Association between the COVID-19 pandemic and childhood development aged 30 to 36 months in South Korea, based on the National health screening program for infants and children database.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on the neurodevelopment of children. However, the precise effects of the virus and the social consequences of the pandemic on pediatric neurodevelopment are not yet fully understood. We aimed to compare the neurodevelopment of children between before and during the COVID-19 pandemic, as well as examine the impact of socioeconomic status (SES) and regional differences on the development. METHODS: The study used the Korean Developmental Screening Test to compare the difference in the risk of neurodevelopmental delay between before and during the COVID-19 pandemic. Multivariable logistic regression analysis was conducted to identify the relationship between experiencing the COVID-19 pandemic and the risk of neurodevelopmental delay. Stratified analyses were performed to determine whether the developmental delays caused by the pandemic's impact varied depending on SES or regional inequality. RESULTS: This study found an association between the experience of COVID-19 and a higher risk of neurodevelopmental delay in communication (adjusted OR [aOR]: 1.21, 95% confidence interval [CI]: 1.19, 1.22; P-value: < 0.0001) and social interaction (aOR: 1.15, 95% CI: 1.13, 1.17; P-value: < 0.0001) domains among children of 30-36 months' ages. Notably, the observed association in the Medicaid group of children indicates a higher risk of neurodevelopmental delay compared to those in the non-Medicaid group. CONCLUSIONS: These findings highlight the need to be concerned about the neurodevelopment of children who experienced the COVID-19 pandemic. The study also calls for increased training and support for Medicaid children, parents, teachers, and healthcare practitioners. Additionally, policy programs focused on groups vulnerable to developmental delays are required.

Regulation of sexually dimorphic placental adaptation in LPS exposure-induced intrauterine growth restriction.

BACKGROUND: Sexual dimorphism in placental physiology affects the functionality of placental adaptation during adverse pregnancy. Defects of placental function compromise fetal programming, affecting the offspring's adult life. However, studies focusing on the relationship between sex-specific placental adaptation and consequent fetal maldevelopment under sub-optimal uterus milieu are still elusive. METHODS: Here, we investigated the effects of maternal lipopolysaccharide (LPS) exposure between placental sex. Pregnant ICR mice received intraperitoneal injection of phosphate-buffered saline or 100, 200, and 400 µg/kg LPS on the gestational day (GD) 15.5. To determine whether prenatal maternal LPS exposure resulted in complicated pregnancy outcomes, survival rate of embryos was calculated and the growth of embryos and placentas was examined. To elucidate global transcriptomic changes occurring in the placenta, total RNA-sequencing (RNA-seq) was performed in female and male placentas. RESULTS: LPS administration induced placental inflammation in both sexes at GD 17.5. Prenatal infection resulted in growth retardation in both sexes of embryos, and especially more prevalently in male. Impaired placental development was observed in a sex-specific manner. LPS 400 µg/kg reduced the percentage area of the labyrinth in females and junctional zone in males, respectively. RNA-sequencing revealed widespread sexually dimorphic transcriptional changes in placenta. In particular, representative changes were involved in biological processes such as trophoblast differentiation, nutrient/ion transporter, pregnancy, and immune system. CONCLUSIONS: Our results present the sexually dimorphic responses of placental physiology in intrauterine growth restriction model and provide tentative relationship further to be elucidated between sex-biased placental functional change and long-term effects on the offspring's later life.

Trend of Women's Health Research in Korea, 2012-2020: Topic and Text Network Analysis.

BACKGROUND: With the epidemiological transition, sociodemographic changes and differential lifetime experiences of women, women's health research improves knowledge of diverse health issues and the impact of policies. To explore the initiatives of women's health research in Korea, the present study examined the trends and topics of research on women's health funded by the government. METHODS: We searched all research projects on women's health funded by the government between 2012 and 2020 in Korea using the National Science & Technology Information Service database. We reviewed all the titles and abstract of the projects and examined the research trends by year. Content analysis was performed using both deductive and inductive approaches. Text network analysis and visualization by topic were conducted for keywords with a minimum of 10 occurrences in the title and abstract. RESULTS: Total number and funding amount of research projects on women's health in 2020 increased by 2.4 and 2.2 times over 2012 levels, respectively. The Ministry of Health and Welfare and the Ministry of Food and Drug Safety funded 20.9% of all projects. The majority of the topics (59.8%) addressed breast and gynecological cancers. Those on sexual and reproductive health accounted for 16.7%, with steep growth in the number (6.1 times) and funding (11.1 times) over 2012 levels. The topic analysis presented a more complex keyword network in 2020 than in 2012; however, the keywords frequently used in 2020 were similar to those of 2012. CONCLUSION: Women's health research projects have been growing in number and funding, with limited diversity in topics. Diversifying the topics and focusing on issues beyond the breast and pregnancy would be needed to reflect the complete life course of women. Institutionalization of diverse communication channels with various interest groups for women's health would be needed to better understand women's health needs from a public health perspective.

Pregnancy loss and Income in the Republic of Korea using National Health Insurance Service Data, 2008-2014.

BACKGROUND: Although unintentional pregnancy loss is common, national representative statistics are lacking in high-income East Asian countries undergoing rapid demographic changes. It is necessary to confirm the income inequality of pregnancy loss even in universal national health insurance. METHOD: Using National Health Insurance Service data between 2008 and 2014, the annual prevalence of pregnancy loss was enumerated, and differences in pregnancy loss according to age and income levels were assessed by multivariable Poisson regression. Joint-point regression was used to examine the trend of pregnancy loss. RESULT: On average, there was a 15.0% annual pregnancy loss among 3,941,020 pregnancy cases from 2008 to 2014. Pregnancy loss inequality increased stepwise with income levels except for the highest income group. After adjusting for income levels, the annual percent change of age-standardized prevalence significantly increased by 2.6% every year since 2011. CONCLUSION: Even in high-income countries with universal national health insurance, income inequality in pregnancy loss is observed. Further appraisal is needed to explain the increasing trend of pregnancy loss between 2011 and 2014 even after adjusting income.

Increased risk of suicide after occupational injury in Korea.

OBJECTIVES: This study sought to investigate the association between occupational injury and subsequent risk of suicide in Korea. METHODS: We linked compensation data for 775 537 workers injured at work during 2003-2014 with National Death Registry through 2015. Suicide among injured workers was compared with the economically active population in Korea separately for men and women by calculating SMRs, with 95% CIs. RESULTS: Injured workers showed higher mortality from suicide for both men (SMR=2.22, 95% CI 2.14 to 2.31) and women (SMR=2.11, 95% CI 1.81 to 2.45) compared with the economically active population in Korea. CONCLUSIONS: Occupational injuries are associated with substantially elevated suicide risk in Korea. The results suggest the importance of social policies to protect and support injured workers as well as intensifying efforts to prevent workplace injuries.

Did the extended coverage policy contribute to alleviating socioeconomic inequality in untreated dental caries of both children and adolescents in South Korea?

BACKGROUND: Dental sealants have been covered by the National Health Insurance Service (NHIS) since December 2009 in South Korea. This study aims to determine whether the socioeconomic inequality in untreated dental caries decreased after implementing the extended coverage policy for dental sealant. METHODS: The data were derived from the fourth (2007-2009) and sixth (2013-2015) waves of the Korean National Health and Nutrition Examination Survey (KNHANES) conducted by the Korea Centers for Disease Control and Prevention (KCDC). Dental caries and sealant experience by income quartiles were tested using the Rao-Scott chi-squared test. In order to examine socioeconomic inequalities and their trends over time, the prevalence ratios (PRs), slope index of inequality (SII), and relative index of inequality (RII) were estimated for each wave and age group. All analyses were conducted using SAS version 9.3. RESULTS: The adjusted PRs of untreated dental caries and sealants in the poorest in the aged 6-11 group were significantly higher and lower, respectively, compared to the most affluent quartile group for the fourth wave; however, all significant differences disappeared for the sixth wave, after the sealant coverage. The gap between the lowest and the highest was similar for the aged 12-18 group but it widened in the untreated dental caries even after the sealant coverage. The statistical significance of the PRs was maintained at the sixth wave for both caries and sealants. Children showed decreases in both SII and RII over time so its significance disappeared. The SII among adolescents decreased over time but the RII of untreated dental caries increased. CONCLUSIONS: This study found that the NHIS coverage expansion of dental care had a positive effect on overall status in dental health among children and adolescents. However, younger children benefited more in terms of inequalities. Our findings indicate that strategies to enhance access to preventive dental services should consider the differential effects for the vulnerable population in terms of socioeconomic status and age from the beginning stage of the policy.

Transcriptional activation of EGFR by HOXB5 and its role in breast cancer cell invasion.

HOX genes are transcription factors that play important roles in body patterning and many cellular processes during embryonic, fetal, and adult development. Given their important function in normal tissues, it is reasonable to assume that abnormal expression of HOX genes in adults could lead to serious diseases such as cancer. Our previous study reported HOXB5 to be significantly up-regulated in breast cancer, and its expression was found to be associated with tumor cell proliferation and invasion. Furthermore, the epidermal growth factor receptor (EGFR), a cellular tyrosine kinase that plays an important role in breast cancer progression, was found significantly up-regulated by HOXB5 in ER-positive breast cancer cells. In the present study, we demonstrated that HOXB5 regulates EGFR expression at the transcriptional level by directly binding to its promoter region and promotes phosphorylation of EGFR as well as its downstream effectors. Patients with ER-positive breast cancer, having high co-expression of HOXB5 and EGFR, had poor prognosis than those with low expression. Knockdown studies validated a key role played by EGFR in the HOXB5-induced invasion of breast cancer cells. These results suggest that targeting EGFR could be an effective strategy to treat breast cancer in patients with high HOXB5 expression.

Three-year income trends in Korean adults commencing haemodialysis: A prospective cohort.

AIM: This study aimed to explore the trends in individual income and to estimate the change in average monthly income for patients undergoing haemodialysis therapy. METHODS: The main data source was the Clinical Research Center (CRC) for End-Stage Renal Disease in Korea. In addition to the cohort data, a survey was conducted to capture personal income for 3 years. To estimate the change in monthly income over time using repeated measures, a random coefficient model using penalized quasi-likelihood methods based on restricted or residual maximum likelihood estimation was used. RESULTS: During the 3-year study period, 138 subjects aged 20 and over who answered the question about pre-dialysis income were traced and analyzed. The median value of monthly income was $US564.4 in the 1st year, $470.4 in the 2nd year, and $733.8 in the 3rd year, representing a 70%, 75%, and 61% decrease compared to pre-dialysis income ($1881.5), respectively. By using mixed analysis, we found that monthly income change was $1283 (95% CI, -1621.5, -945.1), $1182 USD (95% CI, -1540.8, -823.1), and $1041 (95% CI, -1457.6, -623.6) in the 1st , 2nd , and 3rd year, respectively, compared to pre-dialysis income after controlling for other covariates. Women and less educated patients had a relatively higher reduction of income, despite the low starting point. CONCLUSIONS: The monthly income of dialysis patients reduced substantially over the study period, especially at the time of the first survey. Considering the social security system, haemodialysis patients face significant personal financial burdens due to their ESRD unrelated to the direct costs of dialysis treatment.

Retinoic acid and CTCF play key roles in inducing the collinear expression of the Hoxa cluster.

During the development of an embryo, the initiation of the collinear expression of Hox genes is essential for the proper formation of the anteroposterior body axis. Retinoic acid (RA), a natural derivative of vitamin A, plays a role in vertebrate development by regulating Hox gene expression. CCCTC-binding factor (CTCF), an insulator protein that controls gene transcription, also regulates the expression of Hox genes by binding to the CTCF-binding sites (CBSs). It has been reported that upon RA signaling, retinoic acid response elements (RAREs) located in the Hox clusters become occupied. Interestingly, RAREs exist in close proximity with CBSs, and therefore when RA is bound, CTCF cannot bind. Without CTCF and its insulator activities, the repressive domain in the chromatin becomes open for gene transcription. Here, we examine the relationship between RA and CTCF during the RA-induced expression of the Hoxa cluster genes, using F9 murine embryonic teratocarcinoma cells as a model system. We treated F9 cells with RA for different time, confirmed the collinear expression of Hoxa genes, and validated CTCF-binding in F9 cells as well as in CTCF-overexpressing F9 cells, in the presence of RA. The present study suggests that RA and CTCF pose antagonistic effects on each other during vertebrate development to attain Hox gene collinearity.

Inequalities in oral health among adolescents in Gangneung, South Korea.

BACKGROUND: This study aims to evaluate inequality in oral health among adolescents and to explain the mechanisms of such inequalities in Gangneung, South Korea. METHODS: One thousand two hundred sixty-seven students in their first year from four vocational and three general schools participated in the baseline survey of 2011, and 84.7% of them were surveyed again in 2013. Oral examinations by the same dentist and a self-administered questionnaire were repeated during both waves. Outcome measure for oral health was the existence of untreated dental caries (DT). As socioeconomic position (SEP) indicators, school type (general vs. vocational), father's and mother's education, perceived economic status, and Family Affluence Scale (FAS) were measured. Variables measuring oral health related behaviours included tooth brushing frequency, frequency of eating snacks and drinking sodas, smoking, and annual visits to dental clinics. Chi-square tests and panel logistic regression were adopted to examine the associations between dental caries and SEP indicators by STATA version 15.1. RESULTS: Having a less educated father and attending a vocational school were significant predictors for untreated caries after controlling for SEP indicators. However, students from general schools, higher SEP by father's education, perceived economic status, or FAS, or having non-smoking experience or annual visits to dental clinics were more likely to stay caries-free. CONCLUSIONS: There were socioeconomic inequalities in oral health on an adolescent panel. Given that oral health status during adolescents can persist throughout the course of a person's life, intervention to tackle such inequalities and school environments are required.

Prenatal exposure to dexamethasone in the mouse induces sex-specific differences in placental gene expression.

Prenatal stress during pregnancy leads to sex-specific effects on fetal development and disease susceptibility over the life span; however, the origin of sex differences has not been identified. The placenta not only plays a key role in fetal growth and development throughout pregnancy, but also affects the fetal programming underlying subsequent adult health and accounts. Therefore, sex-specific adaptation of the placenta may be central to the sex differences in fetal growth and survival. Here, we analyzed the effects of prenatal dexamethasone (Dex) on sex-specific changes in placental gene expression using RNA-Seq. Placental tissues from males and females were separated into two developmentally distinct fetal and maternal parts at E11.5 stage. The majority of genes in female placentas were downregulated by prenatal Dex, whereas those were mostly maintained or rather upregulated in male placentas. RNA-Seq results were validated using independent biological replicates from the same stage and placental tissue samples from E18.5 by realtime PCR assays. Activation of various inflammatory response-related genes, chemokines and their receptors, particularly in male placentas, strongly implies that prenatal Dex exposure causes sex-specific physiological responses that can lead to inflammatory diseases involving vascular pathology.

Association between interpersonal trust, reciprocity, and suicidal behaviors: A longitudinal cohort study in South Korea.

While a growing body of evidence suggest that social capital including interpersonal trust and reciprocity might be associated with mental health outcomes, few studies have explored the relationship with suicidal behaviors. This research examined the prospective association between interpersonal trust and reciprocity and suicidal behaviors using the Korea Welfare Panel Study, a nationally representative longitudinal cohort dataset in South Korea. Interpersonal trust and reciprocity were assessed at the 7th wave of the survey (2012), and each measure was classified into two categories (low vs. high). Experience of suicidal ideation, planning, and attempt was assessed between the 8th (2013) and 10th wave (2015) of the surveys. After adjusting for confounders including lifetime experience of suicidal behaviors at the 7th wave of the survey (2012) as well as socio-demographic information, the low interpersonal trust group was more likely to experience suicidal ideation (OR: 1.30, 95% CI: 1.11-1.53) compared to the high interpersonal trust group whereas no statistically significant association was observed in the reciprocity analysis.

The histone acetylation mediated by Gcn5 regulates the Hoxc11 gene expression in MEFs.

Hox genes are responsible for encoding transcription factors that are essential for anterior-posterior body patterning at early stages of embryogenesis. However, detailed mechanisms of Hox genes are yet to be defined. Protein kinase B alpha (Akt1) was previously identified as a possible upstream regulator of Hox genes. Furthermore, the Hoxc11 gene has been upregulated in Akt1 null (Akt1-/-) mouse embryonic fibroblasts (MEFs), while repressed in wild-type MEFs. In this study, we propose to investigate the role of Gcn5, a histone acetyltransferase, in the regulation of Hoxc11 expression in MEFs. We showed that the H3 lysine 9 acetylation (H3K9ac) status has the same correlation with Hoxc11 expression and reported that Gcn5 is associated with the upregulation of Hoxc11 expression through H3K9ac in Akt1-/- MEFs. Since Hoxc11 was upregulated through histone acetylation in Akt1-/- MEFs, a functional role of Gcn5 on Hoxc11 expression was analyzed in Akt1-/- MEFs treated with Gcn5 specific inhibitor or transfected with Gcn5-small interfering RNA (Gcn5-siRNA). When the expression of Hoxc11 was analyzed using RT-PCR and real-time PCR, the Hoxc11 mRNA level was found to be similar in both Akt1-/- MEFs and control-siRNA transfected Akt1-/- MEFs. However, the Hoxc11 expression level was decreased in Gcn5-inhibited or Gcn5-knockdown Akt1-/- MEFs. Additionally, to analyze Gcn5-mediated histone acetylation status, chromatin immunoprecipitation assay was carried out in Gcn5-siRNA-transfected Akt1-/- MEFs. The H3K9ac at the Hoxc11 locus was decreased in Gcn5-knockdown Akt1-/- MEFs compared to controls. Based on these findings, we conclude that Gcn5 regulates Hoxc11 gene expression through mediating site-specific H3K9 acetylation in Akt1-/- MEFs.

Prenatal exposure to dexamethasone disturbs sex-determining gene expression and fetal testosterone production in male embryos.

Prenatal stress is known to cause intrauterine fetal growth retardation, and is also associated with various long-term effects in the form of metabolic and neurodevelopmental diseases in adults. Many of the diseases associated with prenatal stress exhibit a sex bias. Perturbations and vulnerability to prenatal stress are often more profound in males, but the mechanisms responsible for this relationship are not clear. We have previously shown that administration of the synthetic glucocorticoid, dexamethasone (Dex), at embryonic days 7.5, 8.5, and 9.5, induces embryonic growth restriction in a sex-dependent manner in a mouse model. Here we examined the effect of prenatal exposure to Dex on gonadal development. During male gonadal development, sex-determining genes, such as Sry, Sox9, and other downstream genes, were found to be dysregulated in response to prenatal Dex, whereas the genes for the ovarian pathway were affected to a lesser degree in females. In addition, fetal testosterone concentrations were decreased by prenatal exposure to Dex, in parallel with reduced numbers of 3ß-hydroxysteroid dehydrogenase (3ß-HSD)-positive cells in the embryonic testis. These results show that prenatal exposure to Dex differentially influences male versus female on the gene expression and hormone production during sex determination. We believe these studies provide valuable insights into possible mechanisms responsible for sex-specific responses to prenatal stress.

CTCF-mediated Chromatin Loop for the Posterior Hoxc Gene Expression in MEF Cells.

Modulation of chromatin structure has been proposed as a molecular mechanism underlying the spatiotemporal collinear expression of Hox genes during development. CCCTC-binding factor (CTCF)-mediated chromatin organization is now recognized as a crucial epigenetic mechanism for transcriptional regulation. Thus, we examined whether CTCF-mediated chromosomal conformation is involved in Hoxc gene expression by comparing wild-type mouse embryonic fibroblast (MEF) cells expressing anterior Hoxc genes with Akt1 null MEFs expressing anterior as well as posterior Hoxc genes. We found that CTCF binding between Hoxc11 and -c12 is important for CTCF-mediated chromosomal loop formation and concomitant posterior Hoxc gene expression. Hypomethylation at this site increased CTCF binding and recapitulated the chromosomal conformation and posterior Hoxc gene expression patterns observed in Akt1 null MEFs. From this work we found that CTCF at the C12|11 does not function as a barrier/boundary, instead let the posterior Hoxc genes switch their interaction from inactive centromeric to active telomeric genomic niche, and concomitant posterior Hoxc gene expression. Although it is not clear whether CTCF affects Hoxc gene expression solely through its looping activity, CTCF-mediated chromatin structural modulation could be an another tier of Hox gene regulation during development. © 2016 IUBMB Life, 68(6):436-444, 2016.

Akt1 mediates the posterior Hoxc gene expression through epigenetic modifications in mouse embryonic fibroblasts.

The evolutionarily conserved Hox genes are organized in clusters and expressed colinearly to specify body patterning during embryonic development. Previously, Akt1 has been identified as a putative Hox gene regulator through in silico analysis. Substantial upregulation of consecutive 5' Hoxc genes has been observed when Akt1 is absent in mouse embryonic fibroblast (MEF) cells. In this study, we provide evidence that Akt1 regulates the 5' Hoxc gene expression by epigenetic modifications. Enrichment of histone H3K9 acetylation and a low level of the H3K27me3 mark were detected at the posterior 5' Hoxc loci when Akt1 is absent. A histone deacetylase (HDAC) inhibitor de-repressed 5' Hoxc gene expression when Akt1 is present, and a DNA demethylating reagent synergistically upregulated HDAC-induced 5' Hoxc gene expression. A knockdown study revealed that Hdac6 is mediated in the Hoxc12 repression through direct binding to the transcription start site (TSS) in the presence of Akt1. Co-immunoprecipitation analysis revealed that endogenous Akt1 directly interacted with Hdac6. Furthermore, exogenous Akt1 was enriched at the promoter region of the posterior Hoxc genes such as Hoxc11 and Hoxc12, not the Akt1-independent Hoxc5 and Hoxd10 loci. The regulation of the H3K27me3 mark by Ezh2 and Kdm6b at the 5' Hoxc gene promoter turned out to be Akt1 dependent. Taken together, these results suggest that Akt1 mediates the posterior 5' Hoxc gene expression through epigenetic modification such as histone methylation and acetylation, and partly through a direct binding to the promoter region of the 5' Hoxc genes and/or Hdac6 in mouse embryonic fibroblast cells.

CTCF negatively regulates HOXA10 expression in breast cancer cells.

HOX genes not only play important roles in defining body patterning during embryonic development, but also control numerous cellular events in adult cells. Deregulated HOX gene expression in different cancers including breast cancer is now increasingly being reported. Given that human HOXA cluster is marked with several CTCF binding sites, we investigated whether the presence of CTCF is associated directly with expression of HOXA genes in breast cancer cells. Several HOX genes, such as HOXA4, HOXA5 and HOXA10, were deregulated by CTCF overexpression and knockdown in MCF-7 cells. Among these genes, HOXA10 is an emerging tumor suppressor for its role in activation of p53 and in countering tumorigenesis in breast cancer. Here we provided evidences that CTCF functions as a negative regulator of HOXA10 in breast cancer cells. The putative promoter region of HOXA10 lies between 5.3 and 6.1 kb upstream of its start codon and its promoter activity was negatively regulated by CTCF. Together with in-silico analysis and in vitro mutation assay we identified a 20 bp CTCF binding motif flanking with core promoter element of HOXA10. HOXA10 promoter region was kept inactivated by maintaining H3K27me3 inactivation marks in the presence of CTCF. Epigenetic silencing of HOXA10 by CTCF in breast cancer cells may contribute towards tumorigenesis by decreasing apoptosis and promoting metastasis.

Pax3 function is required specifically for inner ear structures with melanogenic fates.

Pax3 mutations result in malformed inner ears in Splotch mutant mice and hearing loss in humans with Waardenburg's syndrome type I. In the inner ear, Pax3 is thought to be involved mainly in the development of neural crest. However, recent studies have shown that Pax3-expressing cells contribute extensively to multiple inner ear structures, some of which were considered to be derived from the otic epithelium. To examine the specific functions of Pax3 during inner ear development, fate mapping of Pax3 lineage was performed in the presence or absence of functional Pax3 proteins using Pax3(Cre) knock-in mice bred to Rosa26 reporter (R26R) line. ß-gal-positive cells were widely distributed in Pax3(Cre/+); R26R inner ears at embryonic day (E) 15.5, including the endolymphatic duct, common crus, cristae, maculae, cochleovestibular ganglion, and stria vascularis. In the absence of Pax3 in Pax3(Cre/Cre); R26R inner ears, ß-gal-positive cells disappeared from regions with melanocytes such as the stria vascularis of the cochlea and dark cells in the vestibule. Consistently, the expression of Dct, a melanoblast marker, was also absent in the mutant inner ears. However, when examined at E11.5, ß-gal positive cells were present in Pax3(Cre/Cre) mutant otocysts, whereas Dct expression was absent, suggesting that Pax3 lineage with a melanogenic fate migrated to the inner ear, yet failed to differentiate and survive without Pax3 function. Gross inner ear morphology was generally normal in Pax3(Cre/Cre) mutants, unless neural tube defects extended to the cranial region. Taken together, these results suggest that despite the extensive contribution of Pax3-expressing cells to multiple inner ear tissues, Pax3 function is required specifically for inner ear components with melanogenic fates.

PI3K/Akt pathway regulates retinoic acid-induced Hox gene expression in F9 cells.

Retinoic acid (RA), the most potent natural form of vitamin A, is a key morphogen in vertebrate development and a potent regulator of both adult and embryonic cell differentiation. Specifically, RA regulates clustered Hox gene expression during embryogenesis and is required to establish the anteroposterior body plan. The PI3K/Akt pathway was also reported to play an essential role in the process of RA-induced cell differentiation. Therefore, we tested whether the PI3K/Akt pathway is involved in RA-induced Hox gene expression in a F9 murine embryonic teratocarcinoma cells. To examine the effect of PI3K/Akt signaling on RA-induced initiation of collinear expression of Hox genes, F9 cells were treated with RA in the presence or absence of PI3K inhibitor LY294002, and time-course gene expression profiles for all 39 Hox genes located in four different clusters-Hoxa, Hoxb, Hoxc, and Hoxd-were analyzed. Collinear expression of Hoxa and -b cluster genes was initiated earlier than that of the -c and -d clusters upon RA treatment. When LY294002 was applied along with RA, collinear expression induced by RA was delayed, suggesting that the PI3K/Akt signaling pathway somehow regulates RA-induced collinear expression of Hox genes in F9 cells. The initiation of Hox collinear expression by RA and the delayed expression following LY294002 in F9 cells would provide a good model system to decipher the yet to be answered de novo collinear expression of Hox genes during gastrulation, which make the gastrulating cells to remember their positional address along the AP body axis in the developing embryo.

The health impacts of semiconductor production: an epidemiologic review.

BACKGROUND: Despite concerns over the harmful health effects of semiconductor production, epidemiological studies have shown mixed results. OBJECTIVES: We aim to critically appraise epidemiologic studies to date, and to suggest future research and actions to protect workers in semiconductor industry. METHODS: Epidemiologic studies were identified through electronic database searches, review of reference lists of relevant published works, and expert consultations, and were narratively reviewed. RESULTS: Most evidence suggests reproductive risks from fabrication jobs, including spontaneous abortion (SAB), congenital malformation, and reduced fertility. Although chemicals have been suspected as causal agents, knowledge of the likely contribution(s) from specific exposures is still limited. Evidence of cancer risk seems to be equivocal. However, the available studies had serious limitations including healthy worker effects (HWEs), information bias, and insufficient power, all of which are associated with underestimation. Nevertheless, excess risks for non-Hodgkin's lymphoma (NHL), leukemia, brain tumor, and breast cancer were observed. CONCLUSIONS: Monitoring and innovative research based on international collaboration with a focus on sentinel events are required.