The Company of BiologistsActa Medica Okayama2046-63901522026Gap junction-mediated signaling coordinates Rhodopsin coupling for Drosophila color visionbio062463ENXuanshuoZhangDivision of Biological Sciences, Graduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityRyokiShinjoDivision of Biological Sciences, Graduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityManabuKitamataDivision of Health Science, Advanced Comprehensive Research Organization, Teikyo UniversityShinichiOtsuneDivision of Biological Sciences, Graduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityHidekiNakagoshiDivision of Biological Sciences, Graduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityThe Drosophila compound eye is composed of approximately 800 ommatidia, and every ommatidium contains eight photoreceptor cells, six outer cells (R1-R6) and two inner cells (R7 and R8), and accessory cells (cone and pigment cells). The expression of rhodopsin genes in R7 and R8 is highly coordinated through an instructive signal from R7 to R8. The activity of the homeodomain protein Defective proventriculus in R1 is also required to transmit this instructive signal, suggesting that cell–cell communication between R7, R1, and R8 is important to generate the pattern of Rh expression in R7/R8 (Rhodopsin coupling). As cell junctions play crucial roles in maintaining the structural and functional integrity of tissues, we tested whether cell junction proteins are involved in the interactions between photoreceptor cells. Here, we demonstrate that gap junction proteins innexin 2 and innexin 7 in accessory cells are necessary for transmitting signals from R7 to R8. In addition, Notch-mediated accessory cell development and Rhodopsin coupling in R7/R8 are highly correlated. Our results provide evidence that functional coupling of two different neurons, R7 and R8, is established through gap junction-mediated signaling from adjacent accessory cells.No potential conflict of interest relevant to this article was reported.Pharmaceutical Society of JapanActa Medica Okayama0918-61584922026Functional Transport Properties of Human Zinc Transporter 1: Kinetics and pH-Dependency364370ENYumaYoshiokaDepartment of Molecular Membrane Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTakaakiMiyajiDepartment of Molecular Membrane Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityIntracellular zinc (Zn2+) homeostasis is essential for physiological and pathological processes and is strictly regulated by Zn2+ transporters. Zinc transporter 1 (ZnT1) is a ubiquitously expressed plasma membrane-localized Zn transporter that exports Zn2+ from the cytoplasm to the extracellular space. However, the functional transport properties regarding kinetics and driving forces of ZnT1 remain debatable. In this study, we established a cell-free proteoliposome assay system and demonstrated that ZnT1 transports Zn2+ with high affinity in pH-dependent and pH-independent manners. The Km and Vmax of pH-dependent Zn2+ transport were 0.40 μM and 15.13 nmol/min/mg protein, and those of pH-independent Zn2+ transport were 0.52 μM and 8.88 nmol/min/mg protein (low concentrations of Zn2+), 3.02 μM and 17.59 nmol/min/mg protein (high concentrations of Zn2+), respectively, suggesting biphasic kinetic components of Zn2+ transport. Even without pH gradient formation, ZnT1 exhibits potent Zn2+ transport activity. In pH dependency, Zn2+ transport activity was higher at an inside pH of 6.0 than at 6.5–7.5 for proteoliposomes, despite the same ΔpH of 0.5–1.5. The Zn2+ transport activity decreased at an outside pH of 8.0, despite an increase in ΔpH. Although previous studies have proposed that ZnT1-mediated Zn2+ transport activity is driven by a calcium (Ca2+) gradient and not by a pH gradient, Ca2+ does not enhance Zn2+ transport activity in the presence or absence of a pH gradient. These results strongly suggest that ZnT1 protein transports Zn2+ optimally at a specific pH and exports excess intracellular Zn2+ even without ΔpH.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0143-41601352026Regulation of brain-specific kinases 1 and 2 (BRSK1/2) by Ca2+/calmodulin103134ENNaoyukiWashidaMoeKataokaDepartment of Applied Chemistry and Biotechnology, Faculty of Engineering, Okayama UniversityAnna R.BrunApplied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityUryuTakezakiApplied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityKoHijikawaDepartment of Applied Chemistry and Biotechnology, Faculty of Engineering, Okayama UniversityHarukiYamauchiApplied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversitySatomiOhtsukaApplied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityMasakiMagariApplied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityRyoMorishitaCellFree Sciences Co., Ltd.HiroshiTokumitsuApplied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityWe conducted a genome-wide calmodulin (CaM) interaction screening of 462 GST-fused human protein kinases to identify novel CaM-dependent protein kinases (CaMKs). In addition to known CaMKs, including myosin light chain kinases, CaMK2γ, and death-associated kinase 2, we identified the brain-specific protein kinase 2 (BRSK2, also known as SAD-A) as a novel CaM interactant. Proximity biotinylation and CaM–sepharose chromatography assays revealed that rat BRSK isoforms (BRSK1/2) interact with CaM in a Ca2+-dependent manner in vitro. We found that CaM suppresses the activation-loop phosphorylation of BRSK1 (at Thr189) and BRSK2 (at Thr175) by liver kinase B1 (LKB1), an activating kinase, in a Ca2+-dependent manner (IC50 of ∼7 µM), thereby inhibiting BRSK activation. LKB1-catalyzed phosphorylation of the catalytic domain mutant of BRSK1 (residues 1–294) at Thr189 was suppressed by the addition of Ca2+/CaM, consistent with direct CaM binding of the kinase domain, as well as wild-type BRSK1. We confirmed that the LKB1 activity was not directly suppressed by Ca2+/CaM, supporting the hypothesis that the direct interaction of Ca2+/CaM with the kinase domain blocks the phosphorylation/activation of BRSK1/2 by LKB1. The kinase activity and PP2Cα-catalyzed dephosphorylation of LKB1-phosphorylated BRSK1 were not altered by Ca2+/CaM, although it was demonstrated to bind to Ca2+/CaM like that of unphosphorylated BRSK1. This unrecognized mechanism of BRSK1/2 regulation, involving the direct role of Ca2+/CaM binding, which inhibits phosphorylation/activation by LKB1, may open a new Ca2+ signal transduction pathway in neurons.No potential conflict of interest relevant to this article was reported.岡山大学大学院ヘルスシステム統合科学研究科Acta Medica Okayama2436-322762026The effects of cold compresses on itching in patients with atopic dermatitis: A cross-over controlled pilot trial16ENYukiHIRAMIFormer Department of Nursing, Graduate School of Health Sciences, Okayama UniversityNahokoHARADADepartment of Nursing Science, Faculty of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityMihoONODepartment of Nursing, Faculty of Health, Kagawa Prefectural University of Health SciencesMasahideKODACo-learning Community Healthcare Re-innovation Office, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKiyokoFUKAIProfessor Emeritus, Okayama University, Graduate School of Nursing, The Jikei University School of Medicine10.18926/interdisciplinary/70325This cross-over controlled trial aimed to evaluate the effectiveness and safety of two types of cold compresses (towels and ice packs) in alleviating itching among patients with atopic dermatitis. The study recruited 19 participants diagnosed with atopic dermatitis and suffering from chronic itching for over 6 months. Each participant received both types of cold compress interventions. Itching sensations were assessed repeatedly using a visual analogue scale before and after the application of the cold compress. The mean and standard deviation of itching scores for the towel intervention were 16.9 ± 19.1 (baseline) and 11.4 ± 16.1 (post-application). For the ice pack intervention, the scores were 13.6 ± 14.7 (baseline) and 6.2 ± 9.8 (post-application). Although there was a reduction in mean itching scores following the application of cold compresses, the differences were not statistically significant for either intervention. Despite the lack of statistical significance, this study suggests that cold compresses, which are user-friendly and inexpensive, may safely reduce subjective itching in patients with atopic dermatitis without causing pain or discomfort. However, further research with a larger sample size is needed to confirm these findings.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2045-23221612026Tribolium castaneum with longer duration of tonic immobility have more variations corresponding to the human Parkinson’s disease genomic region8840ENKeisukeTanakaNODAI Genome Research Center, Tokyo University of AgricultureKenSasakiGraduate School of Agriculture, Tamagawa UniversityShunsukeYajimaNODAI Genome Research Center, Tokyo University of AgricultureTakahisaMiyatakeFaculty of Environmental, Life, Natural Science and Technology, Okayama UniversityParkinson’s disease (PD) is a common neurodegenerative syndrome characterized by the loss of dopaminergic neurons and is also a progressive neurodegenerative disorder that is characterized by dopamine deficiency. We established strains artificially selected for longer and shorter durations of tonic immobility, an antipredator behavior that has received much attention recently, in the red flour beetle, Tribolium castaneum, a model insect species for molecular analyses different from Drosophila melanogaster. Previous studies have shown that the long strains (L-strain) have significantly lower levels of dopamine expression in the brain than the short strains (S-strain) and that they have an abnormal pattern of locomotor activity. Furthermore, previous studies have shown that administering dopamine to L-strain beetles reduces the duration of tonic immobility. Transcriptome analysis of brain and thorax of the L- and S-strains also showed differences in mRNA expression of genes involved in dopamine synthesis and tyrosine metabolism. These results indicate that the phenotype and molecular basis of the L-strain are similar to those of Parkinson’s syndrome symptoms. In order to establish a link between T. castaneum and PD, we compared the DNA sequences of the L- and S-strains to human genes affecting dopaminergic pathways. The DNA comparison revealed many mutated regions in these genes in the L-strain. We discuss the relationship between dopaminergic pathway genes and PD-like phenotypes across humans, Drosophila, and the red flour beetle.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0923-181111912025Big data-driven target identification by machine learning: DRD2 as a therapeutic target for psoriasis917ENTakashiSakaiDepartment of Dermatology, Faculty of Medicine, Oita UniversityRyusukeSawadaDepartment of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOtohaIchinoseDepartment of Bioscience and Bioinformatics, Faculty of Computer Science and Systems Engineering, Kyushu Institute of TechnologyTakeshiTerabayashiDepartment of Pharmacology, Faculty of Medicine, Oita UniversityYutakaHatanoDepartment of Dermatology, Faculty of Medicine, Oita UniversityYoshihiroYamanishiDepartment of Complex Systems Science, Graduate School of Informatics, Nagoya UniversityToshimasaIshizakiDepartment of Pharmacology, Faculty of Medicine, Oita UniversityBackground: The development of medical treatments has traditionally relied on researchers leveraging scientific knowledge to hypothesize disease mechanisms and identify therapeutic agents. However, the depletion of novel therapeutic targets has become a significant challenge, resulting in stagnation within pharmaceutical research.<br>
Objective: To address the scarcity of therapeutic targets, we developed a machine learning (ML)-based system capable of predicting therapeutic target molecules for diseases. To validate its utility, we applied this system to psoriasis, aiming to identify novel treatment strategies.<br>
Methods: Our approach utilized a large clinical database to calculate reporting odds ratios for all drugs associated with the prevention of diseases of interest. We identified target proteins by analyzing large chemical structure databases to discover proteins commonly associated with preventive drug candidates. Experimental validation was conducted by administering a predicted therapeutic candidate in an imiquimod-induced psoriasis mouse model.<br>
Results: The ML-based predictions identified drugs for Parkinson’s disease as potential preventive candidates for psoriasis. Further analysis highlighted dopamine receptor D2 (DRD2) as a therapeutic target. Administration of a DRD2 agonist alleviated psoriasis symptoms in mice, evidenced by the downregulation of mRNA expression in the IL-17 pathway and reduced serum tumor necrosis factor-α levels.<br>
Conclusion: This study demonstrates the utility of a novel ML-based system for identifying therapeutic targets, as shown by its successful application in uncovering the role of DRD2 in psoriasis. Beyond psoriasis, this system offers significant potential for exploring pathological mechanisms and discovering therapeutic targets across various diseases.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama2572-1143912026Mechanosensitive Ion Channel PIEZO1 Suppresses BMP2-Induced Ossification of the Annulus Fibrosus Cellse70168ENHisakazuShitozawaDepartment of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyoNakamichiDepartment of Orthopaedic Surgery, Okayama University Graduate School Medicine, Dentistry, and Pharmaceutical SciencesAkiYoshidaDepartment of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasatakaUedaDepartment of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTaichiSaitoDepartment of Orthopaedic Surgery, Okayama University HospitalKojiUotaniDepartment of Orthopaedic Surgery, Okayama University HospitalYoshiakiOdaDepartment of Orthopaedic Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityRyoTakatoriDepartment of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazutakaYamashitaDepartment of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshifumiOzakiDepartment of Orthopaedic Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityObjective: Major cause of low-back pain is intervertebral disc degeneration (IVDD), with mechanical stress playing a crucial role in its progression. A mechanosensitive ion channel, PIEZO1, is involved in various musculoskeletal tissues, but its role in the annulus fibrosus (AF) remains unclear. This study aimed to elucidate the function of PIEZO1 in AF cells under mechanical stimulation.<br>
Methods: Primary rat AF cells were subjected to cyclic tensile strain (CTS) at low (2%) and high (12%) strain levels to investigate strain-dependent effects on osteogenic gene expression. We evaluated the effects of Piezo1, Piezo2, and Trpv4 knockdown by RNA interference to identify the upstream mechanotransducer. Furthermore, PIEZO1 was activated using the agonist Yoda1, followed by RNA-sequencing analysis and evaluation of its effects on BMP2-induced osteogenesis in rat AF cells. We also examined the effects of Yoda1 in primary human AF cells.<br>
Results: Low-strain CTS significantly suppressed osteogenic marker expression, which was not observed with high strain. Piezo1 knockdown reversed this suppression, whereas Piezo2 and Trpv4 had no effect. Piezo1 activation by Yoda1 produced similar anti-osteogenic effects in both rat and human AF cells. RNA sequencing revealed the enrichment of ossification and calcineurin signaling pathways in rat cells. Furthermore, Piezo1 activation inhibited BMP2-induced osteogenesis and nuclear translocation of p-Smad1/5/9.<br>
Conclusions: Piezo1 maintains AF cell homeostasis under mechanical stress by suppressing osteogenic changes via calcineurin-mediated inhibition of BMP signaling, which may represent a novel therapeutic target for IVDD.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2041-48891612025TRPV2 in muscle satellite cells is crucial for skeletal muscle remodelling888ENYanzhuChenDepartment of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKimiakiKatanosakaDepartment of Biomedical Sciences, College of Life and Health Sciences, Chubu UniversityMakotoShibuyaDepartment of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYubingDongDepartment of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityLidanZhangLaboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, The University of OsakaMotoiKanagawaDepartment of Cell Biology and Molecular Medicine, Ehime University Graduate School of MedicineSo-ichiroFukadaLaboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, The University of OsakaKeijiNaruseDepartment of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYukiKatanosakaDepartment of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversitySkeletal muscle remodelling relies on muscle stem cells (MuSCs) for regeneration after injury and hypertrophy in response to mechanical loading. However, the mechanisms that trigger MuSC activation and proliferation remain unclear. Transient receptor potential vanilloid 2 (TRPV2) ion channels respond to insulin-like growth factor-1 and mechanical stimuli to regulate the biological characteristics of various cells. Using a temporally inducible MuSC-specific conditional knockout (cKO) mouse, we show that TRPV2 regulates MuSC function and is essential for muscle remodelling. In cultured myofibre, MuSCs express TRPV2 and exhibit Ca2+ responses to the TRPV2 agonists 2-aminoethoxydiphenyl borate and probenecid, which are abolished upon TRPV2 deletion. TRPV2-deficient MuSCs exhibit reduced paired box 7 (Pax7) expression and impaired proliferation, suggesting TRPV2 is a factor that regulates the early stage of MuSC function. Myotube formation in MuSCs was enhanced by overexpression of TRPV2 and suppressed by TRPV2 deficiency, suggesting that TRPV2 is a factor that promotes myogenesis. Muscle-administered cardiotoxin promoted muscle regeneration and resulted in the appearance of numerous Pax7-positive MuSCs between myofibres. MuSC-specific TRPV2 cKO mice exhibit substantially impaired muscle regeneration after cardiotoxin-induced injury, drastically reducing Pax7-positive MuSCs between myofibres. In floxed mice, mechanical loading via synergist ablation induces hypertrophy and greatly increases the number of myonuclei per myofibre. In contrast, MuSC-specific TRPV2 cKO mice show no changes in myofibre thickness or nuclear number, either at baseline or after mechanical loading. Mechanical loading of floxed mice increased TRPV2+/Pax7+ double-positive MuSCs, but MuSC-specific TRPV2 cKO mice showed no change. Additionally, MuSCs exhibit Ca2+ responses to hypo-osmotic stimuli, which are suppressed by TRPV2 inhibitors and TRPV2 deletion, suggesting that MuSCs exhibit TRPV2-dependent mechanical responses. These results establish TRPV2 as a critical regulator of MuSC-mediated muscle remodelling, an important finding that may lead to therapeutic strategies for muscle repair and adaptation.No potential conflict of interest relevant to this article was reported.eLife Sciences Publications, LtdActa Medica Okayama2050-084X132025Stimulatory and inhibitory G-protein signaling relays drive cAMP accumulation for timely metamorphosis in the chordate CionaRP99825ENAkikoHozumiShimoda Marine Research Center, University of TsukubaNozomu MTotsukaDepartment of Biosciences and Informatics, Faculty of Science and Technology, Keio UniversityArataOnoderaShimoda Marine Research Center, University of TsukubaYanbinWangShimoda Marine Research Center, University of TsukubaMayukoHamadaUshimado Marine Institute, Okayama UniversityAkiraShiraishiBioorganic Research Institute, Suntory Foundation for Life SciencesHonooSatakeBioorganic Research Institute, Suntory Foundation for Life SciencesTakeoHorieLaboratory for Single-cell Neurobiology, Graduate School of Frontier Biosciences, Osaka UniversityKohjiHottaDepartment of Biosciences and Informatics, Faculty of Science and Technology, Keio UniversityYasunoriSasakuraShimoda Marine Research Center, University of TsukubaLarvae of the ascidian Ciona initiate metamorphosis tens of minutes after adhesion to a substratum via their adhesive organ. The gap between adhesion and metamorphosis initiation is suggested to ensure the rigidity of adhesion, allowing Ciona to maintain settlement after losing locomotive activity through metamorphosis. The mechanism producing the gap is unknown. Here, by combining gene functional analyses, pharmacological analyses, and live imaging, we propose that the gap represents the time required for sufficient cyclic adenosine monophosphate (cAMP) accumulation to trigger metamorphosis. Not only the Gs pathway but also the Gi and Gq pathways are involved in the initiation of metamorphosis in the downstream signaling cascade of the neurotransmitter GABA, the known initiator of Ciona metamorphosis. The mutual crosstalk of stimulatory and inhibitory G-proteins functions as the accelerator and brake for cAMP production, ensuring the faithful initiation of metamorphosis at an appropriate time and in the right situation.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama1347-90322026Clinical and Genetic Landscape of Glioblastoma, IDH-Wildtype With FGFR Gene Family AlterationsENYasuhitoKegoyaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshihiroOtaniDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesRyoMizutaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesRyosukeIkemachiDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMakoKamiuraDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesJojiIshidaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShinichiToyookaCenter for Comprehensive Genomic Medicine, Okayama University HospitalDaisukeEnnishiCenter for Comprehensive Genomic Medicine, Okayama University HospitalShutaTomidaCenter for Comprehensive Genomic Medicine, Okayama University HospitalShotaTanakaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesGlioblastoma, isocitrate dehydrogenase wildtype (GBM, IDH-wt), is a highly aggressive brain tumor with a poor prognosis. Alterations in the fibroblast growth factor receptor (FGFR) gene family—such as FGFR::TACC fusions and FGFR1 mutations—have emerged as potential therapeutic targets; however, their clinical and genetic features in GBM, IDH-wt remain unclear. We analyzed 1076 GBM, IDH-wt cases using comprehensive genomic profiling data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database in Japan. FGFR alterations were detected in 8.0% of patients, including FGFR::TACC fusions (3.3%) and FGFR1 mutations (2.9%). The FGFR::TACC fusion-positive group was older at diagnosis and showed higher frequencies of TERT promoter mutation and MDM2 amplification, and lower frequencies of EGFR amplification and TP53 mutation, compared with the fusion-negative group. The FGFR1 mutation-positive group was enriched for ATRX, NF1, and PIK3CA mutations and had significantly fewer TERT promoter and PTEN mutations, compared with the mutation-negative group. No significant differences in overall survival were observed, although both groups tended to have longer median overall survival compared with their respective negative groups. This study represents the largest genomic cohort to date of FGFR alterations in GBM, IDH-wt. FGFR::TACC fusion-positive and FGFR1 mutation-positive GBMs exhibited distinct genetic profiles, highlighting the clinical relevance of molecular subclassification and providing insight for future therapeutic strategies.No potential conflict of interest relevant to this article was reported.岡山大学大学院教育学研究科Acta Medica Okayama1883-24231912026自己変容を通してみたマインドワンダリングの創造性について ― 自己嫌悪場面での４つの内言に着目した検討 ―3145ENTazukoAOKIFaculty of Education, Okayama UniversityMakotoHAGIWARAa public employeeKazuhiroYASUNAGAFaculty of Education, Okayama University10.18926/bgeou/70194 マインドワンダリング(以下MW)は心が自己内の複数の領域をさまようことで, 新たな気づきや発想
が生まれる土壌になるとされる。本稿では，この創造性を検討するため，水間(2003)を参考に，自己嫌悪
場面で生起する4 つの反応についての研究モデルを用いてこの創造性を検討した。その際，MW とその
他の類似の内省を区別するため，自己嫌悪場面で生起する内言として自己注目(省察・反芻), 自己への没
入(MW・空想)の4 つを想定した。またその内言が自己の成長にとって意味のある内言か否かを判断する
指標として本来感を用いた。分析の結果, 本来感高群において, MW による集中力の欠如が人の思考を
多領域にさまよわせ, 内的な個性の創造と内的な個人の成長を促すことが示された。また低群において
省察は自分らしさを求め変容を目指す意識が促進されることが示された。他方, 反芻と空想はいずれの
反応様式にも関わっていないことがわかった。No potential conflict of interest relevant to this article was reported.The Carbon Society of JapanActa Medica Okayama2436-5831432025Synthesis and applications of porous carbonaceous materials with inherited molecular structural features from the precursor molecules179187ENKokiChidaInstitute of Multidisciplinary Research for Advanced Materials, Tohoku UniversityTakeharuYoshiInstitute of Multidisciplinary Research for Advanced Materials, Tohoku UniversityYutaNishinaResearch Institute for Interdisciplinary Science, Okayama UniversityKazuhideKamiyaResearch Center for Solar Energy Chemistry, Graduate School of Engineering Science, The University of OsakaRyotaSakamotoDepartment of Chemistry, Graduate School of Science, Tohoku UniversityFumitoTaniInstitute for Materials Chemistry and Engineering, Kyushu UniversityTomokiOgoshiDepartment of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto UniversityHirotomoNishiharaInstitute of Multidisciplinary Research for Advanced Materials, Tohoku UniversityThe carbonization of organic crystalline materials, such as metal organic frameworks and covalent organic frameworks, has emerged as a promising approach for producing functional porous carbonaceous materials. However, both the chemically defined long-term ordered structures and the local chemical structures derived from these precursor materials are generally lost, resulting in amorphous carbons. As a result, controlling the molecular-level structure of nanoporous carbons remains a significant challenge. We report a new bottom-up synthesis approach for porous carbons with a molecular-level design, involving the carbonization of well-designed precursor molecules by thermal polymerization. Among the resulting carbons, ordered carbonaceous frameworks, which contain a high-density of regularly aligned single-atomic metal species, have been identified as promising platforms for single-atom catalysts. This approach also enables the synthesis of various three-dimensional porous carbons that reflect the structural features of their precursor molecules. Recent progress in the synthesis and applications of porous carbons derived from molecular precursors is summarized, highlighting their potential for the development of functional materials.No potential conflict of interest relevant to this article was reported.大阪府保険医協会Acta Medica Okayama547132026『光が見える』人工網膜の可能性 ― 有機色素分子を部材とする世界初の医療機器「光電変換色素薄膜型人工網膜OUReP」1321ENToshihikoMatsuoTetsuyaUchidaHiroshiIshikane 網膜色素変性や加齢黄斑変性では、光を細胞膜電位に変換する網膜視細胞が死んでいるが、視神経として脳に連絡する神経節細胞は生き残っている。人工網膜は視細胞を代替する人工物で、光を受け電流を出力する電極アレイ型が主流であるが、電流は拡散するため解像度向上が難しい。そこで人工網膜の解像度向上を目指して、光を電位差に変換する光電変換色素分子を絶縁体のポリエチレン薄膜表面に共有結合した光電変換色素薄膜型の人工網膜OURePを開発してきた。この人工網膜OURePは光受容と電位出力の一体型で外部起電力は不要、手術では薄膜を鋏で切って眼内に植込む大きさを自由に選べる。使い捨てインジェクタを使って薄膜を丸め眼球の網膜下に硝子体手術で植込み、網膜下に植込んだ人工網膜OURePは光を受けて電位差を出力し隣接する網膜組織の神経細胞の活動電位を誘発する。クリーンルームで製造品質管理を行い、安全性と有効性を証明して、医師主導治験を準備している。今後、日本の国民皆保険が維持できるよう比較安価な適正価格の人工網膜治療を提供したい。No potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama1999-49231812026Streamlined Radiosynthesis of [18F]Fluproxadine (AF78): An Unprotected Guanidine Precursor Enables Efficient One-Step, Automation-Ready Labeling for Clinical Use123ENXinyuChenNuclear Medicine, Faculty of Medicine, University of AugsburgKaitoOhtaFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHiroyukiKimuraAgency for Health, Safety and Environment, Kyoto UniversityYusukeYagiFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTakanoriSasakiFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNaokoNoseFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMasaruAkehiFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTomohikoYamaneDepartment of Molecular Imaging Research, Kobe City Medical Center General HospitalRudolf A.WernerDepartment of Nuclear Medicine, LMU Hospital, and German Cancer Consortium (DKTK), Partner Site Munich, Ludwig-Maximilians-University of MunichTakahiroHiguchiFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityBackground/Objectives: [18F]Fluproxadine (formerly [18F]AF78) is a PET radiotracer targeting the norepinephrine transporter (NET) with potential applications in cardiac, neurological, and oncological imaging. Its guanidine moiety, while essential for NET binding, presents major radiosynthetic challenges due to high basicity and the harsh deprotection conditions required for protected precursors. Previous methods relied on multistep procedures, strong acids, and complex purification, limiting clinical translation. This study aimed to develop a practical one-step radiosynthesis suitable for routine and automated production. Methods: A direct SN2-type nucleophilic [18F]fluorination was performed using an unprotected guanidine precursor to eliminate deprotection steps. Reaction parameters, including the base system, solvent composition, precursor concentration, and temperature, were optimized under conventional and microwave heating. Radiochemical conversion (RCC) and operational robustness were evaluated, and purification strategies were assessed for automation compatibility. Results: Direct [18F]fluorination using the unprotected precursor reduced the total synthesis time to 60–70 min. Optimal conditions employed a tert-butanol/acetonitrile (4:1) solvent system with K2CO3/Kryptofix222, affording RCC up to 33% under conventional heating. Microwave irradiation further improved efficiency, achieving RCC of up to 64% within 1.5 min at 140 °C. The method showed broad tolerance to variations in the base molar ratio and precursor concentration and enabled isocratic HPLC purification. Conclusions: This one-step radiosynthesis overcomes longstanding challenges in [18F]fluproxadine production by eliminating harsh deprotection and enabling high-yield, automation-ready synthesis, thereby improving clinical feasibility.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2168-81841752025Pseudoachalasia Due to Malignant Pleural Mesothelioma Involving the Esophaguse84161ENManamiHondaDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMasayaIwamuroDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazuyaMiyamotoDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTakehiroTanakaDepartment of Pathology, Okayama University HospitalMotoyukiOtsukaDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesWe report a rare case of pseudoachalasia secondary to malignant pleural mesothelioma involving the esophagus. A 66-year-old man presented with progressive dysphagia, weight loss, and postprandial hiccups. Endoscopic examination showed esophageal dilation with luminal narrowing at the esophagogastric junction, but no mucosal abnormalities. Computed tomography revealed an irregular-shaped mass extending from the peri-esophagogastric junction to the retroperitoneum, accompanied by pleural effusion, right-sided hydronephrosis, and multiple hepatic lesions. Endoscopic ultrasound-guided fine-needle aspiration from the mass lesion through the esophageal lumen revealed epithelioid malignant mesothelioma. This case highlights the importance of considering malignant mesothelioma in the differential diagnosis of pseudoachalasia, particularly when imaging reveals extrinsic esophageal compression without mucosal lesions.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama2950-2217322025Erythromelalgia presenting with posterior reversible encephalopathy syndrome: A pediatric case report100078ENKengoSuzukiDepartment of Pediatrics, Okayama University HospitalKazuhiroUdaDepartment of Pediatrics, Okayama University HospitalMitsuruTsugeDepartment of Pediatric Acute Diseases, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKyosukeArakawaDepartment of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKenjiShigeharaDepartment of Pediatrics, Okayama University HospitalTakafumiObaraDepartment of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKoseiHasegawaDepartment of Pediatrics, Okayama University HospitalHirokazuTsukaharaDepartment of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground: Erythromelalgia is a rare disorder characterized by erythema, warmth, and burning pain in the extremities. We report a pediatric case of erythromelalgia in a patient who developed posterior reversible encephalopathy syndrome (PRES), without any cutaneous signs.<br>
Case presentation: A previously healthy 12-year-old girl presented to our pediatric clinic with burning extremity pain that had persisted for 6 weeks. The patient was treated with analgesics; however, the pain was refractory to these agents. Seven days after the first visit, she developed afebrile seizures and was transferred to our hospital. Her initial blood pressure was 139/105 mmHg (+2.0 SD), and brain magnetic resonance imaging revealed high intensity areas in the bilateral parietal and occipital lobes, leading to a diagnosis of PRES. Her blood pressure was difficult to control with anti-hypertensive agents. Burning pain in her extremities was relieved by cooling and worsened by warming. Although erythema was not observed in her hands or legs, erythromelalgia was suspected based on the characteristic nature of her pain. Intravenous lidocaine was administered for diagnosis, which was dramatically effective. After initiating mexiletine, the burning pain in her extremities disappeared, and hypertension improved. A final diagnosis of erythromelalgia with PRES was made.<br>
Conclusion: A history of temperature-dependent pain relief and deterioration are important indicators of disease diagnosis, even if patients indicate a lack of erythema or warmth. Physicians should be aware that persistent pain due to erythromelalgia can lead to refractory hypertension and development of PRES.No potential conflict of interest relevant to this article was reported.岡山大学農学部Acta Medica Okayama2186-77551152026公表学術論文等リスト 20251326ENNo potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama1999-48931922026A Slide Annotation System with Multimodal Analysis for Video Presentation Review110ENAmma LiesvarastrantaHazDepartment of Information and Communication Systems, Okayama UniversityKomang CandraBrataDepartment of Information and Communication Systems, Okayama UniversityNobuoFunabikiDepartment of Information and Communication Systems, Okayama UniversityHtoo Htoo SandiKyawDepartment of Information and Communication Systems, Okayama UniversityEvianita DewiFajriantiHuman Centric Multimedia Research Laboratory, Department of Informatic and Computer Engineering, Politeknik Elektronika Negeri SurabayaSritrustaSukaridhotoHuman Centric Multimedia Research Laboratory, Department of Informatic and Computer Engineering, Politeknik Elektronika Negeri SurabayaWith the rapid growth of online presentations, there has been an increasing need for efficient review of recorded materials. In typical presentations, speakers verbally elaborate on each slide, providing details not captured in the slides themselves. Automatically extracting and embedding these verbal explanations at their corresponding slide locations can greatly enhance the review process for audiences. This paper presents a Slide Annotation System that employs a robust hybrid two-stage detector to identify slide boundaries, extracts slide text through Optical Character Recognition (OCR), transcribes narration, and employs a multimodal Large Language Model (LLM) to generate concise, context-aware annotations that are added to their corresponding slide locations. For evaluations, the technical performance was validated on five recorded presentations, while the user experience was assessed by 37 participants. The results showed that the system achieved a macro-average 𝐹1 score of 0.879 (𝑆𝐷=0.024, 95% 𝐶𝐼[0.849,0.909]) for slide segmentation and 90.0% accuracy (95% 𝐶𝐼[74.4%,96.5%]) for annotation alignment. Subjective evaluations revealed high annotation validity and usefulness as rated by presenters, and a high System Usability Scale (SUS) score of 80.5 (𝑆𝐷=6.7, 95% 𝐶𝐼[78.3,82.7]). Qualitative feedback further confirmed that the system effectively streamlined the review process, enabling users to locate key information more efficiently than standard video playback. These findings demonstrate the strong potential of the proposed system as an effective automated annotation system.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X8012026Time Course of the Development and Loss of Delta-9-tetrahydrocannabinol Tolerance: Effects on Hypothermia and Spontaneous Locomotor Activity in Mice4754ENYukiomiEguchiDepartment of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka UniversitySoichiroUshioDepartment of Emergency and Disaster Medical Pharmacy, Faculty of Pharmaceutical Sciences, Fukuoka UniversityKeiichiIrieDepartment of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka UniversityYutaYamashitaDepartment of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka UniversityMiyuEguchiDepartment of Emergency and Disaster Medical Pharmacy, Faculty of Pharmaceutical Sciences, Fukuoka UniversityTakafumiNakanoDepartment of Oncology and Infectious Disease Pharmacy, Faculty of Pharmaceutical Sciences, Fukuoka UniversityKenichiMishimaDepartment of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka UniversityOriginal Article10.18926/AMO/70072Deregulation of cannabis use is gradually expanding in Europe and the United States. However, the biological processes driving tolerance to delta-9-tetrahydrocannabinol (Δ9-THC), the main psychoactive component of cannabis, remain unclear. Thus, this study aimed to investigate the mechanisms and time course of tolerance development and loss to Δ9-THC in mice. Male ICR mice (7 weeks old) were administered Δ9-THC once daily for 3 days and then divided into three groups according to the washout period (3-, 10-, and 17-day washout groups). After each washout, changes in body temperature and locomotor activity were measured following re-exposure to Δ9-THC. Furthermore, the mRNA expression levels of CB1 and CB2 receptors in the brain were evaluated using real-time PCR. On day 1, significant hypothermia and reduced spontaneous locomotor activity were observed in the Δ9-THC-treated mice compared with the vehicle-treated mice. Tolerance to the hypothermic and locomotor-suppressing effects of Δ9-THC developed on days 2 and 3, respectively, and dissipated after 3 and 11 days of washout, respectively. These differences in the rates of tolerance development and recovery may reflect distinct underlying mechanisms. No significant changes in receptor mRNA expression were observed. These findings highlight the complexity of Δ9-THC tolerance and its potential implications for long-term cannabis use.No potential conflict of interest relevant to this article was reported.眼科臨床紀要会Acta Medica Okayama1882-517619022026斜視の遺伝子研究113125ENToshihikoMatsuoGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University共同性斜視は遺伝要因と環境要因からなる多因子疾患で、内斜視と外斜視に大別される。遺伝要因は家族歴、一卵性双生児の表現型一致率から推定され、環境要因には妊娠・分娩時の低酸素状態がある。一方、遺伝要因がある非共同性（麻痺性）斜視として上斜筋腱低形成を呈する特発性上斜筋麻痺がある。遺伝統計学の連鎖解析を使って、内斜視と外斜視の小家系群で4番染色体MGST2を疾患感受性遺伝子候補と同定し、MGST2ノックアウトマウスを作成した。小動物用MRIで解析すると、そのホモ接合体では野生型と比べて眼球形状が有意に横長で体積が大きいことを見出した。次いで遺伝統計学別法の全ゲノム関連解析を内斜視、外斜視、特発性上斜筋麻痺を対象として行った。Infinium Asian Screening Array-24 v1.0でSNPを決めた内斜視253検体、外斜視356検体、上斜筋麻痺102検体を疾患群とした。対照集団としては、バイオバンクジャパン (BBJ) の疾患群とは違うアレイ(OmniExpress)でSNPを決めた182,476検体「BBJ (180K)」、疾患群と同じアレイでSNPを決めたBBJの53409検体「BBJ (ASA)」および長浜コホート3570検体を使った。３対照集団との比較で共通して検出された遺伝子は、上斜筋麻痺群で神経細胞移動に関与するDAB1であった。最も大きい対照集団「BBJ (180K)」との比較では内斜視、外斜視、上斜筋麻痺を含む疾患群全体で眼発生に関与するRARB (retinoic acid receptor β) が検出された。斜視関連遺伝子は眼球形態に関与する可能性がある。特発性上斜筋麻痺は共同性斜視とは独立した疾患と理解されるが、共通の遺伝基盤もあるかもしれない。No potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama1873-149X3312026Bridging the Gap Between Static Histology and Dynamic Organ-on-a-Chip Models10ENZheyiWangDepartment of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKeijiNaruseDepartment of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKenTakahashiDepartment of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityFor more than a century, pathology has served as a cornerstone of modern medicine, relying primarily on static microscopic assessment of tissue morphology—such as H&E staining—which remains the “gold standard” for disease diagnosis. However, this conventional paradigm provides only a snapshot of disease states and often fails to capture their dynamic evolution and complex functional mechanisms. Moreover, animal models are constrained by marked interspecies differences, creating a persistent gap in translational research. To overcome these limitations, we propose the concept of New Pathophysiology, a research framework that transcends purely morphological descriptions and aims to resolve functional dynamics in real time. This approach integrates Organ-on-a-Chip (OOC) technology, multi-omics analyses, and artificial intelligence to reconstruct the entire course of disease initiation and to enable personalized medicine. In this review, we first outline the foundations and limitations of traditional pathology and animal models. We then systematically summarize more than one hundred existing OOC disease models across multiple organs—including the kidney, liver, and brain. Finally, we elaborate on how OOC technologies are reshaping the study of key pathological processes such as inflammation, metabolic dysregulation, and fibrosis by converting them into dynamic, mechanistic disease models, and we propose future perspectives in the field. This review adopts a relatively uncommon classification strategy based on pathological mechanisms (mechanism-based), rather than organ-based categorization, allowing readers to recognize shared principles underlying different diseases. Moreover, the focus of this work is not on emphasizing iteration or replacement of existing approaches, but on preserving past achievements from a historical perspective, with an emphasis on overcoming current limitations and enabling new advances.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0753-33221932025Deciphering the structural impact of norepinephrine analog radiopharmaceuticals on organic cation transporter affinity118724ENSaskiaMühligDepartment of Nuclear Medicine and Comprehensive Heart Failure Center, University Hospital WürzburgXinyuChenNuclear Medicine, Faculty of Medicine, University of AugsburgAnnaTutovPharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of WürzburgNaokoNoseFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityConstantinLapaNuclear Medicine, Faculty of Medicine, University of AugsburgRudolf A.WernerDepartment of Nuclear Medicine, LMU Hospital, Ludwig-Maximilians-University of MunichMichaelDeckerPharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of WürzburgTakahiroHiguchiFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityPurpose: Previous studies have investigated the kinetics and affinities of norepinephrine transporter (NET)-targeting radiotracers, including [123I]MIBG, but the role of organic cation transporters (OCTs) remains unclear. This study aimed to evaluate how the structural design of selective NET-targeting tracers affects OCT-mediated non-specific uptake, identifying factors influencing both NET and OCT affinity.<br>
Methods: Cellular uptake assays were conducted using SK-N-SH cells expressing human NET, and human OCT1-, OCT2-, and OCT3-expressing cells with [3H]norepinephrine, [3H]MPP+, and [131I]MIBG. Competitive uptake assays used non-radioactive reference compounds for several NET-targeting radiopharmaceuticals (MIBG, HED, EPI, PHEN, LMI1195, and PHPG), along with a new PET radiotracer [18F]AF78, and its two analogs with meta-iodide [18F]AF78(I) or hydroxyl group [18F]AF78(OH). Dynamic PET imaging in non-human primates assessed the in vivo uptake of [18F]AF78 after NET inhibition with desipramine.<br>
Results: Monoamine-based tracers (EPI, PHEN, HED) exhibited high NET selectivity with minimal OCTs interaction, while guanidine-containing tracers (e.g., MIBG, LMI1195) displayed substantial OCTs affinity. Lower lipophilicity in guanidine-containing compounds, influenced by substitutions on the benzene ring (e.g., PHPG, AF78), correlated with weaker OCT interactions. PET imaging confirmed that cardiac uptake of [18F]AF78 is sensitive to desipramine pretreatment (***P < 0.0005), indicating its NET-specificity, while persistent hepatic retention suggests an OCT-mediated transport mechanism.<br>
Conclusion: This study highlights the critical influence of the compounds’ chemical structure on NET and OCT affinities. Structural modifications that reduce OCT-mediated uptake while maintaining high NET affinity could improve the specificity and theranostic potential of NET-targeting ligands. These findings provide insights for designing next-generation radiotracers with enhanced selectivity and clinical utility.No potential conflict of interest relevant to this article was reported.American Chemical Society (ACS)Acta Medica Okayama0006-296064202025Characterization of Autonomous and Ca2+/Calmodulin-Dependent Activities of CaMKK Isoforms In Vitro and in Mouse Tissues43094317ENSatomiOhtsukaApplied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityYerunChenApplied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityMasakiMagariApplied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityTeruhikoIshikawaDepartment of Science Education, Graduate School of Education, Okayama UniversityHiroyukiSakagamiDepartment of Anatomy, Kitasato University School of MedicineFutoshiSuizuClinical Examination Department, Kagawa Prefectural University of Health SciencesHiroshiTokumitsuApplied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityCa2+/CaM-dependent protein kinase kinase (CaMKK) phosphorylates and activates downstream kinases, including CaMKI, CaMKIV, PKB, and AMPK, regulating various cellular functions such as neuronal morphogenesis, metabolic control, and pathophysiological pathways, such as cancer progression. CaMKKα/1 is tightly regulated by an autoinhibitory mechanism. CaMKKβ/2 activity is highly Ca2+/CaM-independent (autonomous activity) in vitro and Ca2+/CaM-dependent in cultured cells. Whether these two activity states of CaMKKβ/2 exist in vivo and the detailed regulatory mechanisms for the transition of both activity states remain unclear due to the difficulty in distinguishing the two activity states. In this study, we detected Ca2+-dependent and autonomous CaMKK activity in HeLa cells and successfully separated both activity states of CaMKKβ/2 in mouse brain and testis extracts using a recently developed CaMKK inhibitor (TIM-063)-coupled sepharose, which binds to the catalytic domain in the active state but not in the autoinhibited state. Furthermore, lambda protein phosphatase treatment converted the Ca2+/CaM-dependent form to the autonomous form of CaMKKβ/2, which was not affected by Ala mutation of Ser128, Ser132, and Ser136. The two activity forms of CaMKKβ/2 had equivalent Ca2+/CaM-binding ability. The findings demonstrate the presence of autonomous and Ca2+/CaM-dependent forms of CaMKKβ/2 independently in mouse tissues and cultured cells. The transition of these states of CaMKKβ/2 may be dynamically regulated by the phosphorylation/dephosphorylation of serine residues in the N-terminal regulatory domain.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0312-596364122025Evaluation of Fentanyl-Emerged Adverse Events and Pharmacokinetics in Neonates: A Physiologically Based Pharmacokinetic Modeling Approach18111825ENWalaa Yousef BassyouniMahdyDepartment of Pharmacy, Kobe University HospitalKazuhiroYamamotoDepartment of Integrated Clinical and Basic Pharmaceutical Sciences, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityRisaJojiDepartment of Pharmacy, Kobe University HospitalMariHashimotoDepartment of Pharmacy, Kobe University HospitalRukaNakasoneDepartment of Pediatrics, Graduate School of Medicine, Kobe UniversityKazumichiFujiokaDepartment of Pediatrics, Graduate School of Medicine, Kobe UniversityKotaroItoharaDepartment of Pharmacy, Kobe University HospitalYumiKitahiroDepartment of Pharmacy, Kobe University HospitalTomohiroOmuraDepartment of Pharmacy, Kobe University HospitalIkukoYanoDepartment of Pharmacy, Kobe University HospitalBackground Despite its common use for analgesia in neonatal intensive care units, the optimal dosing and safety profile of fentanyl, particularly regarding suspected fentanyl-emerged adverse events (FEAEs), such as hypotension, desaturation, and oliguria, are not well-defined.<br>
Objective This study aimed to develop an optimal therapeutic monitoring and dosing strategy for fentanyl for neonates. A physiologically based pharmacokinetic (PBPK) model for predicting fentanyl pharmacokinetics across various populations, including preterm and term neonates, was developed, and the relationship between predicted fentanyl exposure and FEAE incidence in neonates was assessed.<br>
Methods A PBPK model was developed and validated against the observed values in the literature. The model’s predictive accuracy for fentanyl pharmacokinetics and association with FEAE incidence in an external retrospective cohort of Japanese neonates was evaluated using the predicted concentrations and pharmacokinetic parameters estimated by PBPK simulation.<br>
Results The PBPK model exhibited reasonable predictive performance for serum fentanyl concentrations in actual neonatal patients (mean error: 9.27% [standard error: 5.06%], root mean squared error: 54.7%). The incidence of any FEAE, particularly oxygen desaturation, was associated with the fentanyl concentration-to-dose ratio, but not with some exposure parameters, such as the area under the curve and maximum concentration. The recommended reduced infusion rate allowed serum fentanyl concentrations to fall within the ranges established by the reported values and our data.<br>
Conclusions Our PBPK model and proposed dosing strategy may contribute to safer and more effective fentanyl use in neonates.No potential conflict of interest relevant to this article was reported.International Institute of Anticancer ResearchActa Medica Okayama0250-70054612025Near-infrared Photoimmunotherapy Targeting High-risk Human Neuroblastoma Cells Expressing GD22538ENHIROSHINOUSODepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHIROSHITAZAWADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTERUTAKATANIMOTODepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMORIMICHITANIDepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHINAKOWATANABEDepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTAKANORIOYAMADepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKAZUHIRONOMADepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSHUNSUKEKAGAWADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHISATAKAKOBAYASHIMolecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of HealthTAKUONODADepartment of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSHINJIKURODADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTOSHIYOSHIFUJIWARADepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground/Aim: Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system in infancy. Despite advances in treatment, the prognosis remains poor for high-risk NB patients. Although immunotherapy using anti-GD2 antibodies is available for high-risk NB, the therapeutic efficacy is insufficient. Near-infrared photoimmunotherapy (NIR-PIT) is an antitumor strategy that induces tumor-specific cytotoxicity by combining an antibody-photoabsorber conjugate (APC) with NIR light irradiation. In this study, we investigated the therapeutic efficacy of GD2-targeted NIR-PIT against human NB cells.<br>
Materials and Methods: GD2 expression was analyzed on the surface of high-risk human NB cells (CHP-134, LA-N-5, IMR-32) and non-high-risk human NB cells (SK-N-SH) by flow cytometry. The APC was synthesized by incubating anti-GD2 antibody and IR700. The cytotoxic effect of GD2-targeted NIR-PIT was evaluated using the XTT assay. The distribution of dead cells within tumor spheres was evaluated using a live/dead assay. The in vivo antitumor effect of GD2-targeted NIR-PIT was assessed using a subcutaneous human NB xenograft tumor model.<br>
Results: GD2 protein was expressed on the surface of CHP-134, LA-N-5, and IMR-32 cells but not SK-N-SH cells. GD2-targeted NIR-PIT significantly suppressed the viability of GD2-positive NB cells but not GD2-negative NB cells, compared to the control and monotherapy groups. GD2-targeted NIR-PIT significantly reduced the volume of GD2-positive CHP-134 tumor spheres by inducing the accumulation of dead cells. Subcutaneous CHP-134 xenograft tumor models demonstrated that GD2-targeted NIR-PIT significantly inhibited tumor growth compared with the control and monotherapy groups.<br>
Conclusion: GD2-targeted NIR-PIT is a promising antitumor strategy for treating high-risk NB tumors expressing GD2.No potential conflict of interest relevant to this article was reported.eLife Sciences Publications, LtdActa Medica Okayama2050-084X132025Redistribution of fragmented mitochondria ensures symmetric organelle partitioning and faithful chromosome segregation in mitotic mouse zygotesRP99936ENHarunaGekkoDepartment of Animal Science, Graduate School of Environment and Life Science, Okayama UniversityRuriNomuraDepartment of Animal Science, Graduate School of Environment and Life Science, Okayama UniversityDaikiKuzuharaReproductive Centre, Mio Fertility ClinicMasatoKaneyasuDepartment of Animal Science, Graduate School of Environment and Life Science, Okayama UniversityGenpeiKosekiDepartment of Animal Science, Graduate School of Environment and Life Science, Okayama UniversityDeepakAdhikariDevelopment and Stem Cell Program and Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash UniversityYasuyukiMioReproductive Centre, Mio Fertility ClinicJohnCarrollDevelopment and Stem Cell Program and Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash UniversityTomohiroKonoDepartment of Bioscience, Tokyo University of AgricultureHiroakiFunahashiDepartment of Animal Science, Graduate School of Environment and Life Science, Okayama UniversityTakuyaWakaiDepartment of Animal Science, Graduate School of Environment and Life Science, Okayama UniversityIn cleavage-stage embryos, preexisting organelles partition evenly into daughter blastomeres without significant cell growth after symmetric cell division. The presence of mitochondrial DNA within mitochondria and its restricted replication during preimplantation development makes their inheritance particularly important. While chromosomes are precisely segregated by the mitotic spindle, the mechanisms controlling mitochondrial partitioning remain poorly understood. In this study, we investigate the mechanism by which Dynamin-related protein 1 (Drp1) controls the mitochondrial redistribution and partitioning during embryonic cleavage. Depletion of Drp1 in mouse zygotes causes marked mitochondrial aggregation, and the majority of embryos arrest at the 2 cell stage. Clumped mitochondria are located in the center of mitotic Drp1-depleted zygotes with less uniform distribution, thereby preventing their symmetric partitioning. Asymmetric mitochondrial inheritance is accompanied by functionally inequivalent blastomeres with biased ATP and endoplasmic reticulum Ca2+ levels. We also find that marked mitochondrial centration in Drp1-depleted zygotes prevents the assembly of parental chromosomes, resulting in chromosome segregation defects and binucleation. Thus, mitochondrial fragmentation mediated by Drp1 ensures proper organelle positioning and partitioning into functional daughters during the first embryonic cleavage.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2399-3642812025A genome-wide association study identifies the GPM6A locus associated with age at onset in ALS1720ENRyoichiNakamuraDepartment of Neurology, Aichi Medical University School of MedicineGenkiTohnaiDivision of ALS Research, Aichi Medical University School of MedicineNaokiAtsutaDepartment of Neurology, Aichi Medical University School of MedicineYumiMatsudaPublic Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of MedicineSatoruMorimotoKeio University Regenerative Medicine Research Center, KawasakiDaisukeItoDepartment of Neurology, Nagoya University Graduate School of MedicineMasahisaKatsunoDepartment of Neurology, Nagoya University Graduate School of MedicineYuishinIzumiDepartment of Neurology, Tokushima University Graduate School of Biomedical SciencesMitsuyaMoritaDivision of Neurology, Department of Internal Medicine, Jichi Medical UniversityIkukoIwataDepartment of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityIchiroYabeDepartment of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityTomokoNakazatoDepartment of Neurology, Juntendo University School of MedicineNobutakaHattoriDepartment of Neurology, Juntendo University School of MedicineTakehisaHirayamaDepartment of Neurology, Toho University Faculty of MedicineOsamuKanoDepartment of Neurology, Toho University Faculty of MedicineAsakoTamuraDepartment of Neurology, Mie University Graduate School of MedicineNaokiSuzukiDepartment of Neurology, Tohoku University Graduate School of MedicineMasashiAokiDepartment of Neurology, Tohoku University Graduate School of MedicineKazumotoShibuyaDepartment of Neurology, Graduate School of Medicine, Chiba UniversitySatoshiKuwabaraDepartment of Neurology, Graduate School of Medicine, Chiba UniversityMasayaOdaDepartment of Neurology, Vihara Hananosato HospitalRinaHashimotoDepartment of Neurology, NHO Higashinagoya National HospitalIkukoAibaDepartment of Neurology, NHO Higashinagoya National HospitalTomohikoIshiharaDepartment of Neurology, Brain Research Institute, Niigata UniversityOsamuOnoderaDepartment of Neurology, Brain Research Institute, Niigata UniversityToruYamashitaDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyukiIshiuraDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKotaBokudaDepartment of Neurology, Tokyo Metropolitan Neurological HospitalToshioShimizuDepartment of Neurology, Tokyo Metropolitan Neurological HospitalYoshioIkedaDepartment of Neurology, Gunma University Graduate School of MedicineKazukoHasegawaDivision of Neurology, NHO Sagamihara National HospitalFumiakiTanakaDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineTakanoriYokotaDepartment of Neurology and Neurological Science, NucleoTIDE and PepTIDE Drug Discovery Center (TIDE), Institute of Science TokyoKazuakiKanaiDepartment of Neurology, Fukushima Medical University School of MedicineYu-ichiNotoDepartment of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of MedicineRyujiKajiDepartment of Neurology, Tokushima University Graduate School of Biomedical SciencesHirohisaWatanabeDepartment of Neurology, Fujita Health UniversityTomokoKonishiDivision of ALS Research, Aichi Medical University School of MedicineMikikoHasegawaDivision of ALS Research, Aichi Medical University School of MedicineHozukiFukayaDivision of ALS Research, Aichi Medical University School of MedicineJun-ichiNiwaDepartment of Neurology, Aichi Medical University School of MedicineManabuDoyuDepartment of Neurology, Aichi Medical University School of MedicineYoheiOkadaDepartment of Neurology, Aichi Medical University School of MedicineShihoNakamuraKeio University Regenerative Medicine Research Center, KawasakiFumikoOzawaKeio University Regenerative Medicine Research Center, KawasakiHideyukiOkanoKeio University Regenerative Medicine Research Center, KawasakiMasahiroNakatochiPublic Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of MedicineGenSobueDivision of ALS Research, Aichi Medical University School of MedicineAmyotrophic lateral sclerosis (ALS) exhibits considerable clinical variability, such as differences in age at onset (AAO). Multiple factors, including genetic factors, may underlie this variability; however, the specific determinants remain unclear. To identify genes affecting AAO, we have conducted a genome-wide association study in Japanese patients with ALS (discovery cohort: n = 1808; replication cohort: n = 207). Here, we show that the minor A allele of rs113161727 at the ADAM29-GPM6A locus is associated with a younger AAO in the discovery cohort (effect, -4.27 years; p = 4.60 × 10-8); this finding has been confirmed in the replication cohort (p = 0.0068) and meta-analysis (p = 1.08 × 10−9). Among 65 ALS patients with a SOD1 mutation, the AAO has been found to be 10.2 years younger in those with the A allele than in those without it (p = 0.002). This variant correlates with GPM6A upregulation in iPSC-derived motor neurons, suggesting GPM6A as a candidate AAO modifier. Overall, our study highlights the impact of genetic modifiers on ALS heterogeneity and provides a potential target for delaying disease onset.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama2467-981X102025Favorable outcomes of epilepsy with gait-induced seizures after resection of the unilateral supplementary motor area489492ENSatoshiKodamaDepartment of Neurology, Graduate School of Medicine, The University of TokyoNaotoKuniiDepartment of Neurosurgery, Jichi Medical UniversityYuichiroShirotaDepartment of Neurology, Graduate School of Medicine, The University of TokyoTakuseiChouDepartment of Neurology, Graduate School of Medicine, The University of TokyoMizuhoKawaiDepartment of Neurology, Graduate School of Medicine, The University of TokyoSeijiroShimadaDepartment of Neurosurgery, Graduate School of Medicine, The University of TokyoMeikoMaedaDepartment of Neurology, Graduate School of Medicine, The University of TokyoHiroyukiIshiuraDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasashiHamadaDepartment of Neurology, Graduate School of Medicine, The University of TokyoMasakoIkemuraDepartment of Pathology, Graduate School of Medicine, The University of TokyoYukoSaitoDepartment of Neuropahtology (Brain Bank for Aging Research), Tokyo Metropoliran Institute for Geriatrics and GerontologyNaokiAkamatsuDepartment of Neurology, International University of Health and Walfare Narita HospitalTairaUeharaDepartment of Neurology, International University of Health and Walfare Narita HospitalNobuhitoSaitoDepartment of Neurosurgery, Graduate School of Medicine, The University of TokyoTatsushiTodaDepartment of Neurology, Graduate School of Medicine, The University of TokyoBackground: Gait-induced seizures are a rare manifestation of reflex epilepsy. Pathophysiology of this phenomenon has not been fully understood.<br>
Case presentation: A 28-year-old woman presented with a long history of “falls” following paroxysmal bilateral leg stiffness triggered by walking. Scalp electroencephalogram (EEG) revealed low-amplitude rhythmic beta activity, maximal at the Cz electrode, during these events. Magnetoencephalography demonstrated repetitive sharp waves source-localized to the right primary motor cortex. Multiple anti-seizure medications failed to improve her symptoms; however, the clinical manifestation was consistent with epilepsy with gait-induced seizures. Intracranial subdural EEG recording was performed and confirmed ictal activity originating from the right supplementary motor area. Resection of this area resulted in complete resolution of her symptoms.<br>
Discussion: This is the first reported case of successful resective surgery for epilepsy with gait-induced seizure. Brain networks involving cortical regions responsible for the initiation or execution of walking presumably played a key role in the generation of gait-induced seizures. Careful assessment using non-invasive neurophysiological studies facilitated accurate diagnosis, successful intracranial recordings, and effective resective surgery.No potential conflict of interest relevant to this article was reported.Informa UK LimitedActa Medica Okayama2167-84212025Novel in-frame duplication variant of SOD1 in a Japanese family with familial amyotrophic lateral sclerosisENMasanoriNakajimaDepartment of Neurology, Kyorin University School of MedicineHiroyaNaruseDepartment of Neurology, Graduate School of Medicine, The University of TokyoYuichiRikuDepartment of Neuropathology, Institute for Medical Science of Aging, Aichi Medical UniversityKunihiroUedaDepartment of Neurology, Graduate School of Medicine, The University of TokyoTakashiMatsukawaDepartment of Neurology, Graduate School of Medicine, The University of TokyoJunMitsuiDepartment of Neurology, Graduate School of Medicine, The University of TokyoYoshitsuguNakamuraDivision of Neurology, Department of Internal Medicine IV, Osaka Medical and Pharmaceutical UniversityShimonIshidaDivision of Neurology, Department of Internal Medicine IV, Osaka Medical and Pharmaceutical UniversityTakashiYamadaDepartment of Pathology, Osaka Medical and Pharmaceutical UniversityNaokiMoroDepartment of Neurology, Kyorin University School of MedicineNaokiKotsukiDepartment of Neurology, Kyorin University School of MedicineKentaroNagaiDepartment of Neurology, Kyorin University School of MedicineShin-ichiTokushigeDepartment of Neurology, Kyorin University School of MedicineAyumiUchiboriDepartment of Neurology, Kyorin University School of MedicineChizukoOishiDepartment of Neurology, Kyorin University School of MedicineHiroyukiYabataDepartment of Neurology, Shiga University of Medical ScienceMakotoUrushitaniDepartment of Neurology, Shiga University of Medical ScienceYasushiIwasakiDepartment of Neuropathology, Institute for Medical Science of Aging, Aichi Medical UniversityHiroyukiIshiuraDepartment of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTatsushiTodaDepartment of Neurology, Graduate School of Medicine, The University of TokyoShojiTsujiDepartment of Neurology, Graduate School of Medicine, The University of TokyoYaekoIchikawaDepartment of Neurology, Kyorin University School of MedicineObjectives: To analyze the cases of a family with a novel in-frame duplication variant (NM_000454.5:c.357_357 + 2dup, p.Val120dup) of SOD1 and a structural model of the mutated SOD1 protein. Methods: The clinical profiles of three patients in the family were analyzed, including the neuropathological findings of the proband’s mother. Genetic analyses were conducted for three patients. cDNA and in silico structural analyses were performed to evaluate the effects of duplication variants on the structure of SOD1. Results: The clinical features of the patients included predominant involvement of the lower motor neurons, asymmetric onset of motor symptoms in the lower limbs, and a relatively rapid progression of muscular weakness and respiratory insufficiency. Neuropathological findings revealed severe loss of spinal cord motor neurons, and immunohistochemistry using an anti-misfolded SOD1 antibody revealed aggregates in the spinal cord. Genetic analyses revealed a c.357_357 + 2dup at the exon 4–intron 4 boundary of SOD1 in three patients. cDNA analysis of the proband suggested the presence of a valine (p.Val120dup) duplication in the heterozygous state, and the SOD1 transcript level showed no significant differences from those of healthy controls. In silico structural analyses predicted that p.Val120dup could affect the structure of the β-barrels and copper ion binding site of SOD1, suggesting an abnormal conformation of SOD1 that is predicted to interfere with the binding of copper ions. Conclusion: We identified a novel in-frame duplication variant in the C-terminus of β7 of SOD1. This genotype–structure–phenotype study of SOD1 provides valuable insights into disease-causing mechanisms.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama2328-95032025Dorsolateral Cervical Cord T2 Hyperintensity in KIF1C-Related Disease (Spastic Paraplegia 58): Two Long-Duration CasesENAkihikoMitsutakeDepartment of Neurology, Graduate School of Medicine, The University of TokyoMasaoOsakiDepartment of Neurology, Graduate School of Medicine, The University of TokyoTakashiMatsukawaDepartment of Neurology, Graduate School of Medicine, The University of TokyoMihoOsakoDepartment of Neurology, Tokyo Metropolitan Kita Medical and Rehabilitation Center for the DisabledChisenTakeuchiDepartment of Neurology, Tokyo Metropolitan Kita Medical and Rehabilitation Center for the DisabledHiroyukiIshiuraDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesJunMitsuiDepartment of Precision Medicine Neurology, Graduate School of Medicine, The University of TokyoRyoKurokawaDepartment of Radiology, Graduate School of Medicine, The University of TokyoHarushiMoriDepartment of Radiology, School of Medicine, Jichi Medical UniversityYujiTakahashiDepartment of Neurology, Graduate School of Medicine, The University of TokyoJunGotoDepartment of Neurology, Graduate School of Medicine, The University of TokyoShojiTsujiInstitute of Medical Genomics, International University of Health and WelfareTatsushiTodaDepartment of Neurology, Graduate School of Medicine, The University of TokyoPathogenic variants in KIF1C cause Spastic Paraplegia 58 (SPG58), typically presenting with cerebellar ataxia and spastic paraparesis. We report two unrelated patients with spastic paraparesis, cerebellar ataxia, and tremor. Whole-exome sequence analysis identified novel homozygous variants in the motor domain of KIF1C (NM_006612.6): c.921G>A (p.Trp307Ter) and c.607C>T (p.Arg203Trp). In addition to the canonical brain MRI showing leukoencephalopathy with posterior dominance and hyperintensity along the corticospinal tracts, both patients showed symmetric T2 hyperintensity confined to the lateral and dorsal columns of the cervical cord. Given the long disease durations (22 and 51 years), these findings may represent late-emerging or previously overlooked spinal cord involvement and broaden the neuroradiological spectrum of SPG58.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0010-94521942026Increasing visual uncertainty modulates multisensory decision-making5062ENXiangfuYangGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityWeipingYangDepartment of Psychology, Faculty of Education, Hubei UniversityYinghuaYuGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityYoshimichiEjimaGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityJiajiaYangGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityThe brain integrates and transforms information from multiple senses to make optimal decisions, a process that is critical for navigating complex environments with perceptual uncertainty. Despite a growing consensus that individuals adapt flexibly to uncertain sensory input, whether increasing visual uncertainty influences the decision process itself or other, non-decision sensory processes during multisensory decision-making are unclear. Here, an audiovisual categorization task was used to examine the responses of human participants (N = 30) to visual and audiovisual stimuli under low-, medium-, and high-uncertainty conditions. Modeling the behavioral data using a drift‒diffusion model indicated that increased visual uncertainty in the audiovisual context decreased the evidence accumulation rate but had no effect on non-decision processes. Electrophysiological recordings confirmed and expanded upon these results: increased visual uncertainty in the audiovisual context reduced the amplitude during the late decision-making stage (300–380 msec) but had no effect on the amplitude during the early sensory encoding stage (140–220 msec). More importantly, electroencephalography analyses revealed that audiovisual integration in the early sensory encoding stage occurred robustly across all visual uncertainty conditions, whereas audiovisual integration in the late stage occurred only under medium and high visual uncertainty conditions. This study demonstrated that increased visual uncertainty modulates the decision process itself rather than early sensory encoding during multisensory decision-making. Moreover, multisensory integration strategies dynamically adapt to increasing visual uncertainty by engaging different mechanisms to maintain effective decision-making.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama2049-41731342025Identification of New Repeat Expansion Diseases244249ENHiroyukiIshiuraDepartment of Neurology, Okayama UniversityGraduate School of Medicine, Dentistry and Pharmaceutical SciencesThrough a genetic study of benign adult familial myoclonus epilepsy (BAFME) type 1, TTTCA and TTTTA repeat expansions have been identified in intron 4 of SAMD12. Lengths of expanded repeats inversely correlated with age at onset of epilepsy. Gain-of-toxic function mechanisms are suggested by the presence of UUUCA-repeat-containing RNA foci. From families with BAFME who did not have repeat expansions in SAMD12, we identified expanded TTTCA and TTTTA repeats in TNRC6A and RAPGEF2. These findings indicated a strong correlation between the repeat motif and the phenotype, leading to the identification of other types of BAFME. We then conducted genetic analysis of neuronal intranuclear inclusion disease (NIID), oculopharyngeal myopathy with leukoencephalopathy (OPML), and oculopharyngodistal myopathy (OPDM). From the observation that NIID, OPML, and OPDM, in addition to fragile X-associated tremor/ataxia syndrome, have shared clinical features, a direct search for CGG repeat expansions successfully led to the identification of the causative genes. Here, I review recent studies on repeat expansions.No potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama2076-39211492025Clinical Evaluation of Oxidative Stress Markers in Patients with Long COVID During the Omicron Phase in Japan1068ENOsamuMeseDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiOtsukaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasueSakuradaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazukiTokumasuDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshiakiSoejimaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruMoritaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuhiroNakanoDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyukiHondaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAkikoEguchiBiobank Center, Mie University HospitalSanaeFukudaDepartment of Health Welfare Sciences, Kansai University of Welfare SciencesJunzoNojimaDepartment of Laboratory Medicine, Yamaguchi UniversityFumioOtsukaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTo characterize changes in markers of oxidative stress for the clinical evaluation of patients with long COVID, we assessed oxidative stress and antioxidant activity based on serum samples from patients who visited our clinic between May and November 2024. Seventy-seven patients with long COVID (41 [53%] females and 36 [47%] males; median age, 44 years) were included. Median [interquartile range] serum levels of diacron-reactive oxygen metabolites (d-ROM; CARR Unit), biological antioxidant potential (BAP; μmol/L), and oxidative stress index (OSI) were 533.8 [454.9–627.6], 2385.8 [2169.2–2558.1] and 2.0 [1.7–2.5], respectively. Levels of d-ROMs (579.8 vs. 462.2) and OSI (2.3 vs. 1.8), but not BAP (2403.4 vs. 2352.6), were significantly higher in females than in males. OSI levels positively correlated with age and body mass index, whereas BAP levels negatively correlated with these parameters. d-ROM and OSI levels were significantly associated with inflammatory markers, including C-reactive protein (CRP) and fibrinogen, whereas BAP levels were inversely correlated with CRP and ferritin levels. Notably, serum free thyroxine levels were negatively correlated with d-ROMs and OSI, whereas cortisol levels were positively correlated with d-ROMs. Among long COVID symptoms, patients reporting brain fog exhibited significantly higher OSI levels (2.2 vs. 1.8), particularly among females (d-ROMs: 625.6 vs. 513.0; OSI: 2.4 vs. 2.0). The optimal OSI cut-off values were determined to be 1.32 for distinguishing long COVID from healthy controls and 1.92 for identifying brain fog among patients with long COVID. These findings suggest that oxidative stress markers may serve as indicators for the presence or prediction of psycho-neurological symptoms associated with long COVID in a gender-dependent manner.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama2211-546315102025Osmotic pressure‐induced calcium response states17141722ENZidanGaoDepartment of Cardiovascular Physiology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKeijiNaruseFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Okayama JapanMasatoshiMorimatsuFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Okayama JapanOsmotic pressure is essential for maintaining cellular homeostasis; however, the mechanisms by which cells sense and respond to acute osmotic stress remain incompletely understood. Here, we applied rapid osmotic pressure stimulation to cultured HEK293T cells and observed dynamic intracellular calcium responses. Acute hypotonic stimulation evoked calcium response patterns, whereas hypertonic and isotonic stress did not elicit similar effects. Mechanistically, these calcium signals originated from the endoplasmic reticulum via ryanodine receptor 2 and propagated to neighboring cells through Connexin 43-mediated gap junctions. These findings reveal a previously unrecognized role for calcium signaling in the acute cellular response to osmotic stress, providing new insights into the mechanisms of intercellular communication during osmotic adaptation.No potential conflict of interest relevant to this article was reported.Informa UK LimitedActa Medica Okayama2766-0400512025Linking structure and process in dendritic growth using persistent homology with energy analysis2475735ENMisatoToneDepartment of Material Science and Technology, Tokyo University of ScienceShunsukeSatoDepartment of Material Science and Technology, Tokyo University of ScienceSotaroKuniiDepartment of Material Science and Technology, Tokyo University of ScienceIppeiObayashiCenter for Artificial Intelligence and Mathematical Data Science, Okayama UniversityYasuakiHiraokaKyoto University Institute for Advanced Study, Kyoto UniversityYuiOgawaNTT Basic Research Laboratories, NTT CorporationHirokazuFukidomeResearch Institute of Electrical Communication, Tohoku UniversityAlexandre LiraFoggiattoDepartment of Material Science and Technology, Tokyo University of ScienceChiharuMitsumataDepartment of Material Science and Technology, Tokyo University of ScienceRyunosukeNagaokaDepartment of Material Science and Technology, Tokyo University of ScienceArpitaVaradwajDepartment of Material Science and Technology, Tokyo University of ScienceIwaoMatsudaInstitute for Solid State Physics, The University of TokyoMasatoKotsugiDepartment of Material Science and Technology, Tokyo University of ScienceWe present a material analysis method that links structure and process in dendritic growth using explainable machine learning approaches. We employed persistent homology (PH) to quantitatively characterize the morphology of dendritic microstructures. By using interpretable machine learning with energy analysis, we established a robust relationship between structural features and Gibbs free energy. Through a detailed analysis of how Gibbs free energy evolves with morphological changes in dendrites, we uncovered specific conditions that influence the branching of dendritic structures. Moreover, energy gradient analysis based on morphological feature provides a deeper understanding of the branching mechanisms and offers a pathway to optimize thin-film growth processes. Integrating topology and free energy enables the optimization of a range of materials from fundamental research to practical applications.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2045-23221512025Long intervals between repetitive concussions reduce risk of cognitive impairment and limit microglial activation, astrogliosis, and tauopathy in adolescent rats40522ENYuichiHirataDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University HospitalKyoheiKinDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University HospitalTakayukiNagaseDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University HospitalTatsuyaSasakiDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University HospitalSusumuSasadaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University HospitalChiakiSugaharaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University HospitalTakahiroHirayamaDepartment of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University HospitalKojiKawaiDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University HospitalShunTanimotoDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University HospitalHayatoMiyakeDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University HospitalTomoyaSaijoDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University HospitalHiromichiNaitoDepartment of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University HospitalKaoriMasaiDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakaoYasuharaYasuhara ClinicShotaTanakaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University HospitalAlthough previous studies have demonstrated the effects of concussions do not accumulate as the time interval between injuries increases, little is known about the relationship between this interval and the effects of repetitive concussions. The objective of this study is to explore the relationship between the time interval and changes in behavior and histology following repetitive concussions. Male adolescent rats received concussions by weight drop and were randomly assigned to one of five experimental groups, receiving concussions three times either daily, every other day, once per week, once every 2 weeks, or receiving sham procedures. Only rats that received daily concussions exhibited cognitive impairment, while the other groups did not. No groups showed motor or anxiety-like impairments. Histological analysis revealed accumulation of microglia, as well as astrogliosis, in the prefrontal cortex, corpus callosum, dentate gyrus, and cornu Ammonis 1 region of the hippocampus in rats subjected to daily concussions. Accumulation of phosphorylated tau was also observed in the prefrontal cortex and cornu Ammonis 1. Longer intervals between concussions may reduce the risk of cognitive impairment and limit microglial activation, astrogliosis, and phosphorylated tau accumulation. These findings may help guide decisions on the appropriate timing for return to play in humans.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Vesicular Glutamate Transporter 3 Is Involved in Glutamatergic Signalling in PodocytesENNaokoNISHIIGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Design and Synthesis of Cholesterol 24-Hydroxylase Inhibitors Using 1,3-Oxazole as a Heme-Iron Binding GroupENYoshiteruITOGraduate School of Natural Science and Technology, Okayama universityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Lightweight Deep Learning-Based Intrusion Detection System for Deployment on Raspberry PiENMUHAMMAD BISRI MUSTHAFAGraduate School of Natural Science and Technology, Okayama universityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Functional-morphological relationships of vasopressin in the macaque neuroendocrine systemENAkitoOTSUBOGraduate School of Natural Science and Technology, Okayama universityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Improving Diagnostic Performance for Head and Neck Tumors with Simple Diffusion Kurtosis Imaging and Machine Learning Bi-Parameter AnalysisENSuzukaYOSHIDAGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Importance of Blood Glucose Measurement for Predicting the Prognosis of Long COVID：A Retrospective Study in JapanENShoYOKOYAMAGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Alteration of perineuronal nets and parvalbumin interneurons in prefrontal cortex and hippocampus, and correlation with blood corticosterone in activity-based anorexia model miceENNGUYEN DUY HOANGGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025TRPV2 mediates stress resilience in mouse cardiomyocytesENYUBINGDONGGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Therapeutic effects of intracerebral transplantation of human modified bone marrow-derived stromal cells (SB623) with voluntary and forced exercise in a rat model of ischemic strokeENTakayukiNAGASEGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Repeated non-hemorrhagic and non-contusional mild traumatic brain injury in rats elicits behavioral impairment with microglial activation, astrogliosis, and tauopathy: Reproducible and quantitative model of chronic traumatic encephalopathyENChiakiSUGAHARAGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Spatiotemporal expression pattern of dyslexia susceptibility 1 candidate 1 (DYX1C1) during rat cerebral cortex developmentENKazumasaZENSHOGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Oxford University Press (OUP)Acta Medica Okayama1465-36215542025Current management of neurotrophic receptor tyrosine kinase fusion-positive sarcoma: an updated review313326ENYutaKubotaDepartment of Orthopaedic Surgery, Faculty of Medicine, Oita UniversityMasanoriKawanoDepartment of Orthopaedic Surgery, Faculty of Medicine, Oita UniversityTatsuyaIwasakiDepartment of Orthopaedic Surgery, Faculty of Medicine, Oita UniversityIchiroItonagaDepartment of Orthopaedic Surgery, Faculty of Medicine, Oita UniversityNobuhiroKakuDepartment of Orthopaedic Surgery, Faculty of Medicine, Oita UniversityToshifumiOzakiDepartment of Orthopaedic Surgery , Science of Functional Recovery and Reconstruction, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKazuhiroTanakaDepartment of Orthopaedic Surgery, Faculty of Medicine, Oita UniversityIn recent years, pembrolizumab has demonstrated significant efficacy in treating tumors characterized by a high tumor mutational burden and high microsatellite instability. Tropomyosin receptor kinase (TRK) inhibitors have shown considerable efficacy against tumors harboring neurotrophic receptor tyrosine kinase (NTRK) fusion genes, highlighting the growing importance of personalized medicine in cancer treatment. Advanced sequencing technologies enable the rapid analysis of numerous genetic abnormalities in tumors, facilitating the identification of patients with positive biomarkers. These advances have increased the likelihood of providing effective, tailored treatments. NTRK fusion genes are present in various cancer types, including sarcomas, and the TRK inhibitors larotrectinib and entrectinib have been effectively used for these malignancies. Consequently, the treatment outcomes for NTRK fusion-positive tumors have improved significantly, reflecting a shift toward more personalized therapeutic approaches. This review focuses on NTRK fusion-positive sarcomas and comprehensively evaluates their epidemiology, clinical features, and radiological and histological characteristics. We also investigated the treatment landscape, including the latest methodologies involving TRK inhibitors, and discussed the long-term efficacy of these inhibitors, and their optimal order of use. Notably, larotrectinib has demonstrated a high response rate in infantile fibrosarcoma, and its efficacy has been confirmed even in advanced cases. However, further research is warranted to optimize treatment duration and subsequent management strategies. The accumulation of clinical cases worldwide will play a pivotal role in refining the treatment approaches for tumors associated with NTRK fusion genes.No potential conflict of interest relevant to this article was reported.Frontiers Media SAActa Medica Okayama1664-3224162025A pilot transcriptomic study of a novel multitargeted BRT regimen for anti–MDA5 antibody-positive dermatomyositis: improving survival over conventional therapy1568338ENMoeTokunagaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuNakaiDivision of Rheumatology, Center for Autoimmune Diseases, Japanese Red Cross Okayama HospitalYoshiharuSatoDNA Chip Research Inc., Medical LaboratoryMitoriHiratsukaDNA Chip Research Inc., Medical LaboratoryYoshinoriMatsumotoDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakeshiNakatsueDivision of Rheumatology and Nephrology, Department of Internal Medicine, Nagaoka Red Cross HospitalTakakoSaekiDivision of Rheumatology and Nephrology, Department of Internal Medicine, Nagaoka Red Cross HospitalTakatsuneUmayaharaDivision of Dermatology, Center for Autoimmune Diseases, Japanese Red Cross Okayama HospitalJunWadaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshinobuKoyamaDivision of Rheumatology, Center for Autoimmune Diseases, Japanese Red Cross Okayama HospitalBackground: Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis (MDA5-DM) is associated with severe outcomes, primarily due to rapidly progressive interstitial lung disease (RP-ILD), which is often refractory to standard therapies such as calcineurin inhibitors (e.g., tacrolimus) combined with cyclophosphamide (TC-Tx). This study evaluated the efficacy of a novel multitargeted regimen combining baricitinib, rituximab, and tacrolimus (BRT-Tx) in improving survival outcomes for MDA5-DM patients with poor prognostic factors.<br>
Methods: Fourteen MDA5-DM patients with multiple adverse prognostic factors were studied. Seven received the BRT-Tx regimen, and the remaining seven, previously treated with TC-Tx, served as historical controls. Twelve-month survival was assessed. Transcriptome analysis was performed for six patients (BRT=3, TC=3), beginning with cluster analysis to evaluate whether changes in peripheral blood gene expression varied according to treatment or prognosis. Gene ontology analysis characterized expression profiles in survivors and distinguished treatment effects. Alterations in the type I, II, and III interferon signatures were also assessed.<br>
Results: In the TC-Tx group, four of seven patients succumbed to RP-ILD, whereas all seven BRT-Tx patients survived the 12-month observation period. Only one BRT-Tx patient required combined rescue therapies, including plasma exchange, and one case of unexplained limbic encephalitis (LE) occurred. Cytomegalovirus reactivation was observed in both groups (BRT: 5/7; TC: 6/7). Transcriptomic analysis revealed no treatment-specific clustering of differentially expressed genes (DEGs) before and after therapy. However, survivors and nonsurvivors formed distinct clusters, with survivors showing significant posttreatment suppression of B-cell-related gene expression. Moreover, interferon signature scores were significantly lower after treatment in survivors than in nonsurvivors. BRT-Tx effectively suppressed B-cell-mediated immune responses and maintained a low interferon signature, while TC-Tx resulted in nonspecific gene suppression, and in nonsurvivors, an elevated interferon signature was observed.<br>
Conclusion: BRT-Tx has the potential to improve survival in MDA5-DM patients by effectively targeting hyperactive immune pathways. The combination of rituximab and tacrolimus is expected to disrupt B-cell–T-cell interactions and reduce autoantibody production, whereas baricitinib may suppress both IFN and GM-CSF signaling, regulating excessive autoimmunity mediated by cells such as macrophages. Unlike TC-Tx, BRT-Tx avoids cyclophosphamide-associated risks such as infertility and secondary malignancies. Future randomized controlled trials are warranted to validate its efficacy and safety.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2168-818417102025Bladder Trigone as a Sensory Hub: A Narrative Reviewe94951ENTakuyaSadahiraDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiMaruyamaDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYosukeMitsuiDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakanoriSekitoDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomofumiWatanabeDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasamiWatanabeDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesThe bladder trigone is an anatomically and functionally distinct region within the lower urinary tract (LUT), characterized by a dense network of afferent sensory fibers, specialized urothelial interactions, and prominent mechanotransduction mechanisms. Its intricate neuroarchitecture enables precise detection of bladder filling and coordination of micturition, whereas dysregulation of these pathways contributes to lower urinary tract symptoms (LUTS), including urgency, frequency, and bladder pain. Despite its recognized clinical relevance, the structural and functional basis of trigonal sensory signaling - and its role - remain incompletely understood.<br>
This review synthesizes current evidence on trigonal afferent organization, integrating data from anatomical mapping, receptor profiling, electrophysiological characterization, and translational research. Seminal anatomical observations are combined with recent advances in mechanotransduction and purinergic, peptidergic, and transient receptor potential (TRP) signaling to provide a comprehensive perspective. The trigone exhibits three principal afferent classes: (1) intraepithelial fibers penetrating umbrella cells, marked by P2X purinoceptor 3 (P2X3), transient receptor potential vanilloid 1 (TRPV1), calcitonin gene-related peptide (CGRP), and substance P (SP); (2) subepithelial plexuses surrounding microvasculature, enriched in vasoactive neuropeptides and exhibiting plastic hypertrophy in overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS); and (3) encapsulated corpuscular endings at the lamina propria-detrusor junction, expressing PIEZO1/2 and acid-sensing ion channels (ASICs) for rapid adaptation. In trigeminal dorsal root ganglion (DRG) neurons, high expression of PIEZO2, P2RX3, and voltage-gated sodium channel, type 1.8 (Nav1.8) was observed, revealing their role as the foundation for multisensory information processing. Functional assays highlight distinct mechanotransductive and chemosensory pathways, with aging, inflammation, and neurotrophic factors driving afferent plasticity underlying abnormal bladder sensation, such as urgency, frequency, and pain. Early clinical trials of P2X3 antagonists and intravesical TRPV1 inhibitors demonstrate promising symptomatic benefits. Collectively, evidence positions the bladder trigone as a critical sensory hub where neuronal, urothelial, and immune signals converge to regulate bladder sensation. Understanding its molecular and structural specialization may inform the development of region-specific neuromodulatory therapies targeting sensory urgency and afferent-driven bladder dysfunction.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0006-291X7862025Hydrogen-rich gas enhances mitochondrial membrane potential and respiratory function recovery in Caco-2 cells post-ischemia-reperfusion injury152753ENMizukiSeyaDepartment of Emergency, Critical Care and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshiyukiAokageBiological Process of Aging, Tokyo Metropolitan Institute for Geriatrics and GerontologyYingMengDepartment of Emergency, Critical Care and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakahiroHirayamaDepartment of Emergency, Critical Care and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakafumiObaraDepartment of Emergency, Critical Care and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTsuyoshiNojimaDepartment of Emergency, Critical Care and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKosakiYoshinoriDepartment of Emergency, Critical Care and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTetsuyaYumotoDepartment of Emergency, Critical Care and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAkihiroWatanabeDepartment of Emergency, Disaster and Critical Care Medicine, Hyogo Medical UniversityTaiheiYamadaDepartment of Emergency, Disaster and Critical Care Medicine, Hyogo Medical UniversityHiromichiNaitoDepartment of Emergency, Critical Care and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAtsunoriNakaoDepartment of Emergency, Critical Care and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground: Ischemia-reperfusion (I/R) injury induces oxidative stress, leading to damage in highly susceptible intestinal tissues. Molecular hydrogen (H2) has shown therapeutic potential in I/R injuries, with our prior research showing its efficacy in improving outcomes in rat intestinal transplantation models. However, its impact on mitochondrial function remain insufficiently understood. This study aims to elucidate how H2 modulates mitochondrial function impaired by I/R injury.<br>
Methods: To assess the effects of H2 on I/R injury, cells were divided into three groups: a control group, a hypoxic group (99 % N2, 1 % O2, without H2 for 3, 6, or 24 h), and a hypoxic-H2 group (99 % H2, 1 % O2, for the same durations). After treatment, cells were reoxygenated under normoxic conditions (21 % O2) for 1, 2, 4, or 6 h. Mitochondrial membrane potential, oxygen consumption, and ATP production were measured. Reactive oxygen species production and apoptotic and metabolic regulators were also assessed.<br>
Results: H2 markedly promoting mitochondrial recovery following I/R injury, by enhancing ATP production, restoring mitochondrial membrane potential, and improving oxygen consumption. It also reduced ROS levels and suppressed pro-apoptotic signaling. Notably, H2 suppressed the expression of HIF1α and PDK1, suggesting that H2 may act upstream of hypoxia-driven signaling pathways. These changes promoted oxidative phosphorylation and overall cellular function during reperfusion.<br>
Conclusions: Our findings reveal that H2 therapy supports mitochondrial function, suppresses ROS, and modulates hypoxia-driven pathways in I/R injury. These insights advance the understanding of H2's potential in addressing I/R injury and provide a foundation for its application in other hypoxia-related conditions.No potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama2072-669417172025Refining the Role of Tumor-Associated Macrophages in Oral Squamous Cell Carcinoma2770ENKiyofumiTakabatakeDepartment of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityPiaoTianyanDepartment of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTakumaArashimaDepartment of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityAnqiChangDepartment of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHotakaKawaiDepartment of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHtoo ShweEainDepartment of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYaminSoeDepartment of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityZin ZinMinDepartment of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMasaeFujiiDepartment of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKeisukeNakanoDepartment of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHitoshiNagatsukaDepartment of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityIn the tumor microenvironment, various immune and stromal cells, such as fibroblasts and vascular endothelial cells, contribute to tumor growth and progression by interacting with cancer cells. Tumor-associated macrophages (TAMs) have attracted attention as major players in the tumor microenvironment. The origin of TAMs is believed to be the infiltration of monocytes derived from bone marrow progenitor cells into tumor tissues and their differentiation into macrophages, whereas tissue-resident macrophages derived from yolk sacs have recently been reported. TAMs infiltrating tumor tissues act in a tumor-promoting manner through immunosuppression, angiogenesis, and the promotion of cancer cell invasion. Reflecting the nature of TAMs, increased TAM invasion and TAM-specific gene expression in tumor tissues may be the new biomarkers for cancer. Moreover, new therapeutic strategies targeting TAMs, such as transformation into immunostimulatory macrophages, suppression of TAM infiltration, and promotion of phagocytosis, are being investigated, and many clinical trials are underway. As the origin and function of TAMs are further elucidated, TAM-targeted therapy is expected to become a new option for the immunotherapy of various cancers, including oral cancers.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama2470-92391032025Decreased homovanillic acid and 5‐hydroxyindoleacetic acid levels in the cerebrospinal fluid of patients with Dravet syndrome with parkinsonism965970ENRyoSugiyamaDepartment of Child Neurology, National Center Hospital, National Center of Neurology and PsychiatryTakashiSaitoDepartment of Child Neurology, National Center Hospital, National Center of Neurology and PsychiatryAtsukoKatsumotoDepartment of Neurology, National Center Hospital, National Center of Neurology and PsychiatryShotaYonenoDepartment of Child Neurology, National Center Hospital, National Center of Neurology and PsychiatryTomoyukiAkiyamaDepartment of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University HospitalHirofumiKomakiDepartment of Child Neurology, National Center Hospital, National Center of Neurology and PsychiatryDravet syndrome (DS) is an early onset, developmental, and epileptic encephalopathy characterized by drug-resistant seizures and multiple comorbidities. It has been reported that in adulthood, it may be accompanied by parkinsonism, but the pathogenesis of this condition remains unclear. We performed dopamine transporter single-photon emission computed tomography (DAT SPECT) and measured monoamine metabolite levels in the cerebrospinal fluid (CSF) in two adult patients with DS who developed parkinsonism around the age of 30 years. DAT SPECT showed no abnormalities in either patient, whereas CSF tests revealed significant decreases in the levels of homovanillic and 5-hydroxyindoleacetic acids. One patient with severe symptoms was treated with levodopa–carbidopa, which improved parkinsonism manifestations. The other patient initiated treatment with a low dose and has been continuing the treatment without any reported side effects. In conclusion, CSF testing can detect a decrease in dopamine synthesis and may be useful in monitoring the efficacy of levodopa treatment in patients with DS and parkinsonism.<br>
Plain Language Summary: Dravet syndrome (DS) is an early onset, developmental, and epileptic encephalopathy. DS can lead to the development of parkinsonism in adulthood, a clinical syndrome characterized by tremor, slowed movements, and rigidity. Although parkinsonism is a significant issue for patients, its underlying pathology has not yet been elucidated. In this study, we confirmed that the levels of monoamine metabolites in the CSF were low in two patients, potentially shedding light on the pathology involved.No potential conflict of interest relevant to this article was reported.The Company of BiologistsActa Medica Okayama0950-1991152222025ROS produced by Dual oxidase regulate cell proliferation and haemocyte migration during leg regeneration in the cricketdev204763ENMisaOkumura-HironoDepartment of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTetsuyaBandoDepartment of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshimasaHamadaDepartment of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMotooArakiDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHideyoOhuchiDepartment of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMany animals regenerate lost body parts through several signalling pathways; however, the triggers that initiate regeneration remain unclear. In the present study, we focused on the role of reactive oxygen species (ROS) produced by the NADPH oxidase Dual oxidase (Duox) during cricket leg regeneration. The results showed that ROS levels were upregulated during leg regeneration and decreased by DuoxRNAi. In DuoxRNAi nymphs, wound closure and scab formation were incomplete 2 days after amputation, and hypertrophy occurred in the distal region of the regenerating legs at 5 days after amputation. In addition, the hypertrophic phenotype was induced by DuoxARNAi and NADPH oxidase inhibitor treatment. During hypertrophy, haemocytes, including plasmatocytes, oenocytoids and granulocytes, accumulated. Proliferation of haemocytes in regenerating legs was not increased by DuoxRNAi; however, haemocyte accumulation was regulated by the Spatzle (Spz) family molecules, which are Toll receptor ligands. As the exoskeleton of DuoxRNAi nymphs was thinner than that of the control, excessive haemocyte accumulation can cause hypertrophy in DuoxRNAi nymphs. Thus, Duox-derived ROS are involved in wound healing and haemocyte accumulation through the Spz/Toll signalling pathway during leg regeneration in crickets.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0014-48863862025Therapeutic effects of intracerebral transplantation of human modified bone marrow-derived stromal cells (SB623) with voluntary and forced exercise in a rat model of ischemic stroke115145ENTakayukiNagaseDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakaoYasuharaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKyoheiKinDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSusumuSasadaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoshiKawauchiDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoruYabunoDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesChiakiSugaharaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuichiHirataDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHayatoMiyakeDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTatsuyaSasakiDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKojiKawaiDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShunTanimotoDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomoyaSaijoDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShotaTanakaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesIschemic stroke results in significant long-term disability and mortality worldwide. Although existing therapies, such as recombinant tissue plasminogen activator and mechanical thrombectomy, have shown promise, their application is limited by stringent conditions. Mesenchymal stem cell (MSC) transplantation, especially using SB623 cells (modified human bone marrow-derived MSCs), has emerged as a promising alternative, promoting neurogenesis and recovery. This study evaluated the effects of voluntary and forced exercise, alone and in combination with SB623 cell transplantation, on neurological and psychological outcomes in a rat model of ischemic stroke. Male Wistar rats that had undergone middle cerebral artery occlusion (MCAO) were divided into six groups: control, voluntary exercise (V-Ex), forced exercise (F-Ex), SB623 transplantation, SB623 + V-Ex, and SB623 + F-Ex. Voluntary exercise was facilitated using running wheels, while forced exercise was conducted on treadmills. Neurological recovery was assessed using the modified neurological severity score (mNSS). Psychological symptoms were evaluated through the open field test (OFT) and forced swim test (FST), and neurogenesis was assessed via BrdU labeling. Both exercise groups exhibited significant changes in body weight post-MCAO. Both exercises enhanced the treatment effect of SB623 transplantation. The forced exercise showed a stronger treatment effect on ischemic stroke than voluntary exercise alone, and the sole voluntary exercise improved depression-like behavior. The SB623 + F-Ex group demonstrated the greatest improvements in motor function, infarct area reduction, and neurogenesis. The SB623 + V-Ex group was most effective in alleviating depression-like behavior. Future research should optimize these exercise protocols and elucidate the underlying mechanisms to develop tailored rehabilitation strategies for stroke patients.No potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama1999-492317112025Development of Propofol-Encapsulated Liposomes and the Effect of Intranasal Administration on Bioavailability in Rabbits1446ENHitomiUjitaDepartment of Dental Anesthesiology, Okayama University HospitalHitoshiHiguchiDepartment of Dental Anesthesiology, Okayama University HospitalYukikoNishiokaDepartment of Dental Anesthesiology, Okayama University HospitalSakiMiyakeDepartment of Dental Anesthesiology and Special Care Dentistry, Okayama University Graduate of Medicine, Dentistry and Pharmaceutical SciencesRikoSatoDepartment of Dental Anesthesiology and Special Care Dentistry, Okayama University Graduate of Medicine, Dentistry and Pharmaceutical SciencesTakuyaMiyawakiDepartment of Dental Anesthesiology and Special Care Dentistry, Okayama University Graduate of Medicine, Dentistry and Pharmaceutical SciencesBackground/Objectives: Propofol is frequently used as an intravenous anesthetic and is rapidly metabolized. Therefore, if it could be administered non-invasively (e.g., orally) as premedication, it might hasten emergence from anesthesia, thereby improving patient safety. However, it undergoes extensive first-pass metabolism in the liver and intestines, limiting the route for premedication. We evaluated whether intranasal delivery of a propofol-encapsulated liposome solution improves systemic exposure and bioavailability in rabbits. Methods: A propofol-encapsulated liposome solution was administered to rabbits via the intravenous, oral, and intranasal routes. Blood propofol concentrations were measured for up to 60 min after administration and the area under the concentration–time curve (AUC0–60) and bioavailability of the propofol-encapsulated liposome solution were compared with those of the non-encapsulated propofol formulation. The differences were tested by two-way analysis of variance (ANOVA) with Šidák’s post hoc multiple-comparisons test and the Mann–Whitney test (α = 0.05). Results: The AUC0–60 for blood propofol concentrations after intravenous administration was significantly higher with the propofol-encapsulated liposome solution than with the non-encapsulated propofol formulation (3038.8 ± 661.5 vs. 1929.8 ± 58.2 ng·min/mL; p = 0.0286). By contrast, no increase in blood propofol concentrations was observed after oral administration, whereas intranasal administration increased blood propofol concentrations and yielded significantly higher bioavailability compared with the non-encapsulated propofol formulation (16.4 ± 7.3% vs. 2.0 ± 1.2%; p = 0.0286). Conclusions: The findings of the present study suggest that intranasal liposomal propofol increased systemic availability compared with a non-encapsulated formulation, supporting further evaluation as a candidate premedication approach for propofol.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2051-59601312025Rotenone targets midbrain astrocytes to produce glial dysfunction-mediated dopaminergic neurodegeneration234ENIkukoMiyazakiDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNamiIsookaDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyoKikuokaDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesFuminoriImafukuDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKaoriMasaiDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKanaTomimotoDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasakiyoSakaguchiDepartment of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesChiharuSogawaDepartment of Food and Health Sciences, Faculty of Environmental Studies, Hiroshima Institute of TechnologyNorioSogawaDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihisaKitamuraDepartment of Pharmacotherapy, School of Pharmacy, Shujitsu UniversityMasatoAsanumaDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesExposure to pesticides, such as rotenone or paraquat, is an environmental factor that plays an important role in the pathogenesis of Parkinson's disease (PD). Rotenone induces PD-like pathology and is therefore used to develop parkinsonian animal models. Dopaminergic neurotoxicity caused by rotenone has been attributed to the inhibition of mitochondrial complex I, oxidative stress and neuroinflammation; however, the mechanisms underlying selective dopaminergic neurodegeneration by rotenone remain unclear. To resolve this, we focused on glial diversity and examined whether the brain region-specific glial response to rotenone could determine the vulnerability of dopaminergic neurons using primary cultured neurons, astrocytes and microglia from the midbrain and striatum of rat embryos and rotenone-injected PD model mice. Direct neuronal treatment with low-dose rotenone failed to damage dopaminergic neurons. Conversely, rotenone exposure in the presence of midbrain astrocyte and microglia or conditioned media from rotenone-treated midbrain glial cultures containing astrocytes and microglia produced dopaminergic neurotoxicity, but striatal glia did not. Surprisingly, conditioned media from rotenone-treated midbrain astrocytes or microglia monocultures did not affect neuronal survival. We also demonstrated that rotenone targeted midbrain astrocytes prior to microglia to induce dopaminergic neurotoxicity. Rotenone-treated astrocytes produced secreted protein acidic and rich in cysteine (SPARC) extracellularly, which induced microglial proliferation, increase in IL-1β and TNF-α, and NF-κB (p65) nuclear translocation in microglia, resulting in dopaminergic neurodegeneration. In addition, rotenone exposure caused the secretion of NFAT-related inflammatory cytokines and a reduction in the level of an antioxidant metallothionein (MT)-1 from midbrain glia. Furthermore, we observed microglial proliferation and a decrease in the number of MT-positive astrocytes in the substantia nigra, but not the striatum, of low-dose rotenone-injected PD model mice. Our data highlight that rotenone targets midbrain astrocytes, leading to SPARC secretion, which promotes the neurotoxic conversion of microglia and leads to glial dysfunction-mediated dopaminergic neurodegeneration.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0266-352X1782025End-to-end time-dependent probabilistic assessment of landslide hazards using hybrid deep learning simulator106920ENMengluHuangDepartment of Civil and Environmental Engineering, Okayama UniversityShin-ichiNishimuraDepartment of Civil and Environmental Engineering, Okayama UniversityToshifumiShibataDepartment of Civil and Environmental Engineering, Okayama UniversityZe ZhouWangMarie Skłodowska-Curie Fellow, Department of Engineering, University of CambridgeEarly warning detection of landslide hazards often requires real-time or near real-time predictions, which can be challenging due to the presence of multiple geo-uncertainties and time-variant external environmental loadings. The propagation of these uncertainties at the system level for understanding the spatiotemporal behavior of slopes often requires time-consuming numerical calculations, significantly hindering the establishment of an early warning system. This paper presents a hybrid deep learning simulator, which fuses parallel convolutional neural networks (CNNs) and long short-term memory (LSTM) networks through attention mechanisms, termed PCLA-Net, to facilitate time-dependent probabilistic assessment of landslide hazards. PCLA-Net features two novelties. First, it is capable of simultaneously handling both temporal and spatial information. CNNs specialize in interpreting spatial data, while LSTM excels in handling time-variant data. Coupled with two attention mechanisms, the two modules are combined to probabilistically predict the spatiotemporal behavior of slopes. Second, PCLA-Net realizes end-to-end predictions. In this paper, the Liangshuijing landslide in the Three Gorges Reservoir area of China is used to illustrate PCLA-Net. It is first validated followed by a comparison with existing techniques to demonstrate its improved predictive capabilities. The proposed PCLA-Net simulator can achieve the same level of accuracy with at least 50% reduction in computation resources.No potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama2075-172915112025Kidney Organoids: Current Advances and Applications1680ENHiroyukiNakanohDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKenjiTsujiDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKazuhikoFukushimaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNaruhikoUchidaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversitySoichiroHaraguchiDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShinjiKitamuraDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityJunWadaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKidney organoids, derived from stem cells, including pluripotent stem cells and adult progenitor cells, have been reported as three-dimensional in vitro models that reflect key aspects of kidney development, structure, and function. Advances in differentiation protocols and tissue engineering have enabled the generation of organoids that exhibit nephron-like structures, including glomerular and tubular structures. Kidney organoids have been widely applied in several directions, including disease modeling and therapeutic screening, drug nephrotoxicity evaluation, and regenerative medicine. In particular, kidney organoids offer a promising platform for studying genetic kidney diseases, such as polycystic kidney disease and congenital anomalies of the kidney and urinary tract (CAKUT), by allowing patient-specific modeling for the analysis of pathophysiology and therapeutic screening. Despite several current limitations, such as incomplete maturation, lack of full nephron segmentation, and variability between protocols and cell conditions, further technological innovations such as microfluidics and bioengineering may refine kidney organoid systems. This review highlights recent advances in kidney organoid research, outlines major applications, and discusses future directions to enhance their physiological relevance, functional maturity, and translational integration into preclinical and clinical nephrology.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2168-81841792025The Intranasal Administration of Semaphorin 3A Inhibitor in a Mouse Model of Olfactory Disordere92587ENAyaMuraiOtolaryngology - Head and Neck Surgery, Okayama University HospitalMinoriNodaOtolaryngology - Head and Neck Surgery, Okayama University HospitalAikoShimizuOtolaryngology - Head and Neck Surgery, Okayama University HospitalJunkoTakaharaDivision of Technical Support for Medical Science, Department of Comprehensive Technical Solutions, Okayama UniversitySeiichiroMakiharaOtolaryngology - Head and Neck Surgery, Okayama University HospitalMizuoAndoOtolaryngology - Head and Neck Surgery, Okayama UniversityThis study investigated the effects of intranasal administration of a semaphorin 3A inhibitor (Sema3A-I) in a mouse model of olfactory disorder, where olfactory sensory neuron (OSN) axons had been severely damaged. We performed axotomy (transection of OSN axons) of the OSNs in mice and administered Sema3A‑I intranasally to seven mice and saline to another seven mice. Following treatment, we assessed the thickness of the olfactory epithelium and the regeneration ratio of OSN axons. Intranasal administration of Sema3A-I did not significantly promote OSN regeneration, axonal outgrowth, or improve axonal projection compared to saline administration. Although Sema3A-I administration showed some promotion of axonal outgrowth, the difference was not statistically significant. Continuous subcutaneous administration of Sema3A-I in rats after axotomy promotes OSN regeneration and axonal outgrowth. Given that intranasal administration is minimally invasive, we believe that it may still be a feasible route when combined with additional treatment strategies. Further investigation into administration methods and therapeutic combinations is warranted.No potential conflict of interest relevant to this article was reported.Ovid Technologies (Wolters Kluwer Health)Acta Medica Okayama2376-78391152025Vanishing White Matter Disease With EIF2B2 c.254T >A Variante200293ENToshiyukiKakumotoDepartment of Neurology, Graduate School of Medicine, The University of TokyoTakashiMatsukawaDepartment of Neurology, Graduate School of Medicine, The University of TokyoRyoTokimuraDepartment of Neurology, Graduate School of Medicine, The University of TokyoYokoTsuboyamaDepartment of Neurology, Graduate School of Medicine, The University of TokyoYasufumiHayashiDepartment of Neurology, Graduate School of Medicine, The University of TokyoAkihikoMitsutakeDepartment of Neurology, Graduate School of Medicine, The University of TokyoAtsushiIwataDepartment of Neurology, Graduate School of Medicine, The University of TokyoMeiko HashimotoMaedaDepartment of Neurology, Graduate School of Medicine, The University of TokyoJunShimizuDepartment of Neurology, Graduate School of Medicine, The University of TokyoWataruGonoiDepartment of Radiology, Graduate School of Medicine, The University of TokyoHiroyukiIshiuraDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJunMitsuiDepartment of Neurology, Graduate School of Medicine, The University of TokyoShojiTsujiDepartment of Molecular Neurology, Graduate School of Medicine, The University of TokyoTatsushiTodaDepartment of Neurology, Graduate School of Medicine, The University of TokyoObjectives<br>
Typical MRI findings of vanishing white matter disease (VWM) include diffuse white matter lesions with cystic degeneration. However, mild cases may lack these typical features, posing diagnostic challenges.<br>
Methods<br>
We describe 2 of 3 individuals carrying the homozygous c.254T >A variant in EIF2B2 identified at our hospital, excluding 1 previously reported case.1 Genetic analyses were performed using whole-genome sequence or whole-exome sequence analysis, and detected variants were confirmed by direct nucleotide sequence analysis. Brain MRI findings and clinical features were reviewed for the 2 individuals along with other cases in the literature with the same variant.<br>
Results<br>
A 69-year-old woman presented with recurrent transient dizziness and secondary amenorrhea. MRI of the brain revealed small T2-hyperintense lesions confined to the subcortical white matter with hyperintensities on diffusion-weighted images and mildly elevated apparent diffusion coefficient values. A 28-year-old woman presented with transient dizziness and secondary amenorrhea. MRI of the brain showed mild T2-hyperintense lesions in the cerebral white matter with frontal predominance.<br>
Discussion<br>
This report highlights the clinically mild cases of VWM with subtle abnormalities on brain MRI who had the homozygous c.254T >A in EIF2B2, further expanding the clinical spectrum of VWM and underscoring the importance of genetic assessments in the diagnosis of individuals with mild clinical and MRI findings.No potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama2079-929214112025An Automatic Code Generation Tool Using Generative Artificial Intelligence for Element Fill-in-the-Blank Problems in a Java Programming Learning Assistant System2261ENZihaoZhuDepartment of Information and Communication Systems, Okayama UniversityNobuoFunabikiDepartment of Information and Communication Systems, Okayama UniversityMustikaMentariDepartment of Information and Communication Systems, Okayama UniversitySoe ThandarAungDepartment of Information and Communication Systems, Okayama UniversityWen-ChungKaoDepartment of Electrical Engineering, National Taiwan Normal UniversityYi-FangLeeDepartment of Industrial Education, National Taiwan Normal UniversityPresently, Java is a fundamental object-oriented programming language that can be mastered by any student in information technology or computer science. To assist both teachers and students, we developed the Java Programming Learning Assistant System (JPLAS). It offers several types of practice problems with different levels and learning goals for step-by-step self-study, where any answer is automatically marked in the system. One challenge for teachers that is addressed with JPLAS is the generation of proper exercise problems that meet learning requirements. We implemented programs for generating new problems from given source codes, as collecting and evaluating suitable codes remains time-consuming. In this paper, we present an automatic code generation tool using generative AI to solve this challenge. Prompt engineering is used to help generate an appropriate source code, and the quality is controlled by optimizing the prompt based on the outputs. For applications in JPLAS, we implement a web application system to automatically generate an element fill-in-the-blank problem (EFP) in JPLAS. For evaluation, we select the element fill-in-the-blank problem (EFP) as the target type in JPLAS and generate several instances using this tool. The results confirm the validity and effectiveness of the proposed method.No potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama1422-006725212024Dennd2c Negatively Controls Multinucleation and Differentiation in Osteoclasts by Regulating Actin Polymerization and Protrusion Formation11479ENYuKoyanagiDepartment of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki UniversityEikoSakaiDepartment of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki UniversityYuYamaguchiDepartment of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki UniversityFatimaFarhanaDepartment of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki UniversityYohsukeTairaDivision of Cariology and Restorative Dentistry, Department of Prosthetic Dentistry, Graduate School of Biomedical Sciences, Nagasaki UniversityKuniakiOkamotoDepartment of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHiroshiMurataDivision of Cariology and Restorative Dentistry, Department of Prosthetic Dentistry, Graduate School of Biomedical Sciences, Nagasaki UniversityTakayukiTsukubaDepartment of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki UniversityOsteoclasts are bone-resorbing multinucleated giant cells formed by the fusion of monocyte/macrophage lineages. Various small GTPases are involved in the multinucleation and differentiation of osteoclasts. However, the roles of small GTPases regulatory molecules in osteoclast differentiation remain unclear. In the present study, we examined the role of Dennd2c, a putative guanine nucleotide exchange factor for Rab GTPases, in osteoclast differentiation. Knockdown of Dennd2c promoted osteoclast differentiation, resorption, and expression of osteoclast markers. Morphologically, Dennd2c knockdown induced the formation of larger osteoclasts with several protrusions. In contrast, overexpression of Dennd2c inhibited the multinucleation and differentiation of osteoclasts, bone resorption, and the expression of osteoclast markers. Dennd2c-overexpressing macrophages exhibited spindle-shaped mononuclear cells and long thin protrusions. Treatment of Dennd2c-overexpressing cells with the Cdc42 inhibitor ML-141 or the Rac1 inhibitor 6-thio-GTP prevented protrusion formation. Moreover, treatment of Dennd2c-overexpressing cells with the actin polymerization inhibitor latrunculin B restored multinucleated and TRAP-positive osteoclast formation. These results indicate that Dennd2c negatively regulates osteoclast differentiation and multinucleation by modulating protrusion formation in macrophages.No potential conflict of interest relevant to this article was reported.Universitas Negeri JakartaActa Medica Okayama2614-39841822025Data inventory, processing, and reporting on plant blindness among high school students in three schools in West Java2232ENPuan Helwa RezhaSorayaBiology Education, Faculty of Mathematics and Science Education, Universitas Pendidikan IndonesiaRiniSolihatBiology Education, Faculty of Mathematics and Science Education, Universitas Pendidikan IndonesiaYayanSanjayaBiology Education, Faculty of Mathematics and Science Education, Universitas Pendidikan IndonesiaTaroHaradaGraduate School of Education, Okayama UniversityPlant blindness is a problem related to a person's inability to realize, recognize, and know the benefits and roles of plants. After some research, there was a shift in the term, from Plant Blindness to Plant Awareness Disparity. This study aims to find out the prevalence of Plant Blindness in three high schools in West Java. The method used in this study is descriptive Cross sectional. The results of this study revealed that there were differences in the level of plant awareness in the three schools studied. One of the schools in the city of Bandung showed the highest plant awareness rate. In addition, it was also found that students who had a high level of plant awareness had a high perception of plant awareness. As a follow-up, further research can be carried out to collect more data so that it becomes a whole population. In addition, researchers can then use additional instruments so that more things can be revealed about plant blindness.No potential conflict of interest relevant to this article was reported.American Chemical Society (ACS)Acta Medica Okayama2694-24962025RNA Delivery Using a Graphene Oxide-Polyethylenimine Hybrid Inhibiting Myotube DifferentiationENKojiMatsuuraCNRS, Immunology, Immunopathology and Therapeutic Chemistry, UPR3572, University of Strasbourg, ISISGiacomoReinaCNRS, Immunology, Immunopathology and Therapeutic Chemistry, UPR3572, University of Strasbourg, ISISZhengfengGaoCNRS, Immunology, Immunopathology and Therapeutic Chemistry, UPR3572, University of Strasbourg, ISISYutaNishinaResearch Institute for Interdisciplinary Science, Okayama UniversityAlbertoBiancoCNRS, Immunology, Immunopathology and Therapeutic Chemistry, UPR3572, University of Strasbourg, ISISGraphene oxide (GO) conjugated with short polyethylenimine (PEI) chains (GO-PEI) has been designed as a candidate nanocarrier for small interfering RNA (siRNA) delivery to mammalian cells based on the efficient interaction between the positively charged GO-based platform and the negatively charged siRNA. The function and efficiency of siRNA delivery using GO-PEI were compared to those using the positive control Lipofectamine RNAiMax by analyzing the differentiation to myotubes, and myogenin gene and protein expression in C2C12 cells. RNAiMax transfection induced cellularization and reduction of both myogenin gene and protein expression, suggesting that the differentiation of C2C12 cells was triggered by gene silencing. While GO-PEI also promoted cellularization, the myogenin gene expression remained comparable to scrambled controls, whereas the protein levels were higher than those observed with RNAiMax. Mechanistically, we attributed the reduced gene silencing efficiency of GO-PEI to a poor endosomal escape, despite strong siRNA complexation. This limitation was likely due to a low buffering capacity of GO-PEI, as a significant fraction of nitrogen atoms were already protonated, reducing the availability of free amines necessary for endosomal disruption. An appropriate chemical modification to enhance siRNA release from the endosomes is therefore essential for advancing the development of GO-based platforms as versatile and efficient nanocarriers in gene therapy applications.No potential conflict of interest relevant to this article was reported.Elsevier B.V.Acta Medica Okayama0304-41651869122025The F54L mutation of Thioredoxin shows protein instability and increased fluctuations of the catalytic center130860ENTakumiBabaLife Science Research Infrastructure Group, Advanced Photon Technology Division, RIKEN SPring-8 CenterGoUenoLife Science Research Infrastructure Group, Advanced Photon Technology Division, RIKEN SPring-8 CenterChikaOheLife Science Research Infrastructure Group, Advanced Photon Technology Division, RIKEN SPring-8 CenterShukuSajiStructural Biology Division, Japan Synchrotron Radiation Research InstituteSachikoYamamotoStructural Biology Division, Japan Synchrotron Radiation Research InstituteMasakiYamamotoLife Science Research Infrastructure Group, Advanced Photon Technology Division, RIKEN SPring-8 CenterHiroshiNakagawaMaterials Sciences Research Center, Japan Atomic Energy AgencyNobuoOkazakiNeutron Science and Technology Center, Comprehensive Research Organization for Science and Society (CROSS)MamoruOuchidaDepartment of Molecular Oncology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityIoriKawasaki-OhmoriSection of Developmental Physiology and Pathology, Faculty of Education, Okayama UniversityKoheiTakeshitaLife Science Research Infrastructure Group, Advanced Photon Technology Division, RIKEN SPring-8 CenterThioredoxin is a ubiquitous redox protein that acts as an electron donor via its conserved dithiol motif (C32GPC35), catalyzing dithiol–disulfide exchange to regulate the redox state of target proteins. It supports antioxidant defense via peroxiredoxins, facilitates DNA synthesis by donating electrons to ribonucleotide reductase, and regulates redox-sensitive signaling pathways, including those controlling transcription and apoptosis. Neuronal degeneration and chronic kidney disease have been observed in Txn-F54L mutant rats; however, the details of why the Txn mutation causes these phenomena remain unknown. The present study aimed to elucidate the functional and structural changes caused by the F54L mutation. The Thioredoxin-F54L showed less insulin-reducing activity and more thermosensitivity to denaturation in the body temperature range compared to the wild type. The crystal structure revealed that F54 forms hydrophobic interactions with the surrounding hydrophobic amino acids. In addition, molecular dynamics simulation predicts increased fluctuations around the F54L mutation and a tendency for the distance between residues C32 and C35 at the catalytic center to be widened. The increased distance between residues C32 and C35 of the catalytic center may affect the reducing activity of the enzyme on the substrate. The finding that Thioredoxin-F54L is prone to denaturation at normal body temperature may reduce the normally functioning Thioredoxin. These molecular characteristics of Thioredoxin-F54L may be related to brain and kidney disease development in the Txn-F54L rats.No potential conflict of interest relevant to this article was reported.Oxford University Press (OUP)Acta Medica Okayama1743-60952025Dual-action intranasal oxytocin enhances both male sexual performance and fertility in rats13ENChicaEnomotoDepartment of Biology, Faculty of Environmental, Life, Natural Science and Technology, Okayama UniversityTakumiOtiDepartment of Biology, Faculty of Environmental, Life, Natural Science and Technology, Okayama UniversityTakahiroYamanakaLaboratory of Reproductive Endocrinology, Graduate School of Integrated Sciences for Life, Hiroshima UniversityMasayukiShimadaLaboratory of Reproductive Endocrinology, Graduate School of Integrated Sciences for Life, Hiroshima UniversityHirotakaSakamotoDepartment of Biology, Faculty of Environmental, Life, Natural Science and Technology, Okayama UniversityNo potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama1422-006726172025Anti-HMGB1 Antibody Therapy Ameliorates Spinal Cord Ischemia–Reperfusion Injury in Rabbits8643ENGenyaMuraokaDepartment of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuhiroFujiiDepartment of Translational Research, Center for Innovative Clinical Medicine, Medical Development Field, Okayama UniversityKeyueLiuDepartment of Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHandongQiaoDepartment of Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityDengliWangDepartment of Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityDaikiOusakaDepartment of Medical Technology, Faculty of Science, Okayama University of ScienceSusumuOozawaDivision of Medical Safety Management, Safety Management Facility, Okayama University HospitalShingoKasaharaDepartment of Cardiovascular Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMasahiroNishiboriDepartment of Translational Research and Drug Development, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversitySpinal cord ischemia–reperfusion (SCI/R) injury remains a major clinical challenge with limited therapeutic options. High-mobility group box 1 (HMGB1), a proinflammatory mediator released during cellular stress, has been implicated in the pathogenesis of ischemia–reperfusion-induced neural damage. In this study, we investigated the neuroprotective potential of the anti-HMGB1 monoclonal antibody (mAb) in a rabbit model of SCI/R injury. Male New Zealand White rabbits were anesthetized and subjected to 11 min of abdominal aortic occlusion using a micro-bulldog clamp following heparinization. Anti-HMGB1 mAb or control IgG was administered intravenously immediately after reperfusion and again at 6 h post-reperfusion. Neurological function was assessed at 6, 24, and 48 h after reperfusion using the modified Tarlov scoring system. The rabbits were euthanized 48 h after reperfusion for spinal cord and blood sampling. Treatment with anti-HMGB1 mAb significantly improved neurological outcomes, reduced the extent of spinal cord infarction, preserved motor neuron viability, and decreased the presence of activated microglia and infiltrating neutrophils. Furthermore, it attenuated apoptosis, oxidative stress, and inflammatory responses in the spinal cord, and helped maintain the integrity of the blood–spinal cord barrier. These findings suggest that anti-HMGB1 mAb may serve as a promising therapeutic agent for SCI/R injury.No potential conflict of interest relevant to this article was reported.Institute of Electrical and Electronics Engineers (IEEE)Acta Medica Okayama2169-3536132025Optimized Ensemble Deep Learning for Real-Time Intrusion Detection on Resource-Constrained Raspberry Pi Devices113544113556ENMuhammad BisriMusthafaGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversitySamsulHudaInterdisciplinary Education and Research Field, Okayama UniversityTuy TanNguyenSchool of Informatics, Computing, and Cyber Systems, Northern Arizona UniversityYutaKoderaGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityYasuyukiNogamiGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityThe rapid growth of Internet of Things (IoT) networks has increased security risks, making it essential to have effective Intrusion Detection Systems (IDS) for real-time threat detection. Deep learning techniques offer promising solutions for such detection due to their superior complex pattern recognition and anomaly detection capabilities in large datasets. This paper proposes an optimized ensemble-based IDS designed specifically for efficient deployment on edge hardware. However, deploying such computationally intensive models on resource-limited edge devices remains a significant challenge due to model size and computational overhead on devices with limited processing capabilities. Building upon our previously developed stacked Long Short-Term Memory (LSTM) model integrated with ANOVA feature selection, we optimize it by integrating dual-stage model compression: pruning and quantization to create a lightweight model suitable for real-time inference on Raspberry Pi devices. To evaluate the system under realistic conditions, we combined with a Kafka-based testbed to simulate dynamic IoT environments with variable traffic loads, delays, and multiple simultaneous attack sources. This enables the assessment of detection performance under varying traffic volumes, latency, and overlapping attack scenarios. The proposed system maintains high detection performance with accuracy of 97.3% across all test scenarios, while efficiently leveraging multi-core processing with peak CPU usage reaching 111.8%. These results demonstrate the system’s practical viability for real-time IoT security at the edge.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1432-053314912025Cerebral Braak stage and amygdala granular fuzzy astrocyte status have independent effects on neuronal 3R-tau and 4R-tau accumulations in the olfactory bulb, respectively, in cases with low to intermediate AD neuropathologic change36ENOsamuYokotaDepartment of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomokoMikiDepartment of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHanaeNakashima-YasudaOkayama University Medical SchoolHidekiIshizuOkayama University Medical SchoolTakashiHaraguchiDepartment of Neurology, National Hospital Organization Minami-Okayama Medical CenterAkinoriMiyashitaDepartment of Molecular Genetics, Brain Research Institute, Niigata UniversityTakeshiIkeuchiDepartment of Molecular Genetics, Brain Research Institute, Niigata UniversityMasatoHasegawaDementia Research Project, Tokyo Metropolitan Institute of Medical ScienceNaotoNishikawaDepartment of Neuropsychiatry, Okayama University HospitalShintaroTakenoshitaDepartment of Neuropsychiatry, Okayama University HospitalSeishiTeradaDepartment of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesManabuTakakiDepartment of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNo potential conflict of interest relevant to this article was reported.S. Karger AGActa Medica Okayama1015-97702025Asymptomatic intracranial vascular lesions and cognitive function in a general population of Japanese men: Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA)ENTakahiroItoDepartment of Radiology, Shiga University of Medical ScienceAkiraFujiyoshiDepartment of Radiology, Shiga University of Medical ScienceTakayoshiOhkuboDepartment of Hygiene and Public Health, Teikyo University School of MedicineAkihikoShiinoMolecular Neuroscience Research Center, Shiga University of Medical ScienceSatoshiShitaraDepartment of Neurosurgery, Shiga University of Medical ScienceNaokoMiyagawaDepartment of Preventive Medicine and Public Health, Keio University School of MedicineSayukiToriiDepartment of Radiology, Shiga University of Medical ScienceTakashiHisamatsuDepartment of Public Health, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyoshiSegawaDepartment of Radiology, Shiga University of Medical ScienceKeikoKondoDepartment of Radiology, Shiga University of Medical ScienceAyaKadotaDepartment of Radiology, Shiga University of Medical ScienceIkuoTooyamaMolecular Neuroscience Research Center, Shiga University of Medical ScienceYoshiyukiWatanabeDepartment of Radiology, Shiga University of Medical ScienceKazumichiYoshidaDepartment of Neurosurgery, Shiga University of Medical ScienceKazuhikoNozakiDepartment of Neurosurgery, Shiga University of Medical ScienceKatsuyukiMiuraDepartment of Radiology, Shiga University of Medical ScienceThe SESSA Research GroupIntroduction: Intracranial subclinical vessel diseases are considered important indicators of cognitive impairment. However, a comprehensive assessment of various types of vessel disease, particularly in Asian populations, is lacking. We aimed to compare multiple types of intracranial vessel disease in association with cognitive function among a community-based Japanese male population. Methods: The Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA) randomly recruited and examined a community-based cohort of Japanese men from Shiga, Japan. We analyzed those who underwent the Cognitive Abilities Screening Instrument (CASI) assessment and cranial magnetic resonance imaging/angiogram (MRI/MRA) in 2010–2015. Using MRI/MRA, we assessed lacunar infarction, microbleeds, periventricular hyperintensity (PVH), deep subcortical white matter hyperintensity (DSWMH), and intracranial artery stenosis (ICAS). We divided these subclinical cerebrovascular diseases (SCDs) into three categories according to severity. Using linear regression, we calculated the CASI score according to the grade of each vessel disease, adjusted for age and years of education. Results: In the adjusted models, CASI scores were significantly associated with both PVH and DSWMH. Specifically, multivariable-adjusted CASI scores declined across increasing severity categories of DSWMH (91.7, 91.2, and 90.4; p for trend = 0.011) and PVH (91.5, 90.4, and 89.7; p for trend = 0.006). Other SCDs did not show significant associations. In stratified analyses based on the presence or absence of each SCD, both DSWMH and PVH demonstrated significant inverse trends with CASI scores in the absence of lacunar infarcts and microbleeds and in the presence of ICAS. Additionally, among participants with PVH (+), ≥moderate ICAS was significantly associated with lower CASI scores. Conclusion: PVH and DSWMH showed significant dose-response relationships with cognitive function among community-based Japanese men. These findings suggest that white matter lesions may be an important indicator of early cognitive impairment, and severe ICAS may also play a role in those with PVH.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama2667-2421182025Postnatal expression of Cat-315-positive perineuronal nets in the SAMP10 mouse primary somatosensory cortex244256ENHiroshiUenoDepartment of Medical Technology, Kawasaki University of Medical WelfareYuTakahashiDepartment of Psychiatry, Kawasaki Medical SchoolSachikoMoriDepartment of Psychiatry, Kawasaki Medical SchoolErikoKitanoDepartment of Psychiatry, Kawasaki Medical SchoolShinjiMurakamiDepartment of Psychiatry, Kawasaki Medical SchoolKentaWaniDepartment of Psychiatry, Kawasaki Medical SchoolYosukeMatsumotoDepartment of Neuropsychiatry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMotoiOkamotoDepartment of Medical Technology, Graduate School of Health Sciences, Okayama UniversityTakeshiIshiharaDepartment of Psychiatry, Kawasaki Medical SchoolPerineuronal nets (PNNs) form at the end of the critical period of plasticity in the mouse primary somatosensory cortex. PNNs are said to have functions that control neuroplasticity and provide neuroprotection. However, it is not clear which molecules in PNNs have these functions. We have previously reported that Cat-315-positive molecules were not expressed in the PNNs of the senescence-accelerated model (SAM)P10 strain model mice at 12 months of age. To confirm whether the loss of Cat-315-positive molecules occurred early in life in SAMP10 mice, we examined Cat-315-positive PNNs in the primary somatosensory cortex during postnatal development. This research helps to elucidate the function of PNNs and the mechanism of cognitive decline associated with ageing. To confirm whether Cat-315-positive PNNs changed in an age-dependent manner in SAMP10 mice, we examined the primary somatosensory cortex at 21, 28, and 56 days after birth. We compared these results with those of senescence-accelerated mouse-resistant (SAMR) mice. In SAMP10 mice, Cat-315-positive PNNs were expressed in the primary somatosensory cortex early after birth, but their expression was significantly lower than that in SAMR1 mice. Many other molecules that calibrated the PNN were unchanged between SAMP10 and SAMR1 mice. This study revealed that the expression of the Cat-315 epitope was decreased in the primary somatosensory cortex of SAMP10 mice during postnatal development. SAMP10 mice have had histological abnormalities in their brains since early life. Furthermore, using SAMP10 will be useful in elucidating the mechanism of age-related abnormalities in brain function as well as in elucidating the function and structure of PNNs.No potential conflict of interest relevant to this article was reported.Walter de Gruyter GmbHActa Medica Okayama2081-69361612025Age-related behavioural abnormalities in C57BL/6.KOR–Apoe shl miceENHiroshiUenoDepartment of Medical Technology, Kawasaki University of Medical WelfareYuTakahashiDepartment of Psychiatry, Kawasaki Medical SchoolSachikoMoriDepartment of Psychiatry, Kawasaki Medical SchoolErikoKitanoDepartment of Psychiatry, Kawasaki Medical SchoolShinjiMurakamiDepartment of Psychiatry, Kawasaki Medical SchoolKentaWaniDepartment of Psychiatry, Kawasaki Medical SchoolTetsujiMiyazakiDepartment of Psychiatry, Kawasaki Medical SchoolYosukeMatsumotoDepartment of Neuropsychiatry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMotoiOkamotoDepartment of Medical Technology, Graduate School of Health Sciences, Okayama UniversityTakeshiIshiharaDepartment of Psychiatry, Kawasaki Medical SchoolSpontaneously hyperlipidaemic (Apoeshl) mice were discovered in 1999 as mice lacking apolipoprotein E (ApoE) owing to a mutation in the Apoe gene. However, age-related behavioural changes in commercially available Apoeshl mice have not yet been clarified. The behavioural abnormalities of ApoE-deficient mice, which are genetically modified mice artificially deficient in ApoE, have been investigated in detail, and it has been reported that they can serve as a model of Alzheimer’s disease (AD). To understand whether Apoeshl mice can also serve as a murine model of AD, it is necessary to investigate age-related behavioural abnormalities in Apoeshl mice. In this study, we conducted a series of behavioural experiments on 7- and 11-month-old Apoeshl mice to investigate the behavioural abnormalities associated with ageing in Apoeshl mice. In this study, 7-month-old Apoeshl mice showed decreased body weight and grip strength compared to age-matched wild-type mice. In the open field test, 7-month-old Apoeshl mice showed increased anxiety-like behaviour compared to wild-type mice, whereas 11-month-old Apoeshl mice showed decreased anxiety-like behaviour. Moreover, Apoeshl mice aged 7 and 11 months had increased serum cholesterol levels. These results indicate that the behaviour of Apoeshl mice changes with age. However, 11-month-old Apoeshl mice did not show a decline in cognitive function or memory ability similar to murine models of AD. Our findings indicate that Apoeshl mice can be used to investigate the function of ApoE in the central nervous system.No potential conflict of interest relevant to this article was reported.Walter de Gruyter GmbHActa Medica Okayama2081-69361612025Rearing in an envy-like environment increases anxiety-like behaviour in miceENHiroshiUenoDepartment of Medical Technology, Kawasaki University of Medical WelfareErikoKitanoDepartment of Psychiatry, Kawasaki Medical SchoolYuTakahashiDepartment of Psychiatry, Kawasaki Medical SchoolSachikoMoriDepartment of Psychiatry, Kawasaki Medical SchoolShinjiMurakamiDepartment of Psychiatry, Kawasaki Medical SchoolKentaWaniDepartment of Psychiatry, Kawasaki Medical SchoolYosukeMatsumotoDepartment of Neuropsychiatry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMotoiOkamotoDepartment of Medical Technology, Graduate School of Health Sciences, Okayama UniversityTakeshiIshiharaDepartment of Psychiatry, Kawasaki Medical SchoolInterest in the societal and psychological harm caused by widespread envy and social comparison is increasing. Envy is associated with anxiety and depression, though the mechanism by which envy affects neuropsychiatric disorders, such as depression, remains unclear. Clarifying the neurobiological basis of envy’s effects on behaviour and emotion regulation in experimental mice is essential for developing disease-prevention and treatment strategies. As mice recognize other mice in neighbouring cages, this study investigated whether they recognize neighbouring cages housed in environmentally enriched cages and suffer psychological stress due to envy. After being raised in an envy-like environment for 3 weeks, we revealed changes in the behaviour of the mice through a series of behavioural experiments. Mice raised in an envious environment showed increased body weight and anxiety-like behaviour but decreased social behaviour and serum corticosterone levels compared to control mice. Thus, mice recognize their neighbouring cages and experience psychological stress due to envy. This study revealed a part of the scientific basis for why envy increased anxiety. Using this novel experimental breeding environment, it may be possible to create an experimental animal model of anxiety disorders.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama0953-418020242024Mice Recognise Mice in Neighbouring Rearing Cages and Change Their Social Behaviour9215607ENHiroshiUenoDepartment of Medical Technology, Kawasaki University of Medical WelfareYuTakahashiDepartment of Psychiatry, Kawasaki Medical SchoolSachikoMoriDepartment of Psychiatry, Kawasaki Medical SchoolShinjiMurakamiDepartment of Psychiatry, Kawasaki Medical SchoolKentaWaniDepartment of Psychiatry, Kawasaki Medical SchoolYosukeMatsumotoDepartment of Neuropsychiatry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMotoiOkamotoDepartment of Medical Technology, Graduate School of Health Sciences, Okayama UniversityTakeshiIshiharaDepartment of Psychiatry, Kawasaki Medical SchoolMice are social animals that change their behaviour primarily in response to visual, olfactory, and auditory information from conspecifics. Rearing conditions such as cage size and colour are important factors influencing mouse behaviour. In recent years, transparent plastic cages have become standard breeding cages. The advantage of using a transparent cage is that the experimenter can observe the mouse from outside the cage without touching the cage. However, mice may recognise the environment outside the cage and change their behaviour. We speculated that mice housed in transparent cages might recognise mice in neighbouring cages. We used only male mice in this experiment. C57BL/6 mice were kept in transparent rearing cages with open lids, and the cage positions were maintained for 3 weeks. Subsequently, we examined how mice behaved toward cagemate mice, mice from neighbouring cages, and mice from distant cages. We compared the level of interest in mice using a social preference test. Similar to previous reports, subject mice showed a high degree of interest in unfamiliar mice from distant cages. By contrast, subject mice reacted to mice from neighbouring cages as familiar mice, similar to cagemate mice. This suggests that mice housed in transparent cages with open lids perceive the external environment and identify mice in neighbouring cages. Researchers should pay attention to the environment outside the mouse cage, especially for the social preference test.No potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama2227-903213122025Association Between Chewing Status and Steatotic Liver Disease in Japanese People Aged ≥50 Years: A Cohort Study1399ENKomeiIwaiDepartment of Community Oral Health, School of Dentistry, Asahi UniversityDaisukeEkuniDepartment of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTetsujiAzumaDepartment of Community Oral Health, School of Dentistry, Asahi UniversityTakatoshiYonenagaDepartment of Community Oral Health, School of Dentistry, Asahi UniversityKoichiroTabataDepartment of Community Oral Health, School of Dentistry, Asahi UniversityNaokiToyamaDepartment of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKotaKataokaDepartment of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakayukiMaruyamaDepartment of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakaakiTomofujiDepartment of Community Oral Health, School of Dentistry, Asahi UniversityBackground/Objectives: In this longitudinal study, the relationship between chewing status and steatotic liver disease (SLD) was examined in 3775 people aged ≥50 years who underwent medical checkups at Junpukai Health Maintenance Center in Okayama, Japan. Methods: Participants without SLD at the time of a baseline survey in 2018 were followed until 2022. Chewing status was assessed by a self-administered questionnaire. The presence or absence of SLD was ascertained from the medical records of Junpukai Health Maintenance Center. Results: A total of 541 participants (14%) were diagnosed as having a poor chewing status at baseline. Furthermore, 318 (8%) participants were newly diagnosed with SLD at follow-up. In multivariate logistic regression analyses, the presence or absence of SLD was found to be associated with the following characteristics at baseline: sex (male: odds ratio [ORs] = 1.806; 95% confidence interval [CIs]: 1.399–2.351), age (ORs = 0.969; 95% CIs: 0.948–0.991), body mass index (≥25.0 kg/m2; ORs = 1.934; 95% CIs: 1.467–2.549), diastolic blood pressure (ORs = 1.017; 95% CIs: 1.002–1.032), and chewing status (poor: ORs = 1.472; 95% CIs: 1.087–1.994). Conclusions: The results indicate that a poor chewing status was associated with SLD development after 4 years. Aggressively recommending dental visits to participants with poor chewing status may not only improve their ability to chew well but may also reduce the incidence of SLD.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama2666-33416S12025Basic biology is not just “for the birds”: how avian studies have informed us about vertebrate reproduction712ENGeorge E.BentleyDepartment of Integrative Biology and Helen Wills Neuroscience Institute, University of California at BerkeleySayakaAizawaGraduate School of Natural Science and Technology, Okayama UniversityAvian reproductive physiology has been studied for centuries, largely because of the importance of birds as food animals. It is likely that the ubiquity and ease of access to domesticated chickens led to them being used in some of the first experiments on transplantation of endocrine structures—in this case, the testes. Since then, study of seasonal changes in reproductive physiology (photoperiodism) in different orders of bird species has led to advances in the understanding of endocrine regulation of reproductive physiology and behavior. These include mechanisms of adult neuroplasticity, sexual selection, sperm competition, stress physiology, and circadian physiology. Here, we focus mainly on the discovery in birds of a neuropeptide named gonadotropin-inhibitory hormone that mostly has inhibitory effects on reproduction. This hormone has since been shown to exist in all mammals studied to date, including humans (it is known as RFamide-related peptide in mammals). We discuss the history and implications of avian studies on gonadotropin-inhibitory hormone/RFamide-related peptide for human reproductive biology.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2041-17231512024Neurotransmitter recognition by human vesicular monoamine transporter 27661ENDohyunImDepartment of Cell Biology, Graduate School of Medicine, Kyoto UniversityMikaJormakkaDepartment of Cell Biology, Graduate School of Medicine, Kyoto UniversityNarinobuJugeDepartment of Genomics and Proteomics, Advanced Science Research Center, Okayama UniversityJun-ichiKishikawaDepartment of Applied Biology, Kyoto Institute of TechnologyTakayukiKatoInstitute for Protein Research, Osaka UniversityYukihikoSugitaLaboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto UniversityTakeshiNodaLaboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto UniversityTomokoUemuraDepartment of Cell Biology, Graduate School of Medicine, Kyoto UniversityYukiShiimuraDepartment of Cell Biology, Graduate School of Medicine, Kyoto UniversityTakaakiMiyajiDepartment of Genomics and Proteomics, Advanced Science Research Center, Okayama UniversityHidetsuguAsadaDepartment of Cell Biology, Graduate School of Medicine, Kyoto UniversitySoIwataDepartment of Cell Biology, Graduate School of Medicine, Kyoto UniversityHuman vesicular monoamine transporter 2 (VMAT2), a member of the SLC18 family, plays a crucial role in regulating neurotransmitters in the brain by facilitating their uptake and storage within vesicles, preparing them for exocytotic release. Because of its central role in neurotransmitter signalling and neuroprotection, VMAT2 is a target for neurodegenerative diseases and movement disorders, with its inhibitor being used as therapeutics. Despite the importance of VMAT2 in pharmacophysiology, the molecular basis of VMAT2-mediated neurotransmitter transport and its inhibition remains unclear. Here we show the cryo-electron microscopy structure of VMAT2 in the substrate-free state, in complex with the neurotransmitter dopamine, and in complex with the inhibitor tetrabenazine. In addition to these structural determinations, monoamine uptake assays, mutational studies, and pKa value predictions were performed to characterize the dynamic changes in VMAT2 structure. These results provide a structural basis for understanding VMAT2-mediated vesicular transport of neurotransmitters and a platform for modulation of current inhibitor design.No potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama2673-4087622025An Endocrine-Disrupting Chemical, Bisphenol A Diglycidyl Ether (BADGE), Accelerates Neuritogenesis and Outgrowth of Cortical Neurons via the G-Protein-Coupled Estrogen Receptor53ENIkukoMiyazakiDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesChiharuNishiyamaDepartment of Medical Neurobiology, Okayama University Medical SchoolTakeruNagoshiDepartment of Medical Neurobiology, Okayama University Medical SchoolAkaneMiyakoDepartment of Medical Neurobiology, Okayama University Medical SchoolSuzukaOnoDepartment of Medical Neurobiology, Okayama University Medical SchoolIchikaMisawaDepartment of Medical Neurobiology, Okayama University Medical SchoolAikaIsseDepartment of Medical Neurobiology, Okayama University Medical SchoolKanaTomimotoDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKaoriMasaiDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazumasaZenshoDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasatoAsanumaDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBisphenol A diglycidyl ether (BADGE) is the main component of epoxy resin and is used for the inner coating of canned foods and plastic food containers. BADGE can easily migrate from containers and result in food contamination; the compound is known as an endocrine-disrupting chemical. We previously reported that maternal exposure to bisphenol A bis (2,3-dihydroxypropyl) ether (BADGE·2H2O), which is the most detected BADGE derivative not only in canned foods but also in human specimens, during gestation and lactation, could accelerate neuronal differentiation in the cortex of fetuses and induce anxiety-like behavior in juvenile mice. In this study, we investigated the effects of low-dose BADGE·2H2O (1–100 pM) treatment on neurites and the mechanism of neurite outgrowth in cortical neurons. BADGE·2H2O exposure significantly increased the number of dendrites and neurite length in cortical neurons; these accelerating effects were inhibited by estrogen receptor (ER) antagonist ICI 182,780 and G-protein-coupled estrogen receptor (GPER) antagonist G15. BADGE·2H2O down-regulated Hes1 expression, which is a transcriptional repressor, and increased levels of neuritogenic factor neurogenin-3 (Ngn3) in the cortical neurons; the changes were significantly blocked by G15. These data suggest that direct BADGE·2H2O exposure can accelerate neuritogenesis and outgrowth in cortical neurons through down-regulation of Hes1 and by increasing Ngn3 levels through ERs, particularly GPER.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0022-510X4722025Clinical, neuroimaging and genetic findings in the Japanese case series of CLCN2-related leukoencephalopathy123486ENKentaOrimoDepartment of Neurology, Graduate School of Medicine, The University of TokyoTakashiMatsukawaDepartment of Neurology, Graduate School of Medicine, The University of TokyoAkihikoMitsutakeDepartment of Neurology, Graduate School of Medicine, The University of TokyoTakuseiChoDepartment of Neurology, Graduate School of Medicine, The University of TokyoHiroyaNaruseDepartment of Neurology, Graduate School of Medicine, The University of TokyoYoshioSakiyamaDivision of Neurology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical UniversityKenshoSumiDepartment of Neurology, Mitsui Memorial HospitalNaohiroUchioDepartment of Neurology, Mitsui Memorial HospitalAkaneSatakeDepartment of Neurology, Fuefuki Central HospitalYoshihisaTakiyamaDepartment of Neurology, Fuefuki Central HospitalTakuyaMatsushitaDepartment of Neurology, Kochi Medical School, Kochi UniversityYosukeOmaeGenome Medical Science Project, National Center for Global Health and MedicineYosukeKawaiGenome Medical Science Project, National Center for Global Health and MedicineKatsushiTokunagaGenome Medical Science Project, National Center for Global Health and MedicineJunMitsuiDepartment of Precision Medicine Neurology, Graduate School of Medicine, The University of TokyoHiroyukiIshiuraDepartment of Neurology, Graduate School of Medicine, The University of TokyoShojiTsujiDepartment of Neurology, Graduate School of Medicine, The University of TokyoTatsushiTodaDepartment of Neurology, Graduate School of Medicine, The University of TokyoBiallelic loss-of-function variants in CLCN2 lead to CLCN2-related leukoencephalopathy (CC2L), also called leukoencephalopathy with ataxia (LKPAT). CC2L is characterized clinically by a spectrum of clinical presentations including childhood- to adult-onset mild ataxia, spasticity, cognitive decline, and vision loss as well as typical MRI findings of symmetrical high signal intensities on the DWIs/T2WIs of the middle cerebellar peduncles (MCPs). We searched for pathogenic variants of CLCN2 in a case series of undiagnosed leukoencephalopathy accompanied by MCP signs, which led to the identification of four Japanese patients with CC2L. All the patients carried at least one allele of c.61dupC (p.Leu21Profs*27) in CLCN2, including compound heterozygosity with either the novel pathogenic variant c.983 + 2 T > A or the previously reported pathogenic variant c.1828C > T (p.Arg610*). Of note, all the four previously reported cases from Japan also harbored c.61dupC, and no reports of this variant have been documented from outside Japan. The allele frequency of c.61dupC in the Japanese population is 0.002152, raising the possibility of a relatively high prevalence of CC2L in Japan. Patients in this study developed symptoms after the age of 30, and demonstrated neurological signs including cerebellar ataxia, pyramidal signs, and mild cognitive impairment, consistent with previous reports. One male patient had two children, supporting preserved fertility, and another patient had calcifications in the cerebral and cerebellar surfaces. These findings provide valuable insights into the broader clinical and genetic spectra of CC2L in the Japanese population, and emphasize the importance of considering this disease in the differential diagnoses of leukoencephalopathy with MCP signs.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0168-01022192025Establishment of a transgenic strain for the whole brain calcium imaging in larval medaka fish (Oryzias latipes)104944ENTakahideSekiGraduate School of Life Sciences, Tohoku UniversityKazuhiroMiyanariGraduate School of Science and Engineering, Saitama UniversityAsukaShiraishiGraduate School of Science and Engineering, Saitama UniversitySachikoTsudaGraduate School of Science and Engineering, Saitama UniversitySatoshiAnsaiUshimado Marine Institute, Okayama UniversityHideakiTakeuchiGraduate School of Life Sciences, Tohoku UniversityGCaMP-based calcium imaging is a powerful tool for investigating neural function in specific neurons. We generated transgenic (Tg) medaka strains expressing jGCaMP7s across extensive brain regions under the control of the gap43 promoter. Using these Tg larvae, calcium imaging successfully detected a tricaine-induced suppression of spontaneous neural activity and topographical visual responses in the optic tectum elicited by moving paramecia or optical fiber stimulation. These results indicate that our Tg medaka strains provide a versatile platform for investigating neural dynamics and their responses to various stimuli.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1758-91931612024Impact of amyloid and tau positivity on longitudinal brain atrophy in cognitively normal individuals77ENMotonobuFujishimaDepartment of Radiology, Kumagaya General HospitalYoheiKawasakiDepartment of Biostatistics, Graduate School of Medicine, Saitama Medical UniversityToshiharuMitsuhashiCenter for Innovative Clinical Medicine, Okayama University HospitalHiroshiMatsudaDepartment of Biofunctional Imaging, Fukushima Medical UniversityBackground Individuals on the preclinical Alzheimer's continuum, particularly those with both amyloid and tau positivity (A + T +), display a rapid cognitive decline and elevated disease progression risk. However, limited studies exist on brain atrophy trajectories within this continuum over extended periods.<br>
Methods This study involved 367 ADNI participants grouped based on combinations of amyloid and tau statuses determined through cerebrospinal fluid tests. Using longitudinal MRI scans, brain atrophy was determined according to the whole brain, lateral ventricle, and hippocampal volumes and cortical thickness in AD-signature regions. Cognitive performance was evaluated with the Preclinical Alzheimer's Cognitive Composite (PACC). A generalized linear mixed-effects model was used to examine group × time interactions for these measures. In addition, progression risks to mild cognitive impairment (MCI) or dementia were compared among the groups using Cox proportional hazards models.<br>
Results A total of 367 participants (48 A + T + , 86 A + T − , 63 A − T + , and 170 A − T − ; mean age 73.8 years, mean follow-up 5.1 years, and 47.4% men) were included. For the lateral ventricle and PACC score, the A + T − and A + T + groups demonstrated statistically significantly greater volume expansion and cognitive decline over time than the A − T − group (lateral ventricle: β = 0.757 cm3/year [95% confidence interval 0.463 to 1.050], P < .001 for A + T − , and β = 0.889 cm3/year [0.523 to 1.255], P < .001 for A + T + ; PACC: β = − 0.19 /year [− 0.36 to − 0.02], P = .029 for A + T − , and β = − 0.59 /year [− 0.80 to − 0.37], P < .001 for A + T +). Notably, the A + T + group exhibited additional brain atrophy including the whole brain (β = − 2.782 cm3/year [− 4.060 to − 1.504], P < .001), hippocampus (β = − 0.057 cm3/year [− 0.085 to − 0.029], P < .001), and AD-signature regions (β = − 0.02 mm/year [− 0.03 to − 0.01], P < .001). Cox proportional hazards models suggested an increased risk of progressing to MCI or dementia in the A + T + group versus the A − T − group (adjusted hazard ratio = 3.35 [1.76 to 6.39]).<br>
Conclusions In cognitively normal individuals, A + T + compounds brain atrophy and cognitive deterioration, amplifying the likelihood of disease progression. Therapeutic interventions targeting A + T + individuals could be pivotal in curbing brain atrophy, cognitive decline, and disease progression.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7942025A Study of Periprosthetic Femoral Stem Fractures in Hip Arthroplasty for Femoral Neck Fracture253259ENYoshiakiMiyakeDepartment of Orthopaedic Surgery, Japanese Red Cross Okayama HospitalToruTakagiDepartment of Orthopaedic Surgery, Japanese Red Cross Okayama HospitalTaizoKonishiikeDepartment of Orthopaedic Surgery, Japanese Red Cross Okayama HospitalOriginal Article10.18926/AMO/69150This study investigated the risk factors for bone fragility and perioperative periprosthetic femoral stem fractures in patients undergoing hip arthroplasty for femoral neck fractures. The records of 215 patients (42 male, 173 female; mean age, 84.4 years) were analyzed to assess correlations among periprosthetic fracture rates and sex, age, body mass index (BMI), Dorr classification, femoral stem fixation type (cemented/cementless), and bone mineral density (BMD) of the contralateral proximal femur. The overall prevalence of perioperative periprosthetic fractures was 4.7%. All patients with periprosthetic fractures were female, and all but one were ≥ 80 years of age. Fracture rates were higher in patients with lower BMI, although this difference was not significant. The fracture rates were 0%, 4.7%, and 7.9% for Dorr types A, B, and C, respectively, and 0% and 5.3% for patients who received cemented and cementless stems, respectively. The findings indicated that female patients, those of advanced age, those with lower BMI, and those with Dorr type C had lower BMDs. Although BMD was significantly lower in patients who received cemented stems compared to those who received cementless stems, no fractures were observed in the former group, suggesting that the use of cemented stems is safe for this high-risk population.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama2589-9864312025Investigation of the relationship between 0.5–1200 Hz signal characteristics of cortical high-frequency oscillations and epileptogenicity through multivariate analysis100776ENTakashiShibataDepartment of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University HospitalHirokiTsuchiyaDepartment of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University HospitalMariAkiyamaDepartment of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University HospitalTomoyukiAkiyamaDepartment of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University HospitalMasaoMatsuhashiDepartment of Epilepsy, Movement Disorders and Physiology, Graduate School of Medicine, Kyoto UniversityKatsuhiroKobayashiDepartment of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University HospitalFast ripples (FRs) (250–500 Hz) on the electroencephalogram (EEG) are closely related to epileptogenicity and are important to determine cortical regions resected in epilepsy surgery. However, FR-related epileptogenicity may be variable, and may depend on information associated with FRs. We enrolled nine epilepsy patients who had undergone intracranial 5 kHz-sampling-rate EEG for surgical treatment and had final Engel class I outcomes. Three electrodes were selected from each epileptogenic area (EA) and the unlikely EA (the region outside the EA) in each patient. Up to 100 candidate FRs were automatically detected from interictal nocturnal EEG at each of the selected electrodes and were visually reviewed independently by two researchers. Multivariate logistic regression analysis was performed using the frequency and log-power value of the corresponding FRs, presence of concurrent spike, ripple, very-high-frequency oscillations (vHFO)1 (500–600 Hz), and vHFO2 (600–1200 Hz), and whether the timing of the spectral peak of corresponding FRs was in the peak–trough or trough–peak transition of each slow activity (0.5–1, 1–2, 2–3, 3–4, and 4–8 Hz) as independent variables. Factors significantly related to epileptogenicity were FR power, the concurrent presence of spike and vHFO2, coupling with 0.5–1 and 1–2 Hz slow waves in the peak–trough transition, and coupling with 3–4 and 4–8 Hz slow waves in the trough–peak transition. Multifactorial analysis of FRs may increase their usefulness, potentially leading to improved treatment outcomes in epilepsy surgery.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0387-76044712025Hypotheses of pathophysiological mechanisms in epileptic encephalopathies: A review104318ENKatsuhiroKobayashiDepartment of Pediatrics, Asahigawaso Rehabilitation and Medical CenterTakashiShibataDepartment of Pediatric Neurology, Okayama University Hospital and Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHirokiTsuchiyaDepartment of Pediatric Neurology, Okayama University Hospital and Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMariAkiyamaDepartment of Pediatric Neurology, Okayama University Hospital and Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTomoyukiAkiyamaDepartment of Pediatric Neurology, Okayama University Hospital and Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityIntroduction: Epileptic encephalopathy (EE) is a serious clinical issue that manifests as part of developmental and epileptic encephalopathy (DEE), particularly in childhood epilepsy. In EE, neurocognitive functions and behavior are impaired by intense epileptiform electroencephalogram (EEG) activity. Hypotheses of pathophysiological mechanisms behind EE are reviewed to contribute to an effective solution for EE.<br>
Review: Current hypotheses are as follows: 1) neuronal dysfunction based on genetic abnormalities that may affect neurocognitive functions and epilepsy separately; 2) impairment of synaptic homeostasis during sleep that may be responsible for DEE/EE with spike-and-wave activation in sleep; 3) abnormal subcortical regulation of the cerebral cortex; 4) abnormal cortical metabolism and hemodynamics with impairment of the neural network including default mode network; 5) neurotransmitter imbalance and disordered neural excitability; 6) the effects of neuroinflammation that may be caused by epileptic seizures and in turn aggravate epileptogenesis; 7) the interaction between physiological and pathological high-frequency EEG activity; etc. The causal relationship between epileptiform EEG activity and neurocognitive dysfunctions is small in DEE based on genetic abnormalities and it is largely unestablished in the other hypothetical mechanisms.<br>
Conclusion: We have not yet found answers to the question of whether the single-central or multiple derangements are present and what seizures and intense epileptiform EEG abnormalities mean in EE. We need to continue our best efforts in both aspects to elucidate the pathophysiological mechanisms of DEE/EE and further develop epilepsy treatment and precision medicine.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0340-535427212024Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis36ENSoOkuboDepartment of Neurology, Graduate School of Medicine, The University of TokyoHiroyaNaruseDepartment of Neurology, Graduate School of Medicine, The University of TokyoHiroyukiIshiuraDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAtsushiSudoDepartment of Neurology, Graduate School of Medicine, The University of TokyoKayokoEsakiDepartment of Biotechnology and Life Sciences, Faculty of Biotechnology and Life Sciences, Sojo UniversityJunMitsuiDepartment of Neurology, Graduate School of Medicine, The University of TokyoTakashiMatsukawaDepartment of Neurology, Graduate School of Medicine, The University of TokyoWataruSatakeDepartment of Neurology, Graduate School of Medicine, The University of TokyoPeterGreimelLaboratory for Cell Function Dynamics, RIKEN Centre for Brain SciencesNanokaShingaiDivision of Applied Life Science, Graduate School of Engineering, Sojo UniversityYasushiOyaDepartment of Neurology, National Center of Neurology and PsychiatryTakeoYoshikawaLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceShojiTsujiDepartment of Neurology, Graduate School of Medicine, The University of TokyoTatsushiTodaDepartment of Neurology, Graduate School of Medicine, The University of TokyoIntroduction Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the motor system. Pathogenic variants in SPTLC1, encoding a subunit of serine palmitoyltransferase, cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), and have recently been associated with juvenile ALS. SPTLC1 variants associated with ALS cause elevated levels of sphinganines and ceramides. Reports on ALS associated with SPTLC1 remain limited. This study aimed to investigate the frequency of SPTLC1 variants in ALS and relevant clinical characteristics.<br>
Methods We analyzed whole-exome and whole-genome sequence data from 40 probands with familial ALS and 413 patients with sporadic ALS without previously identified causative variants. Reverse transcription polymerase chain reaction (RT-PCR) analysis and droplet digital PCR (ddPCR) were used to assess splicing and mosaicism, respectively. Plasma sphingolipid levels were quantified to analyze biochemical consequences.<br>
Results The heterozygous c.58G>A, p.Ala20Thr variant was identified in a 21-year-old Japanese female patient presenting with symmetric weakness which slowly progressed over 15 years. RT-PCR analysis showed no splice defects. Plasma sphingolipid levels in the patient were significantly increased compared to her asymptomatic parents. ddPCR revealed that the asymptomatic father harbored a mosaic variant with 17% relative mutant allele abundance in peripheral blood leukocytes.<br>
Conclusions We identified a pathogenic c.58G>A, p.Ala20Thr SPTLC1 variant in a patient with juvenile ALS, likely inherited from an asymptomatic parent with mosaicism. Lipid analysis results are consistent with previous findings on SPTLC1-associated ALS. Further studies are necessary to determine the clinical effect of mosaic variants of SPTLC1.No potential conflict of interest relevant to this article was reported.Japanese Society of Internal MedicineActa Medica Okayama0918-291864122025Subacute Upper Motor Neuron Dysfunction Possibly Associated with the Anti-GM1 Autoantibody19001905ENSoOkuboDepartment of Neurology, Graduate School of Medicine, The University of TokyoMeikoMaedaDepartment of Neurology, Graduate School of Medicine, The University of TokyoKazutoKatsuseDepartment of Neurology, Graduate School of Medicine, The University of TokyoHiroyukiIshiuraDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuichiroShirotaDepartment of Neurology, Graduate School of Medicine, The University of TokyoMasashiHamadaDepartment of Neurology, Graduate School of Medicine, The University of TokyoWataruSatakeDepartment of Neurology, Graduate School of Medicine, The University of TokyoTatsushiTodaDepartment of Neurology, Graduate School of Medicine, The University of TokyoAnti-GM1 antibodies are associated with Guillain-Barré syndrome (GBS), primarily peripheral neuropathy. However, there are cases of anti-GM1 IgG antibody-positive GBS with upper motor neuron (UMN) signs. We herein report a case of gastrointestinal infection followed by subacute gait disturbance with predominant signs of UMN on a neurological examination. The serum and cerebrospinal fluid tests were positive for anti-GM1 and anti-asialo-GM1 IgG antibodies. An electrophysiological evaluation revealed normal nerve conduction and prolonged central motor conduction times. No magnetic resonance imaging abnormalities were observed. The symptoms improved with treatment, which was accompanied by decreased antibody titers. This case highlights the fact that anti-GM1 IgG-associated disorders may present with predominant UMN involvement.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0028-083663880492025Immune evasion through mitochondrial transfer in the tumour microenvironment225236ENHidekiIkedaDivision of Cell Therapy, Chiba Cancer Center Research InstituteKatsushigeKawaseDivision of Cell Therapy, Chiba Cancer Center Research InstituteTatsuyaNishiDepartment of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTomofumiWatanabeDepartment of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKeizoTakenagaDivision of Innovative Cancer Therapeutics, Chiba Cancer Center Research InstituteTakashiInozumeDivision of Cell Therapy, Chiba Cancer Center Research InstituteTakamasaIshinoDepartment of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShoAkiDivision of Nutriomics and Oncology, RCAST, The University of TokyoJasonLinDivision of Cell Therapy, Chiba Cancer Center Research InstituteShusukeKawashimaDivision of Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan Department of Dermatology, Graduate School of Medicine, Chiba UniversityJojiNagasakiDepartment of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYoukiUedaDepartment of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShinichiroSuzukiDepartment of Medical Oncology, Kindai University Faculty of MedicineHidekiMakinoshimaTsuruoka Metabolomics Laboratory, National Cancer CenterMakikoItamiDepartment of Surgical Pathology, Chiba Cancer CenterYukiNakamuraDivision of Cell Therapy, Chiba Cancer Center Research InstituteYasutoshiTatsumiDivision of Cell Therapy, Chiba Cancer Center Research InstituteYusukeSuenagaLaboratory of Evolutionary Oncology, Chiba Cancer Center Research InstituteTakaoMorinagaDivision of Cell Therapy, Chiba Cancer Center Research InstituteAkikoHonobe-TabuchiDepartment of Dermatology, Faculty of Medicine, University of YamanashiTakehiroOhnumaDepartment of Dermatology, Faculty of Medicine, University of YamanashiTatsuyoshiKawamuraDepartment of Dermatology, Faculty of Medicine, University of YamanashiYoshiyasuUmedaDepartment of Skin Oncology/Dermatology, Saitama Medical University International Medical CenterYasuhiroNakamuraDepartment of Skin Oncology/Dermatology, Saitama Medical University International Medical CenterYukikoKiniwaDepartment of Dermatology, Shinshu University School of MedicineEikiIchiharaDepartment of Allergy and Respiratory Medicine, Okayama University HospitalHidetoshiHayashiDepartment of Medical Oncology, Kindai University Faculty of MedicineJun-ichiroIkedaDepartment of Diagnostic Pathology, Graduate School of Medicine, Chiba UniversityToyoyukiHanazawaDepartment of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of MedicineShinichiToyookaDepartment of General Thoracic Surgery and Endocrinological Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHiroyukiManoDivision of Cellular Signalling, National Cancer Center Research InstituteTakujiSuzukiDepartment of Respirology, Graduate School of Medicine, Chiba UniversityTsuyoshiOsawaDivision of Nutriomics and Oncology, RCAST, The University of TokyoMasahitoKawazuDivision of Cell Therapy, Chiba Cancer Center Research InstituteYosukeTogashiDepartment of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityCancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack1. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses2,3,4. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs. Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo. Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama2049-41731252024The Japan MSA registry: A multicenter cohort study of multiple system atrophy271277ENAyakaChikadaDepartment of Neurology, Graduate School of Medicine, The University of TokyoKentaOrimoDepartment of Neurology, Graduate School of Medicine, The University of TokyoJunMitsuiDepartment of Neurology, Graduate School of Medicine, The University of TokyoTakashiMatsukawaDepartment of Neurology, Graduate School of Medicine, The University of TokyoHiroyukiIshiuraDepartment of Neurology, Okayama University Graduate School of Medicine and DentistryTatsushiTodaDepartment of Neurology, Graduate School of Medicine, The University of TokyoHidehiroMizusawaDepartment of Neurology, Graduate School of Medicine, The University of TokyoYujiTakahashiDepartment of Neurology, Graduate School of Medicine, The University of TokyoMasahisaKatsunoDepartment of Neurology, Nagoya University Graduate School of MedicineKazuhiroHaraDepartment of Neurology, Nagoya University Graduate School of MedicineOsamuOnoderaDepartment of Neurology, Brain Research Institute, Niigata UniversityTomohikoIshiharaDepartment of Neurology, Brain Research Institute, Niigata UniversityMasayoshiTadaDepartment of Neurology, Brain Research Institute, Niigata UniversitySatoshiKuwabaraDepartment of Neurology, Graduate School of Medicine, Chiba UniversityAtsuhikoSugiyamaDepartment of Neurology, Graduate School of Medicine, Chiba UniversityYoshitakaYamanakaDepartment of Neurology, Graduate School of Medicine, Chiba UniversityRyosukeTakahashiDepartment of Neurology, Kyoto University Graduate School of MedicineNobukatsuSawamotoDepartment of Human Health Sciences, Kyoto University Graduate School of MedicineYusukeSakatoDepartment of Neurology, Kyoto University Graduate School of MedicineTomoyukiIshimotoDepartment of Neurology, Kyoto University Graduate School of MedicineRitsukoHanajimaDivision of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori UniversityYasuhiroWatanabeDivision of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori UniversityHiroshiTakigawaDivision of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori UniversityTadashiAdachiDivision of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori UniversityKojiAbeDepartment of Neurology, Okayama University Graduate School of Medicine and DentistryToruYamashitaDepartment of Neurology, Okayama University Graduate School of Medicine and DentistryHiroshiTakashimaDepartment of Neurology and Geriatrics, Graduate School of Medical and Dental Sciences, Kagoshima UniversityKeikoHigashiDepartment of Neurology and Geriatrics, Graduate School of Medical and Dental Sciences, Kagoshima UniversityJunichiKiraDepartment of Neurology, Graduate School of Medical Sciences, Kyushu UniversityIchiroYabeDepartment of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityMasaakiMatsushimaDepartment of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityKatsuhisaOgataDepartment of Neurology, Higashi-Saitama National HospitalKinyaIshikawaDepartment of Neurology and Neurological Science, Tokyo Medical and Dental UniversityYoichiroNishidaDepartment of Neurology and Neurological Science, Tokyo Medical and Dental UniversityTaroIshiguroDepartment of Neurology and Neurological Science, Tokyo Medical and Dental UniversityKokoroOzakiDepartment of Neurology and Neurological Science, Tokyo Medical and Dental UniversityTetsuyaNagataDepartment of Neurology and Neurological Science, Tokyo Medical and Dental UniversityShojiTsujiDepartment of Neurology, Graduate School of Medicine, The University of TokyoBackground: Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic failure and various motor symptoms. While MSA-C (cerebellar type) predominates in East Asia, MSA-P (parkinsonian type) predominates in Europe and North America. This nationwide patient registry aimed to (1) conduct a prospective natural history study of MSA in Japan, (2) facilitate patient recruitment for clinical trials, and (3) deposit bioresources and clinical information in a biobank.<br>
Methods: Thirteen institutions participated in this study. Clinical information was obtained by neurologists from the patients visiting the hospital every 12 months to assess the UMSARS Part 2 scores and by telephone interviews by nurses every 6 months to assess UMSARS Part 1 scores and to determine whether clinical events had occurred.<br>
Results: Demographic data from 329 MSA patients (216 MSA-C and 113 MSA-P) were analyzed. The mean age at symptom onset was 58.2 years (standard deviation, 8.9); the mean duration of symptoms at enrollment was 3.5 years (standard deviation, 2.2). The mean 12-month changes in the UMSARS Part 1 and Part 2 scores were 7.9 (standard deviation, 5.6) and 6.4 (standard deviation, 5.9), respectively. The patient registry proved useful in recruiting participants for clinical trials, including those with gene variants. Clinical information and biospecimens were deposited in a biobank.<br>
Discussion: The study highlighted the importance of telephone interviews in minimizing drop-out rates in natural history studies and demonstrated similar MSA progression rates across populations. The deposited bioresources are available to researchers upon request, aiming to contribute to future MSA researches.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1071-269060102024Enhanced design of pCMViR-TSC plasmid vector for sustainably high cargo gene expression in mammalian cells12151227ENMasakiyoSakaguchiDepartment of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineRieKinoshitaDepartment of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineNahokoTomonobuDepartment of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYoshihikoSakaguchiDepartment of Microbiology, Tokushima Bunri UniversityJunichiroFutamiDepartment of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityAkiraYamauchiDepartment of Biochemistry, Kawasaki Medical SchoolHitoshiMurataDepartment of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineKen-ichiYamamotoDepartment of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineTettaTakahashiDepartment of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineYumaGoharaDepartment of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineToshikiOchiDepartment of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineFanJiangDepartment of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineNi Luh Gede YoniKomalasariFaculty of Medicine, Udayana UniversityYouyiChenDepartment of Breast Surgery, The First Affiliated Hospital, Zhejiang University School of MedicineI Made WinarsaRumaFaculty of Medicine, Udayana UniversityI WayanSumardikaFaculty of Medicine, Udayana UniversityJinZhouMedical Oncology Department of Gastrointestinal Tumors, Liaoning Cancer Hospital & Institute, Cancer Hospital of the Dalian University of TechnologyTomokoHonjoDepartment of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityFutoshiKuribayashiDepartment of Biochemistry, Kawasaki Medical SchoolKazumiSagayamaOrganization for Research and Innovation Strategy, Okayama UniversityShinichiToyookaDepartment of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineEisakuKondoDivision of Tumor Pathology, Near InfraRed Photo-Immuno-Therapy Research Institute, Kansai Medical UniversityYusukeInoueFaculty of Science and Technology, Division of Molecular Science, Gunma UniversityThe first-generation pCMViR-TSC, implemented through the promoter sandwich rule, yields 10- to 100-fold higher gene expression than the standard plasmid used with the CMV (cytomegalovirus) or CAG promoter. However, the vector’s shortcomings limit its utility to transient expression only, as it is not suitable for establishing stable transformants in mammalian cells. To overcome this weakness, we here introduce the improved plasmid vector pSAKA-4B, derived from pCMViR-TSC as a second-generation chromosome-insertable vector. This vector facilitates the linear entry of the expression unit into the TTAA site of DNA universally with transposase assistance. The vector is helpful for the indefinite expression of our target gene. The new vector system is proven here to be efficient in establishing stable transformants with a high likelihood of positive clones that exhibit significantly elevated expression levels of the delivered foreign gene. This system, alongside the first-generation vector, is therefore instrumental for diverse basic research endeavors concerning genes, proteins, cells, and animals, and potentially for clinical applications such as gene therapy.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1432-053315012025Biallelic variants in DNAJC7 cause familial amyotrophic lateral sclerosis with the TDP-43 pathology19ENToruYamashitaDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOsamuYokotaDepartment of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDaikiOusakaDepartment of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHongmingSunDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakashiHaraguchiDepartment of Neurology, National Hospital Organisation Minami-Okayama Medical CentreRicardo SatoshiOta-ElliottDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesChikaMatsuokaDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomohitoKawanoDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHanaeNakashima-YasudaDepartment of Psychiatry, Zikei HospitalYusukeFukuiDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYumikoNakanoDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyutaMoriharaDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasatoHasegawaDepartment of Brain and Neurosciences, Tokyo Metropolitan Institute of Medical ScienceYasuyukiHosonoDepartment of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSeishiTeradaDepartment of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesManabuTakakiDepartment of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyukiIshiuraDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. ALS pathology primarily involves the failure of protein quality control mechanisms, leading to the accumulation of misfolded proteins, particularly TAR DNA-binding protein 43 (TDP-43). TDP-43 aggregation is a central pathological feature of ALS. Maintaining protein homeostasis is critical and facilitated by heat shock proteins (HSPs), particularly the HSP40 family, which includes co-chaperones such as DNAJC7. Here, we report a family with three siblings affected by ALS who carry a homozygous c.518dupC frameshift variant in DNAJC7, a member of the HSP40 family. All three patients exhibited progressive muscle weakness, limb atrophy, bulbar palsy, and respiratory failure. Pathological examination revealed degeneration of both upper and lower motor neurons, with phosphorylated TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortices. Immunoblot analysis were consistent with a type B pattern of phosphorylated TDP-43 in the precentral gyrus. Immunohistochemistry and RNA sequencing analyses demonstrated a substantial reduction in DNAJC7 expression at both the protein and RNA levels in affected brain regions. In a TDP-43 cell model, DNAJC7 knockdown impaired the disassembly of TDP-43 following arsenite-induced stress, whereas DNAJC7 overexpression suppressed the assembly and promoted the disassembly of arsenite-induced TDP-43 condensates. Furthermore, in a zebrafish ALS model, dnajc7 knockdown resulted in increased TDP-43 aggregation in motor neurons and reduced survival. To the best of our knowledge, this study provides the first evidence linking biallelic loss-of-function variants in DNAJC7 to familial ALS with TDP-43 pathology.No potential conflict of interest relevant to this article was reported.American Society for MicrobiologyActa Medica Okayama2379-50421062025Mycobacterium tuberculosis bacillus induces pyroptosis in human lung fibroblastse00110-25ENTakemasaTakiiDepartment of Mycobacterium Reference and Research, the Research Institute of Tuberculosis, Japan Anti-Tuberculosis AssociationHiroyukiYamadaDepartment of Mycobacterium Reference and Research, the Research Institute of Tuberculosis, Japan Anti-Tuberculosis AssociationChihiroMotozonoDepartment of Molecular Immunology, Research Institute for Microbial Diseases, The University of OsakaShoYamasakiDepartment of Molecular Immunology, Research Institute for Microbial Diseases, The University of OsakaJordi B.TorrellesTexas Biomedical Research Institute and International Center for the Advancement of Research & Education (I•CARE)JoanneTurnerTexas Biomedical Research Institute and International Center for the Advancement of Research & Education (I•CARE)AoiKimishimaLaboratory of Applied Microbial Chemistry, Ōmura Satoshi Memorial Institute, Kitasato UniversityYukihiroAsamiLaboratory of Applied Microbial Chemistry, Ōmura Satoshi Memorial Institute, Kitasato UniversityNaoyaOharaDepartment of Oral Microbiology, Graduate School of Medicine, Density and Pharmaceutical Sciences, Okayama UniversityShigeakiHidaDepartment of Hygienic Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City UniversityHidetoshiHayashiDepartment of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City UniversityKikuoOnozakiDepartment of Hygienic Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City UniversityWe previously reported that live, but not dead, virulent Mycobacterium tuberculosis (Mtb) H37Rv bacilli induce cell death in human lung fibroblast cell lines, MRC-5, MRC-9, and TIG-1. Here, using two distinct Mtb strains from two different lineages (HN878 lineage 2 and H37Rv lineage 4), we confirmed cell death at day 2 after infection with a device that measures cell growth/cytotoxicity in real time (Maestro-Z [AXION]). Mtb bacilli uptake by the fibroblast was confirmed with a transmission electron microscope on day 2. Expressions of inflammatory cytokines and interleukin (IL)−1β, IL-6, and IL-8 were observed when exposed to live, but not dead bacteria. The cell death of fibroblasts induced by both Mtb strains tested was prevented by caspase-1/4 and NLRP3 inflammasome inhibitors, but not by caspase-3 and caspase-9 inhibitors. Therefore, we classified the fibroblast cell death by Mtb infection as pyroptosis. To investigate the biological and pathological relevance of fibroblast cell death by Mtb infection, we performed dual RNA-Seq analysis on Mtb within fibroblasts and Mtb-infected fibroblasts at day 2. In Mtb bacilli tcrR, secE2, ahpD, and mazF8 genes were highly induced during infection. These genes play roles in survival in a hypoxic environment, production of a calcium-binding protein-inducing cytokine, and regulation of transcription in a toxin-antitoxin system. The gene expressions of IL-1β, IL-6, and IL-8, caspase-4, and NLRP3, but not of caspase-3 and caspase-9, were augmented in Mtb bacilli-infected fibroblasts. Taken together, our study suggests that Mtb bacilli attempt to survive in lung fibroblasts and that pyroptosis of the host fibroblasts activates the immune system against the infection.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0962-88193332024Generation and characterization of cerebellar granule neurons specific knockout mice of Golli-MBP99117ENHarukoMiyazakiDepartment of Molecular Biology and Biochemistry, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineSakiNishiokaDepartment of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka UniversityTomoyukiYamanakaLaboratory of Structural Neuropathology, Graduate School of Brain Science, Doshisha UniversityManabuAbeDepartment of Animal Model Development, Brain Research Institute, Niigata UniversityYukioImamuraLaboratory of Structural Neuropathology, Graduate School of Brain Science, Doshisha UniversityTomohiroMiyasakaFaculty of Life and Medical Sciences, Doshisha UniversityNobutoKakudaFaculty of Life and Medical Sciences, Doshisha UniversityToshitakaOohashiDepartment of Molecular Biology and Biochemistry, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of MedicineTomomiShimogoriLaboratory for Molecular Mechanisms of Brain Development, RIKEN Center for Brain ScienceKazuhiroYamakawaLaboratory for Neurogenetics, RIKEN Center for Brain ScienceMasahitoIkawaDepartment of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka UniversityNobuyukiNukinaLaboratory of Structural Neuropathology, Graduate School of Brain Science, Doshisha UniversityGolli–myelin basic proteins, encoded by the myelin basic protein gene, are widely expressed in neurons and oligodendrocytes in the central nervous system. Further, prior research has shown that Golli–myelin basic protein is necessary for myelination and neuronal maturation during central nervous system development. In this study, we established Golli–myelin basic protein-floxed mice to elucidate the cell-type-specific effects of Golli–myelin basic protein knockout through the generation of conditional knockout mice (Golli–myelin basic proteinsfl/fl; E3CreN), in which Golli–myelin basic proteins were specifically deleted in cerebellar granule neurons, where Golli–myelin basic proteins are expressed abundantly in wild-type mice. To investigate the role of Golli–myelin basic proteins in cerebellar granule neurons, we further performed histopathological analyses of these mice, with results indicating no morphological changes or degeneration of the major cellular components of the cerebellum. Furthermore, behavioral analysis showed that Golli–myelin basic proteinsfl/fl; E3CreN mice were healthy and did not display any abnormal behavior. These results suggest that the loss of Golli–myelin basic proteins in cerebellar granule neurons does not lead to cerebellar perturbations or behavioral abnormalities. This mouse model could therefore be employed to analyze the effect of Golli–myelin basic protein deletion in specific cell types of the central nervous system, such as other neuronal cells and oligodendrocytes, or in lymphocytes of the immune system.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0168-01022182025Alteration of perineuronal nets and parvalbumin interneurons in prefrontal cortex and hippocampus, and correlation with blood corticosterone in activity-based anorexia model mice104922ENHoang DuyNguyenDepartment of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHarukoMiyazakiDepartment of Molecular Biology and Biochemistry, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesHirokiKawaiDepartment of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesZiyiWangDepartment of Molecular Biology and Biochemistry, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesShinjiSakamotoDepartment of Neuropsychiatry, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesManabuTakakiDepartment of Neuropsychiatry, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesToshitakaOohashiDepartment of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAnorexia nervosa (AN) is an eating disorder characterized by restricted energy intake, severely underweight status, and frequent hyperactivity. Previous research has shown structural and functional alterations in the medial prefrontal cortex (mPFC) and hippocampus of AN patients. To investigate the pathological mechanism of AN, we analyzed the expression and distribution of parvalbumin (PV) interneurons and perineuronal nets (PNNs), which are implicated in the pathology of neuropsychiatric disorders, in the mPFC and hippocampus dorsal (HPCd) and ventral (HPCv) using an activity-based anorexia (ABA) mouse model. We found that PNN expression and density increased in the mPFC, with minor alterations in the HPCd and HPCv of ABA mice. The expression and distribution of PV neurons were unchanged in the brains of ABA mice, except for a regional decrease in PV-expressing neuron density in the HPCd. Co-localization analysis showed an increased number of PNNs enwrapping PV-negative neurons in the mPFC of ABA mice. Furthermore, the upregulation of PNN expression in the mPFC was positively correlated with elevated blood corticosterone levels, a well-known stress indicator, in ABA mice. Our findings suggest that the increased expression and distribution of PNNs surrounding PV-negative neurons in the mPFC may indicate the pathological mechanisms of AN.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama0952-34803892025Ultrahigh‐Field MR‐Compatible Mechanical Tactile Stimulator for Investigating Somatosensory Processing in Small‐Bodied Animalse70105ENChenyuWangGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityHirohikoImaiInnovation Research Center for Quantum Medicine, Gifu University School of MedicineMasakiFukunagaSection of Brain Function Information, National Institute for Physiological SciencesHirokiYamamotoGraduate School of Human and Environmental Studies, Kyoto UniversityYinghuaYuGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityKazuhikoSekiDepartment of Neurophysiology, National Center of Neurology and PsychiatryTakashiHanakawaDepartment of Integrated Neuroanatomy and Neuroimaging, Kyoto University Graduate School of MedicineTatsuyaUmedaDepartment of Integrated Neuroanatomy and Neuroimaging, Kyoto University Graduate School of MedicineJiajiaYangGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityCommon marmosets (Callithrix jacchus), small-bodied New World primates that share similar sensory processing pathways with human beings, have gained great interests. Their small body size allows imaging of brain activity with high spatial resolution and on a whole-brain scale using ultrahigh-field (UHF) magnetic resonance imaging (MRI) scanners. However, the strong magnetic field and the small size of the hand and forearm pose challenges in delivering tactile stimulation during fMRI experiments. In the present study, we developed an MR-compatible tactile dual-point stimulator to provide high-precision mechanical stimulation for exploring somatosensory processing in small-bodied animals. The study population consisted of a water phantom and three male common marmosets. Cerebral blood volume (CBV) weighted fMRI data were obtained with a gradient echo (GE), echo-planar imaging (EPI) sequence at 7T scanner. The output performance of the device was tested by a pressure sensor. The MR compatibility of the device was verified by measuring the temporal signal-to-noise ratio (tSNR) of a water phantom. To test the effectiveness of tactile stimulation, we conducted block designed tactile stimulation experiments on marmosets. A one-way repeated measures ANOVA was conducted for comparing the tSNR results. We performed one-sample t-tests to investigate the negative response of the forearm and hand stimulation with a threshold of t > 1.96 (p < 0.05). Performance tests revealed that mechanical stimulation (averaged force: 31.69 g) was applied with a delay of 12 ms. Phantom experiments confirmed that there was no significant difference in the tSNR among three (10 Hz, 1 Hz, and no-stimulus) conditions (F (2, 798) = 0.71, p = 0.49). The CBV activity results showed that the stimulator successfully elicited hand and forearm somatosensory activations in primary somatosensory areas. These results indicated that the device is well suited for small-bodied animal somatosensory studies.No potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama2075-44181552025Review Article: Diagnostic Paradigm Shift in Spine Surgery594ENAras EfeLeventDepartment of Orthopedic Surgery, Okayama Rosai HospitalMasatoTanakaDepartment of Orthopedic Surgery, Okayama Rosai HospitalChetanKumawatDepartment of Orthopedic Surgery, Okayama Rosai HospitalChristianHengDepartment of Orthopedic Surgery, Okayama Rosai HospitalSalamalikisNikolaosDepartment of Orthopedic Surgery, Okayama Rosai HospitalKajetanLatkaDepartment of Orthopedic Surgery, Okayama Rosai HospitalAkiyoshiMiyamotoDepartment of Orthopedic Surgery, Okayama Rosai HospitalTadashiKomatsubaraDepartment of Orthopedic Surgery, Okayama Rosai HospitalShinyaAratakiDepartment of Orthopedic Surgery, Okayama Rosai HospitalYoshiakiOdaDepartment of Orthopedic Surgery, Okayama University HospitalKensukeShinoharaDepartment of Orthopedic Surgery, Okayama University HospitalKojiUotaniDepartment of Orthopedic Surgery, Okayama University HospitalMeticulous clinical examination is essential for spinal disorders to utilize the diagnostic methods and technologies that strongly support physicians and enhance clinical practice. A significant change in the approach to diagnosing spinal disorders has occurred in the last three decades, which has enhanced a more nuanced understanding of spine pathology. Traditional radiographic methods such as conventional and functional X-rays and CT scans are still the first line in the diagnosis of spinal disorders due to their low cost and accessibility. As more advanced imaging technologies become increasingly available worldwide, there is a constantly increasing trend in MRI scans for detecting spinal pathologies and making treatment decisions. Not only do MRI scans have superior diagnostic capabilities, but they also assist surgeons in performing meticulous preoperative planning, making them currently the most widely used diagnostic tool for spinal disorders. Positron Emission Tomography (PET) can help detect inflammatory lesions, infections, and tumors. Other advanced diagnostic tools such as CT/MRI fusion image, Functional Magnetic Resonance Imaging (fMRI), Upright and Kinetic MRI, magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI), and diffusion tensor imaging (DTI) could play an important role when it comes to detecting more special pathologies. However, some technical difficulties in the daily praxis and their high costs act as obstacles to their further spread. Integrating artificial intelligence and advancements in data analytics and virtual reality promises to enhance spinal procedures’ precision, safety, and efficacy. As these technologies continue to develop, they will play a critical role in transforming spinal surgery. This paradigm shift emphasizes the importance of continuous innovation and adaptability in improving the diagnosis and treatment of spinal disorders.No potential conflict of interest relevant to this article was reported.American Chemical Society (ACS)Acta Medica Okayama1554-892919122024Discovery of a Compound That Inhibits IRE1α S-Nitrosylation and Preserves the Endoplasmic Reticulum Stress Response under Nitrosative Stress24292437ENHarunaKurogiDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNobumasaTakasugiDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShoKubotaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityAshutoshKumarLaboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKENTakehiroSuzukiBiomolecular Characterization Unit, Technology Platform Division, RIKEN Center for Sustainable Resource ScienceNaoshiDohmaeBiomolecular Characterization Unit, Technology Platform Division, RIKEN Center for Sustainable Resource ScienceDaisukeSawadaDepartment of Fine Organic Synthesis, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKam Y.J.ZhangLaboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKENTakashiUeharaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityInositol-requiring enzyme 1α (IRE1α) is a sensor of endoplasmic reticulum (ER) stress and drives ER stress response pathways. Activated IRE1α exhibits RNase activity and cleaves mRNA encoding X-box binding protein 1, a transcription factor that induces the expression of genes that maintain ER proteostasis for cell survival. Previously, we showed that IRE1α undergoes S-nitrosylation, a post-translational modification induced by nitric oxide (NO), resulting in reduced RNase activity. Therefore, S-nitrosylation of IRE1α compromises the response to ER stress, making cells more vulnerable. We conducted virtual screening and cell-based validation experiments to identify compounds that inhibit the S-nitrosylation of IRE1α by targeting nitrosylated cysteine residues. We ultimately identified a compound (1ACTA) that selectively inhibits the S-nitrosylation of IRE1α and prevents the NO-induced reduction of RNase activity. Furthermore, 1ACTA reduces the rate of NO-induced cell death. Our research identified S-nitrosylation as a novel target for drug development for IRE1α and provides a suitable screening strategy.No potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama1422-006726112025Induced Pluripotent Stem Cells in Cardiomyopathy: Advancing Disease Modeling, Therapeutic Development, and Regenerative Therapy4984ENQuan DuyVoDepartment of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazufumiNakamuraDepartment of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukihiroSaitoDepartment of Cardiovascular Medicine, Okayama University HospitalSatoshiAkagiDepartment of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToruMiyoshiDepartment of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShinsukeYuasaDepartment of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesCardiomyopathies are a heterogeneous group of heart muscle diseases that can lead to heart failure, arrhythmias, and sudden cardiac death. Traditional animal models and in vitro systems have limitations in replicating the complex pathology of human cardiomyopathies. Induced pluripotent stem cells (iPSCs) offer a transformative platform by enabling the generation of patient-specific cardiomyocytes, thus opening new avenues for disease modeling, drug discovery, and regenerative therapy. This process involves reprogramming somatic cells into iPSCs and subsequently differentiating them into functional cardiomyocytes, which can be characterized using techniques such as electrophysiology, contractility assays, and gene expression profiling. iPSC-derived cardiomyocyte (iPSC-CM) platforms are also being explored for drug screening and personalized medicine, including high-throughput testing for cardiotoxicity and the identification of patient-tailored therapies. While iPSC-CMs already serve as valuable models for understanding disease mechanisms and screening drugs, ongoing advances in maturation and bioengineering are bringing iPSC-based therapies closer to clinical application. Furthermore, the integration of multi-omics approaches and artificial intelligence (AI) is enhancing the predictive power of iPSC models. iPSC-based technologies are paving the way for a new era of personalized cardiology, with the potential to revolutionize the management of cardiomyopathies through patient-specific insights and regenerative strategies.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2045-23221512025Eosinophils as a predictive marker of treatment-related adverse events in mRCC patients treated with first-line immune-checkpoint inhibitor combination therapy27163ENTatsushiKawadaDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSatoshiKatayamaDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakafumiYanagisawaDepartment of Urology, The Jikei University School of MedicineKeiichiroMoriDepartment of Urology, The Jikei University School of MedicineWataruFukuokayaDepartment of Urology, The Jikei University School of MedicineKazumasaKomuraDepartment of Urology, Osaka Medical and Pharmaceutical UniversityTakuyaTsujinoDepartment of Urology, Osaka Medical and Pharmaceutical UniversityRyoichiMaenosonoDepartment of Urology, Osaka Medical and Pharmaceutical UniversityKiyoshiTakaharaDepartment of Urology, Fujita Health University School of MedicineTakuhisaNukayaDepartment of Urology, Fujita Health University School of MedicineLanInokiDepartment of Urology, Kindai University Faculty of MedicineShingoToyodaDepartment of Urology, Kindai University Faculty of MedicineTakeshiHashimotoDepartment of Urology, Tokyo Medical UniversityYosukeHirasawaDepartment of Urology, Tokyo Medical UniversityKoheiEdamuraDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomokoKobayashiDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKensukeBekkuDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShingoNishimuraDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakehiroIwataDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakuyaSadahiraDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYusukeTominagaDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomoakiYamanoiDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKasumiYoshinagaDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazumaTsuboiDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuyukiKobayashiDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAtsushiTakamotoDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKyoheiKuroseDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakahiroKimuraDepartment of Urology, The Jikei University School of MedicineHaruhitoAzumaDepartment of Urology, Osaka Medical and Pharmaceutical UniversityRyoichiShirokiDepartment of Urology, Fujita Health University School of MedicineKazutoshiFujitaDepartment of Urology, Kindai University Faculty of MedicineYoshioOhnoDepartment of Urology, Tokyo Medical UniversityMotooArakiDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesImmune checkpoint inhibitors (ICIs) are a key component of first-line treatment for metastatic renal cell carcinoma (mRCC). However, predicting treatment-related adverse events (TRAEs) remains challenging. This study investigated the utility of eosinophil-related biomarkers as predictors of Common Terminology Criteria for Adverse Events grade ≥ 3 TRAEs in mRCC patients undergoing ICI combination therapy. In this retrospective analysis across 21 hospitals in Japan, we examined 180 patients treated with ICI/ICI therapy and 216 patients treated with ICI/tyrosine kinase inhibitor (TKI) therapy. Grade ≥ 3 TRAEs occurred in 39.4% and 31.9% of patients in the ICI/ICI and ICI/TKI groups, respectively. An elevated eosinophil proportion of ≥ 2.0% (odds ratio [OR]: 2.36; 95% CI [confidence interval] 1.23–4.54, p = 0.01) and a low neutrophil/eosinophil ratio (NER) of ≤ 40.0 (OR: 2.78, 95% CI 1.39–5.53, p = 0.004) were significant predictors of severe TRAEs in the ICI/ICI group. However, no significant associations were found in the ICI/TKI group. These findings may help identify patients who suffer from grade ≥ 3 TRAEs and help determine individualized treatment strategies in patients with mRCC.No potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama2076-261515102025A Canine c-kit Novel Mutation Isolated from a Gastrointestinal Stromal Tumor (GIST) Retains the Ability to Form Dimers but Lacks Autophosphorylation1444ENKeiShimakawaLaboratory of Veterinary Hygiene, School of Veterinary Science, Nippon Veterinary and Life Science UniversitySoDogeLaboratory of Veterinary Pathology, School of Veterinary Science, Nippon Veterinary and Life Science UniversityMasakiMichishitaLaboratory of Veterinary Pathology, School of Veterinary Science, Nippon Veterinary and Life Science UniversityEriTanabeLaboratory of Veterinary Hygiene, School of Veterinary Science, Nippon Veterinary and Life Science UniversityTsuyoshiTajimaLaboratory of Veterinary Pharmacology, School of Veterinary Science, Nippon Veterinary and Life Science UniversityMasatoKobayashiLaboratory of Veterinary Reproduction, School of Veterinary Science, Nippon Veterinary and Life Science UniversityMakotoBonkobaraLaboratory of Veterinary Clinical Pathology, School of Veterinary Science, Nippon Veterinary and Life Science UniversityMasamiWatanabeLaboratory of Urology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKazuhikoOchiaiLaboratory of Veterinary Hygiene, School of Veterinary Science, Nippon Veterinary and Life Science UniversityYoshikazuTanakaLaboratory of Veterinary Hygiene, School of Veterinary Science, Nippon Veterinary and Life Science UniversityGastrointestinal stromal tumors (GISTs) are mesenchymal tumors that develop in the gastrointestinal tract; KIT mutations are present in both canine and human GISTs. In this study, genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) sections of 55 canine GIST cases, and mutation searches were performed for exons 8, 9, and 11. The results revealed novel mutations, A434T and F436S, in exon 8. In contrast to the A434T mutation without functional changes, the F436S mutant retained its dimerization ability, but lost its phosphorylation function and attenuated downstream Akt signaling, which is reflected in wound healing and migration activities. A comparison of the subcellular localization of WT KIT and the F436S mutant revealed no differences. In silico simulations indicated that the F436S mutation alters the structure of the near-membrane region and that its effects may extend to the transmembrane and intracellular domains compared to the WT. F436S is a point mutation that affects the entire molecule because co-mutation with the F436S mutation and the known autophosphorylation mutation reduces the autophosphorylation abilities.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2056-306X1112025Effect of temperature cycles on the sleep-like state in Hydra vulgaris2ENAyaSatoFaculty of Arts and Science, Kyushu UniversityManabuSekiguchiGraduate School of Natural Science and Technology, Okayama UniversityKogaNakadaGraduate School of Systems Life Sciences, Kyushu UniversityTaishiYoshiiGraduate School of Natural Science and Technology, Okayama UniversityTaichi Q.ItohFaculty of Arts and Science, Kyushu UniversityBackground Sleep is a conserved physiological phenomenon across species. It is mainly controlled by two processes: a circadian clock that regulates the timing of sleep and a homeostat that regulates the sleep drive. Even cnidarians, such as Hydra and jellyfish, which lack a brain, display sleep-like states. However, the manner in which environmental cues affect sleep-like states in these organisms remains unknown. In the present study, we investigated the effects of light and temperature cycles on the sleep-like state in Hydra vulgaris.<br>
Results Our findings indicate that Hydra responds to temperature cycles with a difference of up to 5° C, resulting in decreased sleep duration under light conditions and increased sleep duration in dark conditions. Furthermore, our results reveal that Hydra prioritizes temperature changes over light as an environmental cue. Additionally, our body resection experiments show tissue-specific responsiveness in the generation ofthe sleep-like state under different environmental cues. Specifically, the upper body can generate the sleep-like state in response to a single environmental cue. In contrast, the lower body did not respond to 12-h light–dark cycles at a constant temperature.<br>
Conclusions These findings indicate that both light and temperature influence the regulation of the sleep-like state in Hydra. Moreover, these observations highlight the existence of distinct regulatory mechanisms that govern patterns of the sleep-like state in brainless organisms, suggesting the potential involvement of specific regions for responsiveness of environmental cues for regulation of the sleep-like state.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama2041-17231512024A high-protein diet-responsive gut hormone regulates behavioral and metabolic optimization in Drosophila melanogaster10819ENYutoYoshinariMetabolic Regulation and Genetics, Institute for Molecular and Cellular Regulation, Gunma UniversityTakashiNishimuraMetabolic Regulation and Genetics, Institute for Molecular and Cellular Regulation, Gunma UniversityTaishiYoshiiGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityShuKondoDepartment of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of ScienceHiromuTanimotoGraduate School of Life Sciences, Tohoku UniversityTomoeKobayashiDivision of Molecular Genetics, Shigei Medical Research InstituteMakotoMatsuyamaDivision of Molecular Genetics, Shigei Medical Research InstituteRyusukeNiwaLife Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of TsukubaProtein is essential for all living organisms; however, excessive protein intake can have adverse effects, such as hyperammonemia. Although mechanisms responding to protein deficiency are well-studied, there is a significant gap in our understanding of how organisms adaptively suppress excessive protein intake. In the present study, utilizing the fruit fly, Drosophila melanogaster, we discover that the peptide hormone CCHamide1 (CCHa1), secreted by enteroendocrine cells in response to a high-protein diet (HPD), is vital for suppressing overconsumption of protein. Gut-derived CCHa1 is received by a small subset of enteric neurons that produce short neuropeptide F, thereby modulating protein-specific satiety. Importantly, impairment of the CCHa1-mediated gut-enteric neuronal axis results in ammonia accumulation and a shortened lifespan under HPD conditions. Collectively, our findings unravel the crosstalk of gut hormone and neuronal pathways that orchestrate physiological responses to prevent and adapt to dietary protein overload.No potential conflict of interest relevant to this article was reported.SAGE PublicationsActa Medica Okayama0748-73042025Neurotransmitter and Receptor Mapping in Drosophila Circadian Clock Neurons via T2A-GAL4 ScreeningENAyumiFukudaGraduate School of Natural Science and Technology, Okayama UniversityAikaSaitoGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityTaishiYoshiiGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityThe circadian neuronal network in the brain comprises central pacemaker neurons and associated input and output pathways. These components work together to generate coherent rhythmicity, synchronize with environmental time cues, and convey circadian information to downstream neurons that regulate behaviors such as the sleep/wake cycle. To mediate these functions, neurotransmitters and neuromodulators play essential roles in transmitting and modulating signals between neurons. In Drosophila melanogaster, approximately 240 brain neurons function as clock neurons. Previous studies have identified several neurotransmitters and neuromodulators, including the Pigment-dispersing factor (PDF) neuropeptide, along with their corresponding receptors in clock neurons. However, our understanding of the neurotransmitters and receptors involved in the circadian system remains incomplete. In this study, we conducted a T2A-GAL4-based screening for neurotransmitter and receptor genes expressed in clock neurons. We identified 2 neurotransmitter-related genes and 22 receptor genes. Notably, while previous studies had reported the expression of 6 neuropeptide receptor genes in large ventrolateral neurons (l-LNv), we also found that 14 receptor genes—including those for dopamine, serotonin, and γ-aminobutyric acid—are expressed in l-LNv neurons. These findings suggest that l-LNv neurons serve as key integrative hubs within the circadian network, receiving diverse external signals.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0960-982235122025Oxytocin facilitates human touch-induced play behavior in rats29162926.e3ENHimekaHayashiDepartment of Biology, Faculty of Environmental, Life, Natural Science and Technology, Okayama University,SayakaTateishiUshimado Marine Institute (UMI), Faculty of Environmental, Life, Natural Science and Technology, Okayama UniversityAyumuInutsukaDivision of Brain and Neurophysiology, Department of Physiology, Jichi Medical UniversityShoMaejimaUshimado Marine Institute (UMI), Faculty of Environmental, Life, Natural Science and Technology, Okayama UniversityDaisukeHagiwaraDepartment of Neuropeptide Research in Psychiatry, Central Institute of Mental Health, German Center for Psychiatry (DZPG), Medical Faculty Mannheim, University of HeidelbergYasuoSakumaDepartment of Anatomy and Neurobiology, Graduate School of Medical Sciences, Nippon Medical SchoolTatsushiOnakaDivision of Brain and Neurophysiology, Department of Physiology, Jichi Medical UniversityValeryGrinevichDepartment of Neuropeptide Research in Psychiatry, Central Institute of Mental Health, German Center for Psychiatry (DZPG), Medical Faculty Mannheim, University of HeidelbergHirotakaSakamotoDepartment of Biology, Faculty of Environmental, Life, Natural Science and Technology, Okayama University,Pleasant touch sensations play a fundamental role in social bonding, yet the neural mechanisms underlying affinity-like behaviors remain poorly understood. Here, we demonstrate that juvenile-adolescent rats, which naturally engage in social play with peers characterized by rough-and-tumble interactions and 50 kHz ultrasonic vocalizations indicating pleasant sensations, develop a strong affinity for human hands through similar playful contact achieved by repeated tickling with human hands. Using this rat with tickling-induced high affinity for human hands, we discovered that repeated tickling mimicking rough-and-tumble play led to increased oxytocin receptor (OTR) expression in the ventrolateral part of the ventromedial hypothalamus (VMHvl). Inhibition of oxytocin signaling in the VMHvl reduced affinity-like behaviors from rats to human hands. These findings suggest that OTR neurons in VMHvl play an important role in the increase in affinity for human hands induced by pleasant touch sensation with human touch-induced play behavior. Based on retrograde and anterograde tracing studies examining the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) as primary sources of oxytocin, we demonstrate that a subset of oxytocin fibers in the VMHvl originate from the SON, suggesting that affinity-like behavior from rats to human hands may be controlled by oxytocin signaling from magnocellular neurons. Together, this work advances our understanding of how oxytocin shapes social behavior and may inform the development of therapeutic strategies to promote positive social interactions.No potential conflict of interest relevant to this article was reported.MDPI AGActa Medica Okayama2076-39211472025Carnosol, a Rosemary Ingredient Discovered in a Screen for Inhibitors of SARM1-NAD+ Cleavage Activity, Ameliorates Symptoms of Peripheral Neuropathy808ENHitoshiMurataDepartment of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazukiOgawaTama Biochemical Co., Ltd.YuYasuiDepartment of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshikiOchiDepartment of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNahokoTomonobuDepartment of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKen-IchiYamamotoDepartment of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRieKinoshitaDepartment of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYojiWadaTama Biochemical Co., Ltd.HiromichiNakamuraTama Biochemical Co., Ltd.MasahiroNishiboriDepartment of Translational Research and Drug Development, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasakiyoSakaguchiDepartment of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD+) hydrolase involved in axonal degeneration and neuronal cell death. SARM1 plays a pivotal role in triggering the neurodegenerative processes that underlie peripheral neuropathies, traumatic brain injury, and neurodegenerative diseases. Importantly, SARM1 knockdown or knockout prevents the degeneration; as a result, SARM1 has been attracting attention as a potent therapeutic target. In recent years, the development of several SARM1 inhibitors derived from synthetic chemical compounds has been reported; however, no dietary ingredients with SARM1 inhibitory activity have been identified. Therefore, we here focused on dietary ingredients and found that carnosol, an antioxidant contained in rosemary, inhibits the NAD+-cleavage activity of SARM1. Purified carnosol inhibited the enzymatic activity of SARM1 and suppressed neurite degeneration and cell death induced by the anti-cancer medicine vincristine (VCR). Carnosol also inhibited VCR-induced hyperalgesia symptoms, suppressed the loss of intra-epidermal nerve fibers in vivo, and reduced the blood fluid level of phosphorylated neurofilament-H caused by an axonal degeneration event. These results indicate that carnosol has a neuroprotective effect via SARM1 inhibition in addition to its previously known antioxidant effect via NF-E2-related factor 2 and thus suppresses neurotoxin-induced peripheral neuropathy.No potential conflict of interest relevant to this article was reported.BMJActa Medica Okayama2632-6140712025Reversible cerebral vasoconstriction syndrome in idiopathic multicentric Castleman disease under treatment with tocilizumabe000923ENNaoyaKamimuraDepartment of Neurology, Yokohama City University Medical CenterNaohisaUedaDepartment of Neurology, Yokohama City University Medical CenterKatsuoKimuraDepartment of Neurology, Yokohama City University Medical CenterAsamiNishikoriYasuharuSatoHitaruKishidaDepartment of Neurology, Yokohama City University Medical CenterFumiakiTanakaDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineBackground Idiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disorder characterised by systemic inflammation resulting from overproduction of interleukin 6 (IL-6). While iMCD primarily affects the lymph nodes and related tissues, it can also rarely involve the central nervous system.<br>
Case presentation We report the case of a 58-year-old female patient with at least a 3-year history of iMCD, who experienced acute thunderclap headaches due to reversible cerebral vasoconstriction syndrome (RCVS). RCVS occurred 3 months after initiating treatment with tocilizumab, a humanised anti-IL-6 receptor monoclonal antibody, and was accompanied by focal cortical subarachnoid haemorrhage (SAH). Elevated IL-6 levels were found in both serum and cerebrospinal fluid. MR angiography revealed multiple diffuse stenotic lesions in the bilateral middle and posterior cerebral arteries, which, along with bilateral cerebral oedema, resolved within 3 months. The diffuse nature of the cerebral vasospasm and the presence of bilateral brain oedema suggested that cerebral vasospasm was due to RCVS rather than SAH.<br>
Conclusions In patients with Castleman disease, RCVS may occur due to IL-6-dependent chronic cerebral vascular inflammation, either as a primary condition or as a complication of tocilizumab treatment.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama0022-37512025Dual functions of SNAP25 in mouse taste budsENKengoHorieDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKuanyuWangDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHaiHuangDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKeikoYasumatsuTokyo Dental Junior CollegeYuzoNinomiyaDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYoshihiroMitohDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityRyusukeYoshidaDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityType III cells in mouse taste buds are considered to transmit aversive stimuli, such as sourness, to the gustatory nerve through vesicular synapses. Synaptosome-associated protein 25 (SNAP25) might contribute to synaptic vesicular release in sour sensation, although direct evidence has been lacking. Here, we demonstrated that epithelia-specific Snap25 conditional knockout (cKO) mice exhibited a significant reduction in the number of type III cells. Notably, the proportion of 5-ethynyl 2′-deoxyuridine-positive post-mitotic type III cells in Snap25 cKO mice was significantly lower on tracing day 14, but not at day 7, which suggests that SNAP25 contributes to the maintenance of type III cells. In a short-term lick test, Snap25 cKO (sour taste absent) and Snap25/ transient receptor potential vanilloid 1 double KO (sour taste and somatosensory absent) mice exhibit a significantly higher lick response to sour tastants, confirming the role of SNAP25 for sour sensation. Electrophysiological recordings of the chorda tympani nerve reveal nearly abolished ammonium and sour taste responses in Snap25 cKO mice, which concludes sour-dependent synapse transmission in type III cells. Overall, these data suggest that vesicular synapses in taste buds are indispensable for transmission of information from, and the replenishment of, sour-sensitive type III taste cells.No potential conflict of interest relevant to this article was reported.The Endocrine SocietyActa Medica Okayama1945-717016682025Neuromedin U Deficiency Disrupts Daily Testosterone Fluctuation and Reduces Wheel-running Activity in Ratsbqaf102ENMaiOtsukaGraduate School of Natural Science and Technology, Okayama UniversityYuTakeuchiGraduate School of Natural Science and Technology, Okayama UniversityMahoMoriyamaGraduate School of Natural Science and Technology, Okayama UniversitySakuraEgoshiDepartment of Biology, Faculty of Science, Okayama UniversityYukiGotoGraduate School of Natural Science and Technology, Okayama UniversityTingtingGuGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityAtsushi PKimuraDepartment of Biological Sciences, Faculty of Science, Hokkaido UniversityShogoHaraguchiDepartment of Biochemistry, Showa University School of MedicineTaishiYoshiiGraduate School of Natural Science and Technology, Okayama UniversitySakaeTakeuchiGraduate School of Natural Science and Technology, Okayama UniversityMakotoMatsuyamaDivision of Molecular Genetics, Shigei Medical Research InstituteGeorge EBentleyDepartment of Integrative Biology and Helen Wills Neuroscience Institute, University of California at BerkeleySayakaAizawaGraduate School of Natural Science and Technology, Okayama UniversityThe objective of this study was to elucidate the role of endogenous Neuromedin U (NMU) in rats by performing NMU knockout (KO). Male, but not female NMU KO rats exhibited decreased wheel-running activity vs wildtype (WT), although overall home cage activity was not affected. Plasma testosterone in WT rats varied significantly over the course of a day, with a peak at ZT1 and a nadir at ZT18, whereas in NMU KO rats testosterone remained stable throughout the day. Chronic administration of testosterone restored wheel-running activity in NMU KO rats to the same level as in WT rats, suggesting that the decrease in wheel-running activity in NMU KO rats is due to the disruption of the diurnal change of testosterone. Accordingly, expression of the luteinizing hormone beta subunit (Lhb) mRNA in the pars distalis of anterior pituitary was significantly lower in NMU KO rats; immunostaining revealed that the size of luteinizing hormone (LH)–expressing cells was also relatively small in those animals. In the brain of male WT rats, Nmu was highly expressed in the pars tuberalis, and the NMU receptor Nmur2 was highly expressed in the ependymal cell layer of the third ventricle. This study reveals a novel function of NMU and indicates that endogenous NMU in rats plays a role in the regulation of motivated activity via regulation of testosterone.No potential conflict of interest relevant to this article was reported.Japanese Society of Internal MedicineActa Medica Okayama0918-29186452025A Novel De Novo Variant in KCNH5 in a Patient with Refractory Epileptic Encephalopathy759762ENAkihikoMitsutakeDepartment of Neurology, Graduate School of Medicine, The University of TokyoTakashiMatsukawaDepartment of Neurology, Graduate School of Medicine, The University of TokyoTatsuhikoNaitoDepartment of Neurology, Graduate School of Medicine, The University of TokyoHiroyukiIshiuraDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityJunMitsuiDepartment of Neurology, Graduate School of Medicine, The University of TokyoHiroakiHaradaDepartment of Rheumatology and Allergy, Graduate School of Medicine, The University of TokyoKeishiFujioDepartment of Rheumatology and Allergy, Graduate School of Medicine, The University of TokyoJunFujishiroDepartment of Pediatric Surgery, Graduate School of Medicine, The University of TokyoHarushiMoriDepartment of Radiology, School of Medicine, Jichi Medical UniversityShinichiMorishitaDepartment of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of TokyoShojiTsujiDepartment of Neurology, Graduate School of Medicine, The University of TokyoTatsushiTodaDepartment of Neurology, Graduate School of Medicine, The University of TokyoWe herein report a novel de novo KCNH5 variant in a patient with refractory epileptic encephalopathy. The patient exhibited seizures at 1 year and 7 months old, which gradually worsened, leading to a bedridden status. Brain magnetic resonance imaging (MRI) showed cerebral atrophy and cerebellar hypoplasia. A trio whole-exome sequence analysis identified a de novo heterozygous c.640A>C, p.Lys214Gln variant in KCNH5 that was predicted to be deleterious. Recent studies have linked KCNH5 to various epileptic encephalopathies, with many patients showing normal MRI findings. The present case expands the clinical spectrum of the disease, as it is characterized by severe neurological prognosis, cerebral atrophy, and cerebellar hypoplasia.No potential conflict of interest relevant to this article was reported.SAGE PublicationsActa Medica Okayama2214-35992025Recent progress in oculopharyngodistal myopathy research from clinical and genetic viewpointsENHiroyukiIshiuraDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityOculopharyngodistal myopathy (OPDM) is a rare muscular disorder characterized by ocular symptoms, pharyngeal symptoms, facial weakness, and distal predominant limb muscle weakness. The cause of the disease was unknown for a long time. Recently, however, it has been reported that expansions of CGG or CCG repeats in LRP12, LOC642361/NUTM2B-AS1, GIPC1, NOTCH2NLC, RILPL1, and ABCD3 are the causes of the disease. Cases sometimes present with neurological symptoms, and the clinical spectrum of diseases caused by expansions of CGG or CCG repeats has been proposed to be called FNOP-spectrum disorder after the names of fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukoencephalopathy, and OPDM. In this article, the recent progress in the field of OPDM is reviewed, and remaining issues in OPDM are discussed.No potential conflict of interest relevant to this article was reported.Japanese Society of Internal MedicineActa Medica Okayama0918-29182025Two Cases of Autosomal Recessive Spinocerebellar Ataxia-8 Showing Two Novel Variants of SYNE1 in Japanese Families5602-25ENTaijunYunokiDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesChikaMatsuokaDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYosukeOsakadaDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYusukeFukuiDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMamiTakemotoDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyutaMoriharaDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToruYamashitaDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyukiIshiuraDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAutosomal recessive spinocerebellar ataxia-8 (SCAR8) is a neurodegenerative disorder caused by the biallelic pathogenic variants of SYNE1. It is characterized by slowly progressive cerebellar ataxia and atrophy. We identified two SCAR8 families using exome analyses and two novel variants, c.2127delG (p.Met709Ilefs) and c.15943G>T (p.Gly5315*), in SYNE1 (NM_182961.4). Pathogenic variants of SYNE1 cause various symptoms, including cerebellar ataxia, pyramidal tract disorders, and joint disorders, and the pathogenic variants discovered in this study were located in a region prone to cerebellar ataxia.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Analysis of Protein Toxicity and Cellular Phenotypes Triggered by the Maximum Overexpression of Proteins in Yeast ENShotaroNAMBAGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Effect of Radon Inhalation on Murine Brain Proteins : Investigation Using Proteomic and Multivariate AnalysesENShotaNAOEGraduate School of Health Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Study of the Brain Topological Processing Mechanisms in the Human Sensorimotor SystemENCHENYUWANGGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Study on neural mechanisms of attention effects on auditory-tactile multisensory processingENWEICHAOANGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Study on the Influence of Object Compliance on Softness and Pleasantness PerceptionENBINYUEGAOGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Social Factors in Motion: Quantifying the Dynamics of Dyad–Individual Collision AvoidanceENAdrien Thibaud Marie GREGORJGraduate School of Natural Science and Technology, Okayama universityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Sexually dimorphic behavior and its hormonal regulation in rodentsENHimekaHAYASHIGraduate School of Natural Science and Technology, Okayama universityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Development of Enzyme Activity Assays Based on Spectrometric Methods and Paper-Based Analytical Devices ENJIANCHAORENGraduate School of Natural Science and Technology, Okayama universityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025環境中親電子物質によるDNAメチル化制御を介したケモカイン発現誘導機構ENTomokiTSUCHIDAGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025小胞体ストレスセンサー IRE1α に対する S-ニトロシル化阻害薬の同定とその薬効評価ENHarunaKUROGIGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Taste Responses and Ingestive Behaviors to Ingredients of Fermented Milk in MiceENYukoYAMASEGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025The role of GABA in modulation of taste signaling within the taste budENAyakaMIKAMIGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Exploring the Role of Ccn3 in Type III Cell of Mice Taste BudsENKuanyu WangGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Changes in Working Situations of Employed Long COVID Patients: Retrospective Study in Japanese Outpatient ClinicENYuiMATSUDAGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Ameliorating effect of chotosan and its active component, Uncaria hook, on lipopolysaccharide-induced anxiety-like behavior in miceENYasumasaOKAWAGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Preventive effects of vasohibin-2-targeting peptide vaccine for diabetic nephropathyENYuriNAKASHIMAGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Stress-experienced monocytes/macrophages lose anti-inflammatory function via β2-adrenergic receptor in skin allergic inflammationENHitoshiURAKAMIGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Neuroprotective effect of, a flavonoid, sudachitin in mice stroke modelENOTA ELLIOTT RICARDO SATOSHIGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Celiac and superior mesenteric ganglia removal improves glucose tolerance and reduces pancreas islet sizeENSHANSHANXUGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2025Cervical spinal cord stimulation exerts anti-epileptic effects in a rat model of epileptic seizure through the suppression of CCL2-mediated cascadesENYosukeOKAZAKIGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Nature PortfolioActa Medica Okayama2399-3642812025TRPV2 mediates stress resilience in mouse cardiomyocytes715ENYubingDongDepartment of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityGuohaoWangDepartment of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYoshihiroUjiharaDepartment of Electrical and Mechanical Engineering, Graduate School of Engineering, Nagoya Institute of TechnologyYanzhuChenDepartment of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMasashiYoshidaDepartment of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesKazufumiNakamuraDepartment of Cardiovascular Medicine, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesKimiakiKatanosakaDepartment of Biomedical Sciences, College of Life and Health Sciences, Chubu UniversityKeijiNaruseDepartment of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYukiKatanosakaDepartment of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityThe heart dynamically compensates for haemodynamic stress, but how this resilience forms during cardiac growth is not clear. Using a temporally inducible, cardiac-specific knockout in mice we show that the Transient receptor potential vanilloid family 2 (TRPV2) channel is crucial for the maturation of cardiomyocyte stress resilience. TRPV2 defects in growing hearts lead to small morphology, abnormal intercalated discs, weak contractility, and low expression of serum response factor and Insulin-like growth factor-1 (IGF-1) signalling. Individual cardiomyocytes of TRPV2-deficient hearts show reduced contractility with abnormal Ca2+ handling. In cultured neonatal cardiomyocytes, mechanical Ca2+ response, excitation-contraction coupling, sarcoplasmic reticulum Ca2+ content, actin formation, nuclear localisation of Myocyte enhancer factor 2c, and IGF-1 expression require TRPV2. TRPV2-deficient hearts show a defective response to dobutamine stress and no compensatory hypertrophic response to phenylephrine administration, but no stress response to pressure overload. These data suggest TRPV2 mediates the maturation of cardiomyocyte stress resilience, and will advance therapeutic interventions and drug discovery for heart disease.No potential conflict of interest relevant to this article was reported.ElsevierActa Medica Okayama0168-01022142025The Medaka approach to evolutionary social neuroscience3241ENSatoshiAnsaiUshimado Marine Institute, Okayama UniversityTowakoHiraki-KajiyamaGraduate School of Life Sciences, Tohoku UniversityRyutaroUedaGraduate School of Life Sciences, Tohoku UniversityTakahideSekiGraduate School of Life Sciences, Tohoku UniversitySaoriYokoiSchool of Pharmaceutical Sciences, Hokkaido UniversityTakafumiKatsumuraSchool of Medicine, Kitasato UniversityHideakiTakeuchiGraduate School of Life Sciences, Tohoku UniversityPreviously, the integration of comparative biological and neuroscientific approaches has led to significant advancements in social neuroscience. This review highlights the potential and future directions of evolutionary social neuroscience research utilizing medaka fishes (the family Adrianichthyidae) including Japanese medaka (Oryzias latipes). We focus on medaka social cognitive capabilities and mate choice behavior, particularly emphasizing mate preference using visual cues. Medaka fishes are also advantageous due to their abundant genetic resources, extensive genomic information, and the relative ease of laboratory breeding and genetic manipulation. Here we present some research examples of both the conventional neuroscience approach and evolutionary approach involving medaka fishes and other species. We also discuss the prospects of uncovering the molecular and cellular mechanisms underlying the diversity of visual mate preference among species. Especially, we introduce that the single-cell transcriptome technology, particularly in conjunction with 'Adaptive Circuitry Census', is an innovative tool that bridges comparative biological methods and neuroscientific approaches. Evolutionary social neuroscience research using medaka has the potential to unveil fundamental principles in neuroscience and elucidate the mechanisms responsible for generating diversity in mating strategies.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama1424-82202572025Length Estimation of Pneumatic Artificial Muscle with Optical Fiber Sensor Using Machine Learning2221ENYileiNiGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityShuichiWakimotoGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityWeihangTianGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityYuichiroTodaGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityTakefumiKandaGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityDaisukeYamaguchiGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityA McKibben artificial muscle is a soft actuator driven by air pressure, characterized by its flexibility, lightweight design, and high power-to-weight ratio. We have developed a smart artificial muscle that is capable of sensing its motion. To enable this sensing function, an optical fiber was integrated into the sleeve consisting of multiple fibers and serving as a component of the McKibben artificial muscle. By measuring the macrobending loss of the optical fiber, the length of the smart artificial muscle is expected to be estimated. However, experimental results indicated that the sensor's characteristics depend not only on the length but also on the load and the applied air pressure. This dependency arises because the stress applied to the optical fiber increases, causing microbending loss. In this study, we employed a machine learning model, primarily composed of Long Short-Term Memory (LSTM) neural networks, to estimate the length of the smart artificial muscle. The experimental results demonstrate that the length estimation obtained through machine learning exhibits a smaller error. This suggests that machine learning is a feasible approach to enhancing the length measurement accuracy of the smart artificial muscle.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0168-01022132025The potential mechanism maintaining transactive response DNA binding protein 43 kDa in the mouse stroke model128137ENYutingBianDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYusukeFukuiDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityRicardo SatoshiOta-ElliottDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityXinranHuDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHongmingSunDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityZhihongBianDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYunZhaiDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHaiboYuDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityXiaoHuDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHangpingAnDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHongzhiLiuDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityRyutaMoriharaDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHiroyukiIshiuraDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityToruYamashitaDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityThe disruption of transactive response DNA binding protein 43 kDa (TDP-43) shuttling leads to the depletion of nuclear localization and the cytoplasmic accumulation of TDP-43. We aimed to evaluate the mechanism underlying the behavior of TDP-43 in ischemic stroke. Adult male C57BL/6 J mice were subjected to 30 or 60 min of transient middle cerebral artery occlusion (tMCAO), and examined at 1, 6, and 24 h post reperfusion. Immunostaining was used to evaluate the expression of TDP-43, G3BP1, HDAC6, and RAD23B. The total and cytoplasmic number of TDP-43–positive cells increased compared with sham operation group and peaked at 6 h post reperfusion after tMCAO. The elevated expression of G3BP1 protein peaked at 6 h after reperfusion and decreased at 24 h after reperfusion in ischemic mice brains. We also observed an increase of expression level of HDAC6 and the number of RAD23B-positive cells increased after tMCAO. RAD23B was colocalized with TDP-43 24 h after tMCAO. We proposed that the formation of stress granules might be involved in the mislocalization of TDP-43, based on an evaluation of G3BP1 and HDAC6. Subsequently, RAD23B, may also contribute to the downstream degradation of mislocalized TDP-43 in mice tMCAO model.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama1661-65962662025Vesicular Glutamate Transporter 3 Is Involved in Glutamatergic Signalling in Podocytes2485ENNaokoNishiiDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomokoKawaiDepartment of Cell Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHirokiYasuokaDepartment of Neuroscience, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTadashiAbeDepartment of Neuroscience, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNanamiTatsumiDepartment of Neuroscience, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuikaHaradaDepartment of Genomics and Proteomics, Advanced Science Research Center, Okayama UniversityTakaakiMiyajiDepartment of Genomics and Proteomics, Advanced Science Research Center, Okayama UniversityShunaiLiCenter for Innovative Clinical Medicine, Okayama University HospitalMoemiTsukanoCentral Research Laboratory, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasamiWatanabeCenter for Innovative Clinical Medicine, Okayama University HospitalDaisukeOgawaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJunWadaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKohjiTakeiDepartment of Neuroscience, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiYamadaDepartment of Neuroscience, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesGlomerular podocytes act as a part of the filtration barrier in the kidney. The activity of this filter is regulated by ionotropic and metabotropic glutamate receptors. Adjacent podocytes can potentially release glutamate into the intercellular space; however, little is known about how podocytes release glutamate. Here, we demonstrated vesicular glutamate transporter 3 (VGLUT3)-dependent glutamate release from podocytes. Immunofluorescence analysis revealed that rat glomerular podocytes and an immortal mouse podocyte cell line (MPC) express VGLUT1 and VGLUT3. Consistent with this finding, quantitative RT-PCR revealed the expression of VGLUT1 and VGLUT3 mRNA in undifferentiated and differentiated MPCs. In addition, the exocytotic proteins vesicle-associated membrane protein 2, synapsin 1, and synaptophysin 1 were present in punctate patterns and colocalized with VGLUT3 in MPCs. Interestingly, approximately 30% of VGLUT3 colocalized with VGLUT1. By immunoelectron microscopy, VGLUT3 was often observed around clear vesicle-like structures in differentiated MPCs. Differentiated MPCs released glutamate following depolarization with high potassium levels and after stimulation with the muscarinic agonist pilocarpine. The depletion of VGLUT3 in MPCs by RNA interference reduced depolarization-dependent glutamate release. These results strongly suggest that VGLUT3 is involved in glutamatergic signalling in podocytes and may be a new drug target for various kidney diseases.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama1661-65962662025Involvement of a Novel Variant of FGFR1 Detected in an Adult Patient with Kallmann Syndrome in Regulation of Gonadal Steroidogenesis2713ENYoshiakiSoejimaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiOtsukaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMarinaKawaguchiDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKoheiOguniDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKoichiroYamamotoDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuhiroNakanoDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMihoYasudaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazukiTokumasuDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKeigoUedaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKoseiHasegawaDepartment of Pediatrics, Okayama University HospitalNahokoIwataDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesFumioOtsukaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesFibroblast growth factor receptor 1 (FGFR1), also known as KAL2, is a tyrosine kinase receptor, and variants of FGFR1 have been detected in patients with Kallmann syndrome (KS), which is a congenital developmental disorder characterized by central hypogonadism and anosmia. Herein, we report an adult case of KS with a novel variant of FGFR1. A middle-aged male was referred for a compression fracture of a lumbar vertebra. It was shown that he had severe osteoporosis, anosmia, gynecomastia, and a past history of operations for cryptorchidism. Endocrine workup using pituitary and gonadal stimulation tests revealed the presence of both primary and central hypogonadism. Genetic testing revealed a novel variant of FGFR1 (c.2197_2199dup, p.Met733dup). To identify the pathogenicity of the novel variant and the clinical significance for the gonads, we investigated the effects of the FGFR1 variant on the downstream signaling of FGFR1 and gonadal steroidogenesis by using human steroidogenic granulosa cells. It was revealed that the transfection of the variant gene significantly impaired FGFR1 signaling, detected through the downregulation of SPRY2, compared with that of the case of the forced expression of wild-type FGFR1, and that the existence of the variant gene apparently altered the expression of key steroidogenic factors, including StAR and aromatase, in the gonad. The results suggested that the novel variant of FGFR1 detected in the patient with KS was linked to the impairment of FGFR1 signaling, as well as the alteration of gonadal steroidogenesis, leading to the pathogenesis of latent primary hypogonadism.No potential conflict of interest relevant to this article was reported.Frontiers MediaActa Medica Okayama1664-3224162025PARylation-mediated post-transcriptional modifications in cancer immunity and immunotherapy1537615ENKazuyaMatsumotoDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYoshinoriMatsumotoDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityJunWadaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityPoly-ADP-ribosylation (PARylation) is a post-translational modification in which ADP-ribose is added to substrate proteins. PARylation is mediated by a superfamily of ADP-ribosyl transferases known as PARPs and influences a wide range of cellular functions, including genome integrity maintenance, and the regulation of proliferation and differentiation. We and others have recently reported that PARylation of SH3 domain-binding protein 2 (3BP2) plays a role in bone metabolism, immune system regulation, and cytokine production. Additionally, PARylation has recently gained attention as a target for cancer treatment. In this review, we provide an overview of PARylation, its involvement in several signaling pathways related to cancer immunity, and the potential of combination therapies with PARP inhibitors and immune checkpoint inhibitors.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama2075-44181562025Improving Diagnostic Performance for Head and Neck Tumors with Simple Diffusion Kurtosis Imaging and Machine Learning Bi-Parameter Analysis790ENSuzukaYoshidaDepartment of Oral and Maxillofacial Radiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMasahiroKurodaRadiological Technology, Graduate School of Health Sciences, Okayama UniversityYoshihideNakamuraDepartment of Oral and Maxillofacial Radiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYukaFukumuraDepartment of Oral and Maxillofacial Radiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYukiNakamitsuRadiological Technology, Graduate School of Health Sciences, Okayama UniversityWlla E.Al-HammadDepartment of Oral and Maxillofacial Radiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKazuhiroKurodaRadiological Technology, Graduate School of Health Sciences, Okayama UniversityYudaiShimizuDepartment of Oral and Maxillofacial Radiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYoshinoriTanabeRadiological Technology, Graduate School of Health Sciences, Okayama UniversityMasatakaOitaGraduate School of Interdisciplinary Sciences and Engineering in Health Systems, Okayama UniversityIrfanSugiantoDepartment of Oral Radiology, Faculty of Dentistry, Hasanuddin UniversityMajdBarhamDepartment of Dentistry and Dental Surgery, College of Medicine and Health Sciences, An-Najah National UniversityNouhaTekikiDepartment of Oral and Maxillofacial Radiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNurul N.KamaruddinDepartment of Oral Rehabilitation and Regenerative Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMikiHisatomiDepartment of Oral and Maxillofacial Radiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYoshinobuYanagiDepartment of Oral and Maxillofacial Radiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityJunichiAsaumiDepartment of Oral and Maxillofacial Radiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityBackground/Objectives: Mean kurtosis (MK) values in simple diffusion kurtosis imaging (SDI)-a type of diffusion kurtosis imaging (DKI)-have been reported to be useful in the diagnosis of head and neck malignancies, for which pre-processing with smoothing filters has been reported to improve the diagnostic accuracy. Multi-parameter analysis using DKI in combination with other image types has recently been reported to improve the diagnostic performance. The purpose of this study was to evaluate the usefulness of machine learning (ML)-based multi-parameter analysis using the MK and apparent diffusion coefficient (ADC) values-which can be acquired simultaneously through SDI-for the differential diagnosis of benign and malignant head and neck tumors, which is important for determining the treatment strategy, as well as examining the usefulness of filter pre-processing. Methods: A total of 32 pathologically diagnosed head and neck tumors were included in the study, and a Gaussian filter was used for image pre-processing. MK and ADC values were extracted from pixels within the tumor area and used as explanatory variables. Five ML algorithms were used to create models for the prediction of tumor status (benign or malignant), which were evaluated through ROC analysis. Results: Bi-parameter analysis with gradient boosting achieved the best diagnostic performance, with an AUC of 0.81. Conclusions: The usefulness of bi-parameter analysis with ML methods for the differential diagnosis of benign and malignant head and neck tumors using SDI data were demonstrated.No potential conflict of interest relevant to this article was reported.Frontiers MediaActa Medica Okayama1662-5102192025Acetoacetate, a ketone body, attenuates neuronal bursts in acutely-induced epileptiform slices of the mouse hippocampus1551700ENHaoWenDepartment of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNagisaSadaDepartment of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTsuyoshiInoueDepartment of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityThe ketogenic diet increases ketone bodies (beta-hydroxybutyrate and acetoacetate) in the brain, and ameliorates epileptic seizures in vivo. However, ketone bodies exert weak or no effects on electrical activity in rodent hippocampal slices. Especially, it remains unclear what kinds of conditions are required to strengthen the actions of ketone bodies in hippocampal slices. In the present study, we examined the effects of acetoacetate on hippocampal pyramidal cells in normal slices and epileptiform slices of mice. By using patch-clamp recordings from CA1 pyramidal cells, we first confirmed that acetoacetate did not change the membrane potentials and intrinsic properties of pyramidal cells in normal slices. However, we found that acetoacetate weakened spontaneous epileptiform bursts in pyramidal cells of epileptiform slices, which were acutely induced by applying convulsants to normal slices. Interestingly, acetoacetate did not change the frequency of the epileptiform bursts, but attenuated individual epileptiform bursts. We finally examined the effects of acetoacetate on excitatory synaptic barrages during epileptiform activity, and found that acetoacetate weakened epileptiform bursts by reducing synchronous synaptic inputs. These results show that acetoacetate attenuated neuronal bursts in epileptiform slices, but did not affect neuronal activity in normal slices, which leads to seizure-selective actions of ketone bodies.No potential conflict of interest relevant to this article was reported.American Association for Cancer Research (AACR)Acta Medica Okayama0008-54728562025Myeloid Cells Induce Infiltration and Activation of B Cells and CD4+ T Follicular Helper Cells to Sensitize Brain Metastases to Combination Immunotherapy10821096ENToshifumiNinomiyaDepartment of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNaoyaKemmotsuDepartment of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityFumiakiMukoharaDepartment of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMasakiMagariApplied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityAiMiyamotoMedical Protein Engineering, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityYoukiUedaDepartment of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTakamasaIshinoDepartment of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityJojiNagasakiDepartment of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTomohiroFujiwaraDepartment of Orthopaedic Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityHidetakaYamamotoDepartment of Pathology and Oncology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHidetoshiHayashiDepartment of Medical Oncology, Kindai University Faculty of MedicineKotaTachibanaDepartment of Dermatology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityJojiIshidaDepartment of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYoshihiroOtaniDepartment of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShotaTanakaDepartment of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShinichiToyookaDepartment of General Thoracic Surgery, Breast and Endocrinological Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Science, Okayama UniversityIsamuOkamotoDepartment of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu UniversityYosukeTogashiDepartment of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityBrain metastasis is a poor prognostic factor in patients with cancer. Despite showing efficacy in many extracranial tumors, immunotherapy with anti–PD-1 mAb or anti–CTLA4 mAb seems to be less effective against intracranial tumors. Promisingly, recent clinical studies have reported that combination therapy with anti–PD-1 and anti–CTLA4 mAbs has a potent antitumor effect on brain metastasis, highlighting the need to elucidate the detailed mechanisms controlling the intracranial tumor microenvironment (TME) to develop effective immunotherapeutic strategies. In this study, we analyzed the tumor-infiltrating lymphocytes in murine models of brain metastasis that responded to anti–CTLA4 and anti–PD-1 mAbs. Activated CD4+ T follicular helper (TFH) cells with high CTLA4 expression characteristically infiltrated the intracranial TME, which were activated by combination anti–CTLA4 and anti–PD-1 treatment. The loss of TFH cells suppressed the additive effect of CTLA4 blockade on anti–PD-1 mAb. B-cell–activating factor belonging to the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) produced by abundant myeloid cells, particularly CD80hiCD206lo proinflammatory M1-like macrophages, in the intracranial TME induced B-cell and TFH-cell infiltration and activation. Furthermore, the intracranial TME of patients with non–small cell lung cancer featured TFH- and B-cell infiltration as tertiary lymphoid structures. Together, these findings provide insights into the immune cell cross-talk in the intracranial TME that facilitates an additive antitumor effect of CTLA4 blockade with anti–PD-1 treatment, supporting the potential of a combination immunotherapeutic strategy for brain metastases.<br>
Significance: B-cell and CD4+ T follicular helper cell activation via BAFF/APRIL from abundant myeloid cells in the intracranial tumor microenvironment enables a combinatorial effect of CTLA4 and PD-1 blockade in brain metastases.No potential conflict of interest relevant to this article was reported.Nature PortfolioActa Medica Okayama2041-17231612025Keratinocyte-driven dermal collagen formation in the axolotl skin1757ENAyakaOhashiGraduate School of Environment, Life, Natural Science and Technology, Okayama UniversityHirotakaSakamotoGraduate School of Environment, Life, Natural Science and Technology, Okayama UniversityJunpeiKurodaGraduate School of Frontier Biosciences, Osaka UniversityYoheiKondoCenter for One Medicine Innovative Translational Research (COMIT), Nagoya UniversityYasuhiroKameiLaboratory for Biothermology, National Institute for Basic BiologyShigenoriNonakaThe Graduate University for Advanced Studies (SOKENDAI)SayaFurukawaGraduate School of Environment, Life, Natural Science and Technology, Okayama UniversitySakiyaYamamotoGraduate School of Environment, Life, Natural Science and Technology, Okayama UniversityAkiraSatohGraduate School of Environment, Life, Natural Science and Technology, Okayama UniversityType I collagen is a major component of the dermis and is formed by dermal fibroblasts. The development of dermal collagen structures has not been fully elucidated despite the major presence and importance of the dermis. This lack of understanding is due in part to the opacity of mammalian skin and it has been an obstacle to cosmetic and medical developments. We reveal the process of dermal collagen formation using the highly transparent skin of the axolotl and fluorescent collagen probes. We clarify that epidermal cells, not dermal fibroblasts, contribute to dermal collagen formation. Mesenchymal cells (fibroblasts) play a role in modifying the collagen fibers already built by keratinocytes. We confirm that collagen production by keratinocytes is a widely conserved mechanism in other model organisms. Our findings warrant a change in the current consensus about dermal collagen formation and could lead to innovations in cosmetology and skin medication.No potential conflict of interest relevant to this article was reported.Nature PortfolioActa Medica Okayama2045-23221512025A glucocorticoid-regulating molecule, Fkbp5, may interact with mitogen-activated protein kinase signaling in the organ of Corti of mice cochleae7506ENAsukaSatoDepartment of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyotaroOmichiDepartment of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukihideMaedaDepartment of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMizuoAndoDepartment of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesFKBP5 is a 51-Da FK506-binding protein and member of the immunophilin family involved in controlling the signaling of glucocorticoid receptor from the cytosol to nucleus. Fkbp5 has previously been shown to be expressed in murine cochlear tissue, including the organ of Corti (i.e., the sensory epithelium of the cochlea). Fkbp5-/- mice as used in this study show hearing loss in the low-frequency (8-kHz) range and click-evoked auditory brainstem response (ABR) threshold compared to wild-type mice. Both Fkbp5-/- and wild-type mice showed hearing loss at all frequencies and click-ABR thresholds at 24 h and 14 days following acoustic overexposure (AO). Tissues of the organ of Corti were subjected to RNA sequencing and KEGG pathway analysis. In Fkbp5-/- mice before AO, the mitogen-activated protein kinase (MAPK) signaling pathway was dysregulated compared to wild-type mice. In wild-type mice at 12 h following AO, the most significantly modulated KEGG pathway was the TNF signaling pathway and major MAPK molecules p38 and Jun were involved in the TNF signaling pathway. In Fkbp5-/- mice at 12 h following AO, the MAPK signaling pathway was dysregulated compared to wild-type mice following AO. In conclusion, Fkbp5 interacts with MAPK signaling in the organ of Corti in mice cochleae.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama2077-03831442025Course of General Fatigue in Patients with Post-COVID-19 Conditions Who Were Prescribed Hochuekkito: A Single-Center Exploratory Pilot Study1391ENKazukiTokumasuDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNobuyoshiMatsukiDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYukiOtsukaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYokoSakamotoCenter for Innovative Clinical Medicine, Okayama University HospitalKeigoUedaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYuiMatsudaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYasueSakuradaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHiroyukiHondaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYasuhiroNakanoDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityToruHasegawaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityRyosukeTakaseDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityDaisukeOmuraDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityFumioOtsukaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityBackground: After the start of the COVID-19 pandemic, general fatigue in patients with long COVID and post-COVID-19 conditions (PCC) became a medical issue. Although there is a lack of evidence-based treatments, Kampo medicine (traditional Japanese medicine) has gained attention in Japan. At an outpatient clinic in Japan specializing in long COVID, 24% of all prescriptions were Kampo medicines, and 72% of Kampo medicine prescriptions were hochuekkito. However, there has been no prospective, quantitative study on the course of fatigue in patients with long COVID and PCC who were prescribed hochuekkito. The aim of this study was to clarify the course of fatigue in those patients. Methods: This study included patients aged 18 years or older with general fatigue who visited the long COVID specialized outpatient clinic at Okayama University Hospital and consented to participate after being prescribed hochuekkito. We reviewed the backgrounds of the patients, and we evaluated the patients' fatigue assessment scale in person or online. Results: Twenty patients were enrolled in this study from September to December in 2023. The average age of the patients was 42.9 years (SD: 15.8 years) and 12 patients (60%) were female. After hochuekkito administration, the fatigue assessment scale score decreased from 35.9 (SD: 5.9) at the initial visit to 31.2 (SD: 9.4) after 8 weeks, indicating a trend for improvement in fatigue (difference: 4.7; 95% CI: 0.5-8.9). Conclusions: A trend for improvement in fatigue was observed in patients with long COVID and PCC who were prescribed hochuekkito, indicating a potential benefit of hochuekkito for general fatigue in such patients. General fatigue in patients with long COVID or PCC can be classified as post-infectious fatigue syndrome and is considered a condition of qi deficiency in Kampo medicine, for which hochuekkito is appropriately indicated.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0278-69151972025Fraglide-1 from traditional Chinese aromatic vinegar: A natural AhR antagonist for atopic dermatitis115301ENKosukeKatoGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityMikiAkamatsuGraduate School of Environmental and Life Science, Okayama UniversitySayaKakimaruGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityMayukoKoreishiGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityMasahiroTakagiSchool of Materials Science, Japan Advanced Institute of Science and TechnologyMasahiroMiyashitaGraduate School of Agriculture, Kyoto UniversityYoshiyukiMurataGraduate School of Environmental and Life Science, Okayama UniversityYoshimasaNakamuraGraduate School of Environmental and Life Science, Okayama UniversityAyanoSatohGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityYoshioTsujinoGraduate School of Science, Technology and Innovation, Kobe UniversityTraditional Chinese Zhenjiang aromatic vinegar (Kozu) contains Fraglide-1 (FG1), a bioactive lactone with demonstrated peroxisome proliferator-activated receptor gamma (PPARγ) agonist and antioxidant activities. This study explored FG1's novel ability to antagonize the aryl hydrocarbon receptor (AhR) signaling pathway, which regulates artemin expression and contributes to itching and inflammation in atopic dermatitis. Through molecular docking simulations and cell-based assays in human keratinocytes, we demonstrated FG1's potent antagonistic activity against AhR signaling. FG1 effectively suppressed FICZ-induced inflammatory responses, including artemin expression, with potency (half maximal inhibitory concentration, IC50 = 5.1 μM) comparable to the synthetic antagonist StemRegenin 1 (SR1) while demonstrating a superior safety profile (median lethal concentration, LC50 > 100 μM vs. 27.5 μM for SR1). These findings expand our understanding of bioactive compounds from traditional fermented foods and their regulatory effects on AhR signaling, providing a foundation for future studies on FG1's role in modulating skin inflammation.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0031-39982025Spatiotemporal expression pattern of dyslexia susceptibility 1 candidate 1 (DYX1C1) during rat cerebral cortex developmentENKazumasaZenshoDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesIkukoMiyazakiDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAikaIsseDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesIchikaMisawaDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKaoriMasaiDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMakioOkaDepartment of Psychosocial Medicine, National Center for Child Health and DevelopmentHirokazuTsukaharaDepartment of Pediatrics, Okayama University HospitalMasatoAsanumaDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground Developmental dyslexia (DD) is a common learning disorder with significant consequences for affected individuals. Although several candidate genes, including dyslexia susceptibility 1 candidate 1 (DYX1C1), have been implicated in dyslexia, their role in brain development remains unclear. We aimed to elucidate the spatiotemporal expression patterns of DYX1C1 during cerebral cortex development in rats.<br>
Methods We investigated DYX1C1 expression during cerebral cortex development using rat embryos at various gestational stages (E13.5, 15.5, 17.5 and 20.5) by immunohistochemistry (n = 7 embryos/stage), quantitative real-time PCR (n = 6), and in situ hybridization (n = 11–15).<br>
Results The DYX1C1-positive cells were predominantly located in the outermost layers of the cortical plate, particularly at E15.5. DYX1C1 mRNA expression peaked at E15.5 and subsequently declined. DYX1C1-positive cells did not co-localize with reelin-positive Cajal-Retzius cells, but co-localized with neuronal markers expressed during development, and had shorter primary cilia than DYX1C1-negative cells.<br>
Conclusions Our findings highlight the dynamic expression of DYX1C1 in the developing cerebral cortex of rats, implicating its involvement in neurodevelopmental processes. Further investigation of the functional interactions of DYX1C1, particularly its relationship with reelin and its role in cerebrocortical and hippocampal development, may provide insights into the pathophysiology of dyslexia and neurodevelopmental disorders.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7912025Endothelial Cell Polarity in Health and Disease17ENMoeThihaDepartment of Pathophysiology and Drug Discovery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakaoHikitaDepartment of Pathophysiology and Drug Discovery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasanoriNakayamaDepartment of Pathophysiology and Drug Discovery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesReview10.18926/AMO/68353Endothelial cell polarity is fundamental to the organization and function of blood vessels, influencing processes such as angiogenesis, vascular stability, and response to shear stress. This review elaborates on the molecular mechanisms that regulate endothelial cell polarity, focusing on key players like the PAR polarity complex and Rho family GTPases. These pathways coordinate the front–rear, apical–basal and planar polarity of endothelial cells, which are essential for the proper formation and maintenance of vascular structures. In health, endothelial polarity ensures not only the orderly development of blood vessels, with tip cells adopting distinct polarities during angiogenesis, but also ensures proper vascular integrity and function. In disease states, however, disruptions in polarity contribute to pathologies such as coronary artery disease, where altered planar polarity exacerbates atherosclerosis, and cancer, where disrupted polarity in tumor vasculature leads to abnormal vessel growth and function. Understanding cell polarity and its disruption is fundamental not only to comprehending how cells interact with their microenvironment and organize themselves into complex, organ-specific tissues but also to developing novel, targeted, and therapeutic strategies for a range of diseases, from cardiovascular disorders to malignancies, ultimately improving patient outcomes.No potential conflict of interest relevant to this article was reported.岡山大学農学部Acta Medica Okayama2186-77551142025裏表紙・英文目次ENNo potential conflict of interest relevant to this article was reported.岡山大学農学部Acta Medica Okayama2186-77551142025公表学術論文等リスト 20242738ENNo potential conflict of interest relevant to this article was reported.岡山大学農学部Acta Medica Okayama2186-77551142025遺伝子改変ラットを用いた弓状核キスペプチンニューロンの性腺刺激ホルモン放出ホルモンパルスジェネレーターとしての役割解明1120ENMayukoNagaeGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityYoshihisaUenoyamaGraduate School of Bioagricultural Sciences, Nagoya University Strategies for increasing reproductive performance are needed for domestic animals because for example the conception (pregnancy) rate has decreased in dairy cows around the world. Reproductive function is controlled by hormones released by the hypothalamus-pituitary-gonadal axis in mammals, including domestic animals. Of those hormones, tonic (pulsatile) gonadotropin-releasing hormone (GnRH) release is fundamentally important for gonadotropin release and gonadal activity. Therefore, uncovering the mechanism controlling GnRH pulses, that is GnRH pulse generator, is essential to improve reproductive technologies for domestic animals. The present review is focused on the indispensable role of arcuate nucleus (ARC) kisspeptin neurons (also known as KNDy neurons) as the GnRH pulse generator in mammals. First, we give a brief overview of studies on hypothalamic kisspeptin neurons throughout the past two decades. Second, we review studies that have provided direct evidence that ARC kisspeptin neurons serve as the GnRH pulse generator, with a special focus on our gene-modified rat models. Finally, we discuss the mechanism underlying GnRH pulse generation. The knowledge obtained from gene-modified rat models should be clinically important and could be adapted to new tools to improve reproductive performance in livestock by stimulating GnRH/gonadotropin pulses.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama2076-328X1512025The Impact of Task Context on Pleasantness and Softness Estimations: A Study Based on Three Touch Strategies63ENBinyueGaoGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityYinghuaYuGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityYoshimichiEjimaGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityJinglongWuGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityJiajiaYangGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityThis study investigated the two distinct perceptions (pleasantness and softness) of deformable stimuli with different degrees of compliance under conditions with and without a contextual task. Three tactile strategies-grasping, pinching, and pressing-were used to perceive the stimuli. In Experiment 1 (without a contextual task), participants estimated the perceived intensity of softness or pleasantness for each stimulus. In Experiment 2 (with a contextual task), the participants sequentially perceived two stimuli with different compliance levels and indicated which stimulus they perceived as softer and pleasant. The results showed that the psychophysical relationship between compliance and perceived softness was consistent across all tactile strategies in both experiments, with softness estimates increasing as compliance increased. However, the relationship between compliance and pleasantness differed between the two experiments. In Experiment 1, pleasantness estimates increased monotonically with increased compliance. However, in Experiment 2, across all tactile strategies, pleasantness began to decrease within the compliance range of 0.25-2.0 cm2/N, exhibiting an inverted U-shaped trend. These findings indicate that the relationship between compliance and pleasantness is task-dependent, particularly demonstrating significantly different trends when a contextual task is introduced. In contrast, the relationship between compliance and softness remained consistently monotonic.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0378-11199412025Identification of pennaceous barbule cell factor (PBCF), a novel gene with spatiotemporal expression in barbule cells during feather development149244ENMinoriNakaokaGraduate School of Natural Science and Technology, Okayama UniversityHibikiFukuchiGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityMahoOgoshiGraduate School of Natural Science and Technology, Okayama UniversitySayakaAizawaGraduate School of Natural Science and Technology, Okayama UniversitySakaeTakeuchiGraduate School of Natural Science and Technology, Okayama UniversityBird contour feathers exhibit a complex hierarchical structure composed of a rachis, barbs, and barbules, with barbules playing a crucial role in maintaining feather structure and function. Understanding the molecular mechanisms underlying barbule formation is essential for advancing our knowledge of avian biology and evolution. In this study, we identified a novel gene, pennaceous barbule cell factor (PBCF), using microarray analysis, RT-PCR, and in situ hybridization. PBCF is expressed in barbule cells adjacent to the ramus during pennaceous barbule formation, where these cells fuse with the ramus to establish the feather’s branching structure. PBCF expression occurs transiently after melanin pigmentation of the barbule plates but before the expression of barbule-specific keratin 1 (BlSK1). Orthologues of PBCF, predicted to be secreted proteins, are conserved across avian species, with potential homologues detected in reptiles, suggesting an evolutionary lineage-specific adaptation. Additionally, PBCF is expressed in non-vacuolated notochord cells and the extra-embryonic ectoderm of the yolk sac, hinting at its broader developmental significance. The PBCF gene produces two mRNA isoforms via alternative splicing, encoding a secreted protein and a glycophosphatidylinositol (GPI)-anchored membrane-bound protein, indicating functional versatility. These findings suggest that PBCF may be involved as an avian-specific extracellular matrix component in cell adhesion and/or communication, potentially contributing to both feather development and embryogenesis. Further investigation of PBCF’s role in feather evolution and its potential functions in other vertebrates could provide new insights into the interplay between development and evolution.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1029-84284312025Differentially Expressed Nedd4-binding Protein Ndfip1 Protects Neurons Against Methamphetamine-induced Neurotoxicity4ENMasatoAsanumaDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesIkukoMiyazakiDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesJean LudCadetMolecular Neuropsychiatry Section, Intramural Research Program, NIH/ NIDATo identify factors involved in methamphetamine (METH) neurotoxicity, we comprehensively searched for genes which were differentially expressed in mouse striatum after METH administration using differential display (DD) reverse transcription-PCR method and sequent single-strand conformation polymorphism analysis, and found two DD cDNA fragments later identified as mRNA of Nedd4 (neural precursor cell expressed developmentally downregulated 4) WW domain-binding protein 5 (N4WBP5), later named Nedd4 family-interacting protein 1 (Ndfip1). It is an adaptor protein for the binding between Nedd4 of ubiquitin ligase (E3) and target substrate protein for ubiquitination. Northern blot analysis confirmed drastic increases in Ndfip1 mRNA in the striatum after METH injections, and in situ hybridization histochemistry showed that the mRNA expression was increased in the hippocampus and cerebellum at 2 h-2 days, in the cerebral cortex and striatum at 18 h-2 days after single METH administration. The knockdown of Ndfip1 expression with Ndfip1 siRNA significantly aggravated METH-induced neurotoxicity in the cultured monoaminergic neuronal cells. These results suggest that drastic increases in Ndfip1 mRNA is compensatory reaction to protect neurons against METH-induced neurotoxicity.No potential conflict of interest relevant to this article was reported.メディカルレビュー社Acta Medica Okayama1882-14801822024ナトリウムチャネル異常とてんかん125132ENNo potential conflict of interest relevant to this article was reported.American Physiological SocietyActa Medica Okayama1931-857X32662024Preventive effects of vasohibin-2-targeting peptide vaccine for diabetic nephropathyF1054F1065ENYuriNakashimaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKatsuyukiTanabeDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTomoyoMifuneDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTakatoNakadoiDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHirokiHayashiDepartment of Health Development and Medicine, Osaka University Graduate School of MedicineHironoriNakagamiDepartment of Health Development and Medicine, Osaka University Graduate School of MedicineYasufumiSatoNew Industry Creation Hatchery Center, Tohoku UniversityJunWadaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesDiabetic nephropathy remains the leading cause of end-stage kidney disease in many countries, and additional therapeutic targets are needed to prevent its development and progression. Some angiogenic factors are involved in the pathogenesis of diabetic nephropathy. Vasohibin-2 (VASH2) is a novel proangiogenic factor, and our previous study showed that glomerular damage is inhibited in diabetic Vash2 homozygous knockout mice. Therefore, we established a VASH2-targeting peptide vaccine as a tool for anti-VASH2 therapy in diabetic nephropathy. In this study, the preventive effects of the VASH2-targeting peptide vaccine against glomerular injury were examined in a streptozotocin (STZ)-induced diabetic mouse model. The mice were subcutaneously injected with the vaccine at two doses 2 wk apart and then intraperitoneally injected with 50 mg/kg STZ for 5 consecutive days. Glomerular injury was evaluated 20 wk after the first vaccination. Treatment with the VASH2-targeting peptide vaccine successfully induced circulating anti-VASH2 antibody without inflammation in major organs. Although the vaccination did not affect blood glucose levels, it significantly prevented hyperglycemia-induced increases in urinary albumin excretion and glomerular volume. The vaccination did not affect increased VASH2 expression but significantly inhibited renal angiopoietin-2 (Angpt2) expression in the diabetic mice. Furthermore, it significantly prevented glomerular macrophage infiltration. The preventive effects of vaccination on glomerular injury were also confirmed in db/db mice. Taken together, the results of this study suggest that the VASH2-targeting peptide vaccine may prevent diabetic glomerular injury in mice by inhibiting Angpt2-mediated microinflammation.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama2049-41731332025Long-Term Follow-Up of a Patient With SPG11198200ENYosukeOsakadaDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTaijunYunokiDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityChikaMatsuokaDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYusukeFukuiDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKeiichiroTsunodaDepartment of Neurology, Tsuyama Chuo HospitalKentaroDeguchiDepartment of Neurology, Okayama City HospitalRyutaMoriharaDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityToruYamashitaDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHiroyukiIshiuraDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityWe present a case of a male patient with disease-causing variants in SPG11, a causative gene for autosomal recessive spastic paraplegia with a thin corpus callosum (ARHSP-TCC), as well as juvenile amyotrophic lateral sclerosis (ALS5) and Charcot–Marie–Tooth disease (CMT2X). A neurological examination at age 18 revealed dysarthria, muscle weakness in bilateral lower extremities, hyperreflexia in patellar reflex, hyporeflexia in Achilles reflex with an extensor plantar reflex, and intellectual disability. Magnetic resonance imaging revealed a thin corpus callosum and ears of the lynx sign. At the age of 26, weakness and muscle atrophy progressed. While no sensory disturbances were noted, there was a mild decrease in sensory nerve action potentials of the sural nerve over the 8 years between 18 and 26. Clinicians should be aware that SPG11 belongs to the same spectrum of disorders as ALS5 and CMT2X and presents various phenotypes depending on the stage of the disease.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama0022-304216912024Exploring the Role of Ccn3 in Type III Cell of Mice Taste Budse16291ENKuanyuWangDepartment of Oral Physiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYoshihiroMitohDepartment of Oral Physiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKengoHorieDepartment of Oral Physiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityRyusukeYoshidaDepartment of Oral Physiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityDifferent taste cells express unique cell-type markers, enabling researchers to distinguish them and study their functional differentiation. Using single-cell RNA-Seq of taste cells in mouse fungiform papillae, we found that Cellular Communication Network Factor 3 (Ccn3) was highly expressed in Type III taste cells but not in Type II taste cells. Ccn3 is a protein-coding gene involved in various biological processes, such as cell proliferation, angiogenesis, tumorigenesis, and wound healing. Therefore, in this study, we aimed to explore the expression and function of Ccn3 in mouse taste bud cells. Using reverse transcription polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemistry (IHC), we confirmed that Ccn3 was predominantly expressed in Type III taste cells. Through IHC, quantitative real-time RT-PCR, gustatory nerve recordings, and short-term lick tests, we observed that Ccn3 knockout (Ccn3-KO) mice did not exhibit any significant differences in the expression of taste cell markers and taste responses compared to wild-type controls. To explore the function of Ccn3 in taste cells, bioinformatics analyses were conducted and predicted possible roles of Ccn3 in tissue regeneration, perception of pain, protein secretion, and immune response. Among them, an immune function is the most plausible based on our experimental results. In summary, our study indicates that although Ccn3 is strongly expressed in Type III taste cells, its knockout did not influence the basic taste response, but bioinformatics provided valuable insights into the possible role of Ccn3 in taste buds and shed light on future research directions.No potential conflict of interest relevant to this article was reported.IARIAActa Medica Okayama1942-2644173-42024Deep Reinforcement Learning Enabled Adaptive Virtual Machine Migration Control in Multi-Stage Information Processing Systems116125ENYukinobuFukushimaFaculty of Environmental, Life, Natural Science and Technology Okayama UniversityYukiKoujitaniGraduate School of Natural Science and Technology Okayama UniversityKazutoshiNakaneGraduate School of Information Science Nagoya UniversityYuyaTarutaniGraduate School of Engineering Osaka UniversityCelimugeWuGraduate School of Informatics and Engineering The Univ. of Electro-Commun.YushengJiInformation Systems Architecture Research Division National Institute of InformaticsTokumiYokohiraFaculty of Interdisciplinary Science and Engineering in Health Systems Okayama UniversityTutomuMuraseGraduate School of Information Science Nagoya UniversityThis paper tackles a Virtual Machine (VM) migration control problem to maximize the progress (accuracy) of information processing tasks in multi-stage information processing systems. The conventional methods for this problem are effective only for specific situations, such as when the system load is high. In this paper, in order to adaptively achieve high accuracy in various situations, we propose a VM migration method using a Deep Reinforcement Learning (DRL) algorithm. It is difficult to directly apply a DRL algorithm to the VM migration control problem because the size of the solution space of the problem dynamically changes according to the number of VMs staying in the system while the size of the agent’s action space is fixed in DRL algorithms. To cope with this difficulty, the proposed method divides the VM migration control problem into two problems: the problem of determining only the VM distribution (i.e., the proportion of the number of VMs deployed on each edge server) and the problem of determining the locations of all the VMs so that it follows the determined VM distribution. The former problem is solved by a DRL algorithm, and the latter by a heuristic method. This approach makes it possible to apply a DRL algorithm to the VM migration control problem because the VM distribution is expressed by a vector with a fixed number of dimensions and can be directly outputted by the agent. The simulation results confirm that our proposed method can adaptively achieve quasi-optimal accuracy in various situations with different link delays, types of the information processing tasks and the number of VMs.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1871-40801832023Review: Nicotinic acetylcholine receptors to regulate important brain activity—what occurs at the molecular level?769774ENShigetoshiNaraGraduate School of Natural Science and Technology, Okayama UniversityYutakaYamagutiFaculty of Information Engineering, Fukuoka Institute of TechnologyIchiroTsudaChubu University Academy of Emerging Sciences/Center for Mathematical Science and Artificial Intelligence, Chubu UniversityHerein, we briefly review the role of nicotinic acetylcholine receptors in regulating important brain activity by controlled release of acetylcholine from subcortical neuron groups, focusing on a microscopic viewpoint and considering the nonlinear dynamics of biological macromolecules associated with neuron activity and how they give rise to advanced brain functions of brain.No potential conflict of interest relevant to this article was reported.Public Library of ScienceActa Medica Okayama1932-620319122024Phase-dependent trends in the prevalence of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) related to long COVID: A criteria-based retrospective study in Japane0315385ENSatoruMoritaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazukiTokumasuDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiOtsukaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyukiHondaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuhiroNakanoDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNaruhikoSunadaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasueSakuradaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuiMatsudaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshiakiSoejimaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKeigoUedaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesFumioOtsukaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesBackground <br>
The characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) related to COVID-19 have remained uncertain. To elucidate the clinical trend of ME/CFS induced by long COVID, we examined data for patients who visited our outpatient clinic established in a university hospital during the period from Feb 2021 to July 2023.<br>
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Methods <br>
Long COVID patients were classified into two groups, an ME/CFS group and a non-ME/CFS group, based on three diagnostic criteria.<br>
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Results <br>
The prevalence of ME/CFS in the long COVID patients was 8.4% (62 of 739 cases; female: 51.6%) and factors related to ME/CFS were severe illness, smoking and alcohol drinking habits, and fewer vaccinations. The frequency of ME/CFS decreased from 23.9% in the Preceding period to 13.7% in the Delta-dominant period and to 3.3% in the Omicron-dominant period. Fatigue and headache were commonly frequent complaints in the ME/CFS group, and the frequency of poor concentration in the ME/CFS group was higher in the Omicron period. Serum ferritin levels were significantly higher in female patients in the ME/CFS group infected in the Preceding period. In the ME/CFS group, the proportion of patients complaining of brain fog significantly increased from 22.2% in the Preceding period to 47.9% in the Delta period and to 81.3% in the Omicron period. The percentage of patients who had received vaccination was lower in the ME/CFS group than the non-ME/CFS group over the study period, whereas there were no differences in the vaccination rate between the groups in each period.<br>
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Conclusion <br>
The proportion of long COVID patients who developed ME/CFS strictly diagnosed by three criteria was lower among patients infected in the Omicron phase than among patients infected in the other phases, while the proportion of patients with brain fog inversely increased. Attention should be paid to the variant-dependent trends of ME/CFS triggered by long COVID (300 words).No potential conflict of interest relevant to this article was reported.Frontiers Media SAActa Medica Okayama2296-858X112024Perspectives of traditional herbal medicines in treating retinitis pigmentosa1468230ENShihuiLiuGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityToshihikoMatsuoGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityChieMatsuoGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityTakumiAbeGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityJinghuaChenDepartment of Ophthalmology, University of Florida, College of MedicineChiSunDepartment of Ophthalmology and Visual Sciences, Washington University in St. LouisQingZhaoNational Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of SciencesMedicinal plants, also known as herbs, have been discovered and utilized in traditional medical practice since prehistoric times. Medicinal plants have been proven rich in thousands of natural products that hold great potential for the development of new drugs. Previously, we reviewed the types of Chinese traditional medicines that a Tang Dynasty monk Jianzhen (Japanese: Ganjin) brought to Japan from China in 742. This article aims to review the origin of Kampo (Japanese traditional medicine), and to present the overview of neurodegenerative diseases and retinitis pigmentosa as well as medicinal plants in some depth. Through the study of medical history of the origin of Kampo, we found that herbs medicines contain many neuroprotective ingredients. It provides us a new perspective on extracting neuroprotective components from herbs medicines to treat neurodegenerative diseases. Retinitis pigmentosa (one of the ophthalmic neurodegenerative diseases) is an incurable blinding disease and has become a popular research direction in global ophthalmology. To date, treatments for retinitis pigmentosa are very limited worldwide. Therefore, we intend to integrate the knowledge and skills from different disciplines, such as medical science, pharmaceutical science and plant science, to take a new therapeutic approach to treat neurodegenerative diseases. In the future, we will use specific active ingredients extracted from medicinal plants to treat retinitis pigmentosa. By exploring the potent bioactive ingredients present in medicinal plants, a valuable opportunity will be offered to uncover novel approaches for the development of drugs which target for retinitis pigmentosa.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama2024Establishment and Analysis of Novel In Vitro 3D Cell Culture Models of the Fibrotic Tumor Microenvironment in Pancreatic CancerENHiroyoshiTANAKAOkayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2024Power suppression in EEG after the onset of SAH is a significant marker of early brain injury in rat modelsENYujiTAKASUGIGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2024The neural substrates of temporal prediction forming tactile perception in humansENRONGXIARENGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2024Effects of Subjective Cognitive Decline on Audiovisual Integration and Cross-modal TrainingENSHENGNANLIGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2024The neural substrates of motion inhibitory control during Go/No-Go response inhibition taskENNANZHANGGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2024Computer Vision Systems for Estimating Food Consumption in a Hospital SettingENYUITA ARUM SARIGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2024Computer Vision-based Motion Segmentation and Its Application for Sperm Quality EstimationENSIGIT ADINUGROHOGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2024Development of Peptide Nanomicelle for siRNA Delivery into Cancer CellsENTAUFIK FATWA NUR HAKIMGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2024A Study of Integrated Server Platform for IoT Application SystemsENYOHANES YOHANIE FRIDELIN PANDUMANGraduate School of Natural Science and Technology, Okayama universityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2024キイロショウジョウバエ概日時計を制御する時計神経回路の網羅的機能解析ENManabuSEKIGUCHIGraduate School of Natural Science and Technology, Okayama universityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2024Clinical characteristics of female long COVID patients with menstrual symptoms: a retrospective study from a Japanese outpatient clinicENYasueSAKURADAGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2024Role of catecholamine synthases in the maintenance of cancer stem-like cells in malignant peripheral nerve sheath tumorsENHaruyoshiKATAYAMAGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2024Neuroprotective effects of carnosine in a mice stroke model concerning oxidative stress and inflammatory responseENXINRANHUGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2024PRRX1-TOP2A interaction is a malignancy-promoting factor in human malignant peripheral nerve sheath tumoursENShotaTAKIHIRAGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNo potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama2673-62841222023Development of the Follow-Up Human 3D Oral Cancer Model in Cancer Treatment35ENKazuyoIgawaNeutron Therapy Research Center, Okayama UniversityKenjiIzumiDivision of Biomimetics, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata UniversityYoshinoriSakuraiInstitute for Integrated Radiation and Nuclear Science, Kyoto UniversityAs function preservation cancer therapy, targeted radiation therapies have been developed for the quality of life of cancer patients. However, preclinical animal studies evaluating the safety and efficacy of targeted radiation therapy is challenging from the viewpoints of animal welfare and animal protection, as well as the management of animal in radiation-controlled areas under the regulations. We fabricated the human 3D oral cancer model that considers the time axis of the follow up in cancer treatment. Therefore, in this study, the 3D model with human oral cancer cells and normal oral fibroblasts was treated based on clinical protocol. After cancer treatment, the histological findings of the 3D oral cancer model indicated the clinical correlation between tumor response and surrounding normal tissue. This 3D model has potential as a tool for preclinical studies alternative to animal studies.No potential conflict of interest relevant to this article was reported.Institute of Electrical and Electronics Engineers (IEEE)Acta Medica Okayama2169-3536122024Aromug: A Mug-Type Olfactory Interface to Enhance the Sweetness Perception of Beverages7836678378ENDaikiMayumiGraduate School of Science and Technology, Nara Institute of Science and TechnologyYugoNakamuraFaculty of Information Science and Electrical Engineering, Kyushu UniversityYukiMatsudaFaculty of Environmental, Life, Natural Science and Technology, Okayama UniversityShinyaMisakiGraduate School of Science and Technology, Nara Institute of Science and TechnologyKeiichiYasumotoGraduate School of Science and Technology, Nara Institute of Science and TechnologySugary beverages are a significant contributor to sugar consumption, and their excessive consumption is associated with increased risks of elevated blood glucose levels and diabetes. Many individuals have a strong preference for sugary beverages and often find beverages with lower sugar content to be less satisfying. Attempts to switch to less sugary options are frequently short-lived, leading to a return to higher-sugar beverages. Recognizing that 75 – 95% of taste perception is influenced by scent, we investigated a scent-based approach to reduce sugar intake while preserving the perception of sweetness. This study introduces an olfactory interface in the form of a mug named “Aromug,” designed to emit a sweet scent in sync with the drinking action. Aromug incorporates motion sensing and scent presentation functions to enhance the perceived sweetness of a beverage, thereby encouraging a gradual reduction in sugar intake. Our experiments, involving 33 participants, demonstrated that the combined scents of sugar-free coffee and chocolate increased the perception of sweetness (p =1.641×10−2 ). The study also found that the simultaneous presentation of scent and visual cues improved taste satisfaction and sweetness perception. Additionally, we observed variations in sweetness preference related to age and frequency of coffee consumption. It was particularly observed that people in their 20s and those who frequently drink coffee tend to perceive the taste of beverages as sweeter. This suggests a potential for Aromug to customize the scent experience based on individual preferences, offering a novel way to encourage healthier beverage choices.No potential conflict of interest relevant to this article was reported.Japanese Society of Internal MedicineActa Medica Okayama0918-291863192024A Prompt Diagnosis and Treatment of a Case of Nuclear Protein of the Testis Carcinoma Characterized by a Bronchial Lesion and High Serum Alpha-fetoprotein Level Following Genomic Testing26552660ENHiroakiMatsuuraDepartment of Respiratory Medicine, Okayama University HospitalGoMakimotoDepartment of Respiratory Medicine, Okayama University HospitalNaohiroOdaDepartment of Respiratory Medicine, Fukuyama City HospitalKiichiroNinomiyaCenter for Comprehensive Genomic Medicine, Okayama University HospitalHisaoHigoDepartment of Respiratory Medicine, Okayama University HospitalMasanoriFujiiDepartment of Respiratory Medicine, Okayama University HospitalKammeiRaiCenter for Innovative Clinical Medicine, Okayama University HospitalEikiIchiharaDepartment of Respiratory Medicine, Okayama University HospitalKadoakiOhashiDepartment of Respiratory Medicine, Okayama University HospitalKatsuyukiHottaCenter for Innovative Clinical Medicine, Okayama University HospitalMasahiroTabataCenter for Clinical Oncology, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesNuclear protein of the testis carcinoma (NUTC) is a rare and aggressive malignancy. We herein report a case of NUTC in the lung characterized by a bronchial lesion and elevated alpha-fetoprotein levels. A 35-year-old Japanese man presented to our institution with suspected advanced lung cancer based on a histological examination. Subsequently, next-generation sequencing (NGS) yielded a positive BRD4-NUTM1 fusion. In addition, positive NUT immunostaining of the lung biopsy specimen confirmed NUTC in the lungs. Systemic chemotherapy and radiotherapy showed a temporary response, with decreased serum alpha-fetoprotein levels. We highlight this case of a prompt diagnosis by NGS of NUTC in a young individual with a rapidly progressing tumor.No potential conflict of interest relevant to this article was reported.ElsevierActa Medica Okayama1083-351X30032024Methyl vinyl ketone and its analogs covalently modify PI3K and alter physiological functions by inhibiting PI3K signaling105679ENAtsushiMorimotoDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNobumasaTakasugiDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYuexuanPanDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShoKubotaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNaoshiDohmaeBiomolecular Characterization Unit, Technology Platform Division, RIKEN Center for Sustainable Resource ScienceYumiAbikoGraduate School of Biomedical Science, Nagasaki UniversityKojiUchidaLaboratory of Food Chemistry, Graduate School of Agricultural and Life Sciences, The University of TokyoYoshitoKumagaiGraduate School of Pharmaceutical Sciences, Kyushu UniversityTakashiUeharaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityReactive carbonyl species (RCS), which are abundant in the environment and are produced in vivo under stress, covalently bind to nucleophilic residues such as Cys in proteins. Disruption of protein function by RCS exposure is predicted to play a role in the development of various diseases such as cancer and metabolic disorders, but most studies on RCS have been limited to simple cytotoxicity validation, leaving their target proteins and resulting physiological changes unknown. In this study, we focused on methyl vinyl ketone (MVK), which is one of the main RCS found in cigarette smoke and exhaust gas. We found that MVK suppressed PI3K-Akt signaling, which regulates processes involved in cellular homeostasis, including cell proliferation, autophagy, and glucose metabolism. Interestingly, MVK inhibits the interaction between the epidermal growth factor receptor and PI3K. Cys656 in the SH2 domain of the PI3K p85 subunit, which is the covalently binding site of MVK, is important for this interaction. Suppression of PI3K- Akt signaling by MVK reversed epidermal growth factor- induced negative regulation of autophagy and attenuated glucose uptake. Furthermore, we analyzed the effects of the 23 RCS compounds with structures similar to MVK and showed that their analogs also suppressed PI3K-Akt signaling in a manner that correlated with their similarities to MVK. Our study demonstrates the mechanism of MVK and its analogs in suppressing PI3K-Akt signaling and modulating physiological functions, providing a model for future studies analyzing environmental reactive species.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0340-57619922024Therapeutic potential of 4-phenylbutyric acid against methylmercury-induced neuronal cell death in mice563574ENRyoheiMikiDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityRyosukeNomuraDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYutaIijimaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShoKubotaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNobumasaTakasugiDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTakaoIwawakiDivision of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical UniversityMasatakeFujimuraDepartment of International Affairs and Research, National Institute for Minamata DiseaseTakashiUeharaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMethylmercury (MeHg) is an environmental neurotoxin that induces damage to the central nervous system and is the causative agent in Minamata disease. The mechanisms underlying MeHg neurotoxicity remain largely unknown, and there is a need for effective therapeutic agents, such as those that target MeHg-induced endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which is activated as a defense mechanism. We investigated whether intraperitoneal administration of the chemical chaperone, 4-phenylbutyric acid (4-PBA), at 120 mg/kg/day can alleviate neurotoxicity in the brains of mice administered 50 ppm MeHg in drinking water for 5 weeks. 4-PBA significantly reduced MeHg-induced ER stress, neuronal apoptosis, and neurological symptoms. Furthermore, 4-PBA was effective even when administered 2 weeks after the initiation of exposure to 30 ppm MeHg in drinking water. Our results strongly indicate that ER stress and the UPR are key processes involved in MeHg toxicity, and that 4-PBA is a novel therapeutic candidate for MeHg-induced neurotoxicity.No potential conflict of interest relevant to this article was reported.Institute of Electrical and Electronics EngineersActa Medica Okayama2169-3536122024MUSIC Spectrum Based Interference Detection, Localization, and Interference Arrival Prediction for mmWave IRS-MIMO System142592142605ENYafeiHouFaculty of Environmental, Life, Natural Science and Technology, Okayama UniversityKazutoYanoWave Engineering Laboratories, Advanced Telecommunications Research Institute InternationalNorisatoSugaWave Engineering Laboratories, Advanced Telecommunications Research Institute InternationalJulianWebberWave Engineering Laboratories, Advanced Telecommunications Research Institute InternationalSatoshiDennoFaculty of Environmental, Life, Natural Science and Technology, Okayama UniversityToshikazuSakanoWave Engineering Laboratories, Advanced Telecommunications Research Institute InternationalFor a millimeter wave (mmWave) intelligent re-configurable surface (IRS)-MIMO system, if it can correctly detect the interference occurrence and their locations, the patterns of interference signal can be collected and learned using machine learning for the prediction of interference arrival. With the information of interference location and activity pattern, the capacity of the system can be largely improved using many techniques such as beamforming, interference cancellation, and transmission scheduling. This paper aims to detect interference occurrence using a low-complexity MUSIC (MUSIC: multiple signal classification) spectrum-based method, and then localize their sources for mmWave IRS-MIMO system. The MUSIC spectrum of wireless system can be regarded as somehow the 'signature' related to the signals transmitted from different users or interference. We utilize such property to detect the occurrence of interference, and then localize their sources in a low-complexity way. Finally, the pattern of interference occurrence can be learned to predict the interference arrival from the collected data. This paper also proposed an efficient probabilistic neural network (PNN)-based predictor for the interference arrival prediction and showed its prediction accuracy. From simulated results, our proposed method can achieve the correct results with the accuracy near to 100% when the fingerprint samples is over 10. In addition, the localization error can be within 1 m with more than 65% and 43% for Y-axis and X-axis, respectively. Finally, based on the results of the interference occurrence, the proposed PNN-based predictor for the interference arrival prediction can capture correctly the similar distribution function of the coming continuous idle status.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7852024Focal Cerebral Hypoperfusion Detected by Arterial Spin-Labeled Magnetic Resonance Imaging in Patients with Migraine Presenting with Neurological Symptoms Concomitant with or without Headache413421ENKenichiKashiharaOkayama Neurology ClinicMinoruIrisawaDepartment of Radiology, Okayama Kyokuto HospitalWataruTakaoDivision of Radiology, Okayama Kyokuto HospitalCase Report10.18926/AMO/67666We investigated patients with migraine or migraine variants who exhibited focal cerebral hypoperfusion on arterial spin-labeled (ASL) magnetic resonance (MR) imaging along with neurological symptoms. Fourteen patients with migraine demonstrated focal cerebral hypoperfusion. Three other patients did not have a history of recurrent headaches but exhibited comparable cerebral hypoperfusion to migraine patients on ASL-MRI in addition to neurological symptoms. Patients with migraine may present with neurological symptoms associated with cortical spreading depression during, after, or even without a headache phase. Additionally, the isolated neurological symptoms may be caused by a pathophysiology identical to that of migraine but without presenting with recurrent headaches.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7852024Effect of Radon Inhalation on Murine Brain Proteins: Investigation Using Proteomic and Multivariate Analyses387399ENShotaNaoeGraduate School of Health Sciences, Okayama UniversityAyumiTanakaGraduate School of Health Sciences, Okayama UniversityNorieKanzakiNingyo-toge Environmental Engineering Center, Japan Atomic Energy AgencyReijuTakenakaGraduate School of Health Sciences, Okayama UniversityAkihiroSakodaNingyo-toge Environmental Engineering Center, Japan Atomic Energy AgencyTakaakiMiyajiAdvanced Science Research Center, Okayama UniversityKiyonoriYamaokaFaculty of Health Sciences, Okayama UniversityTakahiroKataokaFaculty of Health Sciences, Okayama UniversityOriginal Article10.18926/AMO/67663Radon is a known risk factor for lung cancer; however, it can be used beneficially, such as in radon therapy. We have previously reported the enhancement of antioxidant effects associated with trace amounts of oxidative stress as one of the positive biological effects of radon inhalation. However, the biological effects of radon inhalation are incompletely understood, and more detailed and comprehensive studies are required. Although several studies have used proteomics to investigate the effects of radon inhalation on body proteins, none has focused on brain proteins. In this study, we evaluated the expression status of proteins in murine brains using proteomic and multivariate analyses to identify those whose expressions changed following two days of radon inhalation at a concentration of 1,500 Bq/m3. We found associations of radon inhalation with the expressions of seven proteins related to neurotransmission and heat shock. These proteins may be proposed as biomarkers indicative of radon inhalation. Although further studies are required to obtain the detailed biological significance of these protein alterations, this study contributes to the elucidation of the biological effects of radon
inhalation as a low-dose radiation.No potential conflict of interest relevant to this article was reported.Institute of Electrical and Electronics Engineers (IEEE)Acta Medica Okayama0093-99946052024Superior Efficiency Under PWM Harmonic Current in an Axial-Flux PM Machine for HEV/EV Traction: Comparison With a Radial-Flux PM Machine67366751ENRenTsunataDivision of Industrial Innovation Sciences Graduate School of Natural Science and Technology, Okayama UniversityMasatsuguTakemotoDivision of Industrial Innovation Sciences Graduate School of Natural Science and Technology, Okayama UniversityJunImaiDivision of Industrial Innovation Sciences Graduate School of Natural Science and Technology, Okayama UniversityTatsuyaSaitoSumitomo Electric Industries Ltd.TomoyukiUenoSumitomo Electric Industries Ltd.This paper evaluates the harmonic current caused by a pulse width modulation (PWM) inverter and how it affects the efficiency of a novel axial-flux permanent-magnet machine using a ferrite permanent magnet (AF-FePM) in traction applications. First, differences between the finite element analysis (FEA) and experimental results are discussed using a prototype of the proposed AF-FePM. Second, the AF-FePM is compared with a commercially available radial-flux permanent-magnet machine using a Nd-sintered magnet (RF-NdPM). For both machines, the efficiency and loss are calculated using FEA when applying the sinusoidal and harmonic currents. Additionally, we present the superior efficiency of the AF-FePM under the PWM harmonic current during a WLTC driving cycle because the designed model employs the ferrite magnet and a round copper wire, unlike the RF-NdPM. Finally, motor and inverter losses at different switching frequencies are also evaluated. This paper eventually shows that the proposed AF-FePM would be one of the suitable candidates to enhance high efficiency under PWM harmonic current condition based on comprehensive discussion.No potential conflict of interest relevant to this article was reported.Pharmaceutical Society of JapanActa Medica Okayama0918-615847102024Molecular Diversity of Photosensitive Protein Opsins and Their High Potential for Optogenetic Applications16001609ENKeiichiKojimaFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityBecause G protein coupled receptors (GPCRs) represent the largest family of drug targets in clinical trials, GPCR signaling cascades are closely related to various physiological phenomena, attracting significant attention in pharmaceutical science. Opsins (also known as animal rhodopsins) are photoreceptive proteins containing retinal as a chromophore, which function as GPCRs and underlie the molecular basis of photoreception in animals. Recently, opsins have been progressively applied in an innovative technology called optogenetics to regulate biological activities using light. A wide variety of opsins have been identified in metazoans and characterized at the molecular and physiological levels, providing a foundation for their optogenetic applications. In this review, I briefly introduce the diversity of opsins in terms of their molecular functions, including G protein selectivity and photoreaction properties. This diversity provides a significant advantage for optically manipulating a wide variety of GPCR signaling cascades with high temporal resolution. Additionally, I discuss the rich array of opsin-based optogenetic tools used to control various physiological processes and their potential as therapeutic tools for vision restoration. Based on the introduction, I expect that the optogenetic approach will offer powerful tools to provide valuable insights into the molecular mechanisms of various physiological phenomena and next-generation treatment options for diseases beyond the capacity of traditional drugs.No potential conflict of interest relevant to this article was reported.Frontiers MediaActa Medica Okayama1663-9812152024Ameliorating effect of chotosan and its active component, Uncaria hook, on lipopolysaccharide-induced anxiety-like behavior in mice1471602ENYasumasaOkawaDepartment of Clinical Pharmacy, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversitySoichiroUshioDepartment of Clinical Pharmacy, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYasuhisaIzushiDepartment of Pharmacotherapy, School of Pharmacy, Shujitsu UniversityYoshihisaKitamuraDepartment of Pharmacotherapy, School of Pharmacy, Shujitsu UniversityYoshitoZamamiDepartment of Clinical Pharmacy, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityToshiakiSendoDepartment of Clinical Pharmacy, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityIntroduction: In this study, we aimed to examine the effects of chotosan, a traditional Japanese botanical drug, and its active component, Uncaria hook, on anxiety-like behaviors induced by systemic inflammation in mice. <br>
Methods: To induce systemic inflammation, the mice were treated with lipopolysaccharide (LPS), a bacterial endotoxin. Prior to LPS treatment, the mice were administered chotosan or Uncaria hook orally each day for 14 days. Anxiety-like behavior of the mice was evaluated using the light-dark test 24 h after LPS treatment.<br>
Results: Repeated administration of chotosan prevented anxiety-like behavior in both normal and LPS-treated mice. Similarly, administration of Uncaria hook suppressed LPS-induced anxiety-like behavior in mice. Furthermore, treatment with tandospirone, a 5-HT1A receptor agonist, alleviated anxiety-like behavior in mice, whereas treatment with DOI, a 5-HT2A receptor agonist, enhanced anxiety-like behavior in mice. LPS treatment significantly increased serotonin (5-HT)(2A) receptor mRNA expression in the frontal cortex, whereas 5-HT1A receptor mRNA expression remained unchanged in the hippocampus. Notably, chotosan significantly suppressed the mRNA expression of 5-HT2A receptor. <br>
Discussion: These findings indicate that chotosan exerts anxiolytic-like effects in the context of inflammation-induced anxiety, potentially mediated by the inhibition of 5-HT2A receptor hyperfunction in LPS-treated mice. Consequently, we postulate that chotosan may be effective in managing inflammation-induced anxiety-like behaviors.No potential conflict of interest relevant to this article was reported.American Diabetes AssociationActa Medica Okayama0012-17977352024GRP78 Contributes to the Beneficial Effects of SGLT2 Inhibitor on Proximal Tubular Cells in DKD763779ENAtsukoNakatsukaDivision of Kidney, Diabetes and Endocrine Diseases, Okayama University HospitalSatoshiYamaguchiDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityJunWadaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityThe beneficial effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on kidney function are well-known; however, their molecular mechanisms are not fully understood. We focused on 78-kDa glucose-regulated protein (GRP78) and its interaction with SGLT2 and integrin-β1 beyond the chaperone property of GRP78. In streptozotocin (STZ)-induced diabetic mouse kidneys, GRP78, SGLT2, and integrin-β1 increased in the plasma membrane fraction, while they were suppressed by canagliflozin. The altered subcellular localization of GRP78/integrin-β1 in STZ mice promoted epithelial mesenchymal transition (EMT) and fibrosis, which were mitigated by canagliflozin. High-glucose conditions reduced intracellular GRP78, increased its secretion, and caused EMT-like changes in cultured HK2 cells, which were again inhibited by canagliflozin. Urinary GRP78 increased in STZ mice, and in vitro experiments with recombinant GRP78 suggested that inflammation spread to surrounding tubular cells and that canagliflozin reversed this effect. Under normal glucose culture, canagliflozin maintained sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA) activity, promoted ER robustness, reduced ER stress response impairment, and protected proximal tubular cells. In conclusion, canagliflozin restored subcellular localization of GRP78, SGLT2, and integrin-β1 and inhibited EMT and fibrosis in DKD. In nondiabetic chronic kidney disease, canagliflozin promoted ER robustness by maintaining SERCA activity and preventing ER stress response failure, and it contributed to tubular protection.No potential conflict of interest relevant to this article was reported.Anticancer Research USA Inc.Acta Medica Okayama1109-65352152024Terrein Exhibits Anti-tumor Activity by Suppressing Angiogenin Expression in Malignant Melanoma Cells464473ENTAIRAHIROSEDepartment of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYUKIKUNISADADepartment of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKOICHIKADOYADepartment of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHIROKIMANDAIDepartment of Pharmacy, Faculty of Pharmacy, Gifu University of Medical ScienceYUMISAKAMOTODepartment of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKYOICHIOBATADepartment of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKISHOONODepartment of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHIROAKITAKAKURADepartment of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKAZUHIROOMORIDepartment of Pathophysiology-Periodontal Science, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversitySHOGOTAKASHIBADepartment of Pathophysiology-Periodontal Science, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversitySEIJISUGADivision of Applied Chemistry, Graduate School of Natural Sciences and Technology, Okayama UniversitySOICHIROIBARAGIDepartment of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesBackground/Aim: Malignant melanoma is a tumor with a poor prognosis that can metastasize distally at an early stage. Terrein, a metabolite produced by Aspergillus terreus, suppresses the expression of angiogenin, an angiogenic factor. However, the pharmacological effects of natural terrein have not been elucidated, because only a small amount of terrein can be extracted from large fungal cultures. In this study, we investigated the antineoplastic effects of terrein on human malignant melanoma cells and its underlying mechanisms. Materials and methods: Human malignant melanoma cell lines were cultured in the presence of terrein and analyzed. Angiogenin production was evaluated using ELISA. Ribosome biosynthesis was evaluated using silver staining of the nucleolar organizer region. Intracellular signaling pathways were analyzed using western blotting. Malignant melanoma cells were transplanted subcutaneously into the backs of nude mice. The tumors were removed at 5 weeks and analyzed histopathologically. Results: Terrein inhibited angiogenin expression, proliferation, migration, invasion, and ribosome biosynthesis in malignant melanoma cells. Terrein was shown to inhibit tumor growth and angiogenesis in animal models. Conclusion: This study demonstrated that terrein has anti-tumor effects against malignant melanoma. Furthermore, chemically synthesized non-natural terrein can be mass-produced and serve as a novel potential anti-tumor drug candidate.No potential conflict of interest relevant to this article was reported.Nature PortfolioActa Medica Okayama2045-23221412024Suppression of PTBP1 in hippocampal astrocytes promotes neurogenesis and ameliorates recognition memory in mice with cerebral ischemia20521ENYusukeFukuiDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityRyutaMoriharaDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityXinranHuDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYumikoNakanoDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTaijunYunokiDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMamiTakemotoDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKojiAbeDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityToruYamashitaDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityThe therapeutic potential of suppressing polypyrimidine tract-binding protein 1 (Ptbp1) messenger RNA by viral transduction in a post-stroke dementia mouse model has not yet been examined. In this study, 3 days after cerebral ischemia, we injected a viral vector cocktail containing adeno-associated virus (AAV)-pGFAP-mCherry and AAV-pGFAP-CasRx (control vector) or a cocktail of AAV-pGFAP-mCherry and AAV-pGFAP-CasRx-SgRNA-(Ptbp1) (1:5, 1.0 x 1011 viral genomes) into post-stroke mice via the tail vein. We observed new mCherry/NeuN double-positive neuron-like cells in the hippocampus 56 days after cerebral ischemia. A portion of mCherry/GFAP double-positive astrocyte-like glia could have been converted into new mCherry/NeuN double-positive neuron-like cells with morphological changes. The new neuronal cells integrated into the dentate gyrus and recognition memory was significantly ameliorated. These results demonstrated that the in vivo conversion of hippocampal astrocyte-like glia into functional new neurons by the suppression of Ptbp1 might be a therapeutic strategy for post-stroke dementia.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama1661-659625162024Quercetin Attenuates Acetaldehyde-Induced Cytotoxicity via the Heme Oxygenase-1-Dependent Antioxidant Mechanism in Hepatocytes9038ENKexinLiGraduate School of Environmental and Life Science, Okayama UniversityMinoriKidawaraGraduate School of Environmental and Life Science, Okayama UniversityQiguangChenGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityShintaroMunemasaGraduate School of Environmental and Life Science, Okayama UniversityYoshiyukiMurataGraduate School of Environmental and Life Science, Okayama UniversityToshiyukiNakamuraGraduate School of Environmental and Life Science, Okayama UniversityYoshimasaNakamuraGraduate School of Environmental and Life Science, Okayama UniversityIt is still unclear whether or how quercetin influences the toxic events induced by acetaldehyde in hepatocytes, though quercetin has been reported to mitigate alcohol-induced mouse liver injury. In this study, we evaluated the modulating effect of quercetin on the cytotoxicity induced by acetaldehyde in mouse hepatoma Hepa1c1c7 cells, the frequently used cellular hepatocyte model. The pretreatment with quercetin significantly inhibited the cytotoxicity induced by acetaldehyde. The treatment with quercetin itself had an ability to enhance the total ALDH activity, as well as the ALDH1A1 and ALDH3A1 gene expressions. The acetaldehyde treatment significantly enhanced the intracellular reactive oxygen species (ROS) level, whereas the quercetin pretreatment dose-dependently inhibited it. Accordingly, the treatment with quercetin itself significantly up-regulated the representative intracellular antioxidant-related gene expressions, including heme oxygenase-1 (HO-1), glutamate-cysteine ligase, catalytic subunit (GCLC), and cystine/glutamate exchanger (xCT), that coincided with the enhancement of the total intracellular glutathione (GSH) level. Tin protoporphyrin IX (SNPP), a typical HO-1 inhibitor, restored the quercetin-induced reduction in the intracellular ROS level, whereas buthionine sulphoximine, a representative GSH biosynthesis inhibitor, did not. SNPP also cancelled the quercetin-induced cytoprotection against acetaldehyde. These results suggest that the low-molecular-weight antioxidants produced by the HO-1 enzymatic reaction are mainly attributable to quercetin-induced cytoprotection.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama0031-6768476112024The role of GABA in modulation of taste signaling within the taste bud17611775ENAyakaMikamiDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHaiHuangDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityAikoHyodoDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKengoHorieDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKeikoYasumatsuTokyo Dental Junior CollegeYuzoNinomiyaDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYoshihiroMitohDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversitySeijiIidaDepartment of Oral and Maxillofacial Reconstructive Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityRyusukeYoshidaDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTaste buds contain 2 types of GABA-producing cells: sour-responsive Type III cells and glial-like Type I cells. The physiological role of GABA, released by Type III cells is not fully understood. Here, we investigated the role of GABA released from Type III cells using transgenic mice lacking the expression of GAD67 in taste bud cells (Gad67-cKO mice). Immunohistochemical experiments confirmed the absence of GAD67 in Type III cells of Gad67-cKO mice. Furthermore, no difference was observed in the expression and localization of cell type markers, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2), gustducin, and carbonic anhydrase 4 (CA4) in taste buds between wild-type (WT) and Gad67-cKO mice. Short-term lick tests demonstrated that both WT and Gad67-cKO mice exhibited normal licking behaviors to each of the five basic tastants. Gustatory nerve recordings from the chorda tympani nerve demonstrated that both WT and Gad67-cKO mice similarly responded to five basic tastants when they were applied individually. However, gustatory nerve responses to sweet–sour mixtures were significantly smaller than the sum of responses to each tastant in WT mice but not in Gad67-cKO mice. In summary, elimination of GABA signalling by sour-responsive Type III taste cells eliminates the inhibitory cell–cell interactions seen with application of sour–sweet mixtures.No potential conflict of interest relevant to this article was reported.Nature PortfolioActa Medica Okayama2045-23221412024Cervical spinal cord stimulation exerts anti-epileptic effects in a rat model of epileptic seizure through the suppression of CCL2-mediated cascades14543ENYosukeOkazakiDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTatsuyaSasakiDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKakeruHosomotoDepartment of Neurosurgery, Kure Kyosai HospitalShunTanimotoDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKojiKawaiDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTakayukiNagaseDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesChiakiSugaharaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesSatoruYabunoDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKyoheiKinDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesSusumuSasadaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTakaoYasuharaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesShotaTanakaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesIsaoDateDepartment of Neurosurgery, Okayama Rosai HospitalEpidural spinal cord stimulation (SCS) is indicated for the treatment of intractable pain and is widely used in clinical practice. In previous basic research, the therapeutic effects of SCS have been demonstrated for epileptic seizure. However, the mechanism has not yet been elucidated. In this study, we investigated the therapeutic effect of SCS and the influence of epileptic seizure. First, SCS in the cervical spine was performed. The rats were divided into four groups: control group and treatment groups with SCS conducted at 2, 50, and 300 Hz frequency. Two days later, convulsions were induced by the intraperitoneal administration of kainic acid, followed by video monitoring to assess seizures. We also evaluated glial cells in the hippocampus by fluorescent immunostaining, electroencephalogram measurements, and inflammatory cytokines such as C-C motif chemokine ligand 2 (CCL2) by quantitative real-time polymerase chain reaction. Seizure frequency and the number of glial cells were significantly lower in the 300 Hz group than in the control group. SCS at 300 Hz decreased gene expression level of CCL2, which induces monocyte migration. SCS has anti-seizure effects by inhibiting CCL2-mediated cascades. The suppression of CCL2 and glial cells may be associated with the suppression of epileptic seizure.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1860-89653822020The neurotoxicity of psychoactive phenethylamines “2C series” in cultured monoaminergic neuronal cell lines394408ENMasatoAsanumaDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesIkukoMiyazakiDepartment of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahikoFunadaDivision of Drug Dependence, National Institute of Mental Health, National Center of Neurology and PsychiatryPurpose The aim of this study was to evaluate the neurotoxicity of psychoactive abused 2,5-dimethoxy-substituted phenethylamines “2C series” in monoaminergic neurons.<br>
Methods After the exposure to “2C series”, 2,5-dimethoxy-4-propylthiophenethylamine (2C-T-7), 2,5-dimethoxy-4-isopropylthiophenethylamine (2C-T-4), 2,5-dimethoxy-4-ethylthiophenthylamine (2C-T-2), 2,5-dimethoxy-4-iodophenethylamine (2C-I) or 2,5-dimethoxy-4-chlorophenethylamine (2C-C), we examined their neurotoxicity, morphological changes, and effects of concomitant exposure to 3,4-methylenedioxymethamphetamine (MDMA) or methamphetamine (METH), using cultured neuronal dopaminergic CATH.a cells and serotonin-containing B65 cells.<br>
Results Single dose exposure to “2C series” for 24 h showed significant cytotoxicity as increase in lactate dehydrogenase (LDH) release from both monoaminergic neurons: 2C-T-7, 2C-C (EC50; 100 µM) > 2C-T-2 (150 µM), 2C-T-4 (200 µM) > 2C-I (250 µM) in CATH.a cells and 2C-T-7, 2C-I (150 µM) > 2C-T-2 (250 µM) > 2C-C, 2C-T-4 (300 µM) in B65 cells. The “2C series”-induced neurotoxicity in both cells was higher than that of MDMA or METH (EC50: ≥ 1–2 mM). In addition, apoptotic morphological changes were observed at relatively lower concentrations of “2C series”. The concomitant exposure to non-toxic dose of MDMA or METH synergistically enhanced 2C series drugs-induced LDH release and apoptotic changes in B65 cells, but to a lesser extent in CATH.a cells. In addition, the lower dose of 2C-T-7, 2C-T-2 or 2C-I promoted reactive oxygen species production in the mitochondria of B65 cells, even at the early stages (3 h) without apparent morphological changes.<br>
Conclusion The 2,5-dimethoxy-substitution of “2C series” induced severe neurotoxicity in both dopaminergic and serotonin-containing neurons. The non-toxic dose of MDMA or METH synergistically enhanced its neurotoxicity in serotonergic neurons.No potential conflict of interest relevant to this article was reported.BMCActa Medica Okayama2051-59601212024Pure argyrophilic grain disease revisited: independent effects on limbic, neocortical, and striato-pallido-nigral degeneration and the development of dementia in a series with a low to moderate Braak stage121ENOsamuYokotaDepartment of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomokoMikiDepartment of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHanaeNakashima-YasudaOkayama University Medical School HidekiIshizuOkayama University Medical School TakashiHaraguchiDepartment of Neurology, National Hospital Organization Minami Okayama Medical CenterChikakoIkedaOkayama University Medical School MasatoHasegawaDementia Research Project, Tokyo Metropolitan Institute of Medical ScienceAkinoriMiyashitaDepartment of Molecular Genetics, Brain Research Institute, Niigata UniversityTakeshiIkeuchiDepartment of Molecular Genetics, Brain Research Institute, Niigata UniversityNaotoNishikawaDepartment of Neuropsychiatry, Okayama University HospitalShintaroTakenoshitaDepartment of Neuropsychiatry, Okayama University HospitalKoichiroSudoDepartment of Psychiatry, Tosa HospitalSeishiTeradaDepartment of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesManabuTakakiDepartment of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAgyrophilic grains (AGs) are age-related limbic-predominant lesions in which four-repeat tau is selectively accumulated. Because previous methodologically heterogeneous studies have demonstrated inconsistent findings on the relationship between AGs and dementia, whether AGs affect cognitive function remains unclear. To address this question, we first comprehensively evaluated the distribution and quantity of Gallyas-positive AGs and the severity of neuronal loss in the limbic, neocortical, and subcortical regions in 30 cases of pure argyrophilic grain disease (pAGD) in Braak stages I-IV and without other degenerative diseases, and 34 control cases that had only neurofibrillary tangles with Braak stages I-IV and no or minimal A beta deposits. Then, we examined whether AGs have independent effects on neuronal loss and dementia by employing multivariate ordered logistic regression and binomial logistic regression. Of 30 pAGD cases, three were classified in diffuse form pAGD, which had evident neuronal loss not only in the limbic region but also in the neocortex and subcortical nuclei. In all 30 pAGD cases, neuronal loss developed first in the amygdala, followed by temporo-frontal cortex, hippocampal CA1, substantia nigra, and finally, the striatum and globus pallidus with the progression of Saito AG stage. In multivariate analyses of 30 pAGD and 34 control cases, the Saito AG stage affected neuronal loss in the amygdala, hippocampal CA1, temporo-frontal cortex, striatum, globus pallidus, and substantia nigra independent of the age, Braak stage, and limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) stage. In multivariate analyses of 23 pAGD and 28 control cases that lacked two or more lacunae and/or one or more large infarctions, 100 or more AGs per x 400 visual field in the amygdala (OR 10.02, 95% CI 1.12-89.43) and hippocampal CA1 (OR 12.22, 95% CI 1.70-87.81), and the presence of AGs in the inferior temporal cortex (OR 8.18, 95% CI 1.03-65.13) affected dementia independent of age, moderate Braak stages (III-IV), and LATE-NC. Given these findings, the high density of limbic AGs and the increase of AGs in the inferior temporal gyrus may contribute to the occurrence of dementia through neuronal loss, at least in cases in a low to moderate Braak stage.No potential conflict of interest relevant to this article was reported.Springer Science and Business Media LLCActa Medica Okayama1471-24152412024Pathological findings in enucleated eyes of patients with neurofibromatosis type 1: report of a case with 15-year follow-up and review of 14 patients in the literature341ENToshihikoMatsuoGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityKenjiNishidaDepartment of Pathology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityTakehiroTanakaDepartment of Pathology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityTakayaSenoDepartment of Plastic and Reconstructive Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityKiyoshiYamadaDepartment of Plastic and Reconstructive Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityShigekiOnoDepartment of Neurological Surgery, General Medical Center, Kawasaki Medical SchoolBackgrounds Iris nodules are frequently noted as clinical manifestations of neurofibromatosis type 1 but the other intraocular manifestations are rare. The purpose of this study is to present a patient with a phthisic eye who underwent enucleation for a cosmetic reason after 15-year follow-up and also to review 14 patients with enucleation described in the literature.<br>
Case presentation A 17-year-old man with neurofibromatosis type 1 from infancy underwent the enucleation of phthisic left eye and also had the resection of eyelid subcutaneous mass lesions on the left side for a cosmetic reason. He had undergone four-time preceding surgeries for eyelid and orbital mass reduction on the left side in childhood and had developed total retinal detachment 10 years previously. Pathologically, the enucleated eye showed massive retinal gliosis positive for both S-100 and glial fibrillary acidic protein (GFAP) in the area with involvement of the detached retinal neuronal layer, together with a more fibrotic lesion along the choroid which were, in contrast, negative for both S-100 and GFAP. The choroid, ciliary body, and iris did not show apparent neurofibroma while episcleral neurofibroma was present.<br>
Literature review In review of enucleated eyes of 14 patients in the literature, buphthalmic eyes with early-onset glaucoma on the unilateral side was clinically diagnosed in 9 patients who frequently showed varying extent of hemifacial neurofibromatosis which involved the eyelid and orbit on the same side. Pathologically, neurofibromas in varying extent were found in the choroid of 12 patients. One patient showed choroidal malignant melanoma on the left side and fusiform enlargement of the optic nerve on the right side suspected of optic nerve glioma. The phthisic eye in another patient showed massive retinal gliosis similar to the present patient.<br>
Conclusions In summary of the 15 patients with neurofibromatosis type 1, including the present patient, buphthalmic or phthisic eyes with no vision were enucleated for cosmetic reasons and showed choroidal neurofibroma in most patients and massive retinal gliosis in two patients including the present patient.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama2077-038313142024Importance of Blood Glucose Measurement for Predicting the Prognosis of Long COVID: A Retrospective Study in Japan4099ENShoYokoyamaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyukiHondaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYukiOtsukaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazukiTokumasuDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuhiroNakanoDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasueSakuradaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuiMatsudaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNaruhikoSunadaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToruHasegawaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesRyosukeTakaseDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDaisukeOmuraDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshiakiSoejimaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKeigoUedaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasayukiKishidaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesFumioOtsukaDepartment of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesPurpose: The present study aimed to clarify the effects of a hyperglycemic condition on the clinical consequences of long COVID. Methods: Among 643 patients who visited the outpatient clinic of our hospital from February 2021 to September 2023, long COVID patients were classified into a hyperglycemic (HG) group with casual blood glucose levels above 140 mg/dL and a normoglycemic (NG) group. The patients' backgrounds, clinical symptoms, health status including the QOL evaluation scale (EQ-5D-5L), self-rating depression scale (SDS), and F-scale questionnaire (FSSG), blood test data, and recovery periods were analyzed. Results: The NG group included 607 patients with long COVID and the HG group included 36 patients with long COVID. Patients in the HG group were older than those in the NG group (55 vs. 41 years; p < 0.001) and included a larger percentage of males (67% vs. 44%; p = 0.009). The HG group had a larger percentage of patients with moderate-to-severe conditions in the acute infection phase (28% vs. 12%; p = 0.008), a higher BMI (25 vs. 22 kg/m(2); p < 0.001), higher blood pressure (138/81 vs. 122/72 mmHg; p < 0.001), and a larger percentage of patients with an alcohol drinking habit (53% vs. 34%; p = 0.031). Long COVID symptoms and self-rated scales were not differed between the two groups; however, the laboratory data showed that liver and renal functions and metabolic data were significantly worse in the HG group. Although there was no apparent difference between the two groups in duration from the infection to the first visit, the HG group had a significantly longer period of recovery from long COVID (median period of 421 vs. 294 days; p = 0.019). Conclusion: A hyperglycemic state associated with other lifestyle-related diseases is associated with the prolongation of recovery from long COVID.No potential conflict of interest relevant to this article was reported.Pharmaceutical Society of JapanActa Medica Okayama0918-61584762024Epigenetic Regulation of Carbonic Anhydrase 9 Expression by Nitric Oxide in Human Small Airway Epithelial Cells11191122ENYutoMoriyaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShoKubotaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYutaIijimaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNobumasaTakasugiDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTakashiUeharaDepartment of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityDNA methylation is a crucial epigenetic modification that regulates gene expression and determines cell fate; however, the triggers that alter DNA methylation levels remain unclear. Recently, we showed that S-nitrosylation of DNA methyltransferase (DNMT) induces DNA hypomethylation and alters gene expression. Furthermore, we identified DBIC, a specific inhibitor of S-nitrosylation of DNMT3B, to suppress nitric oxide (NO)-induced gene alterations. However, it remains unclear how NO-induced DNA hypomethylation regulates gene expression and whether this mechanism is maintained in normal cells and triggers disease-related changes. To address these issues, we focused on carbonic anhydrase 9 (CA9), which is upregulated under nitrosative stress in cancer cells. We pharmacologically evaluated its regulatory mechanisms using human small airway epithelial cells (SAECs) and DBIC. We demonstrated that nitrosative stress promotes the recruitment of hypoxia-inducible factor 1 alpha to the CA9 promoter region and epigenetically induces CA9 expression in SAECs. Our results suggest that nitrosative stress is a key epigenetic regulator that may cause diseases by altering normal cell function.No potential conflict of interest relevant to this article was reported.SAGE PublicationsActa Medica Okayama0748-73043952024A Detailed Re-Examination of the Period Gene Rescue Experiments Shows That Four to Six Cryptochrome-Positive Posterior Dorsal Clock Neurons (DN1p) of Drosophila melanogaster Can Control Morning and Evening Activity463483ENManabuSekiguchiGraduate School of Natural Science and Technology, Okayama UniversityNilsReinhardNeurobiology and Genetics, Theodor-Boveri Institute, Biocenter, University of WürzburgAyumiFukudaGraduate School of Natural Science and Technology, Okayama UniversityShunKatohGraduate School of Environmental, Life, Natural Science and Technology, Okayama UniversityDirkRiegerNeurobiology and Genetics, Theodor-Boveri Institute, Biocenter, University of WürzburgCharlotteHelfrich-FörsterNeurobiology and Genetics, Theodor-Boveri Institute, Biocenter, University of WürzburgTaishiYoshiiGraduate School of Natural Science and Technology, Okayama UniversityAnimal circadian clocks play a crucial role in regulating behavioral adaptations to daily environmental changes. The fruit fly Drosophila melanogaster exhibits 2 prominent peaks of activity in the morning and evening, known as morning (M) and evening (E) peaks. These peaks are controlled by 2 distinct circadian oscillators located in separate groups of clock neurons in the brain. To investigate the clock neurons responsible for the M and E peaks, a cell-specific gene expression system, the GAL4-UAS system, has been commonly employed. In this study, we re-examined the two-oscillator model for the M and E peaks of Drosophila by utilizing more than 50 Gal4 lines in conjunction with the UAS-period16 line, which enables the restoration of the clock function in specific cells in the period (per) null mutant background. Previous studies have indicated that the group of small ventrolateral neurons (s-LNv) is responsible for controlling the M peak, while the other group, consisting of the 5th ventrolateral neuron (5th LNv) and the three cryptochrome (CRY)-positive dorsolateral neurons (LNd), is responsible for the E peak. Furthermore, the group of posterior dorsal neurons 1 (DN1p) is thought to also contain M and E oscillators. In this study, we found that Gal4 lines directed at the same clock neuron groups can lead to different results, underscoring the fact that activity patterns are influenced by many factors. Nevertheless, we were able to confirm previous findings that the entire network of circadian clock neurons controls M and E peaks, with the lateral neurons playing a dominant role. In addition, we demonstrate that 4 to 6 CRY-positive DN1p cells are sufficient to generate M and E peaks in light-dark cycles and complex free-running rhythms in constant darkness. Ultimately, our detailed screening could serve as a catalog to choose the best Gal4 lines that can be used to rescue per in specific clock neurons.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama2077-038313132024Changes in Working Situations of Employed Long COVID Patients: Retrospective Study in Japanese Outpatient Clinic3809ENYuiMatsudaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYasueSakuradaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYukiOtsukaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKazukiTokumasuDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYasuhiroNakanoDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNaruhikoSunadaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHiroyukiHondaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityToruHasegawaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityRyosukeTakaseDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityDaisukeOmuraDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKeigoUedaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityFumioOtsukaDepartment of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityPurpose: The present study aimed to uncover the impact of long COVID on the working situations of Japanese patients. Methods: Changes in the working situations of the patients who visited our long COVID clinic were evaluated from medical records for the aspects of physical status, quality of life (QOL), and mental conditions. <br>
Results: Of 846 long COVID patients who visited our clinic from February 2021 to December 2023, 545 employed patients aged between 18 and 65 years were included in this study. A total of 295 patients (54.1%) with long COVID (median age: 43 years, female: 55.6%) experienced changes in their working status. Those patients included 220 patients (40.4%) who took a leave of absence, 53 patients (9.7%) who retired, and 22 patients (4%) with reduced working hours. Most of the patients (93.2%) with changes in working conditions had mild disease severity in the acute phase of COVID-19. The majority of those patients with mild disease severity (58.8%) were infected in the Omicron-variant phase and included 65.3% of the female patients. The major symptoms in long COVID patients who had changes in their working situations were fatigue, insomnia, headache, and dyspnea. Scores indicating fatigue and QOL were worsened in long COVID patients who had changes in their working situations. In addition, 63.7% of the long COVID patients with changes in their working situations had decreases in their incomes. <br>
Conclusions: Changes in the working situation of long COVID patients who were employed had a negative impact on the maintenance of their QOL.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama1661-659625132024Mechanisms and Functions of Sweet Reception in Oral and Extraoral Organs7398ENRyusukeYoshidaDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYuzoNinomiyaDepartment of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityThe oral detection of sugars relies on two types of receptor systems. The first is the G-protein-coupled receptor TAS1R2/TAS1R3. When activated, this receptor triggers a downstream signaling cascade involving gustducin, phospholipase C beta 2 (PLC beta 2), and transient receptor potential channel M5 (TRPM5). The second type of receptor is the glucose transporter. When glucose enters the cell via this transporter, it is metabolized to produce ATP. This ATP inhibits the opening of KATP channels, leading to cell depolarization. Beside these receptor systems, sweet-sensitive taste cells have mechanisms to regulate their sensitivity to sweet substances based on internal and external states of the body. Sweet taste receptors are not limited to the oral cavity; they are also present in extraoral organs such as the gastrointestinal tract, pancreas, and brain. These extraoral sweet receptors are involved in various functions, including glucose absorption, insulin release, sugar preference, and food intake, contributing to the maintenance of energy homeostasis. Additionally, sweet receptors may have unique roles in certain organs like the trachea and bone. This review summarizes past and recent studies on sweet receptor systems, exploring the molecular mechanisms and physiological functions of sweet (sugar) detection in both oral and extraoral organs.No potential conflict of interest relevant to this article was reported.