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Abstract Both the ε4 variant of the apolipoprotein E (APOE) gene and hearing loss are well-known risk factors for Alzheimer's disease. However, previous studies have produced inconsistent findings regarding the association between APOE genotypes and hearing levels, necessitating further investigation. The aim of this study was to investigate the relationship between APOE genotypes and hearing levels. This retrospective study analyzed clinical data from a clinical data warehouse of seven affiliated Catholic Medical Center hospitals. The study included 1,162 participants with records of APOE genotypes, audiometric tests, and cognitive function tests. In Generalized linear mixed model analysis, ε4 carriers exhibited lower pure tone audiometry thresholds with an estimate of -0.353 (SE = 0.126, p = 0.005). However, the interaction term for age and APOE ε4 had a coefficient of 0.577 (SE = 0.214 p = 0.006), suggesting that the APOE ε4 gene may accelerate hearing deterioration with age. Subgroup analysis based on an age cut-off of 75 revealed that ε4 carriers had better hearing at younger ages, but showed no significant difference at older ages. These results indicate that the ε4 allele may have a biphasic effect on hearing levels depending on age.

Abstract This study aimed to investigate whether metabolic dysfunction-associated fatty liver disease (MAFLD) defined by the fatty liver index (FLI) affects the decline in kidney function and whether this relationship is still observed in MAFLD defined by ultrasonography (USG). A retrospective cohort study was conducted using de-identified data from participants who received health checkups at Samsung Changwon Hospital between 2002 and 2018. The primary and secondary exposures were the presence of FLI- and USG-defined MAFLD, respectively. The primary outcome was 5-years slope of eGFR. The secondary outcome was a rapid decline in kidney function, defined as a 5-years slope of estimated glomerular filtration rate (eGFR) of less than − 3 mL/min/1.73 m2 per year. A total of 37,500 participants were included in the analysis. Participants with FLI-defined MAFLD had a larger decline in 5-year eGFR slope than those without FLI-defined MAFLD (beta coefficients − 0.11; 95% CI − 0.14 to − 0.08). Participants with FLI-defined MAFLD had a higher risk of rapid kidney function decline than those without FLI-defined MAFLD (odds ratio 1.33; 95% confidence intervals (CIs) 1.05–1.69). However, USG-defined MAFLD was less related to kidney function decline. In conclusion, the presence of FLI-defined MAFLD was associated with larger and faster kidney function decline.

Abstract Background Targeting the tumor microenvironment represents an emerging therapeutic strategy for cancer. Macrophages are an essential part of the tumor microenvironment. Macrophage polarization is modulated by mitochondrial metabolism, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and reactive oxygen species content. Isocitrate dehydrogenase 2 (IDH2), an enzyme involved in the TCA cycle, reportedly promotes cancer progression. However, the mechanisms through which IDH2 influences macrophage polarization and modulates tumor growth remain unknown. Methods In this study, IDH2-deficient knockout (KO) mice and primary cultured bone marrow-derived macrophages (BMDMs) were used. Both in vivo subcutaneous tumor experiments and in vitro co-culture experiments were performed, and samples were collected for analysis. Western blotting, RNA quantitative analysis, immunohistochemistry, and flow cytometry were employed to confirm changes in mitochondrial function and the resulting polarization of macrophages exposed to the tumor microenvironment. To analyze the effect on tumor cells, subcutaneous tumor size was measured, and growth and metastasis markers were identified. Results IDH2-deficient macrophages co-cultured with cancer cells were found to possess increased mitochondrial dysfunction and fission than wild-type BMDM. Additionally, the levels of M2-associated markers decreased, whereas M1-associated factor levels increased in IDH2-deficient macrophages. IDH2-deficient macrophages were predominantly M1. Tumor sizes in the IDH2-deficient mouse group were significantly smaller than in the wild-type mouse group. IDH2 deficiency in macrophages was associated with inhibited tumor growth and epithelial–mesenchymal transition. Conclusions Our findings suggest that IDH2 deficiency inhibits M2 macrophage polarization and suppresses tumorigenesis. This study underlines the potential contribution of IDH2 expression in macrophages and tumor microenvironment remodeling, which could be useful in clinical cancer research.

Abstract The sliding filament theory and the cross-bridge model have been fundamental in understanding muscle contraction. While the cross-bridge model explains the interaction between a single myosin head and actin filament, the native myosin molecule consists of two heads. This review explores the possibility and mechanism of two-headed binding in myosin II to the actin. Recent studies using electron tomography and resonance energy transfer have provided evidence in support of the occurrence of two-headed binding. The flexibility of the regulatory light chain (RLC) appears to play a significant role in enabling this binding mode. However, high-resolution structures of the RLCs in the two-headed bound state have not yet been reported. Resolving these structures, possibly through sub-tomogram averaging or single-particle analysis, would provide definitive proof of the conformational flexibility of RLCs and their role in facilitating two-headed binding. Further investigations are also required to address questions such as the predominance of two-headed versus single-headed binding and the influence of the state of each of the heads on the other. An understanding of the mechanism of two-headed binding is crucial for developing a comprehensive model of the cross-bridge cycle of the native myosin molecule.

Abstract Since the discovery of graphene and its remarkable properties, researchers have actively explored advanced graphene-patterning technologies. While the etching process is pivotal in shaping graphene channels, existing etching techniques have limitations such as low speed, high cost, residue contamination, and rough edges. Therefore, the development of facile and efficient etching methods is necessary. This study entailed the development of a novel technique for patterning graphene through dry etching, utilizing selective photochemical reactions precisely targeted at single-layer graphene (SLG) surfaces. This process is facilitated by an excimer ultraviolet lamp emitting light at a wavelength of 172 nm. The effectiveness of this technique in selectively removing SLG over large areas, leaving the few-layer graphene intact and clean, was confirmed by various spectroscopic analyses. Furthermore, we explored the application of this technique to device fabrication, revealing its potential to enhance the electrical properties of SLG-based devices. One-dimensional (1D) edge contacts fabricated using this method not only exhibited enhanced electrical transport characteristics compared to two-dimensional contact devices but also demonstrated enhanced efficiency in fabricating conventional 1D-contacted devices. This study addresses the demand for advanced technologies suitable for next-generation graphene devices, providing a promising and versatile graphene-patterning approach with broad applicability and high efficiency.

Abstract Cone-beam computed tomography (CBCT) has proven to be a safe and effective adjunctive imaging tool for interventional radiology. Nevertheless, limited studies have examined the application of CBCT in renal artery embolization (RAE). The objective of this study is to evaluate the role of CBCT in intra-procedural decision-making for RAE. This multicenter retrospective study included 40 consecutive patients (age: 55.9 ± 16.5 years; male, 55%) who underwent CBCT during RAE from January 2019 to January 2023. The additional information provided by CBCT was classified into Category 1 (no additional information), Category 2 (more information without changing the treatment plan), and Category 3 (valuable information that led to a change in the treatment plan). CBCT did not add unique information for four patients (10%) classified as Category 1. CBCT clarified ambiguous angiographic findings and confirmed the existing treatment plan for 19 patients (47.5%) graded as Category 2; complex vascular anatomy was explained (n = 13), and a correlation between vascular territory and target lesion was established (n = 6). CBCT offered valuable information that was not visible on digital subtraction angiography and changed the treatment plan for 17 patients categorized as Category 3; a mismatch between the vascular territory and the target lesion led to the identification of alternative (n = 3) and additional feeders (n = 8); and the extent of embolization was reduced by using automatic feeder detection software (n = 6). CBCT is an efficient tool that aids in the decision-making process during the embolization procedure by providing supplementary imaging information. This additional information enables the confident identification of target vessels, facilitates superselective embolization, prevents non-target embolization, and helps locate missing feeders.

Abstract Age-related macular degeneration (AMD) causes severe blindness in the elderly due to choroidal neovascularization (CNV), which results from the dysfunction of the retinal pigment epithelium (RPE). While normal RPE depends exclusively on mitochondrial oxidative phosphorylation for energy production, the inflammatory conditions associated with metabolic reprogramming of the RPE play a pivotal role in CNV. Although mitochondrial pyruvate dehydrogenase kinase (PDK) is a central node of energy metabolism, its role in the development of CNV in neovascular AMD has not been investigated. In the present study, we used a laser-induced CNV mouse model to evaluate the effects of Pdk4 gene ablation and treatment with pan-PDK or specific PDK4 inhibitors on fluorescein angiography and CNV lesion area. Among PDK isoforms, only PDK4 was upregulated in the RPE of laser-induced CNV mice, and Pdk4 gene ablation attenuated CNV. Next, we evaluated mitochondrial changes mediated by PDK1-4 inhibition using siRNA or PDK inhibitors in inflammatory cytokine mixture (ICM)-treated primary human RPE (hRPE) cells. PDK4 silencing only in ICM-treated hRPE cells restored mitochondrial respiration and reduced inflammatory cytokine secretion. Likewise, GM10395, a specific PDK4 inhibitor, restored oxidative phosphorylation and decreased ICM-induced upregulation of inflammatory cytokine secretion. In a laser-induced CNV mouse model, GM10395 significantly alleviated CNV. Taken together, we demonstrate that specific PDK4 inhibition could be a therapeutic strategy for neovascular AMD by preventing mitochondrial metabolic reprogramming in the RPE under inflammatory conditions.

Abstract Background The target blood pressure (BP) value is unclear for diabetic kidney disease (DKD). Therefore, we aimed to evaluate the effect of strict BP control or ‘on treatment’ BP on clinical outcomes in patients with DKD. Methods A post-hoc analysis of the prespecified secondary outcomes of the FimAsartaN proTeinuriA SusTaIned reduCtion in comparison with losartan in diabetic chronic kidney disease (FANTASTIC) trial, a randomized multicenter double-blind phase III trial. Eligible patients were aged ≥ 19 years with DKD. We assigned 341 participants with DKD to BP control strategy (standard-systolic BP [SBP]

Abstract Background The association between the adiponectin‐to‐leptin ratio (A/L ratio) and the risk of incident chronic kidney disease (CKD) is poorly understood. This study aimed to investigate the association between A/L ratio and the risk of incident CKD and to examine whether such a relationship varied according to sex and body composition. Methods In this prospective community‐based cohort, participants with normal kidney function were analysed (N = 5192). The association between the A/L ratio at baseline and the risk of incident CKD, defined as two or more occasions with an estimated glomerular filtration rate of

Abstract Background Recent studies have reported the inhomogeneity in the light emitted by dental light-curing units (LCUs). It is essential to understand how this uneven light distribution affects the physical properties of resin-based composites (RBCs) at various points across their surfaces. This study aimed to evaluate the effect of LCU beam’s inhomogeneity on the microhardness of RBCs with different shades and thicknesses. Methods Four body (A1B, A2B, A3B, and A4B), one dentin (A3D), and one enamel shade (A3E) of RBC (Filtek Z350 XT) were examined. The specimens were fabricated in four thicknesses (1, 2, 3, and 4 mm) and subjected to a 40-second light-curing. Vickers microhardness testing was performed at the center point, and 3 mm left and right from the center at the bottom surface of each sample. The LCU beam profile was characterized using a beam profiler, while irradiance after specimen passage was measured using a spectrometer. One-way analysis of variance (ANOVA) and Tukey’s post-hoc tests were used to analyze the effects of shades and thicknesses on irradiance and microhardness, respectively. One-way repeated-measures ANOVA was used to compare the microhardness across different points. Pearson’s correlation analysis examined the relationship between irradiance and microhardness. Results The beam profile of LCU revealed inhomogeneous light distribution. Light irradiance was decreased with both the increase in thickness and darker shade of the specimens (p

The effects of air heat treatment were evaluated on six Korean oak woods: Quercus serrata (Qs), Quercus mongolica (Qm), Quercus acutissima (Qac), Quercus aliena (Qal), Quercus dentata (Qd), and Quercus variabilis (Qv). Color change (ΔE*), weight loss, and density loss were examined using flat-sawn heartwood boards before and after treatment at 160 °C, 180 °C, 200 °C, and 220 °C for 2 h. Overall, the ΔE*, weight loss, and density loss increased with temperature. The properties between temperature and species showed distinct differences. A change to a darker color was observed in all species after treatment at 200 °C. Qm and Qd exhibited the highest and lowest L*, a*, and b* values after treatment at 220 °C, respectively. The highest ΔE* values were obtained in Qd at 160 °C, Qs at 180 °C and 200 °C, and Qv at 220 °C. Qd and Qv exhibited the highest and lowest weight losses at 160 °C, respectively. Qac and Qal showed the highest and lowest weight losses at 220 °C, respectively. Qm showed the highest density loss at all temperatures, whereas Qs had the lowest at 160 °C, and Qac had the lowest values at 180 °C, 200 °C, and 220 °C.

Abstract Reducing the size of perovskite crystals to confine excitons and passivating surface defects has fueled a significant advance in the luminescence efficiency of perovskite light-emitting diodes (LEDs). However, the persistent gap between the optical limit of electroluminescence efficiency and the photoluminescence efficiency of colloidal perovskite nanocrystals (PeNCs) suggests that defect passivation alone is not sufficient to achieve highly efficient colloidal PeNC-LEDs. Here, we present a materials approach to controlling the dynamic nature of the perovskite surface. Our experimental and theoretical studies reveal that conjugated molecular multipods (CMMs) adsorb onto the perovskite surface by multipodal hydrogen bonding and van der Waals interactions, strengthening the near-surface perovskite lattice and reducing ionic fluctuations which are related to nonradiative recombination. The CMM treatment strengthens the perovskite lattice and suppresses its dynamic disorder, resulting in a near-unity photoluminescence quantum yield of PeNC films and a high external quantum efficiency (26.1%) of PeNC-LED with pure green emission that matches the Rec.2020 color standard for next-generation vivid displays.

Abstract Twisted bilayer graphene (tBLG) with small twist angles has attracted significant attention because of its unique electronic properties arising from the formation of a moiré superlattice. In this study, we systematically characterized the twist-angle-dependent electronic and transport properties of tBLG grown via chemical vapor deposition. This characterization included parameters such as the charge-neutral point voltage, carrier concentration, resistance, and mobility, covering a wide range of twist angles from 0° to 30°. We experimentally demonstrated that these parameters exhibited twist-angle-dependent moiré period trends, with high twist angles exceeding 9°, revealing more practically useful features, including improved mobilities compared to those of single-layer graphene. In addition, we demonstrated that the doping states and work functions were weakly dependent on the twist angles, as confirmed by additional first-principles calculations. This study provides valuable insights into the transport properties of tBLG and its potential for practical applications in the emerging field of twistronics.

Abstract Mental fitness is a construct that goes beyond a simple focus on subjective emotional wellbeing to encompass more broadly our ability to think, feel, and act to achieve what we want in our daily lives. The measurement and monitoring of multiple (often interacting) domains is crucial to gain a holistic and complete insight into an individual’s mental fitness. We aimed to demonstrate the capability of a new mobile app to characterise the mental fitness of a general population of Australians and to quantify the interrelationships among different domains of mental fitness. Cross-sectional data were collected from 4901 adults from the general population of Australians engaged in work or education who used a mobile app (Innowell) between September 2021 and November 2022. Individuals completed a baseline questionnaire comprised of 26 questions across seven domains of mental fitness (i.e., physical activity, sleep and circadian rhythms, nutrition, substance use, daily activities, social connection, psychological distress). Network analysis was applied at both a domain-level (e.g., 7 nodes representing each cluster of items) and an individual item-level (i.e., 26 nodes representing all questionnaire items). Only 612 people (12%) were functioning well across all domains. One quarter (n = 1204, 25%) had only one problem domain and most (n = 3085, 63%) had multiple problem domains. The two most problematic domains were physical activity (n = 2631, 54%) and social connection (n = 2151, 44%), followed closely by daily activity (n = 1914, 39%). At the domain-level, the strongest association emerged between psychological distress and daily activity (r = 0.301). Psychological distress was the most central node in the network (as measured by strength and expected influence), followed closely by daily activity, sleep and circadian rhythms and then social connection. The item-level network revealed that the nodes with the highest centrality in the network were: hopelessness, depression, functional impairment, effortfulness, subjective energy, worthlessness, and social connectedness. Social connection, sleep and circadian rhythms, and daily activities may be critical targets for intervention due to their widespread associations in the overall network. While psychological distress was not among the most common problems, its centrality may indicate its importance for indicated prevention and early intervention. We showcase the capability of a new mobile app to monitor mental fitness and identify the interrelationships among multiple domains, which may help people develop more personalised insights and approaches.

Abstract Despite the improved outcomes in patients with hematological malignancies, infections caused by multidrug-resistant organisms (MDROs) pose a new threat to these patients. We retrospectively reviewed the patients with hematological cancer and bacterial bloodstream infections (BSIs) at a tertiary hospital between 2003 and 2022 to assess the impact of MDROs on outcomes. Among 328 BSIs, 81 (24.7%) were caused by MDROs. MDRO rates increased from 10.3% (2003–2007) to 39.7% (2018–2022) (P

Optimum genetic delivery for modulating target genes to diseased tissue is a major obstacle for profitable gene therapy. Lipid nanoparticles (LNPs), considered a prospective vehicle for nucleic acid delivery, have demonstrated efficacy in human use during the COVID-19 pandemic. This study introduces a novel biomaterial-based platform, M1-polarized macrophage-derived cellular nanovesicle-coated LNPs (M1-C-LNPs), specifically engineered for a combined gene-immunotherapy approach against solid tumor. The dual-function system of M1-C-LNPs encapsulates Bcl2-targeting siRNA within LNPs and immune-modulating cytokines within M1 macrophage-derived cellular nanovesicles (M1-NVs), effectively facilitating apoptosis in cancer cells without impacting T and NK cells, which activate the intratumoral immune response to promote granule-mediating killing for solid tumor eradication. Enhanced retention within tumor was observed upon intratumoral administration of M1-C-LNPs, owing to the presence of adhesion molecules on M1-NVs, thereby contributing to superior tumor growth inhibition. These findings represent a promising strategy for the development of targeted and effective nanoparticle-based cancer genetic-immunotherapy, with significant implications for advancing biomaterial use in cancer therapeutics.

Abstract Background Human induced pluripotent stem cells (hiPSCs) and their differentiated cell types have a great potential for tissue repair and regeneration. While the primary focus of using hiPSCs has historically been to regenerate damaged tissue, emerging studies have shown a more potent effect of hiPSC-derived paracrine factors on tissue regeneration. However, the precise contents of the transplanted hiPSC-derived cell secretome are ambiguous. This is mainly due to the lack of tools to distinguish cell-specific secretome from host-derived proteins in a complex tissue microenvironment in vivo. Methods In this study, we present the generation and characterization of a novel hiPSC line, L274G-hiPSC, expressing the murine mutant methionyl-tRNA synthetase, L274GMmMetRS, which can be used for tracking the cell specific proteome via biorthogonal non-canonical amino acid tagging (BONCAT). We assessed the trilineage differentiation potential of the L274G-hiPSCs in vitro and in vivo. Furthermore, we assessed the cell-specific proteome labelling in the L274G-hiPSC derived cardiomyocytes (L274G-hiPSC-CMs) in vitro following co-culture with wild type human umbilical vein derived endothelial cells and in vivo post transplantation in murine hearts. Results We demonstrated that the L274G-hiPSCs exhibit typical hiPSC characteristics and that we can efficiently track the cell-specific proteome in their differentiated progenies belonging to the three germ lineages, including L274G-hiPSC-CMs. Finally, we demonstrated cell-specific BONCAT in transplanted L274G-hiPSC-CMs. Conclusion The novel L274G-hiPSC line can be used to study the cell-specific proteome of hiPSCs in vitro and in vivo, to delineate mechanisms underlying hiPSC-based cell therapies for a variety of regenerative medicine applications.

Abstract Optimal strategy for volume control and the clinical implication of achieved volume control are unknown in patients with sepsis-associated acute kidney injury (AKI) receiving continuous renal replacement therapy (CRRT). This randomized controlled trial aimed to compare the survival according to conventional or bioelectrical impedance analysis (BIA)-guided volume control strategy in patients with sepsis-associated AKI receiving CRRT. We also compared patient survival according to achieved volume accumulation rate ([cumulative fluid balance during 3 days × 100]/fluid overload measured by BIA at enrollment) as a post-hoc analysis. We randomly assigned patients to conventional volume control strategy (n = 39) or to BIA-guided volume control strategy (n = 34). There were no differences in 28-day mortality (HR, 1.19; 95% CI, 0.63–2.23) or 90-day mortality (HR, 0.99; 95% CI 0.57–1.75) between conventional and BIA-guided volume control group. In the secondary analysis, achieved volume accumulation rate was significantly associated with patient survival. Compared with the achieved volume accumulation rate of ≤ − 50%, the HRs (95% CIs) for the risk of 90-day mortality were 1.21 (0.29–5.01), 0.55 (0.12–2.48), and 7.18 (1.58–32.51) in that of − 50–0%, 1–50%, and > 50%, respectively. Hence, BIA-guided volume control in patients with sepsis-associated AKI receiving CRRT did not improve patient outcomes. In the secondary analysis, achieved volume accumulation rate was associated with patient survival.

Purpose: We sought to determine the association between the pre-radiation therapy prostate-specific antigen (pre-RT PSA) 0.5 and RT failure in post-radical prostatectomy (post-RP) patients. Our study also investigated the prognostic factors for the failure of RT given concurrently with hormone therapy (HT) after RP. Materials and methods: We retrospectively reviewed our institutional RP data from July 2004 to November 2021. Patients without concurrent hormone therapy were excluded. Propensity score matching was performed. Kaplan–Meier (KM) curve analysis was employed for RT failure-free survival, overall survival (OS), and cancer-specific survival (CSS). Cox regression analysis was used for the RT failure hazard ratio (HR). Results: After propensity score matching, 193 patients were assigned to the pre-RT PSA ≥0.5 (high-P) arm, and 193 patients were assigned to the pre-RT PSA

Abstract Acute biliary pancreatitis (ABP) with cholangitis requires endoscopic retrograde cholangiopancreatography (ERCP) within 24 h to resolve ductal obstruction. However, this recommendation is based on the timing of emergency room (ER) visits. We wanted to determine the optimal timing of ERCP for ABP based on the timing of symptom onset, not the timing of the ER visit. We retrospectively reviewed 162 patients with ABP with cholangitis who underwent urgent ERCP (within 24 h of ER admission). Area under the receiver operating characteristic (ROC) curve (AUC) was analyzed to determine differences in complication rates according to time from symptom onset. A difference in ERCP-related adverse events (AEs) was identified, and Youden’s J statistic was used to determine a cutoff time from symptom onset (18 h). We compared mortality and complications based on this cutoff. Based on time to symptom onset, significantly higher rates of aspiration pneumonia (odds ratio [OR] 4.00, 95% confidence interval [CI] 1.15–13.92, P = 0.021) and post-ERCP hypotension (OR 11.9, 95% CI 1.39–101.33, P = 0.005) were observed in the ≤ 18-h group than in the > 18-h group. The study found that patients who underwent ERCP within 18 h of symptom onset is associated with an increased risk of ERCP-related AEs.

Abstract The metal ion transporter SLC39A8 is associated with physiological traits and diseases, including blood manganese (Mn) levels and inflammatory bowel diseases (IBD). The mechanisms by which SLC39A8 controls Mn homeostasis and epithelial integrity remain elusive. Here, we generate Slc39a8 intestinal epithelial cell-specific-knockout (Slc39a8-IEC KO) mice, which display markedly decreased Mn levels in blood and most organs. Radiotracer studies reveal impaired intestinal absorption of dietary Mn in Slc39a8-IEC KO mice. SLC39A8 is localized to the apical membrane and mediates 54Mn uptake in intestinal organoid monolayer cultures. Unbiased transcriptomic analysis identifies alkaline ceramidase 1 (ACER1), a key enzyme in sphingolipid metabolism, as a potential therapeutic target for SLC39A8-associated IBDs. Importantly, treatment with an ACER1 inhibitor attenuates colitis in Slc39a8-IEC KO mice by remedying barrier dysfunction. Our results highlight the essential roles of SLC39A8 in intestinal Mn absorption and epithelial integrity and offer a therapeutic target for IBD associated with impaired Mn homeostasis.

PURPOSE The aim of this study was to evaluate the power change when increasing angular velocity from 180°/sec to 240°/sec in male athletes during isokinetic knee joint tests. METHODS Isokinetic knee extension/flexion tests were conducted at angular velocities of 60, 180, and 240°/sec in 74 adult male athletes from three sports (judo, field hockey, and canoeing). A basic physical fitness test and an anaerobic Wingate test were also conducted. Peak torque (Nm) and power (watts) were compared for different angular velocities. Correlation analysis was used to evaluate the relationship between power change. In addition, fitness and Wingate test results were compared between groups divided by increased/decreased power change. RESULTS As angular velocity increased, peak torque decreased and muscle power significantly increased (p

Objectives. Air pollution is an increasing global concern, and its effect on allergic inflammation has attracted the attention of many researchers. Particulate matter (PM) is a major component of ambient air pollution, and heavy metals are the primary toxic constituents of PM. As previous studies on the impact of air pollutants on allergic inflammation did not adequately mimic real-world atmospheric exposure, we developed an experimental model to investigate the effects of aerosolized air pollutants on nasal epithelial cells and fibroblasts. Methods. We collected particulate matter 2.5 (PM2.5) samples from ambient 24-hour air samples obtained in Seoul from August 2020 to August 2022, and then conducted component analysis for metallic constituents. Primary nasal epithelial cells and nasal fibroblasts, obtained and cultured from the turbinate tissues of human participants, were treated with PM2.5. The associations of heavy metals identified from the component analysis with cytokine expression were investigated. A three-dimensional (3D)-hybrid culture model, consisting of co-culture of an air-liquid interface and nasal fibroblast spheroids, was constructed to observe the impact of aerosolized air pollutants. Results. Among the heavy metals, Si was the predominant component of PM2.5, and Zn showed the highest correlation with the concentration of PM2.5 in Seoul. PM2.5, Zn, and Si increased the production of epithelial cell-derived cytokines, and PM2.5 and Zn exhibited similar trends with one another. Exposure of the 3D-hybrid model to aerosolized PM2.5 and Zn resulted in elevated periostin, alpha-smooth muscle actin, and fibronectin expression in fibroblast spheroids, and those without an epithelial barrier exhibited a similar increase in periostin expression. Conclusion. Ambient air pollutants in the form of aerosols increase the expression of allergic inflammatory cytokines in both nasal epithelial cells and fibroblasts. Regulations on air pollution will help reduce the global burden of allergic diseases in the future.

Abstract This study investigated intraocular pressure (IOP) in Dutch belted rabbits using two different tonometers, rebound tonometry (TonoVet Plus; TVP) and a Tonopen (Tono-Pen AVIA Vet; TPA). Post-pubescent male Dutch belted rabbits aged 36 weeks (n = 10 animals) were used in the study. IOP measurements were conducted every 2 weeks for 22 weeks using TVP and TPA on both eyes of each rabbit. The average IOP measurements were compared by the paired Student’s t-test. Pairwise Pearson’s correlation coefficients and Bland–Altman statistics were used. The overall mean IOP measured with TPA was significantly higher than that with TVP (23.5 ± 4.9 vs. 21.8 ± 2.4 mmHg for the right eyes; P = 0.045, and 23.0 ± 4.7 vs. 21.5 ± 2.4 mmHg for the left eyes; P = 0.047). Both tonometers tended to show increased IOP readings with age, and positive correlations between IOP and age were observed with both TPA (r = 0.95, P

Abstract Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.

Abstract As there is an increasing need for an efficient solver of combinatorial optimization problems, much interest is paid to the Ising machine, which is a novel physics-driven computing system composed of coupled oscillators mimicking the dynamics of the system of coupled electronic spins. In this work, we propose an energy-efficient nano-oscillator, called OTSNO, which is composed of an Ovonic Threshold Switch (OTS) and an electrical resistor. We demonstrate that the OTSNO shows the synchronization behavior, an essential property for the realization of an Ising machine. Furthermore, we have discovered that the capacitive coupling is advantageous over the resistive coupling for the hardware implementation of an Ising solver by providing a larger margin of the variations of components. Finally, we implement an Ising machine composed of capacitively-coupled OTSNOs to demonstrate that the solution to a 14-node MaxCut problem can be obtained in 40 µs while consuming no more than 2.3 µJ of energy. Compared to a previous hardware implementation of the phase-transition nano-oscillator (PTNO)-based Ising machine, the OTSNO-based Ising machine in this work shows the performance of the increased speed by more than one order while consuming less energy by about an order.

Abstract Previous studies have rarely investigated the role of non-vitamin K oral anticoagulants (NOAC) and warfarin in the secondary prevention of ischemic stroke patients with nonvalvular atrial fibrillation (NVAF). In this study, we compared the effectiveness and safety of NOAC and warfarin for secondary prevention in Korean ischemic stroke patients with NVAF. Based on the Korean National Health Insurance Service Database, this study included 21,064 oral anticoagulants-naïve acute ischemic stroke patients with NVAF between July 2015 and June 2019. The main study outcomes included ischemic stroke, systemic embolism, major bleeding, and death. During the observational periods, NOAC users had a significantly decreased risk of ischemic stroke + systemic embolism (adjusted hazard ratio [aHR] 0.86; 95% confidence interval [CI] 0.78–0.95), ischemic stroke (aHR 0.89; 95% CI 0.81–0.99), major bleeding (aHR 0.78; 95% CI 0.68–0.89), and all-cause death (aHR 0.87; 95% CI 0.81–0.93). Standard-dose NOAC users had a lower risk of ischemic stroke, systemic embolism, and major bleeding events than warfarin users. In contrast, low-dose NOAC users did not differ in risk from warfarin users for all outcomes. In conclusion, NOACs were associated with a lower risk of secondary thromboembolic events and bleeding complications in Korean ischemic stroke patients with NVAF than warfarin.

Abstract Establishing dependable, cost-effective electrical connections is vital for enhancing device performance and shrinking electronic circuits. MXenes, combining excellent electrical conductivity, high breakdown voltage, solution processability, and two-dimensional morphology, are promising candidates for contacts in microelectronics. However, their hydrophilic surfaces, which enable spontaneous environmental degradation and poor dispersion stability in organic solvents, have restricted certain electronic applications. Herein, electrohydrodynamic printing technique is used to fabricate fully solution-processed thin-film transistors with alkylated 3,4-dihydroxy-L-phenylalanine functionalized Ti3C2T x (AD-MXene) as source, drain, and gate electrodes. The AD-MXene has excellent dispersion stability in ethanol, which is required for electrohydrodynamic printing, and maintains high electrical conductivity. It outperformed conventional vacuum-deposited Au and Al electrodes, providing thin-film transistors with good environmental stability due to its hydrophobicity. Further, thin-film transistors are integrated into logic gates and one-transistor-one-memory cells. This work, unveiling the ligand-functionalized MXenes’ potential in printed electrical contacts, promotes environmentally robust MXene-based electronics (MXetronics).

Abstract Thermal losses in photoelectric devices limit their energy conversion efficiency, and cyclic input of energy coupled with pyroelectricity can overcome this limit. Here, incorporating a pyroelectric absorber into a photovoltaic heterostructure device enables efficient electricity generation by leveraging spontaneous polarization based on pulsed light-induced thermal changes. The proposed pyroelectric-photovoltaic device outperforms traditional photovoltaic devices by 2.5 times due to the long-range electric field that occurs under pulse illumination. Optimization of parameters such as pulse frequency, scan speed, and illumination wavelength enhances power harvesting, as demonstrated by a power conversion efficiency of 11.9% and an incident-photon-to-current conversion efficiency of 200% under optimized conditions. This breakthrough enables reconfigurable electrostatic devices and presents an opportunity to accelerate technology that surpasses conventional limits in energy generation.

Abtract Clinical circulating cell-free DNA (cfDNA) testing is now routine, however test accuracy remains limited. By understanding the life-cycle of cfDNA, we might identify opportunities to increase test performance. Here, we profile cfDNA release across a 24-cell line panel and utilize a cell-free CRISPR screen (cfCRISPR) to identify mediators of cfDNA release. Our panel outlines two distinct groups of cell lines: one which releases cfDNA fragmented similarly to clinical samples and purported as characteristic of apoptosis, and another which releases larger fragments associated with vesicular or necrotic DNA. Our cfCRISPR screens reveal that genes mediating cfDNA release are primarily involved with apoptosis, but also identify other subsets of genes such as RNA binding proteins as potential regulators of cfDNA release. We observe that both groups of cells lines identified primarily produce cfDNA through apoptosis. These results establish the utility of cfCRISPR, genetically validate apoptosis as a major mediator of DNA release in vitro, and implicate ways to improve cfDNA assays.

Abstract Nonviral delivery of the CRISPR/Cas9 system provides great benefits for in vivo gene therapy due to the low risk of side effects. However, in vivo gene editing by delivering the Cas9 ribonucleoprotein (RNP) is challenging due to the poor delivery into target tissues and cells. Here, we introduce an effective delivery method for the CRISPR/Cas9 RNPs by finely tuning the formulation of ionizable lipid nanoparticles. The LNPs delivering CRISPR/Cas9 RNPs (CrLNPs) are demonstrated to induce gene editing with high efficiencies in various cancer cell lines in vitro. Furthermore, we show that CrLNPs can be delivered into tumor tissues with high efficiency, as well as induce significant gene editing in vivo. The current study presents an effective platform for nonviral delivery of the CRISPR/Cas9 system that can be applied as an in vivo gene editing therapeutic for treating various diseases such as cancer and genetic disorders.

In this study, Ag-impregnated silica aerogel composites were fabricated via wet impregnation. In this approach, silver salt was reduced with ethylene glycol in the presence of polyvinylpyrrolidone (PVP) at reaction temperature 80°C. PVP was used as a capping agent to protect the Ag nanoparticles (NPs) from agglomeration. Wet impregnation was used to synthesize the Ag/SiO2 composite by combining the reduction of AgNO3 with a silica aerogel slurry. Experimental results showed that the AgNO3 concentration and PVP: AgNO3 ratio had an active influence on the growth of Ag NPs on silica surfaces. The X-ray diffraction (XRD) patterns of the composite material showed no imprints of impurities or parasitic materials except for Ag and SiO2. Scanning electron microscopy (SEM) images revealed that the Ag NPs were well impregnated into the porous silica aerogel structure. It was found that SiO2 aerogel surfaces were homogeneously surrounded by the Ag NPs.

We develop a program for predicting bearing performance, including the maximum contact stress, bearing power loss, minimum lubricating film thickness, static safety factor, and dynamic life, and an optimal design for high-speed angular contact ball bearings in aircraft gearboxes using optimization algorithms. A program is developed to predict bearing performance by calculating the loads and displacements of individual balls based on the bearing’s kinematic and static equilibrium equations. Next, an optimization program is developed with non-dominated sorting genetic algorithm III (NSGA-III), wherein calculated bearing performance indicators serve as constraints or objective functions. The performance of individuals within the final Pareto front is evaluated using the inter-criteria correlation (CRITIC) and weighted product methods. The optimization performances of NSGA-III and NSGA-II are compared based on their hypervolume indicators. A solution of the kinematic and static equilibrium equations under the load cases and duty cycles of real aircraft gearboxes is obtained, enhancing the prediction accuracy. Furthermore, optimization, including bearing performance metrics rarely considered in previous studies, is performed. Optimal specifications superior to reference bearings employed in aircraft gearboxes are obtained, enhancing all three objective functions or specific objective functions. The optimization performance of NSGA-III is confirmed to surpass that of conventional NSGA-II.

RationaleMG53’s known function in facilitating tissue repair and anti-inflammation has broad applications to regenerative medicine. There is controversy regarding MG53’s role in the development of type 2 diabetes mellitus.ObjectiveThis study aims to address this controversy – whether MG53’s myokine function contributes to inhibition of insulin signaling in muscle, heart, and liver tissues.Study designWe determined the binding affinity of the recombinant human MG53 (rhMG53) to the insulin receptor extracellular domain (IR-ECD) and found low affinity of interaction with Kd (>480 nM). Using cultured C2C12 myotubes and HepG2 cells, we found no effect of rhMG53 on insulin-stimulated Akt phosphorylation (p-Akt). We performed in vivo assay with C57BL/6J mice subjected to insulin stimulation (1 U/kg, intraperitoneal injection) and observed no effect of rhMG53 on insulin-stimulated p-Akt in muscle, heart and liver tissues.ConclusionOverall, our data suggest that rhMG53 can bind to the IR-ECD, however has a low likelihood of a physiologic role, as the Kd for binding is ~10,000 higher than the physiologic level of MG53 present in the serum of rodents and humans (~10 pM). Our findings question the notion proposed by Xiao and colleagues – whether targeting circulating MG53 opens a new therapeutic avenue for type 2 diabetes mellitus and its complications.

IntroductionWeight-loss strategies through meal replacements are effective and sustainable options. However, few studies have assessed their effects on weight loss including body composition through protein-supplemented meal replacements targeting the Asian population, including Koreans. This study aimed to assess the effectiveness and safety of a protein-supplemented very-low-calorie diet (PSVLCD) for weight reduction and changes in body composition in individuals with obesity over a 12-month long-term period.MethodsIn total, 106 participants with obesity were randomly assigned to a PSVLCD or control group (food-based calorie-restricted diet). Body weight, waist circumference, body composition, and blood marker levels were measured throughout the study. Statistical analyses were performed to compare outcomes between the groups.ResultsAmong the 106 participants, 84 completed the 12-month follow-up. Intention-to-treat analysis showed that the mean weight loss from baseline to 12 months was −6.86 kg (8.21% of baseline weight) in the PSVLCD group and − 4.66 kg (5.47% of initial body weight) in the control group; the difference was −2.20 kg with a marginally significant interval (95% confidence interval [CI], −4.90; 0.50). Waist circumference (−8.35 cm vs. -4.85 cm; mean difference, −3.49 cm; 95% CI, −6.48 to −0.50) and visceral fat area (−28.28 cm2 vs. −13.26 cm2; mean difference, −15.03cm2; 95% CI, −29.01 to −1.04) also significantly decreased in the PSVLCD group at 12 months.DiscussionThe PSVLCD group demonstrated a substantial initial reduction in waist circumference that was sustained over the study period, alongside a marginally significant decrease in weight. These findings suggest that a protein-supplemented very-low-calorie diet may be an effective strategy for long-term weight management and body composition improvement in individuals with obesity.Clinical trial registrationClinicalTrials.gov, identififer NCT04597788.

IntroductionDespite evidence suggesting that metabolic intermediates like β-HB influence white adipose tissue (WAT) metabolism, the precise molecular mechanisms remain unclear. The aim of this study was to investigate the impact of beta-hydroxybutyrate (β-HB) on the fat browning program and to explore the underlying molecular mechanisms using both in vitro and in vivo models. We assessed the effects of β-HB on fat browning in adipocytes using 3T3-L1 cells and rat models.MethodsWe evaluated the effects of β-HB on fat browning, thermogenesis, lipid accumulation, adipokine expression, and mitochondrial biogenesis by treating mature 3T3-L1 adipocytes with sodium β-HB for 24 h or by continuously exposing preadipocytes to β-HB during the 8-day differentiation process. Male Sprague Dawley rats were divided into control, exercise only (EX), ketogenic diet only (KD), and combined exercise and ketogenic diet (KE) groups for an 8-week intervention involving diet and/or exercise. After intervention, we evaluated WAT histology, plasma lipids and adipokines, and the expression of markers related to fat browning, thermogenesis and mitochondrial biogenesis in WAT of rats.ResultsIn our adipocyte culture experiments, β-HB reduced intracellular lipid accumulation by enhancing lipolysis and stimulated the expression of thermogenic and fat browning genes like uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16), and adipokines such as fibroblast growth factor 21 (FGF21) and Fibronectin type III domain-containing protein 5 (FDNC5). Additionally, β-HB activated the AMPK-SIRT1-PGC-1α pathway, with UCP1 and PRDM16 upregulation mediated by β-HB intracellular action and SIRT1 activity. In animal experiments, KE group raised β-HB levels, decreasing body weight and blood lipids. KD with EX promoted WAT browning possibly via AMPK-SIRT1-PGC-1α, augmenting PRDM16, UCP1, FGF21, and FNDC5 expression.Conclusionβ-HB induction via KD and/or EX shows potential in promoting WAT browning by activating mitochondrial biogenesis, lipolysis, and thermogenesis, suggesting that dietary and physical intervention inducing β-HB may benefit metabolic health.

Poor clearances, misalignments, and carbon deposits in a turbocharger due to high running hours can decrease engine efficiency. This study analyzes the effects of turbocharger reconditioning on the performance and emissions formation of a marine diesel generator engine. The engine test experiments were performed on a university training ship's auxiliary diesel engine with 4309 running hours before and after the TC overhaul. As a result, cylinder peak pressure was increased by a maximum of 3.57 % while fuel saving of 5–8 g/kWh was realized. Lower exhaust gas temperatures and improved charge air pressure by up to 7.7 % were recorded. A significant CO emission reduction of 21.6 % was recorded at idle load whereas NOx and CO2 emissions were reduced to a maximum of 4.86 % and 7.30 % at 50 % engine load. The results indicate that scheduled TC overhaul and maintenance are very useful to improve the engine’s fuel economy, and performance and reduce exhaust emissions.

Alzheimer’s disease (AD) is characterized by cognitive impairment, loss of learning and memory, and abnormal behaviors. Scopolamine (SCOP) is a non-selective antagonist of muscarinic acetylcholine receptors that exhibits the behavioral and molecular hallmarks of AD. Vanillic acid (VA), a phenolic compound, is obtained from the roots of a traditional plant called Angelica sinensis, and has several pharmacologic effects, including antimicrobial, anti-inflammatory, anti-angiogenic, anti-metastatic, and antioxidant properties. Nevertheless, VA’s neuroprotective potential associated with the memory has not been thoroughly investigated. Therefore, this study investigated whether VA treatment has an ameliorative effect on the learning and memory impairment induced by SCOP in rats. Behavioral experiments were utilized to assess the learning and memory performance associated with the hippocampus. Using western blotting analysis and assay kits, the neuronal damage, oxidative stress, and acetylcholinesterase activity responses of hippocampus were evaluated. Additionally, the measurement of long-term potentiation was used to determine the function of synaptic plasticity in organotypic hippocampal slice cultures. In addition, the synaptic vesicles’ density and the length and width of the postsynaptic density were evaluated using electron microscopy. Consequently, the behavioral, biochemical, electrophysiological, and ultrastructural analyses revealed that VA treatment prevents learning and memory impairments caused by SCOP in rats. The study’s findings suggest that VA has a neuroprotective effect on SCOP-induced learning and memory impairment linked to the hippocampal cholinergic system, oxidative damage, and synaptic plasticity. Therefore, VA may be a prospective therapeutic agent for treating AD.

BackgroundAlzheimer’s disease (AD) is a complex neurodegenerative disorder influenced by various factors, including liver function, which may impact the clearance of amyloid-β (Aβ) in the brain. This study aimed to explore how the apolipoprotein E (APOE) ε4 allele affects the relationship of liver function markers with AD pathology and cognition.MethodsWe analyzed data from two independent cohorts, including 732 participants from the Hallym University Medical Center and 483 from the Alzheimer’s Disease Neuroimaging Initiative, each group consisting of individuals with and without the APOE ε4 allele. Cross-sectional analyses evaluated the associations of liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, total bilirubin, and albumin) with AD diagnosis, amyloid positron emission tomography (PET) burden, and cerebrospinal fluid biomarkers for AD (Aβ42, total tau, and phosphorylated tau181) at baseline. Longitudinally, we investigated the associations between these liver enzymes and changes in cognitive performance over the course of a year. Logistic and linear regression models were used to analyze these associations and mediation analyses were conducted to assess whether age and amyloid PET burden mediated these associations.ResultsOnly in the APOE ε4 carrier group, a high AST to ALT ratio and low ALT levels were significantly associated with AD diagnosis, increased amyloid PET burden, and faster longitudinal decline in cognitive function in both cohorts. In particular, the AST to ALT ratio was associated with cerebrospinal fluid Aβ42 levels exclusively in the APOE ε4 carrier group in the Alzheimer’s Disease Neuroimaging Initiative cohort but not with phosphorylated tau181 or total tau levels. Moreover, mediation analyses from both cohorts revealed that in the APOE ε4 carriers group, age did not mediate the associations between liver enzymes and AD diagnosis or amyloid PET burden. However, amyloid PET burden partially mediated the association between liver enzymes and AD diagnosis exclusively in the APOE ε4 carriers group.ConclusionThis study provides valuable insights into the significant association of the APOE ε4 allele with liver enzymes and their potential role in Aβ-related pathogenesis and cognition in AD. Further research is required to elucidate the underlying mechanisms and potential therapeutic implications of these findings.

Abstract Although sodium‐ion batteries (SIBs) offer promising low‐cost alternatives to lithium‐ion batteries (LIBs), several challenges need to be overcome for their widespread adoption. A primary concern is the optimization of carbon anodes. Graphite, vital to the commercial viability of LIBs, has a limited capacity for sodium ions. Numerous alternatives to graphite are explored, particularly focusing on disordered carbons, including hard carbon. However, compared with graphite, most of these materials underperform in LIBs. Furthermore, the reaction mechanism between carbon and sodium ions remains ambiguous owing to the structural diversity of disordered carbon. A straightforward mechanical approach is introduced to enhance the sodium ion storage capacity of graphite, supported by comprehensive analytical techniques. Mechanically activated graphite delivers a notable reversible capacity of 290.5 mAh·g−1 at a current density of 10 mA·g−1. Moreover, it maintains a capacity of 157.7 mAh·g−1 even at a current density of 1 A·g−1, benefiting from the defect‐rich structure achieved by mechanical activation. Soft X‐ray analysis revealed that this defect‐rich carbon employs a sodium‐ion storage mechanism distinct from that of hard carbon. This leads to an unexpected reversible reaction on the solid electrolyte surface. These insights pave the way for innovative design approaches for carbon electrodes in SIB anodes.

Objective The efficacy of previously developed respiratory barrier enclosures to limit healthcare workers’ exposure to aerosols from COVID-19 patients remains unclear; in addition, the design of these devices is unsuitable for transportation or other emergency procedures. Therefore, we developed a novel negative pressure respiratory isolator to improve protection from patient-generated aerosols and evaluated its protective effect in conversion to systemic isolator. Methods This in vitro study simulated droplets by nebulizing 1% glycerol + 99% ethanol solution. We performed cardiopulmonary resuscitation (CPR) and converted a respiratory barrier enclosure into a systemic isolator with a respiratory barrier as well as a respiratory barrier with negative pressure generator (NPG), which were compared with control and room air. During the procedure, particles were counted for 30 seconds and the count was repeated 10 times. Results During CPR, the total number of particles in the respiratory barrier with NPG (280,529; interquartile range [IQR], 205,263–359,195; P=0.970) was similar to that in the control (308,789; IQR, 175,056–473,276). Using NPG with a respiratory barrier reduced the number of particles to 27,524 (IQR, 26,703–28,905; P=0.001). Particle number during conversion of the respiratory barrier into a systemic isolator was also lower than in the control (25,845; IQR, 19,391–29,772; P=0.001). Conclusion The novel isolator was converted to a systemic isolator without air leakage. The aerosol-blocking effect of the isolator was quantified using a particle counter during CPR. Further studies comparing the barrier effect of isolators within various pressure differentials are warranted.