Integrative multi-omic analysis reveals neurodevelopmental gene dysregulation in CIC-knockout and IDH1-mutant cells.

Capicua (CIC)'s transcriptional repressor function is implicated in neurodevelopment and in oligodendroglioma (ODG) aetiology. However, CIC's role in these contexts remains obscure, primarily from our currently limited knowledge regarding its biological functions. Moreover, CIC mutations in ODG invariably co-occur with a neomorphic IDH1/2 mutation, yet the functional relationship between these two genetic events is unknown. Here, we analysed models derived from an E6/E7/hTERT-immortalized (i.e. p53- and RB-deficient) normal human astrocyte cell line. To examine the consequences of CIC loss, we compared transcriptomic and epigenomic profiles between CIC wild-type and knockout cell lines, with and without mutant IDH1 expression. Our analyses revealed dysregulation of neurodevelopmental genes in association with CIC loss. CIC ChIP-seq was also performed to expand upon the currently limited ensemble of known CIC target genes. Among the newly identified direct CIC target genes were EPHA2 and ID1, whose functions are linked to neurodevelopment and the tumourigenicity of in vivo glioma tumour models. NFIA, a known mediator of gliogenesis, was discovered to be uniquely overexpressed in CIC-knockout cells expressing mutant IDH1-R132H protein. These results identify neurodevelopment and specific genes within this context as candidate targets through which CIC alterations may contribute to the progression of IDH-mutant gliomas. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Investigation of gene-environment interactions in relation to tic severity.

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene-environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene-environment studies.

Comparative transcriptome analysis of isogenic cell line models and primary cancers links capicua (CIC) loss to activation of the MAPK signalling cascade.

CIC encodes a transcriptional repressor, capicua (CIC), whose disrupted activity appears to be involved in several cancer types, including type I low-grade gliomas (LGGs) and stomach adenocarcinomas (STADs). To explore human CIC's transcriptional network in an isogenic background, we developed novel isogenic CIC knockout cell lines as model systems, and used these in transcriptome analyses to study the consequences of CIC loss. We also compared our results with analyses of transcriptome data from TCGA for type I LGGs and STADs. We identified 39 candidate targets of CIC transcriptional regulation, and confirmed seven of these as direct targets. We showed that, although many CIC targets appear to be context-specific, the effects of CIC loss converge on the dysregulation of similar biological processes in different cancer types. For example, we found that CIC deficiency was associated with disruptions in the expression of genes involved in cell-cell adhesion, and in the development of several cell and tissue types. We also showed that loss of CIC leads to overexpression of downstream members of the mitogen-activated protein kinase (MAPK) signalling cascade, indicating that CIC deficiency may present a novel mechanism for activation of this oncogenic pathway. © 2017 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach.

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.

Association between defense mechanisms and psychiatric symptoms in North Korean Refugees.

OBJECTIVE: Defense mechanism may contribute to psychiatric symptoms. Refugees are vulnerable to various psychiatric symptoms, such as depression, anxiety, somatization, and those associated with post-traumatic stress disorder (PTSD), due to their traumatic or stressful experiences. We aimed to investigate the mediating role of each defense mechanism in the occurrence of specific psychiatric symptoms in North Korean refugees. METHOD: Among 213 North Korean refugees initially recruited, 201 completed the following questionnaires: the Defense Style Questionnaire, the Center for Epidemiological Studies-Depression Scale (CES-D), the State-Trait Anxiety Inventory-State (STAI-S), the somatization subscale of Symptom Check-List-90-Revised (SCL-90-R), and the Impact of Event Scale-Revised (IES-R). Stepwise regression analysis was performed to determine the defense mechanisms more predominantly associated with specific psychiatric symptoms after controlling for age, sex, number of traumatic experiences, and other psychiatric symptoms (depressive symptoms and/or anxiety). RESULTS: Higher levels of depression were independently predicted by greater use of resignation. More use of acting out and less use of humor and sublimation independently predicted higher levels of anxiety. Somatization was independently predicted by more use of inhibition. PTSD symptoms were independently predicted by more use of undoing and isolation. CONCLUSIONS: Specific psychiatric symptoms were associated with specific defense mechanisms in North Korean refugees. Our findings suggest that the manifest psychiatric symptoms of refugees may be mediated by their dominant defense mechanism.

Contractile reserve determined on exercise echocardiography in patients with severe aortic regurgitation.

BACKGROUND: The aim of this study was to assess contractile reserve (CR) in patients with severe aortic regurgitation (AR), and potential clinical applications of CR in minimally symptomatic patients. METHODS AND RESULTS: Symptom-limited treadmill exercise echocardiography was performed in 58 asymptomatic or mildly symptomatic patients with chronic severe AR (male 69%, 50±14 years). Patients with increased ejection fraction (EF) after exercise were denoted as having CR (+) and those without increased EF were categorized as CR (-). CR (+) was found in 31 and CR (-) in 27 patients. Compared with CR (+), the CR (-) group had lower EF, larger effective regurgitant orifice, regurgitant volume, left ventricular (LV) end-diastolic dimension, LV end-systolic dimension (LVESD), and LV mass index. On multiple logistic regression analysis LVESD index (LVESDI; odds ratio -0.354, P<0.0001) was an independent predictor of CR. One-third of patients with LVESD >50mm, however, were found to be CR (+), while one-third of patients with smaller LVESD were CR (-). CONCLUSIONS: Although CR is best related to baseline resting LVESDI, one-third of patients were found to have discordance between the presence of CR and the LV dimension recommended for aortic valve replacement (AVR) in minimally symptomatic patients with severe AR, suggesting that exercise test may be able to further stratify the current guideline for AVR.

Multi-Omic Analysis of CIC's Functional Networks Reveals Novel Interaction Partners and a Potential Role in Mitotic Fidelity.

CIC encodes a transcriptional repressor and MAPK signalling effector that is inactivated by loss-of-function mutations in several cancer types, consistent with a role as a tumour suppressor. Here, we used bioinformatic, genomic, and proteomic approaches to investigate CIC's interaction networks. We observed both previously identified and novel candidate interactions between CIC and SWI/SNF complex members, as well as novel interactions between CIC and cell cycle regulators and RNA processing factors. We found that CIC loss is associated with an increased frequency of mitotic defects in human cell lines and an in vivo mouse model and with dysregulated expression of mitotic regulators. We also observed aberrant splicing in CIC-deficient cell lines, predominantly at 3' and 5' untranslated regions of genes, including genes involved in MAPK signalling, DNA repair, and cell cycle regulation. Our study thus characterises the complexity of CIC's functional network and describes the effect of its loss on cell cycle regulation, mitotic integrity, and transcriptional splicing, thereby expanding our understanding of CIC's potential roles in cancer. In addition, our work exemplifies how multi-omic, network-based analyses can be used to uncover novel insights into the interconnected functions of pleiotropic genes/proteins across cellular contexts.

Self-Hybridized Exciton-Polaritons in Sub-10-nm-Thick WS2 Flakes: Roles of Optical Phase Shifts at WS2/Au Interfaces.

Exciton-polaritons (EPs) can be formed in transition metal dichalcogenide (TMD) multilayers sustaining optical resonance modes without any external cavity. The self-hybridized EP modes are expected to depend on the TMD thickness, which directly determines the resonance wavelength. Exfoliated WS2 flakes were prepared on SiO2/Si substrates and template-stripped ultraflat Au layers, and the thickness dependence of their EP modes was compared. For WS2 flakes on SiO2/Si, the minimum flake thickness to exhibit exciton-photon anticrossing was larger than 40 nm. However, for WS2 flakes on Au, EP mode splitting appeared in flakes thinner than 10 nm. Analytical and numerical calculations were performed to explain the distinct thickness-dependence. The phase shifts of light at the WS2/Au interface, originating from the complex Fresnel coefficients, were as large as π/2 at visible wavelengths. Such exceptionally large phase shifts allowed the optical resonance and resulting EP modes in the sub-10-nm-thick WS2 flakes. This work helps us to propose novel optoelectronic devices based on the intriguing exciton physics of TMDs.

Exciton Transfer at Heterointerfaces of MoS2 Monolayers and Fluorescent Molecular Aggregates.

Integration of distinct materials to form heterostructures enables the proposal of new functional devices based on emergent physical phenomena beyond the properties of the constituent materials. The optical responses and electrical transport characteristics of heterostructures depend on the charge and exciton transfer (CT and ET) at the interfaces, determined by the interfacial energy level alignment. In this work, heterostructures consisting of aggregates of fluorescent molecules (DY1) and 2D semiconductor MoS2 monolayers are fabricated. Photoluminescence spectra of DY1/MoS2 show quenching of the DY1 emission and enhancement of the MoS2 emission, indicating a strong electronic interaction between these two materials. Nanoscopic mappings of the light-induced contact potential difference changes rule out the CT process at the interface. Using femtosecond transient absorption spectroscopy, the rapid interfacial ET process from DY1 aggregates to MoS2 and a fourfold extension of the exciton lifetime in MoS2 are elucidated. These results suggest that the integration of 2D inorganic semiconductors with fluorescent molecules can provide versatile approaches to engineer the physical characteristics of materials for both fundamental studies and novel optoelectronic device applications.

Enhanced Light Absorption and Efficient Carrier Collection in MoS2 Monolayers on Au Nanopillars.

We fabricated hybrid nanostructures consisting of MoS2 monolayers and Au nanopillar (Au-NP) arrays. The surface morphology and Raman spectra showed that the MoS2 flakes transferred onto the Au-NPs were very flat and nonstrained. The Raman and photoluminescence intensities of MoS2/Au-NP were 3- and 20-fold larger than those of MoS2 flakes on a flat Au thin film, respectively. The finite-difference time-domain calculations showed that the Au-NPs significantly concentrated the incident light near their surfaces, leading to broadband absorption enhancement in the MoS2 flakes. Compared with a flat Au thin film, the Au-NPs enabled a 6-fold increase in the absorption in the MoS2 monolayer at a wavelength of 615 nm. The contact potential difference mapping showed that the electric potential at the MoS2/Au contact region was higher than that of the suspended MoS2 region by 85 mV. Such potential modulation enabled the Au-NPs to efficiently collect photogenerated electrons from the MoS2 flakes, as revealed by the uniform positive surface photovoltage signals throughout the MoS2 surface.

The 1287 G/A polymorphism of the norepinephrine transporter gene (NET) is involved in commission errors in Korean children with attention deficit hyperactivity disorder.

BACKGROUND: Previous evidence supports the role of noradrenergic systems in ADHD, and norepinephrine transporter (NET) is critical in regulating the noradrenergic system. The present study aimed to investigate the association between NET gene polymorphism and the performance measures of the Continuous Performance Test (CPT) in Korean ADHD children. METHODS: Eighty-seven children (mean age = 9.23 ± 1.99 years) with ADHD were recruited from a university hospital. Genotypes of G1287A of the NET gene (SLC6A2) were analyzed. All participants completed the CPT, with performance measures of omission errors, commission errors, reaction time and reaction standardization computed. The relationship between G1287A polymorphisms and CPT performance measures was examined. RESULTS: There were 46 subjects with the G/G genotype, 35 subjects with the G/A genotype and 6 subjects with the A/A genotype. Among the three groups, there were no significant differences in the performance of CPTs. When dichotomized according to whether the subjects have the rare allele or not, subjects with the homozygous G/G genotype showed significantly lower commission errors compared to those without G/G genotypes (by independent T-test, t = -2.18, p = 0.026). DISCUSSION: Our study found a significant association between commission errors of the CPT and the G1287A genotype of the NET gene in Korean ADHD children. These findings suggest a protective role of the G/G genotype of the NET polymorphisms in the deficits of response inhibition in ADHD children.

Comparison of Suicide Attempts and Suicide Deaths by Jumping from a High Place in Korean Children and Adolescents.

Jumping from a high place is the most common method of suicide among Korean children and adolescents. The aim of this study was to examine the personal, family, and school life of Korean children and adolescents who chose jumping from a high place, among suicide attempts and suicide deaths, based on teachers' reports. Data on suicide attempts and suicide deaths by jumping from a high place in children and adolescents were collected through the Ministry of Education in South Korea from 2016 to 2018. We compared sociodemographic variables, suicide-related variables, emotional and behavioral status, school life related variables, and variables related to family problems among suicide deaths (n = 262), actual suicide attempts (n = 50), and interrupted or aborted suicide attempts (n = 210). There were differences in educational stage (p < 0.001), place of suicide (p < 0.001), presence of suicide note (p < 0.05) and previous suicide attempt (p < 0.001) among the three groups. The total difficulty score on the Strength Difficulty Questionnaire of interrupted or aborted suicide attempts was higher than that of the other two groups. Our study suggests that the suicide death group tend to present fewer personal and family pathologies and better school adjustment than the suicide attempt group.

Long-term cognitive, executive, and behavioral outcomes of moderate and late preterm at school age.

BACKGROUND: There is increasing concern that moderate preterm (32-33 weeks' gestation) and late preterm (34-36 weeks' gestation) birth may be associated with minor neurodevelopmental problems affecting poor school performance. PURPOSE: We explored the cognitive function, cognitive visual function, executive function, and behavioral problems at school age in moderate to late preterm infants. METHODS: Children aged 7-10 years who were born at 32+0 to 36+6 weeks of gestation and admitted to the neonatal intensive care unit from August 2006 to July 2011 at the National Health Insurance Service Ilsan Hospital were included. We excluded children with severe neurologic impairments, congenital malformations, or chromosomal abnormalities. Neuropsychological assessments consisted of 5 neuropsychological tests and 3 questionnaires. RESULTS: A total of 37 children (mean age, 9.1±1.2 years) participated. The mean gestational age at birth was 34.6±7.5 weeks, while the mean birth weight was 2,229.2±472.8 g. The mean full-scale intelligence quotient was 92.89±11.90; 24.3% scored between 70 and 85 (borderline intelligence functioning). An abnormal score was noted for at least one of the variables on the attention deficit hyperactivity disorder diagnostic system for 65% of the children. Scores below borderline function for executive quotient and memory quotient were 32.4% and 24.3%, respectively. Borderline or clinically relevant internalizing problems were noted in 13.5% on the Child Behavior Check List. There were no significant associations between perinatal factors or socioeconomic status and cognitive, visual perception, executive function, or behavior outcomes. CONCLUSION: Moderate to late preterm infants are at risk of developing borderline intelligence functioning and attention problems at early school age. Cognitive and executive functions that are important for academic performance must be carefully monitored and continuously followed up in moderate to late preterm infants.

MoS2 Monolayers on Au Nanodot Arrays: Surface Plasmon, Local Strain, and Interfacial Electronic Interaction.

Metal and transition-metal dichalcogenide (TMD) hybrid systems have been attracting growing research attention because exciton-plasmon coupling is a desirable means of tuning the physical properties of TMD materials. Competing effects of metal nanostructures, such as the local electromagnetic field enhancement and luminescence quenching, affect the photoluminescence (PL) characteristics of metal/TMD nanostructures. In this study, we prepared TMD MoS2 monolayers on hexagonal arrays of Au nanodots and investigated their physical properties by micro-PL and surface photovoltage (SPV) measurements. MoS2 monolayers on bare Au nanodots exhibited higher PL intensities than those of MoS2 monolayers on 5-nm-thick Al2O3-coated Au nanodots. The Al2O3 spacer layer blocked charge transfer at the Au/MoS2 interface but allowed the transfer of mechanical strain to the MoS2 monolayers on the nanodots. The SPV mapping results revealed not only the electron-transfer behavior at the Au/MoS2 contacts but also the lateral drift of charge carriers at the MoS2 surface under light illumination, which corresponds to nonradiative relaxation processes of the photogenerated excitons.

Characteristics of First Visit Pediatric Patients with Suicidal Ideation and Behavior: An 8-Year Retrospective Chart Review.

OBJECTIVES: Our study aimed to analyze the demographic and clinical characteristics of children and adolescents during their first visit to psychiatric outpatient departments for the management of suicidal ideation and behavior, and to compare the changes before and in 2012 or later. METHODS: This multicenter study was conducted at five university hospitals in a metropolitan area in South Korea. Medical records of patients aged 6-18 years were retrospectively reviewed from January 2009 to December 2016. Patients were analyzed by classifying them into suicidal and non-suicidal groups based on their visit to the hospital for management of suicidal ideation or suicide attempt and other mental problems, respectively. RESULTS: There were differences in the year of visit, diagnosis, education level, and referral sources between patients in the suicidal and non-suicidal groups. Multiple regression analysis was conducted based on the sex, education level, referral by school, and diagnosis of depression in patients in the suicidal group, which revealed significant association. CONCLUSION: Suicide-related problems were significantly associated with the sex, education level, referral by school, and a diagnosis of depression in the patients. A well-connected referral system would be necessary for professional mental health management of high-risk children and adolescents.

Polarization-Dependent Light Emission and Charge Creation in MoS2 Monolayers on Plasmonic Au Nanogratings.

We fabricated plasmonic hybrid nanostructures consisting of MoS2 monolayer flakes and Au nanogratings with a period of 500 nm. The angle-resolved reflectance and photoluminescence spectra of the hybrid nanostructures clearly indicated a coupling between surface plasmon polaritons (SPPs) and incoming photons. The surface photovoltage (SPV) maps could visualize the spatial distribution of net charges while shining light on the sample. Considerable polarization and wavelength dependence of the SPV signals suggested that the SPP mode enhanced the light-matter interaction and resulting exciton generation in the MoS2 monolayer. From the photoluminescence spectra and the morphology of the suspended MoS2 region, it could be noted that light irradiation did not much raise the temperature of the MoS2 monolayers on the nanogratings. Nanoscopic SPV and surface topography measurements could reveal the local optoelectronic and mechanical properties of MoS2 monolayers. This work provided us insights into the proposal of a high-performance MoS2/metal optoelectronic devices, based on the understanding of the SPP-photon and SPP-exciton coupling.

Opposite Polarity Surface Photovoltage of MoS2 Monolayers on Au Nanodot versus Nanohole Arrays.

We prepared MoS2 monolayers on Au nanodot (ND) and nanohole (NH) arrays. Both these sample arrays exhibited enhanced photoluminescence intensity compared with that of a bare SiO2/Si substrate. The reflectance spectra of MoS2/ND and MoS2/NH had clear features originating from excitation of localized surface plasmon and propagating surface plasmon polaritons. Notably, the surface photovoltages (SPV) of these hybrid plasmonic nanostructures had opposite polarities, indicating negative and positive charging at MoS2/ND and MoS2/NH, respectively. Surface potential maps, obtained by Kelvin probe force microscopy, suggested that the potential gradient led to a distinct spatial distribution of photo-generated charges in these two samples under illumination. Furthermore, the local density of photo-generated excitons, as predicted from optical simulations, explained the SPV spectra of MoS2/ND and MoS2/NH. We show that the geometric configuration of the plasmonic nanostructures modified the polarity of photo-generated excess charges in MoS2. These findings point to a useful means of optimizing optoelectronic characteristics and improving the performance of MoS2-based plasmonic devices.

Influence of Area-Level Characteristics on the Suicide Rate in Korean Adolescents.

OBJECTIVE: We aimed to investigate the influence of area-level factors on adolescent suicide and to determine which variables differ according to age and sex. METHODS: We selected variables that were available for collection through an online database from 2005 to 2015 in the Korean Statistical Information Service and the Korea Labor Institute. We used administrative districts of Korea in 2017 for geographical classification. We examined the relationships between regional suicide rates and area-level variables in male and female subjects aged 10-14 years and 15-19 years. In addition, we analyzed area-level variables in adolescents aged 15-19 years according to sex. RESULTS: Our findings indicated that several area-level variables affected adolescent suicide rates, varying according to age and sex. Economic problems were shown to be more associated with suicide in male adolescents than in female adolescents. On the other hand, social fragmentation and health services were shown to be more associated with suicide in females. CONCLUSION: Suicide in adolescents was attributable to area-level factors such as economic status, social fragmentation, and community health services. By identifying area-level variables affecting adolescent suicide rates, we will be able to contribute to implement mental health policies related to adolescent suicide.

Transcriptomic analysis of CIC and ATXN1L reveal a functional relationship exploited by cancer.

Aberrations in Capicua (CIC) have recently been implicated as a negative prognostic factor in a multitude of cancer types through activation of the MAPK signalling cascade and derepression of oncogenic ETS transcription factors. The Ataxin-family protein ATXN1L has previously been reported to interact with CIC in developmental and disease contexts to facilitate the repression of CIC target genes. To further investigate this relationship, we performed functional in vitro studies utilizing ATXN1LKO and CICKO human cell lines and characterized a reciprocal functional relationship between CIC and ATXN1L. Transcriptomic interrogation of the CIC-ATXN1-ATXN1L axis in low-grade glioma, prostate adenocarcinoma and stomach adenocarcinoma TCGA cohorts revealed context-dependent convergence of gene sets and pathways related to mitotic cell cycle and division. This study highlights the CIC-ATXN1-ATXN1L axis as a more potent regulator of the cell cycle than previously appreciated.

Light-Induced Surface Potential Modification in MoS2 Monolayers on Au Nanostripe Arrays.

In this work, the surface potential (VS) of exfoliated MoS2 monolayers on Au nanostripe arrays with period of 500 nm was investigated using Kelvin probe force microscopy. The surface morphology showed that the suspended MoS2 region between neighboring Au stripes underwent tensile-strain. In the dark, the VS of the MoS2 region on the Au stripe (VS-Au) was larger than that of the suspended MoS2 region (VS-S). However, under green light illumination, VS-Au became smaller than VS-S. To explain the VS modification, band diagrams have been constructed taking into consideration not only the local strain but also the electronic interaction at the MoS2/Au interface. The results of this work provide a basis for understanding the electrical properties of MoS2-metal contacts and improving the performance of MoS2-based optoelectronic devices.