p300 KAT regulates SOX10 stability and function in human melanoma.

SOX10 is a lineage-specific transcription factor critical for melanoma tumor growth, while SOX10 loss-of-function drives the emergence of therapy-resistant, invasive melanoma phenotypes. A major challenge has been developing therapeutic strategies targeting SOX10's role in melanoma proliferation, while preventing a concomitant increase in tumor cell invasion. Here, we report that the lysine acetyltransferase (KAT) EP300 and SOX10 gene loci on Chromosome 22 are frequently co-amplified in melanomas, including UV-associated and acral tumors. We further show that p300 KAT activity mediates SOX10 protein stability and that the p300 inhibitor, A-485, downregulates SOX10 protein levels in melanoma cells via proteasome-mediated degradation. Additionally, A-485 potently inhibits proliferation of SOX10+ melanoma cells while decreasing invasion in AXLhigh/MITFlow melanoma cells through downregulation of metastasis-related genes. We conclude that the SOX10/p300 axis is critical to melanoma growth and invasion, and that inhibition of p300 KAT activity through A-485 may be a worthwhile therapeutic approach for SOX10-reliant tumors.

The CoREST repressor complex mediates phenotype switching and therapy resistance in melanoma.

Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated. Here, we evaluated the corepressor for element 1-silencing transcription factor (CoREST) epigenetic repressor complex and the recently developed bivalent inhibitor corin within the context of melanoma phenotype plasticity and therapeutic resistance. We found that CoREST was a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells led to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin revealed specific effects on histone marks connected to epithelial-mesenchymal transition-associated (EMT-associated) transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor-resistant (BRAFi-R) melanomas with corin promoted resensitization to BRAFi therapy. DUSP1 was consistently downregulated in BRAFi-R melanomas, which was reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity was recapitulated by the p38 MAPK inhibitor BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial for patients with BRAFi-resistant melanoma.

Conductive N, S doped Copolymers as Stable Metal-Free Electrocatalysts for Water Splitting.

Noble metals (Pt) and metal oxides (IrC and RuO2) are heavily utilized as benchmark electrocatalysts for alkaline water splitting; however, these materials possess several drawbacks including high cost, poor selectivity and stability, and high environmental impact. To address these issues, we synthesized a novel metal-free conducting polypyrrole-polythiophene (Ppy-Ptp) copolymer and a separate Ppy electrode material for water-splitting applications. The Ppy-Ptp and Ppy electrocatalysts exhibited remarkable activity in the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER), respectively. The optimal Ppy-Ptp (1:3) formulation, when deposited on a conductive nickel foam (NF) substrate, exhibited an exceptional OER performance with a low overpotential of approximately 250 mV at 20 mAcm-2, thereby outperforming the benchmark IrC/NF electrocatalyst (290 mV, 20 mAcm-2). Additionally, a similarly prepared Ppy/NF electrocatalyst exhibited an extraordinary HER performance with an overpotential of approximately 72 mV at 10 mA cm-2. Furthermore, an alkaline anion-exchange membrane (AEM) electrolyzer incorporating Ppy-Ptp (1:3) and Ppy as the anode and cathode materials, respectively, displayed operating potentials of 1.55, 1.70, and 1.78 V at 10, 50, and 100 mA cm-2, which are lower than those observed in previously reported electrolyzers. This electrolyzer also exhibited considerable operational endurance over 50 h at 50 mA cm-2, over which a negligible decay of 0.02 V was observed. The novel polymer-based metal-free catalysts presented herein therefore exhibit considerable potential as alternative electrocatalytic materials for sustainable industrial-scale H2 synthesis.

Individual Differences in the Association of Lifestyle with Cardiometabolic Risk in Middle-Aged Koreans Based on Traditional Korean Medicine.

Cardiometabolic (CM) risk differs in morbidity and disease progression depending on lifestyle and individual characteristics. This cross-sectional study aimed to analyze the association between CM risk and lifestyle and examine whether this association varies based on Sasang constitution (SC), a Korean medicine classification. Data were analyzed from 1996 individuals participating in the Korean Medicine Daejeon Citizen Cohort study. Individuals with CM risk had two to five CM risk factors. Lifestyle factors included physical activity, sleep duration, and eating index. SC types were Taeeum-in (TE) and non-TE. We estimated the odds ratio (OR) and 95% confidence interval for CM risk based on SC and lifestyle factors. Among the participants, 33.9% had a CM risk, and the TE and non-TE groups were 26.2% and 7.7%, respectively. In the TE group, CM risk was associated with low physical activity (OR, 1.63) and moderate eating index (OR, 1.41). In the non-TE group, CM risk was associated with ≥8 h of sleep (OR, 1.87) and marginally associated with ≤6 h of sleep. In the TE group alone, CM risk was significantly associated with lifestyle patterns that combined the three lifestyle factors and was approximately two-fold higher in patterns involving less physical activity. The effects of lifestyle on CM risk differed across SC types. To decrease the burden of cardiovascular diseases in middle-aged adults, we recommend an individualized management strategy of healthy lifestyle interventions for cardiovascular risks.

Social Sustainability of a Firm: Orientation, Practices, and Performances.

This paper investigates how firms' social sustainability practices can influence their social performance and, ultimately, financial performance. We include two corporate social sustainability practices: employee-oriented (employee well-being and equity) and socially driven (corporate social involvement) practices. Three leading social theories (social identity theory, social exchange theory, and resource-based view) are applied in explaining how firms' social practices influence intermediate and bottom-line performance outcomes. Empirical results of 212 US manufacturing firms reveal that (1) the social orientation of the firm promotes firms' social performances (employee-oriented and community-oriented outcomes) directly; (2) social orientation also indirectly promotes employee-oriented outcomes via employee well-being and equity practices, and so does community-oriented outcome via corporate social involvement practices; and (3) the firms' social performances can enhance financial performance. The theoretical and managerial implications derived from these empirical results are discussed as well.

Downregulation of SETD5 Suppresses the Tumorigenicity of Hepatocellular Carcinoma Cells.

Hepatocellular carcinoma (HCC) is an aggressive and incurable cancer. Although understanding of the molecular pathogenesis of HCC has greatly advanced, therapeutic options for the disease remain limited. In this study, we demonstrated that SETD5 expression is positively associated with poor prognosis of HCC and that SETD5 depletion decreased HCC cell proliferation and invasion while inducing cell death. Transcriptome analysis revealed that SETD5 loss downregulated the interferon-mediated inflammatory response in HCC cells. In addition, SETD5 depletion downregulated the expression of a critical glycolysis gene, PKM (pyruvate kinase M1/2), and decreased glycolysis activity in HCC cells. Finally, SETD5 knockdown inhibited tumor growth in xenograft mouse models. These results collectively suggest that SETD5 is involved in the tumorigenic features of HCC cells and that targeting SETD5 may suppress HCC progression.

Evaluation of thermal sensitivity is of potential clinical utility for the predictive, preventive, and personalized approach advancing metabolic syndrome management.

A possible association between metabolic disorders and ambient temperature has been suggested, and cold exposure as a way of increasing energy expenditure has gained considerable interest for preventative/therapeutic measures toward metabolic disorders. Although thermal sensitivity, which has recently been studied in regard to its utility as a risk assessment/patient stratification for various diseases, might influence physiological responses to ambient temperature on an individual basis, more studies are needed. We aimed to investigate the association between self-identified thermal intolerance/sensation and metabolic syndrome (MetS) to verify the working hypothesis that individuals with altered thermal sensitivity may have a predisposition to MetS. We fitted generalized additive models for thermal intolerance/sensation using body mass index (BMI) and waist-hip ratio in women, and identified those with higher/lower thermal intolerance/sensation than those predicted by the models. Higher heat intolerance, higher heat sensation, and lower cold intolerance were associated with a higher prevalence of MetS. The risk of having MetS was increased in those who had two or three associated conditions compared with those with none of these conditions. In an analysis for MetS components, significant associations of thermal sensitivity were present with high glucose, triglyceride, and blood pressure levels. Overall, higher heat intolerance/sensation and lower cold intolerance were associated with increased prevalence of MetS even at a similar level of obesity. Our study indicates that evaluation of thermal sensitivity may help identify individuals at high risk for MetS, and lead to more advanced patient stratification and personalized treatment strategies for MetS, including cold-induced thermogenesis. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00273-6.

Sex differences in perceived discomfort during seated static posture holding.

This study investigated how sex modifies postural discomfort perception during a sagittally-symmetric, seated static posture holding (SPH) task. Ten male and 10 female participants performed SPH and conducted subjective discomfort ratings in a total of 108 task conditions. A regression analysis found that the impacts of the body joint reactive moments on perceived discomfort were larger for the female group than the male whereas that of the shoulder joint angle was more pronounced for the male than the female. Also, some of the 108 task conditions were found to be more uncomfortable for the male group, while some others, for the female. The observed sex impacts are thought to be due to the sex differences in physical work capacities (muscular strength and joint flexibility). The results suggest that new posture analysis tools allowing sex-specific analyses are needed as they would improve the accuracy and precision of ergonomics posture analyses. Practitioner summary: This study empirically investigated how sex modifies postural discomfort perception during a seated posture holding (SPH) task. Sex was found to modify the impacts of joint reactive moments and the shoulder joint angle. The study results seem to reflect the sex differences in muscular strength and joint flexibility.

ZWC complex-mediated SPT5 phosphorylation suppresses divergent antisense RNA transcription at active gene promoters.

The human genome encodes large numbers of non-coding RNAs, including divergent antisense transcripts at transcription start sites (TSSs). However, molecular mechanisms by which divergent antisense transcription is regulated have not been detailed. Here, we report a novel ZWC complex composed of ZC3H4, WDR82 and CK2 that suppresses divergent antisense transcription. The ZWC complex preferentially localizes at TSSs of active genes through direct interactions of ZC3H4 and WDR82 subunits with the S5p RNAPII C-terminal domain. ZC3H4 depletion leads to increased divergent antisense transcription, especially at genes that naturally produce divergent antisense transcripts. We further demonstrate that the ZWC complex phosphorylates the previously uncharacterized N-terminal acidic domain of SPT5, a subunit of the transcription-elongation factor DSIF, and that this phosphorylation is responsible for suppressing divergent antisense transcription. Our study provides evidence that the newly identified ZWC-DSIF axis regulates the direction of transcription during the transition from early to productive elongation.

Comparison of Thoracic Epidural Access with Lateral Decubitus and Shoulder Rotation Positions for Repeat Thoracic Epidural Blockade.

BACKGROUND: Shoulder rotation has been shown to increase the acoustic window of ultrasound for thoracic epidural access. However, this effect of shoulder rotation has not yet been confirmed in clinical practice. OBJECTIVE: This study aimed to evaluate the effects of shoulder rotation on the thoracic epidural blockade in patients with acute or chronic pain in the thoracic region. STUDY DESIGN: Prospective crossover trial. SETTING: Pain clinic of our university in the Republic of Korea. METHODS: Forty patients aged 20 - 80 years with acute or chronic pain in the thoracic region who were scheduled to undergo thoracic epidural blockade more than twice. INTERVENTIONS: The patients underwent repeated fluoroscopy-guided thoracic epidural blockade via the paramedian approach in the lateral decubitus position either with or without shoulder rotation.The primary outcome measure was the attempt time to the confirmed spread of contrast. The number of attempts, total procedure time, vertical interpedicular distance, contrast spreading length, and complications were compared between the 2 positions. RESULTS: The median attempt times in the lateral decubitus and shoulder rotation positions were 138.8 and 132.5 seconds, respectively, and this difference was significant (P = 0.004). Compared with the lateral decubitus position, the shoulder rotation position was also associated with a significantly lower number of attempts (P = 0.03), shorter total procedure time (P < 0.001), and greater vertical interpedicular and contrast spreading distances (P < 0.001 and P = 0.02, respectively). LIMITATIONS: The operator in this study was not blinded to the patient groups. Other researchers observed the operator's procedure and evaluated and recorded the data in an attempt to overcome this bias. However, it was difficult to completely avoid the bias. Second, epidural blockade was performed at various levels (T3-11), and the anatomical features vary among thoracic spine levels. CONCLUSIONS: The study findings demonstrate the clinical benefits of the shoulder rotation position versus the lateral decubitus position in terms of successful epidural access during thoracic epidural blockade using the paramedian approach.

H2B ubiquitylation enhances H3K4 methylation activities of human KMT2 family complexes.

In mammalian cells, distinct H3K4 methylation states are created by deposition of methyl groups by multiple complexes of histone lysine methyltransferase 2 (KMT2) family proteins. For comprehensive analyses that directly compare the catalytic properties of all six human KMT2 complexes, we employed a biochemically defined system reconstituted with recombinant KMT2 core complexes (KMT2CoreCs) containing minimal components required for nucleosomal H3K4 methylation activity. We found that each KMT2CoreC generates distinct states and different levels of H3K4 methylation, and except for MLL3 all are stimulated by H2Bub. Notably, SET1BCoreC exhibited the strongest H3K4 methylation activity and, to our surprise, did not require H2B ubiquitylation (H2Bub); in contrast, H2Bub was required for the H3K4me2/3 activity of the paralog SET1ACoreC. We also found that WDR5, RbBP5, ASH2L and DPY30 are required for efficient H3K4 methyltransferase activities of all KMT2CoreCs except MLL3, which could produce H3K4me1 in the absence of WDR5. Importantly, deletion of the PHD2 domain of CFP1 led to complete loss of the H3K4me2/3 activities of SET1A/BCoreCs in the presence of H2Bub, indicating a critical role for this domain in the H2Bub-stimulated H3K4 methylation. Collectively, our results suggest that each KMT2 complex methylates H3K4 through distinct mechanisms in which individual subunits differentially participate.

Association between Resting Energy Expenditure and Heat Pattern in Traditional Medicine.

Many symptoms of heat pattern (HP) in traditional medicine are related to thermoregulation; however, research on the association between energy expenditure characteristics and HP is limited. We aimed to study the association between HP and resting energy expenditure (REE). A total of 109 participants were divided into the HP and non-HP groups based on a self-administered questionnaire and their REE was measured using an indirect calorimeter. Multiple logistic regression models were used to calculate the odds ratio (OR) of HP according to the level of REE. No significant differences in age, anthropometric, and body composition characteristics were observed between the HP and the non-HP groups. The likelihood of having an HP significantly increased with higher REE after adjustment for fat-free mass (OR 1.22 [95% CI 1.03-1.46]) and also after additional adjustment for sex and age (OR 1.21 [95% CI 1.01-1.46]). These results suggest that increased REE could be a biological characteristic of HP. Future studies are necessary to investigate the underlying mechanisms associated with the differing energy expenditure in HP.

Transcriptional regulation by the KMT2 histone H3K4 methyltransferases.

Histone lysine methyltransferase 2 (KMT2) proteins form multimeric enzymatic complexes that methylate lysine 4 on histone H3 (H3K4) at transcription regulatory elements in the genome. A strong association of H3K4 methylation with active transcription has led to intense efforts to reveal the functional involvement of KMT2 complexes in transcriptional regulation. A number of biochemical and cellular studies have shown that KMT2 complexes regulate transcription of target genes via H3K4 methylation. However, in many cases, loss of KMT2 complex enzymatic activity fails to fully account for observed transcriptional defects. Accumulating evidence indicates that, in certain contexts, KMT2 complex-mediated transcriptional regulation can occur in an H3K4 methylation-independent manner. Here, we comprehensively review functions of KMT2 complexes in gene expression, focusing on what we currently know about the molecular mechanisms by which the KMT2 complexes regulate transcription. We also discuss how aberrant transcriptional regulation by KMT2 complexes contributes to different human diseases, such as cancer.

Characterization of Surface-Modified Halloysite Nanotubes by Thermal Treatment Under Reducing Atmosphere.

In recent years, the halloysite (Al2Si2O5(OH)4 · 2H2O) has been highlighted owing to its naturally occurring one-dimensionalmicrostructure that enables versatile applications. Due to the demand for enhancing surface interaction, several types of research such as acid/base treatments have been conducted on the halloysite nanotubes. The objective of this study is to investigate the structural and surface properties of thermally treated halloysites under reducing atmosphere. The heat treatment is carried out in a gas-flow furnace at 400-800 °C under various atmosphere, e.g., ambient air, 4% H2-balanced Ar, and 99.99% H2. The thermal treatment of halloysites under reducing atmosphere show a similar phase transition around 500 °C as the heating under air. However, the halloysite reduced in pure hydrogen shows a significant increase of the zeta-potential, -36.7 mV for a 600 °C-treated sample, compared to the other samples. The mechanisms of the zeta-potential increase for the halloysite was also explored.

Validation of source detective system of the radionuclides measured in the atmosphere using a field tracer experiment.

A source detective system has been developed to estimate unknown source regions and release rates of radionuclides released into the air from covert nuclear activities and accidents. This system is composed of trajectory, atmospheric dispersion, and source term estimation models. Simulated results were compared with the measurements of a field tracer experiment performed at the Yeonggwang nuclear power plant in Korea in May 1996. Two trajectories among five computed backward trajectories moved toward the original release point, and the comparative results contained some error due to single operation of the backward trajectory model. An atmospheric dispersion model was used to minimize the error of the trajectory model and to improve the accuracy of the source detective system. The results generated by the trajectory and atmospheric dispersion models together agreed better with the measurements than those obtained using the trajectory model alone.

Effect of Traditional East Asian Medicinal herbal tea (HT002) on insomnia: a randomized controlled pilot study.

BACKGROUND: Complementary and alternative medicine treatment for insomnia has been sought due to the possible adverse effects of conventional pharmacotherapies. We performed a preliminary evaluation of the feasibility of using, and of the effect of a herbal tea (HT002), based on Traditional East Asian Medicine, in mild-to-moderate insomnia. METHODS: Patients (n = 40) with mild-to-moderate insomnia were randomized to the HT002 (n = 20) or waitlist (n = 20) groups. The HT002 group consumed HT002 twice daily for 4 weeks. Outcomes were assessed using the Insomnia Severity Scale (ISI), Pittsburgh Sleep Quality Index (PSQI), and 12-item Short Form Health Survey (SF-12) at baseline and after 4 and 8 weeks. RESULTS: The ISI score differences from baseline at weeks 4 and 8 were significantly greater in the HT002 than that in the waitlist group (week 4: -4.0 ± 0.8 vs. -0.4 ± 0.8, p < 0.05; week 8: -4.8 ± 0.7 vs. -0.9 ± 0.7, p < 0.05). Changes in PSQI and SF-12 physical component scores in the HT002 group were significantly greater at weeks 4 and 8 (p < 0.05), while SF-12 mental component scores were only significantly larger at 4 weeks (p < 0.05). HT002 was well-tolerated, with only one (5.0%) dropout, and no significant mean liver and renal function test changes post-treatment. CONCLUSION: Our preliminary results suggest that a 4-week treatment with HT002 may reduce the severity of insomnia symptoms and improve the quality of life. Further studies devoid of the limitations of our protocol may provide stronger conclusions. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), KCT0001900.

ASSESSMENT OF RADIOLOGICAL DOSES FOR PEOPLE LIVING IN KOREA FOLLOWING ACCIDENTAL RELEASES OF RADIONUCLIDES FROM NUCLEAR POWER PLANTS IN KOREA AND CHINA.

Accidentally released radionuclides are dispersed into the environment and cause human exposure through various pathways. Concerns about radiological impacts of a possible Nuclear power plant (NPP) accident in neighboring countries, especially in China, are increasing in Korea. Dose assessments for the hypothetical nuclear accidents in Korea (Hanbit and Wolsong NPPs) and China (Tianwan NPP) were conducted using the developed Korean code system. The results show that there is a possibility that a Tianwan NPP accident could have a slightly greater or similar impact on certain parts of Korea compared to accidents occurring at domestic NPPs, and could affect Korea within a few days of the accident. This research is expected to be used as basic material for preparing against nuclear accidents in neighboring countries.

The association between cold hypersensitivity in the hands and feet and chronic disease: results of a multicentre study.

BACKGROUND: Cold hypersensitivity in the hands and feet (CHHF) is a common symptom in Korea and patients with CHHF complain of coldness in the hands and feet in an environment that is not considered cold by unaffected people. In traditional East Asian medicine, CHHF is believed to be accompanied by various diseases and symptoms, and is considered a symptom that needs active treatment. CHHF is used for pattern identification in the cold pattern, yang deficiency, and constitution. This study aimed to examine the differences in frequencies of chronic diseases with respect to the presence of CHHF. METHODS: Disease history, CHHF, body measurements, and blood test survey data from 6149 patients collected by 25 medical institutes in Korea were obtained from the Korean Medicine Data Center. The participants were divided into CHHF (n = 1909) and non-CHHF groups (n = 3017) according to the CHHF survey. The differences in frequencies of 18 diseases were analysed using chi-square tests, and the odds ratios (ORs) for each disease according to CHHF status were examined via logistic regression with adjustment for age, sex, and body mass index (BMI). RESULTS: Based on chi-square test results, the CHHF group showed a higher frequency of the following diseases: anaemia, hypotension, chronic gastritis, reflux oesophagitis, chronic rhinitis, dysmenorrhoea, and gastroduodenal ulcer. Diseases found in lower frequencies were as follows: hypertension, diabetes mellitus, impaired fasting glucose, dyslipidaemia, stroke, fatty liver, and angina pectoris. In addition, from the logistic regression with adjustment for age, sex, and BMI, the CHHF group showed a lower OR in diabetes mellitus and dyslipidaemia than the non-CHHF group, but a higher OR in degenerative arthritis, chronic gastritis, gastroduodenal ulcer, reflux oesophagitis, and chronic rhinitis. CONCLUSIONS: This study showed that CHHF is associated with chronic disease. Further large-scale prospective studies are needed to validate these associations.

Perception of cold and heat pattern identification in diseases: a survey of Korean medicine doctors.

BACKGROUND: This study aimed to investigate the extent to which Korean Medicine doctors consider cold and heat pattern identification when prescribing herbal treatment for a disease. METHODS: A survey was sent by e-mail to 15,841 members of the Association of Korean Medicine for whom member information was registered. Of these, 699 (4.4%) members participated in the survey. The survey included questions regarding the frequency of use of cold and heat pattern identification in deciding a herbal treatment prescription, the diseases for which cold and heat pattern identification-related herbal treatment was most efficacious, the type of herbal treatment prescribed, and the duration of the treatment. RESULTS: Of the 699 respondents, 591 (84.5%) reported that they considered cold and heat when prescribing herbal treatment. The diseases for which consideration of cold and heat patterns was effective were, in order, menopausal disorder (124, 18.3%), chronic rhinitis (98, 14.5%), dyspepsia (94, 13.9%), hwa-byung (92, 13.6%), diarrhea (83, 12.3%), dysmenorrhea (61, 9.0%), headache (59, 8.7%), inflammation in the digestive tract (58, 8.6%), coldness in hands and feet (58, 8.6%), and atopic dermatitis (55, 8.1%). The typical treatment duration differed widely for different diseases: atopic dermatitis was most frequently treated for >2 months (38, 34.5%), whereas diarrhea was most frequently treated for ≤ 10 days (73, 43.6%). CONCLUSION: These findings indicate that cold and heat pattern identification is a useful tool employed by Korean Medicine doctors. This study may provide a basis for clinical research investigating the effect of pattern identification-based treatment of diseases.