Central residues in prion protein PrPC are crucial for its conversion into the pathogenic isoform.

Conformational conversion of the cellular prion protein, PrPC, into the amyloidogenic isoform, PrPSc, is a key pathogenic event in prion diseases. However, the conversion mechanism remains to be elucidated. Here, we generated Tg(PrPΔ91-106)-8545/Prnp0/0 mice, which overexpress mouse PrP lacking residues 91-106. We showed that none of the mice became sick after intracerebral inoculation with RML, 22L, and FK-1 prion strains nor accumulated PrPScΔ91-106 in their brains except for a small amount of PrPScΔ91-106 detected in one 22L-inoculated mouse. However, they developed disease around 85 days after inoculation with bovine spongiform encephalopathy (BSE) prions with PrPScΔ91-106 in their brains. These results suggest that residues 91-106 are important for PrPC conversion into PrPSc in infection with RML, 22L, and FK-1 prions but not BSE prions. We then narrowed down the residues 91-106 by transducing various PrP deletional mutants into RML- and 22L-infected cells and identified that PrP mutants lacking residues 97-99 failed to convert into PrPSc in these cells. Our in vitro conversion assay also showed that RML, 22L, and FK-1 prions did not convert PrPΔ97-99 into PrPScΔ97-99, but BSE prions did. We further found that PrP mutants with proline residues at positions 97 to 99 or charged residues at positions 97 and 99 completely or almost completely lost their converting activity into PrPSc in RML- and 22L-infected cells. These results suggest that the structurally flexible and noncharged residues 97-99 could be important for PrPC conversion into PrPSc following infection with RML, 22L, and FK-1 prions but not BSE prions.

Strain-dependent role of copper in prion disease through binding to histidine residues in the N-terminal domain of prion protein.

The cellular prion protein, PrPC , is a copper-binding protein abundantly expressed in the brain, particularly by neurons, and its conformational conversion into the amyloidogenic isoform, PrPSc , plays a key pathogenic role in prion diseases. However, the role of copper binding to PrPC in prion diseases remains unclear. Here, we fed mice with a low-copper or regular diet and intracerebrally inoculated them with two different mouse-adapted RML scrapie and BSE prions. Mice with a low-copper diet developed disease significantly but only slightly later than those with a regular diet after inoculation with BSE prions, but not with RML prions, suggesting that copper could play a minor role in BSE prion pathogenesis, but not in RML prion pathogenesis. We then generated two lines of transgenic mice expressing mouse PrP with copper-binding histidine (His) residues in the N-terminal domain replaced with alanine residues, termed TgPrP(5H > A)-7342/Prnp0/0 and TgPrP(5H > A)-7524/Prnp0/0 mice, and similarly inoculated RML and BSE prions into them. Due to 2-fold higher expression of PrP(5H > A) than PrPC in wild-type (WT) mice, TgPrP(5H > A)-7524/Prnp0/0 mice were highly susceptible to these prions, compared to WT mice. However, TgPrP(5H > A)-7342/Prnp0/0 mice, which express PrP(5H > A) 1.2-fold as high as PrPC in WT mice, succumbed to disease slightly, but not significantly, later than WT mice after inoculation with RML prions, but significantly so after inoculation with BSE prions. Subsequent secondary inoculation experiments revealed that amino acid sequence differences between PrP(5H > A) and WT PrPSc created no prion transmission barrier to BSE prions. These results suggest that copper-binding His residues in PrPC are dispensable for RML prion pathogenesis but have a minor effect on BSE prion pathogenesis. Taken together, our current results suggest that copper could have a minor effect on prion pathogenesis in a strain-dependent manner through binding to His residues in the N-terminal domain of PrPC .

ATP Consumption Is Coupled with Endocytosis in Exudated Neutrophils.

Neutrophil energy metabolism during phagocytosis has been previously reported, and adenosine triphosphate (ATP) plays a crucial role in endocytosis. Neutrophils are prepared by intraperitoneal injection of thioglycolate for 4 h. We previously reported a system established for measuring particulate matter endocytosis by neutrophils using flow cytometry. In this study, we utilized this system to investigate the relationship between endocytosis and energy consumption in neutrophils. A dynamin inhibitor suppressed ATP consumption triggered by neutrophil endocytosis. In the presence of exogenous ATP, neutrophils behave differently during endocytosis depending on ATP concentration. The inhibition of ATP synthase and nicotinamide adenine dinucleotide phosphate oxidase but not phosphatidylinositol-3 kinase suppresses neutrophil endocytosis. The nuclear factor kappa B was activated during endocytosis and inhibited by I kappa B kinase (IKK) inhibitors. Notably, IKK inhibitors restored endocytosis-triggered ATP consumption. Furthermore, data from the NLR family pyrin domain containing three knockout mice suggest that inflammasome activation is not involved in neutrophil endocytosis or concomitant ATP consumption. To summarize, these molecular events occur via endocytosis, which is closely related to ATP-centered energy metabolism.

Implications of refrigerator management on subjective memory complaints among Japanese community-dwelling older adults.

AIM: Older adults with subjective memory complaints (SMC) may experience very minor difficulties in daily activities. Although caregivers and occupational therapists who support community-dwelling older adults are aware of the existence of characteristic behaviours related to refrigerator management, no specific studies have been conducted. This study aimed to examine the implications of refrigerator management for older adults with SMC. METHODS: A self-administered questionnaire was sent to 3000 randomly selected members of Consumer's Co-operative Kagoshima. Of the returned responses, a total of 282 older adults were analyzed. Analyzed subjects were divided into two groups: SMC (+) group (n = 74) and SMC (-) group (n = 192). A questionnaire was created by four occupational therapists and used to assess the characteristics of analyzed subjects and their abilities to manage the refrigerator. The observation list for early signs of dementia was also utilised. A multiple logistic analysis was performed to examine the association between SMC and refrigerator management. RESULTS: The SMC (+) group had a significantly higher number of refrigerator management errors than the SMC (-) group (P = 0.008). The SMC (+) group had more errors than the SMC (-) group in the following four items regarding refrigerator management; the refrigerator has a lot of the same foods / expired food, the person does not know what's in the refrigerator, the person cannot find what he/she needs in the refrigerator. Moreover, SMC was associated with the item 'the person does not know what is in the refrigerator' (odds ratio 7.44, 95% CI 1.51-43.8, P = 0.02). CONCLUSIONS: Our results showed that older adults with SMC had several problems regarding refrigerator management. Evaluating refrigerator management among older adults with SMC may help consider multifaceted support.

Relationship between grave visitation and apathy among community-dwelling older adults.

BACKGROUND: It has been shown that involvement in religious activities has a positive impact on psychological aspects. In this study, the relationship between grave visitation, a standard religious activity in Japan, and depression and apathy symptoms was investigated among older adults in Japan. METHODS: A total of 638 older adults who participated in a community-based health check survey (Tarumizu Study 2019) were interviewed regarding the presence or absence of grave visitation, frequency, travel time, means of transportation, and flower offerings. Apathy and depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15). The participants were categorised into three grave visitation groups, namely, frequent (more than once per week), occasional (less than once per week), and non-visiting. Outcomes were compared between the frequency groups, and Poisson regression analysis was used to investigate the relationship between grave visitation frequency and apathy and depression. RESULTS: Of the participants, 91.8% reported regular grave visitation. The non-visiting group had a significantly higher prevalence of apathy symptoms (44.2%) than the visiting groups. Furthermore, using the frequent group as the reference, Poisson regression analysis adjusted for potential covariates demonstrated that no grave visitation was significantly related to apathy (prevalence ratio, 1.43; 95% confidence interval, 1.00-2.05, P = 0.049). CONCLUSIONS: Not practising grave visitation was significantly related to apathy among older adults. Helping older adults to visit graves may prevent apathy by facilitating motivation and increasing activity.

Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice.

The cellular prion protein, PrPC, is a glycosylphosphatidylinositol anchored-membrane glycoprotein expressed most abundantly in neuronal and to a lesser extent in non-neuronal cells. Its conformational conversion into the amyloidogenic isoform in neurons is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. However, the normal functions of PrPC remain largely unknown, particularly in non-neuronal cells. Here we show that stimulation of PrPC with anti-PrP monoclonal antibodies (mAbs) protected mice from lethal infection with influenza A viruses (IAVs), with abundant accumulation of anti-inflammatory M2 macrophages with activated Src family kinases (SFKs) in infected lungs. A SFK inhibitor dasatinib inhibited M2 macrophage accumulation in IAV-infected lungs after treatment with anti-PrP mAbs and abolished the anti-PrP mAb-induced protective activity against lethal influenza infection in mice. We also show that stimulation of PrPC with anti-PrP mAbs induced M2 polarization in peritoneal macrophages through SFK activation in vitro and in vivo. These results indicate that PrPC could activate SFK in macrophages and induce macrophage polarization to an anti-inflammatory M2 phenotype after stimulation with anti-PrP mAbs, thereby eliciting protective activity against lethal infection with IAVs in mice after treatment with anti-PrP mAbs. These results also highlight PrPC as a novel therapeutic target for IAV infection.

Association between apathy and satisfaction with meaningful activities in older adults with mild cognitive impairment: A population-based cross-sectional study.

OBJECTIVES: This cross-sectional study aimed to clarify the relationship between apathy, meaningful activities, and satisfaction with such activities of older adults with mild cognitive impairment (MCI). METHODS: We analyzed 235 older adults with MCI (≥65 years, mean age: 76.9 ± 6.4 years, women: 63.4%) who participated in a community-based health check survey (Tarumizu Study 2018). MCI was defined as at least 1.5 SD below the reference threshold (age- and education-adjusted score) on one or more of the computerized cognitive test including memory, attention, executive functions, and processing speed. Apathy symptoms were assessed using three of the 15 items of Geriatric Depression Scale. Participants selected meaningful activities from the 95 activities of the Aid for Decision-Making in Occupation Choice and evaluated their satisfaction and performance. RESULTS: Apathy in MCI was prevalent by 23.8%. The categories of meaningful activities revealed no difference, with, or without apathy. Logistic regression analysis showed that activity satisfaction was significantly associated with apathy after adjusting for age, sex, education, instrumental activities of daily living, depressive symptoms, and MCI subtype (OR, 0.62; 95% CI, 0.44-0.88, p = 0.008). CONCLUSIONS: Satisfaction with the activities that are deemed meaningful is associated with apathy among community-dwelling older adults with MCI.

Prion protein protects mice from lethal infection with influenza A viruses.

The cellular prion protein, designated PrPC, is a membrane glycoprotein expressed abundantly in brains and to a lesser extent in other tissues. Conformational conversion of PrPC into the amyloidogenic isoform is a key pathogenic event in prion diseases. However, the physiological functions of PrPC remain largely unknown, particularly in non-neuronal tissues. Here, we show that PrPC is expressed in lung epithelial cells, including alveolar type 1 and 2 cells and bronchiolar Clara cells. Compared with wild-type (WT) mice, PrPC-null mice (Prnp0/0) were highly susceptible to influenza A viruses (IAVs), with higher mortality. Infected Prnp0/0 lungs were severely injured, with higher inflammation and higher apoptosis of epithelial cells, and contained higher reactive oxygen species (ROS) than control WT lungs. Treatment with a ROS scavenger or an inhibitor of xanthine oxidase (XO), a major ROS-generating enzyme in IAV-infected lungs, rescued Prnp0/0 mice from the lethal infection with IAV. Moreover, Prnp0/0 mice transgenic for PrP with a deletion of the Cu-binding octapeptide repeat (OR) region, Tg(PrPΔOR)/Prnp0/0 mice, were also highly susceptible to IAV infection. These results indicate that PrPC has a protective role against lethal infection with IAVs through the Cu-binding OR region by reducing ROS in infected lungs. Cu content and the activity of anti-oxidant enzyme Cu/Zn-dependent superoxide dismutase, SOD1, were lower in Prnp0/0 and Tg(PrPΔOR)/Prnp0/0 lungs than in WT lungs. It is thus conceivable that PrPC functions to maintain Cu content and regulate SOD1 through the OR region in lungs, thereby reducing ROS in IAV-infected lungs and eventually protecting them from lethal infection with IAVs. Our current results highlight the role of PrPC in protection against IAV infection, and suggest that PrPC might be a novel target molecule for anti-influenza therapeutics.

Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91-106.

Conformational conversion of the cellular prion protein, PrPC, into the abnormally folded isoform, PrPSc, is a key pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Transgenic mice expressing PrP with a deletion of the central residues 91-106 were generated in the absence of endogenous PrPC, designated Tg(PrP∆91-106)/Prnp0/0 mice and intracerebrally inoculated with various prions. Tg(PrP∆91-106)/Prnp0/0 mice were resistant to RML, 22L and FK-1 prions, neither producing PrPSc∆91-106 or prions in the brain nor developing disease after inoculation. However, they remained marginally susceptible to bovine spongiform encephalopathy (BSE) prions, developing disease after elongated incubation times and accumulating PrPSc∆91-106 and prions in the brain after inoculation with BSE prions. Recombinant PrP∆91-104 converted into PrPSc∆91-104 after incubation with BSE-PrPSc-prions but not with RML- and 22L-PrPSc-prions, in a protein misfolding cyclic amplification assay. However, digitonin and heparin stimulated the conversion of PrP∆91-104 into PrPSc∆91-104 even after incubation with RML- and 22L-PrPSc-prions. These results suggest that residues 91-106 or 91-104 of PrPC are crucially involved in prion pathogenesis in a strain-dependent manner and may play a similar role to digitonin and heparin in the conversion of PrPC into PrPSc.

Impact of sensory impairments on dementia incidence and symptoms among Japanese older adults.

BACKGROUND: Dementia and behavioural and psychological symptoms of dementia affect older adults' care-need levels. With aging comes an increase in the incidence of sensory impairments, which promotes the development of dementia. We investigated the association between sensory impairments - visual impairment (VI), hearing impairment (HI), and dual sensory impairment (DSI), the behavioural and psychological symptoms of dementia, and dementia incidence. METHODS: This was a retrospective study that used Japanese long-term care insurance certification data from 2010 to 2017 of City A. The 2190 older adults who did not have dementia in 2010 were classified into four impairment categories: VI, HI, DSI, and no sensory impairment. The incidence of dementia was examined using Kaplan-Meier survival analysis and log-rank testing. Cox proportional hazards analysis was used to investigate the risk of developing dementia associated with sensory impairments, compared to the risk for no sensory impairment. Pearson's χ2 tests were used to compare the prevalence of behavioural and psychological symptoms of dementia among the four groups. RESULTS: HI and DSI were associated with a higher cumulative dementia incidence compared to no sensory impairment (log-rank χ2 = 10.42; P  < 0.001, and log-rank χ2 = 39.92; P  < 0.001, respectively), and DSI showed higher cumulative dementia incidence than HI (log-rank χ2 = 11.37; P  = 0.001). Cox proportional hazards analysis showed that DSI is the greatest risk factor for developing dementia among sensory impairments (hazard ratio, 1.45; 95% CI, 1.22-1.71; P < 0.001). Older adults with VI had a significantly higher prevalence of day-night reversal than the other groups. CONCLUSIONS: Our results indicate that older adults with sensory impairments have a high incidence of dementia, with DSI presenting the greatest risk. Older adults with VI were found to be more likely to have day-night reversal symptoms when dementia occurs.

Prion Protein Devoid of the Octapeptide Repeat Region Delays Bovine Spongiform Encephalopathy Pathogenesis in Mice.

Conformational conversion of the cellular isoform of prion protein, PrPC, into the abnormally folded, amyloidogenic isoform, PrPSc, is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals. We previously reported that the octapeptide repeat (OR) region could be dispensable for converting PrPC into PrPSc after infection with RML prions. We demonstrated that mice transgenically expressing mouse PrP with deletion of the OR region on the PrP knockout background, designated Tg(PrPΔOR)/Prnp0/0 mice, did not show reduced susceptibility to RML scrapie prions, with abundant accumulation of PrPScΔOR in their brains. We show here that Tg(PrPΔOR)/Prnp0/0 mice were highly resistant to BSE prions, developing the disease with markedly elongated incubation times after infection with BSE prions. The conversion of PrPΔOR into PrPScΔOR was markedly delayed in their brains. These results suggest that the OR region may have a crucial role in the conversion of PrPC into PrPSc after infection with BSE prions. However, Tg(PrPΔOR)/Prnp0/0 mice remained susceptible to RML and 22L scrapie prions, developing the disease without elongated incubation times after infection with RML and 22L prions. PrPScΔOR accumulated only slightly less in the brains of RML- or 22L-infected Tg(PrPΔOR)/Prnp0/0 mice than PrPSc in control wild-type mice. Taken together, these results indicate that the OR region of PrPC could play a differential role in the pathogenesis of BSE prions and RML or 22L scrapie prions.IMPORTANCE Structure-function relationship studies of PrPC conformational conversion into PrPSc are worthwhile to understand the mechanism of the conversion of PrPC into PrPSc We show here that, by inoculating Tg(PrPΔOR)/Prnp0/0 mice with the three different strains of RML, 22L, and BSE prions, the OR region could play a differential role in the conversion of PrPC into PrPSc after infection with RML or 22L scrapie prions and BSE prions. PrPΔOR was efficiently converted into PrPScΔOR after infection with RML and 22L prions. However, the conversion of PrPΔOR into PrPScΔOR was markedly delayed after infection with BSE prions. Further investigation into the role of the OR region in the conversion of PrPC into PrPSc after infection with BSE prions might be helpful for understanding the pathogenesis of BSE prions.

Effects of prion protein devoid of the N-terminal residues 25-50 on prion pathogenesis in mice.

The N-terminal polybasic region of the normal prion protein, PrPC, which encompasses residues 23-31, is important for prion pathogenesis by affecting conversion of PrPC into the pathogenic isoform, PrPSc. We previously reported transgenic mice expressing PrP with residues 25-50 deleted in the PrP-null background, designated as Tg(PrP∆preOR)/Prnp 0/0 mice. Here, we produced two new lines of Tg(PrP∆preOR)/Prnp 0/0 mice, each expressing the mutant protein, PrP∆preOR, 1.1 and 1.6 times more than PrPC in wild-type mice, and subsequently intracerebrally inoculated RML and 22L prions into them. The lower expresser showed slightly reduced susceptibility to RML prions but not to 22L prions. The higher expresser exhibited enhanced susceptibility to both prions. No prion transmission barrier was created in Tg(PrP∆preOR)/Prnp 0/0 mice against full-length PrPSc. PrPSc∆preOR accumulated in the brains of infected Tg(PrP∆preOR)/Prnp 0/0 mice less than PrPSc in control wild-type mice, although lower in RML-infected Tg(PrP∆preOR)/Prnp 0/0 mice than in 22L-infected mice. Prion infectivity in infected Tg(PrP∆preOR)/Prnp 0/0 mice was also lower than that in wild-type mice. These results indicate that deletion of residues 25-50 only slightly affects prion susceptibility, the conversion of PrPC into PrPSc, and prion infectivity in a strain-specific way. PrP∆preOR retains residues 23-24 and lacks residues 25-31 in the polybasic region. It is thus conceivable that residues 23-24 rather than 25-31 are important for the polybasic region to support prion pathogenesis. However, other investigators have reported that residues 27-31 not 23-24 are important to support prion pathogenesis. Taken together, the polybasic region might support prion pathogenesis through multiple sites including residues 23-24 and 27-31.

Somatosensory cortex excitability changes due to differences in instruction conditions of motor imagery.

Purpose Vivid motor imagery appears to be associated with improved motor learning efficiency. However, the practical difficulties in measuring vivid motor imagery warrant new analytical approaches. The present study aimed to determine the instruction conditions for which vividness in motor imagery could be more easily seen and the excitability of the sensory cortex as it relates to the motor image. Materials and methods In total, 15 healthy, right-handed volunteers were instructed to imagine grasping a rubber ball under a verbal-only instruction condition (verbal condition), a verbal + visual instruction condition (visual condition), and a verbal + execution (physically grasping a real ball) condition (execution condition). We analyzed motor imagery-related changes in somatosensory cortical excitability by comparing somatosensory-evoked potentials in each condition with the rest (control) condition. We also used a visual analogue scale to measure subject-reported vividness of imagery. Results We found the N33 component was significantly lower in the execution condition than in the rest condition (p < 0.05). The results suggested a gating effect via central efferent mechanisms that affected the excitability of areas 3b or 1 in the primary somatosensory cortex, but only in the execution condition. Conclusions These data suggest that experiencing a movement through actual motor execution immediately prior to performing mental imagery of that movement enhances the excitability of motor-related cortical areas. It is suggested that the excitability of the motor-related region increased as a result of the motor imagery in the execution condition acting on the corresponding somatosensory cortex.

Antimicrobial strategy for targeted elimination of different microbes, including bacterial, fungal and viral pathogens.

The continuous emergence of microbial pathogens for which there are no effective antimicrobials threatens global health, necessitating novel antimicrobial approaches. Here, we present a targeted antimicrobial strategy that can be applied to various microbial pathogens. A photoimmuno-conjugate composed of an antibody against the target pathogen and a photoplastic phthalocyanine-derivative probe that generates photo-induced mechanical stress was developed based on photoimmuno-technology. This strategy, named as photoimmuno-antimicrobial strategy (PIAS), eliminates targeted pathogens, regardless of the target species or drug-resistance status. Specifically, PIAS acts on a broad range of microbes, including the bacterial pathogen Staphylococcus aureus, fungal pathogen Candida albicans, including their drug-resistant strains, and viral pathogen SARS-CoV-2, the causative agent of COVID-19. Furthermore, PIAS protects mice from fatal infections without damaging the non-targeted host microbiota and tissues. This study may contribute to the development of next-generation anti-infective therapies.

Association between satisfaction with meaningful activities and social frailty in community-dwelling Japanese older adults.

OBJECTIVES: This cross-sectional study investigates the associations among satisfaction with meaningful activities, and social frailty in community-dwelling Japanese older adults. METHODS: We analyzed data from 596 older adults (mean age 74.2 ± 6.4 years, female 63.6%) who participated in the Tarumizu Study 2019, a community-based health survey. Participants selected meaningful activities from 95 activities using the Aid for Decision-Making in Occupation Choice (ADOC) tool. Satisfaction was evaluated from 1 to 5, and those who were assigned a rating of 4 or 5 were operationally classified as the high satisfaction group (n = 487), with others occupying the low satisfaction group (n = 109). Both groups were evaluated based on the ADOC, social frailty (Makizako's five items), physical function, depressive symptoms, cognitive function, and higher-level competence. RESULTS: Of the 596 participants, 18.7% showed prevalence of social frailty. The low satisfaction group had a significantly higher prevalence of social frailty (low satisfaction 28.4% vs. high satisfaction 16.4%, P = 0.004) and depressive symptoms (low satisfaction 30.3% vs. high satisfaction 17.9%, P<0.01), and poor higher-level competence (P = 0.026) than the high satisfaction group. Logistic regression analysis showed that social frailty (Odds Ratio 1.78, 95% Confidence Interval 1.068-2.990, P = 0.027) was significantly associated with satisfaction with meaningful activity after adjusting for covariates. We found no significant differences in categories of meaningful activities between the low and high satisfaction groups (P = 0.549). CONCLUSIONS: This study suggested that social frailty was associated with satisfaction with meaningful activities, regardless of the degree or category of satisfaction.

Characteristics of meaningful activities in community-dwelling Japanese older adults with pre-frailty and frailty.

OBJECTIVES: This cross-sectional study aimed to clarify the association between physical and social frailty, cognitive impairment, and meaningful activity in older adults. METHODS: Data were obtained from 747 older adults (mean age, 74.7 ± 6.2 years; women, 63.9%) who participated in a community-based health check survey (Tarumizu Study 2018). Physical frailty, cognitive impairment, and social frailty were evaluated using the Fried phenotype model (exhibiting one or more of the criteria, including having a pre-frailty status); computerized cognitive test including memory, attention, executive functions, and processing speed (having a score below an age-education adjusted reference threshold in one or more domains); and Makizako's 5 items (exhibiting one or more of the criteria, including having a pre-frailty status), respectively. Participants selected meaningful activities from the 95 activities included in the Aid for Decision-Making in Occupation Choice, after which their satisfaction and performance were evaluated. Meaningful activities were categorized into physical activity, cognitive activity, social activity, and other daily activity. RESULTS: The physical frailty group was significantly less likely to choose physical activity over other activities (p < 0.05). The cognitive impairment group was significantly less likely to choose cognitive activity over other activities (p < 0.01). The multi-domain frailty group (including cognitive impairment) was significantly less likely to choose social activity over other activities (p < 0.05). No significant differences in satisfaction and performance were observed according to frailty status. CONCLUSIONS: Our findings indicated that physical and social frailty and cognitive impairment may affect participation in meaningful activities corresponding to these domains.

Effects of a brain-engraftable microglial cell line expressing anti-prion scFv antibodies on survival times of mice infected with scrapie prions.

We first verified that a single chain Fv fragment against prion protein (anti-PrP scFv) was secreted by HEK293T cells and prevented prion replication in infected cells. We then stably expressed anti-PrP scFv in brain-engraftable murine microglial cells and intracerebrally injected these cells into mice before or after infection with prions. Interestingly, the injection before or at an early time point after infection attenuated the infection marginally but significantly prolonged survival times of the mice. These suggest that the ex vivo gene transfer of anti-PrP scFvs using brain-engraftable cells could be a possible immunotherapeutic approach against prion diseases.

Crucial vasculoprotective role of the whole nitric oxide synthase system in vascular lesion formation in mice: Involvement of bone marrow-derived cells.

Although all three nitric oxide (NO) synthases (nNOS, iNOS, and eNOS) are expressed in injured arteries, it remains to be elucidated the role of the NOSs in their entirety in the vascular lesion formation. We addressed this issue in mice deficient in all NOS genes. Vascular injury was induced by permanent ligation of a unilateral carotid artery in wild-type (WT), singly, and triply NOS(-/-) mice. Two weeks after the procedure, constrictive vascular remodeling and neointimal formation were recognized in the ligated arteries. While constrictive remodeling was noted in the nNOS(-/-) and iNOS(-/-) genotypes, it was most accelerated in the n/i/eNOS(-/-) genotype. While neointimal formation was evident in the eNOS(-/-) and nNOS(-/-) genotypes, it was also most aggravated in the n/i/eNOS(-/-) genotype. Those lesions were reversed by long-term treatment with isosorbide dinitrate, a NO donor. Finally, we examined the involvement of bone marrow-derived cells in the vascular lesion formation. Bone marrow from the WT, singly, or triply NOS(-/-) mice was transplanted into the WT mice, and then the carotid ligation was performed. Intriguingly, constrictive remodeling and neointimal formation were both similarly most exacerbated in the case of the n/i/eNOS(-/-) bone marrow transplantation. These results indicate that the complete disruption of all the NOS genes causes markedly accelerated vascular lesion formation caused by blood flow disruption in mice in vivo, demonstrating the crucial vasculoprotective role of the whole endogenous NOS system. Our findings also suggest that the NOS system in bone marrow-derived cells may be involved in this vasculoprotective mechanism.

Causes of changes in basic activities of daily living in older adults with long-term care needs.

OBJECTIVE: To elucidate basic activities of daily living (BADL) changes, and the causes, in older adults with long-term care needs. METHODS: This retrospective study utilised long-term care insurance (LTCI) certification survey data from 2010 to 2017 in City A. RESULTS: In decreasing likelihood of requiring assistance, BADL items were grooming, bathing, getting dressed/undressed, mobility, toilet hygiene, functional mobility and self-feeding. Cox proportional hazard regression indicated that age correlated with need for assistance for all BADL items. Male sex corresponded to needing assistance with BADL items other than grooming and functional mobility. Shared living corresponded to needing assistance with BADL items other than grooming and bathing. Visual acuity corresponded to needing assistance with grooming. CONCLUSION: The most significant result was using survival curves to visualise the changes in BADL items of older adults with LTCI. These findings could help develop rehabilitation programs to prevent the need for BADL assistance in older adults.

Long-Term Changes in Older Adults' Independence Levels for Performing Activities of Daily Living in Care Settings: A Nine-Year Follow-Up Study.

This study aimed to clarify the variability in the independence profiles of specific activities of daily living (ADL) among older men and women. The research subjects were 5872 older adults (1143 men and 4729 women) certified as requiring nursing care or support (based on data obtained from the nursing care insurance certification survey database) who could be surveyed in both 2009 and 2018. Using item response theory, this study compared longitudinal data of difficulties faced by older adults during ADL. The results indicated that among the long-term care insurance-certified persons, in 2009, men had higher ADL difficulty than women in all ADL items, and in 2018, there was no significant difference in items other than dressing and excretion. Furthermore, the difference in the rate of ADL difficulty level over 9 years was significantly higher in women than in men. It was shown that the progression of ADL disability due to aging is faster in men on a yearly basis, but it increases in women with aging. Therefore, it was suggested that the rate of ADL difficulty varies depending on age and sex.