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Few studies have focused on a relationship between the built environment and musculoskeletal pain. This study aimed to investigate an association between neighborhood walkability and knee and low back pain in older people. Data were derived from the Japan Gerontological Evaluation Study (JAGES) 2013, a population-based study of independently living people ≥65 years old. A cross-sectional multilevel analysis was performed, of 22,892 participants in 792 neighborhoods. Neighborhood walkability was assessed by residents' perceptions and population density. Dependent variables were knee and low back pain restricting daily activities within the past year. The prevalence of knee pain was 26.2% and of low back pain 29.3%. After adjusting for sociodemographic covariates, the prevalence ratio (PR) of knee and low back pain was significantly lower in neighborhoods with better access to parks and sidewalks, good access to fresh food stores, and higher population densities. After additionally adjusting for population density, easier walking in neighborhoods without slopes or stairs was significantly inversely correlated with knee pain (PR 0.91, 95% confidence interval 0.85-0.99). Neighborhoods with walkability enhanced by good access to parks and sidewalks and fresh food stores, easy walking without slopes or stairs, and high population densities, had lower prevalences of knee and low back pain among older people. Further studies should examine environmental determinants of pain.

Purpose: Community-level group participation is a structural aspect of social capital that may have a contextual influence on individual health. We investigated the contextual effect of community-level prevalence of sports group participation on the risk of cognitive impairment among older individuals., Methods: We analyzed prospective cohort data from the Japan Gerontological Evaluation Study, a nationwide survey of 40,308 functionally independent older individuals from 346 communities. Cognitive impairment was assessed by the nationally standardized dementia scale proposed by the Ministry of Health, Labour and Welfare of Japan. Participation in a sports group 1 d per month or more frequently was defined as "participation." We applied a two-level multilevel survival analysis to calculate hazard ratios (HR) and 95% confidence intervals (CI)., Results: The cumulative incidence of cognitive impairment during the 6-yr follow-up period was 9.8%. The mean proportion of sports group participation was 25.2% (range, 0.0%-56.5%). Higher prevalence of community-level sports group participation was associated with a lower risk of cognitive impairment (HR, 0.92; 95% CI, 0.86-0.99, estimated by 10 percentage points of participation proportion) after adjusting for individual-level sports group participation, sex, age, disease, obesity, social isolation, alcohol, smoking, education, income, depression, daily walking time, population density, and sunlight hours. We found cross-level interaction between individual- and community-level sports group participation (HR, 0.87; 95% CI, 0.76-0.99)., Conclusions: We found a contextual preventive effect of community-level sports group participation on developing cognitive impairment among older individuals. Furthermore, the benefit may favor sports group participants. Therefore, promoting sports groups in a community setting may be effective as a population-based strategy for the prevention of dementia.

Recently, people have become increasingly aware of potential health issues related to indoor environments. In this study, we measure the concentrations of various volatile organic compounds, carbonyl compounds, and semi-volatile organic compounds, as well as the ventilation rates, in 49 new houses with light-gauge steel structures one week after completion. The proper indoor air quality of new residential environments can be ensured by characterizing people's exposure to certain chemicals and assessing future risks. Our results show that the concentrations of the measured compounds were lower than the guideline values set by the Ministry of Health, Labour and Welfare of Japan, and would continue to decrease. However, we observed that unregulated compounds, assumed to be substitutes for regulated solvents, contributed substantially to the total volatile organic compounds. To reduce indoor chemical exposure risks, the concentrations of these unregulated compounds should also be minimized. In addition, their sources need to be identified, and manufacture and use must be monitored. We believe it is important to select low-emission building materials for reducing residents' exposure to indoor chemicals.

This study sought to clarify the association between food store availability and the incidence of disability in older adults. This study utilized a population-based cohort study of independent Japanese adults aged ≥65 years, which was a 6 year follow-up of participants in the Japan Gerontological Evaluation Study. A total of 31,273 respondents were extracted. Food store availability was evaluated based on the existence of food stores within 500/1000 m of the home. We utilized participant-reported subjective measurement as well as geographic information system-based objective measurement for the evaluation. The incidence of disability was determined using municipal data on eligibility for long-term care insurance benefits. There were 7643 (24.4%) community-dwelling participants with low subjective food store availability and 5673 (18.1%) with low objective food store availability. During the follow-up period of 6 years, the cumulative incidence of disability was 20.9%, with a significant association between low subjective food store availability and increased disability. Participants who reported low subjective food store availability had a significantly higher likelihood of developing disability (hazard ratio = 1.18, 95% confidence interval: 1.11-1.25) than those who reported high subjective food store availability after adjusting for age, sex, sociodemographic status, environmental status, walking and going out, dietary food intake, body mass index, and comorbidities. Low subjective food store availability was associated with early onset of disability. Accessibility of food stores might contribute to maintaining a disability-free life., Competing Interests: The authors declare no conflicts of interest.

Mobility management is a transportation policy aiming to change travel behavior from car use to sustainable transportation modes while increasing people's physical activity. Providing pedometers and visualizing step counts, popular interventions in public health practice, may constitute a mobility management program. However, the ease of modal shifts and changeability of walking habits differ across neighborhood environments. Using questionnaire data from 2023 middle-aged and older participants from Yokohama, Japan, in May 2017, this study examined (1) the relationship between the physical and social environments of Yokohama Walking Point Program participants who volunteered to use free pedometers and their modal shifts from cars to walking and public transport, and (2) whether participants' modal shifts were associated with increases in step counts. Multivariate categorical regression analyses identified the frequency of greetings and conversations with neighbors as well as health motivation as important explanatory variables in both analyses. Participants living in neighborhoods far from railway stations and in neighborhoods with a high bus stop density tended to shift to walking and public transport, a modal shift that was highly associated with increased step counts. These results suggest that mobility management should be promoted in collaboration with public health and city planning professionals.

Background: Many factors are associated with hypertension development. We focused on social participation as an aspect of social capital and investigated the contextual relationship between community-level social participation and hypertension using multilevel regression analyses., Methods: We used cross-sectional data from the 2016 Japan Gerontological Evaluation Study-a population-based study of functionally independent adults aged 65 years or older. The sample comprised 116,013 participants nested in 818 communities. Hypertension and social capital were defined by questionnaires. Social capital was assessed at both the individual and the community levels in 3 dimensions: civic participation (as an index of social participation), social cohesion, and reciprocity., Results: The prevalence rate of hypertension was 43.7%, and 44.1% of the respondents were involved in civic participation. Community-level civic participation, but not social cohesion or reciprocity, was negatively associated with hypertension in the total population (prevalence ratio (95% confidence interval): 0.98 (0.96-0.99), P = 0.004) and female group (0.97 (0.95-0.99), P = 0.015), and the association neared significance in the male group (0.98 (0.96-1.005), P = 0.13) after adjustment for individual-level social capital dimensions including civic participation, individual-level covariates, and population density as a community-level covariate. The interaction between community-level civic participation and sex in relation to hypertension was significant (P = 0.012)., Conclusions: We found a contextual preventive relationship between community-level civic participation and hypertension. The design of the contextual characteristics of communities by the promotion of social participation may help reduce the prevalence of hypertension in older people., (© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

This cross-sectional study aimed to compare access to the nearest food stores with perceived access associated with intake frequencies of vegetables/fruits and meat/fish among older Japanese people. We used intake frequencies of vegetables/fruits and meat/fish from a self-administered questionnaire in the Japan Gerontological Evaluation Study among 83,384 adults aged over 65 years. We defined distance over 1 km as poor objective access in community level. We performed multilevel regression analysis to investigate the association of objective and perceived access with intake frequencies of vegetables/fruits and meat/fish, respectively. Participants who lived in poor objective access had a significantly higher intake frequency of vegetables/fruits than those who lived in good access. In contrast, residents with poor perceived access consumed lower frequent intake of vegetables/fruits (beta coefficient (standard error) 0.086 (0.021) for objective access; -0.093 (0.009) for perceived access). There was no significant association between objective access and intake frequency of meat/fish, but poor perceived access showed a significant association with lower intake frequency of meat/fish. There was inconsistency between objective and perceived measurement of access to food stores associated with dietary habits among older Japanese adults. Food access needs to be comprehensively assessed, while considering characteristics of measurements.

Introduction: Interventions targeting built environmental factors may encourage older people to engage in favorable behaviors and decrease dementia risk, but epidemiologic evidence is limited. This study investigated the association between neighborhood food environment and dementia incidence., Methods: A 3-year follow-up (2010-2013) was conducted among participants in the Japan Gerontological Evaluation Study, a population-based cohort study of older adults aged ≥65 years. Dementia incidence for 49,511 participants was assessed through the public long-term care insurance system. Availability of food stores (defined as the number of food stores selling fruits and vegetables within 500 meters or 1 kilometer of residence) was assessed for each participant using objective (GIS-based) and subjective (participant-reported) measurements. Data were analyzed from 2017 to 2018., Results: A total of 3,162 cases of dementia occurred during the follow-up. Compared with the highest quartile for objective availability of food stores, the hazard ratio adjusting for age and sex was 1.60 (95% CI=1.43, 1.78) for the second-lowest quartile. Compared with the highest subjective availability of food stores, the hazard ratio was 1.74 (95% CI=1.49, 2.04) for the lowest category. After successive adjustment for sociodemographic characteristics, health status, and other geographic neighborhood factors (availability of restaurants, convenience stores, and community centers), the hazard ratio remained statistically significant., Conclusions: Lower food store availability was associated with increased dementia incidence. Given that food shopping is a routine activity and a main motive for going out among older adults, increasing the availability of food stores may contribute to dementia prevention., (Copyright © 2018 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Previous research has linked lower availability of food stores selling fruits and vegetables to unhealthy diet. However, the longitudinal association between the availability of healthy food stores and mortality is unknown. This study examined the association between neighborhood availability of food stores and mortality by driving status among older adults., Methods: This study drew upon a three-year follow up of participants in the Japan Gerontological Evaluation Study, a population-based cohort study of Japanese adults aged 65 years or older. Mortality from 2010 to 2013 was analyzed for 49,511 respondents. Neighborhood availability of food stores was defined as the number of food stores selling fruits and vegetables within a 500-m or 1-km radius of a person's residence. Both subjective (participant-reported) and objective (geographic information system-based) measurements were used to assess this variable. Cox regression models were used to estimate hazard ratios (HR) for mortality., Results: A total of 2049 deaths occurred during the follow up. Lower subjective availability of food stores was significantly associated with increased mortality. Compared with participants reporting the highest availability, the age- and sex-adjusted HR for those reporting the lowest availability was 1.28 (95% CI: 1.04-1.58; p = 0.02). The association remained significant after adjustment for sociodemographic (education, income, cohabitation, marital status, and employment status) and environmental (driving status, use of public transportation, and study site) status (HR = 1.24, 95% CI: 1.01-1.53, p = 0.04). This association was stronger among non-car users, among whom the HR for those reporting the lowest availability of food stores was 1.61 (95% CI: 1.08-2.41, p = 0.02). In contrast, no significant association was seen between objective availability and mortality., Conclusions: Lower availability of healthy food stores measured subjectively, but not objectively, was associated with mortality, especially among non-car users. Considering the decline in mobility with age, living in a neighborhood with many options for procuring fruits and vegetables within walking distance may be important for healthy aging.

Purpose: Community-level group participation is a structural aspect of social capital that may have a contextual influence on an individual's health. Herein, we sought to investigate a contextual relationship between community-level prevalence of sports group participation and depressive symptoms in older individuals., Methods: We used data from the 2010 Japan Gerontological Evaluation Study, a population-based, cross-sectional study of individuals 65 yr or older without long-term care needs in Japan. Overall, 74,681 participants in 516 communities were analyzed. Depressive symptoms were diagnosed as a 15-item Geriatric Depression Scale score of ≥5. Participation in a sports group 1 d·month or more often was defined as "participation." For this study, we applied two-level multilevel Poisson regression analysis stratified by sex, calculated prevalence ratios (PR), and 95% confidence intervals (CI)., Results: Overall, 17,420 individuals (23.3%) had depressive symptoms, and 16,915 (22.6%) participated in a sports group. Higher prevalence of community-level sports group participation had a statistically significant relationship with a lower likelihood of depressive symptoms (male: PR, 0.89 (95% CI, 0.85-0.92); female: PR, 0.96 (95% CI, 0.92-0.99), estimated by 10% of participation proportion) after adjusting for individual-level sports group participation, age, diseases, family form, alcohol, smoking, education, equivalent income, and population density. We found statistically significant cross-level interaction terms in male participants only (PR, 0.86; 95% CI, 0.77-0.95)., Conclusions: We found a contextual preventive relationship between community-level sports group participation and depressive symptoms in older individuals. Therefore, promoting sports groups in a community may be effective as a population-based strategy for the prevention of depression in older individuals. Furthermore, the benefit may favor male sports group participants.

The present study aims to predict the maternal-fetal transfer rates of the polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and polybrominated diphenyl ethers (PBDEs), and dioxin-like compounds using a quantitative structure-activity relationship model. The relation between the maternal-fetal transfer rate and the contaminants' physicochemical properties was investigated by multiple linear regression (MLR), partial least square regression (PLS), and random forest regression (RF). The 10-fold cross-validation technique estimated low predictive performances for both MLR and PLS models (R 2 CV  = 0.425 ± 0.0964 for MLR and R 2 CV  = 0.492 ± 0.115 for PLS) and is in agreement with an external test (R 2 pred  = 0.129 for MLR and R 2 pred  = 0.123 for PLS). In contrast, the RF model exhibits good predictive performance, estimated through 10-fold cross-validation (R 2 CV  = 0.566 ± 0.0885) and an external test set (R 2 pred  = 0.519). Molecular weight and polarity were selected in all models as important parameters that may predict the ability of a molecule to cross the placenta to the fetus.

Nasopharynx-associated lymphoid tissue (NALT) is one of the major constituents of the mucosa-associated lymphoid tissue (MALT), and has the ability to induce antigen-specific immune responses. However, the molecular mechanisms responsible for antigen uptake from the nasal cavity into the NALT remain largely unknown. Immunohistochemical analysis showed that CCL9 and CCL20 were co-localized with glycoprotein 2 (GP2) in the epithelium covering NALT, suggesting the existence of M cells in NALT. In analogy with the reduced number of Peyer's patch M cells in CCR6-deficient mice, the number of NALT M cells was drastically decreased in CCR6-deficient mice compared with the wild-type mice. Translocation of nasally administered Salmonella enterica serovar Typhimurium into NALT via NALT M cells was impaired in CCR6-deficient mice, whereas S. Typhimurium demonstrated consistent co-localization with NALT M cells in wild-type mice. When wild-type mice were nasally administered with an attenuated vaccine strain of S. Typhimurium, the mice were protected from a subsequent challenge with wild-type S. Typhimurium. Antigen-specific fecal and nasal IgA was detected after nasal immunization with the attenuated vaccine strain of S. Typhimurium only in wild-type mice but not in CCR6-deficient mice. Taken together, these observations demonstrate that NALT M cells are important as a first line of defense against infection by enabling activation of the common mucosal immune system (CMIS)., (© The Japanese Society for Immunology. 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Bacterial access to the gut immune system is a crucial process to promote host immune responses. The probiotic L-92 strain of Lactobacillus acidophilus exerts anti-allergic immunomodulatory effects upon oral administration in mice. Here, we show that microfold cells (M cells) are responsible for L-92 internalization for evoking L-92-mediated immune responses. L-92 specifically bound to uromodulin, a glycosylphosphatidylinositol-anchored protein expressed exclusively on M cells among intestinal epithelial cells. Internalization of L-92 into M cells was significantly reduced in uromodulin-deficient (Umod-/-) mice compared to Umod+/+ mice. Furthermore, the binding of L-92 to uromodulin was significantly decreased after removal of surface layer protein A (SlpA) from the bacteria. Our study thus revealed a crucial role of uromodulin on the M-cell surface for the uptake of SlpA-positive lactic acid bacteria into M cells, possibly leading to subsequent delivery of the bacteria to dendritic cells closely associated with M cells for immunomodulation. Our study also shed light on the possibility that SlpA and uromodulin could be used as vehicle and target, respectively, for efficient mucosal vaccine delivery., (© The Japanese Society for Immunology. 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Although living in a hilly environment may promote muscular activity in the daily lives of residents, and such activity may prevent diabetes mellitus, few studies have focused on the impact of living in a hilly environment on diabetes mellitus. The purpose of this study was to investigate the impact of a hilly neighborhood environment on DM in older people., Methods: We used data from the Japan Gerontological Evaluation Study, a population-based, cross-sectional study of individuals aged 65 or older without long-term care needs in Japan, which was conducted in 2010. A total of 8904 participants in 46 neighborhoods had responded to the questionnaire and undergone a health check. Diabetes mellitus was diagnosed as HbA 1c  ≥ 6.5% and those undergoing treatment for diabetes mellitus. Poorly controlled diabetes mellitus was diagnosed in those without other chronic diseases who had an HbA 1c > 7.5%, and in those with other chronic diseases if their HbA 1c was >8.0%. Neighborhood environment was evaluated based on the percentage of positive responses in the questionnaire and geographical information system data. A multilevel analysis was performed, adjusted for individual-level risk factors. Furthermore, sensitivity analysis was conducted for those who were undergoing treatment for diabetes mellitus (n = 1007)., Results: After adjustment for other physical environmental and individual covariates, a 1 interquartile range increase (1.48°) in slope in the neighborhood decreased the risk of poorly controlled diabetes mellitus by 18% (odds ratio [OR]: 0.82, 95% confidence interval [CI]: 0.70-0.97). Sensitivity analysis confirmed that larger slopes in the neighborhood showed a significant protective effect against diabetes mellitus among those who were undergoing treatment for diabetes mellitus (OR: 0.73, 95% CI: 0.59-0.90)., Conclusion: A hilly neighborhood environment was not associated with diabetes mellitus, but was protective against poorly controlled diabetes mellitus., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We investigated the relationship between food frequency questionnaire (FFQ) responses and serum polychlorinated biphenyl (PCB) levels of mothers and fathers recruited from the Chiba Regional Center, which is one of the 15 regional centers of the Japan Environment and Children's Study (mothers: n = 1477, fathers: n = 219). The expected PCB values were estimated from the participants' FFQ answers and medical records (age, body mass index and number of deliveries). Based on the stepwise forward selection results of Bayesian regression models, age and fish and egg consumption were positively associated with PCB concentrations and a number of deliveries were negatively associated with PCB concentrations in mothers, whereas only age was positively associated with PCB concentrations in fathers.These findings indicated that the estimation of daily dietary intake may be useful for the prediction of PCB concentration for mothers.

Previous studies have found an association between neighborhood characteristics (i.e., aspects of the physical and social environment) and the incidence of cardiovascular disease (CVD) and elevated CVD risk. This study investigated the relationship between neighborhood characteristics and CVD risk among older people in Japan where research on this association is scarce. Data came from the Japan Gerontological Evaluation Study project; questionnaire data collected from 3,810 people aged 65 years or older living in 20 primary school districts in Aichi prefecture, Japan, was linked to a computed composite CVD risk score based on biomarker data (i.e., hemoglobin A1c, systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and estimated glomerular filtration rate). A sex-stratified multilevel linear regression analysis revealed that for male participants, living in neighborhoods with a higher perceived occurrence of traffic accidents and reduced personal safety was associated with an elevated CVD risk (coefficient = 1.08 per interquartile range increase, 95% confidence interval [CI] = 0.30 to 1.86) whereas males living in neighborhoods with a higher perceived proximity of exercise facilities had a lower risk (coefficient = -1.00, 95% CI = -1.78 to -0.21). For females, there was no statistically significant association between neighborhood characteristics and CVD risk. This study suggests that aspects of the neighborhood environment might be important for CVD morbidity and mortality in Japan, particularly among men., Competing Interests: The authors have declared that no competing interests exist.

M cells in the follicle-associated epithelium (FAE) of Peyer's patches (PPs) serve as a main portal for external antigens and function as a sentinel in mucosal immune responses. The scarcity of these cells has hampered identification of M cell-specific molecules. Recent efforts have begun to provide insight into antigen transcytosis and differentiation of M cells; however, the molecular mechanisms underlying these processes are not fully elucidated. Small non-coding RNAs including microRNA (miRNA) have been reported to regulate gene expression and control various biological processes such as cellular differentiation and function. To evaluate the expression of miRNAs in FAE, including M cells, we previously performed microarray analysis comparing intestinal villous epithelium (VE) and PP FAE. Here we confirmed FAE specific miRNA expression levels by quantitative PCR. To gain insight into miRNA function, we generated mice with intestinal epithelial cell-specific deletion of Dicer1 (DicerΔIEC) and analyzed intestinal phenotypes, including M-cell differentiation, morphology and function. DicerΔIEC mice had a marked decrease in M cells compared to control floxed Dicer mice, suggesting an essential role of miRNAs in maturation of these cells. Furthermore, transmission electron microscopic analysis revealed that depletion of miRNA caused the loss of endosomal structures in M cells. In addition, antigen uptake by M cells was impaired in DicerΔIEC mice. These results suggest that miRNAs play a significant role in M cell differentiation and help secure mucosal immune homeostasis.

Establishing methods for the assessment of fetal exposure to chemicals is important for the prevention or prediction of the child's future disease risk. In the present study, we aimed to determine the influence of molecular weight on the likelihood of chemical transfer from mother to fetus via the placenta. The correlation between molecular weight and placental transfer rates of congeners/isomers of polychlorinated biphenyls (PCBs) and dioxins was examined. Twenty-nine sample sets of maternal blood, umbilical cord, and umbilical cord blood were used to measure PCB concentration, and 41 sample sets were used to analyze dioxins. Placental transfer rates were calculated using the concentrations of PCBs, dioxins, and their congeners/isomers within these sample sets. Transfer rate correlated negatively with molecular weight for PCB congeners, normalized using wet and lipid weights. The transfer rates of PCB or dioxin congeners differed from those of total PCBs or dioxins. The transfer rate for dioxin congeners did not always correlate significantly with molecular weight, perhaps because of the small sample size or other factors. Further improvement of the analytical methods for dioxin congeners is required. The findings of the present study suggested that PCBs, dioxins, or their congeners with lower molecular weights are more likely to be transferred from mother to fetus via the placenta. Consideration of chemical molecular weight and transfer rate could therefore contribute to the assessment of fetal exposure., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Individuals' exposure to various persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs), and its adverse health effects have been a cause of concern. We measured blood PCB concentrations from samples taken from 507 Japanese individuals ranging from infants to those over 80 years of age. The blood PCB levels increased with age for both male (Spearman's r = 0.69, p < 0.001) and female (Spearman's r = 0.70, p < 0.001) participants. Adult men and nulliparous women showed similar increases with age. However, the PCB levels of multiparous women were lower than those of nulliparous women in their thirties (p = 0.005), probably because the PCBs were transferred from the mothers to their children during pregnancy and lactation. Among infants (<2 years of age), some had as high levels of accumulated PCB levels as those in adults >30 years of age. In some cases, the PCB levels were over 0.8 ng/g wet weight, similar to levels observed in adults over 50 years of age. In the future, it will be necessary to do research on the health of the children who are exposed by high concentration level of POPs.

Microfold (M) cells are intestinal epithelial cells specialized for sampling and transport of luminal antigens to gut-associated lymphoid tissue for initiation of both mucosal and systemic immune responses. Therefore, M-cell targeted vaccination has the potential to be a better immunization strategy. Glycoprotein 2 (GP2), an antigen uptake receptor for FimH(+) bacteria on M cells, can be a good target for this purpose. Aptamers are oligonucleotides that bind to a variety of target molecules with high specificity and affinity. Together with its low toxic feature, aptamers serves as a tool of molecular-targeted delivery. In this study, we used Systematic Evolution of Ligands by EXponential enrichment (SELEX) to isolate aptamers specific to murine GP2 (mGP2). After ten rounds of SELEX, eleven different aptamer sequences were selected. Among them, the most frequently appeared sequence (~60%) were aptamer NO. 1 (Apt1), and the second most (~7%) were aptamer NO. 5 (Apt5). In vitro binding experiment confirmed that only Apt1 and Apt5 specifically bound to mGP2 among eleven aptamers initially selected. Apt1 showed the strongest affinity with mGP2, with the Kd value of 110±2.6 nM evaluated by BIACORE. Binding assays with mutants of Apt1 suggest that, in addition to the loop structure, the nucleotide sequence, AAAUA, in the loop is important for binding to mGP2. Furthermore, this aptamer was able to bind to mGP2 expressed on the cell surface. These results suggest that this mGP2-specific aptamer could serve as a valuable tool for testing M-cell-targeted vaccine delivery in the murine model system.

Brucella abortus is a Gram-negative bacterium causing brucellosis. Although B. abortus is known to infect via the oral route, the entry site in the gastrointestinal tract has been unclear. We found that B. abortus was selectively internalized by microfold cells (M cells), a subset of epithelial cells specialized for mucosal Ag uptake. During this process, colocalization of cellular prion protein (PrP(C)) and B. abortus was evident on the apical surface as well as in subapical vacuolar structures in M cells. Internalization of B. abortus by M cells of PrP(C)-deficient (Prnp(-/-)) mice was greatly reduced compared with that in wild-type mice. Furthermore, an oral infection study revealed that translocation of B. abortus into the Peyer's patch was significantly lower in Prnp(-/-) than in wild-type mice. These observations suggest that orally infected B. abortus invades the host through M cells by using PrP(C) on the apical surface of M cells as an uptake receptor.

Phosphatidic acid (PA) is a lipid second messenger and is believed to be involved in cell proliferation and survival. PA is mainly produced by phospholipase D (PLD) and diacylglycerol kinase (DGK). Elevated PLD activity is believed to suppress apoptosis via activation of the mammalian target of rapamycin (mTOR). On the other hand, DGK inhibition has been demonstrated to induce apoptosis, but it is unclear whether DGK can regulate mTOR. Here, we investigated whether DGK inhibition can induce apoptosis and autophagy in neuronal cells, since mTOR is a key mediator of autophagy and the simultaneous activation of apoptosis and autophagy has been detected. A DGK inhibitor, R59022 induced autophagy and apoptosis without serum in NG108-15 cells. Autophagy preceded apoptosis, and apoptosis inhibition did not affect R59022-induced autophagy. R59022-induced autophagy was inhibited by exogenous PA, and protein kinase C activation and increases in intracellular Ca(2+) levels, which are assumed to be caused by diacylglycerol accumulation, did not appear to be involved in R59022-induced autophagy. We also investigated the effects of R59022 on mTOR signaling pathway, and found that the pathway was not inhibited by R59022. These results imply that DGK plays an important role in cell survival via mTOR-independent mechanism., (Copyright © 2011 Elsevier Inc. All rights reserved.)