Infection-specific phosphorylation of glutamyl-prolyl tRNA synthetase induces antiviral immunity.

The mammalian cytoplasmic multi-tRNA synthetase complex (MSC) is a depot system that regulates non-translational cellular functions. Here we found that the MSC component glutamyl-prolyl-tRNA synthetase (EPRS) switched its function following viral infection and exhibited potent antiviral activity. Infection-specific phosphorylation of EPRS at Ser990 induced its dissociation from the MSC, after which it was guided to the antiviral signaling pathway, where it interacted with PCBP2, a negative regulator of mitochondrial antiviral signaling protein (MAVS) that is critical for antiviral immunity. This interaction blocked PCBP2-mediated ubiquitination of MAVS and ultimately suppressed viral replication. EPRS-haploid (Eprs+/-) mice showed enhanced viremia and inflammation and delayed viral clearance. This stimulus-inducible activation of MAVS by EPRS suggests an unexpected role for the MSC as a regulator of immune responses to viral infection.

Long-term impact of socioeconomic status after acute myocardial infarction in Korea.

BACKGROUND AND AIMS: Socioeconomic status (SES) is known to impact the prognosis of acute myocardial infarction (AMI). However, due to the limited scope of previous studies, this study aimed to investigate the impact of SES on the prognosis of AMI patients within the Korean national healthcare insurance system. METHODS AND RESULTS: A retrospective cohort study included patients who were diagnosed with AMI between 2007 and 2008 from the Korean National Health Insurance Service and underwent a national health check-up program. Primary endpoint was all-cause mortality. The median follow-up duration was 13.5 years. The SES was divided into tertile scale based on insurance premiums and economic status. Tertile 1 (T1) was the lowest SES, and tertile 3 (T3) was the highest SES. A total of 5971 patients were included, of whom 4329 were employed insured (EI), and 1642 were self-employed insured (SI). After adjusted confounding variables, the Cox-regression model showed SI was associated with worse outcome compared with EI (hazard ratio (HR) [95 % confidence intervals (CIs)], 1.11 [1.02-1.22]). Among individuals in EI, lower economic status showed a trend of worse outcome, but it was not significant (lower tertile vs. higher tertile group, HR [95 % CIs], 1.01 [0.88-1.14]). However, compared with T3 in SI, HRs (95 % CIs) for all-cause death in T2 and T1 were 1.33 (1.09-1.63) and 1.34 (1.10-1.64), respectively. CONCLUSION: SES significantly affected the long-term outcome in patients with AMI. SI and lower economic status in SI were associated with a higher mortality rate than EI and higher economic status, respectively. Further investigation of the underlying role of SES in increased mortality after AMI is warranted.

Disparities in cause-specific mortality by health insurance type and premium: evidence from Korean NHIS-HEALS cohort study, 2002-2019.

BACKGROUND: Although one's socioeconomic status affects health outcomes, limited research explored how South Korea's National Health Insurance (NHI) system affects mortality rates. This study investigated whether health insurance type and insurance premiums are associated with mortality. METHODS: Based on the National Health Insurance Service-Health Screening cohort, 246,172 men and 206,534 women aged ≥ 40 years at baseline (2002-2003) were included and followed until 2019. Health insurance type was categorized as employee-insured (EI) or self-employed-insured (SI). To define low, medium, and high economic status groups, we used insurance premiums at baseline. Death was determined using the date and cause of death included in the cohort. Cox proportional hazard models were used to analyze the association between insurance factors and the overall and cause-specific mortality. RESULTS: The SI group had a significantly higher risk of overall death compared to the EI group (adjusted hazard ratio (HR) [95% confidence interval]: 1.13 [1.10-1.15] for men and 1.18 [1.15-1.22] for women), after adjusting for various factors. This trend extended to death from the five major causes of death in South Korea (cancer, cardiovascular disease, cerebrovascular disease, pneumonia, and intentional self-harm) and from external causes, with a higher risk of death in the SI group (vs. the EI group). Further analysis stratified by economic status revealed that individuals with lower economic status faced higher risk of overall death and cause-specific mortality in both sexes, compared to those with high economic status for both health insurance types. CONCLUSION: This nationwide study found that the SI group and those with lower economic status faced higher risk of overall mortality and death from the five major causes in South Korea. These findings highlight the potential disparities in health outcomes within the NHI system. To address these gaps, strategies should target risk factors for death at the individual level and governments should incorporate such strategies into public health policy development at the population level. TRIAL REGISTRATION: This study was approved by the Institutional Review Board of Chungbuk National University Hospital (CBNUH-202211-HR-0236) and adhered to the principles of the Declaration of Helsinki (1975).

Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury.

Fibroblast growth factor 23 (FGF23), a hormone generally derived from bone, is important in phosphate and vitamin D homeostasis. In acute kidney injury (AKI) patients, high-circulating FGF23 levels are associated with disease progression and mortality. However, the organ and cell type of FGF23 production in AKI and the molecular mechanism of its excessive production are still unidentified. For insight, we investigated folic acid (FA)-induced AKI in mice. Interestingly, simultaneous with FGF23, orphan nuclear receptor ERR-γ expression is increased in the liver of FA-treated mice, and ectopic overexpression of ERR-γ was sufficient to induce hepatic FGF23 production. In patients and in mice, AKI is accompanied by up-regulated systemic IL-6, which was previously identified as an upstream regulator of ERR-γ expression in the liver. Administration of IL-6 neutralizing antibody to FA-treated mice or of recombinant IL-6 to healthy mice confirms IL-6 as an upstream regulator of hepatic ERR-γ-mediated FGF23 production. A significant (P < 0.001) interconnection between high IL-6 and FGF23 levels as a predictor of AKI in patients that underwent cardiac surgery was also found, suggesting the clinical relevance of the finding. Finally, liver-specific depletion of ERR-γ or treatment with an inverse ERR-γ agonist decreased hepatic FGF23 expression and plasma FGF23 levels in mice with FA-induced AKI. Thus, inverse agonist of ERR-γ may represent a therapeutic strategy to reduce adverse plasma FGF23 levels in AKI.

Metal-Oxide Heterojunction Optoelectronic Synapse and Multilevel Memory Devices Enabled by Broad Spectral Photocarrier Modulation.

Broad spectral response and high photoelectric conversion efficiency are key milestones for realizing multifunctional, low-power optoelectronic devices such as artificial synapse and reconfigurable memory devices. Nevertheless, the wide bandgap and narrow spectral response of metal-oxide semiconductors are problematic for efficient metal-oxide optoelectronic devices such as photonic synapse and optical memory devices. Here, a simple titania (TiO2 )/indium-gallium-zinc-oxide (IGZO) heterojunction structure is proposed for efficient multifunctional optoelectronic devices, enabling widen spectral response range and high photoresponsivity. By overlaying a TiO2 film on IGZO, the light absorption range extends to red light, along with enhanced photoresponsivity in the full visible light region. By implementing the TiO2 /IGZO heterojunction structure, various synaptic behaviors are successfully emulated such as short-term memory/long-term memory and paired pulse facilitation. Also, the TiO2 /IGZO synaptic transistor exhibits a recognition rate up to 90.3% in recognizing handwritten digit images. Moreover, by regulating the photocarrier dynamics and retention behavior using gate-bias modulation, a reconfigurable multilevel (≥8 states) memory is demonstrated using visible light.

Quasi-Fermi level splitting in nanoscale junctions from ab initio.

The splitting of quasi-Fermi levels (QFLs) represents a key concept utilized to describe finite-bias operations of semiconductor devices, but its atomic-scale characterization remains a significant challenge. Herein, the nonequilibrium QFL or electrochemical potential profiles within single-molecule junctions obtained from the first-principles multispace constrained-search density-functional formalism are presented. Benchmarking the standard nonequilibrium Green's function calculation results, it is first established that algorithmically the notion of separate electrode-originated nonlocal QFLs should be maintained within the channel region during self-consistent finite-bias electronic structure calculations. For the insulating hexandithiolate junction, the QFL profiles exhibit discontinuities at the left and right electrode interfaces and across the molecule the accompanying electrostatic potential drops linearly and Landauer residual-resistivity dipoles are uniformly distributed. For the conducting hexatrienedithiolate junction, on the other hand, the electrode QFLs penetrate into the channel region and produce split QFLs. With the highest occupied molecular orbital entering the bias window and becoming a good transport channel, the split QFLs are accompanied by the nonlinear electrostatic potential drop and asymmetric Landauer residual-resistivity dipole formation. Our findings underscore the importance of the first-principles extraction of QFLs in nanoscale junctions and point to a future direction for the computational design of next-generation semiconductor devices.

Improvement of Open-Circuit Voltage Deficit via Pre-Treated NH4 + Ion Modification of Interface between SnO2 and Perovskite Solar Cells.

Passivation is a popular method to increase power conversion efficiency (PCE), reduce hysteresis related to surface traps and defects, and adjust mismatched energy levels. In this paper, an approach is reported using ammonium chloride (AC) to enhance passivation effects by controlling chlorine (Cl) and ammonium ions (NH4 + ) on the front and back side of tin oxides (SnO2 ). AC pre-treatment is applied to indium tin-oxide (ITO) prior to SnO2 deposition to advance the passivation approaches and compare the completely separated NH4 + and Cl passivation effects, and sole NH4 + is successfully isolated on the SnO2 surface, the counterpart of AC-post-treatment, generating ammonia (NH3 ) and Cl. It is demonstrated that multifunctional healing effects of NH4 + are ascribed from AC-pre-treatment being the basis of SnO2 crystallization and adjusting bifacial interface energy levels at ITO/SnO2 and SnO2 /perovskite to enhance photo-carrier transport. As calculated by density functional theory, how the change of the passivation agent from Cl to NH4 + more effectively suppresses non-radiative recombination ascribed to hydrated SnO2 surface defects is explained. Consequently, enhancement of photo-carrier transport significantly improves a superior open-circuit voltage of 1.180 V and suppresses the hysteresis, which leads to the PCE of 22.25% in an AC-pre-treated device 3.000% higher than AC-post-treated devices.

Site-specific impairment of perivascular adipose tissue on advanced atherosclerotic plaques using multimodal nonlinear optical imaging.

Perivascular adipose tissue (PVAT), as a mechanical support, has been reported to systemically regulate vascular physiology by secreting adipokines and cytokines. How PVAT spatially and locally changes as atherosclerosis progresses is not known, however. We aimed to reveal the molecular changes in PVAT in advanced atherosclerosis based on multimodal nonlinear optical (MNLO) imaging. First, using an atherogenic apolipoprotein E knockout mouse model, we precisely assessed the browning level of thoracic PVAT via a correlative analysis between the size and number of lipid droplets (LDs) of label-free MNLO images. We also biochemically demonstrated the increased level of brown fat markers in the PVAT of atherosclerosis. In the initial stage of atherosclerosis, the PVAT showed a highly activated brown fat feature due to the increased energy expenditure; however, in the advanced stage, only the PVAT in the regions of the atherosclerotic plaques, not that in the nonplaque regions, showed site-specific changes. We found that p-smad2/3 and TGF-ß signaling enhanced the increase in collagen to penetrate the PVAT and the agglomeration of LDs only at the sites of atherosclerotic plaques. Moreover, atherosclerotic thoracic PVAT (tPVAT) was an increased inflammatory response. Taken together, our findings show that PVAT changes differentially from the initial stages to advanced stages of atherosclerosis and undergoes spatial impairment focused on atherosclerotic plaques. Our study may provide insight into the local control of PVAT as a therapeutic target.

Melatonin Regulates Iron Homeostasis by Inducing Hepcidin Expression in Hepatocytes.

The pineal hormone, melatonin, plays important roles in circadian rhythms and energy metabolism. The hepatic peptide hormone, hepcidin, regulates iron homeostasis by triggering the degradation of ferroportin (FPN), the protein that transfers cellular iron to the blood. However, the role of melatonin in the transcriptional regulation of hepcidin is largely unknown. Here, we showed that melatonin upregulates hepcidin gene expression by enhancing the melatonin receptor 1 (MT1)-mediated c-Jun N-terminal kinase (JNK) activation in hepatocytes. Interestingly, hepcidin gene expression was increased during the dark cycle in the liver of mice, whereas serum iron levels decreased following hepcidin expression. In addition, melatonin significantly induced hepcidin gene expression and secretion, as well as the subsequent FPN degradation in hepatocytes, which resulted in cellular iron accumulation. Melatonin-induced hepcidin expression was significantly decreased by the melatonin receptor antagonist, luzindole, and by the knockdown of MT1. Moreover, melatonin activated JNK signaling and upregulated hepcidin expression, both of which were significantly decreased by SP600125, a specific JNK inhibitor. Chromatin immunoprecipitation analysis showed that luzindole significantly blocked melatonin-induced c-Jun binding to the hepcidin promoter. Finally, melatonin induced hepcidin expression and secretion by activating the JNK-c-Jun pathway in mice, which were reversed by the luzindole treatment. These findings reveal a previously unrecognized role of melatonin in the circadian regulation of hepcidin expression and iron homeostasis.

Hepatocyte DAX1 Deletion Exacerbates Inflammatory Liver Injury by Inducing the Recruitment of CD4+ and CD8+ T Cells through NF-κB p65 Signaling Pathway in Mice.

Fulminant hepatitis is characterized by rapid and massive immune-mediated liver injury. Dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX1; NR0B1) represses the transcription of various genes. Here, we determine whether DAX1 serves as a regulator of inflammatory liver injury induced by concanavalin A (ConA). C57BL/6J (WT), myeloid cell-specific Dax1 knockout (MKO), and hepatocyte-specific Dax1 knockout (LKO) mice received single intravenous administration of ConA. Histopathological changes in liver and plasma alanine aminotransferase and aspartate aminotransferase levels in Dax1 MKO mice were comparable with those in WT mice following ConA administration. Unlike Dax1 MKO mice, Dax1 LKO mice were greatly susceptible to ConA-induced liver injury, which was accompanied by enhanced infiltration of immune cells, particularly CD4+ and CD8+ T cells, in the liver. Factors related to T-cell recruitment, including chemokines and adhesion molecules, significantly increased following enhanced and prolonged phosphorylation of NF-κB p65 in the liver of ConA-administered Dax1 LKO mice. This is the first study to demonstrate that hepatocyte-specific DAX1 deficiency exacerbates inflammatory liver injury via NF-κB p65 activation, thereby causing T-cell infiltration by modulating inflammatory chemokines and adhesion molecules. Our results suggest DAX1 as a therapeutic target for fulminant hepatitis treatment.

Hepatocyte-Specific Deficiency of DAX-1 Protects Mice from Acetaminophen-Induced Hepatotoxicity by Activating NRF2 Signaling.

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but its overdose can cause acute liver failure. The dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1, NR0B1), is an orphan nuclear receptor that acts as a transcriptional co-repressor of various genes. In this study, we identified the role of DAX-1 in APAP-induced liver injury using hepatocyte-specific Dax-1 knockout (Dax-1 LKO) mice. Mouse primary hepatocytes were used as a comparative in vitro study. APAP overdose led to decreased plasma alanine aminotransferase and aspartate aminotransferase levels in Dax-1 LKO mice compared to C57BL/6J (WT) controls, accompanied by reduced liver necrosis. The expression of the genes encoding the enzymes catalyzing glutathione (GSH) synthesis and metabolism and antioxidant enzymes was increased in the livers of APAP-treated Dax-1 LKO mice. The rapid recovery of GSH levels in the mitochondrial fraction of APAP-treated Dax-1 LKO mice led to reduced reactive oxygen species levels, resulting in the inhibition of the prolonged JNK activation. The hepatocyte-specific DAX-1 deficiency increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) compared with WT controls after APAP administration. These results indicate that DAX-1 deficiency in hepatocytes protects against APAP-induced liver injury by Nrf2-regulated antioxidant defense.

Orphan nuclear receptor ERRγ regulates hepatic TGF-ß2 expression and fibrogenic response in CCl4-induced acute liver injury.

Acute liver injury results from the complex interactions of various pathological processes. The TGF-ß superfamily plays a crucial role in orchestrating fibrogenic response. In contrast to TGF-ß1, a role of TGF-ß2 in hepatic fibrogenic response has not been fully investigated. In this study, we showed that TGF-ß2 gene expression and secretion are induced in the liver of CCl4 (1 ml/kg)-treated WT mice. Studies with hepatocyte specific ERRγ knockout mice or treatment with an ERRγ-specific inverse agonist, GSK5182 (40 mg/kg), indicated that CCl4-induced hepatic TGF-ß2 production is ERRγ dependent. Moreover, IL6 was found as upstream signal to induce hepatic ERRγ and TGF-ß2 gene expression in CCl4-mediated acute toxicity model. Over-expression of ERRγ was sufficient to induce hepatic TGF-ß2 expression, whereas ERRγ depletion markedly reduces IL6-induced TGF-ß2 gene expression and secretion in vitro and in vivo. Promoter assays showed that ERRγ directly binds to an ERR response element in the TGF-ß2 promoter to induce TGF-ß2 transcription. Finally, GSK5182 diminished CCl4-induced fibrogenic response through inhibition of ERRγ-mediated TGF-ß2 production. Taken together, these results firstly demonstrate that ERRγ can regulate the TGF-ß2-mediated fibrogenic response in a mouse model of CC14-induced acute liver injury.

Highly Sensitive Textile-Based Capacitive Pressure Sensors Using PVDF-HFP/Ionic Liquid Composite Films.

Textile-based pressure sensors have garnered considerable interest in electronic textiles due to their diverse applications, including human-machine interface and healthcare monitoring systems. We studied a textile-based capacitive pressure sensor array using a poly(vinylidene fluoride)-co-hexafluoropropylene (PVDF-HFP)/ionic liquid (IL) composite film. By constructing a capacitor structure with Ag-plated conductive fiber electrodes that are embedded in fabrics, a capacitive pressure sensor showing high sensitivity, good operation stability, and a wide sensing range could be created. By optimizing the PVDF-HFP:IL ratio (6.5:3.5), the fabricated textile pressure sensors showed sensitivity of 9.51 kPa-1 and 0.69 kPa-1 in the pressure ranges of 0-20 kPa and 20-100 kPa, respectively. The pressure-dependent capacitance variation in our device was explained based on the change in the contact-area formed between the multi-filament fiber electrodes and the PVDF-HFP/IL film. To demonstrate the applicability and scalability of the sensor device, a 3 × 3 pressure sensor array was fabricated. Due to its matrix-type array structure and capacitive sensing mechanism, multi-point detection was possible, and the different positions and the weights of the objects could be identified.

Orphan Nuclear Receptor ERRγ Is a Transcriptional Regulator of CB1 Receptor-Mediated TFR2 Gene Expression in Hepatocytes.

Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is an important transcription factor modulating gene transcription involved in endocrine control of liver metabolism. Transferrin receptor 2 (TFR2), a carrier protein for transferrin, is involved in hepatic iron overload in alcoholic liver disease (ALD). However, TFR2 gene transcriptional regulation in hepatocytes remains largely unknown. In this study, we described a detailed molecular mechanism of hepatic TFR2 gene expression involving ERRγ in response to an endocannabinoid 2-arachidonoylglycerol (2-AG). Treatment with 2-AG and arachidonyl-2'-chloroethylamide, a selective cannabinoid receptor type 1 (CB1) receptor agonist, increased ERRγ and TFR2 expression in hepatocytes. Overexpression of ERRγ was sufficient to induce TFR2 expression in both human and mouse hepatocytes. In addition, ERRγ knockdown significantly decreased 2-AG or alcohol-mediated TFR2 gene expression in cultured hepatocytes and mouse livers. Finally, deletion and mutation analysis of the TFR2 gene promoter demonstrated that ERRγ directly modulated TFR2 gene transcription via binding to an ERR-response element. This was further confirmed by chromatin immunoprecipitation assay. Taken together, these results reveal a previously unrecognized role of ERRγ in the transcriptional regulation of TFR2 gene expression in response to alcohol.

Flexible Metal Oxide Semiconductor Devices Made by Solution Methods.

For the fabrication of next-generation flexible metal oxide devices, solution-based methods are considered as a promising approach because of their potential advantages, such as high-throughput, large-area scalability, low-cost processing, and easy control over the chemical composition. However, to obtain certain levels of electrical performance, a high process temperature is essential, which can significantly limit its application in flexible electronics. Therefore, this article discusses recent research conducted on developing low-temperature, solution-processed, flexible, metal oxide semiconductor devices, from a single thin-film transistor device to fully integrated circuits and systems. The main challenges of solution-processed metal oxide semiconductors are introduced. Recent advances in materials, processes, and semiconductor structures are then presented, followed by recent advances in electronic circuits and systems based on these semiconductors, including emerging flexible energy-harvesting devices for self-powered systems that integrate displays, sensors, data-storage units, and information processing functions.

Sicyos angulatus Prevents High-Fat Diet-Induced Obesity and Insulin Resistance in Mice.

Obesity is a medical condition in which excess body fat has accumulated to a serious extent. It is a chronic disease that can lead to dyslipidemia, insulin resistance, and type 2 diabetes. In the present study, we investigated the anti-obesity effects of Sicyos angulatus (SA) extract on a high-fat diet (HFD)-induced C57BL/6J obese mice. The mice were divided into vehicle and three SA groups (25, 50, and 100 mg/kg body weight). The mice were fed a HFD with or without SA for 12 weeks. The oral administration of SA reduced body and adipose tissue weight in HFD-fed mice compared to those in the vehicle group (p<0.05). Adipocyte size and inflammation significantly decreased in the SA-administered groups in a dose-dependent manner. In particular, adipocytes larger than 5000 µm2 were remarkably reduced by around 50% in the SA-treated groups (p<0.05). In addition, SA contributes towards reducing insulin resistance (measured as the HOMA-IR index) and glucose intolerance in HFD-induced obese mice (p<0.05; Vehicle 21.5±3.1 vs. SA100 4.7±0.4). These beneficial effects of SA on obesity may be linked to the suppression of lipogenesis and stimulating energy metabolism in white adipose tissue and muscle. In white adipose tissue and muscle, the administration of SA activated AMPK pathway, leading to the inhibition of the development of pathophysiological conditions associated with obesity, including lipogenesis and inflammation. These findings suggest that SA may prevent obesity through inhibiting fat accumulation in HFD-induced obese mice. Therefore, SA is able to exert metabolic benefits in the prevention of obesity and insulin resistance.

Hepatocyte CREBH deficiency aggravates inflammatory liver injury following chemokine-dependent neutrophil infiltration through upregulation of NF-κB p65 in mice.

Fulminant hepatitis is a serious inflammatory condition of the liver characterized by massive necrosis of liver parenchyma following excessive immune cell infiltration into the liver, and possibly causing sudden hepatic failure and medical emergency. However, the underlying mechanisms are not fully understood. Here, we investigated the role of cyclic AMP-responsive element-binding protein, hepatocyte specific (CREBH) in concanavalin A (ConA)-driven hepatitis-evoked liver injury. C57BL/6J (WT) and Crebh knockout (KO) mice injected with ConA (7.5 or 25 mg/kg) and bone marrow (BM) chimeric mice, generated by injection of BM cells into sub-lethally irradiated recipients followed by ConA injection (22.5 or 27.5 mg/kg) 8 weeks later, were used for in vivo study. Primary mouse hepatocytes and HEK293T cells were used for a comparative in vitro study. Crebh KO mice are highly susceptible to ConA-induced liver injury and prone to death due to increased neutrophil infiltration driven by enhanced hepatic expression of neutrophil-attracting chemokines. Notably, BM chimera experiment demonstrated that Crebh-deficient hepatocytes have an enhanced ability of recruiting neutrophils to the liver, thereby promoting hepatotoxicity by ConA. Intriguingly, in vitro assays showed that p65, a subunit of NF-κB and common transcription factor for various chemokines, dependent transactivation was inhibited by CREBH. Furthermore, p65 expression was inversely correlated with CREBH level in ConA-treated mice liver and TNFα-stimulated primary mouse hepatocytes. This is the first demonstration that CREBH deficiency aggravates inflammatory liver injury following chemokine-dependent neutrophil infiltration via NF-κB p65 upregulation. CREBH is suggested to be a novel therapeutic target for treatment of fulminant hepatitis.

An inverse agonist of estrogen-related receptor γ regulates 2-arachidonoylglycerol synthesis by modulating diacylglycerol lipase expression in alcohol-intoxicated mice.

Chronic alcohol feeding increases the levels of 2-arachidonoylglycerol (2-AG) in the liver, which activates hepatic cannabinoid receptor type 1 (CB1R), leading to oxidative liver injury. 2-AG biosynthesis is catalyzed by diacylglycerol lipase (DAGL). However, the mechanisms regulating hepatic DAGL gene expression and 2-AG production are largely unknown. In this study, we show that CB1R-induced estrogen-related receptor γ (ERRγ) controls hepatic DAGL gene expression and 2-AG levels. Arachidonyl-2'-chloroethylamide (ACEA), a synthetic CB1R agonist, significantly upregulated ERRγ, DAGLα, and DAGLß, and increased 2-AG levels in the liver (10 mg/kg) and hepatocytes (10 µM) of wild-type (WT) mice. ERRγ overexpression upregulated DAGLα and DAGLß expressions and increased 2-AG levels, whereas ERRγ knockdown abolished ACEA-induced DAGLα, DAGLß, and 2-AG in vitro and in vivo. Promoter assays showed that ERRγ positively regulated DAGLα and DAGLß transcription by binding to the ERR response element in the DAGLα and DAGLß promoters. Chronic alcohol feeding (27.5% of total calories) induced hepatic steatosis and upregulated ERRγ, leading to increased DAGLα, DAGLß, or 2-AG in WT mice, whereas these alcohol-induced effects did not occur in hepatocyte-specific CB1R knockout mice or in those treated with the ERRγ inverse agonist GSK5182 (40 mg/kg in mice and 10 µM in vitro). Taken together, these results indicate that suppression of alcohol-induced DAGLα and DAGLß gene expressions and 2-AG levels by an ERRγ-specific inverse agonist may be a novel and attractive therapeutic approach for the treatment of alcoholic liver disease.

Locally Controlled Sensing Properties of Stretchable Pressure Sensors Enabled by Micro-Patterned Piezoresistive Device Architecture.

For wearable health monitoring systems and soft robotics, stretchable/flexible pressure sensors have continuously drawn attention owing to a wide range of potential applications such as the detection of human physiological and activity signals, and electronic skin (e-skin). Here, we demonstrated a highly stretchable pressure sensor using silver nanowires (AgNWs) and photo-patternable polyurethane acrylate (PUA). In particular, the characteristics of the pressure sensors could be moderately controlled through a micro-patterned hole structure in the PUA spacer and size-designs of the patterned hole area. With the structural-tuning strategies, adequate control of the site-specific sensitivity in the range of 47~83 kPa-1 and in the sensing range from 0.1 to 20 kPa was achieved. Moreover, stacked AgNW/PUA/AgNW (APA) structural designed pressure sensors with mixed hole sizes of 10/200 µm and spacer thickness of 800 µm exhibited high sensitivity (~171.5 kPa-1) in the pressure sensing range of 0~20 kPa, fast response (100~110 ms), and high stretchability (40%). From the results, we envision that the effective structural-tuning strategy capable of controlling the sensing properties of the APA pressure sensor would be employed in a large-area stretchable pressure sensor system, which needs site-specific sensing properties, providing monolithic implementation by simply arranging appropriate micro-patterned hole architectures.

Orphan Nuclear Receptor ERRγ Is a Novel Transcriptional Regulator of IL-6 Mediated Hepatic BMP6 Gene Expression in Mice.

Bone morphogenetic protein 6 (BMP6) is a multifunctional growth factor involved in organ development and homeostasis. BMP6 controls expression of the liver hormone, hepcidin, and thereby plays a crucial role in regulating iron homeostasis. BMP6 gene transcriptional regulation in liver is largely unknown, but would be of great help to externally modulate iron load in pathologic conditions. Here, we describe a detailed molecular mechanism of hepatic BMP6 gene expression by an orphan nuclear receptor, estrogen-related receptor γ (ERRγ), in response to the pro-inflammatory cytokine interleukin 6 (IL-6). Recombinant IL-6 treatment increases hepatic ERRγ and BMP6 expression. Overexpression of ERRγ is sufficient to increase BMP6 gene expression in hepatocytes, suggesting that IL-6 is upstream of ERRγ. In line, knock-down of ERRγ in cell lines or a hepatocyte specific knock-out of ERRγ in mice significantly decreases IL-6 mediated BMP6 expression. Promoter studies show that ERRγ directly binds to the ERR response element (ERRE) in the mouse BMP6 gene promoter and positively regulates BMP6 gene transcription in IL-6 treatment conditions, which is further confirmed by ERRE mutated mBMP6-luciferase reporter assays. Finally, an inverse agonist of ERRγ, GSK5182, markedly inhibits IL-6 induced hepatic BMP6 expression in vitro and in vivo. Taken together, these results reveal a novel molecular mechanism on ERRγ mediated transcriptional regulation of hepatic BMP6 gene expression in response to IL-6.