On Demand Synthesis of C3-N1' Bisindoles by a Formal Umpolung Strategy: First Total Synthesis of (±)-Rivularin A.

In this work, a straightforward synthesis of C3-N1' bisindolines is achieved by a formal umpolung strategy. The protocols were tolerant of a wide variety of substituents on the indole and indoline ring. In addition, the C3-N1' bisindolines could be converted to C3-N1' indole-indolines and C3-N1'-bisindoles. Also, we have successfully synthesized (±)-rivularin A through a biomimetic late-stage tribromination as a key step.

Formal One Carbon Deletion of Indoline Hemiaminals under Tautomeric Control to Access 2-Aminobenzyl Compounds.

Unprecedented tert-BuOK-mediated one carbon deletion of indoline hemiaminals has been achieved. This novel protocol provides an efficient synthetic tool for the construction of 2-aminobenzyl compounds with high chemoselectivity. In addition, functionalized 2-aminobenzyl compounds are difficult to make, for which few limited means of access currently exist. The key to success is the use of in situ generated Heyns rearrangement products (α-amino carbonyl compounds) as precursors for formal one carbon deletion.

Synthetic strategies for the construction of C3-N1' bisindoles.

C3-N1' bisindoles are unique structures, and the construction of these structures has drawn much attention. However, their synthesis still presents significant challenges that limit the functional group compatibility. This minireview summarizes the recent progress in the methodology for constructing C3-N1' bisindoles. There are two approaches for access to C3-N1' bisindoles: (1) direct approaches including reverse polarity techniques. (2) Stepwise approaches using designed and prefunctionalized substrates enable further functionalization by additional reactions to facilitate access to the target products. I believe that this review will allow its readers to develop novel approaches for the synthesis of C3-N1' bisindoles.

Indoline hemiaminals: a platform for accessing anthranilic acid derivatives through oxidative deformylation.

2-Aminobenzoyl chlorides possess both a nucleophilic nitrogen atom and an electrophilic carbonyl group, and thus selective acylation of nucleophiles is challenging; self-dimerization and sluggish reactions occur. Herein, we introduce a new synthetic protocol using 2-aminobenzoyl surrogates, allowing concise entry to decorated 2-aminobenzoyl derivatives in the absence of transition metals, acid chlorides, and specific reagents.

Sacrificial Mechanical Bond is as Effective as a Sacrificial Covalent Bond in Increasing Cross-Linked Polymer Toughness.

Sacrificial chemical bonds have been used effectively to increase the toughness of elastomers because such bonds dissociate at forces significantly below the fracture limit of the primary load-bearing bonds, thereby dissipating local stress. This approach owes much of its success to the ability to adjust the threshold force at which the sacrificial bonds fail at the desired rate, for example, by selecting either covalent or noncovalent sacrificial bonds. Here, we report experimental and computational evidence that a mechanical bond, responsible for the structural integrity of a rotaxane or a catenane, increases the elastomer's fracture strain, stress, and energy as much as a covalent bond of comparable mechanochemical dissociation kinetics. We synthesized and studied 6 polyacrylates cross-linked by either difluorenylsuccinonitrile (DFSN), which is an established sacrificial mechanochromic moiety; a [2]rotaxane, whose stopper allows its wheel to dethread on the same subsecond time scale as DFSN dissociates when either is under tensile force of 1.5-2 nN; a structurally homologous [2]rotaxane with a much bulkier stopper that is stable at force >5.5 nN; similarly stoppered [3]rotaxanes containing DFSN in their axles; and a control polymer with aliphatic nonsacrificial cross-links. Our data suggest that mechanochemical dethreading of a rotaxane without failure of any covalent bonds may be an important, hitherto unrecognized, contributor to the toughness of some rotaxane-cross-linked polymers and that sacrificial mechanical bonds provide a mechanism to control material fracture behavior independently of the mechanochemical response of the covalent networks, due to their distinct relationships between structure and mechanochemical reactivity.

One-Pot Synthesis of Core Structure of Shewanelline C Using an Azidoindoline.

The unprecedented synthesis of the indolines bearing N3-quinazolin-2,4-dione moiety using an AZIN is reported. The concise synthesis features the tandem Staudinger/chemo-selective aza-Wittig/cyclization sequence of AZINs with isatoic anhydride by a one-pot protocol.

Oxytrofalcatin Puzzle: Total Synthesis and Structural Revision of Oxytrofalcatins B and C.

The previously reported structures of oxytrofalcatins B and C possess a benzoyl indole core. However, following synthesis and NMR comparison of both the proposed structure and the synthesized oxazole, we have revised the structure of oxytrofalcatins B and C as oxazoles. The synthetic route developed herein can further our understanding of the biosynthetic pathways that govern the production of natural 2,5-diaryloxazoles.

Synthesis of Spiro[indole-3,3'-pyrrolidine]-2'-(thi)ones.

Spiro[indole-3,3'-pyrrolidine]-2'-ones were synthesized via one-pot chloroformylation-dearomatizing spirocyclization of tryptamine derivatives. Moreover, the "thio" equivalent spiro[indole-3,3'-pyrrolidine]-2'-thiones, for which the synthesis and properties were previously unreported, were synthesized. The procedures are easily implemented, have a broad scope, and are transition-metal-free and cheap. To demonstrate the utility of the synthetic methodology, the spiro[indole-3,3'-pyrrolidine]-2'-ones were converted into heterocyclic scaffolds, such as an optically active spiroindoline and spirooxindole.

Fluctuations in Cognitive Test Scores and Loss to Follow-Up in Community-Dwelling Older Adults: The IRIDE Cohort Study.

INTRODUCTION: We examined the relationship between previous fluctuations in Mini-Mental State Examination (MMSE) scores, future changes in MMSE scores, and attrition from follow-up surveys, which helps in a more comprehensive interpretation of repeatedly collected MMSE scores. METHODS: This 4-year longitudinal study included 2,073 community-dwelling older adults aged ≥65 years in Japan. The MMSE was administered at baseline (T0), 2 years (T1), and 4 years (T2) follow-up. We performed multinomial logistic regression analysis with the dependent variable, indicating the change in MMSE score from T1 to T2 (categorized as increase, no change [reference category], and decrease) and attrition at T2. The independent variables included the change in MMSE scores from T0 to T1 and MMSE scores at T0 and T1. RESULTS: The mean MMSE score was 29 across the three time points. A one-point decrease in MMSE score from T0 to T1 was associated with 79% (95% confidence interval: 1.62, 1.97) higher odds of an increase in MMSE score from T1 to T2 and 28% (1.17, 1.40) higher odds of attrition at T2. A one-point decrement in the MMSE score at T0 and T1 was also associated with an increase in the MMSE score from T1 to T2 and attrition at T2. CONCLUSION: Focusing on cognitive fluctuation for 2 years, rather than cognitive function at a point in time, would have no remarkable advantage when focusing on future cognitive function and attrition. Our results emphasize the need for further studies to identify factors that distinguish between those who continue to attend follow-up surveys and show improvements in cognitive test scores and those who drop out.

Effects of community-based frailty-preventing intervention on all-cause and cause-specific functional disability in older adults living in rural Japan: A propensity score analysis.

Preventing frailty is crucial in aging societies. We examined the effectiveness of a community-based frailty-prevention program for delaying the onset of functional disability among community-dwelling older adults. From 2014 to 2019, 48 community-based frailty prevention classes (FPC, 60 min/session, once a week), comprising resistance exercise and nutritional or psychosocial programs, were established in Yabu City, Japan. We conducted a baseline survey in 2012 and followed up with participants for up to 6.8 years (4.8 years from establishing the first FPC). We analyzed data from 3350 older people. The primary and secondary outcomes were the onset of functional disability and cause-specific functional disability (including dementia and cardiovascular and orthopedic diseases), respectively. In addition to crude Cox proportional hazard regression, inverse probability of treatment weighting (IPTW) and propensity score matching (PSM; 918 nonparticipants and 459 participants) were used to adjust for confounders. Participants were more likely to be female and have a healthy lifestyle than nonparticipants. During the follow-up, 690 individuals developed a functional disability. The hazard ratio of incident functional disability in the participants was significantly lower than that in nonparticipants in the IPTW (hazard ratio 0.53, 95% confidential interval 0.38-0.75) and PSM (0.52, 0.37-0.71) analyses. In age-stratified analysis, significant associations were observed only in the ≥75-year-old subgroup. In a cause-specific analysis, participation significantly and consistently reduced incident functional disability caused by dementia (IPTW 0.47, 0.25-0.86; PSM 0.45, 0.25-0.83). Community-based FPC may be effective for preventing functional disability, especially caused by dementia, in this population.

Combined Impacts of Physical Activity, Dietary Variety, and Social Interaction on Incident Functional Disability in Older Japanese Adults.

BACKGROUND: This 3.6-year prospective study examined combined impacts of physical activity, dietary variety, and social interaction on incident disability and estimated population-attributable fraction for disability reduction in older adults. METHODS: Participants were 7,822 initially non-disabled residents (3,966 men and 3,856 women) aged 65-84 years of Ota City, Tokyo, Japan. Sufficiency of moderate-to-vigorous-intensity physical activity (MVPA) ≥150 min/week, dietary variety score (DVS) ≥3 (median), and social interaction (face-to-face and/or non-face-to-face) ≥1 time/week was assessed using self-administered questionnaires. Disability incidence was prospectively identified using the long-term care insurance system's nationally unified database. RESULTS: During a follow-up of 3.6 years, 1,046 (13.4%) individuals had disabilities. Independent multivariate-hazard ratios (HRs) and 95% confidence intervals (CIs) of MVPA, DVS, and social interaction sufficiency for incident disability were 0.68 (95% CI, 0.59-0.78), 0.87 (95% CI, 0.77-0.99), and 0.90 (95% CI, 0.79-1.03), respectively. Incident disability HRs gradually reduced with increased frequency of satisfying these behaviors (any one: HR 0.82; 95% CI, 0.65-1.03; any two: HR 0.65; 95% CI, 0.52-0.82; and all three behaviors: HR 0.54; 95% CI, 0.43-0.69), in an inverse dose-response manner (P < 0.001 for trend). Population-attributable fraction for disability reduction in satisfying any one, any two, and all three behaviors were 4.0% (95% CI, -0.2 to 7.9%), 9.6% (95% CI, 4.8-14.1%), and 16.0% (95% CI, 8.7-22.8%), respectively. CONCLUSION: Combining physical activity, dietary variety, and social interaction substantially enhances the impacts on preventing disability among older adults, with evidence of an inverse dose-response manner. Improving insufficient behavior elements through individual habits and preexisting social group activities may be effective in preventing disability in the community.

Association of dietary variety with the risk for dementia: the Yabu cohort study.

OBJECTIVE: The consumption of various foods is internationally recommended in healthy diet although the association between dietary variety and incident dementia is unknown. We aimed to examine the association between dietary variety and the incidence of disabling dementia in older Japanese adults. DESIGN: We conducted a prospective cohort study. Dietary variety was assessed based on the Dietary Variety Score (DVS). DVS was assessed by counting the number of ten food components (meat, fish/shellfish, eggs, milk, soyabean products, green/yellow vegetables, potatoes, fruit, seaweed and fats/oils) that were consumed almost daily using a FFQ. Participants were categorised into low (0-2 points), middle (3-4 points) and high (5-10 points) groups based on the DVS. Data on newly diagnosed disabling dementia were retrieved from the public long-term care insurance database. Cox proportional hazards regression was used to estimate hazard ratios (HR) with 95 % CI. SETTING: Yabu cohort study, Japan. PARTICIPANTS: A total of 4972 community-dwelling adults aged 65 years or older. RESULTS: During the median follow-up of 6·8 years, 884 participants were newly diagnosed with disabling dementia. After adjusting for confounders, the multivariable-adjusted HR for incident disabling dementia was 0·82 (95 % CI, 0·69, 0·97) for participants in the highest DVS category compared with those in the lowest DVS category (Pfor trend = 0·019). CONCLUSIONS: A higher dietary variety is associated with a reduced risk of disabling dementia in older Japanese adults. These results have potential implications for the development of effective public nutritional approaches to prevent dementia in older adults.

Detecting side-to-side differences of lower limb biomechanics during single-legged forward landing after anterior cruciate ligament reconstruction.

BACKGROUND: Motion analysis can be used to evaluate functional recovery after anterior cruciate ligament (ACL) reconstruction; however, the biomechanics parameters of the lower limb that are specifically altered in ACL-reconstructed knees compared to the contralateral side are not well understood. This retrospective study aimed to compare side-to-side differences in lower limb biomechanics during the first 100 milliseconds (ms) after initial contact in a single-leg forward landing task. METHODS: Using three-dimensional motion analysis, lower joint kinematic and kinetic variables were measured 8-10 months postoperatively in 22 patients who had undergone ACL reconstruction. We determined side-to-side differences in lower limb biomechanics over the 100-ms timeframe after landing, and receiver operating characteristic (ROC) curve analyses were performed to calculate the area under the curve (AUC) for parameters showing significant side-to-side differences. RESULTS: During the 100-ms timeframe after landing, 58 kinematic and kinetic items showed significant side-to-side differences. Side-to-side differences in lower limb biomechanics over the 40-ms timeframe after landing existed. The ROC curve analysis identified 11 items with AUC values ≥ 0.70, including hip flexion, abduction moment, and knee joint power, and their AUC values were not significantly different. CONCLUSION: Hip flexion/abduction moment and knee power after GRF max could be used as outcomes for assessing functional recovery in patients who have undergone ACL reconstruction.

Revisiting Cryptocyanine Dye, NK-4, as an Old and New Drug: Review and Future Perspectives.

NK-4 plays a key role in the treatment of various diseases, such as in hay fever to expect anti-allergic effects, in bacterial infections and gum abscesses to expect anti-inflammatory effects, in scratches, cuts, and mouth sores from bites inside the mouth for enhanced wound healing, in herpes simplex virus (HSV)-1 infections for antiviral effects, and in peripheral nerve disease that causes tingling pain and numbness in hands and feet, while NK-4 is used also to expect antioxidative and neuroprotective effects. We review all therapeutic directions for the cyanine dye NK-4, as well as the pharmacological mechanism of NK-4 in animal models of related diseases. Currently, NK-4, which is sold as an over-the-counter drug in drugstores, is approved for treating allergic diseases, loss of appetite, sleepiness, anemia, peripheral neuropathy, acute suppurative diseases, wounds, heat injuries, frostbite, and tinea pedis in Japan. The therapeutic effects of NK-4's antioxidative and neuroprotective properties in animal models are now under development, and we hope to apply these pharmacological effects of NK-4 to the treatment of more diseases. All experimental data suggest that different kinds of utility of NK-4 in the treatment of diseases can be developed based on the various pharmacological properties of NK-4. It is expected that NK-4 could be developed in more therapeutic strategies to treat many types of diseases, such as neurodegenerative and retinal degenerative diseases.

Indole Editing Enabled by HFIP-Mediated Ring-Switch Reactions of 3-Amino-2-Hydroxyindolines.

This work reports the novel reactivity of hemiaminal as a precursor for indole editing at the multi-site. The HFIP-promoted indole editing of indoline hemiaminals affords 2-arylindoles through a ring-switch sequence. The key to success of this transformation is to use a cyclic hemiaminal as an α-amino aldehyde surrogate under transient tautomeric control. This transformation features mild reaction conditions and good yields with broad functional group tolerance. The utility of this transformation is presented through the one-pot protocol and the synthesis of isocryptolepine.

First Total Synthesis of Reassigned Echinosulfonic Acid D.

Echinosulfonic acid D, a sponge metabolite whose structure was recently reassigned, was synthesized for the first time. The key step is the double indolization of dimethylbarbituric acid using the umpolung indole reagent, followed by a hydrolysis/decarboxylation/esterification sequence.

Dose-Response Associations of Physical Activity and Sitting Time with All-Cause Mortality in Older Japanese Adults.

PURPOSE: Although examining the dose-response curves of physical activity (PA) and sitting time with health-related outcomes is an important research agenda, the results for older Japanese adults are extremely limited. We examined the dose-response associations of PA and sitting time with all-cause mortality among older Japanese. METHODS: Initially, 8,069 non-disabled residents (4,073 men; 3,996 women) aged 65-84 years of Ota City, Japan, were recruited. Moderate-to-vigorous PA (MVPA) and sitting time were evaluated using the International Physical Activity Questionnaire-Short Form. Multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of MVPA and sitting time for all-cause mortality were calculated, and the dose-response curves were examined using restricted cubic splines (RCS). RESULTS: During 4.1 years of follow-up, 458 participants (5.7%; 331 men and 127 women) died. Compared with the low MVPA (<600 metabolic equivalents [METs]·minutes/week) group, HR for mortality gradually reduced in moderate (600-3000 METs·minutes/week) and high (>3000 METs·minutes/week) MVPA groups (moderate: HR 0.66; 95% CI, 0.54-0.82; high: HR 0.58; 95% CI, 0.45-0.75; P <0.001 for trend). RCS showed that the HR for mortality reduced linearly up to approximately 2000 METs·minutes/week of MVPA, and maximal risk reduction was seen at approximately 3000-4500 METs·minutes/week of MVPA. No significant dose-response association of sitting time with mortality was observed. CONCLUSIONS: Higher MVPA levels reduced all-cause mortality risk, in a significant inverse non-linear dose-response manner. Sitting time was not significantly associated with all-cause mortality. It is important to disseminate the significance of even a slight increase in the MVPA.

[Development of a risk prediction model and a sample risk chart for long-term care certification based on the functional health of older adults].

Objectives　The first aim of this study was to develop risk prediction models based on age, sex, and functional health to estimate the absolute risk of the 3-year incidence of long-term care certification and to evaluate its performance. The second aim was to produce risk charts showing the probability of the incident long-term care certification as a tool for prompting older adults to engage in healthy behaviors.Methods　This study's data was obtained from older adults, aged ≥65 years, without any disability (i.e., they did not certify≥care level 1) and residing in Yabu, Hyogo Prefecture, Japan (n=5,964). A risk prediction model was developed using a logistic regression model that incorporated age and the Kihon Checklist (KCL) score or the Kaigo-Yobo Checklist (KYCL) score for each sex. The 3-year absolute risk of incidence of the long-term care certification (here defined as≥care level 1) was then calculated. We evaluated the model's discrimination and calibration abilities using the area under the receiver operating characteristic curves (AUC) and the Hosmer-Lemeshow goodness-of-fit test, respectively. For internal validity, the mean AUC was calculated using a 5-fold cross-validation method.Results　After excluding participants with missing KCL (n=4) or KYCL (n=1,516) data, we included 5,960 for the KCL analysis and 4,448 for the KYCL analysis. We identified incident long-term care certification for men and women during the follow-up period: 207 (8.2%) and 390 (11.3%) for KCL analysis and 128 (6.6%) and 256 (10.2%) for KYCL analysis, respectively. For calibration, the χ2 statistic for the risk prediction model using KCL and KYCL was: P=0.26 and P=0.44 in men and P=0.75 and P=0.20 in women, respectively. The AUC (mean AUC) in the KCL model was 0.86 (0.86) in men and 0.83 (0.83) in women. In the KYCL model, the AUC was 0.86 (0.85) in men and 0.85 (0.85) in women. The risk charts had six different colors, suggesting the predicted probability of incident long-term care certification.Conclusions　The risk prediction model demonstrated good discrimination, calibration, and internal validity. The risk charts proposed in our study are easy to use and may help older adults in recognizing their disability risk. These charts may also support health promotion activities by facilitating the assessment and modification of the daily behaviors of older adults in community settings. Further studies with larger sample size and external validity verification are needed to promote the widespread use of risk charts.

[Development and evaluation of a modified version of the dietary variety score for community-dwelling older adults].

Objectives　The dietary variety score (DVS) was developed as an index to assess the variety of food intake among older Japanese adults and has been widely used in epidemiological studies and public health settings. However, this index has not been reviewed since its development in the 1990s and may not adequately reflect the current dietary habits of the older Japanese population. In this study, we developed a modified version of the DVS (MDVS) and examined its validity.Methods　We conducted a cross-sectional study of 357 community-dwelling adults aged ≥65 years (mean age: 76.2±4.6, men: 61.1%) who participated in the 2016 survey of the Hatoyama cohort study. The DVS and MDVS were assessed by the number of food groups eaten almost every day based on the weekly frequency of consumption. The DVS was calculated based on ten components: meat, fish/shellfish, eggs, milk, soybean products, green/yellow vegetables, potatoes, fruits, seaweed, and fats/oils. The components of the MDVS were determined by calculating the contribution of each food group to the total and nutrient intakes from the food groups comprising the main dish, side dish, and soup, based on the data from older adults aged ≥65 years who participated in the 2017 National Health and Nutrition Survey in Japan. Based on the contribution of each food group, we added "other vegetables" and "dairy products" in the MDVS. Dietary intake was assessed using a validated, self-administered diet history questionnaire. We calculated the probability of adequacy for each of the fourteen nutrients selected as per the estimated average requirement in the Dietary Reference Intake for Japanese 2020 and the mean probability of adequacy for all fourteen nutrients. In addition, we assessed the correlation between the DVS, MDVS, and each indicator and the significance of the difference between correlation coefficients.Results　The MDVS was significantly positively correlated with the energy ratios of protein and fat, dietary fiber, potassium, and the modified diet score based on the Japanese Food Guide Spinning Top (r=0.21-0.45) and negatively correlated with the carbohydrate energy ratio (r=-0.32). The MDVS was also correlated with the mean probability of nutrient adequacy (r=0.41). The correlation coefficients between the MDVS and each indicator were not significantly different from those of the DVS.Conclusions　Validity in terms of nutrient intake and diet quality was comparable between the DVS and MDVS. To revise the DVS, it is necessary to conduct nationwide studies based on highly accurate dietary surveys.

Development of risk prediction models for incident frailty and their performance evaluation.

There is currently no tool to predict incident frailty despite various frailty assessment tools. This study aimed to develop risk prediction models for incident frailty and evaluated their performance on discrimination, calibration, and internal validity. This 2-year follow-up study used data from 5076 non-frail older adults (51% women) living in Tokyo at baseline. We used the Kaigo-Yobo checklist, a standardised assessment instrument, to determine frailty. Twenty questionnaire-based variables that include sociodemographic, medical, behavioural, and subjective factors were entered into binary logistic regression analysis with stepwise backward elimination (p < 0.1 for retention in the model). Discrimination and calibration were assessed by area under the receiver operating characteristic curve (AUC) and the Hosmer-Lemeshow test, respectively. For the assessment of internal validity, we used a 5-fold cross-validation method and calculated the mean AUC. At the follow-up survey, 15.0% of men and 10.2% of women were frail. The frailty risk prediction model was composed of 10 variables for men and 11 for women. AUC of the model was 0.71 in men and 0.72 in women. The P-value for the Hosmer-Lemeshow test in both models was more than 0.05. For internal validity, the mean AUC was 0.71 in men and 0.72 in women. Probability of incident frailty rose with an increasing risk score that was calculated from the developed models. These results demonstrated that the developed models enable the identification of non-frail older adults at high risk of incident frailty, which could help to implement preventive approaches in community settings.