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Abstract Synaptic dysfunction is an early feature in Alzheimer’s disease (AD) pathogenesis and a major morphological correlate of memory deficits. Given the main synaptic location of N-methyl-D-aspartate receptors (NMDARs), their dysregulation has been implicated in these pathological effects. Here, to detect possible alterations in the expression and synaptic localisation of the GluN1 subunit in the brain of amyloidogenic APP/PS1 mice, we employed histoblot and SDS-digested freeze-fracture replica labelling (SDS-FRL) techniques. Histoblots showed that GluN1 expression was significantly reduced in the hippocampus in a layer-dependent manner, in the cortex and the caudate putamen of APP/PS1 transgenic mice at 12 months of age but was unaltered at 1 and 6 months. Using quantitative SDS-FRL, we unravelled the molecular organisation of GluN1 in seven excitatory synapse populations at a high spatial resolution in the CA1 and CA3 fields and the DG of the hippocampus in 12-month-old APP/PS1 mice. In the CA1 field, the labelling density for GluN1 in the excitatory synapses established on spines and interneurons, was significantly reduced in APP/PS1 mice compared to age-matched wild-type mice in the stratum lacunosum-moleculare but unaltered in the stratum radiatum. In the CA3 field, synaptic GluN1 was reduced in mossy fibre-CA3 pyramidal cell synapses but unaltered in the A/C-CA3 pyramidal cell synapses. In the DG, the density of GluN1 in granule cell-perforant pathway synapses was reduced in APP/PS1 mice. Altogether, our findings provide evidence of specific alterations of synaptic GluN1 in the trisynaptic circuit of the hippocampus in Aβ pathology. This differential vulnerability in the disruption of NMDARs may be involved in the mechanisms causing abnormal network activity of the hippocampal circuit and cognitive impairment characteristic of APP/PS1 mice.

Abstract Background Intervention for older patients with cardiac disease and subthreshold depression (StD) may be an effective strategy to prevent the development of major depressive disorder. The subliminal priming with supraliminal reward stimulation (SPSRS) website developed by us is an advanced intervention that can improve depressive symptoms in individuals with StD by presenting positive word stimuli in videos. However, its efficacy for treating depressive symptoms in older patients with cardiac disease and StD has not been investigated. Here, we present a pilot randomized controlled trial protocol to investigate the preliminary efficacy of an intervention for older patients with cardiac disease with StD. Methods The study was designed as a single-center, open-label, pilot, randomized, parallel-group trial. The participants will include 30 older patients with cardiac disease and StD who are hospitalized in acute wards. The Experimental group received the SPSRS intervention (video viewing with positive word stimuli; n = 15) and the Control group will receive the YouTube intervention (video viewing without positive word stimuli; n = 15). In both groups, the intervention will be administered for 10 min per day, five times per week for 1 week. The primary outcome will be the change in the scores on the Japanese version of the Beck Depression Inventory-II at 1 week after the baseline assessment. The secondary outcomes will be the changes in the Specific Activity Scale, New York Heart Association functional classification, as well as grip strength at 1 week after the baseline assessment. Discussion This pilot randomized controlled trial will be the first to evaluate the SPSRS intervention for depressive symptoms in older patients with cardiac disease and StD who are admitted to acute wards. The results will provide tentative indications regarding the impact of the intervention on depressive symptoms among older patients with cardiac disease and StD who are admitted to acute wards, and will contribute to the planning of a full-scale study. Trial registration UMIN, UMIN000052155. Registered September 8, 2023, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000059526 . This study was registered with the University Hospital Medical Information Network (UMIN) (UMIN000052155) in Japan.

Abstract Kawasaki disease (KD) causes vascular injury and lifelong remodeling. Excessive intimal proliferation has been observed, resulting in coronary artery lesions (CALs). However, the mechanisms underlying vascular remodeling in CAL and statin treatment have not been comprehensively elucidated. This study aimed to investigate the effects of statins on vascular remodeling using a KD mouse model. Candida albicans water‐soluble substance (CAWS) was intraperitoneally injected in 5‐week‐old male apolipoprotein‐E‐deficient mice. They were categorized as follows (n = 4): control, CAWS, CAWS+statin, and late‐statin groups. The mice were euthanized at 6 or 10 weeks after injection. Statins (atorvastatin) were initiated after CAWS injection, except for the late‐statin group, for which statins were internally administered 6 weeks after injection. Elastica van Gieson staining and immunostaining were performed for evaluation. Statins substantially suppressed the marked neointimal hyperplasia induced by CAWS. Additionally, CAWS induced TGFβ receptor II and MAC‐2 expression around the coronary arteries, which was suppressed by the statins. KD‐like vasculitis might promote the formation of aneurysm by destroying elastic laminae and inducing vascular stenosis by neointimal proliferation. The anti‐inflammatory effects of statins might inhibit neointimal proliferation. Therefore, statin therapy might be effective in adult patients with KD with CAL by inhibiting vascular remodeling.

The quality of written corrective feedback can strongly and positively affect students' writing achievement levels. This study aimed to examine whether written corrective feedback could improve students' achievement levels for essay writing and investigated which one from three different feedback sources--teacher, peer, and self--was effective in increasing senior high school students' achievement levels of English writing in two English as a Foreign Language countries, Indonesia and Japan. The study participants included 81 Indonesian and 81 Japanese senior high school students (Grade XI, 16-17 years old), who were divided into three different groups. Three different feedback sources were utilized for each group. Data collection was from a pretest and posttest to identify the relationship between students' writing achievement level and the written corrective feedback sources they had been exposed to in the classroom. The data were analyzed by employing descriptive statistics, ANOVA, and Bonferroni post hoc test. The study results showed that written corrective feedback from peers effectively improved Indonesian senior high school students' writing achievement levels. In contrast, for the Japanese senior high school students, teachers' written corrective feedback represented the most effective source.

In evaluating the learning achievement of programming-thinking skills, the method of using a rubric that describes evaluation items and evaluation stages is widely employed. However, few studies have evaluated the reliability, validity, and consistency of the rubrics themselves. In this study, we introduced a statistical method for evaluating the characteristics of rubrics using the goal question metric (GQM) method. Furthermore, we proposed a method for measuring four evaluation results and characteristics obtained from rubrics developed using this statistical method. Moreover, we showed and confirmed the consistency and validity of the statistical method using the GQM method of the resulting developed rubrics. We show how to verify the consistency and validity of the rubric using the GQM method.

As production system estates become larger and more complex, ensuring stability through traditional monitoring approaches becomes more challenging. Rule-based monitoring is common in industrial settings, but it has limitations. These include the difficulty of crafting rules capable of detecting unforeseen issues and the burden of manually maintaining rule sets. A potential solution to effectively manage complex system states is log anomaly detection. Workflows for log anomaly detection utilize several fundamental components. These include preprocessors for data cleansing, parsers to extract structured information from raw log data, encoding algorithms to convert extracted data into usable model input features, anomaly detection methods to isolate anomalous signals, and feedback mechanisms to incrementally improve model performance. This study explores the current state of research into online parser-supported log anomaly detection methods, investigates recent research trends, compares the performances of parser and anomaly detection methods using common public datasets and metrics, and assesses their performance evolution over time. Additionally, it classifies available methods using a newly introduced taxonomy, highlights current research gaps, and recommends future research directions.

Early childhood is marked by significant developmental changes in the ability to recognize facial expressions. However, since the COVID-19 outbreak, people have been wearing masks more frequently during social interactions which may hamper the recognition of facial expressions. This study examines whether preschoolers recognize the facial expressions of people with partially covered faces (wearing masks or sunglasses) or uncovered faces better, and whether recognition improves when additional voice information is provided. The participants included 27 Japanese preschoolers (11 boys and 16 girls) aged 3-5 years. The participants were presented with two groups of facial expressions: stimuli showing uncovered faces and those showing faces partially covered with a mask or sunglasses. A two-factor within-participant analysis of variance was conducted on the number of correct facial-expression responses in each trial. The children recognized the expressions of uncovered faces significantly better than those of faces with masks or sunglasses. When voice information was added, they recognized all facial expressions. Therefore, partially covered faces interfere with preschoolers' recognition of facial expressions, and voice information aids facial expression recognition.

Olfactory dysfunctions decrease daily quality of life (QOL) in part by reducing the pleasure of eating. Olfaction plays an essential role in flavor sensation and palatability. The decreased QOL due to olfactory dysfunction is speculated to result from abnormal neural activities in the olfactory and limbic areas of the brain, as well as peripheral odorant receptor dysfunctions. However, the specific underlying neurobiological mechanisms remain unclear. As the olfactory tubercle (OT) is one of the brain’s regions with high expression of endogenous opioids, we hypothesize that the mechanism underlying the decrease in QOL due to olfactory dysfunction involves the reduction of neural activity in the OT and subsequent endogenous opioid release in specialized subregions. In this review, we provide an overview and recent updates on the OT, the endogenous opioid system, and the pleasure systems in the brain and then discuss our hypothesis. To facilitate the effective treatment of olfactory dysfunctions and decreased QOL, elucidation of the neurobiological mechanisms underlying the pleasure of eating through flavor sensation is crucial.

Objectives: Safety and immunogenicity evaluation of a 4-dose series with 20-valent pneumococcal conjugate vaccine (PCV20). Methods: This phase 3, double-blind study randomized healthy Japanese infants to receive 4 doses (3 infant doses, 1 toddler dose) of PCV20 by subcutaneous (SC) or intramuscular (IM) injection or 13-valent PCV (PCV13) SC. A primary immunogenicity objective was to demonstrate noninferiority of PCV20 SC to PCV13 SC for percentages of participants meeting predefined serotype-specific immunoglobulin G concentrations 1 month after Dose 3. The 7 additional PCV20 serotypes were compared with the lowest vaccine serotype result in the PCV13 group. Safety and tolerability were assessed as the primary safety objective. Results: Overall, 668 participants were randomized (PCV20 SC, n = 226; PCV13 SC, n = 224; PCV20 IM, n = 218). The primary noninferiority objective for PCV20 SC to PCV13 SC was met for 11/13 matched and 5/7 additional serotypes. Additional data showed PCV20 SC and IM elicited robust functional opsonophagocytic activity and boosting responses to all 20 vaccine serotypes. PCV20 had a similar safety/tolerability profile to PCV13, although local reactions were less frequent with PCV20 IM. Conclusions: A 4-dose series of PCV20 SC or IM elicited immune responses expected to be protective against all 20 serotypes in Japanese infants. NCT04530838

Although microglia are associated with chronic pain, the role of spinal microglia in the regulation of itch remains unclear. In this study, we characterized spinal microglial activation in a mouse model of imiquimod (IMQ)-induced psoriasis. Hypertrophic (activated) microglia were observed throughout the spinal cord after the topical application of IMQ. Furthermore, the mRNA expression of microglial markers and inflammatory mediators was upregulated. Ablation of itch-related sensory neurons using resiniferatoxin decreased itch-related scratching behavior and the number of hypertrophic microglia in the spinal dorsal horn. Conclusively, sensory neuron input may partially contribute to spinal microglial activation after IMQ application.

Introduction: The regeneration of adipose tissue in patients after breast cancer surgery would be desirable without the use of growth factors or cells to avoid potential recurrence and metastasis. We reported that prolate spheroidal-shaped poly-L-lactic acid (PLLA) mesh implants of approximately 18-mm polar diameter and 7.5-mm greatest equatorial diameter containing collagen sponge (CS) would be replaced by regenerated adipose tissue after implantation, thereby suggesting an innovative method for breast reconstruction. Our study aimed to evaluate the adipose tissue regeneration ability of implant aggregates in a porcine model. Methods: We prepared implant aggregates consisting of thirty PLLA mesh implants containing CS packed in a woven poly (glycolic acid) bag. The implant aggregates were inserted under the mammary glands in the porcine abdomen for a year. Single and double groups were classified by inserting either one or two implant aggregates on each side of the abdomen, respectively. Results: In both groups, the volume of the implant aggregates decreased over time, and the formation of adipose tissue peaked between 6 and 9 months. Histologically, the formation of adipose tissue was confirmed in the area that was in contact with native adipose tissue. Conclusions: Our implant aggregates could induce the autologous adipose tissue after long term implantation in vivo, without the use of any growth factor or cell treatment, presenting a potential novel method of breast reconstruction.

Programmed cell death protein 1 (PD-1) is an immune checkpoint marker commonly expressed on memory T cells and enriched in latently HIV-infected [CD4.sup.+] T cells. We engineered an anti-PD-1 chimeric antigen receptor (CAR) to assess the impact of PD-1 depletion on viral reservoirs and rebound dynamics in SIVmac239-infected rhesus macaques (RMs). Adoptive transfer of anti-PD-1 CAR T cells was done in 2 SIV-naive and 4 SIV-infected RMs on antiretroviral therapy (ART). In 3 of 6 RMs, anti-PD-1 CAR T cells expanded and persisted for up to 100 days concomitant with the depletion of [PD- 1.sup.+] memory T cells in blood and tissues, including lymph node [CD4.sup.+] follicular helper T (TFH) cells. Loss of TFH cells was associated with depletion of detectable SIV RNA from the germinal center (GC). However, following CAR T infusion and ART interruption, there was a marked increase in SIV replication in extrafollicular portions of lymph nodes, a 2-log higher plasma viremia relative to controls, and accelerated disease progression associated with the depletion of [CD8.sup.+] memory T cells. These data indicate anti-PD-1 CAR T cells depleted [PD-1.sup.+] T cells, including GC TFH cells, and eradicated SIV from this immunological sanctuary., Introduction HIV infects cells of the immune system through interaction with CD4, CCR5, and CXCR4 and establishes long-lasting infections that develop into the acquired immunodeficiency syndrome if left untreated. With [...]

Coronary artery lesions (CALs) after Kawasaki disease present complex coronary hemodynamics. We investigated the relationship between coronary fractional flow reserve (FFR), myocardial flow reserve (MFR), and myocardial blood flow volume fraction (MBF) and their clinical usefulness in CALs after Kawasaki disease. Nineteen patients (18 men, 1 woman) who underwent cardiac catheterization and 13N-ammonia positron emission tomography, with 24 coronary artery branches, were included. Five branches had inconsistent FFR and MFR values, two had normal FFR but abnormal MFR, and three had abnormal FFR and normal MFR. The abnormal MFR group had significantly higher MBF at rest than the normal group (0.86 ± 0.13 vs. 1.08 ± 0.09, p = 0.001). The abnormal FFR group had significantly lower MBF at adenosine loading than the normal group (2.23 ± 0.23 vs. 1.88 ± 0.29, p = 0.021). The three branches with abnormal FFR only had stenotic lesions, but the MFR may have been normal because blood was supplied by collateral vessels. Combining FFR, MFR, and MBF will enable a more accurate assessment of peripheral coronary circulation and stenotic lesions in CALs and help determine treatment strategy and timing of intervention.

Abstract A 52‐year‐old female never‐smoker with an abnormal shadow in the right lung detected on radiography was referred to our institution. Contrast‐enhanced computed tomography revealed an irregular nodule in the upper lobe of the right lung, suggestive of a pulmonary vascular abnormality. Angiography revealed a direct communication between the right internal mammary artery (IMA) and the right upper lobe pulmonary artery branches, with dilated and tortuous vascular proliferation. As multiple branch arteries were seen flowing into the upper lobe from the IMA, transcatheter selective embolization of these vessels and right upper lobectomy by video‐assisted thoracoscopic surgery were performed. Contrary to the clinical diagnosis, the pathological finding was a pulmonary adenocarcinoma of the right upper lobe. Additional lymph node dissection was performed later. We report an extremely rare and unprecedented case of pulmonary adenocarcinoma fed by the right IMA, with a literature review.

Abstract Background Tumor size is an important prognostic factor in lung cancer in dogs, and the canine lung carcinoma stage classification (CLCSC) recently has been proposed to subdivide tumor sizes. It is unclear if the same classification scheme can be used for small‐breed dogs. Objectives To investigate whether the tumor size classification of CLCS is prognostic for survival and progression outcomes in small‐breed dogs with surgically resected pulmonary adenocarcinomas (PACs). Animals Fifty‐two client‐owned small‐breed dogs with PAC. Methods Single‐center retrospective cohort study conducted between 2005 and 2021. Medical records of dogs weighing 3 cm to ≤5 cm, >5 cm to ≤7 cm, or >7 cm were 15, 18, 14, and 5, respectively. The median progression‐free interval (PFI) and overall survival time (OST) were 754 and 716 days, respectively. In univariable analysis, clinical signs, lymph node metastasis, margin, and histologic grade were associated with PFI, and age, clinical signs, margin, and lymph node metastasis were associated with OST. Tumor size classification of CLCS was associated with PFI in all categories, and tumor size >7 cm was associated with OST. In multivariable analysis, tumor size >5 cm to ≤7 cm and margin were associated with PFI, and age was associated with OST. Conclusions and Clinical Importance The tumor size classification of CLCS would be an important prognostic factor in small‐breed dogs with surgically resected PACs.

Abstract Aims/Introduction Research on the incidence and underlying mechanisms of rapid renal function decline in patients with type 2 diabetes mellitus with preserved renal function and normoalbuminuria is limited. This study aimed to investigate the involvement of hemoglobin level as a risk factor for rapid decliners among patients with type 2 diabetes with preserved renal function and normoalbuminuria. Materials and Methods This was a retrospective observational study of 242 patients with type 2 diabetes with a baseline estimated glomerular filtration rate of ≥60 mL/min/1.73 m2 and normoalbuminuria (1 year. The annual rate of estimated glomerular filtration rate decline during the follow‐up period was calculated using least square regression analysis; rapid decliners defined at ≥3.3%/year. Risk factors associated with rapid decliners were identified using a logistic regression analysis of variables previously identified as risk factors of rapid decliners. Results The median follow‐up period was 6.7 years, and 34 patients showed rapid decliners. On multivariate analysis, lower baseline hemoglobin level was a risk factor of rapid decliners (odds ratio 0.69, 95% confidence interval 0.47–0.99; P = 0.045). Furthermore, the baseline hemoglobin levels were correlated positively with iron and ferritin levels, implying that an impaired iron metabolism might cause lower hemoglobin levels in rapid decliners. Conclusions In patients with type 2 diabetes with preserved renal function and normoalbuminuria, lower hemoglobin levels were a risk factor for rapid decliners, where disturbed iron metabolism might precede the development of diabetic kidney disease.