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The contamination of ground water by fluoride (F) has been reported worldwide. Since F is filtered by kidneys, human or experimental animals with renal damage may be more affected by F than those with normal kidney function. Tubulointerstitial fibrosis of kidneys can be induced in rats by unilateral ureteral obstruction (UUO) as an experimental animal model for renal damage and urinary stone disease. We examined the effects of F on tubulointerstitial fibrosis in the obstructed kidney of UUO rats. The left ureters of male rats, aged 6-weeks-old, were ligated using silk sutures. Fluoride was administered to the rats for 2 weeks at the concentrations of 0, 75, and 150 ppm in the drinking water. After 2 weeks of administration, the kidneys of the rats were sampled and histological and immunohistochemical staining were used to identify positive areas within the renal cortex and staining-positive cells by image analysis. We found a significant increase in the obstructed kidneys of the UUO rats exposed to 150 ppm of F for areas or number of cells stained with antibody against collagen type I compared with the controls. It is suggested that F exacerbates tubulointerstitial nephropathy resulting from UUO. The UUO rats are useful animal model for the elucidation of the toxic effects of F on humans with renal damage. [ABSTRACT FROM AUTHOR]

Abstract: We have investigated a BC3 covered NbB2(0001) surface using scanning tunneling microscopy (STM), scanning tunneling spectroscopy (STS), and low energy electron diffraction (LEED). The STM images reveal characteristic features of a Moiré pattern reflecting an incommensurate relation of the BC3 sheet with the substrate: bright protrusions with the periodicity of the substrate lattice are modulated in intensity with the periodicity of the BC3 lattice. As a result, the surface exhibits nm-scale patchy regions with either the √3×√3 or the 1×1 structure of the substrate. The two-dimensional Fourier transformation pattern of the STM image is consistent with the LEED pattern proving the epitaxial and incommensurate relationship between BC3 surface sheet and substrate. No feature of a predicted superconducting gap was found in STS spectra measured at 5K. [Copyright &y& Elsevier]

Abstract: We have successfully grown a uniform BC3 honeycomb sheet with high crystalline quality over the entire macroscopic area of the NbB2 (0001) surface by carbon-substituted technique in a boron honeycomb. This is the first macroscopic uniform sheet of single-crystal BC3 with a monolayer thickness. So far, only BC3 micro-crystals with radii of a few nanometres were produced. The properties of the sheet have been investigated by using XPS, AES, LEED, STM, ARUPS and HREELS. All the experimental data and the theoretical calculations, which are concerning with atomic structure, chemical concentration, and phonon structure, indicated that the uniform BC3 honeycomb sheet was grown in an epitaxial manner to the substrate lattice. [Copyright &y& Elsevier]

Nutritional zinc (Zn) deficiency could impair immune function and affect bowel conditions. However, the mechanism by which Zn deficiency affects the immune function of gut-associated lymphoid tissue (GALT) remains unclear. We investigated how Zn deficiency affects the function of GALT and level of secretory IgA (sIgA), a key component of the intestinal immune barrier, its underlying mechanisms, and whether Zn deficiency induces bacterial translocation to the liver. As previous research has indicated that interleukin (IL)-4 administration or Zn supplementation has a beneficial effect on the spleen of Zn-deficient rats, we investigated whether these supplements reverse the GALT immune system. Five-week-old male rats were fed a standard diet, Zn-deficient diet supplemented with saline or IL-4 for 6 weeks, or Zn-deficient diet followed by a standard diet for 4 weeks. Zn deficiency suppressed sIgA secretion in the intestinal tract by affecting GALT function and induced inflammatory responses through bacterial translocation to the liver via the portal vein. Furthermore, IL-4 administration and Zn supplementation in rats with Zn deficiency elicited comparable beneficial effects on GALT function, suggesting that the administration of either IL-4 or Zn could prevent inflammatory response via bacterial translocation to the liver., (© 2025 John Wiley & Sons Ltd.)

Little is known about the effectiveness of pharmacotherapy in dissociative identity disorder (DID). Zinc is essential for proper brain function. Its deficiency can lead to mental health symptoms, possibly contributing to dissociation. L-carnosine is an endogenous dipeptide with a neuroprotective effect. We report on the case of a 30-year-old woman with DID and comorbid bipolar I disorder who had zinc deficiency and was successfully cotreated with zinc and L-carnosine. She displayed three alternate identities and exhibited signs of emotional/mood instability, flashbacks, binge eating, and self-harm. The patient also displayed several physical symptoms of zinc deficiency. She did not respond to aripiprazole (0.75 mg/d) and clonazepam (1.5 mg/d), but responded marginally to five months of zinc (50 mg/d) supplementation. Simultaneous administration of L-carnosine, gradually increased from 0.5 g/d to 2 g/d over four months, markedly improved her symptoms. Five months after adding 2 g/d L-carnosine, the patient's pronounced alternate identities that people around her could notice no longer appeared. However, the identities that were not noticeable to the people remained. They disappeared completely two years later and reappeared only when zinc and L-carnosine were discontinued during the subsequent three-year follow-up. The patient's severity scores for dissociation and depression were reduced. Furthermore, signs of emotional/mood instability, flashbacks, binge eating, and self-harm improved. The physical symptoms of zinc deficiency eventually resolved. Further investigation of cotreatment with zinc and L-carnosine for DID and related conditions, particularly the contribution of zinc deficiency to dissociation, is necessary., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. The Institutional Review Board of Keieikai Yashio Hospital issued approval #29-1. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sakae et al.)

Fibrillin-1, an extracellular matrix (ECM) protein encoded by the FBN1 gene, serves as a microfibril scaffold crucial for elastic fiber formation and homeostasis in pliable tissue such as the skin. Aside from causing Marfan syndrome, some mutations in FBN1 result in scleroderma, marked by hardened and thicker skin which limits joint mobility. Here, we describe a tight skin phenotype in the Fbn1 G234D/G234D mice carrying a corresponding variant of FBN1 in the hybrid1 domain that was identified in a patient with familial aortic dissection. Unlike scleroderma, skin thickness and collagen fiber abundance do not change in the Fbn1 G234D/G234D mutant skin. Instead, increased collagen cross-links were observed. In addition, short elastic fibers were sparsely located underneath the panniculus muscle layer, and an abundance of thin, aberrant elastic fibers was increased within the subcutaneous fascia, which may have tightened skin attachment to the underlying skeletal muscle. Structurally, Fbn1 G234D/G234D microfibrils have a disrupted shoulder region that shares similarities with hybrid1 deletion mutant microfibrils. We then demonstrate the consequence of fibrillin-1 G234D mutation on dermal fibroblast functions. Mutant primary fibroblasts produce fewer elastic fibers, exhibit slower migration and increased cell stiffness. Moreover, secretome from mutant fibroblasts are marked by enhanced secretion of ECM, ECM-modifying enzymes, proteoglycans and cytokines, which are pro-tissue repair/fibrogenic. The transcriptome of mutant fibroblasts displays an increased expression of myogenic developmental and immune-related genes. Our study proposes that imbalanced ECM homeostasis due to a fibrillin-1 G234Dmutation impacts fibroblast properties with potential ramifications on skin function., Competing Interests: Declaration of competing interest The authors declare no conflict of interest, (Copyright © 2024. Published by Elsevier B.V.)

Purpose: To determine the current incidence and impact of chemotherapy-associated food aversions in a variety of cancer types., Methods: Cancer patients aged 18 years and older who received chemotherapy infusions at the outpatient chemotherapy unit of a university hospital between May 2022 and April 2023 were included in the study (n = 243). To monitor the occurrence of food aversions, participants were asked to complete a food preference questionnaire each time they visited the outpatient chemotherapy unit., Results: During the one-year survey period, one in four cancer patients receiving outpatient chemotherapy developed food aversions, and one in four of them complained of interference with daily life due to eating problems at the same time or later. The median time to the onset of food aversion was 46 (interquartile range 36-77) days after the start of chemotherapy. The incidence of food aversions was significantly higher in patients who were women, had a digestive, gynecologic, or breast cancer, and received more cytotoxic agents in chemotherapy. Patients who developed food aversions tended to lose more body weight than those who did not., Conclusion: Food aversions were still common among cancer patients undergoing chemotherapy. Even an aversion to a single food may have affected the patient's nutritional status. Healthcare professionals should closely monitor the occurrence of food aversions, especially in the early days of chemotherapy induction, to detect an increasing risk of malnutrition., Trial Registration: Not applicable., Competing Interests: Declarations. Ethics approval: The study protocol was approved by the Ethics Committee of Jikei University School of Medicine (reference number 33–423(11048)) and has been conducted in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Japanese Government. Consent to participate: All participants received information about the study protocol, and those who signed the informed consent term were included in the study. Consent to publish: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Adrenomedullin (AM) exerts strong pulmonary vasodilatory effects. These effects are mediated in part by nitric oxide. Plasma AM levels are increased in patients with pulmonary hypertension and correlate with disease severity and poor outcomes. Acute administration of AM improves the haemodynamics in patients with pulmonary hypertension, while chronic administration prevents the onset of pulmonary hypertension in animal models and delays its progression. Thus, AM is closely related to the pathophysiology of pulmonary hypertension and may be a promising therapeutic target., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Background: According to the gene-environment interactions (GEi) concept, the mechanism of health impairment can be explained by genetic factors, environmental factors, or their interaction. Physical and mental health effects resulting from environmental exposure may be classified either as toxicity, immune response, and allergic reaction. Moreover, despite the already established therapeutic approaches to bronchial asthma and decreasing mortality due to bronchial asthma, patients with difficult and severe asthma are increasing in number. This review outlines recent topics in the field of allergies, focusing on asthma., Results and Discussion: Living environment-derived pollutants and their involvement in the pathogenesis of asthma and its exacerbation, referred to here as an exposome concept, comprises the three domains of internal, specific external, and general external. Living environment-derived pollutants include exposure to pollutants in workplaces, climate change, air pollution, microplastics, tobacco smoke, biodiversity change and loss, changing dietary habits, and the microbiome. These are associated with the modernization, urbanization, and globalization of human society. Although many novel compounds are currently available, their harmful health effects, such as allergy, are not thoroughly understood. Hence, the means to mitigate these are unknown. Dietary changes from a traditional diet rich in fish to a Western-style diet are considered critical environmental factors and therefore, associated with an increased prevalence of allergies. Cytokines, including TSLP, IL-25, and IL-33, released from the airway epithelium in response to various triggers (exposure to diverse environmental factors) are known as alarmins. Anti-alarmin antibodies are a promising therapeutic approach against severe and difficult allergic disorders. Collaboration between hospitals and clinics and occupational and clinical medicine is imperative for treating and managing severe asthma. In addition to avoiding environmental exposure, understanding the pathogenesis and exacerbation of asthma is essential for future research in the field of allergy and immunotoxicology.

Motile cilia have a so-called "9 + 2" structure, which consists of nine doublet microtubules and a central pair apparatus. The central pair apparatus (CA) is thought to interact mechanically with radial spokes and to control the flagellar beating. Recently, the components of the CA have been identified by proteomic and genomic analyses. Still, the mechanism of how the CA contributes to ciliary motility has much to be revealed. Here, we focused on one CA component with a large molecular weight: FAP47, and its relationship with two other CA components with large molecular weight: HYDIN, and CPC1. The analyses of motility of the Chlamydomonas mutants revealed that in contrast to cpc1 or hydin, which swam more slowly than the wild type, fap47 cells displayed wild-type swimming velocity and flagellar beat frequency, yet interestingly, fap47 cells have phototaxis defects and swim straighter than the wild-type cells. Furthermore, the double mutant fap47cpc1 and fap47hydin showed significantly slower swimming than cpc1 and hydin cells, and the motility defect of fap47cpc1 was rescued to the cpc1 level with GFP-tagged FAP47, indicating that the lack of FAP47 makes the motility defect of cpc1 worse. Cryo-electron tomography demonstrated that the fap47 lacks a part of the C1-C2 bridge of CA. Taken together, these observations indicate that FAP47 maintains the structural stiffness of the CA, which is important for flagellar regulation., (© 2024 The Author(s). Cytoskeleton published by Wiley Periodicals LLC.)

To identify proteins specific to the proximal ciliary axoneme, we used iTRAQ to compare short (~2 μm) and full-length (~11 μm) axonemes of Chlamydomonas. Known components of the proximal axoneme such as minor dynein heavy chains and LF5 kinase as well as the ciliary tip proteins FAP256 (CEP104) and EB1 were enriched in short axonemes whereas proteins present along the length of the axoneme were of similar abundance in both samples. The iTRAQ analysis revealed that FAP93, a protein of unknown function, and protein phosphatase 2A (PP2A) are enriched in the short axonemes. Consistently, immunoblots show enrichment of FAP93 and PP2A in short axonemes and immunofluorescence confirms the localization of FAP93 and enrichment of PP2A at the proximal axoneme. Ciliary regeneration reveals that FAP93 assembles continuously but more slowly than other axonemal structures and terminates at 1.03 μm in steady-state axonemes. The length of FAP93 assembly correlates with ciliary length, demonstrating ciliary length-dependent assembly of FAP93. Dikaryon rescue experiments show that FAP93 can assemble independently of IFT transport. In addition, FRAP analysis of GFP-tagged FAP93 demonstrates that FAP93 is stably anchored in the axoneme. FAP93 may function as a scaffold for assembly of other specific proteins at the proximal axoneme., (© 2024 Wiley Periodicals LLC.)

Background: There is a lack of evidence regarding the trajectories of type 2 diabetes until the first clinic visit, including the untreated period after diagnosis., Objective: We aimed to determine the real-world history of type 2 diabetes until the first clinic visit, including the untreated duration, and to assess the effective timing of the therapeutic intervention., Methods: A total of 23,622 nondiabetic Japanese workers with a mean (SD) age of 38.8 (11.5) years were retrospectively followed from 2008 to 2022 for annual health checkups. The trajectories of glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body mass index (BMI) until the first clinic visit in diabetes individuals were determined. ROC analysis was performed to assess the contribution of each measure to the first visit., Results: During a median follow-up of 12.0 years, 1,725 individuals developed type 2 diabetes, of whom 532 individuals visited clinics. HbA1c and FPG trajectories steeply rose in the year before the first clinic visit after their progressive upward trends. ROC analysis showed cutoff values for each measure. As the untreated duration increased, glycemia increased and BMI decreased among individuals who visited clinics., Conclusions: To prevent the initial worsening of diabetes, early therapeutic intervention is necessary during the increasing trends before the steep rise in glycemia, regardless of the degree of obesity. HbA1c ≥6.5% (47.5 mmol/mol) and an HbA1c ≥0.2% (2.2 mmol/mol)/year increase may be an effective timing for therapeutic intervention., (© The Author(s) 2024. Published by Oxford University Press.)

Background: We aimed to develop a chemoimmunotherapy regimen consisting of a novel Wilms' tumor 1 (WT1) peptide-pulsed dendritic cell (WT1-DC) vaccine and multiagent chemotherapy and to investigate the safety, clinical outcomes, and WT1-specific immune responses of patients with unresectable advanced pancreatic ductal adenocarcinoma (UR-PDAC) who received this treatment., Methods: Patients with UR-PDAC with stage III disease (locally advanced (LA-PDAC; n=6)), stage IV disease (metastatic (M-PDAC; n=3)), or recurrent disease after surgery (n=1) were enrolled in this phase I study. The patients received one cycle of nab-paclitaxel plus gemcitabine alone followed by 15 doses of the WT1-DC vaccine independent of chemotherapy. The novel WT1 peptide cocktail was composed of a multifunctional helper peptide specific for major histocompatibility complex class II, human leukocyte antigen (HLA)-A*02:01, or HLA-A*02:06 and a killer peptide specific for HLA-A*24:02., Results: The chemoimmunotherapy regimen was well tolerated. In the nine patients for whom a prognostic analysis was feasible, the clinical outcomes of long-term WT1 peptide-specific delayed-type hypersensitivity (WT1-DTH)-positive patients (n=4) were significantly superior to those of short-term WT1-DTH-positive patients (n=5). During chemoimmunotherapy, eight patients were deemed eligible for conversion surgery and underwent R0 resection (four patients with LA-PDAC, one patient with M-PDAC, and one recurrence) or R1 resection (one patient with M-PDAC), and one patient with LA-PDAC was determined to be unresectable. Long-term WT1-DTH positivity was observed in three of the four patients with R0-resected LA-PDAC. These three patients exhibited notable infiltration of T cells and programmed cell death protein-1+ cells within the pancreatic tumor microenvironment (TME). All patients with long-term WT1-DTH positivity were alive for at least 4.5 years after starting therapy. In patients with long-term WT1-DTH positivity, the percentage of WT1-specific circulating CD4+ or CD8+ T cells that produced IFN-γ or TNF-α was significantly greater than that in patients with short-term WT1-DTH positivity after two vaccinations. Moreover, after 12 vaccinations, the percentages of both circulating regulatory T cells and myeloid-derived suppressor cells were significantly lower in patients with long-term WT1-DTH-positive PDAC than in short-term WT1-DTH-positive patients., Conclusions: Potent activation of WT1-specific immune responses through a combination chemoimmunotherapy regimen including the WT1-DC vaccine in patients with UR-PDAC may modulate the TME and enable conversion surgery, resulting in clinical benefits (Online supplemental file 1)., Trial Registration Number: jRCTc030190195., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of nonalcoholic fatty liver disease characterised by fat accumulation, inflammation, oxidative stress, fibrosis, and impaired liver regeneration. In this study, we found that heme oxygenase-1 (HO-1) is induced in both MASH patients and in a MASH mouse model. Further, hepatic carbon monoxide (CO) levels in MASH model mice were >2-fold higher than in healthy mice, suggesting that liver HO-1 is activated as MASH progresses. Based on these findings, we used CO-loaded red blood cells (CO-RBCs) as a CO donor in the liver, and evaluated their therapeutic effect in methionine-choline deficient diet (MCDD)-induced and high-fat-diet (HFD)-induced MASH model mice. Intravenously administered CO-RBCs effectively delivered CO to the MASH liver, where they prevented fat accumulation by promoting fatty acid oxidation via AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor induction. They also markedly suppressed Kupffer cell activation and their corresponding anti-inflammatory and antioxidative stress activities in MASH mice. CO-RBCs also helped to restore liver regeneration in mice with HFD-induced MASH by activating AMPK. We confirmed the underlying mechanisms by performing in vitro experiments in RAW264.7 cells and palmitate-stimulated HepG2 cells. Taken together, CO-RBCs show potential as a promising cellular treatment for MASH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)