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Background: Previous research has demonstrated the anti-obesity effects of kimchi in 3T3-L1 adipocytes and mice with diet-induced obesity by assessing the expression of obesity-associated genes. Additionally, recent studies have identified mechanisms involving thermogenesis that support these effects. Objective: This study aims to further investigate the anti-obesity properties of kimchi, focusing on its impact on thermogenic activity in differentiated T37i brown adipocytes. Design: The study first evaluated the antioxidant potential of kimchi using total antioxidant capacity (TAC) and ferric reducing antioxidant power (FRAP) assays. Optimal differentiation conditions for T37i adipocytes were established before proceeding with evaluations of cell viability, intracellular triglyceride (TG) content, lipid accumulation, and the expression of genes and proteins related to obesity and thermogenesis. Results: Kimchi maintained over 90% cell viability in T37i adipocytes at concentrations up to 1,000 µg/mL. Efficient differentiation of T37i preadipocytes was achieved using a medium containing 10% calf serum, 2 nM 3,3',5-triiodo-L-thyronin (T3), and 100 nM insulin. Kimchi significantly reduced intracellular TG levels and lipid accumulation, compared to the control group, and enhanced the expression of genes and proteins related to thermogenesis while reducing the expression of obesity-related genes. Discussion: The findings suggest that kimchi exerts its anti-obesity effects by modulating thermogenic and obesity-related pathways in brown adipocytes, which may be partially attributed to its antioxidant properties. Conclusions: Kimchi shows promise as a preventive measure against obesity by influencing metabolic pathways associated with both obesity and thermogenesis in T37i brown adipocytes.
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OBJECTIVE: Vulnerability to internet gaming disorder (IGD) has increased as internet gaming continues to grow. Cocaine- and amphetamine-regulated transcript (CART) is a hormone that plays a role in reward, anxiety, and stress. The purpose of this study was to identify the role of CART in the pathophysiology of IGD. METHODS: The serum CART levels were measured by enzyme-linked immunosorbent assay, and the associations of the serum CART level with psychological variables were analyzed in patients with IGD (n=31) and healthy controls (HC) (n=42). RESULTS: The serum CART level was significantly lower in the IGD than HC group. The IGD group scored significantly higher than the HC group on the psychological domains of depression, anxiety, the reward response in the Behavioral Activation System and Behavioral Inhibition System. There were no significant correlations between serum CART level and other psychological variables in the IGD group. CONCLUSION: Our results indicate that a decrease in the expression of the serum CART level is associated with the vulnerability of developing IGD. This study supports the possibility that CART is a biomarker in the pathophysiology of IGD.
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The systemic delivery of oligonucleotide therapeutics to the brain is challenging but highly desirable for the treatment of brain diseases undruggable with traditional small-molecule drugs. In this study, a set of DNA nanostructures is prepared and screened them to develop a protein corona-assisted platform for the brain delivery of oligonucleotide therapeutics. The biodistribution analysis of intravenously injected DNA nanostructures reveals that a cube-shaped DNA nanostructure (D-Cb) can penetrate the brain-blood barrier (BBB) and reach the brain tissue. The brain distribution level of D-Cb is comparable to that of other previous nanoparticles conjugated with brain-targeting ligands. Proteomic analysis of the protein corona formed on D-Cb suggests that its brain distribution is driven by endothelial receptor-targeting ligands in the protein corona, which mediate transcytosis for crossing the BBB. D-Cb is subsequently used to deliver an antisense oligonucleotide (ASO) to treat glioblastoma multiforme (GBM) in mice. While free ASO is unable to reach the brain, ASO loaded onto D-Cb is delivered efficiently to the brain tumor region, where it downregulates the target gene and exerts an anti-tumor effect on GBM. D-Cb is expected to serve as a viable platform based on protein corona formation for systemic brain delivery of oligonucleotide therapeutics.
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Aging manifests as many phenotypes, among which age-related changes in brain vessels are important, but underexplored. Thus, in the present study, we constructed a model to predict age using cerebrovascular morphological features, further assessing their clinical relevance using a novel pipeline. Age prediction models were first developed using data from a normal cohort (n = 1181), after which their relevance was tested in two stroke cohorts (n = 564 and n = 455). Our novel pipeline adapted an existing framework to compute generic vessel features for brain vessels, resulting in 126 morphological features. We further built various machine learning models to predict age using only clinical factors, only brain vessel features, and a combination of both. We further assessed deviation from healthy aging using the age gap and explored its clinical relevance by correlating the predicted age and age gap with various risk factors. The models constructed using only brain vessel features and those combining clinical factors with vessel features were better predictors of age than the clinical factor-only model (r = 0.37, 0.48, and 0.26, respectively). Predicted age was associated with many known clinical factors, and the associations were stronger for the age gap in the normal cohort. The age gap was also associated with important factors in the pooled cohort atherosclerotic cardiovascular disease risk score and white matter hyperintensity measurements. Cerebrovascular age, computed using the morphological features of brain vessels, could serve as a potential individualized marker for the early detection of various cerebrovascular diseases.
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Ovomucin (OM), which has insoluble fractions is a viscous glycoprotein, found in egg albumin. Enzymatic hydrolysates of OM have water solubility and bioactive properties. This study investigated that the immunostimulatory effects of OM hydrolysates (OMHs) obtained by using various proteolytic enzymes (Alcalase®, bromelain, α-chymotrypsin, Neutrase®, pancreatin, papain, Protamax®, and trypsin) in RAW 264.7 cells. The results showed that OMH prepared with pancreatin (OMPA) produced the highest levels of nitrite oxide in RAW 264.7 cells, through upregulation of inducible nitric oxide synthase mRNA expression. The production of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6 were increased with the cytokines mRNA expression. The effect of OMPA on mitogen-activated protein kinase signaling pathway was increased the phosphorylation of p38, c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase in a concentration-dependent manner. Therefore, OMPA could be used as a potential immune-stimulating agent in the functional food industry.
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Despite modern advances in food hygiene, food poisoning due to microbial contamination remains a global problem, and poses a great threat to human health. Especially, Listeria monocytogenes and Staphylococcus aureus are gram-positive bacteria found on food-contact surfaces with biofilms. These foodborne pathogens cause a considerable number of food poisoning and infections annually. Ovomucin (OM) is a water-insoluble gel-type glycoprotein in egg whites. Enzymatic hydrolysis can be used to improve the bioactive properties of OM. This study aimed to investigate whether ovomucin hydrolysates (OMHs) produced using five commercial enzymes (Alcalase®, Bromelain, α-Chymotrypsin, Papain, and Pancreatin) can inhibit the biofilm formation of L. monocytogenes ATCC 15313, L. monocytogenes H7962, S. aureus KCCM 11593, and S. aureus 7. Particularly, OMH prepared with papain (OMPP; 500 µg/mL) significantly inhibited biofilm formation in L. monocytogenes ATCC 15313, L. monocytogenes H7962, S. aureus KCCM 11593, and S. aureus 7 by 85.56 %, 80.28 %, 91.70 %, and 79.00 %, respectively. In addition, OMPP reduced the metabolic activity, exopolysaccharide production (EPS), adhesion ability, and gene expression associated with the biofilm formation of these bacterial strains. These results suggest that OMH, especially OMPP, exerts anti-biofilm effects against L. monocytogenes and S. aureus. Therefore, OMPP can be used as a natural anti-biofilm agent to control food poisoning in the food industry.
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Antibacterianos , Biofilmes , Listeria monocytogenes , Ovomucina , Staphylococcus aureus , Biofilmes/efeitos dos fármacos , Listeria monocytogenes/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacologia , Ovomucina/farmacologia , Ovomucina/metabolismo , Hidrólise , Aderência Bacteriana/efeitos dos fármacos , Papaína/metabolismo , Testes de Sensibilidade Microbiana , Quimotripsina/metabolismo , Hidrolisados de Proteína/farmacologia , Hidrolisados de Proteína/metabolismoRESUMO
Patient safety education is necessary for the provision of high-quality medical services. A significant aspect of patient safety education is simulation training, which allows medical students to experience realistic clinical environments. This study aimed to verify the effectiveness of patient safety education using simulation training. We retrospectively analyzed the results of a 30-question questionnaire survey on the perceptions of patient safety before and after simulation training, which was completed by 40 medical students who participated in clinical practice between June and December 2021. A paired t-test was performed by calculating the mean and standard deviation for each item. We found that students' overall perceptions of patient safety improved after training. Specifically, after simulation training, attitudes toward patient safety were maintained at the same level as before training, while students' self-efficacy of patient safety increased. Simulation training is effective in improving students' perceptions of patient safety, and increasing students' confidence can improve their clinical performance. To maintain this effect, repeated learning is required, and theoretical classes and simulation training should be used appropriately for patient safety education in the future.
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Segurança do Paciente , Estudantes de Medicina , Humanos , Estudantes de Medicina/psicologia , Feminino , Masculino , Inquéritos e Questionários , Estudos Retrospectivos , Treinamento por Simulação/métodos , Adulto , Adulto Jovem , Percepção , Competência Clínica , Autoeficácia , Treinamento com Simulação de Alta Fidelidade/métodos , Atitude do Pessoal de SaúdeRESUMO
PURPOSE: To use preoperative MRI data to construct a nomogram to predict survival in patients who have undergone R0 resection for gallbladder cancer. METHODS: The present retrospective study included 143 patients (M:F, 76:67; 67.15 years) with gallbladder cancer who underwent preoperative MRI and subsequent R0 resection between 2013 and 2021 at two tertiary institutions. Clinical and radiological features were analyzed using univariate and multivariate Cox regression analysis to identify independent prognostic factors. Based on the multivariate analysis, we developed an MRI-based nomogram for determining prognoses after curative resections of gallbladder cancer. We also obtained calibration curves for 1-,3-, and 5-year survival probabilities. RESULTS: The multivariate model consisted of the following independent predictors of poor overall survival (OS), which were used for constructing the nomogram: age (years; hazard ratio [HR] = 1.04; 95% confidence interval [CI], 1.04-1.07; p = 0.033); tumor size (cm; HR = 1.40; 95% CI, 1.09-1.79; p = 0.008); bile duct invasion (HR = 3.54; 95% CI, 1.66-7.58; p = 0.001); regional lymph node metastasis (HR = 2.47; 95% CI, 1.10-5.57; p = 0.029); and hepatic artery invasion (HR = 2.66; 95% CI, 1.04-6.83; p = 0.042). The nomogram showed good probabilities of survival on the calibration curves, and the concordance index of the model for predicting overall survival (OS) was 0.779. CONCLUSION: Preoperative MRI findings could be used to determine the prognosis of gallbladder cancer, and the MRI-based nomogram accurately predicted OS in patients with gallbladder cancer who underwent curative resection.
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There is a growing demand for research and development of advanced energy storage devices with high energy density utilizing earth-abundant metal anodes such as sodium metal. Tellurium, a member of the chalcogen group, stands out as a promising cathode material due to its remarkable volumetric capacity, comparable to sulfur, and significantly high electrical conductivity. However, critical issues arise from soluble sodium polytellurides, leading to the shuttle effect. This phenomenon can result in the loss of active materials, self-discharge, and anode instability. Here, we introduce polypyrrole-coated tellurium nanotubes as the cathode materials, where polypyrrole plays a crucial role in preventing the dissolution of polytellurides, as confirmed through operando optical microscopy. The polypyrrole-coated tellurium nanotubes exhibited an outstanding rate performance and long cycle stability in sodium-tellurium batteries. These research findings are anticipated to bolster the viability of polypyrrole-coated tellurium nanotubes as promising cathode materials, making a substantial contribution to the commercialization of sodium-ion battery technology.
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BACKGROUND: The impact of excluding intrahepatic segmental vessels from regions of interest (ROIs) on liver stiffness measurement (LSM) via magnetic resonance elastography (MRE) remains uncertain. PURPOSE: To determine the effect of excluding intrahepatic segmental vessels from ROIs on LSM obtained from MRE. MATERIAL AND METHODS: This retrospective analysis included 95 participants who underwent successful two-dimensional gradient recalled-echo MRE before hepatic tumor resection (n = 49) or living liver donation (n = 46). The conventional LSM was determined by manually drawing ROIs on the elastogram within the 95% confidence region, staying 1 cm within the liver capsule and excluding large hilar vessels, the gallbladder, hepatic lesions, and artifacts. In addition, the modified LSM was determined by excluding intrahepatic segmental vessels. LSMs obtained by the two methods were compared with paired sample signed-rank test. Diagnostic performance for advanced fibrosis was calculated and compared using McNemar's test and Delong's test. The stage of hepatic fibrosis was assessed using surgical specimens by the METAVIR system. RESULTS: The modified LSM was larger than the conventional LSM (2.4 kPa vs. 2.2 kPa in reader 1; 2.7 kPa vs. 2.4 kPa in reader 2; P < 0.001). The modified LSM showed superior sensitivity (0.841 vs. 0.659 in reader 1; 0.864 vs. 0.705 in reader 2; P < 0.05) and area under the curve (0.901 vs. 0.820 in reader 1; 0.912 vs. 0.843 in reader 2; P < 0.05) for detecting advanced fibrosis (≥F3) than conventional LSM. CONCLUSION: The exclusion of intrahepatic segmental vessels from ROIs in MRE affected the LSM and enhanced diagnostic performance for advanced fibrosis.
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PURPOSE: To compare the efficacy of a 0.15% HA with that of 0.1% HA eye drops for DES after cataract surgery. METHODS: This study was double blinded, randomized and prospective study, and conducted in 69 participants (70 eyes) from Pusan National University Yangsan Hospital and executed from February 1, 2022 to November 30, 2022. Participants were adult cataract patients with normal lid position, not suffering from any other ocular disease and not meet the exclusion cirteria of clinical trial. Participants were randomly divided into two groups: 35 participants (17 males and 18 females) in the 0.1% HA group and 34 participants (19 males and 15 females) in the 0.15% HA group, receiving treatment six times daily for 6 weeks following cataract surgery. Subjective and objective assessments were performed at preoperative and postoperative visits, including ocular surface disease index score, tear break up time, corneal staining score, Schirmer's I test score, lipid layer thickness), meiboscore, and biochemical analysis of the eye drops. RESULTS: Throughout the study, the postoperative ocular surface disease index score was significantly lower in the group receiving 0.15% hyaluronic acid than in the group receiving 0.1% hyaluronic acid. Additionally, the postoperative ocular surface disease index score showed a significant positive correlation with the postoperative use of 0.15% hyaluronic acid and the preoperative Schirmer's I test score. In multivariate analysis, treatment with 0.15% hyaluronic acid and the preoperative ocular surface disease index score were significant independent parameters affecting the postoperative ocular surface disease index score. CONCLUSION: The use of 0.15% hyaluronic acid is recommended for its potential advantages in alleviating symptoms following cataract surgery, making it a viable alternative to traditional 0.1% hyaluronic acid treatment. TRIAL REGISTRATION: ISRCTN95830348.
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Extração de Catarata , Ácido Hialurônico , Glândulas Tarsais , Soluções Oftálmicas , Humanos , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/uso terapêutico , Masculino , Feminino , Idoso , Extração de Catarata/efeitos adversos , Estudos Prospectivos , Pessoa de Meia-Idade , Glândulas Tarsais/efeitos dos fármacos , Glândulas Tarsais/metabolismo , Soluções Oftálmicas/administração & dosagem , Método Duplo-Cego , Lipídeos , Resultado do TratamentoRESUMO
Congenital hypothyroidism (CHT) is a diverse condition with various genetic etiologies. This study aimed to investigate the utility of next-generation sequencing (NGS) analysis in guiding treatment decisions and predicting prognosis for CHT patients with gland in situ (GIS). A retrospective analysis was conducted on 33 CHT patients with GIS who underwent NGS analysis at a single institution between 2018 and 2023. Patients were classified as having permanent (PCH), transient congenital hypothyroidism, or ambiguous congenital hypothyroidism (ACH) CHT based on their response to levothyroxine discontinuation at 3 years of age. Among the 33 patients, genetic variants were identified in 26, with the most prevalent variants found in DUOX2 (26.92%), TSHR (30.77%), TG (19.35%), and DUOXA2 (19.23%). Patients with high initial thyroid-stimulating hormone levels (>50 mIU/L) and low free thyroxine levels (<0.89 ng/dL) at diagnosis tended to have compound heterozygous or homozygous variants in DUOX2, DUOXA2, and TG, and were more likely to develop PCH. In contrast, patients with heterozygous variants in these genes often exhibited ACH. TSHR variants were associated with diverse clinical manifestations, ranging from PCH to ACH, and were more common in patients with initial thyroid-stimulating hormone levels <50 mIU/L. The study highlights the potential utility of NGS analysis in predicting the clinical course and guiding treatment decisions for CHT patients with GIS. Genetic analysis may aid in determining the appropriate duration of levothyroxine therapy and monitoring strategies, particularly in cases where traditional clinical indicators are inconclusive.
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Hipotireoidismo Congênito , Oxidases Duais , Sequenciamento de Nucleotídeos em Larga Escala , Receptores da Tireotropina , Tiroxina , Humanos , Hipotireoidismo Congênito/genética , Hipotireoidismo Congênito/tratamento farmacológico , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/sangue , Feminino , Masculino , Estudos Retrospectivos , Oxidases Duais/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Tiroxina/uso terapêutico , Receptores da Tireotropina/genética , Pré-Escolar , Lactente , Recém-Nascido , Tireoglobulina/genética , Tireoglobulina/sangue , Proteínas de MembranaRESUMO
Korean medicine (KM) is used to treat anxiety disorders, but there is limited research on its effects. This study aimed to examine the associations between improved QoL and reduced clinical symptoms and KM in patients with anxiety disorders. The medical records of patients with anxiety who were treated with KM (acupuncture, psychotherapy, Chuna therapy, aromatherapy, or herbal medicine) for at least 4 weeks were retrospectively analyzed. Clinical, QoL, and cost outcomes were measured at baseline and at weeks 4 and 12 (Anxiety: State-Trait Anxiety Inventory [STAI X-1 (state), X-2 (trait)], Beck Anxiety Inventory [BAI]; anger: State-Trait Anger Expression Inventory State [STAXI-S (state), T (trait)], Anger Expression Inventory [AXI-K-I (anger-in), AXI-K-O (anger-out), AXI-K-C (anger-control); depression: Beck Depression Inventory-II [BDI II], QoL: QoL-related instruments Euro Quality of Life 5 Dimensions utility score [EQ-5D], Euro QoL Visual Analog Scale [EQ-VAS]). The total costs for each item were calculated in terms of NHIS-covered costs and patients' out-of-pocket costs from the perspective of the healthcare system. The medical records of 67 patients were evaluated. The KM treatments were found to be associated with decreased anxiety (STAI X-1; STAI X-2; BAI, p < 0.0001), depression (BDI-II, p < 0.0001), and anger (AKI-K-I; AKI-K-O, p < 0.05) and increased QoL (EQ-5D; EQ-VAS, p < 0.0001). An average of USD 1360 was paid for the KM treatments for 4 weeks. The study findings suggested that KM may improve clinical symptoms and QoL outcomes in patients with anxiety disorders.
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In 2D noble metals like copper, the carrier scattering at grain boundaries has obscured the intrinsic nature of electronic transport. However, it is demonstrated that the intrinsic nature of transport by hole carriers in 2D copper can be revealed by growing thin films without grain boundaries. As even a slight deviation from the twin boundary is perceived as grain boundaries by electrons, it is only through the thorough elimination of grain boundaries that the hidden hole-like attribute of 2D single-crystal copper can be unmasked. Two types of Fermi surfaces, a large hexagonal Fermi surface centered at the zone center and the triangular Fermi surface around the zone corner, tightly matching to the calculated Fermi surface topology, confirmed by angle-resolved photoemission spectroscopy (ARPES) measurements and vivid nonlinear Hall effects of the 2D single-crystal copper account for the presence of hole carriers experimentally. This breakthrough suggests the potential to manipulate the majority carrier polarity in metals by means of grain boundary engineering in a 2D geometry.
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Smart wearable sensors are increasingly integrated into everyday life, interfacing with the human body to enable real-time monitoring of biological signals. This study focuses on creating high-sensitivity capacitive-type sensors by impregnating polyester-based 3D spacer fabric with a Carbon Nanotube (CNT) dispersion. The unique properties of conductive particles lead to nonlinear variations in the dielectric constant when pressure is applied, consequently affecting the gauge factor. The results reveal that while the fabric without CNT particles had a gauge factor of 1.967, the inclusion of 0.04 wt% CNT increased it significantly to 5.210. As sensor sensitivity requirements vary according to the application, identifying the necessary CNT wt% is crucial. Artificial intelligence, particularly the Multilayer Perception (MLP) model, enables nonlinear regression analysis for this purpose. The MLP model created and validated in this research showed a high correlation coefficient of 0.99564 between the model predictions and actual target values, indicating its effectiveness and reliability.
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This study aimed to identify plasma proteins that could serve as potential biomarkers for microbial invasion of the amniotic cavity (MIAC) or intra-amniotic inflammation (IAI) in women with preterm labor (PTL). A retrospective cohort comprised singleton pregnant women with PTL (24-34 weeks) who underwent amniocentesis. Pooled plasma samples were analyzed by label-free liquid chromatography-tandem mass spectrometry for proteome profiling in a nested case-control study (concomitant MIAC/IAI cases vs. non-MIAC/IAI controls [n = 10 per group]). Eight target proteins associated with MIAC/IAI were further verified by immunoassays in a large cohort (n = 230). Shotgun proteomic analysis revealed 133 differentially expressed proteins (fold change > 1.5, P < 0.05) in the plasma of MIAC/IAI cases. Further quantification confirmed that the levels of AFP were higher and those of kallistatin and TGFBI were lower in the plasma of women with MIAC and that the levels of kallistatin and TGFBI were lower in the plasma of women with IAI than in those without these conditions. The area under the curves of plasma AFP, kallistatin, and TGFBI ranged within 0.67-0.81 with respect to each endpoint. In summary, plasma AFP, kallistatin, and TGFBI may represent valuable non-invasive biomarkers for predicting MIAC or IAI in women with PTL.
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Biomarcadores , Proteínas Sanguíneas , Trabalho de Parto Prematuro , Proteômica , Humanos , Feminino , Gravidez , Trabalho de Parto Prematuro/sangue , Adulto , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/metabolismo , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Retrospectivos , Proteômica/métodos , Corioamnionite/sangue , Corioamnionite/microbiologia , Inflamação/sangue , Amniocentese , Proteoma/análiseRESUMO
This work highlights the novel approach of incorporating potassium iodide (KI) doping during the synthesis of In0.53P0.47 core quantum dots (QDs) to significantly reduce the concentration of vacancies (i.e., In vacancies; VIn-) within the bulk of the core QD and inhibit the formation of InPOx at the core QD-Zn0.6Se0.4 shell interfaces. The photoluminescence quantum yield (PLQY) of ~97% and full width at half maximum (FWHM) of ~40 nm were achieved for In0.53P0.47/Zn0.6Se0.4/Zn0.6Se0.1S0.3/Zn0.5S0.5 core/multi-shell QDs emitting red light, which is essential for a quantum-dot organic light-emitting diode (QD-OLED) without red, green, and blue crosstalk. KI doping eliminated VIn- in the core QD bulk by forming K+-VIn- substitutes and effectively inhibited the formation of InPO4(H2O)2 at the core QD-Zn0.6Se0.4 shell interface through the passivation of phosphorus (P)-dangling bonds by P-I bonds. The elimination of vacancies in the core QD bulk was evidenced by the decreased relative intensity of non-radiative unpaired electrons, measured by electron spin resonance (ESR). Additionally, the inhibition of InPO4(H2O)2 formation at the core QD and shell interface was confirmed by the absence of the {210} X-ray diffraction (XRD) peak intensity for the core/multi-shell QDs. By finely tuning the doping concentration, the optimal level was achieved, ensuring maximum K-VIn- substitution, minimal K+ and I- interstitials, and maximum P-dangling bond passivation. This resulted in the smallest core QD diameter distribution and maximized optical properties. Consequently, the maximum PLQY (~97%) and minimum FWHM (~40 nm) were observed at 3% KI doping. Furthermore, the color gamut of a QD-OLED display using R-, G-, and B-QD functional color filters (i.e., ~131.1%@NTSC and ~98.2@Rec.2020) provided a nearly perfect color representation, where red-light-emitting KI-doped QDs were applied.
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The human methyltransferase and transcriptional coactivator MLL4 and its paralog MLL3 are frequently mutated in cancer. MLL4 and MLL3 monomethylate histone H3K4 and contain a set of uncharacterized PHD fingers. Here, we report a novel function of the PHD2 and PHD3 (PHD2/3) fingers of MLL4 and MLL3 that bind to ASXL2, a component of the Polycomb repressive H2AK119 deubiquitinase (PR-DUB) complex. The structure of MLL4 PHD2/3 in complex with the MLL-binding helix (MBH) of ASXL2 and mutational analyses reveal the molecular mechanism which is conserved in homologous ASXL1 and ASXL3. The native interaction of the Trithorax MLL3/4 complexes with the PR-DUB complex in vivo depends solely on MBH of ASXL1/2, coupling the two histone modifying activities. ChIP-seq analysis in embryonic stem cells demonstrates that MBH of ASXL1/2 is required for the deubiquitinase BAP1 recruitment to MLL4-bound active enhancers. Our findings suggest an ASXL1/2-dependent functional link between the MLL3/4 and PR-DUB complexes.
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Proteínas de Ligação a DNA , Histona-Lisina N-Metiltransferase , Ligação Proteica , Proteínas Repressoras , Proteínas Supressoras de Tumor , Ubiquitina Tiolesterase , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Humanos , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Animais , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Camundongos , Elementos Facilitadores Genéticos , Células HEK293 , Dedos de Zinco PHD , Histonas/metabolismoRESUMO
Acetaminophen overdose is a leading cause of acute liver failure (ALF), and effective treatment depends on early prediction of disease progression. ALF diagnosis currently requires blood collection 24-72 h after APAP ingestion, necessitating repeated tests and hospitalization. Here, we assessed earlier ALF diagnosis using positron emission tomography (PET) imaging of translocator proteins (TSPOs), which are involved in molecular transport, oxidative stress, apoptosis, and energy metabolism, with the radiotracer [18F]GE180. We intraperitoneally administered propacetamol hydrochloride to male C57BL/6 mice to induce ALF. We performed in vivo PET/CT imaging 3 h later using the TSPO-specific radiotracer [18F]GE180 and quantitatively analyzed the PET images by determining the averaged standardized uptake value (SUVav) in the liver parenchyma. We assessed liver TSPO expression levels via real-time polymerase chain reaction, Western blotting, and immunohistochemistry. [18F]GE180 PET imaging 3 h after propacetamol administration (1500 mg/kg) significantly increased liver SUVav compared to controls (p = 0.001). Analyses showed a 10-fold and 4-fold increase in TSPO gene and protein expression, respectively, in the liver, 3 h after propacetamol induction compared to controls. [18F]GE180 PET visualized and quantified propacetamol-induced ALF through TSPO overexpression. These findings highlight TSPO PET's potential as a non-invasive imaging biomarker for early-stage ALF.