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BACKGROUND: The essential mineral elements play important roles in proper growth, development and maintenance of physiological homeostasis of an organism. Women are at greater risk of mineral deficiency during pregnancy. However, the predictors of mineral element levels in pregnant women remain unclear. This study was conducted to determine the urinary levels of calcium (Ca), iron (Fe), copper (Cu), manganese (Mn) and selenium (Se) in women during early pregnancy and to explore the predictors of urinary exposure to each mineral element and high co-exposure to mineral element mixture. METHODS: 298 pregnant women in first trimester were recruited when they attended antenatal care in a hospital in Jinan, Shandong Province, China. We collected their spot urine samples and questionnaire data on their sociodemographic characteristics, lifestyle habits, food and dietary supplement intake, and residential environment. The concentrations of Ca, Fe, Cu, Mn and Se in all urine samples were measured. LASSO regression, multiple linear regression and binary logistic regression were used to analyze the predictors affecting mineral element levels. RESULTS: The geometric means of creatinine-corrected Ca, Fe, Cu, Mn and Se concentrations were 99.37â¯mg/g, 1.75⯵g/g, 8.97⯵g/g, 0.16⯵g/g and 16.83⯵g/g creatinine, respectively. Factors that influenced the concentrations of individual mineral element were as follows: (1) Se and Ca concentrations increased with maternal age; (2) women taking tap water as family drinking water had higher Ca levels and those taking polyunsaturated fatty acids intermittently had higher Cu levels; (3) Fe was adversely related to consumption frequency of barbecued foods; (4) Pregnant women with more frequent consumption of shellfish/shrimp/crab and living near green spaces or parks had higher Mn exposure, and those with higher frequency of meat consumption had lower Mn exposure. In addition, maternal age and the frequency of egg consumption were associated with odds of exposure to a mixture of high Ca, Fe, Cu and Se. CONCLUSIONS: The pregnant women in this study had comparable concentrations of urinary Cu and Se but lower concentrations of Ca, Fe and Mn compared with those in other areas. Predictors of urinary mineral elements included maternal age (Se and Ca), type of domestic drinking water (Ca), consumption frequency of barbecued food (Fe), polyunsaturated fatty acid use (Cu), the presence of urban green spaces or parks near the home and frequency of meat and shellfish/shrimp/crab intake (Mn). Moreover, maternal age and egg consumption frequency were significant predictors of high-level co-exposure to urinary Ca, Fe, Cu and Se.
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Oligoelementos , Humanos , Feminino , China , Gravidez , Adulto , Oligoelementos/urina , Minerais/urina , Adulto Jovem , Cálcio/urina , Manganês/urina , Cobre/urina , Ferro/urina , Selênio/urinaRESUMO
Biological characteristics of pregnant women during early pregnancy make them susceptible to both poor sleep quality and metal/metalloid exposure. However, the effects of metal(loid) exposure on sleep quality in pregnant women remain unknown and unexplored. We aimed to examine the relationship between exposure to a mixture of metal(loid)s and pregnant women's sleep quality during early pregnancy. We recruited 493 pregnant women in the first trimester from prenatal clinics in Jinan, Shandong Province, China, and collected their spot urine samples. All urine specimens were assessed for eight metal(loid)s: arsenic (As), cadmium (Cd), iron (Fe), zinc (Zn), molybdenum (Mo), lead (Pb), selenium (Se), and mercury (Hg). We used the Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality. Linear regression, logistic regression, generalized additive models (GAMs), quantile g-computation, and Bayesian kernel machine regression (BKMR) were applied to investigate the relationships between metal(loid) exposure and sleep quality. The results from single metal(loid) models, quantile g-computation models, and BKMR models consistently suggested that Fe was positively related to women's sleep quality. Moreover, in the quantile g-computation models, As was the most critical contributor to the negative effects of the metal(loid) mixture on sleep quality. In addition, we found significant As by Fe interaction for scores of PSQI and habitual sleep efficiency, Pb by Fe interaction for PSQI and sleep latency, and Hg by Fe interaction for PSQI, suggesting the interactive effects of As and Fe, Pb and Fe, Hg and Fe on sleep quality and specific sleep components. Our study provided the first-hand evidence of the effects of metal(loid) exposure on pregnant women's sleep quality. The underlying mechanisms need to be explored in the future.
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Qualidade do Sono , Humanos , Feminino , Gravidez , Estudos Transversais , Adulto , China , Poluentes Ambientais/urina , Poluentes Ambientais/toxicidade , Selênio/urina , Arsênio/urina , Arsênio/toxicidade , Metais/urina , Metais/toxicidade , Metais Pesados/urina , Metais Pesados/toxicidade , Mercúrio/urina , Mercúrio/toxicidade , Adulto Jovem , Chumbo/urina , Chumbo/toxicidade , Exposição Materna , Cádmio/urina , Cádmio/toxicidade , Primeiro Trimestre da GravidezRESUMO
Aqueous zinc-bromine batteries (ZBBs) are highly promising because of the advantages of safety and cost. Compared with flow ZBBs, static ones without the assistance of pumping and tank components possess decreased cost and increased energy density and efficiency. Yet, the issues of Zn dendrites and shuttle effect of polybromide ions (Brn-) are more serious in nonflow ZBBs. Meanwhile, the hydrogen evolution reaction (HER) and the sluggish kinetics of the Br2/Br- couple are also in-negligible. Herein, a compressive approach, the cation-exchange membrane (CEM) coating on Zn anodes and N-defect decoration toward carbon felt cathodes, is developed. The CEM with cation-only function can inhibit the formation of Zn dendrites via tuning the Zn2+ flow at the interface, block the noncationic substances, and hence prevent the shuttle of Br2/Brn- and the water decomposition-concerned HER. The optimized nonflow ZBBs can deliver high Coulombic, voltage, and energy efficiencies of 94.1, 92.8, and 87.4%, respectively, which can be well remained in 1000 cycles. Meanwhile, the output voltage is as high as 1.7 V at 10 mA cm-2 with a high areal capacity of 2 mA h cm-2, and a LED with a rated voltage of 1.6 V can be powered successfully, exhibiting high application value.
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The unsustainable and widespread utilization of fossil fuels continues to drive the rapid depletion of global supplies. Biodiesel has emerged as one of the most promising alternatives to conventional diesel, leading to growing research interest in its production. Microbes can facilitate the de novo synthesis of a type of biodiesel in the form of fatty acid methyl esters (FAMEs). In this study, Saccharomyces cerevisiae metabolic activity was engineered to facilitate enhanced FAME production. Initially, free fatty acid concentrations were increased by deleting two acetyl-CoA synthetase genes (FAA1, FAA4) and an acyl-CoA oxidase gene (POX1). Intracellular S-adenosylmethionine (SAM) levels were then enhanced via the deletion of an adenosine kinase gene (ADO1) and the overexpression of a SAM synthetase gene (SAM2). Lastly, the S. cerevisiae strain overproducing free fatty acids and SAM were manipulated to express a plasmid encoding the Drosophila melanogaster Juvenile Hormone Acid O-Methyltransferase (DmJHAMT). Using this combination of engineering approaches, a FAME concentration of 5.79 ± 0.56 mg/L was achieved using these cells in the context of shaking flask fermentation. To the best of our knowledge, this is the first detailed study of FAME production in S. cerevisiae. These results will provide a valuable basis for future efforts to engineer S. cerevisiae strains for highly efficient production of biodiesel.
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Non-flow aqueous zinc-bromine batteries (AZBBs) are highly attractive owing to their lightweight construction and largely reduced cost compared with the flow ones. Yet, their development is restricted by the sluggish reaction kinetics of Br2/Br-, the shuttle of soluble polybromide species (Brn -, n is odd), and the poor stability of Zn-based anode. Herein, an effective alkaline-neutral electrolyte decoupling system is constructed to mitigate these issues, where nitrogen-doped carbon felt with high catalytic activity to Br2/Br- reaction is developed for cathode, a cost-effective cation exchange membrane (CEM) of polyethersulfone/sulfonated polyether ether ketone (PES/SPEEK-M) that can stop Brn - is used as separator, and glucose that can inhibit dendrites is introduced as anolyte additive. The constructed flowless AZBB mainly consists of two separate redox couples, including Zn/Zn(OH)4 2- in alkaline anolyte and Br2/Br- in neutral media, where non-cations (e.g. OH-, Zn(OH)4 2-, H2O, and Brn -) can be restricted to their respective chamber by the PES/SPEEK-M while cations can pass by. In the optimized system, good electrochemical performance is achieved, mainly including a surprising discharge voltage of 2.01 V, a high average Coulombic efficiency of 96.7%, and a good cycling life of ≈1000 cycles without obvious capacity decay at a fixed charge capacity of 2 mAh cm-2.
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BACKGROUND: Toxic heavy metal exposure and insufficiency or excess of essential heavy metals may have negative effects on pregnant women's health and fetal growth. To date, the predictors of pregnant women's heavy metal exposure levels remain unclear and vary with different regions. The study intended to explore potential predictors of exposure to heavy metals individually and high co-exposure to heavy metal mixtures. METHODS: We recruited 298 pregnant women in first trimester from prenatal clinics in Jinan, Shandong Province, China, and collected spot urine samples and questionnaire data on their demographic characteristics, lifestyle habits, consumption of food and dietary supplement, and residential environment. All urine samples were analyzed for seven heavy metals: cobalt (Co), molybdenum (Mo), strontium (Sr), arsenic (As), cadmium (Cd), lead (Pb) and mercury (Hg). RESULTS: Factors associated with single heavy metal concentration were as follows: a) urinary As, Sr and Cd increased with women's age respectively; b) pregnant women with higher monthly household income per capita had lower Sr and Mo levels; c) pregnant women with intermittent folic acid supplementation and those not taking tap water as domestic drinking water had lower Sr concentrations; d) Cd was positively linked with consumption frequency of rice; e) Hg was adversely related to consumption frequency of egg and the women who took purified water as domestic drinking water had lower Hg exposure. In addition, pregnant women's age was positively associated with odds of high co-exposure to Co, As, Sr, Mo, Cd and Pb; while those with an educational level of college had lower odds of high exposure to such a metal mixture compared with those whose educational levels were lower than high school. CONCLUSION: Predictors of single urinary heavy metal concentration included pregnant women's age (As, Sr and Cd), monthly household income per capita (Sr and Mo), folic acid supplementation (Sr), rice consumption frequency (Cd), egg consumption frequency (Hg) and the type of domestic drinking water (Sr and Hg). Pregnant women with older age, lower educational level tended to have high co-exposure to Co, As, Sr, Mo, Cd and Pb.
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Metais Pesados , Humanos , Feminino , China , Gravidez , Adulto , Metais Pesados/urina , Arsênio/urina , Adulto Jovem , Cádmio/urinaRESUMO
Rotenone, a plant-based agricultural insecticide, has been shown to have anti-tumor activity through targeting mitochondrial complex I in cancer cells. However, off-target toxic side effect on nervous systems have greatly restricted the application of rotenone as anticancer drugs. Here, a folic acid-rotenol (FA-rotenol) conjugate was prepared by covalent coupling of the tumor-targeting ligand folic acid with rotenone derivative-rotenol to enhance its accumulation at tumor site. FA-rotenol conjugates present high in vitro cytotoxicties against several cell lines by inducing mitochondrial membrane potential depolarization and increasing the level of intracellular reactive oxygen species (ROS) to activate the mitochondrial pathway of apoptosis and enhance the G2/M cell cycle arrest. Because of the high affinity with over-expressed folate receptors, FA-rotenol conjugate demonstrated more effective in vivo therapeutic outcomes in 4T1 tumor-bearing mice than rotenone and rotenol. In addition, FA-rotenol conjugate can markedly inhibit the cell migration and invasion of HepG-2 cells. These studies confirm the feasibility of tumor-targeted ligand conjugated rotenone derivatives for targeted antitumor therapy; likewise, they lay the foundations for the development of other rotenol-conjugates with antitumor potential.
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Antineoplásicos , Pró-Fármacos , Animais , Camundongos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Ácido Fólico/farmacologia , Ácido Fólico/metabolismo , Ligantes , Rotenona/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologiaRESUMO
Copper ions (Cu2+) play an essential role in various cellular functions, including respiration, nerve conduction, tissue maturation, oxidative stress defense, and iron metabolism. Covalent organic frameworks (COFs) are a class of porous crystalline materials with directed structural designability and high stability due to the combination of different monomers through covalent bonds. In this study, we synthesized a porphyrin-tetrathiazole COF (TT-COF(Zn)) with Zn-porphyrin and tetrathiafulvalene (TTF) as monomers and used it as a photoactive material. The strong light absorption of metalloporphyrin and the electron-rich properties of supplied TTF contribute to its photoelectrochemical performance. Additionally, the sulfur (S) in the TTF can coordinate with Cu2+. Based on these properties, we constructed a highly sensitive photoelectrochemical sensor for detecting Cu2+. The sensor exhibited a linear range from 0.5 nM to 500 nM (R2 = 0.9983) and a detection limit of 0.15 nM for Cu2+. Notably, the sensor performed well when detecting Cu2+ in water samples.
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BACKGROUND: Patients with hematological malignancies received multiple hypodermic injections of recombinant human granulocyte colony-stimulating factor. Procedural pain is one of the most common iatrogenic causes of pain in patients with hematological malignancies. It is also identified as the most commonly occurring problem in clinical care in the Department of Hematology and Oncology at Shenzhen University General Hospital. However, providing immediate relief from pain induced by hypodermic injection of recombinant human granulocyte colony-stimulating factor remains a major challenge. This trial aims to evaluate the safety and analgesic efficacy of a fixed nitrous oxide/oxygen mixture for patients with hematological malignancies and experiencing procedural pain caused by hypodermic injection of recombinant human granulocyte colony-stimulating factor in the department. METHODS: The nitrous oxide/oxygen study is a single-center, randomized, double-blind, placebo-controlled trial involving patients with hematological malignancies who require hypodermic injections of recombinant human granulocyte colony-stimulating factor for treatment. This trial was conducted in the Hematology and Oncology Department of Shenzhen University General Hospital. A total of 54 eligible patients were randomly allocated to either the fixed nitrous oxide/oxygen mixture group (n = 36) or the oxygen group (n = 18). Neither the investigators nor the patients known about the randomization list and the nature of the gas mixture in each cylinder. Outcomes were monitored at the baseline (T0), immediately after hypodermic injection of recombinant human granulocyte colony-stimulating factor (T1), and 5 min after hypodermic injection of recombinant human granulocyte colony-stimulating factor (T2) for each group. The primary outcome measure was the score in the numerical rating scale corresponding to the highest level of pain experienced during hypodermic injection of recombinant human granulocyte colony-stimulating factor. Secondary outcomes included the fear of pain, anxiety score, four physiological parameters, adverse effects, total time of gas administration, satisfaction from both patients and nurses, and the acceptance of the patients. DISCUSSION: This study focused on the safety and analgesic efficacy during hypodermic injection of recombinant human granulocyte colony-stimulating factor procedure. Data on the feasibility and safety of nitrous oxide/oxygen therapy was provided if proven beneficial to patients with hematological malignancies during hypodermic injection of recombinant human granulocyte colony-stimulating factor and widely administered to patients with procedural pain in the department. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR2200061507. Registered on June 27, 2022. http://www.chictr.org.cn/edit.aspx?pid=170573&htm=4.
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Neoplasias Hematológicas , Dor Processual , Humanos , Óxido Nitroso/efeitos adversos , Oxigênio/uso terapêutico , Manejo da Dor/métodos , Resultado do Tratamento , Dor/diagnóstico , Dor/tratamento farmacológico , Dor/etiologia , Analgésicos/uso terapêutico , Método Duplo-Cego , Neoplasias Hematológicas/complicações , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Rechargeable aqueous zinc-ion batteries are considered as promising candidates for safe and green energy storage. Yet, Zn anodes still suffer from serious challenges. Herein, an effective cation-sieve of polyethersulfone-modified sulfonated polyether ether ketone is developed as protective coating layer of the Zn anodes. Cation-only transmission and dense property of the layer can protect the Zn from active water and anions, inhibiting corrosion, hydrogen evolution reaction (HER), and passivation. Zincophilic property of the layer can homogenize Zn2+ flow, and promote uniform plating of Zn. Therefore, protected symmetric Zn||Zn cell can maintain as long as 5600 h with a low polarization at 1.0 mA cm-2 and 0.5 mAh cm-2 , and still long as 800 h at 5.0 mA cm-2 and 5.0 mAh cm-2 . It is found that not only the dendrites but also the popular existed passivation product of Zn4 SO4 (OH)6 ·5H2 O can be inhibited effectively. In asymmetric Zn||Ti cells, average Coulombic efficiency can reach 98.2%, suggesting corrosion and HER are restrained effectively. Matched with MnO2 cathode, full cells using coated Zn exhibit much better cycling performance than that using bare Zn. Moreover, Zn4 O3 (SO4 )·7H2 O (ZSH)-assisted reversible conversion mechanism between the ZSH and Znx Hy MnO2 is revealed through operando Raman.
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There is limited information available to assess the impact of one-time fertilization on the yield, quality, and economic benefits of direct-seeded rice. This study reports the effects of three one-time fertilizer treatments (BBU1, BBU2, and BBU3) on the yield, quality, and economic benefits of direct-seeded rice, where controlled-release nitrogen (N) fertilizer (CRNF) provided 50%, 60%, and 70% of the total N (270 kg N ha-1), and the control treatment (CK) was a split application of conventional urea (CU). The results showed that the yield of direct-seeded rice decreased significantly (p < 0.05) with the increased application ratio of CRNF under one-time fertilization, which was mainly related to N accumulation between the heading time and maturity stages. Compared to CK, the one-time fertilization treatments (BBU1, BBU2, and BBU3) maintained high milling quality, with significantly reduced chalkiness (p < 0.05), which could be related to the slow rate of N release from the CRNF. In addition, the one-time fertilization treatments reduced the protein content and increased the amylose content of the milled rice, which significantly improved the eating quality (p < 0.05). Furthermore, there was no significant difference in yield and economic benefit between BBUI and CK (p > 0.05). Overall, CRNF replacing conventional urea with 50% total N could be helpful to reduce fertilization frequency, achieve high yield and high economic efficiency, and improve rice quality of direct-seeded rice under one-time fertilization.
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BACKGROUND: The incidence of ovarian cancer ranks third among gynecologic malignancies, but the mortality rate ranks first. METHODS: The expression of GAS5 is low in ovarian cancer and is associated with the low survival of ovarian cancer patients according to public ovarian cancer databases. GAS5 overexpression inhibited ovarian malignancy by affecting the proliferation and migratory abilities in OVCAR3 and A2780 cells. GAS5 overexpression increased the rate of cell apoptosis, and the cells were blocked in the G1 phase as assessed by flow cytometry. RESULTS: We found that hnRNPK was a potential target gene, which was regulated negatively by GAS5 based on RNA-pulldown and mass spectrometry analysis. Mechanistically, GAS5 affected the inhibition of the PI3K/AKT/mTOR pathways and bound the protein of hnRNPK, which influenced hnRNPK stability. Furthermore, rescue assays demonstrated hnRNPK was significantly involved in the progression of ovarian cancer. CONCLUSIONS: Our study showed one of the mechanisms that GAS5 inhibited ovarian cancer metastasis by down-regulating hnRNPK expression, and GAS5 can be used to predict the prognosis of ovarian cancer patients.
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BACKGROUND: The development of cotton fiber is regulated by the orchestrated binding of regulatory proteins to cis-regulatory elements associated with developmental genes. The cis-trans regulatory dynamics occurred throughout the course of cotton fiber development are elusive. Here we generated genome-wide high-resolution DNase I hypersensitive sites (DHSs) maps to understand the regulatory mechanisms of cotton ovule and fiber development. RESULTS: We generated DNase I hypersensitive site (DHS) profiles from cotton ovules at 0 and 3 days post anthesis (DPA) and fibers at 8, 12, 15, and 18 DPA. We obtained a total of 1185 million reads and identified a total of 199,351 DHSs through ~ 30% unique mapping reads. It should be noted that more than half of DNase-seq reads mapped multiple genome locations and were not analyzed in order to achieve a high specificity of peak profile and to avoid bias from repetitive genomic regions. Distinct chromatin accessibilities were observed in the ovules (0 and 3 DPA) compared to the fiber elongation stages (8, 12, 15, and 18 DPA). Besides, the chromatin accessibility during ovules was particularly elevated in genomic regions enriched with transposable elements (TEs) and genes in TE-enriched regions were involved in ovule cell division. We analyzed cis-regulatory modules and revealed the influence of hormones on fiber development from the regulatory divergence of transcription factor (TF) motifs. Finally, we constructed a reliable regulatory network of TFs related to ovule and fiber development based on chromatin accessibility and gene co-expression network. From this network, we discovered a novel TF, WRKY46, which may shape fiber development by regulating the lignin content. CONCLUSIONS: Our results not only reveal the contribution of TEs in fiber development, but also predict and validate the TFs related to fiber development, which will benefit the research of cotton fiber molecular breeding.
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Cromatina , Fatores de Transcrição , Cromatina/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Óvulo Vegetal/genética , Óvulo Vegetal/metabolismo , Redes Reguladoras de Genes , Desoxirribonuclease I/genéticaRESUMO
The coronavirus disease 2019 pandemic has impacted and changed consumer behavior because of a prolonged quarantine and lockdown. This study proposed a theoretical framework to explore and define the influencing factors of online consumer purchasing behavior (OCPB) based on electronic word-of-mouth (e-WOM) data mining and analysis. Data pertaining to e-WOM were crawled from smartphone product reviews from the two most popular online shopping platforms in China, Jingdong.com and Taobao.com. Data processing aimed to filter noise and translate unstructured data from complex text reviews into structured data. The machine learning based K-means clustering method was utilized to cluster the influencing factors of OCPB. Comparing the clustering results and Kotler's five products level, the influencing factors of OCPB were clustered around four categories: perceived emergency context, product, innovation, and function attributes. This study contributes to OCPB research by data mining and analysis that can adequately identify the influencing factors based on e-WOM. The definition and explanation of these categories may have important implications for both OCPB and e-commerce.
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COVID-19 , Comportamento do Consumidor , Humanos , COVID-19/epidemiologia , Controle de Doenças Transmissíveis , Modelos Teóricos , Mineração de Dados/métodosRESUMO
The presence of human cytomegalovirus (HCMV) in glioblastoma (GBM) and improved outcomes of GBM patients receiving therapies targeting the virus have implicated HCMV in GBM progression. However, a unifying mechanism that accounts for the contribution of HCMV to the malignant phenotype of GBM remains incompletely defined. Here we have identified SOX2, a marker of glioma stem cells (GSCs), as a key determinant of HCMV gene expression in gliomas. Our studies demonstrated that SOX2 downregulated promyelocytic leukemia (PML) and Sp100 and consequently facilitated viral gene expression by decreasing the amount of PML nuclear bodies in HCMV-infected glioma cells. Conversely, the expression of PML antagonized the effects of SOX2 on HCMV gene expression. Furthermore, this regulation of SOX2 on HCMV infection was demonstrated in a neurosphere assay of GSCs and in a murine xenograft model utilizing xenografts from patient-derived glioma tissue. In both cases, SOX2 overexpression facilitated the growth of neurospheres and xenografts implanted in immunodeficient mice. Lastly, the expression of SOX2 and HCMV immediate early 1 (IE1) protein could be correlated in tissues from glioma patients, and interestingly, elevated levels of SOX2 and IE1 were predictive of a worse clinical outcome. These studies argue that HCMV gene expression in gliomas is regulated by SOX2 through its regulation of PML expression and that targeting molecules in this SOX2-PML pathway could identify therapies for glioma treatment.
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Glioma , Proteínas Imediatamente Precoces , Animais , Humanos , Camundongos , Citomegalovirus/fisiologia , Regulação para Baixo , Expressão Gênica , Glioma/genética , Glioma/patologia , Proteínas Imediatamente Precoces/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Human cytomegalovirus (HCMV) is a leading cause of congenital birth defects. Though the underlying mechanisms remain poorly characterized, mouse models of congenital CMV infection have demonstrated that the neuronal migration process is damaged. In this study, we evaluated the effects of HCMV infection on connexin 43 (Cx43), a crucial adhesion molecule mediating neuronal migration. We show in multiple cellular models that HCMV infection downregulated Cx43 posttranslationally. Further analysis identified the immediate early protein IE1 as the viral protein responsible for the reduction of Cx43. IE1 was found to bind the Cx43 C terminus and promote Cx43 degradation through the ubiquitin-proteasome pathway. Deletion of the Cx43-binding site in IE1 rendered it incapable of inducing Cx43 degradation. We validated the IE1-induced loss of Cx43 in vivo by introducing IE1 into the fetal mouse brain. Noteworthily, ectopic IE1 expression induced cortical atrophy and neuronal migration defects. Several lines of evidence suggest that these damages result from decreased Cx43, and restoration of Cx43 levels partially rescued IE1-induced interruption of neuronal migration. Taken together, the results of our investigation reveal a novel mechanism of HCMV-induced neural maldevelopment and identify a potential intervention target. IMPORTANCE Congenital CMV (cCMV) infection causes neurological sequelae in newborns. Recent studies of cCMV pathogenesis in animal models reveal ventriculomegaly and cortical atrophy associated with impaired neural progenitor cell (NPC) proliferation and migration. In this study, we investigated the mechanisms underlying these NPC abnormalities. We show that Cx43, a critical adhesion molecule mediating NPC migration, is downregulated by HCMV infection in vitro and HCMV-IE1 in vivo. We provide evidence that IE1 interacts with the C terminus of Cx43 to promote its ubiquitination and consequent degradation through the proteasome. Moreover, we demonstrate that introducing IE1 into mouse fetal brains led to neuronal migration defects, which was associated with Cx43 reduction. Deletion of the Cx43-binding region in IE1 or ectopic expression of Cx43 rescued the IE1-induced migration defects in vivo. Our study provides insight into how cCMV infection impairs neuronal migration and reveals a target for therapeutic interventions.
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Conexina 43 , Infecções por Citomegalovirus , Citomegalovirus , Proteínas Imediatamente Precoces , Animais , Humanos , Recém-Nascido , Camundongos , Conexina 43/genética , Conexina 43/metabolismo , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/metabolismo , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismoRESUMO
Food-derived colloidal nanoparticles (CNPs) have been found in many food cooking processes, and their specific effects on human health need to be further explored. Here, we report on the successful isolation of CNPs from duck soup. The hydrodynamic diameters of the obtained CNPs were 255.23 ± 12.77 nm, which comprised lipids (51.2%), protein (30.8%), and carbohydrates (7.9%). As indicated by the tests of free radical scavenging and ferric reducing capacities, the CNPs possessed remarkable antioxidant activity. Macrophages and enterocytes are essential for intestinal homeostasis. Therefore, RAW 264.7 and Caco-2 were applied to establish an oxidative stress model to investigate the antioxidant characteristics of the CNPs. The results showed that the CNPs from duck soup could be engulfed by these two cell lines, and could significantly alleviate 2,2'-Azobis(2-methylpropionamidine) dihydrochloride (AAPH)-induced oxidative damage. It indicates that the intake of duck soup is beneficial for intestinal health. These data contribute to revealing the underlying functional mechanism of Chinese traditional duck soup and the development of food-derived functional components.
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Congenital human cytomegalovirus (HCMV) infection causes severe damage to the fetal brain, and the underlying mechanisms remain elusive. Cytokine signaling is delicately controlled in the fetal central nervous system to ensure proper development. Here we show that suppressor of cytokine signaling 3 (SOCS3), a negative feedback regulator of the IL-6 cytokine family signaling, was upregulated during HCMV infection in primary neural progenitor cells (NPCs) with a biphasic expression pattern. From viral protein screening, pUL97 emerged as the viral factor responsible for prolonged SOCS3 upregulation. Further, by proteomic analysis of the pUL97-interacting host proteins, regulatory factor X 7 (RFX7) was identified as the transcription factor responsible for the regulation. Depletion of either pUL97 or RFX7 prevented the HCMV-induced SOCS3 upregulation in NPCs. With a promoter-luciferase activity assay, we demonstrated that the pUL97 kinase activity and RFX7 were required for SOCS3 upregulation. Moreover, the RFX7 phosphorylation level was increased by either UL97-expressing or HCMV-infection in NPCs, suggesting that pUL97 induces RFX7 phosphorylation to drive SOCS3 transcription. We further revealed that elevated SOCS3 expression impaired NPC proliferation and migration in vitro and caused NPCs migration defects in vivo. Taken together, these findings uncover a novel regulatory mechanism of sustained SOCS3 expression in HCMV-infected NPCs, which perturbs IL-6 cytokine family signaling, leads to NPCs proliferation and migration defects, and consequently affects fetal brain development.
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Infecções por Citomegalovirus , Citomegalovirus , Humanos , Citomegalovirus/fisiologia , Interleucina-6/metabolismo , Proteômica , Fatores de Transcrição/metabolismo , Células-Tronco , Proteína 3 Supressora da Sinalização de Citocinas/metabolismoRESUMO
Conjugated acetylenic polymers (CAPs) have emerged as a unique class of metal-free semiconductors with tunable electrical and optical properties yet their full potential remains largely unexplored. Organic bioelectronics is envisioned to create more opportunities for innovative biomedical applications. Herein, we report a poly(1,4-diethynylbenzene) (pDEB)/NiO gated enhancement-mode poly(ethylene dioxythiophene)-poly(styrene sulfonate) organic photoelectrochemical transistor (OPECT) and its structural evolution toward bioelectronic detection. pDEB was synthesized via copper-mediated Glaser polycondensation of DEB monomers on the NiO/FTO substrate, and the as-synthesized pDEB/NiO/FTO can efficiently modulate the enhancement-mode device with a high current gain. Linking with a sandwich immunoassay, the labeled alkaline phosphatase can catalyze sodium thiophosphate to generate H2S, which will react with the diacetylene group in pDEB through the Michael addition reaction, resulting in an altered molecular structure and thus the transistor response. Exemplified by HIgG as the model target, the developed biosensor achieves highly sensitive detection with a linear range of 70 fg mL-1-10 ng mL-1 and a low detection limit of 28.5 fg mL-1. This work features the dual functional CAP-gated OPECT, providing not only a novel gating module but also a structurally new rationale for bioelectronic detection.
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Acetileno , Técnicas Biossensoriais , Alcinos , Polímeros/química , Técnicas Biossensoriais/métodos , SemicondutoresRESUMO
This work investigates fixed-time time-varying output formation-containment control of heterogeneous general multi-agent systems, which comprises one virtual leader, multiple leaders, and followers. First, fixed-time nonlinear control law is constructed, such that leaders can achieve time-varying output formation in a finite time. Meanwhile, leaders can track the virtual leader's output trajectory. Next, two complete distributed adaptive fixed-time observers are designed aiming to recover a convex hull. This is key to control issue in this paper. Further, nonlinear control law is constructed for followers, such that followers can move into the convex hull formed by multiple leaders. Finally, two examples are provided to verify the feasibility of the theoretical results.