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Abstract Suppressing the oxidation of active-Ir(III) in IrOx catalysts is highly desirable to realize an efficient and durable oxygen evolution reaction in water electrolysis. Although charge replenishment from supports can be effective in preventing the oxidation of IrOx catalysts, most supports have inherently limited charge transfer capability. Here, we demonstrate that an excess electron reservoir, which is a charged oxygen species, incorporated in antimony-doped tin oxide supports can effectively control the Ir oxidation states by boosting the charge donations to IrOx catalysts. Both computational and experimental analyses reveal that the promoted charge transfer driven by excess electron reservoir is the key parameter for stabilizing the active-Ir(III) in IrOx catalysts. When used in a polymer electrolyte membrane water electrolyzer, Ir catalyst on excess electron reservoir incorporated support exhibited 75 times higher mass activity than commercial nanoparticle-based catalysts and outstanding long-term stability for 250 h with a marginal degradation under a water-splitting current of 1 A cm−2. Moreover, Ir-specific power (74.8 kW g−1) indicates its remarkable potential for realizing gigawatt-scale H2 production for the first time.

Abstract The widespread use of body weight control agents might be related to liver enzyme elevation, but this potential association has only been documented in a few case reports. This study aimed to investigate the associations between weight loss agents and elevated liver enzymes at the population-level. We conducted a cross-sectional study using Korea National Health and Nutrition Examination Survey (KNHANES) data from 2013 to 2019. This study included 36,259 participants over 20 years of age who completed the questionnaire and had no history of hepatitis, cancer, or renal failure. In these participants, we analyzed associations between weight loss agents and elevated liver enzymes by constructing multiple logistic regression models with adjustment for confounding factors and stratified by sex, age, and body mass index. The use of weight loss agents related to liver enzyme elevation in men (adjusted odds ratio (aOR): 1.36, 95% confidence interval (CI): 1.08–1.71) and participants aged less than 40 years (aOR: 1.44, 95% CI: 1.12–1.87). Using more types of weight loss agents was associated with liver enzyme elevation (aOR: 1.31, 95% CI: 1.03–1.67 for 1 weight loss agent, aOR: 1.93, 95% CI: 0.93–3.99 for ≥ 2 weight loss agents). Elevated liver enzymes were associated with the use of traditional medicines (aOR: 1.96, 95% CI: 1.14–3.34) and dietary supplements (aOR: 1.33, 95% CI: 1.02–1.72) in men. We observed an association between weight loss agents and liver enzyme elevation in men, particularly for traditional herbal medicines and dietary supplements. To confirm the observed associations, studies higher on the evidence hierarchy are needed.

This paper proposes an effective planar mmWave switched beamforming antenna array with low complexity and wide beam coverage. The proposed structure is configured using multiple linearly polarized self-beam-tilting-antenna (SBTA) elements, eliminating the requirement of a phase-adjustable block for beamforming. Each SBTA element can generate different main beam directions by itself without using complicated feed networks. Moreover, unlike typical Butler matrix-based beamforming arrays, the proposed SBTA array does not require passive hybrid couplers to adjust the phases for beamforming operations. Accordingly, the proposed feed network-less antenna avoids circuit complexity, feed network insertion losses, or increases in size and fabrication costs, rendering it suitable for mmWave compact antenna applications. To verify the proposed concept and beamforming performance, a 1 × 4 SBTA array was fabricated at 28 GHz using a conventional printed circuit board (PCB) process. The size of the fabricated antenna (excluding test connectors) was 1.12 λ0 × 1.68 λ0 × 0.08 λ0 (λ0 for free-space wavelength), and the measured 10-dB impedance bandwidth was approximately 5.9 %. Furthermore, the measured main beam switching directions were found at −34°, −52°, +51°, and +38° with measured gains of 6.7, 6.1, 5.9, and 6.6 dBi, respectively, at 28 GHz.

Abstract Both cancer patients and the elderly are at high risk of developing flu complications, so influenza vaccination is recommended. We aimed to evaluate potential adverse events (AEs) following influenza vaccination in elderly cancer patients using the self-controlled tree-temporal scan statistic method. From a large linked database of Korea Disease Control and Prevention Agency vaccination data and the National Health Insurance Service claims data, we identified cancer patients aged over 65 who received flu vaccines during the 2016/2017 and 2017/2018 seasons. We included all the outcomes occurring on 1–84 days post-vaccination and evaluated all temporal risk windows, which started 1–28 days and ended 2–42 days. Patients who were diagnosed with the same disease during a year prior to vaccination were excluded. We used the hierarchy of ICD-10 to identify statistically significant clustering. This study included 431,276 doses of flu vaccine. We detected signals for 1 set: other dorsopathies on 1–15 days (attributable risk 16.5 per 100,000, P = 0.017). Dorsopathy is a known AE of influenza vaccine. No statistically significant clusters were found when analyzed by flu season. Therefore, influenza vaccination is more recommended for elderly patients with cancer and weakened immune systems.

Background: Smartphone addiction has emerged as a significant social problem. Numerous studies have indicated the association between smartphone use and discomfort in the musculoskeletal system of the upper extremities. Objects: This cross-sectional survey aimed to compare the characteristics of musculoskeletal pain in the neck, trunk, and upper limbs between individuals with smartphone addiction and those without addiction. Methods: We collected a total of 326 healthy individuals’ data from China and Korea who had owned and used smartphones for more than 5 years between 20–50s through an online questionnaire consisting of 84 questions in four major sections. The first part contained basic information on the participant's personal characteristics and smartphones. The second part contained questions about smartphone use and posture. The third part was the smartphone addiction. The fourth part was to investigate musculoskeletal pain in various upper body parts. Results: Smartphone addiction has a weak negative correlation with age (r = –0.20, p < 0.01) and a weak positive correlation with the hours of smartphone use (r = 0.376, p < 0.01). Frequent musculoskeletal pain symptoms related to smartphone use were observed in the neck, shoulder, lower back, and wrists. The hours of smartphone use was slightly positively associated with the prevalence of musculoskeletal pain in the shoulder (r = 0.162, p < 0.05) and lower back (r = 0.125, p < 0.05). The prevalence of musculoskeletal pain in the neck (χ2 = 3.993, p < 0.05), shoulder (χ2 = 6.465, p < 0.05), and wrist (χ2 = 4.645, p < 0.05) was significantly higher among females than males. Conclusion: The results suggest that smartphone addiction should be recognized as a dual concern encompassing both physical health and psychosocial aspects. Furthermore, healthcare professionals, including physicians and physical therapists, should consider clients' smartphone usage patterns when assessing and treating with musculoskeletal pain.

This study investigates the variations in the microstructural characteristics of a pre-twinned Mg alloy with the temperature of the subsequent annealing treatment. To this end, a rolled AZ31 alloy is compressed to 3% plastic strain along the rolling direction (RD) to activate {10-12} twinning and is subsequently annealed at 200, 250, 300, 350, and 400 °C. Numerous {10-12} twins are formed throughout the compressed material, leading to the formation of a RD-oriented texture. At an annealing temperature of 200 °C, no microstructural variations occur during annealing. As the annealing temperature increases from 250 to 400 °C, the residual strain energy and remaining twin boundaries of the annealed material decrease owing to the promoted static recovery and the increased area fraction of twin-free grown grains. Consequently, an increase in the annealing temperature results in a gradual microstructural transition from a fully twinned grain structure to a completely twin-free grain structure. The microstructural evolution during annealing is predominantly governed by the movement of high-angle grain boundaries via a strain-induced boundary migration mechanism, and a few twin boundaries migrate above 350 °C because of their lower boundary energy. The boundary migration behavior and resultant microstructural evolution are discussed in detail based on the variations in boundary mobility and driving force for boundary migration with annealing temperature.

Abstract Introduction This study aimed to assess the role of adenosine triphosphate (ATP) bioluminescence level monitoring for identifying reservoirs of the outbreak pathogen during two consecutive outbreaks caused by Enterococcus faecium and Staphylococcus capitis at a neonatal intensive care unit (NICU). The secondary aim was to evaluate the long-term sustainability of the infection control measures employed one year after the final intervention measures. Methods Two outbreaks occurred during a 53-day period in two disconnected subunits, A and B, that share the same attending physicians. ATP bioluminescence level monitoring, environmental cultures, and hand cultures from healthcare workers (HCW) in the NICU were performed. Pulsed-field gel electrophoresis (PFGE) typing was carried out to investigate the phylogenetic relatedness of the isolated strains. Results Four cases of E. faecium sepsis (patients A-8, A-7, A-9, B-8) and three cases of S. capitis sepsis (patients A-16, A-2, B-8) were diagnosed in six preterm infants over a span of 53 days. ATP levels remained high on keyboard 1 of the main station (2076 relative light unit [RLU]/100 cm2) and the keyboard of bed A-9 (4886 RLU/100 cm2). By guidance with the ATP results, environmental cultures showed that E. faecium isolated from the patients and from the main station’s keyboard 1 were genotypically indistinguishable. Two different S. capitis strains caused sepsis in three patients. A total 77.8% (n = 7/9) of S. capitis cultured from HCW's hands were genotypically indistinguishable to the strains isolated from A-2 and A-16. The remaining 22.2% (n = 2/9) were genotypically indistinguishable to patient B-8. Three interventions to decrease the risk of bacterial transmission were applied, with the final intervention including a switch of all keyboards and mice in NICU-A and B to disinfectable ones. Post-intervention prospective monitoring up to one year showed a decrease in blood culture positivity (P = 0.0019) and catheter-related blood stream infection rate (P = 0.016) before and after intervention. Conclusion ATP monitoring is an effective tool in identifying difficult to disinfect areas in NICUs. Non-medical devices may serve as reservoirs of pathogens causing nosocomial outbreaks, and HCWs' hands contribute to bacterial transmission in NICUs.

Oxidative stress caused by reactive oxygen species (ROS) is one of the major causes of senescence. Strategies to reduce ROS are known to be important factors in reversing senescence, but effective strategies have not been found. In this study, we screened substances commonly used as cosmetic additives to find substances with antioxidant effects. Polygonum cuspidatum (P. cuspidatum) extract significantly reduced ROS levels in senescent cells. A novel mechanism was discovered in which P. cuspidatum extract reduced ROS, a byproduct of inefficient oxidative phosphorylation (OXPHOS), by increasing OXPHOS efficiency. The reduction in ROS by P. cuspidatum extract restored senescence-associated phenotypes and enhanced skin protection. Then, we identified polydatin as the active ingredient of P. cuspidatum extract that exhibited antioxidant effects. Polydatin, which contains stilbenoid polyphenols that act as singlet oxygen scavengers through redox reactions, increased OXPHOS efficiency and subsequently restored senescence-associated phenotypes. In summary, our data confirmed the effects of P. cuspidatum extract on senescence rejuvenation and skin protection through ROS reduction. This novel finding may be used as a treatment in senescence rejuvenation in clinical and cosmetic fields.

In this study, we aimed to develop a novel directional electromagnetic field (EMF) application method for promoting plant growth using a solenoid coil-based cultivation system. The emergence of plant shoots from seeds, shoot elongation, root proliferation, and plant growth hormones were monitored in the presence of a directional EMF using our solenoid coil system. To observe the effect of the directional EMF on seed germination, radish and sugarcane seedlings were cultivated in the system. At the seed germination stage, the EMF applied had no significant effect on germination or growth. However, after germination, shoot growth was sensitive to a directional EMF, as it was promoted by different conditions in a plant-species-dependent manner. The maximum growth promotion rates were 25.65% ± 4.21% and 38.57% ± 12.81% for radish and sugarcane, respectively. Similarly, plant root proliferation and indole-3-acetic acid (IAA) analyses indicated that directional EMF application was associated with root proliferation and hormone synthesis. Plant growth in the experimental system proved controllable; either growth stimulation or reduction were possible as the system operating conditions were made to vary. Our findings indicate that the application of a specific directional EMF could serve as an electrical plant stimulant (or electrical fertilizer).

Acute hepatopancreatic necrosis disease (AHPND) is one of the most important diseases in the global shrimp industry. The emergence of mutant AHPND-associated V. parahaemolyticus (VpAHPND) strains has raised concerns regarding potential misdiagnosis and unforeseen pathogenicity. In this study, we report the first emergence of a type II (pirA−, pirB+) natural mutant, VpAHPND (strain 20-082A3), isolated from cultured Penaeus vannamei in Korea. Phenotypic and genetic analyses revealed a close relationship between the mutant strain 20-082A3 and the virulent Korean VpAHPND strain 19-021-D1, which caused an outbreak in 2019. Detailed sequence analysis of AHPND-associated plasmids showed that plasmid pVp_20-082A3B in strain 20-082A3 was almost identical (>99.9%) to that of strain 19-021-D1. Moreover, strains 20-082A3 and 19-021-D1 exhibited the same multilocus sequence type (ST 413) and serotype (O1:Un-typeable K-serogroup), suggesting that the mutant strain is closely related to and may have originated from the virulent strain 19-021-D1. Similar to previous reports on the natural mutant VpAHPND, strain 20-082A3 did not induce AHPND-related symptoms or cause mortality in the shrimp bioassay. The emergence of a mutant strain which is almost identical to the virulent VpAHPND highlights the need for surveillance of the pathogen prevalent in Korea. Further investigations to elucidate the potential relationship between ST 413 and recent Korean VpAHPND isolates are needed.

Achyranthes japonica Nakai (AJN) is a medicinal plant known to be beneficial for the joints. Since it takes at least two years from sowing to harvesting in an open field, new AJN cultivation strategies are needed to shorten the production period and improve quality. In this study, high-quality AJN is produced as microgreens in a vertical farm using a commercial ginseng soil mix (Myeongpum-Insamsangto, Shinsung Mineral Co., Ltd., Goesan, Republic of Korea) and controlled environmental conditions. The cultivation conditions included a temperature of 23 ± 2 °C, relative humidity of 50 ± 10%, and a photosynthetic photon flux density of 170 ± 15 µmol·m−2·s−1. Pre-harvest intermittent UV-B exposure, with an intensity of 1.0 ± 0.3 W/m−2, was applied for one day before harvest to evaluate its effects, using controlled environmental conditions in the vertical farm. Ultraviolet-B (UV-B) irradiation increases secondary metabolite levels in plants; however, the effect of UV-B on 20-hydroxyecdysone (20E), an indicator of AJN, is unclear. Therefore, we aimed to investigate whether UV-B treatment of AJN microgreens affected growth and secondary metabolites. The treatment group was set to 12 h of continuous UV-B treatment during the day, two 6 h UV-B treatments, and four 3 h UV-B treatments to confirm the effectiveness of regular and intermittent treatment and recovery. Short-term UV-B treatment before harvesting increased phenols, flavonoids, antioxidant capacity, and 20E levels without affecting AJN biomass. The intermittent 6 h UV-B irradiation with a 6 h recovery time stimulated 20E content by approximately 1.4 times compared to the control. These study findings indicate that short-term UV-B treatment before harvesting, an appropriate recovery time, and intermittent UV-B exposure are more effective at increasing 20E content than continuous treatment. This approach provides a promising strategy for improving the nutritional and health benefits of AJN microgreens in vertical farming systems.

Alzheimer’s disease (AD) is a progressive neurodegenerative condition characterized by memory and cognitive decline in older individuals. Beta-amyloid (Aβ), a significant component of senile plaques, is recognized as a primary contributor to AD pathology. Hence, substances that can inhibit Aβ production and/or accumulation are crucial for AD prevention and treatment. Agrimonia pilosa LEDEB. (A. pilosa) (Rosaceae), specifically its aerial parts, was identified in our previous screening study as a promising candidate with inhibitory effects on Aβ production. Therefore, in this study, A. pilosa extract was investigated for its anti-amyloidogenic effects, and its bioactive principles were isolated and identified. The ethanol extract of A. pilosa reduced the levels of sAPPβ and β-secretase by approximately 3% and 40%, respectively, compared to the DMSO-treated control group in APP-CHO cells (a cell line expressing amyloid precursor protein), which were similar to those in the positive control group. In addition, the ethanol extract of A. pilosa also hindered Aβ’s aggregation into fibrils and facilitated the disaggregation of Aβ aggregates, as confirmed by a Thioflavin T (Th T) assay. Subsequently, the active constituents were isolated using a bioassay-guided isolation method involving diverse column chromatography. Eleven compounds were identified—epi-catechin (1), catechin (2), (2S, 3S)-dihydrokaempferol 3-O-β-D-glucopyranoside (3), (-)-epiafzelechin 5-O-β-D-glucopyranoside (4), kaempferol 3-O-β-D-glucopyranoside (5), apigenin 7-O-β-D-glucopyranoside (6), dihydrokaempferol 7-O-β-D-glucopyranoside (7), quercetin 3-O-β-D-glucopyranoside (8), (2S, 3S)-taxifolin 3-O-β-D-glucopyranoside (9), luteolin 7-O-β-D-glucopyranoside (10), and apigenin 7-O-β-D-methylglucuronate (11)—identified through 1D and 2D NMR analysis and comparison with data from the literature. These compounds significantly decreased Aβ production by reducing β- and γ-secretase levels. Moreover, none of the compounds affected the expression levels of sAPPα or α-secretase. Further, compounds 1, 2, 4, 8, and 10 demonstrated a dose-dependent reduction in Aβ aggregation and promoted the disaggregation of pre-formed Aβ aggregates. Notably, compound 8 inhibited the aggregation of Aβ into fibrils by about 43% and facilitated the disassembly of Aβ aggregates by 41% compared to the control group containing only Aβ. These findings underscore the potential of A. pilosa extract and its constituents to mitigate a crucial pathological aspect of AD. Therefore, A. pilosa extract and its active constituents hold promise for development as therapeutics and preventatives of AD.

A resurgence of Mycoplasma pneumoniae (MP)—the leading cause of community-acquired bacterial pneumonia, particularly in children—occurred following the COVID-19 pandemic. We aimed to investigate the clinical manifestations, macrolide resistance patterns, and therapeutic approaches related to the MP pneumonia epidemic. Children and adolescents diagnosed with MP pneumonia in September–December 2023 were screened. Clinical data were retrospectively collected from 13 major hospitals using concordant microbiological criteria, including either a positive PCR result or four-fold increase in serological markers. Demographic characteristics, treatment modalities, and clinical outcomes were analyzed. Of the 474 screened patients, 374 (median age: 7.7 [IQR, 5.4–9.6] years; hospitalization rate: 88.6%) met the microbiological confirmation criteria. Most patients experienced fever (98.9%), and lobular/lobar consolidation (59.1%) was the dominant radiological finding. The macrolide resistance rate remained high at 87.0%; corticosteroids were widely used (55.6%) alongside macrolides, despite resistance. Patients with consolidation had prolonged fever (median 8 vs. 7 days, p = 0.020) and higher hospitalization rates (92.3% vs. 83.0%, p = 0.008). Macrolide resistance did not significantly influence radiological outcomes. This study highlights the ongoing challenge of macrolide resistance in MP pneumonia and need for tailored therapeutic approaches. Despite high resistance, macrolides remain commonly prescribed, often concurrently with corticosteroids.

Summary: To address the challenge of solid tumor targeting in CAR-T therapy, we utilized the A56 antigen, which is uniquely expressed on a diverse range of cancer cells following the systemic administration of an oncolytic vaccinia virus (OVV). Immunohistochemical assays precisely confirmed exclusive localization of A56 to tumor tissues. In vitro studies demonstrated a distinct superiority of A56-dependent CAR-T cytotoxicity across multiple cancer cell lines. Building on these in vitro observations, we strategically administered A56 CAR-T cells, OVV, and hydroxyurea (HU) combination in HCT-116 tumor-bearing non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, leading to a significant reduction in tumor size and an extended time to progression. Consequently, A56-targeting combinatorial immunotherapy provides the benefit of reducing inadvertent CAR-T effects on normal cells while preserving its effectiveness against cancer cells. Furthermore, our approach of implanting A56 via OVV on tumors facilitates a wide therapeutic application of CAR-T cells across various solid tumors.

Direct CO2 conversion into synthetic natural gas (SNG, CH4) with simultaneous small production of light paraffinic C2-C4 hydrocarbons to enhance a heating value of SNG was investigated with ordered mesoporous CoMnAl mixed metal oxides (denoted as m-CoMnAl). CO2 hydrogenation activity to form hydrocarbons with small CO byproduct formed by a reverse water gas shift reaction (RWGS) was strongly affected by the MnO2 promoter content in the ordered Co3O4-Al2O3 mesoporous structures. The m-CoMnAl structures with proper amount of Mn promoter were found to be effective to enhance CO2 conversion to methane with small amount of light hydrocarbons formation, which were mainly attributed to the presence of abundant oxygen vacant sites with a stable preservation of the partially oxidized cobalt nanoparticles in the ordered mesoporous Co3O4-Al2O3 structures even under a reductive hydrogenation condition. Selective methanation of CO2 was found to be more favorable on the highly reduced metallic cobalt nanoparticles formed with smaller amount of Mn promoter (m-CoMnAl(0.05)), however, excessive Mn content such as Mn/Co ratio > 1 (m-CoMnAl(1.0)) revealed less structural stability of ordered mesoporous structures with lower CO2 conversion with relatively higher CO selectivity of 1.4 % with lower olefin selectivity through severe phase segregations of the Co-Mn-Al mixed metal oxides with selective formations of MnCO3 phases.

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the deficiency of the survival motor neuron (SMN) protein, which leads to motor neuron dysfunction and muscle atrophy. In addition to the requirement for SMN in motor neurons, recent studies suggest that SMN deficiency in peripheral tissues plays a key role in the pathogenesis of SMA. Using limb mesenchymal progenitor cell (MPC)-specific SMN-depleted mouse models, we reveal that SMN reduction in limb MPCs causes defects in the development of bone and neuromuscular junction (NMJ). Specifically, these mice exhibited impaired growth plate homeostasis and reduced insulin-like growth factor (IGF) signaling from chondrocytes, rather than from the liver. Furthermore, the reduction of SMN in fibro-adipogenic progenitors (FAPs) resulted in abnormal NMJ maturation, altered release of neurotransmitters, and NMJ morphological defects. Transplantation of healthy FAPs rescued the morphological deterioration. Our findings highlight the significance of mesenchymal SMN in neuromusculoskeletal pathogenesis of SMA and provide insights into potential therapeutic strategies targeting mesenchymal cells for the treatment of SMA.

Ecklonia cava is a nutrient-rich algae species that contains abundant physiological phytochemicals, including peptides, carotenoids, fucoidans, and phlorotannins. However, elucidation of the antiviral effects of this algae and identification of new functional ingredients warrant further investigation. This study was aimed at investigating the potential anti-hepatitis A virus activities of extracts of E. cava prepared in different solvents. E. cava extracts were prepared using hot water and 70 % ethanol. The antioxidant activities of the extracts were confirmed by analyzing the total phenolic content, as well as 2,2-diphenyl-1-picrylhydrazyl and 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid radical scavenging activities. The inhibitory effects of the extracts against hepatitis A virus were analyzed using real-time polymerase chain reaction. The E. cava extract yield was 22.5–27.2 % depending on the extraction solvent. The 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity was 70.44 % and 91.05 % for hot water and ethanol extracts at a concentration of 1000 ppm. The 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid radical scavenging activity of the ethanol extract was the highest (93.57 %) at 1000 μg/mL. Fourier-transform infrared was used to identify the functional groups (phlorotannin and alginate) in the extraction solvents. Ultra-high performance liquid chromatography with quadrupole time-of-flight tandem mass spectrometry analysis revealed a potential bioactive compound previously unidentified in E. cava. Finally, we identified the antiviral activity of E. cava extracts against hepatitis A virus replication. These findings demonstrate that E. cava could be used as an anti-hepatitis A virus functional food and biological material.

Ochratoxin A (OTA), a mycotoxin found in foods, has a deleterious effect on female reproduction owing to its endocrine-disrupting activity mediated through endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production. However, the mechanisms of OTA-induced ER stress in pig embryos during in vitro culture (IVC) are not yet fully understood. In the present study, porcine embryos were cultured for two days in an IVC medium supplemented with 0.5, 1.0, and 5.0 μM OTA, which led to an OTA-induced reduction in the developmental rate of blastocysts. The mRNA-seq transcriptome analysis revealed that the reduced blastocyst development ability of OTA-exposed porcine embryos was caused by ER stress, ultimately resulting in the accumulation of ROS and the occurrence of apoptosis. The expression levels of some UPR/PERK signaling-related genes (DDIT3, EIF2AK3, EIF2S1, NFE2L2, ATF4, EIF2A, and KEAP1) were found to differ in OTA-exposed pig embryos. OTA induces DNA damage by triggering an increase in RAD51/γ-H2AX levels and suppressing p-NRF2 activity. This effect is mediated through intracellular ROS and superoxide accumulation in the nuclei of porcine embryos. The cytotoxicity of OTA increased the activation of the PERK signal pathways (p-PERK, PERK, p-eIF2α, eIF2α, ATF4, and CHOP) in porcine embryos, with abnormal distribution of the ER observed around the nucleus. Collectively, our findings indicate that ER stress is a major cause of decline in the development of porcine embryos exposed to OTA. Therefore, OTA exposure induces ER stress and DNA damage via oxidative stress by disrupting PERK/NRF2 signaling activity in the developmental competence of porcine embryos during IVC.

Summary: To investigate whether the defects in transient receptor potential canonical 4 (TRPC4), which is strongly expressed in the hippocampus, are implicated in ASD, we examined the social behaviors of mice in which Trpc4 was deleted (Trpc4−/−). Trpc4−/− mice displayed the core symptoms of ASD, namely, social disability and repetitive behaviors. In microarray analysis of the hippocampus, microRNA (miR)-138-2, the precursor of miR-138, was upregulated in Trpc4−/− mice. We also found that binding of Matrin3 (MATR3), a selective miR-138-2 binding nuclear protein, to miR-138-2 was prominently enhanced, resulting in the downregulation of miR-138 in Trpc4−/− mice. Some parameters of the social defects and repetitive behaviors in the Trpc4−/− mice were rescued by increased miR-138 levels following miR-138-2 infusion in the hippocampus. Together, these results suggest that Trpc4 regulates some signaling components that oppose the development of social behavioral deficits through miR-138 and provide a potential therapeutic strategy for ASD.

BackgroundImmune checkpoint inhibitors (ICIs) are one of the main pillars of cancer therapy. Since other studies such as clinical trial and retrospective study have limitations for detecting the immune-related adverse events (irAEs) characterized by unpredictable onset, nonspecific symptoms and wide clinical spectrum, we aimed to identify the incidence of irAEs and to detect and evaluate the signals using real-world data.MethodsCancer patients treated with anticancer medications were analyzed using the nationwide health insurance claims database of South Korea from 2017 to 2019, and Clinical Data Warehouse (CDW) database of Asan Medical Center (AMC), a tertiary referral hospital, from 2012 to 2019. AEs of ICI users were compared with those of non-ICI anticancer medication users. PD-1 inhibitors (nivolumab and pembrolizumab) and PD-L1 inhibitors (atezolizumab) were evaluated. We defined an AE as a newly added diagnosis after the ICI prescription using an ICD-10 diagnostic code. A signal was defined as an AE that was detected by any one of the four indices of data mining: hazard ratio (HR), proportional claims ratio (PCR), claims odds ratio (COR), or information component (IC). All detected signals were reviewed and classified into well-known or potential irAEs. Signal verification was performed for targeted AEs using CDW of AMC using diagnostic codes and text mining.ResultsWe identified 118 significant signals related to ICI use. We detected 31 well-known irAEs, most of which were endocrine diseases and skin diseases. We also detected 33 potential irAEs related to disorders in the nervous system, eye, circulatory system, digestive system, skin and subcutaneous tissues, and bones. Especially, portal vein thrombosis and bone disorders such as osteoporosis with pathological fracture and fracture of shoulder, upper arm, femur, and lower leg showed high HR in ICI users than in non-ICI users. The signals from hospital database were verified using diagnostic codes and text mining.ConclusionThis real-world data analysis demonstrated an efficient approach for signal detection and evaluation of ICI use. An effective real-world pharmacovigilance system of the nationwide claims database and the EMR could complement each other in detecting significant AE signals.

Abstract Background The frequency, clinical characteristics, and associated symptoms of comorbid tic disorders in individuals with autism spectrum disorder (ASD) remain unclear. Methods We included subsets of individuals from a larger genetic study who were diagnosed with ASD (n = 679; age: 4–18 years) and completed the Yale Global Tic Severity Scale (YGTSS) questionnaire. Based on the YGTSS score, the individuals were divided into two groups: ASD only (n = 554) and ASD with tics (n = 125). Individuals were assessed using the verbal and non-verbal intelligence quotient (IQ), Vineland Adaptive Behavior Scale (VABS-2), Social Responsiveness Scale-2 (SRS-2), Child Behavior Checklists (CBCL), and Yale-Brown Obsessive–Compulsive Scale (YBOCS), followed by between-group comparisons. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 26. Results Tic symptoms were observed in 125 (18.4%) participants; among them, most participants presented both motor and vocal tics (n = 40, 40.0%). The ASD with tics group had a significantly higher average age and full-scale IQ score than the ASD only group. After adjusting for age, the ASD with tics group had significantly higher scores in the SRS-2, CBCL, and YBOCS subdomains than the ASD only group. Furthermore, all variables except the non-verbal IQ and VABS-2 scores were positively correlated with the YGTSS total score. Finally, the proportion of tic symptoms was significantly higher among individuals with a higher IQ score (≥ 70). Conclusions The IQ score was positively correlated with the proportion of tic symptoms among individuals with ASD. Moreover, the severity of the core and comorbid symptoms of ASD was associated with the occurrence and severity of tic disorders. Our findings suggest the need for appropriate clinical interventions for individuals with ASD. Trial registration This study retrospectively registered participants

Abstract Background Sarcopenia is characterized by a progressive decrease in skeletal muscle mass and function with age. Given that sarcopenia is associated with various metabolic disorders, effective metabolic biomarkers for its early detection are required. We aimed to investigate the metabolic biomarkers related to sarcopenia in elderly men and perform experimental studies using metabolomics. Methods Plasma metabolites from 142 elderly men, comprising a sarcopenia group and an age‐matched control group, were measured using global metabolome profiling. Muscle and plasma samples from an aging mouse model of sarcopenia, as well as cell media and cell lysates during myoblast differentiation, were analysed based on targeted metabolome profiling. Based on these experimental results, fatty acid amides were quantified from human plasma as well as human muscle tissues. The association of fatty acid amide levels with sarcopenia parameters was evaluated. Results Global metabolome profiling showed that fatty acid amide levels were significantly different in the plasma of elderly men with sarcopenia (all Ps

Purpose: Total kidney volume (TKV) measurement is crucial for selecting treatment candidates in autosomal dominant polycystic kidney disease (ADPKD). We developed and investigated the performance of fully-automated 3D-volumetry model and applied it to software as a service (SaaS) for clinical support on tolvaptan prescription in ADPKD patients. Materials and Methods: Computed tomography scans of ADPKD patients taken between January 2000 and June 2022 were acquired from seven institutions. The quality of the images was manually reviewed in advance. The acquired dataset was split into training, validation, and test datasets at a ratio of 8.5:1:0.5. Convolutional, neural network-based automatic segmentation model was trained to obtain 3D segment mask for TKV measurement. The algorithm consisted of three steps: data preprocessing, ADPKD area extraction, and post-processing. After performance validation with the Dice score, 3D-volumetry model was applied to SaaS which is based on Mayo imaging classification for ADPKD. Results: A total of 753 cases with 95,117 slices were included. The differences between the ground-truth ADPKD kidney mask and the predicted ADPKD kidney mask were negligible, with intersection over union >0.95. The post-process filter successfully removed false alarms. The test-set performance was homogeneously equal and the Dice score of the model was 0.971; after post-processing, it improved to 0.979. The SaaS calculated TKV from uploaded Digital Imaging and Communications in Medicine images and classified patients according to height-adjusted TKV for age. Conclusions: Our artificial intelligence-3D volumetry model exhibited effective, feasible, and non-inferior performance compared with that of human experts and successfully predicted the rapid ADPKD progressor.

Abstract Insulin-like growth factor binding protein-3 (IGFBP-3) has been known to inhibit cell proliferation and exert tumor-suppressing effects depending on the cell type. In this study, we aimed to show that IGFBP-3 induces cellular senescence via suppression of the telomerase activity, thereby inhibiting MCF-7 breast cancer cell proliferation. We found that the induction of IGFBP-3 in MCF-7 cells enhanced the loss of cell viability. Flow cytometry revealed a higher percentage of non-cycling cells among IGFBP-3-expressing cells than among controls. IGFBP-3 induction also resulted in morphological alterations, such as a flattened cytoplasm and increased granularity, suggesting that IGFBP-3 induces a senescence-like phenotype. The percentage of IGFBP-3 expressing cells with senescence-associated β-galactosidase activity was 3.4 times higher than control cells. Telomeric repeat amplification and real-time PCR showed that IGFBP-3 decreased telomerase activity by reducing the levels of the RNA component (hTR) and catalytic protein component with reverse transcriptase activity (hTERT) of telomerase in a dose-dependent manner. These results suggest that IGFBP-3 is a negative regulator of MCF-7 breast cancer cell growth by inducing senescence through telomerase suppression.

Abstract Objectives There is little research examining transnational prenatal care (TPC) (i.e., prenatal care in more than one country) among migrant women. Using data from the Migrant-Friendly Maternity Care (MFMC) - Montreal project, we aimed to: (1) Estimate the prevalence of TPC, including TPC-arrived during pregnancy and TPC-arrived pre-pregnancy, among recently-arrived migrant women from low- and middle-income countries (LMICs) who gave birth in Montreal, Canada; (2) Describe and compare the socio-demographic, migration and health profiles and perceptions of care during pregnancy in Canada between these two groups and migrant women who received no TPC (i.e., only received prenatal care in Canada); and (3) Identify predictors of TPC-arrived pre-pregnancy vs. No-TPC. Methods The MFMC study used a cross-sectional design. Data were gathered from recently-arrived (

Background/Aims We conducted a nationwide population-based study to investigate incidence rates of colorectal and biliary cancers according to accompanying primary sclerosing cholangitis in Korean ulcerative colitis patients. Methods We used the Health Insurance Review and Assessment claim database from January 2007 to April 2020. Standardized incidence ratios of colorectal and biliary cancers in ulcerative colitis patients were calculated. Results Among 35,189 newly diagnosed ulcerative colitis patients, 1,224 patients were diagnosed with primary sclerosing cholangitis. During the study period, 122 and 52 patients were diagnosed with colorectal and biliary cancers, respectively. Incidences of colorectal cancer were not higher in ulcerative colitis patients than those in the general population (standardized incidence ratios, 0.83; 95% confidence interval, 0.69–0.99), regardless of accompanied primary sclerosing cholangitis (standardized incidence ratio, 0.73; 95% confidence interval, 0.24–1.71). While incidences of biliary cancer were not higher in ulcerative colitis patients than those in the general population (standardized incidence ratio, 1.14; 95% confidence interval, 0.80–1.58), these were much higher with accompanied primary sclerosing cholangitis (standardized incidence ratio, 10.07; 95% confidence interval, 5.75–16.36). Cumulative incidences of colorectal and biliary cancers increased in patients who were diagnosed with ulcerative colitis at an older age. Conclusions In Korean ulcerative colitis patients, colorectal cancer incidences were not higher than those in the general population regardless of accompanied primary sclerosing cholangitis. However, biliary cancer incidences were much higher in ulcerative colitis patients with primary sclerosing cholangitis than in those without, or in the general population.

Background Nafamostat mesylate is widely used as an anticoagulant in continuous renal replacement therapy (CRRT). The generic versions of nafamostat mesylate have identical main components to the original product. However, it is questionable whether the generic versions have the same efficacy as the original. Therefore, we compared the circuit patency and exchange rates of the original nafamostat mesylate and a generic version to determine which is more efficient as an anticoagulant in CRRT. Methods This retrospective study enrolled 1,255 patients hospitalized to receive CRRT who received the original version of nafamostat mesylate or a generic version between January 2010 and July 2018. We evaluated the filter lifespan, number of filters used per day, mean blood flow, and transmembrane pressure (TMP). Results The mean filter lifespan was 36.3±15.1 hours in the original product group and 22.2±16.2 hours in the generic product group, which was not a statistically significant difference (p=0.060). The mean TMP was 62.2±47.3 mmHg in the original product group and 74.5±45.6 mmHg in the generic product group (p=0.045). Conclusions This retrospective study suggests no meaningful difference in filter lifespan between the original and generic versions of nafamostat mesylate. However, TMP was lower in the original product group than in the generic product group.

Background: The purpose of this study was to investigate the effect of salad dressings on the flowable composite resin surface and the erosion-inhibitory effect of calcium.Methods: The experiment included six groups: oriental dressing, balsamic dressing, lemon-garlic dressing, lemon-garlic dressing supplemented with 3% calcium, mineral water as a negative control group, and orange juice as a positive control group. pH and titratable acidity were measured. The prepared specimens were immersed in the experimental solutions for 1, 3, 5, 15, and 30 minutes. The surface microhardness was measured using the Vickers hardness number before and after the treatment, and the surface of the specimens was observed using a scanning electron microscope (SEM). Results: The pH values of the experimental groups in increasing order were as follows: lemon-garlic dressing (2.49±0.03), balsamic dressing (3.12±0.06), lemon-garlic dressing ＋3% calcium (3.27±0.09), oriental dressing (3.75±0.03), orange juice (3.82±0.02), and mineral water (7.32±0.16). The largest surface hardness reduction value was shown in lemon-garlic dressing (−9.61±1.16), followed by balsamic dressing (−9.17±1.63), oriental dressing (−8.62±1.09), orange juice (−8.19±1.36), lemon-garlic dressing +3% calcium (−6.76±1.23), and mineral water (−1.63±2.47). According to the SEM findings, the experimental and positive control groups showed rough surfaces and micropores, whereas the negative control group showed a smooth surface. Moreover, the lemon-garlic dressing with +3% calcium showed fewer micropores and a smoother surface than the lemon-garlic dressing. Conclusion: The intake of salad dressings at a low pH could weaken the surface microhardness of the flowable composite resin. However, adding calcium to these salad dressings can reduce the risk of microhardness reduction on the flowable composite resin surface.

Abstract Determining the severity of dental crowding and the necessity of tooth extraction for orthodontic treatment planning are time-consuming processes and there are no firm criteria. Thus, automated assistance would be useful to clinicians. This study aimed to construct and evaluate artificial intelligence (AI) systems to assist with such treatment planning. A total of 3,136 orthodontic occlusal photographs with annotations by two orthodontists were obtained. Four convolutional neural network (CNN) models, namely ResNet50, ResNet101, VGG16, and VGG19, were adopted for the AI process. Using the intraoral photographs as input, the crowding group and the necessity of tooth extraction were obtained. Arch length discrepancy analysis with AI-detected landmarks was used for crowding categorization. Various statistical and visual analyses were conducted to evaluate the performance. The maxillary and mandibular VGG19 models showed minimum mean errors of 0.84 mm and 1.06 mm for teeth landmark detection, respectively. Analysis of Cohen’s weighted kappa coefficient indicated that crowding categorization performance was best in VGG19 (0.73), decreasing in the order of VGG16, ResNet101, and ResNet50. For tooth extraction, the maxillary VGG19 model showed the highest accuracy (0.922) and AUC (0.961). By utilizing deep learning with orthodontic photographs, dental crowding categorization and diagnosis of orthodontic extraction were successfully determined. This suggests that AI can assist clinicians in the diagnosis and decision making of treatment plans.

Abstract Background N-methyl-d-aspartate receptors (NMDARs) are considered to be involved in several physiological and pathophysiological processes in addition to the progression of neurological disorders. However, how NMDARs are involved in the glycolytic phenotype of M1 macrophage polarization and the possibility of using them as a bio-imaging probe for macrophage-mediated inflammation remain unclear. Methods We analyzed cellular responses to NMDAR antagonism and small interfering RNAs using mouse bone marrow-derived macrophages (BMDMs) treated with lipopolysaccharide (LPS). An NMDAR targeting imaging probe, N-TIP, was produced via the introduction of NMDAR antibody and the infrared fluorescent dye FSD Fluor™ 647. N-TIP binding efficiency was tested in intact and LPS-stimulated BMDMs. N-TIP was intravenously administered to mice with carrageenan (CG)- and LPS-induced paw edema, and in vivo fluorescence imaging was conducted. The anti-inflammatory effects of dexamethasone were evaluated using the N-TIP-mediated macrophage imaging technique. Results NMDARs were overexpressed in LPS-treated macrophages, subsequently inducing M1 macrophage polarization. Mechanistically, NMDAR-mediated Ca2+ accumulation resulted in LPS-stimulated glycolysis via upregulation of PI3K/AKT/mTORC1 signaling. In vivo fluorescence imaging with N-TIP showed LPS- and CG-induced inflamed lesions at 5 h post-inflammation, and the inflamed lesions could be detected until 24 h. Furthermore, our N-TIP-mediated macrophage imaging technique helped successfully visualize the anti-inflammatory effects of dexamethasone in mice with inflammation. Conclusion This study demonstrates that NMDAR-mediated glycolysis plays a critical role in M1 macrophage-related inflammation. Moreover, our results suggest that NMDAR targeting imaging probe may be useful in research on inflammatory response in vivo.

Abstract Background Although metastasis is the foremost cause of cancer-related death, a specialized mechanism that reprograms anchorage dependency of solid tumor cells into circulating tumor cells (CTCs) during metastatic dissemination remains a critical area of challenge. Methods We analyzed blood cell-specific transcripts and selected key Adherent-to-Suspension Transition (AST) factors that are competent to reprogram anchorage dependency of adherent cells into suspension cells in an inducible and reversible manner. The mechanisms of AST were evaluated by a series of in vitro and in vivo assays. Paired samples of primary tumors, CTCs, and metastatic tumors were collected from breast cancer and melanoma mouse xenograft models and patients with de novo metastasis. Analyses of single-cell RNA sequencing (scRNA-seq) and tissue staining were performed to validate the role of AST factors in CTCs. Loss-of-function experiments were performed by shRNA knockdown, gene editing, and pharmacological inhibition to block metastasis and prolong survival. Results We discovered a biological phenomenon referred to as AST that reprograms adherent cells into suspension cells via defined hematopoietic transcriptional regulators, which are hijacked by solid tumor cells to disseminate into CTCs. Induction of AST in adherent cells 1) suppress global integrin/ECM gene expression via Hippo-YAP/TEAD inhibition to evoke spontaneous cell–matrix dissociation and 2) upregulate globin genes that prevent oxidative stress to acquire anoikis resistance, in the absence of lineage differentiation. During dissemination, we uncover the critical roles of AST factors in CTCs derived from patients with de novo metastasis and mouse models. Pharmacological blockade of AST factors via thalidomide derivatives in breast cancer and melanoma cells abrogated CTC formation and suppressed lung metastases without affecting the primary tumor growth. Conclusion We demonstrate that suspension cells can directly arise from adherent cells by the addition of defined hematopoietic factors that confer metastatic traits. Furthermore, our findings expand the prevailing cancer treatment paradigm toward direct intervention within the metastatic spread of cancer.

The commercial AZ91 alloy and nonflammable SEN9 (AZ91–0.3Ca–0.2Y, wt%) alloy are extruded at 300 °C and 400 °C. Their microstructure, tensile and compressive properties, and low-cycle fatigue (LCF) properties are investigated, with particular focus on the influence of the extrusion temperature. In the AZ91 and SEN9 materials extruded at 300 °C (300-materials), numerous fine Mg17Al12 particles are inhomogeneously distributed owing to localized dynamic precipitation during extrusion, unlike those extruded at 400 °C (400-materials). These fine particles suppress the coarsening of recrystallized grains, decreasing the average grain size of 300-materials. Although the four extruded materials have considerably different microstructures, the difference in their tensile yield strengths is insignificant because strong grain-boundary hardening and precipitation hardening effects in 300-materials are offset almost completely by a strong texture hardening effect in 400-materials. However, owing to their finer grains and weaker texture, 300-materials have higher compressive yield strengths than 400-materials. During the LCF tests, {10–12} twinning is activated at lower stresses in 400-materials than in 300-materials. Because the fatigue damage accumulated per cycle is smaller in 400-materials, they have longer fatigue lives than those of 300-materials. A fatigue life prediction model for the investigated materials is established on the basis of the relationship between the total strain energy density (∆Wt) and the number of cycles to fatigue failure (Nf), and it is expressed through a simple equation (∆Wt = 10·Nf−0.59). This model enables fatigue life prediction of both the investigated alloys regardless of the extrusion temperature and strain amplitude.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is frequently accompanied by comorbidities, with the management of these comorbidities crucial for clinical outcomes. This study investigated the prevalence, incidence, changes over time, and clinical impact of comorbidities in IPF patients, based on nationwide claims data in South Korea. Methods This retrospective cohort study utilised nationwide health claim data in South Korea between 2011 and 2019. Patients with IPF were defined as those with ICD-10 code J84.1 and Rare Intractable Disease code V236 who made at least one claim per year. Patients were classified by sex, age, pirfenidone use and burden of comorbidities, and differences among groups were determined. Results The yearly prevalence rate of IPF increased from 7.50 to 23.20 per 100,000 people, and the yearly incidence rate increased from 3.56 to 7.91 per 100,000 person-years over time. The most common respiratory comorbidity was chronic obstructive pulmonary disease (37.34%), followed by lung cancer (3.34%), whereas the most common non-respiratory comorbidities were gastro-oesophageal reflux disease (70.83%), dyslipidaemia (62.93%) and hypertension (59.04%). The proportion of some comorbidities differed by sex, age and use of pirfenidone. The proportion of lung cancer was higher in patients treated with pirfenidone, whereas the proportion of anxiety and depression were lower in patients not treated with pirfenidone. Charlson comorbidity index ≥ 4 was associated with increases in hospitalisations and total medical costs. Conclusions The yearly prevalence and incidence of IPF and comorbidities in Korea increased over time. These comorbidities affected the use of pirfenidone and medical resources.

The effects of pre-existing {10–12} extension twins on the precipitation behavior of an extruded AZ80 material during aging and on its mechanical properties after peak aging are investigated. The material containing {10–12} twins—which are formed by compression before aging (twinned material)—has a finer grain size and higher dislocation density than the extruded material. Although the peak hardnesses of the twinned and extruded materials are almost the same, the time to reach the peak hardness is considerably shorter in the former material than in the latter (4 h and 24 h, respectively). In the twinned material, the high dislocation density of the {10–12} twins promotes continuous precipitation, which results in the formation of numerous fine Mg17Al12 precipitates within the twins in the early stage of aging. The formation of these continuous precipitates reduces the driving force for discontinuous precipitation, which consequently suppresses the formation and growth of coarse Mg17Al12 precipitates at the grain boundaries. Despite its shorter peak-aging time, the 4 h-peak-aged twinned material shows higher tensile strength and elongation than the 24 h-peak-aged extruded material. These higher mechanical properties of the former material are attributed primarily to the presence of more abundant fine continuous precipitates, which are effective in strengthening the material, and less abundant coarse discontinuous precipitates, which can act as crack initiation sites. These results demonstrate that the introduction of {10–12} twins into wrought Mg–Al-based alloys can accelerate the Mg17Al12 precipitation kinetics considerably and improve the strength and ductility of the peak-aged alloys simultaneously.

Abstract Glaucoma is a multifactorial disease where various systemic features are involved in the progression of the disease. Based on initial systemic profiles in electronic medical records, this study aimed to develop a model predicting factors of long-term rapid retinal nerve fiber layer (RNFL) thinning over 5 years in 505 patients with primary open-angle glaucoma. Eyes with faster or slower RNFL thinning were stratified using a decision tree model, and systemic and ophthalmic data were incorporated into the models based on random forest and permutation methods, with the models interpreted by Shapley additive explanation plots (SHAP). According to the decision tree, a higher lymphocyte ratio (> 34.65%) was the most important systemic variable discriminating faster or slower RNFL thinning. Higher mean corpuscular hemoglobin (> 32.05 pg) and alkaline phosphatase (> 88.0 IU/L) concentrations were distinguishing factors in the eyes with lymphocyte ratios > 34.65% and

Abstract Background The pathogenesis of diabetic kidney disease (DKD) is complex, involving metabolic and hemodynamic factors. Although DKD has been established as a heritable disorder and several genetic studies have been conducted, the identification of unique genetic variants for DKD is limited by its multiplex classification based on the phenotypes of diabetes mellitus (DM) and chronic kidney disease (CKD). Thus, we aimed to identify the genetic variants related to DKD that differentiate it from type 2 DM and CKD. Methods We conducted a large-scale genome-wide association study mega-analysis, combining Korean multi-cohorts using multinomial logistic regression. A total of 33,879 patients were classified into four groups—normal, DM without CKD, CKD without DM, and DKD—and were further analyzed to identify novel single-nucleotide polymorphisms (SNPs) associated with DKD. Additionally, fine-mapping analysis was conducted to investigate whether the variants of interest contribute to a trait. Conditional analyses adjusting for the effect of type 1 DM (T1D)-associated HLA variants were also performed to remove confounding factors of genetic association with T1D. Moreover, analysis of expression quantitative trait loci (eQTL) was performed using the Genotype-Tissue Expression project. Differentially expressed genes (DEGs) were analyzed using the Gene Expression Omnibus database (GSE30529). The significant eQTL DEGs were used to explore the predicted interaction networks using search tools for the retrieval of interacting genes and proteins. Results We identified three novel SNPs [rs3128852 (P = 8.21×10−25), rs117744700 (P = 8.28×10−10), and rs28366355 (P = 2.04×10−8)] associated with DKD. Moreover, the fine-mapping study validated the causal relationship between rs3128852 and DKD. rs3128852 is an eQTL for TRIM27 in whole blood tissues and HLA-A in adipose-subcutaneous tissues. rs28366355 is an eQTL for HLA-group genes present in most tissues. Conclusions We successfully identified SNPs (rs3128852, rs117744700, and rs28366355) associated with DKD and verified the causal association between rs3128852 and DKD. According to the in silico analysis, TRIM27 and HLA-A can define DKD pathophysiology and are associated with immune response and autophagy. However, further research is necessary to understand the mechanism of immunity and autophagy in the pathophysiology of DKD and to prevent and treat DKD.

Abstract This study aimed to investigate the risk of all-cause mortality and incidence of CVD according to metabolic health and body mass index (BMI) in Korean adults. This study was retrospectively designed using the National Health Insurance Service-National Health Screening Cohort data. Participants were divided into six groups according to two category of metabolic syndrome and three categories of BMI. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the composite outcome (all-cause mortality and incidence of CVDs) were estimated using multivariable Cox proportional hazards regression models. 151,706 participants aged ≥ 40 years were enrolled; median follow-up period was 9.7 years in the study. Compared to metabolically healthy normal weight, the fully adjusted HRs (95% CIs) of metabolically healthy overweight, metabolically healthy obese, metabolically unhealthy normal weight, metabolically unhealthy overweight, and metabolically unhealthy obese for composite outcome were 1.07 (1.03–1.12), 1.12 (1.07–1.17), 1.33 (1.25–1.41), 1.28 (1.22–1.34), and 1.31 (1.26–1.37), respectively, in men, and 1.10 (1.05–1.16), 1.22 (1.16–1.29), 1.34 (1.26–1.43), 1.27 (1.19–1.34), and, 1.40 (1.34–1.47), respectively, in women. High BMI and metabolic unhealthiness were associated with an increased risk on the composite of all-cause mortality and incidence of CVD in both sexes.

AbstractCassia tora Linn. is a medicinal herb that has traditionally been used to prevent diseases. The study investigated the changes in bioactive compounds of Cassia tora seeds during 3-days of germination. The seeds were thoroughly cleaned, soaked in deionized water at 20 °C for 2 h, and germinated at 25 °C and 90% relative humidity in a seed germinator. Germinating C. tora seeds were picked up at 24 h intermissions over 3-day germination duration. The germinating C. tora was freeze-dried and pulverized through a 1 mm mesh screen. During the germination process, the crude ash, crude fat, and crude protein content of C. tora seeds increased slightly. The main carotenoid compounds identified in this study were lutein and β-carotenes, and the total carotenoid content increased up to 4.35 µg/g after 72-hours of germination, which was 1.73-times higher compared to that in raw C. tora seeds. The anthocyanin and vitamin C content also increased during the germination period, being 1.44-times and 1.72-times, respectively, higher after 72-hours of germination than that in the raw C. tora seeds. In addition, phenolics and flavonoids in C. tora seeds had a tendency to increase after germination, subsequently increasing in vitro antioxidant activities (ABTS and DPPH-radical scavenging activities). Proper germination of C. tora might be a convenient and efficient method to increase antioxidant bioactive compounds in our diet to exploit the related health benefits.

Age‐related macular degeneration (AMD), the leading cause of vision loss among older individuals, is characterized by damage to photoreceptors and retinal pigment epithelial cells (RPEs). Oxidative stress and chronic inflammation in the retina play notable roles in AMD pathogenesis, rendering them attractive therapeutic targets. Cerium oxide nanoparticles (CeNPs) have shown promise in scavenging reactive oxygen species (ROS) by mimicking antioxidant enzymes, whereas mesoporous materials have emerged as versatile drug carriers. Herein, mesoporous CeNPs (mCeNPs) that integrate the advantages of CeNPs and mesoporous materials are presented. The mCeNPs can be synthesized using 1,1′‐carbonyldiimidazole and imidazole in acetone without heating and pressurization. The resulting mCeNPs exhibit mesoporous structures comprising assembled small CeNPs, exerting excellent ROS‐scavenging capabilities, biocompatibility, and cytoprotective and anti‐inflammatory effects against H2O2‐induced damage in RPEs. Using a sodium iodate‐induced AMD mouse model, it is demonstrated that intravitreal mCeNP administration can exhibit disease‐preventive effects. These findings indicate the therapeutic potential of mCeNPs against AMD.

Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrPSc) that forms insoluble amyloids to impair brain function. PrPSc interacts with the non-pathogenic, cellular prion protein (PrPC) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrPSc but no pharmacological intervention was well established thus far. We, here, report that acylthiosemicarbazides inhibit the prion aggregation. Compounds 7x and 7y showed almost perfect inhibition (EC50 = 5 µM) in prion aggregation formation assay. The activity was further confirmed by atomic force microscopy, semi-denaturing detergent agarose gel electrophoresis and real-time quaking induced conversion assay (EC50 = 0.9 and 2.8 µM, respectively). These compounds also disaggregated pre-existing aggregates in vitro and one of them decreased the level of PrPSc in cultured cells with permanent prion infection, suggesting their potential as a treatment platform. In conclusion, hydroxy-2-naphthoylthiosemicarbazides can be an excellent scaffold for the discovery of anti-prion therapeutics.

Antibiotic-induced gut microbiota disruption constitutes a major risk factor for Clostridioides difficile infection (CDI). Further, antibiotic therapy, which is the standard treatment option for CDI, exacerbates gut microbiota imbalance, thereby causing high recurrent CDI incidence. Consequently, probiotic-based CDI treatment has emerged as a long-term management and preventive option. However, the mechanisms underlying the therapeutic effects of probiotics for CDI remain uninvestigated, thereby creating a knowledge gap that needs to be addressed. To fill this gap, we used a multiomics approach to holistically investigate the mechanisms underlying the therapeutic effects of probiotics for CDI at a molecular level. We first screened Bifidobacterium longum owing to its inhibitory effect on C. difficile growth, then observed the physiological changes associated with the inhibition of C. difficile growth and toxin production via a multiomics approach. Regarding the mechanism underlying C. difficile growth inhibition, we detected a decrease in intracellular adenosine triphosphate (ATP) synthesis due to B. longum–produced lactate and a subsequent decrease in (deoxy)ribonucleoside triphosphate synthesis. Via the differential regulation of proteins involved in translation and protein quality control, we identified B. longum–induced proteinaceous stress. Finally, we found that B. longum suppressed the toxin production of C. difficile by replenishing proline consumed by it. Overall, the findings of the present study expand our understanding of the mechanisms by which probiotics inhibit C. difficile growth and contribute to the development of live biotherapeutic products based on molecular mechanisms for treating CDI.

Objectives: Chronic cough is a frequent condition worldwide that significantly impairs quality of life. Herbal medicine (HM) has been used to treat chronic cough due to the limited effectiveness of conventional medications. This study aimed to summarize and determine the effects of HM on patients with chronic cough.Methods: A comprehensive search of 11 databases was conducted to find randomized controlled clinical trials (RCTs) that reported the effects of HM for patients with chronic cough on 16 March 2023. The primary outcome was cough severity, and the secondary outcomes included cough-related quality of life, cough frequency, total effective rate (TER), and cough recurrence rate. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool, and the certainty of the evidence for effect estimates was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations tool.Results: A total of 80 RCTs comprising 7,573 patients were included. When HM was used as an alternative therapy to conventional medication, there were inconsistent results in improving cough severity. However, HM significantly improved cough-related quality of life and TER and significantly lowered the cough recurrence rate compared with conventional medication. When used as an add-on therapy to conventional medication, HM significantly improved cough severity, cough-related quality of life, and TER and significantly lowered the recurrence rate. In addition, HM had a significantly lower incidence of adverse events when used as an add-on or alternative therapy to conventional medication. The subgroup analysis according to age and cause of cough also showed a statistically consistent correlation with the overall results. The certainty of the evidence for the effect of HM was generally moderate to low due to the risk of bias in the included studies.Conclusion: HM may improve cough severity and cough-related quality of life, and lower the cough recurrence rate and incidence of adverse events in patients with chronic cough. However, due to the high risk of bias and clinical heterogeneity of the included studies, further high-quality placebo-controlled clinical trials should be conducted using a validated and objective assessment tool.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023418736, CRD42023418736.

We identified a new human voltage-gated potassium channel blocker, NnK-1, in the jellyfish Nemopilema nomurai based on its genomic information. The gene sequence encoding NnK-1 contains 5408 base pairs, with five introns and six exons. The coding sequence of the NnK-1 precursor is 894 nucleotides long and encodes 297 amino acids containing five presumptive ShK-like peptides. An electrophysiological assay demonstrated that the fifth peptide, NnK-1, which was chemically synthesized, is an effective blocker of hKv1.3, hKv1.4, and hKv1.5. Multiple-sequence alignment with cnidarian Shk-like peptides, which have Kv1.3-blocking activity, revealed that three residues (3Asp, 25Lys, and 34Thr) of NnK-1, together with six cysteine residues, were conserved. Therefore, we hypothesized that these three residues are crucial for the binding of the toxin to voltage-gated potassium channels. This notion was confirmed by an electrophysiological assay with a synthetic peptide (NnK-1 mu) where these three peptides were substituted with 3Glu, 25Arg, and 34Met. In conclusion, we successfully identified and characterized a new voltage-gated potassium channel blocker in jellyfish that interacts with three different voltage-gated potassium channels. A peptide that interacts with multiple voltage-gated potassium channels has many therapeutic applications in various physiological and pathophysiological contexts.