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Abstract Background Theta-gamma coupling (TGC) describes the modulation of gamma oscillations by the theta phasic activity, which is crucial for processes such as the ordering of information during working memory (WM) performance. The mental arithmetic (MA), which involves performing calculations with numbers, is a crucial tool for evaluating and understanding the sensory processing and management abilities of WM. Evaluating TGC may provide greater insight into the neural mechanisms mediating WM deficits in panic disorder (PD). Methods Medical and electroencephalography (EEG) records of psychiatric outpatient clinic between 1 March 2020 and 30 September 2023 were retrospectively reviewed. A total of 34 PD patients and 34 age- and sex-matched healthy controls (HCs) underwent EEG to assess the overall functional interaction of the brain using multi-channel EEG analysis, focusing on specific brain regions including the frontal, temporal, parietal, and occipital lobes. EEG recordings were conducted during two sessions: a 5-min eyes-closed resting-state (RS) and a subsequent 5-min eyes-closed MA. The TGC and the spectral power of the theta and gamma frequency bands, which are well known to be associated with WM, were analysed. Results Compared to those in HCs, TGC and theta power were significantly attenuated in PD patients. When analysing both HCs and PD patients together, RS TGC and relative theta power were negatively correlated with state anxiety and perceived stress scores, respectively. In contrast, TGC and relative theta power during the MA condition were positively correlated with the MA performance. Specifically, in PD patients, RS theta power across all electrodes was significantly negatively correlated with the Hamilton Anxiety Scale (HAMA) score. Linear regression analysis revealed that theta power in the T5 channel remained negatively correlated with pathological anxiety as measured by the HAMA score, even after controlling for other confounding factors. Conclusions This study highlights significant alterations in TGC and theta power in PD patients. PD patients exhibit reduced TGC and theta power compared to HCs, indicating deficits in the neural mechanisms underlying anxiety and/or WM in PD. These insights contribute to a better understanding of the neural basis of WM deficits in PD and suggest potential avenues for targeted therapeutic interventions.

Abstract This study proposes a synthetic data generation model to create a classification framework for cerebellar ataxia patients using trajectory data from the visuomotor adaptation task. The classification objectives include patients with cerebellar ataxia, age-matched normal individuals, and young healthy subjects. Synthetic data for the three classes is generated based on class conditions and random noise by leveraging a combination of conditional adversarial generative neural networks and reconstruction networks. This synthetic data, alongside real data, is utilized as training data for the patient classification model to enhance classification accuracy. The fidelity of the synthetic data is assessed visually to measure the validity and diversity of the generated data qualitatively while quantitatively evaluating distribution similarity to real data. Furthermore, the clinical efficacy of the patient classification model employing synthetic data is demonstrated by showcasing improved classification accuracy through a comparative analysis between results obtained using solely real data and those obtained when both real and synthetic data are utilized. This methodological approach holds promise in addressing data insufficiency in the digital healthcare domain, employing deep learning methodologies, and developing early disease diagnosis tools.

Abstract Background Helicobacter pylori changes from spiral to coccoid depending on the host state, environmental factors, and surrounding microbial communities. The coccoid form of H. pylori still maintains its complete cellular structure, retains virulence genes, and thus plays a role in pathogenicity. To understand the coccoid form, it is crucial to establish the in vitro generation of the coccoid H. pylori. Although some conditions have been studied for the generation of the coccoid form, few studies have compared these conditions for coccoid generation. Here, we generated coccoid forms via three methods and compared the differences in morphology, viability, culturability, and protein expression. Results The coccoid H. pylori was generated in vitro via three methods: a starvation method, a method using amoxicillin, and a method using the culture supernatant of Streptococcus mitis. The morphology and viability of the cells were examined by fluorescence microscopy after staining with SYTO9 and propidium iodide. The culturability of H. pylori was examined by counting colony-forming units on chocolate agar plates. In the starvation group, no colonies formed after 7 days, but viable coccoids were continuously observed. In the amoxicillin-treated group, the culturability decreased rapidly after 12 h, and showed a viable but non culturable (VBNC) state after the third day. Most cells treated with S. mitis supernatant changed to coccoid forms after 7 days, but colonies were continuously formed, probably due to living spiral forms. We performed proteomics to analyse the differences in protein profiles between the spiral and coccoid forms and protein profiles among the coccoid forms generated by the three methods. Conclusion Amoxicillin treatment changed H. pylori to VBNC cells faster than starvation. Treatment with the S. mitis supernatant prolonged the culturability of H. pylori, suggesting that the S. mitis supernatant may contain substances that support spiral form maintenance. Proteomic analysis revealed that the expression of proteins differed between the spiral form and coccoid form of H. pylori, and this variation was observed among the coccoid forms produced via three different methods. The proteins in the coccoid forms produced by the three methods differed from each other, but common proteins were also observed among them.

Abstract The ability to learn novel motor skills is essential for patients with Parkinson’s disease (PD) to regain activities of daily living. However, the underlying mechanisms of motor learning in PD remain unclear. To identify motor features that are distinctively manifested in PD during motor learning, we quantified a rich set of variables reflecting various aspects of the learning process in a virtual throwing task. While the performance outcome improved similarly over 3 days of practice for both PD patients and age-matched controls, further analysis revealed distinct learning processes between the two groups. PD patients initially performed with a slow release velocity and gradually increased it as practice progressed, whereas the control group began with an unnecessarily rapid release velocity, which they later stabilized at a lower value. Performance characteristics related to the timing of ball release and the inter-release interval did not show significant group differences, although they were modulated across practice in both groups. After one week, both groups retained the performance outcomes and underlying kinematics developed over practice. This study underscores the importance of analyzing the multi-faceted learning process to characterize motor skill learning in PD. The findings may provide insights into PD pathophysiology and inform rehabilitation strategies.

Abstract The phenoconversion trajectory from idiopathic/isolated Rapid eye movement (REM) sleep behavior disorder (iRBD) towards either Parkinson’s Disease (PD) or Dementia with Lewy Bodies (DLB) is currently uncertain. We investigated the capability of baseline brain [18F]FDG-PET in differentiating between iRBD patients eventually phenoconverting to PD or DLB, by deriving the denovoPDRBD-related pattern (denovoPDRBD-RP) from 32 de novo PD patients; and the denovoDLBRBD-RP from 30 de novo DLB patients, both with evidence of RBD at diagnosis. To explore [18F]FDG-PET phenoconversion trajectories prediction power, we applied these two patterns on a group of 115 iRBD patients followed longitudinally. At follow-up (25.6 ± 17.2 months), 42 iRBD patients progressed through overt alpha-synucleinopathy (21 iRBD-PD and 21 iRBD-DLB converters), while 73 patients remained stable at the last follow-up visit (43.2 ± 27.6 months). At survival analysis, both patterns were significantly associated with the phenoconversion trajectories. Brain [18F]FDG-PET is a promising biomarker to study progression trajectories in the alpha-synucleinopathy continuum.

Abstract Background Whole-genome sequencing (WGS) analyses have found higher genetic burden in autistic females compared to males, supporting higher liability threshold in females. However, genomic evidence of sex differences has been limited to European ancestry to date and little is known about how genetic variation leads to autism-related traits within families across sex. Methods To address this gap, we present WGS data of Korean autism families (n = 2255) and a Korean general population sample (n = 2500), the largest WGS data of East Asian ancestry. We analyzed sex differences in genetic burden and compared with cohorts of European ancestry (n = 15,839). Further, with extensively collected family-wise Korean autism phenotype data (n = 3730), we investigated sex differences in phenotypic scores and gene-phenotype associations within family. Results We observed robust female enrichment of de novo protein-truncating variants in autistic individuals across cohorts. However, sex differences in polygenic burden varied across cohorts and we found that the differential proportion of comorbid intellectual disability and severe autism symptoms mainly drove these variations. In siblings, males of autistic females exhibited the most severe social communication deficits. Female siblings exhibited lower phenotypic severity despite the higher polygenic burden than male siblings. Mothers also showed higher tolerance for polygenic burden than fathers, supporting higher liability threshold in females. Conclusions Our findings indicate that genetic liability in autism is both sex- and phenotype-dependent, expanding the current understanding of autism’s genetic complexity. Our work further suggests that family-based assessments of sex differences can help unravel underlying sex-differential liability in autism.

Background: Non-invasive deep brain modulation (DBM) stands as a promising therapeutic avenue to treat brain diseases. Acoustic DBM represents an innovative and targeted approach to modulate the deep brain, employing techniques such as focused ultrasound and shock waves. Despite its potential, the optimal mechanistic parameters, the effect in the brain and behavioral outcomes of acoustic DBM remains poorly understood. Objective: To establish a robust protocol for the shock wave DBM by optimizing its mechanistic profile of external stimulation, and to assess its efficacy in preclinical settings. Methods: We used shockwaves due to their capacity to leverage a broader spectrum of peak intensity (10–127 W/mm2) in contrast to ultrasound (0.1–5.0 W/mm2), thereby enabling a more extensive range of neuromodulation effects. We established various types of shockwave pressure profiles of DBM and compared neural and behavioral responses. To ascertain the anticipated cause of the heightened neural activity response, numerical analysis was employed to examine the mechanical dynamics within the brain. Results: An optimized profile led to an enhancement in neuronal activity within the hypothalamus of mouse models. The optimized profile in the hippocampus elicited a marked increase in neurogenesis without neuronal damage. Behavioral analyses uncovered a noteworthy reduction in locomotion without significant effects on spatial memory function. Conclusions: The present study provides an optimized shock wave stimulation protocol for non-invasive DBM. Our optimized stimulation profile selectively triggers neural functions in the deep brain. Our protocol paves the way for new non-invasive DBM devices to treat brain diseases.

Abstract Background Ectodermal dysplasia (ED) is a rare genetic disorder that affects structures derived from the ectodermal germ layer. Results In this study, we analyzed the genetic profiles of 27 Korean patients with ED. Whole exome sequencing (WES) was performed on 23 patients, and targeted panel sequencing was conducted on the remaining 4 patients. Among the patients in the cohort, 74.1% (20/27) tested positive for ED. Of these positive cases, EDA and EDAR mutations were found in 80% (16/20). Notably, 23.1% (3/13) of EDA-positive cases exhibited copy number variations. Among the 23 patients who underwent WES, we conducted a virtual panel analysis of eight well-known genes, resulting in diagnoses for 56.5% (13/23) of the cases. Additionally, further analysis of approximately 5,000 OMIM genes identified four more cases, increasing the overall positivity rate by approximately 17%. These findings underscore the potential of WES for improving the diagnostic yield of ED. Remarkably, 94.1% of the patients manifesting the complete triad of ED symptoms (hair/skin/dental) displayed detectable EDA/EDAR mutations. In contrast, none of the 7 patients without these three symptoms exhibited EDA/EDAR mutations. Conclusions When conducting molecular diagnostics for ED, opting for targeted sequencing of EDA/EDAR mutations is advisable for cases with classical symptoms, while WES is deemed an effective strategy for cases in which these symptoms are absent.

Abstract The only characteristic of alpha-synuclein (AS) accumulation in the gastrointestinal (GI) tract of Parkinson’s disease (PD) found in pathological studies is the “rostrocaudal gradient,” which describes the more frequent presence of AS accumulation in the upper GI tract than in the lower GI tract. This study aimed to determine the diagnostic accuracy and identify predictors of AS accumulation in the GI tract of PD patients. The frequency of AS accumulation in the GI tract was compared between PD patients (N = 97) who underwent radical GI surgery for cancer and individually matched controls (N = 94). We evaluated AS accumulation in the neural structures using phosphorylated AS immunohistochemistry. A multivariable logistic regression analysis was conducted to determine the predictors of AS accumulation in the GI tract of PD patients. The frequency of AS accumulation was significantly higher in PD patients (75.3%) than in controls (8.5%, p-value

Interest in citrate-based dialysate (Cit-D) is growing due to its benefits, including anticoagulation and dialysis efficacy. However, research on safety and efficiency of Cit-D in high-volume hemodiafiltration (HDF) via central concentrate delivery system (CCDS) is scarce. This study aimed to investigate the safety and efficacy of Cit-D when switching from acetate-based dialysate (Acet-D) in high-volume HDF via CCDS. This is a retrospective analysis of 28 patients who underwent post-dilution online HDF via CCDS, who switched from Acet-D to Cit-D. The study period was divided into 3 periods for analysis: 12 weeks using Acet-D (AD period), the first 12 weeks using Cit-D (CD-1 period), and the second 12 weeks using Cit-D (CD-2 period). We collected the laboratory, dialysis, and safety parameters in each period from electrical medical records. After switching from Acet-D to Cit-D, heparin dosage decreased by 17%, whereas the incidence of complications did not increase. Kt/VBUN and urea reduction ratio increased by 4.6% and 2.1%, respectively. Pre-dialysis beta2-microglobulin concentration decreased after using Cit-D. The corrected calcium levels decreased in the CD-1 period compared to the AD period, but in CD-2, they subsequently increased to levels similar to those observed during the AD period. Symptomatic hypocalcemia did not occur, and there was no significant difference in the incidence of hyperparathyroidism. Endotoxin levels and the bacterial culture of ultrapure dialysate were unremarkable throughout all periods. These results might suggest that Cit-D could potentially offer advantages over Acet-D, such as reducing the heparin dose and increasing dialysis efficiency, in patients undergoing high-volume HDF using CCDS.

Background: Promoting patients’ safe return home at discharge and reducing length of stay in hospital is key for Restorative Rehabilitation Institution (RMI). Objects: This study was designed to identify the factors influencing the return to home and length of stay among various factors. Methods: A total of 120 stroke patients (76 males and 44 females) who were hospitalized in an adult inpatient unit of a RMI for more than 2 months were retrospectively analyzed for this study (multivariate logistic regression analyses, p < 0.001). As predictor variables for assessing the return to home and length of stay, demographic data (sex, age, duration between onset and admission, length of stay, caregiver after discharge, occupation after discharge, reason for discharge, and household type after discharge) were collected. Additionally, following measurements were selectively collected from patient’s medical records: scores of Mini-Mental State Examination Korean version (K-MMSE), modified Barthel Index Korean version (K-MBI), Berg Balance Scale and Functional Ambulation Category were obtained at admission and discharge. Results: The K-MMSE at admission and K-MBI at discharge were found to be the predictors of return to home. Additionally, K-MBI at admission influenced the length of stay. Conclusion: This study suggests cognitive functioning at admission and the level of activities of daily living at discharge predicted the return to home and length of stay.

Summary: Tumor-associated macrophages (TAMs) and other myelomonocytic cells are implicated in regulating responsiveness to immunotherapies, including immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis. We have developed an ex vivo high-throughput approach to discover modulators of macrophage-mediated T cell suppression, which can improve clinical outcomes of ICIs. We screened 1,430 Food and Drug Administration (FDA)-approved small-molecule drugs using a co-culture assay employing bone-marrow-derived macrophages (BMDMs) and splenic-derived T cells. This identified 57 compounds that disrupted macrophage-mediated T cell suppression. Seven compounds exerted prominent synergistic T cell expansion activity when combined with αPD-L1. These include four COX1/2 inhibitors and two myeloid cell signaling inhibitors. We demonstrate that the use of cyclooxygenase (COX)1/2 inhibitors in combination with αPD-L1 decreases tumor growth kinetics and enhances overall survival in triple-negative breast cancer (TNBC) tumor models in a CD8+ T cell-dependent manner. Altogether, we present a rationalized approach for identifying compounds that synergize with ICI to potentially enhance therapeutic outcomes for patients with solid tumors.

Factor V (FV) deficiency is a coagulation disorder (congenital or acquired). Unlike congenital FV deficiency, mixing tests for prothrombin time and activated partial thromboplastin time are not corrected in acquired FV cases. A 79-year-old male was admitted to the intensive care unit after an emergency operation due to gastric ulcer perforation. While receiving antibiotic treatment for septic shock, the coagulation profile began to show prolongation of prothrombin time and activated partial thromboplastin time. FV deficiency (< 1%) following meropenem administration was diagnosed. The patient did not show spontaneous bleeding or bleeding tendency. With fresh frozen plasma transfusion, steroid administration, and discontinuation of meropenem, the blood coagulation profile test result was normalized 20 days after diagnosis. His follow-up FV level increased to 78.7%. Although abnormalities in coagulation profiles are common in sepsis patients, in our patient, timely recognition and hematological consultation allowed early diagnosis and proper management of FV deficiency.

Abstract This study aimed to address the diversity issue in fashion design education by developing two prototypes for Inclusive Fashion Design (IFD) education. The prototypes were constructed based on the 3C3R model of Project-Based Learning (PBL) and incorporated the Persona/Scenario (P/S) toolkit for IFD. Additionally, the study examined the effectiveness of the FEA (Function, Expressive, and Aesthetics) self-checklist and the P/S toolkit in the IFD process. The experiments involved two design instructors, two teaching assistants, and 12 senior-level students divided into four teams. Thematic analysis was conducted on the interview data collected from the participants. The results revealed that FEA factors were highly considered in both education prototypes, regardless of the presence of the P/S toolkit. Maintaining consistency of the IFD concept throughout each stage of the process was found to be crucial, and the use of the P/S toolkit played a significant role in achieving this consistency. Team communication emerged as an essential factor in IFD education, as team collaboration using the P/S toolkit triggered diverse perspectives on targets, facilitated design expansion, and extended individual competences. Overall, this study contributes to the understanding of the diversity issue in fashion design education and promotes the adoption of the IFD education methodology, emphasizing the significance of consistent concept development, effective toolkits, and team collaboration in achieving inclusive design practices.

Eruca sativa is a commonly used edible plant in Italian cuisine. E. sativa 70% ethanol extract (ES) was fractionated with five organic solvents, including n-hexane (EHex), chloroform (ECHCl3), ethyl acetate (EEA), n-butyl alcohol (EBuOH), and water (EDW). Ethyl acetate fraction (EEA) had the highest antioxidant activity, which was correlated with the total polyphenol and flavonoid content. ES and EEA acted as PPAR-α ligands by PPAR-α competitive binding assay. EEA significantly increased cornified envelope formation as a keratinocyte terminal differentiation marker in HaCaT cells. Further, it significantly reduced nitric oxide and pro-inflammatory cytokines (IL-6 and TNF-α) in lipopolysaccharide-stimulated RAW 264.7 cells. The main flavonol forms detected in high amounts from EEA are mono-and di-glycoside of each aglycone. The main flavonol form of EEA is the mono-glycoside of each aglycone detected, and the most abundant flavonol mono-glycoside is kaempferol 3-glucoside 7.4%, followed by quercetin-3-glucoside 2.3% and isorhamnetin 3-glucoside 1.4%. Flavonol mono-glycosides were shown to be a potent PPAR-α ligand using molecular docking simulation and showed the inhibition of nitric oxide. These results suggest that the flavonol composition of E. sativa is suitable for use in improving skin barrier function and inflammation in skin disorders, such as atopic dermatitis.

In reconstructive surgery following partial mandibulectomy, the biomechanical integrity of the fibula free flap applied to the remaining mandibular region directly influences the prognosis of the surgery. The purpose of this study is to evaluate the biomechanical integrity of two fixation materials [titanium (Ti) and hydroxyapatite/poly-L-lactide (HA-PLLA)]. In this study, we simulated the mechanical properties of miniplate and screw fixations in two different systems by finite element analysis. A three-dimensional mandibular model was constructed and a fibula free flap and reconstruction surface were designed. The anterior and posterior end of the free flap was positioned with two miniplates and two additional miniplates were applied to the angled area of the fibula. The masticatory loading was applied considering seven principal muscles. The peak von Mises stress (PVMS) distribution, size of fixation deformation, principal stresses on bones, and gap opening size were measured to evaluate the material properties of the fixation. In the evaluation of properties, superior results were observed with both fixation methods immediately after surgery. However, after the formation of callus between bone segments at 2 months, the performance of Ti fixation decreased over time and the differences between the two fixations became minimal by 6 months after surgery. The result of the study implies the positive clinical potential of the HA-PLLA fixation system applied in fibula free flap reconstruction.

Abstract Objective The Synkinesis Assessment Questionnaire (SAQ) is a reliable tool to assess synkinesis symptoms; however, it is yet to be validated in Korea. Thus, this study aimed to translate and validate the Korean SAQ. Methods This validation study was set in a clinic in Seoul, Korea, that provides general integrative medicine services. A total of 100 participants with facial palsy were enrolled. Participants completed the SAQ, House–Brackmann grade (HB grade), Sunnybrook Facial Grading System (SB), and Facial Disability Index (FDI). The forward–backward translation method was followed. Of the 100 participants, 31 underwent a second assessment for test–retest reliability. Internal consistency and test–retest reliability were evaluated using Cronbach's alpha coefficient. The construct validity of the Korean version of the SAQ was tested using Spearman's rank correlation coefficient. Results The internal consistency score for the SAQ was 0.789, and the test–retest reliability score was 0.787. According to Spearman's rank correlation coefficient, the SAQ correlations to the synkinesis subdomain of SB score, total SB score, HB grade, and physical function domain in the FDI score were 0.366 (p

Abstract Objective To investigate structural and functional connectivity changes in brain olfactory‐related structures in a longitudinal prospective cohort of isolated REM sleep behavior disorder (iRBD) and their clinical correlations, longitudinal evolution, and predictive values for phenoconversion to overt synucleinopathies, especially Lewy body diseases. Methods The cohort included polysomnography‐confirmed iRBD patients and controls. Participants underwent baseline assessments including olfactory tests, neuropsychological evaluations, the Movement Disorders Society–Unified Parkinson's Disease Rating Scale, 3T brain MRI, and 18F‐FP‐CIT PET scans. Voxel‐based morphometry (VBM) was performed to identify regions of atrophy in iRBD, and volumes of relevant olfactory‐related regions of interest (ROI) were estimated. Subgroups of patients underwent repeated volumetric MRI and resting‐state functional MRI (fMRI) scans after four years. Results A total of 51 iRBD patients were included, with 20 of them converting to synucleinopathy (mean time to conversion 3.08 years). Baseline VBM analysis revealed atrophy in the right olfactory cortex and gyrus rectus in iRBD. Subsequent ROI comparisons with controls showed atrophy in the amygdala. These olfactory‐related atrophies tended to be associated with worse depression, anxiety, and urinary problems in iRBD. Amygdala 18F‐FP‐CIT uptake tended to be reduced in iRBD patients with hyposmia (nonsignificant after multiple comparison correction) and correlated with urinary problems. Resting‐state fMRI of 23 patients and 32 controls revealed multiple clusters with aberrant olfactory‐related functional connectivity. Hypoconnectivity between the putamen and olfactory cortex was associated with mild parkinsonian signs in iRBD. Longitudinal analysis of volumetric volumetric MRI in 22 iRBD patients demonstrated four‐year progression of olfactory‐related atrophy. Cox regression analysis revealed that this atrophy significantly predicted phenoconversion. Interpretation Progressive atrophy of central olfactory structures may be a potential indicator of Lewy body disease progression in iRBD.

This study seeks to understand the role of representation in news media, trust in news, and participation in multicultural audiences’ sense of belonging to society. A multimodal survey combining online, CATI, and CAPI methods was conducted in Australia at the end of 2021 and early 2022 (N = 1,084). The top five non-English language communities in Australia (Arabic, Cantonese, Italian, Mandarin, and Vietnamese) were included in the survey, of which n = 851 were born overseas. The findings reveal a significant link between the perception of sufficient representation in Australian news media, trust in news, confidence to participate in society, and sense of belonging. When multicultural audiences see themselves fairly and adequately represented in the news, they are more likely to trust the news and participate in the community by discussing the news and current affairs. This, in turn, leads to a stronger sense of belonging to society. We also found confidence in English and time spent in Australia were important factors contributing to perceptions of representation. While the length of stay has a positive impact on the perception of representation among those with high confidence in English, this perception is significantly lower among those who have lower confidence. This result confirms the significant role language proficiency plays in migrants’ experiences in the host country.

Abstract We compared the efficacy and safety of autologous-serum (AS) and platelet-rich plasma (PRP) eye drops for dry eye (DE) treatment in primary Sjögren’s syndrome (SS). This prospective, randomized, double-blinded clinical study included patients diagnosed with primary SS DE. Thirty-eight participants were randomly assigned to the AS or PRP groups. Corneal and conjunctival staining scores, Schirmer I test, tear film break-up time (TBUT), and ocular surface disease index (OSDI) scores were evaluated at 4 and 12 weeks. Conjunctival impression cytology (CIC) metaplasia grade and goblet cell density grade at 12 weeks were compared with those at baseline. Corneal and conjunctival staining scores and TBUT significantly improved at 4 and 12 weeks in both groups (all p

Abstract Thus far, attempts to develop drugs that target corticotropin-releasing hormone receptor 1 (CRF1R), a drug target in stress-related therapy, have been unsuccessful. Studies have focused on using high-resolution G protein-coupled receptor (GPCR) structures to develop drugs. X-ray free-electron lasers (XFELs), which prevent radiation damage and provide access to high-resolution compositions, have helped accelerate GPCR structural studies. We elucidated the crystal structure of CRF1R complexed with a BMK-I-152 antagonist at 2.75 Å using fixed-target serial femtosecond crystallography. The results revealed that two unique hydrogen bonds are present in the hydrogen bond network, the stalk region forms an alpha helix and the hydrophobic network contains an antagonist binding site. We then developed two antagonists—BMK-C203 and BMK-C205—and determined the CRF1R/BMK-C203 and CRF1R/BMK-C205 complex structures at 2.6 and 2.2 Å, respectively. BMK-C205 exerted significant antidepressant effects in mice and, thus, may be utilized to effectively identify structure-based drugs against CRF1R.

Abstract Background The use of beta-tricalcium phosphate (beta-TCP) in dental surgery is limited owing to its rapid absorption compared to mixed formulations of hydroxyapatite. However, newly developed pure beta-TCP crystals have demonstrated slow absorption; hence, they last longer within the defect and act as a scaffold until new bone formation. The oral environment is unique and can prove unfavorable for bone grafts due to the high infection rate in the oral cavity and the fragile condition of the oral mucosa. The aim of this study was to evaluate the feasibility of using pure beta-TCP bone grafts in various dental treatments. Methods Panoramic X-ray images of 25 patients who underwent bone grafting during dental surgery were analyzed. A specially treated pure beta-TCP crystal, Neo Bone® (Neo Bone®, SN Biologics Co., Ltd, Seoul, Korea), was used in this study. The bone density at the graft site was compared with that of the surrounding bone using the ImageJ software (Wayne Rasband, NIH USA). Results Six months after surgery, the bone graft density was similar to that of the surrounding bone in 20 patients and increased in 5 patients. No adverse effects, such as infection, dehiscence, or graft failure, were observed. Conclusion The newly developed pure beta-TCP crystal was slowly absorbed and served as support until new bone formation at the defect site, thus demonstrating its potential for use in various oral conditions requiring bone grafting.

ABSTRACT Pericytes are located around blood vessels, in close contact with endothelial cells. We discovered that pericytes dampen pro-inflammatory endothelial cell responses. Endothelial cells co-cultured with pericytes had markedly reduced expression of adhesion molecules (PECAM-1 and ICAM-1) and proinflammatory cytokines (CCL-2 and IL-6) in response to bacterial stimuli (Brucella ovis, Listeria monocytogenes, or Escherichia coli lipopolysaccharide). Pericyte-depleted mice intraperitoneally inoculated with either B. ovis, a stealthy pathogen that does not trigger detectable inflammation, or Listeria monocytogenes, developed peritonitis. Further, during Citrobacter rodentium infection, pericyte-depleted mice developed severe intestinal inflammation, which was not evident in control mice. The anti-inflammatory effect of pericytes required connexin 43, as either chemical inhibition or silencing of connexin 43 abrogated pericyte-mediated suppression of endothelial inflammatory responses. Our results define a mechanism by which pericytes modulate inflammation during infection, which shifts our understanding of pericyte biology: from a structural cell to a pro-active player in modulating inflammation.IMPORTANCEA previously unknown mechanism by which pericytes modulate inflammation was discovered. The absence of pericytes or blocking interaction between pericytes and endothelium through connexin 43 results in stronger inflammation, which shifts our understanding of pericyte biology, from a structural cell to a player in controlling inflammation.

Summary: Learning causal relationships is crucial for survival. The human brain’s functional flexibility allows for effective causal inference, underlying various learning processes. While past studies focused on environmental factors influencing causal inference, a fundamental question remains: can these factors be manipulated for strategic causal inference control? This paper presents a task control framework for orchestrating causal learning task design. It utilizes a two-player game setting where a neural network learns to manipulate task variables by interacting with a human causal inference model. Training the task controller to generate experimental designs, we confirm its ability to accommodate complexities of environmental causal structure. Experiments involving 126 human subjects successfully validate the impact of task control on performance and learning efficiency. Additionally, we find that task control policy reflects the intrinsic nature of human causal inference: one-shot learning. This framework holds promising potential for applications paving the way for targeted behavioral outcomes in humans.

Background: Cancer is one of the leading causes of death in most countries with an expected increased burden on healthcare systems. Since integrative medical treatments are not collected within the scope of existing cancer registries, the establishment of the Korean Medicine Cancer Registry (KMCARE), gathering integrative therapies, including conservative care and Korean medicine, is warranted. Methods: A prospective observational study based on the registry will be conducted in 5 Korean medical hospitals. A total of 650 eligible participants undergoing Korean medicine treatments within 1 month of a diagnosis of lung, colorectal, stomach, or breast cancer are anticipated to be enrolled in the registry. Data collected in the KMCARE can be classified into patient information, received treatments, and outcomes. The primary outcome is the Functional Assessment of Cancer Therapy-General Questionnaire score at 3 months. Secondary outcomes include the MD Anderson Symptom Inventory-Core and the Body Constitution Questionnaire at 3 and 6 months. After 6 months of follow-up periods, survival surveillance will be continued for additional 18 months. Descriptive and statistical analysis of primary and secondary outcomes, baseline data, safety, survival, and prognostic factors will be performed. Discussion: This is the first prospective, multi-centered, registry-based observational study of cancer patients in Korean medicine hospitals, which could reveal the current status of cancer patients receiving integrative cancer therapies, and provide better insight into the role of Korean medicine in palliative care for patients with cancer. Trial registration: Clinical Research Information Service (CRIS), KCT0007447.

Objectives: Based on the results from the Korean Total Diet Study (KTDS), the sodium (Na) and potassium (K) intake of Koreans were estimated and compared with intake estimates from the Food & Nutrient Database (FNDB), as in the Korea National Health and Nutrition Examination Survey (KNHANES) to verify the validity of these estimates. Methods: One hundred and thirty-four representative foods (RFs) covering 92.5% of the total food intake of Koreans were selected, and 228 pairs of corresponding ‘RF x representative cooking method’ were derived by reflecting the methods used mainly in terms of frequency and quantity in their cooking. RF samples were collected from three cities with a larger population size in three regions (nine cities) nationwide, and six composite samples were made for each RF, considering its regional and/or seasonal characteristics. One thousand three hundred and sixty-eight ‘RF x representative cooking method’ pair samples were prepared, and the Na and K contents were assessed using inductively coupled plasma atomic emission spectrometry (ICP-MS). The Na and K intake of the Korean population was estimated by linking the content with the food intake data from the 7th KNHANES. Results: The mean Na and K intake of Koreans were 2,807.4 mg and 2,335.0 mg per person per day, respectively. A comparison with the Na and K intake from KNHANES, including only RFs of KTDS, showed comparable results with less than 5% variation. While the contribution and ranking of food items to Na intake were similar between KNHANES and KTDS, there were differences in K intake. This was attributed to the large discrepancies in the K content of rice and coffee between KTDS results and the values in the 9th Revision of the National Food Composition Table used in KNHANES. Conclusions: The Na and K intake of Koreans estimated based on the KTDS, which performed nutrient analysis on samples prepared to a ‘table-ready’ state using foods of the representative collection, was similar and comparable with that of KNHANES. This supports the validity and usefulness of FNDB-based nutrient intake estimation at the population level. The list of nutrients studied in KTDS is expected to be expanded, allowing for intake estimation of nutrients with currently insufficient or absent information in the FNDBs in use.

Abstract Background The isolated rapid-eye-movement sleep behavior disorder (iRBD) is a prodromal condition of Lewy body disease including Parkinson's disease and dementia with Lewy bodies (DLB). We aim to investigate the longitudinal evolution of DLB-related cortical thickness signature in a prospective iRBD cohort and evaluate the possible predictive value of the cortical signature index in predicting dementia-first phenoconversion in individuals with iRBD. Methods We enrolled 22 DLB patients, 44 healthy controls, and 50 video polysomnography-proven iRBD patients. Participants underwent 3-T magnetic resonance imaging (MRI) and clinical/neuropsychological evaluations. We characterized DLB-related whole-brain cortical thickness spatial covariance pattern (DLB-pattern) using scaled subprofile model of principal components analysis that best differentiated DLB patients from age-matched controls. We analyzed clinical and neuropsychological correlates of the DLB-pattern expression scores and the mean values of the whole-brain cortical thickness in DLB and iRBD patients. With repeated MRI data during the follow-up in our prospective iRBD cohort, we investigated the longitudinal evolution of the cortical thickness signature toward Lewy body dementia. Finally, we analyzed the potential predictive value of cortical thickness signature as a biomarker of phenoconversion in iRBD cohort. Results The DLB-pattern was characterized by thinning of the temporal, orbitofrontal, and insular cortices and relative preservation of the precentral and inferior parietal cortices. The DLB-pattern expression scores correlated with attentional and frontal executive dysfunction (Trail Making Test-A and B: R = − 0.55, P = 0.024 and R = − 0.56, P = 0.036, respectively) as well as visuospatial impairment (Rey-figure copy test: R = − 0.54, P = 0.0047). The longitudinal trajectory of DLB-pattern revealed an increasing pattern above the cut-off in the dementia-first phenoconverters (Pearson’s correlation, R = 0.74, P = 6.8 × 10−4) but no significant change in parkinsonism-first phenoconverters (R = 0.0063, P = 0.98). The mean value of the whole-brain cortical thickness predicted phenoconversion in iRBD patients with hazard ratio of 9.33 [1.16–74.12]. The increase in DLB-pattern expression score discriminated dementia-first from parkinsonism-first phenoconversions with 88.2% accuracy. Conclusion Cortical thickness signature can effectively reflect the longitudinal evolution of Lewy body dementia in the iRBD population. Replication studies would further validate the utility of this imaging marker in iRBD.

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the aggregation of misfolded α-synuclein and progressive spreading of the aggregates from a few discrete regions to wider brain regions. Although PD has been classically considered a movement disorder, a large body of clinical evidence has revealed the progressive occurrence of non-motor symptoms. Patients present visual symptoms in the initial stages of the disease, and accumulation of phospho-α-synuclein, dopaminergic neuronal loss, and retinal thinning has been observed in the retinas of PD patients. Based on such human data, we hypothesized that α-synuclein aggregation can initiate in the retina and spread to the brain through the visual pathway. Here, we demonstrate accumulation of α-synuclein in the retinas and brains of naive mice after intravitreal injection of α-synuclein preformed fibrils (PFFs). Histological analyses showed deposition of phospho-α-synuclein inclusions within the retina 2 months after injection, with increased oxidative stress leading to loss of retinal ganglion cells and dopaminergic dysfunction. In addition, we found accumulation of phospho-α-synuclein in cortical areas with accompanying neuroinflammation after 5 months. Collectively, our findings suggest that retinal synucleinopathy lesions initiated by intravitreal injection of α-synuclein PFFs spread to various brain regions through the visual pathway in mice.

Abstract T-cell large granular lymphocyte leukemia (T-LGL) is often accompanied by pure red cell aplasia (PRCA). A high depth of next generation sequencing (NGS) was used for detection of the mutational profiles in T-LGL alone (n = 25) and T-LGL combined with PRCA (n = 16). Beside STAT3 mutation (41.5%), the frequently mutated genes included KMT2D (17.1%), TERT (12.2%), SUZ12 (9.8%), BCOR (7.3%), DNMT3A (7.3%), and RUNX1 (7.3%). Mutations of the TERT promoter showed a good response to treatment. 3 of 41 (7.3%) T-LGL patients with diverse gene mutations were revealed as T-LGL combined with myelodysplastic syndrome (MDS) after review of bone marrow slide. T-LGL combined with PRCA showed unique features (low VAF level of STAT3 mutation, low lymphocyte count, old age). Low ANC was detected in a STAT3 mutant with a low level of VAF, suggesting that even the low mutational burden of STAT3 is sufficient for reduction of ANC. In retrospective analysis of 591 patients without T-LGL, one MDS patient with STAT3 mutation was revealed to have subclinical T-LGL. T-LGL combined with PRCA may be classified as unique subtype of T-LGL. High depth NGS can enable sensitive detection of concomitant MDS in T-LGL. Mutation of the TERT promoter may indicate good response to treatment of T-LGL, thus, its addition to an NGS panel may be recommended.

One’s own voice undergoes unique processing that distinguishes it from others’ voices, and thus listening to it may have a special neural basis for self-talk as an emotion regulation strategy. This study aimed to elucidate how neural effects of one’s own voice differ from those of others’ voices on the implementation of emotion regulation strategies. Twenty-one healthy adults were scanned using fMRI while listening to sentences synthesized in their own or others’ voices for self-affirmation and cognitive defusion, which were based on mental commitments to strengthen one’s positive aspects and imagining metaphoric actions to shake off negative aspects, respectively. The interaction effect between voice identity and strategy was observed in the superior temporal sulcus, middle temporal gyrus, and parahippocampal cortex, and activity in these regions showed that the uniqueness of one’s own voice is reflected more strongly for cognitive defusion than for self-affirmation. This interaction was also seen in the precuneus, suggesting intertwining of self-referential processing and episodic memory retrieval in self-affirmation with one’s own voice. These results imply that unique effects of one’s own voice may be expressed differently due to the degree of engagement of neural sharpening-related regions and self-referential networks depending on the type of emotion regulation.