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.

Comparison of 3- to 6-Month Versus 12-Month Dual Antiplatelet Therapy After Coronary Intervention Using the Contemporary Drug-Eluting Stents With Ultrathin Struts: The HOST-IDEA Randomized Clinical Trial.

BACKGROUND: Limited data are available on short-term dual antiplatelet therapy (DAPT) after percutaneous coronary intervention using third-generation drug-eluting stents with ultrathin struts and advanced polymer technology. We investigated whether 3- to 6-month DAPT was noninferior to 12-month DAPT after implantation of drug-eluting stents with ultrathin struts and advanced polymer technology. METHODS: We performed an open-label, randomized trial at 37 centers in South Korea. We enrolled patients undergoing percutaneous coronary intervention using the Orsiro biodegradable-polymer sirolimus-eluting stents or the Coroflex ISAR polymer-free sirolimus-eluting stents. Patients with ST-segment-elevation myocardial infarction were excluded. Patients were randomly assigned to receive either 3- to 6-month or 12-month DAPT after percutaneous coronary intervention. The choice of antiplatelet medications was at the physician's discretion. The primary outcome was a net adverse clinical event, a composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization, stent thrombosis, or major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 at 12 months. The major secondary outcomes were target lesion failure, a composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization, and major bleeding. RESULTS: A total of 2013 patients (mean age, 65.7±10.5 years; 1487 males [73.9%]; 1110 [55.1%] presented with acute coronary syndrome) were randomly assigned to 3- to 6-month DAPT (n=1002) or 12-month DAPT (n=1011). The primary outcome occurred in 37 (3.7%) patients in the 3- to 6-month DAPT group and 41 (4.1%) in the 12-month DAPT group. The noninferiority of the 3- to 6-month DAPT group to the 12-month DAPT group was met (absolute risk difference, -0.4% [1-sided 95% CI, -∞% to 1.1%]; P<0.001 for noninferiority). There were no significant differences in target lesion failure (hazard ratio, 0.98 [95% CI, 0.56-1.71], P=0.94) or major bleeding (hazard ratio, 0.82 [95% CI, 0.41-1.61], P=0.56) between the 2 groups. Across various subgroups, the treatment effect of 3- to 6-month DAPT was consistent for net adverse clinical event. CONCLUSIONS: Among patients undergoing percutaneous coronary intervention using third-generation drug-eluting stents, 3- to 6-month DAPT was noninferior to 12-month DAPT for net adverse clinical event. Further research is needed to generalize this finding to other populations and to determine the ideal regimen for 3- to 6-month DAPT. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02601157.

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.

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.

HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms.

Hepatocyte nuclear factor 6 (HNF6) is required for liver development, but its role in adult liver metabolism is not known. Here we show that deletion of HNF6 in livers of adult C57Bl/6 mice leads to hepatic steatosis in mice fed normal laboratory chow. Although HNF6 is known mainly as a transcriptional activator, hepatic loss of HNF6 up-regulated many lipogenic genes bound directly by HNF6. Many of these genes are targets of the circadian nuclear receptor Rev-erbα, and binding of Rev-erbα at these sites was lost when HNF6 was ablated in the liver. While HNF6 and Rev-erbα coordinately regulate hepatic lipid metabolism, each factor also affects additional gene sets independently. These findings highlight a novel mechanism of transcriptional repression by HNF6 and demonstrate how overlapping and distinct mechanisms of transcription factor function contribute to the integrated physiology of the liver.

Utilising raw psycho-physiological data and functional data analysis for estimating mental workload in human drivers.

Recent studies have focused on accurately estimating mental workload using machine learning algorithms and extracting features from physiological measures. However, feature extraction leads to the loss of valuable information and often results in binary classifications that lack specificity in the identification of optimum mental workload. This study investigates the feasibility of using raw physiological data (EEG, facial EMG, ECG, EDA, pupillometry) combined with Functional Data Analysis (FDA) to estimate the mental workload of human drivers. A driving scenario with five tasks was employed, and subjective ratings were collected. Results demonstrate that the FDA applied nine different combinations of raw physiological signals achieving a maximum 90% accuracy, outperforming extracted features by 73%. This study shows that the mental workload of human drivers can be accurately estimated without utilising burdensome feature extraction. The approach proposed in this study offers promise for mental workload assessment in real-world applications.

This study aimed to estimate the mental workload of human drivers using physiological signals and Functional Data Analysis (FDA). By comparing models using raw data and extracted features, the results show that the FDA with raw data achieved a high accuracy of 90%, outperforming the model with extracted features (73%).

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.

Efficacy and safety of cilostazol-based triple antiplatelet therapy compared with clopidogrel-based dual antiplatelet therapy in patients with acute ST-elevation myocardial infarction undergoing percutaneous coronary intervention: A multicenter, randomized, open-label, phase 4 trial.

BACKGROUND: Previous studies reported that compared to conventional dual antiplatelet therapy (DAT; aspirin + clopidogrel), triple antiplatelet therapy (TAT), involving the addition of cilostazol to DAT, had better clinical outcomes in patients with ST-elevation myocardial infarction (STEMI). However, the optimal duration of TAT is yet to be determined. METHODS: In total, 985 patients with STEMI who underwent primary percutaneous coronary intervention (PCI) with drug-eluting stents (DESs) were prospectively enrolled in 15 PCI centers in South Korea and China. We randomly assigned patients into 3 groups: DAT (aspirin and clopidogrel for 12 months), TAT 1M (aspirin, clopidogrel, and cilostazol for 1 month), and TAT 6M (aspirin, clopidogrel, and cilostazol for 6 months). The primary endpoint was 1-year major adverse cardiovascular events (MACEs), defined as a composite of all-cause death, recurrent myocardial infarction, stroke, or repeat revascularization. RESULTS: The primary endpoint did not differ among the 3 groups (8.8% in DAT, 11.0% in TAT 1M, and 11.6% in TAT 6M; hazard ratio for TAT 1M vs DAT, 1.302; 95% confidence interval [CI], 0.792-2.141; P = .297; hazard ratio for TAT 6M vs DAT, 1.358; 95% CI, 0.829-2.225; P = .225). With respect to in-hospital outcomes, more bleeding events occurred in the TAT group than in the DAT group (1.3% vs 4.7% vs 2.6%, P = .029), with no significant differences in major bleeding events. Additionally, the TAT group had a higher incidence of headaches (0% vs 1.6% vs 2.6%, P = .020). CONCLUSIONS: The addition of cilostazol to DAT did not reduce the incidence of 1-year MACEs compared with DAT alone. Instead, it may be associated with an increased risk of drug intolerance and side effects, including in-hospital bleeding and headaches.

Immediate versus staged complete revascularization in patients with ST-segment elevation myocardial infarction and multivessel coronary artery disease: results from a prematurely discontinued randomized multicenter trial.

BACKGROUND: We aimed to compare clinical outcomes between immediate and staged complete revascularization in primary percutaneous coronary intervention (PCI) for treating ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD). METHODS: A total of 248 patients were enrolled in a prospective, randomized, and multicenter registry. Immediate revascularization was defined as one-time PCI of culprit and non-culprit lesions at the initial procedure. Staged revascularization was defined as PCI of non-culprit lesions at a later date (mean, 4.4 days; interquartile range, 1-11.4), following initial culprit revascularization. The end points were major adverse cardiovascular events (MACE; composite of total death, recurrent myocardial infarction, and revascularization), any individual components of MACE, cardiac death, stent thrombosis, and stroke at 12 months. RESULTS: During a follow-up of 1 year, MACE occurred in 12 patients (11.6%) in the immediate revascularization group and in 8 patients (7.5%) in staged revascularization group (hazard ratio [HR] 1.60, 95% confidence interval [CI] 0.65-3.91). The incidence of total death was numerically higher in the immediate group than in the staged group (9.7% vs 2.8%, HR 3.53, 95% CI 0.97-12.84); There were no significant differences between the 2 groups in risks of any individual component of MACE, cardiac death, stroke, and in-hospital complications, such as need for transfusion, bleeding, acute renal failure, and acute heart failure. This study was prematurely terminated due to halt of production of everolimus-eluting stents (manufactured as PROMUS Element by Boston Scientific, Natick, Massachusetts). CONCLUSIONS: Due to its limited power, no definite conclusion can be drawn regarding complete revascularization strategy from the present study. Further large randomized clinical trials would be warranted to confirm optimal timing of complete revascularization for patients with STEMI and MVD.

Effects of delayed hospitalization on the 3-year clinical outcomes of patients with or without diabetes who had non-ST-segment-elevation myocardial infarction and underwent new-generation drug-eluting stent implantation.

Clinical outcomes after non-ST-segment-elevation myocardial infarction (NSTEMI) in patients with (symptom-to-door time [SDT] ≥ 24 h) or without (SDT < 24 h) delayed hospitalization among patients with or without diabetes were compared. From the Korea Acute Myocardial Infarction Registry-National Institute of Health, a total of 4517 patients with NSTEMI who underwent new-generation drug-eluting stents implantation were recruited and they were classified into the diabetes mellitus (DM) and non-DM groups. These two groups were subdivided into groups with and without delayed hospitalization. The primary clinical outcome was the occurrence of major adverse cardiac and cerebrovascular events (MACCE), defined as all-cause death, recurrent myocardial infarction, repeat coronary revascularization, and stroke. The secondary clinical outcome was the occurrence of individual components of MACCE and stent thrombosis. Although after multivariable and propensity score-adjusted analyses in the DM group, the primary and secondary clinical outcomes between the SDT < 24 h and SDT ≥ 24 h groups were similar; in the non-DM group, all-cause (p = 0.003 and p = 0.007, respectively) and cardiac (p = 0.001 and p = 0.008, respectively) death rates were significantly higher in the SDT ≥ 24 h group than in the SDT < 24 h group. Our results suggested that there was no significant difference in prognosis between diabetic patients with and without delayed SDT, but delayed SDT was associated with poor prognosis in nondiabetic patients.

Survival outcome of surgical resection compared to non-resection for Bismuth type IV perihilar cholangiocarcinoma.

BACKGROUND/OBJECTIVES: Bismuth type IV perihilar cholangiocarcinoma has been considered an unresectable disease. The aim of the study was to assess whether the surgical resection of type IV perihilar cholangiocarcinoma was associated with better survival rates. METHODS: The data of 117 patients diagnosed with type IV perihilar cholangiocarcinoma at Keimyung University Dongsan Hospital from 2005 to 2020 were retrospectively reviewed. The Bismuth type was assigned based on the patient's radiological imaging findings. The primary outcomes were the surgical results and median overall survival. RESULTS: The demographic characteristics of the 117 patients with type IV perihilar cholangiocarcinoma were comparable between the surgical resection and non-resection groups. Thirty-two (27.4%) patients underwent surgical resections. A left hepatectomy was performed in 16 patients, right hepatectomy in 13 patients, and a central bi-sectionectomy in three patients. The remaining 85 patients received non-surgical treatments. Thirteen (10.9%) received palliative chemotherapy, and 72 (60.5%) patients received conservative treatment including biliary drainage. The patients in the resection group showed significantly longer median overall survival than the patients in the non-resection group (32.4 vs 16.0 months; P = 0.002), even though the positive resection margin rate was high (62.5%). Surgical complications occurred in 15 (46.9%) patients. Complications of Clavien-Dindo classification grade III or higher occurred in 13 (40.6%) patients and grade V in two patients (6.3%). CONCLUSION: Surgical resection for Bismuth type IV perihilar cholangiocarcinoma is technically demanding. The survival of the resection group was significantly better than that of the non-resection group. The resection of selected patients achieved a curative goal with acceptable postoperative morbidity, although the microscopically positive resection margin rate was high.

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.

Two-year outcomes between ST-elevation and non-ST-elevation myocardial infarction in patients with chronic kidney disease undergoing newer-generation drug-eluting stent implantation.

BACKGROUND: We evaluated the 2-year clinical outcomes of ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) in patients with chronic kidney disease (CKD) who received newer-generation drug-eluting stents (DES). METHODS: Overall, 18,875 acute myocardial infarction patients were divided into two groups: CKD (STEMI, n = 1707; NSTEMI, n = 1648) and non-CKD (STEMI, n = 8660; NSTEMI, n = 6860). The occurrence of major adverse cardiac events (MACE), defined as all-cause death, recurrent myocardial infarction (re-MI), any repeat coronary revascularization, and definite or probable stent thrombosis (ST), was evaluated. RESULTS: After multivariable-adjusted analysis, in the CKD group, the MACE (adjusted hazard ratio [aHR]: 1.365, p = 0.004), all-cause death (aHR: 1.503, p = 0.004), noncardiac death (non-CD; aHR: 1.960, p = 0.004), and all-cause death or MI rates (aHR: 1.458, p = 0.002) were significantly higher in the NSTEMI group than in the STEMI group. In the non-CKD group, the non-CD rate (aHR: 1.78, p = 0.006) was also higher in the NSTEMI group. The CD, re-MI, any repeat revascularization, and ST rates were similar between groups. In the CKD group, from 6 months to 2 years after the index procedure, all-cause death, non-CD, and all-cause death or MI rates were significantly higher in the NSTEMI group than in the STEMI group. These results may be related to the higher non-CD rate in the NSTEMI group. CONCLUSIONS: In the era of contemporary newer-generation DES, NSTEMI showed a relatively higher non-CD rate than STEMI in both CKD and non-CKD groups.

Sex Difference in Coronary Artery Spasm Tested by Intracoronary Acetylcholine Provocation Test in Patients with Nonobstructive Coronary Artery Disease.

Introduction: Cardiovascular diseases manifest differently in men and women. The purpose of this study is to compare the sex difference in the characteristics of coronary artery spasm (CAS) in patients with nonobstructive cardiovascular disease (NOCVD) and the clinical outcomes in accordance with sex in CAS patients. Methods: The study analysed 5,491 patients with NOCVD who underwent an acetylcholine provocation test from November 2004 to May 2014 for evaluation of chest pain. CAS was defined as greater than 70% of luminal narrowing of the artery during the acetylcholine provocation test. Results: The patients were divided into men (n = 2,506) and women (n = 2,985). Mean follow-up days were 1,218 ± 577 days. To adjust for confounding factors, the propensity score matching (PSM) analysis was performed in all patients and among the CAS patients. After PSM analysis, a total of 1,201 pairs in all patients and a total of 713 pairs in CAS patients were generated. In all patients, women showed significantly less incidence of CAS compared with men (62.3% vs 50.9%, P < 0.01). Myocardial bridge (MB) and moderate stenosis were less prevalent in women, while transient ST elevation and ischemic chest pain during provocation were more frequent in women. In CAS patients, men had a higher incidence of multivessel spasm than women (35.7% vs. 29.7%, P < 0.01). Old age, dyslipidemia, and MB were independent risk factors of CAS in both men and women. In CAS patients, there was no statistical differences for various individual and composite major outcomes up to five years in either men or women. In men with CAS, old age was a risk factor of a 5-year major adverse cardiac event (MACE), and moderate stenosis was a risk factor of both 5-year MACE and 5-year recurrent angina. In women with CAS, mild stenosis was a risk factor of 5-year MACE, while myocardial bridge was a risk factor of 5-year recurrent angina. Conclusions: In this study, there were sex differences in the angiographic and clinical parameters during the acetylcholine provocation test, incidence of CAS, risk factors of CAS, 5-year MACE, and recurrent angina. Old age, dyslipidemia, and MB were independent risk factors of CAS in both sexes. However, major clinical outcomes up to five years in CAS patients were not different according to sex.

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.

Comparison of oncologic outcomes between open and laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma using data from the KOTUS-BP national database: overcoming selection bias and the necessity of definite indications.

BACKGROUND: Despite the lack of high-level evidence, laparoscopic distal pancreatectomy (LDP) is frequently performed in patients with pancreatic ductal adenocarcinoma (PDAC) owing to advancements in surgical techniques. The aim of this study was to investigate the long-term oncologic outcomes of LDP in patients with PDAC via propensity score matching (PSM) analysis using data from a large-scale national database. METHODS: A total of 1202 patients who were treated for PDAC via distal pancreatectomy across 16 hospitals were included in the Korean Tumor Registry System-Biliary Pancreas. The 5-year overall (5YOSR) and disease-free (5YDFSR) survival rates were compared between LDP and open DP (ODP). RESULTS: ODP and LDP were performed in 846 and 356 patients, respectively. The ODP group included more aggressive surgeries with higher pathologic stage, R0 resection rate, and number of retrieved lymph nodes. After PSM, the 5YOSRs for ODP and LDP were 37.3% and 41.4% (p = 0.150), while the 5YDFSRs were 23.4% and 27.2% (p = 0.332), respectively. Prognostic factors for 5YOSR included R status, T stage, N stage, differentiation, and lymphovascular invasion. CONCLUSION: LDP was performed in a selected group of patients with PDAC. Within this group, long-term oncologic outcomes were comparable to those observed following ODP.