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Shinwon Park,1,* Haejin Hong,1,2,* Rye Young Kim,1,3,* Jiyoung Ma,1 Suji Lee,1 Eunji Ha,1,2 Sujung Yoon,1,2 Jungyoon Kim1,2 1Ewha Brain Institute, Ewha Womans University, Seoul, South Korea; 2Department of Brain and Cognitive Sciences, Ewha Womans University, Seoul, South Korea; 3Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, South Korea*These authors contributed equally to this workCorrespondence: Sujung Yoon Email sujungjyoon@ewha.ac.krJungyoon Kim Email jungyoon.kimm@ewha.ac.krPurpose: To investigate the cerebral blood flow (CBF) alterations associated with poor sleep quality and memory performance in firefighters.Participants and Methods: Thirty-seven firefighters (the FF group) and 37 non-firefighter controls (the control group) with sleep complaints were enrolled in this study. We performed brain arterial spin labeling perfusion magnetic resonance imaging (MRI) and compared the CBF between the two groups using whole-brain voxel-wise analyses. Self-reported sleep problems and actigraphy-measured sleep parameters, including the sleep efficiency, wake after sleep onset (WASO), total sleep time, and sleep latency, were assessed. Spatial working memory and learning performances were evaluated on the day of the MRI scan.Results: The FF group, relative to the control group, had lower CBF in the right hemispheric regions: Middle temporal/lateral occipital, orbitofrontal, and insular cortices. Lower CBF in the right orbitofrontal cortex was linearly associated with poor sleep quality, as indicated by lower sleep efficiency and longer WASO. The CBF of the right insular cortex was also associated with longer WASO. Despite comparable degrees of self-reported sleep problems between the two groups, the FF group had lower sleep efficiency and longer WASO in the actigraphy, and lower spatial working memory and learning performance, relative to the control group. Poor sleep efficiency was linearly associated with lower spatial working memory performance.Conclusion: These results demonstrated an association of poor sleep quality with decreased brain perfusion in the right orbitofrontal and insular cortices, as well as with reduced working memory performance.Keywords: firefighters, sleep efficiency, wake after sleep onset, cerebral blood flow, arterial spin labeling, perfusion magnetic resonance imaging

Sang Min Lee,1 Eunhee Ha,2 Jae-Hong Ryoo3 1Department of Psychiatry, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, Seoul, Korea; 2Department of Occupational and Environment Medicine, College of Medicine, Ewha Womans University, Seoul, Korea; 3Department of Occupational and Environmental Medicine, School of Medicine, Kyung Hee University, Seoul, KoreaCorrespondence: Jae-Hong RyooDepartments of Occupational and Environmental Medicine, School of Medicine, Kyung Hee University, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, KoreaTel +82-10-6235-2208Fax +82-2-969-0792Email armani131@naver.comPurpose: This study examined the relationship between serum gamma-glutamyltransferase concentration and the risk of cerebral infarction in the Koreans.Materials and Methods: A total of 209,481 out of 223,551 participants in the National Health Information Database who received medical checkups in 2009 were included in the final analysis. The diagnosis code ICD I63 was used for identifying cerebral infarction cases and tracked the development of cerebral infarction by 2013. Cox proportional hazards model was used to calculate hazard ratios (HRs) for cerebral infarction and their confidence interval (CI).Results: During a follow-up period of 915,387.5 person-years, 2403 incident cases of cerebral infarction developed between 2009 and 2013. After adjusting for multiple covariates, the hazard ratios (95% confidence interval) for incident cerebral infarction, comparing the second, third, and fourth quartile of serum gamma-glutamyltransferase levels with the first quartile, were 1.11 (0.98– 1.27), 1.39 (1.22– 1.58), and 1.49 (1.29– 1.71), respectively (P for trend < 0.001).Conclusion: Elevated serum gamma-glutamyltransferase levels were independently associated with the future development of cerebral infarction in Koreans.Keywords: gamma-glutamyltransferase, cerebral infarction, stroke

Small molecule modulators of mitochondrial function have been attracted much attention in recent years due to their potential therapeutic applications for neurodegenerative diseases. The mitochondrial translocator protein (TSPO) is a promising target for such compounds, given its involvement in the formation of the mitochondrial permeability transition pore in response to mitochondrial stress. In this study, we performed a ligand-based pharmacophore design and virtual screening, and identified a potent hit compound, 7 (VH34) as a TSPO ligand. After validating its biological activity against amyloid-β (Aβ) induced mitochondrial dysfunction and in acute and transgenic Alzheimer’s disease (AD) model mice, we developed a library of analogs, and we found two most active compounds, 31 and 44, which restored the mitochondrial membrane potential, ATP production, and cell viability under Aβ-induced mitochondrial toxicity. These compounds recovered learning and memory function in acute AD model mice with improved pharmacokinetic properties.

Abstract Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.

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.

BACKGROUND/OBJECTIVES: Maternal serum triglyceride (TG) level is known to be associated with neonatal birth weight. Although Koreans traditionally consume relatively high amounts of grain and grain products, mainly in the form of white rice, and the consumption is positively associated with serum TG levels, no study has investigated the relationship between dietary grain intake, serum TG levels and neonatal birth weight in pregnant women. This study was conducted to identify the association between infant birth weight and maternal intake of grain, as well as serum TG levels. SUBJECTS/METHODS: Subjects were 1011 pregnant women at 12-28 weeks' gestational age and their offspring. Maternal serum TG levels, dietary intake and infant birth weight were measured. RESULTS: Serum TG levels were positively related to neonatal birth weight both at mid-pregnancy (P = 0.0015) and at late pregnancy (P < 0.0001). Such an association only existed in subjects with the highest tertile of grain intake at mid- pregnancy (P = 0.0055) but was observed in all tertiles at late pregnancy (1st P = 0.0186, 2nd P = 0.0146, 3rd P = 0.0099). CONCLUSIONS: The relationship between maternal TG levels and infant birth weight may depend on dietary grain intake and stages of pregnancy in Korean pregnant women. European Journal of Clinical Nutrition (2015) 69, 676-680; doi: 10.1038/ejcn.2014.271; published online 17 December 2014, INTRODUCTION Traditionally, grain consumption is comparably high in Asian populations, including Koreans. The traditional Korean diet is mainly composed of refined white rice (high amylose, about 35% of energy), which [...]

OBJECTIVE: Phthalates can cause immunological disorders and aggravate allergic diseases. Thus, we investigated the relationship between urinary phthalate, skin barrier function, and atopic sensitization in children. PATIENTS AND METHODS: In total, 448 school children [334 with severe allergic disease; and 123 with severe atopic dermatitis (AD)] aged 10-12 years were enrolled in this study between June and July 2017. Four high-molecular-weight phthalates (HMWP) [Σ4HMWP] and three low-molecular-weight phthalates (LMWP) [Σ3LMWP] metabolites in urine samples, specific immunoglobulin E (IgE), and total eosinophil count were measured. Four-part trans epidermal water loss (TEWL) (cheek, leg, and upper/lower arm; Σ4TEWL) was measured to evaluate the skin barrier function. RESULTS: After adjusting for confounding variables, Σ4TEWL was significantly associated with the quartiles of urinary Σ4HMWP [adjusted β=7.897, 95% confidence interval (CI): 0.636-15.158, p=0.033] and Σ3LMWP (adjusted β=9.670, 95% CI: 2.422-16.919, p=0.009). The adjusted analyses revealed that the quartiles of urinary Σ4HMWP and Σ3LMWP were not significantly associated with total eosinophil count, atopic sensitization, and severe AD (p>0.05). According to the quartiles of urinary Σ4HMWP and Σ3LMWP, there were significant differences in the TEWL of the lower arm and leg (p<0.05) but not in cheek and upper arm. CONCLUSIONS: Exposure to HMWPs and LMWPs was significantly associated with skin barrier dysfunction but not with atopic sensitization. These results suggest that children exposed to phthalates may be more susceptible to fragile skin barrier function. [ABSTRACT FROM AUTHOR]

ObjectiveCognitive decline is often considered an inevitable aspect of aging; however, recent research has identified a subset of older adults known as “superagers” who maintain cognitive abilities comparable to those of younger individuals. Investigating the neurobiological characteristics associated with superior cognitive function in superagers is essential for understanding “successful aging.” Evidence suggests that the gut microbiome plays a key role in brain function, forming a bidirectional communication network known as the microbiome-gut-brain axis. Alterations in the gut microbiome have been linked to cognitive aging markers such as oxidative stress and inflammation. This study aims to investigate the unique patterns of the gut microbiome in superagers and to develop machine learning-based predictive models to differentiate superagers from typical agers.MethodsWe recruited 161 cognitively unimpaired, community-dwelling volunteers aged 60 years or from dementia prevention centers in Seoul, South Korea. After applying inclusion and exclusion criteria, 115 participants were included in the study. Following the removal of microbiome data outliers, 102 participants, comprising 57 superagers and 45 typical agers, were finally analyzed. Superagers were defined based on memory performance at or above average normative values of middle-aged adults. Gut microbiome data were collected from stool samples, and microbial DNA was extracted and sequenced. Relative abundances of bacterial genera were used as features for model development. We employed the LightGBM algorithm to build predictive models and utilized SHAP analysis for feature importance and interpretability.ResultsThe predictive model achieved an AUC of 0.832 and accuracy of 0.764 in the training dataset, and an AUC of 0.861 and accuracy of 0.762 in the test dataset. Significant microbiome features for distinguishing superagers included Alistipes, PAC001137_g, PAC001138_g, Leuconostoc, and PAC001115_g. SHAP analysis revealed that higher abundances of certain genera, such as PAC001138_g and PAC001115_g, positively influenced the likelihood of being classified as superagers.ConclusionOur findings demonstrate the machine learning-based predictive models using gut-microbiome features can differentiate superagers from typical agers with a reasonable performance.

Abstract Background Gastrodia elata Blume (GEB), a traditional medicinal herb, has been reported to have pharmacological effect including protection against liver, neuron and kidney toxicity. However, explanation of its underlying mechanisms remains a great challenge. This study investigated the protective effects of GEB extract on vancomycin (VAN)-induced nephrotoxicity in rats and underlying mechanisms with emphasis on the anti-oxidative stress, anti-inflammation and anti-apoptosis. The male Sprague-Dawley rats were randomly divided three groups: control (CON) group, VAN group and GEB group with duration of 14 days. Results The kidney weight and the serum levels of blood urea nitrogen and creatinine in the GEB group were lower than the VAN group. Histological analysis using hematoxylin & eosin and periodic acid Schiff staining revealed pathological changes of the VAN group. Immunohistochemical analysis revealed that the expression levels of N-acetyl-D-glucosaminidase, myeloperoxidase and tumor necrosis factor-alpha in the GEB group were decreased when compared with the VAN group. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells, phosphohistone and malondialdehyde levels were lower in the GEB group than VAN group. The levels of total glutathione in the GEB group were higher than the VAN group. Conclusions The findings of this study suggested that GEB extract prevents VAN-induced renal tissue damage through anti-oxidation, anti-inflammation and anti-apoptosis.

Heavy metals are commonly released into the environment through industrial processes such as mining and refining. The rapid industrialization that occurred in South Korea during the 1960s and 1970s contributed significantly to the economy of the country; however, the associated mining and refining led to considerable environmental pollution, and although mining is now in decline in South Korea, the detrimental effects on residents inhabiting the surrounding areas remain. The bioaccumulation of toxic heavy metals leads to metabolic alterations in human homeostasis, with disruptions in this balance leading to various health issues. This study used metabolomics to explore metabolomic alterations in the plasma samples of residents living in mining and refining areas. The results showed significant increases in metabolites involved in glycolysis and the surrounding metabolic pathways, such as glucose-6-phosphate, phosphoenolpyruvate, lactate, and inosine monophosphate, in those inhabiting polluted areas. An investigation of the associations between metabolites and blood clinical parameters through meet-in-the-middle analysis indicated that female residents were more affected by heavy metal exposure, resulting in more metabolomic alterations. For women, inhabiting the abandoned mine area, metabolites in the glycolysis and pentose phosphate pathways, such as ribose-5-phosphate and 3-phosphoglycerate, have shown a negative correlation with albumin and calcium. Finally, Mendelian randomization(MR) was used to determine the causal effects of these heavy metal exposure-related metabolites on heavy metal exposure-related clinical parameters. Metabolite biomarkers could provide insights into altered metabolic pathways related to exposure to toxic heavy metals and improve our understanding of the molecular mechanisms underlying the health effects of toxic heavy metal exposure.

OBJECTIVE: Previous studies on the relationship of bisphenol-A (BPA) with fractional exhaled nitric oxide (FeNO) had conflicting results, suggesting that other factors may modulate this relationship. Thus, we investigated the modulating effect of vitamin D on the relationship of BPA with FeNO in children PATIENTS AND METHODS: This study recruited 432 children (10 to 12 years old) from the general pediatric population of Korea between June and July 2017. We conducted measurements of urinary BPA, serum vitamin D, specific serum IgE, FeNO, and data from impulse oscillometry (reactance area [AX], airway resistance at 5 Hz [Rrs5] and 20 Hz [Rrs10], and the difference of Rrs5 and Rrs20 [Rrs5-20]). RESULTS: Serum vitamin D (adjusted ß =- 0.014, p=0.002) and urinary BPA (ß = 0.006, p<0.001) level was significantly associated with FeNO. Urinary BPA level was significantly associated with FeNO in children with low vitamin D levels (=23 ng/mL; aß = 0.006, p < 0.001), but not in children with high vitamin D levels (>23 ng/mL). The interaction of vitamin D and BPA had a significant effect on FeNO (pint = 0.005). There was no relationship with the airway lung function (Rrs5, AX, and Rrs5-20) to serum vitamin D and urinary BPA level. Vitamin D ameliorated the BPA-mediated increase of FeNO in children. CONCLUSIONS: These results suggest that children with low vitamin D levels may be more susceptible to airway inflammation due to BPA. [ABSTRACT FROM AUTHOR]

BackgroundThe metabolic score for insulin resistance index (METS-IR) is a novel non insulin-based marker that indicates the risk for metabolic syndrome and type 2 diabetes mellitus (T2DM). However, METS-IR has not been investigated in relation to all–cause mortality. We investigated the longitudinal effect of METS-IR on all–cause mortality in a significantly large cohort of Korean adults over 60 years old.MethodsData were assessed from 30,164 Korean participants over 60 years of age from the Korean Genome and Epidemiology Study-Health Examinees (KoGES-HEXA) cohort data, linked with the death certificate database of the National Statistical Office. The participants were grouped into three according to METS-IR tertiles. We used multivariate Cox proportional-hazard regression models to prospectively assess hazard ratios (HRs) for all-cause mortality with 95% confidence intervals (CIs) over an 11-year postbaseline period.ResultsDuring the mean 11.7 years of follow-up, 2,821 individuals expired. The HRs of mortality for METS-IR tertiles were 1.16 (95% CI, 1.01–1.34) in T3 after adjustment for metabolic parameters, but the T2 did not show statistical significance towards increases for incident mortality respectively. In subgroup analysis depending on the cause of mortality, higher METS-IR was associated with cancer mortality (HR, 1.23, 95% CI, 1.01–1.51) but not with cardiovascular mortality (HR, 1.14, 95% CI, 0.83–1.57) after adjustment for the same confounding variables.ConclusionThe METS-IR may be a useful predictive marker for all-cause mortality and cancer mortality, but not for cardiovascular mortality in subjects over 60 years of age. This implies that early detection and intervention strategies for metabolic syndrome could potentially benefit this identified group.

BackgroundImidazole propionate (IMP) is a histidine metabolite produced by some gut microorganisms in the human colon. Increased levels of IMP are associated with intestinal inflammation and the development and progression of cardiovascular disease and diabetes. However, the anti-inflammatory activity of IMP has not been investigated. This study aimed to elucidate the role of IMP in treating atopic dermatitis (AD). MethodsTo understand how IMP mediates immunosuppression in AD, IMP was intraperitoneally injected into a Dermatophagoides farinae extract (DFE)/1-chloro-2,4 dinitrochlorobenzene (DNCB)-induced AD-like skin lesions mouse model. We also characterized the anti-inflammatory mechanism of IMP by inducing an AD response in keratinocytes through TNF-α/IFN-γ or IL-4 stimulation. ResultsContrary to the prevailing view that IMP is an unhealthy microbial metabolite, we found that IMP-treated AD-like skin lesions mice showed significant improvement in their clinical symptoms, including ear thickness, epidermal and dermal thickness, and IgE levels. Furthermore, IMP antagonized the expansion of myeloid (neutrophils, macrophages, eosinophils, and mast cells) and Th cells (Th1, Th2, and Th17) in mouse skin and prevented mitochondrial reactive oxygen species production by inhibiting mitochondrial energy production. Interestingly, we found that IMP inhibited AD by reducing glucose uptake in cells to suppress proinflammatory cytokines and chemokines in an AD-like in vitro model, sequentially downregulating the PI3K and mTORC2 signaling pathways centered on Akt, and upregulating DDIT4 and AMPK. DiscussionOur results suggest that IMP exerts anti-inflammatory effects through the metabolic reprogramming of skin inflammation, making it a promising therapeutic candidate for AD and related skin diseases.

Worldwide, significant efforts are made to identify energy sources that can help achieve carbon neutrality and promote sustainable development. The development of a catalyst that combines durability and high performance is essential for the commercialization of proton‐exchange membrane fuel cells (PEMFCs). In a fuel cell, carbon corrosion occurs during startup and shutdown due to improper local flooding caused by inadequate water management. In this study, a Pt‐based catalyst is designed with excellent durability and high activity. Introducing a metal oxide layer modified with Pt/multi‐walled carbon nanotubes reduces the direct contact between carbon and the fuel cell environment. This helps prevent carbon corrosion and inhibits the separation, aggregation, and growth of Pt nanoparticles. Moreover, the catalyst exhibits enhanced oxygen reduction activity due to the electronic effect of the metal oxide layer that is coated on it. In this study, by implementing a carbon erosion acceleration protocol, excellent catalytic properties during a load‐cycling experiment consisting of 5,000 cycles are reported. The practical application of the developed catalyst in PEMFCs offers an effective approach to developing Pt‐group metal catalysts with exceptional activity.

Ammonia has attracted the attention as a practical way to reach carbon free power generation. Ammonia co-combustion characteristics in 1000MWe pulverized coal power plant was simulated by using Aspen Plus and evaluated under an excess air ratio of 1.0–1.2, air of 2642–3457 ton/hr, coal of 208.2–355.5 ton/hr, ammonia of 0–186.14 ton/hr and various coals. The influence of co-combustion ratios of different coals on emission characteristics and net efficiency was compared. For carbon dioxide emission reduction, the respective CO2 intensity reduction for KPU and BG was 36.44 and 37.76% in calorific value basis, 32.51 and 31.90% in weight basis. The net efficiencies of the power cycle showed a lower decrease as the fuel was supplied on the weight basis compared to the calorific value basis. Based on the obtained results, the KPU on the weight basis showed the lowest net efficiency decrement of 3.1%, but in terms of CO2 intensity reduction, BG on calorific value basis showed most drastic reduction of 37.76%. Consequently, these results showed an effective carbon reduction with ammonia co-combustion and provides a promising solution for the pulverized coal power plants to compass a meaningful reduction of carbon emissions and conservation of combustion efficiency.

Myasthenia Gravis (MG) patients with anti-acetylcholine receptor (AChR) antibodies frequently show hyperplastic thymi with ectopic germinal centers, where autoreactive B cells proliferate with the aid of T cells. In this study, thymus and peripheral blood (PB) samples were collected from ten AChR antibody-positive MG patients. T cell receptor (TCR) repertoires were analyzed using next-generation sequencing (NGS), and compared with that of an age and sex matched control group generated from a public database. Certain V genes and VJ gene recombination pairs were significantly upregulated in the TCR chains of αβ-T cells in the PB of MG patients compared to the control group. Furthermore, the TCR chains found in the thymi of MG patients had a weighted distribution to longer CDR3 lengths when compared to the PB of MG patients, and the TCR beta chains (TRB) in the MG group's PB showed increased clonality encoded by one upregulated V gene. When TRB sequences were sub-divided into groups based on their CDR3 lengths, certain groups showed decreased clonality in the MG group's PB compared to the control group's PB. Finally, we demonstrated that stereotypic MG patient-specific TCR clonotypes co-exist in both the PB and thymi at a much higher frequency than that of the clonotypes confined to the PB. These results strongly suggest the existence of a biased T cell-mediated immune response in MG patients, as observed in other autoimmune diseases.