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Abstract With the severity of chronic kidney disease worldwide, strategies to recover renal function via tissue regeneration provide alternatives to kidney replacement therapy. To exclude side effects from direct cell transplantation, extracellular vesicles (EVs) are great substitutes representing paracrine cell signaling. To build three-dimensional structures for implantation into the 5/6 nephrectomy model by incorporating bioactive materials, including multifunctional EVs (mEVs), porous PMEZE/mEV scaffolds were developed in combination with edaravone (EDV; E) and mEV based on PMEZ scaffolds with PLGA (P), MH-RA (M), ECM (E), ZnO-ALA (Z). The oxygen free radical scavenger EDV was incorporated to induce tubular regeneration. mEVs were engineered to serve regenerative activities with a combination of two EVs from SDF-1α overexpressed tonsil-derived mesenchymal stem cells (sEVs) and intermediate mesoderm (IM) cells during differentiation into kidney progenitor cells (dEVs). mEVs displayed beneficial effects on regeneration by facilitating migration and inducing differentiation of surrounding stem cells, and EDV improved kidney function by regulating the GDNF/RET pathway and their downstream genes. The promotion of MSC recruitment was confirmed with sEV particles number dependently, and the regulation of the GDNF/RET pathway by the effect of EDV and its enhanced effect by mEVs were elucidated using in vitro analysis. The regeneration of tubules was additionally demonstrated through the increased expression of aquaporin-1 (AQP-1) and cadherin-16 (CDH16) for proximal tubules, and calbindin and PAX2 for distal tubules in the renal defect model. With these, structural regeneration and functional recovery were achieved with kidney regeneration in the 5/6 nephrectomy mice model. Graphical abstract more...

Abstract Background Xerostomia is a pathological condition characterized by decreased salivation due to salivary gland dysfunction and is frequently attributed to irreversible damage as a side effect of radiation therapy. Stem cell–derived organoid therapy has garnered attention as a promising avenue for resolving this issue. However, Matrigel, a hydrogel commonly used in organoid culture, is considered inappropriate for clinical use due to its undefined composition and immunogenicity. In this study, we aimed to develop a method for culturing collagen-based human salivary gland organoids (hSGOs) suitable for clinical applications and evaluated their therapeutic effectiveness. Methods Human salivary gland stem cells were isolated from the salivary gland tissues and cultured in both Matrigel and collagen. We compared the gene and protein expression patterns of salivary gland–specific markers and measured amylase activity in the two types of hSGOs. To evaluate the therapeutic effects, we performed xenogeneic and allogeneic transplantation using human and mouse salivary gland organoids (hSGOs and mSGOs), respectively, in a mouse model of radiation-induced xerostomia. Results hSGOs cultured in Matrigel exhibited self-renewal capacity and differentiated into acinar and ductal cell lineages. In collagen, they maintained a comparable self-renewal ability and more closely replicated the characteristics of salivary gland tissue following differentiation. Upon xenotransplantation of collagen-based hSGOs, we observed engraftment, which was verified by detecting human-specific nucleoli and E-cadherin expression. The expression of mucins, especially MUC5B, within the transplanted hSGOs suggested a potential improvement in the salivary composition. Moreover, the allograft procedure using mSGOs led to increased salivation, validating the efficacy of our approach. Conclusions This study showed that collagen-based hSGOs can be used appropriately in clinical settings and demonstrated the effectiveness of an allograft procedure. Our research has laid the groundwork for the future application of collagen-based hSGOs in allogeneic clinical trials. more...

Abstract Mitochondrial transcription factor A (TFAM) employs DNA bending to package mitochondrial DNA (mtDNA) into nucleoids and recruit mitochondrial RNA polymerase (POLRMT) at specific promoter sites, light strand promoter (LSP) and heavy strand promoter (HSP). Herein, we characterize the conformational dynamics of TFAM on promoter and non-promoter sequences using single-molecule fluorescence resonance energy transfer (smFRET) and single-molecule protein-induced fluorescence enhancement (smPIFE) methods. The DNA-TFAM complexes dynamically transition between partially and fully bent DNA conformational states. The bending/unbending transition rates and bending stability are DNA sequence-dependent—LSP forms the most stable fully bent complex and the non-specific sequence the least, which correlates with the lifetimes and affinities of TFAM with these DNA sequences. By quantifying the dynamic nature of the DNA-TFAM complexes, our study provides insights into how TFAM acts as a multifunctional protein through the DNA bending states to achieve sequence specificity and fidelity in mitochondrial transcription while performing mtDNA packaging. more...

Background: The serratus anterior (SA) is a muscle that performs protraction of the scapulothoracic joint and plays a role in stabilizing the scapula. Imbalances or weaknesses in SA activation are associated with a variety of shoulder dysfunctions, making selective SA strengthening important for rehabilitation. Objects: We aimed to compare the muscle activation of the pectoralis major (PM), SA, external oblique (EO), and internal oblique (IO) during the push-up plus (PUP) exercise with isometric hip adduction (HA) and abdominal drawing-in maneuver (ADIM). Methods: Nineteen healthy male participants performed three PUP exercises: standard PUP, PUP with ADIM, and PUP with HA. Surface electromyography was used to measure and analyze the muscle activity for PM, SA, EO, and IO. Results: PUP with HA showed the lowest PM activity and highest SA activity, and no significant difference was observed between PUP and PUP with ADIM. PUP with ADIM showed significantly the highest EO and IO activity, followed by PUP with HA and PUP. Additionally, PUP with HA showed the lowest PM/SA ratio, and no significant difference was noted between PUP and PUP with ADIM. Conclusion: PUP with HA was able to show high SA muscle activity while reducing PM muscle activity. In addition, PUP with HA can lead to higher EO and IO muscle activity than standard PUP. This exercise could be used as a practical exercise method to selectively strengthen SA and improve scapular muscle stability during early shoulder rehabilitation. more...

Abstract Resilient individuals are less likely to develop psychiatric disorders despite extreme psychological distress. This study investigated the multimodal structural neural correlates of dispositional resilience among healthy individuals. Participants included 92 healthy individuals. The Korean version of the Connor-Davidson Resilience Scale and other psychological measures were used. Gray matter volumes (GMVs), cortical thickness, local gyrification index (LGI), and white matter (WM) microstructures were analyzed using voxel-based morphometry, FreeSurfer, and tract-based spatial statistics, respectively. Higher resilient individuals showed significantly higher GMVs in the inferior frontal gyrus (IFG), increased LGI in the insula, and lower fractional anisotropy values in the superior longitudinal fasciculus II (SLF II). These resilience’s neural correlates were associated with good quality of life in physical functioning or general health and low levels of depression. Therefore, the GMVs in the IFG, LGI in the insula, and WM microstructures in the SLF II can be associated with resilience that contributes to emotional regulation, empathy, and social cognition. more...

Abstract Although the role of the cerebellum in schizophrenia has gained attention, its contribution to cognitive impairment remains unclear. We aimed to investigate volumetric alterations in the cerebro-cerebellar gray matter (GM) in patients with recent-onset schizophrenia (ROS) and chronic schizophrenia (CS) compared with healthy controls (HCs). Seventy-two ROS, 43 CS, and 127 HC participants were recruited, and high-resolution T1-weighted structural magnetic resonance images of the brain were acquired. We compared cerebellar GM volumes among the groups using voxel-based morphometry and examined the cerebro-cerebellar GM volumetric correlations in participants with schizophrenia. Exploratory correlation analysis investigated the functional relevance of cerebro-cerebellar GM volume alterations to cognitive function in the schizophrenia group. The ROS and CS participants demonstrated smaller cerebellar GM volumes, particularly in Crus I and II, than HCs. Extracted cerebellar GM volumes demonstrated significant positive correlations with the cerebral GM volume in the fronto-temporo-parietal association areas engaged in higher-order association. The exploratory analysis showed that smaller cerebellar GM in the posterior lobe regions was associated with poorer cognitive performance in participants with schizophrenia. Our study suggests that cerebellar pathogenesis is present in the early stages of schizophrenia and interconnected with structural abnormalities in the cerebral cortex. Integrating the cerebellum into the pathogenesis of schizophrenia will help advance our understanding of the disease and identify novel treatment targets concerning dysfunctional cerebro-cerebellar interactions. more...

Abstract Subthreshold social anxiety (SSA) is a condition in which individuals experience social anxiety that does not reach the threshold required for a clinical diagnosis of a social anxiety disorder (SAD). Although SSA may not impair lives as severely as SAD, it can affect social functioning. However, only a few studies focused on structural neural correlates of SSA. We recruited 65 individuals with SSA and used the Leibowitz Social Anxiety Scale to assess their social and performance anxiety levels and other relevant measures of social anxiety. Voxel-wise whole-brain correlational analyses showed a positive association between the cortical thickness (CT) of the superior frontal gyrus (SFG) and social anxiety levels and a negative correlation between the CT of the fusiform gyrus (FG) and performance anxiety levels in individuals with SSA. Exploratory Pearson’s correlation analyses showed significant positive correlations between the CT of the SFG and Generalized Anxiety Disorder-7 total scores and negative associations between the CT of the FG and Beck Anxiety Inventory total scores. Our study provides insight into the neural basis of SSA, particularly performance anxiety, by highlighting the association between CT in specific brain regions and SSA characteristics. more...

Abstract Self-compassion (SC) involves taking an emotionally positive attitude towards oneself when suffering. Although SC has positive effects on mental well-being as well as a protective role in preventing symptoms in healthy individuals, few studies on white matter (WM) microstructures in neuroimaging studies of SC has been studied. Brain imaging data were acquired from 71 healthy participants. WM regions of mirroring network were analyzed using tract-based spatial statistics. After the WM regions associated with SC were extracted, exploratory correlation analysis with the self-forgiveness scale, the coping scale, and the world health organization quality of life scale abbreviated version was performed. We found that self-compassion scale total scores were negatively correlated with the fractional anisotropy (FA) values of the superior longitudinal fasciculus (SLF) in healthy individuals. The self-kindness and mindfulness subscale scores were also negatively correlated with FA values of the same regions. These FA values were negatively correlated with the total scores of self-forgiveness scale, and self-control coping strategy and confrontation coping strategy. Our findings suggest levels of SC may be associated with WM microstructural changes of SLF in healthy individuals. These lower WM microstructures may be associated with positive personal attitudes, such as self-forgiveness, self-control and active confrontational strategies. more...

Abstract The conventional differentiation of affective disorders into major depressive disorder (MDD) and bipolar disorder (BD) has insufficient biological evidence. Utilizing multiple proteins quantified in plasma may provide critical insight into these limitations. In this study, the plasma proteomes of 299 patients with MDD or BD (aged 19–65 years old) were quantified using multiple reaction monitoring. Based on 420 protein expression levels, a weighted correlation network analysis was performed. Significant clinical traits with protein modules were determined using correlation analysis. Top hub proteins were determined using intermodular connectivity, and significant functional pathways were identified. Weighted correlation network analysis revealed six protein modules. The eigenprotein of a protein module with 68 proteins, including complement components as hub proteins, was associated with the total Childhood Trauma Questionnaire score (r = −0.15, p = 0.009). Another eigenprotein of a protein module of 100 proteins, including apolipoproteins as hub proteins, was associated with the overeating item of the Symptom Checklist-90-Revised (r = 0.16, p = 0.006). Functional analysis revealed immune responses and lipid metabolism as significant pathways for each module, respectively. No significant protein module was associated with the differentiation between MDD and BD. In conclusion, childhood trauma and overeating symptoms were significantly associated with plasma protein networks and should be considered important endophenotypes in affective disorders. more...

Abstract Self-forgiveness (SF) involves a process through which negative moral emotions directed at the self are replaced by benevolence and acceptance. Lower SF scores can be associated with less self-compassion, higher psychological distress, and lower life dissatisfaction. However, neural correlates of SF have not been investigated yet. We enrolled a total of 79 healthy individuals. The Self-Forgiveness Scale (SFS), Self-Compassion Scale (SCS), Connor-Davidson Resilience Scale (CD-RISC), Beck Depression Inventory-II (BDI-II), and Beck Anxiety Inventory (BAI) were evaluated. Voxel-wise correlational analyses showed a significant positive correlation between the total SFS scores and gray matter volumes (GMVs) in the fusiform gyrus (FG). In addition, the GMVs in the FG were significantly positively associated with the total SCS and CD-RISC scores and negatively correlated with the total BDI-II and BAI scores. These findings suggest that the FG related to the mirror neuron system might be a neural correlate of SF. Furthermore, its increased volumes of FG in healthy individuals can be associated with the capacity to overcome stressful life events. more...

Abstract Data-driven approaches to subtype transdiagnostic samples are important for understanding heterogeneity within disorders and overlap between disorders. Thus, this study was conducted to determine whether plasma proteomics-based clustering could subtype patients with transdiagnostic psychotic-affective disorder diagnoses. The study population included 504 patients with schizophrenia, bipolar disorder, and major depressive disorder and 160 healthy controls, aged 19 to 65 years. Multiple reaction monitoring was performed using plasma samples from each individual. Pathologic peptides were determined by linear regression between patients and healthy controls. Latent class analysis was conducted in patients after peptide values were stratified by sex and divided into tertile values. Significant demographic and clinical characteristics were determined for the latent clusters. The latent class analysis was repeated when healthy controls were included. Twelve peptides were significantly different between the patients and healthy controls after controlling for significant covariates. Latent class analysis based on these peptides after stratification by sex revealed two distinct classes of patients. The negative symptom factor of the Brief Psychiatric Rating Scale was significantly different between the classes (t = −2.070, p = 0.039). When healthy controls were included, two latent classes were identified, and the negative symptom factor of the Brief Psychiatric Rating Scale was still significant (t = −2.372, p = 0.018). In conclusion, negative symptoms should be considered a significant biological aspect for understanding the heterogeneity and overlap of psychotic-affective disorders. more...

Abstract Few studies report the microglia involvement in the pathogenesis of panic disorder (PD), although the crucial role of microglia in other neuropsychiatric diseases is being emphasized. In addition, there is no report to characterize the phenotypic and functional levels of PD patient-derived microglia to find their clinical relevance. Herein, we used a model to induce patient-derived microglia-like cells (iMGs) to clarify the molecular characteristics and function of PD-iMGs. We established iMGs from 17 PD patients and 16 healthy controls (non-psychiatric controls, HC). PD-iMGs showed increased T-cell death-associated gene-8 expression per the proposal of a previous in vivo study. In addition, we found that patient-derived iMGs showed reduced phagocytosis and increased TREM2 expression. We analyzed the phenotype of the PD-iMGs by RNA sequencing. The PD-iMGs clustered together distinct from HC-iMGs. Gene set enrichment analysis revealed the involvement of cholesterol biosynthesis and steroid metabolism in PD-iMGs. Regarding the cholesterol synthesis pathway, we discovered ACAT2 and DHCR7 as the most impacted genes related to a character of PD-iMGs compared to HC-iMGs. The ACAT2, a major cholesterol esterifier, was increased in PD-iMGs. Nevertheless, PD-iMGs did not show lipid droplet accumulation. Interestingly, ACAT2 expression was inversely correlated with the severity of depression and anxiety sensitivity to publicly observable anxiety reactions. We propose that microglia of PD patients have unique characteristics with dysregulation of cholesterol biosynthesis pathway and impaired phagocytosis, reflecting clinical phenotype. more...

Abstract Pancreatic cancer exhibits a characteristic tumor microenvironment (TME) due to enhanced fibrosis and hypoxia and is particularly resistant to conventional chemotherapy. However, the molecular mechanisms underlying TME-associated treatment resistance in pancreatic cancer are not fully understood. Here, we developed an in vitro TME mimic system comprising pancreatic cancer cells, fibroblasts and immune cells, and a stress condition, including hypoxia and gemcitabine. Cells with high viability under stress showed evidence of increased direct cell-to-cell transfer of biomolecules. The resulting derivative cells (CD44 high/SLC16A1 high) were similar to cancer stem cell-like-cells (CSCs) with enhanced anchorage-independent growth or invasiveness and acquired metabolic reprogramming. Furthermore, CD24 was a determinant for transition between the tumorsphere formation or invasive properties. Pancreatic cancer patients with CD44 low/SLC16A1 low expression exhibited better prognoses compared to other groups. Our results suggest that crosstalk via direct cell-to-cell transfer of cellular components foster chemotherapy-induced tumor evolution and that targeting of CD44 and MCT1(encoded by SLC16A1) may be useful strategy to prevent recurrence of gemcitabine-exposed pancreatic cancers. more...

BackgroundSeveral studies have shown that adherence to the Mediterranean diet is associated with a lower risk of depression; however, little is known about the Asian population. This study investigated the relationship between adherence to the Mediterranean diet and depression in a sample of the South Korean population.MethodsIn total, 5,849 adults from the 2014 and 2016 Korea National Health and Nutrition Examination Surveys were included in the study. The Mediterranean diet adherence was measured using a modified alternate Mediterranean diet score (mMED) developed to adjust for Korean dietary patterns. The mMED scores using the Food Frequency Questionnaire were divided into four categories (0–2, 3–4, 5–6, and 7–9 points). Subjects with depression were defined as having moderate-to-severe depressive symptoms using the Patient Health Questionnaire-9, with a cutoff value of 10. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A subgroup analysis was performed based on sex.ResultsThe results of logistic regression analysis indicated that individuals with higher mMED were 42–73% less likely to report depression compared to individuals with the lowest mMED [ORs (95% CIs) =0.58 (0.37–0.90), 0.50 (0.31–0.80), 0.27 (0.15–0.47)] after adjusting for socio-demographic and health-related variables. In women, individuals with mMED of 7–9 had 71% lower odds of depression [ORs (95% CIs): 0.29 (0.13–0.64)]. In men, individuals with mMED of 5–9 had 55% [ORs (95% CIs): 0.45 (0.23–0.91)] to 79% [ORs (95% CIs): 0.21 (0.08–0.57)] lower odds of depression.ConclusionThis study suggests that adherence to the Mediterranean diet is inversely associated with depression in both men and women among Korean adults. This study provides evidence that a Mediterranean diet is crucial in preventing depressive symptoms in Asian populations. more...

Abstract Although happiness or subjective well-being (SWB) has drawn much attention from researchers, the precise neural structural correlates of SWB are generally unknown. In the present study, we aimed to investigate the associations between gray matter (GM) volumes, white matter (WM) microstructures, and SWB in healthy individuals, mainly young adults using multimodal T1 and diffusion tensor imaging studies. We enrolled 70 healthy individuals using magnetic resonance imaging. We measured their SWB using the Concise Measure of Subjective Well-Being. Voxel-wise statistical analysis of GM volumes was performed using voxel-based morphometry, while fractional anisotropy (FA) values were analyzed using tract-based spatial statistics. In healthy individuals, higher levels of SWB were significantly correlated with increased GM volumes of the anterior insula and decreased FA values in clusters of the body of the corpus callosum, precuneus WM, and fornix cres/stria terminalis. A correlational analysis revealed that GM volumes and FA values in these significant regions were significantly correlated with severity of psychological symptoms such as depression, anxiety, and quality of life. Our findings indicate that GM volumes and WM microstructures in these regions may contribute to SWB, and could be the neural basis for psychological symptom severity as well as quality of life in healthy individuals. more...

Orientia tsutsugamushi (Ot) the causing agent of scrub typhus exits infected cells using a unique mechanism that involves budding off the surface of infected cells. Here, Atwal et al. report that Ots that have budded from their host cells are in a distinct developmental stage than intracellular bacteria and provide the first characterization of this extracellular stage. Both forms are infectious but differ in their physical properties, proteome, and entry mechanism into host cells. more...

Abstract Although the potential role of superior longitudinal fasciculus (SLF) in intellectual deficits and treatment response (TR) in patients with schizophrenia (SZ) has been previously described, little is known about the white-matter (WM) integrity of SLF subcomponents (SLF I, II, III, and arcuate fasciculus) and their particular relationships with the clinical presentations of the illness. This study examined the associations between fractional anisotropy (FA) of SLF subcomponents and intelligence level and 6-month treatment response (TR) of negative symptoms (NS) in patients with SZ. At baseline, 101 patients with SZ and 101 healthy controls (HCs) underwent structural magnetic resonance imaging. Voxel-wise group comparison analysis showed significant SLF FA reductions in patients with SZ compared with HCs. Voxel-wise correlation analyses revealed significant positive correlations of FAs of right SLF II with Korean–Wechsler Adult Intelligence Scale at baseline and the percentage reduction of negative syndrome subscale of the Positive and Negative Syndrome Scales at 6 months. These findings suggest that aberrance in WM microstructure in SLF II may be associated with intellectual deficits in patients with SZ and TR of NS, which may support the potential role of SLF II as a novel neuroimaging biomarker for clinical outcomes of the illness. more...

Abstract There is a growing need to develop novel strategies for the diagnosis of schizophrenia using neuroimaging biomarkers. We investigated the robustness of the diagnostic model for schizophrenia using radiomic features from T1-weighted and diffusion tensor images of the corpus callosum (CC). A total of 165 participants [86 schizophrenia and 79 healthy controls (HCs)] were allocated to training (N = 115) and test (N = 50) sets. Radiomic features of the CC subregions were extracted from T1-weighted, apparent diffusion coefficient (ADC), and fractional anisotropy (FA) images (N = 1605). Following feature selection, various combinations of classifiers were trained, and Bayesian optimization was adopted in the best performing classifier. Discrimination, calibration, and clinical utility of the model were assessed. An online calculator was constructed to offer the probability of having schizophrenia. SHapley Additive exPlanations (SHAP) was applied to explore the interpretability of the model. We identified 30 radiomic features to differentiate participants with schizophrenia from HCs. The Bayesian optimized model achieved the highest performance, with an area under the curve (AUC), accuracy, sensitivity, and specificity of 0.89 (95% confidence interval: 0.81–0.98), 80.0, 83.3, and 76.9%, respectively, in the test set. The final model offers clinical probability in an online calculator. The model explanation by SHAP suggested that second-order features from the posterior CC were highly associated with the risk of schizophrenia. The multiparametric radiomics model focusing on the CC shows its robustness for the diagnosis of schizophrenia. Radiomic features could be a potential source of biomarkers that support the biomarker-based diagnosis of schizophrenia and improve the understanding of its neurobiology. more...

Abstract Schizophrenia is a complex brain disorder of unknown etiology. Based on the notion of “cognitive dysmetria,” we aimed to investigate aberrations in structural white matter (WM) connectivity that links the cerebellum to cognitive dysfunction in patients with schizophrenia. A total of 112 participants (65 patients with schizophrenia and 47 healthy controls [HCs]) were enrolled and underwent diffusion tensor imaging. Between-group voxel-wise comparisons of cerebellar WM regions (superior/middle [MCP]/inferior cerebellar peduncle and pontine crossing fibers) were performed using Tract-Based Spatial Statistics. Cognitive function was assessed using the Trail Making Test Part A/B (TMT-A/B), Wisconsin Card Sorting Test (WCST), and Rey-Kim Memory Test in 46 participants with schizophrenia. WM connectivity, measured as fractional anisotropy (FA), was significantly lower in the MCP in participants with schizophrenia than in HCs. The mean FAs extracted from the significant MCP cluster were inversely correlated with poorer cognitive performance, particularly longer time to complete the TMB-B (r = 0.559, p < 0.001) and more total errors in the WCST (r = 0.442, p = 0.003). Our findings suggest that aberrant cerebro-cerebellar communication due to disrupted WM connectivity may contribute to cognitive impairments, a core characteristic of schizophrenia. Our results may expand our understanding of the neurobiology of schizophrenia based on the cerebro-cerebellar interconnectivity of the brain. more...

Abstract Cytochrome P450 2D6 (CYP2D6) is expressed at high levels in the brain and plays a considerable role in the biotransformation and neurotransmission of dopamine. This raises the question of whether CYP2D6 variations and its impact on the brain can confer susceptibility to schizophrenia. We investigated the possible links among the CYP2D6 genotype, white matter (WM) integrity of the hippocampus, and the treatment response to antipsychotic drugs in Korean patients with schizophrenia (n = 106). Brain magnetic resonance imaging and genotyping for CYP2D6 were conducted at baseline. The severity of clinical symptoms and the treatment response were assessed using the Positive and Negative Syndrome Scale (PANSS). After genotyping, 43 participants were classified as intermediate metabolizers (IM), and the remainder (n = 63) were classified as extensive metabolizers (EM). IM participants showed significantly higher fractional anisotropy (FA) values in the right hippocampus compared to EM participants. Radial diffusivity (RD) values were significantly lower in the overlapping region of the right hippocampus in the IM group than in the EM group. After 4 weeks of antipsychotic treatment, the EM group showed more improvements in positive symptoms than the IM group. FAs and RDs in the CYP2D6-associated hippocampal WM region were significantly correlated with a reduction in the positive symptom subscale of the PANSS. Greater improvements in positive symptoms were negatively associated with FAs, and positively associated with RDs in the right hippocampal region. The findings suggest that CYP26D-associated hippocampal WM alterations could be a possible endophenotype for schizophrenia that accounts for individual differences in clinical features and treatment responses. more...

Abstract Brain inflammation is one of hypotheses explaining complex pathomechanisms of depression. Angiotensin II (ANGII), which is associated with hypertension, also induces brain inflammation. However, there is no animal study showing the direct relationship between ANGII and depression. To address this issue, ANGII-containing osmotic pumps were implanted into adult male C57BL/6 mice subcutaneously for subacute (7 days) and chronic (at least 21 days) periods and behavioral and molecular analyses were conducted. Chronic infusion of ANGII into mice induced depressive-like behaviors, including the tail suspension test and forced swimming test, which were reversed by imipramine. Chronic infusion of ANGII also induced microglial activation in the hippocampus with increase of Il-1β mRNA and decrease of Arg1 mRNA. In addition, chronic ANGII infusion activated the hypothalamic–pituitary–adrenal axis (HPA axis) and resulted in decreased hippocampal glucocorticoid receptor level. However, subacute ANGII infusion did not induce significant molecular and behavioral changes in mice compared to that of control. The molecular and behavioral changes by chronic ANGII infusion were reversed by co-treatment of minocycline or telmisartan. In addition, ANGII treatment also induced the pro-inflammatory changes in BV-2 microglial cells. Our results indicate that ANGII can induce depressive-like behaviors via microglial activation in the hippocampus and HPA axis hyperactivation in mice. These might suggest possible mechanism on depressive symptom in chronic hypertensive state. more...

The Korean Society of Laryngology, Phoniatrics and Logopedics appointed a task force to establish clinical practice guidelines for the management of unilateral vocal fold paralysis (UVFP). These guidelines cover a comprehensive range of management-related factors, including the diagnosis and treatment of UVFP, and provide in-depth information based on current, up-to-date knowledge. Detailed evidence profiles are provided for each recommendation. The CORE databases, including OVID Medline, Embase, the Cochrane Library, and KoreaMed, were searched to identify all relevant papers, using a predefined search strategy. When insufficient evidence existed, expert opinions and Delphi questionnaires were used to fill the evidence gap. The committee developed 16 evidence-based recommendations in six categories: initial evaluation (R1–4), spontaneous recovery (R5), medical treatment (R6), surgical treatment (R7–14), voice therapy (R15), and aspiration prevention (R16). The goal of these guidelines is to assist general otolaryngologists and speech-language pathologists who are primarily responsible for treating patients with UVFP. These guidelines are also intended to facilitate understanding of the condition among other health-care providers, including primary care physicians, nurses, and policy-makers. more...

Several regiospecific enantiomers of hydroxy-(S)-equol (HE) were enzymatically synthesized from daidzein and genistein using consecutive reduction (four daidzein-to-equol–converting reductases) and oxidation (4-hydroxyphenylacetate 3-monooxygenase, HpaBC). Despite the natural occurrence of several HEs, most of them had not been studied owing to the lack of their preparation methods. Herein, the one-pot synthesis pathway of 6-hydroxyequol (6HE) was developed using HpaBC (EcHpaB) from Escherichia coli and (S)-equol-producing E. coli, previously developed by our group. Based on docking analysis of the substrate or products, a potential active site and several key residues for substrate binding were predicted to interpret the (S)-equol hydroxylation regioselectivity of EcHpaB. Through investigating mutations on the key residues, the T292A variant was verified to display specific mono-ortho-hydroxylation activity at C6 without further 3′-hydroxylation. In the consecutive oxidoreductive bioconversion using T292A, 0.95 mM 6HE could be synthesized from 1 mM daidzein, while 5HE and 3′HE were also prepared from genistein and 3′-hydroxydaidzein (3′HD or 3′-ODI), respectively. In the following efficacy tests, 3′HE and 6HE showed about 30∼200-fold higher EC50 than (S)-equol in both ERα and ERβ, and they did not have significant SERM efficacy except 6HE showing 10% lower β/α ratio response than that of 17β-estradiol. In DPPH radical scavenging assay, 3′HE showed the highest antioxidative activity among the examined isoflavone derivatives: more than 40% higher than the well-known 3′HD. In conclusion, we demonstrated that HEs could be produced efficiently and regioselectively through the one-pot bioconversion platform and evaluated estrogenic and antioxidative activities of each HE regio-isomer for the first time. more...

Background: Violent acts in patients with schizophrenia are often associated with their hostility and aggression levels. Poor visuospatial processing has been suggested as a possible risk factor of violence in schizophrenia. However, studies investigating the relationship between hostility, aggression, and the visuospatial function have been lacking. Here, we aimed to investigate brain dysconnectivity associated with hostility and aggression in schizophrenia, particularly focusing on the visuospatial function network.Methods: Eighty-eight participants with schizophrenia and 42 healthy controls were enrolled. The visuospatial function network regions of interest were analyzed using Tract-Based Spatial Statistics. The hostility item from the Positive and Negative Syndrome Scale (PANSS), aggressive, and agitated behavior item from the Scale for the Assessment of Positive Symptoms (SAPS), and the Rey Complex Figure Test (R-CFT) were measured.Results: Among the participants with schizophrenia, the SAPS aggressive and agitated behavior scores were significantly correlated with fractional anisotropies (FAs) of the white matter regions in the splenium of the corpus callosum (CC), left posterior thalamic radiations (PTR), and left posterior corona radiata (PCR). Exploratory correlational analysis revealed significant negative correlations between FAs of the splenium of the CC and R-CFT copy and immediate recall scores. In addition, three regions including CC, PTR, and PCR that significantly correlated with the aggression scores showed significant correlations with the total PANSS scores.Conclusion: Our main finding suggests that aggression of patients with schizophrenia may be associated with poor visuospatial ability and underlying white matter dysconnectivity. These may help enhance understanding aggression in patients with schizophrenia. more...

Tyrosinase is generally known as a melanin-forming enzyme, facilitating monooxygenation of phenols, oxidation of catechols into quinones, and finally generating biological melanin. As a homologous form of tyrosinase in plants, plant polyphenol oxidases perform the same oxidation reactions specifically toward plant polyphenols. Recent studies reported synthetic strategies for large scale preparation of hydroxylated plant polyphenols, using bacterial tyrosinases rather than plant polyphenol oxidase or other monooxygenases, by leveraging its robust monophenolase activity and broad substrate specificity. Herein, we report a novel synthesis of functional plant polyphenols, especially quercetin and myricetin from kaempferol, using screened bacterial tyrosinases. The critical bottleneck of the biocatalysis was identified as instability of the catechol and gallol under neutral and basic conditions. To overcome such instability of the products, the tyrosinase reaction proceeded under acidic conditions. Under mild acidic conditions supplemented with reducing agents, a bacterial tyrosinase from Bacillus megaterium (BmTy) displayed efficient consecutive two-step monophenolase activities producing quercetin and myricetin from kaempferol. Furthermore, the broad substrate specificity of BmTy toward diverse polyphenols enabled us to achieve the first biosynthesis of tricetin and 3′-hydroxyeriodictyol from apigenin and naringenin, respectively. These results suggest that microbial tyrosinase is a useful biocatalyst to prepare plant polyphenolic catechols and gallols with high productivity, which were hardly achieved by using other monooxygenases such as cytochrome P450s. more...

The purpose of this study was to analyze the effect of titanium dioxide (TiO2) on reducing nitrogen oxide (NOx) concentrations using the statistical method of the Anderson-Darling test. To compare and analyze this effect, a spray-type form of TiO2 was applied to the asphalt pavement surface on urban roads. Data acquisition for NOx concentration was collected from a test section with TiO2 applied and a reference section without TiO2 applied. The probabilities of occurrence of the NOx concentration in the test and reference section were estimated and compared using the Anderson-Darling test. In sum, most of the NOx concentrations were probabilistically lower in the test section. The average probability of the NOx concentration in the test section in the ‘low’ range was 46.2% higher than in the reference section. In the ‘high’ and ‘moderate’ ranges, the average probability of the NOx concentration compared to that of the reference section was lower by 28.1% and 18.8%, respectively. These results revealed that the photochemical reaction from the TiO2 material applied on asphalt pavement was effective in reducing NOx. more...

In this work, a method that minimizes printed wiring board (PWB) warpage by dummy pattern design is proposed. This work suggests that dummy patterns are placed on a preset discretized location in the PWB to reduce the warpage. On each discretized candidate area, the dummy pattern can be set or unset. The warpage is numerically simulated based on direct modeling of the as-is PWB patterns to evaluate the warpage alongside the dummy pattern design set. The optimal pattern that minimizes warpage is determined using the human-based genetic algorithm where the objective function is evaluated by the structural simulation. The optimization method is realized in a spreadsheet that allows scripting language with which the input and output files of the simulation tool can be modified and read. Two different cases have been tested and the results show that the method can determine the optimal dummy patterns. The measured and simulated deflections agree well with each other. Moreover, it has been shown that certain dummy pattern designs that should reduce the warpage can be sought by the optimization. more...

Background: Impaired verbal communication is a prominent feature in patients with schizophrenia. Verbal communication difficulties adversely affect psychosocial outcomes and worsen schizophrenia's clinical manifestation. In the present study, we aimed to investigate associations among gray matter (GM) volumes in language processing areas (LPAs), verbal ability, and positive symptoms in first-episode patients (FEPs) with schizophrenia spectrum psychosis. Methods: We enrolled 94 FEPs and 52 healthy controls (HCs) and subjected them to structural magnetic resonance imaging. The GM volumes of the bilateral pars opercularis (POp), pars triangularis (PTr), planum temporale (PT), Heschl's gyrus (HG), insula, and fusiform gyrus (FG), were estimated and compared between the FEPs and HCs. Verbal intelligence levels and positive symptom severity were examined for correlations with the left LPA volumes. Results: The GM volumes of the left POp, HG, and FG were significantly smaller in the FEPs than in the HCs, while the right regions showed no significant between-group difference. A multiple linear regression model revealed that larger left PT volume was associated with better verbal intelligence in FEPs. In exploratory correlation analysis, several LPAs showed significant correlations with the severity of positive symptoms in FEPs. The left FG volume had a strong inverse correlation with the severity of auditory verbal hallucinations, while the left PT volume was inversely associated with the severity of positive formal thought disorder and delusions. Moreover, the volume of the left insula was positively associated with the severity of bizarre behavior. Conclusions: The present study suggests that GM abnormalities in the LPAs, which can be detected during the early stage of illness, may underlie impaired verbal communication and positive symptoms in patients with schizophrenia spectrum psychosis. Keywords: Schizophrenia spectrum, Language processing areas, Planum temporale, Fusiform gyrus, Verbal intelligence, Positive symptoms more...

ObjectivesTo investigate the relationships between lymph node metastasis (LNM) and expression of CD31, D2-40 and vascular endothelial growth factors (VEGF)-A and -C in patients with papillary thyroid cancer (PTC).MethodsParaffin-embedded thyroid tissues of 72 patients were evaluated, which included 25 patients with thyroid nodular hyperplasia (TNH), 24 PTC patients without LNM, and 23 PTC patients with LNM. Three pathologists, who were blinded to the patient's clinical information, assessed the immunohistochemical staining results. The amount of expression was scored as high (>25% of cells stained) or low (0-25%).ResultsA higher level of VEGF-A expression was observed in the PTC groups regardless of LNM when compared to the group with TNH (91.3%, 79.2%, 4.0%, respectively). VEGF-C expression in the PTC with LNM group was significantly higher than the other two groups (P more...

ObjectivesWe previously showed that a trained tenor's voice has the conventional singer's formant at the region of 3 kHz and another energy peak at 8-9 kHz. Singers in other operatic voice ranges are assumed to have the same peak in their singing and speaking voice. However, to date, no specific measurement of this has been made.MethodsTenors, baritones, sopranos and mezzo sopranos were chosen to participate in this study of the singer's formant and the speaker's ring resonance. Untrained males (n=15) and females (n=15) were included in the control group. Each subject was asked to produce successive /a/ vowel sounds in their singing and speaking voice. For singing, the low pitch was produced in the chest register and the high notes in the head register. We collected the data on the long-term average spectra of the speaking and singing voices of the trained singers and the control groups.ResultsFor the sounds produced from the head register, a significant energy concentration was seen in both 2.2-3.4 kHz and 7.5-8.4 kHz regions (except for the voices of the mezzo sopranos) in the trained singer group when compared to the control groups. Also, the chest register had a significant energy concentration in the 4 trained singer groups at the 2.2-3.1 kHz and 7.8-8.4 kHz. For speaking sound, all trained singers had a significant energy concentration at 2.2-5.3 kHz and sopranos had another energy concentration at 9-10 kHz.ConclusionThe results of this study suggest that opera singers have more energy concentration in the singer's formant/speaker's ring region, in both singing and speaking voices. Furthermore, another region of energy concentration was identified in opera singer's singing sound and in sopranos' speaking sound at 8-9 kHz. The authors believe that these energy concentrations may contribute to the rich voice of trained singers. more...

SpoIIIE is a membrane-anchored DNA translocase that localizes to the septal midpoint to mediate chromosome translocation and membrane fission during Bacillus subtilis sporulation. Here we use cell-specific protein degradation and quantitative photoactivated localization microscopy in strains with a thick sporulation septum to investigate the architecture and function of the SpoIIIE DNA translocation complex in vivo. We were able to visualize SpoIIIE complexes with approximately equal numbers of molecules in the mother cell and the forespore. Cell-specific protein degradation showed that only the mother cell complex is required to translocate DNA into the forespore, whereas degradation in either cell reverses membrane fission. Our data suggest that SpoIIIE assembles a coaxially paired channel for each chromosome arm comprised of one hexamer in each cell to maintain membrane fission during DNA translocation. We show that SpoIIIE can operate, in principle, as a bi-directional motor that exports DNA. more...

IDGPS (Inverted Differential Global Positioning System) is one of techniques improving the accuracy of GPS positioning and is mostly used for tracking an automatic vehicle. In the IDGPS, the user send it's GPS position and related satellite information to dispatcher, and the corrections are made at the dispatcher to get corrected user position. IDGPS suffered correction degradation as the baseline become large. This problem is resolved using NIDGPS (Network IDGPS). As the experimental results are demonstrated, the improvement of position accuracy using IDGPS and NIDGPS is verified. more...

The frontal cortex might play an important role in the fear network, and white matter (WM) integrity could be related to the pathophysiology of panic disorder (PD). A few studies have investigated alterations of WM integrity in PD. The aim of this study was to determine frontal WM integrity differences between patients with PD without comorbid conditions and healthy control (HC) subjects by using diffusion tensor imaging. Thirty-six patients with PD who had used medication within 1 week and 27 age- and sex-matched HC subjects participated in this study. Structural brain magnetic resonance imaging was performed on all participants. Panic Disorder Severity Scale and Beck Anxiety Inventory (BAI) scores were assessed. Tract-based spatial statistics (TBSS) was used for image analysis. TBSS analysis showed decreased fractional anisotropy (FA) in frontal WM and WM around the frontal lobe, including the corpus callosum of both hemispheres, in patients with PD compared to HC subjects. Moreover, voxel-wise correlation analysis revealed that the BAI scores for patients with PD were positively correlated with their FA values for regions showing group differences in the FA of frontal WM of both hemispheres. Altered integrity in frontal WM of patients with PD without comorbid conditions might represent the structural pathophysiology in these patients, and these changes could be related to clinical symptoms of PD. more...

Recent genome-wide association studies of schizophrenia reported a novel risk variant, rs2312147 at vaccinia-related kinase 2 gene (VRK2), in multiple Asian and European samples. However, its effect on the brain structure in schizophrenia is little known. We analyzed the brain structure of 36 schizophrenia patients and 18 healthy subjects with regard to rs2312147 genotype groups. Brain magnetic resonance scans for gray matter (GM) and white matter (WM) analysis, and genotype analysis for VRK2 rs2312147, were conducted. The Positive and Negative Syndrome Scale and the Digit Symbol Test were assessed for schizophrenia patients. There was no significant difference in either GM volume or WM connectivity with regard to rs2312147 genotype in healthy subjects. In contrast, we found significant differences in the WM connectivity between rs2312147 CC and CT/TT genotype groups of schizophrenia patients. The related brain areas included the splenium of corpus callosum, the left occipital lobe WM, the internal capsule (left anterior limb and right retrolenticular part), the bilateral temporal lobe WM, the left fornix/stria terminalis, the left cingulate gyrus WM, and the left parietal lobe WM. Voxelwise correlation analysis revealed that the Digit Symbol Test scores (age corrected) correlated with the fractional anisotropy in WM tracts that previously showed significant group differences between the CT/TT and CC genotypes in the rs2312147 CT/TT genotype group, while no significant correlation was found in the CC genotype group. Our data may provide evidence for the effect of VRK2 on WM connectivity in patients with schizophrenia. more...

The shadowing property is to find an exact solution to an iterated map that remains close to an approximate solution. In this article, using shadowing property, we show the stability of the following equation in normed group: 4n−2Cn/2−1r2f(∑j=1n(xj/r))+n∑ik∈{0,1}, ∑k=1nik=n/2r2f(∑i=1n(−1)ik(xi/r))=4n⋅n−2Cn/2−1∑i=1nf(xi), where n≥2, r∈R (r2≠n) and f is a mapping. And we prove that the even mapping which satisfies the above equation is quadratic and also the Hyers-Ulam stability of the functional equation in Banach spaces. more...