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The medical metaverse can be defined as a virtual spatiotemporal framework wherein higher-dimensional medical information is generated, exchanged, and utilized through communication among medical personnel or patients. This occurs through the integration of cutting-edge technologies such as augmented reality (AR), virtual reality (VR), artificial intelligence (AI), big data, cloud computing, and others. We can envision a future neurosurgical operating room that utilizes such medical metaverse concept such as shared extended reality (AR/VR) of surgical field, AI-powered intraoperative neurophysiological monitoring, and real-time intraoperative tissue diagnosis. The future neurosurgical operation room will evolve into a true medical metaverse where participants of surgery can communicate in overlapping virtual layers of surgery, monitoring, and diagnosis.

Background: Accurate motor timing requires the coordinated control of actions in response to external stimuli. Over the past few years, several studies have investigated the effect of sensory input on motor timing; however, the evidence remains conflicting. The purpose of this study was to examine the impact of sensory modality and tempo on the accuracy of timed movements and explore strategies for enhancing motor timing., Methods: Participants ( n  = 30) performed synchronization and adaptation circle drawing tasks in virtual reality. In Experiment 1, participants synchronized circle drawing with repeated stimuli based on sensory modalities (auditory, visual, tactile, audio-visual, audio-tactile, and visual-tactile) and tempos (20, 30, and 60 bpm). In Experiment 2, we examined timing adaptation in circle drawing tasks under conditions of unexpected tempo changes, whether increased or decreased., Results: A significant interaction effect between modality and tempo was observed in the comparison of timing accuracy. Tactile stimuli exhibited significantly higher timing accuracy at 60 bpm, whereas auditory stimuli demonstrated a peak accuracy at 30 bpm. The analysis revealed a significantly larger timing error when adapting to changes in the tempo-down condition compared with the tempo-up condition., Discussion: Through Experiment 1, we found that sensory modality impacts motor timing differently depending on the tempo, with tactile modality being effective at a faster tempo and auditory modality being beneficial at a moderate tempo. Additionally, Experiment 2 revealed that adapting to changes by correcting timing errors is more challenging with decreasing tempo than with increasing tempo. Our findings suggest that motor timing is intricately influenced by sensory modality and tempo variation. Therefore, to enhance the motor timing, a comprehensive understanding of these factors and their applications is imperative., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jeong, Nam and Seo.)

Radio-resistant triple negative breast cancer (TNBC) is resistant to conventional drugs and radiation therapy. ortho-topolin riboside (oTR) has been evaluated for its anticancer activity in several types of cancer cells. However, its anti-proliferative activity in radio-resistant TNBC cells has not yet been reported. Therefore, we investigated the anti-proliferative activity of oTR in radio-resistant TNBC cells, and performed metabolome, lipidome, transcriptome, and proteome profiling to reveal the mechanisms of the anticancer activity of oTR. oTR showed cytotoxicity against radio-resistant TNBC cells with an inhibitory concentration (IC 50 ) value of 7.78 μM. Significantly decreased (p value < 0.05) basal and compensatory glycolysis were observed in the oTR-treated group than untreated group. Mitochondrial spare respiratory capacity, which is relevant to cell fitness and flexibility, was significantly decreased (p value < 0.05) in the oTR-treated group. The major metabolic pathways significantly altered by oTR according to metabolome, transcriptome, and proteome profiles were the glycerolipid/glycerophospholipid pathway (log 2 (FC) of MGLL = -0.13, log 2 (FC) of acylglycerol lipase = -1.35, log 2 (FC) of glycerol = -0.81), glycolysis (log 2 (FC) of EGLN1 = 0.16, log 2 (FC) of EGLN1 = 0.62, log 2 (FC) of glucose = -0.76, log 2 (FC) of lactate = -0.81), and kynurenine pathway (log 2 (FC) of KYNU = 0.29, log 2 (FC) of kynureninase = 0.55, log 2 (FC) of alanine = 0.72). Additionally, proline metabolism (log 2 (FC) of PYCR1 = -0.17, log 2 (FC) of proline = -0.73) was significantly altered in the metabolomic and transcriptomic profiles. The MAPK signaling pathway (log 2 (FC) of CCN1 = -0.15, log 2 (FC) of CCN family member 1 = -1.02) and Rap 1 signaling pathway (log 2 (FC) of PARD6B = -0.28, log 2 (FC) of PAR6B = -3.13) were also significantly altered in transcriptomic and proteomic profiles. The findings of this study revealed that oTR has anticancer activity in radio-resistant TNBC cells by affecting various metabolic pathways, suggesting the potential of oTR as a novel anticancer agent for radio-resistant TNBC patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The aim of this study is to identify and classify the different attributes that contribute to peak performance among professional dancers, and to understand how these attributes change over time. We conducted an analysis using inductive content analysis on open-ended survey data collected from 42 formally trained professional dancers. Additionally, we analyzed interview data from seven professional dancers who demonstrated outstanding achievements in the field among the survey participants. The main themes that emerged were related to various temporal events of peak performance experience: pre-stage, on-stage, and post-stage. During the on-stage, peak performance was perceived by both internal and external factors. During the pre-stage, emphasis was placed on technical, cognitive, and artistic strategies during practice, whereas just before going on the stage, attention shifted to psychological and physical strategies. During the post-stage, dancers reported immediate changes in their psychological and physical states following the peak performance experience, and thereafter, the peak performance experience was noted to influence psychological, technical, and cognitive aspects. These findings provide valuable insights into the key characteristics that emerge throughout a series of peak performance experiences and are consistent with previous research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nam, Park and Kim.)

This in vitro study aimed to evaluate the feasibility of quantitative light-induced fluorescence (QLF) technology for detecting the presence and severity of microleakage of pit and fissure sealants. The areas of interest (AOIs) were 160 pits and fissures of 40 extracted permanent teeth. Fluorescent images were acquired using a QLF device, and the maximum fluorescence loss ΔF max of each AOI was analyzed. After staining and cross-sectioning of the teeth, histological dye penetration was scored on a scale of 0 to 3. The relationship between ΔF max and microleakage depth was analyzed, and the areas under the curve (AUCs) were calculated. The │ΔF max │ increased as microleakage depth increased. The ΔF max values of microleakage areas showed a strong significant correlation with the histological scores of dye penetration (r = - 0.72, P = 0.001). AUC analysis showed a high diagnostic accuracy for microleakage depth (AUC = 0.83-0.91). The highest AUC of 0.91 was found when differentiating the outer half microleakage of the sealant (histological score 0 vs. 1-3). QLF technology is effective in assessing the presence and severity of microleakage, suggesting its potential for noninvasive detection and monitoring of sealant microleakage in clinical settings., (© 2024. The Author(s).)

The necessity of bilateral bypass in adult moyamoya disease (MMD) remains unclear despite its recommendation for pediatric and hemorrhagic cases. We aimed to investigate the natural course of hemodynamically stable unoperated hemispheres after bypass surgery for symptomatic and hemodynamically unstable hemispheres in adult patients with ischemic MMD. Among 288 patients, the mean age at the first operation of the unstable hemispheres was 40.8 ± 12.2 years. The mean follow-up period was 62.9 ± 46.5 months. 45 patients (15.6%) experienced stroke events in the unoperated hemisphere, consisting of hemorrhagic stroke in 8 (2.8%) and ischemic stroke in 37 (12.8%), including progressive transient ischemic attack in 25 (8.7%) and infarction in 12 (4.2%). Among them, 39 patients (13.5%) underwent bypass surgery. The annual risk of total stroke is 3.0%/patient-year, with 2.5% for ischemic stroke and 0.5% for hemorrhagic stroke. The 5- and 10-year cumulative risks of ischemic stroke were 13.4% and 18.3%, respectively, and those of hemorrhagic stroke were each 3.2%. The natural course of hemodynamically stable hemispheres contralateral to the operated ones appeared fairly good. Additional bypass surgery on the unoperated hemispheres should be considered for symptomatic and hemodynamically unstable hemispheres in adult patients with ischemic MMD during the follow-up., (© 2024. The Author(s).)

Background: : This study aimed to identify exact anatomical landmarks and ideal injection volumes for safe adductor canal blocks (ACB)., Methods: : Fifty thighs from 25 embalmed adult Korean cadavers were used. The measurement baseline was the line connecting the anterior superior iliac spine (ASIS) to the midpoint of the patellar base. All target points were measured perpendicular to the baseline. The relevant cadaveric structures were observed using ultrasound (US) and confirmed in living individuals. US-guided dye injection was performed to determine the ideal volume., Results: : The apex of the femoral triangle was 25.3 ± 2.2 cm distal to the ASIS on the baseline and 5.3 ± 1.0 cm perpendicular to that point. The midpoint of the superior border of the vasto-adductor membrane (VAM) was 27.4 ± 2.0 cm distal to the ASIS on the baseline and 5.0 ± 1.1 cm perpendicular to that point. The VAM had a trapezoidal shape and was connected as an aponeurosis between the medial edge of the vastus medialis muscle and lateral edge of the adductor magnus muscle. The nerve to the vastus medialis penetrated the muscle proximal to the superior border of the VAM in 70% of specimens. The VAM appeared on US as a hyperechoic area connecting the vastus medialis and adductor magnus muscles between the sartorius muscle and femoral artery., Conclusions: : Confirming the crucial landmark, the VAM, is beneficial when performing ACB. It is advisable to insert the needle obliquely below the superior VAM border, and a 5 mL injection is considered sufficient.

Developmental Coordination Disorder (DCD), also known as Dyspraxia, is characterized by movement difficulties in individuals without discernible neurological disorders or identifiable medical conditions. Previous studies from various countries have highlighted disparities in anthropometric, physical activity, and psychological characteristics between children diagnosed with DCD and their typically developing (TD) peers. These differences are influenced by sociocultural norms and geographical locations. However, little attention has been given to scrutinizing analogous differences in adult populations, particularly within Republic of Korea. This study aims to address this knowledge gap by employing a battery of questionnaires to assess anthropometric, physical activity, and psychological traits in a cohort of 377 Korean adults, encompassing those with DCD ( n = 54) alongside TD counterparts ( n = 323). It was hypothesized that Korean adults with DCD would exhibit higher body mass index and lower ratings in physical activity and psychological characteristics than TD, consistent with the previous studies performed in other countries on children. The results showed no statistically significant differences between the DCD and TD groups in anthropometric characteristics such as weight (kg), height (cm), and body mass index. The prevalence of walking and biking for daily commuting in daily routines within Korean society might have contributed to the mitigation of anthropometric among individuals with/without DCD. Statistically significant differences were found in physical activity levels at work and recreational settings, as shown in physical activity scores and duration. The DCD group also displayed lower scores across several psychological characteristics, including exercise adherence, intrinsic motivation, self-efficacy, physical self-concept, exercise expectations, and intrinsic regulation. These findings underscore the necessity of incorporating sociocultural dynamics when investigating anthropometric, physical activity, and psychological characteristics in adults with DCD. Their perceived difficulties in fine motor skills were also significantly poor than TD. Future research studies are warranted to elucidate the underlying mechanisms driving the observed patterns in this study, thus contributing to a more nuanced comprehension of how DCD manifests within specific sociocultural contexts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Kim, Nam, Kim, Park, Park and Shim.)

Background: Melanoma is one of the most aggressive and metastatic skin cancers. Although overexpression of Dock180 and Elmo1 has been identified in various cancers, including glioma, ovarian cancer, and breast cancer, their expression and functions in melanoma remain unknown., Objective: This study aims to confirm the expression of Dock180 and Elmo1, their underlying mechanisms, and roles in melanoma., Methods: Both immunohistochemical staining and Western blotting were used to confirm expression of Dock180 and Elmo1 in human melanoma. To identify roles of Dock180 and Elmo1 in cell survival, apoptosis and migration, downregulation of Dock180 or Elmo1 in melanoma cells with small interfering RNA (siRNA) was performed., Results: We identified overexpression of Dock180 and Elmo1 in human melanoma compared to normal skin ex vivo . Inhibition of Dock180 or Elmo1 following siRNA in melanoma cells reduced cell viability and increased apoptosis as supported by increased proportion of cells with Annexin V-PE (+) staining and sub-G0/G1 peak in cell cycle analysis. Moreover, inhibition of Dock180 or Elmo1 regulated apoptosis-related proteins, showing downregulation of Bcl-2, caspase-3, and PARP and upregulation of Bax, PUMA, cleaved caspase-3, and cleaved PARP. Furthermore, knockdown of Dock180 and Elmo1 in melanoma cells reduced cell migration and changed cellular signaling pathways including ERK and AKT. Vemurafenib decreased cell viability in concentration-dependent manner, while transfection with Dock180- or Elmo1-specific siRNA in melanoma cells significantly reduced cell viability., Conclusion: Our results suggest that both Dock180 and Elmo1 may be associated with cancer progression, and can be potential targets for treatment of melanoma., Competing Interests: The authors have nothing to disclose., (Copyright © The Korean Dermatological Association and The Korean Society for Investigative Dermatology.)

Background: The vestibulocerebellar tract (VCT) is responsible for maintaining balance, spatial orientation, and coordination. Damage to the vestibular system is accompanied by symptoms of balance disorder or ataxia. This study aimed to compare cerebellar dysfunction according to VCT damage in patients with cerebellar stroke., Methods: Six patients with cerebellum injury were recruited. This study measured ataxia and hand function related to visuomotor integration and manual dexterity using the Purdue pegboard test. The primary and bilateral secondary VCTs were reconstructed to investigate the integrity of pathways using diffusion tensor imaging (DTI)., Results: The ataxia sign was positive in five patients (83%) at onset. In the result of the pegboard test, all patients had hand dysfunction in the dominant hand (100%). Likewise, all patients also had non-dominant hand dysfunction (100%). On the DTI tractography, the left and right primary VCTs of the patients demonstrated a 25% injury rate. Furthermore, the injury rates of ipsilateral and contralateral secondary VCTs were 50% and 58%., Conclusions: Ataxia is related to secondary VCTs, and hand dysfunction is also related to VCTs. Therefore, we believe that the current study will be helpful in evaluating and providing a clinical intervention strategy for patients with ataxia and hand dysfunction following cerebellar injury.

Obesity and heavy metals, such as lead (Pb), are detrimental to the adult brain because they impair cognitive function and structural plasticity. However, the effects of co-administration of Pb and a high-fat diet (HFD) on the developing cerebellum is not clearly elucidated. We investigated the effects of Pb exposure (0.3% lead acetate) on developing cerebellum in the pups of an HFD-fed obese rat model. One week before mating, we fed a chow diet (CD) or HFD to the rats for one week and additionally administered Pb to HFD-fed female SD rats. Thereafter, treatment with Pb and a HFD was continued during the gestational and lactational periods. On postnatal day 21, the pups were euthanized to sample the brain tissue and blood for further analysis. Blood Pb levels were significantly higher in HFD-fed rats than in CD-fed rats. Histologically, the prominent degeneration of Purkinje cells was induced by the co-administration of Pb and HFD. The calbindin-28Kd-, GAD67-, NMDAR1-, and PSD95-immunopositive Purkinje cells and inhibitory synapse-forming pinceau structures were significantly decreased following Pb and HFD co-administration. MBP-immunoreactive myelinated axonal fibers were also impaired by HFD but were significantly damaged by the co-administration of HFD and Pb. Oxidative stress-related Nrf2-HO1 signaling was activated by HFD feeding, and Pb exposure further aggravated oxidative stress, as demonstrated by the consumption of endogenous anti-oxidant in HFD-Pb rats. The pro-inflammatory response was also increased by the co-administration of HFD and Pb in the cerebellum of the rat offspring. The present results suggest that HFD and Pb treatment during the gestational and lactational periods are harmful to cerebellar development.

Background and Objectives : This study aimed to evaluate the effectiveness of a wheelchair skills training program (WSTP) in improving sitting balance and pulmonary function in patients with chronic tetraplegia resulting from cervical spinal cord injury (cSCI). Materials and Methods : Twenty-four patients were randomly divided into WSTP and control groups. The WSTP group participated in the WSTP for eight weeks, while the control group underwent conventional physical therapy for the same eight-week period. Sitting balance was evaluated using the activity-based balance level evaluation (ABLE) scale, and pulmonary function was evaluated using forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow (PEF). Results : The WSTP group showed significant improvements in both sitting balance and pulmonary function during the intervention period ( p < 0.05), whereas the control group did not show any significant changes. A strong positive correlation was found between ABLE scores and all three pulmonary function parameters across all time points. Conclusions : Our results suggest that the WSTP significantly improves sitting balance and specific aspects of lung function in patients with tetraplegia.

Objective: Screening for chronic kidney disease (CKD) requires an estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) from a blood sample and a proteinuria level from a urinalysis. We developed machine-learning models to detect CKD without blood collection, predicting an eGFR less than 60 (eGFR60 model) or 45 (eGFR45 model) using a urine dipstick test., Materials and Methods: The electronic health record data (n = 220 018) obtained from university hospitals were used for XGBoost-derived model construction. The model variables were age, sex, and 10 measurements from the urine dipstick test. The models were validated using health checkup center data (n = 74 380) and nationwide public data (KNHANES data, n = 62 945) for the general population in Korea., Results: The models comprised 7 features, including age, sex, and 5 urine dipstick measurements (protein, blood, glucose, pH, and specific gravity). The internal and external areas under the curve (AUCs) of the eGFR60 model were 0.90 or higher, and a higher AUC for the eGFR45 model was obtained. For the eGFR60 model on KNHANES data, the sensitivity was 0.93 or 0.80, and the specificity was 0.86 or 0.85 in ages less than 65 with proteinuria (nondiabetes or diabetes, respectively). Nonproteinuric CKD could be detected in nondiabetic patients under the age of 65 with a sensitivity of 0.88 and specificity of 0.71., Discussion and Conclusions: The model performance differed across subgroups by age, proteinuria, and diabetes. The CKD progression risk can be assessed with the eGFR models using the levels of eGFR decrease and proteinuria. The machine-learning-enhanced urine-dipstick test can become a point-of-care test to promote public health by screening CKD and ranking its risk of progression., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Drugs produce pharmaceutical and adverse effects that arise from the complex relationship between drug targets and signatures; by considering such relationships, we can begin to understand the cellular mechanisms of drugs. In this study, we selected 463 genes from the DSigDB database corresponding to targets and signatures for 382 FDA-approved drugs with both protein binding information for a drug-target score (KDTN, i.e., the degree to which the protein encoded by the gene binds to a number of drugs) and microarray signature information for a drug-sensitive score (KDSN, i.e., the degree to which gene expression is stimulated by the drug). Accordingly, we constructed two drug-gene bipartite network models, a drug-target network and drug-signature network, which were merged into a multidimensional model. Analysis revealed that the KDTN and KDSN were in mutually exclusive and reciprocal relationships in terms of their biological network structure and gene function. A symmetric balance between the KDTN and KDSN of genes facilitates the possibility of therapeutic drug effects in whole genome. These results provide new insights into the relationship between drugs and genes, specifically drug targets and drug signatures., (© 2023. The Author(s).)

Purpose: Molecular subgrouping of medulloblastoma has become important due to its impact on risk group stratification. Immunohistochemistry (IHC) has been widely used but it has innate limitations. The NanoString assay has been proposed as an alternative method. This study aims to present the characteristics of medulloblastoma subgrouped by the NanoString assay and to compare the subgrouping results with the IHC method., Methods: Pediatric patients with histological diagnosis of medulloblastoma who underwent surgery from 2007 to 2021 were included. Clinical characteristics, pathological findings were reviewed. Molecular subgrouping was performed by IHC and by NanoString nCounter Elements TagSets assay. Test for concordance between two methods was made., Results: Among a total of 101 patients analyzed, subgrouping using the NanoString assay resulted in 14 (13.8%) WNT, 20 (19.8%) SHH, 18 (17.8%) Group 3, and 39 (38.6%) Group 4 subgroup cases. Survival analysis revealed the following from best to worse prognosis: WNT, Group 4, SHH, and Group 3. In SHH subgroup the large cell/anaplastic histology was present in 30% of cases. Seventy-one cases were analyzed for concordance between NanoString and IHC. Cohen's kappa value indicated moderate agreement but identification of Groups 3 and 4 with IHC using NPR3 and KCNA1 markers exhibited poor results., Conclusions: The NanoString assay of Korean medulloblastoma patients revealed a more aggressive clinical course in the SHH subgroup which may be explained by a higher proportion of large cell/anaplastic histology being present in this subgroup. IHC did not distinguish Group 3 or 4 accurately. The NanoString assay may represent a good alternative method for practical use in the clinical field., (© 2022. The Author(s).)

The forward shoulder posture (FSP) results from shoulders being pulled forward by shortened anterior shoulder girdle muscles. The objective of this study was to investigate the short-term effectiveness of the reverse plank exercise on parascapular muscle thickness and forward shoulder angle (FSA) in patients with FSP. Participants were divided into the FSP and non-FSP (NFSP) groups based on the observed angle between the horizontal line of the C7 spinous process and the acromion process. All participants performed a total of five sets of reverse plank exercises at 30 s per set. FSA and muscle thickness of the pectoralis major (PM), serratus anterior (SA), upper trapezius (UT), and lower trapezius (LT) were measured before and after the reverse plank exercise. The muscle thicknesses of the SA and LT, and the FSA, were significantly increased after exercise in the FSP group (p < 0.05). Muscle thickness of the PM and UT significantly decreased after the exercise. In the NFSP group, muscle thickness of the LT was significantly increased, and muscle thickness of the PM and UT were significantly reduced after exercise (p < 0.05). Upon using between-group analysis, there were significant differences between the FSA, SA, UT, and LT groups (p < 0.05). The reverse plank exercise has the short-term benefit of correcting and preventing FSP by increasing SA and LT thickness while decreasing PM and UT thickness. We believe that the reverse plank exercise significantly improved the ability to prevent FSP in FSP-related muscles and was beneficial in achieving optimal postural alignment.

This study investigated the differences of anticipatory postural adjustments (APAs) in a one-leg stance (OLS) that appear according to lower-extremity dominance and dual-task interference. Thirteen young, healthy, male volunteers performed the OLS task under the following six conditions: (1) dominant leg (DL), single-task; (2) DL, dual-task, with a low level of cognitive load (DT1/2); (3) DL, dual-task, with a high level of cognitive load (DT + 1); (4) non-dominant leg (NDL), single-task; (5) NDL, DT1/2; and (6) NDL, DT + 1. In order to measure the subjects' APA, we used the medial-lateral displacement of their centers of pressure and gravity from the force plate and the time-series data of joint angular motions, recorded using a 3D motion analysis system. In the NDL under the dual-task condition, the onset of APA was delayed and the amplitude declined, which resulted in an increase in the duration of the APA period. The number of components identified by principal component analysis differed according to the dominant foot, and the change caused by cognitive load was found only in the NDL. As the cognitive load increased, the variance of the principal component decreased. These findings show that dual-task interference asymmetrically influences APA according to limb dominance, which reorganizes the coordination strategy of joints' angular motion.

Background and Objectives: Visual cue deprivation is the instability of head control is increased. The purpose of this study is to investigate the effects of visual cue deprivation balance training by applying head control feedback to the balance and gait ability of stroke patients. Materials and Methods : The study was conducted on 41 patients diagnosed with hemiplegia due to stroke. Subjects were randomly assigned to any of the following groups: the experimental group I, the experimental group II or the control group. The randomization method used a simple randomization method. To evaluate changes in balance function, a LOS (Limit of Stability) and a BBS (Berg Balance Scale) were performed. In addition, to evaluate changes in ST (stride time), SL (stride length), and cadence, a LEGSys were performed. Results: A two-way repeated ANOVA was conducted to analyze the differences between groups. There were significant differences between groups in all variables for the balance function. There were significant differences between groups in all variables for the balance function. There were significant differences between groups in SL and cadence for the gait function. Conclusions: Visual cue deprivation balance training applying head control feedback is effective in improving dynamic balance ability and cadence. It is necessary to constantly maintain the head orientation by feedback and to properly control the head movement.

We developed a machine-learning-based model that could predict a decrease in one-year graft function after kidney transplantation, and investigated the risk factors of the decreased function. A total of 4317 cases were included from the Korean Organ Transplant Registry (2014−2019). An XGBoost model was trained to predict the recipient’s one-year estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 m2 using 112 pre- and peri-transplantation variables. The network of model factors was drawn using inter-factor partial correlations and the statistical significance of each factor. The model with seven features achieved an area under the curve of 0.82, sensitivity of 0.73, and specificity of 0.79. The model prediction was associated with five-year graft and rejection-free survival. Post-transplantation hospitalization >25 days and eGFR ≥ 88.0 were the prominent risk and preventive factors, respectively. Donor age and post-transplantation eGFR < 59.8 were connected to multiple risk factors on the network. Therefore, careful donor−recipient matching in older donors, and avoiding pre-transplantation risk factors, would reduce the risk of graft dysfunction. The model might improve long-term graft outcomes by supporting early detection of graft dysfunction, and proactive risk factor control.

Background/objectives: Various sodium reduction policies have been implemented. However, there are limitations in the aspect of actual field applicability and efficiency. For effective sodium reduction, cooperation with the field is required and consumer preference must be considered. Thus, this study aimed to develop a low-sodium burger considering field applicability and consumer preference., Materials/methods: Focus group interviews and in-depth interviews on the sodium reduction measures were conducted with nine professionals in related fields to discuss practical methods for sodium reduction from September 7 to 21, 2018. By reflecting the interview results, a burger using a low-sodium sauce was developed, and preference analysis for sodium in the burger sauces and finished products was performed. The consumer preference for low-sodium burgers was evaluated on 51 college students on November 12, 2018., Results: The results of the professional interview showed that it is desirable to practice sodium reduction gradually, and by reflecting this, the burger sauce was prepared by adjusting the ratio of refined salt to 15%, 30%, and 50%. The sodium content of the burger using low-sodium sauce was 399 mg/100 g in the control group, 362 mg/100 g in the H1 group, and 351.5 mg/100 g in the H2 group, showing a 9.3-11.9% decrease in sodium in the H1 and H2 groups. The preference evaluation on the low-sodium burgers showed a higher preference for burgers with 9.3-11.9% sodium reduction, which did not affect the overall taste., Conclusions: This study examined the potential for sodium reduction in the franchise foodservice industry. An approximate 10% sodium reduction resulted in an increase in consumer preference without affecting the strength of the taste. Thus, if applied gradually, sodium reduction at practical levels could increase the consumer preference without changing the taste or quality and could be applied in the franchise foodservice industry., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interests., (©2022 The Korean Nutrition Society and the Korean Society of Community Nutrition.)

Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019, suffer from respiratory and non-respiratory symptoms. Among these symptoms, the loss of smell has attracted considerable attention. The objectives of this study were to determine which cells are infected, what happens in the olfactory system after viral infection, and how these pathologic changes contribute to olfactory loss. For this purpose, Syrian golden hamsters were used. First, we verified the olfactory structures in the nasal cavity of Syrian golden hamsters, namely the main olfactory epithelium, the vomeronasal organ, and their cellular components. Second, we found angiotensin-converting enzyme 2 expression, a receptor protein of SARS-CoV-2, in both structures and infections of supporting, microvillar, and solitary chemosensory cells. Third, we observed pathological changes in the infected epithelium, including reduced thickness of the mucus layer, detached epithelia, indistinct layers of epithelia, infiltration of inflammatory cells, and apoptotic cells in the overall layers. We concluded that a structurally and functionally altered microenvironment influences olfactory function. We observed the regeneration of the damaged epithelium, and found multilayers of basal cells, indicating that they were activated and proliferating to reconstitute the injured epithelium.

We report on the design, construction, and performance of a custom apparatus built to measure the frequency- and temperature-dependent absorptivity of millimeter-wave light by cosmic analog dusts. We highlight the unique challenges faced as well as a few key innovations that are part of the instrument. Among those is an ultra-compact Fourier transform spectrometer. We have measured its effective frequency range and FWHM resolution to be 150-2100 GHz and ∼45 G H z , respectively. Another innovation is a cold sample positioner whose temperature can be controlled within the range of 3.7-50 K. The use of a pulse-tube cryocooler results in a pulse-synchronous signal that dominates the detector (bolometer) signal. Methods used to address that challenge are also presented.

Objectives: Prostaglandin E2 E-prostanoid 2 receptor (PGE2 EP2), downstream of cyclooxygenase-2 (COX-2), plays an important role in inflammatory responses, but there are some reports about synaptic functions of COX-2 and PGE2 EP2 in the hippocampus., Materials and Methods: C57BL/6J mice were sacrificed at postnatal days (P) 1, 7, 14, 28, and 56 for immunohistochemical staining for EP2 and doublecortin as well as western blot for EP2. In addition, COX-2 knockout and its wild-type mice were euthanized for immunohistochemical staining for EP2., Results: EP2 immunoreactivity was observed in the majority of the cells in the dentate gyrus at P1 and P7, while at P14, it was detected in the outer granule cell layer and was confined to its subgranular zone at P28 and P56. EP2 protein levels in the hippocampal homogenates were also highest at P7 and lowest at P56. EP2 immunoreactivity was partially colocalized, with doublecortin (DCX)-immunoreactive neuroblasts appearing in the mid-zone of the granule cell layer at P14 and in the subgranular zone of the dentate gyrus at P28. Co-localization of EP2 and DCX was significantly decreased in the dentate gyrus in the P28 group compared with that in the P14 group. In COX-2 knockout mice, EP2 immunoreactivity was significantly decreased in the hippocampal CA1 region ( P =0.000165) and dentate gyrus ( P =0.00898)., Conclusion: EP2 decreases with age, which is expressed in DCX-immunoreactive neuroblasts in the dentate gyrus. This suggests that EP2 is closely linked to structural lamination and adult neurogenesis in the dentate gyrus.

Background: In epidemiological studies, finding the best subset of factors is challenging when the number of explanatory variables is large., Objective: Our study had two aims. First, we aimed to identify essential depression-associated factors using the extreme gradient boosting (XGBoost) machine learning algorithm from big survey data (the Korea National Health and Nutrition Examination Survey, 2012-2016). Second, we aimed to achieve a comprehensive understanding of multifactorial features in depression using network analysis., Methods: An XGBoost model was trained and tested to classify "current depression" and "no lifetime depression" for a data set of 120 variables for 12,596 cases. The optimal XGBoost hyperparameters were set by an automated machine learning tool (TPOT), and a high-performance sparse model was obtained by feature selection using the feature importance value of XGBoost. We performed statistical tests on the model and nonmodel factors using survey-weighted multiple logistic regression and drew a correlation network among factors. We also adopted statistical tests for the confounder or interaction effect of selected risk factors when it was suspected on the network., Results: The XGBoost-derived depression model consisted of 18 factors with an area under the weighted receiver operating characteristic curve of 0.86. Two nonmodel factors could be found using the model factors, and the factors were classified into direct (P<.05) and indirect (P≥.05), according to the statistical significance of the association with depression. Perceived stress and asthma were the most remarkable risk factors, and urine specific gravity was a novel protective factor. The depression-factor network showed clusters of socioeconomic status and quality of life factors and suggested that educational level and sex might be predisposing factors. Indirect factors (eg, diabetes, hypercholesterolemia, and smoking) were involved in confounding or interaction effects of direct factors. Triglyceride level was a confounder of hypercholesterolemia and diabetes, smoking had a significant risk in females, and weight gain was associated with depression involving diabetes., Conclusions: XGBoost and network analysis were useful to discover depression-related factors and their relationships and can be applied to epidemiological studies using big survey data., (©Sang Min Nam, Thomas A Peterson, Kyoung Yul Seo, Hyun Wook Han, Jee In Kang. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 24.06.2021.)

Entacapone, a catechol-O-methyltransferase inhibitor, can strengthen the therapeutic effects of levodopa on the treatment of Parkinson's disease. However, few studies are reported on whether entacapone can affect hippocampal neurogenesis in mice. To investigate the effects of entacapone, a modulator of dopamine, on proliferating cells and immature neurons in the mouse hippocampal dentate gyrus, 60 mice (7 weeks old) were randomly divided into a vehicle-treated group and the groups treated with 10, 50, or 200 mg/kg entacapone. The results showed that 50 and 200 mg/kg entacapone increased the exploration time for novel object recognition. Immunohistochemical staining results revealed that after entacapone treatment, the numbers of Ki67-positive proliferating cells, doublecortin-positive immature neurons, and phosphorylated cAMP response element-binding protein (pCREB)-positive cells were significantly increased. Western blot analysis results revealed that treatment with tyrosine kinase receptor B (TrkB) receptor antagonist significantly decreased the exploration time for novel object recognition and inhibited the expression of phosphorylated TrkB and brain-derived neurotrophic factor (BDNF). Entacapone treatment antagonized the effects of TrkB receptor antagonist. These results suggest that entacapone treatment promoted hippocampal neurogenesis and improved memory function through activating the BDNF-TrkB-pCREB pathway. This study was approved by the Institutional Animal Care and Use Committee of Seoul National University (approval No. SNU-130730-1) on February 24, 2014., Competing Interests: None

Background: Recently, gintonin and gintonin-enriched fraction (GEF) have been isolated from ginseng, a herbal medicine. Gintonin induces [Ca 2+ ] i transition in cultured hippocampal neurons and stimulates acetylcholine release through LPA receptor activation. Oral administration of GEF is linked to hippocampus-dependent cognitive enhancement and other neuroprotective effects; however, effects of its long-term administration on hippocampal gene expression remains unknown. Here, we used next-generation sequence (NGS) analysis to examine changes in hippocampal gene expressions after long-term oral administration of GEF., Methods: C57BL/6 mice were divided into three groups: control group, GEF50 (GEF 50 mg/kg, p.o. ), and GEF100 (GEF 100 mg/kg, p.o. ). After 22 days, total RNA was extracted from mouse hippocampal tissues. NGS was used for gene expression profiling; quantitative-real-time PCR and western blot were performed to quantify the changes in specific genes and to confirm the protein expression levels in treatment groups., Results: NGS analysis screened a total of 23,282 genes, analyzing 11-related categories. We focused on the neurogenesis category, which includes four genes for candidate markers: choline acetyltransferase (ChAT) gene, β 3 -adrenergic receptor (Adrb3) gene, and corticotrophin-releasing hormone (Crh) gene, and tryptophan 2,3-dioxygenase (Tdo2) gene. Real-time PCR showed a marked overexpression of ChAT, Adrb3, and Crh genes, while reduced expression of Tdo2. Western blot analysis also confirmed increased ChAT and decreased Tdo2 protein levels., Conclusion: We found that GEF affects mouse hippocampal gene expressions, associated with memory, cognitive, anti-stress and anti-anxiety functions, and neurodegeneration at differential degree, that might explain the genetic bases of GEF-mediated neuroprotective effects., (© 2020 Korea Institute of Oriental Medicine. Publishing services by Elsevier B.V.)

Background: Gintonin is an exogenous ginseng-derived G-protein-coupled lysophosphatidic acid (LPA) receptor ligand. LPA induces in vitro morphological changes and migration through neuronal LPA1 receptor. Recently, we reported that systemic administration of gintonin increases blood-brain barrier (BBB) permeability via the paracellular pathway and its binding to brain neurons. However, little is known about the influences of gintonin on in vivo neuron morphology and migration in the brain., Materials and Methods: We examined the effects of gintonin on in vitro migration and morphology using primary hippocampal neural precursor cells (hNPC) and in vivo effects of gintonin on adult brain neurons using real time microscopic analysis and immunohistochemical analysis to observe the morphological and locational changes induced by gintonin treatment., Results: We found that treating hNPCs with gintonin induced morphological changes with a cell rounding following cell aggregation and return to individual neurons with time relapses. However, the in vitro effects of gintonin on hNPCs were blocked by the LPA1/3 receptor antagonist, Ki16425, and Rho kinase inhibitor, Y27632. We also examined the in vivo effects of gintonin on the morphological changes and migration of neurons in adult mouse brains using anti-NeuN and -neurofilament H antibodies. We found that acute intravenous administration of gintonin induced morphological and migrational changes in brain neurons. Gintonin induced some migrations of neurons with shortened neurofilament H in the cortex. The in vivo effects of gintonin were also blocked by Ki16425., Conclusion: The present report raises the possibility that gintonin could enter the brain and exert its influences on the migration and morphology of adult mouse brain neurons and possibly explains the therapeutic effects of neurological diseases behind the gintonin administration., Competing Interests: The authors declare no conflict of interest., (© 2020 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Background: We recently showed that gintonin, an active ginseng ingredient, exhibits antibrain neurodegenerative disease effects including multiple target mechanisms such as antioxidative stress and antiinflammation via the lysophosphatidic acid (LPA) receptors. Amyotrophic lateral sclerosis (ALS) is a spinal disease characterized by neurodegenerative changes in motor neurons with subsequent skeletal muscle paralysis and death. However, pathophysiological mechanisms of ALS are still elusive, and therapeutic drugs have not yet been developed. We investigate the putative alleviating effects of gintonin in ALS., Methods: The G93A-SOD1 transgenic mouse ALS model was used. Gintonin (50 or 100 mg/kg/day, p.o.) administration started from week seven. We performed histological analyses, immunoblot assays, and behavioral tests., Results: Gintonin extended mouse survival and relieved motor dysfunctions. Histological analyses of spinal cords revealed that gintonin increased the survival of motor neurons, expression of brain-derived neurotrophic factors, choline acetyltransferase, NeuN, and Nissl bodies compared with the vehicle control. Gintonin attenuated elevated spinal NAD(P) quinone oxidoreductase 1 expression and decreased oxidative stress-related ferritin, ionized calcium-binding adapter molecule 1-immunoreactive microglia, S100β-immunoreactive astrocyte, and Olig2-immunoreactive oligodendrocytes compared with the control vehicle. Interestingly, we found that the spinal LPA1 receptor level was decreased, whereas gintonin treatment restored decreased LPA1 receptor expression levels in the G93A-SOD1 transgenic mouse, thereby attenuating neurological symptoms and histological deficits., Conclusion: Gintonin-mediated symptomatic improvements of ALS might be associated with the attenuations of neuronal loss and oxidative stress via the spinal LPA1 receptor regulations. The present results suggest that the spinal LPA1 receptor is engaged in ALS, and gintonin may be useful for relieving ALS symptoms., Competing Interests: All the authors declare that they have no conflicts of interest., (© 2020 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Due to the limited supply of vessels and nerves, acute or chronic tendon injuries often result in significant and persistent complications, such as pain and sprains, as well as the loss of joint functions. Among these complications, tendon adhesions within the surrounding soft tissue have been shown to significantly impair the range of motion. In this study, to elucidate the effects of a hyaluronic acid (HA) injection at the site of tenorrhaphy on tendon adhesion formation, we used a full transection model of a rat's Achilles tendon to investigate the anti-adhesive function of HA. Our initial findings showed that significantly lower adhesion scores were observed in the HA-treated experimental group than in the normal saline-treated control group, as determined by macroscopic and histological evaluations. Hematoxylin and eosin, as well as picrosirius red staining, showed denser and irregular collagen fibers, with the larger number of infiltrating inflammatory cells in the control group indicating severe adhesion formation. Furthermore, we observed that the expression of tendon adhesion markers in operated tendon tissue, such as collagen type I, transforming growth factor-β1, and plasminogen activator inhibitor-1, was suppressed at both the gene and protein levels following HA treatment. These results suggest that HA injections could reduce tendon adhesion formation by significantly ameliorating inflammatory-associated reactions.

Background: A dramatic increase in aging populations and low birth rates rapidly drive aging societies and increase aging-associated neurodegenerative diseases. However, functional food or medicinal formulations to prevent geriatric brain disorders are not readily available. Panax ginseng is a candidate, since ginseng has long-been consumed as a rejuvenating agent. However, the underlying molecular mechanisms and the components of ginseng that are responsible for brain rejuvenation and human longevity are unknown. Accumulating evidence shows that gintonin is a candidate for the anti-aging ingredient of ginseng, especially in brain senescence., Methods: Gintonin, a glycolipoprotein complex, contains three lipid-derived G protein-coupled receptor ligands: lysophosphatidic acids (LPAs), lysophosphatidylinositols (LPIs), and linoleic acid (LA). LPA, LPI, and LA act on six LPA receptor subtypes, GPR55, and GPR40, respectively. These G protein-coupled receptors are distributed within the nervous and non-nervous systems of the human body., Results: Gintonin-enriched fraction (GEF) exhibits anti-brain senescence and effects against disorders such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). Oral administration of gintonin in animal models of d-galactose-induced brain aging, AD, HD, and PD restored cognitive and motor functions. The underlying molecular mechanisms of gintonin-mediated anti-brain aging and anti-neurodegenerative diseases include neurogenesis, autophagy stimulation, anti-apoptosis, anti-oxidative stress, and anti-inflammatory activities. This review describes the characteristics of gintonin and GEF, and how gintonin exerts its effects on brain aging and brain associated-neurodegenerative diseases., Conclusion: Finally, we describe how GEF can be applied to improve the quality of life of senior citizens in aging societies., (© 2020 Korea Institute of Oriental Medicine. Publishing services by Elsevier B.V.)

Keloid and hypertrophic scars are skin fibrosis-associated disorders that exhibit an uncontrollable proliferation of fibroblasts and their subsequent contribution to the excessive accumulation of extracellular matrix (ECM) in the dermis. In this study, to elucidate the underlying mechanisms, we investigated the pivotal roles of epidermal growth factor (EGF) in modulating fibrotic phenotypes of keloid and hypertrophic dermal fibroblasts. Our initial findings revealed the molecular signatures of keloid dermal fibroblasts and showed the highest degree of skin fibrosis markers, ECM remodeling, anabolic collagen-cross-linking enzymes, such as lysyl oxidase (LOX) and four LOX-like family enzymes, migration ability, and cell-matrix traction force, at cell-matrix interfaces. Furthermore, we observed significant EGF-mediated downregulation of anabolic collagen-cross-linking enzymes, resulting in amelioration of fibrotic phenotypes and a decrease in cell motility measured according to the cell-matrix traction force. These findings offer insight into the important roles of EGF-mediated cell-matrix interactions at the cell-matrix interface, as well as ECM remodeling. Furthermore, the results suggest their contribution to the reduction of fibrotic phenotypes in keloid dermal fibroblasts, which could lead to the development of therapeutic modalities to prevent or reduce scar tissue formation.

Large-scale wireless sensor networks are characterized by stringent energy and computation restrictions. It is exceedingly difficult to change a sensor network's environment configurations, such as the number of sensor nodes, after deployment of the nodes. Although several simulators are able to variously construct simulation models for sensor networks before their deployment, the configurations should be modified with extra human effort as the simulators cannot freely generate diverse models. In this paper, we propose a novel framework, called a system entity structure and model base for large-scale wireless sensor networks (WSN-SES/MB), which is based on discrete event system specification formalism. Our proposed framework synthesizes the structure and models for sensor networks through our modeling construction process. The proposed framework achieves time and cost savings in constructing discrete event simulation-based models. In addition, the framework increases the diversity of simulation models by the process's pruning algorithm. The simulation results validate that the proposed framework provides up to 8% time savings and up to 23% cost savings as compared to the manual extra effort.

Entacapone, a reversible inhibitor of catechol-O-methyl transferase, is used for patients in Parkinson's disease because it increases the bioavailability and effectiveness of levodopa. In the present study, we observed that entacapone increases novel object recognition and neuroblasts in the hippocampus. In the present study, two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry were performed to compare the abundance profiles of proteins expressed in the hippocampus after entacapone treatment in mice. Results of 2-DE, MALDI-TOF mass spectrometry, and subsequent proteomic analysis revealed an altered protein expression profile in the hippocampus after entacapone treatment. Based on proteomic analysis, 556 spots were paired during the image analysis of 2-DE gels and 76 proteins were significantly changed more than two-fold among identified proteins. Proteomic analysis indicated that treatment with entacapone induced expressional changes in proteins involved in synaptic transmission, cellular processes, cellular signaling, the regulation of cytoskeletal structure, energy metabolism, and various subcellular enzymatic reactions. In particular, entacapone significantly increased proteins related to synaptic trafficking and plasticity, such as dynamin 1, synapsin I, and Munc18-1. Immunohistochemical staining showed the localization of the proteins, and western blot confirmed the significant increases in dynamin I (203.5% of control) in the hippocampus as well as synapsin I (254.0% of control) and Munc18-1 (167.1% of control) in the synaptic vesicle fraction of hippocampus after entacapone treatment. These results suggest that entacapone can enhance hippocampal synaptic trafficking and plasticity against various neurological diseases related to hippocampal dysfunction.

Laminaria japonica is widely cultivated in East Asia, including South Korea. Fucoidan, a main component of L. japonica , protects neurons from neurological disorders such as ischemia and traumatic brain injury. In the present study, we examined the effects of extract from fermented L. japonica on the reduction of proliferating cells and neuroblasts in mice that were physically (with electric food shock) or psychologically (with visual, auditory and olfactory sensation) stressed with the help of a communication box. Vehicle (distilled water) or fermented L. japonica extract (50 mg/kg) were orally administered to the mice once a day for 21 days. On the 19th day of the treatment, physical and psychological stress was induced by foot shock using a communication box and thereafter for three days. Plasma corticosterone levels were significantly increased after exposure to physical stress and decreased Ki67 positive proliferating cells and doublecortin immunoreactive neuroblasts. In addition, western blot analysis demonstrated that physical stress as well as psychological stress decreased the expression levels of brain-derived neurotrophic factor (BDNF) and the number of phosphorylated cAMP response element binding protein (pCREB) positive nuclei in the dentate gyrus. Fermentation of L. japonica extract significantly increased the contents of reduced sugar and phenolic compounds. Supplementation with fermented L. japonica extract significantly ameliorated the increases of plasma corticosterone revels and decline in the proliferating cells, neuroblasts, and expression of BDNF and pCREB in the physically stressed mice. These results indicate that fermented L. japonica extract has positive effects in ameliorating the physical stress induced reduction in neurogenesis by modulating BDNF and pCREB expression in the dentate gyrus.

Background: Diabetes is a progressive disease that increases glucose levels in the blood. While studies have shown that patients with pulmonary disease (both obstructive and restrictive pulmonary disease) have a higher prevalence of type 2 diabetes mellitus (T2DM), there have been more studies on restrictive patterns than chronic obstructive pulmonary disease., Aim: To assess whether restrictive and obstructive pulmonary diseases are associated with T2DM in Koreans., Methods: For our analysis, we used data from the Korea National Health and Nutrition Examination Survey. A total of 2830 subjects were included in this study. Spirometry results were categorized into three patterns: Normal, restrictive pulmonary disease (RPD), and obstructive pulmonary disease (OPD)., Results: The factors used as diabetic indicators ( i.e . homeostatic model assessment of insulin resistance, homeostatic model assessment of beta-cell function, glycated hemoglobin, and fasting insulin) were among the highest in RPD but not in OPD. Based on multivariate logistic regression analysis, subjects with RPD were found with an increased odds ratio [OR: 1.907, 95% confidence interval (CI): 1.110-3.277] for T2DM compared with subjects with normal pulmonary function, whereas in patients with OPD, the OR had not increased. Model 4, which adjusted for the variables that could affect diabetes and pulmonary disease, showed a significant increase in the T2DM OR to RPD (OR: 2.025, 95%CI: 1.264-3.244). On the other hand, no statistically significant difference was shown in OPD (OR: 0.982, 95%CI: 0.634-1.519)., Conclusion: RPD, not OPD, is highly associated with T2DM regardless of the risk factors of various T2DMs that can be confounds., Competing Interests: Conflict-of-interest statement: All the authors have no conflicts of interest related to the manuscript., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

We investigated the effects of pyridoxine deficiency on ischemic neuronal death in the hippocampus of gerbil ( n = 5 per group). Serum pyridoxal 5'-phosphate levels were significantly decreased in Pyridoxine-deficient diet (PDD)-fed gerbils, while homocysteine levels were significantly increased in sham- and ischemia-operated gerbils. PDD-fed gerbil showed a reduction in neuronal nuclei (NeuN)-immunoreactive neurons in the medial part of the hippocampal CA1 region three days after. Reactive astrocytosis and microgliosis were found in PDD-fed gerbils, and transient ischemia caused the aggregation of activated microglia in the stratum pyramidale three days after ischemia. Lipid peroxidation was prominently increased in the hippocampus and was significantly higher in PDD-fed gerbils than in Control diet (CD)-fed gerbils after ischemia. In contrast, pyridoxine deficiency decreased the proliferating cells and neuroblasts in the dentate gyrus in sham- and ischemia-operated gerbils. Nuclear factor erythroid-2-related factor 2 (Nrf2) and brain-derived neurotrophic factor (BDNF) levels also significantly decreased in PDD-fed gerbils sham 24 h after ischemia. These results suggest that pyridoxine deficiency accelerates neuronal death by increasing serum homocysteine levels and lipid peroxidation, and by decreasing Nrf2 levels in the hippocampus. Additionally, it reduces the regenerated potentials in hippocampus by decreasing BDNF levels. Collectively, pyridoxine is an essential element in modulating cell death and hippocampal neurogenesis after ischemia.

In the present study, we investigated the effects of cuprizone on cell death, glial activation, and neuronal plasticity induced by hypothermia after ischemia in gerbils. Food was supplemented with cuprizone at 0.2% ad libitum for eight weeks. At six weeks after diet feeing, gerbils received transient forebrain ischemia with or without hypothermic preconditioning. Cuprizone treatment for 8 weeks increased the number of astrocytes, microglia, and pro-inflammatory cytokine levels in the hippocampus. In addition, cuprizone treatment significantly decreased the number of proliferating cells and neuroblasts in the dentate gyrus. Brain ischemia caused cell death, disruption of myelin basic proteins, and reactive gliosis in CA1. In addition, ischemia significantly increased pro-inflammatory cytokines and the number of proliferating cells and differentiating neuroblasts in the dentate gyrus. In contrast, hypothermic conditioning attenuated these changes in CA1 and the dentate gyrus. However, cuprizone treatment decreased cell survival induced by hypothermic preconditioning after ischemia and increased the number of reactive microglia and astrocytes in CA1 as well as that of macrophages in the subcallosal zone. These changes occurred because the protective effect of hypothermia in ischemic damage was disrupted by cuprizone administration. Furthermore, cuprizone decreased ischemia-induced proliferating cells and neuroblasts in the dentate gyrus.

Pyridoxine, one of the vitamin B 6 vitamers, plays a crucial role in amino acid metabolism and synthesis of monoamines as a cofactor. In the present study, we observed the effects of pyridoxine deficiency on novel object recognition memory. In addition, we examined the levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenethylamine (DA), 3,4-dihydroxyphenylacetic acid, and homovanillic acid and the number of proliferating cells and neuroblasts in the hippocampus. We also examined the effects of pyridoxine deficiency on protein profiles applying a proteomic study. Five-week-old mice fed pyridoxine-deficient diets for 8 weeks and showed a significant decrease in the serum and brain (cerebral cortex, hippocampus, and thalamus) levels of pyridoxal 5'-phosphate, a catalytically active form of vitamin-B 6 , and decline in 5-HT and DA levels in the hippocampus compared to controls fed a normal chow. In addition, pyridoxine deficiency significantly decreased Ki67-positive proliferating cells and differentiated neuroblasts in the dentate gyrus compared to controls. A proteomic study demonstrated that a total of 41 spots were increased or decreased more than two-fold. Among the detected proteins, V-type proton ATPase subunit B2 (ATP6V1B2) and heat shock cognate protein 70 (HSC70) showed coverage and matching peptide scores. Validation by Western blot analysis showed that ATP6V1B2 and HSC70 levels were significantly decreased and increased, respectively, in pyridoxine-deficient mice compared to controls. These results suggest that pyridoxine is an important element of novel object recognition memory, monoamine levels, and hippocampal neurogenesis. Pyridoxine deficiency causes cognitive impairments and reduction in 5-HT and DA levels, which may be associated with a reduction of ATP6V1B2 and elevation of HSC70 levels in the hippocampus.

Gintonin, a novel ginseng-derived lysophosphatidic acid receptor ligand, improves brain functions and protects neurons from oxidative stress. However, little is known about the effects of gintonin against Pb-induced brain maldevelopment. We investigated the protective effects of gintonin on the developing cerebellum after prenatal and postnatal Pb exposure. Pregnant female rats were randomly divided into three groups: control, Pb (0.3% Pb acetate in drinking water), and Pb plus gintonin (100 mg/kg, p.o.). Blood Pb was increased in dams and pups; gintonin treatment significantly decreased blood Pb. On postnatal day 21, the number of degenerating Purkinje cells was remarkably increased while the number of calbindin-, GAD67-, NMDAR1-, LPAR1-immunoreactive intact Purkinje cells, and GABA transporter 1-immunoreactive pinceau structures were significantly reduced in Pb-exposed offspring. Following Pb exposure, gintonin ameliorated cerebellar degenerative effects, restored increased pro-apoptotic Bax, and decreased anti-apoptotic Bcl2. Gintonin treatment attenuated Pb-induced accumulation of oxidative stress (Nrf2 and Mn-SOD) and inflammation (IL-1β and TNFα,), restoring the decreased cerebellar BDNF and Sirt1. Gintonin ameliorated Pb-induced impairment of myelin basic protein-immunoreactive myelinated fibers of Purkinje cells. Gintonin attenuated Pb-induced locomotor dysfunctions. The present study revealed the ameliorating effects of gintonin against Pb, suggesting the potential use of gintonin as a preventive agent in Pb poisoning during pregnancy and lactation., Competing Interests: The authors declare no conflict of interest.

Introduction: We examined the effects of exogenous protein disulfide isomerase A3 (PDIA3) on hippocampal neurogenesis in gerbils under control and ischemic damage., Methods: To facilitate the delivery of PDIA3 to the brain, we constructed Tat-PDIA3 protein and administered vehicle (10% glycerol) or Tat-PDIA3 protein once a day for 28 days. On day 24 of vehicle or Tat-PDIA3 treatment, ischemia was transiently induced by occlusion of both common carotid arteries for 5 min., Results: Administration of Tat-PDIA3 significantly reduced ischemia-induced spontaneous motor activity, and the number of NeuN-positive nuclei in the Tat-PDIA3-treated ischemic group was significantly increased in the CA1 region compared to that in the vehicle-treated ischemic group. Ki67- and DCX-immunoreactive cells were significantly higher in the Tat-PDIA3-treated group compared to the vehicle-treated control group. In vehicle- and Tat-PDIA3-treated ischemic groups, the number of Ki67- and DCX-immunoreactive cells was significantly higher as compared to those in the vehicle- and Tat-PDIA3-treated control groups, respectively. In the dentate gyrus, the numbers of Ki67-immunoreactive cells were comparable between vehicle- and Tat-PDIA3-treated ischemic groups, while more DCX-immunoreactive cells were observed in the Tat-PDIA3-treated group. Transient forebrain ischemia increased the expression of phosphorylated cAMP-response element-binding protein (pCREB) in the dentate gyrus, but the administration of Tat-PDIA3 robustly increased pCREB-positive nuclei in the normal gerbils, but not in the ischemic gerbils. Brain-derived neurotrophic factor (BDNF) mRNA expression was significantly increased in the Tat-PDIA3-treated group compared to that in the vehicle-treated group. Transient forebrain ischemic increased BDNF mRNA levels in both vehicle- and Tat-PDIA3-treated groups, and there were no significant differences between groups., Conclusions: These results suggest that Tat-PDIA3 enhances cell proliferation and neuroblast numbers in the dentate gyrus in normal, but not in ischemic gerbils, by increasing BDNF mRNA and phosphorylation of pCREB., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Background: Dry eye disease (DED) is a complex disease of the ocular surface, and its associated factors are important for understanding and effectively treating DED., Objective: This study aimed to provide an integrative and personalized model of DED by making an explanatory model of DED using as many factors as possible from the Korea National Health and Nutrition Examination Survey (KNHANES) data., Methods: Using KNHANES data for 2012 (4391 sample cases), a point-based scoring system was created for ranking factors associated with DED and assessing patient-specific DED risk. First, decision trees and lasso were used to classify continuous factors and to select important factors, respectively. Next, a survey-weighted multiple logistic regression was trained using these factors, and points were assigned using the regression coefficients. Finally, network graphs of partial correlations between factors were utilized to study the interrelatedness of DED-associated factors., Results: The point-based model achieved an area under the curve of 0.70 (95% CI 0.61-0.78), and 13 of 78 factors considered were chosen. Important factors included sex (+9 points for women), corneal refractive surgery (+9 points), current depression (+7 points), cataract surgery (+7 points), stress (+6 points), age (54-66 years; +4 points), rhinitis (+4 points), lipid-lowering medication (+4 points), and intake of omega-3 (0.43%-0.65% kcal/day; -4 points). Among these, the age group 54 to 66 years had high centrality in the network, whereas omega-3 had low centrality., Conclusions: Integrative understanding of DED was possible using the machine learning-based model and network-based factor analysis. This method for finding important risk factors and identifying patient-specific risk could be applied to other multifactorial diseases., (©Sang Min Nam, Thomas A Peterson, Atul J Butte, Kyoung Yul Seo, Hyun Wook Han. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 20.02.2020.)

Objectives: This study was performed to test the association between lung function and type 2 diabetes mellitus (T2DM) in Korean patients., Methods: Data from the 6 th Korea National Health and Nutrition Examination Survey (2013 to 2015) was used in this study. There were 3,466 individuals aged between 40 and 80 years, with T2DM, who had a smoking and alcohol status listed, and blood analysis (including blood pressure), were included in this study. Lung function, measured by spirometer ventilatory dysfunction was categorized into 3 patterns: normal, restrictive ventilatory dysfunction, and obstructive ventilatory dysfunction (OVD)., Results: Based on multivariate logistic regression analysis, individuals with restrictive ventilatory dysfunction had an increased odds ratio (OR 1.615, 95% CI 1.137-2.294) for T2DM compared with individuals with normal ventilatory function, whereas OVD had no increase in the odds ratio (OR 1.169, 95 % CI 0.857-1.594). Model 1, which adjusted for age and gender, showed that the probability of having restrictive disorder was 1.559 times (95% CI 1.617-2.082) higher for prediabetes patients, and 2.320 times (95% CI 1.611-3.343) higher for T2DM patients, compared to normal individuals. For Model 4, which was fully adjusted for variables, the probability of having a restrictive disorder was 1.837 times higher for T2DM patients (95% CI 1.260-2.679)., Conclusion: Restrictive ventilatory dysfunction, but not OVD, was associated independently with T2DM., Competing Interests: Conflicts of Interest The authors have no conflicts of interest to declare., (Copyright ©2020, Korea Centers for Disease Control and Prevention.)

Background: Ginseng has been widely used as a health-promoting tonic. Gintonin present in ginseng acts as a lysophosphatidic acid (LPA) receptor ligand that activates six LPA receptor subtypes. The LPA6 subtype plays a key role in normal hair growth, and mutations in the LPA6 receptor impair normal human hair growth. Currently, human hair loss and alopecia are concerning issues that affect peoples' social and day-to-day lives., Objective: We investigated the in vitro and in vivo effects of a gintonin-enriched fraction (GEF) on mouse hair growth., Methods: Human hair follicle dermal papilla cells (HFDPCs) and six-week-old male C57BL/6 mice were used. The mice were divided into the four groups: control, 1% minoxidil, 0.75% GEF, and 1.5% GEF. The dorsal hair was removed to synchronize the telogen phase. Each group was treated topically, once a day, for 15 days. We analyzed hair growth activity and histological changes., Results: GEF induced transient [Ca 2+ ] i , which stimulated HFDPC proliferation and caused 5-bromo-2'-deoxyuridine (BrdU) incorporation in a concentration-dependent manner. GEF-mediated HFDPC proliferation was blocked by the LPA receptor antagonist and Ca 2+ chelator. HFDPC treatment with GEF stimulated vascular endothelial growth factor release. Topical application of GEF and minoxidil promoted hair growth in a dose-dependent manner. Histological analysis showed that GEF and minoxidil increased the number of hair follicles and hair weight., Conclusion: Topical application of GEF promotes mouse hair growth through HFDPC proliferation. GEF could be one of the main components of ginseng that promote hair growth and could be used to treat human alopecia., (© 2019 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

The endoplasmic reticulum (ER) is an interconnected organelle that is responsible for the biosynthesis, folding, maturation, stabilization, and trafficking of transmembrane and secretory proteins. Therefore, cells evolve protein quality-control equipment of the ER to ensure protein homeostasis, also termed proteostasis. However, disruption in the folding capacity of the ER caused by a large variety of pathophysiological insults leads to the accumulation of unfolded or misfolded proteins in this organelle, known as ER stress. Upon ER stress, unfolded protein response (UPR) of the ER is activated, integrates ER stress signals, and transduces the integrated signals to relive ER stress, thereby leading to the re-establishment of proteostasis. Intriguingly, severe and persistent ER stress and the subsequently sustained unfolded protein response (UPR) are closely associated with tumor development, angiogenesis, aggressiveness, immunosuppression, and therapeutic response of cancer. Additionally, the UPR interconnects various processes in and around the tumor microenvironment. Therefore, it has begun to be delineated that pharmacologically and genetically manipulating strategies directed to target the UPR of the ER might exhibit positive clinical outcome in cancer. In the present review, we summarize recent advances in our understanding of the UPR of the ER and the UPR of the ER-mitochondria interconnection. We also highlight new insights into how the UPR of the ER in response to pathophysiological perturbations is implicated in the pathogenesis of cancer. We provide the concept to target the UPR of the ER, eventually discussing the potential of therapeutic interventions for targeting the UPR of the ER for cancer treatment.

Objective: Intracranial aneurysms are not common in young age patients. We sought to find the characteristics of the intracranial aneurysms in patients under 20 years of age., Methods: We reviewed 23 consecutive patients ≤20 years of age treated for their intracranial aneurysms during the period from 1995 to 2017. From medical records and imaging studies, we gathered data on age, sex, presentation, associated medical condition, location and characteristics of aneurysms, treatment and clinical outcomes., Results: The patients' ages ranged from 13 months to 20 years (median, 14 years). There were 16 males and seven females (male to female ratio, 2.3 : 1) with 31 aneurysms. Clinical presentations included sudden severe headache in 61%, followed by altered mentality in 17% and seizure in 17%. More than one-fourth patients had specific medical conditions related to the development of the cerebral aneurysms. The majority of aneurysms occurred in the anterior circulation (71%), and were saccular (71%). There were each three patients with false aneurysms (13%) and giant aneurysms (13%), and only one patient with multiple aneurysms (4%). We treated 22 patients : 21 aneurysms with the endovascular methods, three with open surgery, and one with combined treatment. Good functional outcome could be achieved in 86% during the follow-up period., Conclusion: In this series, the young-age patients with intracranial aneurysms were characterized by male predominance, related specific medical conditions, low incidence of multiple aneurysms, high incidence of giant aneurysms and good functional outcome after treatment.

Introduction: The aim of this study was to investigate the effects of cuprizone on adult hippocampal neurogenesis in naïve mice. Additionally, we also studied how melatonin affects the neuronal degeneration induced by cuprizone., Methods: Eight-week-old male C57BL/6J mice were randomly divided into three groups: (a) the control group, (b) the group treated with cuprizone only, and (c) the group treated with both cuprizone and melatonin. Cuprizone was administered with food at 0.2% ad libitum for 6 weeks. Melatonin was also administered with tap water at 6 g/L ad libitum for 6 weeks; the animals were then euthanized for immunohistochemistry with Ki67, doublecortin (DCX), glucose transporter 3 (GLUT3), and phosphorylation of cyclic adenosine monophosphate (AMP) response element binding (pCREB); double immunofluorescence of neuronal nuclei (NeuN) and myelin basic protein (MBP); and Western blot analysis of brain-derived neurotrophic factor (BDNF) expression to reveal the effects of cuprizone and melatonin on cell damage and hippocampal neurogenesis., Results: Administration of cuprizone significantly decreased the number of differentiating (DCX-positive) neuroblasts and proliferating (Ki67-positive) cells in the dentate gyrus. Moreover, cuprizone administration decreased glucose utilization (GLUT3-positive cells) and cell transcription (pCREB-positive cells and BDNF protein expression) in the dentate gyrus. Administration of melatonin ameliorated the cuprizone-induced reduction of differentiating neuroblasts and proliferating cells, glucose utilization, and cell transcription., Conclusion: The results of the study suggest that cuprizone treatment disrupts hippocampal neurogenesis in the dentate gyrus by reducing BDNF levels and decreasing the phosphorylation of CREB. These effects were ameliorated by melatonin treatment., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Purpose: Glaucoma screening can be performed by assessing the vertical-cup-to-disk ratio (VCDR) of the optic nerve head from fundus photography, but VCDR grading is inherently subjective. This study investigated whether computer software could improve the accuracy and repeatability of VCDR assessment., Methods: In this cross-sectional diagnostic accuracy study, 5 ophthalmologists independently assessed the VCDR from a set of 200 optic disk images, with the median grade used as the reference standard for subsequent analyses. Eight non-ophthalmologists graded each image by two different methods: by visual inspection and with assistance from a custom-made publicly available software program. Agreement with the reference standard grade was assessed for each method by calculating the intraclass correlation coefficient (ICC), and the sensitivity and specificity determined relative to a median ophthalmologist grade of ≥0.7., Results: VCDR grades ranged from 0.1 to 0.9 for visual assessment and from 0.1 to 1.0 for software-assisted grading, with a median grade of 0.4 for each. Agreement between each of the 8 graders and the reference standard was higher for visual inspection (median ICC 0.65, interquartile range 0.57 to 0.82) than for software-assisted grading (median ICC 0.59, IQR 0.44 to 0.71); P = 0.02, Wilcoxon signed-rank test). Visual inspection and software assistance had similar sensitivity and specificity for detecting glaucomatous cupping., Conclusion: The computer software used in this study did not improve the reproducibility or validity of VCDR grading from fundus photographs compared with simple visual inspection. More clinical experience was correlated with higher agreement with the ophthalmologist VCDR reference standard., Competing Interests: AS previously worked for Youth Laboratories, LLC, which is developing automated algorithms potential glaucoma detection. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Background: The goal of treatment for zygomaticomaxillary (ZM) complex (ZMC) fractures is to achieve stability and restore aesthetic appearance through three-dimensional reduction and rigid fixation. The purpose of this study was to evaluate the stability and aesthetic appearance outcomes of one-point fixation using a three-dimensional photogrammetric analysis., Methods: From March 2014 to December 2014, 34 patients with ZMC fractures were treated by one-point fixation in the ZM buttress using unsintered hydroxyapatite (u-HA)/poly-L-lactide (PLLA) plates. Differences in soft tissue inter-malar height between the fractured side and unfractured sides were evaluated using photogrammetric analysis with a three-dimensional camera (Morphius®) at the preoperative and 1 week, 1 and 3 months after surgery. The differences in bony inter-malar height between the fractured and unfractured sides were evaluated using computer tomography at the pre-operative and 6 months after surgery. The paired t-test was used to compare differences in malar height., Results: Six months after surgery, 34 patients achieved satisfactory bony stability and symmetric malar appearances. Comparisons of differences in soft-tissue inter-malar height revealed statistically significant differences between the pre-operative period and 1 week and 1 month after surgery (p < .01). There was no statistically significant difference between 1 and 3 months after surgery. Comparison of differences in bony inter-malar height revealed a statistically significant difference between before and 6 months after surgery (p < .01)., Conclusions: When we conducted a three-dimensional photogrammetric analysis, although it has restricted surgical indications, one-point fixation of the ZM buttress using an u-HA / PLLA plate yielded reliable, satisfactory, and safe clinical results in patients with ZMC fractures., Clinical Question / Level of Evidence: Therapeutic, III.