Physical Activity and Health of Middle-Aged and Older Japanese Across the COVID-19 Pandemic: Differential Outcomes Highlight a Problematic Life Stage.

INTRODUCTION: COVID-19 caused major disruptions across the super-aged nation of Japan, yet few studies explored temporal changes among middle-aged and older cohorts from baseline to the height of community transmission. Changes in physical activity and sedentary behavior during global pandemics may alter patterns of morbidity and mortality among susceptible aging populations. OBJECTIVES: This study investigated patterns of physical activity, sitting behavior, and health among representative samples of middle-aged and older adults in Tokyo before and during the pandemic. METHODS: Repeated online surveys were conducted with quota samples of 800 Tokyo residents in 2019 and 2021 using validated Japanese-language measures, including the short form-International Physical Activity Questionnaire and the Basic Ecological Health Scale-6. Statistical analyses included comparative evaluations of activity parameters by age cohort, gender, and selected covariates. Statistical tests included the Kruskal-Wallis test, Mann-Whitney U test, chi-square test for Independence and Hierarchical Regression. RESULTS: Over 34% of respondents were inactive at each data collection point, and 72% reported negative impacts of COVID-19 on their physical activities. Older adults showed no significant changes in their activity and sitting behavior and reported better health compared with those in middle age across the pandemic. Middle-aged males reported a significant decline in total activity of 33% across the pandemic period (U = 16,958, z = -2.64, p = .008, r = .13). Middle-aged females reported the lowest levels of physical activity, and health, and showed a 29% increase in sitting behavior across the pandemic (U = 16,925, z = -2.68, p = .007, r = .13). Subjective health status was consistently associated with higher overall activity and walking before and during the pandemic. CONCLUSION: Differential outcomes were identified between age and gender regarding health, physical activity, walking, and sitting across the pandemic with significantly worse impacts reported among middle-aged samples. IMPLICATIONS: These results have implications for healthy transitions to later life and the design of postpandemic interventions to address activity opportunities in Japan.

Potential of MAIT cells to modulate asthma.

Despite recent advances in asthma treatments, the search for novel therapies remains necessary because there are still patients with recurrent asthma exacerbations and poor responses to the existing treatments. Since group 2 innate lymphoid cells (ILC2) play a pivotal role in asthma by triggering and exacerbating type 2 inflammation, controlling ILC2s function is key to combating severe asthma. Mucosal-associated invariant T (MAIT) cells are innate-like T cells abundant in humans and are activated both in a T cell receptor-dependent and -independent manner. MAIT cells are composed of MAIT1 and MAIT17 based on the expression of transcription factors T-bet and RORγt, respectively. MAIT cells play pivotal roles in host defense against pathogens and in tissue repair and are essential for the maintenance of immunity and hemostasis. Our recent studies revealed that MAIT cells inhibit both ILC2 proliferation and functions in a mouse model of airway inflammation. MAIT cells may alleviate airway inflammation in two ways, by promoting airway epithelial cell barrier repair and by repressing ILC2s. Therefore, reagents that promote MAIT cell-mediated suppression of ILC2 proliferation and function, or designer MAIT cells (genetically engineered to suppress ILC2s or promote repair of airway damage), may be effective therapeutic agents for severe asthma.

REST Inactivation and Coexpression of ASCL1 and POU3F4 Are Necessary for the Complete Transformation of RB1/TP53-Inactivated Lung Adenocarcinoma into Neuroendocrine Carcinoma.

Although recent reports have revealed the importance of the inactivation of both RB1 and TP53 in the transformation from lung adenocarcinoma into neuroendocrine carcinoma (NEC), the requirements for complete transformation into NEC have not been elucidated. To investigate alterations in the characteristics associated with the inactivation of RB1/TP53 and define the requirements for transformation into NEC cells, RB1/TP53 double-knockout A549 lung adenocarcinoma cells were established, and additional knockout of REST and transfection of ASCL1 and POU class 3 homeobox transcription factors (TFs) was conducted. More than 60 genes that are abundantly expressed in neural cells and several genes associated with epithelial-to-mesenchymal transition were up-regulated in RB1/TP53 double-knockout A549 cells. Although the expression of chromogranin A and synaptophysin was induced by additional knockout of REST (which mimics the status of most NECs), the expression of another neuroendocrine marker, CD56, and proneural TFs was not induced. However, coexpression of ASCL1 and POU3F4 in RB1/TP53/REST triple-knockout A549 cells induced the expression of not only CD56 but also other proneural TFs (NEUROD1 and insulinoma-associated 1) and induced NEC-like morphology. These findings suggest that the inactivation of RB1 and TP53 induces a state necessary for the transformation of lung adenocarcinoma into NEC and that further inactivation of REST and coexpression of ASCL1 and POU3F4 are the triggers for complete transformation into NEC.

Twenty-year longitudinal birth cohort study of individuals diagnosed with autism spectrum disorder before seven years of age.

BACKGROUND: Previous longitudinal studies have demonstrated that psychosocial outcomes for autistic adults are very limited. However, most studies are clinic-based and liable to selection bias and major methodological problems. METHODS: We conducted a long-term follow-up study with 278 autistic individuals from our previous birth cohort study comprising 31,426 individuals. All participants were born in northern Yokohama between 1988 and 1996, diagnosed with autism spectrum disorder (ASD) by age seven, and followed up over 20 years. A total of 170 consented to participate in the study. Outcome measures included overall social functioning based on work, independent living, and friendships. Moreover, the time-use data concerning social participation and activities of daily living were compared with the general population. RESULTS: Psychosocial outcomes in adulthood (average age 25) were very good in 13.7%, good in 25.0%, fair in 31.0%, poor in 25.6%, and very poor in 4.8% of the participants. The majority participated in major life areas of and work and education (96.4%), sports (82.1%), and recreational activities and/or hobbies (98.8%). The proportion of participants who engaged in housework and self-care was comparable to that of the general population. Participants with IQ < 50 at age five had significantly worse outcomes than those with higher IQ; however, for those with IQ ≥ 50, outcomes were not significantly associated with IQ levels. CONCLUSIONS: Although complete independence was difficult to accomplish, many autistic adults engaged in organized community activities and housework and self-care. Time-use survey could offer a variety of data in investigating psychosocial outcomes of ASD cross-culturally.

Metabolic changes induced by TGF-ß1 via reduced expression of phosphatidylserine decarboxylase during myofibroblast transition.

Metabolic alteration is increasingly recognized as an important pathogenic process that underlies fibrosis across many organ types, and metabolically targeted therapies could become important strategies for reducing fibrosis. In present study, target enzymes that are involved in changes in phospholipid metabolism during fibroblast-to-myofibroblast transition induced by transforming growth factor beta 1 (TGF-ß1) were examined. Different amounts of phospholipids were found in the 2 groups. In response to TGF-ß1 stimulation, 17 lipids decreased and 17 increased. The latter included the phospholipids phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylethanolamine (PE). Furthermore, among the rate-limiting enzymes that regulate these phospholipids, phosphatidylserine decarboxylase (PISD), which controls conversion of PS to PE and is localized in mitochondria, decreased in response to TGF-ß1. Knockdown of PISD alone without TGF-ß1 stimulation increased expression of α-smooth muscle actin mRNA and production of total collagen. Taken together, these results indicate that PISD is involved in the mechanism of fibrogenesis by regulating phospholipid metabolism.

Physical Activity Among Urban-Living Middle-Aged and Older Japanese During the Build-Up to the Tokyo Olympic and Paralympic Games: A Population Study.

This research examines physical activity (PA) parameters among urban-living middle-aged and older Japanese during the Tokyo Olympic build-up period. Population sampling was employed, and an online survey was administered with 4,000 adults across Japan's five largest cities. The International Physical Activity Questionnaire-Short Form constituted the main outcome variable, with auxiliary measures of Olympic interest and engagement, readiness for PA behavior change, perceived environmental barriers, and demographic information. Despite interest in the Olympics (>60% moderate-high interest), planned engagement with the event was low (>70% planned passive engagement). Higher levels of interest and planned engagement were both significantly correlated with greater self-reported PA participation (p < .001). Across the sample, the PA levels were in the low-moderate range (990 metabolic equivalent of task-min/week), with significant variations observed by the age-cohort and geographic area (p < .001). Age-cohort and geographic variations were also identified with regard to readiness for PA behavior change and perceived environmental barriers to activity (p < .001). Older age (65 years and above) and host city (Tokyo) residence emerged as correlates of higher levels of PA, greater readiness for behavior change, and fewer reported barriers to participation. These findings have implications for Olympic legacy management and successful transitions from middle age to later life in Japan.

Kosen-cha, a Polymerized Catechin-Rich Green Tea, as a Potential Functional Beverage for the Reduction of Body Weight and Cardiovascular Risk Factors: A Pilot Study in Obese Patients.

Previous studies have shown that green tea catechins (GTCs) have beneficial effects on obesity and metabolic syndromes. In this study, we prepared kosen-cha from green tea using high pressure extraction, to reduce the astringent taste of the green tea. We identified a large quantity of polymerized GTCs in kosen-cha. To investigate the effects of kosen-cha containing polymerized GTCs in obese Japanese patients, we designed an open-label pilot study in which 6 obese subjects (body mass index (BMI) >25 kg/m2) were administered kosen-cha (5 g/L/d) for 12 weeks. Body composition, serum lipids, insulin resistance, vascular functions, and cardiac hypertrophy were measured before and 12 weeks after kosen-cha administration. Kosen-cha showed no significant adverse effects on the patients. Body weights, BMI, waist circumferences, serum triglyceride (TG) levels, and homeostasis model assessment as an index of insulin resistance (HOMA-IR) levels were significantly decreased after the 12 weeks of administration. Flow-mediated dilation (FMD) (p = 0.0214), brachial-ankle pulse wave velocity (baPWV)(p = 0.0141), left ventricular mass indexes (p = 0.0120), and plasma brain natriuretic peptide (BNP) (p = 0.0144) were significantly improved. Overall, kosen-cha reduced obesity and improved insulin resistance, vascular function, and cardiac hypertrophy, indicating its preventive potential in obesity and metabolic syndrome.

Induced Pluripotent Stem Cells for Regenerative Medicine: Quality Control Based on Evaluation of Lipid Composition.

Clinical application of induced pluripotent stem cells (iPSCs), which can be differentiated into a wide variety of functional cells, is underway and some clinical trials have already been performed or are ongoing. On the other hand, the risk of carcinogenesis is an issue and the mechanism of cellular reprograming remains unknown. When iPSCs and differentiated cells are used for medical applications, quality control is also important. Here we discuss the possibility of performing quality control of iPSCs by evaluation of phospholipids, which are not just structural components of lipid bilayer membranes, but also have multiple physiological functions. Recently, methods for analysis of lipids have become more widely available and easier to perform. This article reviews the role of iPSCs in regenerative medicine and examines the possibility of using phospholipids for quality control of iPSCs and differentiated cells.

Auto-antibody evaluation in idiopathic interstitial pneumonia and worse survival of patients with Ro52/TRIM21auto-antibody.

Some patients with interstitial pneumonia (IP) have auto-antibodies, but do not fit the criteria for specific connective tissue diseases. Examination of auto-antibodies is recommended for diagnosis idiopathic pulmonary fibrosis. A prospective cohort study was performed in 285 patients with IP. Eleven auto-antibodies were assessed and patients were followed for 2 years. All 285 patients underwent the myositis panel test (MPT) for 11 auto-antibodies. Among them, 23.5% (67/285) of the patients had a positive MPT and 14.7% (42/285) had connective tissue diseases. Among the 49 MPT positive patients without connective tissue diseases, 29 patients (59.2%) were positive for Ro52, including 17 patients with Ro52 mono-positivity. Among interstitial pneumonia patients without connective tissue diseases, the Ro52 mono-positive patients showed worse at 2-years survival than those who were Ro52 negative (p = 0.022, HR = 5.88, 95% CI 1.29-26.75). Most of the Ro52 positive patients also showed a low titer of anti-nucleolar antibody. About 20% of IP patients had auto-antibodies detectable by the MPT, and Ro52 positive patients accounted for more than half of the MPT positive patients without connective tissue diseases. Detection of Ro52 auto-antibodies may be useful for assessing the risk of progression in idiopathic interstitial pneumonia patients without connective tissue diseases and a low anti-nucleolar antibody titer.

Comparison of inducible nitric oxide synthase mRNA expression in different airway portions and association with nitric oxide parameters from patients with asthma.

BACKGROUND: Fractional exhaled nitric oxide concentration (FeNO) is widely used to support diagnosis and monitoring of bronchial asthma (BA). Tsoukias and George proposed a two-compartment model (2CM) for assessing the alveolar concentration of NO, referred to as CANO(2CM), while Condorelli et al proposed a model based on the trumpet shape of the airway tree and axial diffusion (TMAD), referred to as CANO(TMAD). In addition, Högman et al proposed non-linear model, referred to as CANO(non-linear). OBJECTIVE: We examined associations between the expression of inducible nitric oxide synthase (iNOS) mRNA in airway cells (ACs) by bronchoscopy and NO-parameters calculated by the three methods and identified which of them accurately reflected expression of iNOS mRNA from different airway portions. METHODS: We retrospectively analysed data of 18 patients with stable, mild-moderate asthma, including 10 steroid-naïve BA (snBA) patients. Samples were obtained from airway brushings and bronchoalveolar lavage (BAL). Expressions of iNOS protein in tissue samples were evaluated by immunostaining. The iNOS mRNA in ACs was measured by qPCR. NO-parameters calculated by the three methods above and evaluated whether they were associated with iNOS mRNA in ACs derived from proximal (2nd carina), distal (10-15th) airways and alveolar regions. RESULTS: Immunostaining revealed expression of iNOS proteins mainly in epithelial cells in the airways, while it was mainly expressed in macrophages in the alveolar region in the snBA group. The iNOS mRNA expression was increased in both proximal and distal ACs in the snBA group compared with steroid-treated BA group (stBA). CANO(2CM) negatively associated with FEV1 (%predicted) and also associated with iNOS mRNA in distal ACs significantly. However, CANO(TMAD) and CANO(non-linear) showed no correlation with lung function nor iNOS mRNA expression in any portions of ACs. CONCLUSIONS: These results suggested that CANO(2CM) reflected distal airway inflammation in steroid-naïve asthma.

1.54 µm photoluminescence from Er:Ox centers at extremely low concentration in silicon at 300 K.

The demand for single photon emitters at λ=1.54 µm, which follows from the consistent development of quantum networks based on optical fiber technologies, makes Er:Ox centers in Si a viable resource, thanks to the I13/24→I415/2 optical transition of Er3+. While its implementation in high-power applications is hindered by the extremely low emission rate, the study of such systems in the low concentration regime remains relevant for quantum technologies. In this Letter, we explore the room-temperature photoluminescence at the telecomm wavelength from very low implantation doses of Er:Ox in Si. The lower-bound number of optically active Er atoms detected is of the order of 102, corresponding to a higher-bound value for the emission rate per individual ion of about 104 s-1.

Matrix-assisted laser desorption/ionization imaging mass spectrometry reveals changes of phospholipid distribution in induced pluripotent stem cell colony differentiation.

Induced pluripotent stem cells (iPSCs) are opening up new possibilities for medicine. Understanding the regulation of iPSC biology is important when attempting to apply these cells to disease models or therapy. Changes of lipid metabolism in iPSCs were investigated by matrix-assisted laser desorption/ionization time-of-flight imaging mass spectrometry (MALDI-TOF-IMS). Analysis revealed changes of the intensity and distribution of peaks at m/z 782.5 and 798.5 in iPSC colonies during spontaneous differentiation. Two phosphatidylcholines (PCs) were identified: C44H81NO8P, PC(36:4)[M+H]+ at m/z 782.5 and C42H82NO8P, PC(34:1)[M+K]+ at m/z 798.5. The intensity of PC(36:4) showed an inverse relation between undifferentiated and differentiated iPSC colonies. PC(34:1) displayed a diffuse distribution in undifferentiated iPSC colonies, while it showed a concentric distribution in differentiated iPSC colonies, and was localized at the border of the differentiated and undifferentiated areas or the border between undifferentiated iPSC and feeder cells. These findings suggested that the distribution of lipids changes during the growth and differentiation of iPSCs and that MALDI-TOF-IMS was useful for analyzing these changes. PC(36:4) might play a role in maintaining pluripotency, while PC(34:1) might play a role in the differentiation and spread of iPSCs. Graphical Abstract MALDI Imaging for phosphatidylcholine distribution changes during sponteneous differentiaton of induced pluiripotent stem cells colonies.

Dipeptidyl peptidase-4 is highly expressed in bronchial epithelial cells of untreated asthma and it increases cell proliferation along with fibronectin production in airway constitutive cells.

BACKGROUND: Type 2 helper T-cell cytokines including IL-13 play a central role in the pathogenesis of bronchial asthma (BA). During the course of our research, our attention was drawn to dipeptidyl peptidase-4 (DPP4) as one of the molecules that were induced from bronchial epithelial cells (BECs) by IL-13 stimulation. DPP4 could become a new biomarker or therapeutic target. The aim of this study was to investigate the expression of DPP4 in the asthmatic airway, and its role in the pathophysiology of asthma. METHODS: BECs were isolated from patients with inhaled corticosteroid-treated asthma (stBA) and inhaled corticosteroid-naïve asthma (snBA) using bronchoscopy. DPP4 mRNA expression in freshly isolated BECs and primary cultured BECs with or without IL-13 stimulation was investigated by microarray analysis and quantitative real-time PCR (qPCR). The distribution of DPP4 protein was determined by immunostaining of transbronchial lung biopsy specimens from asthma patients. The effect of recombinant human (rh) DPP4 on the proliferation of lung fibroblasts (HFL-1) and bronchial smooth muscle cells (BSMCs) was examined, as well as its effect on the production of fibronectin (FN). RESULTS: DPP4 mRNA was strongly expressed in freshly isolated BECs in snBA, and its expression was significantly enhanced by IL-13 stimulation. DPP4 mRNA expression in BECs of snBA significantly correlated with exhaled nitric oxide. Biopsied tissues of the asthmatic airway revealed strong expression of DPP4 protein in BECs from snBA subjects. rhDPP4 stimulated the proliferation of HFL-1 and BSMCs, and it also enhanced production of FN from these airway cells. CONCLUSION: DPP4 may be involved in the pathologic features of asthmatic airway inflammation and cell proliferation and FN production.

Elemental and immunohistochemical analysis of the lungs and hilar lymph node in a patient with asbestos exposure, a pilot study.

OBJECTIVES: Studies have shown that inhaled mine dust, such as asbestos, can be translocated to various organs including the lymph nodes. Recently, we have established a protocol that enables us to identify inhaled elements using paraffin embedded lung specimens by in-air microparticle-induced X-ray emission (micro-PIXE). However, little research has examined the concentration of these inhaled fibers in various organs or the mechanisms of their translocation. In this study, we compared the concentration of inhaled fibers in the lung parenchyma to the concentration in the hilar lymph node as well as to determine the elemental spatial distribution of the inhaled fibers in a patient with occupational asbestos exposure. METHODS: Lung tissues and hilar lymph node in a patient with asbestos exposure were used in this study. Elemental analysis was performed by in-air micro-PIXE. Immunohistochemical analysis was performed using anti CD163, smooth muscle actin, vimentin and ß-catenin antibody. RESULTS: The analysis revealed that the amount of inhaled silicon was approximately 6 times higher in the lymph node than in the lungs. The spatial analysis showed that silicon, iron and aluminium were co-localized in the hilar lymph node. The immunohistochemical analysis showed localized agreement of the inhaled fibers with macrophages, smooth muscle actin, and vimentin in the hilar lymph node. CONCLUSIONS: This study showed that in-air micro-PIXE could be useful for analyzing the elemental distribution and quantification of inhaled fibers in the human body. Furthermore, immunohistochemistry in combination with in-air micro-PIXE analyses may help to determine the mechanism of mine dust distribution in vivo.

Elemental Distribution in Multilayer Systems by Laser-Assisted Atom Probe Tomography with Various Analysis Directions.

Elemental distributions in a magnetic multilayer system with the structure Si substrate/Ta/NiFe/Ru/CoFeB/Ru/NiFe were studied using atom probe tomography (APT) along different analysis directions. The distributions of Ru and B atoms, which require a high evaporation field, were strongly influenced by the APT analysis direction. In particular, B in the CoFeB layer appeared near the interface with the lower Ru layer when the analysis was anti-parallel to the film growth direction, while B atoms were observed at the other side of the CoFeB layer when the analysis was parallel to the film growth direction. Moreover, when the analysis was perpendicular to the film growth direction, a homogenous distribution of B atoms was found within the CoFeB layer. Owing to this B behavior, the underlying Ru layer was affected in both of these analysis directions. In APT measurements of such a multilayer system composed of a stack of different evaporation field materials, evaluation of the elemental distribution around interfaces should be performed from more than one analysis direction.

Co-localization of iron binding on silica with p62/sequestosome1 (SQSTM1) in lung granulomas of mice with acute silicosis.

The cellular mechanisms involved in the development of silicosis have not been fully elucidated. This study aimed to examine influence of silica-induced lung injury on autophagy. Suspensions of crystalline silica particles were administered transnasally to C57BL/6j mice. Immunohistochemical examination for Fas and p62 protein expression was performed using lung tissue specimens. Two-dimensional and quantitative analysis of silica deposits in the lungs were performed in situ using lung tissue sections by an in-air microparticle induced X-ray emission (in-air micro-PIXE) analysis system, which was based on irrradiation of specimens with a proton ion microbeam. Quantitative analysis showed a significant increase of iron levels on silica particles (assessed as the ratio of Fe relative to Si) on day 56 compared with day 7 (p<0.05). Fas and p62 were expressed by histiocytes in granulomas on day 7, and the expressions persisted for day 56. Fas- and p62-expressing histiocytes were co-localized in granulomas with silica particles that showed an increase of iron levels on silica particles in mouse lungs. Iron complexed with silica induces apoptosis, and may lead to dysregulations of autophagy in histiocytes of granulomas, and these mechanisms may contribute to granuloma development and progression in silicosis.

Cell-Based Therapy for Fibrosing Interstitial Lung Diseases, Current Status, and Potential Applications of iPSC-Derived Cells.

Fibrosing interstitial lung diseases (FILDs), e.g., due to idiopathic pulmonary fibrosis (IPF), are chronic progressive diseases with a poor prognosis. The management of these diseases is challenging and focuses mainly on the suppression of progression with anti-fibrotic drugs. Therefore, novel FILD treatments are needed. In recent years, cell-based therapy with various stem cells has been investigated for FILD, and the use of mesenchymal stem cells (MSCs) has been widely reported and clinical studies are also ongoing. Induced pluripotent stem cells (iPSCs) have also been reported to have an anti-fibrotic effect in FILD; however, these have not been as well studied as MSCs in terms of the mechanisms and side effects. While MSCs show a potent anti-fibrotic effect, the possibility of quality differences between donors and a stable supply in the case of donor shortage or reduced proliferative capacity after cell passaging needs to be considered. The application of iPSC-derived cells has the potential to overcome these problems and may lead to consistent quality of the cell product and stable product supply. This review provides an overview of iPSCs and FILD, followed by the current status of cell-based therapy for FILD, and then discusses the possibilities and perspectives of FILD therapy with iPSC-derived cells.

Pulmonary granulomas confirmed in Blau syndrome using TBLC specimens: Case report.

Blau syndrome (BS), is an autoinflammatory granulomatosis disease characterized by a distinct triad of skin, joint, and eye disorders similar to those of sarcoidosis, but the lung involvement frequently observed in sarcoidosis are rare. Granulomas from patients with BS displayed a distinct morphology indicating an exuberant chronic inflammatory response. Patients with BS may have granulomatous lung lesions, which require early diagnosis. To determine whether therapeutic intervention is needed for lung lesions, examining transbronchial lung cryobiopsy specimens and accumulating cases of BS with lung involvement could be contributed to improving BS management in the future.

Tezepelumab improved chronic eosinophilic pneumonia in severe asthma patients with liver cirrhosis.

Systemic administration of corticosteroids is used in the treatment of chronic eosinophilic pneumonia (CEP). However, in patients with CEP as well as other comorbidities, the adverse effects of corticosteroids should be minimized as much as possible. A 71-year-old woman was presented with aggravating asthma with CEP and sinusitis, and she had uncompensated liver cirrhosis (LC) with a Child-Pugh score of 7. Initial treatment with a low dose of oral corticosteroids (OCSs) in combination with tezepelumab, an anti-thymic stromal lymphopoietin (TSLP) antibody, resulted in rapid improvement of asthma and CEP without deteriorating LC. Sinusitis also improved after ceasing OCS. This case suggested that tezepelumab may be useful as a treatment option for patients with CEP, especially those with liver dysfunction.