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In pixel-based deep reinforcement learning (DRL), learning representations of states that change because of an agent's action or interaction with the environment poses a critical challenge in improving data efficiency. Recent data-efficient DRL studies have integrated DRL with self-supervised learning (SSL) and data augmentation to learn state representations from given interactions. However, some methods have difficulties in explicitly capturing evolving state representations or in selecting data augmentations for appropriate reward signals. Our goal is to explicitly learn the inherent dynamics that change with an agent's intervention and interaction with the environment. We propose masked and inverse dynamics modeling (MIND), which uses masking augmentation and fewer hyperparameters to learn agent-controllable representations in changing states. Our method is comprised of a self-supervised multitask learning that leverages a transformer architecture, which captures the spatiotemporal information underlying in the highly correlated consecutive frames. MIND uses two tasks to perform self-supervised multitask learning: masked modeling and inverse dynamics modeling. Masked modeling learns the static visual representation required for control in the state, and inverse dynamics modeling learns the rapidly evolving state representation with agent intervention. By integrating inverse dynamics modeling as a complementary component to masked modeling, our method effectively learns evolving state representations. We evaluate our method by using discrete and continuous control environments with limited interactions. MIND outperforms previous methods across benchmarks and significantly improves data efficiency. The code is available at https://github.com/dudwojae/MIND.
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INTRODUCTION: The international outcome inventory for hearing aids (IOI-HA) is a questionnaire widely used to assess the subjective benefits of hearing aids. This study aimed to evaluate the relationship between IOI-HA outcomes and target mismatch in real-ear measurement (REM). METHODS: Thirty-four ears of 25 patients who had worn hearing aids were evaluated using the Korean version of the IOI-HA and REM after fitting for 2 months. Real-ear insertion gain (REIG) was measured at three different levels of input intensity-50, 65, and 80 dB sound pressure level (SPL)-and a frequency range of 0.25 to 6 kHz. Factors 1 and 2 and total IOI-HA scores were compared with the mismatches of REIGs and target gains of REM. RESULTS: Factor 1, Factor 2, and total IOI-HA scores were 14.6 ± 3.5, 11.4 ± 2.2, and 25.9 ± 5.1, respectively. The averages of the difference of REIGs and target gains in REM at 50, 65, and 80 dB SPL input levels were -3.1 ± 6.7, -2.3 ± 7.2, and -3.0 ± 8.2, respectively. Factors 1 and 2 scores of the IOI-HA showed significant correlations with target mismatch in REM at 1 kHz and 0.75 kHz frequencies, respectively. Total IOI-HA scores had significant correlations with target mismatches in REM at 0.75 and 1 kHz frequencies. CONCLUSION: IOI-HA scores correlated with target mismatch in REM at mid frequencies. The IOI-HA can be a useful screening measure for evaluating the necessity of further adjustments in hearing aids through REM at mid frequencies.
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Recent evidence of gut microbiota dysbiosis in the context of psoriasis and the increased cooccurrence of inflammatory bowel disease and psoriasis suggest a close relationship between skin and gut immune responses. Using a mouse model of psoriasis induced by the Toll-like receptor (TLR) 7 ligand imiquimod, we found that psoriatic dermatitis was accompanied by inflammatory changes in the small intestine associated with eosinophil degranulation, which impaired intestinal barrier integrity. Inflammatory responses in the skin and small intestine were increased in mice prone to eosinophil degranulation. Caco-2 human intestinal epithelial cells were treated with media containing eosinophil granule proteins and exhibited signs of inflammation and damage. Imiquimod-induced skin and intestinal changes were attenuated in eosinophil-deficient mice, and this attenuation was counteracted by the transfer of eosinophils. Imiquimod levels and the distribution of eosinophils were positively correlated in the intestine. TLR7-deficient mice did not exhibit intestinal eosinophil degranulation but did exhibit attenuated inflammation in the skin and small intestine following imiquimod administration. These results suggest that TLR7-dependent bidirectional skin-to-gut communication occurs in psoriatic inflammation and that inflammatory changes in the intestine can accelerate psoriasis.
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Degranulación de la Célula , Modelos Animales de Enfermedad , Eosinófilos , Imiquimod , Intestino Delgado , Psoriasis , Receptor Toll-Like 7 , Animales , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 7/genética , Psoriasis/patología , Psoriasis/metabolismo , Ratones , Eosinófilos/metabolismo , Eosinófilos/inmunología , Humanos , Intestino Delgado/patología , Intestino Delgado/metabolismo , Piel/patología , Piel/metabolismo , Inflamación/patología , Inflamación/metabolismo , Ratones Noqueados , Células CACO-2 , Glicoproteínas de MembranaRESUMEN
In this study, the impact of lead (Pb) doping on the photoelectrochemical (PEC) water splitting performance of tungsten oxide (WO3) photoanodes was investigated through a combination of experimental and theoretical approaches. Pb-doped WO3 nanostructured thin films were synthesized hydrothermally, and extensive characterizations were conducted to study their morphologies, band edge, optical and photoelectrochemical properties. Pb-doped WO3 exhibited efficient carrier density and charge separations by reducing the charge transfer resistance. The 0.96 at% Pb doping shows a record photocurrent of â¼ 1.49 mAcm-2 and â¼ 3.44 mAcm-2 (with the hole scavenger) at 1.23 V vs. RHE besides yielding a high charge separation and Faradaic efficiencies of â¼ 86 % and > 90 %, respectively. A shift in the Fermi level towards the conduction band was also observed upon the Pb doping. Additionally, density functional theory (DFT) simulations demonstrated the changes in the density of states and bandgap upon Pb doping, exhibiting favorable changes in the surface and bulk properties of WO3.
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Background: Data on the durability of booster dose immunity of COVID-19 vaccines are relatively limited. Methods: Immunogenicity was evaluated for up to 9-12 months after the third dose of vaccination in 94 healthy adults. Results: Following the third dose, the anti-spike immunoglobulin G (IgG) antibody response against the wild-type was boosted markedly, which decreased gradually over time. However, even 9-12 months after the booster dose, both the median and geometric mean of anti-spike IgG antibody levels were higher than those measured 4 weeks after the second dose. Breakthrough infection during the Omicron-dominant period boosted neutralizing antibody titers against Omicron sublineages (BA.1 and BA.5) and the ancestral strain. T-cell immune response was efficiently induced and maintained during the study period. Conclusions: mRNA vaccine booster dose elicited durable humoral immunity for up to 1 year after the third dose and T-cell immunity was sustained during the study period, supporting an annual COVID-19 vaccination strategy.
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OBJECTIVE: Driver characteristics have been linked to the frequency and severity of car crashes. Among these, age and gender have been shown to impact both the possibility and severity of a crash. Previous studies have used standard ordered probit (OP) models to analyze crash data, and some research has suggested heteroskedastic ordered probit (HETOP) could provide improved model fit. The objective of this paper is to evaluate potential improvements of the heteroskedastic ordered probit (HETOP) model compared to the standard ordered probit (OP) model in crash analysis, by examining the effect of gender across age on injury severity among drivers. This paper hypothesizes that the HETOP model can provide a better fit to crash data, by allowing heteroskedasticity in the distribution of injury severity across driver age and gender. METHODS: Data for 20,222 crashes were analyzed for North Carolina from 2016 to 2018, which represents the state with the highest number of fatalities per 100 million vehicle miles traveled amongst available crash data from the Highway Safety Information System. RESULTS: Darker lighting conditions, severe road surface conditions, and less severe weather were associated with increased injury severity. For driver demographics, the probability of severe injuries increased with age and for male drivers. Moreover, the variance of severity increased with age disproportionately within and across genders, and the HETOP was able to account for this. CONCLUSIONS: The results of the two applied approaches revealed that HETOP model outperformed the standard OP model when measuring the effects of age and gender together in injury severity analysis, due to the heteroskedasticity in injury severity within gender and age. The HETOP statistical method presented in this paper can be more broadly applied across other contexts and combinations of independent variables for improved model prediction and accuracy of causal variables in traffic safety.
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Conducción de Automóvil , Heridas y Lesiones , Humanos , Masculino , Femenino , Accidentes de Tránsito , Probabilidad , Tiempo (Meteorología) , Viaje , Heridas y Lesiones/epidemiología , Modelos LogísticosRESUMEN
Despite a high vaccination rate, the COVID-19 pandemic continues with immune-evading Omicron variants. The success of additional antigenic stimulation through breakthrough infection (BI) and updated vaccination in overcoming antigenic imprinting needs to be determined. Participants in a long-term follow-up cohort of healthcare worker (HCW) vaccinee were categorized according to their infection/vaccination status. Anti-SARS-CoV-2 spike/nucleocapsid protein antibodies were measured, and plaque reduction neutralization tests (PRNTs) against wild-type (WT), BA.5, BN.1, and XBB.1.5 were conducted. The neutralization activity of intravenous immunoglobulin (IVIG) products was evaluated to assess the immune status of the general population. Ninety-five HCWs were evaluated and categorized into seven groups. The WT PRNT ND50 value was highest regardless of infection/vaccination status, and groups with recent antigenic stimulation showed high PRNT titers overall. Groups with double Omicron stimulation, either by BI plus BA.4/5 bivalent vaccination or repeated BI, exhibited significantly higher BA.5 and BN.1 PRNT to WT PRNT ratios than those with single Omicron stimulation. Overall group immunity was estimated to be boosted in January 2023, reflecting the effect of the BA.4/5 bivalent booster and additional BIs, but slightly declined in June 2023. A substantial increase in the antibody concentrations of IVIG products was noticed in 2022, and recently produced IVIG products exhibited a substantial level of cross-reactive neutralizing activity against emerging variants. Neutralizing activity against emerging variants could be enhanced by repeated antigenic stimulation via BI and/or updated vaccination. Overall group immunity was elevated accordingly, and IVIG products showed substantial activity against circulating strains.
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Anticuerpos Neutralizantes , COVID-19 , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Infección Irruptiva , Pandemias , COVID-19/prevención & control , SARS-CoV-2 , Anticuerpos Antivirales , VacunaciónRESUMEN
Developing new antibody assays for emerging SARS-CoV-2 variants is challenging. SARS-CoV-2 surrogate virus neutralization tests (sVNT) targeting Omicron BA.1 and BA.5 have been devised, but their performance needs to be validated in comparison with quantitative immunoassays. First, using 1749 PRNT-positive sera, we noticed that log-transformed optical density (OD) ratio of wild-type (WT) sVNT exhibited better titer-correlation with plaque reduction neutralization test (PRNT) than % inhibition value. Second, we tried 798 dilutional titration tests with 103 sera, but nonlinear correlation between OD ratio and antibody concentration limited titration of sVNT. Third, the titer-correlations of two sVNT kits for BA.1 and two quantitative immunoassays for WT were evaluated with BA.1 and BA.5 PRNT. All tested kits exhibited a linear correlation with PRNT titers, but the sVNT kits exhibited high false-negative rates (cPass-BA.1 kit, 45.4% for BA.1 and 44.2% for BA.5; STANDARD F-BA.1 kit, 1.9% for BA.1 and 2.2% for BA.5), while quantitative immunoassays showed 100% sensitivity. Linear mixed-effects model suggested superior titer-correlation with PRNT for quantitative immunoassays compared to sVNT kits. Taken together, the use of quantitative immunoassays for WT, rather than rapid development of new kits, would be practical for predicting neutralizing activities against emerging new variants.
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COVID-19 , SARS-CoV-2 , Humanos , Pruebas de Neutralización , SARS-CoV-2/genética , COVID-19/diagnóstico , Inmunoensayo , Anticuerpos Neutralizantes , Anticuerpos AntiviralesRESUMEN
Citrus fruits are rich in dietary flavonoids and have many health benefits, but their antiadipogenic mechanism of action and their impact on lipid metabolism remain unclear. In this study, we investigated the effect of citrus flavonoids, namely, hesperidin (HES), narirutin (NAR), nobiletin (NOB), sinensetin (SIN), and tangeretin (TAN), on preventing fat cell development by gene expression in 3T3-L1 adipocytes. Among the citrus flavonoids tested, HES and NAR significantly reduced fat storage and triglyceride levels and increased glucose uptake in 3T3-L1 adipocytes. Additionally, HES and NAR treatment increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) while reducing the protein expression of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR). Furthermore, in silico docking revealed that flavonoids activate AMPK. RNA sequencing analysis demonstrated that citrus flavonoids normalized the expression of 40 genes, which were either upregulated by more than 2-fold or downregulated by less than 0.6-fold including Acadv1, Acly, Akr1d1, Awat1, Cyp27a1, Decr1, Dhrs4, Elovl3, Fasn, G6pc, Gba, Hmgcs1, Mogat2, Lrp5, Sptlc3, and Snca to levels comparable to the control group. Altogether, HES and NAR among five citrus flavonoids showed antiadipogenic effects by regulating the expression of specific lipid metabolism genes partially restored to control levels in 3T3-L1 cells.
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Proteínas Quinasas Activadas por AMP , Citrus , Animales , Ratones , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Células 3T3-L1 , Adipogénesis , Citrus/metabolismo , Adipocitos/metabolismo , Flavonoides/farmacología , Flavonoides/metabolismo , Análisis de Secuencia de ARNRESUMEN
The coronavirus disease 2019 pandemic persisted for 3 years and is now transitioning to endemicity. We illustrated the change in group immunity induced by vaccination (monovalent vaccines) and breakthrough infections (BIs) in a healthcare worker (HCW) cohort. Five sampling points were analyzed: before the third dose and 1, 3, 5, and 8 months after the vaccination. The last two points corresponded roughly to 1 and 4 months after omicron BA.1/BA.2 BI. A semi-quantitative anti-spike binding antibody (Sab) assay and plaque reduction neutralization test (PRNT) against circulating variants were conducted. A linear regression model was utilized to deduce correlation equations. Baseline characteristics and antibody titers after the third dose were not different between 106 HCWs with or without BI (54/52). One month after the third dose, BA.1 PRNT increased with wild-type (WT), but 3 months after the third dose, it decreased more rapidly than WT PRNT. After BI, BA.1 PRNT increased robustly and waned slower than WT. A linear equation of waning kinetics was deduced between log10Sab and months, and the slope became gradual after BI. The estimated BA.5 PRNT titers at the beginning of the BA.5 outbreak were significantly higher than the BA.1 PRNT titers of the initial BA.1/BA.2 wave, which might be associated with the smaller size of the BA.5 wave. BA.1/BA.2 BI after the third dose elicited robust and broad neutralizing activity, preferentially maintaining cross-neutralizing longevity against BA.1 and BA.5. The estimated kinetics provide an overview of group immunity through the third vaccination and BA.1/BA.2 BI, correlating with the actual outbreaks. IMPORTANCE This study analyzed changes in group immunity induced by coronavirus disease 2019 (COVID-19) vaccination and BA.1/BA.2 breakthrough infections (BIs) in a healthcare worker cohort. We investigated the longitudinal kinetics of neutralizing antibodies against circulating variants and confirmed that BA.1/BA.2 BIs enhance the magnitude and durability of cross-neutralization against BA.1 and BA.5. Correlation equations between semi-quantitative anti-spike antibody and plaque reduction neutralization test titers were deduced from the measured values using a linear regression model. Based on the equations, group immunity was estimated to last up to 11 months following the third dose of the COVID-19 vaccine. The estimated group immunity suggests that the augmented immunity and flattened waning slope through BI could correlate with the overall outbreak size. Our findings could provide a better understanding to establish public health strategies against future endemicity.
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Deep reinforcement learning (DRL) is a powerful approach that combines reinforcement learning (RL) and deep learning to address complex decision-making problems in high-dimensional environments. Although DRL has been remarkably successful, its low sample efficiency necessitates extensive training times and large amounts of data to learn optimal policies. These limitations are more pronounced in the context of multi-agent reinforcement learning (MARL). To address these limitations, various studies have been conducted to improve DRL. In this study, we propose an approach that combines a masked reconstruction task with QMIX (M-QMIX). By introducing a masked reconstruction task as an auxiliary task, we aim to achieve enhanced sample efficiency-a fundamental limitation of RL in multi-agent systems. Experiments were conducted using the StarCraft II micromanagement benchmark to validate the effectiveness of the proposed method. We used 11 scenarios comprising five easy, three hard, and three very hard scenarios. We particularly focused on using a limited number of time steps for each scenario to demonstrate the improved sample efficiency. Compared to QMIX, the proposed method is superior in eight of the 11 scenarios. These results provide strong evidence that the proposed method is more sample-efficient than QMIX, demonstrating that it effectively addresses the limitations of DRL in multi-agent systems.
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Benchmarking , Políticas , Refuerzo en PsicologíaRESUMEN
BACKGROUND/AIM: We report an in vitro three-dimensional (3D) culture system optimized for the growth of HepG2 hepatocarcinoma cells. MATERIALS AND METHODS: The 3D culture system was fabricated based on polyethylene glycol (PEG)-based hydrogels; their mechanical strength was controlled by differences in the arm number and concentration of PEG-vinylsulfone. Moreover, cellular growth was evaluated after culturing HepG2 cells in PEG-based hydrogels with various mechanical strengths. RESULTS: HepG2 cell culture in the 3D PEG-based hydrogels induced the formation of spherical colonies. Moreover, the highest number of spherical colonies formed from HepG2 cells at the single-cell level, and the formation of spherical colonies with a uniform size was observed in HepG2 cells cultured in 5% (w/v) 8-arm PEG-based hydrogels. CONCLUSION: 5% (w/v) 8-arm PEG-based hydrogels may be developed as a 3D culture system optimized for stimulating the in vitro growth of HepG2 cells.
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Hidrogeles , Polietilenglicoles , Humanos , Polietilenglicoles/farmacología , Células Hep G2 , Hidrogeles/farmacología , Línea Celular , Técnicas de Cultivo de Célula/métodos , Materiales BiocompatiblesRESUMEN
The incidence of colitis-associated colorectal cancer (CAC) has increased due to a high-nutrient diet, increased environmental stimuli and inherited gene mutations. To adequately treat CAC, drugs should be developed by identifying novel therapeutic targets. E3 ubiquitin-protein ligase pellino homolog 3 (pellino 3; Peli3) is a RING-type E3 ubiquitin ligase involved in inflammatory signalling; however, its role in the development and progression of CAC has not been elucidated. In this study, we studied Peli3-deficient mice in an azoxymethane/dextran sulphate sodium-induced CAC model. We observed that Peli3 promotes colorectal carcinogenesis with increased tumour burden and oncogenic signalling pathways. Ablation of Peli3 reduced inflammatory signalling activation at the early stage of carcinogenesis. Mechanistic studies indicate that Peli3 enhances toll-like receptor 4 (TLR4)-mediated inflammation through ubiquitination-dependent degradation of interferon regulatory factor 4, a negative regulator of TLR4 in macrophages. Our study suggests an important molecular link between Peli3 and colonic inflammation-mediated carcinogenesis. Furthermore, Peli3 can be a therapeutic target in the prevention and treatment of CAC.
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Neoplasias Asociadas a Colitis , Receptor Toll-Like 4 , Animales , Ratones , Carcinogénesis/genética , Neoplasias Asociadas a Colitis/genética , Inflamación/complicaciones , Factores Reguladores del Interferón/metabolismo , Ratones Endogámicos C57BL , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The growing use of plastic materials has resulted in a constant increase in the risk associated with microplastics (MPs). Ultra-violet (UV) light and wind break down modify MPs in the environment into smaller particles known as weathered MPs (WMPs) and these processes increase the risk of MP toxicity. The neurotoxicity of weathered polystyrene-MPs remains unclear. Therefore, it is important to understand the risks posed by WMPs. We evaluated the chemical changes of WMPs generated under laboratory-synchronized environmentally mimetic conditions and compared them with virgin MPs (VMPs). We found that WMP had a rough surface, slight yellow color, reduced molecular weight, and structural alteration compared with those of VMP. Next, 2 µg of â¼100 µm in size of WMP and VMP were orally administered once a day for one week to C57BL/6 male mice. Proteomic analysis revealed that the WMP group had significantly increased activation of immune and neurodegeneration-related pathways compared with that of the VMP group. Consistently, in in vitro experiments, the human brain-derived microglial cell line (HMC-3) also exhibited a more severe inflammatory response to WMP than to VMP. These results show that WMP is a more profound inflammatory factor than VMP. In summary, our findings demonstrate the toxicity of WMPs and provide theoretical insights into their potential risks to biological systems and even humans in the ecosystem.
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Microplásticos , Contaminantes Químicos del Agua , Animales , Humanos , Ratones , Masculino , Microplásticos/toxicidad , Plásticos , Poliestirenos/toxicidad , Poliestirenos/análisis , Proteoma , Ecosistema , Proteómica , Ratones Endogámicos C57BL , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/análisis , EncéfaloRESUMEN
PURPOSE: This phase I study was conducted to determine the maximum tolerated dose and the recommended phase II dose of weekly administered Genexol-PM combined with carboplatin in patients with gynecologic cancer. MATERIALS AND METHODS: This open-label, phase I, dose-escalation study of weekly Genexol-PM included 18 patients with gynecologic cancer, who were equally divided into three cohorts of dose levels. Cohort 1 received 100 mg/m2 Genexol-PM and 5 area under the curve (AUC) carboplatin, cohort 2 received 120 mg/m2 Genexol-PM and 5 AUC carboplatin, and cohort 3 received 120 mg/m2 Genexol-PM and 6 AUC carboplatin. The safety and efficacy of each dose were analyzed for each cohort. RESULTS: Of the 18 patients, 11 patients were newly diagnosed and seven patients were recurrent cases. No dose-limiting toxicity was observed. The maximum tolerated dose was not defined, but a dose up to 120 mg/m2 of Genexol-PM in combination with AUC 5-6 of carboplatin could be recommended for a phase II study. In this intention-to-treat population, five patients dropped out of the study (carboplatin-related hypersensitivity, n=1; refusal of consent, n=4). Most patients (88.9%) with adverse events recovered without sequelae, and no treatment-related death occurred. The overall response rate of weekly Genexol-PM in combination with carboplatin was 72.2%. CONCLUSION: Weekly administered Genexol-PM with carboplatin demonstrated an acceptable safety profile in gynecologic cancer pati-ents. The recommended phase II dose of weekly Genexol-PM is up to 120 mg/m2 when combined with carboplatin.
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Micelas , Neoplasias , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/efectos adversos , Neoplasias/tratamiento farmacológico , Paclitaxel/efectos adversos , Polímeros/uso terapéuticoRESUMEN
Widefield microscopy of optically thick specimens typically features reduced contrast due to "spatial crosstalk", in which the signal at each point in the field of view is the result of a superposition from neighbouring points that are simultaneously illuminated. In 1955, Marvin Minsky proposed confocal microscopy as a solution to this problem. Today, laser scanning confocal fluorescence microscopy is broadly used due to its high depth resolution and sensitivity, but comes at the price of photobleaching, chemical, and photo-toxicity. Here, we present artificial confocal microscopy (ACM) to achieve confocal-level depth sectioning, sensitivity, and chemical specificity, on unlabeled specimens, nondestructively. We equipped a commercial laser scanning confocal instrument with a quantitative phase imaging module, which provides optical path-length maps of the specimen in the same field of view as the fluorescence channel. Using pairs of phase and fluorescence images, we trained a convolution neural network to translate the former into the latter. The training to infer a new tag is very practical as the input and ground truth data are intrinsically registered, and the data acquisition is automated. The ACM images present significantly stronger depth sectioning than the input (phase) images, enabling us to recover confocal-like tomographic volumes of microspheres, hippocampal neurons in culture, and 3D liver cancer spheroids. By training on nucleus-specific tags, ACM allows for segmenting individual nuclei within dense spheroids for both cell counting and volume measurements. In summary, ACM can provide quantitative, dynamic data, nondestructively from thick samples, while chemical specificity is recovered computationally.
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The signaling pathways governing acetaminophen (APAP)-induced liver injury have been extensively studied. However, little is known about the ubiquitin-modifying enzymes needed for the regulation of APAP-induced liver injury. Here, we examined whether the Pellino3 protein, which has E3 ligase activity, is needed for APAP-induced liver injury and subsequently explored its molecular mechanism. Whole-body Peli3-/- knockout (KO) and adenovirus-mediated Peli3 knockdown (KD) mice showed reduced levels of centrilobular cell death, infiltration of immune cells, and biomarkers of liver injury, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), upon APAP treatment compared to wild-type (WT) mice. Peli3 deficiency in primary hepatocytes decreased mitochondrial and lysosomal damage and reduced the mitochondrial reactive oxygen species (ROS) levels. In addition, the levels of phosphorylation at serine 9 in the cytoplasm and mitochondrial translocation of GSK3ß were decreased in primary hepatocytes obtained from Peli3-/- KO mice, and these reductions were accompanied by decreases in JNK phosphorylation and mitochondrial translocation. Pellino3 bound more strongly to GSK3ß compared with JNK1 and JNK2 and induced the lysine 63 (K63)-mediated polyubiquitination of GSK3ß. In rescue experiments, the ectopic expression of wild-type Pellino3 in Peli3-/- KO hepatocytes restored the mitochondrial translocation of GSK3ß, but this restoration was not obtained with expression of a catalytically inactive mutant of Pellino3. These findings are the first to suggest a mechanistic link between Pellino3 and APAP-induced liver injury through the modulation of GSK3ß polyubiquitination.
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Acetaminofén , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Animales , Ratones , Acetaminofén/efectos adversos , Fosforilación , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Hígado/metabolismo , Hepatocitos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ratones Endogámicos C57BLRESUMEN
Mechanically silent nociceptors are sensory afferents that are insensitive to noxious mechanical stimuli under normal conditions but become sensitized to such stimuli during inflammation. Using RNA-sequencing and quantitative RT-PCR we demonstrate that inflammation upregulates the expression of the transmembrane protein TMEM100 in silent nociceptors and electrophysiology revealed that over-expression of TMEM100 is required and sufficient to un-silence silent nociceptors in mice. Moreover, we show that mice lacking TMEM100 do not develop secondary mechanical hypersensitivity-i.e., pain hypersensitivity that spreads beyond the site of inflammation-during knee joint inflammation and that AAV-mediated overexpression of TMEM100 in articular afferents in the absence of inflammation is sufficient to induce mechanical hypersensitivity in remote skin regions without causing knee joint pain. Thus, our work identifies TMEM100 as a key regulator of silent nociceptor un-silencing and reveals a physiological role for this hitherto enigmatic afferent subclass in triggering spatially remote secondary mechanical hypersensitivity during inflammation.
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Nociceptores , Dolor , Animales , Ratones , Inflamación/metabolismo , Articulación de la Rodilla , Nociceptores/metabolismo , Dolor/metabolismo , Piel/metabolismoRESUMEN
Dendritic cell (DC)-based immunotherapies have been shown to be a potential treatment option for various cancers; however, the exact strategies in ovarian cancer remain unknown. Here, we report the effectiveness of mouse CD8α+ DCs derived from bone marrow hematopoietic stem cells (BM-HSCs), equivalent to human CD141+ DCs, which have proven to be a highly superior subset. Mono-DCs from monocytes and stem-DCs from HSCs were characterized by CD11c+ CD80+ CD86+ and CD8α+ Clec9a+ expression, respectively. Despite a lower dose compared with Mono-DCs, mice treated with pulsed Stem-DCs showed a reduced amount of ascitic fluid and lower body weights compared with those of vehicle-treated mice. These mice treated with pulsed stem-DCs appeared to have fewer tumor implants, which were usually confined in the epithelium of tumor-invaded organs. All mice treated with DCs showed longer survival than the vehicle group, especially in the medium/high dose pulsed Stem-DC treatment groups. Moreover, the stem-DC-treated group demonstrated a low proportion of myeloid-derived suppressor cells and regulatory T cells, high interleukin-12 and interferon-γ levels, and accumulation of several tumor-infiltrating lymphocytes. Together, these results indicate that mouse CD8α+ DCs derived from BM-HSCs decrease tumor progression and enhance antitumor immune responses against murine ovarian cancer, suggesting that better DC vaccines can be used as an effective immunotherapy in EOC treatment. Further studies are necessary to develop potent DC vaccines using human CD141+ DCs.
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Neoplasias Ováricas , Vacunas , Animales , Ratones , Humanos , Femenino , Células Madre Hematopoyéticas , Interleucina-12/metabolismo , Neoplasias Ováricas/terapia , Neoplasias Ováricas/metabolismo , Células Dendríticas , Vacunas/farmacología , Ratones Endogámicos C57BLRESUMEN
With the development of deep learning technology, deep reinforcement learning (DRL) has successfully built intelligent agents in sequential decision-making problems through interaction with image-based environments. However, learning from unlimited interaction is impractical and sample inefficient because training an agent requires many trial and error and numerous samples. One response to this problem is sample-efficient DRL, a research area that encourages learning effective state representations in limited interactions with image-based environments. Previous methods could effectively surpass human performance by training an RL agent using self-supervised learning and data augmentation to learn good state representations from a given interaction. However, most of the existing methods only consider similarity of image observations so that they are hard to capture semantic representations. To address these challenges, we propose spatio-temporal and action-based contrastive representation (STACoRe) learning for sample-efficient DRL. STACoRe performs two contrastive learning to learn proper state representations. One uses the agent's actions as pseudo labels, and the other uses spatio-temporal information. In particular, when performing the action-based contrastive learning, we propose a method that automatically selects data augmentation techniques suitable for each environment for stable model training. We train the model by simultaneously optimizing an action-based contrastive loss function and spatio-temporal contrastive loss functions in an end-to-end manner. This leads to improving sample efficiency for DRL. We use 26 benchmark games in Atari 2600 whose environment interaction is limited to only 100k steps. The experimental results confirm that our method is more sample efficient than existing methods. The code is available at https://github.com/dudwojae/STACoRe.