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In mammals, hearing loss is irreversible due to the lack of the regenerative capacity of the auditory epithelium. However, stem/progenitor cells in mammalian cochleae may be a therapeutic target for hearing regeneration. The ubiquitin proteasome system plays an important role in cochlear development and maintenance. In this study, we investigated the role of ubiquitin C-terminal hydrolase L1 (UCHL1) in the process of the transdifferentiation of auditory supporting cells (SCs) into hair cells (HCs). The expression of UCHL1 gradually decreased as HCs developed and was restricted to inner pillar cells and third-row Deiters’ cells between P2 and P7, suggesting that UCHL1-expressing cells are similar to the cells with Lgr5-positive progenitors. UCHL1 expression was decreased even under conditions in which supernumerary HCs were generated with a γ-secretase inhibitor and Wnt agonist. Moreover, the inhibition of UCHL1 by LDN-57444 led to an increase in HC numbers. Mechanistically, LDN-57444 increased mTOR complex 1 activity and allowed SCs to transdifferentiate into HCs. The suppression of UCHL1 induces the transdifferentiation of auditory SCs and progenitors into HCs by regulating the mTOR pathway.

In this study, we evaluated the immunostimulatory effect of silk peptide in subjects with peripheral blood leukocyte levels of 4–8 × 103/μl by a randomized, double-blind, placebo-controlled clinical trial. The subjects were randomly assigned to one of two groups, the placebo control or silk peptide intervention group, for 8 weeks. As a result, evaluation of efficacy in 97 subjects showed no significant difference between the groups in immunostimulatory parameters. However, after separate analysis of 61 non-season influenza vaccine subjects, the natural killer cell activity (%) with an effector cell: target cell (E: T) ratio of 10:1 was increased significantly from 30.7 ± 2.28% at week 0 to 41.8 ± 2.71% at week 8 (p

Endoplasmic reticulum (ER) stress is a common stress factor during the aging process. Heat shock factor 1 (HSF1) plays a critical role in ER stress; however, its exact function in age-related hearing loss (ARHL) has not been fully elucidated. The purpose of the present study was to identify the role of HSF1 in ARHL. In this study, we demonstrated that the loss of inner and outer hair cells and their supporting cells was predominant in the high-frequency region (basal turn, 32 kHz) in ARHL cochleae. In the aging cochlea, levels of the ER stress marker proteins p-eIF2α and CHOP increased as HSF1 protein levels decreased. The levels of various heat shock proteins (HSPs) also decreased, including HSP70 and HSP40, which were markedly downregulated, and the expression levels of Bax and cleaved caspase-3 apoptosis-related proteins were increased. However, HSF1 overexpression showed significant hearing protection effects in the high-frequency region (basal turn, 32 kHz) by decreasing CHOP and cleaved caspase-3 and increasing the HSP40 and HSP70 proteins. These findings were confirmed by HSF1 functional studies using an auditory cell model. Therefore, we propose that HSF1 can function as a mediator to prevent ARHL by decreasing ER stress-dependent apoptosis in the aging cochlea.

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are inflammatory diseases of the central nervous system. Although several studies have characterized the metabolome in the cerebrospinal fluid (CSF) from MS and NMOSD patients, comparative analyses between them and between the relapse and the remission of each disease have not been performed. Both univariate and multivariate analyses were used to compare 1H-NMR spectra of CSF from MS, NMOSD, and healthy controls (HCs). The statistical analysis showed alterations of eight metabolites that were dependent on the disease. Levels of 2-hydroxybutyrate, acetone, formate, and pyroglutamate were higher and levels of acetate and glucose were lower in both MS and NMOSD. Citrate was lower in MS patients, whereas lactate was higher in only NMOSD specifically. The shared feature of metabolic changes between MS and NMOSD may be related to altered energy metabolism and fatty acid biosynthesis in the brain. Another analysis to characterize relapse and remission status showed that isoleucine and valine were down-regulated in MS relapse compared to MS remission. The other metabolites identified in the disease comparison showed the same alterations regardless of disease activity. These findings would be helpful in understanding the biological background of these diseases, and distinguishing between MS and NMOSD, as well as determining the disease activity.

Central nervous system (CNS) inflammatory demyelinating diseases (IDDs) are a group of disorders with different aetiologies, characterized by inflammatory lesions. These disorders include multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and idiopathic transverse myelitis (ITM). Differential diagnosis of the CNS IDDs still remains challenging due to frequent overlap of clinical and radiological manifestation, leading to increased demands for new biomarker discovery. Since cerebrospinal fluid (CSF) metabolites may reflect the status of CNS tissues and provide an interfacial linkage between blood and CNS tissues, we explored multi-component biomarker for different IDDs from CSF samples using gas chromatography mass spectrometry-based metabolite profiling coupled to multiplex bioinformatics approach. We successfully constructed the single model with multiple metabolite variables in coordinated regression with clinical characteristics, expanded disability status scale, oligoclonal bands, and protein levels. The multi-composite biomarker simultaneously discriminated four different immune statuses (a total of 145 samples; 54 MS, 49 NMOSD, 30 ITM, and 12 normal controls). Furthermore, systematic characterization of transitional metabolic modulation identified relapse-associated metabolites and proposed insights into the disease network underlying type-specific metabolic dysfunctionality. The comparative analysis revealed the lipids, 1-monopalmitin and 1-monostearin were common indicative for MS, NMOSD, and ITM whereas fatty acids were specific for the relapse identified in all types of IDDs.

Examining teachers' knowledge on a large scale involves addressing substantial measurement and logistical issues; thus, existing teacher knowledge assessments have mainly consisted of selected-response items because of their ease of scoring. Although open-ended responses could capture a more complex understanding of and provide further insights into teachers' thinking, scoring these responses is expensive and time consuming, which limits their use in large-scale studies. In this study, we investigated whether a novel statistical approach, topic modeling, could be used to score teachers' open-ended responses and if so, whether these scores would capture nuances of teachers' understanding. To test this hypothesis, we used topic modeling to analyze teachers' responses to a proportional reasoning task and examined the associations of the topics identified through this method with categories identified by a separate qualitative analysis of the same data as well as teachers' performance on a measure of ratios and proportional relationships. Our findings suggest that topic modeling seemed to capture nuances of teachers' responses and that such nuances differentiated teachers' performance on the same concept. We discuss the implications of this study for education research.

Early identification of suboptimal responders to multiple sclerosis (MS) treatment is critical for optimizing therapeutic decisions. The Rio score (RS) and modified Rio score (MRS) were developed to discriminate the responses to interferon-beta (IFNB) treatment in MS patients. This study was performed to evaluate the utility of RS and MRS in daily clinical practice in Korea.This was a real-world setting, multicenter, retrospective study of MS patients treated with IFNB from 10 hospitals in Korea. We investigated whether the RS and MRS at the early stage of IFNB therapy could predict treatment responses over 3 years. Suboptimal treatment responses at 3 years were defined as the presence of clinical relapse and/or EDSS progression and/or patients who had been treated with INFB for at least for 1 year and therapy was switched due to perceived treatment failure during the 2 years of follow-up.Seventy patients (50 females and 20 males) were enrolled; 92% (12/13) of patients with high RS and 86% (12/14) of patients with high MRS (score 2 or 3) were suboptimal responders, whereas 93% (53/57) of patients with low RS and 93% (52/56) patients with low MRS (score 0 or 1) showed optimal responses. New active lesions on MRI with clinical relapse in high RS and MRS were the most common combination in suboptimal responders.We confirmed that RS and MRS at 6-15 months of IFNB therapy were useful for predicting poor responders over 3 years.

Brain involvement is commonly seen in patients with neuromyelitis optica spectrum disorder (NMOSD). However, little is known about the chronic changes of acute brain lesions on MRI over time. Here, our objective was to evaluate how acute brain MRI lesions in NMOSD changed on follow-up MRI. We reviewed the MRIs of 63 patients with NMOSD who had acute brain lesions and follow-up MRI over an interval of at least 3 months. Of the 211 acute brain lesions, 24% of lesions disappeared completely on T2-weighed images (WI) and a decrease in size ≥50% on T2-WI was observed in 58% of lesions on follow-up MRI. However, 47% of lesions revealed focal T1-hypointensity and, in particular, 18% showed focal cystic changes. Cystic changes were observed most commonly in corticospinal tract and corpus callosal lesions whereas the vast majority of lesions in the cerebellum, basal ganglia and temporal white matter resolved completely. MRI remission on T2-WI occurred in 82% of lesions, while approximately half of the lesions presented foci of T1-hypointensity, which may be considered a severe tissue injury over time. The extent of brain injury following an acute brain lesion in NMOSD may depend on the location of the lesion.

Purpose: This study explored students' experiences of creative problem-solving using a design thinking approach in higher education, mainly focusing on the importance of empathetic approach in the problem identification and definition phase. Design/methodology/approach: The authors used a descriptive qualitative research design and thematic analysis, in which observation and 27 semi-structured reports were used to reveal the impact of design thinking on undergraduate students' experience of creative problem-solving. Findings: The authors found multiple themes in students' responses concerning problem identification and definition in design thinking, which could be described as a systematic innovation process. Four major themes were identified. They included identifying and defining problems in a real-world context, empathizing with people from the target beneficiary group as a process of problem identification and definition, working with a team to expand the empathizing view, and perceiving the need for deep exploration in the empathetic process and defining a problem. Research limitations/implications: This study examined the perceived role of empathy in students' creative problem-solving process. However, the main limitation of this study was the small sample size, which can limit the generalizability of the results of the study. Nonetheless, this study provides valuable insights into understanding the role of empathy and problem identification as an essential process in creative problem-solving. Practical implications: It is worthwhile to integrate design thinking as an effective teaching and learning strategy in university education, particularly for fostering empathy and creative problem-solving skills in students. Among the processes of design thinking, empathy is critical in the problem identification and definition phase. Originality/value: This study adds to existing knowledge by examining the role and ways of perceiving real-world problems in a human-centered mindset in university programs.

This paper aims to quantify the effects of flipped classrooms in higher education by reviewing 43 empirical studies of students' cognitive, affective, and interpersonal outcomes. The innovative pedagogy of a flipped classroom in higher education fosters a sustainable, interactive, and student-centered learning environment (as opposed to the traditional lecture style, in which there is little room for interaction). This study's results show the positive effects of flipped classrooms and highlight the improvement in students' educational outcomes between 2012 and 2017. Overall, effect sizes were medium--effect size (ES) = 0.35, 95% confidence interval (CI) = 0.24 to 0.47--across three outcome domains using a random effects model. In the outcomes, affective (ES = 0.59), interpersonal (ES = 0.53), and cognitive (ES = 0.24) domains were of a higher order than the effect sizes. However, the results indicated that flipped classrooms benefitted students studying chemistry, engineering, mathematics, and physics less than they did students studying other subjects.

The academic use of mobile technology engages students beyond traditional classroom contexts. Over the past few years, higher education institutions have promoted students' learning and growth by supporting their use of mobile technology. Mobile technology offers educational possibilities that can enhance students' growth in higher education. The aim of this study is to examine the relationship between college students' academic use of mobile technology and higher-order thinking skills through their active engagement and learning effort. The sample consisted of 456 students at a university in South Korea, and the data were analyzed using partial least squares structural equation modeling. The results suggest that the academic use of mobile technology influences students' higher-order thinking skills directly, in addition to their learning effort and active engagement in courses. These findings provide valuable information for higher education institutions that seek to introduce interactive and technology-integrated environments.