National Research Foundation of Korea

INTRODUCTION The brain is responsible for cognition, behavior, and much of what makes us uniquely human. The development of the brain is a highly complex process, and this process is reliant on precise regulation of molecular and cellular events grounded in the spatiotemporal regulation of the transcriptome. Disruption of this regulation can lead to neuropsychiatric disorders. RATIONALE The regulatory, epigenomic, and transcriptomic features of the human brain have not been comprehensively compiled across time, regions, or cell types. Understanding the etiology of neuropsychiatric disorders requires knowledge not just of endpoint differences between healthy and diseased brains but also of the developmental and cellular contexts in which these differences arise. Moreover, an emerging body of research indicates that many aspects of the development and physiology of the human brain are not well recapitulated in model organisms, and therefore it is necessary that neuropsychiatric disorders be understood in the broader context of the developing and adult human brain. RESULTS Here we describe the generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood. We observed a widespread transcriptomic transition beginning during late fetal development and consisting of sharply decreased regional differences. This reduction coincided with increases in the transcriptional signatures of mature neurons and the expression of genes associated with dendrite development, synapse development, and neuronal activity, all of which were temporally synchronous across neocortical areas, as well as myelination and oligodendrocytes, which were asynchronous. Moreover, genes including MEF2C , SATB2 , and TCF4 , with genetic associations to multiple brain-related traits and disorders, converged in a small number of modules exhibiting spatial or spatiotemporal specificity. CONCLUSION We generated and applied our dataset to document transcriptomic and epigenetic changes across human development and then related those changes to major neuropsychiatric disorders. These data allowed us to identify genes, cell types, gene coexpression modules, and spatiotemporal loci where disease risk might converge, demonstrating the utility of the dataset and providing new insights into human development and disease. Spatiotemporal dynamics of human brain development and neuropsychiatric risks. Human brain development begins during embryonic development and continues through adulthood (top). Integrating data modalities (bottom left) revealed age- and cell type–specific properties and global patterns of transcriptional dynamics, including a late fetal transition (bottom middle). We related the variation in gene expression (brown, high; purple, low) to regulatory elements in the fetal and adult brains, cell type–specific signatures, and genetic loci associated with neuropsychiatric disorders (bottom right; gray circles indicate enrichment for corresponding features among module genes). Relationships depicted in this panel do not correspond to specific observations. CBC, cerebellar cortex; STR, striatum; HIP, hippocampus; MD, mediodorsal nucleus of thalamus; AMY, amygdala.

INTRODUCTION The human cerebral cortex has undergone an extraordinary increase in size and complexity during mammalian evolution. Cortical cell lineages are specified in the embryo, and genetic and epidemiological evidence implicates early cortical development in the etiology of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disabilities, and schizophrenia. Most of the disease-implicated genomic variants are located outside of genes, and the interpretation of noncoding mutations is lagging behind owing to limited annotation of functional elements in the noncoding genome. RATIONALE We set out to discover gene-regulatory elements and chart their dynamic activity during prenatal human cortical development, focusing on enhancers, which carry most of the weight upon regulation of gene expression. We longitudinally modeled human brain development using human induced pluripotent stem cell (hiPSC)–derived cortical organoids and compared organoids to isogenic fetal brain tissue. RESULTS Fetal fibroblast–derived hiPSC lines were used to generate cortically patterned organoids and to compare oganoids’ epigenome and transcriptome to that of isogenic fetal brains and external datasets. Organoids model cortical development between 5 and 16 postconception weeks, thus enabling us to study transitions from cortical stem cells to progenitors to early neurons. The greatest changes occur at the transition from stem cells to progenitors. The regulatory landscape encompasses a total set of 96,375 enhancers linked to target genes, with 49,640 enhancers being active in organoids but not in mid-fetal brain, suggesting major roles in cortical neuron specification. Enhancers that gained activity in the human lineage are active in the earliest stages of organoid development, when they target genes that regulate the growth of radial glial cells. Parallel weighted gene coexpression network analysis (WGCNA) of transcriptome and enhancer activities defined a number of modules of coexpressed genes and coactive enhancers, following just six and four global temporal patterns that we refer to as supermodules, likely reflecting fundamental programs in embryonic and fetal brain. Correlations between gene expression and enhancer activity allowed stratifying enhancers into two categories: activating regulators (A-regs) and repressive regulators (R-regs). Several enhancer modules converged with gene modules, suggesting that coexpressed genes are regulated by enhancers with correlated patterns of activity. Furthermore, enhancers active in organoids and fetal brains were enriched for ASD de novo variants that disrupt binding sites of homeodomain, Hes1, NR4A2, Sox3, and NFIX transcription factors. CONCLUSION We validated hiPSC-derived cortical organoids as a suitable model system for studying gene regulation in human embryonic brain development, evolution, and disease. Our results suggest that organoids may reveal how noncoding mutations contribute to ASD etiology. Summary of the study, analyses, and main results. Data were generated for iPSC-derived human telencephalic organoids and isogenic fetal cortex. Organoids modeled embryonic and early fetal cortex and show a larger repertoire of enhancers. Enhancers could be divided into activators and repressors of gene expression. We derived networks of modules and supermodules with correlated gene and enhancer activities, some of which were implicated in autism spectrum disorders (ASD).

A growing number of affective computing researches recently developed a computer system that can recognize an emotional state of the human user to establish affective human-computer interactions. Various measures have been used to estimate emotional states, including self-report, startle response, behavioral response, autonomic measurement, and neurophysiologic measurement. Among them, inferring emotional states from electroencephalography (EEG) has received considerable attention as EEG could directly reflect emotional states with relatively low costs and simplicity. Yet, EEG-based emotional state estimation requires well-designed computational methods to extract information from complex and noisy multichannel EEG data. In this paper, we review the computational methods that have been developed to deduct EEG indices of emotion, to extract emotion-related features, or to classify EEG signals into one of many emotional states. We also propose using sequential Bayesian inference to estimate the continuous emotional state in real time. We present current challenges for building an EEG-based emotion recognition system and suggest some future directions.

The smoothly clipped absolute deviation (SCAD) estimator, proposed by Fan and Li, has many desirable properties, including continuity, sparsity, and unbiasedness. The SCAD estimator also has the (asymptotically) oracle property when the dimension of covariates is fixed or diverges more slowly than the sample size. In this article we study the SCAD estimator in high-dimensional settings where the dimension of covariates can be much larger than the sample size. First, we develop an efficient optimization algorithm that is fast and always converges to a local minimum. Second, we prove that the SCAD estimator still has the oracle property on high-dimensional problems. We perform numerical studies to compare the SCAD estimator with the LASSO and SIS–SCAD estimators in terms of prediction accuracy and variable selectivity when the true model is sparse. Through the simulation, we show that the variance estimator of Fan and Li still works well for some limited high-dimensional cases where the true nonzero coefficients are not too small and the sample size is moderately large. We apply the proposed algorithm to analyze a high-dimensional microarray data set.

We report on a continuous method for controlled electrospinning of polymeric nanofibers on two-dimensional (2D) and three dimensional (3D) substrates using low voltage near-field electrospinning (LV NFES). The method overcomes some of the drawbacks in more conventional near-field electrospinning by using a superelastic polymer ink formulation. The viscoelastic nature of our polymer ink enables continuous electrospinning at a very low voltage of 200 V, almost an order of magnitude lower than conventional NFES, thereby reducing bending instabilities and increasing control of the resulting polymer jet. In one application, polymeric nanofibers are freely suspended between microstructures of 3D carbon on Si substrates to illustrate wiring together 3D components in any desired pattern.

Heme oxygenases (HOs) are the rate-limiting enzymes in the catabolism of heme into biliverdin, free iron, and carbon monoxide. Two genetically distinct isoforms of HO have been characterized: an inducible form, HO-1, and a constitutively expressed form, HO-2. HO-1 is a kind of stress protein, and thus regarded as a sensitive and reliable indicator of cellular oxidative stress. The HO system acts as potent antioxidants, protects endothelial cells from apoptosis, is involved in regulating vascular tone, attenuates inflammatory response in the vessel wall, and participates in angiogenesis and vasculogenesis. Endothelial integrity and activity are thought to occupy the central position in the pathogenesis of cardiovascular diseases. Cardiovascular disease risk conditions converge in the contribution to oxidative stress. The oxidative stress leads to endothelial and vascular smooth muscle cell dysfunction with increases in vessel tone, cell growth, and gene expression that create a pro-thrombotic/pro-inflammatory environment. Subsequent formation, progression, and obstruction of atherosclerotic plaque may result in myocardial infarction, stroke, and cardiovascular death. This background provides the rationale for exploring the potential therapeutic role for HO system in the amelioration of vascular inflammation and prevention of adverse cardiovascular outcomes.

OBJECTIVES: To investigate the impact of imipenem resistance on the mortality rate among patients with Acinetobacter bacteraemia. METHODS: A retrospective, pairwise-matched (1:1), risk-adjusted (age, Pitt bacteraemia score) cohort study was performed at three tertiary care hospitals in Korea from January 2000 to June 2005. RESULTS: Forty patients with imipenem non-susceptible Acinetobacter bacteraemia (INAB group) and 40 matched subjects (1:1 ratio) with imipenem-susceptible Acinetobacter bacteraemia (ISAB group) were included. Both groups had similar clinical features related to the severity of illness. The 30 day mortality rate was higher in the INAB group (57.5%) than the ISAB group (27.5%) (P = 0.007). The rate of discordant antimicrobial therapy was higher in the INAB group (65.0%) than the ISAB group (20.0%) (P < 0.001). The 30 day mortality rate was higher in the patients with discordant antimicrobial therapy (67.6%) than concordant antimicrobial therapy (23.9%) (P < 0.001). Multivariate analysis showed that age, the Pitt bacteraemia score, immunosuppressive status, and discordant antimicrobial therapy were independent risk factors for 30 day mortality among patients with Acinetobacter bacteraemia (P < 0.05). When discordant antimicrobial therapy was excluded in the multivariate analysis, the imipenem resistance was associated with 30 day mortality (P = 0.005). CONCLUSIONS: Imipenem resistance has a significant impact on the mortality rate among patients with Acinetobacter bacteraemia, and this is mainly attributable to the higher rate of discordant antimicrobial therapy.

BACKGROUND: There have been few reports on the causes and treatment outcomes for nosocomial spontaneous bacterial peritonitis (SBP) in patients with liver cirrhosis. METHODS: We performed a retrospective cohort study to compare the microbiological and clinical characteristics in nosocomial versus community-acquired SBP. All patients with SBP, for whom culture was proven to be positive for SBP at Samsung Medical Center (Seoul, Republic of Korea) from 1 January 2000 through 31 June 2007, were included. Medical records and laboratory data were reviewed. Nosocomial SBP was defined as SBP diagnosed after 72 h of hospitalization. RESULTS: A total of 236 patients with SBP were enrolled (mean age +/- SD age, 56.6 +/- 10.7 years); 166 patients were women, and 70 were men. Nosocomial and community-acquired SBP occurred in 126 and 110 patients, respectively. Escherichia coli accounted for 102 (43.2%) of 236 isolates, Klebsiella species accounted for 33 isolates (14.0%), and Streptococcus species accounted for 23 isolates (9.8%). The overall 30-day mortality rate for nosocomial SBP was higher than that for community-acquired SBP (58.7% vs. 37.3%; P = .001). Nosocomial isolates of gram-negative organisms were significantly more resistant to third-generation cephalosporins (41% vs. 10.0%; P = .001) and quinolones (50.0% vs. 30.9%; P = .003), compared with community-acquired isolates. Multivariate analysis revealed that nosocomial infection, concomitant hepatocellular carcinoma, presentation with acute renal failure or shock, and resistance to third-generation cephalosporins were significant risk factors for 30-day mortality associated with SBP. CONCLUSIONS: Nosocomial SBP has a poorer outcome than community-acquired SBP. The resistance to third-generation cephalosporins for gram-negative organisms, which are more common in nosocomial cases of SBP than in community-acquired cases of SBP, adversely affects the outcome of SBP in patients with liver cirrhosis.

This study focuses on the ironic situation in which news is more available than ever but people are becoming overwhelmed and thus avoid it. A theoretical model is suggested to investigate the relationships between perceived news overload and its cognitive and attitudinal consequences among South Korean Internet users. A structural model reveals that perceived news overload induced news avoidance by increasing news fatigue and news analysis paralysis. Furthermore, this study finds evidence that news consumers are willing to use news curation services to alleviate news avoidance and thus stay informed.

This study attempts to identify the predictors of e-book reader diffusion with regard to consumer awareness, interest, and intention to use. Specifically, it assesses the relative influence of demographics, media usage/ownership, and personal traits/perception variables in the technology-adoption process. A national consumer survey conducted in South Korea, a leading country in the proliferation of e-book use, found that e-book reader awareness, interest, and adoption intention correlated positively with age, education, income, perceived need for print media, digital media ownership, personal innovativeness, and the perceived attributes of e-book readers. Regarding the relative effects of variable blocks, the most influential factors in predicting e-book reader awareness, e-book reader interest, and intention to use were demographics, personal innovativeness, and the perceived attributes of e-book readers, respectively.

B ackground As presented by Willet and Singer (1991), survival analysis can sensitively reveal rich information about when students leave their majors. Although survival analysis has been used to investigate student and faculty retention, it has not been applied to undergraduate engineering student retention. P urpose (H ypothesis ) The impact of cohort, gender, ethnicity, and SAT math and verbal scores on the loss rate of undergraduate engineering students was investigated to answer the questions: Does the profile of risk of dropout differ among groups with different backgrounds? When are students most likely to leave engineering? Which SAT scores better predict the risk of dropout? D esign /M ethod Using a large longitudinal database that includes 100,179 engineering students from nine universities and spans 19 years, nonparametric survival analysis was adopted to obtain nonparametric estimates of survival and associated hazard functions, and complete rank tests for the association of variables. R esults There are significant differences for early semesters: White or female students tend to leave engineering earlier than other populations. Engineering students leave engineering during the third semester the most, although students who have an SAT math score less than 550 tend to leave engineering during the second semester. SAT math score better predicts the risk of dropout than SAT verbal score. C onclusion The results of this study support using survival analysis to better understand factors that determine student success since student retention is a dynamic problem. Survival analysis allows characteristics such as risk to be evaluated by semester, giving insight to when interventions might be most effective.

This paper presents a case study of an investigation into the responses of the surrounding ground to the horizontal twin-jet grouting method (HTJGM) in soft soil deposits of Shanghai. During the field test, the variation of pore-water pressure, lateral earth pressure, lateral displacements of the subsurface soils, and ground surface heave induced by the installation of five horizontal jet-grouted columns were monitored. The monitoring results indicate that the excess pore-water pressure reached 4 to 6 times the undrained shear strength of the soils, while maximum lateral displacements and ground surface heave were up to 80 and 17 mm, respectively. The influence range due to the installation of jet-grouted columns was between 15 and 20 times the nominal column radius. The development of prediction methods for lateral displacements and ground surface heave induced by the HTJGM installation process are presented and discussed. Results from the investigation suggest that the proposed prediction methods can be used to provide reasonable estimates of ground response and influence range of horizontal jet grouting.

Purpose The purpose of this paper is to develop and suggest a reference Kano model. Design/methodology/approach Existing Kano models have been classified into three types and, for each type, the curves, together with their corresponding evaluation tables, have been studied and a new type of the Kano model developed. Findings Findings imply that the existing types of the Kano model have weaknesses: starting points of the curves are not located in correct position; the sequence and slopes of the curves are not carefully illustrated; and the cells of Kano evaluation table are not coded correctly. Such problems have been resolved in the proposed Kano model. Research limitations/implications Empirical research is needed to examine the proposed type of Kano model, and to investigate the differences between the results of the application of the new and other types of Kano model. Originality/value This study provides a valuable reference model for researchers and practitioners, to be utilized in future investigations.

International collaboration in research activities has been highlighted because it offers higher productivity and has a greater impact than non-international collaboration. Given the importance of international collaboration, researchers make strategic decisions on their collaboration modes in the light of their environments and the expected trade-offs, since long-distance research collaboration entails both costs and benefits. By using national data at the project level, this paper examines the possible factors in international collaboration in various research areas, mainly focusing on research activities by universities. Our empirical results suggest that substantial financial and attentional resources, academic excellence, individual motivation, and active informal communication play significant roles in accomplishing international collaboration. Additionally, this paper refines the understanding of the role of communication and policy in ensuring the most effective use of research resources, helping research managers to promote collaboration in an appropriate decision-making context.

This experimental study (N = 107) aims at investigating how the “most-viewed” recommendation features of online news affect users' news story choices, by employing an unobtrusive measurement for news exposure. The major findings clearly support the thesis that the presence of recommendations influences users' selection of news stories. First, the participants' self-reported assessment of the reasons for their story choices indicates that the incorporation of recommendations heightened their awareness of formal salience features. Second, these recommendations decreased the time for website exploration, and therefore increased the time available for reading news articles. Third, when the recommender system was available, approximately 50% of the participants' total story exposures came through the recommendation features. Fourth, those participants who were in the recommendation condition selected a larger number of the most-viewed stories featured in the recommender system than their counterparts in the no-recommendation condition; and a majority (about 80%) of the former group's access to those most-viewed stories was via the recommender system, in terms of either number or time. Last, the mean exposure time per recommended story did not differ across either recommendation conditions (with vs. without) or access routes (recommender system vs. front/topical sections).

This study assesses the degree of burnout among newspaper firm employees in Korea and investigates the causes and consequences of this phenomenon. A survey of reporters and non-reporting staff members from the 10 national daily newspaper firms in South Korea indicates that employees suffer from burnout. In particular, respondents claimed to have experienced a higher level of exhaustion than cynicism and a diminished sense of professional efficacy. Overload, a non-autonomous, non-supportive work environment, and dissatisfaction with the work itself, level of pay, co-workers, supervisors and promotion opportunities were also contributing factors. As a result of burnout, employees reported diminished commitment to the organization and increased turnover intention.

INTRODUCTION: De-escalation therapy is a strategy currently used for the management of nosocomial pneumonia. In this study, we evaluated clinical outcomes and risk factors related to de-escalation therapy in patients with intensive care unit (ICU)-acquired pneumonia. METHODS: This was a retrospective observational cohort study of ICU patients who developed pneumonia more than 48 hours after admission to the ICU at Samsung Medical Center from September 2004 to December 2007. RESULTS: The 137 patients comprised 44 (32.1%) who received de-escalation therapy and 93 in the non-de-escalation group. The de-escalation group showed a lower pneumonia-related mortality rate than the non-de-escalation group by day 14 (2.3% vs. 10.8%, respectively; P = 0.08) and by day 30 (2.3% vs. 14%, respectively; P = 0.03) after the diagnosis of pneumonia. The variables independently associated with ICU-acquired pneumonia-related mortality included the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and the modified Clinical Pulmonary Infection Score (CPIS) after 5 days with pneumonia. The non-de-escalation group had significantly higher APACHE II score and modified CPIS after 5 days with ICU-acquired pneumonia compared to the de-escalation group. Among all patients, 20.4% (28 of 137) had negative cultures for pathogens, and 42.9% (12 of 28) received de-escalation therapy. The latter 12 patients received de-escalation therapy and survived 30 days after the diagnosis of pneumonia. CONCLUSIONS: Patients in the de-escalation group showed a significantly lower mortality rate compared to patients in the non-de-escalation group. De-escalation therapy can be safely provided to patients with ICU-acquired pneumonia if they are clinically stable by day 5, even in those whose respiratory specimen cultures yield no specific pathogens.

BACKGROUND: Previous randomized controlled trials regarding the effectiveness of perioperative midazolam in preventing postoperative nausea and vomiting (PONV) have produced conflicting results. Consequently, the present systematic review was performed to assess the effect of perioperative administration of midazolam on PONV. METHODS: The MEDLINE®, Embase, and Cochrane Central Register of Controlled Trials databases were searched to identify all randomized controlled trials that investigated the effectiveness of midazolam under general anesthesia. The primary end points were defined as postoperative nausea (PON), postoperative vomiting (POV), and PONV. RESULTS: From 16 studies, 1433 patients were included in the final analysis. Compared with the control group, patients who received midazolam showed a lower overall incidence of PON (risk ratio [RR], 0.51; 95% confidence interval [CI], 0.40-0.65; I = 35%; number needed to treat [NNT] = 6; number of included studies [n] = 11), POV (RR, 0.46; 95% CI, 0.33-0.65; I = 0%; NNT = 8; n = 10), and PONV (RR, 0.45; 95% CI, 0.36-0.57; I = 31%; NNT = 3; n = 7). CONCLUSIONS: Perioperative administration of midazolam was effective in preventing PON, POV, and PONV.

PURPOSE: We evaluated the mean platelet volume (MPV) to platelet ratio to determine its significance as a prognostic marker for early mortality in critically ill patients with suspected sepsis receiving early goal-directed therapy (EGDT). METHODS: We retrospectively reviewed the records from a prospective EGDT registry and screened eligible adult patients who were admitted to the emergency department (ED) with severe sepsis and/or septic shock. The MPV/platelet ratio was estimated as the MPV value divided by the platelet count on each day of hospitalization. The clinical outcome was 28-day mortality. RESULTS: We included 120 patients receiving EGDT. In the multivariate Cox proportional hazard models, higher MPV/platelet ratios on admission (HR: 1.04; 95% CI: 1.015-1.066; P = 0.002) and at 24 h (HR: 1.032; 95% CI: 1.012-1.054; P = 0.002) were significant risk factors for mortality at 28 days. An increased trend for 28-day mortality was associated with a MPV/platelet ratio >3.71 on admission (HR: 4.274; 95% CI: 1.228-14.874; P = 0.023) and a higher MPV/platelet ratio (>6.49) at 24 h (HR: 2.719; 95% CI: 1.048-7.051; P = 0.04) in patients with severe sepsis receiving EGDT. CONCLUSION: In our study, MPV or platelet count alone did not predict shock and 28-day mortality in patients with severe sepsis receiving EGDT. However, the MPV/platelet ratio at ED admission and on day 1 is a promising prognostic marker for 28-day mortality in patients with severe sepsis.

Hexagonal boron nitride (h-BN) has been previously manufactured using mechanical exfoliation and chemical vapor deposition methods, which make the large-scale synthesis of uniform h-BN very challenging. In this study, we produced highly uniform and scalable h-BN films by plasma-enhanced atomic layer deposition, which were characterized by various techniques including atomic force microscopy, transmission electron microscopy, Raman spectroscopy, and X-ray diffraction. The film composition studied by X-ray photoelectron spectroscopy and Auger electron spectroscopy corresponded to a B:N stoichiometric ratio close to 1:1, and the band-gap value (5.65 eV) obtained by electron energy loss spectroscopy was consistent with the dielectric properties. The h-BN-containing capacitors were characterized by highly uniform properties, a reasonable dielectric constant (3), and low leakage current density, while graphene on h-BN substrates exhibited enhanced electrical performance such as the high carrier mobility and neutral Dirac voltage, which resulted from the low density of charged impurities on the h-BN surface.