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Due to its role in apoptosis, differentiation, cell cycle arrest, and DNA damage repair in stress responses (oxidative stress, hypoxia, chemotherapeutic drugs, and UV irradiation or radiotherapy), FOXO3a is considered a key tumor suppressor that determines radiotherapeutic and chemotherapeutic responses in cancer cells. Mutations in the FOXO3a gene are rare, even in cancer cells. Post-translational regulations are the main mechanisms for inactivating FOXO3a. The subcellular localization, stability, transcriptional activity, and DNA binding affinity for FOXO3a can be modulated via various post-translational modifications, including phosphorylation, acetylation, and interactions with other transcriptional factors or regulators. This review summarizes how proteins that interact with FOXO3a engage in cancer progression.
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Proteína Forkhead Box O3 , Neoplasias , Humanos , Acetilação , Apoptose , Diferenciação Celular , Neoplasias/genética , Fatores de Transcrição , Proteína Forkhead Box O3/genéticaRESUMO
Chromatin complexes control a vast number of epigenetic developmental processes. Filamentous fungi present an important clade of microbes with poor understanding of underlying epigenetic mechanisms. Here, we describe a chromatin binding complex in the fungus Aspergillus nidulans composing of a H3K4 histone demethylase KdmB, a cohesin acetyltransferase (EcoA), a histone deacetylase (RpdA) and a histone reader/E3 ligase protein (SntB). In vitro and in vivo evidence demonstrate that this KERS complex is assembled from the EcoA-KdmB and SntB-RpdA heterodimers. KdmB and SntB play opposing roles in regulating the cellular levels and stability of EcoA, as KdmB prevents SntB-mediated degradation of EcoA. The KERS complex is recruited to transcription initiation start sites at active core promoters exerting promoter-specific transcriptional effects. Interestingly, deletion of any one of the KERS subunits results in a common negative effect on morphogenesis and production of secondary metabolites, molecules important for niche securement in filamentous fungi. Consequently, the entire mycotoxin sterigmatocystin gene cluster is downregulated and asexual development is reduced in the four KERS mutants. The elucidation of the recruitment of epigenetic regulators to chromatin via the KERS complex provides the first mechanistic, chromatin-based understanding of how development is connected with small molecule synthesis in fungi.
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Aspergillus nidulans , Cromatina , Acetiltransferases/metabolismo , Aspergillus nidulans/genética , Aspergillus nidulans/metabolismo , Cromatina/genética , Cromatina/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica , Genes Fúngicos , Genes Reguladores , Histona Desacetilases/metabolismo , Histona Desmetilases/metabolismo , Histonas/genética , Histonas/metabolismo , Esterigmatocistina/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Gliomas are the most prevalent primary malignant brain tumors worldwide. Growing evidences indicate that circular RNAs (circRNAs) play an important role in the regulation of biological behavior of tumors. We aimed to investigate the role and mechanism of circVCAN in glioma. RNase R treatment was utilized to assess the cyclic properties of circVCAN. CircVCAN, miR-488-3p, and myocyte enhancer factor 2C (MEF2C) levels in glioma tissues and cells were detected by reverse transcription real-time polymerase chain reaction (RT-qPCR), and the localization of them in glioma cells was determined with fluorescence in situ hybridization. Furthermore, a variety of biologically functional assessments were used to validate the role of circVCAN in glioma. The regulatory mechanisms of circVCAN, miR-488-3p, and MEF2C were further confirmed by double luciferase reporter gene assay, RNA immunoprecipitation and RNA pull-down assay, and the binding of MEF2C to JAGGED1 was revealed by chromatin immunoprecipitation. Additionally, a xenograft tumor model was constructed to demonstrate the effect of circVCAN on tumor growth in vivo. Our results indicated that circVCAN was more stable than its linear RNA and was significantly upregulated in gliomas. CircVCAN overexpression stimulated glioma cells to proliferate and metastasize, but circVCAN silencing exerted the opposite effect. Meanwhile, silencing circVCAN inhibited tumor growth in vivo. Moreover, we found that circVCAN interacted with miR-488-3p to regulate MEF2C expression, and miR-488-3p inhibition or MEF2C overexpression reversed the inhibitory effect on malignant bio-behaviors mediated by circVCAN knockdown in glioma cells. MEF2C promoted the transcription of JAGGED1, and circVCAN knockdown reduced the binding between MEF2C and JAGGED1. Collectively, circVCAN is a carcinogenic circRNA in glioma, and the circVCAN/miR-488-3p/MEF2C-JAGGED1 axis could serve as a potential target for the management of glioma.
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Neoplasias Encefálicas , Glioma , Proteína Jagged-1 , Fatores de Transcrição MEF2 , MicroRNAs , RNA Circular , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Glioma/genética , Glioma/patologia , RNA Circular/genética , RNA Circular/metabolismo , Linhagem Celular Tumoral , Animais , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Camundongos Nus , Camundongos , Camundongos Endogâmicos BALB C , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Masculino , Progressão da DoençaRESUMO
To address shortages in construction materials for island engineering, tackle the accumulation of solid waste, and inhibit the shrinkage of geopolymers, coral waste was utilized as the internal curing material to prepare high-performance marine geopolymer concrete (MGC) with seawater, sea-sand, and normal limestone aggregate (LsA). The coral coarse aggregate (CorA) used in this investigation has a total porosity ranging from 50% to 58.3% with internal pore diameters spanning 50-400 µm. The water desorption of CorA followed a two-stage pattern within a relative humidity (RH) range of 75%-85%, becoming nonlinear above 90% RH, which released about 85% of its moisture within 200 h at 97% RH, demonstrating potential for internal curing. Adding a small amount of CorA to MGC increased slump and setting time by providing internal curing water. However, as CorA content exceeded 30%, the slump significantly decreased due to reduced mixing water and elevated activator concentration, while the initial setting time slightly decreased. Furthermore, the inclusion of saturated CorA in MGC significantly reduced autogenous shrinkage, with higher CorA contents (exceeding 30%) leading to slight expansion in the early stages and nearly eliminating shrinkage at contents above 40%. The greater drying shrinkage in geopolymer systems compared to ordinary Portland cement is due to capillary pressure compressing the product framework, converting larger gel pores into smaller ones. Additionally, the layered calcium aluminosilicate hydrate (C-A-S-H) gel exhibits more pronounced creep characteristics under low internal humidity conditions. The higher CorA content in MGC promoted the formation of hybrid C, N-A-S-H gel and hydrotalcite-like phases, and reduced carbonation issues. The interfacial transition zone (ITZ) between CorA and the geopolymer matrix formed a robust mechanical interlock, enhancing tensile strength and minimizing shrinkage-induced cracks. Based on overall performance and marine material utilization, an optimal substitution rate of CorA between 40% and 50% is recommended.
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Lipid metabolism is crucial to tumor growth and immune microenvironment as well as drug sensitivity in glioma. Identifying prognostic indicators of glioma and elucidating the mechanisms of glioma progression are critical for improving the prognosis of glioma patients. In this study, we investigated the role and prognostic value of metabolism-related genes in glioma by integrative analysis of datasets from GEO, CGGA, and TCGA. Based on clinical data and transcriptome data, we found that the expression pattern of three major pathways related to lipid metabolism is fatty acidhigh-phospholipidhigh-triglyceridelow, which is associated with better prognosis and immune infiltration. The genes involved in these three pathways were used to generate a prognostic model, which showed high stability and efficiency in the test set and validation set. The spatial transcriptome of glioma patients revealed that the microenvironment of the regions with high expression of risk genes CAV1 and SCD is in a state of hypoxia, EMT, and cell cycle arrest, and thus can be used as markers of metabolic reprogramming in the tumor microenvironment. In the high-risk group, M0 macrophages and M1 macrophages were significantly enriched, and the risk score was significantly correlated with gene mutation and methylation of risk genes. We further performed drug sensitivity screening corresponding to different risk genes. This study provided novel insights into the differential immune microenvironment with different expression patterns of metablism-related genes and highlighted the spatial and temporal synergy of tumor progression and metabolic reprogramming.
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Glioma , Metabolismo dos Lipídeos , Humanos , Metabolismo dos Lipídeos/genética , Glioma/genética , Ácidos Graxos , Hipóxia , Macrófagos , Microambiente Tumoral/genéticaRESUMO
The filamentous fungus Aspergillus flavus is a plant and human pathogen predominantly found in the soil as spores or sclerotia and is capable of producing various secondary metabolites (SM) such as the carcinogenic mycotoxin aflatoxin. Recently, we have discovered a novel nuclear chromatin binding complex (KERS) that contains the JARID1-type histone demethylase KdmB, a putative cohesion acetyl transferase EcoA, a class I type histone deacetylase RpdA and the PHD ring finger reader protein SntB in the model filamentous fungus Aspergillus nidulans. Here, we show the presence of the KERS complex in A. flavus by immunoprecipitation-coupled mass spectrometry and constructed kdmBΔ and rpdAΔ strains to study their roles in fungal development, SM production and histone post-translational modifications (HPTMs). We found that KdmB and RpdA couple the regulation of SM gene clusters with fungal light-responses and HPTMs. KdmB and RpdA have opposing roles in light-induced asexual conidiation, while both factors are positive regulators of sclerotia development through the nsdC and nsdD pathway. KdmB and RpdA are essential for the productions of aflatoxin (similar to findings for SntB) as well as cyclopiazonic acid, ditryptophenaline and leporin B through controlling the respective SM biosynthetic gene clusters. We further show that both KdmB and RpdA regulate H3K4me3 and H3K9me3 levels, while RpdA also acts on H3K14ac levels in nuclear extracts. Therefore, the chromatin modifiers KdmB and RpdA of the KERS complex are key regulators for fungal development and SM metabolism in A. flavus.
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Aflatoxinas , Aspergillus flavus , Humanos , Cromatina/metabolismo , Metabolismo Secundário/genética , Virulência , Proteínas Fúngicas/metabolismo , Aflatoxinas/genética , Regulação Fúngica da Expressão GênicaRESUMO
Gene expression and immune status in human tissues are changed with aging. There is a need to develop a comprehensive platform to explore the dynamics of age-related gene expression and immune profiles across tissues in genome-wide studies. Here, we collected RNA-Seq datasets from GTEx project, containing 16 704 samples from 30 major tissues in six age groups ranging from 20 to 79 years old. Dynamic gene expression along with aging were depicted and gene set enrichment analysis was performed among those age groups. Genes from 34 known immune function categories and immune cell compositions were investigated and compared among different age groups. Finally, we integrated all the results and developed a platform named ADEIP (http://gb.whu.edu.cn/ADEIP or http://geneyun.net/ADEIP), integrating the age-dependent gene expression and immune profiles across tissues. To demonstrate the usage of ADEIP, we applied two datasets: severe acute respiratory syndrome coronavirus 2 and human mesenchymal stem cells-assoicated genes. We also included the expression and immune dynamics of these genes in the platform. Collectively, ADEIP is a powerful platform for studying age-related immune regulation in organogenesis and other infectious or genetic diseases.
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COVID-19/genética , Especificidade de Órgãos/genética , SARS-CoV-2/genética , Adulto , Idoso , COVID-19/virologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Feminino , Regulação da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , RNA-Seq , Adulto JovemRESUMO
Heart failure (HF) combined with persistent atrial fibrillation (AF) often coexist and may promote the pathological conditions of cardiac dysfunction, leading to poor prognosis. Cardiac resynchronization therapy (CRT) combined with atrioventricular junction ablation (AVJA) is a highly effective treatment for HF patients with underlying AF who either have failed or are not suitable for catheter ablation. The CRT-AVJA combination therapy can improve clinical outcomes in HF patients. Currently, clinical CRT methods are categorized into biventricular pacing (BVP) - based and conduction system pacing (CSP) - based methods. These procedures have inherent advantages and disadvantages, in addition to their considerable differences in clinical applications. This article aims to review the clinical progress of AVJA combined with different CRT strategies for treating HF patients with persistent AF and propose that conversion CRT strategy (BVP/CSP-CRT) combined with AVJA may be a perspective alternative. Meanwhile, we generalize that 7 categories of HF patients with persistent AF may need to consider the CRT-AVJA combination therapy.
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Fibrilação Atrial , Terapia de Ressincronização Cardíaca , Insuficiência Cardíaca , Humanos , Fibrilação Atrial/complicações , Nó Atrioventricular/cirurgia , Resultado do TratamentoRESUMO
Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges.
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Proteínas Tirosina Quinases , Transdução de Sinais , Quinase Syk , Inibidores de Proteínas Quinases/farmacologiaRESUMO
BACKGROUND: Immunogenic cell death (ICD) stimulates adaptive immunity and holds significant promise in cancer therapy. Nevertheless, the influence of ICD-associated long non-coding RNAs (lncRNAs) on the prognosis of patients with lung squamous cell carcinoma (LUSC) remains unexplored. METHODS: We employed data from the The Cancer Genome Atlas (TCGA)database to identify ICD-related lncRNAs associated with the prognosis of LUSC using univariate Cox regression analysis. Subsequently, we utilized the LOSS regression model to construct a predictive risk model for assessing the prognosis of LUSC patients based on ICD-related lncRNAs. Our study randomly allocated187 TCGA patients into a training group and 184 patients for testing the predictive model. Furthermore, we conducted quantitative polymerase chain reaction (qPCR) analysis on 43 tumor tissues from LUSC patients to evaluate lncRNA expression levelsPearson correlation analysis was utilized to analyze the correlation of risk scores with positron emission tomography/computed tomography (PET/CT) parameters among LUSC patients. RESULTS: The findings from the univariate Cox regression revealed 16 ICD-associated lncRNAs linked to LUSC prognosis, with 12 of these lncRNAs integrated into our risk model utilizing the LOSS regression. Survival analysis indicated a markedly higher overall survival time among patients in the low-risk group compared to those in the high-risk group. The area under the Receiver operating characteristic (ROC) curve to differentiate high-risk and low-risk patients was 0.688. Additionally, the overall survival rate was superior in the low-risk group compared to the high-risk group. Correlation analysis demonstrated a positive association between the risk score calculated based on the ICD-lncRNA risk model and the maximum standard uptake value (SUVmax) (r = 0.427, P = 0.0043) as well as metabolic volume (MTV)of PET-CT (r = 0.360, P = 0.0177) in 43 LUSC patients. CONCLUSION: We have successfully developed a risk model founded on ICD-related lncRNAs that proves effective in predicting the overall survival of LUSC patients.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Morte Celular Imunogênica , Regulação Neoplásica da Expressão Gênica , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/patologia , Prognóstico , Pulmão/patologiaRESUMO
Aspergillus fumigatus is an opportunistic fungal pathogen that secretes an array of immune-modulatory molecules, including secondary metabolites (SMs), which contribute to enhancing fungal fitness and growth within the mammalian host. Gliotoxin (GT) is a SM that interferes with the function and recruitment of innate immune cells, which are essential for eliminating A. fumigatus during invasive infections. We identified a C6 Zn cluster-type transcription factor (TF), subsequently named RglT, important for A. fumigatus oxidative stress resistance, GT biosynthesis and self-protection. RglT regulates the expression of several gli genes of the GT biosynthetic gene cluster, including the oxidoreductase-encoding gene gliT, by directly binding to their respective promoter regions. Subsequently, RglT was shown to be important for virulence in a chemotherapeutic murine model of invasive pulmonary aspergillosis (IPA). Homologues of RglT and GliT are present in eurotiomycete and sordariomycete fungi, including the non-GT-producing fungus A. nidulans, where a conservation of function was described. Phylogenetically informed model testing led to an evolutionary scenario in which the GliT-based resistance mechanism is ancestral and RglT-mediated regulation of GliT occurred subsequently. In conclusion, this work describes the function of a previously uncharacterised TF in oxidative stress resistance, GT biosynthesis and self-protection in both GT-producing and non-producing Aspergillus species.
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Aspergilose , Aspergillus fumigatus/patogenicidade , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica/fisiologia , Gliotoxina/biossíntese , Fatores de Transcrição/metabolismo , Animais , Aspergilose/metabolismo , Aspergilose/microbiologia , Aspergillus fumigatus/metabolismo , Camundongos , Estresse Oxidativo/fisiologia , Virulência/fisiologiaRESUMO
BACKGROUND: Although the prevalence of hepatitis B in Guangzhou, China, is high, the epidemiological trends are not well-documented. We aimed to analyse newly reported hepatitis B cases in Guangzhou between 2009 and 2020 to explore the epidemiological trends and provide insights for the development of control measures. METHODS: Information on the population and new cases of hepatitis B in Guangzhou between 2009 and 2020 was obtained from the China Information System for Disease Control and Prevention, which was used to calculate the annual notification rates of hepatitis B by sex, age group (0-9; 10-19; 20-29; 30-39; 40-49; 50-59; ≥ 60 years), and location (urban or rural). Joinpoint regression analysis was used to analyse the temporal trends and calculate the average annual percentage change (AAPC) and annual percentage change (APC) for each identified trend line segment. RESULTS: Between 2009 and 2020, 287,034 new cases of hepatitis B were cumulatively reported. The average annual notification rate was 181.13/100,000, and the notification rate showed a long-term downward trend during the period 2009-2020, with an annual decrease of 6.30% (APC - 6.30%; 95% CI - 7.56 to - 5.02%). Men had a significantly higher notification rate than women; however, the sex ratio decreased from a maximum of 2.34 in 2010 to a minimum of 1.54 in 2020. A downward trend in the notification rate was observed in urban areas and an upward trend was observed in rural areas, with an increase in the rural/urban ratio from 0.46 in 2012 to 1.57 in 2020. The notification rate for all age groups showed a decreasing trend from 2009, with the exception of the 50-59 years and ≥ 60 years groups, whose notification rates began to decrease from 2014 and 2015, respectively. CONCLUSIONS: Although the overall notification rate of hepatitis B in Guangzhou decreased annually, it remained high. Further, in rural areas, the notification rate has been increasing, and effective measures should be taken to control hepatitis B infection in Guangzhou.
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Hepatite B , Razão de Masculinidade , Feminino , Humanos , Pessoa de Meia-Idade , China/epidemiologia , Estudos Epidemiológicos , Hepatite B/epidemiologiaRESUMO
BACKGROUND: The mortality rate of colorectal cancer (CRC) remains high in developing countries. Interventions that can inhibit the proliferation of tumor cells represent promising strategies in CRC treatment. Deltex E3 ubiquitin ligase 3 (DTX3) plays an essential role in tumor development and may predict the outcome of cancer patients. This study aimed to investigate the regulatory mechanisms of DTX3 in CRC progression. METHODS AND RESULTS: The expression of DTX3 was significantly downregulated in CRC tissues relative to normal colorectal tissues. DTX3 overexpression inhibited, while DTX3 knockout promoted the colony-forming capacity and proliferation of CRC cells. E2F transcription factor 1 (E2F1) is a key mediator of cell cycle progression that participates in the progression, metastasis, and chemoresistance of CRC. Further analysis revealed that DTX3 regulated the transcriptional activity of E2F1 in CRC cells. The transcription by E2F1 was significantly reduced with the increase in the cellular level of DTX3, while DTX3 knockout exerted an opposite effect. DTX3 knockout also increased the expression of E2F1 target genes involved in cell cycle progression, CDC2 and Cyclin D3, while PD 0332991, an inhibitor of E2F1 transcription, inhibited the expression of both proteins. CONCLUSIONS: In conclusion, DTX3 regulated CRC cell growth via regulating E2F1 and its downstream genes. These findings support further exploration of DTX3 as a potential therapeutic target for CRC.
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Neoplasias Colorretais , Fator de Transcrição E2F1 , Ciclo Celular/genética , Divisão Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/metabolismo , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Human beings have a strong preference for the fair distribution of resources in situations of both advantageous and disadvantageous inequity. Neuroimaging studies have shown that the process of advantageous and disadvantageous inequity aversion involves distinct brain regions. However, little is known about the causal roles of the dorsal medial prefrontal cortex (dmPFC) in these two types of inequity aversion. To clarify the roles of the dmPFC in both types of inequity aversion, 70 subjects were recruited and randomly assigned to two anodal transcranial direct current stimulation (tDCS) groups: tDCS over the dmPFC and tDCS over the primary visual cortex. Participants then completed a dictator game, which was used to measure the aversion to inequity. This study found that tDCS over the dmPFC decreased the aversion to disadvantageous inequity, but not that to advantageous inequity, and the treatment effect was modulated by equity cost. These results show that the dmPFC plays different roles in these two types of inequity aversion.
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Estimulação Transcraniana por Corrente Contínua , Humanos , Estimulação Transcraniana por Corrente Contínua/métodos , Córtex Pré-Frontal/fisiologia , Encéfalo , Neuroimagem , AfetoRESUMO
Microplastics (MPs) contamination in rivers and lakes is of paramount environmental importance as freshwater systems transport MPs from land to ocean. However, information regarding the spatio-vertical distributions of MPs in rivers, and their associations with surrounding industrial activities, is scarce and unclear. This study investigated MPs in the Taipu River, where there is a highly developed textile industry in Yangtze River Delta, China. Results showed a widespread occurrence of MPs particles with concentrations in the range of 0.65-6.07 items/L and 0.30-3.63 items/L in surface and bottom waters. A higher abundance of MPs was observed in surface waters than in bottom waters (t = 5.423, p = 0.024). The MPs distributions varied markedly in space, with the highest abundances being found in textile manufacturing zones as a consequence of industrial release (F = 14.642, p < 0.001). Transparent fibers were the major MPs compositions with 100-500 µm in size. Polyethylene terephthalate (PET) accounted for 71.4% and 59.73% of the total MPs identified in surface and bottom water, respectively. These PET polymers were predominantly presented in "fibrous" shapes, further reflecting the point sources of textile wastewater. Moreover, polyvinyl acetate (PVAC), used as fabric coating and resin matrix to form nonwoven fabrics, was firstly highlighted at a watershed scale. Although risk assessments revealed a light to moderate risks of MPs in the Taipu River, textile wastewater appears to cause a high "grey water" footprint and increase the risks of MPs pollution from textile life-cycle production. This study bridged gaps between field data and policy-making for MPs control and shed insight into the cleaner production of the textile industry.
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Microplásticos , Poluentes Químicos da Água , China , Monitoramento Ambiental , Lagos , Plásticos , Indústria Têxtil , Águas Residuárias , Água , Poluentes Químicos da Água/análiseRESUMO
Cancer is the second leading cause of death globally. Abnormity in gene expression regulation characterizes the trajectory of tumor development and progression. RNA-binding proteins (RBPs) are widely dysregulated, and thus implicated, in numerous human cancers. RBPs mainly regulate gene expression post-transcriptionally, but emerging studies suggest that many RBPs can impact transcription by acting on chromatin as transcription factors (TFs) or cofactors. Here, we review the evidence that RBM38, an intensively studied RBP, frequently plays a tumor-suppressive role in multiple human cancer types. Genetic studies in mice deficient in RBM38 on different p53 status also establish RBM38 as a tumor suppressor (TS). By uncovering a spectrum of transcripts bound by RBM38, we discuss the diversity in its mechanisms of action in distinct biological contexts. Examination of the genomic features and expression pattern of RBM38 in human tissues reveals that it is generally lost but rarely mutated, in cancers. By assessing future trends in the study of RBM38 in cancer, we signify the possibility of targeting RBM38 and its related pathways as therapeutic strategies against cancer.
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Neoplasias/patologia , Proteínas de Ligação a RNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Mutação , Neoplasias/metabolismo , Estabilidade de RNA , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Endogenous retroviruses (ERVs) were usually silenced by various histone modifications on histone H3 variants and respective histone chaperones in embryonic stem cells (ESCs). However, it is still unknown whether chaperones of other histones could repress ERVs. Here, we show that H2A/H2B histone chaperone FACT plays a critical role in silencing ERVs and ERV-derived cryptic promoters in ESCs. Loss of FACT component Ssrp1 activated MERVL whereas the re-introduction of Ssrp1 rescued the phenotype. Additionally, Ssrp1 interacted with MERVL and suppressed cryptic transcription of MERVL-fused genes. Remarkably, Ssrp1 interacted with and recruited H2B deubiquitinase Usp7 to Ssrp1 target genes. Suppression of Usp7 caused similar phenotypes as loss of Ssrp1. Furthermore, Usp7 acted by deubiquitinating H2Bub and thereby repressed the expression of MERVL-fused genes. Taken together, our study uncovers a unique mechanism by which FACT complex silences ERVs and ERV-derived cryptic promoters in ESCs.
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Proteínas de Ligação a DNA/fisiologia , Retrovirus Endógenos/genética , Proteínas de Grupo de Alta Mobilidade/fisiologia , Chaperonas de Histonas/fisiologia , Regiões Promotoras Genéticas , Fatores de Transcrição/fisiologia , Animais , Linhagem Celular , Regulação da Expressão Gênica , Histonas/metabolismo , Camundongos , Células-Tronco Embrionárias Murinas , Peptidase 7 Específica de Ubiquitina/fisiologiaRESUMO
Terrestrosin D (TED) is the active ingredient of Tribulus terrestris L., which is used in traditional Chinese medicine (TCM) formulations and has a wide range of pharmacological activities. A previous study showed that TED alleviated bleomycin (BLM)-induced pulmonary fibrosis (PF) in mice. However, the mechanisms underlying the therapeutic effect of TED are still unclear and need further investigation. In this study, we evaluated the effect of TED in a mice of BLM-induced PF in terms of histopathological and biochemical indices. UHPLC-MS-based plasma metabolomics combined with network pharmacology was used to explore the pathological basis of PF and the mechanism of action of TED. Histological and biochemical analyses showed that TED mitigated inflammatory injury in the lungs, especially at the dosage of 20 mg/kg. Furthermore, BLM changed the plasma metabolite profile in the mice, which was reversed by TED via regulation of amino acid and lipid metabolism. Subsequently, a biomarkers-targets-disease network was constructed, and tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-ß1 were identified as the putative therapeutic targets of TED. Both factors were quantitatively analyzed using enzyme-linked immunosorbent assay (ELISA). Taken together, the combination of UHPLC-MS-based metabolomics and network pharmacology can unveil the mechanisms of diseases and drug action.
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Fibrose Pulmonar , Saponinas , Animais , Bleomicina , Metabolômica , Camundongos , Farmacologia em Rede , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Saponinas/farmacologia , Fator de Necrose Tumoral alfaRESUMO
In daily life, trust is important in interpersonal interactions. However, little is known about interpersonal brain synchronization with respect to trust; in particular, the differences between individuals with and without siblings are not clear. Therefore, this study applied functional near-infrared spectroscopy hyperscanning in a sequential reciprocal-trust task. We divided pairs of participants (strangers) into two groups according to their only-child status. The two strangers interacted with one another in an online trust game while their brain activities in the medial prefrontal cortex (mPFC) and the right temporoparietal junction (rTPJ) were measured. The behavioral results revealed that compared with the non-only-child group, the only-child group exhibited lower repayment, less reciprocation, and less cooperative decisions during the process. In addition, the brain imaging results showed that the interpersonal synchronization of the mPFC in the only-child group was significantly weaker than that in the non-only-child group. Our findings demonstrate neurobehavioral support for the only-child effect in terms of the trust by revealing that an only child shows less trust than does a non-only-child, resulting in lower inter-brain coherence.
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Filho Único , Confiança , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Criança , Humanos , Relações Interpessoais , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
Immunotherapy via immune checkpoints blockade has aroused the attention of researchers worldwide. Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has been one of the most promising immunotherapy strategies. Several neutralizing antibodies targeting this interaction have been developed, which have already achieved considerable clinical success. Additionally, numerous pharmaceutical companies have been committed to develop small molecules which could block the interaction between PD-1 and PD-L1. In this study, a novel PROTAC molecule 21a was developed, and effectively induced the degradation of PD-L1 protein in various malignant cells in a proteasome-dependent manner. Moreover, compound 21a could significantly reduce PD-L1 protein levels of MC-38 cancer cells in vivo, by which promoted the invasion of CD8+ T cells and inhibited the growth of MC-38 in vivo. This PROTAC molecule could be used as a novel and alternative strategy for cancer immunotherapy.