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Virulence Potential of Nonclinical Vibrio parahaemolyticus Isolates From Vietnam: Evidence for Functional T3SS2-Mediated Enterotoxicity
No full textNagasaki University (長崎大学)博士(医学)Vibrio parahaemolyticus is a leading cause of seafood-borne gastroenteritis worldwide, and its pathogenic strains typically harbor thermostable direct hemolysin (TDH) and type III secretion system 2 (T3SS2). Although these virulence factors are associated primarily with clinical isolates, their presence in nonclinical environmental and food isolates raises concerns about their potential infection risk. In this study, we investigated the pathogenic potential of nonclinical V. parahaemolyticus isolates from Vietnam, which share serotypic and genotypic characteristics with pandemic strains. Serotyping and genetic analysis of 56 isolates (35 clinical and 21 nonclinical) revealed that two nonclinical isolates from shrimp and environmental water carried the tdh gene, T3SS2α genes, and pandemic markers that clustered phylogenetically with the pandemic strains. Protein expression assays confirmed that these isolates secreted TDH and the T3SS2 translocator (VopD2) at levels similar to those in the clinical reference strain. Bile exposure induced T3SS2-related gene expression, which suggests a conserved gene regulatory mechanism. Enterotoxicity evaluated using a rabbit ileal loop assay showed that two nonclinical isolates induced significant fluid accumulation. Genetic deletion and complementation experiments confirmed that T3SS2 was essential for enterotoxicity. These findings provide the first experimental evidence that nonclinical pandemic strains of V. parahaemolyticus possess functional enteric virulence mechanisms and suggest their potential as infection sources in endemic regions.長崎大学学位論文 学位記番号:博(医歯薬)甲第1721号 学位授与年月日:令和7年9月3日Author: Moses Lorenzo Akyeh, Masatomo Morita, Sarunporn Tandhavanant, Ballamoole Krishna Kumar, Pham Hong Quynh Anh, Tran Thi Hien, Pham Tuyet Ngoc Linh, Nguyen Dong Tu, Vu Thi Mai Hien, Taichiro Takemura, Hiroyuki Terashima, Hirotaka Hiyoshi, Kazuhisa Okada, Toshio KodamaCitation: Microbiology and Immunology, 69(8), pp.429-445: 2025Nagasaki University (長崎大学), 博士(医学) (2025-09-03)doctoral thesi
Crimean-Congo hemorrhagic fever virus NSm protein inhibits the type I interferon signaling by binding to STAT2
No full textThe type I interferon (IFN-I) response, which includes IFN-I induction and signaling, plays an important role in a host’s defence against viral infections. Many pathogenic viruses target it to evade the host immunity. Crimean-Congo hemorrhagic fever virus (CCHFV), the causative agent of Crimean-Congo hemorrhagic fever, which features high mortality in humans, has been reported in southeastern Europe, Africa, the Middle East, and Asia. Although a previous study reported that CCHFV antagonizes IFN-I signaling in human cell lines, it is unclear how it inhibits IFN-I signaling. Here we demonstrated that the non-structural protein of CCHFV, NSm, suppresses IFN-I signaling in human cell lines. Furthermore, we discovered that NSm binds to STAT2, an important host protein in IFN-I signaling, and induces its degradation within cells. Taken together, our results imply that NSm suppresses IFN-I signaling by targeting human STAT2.PLOS Neglected Tropical Diseases, 19(11), art. no. e0013695; 2025journal articl
Case Report: Novel IRF2BP2 variant in a Japanese patient with impaired B-cell differentiation, Th1 polarization, and systemic immune dysregulation
No full textInterferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional corepressor involved in immune regulation via IRF1-mediated interferon signaling inhibition. Pathogenic IRF2BP2 variants are associated with common variable immunodeficiency, primarily affecting B-cell maturation. We report a 47-year-old female with immunodeficiency and systemic inflammation, including primary biliary cholangitis and unclassified arthritis, who was detected to carry a novel heterozygous de novo missense variant in the IRF2BP2 gene (c.1663T>A; p. Cys555Ser). Immunophenotyping revealed naïve B-cell predominance, with a loss of memory B cells and impaired plasmablast differentiation, indicating late-stage disturbed B-cell differentiation/maturation. CD4+ T cells demonstrated Th1 polarization with reduced Th2 subsets, whereas Th17 and Treg populations exhibited no obvious changes. Considering that IRF2BP2 negatively regulates STAT1-driven transcription via IRF1 suppression, the observed Th1 polarization suggests improved STAT1 activity. This case underscores the combined humoral and cellular immune dysregulation due to IRF2BP2 dysfunction, expanding the clinical spectrum to encompass inflammatory phenotype.Frontiers in Immunology, 16, art. no. 1662899; 2025journal articl
Pre-dialysis medical social worker support and survival in patients with kidney failure: impact on unplanned dialysis, hospitalization, and prognosis
No full textThe role of medical social workers (MSWs) in managing patients with end-stage kidney disease (ESKD) undergoing hemodialysis remains unknown. This study evaluated the prognostic impact of pre-dialysis MSW support in patients undergoing renal replacement therapy. This retrospective analysis included 257 patients who started hemodialysis at the Nagasaki Harbor Medical Center between 2016 and 2023. Patients were divided into MSW (+) and MSW (−) groups based on whether they received pre-dialysis MSW support. Outcomes were assessed, including unplanned dialysis initiation, length of hospital stay, and post-hemodialysis survival. The MSW (+) group showed a lower rate of unplanned dialysis initiation, shorter hospital stays and improved post-hemodialysis prognosis compared with the MSW (−) group. In the multivariable Cox regression analysis, pre-dialysis MSW support (hazard ratio 0.58, 95% confidence interval 0.34–0.98, p = 0.04) was associated with lower patient mortality in addition to age, male sex, serum albumin levels 1 month before hemodialysis initiation, and serum creatinine levels 1 month before hemodialysis initiation. Stratified analyses showed a marked positive impact of MSW support in patients aged ≥70 years, male sex, living with family, and malnutrition. MSW support facilitated smoother transitions to maintenance hemodialysis centers through pre-settlement dialysis centers, alleviated patient anxiety, and ensured transportation arrangements. This study highlights the critical role of MSWs in improving clinical outcomes for patients with ESKD who are at higher social risks. Future multicenter studies are warranted to validate these findings and enhance their generalizability.Renal Failure, 47(1), art. no. 2578417; 2025journal articl
Radiosensitization Effect of PARP Inhibitor Talazoparib Involves Decreasing Mitochondrial Membrane Potential and Induction of Cellular Senescence
No full textPoly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) with radiation therapy can enhance the sensitivity of cancer cells by inhibiting DNA repair pathways. To determine the most suitable PARP inhibitor for radiosensitization in cancer cells, we compared various types of clinically used PARPis in lung cancer A549 cells. We found that most PARP inhibitors showed radiosensitization effects on A549 cells. ER10 values for talazoparib, olaparib rucaparib, ABT888 and niraparib were 1.5, 1.8, 2.8, 1.4, and 1.4, respectively. Talazoparib showed a radiosensitization effect at its lowest concentration. Talazoparib is a potent PARP inhibitor and has been used in clinical settings for several types of cancer as an anti-cancer agent. We thus focused on how talazoparib causes radiosensitization in lung cancer A549 cells. As a result of the combination of talazoparib and γ-irradiation, we observed an increased level of cellular senescence accompanied by a decrease in mitochondrial membrane potential. When the p21 gene was knocked down, both the decrease in mitochondrial membrane potential and senescence level were attenuated, suggesting that p21 is involved in senescence induction after γ-irradiation combined with talazoparib treatment. Taken together, we showed that PARP inhibitor talazoparib treatment in combination with γ-irradiation causes cellular senescence in lung cancer cells, involving p21 function.Current Issues in Molecular Biology, 47(11), art. no. 908; 2025journal articl
Early determination of the dorsal-ventral axis in endochondral ossification in mice
No full textEndochondral ossification is a highly coordinated process involving distinct progenitor cell populations within the mesenchymal condensation and subsequent cartilage anlage and perichondrium, all of which drive skeletal formation. Cell-type specific lineage tracing conducted to understand fetal bone development has revealed various fates of early skeletal cells. However, the underlying continuous and precise cellular dynamics of fetal skeletal cells, particularly along the dorsoventral axis, remain unclear. Here, we show that spatiotemporally specific skeletal progenitor cells in the early developmental stage contribute to the dorsal-ventral axis in a manner that is strictly determined during initial developmental stages. Lineage-tracing experiments using Fgfr3-creER and Dlx5-creER lines revealed that Fgfr3+ cells in mesenchymal condensation exclusively contributed to hypertrophic chondrocytes and the dorsal side of the resting and proliferating zones within the cartilage anlage. These cells made dorsal-restricted contributions to skeletal development, including growth plate chondrocytes, trabecular and cortical osteoblasts, and bone marrow stromal cells. Functional ablation of Fgfr3+ cells using the Rosa26iDTA (inducible diphtheria toxin fragment A) allele during the mesenchymal condensation stage caused severe disruption in long-bone development, underscoring its indispensable role in initiating skeletal growth. Collectively, these findings suggest that the condensation stage is pivotal for the formation of skeletal progenitors and dorsoventral patterning during bone development. Understanding these mechanisms will provide insight into skeletal growth disorders and therapeutic strategies for bone regeneration.Journal of Bone and Mineral Research, 40(12), pp.1385-1396: 2025journal articl
Mapping cognitive diversity in older adults through community-based digital screening via mobile devices: a cross-sectional latent class analysis
No full textIntroduction: Early detection of objective cognitive impairment is essential to delay or prevent dementia; however, traditional in-person screening often faces practical barriers, including limited accessibility and substantial personnel demands. Web-based cognitive tools are promising for scalable screening. This study aimed to identify cognitive subgroups among community-dwelling older adults using latent class analysis (LCA) based on data collected through a freely accessible web-based cognitive screening platform that enables convenient participation anytime and anywhere using older adults' own mobile devices. Methods: Between September and December 2024, adults aged ≥65 from Sapporo and Ebetsu, Japan, were recruited via newspaper insert flyers (92,290 households) and community posters. QR codes linked to the study website were optimized for various devices. After obtaining electronic consent, participants completed web-based demographic surveys and cognitive assessments of memory, attention, and processing speed. Subjective health and memory complaints were recorded. LCA identified cognitive subgroups based on performance, complaints, and sociodemographic factors. Results: Among the 528 participants (mean age = 71.2; 57% female), most reported good health (86%) and daily conversations (92%). Cognitive function was generally preserved. LCA revealed four clusters: socially isolated females with high subjective memory complaints (SMCs); cohabiting males with high SMCs; cohabiting females with high health perception and preserved cognition; and older adults with cognitive decline. Discussion: The combination of mass outreach and web-based screening is feasible and effective in identifying diverse cognitive profiles. These findings highlight the mismatch between subjective and objective cognition and the relationship between social context, supporting scalable, tailored approaches and cognitive health.Frontiers in Digital Health, 7, art. no. 1719318; 2025journal articl
Direct nanofiltration treatment using flat-sheet membrane modules reconfigured from spiral-wound elements
No full textDirect nanofiltration (NF) treatment without pretreatment has attracted attention for achieving low-energy advanced drinking water treatment in drinking water applications. However, the validity of submerged NF systems for large-scale modules and variable feed water quality remains unexplored. This study aimed to assess the viability of pump-operated and gravity-driven membrane (GDM) filtration of lake water without pretreatment using NF membrane modules reconfigured from commercially available NF membrane elements typically suited for pressurized operation. The permeate flux of the pump-operated NF system gradually declined from 2.3 to 1.2 L/m2h at a feed temperature of 7–11°C until 12 d; thereafter, the permeate flux remained stable until 36 d. Cleaning the membrane surface by sponge wiping achieved near-full recovery of the permeance. The removal of dissolved organic matter and conductivity were relatively low, at 30–50 % and 10–30 % respectively. The specific energy consumption (SEC) of the pump-operated NF system could be as low as 116 Wh/m3, based on the pilot-scale tests. In contrast, the permeate flux of GDM filtration using the reconfigured NF membrane modules remained constant at approximately 0.28–0.37 L/m2h at a feed temperature of 5–22°C for over 78 d despite the limited water head available. The separation performance of GDM filtration was comparable to that of the pump-operated NF system, while the removal of conductivity (ions) was negligible. Despite the limitations of permeance and separation performance, both pump-operated and gravity-driven systems with reconfigured NF membrane modules have the potential to achieve low-energy and decentralized water supply systems.Environmental Technology and Innovation, 41, art. no. 104678; 2025journal articl