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Introduction: Although the prevalence of Alzheimer’s disease (AD) is higher in older people compared to younger people, dementia has also been documented in younger adults. Although early-onset dementia and late-onset dementia had been considered a single disease in pathological investigations, many studies revealed differences in cognitive and neuroimaging changes between them. We evaluated differences in cognitive and neuroimaging changes among the following groups: individuals with early-onset AD (EOAD), late-onset AD (LOAD), early-onset mild cognitive impairment (EOMCI), or late-onset MCI (LOMCI), and healthy controls (HCs). Methods: Patients underwent both a 1.5 Tesla magnetic resonance imaging scan and the Mini-Mental State Examination (MMSE). Differences in regional gray matter volumes and MMSE subscales were investigated among the five diagnostic groups. Results: Compared to the EOAD group, the LOAD group had significantly higher scores on orientation in place. Compared to the LOMCI patients, the EOMCI patients achieved significantly higher recall scores. The LOAD and LOMC groups showed significant volume reductions in bilateral medial temporal regions compared to the HCs. The EOAD and EOMCI groups did not show significant atrophy of the medial temporal region compared to the HC group. Conclusions: The hippocampal volume and memory were preserved in the patients with EOMCI or EOAD compared to those with LOMCI or LOAD. These findings may indicate that the distinct and differing patterns of neuropsychological changes between EOAD and LOAD are also common in MCI, which is intermediate between normal cognition and AD.

Objective: To identify factors associated with earlier independence in “real-life walking” during hospitalization in subacute stroke patients. Design: Retrospective cohort study. Subjects/Patients: Two hundred and six hemiplegic patients. Methods: Functional Independence Measure (FIM) walking items were measured biweekly from admission to discharge. Patients were grouped by achieving independent “real-life walking” (FIM-walking score ≥6). Time to independence, stratified by age, FIM motor score (FIM-M), FIM cognitive score (FIM-C), and Functional Ambulation Categories (FAC) scores were compared using Kaplan– Meier plots and log-rank tests. Hazard ratios were calculated via multivariable Cox proportional hazard models. Results: The median time to independence was 4 weeks, with significant differences (p

In recent years, it has become clear that the cytotoxicity of γ-irradiation of cells is increased under microgravity conditions. However, there has been no study of the effect of the gravity vector direction, rather than the magnitude, on γ-ray-induced cytotoxicity. Therefore, in this study, we inverted cultures of human bronchial epithelium BEAS-2B cells and human lung cancer A549 cells in order to change the gravity vector direction by 180° with respect to the cells and observed the cellular response to radiation in this state. We found that cells in inverted culture showed increased irradiation-induced production of reactive oxygen species and decreased expression of the antioxidant protein thioredoxin-1 compared to cells in normal culture. Furthermore, the DNA damage response was delayed in γ-irradiated cells in inverted culture, and the number of unrepaired DNA sites was increased, compared to irradiated cells in normal culture. γ-Ray-induced cell death and the number of G2-M arrested cells were increased in inverted culture, in accordance with the decreased capacity for DNA repair. Our findings suggest that the gravity vector direction, as well as its magnitude, alters the cellular response to radiation.

Idiopathic pulmonary fibrosis (IPF) is the most common type of fibrosis in lungs, characterized as a chronic and progressive interstitial lung disease involving pathological findings of fibrosis with a median survival of 3 years. Despite the knowledge accumulated regarding IPF from basic and clinical research, an effective medical therapy for the condition remains to be established. Thus, it is necessary for further research, including stem cell therapy, which will provide new insights into and expectations for IPF treatment. Recently, it has been reported that one of the new therapeutic candidates for IPF is adipose-derived mesenchymal stem cells (ADSCs), which have several benefits, such as easy accessibility and minimal morbidity compared to bone marrow-derived mesenchymal stem cells. Therefore, we investigated the possibility of ADSCs as a therapeutic candidate for IPF. Using human lung fibroblasts (LFs) from IPF patients, we demonstrated that human IPF LFs cocultured with ADSCs led to reduced fibrosis-related genes. Further analysis revealed that ADSCs prevented the activation of the ERK signaling pathway in IPF LFs via the upregulation of protein tyrosine phosphatase receptor-type R (PTPRR), which negatively regulates the ERK signaling pathway. Moreover, we demonstrated that intravascular administration of ADSCs improved the pathogenesis of bleomycin-induced pulmonary fibrosis with reduced collagen deposition in histology and hydroxyproline quantification and collagen markers such as the gene expression of types I and III collagen and α-smooth muscle actin (α-SMA) in a murine model. ADSC transfer was also investigated in a humanized mouse model of lung fibrosis induced via the infusion of human IPF LFs, because the bleomycin installation model does not fully recapitulate the pathogenesis of IPF. Using the humanized mouse model, we found that intravascular administration of ADSCs also improved fibrotic changes in the lungs. These findings suggest that ADSCs are a promising therapeutic candidate for IPF.

Abstract Wood decay fungi alter the abiotic and biotic properties of deadwood, which are important as nurse logs for seedling regeneration. However, the relationship between fungal decay type and seedling performance has not been evaluated experimentally. In this study, we examined the germination, growth, and survival of six arbuscular mycorrhizal (AM) and six ectomycorrhizal (ECM) tree species on three substrates (pine logs with brown and white rot and soil) by conducting seed‐sowing experiments in a mixed forest dominated by Pinus densiflora and Quercus serrata. Analysis using ribosomal DNA internal transcribed spacer 1 (rDNA ITS1) sequencing revealed that the fungal community was significantly different across three substrates. The richness of operational taxonomic units (OTUs) of AM and ECM fungi was the largest on brown rot logs and soil, respectively. The substrate significantly affected the seedling performance when comparing wood decay types, but these were not consistent across the mycorrhizal status of the seedlings. Nevertheless, seedlings of some AM trees showed better growth and enhanced mycorrhizal colonization on brown rot logs than on white rot logs. The wood decay type influenced fungal communities in the logs and the performance of some seedling species partly by different mycorrhizal colonization rates. However, the effect was seedling species dependent and showed no apparent difference between AM and ECM trees.

This review, which was adapted from a Tenth International Workshop on Tropical Cyclones (IWTC-10) report, discusses research findings and operational practices relevant to cyclone types and phase transitions (extratropical, subtropical, and tropical). The cyclone phase space (CPS) method is widely used in both historical investigations and real-time evaluation of cyclone type and transition; however, CPS parameter values depend on input data resolution, and universal thresholds do not currently exist to delineate when a cyclone transitions from one type to another. Assessments of phase transitions in a changing climate highlight potential latitude shifts in extratropical transition and increased potential for tropical transition, but realistic projections of future trends likely require high-resolution simulations that can capture the cyclone warm core.Operational meteorological centers apply varied approaches to cyclone classification via CPS parameters and other criteria, some of which depend on the tropical basin, yet these approaches cannot fully address challenges in operational classification and subsequently in communicating risks associated with these phase transitions. We recommend a multivariate historical assessment of tropical and subtropical cyclones across all basins in which they occur, including the South Atlantic Ocean and the Mediterranean Sea, to identify the potential for a more universal cyclone classification approach that meets operational needs.

Upogebia major (De Haan, 1841) is known for forming huge burrows in sandy, intertidal areas that can extend to depths of over 2 m. Despite its widespread distribution in East Asia and Russia, the genetic relatedness of its regional populations remains uncertain, likely owing to difficulties in specimen collection. Therefore, to appraise the phylogeographic patterns, genetic diversity, and morphological variety of U. major, the mitochondrial DNA of specimens collected from Japan, Korea and China were subjected to molecular phylogenetic analyses of COI genes, alongside morphological assessment. As a result, we discovered four principal groups; of these, Group 1 consisted predominantly of Japanese specimens, while Groups 3 and 4 were interpreted as having originated from the continent. Group 2 exhibited genetic segregation from both continental and Japanese descent. Group 1 mostly comprising Japanese specimens implies that the planktonic larvae of U. major were disseminated north and south by ocean currents encompassing the Japanese archipelago. In contrast, individuals probably originating from the continent were discovered in Lake Notoro, Hokkaido and Matsukawa-ura, Fukushima in northeastern Japan, indicating possible introduction from the continent through ocean currents or unintentional introduction with other organisms imported. Additionally, one of the specimens collected from Matsukawa-ura exhibited significant genetic and morphological differences from other specimens, suggesting the possibility of being a subspecies. The outcomes of this study not only offer valuable insights into the origins of distribution of U. major but also introduce a novel challenge of assessing the coexistence of two routes: natural and anthropogenic dispersion.

Background: It has not been determined whether mentally active sedentary behavior (MASB) and passive sedentary behavior (PSB) differentially affect cognitive function and whether these associations differ according to physical activity (PA) level. We examined the comparative impacts of MASB and PSB on dementia onset and aimed to understand whether the associations differed by PA level. Methods: We conducted a 5-year longitudinal study involving all community-dwelling older adults in a rural area in Japan (n = 5,323). Dementia onset was examined using long-term care insurance data. PA was evaluated using the International Physical Activity Questionnaire and categorized as low (

BackgroundOne life event that requires extensive resilience and adaptation is parenting. However, resilience and perceived support in child-rearing vary, making the real-world situation unclear, even with postpartum checkups. ObjectiveThis study aimed to explore the psychosocial status of mothers during the child-rearing period from newborn to toddler, with a classifier based on data on the resilience and adaptation characteristics of mothers with newborns. MethodsA web-based cross-sectional survey was conducted. Mothers with newborns aged approximately 1 month (newborn cohort) were analyzed to construct an explainable machine learning classifier to stratify parenting-related resilience and adaptation characteristics and identify vulnerable populations. Explainable k-means clustering was used because of its high explanatory power and applicability. The classifier was applied to mothers with infants aged 2 months to 1 year (infant cohort) and mothers with toddlers aged >1 year to 2 years (toddler cohort). Psychosocial status, including depressed mood assessed by the Edinburgh Postnatal Depression Scale (EPDS), bonding assessed by the Postpartum Bonding Questionnaire (PBQ), and sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI) between the classified groups, was compared. ResultsA total of 1559 participants completed the survey. They were split into 3 cohorts, comprising populations of various characteristics, including parenting difficulties and psychosocial measures. The classifier, which stratified participants into 5 groups, was generated from the self-reported scores of resilience and adaptation in the newborn cohort (n=310). The classifier identified that the group with the greatest difficulties in resilience and adaptation to a child’s temperament and perceived support had higher incidences of problems with depressed mood (relative prevalence [RP] 5.87, 95% CI 2.77-12.45), bonding (RP 5.38, 95% CI 2.53-11.45), and sleep quality (RP 1.70, 95% CI 1.20-2.40) compared to the group with no difficulties in perceived support. In the infant cohort (n=619) and toddler cohort (n=461), the stratified group with the greatest difficulties had higher incidences of problems with depressed mood (RP 9.05, 95% CI 4.36-18.80 and RP 4.63, 95% CI 2.38-9.02, respectively), bonding (RP 1.63, 95% CI 1.29-2.06 and RP 3.19, 95% CI 2.03-5.01, respectively), and sleep quality (RP 8.09, 95% CI 4.62-16.37 and RP 1.72, 95% CI 1.23-2.42, respectively) compared to the group with no difficulties. ConclusionsThe classifier, based on a combination of resilience and adaptation to the child’s temperament and perceived support, was able identify psychosocial vulnerable groups in the newborn cohort, the start-up stage of childcare. Psychosocially vulnerable groups were also identified in qualitatively different infant and toddler cohorts, depending on their classifier. The vulnerable group identified in the infant cohort showed particularly high RP for depressed mood and poor sleep quality.

Abstract Japanese cedar, Cryptomeria japonica, is an evergreen conifer native to Japan and is often used as a building material. The humidity control properties of wood are known, but there have been few detailed analyses of its effects on living organisms. Therefore, we investigated the effects of cedar water-soluble components on human macrophages, which are essential for maintaining biological homeostasis and innate immunity. In this study, we prepared aqueous extracts from Cryptomeria japonica in Yoshino, Nara prefecture (called as Yoshino cedar). Yoshino cedar aqueous extracts stimulated macrophages toward the classically activated phenotype and inhibited the macrophage phenotype thought to mediate allergic responses. Next, we measured the lipopolysaccharide (LPS) concentration in the Yoshino cedar aqueous extract and found it was present at a high concentration. The major receptor of LPS is Toll-like receptor 4 (TLR4). To confirm whether LPS in Yoshino cedar aqueous extracts activate macrophages through the LPS/TLR4 pathway, we analyzed its effects on TLR4-deficient mouse embryonic fibroblasts (MEF) and wild-type (WT) MEF. TLR4-deficient MEF did not produce the proinflammatory cytokines seen in WT MEF. This result showed that LPS in the Yoshino cedar aqueous extracts activate macrophages via TLR4. This information will help us better understand the benefits of cedar for human health, including allergies.

BackgroundEssential tremor (ET) is a common involuntary movement disorder (IMD). Radiofrequency ablation (RFA) targeting the ventral intermediate nucleus (Vim) of the thalamus is a stereotactic neurosurgery performed in individuals with ET when pharmacotherapy is no longer effective. Though the reasons remain largely unclear, certain adverse events are known to appear post-RFA. These may be due to functional changes in the Vim, related to RFA-induced tremor reduction, or an adverse reaction to compensatory movement patterns used to perform movements in the presence of tremor symptoms.ObjectiveThis study aimed to understand the characteristics of post-RFA symptoms in individuals with ET.MethodsIn a longitudinal case–control study, we compared post-RFA symptoms between individuals with ET who underwent Vim-targeted RFA and those with IMD who underwent non-Vim-targeted RFA. Symptoms were compared preoperatively and 1-week and 1-month postoperatively. Quantitative assessments included center-of-pressure (COP) parameters, grip strength, Mini-Mental State Examination, two verbal fluency tests, and three types of physical performance assessments (upper extremity ability, balance ability, and gait ability).ResultsIndividuals with ET after RFA showed horizontal displacements of the COP to the treated side (the dominant side of the RFA target's hemisphere) at 1-week postoperatively compared to the preoperative period. The horizontal COP displacement was associated with balance dysfunction related to postural stability post-RFA. Other COP parameters did not significantly differ between the ET and IMD groups.ConclusionCOP displacement to the treated side may be due to a time lag in adjusting postural holding strategies to the long-standing lateral difference in tremor symptoms associated with tremor improvement after RFA.

Terminator-assisted solid-phase cDNA amplification and sequencing (TASseq) uses a terminator, terminal transferase and bead-based platform to improve generation of single-cell RNA-seq libraries.

Idiopathic pulmonary fibrosis (IPF) is the most common type of fibrosis in lungs, characterized as a chronic and progressive interstitial lung disease involving pathological findings of fibrosis with a median survival of 3 years. Despite the knowledge accumulated regarding IPF from basic and clinical research, an effective medical therapy for the condition remains to be established. Thus, it is necessary for further research, including stem cell therapy, which will provide new insights into and expectations for IPF treatment. Recently, it has been reported that one of the new therapeutic candidates for IPF is adipose-derived mesenchymal stem cells (ADSCs), which have several benefits, such as easy accessibility and minimal morbidity compared to bone marrow-derived mesenchymal stem cells. Therefore, we investigated the possibility of ADSCs as a therapeutic candidate for IPF. Using human lung fibroblasts (LFs) from IPF patients, we demonstrated that human IPF LFs cocultured with ADSCs led to reduced fibrosis-related genes. Further analysis revealed that ADSCs prevented the activation of the ERK signaling pathway in IPF LFs via the upregulation of protein tyrosine phosphatase receptor-type R (PTPRR), which negatively regulates the ERK signaling pathway. Moreover, we demonstrated that intravascular administration of ADSCs improved the pathogenesis of bleomycin-induced pulmonary fibrosis with reduced collagen deposition in histology and hydroxyproline quantification and collagen markers such as the gene expression of types I and III collagen and α-smooth muscle actin (α-SMA) in a murine model. ADSC transfer was also investigated in a humanized mouse model of lung fibrosis induced via the infusion of human IPF LFs, because the bleomycin installation model does not fully recapitulate the pathogenesis of IPF. Using the humanized mouse model, we found that intravascular administration of ADSCs also improved fibrotic changes in the lungs. These findings suggest that ADSCs are a promising therapeutic candidate for IPF. [ABSTRACT FROM AUTHOR]

Neutralizing antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being developed world over. We investigated the possibility of producing artificial antibodies from the formalin fixation and paraffin-embedding (FFPE) lung lobes of a patient who died by coronavirus disease 2019 (COVID-19). The B-cell receptors repertoire in the lung tissue where SARS-CoV-2 was detected were considered to have highly sensitive virus-neutralizing activity, and artificial antibodies were produced by combining the most frequently detected heavy and light chains. Some neutralizing effects against the SARS-CoV-2 were observed, and mixing two different artificial antibodies had a higher tendency to suppress the virus. The neutralizing effects were similar to the immunoglobulin G obtained from healthy donors who had received a COVID-19 mRNA vaccine. Therefore, the use of FFPE lung tissue, which preserves the condition of direct virus sensitization, to generate artificial antibodies may be useful against future unknown infectious diseases.

Abstract Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread across the world. Inactivating the virus in saliva and the oral cavity represents a reasonable approach to prevent human-to-human transmission because the virus is easily transmitted through oral routes by dispersed saliva. Persimmon-derived tannin is a condensed type of tannin that has strong antioxidant and antimicrobial activity. In this study, we investigated the antiviral effects of persimmon-derived tannin against SARS-CoV-2 in both in vitro and in vivo models. We found that persimmon-derived tannin suppressed SARS-CoV-2 titers measured by plaque assay in vitro in a dose- and time-dependent manner. We then created a Syrian hamster model by inoculating SARS-CoV-2 into hamsters’ mouths. Oral administration of persimmon-derived tannin dissolved in carboxymethyl cellulose before virus inoculation dramatically reduced the severity of pneumonia with lower virus titers compared with a control group inoculated with carboxymethyl cellulose alone. In addition, pre-administration of tannin to uninfected hamsters reduced hamster-to-hamster transmission of SARS-CoV-2 from a cohoused, infected donor cage mate. These data suggest that oral administration of persimmon-derived tannin may help reduce the severity of SARS-CoV-2 infection and transmission of the virus.

Abstract We have reported that the transcription factor Olig2 labels a subpopulation of astrocytes (Olig2-astrocytes), which show distribution patterns different from those of GFAP-expressing astrocytes (GFAP-astrocytes) in the adult brain. Here, to uncover the specific functions of Olig2-astrocytes, we first analyzed public single-cell RNA-seq databases of adult mouse brains. Unbiased classification of gene expression profiles and subsequent gene ontology analyses revealed that the majority of Olig2-astrocytes belonged to an astrocytic cluster that is enriched for transporter-related genes. SLC7A10 (also known as ASC-1) was one of the representative neutral amino acid transporter genes in the cluster. To complement the in silico data analyses, we differentially isolated Olig2- and GFAP-astrocytes from the same frozen section of the lateral globus pallidus using laser microdissection and compared their gene expression by quantitative reverse transcription PCR. We confirmed that Olig2 and GFAP mRNAs were preferentially expressed in the Olig2- and GFAP-astrocytes, respectively, indicating that the laser microdissection method yielded minimal cross-contamination between two types of cells. The Olig2-astrocytes expressed significantly higher levels of SLC7A10 mRNA than the GFAP-astrocytes, corroborating the in silico data. We next localized SLC7A10 protein by immunohistochemistry in the lateral globus pallidus, which was also genetically labeled for Olig2. SLC7A10 co-localized with Olig2-genetic labeling, especially on the fine processes of Olig2-astrocytes. These results are consistent with the recent discovery that SLC7A10 is expressed not only in neurons but also in a subset of astrocytes. Taken together, our findings suggest that SLC7A10 exerts specific functions in Olig2-astrocytes of the adult brain.

Nobuhiro Fujioka,1 Masahiro Kitabatake,2 Noriko Ouji-Sageshima,2 Takahiro Ibaraki,1 Makiko Kumamoto,1 Yukio Fujita,1 Shigeto Hontsu,1 Motoo Yamauchi,1 Masanori Yoshikawa,1 Shigeo Muro,1 Toshihiro Ito2 1Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan; 2Department of Immunology, Nara Medical University, Kashihara, Nara, JapanCorrespondence: Toshihiro ItoDepartment of Immunology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, JapanTel +81-744-22-3051Fax +81-744-29-7503Email toshi-ito@naramed-u.ac.jpPurpose: Chronic obstructive pulmonary disease (COPD) is a worldwide problem because of its high prevalence and mortality. However, there is no fundamental treatment to ameliorate their pathological change in COPD lung. Recently, adipose-derived mesenchymal stem cells (ADSCs) have attracted attention in the field of regenerative medicine to repair damaged organs. Moreover, their utility in treating respiratory diseases has been reported in some animal models. However, the detailed mechanism by which ADSCs improve chronic respiratory diseases, including COPD, remains to be elucidated. We examined whether human ADSCs (hADSCs) ameliorated elastase-induced emphysema and whether hADSCs differentiated into alveolar epithelial cells in a murine model of COPD.Methods: Female SCID-beige mice (6 weeks old) were divided into the following four groups according to whether they received an intratracheal injection of phosphate-buffered saline or porcine pancreatic elastase, and whether they received an intravenous injection of saline or hADSCs 3 days after intratracheal injection; Control group, hADSC group, Elastase group, and Elastase-hADSC group. We evaluated the lung function, assessed histological changes, and compared gene expression between hADSCs isolated from the lung of Elastase-hADSC group and naïve hADSCs 28 days after saline or elastase administration.Results: hADSCs improved the pathogenesis of COPD, including the mean linear intercept and forced expiratory volume, in an elastase-induced emphysema model in mice. Furthermore, hADSCs were observed in the lungs of elastase-treated mice at 25 days after administration. These cells expressed genes related to mesenchymal–epithelial transition and surface markers of alveolar epithelial cells, such as TTF-1, β-catenin, and E-cadherin.Conclusion: hADSCs have the potential to improve the pathogenesis of COPD by differentiating into alveolar epithelial cells by mesenchymal–epithelial transition.Keywords: chronic obstructive pulmonary disease, mesenchymal–epithelial transition, adipose derived mesenchymal stem cell, pulmonary function test

ObjectivesClose contact with patients with COVID-19 is speculated to be the most common cause of viral transmission, but the pathogenesis of COVID-19 by close contact remains to be elucidated. In addition, despite olfactory impairment being a unique complication of COVID-19, the impact of SARS-CoV-2 on the olfactory cell lineage has not been fully validated. This study aimed to elucidate close-contact viral transmission to the nose and lungs and to investigate the temporal damage in the olfactory receptor neuron (ORN) lineage caused by SARS-CoV-2.MethodsSyrian hamsters were orally administered SARS-CoV-2 nonvariant nCoV-19/JPN/TY/WK521/2020 as direct-infection models. On day 3 after inoculation, infected and uninfected hamsters were housed in the same cage for 30 minutes. These uninfected hamsters were subsequently assigned to a close-contact group. First, viral presence in the nose and lungs was verified in the infection and close-contact groups at several time points. Next, the impacts on the olfactory epithelium, including olfactory progenitors, immature ORNs, and mature ORNs were examined histologically. Then, the viral transmission status and chronological changes in tissue damage were compared between the direct-infection and close-contact groups.ResultsIn the close-contact group, viral presence could not be detected in both the nose and lungs on day 3, and the virus was identified in both tissues on day 7. In the direct-infection group, the viral load was highest in the nose and lungs on day 3, decreased on day 7, and was no longer detectable on day 14. Histologically, in the direct-infection group, mature ORNs were most depleted on day 3 (p

Keiji Kawatani et al. developed a panel of Down syndrome (DS) isogenic astrocytes derived from iPSCs to observe the consequence of DS on astrocyte precursor proliferation, differentiation, and gene expression. Their results suggest a dose-dependent effect of DYRK1A and PIGP on DS-derived astrocyte precursor proliferation, and represent a valuable resource and cellular model for future DS research.

Inactivation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the mouth has the potential to reduce the spread of coronavirus disease 2019 (COVID-19), due to the virus being readily transmitted by dispersed saliva. Persimmon-derived tannin has strong antioxidant and antimicrobial activity owing to its strong adhesion to proteins, and it also exhibited antiviral effects against non-variant and Alpha-variant SARS-CoV-2 in our previous study. In this study, we first demonstrated the antiviral effects of persimmon-derived tannin against the Delta variant of SARS-CoV-2 in vitro via the plaque assay method. We then examined the effects of candy containing persimmon-derived tannin. Remarkably, the saliva samples provided by healthy volunteers while they were eating tannin-containing candy showed that the virus titers of the SARS-CoV-2 Delta variant were suppressed. In addition, we found that the SARS-CoV-2 viral load in saliva from patients with COVID-19 collected immediately after they had eaten the tannin-containing candy was below the level of detection via PCR for SARS-CoV-2. These data suggest that adding persimmon-derived tannin to candy and holding such candy in the mouth is an effective method for inactivating SARS-CoV-2 in saliva, and the application of this approach shows potential for inhibiting the transmission of COVID-19.

Abstract Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) induced by dysregulation of the immune response in the intestinal mucosa. Although the underlying mechanisms of UC development are not fully understood, disruption of gut microbiota, “dysbiosis”, is thought to lead to the development of IBD. Persimmon (Ebenaceae Diospyros kaki Thunb.)-derived tannin, which is a condensed polymeric tannin consisting of catechin groups, has antioxidant, anti-inflammatory, and antimicrobial activities. In this study, we assessed the effect of persimmon-derived tannin on a murine model of UC established by dextran sulfate sodium-induced colitis in female mice. Dietary supplementation of tannin significantly decreased disease activity and colon inflammation. A hydrolysate of tannin directly suppressed expression of inflammatory genes in macrophages in vitro. In faecal microbiota, the relative abundance of Bacteroides was increased significantly by tannin supplementation. Alpha-diversity indices in colitis-induced mice were significantly higher in the tannin diet group compared with the control diet group. Additionally, expansion of Enterobacteriaceae and Enterococcus, which is associated with disease progression of IBD, was remarkably suppressed in the tannin diet group. These results suggest that persimmon-derived tannin ameliorates colon inflammation in UC through alteration of the microbiota composition and immune response, which may be a promising candidate for IBD therapy.

Excessive proinflammatory cytokine production induced by abnormal activation of Toll-like receptor (TLR) signaling, for example, by SARS-CoV-2 infection, can cause a fatal cytokine storm. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine, used to treat depression, were recently reported to reduce the risk of severe disease in patients with coronavirus disease 2019 (COVID-19), but the mechanisms of the anti-inflammatory effects of SSRIs, and which SSRI would be most suitable as an anti-inflammatory drug, remain unclear. Here, we examined the inhibitory effects of 5 FDA-approved SSRIs, paroxetine, fluoxetine, fluvoxamine, sertraline and escitalopram, on the production of interleukin-6 (IL-6) induced by stimulation with multiple TLR agonists in murine macrophages and dendritic cells, and on the production of cytokines induced by concanavalin A in murine lymphocytes. In J774.1 murine macrophage cells, pretreatment with SSRIs significantly suppressed IL-6 release induced by TLR3 agonist poly(I:C), TLR4 agonist LPS or TLR9 agonist CpG ODN, but did not affect IL-6 release induced by TLR7 agonists imiquimod or resiquimod. In accordance with the results obtained in J774.1 cells, pretreatment with SSRIs also suppressed IL-6 release induced by a TLR3, TLR4 or TLR9 agonist in bone marrow-derived dendritic cells and peritoneal cells of C57BL/6 mice. On the other hand, interestingly, sertraline alone among the SSRIs amplified IL-6 production induced by TLR7 agonists in murine dendritic cells, though not in macrophages. Concanavalin A-induced production of IL-6 or IL-2 in murine lymphocytes was suppressed by SSRIs, suggesting that SSRIs also inhibit TLRs-independent IL-6 production. Since SSRIs suppressed both IL-6 production induced by multiple TLR agonists in macrophages or dendritic cells and TLR-independent IL-6 production in lymphocytes, they are promising candidates for treatment of patients with cytokine storm, which is mediated by overactivation of multiple TLRs in a complex manner, leading to the so-called IL-6 amplifier, an IL-6 overproduction loop. However, the 5 SSRIs examined here all showed different effects. Overall, our results suggest that fluoxetine may be the most promising candidate as an anti-inflammatory drug. An examination of the structural requirements indicated that the N-methyl group of fluoxetine has a critical role in the inhibition of IL-6 production.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can cause long-lasting anosmia, but the impact of SARS-CoV-2 infection, which can spread to the nasal cavity via the oral route, on the olfactory receptor neuron (ORN) lineage and olfactory bulb (OB) remains undetermined. Using Syrian hamsters, we explored whether oral SARS-CoV-2 inoculation can lead to nasal viral infection, examined how SARS-CoV-2 affects the ORN lineage by site, and investigated whether SARS-CoV-2 infection can spread to the OB and induce inflammation. On post-inoculation day 7, SARS-CoV-2 presence was confirmed in the lateral area (OCAM-positive) but not the nasal septum of NQO1-positive and OCAM-positive areas. The virus was observed partially infiltrating the olfactory epithelium, and ORN progenitor cells, immature ORNs, and mature ORNs were fewer than in controls. The virus was found in the olfactory nerve bundles to the OB, suggesting the nasal cavity as a route for SARS-CoV-2 brain infection. We demonstrated that transoral SARS-CoV-2 infection can spread from the nasal cavity to the central nervous system and the possibility of central olfactory dysfunction due to SARS-CoV-2 infection. The virus was localized at the infection site and could damage all ORN-lineage cells.

To elucidate the effects of maturity and the stem growth habit on the planting density-dependent branching plasticity of soybean cultivars, we studied the branch traits of 12 cultivars or lines planted at different densities (8.3, 16.7, and 22.2 plants m−2) in Sapporo (2012) and Ebetsu (2013). The 12 cultivars and lines consisted of three determinate cultivars from Hokkaido, three indeterminate cultivars from the northern US, and near-isogenic lines with the backgrounds of Canadian, US, and Japanese cultivars exhibiting diverse stem growth habits. We investigated the relationship between the maturity or stem growth habit and branching plasticity, which was calculated based on the ratios of different branch traits under sparse and dense planting conditions. The use of the ratios of the total branch length and the number of nodes per branch under sparse and dense planting conditions as a measure of branching plasticity revealed varietal differences across years. For the determinate and indeterminate cultivars in both years, branching plasticity was positively correlated with the number of days until stage R5 (onset of seed filling), which is when branches cease to elongate. Comparisons of Japanese and US cultivars and near-isogenic lines for the Dt1 gene (mediating the stem growth habit) indicated that the branching plasticity of indeterminate cultivars and lines is greater than that of determinate cultivars, with a large variation among backgrounds and cultivars. The results of this study imply that branching plasticity is greater in late-maturing soybean cultivars. Moreover, the indeterminate growth habit substantially enhances branching plasticity.

Abstract Individuals with Down syndrome (DS) commonly show unique pathological phenotypes throughout their life span. Besides the specific effects of dosage-sensitive genes on chromosome 21, recent studies have demonstrated that the gain of a chromosome exerts an adverse impact on cell physiology, regardless of the karyotype. Although dysregulated transcription and perturbed protein homeostasis are observed in common in human fibroblasts with trisomy 21, 18, and 13, whether and how this aneuploidy-associated stress acts on other cell lineages and affects the pathophysiology are unknown. Here, we investigated cellular stress responses in human trisomy 21 and 13 neurons differentiated from patient-derived induced pluripotent stem cells. Neurons of both trisomies showed increased vulnerability to apoptotic cell death, accompanied by dysregulated protein homeostasis and upregulation of the endoplasmic reticulum stress pathway. In addition, misfolded protein aggregates, comprising various types of neurodegenerative disease-related proteins, were abnormally accumulated in trisomic neurons. Intriguingly, treatment with sodium 4-phenylbutyrate, a chemical chaperone, successfully decreased the formation of protein aggregates and prevented the progression of cell apoptosis in trisomic neurons. These results suggest that aneuploidy-associated stress might be a therapeutic target for the neurodegenerative phenotypes in DS.

Low-branching soybean cultivars have few nodes per plant, and there have been many cases in northern Japan where growing these cultivars at high plant densities did not improve yield. Soybean cultivar ‘Tokei 1122ʹ (T22), which has a long terminal raceme, was bred to improve the yield of low-branching cultivars under dense planting conditions. To elucidate the effects of long racemes on the suitability of T22 for dense planting, we compared the yield and yield components of T22 and ‘Toyoharuka’ (TH), which is a low-branching cultivar, at various planting densities. There was no significant difference in the seed yield of these cultivars at low planting densities, whereas the seed yield of T22 was significantly greater than that of TH under dense planting conditions. The increase in the number of seeds per unit area was greater for T22 than for TH. An analysis of variance revealed a significant interaction between cultivar and planting density for seed yield, number of pods, and number of pods per node. Moreover, the low-branching cultivar ‘Tokei 1122ʹ with long terminal racemes produced a higher yield under non-lodging conditions than the conventional low-branching cultivar at planting densities of 33 plants m−2 or higher. The greater yield of T22 is likely because of its long terminal raceme, which increases the number of pods per node and the sink capacity (number of seeds) at high planting densities.

Objectives To clarify the association between moderate-to-vigorous physical activity (MVPA) and/or sedentary behaviour (SB) and the incidence of functional disability (FD) in older adults.Design Prospective cohort study.Setting Local municipality of Tsuru, Yamanashi, Japan. We conducted a baseline survey in January 2016. Follow-up was commenced on 1 February 2016 and completed on 31 October 2018.Participants All individuals (6661 people) aged >65 years who were independently living in the community were eligible.Methods and outcome measures MVPA (min/week) and SB (min/day) were measured using self-administered questionnaires in 5311 independently living older adults who participated in this study. The follow-up period was 33 months, and the incidence of FD was objectively determined by experts. The participants were divided into three groups based on MVPA distribution (non-MVPA, 0 min; short-MVPA, 1–299 min and long-MVPA, ≥300 min/week) and into two groups based on the median value of SB (short-SB,

Oxidative stress causes various diseases, such as type II diabetes and dyslipidemia, while antioxidants in foods may prevent a number of diseases and delay aging by exerting their effects in vivo. Phenolic compounds are phytochemicals such as flavonoids which consist of flavonols, flavones, flavanonols, flavanones, anthocyanidins, isoflavones, lignans, stilbenoids, curcuminoids, phenolic acids, and tannins. They have phenolic hydroxyl groups in their molecular structures. These compounds are present in most plants, are abundant in nature, and contribute to the bitterness and color of various foods. Dietary phenolic compounds, such as quercetin in onions and sesamin in sesame, exhibit antioxidant activity and help prevent cell aging and diseases. In addition, other kinds of compounds, such as tannins, have larger molecular weights, and many unexplained aspects still exist. The antioxidant activities of phenolic compounds may be beneficial for human health. On the other hand, metabolism by intestinal bacteria changes the structures of these compounds with antioxidant properties, and the resulting metabolites exert their effects in vivo. In recent years, it has become possible to analyze the composition of the intestinal microbiota. The augmentation of the intestinal microbiota by the intake of phenolic compounds has been implicated in disease prevention and symptom recovery. Furthermore, the “brain–gut axis”, which is a communication system between the gut microbiome and brain, is attracting increasing attention, and research has revealed that the gut microbiota and dietary phenolic compounds affect brain homeostasis. In this review, we discuss the usefulness of dietary phenolic compounds with antioxidant activities against some diseases, their biotransformation by the gut microbiota, the augmentation of the intestinal microflora, and their effects on the brain–gut axis.

This study aimed to identify salivary metabolomic biomarkers for predicting the prognosis of oral squamous cell carcinoma (OSCC) based on comprehensive metabolomic analyses. Quantified metabolomics data of unstimulated saliva samples collected from patients with OSCC (n = 72) were randomly divided into the training (n = 35) and validation groups (n = 37). The training data were used to develop a Cox proportional hazards regression model for identifying significant metabolites as prognostic factors for overall survival (OS) and disease-free survival. Moreover, the validation group was used to develop another Cox proportional hazards regression model using the previously identified metabolites. There were no significant between-group differences in the participants’ characteristics, including age, sex, and the median follow-up periods (55 months [range: 3–100] vs. 43 months [range: 0–97]). The concentrations of 5-hydroxylysine (p = 0.009) and 3-methylhistidine (p = 0.012) were identified as significant prognostic factors for OS in the training group. Among them, the concentration of 3-methylhistidine was a significant prognostic factor for OS in the validation group (p = 0.048). Our findings revealed that salivary 3-methylhistidine is a prognostic factor for OS in patients with OSCC.

Abstract Background Circulating endotoxins including lipopolysaccharides (LPS) cause brain responses such as fever and decrease of food and water intake, while pre-injection of endotoxins attenuates these responses. This phenomenon is called endotoxin tolerance, but the mechanisms underlying it remain unclear. The subfornical organ (SFO) rapidly produces proinflammatory cytokines including interleukin-1β (IL-1β) in response to peripherally injected LPS, and repeated LPS injection attenuates IL-1β production in the SFO, indicating that the SFO is involved in endotoxin tolerance. The purpose of this study is to investigate features of the IL-1β source cells in the SFO of LPS-non-tolerant and LPS-tolerant mice. Methods We first established the endotoxin-tolerant mouse model by injecting LPS into adult male mice (C57BL/6J). Immunohistochemistry was performed to characterize IL-1β-expressing cells, which were perivascular macrophages in the SFO. We depleted perivascular macrophages using clodronate liposomes to confirm the contribution of IL-1β production. To assess the effect of LPS pre-injection on perivascular macrophages, we transferred bone marrow-derived cells obtained from male mice (C57BL/6-Tg (CAG-EGFP)) to male recipient mice (C57BL/6N). Finally, we examined the effect of a second LPS injection on IL-1β expression in the SFO perivascular macrophages. Results We report that perivascular macrophages but not parenchymal microglia rapidly produced the proinflammatory cytokine IL-1β in response to LPS. We found that peripherally injected LPS localized in the SFO perivascular space. Depletion of macrophages by injection of clodronate liposomes attenuated LPS-induced IL-1β expression in the SFO. When tolerance developed to LPS-induced sickness behavior in mice, the SFO perivascular macrophages ceased producing IL-1β, although bone marrow-derived perivascular macrophages increased in number in the SFO and peripherally injected LPS reached the SFO perivascular space. Conclusions The current data indicate that perivascular macrophages enable the SFO to produce IL-1β in response to circulating LPS and that its hyporesponsiveness may be the cause of endotoxin tolerance.

Oxidative stress causes the progression of diabetes and its complications; thus, maintaining the balance between reactive oxygen species produced by hyperglycemia and the antioxidant defense system is important. We herein examined the antioxidant potential of non-extractable fractions of dried persimmon (NEP) against oxidative stress in diabetic rats. Rats with streptozotocin-induced type 1 diabetes (50 mg/kg body weight) were administered NEP for 9 weeks. Antioxidant enzyme activities and concentration of antioxidants in liver tissues were analyzed with a microplate reader. Extensor digitorum longus (EDL) and soleus muscle fibers were stained with succinate dehydrogenase and muscle fiber sizes were measured. The administration of NEP increased the body weight of diabetes rats. Regarding antioxidant activities, the oxygen radical absorbance capacity and superoxide dismutase activity in liver tissues significantly increased. In addition, increases in glutathione peroxidase activity in liver tissues and reductions in the cross-sectional area of EDL muscle fibers were significantly suppressed. In these results, NEP improved the antioxidant defense system in the liver tissues of diabetic rats, in addition to attenuating of muscle fibers atrophy against oxidative damage induced by hyperglycemia.

Core Ideas Five Canadian soybean cultivars achieved high yields in Hokkaido, northern Japan, in screening tests. OAC Dorado soybean produced a significantly greater yield than a Hokkaido's leading cultivar. OAC Dorado soybean had six characteristics that were distinct from the Hokkaido cultivars. OAC Dorado soybean is an important germplasm for high‐yield breeding. The broadening of genetic diversity is essential to improving soybean [Glycine max (L.) Merr.] seed yields, and exotic germplasms can be a source of new alleles that improve yield. The stem termination habit is an important trait affecting seed yield in soybean, and this habit can be used to classify soybean into indeterminate, semi‐determinate, and determinate phenotypes. The genetic background and environment determine whether indeterminate phenotypes have a higher yield than determinate phenotypes. Most soybean cultivars developed in high latitude countries such as Canada, Switzerland, and Poland have an indeterminate growth habit, but this is not found in any of the commercial Japanese cultivars. This study investigated high‐yielding Canadian soybean cultivars growing in Hokkaido, northern Japan. Five Canadian cultivars, Haroson, RCAT Angora, Block, RCAT Alliance, and OAC Dorado, produced significantly greater than Hokkaido's leading cultivar Yukihomare in the preliminary screening tests. OAC Dorado also produced a significantly greater yield than Yukihomare in the trials (116%). OAC Dorado had six characteristics that were distinct from the Hokkaido cultivars: an indeterminate growth habit; high pod number, especially on branches; high seed number per pod; long reproductive period; low protein content; and short lower internodes. Our findings indicate that OAC Dorado is an important germplasm for high‐yield breeding and suggest that it may be possible to breed a high‐yielding cultivar with an indeterminate growth habit in Hokkaido.