Contrasting Effects of Cancer-Associated Mutations in EphA3 and EphB2 Kinases.

Erythropoietin-producing hepatoma (Eph) receptors are a family of tyrosine kinases that can act as tumor promoters or tumor suppressors, depending on the receptor and cancer cell type. Cancer-associated somatic mutations have been identified in all Eph receptors, but in most cases, the functional effects of the mutations are unknown. In this study, we expressed and purified the kinase domains of wild-type (WT) EphA3 and EphB2 along with 16 cancer-associated mutants. We identified mutations that decrease EphA3 activity and both activating and inhibitory mutations in EphB2. To shed light on the mechanisms by which the mutations altered kinase activity, we measured the thermal stabilities of the enzymes and performed steady-state kinetic experiments. We also expressed the full-length receptors in HEK293T cells to determine the cellular effects. WT EphB2 promoted downstream ERK signaling, while a kinase-inactive mutant (S706F) was similar to the control cells. In contrast, WT EphA3 (but not loss-of-function mutants) inhibited ERK signaling. The reciprocal effects of EphB2 and EphA3 on ERK phosphorylation in HEK293T cells were also evident in Ras-GTP loading. Thus, consistent with the dual roles of Eph receptors as tumor promoters and tumor suppressors, somatic mutations have the potential to increase or decrease Eph function, resulting in changes in the downstream signaling transduction.

Colorectal cancer-associated mutations impair EphB1 kinase function.

Erythropoietin-producing hepatoma (Eph) receptor tyrosine kinases regulate the migration and adhesion of cells that are required for many developmental processes and adult tissue homeostasis. In the intestinal epithelium, Eph signaling controls the positioning of cell types along the crypt-villus axis. Eph activity can suppress the progression of colorectal cancer (CRC). The most frequently mutated Eph receptor in metastatic CRC is EphB1. However, the functional effects of EphB1 mutations are mostly unknown. We expressed and purified the kinase domains of WT and five cancer-associated mutant EphB1 and developed assays to assess the functional effects of the mutations. Using purified proteins, we determined that CRC-associated mutations reduce the activity and stability of the folded structure of EphB1. By mammalian cell expression, we determined that CRC-associated mutant EphB1 receptors inhibit signal transducer and activator of transcription 3 and extracellular signal-regulated kinases 1 and 2 signaling. In contrast to the WT, the mutant EphB1 receptors are unable to suppress the migration of human CRC cells. The CRC-associated mutations also impair cell compartmentalization in an assay in which EphB1-expressing cells are cocultured with ligand (ephrin B1)-expressing cells. These results suggest that somatic mutations impair the kinase-dependent tumor suppressor function of EphB1 in CRC.

Biochemical Studies of Systemic Lupus Erythematosus-Associated Mutations in Nonreceptor Tyrosine Kinases Ack1 and Brk.

Tyrosine kinases (TKs) play essential roles in signaling processes that regulate cell survival, migration, and proliferation. Dysregulation of tyrosine kinases underlies many disorders, including cancer, cardiovascular and developmental diseases, as well as pathologies of the immune system. Ack1 and Brk are nonreceptor tyrosine kinases (NRTKs) best known for their roles in cancer. Here, we have biochemically characterized novel Ack1 and Brk mutations identified in patients with systemic lupus erythematosus (SLE). These mutations are the first SLE-linked polymorphisms found among NRTKs. We show that two of the mutants are catalytically inactive, while the other three have reduced activity. To understand the structural changes associated with the loss-of-function phenotype, we solved the crystal structure of one of the Ack1 kinase mutants, K161Q. Furthermore, two of the mutated residues (Ack1 A156 and K161) critical for catalytic activity are highly conserved among other TKs, and their substitution in other members of the kinase family could have implications in cancer. In contrast to canonical gain-of-function mutations in TKs observed in many cancers, we report loss-of-function mutations in Ack1 and Brk, highlighting the complexity of TK involvement in human diseases.

GPU-Accelerated PD-IPM for Real-Time Model Predictive Control in Integrated Missile Guidance and Control Systems.

This paper addresses the problem of real-time model predictive control (MPC) in the integrated guidance and control (IGC) of missile systems. When the primal-dual interior point method (PD-IPM), which is a convex optimization method, is used as an optimization solution for the MPC, the real-time performance of PD-IPM degenerates due to the elevated computation time in checking the Karush-Kuhn-Tucker (KKT) conditions in PD-IPM. This paper proposes a graphics processing unit (GPU)-based method to parallelize and accelerate PD-IPM for real-time MPC. The real-time performance of the proposed method was tested and analyzed on a widely-used embedded system. The comparison results with the conventional PD-IPM and other methods showed that the proposed method improved the real-time performance by reducing the computation time significantly.

Effect of herbal extracts and supplement mixture on alcohol metabolism in Sprague Dawley-rats.

This study aimed to investigate the effect of mixture of herbal extracts and supplementary formula (FNP-C) on hangovers and antioxidant enzymes in alcohol-induced liver damage in rats. HepG2 cells were used as the experimental cells and divided into five groups: non-treated control (normal), alcohol-induced control (control), mixture of herbal extracts (FNP-B), FNP-C, and a commercial treatment of liver diseases (Livers®); inhibition of detoxification and alcohol-induced damage was confirmed in vivo. Blood alcohol and acetaldehyde concentration after alcohol consumption were measured in a timely manner; alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), superoxide dismutase (SOD), glutathione (GSH), glutathione transferase (GST), and lactate dehydrogenase (LDH) levels were measured in the liver. FNP-C exhibited the highest effect. When FNP-C was administered to alcohol-induced animals, blood alcohol and acetaldehyde concentration decreased compared to FNP-B and Livers®. FNP-C reduced ADH levels and improved LDH, GSH, GST, and SOD levels. The FNP-C group was effective in preventing alcohol-induced hangovers and liver damage. Thus, FNP-C improves hangovers and increases antioxidant activity in an alcohol-induced model. Adding amino acids and vitamins to natural ingredients can potentially enhance the effect of improving hangovers.

Quercetin-glutamic acid conjugate with a non-hydrolysable linker; a novel scaffold for multidrug resistance reversal agents through inhibition of P-glycoprotein.

Previously, we have reported remarkable effect of a quercetin-glutamic acid conjugate to reverse multidrug resistance (MDR) of cancer cells to a broad spectrum of anticancer agents through inhibition of P-glycoprotein (Pgp)-mediated drug efflux. Due to the hydrolysable nature, MDR-reversal activity of the quercetin conjugate was attributed to its hydrolysis product, quercetin. However, several lines of evidence demonstrated that the intact quercetin-glutamic acid conjugate has stronger MDR-reversal activity than quercetin. In order to evaluate this hypothesis and to identify a novel scaffold for MDR-reversal agents, we prepared quercetin conjugates with a glutamic acid attached at the 7-O position via a non-hydrolysable linker. Pgp inhibition assay, Pgp ATPase assay, and MDR-reversal activity assay were performed, and the non-hydrolysable quercetin conjugates showed significantly higher activities compared with those of quercetin. Unfortunately, the quercetin conjugates were not as effective as verapamil in Pgp-inhibition and thereby reversing MDR, but it is worth to note that the structurally modified quercetin conjugates with a non-cleavable linker showed significantly improved MDR-reversal activity compared with quercetin. Taken together, the quercetin conjugates with appropriate structural modifications were shown to have a potential to serve as a scaffold for the design of novel MDR-reversal agents.

Sasang constitution may act as a risk factor for prehypertension.

BACKGROUND: Prehypertension (pre-HTN), similar to hypertension, has been associated with an elevated risk of cardiovascular disease. The aim of this study was to determine whether the Sasang constitution (SC) types could also be independent risk factors for pre-HTN. METHODS: A total of 2,806 eligible subjects, older than 20 years old from 25 medical clinics, participated. Clinical data, including the blood pressure, age, height, weight, and data from blood tests, were collected. One-way ANOVA with Scheffé's post-hoc analysis and the chi-square test were used, according to the SC and sex. Logistic regression was used to generate the odds ratios (ORs) and 95% confidence interval (CI) for pre-HTN. RESULTS: The pre-HTN prevalence rates of the Soeumin type, Soyangin type and Tae-eumin type were 59.4%, 60.1% and 74.9%, respectively, in men (p < 0.001) and 41.7%, 44.4% and 58.3% in women (p < 0.001). The Soyangin type was not more associated with increased ORs than the Soeumin type in any of the subjects with pre-HTN. Even after adjusting for sex, BMI, FBG, TC, TGs, HDL, and LDL, the Tae-eumin type in men was associated with increased ORs of pre-HTN compared with the Soeumin type (OR 1.57, 95% CI 1.03-2.39), but the Tae-eumin type in women was not associated with pre-HTN. CONCLUSIONS: This study suggested that the Tae-eumin type combined with sex might be significantly and independently associated with pre-HTN, especially high pre-HTN.

Long-Term Care Insurance for Older Adults in Terms of Community Care in South Korea: Using the Framework Method.

This study aimed to analyze the long-term care insurance for older adults in South Korea in terms of community care. An analytical framework was designed for the study, focusing on comprehensiveness, adequacy, and integration. The findings suggest that Korean LTCI is significantly limited for the development of community care. First, in terms of comprehensiveness, the use of visiting nurses and the availability of short-stay services have been significantly reduced, and the supporting services for informal caregivers are at the beginning stage of their introduction. Second, in terms of adequacy, the quantity of benefits, such as three to four hours of care a day, are insufficient to meet older adults' substantial needs. Furthermore, the overall quality of home care services is low, particularly with regard to short-stay services and welfare equipment. Finally, in terms of integration, basic linkage of organizations has not been properly conducted in local areas, and there remains an absence of care managers in the LTCI system. To cope with these challenging issues, the following policy measures are suggested: the activation of rehabilitation services, the expansion of benefit quantities, the improvement of service quality, and the creation of organizational linkages through local authorities and long-term care centers.

Factors Influencing Suicidal Ideation According to the Deprivation Indices of Different Regions in Korea.

OBJECTIVES: This study examined how deprivation differed by region and the effect those differences had on suicidal ideation among the local population. METHODS: Data collected over 10 years (2012-2021) in the Korea Welfare Panel Study were organized into 3 categories: metropolitan, city, and rural. A panel analysis was conducted on the impact of deprivation indices, socio-demographic characteristics, and life satisfaction on suicidal ideation in each category. RESULTS: Income, divorce status, family relationship satisfaction, and medical deprivation had a significant impact on suicidal ideation in metropolitan areas, whereas these variables did not have significant effects in rural areas. In other words, income, family, and medical support were more impactful in city areas. CONCLUSIONS: Although the deprivation index was higher in rural areas than in city areas due to an aging population and reduced income levels, the mental health of rural residents was found to be generally better than that of city residents. The possibility that this is related to the strength of relationships within the respective communities should be considered in light of recent discussions on relational welfare.

Factors of Capital on Depression in Older Adulthood: A Comparison of Urban and Rural Regions in Korea.

This study analyses old-age capital in its economic, cultural, and social components, in terms of how it impacts on depression in the elderly, comparing urban and rural regions. Our comparative analysis in urban and rural areas focuses on South Korea, using the Korean Welfare Panel Data from 2012 to 2020. Time-series trends and variables measuring capital and depression in older adults were examined in panel data analyses. Depression among the Korean elderly was at a similar level in urban and rural areas, whereas satisfaction regarding income levels, leisure life, and social relationships was higher for older adults in rural areas. We also found that the higher the economic capital, the higher the leisure life satisfaction (cultural capital), and the higher the social relationship satisfaction (social capital), the lower the rates of depression. Finally, depression among the urban elderly did not decrease as house prices increased as a component of economic capital, and depression decreased among groups participating in volunteer activities as part of the social capital of the rural elderly. In accordance with the socioemotional selectivity theory, older adults in rural areas in Korea have an advantage in terms of cultural capital due to their environment, whereas the psychosocial environment theory is relevant to urban elderly people experiencing relative deprivation in terms of economic capital.

Comparative Analysis of Long-Term Care in OECD Countries: Focusing on Long-Term Care Financing Type.

This study aims to examine the characteristics of long-term care (LTC) financing in Organization for Economic Cooperation Development (OECD) countries. To this end, the 26 OECD countries that have introduced LTC systems were classified into three types of models: tax-based, health insurance, and LTC insurance (LTCI) systems. Thereafter, these systems were analyzed using Gilbert and Terrell's policy analysis framework. The results indicated differences in the characteristics of each type of financing in terms of allocation, benefit provision, service delivery, and finance. It is likely that while the LTC insurance model was mainly based on universalism and showed the highest level of coverage, the tax-based and health insurance models adopted selectivism with lower level of benefits per capita. In terms of service delivery, local authorities tended to have the responsibility to decide LTC service users and provide services in many countries, regardless of the type of model. In terms of finance, LTC insurance-based countries had the highest LTC expenditure as a percentage of GDP, followed by countries with tax-based and health insurance systems.

Sasang Constitution May Act as a Risk Factor for Depressive Symptoms-A Survey for Local Residence.

This study investigated whether a person's Sasang constitution (SC) could be a risk factor for depressive symptoms. We classified the SC of 653 participants into Taeeumin (TE), Soeumin (SE), and Soyangin (SY), using the KS−15 questionnaire. We also categorized them into depressive and non-depressive symptom groups using the Center for Epidemiologic Studies Depression scale questionnaire. A t-test and chi-square test were used to compare the general characteristics of the depressive and non-depressive symptom groups. A one-way analysis of variance compared the scores of depressive symptoms according to SC, and a multiple logistic regression obtained the odds ratios (ORs); p < 0.05. The depressive symptom score for SE (13.6 ± 9.97) was significantly higher than that for SY (9.2 ± 6.51) and TE (10.8 ± 7.70; p < 0.001; SE > TE, SY, Scheffé). SE was associated with an increased prevalence of depressive symptoms compared with SY (OR: 2.315; 95% confidence interval [CI]: 1.389−3.860, p < 0.01) and TE (OR: 1.660; 95% CI: 1.076−2.561, p < 0.05), as well as an increased prevalence of depressive symptoms compared with SY (OR: 2.907; 95% CI: 1.379−6.144, p < 0.01) after adjusting for average height and distribution of living with family, medication, and drinking. This study reveals that SC, particularly SE, could be significantly associated with and be considered a risk factor for depressive symptoms.

Low Self-Rated Health as A Risk Factor for Depression in South Korea: A Survey of Young Males and Females.

This is a cross-sectional study aimed to examine whether low self-rated health (SRH) is a risk factor for depression among young males and females. Data from the SRH, quality of life (QoL) and depression questionnaires as well as general information, were collected from 512 males and females aged 20-29 years in South Korea. Chi-square test was used to analyze the distribution of depression between the high and low SRH groups. Logistic regression was used to analyze the relationship between SRH and depression after adjusting for covariates. There were 32.6% males and 30.1% females who were at risk for depression. A significant difference in the distribution of depression between the low and high SRH groups in both males and females was found. The low SRH group had a higher prevalence of depression than the high SRH group in both males and females in the crude analysis. However, when the BMI, economic status, and mental component score were adjusted, the OR of the low SRH group was still significant in males. Low SRH may be a risk factor for depression especially in males. Further studies to improve SRH by developing preventive measures against depression status while considering gender characteristics are needed.

Acai berry extract as a regulator of intestinal inflammation pathways in a Caco-2 and RAW 264.7 co-culture model.

The aim of this study was to assess the anti-inflammatory effects of acai berries in a Caco-2 and RAW 264.7 macrophage co-culture model. The acai berry extract (ABE) was prepared using 70% ethanol, and total anthocyanin, polyphenol, and flavonoid contents in ABE were analyzed. To the antioxidant activity of ABE, we measured radical scavenging activity as well as ferric reducing antioxidant power values. Prior to inducing inflammation, Caco-2 cells were co-cultured with RAW 264.7. Inflammation was induced using lipopolysaccharides (LPS) in RAW 264.7 cells. The transepithelial electrical resistance value was significantly recovered and the mRNA level of tight junction proteins, including ZO-1, JAM-1, and claudin-4, tended to increase compared with that in the LPS group. LPS-induced interleukin (IL)-6, IL-8, and prostaglandin E2 levels reduced significantly following treatment with the highest ABE concentration. In the highest ABE concentration, the phosphorylation of p65, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase was downregulated compared with the LPS group. The phosphorylation of extracellular signal-regulated kinase showed a decreased tendency. These results suggest that acai berry may improve gastrointestinal health. PRACTICAL APPLICATIONS: Acai berry is known to have abundant anthocyanin, which has many biological activities, including anti-inflammatory, antioxidant, antihypertensive, and anticytotoxic/cytoprotective activities. This study demonstrated the anti-inflammatory effects of acai berry extracts via TEER value, expression of tight junction protein, and production of inflammatory mediators and cytokines in the Caco-2 and RAW 264.7 co-culture model. Therefore, acai berry has the potential to prevent intestinal inflammatory diseases.

Drinking Trajectories and Factors in Koreans.

This study aimed to explore the drinking culture in Korea by sex, age, household type, occupation, and income level to identify demographic groups with prominent drinking behaviors and factors affecting their drinking. Furthermore, we evaluated recent changes, including those due to COVID-19, in drinking behavior, using data from the Korea Welfare Panel Study from 2010 to 2020. Panel analysis was performed to reveal the effects of material deprivation, depression, and sociodemographic factors on drinking behavior. We used the AUDIT 3 scale including frequency of drinking, average amount of drinking, and frequency of excessive drinking. The two characteristics of Korean drinking are consistent with the claim of the ecological system theory that humans, as social beings, drink to facilitate social communication or promote problematic drinking when social communication is difficult. Drinking among Koreans is characterized by a pattern that alternates between social drinking and problem drinking. Our study recognizes drinking as a social problem that should be managed at social as well as national levels.

Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer.

Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.

Reasons for Turnover Intention among Direct Care Workers in Korea's Long-Term Care Insurance.

This study explored reasons for turnover intention among direct care workers under the Korean long-term care insurance (LTCI) system. The author conducted semi-structured interviews with 19 care workers. The study revealed four main themes underlying the intention of care workers to change or leave their jobs. Care workers struggled with demanding working conditions, and their salaries were low. Moreover, the relationships with their directors and supervisors was not good, since some care workers felt that their directors despised them or gave them inappropriate instructions, and their supervisors did not complete administrative work fairly. Lastly, some workers' health conditions prevented them from carrying out their care work. The results have implications for working practices of care workers, prices of LTCI services, training of directors and supervisors, and coverage of occupational health and safety insurance for care workers.

A Study of Care Workers' Wages and Relevant Factors in South Korea.

The purpose of this study is to analyze the wages of South Korea's care workers as reported by the Korean national health insurance services database. We also try to identify the factors determining the wages of these 1,221,085 care workers. According to the results of the analysis, first, the wage level of care workers is fundamentally low compared to other jobs; second, the labor conditions of home care facilities (compared to those in residential care facilities) are poor, because these depend on wages, which in turn depend on the external environment, such as care institutes' management; and third, it was verified that the locations of care institutes affect the wages of care workers. As the South Korean population continues to age, the supply of high-quality care workers has important clinical implications for improving the quality of care received by the elderly. Throughout this study, it is argued that the establishment of a social service corporation has become desirable in terms of strengthening public care institutes in Korea.

Comparison of digital fundus photographic and echographic measurements for maximal linear dimension from eyes with choroidal melanoma.

PURPOSE: Accurate assessment of tumor size is crucial in the treatment of choroidal melanoma. Digital fundus photographic systems can create a montage that clearly documents the tumor margins. These images can be used to measure tumor maximal linear dimension (MLD). This study evaluates the potential value of a digital imaging system compared with echography in measuring the MLD of choroidal melanoma. METHODS: Echographic measurements were performed in a standardized fashion following Collaborative Ocular Melanoma Study (COMS) methods. For photographic measurements, the tumor margin was outlined with an electronic pen and the MLD were calculated by software (ANKA-ProView, Topcon Medical Systems, Paramus, NJ). RESULTS: The mean MLD before I-125 brachytherapy was 9.32 mm by echography and 10.57 mm by digital photography analysis. This difference was statistically significant (P < 0.001). The 2 measurements of MLD agreed within 1.1 mm for 11 eyes (52%) and 2.2 mm for 20 eyes (95%). Digital photographic analysis estimated a larger MLD in 19 of the 21 eyes compared with echography. CONCLUSION: This discrepancy likely results from the photographic measurement more accurately assessing the flat portion of the tumor. Digital photographic analysis may allow clinicians to determine the MLD of tumors more accurately than echography. This could increase the rate of successful treatment with brachytherapy.

High glucose inhibits gene expression of tyrosyl-tRNA synthetase in osteoblast cells.

It has been suggested that bone metabolism disorders are one of the major complications of diabetes mellitus. However, the exact mechanisms as to how diabetes affects bone metabolism are yet to be determined. In the present study, we have searched for high glucose regulated genes in osteoblast-like UMR-106 cells. UMR-106 cells were treated with normal glucose (5.5 mM), high glucose (16.5 mM or 30.5 mM) and mannitol (16.5 mM) as a hyperosmotic control. Following the isolation of total RNA, GeneFishing differential display-PCR (DDPCR) was carried out and followed by cloning, sequencing and searching in a gene bank data base to identify the high glucose induced gene(s). Through the DD-PCR technique which employs Annealing Control Primer, or ACP, it has been found that expression of a PCR product was significantly decreased by high glucose treatment: it was identified as tyrosyl-tRNA synthetase. Furthermore, reverse transcriptase PCR analysis confirmed that high glucose significantly decreases mRNA expression of tyrosyl-tRNA synthetase, whereas mannitol treatment does not cause any change in such expression. These results suggest that high glucose may play a significant role in the protein synthesis process of osteoblast cells by decreasing expression of tyrosyl-tRNA synthetase. In a Western blot analysis, the protein expression of tyrosyl-tRNA synthetase was also decreased by high glucose treatment. Taken together, these results suggest that high glucose could affect bone metabolism by regulating the expression of tyrosyl-tRNA synthetase genes.