Wnt-activating human skin organoid model of atopic dermatitis induced by Staphylococcus aureus and its protective effects by Cutibacterium acnes.

A recently developed human PSC-derived skin organoid model has opened up new avenues for studying skin development, diseases, and regeneration. The current model has limitations since the generated organoids are enclosed, circular aggregates with an inside-out morphology with unintended off-target development of cartilage. Here, we first demonstrated that Wnt signaling activation resulted in larger organoids without off-target cartilage. We optimized further using an air-liquid interface (ALI) culture method to recapitulate structural features representative of human skin tissue. Finally, we used the ALI-skin organoid platform to model atopic dermatitis by Staphylococcus aureus (SA) colonization and infection. SA infection led to a disrupted skin barrier and increased production of epidermal- and dermal-derived inflammatory cytokines. Additionally, we found that pre-treatment with Cutibacterium acnes had a protective effect on SA-infected organoids. Thus, this ALI-skin organoid platform may be a useful tool for modeling human skin diseases and evaluating the efficacy of novel therapeutics.

Abnormal shoot growth in Korean red pine as a response to microclimate changes due to urbanization in Korea.

Impacts of climate change (e.g., abnormal growth in plants, early flowering, and shifting vegetation zones) are being detected throughout the world. Urban land use and its resulting microclimates work in conjunction with the impacts of climate change. Among the principal environmental signals that modulate bud flush, only temperature has changed significantly in recent years. Throughout South Korea, abnormal shoots (usually known as lammas shoots) in Korean red pine (Pinus densiflora), which were once a rare phenomenon, have become notably more common in recent years. The phenomenon is prominent in urban site of each local area. These abnormal shoots appear at a higher frequency and grow to longer lengths in Seoul's hotter urban center than in suburban sites and showed a close positive correlation with urban density and a close negative correlation with vegetation cover expressed as NDVI. Differences in temperature among the urban center, urban edge, and suburban greenbelt were significantly correlated with land-use intensity. Korean red pines planted in urban parks at sites in urban centers showed a lower frequency of abnormal shoots, and the length of the shoots was shorter, compared with those at the other urban sites. Furthermore, the phenology of Korean red pines in an urban park with a fountain showed a spatial difference, depending upon the distance from the fountain: pine trees close to the fountain did not produce abnormal shoots, but abnormal shoot growth increased with the distance from the fountain. These results are noteworthy because they are related to the cooling effects of evapotranspiration from vegetated landscapes and evaporation from a water body. From the results of this study, we could confirm that microclimate change due to urbanization accelerates the impacts of climate change on plant phenology. Furthermore, we identified the possibility that judicious land-use planning could contribute to minimizing the adverse effects of climate change.

Efficacy of Antidepressants in the Treatment of Obstructive Sleep Apnea Compared to Placebo. A Systematic Review with Meta-Analyses.

PURPOSE: To establish the efficacy of oral antidepressants compared to placebo in improving obstructive sleep apnea (OSA) as measured on a polysomnography study. Secondary outcomes included self-reported sleepiness. METHODS: Authors identified prospective randomized placebo-controlled studies from MEDLINE through PubMed, Web of Science, the Cochrane Library and EMBASE up to February 2019 in English language. Antidepressants included tricyclic antidepressants (TCA), tetracyclic antidepressants (TeCA), selective serotonin reuptake inhibitors (SSRI), and serotonin receptor modulators (SRM). Studies were assessed for inclusion and exclusion criteria, as well as risk of bias based on the Cochrane handbook. RESULTS: The initial search yielded 254 unduplicated references ultimately reduced to 8 relevant studies, in which 198 OSA participants were included. Patients with an average baseline AHI of 26.7 events/hour taking 15-45mg mirtazapine had a statistically significant reduction in apnea-hypopnea index compared to placebo by -10.5 events/hour (p<0.001), apnea index by -3.6 events/hour (p=0.001) and hypopnea index by -5.9 events/hour (p=0.037). In one study, patients taking 100mg trazodone 1 night improved significantly in AHI compared to placebo group (p<0.001). Arousal index, sleepiness, and sleep efficiency were not statistically significantly reduced with any antidepressant medication compared to placebo (p>0.05). CONCLUSIONS: Of the five antidepressant medications studied, only mirtazapine and trazadone showed a statistically significant reduction in AHI in the treated groups but not in sleepiness scale nor an increase in sleep efficiency. In this review, the total sample sizes were small, adverse side effects of some of the antidepressant medications were clinically significant, overall risk of bias of the studies was high or unclear, and overall quality of the evidence was low. Based on the evidence available at this time, we cannot recommend the antidepressants studied in the treatment of OSA.

Youth Suicide in Korea Across the Educational Stages.

Background: Youth suicides have diverse characteristics according to the young people's developmental stages. Warning signs and communication of suicidal intent can be vague among early adolescents, while mental health problems may be more evidently related to suicidal ideation in older adolescents. Understanding the developmental characteristics of youth suicide is necessary for effective suicide prevention. Aims: We explored the differences between children and adolescents who died by suicide and the characteristics of these young people as observed by their school teachers. Method: We analyzed teachers' mandatory postmortem reports of suicides among 308 Korean students. We compared: suicide-related information including personal, familial, and school factors; stressful life events; and participation in interventions among elementary, middle, and high school students who died by suicide. We also assessed the distribution of student suicides per month. Results: Suicide among elementary school students increased during school vacations, and suicide among middle and high school students increased during the school semester. According to the teachers' reports, elementary school students who died by suicide were more extroverted and had better academic achievements than their high school peers, and had significantly lower levels of substance/tobacco use. Elementary school students who died by suicide showed significantly less academic stress and use of external professional help than did other groups. Limitations: Because this research is based on mandatory teacher reports, the subjective opinions of teachers may have affected the reliability of the data. Suicide by out-of-school youth was not included. Conclusion: School-based suicide prevention should be implemented in accordance with young people's developmental characteristics.

Four-year trajectory of Korean youth mental health and impacts of school environment and school counselling: a observational study using national schools database.

OBJECTIVES: This study aimed to investigate changes in the mental health status of South Korean adolescents at a school level and identify school-related factors affecting these changes. DESIGN: A retrospective data analysis, population study. SETTING: South Korean high schools from 2013 to 2016. PARTICIPANTS: Randomly sampled 827 schools (316 834 boys and 299 304 girls) PRIMARY OUTCOME MEASURES: Mean scores of the Adolescent Mental Health and Problem Behavior Questionnaire-II (AMPQ-II), a school-based mental health screening test, were used to explore changes in youth mental health. Data regarding the school environment and school counselling were gathered from the 'School info' website. A multilevel growth model was used to determine relationships between students' mental health and school-related factors. RESULTS: Students' mental health statuses in South Korea gradually improved over time (coefficient=-1.46 to -1.70, p<0.001). School mobility rates (coefficient=0.93 to 1.00, p<0.05), school dropout rates (coefficient=0.38 to 0.40, p<0.001), school budgets per student (coefficient=-0.05 to -0.06, p<0.01) and number of school counselling sessions (coefficient=0.14, p<0.01) were significantly associated with baseline AMPQ-II scores. The rate of change in AMPQ-II score increased when the number of school counselling sessions was higher (coefficient=-0.03, p<0.05) or the school budget was lower (coefficient=0.02, p<0.001). School environment explained 21.6% of the AMPQ-II baseline score variance and 9.3% of the rate of change variance. School counselling further explained 2.0% of the variance in baseline AMPQ-II scores and 2.3% of the rate of change variance. CONCLUSIONS: This study suggests that school environment stability and active provision of school-based mental health services have a positive impact on youth mental health.

The KRAS-variant and its impact on normal breast epithelial cell biology.

MicroRNA (miRNA)-binding site variants in 3' untranslated regions (3'UTRs) are a novel class of germ-line, functional mutations, which are now recognized as powerful biomarkers of human cancer risk and biology. The first mutation discovered in this class is the KRAS-variant, a let-7-binding site mutation in the 3'UTR of the KRAS oncogene. The KRAS-variant predicts increased cancer risk for certain populations, is a predictive biomarker of cancer treatment response across cancer types, leads to conserved tumor biology and elevated AKT signaling in KRAS-variant patient tumors, and was recently found to predict elevated TGF-ß and immunosuppression in cancer patients. Based on the functional biology of the KRAS-variant in cancer patients, here we chose to investigate altered normal cellular biology in the presence of the KRAS-variant, through interrogation of an isogenic normal breast epithelial cell line model with and without the KRAS-variant. We find that KRAS-variant normal breast epithelial cells exhibit a mesenchymal phenotype, which appears to be due to numerous molecular changes, including miRNA dysregulation and autocrine pathway alterations, including elevated TGF-ß, resulting in ZEB and SNAIL upregulation. Our findings support the hypothesis that the KRAS-variant has a fundamental biological impact on normal cellular biology, that is conserved in these patients when they develop cancer.

Gender differences in Korean adolescents who died by suicide based on teacher reports.

BACKGROUND: We investigated the characteristics of adolescents who committed suicide in South Korea, and how these characteristics differed by gender. METHOD: Data from middle and high school students who committed suicide between 2014 and 2016 were analyzed. We evaluated differences in suicide method and place, personal characteristics, and school life characteristics by gender using the Chi square test and t test. RESULTS: Jumping from a high place was the most common suicide method for both male and female students. A significantly greater proportion of female adolescents had experienced depressive symptoms, previous self-injury, previous suicide attempts, and had problems with school attendance and peers. Additionally, they were more likely to be classified as high risk according to a school-based mental health screening test and to utilize professional mental health treatment services. CONCLUSION: Our results demonstrate that adolescents who committed suicide exhibited gender differences in personal characteristics and school life. These characteristics might aid in the development of adolescent suicide policies and intervention programs.

Subtypes of suicidal ideation in Korean adolescents: A multilevel latent profile analysis.

OBJECTIVE: This study intended to classify subtypes of Korean adolescents with suicidal ideation based on mental health problems and to explore the relationship between such subtypes and individual-, school- and community-level factors. METHOD: Data from high school freshmen who participated in the 2013 school-based mental health screening test and data about school and community variables obtained from public sources were combined and analyzed. A multilevel latent profile analysis using mental health issues as class indicators that included several predictors was conducted. RESULTS: Three latent profiles were identified: Group 1 (6.5%) had high scores for both the internalizing and externalizing problems; Group 2 (40.2%) had high scores for internalizing problems, such as depression and mood related symptoms; and Group 3 (53.3%) had lower scores for all mental health problems compared to Groups 1 and 2. Gender, peer conflict, family conflict and academic problems were significant predictors at the individual level; school dropout rate was a significant school-level variable; and percent of youth in the total population, availability of mental health services, number of social welfare facilities and percentage of the total budget devoted to education/welfare were significant community-level variables. CONCLUSION: The present findings suggest that adolescents with suicidal ideation can be classified into several distinct subtypes based on mental health problems. These profiles and their associated covariates will aid in the establishment of youth suicide prevention policies.

Antiviral activity of Schizonepeta tenuifolia Briquet against noroviruses via induction of antiviral interferons.

Human noroviruses are the causative agents of non-bacterial gastroenteritis worldwide. The rapid onset and resolution of disease symptoms suggest that innate immune responses are critical for controlling norovirus infection; however, no effective antivirals are yet available. The present study was conducted to examine the antiviral activities of Schizonepeta tenuifolia Briquet extract (STE) against noroviruses. Treatment of human norovirus replicon-bearing HG23 cells with STE at 5 and 10 mg/ml concentrations resulted in the reduction in the viral RNA levels by 77.2% and 85.9%, respectively. STE had no cytotoxic effects on HG23 cells. Treatment of RAW 264.7 cells infected with murine norovirus 1 (MNV-1), a surrogate virus of human noroviruses, with STE at 10 and 20 µg/ml concentrations resulted in the reduction of viral replication by 58.5% and 84.9%, respectively. STE treatment induced the expression of mRNAs for type I and type II interferons in HG23 cells and upregulated the transcription of interferon-ß in infected RAW 264.7 cells via increased phosphorylation of interferon regulatory factor 3, a critical transcription regulator for type I interferon production. These results suggest that STE inhibits norovirus replication through the induction of antiviral interferon production during virus replication and may serve as a candidate antiviral substance for treatment against noroviruses.

The impact of psychological problems and adverse life events on suicidal ideation among adolescents using nationwide data of a school-based mental health screening test in Korea.

The aim of this study was to investigate the risk factors for suicidal ideation in adolescents by gender and age. This study used 2013 nationwide school-based mental health screening test data from 591,303 seventh grade students and 618,271 tenth grade students in Korea. Suicidal ideation, four psychological problems, and three adverse life events were evaluated using the Adolescents Mental Health and Problem Behavior Screening Questionnaire-II. Of all students, 12.9-14.7% of the boys and 17.1-23.2% of the girls had suicidal ideation. Mood had the greatest impact on the risk for suicidal ideation and other factors also significantly increased the risk of suicidal ideation. Distractibility was positively related to suicidal ideation only in seventh grade students and behavioral problems increased suicidal ideation more in girls than in boys. Violence constituted the most powerful factor for suicidal ideation among the events; however, bullying constituted the most important event that increased suicidal ideation in seventh grade girls. All factors except 'Distractibility' increased the risk of severe suicidal ideation. The risk factors for suicidal ideation in adolescents differed by gender and age. Interventions should be made according to these characteristics to reduce suicidal ideation in adolescents.

Estrogen withdrawal, increased breast cancer risk and the KRAS-variant.

The KRAS-variant is a biologically functional, microRNA binding site variant, which predicts increased cancer risk especially for women. Because external exposures, such as chemotherapy, differentially impact the effect of this mutation, we evaluated the association of estrogen exposures, breast cancer (BC) risk and tumor biology in women with the KRAS-variant. Women with BC (n = 1712), the subset with the KRAS-variant (n = 286) and KRAS-variant unaffected controls (n = 80) were evaluated, and hormonal exposures, KRAS-variant status, and pathology were compared. The impact of estrogen withdrawal on transformation of isogenic normal breast cell lines with or without the KRAS-variant was studied. Finally, the association and presentation characteristics of the KRAS-variant and multiple primary breast cancer (MPBC) were evaluated. KRAS-variant BC patients were more likely to have ovarian removal pre-BC diagnosis than non-variant BC patients (p = 0.033). In addition, KRAS-variant BC patients also appeared to have a lower estrogen state than KRAS-variant unaffected controls, with a lower BMI (P < 0.001). Finally, hormone replacement therapy (HRT) discontinuation in KRAS-variant patients was associated with a diagnosis of triple negative BC (P < 0.001). Biologically confirming our clinical findings, acute estrogen withdrawal led to oncogenic transformation in KRAS-variant positive isogenic cell lines. Finally, KRAS-variant BC patients had greater than an 11-fold increased risk of presenting with MPBC compared to non-variant patients (45.39% vs 6.78%, OR 11.44 [3.42-37.87], P < 0.001). Thus, estrogen withdrawal and a low estrogen state appear to increase BC risk and to predict aggressive tumor biology in women with the KRAS-variant, who are also significantly more likely to present with multiple primary breast cancer.

Quantitative bioluminescence imaging of transgene expression in intact porcine antral follicles in vitro.

BACKGROUND: The porcine oocyte maturation in vivo occurs within the ovarian follicle and is regulated by the interactions between oocytes and surrounding follicular components, including theca, granulosa, and cumulus cells, and follicular fluid. Therefore, the antral follicle is an essential microenvironment for efficient oocyte maturation and its developmental competence. Quantitative bioluminescence imaging of firefly luciferase reporter genes in an intact antral follicle would allow investigation of changes in cellular and molecular events and in the context of the whole follicles. In this study, we investigate factors influencing bioluminescence measurements as a first step towards developing a new bioluminescence imaging system for intact antral follicles. METHODS: We analyzed the time course of bioluminescence emitted from transfected living intact follicles using a cationic lipid mediated gene transfer method with increasing doses (1-3 µg) of firefly luciferase reporter gene (pGL4). In addition, a standard luciferase assay was used to confirm the luciferase expression in granulosa cells in the transfected intact antral follicles. Finally, the dose effects of substrate, D-luciferin, were determined for optimal quantitative bioluminescence imaging of intact porcine antral follicles in vitro. RESULTS: The level of luciferase activity of follicles with 3 µg pGL4 was significantly (P < 0.05) greater than the 1 µg and 2 µg groups at 1 min after D-luciferin injection. The bioluminescence intensity of transfected follicles reached a peak at 1 min, and then it was significantly (P < 0.05) reduced within 2 min after injection of D-luciferin; with the level of bioluminescence emission remained constant from 2.5 to 10 min. The bioluminescence emission was maximal with 300 µg of D-luciferin. CONCLUSIONS: The results of this study suggested that the investigation of factors influencing bioluminescence measurements is a critical step toward developing a new bioluminescence imaging model. This study is the first to demonstrate that reporter genes can be transferred to intact granulosa cells with a lipid-mediated gene transfer method within intact follicles in vitro, and the level of transgene expression can be assessed by bioluminescence imaging in living intact antral follicles.

Hip2 ubiquitin-conjugating enzyme overcomes radiation-induced G2/M arrest.

Radiation induces cell cycle arrest and/or cell death in mammalian cells. In the present study, we show that Hip2, a ubiquitin-conjugating enzyme, can overcome radiation-induced G2/M cell cycle arrest and trigger the entry into mitosis. Ionizing radiation increased the levels of Hip2 by preventing its degradation but not its gene transcription. The stability of Hip2 in irradiated cells was further confirmed using live cell fluorescence imaging. Flow cytometric and molecular analyses revealed that Hip2 abrogated radiation-induced G2/M arrest, promoting entry into mitosis. Bimolecular fluorescence complementation assays and co-immunoprecipitation experiments showed that Hip2 interacted with and targeted p53 for degradation via the ubiquitin proteasome system, resulting in the activation of cdc2-cyclin B1 kinase to promote mitotic entry. These results contribute to our understanding of the mechanisms that regulate cell cycle progression and DNA damage-induced G2/M checkpoint cellular responses.