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.

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.

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.

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.

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.

Meaningful Activities and Psychosomatic Functions in Japanese Older Adults after Driving Cessation.

The purpose of this cross-sectional study was to analyse the differences in meaningful activities and psychosomatic function depending on the driving status of community-dwelling older adults. Data from 594 older adults were obtained, including activities meaningful to individuals and psychosomatic functions, such as grip strength, depression, cognitive function, and ability of activity. Participants were divided into active driving (n = 549) and after driving cessation (n = 45) groups. In addition, the active driving group was operationally divided into three groups: high-frequency group (n = 387), medium group (n = 119), and infrequent group (n = 42). In the after driving cessation group, grip strength, and Japan Science and Technology Agency Index of Competence scores were significantly lower. Furthermore, the proportion of apathy and physical and social frailty was significantly higher in the after driving cessation group. Regarding meaningful activity, domestic life scores in the after driving cessation group were significantly higher than those of the active driving group. Decreased driving frequency in the active driving group was associated with weak muscle strength, lack of interest, and low activity. This study demonstrated that meaningful activity differed based on the driving status. Hence, we should support the activities of older adults who are considering driving cessation.

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.

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.

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.

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.

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.

Effects of prism adaptation on auditory spatial attention in patients with left unilateral spatial neglect: a non-randomized pilot trial.

A short period of adaptation to a prismatic shift of the visual field to the right briefly but significantly improves left unilateral spatial neglect. Additionally, prism adaptation affects multiple modalities, including processes of vision, auditory spatial attention, and sound localization. This non-randomized, single-center, controlled trial aimed to examine the immediate effects of prism adaptation on the sound-localization abilities of patients with left unilateral spatial neglect using a simple source localization test. Subjects were divided by self-allocation into a prism-adaptation group (n = 11) and a control group (n = 12). At baseline, patients with left unilateral spatial neglect showed a rightward deviation tendency in the left space. This tendency to right-sided bias in the left space was attenuated after prism adaptation. However, no changes were observed in the right space of patients with left unilateral spatial neglect after prism adaptation, or in the control group. Our results suggest that prism adaptation improves not only vision and proprioception but also auditory attention in the left space of patients with left unilateral spatial neglect. Our findings demonstrate that a single session of prism adaptation can significantly improve sound localization in patients with left unilateral spatial neglect. However, in this study, it was not possible to accurately determine whether the mechanism was a chronic change in head orientation or a readjustment of the spatial representation of the brain; thus, further studies need to be considered.

Associations between Depressive Symptoms and Satisfaction with Meaningful Activities in Community-Dwelling Japanese Older Adults.

The aim of this cross-sectional study was to investigate relationships between individuals' ratings of satisfaction and performance of activities that they found meaningful and depressive symptoms. Data was obtained from 806 older adults (mean age 74.9 ± 6.3 years, women = 63.0%) who participated in a community-based health check survey (Tarumizu Study 2018). Participants selected meaningful activities from 95 activities using the Aid for Decision-Making in Occupation Choice and evaluated their satisfaction and performance. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15) and defined by a GDS-15 score of ≥5. Non-linear logistic regression analyses were used separately by gender to examine the association between satisfaction and performance of meaningful activities and depressive symptoms. The prevalence of depressive symptoms was 15.8%. We found no significant difference between meaningful activity choice between older adults with depressive symptoms and those without, in both men and women. After adjusting for potential covariates, satisfaction was associated with depressive symptoms in both men (OR 0.52, 95% CI 0.35-0.77) and women (OR 0.67, 95% CI 0.49-0.91), but performance was limited in women (OR 0.87, 95% CI 0.77-0.99). Our findings suggest that depressive symptoms are associated with satisfaction in meaningful activities regardless of activity categories.

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.

The N-Terminal Polybasic Region of Prion Protein Is Crucial in Prion Pathogenesis Independently of the Octapeptide Repeat Region.

Conformational conversion of the cellular isoform of prion protein, designated PrPC, into the abnormally folded, amyloidogenic isoform, PrPSc, is an essential pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Lines of evidence indicate that the N-terminal domain, which includes the N-terminal, positively charged polybasic region and the octapeptide repeat (OR) region, is important for PrPC to convert into PrPSc after infection with prions. To further gain insights into the role of the polybasic region and the OR region in prion pathogenesis, we generated two different transgenic mice, designated Tg(PrP3K3A)/Prnp0/0 and Tg(PrP3K3A∆OR)/Prnp0/0 mice, which express PrPC with lysine residues at codons 23, 24, and 27 in the polybasic region mutated with or without a deletion of the OR region on the Prnp0/0 background, respectively, and intracerebrally inoculated them with RML and 22L prions. We show that Tg(PrP3K3A)/Prnp0/0 mice were highly resistant to the prions, indicating that lysine residues at 23, 24, and 27 could be important for the polybasic region to support prion infection. Tg(PrP3K3A∆OR)/Prnp0/0 mice also had reduced susceptibility to RML and 22L prions equivalent to Tg(PrP3K3A)/Prnp0/0 mice. The pre-OR region, including the polybasic region, of PrP3K3A∆OR, but not PrP3K3A, was unusually converted to a protease-resistant structure during conversion to PrPSc3K3A∆OR. These results suggest that, while the OR region could affect the conformation of the polybasic region during conversion of PrPC into PrPSc, the polybasic region could play a crucial role in prion pathogenesis independently of the OR region.

Impact of Outpatient Rehabilitation Service in Preventing the Deterioration of the Care-Needs Level Among Japanese Older Adults Availing Long-Term Care Insurance: A Propensity Score Matched Retrospective Study.

Outpatient rehabilitation (OR) and outpatient day long-term care (ODLC) services are frequently used by older adult patients in Japan. However, there is a need to clarify that OR service, which has more rehabilitation professionals than ODLC, has the role of providing rehabilitation. This retrospective study examined the impact of OR services by comparing the two services based on City A data from the care-needs certification survey conducted between 2015 to 2017. We performed a propensity score matched analysis to compare the changes in the care level and function of OR and ODLC users after two years. The results showed that OR users showed a lower deterioration in care levels and less decline in the activities of daily living (ADL) in dementia and adaptation to social life. In the analysis of older adults requiring support, OR users had a lower deterioration in care levels and less decline in the ADL in dementia and behavioral and psychological symptoms than ODLC users did. There was no difference between the two services with respect to older adults requiring long-term care. The OR service has had an increasingly preventive effect on the deterioration of care levels compared to the ODLC service, which was particularly evident in older adults requiring support.

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.