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Objectives: Phosphate (Pi) induces differentiation of arterial smooth muscle cells to the osteoblastic phenotype by inducing the type III Na-dependent Pi transporter Pit-1/solute carrier family member 1. This induction can contribute to arterial calcification, but precisely how Pi stress acts on the vascular wall remains unclear. We investigated the role of extracellular Pi in inducing microstructural changes in the arterial wall. Methods: Aortae of Pit-1-overexpressing transgenic (TG) rats and their wild-type (WT) littermates were obtained at 8 weeks after birth. The thoracic descending aorta from WT and TG rats was used for the measurement of wall thickness and uniaxial tensile testing. Structural and ultrastructural analyses were performed using light microscopy and transmission electron microscopy. Gene expression of connective tissue components in the aorta was quantified by quantitative real-time polymerase chain reaction. Results: Aortic wall thickness in TG rats was the same as that in WT rats. Uniaxial tensile testing showed that the circumferential breaking stress in TG rats was significantly lower than that in WT rats (p

Abstract Background Chemotherapy including cisplatin is recommended for the treatment of advanced bladder cancer, but its effectiveness is limited due to the acquisition of drug resistance. Although several mechanisms of cisplatin resistance have been reported, there are still many unknowns, and treatment of cisplatin-resistant bladder cancer remains difficult. Accordingly, in this study, we aimed to identify and characterize microRNAs involved in cisplatin resistance. Methods Small RNA sequencing analysis was performed to search for microRNAs related to cisplatin resistance. The identified microRNAs were then characterized using gain-of-function studies, sensitivity analysis, target gene analysis, and cellular assays. Results We identified miR-424-5p as a candidate microRNA that was downregulated in cisplatin-resistant strains compared with parental strains. Notably, in gain-of-function studies, miR-424-5p suppressed the proliferative ability of cisplatin-resistant bladder cancer (CDDP-R BC). Furthermore, miR-424-5p restored sensitivity to cisplatin. RNA sequence analysis revealed seven candidate genes targeted by this microRNA. Among them, cyclin E1 (CCNE1) was chosen for subsequent analyses because its expression was upregulated in cisplatin-resistant cells compared with parental cells and because recent studies have shown that CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Therefore, we performed functional analysis using the PKMYT1 inhibitor RP-6306 and demonstrated that RP-6306 inhibited cell growth through suppression of mitotic entry and restored cisplatin sensitivity in CDDP-R BC. Conclusions Overall, our findings provided insights into the development of novel therapeutic strategies for CDDP-R BC.

Abstract Background With the use of heated tobacco products (HTPs) becoming more widespread in Japan, interest in the health effects of HTP has grown. Since the majority of HTP users are former smokers, information about the user’s smoking history and health status before HTP use is needed when assessing the health effects of HTP use. The limited epidemiological studies available did not consistently consider this information adequately, therefore we conducted a cross-sectional study investigating the association between HTP use and respiratory chronic diseases and symptoms. Methods The questionnaires were sent to a research panel members in Japan via the Internet, and individuals who met the study criteria and were either current exclusive HTP users, current exclusive cigarette users or those had never used tobacco products were selected. Information about the participants’ smoking history and health status before they used HTPs was obtained. The effects of participant smoking history before HTP use and the impacts on outcomes upon switching to HTP were assessed using a logistic regression model. The odds ratio (OR) for current exclusive HTP users relative to never tobacco users was calculated. The OR was calculated under two scenarios, one in which the smoking history was ignored or one in which the smoking history was considered. Results Of the participants from whom responses to the questionnaires were obtained, 17,406 participants were included in the analysis. Almost all participating current exclusive HTP users had a history of long-term smoking (mean: 30.8 years), and the occurrence of outcomes both before and after the start using HTP was reported. The ORs, without adjustment and with adjustment for smoking history before HTP use were, 3.23 (95% CI: 1.37–7.61) and 1.85 (95% CI: 0.70–4.89) respectively in COPD, same as other outcomes. Conclusions These results suggest that smoking history before HTP using affects the occurrence of outcomes, and underscore the importance of considering smoking history when assessing the health effect of HTP use. Since the duration of HTP use is considerably shorter than that of cigarette use at present, further research, such as follow-up surveys assessing the long-term respiratory effects of HTP use, will be necessary.

Abstract The reflexive excitation of the sympathetic nervous system in response to psychological stress leads to elevated blood pressure, a condition that persists even after the stress has been alleviated. This sustained increase in blood pressure, which may contribute to the pathophysiology of hypertension, could be linked to neural plasticity in sympathetic nervous activity. Given the critical role of astrocytes in various forms of neural plasticity, we investigated their involvement in maintaining elevated blood pressure during the post-stress phase. Specifically, we examined the effects of arundic acid, an astrocytic inhibitor, on blood pressure and heart rate responses to air-jet stress. First, we confirmed that the inhibitory effect of arundic acid is specific to astrocytes. Using c-Fos immunohistology, we then observed that psychological stress activates neurons in cardiovascular brain regions, and that this stress-induced neuronal activation was suppressed by arundic acid pre-treatment in rats. By evaluating astrocytic process thickness, we also confirmed that astrocytes in the cardiovascular brain regions were activated by stress, and this activation was blocked by arundic acid pre-treatment. Next, we conducted blood pressure measurements on unanesthetized, unrestrained rats. Air-jet stress elevated blood pressure, which remained high for a significant period during the post-stress phase. However, pre-treatment with arundic acid, which inhibited astrocytic activation, suppressed stress-induced blood pressure elevation both during and after stress. In contrast, arundic acid had no significant impact on heart rate. These findings suggest that both neurons and astrocytes play integral roles in stress-induced blood pressure elevation and its persistence after stress, offering new insights into the pathophysiological mechanisms underlying hypertension.

Abstract The prevalence of obesity is increasing worldwide, resulting in various health issues such as hypertension, dyslipidemia, diabetes mellitus, heart disease, and a lower life expectancy. Importantly, several psychiatric disorders and the use of psychotropic medications have been linked to obesity, and the possible risk factors need further investigation. This study examined the prevalence of obesity and its associated factors using a self‐administered questionnaire. Participants were recruited from three outpatient clinics and individuals who met one or more of the ICD‐10 F0‐F9, G4 diagnoses were included. In total, 1384 participants completed the questionnaire about their lifestyle. Statistical analysis compared the demographic and clinical characteristics of the individuals who were obese (Body Mass Index: BMI ≥25) and those who were non‐obese (BMI

Abstract Constipation is a prevalent gastrointestinal disorder that affects people globally, decreasing their quality of life and life expectancy. Individuals with schizophrenia often suffer from constipation, which could be a result of the illness itself or the side effects of psychotropic medications. However, little research has been conducted on factors contributing to constipation in individuals with schizophrenia. To address this issue, we conducted a survey using self‐administered questionnaires and medical records to identify factors associated with constipation in psychiatric outpatients. This study included 399 patients with schizophrenia, resulting in a high prevalence of constipation (43.4%). The analysis suggested that female gender, the doses of antiparkinsonian medications, and benzodiazepine sleeping pills may be associated with constipation.

Abstract Hypertension is a significant contributor to premature mortality, and the regular monitoring of blood pressure (BP) enables the early detection of hypertension and cardiovascular disease. There is an urgent need for the development of highly accurate cuffless BP devices. We examined BP measurements based on a target spectral camera’s recordings and evaluated their accuracy. Images of 215 adults’ palms and faces were recorded, and BP was measured. The camera captured RGB wavelength data at 640 × 480 pixels and 150 frames per second (fps). These recordings were analyzed to extract pulse transit time (PTT) values between the face and palm, a key parameter for estimating BP. Continuous BP measurements were taken using a CNAPmonitor500 for validation. Three frequency wavelengths were measured from video images. A machine learning model was constructed to determine hypertension, defined as a systolic BP of 130 mmHg or higher or a diastolic BP of 80 mmHg or higher, using the visualized data. The discrimination between hypertension and normal BP was 95.0% accurate within 30 s and 90.3% within 5 s, based on the captured images. The results of heartbeat-by-heartbeat analyses can be used to determine hypertension based on only one second of camera footage or one heartbeat. The data extracted from a video recorded by a target spectral camera enabled accurate hypertension diagnoses, suggesting the potential for simplified BP monitoring.

Abstract Human 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.

Abstract Background Gene editing of immunomodulating molecules is a potential transplantation strategy to control immune rejection. As we noticed the successful transplantation of retinal pigment epithelium (RPE) derived from embryonic stem cells of a cynomolgus monkey that accidentally lacked MHC class II (MHC-II) molecules, we hypothesized immune rejection could be evaded by suppressing MHC-II. Methods Gene editing by the Crispr/Cas9 system was performed in induced pluripotent stem cells derived from a cynomolgus monkey (miPSCs) for targeted deletion of the gene coding class II MHC trans-activator (CIITA). Then the CIITA-knocked out miPSCs were differentiated into RPE cells to generate miPSC-derived MHC-II knockout RPE. The MHC-II knockout or wild-type RPEs were transplanted into the eyes of healthy cynomolgus monkeys. All monkeys used in this study were male. Results Here we show when MHC-II knockout RPE are transplanted into monkey eyes, they show suppressed immunogenicity with no infiltration of inflammatory cells, leading to successful engraftment. Conclusions Our results reasonably evidence the efficacy of MHC-II knockout iPSC-RPE transplants for clinical application.

Abstract Background Corynebacterium striatum (C. striatum) is a gram-positive, anaerobic bacillus found both environmentally and in human skin and nasal mucosa flora. It is reportedly the etiologic agent of community-acquired and nosocomial diseases and is significantly associated with bacteremia and medical endovascular devices. This is the rare case of mitral valve native valve endocarditis (NVE) caused by C. striatum occurring in a young adult without underlying structural heart disease or indwelling cardiovascular medical devices successfully treated with multidisciplinary therapy. Case presentation The patient was a 28-year-old female with no medical history. She was transferred our hospital due to sudden onset of vertigo and vomit. A computed tomography on day 2 revealed the hydrocephalus due to the cerebellar infarction, and she underwent posterior fossa decompression for cerebellar infarction. An angiography on day 8 revealed a left vertebral artery dissection, which was suspected be the etiology. Afterwards, a sudden fever of 39 degrees developed on day 38. She was diagnosed with aspiration pneumonia and treated with ampicillin/sulbactam but was still febrile at the time of transfer for rehabilitation. Treatment continued with levofloxacin, the patient had no fever decline, and she was readmitted to our hospital. Readmission blood cultures (3/3 sets) revealed C. striatum, and an echocardiogram revealed an 11 mm long mitral valve vegetation, leading to NVE diagnosis. On the sixth illness day, cardiac failure symptoms manifested. Echocardiography revealed mitral valve rupture. She was transferred again on the 11th day of illness, during which time her mitral valve was replaced. C. striatum was detected in the vegetation. Following surgery, she returned to our hospital, and vancomycin administration continued. The patient was discharged after 31 total days of postoperative antimicrobial therapy. The patient experienced no exacerbations thereafter. Conclusions We report the rare case of C. striatum mitral valve NVE in a young adult without structural heart disease or indwelling cardiovascular devices. Clinical trial number Not applicable.

Abstract Colonoscopies are widely available, but there are cases where insertion can be difficult, even for experienced endoscopists. EC-760XP/L, a new ultrasmall-diameter long scope, may be useful in such cases. This single-center retrospective study included 39 cases where colonoscope insertion was difficult even when previously conducted by an experienced endoscopist. The primary outcome was the cecal intubation time using EC-760XP/L compared to the time used in a previous examination with a standard scope. The secondary outcomes were the cecum intubation rate, intestinal cleanliness level, adenoma detection rate, polyp detection rate, sedative use rate, occurrence of adverse events, and pain experience. A comparison of cecal intubation times between EC-760XP/L and the standard scope showed that insertion times were significantly lower with EC-760XP/L (9.5 min) compared to the standard scope (19 min) (p

Soft tissue adhesion and sealing around dental and maxillofacial implants, related prosthetic components, and crowns are a clinical imperative to prevent adverse outcomes of periodontitis and periimplantitis. Zirconia is often used to fabricate implant components and crowns. Here, we hypothesized that UV treatment of zirconia would induce unique behaviors in fibroblasts that favor the establishment of a soft tissue seal. Human oral fibroblasts were cultured on zirconia specimens to confluency before placing a second zirconia specimen (either untreated or treated with one minute of 172 nm vacuum UV (VUV) light) next to the first specimen separated by a gap of 150 µm. After seven days of culture, fibroblasts only transmigrated onto VUV-treated zirconia, forming a 2.36 mm volume zone and 5.30 mm leading edge. Cells migrating on VUV-treated zirconia were enlarged, with robust formation of multidirectional cytoplastic projections, even on day seven. Fibroblasts were also cultured on horizontally placed and 45° and 60° tilted zirconia specimens, with the latter configurations compromising initial attachment and proliferation. However, VUV treatment of zirconia mitigated the negative impact of tilting, with higher tilt angles increasing the difference in cellular behavior between control and VUV-treated specimens. Fibroblast size, perimeter, and diameter on day seven were greater than on day one exclusively on VUV-treated zirconia. VUV treatment reduced surface elemental carbon and induced superhydrophilicity, confirming the removal of the hydrocarbon pellicle. Similar effects of VUV treatment were observed on glazed zirconia specimens with silica surfaces. One-minute VUV photofunctionalization of zirconia and silica therefore promotes human oral fibroblast attachment and proliferation, especially under challenging culture conditions, and induces specimen-to-specimen transmigration and sustainable photofunctionalization for at least seven days.