeloid cells, but its role in aneurysms remains to be fully clarified. In this study, therefore, the aneurysm mouse model with myeloid-specific knockout of Notch-1 was established to observe the role of Notch-1 in aneurysm progression. METHODS AND RESULTS: The effect of Notch-1 was assessed by pathological staining and Western blotting. It was found that after myeloid-specific knockout of Notch-1 in the aneurysm mouse model, the area of aneurysms and the macrophage infiltration were significantly reduced, the damage to arterial elastic plates was significantly relieved, and the oxidative stress level significantly declined. The results of Western blotting showed that after myeloid-specific knockout of Notch-1, the levels of oxidative stress-related proteins p22 and p47 in aneurysm tissues significantly declined, accompanied by a significant increase in the protein level of Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2). In addition, the levels of phosphorylated myeloid differential protein-88 (MyD88), TIR domain-containing adaptor-inducing interferon-ß (TRIF) and nuclear factor-κB (NF-κB), and inflammatory cytokines interferon-γ (IFN-γ), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) also significantly decreased after myeloid-specific knockout of Notch-1. Following myeloid-specific knockout of Notch-1, the phagocytic capacity of macrophages was enhanced by promoting the SHP2 signaling pathway. CONCLUSION: Notch-1 in monocytes/macrophages can activate the Toll-like receptor (TLR)-mediated inflammatory and stress responses by activating oxidative stress and inhibiting the SHP2 protein expression, thus facilitating aneurysm progression.
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Aneurisma , Factor 88 de Diferenciación Mieloide , Receptor Notch1 , Animales , Ratones , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo , Transducción de Señal , Receptor Notch1/genéticaRESUMEN
Family with sequence similarity 20 member C (FAM20C) is a Golgi casein kinase that phosphorylates extracellularly-secreted regulatory proteins involved in bone development and mineralization, but its specific role in bone development is still largely unknown. In this study, to examine the specific mechanisms that FAM20C influences bone development, we cross-bred Osx-Cre with FAM20Cflox/flox mice to establish a Osx-Cre; FAM20Cflox/flox knockout (oKO) mouse model; FAM20C was KO in pre-osteoblasts. oKO development was examined at 1-10 weeks, in which compared to control FAM20Cflox/flox, they had lower body weights and bone tissue mineralization. Furthermore, oKO had lower bone volume fractions, thickness, and trabecular numbers, along with higher degrees of trabecular separation. These mice also had decreased femoral metaphyseal cartilage proliferation layer, along with thickened hypertrophic layer and increased apoptotic cell counts. Transcriptomic analysis found that differentially-expressed genes in oKO were concentrated in the osteoclast differentiation pathway, in line with increased osteoclast presence. Additionally, up-regulation of osteoclast-related, and down-regulation of osteogenesis-related genes, were identified, in which the most up-regulated genes were signal regulatory protein ß-1 family (Sirpb1a-c) and mitogen-activated protein kinase 13. Overall, FAM20C KO in pre-osteoblasts leads to abnormal long bone development, likely due to subsequent up-regulation of osteoclast differentiation-associated genes.
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Desarrollo Óseo , Proteínas de Unión al Calcio , Quinasa de la Caseína I , Diferenciación Celular , Ratones Noqueados , Osteoblastos , Osteoclastos , Osteogénesis , Regulación hacia Arriba , Animales , Ratones , Desarrollo Óseo/genética , Quinasa de la Caseína I/metabolismo , Quinasa de la Caseína I/genética , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogénesis/genética , Masculino , FemeninoRESUMEN
In 2014, the Chinese government unveiled the New Urbanization Plan and Document No. 46, which profoundly influenced the development trajectory of the regional economy and sports industry. Using the coupling coordination model, this study aimed to assess the development progress of the sports industry and urban clusters economy. This study sampled Greater Bay Area urban clusters (GBAUC) and Yangtze River Delta urban clusters (YRDUC). The statistics covered one year after the release of the policies to date. We developed a total of 15 macro indicators to evaluate the sports industry and urban cluster economy as two distinct, yet interdependent, economic systems. Using the entropy weight method, we determined the standardized values and weights for the two systems before calculating the coupling coordination degree (D). Between 2015 and 2021, the sampled sports industry and urban clusters economy exhibited coordinated high growth across all economic metrics, with multiple sports industry metrics exhibiting double-digit growth. In 2015, both showed extreme imbalance: D of GBAUC = 0.092, D of YRDUC = 0.091. In 2017, both improved to bare coordination: D of GBAUC = 0.600, D of YRDUC = 0.566. In 2019, both reached well coordination: D of GBAUC = 0.851, D of YRDUC = 0.814. By 2021, both achieved quality coordination: D of GBAUC = 0.990, D of YRDUC = 1. This study provides the first evidence from the sports industry that China's new urbanization model and Document No. 46 are highly effective for synergistic regional economic growth.
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Desarrollo Económico , Urbanización , Industrias , Ríos , China , CiudadesRESUMEN
Objective: Aging is associated with decreased nicotinamide adenine dinucleotide (NAD) levels, which in turn cause dysfunctional mitochondria and indirectly affect a myriad of diseases. Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) serves as a central rate-limiting enzyme in NAD synthesis, making it an indispensable health mediator. This meta-analysis examined the effect of exercise training on the expression of iNAMPT in humans. Methods: We searched PubMed, Scopus, ClinicalTrials.gov, and the International Clinical Trials Registry Platform for studies published between the inception of the database and July 5, 2023. Using the common-effect model, evidence for the change in iNAMPT following exercise training was synthesized as Cohen's d. Results: The search yielded five eligible studies. The overall effect size is 0.81, with a 95% confidence interval of 0.55 to 1.07. Therefore, a random adult will have a 71.7% probability that iNAMPT will be up-regulated following exercise training. In general, exercise training resulted in a 1.46-fold increase in iNAMPT. Our probability statistics indicate that subgroups of interest may differ practically. Specifically, there is a 79.3% probability of increased iNAMPT in men, compared to a 69.0% probability in the overall population; young adults have a 75.6% probability of having an increased iNAMPT, whereas aged adults have a 68.7% probability; and, iNAMPT has a 75.1% probability increase after aerobic exercise and a 66.4% probability increase after resistance exercise. Conclusion: Exercise training is effective for increasing iNAMPT levels in skeletal muscles. This essential enzyme regulates not only cellular energetics but also healthspan. Therefore, exercise should be promoted as a natural slow-aging lifestyle.
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Ejercicio Físico , NAD , Nicotinamida Fosforribosiltransferasa , Humanos , Envejecimiento/fisiología , Músculo Esquelético/metabolismo , NAD/metabolismo , Nicotinamida Fosforribosiltransferasa/metabolismoRESUMEN
Background: Acute coronary syndrome (ACS) is the most common cause of death in patients with coronary artery disease. The aim of the study was to identify the predictors of both comprehensive clinical risk and severity of coronary lesions by comprehensive use of GRACE and SYNTAX scores in patients with ACS. Methods: Clinical data of 225 ACS patients who underwent coronary angiography between 2015 and 2016 were collected. Multiple logistic regression analysis (stepwise) was used to identify the predictors. The predictive ability of predictors and the model were determined using receiver operating characteristics analyses. Results: Multivariable logistic regression analyses showed that high aspartate aminotransferase (AST) predicted the comprehensive clinical risk with odds ratios (ORs) and 95% confidence intervals (CIs) of 1.011 (1.002-1.021). High total cholesterol (TC) and red blood cell distribution width (RDW) predicted the severity of coronary lesions with ORs and 95% CIs of 1.517 (1.148-2.004) and 1.556 (1.195-2.028), respectively. Low prealbumin predicted both severity of coronary lesions and comprehensive clinical risk of ACS patients with ORs and 95% CIs of 0.743 (0.672-0.821) and 0.836 (0.769-0.909), respectively. The model with a combination of prealbumin and AST had the highest predictive efficacy for comprehensive clinical risk, and the combination of prealbumin, TC, and RDW had the highest predictive efficacy for the severity of coronary lesions. The sensitivity and specificity, and the optimal cut-off values of these four indexes were determined. Conclusions: Four predictors for the comprehensive clinical risk and severity of coronary lesions of ACS were identified, which provided important information for the early diagnosis and appropriate treatment of ACS.
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BACKGROUND: Morbidity and mortality associated with cardiovascular diseases, such as myocardial infarction, stem from the inability of terminally differentiated cardiomyocytes to regenerate, and thus repair the damaged myocardial tissue structure. The molecular biological mechanisms behind the lack of regenerative capacity for those cardiomyocytes remains to be fully elucidated. Recent studies have shown that c-Jun serves as a cell cycle regulator for somatic cell fates, playing a key role in multiple molecular pathways, including the inhibition of cellular reprogramming, promoting angiogenesis, and aggravation of cardiac hypertrophy, but its role in cardiac development is largely unknown. This study aims to delineate the role of c-Jun in promoting early-stage cardiac differentiation. METHODS: The c-Jun gene in mouse embryonic stem cells (mESCs) was knocked out with CRISPR-Cas9, and the hanging drop method used to prepare the resulting embryoid bodies. Cardiac differentiation was evaluated up to 9 days after c-Jun knockout (ko) via immunofluorescence, flow cytometric, and qPCR analyses. RESULTS: Compared to the wild-type control group, obvious beating was observed among the c-Jun-ko mESCs after 6 days, which was also associated with significant increases in myocardial marker expression. Additionally, markers associated with mesoderm and endoderm cell layer development, essential for further differentiation of ESCs into cardiomyocytes, were also up-regulated in the c-Jun-ko cell group. CONCLUSIONS: Knocking out c-Jun directs ESCs toward a meso-endodermal cell lineage fate, in turn leading to generation of beating myocardial cells. Thus, c-Jun plays an important role in regulating early cardiac cell development.
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Cuerpos Embrioides , Miocitos Cardíacos , Proteínas Proto-Oncogénicas c-jun , Animales , Ratones , Diferenciación Celular , Linaje de la Célula , Células Madre Embrionarias de Ratones , Miocardio , Miocitos Cardíacos/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismoRESUMEN
Introduction: The FIFA World Cup is not only the most lucrative athletic event globally, but it also functions as a platform for promoting peace owing to FIFA's new vision. Nevertheless, the determinants of TV viewership ratings, especially in the Chinese market, which is a critical revenue stream for FIFA TV broadcasting, are still unsolved. Using a distributional regression, this study aimed to quantify the dynamics of viewership ratings for the FIFA World Cup 2022 in mainland China. Methods: The CCTV viewership ratings were modeled using 12 covariables related to Chinese TV consumer behavior. Given the data structure, a Logit Normal regression model was chosen to fit the location and dispersion parameters of viewership ratings to explanatory variables. Results: In the fitted heteroscedastic model, the viewership ratings dynamics in mainland China were driven by the match kick-off time: µ^=logistic[-4.874+0.043×matchkick-offtime]. In addition, the model captures the factors that influence the variations in viewership ratings: σ^=exp[-14.26-1.346 (if, FIFA World Cup champion = "Yes") + 0.004 × FIFA world ranking]. Thus, it shows that the FIFA World Cup champions tamp down such variations, leading to a more stable viewing behavior among Chinese consumers. Conclusions: Time- and team-sensitive strategies are proposed to aid in crafting uncertainty-suppressing business decisions for the FIFA World Cup 2026. Ultimately, in the more insecure 2020s, a broader live coverage of the FIFA World Cup would be invaluable for promoting peace.
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Automatic estimation of the poses of dairy cows over a long period can provide relevant information regarding their status and well-being in precision farming. Due to appearance similarity, cow pose estimation is challenging. To monitor the health of dairy cows in actual farm environments, a multicow pose estimation algorithm was proposed in this study. First, a monitoring system was established at a dairy cow breeding site, and 175 surveillance videos of 10 different cows were used as raw data to construct object detection and pose estimation data sets. To achieve the detection of multiple cows, the You Only Look Once (YOLO)v4 model based on CSPDarkNet53 was built and fine-tuned to output the bounding box for further pose estimation. On the test set of 400 images including single and multiple cows throughout the whole day, the average precision (AP) reached 94.58%. Second, the keypoint heatmaps and part affinity field (PAF) were extracted to match the keypoints of the same cow based on the real-time multiperson 2D pose detection model. To verify the performance of the algorithm, 200 single-object images and 200 dual-object images with occlusions were tested under different light conditions. The test results showed that the AP of leg keypoints was the highest, reaching 91.6%, regardless of day or night and single cows or double cows. This was followed by the AP values of the back, neck and head, sequentially. The AP of single cow pose estimation was 85% during the day and 78.1% at night, compared to double cows with occlusion, for which the values were 74.3% and 71.6%, respectively. The keypoint detection rate decreased when the occlusion was severe. However, in actual cow breeding sites, cows are seldom strongly occluded. Finally, a pose classification network was built to estimate the three typical poses (standing, walking and lying) of cows based on the extracted cow skeleton in the bounding box, achieving precision of 91.67%, 92.97% and 99.23%, respectively. The results showed that the algorithm proposed in this study exhibited a relatively high detection rate. Therefore, the proposed method can provide a theoretical reference for animal pose estimation in large-scale precision livestock farming.
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Algoritmos , Leche , Animales , Bovinos , Industria Lechera/métodos , Granjas , Femenino , LactanciaRESUMEN
Atherosclerosis is the most notable cardiovascular disease, the latter being the main cause of death globally. Endothelial cell dysfunction plays a major role in the pathogenesis of atherosclerosis. However, it is currently unclear which genes are involved between endothelial cell dysfunction and atherosclerosis. This study was aimed at identifying these genes. Based on the GSE83500 dataset, the quantification of endothelial cell function was conducted using single-sample gene set enrichment analysis; the coexpression modules were conducted using weighted correlation network analysis. After building module-trait relationships, tan and yellow modules were regarded as hub modules. 10 hub genes from each hub module were identified by the protein-protein interaction network analysis. The key genes (RAB5A, CTTN, ITGB1, and MMP9) were obtained by comparing the expression differences of the hub gene between atherosclerotic and normal groups from the GSE28829 and GSE43292 datasets, respectively. ROC analysis showed the diagnostic value of key genes. Moreover, the differential expression of key genes in normal and atherosclerotic aortic walls was verified. In vitro, we establish a model of ox-LDL-injured endothelial cells and transfect RAB5A overexpression and shRNA plasmids. The results showed that overexpression of RAB5A ameliorates the proliferation and migration function of ox-LDL-injured endothelial cells, including the ability of tubule formation. It was speculated that the interferon response, Notch signaling pathways, etc. were involved in this function of RAB5A by using gene set variation analysis. With the multiple bioinformatics analysis methods, we detected that yellow and tan modules are related to the abnormal proliferation and migration of endothelial cells associated with atherosclerosis. RAB5A, CTTN, ITGB1, and MMP9 can be used as potential targets for therapy and diagnostic markers. In vitro, overexpression of RAB5A can ameliorate the proliferation and migration function of ox-LDL-injured endothelial cells, and the possible molecules involved in this process were speculated.
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Aterosclerosis , Bases de Datos Genéticas , Células Endoteliales/metabolismo , Regulación de la Expresión Génica , Aterosclerosis/genética , Aterosclerosis/metabolismo , Línea Celular , Biología Computacional , HumanosRESUMEN
Atherosclerosis (AS) is a life-threatening vascular disease. RNA N6-methyladenosine (m6A) modification level is dysregulated in multiple pathophysiologic processes including AS. In this text, the roles and molecular mechanisms of m6A writer METTL3 in AS progression were explored in vitro and in vivo. In the present study, cell proliferative, migratory, and tube formation capacities were assessed through CCK-8, Transwell migration, and tube formation assays, respectively. RNA m6A level was examined through a commercial kit. RNA and protein levels of genes were measured through RT-qPCR and western blot assays, respectively. VEGF secretion level was tested through ELISA assay. JAK2 mRNA stability was detected through actinomycin D assay. The relationship of METTL3, IGF2BP1, and JAK2 was investigated through bioinformatics analysis, MeRIP, RIP, RNA pull-down, and luciferase reporter assays. An AS mouse model was established to examine the effect of METTL3 knockdown on AS development in vivo. The angiogenetic activity was examined through chick chorioallantoic membrane assay in vivo. The results showed that METTL3 was highly expressed in ox-LDL-induced dysregulated HUVECs. METTL3 knockdown inhibited cell proliferation, migration, tube formation, and VEGF expression/secretion in ox-LDL-treated HUVECs, hampered AS process in vivo, and prevented in vivo angiogenesis of developing embryos. METTL3 positively regulated JAK2 expression and JAK2/STAT3 pathway in an m6A dependent manner in HUVECs. IGF2BP1 positively regulated JAK2 expression through directly binding to an m6A site within JAK2 mRNA in HUVECs. METTL3 knockdown weakened the interaction of JAK2 and IGF2BP1. METTL3 exerted its functions through JAK2/STAT3 pathway. In conclusion, METTL3 knockdown prevented AS progression by inhibiting JAK2/STAT3 pathway via IGF2BP1.
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Bacterial infection causes enhanced reactive oxygen species (ROS) levels in insects. Oxidation resistance 1 (OXR1) plays an antioxidant role in eukaryotic organisms, including insects. In this report, we demonstrated that Pseudomonas aeruginosa and Staphylococcus aureus infection and hydrogen peroxide (H2 O2 ) injection induced the expression of specific transcriptional isoforms of OXR1 in larval silkworms. We further showed that a Jun kinase (JNK) pathway inhibitor, SP600125, down-regulated expression of OXR1 during infection, leading to elevated H2 O2 levels in the hemolymph, resulting in lower viability of the injected bacteria inside the silkworm larvae. Our study suggests that OXR1 participates in protecting larval silkworms from oxidative stress and bacterial infection through the JNK pathway.