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Bitter rot caused by the fungal genus Colletotrichum is a well-known, common disease of apple and causes significant yield loss. In 2013, six fungal strains were isolated from Fuji apple fruits exhibiting symptoms of bitter rot from Andong, Korea. These strains were identified as Colletotrichum fructicola and C. siamense based on morphological characteristics and multilocus sequence analysis of the internal transcribed spacer rDNA, actin, calmodulin, chitin synthase, and glyceraldehyde-3-phosphate dehydrogenase Pathogenicity tests confirmed the involvement of C. fructicola and C. siamense in the development of disease symptoms on apple fruits. This is the first report of C. fructicola and C. siamense causing bitter rot on apple fruit in Korea.

It remains an open question whether second language (L2) learners can process linguistic properties at the syntax-discourse interface. This study examines this issue in the context of the L2 processing of Korean dative sentences under different information structure requirements. Given that discourse constraints associated with information structure tend to manifest more strongly in noncanonical than in canonical structures, we tested whether L2 learners of Korean show sensitivity to such constraints during online processing. In a story-continuation task, both native and nonnative speaker groups showed a strong preference for producing canonical dative patterns, indicating their comparable knowledge of the canonical status of Korean dative sentences. In a self-paced reading task, both groups spent longer reading times when the word order of dative sentences did not follow given-new information structure, but only for the noncanonical and not the canonical structure. These results suggest that L2 processing of dative structures at the syntax-discourse interface relies on the same parsing architecture that guides native-speaker processing.

The social responsibility of college students in the later stages of adolescence for sustainable development is emphasized, and the role of universities has become a crucial task. This study aimed to explore the level of college students' cognition, attitude, and behavior towards sustainable development and the association among them through the moderation effect of informal online learning. The difference verification and structural equation modeling were applied to 559 students who majored in science, and statistical validity was confirmed. Regarding the sustainable development level of college students, there was a significant difference in cognition, attitude, and behavior towards sustainable development between males and females, formal education, and informal online learning. Further, college students' attitudes towards sustainable development played a significant mediating role between cognition and behavior. The study also found a significant moderation effect of informal online learning on students' cognition and attitude toward sustainable development behavior. Accordingly, this study suggests that universities should systematically design educational programs to promote college students' behavioral change toward sustainable development through personal life-oriented learning courses.

Abstract Early peritoneal dialysis (PD)-related infection is a severe complication. This study investigated the relationship between patient–doctor contact (PDC) duration and early PD-related infection. In the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) Korea, incident dialysis patients receiving PD were divided into two groups based on PDC duration (

Reinforced concrete structures are subject to exposure to chloride ions in the air, leading to chloride penetration, and carbonation attacks resulting from exposure to carbon dioxide. This chemical degradation process induces corrosion of reinforcing bars within concrete, significantly impacting durability. Structures situated in coastal areas, such as nuclear power plants, are particularly susceptible to rapid chloride penetration due to the high chloride concentration in the air. This study utilizes existing experimental data to forecast the chloride diffusion coefficient employing artificial neural network (ANN technology). The total number of experimental data was 535 gathered from 18 papers. Through analysis of the chloride coefficient and predicted degradation depth, the effective cross-sectional area of concrete is examined, and the deterioration of wall performance is forecasted.

Abstract Breast cancer categorized into hormone receptor-positive (HR+), HER2-positive (HER2+), and triple-negative (TNBC) subtypes, exhibits varied outcomes based on the number of tumor-infiltrating lymphocytes (TILs). To explore the divergent roles of TIL levels across different subtypes, we employed single-cell RNA sequencing on 31 patients with breast cancer. HR+ breast cancer with high TIL levels (TIL-high) revealed increased SPP1+ macrophages, increased SPP1 expression in other monocytes/macrophages (mono/macro) subgroups, and enriched pathways associated with extracellular matrix (ECM) remodeling in mono/macro. Moreover, cell–cell interaction analyses revealed enhanced SPP1, MIF, and FN1 signaling in the interaction between SPP1+ macrophages and T-cells in TIL-high HR+ breast cancer. Spatial transcriptomics data highlighted the close proximity of SPP1+ macrophages, CD8+ T-cells, and CD4+ T-cells in TIL-high HR+ breast cancer. Our findings unveil the novel influence of SPP1+ macrophages on T-cells in TIL-high HR+ breast cancer, potentially explaining the poor prognosis and offering insights for targeted interventions.

Abstract Background Breast cancer (BC) is a complex disease with profound genomic aberrations. However, the underlying molecular disparity influenced by age and ethnicity remains elusive. Methods In this study, we aimed to investigate the molecular properties of 843 primary and metastatic BC patients enrolled in the K-MASTER program. By categorizing patients into two distinct age subgroups, we explored their unique molecular properties. Additionally, we leveraged large-scale genomic data from the TCGA and MSK-IMPACT studies to examine the ethnic-driven molecular and clinical disparities. Results We observed a high prevalence of PI3KCA mutations in K-MASTER HER2 + tumors, particularly in older patients. Moreover, we identified increased mutation rates in DNA damage response molecules, including ARID1A, MSH6, and MLH1. The K-MASTER patients were mainly comprised of triple-negative breast cancer (TNBC) and HER2-positive tumors, while the TCGA and MSK-IMPACT cohorts exhibited a predominance of hormone receptor-positive (HR +) subtype tumors. Importantly, GATA3 mutations were less frequently observed in East Asian patients, which correlated with poor clinical outcomes. In addition to characterizing the molecular disparities, we developed a gradient-boosting multivariable model to identify a new molecular signature that could predict the therapeutic response to platinum-based chemotherapy. Conclusions Our findings collectively provide unprecedented insights into the significance of age and ethnicity on the molecular and clinical characteristics of BC patients.

Calcified amorphous tumors (CATs) of the heart are rare non-neoplastic cardiac masses primarily found in the mitral valve or annulus. However, their exact pathogenesis remains unknown. In this case report, we describe the CT and MRI findings and differentiating features of cardiac a CAT in the left atrium of a 79-year-old female.

Abstract Background Fournier’s gangrene is a severe form of infectious necrotizing fasciitis affecting the perineum, perianal, and genital areas; it is associated with substantial morbidity and mortality. Hence, it is important to identify prognostic factors that can predict clinical outcomes and guide treatment strategies. Thus, our study aimed to analyze patient characteristics and determine prognostic factors affecting clinical outcomes in Fournier’s gangrene. Methods This retrospective study involved examining medical records spanning 18 years for patients with Fournier’s gangrene at our institution. Considering the exclusion criteria, data from 35 patients were included in this study. Results A total of 35 patients were included in the analysis. The mean age of the patients showed no statistically significant difference between the survivor and non-survivor groups. The Charlson Comorbidity Index, American Society of Anesthesiologists score, and Acute Physiology and Chronic Health Evaluation II score were not significantly different between the two groups. Notably, the initial Sequential Organ Failure Assessment score was significantly higher in the non-survivor group than that in the survivor group. The overall in-hospital mortality rate was 17.1%. Moreover, the prevalence of multidrug resistant bacterial infection was markedly higher in the non-survivor group than that in the survivor group. Coagulation dysfunction was significantly more prevalent in the non-survivor group than that in the survivor group, and had the most significant impact on in-hospital mortality. A multivariable logistic regression analysis identified multidrug resistant bacterial infection to be independently associated with high in-hospital mortality. Conclusions Coagulation dysfunction and multidrug resistant bacterial infection were identified as independent negative prognostic factors, highlighting the need for prompt monitoring and proactive strategies against Fournier’s gangrene.

Abstract In the phase 3 KEYNOTE-355 study (NCT02819518), pembrolizumab plus chemotherapy demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy among patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) and programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 10 tumors. We analyzed outcomes for the subgroup of patients enrolled in Asia in KEYNOTE-355. Patients received pembrolizumab 200 mg or placebo (2:1 randomization) every 3 weeks for 35 cycles plus investigator’s choice chemotherapy. Primary endpoints were PFS per Response Evaluation Criteria in Solid Tumors version 1.1 and OS. Among patients enrolled in Hong Kong, Japan, Korea, Malaysia and Taiwan (pembrolizumab plus chemotherapy, n = 113; placebo plus chemotherapy, n = 47), 117 (73.1%) had PD-L1 CPS ≥ 1 and 56 (35.0%) had PD-L1 CPS ≥ 10. Median time from randomization to data cutoff (June 15, 2021) was 43.8 (range, 36.8‒53.2) months (intent-to-treat [ITT] population). Hazard ratios (HRs [95% CI]) for PFS in the CPS ≥ 10, CPS ≥ 1, and ITT populations were 0.48 (0.24‒0.98), 0.58 (0.37‒0.91), and 0.66 (0.44‒0.99), respectively. Corresponding HRs (95% CI) for OS were 0.54 (0.28‒1.04), 0.62 (0.40‒0.97), and 0.57 (0.39‒0.84). Grade 3/4 treatment-related adverse events (AEs) occurred in 77.9% versus 78.7% of patients with pembrolizumab plus chemotherapy versus placebo plus chemotherapy. No grade 5 AEs occurred. Clinically meaningful improvement in PFS and OS with manageable toxicity were observed with pembrolizumab plus chemotherapy versus placebo plus chemotherapy in patients enrolled in Asia with previously untreated, inoperable or metastatic TNBC. Trial registration: ClinicalTrials.gov, NCT02819518.

Background: Identifying the underlying etiology of developmental delay/intellectual disability (DD/ID) is challenging but important. The genetic diagnosis of unexplained DD/ID helps in the treatment and prognosis of the disability in patients. In this study, we reported our experience of using whole exome sequencing (WES) of children with unexplained DD/ID. Methods: We conducted a retrospective analysis of WES results of children under 19 years of age with unexplained DD/ID between January 2020 and December 2021. The demographic data of all patients and variants identified through WES were evaluated. Furthermore, we evaluated the clinical characteristics that influenced the identification of genetic causes. Results: Forty-one patients with DD/ID were included, of whom 21 (51.2 %) were male. The average age at symptom onset was 1.6 ± 1.3 years, and the duration from symptom onset to diagnosis was 3.1 ± 3.7 years. Hypotonia was the most common symptom (17 patients, 41.5 %), and epilepsy was confirmed in 10 patients (24.4 %). Twenty-two pathogenic/likely pathogenic variants were identified in 20 patients, and three variants of uncertain significance were identified in three patients. Family-based trio Sanger sequencing for candidate variants of 12 families was conducted; 10 variants were de novo, one variant paternally inherited, and two variants compound heterozygous. The diagnostic yield of WES for DD/ID was 48.8 % and was significantly high in patients with an early onset of DD/ID and facial dysmorphism. In contrast, patients with autism spectrum disorder (ASD) were more likely to have negative WES results compared with others without ASD. Conclusion: The diagnostic yield of WES was 48.8 %. We conclude that patients’ characteristics, such as dysmorphic features and the age of symptom onset, can predict the likelihood that WES will identify a causal variant of a phenotype.

Abstract We previously demonstrated that felodipine, an L-type calcium channel blocker, inhibits LPS-mediated neuroinflammatory responses in BV2 microglial cells and wild-type mice. However, the effects of felodipine on tau pathology, a hallmark of Alzheimer's disease (AD), have not been explored yet. Therefore, in the present study, we determined whether felodipine affects neuroinflammation and tau hyperphosphorylation in 3-month-old P301S transgenic mice (PS19), an early phase AD mice model for tauopathy. Felodipine administration decreased tauopathy-mediated microglial activation and NLRP3 expression in PS19 mice but had no effect on tauopathy-associated astrogliosis. In addition, felodipine treatment significantly reduced tau hyperphosphorylation at S202/Thr205 and Thr212/Ser214 residues via inhibiting JNK/P38 signaling in PS19 mice. Collectively, our results suggest that felodipine significantly ameliorates tau hyper-phosphorylation and tauopathy-associated neuroinflammatory responses in AD mice model for tauopathy and could be a novel therapeutic agent for AD.

The aging population has significantly increased in South Korea because of the factors such as longer life expectancy and lower birth rate. Healthy aging requires to preserve the cognitive function. Cognitive decline can hinder daily independent living. It is imperative to understand determinants of cognitive function in older adults for formulating effective interventions and policies. This study analyzed the data of Korean Longitudinal Study of Aging (KLoSA) from 2006 to 2020. A total of 4001 participants (1695 men and 2306 women) aged 65 and older were included in the final analysis. The sex-specific differences in cognitive function were assessed using statistical analyses including panel regression and panel quantile regression. Cognitive function had significant difference between men and women. Men showed higher cognitive function scores than women. Both men and women depicted significant influence on cognitive function based on age, employment status and depression. These factors had varying effects depending on the cognitive function level. Men’s age, working status, and depression were associated with dementia regardless of cognitive function, whereas women’s factors were more pronounced with low cognitive function. This study emphasizes the tailored sex-specific interventions and policies to improve cognitive function in older adults by considering sex-specific differences and varying cognitive function levels.

Objectives This study was conducted to evaluate the effects of a nutrition education program on metabolic syndrome in middle-aged Korean adults. Methods A total of 411 Korean adults 30–59 years of age were allocated randomly into three groups: the nutrition education group for promoting Han-sik consumption (HG), the nutrition education group for eating balanced diet (EG), and the control group (CG). The HG and EG received four face-to-face nutrition education sessions over 16 weeks to improve nutritional problems based on the individual’ usual diet. Effectiveness of the program was evaluated with the differences of self-reported dietary behaviors, dietary intakes, anthropometric measurements and biochemical indices between the baseline and the end of the nutrition education program. The changes within groups were analyzed using paired t-test and McNemar test and effectiveness among three groups was analyzed by repeated analysis of variance. Results After the nutrition education, the percentages of participants who achieved the recommended food group consumption in the Korean Food Guidance Systems significantly increased in HG (P = 0.022). Body weight (P = 0.007), body mass index (P = 0.002), and triglycerides (P = 0.002) significantly decreased in HG. Waist circumference and diastolic blood pressure decreased in all three groups (P < 0.05). Conclusions This study found that tailored nutrition education program for middle aged Korean adults showed beneficial effects on improving dietary behaviors and metabolic syndrome risk factors. Further studies are needed to assess the long-term effects of the nutrition education programs on metabolic syndrome risks.

Summary: Purpose: This methodological study evaluated the psychometric properties of the Self-Care of Coronary Heart Disease Inventory version 3 (SC-CHDI v3) in a Korean context. Methods: The SC-CHDI v3 was translated into Korean following a rigorous translation process. Participants were 452 patients who had experienced coronary heart disease (CHD), all recruited from a tertiary hospital in Korea. Exploratory and confirmatory factor analyses were performed to test construct validity. Concurrent validity was examined by correlating scores from the Korean version of the SC-CHDI v3 with those from the Cardiac Self-Efficacy Scale. Internal consistency was analyzed using Cronbach's alpha and McDonald's omega. Results: The Korean version of the SC-CHDI v3 consists of 21 items, excluding two from the original instrument. The self-care maintenance subscale identified a two-factor structure: “treatment adherence” and “health-promoting behaviors.” The goodness-of-fit indices were satisfied: χ2 = 18.19, p = .110, comparative fit index (CFI) = .97, Tucker-Lewis Index (TLI) = .95, and standardized root mean square residual (SRMR) = .04. The self-care monitoring subscale consisted of a one-dimensional structure (“monitoring behaviors”) and the goodness-of-fit indices were satisfied: χ2 = 19.19, p = .059, CFI = .99, TLI = .99, and SRMR = .04. The self-care management subscales had a two-factor structure of “consulting behaviors” and “problem-solving behaviors.” The goodness-of-fit indices were satisfied: χ2 = 16.44, p = .037, CFI = .99, TLI = .98, and SRMR = .03. Scores from the Cardiac Self-Efficacy Scale showed a positive correlation with the Korean version of SC-CHDI v3 subscales. Reliability estimates were ≥ .80 for all subscales except for the self-care maintenance subscale. Conclusions: The Korean version of the SC-CHDI v3 consists of 21 items in 3 subscales and is a valid and reliable instrument. Therefore, healthcare providers can effectively utilize it to assess the self-care levels of patients with CHD.

Abstract Background Mitochondria are known to synthesize adenosine triphosphate (ATP) through oxidative phosphorylation. Understanding and accurately measuring mitochondrial ATP synthesis rate can provide insights into the functional status of mitochondria and how it contributes to overall cellular energy homeostasis. Traditional methods only estimate mitochondrial function by measuring ATP levels at a single point in time or through oxygen consumption rates. This study introduced the relative mitochondrial ATP synthesis response against inhibiting and stimulating substrates (MitoRAISE), designed to detect real-time changes in ATP levels as the cells respond to substrates. Methods The sensitivity and specificity of the MitoRAISE assay were verified under various conditions, including the isolation of mitochondria, variations in cell numbers, cells exhibiting mitochondrial damage, and heterogeneous mixtures. Using peripheral blood mononuclear cells (PBMCs), we analyzed MitoRAISE data from 19 patients with breast cancer and 23 healthy women. Results The parameters observed in the MitoRAISE data increased depending on the quantity of isolated mitochondria and cell count, whereas it remained unmeasured in mitochondrial-damaged cell lines. Basal ATP, rotenone response, malonate response, and mitochondrial DNA copy numbers were lower in PBMCs from patients with breast cancer than in those from healthy women. Conclusions The MitoRAISE assay has demonstrated its sensitivity and specificity by measuring relative ATP synthesis rates under various conditions. We propose MitoRAISE assay as a potential tool for monitoring changes in the mitochondrial metabolic status associated with various diseases.

Abstract Trastuzumab emtansine (T-DM1) is widely utilized as a second-line and subsequent treatment for metastatic HER2+ breast cancer and has shown promise in early breast cancer treatment, particularly in adjuvant settings for residual disease after neoadjuvant chemotherapy. However, concerns have arisen regarding long-term hepatic adverse drug reactions (ADRs) not identified in clinical trials. We investigated potential safety signals of T-DM1 in hepatobiliary disorders and the time-to-onset of ADRs using the FDA Adverse Event Reporting System (FAERS) database. Suspected ADRs were extracted and divided into two groups: T-DM1 (N = 3387) and other drugs (N = 11,833,701). Potential signal for T-DM1 in hepatobiliary disorder were identified (reporting odds ratio [ROR] = 5.66, 95% confidence interval [CI] = 5.11–6.27; information component [IC] = 2.35, 95% Credibility Interval [Crl] = 2.18–2.51). A breast cancer indicated subgroup analysis (2519 T-DM1; 172,329 other drugs) also identified a potential safety signal (ROR = 3.28, 95% CI = 2.92–3.68; IC = 1.53, 95%CrI = 1.35–1.71). The median time-to-onset for T-DM1-associated hepatobiliary disorders was 41 days. For prolonged and chronic hepatobiliary disorders, median times were 322.5 and 301.5 days, respectively. These findings highlight the need for further research to inform clinical decisions on optimal T-DM1 treatment duration, balancing benefits with potential adverse reactions.

Abstract Background The increasing complexity of the healthcare environment and the necessity of multidisciplinary teamwork have highlighted the importance of interprofessional education (IPE). IPE aims to enhance the quality of patient care through collaborative education involving various healthcare professionals, such as doctors, nurses, and pharmacists. This study sought to analyze how game-based IPE activities influence students’ perceptions and reflective thinking. It also aimed to identify the shifts in perception and effectiveness caused by this educational approach. Methods The study is based on a game-based IPE program conducted at University A, involving medical and nursing students in structured learning and team-based activities. Data were collected using essays written by the students after they had participated in IPE activities. Text network analysis was conducted by extracting key terms, performing centrality analysis, and visualizing topic modeling to identify changes in students’ perceptions and reflective thinking. Results Keywords such as “patient,” “thought,” “group,” “doctor,” “nurse,” and “communication” played a crucial role in the network, indicating that students prioritized enhancing their communication and problem-solving skills within the educational environment. The topic modeling results identified three main topics, each demonstrating the positive influence of game-based collaborative activities, interprofessional perspectives, and interdisciplinary educational experiences on students. Topic 3 (interdisciplinary educational experience) acted as a significant mediator connecting Topic 1 (game-based collaborative activity experience) and Topic 2 (interprofessional perspectives). Conclusion This study demonstrates that game-based IPE activities are an effective educational approach for enhancing students’ team building skills, particularly communication and interprofessional perspectives. Based on these findings, future IPE programs should focus on creating collaborative learning environments, strengthening communication skills, and promoting interdisciplinary education. The findings provide essential insights for educational designers and medical educators to enhance the effectiveness of IPE programs. Future research should assess the long-term impacts of game-based IPE on clinical practice, patient outcomes, and participants’ professional development.

Abstract Spaceborne radar remote sensing of the earth system is essential to study natural and man-made changes in the ecosystem, water and energy cycles, weather and air quality, sea level, and surface dynamics. A major challenge with current approaches is the lack of broad spectrum tunability due to narrow band microwave electronics, that limit systems to specific science variable retrievals. This results in a significant limitation in studying dynamic coupled earth system processes such as surface and subsurface hydrology from a single compact instrument, where co-located broad spectrum radar remote sensing is needed to sense multiple variables simultaneously or over a short duration. Rydberg atomic sensors are highly sensitive broad-spectrum quantum detectors that can be dynamically tuned to cover micro-to-millimeter waves with no requirement for RF band-specific electronics. Rydberg atomic sensors can use existing transmitted signals such as from navigation and communication satellites to enable remote sensing. We demonstrate remote sensing of soil moisture, an important earth system variable, via ground-based radar reflectometry with Rydberg atomic systems. To do this, we sensitize the atoms to XM satellite radio signals and use signal correlations to demonstrate use of these satellite signals for remote sensing of soil moisture.

Purpose: As university faculty faced new challenges, such as rapid digital social and the coronavirus disease 2019 (COVID-19) response, this study aimed to identify the daily changes in the interaction between the faculty and the organizational environment (colleague, policy and new issue) by exploring their recent dynamic educational efforts and the professional development. Design/methodology/approach: This is a study wherein perceptions of 20 faculty from 15 universities and colleges were collected through in-depth online interviews. The authors analyzed interview data by arranging and visualizing the analyzed data using network clustering. Further, they applied the Latent Dirichlet allocation of the topic modeling to monitor the appropriate number of clusters, ultimately determined as four clusters using partial clustering. Findings: The results showed that university faculty spontaneously tried to solve the problems through informal learning while the commitment to peer learning was deepening, reflecting the collectivist orientation nature of Chinese culture. Besides, the faculty also required support to reflect on their daily efforts for professional development. These results about their various learning routines prove the justification for the faculty's professional development to be discussed from the "learning by doing" perspective of lifelong learning. Originality/value: This study proved the significance of informal learning for university faculty's professional development and the reasonable value of peer learning, and provided insights into how the Chinese context may influence university faculty's informal learning experience.

Soybean mosaic virus (SMV) is a prevalent pathogen that causes significant yield reduction in soybean production worldwide. SMV belongs to potyvirus and causes typical symptoms such as mild mosaic, mosaic and necrosis. SMV is seed-borne and also transmitted by aphid. Eleven SMV strains, G1 to G7, G5H, G6H, G7H, and G7a were reported in soybean varieties in Korea. A reverse transcription loop-mediated isothermal amplification (RT-LAMP) method allowed one-step detection of gene amplification by simple procedure and needed only a simple incubator for isothermal template. This RT-LAMP method allowed direct detection of RNA from virus-infected plants without thermal cycling and gel electrophoresis. In this study, we designed RT-LAMP primers named SML-F3/B3/FIP/BIP from coat protein gene sequence of SMV. After the reaction of RT-LAMP, products were identified by electrophoresis and with the detective fluorescent dye, SYBR Green I under daylight and UV light. Optimal reaction condition was at 58°C for 60 min and the primers of RT-LAMP showed the specificity for nine SMV strains tested in this study.

ABSTRACTTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has chemotherapeutic potential as a regulator of an extrinsic apoptotic ligand, but its effect as a drug is limited by innate and acquired resistance. Recent findings suggest that an intermediate drug tolerance could mediate acquired resistance, which has made the main obstacle for limited utility of TRAIL as an anti-cancer therapeutics. We propose miRNA-dependent epigenetic modification drives the drug tolerant state in TRAIL-induced drug tolerant (TDT). Transcriptomic analysis revealed miR-29 target gene activation in TDT cells, showing oncogenic signature in lung cancer. Also, the restored TRAIL-sensitivity was associated with miR-29ac and 140-5p expressions, which is known as tumor suppressor by suppressing oncogenic protein RSK2 (p90 ribosomal S6 kinase), further confirmed in patient samples. Moreover, we extended this finding into 119 lung cancer cell lines from public data set, suggesting a significant correlation between TRAIL-sensitivity and RSK2 mRNA expression. Finally, we found that increased RSK2 mRNA is responsible for NF-κB activation, which we previously showed as a key determinant in both innate and acquired TRAIL-resistance. Our findings support further investigation of miR-29ac and -140-5p inhibition to maintain TRAIL-sensitivity and improve the durability of response to TRAIL in lung cancer.

Background This study examines integrating physical and mental healthcare for disadvantaged persons with type 2 diabetes mellitus and mild-to-moderate depression in the community, using a mobile application within a public-private-academic partnership. Methods The Korean Diabetes Association has developed a mobile application combining behavioral activation for psychological well-being and diabetes self-management, with conventional medical therapy. Participants were randomly assigned to receive the application with usual care or only usual care. Primary outcomes measured changes in psychological status and diabetes self-management through questionnaires at week 12 from the baseline. Secondary outcomes assessed glycemic and lipid control, with psychological assessments at week 16. Results Thirty-nine of 73 participants completed the study (20 and 19 in the intervention and control groups, respectively) and were included in the analysis. At week 12, the intervention group showed significant reductions in depression severity and perceived stress compared to the control group. Additionally, they reported increased perceived social support and demonstrated improved diabetes self-care behavior. These positive effects persisted through week 16, with the added benefit of reduced anxiety. While fasting glucose levels in the intervention group tended to improve, no other significant differences were observed in laboratory assessments between the groups. Conclusion This study provides compelling evidence for the potential efficacy of a mobile application that integrates physical and mental health components to address depressive symptoms and enhance diabetes self-management in disadvantaged individuals with type 2 diabetes mellitus and depression. Further research involving larger and more diverse populations is warranted to validate these findings and solidify their implications.

Breast lymphomas are rare, malignant breast neoplasms with a heterogeneous pattern of clinical symptoms. Burkitt’s lymphoma is a rare, highly aggressive, and rapidly growing B-cell non-Hodgkin lymphoma. We report about a 27-year-old woman diagnosed as having secondary breast Burkitt’s lymphoma, probably originating from the stomach, with multiple distant metastases. Breast ultrasonography revealed multiple, variable sized, heterogeneous masses with posterior acoustic enhancement and echogenic rims. These imaging findings may sometimes overlap with those of other breast malignancies. However, unlike other breast malignancies, lymphoma can be diagnosed by biopsy and does not require surgical excision. To avoid unnecessary treatment, radiologists and clinicians should be aware of the characteristic imaging features of breast lymphomas.

Abstract Genomic analysis of structural variants(SVs) in breast cancer (BC) patients has been conducted, but the relationship between genomic alterations and BC prognosis remains unclear. We performed RNA sequencing of 297 early BC fresh-frozen tissues. We identified SVs using three tools (STAR.Arriba, STAR.fusion, and STAR.SEQR) with the COSMIC and Mitelman databases as guide references. We found a median of five to eight fusions per sample. In BC intrinsic subtypes, normal subtype had the fewest fusions (median: 1, interquartile range [IQR]: 0, 3) followed by luminal A (median: 5.5, IQR: 2.75, 10.25), luminal B (median: 9, IQR: 6, 16.5), HER2-enriched (median: 9, IQR: 6, 16.5) and basal (median 10, IQR: 6, 15.5) subtypes (p

Wire and arc additive manufacturing (WAAM) technique has introduced a novel approach for producing complex Ti–6Al–4V parts with metric dimensions. However, the produced part leads to the development of a strong texture and anisotropic mechanical properties due to the formation of large columnar β grains. To resolve this issue, the plastic deformation of each deposited track through hammer peening was developed as a means to refine these large β grains. In this study, we have investigated an innovative approach to further enhance the efficiency of β grain refinement by minimizing the arc heat input associated with previous deposited layer, which is achieved by employing a C-type filler wire. Our findings reveal a notable enhancement in grain refinement efficiency through the utilization of a C-type filler wire with peening process, as compared to available conventional commercial round shape filler wire. Specifically, the employment of the C-type filler wire results in a reduced melt pool penetration depth of WAAM Ti–6Al–4V (3.3 mm), compared to the commercially available round shape (R-Type) filler wire (4.48 mm). Within the plastically deformed region by peening, fine and randomly oriented β grains are observed, extending to a depth of deformation reaching 844 ± 32.65 μm. Peening WAAM Ti–6Al–4V with the C-type filler wire leads to the development of isotropic mechanical properties in both horizontal and vertical directions, offering high strength due to the presence of small equiaxed β grains and thin α laths (0.56 ± 0.18 μm), in contrast to the use of conventional commercial round shape filler wire.

Abstract Breast cancer is the most commonly diagnosed cancer among women worldwide. Breast cancer patients experience significant distress relating to their diagnosis and treatment. Managing this distress is critical for improving the lifespan and quality of life of breast cancer survivors. This study aimed to assess the level of distress in breast cancer survivors and analyze the variables that significantly affect distress using machine learning techniques. A survey was conducted with 641 adult breast cancer patients using the National Comprehensive Cancer Network Distress Thermometer tool. Participants identified various factors that caused distress. Five machine learning models were used to predict the classification of patients into mild and severe distress groups. The survey results indicated that 57.7% of the participants experienced severe distress. The top-three best-performing models indicated that depression, dealing with a partner, housing, work/school, and fatigue are the primary indicators. Among the emotional problems, depression, fear, worry, loss of interest in regular activities, and nervousness were determined as significant predictive factors. Therefore, machine learning models can be effectively applied to determine various factors influencing distress in breast cancer patients who have completed primary treatment, thereby identifying breast cancer patients who are vulnerable to distress in clinical settings.

Abstract Introduction Deucravacitinib demonstrated superior efficacy to apremilast in patients with moderate to severe plaque psoriasis in the POETYK PSO-1 and PSO-2 clinical trials. In the study reported here, we aimed to determine the overall 52-week cumulative clinical benefit of treatment initiated with deucravacitinib versus apremilast and to compare the 52-week cumulative benefit of initiating and staying on deucravacitinib versus initiating apremilast and continuing or switching to deucravacitinib at week 24 of treatment. Methods This post hoc analysis of POETYK PSO-1 data (ClinicalTrials.gov identifier: NCT03624127) determined the cumulative clinical benefit of deucravacitinib 6 mg once daily and apremilast 30 mg twice daily in adults with moderate to severe plaque psoriasis. Patients treated with apremilast who did not achieve a 50% reduction in the Psoriasis Area and Severity Index (PASI 50) at week 24 were switched to deucravacitinib. The cumulative clinical benefit of deucravacitinib versus apremilast over 52 weeks was based on cumulative measures of ≥ 75% improvement from baseline in PASI score (PASI 75) and the proportion of patients with a static Physician Global Assessment score of 0 or 1 (sPGA 0/1). Ratios of area under the curve estimates between treatments were calculated and compared based on analysis of covariance regression models. Results Patients initiating deucravacitinib (N = 332) had a greater cumulative benefit as measured by the PASI 75 and sPGA 0/1 than those initiating apremilast (N = 168). Over 52 weeks, those initiating deucravacitinib experienced 50% more benefit as measured by PASI 75 and 58% more benefit as measured by sPGA 0/1 than those initiating apremilast. Results were consistent with the primary analysis when patients were classified by prior systemic and prior biologic therapy exposure. Conclusion Results from this analysis corroborate the primary efficacy analysis supporting the use of deucravacitinib compared with apremilast for moderate to severe plaque psoriasis, regardless of prior systemic or biologic use.

Abstract This paper aims to elucidate the variations in wage inequality within the service industry across different nations. Scholars have emphasised the pivotal role of policies designed to balance flexibility and job security in the service sector, crucial for fostering its growth while mitigating wage disparities. We argue that the balance between flexibility and security of service sector employment is most likely to emerge under centre party governments in high-magnitude electoral systems. Centre parties, owing to their political detachment from organised labour and industry, encounter fewer obstacles in representing the unorganised interests of service sector workers. Furthermore, high-district magnitude systems incentivise centre parties to build comprehensive coalitions that address the diverse concerns of service sector workers. Our empirical analysis, spanning 14 OECD countries from 1995 to 2007, demonstrates that service sector wage inequality diminishes as district magnitude and the cabinet share of centre parties increase.

Abstract Epithelial-to-mesenchymal transition (EMT) is one of the main causes of peritoneal fibrosis. However, the pathophysiological mechanisms of EMT, specifically its relationship with autophagy, are still unknown. This study aimed to evaluate the role of autophagy in transforming growth factor-beta 1 (TGF-β1)-induced EMT in human peritoneal mesothelial cells (HPMCs). Primary cultured HPMCs were treated with TGF-β1 (2 and 5 ng/mL) and changes in autophagy markers and the relationship between autophagy and EMT were evaluated. We also identified changes in EMT- and autophagy-related signaling pathways after autophagy and NADPH oxidase 4 (NOX4) inhibition. TGF-β1 increased the generation of NOX4 and reactive oxygen species (ROS) in HPMCs, resulting in mitochondrial damage. Treatment with GKT137831 (20 μM), a NOX1/4 inhibitor, reduced ROS in the mitochondria of HPMC cells and reduced TGF-β1-induced mitochondrial damage. Additionally, the indirect inhibition of autophagy by GKT137831 (20 μM) downregulated TGF-β1-induced EMT, whereas direct inhibition of autophagy using 3-methyladenine (3-MA) (2 mM) or autophagy-related gene 5 (ATG5) gene silencing decreased the TGF-β1-induced EMT in HPMCs. The suppressor of mothers against decapentaplegic 2/3 (Smad2/3), autophagy-related phosphoinositide 3-kinase (PI3K) class III, and protein kinase B (Akt) pathways, and mitogen-activated protein kinase (MAPK) signaling pathways, such as extracellular signal-regulated kinase (ERK) and P38, were involved in TGF-β1-induced EMT. Autophagy and NOX4 inhibition suppressed the activation of these signaling pathways. Direct inhibition of autophagy and its indirect inhibition through the reduction of mitochondrial damage by upstream NOX4 inhibition reduced EMT in HPMCs. These results suggest that autophagy could serve as a therapeutic target for the prevention of peritoneal fibrosis in patients undergoing peritoneal dialysis.

Abstract Background HER2-positive, estrogen receptor-positive breast cancer (HER2+, ER+ BC) is a distinct disease subtype associated with inferior response to chemotherapy plus HER2-targeted therapy compared with HER2+, ER-negative BC. Bi-directional crosstalk leads to cooperation of the HER2 and ER pathways that may drive treatment resistance; thus, simultaneous co-targeting may optimize treatment impact and survival outcomes in patients with HER2+, ER+ BC. First-line (1L) treatment for patients with HER2+ metastatic BC (mBC) is pertuzumab, trastuzumab, and taxane chemotherapy. In clinical practice, dual HER2 blockade plus a fixed number of chemotherapy cycles are given as induction therapy to maximize tumor response, with subsequent HER2-targeted maintenance treatment given as a more tolerable regimen for long-term disease control. For patients whose tumors co-express ER, maintenance endocrine therapy (ET) can be added, but uptake varies due to lack of data from randomized clinical trials investigating the superiority of maintenance ET plus dual HER2 blockade versus dual HER2 blockade alone. Giredestrant, a novel oral selective ER antagonist and degrader, shows promising clinical activity and manageable safety across phase I–II trials of patients with ER+, HER2-negative BC, with therapeutic potential in those with HER2 co-expression. Methods This phase III, randomized, open-label, two-arm study aims to recruit 812 patients with HER2+, ER+ locally advanced (LA)/mBC into the induction phase (fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] plus a taxane) to enable 730 patients to be randomized 1:1 to the maintenance phase (giredestrant plus PH FDC SC or PH FDC SC [plus optional ET]), stratified by disease site (visceral versus non-visceral), type of LA/metastatic presentation (de novo versus recurrent), best overall response to induction therapy (partial/complete response versus stable disease), and intent to give ET (yes versus no). The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, safety, and patient-reported outcomes. Discussion heredERA BC will address whether giredestrant plus dual HER2 blockade is superior to dual HER2 blockade alone, to inform the use of this combination in clinical practice for maintenance 1L treatment of patients with HER2+, ER+ LA/mBC. Trial registration ClinicalTrials.gov, NCT05296798; registered on March 25, 2022. Protocol version 3.0 (November 18, 2022). Sponsor: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124 4070, Basel, Switzerland.

Abstract Mature osteoclasts degrade bone matrix by exocytosis of active proteases from secretory lysosomes through a ruffled border. However, the molecular mechanisms underlying lysosomal trafficking and secretion in osteoclasts remain largely unknown. Here, we show with GeneChip analysis that RUN and FYVE domain-containing protein 4 (RUFY4) is strongly upregulated during osteoclastogenesis. Mice lacking Rufy4 exhibited a high trabecular bone mass phenotype with abnormalities in osteoclast function in vivo. Furthermore, deleting Rufy4 did not affect osteoclast differentiation, but inhibited bone-resorbing activity due to disruption in the acidic maturation of secondary lysosomes, their trafficking to the membrane, and their secretion of cathepsin K into the extracellular space. Mechanistically, RUFY4 promotes late endosome-lysosome fusion by acting as an adaptor protein between Rab7 on late endosomes and LAMP2 on primary lysosomes. Consequently, Rufy4-deficient mice were highly protected from lipopolysaccharide- and ovariectomy-induced bone loss. Thus, RUFY4 plays as a new regulator in osteoclast activity by mediating endo-lysosomal trafficking and have a potential to be specific target for therapies against bone-loss diseases such as osteoporosis.

Abstract Background Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity. Methods Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-β1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed. Results High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-β1, IL-1β, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-β1 over-expressed transgenic mice with normal diet. Conclusions Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity. Graphical abstract

Abstract Background Circulating tumor DNA (ctDNA) has emerged as a prognostic and predictive biomarker for detection of minimal residual disease (MRD), monitoring treatment response, and early detection of recurrence in cancer patients. In this study, we explored the utility of ctDNA‐based MRD detection to predict recurrence in a real‐world cohort of primarily early‐stage non‐small cell lung cancer (NSCLC) patients treated with curative intent. Methods Longitudinal plasma samples were collected post curative‐intent treatment from 36 patients with stage I–IV NSCLC. A personalized, tumor‐informed assay was used to detect and quantify ctDNA in plasma samples. Results Of the 24 patients with plasma samples available during the MRD window (within 6 months of curative surgery and before adjuvant therapy), ctDNA was detectable in two patients. Patients with ctDNA‐positivity during the MRD window were 15 times more likely to recur compared to ctDNA‐negative patients (HR: 15.0, 95% CI: 1.0–253.0, p = 0.010). At any time post‐curative intent treatment, ctDNA‐positivity was associated with significantly poorer recurrence‐free survival compared to persistently ctDNA‐negative patients (p

The gram-negative bacterium lipopolysaccharide (LPS) is frequently administered to generate models of systemic inflammation. However, there are several side effects and no effective treatment for LPS-induced systemic inflammation. PEGylated PDZ peptide based on zonula occludens-1 (ZO-1) was analyzed for its effects on systemic inflammation induced by LPS. PDZ peptide administration led to the restoration of tissue injuries (kidney, liver, and lung) and prevented alterations in biochemical plasma markers. The production of pro-inflammatory cytokines was significantly decreased in the plasma and lung BALF in the PDZ-administered mice. Flow cytometry analysis revealed the PDZ peptide significantly inhibited inflammation, mainly by decreasing the population of M1 macrophages, and neutrophils (immature and mature), and increasing M2 macrophages. Using RNA sequencing analysis, the expression levels of the NF-κB-related proteins were lower in PDZ-treated cells than in LPS-treated cells. In addition, wild-type PDZ peptide significantly increased mitochondrial membrane integrity and decreased LPS-induced mitochondria fission. Interestingly, PDZ peptide dramatically could reduce LPS-induced NF-κB signaling, ROS production, and the expression of M1 macrophage marker proteins, but increased the expression of M2 macrophage marker proteins. These results indicated that PEGylated PDZ peptide inhibits LPS-induced systemic inflammation, reducing tissue injuries and reestablishing homeostasis, and may be a therapeutic candidate against systemic inflammation.

IntroductionErlotinib is an epidermal growth factor receptor (EGFR) inhibitor that is approved by the FDA to treat non-small cell lung cancer (NSCLC). Several membrane receptors, including EGFR, interact with amyloid β (Aβ), raising the possibility that erlotinib could have therapeutic effects on Alzheimer's disease (AD). However, the effects of erlotinib on Aβ/tau-related pathology and cognitive function in mouse models of AD and its mechanisms of action have not been examined in detail.MethodsTo investigate the effects of erlotinib on cognitive function and AD pathology, 3 to 6-month-old PS19 mice and 3 to 3.5-month-old 5xFAD mice and WT mice were injected with vehicle (5% DMSO + 10% PEG + 20% Tween80 + 65% D.W.) or erlotinib (20 mg/kg, i.p.) daily for 14 or 21 days. Then, behavioral tests, Golgi staining, immunofluorescence staining, western blotting ELISA, and real-time PCR were conducted.Results and discussionWe found that erlotinib significantly enhanced short-term spatial memory and dendritic spine formation in 6-month-old P301S tau transgenic (PS19) mice. Importantly, erlotinib administration reduced tau phosphorylation at Ser202/Thr205 (AT8) and Thr231 (AT180) and further aggregation of tau into paired helical fragments (PHFs) and neurofibrillary tangles (NFTs) in 3-month-old and/or 6-month-old PS19 mice by suppressing the expression of the tau kinase DYRK1A. Moreover, erlotinib treatment decreased astrogliosis in 6-month-old PS19 mice and reduced proinflammatory responses in primary astrocytes (PACs) from PS19 mice. In 3- to 3.5-month-old 5xFAD mice, erlotinib treatment improved short-term spatial memory and hippocampal dendritic spine number and diminished Aβ plaque deposition and tau hyperphosphorylation. Furthermore, erlotinib-treated 5xFAD mice exhibited significant downregulation of astrocyte activation, and treating PACs from 5xFAD mice with erlotinib markedly reduced cxcl10 (reactive astrocyte marker) and gbp2 (A1 astrocyte marker) mRNA levels and proinflammatory cytokine mRNA and protein levels. Taken together, our results suggest that erlotinib regulates tau/Aβ-induced AD pathology, cognitive function, and Aβ/tau-evoked astrogliosis and therefore could be a potent therapeutic drug for ameliorating AD symptoms.

Abstract This study explores a symmetric configuration approach in anion exchange membrane (AEM) water electrolysis, focusing on overcoming adaptability challenges in dynamic conditions. Here, a rapid and mild synthesis technique for fabricating fibrous membrane‐type catalyst electrodes is developed. Our method leverages the contrasting oxidation states between the sulfur‐doped NiFe(OH)2 shell and the metallic Ni core, as revealed by electron energy loss spectroscopy. Theoretical evaluations confirm that the S–NiFe(OH)2 active sites optimize free energy for alkaline water electrolysis intermediates. This technique bypasses traditional energy‐intensive processes, achieving superior bifunctional activity beyond current benchmarks. The symmetric AEM water electrolyzer demonstrates a current density of 2 A cm−2 at 1.78 V at 60°C in 1 M KOH electrolyte and also sustains ampere‐scale water electrolysis below 2.0 V for 140 h even in ambient conditions. These results highlight the system's operational flexibility and structural stability, marking a significant advancement in AEM water electrolysis technology.

Background: Several biologics have been developed and used to treat severe asthma. However, commercialized biologics have limitations in treating T2-low asthma because their main target is the T2 inflammation marker. Therefore, there is an unmet need for treating T2-low severe asthma. Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is an auxiliary protein in the mammalian multi-aminoacyl-tRNA synthetase complex. AIMP1 also acts as a cytokine and induces the secretion of proinflammatory cytokines. Since anti-AIMP1 has been shown to reduce interleukin (IL)-6, tumor necrosis factor-α, and IL-17A levels in a mouse model, it could be effective in the treatment of T2-low severe asthma. Methods: Wild-type BALB/c mice were sensitized and challenged with intranasal inoculation of a crude HDM extract. Atliximab, a chimeric AIMP1 antibody, was administered once (20 μg, 40 μg, 100 μg) on Day 14. We evaluated airway hyperresponsiveness (AHR), performed cellular analyses of the bronchoalveolar lavage fluid (BALF), measured inflammatory cytokine levels, and examined peribronchial histological features. Results: Atliximab reduced AIMP1 levels in asthmatic mice in a dose-dependent manner. AHR and Inflammatory cells such as neutrophils and eosinophils in the BALF decreased in asthmatic mice treated with atliximab. The levels of IL-6, IL-13, and transforming growth factor-β (TGF-β) in the lung tissue decreased in asthmatic mice treated with a high dose of atliximab (100 μg). Atliximab also reduced goblet cell hyperplasia and peribronchial fibrosis. Conclusions: Atliximab improved asthmatic airway inflammation including neutrophilic inflammation in HDM-induced asthma mice. These data suggest that anti-AIMP1 plays an important role in the treatment of severe T2-low asthma.

Background: Korean red ginseng extract (KRGE) (Family: Araliaceae) is one of the most widely used traditional herbs in Asia. Multiple studies have shown that KRGE has anti-inflammation, anti-fatigue, anti-obesity, anti-oxidant, and anti-cancer effects. Methods: Sprague-Dawley rats were divided into five groups for PTU-induced hypothyroidism and six groups for LT4-induced hyperthyroidism. At the experiment's conclusion, rats were sacrificed, and blood, thyroid gland, and liver samples were collected. Body weight was recorded weekly, and serum hormone levels were assessed using enzyme-linked immunoassay. Thyroid gland and liver tissues were stained with hematoxylin and eosin. KRGE was prepared in 0.5% CMC and stored at 4 °C before administration. Results: In the LT4-induced hyperthyroidism model, KRGE prevented decreases in body weight, thyroid gland weight, liver weight, serum glucose, and thyroid hormone levels compared to the PTU group. It also reduced increases in T3, T4, and serum aspartate aminotransferase levels after LT4 treatment. Additionally, KRGE improved thyroid gland and liver histopathology, effects not observed in the PTU-induced hypothyroidism model. Conclusion: All things considered, our research points to KRGE's potential protective role in rat hyperthyroidism caused by LT4 by lowering thyroid hormone production.

Objective: Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH). Methods: Unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity in vitro and in vivo. Results: We observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH. Interestingly, proteomic analysis showed that Rplp1, which regulates ribosome and translation pathways, was one of the most downregulated proteins. Moreover, decreased Esrra expression and binding to the Rplp1 promoter, diminished Rplp1 gene expression during lipotoxicity. This, in turn, reduced global protein translation and Esrra/Rplp1-dependent translation of lysosome (Lamp2, Ctsd) and autophagy (sqstm1, Map1lc3b) proteins. Of note, Esrra did not increase its binding to these gene promoters or their gene transcription, confirming its regulation of their translation during lipotoxicity. Notably, hepatic Esrra-Rplp1-dependent translation of lysosomal and autophagy proteins also was impaired in MASH patients and liver-specific Esrra knockout mice. Remarkably, alternate day fasting induced Esrra-Rplp1-dependent expression of lysosomal proteins, restored autophagy, and reduced lipotoxicity, inflammation, and fibrosis in hepatic cell culture and in vivo models of MASH. Conclusions: Esrra regulation of Rplp1-mediated translation of lysosome/autolysosome proteins was downregulated during MASH. Alternate day fasting activated this novel pathway and improved MASH, suggesting that Esrra and Rplp1 may serve as therapeutic targets for MASH. Our findings also provided the first example of a nuclear hormone receptor, Esrra, to not only regulate transcription but also protein translation, via induction of Rplp1.

Abstract Dopamine plays important roles in cognitive function and inflammation and therefore is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Drugs that increase or maintain dopamine levels in the brain could be a therapeutic strategy for AD. However, the effects of dopamine and its precursor levodopa (L-DOPA) on Aβ/tau pathology in vivo and the underlying molecular mechanisms have not been studied in detail. Here, we investigated whether L-DOPA treatment alters neuroinflammation, Aβ pathology, and tau phosphorylation in 5xFAD mice, a model of AD. We found that L-DOPA administration significantly reduced microgliosis and astrogliosis in 5xFAD mice. In addition, L-DOPA treatment significantly decreased Aβ plaque number by upregulating NEP and ADAM17 levels in 5xFAD mice. However, L-DOPA-treated 5xFAD mice did not exhibit changes in tau hyperphosphorylation or tau kinase levels. These data suggest that L-DOPA alleviates neuroinflammatory responses and Aβ pathology but not tau pathology in this mouse model of AD.

Background: Sleep accounts for approximately one-third of a person’s lifetime. It is a relaxing activity that relieves mental and physical fatigue. Pillows of different sizes, shapes, and materials have been designed to improve sleep quality by achieving an optimal sleep posture. Objects: This study aimed to determine which pillow provides the most comfortable and supports the head and neck during sleep, which may enhance sleep quality. Methods: Twenty-eight healthy adults (19 males and 9 females) with an average age of 29 years participated in this cross-sectional study. This experiment was conducted while the participants laid down for 5 minutes in four different pillow conditions: (1) no pillow (NP), (2) neck support foam pillow (NSFP), (3) standard microfiber filled pillow (SFP), and (4) hybrid foam pillow (HFP). The head-neck peak pressure, cranio-vertebral angle in supine (CVAs), cranio-horizontal angle in supine (CHAs), chin-sternum distance (CSD), and muscle tone of sternocleidomastoid were analyzed using one-way repeated measures analysis of variance (ANOVA). The significance level was set at p < 0.05. Results: The head-neck peak pressure was the highest in the NSFP condition, followed by the NP, SFP, and HFP conditions. The CVAs, CHAs, and CSD of the SFP were lower than those of the other pillows. Muscle tone was the highest in the NP condition, followed by the of NSFP, HFP, and SFP conditions. The participants subjective comfort level in both the supine and side-lying postures was highest in the HFP condition, followed by the SFP and NSFP conditions. Conclusion: This study can be used to establish the importance of pillow selection for highquality sleep. The results of this study, suggest that a hybrid pillow with a good supportive core and appropriate fluffiness can maintain comfort and correct cervical spine alignment during sleep.

Purpose Electroencephalography (EEG) is useful for clarifying the association between cortical activity and cognitive processes in children. We investigated whether EEG abnormalities were correlated with developmental delay/intellectual disability (DD/ID) in the absence of clinical seizures. Methods We retrospectively identified 166 children with DD/ID who underwent EEG at Pusan National University Hospital between January 2011 and December 2021. We compared clinical characteristics and test results between those with normal and those with abnormal EEGs. Additionally, we analyzed EEG abnormalities in relation to neurodevelopmental disorders, specifically autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Results Of the 166 patients, 39 (23.5%) displayed abnormal EEGs, while 127 (76.5%) had normal EEGs. Of the former, 25 (64.1%) patients exhibited epileptiform discharges, including 22 (56.3%) with focal and three (7.7%) with generalized discharges. Focal discharges most frequently affected the central area (35.9%). Twenty patients (51.3%) exhibited rhythmic slowing patterns. Epilepsy diagnoses were significantly more common among patients with abnormal EEGs (n=8, 20.5%) than among those with normal EEGs (n=9, 7.1%) (P

Abstract Background Primary focal segmental glomerulosclerosis (FSGS) is a glomerular disease that sometimes recurs in patients after kidney transplantation (KT) and increases the risk of graft loss. Proteinuria is a common early sign of recurrent FSGS, but an abrupt decrease in urine volume is rare. Herein, we report a patient with early recurrence of FSGS with anuria following KT. Case presentation A 55-year-old man with end-stage kidney disease caused by primary FSGS experienced anuria on postoperative day 2 following deceased donor KT. Laboratory results revealed that serum tacrolimus trough levels were consistently elevated at the time of anuria. At first, we considered acute calcineurin inhibitor (CNI) nephrotoxicity based on graft biopsy on light microscopy, laboratory findings, and clinical courses. However, the allograft function did not recover even after discontinuation of CNI, and recurrent FSGS was diagnosed 2 weeks later on electron microscopy. A total of 13 sessions of plasmapheresis and two administrations of rituximab (375 mg/m2) were required to treat recurrent FSGS. The patient achieved a partial response, and the spot urine protein-to-creatinine ratio decreased from 15.5 g/g creatinine to 5.2 g/g creatinine. At 5 months following KT, the serum creatinine level was stable at 1.15 mg/dL. Conclusions These findings highlight that anuria can occur in cases of early recurrence of FSGS combined with acute CNI nephrotoxicity.

Background We aimed to identify the risk of incident depression according to cumulative exposure to a low-household income status in individuals with type 2 diabetes mellitus (T2DM). Methods For this retrospective longitudinal population-based cohort study, we used Korean National Health Insurance Service data from 2002 to 2018. Risk of depression was assessed according to cumulative exposure to low-household income status (defined as Medical Aid registration) during the previous 5 years among adults (aged ≥20 years) with T2DM and without baseline depression who underwent health examinations from 2009 to 2012 (n=2,027,317). Results During an average 6.23 years of follow-up, 401,175 incident depression cases occurred. Advance in cumulative number of years registered for medical aid during the previous 5 years from baseline was associated with an increased risk of depression in a dose-dependent manner (hazard ratio [HR], 1.44 [95% confidence interval (CI), 1.38 to 1.50]; HR, 1.40 [95% CI, 1.35 to 1.46]; HR, 1.42, [95% CI, 1.37 to 1.48]; HR, 1.46, [95% CI, 1.40 to 1.53]; HR, 1.69, [95% CI, 1.63 to 1.74] in groups with 1 to 5 exposed years, respectively). Insulin users exposed for 5 years to a low-household income state had the highest risk of depression among groups categorized by insulin use and duration of low-household income status. Conclusion Cumulative duration of low-household income status, defined as medical aid registration, was associated with an increased risk of depression in a dose-response manner in individuals with T2DM.

Abstract Polyhexamethylene guanidine phosphate (PHMG-p) is a major component in humidifier disinfectants, which cause life-threatening lung injuries. However, to our knowledge, no published studies have investigated associations between PHMG-p dose and lung damage severity with long-term follow-up. Therefore, we evaluated longitudinal dose-dependent changes in lung injuries using repeated chest computed tomography (CT). Rats were exposed to low (0.2 mg/kg, n = 10), intermediate (1.0 mg/kg, n = 10), and high (5.0 mg/kg, n = 10) doses of PHMG-p. All rats underwent repeated CT scans after 10 and 40 weeks following the first exposure. All CT images were quantitatively analyzed using commercial software. Inflammation/fibrosis and tumor counts underwent histopathological evaluation. In both radiological and histopathologic results, the lung damage severity increased as the PHMG-p dose increased. Moreover, the number, size, and malignancy of the lung tumors increased as the dose increased. Bronchiolar–alveolar hyperplasia developed in all groups. During follow-up, there was intergroup variation in bronchiolar–alveolar hyperplasia progression, although bronchiolar–alveolar adenomas or carcinomas usually increase in size over time. Thirty-three carcinomas were detected in the high-dose group in two rats. Overall, lung damage from PHMG-p and the number and malignancy of lung tumors were shown to be dose-dependent in a rat model using repeated chest CT scans during a long-term follow-up.

Abstract Intracranial arterial dolichoectasia (IADE) is associated with the interaction of hypertension and inflammation, and microcurrent can be effective in hypertension. Therefore, this study aimed to investigate the therapeutic effect of microcurrent electrical stimulation in a mouse IADE model. This study randomly categorized 20 mice into five groups: group 1-C (healthy control), group 2-D (IADE model), group 3-M + D (microcurrent administration before nephrectomy and until brain surgery), group 4-D + M (microcurrent administration for 4 weeks following brain surgery), and group 5-M (microcurrent administration for 4 weeks). Cerebral artery diameter and thickness and cerebral arterial wall extracellular matrix components were assessed. Among the five groups, group 2-D showed significantly higher cerebral arterial wall diameter (117.79 ± 17.05 µm) and proportion of collagen (42.46 ± 14.12%) and significantly lower arterial wall thickness (9.31 ± 2.26 µm) and proportion of smooth muscle cell (SMC) and elastin in the cerebral arterial wall (SMC: 38.05 ± 10.32%, elastin: 11.11 ± 6.97%). Additionally, group 4-D + M exhibited a non-significantly lower diameter (100.28 ± 25.99 µm) and higher thickness (12.82 ± 5.17 µm). Group 5-M demonstrated no evidence of toxicity in the liver and brain. The pilot study revealed that microcurrent is effective in preventing IADE development, although these beneficial effects warrant further investigation.