Transcription factor Tox2 is required for metabolic adaptation and tissue residency of ILC3 in the gut.

Group 3 innate lymphoid cells (ILC3) are the major subset of gut-resident ILC with essential roles in infections and tissue repair, but how they adapt to the gut environment to maintain tissue residency is unclear. We report that Tox2 is critical for gut ILC3 maintenance and function. Gut ILC3 highly expressed Tox2, and depletion of Tox2 markedly decreased ILC3 in gut but not at central sites, resulting in defective control of Citrobacter rodentium infection. Single-cell transcriptional profiling revealed decreased expression of Hexokinase-2 in Tox2-deficient gut ILC3. Consistent with the requirement for hexokinases in glycolysis, Tox2-/- ILC3 displayed decreased ability to utilize glycolysis for protein translation. Ectopic expression of Hexokinase-2 rescued Tox2-/- gut ILC3 defects. Hypoxia and interleukin (IL)-17A each induced Tox2 expression in ILC3, suggesting a mechanism by which ILC3 adjusts to fluctuating environments by programming glycolytic metabolism. Our results reveal the requirement for Tox2 to support the metabolic adaptation of ILC3 within the gastrointestinal tract.

Epithelial-derived interleukin-23 promotes oral mucosal immunopathology.

At mucosal surfaces, epithelial cells provide a structural barrier and an immune defense system. However, dysregulated epithelial responses can contribute to disease states. Here, we demonstrated that epithelial cell-intrinsic production of interleukin-23 (IL-23) triggers an inflammatory loop in the prevalent oral disease periodontitis. Epithelial IL-23 expression localized to areas proximal to the disease-associated microbiome and was evident in experimental models and patients with common and genetic forms of disease. Mechanistically, flagellated microbial species of the periodontitis microbiome triggered epithelial IL-23 induction in a TLR5 receptor-dependent manner. Therefore, unlike other Th17-driven diseases, non-hematopoietic-cell-derived IL-23 served as an initiator of pathogenic inflammation in periodontitis. Beyond periodontitis, analysis of publicly available datasets revealed the expression of epithelial IL-23 in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human disease. Collectively, this work highlights an important role for the barrier epithelium in the induction of IL-23-mediated inflammation.

Deficiency of G protein-coupled receptor Gpr111/Adgrf2 causes enamel hypomineralization in mice by alteration of the expression of kallikrein-related peptidase 4 (Klk4) during pH cycling process.

Enamel is formed by the repetitive secretion of a tooth-specific extracellular matrix and its decomposition. Calcification of the enamel matrix via hydroxyapatite (HAP) maturation requires pH cycling to be tightly regulated through the neutralization of protons released during HAP synthesis. We found that Gpr115, which responds to changes in extracellular pH, plays an important role in enamel formation. Gpr115-deficient mice show partial enamel hypomineralization, suggesting that other pH-responsive molecules may be involved. In this study, we focused on the role of Gpr111/Adgrf2, a duplicate gene of Gpr115, in tooth development. Gpr111 was highly expressed in mature ameloblasts. Gpr111-KO mice showed enamel hypomineralization. Dysplasia of enamel rods and high carbon content seen in Gpr111-deficient mice suggested the presence of residual enamel matrices in enamel. Depletion of Gpr111 in dental epithelial cells induced the expression of ameloblast-specific protease, kallikrein-related peptidase 4 (Klk4), suggesting that Gpr111 may act as a suppressor of Klk4 expression. Moreover, reduction of extracellular pH to 6.8 suppressed the expression of Gpr111, while the converse increased Klk4 expression. Such induction of Klk4 was synergistically enhanced by Gpr111 knockdown, suggesting that proper enamel mineralization may be linked to the modulation of Klk4 expression by Gpr111. Furthermore, our in vitro suppression of Gpr111 and Gpr115 expression indicated that their suppressive effect on calcification was additive. These results suggest that both Gpr111 and Gpr115 respond to extracellular pH, contribute to the expression of proteolytic enzymes, and regulate the pH cycle, thereby playing important roles in enamel formation.

G protein-coupled receptor Gpr115 (Adgrf4) is required for enamel mineralization mediated by ameloblasts.

Dental enamel, the hardest tissue in the human body, is derived from dental epithelial cell ameloblast-secreted enamel matrices. Enamel mineralization occurs in a strictly synchronized manner along with ameloblast maturation in association with ion transport and pH balance, and any disruption of these processes results in enamel hypomineralization. G protein-coupled receptors (GPCRs) function as transducers of external signals by activating associated G proteins and regulate cellular physiology. Tissue-specific GPCRs play important roles in organ development, although their activities in tooth development remain poorly understood. The present results show that the adhesion GPCR Gpr115 (Adgrf4) is highly and preferentially expressed in mature ameloblasts and plays a crucial role during enamel mineralization. To investigate the in vivo function of Gpr115, knockout (Gpr115-KO) mice were created and found to develop hypomineralized enamel, with a larger acidic area because of the dysregulation of ion composition. Transcriptomic analysis also revealed that deletion of Gpr115 disrupted pH homeostasis and ion transport processes in enamel formation. In addition, in vitro analyses using the dental epithelial cell line cervical loop-derived dental epithelial (CLDE) cell demonstrated that Gpr115 is indispensable for the expression of carbonic anhydrase 6 (Car6), which has a critical role in enamel mineralization. Furthermore, an acidic condition induced Car6 expression under the regulation of Gpr115 in CLDE cells. Thus, we concluded that Gpr115 plays an important role in enamel mineralization via regulation of Car6 expression in ameloblasts. The present findings indicate a novel function of Gpr115 in ectodermal organ development and clarify the molecular mechanism of enamel formation.

Fibulin-7 C-terminal fragment and its active synthetic peptide suppress choroidal and retinal neovascularization.

Wet age-related macular degeneration (AMD) and diabetic retinopathy are the leading causes of blindness through increased angiogenesis. Although VEGF-neutralizing proteins provide benefit, inconsistent responses indicate a need for new therapies. We previously identified the Fibulin-7 C-terminal fragment (Fbln7-C) as an angiogenesis inhibitor in vitro. Here we show that Fbln7-C inhibits neovascularization in vivo, in both a model of wet AMD involving choroidal neovascularization (CNV) and diabetic retinopathy involving oxygen-induced ischemic retinopathy. Furthermore, a short peptide sequence from Fbln7-C is responsible for the anti-angiogenic properties of Fbln7-C. Our work suggests Fbln7-C as a therapeutic candidate for wet AMD and ischemic retinopathy.

[Impact of lifestyle-related diseases and frailty on the incidence of loss of independence in Japanese community-dwelling older adults: A Longitudinal Study on Aging and Health in Kusatsu].

Objectives　This study aimed to determine risk factors for frailty and lifestyle-related diseases impacting the incidence of loss of independence among Japanese community-dwelling older adults, and to measure the magnitude of these associations.Methods　We conducted an 8.1-year prospective study involving 1,214 residents of the town of Kusatsu, aged 65 years and over, who were initially free of disability and underwent the comprehensive geriatric assessment between 2002 and 2011. Loss of independence was defined as the incidence of disability or having died before the occurrence of disability was certified by the Long-Term Care Insurance program in Japan. Risk factors for lifestyle-related diseases and health status comprised hypertension, diabetes mellitus, overweight, chronic kidney disease, current smoking, past history of stroke, heart disease and cancer, frailty, underweight, anemia, hypoalbuminemia, and cognitive decline. Frailty was defined as the presence of three or more of the following criteria: Weight loss, weakness, exhaustion, slowness, and low levels of physical activity. Prefrailty was defined as the presence of one or two of these same criteria. Cox proportional-hazard regression model was used to estimate hazard ratios (HR) and the population attributable fraction (PAF) of loss of independence.Results　During the follow-up, 475 cases, including 372 disabilities and 103 deaths, were identified as having experienced loss of independence. The multivariable HRs for the loss of independence were 1.3 to 2.2-fold higher for the presence of frailty, past history of stroke, cognitive decline, prefrailty, and smoking. The PAF of loss of independence was the greatest for prefrailty (19%), followed by frailty (12%). The PAF was relatively large for prefrailty (19%) and smoking (11%) in men, and frailty (18%), prefrailty (18%), and chronic kidney disease (11%) in women. Stratified by age category, participants aged 65-74 years having frailty and several lifestyle-related diseases showed significantly higher HRs for loss of independence and greater PAFs for prefrailty (18%), frailty (13%), and smoking (11%).Conclusions　Loss of independence among Japanese community-dwelling older adults who underwent screening examinations was largely attributed to frailty and prefrailty. Our findings suggest that the screening and the intervention for frailty and lifestyle-related diseases in the early stages of old age might be beneficial in prolonging healthy life expectancy of Japanese community-dwelling older adults.

Fibulin-7 is overexpressed in glioblastomas and modulates glioblastoma neovascularization through interaction with angiopoietin-1.

Glioblastoma (GBM) is pathologically characterized by highly malignant neoplastic cells, focal necrosis and aberrant blood vessels composed of disorganized endothelial cells and pericytes. The recent cancer microarray database revealed upregulation of fibulin-7 (Fbln7), a member of the fibulin family, but provided no information on the tissue localization or biological function. In the present study, we demonstrated that Fbln7 is markedly overexpressed by the GBM tissue among astrocytic tumors, and immunolocalized mainly to endothelial cells and pericytes of the glomeruloid and hypertrophied microvessels. The production of Fbln7 by endothelial cells and pericytes was confirmed in cultured human umbilical vein endothelial cells (HUVEC) and human brain vascular pericytes (HBVP) and vascular endothelial growth factor (VEGF) stimulated the Fbln7 expression in HUVEC. Fbln7 bound to angiopoietin-1, but not angiopoietin-2 or Tie2 receptor, through interaction between the N-terminal portions of Fbln7 and angiopoietin-1, and it blocked phosphorylation of Tie2 receptor in HUVEC. In a coculture assay using HUVEC and HBVP, multilayered and irregular-shaped tube-like structures of HUVEC were induced by treatment with a high concentration of VEGF. This was accompanied by Fbln7 overproduction by HUVEC and angiopoietin-1 expression by HBVP. The production of aberrant VEGF-induced tube-like structures was attenuated by treatment with antibody or synthetic peptides specific to the Fbln7 N-terminal domain or knockdown of Fbln7. These data demonstrate that Fbln7 is overexpressed by endothelial cells and pericytes of the abnormal microvessels in GBM, and suggest that Fbln7 may contribute to the aberrant vessel formation by modulation of the angiopoietin-1/angiopoietin-2-Tie2 axis.

Cell adhesion protein fibulin-7 and its C-terminal fragment negatively regulate monocyte and macrophage migration and functions in vitro and in vivo.

Fibulin-7 (Fbln7) has been identified as the latest member of the fibulin family of secreted glycoproteins in developing teeth, functioning as a cell adhesion molecule and interacting with other matrix proteins, receptors, and growth factors. More recently, we have shown that the C-terminal Fbln7 fragment (Fbln7-C) has antiangiogenic activity in vitro. Fbln7 is also expressed in immune-privileged tissues, such as eye and placenta, but its functional significance is unknown. In the current study, we show that human monocytes adhere to both full-length Fbln7 (Fbln7-FL) and Fbln7-C, in part, via integrins α5ß1 and α2ß1. Morphologic studies and surface expression analyses of CD14, mannose receptor (CD206), major histocompatibility complex II, and CD11b receptors revealed that both Fbln7-FL and Fbln7-C inhibit M-CSF-induced monocyte differentiation. Fbln7-C had significantly greater negative effects on cell spreading and stress fiber formation, including the production of IL-6 and metalloproteinase-1/-9 compared with Fbln7-FL. Furthermore, in an LPS-induced systemic inflammation model, Fbln7-C and Fbln7-FL reduced the infiltration of immune cells, such as neutrophils and macrophages, to the inflamed peritoneum. Thus, these results suggest that Fbln7 and Fbln7-C could modulate the activity of immune cells and have therapeutic potential for inflammatory diseases.-Sarangi, P. P., Chakraborty, P., Dash, S. P., Ikeuchi, T., de Vega, S., Ambatipudi, K., Wahl, L., Yamada, Y. Cell adhesion protein fibulin-7 and its C-terminal fragment negatively regulate monocyte and macrophage migration and functions in vitro and in vivo.

Albumin and Hemoglobin Trajectories and Incident Disabling Dementia in Community-Dwelling Older Japanese.

BACKGROUND: Serum albumin and hemoglobin levels are independently associated with subsequent cognitive deterioration in older adults. This prospective study used repeated measures analysis to identify aging trajectories in serum albumin and hemoglobin levels and investigated if these trajectories were associated with incident disabling dementia among community-dwelling older Japanese. METHODS: A total of 2,005 adults aged 65-90 years participated in annual geriatric health assessments during the period from June 2002 through July 2017; the total number of observations was 9,330. A review of a municipal database of the Japanese public long-term care insurance system identified 1,999 of 2,005 adults without dementia at baseline, 278 (13.9%) of whom developed disabling dementia during the follow-up period (June 2002 through December 2017). RESULTS: We identified three trajectory patterns (high, moderate, and low) for serum albumin and hemoglobin levels for the age period 65 through 90 years. After controlling for potential confounders, participants with moderate and low trajectories for serum albumin level had hazard ratios of 1.27 (95% confidence interval 0.94-1.72) and 2.07 (1.37-3.11), respectively, for the development of incident disabling dementia, with the high trajectory group as reference. The respective hazard ratios for hemoglobin level were 1.31 (0.93-1.85) and 1.58 (1.04-2.40), respectively. CONCLUSION: Dementia risk was higher for individuals with low trajectories for serum albumin and hemoglobin levels. This finding highlights the importance of interventions that improve nutritional status and control relevant diseases in middle-aged and older adults with low serum albumin and hemoglobin levels.

Frequency of Balanced-Meal Consumption and Frailty in Community-Dwelling Older Japanese: A Cross-Sectional Study.

BACKGROUND: Although meals that combine a staple food, main dish, and side dish (balanced meals) are recommended in Japan, the health effects of such meals are unclear. We investigated the association of frequency of eating balanced meals with frailty among community-dwelling older Japanese. METHODS: We analyzed data from 912 persons aged 65 years or older who participated in the Hatoyama Cohort Study or Kusatsu Longitudinal Study. The frequency of eating two or more balanced meals daily was self-reported as ≤1 day/week, 2 or 3 days/week, 4 or 5 days/week, and daily. Frailty was defined as the presence of at least three, and pre-frailty as the presence of one or two, of the following criteria: weight loss, muscle weakness, exhaustion, slowness, and low physical activity. Adjusted logistic regression was used to study associations of frequency of balanced-meal consumption with frailty (prefrailty and frailty combined) and frailty criteria. RESULTS: Participants reporting a frequency of balanced-meal consumption of ≤2 or 3 days/week had a higher prevalence of frailty (odds ratio [OR], 1.79; 95% confidence interval [CI], 1.21-2.64) than did those reporting a frequency of daily. Lower frequency of balanced-meal consumption was also associated with higher prevalences of weight loss (OR, 4.10; 95% CI, 1.90-8.85), exhaustion (OR, 6.35; 95% CI, 2.49-16.17), and low physical activity (OR, 1.92; 95% CI, 1.22-3.01). CONCLUSIONS: Our findings suggest that more frequent twice daily consumption of meals with a staple food, main dish, and side dish decreases the risks of prefrailty and frailty.

A Community-Wide Intervention Trial for Preventing and Reducing Frailty Among Older Adults Living in Metropolitan Areas: Design and Baseline Survey for a Study Integrating Participatory Action Research With a Cluster Trial.

BACKGROUND: Preventing and reducing frailty is an important challenge for Japan in the next decade, especially in metropolitan areas. We launched a community-wide intervention trial (the Ota Genki Senior Project) in 2016 to develop effective community-based strategies for frailty prevention in metropolitan areas. This report describes the study design and baseline survey. METHODS: This study is a community-wide intervention trial that integrates participatory action research into a cluster non-randomized controlled trial for adults aged 65 years or older living in Ota City, Tokyo. We allocated 3 of 18 districts to an intervention group and the other 15 to a control group. Using a mailed self-administered questionnaire, we conducted a baseline survey of 15,500 residents (8,000 and 7,500 in the intervention and control groups, respectively) from July through August 2016. In addition to socioeconomic status and lifestyle variables, we assessed frailty status (primary outcome) and physical, nutritional, and psychosocial variables (secondary outcomes). Based on the baseline findings, an intervention to improve outcomes will be implemented as participatory action research. Follow-up surveys will be conducted in the same manner as the baseline survey. RESULTS: A total of 11,925 questionnaires were returned (76.9% response rate; 6,105 [76.3%] and 5,820 [77.6%] in the intervention and control groups, respectively), and 11,701 were included in the analysis (mean age, 74.3 [standard deviation, 5.5] years; 48.5% were men). CONCLUSIONS: This study is expected to contribute to development of a prototype of a community-wide frailty prevention strategy, especially in metropolitan areas in Japan. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000026515).

Pannexin 3 and connexin 43 modulate skeletal development through their distinct functions and expression patterns.

Pannexin 3 (Panx3) and connexin 43 (Cx43; also known as GJA1) are two major gap junction proteins expressed in osteoblasts. Here, we studied their functional relationships in skeletal formation by generating Panx3(-/-) and Panx3(-/-);Cx43(-/-) mice and comparing their skeletal phenotypes with Cx43(-/-) mice. Panx3(-/-) mice displayed defects in endochondral and intramembranous ossification, resulting in severe dwarfism and reduced bone density. The skeletal abnormalities of Panx3(-/-);Cx43(-/-) mice were similar to those in Panx3(-/-) mice. The gross appearance of newborn Cx43(-/-) skeletons showed no obvious abnormalities, except for less mineralization of the skull. In Panx3(-/-) mice, proliferation of chondrocytes and osteoblasts increased and differentiation of these cells was inhibited. Panx3 promoted expression of osteogenic proteins such as ALP and Ocn (also known as ALPL and BGLAP, respectively), as well as Cx43, by regulating Osx (also known as SP7) expression. Panx3 was induced in the early differentiation stage and reduced during the maturation stage of osteoblasts, when Cx43 expression increased in order to promote mineralization. Furthermore, only Panx3 functioned as an endoplasmic reticulum (ER) Ca(2+) channel to promote differentiation, and it could rescue mineralization defects in Cx43(-/-) calvarial cells. Our findings reveal that Panx3 and Cx43 have distinct functions in skeletal formation.

Individual- and community-level neighbor relationships and physical activity among older Japanese adults living in a metropolitan area: a cross-sectional multilevel analysis.

BACKGROUND: Informal neighbor relationships (NRs) are considered a structural aspect of social relationships. Although NRs might affect physical activity (PA), no previous study has simultaneously examined compositional and contextual associations of NRs with PA. In this study, we examined whether individual- and community-level NRs were independently associated with PA. METHODS: We analyzed cross-sectional data from 8592 (4340 men and 4252 women) non-disabled residents aged 65-84 years from all 18 districts of Ota City, Tokyo. PA was assessed by using the International Physical Activity Questionnaire-Short Form. In addition, we calculated moderate-to-vigorous PA (MVPA), its components (vigorous PA [VPA], moderate PA [MPA], and walking time [WT]), and sitting time (ST). Individual-level NRs were categorized as "visiting each other," "standing and chatting," "exchange of greetings," or "none." Community-level NRs were defined as the proportions of residents with active NRs (i.e., those in the categories visiting each other and standing and chatting) in the 18 districts. Using multilevel regression analyses, we examined independent associations of individual- and community-level NRs with PA variables and adjusted for important confounders. RESULTS: Individual-level NRs were consistently positively associated with MVPA and its components (VPA, MPA [in men], and WT) in both sexes, and the dose-response relationships were significant (all P < 0.041 for trend). In men, community-level NRs (by 1% estimation) were positively associated with individual MVPA (2.1 metabolic equivalent-hours/week, 95% confidence interval: 0.7-3.4), VPA (8.6 min/week, 2.7-14.4), and WT (11.6 min/week, 2.2-20.9), regardless of the degree of individual-level NRs. Significant cross-level interactions of NRs with MVPA and VPA were observed among men, and the dose-response relationships were significant (both P < 0.037 for trend). Neither individual- nor community-level NRs were associated with ST in either sex. CONCLUSIONS: Men and women with inaccessible neighbors engaged in less MVPA, while men living in communities with active NRs engaged in more MVPA, regardless of individual-level NRs. NRs at the individual and community level might help prevent physical inactivity among men.

Higher education in gerontology: A comparison of master's programs in Japan, Taiwan, and Turkey.

As of 2015, there is only one master's program of gerontology acknowledged by each of the following countries: Japan, Taiwan, and Turkey. All three programs have fewer than 15 years of history. These three countries differ in society types based on the proportion of older adults, rate of population aging, and population size. However, in terms of gerontological education, they seem to share great commonalities. Common challenges are a lack of awareness of the field of gerontology, insufficient numbers of gerontology programs and faculty members to produce trained gerontologists within society, and the inadequacy of opportunities for trained gerontologists to play an active role in various fields. This study intends not only to compare the differences and similarities among three countries and programs, but also to elucidate characteristics of a unique gerontology program in each country and identify challenges and possibilities from the perspective of gerontological educators.

Identification of peptides derived from the C-terminal domain of fibulin-7 active for endothelial cell adhesion and tube formation disruption.

Despite the research done on pathological angiogenesis, there is still a need for the development of new therapies against angiogenesis-related diseases. Fibulin-7 (Fbln7) is a member of the extracellular matrix fibulin protein family. The Fbln7 C-terminal fragment, Fbln7-C, binds to endothelial cells and inhibits their tube formation in culture. In this study, we screened 12 synthetic peptides, covering the fibulin-globular domain of Fbln7-C, to identify active sites for endothelial cell adhesion and in vitro antiangiogenic activity. Three peptides, fc10, fc11, and fc12, promoted Human Umbilical Vein Endothelial Cells (HUVECs) adhesion, and the morphology of HUVECs on fc10 was similar to that on Fbln7-C. EDTA and the anti-integrin ß1 function-blocking antibody inhibited HUVECs adhesion to both fc10 and fc12, and heparin inhibited HUVECs adhesion to both fc11 and fc12. fc10 and fc11 inhibited HUVECs tube formation. Our results suggest that three peptides from Fbln7-C are biologically active for endothelial cell adhesion and disrupt the tube formation, suggesting a potential therapeutic use of these peptides for angiogenesis-related diseases. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 184-195, 2016.

Dissociation of murine oral mucosal tissues for single cell applications.

Single-cell RNA sequencing and flow cytometry approaches have been instrumental in understanding cellular states within various tissues and organs. However, tissue dissociation methods can potentially alter results and create bias due to preferential recovery of particular cell types. Here we present efforts to optimize methods for dissociation of murine oral mucosal tissues and provide three different protocols that can be utilized to isolate major cell populations in the oral mucosa. These methods can be used both in health and in states of inflammation, such as periodontitis. The optimized protocols use different enzymatic approaches (collagenase II, collagenase IV and the Miltenyi whole skin dissociation kit) and yield preferential recovery of immune, stromal and epithelial cells, respectively. We suggest choosing the dissociation method based on the cell population of interest to study, while understanding the limitations of each approach.

Exploratory study on the factors related with the early detection of missing older persons with dementia living alone in Japan.

AIM: To clarify the factors related to the early detection of missing older persons with dementia (PwD) who lived alone in Japan. METHODS: We carried out a multiple regression analysis with data from 88 missing PwD. RESULTS: The location of the discovery was within the municipality where the missing PwD lived. Furthermore, the use of long-term care insurance services was significantly associated with early detection. CONCLUSION: Missing PwD were located within the municipality in which they lived, which meant that the individual was found before they went far. In addition, with the long-term care insurance services, professionals should regularly visit the home of PwD according to a care plan. Planned regular visits might trigger the early recognition of a missing person with dementia and enable early search activities. Therefore, use of long-term care insurance services might lead to the early detection of missing PwD living alone. Geriatr Gerontol Int 2023; 23: 362-365.

Does Smartphone Use Make Older Adults Feel Younger? A Cross-Sectional Online Survey during the COVID-19 Pandemic.

Subjective age (i.e., how old one feels) has been found to be a biopsychosocial marker of aging. This study examined the associations between subjective age and the frequency of information and communication technology (ICT) usage by older adults. Data were collected via an online survey conducted in 2020 during the COVID-19 pandemic. The study analyzed responses from participants aged 65 to 89 (M = 71.9, SD = 3.9) who resided in Japan (N = 1631, 52.8% female). Subjective age was indexed by asking participants to specify in years how old they felt. Proportional discrepancy scores (PDS) were calculated to indicate younger or older subjective age and were used as an independent variable. Participants were asked about the frequency of computer, smartphone, flip phone, tablet, and social networking service (SNS) use. Two-thirds of the participants (63.6%) reported feeling younger than their actual age. Nearly 90% reported using computers for more than 2-3 days a week, while 64.3% reported smartphone use, 22.9% reported flip phone use, and 36.6% reported SNS use. Logistic regression analyses revealed that a lower PDS (i.e., feeling younger) was associated with a significantly higher frequency of smartphone use (OR: 0.77; 95% CI: 0.60, 0.98) after adjusting for potential confounders. No such association was found for computer, flip phone, tablet, or SNS use. Our study found that feeling younger was associated with a higher frequency of smartphone use. The daily use of smartphones may have helped older adults stay in touch with family and friends and obtain the information that they needed, which may have contributed to better psychological well-being outcomes, especially during the COVID-19 pandemic.

Protective effects of dog ownership against the onset of disabling dementia in older community-dwelling Japanese: A longitudinal study.

This prospective study examined the associations of dog/cat ownership with incident disabling dementia using propensity score matching based on the physical, social, and psychological characteristics of dog and cat owners. We also examined associations of the interaction between dog/cat ownership and exercise habit and social isolation with dementia. Overall, 11,194 older adults selected using stratified and random sampling strategies in 2016 were analyzed. Dog/cat ownership was defined as "current" or "past and never". Disabling dementia was defined according to physicians' rating in the long-term care insurance system in Japan during the approximately 4-year follow-up period. Statistical analysis was weighted by the inverse of the propensity score in the generalized estimating equation after adjusting for follow-up period. Current dog owners (8.6 %) had an odds ratio (OR) of 0.60 (95 %CI: 0.37-0.977) of having disabling dementia compared to past and never owners. For cat ownership, the corresponding OR was 0.98 (95 %CI: 0.62-1.55). Current dog owners with a regular exercise habit had an OR of 0.37 (0.20-0.68) compared to past and never dog owners with no exercise habit. Further, current dog owners with no social isolation had an OR of 0.41 (0.23-0.73) compared to past and never dog owners with social isolation. Dog ownership had a suppressive effect on incident disabling dementia after adjusting for background factors over a 4-year follow-up period. Specifically, dog owners with an exercise habit and no social isolation had a significantly lower risk of disabling dementia.

Neutrophil extracellular traps and extracellular histones potentiate IL-17 inflammation in periodontitis.

Neutrophil infiltration is a hallmark of periodontitis, a prevalent oral inflammatory condition in which Th17-driven mucosal inflammation leads to destruction of tooth-supporting bone. Herein, we document that neutrophil extracellular traps (NETs) are early triggers of pathogenic inflammation in periodontitis. In an established animal model, we demonstrate that neutrophils infiltrate the gingival oral mucosa at early time points after disease induction and expel NETs to trigger mucosal inflammation and bone destruction in vivo. Investigating mechanisms by which NETs drive inflammatory bone loss, we find that extracellular histones, a major component of NETs, trigger upregulation of IL-17/Th17 responses, and bone destruction. Importantly, human findings corroborate our experimental work. We document significantly increased levels of NET complexes and extracellular histones bearing classic NET-associated posttranslational modifications, in blood and local lesions of severe periodontitis patients, in the absence of confounding disease. Our findings suggest a feed-forward loop in which NETs trigger IL-17 immunity to promote immunopathology in a prevalent human inflammatory disease.